光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法

1.本发明属于有机合成技术领域，具体涉及一种光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法。


背景技术：

2.4-吡咯啉-2-酮(也称1,3-二氢吡咯-2-酮或α,β-不饱和γ-内酰胺)衍生物广泛存在于如cyanogramide，violacein，diaporthalasin，sagassumlactam，cespitulactam k，denigrin d和at-2hm-iso-dncc-431等天然生物碱或临床药物分子中。
[0003][0004]
传统上，4-吡咯啉-2-酮可以在ru3(co)
12
催化和高温高压条件下从α,β-不饱和亚胺、co和烯烃合成。2004年，sames课题组开发了[ir(coe)2cl]2催化的2,2-二甲基-1-(吡咯烷-1-基)-3-丁烯酮的氧化环合反应，该反应需要使用4当量降冰片烯和2当量配体，但只合成得到3个4-吡咯啉-2-酮产物(b.deboef,s.j.pastine,d.sames,j.am.chem.soc.2004,126,6556
–
6557)。2017年，吕允贺和张前开发了炔烃和α-二氟溴乙酰胺的铜催化胺化双氟烷基化反应，合成了3,3-二氟-4-吡咯啉-2-酮(y.lv,w.pu,q.chen,q.wang,j.niu,q.zhang,j.org.chem.2017,82,8282-8289.。2020年，novikov课题组通过三唑与重氮酯的rh催化脱氮环化反应实现了3-烷氧基-4-吡咯啉-2-酮合成(a.n.koronatov,n.v.rostovskii,a.f.khlebnikov,m.s.novikov,org.lett.2020,22,7958-7963.)。最近，苏伟平课题组实现了从烷基芳基酮和伯胺出发的3,3-双芳基-4-吡咯啉-2-酮合成，该反应需要使用铜催化剂和3当量2,2,6,6-四甲基哌啶氧化物(tempo)作为氧化剂(r.hu,y.tao,x.zhang,w.su,angew.chem.int.ed.2021,60,8425
–
8430；angew.chem.2021,133,8506
–
8511.)。虽然4-吡咯啉-2-酮衍生物的合成已经取得了一些进展，但以上反应需要激烈的反应条件和昂贵或有毒的过渡金属催化剂。因此，从易得原料出发开发温和、经济、绿色的官能团化4-吡咯啉-2-酮及其衍生物的合成方法仍然十分必要。


技术实现要素：

[0005]
为了解决现有技术中的问题，本发明提供一种光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法。该反应温和、清洁、高效、底物范围广，无需过渡金属催化剂，且可轻易放大到克级规模，同时兼具操作简便、绿色环保等特点。
[0006]
为实现上述目的，本发明的技术方案为：
[0007]
一种光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法，其特征在于，采用如下路线：
[0008][0009]
其中
[0010]
r1为r5为h、一个或多个c
1-6
烷基或环烷基、一个或多个oc
1-6
烷氧基、一个或多个卤素或一个或多个卤素取代的卤代c
1-6
烷基；
[0011]
r2为c
1-6
烷基或环烷基、-ch2ch＝ch2或-ch2c≡ch，其中r6为h或一个或多个卤素；r7为c
1-6
烷基或环烷基、oc
1-6
烷氧基或卤素取代的卤代c
1-6
烷基；r3为h或c
1-6
烷基；r4为h、c
1-6
烷基或cor8，x为卤素；y为氰基、cor8或卤素；r8为oc
1-6
烷氧基、苯基或nr
9 r
10
；r9和r
10
各自独立为c
1-6
烷基。
[0012]
上述方法中，当原料化合物1的r3为h时，制备的产物为化合物3；当原料化合物1的r3为c
1-6
烷基时，制备的产物为化合物4。
[0013]
本文所用的术语“卤素”是指氟、氯、溴或碘。本文所用的术语“c
1-6
烷基或环烷基”是指具有1-6个碳原子的饱和的直链或支链烃基或环烷基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、叔丁基、异丁基、环丙基、环戊基或环己基。本发明所用的术语
“‑
o-c
1-6
烷基”，是指具有1-6个碳原子的饱和的直链或支链烷氧基，例如甲氧基、乙氧基、叔丁氧基等。本文所用术语“卤素取代的c
1-6
烷基”指的是一个或多个卤素取代的具有1-6个碳原子的饱和的直链或支链烃基，比如二氟甲基、三氟甲基等。
[0014]
本文化合物中，r5可以独立的为邻位、间位或对位，可以邻位、间位或/和对位同时取代，也可以单独取代。r6可以独立的为邻位、间位或对位，可以邻位、间位或/和对位同时取代，也可以单独取代。
[0015]
优选的，上述方法中，r1为其中r5为h、4-tbu、4-meo、4-i、4-br、4-cl、4-f、4-cf3、3-br、2-f、3,5-(cf3)2；r2为ipr或cy，其中r6为h、cl、f；r6为t-bu、ome；r3为h，me、et或pr；r4为h，me，cor8；x为br；y为氰基、cor8、卤素；r8为ome或oet。
二氢-1h-吡咯-3-基)丙酸乙酯(3f1),
[0035]
3-(4-(2-乙氧基-2-氧乙基)-1-(4-氟苄基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3f2),
[0036]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-1-异丙基-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3g1),
[0037]
3-(1-环己基-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3g2),
[0038]
3-(1-烯丙基-3,4-二甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4h1),
[0039]
3-(1-烯丙基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4h2),
[0040]
3-(5-(4-氟苯基)-3,4-二甲基-2-氧代-1-(2-丙炔-1-基)-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4i),
[0041]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-1-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3j1),
[0042]
3-(1-(4-叔丁苯基-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3j2),
[0043]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-1-(4-甲氧基苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3j3),
[0044]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸甲酯(4k1),
[0045]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸苯酯(4k2),
[0046]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)-n,n-二甲基丙酰胺(4k3),
[0047]
1-苄基-5-(4-氟苯基)-3,4-二甲基-3-(3-氧代-3-苯基丙基)-1,3-二氢-2h-吡咯-2-酮(4k4),
[0048]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)-2-甲基丙酸甲酯(4l),
[0049]
2-((1-苄基-4-(2-乙氧基-2-氧代-1-丙酰氧基乙基)-3-甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)甲基)丙二酸二乙酯(3m),
[0050]
1-苄基-5-(4-氟苯基)-3,4-二甲基-3-(2,2,2-三氯乙基)-1,3-二氢-2h-吡咯-2-酮(4n)。
[0051]
本发明制备的3,4-双烷基化-4-吡咯啉-2-酮衍生物可以作为原料或中间体合成如cyanogramide，violacein，diaporthalasin，sagassumlactam，cespitulactam k，denigrin d和at-2hm-iso-dncc-431等天然生物碱或临床药物分子；也可作为这些天然生物碱或临床药物分子的杂质对照品。
[0052]
有益效果：
[0053]
本发明提供一种光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法，通过可
见光诱导的n-烯基丙烯酰胺与活化烷基溴的区域选择性串联烯酰胺β-c(sp2)-h烷基化/丙烯酰胺烷基化/烯基化环化反应制备获得3,4-双烷基化-4-吡咯啉-2-酮衍生物。本发明反应条件温和、效率高、底物范围广，并呈现高度的区域选择性，为3,4-双烷基化的4-吡咯啉-2-酮合成提供了便捷方法。
具体实施方式
[0054]
下面通过具体实施例对本发明进行具体描述，在此指出以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术熟练人员可以根据上述发明内容对本发明作出一些非本质的改进和调整。本发明所述原料及试剂均为市售产品。
[0055]
产物合成步骤：
[0056]
4-吡咯啉-2-酮合成一般步骤：
[0057]
氩气气氛下，向装有磁力搅拌子的25ml schlenk反应管中，依次加入n-烯基丙烯酰胺1(0.3mmol)，fac-ir(ppy)(1mol％，0.003mmol，2mg)，na2co3(1.5当量，0.45mmol，48mg)，除氧mecn(3.0ml)和烷基溴2(0.66或0.33mmol)。无氧环境中混合液在室温和蓝光led照射下搅拌2小时。蒸干溶剂，残余物通过硅胶柱层析分离提纯(石油醚-乙酸乙酯)，得到产物4-吡咯啉-2-酮3或4。
[0058]
底物n-烯基丙烯酰胺1合成
[0059]
底物1的按文献方法合成(m.kobayashi,t.suda,k.noguchi,k.tanaka,angew.chem.,int.ed.2011,50,1664
–
1667)
[0060][0061]
甲苯(14ml)的伯胺(13.9mmol)、酮(13.9mmol)和分子筛(4.5g)的混合溶液在120℃反应6h，得到粗亚胺的混合溶液。冷却后，滤除分子筛，再用甲苯(3ml)洗涤。冰水浴冷却下向滤液中加入三乙胺(2当量，27.8mmol)和甲基丙烯酰氯(1.2当量，16.7mmol)，然后自然恢复到室温并继续在室温搅拌12小时。用水(50ml)淬灭反应，并用ch2cl2(25ml
×
4)萃取。蒸干溶剂得到的残余物通过硅胶柱层析分离提纯(石油醚-乙酸乙酯)，得到n-烯基丙烯酰胺1。
[0062]
使用n-苄基-n-(1-苯乙烯基)甲基丙烯酰胺1a和2-溴乙腈2a作为反应原料，ir(ppy)3作为光催化剂(pc)，在2当量na2co3存在下在乙腈溶剂中进行，并同时使用蓝光led进行照射，反应结果如表1所示)。12h后以56％的产率生成双烷基化/环化产物4-吡咯啉-2-酮3a(序号1)。乙腈是最优反应溶剂，其它溶剂中进行的反应结果都不如乙腈溶剂中的反应(序号2-4)。不加入na2co3时，反应体系分解，而其它碱(无论是无机碱还是有机碱)的使用效果都不如na2co3(序号6-8)。使用ir(ppy)3作为光催化剂对该反应至关重要，其它光催化剂(如[ir(dtbbpy)(ppy)2]pf6、ru(bpy)3cl2和eosin y)催化时，双烷基化/环化产物3a都不会生成(序号9-11)。该反应速度快、效率高，仅用蓝光照射2小时并降低na2co3用量到1.5当量，
4-吡咯啉-2-酮3a的产率仍能达到56％(序号12)。
[0063]
表1.反应条件优化
[0064][0065][0066]
[a]
反应条件：1a(0.3mmol),2a(0.66mmol),fac-ir(ppy)3(0.003mmol),na2co3(0.6mmol),ch3cn(3.0ml),6w蓝光led(455nm),ar,室温,12h。
[0067]
参照上述方法，在最优的反应条件下，发明人研究了该反应的适用范围(表2)。溴乙酸乙酯2b与n-乙烯基丙烯酰胺1a反应以65％产率生成3,4-双烷基化的4-吡咯啉-2-酮3b1。对位或间位取代的富电子(3b2-3b3)和贫电子的烯胺1-位芳基基团(3b4和3b9)都能被该反应兼容，生成一系列双烷基化4-吡咯啉-2-酮产物。反应对活化芳基卤(3b4-3b6和3b9)的兼容为进一步的金属催化偶联反应预留了反应位点。该反应可能对空间位阻较为敏感，烯胺1-芳基邻位被氟原子取代的底物参加反应时需要使用2mol％的ir(ppy)3，反应12h后对应双烷基化产物3b10的产率也仅有44％。值得注意的是，α-(吡啶-2-基)烯酰胺底物也可以与2b反应生成对应双烷基化γ-内酰胺3c，产率为57％。二烯底物的烯胺2-位被甲基、乙基或丙基等基团占位时，则生成单烷基化4-吡咯啉-2-酮产物(4d和4e)。对烯胺氮原子上取代基的测试结果表明，氮原子被烷基(3f和3g)或芳基保护(3j1-3j3)的n-乙烯基丙烯酰胺都是高活性底物，都能顺利与溴乙酸乙酯2b发生预期反应生成对应γ-内酰胺。令人意外的是，带有非活化烯基或非活化炔基的二烯和三烯底物也都能被该反应兼容。虽然对应n-烯丙基产物4h1和4h2的产率较低，但对应n-炔丙基产物4i的产率与其它反应相当。这些结果再次表明，该反应有惊人的区域选择性和化学选择性。随后发明人研究了α-活化烷基溴的适用范围，包括溴乙酸甲酯(4k1)，溴乙酸苯酯(4k2)，2-溴-n,n-二甲基乙酰胺(4k3)和α-溴代苯乙酮(4k4)，对应4-吡咯啉-2-酮产物都顺利生成。2-溴丙酸甲酯和2-溴丙二酸二乙酯
都顺利反应生成对应4-吡咯啉-2-酮产物4l和3m。有趣的是，在加强的条件下ccl4也可以作为该环合反应的卤代烃，对应含ccl
3 4-吡咯啉-2-酮4n的产率为55％。
[0068]
表2.底物范围
[a]
[0069]
[0070]
[a]
反应条件：1(0.3mmol),2(0.66mmol),fac-ir(ppy)3(0.003mmol),na2co3(0.45mmol),ch3cn(3.0ml),6w蓝光led(455nm),ar,室温,2h。
[b]
ir(ppy)3(0.006mmol),12h。
[c]
使用1.1当量2。
[0071]
发明人开展了13倍放大实验证明了该反应的工业放大能力(3a)。3-氮杂-1,5-二烯1b7与溴乙酸乙酯2b的4mmol规模反应顺利生成4-吡咯啉-2-酮3b7，产率仅有轻微的下降(63％，1.17g)。随后发明人尝试使用天然太阳光诱导双烯1d1和2b的反应，发现对应4-吡咯啉-2-酮4d1的产率比标准条件下的产率还要高一些(3b)。
[0072][0073]
综上所述，本发明提供的光催化合成3,4-双烷基化-4-吡咯啉-2-酮衍生物的方法，通过可见光诱导的n-烯基丙烯酰胺与活化烷基溴的区域选择性串联烯酰胺β-c(sp2)-h烷基化/丙烯酰胺烷基化/烯基化环化反应制备获得3,4-双烷基化-4-吡咯啉-2-酮衍生物。本发明反应条件温和、效率高、底物范围广，并呈现高度的区域选择性，为3,4-双烷基化的4-吡咯啉-2-酮合成提供了便捷方法。
[0074]
产物光谱表征
[0075][0076]
3-(1-苄基-4-氰甲基-3-甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)丙腈(3a),快速柱层析分离(石油醚/乙酸乙酯＝12:1,v/v),56％产率(60mg),微黄色油状物.rf(石油醚/etoac＝4:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.50
–
7.41(m,3h),7.21
–
7.15(m,5h),6.84
–
6.82(m,2h),4.58(d,j＝15.2hz,1h),4.53(d,j＝15.2hz,1h),3.20(d,j＝18.0hz,1h),3.10(d,j＝18.0hz,1h),2.31
–
2.22(m,2h),2.19
–
2.05(m,2h),1.48(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ180.2,143.9,136.7,130.1,129.3,129.1,128.6,128.0,127.7,127.5,118.9,117.1,109.4,50.6,44.5,31.1,22.3,13.4,12.9.hrms(esi-tof)calcd for c
23h22
n3o
+
([m+h]
+
)356.1757.found 356.1751.
[0077][0078]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b1),快速柱层析分离(石油醚/乙酸乙酯＝20:1,v/v),65％产率(88mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.39
–
7.30(m,3h),7.19
–
7.14(m,5h),6.89
–
6.84(m,2h),4.60(d,j＝15.4hz,1h),4.49(d,j＝15.3hz,1h),4.15
–
4.03(m,4h),2.99(d,j＝16.0hz,1h),2.95(d,j＝16.0hz,1h),2.23
–
2.07(m,3h),1.94(ddd,j＝13.0,10.1,5.4hz,1h),1.31(s,3h),1.24(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.5,173.0,171.2,141.9,137.4,129.8,129.5,129.1,128.4,128.3,127.4,127.1,115.0,61.0,60.4,50.8,44.3,30.9,30.4,29.4,22.1,14.2,14.0.hrms(esi-tof)calcd for c
27h32
no
5+
([m+h]
+
)450.2275.found 450.2271.
[0079][0080]
3-(1-苄基-5-(4-叔丁苯基-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b2),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),53％产率(81mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.34
–
7.31(m,2h),7.17
–
7.13(m,3h),7.12
–
7.09(m,2h),6.87
–
6.84(m,2h),4.59(d,j＝15.3hz,1h),4.49(d,j＝15.3hz,1h),4.15
–
4.03(m,4h),3.02(d,j＝15.9hz,1h),2.96(d,j＝15.9hz,1h),2.23
–
2.06(m,3h),1.93(ddd,j＝13.0,10.5,5.1hz,1h),1.32(s,9h),1.30(s,3h),1.24(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.6,173.1,171.4,152.3,142.0,137.5,129.4,128.2,127.5,127.1,126.4,125.3,114.7,61.0,60.4,50.8,44.3,34.7,31.3,30.9,30.5,29.4,22.1,14.2,14.1.hrms(esi-tof)calcd for c
31h40
no
5+
([m+h]
+
)506.2901.found 506.2903.
[0081][0082]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-5-(4-甲氧基苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b3),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),45％产率(65mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.23
–
7.18(m,3h),7.14
–
7.10(m,2h),6.92(dd,j＝7.1,2.4hz,2h),6.88
–
6.84(m,2h),4.61(d,j＝15.3hz,1h),4.49(d,j＝15.3hz,1h),4.16
–
4.04(m,4h),3.84(s,3h),3.00(d,j＝15.9hz,1h),2.96(d,j＝15.9hz,1h),2.24
–
2.07(m,3h),1.95(ddd,j＝13.0,10.2,5.3hz,
1h),1.31(s,3h),1.25(t,j＝7.0hz,3h),1.24(t,j＝7.0hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.6,173.0,171.4,160.1,141.8,137.6,131.2,128.3,127.4,127.1,121.6,114.8,113.8,61.0,60.4,55.3,50.8,44.3,30.9,30.5,29.4,22.1,14.2,14.1.hrms(esi-tof)calcd for c
28h34
no
6+
([m+h]
+
)480.2381.found 480.2388.
[0083][0084]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-5-(4-碘苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b4),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),57％产率(99mg),无色油状物.rf(石油醚/etoac＝8:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.67
–
7.64(m,2h),7.20
–
7.17(m,3h),6.92
–
6.87(m,4h),4.59(d,j＝15.4hz,1h),4.47(d,j＝15.4hz,1h),4.14
–
4.02(m,4h),2.94(s,2h),2.18
–
2.06(m,3h),2.00
–
1.90(m,1h),1.30(s,3h),1.23(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.9,171.1,141.0,137.6,137.2,131.5,129.0,128.4,127.32,127.31,115.7,95.4,61.1,60.5,50.9,44.4,30.9,30.3,29.4,22.1,14.2,14.1.hrms(esi-tof)calcd for c
27h31
ino
5+
([m+h]
+
)576.1241.found 576.1249.
[0085][0086]
3-(1-苄基-5-(4-氯苯基)-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b5),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),57％产率(91mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.47
–
7.43(m,2h),7.20
–
7.17(m,3h),7.06
–
7.03(m,2h),6.88(dd,j＝6.8,2.7hz,2h),4.60(d,j＝15.4hz,1h),4.47(d,j＝15.4hz,1h),4.14
–
4.02(m,4h),2.94(s,2h),2.23
–
2.07(m,3h),2.01
–
1.91(m,1h),1.30(s,3h),1.24(t,j＝7.2hz,3h),1.21(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.9,171.1,140.9,137.2,131.6,131.4,128.42,128.40,127.3,123.6,115.7,61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0.hrms(esi-tof)calcd for c
27h31
brno
5+
([m+h]
+
)528.1380.found 528.1383.
[0087][0088]
3-(1-苄基-5-(4-氯苯基)-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b6),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),54％产率(81mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.31
–
7.28
(m,2h),7.20
–
7.16(m,3h),7.12
–
7.09(m,2h),6.89
–
6.86(m,2h),4.60(d,j＝15.4hz,1h),4.47(d,j＝15.4hz,1h),4.15
–
4.03(m,4h),2.94(s,2h),2.19
–
2.07(m,3h),1.97
–
1.91(m,1h),1.30(s,3h),1.24(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.9,171.1,140.8,137.2,135.3,131.1,128.7,128.4,127.9,127.32,127.30,115.7,61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0.hrms(esi-tof)calcd for c
27h31
clno
5+
([m+h]
+
)484.1885.found 484.1881.
[0089][0090]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b7),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),70％产率(99mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.18
–
7.12(m,5h),7.03
–
6.97(m,2h),6.86(dd,j＝6.7,2.9hz,2h),4.60(d,j＝15.4hz,1h),4.46(d,j＝15.4hz,1h),4.15
–
4.03(m,4h),2.94(s,2h),2.33
–
2.07(m,3h),2.01
–
1.91(m,1h),1.31(s,3h),1.24(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.9,171.1,163.1(d,j＝249.5hz),141.0,137.3,131.8(d,j＝8.3hz),128.4,127.32,127.26,125.5(d,j＝3.4hz),115.6,115.5(d,j＝21.7hz),61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0.
19
f nmr(376mhz,cdcl3)δ-111.34(ddd,j＝13.7,8.7,5.6hz,1f).hrms(esi-tof)calcd for c
27h31
fno
5+
([m+h]
+
)468.2181.found 468.2182.
[0091][0092]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-5-(4-三氟甲基苯基)-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b8),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),49％产率(76mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.57(d,j＝8.1hz,2h),7.30(d,j＝8.0hz,2h),7.18
–
7.13(m,3h),6.85
–
6.82(m,2h),4.62(d,j＝15.4hz,1h),4.48(d,j＝15.4hz,1h),4.15
–
4.03(m,4h),2.95(s,2h),2.25
–
2.09(m,3h),2.03
–
1.93(m,1h),1.33(s,3h),1.24(t,j＝7.1hz,3h),1.21(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.3,172.8,170.9,140.6,137.0,133.3(q,j＝1.5hz),131.2(q,j＝32.7hz),130.2,128.5,127.4,127.3,125.3(q,j＝3.8hz),123.8(q,j＝272.4hz),116.3,61.2,60.5,51.0,44.4,30.9,30.3,29.4,22.1,14.2,14.0.
19
f nmr(376mhz,cdcl3)δ-62.86(s,3f).hrms(esi-tof)calcd for c
28h31
f3no
5+
([m+h]
+
)518.2149.found 518.2146.
[0093][0094]
3-(1-苄基-5-(3-氯苯基)-4-(2-乙氧基-2-氧乙基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b9),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),54％产率(86mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.50(ddd,j＝8.0,2.0,1.2hz,1h),7.26(dd,j＝1.8,1.8hz,1h),7.21
–
7.17(m,4h),7.11(ddd,j＝7.7,1.4,1.4hz,1h),6.87(dd,j＝6.7,2.9hz,2h),4.59(d,j＝15.4hz,1h),4.48(d,j＝15.3hz,1h),4.15
–
4.03(m,4h),2.95(s,2h),2.19
–
2.08(m,3h),2.02
–
1.92(m,1h),1.31(s,3h),1.24(t,j＝7.2hz,3h),1.22(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.3,172.9,170.9,140.5,137.1,132.7,132.3,131.5,129.9,128.4,127.44,127.36,122.3,116.0,61.1,60.5,51.0,44.4,30.8,30.4,29.4,22.0,14.2,14.1.hrms(esi-tof)calcd for c
27h31
brno
5+
([m+h]
+
)528.1380.found 528.1396.
[0095][0096]
3-(1-苄基-4-(2-乙氧基-2-氧乙基)-5-(2-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3b10),2:3非对映异构体混合物,快速柱层析分离(石油醚/乙酸乙酯＝30:1,v/v),44％产率(62mg),微黄色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.42
–
7.34(stack,1h major and 1h minor),7.14
–
7.00(stack,6h major and 6h minor),6.83
–
6.79(stack,2h major and 2h minor),4.89
–
4.81(stack,1h major and 1h minor),4.25
–
4.17(stack,1h major and 1h minor),4.16
–
3.93(stack,4h major and 4h minor),3.00
–
2.91(stack,2h major and 2h minor),2.25
–
1.88(stack,4h major and 4h minor),1.34(s,3h minor),1.31(s,3h major),1.24(t,j＝7.1hz,3h major and 3h minor),1.18(t,j＝7.1,3h major),1.17(t,j＝7.1,3h minor).
13
c{1h}nmr(101mhz,cdcl3)δ180.89(major),180.86(minor),173.05(major),172.98(minor),170.75(major),170.69(minor),160.0(d,j＝248.3hz,minor),160.1(d,j＝248.8hz,major),137.2(major),137.1(minor),136.2(minor),135.9(major),132.39(d,j＝11.4hz,major),132.36(d,j＝11.3hz,minor),131.52(d,j＝8.0hz,minor),131.46(d,j＝8.0hz,major),128.3(major),128.2(minor),127.6,127.24(major),127.21(minor),127.1,124.18(d,j＝2.7hz),124.15(d,j＝3.3hz),117.6(d,j＝15.8hz,minor),117.5(d,j＝16.0hz,major),117.25(minor),117.19(major),115.7(d,j＝21.3hz,minor),115.6(d,j＝21.3hz,major),61.03(minor),60.96(major),60.42(major),60.35(minor),51.2(major),51.1(minor),44.3(d,j＝2.0hz,minor),44.1(d,j＝1.8hz,major),30.84(minor),30.75(major),30.4(minor),30.3(major),29.4(minor),29.1(major),22.2(minor),21.9(major),14.2(major and minor),14.0(major),13.9(minor).
19
f nmr
3-基)丙酸乙酯(4d2),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),64％产率(98mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.83(s,1h),7.39(s,2h),7.19
–
7.12(m,3h),6.77(dd,j＝7.4,2.2hz,2h),4.65(d,j＝15.5hz,1h),4.41(d,j＝15.6hz,1h),4.18
–
4.06(m,2h),2.33
–
2.07(m,3h),2.05
–
1.94(m,1h),1.60(s,3h),1.35(s,3h),1.26(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.5,172.8,136.8,134.6,132.7,131.8(q,j＝33.7hz),129.9(q,j＝3.9hz),128.6,127.6,127.2,122.9(q,j＝273.0hz),122.4(hept,j＝3.8hz),121.6,60.6,51.1,44.5,30.6,29.7,22.0,14.2,8.8.
19
f nmr(376mhz,cdcl3)δ-62.96(s,6f).hrms(esi-tof)calcd for c
26h26
f6no
3+
([m+h]
+
)514.1811.found 514.1808.
[0103][0104]
3-(1-苄基-4-乙基-3-甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4e1),快速柱层析分离(石油醚/乙酸乙酯＝50:1,v/v),73％产率(86mg),微黄色油状物.rf(石油醚/etoac＝10:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.38
–
7.29(m,3h),7.16
–
7.13(m,3h),7.07
–
7.04(m,2h),6.85
–
6.81(m,2h),4.56(d,j＝15.2hz,1h),4.42(d,j＝15.2hz,1h),4.16
–
4.04(m,2h),2.20
–
1.93(m,6h),1.35(s,3h),1.25(t,j＝7.1hz,3h),0.92(t,j＝7.6hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.6,173.1,138.2,137.7,130.6,129.9,128.7,128.3,128.2,127.6,127.0,124.1,60.4,51.2,44.1,31.2,29.6,22.9,17.5,15.1,14.2.hrms(esi-tof)calcd for c
25h30
no
3+
([m+h]
+
)392.2220.found 392.2222.
[0105][0106]
3-(1-苄基-3-甲基-2-氧代-5-苯基-4-丙基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4e2),快速柱层析分离(石油醚/乙酸乙酯＝50:1,v/v),77％产率(93mg),无色油状物.rf(石油醚/etoac＝10:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.38
–
7.29(m,3h),7.16
–
7.13(m,3h),7.05
–
7.02(m,2h),6.85
–
6.80(m,2h),4.55(d,j＝15.2hz,1h),4.42(d,j＝15.2hz,1h),4.11(qd,j＝7.1,5.2hz,2h),2.19
–
1.88(m,6h),1.41
–
1.23(m,8h),0.75(t,j＝7.3hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.6,173.1,138.5,137.7,130.7,129.9,128.6,128.3,128.2,127.5,127.0,122.7,60.4,51.1,44.1,31.2,29.6,26.8,23.5,22.8,14.5,14.2.hrms(esi-tof)calcd for c
26h32
no
3+
([m+h]
+
)406.2377.found 406.2376.
[0107][0108]
3-(1-(4-氯苄基)-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3f1),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),
51％产率(76mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.19
–
7.14(m,4h),7.07
–
7.01(m,2h),6.80(d,j＝8.5hz,2h),4.55(d,j＝15.4hz,1h),4.44(d,j＝15.4hz,1h),4.08(dtd,j＝14.2,7.1,3.8hz,4h),2.94(s,2h),2.23
–
2.04(m,3h),2.00
–
1.89(m,1h),1.29(s,3h),1.24(t,j＝7.1hz,3h),1.22(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.8,171.1,163.1(d,j＝249.9hz),140.6,135.8,133.2,131.7(d,j＝8.4hz),128.8,128.6,125.3(d,j＝3.6hz),115.8,115.7(d,j＝21.6hz),61.1,60.5,50.9,43.6,30.8,30.2,29.4,22.0,14.2,14.0.
19
f nmr(376mhz,cdcl3)δ-62.96(s,1f).hrms(esi-tof)calcd for c
27h30
clfno
5+
([m+h]
+
)502.1791.found 502.1799.
[0109][0110]
3-(4-(2-乙氧基-2-氧乙基)-1-(4-氟苄基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3f2),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),64％产率(94mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.16(ddd,j＝8.3,5.3,2.5hz,2h),7.07
–
7.01(m,2h),6.90
–
6.80(m,4h),4.55(d,j＝15.3hz,1h),4.45(d,j＝15.3hz,1h),4.14
–
4.02(m,4h),2.94(s,2h),2.19
–
2.04(m,3h),2.00
–
1.89(m,1h),1.29(s,3h),1.24(t,j＝7.1hz,3h),1.22(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,172.8,171.1,163.1(d,j＝249.8hz),162.0(d,j＝245.8hz),140.7,133.1(d,j＝3.3hz),131.7(d,j＝8.3hz),129.2(d,j＝8.2hz),125.5(d,j＝3.5hz),115.8,115.6(d,j＝21.7hz),115.3(d,j＝21.6hz),61.1,60.5,50.9,43.6,30.9,30.3,29.4,22.0,14.2,14.0.
19
f nmr(376mhz,cdcl3)δ-111.03(ddd,j＝13.8,8.7,5.5hz,1f),-115.00(p,j＝8.1,7.7hz,1f).hrms(esi-tof)calcd for c
27h30
f2no
5+
([m+h]
+
)486.2087.found 486.2093.
[0111][0112]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-1-异丙基-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3g1),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),63％产率(79mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.39
–
7.34(m,2h),7.14(dd,j＝8.7,8.7hz,2h),4.12
–
4.04(m,4h),3.63(hept,j＝6.9hz,1h),2.88(s,2h),2.17
–
2.13(m,2h),2.03(ddd,j＝13.6,9.4,6.8hz,1h),1.92
–
1.85(m,1h),1.32(s,3h),1.30(s,3h),1.26
–
1.21(m,9h).
13
c{1h}nmr(101mhz,cdcl3)δ181.5,173.0,171.3,163.1(d,j＝249.6hz),141.8,131.8(d,j＝8.3hz),126.3(d,j＝3.5hz),115.8(d,j＝21.6hz),115.2,61.0,60.4,50.9,46.3,31.0,30.6,29.3,21.9,20.2,20.1,14.2,14.1.
19
f nmr(376mhz,cdcl3)δ-111.36(ddd,j＝13.8,8.7,5.5hz,1f).hrms(esi-tof)calcd for c
23h31
fno
5+
([m+h]
+
)420.2181.found 420.2190.
[0113][0114]
3-(1-环己基-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3g2),快速柱层析分离(石油醚/乙酸乙酯＝40:1,v/v),65％产率(89mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.37
–
7.32(m,2h),7.17
–
7.11(m,2h),4.12
–
4.04(m,4h),3.15(tt,j＝12.1,3.8hz,1h),2.87(s,2h),2.16
–
2.08(m,3h),2.02(ddd,j＝13.6,9.6,6.8hz,1h),1.91
–
1.84(m,1h),1.73
–
1.50(m,6h),1.26
–
1.21(m,9h),1.10
–
0.97(m,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.5,173.0,171.3,163.1(d,j＝249.3hz),142.0,131.7(d,j＝8.5hz),126.4(d,j＝3.5hz),115.8(d,j＝21.5hz),115.1,61.0,60.4,54.6,50.9,31.0,30.6,29.9,29.8,29.3,26.03,26.01,25.0,21.9,14.2,14.1.
19
f nmr(376mhz,cdcl3)δ-111.36(tt,j＝9.2,5.5hz,1f).hrms(esi-tof)calcd for c
26h35
fno
5+
([m+h]
+
)460.2494.found 460.2493.
[0115][0116]
3-(1-烯丙基-3,4-二甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4h1),快速柱层析分离(石油醚/乙酸乙酯＝50:1,v/v),34％产率(33mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.44
–
7.37(m,3h),7.28
–
7.24(m,2h),5.60(ddt,j＝17.2,10.5,5.3hz,1h),4.99(dq,j＝10.3,1.5hz,1h),4.86(dq,j＝17.2,1.6hz,1h),4.10(qd,j＝7.2,2.6hz,2h),4.00
–
3.89(m,2h),2.25
–
2.05(m,3h),1.99
–
1.87(m,1h),1.63(s,3h),1.27
–
1.22(m,6h).
13
c{1h}nmr(101mhz,cdcl3)δ181.6,173.1,137.3,133.2,130.3,129.7,128.7,128.4,118.5,116.5,60.5,50.6,42.7,30.6,29.7,21.9,14.2,8.8.hrms(esi-tof)calcd for c
20h26
no
3+
([m+h]
+
)328.1907.found 328.1909.
[0117][0118]
3-(1-烯丙基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4h2),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),37％产率(38mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.28
–
7.22(m,2h),7.14
–
7.08(m,2h),5.61(ddt,j＝17.1,10.4,5.3hz,1h),5.01(dq,j＝10.3,1.4hz,1h),4.86(dq,j＝17.1,1.6hz,1h),4.10(qd,j＝7.1,2.1hz,2h),3.99
–
3.87(m,2h),2.24
–
2.02(m,3h),1.98
–
1.86(m,1h),1.61(s,3h),1.27(s,3h),1.24(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.5,173.0,162.8(d,j＝248.7hz),136.3,133.1,131.6(d,j＝8.2hz),126.2(d,
j＝3.5hz),119.0,116.5,115.5(d,j＝21.6hz),60.5,50.6,42.7,30.6,29.7,21.9,14.2,8.8.
19
f nmr(376mhz,cdcl3)δ-112.12(td,j＝8.6,4.5hz,1f).hrms(esi-tof)calcd for c
20h25
fno
3+
([m+h]
+
)346.1813.found 346.1811.
[0119][0120]
3-(5-(4-氟苯基)-3,4-二甲基-2-氧代-1-(2-丙炔-1-基)-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(4i),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),56％产率(59mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.39
–
7.34(m,2h),7.18
–
7.13(m,2h),4.15
–
4.04(m,3h),4.00(dd,j＝17.6,2.5hz,1h),2.24
–
2.02(m,4h),1.98
–
1.88(m,1h),1.63(s,3h),1.26(s,3h),1.24(t,j＝7.1hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,173.0,162.9(d,j＝249.1hz),135.5,131.7(d,j＝8.3hz),125.7(d,j＝3.4hz),119.4,115.8(d,j＝21.7hz),78.8,71.2,60.5,50.6,30.8,30.2,29.5,21.5,14.2,8.8.
19
f nmr(376mhz,cdcl3)δ-111.77(tt,j＝8.9,5.3hz,1f).hrms(esi-tof)calcd for c
20h23
fno
3+
([m+h]
+
)344.1656.found 344.1654.
[0121][0122]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-1-苯基-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3j1),快速柱层析分离(石油醚/乙酸乙酯＝25:1,v/v),56％产率(77mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.26
–
7.21(m,4h),7.19
–
7.14(m,1h),7.00
–
6.91(m,4h),4.19
–
4.03(m,4h),3.14(d,j＝15.9hz,1h),3.10(d,j＝15.9hz,1h),2.36
–
2.12(m,3h),2.02(ddd,j＝13.7,10.7,5.3hz,1h),1.38(s,3h),1.29(t,j＝7.1hz,3h),1.22(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ180.4,172.8,171.4,162.7(d,j＝249.5hz),140.9,135.0,131.3(d,j＝8.3hz),128.7,126.9,126.8,125.6(d,j＝3.5hz),115.9,115.4(d,j＝21.7hz),61.3,60.5,51.3,31.4,30.7,29.4,22.1,14.2,14.1.
19
f nmr(376mhz,cdcl3)δ-111.55(tt,j＝8.8,5.4hz,1f).hrms(esi-tof)calcd for c
26h29
fno
5+
([m+h]
+
)454.2024.found 454.2029.
[0123][0124]
3-(1-(4-叔丁苯基-4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-3-甲基-2-氧代-2,
3-二氢-1h-吡咯-3-基)丙酸乙酯(3j2),快速柱层析分离(石油醚/乙酸乙酯＝40:1,v/v),50％产率(76mg),微黄色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.26
–
7.22(m,4h),6.97
–
6.92(m,2h),6.91
–
6.87(m,2h),4.19
–
4.03(m,4h),3.14(d,j＝15.9hz,1h),3.09(d,j＝15.8hz,1h),2.35
–
2.11(m,3h),2.00(ddd,j＝13.6,10.8,5.2hz,1h),1.37(s,3h),1.29(t,j＝7.1hz,3h),1.25(s,9h),1.22(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ180.5,172.9,171.5,162.7(d,j＝249.1hz),149.8,141.0,132.2,131.3(d,j＝8.3hz),126.2,125.7(d,j＝3.3hz),125.6,115.7,115.4(d,j＝21.7hz),61.3,60.5,51.2,34.5,31.4,31.3,30.8,29.4,22.1,14.2,14.1.
19
f nmr(376mhz,cdcl3)δ-111.73(ddd,j＝13.8,8.8,5.5hz,1f).hrms(esi-tof)calcd for c
30h37
fno
5+
([m+h]
+
)510.2650.found 510.2635.
[0125][0126]
3-(4-(2-乙氧基-2-氧乙基)-5-(4-氟苯基)-1-(4-甲氧基苯基)-3-甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸乙酯(3j3),快速柱层析分离(石油醚/乙酸乙酯＝30:1,v/v),60％产率(87mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.26
–
7.21(m,2h),6.97
–
6.88(m,4h),6.78
–
6.74(m,2h),4.15(q,j＝7.1hz,2h),4.09(qd,j＝7.1,3.0hz,2h),3.74(s,3h),3.11(d,j＝2.4hz,2h),2.35
–
2.11(m,3h),2.00(ddd,j＝13.7,10.7,5.4hz,1h),1.37(s,3h),1.28(t,j＝7.2hz,3h),1.23(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ180.6,172.9,171.4,162.7(d,j＝249.3hz),158.2,141.1,131.4(d,j＝8.2hz),128.2,127.9,125.6(d,j＝3.5hz),115.5,115.4(d,j＝21.5hz),114.0,61.3,60.5,55.4,51.1,31.4,30.7,29.4,22.0,14.2,14.1.
19
f nmr(376mhz,cdcl3)δ-111.67(dt,j＝8.9,5.1hz,1f).hrms(esi-tof)calcd for c
27h31
fno
6+
([m+h]
+
)484.2130.found 484.2135.
[0127][0128]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸甲酯(4k1),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),63％产率(73mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.18
–
7.14(m,3h),7.00(d,j＝7.0hz,4h),6.85(dd,j＝5.6,4.1hz,2h),4.60(d,j＝15.4hz,1h),4.44(d,j＝15.3hz,1h),3.64(s,3h),2.26
–
2.04(m,3h),1.99
–
1.89(m,1h),1.57(s,3h),1.30(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.7,173.4,162.7(d,j＝248.8hz),137.6,136.3,131.7(d,j＝8.2hz),128.3,127.4,127.2,126.3(d,j＝3.4hz),119.2,115.4(d,j＝21.6hz),51.6,50.7,44.1,
30.6,29.4,21.9,8.7.
19
f nmr(376mhz,cdcl3)δ-112.18(p,j＝6.9hz,1f).hrms(esi-tof)calcd for c
23h25
fno
3+
([m+h]
+
)382.1813.found 382.1812.
[0129][0130]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)丙酸苯酯(4k2),快速柱层析分离(石油醚/乙酸乙酯＝24:1,v/v),64％产率(85mg),无色油状物.rf(石油醚/etoac＝6:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.36(tt,j＝7.9,2.2hz,2h),7.24
–
7.15(m,4h),7.06
–
6.99(m,6h),6.90
–
6.85(m,2h),4.64(d,j＝15.3hz,1h),4.46(d,j＝15.3hz,1h),2.48
–
2.22(m,3h),2.06(ddd,j＝13.5,10.6,5.1hz,1h),1.62(s,3h),1.34(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.8,171.5,162.8(d,j＝249.0hz),150.6,137.5,136.4,131.7(d,j＝8.2hz),129.4,128.4,127.4,127.2,126.2(d,j＝3.6hz),125.8,121.5,119.2,115.5(d,j＝21.6hz),50.7,44.2,30.5,29.7,21.9,8.8.
19
f nmr(376mhz,cdcl3)δ-112.06(p,j＝7.0hz,1f).hrms(esi-tof)calcd for c
28h27
fno
3+
([m+h]
+
)444.1969.found 444.1958.
[0131][0132]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)-n,n-二甲基丙酰胺(4k3),快速柱层析分离(石油醚/乙酸乙酯＝1:1,v/v),50％产率(59mg),浅黄色油状物.rf(石油醚/etoac＝2:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.17
–
7.13(m,3h),7.06
–
7.00(m,4h),6.89
–
6.85(m,2h),4.63(d,j＝15.2hz,1h),4.44(d,j＝15.2hz,1h),2.91(s,3h),2.87(s,3h),2.23
–
1.94(m,4h),1.59(s,3h),1.30(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ182.1,172.3,162.7(d,j＝248.8hz),137.7,135.7,131.7(d,j＝8.2hz),128.3,127.6,127.2,126.4(d,j＝3.5hz),120.0,115.5(d,j＝21.6hz),50.7,44.0,37.2,35.4,31.0,28.4,21.7,8.7.
19
f nmr(376mhz,cdcl3)δ-112.13(p,j＝6.9hz,1f).hrms(esi-tof)calcd for c
24h28
fn2o
2+
([m+h]
+
)395.2129.found 395.2129.
[0133][0134]
1-苄基-5-(4-氟苯基)-3,4-二甲基-3-(3-氧代-3-苯基丙基)-1,3-二氢-2h-吡咯-2-酮(4k4),快速柱层析分离(石油醚/乙酸乙酯＝50:1,v/v),69％产率(89mg),无色油状物.rf(石油醚/etoac＝10:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.80
–
7.78(m,2h),7.58
–
7.53(m,1h),7.44
–
7.40(m,2h),7.23
–
7.16(m,3h),7.04
–
6.99(m,2h),6.97
–
6.90(m,4h),
4.69(d,j＝15.1hz,1h),4.44(d,j＝15.1hz,1h),2.84(ddd,j＝16.9,10.3,5.8hz,1h),2.62(ddd,j＝16.9,9.9,5.4hz,1h),2.15(qdd,j＝13.9,10.0,5.5hz,2h),1.56(s,3h),1.33(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ199.3,182.1,162.7(d,j＝248.8hz),137.8,136.7,136.1,133.0,131.7(d,j＝8.2hz),128.6,128.4,128.0,127.8,127.3,126.3(d,j＝3.6hz),119.7,115.5(d,j＝21.6hz),50.7,44.1,33.5,30.0,21.8,8.7.
19
f nmr(376mhz,cdcl3)δ-112.10(ddd,j＝13.7,8.8,5.6hz,1f).hrms(esi-tof)calcd for c
28h27
fno
2+
([m+h]
+
)428.2020.found 428.2032.
[0135][0136]
3-(1-苄基-5-(4-氟苯基)-3,4-二甲基-2-氧代-2,3-二氢-1h-吡咯-3-基)-2-甲基丙酸甲酯(4l),3:2非对映异构体混合物,快速柱层析分离(石油醚/乙酸乙酯＝40:1,v/v).rf(石油醚/etoac＝5:1,v/v)0.33.主要异构体:32％产率(38mg),无色油状物.1h nmr(400mhz,cdcl3)δ7.17
–
7.14(m,3h),7.03
–
6.97(m,4h),6.87(dd,j＝6.5,3.1hz,2h),4.67(d,j＝15.3hz,1h),4.41(d,j＝15.4hz,1h),3.51(s,3h),2.28(dtd,j＝13.5,6.8,3.2hz,1h),2.19(dd,j＝13.7,9.2hz,1h),1.84(dd,j＝13.7,3.4hz,1h),1.52(s,3h),1.26(s,3h),1.14(d,j＝6.9hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ182.0,176.7,162.6(d,j＝248.6hz),137.5,136.2,131.6(d,j＝8.2hz),128.2,127.4,127.1,126.4(d,j＝3.4hz),119.2,115.3(d,j＝21.5hz),51.6,51.3,44.2,39.6,36.6,22.9,19.6,8.8.
19
f nmr(376mhz,cdcl3)δ-112.38(p,j＝7.2hz,1f).hrms(esi-tof)calcd for c
24h27
fno
3+
([m+h]
+
)396.1969.found 396.1960.次要异构体:23％产率(27mg),无色油状物.1h nmr(400mhz,cdcl3)δ7.16
–
7.13(m,3h),7.04
–
6.97(m,4h),6.85
–
6.81(m,2h),4.76(d,j＝15.4hz,1h),4.22(d,j＝15.4hz,1h),3.67(s,3h),2.47(dtd,j＝13.8,6.9,4.7hz,1h),2.37(dd,j＝14.0,8.2hz,1h),1.61(dd,j＝14.0,4.8hz,1h),1.58(s,3h),1.27(s,3h),1.13(d,j＝7.0hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ181.4,176.6,162.7(d,j＝248.4hz),137.7,136.0,131.6(d,j＝8.3hz),128.2,127.3,127.0,126.5(d,j＝3.4hz),119.6,115.3(d,j＝21.6hz),51.7,50.6,43.9,39.2,36.6,22.9,18.6,9.0.
19
f nmr(376mhz,cdcl3)δ-112.43(p,j＝7.0hz,1f).hrms(esi-tof)calcd for c
24h27
fno
3+
([m+h]
+
)396.1969.found 396.1963.
[0137][0138]
2-((1-苄基-4-(2-乙氧基-2-氧代-1-丙酰氧基乙基)-3-甲基-2-氧代-5-苯基-2,3-二氢-1h-吡咯-3-基)甲基)丙二酸二乙酯(3m),快速柱层析分离(石油醚/乙酸乙酯＝20:1,v/v),73％产率(129mg),无色油状物.rf(石油醚/etoac＝5:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.34
–
7.15(m,5h),7.14
–
7.11(m,3h),6.81
–
6.77(m,2h),4.77(d,j＝15.4hz,1h),
4.26
–
4.03(m,8h),3.70
–
3.54(m,3h),2.50(dd,j＝14.7,9.4hz,1h),2.35(dd,j＝14.7,3.2hz,1h),1.30(t,j＝7.1hz,3h),1.29(s,3h),1.25(t,j＝7.1hz,3h),1.19(t,j＝7.1hz,3h),1.05(t,j＝7.2hz,3h).
13
c{1h}nmr(101mhz,cdcl3)δ179.9,169.4,169.1,167.8,167.3,143.4,137.2,130.3(br),129.2,129.0,128.2,127.8,127.2,127.0,113.3,61.8,61.604,61.597,61.5,50.3,49.0,48.0,43.9,34.1,21.8,14.02,14.00,13.9,13.5.hrms(esi-tof)calcd for c
33h40
no
9+
([m+h]
+
)594.2698.found 594.2705.
[0139][0140]
1-苄基-5-(4-氟苯基)-3,4-二甲基-3-(2,2,2-三氯乙基)-1,3-二氢-2h-吡咯-2-酮(4n),快速柱层析分离(石油醚/乙酸乙酯＝60:1,v/v),55％产率(71mg),无色油状物.rf(石油醚/etoac＝10:1,v/v)0.33.1h nmr(400mhz,cdcl3)δ7.19
–
7.15(m,3h),7.07
–
7.00(m,4h),6.92
–
6.87(m,2h),4.70(d,j＝15.3hz,1h),4.33(d,j＝15.3hz,1h),3.51(d,j＝15.2hz,1h),3.11(d,j＝15.2hz,1h),1.73(s,3h),1.32(s,3h).
13
c{1h}nmr(101mhz,cdcl3)δ180.1,162.8(d,j＝248.9hz),137.4,137.1,131.7(d,j＝8.2hz),128.3,127.8,127.2,126.4(d,j＝3.3hz),116.8,115.5(d,j＝21.6hz),96.3,59.1,51.0,44.6,24.3,10.6.
19
f nmr(376mhz,cdcl3)δ-111.92(p,j＝6.9hz,1f).hrms(esi-tof)calcd for c
21h20
cl3fno
+
([m+h]
+
)426.0589.found 426.0588.