Synthesis of (3RS,3aSR,8aSR)-3-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one via the aza-Cope-Mannich rearrangement

Article abstract of DOI:10.1016/j.tet.2011.09.047

A convenient and scalable method for the preparation of (3RS,3aSR,8aSR)-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one based on the aza-Cope-Mannich rearrangement is described. This approach allows us to synthesize the target compound in nine steps in a high overall yield (42%) with complete stereocontrol and up to 100 g scale.

Full text of DOI:10.1016/j.tet.2011.09.047

Tetrahedron 67 (2011) 9214e9218
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Tetrahedron
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Synthesis of (3RS,3aSR,8aSR)-3-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one
via the aza-CopeeMannich rearrangement
*
Dmitry S. Belov, Evgeny R. Lukyanenko, Alexander V. Kurkin , Marina A. Yurovskaya
Department of Chemistry, Moscow State University, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2011
Received in revised form 23 August 2011
Accepted 12 September 2011
Available online 16 September 2011
A convenient and scalable method for the preparation of (3RS,3aSR,8aSR)-phenyloctahydrocyclohepta[b]
pyrrol-4(1H)-one based on the aza-CopeeMannich rearrangement is described. This approach allows us
to synthesize the target compound in nine steps in a high overall yield (42%) with complete stereocontrol
and up to 100 g scale.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aza-CopeeMannich
cis-Cyclohepta[b]pyrrolidine
Allyl protective group
Multigram preparation
Natural-like compounds
1. Introduction
Since the cis-cyclohepta[b]pyrrolidine scaffold was found in
many alkaloids with a broad spectrum of biological activities, it
started attracting considerable interest from medicinal chemists.
Such compounds as ajmaline, stemofoline, gelsemine, actinophyllic
acid, and daphnicyclidins were synthesized during the past years1
(Fig. 1). However, the total synthesis of such complex compounds
is a difficult task. At the same time natural-like scaffolds with re-
duced molecular complexity are of great interest nowadays. As
a result, compound 1 (Fig. 1) and analogous structures containing
two easily modified functional groups may be useful in the design
of natural-like compound libraries.
Fig. 1. Representative examples of cyclohepta[b]pyrrolidine-containing natural com-
pounds and the target molecule (R¼Ar, Het, Alk, H).
(35%). Almost all the steps of the synthesis are easy to put into
practice. The key step of this method is the aza-CopeeMannich
reaction of amino alcohol 3 with formalin proceeding under mild
conditions with complete stereochemical control of the formation
of three stereogenic centers of pyrrolidinocyclohexanone 2.
Using the scheme suggested by Overman for the synthesis of 1
(Scheme 2) we encountered a number of problems: (1) The in-
troduction of a protecting cyanomethyl group at the nitrogen atom
suggested in the original approach turned out to be extremely in-
effective for producing multigram amounts of the target product,
because the addition of the phenylcerium reagent to amino ketone
4 gives a 2.5:1 mixture of cis and trans isomers of amino alcohol 5
difficult to separate by column chromatography. (2) Treating the
mixture of the cis and trans isomers of amino alcohol 5 with AgNO3
2. Results and discussion
In our research aimed at obtaining new biologically active
compounds we have encountered a severe problem of developing
a convenient method for synthesizing multigram amounts of the
(3aRS,8aRS)-octahydrocyclohepta[b]pyrrol-4(1H)-one with various
aryl, hetaryl, and alkyl fragments at position 3. Analyzing the lit-
erature data we took notice of the method developed by Overman
et al2e4 for the preparation of compound 2dan intermediate for
the synthesis of (ꢀ)-pancracine (Scheme 1) in a high total yield
* Corresponding author. Tel.: þ7 495 939 1714; fax: þ7 495 939 2288; e-mail
address: kurkin@direction.chem.msu.ru (A.V. Kurkin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.047

D.S. Belov et al. / Tetrahedron 67 (2011) 9214e9218
9215
These facts led us to suggest that we needed another protecting
group to make the preparation of the aminoethanol moiety more
straightforward. Considering other protecting groups for our syn-
thetic approach we chose the allyl protection of the nitrogen atom.5
Our choice was due to the fact that, first, this group is readily in-
troduced by direct alkylation of the substrate with an excess of allyl
bromide, and second, this protecting group is easily removed by the
action of 1,3-dimethylbarbituric acid (DMBA) in the presence of
a catalytic amount of Pd(Ph3P)4.
The initial amino ketone 8 was obtained in three steps from
cyclohexene oxide in a high overall yield (w90%, Scheme 3). It is
noteworthy that all the steps require no chromatographic purifi-
cation. Besides, we tried to accomplish an alternative one-step
Scheme 1. Overman’s route to pancracine.
results in a mixture of equal amounts of cis amino alcohol 6, cis
amino acetal 7 and other products (from trans-5) difficult to sep-
arate by column chromatography. (3) The individual cis amino ac-
etal 7 cannot be transformed into 6 with a good yield. Even its
heating in an ultrasound bath for several hours under the condi-
tions of considerable dilution (c w0.1 M) stops after w50% con-
version giving a mixture of approximately equal amounts of
compounds cis 6 and cis 7. All the above difficulties make it im-
possible to obtain multigram amounts of compound 1 and con-
siderably lower the overall reaction yield.
synthesis of this compound from commercially available a-chlor-
ocyclohexanone and allylbenzylamine. Unfortunately, this was
unacceptable for our purposes, because the yield of compound 8
was only 40% after chromatographic purification.
The reaction of cerium phenylacetylenide with amino ketone 8
gives amino alcohol 9 (a mixture of cis and trans isomers, 3:1) in
90% yield. We found that, as the amount of cerium chloride with
respect to lithium phenylacetylenide was decreased from 1 equiv to
0.5 equiv, the yield and stereochemical result of this reaction did
not change. Decreasing the amount of cerium chloride used con-
siderably facilitates carrying out the reaction when working with
multigram amounts. Further decrease in the amount of cerium
chloride to 0.33 equiv results in side reactions, and the isolation of
compound 9 requires chromatographic purification. In order to
facilitate the procedure of phenylacetylene addition to amino ke-
tone 8 we made an attempt of replacing cerium phenylacetylenide
with lithium phenylacetylenide. However, the attempt was un-
successful: the yield was low, and the reaction gave a mixture of cis
and trans isomers 9 (1:1 ratio) difficult to separate by column
chromatography because of the small difference in chromato-
graphic mobility (D Rf <0.1). For the synthesis of multigram
amounts of 1 it is possible to neglect the separation of isomers 9 at
this step. It is considerably more convenient to separate the isomers
at a later step of the suggested scheme.
Unfortunately, the literature method5 for removing the pro-
tecting allyl group from substrate 9 (the 3:1 cisetrans mixture)
under the action of DMBA in the presence of catalytic amounts of
Pd(Ph3P)2Cl2 did not give the required amino alcohol 10. Instead,
pyrrole 11 was isolated in a high yield. We suppose that it is formed
from 10 as a result of intramolecular addition of the amino group to
the triple bond under the action of palladium followed by de-
hydration.6 So, at the next step we reduced the triple bond in
Scheme 2. Reagents and conditions: (a) PhCH2NH2, 150 ꢁC, 99%; (b) KCN, CH2O, HCl,
93%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢂ78 ꢁC to rt, 90%; (d) PhCCH, BuLi, CeCl3, THF,
ꢂ78 ꢁC, 95%; (e) AgNO3, H2O, EtOH, sonication; (f) H2O, EtOH, sonication, 50%.
Ph
HO
O
Cl
f
d
NH
Ph
cis- and trans-10
Ph
Ph
HO
e
HO
O
+
N
N
N
a-c
Ph
Ph
trans-9
Ph
3 : 1
8
cis-9
O
Ph
N
g,f
Ph
11
Ph
Ph
O
HO
HO
Ph
O
H
Ph
+
H
Ph
H
h
H
i
j
O
N
h
1*HCl
N
H
< 5 O
C
> 5 O
C
NH
Ph
cis-12
NH
Ph
trans-12
N
Ph
Ph
H
Ph
15
14
13
Scheme 3. Reagents and conditions: (a) PhCH2NH2, 150 ꢁC, 99%; (b) AllBr, K2CO3, CH3CN, 96%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢂ78 ꢁC to rt, 93%; (d) Bn(All)NH, K2CO3, CH3CN, 40%.
(e) PhCCH, BuLi, CeCl3, THF, ꢂ78 ꢁC, dr¼3:1, 90%; (f) [Pd(PPh3)2]Cl2 1%, N,N0-dimethylbarbituric acid, CH2Cl2, 94%; (g) 3 equiv NaAlH2(OCH2OCH3)2, THF, 0 ꢁC, 93%; (h) CSA, 2.2 equiv
CH2O, CH2Cl2, Na2SO4, 100% (i) BF3$Et2O, CH2Cl2, ꢂ10 ꢁC to rt, 95%; (j) H2, 1 atm, 10% Pd/C, MeOH, HCl, 90%.

9216
D.S. Belov et al. / Tetrahedron 67 (2011) 9214e9218
substrate 9 into the double bond, and then removed the protecting
allyl group. After the allyl deprotection, this sequence of trans-
formations gave compound 12 as a mixture of cis and trans isomers
(3:1 ratio) in a high overall yield (87%) for two steps.
1H;
million (
d
39.51 ppm, 13C). Chemical shifts are reported in parts per
); multiplicities are indicated by s (singlet), d (doublet), t
d
(triplet), q (quartet), m (multiplet), and br (broad). Coupling con-
stants, J, are reported in hertz. Infrared (IR) spectra were obtained
on FT-IR spectrometer. Flash column chromatography was per-
formed on 60e200 mesh silica gel. Analytical thin-layer chroma-
Treating the mixture of cis and trans 12 with 0.9 equiv of for-
malin in the presence of 0.1 equiv of CSA for 15 min at the tem-
perature below 5 ꢁC gives the mixture of only 13 and trans-12. The
transformation of cis-12 into 13 proceeds quantitatively. Due to the
considerable difference in chromatographic mobility 13 and trans-
12 were easily separated by column chromatography and isolated
in the individual state in 70% and 25% yields, respectively. It is
worth noting that increase of the reaction time and higher tem-
perature (>5 ꢁC) leads to the formation of a third component in the
reaction mixture: trans-fused bicyclic amino ketone 15 formed by
the aza-CopeeMannich reaction from trans amino alcohol 12. The
presence of amino ketone 15 in the reaction mixture considerably
complicated the chromatographic purification of 13, because amino
ketone 15 has an intermediate chromatographic mobility between
trans-12 and 13, which complicates the isolation of 13 in the in-
dividual state.
ꢀ
tography was performed with aluminum backed plates (60 A, F254).
THF was distilled from Na/benzophenone under argon. All mate-
rials were purchased from commercial sources and used without
purification. Reactions were carried out under an air atmosphere
unless otherwise stated. (1RS,2RS)-2-(benzylamino)cyclohexanol
was prepared according to reported procedure.7
4.2. Synthesis
4.2.1. (1RS,2RS)-2-[Allyl(benzyl)amino]cyclohexanol. Yield 43.1 g of
(1RS,2RS)-2-(benzylamino)cyclohexanol (0.21 mol) was dissolved
in acetonitrile (420 mL). Potassium carbonate (72.4 g, 2.5 equiv,
0.52 mol) and then allyl bromide (32.8 g, 1.3 equiv, 0.27 mol) were
added in one portion. The reaction mixture was warmed to
40e50 ꢁC and stirred 6 h at this temperature. The mixture was then
allowed to cool to room temperature, quenched with 500 mL of
water and then extracted with CH2Cl2 (3ꢃ100 mL). The organic
layer was dried over Na2SO4 and concentrated. The title compound
was obtained as a colorless liquid. Yield 49.5 g (96%); [Found: C,
78.02; H, 9.07; N, 5.67. C16H23NO requires C, 78.32; H, 9.45; N,
5.71%]; nmax (KBr) 3467, 3064, 3028, 2929, 2858, 1643, 1495, 1452,
The aza-CopeeMannich reaction of amino acetal 13 at ꢂ20 ꢁC
proceeds quantitatively and results in the formation of stereo-
chemically pure cis-fused amino ketone 14 (Scheme 4). Note that
increasing temperature to 0 ꢁC gives by-products, and the reaction
yield dramatically falls. After removal of the benzyl group from 14
the target amino ketone 1 was isolated in 90% yield. Thus, we
succeeded in accomplishing the suggested synthetical sequence.
1404, 1358, 1281, 1151, 1074, 987, 918, 873, 740, 700 cmꢂ1
; dH
(300 MHz, CDCl3) 7.35e7.24 (5H, m, Ph), 5.89e5.73 (1H, m), 5.17
(1H, d, J 16.9 Hz), 5.12 (1H, d, J 9.5 Hz), 3.89 (1H, d, J 13.9 Hz,
PhCHaHb), 3.90e3.73 (1H, br s, OH), 3.51e3.40 (1H, m), 3.36 (1H, d, J
13.9 Hz, PhCHaHb), 3.30e3.24 (1H, m), 2.98 (1H, dd, J 14.1, 8.4 Hz),
2.51e2.38 (1H, m), 2.17e2.03 (1H, m), 1.95e1.83 (1H, m), 1.83e1.66
(2H, m), 1.29e1.08 (4H, m); dC (100.6 MHz, CDCl3) 139.6, 136.8,
128.8 (2C), 128.4 (2C), 127.1, 117.3, 69.2, 65.0, 53.5, 52.8, 33.2, 25.5,
24.2, 22.6; m/z (Irel) 245 (3MHþ),186 (17),173 (16), 91 (100), 65 (14),
41 (46), 39 (21%).
Scheme 4. Possible conformation of transition state, R¼Bn.
The cis configuration of 14 was confirmed by the NOE-
correlation between protons 3a and 8a and the magnitude of
their coupling constant (w11 Hz). For the proton pairs 3-3a, 3-8a
NOE was not observed.
4.2.2. (2RS)-2-[Allyl(benzyl)amino]cyclohexanone (8). A solution of
Me2SO (73.0 mL, 1.03 mol, 2.2 equiv) in CH2Cl2 (100 mL) was added
dropwise to a solution of oxalyl chloride (47.5 mL, 0.56 mol,
1.2 equiv) in CH2Cl2 (850 mL) at ꢂ60 to ꢂ80 ꢁC. The resulting so-
lution was stirred for 10 min and a solution of (1RS,2RS)-2-[allyl(-
benzyl)amino]cyclohexanol (114.25 g, 0.47 mol) in 170 mL CH2Cl2,
was added dropwise at the same temperature. After 15 min, Et3N
(342 mL, 2.45 mol, 5.3 equiv) was added, and after 5 min the re-
action mixture was allowed to warm to ambient temperature.
Aqueous workup (CH2Cl2, Na2SO4) gave a title compound as
a slightly yellow oil. Yield 106.4 g (93%). 1H NMR and 13C NMR
spectra of 8 correspond to the literature.8
3. Conclusion
Thus, this scheme enabled the synthesis of 1 by nine pre-
paratively simple operations in a high overall yield (42%). Abso-
lutely all the steps of this scheme are easily scalable to amounts of
0.6e3 mol per one reaction, and they are carried out in an ordinary
5 L laboratory reactor. Due to the high yields an easy chromato-
graphic purification of the products is used only at three steps:
purification of amino alcohol 9 from the excess of phenylacetylene;
purification of amino alcohol cis-12 from diallylbarbituric acid
formed upon the removal of the protecting allyl group; and puri-
fication of amino acetal 13 from amino alcohol trans-12. At present
this scheme is being used for the production of (3aRS,8aRS)-octa-
hydrocyclohepta[b]pyrrol-4(1H)-one with other substituents at
position 3.
4.2.3. (1RS,2RS)-2-[Allyl(benzyl)amino]-1-(phenylethynyl)cyclo-
hexanol (9). Anhydrous CeCl3 was freshly prepared from 93.2 g of
CeCl3$7H2O (0.25 mol).9 Freshly distilled THF (510 mL) was added
rapidly to the cooled CeCl3 at 0 ꢁC and the resulting slurry was
stirred under Ar at room temperature for 24 h. In a separate flask
containing 56.2 g (0.55 mol) of phenylacetylene and 550 mL of THF
was added 200 mL of n-BuLi (2.5 M in hexane, 0.5 mol) dropwise at
ꢂ78 ꢁC and the resulting solution was maintained for 30 min at
0 ꢁC. This solution was then cooled to ꢂ78 ꢁC and transferred to the
precooled CeCl3 slurry in THF at ꢂ78 ꢁC via a cannula. The resulting
mixture was stirred for 1 h at ꢂ78 ꢁC before a solution of 8 (81.1 g,
0.33 mol) in 330 mL of THF was added dropwise at ꢂ78 ꢁC. The
mixture was stirred for 2 h at this temperature and than was
poured into water (400 mL) containing acetic acid (29 mL, 0.5 mol),
Et2O/hexane mixture (1:1, 400 mL). The organic layer was
4. Experimental section
4.1. General methods and materials
1H and 13C NMR spectra were recorded on 300 and 400 MHz
Bruker Avance spectrometers. Spectra were referenced to residual
chloroform (d d d 2.50 ppm,
7.28 ppm, 1H; 77.00 ppm, 13C) or DMSO (

D.S. Belov et al. / Tetrahedron 67 (2011) 9214e9218
9217
separated and water layer extracted with Et2O/hexane mixture (2:1,
2ꢃ200). Combined organic layers were dried over Na2SO4. Evapo-
ration of solvent gave the crude residue, which was purified by
means of flash chromatography on silica gel (mainly from excess of
phenylacetylene). The title compound was obtained as a mixture of
two diastereomers (3:1) in 90% yield (102.6 g). Analytical data
shown for main diastereomer. [Found: C, 83.39; H, 7.65; N, 4.25.
C24H27NO requires C, 83.44; H, 7.88; N, 4.05%]; nmax (KBr): 3527,
3446, 3061, 3026, 2935, 2858, 2798, 1599, 1491, 1444, 1367, 1140,
(15), 132 (12), 131 (24), 120 (24), 106 (27), 103 (19), 91 (100), 77 (18),
65 (21), 56 (12%).
4.2.6. (3aRS,7aRS)-3-Benzyl-7a-[(E)-2-phenylvinyl]octahydro-1,3-
benzoxazole (13). To a mixture containing 6 (182 g, 0.59 mol),
anhydrous Na2SO4 (286 g, 2 mol, 3.4 equiv), camphorsulfonic acid
(29 g, 0.12 mol, 0.21 equiv), and CH2Cl2 (590 mL) 98 mL of for-
malin (37% in water, 1.31 mol, 2.2 equiv) was added dropwise at
0
ꢁC. The reaction mixture was vigorously stirred at 23 ꢁC for 6 h.
1070.3, 1028, 970, 916, 756, 739, 692 cmꢂ1
;
dH (300 MHz, CDCl3)
The mixture was washed with saturated NaHCO3 solution
(500 mL) and dried (Na2SO4). Concentration gave 188 g an oil,
which was purified on silica gel flash chromatography using pe-
troleum/EtOAc (10:1) to furnish 131.9 g of 13 (70%) and unreacted
trans-12 (45 g, 25%). [Found: C, 82.32; H, 7.80; N, 4.17. C22H25NO
requires C, 82.72; H, 7.89; N, 4.38%]; nmax (KBr) 3026, 2932, 2857,
2802, 1681, 1494, 1448, 1226, 1072, 1029, 968, 745, 694; dH
(400 MHz, CDCl3) 7.52e7.23 (10H, m), 6.79 (1H, d, J 16.1 Hz), 6.43
(1H, d, J 15.9 Hz), 4.70 (1H, d, J 2.2 Hz), 4.19 (1H, d, J 2.2 Hz), 4.07
(1H, d, J 13.5 Hz), 3.40 (1H, d, J 13.4 Hz), 2.72 (1H, dd, J 3.9, 3.9 Hz),
2.09e1.97 (1H, m), 1.97e1.87 (1H, m), 1.87e1.70 (3H, m), 1.70e1.60
(1H, m), 1.52e1.38 (2H, m); dC (100.6 MHz, CDCl3) 139.3, 137.2,
131.9, 128.8, 128.6 (2C), 128.4 (2C), 128.2 (2C), 127.5, 127.1, 126.5
(2C), 85.9, 82.4, 65.9, 55.7, 33.4, 25.0, 22.7, 20.2; m/z (Irel) 319
(2MHþ), 131 (26), 117 (12), 115 (11), 106 (9), 105 (10), 104 (8), 103
(22), 92 (10), 91 (100), 77 (13), 65 (8), 41 (8%).
7.73e7.39 (4H, m), 7.38e7.16 (6H, m), 6.10e5.82 (1H, m), 5.33e4.99
(2H, m), 4.29 (1H, d, J 14.7 Hz), 3.80 (1H, d, J 14.7 Hz), 3.55 (1H, dd, J
15.2, 5.2 Hz), 3.26 (1H, dd, J 15.8, 6.6 Hz), 2.97 (1H, dd, J 8.9, 8.9 Hz),
2.45 (1H, br s, OH), 2.20e2.08 (1H, m), 1.94e1.72 (4H, m), 1.63e1.49
(2H, m), 1.41e1.18 (1H, m); dC (75.5 MHz, CDCl3) 141.3, 137.4, 131.7
(2C), 128.4 (2C), 128.3 (3C), 128.1 (2C), 126.7, 123.5, 116.6, 94.9, 83.5,
72.2, 64.9, 55.4, 55.3, 40.3, 25.8, 23.2, 20.9; m/z (Irel) 345 (2MHþ),
186 (32), 173 (29), 160 (26), 158 (24), 132 (30), 129 (23), 92 (24), 91
(100), 65 (28), 55 (26), 41 (76), 39 (22%).
4.2.4. (1RS,2RS)-2-[Allyl(benzyl)amino]-1-[(E)-2-phenylvinyl]cyclo-
hexanol. A solution of amino alcohol 9 (30 g, 0.087 mmol) and
217 mL of THF was slowly added dropwise to a solution of RedAl
(105 mL, 0.261 mmol, 3 equiv) in 217 mL of THF at 0 ꢁC. After gas
evolution subsided, the mixture was then allowed to warm to
room temperature and stirred overnight. Excess hydride was
quenched by successive dropwise addition 12 mL of water, 18 mL
10% NaOH and 12 mL of water to reaction mixture at ꢂ10 ꢁC. The
reaction mixture was allowed to warm to room temperature
stirred for an hour and then filtered through thin layer of silica.
The precipitate was washed with THF. The organic layer was
concentrated to give dark oil, which solidified upon standing
(28.4 g, 94%). Mp¼52 ꢁC; [Found: C, 82.79; H, 8.23; N, 4.26.
C24H29NO requires C, 82.95; H, 8.41; N, 4.03%]; nmax (KBr) 3562,
3460, 3061, 3026, 2931, 2856, 2800, 1641, 1601, 1493, 1448, 1367,
4.2.7. (3RS,3aRS,8aSR)-1-Benzyl-3-phenyloctahydrocyclohepta[b]
pyrrol-4(1H)-one (14). To a solution of 13 (169 g, 0.53 mol) in
CH2Cl2 (530 mL) BF3$Et2O (160 mL, 1.3 mol, 2.4 equiv) was added
dropwise at ꢂ20 ꢁC for 30 min and then the reaction solution was
allowed to warm to 23 ꢁC. After 15 min, the resulting solution was
washed with 1.0 N NaOH solution and water phase was extracted
with CH2Cl2 (2ꢃ100 mL). The organic portions were dried (Na2SO4)
and concentrated to give 160.8 g (95%) of a white solid compound.
The product was homogeneous by TLC analysis. Mp¼125e7 ꢁC;
[Found: C, 82.36; H, 7.54; N, 4.37. C22H25NO requires C, 82.72; H,
7.89; N, 4.38%]; nmax (KBr) 3424 (w), 2933, 1698, 1454, 1263, 1201,
1265, 1146, 1070, 966, 910, 743, 696 cmꢂ1
; dH (400 MHz, CDCl3)
7.45e7.21 (10H, m, 2Ph), 6.62 (1H, d, J 16.2 Hz), 6.36 (1H, d, J
16.2 Hz), 5.94e5.82 (1H, m), 5.19 (1H, dd, J 17.3, 0.9 Hz), 5.11 (1H,
d, J 10.3 Hz), 4.11 (1H, d, J 14.4 Hz), 3.55 (1H, d, J 14.4 Hz),
3.55e3.48 (1H, m), 3.06 (1H, dd, J 14.6, 7.5 Hz), 2.72e2.64 (1H, m),
1.96e1.53 (8H, m), 1.38e1.25 (1H, m); dC (100.6 MHz, CDCl3) 141.2,
139.1, 137.9, 137.6, 128.6 (4C), 128.2 (2C), 127.0, 126.6, 126.3 (2C),
1169, 1064, 757, 701 cmꢂ1
; dH (400 MHz, CDCl3) 7.37e7.31 (4H, m),
7.31e7.22 (5H, m), 7.22e7.16 (1H, m), 4.07 (1H, d, J 13.2 Hz), 3.85
(1H, ddd, J 11.30, 8.80, 6.60 Hz), 3.42 (1H, dd, J 10.3, 9.1 Hz), 3.29
(1H, d, J 13.0 Hz), 3.26 (1H, dd, J 8.8, 6.9 Hz), 3.07 (1H, ddd, J 2.40,
10.6, 10.6 Hz), 2.60e2.50 (1H, m), 2.42 (1H, dd, J 11.2, 8.90 Hz),
2.48e2.38 (1H, m), 2.05e1.94 (1H, m), 1.94e1.81 (2H, m), 1.81e1.72
(1H, m), 1.72e1.61 (1H, m), 1.56e1.44 (1H, m); dC (100.6 MHz,
CDCl3) 211.0, 142.2, 138.8, 128.8 (2C), 128.4 (2C), 128.3 (2C), 127.8
(2C), 127.0, 126.4, 64.6, 62.5, 60.5, 57.8, 42.6, 42.4, 29.9, 24.4, 24.2;
m/z (Irel) 319 (13MHþ), 277 (24), 262 (11), 235 (18), 234 (16), 209
(22), 144 (13), 115 (17), 91 (100), 65 (14%).
126.2, 116.3, 76.7, 63.9, 55.5, 55.0, 39.4, 26.1, 21.8, 21.4; m/z (Irel
)
347 (7MHþ), 186 (10), 160 (28), 131 (17), 103 (15), 92 (15), 91 (100),
77 (16), 65 (21), 55 (14), 41 (52), 39 (18%).
4.2.5. (1RS,2RS)-2-(Benzylamino)-1-[(E)-2-phenylvinyl]cyclohexanol
(12). To solution containing 32.1 g (92.3 mmol) (1RS,2RS)-2-
[allyl(benzyl)amino]-1-[(E)-2-phenylvinyl]cyclohexanol and 28.7 g
N,N0-dimethylbarbituric acid (183.8 mmol, 2 equiv) in l80 mL
CH2Cl2, 0.65 g of [Pd(PPh3)2]Cl2 (1 mol %) was added and under
argon. The mixture was stirred for 2e4 h under reflux (TLC control).
After cooling, the CH2Cl2 was extracted twice with 5% aqueous
K2CO3 to remove the unreacted NDMBA and its mono C-allyl de-
rivative. The organic phase was dried over Na2SO4 and concen-
trated. Purification flash column chromatography (1:5 CH2Cl2/
hexane) gave an oil, which solidified upon standing (26.3 g, 93%).
Mp¼65 ꢁC; [Found: C, 81.94; H, 8.02; N, 4.37. C21H25NO requires C,
82.04; H, 8.20; N, 4.56%]; nmax (KBr) 3059, 3024, 2912, 2850, 1682,
4.2.8. (3RS,3aRS,8aSR)-3-Phenyloctahydrocyclohepta[b]pyrrol-
4(1H)-one hydrochloride (1). A solution of 151 g of 14 in MeOH
(470 mL) was acidified with aqueous HCl to pH w3 (approximately
40 mL needed). Pd/C (l0%, 15 g) was added, and the mixture was
degassed and stirred under 1 atm of hydrogen gas at 30 ꢁC for 2 h.
The catalyst was then removed by filtration and the filtrate was
concentrated under reduced pressure. Recrystallization from eth-
anol 112.4 g (90%) gave white solid amine 9 in hydrochloride form.
Mp¼255e260 ꢁC (decomp.); [Found: C, 67.59; H, 7.40; N, 5.21.
C15H20NOCl requires C, 67.79; H, 7.58; N, 5.27%]; nmax (KBr) 3437
(w), 2929, 2866, 2740, 1701, 1632, 746, 699; dH (400 MHz, DMSO-d6)
10.10e9.50 (2H, br s), 7.40e7.28 (4H, m), 7.28e7.20 (1H, m), 4.22
(1H, dd, J 10.5, 10.5 Hz), 3.94e3.79 (2H, m), 3.56 (1H, dd, J 11.2,
6.8 Hz), 3.11 (1H, dd, J 11.5. 11.5 Hz), 2.61e2.52 (1H, m), 2.30e2.25
(1H, m), 2.07e1.98 (1H, m), 1.98e1.86 (1H, m), 1.81e1.70 (1H, m),
1.68e1.56 (1H, m), 1.56e1.43 (2H, m); dC (100.6 MHz, DMSO-d6)
208.8, 139.3, 129.0 (2C), 128.4 (2C), 127.6, 58.7, 58.6, 49.8, 43.1, 42.4,
1601,1460,1446, 995, 987, 814, 746, 698, cmꢂ1
; dH (400 MHz, CDCl3)
7.43e7.37 (2H, m, Ph), 7.37e7.29 (4H, m, Ph), 7.29e7.23 (4H, m, Ph),
6.81 (1H, d, J 15.8 Hz), 6.19 (1H, d, J 15.9 Hz), 3.85 (1H, d, J 13.3 Hz),
3.77 (1H, d, J 13.5 Hz), 3.70e3.20 (1H, br s), 2.65 (1H, dd, J 4.3,
10.8 Hz), 1.85e1.24 (9H, m); dC (100.6 MHz, CDCl3) 140.5, 137.2 (2C),
128.6 (2C), 128.5 (2C), 128.3, 127.9 (2C), 127.3, 127.0, 126.4 (2C), 73.1,
60.5, 51.5, 36.3, 27.3, 24.3, 20.8; m/z (Irel) 307 (8MHþ), 198 (13), 146

9218
D.S. Belov et al. / Tetrahedron 67 (2011) 9214e9218
29.1, 24.5, 23.3; m/z (Irel) 229 (11MHþ), 172 (15), 144 (27), 119 (100),
116 (19), 91 (19), 83 (12), 77 (12), 70 (13), 68 (23), 56 (18), 55 (16), 41
(21%).
Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18046e18053; (d) Martin, C. L.; Overman,
L. E.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 7568e7569; (e) Dunn, T. B.; Ellis, J.
M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett. 2009, 11, 5658e5661.
2. Overman, L. E.; Jacobsen, E. J. Tetrahedron Lett. 1982, 23, 2737e2740.
3. Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329e4336.
4. Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662e4672.
5. Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109e6113.
6. Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22, 4277e4278.
7. Schiffers, I.; Bolm, C. Org. Synth. 2008, 85, 106e117.
References and notes
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E.; Madin, A.; Meier, G. P.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.;
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