Chapter 15 1

CHAPTER 15

1. Give a mechanistic explanation for the following transformation:

1. This mechanistic rationale is taken from J. Org. Chem. 2004, 69, 112. Formation and trapping of the
enolate anion is followed by an Ireland-Claisen reagent. Hydrolysis liberates the carboxylic acid product
from the silyl-ester.

LiN(TMS)2 5
1
Me2t-BuSiCl
6
O HMPA , THF O PhH , reflux
O O O OSiMe2t-Bu
2

O O

OMe OMe
5 2
1 O
6 1 H2O
O O 5
O OSiMe2t-Bu
2 THF CO2H
CO2SiMe2t-Bu O
O O 6
OMe
OMe OMe

2. Give a mechanistic rationale for the transformation that accounts for one product being formed
preferentially and also accounts for the stereochemistry of both products.
2. Heating to 220 °C induces a vinyl-cyclopropane rearrangement, which is a [1,3]-sigmatropic carbon
shift. The allowed processes are a suprafacial inversion and an antarafacial retention migration.
Forbidden pathways are the suprafacial retention and the antarafacial inversion. The major product arises
by an allowed suprafacial inversion process, as indicated.

D
Allowed antarafacial Allowed suprafacial
D retention inversion
D
Ph
14% 86%
H Ph H
H Ph
see J. Org. Chem. 1999, 64, 3567
2 Organic Synthesis Solutions Manual

3. Explain the different stereochemical outcomes of these reactions:

3. As allene approaches the fused six-membered rings, the A strain imparted by the axial hydrogen atoms
destabilizes approach from that face. Approach is from the lower-energy bottom face. If attack occurred
from the top face, one six-membered ring would have to distort more to accommodate the ring flattening
induced by the presence of the fused four-membered ring (1.5.2). In the five-membered ring system, the
relatively planar cyclopentanone causes the second ring to distort, and the allene approaches opposite that
fragment. In both cases, the fact that two hydrogen atoms are coplanar with the carbon atoms and two
hydrogen atoms are perpendicular to that plane exacerbates the steric interactions when approaching the
conjugated ketone moiety.

H H H
H H H
H
H
H C H
H H C H
C
O C O
H C H H O
C O
H see Tetrahedron 1980, 36, 719; and 1975, 31, 4981, 1655

4. Explain the following transformation:

4. Upon heating, the cycloheptatriene unit undergoes an electrocyclic ring closure to give the
norcaradiene system via 1,5-sigmatropic shifts of the norcaradiene ring, the CMe(CO2Me) unit can
"walk" around the ring, as shown. Finally, the norcaradiene unit opens to give the new cycloheptatriene.

MeO2C
Me Me Me
CO2Me CO2Me
Me
Me Me

MeO2C Me MeO2C Me
Me
Me

see J. Am. Chem. Soc. 1999, 121, 4524

 Chapter 15 3

5. Explain the following transformation:

5. This transformation is taken from J. Am. Chem. Soc. 2004, 126, 2194. Initial oxidation to the
selenoxide (3.7.4), which did not spontaneously undergo syn-elimination product, but was isolated. Upon
heating, in the presence of DBU, the vinyl ether was formed and a Claisen rearrangement (15.5.5) led to
the observed product.

PhMe2Si Ph OTBS
PhMe2Si Ph
NaIO4 , MeOH OMe
O O
O O
NaHCO3 , H2O DBU , xylene
Ph sealed tube
Se 185 °C
SePh
O

Ph
PhMe2Si Ph Claisen
rearrangement
O
O O PhMe2Si

6. Draw a reasonable transition state for the following reaction.

6. This example is taken from Org. Lett. 2003, 5, 4037. This reaction proceeds by the enol form of the
keto-ester, which is stabilized by hydrogen-bonding with the keto moiety. The [3+3]-sigmatropic
rearrangement proceeds to give the keto-acid, and decarboxylation leads to the final product.

OBn

OBn OBn

OMOM neutral Al2O3

60 °C
OMOM OMOM
O O O O
O
O H O H
O OBn
O

-CO2
OMOM

O
4 Organic Synthesis Solutions Manual

7. Give the product for this reaction, and rationalize its formation.
7. When the starting material is viewed as a conformational drawing, it is clear that the carbonyl on the 8-
membered ring and the alkene unit of the cyclohexenone unit are in close proximity. With photolysis, a
Paterno-Büchi reaction is possible that forms another oxetane ring in the molecule, as shown.
AcO O Me OTES Me OTES
OTES OAc O OAc O
Me Me
Me Me
OAc hν OAc
O OBz OBz
Me O Me O
O
AcO Me Me
BzO see J. Org. Chem. 1997, 62, 4900
O O

8. Reaction of N-tosylimines and allylic sulfonium salts under basic conditions leads to aziridines in
this particular work. When the imine shown was treated with the sulfonium salt given in the
reaction, a mixture of aziridine and a dihydroazepine were formed. Draw both products and
explain formation of the dihydroazepine.
8. Sulfonium salts react with base to form sulfur ylids (12.5.2), and they reacted with ketones and
aldehydes to give epoxides. Sulfur ylids also react with imines to give aziridines, and this explains
formation of the aziridine product, as shown. Close inspection of this particular aziridine, however,
reveals that it is a 1,5-diene with a three-membered ring that can accelerate a Cope rearrangement
(15.5.4). Cope rearrangement leads to the dihydroazepine product shown.

Ts Ts Ts
SMe2 N
SMe2
KOH N N
Ph Ph SMe2 Cope-rearrangement
Ph
N Ts
Ph
Ph see J. Org. Chem. 1996, 61, 4641 Ph Ph Ph Ph

9. Use the tables in this chapter (where possible) to estimate the correct regiochemistry for the
products in the following reactions.
9. (a) Using the coefficients for a simple nitrile oxide, and estimating that the carbon bearing the alkyl
group on the alkyne will have the largest coefficient, the regiochemistry of the product can be estimated
as shown. See J. Chem. Soc., Chem. Commun. 1978, 962.
(b) The nitrile oxide reacts with the alkene moiety to give the product. Using the coefficients for
a simple nitrile oxide and the coefficients of prop-1-ene from Table 11.1 to approximate those of the
alkenyl aldehyde, the regiochemistry shown is predicted. See J. Am. Chem. Soc. 1978, 100, 7069.

HOMO
1.24 N
Me O
R C N O
0.81

LUMO
S
H2C C R1 CHO
* S
R = Me ; R1 = see structure
 Chapter 15 5

(c) The "carbanion" is within the ring, leading to the bicyclic product shown.

10. For each of the following reactions give the major product, with correct regiochemistry and
stereochemistry:
10.
O Ph
O
Ph N t-Bu
MOMO N
(a) OBn (b) t-Bu N (c)
O
Ph

Org. Lett. 2003, 5, 3839 see Tetrahedron 1999, 55, 11595 see J. Am. Chem. Soc. 1999, 121, 3845
Via internal Diels-Alder reaction Via a [1,5]-H shift
of an acylnitroso compound
OBn Me
OBn OH O
O

(d) (e) (f) O

SiMe3
Me Me
N H EtO2C
OBn
Angew. Chem. Int. Ed. 2002, 41, 4688 see J. Chem. Soc., Chem. Commun. 1973, 598 see Tetrahedron Lett. 2000, 41, 4173
SiPh2t-Bu
O H t-BuO H CO2Et
OBz
(g) (h) HN (i)

BnO Ot-Bu N
O O Br
H
J. Am. Chem. Soc. 2003, 125, 3793 J. Am. Chem. Soc. 2002, 124, 11342 Eur. J. Org. Chem. 2003, 4373

O O
O
(k) H
O (l)
OBn H
(j) [3,3]-sigmatropic
rearrangement Bn N t-BuMe2SiO 1.8:1 dr
CO2Bn H
O O
see Synthesis 1994, 601 J. Am. Chem. Soc. 2002, 124, 10998

O
OBn J. Org. Chem. 2003, 68, 3981
O
OMe
EtO2C
(m) (n) (o) H O
N N
H OTBS
Me
O
Org. Lett. 2002, 4, 1611 J. Am. Chem. Soc. 2005, 127, 18046 Tetrahedron 2002, 58, 6531

Me
(q) Ph
(p) (r)
Bn N
Bn N
O OH Ph
see J. Am. Chem. Soc. 1999, 121, 1976 Tetrahedron 2002, 58, 6179 see Synlett 1999, 590
Via Fries rearrangment & then cyclization
6 Organic Synthesis Solutions Manual

(s)

O
Tetrahedron Lett. 2004, 45, 9653
CO2Et

11. In each case, provide a suitable synthesis. Show all intermediate products and all reagents.
11. Some of the following problems were taken from published syntheses. If you devise your own
synthesis, you may find that some of the steps you used were tried in the literature and discussed. Other
solutions are possible, however. You may also devise a novel and useful alternative synthesis. In all
cases, your syntheses should be critiqued by and discussed with your instructor.

(a) All reagents are taken from the cited reference. The ketone is converted to an alkene by Horner-
Wadsworth-Emmons olefination ([Link]) and catalytic hydrogenation of the double bond is followed by
LiAlH4 reduction of the ester to an alcohol (7.6.1). Conversion of the alcohol to the bromide using
CBr4/PPh3 (3.4.1) allowed a substitution reaction with the methyl malonate anion (13.3.1), and Krapcho
decarboxylation gave the ester. Condensation with the anion from CH2Br2 was followed by an internal
Diels-Alder reaction (14.7) to give the target.

b c d
a O
O O
O
O
CO2Et EtO2C
HO

Me
e O O g O h
O f O
Br2HC
EtO2C
EtO2C Br
Br O Me
EtO2C O
(a) (EtO)2P)=CHNaCO2Et , toluene , reflux (b) H2 , Pd-C , EtOH (c) LiAlH4 , ether
(d) CBr4 , ether , PPh3 (e) MeCNa(CO2Et)2 , DMF , 100°C (f) LiCl , DMSO-H2O , 180 °C see Tetrahedron Lett. 2000, 41, 1375
(g) CH2Br2 , LDA , THF , -78 °C (h) CF3CH2ONa/CF3CH2OH , RT , 6 d

(b) All reagents are taken from the cited reference. When the amine is converted to the N-allyl
derivative, heating with BF3 led to a Claisen rearrangement (15.5.5), placing the allyl group on the
benzene ring. Protection of the amine as the N-Boc derivative ([Link]) is followed by oxidative cleavage
of the C=C unit with OsO4/periodate ([Link]), and reaction of the aldehyde with the vinyl Grignard
reagent shown to give an alcohol ([Link]). When the alcohol reacts with the ortho ester, a Johnson ester
Claisen rearrangement ([Link]) follows and deprotection of the amine gives the target.
 Chapter 15 7

a b c d N
N N N
N H
H Boc Boc
OHC

N N
N f g H
e
Boc
Boc see Tetrahedron 2000, 56, 2583

OH
MeO2C MeO2C
(a) allyl bromide , NEt3 , DMF (b) BF3•OEt2 , sulfolane , 210 °C (c) Boc2O , dioxoane (d) OsO4 , NaIO4 , aq THF (e) CH2=CMeBr , Mg , THF
(f) MeC(OMe)3 , EtCO2H , 110 °C (g) 4M HCl, dioxane

(c) All reagents are taken from the cited reference. An initial [3+2]-nitrone cycloaddition (15.4.4) is
followed by hydrogenation to give the amino alcohol. Acetylation of the amine incorporates the second
aryl unit, and Collins oxidation ([Link]) gives the ketone. Aldol condensation (13.4.1) leads to the lactam
and the indolizidine structure, and a final LiAlH4 reduction removes the lactam carbonyl (7.6.1) to give
the final product.

MeO N
N N
H OH
a O b c O d
OH MeO
MeO
MeO MeO
MeO MeO
MeO MeO OMe MeO OMe
MeO MeO MeO
N
O
MeO O e f

N N

O
MeO MeO
MeO OMe OMe OMe
(a) N O , toluene , reflux (b) H2, Pd-C, MeOH (c) (3,4-dimethoxyphenyl)acetyl chloride
see Synthesis 1999, 907
(d) Collins oxidation (e) KOH (f) LiAlH4 , AlCl3 , ether-THF

(d) All reagents are taken from Tetrahedron Lett. 2002, 43, 2297. An initial Wittig reaction ([Link])
generates the allyl vinyl ether required for a Claisen rearrangement (15.5.5). A Robinson annulation
sequence using methyl vinyl ketone (13.7.3) sets the cyclohexenone unit, and oxidative cleavage with
osmium tetroxide/sodium periodate ([Link]) liberates the aldehyde. Jones oxidation with chromium
trioxide in acetone/sulfuric acid gives the acid ([Link]), which forms the lactone under the reaction
conditions (4.2.3). Final reaction with methylamine converts the lactone to the N-methyl lactam (4.2.3).
8 Organic Synthesis Solutions Manual

MeO MeO MeO

MeO
a b c
MeO O MeO MeO
MeO CHO
CHO OMe O
O
MeO MeO
MeO
CHO O
d e f
MeO
MeO H
O
O
O N
O H
(a) CH2=CHCH2PCH2PPh3Cl , KOt-Bu , THF , 0 °C (b) xylene , reflux (c) MVK , cat EtOH/KOH , ether Me
(d) cat. OsO4 , 1.5 NaIO4 (e) Jones oxidation (f) MeNH2 , MeOH , 80 °C (sealed tube)

(e) All reagents are taken from J. Am. Chem. Soc. 2003, 125, 10772. A photo-[2+2]-cycloaddition gave
the four-membered ring (15.2.3), and heating with Zn led to elimination to the cyclobutene (7.11.6).
Reduction of the anhydride unit to the diol with LiAlH4 (7.6.1) was followed by protection of the
hydroxyl units and their benzyl ethers ([Link]). Dihydroxylation with OsO4 ([Link]) followed by Swern
oxidation ([Link]) gave the diketone, and a Grignard reaction ([Link]) led to the final target.

O O O OH OBn
Cl
a b c d
O O O

Cl
O O O OH OBn
OBn OBn HO
HO O
e f g OBn

OBn
HO O
OBn OBn HO
(a) ClCH=CHCl , hν , acetone (b) Zn , TMSCl, Ac2O , toluene , 85 °C (c) LiAlH4 , THF (d) 2 eq BnBr , 2 eq NaH , THF/DMF
(e) OsO4 , NMO , aq t-BuOH/t-BuOMe (f) (COCl)2 , DMSO , NEt3 , CH2Cl2 , -78 °C (g) 2 eq allylmagneisum bromide
 Chapter 15 9

(f) The reagents in steps b-i are taken from the cited reference. The actual starting material here was
cyclohexa-1,4-diene, but we begin with benzene, and a Birch reduction gives the diene. Generation of
dichloroketene and a [2+2]-cycloaddition gives the bicyclic ketone (15.2.1), and Zn/acetic acid are used to
reduce the chlorine atoms (7.11.6). Hydrogen peroxide reacts with the cyclobutanone to give the lactone
via a Baeyer-Villiger reaction (6.6.1), and enolate alkylation with LDA and MeI give the methylated
lactone (13.3.1). Reduction with Dibal-H ([Link]) gives the aldehyde-alcohol (which probably exists as
the hemi-acetal), but the aldehyde can be trapped as the dithiolane as shown ([Link]). Reaction with
Raney nickel removes the dithiane unit to give a methyl group, and a modified Chugaev sequence (3.7.3)
leads to the diene.

O O O O
Cl O O
a b H c H d H e H
Me
Cl
H H H H

CHO S S Me
OH OH
f Me g OH h Me i
Me
H H
H

(a) Na/NH3 /EtOH (b) CCl3COCl , Zn , ether (c) Zn , AcOH (d) H2O2 , AcOH (e) 1. LDA 2. MeI see J. Org. Chem. 1996, 61, 4617
(f) DIBAL-H (g) BF3•OEt2 , HSCH2CH2SH (h) Raney Ni , EtOH , trace acetone (i) 1. BuLi 2. PhOCSCl 3. heat

(g) Taken from J. Org. Chem. 2004, 69, 4185. Initial epoxidation with basic hydroperoxide (6.4.2) was
followed by bromination-elimination (2.5.2 and 3.5.1) to give the vinyl bromide. Addition of the
vinyllithium reagent to the carbonyl (11.6.4) was followed by trapping the alkoxide product with
propanoic anhydride to give the vinyl ether (4.2.3). Treatment with base induced the Ireland-Claisen
rearrangement ([Link]) to give the final product.

O O O
Br
Br O O
a b c,d e O
O O Br
OTMS
O MeO
MeO OMe MeO OMe MeO OMe MeO O
MeO OMe
(a) H2O2 , K2CO3 , aq THF (b) Br2 , NEt3 , hexane-ether (c) E-propenyl Li , THF (d) (EtCO)2O (e) KHMDS , TMSCl , ether , -78 °C → rt
10 Organic Synthesis Solutions Manual

12. In each case, devise a retrosynthetic strategy that will lead to a suitable starting material that
costs $1.00-5.00 per g. Show the complete synthesis, with all intermediate products and all
reagents.
12. As in Chapter 8, all syntheses should be discussed with your instructor. There may be many possible
syntheses based on different retrosynthetic analyses using reactions from all previous chapters.