Asymmetric synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with an N-magnesio arylamine

Article abstract of DOI:10.1016/j.tetasy.2009.06.024

The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from ω-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substitution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction. Proline and pipecolic acid derivatives were also synthesized from ω-(arylamino)-1-chloroalkyl p-tolyl sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,R_S)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained. The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these reactions is also discussed.

Full text of DOI:10.1016/j.tetasy.2009.06.024

Tetrahedron: Asymmetry 20 (2009) 1697–1708
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of cyclic a-amino acid derivatives
by the intramolecular reaction of magnesium carbenoid
with an N-magnesio arylamine
Shintaro Mitsunaga, Tohru Ohbayashi, Shimpei Sugiyama, Takahito Saitou,
*
Makoto Tadokoro, Tsuyoshi Satoh
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from
nyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substi-
tution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction.
x-(2-aminophe-
Received 5 June 2009
Accepted 24 June 2009
Available online 17 July 2009
Proline and pipecolic acid derivatives were also synthesized from
x-(arylamino)-1-chloroalkyl p-tolyl
sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,RS)-1-chloro-3-[2-(N-methyl-
amino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained.
The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio
arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these
reactions is also discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
version of the aforementioned reaction and found that it was suc-
cessful.5 The essence of this investigation is shown in Scheme 1.
a
-Amino acids are obviously one of the most important sets of
Thus, treatment of
oxide 5 with i-PrMgCl followed by ethyl chloroformate gave cyclic
-amino acid derivative 7 through -amino-substituted alkylmag-
nesium intermediate 6. When enantiomerically pure (1S,RS)-1-
chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide
x-(2-aminophenyl)-1-chloroalkyl p-tolyl sulf-
compounds in organic chemistry. They are fundamental building
blocks of peptides, proteins, and many natural products and play
essential roles in living organisms. Innumerable studies concerning
a
a
the chemistry and synthesis of
a-amino acids and their derivatives
5
have been performed and reviewed.1 Cyclic
a
-amino acids and
(n = 1) was used as the starting material, enantiomerically pure
(R)-pipecolic acid derivative 7 (n = 1) was obtained. In a similar
their derivatives have recently received considerable attention.
They are conformationally constrained, and used in controlling
peptide secondary structures in medicinal chemistry.2
manner, treatment of
ide 8 with i-PrMgCl followed by ethyl chloroformate gave the pro-
line derivative and pipecolic acid derivative 10 through -amino-
x-(arylamino)-1-chloroalkyl p-tolyl sulfox-
We have also been interested in the synthesis of
a-amino acid
a
derivatives and reported several new methods for their synthesis.3
In addition, we recently reported a novel one-pot synthesis of
substituted alkylmagnesium intermediate 9. Details of the afore-
mentioned procedure and the stereochemistry of the reactions
are described herein.
a
-amino acid derivatives 4 from 1-chloroalkyl phenyl sulfoxides 1
by the intermolecular nucleophilic substitution of magnesium
carbenoid with N-lithio arylamines as the key reaction (Scheme 1).
Thus, magnesium carbenoid 2 was generated from 1 with i-PrMgCl
via the sulfoxide–magnesium exchange reaction; compound 2 was
2. Results and discussion
2.1. Synthesis of cyclic
a-amino acid derivatives from x-(2-ami-
then treated with an N-lithio arylamine to afford N-
a
3
-magnesioalkyl
was trapped
a-amino acid ester 4 in good
nophenyl)-1-chloroalkyl p-tolyl sulfoxides
arylamine 3. Finally, the -amino carbanion
a
with ethyl chloroformate to give
In order to examine the feasibility of the intramolecular version
of the key reaction, we first synthesized -(2-aminophenyl)-1-
yield.4
x
In continuation of our interest in the synthesis of a-amino acids
by our original method, we recently investigated an intramolecular
chloroalkyl p-tolyl sulfoxides with different lengths of the methy-
lene chain 5a–5d as shown in Scheme 2. 2-(2-Aminophenyl)-1-
chloroethyl p-tolyl sulfoxide 5a was synthesized from the known
benzyl bromide 11.6 Alkylation of the
a
-sulfinyl carbanion of
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
chloromethyl p-tolyl sulfoxide with 11 in THF containing HMPA
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.024

1698
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
R
Cl
COOEt
N(Ar)R
MgCl
N(Ar)R
Cl
LiNAr
ClCOOEt
i-PrMgCl
R
R
R
R
SPh
O
MgCl
4
3
2
1
Cl
*
*
STol
i-PrMgCl
n
ClCOOEt
n
n
*
*
N
NH
N
O
MgCl
COOEt
Me
Me
Me
6
7
5
(n= 1, 2)
Ar
N
Ar
N
Cl
H
N
MgCl
i-PrMgCl
COOEt
ClCOOEt
STol
O
n
MeO
n
n
9
10
8 (n= 1, 2)
Scheme 1.
afforded 12 in 65% yield. The Boc group was removed with trifluo-
roacetic acid (TFA) to give the desired 5a in high yield.
five- and eight-membered cyclic a-amino acid derivatives from
5a and 5d was problematic. The same treatment of 5a with i-
PrMgCl followed by ethyl chloroformate gave styrene derivative
23 in 83% yield. Production of the thermodynamically stable olefin
conjugated with an aromatic ring is thought to be the reason for
the difficulty of the cyclization. The same treatment of 5d again
did not give the desired cyclic a-amino acid derivative but instead
gave olefin 24 in 46% yield. From this result, it was proven that the
formation of 8-membered ring by this method is quite difficult.
3-(2-Aminophenyl)-1-chloropropylp-tolylsulfoxide5bwassyn-
thesized from 3,4-dihydro-2(1H)-quinolinone 13. Thus, a methoxy-
methyl group was introduced on the nitrogen of 13 and the product
was reduced with NaBH4 to give aminoalcohol 14 in high overall
yield.7 The nitrogen in 14 was protected by a Boc group to afford
l5, which was converted to sulfide 16 via a conventional procedure.
Chlorination followed by oxidation of 16 gave sulfoxide 17 in good
overall yield. Finally, the Bocprotectinggroup was removedto afford
the desired 5b.
2.2. Synthesis of cyclic
a-amino acid derivatives from x-(aryla-
4-(2-Aminophenyl)-1-chlorobutyl p-tolyl sulfoxide 5c was syn-
thesized from 15. Thus, the hydroxyl group in 15 was converted to
mino)-1-chloroalkyl p-tolyl sulfoxides
an iodo group to give iodide 18. Alkylation of lithium
a
-sulfinyl
In continuation of the study described above, we investigated the
intramolecular reaction with -(arylamino)-1-chloroalkyl p-tolyl
sulfoxides 8. Starting materials 8a–c were synthesized from 4-iodo-
anisole and -amino-1-alkanols as shown in Scheme 4. The synthe-
sis of 8a is described as a representative example. Thus, coupling of
carbanion of chloromethyl p-tolyl sulfoxide with 18 in THF affor-
ded 19, which was treated with TFA to give the desired 5c in good
overall yield.
5-(2-Aminophenyl)-1-chloropentyl p-tolyl sulfoxide 5d was
synthesized from 18. At first, tert-butyl acetate was alkylated with
iodide 18 to give ester 20 in quantitative yield. The ester group was
reduced with DIBAL-H to give an alcohol, which was converted to
sulfide to give 21. Sulfide 21 was chlorinated and then oxidized as
above to give sulfoxide 22 in high overall yield. Finally, the Boc
group was removed with TFA to afford the desired 5d.
The key reaction, intramolecular nucleophilic substitution reac-
tion of the magnesium carbenoid with N-magnesio arylamine, was
at first investigated with amino sulfoxide 5b as a representative
example (Scheme 3). Examination for the optimized conditions
was carried out and the results were reported.5 Thus, to a solution
of 5b in toluene at ꢀ40 °C was added t-BuMgCl (1.3 equiv) and the
reaction mixture was stirred for 5 min to generate magnesium
amide. Then, i-PrMgCl (2.5 equiv) was added to the reaction mix-
ture and the reaction mixture was stirred for 5 min (the magne-
sium carbenoid was generated and the intramolecular reaction
proceeded to afford intermediate 6a) after which ethyl chlorofor-
mate (5 equiv) was added. By these treatments the desired pipeco-
lic acid derivative 7a was obtained in 66% yield. The same
treatment of 5c gave homopipecolic acid derivative 7b, via inter-
mediate 6b, in 68% yield.
x
x
4-iodoanisole and 3-amino-1-propanol promoted by L-proline gave
aminoalcohol 25.8 The nitrogen in 25 was protected with Boc group
and the hydroxyl group was converted to an iodo group to give
iodide 26 in quantitative yield. Alkylation of the lithium a-sulfinyl
carbanion of chloromethyl p-tolyl sulfoxide with 26 followed
by deprotection of the Boc group with TFA afforded the desired
8a in 77% overall yield from 3-amino-1-propanol. 5-(4-Methoxy-
phenylamino)-1-chloropentyl p-tolyl sulfoxide 8b and 6-(4-
methoxyphenylamino)-1-chlorohexyl p-tolyl sulfoxide 8c were
synthesized from 4-iodoanisole and 4-amino-1-butanol and 5-ami-
no-1-pentanol, respectively, in the same way as described above.
The intramolecular nucleophilic substitution reaction of the
magnesium carbenoid with N-magnesio arylamine, the key reac-
tion, was investigated using 8a as a representative example
(Scheme 4). Examination for the optimized conditions was carried
out and the results were reported.5 Thus, 3.5 equiv of i-PrMgCl was
added to a solution of 8a in THF at ꢀ78 °C and the temperature of
the reaction mixture was allowed to warm to ꢀ40 °C. Ethyl chloro-
formate (5 equiv) was added to the reaction mixture to give the de-
sired proline derivative 10a in 59% yield.
The reaction is thought to proceed as follows: Removal of the
hydrogen on the nitrogen and the sulfoxide–magnesium exchange
reaction proceeded simultaneously to afford magnesium carbenoid
Although the synthesis of six- and seven-membered cyclic
amino acid derivatives 7a and 7b was successful, the synthesis of
a-

S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
1699
Cl
Cl
TolS(O)CH2Cl / LDA
TFA
Br
S(O)Tol
S(O)Tol
CH2Cl2, 0 oC, 93%
NH
Me
NBoc
Me
THF-HMPA, –78~ 0 °C,
NBoc
Me
65%
11
5a
12
1) MOMCl / NaH
DMF / THF, 99%
(Boc)2O
(TolS)2, n-Bu3P
OH
OH
2) NaBH4 / EtOH, 93%
N
NH
Me
NBoc
Me
O
THF, reflux,
99%
THF, 89%
H
13
14
15
Cl
Cl
STol
1) NCS / CCl4
TFA
CH2Cl2, 0 oC, 99%
S(O)Tol
S(O)Tol
NBoc
Me
2) mCPBA / CH2Cl2
NH
Me
NBoc
Me
88% (two steps)
16
5b
17
S(O)Tol
I2, Ph3P, Imid.
CH2Cl2, r.t., 83%
TolS(O)CH2Cl / LDA
I
15
Cl
THF, –78~ –30 °C, 81%
NBoc
Me
NBoc
Me
18
19
S(O)Tol
TFA
CH2Cl2, 0 oC, 94%
Cl
NH
Me
5c
COOBut
CH3COOBut / LDA
STol
1) DIBAL-H, Toluene, 0 °C, 70%
( )2
18
NBoc
Me
THF-HMPA, –78 °C, 99%
NBoc
Me
2) (TolS)2, n-Bu3P, THF, r.t., 80%
20
21
S(O)Tol
1) NCS / CCl4
S(O)Tol
TFA
( )2
( )2
NH
Me
Cl
2) mCPBA / CH2Cl2
CH2Cl2, 0 oC, 98%
Cl
NBoc
Me
91% (two steps)
22
5d
Scheme 2. Synthesis of
x-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides 5a–5d.
intermediate 27. The nucleophilic substitution reaction of the mag-
nesium carbenoid with N-magnesio arylamine took place intramo-
ment of the one-carbon homologated sulfoxide 8c gave a rather
complex mixture from which the desired 10c was obtained in only
4% yield.
lecularly to afford
a-aminoalkylmagnesium intermediate 9a,
which reacted with ethyl chloroformate to give proline derivative
10a.
2.3. Asymmetric synthesis of pipecolic acid derivative from en-
antiomerically pure (1S,RS)-1-chloro-3-(2-methylaminophenyl)-
propyl p-tolyl sulfoxide through a chiral magnesium carbenoid
In order to investigate the scope and limitations of this
reaction,
x-(arylamino)-1-chloroalkyl p-tolyl sulfoxides with a
longer carbon chain than 8a were treated with i-PrMgCl followed
by ethyl chloroformate (Scheme 4). Treatment of 8b with i-PrMgCl
followed by ethyl chloroformate afforded the desired N-arylpipe-
colic acid ethyl ester 10b in 60% yield. Unfortunately, similar treat-
In order to investigate if the above-mentioned procedure could
be expanded to an asymmetric synthesis of cyclic
a-amino acid
derivatives and to investigate the stereochemistry of the key

1700
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
Cl
ClCOOEt (5.0 eq)
1) t-BuMgCl (1.3 eq)
STol
O
N
N
2) i-PrMgCl (2.5 eq)
Toluene, – 40 °C
COOEt
NH
Me
66%
MgCl
Me
Me
7a
6a
5b
O
ClCOOEt (5.0 eq)
68%
STol
1) t-BuMgCl (1.3 eq)
Cl
2) i-PrMgCl (2.5 eq)
Toluene, –40 °C
N
N
COOEt
NH
Me
MgCl
Me
Me
6b
5c
7b
O
R
STol
1) t-BuMgCl (1.3 eq)
n
Cl
2) i-PrMgCl (2.5 eq)
Toluene, – 40 °C
NH
Me
NH
Me
3) ClCOOEt
23
; R= CH=CH2, 83%
5a; n=1
5d
24; R= (CH2)3CH=CH2, 46%
; n=4
Scheme 3. Intramolecular reaction of magnesium carbenoid with N-magnesio arylamine.
K2CO3, CuI,
L-Proline
Boc
N
I
1) (Boc)2O, 99%
H
N
I
OH
H2N
OH
+
Ar
Ar
DMSO, 80 °C
84%
2) I2, Ph3P, Imid.
99%
MeO
26
25
Cl
Cl
H
H
N
N
1) TolS(O)CH(Li)Cl (95%)
2) TFA (99%)
STol
O
STol
O
n
MeO
MeO
8a
8b
8c n=3
n=2
OMe
MgCl
N
PMP
N
PMP
i-PrMgCl (3.5 eq)
ClCOOEt (5.0 eq)
59%
MgCl
Cl
MgCl
8a
THF, –78~ – 40 °C
N
COOEt
9a
27
10a
OMe
OMe
8b
8c
COOEt
N
N
COOEt
60%
10c (4%)
10b
Scheme 4. Synthesis of
x-(arylamino)-1-chloroalkyl p-tolyl sulfoxides and the intramolecular reaction.

S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
1701
OH
NaBH4
(Boc)2O
NaH, MOMCl
O
O
EtOH, r.t.,
95%
N
MOM
N
H
DMF / THF, r.t.,
99%
THF, reflux
99%
NH
Me
30
28
29
Cl
Tol
Cl
Li
S
Tol
H
OH
MsCl, NEt3
O
S
IBX
O
NBoc
OH
NBoc
DMSO, r.t., 88%
CH2Cl2, r.t.
86%
O
THF, –78~ –60 °C
NBoc
Me
Me
98%
Me
32
33
31
Cl
Tol
S
Cl
Cl
Tol
Tol
LiBH4
DMI, 65 °C, 68%
S
S
OMs
NBoc
Me
O
O
O
NBoc
Me
NBoc
Me
34
36
35
Cl
Cl
Cl
Tol
Tol
Tol
TFA
CH2Cl2, 0 °C, 99%
S
Separation
S
S
O
O
O
NH
Me
37b (oil, 41%)
NH
Me
37a (crystal, 59%)
NH
Me
37
Scheme 5. Synthesis of (1S,RS)-3-(2-methylaminophenyl)-1-chloropropyl p-tolyl sulfoxide 37a.
reaction, we tried the procedure with optically active starting
material. At first, enantiomerically pure starting material, (1S,RS)-
1-chloro-3-(2-methylaminophenyl)propyl p-tolyl sulfoxide 37a
was synthesized from oxindole 28 (Scheme 5).
A methoxymethyl group was introduced on the nitrogen of 28
to give 29, which was reduced with NaBH4 to give aminoalcohol
30 in high overall yield.7 The nitrogen of 30 was protected with a
Boc group and the hydroxyl group was oxidized with IBX in DMSO
to give aldehyde 32 in good yield. Aldehyde 32 was treated with
the lithium a-sulfinyl carbanion of (R)-chloromethyl p-tolyl sulfox-
Figure 1. Crystal structure of 37a.
ide9 to afford a mixture of adducts 33,10 which was treated with
methanesulfonyl chloride to give mesylate 34 as a mixture of
two diastereomers.
chloroformate under the conditions described above to give the
optically active pipecolic acid derivative 38 in 66% yield (Scheme
6). The enantiomeric excess was measured by a chiral stationary
column, CHIRALCEL-OD (hexane/i-PrOH = 30:1), and was found
to be over 99%. The high enantiomeric excess of product 38
means that almost no racemization occurred throughout the reac-
tions. At this point, the absolute configuration of the product was
unclear.
The absolute configuration of 38 was determined by comparing
38 with the compound whose absolute configuration is known as
follows: At first, (R)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid
39 was synthesized from quinaldinic acid by Nagata’s procedure.13
The carboxylic acid was converted to ethyl ester 40 in ethanol with
thionyl chloride. Methylation of the nitrogen in 40 was carried out
with the conventional procedure to afford 380 in high yield. Both
the sign and value of the specific rotation of 38 derived from 37a
were consistent with those of 380. From these results, product 38
derived from 37a was determined to be (R)-1-methyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylic acid ethyl ester.14
Reductive removal of the mesyl group was found to be prob-
lematic. After some investigation, treatment of 34 with LiBH4 in
1,3-dimethylimidazolidin-2-one (DMI) at 65 °C was found to be
the conditions of choice. This reduction gave 1-chloroalkyl p-tolyl
sulfoxide 36; however, unexpectedly, the product was an insepara-
ble mixture of two diastereomers with respect to the carbon bear-
ing the chlorine atom. This reduction was thought to proceed via b-
elimination (to give vinyl sulfoxide 35)11 followed by conjugate
addition of the hydride to the double bond. The evidence for the
above assumption is that in some experiments, a trace of vinyl sulf-
oxide 35 was obtained. Deprotection of the Boc group in 36 gave 37
and, fortunately, diasteromers 37a and 37b were separable by sil-
ica gel column chromatography. Main product 37a is a crystalline
compound and its absolute configuration was determined by X-ray
crystallographic analysis and the ORTEP drawing is shown in
Figure 1.12
Finally, enantiomerically pure 1-chloroalkyl-p-tolyl sulfoxide
37a was treated with t-BuMgCl followed by i-PrMgCl and ethyl

1702
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
Cl
1) t-BuMgCl (1.3 eq), 5 min
ClCOOEt
Tol
(5.0 eq)
2) i-PrMgCl (2.5 eq), 5 min
S
(S)
∗
N
COOEt
66%
O
Toluene, – 40°C
NH
Me
Me
37a
38
(99% ee)
[α]D26 = –32.1
(c 0.5, EtOH)
HCHO, NaBH3CN
SOCl2, EtOH
r.t., 82 %
(R)
COOEt
(R)
COOH
N
H
N
H
N
Me
COOEt
AcOH, CH3CN,
r.t., 92%
38' (over 99% ee)
40
39
(over 99% ee)
26
[α]D = -31.9
(c 1.4, EtOH)
Cl
Cl
inversion of the
Tol
carbenoid carbon
i-PrMgCl
t-BuMgCl
S
MgCl
37a
O
N
MgCl
NMgCl
Me
Me
42
41
ClCOOEt
(S)
MgCl
(R)
COOEt
N
Me
N
Me
38
43
Scheme 6.
As we could determine the absolute configuration of 38, the
whole stereochemistry of the reaction can be inferred as shown
in Scheme 6. At first, treatment of 37a with t-BuMgCl resulted in
the formation of magnesium amide 41. As the sulfoxide–magne-
sium exchange reaction is known to take place with retention of
the configuration of the carbon bearing the sulfinyl group,15,16 sulf-
oxide 41 gave magnesium carbenoid 42 with an (S)-absolute con-
figuration. The key intramolecular cyclization proceeds with
of the magnesium carbenoid with N-magnesio arylamine was
proven to take place with inversion of the carbenoid carbon. The
results described in this paper contribute to the further develop-
ment of the synthesis, including asymmetric synthesis, of cyclic
a-amino acid derivatives and also the chemistry of magnesium
carbenoids.
4. Experimental
inversion of the carbenoid carbon16 to afford
a-amino carbanion
43 with an (S)-absolute configuration. Finally, the anion was
trapped by ethyl chloroformate with retention of configuration of
the carbanion to afford the final product 38.
Melting points were measured on a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured in a CDCl3
solution with JEOL JNM-LA 500 and BRUKER UltraShield 400,
300 spectrometer. IR spectra were recorded on a Perkin–Elmer
spectrum One FT-IR instrument. Electron-impact mass spectra
(MS) were obtained at 70 eV by direct insertion with JEOL
JMS-SX102A. Silica gel 60N (KANTO CHEMICAL) containing 0.5%
fluorescence reagent 254 and a quartz column were used for col-
umn chromatography and the products having UV absorption were
detected by UV irradiation. In experiments requiring a dry solvent
and reagents, toluene and DMF were distilled from CaH2. Diethyl
ether was distilled from Na and THF was distilled from diphenylke-
3. Conclusion
In conclusion, a novel synthesis of cyclic
a-amino acid deriva-
tives (proline, pipecolic acid,14 and homopipecolic acid derivatives)
was achieved by the intramolecular reaction of magnesium carbe-
noids with N-magnesio arylamine as the key reaction. An asym-
metric synthesis of an enantiomerically pure (R)-pipecolic acid
derivative was achieved starting from enantiomerically pure
(1S,RS)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulf-
oxide 37a. The intramolecular nucleophilic substitution reaction
tyl. HMPA was dried over CaSO4 and distilled before use. In the 1
NMR spectra, br s refers to a broad singlet.
H

S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
1703
4.1. N-{2-[2-Chloro-2-(toluene-4-sulfinyl)ethyl]phenyl}-N-meth-
ylcarbamic acid tert-butyl ester 12
at room temperature for 18 h. The reaction mixture was diluted
with benzene and the organic layer was washed twice with 5% aq
NaOH followed by satd aq NH4Cl. The organic layer was dried over
MgSO4 and the solvent was evaporated. The residue was purified by
silica gel column chromatography to afford 16 (0.86 g; 89%) as a
colorless oil; IR (neat) 2975, 2929, 1699 (CO), 1602, 1581, 1494,
1454, 1366, 1305, 1254, 1154, 1120, 1090, 1043, 1018, 977, 869,
To a solution of LDA (3 mmol) and HMPA (5 mmol) in 13 mL of
dry THF in a flame-dried flask at ꢀ78 °C under an argon atmosphere
was added a solution of chloromethyl p-tolyl sulfoxide (0.47 g;
2.5 mmol) in 2 mL of dry THF dropwise with stirring. After
10 min, to the solution of lithio chloromethyl p-tolyl sulfoxide
was added a solution of 11 (0.77 g; 3.01 mmol) in 2 mL of dry THF
with stirring. The reaction mixture was stirred and slowly allowed
to warm to 0 °C for 2 h. The reaction was quenched with satd aq
NH4Cl. The whole was extracted with CHCl3 and the organic layer
was washed with satd aq NH4Cl and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 12
(0.79 g; 65%) as a colorless oil; IR (neat) 3006, 2978, 2930, 1694
(CO), 1598, 1583, 1495, 1477, 1454, 1392, 1436, 1367, 1305,
1279, 1255, 1217, 1155, 1088, 1058 (SO), 1017, 977, 926, 864,
805, 761 cmꢀ1 1H NMR d 1.30 (7H, br s, t-Bu), 1.51 (2H, br s,
.
t-Bu), 1.82–2.00 (2H, m), 2.31 (3H, s), 2.65 (2H, t, J = 7.5 Hz), 2.86
(2H, t, J = 7.2 Hz), 3.11 (3H, s), 7.08 (3H, d, J = 7.9 Hz), 7.12–7.27
(5H, m). MS m/z (%) 371 (M+, 37), 315 (53), 148 (95), 120 (28), 57
(36). Calcd for C22H29NO2S: M, 371.1919. Found: m/z 371.1918.
4.5. N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-
methylcarbamic acid tert-butyl ester 17
N-Chlorosuccinimide (NCS; 0.32 g; 2.38 mmol) was added to a
solution of 16 (0.81 g; 2.17 mmol) in 3.5 mL of carbon tetrachloride
and the suspension was stirred at room temperature overnight.
The precipitate was filtered off and the solvent was evaporated
811 cmꢀ1 1H NMR d 1.27 (5H, br s, t-Bu), 1.51 (4H, br s, t-Bu),
.
2.43 (3H, s), 2.68–3.28 (4H, m), 3.36–3.76 (1H, m), 4.62–5.06 (1H,
m), 6.95–7.40 (6H, m), 7.42–7.68 (2H, m). MS m/z (%) 407 (M+,
trace), 212 (50), 140 (25), 132 (95), 91 (23), 57 (81). Calcd for
C21H26ClNO3S: M, 407.1322. Found: m/z 407.1322.
to afford crude
a-chlorosulfide.
A solution of the crude
a-chlorosulfide in 4.3 mL of CH2Cl2 was
cooled to ꢀ40 °C. To this solution was added m-CPBA (0.56 g;
2.38 mmol) and the reaction mixture was stirred for 1 h. The reac-
tion was quenched with satd aq Na2SO3 and the reaction mixture
was diluted with CH2Cl2. The organic layer was washed twice with
5% aq NaOH followed by satd aq NH4Cl. The organic layer was dried
over MgSO4 and the solvent was evaporated. The product was puri-
fied by silica gel column chromatography to afford 17 (0.81 g; 88%)
as a colorless oil; IR (neat) 2977, 1702 (CO), 1598, 1494, 1453, 1367,
1304, 1255, 1155, 1087, 1056 (SO), 1017, 977, 867, 812, 759,
4.2. N-{2-[2-Chloro-2-(toluene-4-sulfinyl)ethyl]phenyl}-N-meth-
ylamine 5a
A solution of 12 (0.66 g; 1.62 mmol) in 4 mL of CH2Cl2 was
cooled in an ice bath. To this solution was added TFA (1.54 mL) with
stirring. After 3 h, the reaction was quenched with 5% aq NaOH. The
whole was extracted with CH2Cl2 and the organic layer was washed
with 5% aq NaOH and dried over MgSO4. The product was purified
by silica gel column chromatography to afford 5a (0.47 g; 93%;
approximately a 7:3 mixture of two diastereomers) as a colorless
oil; IR (neat) 3392 (NH), 3044, 2922, 2814, 1606, 1586, 1517,
1469, 1450, 1426, 1307, 1270, 1171, 1085, 1045 (SO), 1016, 938,
664 cmꢀ1 1H NMR d 1.26, 1.32, 1.45, 1.48 (each br s, total 9H,
.
t-Bu), 1.70–2.24 (1H, m), 2.42 (3H, s), 2.48–2.64 (1H, m), 2.65–
2.80 (1H, m), 2.82–3.00 (1H, m), 3.07 (1.5H, s), 3.13 (1.5H, s), 4.49
(1H, d, J = 9.3 Hz), 7.02–7.36 (6H, m), 7.52 (2H, d, J = 7.4 Hz).
. d 2.41 (3H, s), 2.82 (3H, d,
921, 811, 750 cmꢀ1 1H NMR
J = 11.3 Hz), 3.02 (0.5H, d, J = 9.4 Hz), 3.08 (0.5H, d, J = 9.3 Hz),
3.53–3.64 (1H, m), 3.98–4.38 (1H, br s), 4.52 (0.3H, dd, J = 9.3,
2.2 Hz), 4.76 (0.7H, q, J = 4.2 Hz), 6.58–6.70 (2H, m), 7.00 (0.7H, d,
J = 7.4 Hz), 7.09 (0.3H, d, J = 7.4 Hz), 7.16–7.24 (1H, m), 7.30–7.36
(2H, m), 7.58 (1.4H, d, J = 8.3 Hz), 7.64 (0.6H, d, J = 8.2 Hz). MS m/z
(%) 307 (M+, 20), 168 (60), 132 (100), 118 (45), 91 (18), 77 (8), 65
(5). Calcd for C16H18ClNOS: M, 307.0797. Found: m/z 307.0796.
4.6. N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-me-
thylamine 5b
A solution of 17 (0.69 g; 1.63 mmol) in 4 mL of CH2Cl2 was cooled
in an ice bath. To this solution was added TFA (1.55 mL) with stirring.
After 3 h, the reaction was quenched with 5% aq NaOH. The whole
was extracted with CH2Cl2. The organic layer was washed with 5%
aq NaOH and dried over MgSO4. The product was purified by silica
gel column chromatography to afford 5b (0.53 g; 99%; approxi-
mately a 7:3 mixture of two diastereomers) as a colorless oil; IR
(neat) 3398 (NH), 2924, 2814, 1914, 1734, 1605, 1585, 1516, 1494,
1471, 1427, 1400, 1375, 1310, 1265, 1218, 1170, 1085, 1048 (SO),
4.3. N-[2-(3-Hydroxypropyl)phenyl]-N-methylcarbamic acid
tert-butyl ester 15
To a solution of 147 (0.547 g; 3.31 mmol) in 3 mL of THF was
added (Boc)2O (0.8 mL; 3.48 mmol) with stirring. After the mixture
was refluxed overnight, the solvent was evaporated. The residue
was purified by silica gel column chromatography to afford 15
(0.866 g; 99%) as a colorless oil; IR (neat) 3435 (OH), 2976, 1698
(CO), 1063, 1581, 1494, 1454, 1367, 1305, 1255, 1155, 1094, 1060,
1016, 927, 841, 811, 750 cmꢀ1 1H NMR d 1.87–1.97 (0.3H, m),
.
2.24–2.34 (0.7H, m), 2.40–2.88 (9H, m), 3.60–4.20 (1H, m), 4.46
(0.7H, dd, J = 7.7, 3.5 Hz), 4.53 (0.3H, dd, J = 9.5, 4.1 Hz), 6.58–6.68
(2H, m), 6.96–7.02 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.27–7.34 (2H,
m), 7.51 (0.6H, d, J = 8.2 Hz), 7.60 (1.4H, d, J = 8.2 Hz). MS m/z (%)
321 (M+, 43), 182 (25), 146 (33), 120 (100), 118 (10), 91 (23), 65
(6). Calcd for C17H20ClNOS: M, 321.0954. Found: m/z 321.0954.
979, 916, 867, 760 cmꢀ1 1H NMR d 1.25 (5H, br s, t-Bu), 1.52 (4H,
.
br s, t-Bu), 1.82–2.10 (2H, br s), 2.64 (2H, t, J = 7.1 Hz), 3.15 (3H, s),
3.50–3.72 (2H, br s), 7.00–7.34 (4H, m). MS m/z (%) 265 (M+, 5),
209 (30), 165 (100), 120 (55), 118 (25), 57 (93). Calcd for
C15H23NO3: M, 265.1678. Found: m/z 265.1697.
4.7. N-[2-(3-Iodopropyl)phenyl]-N-methylcarbamic acid tert-
butyl ester 18
4.4. N-Methyl-N-[2-(3-p-tolylsulfanylpropyl)phenyl]carbamic
acid tert-butyl ester 16
To a solution of 15 (0.86 g; 3.23 mmol) in 13 mL of CH2Cl2 at
room temperature were successively added imidazole (0.33 g;
4.85 mmol), Ph3P (1.27 g; 4.85 mmol), and I2 (1.23 g; 4.85 mmol)
with stirring. After 2 h, the reaction was quenched with satd aq
Na2SO3. The whole was extracted with CH2Cl2 and the organic layer
was successively washed with satd aq Na2SO3 and satd aq NaHCO3.
The organic layer was dried over MgSO4. The product was purified
A solution of 15 (0.69 g; 2.60 mmol) and ditolyl disulfide
(0.833 g; 3.38 mmol) in 8.7 mL of THF was cooled in an ice bath.
To this solution was added tributylphosphine (0.9 mL; 3.64 mmol)
with stirring. The reaction mixture was stirred at 0 °C for 5 min and

1704
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
by silica gel column chromatography to afford 18 (1.0 g; 83%) as a
colorless oil; IR (neat) 3063, 3004, 2975, 2931, 1697 (CO), 1602,
1581, 1494, 1478, 1453, 1390, 1365, 1305, 1256, 1215, 1153,
The organic layer was washed with satd aq NH4Cl and dried over
MgSO4. The product was purified by silica gel column chromatogra-
phy to afford 20 (1.70 g; 99%) as a colorless oil; IR (neat) 2976, 1702
(CO), 1602, 1580, 1493, 1458, 1365, 1305, 1255, 1155, 1092, 977,
1112, 1084, 1042, 977, 869, 771, 760, 663, 605, 582, 499 cmꢀ1 1H
.
NMR d 1.33 (6H, br s, t-Bu), 1.52 (3H, br s, t-Bu), 2.00–2.23 (2H,
m), 2.66 (2H, t, J = 7.5 Hz), 3.15 (3H, s), 3.16–3.26 (2H, m), 7.02–
7.28 (4H, m). MS m/z (%) 375 (M+, 5), 319 (95), 275 (22), 192 (24),
148 (65). Calcd for C15H22INO2: M, 375.0695. Found: m/z 375.0702.
869, 759 cmꢀ1 1H NMR d 1.32, 1.52 (each br s, total 9H, t-Bu),
.
1.44 (9H, s), 1.58–1.68 (4H, br s), 2.20–2.27 (2H, m), 2.50–2.60
(2H, m), 3.14 (3H, s), 7.02–7.27 (4H, m). MS m/z (%) 363 (M+, 1),
307 (5), 262 (20), 251 (32), 234 (40), 207 (100), 120 (28), 57 (46).
Calcd for C21H33NO4: M, 363.2410. Found: m/z 363.2412.
4.8. N-{2-[4-Chloro-4-(toluene-4-sulfinyl)butyl]phenyl}-N-me-
thylcarbamic acid tert-butyl ester 19
4.11. N-Methyl-N-{2-[5-(p-tolylsulfanyl)pentyl]phenyl}carba-
mic acid tert-butyl ester 21
To a solution of LDA (0.64 mmol) in 2 mL of dry THF in a flame-
dried flask at ꢀ78 °C under an argon atmosphere was added drop-
To a solution of 20 (90 mg; 0.248 mmol) in 2.5 mL of dry toluene
in a flame-dried flask at 0 °C under an argon atmosphere was added
a solution of DIBAL-H (0.98 M; 0.98 mL; 0.744 mmol) with stirring.
After 30 min, the reaction was quenched with satd aq NH4Cl. The
whole was extracted with CHCl3. The organic layer was washed
with 5% HCl and dried over MgSO4. The produced alcohol was puri-
fied by silica gel column chromatography to afford an alcohol
(51 mg; 70%) as a colorless oil; IR (neat) 3436 (OH), 2932, 1701
(CO), 1603, 1581, 1495, 1455, 1367, 1305, 1255, 1155, 1042, 979,
wise
a solution of chloromethyl p-tolyl sulfoxide (0.12 g;
0.64 mmol) in 0.8 mL of dry THF with stirring. After 10 min, to the
solution of the -lithio chloromethyl p-tolyl sulfoxide was added
a
a solution of 18 (0.2 g; 0.533 mmol) in 0.8 mL of dry THF with stir-
ring. The reaction mixture was stirred and slowly allowed to warm
to ꢀ30 °C for 1.5 h. The reaction was quenched with satd aq NH4Cl.
The whole was extracted with CHCl3 and the organic layer was
washed with satd aq NH4Cl and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 19
(approximately a 1:1 mixture of two diastereomers; 0.19 g; 81%)
as a colorless oil; IR (neat) 2978, 1917, 1694 (CO), 1598, 1581,
1495, 1455, 1367, 1305, 1253, 1155, 1088, 1056 (SO), 1017, 978,
868, 761 cmꢀ1 1H NMR d 1.20–1.76 (15H, m), 2.54 (2H, t,
.
J = 7.7 Hz), 3.14 (3H, s), 3.64 (2H, t, J = 6.5 Hz), 7.02–7.28 (4H, m).
MS m/z (%) 293 (M+, 2), 237 (32), 193 (100), 120 (63), 57 (63), 28
(29). Calcd for C17H27NO3: M, 293.1988. Found: m/z 293.1991.
To a solution of the alcohol (0.45 g; 1.54 mmol) was added ditol-
yl disulfide (0.5 g; 2 mmol) in 5 mL of THF and cooled in an ice bath.
To this solution was added tributylphosphine (0.55 mL; 2 mmol)
with stirring. The reaction mixture was stirred at 0 °C for 5 min
and at room temperature for 18 h. The reaction mixture was diluted
with benzene and the organic layer was washed twice with 5%
NaOH followed by satd aq NH4Cl. The organic layer was dried over
MgSO4 and the solvent was evaporated. The residue was purified by
silica gel column chromatography to afford 21 (0.49 g; 80%) as a col-
orless oil; IR (neat) 2930, 2860, 1698 (CO), 1602, 1580, 1493, 1454,
868, 812, 757 cmꢀ1 1H NMR d 1.30 (6H, br s, t-Bu), 1.30 (3H, br s,
.
t-Bu), 1.60–2.12 (3H, m), 2.27 (1H, br s), 2.44 (3H, s), 2.48–2.66
(2H, m), 3.09–3.17 (3H, m), 4.40 (0.5H, dd, J = 8.8, 3.2 Hz), 4.52
(0.5H, br s), 7.02–7.24 (4H, m), 7.34 (2H, d, J = 7.7 Hz), 7.54 (1H, d,
J = 8.1 Hz), 7.62 (1H, d, J = 8.1 Hz). MS m/z (%) 435 (M+, trace), 240
(95), 204 (60), 160 (70), 120 (75), 57 (85). Calcd for C23H30ClNO3S:
M, 435. 1635. Found: m/z 435.1627.
4.9. N-{2-[4-Chloro-4-(toluene-4-sulfinyl)butyl]phenyl}-N-me-
thylamine 5c
1364, 1304, 1254, 1154, 1092, 1038, 1018, 977, 869, 804, 760 cmꢀ1
.
A solution of 19 (0.22 g; 0.5 mmol) in 1.2 mL of CH2Cl2 was
cooled in an ice bath. To this solution was added TFA (0.47 mL) with
stirring. After 3 h, the reaction was quenched with 5% aq NaOH. The
whole was extracted with CH2Cl2. The organic layer was washed
with 5% aq NaOH and dried over MgSO4. The product was purified
by silica gel column chromatography to afford 5c (approximately
a 1:1 mixture of two diastereomers; 0.157 g; 94%) as a colorless
oil; IR (neat) 3401 (NH), 2929, 2813, 1605, 1585, 1515, 1470,
1H NMR d 1.31 (6H, s, t-Bu), 1.51 (3H, br s, t-Bu), 1.40–1.70 (6H, m),
2.31 (3H, s), 2.52 (2H, t, J = 7.7 Hz), 2.87 (2H, t, J = 7.4 Hz), 3.13 (3H,
s), 7.01–7.28 (8H, m). MS m/z (%) 399 (M+, 30), 343 (50), 299 (45),
176 (97), 120 (60), 57 (46). Calcd for C24H33NO2S: M, 399.2232.
Found: m/z 399.2230.
4.12. N-{2-[5-Chloro-5-(toluene-4-sulfinyl)pentyl]phenyl}-N-
methylcarbamic acid tert-butyl ester 22
1307, 1265, 1169, 1086, 1049 (SO), 1016, 811, 788, 749 cmꢀ1 1H
.
NMR d 1.56–2.12 (3H, m), 2.25–2.40 (1H, m), 2.43 (3H, s), 2.46–
2.54 (2H, m), 2.87 (3H, d, J = 2.3 Hz), 3.65 (1H, br s), 4.43 (0.5H,
dd, J = 9.0, 3.4 Hz), 4.54 (0.5H, dd, J = 9.0, 4.0 Hz), 6.60–6.71 (2H,
m), 6.99 (1H, t, J = 8.7 Hz), 7.16 (1H, t, J = 7.7 Hz), 7.33 (2H, d,
J = 7.9 Hz), 7.53 (1H, t, J = 8.3 Hz), 7.62 (1H, d, J = 8.1 Hz). MS m/z
(%) 335 (M+, 65), 196 (55), 160 (100), 139 (20), 120 (95), 118 (48),
91 (46), 77 (15), 65 (13), 39 (3). Calcd for C18H22ClNOS: M,
335.1110. Found: m/z 335.1111.
N-Chlorosuccinimide (0.176 g; 1.32 mmol) was added to a solu-
tion of 21 (0.48 g; 1.2 mmol) in 1.8 mL of carbon tetrachloride and
the suspension was stirred at room temperature overnight. The
precipitate was filtered off and the solvent was evaporated to af-
ford the crude
a-chlorosulfide.
A solution of the crude
a-chlorosulfide in 3 mL of CH2Cl2 was
cooled to ꢀ40 °C. To this solution was added m-chloroperbenzoic
acid (0.31 g; 1.32 mmol) and the reaction mixture was stirred for
1 h. The reaction was quenched with satd aq Na2SO3 and the solu-
tion was diluted with CH2Cl2. The organic layer was washed twice
with 5% NaOH followed by satd aq NH4Cl. The organic layer was
dried over MgSO4 and the solvent was evaporated. The product
was purified by silica gel column chromatography to afford 22
(0.493 g; 91%; approximately a 3:1 mixture of two diastereomers)
as a colorless oil; IR (neat) 2932, 2685, 1695 (CO), 1598, 1580,
1495, 1455, 1367, 1305, 1255, 1155, 1088, 1055 (SO), 1017, 977,
4.10. 5-[2-(N-tert-Butoxycarbonyl-N-methylamino)phenyl]
pentanoic acid tert-butyl ester 20
To a solution of LDA (14.1 mmol) and HMPA (14.1 mmol) in
44 mL of dry THF in a flame-dried flask at ꢀ78 °C under an argon
atmosphere was added dropwise a solution of tert-butyl acetate
(1.89 mL; 14.1 mmol) with stirring. After 10 min, to the solution
of the
a
-lithio tert-butyl acetate was added a solution of 18
868, 812, 759 cmꢀ1 1H NMR d 1.31 (6H, br s, t-Bu), 1.51 (3H, br s,
.
(1.76 g; 4.70 mmol) in 3 mL of dry THF with stirring. The reaction
mixture was stirred at ꢀ78 °C for 15 min, then the reaction was
quenched with satd aq NH4Cl. The whole was extracted with CHCl3.
t-Bu), 1.58–2.04 (4H, m), 2.19–2.34 (1H, m), 2.43 (3H, s), 2.55 (2H,
t, J = 7.5 Hz), 3.13 (3H, s), 4.38 (0.75H, d, J = 9.8 Hz), 4.50 (0.25H,
dd, J = 9.5, 3.8 Hz), 7.02–7.23 (4H, m), 7.34 (2H, d, J = 7.9 Hz), 7.55

S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
1705
(0.5H, d, J = 8.1 Hz), 7.62 (1.5H, d, J = 7.9 Hz). MS m/z (%) 449 (M+, 1),
392 (10), 349 (20), 254 (100), 210 (45), 174 (27), 120 (41), 57 (62).
Calcd for C24H32ClNO3S: M, 449.1791. Found: m/z 449.1799.
1.5 Hz), 5.60 (1H, dd, J = 17.5, 1.7 Hz), 6.58–6.79 (3H, m), 7.15–
7.28 (2H, m). MS m/z (%) 133 (M+, 55), 118 (100), 105 (7), 91
(35), 77 (20), 63 (13). Calcd for C9H11N: M, 133.0890. Found: m/z
133.0887.
4.13. N-{2-[5-Chloro-5-(toluene-4-sulfinyl)pentyl]phenyl}-N-
methylamine 5d
4.17. N-Methyl-N-[2-(4-pentenyl)phenyl]amine 24
A solution of 22 (0.474 g; 1.05 mmol) in 2.5 mL of CH2Cl2 was
cooled in an ice bath. To this solution was added TFA (1 mL) with
stirring. After 3 h, the reaction was quenched with 5% aq NaOH
and the whole was extracted with CH2Cl2. The organic layer was
washed with 5% aq NaOH and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 5d
(0.361 g; 98%; approximately a 3:1 mixture of two diastereomers)
as a colorless oil; IR (neat) 3403 (NH), 3003, 2931, 2863, 2813,
1912, 1604, 1584, 1515, 1494, 1463, 1427, 1400, 1379, 1306,
Colorless oil; IR (neat) 3444 (NH), 2929, 1639, 1605, 1585, 1508,
1461, 1307, 1262, 1167, 1044, 911, 747 cmꢀ1 1H NMR d 1.71 (2H,
.
quintet, J = 7.0 Hz), 2.15 (2H, q, J = 7.0 Hz), 2.47 (2H, t, J = 7.9 Hz),
2.88 (3H, s), 3.65 (1H, br s, NH), 5.01 (1H, m), 5.03 (1H, m), 5.78–
5.93 (1H, m), 6.62 (1H, dd, J = 8.1, 2.1 Hz), 6.69 (1H, dt, J = 8.5,
2.0 Hz), 7.04 (1H, dd, J = 7.4, 1.2 Hz), 7.15 (1H, dt, J = 7.9, 1.2 Hz).
MS m/z (%) 175 (M+, 30), 134 (12), 120 (100), 106 (15), 91 (25),
77 (10), 65 (9). Calcd for C12H17N: M, 175.1366. Found: m/z
175.1360.
1263, 1217, 1168, 1086, 1050 (SO), 1016, 839, 811, 751 cmꢀ1
.
1H
NMR 1.22–1.32 (0.25H, m), 1.44–1.89 (4H, m), 1.94–2.10
d
4.18. 3-(4-Methoxyphenylamino)-1-propanol 25
(0.75H, m), 2.20–2.36 (1H, m), 2.36–2.54 (2H, m), 2.43 (3H, s),
2.88 (3H, s), 3.64 (1H, br s), 4.39 (0.75H, dd, J = 9.7 Hz, 3.0 Hz) ,
4.51 (0.25H, dd, J = 13.5 Hz, 4.0 Hz), 6.60–6.74 (2H, m), 6.97–7.03
(1H, m), 7.16 (1H, t, J = 7.9 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.54 (0.5H,
d, J = 8.3 Hz), 7.63 (1.5H, d, J = 6.6 Hz). MS m/z (%) 349 (M+, 73),
210 (85), 174 (45), 172 (7), 133 (13), 120 (100), 91 (38), 77 (8). Calcd
for C19H24ClNOS: M, 349.1267. Found: m/z 349.1266.
To a solution of 4-iodoanisole (4.68 g; 20 mmol) in 12 mL of dry
DMSO in a flame-dried flask at 80 °C under an argon atmosphere
was successively added a solution of 3-aminoalcohol (2.3 mL;
30 mmol), K2CO3 (5.53 g; 40 mmol), CuI (381 mg; 2 mmol), and
L-proline (461 mg; 4 mmol) with stirring. After 12 h, the reaction
was quenched with water. The whole was extracted with AcOEt.
The organic layer was washed with H2O and dried over MgSO4.
The product was purified by silica gel column chromatography to
afford 25 (3.05 g; 84%) as a colorless oil; IR (neat) 3367 (OH, NH),
2937, 2062, 1849, 1729, 1618, 1591, 1514, 1465, 1409, 1374,
4.14. 1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid
ethyl ester 7a
To a solution of 5b (20 mg; 0.062 mmol) in 3 mL of dry toluene
in a flame-dried flask at ꢀ40 °C under an argon atmosphere was
added a solution of t-BuMgCl (1.0 M solution in THF, 0.08 mL;
0.08 mmol) dropwise with stirring. After 5 min, a solution of i-
PrMgCl (2.0 M solution in Et2O, 0.078 mL; 0.155 mmol) was added
dropwise to the reaction mixture with stirring. After 5 min, to the
1235, 1180, 1124, 1036, 930, 821 cmꢀ1 1H NMR d 1.83–1.91 (2H,
.
m), 2.20–3.15 (2H, br s), 3.24 (2H, t, J = 6.3 Hz), 3.75 (3H, s), 3.82
(2H, t, J = 5.8 Hz), 6.61–6.65 (2H, m), 6.77–6.84 (2H, m).
4.19. N-(3-Iodopropyl)-N-(4-methoxyphenyl)carbamic acid
tert-butyl ester 26
solution of
a-aminoalkylmagnesium intermediate 6a was added
ethyl chloroformate (0.03 mL; 0.31 mmol) dropwise at ꢀ40 °C with
stirring. After 10 min, the reaction was quenched with satd aq
NH4Cl. The whole was extracted with CH2Cl2. The organic layer
was washed with satd aq NH4Cl and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 7a
(9 mg; 66%) as a colorless oil; IR (neat) 2935, 1740 (CO), 1604,
To a solution of 25 (3.05 g; 16.8 mmol) in 160 mL of CH2Cl2 in a
flask at room temperature was added a solution of TEA (3.5 mL;
25.2 mmol) followed by (Boc)2O (5.79 mL; 25.2 mmol) with stirring.
After being stirred at room temperature for 12 h, the solvent was
evaporated. The crude product was purified by silica gel column
chromatography to afford carbamic acid tert-butyl ester (5.8 g;
99%) as a colorless oil; IR (neat) 3445 (OH), 2977, 1695 (CO), 1611,
1586, 1515, 1456, 1394, 1368, 1269, 1249, 1166, 1107, 1037, 999,
1502, 1374, 1336, 1185, 1102, 1038, 746 cmꢀ1 1H NMR d 1.24
.
(3H, t, J = 7.1 Hz), 2.07–2.16 (1H, m), 2.26–2.32 (1H, m), 2.68–2.72
(2H, m), 2.95 (3H, s), 4.01 (1H, dd, J = 5.2, 4.5 Hz), 4.10–4.24 (2H,
m), 6.60–6.66 (2H, m), 6.93 (1H, d, J = 7.6 Hz), 7.10 (1H, t,
J = 7.8 Hz). MS m/z (%) 219 (M+, 14), 146 (100), 130 (10). Calcd for
C13H17NO2: M, 219.1259. Found: m/z 219.1261.
836, 768 cmꢀ1 1H NMR d 1.38 (9H, s), 1.60–1.68 (3H, m), 3.65–
.
3.72 (2H, m), 3.75 (2H, t, J = 6.2 Hz), 3.81 (3H, s), 6.86 (2H, d,
J = 6.8 Hz), 7.04 (2H, d, J = 8.0 Hz).
To a solution of the carbamic acid tert-butyl ester (4.29 g;
15.2 mmol) in 60 mL of CH2Cl2 at room temperature were
successively added imidazole (2.07 g; 30.4 mmol), Ph3P (7.97 g;
30.4 mmol), and I2 (7.72 g; 30.4 mmol) with stirring. After 2 h, the
reaction was quenched with satd aq Na2SO3. The whole was ex-
tracted with CH2Cl2. The organic layer was washed with satd aq
Na2SO3 followed by satd aq NaHCO3 and brine and dried over
MgSO4. The product was purified by silica gel column chromatogra-
phy to afford 26 (5.8 g; 99%) as a colorless oil; IR (neat) 2975, 1694
4.15. 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carbo-
xylic acid ethyl ester 7b
Colorless oil; IR (neat) 2936, 1732 (CO), 1599, 1492, 1179, 1056,
756 cmꢀ1. 1H NMR d 1.23 (3H, t, J = 7.1 Hz), 1.54–1.85 (3H, m), 1.91–
2.03 (1H, m), 2.70 (1H, quintet, J = 6.8 Hz), 2.90 (1H, quintet,
J = 6.8 Hz), 2.93 (1H, s), 3.76 (1H, dd, J = 5.3, 4.0 Hz), 4.05–4.22
(2H, m), 6.88 (1H, t, J = 7.4 Hz), 6.98 (1H, d, J = 7.9 Hz), 7.04 (1H, d,
J = 7.4 Hz), 7.17 (1H, dt, J = 7.9, 1.7 Hz). MS m/z (%) 233 (M+, 10),
160 (100), 144 (10), 132 (9), 117 (8), 91 (10). Calcd for
C14H19NO2: M, 233.1415. Found: m/z 233.1416.
(CO), 1610, 1512, 1458, 1391, 1247, 1153, 1036, 835, 768, 475 cmꢀ1
.
1H NMR d 1.42 (9H, s), 2.02–2.12 (2H, m), 3.13 (2H, t, J = 7.0 Hz), 3.66
(2H, t, J = 7.0 Hz), 3.80 (3H, s), 6.86 (2H, d, J = 8.9), 7.02–7.15 (2H, m).
4.20. N-[4-Chloro-4-(toluene-4-sulfinyl)butyl]-N-(4-methoxy-
4.16. N-Methyl-N-(2-vinylphenyl)amine 23
phenyl)amine 8a
Colorless oil; IR (neat) 3436 (NH), 2917, 2814, 1623, 1603, 1577,
To a solution of LDA (12.7 mmol) in 35 mL of dry THF in a flame-
1510, 1461, 1426, 1307, 1262, 1166, 1064, 993, 910, 747 cmꢀ1
.
1H
dried flask at ꢀ78 °C under an argon atmosphere was added drop-
NMR d 2.87 (3H, s), 3.74–3.96 (1H, br s), 5.31 (1H, dd, J = 10.9,
wise
a
solution of chloromethyl p-tolyl sulfoxide (2.0 g;

1706
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
10.6 mmol) in 10 mL of dry THF with stirring. After 10 min, to the
solution of the -lithio chloromethyl p-tolyl sulfoxide was added a
with stirring. After 10 min, the reaction was quenched with satd
aq NH4Cl. The whole was extracted with CHCl3. The organic layer
was washed with satd aq NH4Cl and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 10a
(18 mg; 59%) as a colorless oil; IR (neat) 2978, 2833, 1746 (CO),
a
solution of 26 (4.95 g; 12.7 mmol) in 8 mL of dry THF at ꢀ75 °C
with stirring. The reaction mixture was slowly allowed to warm
to 0 °C for 2 h and the reaction was quenched with satd aq NH4Cl.
The product was purified by silica gel column chromatography to
afford the sulfoxide as approximately a 1:1 mixture of two diaste-
reomers (4.5 g; 95%) as a colorless oil; IR (neat) 2931, 1694 (CO),
1514, 1455, 1394, 1367, 1295, 1248, 1159, 1086, 1055 (SO), 835,
1621, 1515, 1464, 1367, 1242, 1178, 1094, 1039, 978, 813 cmꢀ1
.
1H NMR d 1.24 (3H, t, J = 7.1 Hz), 2.02–2.30 (4H, m), 3.28–3.34
(1H, m), 3.52–3.57 (1H, m), 3.74 (3H, s), 4.11–4.23 (3H, m), 6.50
(2H, d, J = 9.1 Hz), 6.82 (2H, d, J = 9.1 Hz). MS m/z (%) 249 (M+, 20),
176 (100). Calcd for C14H19NO3: M, 249.1363. Found: m/z 249.1361.
812, 756 cmꢀ1 1H NMR d 1.39 (9H, s), 1.55–1.75 (1.5H, m), 1.75–
.
2.05 (1.5H, m), 2.15–2.30 (1H, m), 2.43 (3H, s), 3.50–3.78 (2H,
m), 3.80 (3H, s), 4.35–4.45 (0.5H, m), 4.50–4.70 (0.5H, m), 6.84
(2H, d, J = 8.8 Hz), 6.95–7.10 (2H, m), 7.33 (2H, d, J = 8.0 Hz), 7.53
(1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 8.2 Hz).
4.24. 1-(4-Methoxyphenyl)piperidine-2-carboxylic acid ethyl
ester 10b
To a solution of the sulfoxide (3.25 g; 7.2 mmol) in 17 mL of
CH2Cl2 at room temperature was added TFA (17 mL) with stirring.
After 2 h, the reaction was quenched with 5% aq NaOH. The whole
was extracted with CH2Cl2. The organic layer was washed with 5%
aq NaOH and dried over MgSO4. The product was purified by silica
gel column chromatography to afford 8a as a 1:1 mixture of two
diastereomers (2.5 g; 99%) as a colorless oil; IR (neat) 3360 (NH),
2945, 1732, 1620, 1596, 1516, 1374, 1235, 1179, 1086, 1044 (SO),
Colorless oil; IR (neat) 2934, 2856, 1738 (CO), 1511, 1465, 1248,
1180, 1034, 820 cmꢀ1 1H NMR d 1.13 (3H, t, J = 7.1 Hz), 1.48–1.70
.
(3H, m), 1.75–1.88 (1H, m), 1.92–2.00 (1H, m), 2.06–2.11 (1H, m),
3.12–3.18 (1H, m), 3.35–3.42 (1H, m), 3.75 (3H, s), 4.00–4.12 (2H,
m), 4.24 (1H, t, J = 4.8 Hz), 6.81 (2H, d, J = 6.8 Hz), 6.91 (2H, d,
J = 6.8 Hz). MS m/z (%) 263 (M+, 15), 190 (100), 134 (10). Calcd
for C15H21NO3: M, 263.1519. Found: m/z 263.1519.
821 cmꢀ1
.
1H NMR d 1.26–2.11 (4H, m), 2.33–2.42 (1H, m), 2.43
4.25. 1-(4-Methoxyphenyl)azepane-2-carboxylic acid ethyl
ester 10c
(3H, s), 3.10–3.17 (2H, m), 3.75 (3H, s), 4.43 (0.5H, dd, J = 9.4,
3.2 Hz), 4.58 (0.5H, dd, J = 9.8, 3.8 Hz), 6.54–6.58 (2H, m), 6.78
(2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 10.0 Hz), 7.53 (1H, d, J = 8.2 Hz),
7.62 (1H, d, J = 8.2 Hz). MS m/z (%) 351 (M+, 95), 350 (100), 335
(10), 297 (13) 278 (15), 246 (20), 214 (95), 200 (90), 175 (70), 136
(65). Calcd for C18H22ClNO2S: M, 351.1060. Found: m/z 351.1048.
Colorless oil; IR (neat) 2930, 1743 (CO), 1514, 1465, 1388, 1244,
1180, 1041, 812 cmꢀ1 1H NMR d 1.26 (3H, t, J = 7.1 Hz), 1.31–1.43
.
(2H, m), 1.62–1.90 (5H, m), 2.35–2.42 (1H, m), 3.46–3.60 (2H, m),
3.74 (3H, s), 3.98–4.03 (1H, m), 4.10–4.25 (2H, m), 6.60 (2H, d,
J = 9.2 Hz), 6.81 (2H, d, J = 9.2 Hz). MS m/z (%) 277 (M+, 15), 204
(100), 149 (5), 134 (5). Calcd for C16H23NO3: M, 277.1676. Found:
m/z 277.1677.
4.21. N-[5-Chloro-5-(toluene-4-sulfinyl)pentyl]-N-(4-methoxy-
phenyl)amine 8b
4.26. N-[2-(2-Hydroxyethyl)phenyl]-N-methylcarbamic acid
tert-butyl ester 31
Colorless oil (approximately a 7:3 mixture of two diastereo-
mers); IR (neat) 3361 (NH), 3052, 2862, 2832, 2934, 1729, 1596,
1516, 1235, 1179, 1085, 1044 (SO), 817, 737 cmꢀ1 1H NMR d
.
To a solution of 30 (1.1 g; 7.26 mmol) in 6.6 mL of THF was
added (Boc)2O (1.75 mL; 7.62 mmol) with stirring. The mixture
was refluxed overnight and the solvent was evaporated. The crude
product was purified by silica gel column chromatography to af-
ford 31 (1.8 g; 99%) as a colorless oil; IR (neat) 3431 (OH), 3064,
2977, 2933, 1683 (CO), 1603, 1581, 1495, 1454, 1369, 1305,
1.59–1.73 (6H, m), 2.43 (3H, s), 3.06–3.11 (2H, m), 3.75 (3H, s),
4.39 (0.3H, dd, J = 9.5, 3.0 Hz), 4.51–4.54 (0.7H, m), 6.55–6.58
(2H, m), 6.78 (2H, d, J = 7.7 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.54
(1.4H, d, J = 8.2 Hz), 7.63 (0.6H, d, J = 8.2 Hz). MS m/z (%) 365 (M+,
15), 313 (15), 226 (48), 189 (30), 174 (20), 136 (100), 124 (18).
Calcd for C19H24ClNO2S: M, 365.1216. Found: m/z 365.1212.
1278, 1255, 1155, 1092, 1047, 979, 867, 760 cmꢀ1 1H NMR d
.
1.33 (5H, br s, t-Bu), 1.52 (4H, br s, t-Bu), 1.68 (0.5H, br s), 2.62
(0.5H, br s), 2.73–2.90 (2H, m), 3.16 (3H, s), 3.78–3.98 (2H, m),
7.04–7.38 (4H, m). MS m/z (%) 251 (M+, 13), 221 (13), 195 (6),
178 (13), 165 (58), 151 (55), 132 (39), 120 (90), 118 (20), 91
(13), 77 (10), 57 (100). Calcd for C14H21NO3: M, 251.1522. Found:
m/z 251.1520.
4.22. N-[6-Chloro-6-(toluene-4-sulfinyl)hexyl]-N-(4-methoxy-
phenyl)amine 8c
Colorless oil (approximately a 1:1 mixture of two diastereo-
mers); IR (neat) 3355 (NH), 2995, 2935, 1596, 1515, 1463, 1304,
1235, 1179, 1085, 1048 (SO), 816, 756 cmꢀ1 1H NMR d 1.33–1.81
.
(7H, m), 1.65–2.00 (1H, m), 2.23–2.27 (1H, m), 2.43 (3H, s), 3.03–
3.08 (2H, m), 3.74 (3H, s), 4.39 (0.5H, dd, J = 9.7, 3.0 Hz), 4.51
(0.5H, dd, J = 9.5, 3.7 Hz), 6.55–6.59 (2H, m), 6.77 (2H, d,
J = 7.8 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.54 (1H, d, J = 8.2 Hz), 7.63 (1H,
d, J = 8.2 Hz). MS m/z (%) 379 (M+, 10), 327 (5), 239 (30), 162 (15),
136 (100). Calcd for C20H26ClNO2S: M, 379.1372. Found m/z
379.1373.
4.27. N-Methyl-N-[2-(2-oxoethyl)phenyl]carbamic acid tert-
butyl ester 32
To a solution of 31 (1.79 g; 7.13 mmol) in 28 mL of DMSO at room
temperature was added IBX (2.39 g; 8.55 mmol) with stirring. After
the reaction mixture was stirred for 2 h, the reaction was quenched
with ice water. The whole was filtered off and extracted with AcOEt.
The organic layer was washed twice with water and dried over
MgSO4. The product was purified by silica gel column chromatogra-
phy to afford 32 (1.54 g; 88%) as a colorless oil; IR (neat) 2978, 2725
(CHO), 1699 (CO), 1603, 1496, 1367, 1306, 1255, 1155, 1091, 1044,
977, 866 cmꢀ1. 1H NMR d 1.32 (6H, br s, t-Bu), 1.50 (3H, br s, t-Bu),
3.14 (3H, s), 3.63 (2H, s), 7.13–7.37 (4H, m), 9.69 (1H, s). MS m/z
(%) 249 (M+, trace), 235 (trace), 221 (10), 176 (8), 165 (90), 149
(23), 120 (45), 118 (13), 91 (22), 77 (7), 57 (100). Calcd for
C14H19NO3: M, 249.1365. Found: m/z 249.1368.
4.23. 1-(4-Methoxyphenyl)pyrrolidine-2-carboxylic acid ethyl
ester 10a
To a solution of 8a (43 mg; 0.12 mmol) in 6 mL of dry THF in a
flame-dried flask at ꢀ78 °C under an argon atmosphere was added
a solution of i-PrMgCl (2.0 M solution in THF, 0.22 mL; 0.43 mmol)
with stirring. After 1 min, ethyl chloroformate (0.058 mL;
0.6 mmol) was added dropwise to the reaction mixture at ꢀ78 °C

S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
1707
4.28. Mesylate 34
with stirring. After 3 h, the reaction was quenched with 5% aq
NaOH. The whole was extracted with CH2Cl2. The organic layer
was washed with 5% aq NaOH and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 37a
(52 mg; 59%) and 37b (37 mg; 41%). Compound 37a: Colorless
crystals; mp 92.5–93.5 °C (AcOEt–hexane); IR (neat) 3395 (NH),
2923, 2813, 1605, 1585, 1516, 1493, 1470, 1427, 1363, 1310,
1266, 1172, 1085, 1047(SO), 1016, 905, 841, 811, 750, 623,
To a solution of LDA (2.46 mmol) in 8 mL of dry THF in a flame-
dried flask at ꢀ78 °C under an argon atmosphere was added drop-
wise a solution of (R)-chloromethyl p-tolyl sulfoxide (0.422 g;
2.24 mmol; over 99% ee) in 2 mL of dry THF with stirring. After
10 min, to the solution of the (R)-a-lithio chloromethyl p-tolyl sulf-
oxide was added dropwise a solution of 32 (1.39 g; 5.59 mmol) in
2 mL of dry THF with stirring. The reaction mixture was slowly
allowed to warm to ꢀ60 °C for 35 min, then the reaction was
quenched with satd aq NH4Cl. The whole was extracted with
CHCl3. The organic layer was washed with satd aq NH4Cl and dried
over MgSO4. The product was purified by silica gel column chroma-
tography to afford adduct 33 (0.96 g; 98%; a mixture of 2,3-syn and
2,3-anti diastereomers). IR (neat) 3379 (OH), 2977, 1931, 1699
(CO), 1598, 1581, 1495, 1478, 1454, 1367, 1305, 1255, 1156,
1089, 1047 (SO), 1015, 978, 862, 814, 757, 664, 624, 604, 581,
515 cmꢀ1 1H NMR d 2.24–2.39 (1H, m), 2.43 (3H, s), 2.41–2.55
.
(1H, m), 2.68–3.02 (2H, m), 2.87 (3H, s), 4.07 (1H, br s), 4.47 (1H,
dd, J = 7.0, 3.6 Hz), 6.64 (2H, dq, J = 7.8, 1.0 Hz), 7.02 (1H, d,
J = 7.4 Hz), 7.18 (1H, t, J = 7.8 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.48
(2H, d, J = 8.2 Hz). MS m/z (%) 321 (M+, 43), 182 (25), 146 (33),
120 (100), 118 (10), 91 (23). Calcd for C17H20ClNOS: M, 321.0954.
Found: m/z 321.0954. ½a D29
¼ ꢀ158 (c 1.35, CHCl3). Both diastereo-
ꢁ
meric excess and enantiomeric excess of 37a were determined to
be over 99% by HPLC using CHIRALCEL OD (hexane/i-PrOH = 9:1)
as a chiral stationary column.
514, 472 cmꢀ1 1H NMR d 1.22–1.62 (9H, m), 2.40–2.45 (3H, m),
.
2.75–3.27 (5H, m), 4.10–4.80 (1.5H, m), 4.98–5.15 (0.5H, m),
7.05–7.59 (7.7H, m), 7.70 (0.3H, d, J = 8.2 Hz). MS m/z (%) 437
(M+, 3), 381 (5), 337 (8), 298 (4), 242 (65), 198 (58), 164 (60),
139 (40), 120 (100), 118 (27), 57 (68), 41 (9), 28 (8). Calcd for
C22H28NO4SCl: M, 437.1427. Found: m/z 437.1427.
4.31. (R,Rs)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-
N-methylamine 37b
Colorless oil; IR (neat) 3400 (NH), 3044, 2924, 1604, 1584, 1515,
1470, 1308, 1265, 1170 1086, 1049, 910, 810 cmꢀ1. 1H NMR d 1.88–
1.96 (1H, m), 2.42 (3H, s), 2.52–2.58 (1H, m), 2.65–2.70 (1H, m),
2.79–2.84 (1H, m), 2.85 (3H, s), 3.73 (1H, br s), 4.54 (1H, dd,
J = 9.6, 3.6 Hz), 6.62 (1H, dd, J = 8.4, 0.6 Hz), 6.67 (1H, dt, J = 12.0,
1.2 Hz), 7.01 (1H, dd, J = 7.8, 1.8 Hz), 7.18 (1H, dt, J = 6.0, 1.8 Hz),
7.32 (2H, d, J = 7.8 Hz), 7.52 (2H, d, J = 8.4 Hz). MS m/z (%) 321
(M+, 43), 182 (25), 146 (48), 130 (17), 120 (100), 91 (37). Calcd
To a solution of adduct 33 (1.10 g; 2.51 mmol) in 14 mL of
CH2Cl2 at room temperature was added a solution of MsCl
(0.77 mL; 8.77 mmol) followed by TEA (1.2 mL; 7.52 mmol) with
stirring. After 45 min, the reaction was quenched with satd aq
NH4Cl. The whole was extracted with CHCl3. The organic layer
was washed with satd aq NH4Cl and dried over MgSO4. The product
was purified by silica gel column chromatography to afford 34
(1.12 g; 86%; a mixture of 1,2-syn and 1,2-anti diastereomers). IR
(neat) 3008, 2977, 2931, 1683 (CO), 1597, 1496, 1480, 1455,
1367, 1305, 1279, 1255, 1176, 1093, 1065 (SO), 1016, 963, 905,
for C17H20ClNOS: M, 321.0954. Found m/z 321.0949. ½a D25
¼ ꢀ80:8
ꢁ
(c 0.45, ethanol).
809, 772, 758 cmꢀ1
.
1H NMR d 1.21–1.53 (9H, m), 2.33–2.50 (6H,
4.32. (R)-(ꢀ)-1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxy-
m), 2.96–3.32 (5H, m), 3.45 (1H, dt, J = 14.1, 2.0 Hz), 4.78–5.14
(1H, m), 7.12–7.56 (8H, m). MS m/z (%) 515 (M+, 5), 442 (5), 415
(20), 363 (5), 347 (4), 320 (27), 276 (10), 266 (18), 224 (92), 180
(56), 144 (100), 120 (85), 91 (19). Calcd for C23H30NO6S2Cl: M,
515.1204. Found: m/z 515.1198.
lic acid ethyl ester 38
Colorless oil; ½a D26
¼ ꢀ32:1 (c 0.5, ethanol). All spectral data
ꢁ
were consistent with those of 7a.
4.33. (R)-1,2,3,4-Tetrahydroquinoline-2-carboxylic acid ethyl
4.29. (Rs)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-
N-methylcarbamic acid tert-butyl ester 36
ester 40
Thionyl chloride (1.14 g; 14.8 mmol) was added to a solution of
39 (1.81 g; 10.2 mmol) in 10 mL of ethanol at 0 °C and the reaction
mixture was stirred at room temperature overnight. The reaction
was quenched with satd aq K2CO3 and the whole was extracted
with AcOEt. The organic layer was washed with satd aq K2CO3
and dried over MgSO4. The product was purified by silica gel col-
umn chromatography to afford 40 (1.72 g; 82%) as a colorless oil.
IR (neat) 3400 (NH), 2979, 2933, 1733 (CO), 1608, 1587, 1497,
To a solution of 34 (27 mg; 0.052 mmol) in 0.52 ml of DMI at
room temperature was added a solution of LiBH4 (2.0 M solution
in THF, 0.078 mL; 0.156 mmol) with stirring. The reaction mixture
was allowed to warm to 65 °C for 2.5 h. The reaction was quenched
with satd aq NH4Cl. The whole was extracted with CHCl3. The organ-
ic layer was washed with satd aq NH4Cl and dried over MgSO4. The
product was purified by silica gel column chromatography to afford
36 (16 mg; 68%) as a mixture of syn and anti diastereomers (syn:an-
ti = 2:3); IR (neat) 2929, 1695 (CO), 1598, 1495, 1455, 1368, 1305,
1371, 1341, 1299, 1209, 1028, 748 cmꢀ1 1H NMR d 1.29 (3H, t,
.
J = 7.1 Hz), 1.91–2.05 (1H, m), 2.24–2.35 (1H, m), 2.69–2.90 (2H,
m), 4.01 (1H, dd, J = 9.0, 3.7 Hz), 4.15–4.31 (2H, m), 4.32–4.42
(1H, br s), 6.56–6.70 (2H, m), 6.92–7.05 (2H, m). MS m/z (%) 205
(M+, 18), 132 (100), 130 (13), 117 (7), 103 (3), 77 (4). Calcd for
C12H15NO2: M, 205.1105. Found: m/z 205.1103.
1257, 1154, 1088, 1058 (SO), 1017, 977, 907, 867, 811, 760 cmꢀ1
.
1H NMR d 1.26, 1.29, 1.32, 1.49 (each br s, total 9H, t-Bu), 1.70–
1.91 (0.4H, br s), 2.08–2.24 (0.6H, br s), 2.42 (2.3H, s), 2.43 (0.7H,
s), 2.50–2.62 (1H, m), 2.66–2.80 (1H, m), 2.82–3.02 (1H, m), 3.04–
3.16 (3H, m), 4.34–4.46 (0.6H, m), 4.47–4.56 (0.4H, m), 7.04–7.40
(6H, m), 7.46–7.64 (2H, m). MS m/z (%) 421 (M+, 5), 365 (13), 348
(7), 321 (9), 226 (100), 190 (15), 164 (34), 146 (38), 120 (37), 118
(11). Calcd for C22H28ClNO3S: M, 421.1479. Found: m/z 421.1483.
4.34. (R)-1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic
acid ethyl ester 380
To a solution of 40 (13 mg; 0.063 mmol) and 37% aqueous form-
aldehyde (0.077 mL; 0.95 mmol) in 0.7 mL of acetonitrile was
added NaBH3CN (19 mg; 0.29 mmol) with stirring. Acetic acid
(0.019 mL) was added to the reaction mixture and the whole was
stirred at room temperature for 30 min. Acetic acid (0.019 mL)
was added to the reaction mixture and the whole was stirred for
4.30. (S,Rs)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-
N-methylamine 37a
A solution of 36 (117 mg; 0.278 mmol) in 0.7 mL of CH2Cl2 was
cooled in an ice bath. To this solution was added TFA (0.265 mL)

1708
S. Mitsunaga et al. / Tetrahedron: Asymmetry 20 (2009) 1697–1708
4. (a) Satoh, T.; Osawa, A.; Kondo, A. Tetrahedron Lett. 2004, 45, 6703; (b) Satoh, T.;
Osawa, A.; Ohbayashi, T.; Kondo, A. Tetrahedron 2006, 62, 7892.
5. The preliminary results of this study were reported as a Letter: Ohbayashi, T.;
Mitsunaga, S.; Satoh, T. Tetrahedron Lett. 2007, 48, 7829.
6. Babu, G.; Orita, A.; Otera, J. Org. Lett. 2005, 7, 4641.
7. Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725.
another 30 min. The reaction mixture was diluted with ether and
the organic layer was washed with aq NaOH followed by brine.
The organic layer was dried over MgSO4 and the product was puri-
fied by silica gel column chromatography to afford 380 (13 mg;
92%) as a colorless oil. ½a D26
¼ ꢀ31:9 (c 1.4, ethanol). All spectro-
ꢁ
8. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
9. Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. J. Org. Chem. 1989, 54,
scopic data were consistent with those of 7a.
3130.
10. Satoh, T.; Yamakawa, K. Synlett 1992, 455.
Acknowledgments
11. Satoh, T.; Hayashi, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1993, 66, 1866.
12. Crystal data for 37a: C17H20ClNOS, M = 321.85, Monoclinic, space group
P21(#4), a = 6.4147(7) Å, b = 7.9729(9) Å, c = 16.2436(18) Å, b = 92.156(2)°,
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and TUS Grant for Research
Promotion from Tokyo University of Science, which are gratefully
acknowledged.
V = 830.17(16) Å3, Z = 2, F(0 0 0) = 340, Dcalcd = 1.288 g cmꢀ3
,
l
(Mo
Ka) =
3.54 cmꢀ1, T = 293 K, radiation = 0.71073 Å, R1 = 0.0379 for I > 2.0
r(I), wR2
=
0.1074 for all data (3401 reflections), GOF = 1.025 (192 parameters), crystal
dimensions 0.39 ꢂ 0.37 ꢂ 0.27 mm3. The single crystal of 37a was mounted on
a glass fiber. Diffraction data were measured on a Bruker APEX CCD-Detector
X-ray diffractometer with monochromated Mo K
anode source apparatus. The data reduction, structure solution and refinement,
and all the necessary computational data processes were performed using APEX
SHELXTL programs. Crystallographic data excluding structures have been
a radiation from a rotating
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