手性磷酸催化芳香胺与硝基烯烃的不对称加成反应_英文_

2011

文章编号: 0253-9837(2011)10-1573-04

Chinese Journal of Catalysis

国际版DOI: 10.1016/S1872-2067(10)60261-6

Vol. 32 No. 10

研究快讯: 1573~1576

手性磷酸催化芳香胺与硝基烯烃的不对称加成反应

杨 磊, 夏春谷, 黄汉民*

中国科学院兰州化学物理研究所羰基合成与选择氧化国家重点实验室, 甘肃兰州 730000

摘要：以轴手性联萘酚为原料, 合成了一系列手性磷酸催化剂, 并首次将其应用于催化芳香胺和硝基烯烃的不对称氮杂迈克尔加成反应中, 产物 β-硝基胺的产率和对映选择性分别达 65%~95% 和 16%~70%. 关键词：手性磷酸; 芳香胺; 硝基烯烃; 氮杂迈克尔加成 中图分类号：O643 文献标识码：A 收稿日期: 2011-07-07. 接受日期: 2011-08-06.

*通讯联系人. 电话: (0931)4968326; 传真: (0931)4968129; 电子信箱: [email protected] 基金来源: 国家自然科学基金 (20802085).

本文的英文电子版(国际版)由Elsevier出版社在ScienceDirect上出版(http://www.sciencedirect.com/science/journal/18722067).

Chiral Phosphoric Acid Catalyzed Enantioselective Aza-Michael

Addition of Aromatic Amines to Nitroolefins

YANG Lei, XIA Chungu, HUANG Hanmin*

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,

Chinese Academy of Sciences, Lanzhou 730000, Gansu, China

Abstract: Chiral phosphoric acid was found to be an effective organocatalyst in the enantioselective aza-Michael addition of aromatic amines to nitroolefins giving the corresponding β-nitroamine products in good yields (65%–95%) with moderate to good enantiomeric ex-cesses (16%–70%). This study represents the first example of a chiral phosphoric acid catalyzed asymmetric aza-Michael addition reaction. Key words: chiral phosphoric acid; aromatic amine; nitroolefin; aza-Michael addition

Received 7 July 2011. Accepted 6 August 2011.

*Corresponding author. Tel: +86-931-4968326; Fax: +86-931-4968129; E-mail: [email protected] This work was supported by the National Natural Science Foundation of China (20802085).

English edition available online at Elsevier ScienceDirect (http://www.sciencedirect.com/science/journal/18722067).

cleophilic addition of nitroalkanes to imines and related β-nitroamines are ubiquitous structural motifs found in

compounds (aza-Henry or nitro-Mannich reaction) [3,4] is a biologically important natural products and pharmaceuti-powerful synthetic methodology that allows for the creation cally active compounds, and they are also useful synthetic

of two vicinal stereogenic centers bearing nitro and amino building blocks in organic synthesis especially for the syn-thesis of nitrogen-containing compounds [1]. Using functional groups. Alternatively, because of its simplicity

well-established transformation chemistry, the and atom economy the 1,4-addition of nitrogen nucleophiles

to nitroolefins (aza-Michael reaction) is a convenient way to β-nitroamines can be easily converted into α-amino acids or

introduce this amine-based functionality to β-carbons that other α-aminocarbonyl compounds and vicinal diamines

are attached to nitro groups (Scheme 1) [5–16]. Neverthe-through the Nef reaction by the reduction of the nitro group

less, compared with the former method for generating [2]. Therefore, the development of an efficient synthetic

β-nitroamines, only a few reports of the corresponding method leading to β-nitroamines and their derivatives has

aza-Michael addition of nitrogen reagents to nitroolefins attracted much attention in organic synthesis. Among the

have been documented in the literature wherein their traditional methods used to generate β-nitroamines, the nu-

1574 催 化 学 报 Chin. J. Catal., 2011, 32: 1573–1576

NR

PG

+

NO2

R'

NO2

+NH2PG

2R

COOH

R

R'2

Scheme 1. Synthesis and transformation of β-nitroamines.

asymmetric construction was achieved mainly through the use of chiral substrates [17]. For example, Mioskowski and co-workers recently described the first diastereoselective synthesis of 1,2-diamino-3,3,3-trifluoropropane using read-ily available optically pure 4-phenyl-2-oxazolidinone as a nitrogen nucleophile [18–20]. In contrast, only one very recent example exists of the asymmetric catalytic aza-Michael addition of aromatic amines to nitroolefins. Ooi and co-workers reported the first highly enantioselec-tive conjugate addition of 2,4-dimethoxyaniline to nitroole-fins using chiral aminophosphonium cations as catalysts [21]. Obviously, the development of the catalytic asymmet-ric aza-Michael addition for the synthesis of chiral β-nitroamines remains challenging and elusive.

Over the last few years, novel chiral Brönsted acids have emerged as versatile enantioselective catalysts and their use in a variety of enantioselective transformations has been widely reported [22–26]. In this context, chiral phosphoric acids have been shown to be excellent chiral organocata-lysts for the asymmetric activation of various substrates through hydrogen bonding interactions and these include imines, enamides, nitroolefins as well as ketones [27–30]. Recently, we have demonstrated that a cooperative catalytic system, produced by the combination of an iron salt and a chiral phosphoric acid, is able to catalyze the enantioselec-tive Friedel-Crafts alkylation of indoles with β-aryl α′-hydroxy enones [31]. Inspired by our successful em-ployment of chiral phosphoric acid catalysts [32] and fol-lowing our long-standing interest in aza-Michael reactions [33–37], we envisioned that the synthesis of chiral β-nitroamines might be achievable by exploring the chiral phosphoric acid catalyzed aza-Michael addition reaction of aromatic amines to nitroolefins. Herein, we would like to report our preliminary results on the chiral phosphoric acid catalyzed enantioselective aza-Michael addition of aromatic amines to nitroolefins.

The general procedure for the catalytic asymmetric aza-Michael addition was as follows. To a flame-dried reac-tion tube was added 2-nitrovinylbenzene (2a, 0.2 mmol), chiral phosphoric acid (1a, 5 mol%), and a solvent (1 ml) at room temperature and under Ar. After 20 min of stirring at the same temperature the reactor was cooled to –20 °C and

the aromatic amine (3a, 0.3 mmol) was also added at the same temperature. After the reaction was complete the crude product was purified directly by flash chromatogra-phy using ethyl acetate/petroleum ether (1:10) to afford the desired pure addition product. The enantiomeric excess (ee) was determined by chiral HPLC on Chiralpak IA, AS-H or OD-H columns. The spectral data of some representative products are given below. 4aa: yellow oil. (Chiral HPLC was performed on a HP series 1200 and Chiralpak AS-H column. hexane/2-propanol = 9, 1.0 ml/min, 210 nm) tminor: 47.56 min, tmajor: 39.33 min, 26% ee; [α]D20= –3.4 (c 0.21, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.31–7.29 (m, 5H), 6.66–6.64 (m, 2H), 6.52–6.49 (m, 2H), 5.00 (m, 1H), 4.61 (d, 2H, J = 6.4 Hz), 4.09 (s, 1H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.1, 138.6, 137.0, 128.2, 127.6, 125.5, 113.9, 113.8, 79.1, 56.7, 54.6. 4af: yellow oil. (Chiral HPLC was performed on a HP series 1200 and Chiralpak IA column. hexane/2-propanol = 9, 1.0 ml/min, 210 nm) tminor: 15.33 min, tmajor: 16.74 min, 54% ee; [α]D20= –9.2 (c 0.54, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.40–7.30 (m, 5H), 7.23–7.18 (m, 2H), 6.49–6.45 (m, 2H), 5.14–5.09 (m, 1H), 4.73–4.64 (m, 2H), 4.48 (d, 1H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 144.7, 137.2, 132.1, 129.4, 128.9, 126.4, 115.6, 110.8, 80.0, 56.7. 4ah: yellow viscous oil. (Chiral HPLC was performed on a HP series 1200 and Chiralpak AS-H column. hexane/2-propanol = 9, 1.0 ml/min, 210 nm) tminor: 22.70 min, tmajor: 25.25 min, 16% ee; [α]D20= –3.6 (c 0.11, CH2Cl2). The absolute configura-tion was assigned as (R) by comparison of the optical rota-tion with the reported value[21]: [α]D29= 10.8 (c 1.77, CHCl3), 95% ee for (S)-isomer. 1H NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 5H), 6.44–6.42 (m, 2H), 6.29 (1H, dd, J = 8.8, 2.4 Hz), 5.11 (s, 1H), 4.76–4.66 (m, 2H), 3.82 (s, 3H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.9, 148.4, 138.2, 129.7, 129.2, 128.5, 126.5, 112.0, 103.7, 99.3, 80.2, 57.4, 55.7, 55.6.

Our initial focus was on the optimization of the reaction conditions (Table 1). Using toluene as the solvent and 4-methoxyaniline as the nitrogen nucleophile, a series of chiral phosphoric acids with different substituents at the 3,3′-positions of the binaphthyl scaffold were prepared and screened to find the best catalyst (entries 1–9). The results revealed that the chiral phosphoric acid 1a was superior in terms of the observed selectivity of the aza-Michael addi-tion product of nitrostyrene and 4-methoxyaniline (entry 1). The solvent also had a major effect on both the enantiose-lectivity and reactivity of the product. The use of nonpolar and weakly polar solvents gave promising results in terms of the product yield (entries 10–12). The more polar solvent resulted in a lower ee and a lower yield of the addition product compared with the weakly polar solvents (entry 13).

From the solvent study, we determined that Tetrahydrofuran

www.chxb.cn 杨 磊 等: 手性磷酸催化芳香胺与硝基烯烃的不对称加成反应 1575

Table 2 Chiral phosphoric acid 1a catalyzed asymmetric

OMe

NHNO2

+3a4aa

1a: 2-naphthyl1b: phenyl1c: SiPh3

1d: 9-phenanthryl1e: 2,4,6-(i-Pr)3C6H21f: 3,5-(CF3)2C6H3

1g: 4-(2-naphthyl)C6H41h: 9-anthryl1i: 1-naphthyl

2

Table 1 Optimization of the aza-Michael addition

aza-Michael addition of aromatic amines to 2-nitrovinylbenzene

NO2

2a

+

1

4

NO2

2a

EntryR1 in 3 Time (h) 4 Yield (%)ee/%

1 H 3b 36 4ab 2 4-Me 3c 36 4ac 4ad 3 4-CF3 3d 48 4 4-Cl 3e 48 4ae

ee/%

5 4-Br 3f 48 4af 6 4-F 3g 48 4ag 7 2,4-(OMe)2 3h

36

4ah

80 40 85 30 — — 65 43 70 54 80 43 76 16

(R)-1

Entry 1 2 3 4 5 6 7 8

Catalyst 1a 1b 1c 1d 1e 1f 1g 1h

Solvent Time (h) Yield (%)

toluene 24 80 14 toluene 24 95 9 toluene 24 70 0 toluene 24 85 7 toluene 24 85 10 toluene 24 92 8 toluene 24 87 4 toluene 24 90 0

Reaction conditions: 5 mol% 1a, 0.2 mmol 2a, 0.3 mmol 3, 1 ml THF, 0.3 nm molecular sieves (100 mg), at –20 °C, in Ar.

a

The absolute configuration of 4ah was assigned as (R) by comparison

of the optical rotation with the reported value [21].

It should be noted that when the phenyl ring of the aromatic amines had more electron-withdrawing groups such as CF3

9 1i toluene 24 90 9

the aza-Michael reaction did not occur at all (entry 3).

10 1a THF 24 85 20

Further exploration of this novel chiral phosphoric acid

8 11 1a CHCl3 24 80

catalyzed asymmetric aza-Michael addition of

12 1a xylene 24 95 11

4-bromoaniline 3f was conducted using various substituted

13 1a 1,4-dioxane24 60 0

1a THF 48 86 23 nitroolefins. As listed in Table 3, the halogenated nitroole-14a

1a THF 48 89 26 fins gave the corresponding products in good yields with 15a,b

moderate ee values (entries 1–2). An increase in ee values Reaction conditions: 5 mol% 1, 0.2 mmol 2a, 0.3 mmol 3a, 1 ml sol-was observed when the steric hindrance of the aromatic ring vent, under Ar.

a

in the nitroolefin was increased (entry 5). To our delight The reaction was run at –20 °C.

b

moderate to good product yields and ee values were ob-0.3 nm molecular sieves (100 mg) were added.

(THF) was the best choice (entry 10). Decreasing the reac-tion temperature to –20 °C resulted in increased ee of the addition product (entry 14). Further optimization of the re-action conditions revealed that the addition of 0.3 nm mo-lecular sieves could improve the ee of the addition product (entry 15).

With the optimized reaction conditions in hand, we turned our attention to the effect of substituent groups on the various aromatic amines (Table 2). A variety of amines were investigated for the generality of this reaction under the optimized reaction conditions. As shown in Table 2, amine 3b, which had no substituent on the phenyl ring (en-try 1) and the amines containing electron-withdrawing groups on the phenyl ring (entries 4–6) were good sub-strates. They provided the addition products in good yields with high ee values. In contrast, a slight decrease in ee was observed for the amine bearing electron-donating group on the phenyl ring (entry 2). Along with the electronic effect, the steric effect was also obvious in this reaction (entry 7).

Table 3 Scope of the enantioselective aza-Michael addition cata-lyzed by chiral phosphoric acid

1a

2

+H2NAr

3

Ar2

Entry 1 2 3 4 5 6 7 8 9

R in 2 Ar in 3 4 4-Br 2b 4-BrC6H4 3f 4-Cl 2c 4-BrC6H4 3f 2-OMe 2d 4-BrC6H4 3f 4-OMe 2e 4-BrC6H4 3f 2-Br 2f 4-BrC6H4 3f 2,3-(OMe)2 2g

4-BrC6H4 3f

4bf 4cf 4df 4ef 4ff 4gf 4hc 4hg

Yield (%)

ee/%

82 19 81 30 65 44 — — 85 45 85 70 70 30 75 30 70 42 64 48

4-Me 2h Ph 3b 4hb 4-Me 2h 4-MeC6H4 3c 4-Me 2h 4-FC6H4 3g

10 4-Me 2h 2-Naphthyl 3i 4hi

Reaction conditions: 5 mol% 1a, 0.2 mmol 2, 0.3 mmol 3, 1 ml THF, 0.3 nm molecular sieves (100 mg), –20 °C, 48 h, in Ar.

a

At –20 °C for 36 h.

1576 催 化 学 报 Chin. J. Catal., 2011, 32: 1573–1576

tained when election-donating groups such as OMe were present on the phenyl ring of the nitroolefins (entries 3 and 6). It was surprising that no product was observed when 4-methoxynitrostyrene 2e was employed (entry 4). Finally, various substituted aromatic amines were also investigated in the aza-Michael addition reaction with 4-methylnitrostyrene 2h as the substrate. The electronic and steric effects of the aromatic amines were all important for the enantioselectivities of the addition products (entries 7–10). Although the exact mechanism of this addition reac-tion is not clear at current stage, on the basis of the results that we obtained here and previously [32], a plausible tran-sition state model which involves the acidic proton of phosphoric acid for activation the nitro moiety and the phosphoryl oxygen atom activation the aromatic amine N–H moiety through the hydrogen bond is the most likely in-volved.

To demonstrate the synthetic use of the current method-ology for the synthesis of vicinal diamine derivatives, the reduction of the nitroamine derivative was evaluated. As shown in Scheme 2, after a work-up of the reaction of ni-troamine 4af (54% ee) with LiAlH4, the desired diamine derivative 5 was obtained in 74% yield with 34% ee, which indicated a slight racemization during the reduction process.

Br

4af

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Br

NO2THF

*5

NH2

21

Scheme 2. Reduction of the β-nitroamine product.

In conclusion, we developed an efficient method for the enantioselective aza-Michael addition reaction between aromatic amines and nitroolefins using chiral phosphoric acids as catalyst for the first time. The aza-Michael addition products were generally obtained in good yields (65%–95%) with moderate to good enantiomeric excesses (16%–70%). Further studies into improving the selectivity and the scope of this reaction and related aza-Michael reac-tions catalyzed by chiral Brönsted acids are ongoing in our lab and will be reported in due course.

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

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