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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 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 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 -nitro esters containing chiral quaternary carbon centers (up to 99% ee). On the basis of acombination of several techniques including the 1H NMR, ESI-HRMS, and MM2 calculations, the proposedmechanism was presented to explain the origin of reactivity and asymmetric inductivity.
Asymmetric Allylation and Henry Reaction
Catalyzed by N,N-Dioxide-Metal Complex
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 beenapplied in many reactions as organocatalysts.2,3 In these reac-tions, the mechanism was mainly based on the activation of Siatom by N-oxide as Lewis base, which confined the applicationof N-oxide in asymmetric catalysis. On the other hand, there ligand for the highly enantioselective reactions. In light of our have been few attempts to employ N-oxides as chiral ligands recent success of enantioselective allylation and cyanation of to achieve high levels of efficiency in asymmetric reaction.4 carbonyl compound utilizing chiral N,N′-dioxides as ligands,5 Therefore, it is still a challenge to develop the N-oxide as a we investigated the asymmetric Henry (nitroaldol) reaction(Scheme 1).
† Key Laboratory of Green Chemistry & Technology.
The Henry (nitroaldol) reaction has long been known as a ‡ State Key Laboratory of Biotherapy.
powerful and efficient method for the construction of carbon- (1) For review of the chiral ligand design, see: (a) Desimoni, G.; Faita, carbon bonds in organic chemistry.6,7 It provided an efficient 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-
access to valuable functionalized structural motifs such as 1,2- 7715. (c) Fonseca, M. H.; Ko¨nig, B. AdV. Synth. Catal. 2003, 345, 1173-
amino alcohols and R-hydroxy carboxylic acid.8 Since the first example was reported by Shibasaki and co-workers in 1992,9 (2) For review of chiral N-oxide, see: (a) Malkov, A. V.; Kocˇovsky´, P.
interests in the enantioselective Henry reactions had been Eur. J. Org. Chem. 2007, 29-36. (b) Chelucci, G.; Murineddu, G.; Pinna,
G. A. Tetrahedron: Asymmetry 2004, 15, 1373-1389.
triggered involving several chiral metal complexes10 and chiral 10.1021/jo701898r CCC: $37.00 2007 American Chemical SocietyPublished on Web 11/01/2007 J. Org. Chem. 2007, 72, 9323-9328
organocatalysts.11,12 However, few examples have been madeto employ an efficient catalytic system for both aldehydes andketones 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 includingaldehydes and R-ketoesters.
FIGURE 1. Chiral N,N′-dioxides as ligands for the asymmetric Henry
Results and Discussion
Our initial studies of catalytic asymmetric Henry reaction TABLE 1. Screening of Central Metals and N,N-Dioxide Ligands
focused on the addition of nitromethane to benzaldehyde in the in the Asymmetric Henry Reaction of Benzaldehydea
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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.
(4) (a) Shen, Y. C.; Feng, X. M.; Li, Y.; Zhang, G. L.; Jiang, Y. Z. Eur. 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-
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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-
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 (6) Henry, L. C. R. Hebd. Seances. Acad. Sci. 1895, 120, 1265-1268.
yield. c Enantiomeric excesses were determined by HPLC on a Chiral OD-H (7) For reviews for the Henry (nitroaldol) reaction, see: (a) Palomo, C.; column. The absolute configurations were established by comparison of Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561-2574. (b) Palomo,
the sign of the optical rotation values with that in the literature.10i d Not C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442-
detected. e Reactions were performed with (CuOTf) ‚ 5444. (c) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
2006, 17, 3315-3326.
(8) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New presence of the complex of chiral N,N′-dioxide 1a as a ligand
York, 2001. (b) Rosini, G. In ComprehensiVe Organic Synthesis, Vol. 2; (Figure 1). Unfortunately, the N,N′-dioxide 1a-InBr3 complex
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.
could not catalyze the Henry reaction, unlike its efficiency in (9) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. the enantioselective allylation of ketones (Table 1, entry 1).5a Chem. Soc. 1992, 114, 4418-4420. (b) Sasai, H.; Suzuki, T.; Itoh, N.;
While using the catalysts with Zn(OTf)2, Cu(OTf)2, and Ti- 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. 4 as central metals, the corresponding product 4a could
Soc. 1993, 115, 10372-10373.
not be obtained (Table 1, entries 2-3 and 6). Fortunately, 1a-
(10) (a) Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 2 4H2O and 1a-(CuOTf)2 C7H8 complexes could cata-
1996, 37, 9081-9084. (b) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.;
lyze the Henry reaction, and moderate enantioseletivity (45% 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,
5). After screening the steric and electronic effect of N,N′- 861-863. (e) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. dioxides, we found that the reactivity and enantioselectivities 2002, 4, 2621-2623. (f) Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron:
were closely dependent on both the chiral backbone and the R Asymmetry 2004, 15, 771-776. (g) Gao, J.; Martell, A. E. Org. Biomol.
2003, 1, 2801-2806. (h) Palomo, C.; Oiarbide, M.; Laso, A. Angew.
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L-piperidinamide derivative 1d was superior to L-proline-derived
M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003,
1f in both the yield and ee value (Table 1, entry 9 vs 11). Poor
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results were obtained using the bulkier 2,6-diisopropylphenyl M. M. Tetrahedron: Asymmetry 2006, 17, 725-728. (l) Blay, G.; Climent,
(Table 1, entry 7). When the amide R was tert-butyl or (S)- E.; Ferna´ndez, I.; Herna´ndez-Olmos, V.; Pedro, J. R. Tetrahedron:
2006, 17, 2046-2049. (m) Maheswaran, H.; Prasanth, K. L.;
Krishna, G. G.; Ravikumar, K.; Sridhar, B.; Kantam, M. L. Chem. Commun.
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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
mol % catalyst (Table 2). While no products were obtained in Reaction of Benzaldehydea
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 othersolvents in terms of the enantioselectivity (Table 2, entries 1-3).
THF exhibited the best performance (Table 2, entry 1).
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 a Reactions were carried out on a 0.1 mmol scale of benzaldehyde in to -20 °C, whereas the reaction hardly proceeded at -45 °C 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 Isolatedyield. c Enantiomeric excesses were determined by HPLC on a Chiral OD-H When the catalyst loading was only 5 mol % at -20 °C, the column. The absolute configuration (R) was established by comparison of reactivity was decreased sharply (Table 4, entry 2). To increase the sign of the optical rotation values with that in the literature.10i d Not the reactivity, some additives were screened in this reaction.
As expected, the yields of nitroaldol products were improveddramatically when using the 3 Å or 4 Å molecular sieve (Table TABLE 3. Screening of the Ratio of Ligand/Metal and
4, entries 3 and 4), whereas the 5 Å molecular sieve had no Temperature in the Asymmetric Henry Reacion of Benzaldehydea
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 % a Reactions were carried out on a 0.1 mmol scale of benzaldehyde with iPr2NEt, the enhanced reactivity was observed with maintaining nitromethane (20 equiv) in THF (0.5 mL). b Isolated yield. c Enantiomeric the high enantioselectivity (Table 4, entry 10). When N- excesses were determined by HPLC on a Chiral OD-H column. The absolute methylmorpholine as a weak base was added, the enantiose- configuration (R) was established by comparison of the sign of the optical lectivity was decreased with the low reactivity (Table 4, entry rotation values with that in the literature.10i d Not detected.
11). In addition, Et3N also increased the reaction rate (Table 4, phenylethyl moiety, the reaction gave the unexpectedly low entry 12). The results showed that the strong organic base could enantioselectivities (Table 1, entries 8 and 10). The enantiose- lectivity could dramatically increase when the cyclopentyl As shown in Table 5, the scope of the catalytic enantiose- moiety instead of phenyl moiety was used (Table 1, entry 9 vs lective Henry reaction was demonstrated by treatment of various 4). The linker length of three carbons was also essential for aromatic aldehydes with nitromethane in the presence of 10 mol good enantioselectivity (Table 1, entry 9 vs 12 and 13).
% N,N′-dioxide 1d-CuOTf complex, 5 mol % iPr2Net, and 200
Encouraged by the initial results in the asymmetric Henry mg/mmol 4 Å MS in THF. In all cases, the reactions were clean reaction, various solvents were screened in the presence of 10 and proceeded in good yields with good to excellent enanti- TABLE 4. Screening of Additive and Base in the Asymmetric Henry Reacion of Benzaldehydea
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 rotationvalues with that in the literature.10i d Not detected.
J. Org. Chem, Vol. 72, No. 24, 2007 9325
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 configurationsof nitroaldol adducts were assigned by comparison with literature compounds.10d,10h,10i,10p d Relatively lower reactive rate than other entries while no sidereaction was observed.
oselectivities. Aromatic aldehydes bearing the electron-donatinggroups required longer reaction times, but the reaction obtainedhigher 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 (Table5, entries 8-10). 4-Chlorobenzaldehyde could also react FIGURE 2. Diamide 6 and single-side N-oxide 7.
smoothly with good enantioselectivity (86% ee, Table 5, entry
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
adducts 4n and 4o in good yields with excellent enantioselec-
(14) (a) Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566-
tivities (98% ee and 95% ee, Table 5, entries 14 and 15).
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.
To date, only a few catalyst systems had been identified to J. Tetrahedron 2001, 57, 1865-1882.
afford synthetically meaningful enantioselectivity for the addi- (15) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001,
tion of nitromethane to R-ketoesters.13,15 On the other hand, such 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.
a reaction, in combination with the synthetic versatility of the Am. Chem. Soc. 2006, 128, 732-733. (e) Mandal, T.; Samanta, S.; Zhao,
ester and the nitro groups, will provide enantioselective access C. G. Org. Lett. 2007, 9, 943-945.
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.
reports,10i,10j,10o,15b a proposed working model for this Henryreaction was depicted in Figure 4. A complex that binded the FIGURE 4. Proposed working model for the Henry reaction of
reaction partners was presented. The benzaldehyde, the elec- trophile, for maximal activation, should be positioned in oneof the Lewis acidic equatorial sites in the N2O plane which transformed to methylcusteine by Deng, which was the key accords with steric and electronic considerations,10i while the intermediate in the total syntheses of mirabazoles and thianga- nitronate was positioned by the hydrogen bonding. In this transition state, the nitronate would attack the benazldehyde from To elucidate the mechanism of the N,N′-dioxide-CuI-catalyzed the Si face, thus the corresponding nitro-alcohol was obtained asymmetric Henry reaction, a combination of several techniques including the ESI-HRMS, 1H NMR, and MM2 calculations wasexplored. The complex of N,N′-dioxide-CuI was directed by ESI- Conclusion
25H43CuN4O4 : 526.2580; found: 526.2580], In summary, we have developed a new class of C2-symmetric and poly-complex was not found. It was assumed that a N,N′-dioxide-CuI catalyst for the asymmetric Henry reaction of monomeric Cu/1d ) 1:1 complex without OTf moiety could
both aldehydes and R-ketoesters in good yield with good to be the active species for the Henry reaction.
excellent enantioselectivities (up to 99% ee). The catalytic 1H NMR spectroscopy of N,N′-dioxide 1d was studied to get
system could be tolerant of air and moisture. Further investiga- a preliminary insight into the function of NH moiety. The NH tions into other versions of asymmetric catalysis are in pro- proton showed a strong deshielding effect at 10.91 ppm, which was assigned to strong intramolecular hydrogen bondingbetween N-oxide and the NH proton. However, when an equal Experimental Section
equivalent of CuOTf was mixed with the ligand 1d, the signal
Typical Experimental Procedure. The mixture of ligand 1d
of NH proton disappeared. It showed that the hydrogen bond was broken entirely, which was caused by the coordination of 4 Å molecular sieves (20 mg) was stirred in THF (0.3 mL) at room N,N′-dioxide ligand 1d with CuI.
temperature under air atmosphere for 10 min to form the catalyst, To investigate the function of the N,N′-dioxide moiety, the then nitromethane (240 µL) and iPr2NEt (25 uL, c ) 0.2 mol/L in diamide 6 and single-side N-oxide 7 were synthesized and
THF, 5 mol %) were added to the mixture. After the addition, the explored in the Henry reaction (Figure 2). While using 6 or 7
resulting mixture was cooled to -45 °C, benzaldehyde (10 µL,0.1 mmol) in THF (0.2 mL) was added, and stirring continued for as ligands, no product was observed under the same reaction 36 h. The reaction mixture was directly purified by column conditions. The results suggested that only the 1d-CuI complex
chromatography on silica gel and eluted (ether:petroleum ether, 1:3) could form the active catalyst due to the double N-oxidemoieties.
(16) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539. (b)
On the basis of the studies of ESI-HRMS, 1H NMR, and 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.
previous works,16 we speculated that the N,N′-dioxide 1d
1991, 30, 1564-1569. (d) Antolovich, M.; Phillips, D. J.; Rae, A. D. Inorg.
coordinated to the copper via the amide nitrogens and N-oxide Chim. Acta 1989, 156, 189-193.
J. Org. Chem, Vol. 72, No. 24, 2007 9327
to afford the nitroaldol product 4a (15.9 mg, 95% yield) as a
support. We also thank Sichuan University Analytical & Testing colorless oil, Chiralcel OD-H hexane/iPrOH 85:15, 0.8 mL/min, Center for NMR analysis and the State Key Laboratory of -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- Supporting Information Available: Experimental procedures
4.57 (m, 2H), 3.26 (d, J ) 3.5 Hz, 1H) ppm. The absolute and characterization of products for catalysts and racemates, 1H configurations of nitroaldol adducts (R) were assigned by com- NMR and 13C NMR spectra, HRMS and HPLC conditions, etc.
This material is available free of charge via the Internet at
Science Foundation of China (No. 20702033) for financial 9328 J. Org. Chem., Vol. 72, No. 24, 2007


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