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Chinese Chemical Letters 22 (2011) 923–926

Asymmetric aza-Henry reaction with a-substituted nitroacetates

catalyzed by a bifunctional thiourea-guanidine catalyst

Bo Han a, Wei Huang a,*, Zhen Rui Xu b, Xiao Ping Dong a,*a State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources,

School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Chinab State Key Laboratory of Oral Diseases, Department of Orthodontics, West China College of Stomatolgy, Sichuan University,

Chengdu 610041, China

Received 9 November 2010

Available online 18 May 2011

Abstract

The asymmetric aza-Henry reaction of a-substituted nitroacetates and N-Boc imines was achieved with a new-type thiourea-

guanidine bifunctional organocatalyst. The novel transformations exhibited high diastereoselectivities, and the adducts bearing

adjacent quaternary and tertiary chiral centers were generally obtained in moderate to good enantioselectivities (up to 88% ee).

# 2011 Wei Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Aza-Henry reaction; Thiourea; Guanidine; Nitroacetate; Organocatalysis

The nucleophilic addition of nitroalkanes to the C N bond of imines, known as the aza-Henry (or nitro-Mannich)

reaction, is a useful carbon–carbon bond-forming process in organic synthesis [1]. The resulting b-nitroamine

derivatives can be readily transformed into valuable building blocks or biologically active compounds, such as vicinal

diamines via reduction of the nitro group [2] and a-amino acids by means of the Nef reaction [3]. As a result, its

asymmetric variant has provoked much interest in the last years [4]. Good stereocontrol has been achieved in the

reactions of simple nitroalkanes and nitroacetates with various imines. However, despite these important advances, the

applications of a-substituted nitroacetates in this field, in which adjacent quaternary and tertiary chiral centers must be

constructed concurrently [5], are rarely explored [4d,6]. It is noteworthy that the chiral a-tetrasubstituted a, b-diamino

acids can be used as chiral building blocks for pharmaceuticals and artificial peptides in many cases [7].

Chiral organocatalysts have become a field of central importance for enantioselective transformations of organic

molecules [8]. In particular, thiourea-based organic molecules have become the most prominent hydrogen-bond donor

catalysts in a wide variety of organic reactions [9]. Despite their tremendous utility, these bifunctional catalysts are

derived from a very limited range of chiral structural scaffolds, including cyclohexane-1,2-diamine, 1,10-binaphthyl-

2,20-diamine, and cinchona alkaloids. The development of readily accessible novel bifunctional catalysts of this nature

would be highly desirable. Very recently, Nagasawa and co-workers have developed thiourea-guanidine bifunctional

catalyst and applied it to Henry and Mannich reactions [10]. This new bifunctional thiourea catalyst is expected to be

* Corresponding authors.

E-mail addresses: phdhuangwei@yahoo.cn (W. Huang), dongxiaoping11@126.com (X.P. Dong).

1001-8417/$ – see front matter # 2011 Wei Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2011.01.038

B. Han et al. / Chinese Chemical Letters 22 (2011) 923–926924

applied in nitro-Mannich reaction of N-Boc imines and a-substituted nitroacetates to afford a,b-diamino acid with two

contiguous nitrogen-bearing stereogenic centers, one of which is quaternary. In this reaction, we envisaged the

guanidinium group and thiourea group selectively coordinate to nucleophiles (nitroacetates) and electrophiles

(imines) through ionic and hydrogen-bonding interation, respectively, and the chiral induction is controlled by the

chiral skeleton. In this paper, we describe an efficient, general, and practical asymmetric aza-Henry reaction with a-

substituted nitroacetates catalyzed by a bifunctional thiourea-guanidine catalyst.

Initially, we evaluated the catalytic activity and enantioselectivity using the model reaction of ethyl 2-

nitropropanoinate 2a with N-Boc imine 3a (Table 1). Bifunctional thiourea-guanidine catalyst 1a–1f with diverse

substituents in the guanidine group and the chiral spacer were screened in the presence of equivalent K2CO3 in toluene at

0 8C (entries 1�6). Catalysts 1a and 1b with mono-substituted guanidines failed to give significant chiral induction,

though good yields can be achieved in 2 h (entries 1�2). To our gratification, in the case of bis-substituted guanidine 1c,

the enantioselectivity of the major isomer 4a was increased to 61% ee with moderate diastereoselectivity (entry 3).

Moreover, better stereocontrol (78% ee and 4.2:1 d.r.) could be attained with catalyst 1d bearing a cyclic amine-

substituted guanidine (entry 4). The absolute configuration of 4a was determined by comparison of the 1H NMR data and

the HPLC retention time with that of literature data [6a,6c]. Consequently, the R3 group on the chiral skeleton was varied.

However, much lower ee values and d.r. were obtained for catalysts 1e and 1f bearing linear and branch alkyl groups

(entries 5 and 6). Other solvents and inorganic bases were also screened in the presence of 1d (entries 7�11). Among

the solvents tested, THF was proven to be the best one in terms of both chemical yield and stereocontrol (entry 9).

Table 1

Screening studies of organocatalytic aza-Henry reaction of nitroacetate 2a and N-Boc imine 3aa.[TD$INLINE]

COOEt

NO2 NBoc

Ph

NH

Ph

Boc

COOEt

NO2

NH

NH

NR1 R2

HN

HN

S

Ar

HN

R3 R3

HN

S

Ar

Cl

+(s, s)-1 (5 mol%), solvent

Base (100 mol% ), 0 oC, 2 h

Ar = 3,5-(CF3)2C6H3

1a R1 = n-Bu, R2 = H, R3 = Bn 1b R1 = i-Pr, R2 = H, R3 = Bn

1c R1 = n-Bu, R2 = n-Bu, R3 = Bn 1d R1, R2 = CH2(CH3)2CH2, R3 = Bn

1e R1, R2 = CH2(CH3)2CH2, R3 = Me 1f R1, R2 = CH2(CH3)2CH2, R3 = i-Pr

a4a3a2(2S, 3S)

.

Entry Cat. Solvent Base Yield (%)b d.r.c (anti/syn) ee(%)d (config)e

1 1a Toluene K2CO3 41(40) 1:1 <10%

2 1b Toluene K2CO3 39(39) 1:1 <10%

3 1c Toluene K2CO3 59(20) 3.0:1 61%

4 1d Toluene K2CO3 67(17) 3.9:1 78%

5 1e Toluene K2CO3 49(31) 1.6:1 35%

6 1f Toluene K2CO3 55(27) 2.0:1 28%

7 1d MeCN K2CO3 60(18) 3.3:1 72%

8 1d CH2Cl2 K2CO3 47(13) 3.6:1 75%

9 1d THF K2CO3 73(14) 5.2:1 84%

10 1d THF Na2CO3 62(13) 4.8:1 80%

11 1d THF CsOH 65(15) 4.3:1 78%

12f 1d THF K2CO3 72(11) 6.5:1 86%

a Reactions were performed with 2a (0.1 mmol), 3a (0.15 mmol) and 1 (5 mol%) in 1 mL solvent at 0 8C for 2 h.b Isolated yield of pure diastereomer. Data in parenthesis is related to the isolated minor isomer.c Calculated from the isolated yield of 4a and its isomer.d The ee values of the anti isomers were determined by chiral HPLC analysis.e The absolute configuration was determined to be 2S,3S by comparison of the HPLC retention time with that of literature data.f At �20 8C for 12 h.

B. Han et al. / Chinese Chemical Letters 22 (2011) 923–926 925

Table 2

Asymmetric aza-Henry reaction of a-substituted nitroacetates 2 and N-Boc aldimines 3a.[TD$INLINE]

R COOEt

NO2 NBoc

R1

NH

R1

Boc

COOEt

R NO2

+(s, s)-1d (5 mol%), THF

K2CO3 (100 mol%), -20 oC, 12 h

432 (2S, 3S)

.

Entry R imines 3 R1 Yield (%)b d.r.c (anti/syn) ee(%)d

1 Me 3a Ph 4a-72 6.5:1 86

2 Me 3b o-ClC6H4 4b-71 7.1:1 81

3 Me 3c m-BrC6H4 4c-80 5.7:1 85

4 Me 3d p-FC6H4 4d-78 5.2:1 82

5 Me 3e p-MeC6H4 4e-61 7.6:1 88

6 Me 3f 1-naphthyl 4f-69 4.6:1 76

7 Me 3g 2-furyl 4g-52 3.3:1 65

8 Me 3h 2-thienyl 4h-46 3.5:1 62

9 Me 3i n-Bu - - -

10 Bn 3j Ph 4j-77 4.3:1 84

11 iPr 3k Ph 4k-42 4.7:1 87

a Reactions were performed with 2 (0.1 mmol), 3 (0.15 mmol), and 1d (5 mol%) in 1 mL THF at �20 8C for 12 h.b Isolated yield of pure diastereomer.c Calculated from the isolated yield of 4 and its isomer.d The ee values of the anti isomers were determined by chiral HPLC analysis.

Model reaction runs with Na2CO3, and CsOH essentially gave no better enantioselectivity (entries 10 and 11). It was

pleasing to find that the diastereomeric ratio could be improved to 6.5:1 without affecting the high conversion by lowering

the reaction temperature to �20 8C, while the time was extended to 12 h (entry 12).

With the optimal reaction conditions in hand, we then examined a variety of a-substituted nitroacetates 2 and N-

Boc imines 3 to establish the general utility of this novel asymmetric transformation. The reaction scopes generally

proved to be broad with respect to both reactants. Table 2 summarizes the results of the reactions. In all cases, the

major chiral isomers 4 could be directly isolated in pure form in good to high yields. Introduction of electron-

donating or electron-withdrawing groups on the aromatic ring of imines has limited influences on the stereo

outcome, and satisfactory data were generally attained (entries 1�5). Similarly, the sterically hindered imine 3f

also provided a-nitroamine 4f with good diastereoselectivity and enantioselectivity (76% ee, 4.6:1 dr, entry 6).

When imines 3g and 3h possessing a heteroaromatic rings were used as substrates, the enantioselectivity of the

adducts 4g and 4h slightly decreased (entries 7�8). However, alkyl imines exhibited quite low reactivity toward 2a

(entry 9). Finally, we investigated the reaction of other a-substituted nitroacetates such a-benzyl and a-isopropyl

derivatives with N-Boc phenyl imines. Interestingly, under the same reaction conditions, the reactions proceeded

smoothly to afford the corresponding products 4j in 84% ee and 4k in 87% ee, respectively (entries 10 and 11).

There was no observable effect of the substituted groups on nitroacetates on the efficiency of the aza-Henry

reactions.

In conclusion, we have successfully presented the stereoselective aza-Henry reaction of a-substituted nitroacetates

and N-Boc imines by employing bifunctional thiourea-guanidine catalyst [11]. In general, good diastereo- and

enantioselectivities could be obtained for a spectrum of substrates. This novel methodology provides facile access to

b-nitroamine derivatives with adjacent quaternary and tertiary chiral centers. Current studies are underway to expand

the utility of the new bifunctional organocatalyst in other asymmetric transformations.

Acknowledgments

We thank the Scientific Research Fund of Sichuan Provincial Education Department (No. 310-347) and Technology

Department of Chengdu University of TCM (Nos. 310-446 and 310-448) for financial support.

B. Han et al. / Chinese Chemical Letters 22 (2011) 923–926926

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[11] Typical procedure of the asymmetric aza-Henry reaction to afford 4a: To a mixture of N-Boc imine 3a (0.15 mmol), chiral catalyst (s,s)-1d

(0.005 mmol, 5 mol%) and k2CO3 (0.1 mmol) in THF (1.0 mL) at�20 8C was added ethyl 2-nitropropanoinate 2a (0.1 mmol) in one portion.

The resulting mixture was stirred at �20 8C for 12 h. Then saturated NH4Cl aq was added, and the organic layer was extracted with ethyl

acetate. The extracts were dried over MgSO4, filtered and concentrated in vacuum, 4a was obtained as a white solid in 84% yield after flash

chromatography (petroleum ether/ethyl acetate = 50:1) and the enantiomeric excess was determined to be 86% by HPLC on Chiralpak AD

column (10% 2-propanol/n-hexane, 1 mL/min), UV 220 nm, tmajor = 7.5 min, tminor = 11.0 min mp 79–80 8C. 1H NMR (300 MHz, CDCl3): d:

7.20�7.38 (m, 5H), 6.41 (brs, 1H), 5.50 (d, 1H, J = 9.6 Hz), 4.34�4.21 (m, 2H), 1.73 (s, 3H), 1.38 (s, 9H), 1.26.(t, 3H, J = 7.2 Hz).