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• 不对称Michael加成反应是形成碳碳键的重要方式之一^[1], 通过1, 3-二羰基化合物对硝基烯烃的不对称加成反应构建手性中心一直是研究的热点^[2].在过去的十几年中, 手性双功能有机小分子催化剂因其能够对亲电和亲核位点同时活化, 已成功应用于催化1, 3-二羰基化合物对硝基烯烃的加成反应, 这类催化剂包括二胺类^[3]、硫脲类^[4]、金鸡纳碱类^[5]、方酰胺类^[6], 其中硫脲基团因其对硝基独特的活化作用而备受关注.在硫脲类催化剂的设计中, 往往需要同时具备仲胺或叔胺单元来实现双功能基团的协同, 考虑到脯氨酸及其衍生物^[7]在不对称催化中的重要作用, Tang课题组^[8]设计了吡咯烷-硫脲类催化剂(图 1), 并将其成功应用于环己酮对硝基烯烃的加成反应中.随后, 新的吡咯烷-硫脲类催化剂不断被合成出来, 用于催化环己酮^[9]、1, 3-二酮^[10]对硝基烯烃的加成.尽管此类催化剂在催化产率及选择性上均较为理想, 然而其催化作用比较依赖于催化剂的用量, 通常需要5~20 mol%才能达到较好的效果, 因此, 开发选择性好、用量少的催化剂仍然具有重要意义.在此基础上, 本文报道了一类基于吡咯烷的硫脲-酰胺类手性催化剂, 并将其应用于2, 4-戊二酮对硝基烯烃的不对称Michael加成反应中(图 2), 在1 mol%催化剂用量下, 加成产物最高ee值达到了94%.

  图 1

  

  图 1.  报道的吡咯烷-硫脲催化剂

  Figure 1.  Previous works of pyrrolidine-thiourea organo- catalysts

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  图 2

  

  图 2.  硫脲-酰胺催化剂

  Figure 2.  Structure of thiourea-amide organocatalysts

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  1.   结果与讨论

  硫脲-酰胺类催化剂合成方法如Scheme 1所示.首先以3, 5-双(三氟甲基)苯基异硫氰酸酯和(1R, 2R)-环己二胺为原料合成了化合物2.对N-取代脯氨醇进行氧化得到相应的醛3a~3d.化合物2与3通过亚胺还原得到催化剂1a~1d.催化剂1d在三氟乙酸存在下进行水解得到催化剂1e.对于催化剂1f, 由于N-甲基-脯氨醛制备非常困难^[11], 设计了新的反应路线, 通过溴代物4与2反应成功合成1f.作为对比, 同时合成了与文献报道类似的催化剂1g~1h^[12].

  图式 1

  

  图式 1.  催化剂1a~1f合成路线

  Scheme 1.  Synthetic routes of 1a~1f

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  首先考察了催化剂1a~1h在2, 4-戊二酮6a对硝基苯乙烯5a的加成反应中的催化效果, 其结果如表 1所示.尽管催化剂1a~1h结构比较类似, 但其催化产率及选择性均差异较大. 1f是最初设计的催化剂, 预期其吡咯烷部分的叔胺基团能够对1, 3二羰基进行活化, 出人意料的是1f在加成反应中没有任何催化效果(Entry 6);而吡咯烷N-酰基催化剂1a~1d在10 mol%催化剂量情况下, 能够迅速催化戊二酮对硝基苯乙烯的加成反应, 其中N-丙酰基催化剂1b在以二氯甲烷为反应溶剂时, 其ee值能够达到85% (Entry 2);当吡咯烷N没有取代基时, 如催化剂1e, 其催化活性急剧下降, 72 h内产物产率仅有40%, 且没有对映选择性(Entry 5).意外的是, 催化剂1g~1h尽管具有吡咯烷N-酰基结构, 但仍然没有任何活性(Entries 7~8).

  表 1

  

  表 1  催化剂筛选^a

  Table 1.  Screening of catalysts

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  Entry	Catalyst	Time/h	Yieldb/%	eec/%	Config.d
  1	1a	3	92	84	R
  2	1b	3	90	85	R
  3	1c	3	93	82	R
  4	1d	3	92	80	R
  5	1e	72	40	0	—
  6	1f	96	Trace	—	—
  7	1g	96	Trace	—	—
  8	1h	96	Trace	—	—
  a Reaction condition: 5a (0.2 mmol), 6 (0.4 mmol), catalyst (10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC. d The configuration was determined by comparing optical rotation data and HPLC retention times with literatures.

  接下来以催化剂1a和1b为对象, 考察了溶剂对其催化效果的影响, 结果见表 2.开始对比了2, 4-二酮对硝基烯烃加成反应常用的二氯甲烷和甲苯, 在以甲苯为溶剂时, 1a和1b催化加成产物(R)-7a均具有较高产率, 其相应ee值分别为92%和90% (Entries 1~4).而当以CH₃CN (Entry 5)、THF (Entry 6)、EtOAc (Entry 7)为溶剂以及无溶剂反应(Entry 9)时, 催化剂的选择性均不理想.同时考察催化剂用量对催化结果的影响, 当1a用量低至1 mol%, 反应时间有所延长, 但其加成产物ee值仍达到92 % (Entry 11), 说明催化剂用量能够影响反应速率, 但对反应选择性影响不大.同时对温度进行考察可以发现, 温度对加成产物ee值的影响不大(Entries 12~13).

  表 2

  

  表 2  反应条件优化^a

  Table 2.  Optimization of reaction conditions

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  Entry	Catalyst	Loading/ mol%	T/℃	Solvent	Yieldb/%	eec/%
  1	1a	10	25	CH2Cl2	92	84
  2	1a	10	25	Toluene	94	92
  3	1b	10	25	CH2Cl2	90	85
  4	1b	10	25	Toluene	93	90
  5	1a	10	25	CH3CN	96	53
  6	1a	10	25	THF	21	70
  7	1a	10	25	EtOAc	90	78
  8	1a	10	25	CHCl3	89	79
  9	1a	10	25	Neat	82	68
  10	1a	5	25	Toluene	92	91
  11	1a	1	25	Toluene	92	92
  12	1a	1	0	Toluene	86	90
  13	1a	1	-20	Toluene	85	91
  a Reaction condition: 5a (0.2 mmol), 6a (0.4 mmol), catalysts (1~10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC.

  基于对催化反应溶剂、温度、催化剂用量的考察, 我们确定了优化的反应条件: 1 mol%催化剂用量, 以甲苯为溶剂在室温下反应.根据优化后的反应条件, 进一步考察了催化剂1a对不同取代硝基烯烃参与的加成反应的催化效果.如表 3所示, 在对含有不同电子效应基团的各种硝基苯乙烯的加成反应中, 催化剂1a均能以较高产率及较好的对映选择性得到加成产物(Entries 1~12).其中在对2-氯硝基苯乙烯的加成反应中, 产物ee值达到了94% (Entry 2);催化剂1a对杂环及稠环硝基烯烃参与的加成反应也具有中等的对映选择性, 其加成产物ee值分别为85% (Entry 13)、89% (Entry 14).同时我们也考察了催化剂对脂肪族硝基烯烃加成反应的选择性, 其加成产物ee值为91% (Entry 15), 说明催化剂1a对亲电底物具有较强的适用性.

  表 3

  

  表 3  1a催化2, 4-戊二酮对取代硝基烯烃的加成反应^a

  Table 3.  Addition of 2, 4-pentandione to nitroalkenes catalyzed by 1a

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  Entry	R	Product	Yieldb/%	eec/%	Config.d
  1	Ph	7a	94	92	R
  2	2-FC6H4	7b	91	94	R
  3	4-FC6H4	7c	89	80	R
  4	2-BrC6H4	7d	95	90	R
  5	2, 4-Cl2C6H4	7e	86	88	R
  6	4-ClC6H4	7f	93	91	R
  7	4-MeOC6H4	7g	92	89	R
  8	3-MeOC6H4	7h	90	93	R
  9	2-MeOC6H4	7i	95	92	R
  10	4-MeC6H4	7j	92	84	R
  11	2-O2NC6H4	7k	92	91	R
  12	4-BnOC6H4	7l	89	91	R
  13	2-Furyl	7m	95	85	S
  14	1-Naphthyl	7n	94	90	R
  15	i-Bu	7o	96	90	S
  a Reaction condition: 5 (0.2 mmol), 6a (0.4 mmol), 1a (1 mol%), toluene (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC. d The configuration was determined by comparing optical rotation data and HPLC retention times with literatures.

  接下来, 我们对亲核底物的适用性进行了拓展.如表 4所示, 当亲核底物两个羰基均为酯基时(Entry 1), 催化反应进行较慢, 反应完全需要48 h, 其对映选择性相比二酮有所下降, ee值为80%;当亲核底物为不对称二羰基时(Entries 2~3), 催化反应均进行的非常迅速, 4 h即反应完全, 其中亲核底物为乙酰乙酸甲酯时, 反应立体选择性较差(Entry 2), 两个非对映异构体比例相当; 而当亲核底物为环戊酮乙酸甲酯时, 反应具有较好的立体选择性和对映选择性(Entry 3, dr 4.7:1, 88% ee); 当亲核底物为芳基二酮时, 其对映选择性略低于戊二酮, ee值为89% (Entry 4), 说明催化剂1a对二羰基底物具有较强的适用性.

  表 4

  

  表 4  1a催化1, 3-二羰基化合物对硝基苯乙烯的加成反应^a

  Table 4.  Addition of various 1, 3-dicarbonyl compounds to nitrostyrene catalyzed by 1a

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  Entry	Nucleophile	Product	Time/h	Yieldb/%	drc	eed/%
  1		7p	48	92	—	81
  2		7q	4	95	1:1	79, 80
  3		7r	4	96	4.7:1	88, 84
  4		7s	16	96	—	89
  5		7t	12	97	1.5:1	86, 84
  a Reaction condition: 5a (0.2 mmol), 6a (0.4 mmol), catalysts (1~10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC.

  Michael加成产物可以进一步转化为有价值的活性化合物或中间体^{[6b, 13]}, 因此我们对1a催化的加成产物7a和7b进行了转化.如Scheme 2所示, 加成产物与水合肼反应得到相应的吡唑类转化产物8a和8b, 与盐酸羟胺反应得到相应的异噁唑类转化产物9a和9b, 产率在93%~97%之间.

  图式 2

  

  图式 2.  加成产物7的转化

  Scheme 2.  Transformations of adduct 7 to heterocycles

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  双功能硫脲催化剂在催化1, 3-二羰基化合物对硝基烯烃加成反应时, 往往需要硫脲与叔胺基团协同作用, 即硫脲部分通过氢键与硝基结合, 叔胺部分通过去质子化作用对1, 3-二羰基化合物烯醇式进行活化^[14].然而本文所设计的催化剂1f虽然也具有叔胺基团, 但却没有起到任何催化作用, 相反, 有效的催化剂1a~1d在吡咯烷部分均具有酰胺基团, 由此可以初步推断, 催化剂 1a~1d可能是通过酰胺键上的氧原子对1, 3-二羰基化合物烯醇式进行活化而产生催化作用(图 3).另外, 化合物1g~1h并没有表现出催化活性, 这可能是环己二胺部分酰胺键优先与1, 3-二羰基化合物进行结合, 难以形成有效的反应过渡态, 从而影响催化剂的活性.

  图 3

  

  图 3.  双活化催化反应模式

  Figure 3.  Proposed catalytic reaction mode through double activation

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  2.   结论

  设计合成了一类新的硫脲-酰胺手性催化剂, 并将该催化剂应用于1, 3-二羰基化合物对硝基烯烃的不对称Michael加成反应中, 在催化剂用量为1 mol%情况下, 获得了较高的产率及中等到优异的对映选择性.初步的构效关系研究表明, 吡咯烷N-酰基在催化反应中起着重要作用.

  3.   实验部分

  3.1   仪器与试剂

  Waters高效液相色谱仪(1525泵、2489紫外-可见检测器); 上海申光SGWzz-1旋光仪; Bruker AVANCE Ⅲ 600核磁共振波谱仪; Thermo LTQ XL质谱仪; AB Sciex TripleTOF 6600高分辨质谱仪.

  3, 5-双(三氟甲基)苯基异硫氰酸酯、(1R, 2R)-环己二胺、取代硝基烯烃、1, 3-二羰基化合物、取代脯氨醇及取代脯氨酸均购自百灵威(北京)科技有限公司; 其它试剂均购自国药集团化学试剂有限公司.

  3.2   实验方法

  3.2.1   1-((1R, 2R)-2-氨基环己基)-3-(3, 5-二取代)苯基)硫脲(2)的合成

  (1R, 2R)-环己二胺(0.74 g, 6.5 mmol)溶于无水CH₂Cl₂ (30 mL)中, 冷至0 ℃, 加入3, 5-双(三氟甲基)苯基异硫氰酸酯(1.35 g, 5 mmol), 0 ℃继续搅拌4 h, 蒸除溶剂, 残留物进行硅胶柱层析, V(CH₂Cl₂)/V(MeOH)＝30/1~10/1洗脱, 得到淡黄色固体1.45 g, 产率75%. m.p. 72~74 ℃ (Lit.^[15] 71~73 ℃); ¹H NMR (600 MHz, DMSO-d₆) δ: 8.27 (s, 2H), 7.72 (s, 1H), 4.04 (br s, 1H), 2.72 (br s, 1H), 2.07 (br s, 1H), 1.88 (br s, 1H), 1.65 (s, 2H), 1.22 (br s, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 180.5, 142.5, 130.2 (q, J＝32.7), 123.4 (q, J＝272.8), 122.5, 121.9, 115.9, 58.6, 53.7, 33.2, 30.7, 24.4, 24.2; MS-ESI m/z: 386 [M+H]⁺.

  3.2.2   化合物3a~3b的合成

  N-乙酰基脯氨醇(Prolinol) (214 mg, 1.5 mmol)溶于CH₂Cl₂中, 冷至0 ℃, 加入Dess-Martin试剂(0.95 g, 2.2 mmol), 该温度下搅拌20 min后加入5 mL饱和NaHCO₃溶液及2 mL饱和Na₂S₂O₃溶液, 水相用CH₂Cl₂萃取三次, 合并有机相, 无水Na₂SO₄干燥蒸除溶剂, 残留物进行硅胶柱层析, EtOAc洗脱, 得到无色油状物3a 160 mg, 产率76%.

  N-乙酰基脯氨醛(3a)^[16]: ¹H NMR (600 MHz, CDCl₃) rotamers (5:1), major rotamer δ: 9.57 (d, J＝2.0 Hz, 1H), 4.46 (dd, J＝7.0, 5.1 Hz, 1H), 3.64~3.60 (m, 1H), 3.56~3.52 (m, 1H), 2.14 (s, 4H), 2.09~1.89 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) major rotamer δ: 199.4, 169.9, 64.7, 47.9, 26.2, 25.0, 22.2; MS-ESI m/z: 142 [M+H]⁺.

  N-丙酰基脯氨醛(3b):无色油状物, 产率73%. ¹H NMR (600 MHz, CDCl₃) rotamers (5:1) δ: 9.56 (d, J＝1.9 Hz, 1H, minor), 9.54 (d, J＝1.8 Hz, 1H, major), 4.46~3.4.44 (m, 1H, major), 4.30~4.28 (m, 1H, minor), 2.42~2.34 (m, 2H, major and minor), 2.06~1.96 (m, 4H, major and minor), 1.18 (t, J＝7.4 Hz, 3H, major), 1.14 (t, J＝7.3 Hz, 3H, minor); ¹³C NMR (150 MHz, CDCl₃) major rotamer δ: 199.3, 173.0, 64.5, 46.8, 27.4, 25.8, 24.7, 8.5; HR- MS-ESI calcd for C₈H₄NO₂ [M+H]⁺ 156.1019, found 156.1018.

  3.2.3   化合物3c~3d的合成

  N-苯甲酰脯氨醇(410 mg, 2 mmol)溶于CH₂Cl₂中, 依次加入TEMPO (31 mg, 0.2 mmol)、PhI(OAc)₂ (708 mg, 2.2 mmol), 室温反应10 h, 然后加入1 mL饱和Na₂S₂O₃溶液, 水相用CH₂Cl₂萃取三次, 合并有机相, 无水Na₂SO₄干燥蒸除溶剂, 残留物进行硅胶柱层析, V(石油醚)/V(EtOAc)＝2/1洗脱, 得到无色油状物3c^[17] 360 mg, 产率88%.

  N-苯甲酰脯氨醛(3c)^[17]: ¹H NMR (600 MHz, CDCl₃) rotamers (6:1), major rotamer δ: 9.69 (d, J＝1.0 Hz, 1H), 7.59 (d, J＝6.9 Hz, 2H), 7.50~7.39 (m, 3H), 4.67 (t, J＝6.8 Hz, 1H), 3.66~3.62 (m, 1H), 3.60~3.56 (m, 1H), 2.43~1.73 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) major rotamer δ: 199.4, 170.2, 135.7, 130.5, 128.4, 127.4, 65.1, 50.2, 26.3, 25.5; MS-ESI m/z: 204 [M+H]⁺.

  N-叔丁基羰基脯氨醛(3d)^[16]:无色油状物300 mg, 产率75%. ¹H NMR (600 MHz, CDCl₃) rotamers (1.8:1), major rotamer δ: 9.46 (d, J＝3.0, 1 H), 4.08~4.02 (m, 1H), 3.43~3.52 (m, 2H), 1.86~2.16 (m, 6H), 1.43 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) major rotamer δ: 200.6, 154.0, 80.7, 65.0, 46.7, 28.3, 28.0, 24.0; MS-ESI m/z: 200 [M+H]⁺.

  3.2.4   (S)-2-(溴甲基)-1-甲基吡咯烷(4)的合成

  N-甲基-脯氨醇(500 mg, 4.3 mmol)溶于CH₂Cl₂中, 加入三苯基膦(1.8 g, 6.5 mmol)、四溴化碳(1.7 g, 5.2 mmol), 室温反应4 h, 蒸除溶剂, 残留物进行硅胶柱层析, V(石油醚)/V(EtOAc)＝4/1洗脱, 得到无色油状物650 mg, 产率86%. ¹H NMR (600 MHz, CDCl₃) δ: 4.16 (m, 1H), 3.05 (m, 1H), 2.68 (m, 1H), 2.37 (m, 1H), 2.31 (s, 3H), 2.20~2.14 (m, 2H), 1.83~1.81 (m, 1H), 1.73~1.68 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 63.9, 55.0, 47.7, 46.0, 34.8, 25.5; MS-ESI m/z: 178 [M+H]⁺.

  3.2.5   化合物1a~1d的合成

  化合物3 (1 mmol)及化合物2 (322 g, 0.9 mmol)溶于10 mL无水CH₂Cl₂中, 完全溶解后蒸除溶剂, N₂保护下r.t.放置12 h.残留物以甲醇溶解, 加入NaBH₄ (40 mg, 1 mmol)搅拌10 min, 蒸除甲醇, 加入水溶解, EtOAc萃取3次, 无水Na₂SO₄干燥, 蒸除溶剂, 残留物进行硅胶柱层析, V(CH₂Cl₂)/V(CH₃OH/)＝100/1~40/1洗脱.

  1-((1R, 2R)-2-((((S)-1-乙酰吡咯烷)-2-甲基)氨基)环己基)-3-(3, 5-双(三氟甲基)苯基)硫脲(1a):白色粉末, 产率73%. m.p. 79~81 ℃; [α]_D²⁰-26.1 (c 1.0, CHCl₃); ¹H NMR (600 MHz, DMSO-d₆+CD₃COOD) rotamers (2:1) δ: 8.40 (s, 2H, major and minor), 7.69 (s, 1H, minor), 7.68 (s, 1H, major), 4.49~4.48 (m, 1H, major), 4.41 (br s, 1H, minor), 4.15~4.14 (m, 1H, major), 4.09~4.05 (m, 1H, minor), 3.45~2.94 (m, 5H, major and minor), 2.09~1.69 (m, 11H, major and minor), 1.42~1.26 (m, 4H, major and minor); ¹³C NMR (150 MHz, DMSO-d₆-CD₃COOD) major rotamer δ: 181.1, 171.9, 142.9, 130.2 (q, J＝32.6 Hz), 123.6 (q, J＝272.6 Hz), 122.3, 115.9, 60.0, 55.2, 54.3, 49.5, 48.3, 31.2, 29.3, 27.2, 24.2, 23.8, 23.7, 22.5. IR (KBr) ν: 3313, 2937, 1612, 1388, 1270, 1181, 1138, 969, 885, 681 cm^-1; HR-MS-ESI calcd for C₂₂H₂₉F₆N₄OS [M+H]⁺ 511.1961, found 511.1965.

  1-((1R, 2R)-2-((((S)-1-丙酰基酰吡咯烷)-2-甲基)氨基)环己基)-3-(3, 5-双(三氟甲基)苯基)硫脲(1b):白色粉末, 产率80%. m.p. 99~100 ℃; [α]_D²⁰-2.4 (c 0.8, CH₂Cl₂); ¹H NMR (600 MHz, DMSO-d₆+CD₃COOD) rotamers (9:1) δ: 8.41 (s, 2H, major), 8.35 (s, 2H, minor), 7.68 (s, 1H, major and minor), 4.50 (br s, 1H, minor), 4.43 (br s, 1H, major), 4.17 (br s, 1H, minor), 4.08 (br s, 1H, major), 3.44~2.95 (m, 5H, major and minor), 2.23~1.70 (m, 10H, major and minor), 1.42~1.26 (m, 4H, major and minor), 0.95 (s, 3H, minor), 0.81 (s, 3H, major); ¹³C NMR (150 MHz, DMSO-d₆-CD₃COOD) major rotamer δ: 181.1, 175.0, 142.9, 130.3 (q, J＝32.6 Hz), 123.8 (q, J＝272.5 Hz), 122.2, 116.1, 60.3, 55.5, 54.5, 50.0, 47.5, 31.3, 29.4, 27.5, 27.2, 24.3, 23.9, 23.84, 8.6; IR (KBr) ν: 3278, 2938, 1615, 1386, 1270, 1178, 1133, 969, 885, 681 cm^-1; HR- MS-ESI calcd for C₂₃H₃₁F₆N₄OS [M+H]⁺ 525.2117, found 525.2118.

  1-((1R, 2R)-2-((((S)-1-苯甲酰基吡咯烷)-2-甲基)氨基)环己基)-3-(3, 5-双(三氟甲基)苯基)硫脲(1c): 白色粉末, 产率83%. m.p. 103~105 ℃; [α]_D²⁰-3.8 (c 1.08, CH₂Cl₂); ¹H NMR (600 MHz, DMSO-d₆+CD₃COOD) δ: 8.26 (s, 2H), 7.61 (s, 1H), 7.45~7.26 (m, 5H), 4.51 (br s, 1H), 4.28 (br s, 1H), 3.45~3.36 (m, 3H), 3.18~3.16 (m, 2H), 2.16 (br s, 2H), 1.87~1.27 (m, 10H); ¹³C NMR (150 MHz, DMSO-d₆-CD₃COOD) δ: 181.2, 171.6, 142.6, 136.3, 130.4, 130.3 (q, J＝32.7 Hz), 128.3, 127.4, 123.7 (q, J＝272.6 Hz), 122.4, 116.1, 60.5, 56.1, 54.5, 50.7, 49.8, 31.9, 29.9, 27.2, 24.6, 24.3, 23.8; IR (KBr) ν: 3304, 2935, 1602, 1386, 1270, 1177, 1133, 967, 883, 698 cm^-1; HR-MS-ESI calcd for C₂₇H₃₁F₆N₄OS [M+H]⁺ 573.2117, found 573.2124.

  1-((1R, 2R)-2-((((S)-1-叔丁氧羰基吡咯烷)-2-甲基)氨基)环己基)-3-(3, 5-双(三氟甲基)苯基)硫脲(1d):白色粉末, 产率75%. m.p. 82~83 ℃; [α]_D²⁰+27.9 (c 1.02, CH₂Cl₂); ¹H NMR (600 MHz, DMSO-d₆+CD₃COOD) rotamers (2:1) δ: 8.43 (s, 2H, major), 8.35 (s, 2H, minor), 7.68 (s, 1H, minor), 7.65 (s, 1H, major), 4.42 (br s, 1H, major), 4.32 (br s, 1H, minor), 3.89 (br s, 1H, major), 3.83 (br s, 1H, minor), 3.27~2.95 (m, 5H, major and minor), 2.13~1.70 (m, 8H, major and minor), 1.38~1.26 (m, 13H, major and minor); ¹³C NMR (150 MHz, DMSO-d₆- CD₃COOD) major rotamer δ: 180.6, 155.8, 142.7, 130.2 (q, J＝32.7 Hz), 123.6 (q, J＝272.6 Hz), 121.5, 115.6, 79.8, 59.7, 55.1, 54.5, 49.0, 47.1, 31.1, 29.5, 28.0, 27.2, 24.2, 23.7, 23.4; IR (KBr) ν: 3295, 2936, 1671, 1389, 1270, 1176, 1133, 967, 885, 681 cm^-1; HR-MS-ESI calcd for C₂₅H₃₅F₆N₄O₂S [M+H]⁺ 569.2379, found 569.2384.

  3.2.6   1-((1R, 2R)-2-(((S)-吡咯烷-2-甲基)氨基)环己基)- 3-(3, 5-双(三氟甲基)苯基)硫脲(1e)的合成

  1d (570 mg, 1 mmol)溶于无水CH₂Cl₂ (5 mL)中, 0 ℃下加入三氟乙酸(1.5 mL), 继续反应3 h, 加入饱和NaHCO₃ (5 mL)继续搅拌20 min, 水相用CH₂Cl₂萃取, 合并有机相, 饱和NaCl溶液洗涤3次, 无水Na₂SO₄干燥, 蒸除溶剂, 残留物上硅胶柱层析, V(CH₂Cl₂)/ V(CH₃OH)＝30/1洗脱, 得到白色粉末390 mg, 产率83%. m.p. 82~84 ℃; [α]_D²⁰+4.2 (c 1.16, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 8.28 (s, 2H), 7.54 (s, 1H), 3.85 (br s, 1H), 3.48 (br s, 1H), 3.35~3.31 (m, 1H), 3.17~3.11 (m, 2H), 2.60~2.59 (m, 1H), 2.47 (br s, 2H), 2.07~2.05 (m, 1H), 1.98~1.93 (m, 2H), 1.89~1.83 (m, 1H), 1.76~1.70 (m, 2H), 1.59~1.56 (m, 1H), 1.36~1.29 (m, 1H), 1.24~1.21 (m, 1H), 1.10~1.03 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 180.2, 141.5, 131.4 (q, J＝33.3 Hz), 123.2 (q, J＝272.7 Hz), 122.0, 116.8, 61.1, 60.3, 58.2, 47.9, 44.8, 31.9, 28.0, 24.8, 24.3, 23.5; IR (KBr) ν: 3303, 2938, 1545, 1392, 1277, 1124, 969, 883, 589 cm^-1; HR- MS-ESI calcd for C₂₀H₂₇F₆N₄S [M+H]⁺ 469.1855, found 469.1862.

  3.2.7   1-((1R, 2R)-2-((((S)-1-甲基吡咯烷)-2-甲基)氨基)环己基)-3-(3, 5-双(三氟甲基)苯基)硫脲(1f)的合成

  2 (300 mg, 0.78 mmol)溶于无水DMF(4 mL)中, 依次加入NaHCO₃ (131 mg, 1.56 mmol)、4 (65 mg, 0.94 mmol), 加毕r.t.搅拌12 h.反应液倾入冰水中(60 mL), EtOAc萃取5次, 合并有机相, 无水Na₂SO₄干燥.蒸除溶剂, 残留物进行硅胶柱层析, V(CH₂Cl₂)/V(CH₃OH)＝80/1洗脱, 得到白色粉末210 mg, 产率56%. m.p. 87~88 ℃; [α]_D²⁰+10.6 (c 0.84, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.50 (s, 1H), 4.07~3.95 (m, 2H), 3.39 (dd, J＝13.0, 3.4 Hz, 1H), 3.33~3.22 (m, 1H), 2.89 (s, 3H), 2.84 (ddd, J＝11.1, 9.1, 6.5 Hz, 1H), 2.75 (t, J＝12.3 Hz, 1H), 2.62 (td, J＝11.0, 3.6 Hz, 1H), 2.46 (d, J＝11.6 Hz, 1H), 2.26~2.08 (m, 4H), 1.85~1.71 (m, 2H), 1.41~1.15 (m, 5H); ¹³C NMR (150 MHz, CDCl₃) δ: 180.3, 141.7, 131.3 (q, J＝33.2) Hz), 123.3 (q, J＝272.7 Hz), 121.5, 116.5, 70.3, 61.6, 57.9, 57.5, 49.6, 44.3, 32.8, 32.2, 28.9, 25.0, 24.5, 23.9; IR (KBr) ν: 3255, 3067, 2935, 1547, 1392, 1277, 1176, 1135, 967, 863, 678 cm^-1; HR- MS-ESI calcd for C₂₁H₂₈F₆N₄S [M+H]⁺ 483.2012, found 483.2012.

  3.2.8   化合物1g~1h的合成

  N-取代-L-脯氨酸(0.31 mmol)、二异丙基乙胺(52 mg, 0.4 mmol)、HATU (152 mg, 0.4 mmol)溶于无水CH₂Cl₂中, 0 ℃反应2 h, 然后加入化合物5 (100 mg, 0.26 mmol).该温度下搅拌0.5 h后, 反应液以饱和NaCl溶液洗涤, 无水Na₂SO₄干燥, 蒸除溶剂, 残留物进行硅胶柱层析, V(CH₂Cl₂)/V(CH₃OH)＝100/1洗脱得到1g~1h.

  (S)-1-乙酰基-N-((1R, 2R)-2-(3-(3, 5-双(三氟甲基)苯基)硫脲)环己基)吡咯烷-2-甲酰胺(1g):白色粉末, 产率91%. m.p. 116~118 ℃. [α]_D²⁰+112.2 (c 0.66, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 7.83 (s, 2H), 7.44 (s, 1H), 4.38 (br s, 1H), 4.31 (br s, 1H), 3.80 (br s, 1H), 3.64 (br s, 1H), 3.54 (br s, 1H), 2.12~1.67 (m, 12H), 1.39 (br s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 183.1, 171.7, 170.9, 141.1, 131.1 (q, J＝33.4 Hz), 124.7, 123.1 (q, J＝272.7 Hz), 117.9, 60.8, 57.0, 55.6, 48.6, 32.6, 31.0, 30.0, 24.9, 24.8, 24.5, 22.3; IR (KBr) ν: 3285, 2927, 1636, 1394, 1291, 1116, 969, 874, 681 cm^-1; HR-MS-ESI calcd for C₂₂H₂₇F₆N₄O₂S [M+H]⁺ 525.1753, found 525.1760.

  (S)-1-叔丁基羰基-N-((1R, 2R)-2-(3-(3, 5-双(三氟甲基)苯基)硫脲)环己基)吡咯烷-2-甲酰胺(1h):白色粉末, 产率95%. m.p. 77~78 ℃; [α]_D²⁰+22.7 (c 0.82, CH₂Cl₂); ¹H NMR (600 MHz, DMSO-d₆+CD₃COOD) rotamers δ: 8.23 (s, 2H), 7.72 (s, 1H), 4.25 (br s, 1H), 4.02 (br s, 1H), 3.67 (br s, 1H), 3.44 (br s, 1H), 3.22 (br s, 1H), 2.08~1.39 (m, 8H), 1.39~1.27 (m, 13H); ¹³C NMR (150 MHz, DMSO-d₆-CD₃COOD) major rotamer δ: 180.5, 172.9, 165.1, 153.7, 142.1, 130.6 (q, J＝33.7 Hz), 123.7 (q, J＝272.7 Hz), 122.3, 116.5, 79.0, 60.7, 57.1, 52.9, 47.0, 32.1, 32.0, 31.5, 30.4, 24.7, 24.1, 23.3; IR (KBr) ν: 3307, 2939, 1652, 1543, 1386, 1276, 1176, 1133, 967, 885, 681 cm^-1; HR-MS-ESI calcd for C₂₅H₃₃F₆N₄O₃S [M+H]⁺ 583.2172, found 583.2179.

  3.2.9   化合物7a~7t的合成

  硝基烯烃5 (0.2 mmol)、催化剂1a (0.002 mmol, 1 mol%)、1, 3-二羰基化合物6 (0.4 mmol)溶于甲苯(0.6 mL)中, r.t反应, 反应完毕进行硅胶柱层析石油醚/ EtOAc洗脱, 得到化合物7a~7t.

  (R)-3-(2-硝基-1-苯乙基)-2, 4-戊二酮(7a):产率94%, 92% ee [HPLC: chiralcel AS-H column, V(hexane)/ V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝18.0 min (S), t_major＝29.3 min (R)]. [α]_D²⁰-169.2 (c 0.26, CH₂Cl₂) (Lit.^[18] [α]_D²⁰-159.7 (c 1.0, CHCl₃, 92% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.36~7.27 (m, 3H), 7.21~7.15 (m, 2H), 4.65 (dd, J＝12.4, 8.0 Hz, 1H), 4.61 (dd, J＝12.4, 4.7 Hz, 1H), 4.38 (d, J＝10.8 Hz, 1H), 4.28~4.20 (m, 1H), 2.30 (s, 3H), 1.94 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.8, 201.0, 136.0, 129.4, 128.6, 127.9, 78.2, 70.7, 42.8, 30.4, 29.5.

  (R)-3-(2-硝基-1-(2-氟苯乙基))-2, 4-戊二酮(7b):产率91%, 94% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝95/5, 1 mL/min, 210 nm, t_minor＝14.0 min (S); t_major＝16.5 min (R)]. [α]_D²⁰-177.8 (c 0.22, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+196 (c 0.44, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.33~7.27 (m, 1H), 7.17 (td, J＝7.6, 1.7 Hz, 1H), 7.13~7.05 (m, 1H), 4.77~4.70 (m, 1H), 4.66~4.60 (m, 1H), 4.52~4.46 (m, 1H), 2.30 (s, 2H), 2.02 (s, 2H); ¹³C NMR (151 MHz, CDCl₃) δ: 201.4, 200.7, 161.6, 159.9, 130.5 (dd, J＝8.9, 6.4 Hz), 125.0 (d, J＝3.5 Hz), 122.8 (d, J＝13.3 Hz), 116.3 (d, J＝22.0 Hz), 76.6, 69.1, 37.9, 30.5, 29.2.

  (R)-3-(2-硝基-1-(4-氟苯乙基))-2, 4-戊二酮(7c):产率89%, 80% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝90/10, 1 mL/min, 210 nm, t_minor＝14.4 min (S); t_major＝27.5 min (R)]. [α]_D²⁰-115.2 (c 0.25, CH₂Cl₂) (Lit.^[20] [α]_D²⁰+12.9 (c 1.0, CHCl₃, 81% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.9~7.06 (m, 2H), 7.04~7.02 (m, 2H), 4.60~4.62 (m, 2H), 4.33 (d, J＝10.8 Hz, 1H), 4.27~4.21 (m, 1H), 2.30 (s, 3H), 1.97 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.5, 200.7, 163.3, 161.7, 131.8 (d, J＝3.4 Hz), 129.7 (d, J＝8.2 Hz), 116.4 (d, J＝21.6 Hz), 78.2, 70.7, 42.1, 30.4, 29.6.

  (R)-3-(2-硝基-1-(2-溴苯乙基))-2, 4-戊二酮(7d):产率95%, 90% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝95/5, 1 mL/min, 210 nm, t_minor＝14.9 min (S); t_major＝15.8 min (R)]. [α]_D²⁰-162.0 (c 0.30, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+182 (c 0.29, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.63 (d, J＝8.0 Hz, 1H), 7.29 (t, J＝7.5 Hz, 1H), 7.18 (td, J＝7.8, 1.4 Hz, 1H), 7.14 (dd, J＝7.7, 1.0 Hz, 1H), 4.83 (dd, J＝12.4, 6.4 Hz, 1H), 4.77~4.70 (m, 1H), 4.67 (dd, J＝12.4, 4.1 Hz, 1H), 4.60 (d, J＝9.8 Hz, 1H), 2.30 (s, 3H), 2.05 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 202.0, 200.9, 135.0, 134.1, 130.0, 128.3, 76.3, 69.2, 41.07, 31.0, 28.3.

  (R)-3-(2-硝基-1-(2, 4-二氯苯乙基))-2, 4-戊二酮(7e):产率86%, 88% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝90/10, 0.8 mL/min, 210 nm, t_minor＝12.9 min (S); t_major＝16.3 min (R)]. [α]_D²⁰-131.6 (c 0.31, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+153 (c 0.03, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.46 (d, J＝2.0 Hz, 1H), 7.23 (dd, J＝8.4, 2.0 Hz, 1H), 7.10 (d, J＝8.4 Hz, 1H), 4.83 (dd, J＝12.6, 6.8 Hz, 1H), 4.73~4.66 (m, 1H), 4.64 (dd, J＝12.6, 4.0 Hz, 1H), 4.55 (d, J＝9.9 Hz, 1H), 2.30 (s, 3H), 2.06 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.6, 200.5, 135.1, 134.5, 132.1, 130.5, 128.0, 76.0, 68.9, 38.4, 30.9, 28.6.

  (R)-3-(2-硝基-1-(4-氯苯乙基))-2, 4-戊二酮(7f):产率93%, 91% ee. [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝80/20, 1 mL/min, 210 nm, t_minor＝9.5 min (S); t_major＝23.0 min (R)]. [α]_D²⁰-127.3 (c 0.26, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+144 (c 0.22, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.31 (d, J＝7.2 Hz, 1H), 7.14 (d, J＝7.3 Hz, 1H), 4.62~4.60 (m, 1H), 4.33 (d, J＝10.4 Hz, 1H), 4.24~4.22 (m, 1H), 2.30 (s, 1H), 1.98 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.4, 200.6, 134.0, 134.5, 129.6, 129.3, 77.9, 70.5, 42.1, 30.5, 29.7.

  (R)-3-(2-硝基-1-(4-甲氧基苯乙基))-2, 4-戊二酮(7g):产率92%, 89% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝90/10, 1 mL/min, 210 nm, t_minor＝16.0 min (S); t_major＝24.5 min (R)]. [α]_D²⁰-158.5 (c 0.29, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+149 (c 0.26, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.10 (d, J＝8.5 Hz, 1H), 6.85 (d, J＝8.5 Hz, 1H), 4.61~4.56 (m, 1H), 4.33 (d, J＝10.9 Hz, 1H), 4.25~4.16 (m, 1H), 3.77 (s, 1H), 2.29 (s, 1H), 1.94 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.9, 201.2, 159.5, 129.1, 127.6, 114.7, 78.5, 71.0, 55.3, 42.1, 30.4, 29.5.

  (R)-3-(2-硝基-1-(3-甲氧基苯乙基))-2, 4-戊二酮(7h):产率90%, 93% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝10.1 min (S); t_major＝13.1 min (R)]. [α]_D²⁰-162.7 (c 0.28, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+196 (c 0.28, CH₂Cl₂, 98% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.24 (t, J＝8.0 Hz, 1H), 6.82 (d, J＝8.1 Hz, 1H), 6.76 (d, J＝7.5 Hz, 1H), 6.71 (s, 1H), 4.72~4.55 (m, 2H), 4.37 (d, J＝10.7 Hz, 1H), 4.26~4.17 (m, 1H), 3.78 (s, 3H), 2.30 (s, 3H), 1.97 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 200.8, 200.0, 159.2, 136.6, 129.5, 119.0, 113.2, 112.7, 77.2, 69.7, 54.3, 41.8, 29.6, 28.7.

  (R)-3-(2-硝基-1-(2-甲氧基苯乙基))-2, 4-戊二酮(7i):产率95%, 92% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝97/3, 0.5 mL/min, 210 nm, t_minor＝34.8 min (S); t_major＝37.3 min (R)]. [α]_D²⁰-156.5 (c 0.25, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+185 (c 0.23, CH₂Cl₂, 99% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.30~7.24 (m, 1H), 7.08 (dd, J＝7.7, 1.5 Hz, 1H), 6.91~6.86 (m, 2H), 4.78 (dd, J＝12.2, 8.0 Hz, 1H), 4.62~4.56 (m, 2H), 4.52~4.45 (m, 1H), 3.88 (s, 3H), 2.28 (s, 3H), 1.94 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 202.3, 201.6, 157.0, 130.2, 129.8, 123.5, 121.2, 111.2, 76.6, 69.0, 55.4, 38.9, 30.5, 28.7.

  (R)-3-(2-硝基-1-(4-甲基苯乙基))-2, 4-戊二酮(7j):产率92%, 84% ee [HPLC: AS-H column, V(hexane)/ V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝12.5 min (S); t_major＝20.6 min (R)]. [α]_D²⁰-160.2 (c 0.21, CH₂Cl₂) (Lit.^[6e] [α]_D²⁰-194.1 (c 1.0, CHCl₃, 97% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.13 (d, J＝7.9 Hz, 2H), 7.06 (d, J＝8.1 Hz, 2H), 4.66~4.54 (m, 2H), 4.35 (d, J＝10.9 Hz, 1H), 4.25~4.16 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 1.94 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.4, 200.6, 137.9, 132.3, 129.5, 127.3, 77.9, 70.4, 42.0, 29.9, 28.9, 20.6.

  (R)-3-(2-硝基-1-(2-硝基苯乙基))-2, 4-戊二酮(7k):产率92%, 91% ee [HPLC: OD-H column, V(hexane)/ V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝26.3 min (S); t_major＝31.3 min (R)]. [α]_D²⁰-111.3 (c 0.29, CH₂Cl₂) (Lit.^[6e] [α]_D²⁰-123.1 (c 1.0, CHCl₃, 97% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.59 (td, J＝7.7, 1.3 Hz, 1H), 7.49 (td, J＝8.2, 1.3 Hz, 1H), 7.36 (dd, J＝7.9, 1.1 Hz, 1H), 4.98 (dd, J＝13.3, 7.2 Hz, 1H), 4.84 (dd, J＝13.3, 3.7 Hz, 1H), 4.77~4.71 (m, 1H), 4.68 (d, J＝8.8 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.6, 200.6, 149.8, 133.5, 131.2, 129.4, 129.3, 125.6, 76.6, 69.1, 37.2, 31.3, 29.3..

  (R)-3-(2-硝基-1-(4-苄氧基苯乙基))-2, 4-戊二酮(7l):产率89%, 91% ee [HPLC: AD-H column, V(hexane)/ V(2-propanol)＝70/30, 1 mL/min, 210 nm, t_minor＝10.3 min (S); t_major＝13.6 min (R)]. [α]_D²⁰-124.3 (c 0.35, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+129 (c 0.29, CH₂Cl₂, 92% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.41~7.32 (m, 5H), 7.10 (d, J＝8.7 Hz, 2H), 6.92 (d, J＝8.7 Hz, 2H), 5.01 (s, 2H), 4.63~4.57 (m, 2H), 4.33 (d, J＝10.9 Hz, 1H), 4.23~4.11 (m, 1H), 2.28 (s, 3H), 1.94 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ: 201.87, 201.2, 158.8, 136.6, 129.1, 128.6, 128.1, 127.9, 127.6, 115.6, 78.4, 70.9, 70.1, 42.1, 30.4, 29.5.

  (S)-3-(2-硝基-1-呋喃乙基)-2, 4-戊二酮(7m):产率95%, 85% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝9.5 min (R); t_major＝11.1 min (S)]. [α]_D²⁰-149.7 (c 0.26, CH₂Cl₂) (Lit.^[6e] [α]_D²⁰-162.1 (c 1.0, CHCl₃, 97% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.36 (d, J＝1.1 Hz, 1H), 6.30 (dd, J＝3.2, 1.9 Hz, 1H), 6.18 (d, J＝3.3 Hz, 1H), 4.67 (d, J＝5.7 Hz, 2H), 4.42~4.30 (m, 2H), 2.29 (s, 3H), 2.09 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.5, 200.8, 149.4, 142.9, 110.8, 108.9, 75.8, 67.9, 36.6, 30.6, 29.3.

  (R)-3-(2-硝基-1-(1-萘乙基))-2, 4-戊二酮(7n):产率94%, 90% ee [HPLC: AS-H column, V(hexane)/V(2-propanol)＝80/20, 1 mL/min, 210 nm, t_major＝14.1 min (S); t_minor＝19.2 min (R)]. [α]_D²⁰-162.1 (c 0.37, CH₂Cl₂) (Lit.^[6e] [α]_D²⁰-182.0 (c 1.1, CHCl₃, 95% ee); ¹H NMR (600 MHz, CDCl₃) δ: 8.18 (d, J＝8.4 Hz, 1H), 7.90 (d, J＝8.1 Hz, 1H), 7.81 (d, J＝8.2 Hz, 1H), 7.67~7.62 (m, 1H), 7.55 (t, J＝7.5 Hz, 1H), 7.46~7.39 (m, 1H), 7.27 (d, J＝7.2 Hz, 1H), 4.82 (dd, J＝12.2, 6.6 Hz, 1H), 4.76~4.68 (m, 2H), 2.33 (s, 3H), 1.87 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 202.4, 200.8, 134.3, 131.9, 130.8, 129.5, 129.2, 127.4, 126.4, 125.3, 124.8, 121.9, 77.8, 70.5, 36.3, 31.1, 28.6.

  (S)-3-(1-硝基-2-异戊基)-2, 4-戊二酮(7o):产率96%, 90% ee [HPLC: AD-H column, V(hexane)/V(2-pro-panol)＝99/1, 1 mL/min, 210 nm, t_minor＝13.8 min (R); t_major＝14.3 min (S)]. [α]_D²⁰-127.6 (c 0.38, CH₂Cl₂) (Lit.^[22] [α]_D²⁰-43.0 (c 1.0, CHCl₃, 59% ee); ¹H NMR (600 MHz, CDCl₃) δ: 4.57~4.48 (m, 2H), 4.00 (d, J＝8.5 Hz, 1H), 2.94~2.87 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.77~1.64 (m, 1H), 1.37 (ddd, J＝14.8, 10.3, 4.8 Hz, 1H), 1.00 (ddd, J＝14.1, 9.5, 4.5 Hz, 1H), 0.92 (t, J＝6.4 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ: 202.9, 202.3, 75.7, 69.5, 38.3, 34.8, 31.2, 29.8, 24.9, 23.2, 21.2.

  (R)-2-(2-硝基-1-苯乙基)-丙二酸二甲酯(7p):产率92%, 81% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_major＝12.4 min (R); t_minor＝19.3 min (S)]. [α]_D²⁰+2.9 (c 0.28, CH₂Cl₂) (Lit.^[23] [α]_D²⁰+2.7 (c 0.95, CHCl₃, 98% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.42~7.17 (m, 5H), 4.90 (qd, J＝13.2, 7.0 Hz, 2H), 4.25 (td, J＝9.0, 5.0 Hz, 2H), 3.87 (d, J＝9.1 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.9, 167.2, 136.1, 129.0, 128.4, 127.9, 77.4, 54.7, 53.0, 52.9, 42.9.

  3-(2-硝基-1-苯乙基)-乙酰乙酸甲酯(7q):产率95%, dr＝1:1, 79%, 88% ee [HPLC: AD-H column, V(he-xane)/V(2-propanol)＝95/5, 1 mL/min, 210 nm. First diastereomer: t_major＝15.7 min; t_minor＝21.9 min, ee＝79%. Second diastereomer; t_minor＝22.8 min; t_major＝28.1 min]. First diastereomer: ¹H NMR (600 MHz, CDCl₃) δ: 7.31~7.19 (m, 5H), 4.79~4.75 (m, 2H), 4.22~4.18 (m, 1H), 4.14 (d, J＝9.6 Hz, 1H), 3.53 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 201.2, 167.4, 136.4, 129.0, 128.3, 127.8, 77.7, 61.8, 52.8, 42.3, 30.3. Second diastereomer: ¹H NMR (600 MHz, CDCl₃) δ: 7.31~7.19 (m, 5H), 4.85~4.82 (m, 2H), 4.27~4.22 (m, 1H), 4.05 (d, J＝9.8 Hz, 1H), 3.78 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 200.2, 168.0, 136.3, 129.2, 128.4, 127.9, 77.8, 61.5, 53.0, 42.6, 30.4.

  1-(2-硝基-1-苯乙基)-2-氧代环戊烷羧酸甲酯(7r):产率96%, dr＝4.7:1, 88%, 84% ee [HPLC: OD-H column, V(hexane)/V(2-propanol)＝90/10, 1 mL/min, 210 nm. Major diastereomer: t_minor＝14.8 min; t_major＝23.3 min, ee＝88 %. Minor diastereomer; t_minor＝12.9min; t_major＝18.5 min]. Major diastereomer: ¹H NMR (600 MHz, CDCl₃) δ: 7.32~7.24 (m, 5H), 5.16 (dd, J＝13.7, 3.9 Hz, 1H), 5.01 (dd, J＝13.7, 10.9 Hz, 1H), 4.08 (dd, J＝10.9, 3.9 Hz, 1H), 3.76 (s, 3 H), 2.43~2.29 (m, 2H), 2.08~1.74 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 212.2, 169.8, 135.2, 129.3, 128.9, 128.3, 76.4, 62.5, 53.0, 46.2, 37.9, 31.2, 19.3. Minor diastereomer: ¹H NMR (600 MHz, CDCl₃) δ: 7.32~7.24 (m, 5H), 5.27 (dd, J＝13.5, 11.1 Hz, 1H), 4.83 (dd, J＝13.5, 3.6 Hz, 1H), 4.20 (dd, J＝11.0, 3.6 Hz, 1H), 3.76 (s, 3H), 2.43~2.29 (m, 2H), 2.08~1.74 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 215.4, 171.5, 135.4, 129.1, 129.0, 128.5, 76.9, 62.2, 53.1, 47.3, 39.6, 33.5, 19.6.

  2-(2-硝基-1-(1-苯乙基))-1, 3-二苯基-1, 3-丙二酮(7s):产率96%, 89% ee [HPLC: OD-H column, V(hexane)/ V(2-propanol)＝80/20, 1 mL/min, 254 nm, t_minor＝14.6 min (S); t_major＝23.9 min (R)]. [α]_D²⁰-14.2 (c 0.38, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+17 (c 0.36, CH₂Cl₂, 97% ee); ¹H NMR (600 MHz, CDCl₃) δ: 7.86 (d, J＝8.2 Hz, 2H), 7.78 (d, J＝8.3 Hz, 2H), 7.53 (t, J＝7.4 Hz, 1H), 7.49 (t, J＝7.4 Hz, 1H), 7.38 (t, J＝7.8 Hz, 2H), 7.34 (t, J＝7.8 Hz, 2H), 7.27~7.14 (m, 5H), 5.85 (d, J＝8.0 Hz, 1H), 4.99 (d, J＝7.1 Hz, 2H), 4.63 (dd, J＝14.3, 7.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 193.6, 136.8, 136.2, 135.8, 134.1, 133.8, 129.0, 129.0, 128.9, 128.8, 128.6, 128.3, 128.2, 77.3, 59.8, 44.1.

  (R)-1-苯甲酰基-1-(2-硝基-1-苯乙基)-丙酮(7t):产率97%, dr＝1.5:1, 86%, 84% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝98/2, 1 mL/min, 210 nm). Major diastereomer: t_minor＝44.8 min; t_major＝57.6 min, ee＝86 %. Minor diastereomer; t_minor＝35.4 min; t_major＝51.4 min]. [α]_D²⁰-19.7 (c 0.29, CH₂Cl₂) (Lit.^[19] [α]_D²⁰+22 (c 0.22, CH₂Cl₂, 97% ee); ¹H NMR (600 MHz, CDCl₃) for the major diastereomer δ: 8.02 (dd, J＝8.3, 1.0 Hz, 2H), 7.64 (t, J＝7.4 Hz, 1H), 7.51 (t, J＝7.8 Hz, 2H), 7.36~7.27 (m, 5H), 5.17 (d, J＝10.1 Hz, 1H), 4.72 (dd, J＝12.6, 4.5 Hz, 1H), 4.66 (dd, J＝12.6, 8.6 Hz, 1H), 4.56~4.50 (m, 1H), 1.94 (s, 2H); ¹H NMR (600 MHz, CDCl₃) for the minor diastereomer δ: 7.81 (dd, J＝8.3, 1.0 Hz, 2H), 7.57 (t, J＝6.4 Hz, 1H), 7.43 (t, J＝7.8 Hz, 2H), 7.22~7.14 (m, 5H), 5.19 (d, J＝10.1 Hz, 1H), 4.85 (dd, J＝12.8, 8.6 Hz, 1H), 4.76 (dd, J＝12.8, 4.3 Hz, 1H), 4.43 (ddd, J＝10.0, 8.7, 4.3 Hz, 1H), 2.23 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) for both diastereomer δ: 201.7, 200.8, 194.0, 193.7, 136.5, 136.3, 136.1, 136.0, 134.5, 134.1, 129.3, 129.1, 129.0, 129.0, 129.0, 128.6, 128.2, 128.2, 128.0, 78.2, 78.1, 65.4, 64.8, 43.4, 43.3, 29.8, 28.5.

  3.2.10   化合物8a~8b的合成

  7 (0.37 mmol)、水合肼(21 mg, 0.41 mmol)溶于4 mL甲醇中, 室温反应12 h, 然后用10 mL乙酸乙酯稀释, 饱和NaCl溶液洗涤, 有机相无水Na₂SO₄干燥, 蒸除溶剂得到8a和8b.

  (R)-3, 5-二甲基-4-(2-硝基-1-苯乙基)-吡唑(8a)^[6b]:淡黄色油状物, 产率95%, 91% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 254 nm, t_minor＝11.1 min (S); t_major＝12.7 min (R)]. [α]_D²⁰ -35.3 (c 0.40, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 7.32 (t, J＝7.6 Hz, 2H), 7.28~7.22 (m, 1H), 7.16 (d, J＝7.4 Hz, 1H), 5.10~5.01 (m, 1H), 4.94~4.83 (m, 1H), 2.19 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ: 11.6, 38.7, 78.0, 112.8, 127.1, 127.3, 128.9, 138.5, 142.6; HR-MS-ESI calcd for C₁₃H₁₆- N₃O₂ [M+H]⁺ 246.1237, found 246.1243.

  (R)-3, 5-二甲基-4-(2-硝基-1-(2-氟苯乙基))-吡唑(8b):淡黄色油状物, 产率97%, 94% ee [HPLC: AD-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝9.1 min (S); t_major＝12.1 min (R)]. [α]_D²⁰-71.0 (c 0.41, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 7.30~7.22 (m, 1H), 7.17 (t, J＝7.6 Hz, 1H), 7.11 (t, J＝7.5 Hz, 1H), 7.06 (dd, J＝10.6, 8.3 Hz, 1H), 5.17~5.03 (m, 2H), 4.90 (dd, J＝12.3, 9.3 Hz, 1H), 2.24 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ: 160.6 (d, J＝246.9 Hz), 142.8, 129.3 (d, J＝8.5 Hz), 128.1 (d, J＝3.8 Hz), 125.3 (d, J＝13.8 Hz), 124.3 (d, J＝3.5 Hz), 116.1 (d, J＝22.1 Hz), 111.3, 76.6, 33.5 (d, J＝2.4 Hz), 11.6; HR-MS-ESI calcd for C₁₃H₁₅FN₃O₂ [M+H]⁺ 264.1143, found 264.1135.

  3.2.11   化合物9a~9b的合成

  7 (0.37 mmol)、盐酸羟胺(38 mg, 0.56 mmol)溶于4 mL乙醇中, 60 ℃反应20 h, 然后用10 mL乙酸乙酯稀释, 饱和NaCl溶液洗涤, 有机相无水Na₂SO₄干燥, 蒸除溶剂得到9a和9b.

  (R)-3, 5-二甲基-4-(2-硝基-1-苯乙基)-异噁唑(9a)^{[6b, 13e]}:褐色油状物, 产率93%, 92% ee [HPLC: AS-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 210 nm), t_minor＝24.6 min (S); t_major＝28.2 min (R)]. [α]_D²⁰-71.2 (c 0.41, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 7.36 (t, J＝7.5 Hz, 2H), 7.30 (t, J＝7.3 Hz, 1H), 7.14 (d, J＝7.6 Hz, 2H), 5.03 (dd, J＝12.3, 6.6 Hz, 1H), 4.87 (dd, J＝12.3, 9.8 Hz, 1H), 4.82 (dd, J＝9.7, 6.6 Hz, 1H), 2.38 (s, 3H), 2.13 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 10.9, 11.7, 37.9, 77.3, 111.5, 126.9, 128.0, 129.2, 136.8, 158.9, 166.5; HR-MS-ESI calcd for C₁₃H₁₅N₂O₃ [M+H]⁺ 247.1077, found 247.1080.

  (R)-3, 5-二甲基-4-[2-硝基-1-(2-氟苯乙基)]-异噁唑(9b):褐色油状物, 产率94%, 93% ee [HPLC: AS-H column, V(hexane)/V(2-propanol)＝85/15, 1 mL/min, 210 nm, t_minor＝22.8 min (S); t_major＝24.1 min (R)]. [α]_D²⁰-68.6 (c 0.52, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ: 7.34~7.30 (m, 1H), 7.18~7.14 (m, 2H), 7.10 (dd, J＝10.5, 8.4 Hz, 1H), 5.05~4.99 (m, 2H), 4.91 (dd, J＝11.5, 8.5 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.7, 161.3, 159.3 (d, J＝120.6 Hz), 129.9 (d, J＝8.5 Hz), 127.7 (d, J＝3.5 Hz), 124.6 (d, J＝3.6 Hz), 123.9 (d, J＝13.7 Hz), 116.4 (d, J＝21.8 Hz), 110.23, 75.9 (d, J＝2.1 Hz), 32.67 (d, J＝2.5 Hz), 11.69 (d, J＝1.3 Hz), 10.8; HR-MS-ESI calcd for C₁₃H₁₄FN₂O₃ [M+H]⁺265.0983, found 265.0984.

  辅助材料(Supporting Information)  催化剂的NMR图谱, 加成产物的HPLC谱图、NMR谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载

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  图 1  报道的吡咯烷-硫脲催化剂

  Figure 1  Previous works of pyrrolidine-thiourea organo- catalysts

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  图 2  硫脲-酰胺催化剂

  Figure 2  Structure of thiourea-amide organocatalysts

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  图式 1  催化剂1a~1f合成路线

  Scheme 1  Synthetic routes of 1a~1f

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  图式 2  加成产物7的转化

  Scheme 2  Transformations of adduct 7 to heterocycles

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  图 3  双活化催化反应模式

  Figure 3  Proposed catalytic reaction mode through double activation

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  表 1  催化剂筛选^a

  Table 1.  Screening of catalysts

  Entry	Catalyst	Time/h	Yieldb/%	eec/%	Config.d
  1	1a	3	92	84	R
  2	1b	3	90	85	R
  3	1c	3	93	82	R
  4	1d	3	92	80	R
  5	1e	72	40	0	—
  6	1f	96	Trace	—	—
  7	1g	96	Trace	—	—
  8	1h	96	Trace	—	—
  a Reaction condition: 5a (0.2 mmol), 6 (0.4 mmol), catalyst (10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC. d The configuration was determined by comparing optical rotation data and HPLC retention times with literatures.

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  表 2  反应条件优化^a

  Table 2.  Optimization of reaction conditions

  Entry	Catalyst	Loading/ mol%	T/℃	Solvent	Yieldb/%	eec/%
  1	1a	10	25	CH2Cl2	92	84
  2	1a	10	25	Toluene	94	92
  3	1b	10	25	CH2Cl2	90	85
  4	1b	10	25	Toluene	93	90
  5	1a	10	25	CH3CN	96	53
  6	1a	10	25	THF	21	70
  7	1a	10	25	EtOAc	90	78
  8	1a	10	25	CHCl3	89	79
  9	1a	10	25	Neat	82	68
  10	1a	5	25	Toluene	92	91
  11	1a	1	25	Toluene	92	92
  12	1a	1	0	Toluene	86	90
  13	1a	1	-20	Toluene	85	91
  a Reaction condition: 5a (0.2 mmol), 6a (0.4 mmol), catalysts (1~10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC.

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  表 3  1a催化2, 4-戊二酮对取代硝基烯烃的加成反应^a

  Table 3.  Addition of 2, 4-pentandione to nitroalkenes catalyzed by 1a

  Entry	R	Product	Yieldb/%	eec/%	Config.d
  1	Ph	7a	94	92	R
  2	2-FC6H4	7b	91	94	R
  3	4-FC6H4	7c	89	80	R
  4	2-BrC6H4	7d	95	90	R
  5	2, 4-Cl2C6H4	7e	86	88	R
  6	4-ClC6H4	7f	93	91	R
  7	4-MeOC6H4	7g	92	89	R
  8	3-MeOC6H4	7h	90	93	R
  9	2-MeOC6H4	7i	95	92	R
  10	4-MeC6H4	7j	92	84	R
  11	2-O2NC6H4	7k	92	91	R
  12	4-BnOC6H4	7l	89	91	R
  13	2-Furyl	7m	95	85	S
  14	1-Naphthyl	7n	94	90	R
  15	i-Bu	7o	96	90	S
  a Reaction condition: 5 (0.2 mmol), 6a (0.4 mmol), 1a (1 mol%), toluene (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC. d The configuration was determined by comparing optical rotation data and HPLC retention times with literatures.

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  表 4  1a催化1, 3-二羰基化合物对硝基苯乙烯的加成反应^a

  Table 4.  Addition of various 1, 3-dicarbonyl compounds to nitrostyrene catalyzed by 1a

  Entry	Nucleophile	Product	Time/h	Yieldb/%	drc	eed/%
  1		7p	48	92	—	81
  2		7q	4	95	1:1	79, 80
  3		7r	4	96	4.7:1	88, 84
  4		7s	16	96	—	89
  5		7t	12	97	1.5:1	86, 84
  a Reaction condition: 5a (0.2 mmol), 6a (0.4 mmol), catalysts (1~10 mol%), solvent (0.6 mL). b Isolated yield. c ee was determined by chiral HPLC.

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