Enantioselective C-C bond formation to sulfonylimines through use of the 2-pyridinesulfonyl group as a novel stereocontroller

Article abstract of DOI:10.1002/chem.200701425

Enantioselective C-C bond formation to 2-pyridinesulfonylimines afforded products with good enantioselectivity. Dynamic induction of chirality on the sulfur by coordination of a chiral Lewis acid to the pyridine nitrogen and one of the prochiral sulfonyl oxygens induces enantioselectivity. Since the 2-pyridine-sulfonyl group can easily be removed after the reaction, it acts not only as an activating group but also as an efficient Stereocontroller.

Full text of DOI:10.1002/chem.200701425

FULL PAPER
DOI: 10.1002/chem.200701425
À
Enantioselective C C Bond Formation to Sulfonylimines through Use of the
2-Pyridinesulfonyl Group as a Novel Stereocontroller
Shuichi Nakamura,* Hiroki Nakashima, Hideki Sugimoto, Hideaki Sano,
Masataka Hattori, Norio Shibata, and Takeshi Toru*[a]
À
Abstract: Enantioselective C C bond formation to 2-pyridinesulfonylimines af-
forded products with good enantioselectivity. Dynamic induction of chirality on
the sulfur by coordination of a chiral Lewis acid to the pyridine nitrogen and one
of the prochiral sulfonyl oxygens induces enantioselectivity. Since the 2-pyridine-
sulfonyl group can easily be removed after the reaction, it acts not only as an acti-
vating group but also as an efficient stereocontroller.
Keywords: asymmetric synthesis ·
Grignard reactions · Mannich-type
reactions
·
stereocontroller
·
Strecker-type reaction
Introduction
reported chiral induction in radical reactions of benzimida-
zolyl or 2-pyridyl vinyl sulfones, for which we proposed the
discriminative coordination of a chiral Lewis acid between
one of the prochiral sulfonyl oxygens and the heteroaryl ni-
trogen as playing a key role in inducing enantioselectivity;[6]
namely, this induction can be termed a chiral relay process.[7]
We thus designed novel 2-pyridinesulfonylimines possessing
bifunctional coordinative sulfonyl groups, which can control
their conformational change by the chiral relay process. The
2-pyridinesulfonyl group has the following advantages: 1) its
electron-withdrawing properties increase the reactivity of
imines towards the nucleophilic addition, 2) coordination of
a Lewis acid to the pyridine nitrogen and one of the prochi-
ral sulfonyl oxygens controls the stereoselectivity as well as
the stereochemistry, and 3) the 2-pyridinesulfonyl group is
easily removable from the products. Carretero and co-work-
ers have independently reported excellent enantioselective
conjugate additions,[8] conjugate reductions,[9] 1,3-dipolar cy-
cloadditions,[10] and aza-Diels–Alder reactions of 2-pyridine-
sulfonyl substrates,[11] and have very recently disclosed Man-
nich-type reactions of N-(2-thiophenesulfonyl)imines in the
presence of their own chiral Lewis acid.[12] Shibasaki and co-
workers have reported outstanding stereocontrol in direct
asymmetric Mannich-type reactions in the presence of N-(2-
thiophenesulfonyl)imines.[13] Here we report catalytic enan-
Optically active amines, such as chiral a-amino acids and b-
amino acids, as well as chiral amines, have been used in syn-
theses of natural products and physiologically active com-
pounds. The stereoselective nucleophilic addition reaction of
various nucleophiles to C=N bonds is one of the most effi-
cient methods for the preparation of chiral amines, and dia-
stereoselective reactions of imines possessing various chiral
auxiliaries have been extensively studied.[1] Enantioselective
additions of nucleophiles to imines have also been devel-
oped in the reactions of N-aryl- or N-alkyl-substituted
imines, diphenylphosphinoylimines, N-acylimines, and N-sul-
fonylimines.[2,3] There are several reports of asymmetric nu-
cleophilic addition reactions to imines through bidentate fix-
ation between activation groups and a chiral Lewis acid;[4]
however, it is often difficult to remove the protecting group
from the products in these reactions. The N-sulfonyl group
is attractive since it enhances the imine reactivity and high
crystallinity in the adducts; however, removal of the p-tolue-
nesulfonyl group is often problematic.[5] We have previously
[a]Prof. S. Nakamura, H. Nakashima, Dr. H. Sugimoto, H. Sano,
M. Hattori, Prof. N. Shibata, Prof. T. Toru
Department of Applied Chemistry
Graduate School of Engineering
Nagoya Institute of Technology, Gokiso, Showa-ku
Nagoya 466-8555 (Japan)
À
tioselective C C bond formation in N-(2-pyridinesulfonyl)i-
mines in the presence of commercially available chiral bi-
s(oxazoline) ligands (Figure 1).[14]
Fax : (+81)52-735-5442
E-mail: snakamur@nitech.ac.jp
toru@nitech.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 2145 – 2152
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2145

Figure 1. The 2-pyridinesulfonyl group as a new coordinative protecting
and activating group and also as a stereocontroller.
Results
We first examined enantioselective reactions between sulfo-
nylimines and Grignard reagents in the presence of various
chiral ligands. Sulfonylimines and chiral ligands examined
are shown in Figure 2. Although there are many reports of
enantioselective reactions between imines and organolithi-
um or organozinc reagents,[2a,15] there are no reports of
enantioselective reactions involving Grignard reagents, be-
cause of their low reactivities.[16] The reactions between vari-
ous sulfonylimines and CH3MgI (2.0 equiv) in the presence
of various chiral ligands (1.5 equiv) were examined, and the
results are shown in Table 1. Bis(oxazoline)-Ph A (Figure 2)
was found to be an efficient ligand for the reactions of N-
Figure 2. Structures of the sulfonylimines and chiral ligands.
A specific reaction feature of the 2-pyridinesulfonyl group
in reactions with Grignard reagents is shown by the follow-
ing results. The N-(2-pyridinemethyl)aldimine 1b did not
show enough reactivity toward CH3MgBr because of the
lack of a sulfonyl group (entry 9). In addition, N-benzyli-
dene-p-methoxyaniline (1c), which is often used in enantio-
selective additions of organolithium reagents, was inert to
the addition of CH3MgI (entry 10). Furthermore, N-benzyli-
dene-p-toluenesulfonamide (1d) and N-benzylidene-2,4,6-
triisopropylbenzenesulfonamide (1e) were also not suitable
choices as substrates, their reactions with CH3MgI at À788C
in the presence of A affording the products 2d and 2e, re-
spectively, but with low enantioselectivities (entries 11 and
12). The reaction of N-benzylidene-8-quinolinesulfonamide
(1 f) afforded the racemic product 2 f (entry 13).
The reactions of various N-(2-pyridinesulfonyl)imines 1i–
p (R2 =p-tolyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-chlor-
ophenyl, 1-naphthyl, cinnamyl, and 2-furyl) with CH3MgBr
were also examined, and it was found that the correspond-
ing sulfonamides 2i–p were formed in good yields and with
good enantioselectivities (Table 2, entries 1–7). To the best
of our knowledge, these reactions are the first highly enan-
tioselective additions of Grignard reagents to imines.[18] The
Table 1. Enantioselective additions of organometallic reagents to imines
1a–f with MeMgI.
Entry
1
R1
Ligand T [8C]
2
Yield
[%]
ee[a]
[%]
1
2
3
4
5
6
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1b 2-PyCH2
1c p-MeOC6H4
1d p-TolSO2
1e TipSO2
A
B
C
D
E
A
A
A
A
A
A
A
A
À78
À78
À78
À78
À78
À95
À95
À95
À95
À95
À78
À78
À78
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2 f
75
31
56
77
90
27
87
53
0
59
7
40
0
0
72
7[b]
8[d]
9[b]
10
11
12
13
83 (>99)[c]
86
–
–
11
20
0
0
92
69
52
ꢀ
reactions of 1a with EtMgBr, BuMgBr, and PhC CMgBr
1 f 8-QnSO2
gave products 2q–s in good yields, but with lower enantiose-
lectivities than those achieved with CH3MgBr (entries 8–11
vs. Table 1, entry 7). The reactions of 1i with PhMgI and
PhMgBr gave product 2t in good yields and enantioselectiv-
ities (entries 12 and 13). The nucleophilic addition of Et2Zn
to sulfonylimine 1a did not proceed with high enantioselec-
tivity (entry 14), whereas the nucleophilic addition of MeLi
preferably gave the R isomer (entry 15). As most of the
products were crystalline, enantiomerically pure sulfon-
amides were easily obtainable by recrystallization. For ex-
[a]Determined by HPLC analysis. [b]CH 3MgBr was used. [c] ee in pa-
rentheses is that obtained after a single recrystallization. [d]CH 3MgCl
was used.
benzylidene-2-pyridinesulfonamide (1a) (entries 1–5).[17]
Performing the reaction at À958C increased enantioselectiv-
ity (entry 6). The reactions of 1a with CH3MgBr gave better
results than those with CH3MgI or CH3MgCl (entries 7 and
8).
2146
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Chem. Eur. J. 2008, 14, 2145 – 2152

À
Enantioselective C C Bond Formation to Sulfonylimines
FULL PAPER
Table 2. Enantioselective additions of organometallic reagents to imines
Table 3. Catalytic enantioselective Strecker-type reactions with imines
1a and 1i–p.
1a–f and TMSCN.
Entry
1
R2
Nucleophile
CH3MgBr
T
[8C]
2
Yield
[%]
ee[a]
[%]
Entry
1
R1
Lewis acid
Ligand
3
Yield
[%]
ee
[%][a]
1
2
3
4
1i
1j
p-Tol
À95 2i
À95 2j
À95 2k
À95 2l
À95 2m
À95 2o
À95 2p
À78 2q
À95 2r
67
98
74
77
74
38
98
74
69
46
60
41
72
49
35
83
80 (85)[b]
88
1
2
3
4
5
6
7
8
1a 2-PySO2
1b 2-PyCH2
1c p-MeOC6H4 Mg
Mg
Mg
C
A
A
A
A
A
A
A
A
A
A
A
F
G
H
I
A
A
A
A
3a
3b
3c
3d
3e
3 f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
81
0
0
70
0
75 (R)
–
–
0
–
p-MeOC6H4 CH3MgBr
1k m-MeOC6H4 CH3MgBr
1l
1m 1-naphthyl
1o 2-furyl
1p cinnamyl
1a Ph
1a Ph
1a Ph
1a Ph
1i
1i
C
p-ClC6H4
CH3MgBr
CH3MgBr
CH3MgBr
CH3MgBr
EtMgBr
76
5[c]
6[c]
7
76 (95)[b]
87
1d p-TolSO2
1e TipSO2
1 f 8-QnSO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
Mg
Mg
Mg
Mg
C
49
91
92
27
46
10
99
71
82
89
99
48
99
99
16
82
50
51
76
78
66
61
49 (R)
21 (R)
71 (R)
91 (R)
94 (R)
80 (S)
51 (S)
13 (R)
66 (S)
72 (R)
86 (R)
75 (R)
79 (R)
8
9
MgBr2OEt2
BuMgBr
9
Cu
Cu
Cu
ACHTREUNG
ꢀ
10
11[d]
12
13
14[e]
15
PhC CMgBr À78 2 s
10[b]
11[c]
12
13
14
15
16[d]
17[d]
18[d,e]
ACHTREUNG
ꢀ
PhC CMgBr À78 2 s
AHCTREUNG
p-Tol
p-Tol
PhMgI
PhMgBr
Et2Zn
À95 2t
À95 2t
À78 2q
À78 2a
Mg
Mg
Mg
Mg
Mg
ACHTREUNG
A
1a Ph
1a Ph
46
35[f]
AHCTREUNG
MeLi
AHCTREUNG
[a]Determined by HPLC analysis. [b] ee in parentheses is that obtained
after a single recrystallization. [c]Bis(oxazoline) A (2 equiv) was used.
[d]Diethyl-substituted Box A was used. [e]Et 2Zn was added at À408C.
[f]The R isomer was obtained.
G
Cu
ACHTREUNG
Mg
Mg
ACHTREUNG
19[d–f] 1a 2-PySO2
ACHTREUNG
[a]Determined by HPLC analysis with Chiralcel OD-H, Chiralpak AD-
H, or Chiralpak AS-H. [b]Lewis acid (1.0 equiv) was used with
(1.1 equiv). [c]MS (4Š) were added. [d]Reaction was carried out in
ClCH2CH2Cl. [e]Catalyst loading is 10 mol%. [f]Reaction was carried
out at 08C.
3
ample, recrystallization of 2a with 83% ee from hexane/
CH2Cl2 afforded enantiomerically pure (S)-2a (Table 1,
entry 7).
We next examined catalytic enantioselective Strecker-type
reactions of N-(2-pyridinesulfonyl)imines. The enantioselec-
tive Strecker-type reaction is one of the most important
methods for the synthesis of optically active a-amino acid
derivatives, so a variety of chiral catalysts with which to ach-
ieve high levels of asymmetric induction in the addition of
cyanide to imines have been developed.[2,3,19] Although the
N-sulfonyl group certainly increases the electrophilicity of
the imino carbon center and enhances the reactivity toward
the attack of a cyanide, there have been only limited reports
on catalytic enantioselective Strecker-type reactions with N-
sulfonylimines.[20,21]
Enantioselective Strecker-type reactions were carried out
in the presence of a variety of bis(oxazoline) ligands in com-
bination with Lewis acids; the results are shown in Table 3.
The reactions of N-aryl- and N-alkyl-substituted imines 1b
and 1c with TMSCN (1.3 equiv) in the presence of catalytic
(entry 9).[23] Enantioselectivity was improved by the use of a
stoichiometric amount of the Cu(OTf)2/A complex or by the
G
addition of molecular sieves (4 Š) to the reaction mixture,
although the yields still remained moderate to low (en-
tries 10 and 11).
It should be noted that 3a obtained with the Mg
complex in high yield and with high enantioselectivity has
the opposite configuration to that obtained with Mg(OTf)2/
Box A (entry 12).[24] The Mg
(ClO4)2/DBFOX I complex also
A
ACHTREUNG
AHCTREUNG
catalyzed the reaction to give good enantioselectivity
(entry 15).[25] Carrying out the reaction with 1a in dichloro-
ethane improved the yield and enantioselectivity of 3a (en-
tries 16 and 17). In all these reactions, 30 mol% of the chiral
catalyst was used, but it was found that the catalyst loading
of the Mg(OTf)2/A complex can be reduced to 10 mol% in
E
amounts of Mg
A
dichloroethane (entry 18). Enantioselectivity was improved
when the reaction was performed at 08C (entry 19).
The reactions of various N-(2-pyridinesulfonyl)imines 1i–
n with TMSCN in the presence of 10 mol% of the Mg-
(0.31 equiv) as a chiral Lewis acid did not give products (en-
tries 2 and 3). On the other hand, the reaction of sulfonyli-
mine 1a afforded the product 3a with good enantioselectivi-
ty (entry 1).[22] N-(p-Toluenesulfonyl)-, N-(2,4,6-triisopropyl-
benzene)sulfonyl-, and N-(8-quinolinesulfonyl)imines 1d–f
did not give good results (entries 4–6). Chiral Lewis acids
(OTf)2/A complex also gave the products 3i–n in good
yields and with good enantioselectivities (Table 4, entries 1–
6).[26]
derived from other magnesium salts such as Mg
MgBr2·OEt2 were also examined in the reaction of 1a, and
gave 3a in high yields but with low enantioselectivities (en-
A
Catalytic enantioselective Mannich-type reactions of N-
(2-pyridinesulfonyl)imines were also examined. b-Amino
acid derivatives have established utility as building blocks
for the preparation of pharmaceutical targets,[27] natural
products,[28] and peptidic materials with unique structural
tries 7 and 8). When Cu
A
was obtained with good enantioselectivity but in low yield
Chem. Eur. J. 2008, 14, 2145 – 2152
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2147

T. Toru, S. Nakamura et al.
Table 4. Catalytic enantioselective Strecker-type reactions with imines
Table 5. Catalytic enantioselective Mannich-type reactions with imines
1a–n and TMSCN.
1a, 1d, and 1 f–h.
Entry
Imine
R2
Product
Yield
[%]
ee
[%][a]
Entry
1
R1
Lewis acid Ligand
4
Yield
[%]
ee
1[b]
2
1i
1j
1k
1l
1m
1n
p-tolyl
3i
3j
3k
3l
3m
3n
94
99
93
99
99
99
77 (R)
84 (R)
78 (R)
72 (R)
75 (R)
73 (R)
[%][a]
p-MeOC6H4
m-MeOC6H4
p-ClC6H4
1-naphthyl
2-naphthyl
1[b]
2
3
4
5
1a 2-PySO2
1a 2-PySO2
1d p-TolSO2
1 f 8-QnSO2
Mg
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(OTf)2
Cu(OTf)2
Cu(OTf)2
CuOTf
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
A
A
A
A
A
A
A
A
A
A
C
4a
4a
4d trace
37
80
29
3[b]
4
A
86 (>99)[c]
N
–
1
0
5
6
R
4 f
4g
4h
4a
4a
4a
4a
4a
4a
4a
19
47
59
55
32
16
41
24
30
42
1g 2-thienylSO2 Cu
N
[a] ee values were determined by HPLC analysis with Chiralcel OD-H,
Chiralpak AD-H, or Chiralpak AS-H. [b]Reaction was carried out at
08C.
6
1h 2-furylSO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
1a 2-PySO2
T
8
7[d]
8[b]
9[b]
10[b]
11
12
13[b]
A
86
38
62
2
71
64
62
AHCTREUNG
AHCTREUNG
E
F
H
H
properties.[29] Although various diastereoselective ap-
proaches to Mannich-type reactions have been reported for
the synthesis of b-amino acids, enantioselective additions of
ester enolate equivalents to imines are one of the most im-
portant methods for the synthesis of optically active b-
amino acids.[2,3,30,31] However, only a few studies on catalytic
enantioselective Mannich-type reactions of N-sulfonylimines
without other electron-withdrawing groups have been re-
ported.[32]
N
AHCTREUNG
[a]Determined by HPLC analysis with Chiralcel OD-H or Chiralpa-
k AD-H. [b]Catalyst loading is 30 mol%. [c] ee in parentheses is that ob-
tained after a single recrystallization. [d]The reaction was performed for
72 h.
Table 6. Catalytic enantioselective Mannich-type reactions with imines
1i–p.
Enantioselective Mannich-type reactions of various N-
(arenesulfonyl)imines 1 in the presence of catalytic amounts
of chiral Lewis acids prepared from various bis(oxazoline)s
and Lewis acids were examined, and the results are shown
in Table 5. The enantioselective reaction of 1a in the pres-
Entry
Imine
R2
Product
Yield
[%]
ee
ence of 30 mol% of Mg
with low enantioselectivity, whereas the reaction in the pres-
ence of Cu(OTf)2/A gave the product with good enantiose-
lectivity (entries 1 and 2). However, N-(toluenesulfonyl)i-
mines 1d did not afford the product with Cu(OTf)2/A
(OTf)2/A afforded the product 4a
[%][a,b]
1
1i
1j
1l
1m
1n
1o
1p
p-tolyl
4i
4j
4l
4m
4n
4o
4p
40
58
52
76
89
86
89
70 (95)
83 (>99)
75 (90)
73 (94)
63 (>99)
81 (99)
ACHTREUNG
2[c]
3[c]
4[c]
5
p-MeOC6H4
p-ClC6H4
1-naphthyl
2-naphthyl
2-furyl
AHCTREUNG
(entry 3). The reactions in the presence of other N-(hetero-
arenesulfonyl)imines 1 f–h did not show good enantioselec-
tivities (entries 4–6). The yield of 4a in the reaction of 1a
was improved by use of a longer reaction time (entry 7).[33]
6
7[c]
cinnamyl
83 (>99)
[a]Determined by HPLC analysis with Chiralcel OD-H or Chiralpa-
k AD-H. [b] ee in parentheses are those obtained after single recrystalli-
zations. [c]Catalyst loading is 30 mol%.
Other chiral Lewis acids derived from CuOTf and Zn(OTf)2
U
also afforded the product 4a but with low enantioselectivi-
ties (entries 8 and 9). The chiral Lewis acids derived from
other bis(oxazoline) ligands C, F, and H also catalyzed the
reaction but with lower enantioselectivities than were ob-
treatment with magnesium in MeOH[34] to give the chiral
tained with Cu
The reactions of various N-(2-pyridinesulfonyl)imines 1i–
p in the presence of Cu(OTf)2/A were also found to give
A
AHCTREUNG
products in moderate yields but with good enantioselectivi-
ties (Table 6, entries 1–7). Enantiomerically pure sulfona-
mides were easily obtainable by recrystallization.
To validate the synthetic potential of this stereoselective
preparation of chiral amines, we confirmed the easy removal
of the 2-pyridinesulfonyl group. Removal of arenesulfonyl
groups generally requires drastic reaction conditions.[5] The
optically active (S)-2a and (R)-4a were desulfonylated on
Scheme 1. Desulfonylation of (S)-2a and (R)-4a.
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Chem. Eur. J. 2008, 14, 2145 – 2152

À
Enantioselective C C Bond Formation to Sulfonylimines
FULL PAPER
amine (S)-5 and the chiral b-amino acid (R)-6 without sig-
nificant loss of optical purity (Scheme 1).
ordinated complex I containing an (E)-imine was more
stable than the (Z)-imine complex II. Nucleophiles thus ap-
proach the Si face of the imine in complex I to form prod-
ucts with good ees. Dynamically induced chirality on the
sulfur indeed plays a definitive role in induction of enantio-
selectivity. It can be categorized as a new type of chiral
relay.[7]
Discussion
The enantioselective nucleophilic additions of Grignard re-
agents and the Strecker-type reactions of N-(2-pyridinesulfo-
nyl)imines 1a, 1 f, and 1i–p gave the products in good yields
and with good enantioselectivities, but the reactions of N-
(p-toluenesulfonyl)imine 1d and of N-aryl- and N-alkyli-
mines 1b and 1c did not afford good results. From these
findings it was confirmed that the 2-pyridinesulfonyl group
acts not only as an activating group but also as an efficient
stereocontroller. If it is assumed that MgII forms a tetrahe-
dral bidentate-coordinating complex with the substrate
1a,[35,36] there are two types of coordination for the complex
that may be considered. One is the N,O-type complex, in
which MgII coordinates to the
The enantioselective Strecker-type reactions and Man-
nich-type reactions of N-(2-pyridinesulfonyl)imines in the
presence of Cu(OTf)2 as a Lewis acid gave the products
U
with good enantioselectivities. The CuII ion would form a
distorted square-planar bidentate-coordinated complex with
1a and Box A (Figure 4). In the most stable complex 1a–A,
optimized by the Spartan ’06 PM3 method,
a sulfonyl
oxygen and a pyridine nitrogen coordinate to CuII. Further-
more, selective coordination between
a pro-S sulfonyl
oxygen in 1a and CuII affords less steric interaction than in
other complexes. TMSCN and silyl ketene acetal thus ap-
pyridine nitrogen and to one of
the sulfonyl oxygens, while the
other is the N,N-type complex,
in which MgII coordinates to the
imino nitrogen and to the pyri-
dine nitrogen. In order to esti-
mate the stabilities of these
complexes, we studied MO cal-
culations of the complexes
formed between 1c and 3 with
Spartan ’06 PM3[37] and Gaussi-
an 03[38] HF/3-21+G*. Struc-
tures were first optimized with
Spartan ’06 PM3 and were then
fully optimized at the HF/3-
21+G* level of theory.[39,40] The
relative energies of the transi-
tion state structures and the op-
timized structures are depicted
in Figure 3. The calculation
showed that the N,O-type com-
plexes I, II, and III are more Figure 3. Geometry optimization of 1a–A complexes with Spartan ’06 PM3 and Gaussian 03 HF/3-21+G*.
stable than complex IV depict-
ed as one of the most stable
N,N-type complexes.
In order to exert high enan-
tioselectivity in the N,O-type
complex, one of the sulfonyl
oxygens should be selectively
coordinated. Indeed, complex I,
in which the pro-S sulfonyl
oxygen is coordinated to MgII,
was shown to be much more
stable than the pro-R sulfonyl
oxygen-coordinated
complex
III, because more severe steric
interaction exists in the latter
complex. The pro-S oxygen-co- Figure 4. Proposed reaction direction in the most stable complex 1a–A optimized with Spartan ’06 PM3.
Chem. Eur. J. 2008, 14, 2145 – 2152
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2149

T. Toru, S. Nakamura et al.
3H), 4.61 (dq, J=7.0, 8.2 Hz, 1H), 5.18 (d, J=8.2 Hz, 1H), 7.11–7.20 (m,
5H), 7.33–7.40 (m, 1H), 7.70–7.80 (m, 2H), 8.56–8.59 ppm (m, 1H);
13C NMR: d=23.5, 54.3, 121.9, 126.0, 126.1, 127.2, 128.1, 137.4, 141.4,
149.5, 157.4 ppm; IR (KBr): n˜ =3091, 1330, 1178, 1119, 614, 541 cmÀ1; MS
(70 eV): m/z (%): 262 [M]+ (4), 77 (40), 78 (28), 119 (100), 182 (15); ele-
mental analysis calcd (%) for C13H14N2O2S: C 59.52, H 5.38, N 11.37;
found: C 59.51, H 5.42, N 10.44; HPLC (Chiralcel OJ-H, hexane/iPrOH
70:30, flow rate 1.2 mLminÀ1), tR =11 (S), 33 min (R).
proach the Si face of the imine, avoiding interaction with
the phenyl group in bis(oxazoline)-Ph A, to form (R)-3a
and (R)-4a.
Conclusion
General procedure for the reactions of imines with TMSCN—2-(2-Pyridi-
nesulfonyl)amino-2-phenylacetonitrile (3a): A solution of bis(oxazoline)-
We have found that the 2-pyridinesulfonyl group works not
only as a good activating group for the imino group in reac-
tions with nucleophiles, but also as a stereocontroller that
shows excellent enantioselectivity through dynamically con-
trolled chirality on the sulfur atom. The first highly enantio-
selective reactions between imines and Grignard reagents
have been achieved in the presence of bis(oxazoline)s. Cata-
lytic enantioselective Strecker-type reactions and Mannich-
type reactions with N-(2-pyridinesulfonyl)imines in the pres-
ence of bis(oxazoline)s afforded chiral sulfonamides with
good enantioselectivities. The MO calculations suggested
that these reactions each proceed through a complex in
which one of the sulfonyl oxygens is preferentially coordi-
nated to MgII and CuII. The 2-pyridinesulfonyl group was
shown to be an easily removable and efficient protective
group, which has notable properties of high chiral inducibili-
ty and activation of the imino group toward the addition of
nucleophiles. Further extension of work on 2-heteroarene-
sulfonyl groups as powerful stereocontrollers in combination
with chiral ligands is now in progress.
Ph (3.0 mg, 11 mol%) and Mg(OTf)2 (2.6 mg, 10 mol%) in ClCH2CH2Cl
N
(1.0 mL) was stirred for 30 min at room temperature under nitrogen. A
solution of imine 1a (20.0 mg, 0.081 mmol) in ClCH2CH2Cl (1.0 mL) was
added to the reaction mixture. After the reaction mixture had been
stirred for 15 min at room temperature, trimethylsilyl cyanide (32 mL,
0.24 mmol) was added over a period of 5 min. The reaction mixture was
stirred for 12 h until complete by TLC. Sat. aqueous Na2CO3 (2.0 mL)
was added, and the mixture was stirred for 30 min at room temperature.
The organic phase was separated, and the aqueous phase was extracted
with CH2Cl2 (3”5 mL). The combined organic phase was dried over
MgSO4 and concentrated. The residue was purified by chromatography
(benzene/ethyl acetate 90:10) to afford 3a (22.1 mg, 99%, 74% ee) as a
white solid. Rf =0.32 (benzene/ethyl acetate 8:2); m.p. 158.0–159.08C;
1
[a]2D6 =+35 (c=0.03, CHCl3, 74% ee); H NMR ([D6]DMSO): d=5.90 (d,
J=8.5 Hz, 1H), 7.36–7.40 (m, 5H), 7.64–7.70 (m, 1H), 7.92–7.96 (m,
1H), 8.03–8.12 (m, 1H), 8.71 (m, 1H), 9.58 ppm (d, J=8.5 Hz, 1H);
13C NMR ([D6]DMSO): d=47.8, 117.8, 121.6, 126.9, 127.4, 128.7, 128.9,
133.9, 149.9, 156.8 ppm; IR (KBr): n˜ =3097, 1348, 1185 cmÀ1; MS (70 eV):
m/z (%): 273 [M]+ (0.4), 208 (11), 130 (12), 78 (100), 77 (24); elemental
analysis calcd (%) for C13H11N3O2S: C 57.13, H 4.06, N 15.37; found: C
57.24, H 3.99, N 15.33; HPLC (Daicel Chiralpak AS, hexane/iPrOH
75:25; 2.0 mLminÀ1; tR =18.2 (minor), tR =27.7 min (major)).
General procedure for the Mannich-type reactions of imines—Methyl
(R)-2,2-dimethyl-3-phenyl-3-[(2-pyridinesulfonyl)amino]propionate (4a):
A solution of bis(oxazoline)-Ph (3.9 mg, 0.011 mmol, 11 mol%) and Cu-
Experimental Section
(OTf)2 (3.8 mg, 0.010 mmol, 10 mol%) in CH2Cl2 (1.0 mL) was stirred for
30 min at room temperature under nitrogen. A solution of imine 1a
(25.0 mg, 0.104 mmol) in CH2Cl2 (1.0 mL) was added to the reaction mix-
ture. After the reaction mixture had been cooled to À788C, silylketene
acetal (27 mL, 0.135 mmol) was added over a period of 5 min. The reac-
tion mixture was stirred for 24 h until complete by TLC. Sat. aqueous
NH4Cl (10 mL) was added, the organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (5”5 mL). The combined or-
ganic phase was dried over Na2SO4 and concentrated. The residue was
purified by chromatography (benzene/ethyl acetate 85:15) to afford 4a
(28.9 mg, 80%, 86% ee) as a white solid. Rf =0.55 (benzene/ethyl acetate
7:3); m.p. 146.0–147.58C; [a]2D0 =À26.6 (c=1.0, CHCl3, 99% ee);
1H NMR: d=1.08 (s, 3H), 1.39 (s, 3H), 3.65 (s, 3H), 4.42 (d, J=10 Hz,
1H), 6.50 (d, J=10 Hz, 1H), 6.88–6.99 (m, 5H), 7.14–7.17 (m, 1H), 7.41–
7.51 (m, 2H), 8.40 ppm (s, 1H); 13C NMR: d=22.5, 24.7, 47.1, 52.2, 65.0,
121.6, 125.6, 127.1, 127.4, 127.7, 136.3, 136.9, 149.2, 156.9, 175.8 ppm; IR
General methods and additional synthesis details are available in the
Supporting Information.
Typical procedure for the preparation of N-benzylidene-2-pyridinesulfon-
amide (1a): A solution of 2-pyridinesulfonamide (501 mg, 3.17 mmol) in
THF (8 mL) was added at 08C to a solution of benzaldehyde (0.32 mL,
3.17 mmol), triethylamine (1.32 mL, 9.50 mmol), and titanium(iv) chlo-
ride (1.46 molLÀ1 in CH2Cl2, 2.25 mL, 3.17 mmol), and the mixture was
stirred for 2 h. The mixture was filtered through Celite and washed with
CH2Cl2. The combined organic solution was extracted with CH2Cl2,
washed with saturated aqueous NH4Cl, and dried over Na2SO4, and con-
centrated under reduced pressure to leave a residue that was recrystal-
lized with hexane/ethyl acetate to afford 1a (368 mg, 47%). Rf =0.35
(hexane/ethyl acetate 6:4); m.p. 103.8–105.08C; 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=7.48–7.67 (m, 4H), 7.96–8.02 (m, 3H), 8.24–8.28
(m, 1H), 8.72–8.75 (m, 1H), 9.27 ppm (s, 1H); 13C NMR: d=121.8, 125.8,
127.6, 130.1, 130.7, 133.9, 136.6, 148.8, 154.2, 172.7 ppm; IR (KBr): n˜ =
1599, 1572, 1314, 1171, 1114, 816 cmÀ1; MS (70 eV): m/z (%): 246 [M]+
(6), 78 (100); elemental analysis calcd (%) for C12H10N2O2S: C 58.52, H
4.09, N 11.37; found: C 58.36, H 4.34, N 11.28.
(KBr): n˜ =3167, 1734, 1289, 1582, 1337, 1180, 1131, 710 cmÀ1
(70 eV): m/z (%): 348 [M]+ (35), 315 (40), 256 (70), 247
(100), 199 (45);
; MS
AHCTREUNG
elemental analysis calcd (%) for C17H20N2O4S: C 58.60, H 5.79, N 8.04;
found: C 58.90, H 5.49, N 7.91; HPLC (Chiralpak AD-H, hexane/iPrOH
80:20, 1.0 mLminÀ1): tR = 11.3 (major), 14.8 min (minor).
(S)-1-Phenylethylamine hydrochloride [(S)-5]:
A mixture of (S)-2a
Typical procedure for enantioselective addition of Grignard reagents to
(20.2 mg, 0.077 mmol) and Mg powder (9.3 mg, 0.385 mmol) in MeOH
(2 mL) and THF (0.5 mL) was stirred for 2 h at 08C. Then, diethyl ether
(3 mL) and saturated aq. NH4Cl (3 mL) were added, and the reaction
mixture was stirred for 2 h at room temperature. The aqueous layer was
extracted with Et2O, and the combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure to leave an oil that was
purified by column chromatography (CH2Cl2/MeOH/aq. NH3 90:10:0.5)
to afford the amine. The amine was dissolved in THF (2 mL), and HCl
solution (2n) was added to the solution. After stirring for 30 min at room
temperature, the solution was concentrated under reduced pressure to
1a—N-(1-Phenylethyl)-2-pyridinesulfonamide
[(S)-2a]:
MeMgBr
(1.04 molLÀ1 in Et2O, 0.937 mL, 0.974 mmol) was added at À958C to a
solution of bis(oxazoline)-Ph (244 mg, 0.731 mmol) and imine 1a
(120 mg, 0.487 mmol) in toluene (10 mL), and the reaction mixture was
stirred for 1 h. The reaction mixture was quenched with HCl (1m) and
extracted with Et2O, dried over Na2SO4, and concentrated under reduced
pressure to leave a residue that was purified by column chromatography
(silica gel 20 g, benzene/ethyl acetate 90:10) to afford (S)-2a (101 mg,
79%, 83% ee). Recrystallization from hexane/CH2Cl2 afforded (S)-2a
with 99% ee. Rf =0.35 (hexane/ethyl acetate 6:4); m.p. 103.8–105.08C;
[a]2D0 =À42.3 (c=0.29, CHCl3, 99% ee); 1H NMR: d=1.48 (d, J=7.0 Hz,
give (S)-5 (10.9 mg, 90%). [a]2D5 =À4.5 (c=0.36, MeOH) [lit.[41] [a]2D3
=
2150
www.chemeurj.org
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Chem. Eur. J. 2008, 14, 2145 – 2152

À
Enantioselective C C Bond Formation to Sulfonylimines
FULL PAPER
À4.6 (c=4, MeOH, 99% ee)]. In order to determine the enantiopurity,
(S)-5 was treated with benzoyl chloride and triethylamine in CH2Cl2 at
room temperature. N-Benzoyl-1-phenylethylamine was analyzed by
HPLC: 99% ee [Chiralcel OD-H hexane/iPrOH 90:10, 1.0 mLminÀ1: tR
= 16 min (S)].
Watanabe, N. Mase, R. Furue, T. Toru, Tetrahedron Lett. 2001, 42,
2981–2984.
[7]For a recent review on chiral relay effects, see: a) O. Corminboeuf,
L. Quaranta, P. Renaud, M. Liu, C. P. Jasperse, M. P. Sibi, Chem.
Eur. J. 2003, 9, 28–35; for a recent contribution, see: b) M. P. Sibi,
L. M. Stanley, X. Nie, L. Venkatraman, M. Liu, C. P. Jasperse, J.
Am. Chem. Soc. 2007, 129, 395–405.
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1798.
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129, 1480–1481.
[12]A. S. Gonzµlez, R. G. Arrayµs, J. C. Carretero, Org. Lett. 2006, 8,
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[13]H. Morimoto, G. Lu, N. Aoyama, S. Matsunaga, M. Shibasaki, J.
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[14]For preliminary reports, see: a) S. Nakamura, N. Sato, M. Sugimoto,
T. Toru, Tetrahedron: Asymmetry 2004, 15, 1513–1516; b) H. Sugi-
moto, S. Nakamura, M. Hattori, S. Ozeki, N. Shibata, T. Toru, Tetra-
hedron Lett. 2005, 46, 8941–8944; c) S. Nakamura, H. Nakashima,
H. Sugimoto, N. Shibata, T. Toru, Tetrahedron Lett. 2006, 47, 7599–
7602; d) S. Nakamura, H. Sano, H. Nakashima, K. Kubo, N. Shibata,
T. Toru, Tetrahedron Lett., 2007, 48, 5565–5568.
Methyl (R)-3-amino-2,2-dimethyl-3-phenylpropionate [(R)-6]: A mixture
of (R)-4a (200 mg, 0.574 mmol) and Mg powder (418.6 mg, 17.2 mmol) in
MeOH (10 mL) was stirred for 6 h at À308C. Then, diethyl ether
(10 mL) and saturated aq. NH4Cl (15 mL) were added to the reaction
mixture. The aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were dried over Na2SO4 and concentrated under reduced
pressure to leave a white solid that was purified by column chromatogra-
phy (benzene/ethyl acetate 90:10) to afford product (R)-6 (159.2 mg,
91%). [a]2D0 =+30.8 (c=1, 1m HCl, 87% ee) [lit.[42] [a]2D0 =À32.4 (c=1,
1n HCl, 98% ee)]; 1H NMR: d=1.08 (s, 3H), 1.14 (s, 3H), 1.71 (s, 2H),
3.68 (s, 3H), 4.22 (s, 1H), 7.26 ppm (s, 5H); 13C NMR: d=19.5, 23.7,
47.8, 51.8, 61.9, 127.0, 127.5, 127.8, 141.5, 177.3 ppm; IR (KBr): n˜ =2950,
1725, 1453, 1259, 1141, 705 cmÀ1; MS (70 eV): m/z (%): 207 [M]+ (70),
199 (60), 171 (56), 152 (100); elemental analysis calcd (%) for
C12H17NO2: C 69.54, H 8.27, N 6.76; found: C 69.65, H 8.36, N 6.85;
HPLC (Chiralcel AS-H, hexane/iPrOH 95:5, 0.30 mLminÀ1): tR = 24.5
(major), 30.7 min (minor).
Acknowledgements
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[16]Although the reactivities of Grignard reagents towards imines are
This work was supported by the Daiko Foundation, the Tatematsu Foun-
dation, the Yazaki Foundation, and the Sankyo Award in Synthetic Or-
ganic Chemistry, Japan.
generally low, they are improved by the addition of Sc(OTf)3, see: S.
C
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Chem. Eur. J. 2008, 14, 2145 – 2152
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2151

T. Toru, S. Nakamura et al.
[22]We also examined the reaction with Bu 3SnCN, TMSCN, TBDPSCN,
and KCN as a cyanation reagent, obtaining the product 3a in low
yield.
[33]High enantioselectivity was not shown in reactions in other solvents
or with various other copper(II) salts.
[34]a) C. Goulaouic-Dubois, A. Guggisberg, M. Hesse, J. Org. Chem.
1995, 60, 5969–5972; b) C. S. Pak, D. S. Lim, Synth. Commun. 2001,
[23]Various chiral Lewis acids such as Zn
A
ACHTREUNG
31, 2209–2214.
[35]The tetrahedral Mg
A
G
U
ACHTREUNG
II
complex has been proposed, see: a) E. J.
BINAP, AgOTf/BINAP, Me3Al/BINOL, ZrCl4/BINOL, AlCl3/H,
and chiral salen/AlCl complexes afforded the product 3a either in
low yields or with low enantioselectivities.
Corey, K. Ishihara, Tetrahedron Lett. 1992, 33, 6807–6810; b) M. P.
Sibi, J. B. Sausker, J. Am. Chem. Soc. 2002, 124, 984–991. The octa-
hedral structure has been also proposed: c) M. P. Sibi, G. Petrovic, J.
Zimmerman, J. Am. Chem. Soc. 2005, 127, 2390–2391; d) K. V.
Gothelf, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 1998, 63,
5483–5488.
[24]Similar observations of the reversal of stereochemistry have been re-
ported, see: a) M. P. Sibi, J. Ji, J. Org. Chem. 1997, 62, 3800–3801;
b) M. P. Sibi, H. Matsunaga, Tetrahedron Lett. 2004, 45, 5925–5929.
[25]The Mg
[26]The Mg
ACHTREUNG
[36]Another plausible reaction mechanism through a seven-membered
transition state in which the pyridine nitrogen is coordinated to
magnesium may be considered, but it is ruled out because the transi-
tion state would form the R isomer preferentially.
ACHTREUNG
reactions of 1a, but the Stecker-type reactions with other sulfonyli-
mines 1i–n and this catalyst afford the product in low yield and with
low enantioselectivity.
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[39]All optimized structures were confirmed to have no negative fre-
quency by frequency calculations. All transition structures were
found to have only one negative eigenvalue with the corresponding
À
eigenvector involving the formation of newly created C C bonds.
The transition states reported were shown to belong to the studied
reaction through the intrinsic reaction coordinate (IRC).
[40]The calculation of the octahedral Mg II complex did not result in con-
vergence.
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Received: September 11, 2007
Published online: December 14, 2007
2152
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