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• 天然产物往往具有独特的骨架及多样的药理活性, 是生物活性分子设计的先导化合物来源^[1].萘并吡喃酮骨架广泛存在于天然产物和药物分子中^[2].例如Splito- micin是一种组蛋白脱乙酰酶抑制剂^[3]; 核心骨架为萘并吡喃酮的Cephanolide是一种存在于粗榧杉中的天然产物, 因其具有潜在的抗肿瘤活性而受到学者们的广泛关注^[4]; 萘并吡喃酮衍生物Terretonin L具有抗炎效用; 黄藤内酯(Columbin)是一种多取代的萘并吡喃酮化合物, 由于具有较好的消炎作用而获得广泛应用^[5](图 1).此外一些萘并吡喃酮类化合物还具有镇痛、抗艾滋病病毒(HIV)和抗抑郁等作用, 所以该骨架的构建与修饰一直是有机合成的研究热点之一.

  图 1

  

  图 1.  含有萘并吡喃酮的天然产物或生物活性分子

  Figure 1.  Naphthopyranone-based natural products or biologically relevant compounds

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  对于此类化合物的合成已经有许多报道. 2003年, Cho课题组^[6]报道了利用钯催化3, 5-二溴-2-吡喃酮发生分子内Diels-Alder串联环化(IMDA)反应, 以良好至优异的产率得到萘并吡喃酮衍生物, 为该类化合物的简洁高效合成提供了新策略(Scheme 1a).随后, Chi课题组^[7]报道了在路易斯酸存在下, 由N-杂环卡宾(NHC)促进的邻二烯酮与烯醛的串联环化, 以高区域选择性和立体选择性构建萘并吡喃酮骨架(Scheme 1b). 2011年, Chen课题组^[8]报道了利用二苯基脯氨醇的硅醚在0 ℃下催化α, β-不饱和醛与β-四氢萘酮发生串联环化, 经两步反应成功合成了一系列官能化萘并吡喃酮衍生物, 具有较优异的产率和对映选择性(Scheme 1c).尽管这些方案都可以成功合成目标产物, 但是往往需要用到昂贵的金属催化剂, 此外苛刻的反应条件也限制了反应的进一步应用.因此亟需开发一种成本低廉、操作简洁、条件温和、适用性强且行之有效的方案来获得萘并吡喃酮衍生物.

  图式 1

  

  图式 1.  官能化萘并吡喃酮的合成

  Scheme 1.  Syntheses of functionalized naphthopyranones

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  在有机合成反应中, 利用有机小分子催化实现碳-碳键的构建, 具有举足轻重的意义.代表性的有机小分子催化剂如NHC^[9]、叔膦^[10]、胺^[11]等, 这其中NHC是一类重要的有机小分子催化剂.经过几十年的发展, 研究人员发现NHC可以与底物反应形成多种中间体, 如Breslow中间体、烯醇负离子、高烯醇负离子、烯基烯醇负离子和α, β-不饱和酰基唑离子等^[12].其中α, β-不饱和酰基唑离子是一类重要的有机合成中间体, 可以由α, β-不饱和醛^[13]、酸^[14]、酯^[15]、酰卤^[16]、溴代烯醛^[17]等底物转化而成.由于该中间体具有成键高效性, 可以作为C3合成子参与稠环类化合物的串联合成.例如, Hui课题组^[18]和Chi课题组^[19]将NHC催化形成的该中间体用于串联环化, 以良好的收率构建了官能化的吡咯并[3, 2-c]喹啉和四氢喹啉, 具有优异的非对映选择性和对映选择性(Schemes 2a~2c). 2017年, Xu课题组^[20]报道了一个高效的NHC催化的“sulfa-Michael加成- Michael加成-分子内酯化”串联反应策略, 合成了一系列硫代色满衍生物.该策略具有原子经济性高, 反应条件温和, 产率较高等优点, 并且具有优异的非对映选择性和对映选择性(Scheme 2d).

  图式 2

  

  图式 2.  NHC的串联催化反应

  Scheme 2.  NHC-catalyzed cascade reaction

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  鉴于萘并吡喃酮衍生物在医药以及农业领域的重要性, 在课题组之前的NHC催化杂环串联构建的研究基础上, 我们设计利用NHC催化α-溴代烯醛经过a³-d³极性反转、脱溴, 形成的α, β-不饱和酰基唑离子中间体作为C3合成子, 与一分子硝基取代的邻甲基查尔酮经过“Michael加成-Michael加成-内酯化”的串联过程, 合成官能化的萘并吡喃酮衍生物(Scheme 1d).

  1.   结果与讨论

  1.1   反应条件的优化

  以硝基取代的邻甲基查尔酮(1a)和α-溴代肉桂醛(2a)合成官能化萘并吡喃酮(3a)作为模板反应, 对反应的最佳条件进行筛选(表 1).首先, 在二氯乙烷(DCE)作溶剂, K₂CO₃作碱的条件下对催化剂进行筛选, 结果发现咪唑盐A和B均可以催化该反应, 产率分别为65%和37%(表 1, Entries 1, 2).当使用三唑盐C1, C2, C3时, 未检测到产物点.接着, 以DCE为溶剂, 以咪唑盐A为催化剂, 对反应体系的碱进行筛选, 结果发现相较于Cs₂CO₃, NaOAc, t-BuOK和1, 4-二氮杂二环[2.2.2]辛烷(DABCO), K₂CO₃作碱时反应产率更高(表 1, Entry 1).随后, 以咪唑盐A为催化剂, K₂CO₃作碱对溶剂进行筛选, 确定最佳溶剂为二氯甲烷(DCM) (表 1, Entry 13).最后, 对温度进行筛选, 发现在0 ℃下反应产率最高.综上, 最终确定该反应最佳反应条件为咪唑盐A为催化剂前体, K₂CO₃为碱, 在DCM溶液中置于0 ℃中反应(表 1, Entry 16).

  表 1

  

  表 1  合成多官能化萘并吡喃酮的反应条件优化^a

  Table 1.  Reaction optimization for the synthesis of multi- functionalized naphthopyranone

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  Entry	Cat.	Solvent	Base	Yieldb/%	dr c/%
  1	A	DCE	K2CO3	65	56:44
  2	B	DCE	K2CO3	37	53:47
  3	C1	DCE	K2CO3	N.D	—
  4	C2	DCE	K2CO3	N.D	—
  5	C3	DCE	K2CO3	N.D	—
  6	A	DCE	Cs2CO3	54	51:49
  7	A	DCE	NaOAc	46	55:45
  8	A	DCE	t-BuOK	43	53:47
  9	A	DCE	DABCO	Trace	—
  10	A	THF	K2CO3	Trace	—
  11	A	ACN	K2CO3	36	65:35
  12	A	Toluene	K2CO3	Trace	—
  13	A	DCM	K2CO3	76	72:28
  14d	A	DCM	K2CO3	82	69:31
  15e	A	DCM	K2CO3	87	59:41
  16f	A	DCM	K2CO3	94	80:20
  a All reactions were performed in a 10 mL Schleck tube on a 0.15 mmol scale with 1a(46.8 mg, 0.15 mmol, 1.0 equiv.), 2a (38.0 mg, 0.18 mmol, 1.2 equiv.), cat. (0.03 mmol, 20 mol%) and base (0.30 mmol, 2.0 equiv.) in an anhydrous solvent (2.0 mL) at 25 ℃ under N2. b Isolated yields based on 1a. DABCO＝triethylenediamine; N.D.＝not determined. c Diastereomeric ratio was determined by 1H NMR analysis of the crude product. d Reaction was performed at 15 ℃. e Reaction was performed at 5 ℃. f Reaction was performed at 0 ℃.

  随后, 对该方法的适用范围进行了探究.首先尝试改变α-溴代烯醛苯环上的取代基, 发现当其苯环的邻位、间位和对位上分别连有吸电子取代基(4-Cl, 4-F, 2-Br, 3-Cl)时, 该反应能够顺利进行, 并以优异的产率给出相应的稠环化合物(表 2, Entries 2~5).接着对不饱和溴代醛苯环上连有供电子基团时的反应进行了尝试, 结果显示当苯环上连有甲基、甲氧基时, 反应效果良好(表 2, Entries 6, 7).随后尝试改变查尔酮衍生物苯环上的取代基.结果显示, 其苯环上不管是连有吸电子基还是供电子基(4-Cl, 4-Me, 4-Br, 4-MeO), 该方法仍然适用, 并以优异的产率和非对应选择性(3h, 93:7)得到目标产物(表 2, Entries 8~13).此外当将R²基团换成甲基时, 该反应仍能以中等产率得到目标产物(表 2, Entry 14).这些结果显示, 该方法具有广泛的底物范围.

  表 2

  

  表 2  NHC催化下多取代官能化萘并吡喃酮的合成^a

  Table 2.  NHC-catalyzed syntheses of multi-functionalized naphthopyranones

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  Entry	R1	R2	Product	Yieldb/%	drc/%
  1	Ph	Ph	3a	94	80:20
  2	Ph	4-ClC6H4	3b	92	81:19
  3	Ph	4-FC6H4	3c	87	80:20
  4	Ph	2-BrC6H4	3d	75	90:10
  5	Ph	3-ClC6H4	3e	68	85:15
  6	Ph	3-MeC6H4	3f	85	78:22
  7	Ph	4-MeOC6H4	3g	87	66:34
  8	4-ClC6H4	Ph	3h	89	93:7
  9	4-BrC6H4	Ph	3i	91	91:9
  10	4-MeOC6H4	Ph	3j	86	81:19
  11	3-MeC6H4	4-MeC6H4	3k	78	75:25
  12	4-ClC6H4	4-ClC6H4	3l	70	95:5
  13	4-MeOC6H4	4-MeOC6H4	3m	85	76:24
  14	Ph	Me	3n	52	73:27
  a All reactions were performed in a 10 mL Schleck tube on a 0.15 mmol scale with 1(0.15 mmol, 1.0 equiv.), 2 (0.18 mmol, 1.2 equiv.), A (10.2 mg, 0.03 mmol, 20 mol%) and K2CO3 (41.4 mg, 0.30 mmol, 2.0 equiv.) in DCM (2.0 mL) at 0 ℃ under N2. b Isolated yields. c Diastereomeric ratio was determined by 1H NMR analysis of the crude product.

  此外, 为了验证这一方法的实用性, 以化合物3a的合成为例, 进行了1 mmol的放大量实验.结果显示该反应仍然能顺利进行, 并以90%的产率得到目标产物(Scheme 3), 证实该体系在放大量时反应效果可以保持, 具有较好的实用性.

  图式 3

  

  图式 3.  1 mmol规模合成

  Scheme 3.  Reaction on 1 mmol scale

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  所有产物均经过NMR、IR和HRMS的表征.根据产物的结构推测了反应的可能机理(图 2).首先在碱的作用下, 催化剂前体A脱去质子, 形成带有孤对电子的NHC.其孤对电子进攻α-溴代烯醛2生成Breslow中间体, 经电子转移发生a³-d³极性反转, 脱去溴离子互变异构形成α, β-不饱和酰基唑离子I.紧接着, 邻甲基查尔酮1在碱作用下失去质子形成碳负离子中间体II, 进攻作为Michael受体的中间体I的β位碳原子, 进行第一次Michael加成.后续经电子转移和环化过程给出中间体III.接着进行第二次Michael加成反应, 生成中间体IV.最后经过分子内酯化, 脱去NHC得到最终产物3, 完成催化循环.

  图 2

  

  图 2.  可能的反应机理

  Figure 2.  Possible mechanism

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  2.   结论

  NHC和α-溴代烯醛形成的α, β-不饱和酰基唑离子可以作为C3合成子, 与硝基取代的邻甲基查尔酮经过“Michael加成-Michael加成-内酯化”等串联过程, 在温和条件下一步构建萘并吡喃酮骨架, 具有操作简便, 产率高等优点, 为该类稠环化合物的合成提供了新途径.

  3.   实验部分

  3.1   仪器与试剂

  所需溶剂均已做无水处理.柱层析所用石油醚需蒸馏并收集60~90 ℃馏分, 使用100~200目硅胶.核磁共振仪: ¹H NMR Bruker DPX, 测试频率400 MHz, ¹³C NMR Bruker DPX, 测试频率100 MHz, 并以CDCl₃或DMSO-d₆为溶剂, 以四甲基硅烷(TMS)为内标. HRMS谱由micr- OTOF-QII高分辨质谱仪测定, 熔点测定使用XT-5型显微熔点测定仪, 温度计未经校正.溶剂及其他实验药品在安耐吉、北京伊诺凯科技有限公司、网化商城等公司购买.

  取干燥的10 mL Schlenk反应管作反应器, 加入查尔酮衍生物1 (0.15 mmol), α-溴烯醛2 (0.18 mmol), 咪唑催化剂前体A (0.03 mmol, 10.2 mg), K₂CO₃ (0.30 mmol, 41.4 mg)的混合物, 通入氮气置换空气, 随后使用注射器将2.0 mL干燥DCM注入Schlenk管.将反应体系置于0 ℃, 搅拌反应.利用薄层色谱(TLC)跟踪, 监测到反应结束后, 用旋转蒸发仪除去溶剂, 采用柱层析提纯产物[洗脱剂: V(石油醚):V(乙酸乙酯)＝10:1], 得到黄色固体3a~3n.

  7, 9-二硝基-2, 5-二苯基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并-4-酮(3a):黄色固体62.2 mg, 产率94%. m.p. 56~57 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.69 (d, J＝2.3 Hz, 1H), 8.63 (d, J＝2.3 Hz, 1H), 8.04 (d, J＝7.7 Hz, 2H), 7.56 (q, J＝7.8, 7.4 Hz, 5H), 7.45~7.32 (m, 3H), 7.24 (s, 1H), 5.66 (dd, J＝7.9, 3.6 Hz, 1H), 4.60 (t, J＝6.8 Hz, 1H), 4.01~3.82 (m, 2H), 3.26 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 197.30, 149.31, 146.21, 142.57, 137.26, 136.23, 134.95, 133.85, 129.97, 129.36, 129.35, 129.17, 128.78, 128.75, 124.74, 124.49, 118.56, 77.10, 73.86, 44.68, 31.77; IR (KBr) v: 1684.3, 1554.0, 1345.3, 1102.8, 754.5, 691.6 cm^－1; HRMS (APCI) calcd for C₂₅H₁₉N₂O₆ [M+H]⁺ 443.1243, found 443.1242.

  5-(4-氯苯基)-7, 9-二硝基-2-苯基-4a, 5, 6, 10b-四氢- 4H-苯并[f]异苯并-4-酮(3b):黄色固体65.7 mg, 产率92%. m.p. 67~68 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.69 (s, 1H), 8.62 (s, 1H), 8.04 (d, J＝6.5 Hz, 1H), 7.68~ 7.50 (m, 6H), 7.45 (d, J＝8.3 Hz, 2H), 7.22 (s, 1H), 5.73~ 5.61 (m, 1H), 4.58 (t, J＝6.7 Hz, 1H), 3.98~3.78 (m, 2H), 3.32 (d, J＝6.1 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 196.86, 148.89, 145.82, 142.16, 136.87, 135.78, 133.45, 133.02, 130.74, 128.81, 128.77, 128.44, 128.38, 128.35, 125.22, 124.11, 118.16, 76.68, 73.50, 44.31, 31.34; IR (KBr) v: 1712.6, 1617.2, 1400.8, 1224.9, 1146.5, 849.3, 670.5 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈ClN₂O₆[M+H]⁺ 477.0853, found 477.0832.

  5-(4-氟苯基)-7, 9-二硝基-2-苯基甲基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3c):黄色固体60.0 mg, 产率87%. m.p. 66~67 ℃; ¹H NMR (400 MHz, DMSO- d₆) δ: 8.70 (d, J＝2.2 Hz, 1H), 8.64 (dd, J＝8.7, 2.3 Hz, 1H), 8.11~8.00 (m, 2H), 7.64 (td, J＝5.6, 2.4 Hz, 3H), 7.54 (t, J＝7.6 Hz, 2H), 7.28~7.19 (m, 3H), 5.70~5.62 (m, 1H), 4.59 (dd, J＝7.5, 5.9 Hz, 1H), 4.09~3.75 (m, 2H), 3.33 (d, J＝6.8 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 197.23, 162.18 (J＝246.5 Hz), 149.27, 146.19, 142.55, 137.24, 136.20, 133.81, 131.56 (J＝8.4 Hz), 131.37 (J＝3.4 Hz), 129.14, 128.93, 128.72, 125.42, 124.48, 118.52, 115.71 (J＝24.1 Hz), 77.10, 73.86, 44.71, 31.75; IR (KBr) v: 1706.5, 1616.3, 1463.9, 1146.6, 1019.1, 783.1, 668.5 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈FN₂O₆ [M+H]⁺ 461.1149, found 461.1144.

  5-(2-溴苯基)-7, 9-二硝基-2-苯基甲基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3d):黄色固体58.6 mg, 产率75%. m.p. 65~66 ℃; ¹H NMR (400 MHz, DMSO- d₆) δ: 8.64 (d, J＝2.2 Hz, 1H), 8.58 (d, J＝2.3 Hz, 1H), 8.04~7.96 (m, 2H), 7.63~7.56 (m, 2H), 7.54~7.44 (m, 3H), 7.36 (t, J＝7.6 Hz, 1H), 7.23 (td, J＝7.7, 1.8 Hz, 1H), 7.13 (s, 1H), 5.63 (dd, J＝8.1, 3.5 Hz, 1H), 4.62 (dd, J＝10.4, 3.0 Hz, 1H), 4.00~3.71 (m, 2H), 3.26~3.20 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 197.31, 149.28, 146.24, 142.58, 137.25, 136.04, 135.85, 133.84, 132.84, 131.25, 130.57, 129.26, 129.21, 129.17, 128.75, 128.06, 127.95, 124.50, 123.22, 118.61, 76.22, 73.91, 44.62, 31.88; IR (KBr) v: 1683.3, 1596.5, 1523.4, 1084.5, 754.3, 689.1 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈BrN₂O₆[M+H]⁺ 521.0348, found 521.0349.

  5-(3-氯苯基)-7, 9-二硝基-2-苯基-4a, 5, 6, 10b-四氢- 4H-苯并[f]异苯并-4-酮(3e):黄色固体48.5 mg, 产率68%. m.p. 71~72 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.64 (d, J＝2.3 Hz, 1H), 8.60 (s, 1H), 8.13 (d, J＝6.5 Hz, 1H), 7.70~7.49 (m, 6H), 7.43 (d, J＝8.1 Hz, 2H), 7.20 (s, 1H), 5.69~5.57 (m, 1H), 4.49 (t, J＝6.6 Hz, 1H), 3.97~ 3.78 (m, 2H), 3.34 (d, J＝6.0 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 196.86, 148.70, 145.79, 142.15, 136.87, 135.76, 133.45, 129.96, 130.70, 128.81, 128.78, 128.45, 128.38, 128.35, 125.22, 124.10, 116.50, 75.68, 73.50, 44.31, 31.24; IR (KBr) v: 1636.2, 1534.5, 1490.0, 1402.8, 1345.6, 1084.8, 749.8, 689.2 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈ClN₂O₆[M+H]⁺ 477.0853, found 477.0841.

  7, 9-二硝基-2-苯基-5-(间甲苯基)-4a, 5, 6, 10b-四氢- 4H-苯并[f]异色烯-4-酮(3f):黄色固体58.2 mg, 产率85%. m.p. 63~64 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.74 (t, J＝3.2 Hz, 1H), 8.33 (d, J＝2.3 Hz, 1H), 8.06~8.01 (m, 2H), 7.66~7.57 (m, 1H), 7.54~7.48 (m, 2H), 7.36 (d, J＝8.8 Hz, 1H), 7.29 (s, 1H), 7.14 (t, J＝6.4 Hz, 1H), 7.02 (s, 1H), 5.72 (t, J＝5.6 Hz, 1H), 4.39 (t, J＝6.8 Hz, 1H), 3.85 (dd, J＝16.6, 6.6 Hz, 1H), 3.55 (dd, J＝16.5, 4.6 Hz, 1H), 3.51~3.43 (m, 2H), 2.34 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.56, 149.32, 146.11, 142.35, 137.81, 136.73, 136.50, 134.51, 133.82, 129.88, 129.27, 129.22, 128.83, 128.51, 128.07, 126.11, 123.50, 122.49, 118.58, 77.89, 74.23, 44.95, 32.27, 21.43; IR (KBr) v: 1635.9, 1540.3, 1339.7, 1084.3, 668.8 cm^－1; HRMS (APCI) calcd for C₂₆H₂₁N₂O₆ [M+H]⁺ 457.1399, found 457.1387.

  5-(4-甲氧基苯基)-7, 9-二硝基-2-苯基甲基- 4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3g):黄色固体61.6 mg, 产率87%. m.p. 87~88 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (d, J＝2.2 Hz, 1H), 8.61 (dd, J＝9.6, 2.3 Hz, 1H), 8.07~8.04 (m, 2H), 7.66 (dt, J＝7.4, 1.7 Hz, 2H), 7.31~7.23 (m, 4H), 7.19 (t, J＝7.1 Hz, 2H), 5.65 (d, J＝6.5 Hz, 1H), 4.58 (t, J＝6.8 Hz, 1H), 3.98 (d, J＝3.4 Hz, 2H), 3.33 (d, J＝6.6 Hz, 1H), 2.32 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 197.32, 149.30, 146.20, 142.56, 137.91, 137.27, 137.11, 136.25, 133.84, 133.67, 130.00, 129.87, 129.18, 129.11, 128.77, 128.66, 128.40, 126.37, 124.51, 77.09, 73.90, 44.65, 36.26, 31.80, 21.42; IR (KBr) v: 1684.2, 1605.1, 1534.5, 1509.9, 1345.7, 1251.9, 1179.0, 755.2, 689.9 cm^－1; HRMS (APCI) calcd for C₂₆H₂₁N₂O₇[M+H]⁺ 473.1349, found: 473.1721.

  2-(4-氯苯基)-7, 9-二硝基-2-苯基甲基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3h):黄色固体63.6 mg, 产率89%. m.p. 78~79 ℃; ¹H NMR (400 MHz, DMSO- d₆) δ: 8.69 (d, J＝2.2 Hz, 1H), 8.62 (d, J＝2.3 Hz, 1H), 8.03 (d, J＝8.3 Hz, 2H), 7.64~7.52 (m, 4H), 7.37 (dt, J＝14.2, 7.2 Hz, 3H), 7.21 (s, 1H), 5.64 (dd, J＝7.6, 3.5 Hz, 1H), 4.58 (t, J＝6.7 Hz, 1H), 4.02~3.71 (m, 2H), 3.33 (t, J＝8.6 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 196.42, 149.28, 146.18, 142.39, 138.80, 136.25, 135.94, 134.90, 130.70, 129.91, 129.34, 129.26, 128.91, 128.76, 124.63, 124.53, 118.59, 77.11, 73.89, 44.68, 31.78; IR (KBr) v: 1683.6, 1648.7, 1539.9, 1346.3, 1084.9, 827.4 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈ClN₂O₆[M+H]⁺ 477.0853, found 477.0837.

  2-(4-溴苯基)-7, 9-二硝基-2-苯基甲基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3i):黄色固体71.0 mg, 产率91%. m.p. 82~83 ℃; ¹H NMR (400 MHz, DMSO- d₆) δ: 8.70 (d, J＝2.2 Hz, 1H), 8.63 (d, J＝2.3 Hz, 1H), 7.99 (d, J＝8.3 Hz, 2H), 7.75 (d, J＝8.1 Hz, 2H), 7.57 (d, J＝7.5 Hz, 2H), 7.45~7.31 (m, 3H), 7.20 (s, 1H), 5.65 (dd, J＝7.8, 3.5 Hz, 1H), 4.59 (dd, J＝7.9, 5.5 Hz, 1H), 4.02~3.70 (m, 2H), 3.32 (d, J＝7.0 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 196.66, 149.28, 146.19, 142.37, 136.27, 136.24, 134.89, 132.28, 132.22, 130.81, 129.88, 129.35, 128.92, 128.78, 128.02, 124.62, 124.54, 118.60, 77.09, 73.90, 44.64, 31.78; IR (KBr) v: 1683.6, 1596.1, 1534.0, 1344.8, 1091.2, 752.2, 687.3 cm^－1; HRMS (APCI) calcd for C₂₅H₁₈BrN₂O₆[M+H]⁺ 521.0348, found 521.0339.

  2-(4-甲氧基苯基)-7, 9-二硝基-2-苯基甲基- 4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3j):黄色固体60.7 mg, 产率86%. m.p. 60~61 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.71 (d, J＝2.2 Hz, 1H), 8.59 (d, J＝2.3 Hz, 1H), 8.04 (d, J＝8.9 Hz, 2H), 7.57 (d, J＝7.3 Hz, 2H), 7.47~7.32 (m, 3H), 7.22 (s, 1H), 7.05 (d, J＝9.0 Hz, 2H), 5.62 (dd, J＝7.7, 3.7 Hz, 1H), 4.59 (dd, J＝8.0, 5.4 Hz, 1H), 3.90~3.72 (m, 5H), 3.33 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 195.64, 163.75, 149.30, 146.18, 142.69, 136.21, 134.93, 131.17, 130.27, 129.88, 129.35, 128.92, 128.78, 124.73, 124.46, 118.53, 114.39, 114.33, 77.08, 74.03, 56.03, 44.27, 31.80; IR (KBr) v: 1688.5, 1540.6, 1457.6, 1083.0, 805.8, 755.0, 690.4 cm^－1; HRMS (APCI) calcd for C₂₆H₂₁N₂O₇ [M+H]⁺ 473.1349, found 473.1732.

  7, 9-二硝基-2-(间甲苯基)-5-(对甲苯基)-4a, 5, 6, 10b-四氢-4H-苯并[f]异色烯-4-酮(3k):黄色固体55.0 mg, 产率78%. m.p. 70~71 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.74 (d, J＝2.3 Hz, 1H), 8.60 (d, J＝2.3 Hz, 1H), 8.05 (d, J＝7.7 Hz, 2H), 7.55 (q, J＝7.8, 7.4 Hz, 4H), 7.46~7.30 (m, 2H), 7.26 (s, 1H), 5.64 (dd, J＝7.9, 3.6 Hz, 1H), 4.58 (t, J＝6.8 Hz, 1H), 4.00~3.81 (m, 2H), 3.23 (s, 1H), 2.55 (s, 3H), 2.43 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 197.30, 149.31, 146.21, 142.56, 137.26, 136.23, 134.94, 133.85, 129.98, 129.36, 129.35, 129.17, 128.78, 128.75, 124.74, 124.49, 118.56, 77.10, 73.86, 44.68, 31.77, 28.41, 24.76; IR (KBr) v: 1685.2, 1636.3, 1537.7, 1398.1, 1084.1, 734.2, 686.9 cm^－1; HRMS (APCI) calcd for C₂₇H₂₃N₂O₆ [M+H]⁺ 471.1556, found 471.1543.

  2, 5-双(4-氯苯基)-7, 9-二硝基-4a, 5, 6, 10b-四氢-4H-苯并[f]异色烯-4-酮(3l):黄色固体53.4 mg, 产率70%. m.p. 99~100 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.71 (d, J＝2.3 Hz, 1H), 8.64 (d, J＝2.3 Hz, 1H), 8.06 (d, J＝8.4 Hz, 2H), 7.60 (dd, J＝8.5, 3.6 Hz, 4H), 7.46 (d, J＝8.5 Hz, 2H), 7.21 (s, 1H), 5.64 (dd, J＝7.8, 3.4 Hz, 1H), 4.58 (t, J＝6.7 Hz, 1H), 4.01~3.71 (m, 2H), 3.31 (d, J＝6.8 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 196.37, 149.28, 146.19, 142.36, 138.79, 136.16, 135.91, 133.80, 133.40, 131.12, 130.70, 129.27, 128.86, 128.84, 125.58, 124.53, 118.59, 77.03, 73.84, 44.67, 31.69; IR (KBr) v: 1646.6, 1539.9, 1507.2, 1340.5, 1084.1, 755.8, 693.4 cm^－1; HRMS (APCI) calcd for C₂₅H₁₇Cl₂N₂O₆[M+H]⁺ 511.0463, found 511.0459.

  2, 5-双(4-甲氧基苯基)-7, 9-二硝基-4a, 5, 6, 10b-四氢- 4H-苯并[f]异色烯-4-酮(3m):黄色固体64.0 mg, 产率85%. m.p. 75~76 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.72 (d, J＝2.3 Hz, 1H), 8.30 (d, J＝2.3 Hz, 1H), 8.00 (d, J＝8.9 Hz, 2H), 7.53 (d, J＝8.8 Hz, 2H), 7.01~6.82 (m, 5H), 5.68 (t, J＝5.6 Hz, 1H), 4.44~4.31 (m, 1H), 3.85 (d, J＝8.3 Hz, 3H), 3.79 (d, J＝1.4 Hz, 3H), 3.53~3.32 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.02, 164.04, 159.61, 149.26, 146.06, 142.56, 136.52, 130.93, 130.75, 130.68, 129.83, 128.67, 126.97, 123.60, 120.70, 118.50, 114.04, 113.94, 113.59, 113.55, 78.05, 74.31, 55.59, 55.30, 44.70, 32.28; IR (KBr) v: 1649.9, 1540.5, 1339.8, 1084.1, 754.2 cm^－1; HRMS (APCI) calcd for C₂₇H₂₃N₂O₆ [M+ H]⁺ 503.1454, found 503.1436.

  5-甲基-7, 9-二硝基-2-苯基甲基-4a, 5, 6, 10b-四氢-4H-苯并[f]异苯并吡喃-4-酮(3n):黄色固体29.7 mg, 产率52%. m.p. 53~54 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.70 (d, J＝2.2 Hz, 1H), 8.65 (d, J＝2.3 Hz, 1H), 7.96 (d, J＝8.3 Hz, 2H), 7.58 (d, J＝7.5 Hz, 2H), 7.32 (s, 1H), 5.67 (dd, J＝7.8, 3.5 Hz, 1H), 4.58 (dd, J＝7.9, 5.5 Hz, 1H), 4.02~3.70 (m, 2H), 3.32 (d, J＝7.0 Hz, 2H), 1.34. (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆)δ: 196.66, 149.28, 146.19, 137.25, 134.90, 132.28, 130.82, 129.88, 128.92, 128.77, 128.02, 124.62, 118.61, 77.09, 73.90, 44.57, 32.78, 20.31; IR (KBr) v: 1717.6, 1607.4, 1214.9, 1015.6, 786.9, 685.5 cm^－1; HRMS (APCI) calcd for C₂₀H₁₇N₂O₆ [M+ H]⁺ 381.1086, found 381.1079.

  辅助材料(Supporting Information)化合物3a~3n的¹H NMR和¹³C 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  含有萘并吡喃酮的天然产物或生物活性分子

  Figure 1  Naphthopyranone-based natural products or biologically relevant compounds

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  图式 1  官能化萘并吡喃酮的合成

  Scheme 1  Syntheses of functionalized naphthopyranones

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  图式 2  NHC的串联催化反应

  Scheme 2  NHC-catalyzed cascade reaction

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  图式 3  1 mmol规模合成

  Scheme 3  Reaction on 1 mmol scale

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  图 2  可能的反应机理

  Figure 2  Possible mechanism

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  表 1  合成多官能化萘并吡喃酮的反应条件优化^a

  Table 1.  Reaction optimization for the synthesis of multi- functionalized naphthopyranone

  Entry	Cat.	Solvent	Base	Yieldb/%	dr c/%
  1	A	DCE	K2CO3	65	56:44
  2	B	DCE	K2CO3	37	53:47
  3	C1	DCE	K2CO3	N.D	—
  4	C2	DCE	K2CO3	N.D	—
  5	C3	DCE	K2CO3	N.D	—
  6	A	DCE	Cs2CO3	54	51:49
  7	A	DCE	NaOAc	46	55:45
  8	A	DCE	t-BuOK	43	53:47
  9	A	DCE	DABCO	Trace	—
  10	A	THF	K2CO3	Trace	—
  11	A	ACN	K2CO3	36	65:35
  12	A	Toluene	K2CO3	Trace	—
  13	A	DCM	K2CO3	76	72:28
  14d	A	DCM	K2CO3	82	69:31
  15e	A	DCM	K2CO3	87	59:41
  16f	A	DCM	K2CO3	94	80:20
  a All reactions were performed in a 10 mL Schleck tube on a 0.15 mmol scale with 1a(46.8 mg, 0.15 mmol, 1.0 equiv.), 2a (38.0 mg, 0.18 mmol, 1.2 equiv.), cat. (0.03 mmol, 20 mol%) and base (0.30 mmol, 2.0 equiv.) in an anhydrous solvent (2.0 mL) at 25 ℃ under N2. b Isolated yields based on 1a. DABCO＝triethylenediamine; N.D.＝not determined. c Diastereomeric ratio was determined by 1H NMR analysis of the crude product. d Reaction was performed at 15 ℃. e Reaction was performed at 5 ℃. f Reaction was performed at 0 ℃.

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  表 2  NHC催化下多取代官能化萘并吡喃酮的合成^a

  Table 2.  NHC-catalyzed syntheses of multi-functionalized naphthopyranones

  Entry	R1	R2	Product	Yieldb/%	drc/%
  1	Ph	Ph	3a	94	80:20
  2	Ph	4-ClC6H4	3b	92	81:19
  3	Ph	4-FC6H4	3c	87	80:20
  4	Ph	2-BrC6H4	3d	75	90:10
  5	Ph	3-ClC6H4	3e	68	85:15
  6	Ph	3-MeC6H4	3f	85	78:22
  7	Ph	4-MeOC6H4	3g	87	66:34
  8	4-ClC6H4	Ph	3h	89	93:7
  9	4-BrC6H4	Ph	3i	91	91:9
  10	4-MeOC6H4	Ph	3j	86	81:19
  11	3-MeC6H4	4-MeC6H4	3k	78	75:25
  12	4-ClC6H4	4-ClC6H4	3l	70	95:5
  13	4-MeOC6H4	4-MeOC6H4	3m	85	76:24
  14	Ph	Me	3n	52	73:27
  a All reactions were performed in a 10 mL Schleck tube on a 0.15 mmol scale with 1(0.15 mmol, 1.0 equiv.), 2 (0.18 mmol, 1.2 equiv.), A (10.2 mg, 0.03 mmol, 20 mol%) and K2CO3 (41.4 mg, 0.30 mmol, 2.0 equiv.) in DCM (2.0 mL) at 0 ℃ under N2. b Isolated yields. c Diastereomeric ratio was determined by 1H NMR analysis of the crude product.

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