白亞茹, 盧新宇, 牛 瑞, 張琰圖, 藺軍兵
(延安大學(xué) 化學(xué)與化工學(xué)院,陜西 延安 716000)
四氫噻吩是一類結(jié)構(gòu)獨特、用途廣泛的含硫五元雜環(huán),廣泛存在于天然產(chǎn)物分子和藥用分子中(如生物素和替曲硫定)[1-5]。取代的四氫噻吩可以作為親核有機小分子催化劑[6-7]和硫葉立德前體[8-9]。因此,開發(fā)新穎有機合成方法,高效簡潔的構(gòu)筑結(jié)構(gòu)復(fù)雜的四氫噻吩類化合物,具有重要的現(xiàn)實意義[10-15]。
有機小分子催化的串聯(lián)反應(yīng)[16-17]具有操作簡單、環(huán)境友好、可同時構(gòu)筑多個化學(xué)鍵、無需分離純化中間體等特點,能夠?qū)崿F(xiàn)從簡單原料到多手性中心復(fù)雜分子的快速轉(zhuǎn)化[18]。有機小分子催化的2,5-二羥基-1,4-二噻烷(巰基乙醛二聚體)和活潑烯烴如不飽和醛[19]、查爾酮和取代不飽和酮[20-26]、硝基烯烴[27-28]、靛紅衍生的不飽和酯[29]等的Sulfa-Michael-Aldol串聯(lián)反應(yīng)是構(gòu)筑多取代四氫噻吩分子的重要方法[30-31]。鄰羥基苯乙酮可以通過形成分子內(nèi)氫鍵對羰基進行親電活化。因此,羥基取代查爾酮[32]作為Michael受體比普通查爾酮活性更高。使用簡單的有機叔胺,將羥基取代查爾酮應(yīng)用到sulfa-Michael-aldol串聯(lián)反應(yīng),高效合成含酚羥基的多取代的四氫噻吩類化合物值得探究。
本文以羥基取代的查爾酮(1)及2,5-二羥基-1,4-二噻烷(2)為原料,經(jīng)過叔胺DABCO催化的sulfa-Michael-aldol串聯(lián)反應(yīng),高效合成了15個含酚羥基的多取代的四氫噻吩衍生物(3a~3o, Scheme 1),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR, IR 和HR-MS(ESI)確認,其中代表性化合物3a由X-ray單晶衍射確認。產(chǎn)物的dr值通過1H NMR測定。
Scheme 1
XT-4型顯微熔點儀;JEOL-400 MHz型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標);IRAFFINITY-1S型紅外光譜儀(KBr壓片);Bruker Daltonics MicrOTOF-Q II型高分辨質(zhì)譜儀。
按文獻[33]方法合成化合物1a~1o;其余所用試劑均為分析純。
(1)3a~3o的合成(以3a為例)
在10 mL反應(yīng)管中,依次將2,5-二羥基-1,4-二噻烷2(0.3 mmol)、查爾酮1a(0.2 mmol)和DABCO(0.02 mmol)加入到干燥甲苯(1.0 mL)中,于80 ℃油浴中攪拌至反應(yīng)完全(TLC監(jiān)測)。反應(yīng)液直接經(jīng)硅膠柱層析[洗脫劑:V(石油醚)/V(乙酸乙酯)=10/1~5/1]純化得3a。
用類似的方法合成化合物3b~3o。
3a: 白色固體,收率70%, m.p.124~126 ℃;1H NMRδ: 11.98(s, 1H), 7.37(q,J=7.5 Hz, 4H), 7.19~7.16(m, 3H), 6.87(d,J=8.3 Hz, 1H), 6.69(t,J=7.7 Hz, 1H), 5.17(d,J=10.7 Hz, 1H), 4.92(d,J=3.4 Hz, 1H), 4.07~4.02(m, 1H), 3.56(dd,J=11.7 Hz, 3.9 Hz, 1H), 3.18(d,J=4.9 Hz, 1H), 3.10(dd,J=11.7 Hz, 1.0 Hz, 1H);13C NMRδ: 203.97, 162.98, 139.31, 137.19, 129.70, 128.67, 127.94, 127.84, 119.39, 119.02, 118.81, 77.85, 62.35, 50.99, 41.17; IRν: 3433, 2951, 1630, 1248, 1042, 752 cm-1; HR-MS(ESI)m/z: Calcd for C17H16O3S{[M+Na]+}323.0718, found 323.0724。
3b: 白色固體,收率45%, m.p.99~101 ℃;1H NMRδ: 12.03(s, 1H), 7.65(d,J=7.3 Hz, 1H), 7.50~7.42(m, 2H), 7.20~7.14(m, 1H), 7.09~7.00(m, 2H), 6.94(dd,J=8.3 Hz, 1.0 Hz, 1H), 6.80-6.76(m, 1H), 5.52(d,J=10.4 Hz, 1H), 5.01(d,J=3.6 Hz, 1H), 4.24(dd,J=10.5 Hz, 3.2 Hz, 1H), 3.64(dd,J=11.9 Hz, 3.6 Hz, 1H), 3.28(d,J=4.7 Hz, 1H), 3.18(dd,J=11.7 Hz, 1.3 Hz, 1H), 2.35(s, 3H);13C NMRδ: 204.49, 163.00, 137.28, 136.79, 130.61, 129.75, 127.47, 126.93, 126.57, 119.32, 119.07, 118.81, 77.62, 61.25, 46.34, 41.09, 19.61; IRν: 3429, 2970, 1620, 1254, 1038, 743 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S{[M+Na]+}337.0869, found 337.0871。
3c: 白色固體,收率61%, m.p.100~102 ℃;1H NMRδ: 12.06(s, 1H), 7.48~7.41(m, 2H), 7.26~7.23(m, 2H), 7.13(t,J=7.8 Hz, 1H), 7.00~6.93(m, 2H), 6.79~6.75(m, 1H), 5.20(d,J=10.4 Hz, 1H), 4.98(t,J=1.8 Hz, 1H), 4.11(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.62(dd,J=11.7 Hz, 3.9 Hz, 1H), 3.21(d,J=5.2 Hz, 1H), 3.16(dd,J=11.7 Hz, 1.3 Hz, 1H), 2.28(s, 3H);13C NMRδ: 203.92, 162.95, 139.23, 138.34, 137.15, 129.72, 128.61, 128.56, 128.42, 124.92, 119.41, 118.99, 118.78, 77.88, 62.27, 50.81, 41.18, 21.34; IRν: 3431, 2955, 1634, 1248, 1040, 754 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S{[M+Na]+}337.0869, found 337.0877。
3d: 白色固體,收率59%, m.p.108~110 ℃;1H NMRδ: 12.02(s, 1H), 7.53~7.43(m, 3H), 7.31~7.26(m, 1H), 7.18~7.16(m, 2H), 6.96(dd,J=8.3 Hz, 1.0 Hz, 1H), 6.81(td,J=7.8 Hz, 1.0 Hz, 1H), 5.22(d,J=10.4 Hz, 1H), 5.00(s, 1H), 4.06(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.64(dd,J=11.9 Hz, 3.6 Hz, 1H), 3.17~3.14(m, 2H);13C NMRδ: 203.08, 162.97, 141.67, 137.31, 134.47, 129.87, 129.53, 128.02, 126.41, 119.23, 119.11, 118.91, 77.85, 62.73, 50.06, 41.19; IRν: 3431, 2961, 1634, 1408, 1259, 754 cm-1; HR-MS(ESI)m/z: Calcd for C17H15ClO3S{[M+Na]+}357.0323, found 357.0324。
3e: 白色固體,收率63%, m.p.105~107 ℃;1H NMRδ: 12.02(s, 1H), 7.67(t,J=1.8 Hz, 1H), 7.49~7.43(m, 2H), 7.35~7.30(m, 2H), 7.10(t,J=7.8 Hz, 1H), 6.95(d,J=8.3 Hz, 1H), 6.83~6.79(m, 1H), 5.21(d,J=10.4 Hz, 1H), 5.00(s, 1H), 4.05(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.63(dd,J=11.9 Hz, 3.6 Hz, 1H), 3.20~3.13(m, 2H);13C NMRδ: 202.97, 162.91, 141.95, 137.29, 130.92, 130.13, 129.52, 126.91, 122.63, 119.20, 119.11, 118.88, 77.85, 62.79, 49.95, 41.15; IRν: 3431, 1628, 1458, 1258, 1036, 754 cm-1; HR-MS(ESI)m/z: Calcd for C17H15BrO3S{[M+Na]+}400.9817, found 400.9820。
3f: 白色固體,收率73%, m.p.102~105 ℃;1H NMRδ: 12.06(s, 1H), 7.48~7.41(m, 2H), 7.33(t,J=7.8 Hz, 2H), 7.09~7.04(m, 2H), 6.95~6.93(m, 1H), 6.80~6.76(m, 1H), 5.22(d,J=10.4 Hz, 1H), 4.97(d,J=3.6 Hz, 1H), 4.11(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.62(dd,J=11.9 Hz, 3.6 Hz, 1H), 3.21~3.13(m, 2H), 2.26(s, 3H);13C NMRδ: 203.97, 162.94, 137.57, 137.14, 136.12, 129.72, 129.32, 127.79, 119.39, 119.01, 118.78, 77.82, 62.30, 50.64, 41.11, 21.01; IRν: 3445, 2940, 1730, 1630, 1248, 752 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S{[M+Na]+}337.0869, found 337.0879。
3g: 白色固體,收率60%, m.p.100~102 ℃;1H NMRδ: 12.02(s, 1H), 7.47~7.39(m, 4H), 7.21~7.26(m, 2H), 6.95(dd,J=8.8 Hz, 1.0 Hz, 1H), 6.82~6.78(m, 1H), 5.23(d,J=10.9 Hz, 1H), 4.99(s, 1H), 4.04(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.63(dd,J=11.9 Hz, 3.6 Hz, 1H), 3.19~3.14(m, 2H);13C NMRδ: 203.36, 162.96, 137.85, 137.35, 133.48, 129.51, 129.38, 128.79, 119.25, 119.14, 118.91, 77.77, 62.65, 50.11, 41.11; IRν: 3431, 1742, 1634, 1244, 1038, 756 cm-1; HR-MS(ESI)m/z: Calcd for C17H15ClO3S{[M+Na]+}357.0323 found 357.0325。
3h: 白色固體,收率71%, m.p.116~118 ℃;1H NMRδ: 12.02(s, 1H), 7.43~7.47(m, 2H), 7.36(qd,J=6.5 Hz, 2.5 Hz, 4H), 6.95(dd,J=9.1 Hz, 1.3 Hz, 1H), 6.78~6.82(m, 1H), 5.22(d,J=10.9 Hz, 1H), 4.99(d,J=2.1 Hz, 1H), 4.04(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.63(dd,J=11.7 Hz, 3.9 Hz, 1H), 3.16~3.13(m, 2H);13C NMRδ: 203.25, 162.97, 138.44, 137.34, 131.74, 129.73, 129.49, 121.58, 119.24, 119.14, 118.92, 77.79, 62.67, 50.10, 41.13; IRν: 3429, 1634, 1396, 1244, 1038, 750 cm-1; HR-MS(ESI)m/z: Calcd for C17H15BrO3S{[M+Na]+}400.9817, found 400.9823。
3i: 白色固體,收率50%, m.p.98~100 ℃;1H NMRδ: 12.00(s, 1H), 7.60(d,J=7.8 Hz, 2H), 7.51(d,J=8.0 Hz, 2H), 7.43~7.47(m, 2H), 6.95(dd,J=8.6 Hz, 1.3 Hz, 1H), 6.77~6.81(m, 1H), 5.31(d,J=10.9 Hz, 1H), 5.03(s, 1H), 4.08(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.66(dd,J=11.7 Hz, 3.9 Hz, 1H), 3.13~3.19(m, 2H);13C NMRδ: 202.86, 162.97, 143.71, 137.37, 130.15, 129.82, 129.38, 128.48, 125.62, 125.58, 125.55, 125.21, 119.17, 119.13, 118.95, 77.85, 62.85, 50.01, 41.21; IRν: 3431, 1634, 1321, 1136, 1045, 750 cm-1; HR-MS(ESI)m/z: Calcd for C18H15F3O3S{[M+Na]+}391.0586, found 391.0589。
3j: 白色固體,收率67%, m.p.107~109 ℃;1H NMRδ: 12.07(s, 1H), 7.44~7.50(m, 2H), 7.40(dt,J=8.8 Hz, 2.1 Hz, 2H), 7.15(dd,J=6.5 Hz, 1.8 Hz, 2H), 6.97(dd,J=8.3 Hz, 1.0 Hz, 1H), 6.79~6.83(m, 1H), 5.24(d,J=10.9 Hz, 1H), 5.00(d,J=3.1 Hz, 1H), 4.10(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.65(dd,J=11.4 Hz, 3.6 Hz, 1H), 3.16-3.21(m, 2H), 2.44(s, 3H);13C NMRδ: 203.70, 162.95, 138.05, 137.24, 135.97, 129.63, 128.42, 126.68, 119.33, 119.09, 118.85, 77.79, 62.42, 50.45, 41.11, 15.73; IRν: 3437, 2947, 1628, 1246, 1040, 754 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S2{[M+Na]+}369.0590, found 369.0594。
3k: 白色固體,收率46%, m.p.115~117 ℃;1H NMRδ: 12.08(s, 1H), 7.51(dd,J=8.3 Hz, 1.6 Hz, 1H), 7.43(td,J=7.8 Hz, 1.6 Hz, 1H), 7.16~7.20(m, 2H), 7.01(d,J=7.8 Hz, 1H), 6.94(dd,J=8.3 Hz, 1.0 Hz, 1H), 6.79(td,J=7.8 Hz, 1.0 Hz, 1H), 5.20(d,J=10.4 Hz, 1H), 4.97(d,J=3.6 Hz, 1H), 4.11~4.15(m, 1H), 3.62(dd,J=11.7 Hz, 3.9 Hz, 1H), 3.13~3.16(m, 2H), 2.18(d,J=8.8 Hz, 6H);13C NMRδ: 203.87, 162.94, 137.08, 136.86, 136.56, 136.24, 129.86, 129.75, 129.11, 125.20, 119.44, 118.97, 118.77, 77.88, 62.28, 50.45, 41.15, 19.76, 19.36; IRν: 3431, 1622, 1472, 1252, 1042, 750 cm-1; HR-MS(ESI)m/z: Calcd for C19H20O3S{[M+Na]+}351.1025, found 351.1033。
3l: 白色固體,收率79%, m.p.150~152 ℃;1H NMRδ: 12.07(s, 1H), 7.85(s, 1H), 7.73~7.78(m, 3H), 7.63(dd,J=8.6 Hz, 1.8 Hz, 1H), 7.35~7.50(m, 4H), 6.90(d,J=8.3 Hz, 1H), 6.71(dd,J=8.3 Hz, 7.3 Hz, 1H), 5.44(d,J=10.4 Hz, 1H), 5.02(d,J=2.6 Hz, 1H), 4.24(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.68(dd,J=11.4 Hz, 3.6 Hz, 1H), 3.29(d,J=5.2 Hz, 1H), 3.18~3.21(m, 1H);13C NMRδ: 203.58, 162.91, 137.17, 136.55, 133.08, 132.87, 129.57, 128.64, 127.77, 127.52, 127.20, 126.27, 126.06, 125.28, 119.32, 119.01, 118.78, 77.94, 62.32, 50.99, 41.33; IRν: 3431, 1722, 1630, 1248, 1040, 754 cm-1; HR-MS(ESI)m/z: Calcd for C21H18O3S{[M+Na]+}373.0869, found 373.0866。
3m: 白色固體,收率65%, m.p.106~109 ℃;1H NMRδ: 12.05(s, 1H), 7.45~7.52(m, 2H), 7.15(dd,J=5.2 Hz, 1.0 Hz, 1H), 6.93~6.98(m, 2H), 6.79~6.84(m, 2H), 5.54(d,J=9.8 Hz, 1H), 4.96(d,J=3.1 Hz, 1H), 4.13(dd,J=10.4 Hz, 3.1 Hz, 1H), 3.63(dd,J=11.4 Hz, 3.6 Hz, 1H), 3.25(d,J=3.6 Hz, 1H), 3.15(dd,J=11.5 Hz, 1.2 Hz, 1H);13C NMRδ: 203.87, 162.99, 143.81, 137.38, 129.71, 126.93, 126.11, 125.02, 119.49, 119.17, 118.85, 77.61, 63.10, 46.48, 40.94; IRν: 3431, 2951, 1622, 1244, 1040, 729 cm-1; HR-MS(ESI)m/z: Calcd for C15H14O3S2{[M+Na]+}329.0277, found 329.0283。
3n: 白色固體,收率71%, m.p.119~121 ℃;1H NMRδ: 12.09(s, 1H), 7.43~7.45(m, 2H), 7.15~7.30(m, 4H), 6.72(s, 1H), 6.55(dd,J=8.3 Hz, 1.6 Hz, 1H), 5.21(d,J=10.4 Hz, 1H), 4.94(s, 1H), 4.05(dd,J=10.9 Hz, 3.1 Hz, 1H), 3.59(dd,J=11.4 Hz, 3.6 Hz, 1H), 3.49(s, 1H), 3.15(dd,J=11.7 Hz, 1.3 Hz, 1H), 2.28(s, 3H);13C NMRδ: 203.37, 163.04, 149.14, 139.24, 129.57, 128.58, 127.91, 127.75, 120.38, 118.67, 117.25, 77.77, 61.91, 51.18, 41.05, 21.92; IRν: 3414, 2938, 1626, 1236, 1024, 716 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S{[M+Na]+}337.0869, found 337.0884。
3o: 白色固體,收率58%, m.p.143~145 ℃;1H NMRδ: 11.79(s, 1H), 7.38(d,J=6.8 Hz, 2H), 7.11~7.21(m, 5H), 7.02(s, 1H), 6.76(d,J=8.8 Hz, 1H), 5.12(d,J=10.2 Hz, 1H), 4.91(d,J=2.4 Hz, 1H), 3.98(dd,J=10.5 Hz, 3.2 Hz, 1H), 3.55(dd,J=11.7 Hz, 3.4 Hz, 1H), 3.43(d,J=3.9 Hz, 1H), 3.09(d,J=11.7 Hz, 1H), 2.09(s, 3H);13C NMRδ: 204.26, 160.92, 139.32, 138.36, 129.44, 128.58, 128.12, 127.99, 127.82, 119.05, 118.45, 77.79, 61.98, 51.37, 41.04, 21.03; IRν: 2393, 1622, 1481, 1271, 1018, 723 cm-1; HR-MS(ESI)m/z: Calcd for C18H18O3S{[M+Na]+}337.0869, found 337.0882。
以1a和2的反應(yīng)為模板反應(yīng),對反應(yīng)條件進行了優(yōu)化,結(jié)果見表1。由表1可知,1,8-二氮雜雙環(huán)[5.4.0]十一碳-7-烯(DBU)為催化劑,甲苯作溶劑,反應(yīng)2 h,以51%的收率,3/1的dr值得到目標產(chǎn)物3a(Entry 1)。其他有機堿4-二甲氨基吡啶(DMAP),四甲基胍(TMG)均能夠催化反應(yīng),但反應(yīng)的非對映選擇性較差(Entry 2~3)。當(dāng)N-甲基嗎啉(NMM)做催化劑,反應(yīng)6 h,給出20%的收率(Entry 4),而三乙胺(Et3N)給出43%產(chǎn)率和5/1的非對映選擇性(Entry 5)。繼續(xù)研究發(fā)現(xiàn),DABCO給出70%的收率和9/1的非對映選擇性(Entry 6),而無機堿Na2CO3給出39%的收率和2/1的非對映選擇性(Entry 7)。因此,將DABCO作為最優(yōu)催化劑,在甲苯中反應(yīng)。
表1 反應(yīng)條件的優(yōu)化a
在最優(yōu)反應(yīng)條件下,對反應(yīng)底物進行了拓展,結(jié)果見Scheme 1。結(jié)果表明,反應(yīng)普適性較好,含有供電子、吸電子、鹵素、多取代基、萘環(huán)、雜環(huán)取代基的羥基查爾酮都能與2,5-二羥基-1,4-二噻烷發(fā)生反應(yīng),以5/1~9/1的非對映選擇性和45%~79%的收率得到一系列含有酚羥基的多取代四氫噻吩類化合物(3a~3o)。而當(dāng)羥基查爾酮苯環(huán)上含鄰位取代基時,反應(yīng)產(chǎn)率較低(3b)。同時,R1為連有兩個甲基的苯環(huán)時,反應(yīng)產(chǎn)率也較低(3k)。此外,當(dāng)R2為甲基時,可以高效得到目標產(chǎn)物3n和3o。產(chǎn)物3a的結(jié)構(gòu)經(jīng)X-ray單晶衍射確認(CCDC: 2083166)。
在80 ℃下,甲苯作溶劑,以叔胺DABCO為催化劑,催化羥基取代查爾酮和2,5-二羥基-1,4-二噻烷進行sulfa-Michael-aldol串聯(lián)反應(yīng),高效合成了一系列含酚羥基的多取代四氫噻吩衍生物。該反應(yīng)操作簡單、條件溫和、底物范圍廣。該方法為含酚羥基的多取代四氫噻吩的高效合成提供了一種新的途徑。