Enantioselective Aza-Henry Reaction Catalyzed by a Bifunctional Organocatalyst

Article abstract of DOI:10.1021/ol0364531

(Matrix presented) The aza-Henry reaction of imines with nitroalkanes was promoted by chiral thiourea with an N,N-dimethylamino group to give β-nitroamines with good enantioselectivity. Various N-protected imines were examined as substrates. N-Phosphinoyl

Full text of DOI:10.1021/ol0364531

ORGANIC
LETTERS
2004
Vol. 6, No. 4
625-627
Enantioselective Aza-Henry Reaction
Catalyzed by a Bifunctional
Organocatalyst
Tomotaka Okino, Satoru Nakamura, Tomihiro Furukawa, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received December 17, 2003
ABSTRACT
The aza-Henry reaction of imines with nitroalkanes was promoted by chiral thiourea with an N,N-dimethylamino group to give â-nitroamines
with good enantioselectivity. Various N-protected imines were examined as substrates. N-Phosphinoylimine gave the best result in terms of
chemical yield and enantioselectivity (up to 91% yield, up to 76% ee).
The aza-Henry reaction, the nucleophilic addition of nitro-
alkanes to imines to give â-nitroamine derivatives, is a useful
carbon-carbon bond-forming process in organic chemistry.
The diversity of the transformations of the â-nitroamines,
such as reduction to 1,2-diamines1 and Nef reaction to
R-amino acids,2 provides numerous applications of this
process.3-6 The enantioselective version of this reaction was
not known until quite recently.7-10 To the best of our
knowledge, there were only two groups that had reported
on catalytic asymmetric aza-Henry reaction and all of the
reactions reported were metal-catalyzed. Shibasaki et al.
reported that heterobimetallic complexes with lanthanide
BINOL systems promoted the aza-Henry reaction to give
â-nitroamines with high enantioselectivity.9 Jørgensen et al.
also developed a catalytic asymmetric version of this reaction
with bisoxazoline copper(II) complexes.10
Although urea derivatives are known to act as acid
catalysts in several reactions,11 enantioselective reactions
were rare (Figure 1).12 We have recently reported novel
(1) (a) Beck, A. K.; Seebach, D. Chem. Ber. 1991, 124, 2897-2911.
(b) Poupart, M. A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem. 1999,
64, 1356-1361. (c) Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett.
1988, 29, 5733-5734. (d) Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986,
51, 4294-4295.
(2) Pinnick, H. W. Org. React. 1990, 38, 655-792.
(3) Calderari, G.; Seebach, D. HelV. Chim. Acta 1985, 68, 1592-1604.
(4) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423-434.
(5) (a) Meyer, V.; Wurster, C. Ber. Dtsch. Chem. Ges. 1873, 6, 1168-
1172. (b) Kamlet, M. J.; Kaplan, L. A.; Dacons, J. C. J. Org. Chem. 1961,
26, 4371-4375.
(6) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-
5342.
(7) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151-153.
(8) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org.
Chem. 1998, 63, 9932-9934.
(9) (a) Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1999, 38, 3504-3506. (b) Yamada, K.; Moll, G.;
Shibasaki, M. Synlett 2001, 980-982. (c) Tsuritani, N.; Yamada, K.;
Yoshikawa, N.; Shibasaki, M. Chem. Lett. 2002, 276-277.
(10) (a) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843-5844. (b) Nishiwaki,
N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2992-2995.
(11) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003,
44, 2817-2821. (b) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59,
3259-3261. (c) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36,
6647-6650. (d) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-
220. (e) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407-414.
(f) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-296.
10.1021/ol0364531 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/27/2004

Table 1. Effect of Thiourea Catalystsa
yieldb
(%)
entry
PG
additive
adduct
1
2
3
4
5
Ph (2a )
Ts (2b)
P(O)Ph2 (2c)
P(O)Ph2 (2c)
P(O)Ph2 (2c)
TEA
TEA
TEA
1a
3a
3b
3c
3c
3c
0
74
57
0
TEA + 1a
49
Figure 1. Structure of thiourea derivatives.
a Reaction was conducted with additive (0.1 equiv), 4a (10 equiv), and
CH2Cl2 at room temperature for 24 h. b Isolated yield.
thiourea derivatives with several tertiary amino groups, which
act as bifunctional organocatalysts on enantioselective Michael
reaction of malonates to nitroolefins.13 In this reaction, the
thiourea seems to interact with a nitro group of the nitroole-
fins and enhance electrophilicity of nitroolefins (Figure 2).14
treatment of 2c with thiourea 1a did not give 3c at all. Then,
with the expectation that coexistence of TEA and 1a would
promote the generation of the nitrate anion from 4a, the
reaction of 2c was carried out in the presence of TEA and
1a, but 3c was only obtained in moderate yield (49%, entry
5).
This result indicates that the thiourea and amine seem to
mutually weaken their reactivities. However, the bifunctional
thiourea 1b, whose amino group and thiourea moiety are
located in appropriate positions, can be used for this purpose
(Figure 2). Hence, we investigated the reaction of imines
2a-c with nitromethane 4a in the presence of bifunctional
organocatalyst 1b13 (Table 2, entries 1-3). In practice,
Figure 2. Working hypothesis.
Hence, we expected that the corresponding nitronate could
be produced from nitroalkane with the bifunctional thiourea
via the hydrogen-bonding activation with the thiourea moiety
and subsequent deprotonation by the neighboring tertiary
amino group. If so, the catalyst would promote the asym-
metric aza-Henry reaction (eq 1). Herein we report the first
enantioselective aza-Henry reaction catalyzed by a bifunc-
tional organocatalyst.
Table 2. Optimization of Reaction Conditionsa
time yieldb
% eec
We first investigated the racemic reaction of imines 2a-c
bearing various protecting groups (PG) with nitromethane
4a in the presence of Et3N (TEA) and thiourea 1a (Table
1). The reaction of N-phenylimine 2a with 0.1 equiv of TEA
afforded no desired â-nitroamine 3a due to the low reactivity
of 2a (entry 1). On the other hand, subjection of N-tosylimine
2b under the same reaction conditions gave â-nitroamines
3b15 in good yield (entry 2, 74%). In the case of N-
phosphinoylimine 2c,16 the desired adduct 3c was obtained
in 57% yield in the presence of 0.1 equiv of TEA, while
entry
PG
solvent adduct
(h)
(%)
(configd)
1
2
3
4
5
6
7
8
Ph (2a ) CH2Cl2
Ts (2b) CH2Cl2
3a
3b
3c
3c
3c
3c
3c
3c
24
4.5 99
24
48
48
140
48
75
e
e
4 (-)e
67 (S)
e
P(O)Ph2 (2c) CH2Cl2
P(O)Ph2 (2c) MeCN
P(O)Ph2 (2c) MeOH
P(O)Ph2 (2c) toluene
P(O)Ph2 (2c) THF
P(O)Ph2 (2c) dioxane
87
e
44
47
43
73
33 (S)
62 (S)
75 (S)
76 (S)
a Reaction was conducted with 1b (0.1 equiv), 4a (10 equiv), and several
solvents at room temperature. b Isolated yield. c Enantiomeric excess was
determined by HPLC analysis of 3b and 3c using a chiral column. d Absolute
configuration was determined by comparison of the HPLC retention time
with that of literature data.9a e Not determined.
(12) (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867-870. (b)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012-10014.
(c) Wenzel, A. G,; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964-
12965.
(13) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672-12673.
(14) (a) Bordwell, F. G.; Ji, G. J. Am. Chem. Soc. 1991, 113, 8398-
8401. (b) Etter, M. C.; Urban˜czyk-Lipkowska, Z.; Zia-Ebrahimi, M.;
Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415-8426. (c) Kelly, T.
R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072-7080.
(15) Qian, C.; Gao, F.; Chen, R. Tetrahedron Lett. 2001, 42, 4673-
4675.
whereas the reaction of 2a in CH2Cl2 afforded no desired
â-nitroamines 3a, 2b and 2c reacted with nitromethane
efficiently to give the desired adducts 3b and 3c in good
yield (entries 1-3). In the case of 2c, the enantioselectivity
of the adduct 3c was 67% ee, while 2b gave an almost
(16) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561-5568.
626
Org. Lett., Vol. 6, No. 4, 2004

racemic adduct 3b. The enantiomeric excess was determined
by HPLC analysis of 3c using a chiral column, and the
absolute configuration of 3c was determined by comparison
of the HPLC retention time with that of literature data. We
selected 2c as a substrate and optimized the reaction solvent.
The adduct 3c was negligibly obtained or obtained with low
enantioselectivity in a polar solvent (MeCN, MeOH), since
these solvents probably inhibit hydrogen-bonding interaction
between nitromethane 4a and the thiourea moiety of 1b
(Table 1, entries 4 and 5). In contrast, nonpolar solvents such
as toluene provided 3c with good enantioselectivities (62%
ee, entry 6), while the reaction rate decreased dramatically.
On the other hand, when the reaction was carried out in ether
solvents (THF or 1,4-dioxane), the adduct 3c was obtained
with up to 76% ee after a slightly prolonged reaction time
(75 h, entries 7 and 8).
Table 3. Aza-Henry Reaction of N-Phosphinoylimines
Catalyzed by Bifunctional Organocatalysta
yieldb
% eec
(drd)
entry
Ar
Ph (2c)
4 (R) adduct
(%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
3c
3d
3e
3f
3g
3h
3i
87
72
76
78
85
91
57
68
83
67
63
67
70
76
68
64
65
4-MeC6H4 (2d )
4-ClC6H4 (2e)
2-naph (2f)
2-furyl (2g)
2-pyridyl (2h )
2-thieny (2i)
cinnamyl (2j)
Ph (2c)
We examined the reaction of various phosphinoylimines
2c-j with nitroalkanes 4a and 4b in CH2Cl2 due to the
reasonable reaction rate. Table 3 summarizes the results of
the reactions. In all cases, the corresponding â-nitroamines
3c-j were obtained in good yields with moderate to good
enantioselectivities. Introduction of electron-donating or
electron-withdrawing groups on the aromatic ring of imines
did not affect the enantioselectivities (entries 1-3). When
sterically hindered imine 2f was used as a substrate, the
enantioselectivity of the adduct 3f slightly increased (70%
ee, entry 4). Similarly, imines 2g-i possessing a heteroaro-
matic ring provided â-nitroamines with good enantioselec-
tivities (64-76% ee, entries 5-7). The same reaction of
imine 2j, prepared from cinnamylaldehyde, proceeded re-
gioselectively to give the 1,2-addition adduct 3j as the single
product with moderate stereoselectivity (entry 8). Finally,
we examined enantio- and diastereoselective aza-Henry
reaction of 2c with nitroethane 4b in the presence of 1b (entry
9). When nitroethane 4b was reacted with imine 2c under
the same reaction conditions, the corresponding desired
products 3k were obtained as a diastereomixture (the ratio
of 3:1), while the enantioselectivity of the major diastereomer
was kept to a good level (67% ee).
H
3j
Me
3k
67e (73/27)
a Reaction was carried out with 1b (0.1 equiv), 4a or 4b (10 equiv), and
CH2Cl2 at room temperature. b Isolated yield. c Enantiomeric excess was
determined by HPLC analysis of 3c-k using a chiral column. d Diastereo-
1
meric ratio was determined by H NMR. e Major diastereomer.
with moderate to good enantioselectivity. This is the first
example of enantioselective aza-Henry reaction with an
organocatalyst. Further investigations to improve the enan-
tioselectivity with other thiourea catalysts are under way in
these laboratories.
Acknowledgment. This work was partialy supported by
grants from 21st Century COE Program “Knowledge Infro-
mation Infrastructure for Genome Science”, the NOVARTIS
Foundation (Japan) for the promotion of Science, the Japan
Health Sciences, and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for products 3c-k. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, thiourea 1b worked well as a chiral organo-
catalyst in the aza-Henry reaction of various phosphi-
noylimines with nitroalkanes, and gave the â-nitroamines
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