S1

Supporting Information
for

Preparation of Enantiopure 3-Aminopiperidine and 3-Aminoazepane

Derivatives from Ornithine and Lysine. Consecutive Syntheses of

Pharmacologically Active Analogs, such as Besifloxacin

Ingo Schiffers,a Marcus Frings,a Britta Maria Kübber,a Khai-Nghi Truong,b Kari Rissanenb

and Carsten Bolm*,a

a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen,
Germany
b
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, Survontie 9B, FI-40014
Jyväskylä, Finland

E-Mail: [Link]@[Link]

___________________________________________________________________________

Table of Contents

1. General information S1
2. General procedures S3
3. Detailed preparations and full analytical data S5
4. X-ray crystallography S64
5. References S66
6. NMR spectra S69
7. HPLC analyses S133

1. General information
Unless otherwise stated, all reactions were carried out in air-dried glassware under ambient
conditions and using magnetic stirring. Anhydrous solvents were purchased from commercial
suppliers and stored over molecular sieves. 4-Chlorobenzo[b]thiophene-2-carboxylic acid,1 7-
bromobenzo[b]thiophene-2-carboxylic acid1 and 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid2 were prepared following published protocols. All
other chemicals were obtained from commercial suppliers and used as received. The supplier’s
 S2

specified purities of the reactants were taken into consideration whenever the reaction batches
were calculated. Mechanical grinding was performed in the FRITSCH planetary micro mill
Pulverisette 7 classic line using zirconium dioxide milling vessels and balls. Heating under
microwave irradiation was conducted with the microwave synthesizer Discover from CEM.
Flash column chromatography (FCC) was carried out with Merck silica gel 60 (0.040‒0.063
mm) using solvents of technical grade. Mixing ratios of solvents for eluents were measured by
volume. Analytical thin layer chromatography (TLC) was performed on Merck F254 silica gel
plates. Spots were visualized first under ultraviolet light (l = 254 nm). Then the TLC plate was
dipped into an ethanolic ninhydrin solution (0.5% w/v) and dried in a hot stream of air (using
an electric heating gun). Melting points (mp) were determined in open-end capillary tubes on a
Büchi B-540 melting point apparatus. Nuclear magnetic resonance (NMR) spectra were
recorded at room temperature (unless specified otherwise) in solvents as indicated either on a
Varian Mercury 300, an Agilent VNMR 400, a Bruker Avance Neo 400 or an Agilent VNMR
600 spectrometer. All NMR data were manually processed and analyzed with MestReNova
from Mestrelab Research. Chemical shifts d are given in ppm (parts per million) and were
referenced for 1H NMR to tetramethylsilane (d = 0.00 ppm) or to the residual non-deuterated
solvent signal, and for 13C NMR to the peak of the deuterated solvent as an internal reference.
For 19F NMR the chemical shift scale was set by measuring the absolute frequency of the lock
signal by the 2H resonance signal of the respective deuterated solvent. In general, the peak shifts
13
in all C NMR spectra were rounded to the nearest 0.1 ppm unless a greater precision was
needed to distinguish closely spaced peaks. Coupling constants J are reported in Hz, and
coupling patterns are described as br (broad), s (singlet), d (doublet), t (triplet), q (quartet), p
(pentet), sept (septet), m (multiplet) or as respective combinations thereof. All 13C NMR data
were collected with full decoupling of 1H nuclei. Infrared (IR) spectra were recorded with
attenuated total reflectance (ATR) technique on a PerkinElmer Spectrum 100 spectrometer with
an attached UATR device Diamond KRS-5. Wave numbers n of the absorptions are reported in
cm-1. Regular mass (MS) spectra were acquired on a Finnigan SSQ 7000 spectrometer [electron
ionization (EI): 70 eV; chemical ionization (CI): 100 eV, methane as reactant gas] or a Thermo
Scientific LTQ Qrbitrap XL [electrospray ionization (ESI) in positive ion mode]. High
resolution mass (HRMS) spectra were recorded on a Finnigan MAT95 XP spectrometer (EI,
ion trap) and a Thermo Scientific LTQ Qrbitrap XL (ESI in positive ion mode, ion trap). The
mass error for the HRMS analysis is expressed in ppm and calculated according to ppm = 106 ∙
Dm/mtheory (Dm is the difference between theoretical and experimentally observed mass). Peaks
of characteristic fragmentation patterns are listed according to their m/z values. The percentage
 S3

of intensity is given in parentheses. Elemental analyses (EA) were measured on an Elementar

Vario EL instrument. All measurements of optical rotations were conducted on a PerkinElmer
Model 241 polarimeter with a monochromatic sodium lamp (l = 589 nm) at room temperature
in the solvent as indicated. The unit of the corresponding specific rotation [a] is given in deg ∙
cm3 ∙ g-1 · dm-1; the concentration c is listed in g ∙ (100 mL)-1. Analytical high-performance
liquid chromatography (HPLC) measurements for the determination of enantiomeric ratios
were performed on systems of an Agilent 1100-series or 1200-series and with chiral stationary
phases (250 mm ∙ 4.6 mm) from Chiral Technologies Inc.

2. General procedures
General procedure 1 (GP-1) for the synthesis of amino acid methyl esters
In a round bottom flask thionyl chloride (1.1 equiv) was slowly added to a cooled suspension
(ice bath) of the respective amino acid monohydrochloride in anhydrous methanol (2.0-2.5
mL/mmol amino acid). The flask was equipped with a plastic stopper and the clear solution
stirred at rt overnight. After removing the solvent under reduced pressure the solid residue was
dried in high vacuum. The obtained methyl ester dihydrochlorides showed no or neglectable
impurities in NMR spectra and were used without further purification.

General procedure 2 (GP-2) for the reduction of lactam 21b

In a 250 mL round bottom flask flushed with argon anhydrous tetrahydrofuran (100 mL) was
cooled (ice bath), and lithium aluminum hydride (3.37 g, 88.8 mmol, 3.0 equiv) was carefully
added in small portions. Then, (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g, 29.60 mmol)
was added over a period of 30 min. The flask was equipped with a gas bubbler, the ice bath was
removed, and stirring was continued at rt overnight. Next, the red colored suspension was
refluxed for 2 h (oil bath). Afterwards, the mixture was cooled (ice bath), and water (3 mL) was
added dropwise (caution: formation of hydrogen). Under continued cooling, the reaction
mixture was then treated dropwise with an aqueous solution of sodium hydroxide (3 mL, c =
5.0 mol/L), and again water (10 mL) over a period of 45 min, until all remaining lithium
aluminum hydride had been destroyed. The resulting white suspension was stirred at rt for 1 h,
and dichloromethane (100 mL) followed by magnesium sulfate (50 g) were added. The mixture
was stirred for additional 30 min, filtered over a Büchner funnel, and the filter cake was
thoroughly washed with dichloromethane (200 mL). The combined filtrates were concentrated
under reduced pressure, and the resulting viscous oil was dried in high vacuum. This material
was used for the following synthetic steps without further purification.
 S4

General procedure 3 (GP-3) for the reduction of lactam 22b

In a 250 mL round bottom flask flushed with argon anhydrous tetrahydrofuran (60 mL) was
cooled (ice bath), and lithium aluminum hydride (4.78 g, 126 mmol, 3.0 equiv) was carefully
added in small portions. Next, (S)-3-(tritylamino)azepan-2-one (22b) containing 7% ethanol
(15.71 g, 42.01 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (40 mL) and
anhydrous ethanol (2.3 mL, 39 mmol, a total of 1.0 equiv considering the ethanol content of the
lactam substrate). Then, the solution was slowly trickled into the suspension of lithium
aluminum hydride over a period of 20 min while cooling was continued. Afterwards, the
reaction mixture was refluxed (oil bath) for 18 h, cooled (ice bath) and water (4.2 mL) was
added dropwise (caution: formation of hydrogen). Under continued cooling, the reaction
mixture was then treated dropwise with an aqueous solution of sodium hydroxide (4.2 mL, c =
5.0 mol/L), and again water (14 mL) over a period of 45 min, until all remaining lithium
aluminum hydride had been destroyed. The resulting white suspension was stirred at rt for 1 h,
and dichloromethane (150 mL) followed by magnesium sulfate (55 g) were added. The mixture
was stirred for additional 30 min, filtered over a Büchner funnel, and the filter cake was
thoroughly washed with dichloromethane (300 mL). The combined filtrates were concentrated
under reduced pressure, and the resulting viscous oil was dried in high vacuum. This material
was used for the following synthetic steps without further purification.

General procedure 4 (GP-4) for the cleavage of the trityl-protecting group

Under cooling (ice bath) acetyl chloride (6.0 equiv) was slowly added to anhydrous methanol
(0.8 mL/mmol acetyl chloride). The ice bath was removed and the solution stirred at rt for 3 h.
This acidic methanolic solution was then transferred to an appropriate round bottom flask
containing the trityl-protected amine. The reaction mixture was stirred at rt overnight,
subsequently concentrated under reduced pressure, and dried in high vacuum. Diethyl ether (3‒
5 mL per mmol amine) was added and the solid intensively ground inside the flask with a test
tube-like glass rod. The supernatant ether layer had been taken off with a Pasteur pipette and
the procedure repeated four times. Remaining diethyl ether was removed by rotary evaporation
and the colorless solid dried in high vacuum. Unless otherwise stated, the amine hydrochloride
salts thus obtained showed no or negligible impurities in NMR spectra and were used without
further purification.
 S5

General procedure 5 (GP-5) for the preparation of acid chlorides from the
corresponding carboxylic acids
Under cooling (ice bath), oxalyl chloride (2.0 equiv) was slowly added to a mixture of the
corresponding carboxylic acid in dichloromethane (2.0 mL/mmol acid). Then, a catalytic
amount of DMF was added with a Pasteur pipette (approximately 2‒4 drops per 10 mmol of
carboxylic acid). The flask was equipped with a gas bubbler, the ice bath removed, and the
solution stirred at rt for 2 h. Afterwards, the reaction mixture was concentrated under reduced
pressure and the remaining product dried in high vacuum. The obtained carboxylic acid
chlorides showed no or negligible impurities in GCMS analysis and were used without further
purification.

3. Detailed preparations and full analytical data

L-Lysine methyl ester (unnumbered; liberated from 20):

According to GP-1, L-lysine monohydrochloride (18 ∙ HCl) (18.26 g, 100.0 mmol) was
converted into its corresponding methyl ester by treatment with thionyl chloride (8.0 mL, 0.11
mol, 1.1 equiv) in anhydrous methanol (250 mL). The colorless solid was suspended in
methanol (200 mL) and the mixture stirred under cooling (ice bath) for 30 min prior to addition
of sodium hydroxide pellets (8.00 g, 200 mmol, 2.0 equiv). The cooled reaction mixture was
continuously stirred for additional 45 min and then concentrated under reduced pressure. The
residue was dried in high vacuum for 5 min, then methyl tert-butyl ether (250 mL) followed by
potassium carbonate (25 g) were added, and the mixture was vigorously stirred for 10 min. The
suspension was filtered over a Büchner funnel, and the filter cake was thoroughly washed with
methyl tert-butyl ether (150 mL). The combined filtrates were concentrated under reduced
pressure, and the resulting oil was dried in high vacuum for 5 min. The NMR spectra indicates
that the product contained 5.7% of the already cyclized compound. Yield: 92% (15.51 g, 92.37
mmol); 1H NMR (600 MHz, CDCl3): d = 3.56 (s, 3H), 3.29 (dd, J = 7.6, 5.4 Hz, 1H), 2.53 (t,
J = 6.8 Hz, 2H), 1.58 (ddt, J = 13.2, 9.3, 5.9 Hz, 1H), 1.41 (dddd, J = 13.1, 9.5, 7.6, 5.4 Hz,
1H), 1.35‒1.14 (m, 8H); 13C{1H} NMR (151 MHz, CDCl3): d = 176.4, 54.2, 51.8, 41.9, 34.6,
33.4, 22.8; IR (ATR): n = 3360, 3293, 2927, 2858, 2329, 2201, 2103, 1994, 1959, 1908, 1799,
1732, 1657, 1599, 1440, 1373, 1173, 1036, 989, 842, 768, 732, 668; EI-MS: m/z = 161 (52) [M
+ H]+, 144 (12), 129 (7), 101 (8), 85 (7), 84 (100), 72 (13), 57 (6), 56 (39); CI-MS: m/z = 321
 S6

(14) [2M + H]+, 291 (5), 290 (34), 273 (5), 257 (15), 212 (10), 169 (6), 162 (8), 161 (100) [M
+ H]+, 157 (7), 144 (38), 129 (55), 101 (5), 84 (31); EA for C7H16N2O: calcd. C 52.48, H 10.07,
N 17.49, found C 52.52, H 9.95, N 18.04 (taking into account 5.7% of the lactam C6H12N2O,
the following molecular formula results: C7.36H16.72N2.12O2.06: calcd. C 52.65, H 10.04, N
17.69); optical rotation: [a]D = +22.1 (c = 1.51 in CHCl3). The racemic product and the (R)-
enantiomer were prepared analogously. To determine the enantiomeric excess of the title
compound, the following ditosylated derivative (unnumbered) was prepared.

N,N'-Ditosyl-L-lysine methyl ester (unnumbered):

The lysine methyl ester liberated from the hydrochloric salt 20 (0.517 g, 3.08 mmol) was
dissolved in dichloromethane (20 mL), and triethylamine (1.1 mL, 7.9 mmol, 2.6 equiv) was
added. The cooled reaction mixture (ice bath) was then treated with tosyl chloride (1.174 g,
6.160 mmol, 2.0 equiv) and stirred at rt for 6 h. Next, dichloromethane (20 mL) and a saturated,
aqueous solution of sodium carbonate (10 mL) were added, the phases separated, and the crude
product was extracted from the aqueous layer with dichloromethane (three times with a total of
30 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The product was purified by FCC (diethyl ether) and
isolated as a highly viscous mass. Yield: 91% (1.312 g, 2.800 mmol); 1H NMR (400 MHz,
CDCl3): d = 7.74 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.35‒7.23 (m, 4H), 5.39 (d, J =
9.2 Hz, 1H), 4.89 (t, J = 6.2 Hz, 1H), 3.89‒3.79 (m, 1H), 3.47 (s, 3H), 2.87 (td, J = 8.0, 4.0 Hz,
2H), 2.42 (d, J = 7.0 Hz, 6H), 1.73‒1.62 (m, 1H), 1.60‒1.51 (m, 1H), 1.49‒1.38 (m, 2H), 1.38‒
1.28 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): d = 171.9, 143.7, 143.4, 136.9, 136.6, 129.7,
129.6, 127.2, 127.1, 55.4, 52.4, 42.7, 32.5, 28.8, 21.9, 21.5; IR (ATR): n = 3278, 3028, 2948,
2869, 2174, 2038, 1920, 1738, 1598, 1494, 1433, 1324, 1214, 1154, 1090, 974, 881, 813, 754,
663; EI-MS: m/z = 297 (8), 296 (40), 253 (5), 240 (5), 239 (15), 238 (100), 226 (10), 156 (8),
155 (20), 142 (6), 139 (5), 91 (21); ESI-HRMS for C21H28N2NaO6S2 as [M + Na]+: calcd. m/z
= 491.12810, found m/z = 491.12811 with D = 0.02 ppm; HPLC: >99% ee, tr = 13.2 min (minor)
 S7

[R], 17.2 min (major) [S] (Chiralpak IA, n-heptane/ethanol/methanol = [Link], 0.7 mL/min,
l = 230 nm, 20 °C); optical rotation: [a]D = +30.6 (c = 1.03 in CHCl3). The racemic product
and the (R)-enantiomer were prepared analogously.

(S)-3-Aminopiperidin-2-one (21a):

According to GP-1, L-ornithine monohydrochloride (17 ∙ HCl) (25.29 g, 150.0 mmol) was
converted into its corresponding methyl ester by treatment with thionyl chloride (12.00 mL,
0.165 mol, 1.1 equiv) in methanol (300 mL). The colorless solid was dissolved in methanol
(300 mL). Then triethylamine (43.9 mL, 315 mmol, 2.1 equiv) was added, and the solution was
stirred at rt overnight. The mixture was cooled (ice bath), and sodium hydroxide pellets (12.0
g, 300 mmol, 2.0 equiv) were added. Stirring was continued for 1 h under cooling before the
reaction mixture was concentrated under reduced pressure. The residue was dried in high
vacuum for 10 min. Then, ethyl acetate (300 mL) and potassium carbonate (30 g) were added,
and the suspension was vigorously stirred at rt for 1 h. Afterwards, the mixture was filtered over
a Büchner funnel and the filter cake was thoroughly washed with ethyl acetate (150 mL). The
combined filtrates were concentrated under reduced pressure. The resulting viscous oil started
to crystallize within a few minutes. The crystals had been crushed and dried in high vacuum,
delivering an ivory colored powder. Yield: 94% (16.15 g, 141.5 mmol); mp: 85.5 °C {lit.3 mp:
86‒87 °C}; 1H NMR (600 MHz, CDCl3): d = 7.04 (br s, 1H), 3.26‒3.17 (m, 3H), 2.12‒2.05
(m, 1H), 1.85‒1.78 (m, 1H), 1.76‒1.67 (m, 1H), 1.64 (s, 2H), 1.52‒1.43 (m, 1H); 13C{1H} NMR
(151 MHz, CDCl3): d = 175.3, 51.4, 42.2, 29.7, 21.4; IR (ATR): n = 3340, 3258, 3187, 3093,
2939, 2870, 2325, 2179, 2083, 1995, 1834, 1636, 1485, 1449, 1404, 1347, 1302, 1247, 1193,
1163, 1129, 1108, 1068, 998, 935, 885, 783, 676; EI-MS: m/z = 230 (13), 229 (100) [2M + H]+,
155 (9), 116 (6), 115 (92) [M + H]+, 114 (7) M+•, 86 (5), 85 (12), 70 (24), 69 (50), 58 (59), 57
(27), 56 (91), 54 (11); ESI-HRMS for C5H10N2NaO as [M + Na]+: calcd. m/z = 137.06853,
found m/z = 137.06890 with D = 2.70 ppm; EA for C5H10N2O: calcd. C 52.61, H 8.83, N 24.54,
found C 52.57, H 8.61, N 24.74; optical rotation: [a]D = -15.0 (c = 1.13 in CHCl3) {lit.3 [a]D
= -12.4 (c = 3.44 in CHCl3)}, [a]D = -23.6 (c = 1.16 in CH2Cl2), [a]D = -1.9 (c = 1.19 in
MeOH).
For the determination of the enantiomeric ratio, the trityl protected lactam 21b was prepared.
The title product 21a (231 mg, 2.02 mmol) was dissolved in dichloromethane (5 mL),
 S8

triethylamine (850 µL, 6.10 mmol, 3.0 equiv) followed by trityl chloride (563 mg, 2.02 mmol,
1.0 equiv) were added and the reaction mixture was stirred at rt overnight. Next,
dichloromethane (10 mL) and a saturated, aqueous solution of sodium carbonate (10 mL) were
added, the layers separated, and the crude product was extracted from the aqueous phase with
dichloromethane (three times with a total of 30 mL). The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale
yellow solid was subjected to FFC (diethyl ether), delivering product 21b as an ivory solid.
Yield: 92% (664 mg, 1.86 mmol); HPLC: 99% ee, tr = 7.5 min (major) [S], 9.1 min (minor)
[R] (Chiralpak IA, n-heptane/2-propanol = 80:20, 0.8 mL/min, l = 210 nm, 20 °C); for the
analytical data, see the following section.

(S)-3-(Tritylamino)piperidin-2-one (21b):

According to GP-1, L-ornithine monohydrochloride (17 ∙ HCl) (16.86 g, 100.0 mmol) was
converted into its corresponding methyl ester by treatment with thionyl chloride (8.0 mL, 0.11
mol, 1.1 equiv) in methanol (250 mL). The colorless solid was dissolved in methanol (200 mL),
then triethylamine (29.3 mL, 210 mmol, 2.1 equiv) was added and the solution was stirred at rt
overnight. The mixture was concentrated under reduced pressure and the residue dried in high
vacuum. In order to remove remaining traces of methanol, first chloroform (75 mL) and then
ethyl acetate (75 mL) were added, delivering a homogeneous suspension which was
subsequently concentrated under reduced pressure. The solvent addition/evaporation procedure
was repeated and the remaining mixture of lactam and triethyl amine hydrochloride was dried
in high vacuum. Next, dichloromethane (200 mL) and triethylamine (41.8 mL, 300 mmol, 3.0
equiv) were added, and the mixture was treated with trityl chloride (27.88 g, 100.0 mmol, 1.0
equiv) at rt (water bath). After stirring the suspension at rt overnight, dichloromethane (100
mL) and a saturated, aqueous solution of sodium carbonate (150 mL) were added. The layers
were separated, water (100 mL) was added, and the crude product was extracted from the
aqueous phase with dichloromethane (three times with a total of 450 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure, delivering a pale, beige solid. Whenever the crude product was obtained as a viscous
 S9

mass, which turned into a foam after drying in high vacuum, diethyl ether (100 mL) was added
and removed subsequently by rotary evaporation at atmospheric pressure.
Purification procedure A: The remaining solid was suspended in diethyl ether (100 mL) and
intensively ground inside the flask with a test tube-like glass rod.4 The supernatant ethereal
layer had been taken off with a Pasteur pipette, and the procedure was repeated four times using
a total of 120 mL of diethyl ether. Excess of diethyl ether was removed from the product cake
by rotary evaporation. The remaining ivory colored solid was dried in high vacuum, delivering
31.05 g (87.10 mmol) of the product. The combined ether phases were concentrated under
reduced pressure and submitted to FCC (using one third of the standard amount of silica) with
diethyl ether as eluent. Afterwards the product was also ground four times with diethyl ether (a
total of 20 mL), delivering additional 1.43 g (4.01 mmol) of the product as an ivory solid. Yield:
91% (32.48 g, 91.11 mmol).
Purification procedure B: The crude solid was suspended in methyl tert-butyl ether (80 mL)
and intensively ground inside the flask with a test tube-like glass rod. The supernatant ethereal
layer was taken off with a Pasteur pipette, and the procedure was repeated three times using a
total of 120 mL of methyl tert-butyl ether. Excess of methyl tert-butyl ether was removed from
the product cake by rotary evaporation. The remaining ivory colored solid was dried in high
vacuum, delivering 30.60 g (85.84 mmol) of the product. The combined ether phases were
concentrated under reduced pressure and submitted to FCC (using one third of the standard
amount of silica) with diethyl ether as eluent. Then, the product was also ground four times
with methyl tert-butyl ether (a total of 14 mL), providing additional 1.79 g (5.02 mmol) of the
product as an ivory solid. Yield: 91% (32.39 g, 90.86 mmol).
Purification procedure C: The crude solid was divided into six portions and each of them filled
in a milling jar (45 mL sample volume) equipped with three balls of 10 mm diameter. Diethyl
ether (18 mL) was added, and the samples were ground in pairs (300 rpm, 2 min milling, 1 min
pause, 4 cycles in reverse mode). Next, the mounting was carefully released (caution: excess
pressure might occur) and excess diethyl ether had been taken off with a Pasteur pipette. Then
again diethyl ether (12 mL) was added, and the overlaying organic phase had been taken off
after sedimentation. The latter step was repeated three times with n-pentane (a total of 36 mL).
The solid was dried at atmospheric pressure at 80 °C, delivering 32.04 g (89.88 mmol) of
product after merging all samples. The combined organic phases were concentrated under
reduced pressure and submitted to FCC (using one third of the standard amount of silica) with
diethyl ether as eluent. Then, most of the diethyl ether was removed by a rotary evaporator,
leaving the solid with a small amount of solvent (about 5 mL) in the flask that had been taking
 S10

off by a Pasteur pipette. The product was washed with additional diethyl ether (5 mL), and after
sedimentation the overlaying ether phase had been removed again. Remaining solvent was
removed with a rotary evaporator and the product dried in high vacuum leading to 1.39 g (3.90
mmol) of an ivory solid. Yield: 94% (33.43 g, 93.78 mmol).
Purification procedure D: The crude product was dissolved in a boiling mixture (oil bath) of
ethyl acetate (180 mL) and ethanol (18 mL). Subsequently, the solution was stored in a sealed
flask at -18 °C overnight. Next, the crystals were filtered over a Büchner funnel and dried in
high vacuum, delivering 20.32 g (57.00 mmol) of product. The mother liquor of the filtration
was concentrated under reduced pressure. After FCC (diethyl ether) the crude product was
ground with diethyl ether as described in the purification procedure A. Thus, 10.05 g (28.19
mmol) of 21b were recovered from the mother liquor. Yield: 85% (30.37 g, 85.20 mmol); mp:
187‒188 °C (decompn.); 1H NMR (400 MHz, CDCl3): d = 7.59‒7.55 (m, 6H), 7.29‒7.24 (m,
6H), 7.20‒7.16 (m, 3H), 5.75 (s, 1H), 3.93 (s, 1H), 3.19 (ddd, J = 10.7, 8.4, 3.4 Hz, 1H), 3.11
(ddd, J = 11.2, 5.8, 2.9 Hz, 1H), 2.88 (dd, J = 10.6, 5.7 Hz, 1H), 1.65‒1.56 (m, 1H), 1.43‒1.31
(m, 2H), 1.18‒1.10 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): d = 174.4, 146.6, 129.1, 127.9,
126.5, 71.2, 54.8, 41.8, 29.0, 21.3; IR (ATR): n = 3403, 3301, 3199, 3052, 2940, 2876, 2813,
2288, 2108, 1988, 1659, 1594, 1488, 1446, 1418, 1323, 1282, 1181, 1148, 1111, 1032, 988,
928, 883, 850, 763, 743, 704; EI-MS: m/z = 356 (2) M+•, 280 (17), 279 (83), 258 (21), 244 (25),
243 (100) [C19H15+ = Mtrityl+], 228 (6), 182 (12), 166 (8), 165 (51), 104 (6), 99 (7); EA for
C24H24N2O: calcd. C 80.87, H 6.79, N 7.86, found C 80.96, H 6.95, N 7.84; HPLC: >99% ee,
tr = 7.4 min (major) [S], 9.2 min (minor) [R] (Chiralpak IA, n-heptane/2-propanol = 80:20, 0.8
mL/min, l = 210 nm, 20 °C); optical rotation: [a]D = +37.5 (c = 1.10 in CHCl3). The racemic
product and the (R)-enantiomer ent-21b were prepared analogously.

(S)-3-Aminoazepan-2-one hydrochloride (22a):

A solution of L-lysine methyl ester liberated from the hydrochloric salt 20 (14.49 g, 90.44
mmol) in methanol (220 mL) was refluxed (oil bath) for 32 h. After the mixture had cooled
down, it was concentrated under reduced pressure, and the remains were dried in high vacuum.
The residue was dissolved in ethanol (200 mL), cooled (ice bath), and treated dropwise with
concentrated hydrochloric acid (assay: 37% w/w aqueous solution, 8.20 mL, 99.0 mmol, 1.1
equiv).5 The flask was sealed with a septum and stored at -18 °C overnight. Then, the crystalline
 S11

mass was filtered over a Büchner funnel, washed with ice-cold ethanol (20 mL) followed by n-
pentane (100 mL), and dried in high vacuum, delivering the title product as a colorless solid.
Yield: 57% (8.487 g, 51.55 mmol); mp: 305 °C (decompn.) {lit.5a mp: 300‒305 °C}; 1H NMR
(400 MHz, D2O): d = 4.39‒4.26 (m, 1H), 3.40‒3.22 (m, 2H), 2.14‒2.00 (m, 2H), 1.94‒1.84 (m,
13
1H), 1.83‒1.70 (m, 2H), 1.43 (dtt, J = 14.9, 11.4, 3.4 Hz, 1H); C{1H} NMR (101 MHz,
D2O): d = 173.8, 52.9, 41.3, 28.2, 27.4, 26.9; IR (ATR): n = 3323, 3177, 3097, 2935, 2726,
2599, 2506, 2414, 2322, 2259, 2195, 2060, 2018, 1986, 1956, 1662, 1604, 1563, 1481, 1433,
1380, 1354, 1308, 1255, 1187, 1161, 1127, 1075, 1030, 1005, 961, 929, 877, 824, 748, 689;
ESI-MS: m/z = 234 (7), 230 (4), 151 (5), 130 (7), 129 (100) [Mamine + H]+, 115 (6), 84 (13);
ESI-HRMS for C6H13N2O as [Mamine + H]+: calcd. m/z = 129.10224, found m/z = 129.10223
with D = 0.08 ppm; EA for C6H13ClN2O: calcd. C 43.77, H 7.96, N 17.02, found C 43.64, H
7.72, N 17.08; optical rotation: [a]D = -28.0 (c = 1.02 in H2O) {lit.3 [a]D = -27.0 (c = 2.98 in
1N HCl aq.)}.
To determine the enantiomeric excess of the title compound, the trityl protected derivative 22b
was prepared: The lactam hydrochloride (22a) (1.646 g, 9.998 mmol) was suspended in
dichloromethane (25 mL) and triethylamine (4.20 mL, 30.0 mmol, 3.0 equiv) was added. The
reaction mixture was then treated with trityl chloride (2.79 g, 10.0 mmol, 1.0 equiv) and stirred
at rt overnight. Afterwards, dichloromethane (20 mL) and a saturated, aqueous solution of
sodium carbonate (25 mL) were added, the phases separated, and the crude product was
extracted from the aqueous layer with dichloromethane (three times with a total of 60 mL). The
combined organic phases were dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The product was purified by FCC (ethyl acetate/n-pentane = 1:1) and isolated
as a colorless solid. Yield: 93% (3.461 g, 9.342 mmol); HPLC: >99% ee, tr = 6.1 min (minor)
[R], 8.4 min (major) [S] (Chiralpak IA, n-heptane/2-propanol = 80:20, 0.8 mL/min, l = 230 nm,
20 °C); for the analytical data, see the section below with the one-pot synthesis of compound
22b.

(S)-3-(Tritylamino)azepan-2-one (22b):
 S12

Method A: According to GP-1, L-lysine monohydrochloride (18 ∙ HCl) (18.26 g, 100.0 mmol)
was converted into its corresponding methyl ester by treatment with thionyl chloride (8.0 mL,
0.11 mol, 1.1 equiv) in methanol (250 mL). The colorless solid was suspended in methanol (200
mL) and treated at rt with an ice-cooled solution of sodium methoxide in methanol (104.0 mL,
c = 0.965 mol/L, 100.4 mmol, 1.0 equiv) which was prepared by dilution of commercially
available sodium methoxide in methanol (37.00 mL, c = 5.400 mol/L, 199.8 mmol, 2.0 equiv)
with anhydrous methanol (170 mL).5 After the swift addition of sodium methoxide, the
dissolution of the ester could be observed, which was followed instantaneously by the
precipitation of sodium chloride. The reaction mixture was stirred at rt for 30 min before the
second portion of the cooled sodium methoxide solution (103.0 mL, c = 0.965 mol/L, 99.40
mmol, 1.0 equiv) was added at rt over a period of 10 min. The suspension was stirred at rt for
additional 30 min and then refluxed (oil bath) for 24 h. After the mixture had cooled down, it
was concentrated under reduced pressure and the remains were dried in high vacuum. In order
to remove remaining traces of methanol, chloroform (250 mL) was added, delivering a
homogeneous suspension which was subsequently concentrated under reduced pressure. The
solvent addition/evaporation procedure was repeated and the remaining mixture of lactam and
sodium chloride was dried in high vacuum. Next, dichloromethane (250 mL) and triethylamine
(41.8 mL, 300 mmol, 3.0 equiv) were added and the mixture was treated at rt (water bath) with
trityl chloride (29.27 g, 105.0 mmol, 1.05 equiv). After stirring the suspension at rt overnight,
dichloromethane (100 mL) and a saturated, aqueous solution of sodium carbonate (150 mL)
were added. The layers were separated, water (100 mL) was added and the crude product
extracted from the aqueous phase with dichloromethane (three times with a total of 450 mL).
The combined organic layers were dried over magnesium sulfate, filtered and concentrated
under reduced pressure. Then, dichloromethane (400 mL) was added to the residue. The mixture
was stirred at rt for 10 min, filtered and concentrated under reduced pressure. Next, ethanol
(270 mL) was added, the mixture heated to reflux (oil bath), and the hot suspension was filtered
once more. The flask with the hot filtrate was sealed with a septum and stored at -18 °C
overnight. Then, the crystalline mass was filtered over a Büchner funnel, washed with ice-cold
ethanol (15 mL) followed by n-pentane (100 mL), and dried in high vacuum for 1 d. The
procedure yielded 26.67 g of the title product as a colorless solid that contained 7% ethanol
(71.32 mmol). The combined filtrates were concentrated under reduced pressure and the
remaining solid was subjected to FCC (ethyl acetate/n-pentane = 1:1). The resulting colorless
solid was recrystallized from ethanol (31 mL) as described above. In this fashion, 5.044 g of
 S13

the title product containing 50% ethanol (12.11 mmol) were obtained. Yield: 83% (83.43
mmol). The racemic product and the (R)-enantiomer were prepared analogously.
Method B: According to GP-1, L-lysine monohydrochloride (18 ∙ HCl) (18.26 g, 100.0 mmol)
was converted into its corresponding methyl ester by treatment with thionyl chloride (8.0 mL,
0.11 mol, 1.1 equiv) in anhydrous methanol (250 mL). The colorless solid was suspended in
anhydrous methanol (260 mL) and treated with mortared sodium carbonate (31.80 g, 300.0
mmol, 3.0 equiv). The flask was equipped with a gas bubbler and the reaction mixture stirred
at rt overnight. Next, the suspension was refluxed (oil bath) for 24 h, cooled, concentrated under
reduced pressure, and dried in high vacuum. In order to remove remaining traces of methanol,
chloroform (250 mL) was added, delivering a homogeneous suspension which was
subsequently concentrated under reduced pressure. The solvent addition/evaporation procedure
was repeated and the remaining mixture of lactam and sodium chloride was dried in high
vacuum. Then, dichloromethane (250 mL) and triethylamine (41.8 mL, 300 mmol, 3.0 equiv)
were added and the mixture was treated at rt (water bath) with trityl chloride (29.27 g, 105.0
mmol, 1.05 equiv). After stirring the suspension overnight at rt, dichloromethane (100 mL) and
a saturated, aqueous solution of sodium carbonate (150 mL) were added. The layers were
separated, water (100 mL) was added and the crude product was extracted from the aqueous
phase with dichloromethane (three times with a total of 450 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Next,
ethanol (270 mL) was added, the mixture heated to reflux (oil bath), and the hot suspension was
filtered. The flask with the hot filtrate was sealed with a septum and stored at -18 °C overnight.
Then, the crystalline mass was filtered over a Büchner funnel, washed with ice-cold ethanol (15
mL) followed by n-pentane (100 mL) and dried in high vacuum for 1 d. The procedure yielded
17.53 g of the title product as a colorless solid that contained 47% ethanol (42.66 mmol). The
combined filtrates were concentrated under reduced pressure and the remaining solid was
subjected to FCC (ethyl acetate/n-pentane = 1:1). The resulting colorless solid was
recrystallized from ethanol (25 mL) as described above. In this fashion, 2.483 g of the title
product containing 52% ethanol (5.906 mmol) were obtained. Yield: 49% (48.57 mmol).
Method C: A solution of L-lysine methyl ester liberated from the dihydrochloride of 20 (14.80
g, 92.35 mmol) in anhydrous methanol (250 mL) was refluxed (oil bath) for 32 h. After the
mixture had reached rt, it was concentrated under reduced pressure, and the remains were dried
in high vacuum. In order to remove remaining traces of methanol, chloroform (250 mL) was
added, delivering a homogeneous suspension which was subsequently concentrated under
reduced pressure. The solvent addition/evaporation procedure was repeated and the remaining
 S14

lactam dried in high vacuum. Then, dichloromethane (250 mL) and triethylamine (38.6 mL,
277 mmol, 3.0 equiv) were added, and the mixture was treated at rt (water bath) with trityl
chloride (27.03 g, 97.0 mmol, 1.05 equiv). After stirring the suspension at rt overnight,
dichloromethane (100 mL) and a saturated, aqueous solution of sodium carbonate (150 mL)
were added. The layers were separated, water (100 mL) was added and the crude product was
extracted from the aqueous phase with dichloromethane (three times with a total of 450 mL).
The combined organic layers were dried over magnesium sulfate, filtered and concentrated
under reduced pressure. Next, ethanol (200 mL) was added, the mixture heated to reflux (oil
bath), the flask sealed with a septum and stored at -18 °C overnight. Then, the crystalline mass
was filtered over a Büchner funnel, washed with ice-cold ethanol (15 mL) followed by n-
pentane (100 mL) and dried in high vacuum for 1 d. The procedure yielded 28.67 g of the title
product as a colorless solid that contained 44% ethanol (70.50 mmol). The combined filtrates
were concentrated under reduced pressure and the remaining solid was subjected to FCC (ethyl
acetate/n-pentane = 1:1). The resulting colorless solid was recrystallized from ethanol (40 mL)
as described above. In this fashion, 3.151 g of the title product containing 54% ethanol (7.420
mmol) were obtained. Yield: 84% (77.92 mmol).
If necessary, the content of ethanol was removed from the product by repetitive addition of
ethyl acetate (10 mL per g of solid material) and evaporation of the solvent four times under
reduced pressure. The pure compound was dried in high vacuum: mp: 167 °C (lit.6 mp: 187
°C); 1H NMR (300 MHz, CDCl3): d = 7.53‒7.45 (m, 6H), 7.31‒7.22 (m, 6H), 7.21‒7.13 (m,
3H), 5.60 (br t, J = 6.4 Hz, 1H), 3.87 (br s, 1H), 3.35 (d, J = 8.5 Hz, 1H), 3.05‒2.78 (m, 2H),
1.80‒1.66 (m, 2H), 1.65‒1.55 (m, 1H), 1.53‒1.39 (m, 1H), 1.36‒1.13 (m, 2H); 13C{1H} NMR
(75 MHz, CDCl3): d = 178.5, 146.6, 129.1, 127.8, 126.4, 72.1, 55.2, 41.7, 34.5, 28.9, 28.1; IR
(ATR): n = 3297, 3228, 3061, 2926, 2860, 2647, 2318, 2076, 1942, 1662, 1446, 1322, 1267,
1189, 1126, 1070, 1029, 901, 752, 699; EI-MS: m/z = 370 (3) M+•, 294 (7), 293 (31), 258 (18),
244 (17), 243 (100) [C19H15+ = Mtrityl+], 165 (14); EA for C25H26N2O: calcd. C 81.05, H 7.07, N
7.56, found C 80.93, H 7.31, N 7.47; HPLC: 99% ee, tr = 6.1 min (minor) [R], 8.4 min (major)
[S] (Chiralpak IA, n-heptane/2-propanol = 80:20, 0.8 mL/min, l = 230 nm, 20 °C); optical
rotation: [a]D = +30.4 (c = 1.14 in CHCl3) {lit.6 [a]D = +28.0 (c = 1.00 in CHCl3)}. The racemic
product and the (R)-enantiomer ent-22b were prepared according to method A.
 S15

(S)-3-(Tritylamino)piperidine (23):

For analytical data, a sample of the product received according to GP-2 was purified by FCC
(ethanol/triethylamine = 50:1). In order to remove traces of triethylamine, the resulting product
was treated with toluene followed by concentration under reduced pressure. The solvent
addition/evaporation procedure was repeated two times, and the remaining pale yellow solid
was dried in high vacuum at 50 °C (oil bath) for 20 h; mp: 50‒52 °C; 1H NMR (600 MHz,
CDCl3): d = 7.61‒7.54 (m, 6H), 7.28‒7.18 (m, 6H), 7.15‒7.10 (m, 3H), 2.66 (dt, J = 11.6, 4.1
Hz, 1H), 2.47‒2.38 (m, 3H), 1.91 (dd, J = 11.7, 8.3 Hz, 1H), 1.72‒1.57 (m, 2H), 1.54‒1.50 (m,
1H), 1.28‒1.16 (m, 2H), 1.13‒1.05 (m, 1H); 13
C{1H} NMR (151 MHz, CDCl3): d = 147.2,
128.6, 127.7, 126.1, 71.1, 53.7, 50.0, 46.4, 33.9, 25.6; IR (ATR): n = 3303, 3056, 2931, 2067,
1594, 1486, 1447, 1207, 1104, 1030, 901, 854, 769, 746, 699; EI-MS: m/z = 243 (5) [C19H15+
= Mtrityl+], 242 (5), 241 (7), 240 (6), 239 (5), 165 (25), 163 (27), 99 (81), 83 (12), 82 (21), 71
(100), 57 (10); CI-MS: m/z = 372 (6) [M + C2H5]+, 371 (6), 345 (9), 344 (34) [M + H]+, 343
(35), 342 (23), 271 (9), 269 (8), 244 (8), 243 (85) [C19H15+ = Mtrityl+], 242 (100), 241 (73), 240
(42); ESI-HRMS for C24H27N2 as [M + H]+: calcd. m/z = 343.21687, found m/z = 343.21685
with D = 0.06 ppm; EA for C24H26N2: calcd. C 84.17, H 7.65, N 8.18, found C 84.00, H 7.67,
N 8.30; optical rotation: [a]D = +5.6 (c = 1.53 in CHCl3). The racemic product and the (R)-
enantiomer ent-23 were prepared analogously. To determine the enantiomeric excess of the title
compound, the tosylated piperidine derivative 25d was prepared.

(S)-3-(Tritylamino)azepane (24):

For analytical data, a sample of the product received according to GP-3 was purified by FCC
(ethanol/triethylamine = 50:1). In order to remove traces of triethylamine, the resulting product
 S16

was treated with toluene followed by concentration under reduced pressure. The solvent
addition/evaporation procedure was repeated two times, and the remaining highly viscous
product was dried in high vacuum at 50 °C for 20 h; 1H NMR (600 MHz, CDCl3): d = 7.59‒
7.55 (m, 6H), 7.27‒7.22 (m, 6H), 7.17‒7.12 (m, 3H), 2.88‒2.79 (m, 1H), 2.69 (tt, J = 6.7, 3.8
Hz, 1H), 2.63 (ddd, J = 12.6, 7.4, 5.2 Hz, 1H), 2.35 (dd, J = 13.7, 3.5 Hz, 1H), 2.08 (br s, 1H),
1.94 (dd, J = 13.7, 6.1 Hz, 1H), 1.67‒1.51 (m, 3H), 1.46 (dddd, J = 14.0, 9.3, 6.9, 2.4 Hz, 1H),
13
1.38 (dddd, J = 13.8, 9.0, 4.7, 2.7 Hz, 1H), 1.34‒1.25 (m, 1H); C{1H} NMR (151 MHz,
CDCl3): d = 147.4, 128.9, 127.8, 126.3, 71.5, 53.9, 53.2, 49.2, 36.3, 30.4, 22.9; IR (ATR): n =
3279, 3057, 3027, 2925, 2849, 2743, 2663, 2322, 2164, 1957, 1896, 1817, 1594, 1486, 1449,
1326, 1258, 1209, 1153, 1101, 1027, 900, 848, 750, 701; EI-MS: m/z = 358 (10), 357 (100) [M
+ H]+, 245 (5), 244 (41), 243 (72) [C19H15+ = Mtrityl+], 242 (12), 165 (8), 113 (12), 98 (8), 85
(14), 83 (19); ESI-HRMS for C25H29N2 as [M + H]+: calcd. m/z = 357.23252, found m/z =
357.23203 with D = 1.37 ppm; optical rotation: [a]D = +10.4 (c = 1.80 in CHCl3). The racemic
product and the (R)-enantiomer were prepared analogously. To determine the enantiomeric
excess of the title compound, the tosylated azepane derivative 26d was prepared.

(S)-1-Methyl-3-(tritylamino)piperidine (25a):

Method A: The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b)

(10.55 g, 29.60 mmol) according to GP-2 was dissolved in methanol (100 mL, technical grade)
and treated with formalin (assay: 37% w/w aqueous solution, 2.70 mL, 36.3 mmol, 1.2 equiv).
Upon addition of formalin a precipitate had formed, which dissolved within a few minutes. The
resulting clear yellow solution was stirred at rt for 1 h to complete the imine formation. Then
the reaction mixture was cooled (ice bath), and sodium borohydride (1.68 g, 44.9 mmol, 1.5
equiv) was added in portions. After the effervescence had ceased, the reaction mixture was
stirred at rt for 30 min, concentrated under reduced pressure, and treated with an aqueous
solution of sodium hydroxide (80 mL, c = 1.0 mol/L). Brine (30 mL) was added and the crude
product was extracted from the mixture with dichloromethane (four times with a total of 400
mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The product was purified by FCC (diethyl ether/n-
 S17

pentane/triethylamine = [Link].5) and isolated as a highly viscous oil that solidified during the
storage at -18 °C. Yield: 80% (8.44 g, 23.7 mmol).
Method B: In a 250 mL round bottom flask flushed with argon, anhydrous tetrahydrofuran (40
mL) was cooled (ice bath) and lithium aluminum hydride (1.62 g, 42.7 mmol, 3.0 equiv) was
carefully added in small portions. A solution of tert-butyl (S)-3-(tritylamino)piperidine-1-
carboxylate (25e) (6.29 g, 14.2 mmol) in anhydrous tetrahydrofuran (30 mL) was added over a
period of 15 min while continuing cooling. The flask was equipped with a gas bubbler, the ice
bath was removed, and stirring continued at rt overnight. Next, the suspension was refluxed for
1 h (oil bath). Afterwards, the mixture was cooled (ice bath), and water (1.4 mL) was added
dropwise (caution: formation of hydrogen). Under continued cooling the reaction mixture was
then treated with an aqueous solution of sodium hydroxide (1.4 mL, c = 5.0 mol/L), and again
water (4.9 mL) over a period of 45 min, until all remaining lithium aluminum hydride had been
destroyed. The resulting white suspension was stirred at rt for1 h, and dichloromethane (100
mL) followed by magnesium sulfate (50 g) were added. The mixture was stirred for additional
30 min, filtered over a Büchner funnel, and the filter cake was thoroughly washed with
dichloromethane (100 mL). The combined filtrates were concentrated under reduced pressure,
and the resulting viscous oil was purified according to method A. Yield: 92% (4.66 g, 13.1
mmol); mp: 41 °C; 1H NMR (600 MHz, CDCl3): d = 7.58‒7.56 (m, 6H), 7.25‒7.22 (m, 6H),
7.16‒7.13 (m, 3H), 2.62 (s, 1H), 2.25 (br s, 1H), 2.07‒1.74 (m, 6H), 1.63 (br s, 1H), 1.34 (br s,
1H), 1.16 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3): d = 147.4, 128.8, 127.9, 126.3, 71.0, 62.3,
55.9, 49.2, 46.5, 32.9, 23.9; IR (ATR): n = 3307, 3062, 2933, 2843, 2776, 2319, 2079, 1950,
1818, 1594, 1447, 1373, 1290, 1257, 1206, 1152, 1094, 1027, 903, 857, 770, 744, 701; EI-MS:
m/z = 357 (3) [M + H]+, 356 (9) M+•, 285 (5), 244 (24), 243 (100) [C19H15+ = Mtrityl+], 166 (5),
165 (31), 113 (45), 84 (8), 73 (8), 71 (7), 70 (29), 59 (13); ESI-HRMS for C25H29N2 as [M +
H]+: calcd. m/z = 357.23252, found m/z = 357.23253 with D = 0.03 ppm; optical rotation: [a]D
= +19.0 (c = 3.43 in CHCl3). The (R)-enantiomer ent-25a was prepared according to method
B.
 S18

(S)-1-Isopropyl-3-(tritylamino)piperidine (25b):

The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g,

29.60 mmol) according to GP-2 was dissolved in a mixture of methanol (150 mL, technical
grade) and acetone (40 mL). Then, sodium cyanoborohydride (assay: 95%, 3.92 g, 59.3 mmol,
2.0 equiv) was added, and the reaction mixture was stirred at rt for 2 d. Next, the mixture was
concentrated under reduced pressure, and dichloromethane (200 mL) and a saturated, aqueous
solution of sodium carbonate (50 mL) were added. The phases were separated, and the crude
product was extracted from the aqueous layer with dichloromethane (three times with a total of
240 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The product was purified by FCC (diethyl
ether/triethylamine = 50:1) and isolated as a highly viscous oil. Yield: 94% (10.70 g, 27.82
mmol); 1H NMR (600 MHz, CDCl3): d = 7.58‒7.56 (m, 6H), 7.25‒7.23 (m, 6H), 7.16‒7.13 (m,
3H), 2.62 (br s, 1H), 2.44‒2.38 (m, 2H), 2.13 (br s, 1H), 2.00 (d, J = 10.8 Hz, 1H), 1.80 (br s,
1H), 1.65 (br s, 1H), 1.38‒1.26 (m, 3H), 1.19 (br s, 1H), 0.78 (d, J = 6.7 Hz, 3H), 0.76 (d, J =
6.7 Hz, 3H); 13
C{1H} NMR (151 MHz, CDCl3): d = 147.4, 128.7, 127.7, 126.1, 71.2, 55.2,
54.4, 49.51, 49.45, 33.9, 24.2, 18.2, 18.0; IR (ATR): n = 3300, 3059, 2935, 2791, 2176, 1959,
1815, 1667, 1594, 1450, 1383, 1322, 1180, 1102, 1033, 971, 900, 750, 700; EI-MS: m/z = 386
(7) [M + H]+, 385 (11) M+•, 244 (27), 243 (97) [C19H15+ = Mtrityl+], 166 (7), 165 (46), 146 (7),
142 (10), 141 (100), 100 (14), 99 (42), 86 (57), 84 (13), 70 (30), 56 (7); ESI-HRMS for
C27H33N2 as [M + H]+: calcd. m/z = 385.26382, found m/z = 385.26367 with D = 0.39 ppm;
optical rotation: [a]D = +13.2 (c = 3.00 in CHCl3).

(S)-1-Benzyl-3-(tritylamino)piperidine (25c):
 S19

The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g,

29.60 mmol) according to GP-2 was dissolved in dichloromethane (60 mL), and triethylamine
(12.4 mL, 89.0 mmol, 3.0 equiv) was added. The mixture was cooled (ice bath), slowly treated
with benzyl bromide (assay: 98%, 3.60 mL, 29.7 mmol, 1.0 equiv), and subsequently stirred at
rt overnight. Then, dichloromethane (100 mL) and an aqueous solution of sodium hydroxide
(50 mL, c = 1.0 mol/L) were added, the phases separated, and the crude product was extracted
from the aqueous layer with dichloromethane (three times with a total of 240 mL). The
combined organic phases were dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The product was purified by FCC (diethyl ether) and isolated as a viscous oil
that solidified at -18 °C. Yield: 85% (10.88 g, 25.15 mmol); mp: 128 °C; 1H NMR (600 MHz,
CDCl3): d = 7.55‒7.51 (m, 6H), 7.28‒7.17 (m, 9H), 7.15‒7.10 (m, 5H), 3.23‒3.14 (m, 2H),
2.63 (br s, 1H), 2.23 (br s, 1H), 2.13 (br s, 1H), 1.96 (br s, 2H), 1.65 (br s, 1H), 1.36‒1.32 (m,
1H), 1.27‒1.22 (m, 2H), 1.19‒1.15 (m, 1H); 13
C{1H} NMR (151 MHz, CDCl3): d = 147.3,
138.5, 129.1, 128.6, 128.0, 127.7, 126.7, 126.1, 71.2, 63.1, 60.1, 53.4, 49.0, 33.1, 23.5; IR
(ATR): n = 3318, 3058, 3026, 2964, 2931, 2854, 2794, 2757, 2697, 2320, 2205, 2164, 2077,
2016, 1987, 1819, 1595, 1488, 1446, 1353, 1302, 1250, 1204, 1158, 1118, 1094, 1027, 976,
938, 899, 805, 769, 740, 700; EI-MS: m/z = 433 (8) [M + H]+, 244 (22), 243 (97) [C19H15+ =
Mtrityl+], 241 (5), 227 (6), 190 (19), 189 (100), 166 (5), 165 (39), 147 (16), 146 (9), 134 (31), 91
(39), 84 (7), 70 (9); CI-MS: m/z = 433 (16) [M + H]+, 271 (9), 244 (20), 243 (95) [C19H15+ =
Mtrityl+], 236 (9), 220 (9), 190 (13), 189 (100), 174 (7), 165 (9), 147 (5), 134 (8), 91 (16); ESI-
HRMS for C31H33N2 as [M + H]+: calcd. m/z = 433.26382, found m/z = 433.26376 with D =
0.14 ppm; optical rotation: [a]D = -6.9 (c = 1.10 in CHCl3). The (R)-enantiomer ent-25c was
prepared analogously.

(S)-1-Tosyl-3-(tritylamino)piperidine (25d):

According to GP-2, (S)-3-(tritylamino)piperidin-2-one (21b) (624 mg, 1.75 mmol) was

reduced, the product dissolved in dichloromethane (10 mL), and triethylamine (732 µL, 5.25
 S20

mmol, 3.0 equiv) was added. The cooled reaction mixture (ice bath) was then treated with tosyl
chloride (334 mg, 1.75 mmol, 1.0 equiv) and stirred at rt overnight. Afterwards,
dichloromethane (20 mL) and a saturated, aqueous solution of sodium carbonate (10 mL) were
added, the phases separated, and the crude product was extracted from the aqueous layer with
dichloromethane (three times with a total of 30 mL). The combined organic phases were dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The product was
purified by FCC (diethyl ether/n-pentane = 1:2) and isolated as a colorless solid. Yield: 92%
(800 mg, 1.61 mmol); mp: 82 °C; 1H NMR (600 MHz, CDCl3): d = 7.56‒7.50 (m, 6H), 7.43
(d, J = 8.1 Hz, 2H), 7.30‒7.26 (m, 6H), 7.25‒7.17 (m, 5H), 3.10 (dd, J = 10.8, 5.3 Hz, 1H), 2.85
(dd, J = 11.5, 3.6 Hz, 1H), 2.65‒2.53 (m, 2H), 2.39 (s, 3H), 1.90 (dd, J = 11.4, 8.0 Hz, 1H),
13
1.74‒1.58 (m, 2H), 1.40‒1.29 (m, 1H), 1.07‒0.95 (m, 2H); C{1H} NMR (151 MHz,
CDCl3): d = 146.7, 143.2, 133.5, 129.5, 128.6, 128.0, 127.6, 126.4, 71.2, 52.6, 48.5, 46.4, 32.4,
23.2, 21.5; IR (ATR): n = 3345, 3054, 2933, 2858, 2312, 2095, 1819, 1593, 1454, 1325, 1155,
1036, 948, 820, 773, 706; EI-MS: m/z = 419 (1), 341 (7), 244 (23), 243 (100), 165 (24), 91 (6),
239 (5), 165 (25), 163 (27), 99 (81), 83 (12), 82 (21), 71 (100), 57 (10); CI-MS: m/z = 343 (2),
342 (3), 286 (5), 274 (17), 271 (6), 256 (6), 255 (17), 244 (24), 243 (100) [C19H15+ = Mtrityl+],
242 (8), 238 (15), 229 (5), 228 (52), 183 (16); EA for C31H32N2O2S: calcd. C 74.97, H 6.49, N
5.64, found C 74.68, H 6.39, N 5.54; HPLC: 99% ee, tr = 7.7 min (major) [S], 11.2 min (minor)
[R] (Chiralpak IA, n-heptane/2-propanol = 70:30, 0.8 mL/min, l = 254 nm, 20 °C); optical
rotation: [a]D = -47.2 (c = 1.08 in CHCl3). The racemic product and the (R)-enantiomer ent-
25d were prepared analogously.

(S)-1-(tert-Butoxycarbonyl)-3-(tritylamino)piperidine (25e):

The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g,

29.60 mmol) according to GP-2 was dissolved in dichloromethane (100 mL), and triethylamine
(4.10 mL, 29.4 mmol, 1.0 equiv) was added. Then, di-tert-butyl dicarbonate (assay: 99%, 6.53
g, 29.6 mmol, 1.0 equiv) was added to the cooled solution (ice bath). The flask was equipped
with a gas bubbler and the reaction mixture stirred at rt overnight. Dichloromethane (100 mL)
 S21

and citric acid (assay: 10% w/w aqueous solution, 50 mL) were added, the phases separated,
and the crude product was extracted from the aqueous layer with dichloromethane (three times
with a total of 240 mL). The combined organic phases were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The product was purified by FCC (diethyl
ether/n-pentane = 1:2) and isolated as a pale pink colored solid. Yield: 97% (12.71 g, 28.72
mmol); mp: 125 °C; 1H NMR (600 MHz, CDCl3): d = 7.60‒7.52 (m, 6H), 7.30‒7.22 (m, 6H),
7.17 (t, J = 7.3 Hz, 3H), 3.79 (br s, 1H), 3.59 (br s, 1H), 2.83‒2.72 (m, 2H), 2.44 (br s, 1H),
1.51‒1.49 (m, 1H), 1.43 (s, 9H), 1.40‒1.37 (m, 1H), 1.08 (dtt, J = 14.4, 10.2, 4.1 Hz, 1H), 0.80
(br s, 1H), 0.77‒0.68 (m, 1H); 13
C{1H} NMR (151 MHz, CDCl3): d = 154.9, 147.0, 128.7,
127.9, 126.4, 79.3, 71.3, 51.9, 49.3, 43.5, 32.7, 28.6, 23.8; IR (ATR): n = 3336, 3021, 2973,
2931, 2855, 2323, 2211, 2158, 2117, 2042, 1981, 1679, 1595, 1484, 1455, 1423, 1365, 1332,
1263, 1169, 1142, 1109, 1030, 971, 949, 901, 858, 756, 719; CI-MS: m/z = 443 (4) [M + H]+,
442 (8) M+, 365 (8), 258 (6), 244 (25), 243 (100) [C19H15+ = Mtrityl+], 228 (4), 199 (4), 165 (25);
ESI-HRMS for C29H34O2N2Na as [M + Na]+: calcd. m/z = 465.25125, found m/z = 465.25064
with D = 1.31 ppm; EA for C29H34N2O2: calcd. C 78.70, H 7.74, N 6.33, found C 78.47, H 7.72,
N 6.26; optical rotation: [a]D = -62.6 (c = 1.40 in CHCl3). The (R)-enantiomer ent-25e was
prepared analogously.

(S)-1-Methyl-3-(tritylamino)azepane (26a):

According to GP-3, (S)-3-(tritylamino)azepan-2-one (22b) containing 14% of ethanol (11.34 g,

30.00 mmol) was reduced. The product was dissolved in methanol (technical grade, 100 mL),
and treated with formalin (assay: 37% w/w aqueous solution, 7.5 mL, 90 mmol, 3.0 equiv). The
reaction mixture was cooled (ice bath), and sodium cyanoborohydride (assay: 95%, 3.97 g, 60.0
mmol, 2.0 equiv) was added in portions. After the effervescence had ceased, dichloromethane
was added (10 mL) and the reaction mixture stirred overnight at rt. Next, the mixture was
concentrated under reduced pressure, and a saturated, aqueous solution of sodium carbonate
(50 mL) and dichloromethane (200 mL) were added. The phases were separated, and the crude
product was extracted from the aqueous layer with dichloromethane (three times with a total of
240 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
 S22

concentrated under reduced pressure. The residue was subjected to FCC (diethyl
ether/triethylamine = 50:1) yielding the title product as a highly viscous substance in the second
fraction. Yield: 79% (8.831 g, 23.83 mmol); 1H NMR (600 MHz, CDCl3): d = 7.63‒7.53 (m,
6H), 7.27‒7.22 (m, 6H), 7.18‒7.13 (m, 3H), 2.73 (br s, 1H), 2.56‒2.44 (m, 1H), 2.28‒2.18 (m,
2H), 1.97 (s, 3H), 1.92 (br d, J = 13.3, 1H), 1.73 (dddd, J = 14.2, 8.6, 7.3, 3.4 Hz, 1H), 1.69‒
1.61 (m, 2H), 1.57 (dtt, J = 14.6, 7.5, 4.2 Hz, 1H), 1.50 (dddd, J = 13.8, 8.7, 4.9, 3.4 Hz, 1H),
1.45‒1.40 (m, 1H), 1.40‒1.33 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 147.6, 129.0,
127.8, 126.2, 71.6, 62.5, 58.9, 51.7, 48.1, 37.0, 29.1, 22.9; IR (ATR): n = 3283, 3059, 2928,
2847, 1791, 2319, 2159, 1956, 1894, 1816, 1595, 1449, 1380, 1272, 1206, 1090, 1031, 971,
899, 845, 751, 701; EI-MS: m/z = 372 (4), 371 (13) [M + H]+, 370 (8) M+•, 244 (15), 243 (77)
[C19H15+ = Mtrityl+], 241 (8), 239 (6), 228 (7), 166 (10), 165 (62), 128 (9), 127 (100), 98 (31), 84
(78), 82 (7), 58 (23), 56 (12); CI-MS: m/z = 372 (17), 371 (61) [M + H]+, 370 (15) M+•, 369
(5), 293 (7), 271 (14), 244 (13), 243 (100) [C19H15+ = Mtrityl+], 127 (35), 112 (6); ESI-HRMS
for C26H31N2 as [M + H]+: calcd. m/z = 371.24817, found m/z = 371.24768 with D = 1.32 ppm;
optical rotation: [a]D = +31.6 (c = 1.03 in CHCl3). The (R)-enantiomer ent-26a was prepared
analogously.

(S)-1-Isopropyl-3-(tritylamino)azepane (26b):

According to GP-3, (S)-3-(tritylamino)azepan-2-one (22b) containing 43% of ethanol (8.555 g,

21.09 mmol) was reduced, and the product dissolved in a mixture of methanol (technical grade,
120 mL) and acetone (35 mL). Then sodium cyanoborohydride (assay: 95%, 2.790 g, 42.18
mmol, 2.0 equiv) was added, and the reaction mixture was stirred at rt for 2 d. Next, the mixture
was concentrated under reduced pressure, and dichloromethane (200 mL) and a saturated,
aqueous solution of sodium carbonate (50 mL) were added. The phases were separated, and the
crude product was extracted from the aqueous layer with dichloromethane (three times with a
total of 240 mL). The combined organic phases were dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. The product was purified by FCC (diethyl
ether/triethylamine = 50:1) and isolated as a colorless solid. Yield: 97% (8.136 g, 20.41 mmol);
 S23

mp: 74 °C; 1H NMR (600 MHz, CDCl3): d = 7.61‒7.54 (m, 6H), 7.28‒7.20 (m, 6H), 7.17‒7.13
(m, 3H), 2.70 (br s, 1H), 2.54 (dt, J = 12.0, 5.8 Hz, 1H), 2.50‒2.41 (m, 1H), 2.31 (ddd, J = 12.5,
7.5, 5.3 Hz, 1H), 2.15 (dd, J = 13.2, 3.5 Hz, 1H), 2.07 (br s, 1H), 1.71‒1.62 (m, 2H), 1.58‒1.46
(m, 3H), 1.38‒1.27 (m, 2H), 0.80 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H); 13C{1H} NMR
(151 MHz, CDCl3): d = 147.7, 129.0, 127.8, 126.2, 71.5, 58.3, 56.0, 52.2, 51.2, 36.1, 30.0, 22.8,
19.1, 17.6; IR (ATR): n = 3264, 3055, 3024, 2917, 2854, 2339, 2196, 2170, 2111, 1994, 1820,
1595, 1487, 1445, 1390, 1358, 1331, 1292, 1261, 1202, 1164, 1106, 1064, 1029, 994, 951, 897,
847, 782, 748, 701, 668; EI-MS: m/z = 400 (9), 399 (36) [M + H]+, 398 (32) M+•, 244 (21), 243
(95) [C19H15+ = Mtrityl+], 242 (6), 241 (9), 239 (7), 228 (7), 166 (6), 165 (37), 156 (11), 155
(100), 126 (8), 112 (43), 98 (11), 86 (10), 84 (10), 56 (6); ESI-HRMS for C28H35N2 as [M +
H]+: calcd. m/z = 399.27947, found m/z = 399.27913 with D = 0.85 ppm; EA for C28H34N2:
calcd. C 84.37, H 8.60, N 7.03, found C 84.06, H 8.48, N 6.96; optical rotation: [a]D = +9.1
(c = 1.26 in CHCl3).

(S)-1-Benzyl-3-(tritylamino)azepane (26c):

According to GP-3, (S)-3-(tritylamino)azepan-2-one (22b) containing 44% of ethanol (2.001 g,

4.920 mmol) was reduced. The product was dissolved in dichloromethane (12 mL), and
triethylamine (2.05 mL, 14.7 mmol, 3.0 equiv) was added. The mixture was cooled (ice bath),
slowly treated with benzyl bromide (assay: 98%, 0.60 mL, 4.92 mmol, 1.0 equiv), and stirred
at rt overnight. Then, dichloromethane (20 mL) and an aqueous solution of sodium hydroxide
(10 mL, c = 1.0 mol/L) were added, the phases separated, and the crude product was extracted
from the aqueous layer with dichloromethane (three times with a total of 45 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/n-pentane/triethylamine = [Link])
and isolated as a colorless solid. Yield: 81% (1.785 g, 3.997 mmol); mp: 122 °C; 1H NMR
(600 MHz, CDCl3): d = 7.57‒7.49 (m, 6H), 7.25‒7.18 (m, 8H), 7.18‒7.11 (m, 6H), 3.25 (d, J =
13.5 Hz, 1H), 3.22 (d, J = 13.5 Hz, 1H), 2.75 (br s, 1H), 2.55 (dt, J = 12.2, 6.1 Hz, 1H), 2.41
(br s, 1H), 2.18 (m, 1H), 2.13 (dd, J = 13.2, 2.7 Hz, 1H), 1.81‒1.73 (m, 1H), 1.73‒1.67 (m, 1H),
1.65‒1.57 (m, 2H), 1.54‒1.48 (m, 1H), 1.44 (ddt, J = 13.5, 8.8, 3.8 Hz, 1H), 1.38 (ddt, J = 13.5,
 S24

8.8, 3.8 Hz, 1H); 13

C{1H} NMR (151 MHz, CDCl3): d = 147.6, 140.2, 129.0, 128.8, 128.2,
127.8, 126.8, 126.2, 71.5, 64.0, 61.1, 55.5, 51.7, 36.9, 29.2, 22.8; IR (ATR): n = 3285, 3058,
3027, 2927, 2851, 2809, 2334, 2162, 2053, 1961, 1886, 1814, 1595, 1487, 1449, 1352, 1263,
1211, 1150, 1070, 1028, 975, 900, 847, 747, 700; EI-MS: m/z = 448 (16) [M + H]+, 447 (9)
M+•, 333 (5), 244 (18), 243 (100) [C19H15+ = Mtrityl+], 241 (13), 239 (9), 228 (10), 215 (6), 204
(30), 203 (91), 202 (5), 174 (19), 166 (8), 165 (48), 161 (8), 160 (55), 134 (19), 120 (6), 98
(18), 91 (48), 84 (11); CI-MS: m/z = 244 (25), 243 (21) [C19H15+ = Mtrityl+], 204 (8), 203 (100),
165 (7), 160 (16), 91 (11); ESI-HRMS for C32H35N2 as [M + H]+: calcd. m/z = 447.27947,
found m/z = 447.27951 with D = 0.09 ppm; optical rotation: [a]D = +7.7 (c = 1.37 in CHCl3).

(S)-1-Tosyl-3-(tritylamino)azepane (26d):

According to GP-2, (S)-3-(tritylamino)azepan-2-one (22b) containing 44% of ethanol (582 mg,

1.43 mmol) was reduced, the product dissolved in dichloromethane (10 mL), and triethylamine
(600 µL, 4.31 mmol, 3.0 equiv) was added. The cooled reaction mixture (ice bath) was then
treated with tosyl chloride (273 mg, 1.43 mmol, 1.0 equiv) and stirred overnight at rt. Next,
dichloromethane (20 mL) and a saturated, aqueous solution of sodium carbonate (10 mL) were
added, the phases separated, and the crude product was extracted from the aqueous layer with
dichloromethane (three times with a total of 30 mL). The combined organic phases were dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The product was
purified by FCC (diethyl ether/n-pentane = 1:2) and isolated as a colorless solid. Yield: 76%
(558 mg, 1.09 mmol); mp: 157 °C; 1H NMR (600 MHz, CDCl3): d = 7.61‒7.54 (m, 6H), 7.40
(d, J = 8.2 Hz, 2H), 7.29‒7.22 (m, 6H), 7.22‒7.15 (m, 5H), 3.39 (dt, J = 13.4, 4.8 Hz, 1H), 2.80
(br s, 1H), 2.74‒2.63 (m, 2H), 2.43 (dd, J = 14.5, 5.2 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 1H), 1.70‒
1.58 (m, 4H), 1.48 (ddd, J = 12.7, 10.7, 8.9 Hz, 1H), 1.16‒1.06 (m, 1H); 13C{1H} NMR (151
MHz, CDCl3): d = 147.0, 142.7, 136.3, 129.4, 128.8, 127.8, 126.8, 126.2, 71.3, 54.9, 52.7, 50.9,
35.3, 30.2, 23.0, 21.4; IR (ATR): n = 3331, 3061, 2936, 2860, 2595, 2533, 2467, 2219, 2165,
2100, 2063, 2017, 1951, 1893, 1773, 1594, 1489, 1451, 1320, 1224, 1153, 1088, 1010, 901,
818, 773, 708, 657; EI-MS: m/z = 244 (24), 243 (100) [C19H15+ = Mtrityl+], 241 (5), 228 (9), 165
 S25

(59), 155 (6), 91 (24); CI-MS: m/z = 551 (7), 541 (10), 540 (32), 539 (100) [M + C2H5]+, 513
(5), 512 (17), 511 (61) [M + H]+, 509 (22), 434 (7), 433 (25), 356 (11), 355 (42), 297 (10), 283
(6), 271 (11), 269 (25), 252 (9), 245 (5), 244 (29), 243 (90) [C19H15+ = Mtrityl+], 167 (8); EA for
C32H34N2O2S: calcd. C 75.26, H 6.71, N 5.49, found C 75.20, H 6.72, N 5.46; HPLC: 99% ee,
tr = 7.3 min (minor) [R], 9.2 min (major) [S] (Chiralpak IA, n-heptane/2-propanol = 80:20, 0.8
mL/min, l = 230 nm, 20 °C); optical rotation: [a]D = -34.3 (c = 1.18 in CHCl3). The racemic
product and the (R)-enantiomer ent-26d were prepared analogously.

(S)-1-(tert-Butoxycarbonyl)-3-(tritylamino)azepane (26e):

According to GP-3, (S)-3-(tritylamino)azepan-2-one (22b) containing 44% of ethanol (2.001 g,

4.920 mmol) was reduced. The product was dissolved in dichloromethane (20 mL), and
triethylamine (690 µL, 4.95 mmol, 1.0 equiv) was added. Then, to the cooled solution (ice bath)
was added di-tert-butyl dicarbonate (assay: 99%, 1.085 g, 4.920 mmol, 1.0 equiv). The flask
was equipped with a gas bubbler and the reaction mixture stirred at rt overnight. Next,
dichloromethane (10 mL) and a saturated, aqueous solution of sodium carbonate (20 mL) were
added. The phases were separated, and the crude product was extracted from the aqueous layer
with dichloromethane (three times with a total of 60 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product
was purified by FCC (diethyl ether/n-pentane = 2:1) and isolated as a highly viscous substance.
Yield: 94% (2.107 g, 4.614 mmol). At rt two sets of signals could be identified in the NMR
spectrum, indicating the presence of two rotamers in a ratio of A:B = 1.25:1 in CDCl3 solution:
1
H NMR (600 MHz, CDCl3): d = 7.62‒7.51 (m, 6H of A, 6H of B), 7.33‒7.21 (m, 6H of A, 6H
of B), 7.20‒7.09 (m, 3H of A, 3H of B), 3.38 (dt, J = 14.3, 5.1 Hz, 1H of B), 3.30 (dd, J = 13.2,
4.8 Hz, 1H of A), 3.27‒3.19 (m, 2H of A), 3.09 (dt, J = 14.3, 6.3 Hz, 2H of B), 2.91‒2.79 (m,
2H of A, 2H of B), 2.09 (br s, 2H of B), 1.80 (br s, 2H of A), 1.58‒1.45 (m, 3H of A, 3H of B),
1.43 (s, 9H of B), 1.34 (s, 9H of A), 1.23‒1.12 (m, 1H of A, 1H of B), 1.12‒0.91 (m, 2H of A,
2H of B); 13C{1H} NMR (151 MHz, CDCl3): d = 156.0 (B), 155.4 (A), 147.4 (B), 147.2 (A),
128.9 (B), 128.8 (A), 128.0 (A), 127.9 (B), 126.4 (A), 126.3 (B), 79.4 (A), 79.0 (B), 71.5 (A+B),
 S26

54.4 (A), 53.6 (B), 53.4 (B), 52.8 (A), 49.1 (A), 48.8 (B), 34.3 (A), 34.1 (B), 28.6 (A+B), 28.2
(A+B), 24.0 (B), 23.0 (A); IR (ATR): n = 3608, 3494, 3379, 3062, 2971, 2917, 2858, 2637,
2463, 2330, 2239, 2169, 2092, 2045, 1979, 1865, 1696, 1595, 1457, 1414, 1363, 1303, 1254,
1216, 1160, 1093, 1055, 1025, 972, 897, 760, 701; EI-MS: m/z = 457 (4) M+•, 379 (6), 258 (8),
244 (17), 243 (100) [C19H15+ = Mtrityl+], 228 (6), 213 (10), 166 (7), 165 (48), 157 (17), 113 (16),
84 (6), 70 (9), 57 (39); CI-MS: m/z = 458 (15) [M + H]+, 457 (8) M+, 271 (9), 244 (20), 243
(100) [C19H15+ = Mtrityl+], 167 (6), 57 (5); ESI-HRMS for C30H36O2N2Na as [M + Na]+: calcd.
m/z = 479.26690, found m/z = 479.26566 with D = 2.76 ppm; optical rotation: [a]D = -17.3 (c
= 1.36 in CHCl3).

(S)-3-Aminopiperidine dihydrochloride (2 ∙ 2 HCl):

Method A: In a 250 mL round bottom flask flushed with argon, anhydrous tetrahydrofuran (100
mL) was cooled (ice bath) and lithium aluminum hydride (3.37 g, 88.8 mmol, 3.0 equiv) added
carefully in small portions. Then (S)-3-aminopiperidin-2-one (21a) (3.379 g, 29.60 mmol) was
added as solid in small portions over a period of 30 min while cooling had been continued. The
flask was equipped with a gas bubbler, the ice bath was removed, and stirring continued at rt
overnight. Next, the suspension was refluxed for 2 h (oil bath). Afterwards, the mixture was
cooled (ice bath), and water (3 mL) was added dropwise (caution: formation of hydrogen).
Under continued cooling, the reaction mixture was then treated dropwise with an aqueous
solution of sodium hydroxide (3 mL, c = 5.0 mol/L) and additional water (10 mL) over a period
of 45 min, until all remaining lithium aluminum hydride had been destroyed. The resulting
white suspension was stirred at rt for 1 h, and dichloromethane (100 mL) followed by potassium
carbonate (50 g) were added. The suspension was stirred for additional 30 min, filtered over a
Büchner funnel, and the filter cake was thoroughly washed with dichloromethane (200 mL).
The combined filtrates were treated with a cooled solution (ice bath) of hydrogen chloride in
anhydrous methanol (124 mL, c = 0.5 mol/L, 62.2 mmol, 2.1 equiv), concentrated under
reduced pressure, and dried in high vacuum. The resulting pale yellow solid was intensively
ground in the presence of a mixture of diethyl ether (20 mL) and acetone (2 mL) inside the flask
with a test tube-like glass rod. The organic layer had been taken off with a Pasteur pipette, and
the procedure was repeated four times with diethyl ether (a total of 80 mL). Remaining diethyl
ether was removed by rotary evaporation and the pale yellow solid dried in high vacuum. Yield:
 S27

92% (4.730 g, 27.33 mmol). For recrystallization, the solid product was dissolved in methanol
(100 mL), then 2-propanol was added (30 mL), and the volume of the mixture was reduced at
80 °C and atmospheric pressure, until most of the solvent was evaporated and a crystalline
material had been formed. Remaining mother liquor (8 mL) was decanted off, and the
crystalline solid was intensively ground in the presence of an acetone/ethanol mixture (1:2, 25
mL) with a test tube-like glass rod. The overlaying clear, orange solution had been taken off
with a Pasteur pipette, and the procedure was repeated first with ethyl acetate (30 mL), then
two times with diethyl ether (a total of 100 mL). Remaining diethyl ether was removed by rotary
evaporation and the beige colored solid dried in high vacuum. Yield: 84% (4.303 g, 24.86
mmol).
Method B: Following GP-2, (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g, 29.60 mmol)
was reduced and the product subjected to deprotection according to GP-4. The title compound
was obtained as an ivory solid. Yield: 93% (4.781 g, 27.62 mmol); mp: 204 °C (decompn.); 1H
NMR (600 MHz, D2O): d = 3.77‒3.70 (m, 1H), 3.67 (tt, J = 11.7, 4.2 Hz, 1H), 3.49 (dddt, J =
12.9, 4.0, 2.6, 1.3 Hz, 1H), 3.12 (t, J = 12.0 Hz, 1H), 3.04 (td, J = 12.0, 3.4 Hz, 1H), 2.33‒2.25
(m, 1H), 2.18‒2.09 (m, 1H), 1.86 (dtt, J = 14.9, 12.9, 4.0 Hz, 1H), 1.75 (tdd, J = 12.8, 11.6, 3.9
Hz, 1H); 13C{1H} NMR (151 MHz, D2O): d = 44.9, 44.6, 43.4, 26.2, 20.1; IR (ATR): n = 3840,
3417, 2945, 2546, 2430, 2083, 2026, 1989, 1714, 1600, 1565, 1527, 1468, 1418, 1360, 1298,
1272, 1212, 1157, 1127, 1093, 1070, 1031, 1003, 945, 897, 858, 801, 767, 702, 656; ESI-MS:
m/z = 120 (13), 113 (8), 106 (5), 101 (100) [Mdiamine + H]+, 86 (3), 84 (82); ESI-HRMS for
C5H13N2 as [Mdiamine + H]+: calcd. m/z = 101.10732, found m/z = 101.10719 with D = 1.29 ppm;
EA for C5H14Cl2N2: calcd. C 34.70, H 8.15, N 16.19, found C 34.75, H 8.01, N 16.14; optical
rotation: [a]D = +2.1 (c = 1.32 in H2O) {lit.7 [a]D = +2.3 (c = 1.00 in H2O)}, [a]D = -4.2 (c =
1.11 in DMSO). The racemic product and the (R)-enantiomer ent-2 were prepared analogously
to method B. To determine the enantiomeric excess of the title compound, the ditosylated
derivative 31a was prepared.

(S)-3-Amino-1-methylpiperidine dihydrochloride (27a):

According to GP-4, the title compound was obtained from (S)-1-methyl-3-

(tritylamino)piperidine (25a) (5.604 g, 15.72 mmol) as a hygroscopic, colorless solid. Yield:
88% (2.595 g, 13.87 mmol); mp: 280‒290 °C (decompn.); 1H NMR (400 MHz, D2O): d = 3.84
 S28

(d, J = 11.5 Hz, 1H), 3.72‒3.60 (m, 2H), 3.19‒3.04 (m, 2H), 3.02 (s, 3H), 2.30 (d, J = 12.5 Hz,
1H), 2.19 (d, J = 15.0 Hz, 1H), 1.95‒1.84 (m, 1H), 1.76‒1.66 (m, 1H); 13C{1H} NMR (101
MHz, D2O): d = 54.3, 54.0, 45.6, 44.0, 25.7, 21.2; IR (ATR): n = 3207, 3010, 2780, 2647,
2545, 2071, 1994, 1955, 1912, 1828, 1740, 1605, 1533, 1477, 1450, 1435, 1401, 1347, 1313,
1285, 1255, 1228, 1200, 1154, 1120, 1093, 1068, 1033, 1018, 987, 966, 922, 889, 878, 846,
775; ESI-MS: m/z = 229 (2) [2Mdiamine + H]+, 115 (85) [Mdiamine + H]+, 98 (100), 70 (9); EA for
C6H16Cl2N2: calcd. C 38.52, H 8.62, N 14.97, found C 38.57, H 8.58, N 14.75; optical rotation:
[a]D = +2.4 (c = 1.25 in MeOH). The (R)-enantiomer ent-27a was prepared analogously.

(S)-3-Amino-1-isopropylpiperidine dihydrochloride (27b):

According to GP-4, the title compound was obtained from (S)-1-isopropyl-3-

(tritylamino)piperidine (25b) (11.31 g, 29.41 mmol) as a hygroscopic, colorless solid. Yield:
94% (5.950 g, 27.65 mmol); mp: 211 °C (decompn.); 1H NMR (400 MHz, D2O): d = 3.73‒
3.61 (m, 3H), 3.53 (d, J = 11.4 Hz, 1H), 3.11‒3.02 (m, 2H), 2.29‒2.24 (m, 1H), 2.22‒2.15 (m,
13
1H), 1.94‒1.81 (m, 1H), 1.69 (dd, J = 12.7, 4.0 Hz, 1H), 1.38 (d, J = 6.7 Hz, 6H); C{1H}
NMR (101 MHz, D2O): d = 59.5, 48.9, 47.9, 45.6, 26.1, 20.6, 15.9, 15.8; IR (ATR): n = 3409,
2530, 2071, 1861, 1600, 1455, 1395, 1290, 1244, 1132, 1028, 924, 866, 709; ESI-MS: m/z =
167 (13), 144 (6), 143 (100) [Mdiamine + H]+, 135 (15), 127 (6), 126 (73), 113 (3); ESI-HRMS
for C8H19N2 as [Mdiamine + H]+: calcd. m/z = 143.15427, found m/z = 143.15416 with D = 0.77
ppm; optical rotation: [a]D = +6.9 (c = 1.65 in MeOH).

(S)-3-Amino-1-benzylpiperidine dihydrochloride (27c):

Method A: To a cooled suspension (ice bath) of (S)-3-aminopiperidine dihydrochloride (2 ∙ 2

HCl) (1.945 g, 11.24 mmol) in dichloromethane (22 mL) was added triethylamine (6.3 mL, 45
mmol, 4.0 equiv). Next, the mixture was slowly treated with benzyl bromide (assay: 98%, 1.34
mL, 11.3 mmol, 1.0 equiv) and subsequently stirred at rt overnight. Then, dichloromethane (20
mL) and an aqueous solution of sodium hydroxide (20 mL, c = 1.0 mol/L) were added, the
 S29

phases separated, and the crude product was extracted from the aqueous layer with
dichloromethane (three times with a total of 60 mL). The combined organic phases were dried
over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was
subsequently treated with an ice-cold solution of hydrogen chloride in anhydrous methanol
(47.2 mL, c = 0.5 mol/L, 23.6 mmol, 2.1 equiv). The solution was then again concentrated under
reduced pressure and the residue dried in high vacuum. Diethyl ether (10 mL) was added and
the solid intensively ground with a test tube-like glass rod. The diethyl ether layer had been
taken off with a Pasteur pipette, and the procedure was repeated three times. Remaining diethyl
ether was removed by rotary evaporation and the colorless solid product dried in high vacuum.
Yield: 66% (1.952 g, 7.416 mmol).
Method B: According to the GP-4, the title compound was obtained from (S)-1-benzyl-3-
(tritylamino)piperidine (25c) (10.88 g, 25.15 mmol) as a hygroscopic, colorless solid. Yield:
94% (6.233 g, 23.68 mmol); mp: 188‒190 °C (decompn.); 1H NMR (400 MHz, D2O): d = 7.56
(s, 5H), 4.45 (s, 2H), 3.79 (d, J = 11.7 Hz, 1H), 3.72‒3.62 (m, 1H), 3.58 (d, J = 12.0 Hz, 1H),
3.18‒3.00 (m, 2H), 2.27 (d, J = 12.3 Hz, 1H), 2.14 (d, J = 14.6 Hz, 1H), 1.92‒1.77 (m, 1H),
1.70 (ddd, J = 13.0, 12.5, 3.3 Hz, 1H); 13C{1H} NMR (101 MHz, D2O): d = 131.3, 130.4, 129.3,
127.8, 61.2, 51.9, 51.5, 45.3, 25.9, 20.5; IR (ATR): n = 3846, 3404, 2530, 2075, 1994, 1911,
1827, 1598, 1450, 1214, 1171, 1030, 926, 855, 818, 750, 699; ESI-MS: m/z = 193 (12), 191
(85) [Mdiamine + H]+, 176 (7), 174 (100), 167 (3); ESI-HRMS for C12H19N2 as [Mdiamine + H]+:
calcd. m/z = 191.15427, found m/z = 191.15405 with D = 1.15 ppm; optical rotation: [a]D =
+21.3 (c = 1.17 in MeOH). The (R)-enantiomer ent-27c was prepared analogously to method
B.

(S)-3-Aminoazepane dihydrochloride (14 ∙ 2 HCl):

Method A: In a 250 mL round bottom flask flushed with argon, anhydrous tetrahydrofuran (100
mL) was cooled (ice bath) and lithium aluminum hydride (3.42 g, 90.0 mmol, 3.0 equiv)
carefully added in small portions. While cooling was continued, (S)-3-aminoazepan-2-one
hydrochloride (22a) (4.94 g, 30.0 mmol) was added in small portions over a period of 30 min,
followed by dropwise addition of anhydrous ethanol (1.75 mL, 30.0 mmol, 1.0 equiv). Next,
the reaction mixture was refluxed (oil bath) for 18 h. Afterwards, the mixture was cooled (ice
bath), and water (3 mL) was added dropwise (caution: formation of hydrogen). Under
 S30

continued cooling, the reaction mixture was then treated dropwise with an aqueous solution of
sodium hydroxide (3 mL, c = 5.0 mol/L), and again water (10 mL) over a period of 45 min,
until all remaining lithium aluminum hydride had been destroyed. The resulting white
suspension was stirred at rt for 1 h and dichloromethane (100 mL) followed by potassium
carbonate (50 g) were added. The suspension was stirred for additional 30 min, filtered over a
Büchner funnel, and the filter cake was thoroughly washed with dichloromethane (200 mL).
The combined filtrates were treated with an ice-cooled solution of hydrogen chloride in
anhydrous methanol (50.4 mL, c = 1.25 mol/L, 63.0 mmol, 2.1 equiv), concentrated under
reduced pressure, and the remains dried in high vacuum. The resulting yellow solid was
intensively ground in the presence of a mixture of ethanol (50 mL) and ethyl acetate (30 mL)
with a test tube-like glass rod. The organic layer had been taken off with a Pasteur pipette, and
the procedure was repeated with a 1:1 mixture of ethanol/ethyl acetate (30 mL). Then, the
product was washed two times with n-pentane (a total of 200 mL) by mixing the remains with
the solvent, allowing the solid to settle down, and carefully decanting off the supernatant
organic layer. Remaining n-pentane was removed by rotary evaporation before the pale yellow
solid was dried in high vacuum. Yield: 94% (5.254 g, 28.08 mmol).
Method B: Following GP-3, (S)-3-(tritylamino)azepan-2-one (22b) with an ethanol content of
13% (12.58 g, 33.34 mmol) was reduced and the product subjected to deprotection according
to GP-4, but using a mixture of ethanol (50 mL) and ethyl acetate (30 mL) for the first, and a
1:1 mixture of ethanol/ethyl acetate (30 mL) for the second grinding step. Then, the product
was washed two times with n-pentane (a total of 200 mL) by mixing the remains with the
solvent, allowing the solid to settle down and carefully decanting off the supernatant organic
layer. Remaining n-pentane was removed by rotary evaporation before the ivory colored solid
was dried in high vacuum. Yield: 90% (5.608 g, 29.97 mmol). The 1H NMR spectrum of this
material indicated traces of impurities in the aromatic area, which had no detrimental impact on
the subsequent synthetic steps. For recrystallization, the solid product was dissolved in
methanol (100 mL), then 2-propanol was added (30 mL) and the volume of mixture was reduced
at 80 °C and atmospheric pressure, until most of the solvent was evaporated and a crystalline
material had been formed. Remaining mother liquor (5 mL) was decanted off, and the
crystalline residue was intensively ground in the presence of a mixture of ethanol (32 mL) and
ethyl acetate (20 mL) with a test tube-like glass rod. The overlaying clear, yellow solution had
been taken off with a Pasteur pipette and the procedure was repeated with a 1:1 mixture of
ethanol/ethyl acetate (30 mL). Then, the product was washed two times with n-pentane (a total
of 200 mL), by mixing the remains with the solvent, allowing the solid to settle down and
 S31

carefully decanting off the supernatant organic layer. Remaining n-pentane was removed by
rotary evaporation before the pale, off-white colored solid was dried in high vacuum. Yield:
78% (4.947 g, 26.44 mmol); mp: 195 °C (decompn.); 1H NMR (600 MHz, D2O): d = 3.83 (tt,
J = 10.3, 4.0 Hz, 1H), 3.69 (ddd, J = 13.8, 3.9, 1.4 Hz, 1H), 3.48‒3.38 (m, 2H), 3.33 (ddd, J =
13.6, 9.4, 3.5 Hz, 1H), 2.33‒2.23 (m, 1H), 2.09‒1.97 (m, 2H), 1.95‒1.89 (m, 1H), 1.89‒1.81
(m, 1H), 1.74‒1.63 (m, 1H); 13C{1H} NMR (151 MHz, D2O): d = 48.2, 47.3, 46.9, 30.9, 24.0,
21.9; IR (ATR): n = 3842, 3391, 2741, 2574, 2520, 2441, 2344, 2158, 2108, 1979, 1922, 1877,
1752, 1628, 1589, 1515, 1462, 1406, 1316, 1287, 1242, 1194, 1116, 1067, 1041, 993, 962, 935,
885, 849, 781, 695; ESI-MS: m/z = 411 (16), 410 (53), 174 (5), 115 (71) [Mdiamine + H]+, 98
(100); ESI-HRMS for C6H15N2 as [Mdiamine + H]+: calcd. m/z = 115.12297, found m/z =
115.12289 with D = 0.70 ppm; EA for C6H16Cl2N2: calcd. C 38.52, H 8.62, N 14.97, found C
38.22, H 8.66, N 15.09; optical rotation: [a]D = +2.3 (c = 1.32 in H2O), [a]D = -3.3 (c = 1.27
in DMSO). The racemic product and the (R)-enantiomer ent-14 were prepared analogously to
method B. To determine the enantiomeric excess of the title compound, the ditosylated
derivative 32a was prepared.

(S)-3-Amino-1-methylazepane dihydrochloride (28a):

According to GP-4, the title compound was obtained from (S)-1-methyl-3-(tritylamino)azepane

(26a) (1.461 g, 3.943 mmol) as a hygroscopic, colorless solid. Yield: 93% (0.741 g, 3.684
mmol); mp: 183 °C; 1H NMR (400 MHz, D2O): d = 3.96‒3.80 (m, 1H), 3.71‒3.56 (m, 2H),
3.52‒3.37 (m, 2H), 3.03 (s, 3H), 2.29‒2.17 (m, 1H), 2.05‒1.90 (m, 3H), 1.90‒1.80 (m, 1H),
1.79‒1.65 (m, 1H); 13C{1H} NMR (101 MHz, D2O, 80 °C): d = 58.9, 57.7, 47.9, 46.1, 31.1,
23.7, 22.3; IR (ATR): n = 3415, 2844, 2637, 2074, 2000, 1603, 1520, 1469, 1224, 1194, 1118,
1029, 968, 884, 761, 703; ESI-MS: m/z = 309 (8), 264 (4), 243 (14), 167 (18) [Mdiamine + K]+,
165 (9), 130 (7), 129 (100) [Mdiamine + H]+, 99 (7), 98 (90); ESI-HRMS for C7H17N2 as [Mdiamine
+ H]+: calcd. m/z = 129.13862, found m/z = 129.13879 with D = 1.32 ppm; optical rotation:
[a]D = -2.1 (c = 1.03 in H2O). At rt the methylene carbon atoms of the azepane ring showed
very broad signal peaks in the NMR spectrum, whereas measuring the spectrum at 80 °C
resulted in a distinctive set of signals. The (R)-enantiomer ent-28a was prepared analogously.
 S32

(S)-3-Amino-1-isopropylazepane dihydrochloride (28b):

Modifying GP-4 by exchange of diethyl ether with a hot mixture of ethanol and ethyl acetate
(2:1) for the purification, the title compound was obtained from (S)-1-isopropyl-3-
(tritylamino)azepane (26b) (7.854 g, 19.71 mmol) as a hygroscopic, colorless solid. Yield: 85%
(3.838 g, 16.75 mmol); mp: 262‒263 °C (decompn.); 1H NMR (400 MHz, D2O): d = 3.86 (br
s, 1H), 3.78 (sept, J = 6.7 Hz, 1H), 3.67‒3.35 (m, 4H), 2.36‒2.21 (m, 1H), 2.14‒1.74 (m, 5H),
1.42 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (101 MHz, D2O): d = 61.4, 52.0, 51.0, 48.1, 30.5, 23.1,
20.8, 15.94, 15.86; IR (ATR): n = 3413, 2641, 2076, 1959, 1858, 1743, 1604, 1519, 1464, 1395,
1313, 1248, 1226, 1180, 1141, 1041, 1004, 950, 887, 766, 702; ESI-MS: m/z = 158 (10), 157
(100) [Mdiamine + H]+, 148 (3), 141 (7), 140 (70), 102 (4), 98 (5); ESI-HRMS for C9H21N2 as
[Mdiamine + H]+: calcd. m/z = 157.16992, found m/z = 157.16983 with D = 0.57 ppm; EA for
C9H22Cl2N2: calcd. C 47.17, H 9.68, N 12.22, found C 47.08, H 9.76, N 12.19; optical rotation:
[a]D = -2.1 (c = 1.00 in MeOH).

(S)-3-Amino-1-benzylazepane dihydrochloride (28c):

According to GP-4, the title compound was obtained from (S)-1-benzyl-3-(tritylamino)azepane

(26c) (1.557 g, 3.486 mmol) as a colorless, very hygroscopic solid. Yield: 93% (6.233 g, 3.257
mmol); 1H NMR (400 MHz, D2O): d = 7.63‒7.50 (m, 5H), 4.50 (d, J = 13.1 Hz, 1H), 4.45 (d,
J = 13.1 Hz, 1H), 3.85 (br s, 1H), 3.66 (d, J = 13.5 Hz, 1H), 3.55 (dd, J = 13.6, 9.8 Hz, 1H),
3.40 (br s, 2H), 2.28‒2.14 (m, 1H), 2.00‒1.79 (m, 4H), 1.73 (br s, 1H); 13C{1H} NMR (101
MHz, D2O): d = 131.3, 130.5, 129.5, 128.6, 61.9, 55.4, 54.5, 47.0, 30.8, 22.5; IR (ATR): n =
3857, 3401, 2866, 2564, 2080, 1992, 1745, 1602, 1455, 1418, 1213, 1184, 1112, 1079, 1018,
893, 749, 700; ESI-MS: m/z = 205 (4) [Mdiamine + H]+, 189 (14), 188 (100), 170 (20), 167 (22);
ESI-HRMS for C13H22N2 as [Mdiamine + H]+: calcd. m/z = 205.16992, found m/z = 205.16945
with D = 2.29 ppm; optical rotation: [a]D = +15.4 (c = 1.47 in MeOH). A characteristic melting
point could not be measured under standard conditions.
 S33

(S,E)-3-(Benzylideneamino)piperidin-2-one (29):

According to GP-1, L-ornithine monohydrochloride (17 ∙ HCl) (8.431 g, 50.0 mmol) was
converted into its corresponding methyl ester by treatment with thionyl chloride (4.0 mL, 55
mmol, 1.1 equiv) in methanol (125 mL). The colorless solid was dissolved again in methanol
(100 mL), then triethylamine (14.6 mL, 105 mmol, 2.1 equiv) was added and the solution stirred
at rt overnight. Benzaldehyde (7.6 mL, 75 mmol, 1.5 equiv) was added, and stirring was
continued at rt for 4 h before the volume of the reaction mixture was decreased under reduced
pressure and the residue dried in high vacuum for 10 min. Then, dichloromethane (100 mL),
water (100 mL), and a saturated, aqueous solution of sodium carbonate (50 mL) were added.
The layers were separated, and the crude product was extracted from the aqueous phase with
dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The remaining solid was treated with diethyl
ether (30 mL) and intensively ground with a test tube-like glass rod. The ethereal layer had been
taken off with a Pasteur pipette, and the procedure was repeated three times using 20 mL of
diethyl ether. Excess diethyl ether was removed from the product cake by rotary evaporation,
and the remaining pale yellow solid was dried in high vacuum. Yield: 82% (8.304 g, 41.06
mmol); mp: 123 °C; 1H NMR (600 MHz, CDCl3): d = 8.38 (s, 1H), 7.78‒7.74 (m, 2H), 7.41‒
7.35 (m, 3H), 7.27‒7.23 (m, 1H), 3.89 (dd, J = 6.6, 5.6 Hz, 1H), 3.37 (dddd, J = 12.1, 7.2, 5.0,
2.3 Hz, 1H), 3.30 (dddd, J = 12.1, 7.2, 5.2, 2.4 Hz, 1H), 2.17‒1.96 (m, 3H), 1.77 (ddddd, J =
11.9, 10.4, 8.4, 5.3, 3.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 170.9, 163.6, 136.0,
130.8, 128.50, 128.46, 68.9, 42.5, 29.5, 19.6. Because of the fact that the selective excitation of
the hydrogen atoms in ortho position of the benzyl group showed no interaction with hydrogen
atoms of the piperidone ring in a NOESY experiment, the E-configuration was assigned for the
absolute stereochemistry of the imine double bond; IR (ATR): n = 3257, 3083, 2944, 2868,
2325, 2203, 2086, 2000, 1916, 1663, 1580, 1484, 1400, 1319, 1277, 1206, 1093, 1064, 975,
944, 888, 793, 756, 696, 659; EI-MS: m/z = 203 (3) [M + H]+, 104 (9), 100 (7), 99 (100), 98
(33), 90 (8), 89 (8), 77 (6), 70 (21); CI-MS: m/z = 406 (11), 405 (35) [2M + H]+, 204 (14), 203
(100) [M + H]+; EA for C12H14N2O: calcd. C 71.26, H 6.98, N 13.85, found C 71.37, H 7.19,
 S34

N 13.88; optical rotation: [a]D = -155.0 (c = 1.05 in CHCl3), [a]D = -111.7 (c = 1.28 in
MeOH).

(S)-1-Benzyl-3-(benzylamino)piperidine (30):

Method A: Under cooling (ice bath) acetyl chloride (12.60 mL, 177.6 mmol, 6.0 equiv) was
slowly added to anhydrous methanol (150 mL). The ice bath was removed and the solution
stirred at rt for 3 h. This acidic methanol solution was transferred into a flask containing (S)-3-
(tritylamino)piperidine (23), which was prepared by the reduction of (S)-3-(tritylamino)-
piperidin-2-one (21b) (10.55 g, 29.60 mmol) according to GP-2. The reaction mixture was
stirred at rt overnight and afterwards concentrated under reduced pressure. Then, diethyl ether
(100 mL) and acetone (15 mL) were added, and the mixture was stirred at rt for 5 min. The
solvent had been decanted off and the latter step repeated two times with diethyl ether (100
mL). Next, excess diethyl ether was removed by rotary evaporation and the residue dried in
high vacuum. The remaining solid was dissolved in methanol (technical grade, 60 mL) and
treated with benzaldehyde (7.5 mL, 74 mmol, 2.5 equiv). The reaction was stirred at rt for 3 h
to complete the imine formation. The reaction mixture was cooled (ice bath), and sodium
borohydride (3.32 g, 88.8 mmol, 3.0 equiv) was added in portions. After the effervescence had
ceased, the reaction mixture was stirred at rt for 30 min, cooled again (ice bath), carefully
acidified with a hydrochloric acid solution (100 mL, c = 1.0 mol/L), and subsequently extracted
three times with ethyl acetate (a total of 300 mL). The organic layers were discarded, and the
aqueous phase was carefully adjusted to pH = 8‒9 with an aqueous solution of sodium
hydroxide (c = 5.0 mol/L). The crude product was extracted from the aqueous phase with
dichloromethane (three times with a total of 300 mL), and the combined organic phases were
dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product
was purified by FCC (diethyl ether/triethylamine = 50:1) and isolated as a colorless oil. Yield:
75% (6.253 g, 22.30 mmol).
Method B: In a 500 mL round bottom flask flushed with argon, anhydrous tetrahydrofuran (175
mL) was cooled (ice bath) and lithium aluminum hydride (6.23 g, 164 mmol, 4.0 equiv)
carefully added in small portions. Then, (S,E)-3-(benzylideneamino)piperidin-2-one (29)
(8.304 g, 41.06 mmol) was added over a period of 30 min while cooling had been continued.
The flask was equipped with a gas bubbler, the ice bath was removed, and stirring was
 S35

continued at rt overnight. Next, the suspension was refluxed for 2 h (oil bath). Afterwards, the
mixture was cooled (ice bath), and water (4.2 mL) was added dropwise (caution: formation of
hydrogen). Under continued cooling, the reaction mixture was treated dropwise with an aqueous
solution of sodium hydroxide (4.2 mL, c = 5.0 mol/L), and additional water (13.9 mL) over a
period of 45 min, until all remaining lithium aluminum hydride had been destroyed. The
resulting white suspension was stirred at rt for 1 h, and dichloromethane (150 mL) followed by
magnesium sulfate (70 g) were added. The suspension was stirred for additional 30 min, filtered
over a Büchner funnel, and the filter cake was thoroughly washed with dichloromethane (300
mL). The combined filtrates were concentrated under reduced pressure, and the resulting pale
yellow oil was dried in high vacuum. The remaining product was dissolved in dichloromethane
(80 mL), and triethylamine (17.2 mL, 123 mmol, 3.0 equiv) was added. The ice-cold mixture
was slowly treated with benzyl bromide (assay: 98%, 5.00 mL, 41.1 mmol, 1.0 equiv), and
subsequently stirred at rt overnight. Then, dichloromethane (100 mL) and an aqueous solution
of sodium hydroxide (50 mL, c = 1.0 mol/L) were added, the phases separated, and the crude
product was extracted from the aqueous layer with dichloromethane (three times with a total of
240 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The product was purified by FCC (diethyl
ether/triethylamine = 50:1) and isolated as a colorless oil. Yield: 85% (9.834 g, 35.07 mmol);
1
H NMR (600 MHz, CDCl3): d = 7.35‒7.18 (m, 10H), 3.74 (d, J = 13.8 Hz, 2H), 3.49 (d, J =
13.8 Hz, 2H), 2.79 (br s, 1H), 2.73 (tt, J = 8.2, 3.5 Hz, 1H), 2.58 (br s, 1H), 2.10 (br s, 1H), 2.01
(br s, 1H), 1.81 (br s, 1H), 1.67 (dt, J = 13.8, 4.6 Hz, 1H), 1.53 (dddd, J = 14.0, 10.0, 9.3, 4.9
Hz, 1H), 1.35 (br s, 1H), 1.23 (br s, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 140.7, 138.5,
129.1, 128.3, 128.11, 128.05, 126.9, 126.8, 63.3, 59.3, 53.8, 53.5, 51.1, 30.9, 23.6; IR (ATR):
n = 3320, 3033, 2921, 2792, 2325, 2093, 1753, 1604, 1456, 1351, 1116, 879, 717; EI-MS: m/z
= 280 (5) M+•, 175 (17), 160 (7), 148 (20), 147 (64), 146 (50), 134 (45), 132 (11), 120 (6), 92
(13), 91 (100), 84 (12), 70 (8), 65 (18); CI-MS: m/z = 371 (10), 282 (25), 281 (100) [M + H]+,
280 (41) M+, 279 (22), 203 (6), 202 (7), 194 (11), 190 (6), 189 (10), 175 (25), 174 (29), 173
(10), 148 (11), 147 (40), 146 (6), 134 (10), 107 (7), 105 (10), 87 (9), 85 (40), 83 (70); EA for
C19H24N2: calcd. C 81.38, H 8.63, N 9.99, found C 81.06, H 8.59, N 10.26; optical rotation:
product of method A: [a]D = -12.6 (c = 1.02 in CHCl3); product of method B: [a]D = -5.0 (c
= 1.72 in CHCl3).
 S36

(S)-1-Tosyl-3-(tosylamido)piperidine (31a):

The dihydrochloride of 2 (515 mg, 2.98 mmol) was suspended in dichloromethane (10 mL),
and triethylamine (1.66 mL, 11.9 mmol, 4.0 equiv) was added. The cooled mixture (ice bath)
was then treated with tosyl chloride (1.136 g, 5.960 mmol, 2.0 equiv) and stirred at rt overnight.
Next, dichloromethane (30 mL) and a hydrochloric acid solution (15 mL, c = 2.0 mol/L, 10
equiv) were added, the phases separated, and the crude product was extracted from the aqueous
layer with dichloromethane (three times with a total of 30 mL). The combined organic phases
were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The
product was purified by FCC (ethyl acetate/n-pentane = 1:1) and isolated as a colorless solid.
Yield: 86% (1.047 g, 2.563 mmol); mp: 204 °C; 1H NMR (600 MHz, CDCl3): d = 7.70 (d, J =
8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.27‒7.24 (m, 2H), 7.23‒7.20 (m, 2H), 5.14 (d, J = 8.0
Hz, 1H), 3.38‒3.24 (m, 1H), 3.04‒2.97 (m, 1H), 2.91‒2.83 (m, 1H), 2.81‒2.73 (m, 1H), 2.52
(dd, J = 11.7, 7.0 Hz, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 1.66 (dddd, J = 15.8, 9.2, 7.6, 4.3 Hz, 1H),
1.51‒1.41 (m, 2H), 1.35‒1.26 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 143.9, 143.7,
137.7, 133.0, 129.9, 129.8, 127.7, 127.1, 51.2, 48.7, 46.2, 30.1, 22.0, 21.65, 21.61; IR (ATR):
n = 3232, 2930, 2858, 2320, 2181, 2095, 2022, 1916, 1597, 1493, 1454, 1401, 1314, 1227,
1159, 1094, 1019, 942, 919, 875, 816, 745, 677, 657; EI-MS: m/z = 255 (5), 254 (14), 253
(100) [M - C7H7O2S]+, 237 (24), 236 (10), 224 (10), 155 (17), 91 (23), 70 (7); ESI-HRMS for
C38H48N4NaO8S4 as [2M + Na]+: calcd. m/z = 839.22472, found m/z = 839.22335 with D = 1.63
ppm; EA for C19H24N2O4S2: calcd. C 55.86, H 5.92, N 6.86, found C 55.69, H 5.81, N 6.82;
HPLC: 98% ee (product of method A), >99% ee (product of method B), tr = 14.3 min (major)
[S], 44.5 min (minor) [R] (Chiralpak IA, n-heptane/2-propanol = 50:50, 0.6 mL/min, l = 230
nm, 20 °C); optical rotation: [a]D = -11.9 (c = 1.28 in CHCl3). The racemic product and the
(R)-enantiomer ent-31a were prepared analogously.
 S37

(S)-1-Methyl-3-(tosylamido)pipridine (31b):

To a cooled suspension (ice bath) of (S)-3-amino-1-methylpiperidine dihydrochloride (27a)

(571 mg, 3.05 mmol) in dichloromethane (25 mL) was added triethylamine (1.70 mL, 12.2
mmol, 4.0 equiv) and tosyl chloride (618 mg, 3.24 mmol, 1.06 equiv). The ice bath was removed
and the reaction mixture stirred at rt overnight. Then, dichloromethane (20 mL) and a saturated,
aqueous solution of sodium carbonate (10 mL) were added, the phases separated, and the crude
product was extracted from the aqueous layer with dichloromethane (three times with a total of
30 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The product was purified by FCC (diethyl
ether/triethylamine = 50:1) and isolated as a colorless solid. Yield: 93% (764 mg, 2.85 mmol);
mp: 128 °C; 1H NMR (300 MHz, CDCl3): d = 7.81‒7.75 (m, 2H), 7.32‒7.26 (m, 2H), 5.28 (br
s, 1H), 3.38 (br s, 1H), 2.42 (s, 3H), 2.39‒2.16 (m, 3H), 2.14 (s, 3H), 2.10‒1.98 (m, 1H), 1.74‒
1.58 (m, 1H), 1.54‒1.33 (m, 3H); 13C{1H} NMR (75 MHz, CDCl3): d = 143.2, 138.2, 129.6,
127.0, 60.7, 55.3, 49.5, 46.3, 29.9, 22.2, 21.5; IR (ATR): n = 3058, 2939, 2859, 2787, 2722,
2290, 2101, 1926, 1813, 1661, 1597, 1497, 1470, 1447, 1399, 1372, 1349, 1301, 1261, 1207,
1184, 1148, 1085, 977, 919, 884, 816, 782, 740, 705, 671; EI-MS: m/z = 269 (4) [M + H]+, 113
(30), 96 (5), 91 (29), 89 (5), 84 (45), 71 (6), 70 (100), 68 (6), 65 (19), 57 (15); EA for
C13H20N2O2S: calcd. C 58.18, H 7.51, N 10.44, found C 57.80, H 7.62, N 10.37; optical
rotation: [a]D = -15.1 (c = 1.23 in CHCl3). The dihydrochloride of 27a, which had been
prepared from glutamic acid,8 delivered the title product with an identical specific rotation of
[a]D = -15.1 (c = 3.00 in CHCl3).

(S)-1-Tosyl-3-(tosylamido)-azepane (32a):
 S38

The dihydrochloride of 14 (606 mg, 3.24 mmol) was suspended in dichloromethane (10 mL),
and triethylamine (1.8 mL, 13 mmol, 4.0 equiv) was added. Then, the cooled mixture (ice bath)
was treated with tosyl chloride (1.235 g, 6.478 mmol, 2.0 equiv) and stirred at rt overnight.
Dichloromethane (30 mL) and a hydrochloric acid solution (16.2 mL, c = 2.0 mol/L, 10.0 equiv)
were added, the phases separated, and the crude product was extracted from the aqueous layer
with dichloromethane (three times with a total of 30 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product
was purified by FCC (dichloromethane/diethyl ether = 1:4) and isolated as a colorless solid.
Yield: 79% (1.082 g, 2.561 mmol); mp: 154 °C; 1H NMR (400 MHz, CDCl3): d = 7.82 (d, J =
8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.45
(d, J = 8.2 Hz, 1H), 3.60‒3.44 (m, 2H), 3.10‒2.93 (m, 2H), 2.83 (ddd, J = 13.2, 8.3, 5.3 Hz,
13
1H), 2.44 (s, 3H), 2.40 (s, 3H), 1.89‒1.57 (m, 5H), 1.44‒1.29 (m, 1H); C{1H} NMR (101
MHz, CDCl3): d = 143.6, 143.3, 138.1, 135.7, 129.82, 129.76, 127.4, 126.9, 52.9, 52.7, 50.5,
35.0, 29.6, 21.67, 21.64, 21.58; IR (ATR): n = 3276, 3058, 2928, 2870, 2294, 2182, 2071, 1982,
1927, 1814, 1660, 1594, 1493, 1444, 1402, 1324, 1214, 1150, 1071, 1011, 965, 926, 866, 814,
753, 706, 664; EI-MS: m/z = 269 (5), 268 (15), 267 (100), 155 (11), 91 (35), 84 (6); ESI-MS:
m/z = 867 (62) [2M + Na]+, 851 (6), 653 (16), 627 (10), 461 (17), 445 (100) [M + Na]+, 423
(58) [M + H]+, 252 (36); ESI-HRMS for C40H52N4NaO8S4 as [2M + Na]+: calcd. m/z =
867.25602, found m/z = 867.25537 with D = 0.75 ppm; EA for C20H26N2O4S2: calcd. C 56.85,
H 6.20, N 6.63, found C 56.74, H 6.29, N 6.60; HPLC: >99% ee (products of method A and
B), tr = 15.5 min (major) [S], 19.2 min (minor) [R] (Chiralpak IA, n-heptane/2-propanol =
50:50, 0.6 mL/min, l = 254 nm, 20 °C); optical rotation: [a]D = +9.9 (c = 1.12 in CHCl3). The
racemic product and the (R)-enantiomer ent-32a were prepared analogously.

(S)-1-(Cyanomethyl)-3-(tritylamino)piperidine (33):

The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g,

29.60 mmol) according to GP-2 was dissolved in methanol (technical grade, 75 mL) and treated
with formalin (assay: 37% w/w aqueous solution, 2.70 mL, 36.3 mmol, 1.2 equiv). Upon
addition of formalin, a precipitate had formed, which dissolved within a few minutes. The clear
 S39

yellow solution was stirred at rt for 1 h to complete the imine formation. Then, potassium
cyanide (2.89 g, 44.4 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at rt
overnight. Afterwards, the mixture was concentrated under reduced pressure, and
dichloromethane (200 mL) and a saturated, aqueous solution of sodium carbonate (50 mL) were
added. The phases were separated, and the crude product was extracted from the aqueous layer
with dichloromethane (three times with a total of 240 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product
was purified by FCC (diethyl ether/n-pentane/triethylamine = [Link]) and isolated as a
colorless solid. Yield: 78% (8.81 g, 23.1 mmol); mp: 49.5‒50.5 °C; 1H NMR (600 MHz,
CDCl3): d = 7.60‒7.59 (m, 6H), 7.30‒7.27 (m, 6H), 7.22‒7.19 (m, 3H), 3.22 (d, J = 17.0 Hz,
1H), 3.11 (d, J = 17.0 Hz, 1H), 2.72 (s, 1H), 2.38‒2.36 (m, 2H), 1.97 (br s, 1H), 1.91 (d, J =
10.5 Hz, 1H), 1.81 (br s, 1H), 1.50‒1.35 (m, 2H), 1.30‒1.24 (m, 2H); 13C{1H} NMR (151 MHz,
CDCl3): d = 147.2, 128.7, 128.0, 126.4, 114.7, 71.3, 58.1, 52.2, 48.6, 46.5, 32.1, 22.9; IR
(ATR): n = 3317, 3057, 2937, 2803, 2322, 2107, 1896, 1819, 1745, 1594, 1488, 1448, 1314,
1262, 1206, 1159, 1108, 1058, 1029, 975, 900, 851, 770, 743, 702; EI-MS: m/z = 244 (22), 243
(100) [C19H15+ = Mtrityl+], 241 (4), 228 (5), 166 (4), 165 (29), 138 (10), 109 (5), 70 (9); ESI-
HRMS for C26H27N3Na as [M + Na]+: calcd. m/z = 404.20972, found m/z = 404.21008 with D
= 0.89 ppm; optical rotation: [a]D = +15.9 (c = 1.48 in CHCl3).

(S)-1-(Cyanomethyl)-3-(tritylamino)azepane (34):

The title compound was obtained as a side product during the synthesis of (S)-1-methyl-3-
(tritylamino)azepane (26a). After the solvent of the first fractions of the performed FCC (see
experimental section of compound 26a) was removed under reduced pressure, a viscous oil was
isolated, which had been identified as the depicted title compound. Yield: 6% (0.700 g, 1.769
mmol); 1H NMR (600 MHz, CDCl3): d = 7.53‒7.46 (m, 6H), 7.22‒7.16 (m, 6H), 7.13‒7.09 (m,
3H), 3.06 (d, J = 17.0 Hz, 1H), 2.87 (d, J = 16.9 Hz, 1H), 2.75‒2.68 (m, 1H), 2.52 (dt, J = 12.3,
6.4 Hz, 1H), 2.43 (ddd, J = 12.0, 7.3, 5.3 Hz, 1H), 2.10 (br s, 1H), 1.96 (dd, J = 13.3, 2.2 Hz,
1H), 1.73‒1.66 (m, 2H), 1.65‒1.60 (m, 1H), 1.56‒1.45 (m, 2H), 1.43‒1.34 (m, 1H), 1.28 (dd, J
= 13.4, 6.0 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 147.3, 128.8, 128.0, 126.4, 115.8,
 S40

71.5, 58.0, 55.1, 51.1, 48.0, 37.6, 28.4, 22.3; IR (ATR): n = 3300, 3057, 3027, 2929, 2852,
2164, 1820, 1595, 1487, 1448, 1322, 1267, 1207, 1149, 1080, 1029, 984, 947, 899, 858, 770,
744, 702; EI-MS: m/z = 396 (1) [M + H]+, 244 (21), 243 (100) [C19H15+ = Mtrityl+], 241 (10),
239 (8), 228 (9), 215 (6), 166 (9), 165 (58), 152 (16), 123 (11), 84 (6), 56 (5); ESI-HRMS for
C26H27N3Na as [M + Na]+: calcd. m/z = 418.22537, found m/z = 418.22499 with D = 0.91 ppm;
optical rotation: [a]D = +22.2 (c = 1.60 in CHCl3).

(R)-3-(4'-Chlorobenzo[b]thiophene-2'-carboxamido)-1-methylpiperidine (35a):

According to GP-5, 4-chlorobenzo[b]thiophene-2-carboxylic acid1 (2.380 g, 11.19 mmol, 1.0

equiv) was converted into its corresponding acid chloride, dissolved in dichloromethane (20
mL), and slowly added to a cooled mixture (ice bath) of (R)-3-amino-1-methylpiperidine
dihydrochloride (ent-27a) (2.084 g, 11.19 mmol) and triethylamine (6.2 mL, 45 mmol, 4.0
equiv) in dichloromethane (40 mL). Then, the ice bath was removed and the reaction mixture
stirred overnight at rt. Afterwards, dichloromethane (30 mL) and a saturated, aqueous solution
of sodium carbonate (50 mL) were added, the phases separated, and the crude product was
extracted from the aqueous layer with dichloromethane (three times with a total of 120 mL).
The combined organic phases were dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The product was purified by FCC (diethyl
ether/methanol/triethylamine = [Link]) and isolated as an ivory solid. Yield: 88% (3.033 g,
9.821 mmol); mp: 151 °C; 1H NMR (400 MHz, CDCl3): d = 7.80 (s, 1H), 7.63 (d, J = 7.9 Hz,
1H), 7.33‒7.17 (m, 2H), 6.90 (br s, 1H), 4.21 (br s, 1H), 2.55‒2.33 (m, 3H), 2.19 (s, 3H), 2.10
(br s, 1H), 1.77‒1.62 (m, 2H), 1.59‒1.48 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): d = 160.9,
141.9, 140.5, 137.5, 129.7, 126.7, 124.7, 122.2, 121.2, 60.0, 55.8, 46.6, 45.9, 28.4, 21.9; IR
(ATR): n = 3289, 3075, 2937, 2844, 2781, 2325, 2199, 2083, 1912, 1835, 1756, 1625, 1535,
1447, 1413, 1375, 1314, 1286, 1254, 1195, 1164, 1140, 1099, 1065, 1014, 957, 887, 852, 818,
764, 715, 682; EI-MS: m/z = 311 (23), 310 (11), 309 (52) [M + H]+, 195 (11), 167 (7), 123 (6),
98 (27), 97 (100), 96 (20), 85 (29), 83 (44), 83 (11); EA for C15H17ClN2OS: calcd. C 58.34, H
5.55, N 9.07, found C 58.12, H 5.54, N 9.06; optical rotation: [a]D = -19.1 (c = 1.31 in CHCl3).
Preparation of the hydrochloric salt 35b of the title compound: amine 35a (2.951 g, 9.556
mmol) was treated with a cooled solution (ice bath) of hydrogen chloride in anhydrous methanol
 S41

(21.0 mL, c = 0.5 mol/L, 10.5 mmol, 1.1 equiv). The solution was concentrated under reduced
pressure and the residue dried in high vacuum. Next, ethyl acetate (15 mL) and ethanol (2 mL)
were added to the pale yellow solid, and the mixture was heated to 50 °C (oil bath). Then, the
solid was intensively ground with a test tube-like glass rod. The organic layer had been taken
off with a Pasteur pipette, and grinding was repeated four times with diethyl ether (a total of
120 mL). Remaining diethyl ether was removed by rotary evaporation and the colorless solid
dried in high vacuum. According to NMR analysis, the product contained 6% of ethanol. Yield:
93% (3.106 g, 8.919 mmol); mp: 273 °C (decompn.); 1H NMR (600 MHz, D2O): d = 7.47 (s,
1H), 7.20 (dd, J = 5.4, 3.5 Hz, 1H), 6.85‒6.80 (m, 2H), 4.14 (br s, 1H), 3.55 (br s, 2H), 3.01‒
2.89 (m, 5H), 2.10 (br d, J = 14.9 Hz, 1H), 2.02 (br d, J = 11.8 Hz, 1H), 1.93‒1.81 (m, 1H),
1.73‒1.60 (m, 1H); 13
C{1H} NMR (151 MHz, D2O): d = 163.3, 142.0, 138.1, 137.1, 129.6,
127.5, 124.9, 124.2, 121.4, 56.6, 54.6, 45.6, 44.2, 27.6, 22.4; IR (ATR): n = 3874, 3179, 3057,
2945, 2624, 2508, 2107, 1978, 1794, 1630, 1540, 1468, 1447, 1383, 1317, 1288, 1255, 1202,
1144, 1098, 1052, 1024, 991, 958, 934, 868, 817, 784, 687, 658; ESI-MS: m/z = 357 (9), 320
(35), 309 (100) [Mamine + H, 35Cl]+, 278 (4), 194 (4); ESI-HRMS for C15H18ClN2OS as [Mamine
+ H, 35
Cl]+: calcd. m/z = 309.08229, found m/z = 309.08255 with D = 0.84 ppm; EA for
C15H18Cl2N2OS: calcd. C 52.18, H 5.25, N 8.11, found C 51.92, H 5.14, N 7.96 (taking into
account 6% of ethanol, the following molecular formula results: C15.13H18.38Cl2N2O1.06S: calcd.
C 52.18, H 5.32, N 8.05); optical rotation: [a]D = -17.3 (c = 1.16 in MeOH).

(R)-1-Benzyl-3-(7'-bromobenzo[b]thiophene-2'-carboxamido)piperidine (36):

According to GP-5, 7-bromobenzo[b]thiophene-2-carboxylic acid1 (3.795 g, 14.76 mmol, 1.0

equiv) was converted into its corresponding acid chloride, dissolved in dichloromethane (40
mL), and slowly added to a cooled mixture (ice bath) of (R)-3-amino-1-benzylpiperidine
dihydrochloride (ent-27c) (3.885 g, 14.76 mmol) and triethylamine (8.2 mL, 59 mmol, 4.0
equiv) in dichloromethane (60 mL). The ice bath was removed and the reaction mixture stirred
at rt overnight. Next, dichloromethane (40 mL) and a saturated, aqueous solution of sodium
carbonate (80 mL) were added, the phases separated, and the crude product was extracted from
 S42

the aqueous layer with dichloromethane (three times with a total of 150 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/triethylamine = 50:1) and isolated as
a colorless solid. Yield: 85% (5.406 g, 12.59 mmol); mp: 129 °C; 1H NMR (600 MHz, CDCl3):
d = 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.40‒7.32 (m, 4H), 7.31‒
7.24 (m, 2H), 6.94 (br s, 1H), 4.25 (br s, 1H), 3.60 (d, J = 13.1 Hz, 1H), 3.45 (d, J = 13.1 Hz,
1H), 2.73 (br s, 1H), 2.60 (br s, 1H), 2.44 (br s, 1H), 2.25 (br s, 1H), 1.85 (br s, 1H), 1.81‒1.73
(m, 1H), 1.65‒1.55 (m, 2H); 13C{1H} NMR (151 MHz, CDCl3): d = 160.7, 142.4, 139.9, 139.6,
138.3, 128.9, 128.4, 127.3, 126.2, 125.9, 124.0, 115.9, 62.9, 57.5, 54.0, 45.8, 28.7, 21.8; IR
(ATR): n = 3788, 3281, 3031, 2937, 2859, 2769, 2327, 2248, 2193, 2080, 2051, 1986, 1917,
1629, 1537, 1448, 1392, 1309, 1248, 1187, 1097, 1030, 959, 911, 855, 773, 734, 690; EI-MS:
m/z = 241 (6), 238 (6), 174 (15), 173 (100), 172 (10), 132 (5), 91 (18); ESI-HRMS for
C21H22BrN2OS as [M + H, 79Br]+: calcd. m/z = 429.06307, found m/z = 429.06305 with D =
0.05 ppm; EA for C21H21BrN2OS: calcd. C 58.74, H 4.93, N 6.52, found C 58.61, H 4.77, N
6.43; optical rotation: [a]D = -97.7 (c = 1.34 in CHCl3).

(R)-3-(7'-Bromobenzo[b]thiophene-2'-carboxamido)-1-(2'',2'',2''-trichloroethoxy-
carbonyl)piperidine (37a):

A suspension of (R)-1-benzyl-3-(7'-bromobenzo[b]thiophene-2'-carboxamido)piperidine (36)

(5.226 g, 12.17 mmol) in acetonitrile (40 mL) was treated with 2,2,2-trichloroethyl
chloroformate (assay: 96%, 1.75 mL, 12.2 mmol, 1.0 equiv). After stirring the reaction mixture
for 10 min, a clear solution was obtained. Stirring was continued for additional 3 h at rt, then
the solvent was removed by rotary evaporation and the residue subjected to FCC (diethyl ether),
delivering the title compound as a colorless solid. Yield: 97% (6.076 g, 11.81 mmol); mp: 79
°C. At rt two sets of signals were observed in NMR, indicating the presence of two product
rotamers in a ratio of 1:1 in CDCl3 solution: 1H NMR (600 MHz, CDCl3): d = 7.85 (br s, 1H),
7.79 (br s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 7.7 Hz, 2H), 7.27 (s, 2H), 6.51 (br s, 1H),
6.33 (br s, 1H), 4.95 (d, J = 12.1 Hz, 1H), 4.89 (d, J = 11.9 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H),
4.64 (d, J = 11.8 Hz, 1H), 4.22 (s, 2H), 3.84 (d, J = 13.2 Hz, 1H), 3.75 (d, J = 13.5 Hz, 1H),
 S43

3.61 (dd, J = 13.3, 6.4 Hz, 3H), 3.54 (br s, 3H), 1.95 (br s, 3H), 1.87‒1.74 (m, 3H), 1.67 (br s,
2H); 13C{1H} NMR (151 MHz, CDCl3): d = 161.6, 161.5, 154.5, 153.7, 142.6, 139.8, 139.1,
138.9, 129.2, 126.4, 126.3, 126.1, 124.1, 116.0, 95.8, 95.6, 75.2, 48.9, 48.7, 46.5, 45.7, 45.1,
44.6, 29.6, 29.4, 22.7, 22.3. Measuring the sample at 55 °C delivered spectra with single sets of
signals: 1H NMR (600 MHz, CDCl3, 55 °C): d = 7.79 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.53
(d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 6.28 (br s, 1H), 4.76 (br s, 2H), 4.24‒4.15 (m, 1H), 3.76 (br d,
J = 13.4 Hz, 1H), 3.61 (dd, J = 13.3, 6.3 Hz, 2H), 3.50 (ddd, J = 12.9, 7.7, 3.8 Hz, 1H), 1.96
(ddd, J = 12.9, 8.4, 3.7 Hz, 1H), 1.91‒1.72 (m, 2H), 1.71‒1.60 (m, 1H); 13C{1H} NMR (151
MHz, CDCl3, 55 °C): d = 161.6, 154.2, 142.8, 140.0, 139.2, 129.3, 126.5, 126.3, 124.1, 116.1,
95.9, 75.4, 49.0, 46.3, 45.0, 29.6, 22.6; IR (ATR): n = 3825, 3309, 3067, 3009, 2945, 2862,
2325, 2198, 2096, 2016, 1975, 1924, 1710, 1628, 1535, 1435, 1313, 1229, 1147, 1103, 1057,
949, 915, 855, 827, 776, 754, 711; EI-MS: m/z = 305 (6), 304 (8), 303 (10), 261 (16), 260 (6),
259 (59), 258 (13), 257 (61), 256 (10), 241 (26), 240 (16), 239 (56), 238 (6), 213 (7), 211 (7),
182 (7), 167 (7), 155 (26), 148 (14), 135 (16), 134 (5), 133 (18), 132 (44), 125 (10), 118 (13),
92 (12), 91 (100), 85 (12), 83 (21), 77 (12), 65 (20); CI-MS: m/z = 366 (10), 310 (7), 305 (9),
304 (44), 261 (14), 246 (11), 219 (13), 218 (57), 185 (16), 183 (15), 178 (10), 167 (20), 163
(7), 162 (25), 159 (10), 158 (11), 157 (100), 150 (50), 135 (15), 125 (10), 111 (10), 93 (10), 83
(18), 80 (37), 79 (11); ESI-HRMS for C17H16BrCl3N2NaO3S as [M + Na, {35Cl, 35Cl, 35Cl,
79
Br}]+: calcd. m/z = 534.90228, found m/z = 534.90228 with D = 0.00 ppm; optical rotation:
[a]D = -33.1 (c = 1.24 in CHCl3).

(R)-3-(Benzo[b]thiophene-2'-carboxamido)-1-(2'',2'',2''-trichloroethoxy-
carbonyl)piperidine (37b):

A solution of (R)-1-benzyl-3-(7'-bromobenzo[b]thiophene-2'-carboxamido)piperidine (36)

(2.37 g, 5.52 mmol) in anhydrous methanol (15 mL) was treated with a solution of hydrogen
chloride in anhydrous methanol (c = 0.5 mol/L, 15 mL, 7.5 mmol, 1.4 equiv). Then, ammonium
formate (assay: 97%, 2.87 g, 44.2 mmol, 8.0 equiv) and palladium on charcoal (10% Pd basis,
500 mg, 0.470 mmol, 8.5 Mol-%) were added, and the suspension was refluxed (oil bath) for 8
h. Next, the reaction mixture was filtered, concentrated under reduced pressure, and dried in
 S44

high vacuum. Acetonitrile (15 mL) and 2,2,2-trichloroethyl chloroformate (assay: 96%, 0.79
mL, 5.5 mmol, 1.0 equiv) were added, and the solution was stirred at rt for 3 h. The solvent was
removed by rotary evaporation and the residue subjected to FCC (diethyl ether). The title
compound was isolated from the first fractions as a colorless solid. Yield: 62% (1.491 g, 3.42
mmol); mp: 176 °C. At rt two sets of signals were observed in NMR, indicating the presence
of two product rotamers in a ratio of 1:1 in CDCl3 solution: 1H NMR (600 MHz, CDCl3): d =
7.83 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 7.7 Hz, 2H), 7.77‒7.70 (m, 2H), 7.44‒7.35 (m, 4H), 6.48
(br s, 1H), 6.31 (br s, 1H), 4.94 (d, J = 12.1 Hz, 1H), 4.86 (d, J = 11.8 Hz, 1H), 4.69 (d, J = 11.9
Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.21 (br s, 2H), 3.82 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 13.2
Hz, 1H), 3.67‒3.47 (m, 6H), 1.94 (br s, 3H), 1.82‒1.74 (m, 3H), 1.66 (br s, 2H); 13C{1H} NMR
(151 MHz, CDCl3): d = 162.0, 161.9, 154.5, 153.8, 140.9, 139.1, 138.3, 138.2, 126.5, 125.50,
125.45, 125.2, 125.1, 122.8, 95.8, 95.6, 75.2, 49.0, 48.7, 46.5, 45.6, 45.1, 44.6, 29.6, 29.5, 22.7,
22.3; IR (ATR): n = 3384, 3060, 3007, 2951, 2889, 2655, 2325, 2209, 2163, 2042, 1981, 1945,
1695, 1642, 1532, 1443, 1343, 1313, 1264, 1234, 1205, 1153, 1106, 1059, 973, 944, 877, 855,
825, 794, 756, 717, 676; EI-MS: m/z = 435 (5) M+•, 287 (15), 261 (29), 260 (10), 259 (100),
258 (11), 257 (95), 179 (6), 178 (53), 177 (6), 162 (8), 161 (71), 133 (23), 130 (6), 127 (9), 126
(10), 89 (16), 82 (7); CI-MS: m/z = 437 (10) [M + H, {35Cl, 35Cl, 37Cl}]+, 435 (10) [M + H,
{35Cl, 35Cl, 35Cl}]+, 401 (9), 399 (5), 355 (6), 313 (7), 301 (16), 287 (16), 274 (14), 273 (100),
272 (6), 261 (6), 242 (6), 241 (50), 152 (9), 103 (13), 101 (20), 85 (28), 83 (40); ESI-HRMS
for C17H17Cl3N2NaO3S as [M + Na, {35Cl, 35Cl, 35Cl}]+: calcd. m/z = 456.99177, found m/z =
456.99146 with D = 0.68 ppm; EA for C17H17Cl3N2O3S: calcd. C 46.86, H 3.93, N 6.43, found
C 46.88, H 4.13, N 6.36; optical rotation: [a]D = -40.6 (c = 1.13 in CHCl3).
After the solvent of the second fractions of the performed FCC had been removed under reduced
pressure, the residue was dried in high vacuum. The remaining solid had been identified as
compound 37a. Yield: 25% (710 mg, 1.38 mmol).

(R)-3-(7'-Bromobenzo[b]thiophene-2'-carboxamido)piperidine hydrochloride
monohydrate (38b):

Method A: Water (40 mL), acetic acid (assay: 98%, 3.70 mL, 63.4 mmol, 5.2 equiv), and zinc
dust (3.96 g, 60.6 mmol, 5.0 equiv) were added to a solution of (R)-3-(7'-
 S45

bromobenzo[b]thiophene-2'-carboxamido)-1-(2'',2'',2''-trichloroethoxycarbonyl)piperidine
(37a) (6.250 g, 12.14 mmol) in tetrahydrofuran (40 mL). The flask was equipped with a gas
bubbler and the reaction mixture stirred at rt. After 4 h, acetic acid (0.70 mL, 12 mmol, 1.0
equiv) and zinc dust (793 mg, 12.1 mmol, 1.0 equiv) were added, and stirring was continued
for 3 h. A saturated, aqueous solution of potassium carbonate was slowly added and the aqueous
phase adjusted to pH = 8‒9. Next, dichloromethane (100 mL) was added, the phases were
separated, and the crude product was extracted from the aqueous layer with dichloromethane
(three times with a total of 240 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. Then, the residue was treated with a
cooled solution (ice bath) of hydrogen chloride in anhydrous methanol (26.7 mL, c = 0.5 mol/L,
13.4 mmol, 1.1 equiv). Afterwards, the solution was concentrated under reduced pressure and
the residue dried in high vacuum. The remaining solid was intensively ground with a test tube-
like glass rod inside the flask in the presence of a mixture of diethyl ether (30 mL) and acetone
(technical grade, 3 mL). The supernatant solvent layer had been taken off with a Pasteur pipette,
and the procedure was repeated once with the same amount of solvents, then two times with
only diethyl ether (a total of 40 mL). Remains of diethyl ether were removed by rotary
evaporation and the residue dried in high vacuum, delivering the title product as a colorless
solid. Yield: 83% (3.969 g, 10.08 mmol).
Method B: According to the GP-4, the title compound was obtained from (R)-3-(7'-
bromobenzo[b]thiophene-2'-carboxamido)-1-(tert-butoxycarbonyl)piperidine (39) (1.075 g,
2.447 mmol) using the purification procedure described above. Yield: 91% (0.873 g, 2.22
mmol); mp: 143 °C (decompn.); 1H NMR (600 MHz, CD3OD): d = 8.13 (s, 1H), 7.80 (d, J =
7.9 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.25 (dd, J = 7.9, 7.6 Hz, 1H), 4.28 (tt, J = 10.3, 4.0 Hz,
1H), 3.51 (dd, J = 12.3, 4.1 Hz, 1H), 3.36‒3.29 (m, 1H), 3.07‒2.97 (m, 2H), 2.14‒2.00 (m, 2H),
1.92‒1.75 (m, 2H); 13C{1H} NMR (151 MHz, CD3OD): d = 163.9, 143.7, 141.4, 140.4, 130.3,
127.7, 127.6, 125.6, 116.4, 47.8, 45.7, 44.8, 29.0, 22.2; IR (ATR): n = 3855, 3244, 2943, 2706,
2503, 2395, 2200, 2080, 1996, 1939, 1853, 1770, 1707, 1636, 1542, 1445, 1388, 1297, 1203,
1144, 1095, 1030, 962, 911, 856, 776, 705; EI-MS: m/z = 341 (12) [Mamine + H, 81Br]+, 339
(10) [Mamine + H, 79Br]+, 241 (15), 239 (15), 213 (7), 211 (7), 131 (16), 84 (8), 83 (100), 82 (11),
70 (6), 68 (7); CI-MS: m/z = 343 (6), 342 (16), 341 (100) [Mamine + H, 81Br]+, 340 (12), 339
(97) [Mamine + H, 79Br]+, 289 (8), 287 (7), 262 (12), 261 (67), 259 (11), 127 (14), 87 (10), 84
(22), 83 (28); ESI-HRMS for C14H16BrN2OS as [Mamine + H, 79Br]+: calcd. m/z = 339.01612,
found m/z = 339.01608 with D = 0.12 ppm; EA for C14H18BrClN2O2S: calcd. C 42.71, H 4.61,
 S46

N 7.12, found C 42.77, H 4.58, N 7.07; optical rotation: [a]D = +1.4 (c = 1.29 in MeOH), [a]D
= -38.2 (c = 1.34 in DMF).
At this point, it is unclear to us whether the equimolar amount of water per molecule of product
stems from the aqueous deprotection step or if it originates from the atmospheric moisture and
was incorporated by grinding the hygroscopic compound (see also compound 44b). However,
the x-ray analysis of a crystalline sample revealed the presence of one molecule of water in the
unit cell.
Preparation of the free amine 38a: Title compound 38b (765 mg, 1.94 mmol) was dissolved in
methanol (10 mL) and treated with potassium carbonate (403 mg, 2.92 mmol, 1.5 equiv). After
the effervescence had ceased, dichloromethane (40 mL) and potassium carbonate (5 g) were
added. Then, the suspension was filtered over basic diatomaceous earth by suction and the filter
cake washed with dichloromethane (20 mL). The combined filtrates were concentrated under
reduced pressure, and the residue was dried in high vacuum, delivering the free amine as a pale
yellow solid. Yield: 91% (600 mg, 1.77 mmol); mp: 152 °C; 1H NMR (600 MHz, CDCl3): d
= 7.88 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.31‒7.21 (m, 1H), 6.96 (br
s, 1H), 4.16 (br s, 1H), 3.06 (dd, J = 11.7, 3.0 Hz, 1H), 2.88‒2.74 (m, 3H), 1.83‒1.69 (m, 4H),
1.59‒1.50 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 161.2, 142.6, 139.94, 139.90, 129.0,
126.2, 125.7, 124.0, 115.9, 51.5, 46.7, 46.3, 30.0, 23.5; IR (ATR): n = 3496, 3281, 3051, 2935,
2851, 2798, 2728, 2655, 2317, 2185, 2114, 1986, 1913, 1625, 1536, 1444, 1385, 1307, 1250,
81
1195, 1103, 1059, 956, 913, 850, 774, 683; EI-MS: m/z = 341 (3) [M, Br]+•, 339 (3) [M,
79
Br]+•, 241 (7), 239 (7), 132 (12), 84 (7), 83 (100), 82 (10), 70 (8), 68 (8); EA for
C14H15BrN2OS: calcd. C 49.57, H 4.46, N 8.26, found C 49.32, H 4.50, N 8.08; optical
rotation: [a]D = +4.8 (c = 1.33 in CHCl3), [a]D = -4.3 (c = 1.27 in DMF).

Preparation of the trifluoroacetic acid salt 38c from 39: Trifluoroacetic acid (1.11 mL, 14.4
mmol, 6.0 equiv) was added to a solution of (R)-3-(7'-bromobenzo[b]thiophene-2'-
carboxylamido)-1-(tert-butoxycarbonyl)piperidine (39) (1.057 g, 2.441 mmol) in
dichloromethane (10 mL). The flask was equipped with a gas bubbler and the solution stirred
at rt overnight. Then, the reaction mixture was concentrated under reduced pressure and treated
with ethyl acetate (10 mL). The heterogeneous mixture was stirred at rt for 15 min, and the
solvent was carefully decanted off. The purification procedure was repeated with diethyl ether
(10 mL) and excess of solvent removed under reduced pressure. The product was dried in high
vacuum and obtained as a hygroscopic, pale yellow solid. Yield: 93% (1.019 g, 2.248 mmol);
mp: 72 °C; 1H NMR (400 MHz, CD3OD): d = 8.04 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.53 (d,
 S47

J = 7.7 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 4.21 (tt, J = 10.3, 3.9 Hz, 1H), 3.49 (dd, J = 12.4, 4.2
Hz, 1H), 3.35‒3.26 (m, 1H), 3.00‒2.89 (m, 2H), 2.11‒1.97 (m, 2H), 1.88‒1.66 (m, 2H);
13
C{1H} NMR (101 MHz, CD3OD): d = 164.0, 161.7 (q, 2JC-F = 37.4 Hz), 143.8, 141.5, 140.5,
130.4, 127.6, 125.6, 117.5 (q, 1JC-F = 290.9 Hz), 113.2, 47.8, 45.8, 44.8, 29.0, 22.2; 19F NMR
(376 MHz, CD3OD): d = -77.23 (s); IR (ATR): n = 3315, 3040, 2968, 2834, 2543, 2438, 2159,
1922, 1777, 1670, 1629, 1549, 1451, 1391, 1312, 1260, 1140, 913, 789, 705; EI-MS: m/z = 341
(16) [Mamine + H, 81Br]+, 340 (14), 339 (11) [Mamine + H, 79Br]+, 338 (17), 241 (18), 239 (18),
213 (6), 211 (6), 188 (5), 132 (13), 84 (9), 83 (100), 69 (6), 68 (6), 50 (7); ESI-HRMS for
C14H16BrN2OS as [Mamine + H, 79Br]+: calcd. m/z = 339.01612, found m/z = 339.01611 with D
= 0.03 ppm; optical rotation: [a]D = +0.8 (c = 1.28 in MeOH), [a]D = -25.2 (c = 1.09 in DMF).

(R)-3-(Benzo[b]thiophene-2'-carboxamido)piperidine hydrochloride (38d):

Water (4 mL), acetic acid (assay: 98%, 280 µL, 4.79 mmol, 5.2 equiv), and zinc dust (302 mg,
4.62 mmol, 5.0 equiv) were added to a solution of (R)-3-(benzo[b]thiophene-2'-
carbonylamino)-1-(2'',2'',2''-trichloroethoxycarbonyl)piperidine (37b) (402 mg, 0.923 mmol) in
tetrahydrofuran (4 mL). The flask was equipped with a gas bubbler and the reaction mixture
stirred at rt for 6 h. A saturated, aqueous solution of potassium carbonate was slowly added and
the aqueous phase adjusted to pH = 8‒9. Next, dichloromethane (20 mL) was added, the phases
were separated, and the crude product was extracted from the aqueous layer with
dichloromethane (three times, a total of 30 mL). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated under reduced pressure. Then, the residue was
treated with a cooled solution (ice bath) of hydrogen chloride in anhydrous methanol (2.0 mL,
c = 0.5 mol/L, 1.0 mmol, 1.1 equiv). Afterwards, the solution was concentrated under reduced
pressure and the residue dried in high vacuum. Diethyl ether (5 mL) was added and the solid
intensively ground with a test tube-like glass rod. The diethyl ether layer had been taken off
with a Pasteur pipette, and the procedure was repeated two times. Remaining diethyl ether was
removed by rotary evaporation and the colorless solid product dried in high vacuum. Yield:
75% (206 mg, 0.695 mmol); mp: 218 °C (decompn.); 1H NMR (600 MHz, CD3OD): d = 8.06
(s, 1H), 7.92‒7.88 (m, 2H), 7.48‒7.39 (m, 2H), 4.27 (tt, J = 10.5, 4.0 Hz, 1H), 3.53 (dd, J =
12.3, 4.3 Hz, 1H), 3.35 (dd, J = 12.7, 3.9 Hz, 1H), 3.06‒2.96 (m, 2H), 2.17‒2.05 (m, 2H), 1.95‒
 S48

1.75 (m, 2H); 13C{1H} NMR (151 MHz, CD3OD): d = 164.5, 142.5, 140.7, 139.4, 127.7, 127.1,
126.4, 126.1, 123.6, 47.9, 45.8, 44.9, 29.1, 22.3; IR (ATR): n = 3300, 2947, 2763, 2704, 2534,
2498, 2404, 2249, 2162, 2045, 1984, 1944, 1731, 1632, 1536, 1451, 1344, 1303, 1244, 1203,
1163, 1131, 1099, 1043, 989, 949, 907, 866, 749; ESI-MS: m/z = 262 (14), 261 (100) [Mamine
+ H]+, 244 (11), 231 (5), 218 (3), 181 (3), 161 (21); ESI-HRMS for C14H17N2OS as [Mamine +
H]+: calcd. m/z = 261.10561, found m/z = 261.10535 with D = 1.00 ppm; optical rotation: [a]D
= -6.0 (c = 0.50 in MeOH).

(R)-3-(7'-Bromobenzo[b]thiophene-2'-carboxamido)-1-(tert-butoxycarbonyl)piperidine
(39):

To a solution of (R)-1-(tert-butoxycarbonyl)-3-(tritylamino)piperidine (ent-25e) (5.793 g,

13.09 mmol) in anhydrous tetrahydrofuran (60 mL), palladium on charcoal (10% Pd basis,
1.395 g, 13.11 mmol, 0.1 equiv) was added. The suspension was transferred into an autoclave,
set under 30 bar of hydrogen pressure, and stirred at 85 °C for 16 h. The suspension was allowed
to cool down, before it was filtered and submitted to FCC (using one fourth of the standard
amount of silica) with diethyl ether as eluent. When all of the triphenylmethane was eluted, the
silica gel was dried in a stream of air, transferred to a beaker, and suspended in a mixture of
dichloromethane (200 mL), triethylamine (10 mL) and methanol (10 mL). The mixture was
filtered and the filter cake thoroughly washed with dichloromethane (100 mL). The filtrate was
concentrated under reduced pressure and the residue dried in high vacuum. Ddichloromethane
(40 mL) and triethylamine (5.50 mL, 39.5 mmol, 3.0 equiv) were added and the solution was
cooled (ice bath). According to GP-5, 7-bromobenzo[b]thiophene-2-carboxylic acid1 (3.368 g,
13.10 mmol, 1.0 equiv) was converted into its corresponding acid chloride, dissolved in
dichloromethane (20 mL), and slowly added to the cooled amine solution. Then, the ice bath
was removed and the reaction mixture stirred at rt overnight. Afterwards, dichloromethane (50
mL) and a saturated, aqueous solution of sodium carbonate (60 mL) were added, the phases
separated, and the crude product was extracted from the aqueous layer with dichloromethane
(three times with a total of 150 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The product was purified by FCC
 S49

(diethyl ether) and isolated as a colorless solid. Yield: 44% (2.544 g, 5.790 mmol); mp: 77 °C.
The NMR spectra were recorded at 80 °C since a broadening of the signals had been observed
at rt: 1H NMR [600 MHz, (CD3)2SO, 80 °C]: d = 8.37 (d, J = 7.2 Hz, 1H), 8.24 (s, 1H), 7.96
(dd, J = 8.0, 0.9 Hz, 1H), 7.67 (dd, J = 7.7, 1.0 Hz, 1H), 7.39 (dd, J = 8.4, 7.2 Hz, 1H), 3.93
(dd, J = 12.5, 4.1 Hz, 1H), 3.87‒3.78 (m, 1H), 3.73 (dd, J = 13.1, 4.1 Hz, 1H), 2.99‒2.84 (m,
2H), 2.03‒1.91 (m, 1H), 1.77 (dt, J = 13.3, 4.2 Hz, 1H), 1.66‒1.54 (m, 1H), 1.55‒1.43 (m, 1H),
1.40 (s, 9H); 13
C{1H} NMR [151 MHz, (CD3)2SO, 80 °C]: d = 160.4, 153.7, 141.2, 140.3,
139.7, 128.4, 126.2, 125.5, 124.1, 114.5, 78.3, 47.5, 46.0, 43.2, 29.2, 27.7, 23.0; IR (ATR): n
= 3854, 3522, 3306, 3073, 2972, 2934, 2859, 2324, 2162, 2072, 2031, 2006, 1879, 1630, 1536,
1420, 1364, 1311, 1240, 1147, 1097, 949, 913, 857, 773, 708; EI-MS: m/z = 440 (1) [M, 81Br]+
•
, 438 (1) [M, 79Br]+ •, 367 (11), 365 (9), 339 (7), 337 (6), 258 (8), 256 (7), 241 (32), 239 (31),
213 (9), 211 (8), 184 (9), 183 (88), 132 (13), 128 (7), 127 (100), 93 (39), 57 (31); CI-MS: m/z
= 469 (6) [M + C2H5, 81Br]+, 467 (6) [M + C2H5, 79Br]+, 413 (8), 411 (8), 389 (5), 386 (10), 385
(100), 384 (19), 383 (100), 341 (33), 339 (32), 333 (6), 306 (8), 305 (79), 261 (24), 183 (5);
ESI-HRMS for C19H23BrN2NaO3S as [M + Na, 79Br]+: calcd. m/z = 461.05050, found m/z =
461.04959 with D = 1.97 ppm; optical rotation: [a]D = -28.5 (c = 1.26 in CHCl3).

(S)-3-(tert-Butoxycarbonylamino)-1-isopropylpiperidine (precursor for compound 40):

Di-tert-butyl dicarbonate (assay: 97%, 4.52 g, 20.1 mmol, 1.0 equiv) and triethylamine (8.4
mL, 60 mmol 3.0 equiv) were added to a cooled suspension (ice bath) of (S)-3-amino-1-
isopropylpiperidine dihydrochloride (27b) (4.31 g, 20.0 mmol) in dichloromethane (50 mL).
The flask was equipped with a gas bubbler and the reaction mixture stirred at rt overnight.
Afterwards, dichloromethane (100 mL) and a saturated, aqueous solution of sodium carbonate
(20 mL) were added, the phases separated, and the crude product was extracted from the
aqueous layer with dichloromethane (three times with a total of 150 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The product was purified by FCC (diethyl ether/triethylamine = 50:1) and isolated as a colorless
oil. Yield: 90% (4.36 g, 18.0 mmol); 1H NMR (600 MHz, CDCl3): d = 5.03 (br s, 1H), 3.72 (br
s, 1H), 2.70 (hept, J = 6.6 Hz, 1H), 2.56 (br d, J = 10.7 Hz, 1H), 2.46 (br s, 1H), 2.35 (br s, 2H),
 S50

1.72‒1.63 (m, 1H), 1.61‒1.48 (m, 3H), 1.45 (s, 9H), 0.98 (d, J = 6.6 Hz, 6H); 13C{1H} NMR
(151 MHz, CDCl3): d = 155.2, 78.8, 54.5, 53.6, 49.2, 46.4, 30.1, 28.4, 22.6, 18.1, 17.8; IR
(ATR): n = 3365, 2964, 2928, 2800, 2328, 2192, 2001, 1952, 1681, 1524, 1451, 1387, 1365,
1305, 1238, 1167, 1095, 1050, 995, 952, 889, 868, 769; EI-MS: m/z = 243 (2) [M + H]+, 242
(1) M+•, 171 (15), 153 (26), 125 (38), 110 (44), 98 (12), 84 (12), 82 (12), 70 (22), 59 (57), 57
(100), 56 (33), 55 (15); CI-MS: m/z = 244 (8), 243 (67) [M + H]+, 242 (4), 241 (20), 227 (14),
215 (23), 188 (10), 187 (100), 169 (12), 125 (16); ESI-HRMS for C13H27N2O2 as [M + H]+:
calcd. m/z = 243.20670, found m/z = 243.20709 with D = 1.60 ppm; EA for C13H26N2O2: calcd.
C 64.43, H 10.81, N 11.56, found C 64.44, H 10.41, N 11.44; optical rotation: [a]D = +3.5 (c
= 1.22 in CHCl3).

(S)-3-(Methylamino)-1-isopropylpiperidine dihydrochloride (40):

In a 250 mL round bottom flask flushed with argon, anhydrous tetrahydrofuran (40 mL) was
cooled (ice bath) and lithium aluminum hydride (1.60 g, 42.2 mmol, 3.0 equiv) was carefully
added in small portions. While cooling was continued, a solution of (S)-3-(tert-
butoxycarbonylamino)-1-isopropylpiperidine (precursor for compound 40) (3.41 g, 14.1 mmol)
in anhydrous tetrahydrofuran (30 mL) was then added over a period of 15 min. The flask was
equipped with a gas bubbler, the ice bath was removed, and stirring extended at rt overnight.
Next, the suspension was refluxed for 1 h (oil bath). Afterwards the reaction mixture was cooled
(ice bath), and water (1.4 mL) was added dropwise (caution: formation of hydrogen). Under
continued cooling the mixture was treated with an aqueous solution of sodium hydroxide (1.4
mL, c = 5.0 mol/L), and again water (4.8 mL) over a period of 45 min, until all remaining
lithium aluminum hydride had been destroyed. The resulting white suspension was stirred at rt
for 1 h and dichloromethane (100 mL) followed by magnesium sulfate (50 g) were added. The
mixture was stirred for additional 30 min, filtered over a Büchner funnel, and the filter cake
was thoroughly washed with dichloromethane (100 mL). The combined filtrates were
concentrated under reduced pressure and subsequently treated with a cooled solution (ice bath)
of hydrogen chloride in anhydrous methanol (62 mL, c = 0.5 mol/L, 31 mmol, 2.2 equiv). The
solution was then again concentrated under reduced pressure and the residue dried in high
vacuum. Diethyl ether (40 mL) was added and the remaining solid intensively ground with a
 S51

test tube-like glass rod. The ethereal layer had been taken off with a Pasteur pipette, and the
procedure was repeated four times. Remaining diethyl ether was removed by rotary evaporation
and the colorless solid product dried in high vacuum. Yield: 89% (2.86 g, 12.5 mmol); mp: 226
°C (decompn.); 1H NMR (400 MHz, D2O): d = 3.74 (br d, J = 11.4 Hz, 1H), 3.65 (hept, J = 6.4
Hz, 1H), 3.58 (br d, J = 11.8 Hz, 1H), 3.50 (br d, J = 12.5 Hz, 1H), 3.15‒3.01 (m, 2H), 2.80 (s,
3H), 2.39‒2.28 (m, 1H), 2.19 (dt, J = 15.4, 3.6 Hz, 1H), 1.86 (ddt, J = 16.6, 7.7, 3.9 Hz, 1H),
1.67 (dt, J = 12.5, 4.0 Hz, 1H), 1.37 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (101 MHz, D2O): d =
59.5, 52.9, 48.0, 47.8, 30.4, 24.5, 20.4, 16.0, 15.8; IR (ATR): n = 3730, 3360, 3181, 2977, 2676,
2374, 2065, 1995, 1900, 1601, 1457, 1392, 1339, 1239, 1199, 1115, 1049, 1009, 942, 790; ESI-
MS: m/z = 158 (8), 157 (100) [Mdiamine + H]+, 128 (3), 126 (34); ESI-HRMS for C9H21N2 as
[Mdiamine + H]+: calcd. m/z = 157.16992, found m/z = 157.16988 with D = 0.26 ppm; optical
rotation: [a]D = +5.3 (c = 1.41 in MeOH).

(S)-1-Isopropyl-3-(N-methyl-3'-phenoxyphenylcarboxamido)piperidine hydrochloride
(41):
Me
HCl
N Me

N
Me O
O
According to GP-5, 3-phenoxybenzoic acid (assay: 98%, 1.241 g, 5.677 mmol, 1.2 equiv) was
converted into its corresponding acid chloride, dissolved in dichloromethane (10 mL), and
slowly added to an ice-cold mixture of (S)-3-(methylamino)-1-isopropylpiperidine
dihydrochloride (40) (1.080 g, 4.712 mmol) and triethylamine (2.6 mL, 19 mmol, 4.0 equiv) in
dichloromethane (10 mL). Then, the ice bath was removed and the reaction mixture stirred at rt
overnight. Next, dichloromethane (25 mL) and a saturated, aqueous solution of sodium
carbonate (15 mL) were added, the phases separated, and the crude product was extracted from
the aqueous layer with dichloromethane (three times with a total of 30 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/triethylamine = 50:1) and isolated as
a viscous oil which was subsequently treated with a cooled solution (ice bath) of hydrogen
chloride in anhydrous methanol (10.4 mL, c = 0.5 mol/L, 5.20 mmol, 1.1 equiv). Next, the
solution was concentrated under reduced pressure and the residue dried in high vacuum. The
remaining solid was intensively ground in the presence of hot ethyl acetate (8 mL) with a test
 S52

tube-like glass rod. The liquid phase had been taken off with a Pasteur pipette, and the procedure
was repeated once with hot ethyl acetate (8 mL) and then two times with diethyl ether (a total
of 40 mL). Remaining solvent was removed by rotary evaporation and the colorless solid
product dried in high vacuum. Yield: 88% (1.617 g, 4.158 mmol); mp: 192 °C; 1H NMR (600
MHz, CDCl3): d = 11.84 (br s, 1H), 7.41‒7.31 (m, 3H), 7.15 (t, J = 7.4 Hz, 1H), 7.11‒6.96 (m,
5H), 4.30 (br s, 1H), 3.88 (br s, 1H), 3.47 (dd, J = 9.4, 4.6 Hz, 1H), 3.42‒3.31 (m, 2H), 3.02 (s,
3H), 2.82‒2.72 (m, 1H), 2.43 (br s, 2H), 2.00 (br s, 2H), 1.45 (s, 6H); 13C{1H} NMR (151 MHz,
CDCl3): d = 171.7, 157.6, 156.3, 137.8, 130.1, 129.9, 123.9, 121.3, 120.1, 119.3, 116.8, 58.4,
55.5, 48.7, 47.8, 39.4, 24.4, 21.5, 17.0, 16.7; IR (ATR): n = 3839, 3492, 3385, 2939, 2634,
2458, 2398, 2166, 2052, 1999, 1893, 1720, 1627, 1580, 1485, 1403, 1319, 1242, 1157, 1073,
1020, 932, 895, 812, 752, 693; ESI-MS: m/z = 354 (24), 353 (100) [Mamine + H]+, 242 (2), 197
(3), 142 (2), 127 (5), 126 (53), 102 (5); ESI-HRMS for C22H29N2O2 as [Mamine + H]+: calcd.
m/z = 353.22235, found m/z = 353.22238 with D = 0.09 ppm; EA for C22H29ClN2O2: calcd. C
67.94, H 7.52, N 7.20, found C 67.76, H 7.47, N 7.18; optical rotation: [a]D = +8.8 (c = 1.25
in CH2Cl2).

(S,E)-3-(3'-{Benzo[d][1'',3'']dioxol-5''-yl}-N-methylacrylamido)-1-isopropylpiperidine
hydrochloride (42):
Me
HCl
N Me
O
N O
Me
O
According to GP-5, (E)-3,4-(methylenedioxy)cinnamic acid (assay: 99%, 1.65 g, 8.50 mmol,
1.3 equiv) was converted into its corresponding acid chloride, dissolved in dichloromethane (15
mL), and slowly added to an ice-cold mixture of (S)-3-(methylamino)-1-isopropylpiperidine
dihydrochloride (40) (1.50 g, 6.54 mmol) and triethylamine (3.7 mL, 26 mmol, 4.0 equiv) in
dichloromethane (15 mL). Then the ice bath was removed and the reaction mixture stirred at rt
overnight. Afterwards, dichloromethane (25 mL) and a saturated, aqueous solution of sodium
carbonate (15 mL) were added, the phases separated, and the crude product was extracted from
the aqueous layer with dichloromethane (three times with a total of 30 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/methanol/triethylamine = [Link]) and
isolated as a viscous oil, which was subsequently treated with a cooled solution (ice bath) of
 S53

hydrogen chloride in anhydrous methanol (14.4 mL, c = 0.5 mol/L, 7.20 mmol, 1.1 equiv).
Next, the solution was concentrated under reduced pressure and the residue dried in high
vacuum. Diethyl ether (15 mL) was added and the solid intensively ground with a test tube-like
glass rod. The diethyl ether layer had been taken off with a Pasteur pipette, and the procedure
was repeated three times. Remaining diethyl ether was removed by rotary evaporation and the
colorless solid product dried in high vacuum. Yield: 84% (2.019 g, 5.503 mmol); mp: 243 °C
(decompn.). At rt two sets of signals were observed in NMR, indicating the presence of two
product rotamers in a ratio of A:B = 2.5:1 in D2O solution: 1H NMR (600 MHz, D2O): d = 7.22
(d, J = 15.3 Hz, 1H of A, 1H of B), 7.02 (s, 1H of B), 6.93‒6.88 (m, 2H of A, 1H of B), 6.71
(d, J = 7.9 Hz, 1H of A, 1H of B), 6.67 (d, J = 15.3 Hz, 1H of B), 6.52 (d, J = 15.4 Hz, 1H of
A), 5.88 (s, 2H of A, 2H of B), 4.66 (tt, J = 11.9, 4.5 Hz, 1H of A), 4.39 (tt, J = 10.8, 4.3 Hz,
1H of B), 3.56‒3.46 (m, 1H of A, 1H of B), 3.43 (d, J = 12.4 Hz, 1H of A, 1H of B), 3.25‒3.12
(m, 1H of A, 2H of B), 3.05 (t, J = 11.8 Hz, 1H of A), 2.95 (s, 3H of A, 3H of B), 2.84 (s, 1H
of A, 1H of B), 2.14‒2.08 (m, 1H of A, 1H of B), 1.93‒1.75 (m, 3H of A, 3H of B), 1.32 (d, J
= 6.7 Hz, 6H of A, 6H of B); 13C{1H} NMR (151 MHz, D2O): d = 168.9 (B), 168.6 (A), 148.9
(A), 148.8 (B), 147.61 (A), 147.58 (B), 143.5 (B), 143.3 (A), 128.8 (A+B), 124.7 (A+B), 114.5
(A), 113.9 (B), 108.3 (A+B), 106.4 (B), 106.3 (A), 101.6 (A+B), 59.0 (A+B), 51.8 (B), 49.6
(B), 49.2 (A), 48.5 (A), 48.2 (A), 47.4 (B), 30.3 (A), 28.0 (B), 25.9 (B), 24.8 (A), 21.5 (A+B),
16.2 (B), 16.1 (A), 15.9 (A), 15.7 (B). The measurements, which had been recorded at 90 °C,
resulted in NMR spectra with only a single set of signals: 1H NMR (400 MHz, D2O, 90 °C): d
= 7.99 (d, J = 15.4 Hz, 1H), 7.72‒7.65 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 15.5 Hz,
1H), 6.59 (s, 2H), 5.23 (br s, 1H), 4.18 (hept, J = 6.8 Hz, 1H), 4.10 (d, J = 12.1 Hz, 1H), 3.99‒
3.92 (m, 1H), 3.70 (t, J = 11.9 Hz, 1H), 3.66‒3.48 (m, 4H), 2.85‒2.71 (m, 1H), 2.56‒2.46 (m,
3H), 1.98 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (101 MHz, D2O, 90 °C): d = 169.7, 149.5, 148.4,
143.6, 129.9, 124.8, 116.4, 109.3, 107.4, 102.3, 60.0, 49.9, 49.1, 25.8, 22.2, 16.8; IR (ATR): n
= 3022, 2951, 2889, 2791, 2633, 2496, 2409, 2238, 2191, 2078, 2023, 1970, 1866, 1791, 1647,
1597, 1485, 1440, 1352, 1330, 1292, 1247, 1157, 1095, 1038, 983, 930, 856, 810, 702; ESI-
MS: m/z = 363 (1), 332 (20), 331 (100) [Mamine + H]+, 175 (7); ESI-HRMS for C19H27N2O3 as
[Mamine + H]+: calcd. m/z = 331.20162, found m/z = 331.20175 with D = 0.39 ppm; EA for
C19H27ClN2O3: calcd. C 62.20, H 7.42, N 7.64, found C 61.98, H 7.42, N 7.49; optical rotation:
[a]D = -42.1 (c = 1.41 in MeOH).
 S54

(R)-3-(Tritylamino)-(1,4'-bipiperidine)-1'-carboxylic acid ethyl ester (precursor for

compound 43):

The product resulting from the filtrates of the lithium aluminum hydride reduction of (R)-3-
(tritylamino)piperidin-2-one (ent-21b) (10.55 g, 29.60 mmol) was dissolved in
dichloromethane (150 mL) and treated with 4-oxo-piperidine-1-carboxylic acid ethyl ester
(assay: 98%, 5.0 mL, 33 mmol, 1.1 equiv). Then, sodium triacetoxyborohydride (assay: 97%,
12.93 g, 59.18 mmol, 2.0 equiv) was added, the reaction mixture stirred at rt for 2 d. Afterwards
the mixture was treated with an additional amount of 4-oxo-piperidine-1-carboxylic acid ethyl
ester (2.3 mL, 15 mmol, 0.5 equiv) and sodium triacetoxyborohydride (3.880 g, 17.76 mmol,
0.6 equiv). After stirring the reaction mixture at rt for another day, dichloromethane (50 mL)
and a saturated, aqueous solution of sodium carbonate (80 mL) were added. The phases were
separated, and the crude product was extracted from the aqueous layer with dichloromethane
(three times with a total of 240 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The product was purified by FCC
(diethyl ether/triethylamine = 50:1) and isolated as a colorless, viscous oil that slowly solidified
at rt. Yield: 93% (13.69 g, 27.51 mmol); mp: 47 °C; 1H NMR (600 MHz, CDCl3): d = 7.59‒
7.54 (m, 6H), 7.28‒7.22 (m, 6H), 7.19‒7.13 (m, 3H), 4.11 (q, J = 7.1 Hz, 2H), 4.06‒3.95 (m,
1H), 2.62 (br s, 3H), 2.41 (br s, 1H), 2.22 (br s, 1H), 2.10 (br t, J = 11.0 Hz, 1H), 2.03‒1.95 (m,
2H), 1.85 (br s, 1H), 1.68 (br s, 1H), 1.55‒1.43 (m, 2H), 1.39‒1.31 (m, 2H), 1.30‒1.27 (m, 1H),
13
1.25 (t, J = 7.1 Hz, 3H), 1.11 (ddt, J = 16.3, 12.2, 7.0 Hz, 2H); C{1H} NMR (151 MHz,
CDCl3): d = 155.5, 147.3, 128.7, 127.8, 126.2, 71.2, 62.0, 61.2, 55.8, 49.9, 49.2, 43.5, 33.7,
27.9, 24.1, 14.8; IR (ATR): n = 3303, 3057, 2934, 2854, 2792, 2315, 2164, 2018, 1979, 1820,
1693, 1595, 1438, 1381, 1328, 1272, 1237, 1159, 1101, 1028, 971, 935, 900, 748, 702; EI-MS:
m/z = 356 (5), 254 (5), 244 (22), 243 (94) [C19H15+ = Mtrityl+], 242 (5), 182 (11), 166 (6), 165
(40), 125 (7), 114 (5), 113 (61), 87 (10), 85 (60), 84 (13), 82 (100), 71 (9), 70 (29); CI-MS: m/z
= 358 (19), 357 (5), 280 (10), 272 (10), 245 (21), 243 (100) [C19H15+ = Mtrityl+], 242 (5), 182
(5), 166 (5), 165 (32), 113 (36), 104 (9), 96 (6), 85 (6), 84 (15), 83 (8), 78 (7), 77 (17), 71 (11),
 S55

70 (42), 68 (5); ESI-HRMS for C32H40N3O2 as [M + H]+: calcd. m/z = 498.31150, found m/z =
498.31140 with D = 0.20 ppm; optical rotation: [a]D = +7.8 (c = 1.57 in CHCl3).

(R)-3-Amino-(1,4'-bipiperidine)-1'-carboxylic acid ethyl ester dihydrochloride (43):

According to GP-4, the title compound was obtained from (R)-3-(tritylamino)-[1,4'-

bipiperidine]-1'-carboxylic acid ethyl ester (precursor for compound 43) (13.69 g, 27.51 mmol)
as a hygroscopic, colorless solid. Yield: 96% (8.669 g, 26.41 mmol); mp: 138 °C (decompn.);
1
H NMR (400 MHz, D2O): d = 4.30 (br s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 11.1 Hz,
1H), 3.76‒3.55 (m, 4H), 3.22‒3.06 (m, 2H), 3.03‒2.88 (m, 3H), 2.29 (d, J = 11.8 Hz, 1H), 2.25‒
2.13 (m, 3H), 1.99‒1.84 (m, 1H), 1.82‒1.67 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, D2O): d = 156.7, 64.4, 62.7, 49.6, 48.8, 45.6, 42.1, 26.0, 25.8, 20.6, 13.8; IR (ATR):
n = 3848, 3417, 2934, 2679, 2526, 2330, 2207, 2072, 1944, 1685, 1437, 1239, 1177, 1130,
1091, 1026, 939, 869, 765, 697; ESI-MS: m/z = 257 (7), 256 (54) [Mamine + H]+, 240 (15), 239
(100), 156 (19), 128 (13), 124 (4), 112 (5); ESI-HRMS for C13H26N3O2 as [Mamine + H]+: calcd.
m/z = 256.20195, found m/z = 256.20172 with D = 0.90 ppm; optical rotation: [a]D = +2.4 (c
= 1.37 in CHCl3), [a]D = -4.4 (c = 1.28 in MeOH).

(R)-3-(2-Methylbenzamido)-(1,4'-bipiperidine)-1'-carboxylic acid ethyl ester (44a):

o-Toluoyl chloride (assay: 98%, 4.50 mL, 33.9 mmol, 1.3 equiv) was slowly added to an ice-
cold mixture of (R)-3-amino-[1,4'-bipiperidine]-1'-carboxylic acid ethyl ester dihydrochloride
(43) (8.570 g, 26.11 mmol) and triethylamine (14.6 mL, 104 mmol, 4.0 equiv) in
dichloromethane (100 mL). Then, the ice bath was removed and the reaction mixture stirred at
rt overnight. Next, dichloromethane (100 mL) and a saturated, aqueous solution of sodium
 S56

carbonate (100 mL) were added, the phases separated, and the crude product was extracted from
the aqueous layer with dichloromethane (three times with a total of 240 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/methanol/triethylamine = [Link] to
[Link]) and isolated as a viscous oil. Yield: 92% (9.003 g, 24.10 mmol); 1H NMR (600 MHz,
CDCl3): d = 7.36 (d, J = 8.0 Hz, 1H), 7.33‒7.26 (m, 1H), 7.24‒7.17 (m, 2H), 6.46 (br s, 1H),
4.31‒4.14 (m, 3H), 4.11 (q, J = 7.1 Hz, 2H), 2.76‒2.57 (m, 5H), 2.45 (s, 3H), 2.44‒2.34 (m,
2H), 1.82‒1.65 (m, 4H), 1.61 (ddt, J = 11.0, 9.7, 4.9 Hz, 2H), 1.41 (dddd, J = 16.7, 11.9, 9.4,
4.3 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13
C{1H} NMR (151 MHz, CDCl3): d = 169.0, 155.4,
136.9, 135.8, 130.9, 129.7, 126.8, 125.7, 62.2, 61.3, 54.1, 49.9, 45.3, 43.5, 29.4, 27.8, 22.4,
19.8, 14.7; IR (ATR): n = 3296, 2936, 2858, 2802, 2159, 2017, 1975, 1810, 1688, 1642, 1530,
1476, 1435, 1381, 1351, 1322, 1271, 1239, 1166, 1105, 1028, 970, 939, 869, 748, 661; EI-MS:
m/z = 374 (8) [M + H]+, 239 (28), 238 (100), 209 (5), 165 (6), 156 (23), 122 (8), 119 (14), 91
(8); EI-HRMS for C21H31N3O3 as M+•: calcd. m/z = 373.23599, found m/z = 373.23633 with D
= 0.91 ppm; optical rotation: [a]D = -16.4 (c = 1.16 in CHCl3).

Preparation of the hydrochloride monohydrate 44b: Title compound 44a (9.003 g, 24.10 mmol)
was treated with an ice-cold solution of hydrogen chloride in anhydrous methanol (53.0 mL, c
= 0.5 mol/L, 26.5 mmol, 1.1 equiv). The solution was concentrated under reduced pressure and
the residue dried in high vacuum. The remaining solid was intensively ground in the presence
of diethyl ether (technical grade, 50 mL) inside the flask with a test tube-like glass rod. The
ether layer had been taken off with a Pasteur pipette, and the procedure was repeated three
times. Remaining diethyl ether was removed by rotary evaporation and the colorless solid
product dried in high vacuum. Yield: 89% (9.202 g, 21.50 mmol); mp: 186.5 °C; 1H NMR
(600 MHz, D2O): d = 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.32‒7.25 (m,
2H), 4.32‒4.18 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 3.62 (br d, J = 9.9 Hz, 1H), 3.54‒3.44 (m,
2H), 3.08‒2.95 (m, 2H), 2.89‒2.83 (m, 2H), 2.32 (s, 3H), 2.10 (br d, J = 11.0 Hz, 4H), 1.88 (br
dd, J = 12.0, 4.5 Hz, 1H), 1.64 (br dd, J = 12.3, 4.4 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (151 MHz, D2O): d = 172.8, 156.6, 135.3, 134.7, 130.7, 130.5, 126.7, 125.8, 63.6, 62.6,
51.1, 49.0, 44.8, 42.1, 27.2, 25.8, 21.0, 18.5, 13.7; IR (ATR): n = 3747, 3421, 3228, 2953, 2867,
2613, 2480, 2173, 2038, 1976, 1706, 1656, 1529, 1434, 1320, 1283, 1240, 1158, 1106, 1032,
939, 869, 746, 687; ESI-MS: m/z = 396 (3) [Mamine + Na]+, 375 (24), 374 (100) [Mamine + H]+,
328 (1), 240 (3), 239 (24), 211 (2), 202 (5), 156 (6); ESI-HRMS for C21H32N3O3 as [Mamine +
H]+: calcd. m/z = 374.24382, found m/z = 374.24387 with D = 0.13 ppm; EA for
 S57

C21H34ClN3O4S: calcd. C 58.94, H 8.01, N 9.82, found C 58.98, H 7.89, N 9.73; optical
rotation: [a]D = -22.9 (c = 1.11 in CHCl3), [a]D = +4.4 (c = 1.12 in MeOH).
At this point, it is unclear to us whether the equimolar amount of water per molecule of product
stems from the diethyl ether that was used in technical grade, or if it originates from the
atmospheric moisture and was incorporated by grinding the hygroscopic compound. However,
comparison of the solvent residual peak in the 1H spectrum of the product with that of an
equimolar triethylamine-sample in the same volume of D2O indicated the presence of one
molecule of water in the product. In addition, the consistent results of elemental analyses of
three different samples confirmed the presence of the monohydrate (EA2 found C 59.09, H
7.82, N 9.73; EA3 found C 58.75, H 7.82, N 9.64).

(S)-1-(Thiophene-2-carbonyl)-3-(tritylamino)piperidine (precursor for compound 45):

The product resulting from the reduction of (S)-3-(tritylamino)piperidin-2-one (21b) (10.55 g,

29.60 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (12.4 mL, 89.0
mmol, 3.0 equiv) was added. The mixture was cooled (ice bath), slowly treated with thiophene-
2-carbonyl chloride (assay: 98%, 3.22 mL, 29.6 mmol, 1.0 equiv), and stirred at rt overnight.
Then, dichloromethane (50 mL) and a saturated, aqueous solution of sodium carbonate (50 mL)
were added, the phases separated, and the crude product was extracted from the aqueous layer
with dichloromethane (three times with a total of 240 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product
was purified by FCC (diethyl ether/n-pentane = 3:1) and isolated as a colorless solid. Yield:
88% (11.76 g, 25.98 mmol); mp: 67.5 °C; 1H NMR (600 MHz, CDCl3): d = 7.53‒7.43 (m, 6H),
7.40 (d, J = 5.0 Hz, 1H), 7.25‒7.18 (m, 6H), 7.17‒7.12 (m, 3H), 7.08 (br s, 1H), 6.98 (dd, J =
5.0, 3.6 Hz, 1H), 4.06 (dd, J = 13.1, 3.9 Hz, 1H), 4.00 (br s, 1H), 3.03‒2.88 (m, 2H), 2.53 (br
s, 1H), 1.55‒1.48 (m, 2H), 1.22 (ddt, J = 14.7, 10.9, 3.9 Hz, 1H), 0.99 (br s, 1H), 0.94‒0.87 (m,
1H); 13C{1H} NMR (151 MHz, CDCl3): d = 163.8, 146.6, 137.6, 128.6, 128.5, 128.3, 127.9,
126.6, 126.4, 71.2, 49.9, 33.1, 24.0 (the two signals of the carbon atoms neighboring the
nitrogen of the piperidine ring were not detected at rt, see also 13C spectra of product 46); IR
 S58

(ATR): n = 3309, 3057, 2929, 2852, 2665, 2323, 2036, 1900, 1814, 1611, 1521, 1436, 1259,
1095, 1030, 969, 901, 850, 808, 701; EI-MS: m/z = 452 (1) M+•, 375 (8), 258 (6), 244 (20), 243
(100) [C19H15+ = Mtrityl+], 228 (10), 215 (15), 180 (10), 166 (14), 165 (91), 111 (82), 83 (8), 82
(7); ESI-HRMS for C29H28N2NaOS as [M + Na]+: calcd. m/z = 475.18145, found m/z =
475.18085 with D = 1.26 ppm; optical rotation: [a]D = -61.7 (c = 1.40 in CHCl3).

(S)-3-Amino-1-(thiophene-2-carbonyl)piperidine hydrochloride (45):

According to the GP-4, the title compound was obtained from (S)-1-(thiophene-2-carbonyl)-3-
(tritylamino)piperidine (precursor for compound 45) (11.37 g, 25.12 mmol). Yield: 98% (6.083
g, 24.65 mmol);9 mp: 105 °C; 1H NMR (400 MHz, D2O): d = 7.71 (d, J = 5.0 Hz, 1H), 7.46
(d, J = 3.7 Hz, 1H), 7.19 (dd, J = 5.0, 3.7 Hz, 1H), 4.30 (dd, J = 16.0, 7.7 Hz, 1H), 3.99 (br s,
1H), 3.58‒3.40 (m, 3H), 2.33‒2.09 (m, 1H), 1.94‒1.75 (m, 2H), 1.69 (ddt, J = 13.7, 9.5, 5.4 Hz,
1H); 13C{1H} NMR (101 MHz, D2O): d = 166.1, 134.5, 130.3, 130.2, 127.4, 46.9, 44.6, 43.3,
27.5, 22.2; IR (ATR): n = 3838, 3422, 2862, 2069, 2009, 1821, 1711, 1598, 1518, 1436, 1265,
1166, 1111, 1041, 966, 910, 854, 800, 726; ESI-MS: m/z = 243 (10) [Mamine + H + MeOH]+,
212 (10), 211 (100) [Mamine + H]+, 194 (7), 165 (1), 110 (2); ESI-HRMS for C10H15N2OS as
[Mamine + H]+: calcd. m/z = 211.08996, found m/z = 211.09003 with D = 0.33 ppm; optical
rotation: [a]D = +27.8 (c = 1.30 in CHCl3).

(S)-3-([1'-Ethoxycarbonylpiperidine-4'-yl]amino)-1-(thiophene-2-carbonyl)piperidine
hydrochloride (46):

4-Oxo-piperidine-1-carboxylic acid ethyl ester (assay: 98%, 1.870 mL, 12.15 mmol, 1.2 equiv)
and triethylamine (2.20 mL, 15.2 mmol, 1.5 equiv) were added to an ice-cold solution of (S)-3-
amino-1-(thiophene-2-carbonyl)piperidine hydrochloride (45) (2.499 g, 10.13 mmol) in
 S59

methanol (50 mL). Next, the reaction mixture was treated with sodium cyanoborohydride
(assay: 95%, 1.340 g, 20.26 mmol, 2.0 equiv), stirred at rt for 2 d, and concentrated under
reduced pressure. Dichloromethane (100 mL) and a saturated, aqueous solution of sodium
carbonate (30 mL) were added, the phases separated, and the crude product was extracted from
the aqueous layer with dichloromethane (three times with a total of 90 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The product was purified by FCC (diethyl ether/methanol/triethylamine = [Link]).
The obtained viscous oil was then treated with an ice-cold solution of hydrogen chloride in
anhydrous methanol (22.3 mL, c = 0.5 mol/L, 11.1 mmol, 1.1 equiv). The solution was
concentrated under reduced pressure and the residue dried in high vacuum. Diethyl ether (15
mL) was added and the solid intensively ground with a test tube-like glass rod. The diethyl ether
layer had been taken off with a Pasteur pipette, and the procedure was repeated three times.
Remaining diethyl ether was removed by rotary evaporation and the colorless solid product
dried in high vacuum. Yield: 82% (3.348 g, 8.328 mmol); mp: 249 °C (decompn.); 1H NMR
(400 MHz, CDCl3): d = 9.69 (s, 2H), 7.49 (d, J = 5.0 Hz, 1H), 7.37 (d, J = 3.3 Hz, 1H), 7.07
(dd, J = 5.0, 3.6 Hz, 1H), 4.76 (d, J = 12.3 Hz, 1H), 4.26 (br s, 3H), 4.12 (q, J = 7.1 Hz, 2H),
3.45‒3.17 (m, 4H), 2.77 (br s, 2H), 2.39 (d, J = 10.0 Hz, 1H), 2.28‒2.16 (m, 2H), 2.15‒2.05
(m, 1H), 1.94 (dd, J = 10.4, 7.1 Hz, 1H), 1.91‒1.79 (m, 2H), 1.56 (tdd, J = 16.2, 11.0, 4.3 Hz,
1H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3, 45 °C): d = 164.2, 155.0, 136.2,
129.5, 129.1, 126.9, 61.5, 52.8, 50.4, 46.9, 45.3, 42.1, 28.6, 28.1, 27.6, 24.3, 14.5 (for the two
signals which had been assigned to the carbon atoms neighboring the nitrogen of the piperidine
ring, a broadening was observed at rt; the NMR spectrum measured at 45 °C showed for these
carbon atoms more distinct signal peaks); IR (ATR): n = 3729, 3100, 2952, 2863, 2706, 2662,
2544, 2487, 2463, 2412, 2375, 2286, 2212, 2163, 2098, 2043, 2015, 1931, 1703, 1616, 1520,
1431, 1381, 1310, 1236, 1202, 1136, 1090, 1035, 973, 951, 854, 813, 769, 737; ESI-MS: m/z
= 411 (19), 407 (5), 405 (13), 388 (28) [Mamine + Na]+, 366 (19) [Mamine + H]+, 329 (3), 307 (10),
269 (2), 253 (6), 240 (13), 194 (100), 192 (14), 156 (36), 152 (2); ESI-HRMS for C18H28N3O3S
as [Mamine + H]+: calcd. m/z = 366.18459, found m/z = 366.18414 with D = 1.23 ppm; EA for
C18H28ClN3O3S: calcd. C 53.79, H 7.02, N 10.45, found C 53.81, H 7.20, N 10.59; optical
rotation: [a]D = +31.9 (c = 1.14 in MeOH).
 S60

(R)-3-([5'-Chloro-2'-methyl-pyridazin-3'-on-4'-yl]amino)-1-methylazepane (47):

Method A: 4,5-dichloro-2-methylpyridazin-3(2H)-one (0.659 g, 3.682 mmol, 1.0 equiv) and

potassium carbonate (1.527 g, 11.05 mmol 3.0 equiv) were added to a suspension of (R)-3-
amino-1-methylazepane dihydrochloride (ent-28a) (0.741 mg, 3.684 mmol) in acetonitrile (30
mL). The reaction mixture was stirred under reflux (oil bath) for 16 h and subsequently
concentrated under reduced pressure. The obtained mixture of regioisomers was then subjected
to FCC (diethyl ether/triethylamine = 50:1), delivering in the first fractions the title product as
a pale yellow oil that slowly solidified. Yield: 35% (0.350 g, 1.293 mmol).
Method B: A microwave vial was charged with (R)-3-amino-1-methylazepane dihydrochloride
(ent-28a) (1.000 g, 4.972 mmol) and 4,5-dichloro-2-methylpyridazin-3(2H)-one (0.890 g,
4.972 mmol, 1.0 equiv).10 Then 1-butanol (4 mL) and diisopropylamine (2.10 mL, 14.9 mmol,
3.0 equiv) were added, the vial was sealed and the reaction mixture heated under microwave
irradiation, holding a constant temperature of 160 °C for 1 h. After the liquid had been allowed
to cool down, the reaction mixture was concentrated under reduced pressure. Dichloromethane
(30 mL) and a saturated, aqueous solution of sodium carbonate (20 mL) were added, the phases
separated, and the crude product was extracted from the aqueous layer with dichloromethane
(three times with a total of 45 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. Further purification steps were
performed analogously to method A. Yield: 34% (0.452 g, 1.671 mmol); mp: 37.5 °C; 1H NMR
(600 MHz, CDCl3): d = 7.41 (s, 1H), 6.95 (br d, J = 8.7 Hz, 1H), 4.55‒4.37 (m, 1H), 3.66 (s,
3H), 2.76 (dd, J = 13.5, 2.1 Hz, 1H), 2.69 (dddd, J = 11.8, 9.0, 6.3, 1.1 Hz, 1H), 2.54 (dd, J =
13.5, 5.8 Hz, 1H), 2.44‒2.40 (m, 1H), 2.39 (s, 3H), 1.79‒1.69 (m, 2H), 1.66‒1.55 (m, 2H),
1.54‒1.41 (m, 2H); 13C{1H} NMR (151 MHz, CDCl3): d = 156.6, 139.3, 138.8, 106.2, 59.2,
57.5, 50.9, 47.9, 40.0, 36.6, 28.5, 21.1; IR (ATR): n = 3296, 2937, 2846, 2795, 2159, 2022,
1749, 1607, 1545, 1471, 1409, 1361, 1275, 1243, 1207, 1157, 1127, 1094, 1073, 1043, 1007,
968, 938, 910, 858, 792, 757, 683; EI-MS: m/z = 272 (13) [M, 37Cl]+•, 271 (8) [M + H, 35Cl]+,
270 (38) [M, 35Cl]+•, 228 (6), 226 (16), 172 (5), 158 (12), 144 (9), 111 (100), 110 (13), 98 (8),
96 (18), 84 (23), 82 (5), 70 (6), 58 (37), 57 (13); ESI-HRMS for C12H20ClON4 as [M + H,
35
Cl]+: calcd. m/z = 271.13201, found m/z = 271.13187 with D = 0.52 ppm; optical rotation:
[a]D = -98.4 (c = 1.42 in CHCl3).
 S61

(R)-3-([4'-Chloro-2'-methyl-pyridazin-3'-on-5'-yl]amino)-1-methylazepane (48):

The title compound eluted as second fraction in the FCC during the synthesis of 47 and was
isolated as a pale yellow solid.11 Method A: Yield: 29% (0.284 g, 1.049 mmol); Method B:
Yield: 45% (0.610 g, 2.253 mmol); mp: 63.5 °C; 1H NMR (600 MHz, CDCl3): d = 7.45 (s,
1H), 6.04 (d, J = 8.7 Hz, 1H), 3.69 (s, 4H), 2.78 (dd, J = 13.6, 1.6 Hz, 1H), 2.76‒2.70 (m, 1H),
2.58 (dd, J = 13.5, 5.5 Hz, 1H), 2.48‒2.41 (m, 1H), 2.40 (s, 3H), 1.91‒1.69 (m, 2H), 1.67‒1.57
(m, 2H), 1.51 (dddd, J = 15.1, 8.5, 6.5, 4.0 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3): d =
158.0, 143.2, 126.1, 107.3, 58.5, 57.4, 50.6, 47.9, 40.1, 35.1, 28.2, 21.1; IR (ATR): n = 3343,
2986, 2933, 2852, 2795, 2189, 2027, 1743, 1634, 1604, 1518, 1447, 1404, 1348, 1322, 1271,
1229, 1155, 1123, 1095, 1067, 1042, 1016, 969, 869, 849, 798, 741, 697, 664; EI-MS: m/z =
271 (2) [M + H, 35Cl]+, 270 (1) [M, 35Cl]+•, 236 (14), 235 (100), 204 (5), 190 (11), 84 (9), 58
35
(18); ESI-HRMS for C12H20ClON4 as [M + H, Cl]+: calcd. m/z = 271.13201, found m/z =
271.13193 with D = 0.30 ppm; EA for C12H19ClN4O: calcd. C 53.23, H 7.07, N 20.69, found C
53.14, H 7.04, N 20.86; optical rotation: [a]D = -43.4 (c = 1.44 in CHCl3).

N-Tritylbesifloxacin (49):

According to GP-3, (R)-3-(tritylamino)azepan-2-one (ent-22b) containing 41% of ethanol

(16.92 g, 42.04 mmol, 1.4 equiv) was reduced, and the product dissolved in a mixture of
acetonitrile (60 mL) and triethylamine (12.6 mL, 90.4 mmol, 3.0 equiv). Then, 8-chloro-1-
cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.998 g, 30.03 mmol)
was added and the reaction mixture heated under reflux (oil bath) for 20 h.12 Next, the mixture
was concentrated under reduced pressure. The residue was subjected to FCC (ethyl acetate).
Compared to a standard FCC, one fourth of the average amount of silica was used. After the
solvent of the product fraction was removed under reduced pressure, a yellow solid was
isolated, which was ground in the presence of a mixture of diethyl ether/n-pentane (5:1, 50 mL).
 S62

The procedure was repeated three times with a mixture of diethyl ether/n-pentane (a total of 90
mL) and afterwards three times with n-pentane (1:1, a total of 90 mL). Remaining solvents were
removed by a rotary evaporation, and the resulting yellow solid was dried in high vacuum.
Yield: 67% (12.84 g, 20.18 mmol); mp: 227 °C; 1H NMR (600 MHz, CDCl3): d = 14.37 (br s,
1H), 8.90 (s, 1H), 7.95 (d, J = 10.4 Hz, 1H), 7.54‒7.42 (m, 6H), 7.09‒7.02 (m, 9H), 4.24 (tt, J
= 7.2, 4.0 Hz, 1H), 3.23‒3.11 (m, 1H), 3.03‒2.92 (m, 2H), 2.90‒2.80 (m, 1H), 2.70 (br s, 1H),
2.11‒1.91 (m, 3H), 1.81‒1.64 (m, 3H), 1.57‒1.49 (m, 1H), 1.29‒1.18 (m, 1H), 1.05‒0.90 (m,
2H), 0.82‒0.73 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3): d = 177.0, 166.1, 158.6 (d, 1JC-F =
254.0 Hz), 152.1, 147.3, 147.2, 137.1, 128.6, 127.7, 126.2, 125.0 (d, 3JC-F = 8.4 Hz), 123.4 (d,
3
JC-F = 4.5 Hz), 111.7 (d, 2JC-F = 23.5 Hz), 108.6, 71.5, 56.8, 54.2, 51.6, 41.5, 38.9, 29.2, 22.9,
11.6, 11.3; 19F NMR (565 MHz, CDCl3): d = -115.7 (d, J = 10.6 Hz); IR (ATR): n = 3846,
3650, 3312, 3060, 2924, 2854, 2695, 2499, 2279, 2241, 2205, 2108, 2028, 1944, 1728, 1603,
1561, 1529, 1490, 1432, 1319, 1257, 1187, 1086, 1028, 893, 827, 805, 771, 704; ESI-MS: m/z
= 974 (61), 732 (5), 658 (3) [M + Na, 35Cl]+, 636 (4) [M + H, 35Cl]+, 482 (8), 378 (5), 243 (100)
[C19H15+ = Mtrityl+], 228 (17), 165 (83); ESI-HRMS for C38H36ClFN3O3 as [M + H, 35Cl]+: calcd.
m/z = 636.24237, found m/z = 636.24034 with D = 3.19 ppm; EA for C38H35ClFN3O3: calcd. C
71.75, H 5.55, N 6.61, found C 71.55, H 5.51, N 6.51; optical rotation: [a]D = +161.6 (c =
1.24 in CHCl3).

Besifloxacin monohydrochloride (16):

N-Tritylbesifloxacin (49) (12.53 g, 19.70 mmol, 1.0 equiv) was suspended in ethanol (technical
grade, 100 mL) and treated with concentrated hydrochloric acid (assay: 37% w/w aqueous
solution, 3.10 mL, 37.4 mmol, 1.9 equiv).13 The reaction mixture was heated to 50 °C (oil bath)
until a clear solution was obtained and stirred at rt overnight. Next, the cooled suspension (ice
bath) was filtered over a Büchner funnel and the solid washed with ice-cold ethanol (6 mL)
followed by diethyl ether (10 mL). After drying the remaining solid in high vacuum, it was
intensively ground in the presence of a hot mixture of ethyl acetate (25 mL) and
dimethylformamide (10 mL) with a test tube-like glass rod. The supernatant solvent layer had
been taken off with a Pasteur pipette, and the procedure was repeated with an identical solvent
mixture, then five times with diethyl ether (30 mL). Remaining solvents were removed by rotary
 S63

evaporation, and the residue was dried in high vacuum, delivering the title product as a pale
yellow solid.14 Yield: 70% (5.952 g, 13.83 mmol); mp: 301 °C (decompn.); 1H NMR [600
MHz, (CD3)2SO]: d = 14.39 (br s, 1H), 8.84 (s, 1H), 8.28 (br s, 3H), 7.98 (d, J = 10.6 Hz, 1H),
4.40 (tt, J = 7.3, 3.9 Hz, 1H), 3.60 (dd, J = 13.9, 2.5 Hz, 1H), 3.51 (dd, J = 13.9, 9.0 Hz, 1H),
3.30‒3.17 (m, 3H), 2.16‒2.04 (m, 1H), 1.97‒1.84 (m, 2H), 1.78‒1.65 (m, 3H), 1.28‒1.21 (m,
1H), 1.21‒1.15 (m, 1H), 1.10‒0.98 (m, 2H); 13C{1H} NMR [151 MHz, (CD3)2SO]: d = 176.2,
165.0, 157.1 (d, 1JC-F = 250.5 Hz), 152.9, 145.0 (d, 2JC-F = 15.0 Hz), 137.5, 124.6 (d, 3JC-F = 8.2
Hz), 123.6, 110.5 (d, 2JC-F = 23.2 Hz), 107.7, 54.9, 53.7, 51.9, 41.6, 32.2, 28.3, 21.6, 11.2, 10.7;
19
F NMR [564 MHz, (CD3)2SO]: d = -117.9 (d, J = 10.6 Hz); IR (ATR): n = 3454, 3218, 3055,
2866, 2638, 2551, 2476, 2324, 2172, 2076, 1986, 1958, 1925, 1834, 1727, 1611, 1559, 1449,
1358, 1320, 1269, 1191, 1107, 1051, 1026, 991, 917, 872, 807, 733, 659; ESI-MS: m/z = 787
(22) [2Mamine + H, {35Cl, 35Cl}]+, 560 (3), 490 (2), 408 (12), 394 (100) [Mamine + H, 35Cl]+, 377
(11), 360 (4); ESI-HRMS for C19H22ClFN3O3 as [Mamine + H, 35Cl]+: calcd. m/z = 394.13282,
found m/z = 394.13270 with D = 0.31 ppm; EA for C19H22Cl2FN3O3: calcd. C 53.03, H 5.15, N
9.77, found C 52.99, H 5.21, N 9.68; optical rotation: [a]D = -49.5 (c = 1.35 in MeOH).

The consistent results of elemental analyses with four different samples confirmed that the
mono hydrochloride salt was obtained. (EA2 found C 52.92, H 5.26, N 9.68; EA3 found C
53.20, H 5.25, N 9.46; EA4 found C 53.33, H 5.15, N 9.58).

The cleavage of the protecting group of N-tritylbesifloxacin (3.306 g, 5.197 mmol) following
GP-4 led to a mixture of the mono- and dihydrochloride salt. The latter was obtained in
analytical pure form by grinding the crude mixture two times in the presence of hot ethanol (a
total of 20 mL). The residue was dried in high vacuum, delivering besifloxacin dihydrochloride
as an ivory colored solid. Yield: 11% (0.275 g, 0.589 mmol); mp: 290 °C (decompn.); 1H NMR
[600 MHz, (CD3)2SO]: d = 14.39 (br s, 1H), 8.84 (s, 1H), 8.22 (s, 3H), 7.98 (d, J = 10.4 Hz,
1H), 4.43‒4.32 (m, 1H), 3.63‒3.44 (m, 3H), 3.31‒3.17 (m, 3H), 2.14‒2.03 (m, 1H), 1.95‒1.82
(m, 2H), 1.79‒1.63 (m, 3H), 1.30‒1.11 (m, 2H), 1.09‒0.95 (m, 2H); 13C{1H} NMR [151 MHz,
(CD3)2SO]: d = 176.2, 165.1, 157.2 (d, 1JC-F = 250.4 Hz), 152.9, 145.00 (d, 2JC-F = 15.0 Hz),
137.5, 124.6 (d, 3JC-F = 8.1 Hz), 123.6, 110.52 (d, 2JC-F = 23.2 Hz), 107.7, 54.9, 53.7, 51.9, 41.6,
32.3, 28.3, 21.6, 11.2, 10.7; 19F NMR [565 MHz, (CD3)2SO]: d = -117.9 (d, J = 11.0 Hz); IR
(ATR): n = 3836, 3450, 3220, 3053, 2866, 2637, 2559, 2196, 2062, 1983, 1840, 1728, 1610,
1559, 1448, 1319, 1269, 1190, 1107, 1025, 918, 872, 807, 733, 659; ESI-MS: m/z = 787 (39)
[2Mamine + H, {35Cl, 35Cl}]+, 723 (39), 476 (2), 408 (4), 394 (100) [Mamine + H, 35Cl]+, 377 (13),
 S64

330 (26); ESI-HRMS for C19H22ClFN3O3 as [Mamine + H, 35Cl]+: calcd. m/z = 394.13282, found
m/z = 394.13223 with D = 1.50 ppm; EA for C19H23Cl3FN3O3: calcd. C 48.89, H 4.97, N 9.00,
found C 48.81, H 5.35, N 9.12; optical rotation: [a]D = -45.6 (c = 0.50 in MeOH).

4. X-ray crystallography
Single crystals of 38b and 48 were measured using a dual-source Rigaku SuperNova
diffractometer equipped with an Atlas detector and an Oxford Cryostream cooling system using
mirror-monochromated Mo-Ka radiation (l = 0.71073 Å) for 38b and Cu-Ka radiation (l =
1.54184 Å) for 48. Data collection and reduction were performed using the program
COLLECT15 and HKL DENZO AND SCALEPACK,16 respectively, and the intensities were
corrected for absorption using SADABS.17 The structures were solved with Direct Methods
(SHELXS)18 and refined by full-matrix least-squares based on F2 using SHELXL-2015.17 Non-
hydrogen atoms were assigned anisotropic displacement parameters unless stated otherwise.
Hydrogen atoms were placed in idealized positions and included as riding. Isotropic
displacement parameters for all hydrogen atoms were constrained to multiples of the equivalent
displacement parameters of their parent atoms with Uiso(H) = 1.2 Ueq(parent atom). The X-ray
single crystal data, experimental details and CCDC numbers are given below.

Single crystals of 38b were prepared by heating 200 mg of the solid in 4 mL of a mixture of
ethanol/ethyl acetate (1:1) to reflux, passing the hot mixture through cotton and storing the
mixture in a closed vial at -18 °C.

Crystal data for 38b: CCDC- 2173017, C14H18BrClN2O2S, M = 393.72 gmol-1, yellow plate,
0.10 ´ 0.25 ´ 0.29 mm3, orthorhombic space group P212121 (No. 19), a = 5.4296(2) Å, b =
10.3514(8) Å, c = 29.271(2) Å, V = 1645.2(2) Å3, Z = 4, Dcalc = 1.590 gcm-3, F(000) = 800,
µ = 2.793 mm-1, T = 170.0(1) K, qmax = 26.242°, 7649 total reflections, 2219 with Io > 2s(Io),
Rint = 0.0566, 3067 data, 196 parameters, 2 restraints, GooF = 1.045, R1 = 0.0488 and wR2 =
0.093 [Io > 2s(Io)], R1 = 0.0809 and wR2 = 0.1032 (all reflections), -0.347 < dDr < 0.385 eÅ-3.

Single crystals of 48 were prepared by heating 100 mg of the solid in 5 mL of n-pentane to

reflux and adding diethyl ether until a clear solution was obtained (approx. 2 mL). The flask
was then equipped with a septum and stored at -18 °C. After crystals had been formed, the cold
solvent was removed immediately to avoid the quick redissolution at rt. The crystals are not
stable, they age and tarnish within days.
 S65

Crystal data for 48: CCDC-2173018, C12H19ClN4O, M = 270.76 gmol-1, colorless block, 0.29
´ 0.31 ´ 0.32 mm3, orthorhombic space group P212121 (No. 19), a = 7.2223(2) Å, b = 8.8463(3)
Å, c = 21.1228(6) Å, V = 1349.55(7) Å3, Z = 4, Dcalc = 1.333 gcm-3, F(000) = 576, µ = 2.468
mm-1, T = 120.0(1) K, qmax = 69.98°, 23305 total reflections, 2555 with Io > 2s(Io), Rint =
0.0229, 2557 data, 165 parameters, 0 restraints, GooF = 1.059, R1 = 0.0213 and wR2 = 0.0565
[Io > 2s(Io)], R1 = 0.0213 and wR2 = 0.0565 (all reflections), -0.206 < dDr < 0.227 eÅ-3.

Figure S1. ORTEP3 plot of 38b. Displacement ellipsoids are drawn at the 50% probability
level.
 S66

Figure S2. ORTEP3 plot of 48. Displacement ellipsoids are drawn at the 50% probability level.

5. References
(1) Kamenecka, T. M.; Kenny, P.; Lindstrom, J. M.; Wang, J.; Jin, Z.; Doeblin, C.
Modulators for nicotinic acetylcholine receptor a2 and a4 subunits. Patent application
WO2016191366A1, 2016.
(2) (a) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. A Safe, Economical Method
for the Preparation of b-Oxo Esters. Synthesis 1993, 290‒292. (b) For the hydrolysis of
the ethyl ester, see: Keiji, H.; Tsutomu, I.; Takayoshi, I.; Satoshi, M.; Seijo, S.
Quinolonecarboxylic acid derivatives. Patent application EP000000195316A1, 1986.
(3) Pellegata, R.; Pinza, M.; Pifferi, G. An Improved Synthesis of d-, g-, and e-Lactams.
Synthesis 1978, 614‒616.
(4) (a) Caution: when diethyl ether is exposed to ambient air diethyl ether peroxide is slowly
formed by photooxygenation. The peroxide is exceptionally prone to violent
decomposition that can be initiated by heat, mechanical impact, or friction, see: Clark, D.
E. Peroxides and peroxide-forming compounds. Chem. Health Saf. 2001, 8, 12‒22. (b) It
is strongly recommended that diethyl ether will be tested on peroxides prior to use:
Jackson, H. L.; McCormack, W. B.; Rondestvedt, C. S.; Smeltz, K. C.; Viele, I. E. Control
of peroxidizable compounds. J. Chem. Educ. 1970, 47, A175‒A188. (c) When grinding
 S67

the product in the flask manually, the energy introduced is not sufficient to cause heating
of the solvent to our expertise. At least, in all grinding experiments we have done, an
increasing temperature of the diethyl ether inside the flask was never observed. In
contrary, using an ultrasonic bath for the purification, the diethyl ether started to boil after
a few minutes.
(5) The procedure had been modified compared to the protocols published in: (a) Boyle Jr.;
W. J.; Sifniades, S.; Van Peppen, J. F. Asymmetric transformation of a-amino-e-
caprolactam, a lysine precursor. J. Org. Chem. 1979, 44, 4841‒4847. (b) Stranix, B. R.;
Sauve, G.; Bouzide, A.; Cote, A.; Berube, G.; Soucy, P.; Zhao, Y.; Yelle, J. HIV protease
inhibitors based on amino acid derivatives. Patent application WO2002064551A1, 2002.
(6) Belyaev, A. A.; Krasko, E. V. A Novel Synthetic Route to N 6-Methyl-L-lysine and N 5-
Methyl-L-ornithine via N 3-Protected (S)-3-Aminolactams. Synthesis 1991, 417‒419.
(7) Zhou, Y.; He, X.; Liu, Y.; Wang, Y. Process for preparation of linagliptin and
intermediates thereof. Patent application CN014387315A, 2015.
(8) (a) Jörres, M.; Schiffers, I.; Atodiresei, I.; Bolm, C. Asymmetric Michael Additions of a-
Nitrocyclohexanone to Aryl Nitroalkenes Catalyzed by Natural Amino Acid-Derived
Bifunctional Thioureas. Org. Lett. 2012, 14, 4518‒4521. (b) Jörres, M.; Mersmann, S.;
Raabe, G.; Bolm, C. Organocatalytic solvent-free hydrogen bonding-mediated
asymmetric Michael additions under ball milling conditions. Green Chem. 2013, 15, 612‒
616.
(9) The yield was calculated on the basis of a pure material. The NMR spectra of the product,
however, indicated impurities, which could not be removed or identified by standard
procedures. However, the title compound had been regarded as a substance of sufficient
purity, since the impurities had no limiting influence and the final product of the three
step sequence was formed in high yield and purity (see also compound 46).
(10) The procedure is a slightly modified version of the original protocol, which had been
published in: Albrecht, B. K.; Burdick, D. J.; Cote, A.; Duplessis, M.; Nasveschuk, Ch.
G.; Taylor, A. M. Pyridazinone derivatives and their use in the treatment of cancer. Patent
application WO2016112298A1, 2016.
(11) A single crystal X-ray analysis of a sample recrystallized from a mixture of n-
pentane/diethyl ether allowed the explicit assignment of the regioisomeric products, for
further information see the crystallographic section.
(12) The procedure is a modified version of the protocol, which had been published in:
Bhavsar, J.; Bhashkar, B.; Kumar, A. Fluoroquinolone carboxylic acid compounds and
 S68

the use thereof for the preparation of Besifloxacin hydrochloride. Patent application
WO2016120813A1, 2016.
(13) This procedure is analogous to the protocol, published in: Chen, Z.; Xia, Z.; Jiang, L.;
Wang, M.; Zhang, M.; Lin, S.; Ji, X.; Ma, Y. Method for preparation of Besifloxacin
hydrochloride. Patent application CN102659761A, 2012.
(14) According to 1H NMR analysis, the product contained traces of dimethylformamide.
Selecting a mixture of ethanol and methanol (1:1) as entrainer, the dimethylformamide
could be removed under reduced pressure. However, after drying the residue in high
vacuum, the product showed in 1H NMR neither signals anymore for the protons
stemming from the amine function nor for the carboxylic acid proton: 1H NMR [600
MHz, (CD3)2SO]: d = 8.83 (s, 1H), 7.96 (d, J = 10.5 Hz, 1H), 4.39 (tt, J = 7.4, 3.9 Hz,
1H), 3.60 (d, J = 14.1 Hz, 1H), 3.51 (dd, J = 14.0, 9.0 Hz, 1H), 3.30‒3.18 (m, 3H), 2.18‒
2.05 (m, 1H), 1.97‒1.85 (m, 2H), 1.77‒1.66 (m, 3H), 1.31‒1.21 (m, 1H), 1.21‒1.14 (m,
1H), 1.10‒0.97 (m, 2H); see spectrum in the corresponding section.
(15) Hooft, R. W. W. COLLECT 1998, Nonius BV, Delft, the Netherlands.
(16) Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation
moder. In Methods in Enzymology, Macromolecular Crystallography, Part A, Carter Jr.,
C. W.; Sweet, R. M., Eds.; Academic Press: New York, 1997, 276, pp 307‒326.
(17) Sheldrick, G. M. SADABS Version 2008/2 1996, University of Göttingen, Germany.
(18) (a) Sheldrick, G. M. A short history of ShelXL. Acta Cryst. 2008, A64, 112‒122. (b)
Sheldrick, G. M. SHELXL13. Program package for crystal structure determination from
single crystal diffraction data, University of Göttingen, Germany, 2013. (c) Sheldrick, G.
M. Crystal structure refinement with ShelXL. Acta Cryst. 2015, C71, 3‒8.
 S69

6. NMR Spectra
S70
S71
S72
S73
S74
S75
S76
S77
S78
S79
S80
S81
S82
S83
S84
S85
 S86

O
N
Ot-Bu

NH

26e

O
N
Ot-Bu

NH

26e
 S87

NH

NH2 2 HCl
2 2 HCl

NH

NH2 2 HCl
2 2 HCl
S88
S89
S90
S91
S92
 S93

Me
N
Me

NH2 2 HCl
28b

Me
N
Me

NH2 2 HCl
28b
S94
S95
S96
S97
S98
S99
 S100

N CN

NH

33

N CN

NH

33
S101
S102
S103
S104
S105
S106
S107
S108
S109
 S110

O
S Br
HN

N
H HOOCCF3
38c

O
S Br
HN

N
H HOOCCF3
38c
 S111

O
S Br
HN

N
H HOOCCF3
38c
S112
S113
S114
S115
S116
S117
S118
S119
S120
S121
S122
S123
S124
S125
S126
S127
S128
S129
S130
 S131

O O
F
OH
H2 N
N N HCl
Cl

16
(see reference 14 in section 5)
S132
 S133

7. HPLC analyses
HPLC chromatogram of racemic N,N'-ditosyl-lysine methyl ester (unnumbered):
 S134

HPLC chromatogram of (S)-N,N'-ditosyl-lysine methyl ester (unnumbered):

HPLC chromatogram of (R)-N,N'-ditosyl-lysine methyl ester (unnumbered):

 S135

HPLC chromatogram of rac-21b:

HPLC chromatogram of 21b:

 S136

HPLC chromatogram of ent-21b:

HPLC chromatogram of rac-22b:

 S137

HPLC chromatogram of 22b (before recrystallization):

HPLC chromatogram of 22b (after recrystallization):

 S138

HPLC chromatogram of ent-22b:

HPLC chromatogram of rac-25d:

 S139

HPLC chromatogram of 25d:

HPLC chromatogram of rac-26d:

 S140

HPLC chromatogram of 26d:

HPLC chromatogram of rac-31a:

 S141

HPLC chromatogram of 31a (prepared from 21a):

HPLC chromatogram of 31a (prepared from 21b):

 S142

HPLC chromatogram of ent-31a:

HPLC chromatogram of rac-32a:

 S143

HPLC chromatogram of 32a:

HPLC chromatogram of ent-32a: