Enantioselective direct amination of α-cyanoacetates catalyzed by bifunctional chiral Ru and Ir amido complexes

Article abstract of DOI:10.1021/ja710273s

The bifunctional chiral amido Ir complex catalyzed asymmetric electrophilic direct amination of α-substituted α-cyanoacetates using azodicarboxylates proceeds rapidly to provide the corresponding hydrazine adducts in high yields and with excellent ee values. Copyright

Full text of DOI:10.1021/ja710273s

Published on Web 01/26/2008
Enantioselective Direct Amination of r-Cyanoacetates Catalyzed by
Bifunctional Chiral Ru and Ir Amido Complexes
Yasuharu Hasegawa,† Masahito Watanabe,‡ Ilya D. Gridnev,† and Takao Ikariya*,†
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552 Japan, and Central Research Laboratory, Technology and DeVelopment
DiVision, Kanto Chemical Co., Inc., Soka, Saitama, 340-0003, Japan
Received November 13, 2007; E-mail: tikariya@apc.titech.ac.jp
Scheme 1
The catalytic, enantioselective, and direct C-N bond formation
using unmodified nucleophiles and a nitrogen source such as
azodicarboxylates would offer a simple and straightforward pro-
cedure for construction of a stereogenic carbon center attached to
a nitrogen atom.1 There are many reports on enantioselective direct
amination via C-N bond forming reaction catalyzed by chiral
catalyst systems. They include chiral Lewis acid catalysts for direct
R-amination of â-keto esters,2a-c and pyruvic acid derivatives,2d
and chiral organocatalysts for R-amination of aldehydes,3a-d,m
ketones,3e-g and â-keto esters,3h-j or R-substituted R-cyanoacetates.3k,l
In particular, the electrophilic amination of R-substituted â-keto
Table 1. Asymmetric Amination of R-Substituted R-Cyanoacetates
esters or R-substituted R-cyanoacetates provides an attractive
procedure to access chiral nitrogen-containing compounds bearing
a quaternary carbon center. Among these enantioselective methods,
only a very limited number of chiral metal-based catalytic asym-
metric direct aminations have been reported.2,4 We have recently
developed a conceptually new bifunctional chiral amido transition-
metal catalyst, Ru(Tsdpen)(η6-arene)5 (TsDPEN: N-(p-toluene-
sulfonyl)-1,2-diphenylethylenediamine) (1), for a catalytic asym-
metric Michael reaction of 1,3-dicarbonyl compounds to cyclic
enones and nitro alkenes.6 The Brønsted basic amide catalyst is
responsible for high reactivity and selectivity in the enantioselective
C-C bond formation. We have extended the concept of the
bifunctional molecular catalysis to the C-N bond-forming reaction
and found that the electrophilic direct amination of R-substituted
R-cyanoacetates using dialkyl azodicarboxylates with a chiral amido
Ir complex, Cp*Ir(Tsdpen)7 (2b), which has a structure isoelectronic
with 1, proceeded smoothly to provide the corresponding hydrazine
adducts in high yields and with excellent ee values.
Using Azodicarboxylates Catalyzed by Chiral Amide Complexesa
chiral
cyano-
acetate
azo-
temp
yield
ee
b
c
catalyst
dicarboxylate
solvent
°
C
%
%
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4a
4a
4a
4a
toluene
0
0
30
0
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
1a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
toluene
toluene
toluene
toluene
toluene
toluene
THF
C2H5(CH3)2COH
acetone
CH2Cl2
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
66
90
95
97
89
98
83
83
73
67
10
91
66
91
95
96
95
-40
0
0
0
0
0
0
0
0
0
0
0
0
0
A chiral amido Ir complex (S,S)-2a7 has proven to effect efficient
asymmetric amination of tert-butyl R-phenyl-R-cyanoacetate (3a)
using dimethyl azodicarboxylate (4a) (a substrate/catalyst ratio, S/C
) 100, 3a/4a ) 1:1) in a 0.1 M toluene solution at 0 °C for 2 h to
furnish the corresponding adduct in an excellent yield, 99% and
with 85% ee (Scheme 1). Since the uncatalyzed reaction of 3a and
4a under otherwise identical condition gave the racemic product,
5a, quantitatively, it can compete with the catalytic enantioselective
reaction, leading to low enantioselctivity. Noticeably, a slow
addition of azodicarboxylate, 4, to a toluene solution of 3 containing
the Ir catalyst with a syringe pump for 20 min at 0 °C followed by
stirring of the reaction mixture for 2 h improved significantly the
ee value of the product, reaching 95% ee as listed in Table 1.
Decreasing the reaction temperature to -40 °C resulted in an
additional increase in the ee value of 5, to 97%. In contrast to the
Ir system, the chiral Ru complex, Ru[(S,S)-PMsdpen](η6-hmb) (PMs
) C6(CH3)5SO2, HMB ) hexamethylbenzene) (1a),6b exhibited
a Unless otherwise noted, the reaction was carried out by a slow addition
of 4 to a toluene solution of 3 containing the chiral amide catalyst with a
syringe pump for 20 min followed by stirring for 2 h in 5 mL solvent. The
molar ratio of metal/azodicarboxylate/cyanoacetate is 1:100:100 (see
Supporting Information). b Isolated yield after flash chromatograpgy on silica
gel. c Determined by HPLC analysis using CHIRALPAK AD (4.6 mm ×
250 mm).
unsatisfactory enantioselectivity even after structural optimization
of the Ru catalyst (see Supporting Information).
The stereochemical outcome of the reaction with the chiral Ir
catalyst was delicately influenced by the structures of the Ir
complexes as well as reaction conditions (Table 1). The TsDPEN
complex 2b provided lower enantioselectivity, while the CsDPEN
complex 2c7b gave the best catalyst performance in terms of the
selectivity, the ee value of the product reaching up to 98% ee.
Toluene, C2H5(CH3)2COH, and THF worked well, while CH2Cl2
and acetone gave a slightly lower ee values. The enantioselectivity
of the reaction in CH2Cl2 improved significantly when the reaction
mixture was cooled down to -40 °C, the ee value reaching up to
92%. Notably, acetonitrile gave unsatisfactory results possibly due
† Tokyo Institute of Technology.
‡ Kanto Chemical Co., Inc.
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10.1021/ja710273s CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
chiral amide complex would lead to the formation of the N-bound
nitrile complexes. We are now working on further expansion of
the substrate scope and further studies aimed at clarifying the
mechanism.
Acknowledgment. This work was financially supported by a
grant-in-aid from the Ministry of Education, Science, Sports and
Culture of Japan (No. 18065007) and partially supported by The
21st Century COE and G-COE Programs.
to its strong bonding ability toward the metal center.8 An increase
in the steric bulkiness in the ester group of 4 caused a decrease in
the ee value of the products. The aromatic ring-substituted R-phenyl-
R-cyanoacetates (3b-d) reacted with 4a in toluene containing chiral
Ir catalyst at 0 °C for 2 h to give the chiral adduct with 91-96%
ee in excellent yields regardless of the electronic effect of the
substituent. Similarly, R-cyanoacetate with thienyl group (3e)
provided the adduct with 95% ee.3k
Supporting Information Available: Experimental procedures of
the catalytic direct amination reaction, spectroscopic data for com-
pounds, and NMR and computational (B3LYP/SDD) analysis data. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Examples of C-N bond formation using azodicarboxylates as nitrogen
sources: (a) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119,
6452-6453. (b) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595-
598. (c) Yamashita, Y.; Ishitani, H.; Kobayashi, S. J. Can. Chem. 2000,
78, 666-672. (d) Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.;
Deng, Y.; Chen, G. Org. Lett. 2004, 6, 2193-2196.
A stoichiometric reaction of the amido Ir complex with tert-
butyl R-cyanoacetate 3a provided further insight into the reaction
mechanism. The reaction of 3a with the amido Ir complex, 2a (2a/
3a ) 1:1-1.5) in CH2Cl2 proceeded rapidly to give a mixture of
two N-bound nitrile complexes, Cp*Ir[NCC(C6H5)(COOC(CH3)3)]-
(2) (a) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420-2021.
(b) Margio, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 1367-1369. (c) Kan, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47,
4565-4568. (d) Comelles, J.; Pericas, AÅ .; Moreno-Man˜as, M.; Vallribera,
A.; Drudis-Sole´, G.; Lledos, A.; Parella, T.; Roglans, A.; Garc´ıa-Granda,
S.; Roces-Ferna´ndez, L. J. Org. Chem. 2007, 72, 2077-2087.
(3) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657. (b) Bøgevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790-1793. (c) Chowdari, N. S.; Barbas, C.
F., III. Org. Lett. 2005, 7, 867-870. (d) Suri, J. T.; Steiner, D. D.; Barbas,
C. F., III. Org. Lett. 2005, 7, 3885-3888. (e) Kumaragurubaran, N.; Juhl,
K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
124, 6254-6255. (f) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42,
975-978. (g) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am.
Chem. Soc. 2004, 126, 11770-11771. (h) Xu, X.; Yabuta, T.; Yuan, P.;
Takemoto, Y. Synlett 2006, 137-140. (i) Terada, M.; Nakano, M.; Ube,
H. J. Am. Chem. Soc. 2006, 128, 16044-16045. (j) Pihko, P. M.;
Pohjakallio, A. Synlett 2004, 2115-2118. (k) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120-8121. (l) Liu, X.;
Li, H.; Deng, L. Org. Lett. 2005, 7, 167-169. (m)Jiang, H.; Nielsen, J.
B.; Nielsen, M.; Jørgensen, K. A. Chem. Eur. J. 2007, 13, 9068-9075.
(4) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2007, 129, 11342-11343.
1
[(S,S)-Msdpen] (6a,b) (Scheme 2). H and 13C NMR spectra of
the reaction mixture at -50 °C showed two sets of sharp signals
1
due to 6a and 6b.9 The assignment of signals in the H NMR
spectrum was accomplished by the COSY experiment. Two NH2
1
protons in the H spectrum of the minor isomer 6a resonate at δ
4.02 (triplet, trans to the CHC6H5) and 4.48 (doublet, cis to the
1
CHC6H5). In the H NMR spectrum of the major isomer 6b, the
corresponding doublet resonates very close to that of 6a (δ 4.22),
whereas the triplet is strongly downfield shifted (δ 6.21), indicating
the presence of the intramolecular hydrogen bond in 6b that is
absent in 6a.9 On raising the temperature, the signals in the 1H and
13C NMR spectra of 6a and 6b broadened reversibly, indicating
that 6a and 6b are equilibrating in solution. The IR spectrum of 6
in KBr showed that a CN stretching band appears at 2174 cm-1
,
(5) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. 1997, 36, 285-288. (b) Noyori, R.; Hashiguchi, S. Acc
Chem. Res. 1997, 30, 97-102. (c) Ikariya, T.; Murata, K.; Noyori, R.
Org. Biomol. Chem. 2006, 4, 393-406. (d) Ikariya, T.; Blacker, A. J.
Acc. Chem. Res. 2007, 40, 1300-1308.
which is lower than that in free cyanoacetate (2263 cm-1), indicating
that 6 has a structure bearing the N-bonded nitrile group, as
observed in the reported cyanoester complexes.10
(6) (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125,
7508-7509. (b) Watanabe, M.; Ikagawa, A.; Wang, W.; Murata, K.;
Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148-11149.
On the basis of the absolute configuration, R, of the R-aminated
product3l and the results of a combined NMR9 and computational
(B3LYP/SDD) analysis (Supporting Information), we concluded
that the enantioselection in the reaction may occur through a
concerted formation of C-N and H-N bonds taking place in the
N-bound cyanoester complex 6a as shown in Scheme 2. The
azodicarboxylate might approach the N-bound cyanoester anion by
interaction of incoming nitrogen atom with the NH proton of the
amino group in the Ir complex 6a. On the other hand, the
intramolecular hydrogen bonding to the equatorial NH proton in
the conformer 6b cannot participate in the formation of a similar
transition state. Thus, the reactants 3 and 4 are activated sequentially
by the bifunctional catalyst to facilitate the enantioselective C-N
bond forming reaction.
(7) (a) Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186-
2187. (b) Li, X.; Blacker, J.; Houson, I.; Wu, X.; Xiao, J. Synlett 2006,
1155-1160.
(8) An increase in the S/C to 500 caused a serious decrease in the ee value
of the product possibly due to the substrate inhibition as observed in CH3-
CN.
(9) 13C NMR and DEPT spectra at -50 °C showed that the deprotonated
anionic carbon resonates at δ 58.6 in 6b (anionic carbon for minor product
6a had not been observed), whereas the metal-bonded nitrile carbon atom
appears between δ 135.2 and 140.2 in 6b and δ 137.1 and 139.2 in 6a,
which is notably down-field shifted compared to free 4 (δ 116.0).
(10) (a) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem.
Soc. 2002, 124, 6482-6843. (b) Murahashi, S.-I.; Naota, T.; Taki, H.;
Mizuno, M.; Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka,
M.; Hirano, M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436-12451.
(c) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309-
3310. (d) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71-
72. (e) Hirano, M.; Takenaka, A.; Mizuno, Y.; Hiraoka, M.; Komiya, S.
J. Chem. Soc., Dalton Trans. 1999, 3209-3216. (f) Hirano, M.; Kiyota,
S.; Imoto, M.; Komiya, S. Chem. Commun. 2000, 1679-1680. (g)
Murahashi S.-I.; Take, K.; Naota, T.; Takaya, H. Synlett 2000, 7, 1016-
1018. (h) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20,
4049-4960.
In summary, the bifunctional chiral amido Ir complex 2 catalyzed
asymmetric electrophilic direct amination of R-substituted R-cy-
anoacetates using azodicarboxylates proceeds rapidly to provide
the corresponding hydrazine adducts in high yields and with
excellent ee values. The deprotonation of cyanoacetates with the
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J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008 2159