Highly enantioselective Henry (nitroaldol) reaction of aldehydes and α-ketoesters catalyzed by N,N′-dioxide-copper(I) complexes

Article abstract of DOI:10.1021/jo701898r

(Chemical Equation Presented) A new chiral N,N′-dioxide-Cu ^I catalyst has been developed for the asymmetric Henry (nitroaldol) reaction. The approach benefited from the easy modification of the chiral space. As the highly effective N-oxide liga

Full text of DOI:10.1021/jo701898r

Highly Enantioselective Henry (Nitroaldol) Reaction of Aldehydes
and r-Ketoesters Catalyzed by N,N′-Dioxide-Copper(I) Complexes
Bo Qin,† Xiao Xiao,† Xiaohua Liu,† Jinglun Huang,† Yuehong Wen,† and
Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, China, and State Key Laboratory of Biotherapy, Sichuan
UniVersity, Chengdu 610041, China
xmfeng@scu.edu.cn
ReceiVed August 29, 2007
A new chiral N,N′-dioxide-CuI catalyst has been developed for the asymmetric Henry (nitroaldol) reaction.
The approach benefited from the easy modification of the chiral space. As the highly effective N-oxide
ligand, 1d has been adopted for the Henry reaction with both aromatic and heteroaromatic aldehydes.
The corresponding nitro-alcohol products were obtained in good yields with high enantiomeric excesses
up to 98%. Moreover, R-ketoesters were also catalyzed by this catalyst to give attractive optically active
R-hydroxy â-nitro esters containing chiral quaternary carbon centers (up to 99% ee). On the basis of a
combination of several techniques including the 1H NMR, ESI-HRMS, and MM2 calculations, the proposed
mechanism was presented to explain the origin of reactivity and asymmetric inductivity.
SCHEME 1. Asymmetric Allylation and Henry Reaction
Catalyzed by N,N′-Dioxide-Metal Complex
Introduction
The discovery and development of novel chiral ligands are
of significant importance in asymmetric catalysis.1 N-oxides,
known for their notable electron-donating property, have been
applied in many reactions as organocatalysts.2,3 In these reac-
tions, the mechanism was mainly based on the activation of Si
atom by N-oxide as Lewis base, which confined the application
of N-oxide in asymmetric catalysis. On the other hand, there
have been few attempts to employ N-oxides as chiral ligands
to achieve high levels of efficiency in asymmetric reaction.4
Therefore, it is still a challenge to develop the N-oxide as a
ligand for the highly enantioselective reactions. In light of our
recent success of enantioselective allylation and cyanation of
carbonyl compound utilizing chiral N,N′-dioxides as ligands,5
we investigated the asymmetric Henry (nitroaldol) reaction
(Scheme 1).
† Key Laboratory of Green Chemistry & Technology.
‡ State Key Laboratory of Biotherapy.
(1) For review of the chiral ligand design, see: (a) Desimoni, G.; Faita,
G.; Jørgensen, K. A. Chem. ReV. 2006, 106, 3561-3651. (b) Arraya´s, R.
G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674-
7715. (c) Fonseca, M. H.; Ko¨nig, B. AdV. Synth. Catal. 2003, 345, 1173-
1185.
(2) For review of chiral N-oxide, see: (a) Malkov, A. V.; Kocˇovsky´, P.
Eur. J. Org. Chem. 2007, 29-36. (b) Chelucci, G.; Murineddu, G.; Pinna,
G. A. Tetrahedron: Asymmetry 2004, 15, 1373-1389.
The Henry (nitroaldol) reaction has long been known as a
powerful and efficient method for the construction of carbon-
carbon bonds in organic chemistry.6,7 It provided an efficient
access to valuable functionalized structural motifs such as 1,2-
amino alcohols and R-hydroxy carboxylic acid.8 Since the first
example was reported by Shibasaki and co-workers in 1992,9
interests in the enantioselective Henry reactions had been
triggered involving several chiral metal complexes10 and chiral
10.1021/jo701898r CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/01/2007
J. Org. Chem. 2007, 72, 9323-9328
9323

Qin et al.
organocatalysts.11,12 However, few examples have been made
to employ an efficient catalytic system for both aldehydes and
ketones in enantioselective Henry reactions.13
Herein, we wish to describe our efforts in the application of
chiral N,N′-dioxide-copper(I) complex to the highly enantiose-
lective Henry reaction with a broad range of substrates including
aldehydes and R-ketoesters.
FIGURE 1. Chiral N,N′-dioxides as ligands for the asymmetric Henry
reaction.
Results and Discussion
TABLE 1. Screening of Central Metals and N,N′-Dioxide Ligands
Our initial studies of catalytic asymmetric Henry reaction
focused on the addition of nitromethane to benzaldehyde in the
in the Asymmetric Henry Reaction of Benzaldehydea
(3) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
Soc. 1998, 120, 6419-6420. (b) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi,
T. Org. Lett. 2002, 4, 2799-2801. (c) Malkov, A. V.; Orsini, M.; Pernazza,
D.; Muir, K. W.; Langer, V.; Meghani, P.; Kocˇovsky´, P. Org. Lett. 2002,
4, 1047-1049. (d) Malkov, A. V.; Dufkova´, L.; Farrugia, L.; Kocˇovsky´,
P. Angew. Chem., Int. Ed. 2003, 42, 3674-3677. (e) Pignataro, L.; Benaglia,
M.; Annunziata, R.; Cinquini, M.; Cozzi, F. J. Org. Chem. 2006, 71, 1458-
1463. (f) Traverse, J. F.; Zhao,Y.; Hoveyda, A. H.; Snapper, M. L. Org.
Lett. 2005, 7, 3151-3154.
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J. Org. Chem. 2004, 129-137. (b) Saito, M.; Nakajima, M.; Hashimoto,
S. Chem. Commun. 2000, 1851-1852. (c) Nakajima, M.; Yamamoto, S.;
Yamaguchi, Y.; Nakamura, S.; Hashimoto, S. Tetrahedron 2003, 59, 7307-
7313. (d) Wong, W. L.; Lee, W. S.; Kwong, H. L. Tetrahedron: Asymmetry
2002, 13, 1485-1492. (e) Dyker, G.; Ho¨lzer, B.; Henkel, G.; Tetrahe-
dron: Asymmetry 1999, 10, 3297-3307. (f) Derdau, V.; Laschat, S.; Hupe,
E.; Ko¨nig, W. A.; Dix, I.; Jones, P. G. Eur. J. Inorg. Chem. 1999, 1001-
1007. (g) Kerr, W. J.; Lindsay, D. M.; Rankin, E. M.; Scott, J. S.; Watson,
S. P. Tetrahedron Lett. 2000, 41, 3229-3233.
(5) (a) Zhang, X.; Chen, D. H.; Liu, X. H.; Feng, X. M. J. Org. Chem.
2007, 72, 5227-5233. (b) Zheng, K.; Qin, B.; Liu, X. H.; Feng, X. M.
accepted by J. Org. Chem. 2007, 72, 8478-8483. (c) Li, Q. H.; Liu, X. H.;
Wang, J.; Shen, K.; Feng, X. M. Tetrahedron Lett. 2006, 47, 4011-4014.
(d) Li, Q. H.; Chang, L.; Liu, X. H.; Feng, X. M. Synlett 2006, 1675-
1678.
(6) Henry, L. C. R. Hebd. Seances. Acad. Sci. 1895, 120, 1265-1268.
(7) For reviews for the Henry (nitroaldol) reaction, see: (a) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561-2574. (b) Palomo,
C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442-
5444. (c) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
Asymmetry 2006, 17, 3315-3326.
t
yield
(%)b
ee
entry
ligand
metal
InBr3
Zn(OTf)2
Cu(OTf)2
(CuOTf)2‚C7H8
Ni(OAc)2‚4H2O
Ti(OiPr)4
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(CuOTf)2‚C7H8
(h)
(%)c
1
2
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
36
36
36
12
12
36
12
12
12
12
12
12
12
NDd
NDd
NDd
77
-
-
3
-
4e
5
45 (R)
26 (R)
-
60
6
NDd
trace
70
7e
8e
9e
10e
11e
12
13
0
20 (R)
80 (R)
11 (R)
7 (S)
20 (S)
16 (S)
97
85
88
77
1g
1h
46
a Reactions were carried out on a 0.1 mmol scale of benzaldehyde in
the mixture of THF (0.5 mL) and nitromethane (20 equiv) at 0 °C. b Isolated
yield. c Enantiomeric excesses were determined by HPLC on a Chiral OD-H
column. The absolute configurations were established by comparison of
the sign of the optical rotation values with that in the literature.10i d Not
detected. e Reactions were performed with (CuOTf)2‚C7H8 (5 mol %).
(8) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001. (b) Rosini, G. In ComprehensiVe Organic Synthesis, Vol. 2;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: New York,
1991; pp. 321-340. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945.
(9) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418-4420. (b) Sasai, H.; Suzuki, T.; Itoh, N.;
Shibasaki, M. Tetrahedron Lett. 1993, 34, 851-854. (c) Sasai, H.; Suzuki,
T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem.
Soc. 1993, 115, 10372-10373.
presence of the complex of chiral N,N′-dioxide 1a as a ligand
(Figure 1). Unfortunately, the N,N′-dioxide 1a-InBr3 complex
could not catalyze the Henry reaction, unlike its efficiency in
the enantioselective allylation of ketones (Table 1, entry 1).5a
While using the catalysts with Zn(OTf)2, Cu(OTf)2, and Ti-
(OiPr)4 as central metals, the corresponding product 4a could
not be obtained (Table 1, entries 2-3 and 6). Fortunately, 1a-
Ni(OAc)2‚4H2O and 1a-(CuOTf)2‚C7H8 complexes could cata-
lyze the Henry reaction, and moderate enantioseletivity (45%
ee) was obtained with (CuOTf)2‚C7H8 (Table 1, entries 4 and
5). After screening the steric and electronic effect of N,N′-
dioxides, we found that the reactivity and enantioselectivities
were closely dependent on both the chiral backbone and the R
substituents of the amide moiety. The results showed that
L-piperidinamide derivative 1d was superior to L-proline-derived
1f in both the yield and ee value (Table 1, entry 9 vs 11). Poor
results were obtained using the bulkier 2,6-diisopropylphenyl
(Table 1, entry 7). When the amide R was tert-butyl or (S)-
(10) (a) Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M. Tetrahedron Lett.
1996, 37, 9081-9084. (b) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.;
Sasai, H.; Shibasaki, M. Chem. Eur. J. 1996, 2, 1368-1372. (c) Saa´, J.
M.; Tur, F.; Gonza´lez, J.; Vega, M.; Tetrahedron: Asymmetry 2006, 17,
99-106. (d) Trost, B. M.; Yeh, V. S. C.; Angew. Chem., Int. Ed. 2002, 41,
861-863. (e) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett.
2002, 4, 2621-2623. (f) Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron:
Asymmetry 2004, 15, 771-776. (g) Gao, J.; Martell, A. E. Org. Biomol.
Chem. 2003, 1, 2801-2806. (h) Palomo, C.; Oiarbide, M.; Laso, A. Angew.
Chem., Int. Ed. 2005, 44, 3881-3884. (i) Evans, D. A.; Seidel, D.; Rueping,
M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003,
125, 12692-12693. (j) Du, D. M.; Lu, S. F.; Fang, T.; Xu, J. J. Org. Chem.
2005, 70, 3712-3715. (k) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou,
M. M. Tetrahedron: Asymmetry 2006, 17, 725-728. (l) Blay, G.; Climent,
E.; Ferna´ndez, I.; Herna´ndez-Olmos, V.; Pedro, J. R. Tetrahedron:
Asymmetry 2006, 17, 2046-2049. (m) Maheswaran, H.; Prasanth, K. L.;
Krishna, G. G.; Ravikumar, K.; Sridhar, B.; Kantam, M. L. Chem. Commun.
2006, 4066-4068. (n) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama,
N.; Yanagisawa, A. Angew. Chem., Int. Ed. 2006, 45, 5978-5981. (o) Ma,
K.; You, J. Chem. Eur. J. 2007, 13, 1863-1871. (p) Xiong, Y.; Wang, F.;
Huang, X.; Wen, Y. H.; Feng, X. M. Chem. Eur. J. 2007, 13, 829-833.
(q) Lu, S.-F; Du, D.-M; Zhang, S.-W; Xu, J. Tetrahedron: Asymmetry 2004,
15, 3433-3441.
(12) (a) Chinchilla, R.; Na´jera, C.; Sa´nchez-Agullo´, P. Tetrahedron:
Asymmetry 1994, 5, 1393-1402. (b) Allingham, M. T.; Howard-Jones, A.;
Murphy, P. J.; Thomas, D. A.; Caulkett, P.W. R. Tetrahedron Lett. 2003,
44, 8677-8680. (c) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. AdV. Synth.
Catal. 2005, 347, 1643-1648. (d) Sohtome, Y.; Hashimoto, Y.; Nagasawa,
K. Eur. J. Org. Chem. 2006, 2894-2897. (e) Marcelli, T.; van der Haas,
R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006,
45, 929-931.
(11) (a) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
2054-2055. (b) Risgaard, T.; Gothelf, K. V.; Jørgensen, K. A. Org. Biomol.
Chem. 2003, 1, 153-156.
(13) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167-13171.
9324 J. Org. Chem., Vol. 72, No. 24, 2007

N,N′-Dioxide-CuI Catalyst for the Henry Reaction
TABLE 2. Screening of the Solvents in the Asymmetric Henry
Reaction of Benzaldehydea
mol % catalyst (Table 2). While no products were obtained in
halogenated solvents or polar solvents, such as CH2Cl2, ClCH2-
CH2Cl, DMF, or methanol (Table 2, entries 4-5, 8-9), CH3-
CN and toluene gave moderate yields and ee values (Table 2,
entries 6 and 7). Ethers were found to be superior to other
solvents in terms of the enantioselectivity (Table 2, entries 1-3).
THF exhibited the best performance (Table 2, entry 1).
yield
(%)b
ee
entry
solvent
THF
(%)c
When the ratio of ligand 1d to copper(I) was 1:1, the results
were superior to that of the ratio of 2:1 in better yield and
enantioselectivity (Table 3, entry 2 vs 1). With the 1:2 ratio of
ligand 1d to copper(I), the reaction did not occur (Table 3, entry
3), which suggested that one molecule of N,N′-dioxide might
combine with two molecules of copper(I) and the catalyst
structure was changed, forming an inactive species. Then further
optimization revealed that excellent enantioselectivity was
obtained when the reaction temperature decreased from 0 °C
to -20 °C, whereas the reaction hardly proceeded at -45 °C
(Table 3, entries 4 and 5).
1
2
3
4
5
6
7
8
9
97
72
45
80
76
77
-
Et2O
t-BuOMe
CH2Cl2
ClCH2CH2Cl
CH3CN
toluene
NDd
NDd
58
-
71
72
-
67
DMF
methanol
NDd
NDd
-
a Reactions were carried out on a 0.1 mmol scale of benzaldehyde in
the presence of (CuOTf)2‚C7H8 (5 mol %) and ligand 1d (10 mol %) using
nitromethane (20 equiv) in solvent (0.5 mL) at 0 °C for 12 h. b Isolated
yield. c Enantiomeric excesses were determined by HPLC on a Chiral OD-H
column. The absolute configuration (R) was established by comparison of
the sign of the optical rotation values with that in the literature.10i d Not
detected.
When the catalyst loading was only 5 mol % at -20 °C, the
reactivity was decreased sharply (Table 4, entry 2). To increase
the reactivity, some additives were screened in this reaction.
As expected, the yields of nitroaldol products were improved
dramatically when using the 3 Å or 4 Å molecular sieve (Table
4, entries 3 and 4), whereas the 5 Å molecular sieve had no
effect on the reaction (Table 4, entry 5). However, some acidic
additives, such as phenol and TsOH, were extremely harmful
for the reaction (Table 4, entries 6 and 7). Furthermore, when
decreasing the reaction temperature (-45 °C), the reaction could
not be performed smoothly, even though the catalyst loading
was increased to 10 mol % (Table 4, entries 8 and 9).
Enlightened by the concept of dual acid/base catalysis,14 we
added some amines into the reaction system. Using 5 mol %
iPr2NEt, the enhanced reactivity was observed with maintaining
the high enantioselectivity (Table 4, entry 10). When N-
methylmorpholine as a weak base was added, the enantiose-
lectivity was decreased with the low reactivity (Table 4, entry
11). In addition, Et3N also increased the reaction rate (Table 4,
entry 12). The results showed that the strong organic base could
improve the reactivity.
TABLE 3. Screening of the Ratio of Ligand/Metal and
Temperature in the Asymmetric Henry Reacion of Benzaldehydea
ligand
1d
CuI
T
(°C)
t
yield
(%)b
ee
entry
(mol %)
(mol %)
(h)
(%)c
1
2
3
4
5
20
10
10
10
10
10
10
20
10
10
-20
-20
-20
0
24
24
24
12
36
60
85
90
-
80
-
80
NDd
97
-45
NDd
a Reactions were carried out on a 0.1 mmol scale of benzaldehyde with
nitromethane (20 equiv) in THF (0.5 mL). b Isolated yield. c Enantiomeric
excesses were determined by HPLC on a Chiral OD-H column. The absolute
configuration (R) was established by comparison of the sign of the optical
rotation values with that in the literature.10i d Not detected.
phenylethyl moiety, the reaction gave the unexpectedly low
enantioselectivities (Table 1, entries 8 and 10). The enantiose-
lectivity could dramatically increase when the cyclopentyl
moiety instead of phenyl moiety was used (Table 1, entry 9 vs
4). The linker length of three carbons was also essential for
good enantioselectivity (Table 1, entry 9 vs 12 and 13).
Encouraged by the initial results in the asymmetric Henry
reaction, various solvents were screened in the presence of 10
As shown in Table 5, the scope of the catalytic enantiose-
lective Henry reaction was demonstrated by treatment of various
aromatic aldehydes with nitromethane in the presence of 10 mol
% N,N′-dioxide 1d-CuOTf complex, 5 mol % iPr2Net, and 200
mg/mmol 4 Å MS in THF. In all cases, the reactions were clean
and proceeded in good yields with good to excellent enanti-
TABLE 4. Screening of Additive and Base in the Asymmetric Henry Reacion of Benzaldehydea
loading of
additive
loading of
base (mol %)
catalyst
loading (mol %)
T
(°C)
yield
(%)b
ee
entry
additive
base
(%)c
1
2
3
4
5
6
7
8
none
none
-
none
none
none
none
none
none
none
none
none
iPr2NEt
-
-
-
-
-
-
-
-
-
5
10
5
5
5
5
5
5
5
10
10
10
10
-20
-20
-20
-20
-20
-20
-20
-45
-45
-45
-45
-45
97
34
97
98
90
84
90
90
89
-
-
3 Å MS
4 Å MS
5 Å MS
phenol
TsOH
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
20 mg
20 mg
20 mg
10 mol %
10 mol %
20 mg
20 mg
20 mg
20 mg
20 mg
43
NDd
NDd
NDd
50
-
-
9
95
95
37
93
10
11
12
95
trace
95
N-methylmorpholine
Et3N
5
5
a Reactions were carried out on a 0.1 mmol scale of benzaldehyde with nitromethane (20 equiv) in THF (0.5 mL). b Isolated yield. c Enantiomeric excesses
were determined by HPLC on a Chiral OD-H column. The absolute configuration (R) was established by comparison of the sign of the optical rotation
values with that in the literature.10i d Not detected.
J. Org. Chem, Vol. 72, No. 24, 2007 9325

Qin et al.
TABLE 5. Substrate Scope of Catalytic Asymmetric Henry Reaction of Aldehydes and r-Ketoestersa
a Reactions were carried out on a 0.1 mmol scale of aldehyde with (CuOTf)2‚C7H8 (5 mol %), ligand 1d (10 mol %), 20 mg 4 Å MS, and iPr2NEt (5 mol
%) with nitromethane (20 equiv) in THF (0.5 mL) at -45 °C. b Isolated yield. c Enantiomeric excesses were determined by HPLC. The absolute configurations
of nitroaldol adducts were assigned by comparison with literature compounds.10d,10h,10i,10p d Relatively lower reactive rate than other entries while no side
reaction was observed.
oselectivities. Aromatic aldehydes bearing the electron-donating
groups required longer reaction times, but the reaction obtained
higher enantioselectivities (91-95% ee, Table 5, entries 3-7).
Aldehydes bearing the electron-withdrawing nitro groups typi-
cally furnished the nitroaldol products in 1 day or less (Table
5, entries 8-10). 4-Chlorobenzaldehyde could also react
smoothly with good enantioselectivity (86% ee, Table 5, entry
FIGURE 2. Diamide 6 and single-side N-oxide 7.
11). On the other hand, 2b and 2h with the ortho substituent
to a broad range of optically active tertiary carbinols. Encour-
gave lower ee (88% ee and 73% ee, Table 5, entries 2 and 8),
aged by the results achieved with a variety of aldehydes under
which was caused by larger sterehindrance of the ortho
N,N′-dioxide-CuI catalysis, some R-ketoesters were subjected
substituent in the catalyst. Even with the bulker aldehydes such
to the asymmetric Henry reaction. Ethyl pyruvate 3a and 3b
as 1-naphthaldehyde and 2-naphthaldehyde, the reactivity and
reacted respectively with nitromethane to give 5a in 99% yield
enantioselectivity were still maintained (93% ee and 95% ee,
with 98% ee and 5b in 79% yield with 99% ee (Table 5, entries
Table 5, entries 12 and 13). Noteworthily, the heteroaromatic
16 and 17). It should be noted that the product 5a had been
aldehydes also reacted with nitromethane in the presence of 10
mol % 1d-CuOTf complex to give the optically active nitroaldol
(14) (a) Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566-
4583. (b) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187-
2210. (c) Gro¨ger, H. Chem. Eur. J. 2001, 7, 5246-5251. (d) Rowlands, G.
J. Tetrahedron 2001, 57, 1865-1882.
(15) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001,
2222-2223. (b) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2002, 67, 4875-4881. (c) Li, H.; Wang, B.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 732-733. (e) Mandal, T.; Samanta, S.; Zhao,
C. G. Org. Lett. 2007, 9, 943-945.
adducts 4n and 4o in good yields with excellent enantioselec-
tivities (98% ee and 95% ee, Table 5, entries 14 and 15).
To date, only a few catalyst systems had been identified to
afford synthetically meaningful enantioselectivity for the addi-
tion of nitromethane to R-ketoesters.13,15 On the other hand, such
a reaction, in combination with the synthetic versatility of the
ester and the nitro groups, will provide enantioselective access
9326 J. Org. Chem., Vol. 72, No. 24, 2007

N,N′-Dioxide-CuI Catalyst for the Henry Reaction
FIGURE 3. MM2 optimized geometry for N,N′-dioxide 1d-CuI complex.
oxygens. The catalyst model was investigated by the ChemBats3D
program package. The geometries of the catalyst were optimized
at the MM2 level (Figure 3). The MM2 calculation illustrated
that the N,N′-dioxide 1d coordinates as a tetrahedral N2O2 donor
via the amide nitrogens and the N-oxide oxygens. A N-oxide
oxygen, the amide nitrogens, and the copper are in a distorted
plane (the N2O plane), while another N-oxide oxygen is almost
perpendicular to the N2O plane.
According to our investigations and the previous
reports,10i,10j,10o,15b a proposed working model for this Henry
reaction was depicted in Figure 4. A complex that binded the
reaction partners was presented. The benzaldehyde, the elec-
trophile, for maximal activation, should be positioned in one
of the Lewis acidic equatorial sites in the N2O plane which
accords with steric and electronic considerations,10i while the
nitronate was positioned by the hydrogen bonding. In this
transition state, the nitronate would attack the benazldehyde from
the Si face, thus the corresponding nitro-alcohol was obtained
with R configruation.
FIGURE 4. Proposed working model for the Henry reaction of
aldehyde with nitromethane.
transformed to methylcusteine by Deng, which was the key
intermediate in the total syntheses of mirabazoles and thianga-
zole.15c
To elucidate the mechanism of the N,N′-dioxide-CuI-catalyzed
asymmetric Henry reaction, a combination of several techniques
including the ESI-HRMS, 1H NMR, and MM2 calculations was
explored. The complex of N,N′-dioxide-CuI was directed by ESI-
Conclusion
+
HRMS [calcd for C25H43CuN4O4 : 526.2580; found: 526.2580],
In summary, we have developed a new class of C2-symmetric
N,N′-dioxide-CuI catalyst for the asymmetric Henry reaction of
both aldehydes and R-ketoesters in good yield with good to
excellent enantioselectivities (up to 99% ee). The catalytic
system could be tolerant of air and moisture. Further investiga-
tions into other versions of asymmetric catalysis are in pro-
gress.
and poly-complex was not found. It was assumed that a
monomeric Cu/1d ) 1:1 complex without OTf moiety could
be the active species for the Henry reaction.
1H NMR spectroscopy of N,N′-dioxide 1d was studied to get
a preliminary insight into the function of NH moiety. The NH
proton showed a strong deshielding effect at 10.91 ppm, which
was assigned to strong intramolecular hydrogen bonding
between N-oxide and the NH proton. However, when an equal
equivalent of CuOTf was mixed with the ligand 1d, the signal
of NH proton disappeared. It showed that the hydrogen bond
was broken entirely, which was caused by the coordination of
N,N′-dioxide ligand 1d with CuI.
Experimental Section
Typical Experimental Procedure. The mixture of ligand 1d
(4.7 mg, 0.01 mmol), (CuOTf)2‚C7H8 (2.6 mg, 0.005 mmol), and
4 Å molecular sieves (20 mg) was stirred in THF (0.3 mL) at room
temperature under air atmosphere for 10 min to form the catalyst,
then nitromethane (240 µL) and iPr2NEt (25 uL, c ) 0.2 mol/L in
THF, 5 mol %) were added to the mixture. After the addition, the
resulting mixture was cooled to -45 °C, benzaldehyde (10 µL,
0.1 mmol) in THF (0.2 mL) was added, and stirring continued for
36 h. The reaction mixture was directly purified by column
chromatography on silica gel and eluted (ether:petroleum ether, 1:3)
To investigate the function of the N,N′-dioxide moiety, the
diamide 6 and single-side N-oxide 7 were synthesized and
explored in the Henry reaction (Figure 2). While using 6 or 7
as ligands, no product was observed under the same reaction
conditions. The results suggested that only the 1d-CuI complex
could form the active catalyst due to the double N-oxide
moieties.
(16) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539. (b)
Balahura, R. J.; Jordan, R. B. J. Am. Chem. Soc. 1970, 92, 1533-1539. (c)
Fairlie, D. P.; Angus, P. M.; Fenn, M. D.; Jackson, W. G.; Inorg. Chem.
1991, 30, 1564-1569. (d) Antolovich, M.; Phillips, D. J.; Rae, A. D. Inorg.
Chim. Acta 1989, 156, 189-193.
1
On the basis of the studies of ESI-HRMS, H NMR, and
previous works,16 we speculated that the N,N′-dioxide 1d
coordinated to the copper via the amide nitrogens and N-oxide
J. Org. Chem, Vol. 72, No. 24, 2007 9327

Qin et al.
to afford the nitroaldol product 4a (15.9 mg, 95% yield) as a
colorless oil, Chiralcel OD-H hexane/iPrOH 85:15, 0.8 mL/min,
support. We also thank Sichuan University Analytical & Testing
Center for NMR analysis and the State Key Laboratory of
Biotherapy for HRMS analysis.
25
R: tR(major) ) 11.55 min, S: tR(minor) ) 13.96 min; [R]D
)
-43.5 (c ) 0.40 in CH2Cl2, 95% ee); 1H NMR (300 MHz, CDCl3)
8.33-8.20 (m, 2H), 7.79-7.59 (m, 2H), 5.63-5.60 (m, 1H), 4.67-
4.57 (m, 2H), 3.26 (d, J ) 3.5 Hz, 1H) ppm. The absolute
configurations of nitroaldol adducts (R) were assigned by com-
parison with literature compounds.10d
Supporting Information Available: Experimental procedures
1
and characterization of products for catalysts and racemates, H
NMR and 13C NMR spectra, HRMS and HPLC conditions, etc.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We appreciate the National Natural
Science Foundation of China (No. 20702033) for financial
JO701898R
9328 J. Org. Chem., Vol. 72, No. 24, 2007