Electroreductive five- and six-membered cyclization of aromatic β- And γ-imino esters derived from (S)-aspartic acid and (S)-glutamic acid

Article abstract of DOI:10.1016/j.tet.2012.01.100

The electroreduction of aromatic β-dimethylcarbamoyl-β-imino esters, prepared from (S)-aspartic acid, in the presence of chlorotrimethylsilane gave five-membered cyclized products, 1-benzoyl-4-hydroxy- 5-aryl-N,N-dimethylpyrrolidine-2-carboxamides and 5-(

Full text of DOI:10.1016/j.tet.2012.01.100

Tetrahedron 68 (2012) 2579e2589
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Electroreductive five- and six-membered cyclization of aromatic
esters derived from (S)-aspartic acid and (S)-glutamic acid
b- and g-imino
*
Yosei Takenaga, Yujiro Umesaki, Toshihiko Sakurai, Naoki Kise
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101, Koyama-cho Minami, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The electroreduction of aromatic b-dimethylcarbamoyl-b-imino esters, prepared from (S)-aspartic acid,
Received 19 January 2012
Received in revised form 31 January 2012
Accepted 31 January 2012
Available online 7 February 2012
in the presence of chlorotrimethylsilane gave five-membered cyclized products, 1-benzoyl-4-hydroxy-5-
aryl-N,N-dimethylpyrrolidine-2-carboxamides and 5-(dimethylcarbamoyl)-2-aryl-1H-pyrrol-3-yl ben-
zoates, depending on the post-treatment after the electroreduction. The electroreduction of aromatic
g-
dialkylcarbamoyl- -imino and -methoxylmethyl- -imino esters, prepared from (S)-glutamic acid, and
g
g
g
following transformation gave six-membered cyclized products, 1-benzoyl-5-hydroxy-N,N-dialkyl-6-
phenylpiperidine-2-carboxamides and 3-hydroxy-6-(methoxymethyl)-2-phenylpiperidin-1-yl)(phenyl)
methanones, respectively.
Keywords:
Electroreduction
Reductive cyclization
Imino esters
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrrolidines
Piperidines
1. Introduction
TMSO OR1
Ar
Ar
1) + e, TMSCl
2) BzCl/TEA
Reductive intramolecular coupling of imino esters is a efficient
method for thesynthesis of cyclic amines and has beenrealized byus
using electroreduction in the presence of chlorotrimethylsilane
(TMSCl). That is, we have reported that the electroreductive intra-
R2
N
CO2R1
Ar
N
Bz
R2
molecular coupling of aromatic
a-, b-, and g-imino esters gave
cyclized products as azetidines,1 pyrrolidines,2 and piperidines,2
respectively (Scheme 1). We also disclosed that the electro-
reductive coupling of aromatic imino diesters prepared from (S)-
aspartic acid and (S)-glutamic acid dimethyl diesters afforded aze-
tidines, inparticular, exclusively in the latter case (Scheme 2).3 These
results show that the four-membered cyclization is equivalent to the
five-membered cyclization and much more favorable than the six-
membered cyclization in the electroreductive intramolecular cou-
1) + e, TMSCl
O
2) ClCO2Me/TEA
n
CO2Me
N
n
Ar
N
3) H3O+
n = 1, 2
CO2Me
Scheme 1. Electroreductive intramolecular coupling of
a
-,
b-, and g-imino esters.
pling of the imino esters.4 Therefore, we investigated the other
and -imino esters derived from (S)-aspartic and (S)-glutamic acids
b-
g
electroreduction (Scheme 3). Although the six-membered cycliza-
tion of imino esters was presumed to be more difficult from the
results in Scheme 2, we also found that the electroreduction of ar-
omatic g-dialkylcarbamoyl-g-imino and g-methoxylmethyl-g-im-
ino esters prepared from (S)-glutamic acid formed six-membered
as the substrates for the electroreductive intramolecular coupling in
order to obtain five- and six-membered cyclized products selec-
tively. In this paper, we report that the electroreduction of aromatic
b
-dimethylcarbamoyl-b-imino esters prepared from (S)-aspartic
acid gave five-membered cyclized products exclusively. The cyclized
products were obtained as 5-aryl-2-(dimethylcarbamoyl)pyrroli-
dine-4-ones and 5-(dimethylcarbamoyl)-2-aryl-1H-pyrrol-3-yl
benzoates depending on the post-treatment after the
cyclized products, piperidine-5-ones (Scheme 4).
2. Results and discussion
According to our reported method,3 the electroreduction of
b-dimethylcarbamoyl-b-imino ester 1a, prepared from (S)-aspartic
* Corresponding author. Fax: þ81 857 31 5636; e-mail address: kise@bio.tottori-
u.ac.jp (N. Kise).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.100

2580
Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
1) + e, TMSCl
2) BzCl/TEA
OTMS
TMSO OMe
Ph
Ph
1) + e, TMSCl
2) BzCl/TEA
MeO
Ph
CO2Me
CO2Me
Ph
N
N
N
CONMe2
CO2Me
O
3) H3O+
N
Bz
Bz
CONMe2
CO2Me
36%
2a
1a
O
O
+
+
CO2Me
Ph
CO2Me
Ph
N
1M HCl
NaBH4
MeOH
N
Bz
Bz
CONMe2
Ph
N
Bz
17%
20%
3a 63% (ca. 50:50)
HO
Ph
CO2Me
HO
HO
TMSO OMe
Ph
4S
4R
4S
1) + e, TMSCl
2) BzCl/TEA
2SCONMe2
+
2SCONMe2
2SCONMe2
+
Ph 5S
Ph5R
Ph5R
N
N
N
N
N
CO2Me
Bz
Bz
Bz
Bz
CO2Me
4a 29%
6a 7%
5a 25%
56%
Scheme 5. Electroreductive cyclization of 1a and subsequent transformation of 2a to
3a, 4a, 5a, and 6a.
Scheme 2. Electroreductive intramolecular coupling of imino diesters prepared from
(S)-aspartic acid and (S)-glutamic acid dimethyl esters.
Ph
Ph
O
CO2Me
CO2Me
MeO
Ph
1) + e, TMSCl
+2e
O
Ar
N
TMSN
CO2Me
2) BzCl/TEA
CONMe2
CONMe2
+TMSCl
N
CONMe2
N
CONMe2
TMS
B
CONMe2
Ar
1a
3) H3O+
N
A
Bz
CONMe2
OTMS
OTMS
MeO
Ph
MeO
Ph
BzCl
+TMSCl
CONMe2
N
N
Bz
BzO
Ar
TMS
1) + e, CTMS
C
2a
2) H3O+, air
Scheme 6. Reaction mechanism of electroreductive cyclization of 1a.
CONMe2
N
H
3) BzCl/TEA
Scheme 3. Electroreductive intramolecular coupling of
esters prepared from (S)-aspartic acid.
b-dimethylcarbamoyl-b-imino
1) + e, TMSCl
2) BzCl/TEA
Ph
CO2Me
O
N
3) H3O+
Ph
N
X
Bz
X
X = CONMe2, CONEt2, CH2OMe
Scheme 4. Electroreductive intramolecular coupling of
g-dialkylcarbamoyl- and g-
Fig. 1. X-ray crystal structures of 4a and 5a.
methoxymethyl- -imino esters prepared from (S)-glutamic acid.
g
acid and benzaldehyde, and subsequent N-benzoylation of the
resulting mixture were carried out to give five-membered cyclized
product as mixed ketal 2a (Scheme 5). The reaction mechanism of
the electroreductive cyclization of 1a is speculated as illustrated in
Scheme 6. Two electron transfer and N-silylation to 1a generate
carbanion A. Cyclization of A and successive O-silylation of result-
ing B form C. Subsequent treatment of C with benzoyl chloride
gives 2a. The diastereomeric mixture of 2a was transformed to
ketone 3a (63% yield from 1a) by treatment with 1 M HCl (Scheme
5). Since the two diastereomers of 3a (ca. 50:50 mixture) could not
be separated, the mixture of 3a was reduced to alcohols with NaBH4
in methanol. Three diastereomeric alcohols 4a, 5a, and 6a were
isolated by column chromatography in 29%, 25%, and 7% yields from
1a, respectively. Of the three diastereomers, the stereostructures of
4a and 5a were confirmed to be 2S,4S,5S and 2S,4S,5R, respectively,
by X-ray crystallography (Fig. 1). The stereoconfiguration of 6a was
assigned to be 2S,4R,5R as described below. Thus, the cis:trans ratio
at 2,5-positions was 48:52 (4a:5aþ6a).
We therefore examined the electroreduction of a variety of ar-
omatic -dimethylcarbamoyl- -imino esters 1beh and the sub-
b
b
sequent sequential treatments; N-benzoylation, acid hydrolysis,
and reduction with NaBH4. The results are summarized in Table 1. In
all cases, three diastereomeric five-membered cyclized products 4,
5, and 6 were obtained in 46e65% combined yields from 1. The
cis:trans ratios at 2,5-positions (4:5þ6) were about 50:50 in most
cases, although the electroreduction of electron-withdrawing p-
fluoro and p-cyano substituted imino esters 1e and 1f brought
about 64% and 81% 2,5-trans selectivities, respectively. The increase
of the diastereoselectivity is presumed to be due to the stabilization
of the intermediate carbanion corresponding to B in Scheme 6. Of
the cyclized products 4e6, the stereostructures of 4e, 4g, 5b, 6c, and
6h were determined by X-ray crystallography (Fig. 2). The stereo-
structures of the other products were assigned by the correlation of
their 1H NMR spectra as shown in Tables 2e4.
On the other hand, the electroreduction of 1a and following
hydrolysis with 1 M HCl in contact with the atmosphere produced

Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
2581
Table 1
Table 2
Electroreduction of 1 and subsequent transformation to 4, 5, and 6
1H NMR chemical shifts (
d, ppm) of 4aeh
Ar
4
Chemical shift (multitude)2-H, 4-H, 5-H
1) + e, TMSCl
2) BzCl/TEA
CO2Me
4aa
4b
4c
4.28e5.44 (m)
4.17e5.40 (m)
4.31e5.43 (m)
4.17e5.30 (m), 5.51e5.72 (m)
4.21e5.53 (m)
4.27e5.81(m)
4.20e5.47 (m), 5.88e6.26 (m)
4.23e5.54 (m)
N
3) 1M HCl
4) NaBH4
CONMe2
4d
4ea
4f
1a-h
4ga
4h
HO
HO
HO
4S
4S
4R
2SCONMe2
Bz
4a-h
2SCONMe2
Bz
5a-h
5S
2SCONMe2
Bz
6a-h
Ar 5R
a
Ar 5R
+
+
The stereostructure was confirmed by X-ray crystallography.
Ar
N
N
N
Table 3
1H NMR chemical shifts (
Yielda (%)
2,5-cis:trans
d, ppm) of 5aeh
1
Ar
5
Chemical shift (multitude)
4
5
6
4þ5þ6
1a
1b
1c
1d
1e
1f
Ph
29
25
31
32
20
10
25
37
25
16
28
23
29
34
23
21
7
5
5
8
7
8
7
7
61
46
64
63
56
52
55
65
48:52
54:46
48:52
51:49
36:64
19:81
45:55
57:43
2-H
4-H
5-H
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-FC6H4
p-NCC6H4
1-Naphthyl
2-Naphthyl
5aa
5ba
5c
5d
5e
5f
5g
5h
5.35 (d)
5.32 (d)
5.32 (d)
5.34 (d)
5.35 (d)
5.38 (d)
5.46 (d)
5.45 (d)
4.18 (dd)
4.13 (dd)
4.19 (dd)
4.17 (dd)
4.14 (d)
4.12e4.20 (m)
4.35 (dd)
4.27 (dd)
6.76 (d)
6.69 (d)
6.76 (d)
6.58 (d)
6.99 (d)
6.88 (d)
6.82 (d)
6.80 (d)
1g
1h
a
Isolated yields from 1aeh.
a
The stereostructure was confirmed by X-ray crystallography.
Table 4
1H NMR chemical shifts (
d, ppm) of 6aeh
6
Chemical shift (multitude)
2-H
4-H
5-H
6a
6b
6ca
6d
6e
5.35 (dd)
5.27e5.31 (m)
5.32 (dd)
5.30e5.36 (m)
5.34 (dd)
5.34 (dd)
4.78e4.86 (m)
4.74 (dd)
4.76e4.84 (m)
4.58 (dd)
4.80 (dd)
4.88 (dd)
5.07e5.11 (m)
4.99 (d)
5.00e5.08 (m)
5.63 (d)
5.06e5.10 (m)
5.12 (d)
6f
6g
5.33e5.41 (m)
5.46 (dd)
4.77e5.00 (m)
4.89e4.97 (m)
5.92e6.04 (m)
5.28 (d)
6ha
a
The stereostructure was confirmed by X-ray crystallography.
HO
Ph
Ph
1) + e, TMSCl
2) 1M HCl, air
CO2Me
N
CONMe2
N
H
CONMe2
7a 52%
1a
BzO
BzCl/TEA
CONMe2
Ph
N
H
8a 54% from 1a
Fig. 2. X-ray crystal structures of 4e. 4g, 5b, 6c, and 6h.
Scheme 7. Electroreductivecyclizationof 1a and subsequent transformation to 7a and 8a.
4-hydroxypyrrole 7a in 52% isolated yield from 1a. Alternatively, to
facilitate the isolation of the somewhat unstable 7a, the crude 7a
was treated with benzoyl chloride to give 4-benzyloxypyrrole 8a in
54% yield from 1a (Scheme 7). The pyrroles 7a and 8a were iden-
obtained in moderate yields. However, the yields of electron-
donating p- and o-methoxy substituted products 8b and 8d were
relatively low, since 4-hydroxypyrroles 7b and 7d were probably
unstable to the atmospheric conditions.
tified by X-ray crystallography (Fig. 3). The other
b-dime-
Next, we examined the electroreduction of aromatic
lkylcarbamoyl- -imino esters 9a,b and -methoxylmethyl-
ester 9c, prepared from (S)-glutamic acid and benzaldehyde, and
g
-dia-
thylcarbamoyl- -imino esters 1beh were electrolyzed, hydrolyzed,
and then O-benzoylated in a similar manner. The results are sum-
marized in Table 5. In most cases, 4-benzyloxypyrroles 8 were
b
g
g
g-imino

2582
Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
Fig. 3. X-ray crystal structures of 7a and 8a.
Table 5
Electroreduction of 1 and subsequent transformation to 8
Ar
BzO
1) + e, TMSCl
2) 1M HCl, air
CO2Me
N
CONMe2
Ar
N
H
3) BzCl/TEA
CONMe2
8a-h
1a-h
1
Ar
Yield of 8a (%)
Fig. 4. X-ray crystal structures of 12a, 13a, and 14.
1a
1b
1c
1d
1e
1f
Ph
54
20
53
23
56
48
44
52
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-FC6H4
p-NCC6H4
1-Naphthyl
2-Naphthyl
of the diastereomers was 50:50. The stereostructures of 12a and
13a were determined to be 2S,5S,6S and 2S,5R,6R by X-ray crys-
tallography, respectively (Fig. 4). The stereoconfigurations of 12b
and 13b were assigned by their 1H NMR correlation with those of
12a and 13a. Since the cyclized products 12c and 13c could not be
still separated, these alcohols were further transformed to sepa-
rable benzoates 14 and 15 (Scheme 8). The stereostructure of 14
was confirmed to be 2S,3S,6S by X-ray crystallography (Fig. 4). The
stereoconfiguration of 13c was assigned to be 2R,3R,6S by 1H NMR
(difNOE and COSY) analyses for the pure sample obtained by the
hydrolysis of 15 (Scheme 8).
1g
1h
a
Isolated yields from 1aeh.
subsequent N-benzoylation and acid hydrolysis. Six-membered
cyclized products piperidine-5-ones 10aec were obtained as mix-
tures of two diastereomers together with uncyclized products
11aec. Since the diastereomers of 10aec could not be separated,
the mixtures of 10aec were treated with NaBH4 to give two di-
astereomeric alcohols 12aec and 13aec. The results are summa-
rized in Table 6. From 9a and 9b, the piperidines 12a,b and 13a,b
were obtained in poor yields, 12% and 20% combined yields, re-
spectively. On the contrary, the reaction of 9c afforded the cyclized
piperidines 12c and 13c in 44% combined yield, although the ratio
3. Conclusion
This paper describes that the electroreductive intramolecular
coupling of aromatic
b-dimethylcarbamoyl-b-imino esters 1aeh
prepared from (S)-aspartic acid in the presence of TMSCl followed
by N-benzoylation, acid hydrolysis, and reduction with NaBH4
Table 6
Electroreduction of 9 and subsequent transformation to 12 and 13
1) + e, TMSCl
2) BzCl/TEA
TMS
Ph
HN
CO2Me
Ph
CO2Me
O
N
+
3) H3O+
Ph
N
X
Bz
10a-c
X
11a-c
X
9a-c
5R
5S
HO
HO
NaBH4
MeOH
6S
2S
2S
6R
+
Ph
N
Ph
N
X
X
Bz
13a-c
Bz
12a-c
9
X
Yielda (%)
12
13
11
9a
9b
9c
CONMe2
CONEt2
CH2OMe
9
15
22
3
5
22
34
24
8
a
Isolated yields from 9aec.

Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
2583
CHCl3); 1H NMR (CDCl3)
d
2.73 (dd, 1H, J¼16.5, 6.4 Hz), 3.00 (s, 3H),
3S
HO
3S
BzO
BzCl/py
3.08 (s, 3H), 3.16 (dd, 1H, J¼16.5, 7.6 Hz), 3.67 (s, 3H), 3.84 (s, 3H),
2S
6S
2S
6S
5.01 (dd, 1H, J¼7.6, 6.4 Hz), 6.97e7.02 (m, 1H), 7.24e7.37 (m, 3H),
Ph
N
CH2OMe
Ph
N
CH2OMe
CH2OMe
1M NaOH
8.31 (s, 1H); 13C NMR (CDCl3)
d 36.0 (q), 37.0 (q), 37.3 (t), 51.7 (q),
Bz
12c
Bz
14
55.3 (q), 64.4 (d), 111.6 (d), 118.0 (d), 121.8 (d), 129.5 (d), 137.0 (s),
159.8 (s), 163.1 (d), 169.8 (s), 171.9 (s).
3R
HO
3R
BzO
BzCl/py
4.2.4. (S,E)-Methyl 4-(dimethylamino)-3-(2-methoxybenzylidene-
6S
2R
6S
2R
21
amino)-4-oxobutanoate (1d). Colorless paste; [
a
]
ꢁ126 (c 1.15,
D
Ph
N
CH2OMe
Ph
N
CHCl3); 1H NMR (CDCl3)
d
2.68 (dd, 1H, J¼16.9, 6.1 Hz), 2.99 (s, 3H),
Bz
1M NaOH
Bz
15
3.08 (s, 3H), 3.20 (dd, 1H, J¼16.9, 8.3 Hz), 3.67 (s, 3H), 3.86 (s, 3H),
4.97 (dd, 1H, J¼8.3, 6.1 Hz), 6.88e7.06 (m, 2H), 7.35e7.43 (m, 1H),
13c
7.94e8.01 (m, 1H), 8.79 (s, 1H); 13C NMR (CDCl3)
d 36.0 (q), 37.0 (q),
Scheme 8. Benzoylation of 12c and 13c and hydrolysis of 14 and 15.
37.5 (t), 51.7 (q), 55.4 (q), 65.3 (d), 110.9 (d), 120.7 (d), 124.1 (s), 127.3
(d), 132.5 (d), 158.9 (s), 159.4 (d), 170.1 (s), 172.0 (s).
produced five-membered cyclized products 1-benzoyl-4-hydroxy-
5-aryl-N,N-dimethylpyrrolidine-2-carboxamides as mixtures of
three diastereomers, 4aeh, 5aeh, and 6aeh. On the other hand, the
electroreduction of 1aeh followed by acid hydrolysis under open-
air conditions and O-benzoylation gave 5-(dimethylcarbamoyl)-2-
aryl-1H-pyrrol-3-yl benzoates 8aeh as the cyclized products. In
4.2.5. (S,E)-methyl 4-(dimethylamino)-3-(4-fluorobenzylidene-
21
amino)-4-oxobutanoate (1e). Pale yellow solid; [
a]
ꢁ109 (c 1.16,
D
CHCl3); 1H NMR (CDCl3)
d
2.74 (dd, 1H, J¼16.9, 6.2 Hz), 3.00 (s, 3H),
3.09 (s, 3H), 3.14 (dd, 1H, J¼16.9, 7.7 Hz), 3.67 (s, 3H), 4.98e5.04 (m,
1H), 7.06e7.14 (m, 2H), 7.71e7.80 (m, 2H), 8.31 (s, 1H); 13C NMR
addition, the electroreduction of aromatic
g-dialkylcarbamoyl-
g
-imino and -methoxylmethyl- -imino esters 9aec prepared
g
g
(CDCl3)
d 35.9 (q), 37.0 (q), 37.2 (t), 51.7 (q), 64.3 (d), 115.6 (d,
from (S)-glutamic acid followed by N-benzoylation, acid hydrolysis,
and reduction with NaBH4 afforded six-membered cyclized
products 1-benzoyl-5-hydroxy-N,N-dialkyl-6-phenylpiperidine-2-
carboxamides, 12a,b and 13a,b, and 3-hydroxy-6-((methox-
ymethyl)-2-phenylpiperidin-1-yl)(phenyl)methanones, 12c and
13c, as mixtures of two diastereomers.
JCC¼22.1 Hz), 130.3 (d, JCCCF¼8.6 Hz), 131.9 (s, JCCCCF¼2.9 Hz), 161.6
(d), 164.5 (s, JCF¼251.9 Hz), 169.8 (s), 171.8 (s).
4.2.6. (S,E)-Methyl 4-(dimethylamino)-3-(4-cyanobenzylidene-
23
amino)-4-oxobutanoate (1f). Pale yellow paste; [
a]
ꢁ77.7 (c
D
1.10, CHCl3); 1H NMR (CDCl3)
d
2.77 (dd, 1H, J¼17.2, 7.0 Hz), 3.00
(s, 3H), 3.10 (s, 3H), 3.14 (dd, 1H, J¼17.2, 7.0 Hz), 3.68 (s, 3H), 5.10
(t, 1H, J¼7.0 Hz), 7.69e7.73 (m, 2H), 7.84e7.88 (m, 2H), 8.37 (s,
4. Experimental section
4.1. General
1H); 13C NMR (CDCl3)
d 36.0 (q), 37.0 (t), 37.0 (q), 51.8 (d), 64.2
(q), 114.5 (s), 118.3 (s), 128.8 (d), 132.4 (d), 139.3 (s), 161.2 (d),
169.4 (s), 171.7 (s).
Column chromatography was performed on silica gel 60. THF
and 1,4-dioxane were distilled from sodium benzophenone ketyl
radical. TMSCl, TEA, and DMF were distilled from CaH2.
4.2.7. (S,E)-Methyl 4-(dimethylamino)-3-(naphthalen-1-ylmethylene-
22
amino)-4-oxobutanoate (1g). Pale yellow paste; [
a
]
ꢁ99.4 (c 1.09,
D
CHCl3); 1H NMR (CDCl3)
d
2.85 (dd, 1H, J¼16.6, 6.9 Hz), 3.02 (s, 3H),
4.2. Starting materials
3.12 (s, 3H), 3.24 (dd, 1H, J¼16.6, 6.9 Hz), 3.68 (s, 3H), 5.10 (t, 1H,
J¼6.9 Hz), 7.47e7.63 (m, 3H), 7.83e7.95 (m, 3H), 8.86e8.91 (m, 1H),
Aromatic
b
- and
g
-imino esters were prepared by treatment of
8.99 (s,1H); 13C NMR (CDCl3)
d 36.0 (q), 37.1 (q), 37.5 (t), 51.7 (q), 65.7
u
-methyl esters derived from (S)-aspartic acid and (S)-glutamic
(d), 124.2 (d), 125.1 (d), 126.1 (d), 127.4 (d), 128.6 (d), 129.5 (d), 130.9
(s), 131.1 (s), 131.7 (d), 133.7 (s), 163.5 (d), 169.9 (s), 172.0 (s).
acid with aromatic aldehydes in dichloromethane in the presence
of magnesium sulfate at 25 ꢀC and isolated by recrystallization from
hexanes/ethyl acetate or used without purification.
4.2.8. (S,E)-Methyl 4-(dimethylamino)-3-(naphthalen-2-
22
ylmethyleneamino)-4-oxobutanoate (1h). Pale yellow solid; [a]
D
4.2.1. (S,E)-Methyl 3-(benzylideneamino)-4-(dimethylamino)-4-
oxobutanoate (1a). Pale yellow solid; mp 92e93 ꢀC (recryst from
ꢁ108 (c 1.05, CHCl3); 1H NMR (CDCl3)
2.79 (dd, 1H, J¼16.6, 6.3 Hz),
d
3.01 (s, 3H), 3.11 (s, 3H), 3.20 (dd, 1H, J¼16.6, 7.7 Hz), 3.68 (s, 3H),
5.05e5.10 (m, 1H), 7.48e7.56 (m, 2H), 7.81e8.08 (m, 5H), 8.49 (s,
20
hexanes/ethyl acetate¼2:1); [
a]
ꢁ120 (c 1.01, CHCl3); IR (KBr)
D
1733, 1637, 1579, 1498, 761, 744, 698 cmꢁ1
;
1H NMR (CDCl3)
d
2.74
1H); 13C NMR (CDCl3)
d 36.0 (q), 37.1 (q), 37.4 (t), 51.7 (q), 64.6 (d),
(dd, 1H, J¼6.0, 16.5 Hz), 3.00 (s, 3H), 3.09 (s, 3H), 3.16 (dd, 1H, J¼7.8,
123.6 (d), 126.6 (d), 127.4 (d), 127.8 (d), 128.5 (d), 128.7 (d), 130.7 (d),
132.9 (s), 133.3 (s), 134.9 (s), 163.2 (d), 169.9 (s), 172.0 (s).
16.5 Hz), 3.67 (s, 3H), 5.00e5.04 (m, 1H), 7.39e7.48 (m, 3H),
7.73e7.78 (m, 2H), 8.34 (s, 1H); 13C NMR (CDCl3)
d 35.8 (q), 36.9 (q),
37.2 (t), 51.5 (q), 64.4 (d), 128.2 (d), 128.4 (d), 131.1 (d), 135.5 (s),
163.1 (d), 169.7 (s), 171.7 (s).
4.2.9. (S,E)-Methyl 4-(benzylideneamino)-5-(dimethylamino)-5-
20
oxopentanoate (9a). Pale yellow paste;
[
a
]
ꢁ44.3 (c 1.20,
1H
d 2.12e2.20 (m, 1H), 2.26e2.34 (m, 1H), 2.38e2.44 (m,
D
CHCl3); IR (neat) 1733, 1699, 1647, 1579, 1497, 758, 696 cmꢁ1
NMR (CDCl3)
;
4.2.2. (S,E)-Methyl 4-(dimethylamino)-3-(4-methoxybenzylidene-
22
amino)-4-oxobutanoate (1b). Colorless paste; [
a
]
ꢁ108 (c 1.32,
2H), 2.98 (s, 3H), 3.13 (s, 3H), 3.65 (s, 3H), 4.50e4.53 (m, 1H),
D
1
CHCl3); H NMR (CDCl3)
d
2.71 (dd, 1H, J¼16.5, 6.2 Hz), 2.99 (s, 3H),
7.38e7.47 (m, 3H), 7.73e7.78 (m, 2H), 8.30 (s, 1H); 13C NMR (CDCl3)
3.08 (s, 3H), 3.14 (dd,1H, J¼16.5, 8.3 Hz), 3.67 (s, 3H), 3,84 (s, 3H), 4.16
(dd, 1H, J¼8.3, 6.2 Hz), 6.90e6.95 (m, 2H), 7.67e7.72 (m, 2H), 8.26 (s,
d 28.1 (t), 30.2 (t), 35.8 (q), 36.8 (q), 51.4 (q), 68.8 (d), 128.2 (d), 128.4
(d), 130.9 (d), 135.5 (s), 162.5 (d), 170.5 (s), 173.4 (s).
1H); 13C NMR (CDCl3)
d 35.9 (q), 37.0 (q), 37.4 (t), 51.6 (q), 55.3 (q),
64.4 (d), 113.9 (d), 128.6 (s), 130.0 (d), 162.1 (s), 162.4 (d), 170.1 (s),
172.0 (s).
4.2.10. (S,E)-Methyl 4-(benzylideneamino)-5-(diethylamino)-5-
22
oxopentanoate (9b). Pale yellow paste; [
a
]
ꢁ32.3 (c 1.03, CHCl3);
D
1H NMR (CDCl3)
d
1.13 (t, 3H, J¼7.2 Hz), 1.16 (t, 3H, J¼7.1 Hz),
4.2.3. (S,E)-Methyl 4-(dimethylamino)-3-(3-methoxybenzylidene-
2.10e2.50 (m, 4H), 3.28e3.60 (m, 4H), 3.65 (s, 3H), 4.51 (t, 1H,
J¼7.0 Hz), 7.38e7.47 (m, 3H), 7.73e7.78 (m, 2H), 8.31 (s, 1H); 13C
20
amino)-4-oxobutanoate (1c). Colorless paste; [
a]
ꢁ104 (c 1.22,
D

2584
Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
NMR (CDCl3)
d
12.7 (q), 14.4 (q), 28.4 (t), 30.2 (t), 40.2 (t), 41.3 (t),
Calcd for C20H22N2O3: C, 70.99%; H, 6.55%; N, 8.28%. Found: C,
70.97%; H, 6.56%; N, 8.15%.
51.2 (q), 68.0 (d), 128.1 (d), 128.3 (d), 130.8 (d), 135.6 (s), 162.0 (d),
169.7 (s), 173.3 (s).
4.3.3. (2S,4S,5S)-1-Benzoyl-4-hydroxy-5-(4-methoxyphenyl)-N,N-di-
methylpyrrolidine-2-carboxamide (4b). White solid; Rf 0.3 (ethyl
acetate/ethanol¼10:1); mp 182e183 ꢀC (recryst from ethyl ace-
4.2.11. (S,E)-Methyl 4-(benzylideneamino)-5-methoxypentanoate
25
(9c). Pale yellow paste; [
(CDCl3)
a
]
ꢁ65.7 (c 1.04, CHCl3); 1H NMR
D
d
1.90e2.06 (m, 2H), 2.23e2.39 (m, 2H), 3.33 (s, 3H),
tate); [a] d 1.94e2.67 (m, 2H),
21 146 (c 1.10, CHCl3); 1H NMR (CDCl3)
D
3.39e3.55 (m, 3H), 3.62 (s, 3H), 7.37e7.44 (m, 3H), 7.71e7.79 (m,
2.80e3.89 (m, 9H), 4.17e5.40 (m, 4H), 6.47e7.76 (m, 9H); 13C NMR
(DMSO-d6) 33.0 (t), 36.0 (q), 36.5 (q), 37.1 (q), 55.2 (d), 66.3 (d),
2H), 8.27 (s, 1H); 13C NMR (CDCl3)
d
27.6 (t), 30.6 (t), 51.4 (q), 58.9
d
(q), 69.7 (d), 76.0 (t), 128.2 (d), 128.4 (d), 130.6 (d), 135.9 (s), 161.8
(d), 173.7 (s).
71.3 (d), 113.1 (d), 127.0 (d), 127.9 (d), 129.97 (d), 130.04 (d), 131.9 (s),
136.4 (s), 158.4 (s), 170.9 (s), 171.4 (s). Anal. Calcd for C21H24N2O4: C,
68.46%; H, 6.57%; N, 7.60%. Found: C, 68.57%; H, 6.64%; N, 7.45%.
4.3. Typical procedure for electroreduction of imino esters 1
and subsequent transformation to 4, 5, and 6
4.3.4. (2S,4S,5S)-1-Benzoyl-4-hydroxy-5-(3-methoxyphenyl)-N,N-di-
methylpyrrolidine-2-carboxamide (4c). Colorless paste; Rf 0.3 (ethyl
24
acetate/ethanol¼10:1); [
a]
124 (c 1.20, CHCl3); 1H NMR (CDCl3)
D
A 0.3 M solution of Bu4NClO4 in THF (15 mL) was placed in the
cathodic chamber of a divided cell (40 mL beaker, 3 cm diameter,
6 cm height) equipped with a lead cathode (5ꢂ5 cm2), a platinum
anode (2ꢂ1 cm2), and a ceramic cylindrical diaphragm (1.5 cm di-
ameter). A 0.3 M solution of Bu4NClO4 in DMF (4 mL) was placed in
the anodic chamber (inside the diaphragm). Imino ester (1a)
(262 mg, 1 mmol), TMSCl (0.64 mL, 5 mmol), and TEA (0.70 mL,
5 mmol) were added to the cathodic chamber. After 300 C of
electricity was passed at a constant current of 100 mA at 25 ꢀC, the
catholyte was evaporated in vacuo. The residue was dissolved in
Et2O (20 mL) and insoluble solid was filtered off. After removal of
the solvent, the residue was dissolved in THF (5 mL). To the solution
were added benzoyl chloride (0.12 mL, 1 mmol) and TEA (0.21 mL,
1.5 mmol) at 25 ꢀC. After the suspended mixture was stirred for 2 h,
1 M HCl (5 mL) was added to the mixture. The mixture was stirred
at 25 ꢀC for 1 h, diluted with H2O (10 mL), and then extracted with
ethyl acetate three times. After the solvent was removed, the res-
idue was purified by column chromatography on silica gel (hex-
anes/ethyl acetate) to give 3a in 63% yield as a about 50:50 mixture
of two diastereomers. Recrystallization of the mixture from hex-
ane/ethyl acetate¼1:5 gave trans-3a as a pure solid.
d
2.11e2.27 (m, 1H), 2.38e2.67 (m, 1H), 2.94e3.95 (m, 9H),
4.31e5.43 (m, 4H), 6.54e7.63 (m, 9H); 13C NMR (CDCl3)
d
35.0 (t),
36.2 (q), 37.4 (q), 54.9 (q), 56.1 (d), 68.9 (d), 73.7 (d), 112.8 (d), 113.7
(d), 120.7 (d), 126.4 (d), 127.3 (d), 128.5 (d), 129.2 (d), 135.7 (s), 138.9
(s), 158.9 (s), 171.0 (s), 172.6 (s); HRMS (ESI) calcd for C21H25N2O4
(MþH)þ 369.1816, found 369.1808.
4.3.5. (2S,4S,5S)-1-Benzoyl-4-hydroxy-5-(2-methoxyphenyl)-N,N-di-
methylpyrrolidine-2-carboxamide (4d). Colorless paste; Rf 0.45
24
(ethyl acetate/ethanol¼10:1); [
(CDCl3)
6.44e7.96 (m, 9H); 13C NMR (CDCl3)
a]
89.0 (c 1.13, CHCl3); 1H NMR
D
d
1.98e3.96 (m, 11H), 4.17e 5.30 (m, 3H), 5.51e5.72 (m, 1H),
35.9 (t), 36.5 (q), 37.8 (q), 55.1
d
(d), 56.6 (q), 62.8 (d), 73.2 (d), 109.5 (d), 120.3 (d), 125.2 (s), 126.3
(d), 127.2 (d), 128.0 (d), 129.1 (d), 130.2 (d), 136.1 (s), 155.7 (s), 170.9
(s), 173.4 (s); HRMS (ESI) calcd for C21H25N2O4 (MþH)þ 369.1816,
found 369.1809.
4.3.6. (2S,4S,5S)-1-Benzoyl-5-(4-fluorophenyl)-4-hydroxy-N,N-di-
methylpyrrolidine-2-carboxamide (4e). White solid; Rf 0.3 (ethyl
24
acetate/ethanol¼10:1); mp 259e260 ꢀC (recryst from CH2Cl2); [
a]
D
182 (c 1.10, CHCl3); IR (KBr) 3372, 1643, 1628, 1603, 1578, 1508, 866,
To a solution of the crude 3a in methanol (5 mL) was added
NaBH4 (38 mg, 1.0 mmol) at 0 ꢀC. After being stirred for 30 min at
this temperature, the mixture was diluted with water (10 mL) and
extracted with ethylacetate three times. After the solvent was re-
moved, the residue was column chromatographed on silica gel
(hexanes/ethyl acetate) to give alcohols 4a, 5a, and 6a in 29%, 25%,
and 7% yields, respectively.
831, 812, 745, 731, 700 cmꢁ1; 1H NMR (CDCl3)
2.83e3.63 (m, 6H), 4.21e5.53 (m, 4H), 6.60e7.80 (m, 9H); 13C NMR
(DMSO-d6) 33.0 (t), 35.6 (q), 36.8 (q), 54.9 (d), 65.9 (d), 71.0 (d),
d 2.02e2.74 (m, 2H),
d
113.8 (d, JCCF¼22.1 Hz), 126.5 (d), 127.5 (d), 129.5 (d), 130.3 (d,
JCCCF¼6.7 Hz), 135.6 (s), 136.1 (s), 161.2 (s, JCF¼246.2 Hz), 170.3 (s),
171.1 (s). Anal. Calcd for C20H21FN2O3: C, 67.40%; H, 5.94%; N, 7.86%.
Found: C, 67.48%; H, 5.92%; N, 7.74%.
4.3.1. (2S,5R)-1-Benzoyl-N,N-dimethyl-4-oxo-5-phenylpyrrolidine-2-
carboxamide (trans-3a). White solid; Rf 0.25 (hexane/ethyl
acetate¼1:5); mp 220e221 ꢀC (recryst from hexane/ethyl
4.3.7. (2S,4S,5S)-1-Benzoyl-5-(4-cyanophenyl)-4-hydroxy-N,N-di-
methylpyrrolidine-2-carboxamide (4f). White solid; Rf 0.35 (ethyl
22
acetate/ethanol¼10:1); mp 289e291 ꢀC (recryst from CH2Cl2); [
a]
D
acetate¼1:5); [
a
]
D
20 ꢁ166 (c 0.86, CHCl3); IR (KBr) 1749, 1635, 1600,
215 (c 1.00, CHCl3); 1H NMR (CDCl3)
d 2.04e3.56 (m, 8H), 4.27e5.81
1577, 1492, 731, 704 cmꢁ1; 1H NMR (CDCl3)
d
2.62 (d, 1H, J¼17.9 Hz),
(m, 4H), 6.85e7.92 (m, 9H); 13C NMR (DMSO-d6)
d 33.2 (t), 35.6 (q),
3.00 (dd, 1H, J¼10.1, 17.9 Hz), 3.04 (s, 3H), 3.35 (s, 3H), 5.19 (s, 1H),
36.7 (q), 54.9 (d), 66.1 (d), 71.0 (d), 109.4 (s), 119.2 (s), 126.4 (d),
127.8 (d), 129.0 (d), 129.6 (d), 131.2 (d), 136.2 (s), 145.8 (s), 170.2 (s),
171.0 (s). Anal. Calcd for C21H21N3O3: C, 69.41%; H, 5.82%; N, 11.56%.
Found: C, 69.40%; H, 5.85%; N, 11.38%.
5.80 (d, 1H, J¼10.1 Hz), 6.87e6.93 (m, 2H), 7.07e7.21 (m, 8H); 13C
NMR (CDCl3)
d 35.6 (q), 35.8 (q), 36.1 (q), 37.0 (q), 38.2 (t), 52.1 (d),
68.1 (d), 125.6 (d), 126.0 (d), 127.1 (d), 127.4 (d), 127.5 (d), 128.0 (d),
128.3 (d), 129.1 (d), 129.4 (d), 135.3 (s), 136.0 (s), 137.2 (s), 171.3 (s),
171.4 (s), 205.9 (s). Anal. Calcd for C20H20N2O3: C, 71.41%; H, 5.99%;
N, 8.33%. Found: C, 71.46%; H, 6.02%; N, 8.18%.
4.3.8. (2S,4S,5S)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naphthalen-
1-yl)pyrrolidine-2-carboxamide (4g). White solid; Rf 0.3 (ethyl ac-
25
etate/ethanol¼10:1); mp 269e271 ꢀC (recryst from CH2Cl2); [
a]
D
4.3.2. (2S,4S,5S)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-
9.1 (c 1.13, CHCl3); IR (KBr) 3406, 1647, 1624, 1597, 1576, 800, 791,
phenylpyrrolidine-2-carboxamide (4a). White solid; Rf 0.25 (ethyl
731 cmꢁ1; 1H NMR (CDCl3)
d
2.10e3.61 (m, 8H), 4.20e5.47 (m, 3H),
35.8 (t),
acetate); mp 194e196 ꢀC (recryst from ethyl acetate); [
a]
24 194 (c
5.88e6.26 (m, 1H), 6.65e8.36 (m, 12H); 13C NMR (CDCl3)
d
D
1.06, CHCl3); IR (KBr) 3368, 1645, 1628, 1601, 1497, 789, 758, 743,
702 cmꢁ1; 1H NMR (CDCl3)
2.08e2.62 (m, 2H), 2.89e3.51 (m, 6H),
4.28e5.44 (m, 4H), 6.83e7.77 (m, 10H); 13C NMR (CDCl3)
35.2 (t),
36.3 (q), 37.5 (q), 56.3 (d), 69.4 (d), 74.0 (d),126.4 (d),126.7 (d),127.5
(d), 128.3 (d), 129.1 (d), 135.9 (s), 137.2 (s), 171.0 (s), 173.0 (s). Anal.
36.2 (q), 36.5 (q), 37.3 (q), 37.7 (q), 38.3 (t), 56.5 (d), 59.0 (d), 65.3
(d), 65.4 (d), 72.5 (d), 73.4 (d), 121.6 (d), 122.4 (d), 124.1 (d), 125.0
(d), 125.4 (d), 125.6 (d), 126.8 (d), 127.2 (d), 127.5 (d), 128.2 (d), 128.6
(d), 128.9 (d), 130.5 (d), 130.7 (s), 132.4 (s), 133.0 (s), 133.7 (s), 135.7
(s), 136.9 (s), 171.0 (s), 171.9 (s), 173.2 (s), 174.5(s). Anal. Calcd for
d
d

Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
2585
C24H24N2O3: C, 74.21%; H, 6.23%; N, 7.21%. Found: C, 74.20%; H,
6.18%; N, 7.09%.
C21H24N2O4: C, 68.46%; H, 6.57%; N, 7.60%. Found: C, 68.49%; H,
6.53%; N, 7.42%.
4.3.14. (2S,4S,5R)-1-Benzoyl-5-(4-fluorophenyl)-4-hydroxy-N,N-di-
4.3.9. (2S,4S,5S)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naphthalen-
methylpyrrolidine-2-carboxamide (5e). White solid; Rf 0.3 (ethyl
2-yl)pyrrolidine-2-carboxamide (4h). White solid; Rf 0.4 (ethyl ac-
22
acetate); mp 213e214 ꢀC (ethyl acetate/ethanol¼1:1); [
a
]
ꢁ50.4
22
etate/ethanol¼10:1); mp 194e195 ꢀC (recryst from CH2Cl2); [
a
]
D
D
(c 1.08, CHCl3); 1H NMR (CDCl3)
d
1.93 (d, 1H, J¼14.4 Hz),
214 (c 1.08, CHCl3); 1H NMR (CDCl3)
d 2.09e2.59 (m, 2H), 2.93e3.48
(m, 6H), 4.23e5.54 (m, 4H), 6.74e8.14 (m, 12H); 13C NMR (DMSO-
d6) 33.2 (t), 36.0 (q), 37.1 (q), 55.4 (d), 66.9 (d), 71.6 (d), 125.7 (d),
2.34e2.41 (m, 1H), 3.10 (s, 3H), 3.43 (s, 3H), 4.14 (d, 1H, J¼4.6 Hz),
5.14 (s, 1H), 5.35 (d, 1H, J¼9.6 Hz), 6.94e7.02 (m, 4H), 7.18e7.33
d
(m, 6H); 13C NMR (CDCl3)
d 32.3 (t), 36.7 (q), 38.2 (q), 56.0 (d),
125.9 (d), 126.7 (d), 126.9 (d), 127.3 (d), 127.5 (d), 127.6 (d), 127.8 (d),
128.1 (d), 130.0 (d), 132.4 (s), 133.0 (s), 136.3 (s), 137.8 (s), 170.8 (s),
171.5 (s). Anal. Calcd for C24H24N2O3: C, 74.21%; H, 6.23%; N, 7.21%.
Found: C, 74.25%; H, 6.16%; N, 7.10%.
73.4 (d), 78.9 (d), 115.6 (d, JCCF¼21.1 Hz), 126.4 (d), 126.8 (d,
JCCCF¼7.7 Hz), 128.0 (d), 129.8 (d), 135.7 (s), 136.3 (s,
JCCCCF¼2.9 Hz), 161.8 (s, JCF¼246.7 Hz), 171.6 (s), 173.6 (s). Anal.
Calcd for C20H21FN2O3: C, 67.40%; H, 5.94%; N, 7.86%. Found: C,
67.51%; H, 6.00%; N, 7.75%.
4.3.10. (2S,4S,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-
phenylpyrrolidine-2-carboxamide (5a). White solid; Rf 0.45 (ethyl
acetate); mp 206e207 ꢀC (recryst from hexanes/ethyl
4.3.15. (2S,4S,5R)-1-Benzoyl-5-(4-cyanophenyl)-4-hydroxy-N,N-di-
methylpyrrolidine-2-carboxamide (5f). White solid; Rf 0.5 (ethyl
acetate¼1:2); [
a
]
22 ꢁ55.4 (c 1.12, CHCl3); IR (KBr) 3341, 1640, 1626,
D
22
acetate/ethanol¼10:1); mp 242e243 ꢀC (recryst from CH2Cl2); [
a]
D
1599, 1493, 783, 766, 754, 710, 702 cmꢁ1; 1H NMR (CDCl3)
d
1.91 (d,
ꢁ143 (c 1.17, CHCl3); 1H NMR (CDCl3)
1.92 (d, 0.1H, J¼14.2 Hz),1.97
d
1H, J¼14.5 Hz), 2.35e2.42 (m, 1H), 3.10 (s, 3H), 3.44 (s, 3H), 4.18 (dd,
1H, J¼4.1, 11.4 Hz), 5.16 (s, 1H), 5.35 (d, 1H, J¼9.6 Hz), 6.76 (d, 1H,
J¼11.3 Hz), 7.03e7.07 (m, 2H), 7.17e7.31 (m, 8H); 13C NMR (CDCl3)
(d, 0.9H, J¼14.5 Hz), 2.23e2.37 (m, 0.9H), 2.39e2.46 (m, 0.1H), 2.50
(s, 0.3H), 2.69 (s, 0.3H), 3.10 (s, 2.7H), 3.44 (s, 2.7H), 4.12e4.20 (m,
1H), 5.03 (d, 0.1H, J¼9.7 Hz), 5.21 (s, 0.9H), 5.38 (d, 0.9H J¼9.8 Hz),
5.65 (d, 0.1H, J¼12.2 Hz), 5.72 (s, 0.1H), 6.88 (d, 0.9H, J¼11.9 Hz),
d
33.2 (t), 36.6 (q), 38.0 (q), 55.9 (d), 73.9 (d), 78.8 (d), 125.0 (d),
126.4 (d), 127.3 (d), 127.8 (d), 128.6 (d), 129.6 (d), 135.7 (s), 140.4 (s),
171.4 (s), 173.7 (s). Anal. Calcd for C20H22N2O3: C, 70.99%; H, 6.55%;
N, 8.28%. Found: C, 71.04%; H, 6.53%; N, 8.20%.
7.13e7.70 (m, 9H); 13C NMR (CDCl3)
d 33.3 (t), 36.7 (q), 38.1 (q), 56.0
(d), 73.8 (d), 78.8 (d),111.4 (s),118.1 (s),126.0 (d),126.3 (d),128.1 (d),
129.9 (d),132.5 (d), 135.4 (s), 145.7 (s),171.3 (s), 173.4 (s). Anal. Calcd
for C21H21N3O3: C, 69.41%; H, 5.82%; N, 11.56%. Found: C, 69.45%; H,
5.77%; N, 11.43%.
4.3.11. (2S,4S,5R)-1-Benzoyl-4-hydroxy-5-(4-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (5b). White solid; Rf 0.25 (ethyl
acetate); mp 201e202 ꢀC (recryst from ethyl acetate); [
a
]
22 ꢁ89.3 (c
D
4.3.16. (2S,4S,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naph-
1.05, CHCl3); IR (KBr) 3198, 3187, 1636, 1618, 1584, 1578, 1506, 849,
808, 795, 731, 704 cmꢁ1; 1H NMR (CDCl3)
d
1.89 (d, 1H, J¼14.3 Hz),
thalen-1-yl)pyrrolidine-2-carboxamide (5g). White solid; Rf 0.5
(ethyl acetate/ethanol¼10:1); mp 222e224 ꢀC (recryst from
2.34e2.42 (m, 1H), 3.09 (s, 3H), 3.43 (s, 3H), 3.77 (s, 3H), 4.13 (dd,
1H, J¼11.5, 4.1 Hz), 5.10 (s, 1H), 5.32 (d, 1H, J¼9.4 Hz), 6.69 (d, 1H,
J¼11.5 Hz), 6.78e6.84 (m, 2H), 6.93e6.98 (m, 2H), 7.17e7.31 (m,
22
CH2Cl2); [
a]
44.3 (c 1.13, CHCl3); 1H NMR (CDCl3)
d 1.96 (d, 1H,
D
J¼14.3 Hz), 2.31e2.38 (m, 1H), 3.12 (s, 3H), 3.46 (s, 3H), 4.35 (dd, 1H,
J¼11.7, 4.1 Hz), 5.46 (d, 1H, J¼9.7 Hz), 5.84 (s, 1H), 6.82 (d, 1H,
J¼11.7 Hz), 7.05e7.50 (m, 9H), 7.73e7.96 (m, 3H); 13C NMR (CDCl3)
5H); 13C NMR (CDCl3)
d 33.3 (t), 36.7 (q), 38.2 (q), 55.2 (q), 56.0 (d),
73.5 (d), 79.0 (d), 114.1 (d), 126.4 (d), 126.6 (d), 127.9 (d), 129.7 (d),
132.7 (s), 135.8 (s), 158.8 (s), 171.6 (s), 173.8 (s). Anal. Calcd for
C21H24N2O4: C, 68.46%; H, 6.57%; N, 7.60%. Found: C, 68.51%; H,
6.56%; N, 7.53%.
d
33.6 (t), 36.7 (q), 38.2 (q), 56.5 (d), 71.8 (d), 77.7 (d),122.1 (d),122.9
(d),125.0 (d),126.0 (d), 126.4 (d), 126.5 (d), 127.9 (d), 128.3 (d),128.6
(d), 129.7 (d and s), 133.6 (s), 135.6 (s), 136.1 (s), 171.5 (s), 173.9 (s).
Anal. Calcd for C24H24N2O3: C, 74.21%; H, 6.23%; N, 7.21%. Found: C,
74.32%; H, 6.22%; N, 7.13%.
4.3.12. (2S,4S,5R)-1-Benzoyl-4-hydroxy-5-(3-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (5c). White solid; Rf 0.5 (ethyl
acetate/ethanol¼10:1); mp 192e194 ꢀC (recryst from ethyl acetate/
4.3.17. (2S,4S,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naph-
thalen-2-yl)pyrrolidine-2-carboxamide (5h). White solid; Rf 0.3
ethanol¼1:1); [
a
]
23 ꢁ50.7 (c 1.10, CHCl3); 1H NMR (CDCl3)
d 1.90 (d,
21
D
(ethyl acetate); mp 255e256 ꢀC (recryst from CH2Cl2); [
a]
ꢁ209
D
1H, J¼14.2 Hz), 2.35e2.43 (m, 1H), 3.10 (s, 3H), 3.43 (s, 3H), 3.75 (s,
3H), 4.19 (dd, 1H, J¼11.4, 4.0 Hz), 5.12 (s, 1H), 5.32 (d, 1H, J¼9.6 Hz),
6.56e6.67 (m, 2H), 6.74e6.78 (m, 2H), 7.17e7.23 (m, 6H); 13C NMR
(c 1.05, CHCl3); 1H NMR (CDCl3)
d
1.93 (d, 1H, J¼14.2 Hz),
2.37e2.45 (m, 1H), 3.12 (s, 3H), 3.47 (s, 3H), 4.27 (dd, 1H, J¼11.5,
4.2 Hz), 5.32 (s, 1H), 5.45 (d, 1H, J¼9.5 Hz), 6.80 (d, 1H, J¼11.5 Hz),
(CDCl3)
d 33.4 (t), 36.7 (q), 38.2 (q), 55.1 (q), 56.1 (d), 73.9 (d), 79.0
7.11e7.91 (m, 12H); 13C NMR (CDCl3)
d 33.3 (t), 36.7 (q), 38.2 (q),
(d), 111.3 (d), 112.3 (d), 117.3 (d), 126.6 (d), 127.9 (d), 129.7 (d), 129.8
(d), 135.8 (s), 142.3 (s), 159.8 (s), 171.5 (s), 173.8 (s). Anal. Calcd for
C21H24N2O4: C, 68.46%; H, 6.57%; N, 7.60%. Found: C, 68.59%; H,
6.66%; N, 7.58%.
56.2 (d), 74.0 (d), 78.8 (d), 123.4 (d), 123.5 (d), 126.1 (d), 126.48
(d), 126.52 (d), 127.6 (d), 127.7 (d), 127.9 (d), 128.7 (d), 129.7 (d),
132.5 (s), 133.1 (s), 135.7 (s), 138.1 (s), 171.7 (s), 178.8 (s). Anal.
Calcd for C24H24N2O3: C, 74.21%; H, 6.23%; N, 7.21%. Found: C,
74.26%; H, 6.25%; N, 7.05%.
4.3.13. (2S,4S,5R)-1-Benzoyl-4-hydroxy-5-(2-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (5d). White solid; Rf 0.6 (ethyl
4.3.18. (2S,4R,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-
phenylpyrrolidine-2-carboxamide (6a). White solid; Rf 0.1 (ethyl
acetate/ethanol¼10:1); mp 179e180 ꢀC (recryst from hexanes/
24
ꢁ9.8 (c 1.07, CHCl3); 1H NMR (CDCl3)
acetate); mp 218e219 ꢀC (recryst from ethyl acetate); [
a]
25 ꢁ56.6 (c
ethyl acetate¼1:5); [
a
]
D
D
1.03, CHCl3); 1H NMR (CDCl3)
d
1.45 (d, 0.8H, J¼7.6 Hz),1.52 (d, 0.2H,
d
1.88 (d, 1H, J¼13.8 Hz), 2.29e2.37 (m, 1H), 3.10 (s, 3H), 3.43 (s,
3H), 3.70 (s, 3H), 4.17 (dd, 1H, J¼11.5, 4.6 Hz), 5.34 (d, 1H,
J¼9.2 Hz), 5.39 (s, 1H), 6.58 (d, 1H, J¼11.5 Hz), 6.75e6.79 (m, 1H),
J¼4.8 Hz), 2.12e2.24 (m, 2H), 2.56 (s, 0.6H), 2.62 (s, 0.6H), 3.04 (s,
2.4H), 3.26 (s, 2.4H), 4.59e4.65 (m, 0.2H), 4.78e4.86 (m, 0.8H),
5.07e5.11 (m, 1H), 5.35 (dd, 0.8H, J¼3.8, 8.4 Hz), 5.49 (d, 0.2H,
6.89e7.04 (m, 2H), 7.14e7.29 (m, 6H); 13C NMR (CDCl3)
d 33.6 (t),
J¼5.8 Hz), 6.95e7.50 (m, 10H); 13C NMR (CDCl3)
d 34.2 (t), 36.2 (q),
36.7 (q), 38.1 (q), 55.2 (q), 56.2 (d), 69.5 (d), 77.0 (d), 110.5 (d),
120.4 (d), 125.4 (d), 126.6 (d), 127.8 (d), 128.66 (d), 128.73 (s), 129.5
(d), 135.8 (s), 155.8 (s), 171.4 (s), 173.9 (s). Anal. Calcd for
37.3 (q), 55.4 (d), 66.6 (d), 71.4 (d), 126.4 (d), 127.60 (d), 127.62 (d),
128.2 (d), 129.2 (d), 136.5 (s), 137.6 (s), 171.2 (s), 171.5 (s). Anal. Calcd

2586
Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
for C20H22N2O3: C, 70.99%; H, 6.55%; N, 8.28%. Found: C, 71.08%; H,
6.60%; N, 8.12%.
(dd, 0.7H, J¼8.3, 3.4 Hz), 5.46 (d, 0.3H, J¼5.6 Hz), 7.02e7.72 (m, 9H);
13C NMR (DMSO-d6)
33.7 (t), 35.6 (q), 36.1 (q), 36.5 (t), 36.6 (q),
d
37.1 (q), 55.7 (d), 57.9 (d), 64.9 (d), 66.4 (d), 69.7 (d), 70.7 (d), 109.7
(s), 110.0 (s), 119.1 (s), 119.4 (s), 126.4 (d), 127.1 (d), 128.1 (d), 128.2
(d), 128.8 (d), 129.1 (d), 129.6 (d), 130.0 (d), 131.6 (d), 131.7 (d), 136.9
(s), 145.3 (s), 170.5 (s), 171.1 (s), 171.4 (s), 171.6 (s). Anal. Calcd for
C21H21N3O3: C, 69.41%; H, 5.82%; N, 11.56%. Found: C, 69.50%; H,
5.83%; N, 11.40%.
4.3.19. (2S,4R,5R)-1-Benzoyl-4-hydroxy-5-(4-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (6b). White solid; Rf 0.2 (ethyl
acetate/ethanol¼10:1); mp 165e167 ꢀC (recryst from hexanes/
21
ethyl acetate¼1:5); [
a
]
D
ꢁ75.2 (c 1.21, CHCl3); 1H NMR (CDCl3)
d
1.22e1.30 (m, 0.2H), 2.00e2.31 (m, 2.8H), 2.54 (s, 0.6H), 2.57 (s,
0.6H), 3.00 (s, 2.4H), 3.22 (s, 2.4H), 3.74 (s, 2.4H), 3.78 (s, 0.6H),
4.54e4.60 (m, 0.2H), 4.74 (dd, 0.8H, J¼14.4, 7.0 Hz), 4.99 (d, 0.8H,
J¼7.0 Hz), 5.03 (dd, 0.2H, J¼7.8, 5.2 Hz), 5.27e5.31 (m, 0.8H), 5.42
4.3.24. (2S,4R,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naph-
thalen-1-yl)pyrrolidine-2-carboxamide (6g). Colorless paste; Rf 0.3
25
(d, 0.2H, J¼6.0 Hz), 6.70e7.46 (m, 9H); 13C NMR (CDCl3)
d
34.1 (t),
(ethyl acetate/ethanol¼10:1); [
a
]
39.9 (c 1.16, CHCl3); 1H NMR
D
36.1 (q), 37.2 (q), 55.1 (q), 55.3 (d), 66.0 (d), 71.3 (d), 113.7 (d), 126.4
(d), 127.6 (d), 128.7 (d), 129.1 (s), 129.5 (d), 136.5 (s), 159.0 (s), 171.2
(s), 171.5 (s). Anal. Calcd for C21H24N2O4: C, 68.46%; H, 6.57%; N,
7.60%. Found: C, 68.47%; H, 6.57%; N, 7.54%.
(CDCl3) d 1.95e2.33 (m, 3H), 2.52 (s, 0.6H), 2.59 (s, 0.6H), 3.00 (s,
2.4H), 3.22 (s, 2.4H), 4.77e5.00 (m, 1H), 5.08e5.17 (m, 0.2H),
5.33e5.41 (m, 0.8H), 5.92e6.04 (m, 0.8H), 6.34 (d, 0.2H, J¼5.5 Hz),
6.79e7.91 (m, 12H); 13C NMR (CDCl3)
d 34.3 (t), 35.7 (q), 36.2 (q),
36.5 (q), 37.1 (t), 37.3 (q), 55.5 (d), 58.1 (d), 62.2 (d), 70.4 (d), 71.5
(d), 122.8 (d), 123.4 (d), 124.8 (d), 125.1 (d), 125.6 (d), 125.7 (d),
126.1 (d), 126.2 (d), 127.1 (d), 127.2 (d), 127.4 (d), 127.9 (d), 128.1
(d), 128.3 (d), 128.4 (d), 128.7 (d), 128.9 (d), 129.8 (d), 131.3 (s),
133.2 (s), 133.9 (s), 134.1 (s), 136.2 (s), 171.2 (s), 171.4 (s), 171.6 (s);
HRMS (ESI) calcd for C24H25N2O3 (MþH)þ 389.1867, found
389.1860.
4.3.20. (2S,4R,5R)-1-Benzoyl-4-hydroxy-5-(3-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (6c). White solid; Rf 0.25 (ethyl
24
acetate/ethanol¼10:1); mp 197e198 ꢀC (recryst from CH2Cl2); [
a]
D
ꢁ87.3 (c 1.00, CHCl3); IR (KBr) 3430, 1636, 1613, 1603, 1582, 795,
700 cmꢁ1
;
1H NMR (CDCl3)
d
1.68 (d, 1H, J¼4.2 Hz), 2.08e2.31 (m,
2H), 2.56 (s, 0.6H), 2.59 (s, 0.6H), 3.02 (s, 2.4H), 3.25 (s, 2.4H), 3.72
(s, 2.4H), 3.81 (s, 0.6H), 4.59e4.65 (m, 0.2H), 4.76e4.86 (m, 0.8H),
5.00e5.08 (m, 1H), 5.32 (dd, 0.8H, J¼7.6, 4.4 Hz), 5.44e5.48 (m,
4.3.25. (2S,4R,5R)-1-Benzoyl-4-hydroxy-N,N-dimethyl-5-(naph-
0.2H), 6.45e7.51 (m, 9H); 13C NMR (CDCl3)
d
34.4 (t), 36.2 (q), 37.3
thalen-2-yl)pyrrolidine-2-carboxamide (6h). White solid; Rf 0.3
(q), 55.2 (q), 55.4 (d), 66.5 (d), 71.6 (d), 113.1 (d), 113.6 (d), 119.9 (d),
126.5 (d), 127.7 (d), 129.2 (d), 129.5 (d), 136.6 (s), 139.2 (s), 159.6 (s),
171.2 (s), 171.5 (s). Anal. Calcd for C21H24N2O4: C, 68.46%; H, 6.57%;
N, 7.60%. Found: C, 68.40%; H, 6.55%; N, 7.51%.
(ethyl acetate/ethanol¼10:1); mp >300 ꢀC (recryst from ethanol);
22
[a
]
ꢁ158.5 (c 0.10, methanol); IR (KBr) 3430, 1645, 1628, 1601,
D
1578, 835, 764, 706 cmꢁ1 1H NMR (CDCl3)
; d 1.04e1.40 (m, 1H),
2.17e2.43 (m, 2H), 2.59 (s, 0.6H), 2.66 (s, 0.6H), 3.07 (s, 2.4H), 3.31
(s, 2.4H), 4.69e4.73 (m, 0.2H), 4.89e4.97 (m, 0.8H), 5.17e5.21 (m,
0.2H), 5.28 (d, 0.8H, J¼7.0 Hz), 5.46 (dd, 0.8H, J¼8.3, 3.7 Hz), 5.67 (d,
0.2H, J¼5.7 Hz), 6.98e7.18 (m, 5H), 7.37e7.56 (m, 4H), 7.70e7.91 (m,
3H). Anal. Calcd for C24H24N2O3: C, 74.21%; H, 6.23%; N, 7.21%.
Found: C, 74.17%; H, 6.30%; N, 7.16%.
4.3.21. (2S,4R,5R)-1-Benzoyl-4-hydroxy-5-(2-methoxyphenyl)-N,N-
dimethylpyrrolidine-2-carboxamide (6d). White solid; Rf 0.3 (ethyl
acetate/ethanol¼10:1); mp 171e172 ꢀC (recryst from hexanes/ethyl
acetate¼1:5); [
a
]
24 ꢁ37.2 (c 1.06, CHCl3); 1H NMR (CDCl3)
d 1.93 (br
D
s,1H), 2.06e2.30 (m, 2H), 2.57 (s, 0.6H), 2.61 (s, 0.6H), 3.04 (s, 2.4H),
3.26 (s, 2.4H), 3.61 (s, 2.4H), 3.90 (s, 0.6H), 4.77 (dd, 0.2H, J¼12.3,
6.2 Hz), 4.85 (dd, 0.8H, J¼14.1, 6.8 Hz), 5.06 (dd, 0.2H, J¼8.2, 5.0 Hz),
5.30e5.36 (m, 0.8H), 5.63 (d, 0.8H, J¼6.8 Hz), 5.93 (d, 0.2H,
4.3.26. (4S)-Methyl 5-(dimethylamino)-5-oxo-4-(phenyl(trimethylsilyl)
methylamino)pentanoate (11a) (8:2 diastereomeric mixture). Pale yel-
low paste; Rf 0.75 (hexanes/ethyl acetate¼1:1); 1H NMR (CDCl3)
J¼6.2 Hz), 6.65e7.51 (m, 9H); 13C NMR (CDCl3)
d
34.3 (t), 36.2 (q),
d
ꢁ0.03 (s, 7.2H), ꢁ0.02 (s,1.8H),1.57e1.87 (m, 2H), 2.18e2.47 (m, 2H),
37.4 (q), 55.58 (d), 55.60 (q), 70.1 (d), 71.5 (d), 110.7 (d), 120.9 (d),
126.3 (s), 126.4 (d), 127.4 (d), 128.2 (d), 128.9 (d), 129.0 (d), 136.6 (s),
156.6 (s), 171.1 (s), 171.6 (s). Anal. Calcd for C21H24N2O4: C, 68.46%;
H, 6.57%; N, 7.60%. Found: C, 68.50%; H, 6.58%; N, 7.67%.
2.63 (s, 0.6H), 2.73 (s, 0.6H), 2.77 (s, 2.4H), 3.00 (s, 2.4H), 3.07 (s, 0.8H),
3.23 (s, 0.2H), 3.38e3.47 (m, 1H), 3.63 (s, 2.4H), 3.69 (s, 0.6H),
7.03e7.30 (m, 5H).
4.3.27. (4S)-Methyl 5-(diethylamino)-5-oxo-4-(phenyl(trimethylsilyl)
methylamino)pentanoate (11b) (7:3 diastereomeric mixture). Pale yel-
low paste; Rf 0.55 (hexanes/ethyl acetate¼2:1); 1H NMR (CDCl3)
4.3.22. (2S,4R,5R)-1-Benzoyl-5-(4-fluorophenyl)-4-hydroxy-N,N-di-
methylpyrrolidine-2-carboxamide (6e). White solid; Rf 0.3 (ethyl
acetate/ethanol¼10:1); mp 243e245 ꢀC (recryst from ethyl acetate/
d
ꢁ0.04 (s, 2.7H), ꢁ0.03 (s, 6.3H), 0.70 (t, 0.9H, J¼7.3 Hz), 0.82 (t, 2.1H,
24
ethanol¼1:1);
[
a
]
D
ꢁ74.8 (c 0.82, CHCl3). 1H NMR (CDCl3)
J¼7.3 Hz), 0.97 (t, 0.9H, J¼7.3 Hz), 1.10 (t, 2.1H, J¼7.3 Hz), 1.60e1.75
(m, 2H), 2.35e2.76 (m, 2H), 2.85e2.95 (m, 1H), 3.01e3.31 (m, 4H),
3.56e3.64 (m, 3.1H), 3.68 (s, 0.9H), 7.03e7.23 (m, 5H); 13C NMR
d
2.11e2.31 (m, 2H), 2.56 (s, 0.6H), 2.61 (s, 0.6H), 3.03 (s, 2.4H), 3.25
(s, 2.4H), 4.60 (dd, 0.2H, J¼11.5, 5.2), 4.80 (dd, 0.8H, J¼14.3, 6.7 Hz),
5.06e5.10 (m, 1H), 5.34 (dd, 0.8H, J¼7.7, 3.1 Hz), 5.46 (d, 0.2H,
(CDCl3) major:
40.9 (t), 51.3 (q), 54.8 (d), 55.6 (d), 125.0 (d), 126.9 (d), 127.7 (d), 142.5
(s), 173.9 (s), 174.0 (s), minor:
d
ꢁ4.0 (q), 13.0 (q), 14.2 (q), 28.5 (t), 30.2 (t), 40.31 (t),
J¼6.6 Hz), 6.86e7.48 (m, 9H); 13C NMR (CDCl3)
d 34.3 (t), 36.2 (q),
37.3 (q), 55.4 (d), 66.1 (d), 71.5 (d), 115.3 (d, JCCF¼21.1 Hz), 126.4 (d),
127.1 (d), 127.8 (d), 129.3 (d, JCCCF¼8.6 Hz), 133.4 (s, JCCCCF¼2.6 Hz),
136.5 (s), 162.2 (s, JCF¼247.4 Hz), 171.3 (s), 171.5 (s). Anal. Calcd for
C20H21FN2O3: C, 67.40%; H, 5.94%; N, 7.86%. Found: C, 67.56%; H,
6.09%; N, 7.72%.
d
ꢁ3.7 (q), 12.7 (q), 13.6 (q), 29.2 (t), 29.6
(t), 40.27 (t), 41.3 (t), 51.3 (q), 56.7 (d), 56.8 (d), 125.1 (d), 127.0 (d),
127.8 (d), 143.2 (s), 174.2 (s), 174.5 (s).
4.3.28. (2S,5S,6S)-1-Benzoyl-5-hydroxy-N,N-dimethyl-6-
phenylpiperidine-2-carboxamide (12a). White solid; Rf 0.25 (ethyl
22
4.3.23. (2S,4R,5R)-1-Benzoyl-5-(4-cyanophenyl)-4-hydroxy-N,N-di-
methylpyrrolidine-2-carboxamide (6f). White solid; Rf 0.35 (ethyl
acetate); mp 179e181 ꢀC (recryst from ethyl acetate); [
a]
106 (c
D
0.83, CHCl3); 1H NMR (CDCl3)
d 1.86e1.95 (m, 1H), 1.97e2.06 (m,
23
acetate/ethanol¼10:1); mp 247e248 ꢀC (recryst from CH2Cl2); [
a
]
2H), 2.19e2.29 (m, 1H), 2,86 (s, 3H), 3.08 (s, 3H), 3.89 (br s, 1H),
4.12e4.19 (m, 1H), 5,04 (d, 1H, J¼5.1 Hz), 5.20e5.25 (m, 1H),
D
ꢁ107 (c 1.06, CHCl3); 1H NMR (CDCl3)
d 1.21e1.36 (m, 1H),
2.09e2.40 (m, 2H), 2.56 (s, 0.9H), 2.60 (s, 0.9H), 3.01 (s, 2.1H), 3.52
(s, 2.1H), 4.66 (dd, 0.3H, J¼11.3, 5.6 Hz), 4.88 (dd, 0.7H, J¼14.3,
6.9 Hz), 5.08 (dd, 0.3H, J¼7.7, 5.6 Hz), 5.12 (d, 0.7H, J¼6.9 Hz), 5.34
7.18e7.34 (m, 8H), 7.56e7.61 (m, 2H); 13C NMR
d 21.5 (t), 26.2 (t),
36.3 (q), 37.2 (q), 49.6 (d), 63.3 (d), 68.6 (d),126.5 (d),127.0 (d),127.9
(d), 128.2 (d), 129.8 (d), 135.9 (s), 138.6 (s), 172.9 (s), 173.5 (s). Anal.

Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
2587
Calcd for C21H24N2O3: C, 71.57%; H, 6.86%; N, 7.95%. Found: C,
71.60%; H, 6.85%; N, 7.88%.
4.4.1. (2S,3S,6S)-1-Benzoyl-6-(methoxymethyl)-2-phenylpiperidin-3-
yl benzoate (14). White solid; Rf 0.6 (hexanes/ethyl acetate¼2:1);
20
mp 114e115 ꢀC (recryst from hexanes/ethyl acetate¼2:1); [
a
]
76
D
4.3.29. (2S,5S,6S)-1-Benzoyl-5-hydroxy-N,N-diethyl-6-
(c 1.07, CHCl3); IR (KBr) 1715, 1628, 1601, 1582, 727, 718, 698 cmꢁ1
;
phenylpiperidine-2-carboxamide (12b). White solid; Rf 0.3 (hex-
1H NMR (CDCl3)
(m, 1H), 2.79e2.97 (m, 5H), 4.00e4.59 (m, 1H), 5.48e5.61 (m, 1H),
6.10e6.60 (m, 1H), 7.24e8.01 (m, 15H); 13C NMR (CDCl3)
22.3 (t),
d 1.81e1.98 (m, 2H), 2.12e2.21 (m, 1H), 2.40e2.54
anes/ethyl acetate¼1:2); mp 179e180 ꢀC (recryst from ethyl ace-
21
tate); [
a
]
125 (c 0.75, CHCl3); 1H NMR (CDCl3)
d
1.19 (t, 3H,
d
D
J¼7.3 Hz), 1.24 (t, 3H, J¼7.3 Hz), 1.85e1.97 (m, 2H), 2.11e2.28 (m,
2H), 3.27e3.48 (m, 3H), 3.65e3.76 (m, 1H), 4.16e4.23 (m, 1H), 4.61
(d, 1H, J¼9.2 Hz), 5.00 (d, 1H, J¼5.0 Hz), 5.22 (t, 1H, J¼7.3 Hz),
7.14e7.21 (m, 5H), 7.22e7.30 (m, 3H), 7.48e7.53 (m, 2H); 13C NMR
24.9 (t), 52.4 (d), 58.0 (q), 71.6 (t), 72.2 (d), 126.5 (d), 127.0 (d), 128.0
(d), 128.1 (d), 128.3 (d), 128.4 (d), 129.3 (d), 129.5 (d), 129.7 (s), 133.1
(d),136.3 (s),138.5 (s),165.3 (s),172.4 (s). Anal. Calcd for C27H27NO4:
C, 75.50%; H, 6.34%; N, 3.26%. Found: C, 75.52%; H, 6.31%; N, 3.20%.
(CDCl3) d 12.7 (q), 14.3 (q), 21.6 (t), 26.3 (t), 41.3 (t), 42.2 (t), 50.0 (d),
64.1 (d), 68.0 (d), 126.5 (d), 126.7 (d), 127.7 (d), 127.9 (d), 128.0 (d),
129.6 (d), 136.1 (s), 139.6 (s), 172.9 (s), 174.1 (s). Anal. Calcd for
C23H28N2O3: C, 72.60%; H, 7.42%; N, 7.36%. Found: C, 72.68%; H,
7.45%; N, 7.20%.
4.4.2. (2S,3R,6R)-1-Benzoyl-6-(methoxymethyl)-2-phenylpiperidin-
3-yl benzoate (15). Colorless paste; Rf 0.5 (hexanes/ethyl
21
acetate¼2:1);
[a
]
ꢁ56.8 (c 1.24, CHCl3); 1H NMR (CDCl3)
D
d
1.87e2.21 (m, 4H), 3.37 (s, 3H), 3.66e3.94 (m, 2H), 4.24e4.36 (m,
1H), 5.23 (d, 1H, J¼4.5 Hz), 5.58e5.66 (m, 1H), 7.11e8.10 (m, 15H);
4.3.30. ((2S,3S,6S)-3-Hydroxy-6-(methoxymethyl)-2-phenylpiperidin-
13C NMR (CDCl3)
d
21.3 (t), 23.0 (t), 52.6 (d), 58.9 (q), 60.3 (d), 71.2
1-yl)(phenyl)methanone (12c). Colorless paste; Rf 0.3 (hexanes/ethyl
(d), 73.6 (t), 126.95 (d), 127.05 (d), 128.2 (d), 128.26 (d), 128.29 (d),
129.4 (d), 129.7 (s), 129.87 (d), 129.90 (d), 130.0 (d), 136.5 (s), 138.4
(s), 165.3 (s), 174.2 (s); HRMS (ESI) calcd for C27H28NO4 (MþH)þ
430.2020, found 430.2011.
acetate¼1:1); [
(m, 3H), 2.19e2.31 (m, 1H), 2.77e3.02 (m, 5H), 4.08e4.24 (m, 2H),
5.84e6.33 (m, 1H), 7.17e7.74 (m, 10H); 13C NMR (CDCl3)
24.4 (t),
a] d 1.66e1.92
23 91.1 (c 1.00, CHCl3); 1H NMR (CDCl3)
D
d
24.7 (t), 52.5 (d), 54.9 (d), 58.0 (q), 70.2 (d), 72.0 (t), 126.3 (d), 126.7
(d), 127.9 (d), 128.3 (d), 128.4 (d), 129.2 (d), 136.6 (s), 138.8 (s), 172.8
(s); HRMS (ESI) calcd for C20H24NO3 (MþH)þ 326.1758, found
326.1754.
4.5. Typical procedure for electroreduction of imino esters 1
and subsequent transformation to 8
After electroreduction of 1a (1 mmol) was carried out as de-
scribed above, the catholyte was evaporated in vacuo. The residue
was dissolved in Et2O (20 mL) and insoluble solid was filtered off.
After the solvent was removed, the residue was dissolved in di-
oxane (5 mL) and 1 M HCl (5 mL). The mixture was stirred at 25 ꢀC
for 12 h with vigorous stirring under open-air conditions, and then
the solvent was evaporated in vacuo. The residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate) to
give 7a in 52% yield.
4.3.31. (2S,5R,6R)-1-Benzoyl-5-hydroxy-N,N-dimethyl-6-
phenylpiperidine-2-carboxamide (13a). White solid; Rf 0.25 (ethyl
acetate); mp 215e216 ꢀC (recryst from ethyl acetate); [
a]
22 ꢁ58.3 (c
D
1.03, CHCl3); 1H NMR (CDCl3)
d 0.62 (br s, 1H), 1.36e1.56 (m, 3H),
1.78e1.88 (m, 1H), 2.13 (br s, 3H), 2.66 (br s, 3H), 4.49e4.57 (m, 1H),
5.02e5.08 (m, 1H), 5.21e5.27 (m, 1H), 6.91e7.23 (m, 10H). Anal.
Calcd for C21H24N2O3: C, 71.57%; H, 6.86%; N, 7.95%. Found: C,
71.65%; H, 6.89%; N, 7.82%.
To a solution of the crude 7a in dioxane (5 mL) were added
benzoyl chloride (0.12 mL, 1 mmol) and TEA (0.21 mL, 1.5 mmol) at
25 ꢀC. The mixture was stirred for 6 h, diluted with water (10 mL),
and then extracted with ethyl acetate three times. After the solvent
was removed, the residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate) to give 8a in 54% yield.
4.3.32. (2S,5R,6R)-1-Benzoyl-5-hydroxy-N,N-diethyl-6-
phenylpiperidine-2-carboxamide (13b). White solid; Rf 0.4 (hex-
anes/ethyl acetate, 1:5); mp 183e184 ꢀC (recryst from ethyl ace-
21
tate); [
a]
ꢁ66.0 (c 1.01, CHCl3); 1H NMR (CDCl3)
d 1.05e2.07 (m,
D
9H), 2.29e2.47 (m, 1H), 3.16e3.69 (m, 4H), 4.37e4.69 (m, 1H),
4.92e5.40 (m, 2H), 7.03e7.43 (m,10H); 13C NMR
d (CDCl3) d 12.7 (q),
13.8 (q), 22.3 (t), 25.0 (t), 40.8 (t), 41.9 (t), 51.6 (d), 62.2 (d), 67.3 (d),
126.6 (d), 126.8 (d), 127.6 (d), 127.9 (d), 128.0 (d), 129.1 (d), 136.5 (s),
139.9 (s), 171.5 (s), 174.2 (s). Anal. Calcd for C23H28N2O3: C, 72.60%;
H, 7.42%; N, 7.36%. Found: C, 72.74%; H, 7.51%; N, 7.21%.
4.5.1. 4-Hydroxy-N,N-dimethyl-5-phenyl-1H-pyrrole-2-carboxamide
(7a). Pale yellow solid; Rf 0.5 (hexanes/ethyl acetate¼1:5); mp
246e248 ꢀC (recryst from methanol); IR (KBr) 3229, 1605, 1568,
1539, 1526, 1489, 773, 745, 698, 691, 662 cmꢁ1; 1H NMR (DMSO-d6)
d
2.86 (br s, 6H), 5.89e5.93 (m,1H), 6.84e6.90 (m,1H), 7.04e7.11 (m,
2H), 7.64e7.69 (m, 2H), 8.67 (s,1H),10.63 (br s,1H); 13C NMR (DMSO-
d6) 37.3 (q), 103.4 (d), 116.9 (s), 121.2 (s), 124.5 (d), 125.0 (d), 128.3
(d), 132.1 (s), 142.1 (s), 162.3 (s). Anal. Calcd for C20H18N2O3: C,
71.84%; H, 5.43%; N, 8.38%. Found: C, 71.89%; H, 5.41%; N, 8.28%.
4. 3. 33. ((2S, 3R, 6R)-3-Hydroxy-6-(methoxymethyl)-2-
phenylpiperidin-1-yl)(phenyl)methanone (13c). Colorless paste; Rf
d
0.3 (hexanes/ethyl acetate¼1:1); [
a
]
24 ꢁ122 (c 1.01, CHCl3); 1H NMR
D
(CDCl3)
d
1.50e1.96 (m, 3H), 2.07e2.17 (m, 1H), 3.41 (s, 3H),
3.54e3.64 (m, 1H), 3.80e3.85 (m, 1H), 4.29e4.36 (m, 1H),
4.42e4.50 (m, 1H), 4.70e4.78 (m, 1H), 7.19e7.73 (m, 10H); 13C NMR
(CDCl3) d 21.4 (t), 24.6 (t), 27.4 (d), 59.1 (q), 67.7 (d), 70.2 (d), 72.2 (t),
126.3 (d), 126.8 (d), 128.2 (d), 128.4 (d), 129.9 (d), 130.7 (d), 135.6 (s),
138.5 (s), 175.8 (s); HRMS (ESI) calcd for C20H24NO3 (MþH)þ
326.1758, found 326.1751.
4.5.2. 5-(Dimethylcarbamoyl)-2-phenyl-1H-pyrrol-3-yl benzoate (8a).
White solid; Rf 0.65 (hexanes/ethyl acetate¼1:5); mp 181e183 ꢀC
(recryst from ethyl acetate); IR (KBr) 3204, 1728, 1601, 1570, 1520,
1489, 826, 760, 704, 689 cmꢁ1; 1H NMR (CDCl3)
d 3.15 (br s, 3H), 3.34
(br s, 3H), 6.80e6.88 (m, 1H), 7.24e7.32 (m, 1H), 7.35e7.44 (m, 2H),
7.48e7.57 (m, 2H), 7.61e7.71 (m, 3H), 8.18e8.26 (m, 2H), 10.08 (br s,
4.4. O-Benzoylation of 12c and 13c
1H); 13C NMR (CDCl3)
d 36.8 (q), 38.9 (q), 107.4 (d), 121.5 (s), 123.5 (s),
126.1 (d), 127.2 (d), 128.57 (d), 128.60 (d), 129.4 (s), 130.0 (s), 130.1 (d),
133.5 (d), 134.0 (s), 162.2 (s), 164.6 (s). Anal. Calcd for C27H22N2O4: C,
73.96%; H, 5.06%; N, 6.39%. Found: C, 74.07%; H, 5.10%; N, 6.25%.
To the 1:1 mixture of 12c and 13c (143 mg, 0.44 mmol) was
added pyridine (1 mL) and benzoyl chloride (0.12 mL, 1 mmol). The
solution was stirred at 25 ꢀC for 12 h and then evaporated in vacuo.
The residue was purified by column chromatography on silica gel
(hexanes/ethyl acetate) to give 14 and 15 in quantitative yields,
respectively.
4.5.3. 5-(Dimethylcarbamoyl)-2-(4-methoxyphenyl)-1H-pyrrol-3-yl
benzoate (8b). White solid; Rf 0.6 (hexanes/ethyl acetate¼1:5); mp
147e149 ꢀC (recryst from hexanes/ethyl acetate¼1:5); 1H NMR

2588
Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
(CDCl3)
d
3.23 (br s, 6H), 3.80 (s, 3H), 6.78e6.98 (m, 3H), 7.47e7.68
36.9
(s), 127.9 (d), 128.1 (d), 128.6 (d), 129.4 (s), 130.0 (d), 132.3 (s),
133.3 (s), 133.5 (d), 134.5 (s), 162.3 (s), 164.5 (s). Anal. Calcd for
C31H24N2O4: C, 76.21%; H, 4.95%; N, 5.73%. Found: C, 76.32%; H,
(m, 5H), 8.16e8.24 (m, 2H), 10.08 (br s, 1H); 13C NMR (CDCl3)
d
(q), 38.4 (q), 55.2 (q), 107.4 (d), 114.2 (d), 120.9 (s), 122.8 (s), 123.5
(s), 127.5 (d), 128.6 (d), 129.5 (s), 130.0 (d), 133.4 (s), 133.5 (d), 158.9
(s), 162.2 (s), 164.7 (s). Anal. Calcd for C28H24N2O5: C, 71.78%; H,
5.16%; N, 5.98%. Found: C, 71.82%; H, 5.18%; N, 5.85%.
5.02%; N, 5.63%.
4.6. X-ray crystallographic analysis
All measurements were made on a Rigaku RAXIS imaging plate
4.5.4. 5-(Dimethylcarbamoyl)-2-(3-methoxyphenyl)-1H-pyrrol-3-yl
benzoate (8c). White solid; Rf 0.6 (hexanes/ethyl acetate¼1:5); mp
81e83 ꢀC (recryst from hexanes/ethyl acetate¼1:5); 1H NMR (CDCl3)
area detector with graphite monochromated Mo Ka radiation. The
structure was solved by direct methods with SIR-97 and refined
with SHELXL-97. The non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were refined isotropically. All calcula-
tions were performed with the YADOKARI-XG software package.
Crystal data are as follows: CCDC 862781e862792 contain the
supplementary crystallographic data. These data can be obtained
free of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
d
3.02e3.49 (m, 6H), 3.74 (s, 3H), 6.79e6.86 (m, 2H), 7.17e7.68 (m,
6H), 8.18e8.25(m, 2H), 9.83(brs,1H); 13C NMR (CDCl3)
d 36.8(q), 38.8
(q), 55.1 (q), 107.5 (d), 111.0 (d), 113.6 (d), 118.3 (d), 121.5 (s), 123.2 (s),
128.6 (d), 129.4 (s), 129.8 (d), 130.1 (d), 131.2 (s), 133.6 (d), 134.3 (s),
159.9 (s), 162.0 (s), 164.6 (s). Anal. Calcd for C28H24N2O5: C, 71.78%; H,
5.16%; N, 5.98%. Found: C, 71.77%; H, 5.21%; N, 5.92%.
4.5.5. 5-(Dimethylcarbamoyl)-2-(2-methoxyphenyl)-1H-pyrrol-3-yl
benzoate (8d). White solid; Rf 0.65 (hexanes/ethyl acetate¼1:5);
mp 143e144 ꢀC (recryst from hexanes/ethyl acetate¼1:5); 1H NMR
4.6.1. Crystal data for 4a (CCDC 862784). C20H22N2O3, FW¼338.40,
mp 194e196 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
(CDCl3)
d
3.26 (br s, 6H), 3.93 (s, 3H), 6.73e7.87 (m, 9H), 8.17e8.25
a¼6.2349(12) A, b¼9.3862(16) A, c¼29.881(5) A, V¼1748.7(5) A ,
(m, 1H), 10.43 (br s, 1H); 13C NMR (CDCl3)
d
37.6 (q), 55.6 (q), 106.5
T¼298 K, Z¼4, Dcalcd¼1.285 g/cm3,
m
¼0.87 cmꢁ1, GOF¼0.923.
(d), 111.4 (d), 118.5 (s), 120.26 (s), 120.34 (s), 121.0 (d), 128.1 (d),
128.3 (d), 128.6 (d), 129.5 (s), 130.0 (d), 133.5 (d), 134.5 (s), 155.6 (s),
161.9 (s), 164.6 (s). Anal. Calcd for C28H24N2O5: C, 71.78%; H, 5.16%;
N, 5.98%. Found: C, 71.92%; H, 5.16%; N, 5.80%.
4.6.2. Crystal data for 4e (CCDC 862785). C20H21FN2O3, FW¼356.39,
mp 259e260 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼6.2101(7) A, b¼9.4330(13) A, c¼29.665(3) A, V¼1737.8(4) A ,
T¼298 K, Z¼4, Dcalcd¼1.362 g/cm3,
m
¼0.99 cmꢁ1, GOF¼1.015.
4.5.6. 5-(Dimethylcarbamoyl)-2-(4-fluorophenyl)-1H-pyrrol-3-yl
benzoate (8e). Yellow solid; Rf 0.5 (hexanes/ethyl acetate¼1:5); mp
194e195 ꢀC (recryst from hexanes/ethyl acetate¼1:2); 1H NMR
4.6.3. Crystal data for 4g (CCDC 862786). C24H24N2O3, FW¼388.45,
mp 269e271 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
(CDCl3)
d
3.12 (br s, 3H), 3.34 (br s, 3H), 6.78e6.84 (m, 1H),
a¼9.4429(13) A, b¼9.5870(14) A, c¼22.697(3) A, V¼2054.7(5) A ,
7.02e7.12 (m, 2H), 7.48e7.71 (m, 5H), 8.14e8.24 (m, 2H), 10.44 (br s,
T¼296 K, Z¼4, Dcalcd¼1.256 g/cm3,
m
¼0.83 cmꢁ1, GOF¼0.946.
1H); 13C NMR (CDCl3)
d
37.1 (q), 39.0 (q), 107.4 (d), 115.5 (d,
JCCF¼22.1 Hz), 121.5 (s), 123.0 (s), 126.4 (s, JCCCCF¼2.9 Hz), 128.1 (d,
JCCCF¼7.7 Hz), 128.6 (d), 129.3 (s), 130.0 (d), 133.5 (d), 133.8 (s), 161.9
(s, JCF¼247.8 Hz), 162.3 (s), 164.6 (s). Anal. Calcd for C27H21FN2O4: C,
71.04%; H, 4.64%; N, 6.14%. Found: C, 71.18%; H, 4.71%; N, 6.12%.
4.6.4. Crystal data for 5a (CCDC 862787). C20H22N2O3, FW¼338.40,
mp 206e207 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼5.8642(10) A, b¼9.5412(17) A, c¼31.703(5) A, V¼1773.8(5) A ,
T¼298 K, Z¼4, Dcalcd¼1.267 g/cm3,
m
¼0.86 cmꢁ1, GOF¼1.020.
4.5.7. 5-(Dimethylcarbamoyl)-2-(4-cyanophenyl)-1H-pyrrol-3-yl
benzoate (8f). White solid; Rf 0.55 (hexanes/ethyl acetate¼1:5); mp
233e234 ꢀC (recryst from hexanes/ethyl acetate¼1:5); 1H NMR
4.6.5. Crystal data for 5b (CCDC 862788). C21H24N2O4, FW¼368.42,
mp 201e202 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼16.140 A, b¼6.064 A, c¼19.062 A, V¼1865.7 A , T¼298 K, Z¼4,
(CDCl3)
d
3.11 (br s, 3H), 3.38 (br s, 3H), 6.82e6.85 (m,1H), 7.51e7.87
Dcalcd¼1.312 g/cm3,
m
¼0.91 cmꢁ1, GOF¼1.043.
(m, 7H), 8.16e8.29 (m, 2H), 11.08 (br s, 1H); 13C NMR (CDCl3)
d 36.9
(q), 39.1 (q), 107.7 (d), 110.0 (s), 118.8 (s), 121.7 (s), 123.2 (s), 126.3
(d), 128.7 (d), 129.0 (s), 130.0 (d), 132.3 (d), 133.8 (d), 134.5 (s), 135.6
(s), 162.2 (s), 164.3 (s). Anal. Calcd for C28H21N3O4: C, 72.56%; H,
4.57%; N, 9.07%. Found: C, 72.48%; H, 4.49%; N, 8.97%.
4.6.6. Crystal data for 6c (CCDC 862789). C21H24N2O4, FW¼368.42,
mp 197e198 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼9.681(3) A, b¼13.873(6) A, c¼14.908(7) A, V¼2002.3(15) A ,
T¼298 K, Z¼4, Dcalcd¼1.222 g/cm3,
m
¼0.85 cmꢁ1, GOF¼1.017.
4.5.8. 5-(Dimethylcarbamoyl)-2-(naphthalen-1-yl)-1H-pyrrol-3-yl
4.6.7. Crystal data for 6h (CCDC 862790). C24H24N2O3, FW¼388.45,
mp >300 ꢀC, orthorhombic, P212121 (no. 19), colorless block,
benzoate (8g). White solid; Rf 0.65 (hexanes/ethyl acetate¼1:5); mp
236e238 ꢀC (recryst from ethyl acetate); 1H NMR (CDCl3)
d
2.70e3.60
a¼14.1824(9) A, b¼14.2274(11) A, c¼10.1258(7) A, V¼2043.2(2) A ,
3
ꢀ
ꢀ
ꢀ
ꢀ
(m, 6H), 5.00e5.25 (m, 0.3H), 6.33e6.37 (m, 0.3H), 6.88e6.91 (m,
0.7H), 7.24e8.07 (m, 11.7H), 9.47e9.62 (m, 0.3H), 10.00e10.21 (m,
T¼298 K, Z¼4, Dcalcd¼1.263 g/cm3,
m
¼0.84 cmꢁ1, GOF¼1.015.
0.7H);13C NMR(CDCl3)
d
36.7(q), 38.5(q),106.7(d),121.9(s),122.8(s),
4.6.8. Crystal data for 7a (CCDC 862791). C13H14N2O2, FW¼230.26,
mp 246e248 ꢀC, orthorhombic, Pbcn (no. 60), colorless block,
125.2 (d), 125.9 (d), 126.0 (d), 126.5 (d), 127.8 (s), 128.0 (d), 128.2 (d),
128.3 (d), 128.7 (d), 129.3 (s), 129.9 (d), 131.5 (s), 133.2 (d), 133.7 (s),
134.7 (s), 162.0 (s), 164.6 (s). Anal. Calcd for C31H24N2O4: C, 76.21%; H,
4.95%; N, 5.73%. Found: C, 76.20%; H, 4.92%; N, 5.68%.
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼9.5243(7) A, b¼11.1522(7) A, c¼22.0081(13) A, V¼2337.6(3) A ,
T¼298 K, Z¼8, Dcalcd¼1.309 g/cm3,
m
¼0.90 cmꢁ1, GOF¼1.053.
4.6.9. Crystalꢀdata for 8a (CCDC 862792). C20H18N2O3, FW¼334.36,
ꢀ
4.5.9. 5-(Dimethylcarbamoyl)-2-(naphthalen-2-yl)-1H-pyrrol-3-yl
benzoate (8h). White solid; Rf 0.6 (hexanes/ethyl acetate¼1:5);
mp 183e185 ꢀC (recryst from hexanes/ethyl acetate¼1:5); 1H
mp 181e183 C, triclinic, P-1 (no. 2), colorless block, a¼8.880(9) A,
ꢀ
ꢀ
b¼9.593(6) A, c¼10.110(7) A,
a
¼108.13(8),
b
¼92.52(8), ¼96.80(7),
g
V¼809.7(11) A , T¼298 K, Z¼2, Dcalcd¼1.371 g/cm3,
m
¼0.93 cmꢁ1
,
3
ꢀ
NMR (CDCl3)
d 3.15 (br s, 3H), 3.35 (br s, 3H), 6.87e6.93 (m, 1H),
GOF¼1.068.
7.40e7.91 (m, 9H), 8.08e8.14 (m, 1H), 8.21e8.29 (m, 2H), 10.16 (br
s, 1H); 13C NMR (CDCl3)
36.4 (q), 38.8 (q), 107.5 (d), 121.8 (s),
123.7 (s), 124.3 (d), 125.1 (d), 125.9 (d), 126.2 (d), 127.52 (d), 127.54
d
4.6.10. Crystal data for 12a (CCDC 862781). C21H24N2O3,
FW¼352.42, mp 179e181 ꢀC, orthorhombic, P212121 (no. 19),

Y. Takenaga et al. / Tetrahedron 68 (2012) 2579e2589
2589
3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
colorless block, a¼7.9183(4) A, b¼12.2737(8) A, c¼20.0040(10) A,
a¼8.73(3) A, b¼8.26(3) A, c¼16.35(6) A, ¼101.8(3), V¼1155(7) A ,
b
V¼1944.13(19) A , T¼298 K, Z¼4, Dcalcd¼1.204 g/cm3,
m
¼0.81 cmꢁ1
,
T¼298 K, Z¼2, Dcalcd¼1.235 g/cm3,
m
¼0.83 cmꢁ1, GOF¼1.051.
3
ꢀ
GOF¼1.019.
References and notes
4.6.11. Crystal data for 13a (CCDC 862782). C21H24N2O3,
FW¼352.42, mp 215e216 ꢀC, monoclinic, P21 (no. 4), colorless
1. Kise, N.; Ozaki, H.; Moriyama, N.; Kitagishi, Y.; Ueda, N. J. Am. Chem. Soc. 2003,
125, 11591.
2. Kise, N.; Ohya, K.; Arimoto, K.; Yamashita, Y.; Hirano, Y.; Ono, T.; Ueda, N. J. Org.
Chem. 2004, 69, 7710.
3. Kise, N.; Hirano, Y.; Tanaka, Y. Org. Lett. 2006, 8, 1323.
4. We have recently reported that the electroreductive four-membered cyclization
ꢀ
ꢀ
ꢀ
b
block, a¼19.323(5) A, b¼7.8956(14) A, c¼19.226(5) A, ¼18.399(3),
V¼925.8(4) A , T¼298 K, Z¼4, Dcalcd¼1.264 g/cm3,
m
¼0.85 cmꢁ1
,
3
ꢀ
GOF¼1.044.
of
a-imino esters is much more favorable than their intermolecular coupling
4.6.12. Crystal data for 14 (CCDC 862783). C27H27NO4, FW¼429.50,
mp 114e115 ꢀC, monoclinic, P21 (no. 4), colorless block,
with ketones: Kise, N.; Yamane, A.; Nakano, S.; Takebe, A.; Sakurai, T. Tetrahe-
dron: Asymmetry 2011, 22, 1906.