Asymmetric aza-Henry reaction with α-substituted nitroacetates catalyzed by a bifunctional thiourea-guanidine catalyst

Article abstract of DOI:10.1016/j.cclet.2011.01.038

The asymmetric aza-Henry reaction of α-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).

Full text of DOI:10.1016/j.cclet.2011.01.038

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 923–926
www.elsevier.com/locate/cclet
Asymmetric aza-Henry reaction with a-substituted nitroacetates
catalyzed by a bifunctional thiourea-guanidine catalyst
b
a,
Bo Han a, Wei Huang a, , Zhen Rui Xu , Xiao Ping Dong
*
*
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, China
b 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

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B. Han et al. / Chinese Chemical Letters 22 (2011) 923–926
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 1ꢀ6). Catalysts 1a and 1b with mono-substituted guanidines failed to give significant chiral induction,
though good yields can be achieved in 2 h (entries 1ꢀ2). 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 4awas determined by comparison of the 1H NMR data and
the HPLC retention timewith 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 7ꢀ11). 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 3a .
[D$LINE]
a T
Boc
Ph
Boc
NH
(s, s)-1 (5 mol%), solvent
NO
2
N
+
COOEt
NO
o
COOEt
Base (100 mol% ), 0 C, 2 h
Ph
2
2a
3a
4a
2
1
R
R
(2S, 3S)
Cl
N
H
H
N
H
N
H
N
N
Ar = 3,5-(CF ) C H
3 2
6
3
Ar
N
N
H
Ar
2
H
3
3
S
R
R
S
1
2
3
1
3
1a R = n-Bu, R = H, R = Bn
1b R = i-Pr, R = H, R = Bn
1
2
3
1
2
3
1c R = n-Bu, R = n-Bu, R = Bn
1d R , R = CH (CH ) CH , R = Bn
2 3 2 2
1
2
3
1
2
3
1e R , R = CH (CH ) CH , R = Me 1f R , R = CH (CH ) CH , R = i-Pr
2
3 2
2
2
3 2
2
.
Entry
Cat.
Solvent
Base
Yield (%)b
d.r.c (anti/syn)
ee(%)d (config)e
1
1a
1b
1c
1d
1e
1f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MeCN
CH2Cl2
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
CsOH
41(40)
39(39)
59(20)
67(17)
49(31)
55(27)
60(18)
47(13)
73(14)
62(13)
65(15)
72(11)
1:1
1:1
<10%
<10%
61%
78%
35%
28%
72%
75%
84%
80%
78%
86%
2
3
3.0:1
3.9:1
1.6:1
2.0:1
3.3:1
3.6:1
5.2:1
4.8:1
4.3:1
6.5:1
4
5
6
7
1d
1d
1d
1d
1d
1d
8
9
10
11
12f
THF
THF
THF
K2CO3
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.
Isolated yield of pure diastereomer. Data in parenthesis is related to the isolated minor isomer.
Calculated from the isolated yield of 4a and its isomer.
b
c
d
e
f
The ee values of the anti isomers were determined by chiral HPLC analysis.
The absolute configuration was determined to be 2S,3S by comparison of the HPLC retention time with that of literature data.
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 3 .
[D$LINE]
a T
Boc
Boc
NH
(s, s)-1d (5 mol%), THF
NO
2
N
+
COOEt
NO
1
R
o
R
COOEt
1
K CO (100 mol%), -20 C, 12 h
R
2
3
R
2
2
3
4 (2S, 3S)
.
Entry
R
imines 3
R1
Ph
Yield (%)b
d.r.c (anti/syn)
ee(%)d
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
3a
3b
3c
3d
3e
3f
4a-72
4b-71
4c-80
4d-78
4e-61
4f-69
4g-52
4h-46
-
6.5:1
7.1:1
5.7:1
5.2:1
7.6:1
4.6:1
3.3:1
3.5:1
-
86
81
85
82
88
76
65
62
-
2
o-ClC6H4
m-BrC6H4
p-FC6H4
p-MeC6H4
1-naphthyl
2-furyl
3
4
5
6
7
3g
3h
3i
8
2-thienyl
n-Bu
9
10
11
3j
3k
Ph
4j-77
4k-42
4.3:1
4.7:1
84
87
iPr
Ph
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.
Isolated yield of pure diastereomer.
b
c
d
Calculated from the isolated yield of 4 and its isomer.
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 tofindthatthe diastereomericratiocouldbeimprovedto6.5:1without affectingthehighconversionbylowering
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 1ꢀ5). 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 7ꢀ8). 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.

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B. Han et al. / Chinese Chemical Letters 22 (2011) 923–926
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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:
7.20ꢀ7.38 (m, 5H), 6.41 (brs, 1H), 5.50 (d, 1H, J = 9.6 Hz), 4.34ꢀ4.21 (m, 2H), 1.73 (s, 3H), 1.38 (s, 9H), 1.26.(t, 3H, J = 7.2 Hz).