280 Rádl, Hezký, Urbánková, Váchal, Krejčí:

SYNTHESIS AND ANALGESIC ACTIVITY OF SOME 1-BENZOFURANS,

1-BENZOTHIOPHENES AND INDOLES

Stanislav RÁDLa1,*, Petr HEZKÝa, Jitka URBÁNKOVÁb, Petr VÁCHALb

and Ivan KREJČÍa
a
Research Institute of Pharmacy and Biochemistry, Kouřimská 17, 130 60 Prague 3,
Czech Republic; e-mail: 1 [email protected]
b
Department of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic

Received November 29, 1999

Accepted January 19, 2000

3-Unsubstituted 1-benzofurans 1e and 1f, 3-methyl-1-benzofurans 1a–1d, and 3-amino-

1-benzofurans 2a–2l, as well as 3-amino-1-benzothiophenes 3a, 3b and 3-aminoindoles
4a–4f, 11a, and 11b were prepared and tested as analgesics. The 3-amino-1-benzofurans 2
were prepared from the corresponding 2-hydroxybenzonitriles 5 and phenacyl bromides 6
via intermediates 7. Similar treatment of 2-sulfanylbenzonitrile (8) provided
3-amino-1-benzothiophenes 3. Appropriately substituted 2-aminobenzonitriles 9 then pro-
vided N-substituted 3-aminoindoles 4. 1-(Ethoxycarbonyl)indoles 4e and 4f were success-
fully deprotected giving indoles 11a and 11b, respectively.
Key words: Benzofurans; Benzothiophenes; Indoles; Xanthoxyline analogs; Analgesics.

Antinociceptive activity of 2-(4-bromobenzoyl)-4,6-dimethoxy-3-methyl-

1-benzofuran (1a) has recently been reported1,2. This compound, which
was prepared from naturally occurring 1-(2-hydroxy-4,6-dimethoxy-
phenyl)ethan-1-one (xanthoxyline), represents a new structural type exert-
ing analgesic effect. Quite unusually, no other 1-benzofuran derivative of
the active compound 1a was mentioned and therefore we decided to pre-
pare the compound itself and also its derivatives 1b–1f.
There are several well-documented methods of preparation of
3-unsubstituted and 3-methyl-2-benzoyl-1-benzofurans3. Synthesis of com-
pound 1d from the corresponding 6-hydroxy derivative has been pub-
lished4. A low yield of compound 1f was formed, in addition to several
other products, during formylation of 2-(3,5-dimethoxyphenoxy)-
1-phenylethan-1-one5. We decided to prepare all the compounds 1 from
appropriate 2-hydroxyacetophenones or 2-hydroxybenzaldehydes and
2-bromo-1-phenylethan-1-ones by a modification of the published proce-

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 281

dure6. First we decided to prepare 1a to prove the reported activity. The de-
scribed methods of preparation of xanthoxyline are mostly nonselective
and include the Friedel–Crafts acetylation of 3,5-dimethoxyphenole7 or
methylation of 1-(2,4,6-trihydroxyphenyl)ethan-1-one8,9 under various
conditions. Demethylation of 1-(2,4,6-trimethoxyphenyl)ethan-1-one with
aluminum chloride is also nonselective providing a mixture of all possible
mono-, di-, and trihydroxy derivatives10. We applied a published proce-
dure11 of selective demethylation of ortho-methoxy aromatic ketones. This
procedure monodemethylated 1-(2,4,6-trimethoxyphenyl)ethan-1-one to
give acceptable yields of xanthoxyline. This compound treated with
2-bromo-1-(4-bromophenyl)ethan-1-one in the presence of potassium hy-
droxide provided 1a. Since the reported analgesic activity of 1a was proved,
compounds 1b–1d were prepared from the corresponding 1-(2-hydroxy-
phenyl)ethan-1-ones by the same procedure. Similarly, starting from
2-hydroxy-4,6-dimethoxybenzaldehyde and the corresponding 2-bromo-
1-phenylethan-1-ones, compounds 1e and 1f were prepared. In this case, the
use of potassium carbonate in butan-2-one under reflux was sufficient for a
smooth reaction.
Analgesic screening found compound 1a the most active of the series.
However, all these compounds were found active only for i.p. or s.c. appli-
cation and only slightly active or inactive after p.o. application. In order to
obtain compounds with better pharmacological profile, we decided to pre-
pare some more different analogs of 1a. First we decided to prepare
3-amino-substituted 1-benzofurans 2, 1-benzothiophenes 3, and indoles 4,
since we expected that these compounds could form water-soluble salts.

R1

R3 R2 NH2 NH2
R

MeO O O X O O O

1 R1 R2 R3
a Br Me MeO 2, X = O 12 R
b H Me MeO 3, X = S a Me
c Br Me H 4, X = NR b OEt
d H Me H
e Br H MeO
f H H MeO

Synthesis of 1-benzofuran 2a starting from 2-hydroxybenzonitrile (5a)

and 6a has been described12,13. When the reaction was done with sodium

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

282 Rádl, Hezký, Urbánková, Váchal, Krejčí:

hydroxide in 2-methoxyethan-1-ol, the intermediate benzoylmethoxy de-

rivative 7a was isolated and characterized12. Using potassium carbonate in
acetone led directly to 1-benzofuran 2a. We usually prepared 1-benzofuran
derivatives 2a–2l from the appropriate benzonitrile 5 and bromo derivative
6 via the corresponding benzoylmethoxy derivatives 7, basically as de-
scribed12 for 2a. We used sodium hydroxide in 2-methoxyethan-1-ol or so-
dium hydrogencarbonate in DMF at room temperature to get compounds 7,
which were after isolation cyclized with sodium methoxide or potassium
tert-butoxide in methanol at room temperature to give good yields of com-
pounds 2 (Scheme 1). Starting 2-hydroxy-3-methoxybenzonitrile (5b) and
2-hydroxy-4,6-dimethoxybenzonitrile (5c) were prepared from the appro-
priate commercially available benzaldehydes via the corresponding oximes,
which were dehydrated in situ with formic acid to the required benzo-
nitriles14.

R1
CN R4
1
R R1 NH2
R2 OH CN R4
R3
5
R2 O R2 O O
+ O
R3 O
Br 7 R3 2
2, 7 R1 R2 R3 R4
R4 6 a H H H H
b H H H Br
c H H H Ph
5 R1 R2 R3 6 R4
d H H H 2,4-F2C6H3
a H H H a H e H H MeO H
b H H MeO b Br f H H MeO Br
c MeO MeO H c Ph g H H MeO Ph
d 2,4-F2C6H3 h H H MeO 2,4-F2C6H3
i MeO MeO H H
j MeO MeO H Br
k MeO MeO H Ph
l MeO MeO H 2,4-F2C6H3

SCHEME 1

Formation of 3a from 2-sulfanylbenzonitrile (8) and 2-chloro-1-phenyl-

ethan-1-one in an aqueous sodium hydroxide solution has been reported
without any experimental details15. We prepared 1-benzothiophene deriva-
tives 3 under analogous conditions described above for the preparation of
1-benzofurans 2. The reaction of 2-fluorobenzonitrile with phenyl-
methanethiol provided in good yield starting 2-(benzylsulfanyl)benzo-
nitrile. Similar preparation of this compound from 2-nitrobenzonitrile has

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 283

been published16. The required 2-sulfanylbenzonitrile (8) was prepared by

debenzylation of this compound with aluminum chloride. In our hands,
this method provided purer product, which did not require distillation,
than the described method17 starting from 2-bromobenzonitrile and ethyl
3-sulfanylpropionate. In the case of 1-benzothiophenes, the expected open
intermediates cannot be isolated and the target compounds 3a and 3b were
directly formed under the used conditions (Scheme 2).

O CN R
CN
Br
+
SH S
R O
8 6 R R
a H
b Br NH2
3 R
a H
b Br S O

SCHEME 2

The use of addition of an activated CH2 group to a nitrile functionality

for the synthesis of 3-aminoindoles is rare18. Our attempts to use
N-unsubstituted 2-aminobenzonitrile for similar preparation of indole de-
rivatives failed. The reaction with 2-bromo-1-(4-bromophenyl)ethan-1-one
under milder conditions did not proceed; under more harsh conditions, it
provided complex mixtures. Therefore, we prepared N-activated derivatives
9a–9d as suitable starting compounds. Reaction of 9a or 9b with bromo de-
rivatives 6a or 6b provided smoothly intermediates 10, together with small
amounts of the corresponding indoles 4. The same treatment of 9c pro-
vided directly indoles 4e and 4f, respectively. On the other hand, the same
reaction of acetyl derivative 9d under different conditions provided com-
plex mixtures. Compounds 10 were purified by crystallization and then
cyclized into indoles 4 with sodium methoxide. With compounds 10c and
10d, the use of triethylamine in ethanol provided cleaner reaction mixtures
and higher yields of indoles 4c and 4d, respectively. We tried to deprotect
compounds 4 to get the corresponding N-unsubstituted indoles under vari-
ous conditions. After several failures we succeeded in deprotection of
N-ethoxycarbonyl derivatives 4e and 4f by alkaline hydrolysis to yield
N-unsubstituted indoles 11a and 11b, respectively (Scheme 3).
Analogously to compounds 2, the known 2-acetyl-3-amino-1-benzofuran
(12a) and ethyl 3-amino-1-benzofuran-2-carboxylate (12b) were prepared

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

284 Rádl, Hezký, Urbánková, Váchal, Krejčí:

from 2-hydroxybenzonitrile (5a) and chloroacetone or ethyl bromoacetate,

by modifications of the published procedures12,13.

CN O CN R2
+ Br
NH N
R1 R2 R1 O
10 4,10 R1 R2
9 R1 6 R2 a MeSO2 H
a MeSO2 a H b MeSO2 Br
b 4-Me-C6H4SO2 b Br c 4-Me-C6H4SO2 H
c CO2Et R R2 d 4-Me-C6H4SO2 Br
d MeCO e CO2Et H
NH2 NH2 f CO2Et Br
11 R
a H N O N O 4
b Br R1
H

SCHEME 3

Structures of all new compounds were proved by elemental analysis and

NMR spectroscopy. IR and UV spectra of selected compounds were also
measured. In these cases, IR spectra showed characteristic vibrations of the
functional groups present. UV spectra of all measured 1-benzofurans,
1-benzothiophenes, and indoles were found to exhibit similar patterns.
All the prepared target compounds, i.e. 1-benzofurans 1, 2, and 12,
1-benzothiophenes 3 as well as indoles 4 and 11, were evaluated for their
antinociceptive activity in two basic tests, the hot-plate test and
intraperitoneal writhing test in mice. Selected compounds were tested also
in the tail-flick test in rats. Analgesic activity of compounds having at least
in one of the tests activity higher than 30% is shown in Table I. It is evi-
dent that the model compound 1a is highly active after subcutaneous ap-
plication and only slightly active after oral application. The same pattern is
observed also with other compounds 1. In this subset, only compounds
having the 4,6-dimethoxy substituents are fairly active. No such pattern
can be seen in the group of 3-amino-1-benzofurans 2, where the good anal-
gesic activity after subcutaneous application was found in compound 2a, as
well as in 7-methoxy derivative 2e and 4,6-dimethoxy derivative 2k. Both
tested compounds 12a and 12b, which do not contain the 2-benzoyl group,
were found only slightly active. Also both tested 1-benzothiophenes 3a and
3b were only slightly active. No improvement in the analgesic activity was
found also in indoles 4, compound 4f being the only active N-substituted
indole of this group. On the other hand, both N-unsubstituted indoles 11
were active. However, their activity was not quite convincing.

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 285

In conclusion, a series of new 1-benzofurans, 1-benzothiophenes, and

indoles were synthesized and tested as analgesics. Some of them, e.g., com-
pounds 2a, 2k, 4f, 11a, and 11b, are in doses of 30 mg/kg active in the used
analgesic models. However, their activity is not high enough to justify their
further development as analgesic agents.

EXPERIMENTAL

Melting points were measured on a Kofler block and are uncorrected. 1H NMR spectra were
recorded on a Bruker instrument (250 MHz). Chemical shifts are given in ppm (δ-scale), cou-
pling constants (J) in Hz. IR spectra (KBr) were recorded on a Unicam SP 2006 spectrometer,
wavenumbers are given in cm–1. UV spectra were measured on a Shimadzu UV-260 spec-
trometer in ethanol, wavelengths are given in nm. Flash chromatography was done on silica
gel 60 (230–400 mesh) and preparative TLC on pre-coated PLC plates (silica gel 60) from EM
Science.
The following starting compounds were prepared by the previously described methods:
1-(biphenyl-4-yl)-2-bromoethan-1-one19 (6c), 2-bromo-1-(2′,4′-difluorobiphenyl-4-yl)ethan-
1-one20 (6d), N-(2-cyanophenyl)methanesulfonamide21 (9a), N-(2-cyanophenyl)-4-methyl
benzenesulfonamide 22 (9b), ethyl N-(2-cyanophenyl)carbamate 23 (9c), and N-(2-cyano-
phenyl)acetamide24 (9d). The known 1-benzofurans 12a and 12b were prepared analogously
as described in the literature12,13.

TABLE I
Analgesic activitya of active compounds 1–4, 11

Compound Hot plate, % Writhing, % Tail flick, %

1a –/63 22/– –/47

1e –/27 1/– –/32
1f –/7 15/– –/45
2a 14/39 7/37 –/52
2e 5/44 33/– –/–
2k –/44 –/70 –/–
4f –/29 33/– 1/93
11a –/27 32/– 10/–
11b 18/17 31/– 3/–

a
– p.o./s.c., 30 mg/kg.

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

286 Rádl, Hezký, Urbánková, Váchal, Krejčí:

1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one

Butyllithium (10 ml of a 2.5 M solution in hexanes, 25 mmol) was added to a toluene solu-
tion (25 ml) of 1-methylpiperazine (2.5 g, 25 mmol) under argon at 0 °C and the mixture
was stirred at room temperature for 20 min. The mixture was cooled to 0 °C and a solution
of 1-(2,4,6-trimethoxyphenyl)ethan-1-one (4.2 g, 20 mmol) in toluene (50 ml) was added
dropwise keeping the temperature below 15 °C. After addition of butyllithium (10 ml of a
2.5 M solution in hexanes, 25 mmol), the mixture was stirred at room temperature for 30
min and then at 80 °C for 10 h. The cold mixture was quenched with 5% hydrochloric acid
(20 ml) and the aqueous layer was extracted with diethyl ether. The combined organic ex-
tracts were dried with magnesium sulfate, the residue after evaporation (2.7 g) was crystal-
lized twice from hexane to give the required product (2.7 g, 71%) as white crystals; m.p.
84–85 °C (ref. 25 87 °C). 1H NMR (CDCl3): 2.61 s, 3 H (CH3); 3.82 s, 3 H (CH3O); 3.85 s, 3 H
(CH3O); 5.92 d, 1 H, J = 2.5 (H-5); 6.06 d, 1 H, J = 2.5 (H-3); 14.01 s, 1 H (OH).

Preparation of 2-Benzoyl-3-methyl-1-benzofurans 1a–1d. General Procedure

A solution of an appropriate 2-bromo-1-phenylethan-1-one (10 mmol) in ethanol (20 ml)

was added to a stirred solution of 1-(2-hydroxyphenyl)ethan-1-one (10 mmol) and potas-
sium hydroxide (1 g, 18 mmol) in ethanol (30 ml) and the mixture was stirred overnight.
The insoluble portion was filtered off and crystallized from ethanol (charcoal) to give 1.
2-(4-Bromobenzoyl)-4,6-dimethoxy-3-methyl-1-benzofuran (1a). Yield 82%; m.p. 180–184 °C
(ref.2 185 °C). For C 18H15BrO4 (375.2) calculated: 57.62% C, 4.03% H, 21.30% Br; found:
57.67% C, 4.54% H, 21.62% Br. 1H NMR (CDCl3): 2.75 s, 3 H (CH3); 3.86 s, 3 H (CH3O);
3.90 s, 3 H (CH3O); 6.29 d, 1 H, J = 1.9 (H-5); 6.56 d, 1 H, J = 1.9 (H-7); 7.63 dt, 2 H, J = 8.7,
2.2 (benzoyl); 7.91 dt, 2 H, J = 8.7, 2.2 (benzoyl).
2-Benzoyl-4,6-dimethoxy-3-methyl-1-benzofuran (1b). Yield 88%; m.p. 123–126 °C. For
C18H16O4 (296.3) calculated: 72.96% C, 5.44% H; found: 73.27% C, 5.55% H. 1H NMR
(CDCl3): 2.74 s, 3 H (CH3); 3.85 s, 3 H (CH3O); 3.90 s, 3 H (CH3O); 6.29 d, 1 H, J = 1.9
(H-5); 6.58 d, 1 H, J = 1.9 (H-7); 7.38–7.63 m, 3 H (benzoyl); 8.01 m, 2 H (benzoyl).
2-(4-Bromobenzoyl)-6-methoxy-3-methyl-1-benzofuran (1c). Yield 90%; m.p. 117–119 °C. For
C17H13BrO3 (345.2) calculated: 59.15% C, 3.80% H, 23.15% Br; found: 58.88% C, 3.70% H,
22.66% Br. UV, λ (log ε): 205 (4.51), 244 (4.00), 264 (4.11), 349 (4.40). 1H NMR (CDCl3):
2.63 s, 3 H (CH3); 3.88 s, 3 H (CH3O); 6.93–7.03 m, 2 H (H-5, H-7); 7.55 dd, 1 H, J = 8.3, 0.9
(H-4); 7.65 dt, 2 H, J = 8.6, 1.9 (benzoyl); 7.96 dt, 2 H, J = 8.6, 1.9 (benzoyl).
2-Benzoyl-6-methoxy-3-methyl-1-benzofuran (1d). Yield 54%; m.p. 74–75 °C (ref. 4 76 °C). For
C17H14O3 (266.3) calculated: 76.68% C, 5.30% H; found: 76.34% C, 4.92% H. IR (KBr): 1 621
(C=O). UV, λ (log ε): 205 (4.42), 241 (4.03), 256 (4.11), 344 (4.33). 1H NMR (CDCl3): 2.61 s,
3 H (CH3); 3.88 s, 3 H (CH3O); 6.94 m, 2 H (H-5, H-7); 7.46–7.63 m, 4 H (H-4, benzoyl);
8.02 m, 2 H (benzoyl).

Preparation of 2-Benzoyl-1-benzofurans 1e, 1f. General Procedure

A mixture of 2-hydroxy-4,6-dimethoxybenzaldehyde (1.8 g, 10 mmol), an appropriate

2-bromo-1-phenylethan-1-one (10 mmol), potassium carbonate (2 g, 14 mmol) and
butan-2-one (50 ml) was refluxed for 6 h. The insoluble portion was filtered off, the filtrate
was evaporated and crystallized twice from ethanol (charcoal) to give the required product.

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 287

2-(4-Bromobenzoyl)-4,6-dimethoxy-1-benzofuran (1e). Yield 53%; m.p. 179–181 °C. For

C17H13BrO4 (361.2) calculated: 56.53% C, 3.63% H, 22.12% Br; found: 56.72% C, 3.52% H,
21.78% Br. UV, λ (log ε): 207 (4.56), 230 (3.92), 255 (4.04), 286 (3.89). 1H NMR (CDCl3):
3.87 s, 3 H (CH3O); 3.91 s, 3 H (CH3O); 6.34 d, 1 H, J = 1.9 (H-5); 6.69 dd, 1 H, J = 1.9, 1.0
(H-7); 7.52 d, 1 H, J = 1.0 (H-3); 7.64 dt, 2 H, J = 8.8, 2.0 (benzoyl); 7.88 dt, 2 H, J = 8.8, 2.0
(benzoyl).
2-Benzoyl-4,6-dimethoxy-1-benzofuran (1f). Yield 57%; m.p. 135–136 °C (ref. 5 140–141 °C).
For C17H14O4 (282.3) calculated: 72.33% C, 5.00% H; found: 72.50% C, 5.33% H. IR (KBr):
1 631 (C=O). UV, λ (log ε): 205 (4.44), 254 (4.14), 352 (4.28). 1H NMR (CDCl3): 3.87 s, 3 H
(CH3O); 3.91 s, 3 H (CH3O); 6.34 d, 1 H, J = 1.9 (H-5); 6.70 dd, 1 H, J = 1.9, 0.9 (H-7);
7.50 m, 3 H (benzoyl); 7.54 d, 1 H, J = 0.9 (H-3); 7.94 m, 2 H (benzoyl).

2-Hydroxy-3-methoxybenzonitrile (5b)

A mixture of 2-hydroxy-3-methoxybenzaldehyde (7.6 g, 50 mmol), hydroxylamine hydro-

chloride (4.4 g, 63 mmol), dry sodium acetate (4.5 g, 55 mmol), and anhydrous formic acid
(60 ml) was refluxed under nitrogen for 3 h. The mixture was evaporated under reduced
pressure, the residue was poured into water, the mixture was extracted with ether, the or-
ganic layer was washed with brine and dried with magnesium sulfate. The residue was puri-
fied by flash chromatography (petroleum ether–acetone, from 20 : 1 to 8 : 2) followed by
crystallization from hexane to give 5.6 g (75%) of white crystals, m.p. 56–57 °C (ref. 14
47–48 °C; ref. 26 59 °C). For C 8H7NO2 (149.1) calculated: 64.42% C, 4.73% H, 9.39% N;
found: 64.03% C, 4.83% H, 9.24% N. 1H NMR (CDCl3): 3.93 s, 3 H (CH3); 6.63 bs, 1 H (OH);
6.89 dd, 1 H, J = 8.4, 7.8 (H-5); 7.05 m, 2 H (H-4, H-6).

2-Hydroxy-4,6-dimethoxybenzonitrile (5c)

A mixture of 2-hydroxy-4,6-dimethoxybenzaldehyde (10 g, 55 mmol), hydroxylamine hy-

drochloride (4.4 g, 63 mmol), dry sodium acetate (4.5 g, 55 mmol), and anhydrous formic
acid (40 ml) was refluxed under nitrogen for 3 h. The mixture was worked up as above and
purified by flash chromatography (petroleum ether–acetone, 20 : 1) to give 3.35 g (33.5%)
of the starting aldehyde and 4.0 g (40%) of white crystals, m.p. 203–206 °C (ethanol–water,
1 : 1). For C9H9NO3 (179.2) calculated: 60.33% C, 5.06% H, 7.82% N; found: 60.12% C,
5.28% H, 7.56% N. 1H NMR (CDCl3): 3.87 s, 3 H (CH3); 3.95 s, 3 H (CH3); 6.05 d, 1 H, J =
2.0 (H-3 or H-5); 6.08 d, 1 H, J = 2.0 (H-3 or H-5); 10.95 bs, 1 H (OH). 13C NMR (CDCl3):
55.54 (CH3), 56.12 (CH3), 88.88 (C-1), 90.20 (C-5), 93.46 (C-3), 114.85 (CN), 162.52 (C-2),
163.01 (C-4), 164.73 (C-6).

Preparation of 2-(2-Oxo-2-phenylethoxy)benzonitriles 7. General Procedure

Method A. A solution of sodium hydroxide (1 g, 25 mmol) in water (2 ml) was added to a

stirred mixture of an appropriate 2-hydroxybenzonitrile 5 (25 mmol) and a 2-bromo-
1-phenylethan-1-one 6 (10 mmol) in 2-methoxyethan-1-ol (20 ml) and the mixture was
refluxed for 15 min. Then the mixture was cooled, the insoluble portion was filtered and
crystallized from ethanol to give 7.
Method B. A mixture of 2-hydroxybenzonitrile 5 (10 mmol), 2-bromo-1-phenyl-
ethan-1-one 6 (11 mmol), and potassium carbonate (1.5 g, 15 mmol) in DMF (20 ml) was

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

288 Rádl, Hezký, Urbánková, Váchal, Krejčí:

stirred at room temperature for 2 h. The mixture was poured into water (100 ml), the insolu-
ble portion was filtered off, washed with water and crystallized from ethanol to give pure 7.
2-(2-Oxo-2-phenylethoxy)benzonitrile (7a). Yield 83% (Method A), 79% (Method B); white
crystals, m.p. 147–148 °C (ref. 12 148–149 °C). For C 15H11NO2 (237.3) calculated: 75.94% C,
4.67% H, 5.90% N; found: 75.57% C, 4.74% H, 6.01% N. 1H NMR (CDCl3): 5.43 s, 2 H
(CH2); 6.83 d, 1 H, J = 8.5 (H-3); 7.03 dt, 1 H, J = 7.5, 1.0 (H-5); 7.54 m, 5 H (H-4, H-6, H-3′,
H-4′, H-5′); 8.01 bd, 2 H (H-2′, H-6′).
2-[2-(4-Bromophenyl)-2-oxoethoxy]benzonitrile (7b). Yield 57% (Method A); white crystals,
m.p. 141–150 °C (ref. 12 164–165 °C; crystallized from CHCl 3 –CCl 4 ). For C 15 H 10 BrNO 2
(316.1) calculated: 56.99% C, 3.19% H, 25.27% Br, 4.43% N; found: 56.67% C, 3.44% H,
24.89% Br, 4.57% N. IR (KBr): 1 692 (C=O), 2 223 (CN).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]benzonitrile (7c). Yield 82% (Method A); white crystals,
m.p. 148–151 °C. For C 21H15NO2 (313.4) calculated: 80.49% C, 4.82% H, 4.47% N; found:
80.19% C, 5.01% H, 4.43% N. IR (KBr): 1 688 (C=O), 2 226 (CN). UV, λ (log ε): 207 (4.72),
291 (4.52). 1H NMR (CDCl3): 5.44 s, 2 H (CH2); 6.85 d, 1 H, J = 7.8 (H-3); 7.02 dt, 1 H, J =
7.8, 1.6 (H-4); 7.46 m, 4 H (H-5, H-2′′, H-4′′, H-6′′); 7.57 dd, 1 H, J = 7.5, 1.6 (H-6); 7.62 bd,
2 H (H-3′′, H-5′′); 7.72 d, 2 H, J = 8.5 (H-3′, H-5′); 8.08 d, 2 H, J = 8.5 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]benzonitrile (7d). Yield 49% (Method B); white
crystals, m.p. 141–143 °C. For C 21H13F2NO2 (349.3) calculated: 72.20% C, 3.75% H, 10.88% F,
4.01% N; found: 72.13% C, 4.09% H, 10.57% F, 3.57% N. 1H NMR (CDCl3): 5.44 s, 2 H
(CH2); 6.86 d, 1 H, J = 8.5 (H-3); 6.99 m, 3 H (H-5, H-3′′, H-5′′); 7.46 m, 2 H (H-4, H-6′′);
7.59 dd, 1 H, J = 7.9, 1.9 (H-6); 7.65 dd, 2 H, J = 8.5, 1.6 (H-3′, H-5′); 8.09 d, 2 H, J = 8.5
(H-2′, H-6′). 19F NMR (CDCl3): –109.68 (F-2′′), –113.21 (F-4′′).
3-Methoxy-2-(2-oxo-2-phenylethoxy)benzonitrile (7e). Yield 67% (Method B); white crystals,
m.p. 83–84 °C. For C 16H13NO3 (267.3) calculated: 71.90% C, 4.90% H, 5.24% N; found:
71.66% C, 4.68% H, 5.02% N. 1H NMR (CDCl3): 3.77 s, 3 H (CH3); 5.50 s, 2 H (CH2);
7.09–7.17 m, 3 H (H-4, H-5, H-6); 7.49 m, 2 H (H-3′, H-5′); 7.60 m, 1 H (H-4′); 7.97 m, 2 H
(H-2′, H-6′).
3-Methoxy-2-[2-(4-bromophenyl)ethoxy-2-oxo]benzonitrile (7f). Yield 79% (Method B); white
crystals, m.p. 132–133 °C. For C 16H12BrNO3 (346.2) calculated: 55.51% C, 3.49% H, 23.08%
Br, 4.05% N; found: 55.49% C, 3.68% H, 23.55% Br, 3.60% N. 1H NMR (CDCl3): 3.78 s, 3 H
(CH3); 5.41 s, 2 H (CH2); 7.09–7.17 m, 3 H (H-4, H-5, H-6); 7.63 d, 2 H, J = 8.7 (H-3′, H-5′);
7.86 d, 2 H, J = 8.7 (H-2′, H-6′).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]-3-methoxybenzonitrile (7g). Yield 87% (Method B); white
crystals, m.p. 122–125 °C. For C 22H17NO3 (343.4) calculated: 76.95% C, 4.99% H, 4.08% N;
found: 76.82% C, 5.33% H, 3.71% N. IR (KBr): 1 693 (C=O), 2 231 (CN). UV, λ (log ε): 208
(4.68), 289 (4.41). 1H NMR (CDCl3): 3.79 s, 3 H (CH3); 5.52 s, 2 H (CH2); 7.09–7.18 m, 3 H
(H-4, H-5, H-6); 7.45 m, 3 H (H-3′′, H-4′′, H-5′′); 7.63 m, 2 H (H-2′′, H-6′′); 7.71 d, 2 H, J =
8.3 (H-3′, H-5′); 8.06 d, 2 H, J = 8.3 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]-3-methoxybenzonitrile (7h). Yield 77% (Method B);
white crystals, m.p. 126–128 °C. For C 22H15F2NO3 (379.4) calculated: 69.65% C, 3.99% H,
10.02% F, 3.69% N; found: 69.57% C, 4.24% H, 9.67% F, 3.51% N. IR (KBr): 1 674 (C=O),
232 (CN). UV, λ (log ε): 209 (4.72), 282 (4.30). 1H NMR (CDCl3): 3.80 s, 3 H (CH3); 5.51 s,
2 H (CH2); 6.97 m, 2 H (H-3′′, H-5′′); 7.10–7.18 m, 3 H (H-4, H-5, H-6); 7.44 m, 1 H (H-6′′);
7.63 dd, 2 H, J = 8.8, 1.6 (H-3′, H-5′); 8.06 d, 2 H, J = 8.8 (H-2′, H-6′). 19F NMR (CDCl3):
–109.76 (F-2′′), –113.19 (F-4′′).

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 289

4,6-Dimethoxy-2-(2-oxo-2-phenylethoxy)benzonitrile (7i). Yield 95% (Method B); white crys-

tals, m.p. 148–150 °C. For C 17H15NO4 (297.3) calculated: 68.68% C, 5.09% H, 4.71% N;
found: 68.86% C, 5.24% H, 4.62% N. IR (KBr): 1 701 (C=O), 2 220 (CN). UV, λ (log ε): 205
(4.57), 216 (4.60), 250 (4.44). 1H NMR (CDCl3): 3.78 s, 3 H (CH3O); 3.87 s, 3 H (CH3O);
5.33 s, 2 H (CH2); 5.96 d, 1 H, J = 1.9 (H-3 or H-5); 6.08 d, 1 H, J = 1.9 (H-3 or H-5); 7.50 bt,
2 H (H-3′, H-5′); 7.62 bt, 1 H (H-4′); 8.01 bd, 2 H (H-2′, H-6′).
2-[2-(4-Bromophenyl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7j). Yield 99% (Method B);
white crystals, m.p. 191–192 °C. For C 17H14BrNO4 (376.2) calculated: 54.28% C, 3.75% H,
21.24% Br, 3.72% N; found: 54.59% C, 3.84% H, 21.09% Br, 3.59% N. IR (KBr): 1 694
(C=O), 2 217 (CN). UV, λ (log ε): 205 (4.44), 216 (4.62), 258 (4.52). 1H NMR (CDCl3): 3.79 s,
3 H (CH3); 3.87 s, 3 H (CH3); 5.26 s, 2 H (CH2); 5.96 d, 1 H, J = 2.2 (H-3 or H-5); 6.08 d,
1 H, J = 2.2 (H-3 or H-5); 7.65 d, 2 H, J = 8.5 (H-3′, H-5′); 7.90 d, 2 H, J = 8.5 (H-2′, H-6′).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7k). Yield 29% (Method B);
creamy crystals, m.p. 142–143 °C. For C 23H19NO4 (373.4) calculated: 73.98% C, 5.13% H,
3.75% N; found: 73.65% C, 5.20% H, 3.94% N. IR (KBr): 1 688 (C=O), 2 219 (CN). 1H NMR
(CDCl3): 3.79 s, 3 H (CH3); 3.87 s, 3 H (CH3); 5.35 s, 2 H (CH2); 5.99 d, 1 H, J = 2.2 (H-3 or
H-5); 6.08 d, 1 H, J = 2.2 (H-3 or H-5); 7.44 m, 3 H (H-3′′, H-4′′, H-5′′); 7.63 m, 2 H (H-2′′,
H-6′′); 7.72 d, 2 H, J = 8.2 (H-3′, H-5′); 8.10 d, 2 H, J = 8.2 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7l). Yield 44%
(Method B); creamy crystals, m.p. 142–146 °C. For C 23H17F2NO4 (409.4) calculated: 67.48%
C, 4.19% H, 9.28% F, 3.42% N; found: 67.66% C, 4.34% H, 8.92% F, 3.25% N. IR (KBr):
1 689 (C=O), 2 215 (CN). UV, λ (log ε): 217 (4.67), 260 (4.41). 1H NMR (CDCl3): 3.79 s, 3 H
(CH3); 3.87 s, 3 H (CH3); 5.35 s, 2 H (CH2); 5.99 d, 1 H, J = 1.9 (H-3 or H-5); 6.08 d, 1 H, J =
1.9 (H-3 or H-5); 6.96 m, 2 H (H-3′′, H-5′′); 7.44 m, 1 H (H-6′′); 7.64 dd, 2 H, J = 8.5, 1.6
(H-3′, H-5′); 8.09 d, 2 H, J = 8.5 (H-2′, H-6′). 19F NMR (CDCl3): –109.80 (F-2′′), –113.18
(F-4′′).

Preparation of 2-Benzoyl-1-benzofuran-3-amines 2. General Procedure

Sodium methoxide (0.55 g, 10 mmol) was added to a stirred solution of 7 (10 mmol) in
methanol (20 ml) and the mixture was stirred at room temperature for 30 min. The mixture
was poured into water (25 ml), the insoluble portion was filtered off, washed with water and
crystallized from ethanol to give 2.
2-Benzoyl-1-benzofuran-3-amine (2a). Yield 89%; yellow crystals, m.p. 124–126 °C (ref. 12
125–126 °C). For C 15 H 11 NO 2 (237.3) calculated: 75.94% C, 4.67% H, 5.90% N; found:
76.11% C, 4.53% H, 5.97% N. IR (KBr): 1 621 (C=O); 3 296, 3 422 (NH2). UV, λ (log ε): 208
(4.13), 252 (4.23), 312 (3.99), 380 (4.26).
2-(4-Bromobenzoyl)-1-benzofuran-3-amine (2b). Yield 90%; yellow crystals, m.p. 198–200°C
(ref.12 203–204 °C). For C 15H10BrNO2 (316.1) calculated: 56.99% C, 3.19% H, 25.27% Br,
4.43% N; found: 56.90% C, 3.26% H, 24.88% Br, 4.03% N. IR (KBr): 1 613 (C=O); 3 297,
3 420 (NH2). UV, λ (log ε): 203 (4.32), 221 (4.10), 357 (4.28), 314 (3.98), 385 (4.33). 1H NMR
(CDCl3, 60 °C): 5.83 bs, 2 H (NH2); 7.30 m, 1 H (H-5); 7.47 m, 1 H (H-7); 7.56 m, 1 H (H-6);
7.65 m, 1 H (H-4); 7.69 d, 2 H, J = 8.8 (benzoyl); 8.17 d, 2 H, J = 8.8 (benzoyl).
2-(Biphenyl-4-ylcarbonyl)-1-benzofuran-3-amine (2c). Yield 87%; yellow crystals, m.p.
167–169 °C. For C 21H15NO2 (313.4) calculated: 80.49% C, 4.82% H, 4.47% N; found: 80.38% C,
5.00% H, 4.29% N. IR (KBr): 1 615 (C=O); 3 316, 3 418 (NH2). UV, λ (log ε): 206 (4.56), 226
(4.19), 249 (4.12), 295 (4.22), 387 (4.31). 1H NMR (CDCl3, 60 °C): 6.01 bs , 2 H (NH2);

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

290 Rádl, Hezký, Urbánková, Váchal, Krejčí:

7.22 m, 1 H (H-5); 7.41 m, 4 H (H-6, H-7, H-3′′, H-4′′, H-5′′); 7.61 m, 3 H (H-4, H-2′′, H-6′′);
7.72 d, 2 H, J = 8.2 (H-3′, H-5′); 8.33 d, 2 H, J = 8.2 (H-2′, H-6′).
2-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]-1-benzofuran-3-amine (2d). Yield 51%; yellow crys-
tals, m.p. 173–176 °C. For C 21H13F2NO2 (349.3) calculated: 72.20% C, 3.75% H, 10.88% F,
4.01% N; found: 72.13% C, 4.02% H, 10.98% F, 3.75% N. IR (KBr): 1 613 (C=O); 3 304,
3 406 (NH2). UV, λ (log ε): 204 (4.57), 224 (4.22), 258 (4.24), 284 (4.18), 386 (4.33). 1H NMR
(CDCl3, 60 °C): 6.03 bs, 2 H (NH2); 6.94 m, 2 H (H-3′′, H-5′′); 7.24 bt, 1 H (H-5); 7.46 m, 3 H
(H-6, H-7, H-6′′); 7.63 m, 3 H (H-4, H-3′, H-5′); 8.33 d, 2 H, J = 8.2 (H-2′, H-6′). 19F NMR
(CDCl3): –110.91 (F-2′′), –113.06 (F-4′′).
2-Benzoyl-7-methoxy-1-benzofuran-3-amine (2e). Yield 75%; yellow crystals, m.p. 166–168 °C.
For C16H13NO3 (267.3) calculated: 71.90% C, 4.90% H, 5.24% N; found: 71.99% C, 5.01% H,
5.26% N. IR (KBr): 1 621 (C=O); 3 316, 3 442 (NH2). UV, λ (log ε): 204 (4.39), 251 (4.34),
319 (3.90), 380 (4.25). 1H NMR (CDCl3): 3.99 s, 3 H (CH3); 6.01 bs, 2 H (NH2); 6.96 dd, 1 H,
J = 6.8, 2.0 (H-6); 7.16 m, 2 H (H-4, H-5); 7.49 dd, 3 H, J = 5.2, 1.9 (H-3′, H-5′); 8.27 m, 2 H
(H-2′, H-6′).
2-(4-Bromobenzoyl)-7-methoxy-1-benzofuran-3-amine (2f). Yield 64%; yellow crystals, m.p.
201–204°C. For C 16H12BrNO3 (346.2) calculated: 55.51% C, 3.49% H, 23.08% Br, 4.05% N;
found: 55.30% C, 3.60% H, 23.27% Br, 3.88% N. IR (KBr): 1 620 (C=O); 3 322, 3 440 (NH2).
1
H NMR (CDCl3, 60 °C): 4.01 s, 3 H (CH3); 5.94 bs, 2 H (NH2); 6.98 m, 1 H (H-6); 7.18 m, 2 H
(H-4, H-5); 7.65 d, 2 H, J = 7.9 (H-3′, H-5′); 8.16 d, 2 H, J = 7.9 (H-2′, H-6′).
2-(Biphenyl-4-ylcarbonyl)-7-methoxy-1-benzofuran-3-amine (2g). Yield 92%; yellow crystals,
m.p. 208–210 °C. For C 22H17NO3 (343.4) calculated: 76.95% C, 4.99% H, 4.08% N; found:
77.27% C, 5.39% H, 3.92% N. 1H NMR (CDCl3): 4.03 s, 3 H (CH3); 5.99 bs, 2 H (NH2); 7.00 m,
1 H (H-6); 7.20 m, 2 H (H-4, H-5); 7.39 tt, 1 H (H-4′′); 7.48 m, 2 H (H-3′′, H-5′′); 7.68 m, 2 H
(H-2′′, H-6′′); 7.76 bd, 2 H, J = 8.6 (H-3′, H-5′); 8.37 bd, 2 H, J = 8.6 (H-2′, H-6′).
2-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]-7-methoxy-1-benzofuran-3-amine (2h). Yield 97%; yel-
low crystals, m.p. 178–180 °C. For C 22H15F2NO3 (379.4) calculated: 69.65% C, 3.99% H,
10.02% F, 3.69% N; found: 69.27% C, 4.22% H, 9.79% F, 3.49% N. IR (KBr): 1 617 (C=O);
3 348, 3 449 (NH2). UV, λ (log ε): 204 (4.58), 253 (4.22), 281 (4.22), 321 (3.92), 387 (4.34).
1
H NMR (CDCl3, 60 °C): 4.03 s, 3 H (CH3); 6.02 bs, 2 H (NH2); 6.96 m, 2 H (H-3′′, H-5′′);
7.00 m, 1 H (H-6); 7.20 m, 2 H (H-4, H-5); 7.48 m, 1 H (H-6′′); 7.67 bdd, 2 H, J = 8.5, 1.6
(H-3′, H-5′); 8.36 bd, 2 H, J = 8.5 (H-2′, H-6′). 19F NMR (CDCl3): –110.98 (F-2′′), –113.28
(F-4′′).
2-Benzoyl-4,6-dimethoxy-1-benzofuran-3-amine (2i). Yield 92%; yellow crystals, m.p.
112–113 °C. For C 17H15NO4 (297.3) calculated: 68.68% C, 5.09% H, 4.71% N; 68.54% C,
5.27% H, 4.73% N. IR (KBr): 1 624 (C=O); 3 333, 3 435 (NH2). UV, λ (log ε): 204 (4.44), 255
(4.20), 311 (3.90), 384 (4.41). 1H NMR (CDCl3, 60 °C): 3.83 s , 3 H (CH3O); 3.92 s, 3 H
(CH3O); 6.20 d, 1 H, J = 1.6 (H-5); 6.39 bs, 2 H (NH2); 6.47 d, 1 H, J = 1.6 (H-7); 7.47 m, 3 H
(benzoyl); 8.17 m, 2 H (benzoyl).
2-(4-Bromobenzoyl)-4,6-dimethoxy-1-benzofuran-3-amine (2j). Yield 95%; yellow crystals,
m.p. 225–226 °C. For C 17H14BrNO4 (376.2) calculated: 54.28% C, 3.75% H, 21.24% Br,
3.72% N; found: 54.56% C, 3.85% H, 21.06% Br, 3.66% N. IR (KBr): 1 624 (C=O); 3 331,
3 452 (NH2). UV, λ (log ε): 204 (4.37), 259 (4.17), 312 (3.84), 388 (4.35). 1H NMR (CDCl3):
3.84 s, 3 H (CH3); 3.92 s, 3 H (CH3); 6.20 d, 1 H, J = 1.9 (H-5); 6.42 bs, 2 H (NH2); 6.46 d,
1 H, J = 1.9 (H-7); 7.60 d, 2 H, J = 8.5 (H-3′, H-5′); 8.06 d, 2 H, J = 8.5 (H-2′, H-6′).
2-(Biphenyl-4-ylcarbonyl)-4,6-dimethoxy-1-benzofuran-3-amine (2k). Yield 75%; yellow crys-
tals, m.p. 177–183 °C. For C 23H19NO4 (373.4) calculated: 73.98% C, 5.13% H, 3.75% N;

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 291

found: 73.94% C, 5.20% H, 4.02% N. IR (KBr): 1 624 (C=O); 3 333, 3 456 (NH2). UV, λ (log ε):
205 (4.77), 224 (4.29), 260 (4.20), 285 (4.35), 391 (4.37). 1H NMR (CDCl3, 60 °C): 3.86 s, 3 H
(CH3); 3.98 s, 3 H (CH3); 6.20 d, 1 H, J = 1.8 (H-5); 6.44 bs, 2 H (NH2); 6.50 d, 1 H, J = 1.8
(H-7); 7.34–7.52 m, 3 H (H-3′, H-5′, H-4′′); 7.65–7.82 m, 4 H (H-2′′, H-3′′, H-5′′, H-6′′);
8.28 bd, 2 H, J = 8.4 (H-2′, H-6′).
2-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]-4,6-dimethoxy-1-benzofuran-3-amine (2l). Yield 55%;
yellow crystals, m.p. 199–201 °C. For C 23H17F2NO4 (409.4) calculated: 67.48% C, 4.19% H,
9.28% F, 3.42% N; found: 67.18% C, 4.15% H, 9.26% F, 3.10% N. IR (KBr): 1 628 (C=O);
3 326, 3 428 (NH2). UV, λ (log ε): 205 (4.55), 261 (4.28), 278 (4.28), 390 (4.42). 1H NMR
(CDCl3, 60 °C): 3.85 s, 3 H (CH3); 3.94 s, 3 H (CH3); 6.43 bs, 2 H (NH2); 6.22 d, 1 H, J = 1.9
(H-5); 6.49 d, 1 H, J = 1.9 (H-7); 6.94 m, 2 H (H-3′′, H-5′′); 7.45 m, 1 H (H-6′′); 7.61 dd, 2 H,
J = 8.2, 1.6 (H-3′, H-5′); 8.26 d, 2 H, J = 8.2 (H-2′, H-6′). 19F NMR (CDCl3): –111.30 (F-2′′),
–113.17 (F-4′′).

2-(Benzylsulfanyl)benzonitrile

A mixture of 2-fluorobenzonitrile (12 g, 0.1 mol), phenylmethanethiol (13.7 g, 0.11 mmol),

potassium carbonate (35 g, 0.25 mol), and butan-2-one (125 ml) was stirred at room temper-
ature under nitrogen. The insoluble portion was filtered off, the filtrate was evaporated to
dryness and purified twice by flash chromatography (silica gel, petroleum ether–acetone,
from 40 : 1 to 10 : 1) followed by crystallization from hexane to give 5.45 g (24%) of the title
compound; m.p. 59–61 °C (ref. 27 57–58 °C; ref. 16 62–64 °C). For C 14H11NS (225.3) calcu-
lated: 74.63% C, 4.93% H, 6.22% N, 14.23% S; found: 74.92% C, 5.24% H, 6.37% N,
14.17% S.

2-Sulfanylbenzonitrile (8)

A solution of 2-(benzylsulfanyl)benzonitrile (6.45 g, 28.6 mmol) in benzene (50 ml) was

added dropwise to a suspension of aluminum chloride (5.8 g, 43 mmol) in benzene (50 ml)
stirred under argon and the mixture was stirred at room temperature for 30 h. The mixture
was poured into cold water (150 ml) and the organic layer was washed with 5% solution of
sodium hydroxide (2 × 50 ml). The combined aqueous solution was acidified with 10%
hydrochloric acid and the mixture was extracted with ether (2 × 60 ml, 2 × 30 ml). The organic
extract was dried with anhydrous magnesium sulfate to give 3.6 g (93%) of the title com-
pound, which was used for further reactions without purification.

Preparation of 2-Benzoyl-1-benzothiophen-3-amines 3. General Procedure

Sodium hydride (0.5 g, 50% dispersion in mineral oil, 10 mmol) was added to a solution of
2-sulfanylbenzonitrile (8) (10 mmol) in DMF (30 ml) and the mixture was stirred under ar-
gon for 1 h. Then a solution of an appropriate 2-bromo-1-phenylethan-1-one 6 (10 mmol)
was added and the mixture was stirred at room temperature for 24 h. The mixture was
poured into water (250 ml), the insoluble portion was filtered off, washed with water and
crystallized from ethanol.
2-Benzoyl-1-benzothiophen-3-amine (3a). Yield 52%; yellow crystals, m.p. 124–125 °C (ref. 15
gives a different m.p. 103–104 °C). For C 15H11NOS (253.3) calculated: 71.12% C, 4.38% H,
5.53% N, 12.66% S; found: 71.28% C, 4.77% H, 5.47% N, 12.49% S. IR (KBr): 1 598 (C=O);
3 321, 3 433 (NH2). UV, λ (log ε): 204 (4.40), 279 (4.18), 310 (3.84), 319 (3.92), 404 (4.00).

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

292 Rádl, Hezký, Urbánková, Váchal, Krejčí:

1
H NMR (CDCl3): 7.04 bs, 2 H (NH2); 7.35 td, 1 H, J = 7.3, 1.2 (H-4′); 7.43–7.53 m, 4 H
(H-2′, H-3′, H-5′, H-6′); 7.70 m, 2 H (H-5, H-6); 7.98 dd, 2 H, J = 7.3, 1.5 (H-4, H-7).
2-(4-Bromobenzoyl)-1-benzothiophen-3-amine (3b). Yield 41%; yellow crystals, m.p. 119–124 °C.
For C15H10BrNOS (332.2) calculated: 54.23% C, 3.03% H, 24.05% Br, 4.22% N, 9.65% S;
found: 54.55% C, 3.17% H, 24.48% Br, 4.07% N, 9.58% S. IR (KBr): 1 602 (C=O); 3 318,
3 430 (NH2). UV, λ (log ε): 205 (4.33), 274 (4.11), 322 (3.82), 404 (4.12). 1H NMR (CDCl3):
7.05 bs, 2 H (NH2); 7.37–7.50 m, 2 H (H-2′, H-6′); 7.60–7.69 m, 4 H (arom. H, H-3′, H-5′);
7.75 m, 2 H (arom. H).

Preparation of Benzonitriles 10. General Procedure

Sodium hydride (0.5 g, 50% dispersion in mineral oil, 10 mmol) was added to a stirred
N-substituted 2-aminobenzonitrile 9 (10 mmol) in DMF (30 ml) and the mixture was stirred
for 1 h. Then a solution of an appropriate 2-bromo-1-phenylethan-1-one 6 (10 mmol) was
added and the mixture was stirred at room temperature for 2–24 h (TLC). The mixture was
poured into water (250 ml), the insoluble portion was filtered off, washed with water and
crystallized from a suitable solvent.
N-(2-Cyanophenyl)-N-(2-oxo-2-phenylethyl)methanesulfonamide (10a). Yield 86%; white crys-
tals, m.p. 189–192 °C (ethanol). For C 16H14N2O3S (314.4) calculated: 61.13% C, 4.49% H,
8.91% N, 10.20% S; found: 61.55% C, 4.32% H, 8.68% N, 9.92% S. IR (KBr): 1 153, 1 340 (SO2);
1 709 (C=O); 2 237 (CN). UV, λ (log ε): 204 (4.52), 243 (4.18). 1H NMR (CDCl3): 3.25 s, 3 H
(CH3); 5.28 s, 2 H (CH2); 7.48 m, 3 H (arom. H); 7.62–7.75 m, 3 H (arom. H); 7.93 d, 2 H, J =
7.5 (H-2, H-6, benzoyl); 8.00 d, 1 H, J = 8.5 (H-3, cyanophenyl).
N-[2-(4-Bromophenyl)-2-oxoethyl]- N-(2-cyanophenyl)methanesulfonamide (10b). Yield 88%;
white crystals, m.p. 154-159 °C (ethanol). For C 16H13BrN2O3S (393.2) calculated: 48.87% C,
3.33% H, 20.32% Br, 7.12% N, 8.15% S; found: 48.44% C, 3.21% H, 20.72% Br, 6.87% N,
7.76% S. IR (KBr): 1 158, 1 345 (SO2); 1 733 (C=O); 2 241 (CN). UV, λ (log ε): 205 (4.44),
248 (4.02). 1H NMR (CDCl3, 60 °C): 3.21 s, 3 H (CH 3); 5.20 s, 2 H (CH2); 7.46 dt, 1 H, J =
7.5, 1.3 (H-4, cyanophenyl); 7.61 d, 2 H, J = 8.8 (H-3, H-5, benzoyl); 7.67 m, 2 H (H-5, H-6,
cyanophenyl); 7.78 d, 2 H, J = 8.8 (H-2, H-6, benzoyl); 7.94 bd, 1 H (H-3, cyanophenyl).
N-(2-Cyanophenyl)-N-(2-oxo-2-phenylethyl)-4-methylbenzene-1-sulfonamide (10c). Yield 44%;
white crystals, m.p. 146–148 °C (methanol). For C 22H18N2O3S (390.5) calculated: 67.68% C,
4.65% H, 7.17% N, 8.21% S; found: 67.33% C, 4.91% H, 7.03% N, 8.05% S. IR (KBr): 1 162,
1 345 (SO2); 1 697 (C=O); 2 229 (CN). 1H NMR (CDCl3): 2.44 s, 3 H (CH3); 5.24 s, 2 H
(CH2); 7.30 d, 2 H, J = 8.05 (H-3, H-5); 7.40 m, 1 H (H-5, cyanophenyl); 7.48 d, 2 H, J = 8.05
(H-2, H-6); 7.60 m, 5 H (H-4, H-6, cyanophenyl; H-3, H-4, H-5, benzoyl); 7.79 dd, 1 H (H-3,
cyanophenyl); 7.92 m, 2 H (H-2, H-6, benzoyl).
N-[2-(4-Bromophenyl)-2-oxoethyl]-N-(2-cyanophenyl)-4-methylbenzenene-1-sulfonamide (10d).
Yield 40%; white crystals, m.p. 162-166 °C (ethanol). For C 22H17BrN2O3S (469.3) calculated:
56.30% C, 3.65% H, 17.02% Br, 5.97% N, 6.83% S; found: 55.99% C, 3.72% H, 16.85% Br,
5.86% N, 7.03% S. IR (KBr): 1 145, 1 352 (SO2); 1 694 (C=O); 2 235 (CN). 1H NMR (CDCl3):
2.44 s, 3 H (CH3); 5.17 s, 2 H (CH2); 7.26 m, 2 H (H-3, H-5); 7.31 t, 1 H, J = 7.8 (H-5,
cyanophenyl); 7.61 m, 6 H (H-2, H-6, H-3, H-4, cyanophenyl; H-2, H-6, benzoyl); 7.80 m,
3 H (H-6, cyanophenyl; H-3, H-5, benzoyl).

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 293

Preparation of N-(Alkanesulfonyl)-2-benzoylindol-3-amines 4a–4d. General Procedure

Method A. Sodium methoxide (55 mg, 1 mmol) was added to a stirred solution of 10 (1
mmol) in ethanol (5–20 ml) and the mixture was stirred at room temperature for 10 h. The
mixture was poured into water (25 ml), the insoluble portion was filtered off, washed with
water and crystallized from ethanol to give 4.
Method B. Triethylamine (0.2 g, 2 mmol) was added to a stirred solution of 10 (1 mmol)
in ethanol (5–20 ml) and the mixture was stirred at room temperature for 10 h. The mixture
was evaporated to dryness and crystallized from ethanol to give 4.
2-Benzoyl-1-(methanesulfonyl)indol-3-amine (4a). Yield 45% (Method A); yellow crystals,
m.p. 190–191 °C. For C 16H14N2O3S (314.4) calculated: 61.13% C, 4.49% H, 8.91% N, 10.20% S;
found: 60.68% C, 4.74% H, 8.57% N, 9.85% S. IR (KBr): 1 144, 1 339 (SO2); 1 631 (C=O); 3 333,
3 449 (NH2). UV, λ (log ε): 203 (4.44), 259 (4.08), 308 (3.67), 368 (4.13). 1H NMR (CDCl3):
2.43 s, 3 H (CH3); 6.01 bs, 2 H (NH2); 7.44 m, 4 H (H-4, H-5, H-6, H-4′); 7.62 m, 2 H (H-3′,
H-5′); 7.93 dd, 2 H, J = 7.6, 1.9 (H-2′, H-6′); 8.04 d, 1 H, J = 8.2 (H-7).
2-(4-Bromobenzoyl)-1-(methanesulfonyl)indol-3-amine (4b). Yield 59% (Method A); yellow
crystals, m.p. 208–212 °C. For C 16 H 13 BrN 2 O 3 S (393.2) calculated: 48.87% C, 3.33% H,
20.32% Br, 7.12% N, 8.15% S; found: 48.43% C, 3.11% H, 19.87% Br, 7.36% N, 8.43% S. IR
(KBr): 1 164, 1 345 (SO2); 1 620 (C=O); 3 349, 3 461 (NH2). UV, λ (log ε): 213 (4.41), 263
(4.24), 308 (3.80), 370 (4.19). 1H NMR (DMSO-d6): 2.51 s, 3 H (CH3); 7.16 bs, 2 H (NH2);
7.45 ddd, 1 H, J = 8.0, 7.3, 1.0 (H-6); 7.60 d, 2 H, J = 8.7 (H-3′, H-5′); 7.63 ddd, 1 H, J = 8.3,
7.3, 1.2 (H-5); 7.71 d, 2 H, J = 8.7 (H-2′, H-6′); 7.86 dt, 1 H, J = 8.3, 0.8 (H-4); 8.08 ddd, 1 H,
J = 8.0, 1.2, 0.8 (H-7).
2-Benzoyl-1-(4-methylbenzene-1-sulfonyl)indol-3-amine (4c). Yield 46% (Method A), 85%
(Method B); yellow crystals, m.p. 189–191 °C. For C 22H18N2O3S (390.5) calculated: 67.68% C,
4.65% H, 7.17% N, 8.21% S; found: 67.38% C, 4.84% H, 7.13% N, 8.08% S. IR (KBr): 1 172,
1 350 (SO2); 1 626 (C=O); 3 339, 3 449 (NH2). UV, λ (log ε): 203 (4.46), 257 (4.22), 308
(3.82), 372 (4.11). 1H NMR (CDCl3): 2.22 s, 3 H (CH3); 5.90 bs, 2 H (NH2); 6.96 d, 2 H, J = 8.0
(H-3, H-5, tosyl); 7.29 m, 4 H (H-4, H-5, H-2, H-6, tosyl); 7.49 m, 4 H (H-6, H-3′, H-4′, H-5′);
8.05 m, 2 H (H-2′, H-6′); 8.14 d, 1 H, J = 8.3 (H-7).
2-(4-Bromobenzoyl)-1-(4-methylbenzene-1-sulfonyl)indol-3-amine (4d). Yield 66% (Method A),
82% (Method B); yellow crystals, m.p. 187–195 °C. For C 22H17BrN2O3S (469.3) calculated:
56.30% C, 3.65% H, 17.02% Br, 5.97% N, 6.83% S; found: 55.87% C, 3.85% H, 16.77% Br,
5.77% N, 7.11% S. IR (KBr): 1 174, 1 355 (SO2); 1 623 (C=O); 3 333, 3 442 (NH2). UV, λ (log ε):
203 (4.56), 264 (4.31), 308 (3.71), 375 (4.10). 1H NMR (CDCl3): 2.23 s, 3 H (CH3); 5.93 bs,
2 H (NH2); 6.97 bd, 2 H, J = 8.3 (H-3, H-5, tosyl); 7.22–7.36 m, 4 H (H-5, H-6, H-2, H-6,
tosyl); 7.60 m, 3 H (H-7, H-3′, H-5′); 7.93 dt, 2 H, J = 8.6, 2.3 (H-2′, H-6′); 8.14 d, 1 H, J = 8.2
(H-7).

Preparation of 2-Benzoyl-1-(ethoxycarbonyl)indole-3-amines 4e, 4f. General Procedure

Sodium hydride (0.5 g, 50% dispersion in mineral oil, 10 mmol) was added to a solution of
2-aminobenzonitrile 9 (10 mmol) in DMF (30 ml) and the mixture was stirred for 1 h. Then
a solution of an appropriate 2-bromo-1-phenylethan-1-one 6 (10 mmol) was added and the mixture
was stirred at room temperature for 24 h. The mixture was poured into water (250 ml), the in-
soluble portion was filtered off, washed with water and crystallized from ethanol.
2-Benzoyl-1-(ethoxycarbonyl)indol-3-amine (4e). Yield 68%; yellow crystals, m.p. 129–131 °C
(ref. 18 131–133 °C). For C 18 H 16 N 2 O 3 (308.3) calculated: 70.12% C, 5.23% H, 9.09% N;

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

294 Rádl, Hezký, Urbánková, Váchal, Krejčí:

found: 69.98% C, 5.14% H, 8.68% N. IR (KBr): 1 612 (C=O); 1 726 (COO); 3 349, 3 467
(NH2). 1H NMR (CDCl3): 0.84 t, 3 H, J = 7.2 (CH3); 3.73 q, 2 H, J = 7.2 (CH2); 5.19 bs, 2 H
(NH2); 7.31 ddd, 1 H, J = 7.8, 7.2, 0.9 (H-4′); 7.38–7.48 m, 3 H (H-5, H-3′, H-5′); 7.55 ddd,
1 H, J = 8.4, 7.2, 1.2 (H-6); 7.62 ddd, 1 H, J = 7.8, 1.2, 0.8 (H-4); 7.76 m, 2 H (H-2′, H-6′);
8.21 dt, 1 H, J = 8.4, 0.8 (H-7).
2-(4-Bromobenzoyl)-1-(ethoxycarbonyl)indol-3-amine (4f).Yield 67%; yellow crystals, m.p.
118–120 °C. For C 18H15BrN2O3 (387.2) calculated: 55.83% C, 3.90% H, 20.63% Br, 7.23% N;
found: 55.52% C, 4.15% H, 21.17% Br, 6.93% N. IR (KBr): 1 612 (C=O); 1 722 (COO); 3 350,
3 390 (NH2). UV, λ (log ε): 213 (4.40), 263 (4.53), 308 (3.79), 370 (4.19). 1H NMR (CDCl3, 60 °C):
0.93 t, 3 H, J = 7.1 (CH3); 3.84 q, 2 H, J = 7.1 (CH2); 5.78 bs, 2 H (NH2); 7.31 bt, 1 H, J = 7.4
(H-5); 7.56 m, 6 H (H-4, H-6, benzoyl); 8.20 d, 1 H, J = 8.3 (H-7).

2-Benzoylindol-3-amine (11a)

A solution of sodium hydroxide (0.4 g, 10 mmol) in water (2 ml) was added to a stirred so-
lution of 4e (0.31 g, 1 mmol) in ethanol (3 ml) and the mixture was refluxed for 10 min.
The mixture was evaporated to dryness, the residue was triturated with water (5 ml) and ex-
tracted with dichloromethane (2 x 5 ml). The extract was washed with water to neutral reac-
tion of the aqueous layer and dried with magnesium sulfate. The residue after evaporation
was crystallized three times from hexane to give 11a as a brown solid (0.15 g, 63%); m.p.
51–52 °C. The compound darkens on light. For C 15H12N2O (236.3) calculated: 76.25% C,
5.12% H, 11.86% N; found: 76.26% C, 5.49% H, 11.45% N. 1H NMR (CDCl3): 5.57 bs, 2 H
(NH2); 7.06 dt, 1 H (H-7); 7.21 bd, 1 H, J = 8.4 (H-4); 7.35 dt, 1 H (H-5); 7.45–7.60 m, 5 H
(H-1, H-6, benzoyl); 7.82 m, 2 H (benzoyl).

2-(4-Bromobenzoyl)indol-3-amine (11b)

According to the procedure described for compound 11a, compound 11b was obtained from
4f as a brown solid (51%); m. p. 44–46 °C (cyclohexane). The compound darkens on light.
For C 15 H 11 BrN 2 O (315.2) calculated: 57.16% C, 3.52% H, 25.35% Br, 8.89% N; found:
57.55% C, 3.64% H, 24.97% Br, 8.63% N. IR (KBr): 1 599 (C=O); 3 319, 3 435 (NH2). UV, λ (log ε):
204 (4.74), 228 (4.23), 264 (4.29), 333 (4.20), 426 (3.91). 1H NMR (CDCl3): 5.53 bs, 2 H
(NH2); 7.04 dt, 1 H, J = 8.0, 0.8 (H-7); 7.22 m, 1 H (H-4); 7.35 dt, 1 H, J = 8.1, 0.8 (H-5);
7.55–7.70 m, 6 H (H-1, H-6, benzoyl).

Biological Evaluation

Hot-Plate Test

The hot-plate test was used to measure the response latencies according to the method de-
scribed earlier28, with minor modifications. All animals (male NMRI mice) were selected on
the basis of their reactivity in the model. The selected animals were placed into a glass cyl-
inder and the plate temperature was maintained at 54 °C. The time necessary to induce the
licking reflex of the forepaws or jumping was recorded. The measurement was done 30 and
60 min after administration of 30 mg/kg of the tested compound and the results were ex-
pressed as prolongation of the licking latencies (%).

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles 295

Acetic Acid-Induced Writhing

Writhing was induced by intraperitoneal injection of 0.2 ml of 0.7% solution of acetic acid
to male NMRI mice 30 min after the administration of 30 mg/kg of the tested compound29.
Writhings were counted for 20 min, compared with the control and expressed as decrease in
the stretching movements (%).

Tail-Flick Test

A slightly modified method of D’Amour and Smith 30 was used. The animals (male
Wistar–Hannover rats) were placed in a Ugo Basile (Varese, Italy) apparatus and the predrug
latency to removal of the tail from a radiant heat source (light beam focused 3 cm from the
end of the tail) was determined twice for each rat. The animals were then administered the
appropriate tested compound (30 mg/kg) and were placed in the holding apparatus. Thirty
and sixty minutes later, a postdrug latency was measured. A postdrug latency was expressed
as a decrease in latency of the control (%).

The authors are indebted to T. Pilarčík and M. Bartůněk for the NMR, and Ms M. Švorčíková for the
UV and IR measurements. This work was supported by the Grant Agency of the Ministry of Industry
and Trade of the Czech Republic (grant No. PP-Z1/08) and by Léčiva Co. Praha.

REFERENCES

1. Vaz Z. R., Cechinel-Filho V., Yunes R. A., Calixto J. B.: J. Pharmacol. Exp. Ther. 1996, 278,
304.
2. Cechinel-Filho V., Vaz Z. R., Zunino L., Calixto J. B., Yunes R. A.: Eur. J. Med. Chem.
1996, 31, 833.
3. Livingstone R. in: Rodd’s Chemistry of Carbon Compounds (S. Coffey, Ed.), Vol. IV, Part A,
p. 83. Elsevier, Amsterdam 1973.
4. Mackenzie J. B. D., Robertson A., Bushra A., Towcis R.: J. Chem. Soc. 1949, 2057.
5. Hirota T., Fujita H., Sasaki K., Namba T., Hayakawa S.: Heterocycles 1986, 24, 771.
6. Bisagni M., Buu-Hoi N. P., Royer R.: J. Chem. Soc. 1955, 3693.
7. Sonn A., Bülow W.: Chem. Ber. 1925, 58, 1691.
8. Dean F. M., Robertson A.: J. Chem. Soc. 1953, 1241.
9. Srivastava S. D., Srivastava S. K.: Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1987, 26, 57.
10. Malterud K. E., Undheim J., Erdal J. E.: Tetrahedron Lett. 1985, 26, 4807.
11. Gillies I., Loft M.: Synth. Commun. 1988, 18, 191.
12. Gewald K., Jansch H.-J.: J. Prakt. Chem. 1973, 315, 779.
13. Vaidya V. P., Mahajan S. B., Agasimundin Y. S. : Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1981, 20, 391.
14. Rahman L. K. A., Scrowton R. M.: J. Chem. Soc., Perkin Trans. 1 1983, 2973.
15. Carrington D. E. L., Clarke K., Scrowston R. M.: J. Chem. Soc. C 1971, 3903.
16. Beck J. R.: J. Heterocycl. Chem. 1978, 15, 513.
17. Beugelmans R., Bois-Choussy M., Boudet B.: Tetrahedron 1983, 39, 4153.
18. Garcia E. E., Benjamin L. E., Fryer R. I.: J. Heterocycl. Chem. 1973, 10, 51.
19. Pirkle W. H., Simmons K. A.: J. Org. Chem. 1983, 48, 2520.

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

 296 Rádl, Hezký, Urbánková, Váchal, Krejčí:

20. Fišnerová L., Brůnová B., Kocfeldová Z., Tíkalová J., Matunová E., Grimová J.: Collect.
Czech. Chem. Commun. 1991, 56, 2373.
21. Abramovitch R. A., Knaus G. N., Uma V.: J. Org. Chem. 1974, 39, 1101.
22. Auwers K.: Chem. Ber. 1925, 58, 2081.
23. Schroeder H. E., Rigby G. W.: J. Am. Chem. Soc. 1949, 71, 2205.
24. Auwers K., Frese E.: Justus Liebigs Ann. Chem. 1926, 450, 273.
25. Brandt E. V., Ferreira D., Roux D. G.: J. Chem. Soc., Perkin Trans. 1 1981, 514.
26. Borsche W., Hahn-Weinheimer P.: Justus Liebigs Ann. Chem. 1950, 570.
27. Bates D. K.: J. Org. Chem. 1977, 42, 3452.
28. Eddy N. B., Leimbach D.: J. Pharmacol. Exp. Ther. 1953, 80, 385.
29. Koster R., Anderson M., De Beer J.: Fed. Proc. 1959, 18, 412.
30. D’Amour F. E., Smith D. L. J.: Pharmacol. Exp. Ther. 1941, 72, 74.

Collect. Czech. Chem. Commun. (Vol. 65) (2000)

The author has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate.