一鍋法高效合成氧雜卓并[2,3-c]吡唑類化合物

鄧俊豐,孫楓欽,何鑫星,牟清瀾,李詩(shī)媛,楊開川*

(1.成都大學(xué) 藥學(xué)院,四川 成都 610106; 2.四川大學(xué) 華西藥學(xué)院,四川 成都 610207)

含氧雜環(huán)化合物,尤其氧雜卓類化合物具有廣泛的生物活性,在抑制生長(zhǎng)、抗病毒、抗抑郁以及抗真菌等領(lǐng)域都發(fā)揮著重要的作用[1-2]。如Radulanin A具有抑制植物生長(zhǎng)活性,可以用于除草劑[3],而從紫金花Bauhinia saccocalyx根部分離出的化合物Bauhinoxepin A具有抗菌活性[4],Aranotin具有EGF受體拮抗劑活性[5](圖1)。另一方面,含吡唑結(jié)構(gòu)單元的化合物通常具有抗炎、鎮(zhèn)痛、抗菌、抗驚厥、抗腫瘤以及農(nóng)業(yè)驅(qū)蟲等活性[6-11],許多治療人類疾病的藥物分子中也含有吡唑核心結(jié)構(gòu)[12-14]。

圖1 含氧雜卓環(huán)和吡唑結(jié)構(gòu)單元的活性物質(zhì)

基于新藥設(shè)計(jì)理念中將優(yōu)勢(shì)藥物骨架多樣化組合的合成策略[15-16],把具有生物活性的多個(gè)砌塊拼接到同一分子中,密集其活性功能,拓展結(jié)構(gòu)多樣性,發(fā)現(xiàn)更多高價(jià)值的藥物先導(dǎo)化合物,成為近年來藥物研究的熱點(diǎn)方向之一。因此,將氧雜卓環(huán)和吡唑環(huán)這2種優(yōu)勢(shì)的活性骨架進(jìn)行組合,合成一系列新型氧雜卓并吡唑稠環(huán)化合物,可以為后續(xù)的生物活性篩選提供更多的化合物源。對(duì)于該類化合物的合成,可以通過烯丙基硫葉立德與吡唑缺電子烯烴受體在堿的作用下[17]制備,但該方法需要先行制備烯丙基硫葉立德硫鹽,其極易吸水,保存周期短,不利于后續(xù)成環(huán)反應(yīng)的使用以及操作,并且該硫鹽原料制備需要使用易制毒丙酮作溶劑[18],使得該路線的環(huán)境友好性大幅度降低,實(shí)際應(yīng)用也會(huì)受到限制。因此,發(fā)掘更高效、更友好的合成方法尤為重要。

本文以吡唑類缺電子烯烴作為受體,在堿作用下,與二甲硫醚和4-溴丙烯酸酯通過具有步驟經(jīng)濟(jì)性和操作簡(jiǎn)便性的一鍋法[19-21]合成了系列氧雜卓并[2,3-c]吡唑類化合物,其結(jié)構(gòu)經(jīng)1H NMR、13C NMR和HR-MS(ESI-TOF)確證。對(duì)堿、溶劑以及物質(zhì)的量之比等因素進(jìn)行了考察,獲得了最優(yōu)反應(yīng)條件。

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

Büchi B-545型顯微熔點(diǎn)儀;Bruker-400型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標(biāo));Bruker Q TOF型高分辨質(zhì)譜儀。

實(shí)驗(yàn)所用試劑和溶劑均為分析純。

1.2 3a～3u的合成

在15 mL試管中依次加入吡唑底物1a(52.5 mg,0.2 mmol,1.0 eq)、4-溴巴豆酸乙酯(58.0 mg,0.4 mmol,2.0 eq)、二甲硫醚(37.2 mg,0.6 mmol,3.0 eq)、碳酸鉀(41.5 mg,0.3 mmol,1.5 eq)和乙腈2.0 mL,室溫下攪拌過夜,TLC監(jiān)測(cè)至反應(yīng)完全。減壓蒸餾除去溶劑,殘余物經(jīng)硅膠柱層析(洗脫劑:石油醚∶乙酸乙酯=40∶1～30∶1,V∶V)純化得到產(chǎn)物3a。

采用類似方法合成化合物3b～3u。

3a:白色粉末,收率86%,m.p.103～106 ℃;1H NMR(400 MHz,CDCl3)δ:7.69(d,J=8.8 Hz,2H),7.40(t,J=7.6 Hz,2H),7.32～7.18(m,7H),7.08(t,J=6.8 Hz,1H),5.32(s,1H),4.75(dd,J=13.6 Hz,7.2 Hz,1H),4.56(dd,J=13.6 Hz,6.4 Hz,1H),4.35～4.27(m,2H),2.18(s,3H),1.35(t,J=7.6 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.8,151.1,148.3,143.3,141.8,138.7,132.7,129.0,128.6,127.7,126.7,126.2,122.0,99.6,65.2,61.8,37.8,14.4,12.8; HR-MS(ESI-TOF)m/z:calculated for C23H22N2O3{[M+Na]+} 397.1523,found 397.1535。

3b:白色粉末,收率78%,m.p.111～113 ℃;1H NMR(400 MHz,CDCl3)δ:7.69(d,J=7.6 Hz,2H),7.44～7.37(m,2H),7.27～7.14(m,2H),7.12～6.99(m,4H),5.28(s,1H),4.77(dd,J=13.2 Hz,7.2 Hz,1H),4.55(dd,J=13.6 Hz,6.8 Hz,1H),4.36～4.26(m,2H),2.31(s,3H),2.18(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.7,151.0,148.3,143.2,141.9,138.7,138.2,132.6,128.9,128.4,128.1,127.5,126.1,124.6,121.9,99.5,65.2,61.8,37.6,21.7,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O3{[M+Na]+} 411.1679,found 411.1684。

3c:白色粉末,收率81%,m.p.120～122 ℃;1H NMR(400 MHz,CDCl3)δ:7.68(d,J=7.6 Hz,2H),7.45～7.37(m,2H),7.32～7.17(m,5H),7.10(t,J=6.8 Hz,1H),5.27(s,1H),4.72(dd,J=13.6 Hz,6.8 Hz,1H),4.58(dd,J=13.6 Hz,6.8 Hz,1H),4.36～4.25(m,2H),2.18(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.5,151.0,148.0,145.3,140.7,138.5,134.5,133.2,129.8,128.9,127.6,126.9,126.2,125.7,121.9,99.3,65.3,61.9,37.6,14.3,12.7; HR-MS(ESI-TOF)m/z:calculated for C23H21ClN2O3{[M+Na]+}431.1133,found 431.1147。

3d:白色粉末,收率77%,m.p.138～141 ℃;1H NMR(400 MHz,CDCl3)δ:7.69(d,J=7.6 Hz,2H),7.47～7.31(m,4H),7.28～7.21(m,2H),7.15(t,J=8.0 Hz,1H),7.09(t,J=6.8 Hz,1H),5.27(s,1H),4.71(dd,J=13.6 Hz,7.2 Hz,1H),4.58(dd,J=14.0 Hz,6.4 Hz,1H),4.35～4.25(m,2H),2.18(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.5,151.0,148.0,145.6,140.7,138.5,133.2,130.5,130.1,129.872,129.865,128.9,126.2,122.8,121.9,99.3,65.3,61.9,37.6,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C23H21BrN2O3{[M+Na]+}475.0628,found 475.0649。

3e:白色粉末,收率78%,m.p.107～110 ℃;1H NMR(600 MHz,CDCl3)δ:7.68(d,J=7.2 Hz,2H),7.44～7.36(m,2H),7.26～7.17(m,2H),7.07(t,J=6.0 Hz,1H),6.92～6.86(m,2H),6.76～6.72(m,1H),5.29(s,1H),4.78(dd,J=13.2 Hz,7.2 Hz,1H),4.54(dd,J=13.2 Hz,6.8 Hz,1H),4.35～4.26(m,2H),3.76(s,3H),2.19(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:166.7,159.8,151.1,148.2,144.9,141.7,138.6,132.7,129.5,128.9,126.1,122.0,120.0,114.0,111.4,99.4,66.1,61.8,55.3,37.6,14.3,12.7; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O4{[M+Na]+}427.1628,found 427.1643。

3f:白色粉末,收率82%,m.p.115～118 ℃;1H NMR(600 MHz,CDCl3)δ:7.68(d,J=7.2 Hz,2H),7.45～7.37(m,2H),7.28～7.17(m,3H),7.12～7.03(m,3H),5.28(s,1H),4.76(dd,J=13.6 Hz,7.2 Hz,1H),4.54(dd,J=13.2 Hz,6.8 Hz,1H),4.35～4.26(m,2H),2.30(s,3H),2.17(s,3H),1.34(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:166.8,151.1,148.2,141.9,140.3,138.7,136.3,132.6,129.3,128.9,127.4,126.1,121.9,99.7,65.2,61.7,37.4,21.1,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O3{[M+Na]+} 411.1679,found 411.1691。

3g:白色粉末,收率79%,m.p.141～143 ℃;1H NMR(400 MHz,CDCl3)δ:7.68(d,J=8.0 Hz,2H),7.43～7.36(m,2H),7.27～7.19(m,3H),7.05(t,J=6.8 Hz,1H),6.85～6.79(m,2H),5.25(s,1H),4.76(dd,J=13.6 Hz,6.8 Hz,1H),4.55(dd,J=13.6 Hz,6.8 Hz,1H),4.35～4.26(m,2H),3.76(s,3H),2.17(s,3H),1.34(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.8,158.3,151.1,148.1,141.8,138.6,135.3,132.5,128.9,128.5,126.0,121.9,113.9,99.9,65.2,61.7,55.3,37.1,14.3,12.7; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O4{[M+Na]+} 427.1628,found 427.1656。

3h:白色粉末,收率81%,m.p.107～109 ℃;1H NMR(600 MHz,CDCl3)δ:7.68(d,J=7.2 Hz,2H),7.40(t,J=7.6 Hz,2H),7.33～7.19(m,3H),7.07(t,J=6.0 Hz,1H),6.96(t,J=8.8 Hz,2H),5.27(s,1H),4.72(dd,J=13.6 Hz,6.8 Hz,1H),4.56(dd,J=13.6 Hz,6.8 Hz,1H),4.34～4.25(m,2H),2.17(s,3H),1.33(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:166.6,161.6(d,J=244.0 Hz,1C),151.0,147.9,141.0,138.9,138.5,132.9,128.9,126.1,121.8,115.4,115.2,99.8,65.2,61.7,37.2,14.2,12.7; HR-MS(ESI-TOF)m/z:calculated for C23H21FN2O3{[M+Na]+} 415.1428,found 415.1411。

3i:白色粉末,收率80%,m.p.124～127 ℃;1H NMR(600 MHz,CDCl3)δ:7.67(d,J=7.2 Hz,2H),7.47～7.36(m,2H),7.32～7.24(m,5H),7.08(t,J=6.0 Hz,1H),5.26(s,1H),4.71(dd,J=13.6 Hz,6.8 Hz,1H),4.58(dd,J=13.6 Hz,6.8 Hz,1H),4.35～4.26(m,2H),2.16(s,3H),1.34(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:166.6,151.1,148.0,141.8,141.0,138.5,133.1,132.6,129.0,128.9,128.7,126.3,122.0,99.6,66.4,61.9,37.5,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C23H21ClN2O3{[M+Na]+}431.1133,found 431.1135。

3j:白色粉末,收率76%,m.p.112～115 ℃;1H NMR(600 MHz,CDCl3)δ:7.67(d,J=7.2 Hz,2H),7.44～7.37(m,4H),7.27～7.18(m,3H),7.08(t,J=7.2 Hz,1H),5.24(s,1H),4.70(dd,J=13.6 Hz,6.8 Hz,1H),4.57(dd,J=13.6 Hz,6.8 Hz,1H),4.36～4.25(m,2H),2.16(s,3H),1.34(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:166.6,151.0,148.0,142.3,140.8,138.5,133.1,131.6,129.3,128.9,126.3,121.9,120.8,99.5,65.3,61.8,37.5,14.1,12.7; HR-MS(ESI-TOF)m/z:calculated for C23H21BrN2O3{[M+Na]+}475.0628,found 475.0637。

3k:白色粉末,收率83%,m.p.109～111 ℃;1H NMR(400 MHz,CDCl3)δ:7.70(d,J=7.6 Hz,2H),7.45～7.37(m,2H),7.26～7.15(m,3H),6.91～6.82(m,2H),6.76(t,J=7.6 Hz,1H),5.38(s,1H),4.81(dd,J=12.8 Hz,7.2 Hz,1H),4.44(dd,J=13.2 Hz,6.8 Hz,1H),4.34～4.26(m,2H),3.79(s,3H),2.17(s,3H),1.36(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:167.2,156.3,151.4,148.2,143.4,138.7,131.5,129.4,128.95,128.90,128.1,126.0,121.9,120.4,110.7,98.3,64.5,61.3,55.1,33.9,14.5,12.6; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O4{[M+Na]+}427.1628,found 427.1683。

3l:白色粉末,收率75%,m.p.96～99 ℃;1H NMR(400 MHz,CDCl3)δ:7.66(d,J=8.0 Hz,2H),7.52(d,J=7.6 Hz,2H),7.45～7.31(m,3H),7.29～7.10(m,3H),6.96(t,J=6.8 Hz,1H),5.56(s,1H),4.91(dd,J=15.6 Hz,6.8 Hz,1H),4.67(dd,J=15.6 Hz,4.8 Hz,1H),4.26～4.18(m,2H),2.27(s,3H),1.29(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.7,150.9,147.6,141.0,138.4,138.2,133.4,133.0,130.4,130.1,129.0,128.2,127.0,126.3,122.0,102.8,66.8,61.7,36.4,14.2,13.3; HR-MS(ESI-TOF)m/z:calculated for C23H21ClN2O3{[M+Na]+}431.1133,found 431.1182。

3m:白色粉末,收率79%,m.p.127～129 ℃;1H NMR(400 MHz,CDCl3)δ:7.64(d,J=8.4 Hz,2H),7.49(d,J=8.0 Hz,1H),7.45～7.36(m,3H),7.26(t,J=7.2 Hz,1H),7.19～7.15(m,1H),7.02～6.97(m,1H),5.52(s,1H),4.90(dd,J=12.0 Hz,6.4 Hz,1H),4.71(dd,J=16.0 Hz,4.4 Hz,1H),4.26～4.18(m,2H),2.27(s,3H),1.29(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.5,150.9,147.4,139.8,138.3,137.0,134.3,133.6,133.2,131.3,129.7,129.0,127.5,126.5,122.0,103.4,67.2,61.8,36.1,14.3,13.4; HR-MS(ESI-TOF)m/z:calculated for C23H20Cl2N2O3{[M+Na]+}465.0743,found 465.0784。

3n:白色粉末,收率67%,m.p.105～107 ℃;1H NMR(400 MHz,CDCl3)δ:7.67(d,J=7.6 Hz,2H),7.42～7.35(m,2H),7.22(t,J=7.2 Hz,1H),7.16～7.08(m,2H),6.91～6.82(m,2H),5.48(s,1H),4.91(dd,J=12.8 Hz,6.8 Hz,1H),4.57(dd,J=12.8 Hz,7.2 Hz,1H),4.36～4.26(m,2H),2.12(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:167.0,151.0,147.9,147.3,141.3,138.5,133.1,128.8,126.7,126.1,124.6,124.3,121.9,99.4,64.8,61.7,33.9,14.2,12.7; HR-MS(ESI-TOF)m/z:calculated for C21H20N2O3S{[M+Na]+}403.1087,found 403.1001。

3o:白色粉末,收率84%,m.p.131～132 ℃;1H NMR(400 MHz,CDCl3)δ:8.43(d,J=8.4 Hz,1H),7.73(d,J=7.2 Hz,1H),7.75～7.62(m,4H),7.59～7.53(m,1H),7.51～7.46(m,1H),7.45～7.36(m,3H),7.29～7.23(m,1H),7.01～6.95(m,1H),5.99(s,1H),5.13(dd,J=14.4 Hz,6.4 Hz,1H),4.65(dd,J=14.8 Hz,5.2 Hz,1H),4.24～4.16(m,2H),2.15(s,3H),1.21(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:167.0,151.1,147.6,139.7,139.4,138.6,134.2,133.5,131.2,129.0,127.8,127.1,126.25,126.17,125.7,125.5,124.2,122.07,122.06,102.8,66.0,61.7,35.3,14.2,13.3; HR-MS(ESI-TOF)m/z:calculated for C27H24N2O3{[M+Na]+}447.1679,found 447.1634。

3p:白色粉末,收率86%,m.p.115～117 ℃;1H NMR(400 MHz,CDCl3)δ:7.82～7.65(m,6H),7.52～7.37(m,5H),7.28～7.21(m,1H),7.10(t,J=7.2 Hz,1H),5.48(s,1H),4.81(dd,J=13.6 Hz,7.2 Hz,1H),4.53(dd,J=13.6 Hz,6.8 Hz,1H),4.41～4.25(m,2H),2.21(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.8,151.2,148.3,141.5,140.7,138.7,133.3,133.0,132.3,128.9,128.4,127.9,127.6,126.3,126.1,126.0,125.9,125.8,121.9,99.4,65.1,61.8,37.9,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C27H24N2O3{[M+Na]+}447.1679,found 447.1662。

3q:白色粉末,收率81%,m.p.106～109 ℃;1H NMR(400 MHz,CDCl3)δ:7.67(d,J=7.6 Hz,2H),7.44～7.37(m,2H),7.28～7.21(m,5H),7.07(t,J=6.8 Hz,1H),5.25(s,1H),4.71(dd,J=13.6 Hz,6.8 Hz,1H),4.57(dd,J=14.0 Hz,6.4 Hz,1H),3.84(s,3H),2.16(s,3H);13C NMR(100 MHz,CDCl3)δ:167.1,151.0,148.0,141.7,140.6,138.5,133.4,132.6,129.0,128.9,128.7,126.2,121.9,99.6,65.3,52.8,37.5,12.7; HR-MS(ESI-TOF)m/z:calculated for C22H19ClN2O3{[M+Na]+}417.0976,found 417.0931。

3r:白色粉末,收率84%,m.p.118～120 ℃;1H NMR(400 MHz,CDCl3)δ:7.68(d,J=8.0 Hz,2H),7.41(t,J=7.6 Hz,2H),7.28～7.24(m,5H),7.06(t,J=7.6 Hz,1H),5.26(s,1H),5.20～5.10(m,1H),4.70(dd,J=13.2 Hz,6.8 Hz,1H),4.57(dd,J=13.6 Hz,6.4 Hz,1H),2.16(s,3H),1.32(t,J=6.0 Hz,

6H);13C NMR(100 MHz,CDCl3)δ:167.1,151.1,148.0,141.8,141.3,138.5,132.8,132.5,128.95,128.91,128.7,126.2,121.9,99.5,69.5,65.3,37.4,21.96,21.90,12.7; HR-MS(ESI-TOF)m/z:calculated for C24H23ClN2O3{[M+Na]+}445.1289,found 445.1233。

3s:白色粉末,收率80%,m.p.113～116 ℃;1H NMR(400 MHz,CDCl3)δ:7.55(d,J=8.4 Hz,2H),7.36～7.26(m,5H),7.24～7.18(m,3H),7.08(t,J=7.2 Hz,1H),5.32(s,1H),4.74(dd,J=13.2 Hz,7.2 Hz,1H),4.55(dd,J=13.6 Hz,6.8 Hz,1H),4.36～4.26(m,2H),2.37(s,3H),2.18(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.8,151.0,147.9,143.4,141.7,136.2,136.0,132.85,129.5,128.6,127.5,126.7,122.1,99.5,65.2,61.8,37.8,21.1,14.4,12.8; HR-MS(ESI-TOF)m/z:calculated for C24H24N2O3{[M+Na]+}411.1679,found 411.1637。

3t:白色粉末,收率72%,m.p.107～109 ℃;1H NMR(400 MHz,CDCl3)δ:7.87(d,J=7.2 Hz,2H),7.50～7.40(m,3H),7.35～7.26(m,4H),7.10(t,J=6.8 Hz,1H),5.35(s,1H),4.77(dd,J=13.6 Hz,7.2 Hz,1H),4.57(dd,J=13.6 Hz,6.8 Hz,1H),4.38～4.25(m,2H),2.22(s,3H),1.34(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.7,150.0(d,J=289.5 Hz,1C),143.2,141.7,133.5,132.7,128.6,128.1,127.5,126.7,126.6,121.1,119.2,99.8,65.2,61.8,37.8,14.3,12.8; HR-MS(ESI-TOF)m/z:calculated for C23H21FN2O3{[M+Na]+}415.1428,found 415.1458。

3u:白色粉末,收率81%,m.p.129～131 ℃;1H NMR(400 MHz,CDCl3)δ:7.68～7.62(m,3H),7.37～7.17(m,6H),7.12～7.04(m,4H),5.32(s,1H),4.74(dd,J=13.6 Hz,7.2 Hz,1H),4.54(dd,J=13.6 Hz,7.2 Hz,1H),4.36～4.26(m,2H),2.17(s,3H),1.35(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.7,162.1,159.6,151.0,148.3,143.2,141.9,134.8,132.6,129.2,128.6,127.5,126.7,123.74,123.66,115.8,115.7,115.6,99.4,65.2,61.8,37.7,14.3,12.7; HR-MS(ESI-TOF)m/z:calculated for C27H24N2O3{[M+Na]+}447.1679,found 447.1684。

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化分析

以吡唑底物(1a)和4-溴巴豆酸乙酯(2a1)以及二甲硫醚(2a2)的一鍋法反應(yīng)為模板反應(yīng),對(duì)合成氧雜卓并[2,3-c]吡唑類化合物的反應(yīng)條件進(jìn)行篩選,實(shí)驗(yàn)結(jié)果如表1所示。

表1 反應(yīng)條件的優(yōu)化a

首先,在室溫下的乙腈溶劑體系中研究了化合物1a和化合物2a1以及化合物2a2在堿的作用下一鍋法反應(yīng)的可行性。結(jié)果表明:室溫下以NaHCO3為堿,乙腈為溶劑時(shí)反應(yīng)可以順利進(jìn)行,以36%的收率得到氧雜卓并[2,3-c]吡唑類化合物3a(No.1)。再篩選無機(jī)堿和有機(jī)堿,結(jié)果表明:K2CO3作堿時(shí)反應(yīng)效果最好(No.4,收率83%)。于是以K2CO3為堿,對(duì)溶劑進(jìn)行進(jìn)一步篩選,發(fā)現(xiàn)乙腈仍然是最優(yōu)反應(yīng)溶劑(No.7～11在同等條件下將乙腈變換成其它溶劑THF,DCM,DCE等,收率都較乙腈低)。再對(duì)參與反應(yīng)的物質(zhì)的量之比進(jìn)行優(yōu)化,發(fā)現(xiàn)增大2a的比率可以進(jìn)一步提高反應(yīng)的收率至86%(No.13)。因此,最后反應(yīng)條件確定為:室溫下,以乙腈為溶劑,K2CO3作堿,參與反應(yīng)的各物質(zhì)的量之比為1.0∶2.0∶3.0∶1.5(No.13),反應(yīng)過夜。

2.2 底物擴(kuò)展分析

在最優(yōu)反應(yīng)條件下,本文對(duì)反應(yīng)底物進(jìn)行了擴(kuò)展,實(shí)驗(yàn)結(jié)果如圖2所示。實(shí)驗(yàn)結(jié)果表明:吡唑底物1a和4-溴巴豆酸乙酯以及二甲硫醚在堿的作用下一鍋法反應(yīng)都可以順利進(jìn)行,吡唑Michael受體β位苯環(huán)上的取代基無論在鄰位、間位或?qū)ξ欢伎梢赃M(jìn)行反應(yīng),取代基的電子屬性對(duì)反應(yīng)沒有明顯影響,可以中等到較高收率得到一系列氧雜卓并[2,3-c]吡唑類化合物(3b～3m);而β位為其它芳香環(huán)如噻吩和萘環(huán)時(shí),反應(yīng)也可以順利進(jìn)行(3n～3p);然后4-溴巴豆酸乙酯變?yōu)橄鄳?yīng)的甲酯或者異丙酯的時(shí),對(duì)反應(yīng)沒有明顯影響(3q～3r),最后改變吡唑環(huán)N連接苯環(huán)上的取代基或者換成萘環(huán)時(shí),同樣能夠以中等到良好的收率(72%～81%)得到目標(biāo)產(chǎn)物(3s～3u)。

圖2 底物拓展

2.3 放大反應(yīng)及衍生轉(zhuǎn)化分析

為了驗(yàn)證該反應(yīng)的實(shí)用性,本文將該反應(yīng)放大到克級(jí),反應(yīng)能順利進(jìn)行但是收率會(huì)降至61%(圖3),同時(shí)將產(chǎn)物進(jìn)行了衍生轉(zhuǎn)化,利用鈀催化的偶聯(lián)反應(yīng)得到了功能更密集的聯(lián)苯類化合物4,白色粉末,收率56%; m.p.123～126 ℃;1H NMR(400 MHz,CDCl3)δ:7.70(d,J=7.6 Hz,2H),7.58～7.48(m,4H),7.44～7.36(m,6H),7.32(t,J=7.2 Hz,1H),7.27～7.21(m,1H),7.11(t,J=6.8 Hz,1H),5.35(s,1H),4.80(dd,J=13.2 Hz,6.8 Hz,1H),4.58(dd,J=13.6 Hz,6.8 Hz,1H),4.39～4.26(m,2H),2.21(s,3H),1.36(t,J=7.2 Hz,3H);13C NMR(100 MHz,CDCl3)δ:166.8,151.2,148.3,142.3,141.6,140.8,139.6,138.7,132.9,129.0,128.9,127.9,127.3,127.1,126.2,123.7,122.0,99.7,66.3,61.8,37.6,14.4,12.8; HR-MS(ESI-TOF)m/z:calculated for C29H26N2O3{[M+Na]+}473.1836,found 473.1845。

圖3 克級(jí)反應(yīng)和衍生轉(zhuǎn)化

2.4 反應(yīng)機(jī)理的探討分析

根據(jù)產(chǎn)物的結(jié)構(gòu)式以及相關(guān)文獻(xiàn)報(bào)道[22],本文提出了該反應(yīng)可能的反應(yīng)機(jī)理(圖4):二甲硫醚與4-溴巴豆酸酯反應(yīng)生成烯丙基硫葉立德后,在K2CO3堿性作用下,生成烯丙基碳負(fù)離子AB共振式,然后與吡唑底物1a發(fā)生Michael加成反應(yīng)生成中間體C,經(jīng)過2步質(zhì)子轉(zhuǎn)移生成中間體F,再經(jīng)過分子內(nèi)親核取代發(fā)生關(guān)環(huán)得到最終產(chǎn)物3a。

圖4 反應(yīng)機(jī)理推測(cè)

3 結(jié)論

在無機(jī)堿K2CO3作用下,吡唑類缺電子烯烴、二甲硫醚以及4-溴丙烯酸酯通過具有步驟經(jīng)濟(jì)性和操作簡(jiǎn)便性的一鍋法發(fā)生[4+3]環(huán)合反應(yīng),合成了一系列氧雜卓并[2,3-c]吡唑類化合物3a～3u,收率67%～86%,其結(jié)構(gòu)經(jīng)1H NMR、13C NMR和HR-MS(ESI-TOF)確證,為后續(xù)生物活性篩選提供了候選化合物。