Enantioselective nucleophilic addition to N-(2-pyridylsulfonyl)imines by use of dynamically induced chirality

Article abstract of DOI:10.1016/j.tetlet.2005.10.085

Enantioselective nucleophilic addition of Grignard reagents to N-(2-pyridylsulfonyl)imines in the presence of bis(oxazoline) afforded products with good enantioselectivity. Dynamically induced chiralitxy on the sulfur by coordination of a chiral Lewis aci

Full text of DOI:10.1016/j.tetlet.2005.10.085

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8941–8944
Enantioselective nucleophilic addition to
N-(2-pyridylsulfonyl)imines by use of dynamically induced chirality
Hideki Sugimoto, Shuichi Nakamura, Masataka Hattori, Sachiko Ozeki,
Norio Shibata and Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japan
Received 21 September 2005; revised 7 October 2005; accepted 14 October 2005
Available online 7 November 2005
Abstract—Enantioselective nucleophilic addition of Grignard reagents to N-(2-pyridylsulfonyl)imines in the presence of bis(oxazo-
line) afforded products with good enantioselectivity. Dynamically induced chirality on the sulfur by coordination of a chiral Lewis
acid to a pyridyl nitrogen and one of the sulfonyl oxygens fixes the conformation of the complex and induces enantioselectivity.
Since the 2-pyridylsulfonyl group can be easily removed after the addition reaction, it acts not only as a protecting group but also
as an efficient stereocontroller.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the products. Enantioselective reactions of imines de-
scribed above have been performed by alkylation with
organolithium or organozinc reagents, but there are no
reports of the enantioselective reaction using Grignard
reagents. It is important to develop an easily removable
protecting group, which also has sufficient activating
property for imines to react with Grignard reagents.
Thus, we designed the 2-pyridylsulfonyl group as a
new coordinative protecting and activating group as
well as a stereocontroller:9 The 2-pyridylsulfonyl group
may have the following advantages: (1) the electron-
withdrawing property increases the reactivity of imines
for the nucleophilic addition, (2) coordination of a
Lewis acid to the pyridyl nitrogen and one of the sulfo-
nyl oxygens controls the stereoselectivity and stereo-
chemistry, and (3) the 2-pyridylsulfonyl group is easily
removable from the products (Fig. 1). We now report
a new enantioselective nucleophilic addition to 2-pyr-
idylsulfonylimines with Grignard reagents and conver-
sion to chiral amines.10,11
The stereoselective nucleophilic addition reaction of
organometallic reagents to C@N bonds is one of the
most efficient methods for the preparation of chiral
amines. For the preparation of chiral amines, diastereo-
selective reactions of imines having various chiral auxil-
iaries with organometallic reagents have been
extensively studied.1 Enantioselective addition of orga-
nometallic reagents to imines has also been developed2
in the reaction of N-substituted imines,3 diphenyl-
phosphinoylimines,4 N-acylimines,5 and sulfonyl imines6
since the first report of chiral ligand-mediated addition
of organolithium reagents to a C@N bond.7 In these
reactions, various Lewis acids and chiral ligands have
been examined to coordinate to the imino nitrogen in
a monodentate manner for the stereoselective intermo-
lecular alkylation of imines. Exceptionally, there are
only a few reports for asymmetric nucleophilic addition
reaction to imines through bidentate fixation with a chi-
ral Lewis acid;8 however, it is often found difficult in
these reactions to remove the protecting group from
L*
R'
L* M
1) nucleophile
2) deprotection
O O
S
O O
S
*
ML2
N
N
H2N
R
*
N
R
N
R
*
Keywords: 2-Pyridylsulfonyl group; Grignard reagents; Stereocontrol-
ler; Imine.
*
Figure 1. 2-Pyridylsulfonyl group as a new coordinative protecting
Corresponding author. Tel./fax: +81 52 735 5217; e-mail: toru@
and activating group as well as a stereocontroller.
nitech.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.085

8942
H. Sugimoto et al. / Tetrahedron Letters 46 (2005) 8941–8944
2. Results and discussion
2-pyridylsulfonylimines 1b–f (R2 = p-tolyl, 4-chloro-
phenyl, 1-naphthyl, cinnamyl, 2-furyl) with CH3MgBr
were examined and it was found that the corresponding
sulfonamides 2b–f were formed in good yields with good
enantioselectivities (entries 9–13). To our knowledge,
this reaction is the first highly enantioselective addition
of Grignard reagents to imines.14 Efficiency of 2-pyrid-
ylsulfonyl group in the reaction with Grignard reagents
is shown by the following results. N-(2-Pyridylmeth-
yl)aldimine 1g did not show enough reactivity toward
CH3MgBr because of the lack of a sulfonyl group (entry
14). In addition, N-benzylidene-p-methoxyaniline 1h,
which is often used in the enantioselective addition of
organolithium reagents was not a good substrate for
the addition with CH3MgI (entry 15).15 Furthermore,
N-benzylidene-p-toluenesulfonamide 1i and N-benzyli-
dene-2,4,6-triisopropylbenzenesulfonamide 1j were also
not proper choice as substrates and their reaction with
CH3MgI at À78 °C in the presence of bis(oxazoline)-
We examined the reaction of N-benzylidene-2-pyridine-
sulfonamide 1a with CH3MgI (2 equiv) using various
chiral ligands (1.5equiv) such as bis(oxazoline)s 3–6
and (À)-sparteine 7 (Scheme 1). As a result, bis(oxazo-
line)-Ph 3 was found to be an efficient ligand for this
reaction (entries 1–5).12 Performing the reaction at
À95 °C increased enantioselectivity (entry 6). Reaction
of 1a with CH3MgBr gave better results in comparison
with CH3MgI and CH3MgCl to give the S-isomer with
83% ee in 79% yield (entry 7).13 The reactions of various
X
chiral ligand
R1
R1
nucleophile (X)
N
R2
O
N
R2
*
toluene, temp.
H
1a-k
2a-p
O
N
N
N
N
Me
Me
Ph
O O
S
R3
R3
1) Mg/MeOH
2) HCl
N
3: R3 = Ph
4: R3 = iPr
5: R3 = tBu
6: R3 = Bn
N
Ph
Cl H3N
7
H
(S)-2a
99% ee
(S)-8
90%, 99% ee
Scheme 1.
Scheme 2.
Table 1. Enantioselective addition of organometallic reagents to aldimines 1a–k
Entry
Imine
R1
R2
Nucleophile
Ligand
Temperature (°C)
Product
Yield (%)
eea (%)
7
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PyCH2
p-MeOC6H4
p-TolSO2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3MgI
CH3MgI
CH3MgI
CH3MgI
CH3MgI
CH3MgI
CH3MgBr
CH3MgCl
CH3MgBr
CH3MgBr
CH3MgBr
CH3MgBr
CH3MgBr
CH3MgI
CH3MgI
CH3MgI
CH3MgI
CH3MgI
EtMgBr
BuMgBr
iPrMgBr
tBuMgBr
PhMgI
3
4
5
6
7
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
À78
À78
À78
À78
À78
À95
À95
À95
À95
À95
À95
À95
À95
À95
À95
À78
À78
À78
À95
À95
À95
À78
À95
À95
À40
À78
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
9
755
31
5
77
90
27
79
5
67
77
74
98
38
0
6
40
86
0
0
72
83 (>99)b
3
9
p-Tol
p-ClC6H4
1-Naphthyl
Cinnamyl
2-Furyl
Ph
Ph
Ph
Ph
Ph
83
76
76 (95)b
82
87
—
—
11
10
11c
12
13c
14
15
16
17
18
19
20
21
22c,f
23
24
25g
26
1g
1h
1i
2g
2h
2i
0
92
69
5
d
1j
TipSO2
8-QnSO2
2j
20
e
1k
1a
1a
1a
1a
1b
1b
1a
1a
2k
2l
2
0
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
2-PySO2
Ph
Ph
Ph
Ph
74
69
87
156
41
72
49
3535
50
51
6
2m
2n
2o
2p
2p
2l
Ph
66
61
p-Tol
p-Tol
Ph
PhMgBr
Et2Zn
MeLi
46
g
2a
a ee was determined by the HPLC analysis.
b ee in parentheses is that obtained after single recrystallization.
c Bis(oxazoline) 3 (2 equiv) was used.
d TipSO2 = (2,4,6-triisopropylphenyl)sulfonyl.
e 8-QnSO2 = (8-quinolyl)sulfonyl.
f N-(2-Pyridylsulfonyl)benzylamine was obtained in 35% yield.
g The R-isomer was obtained.

H. Sugimoto et al. / Tetrahedron Letters 46 (2005) 8941–8944
8943
Ph 3 afforded the products 2i and 2j, respectively, in
poor yields with low enantioselectivities (entries 16 and
17). The reaction of N-benzylidene-8-quinolinesulfon-
amide 1k afforded the racemic product 2k (entry 18).
The reaction of 1a with EtMgBr, BuMgBr, and iPrMgBr
gave products 2l–n in good yields but with enantioselec-
tivity lower than that with CH3MgBr (entries 19–21 vs
nitrogen and a pro-S sulfonyl oxygen (Fig. 2). CH3MgX
approaches the Si-face of this imine complex to form
(S)-2a. Dynamically induced chirality on the sulfur in-
deed plays a definitive role in induction of enantioselec-
tivity: It can be categorized as a new type of chiral
relay.23
t
entry 7). The reaction using BuMgBr resulted in a
low yield of the product 2o besides the formation of
an abnormal Grignard product16 (entry 22). The reac-
tion of 1a with PhMgI and PhMgBr gave products 2p
in good yields and enantioselectivity (entries 23 and
24). The nucleophilic addition of Et2Zn to N-benzyl-
idene-2-pyridinesulfonamide 1a did not proceed with
high enantioselectivity (entry 25), whereas the nucleo-
philic addition of MeLi mainly gave the R-isomer (entry
26).
3. Conclusion
The first highly enantioselective reaction of imines with
Grignard reagents was achieved in the presence of
bis(oxazoline)s by using a pyridylsulfonyl group as a
protective group. The reaction was suggested by the
MOPAC 93/PM3 calculation to proceed through a
complex in which one of the sulfonyl oxygens is prefer-
ably coordinated to Mg(II). The 2-pyridylsulfonyl group
was shown to be an easily removable, efficient protective
group, which has notable properties of high chiral
inducibility and activation of the imino group toward
the addition of Grignard reagents.24
Since most of the products were crystalline, enantio-
merically pure sulfonamides were easily obtainable by
recrystallization. For example, recrystallization of 2a
(83% ee) from hexane/CH2Cl2 afforded enantiomerically
pure (S)-2a. To realize the synthetic potential of this
stereoselective preparation of chiral amines, we con-
firmed the easy removal of the 2-pyridylsulfonyl group.
Although removal of arylsulfonyl groups generally
needs drastic reaction conditions,17 the pyridylsulfonyl
group could be removed from the optically active (S)-
2a on treatment with magnesium in MeOH at 0 °C18
and chiral amine (S)-8 was found to be formed without
loss of optical purity (Scheme 2).19
Acknowledgment
This work was supported by the Daiko Foundation and
by the Tatematsu Foundation.
References and notes
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The reaction of p-tolylsulfonylimine 1i and 2,4,6-tri-
isopropylphenylsulfonylimine 1j with CH3MgI afforded
products 2i and 2j with low enantioselectivities, whereas
the reaction of 2-pyridylsulfonylimine 1a showed high
enantioselectivity (Table 1, entries 16 and 17 vs entry
1), showing that 2-pyridylsulfonyl group acts not only
as an activating group but also as an efficient stereocon-
troller. Assuming that Mg(II) forms a tetrahedral biden-
tate-coordinating complex with the substrate 1a,20 there
would be two types of coordination for the complex to
be considered:21 One is the N,N-type complex, in which
Mg(II) coordinates to the imino and pyridyl nitrogens
and the other is the N,O-type complex, in which Mg(II)
coordinates to a pyridyl nitrogen and one of the sulfonyl
oxygens. Energies of the Mg(II) complexes of 2-pyrid-
ylsulfonylimine 1a and bis(oxazoline)-Ph 3, were calcu-
lated by the MOPAC 93/PM3 method,22 showing the
stable complex in which Mg(II) coordinates to a pyridyl
4. For enantioselective reactions of phosphinoylimines with
dialkylzinc reagents, see: (a) Soai, K.; Hatanaka, T.;
Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992, 1097–
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Figure 2. Geometry optimization of 1a–3 complex by MOPAC 93/
PM3.

8944
H. Sugimoto et al. / Tetrahedron Letters 46 (2005) 8941–8944
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79%, 83% ee). Recrystallization from hexane/CH2Cl2
afforded (S)-2a with 99% ee.
5941.
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7. Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron
Lett. 1990, 31, 6681–6684.
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ones, see: (a) Hirabayashi, R.; Ogawa, C.; Sugiura, M.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 9493–
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J. Am. Chem. Soc. 2003, 125, 9596–9597; For the reaction
of N-(2-hydroxyphenyl)imines, see: (c) Ishitani, H.;
Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357–7360; (d)
Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
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Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S.
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14. There are some examples for the enantioselective reaction
of nitrones with Grignard reagents: (a) Ukaji, Y.; Hata-
naka, T.; Ahmed, A.; Inomata, K. Chem. Lett. 1993,
1313–1316; (b) Merchan, F. L.; Merino, P.; Rojo, I.;
Tejero, T.; Dondoni, A. Tetrahedron: Asymmetry 1996, 7,
667–670.
15. Generally, the reactivity of Grignard reagents to imines is
low: Saito, S.; Hatanaka, K.; Yamamoto, H. Synlett 2001,
1859–1861.
16. (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima,
T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392–4398;
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121; (b) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.;
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1967, 89, 5311–5312; (c) DÕSouza, L.; Day, R. A. Science
1968, 160, 882–883; Conversion to N-alkyl-N-sulfonyl
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primary amines, see: (d) Nyasse, B.; Grehn, L.; Ragnars-
son, U. Chem. Commun. 1997, 1017–1018, and references
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nitrogen in the heteroarylsulfonyl group: (a) Sugimoto,
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10. The 2-pyridylsulfonyl group has been used for the
synthesis of sulfonamides: (a) Han, H.; Bae, I.; Yoo, E.
J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109–
4112; (b) Arrayaˆs, R. G.; Cabrera, S.; Carretero, J. C. Org.
Lett. 2005, 7, 219–221.
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been reported to have an inhibitory activity to the
osteoclast-specific cysteine protease cathepsin K: (a) Mar-
quis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.; Yamash-
ita, D. S.; Oh, H.-J.; Erhard, K. F.; Davis, L. D.;
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12. The reaction of 1a with a catalytic amount (0.3 equiv) of
bis(oxazoline) 3 and MeMgBr gave 2a with 29% ee.
13. Typical procedure for enantioselective addition of Grig-
nard reagents to 1a: Preparation of N-(1-phenylethyl)-2-
pyridinesulfonamide (S)-2a. To a solution of bis(oxazo-
line)-Ph (244 mg, 0.731 mmol) and imine 1a (120 mg,
0.487 mmol) in toluene (10 mL) was added MeMgBr
(1.04 mol LÀ1 in Et2O, 0.937 mL, 0.974 mmol) at À95 °C
and the reaction mixture was stirred for 1 h. The reaction
was quenched with 1 N HCl and extracted with Et2O. The
combined extracts were dried over Na2SO4 and concen-
trated under reduced pressure to leave a residue, which
was purified by column chromatography (SiO2 20 g,
benzene/ethyl acetate = 90/10) to afford (S)-2a (101 mg,
18. (a) Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. J.
Org. Chem. 1995, 60, 5969–5972; (b) Pak, C. S.; Lim, D. S.
Synth. Commun. 2001, 31, 2209–2214.
19. Preparation of (S)-1-phenylethylamine hydrochloride (S)-
8: A mixture of (S)-2a (20.2 mg, 0.077 mmol) and Mg
powder (9.3 mg, 0.385mmol) in MeOH (2 mL) and THF
(0.5mL) was stirred for 2 h at 0 °C. Then, diethyl ether
(3 mL) and saturated aq NH4Cl (3 mL) were added and
the reaction mixture was stirred for 2 h at room temper-
ature. The aqueous layer was extracted with Et2O. The
combined organic extracts were dried over Na2SO4 and
concentrated under reduced pressure to leave the oil,
which 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 to the resultant
solution was added a 2 N HCl solution. After stirring for
30 min at room temperature, the solution was concen-
trated under reduced pressure to give (S)-8 (10.9 mg, 90%).
In order to determine the enantiopurity, (S)-8 was
transformed to N-benzoyl-1-phenylethylamine on treat-
ment with benzoyl chloride and triethylamine in CH2Cl2
at room temperature. This amide was found to be 99% ee
by HPLC analysis using CHIRALCEL OD-H.
20. Tetrahedral Mg(II) complex has been proposed: (a) Corey,
E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807–6810;
(b) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124,
984–991; The octahedral structure has been also proposed:
(c) Sibi, M. P.; Petrovic, G.; Zimmerman, J. J. Am. Chem.
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