一種制備1-三氟甲基-3-磺酰甲基吡咯衍生物的方法
【技術(shù)領(lǐng)域】
[0001] 本發(fā)明涉及一種由堿催化的氮雜烯炔衍生物經(jīng)環(huán)合異構(gòu)化合成1-三氟甲 基-3-磺酰甲基吡咯衍生物方法。
【背景技術(shù)】
[0002] 三氟甲基由于其獨特的性質(zhì)引起了化學(xué)家極大的興趣,因而廣泛應(yīng)用在農(nóng) 藥、醫(yī)藥和材料科學(xué)等領(lǐng)域(文獻(xiàn) 1 : (a)Tomaschenko, 0· A. ;Grushin, V. V. Chem. Rev. 2011, 111, 4475. (b)Purser, S. ;Moore, P. R. ;Swallowb, S. ;Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c)Milller, K. ;Faeh, C. ;Diederich, F. Science 2007,317,1881. (d) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications ;ffi ley-VCH:Weinhiem, Germany, 2004.)。吡略是最重要的雜環(huán)化合物之一。如果把三氟甲基 引入到吡咯環(huán)上就有可能改變吡咯衍生物的性質(zhì)。常用的合成三氟甲基取代的吡咯衍生 物的方法是先得到吡咯衍生物母體,再通過三氟甲基化反應(yīng)把三氟甲基聯(lián)在吡咯環(huán)上(文 南犬 1 : (a)Kino, T. ;Nagase, Y. ;0htsuka, Y. ;Yamamoto, K. ;Uraguchi, D. ;Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98 ; (b)Yang, J. -J. ;Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63, 2656.)。這類傳統(tǒng)的方法有著三氟甲基試劑昂貴和反 應(yīng)條件苛刻等缺點。本文描述了一種以含三氟甲基的氮雜烯炔為原料來合成三氟甲基取取 代的吡咯的方法。
【發(fā)明內(nèi)容】
[0003] 本發(fā)明的目的在于提供一種合成1-三氟甲基-3-磺酰甲基吡咯衍生物的新方法。
[0004]
[0005] 反應(yīng)方程式1 :合成1-三氟甲基-3-磺酰甲基吡咯衍生物具體操作步驟如下(反 應(yīng)方程式1):
[0006] 于反應(yīng)器中進(jìn)行反應(yīng),反應(yīng)器抽真空后通氬氣置換,依次加入氮雜烯炔衍生物(1) 和催化劑,然后加入溶劑,于60°C -140°C下反應(yīng)12-48小時。反應(yīng)結(jié)束后,用抽掉溶劑,固 體溶于二氯甲烷上樣進(jìn)行硅膠柱層析,得到1-三氟甲基-3-磺酰甲基-吡咯衍生物(2)。
[0007] 本發(fā)明有以下優(yōu)點:
[0008] 1.反應(yīng)物易于合成。
[0009] 2.產(chǎn)物含有三氟甲基和磺酰甲基,高度官能化。
[0010] 3.反應(yīng)操作簡單,收率較高。
【具體實施方式】
[0011] 為了更好地理解本發(fā)明,通過以下實例進(jìn)行說明。
[0012]
[0013] 于反應(yīng)器中進(jìn)行反應(yīng),反應(yīng)器抽真空后通氬氣置換,加入氮雜烯炔衍生物 l(0.2mmol)、Cs0Piv(4.7mg,10mol%)和 DMF(lmL)。在 100°C下攪拌反應(yīng) 24 小時。反應(yīng) 結(jié)束后,抽掉溶劑,固體溶于二氯甲烷上樣進(jìn)行硅膠柱層析,洗脫劑為石油醚:乙酸乙酯= 20:1 (體積比)的混合溶劑,得到1-三氟甲基-3-磺酰甲基吡咯衍生物2。
[0014] 下表給出14個實施例的情況:
[0015]
[0016] 各產(chǎn)物的的表征數(shù)據(jù)如下:
[0017] Methyl
[0018] 5-phenyl-4 -(phenyl (tosyl) methyl)-2 -(trifluoromethyl) -lH-pyrr ole-3-carbo xylate (2a) : white solid ;mp 210-211 °C NMR (400MHz, CDC13) δ 8. 93 (s, 1H), 7. 49 (d, J = 8. 0Hz, 2H) , 7. 32 (t, J = 7. 4Hz, 1H), 7. 24 (d, J = 7. 8Hz, 2H), 7. 19 (t, J = 7. 6Hz, 2H), 7. 13 (d, J = 8. 1Hz, 2H), 7. 08 (t, J = 7. 3Hz, 1H), 7. 05 -6.96(m,4H),6.68(s,lH),3.74(s,3H),2.35(s,3H) ;13C NMR(100MHz,CDC13) δ163·9,144·3 ,136. 1, 135. 3, 133. 1, 130. 7, 130. 3, 129. 8, 129. 3, 129. 2, 129. 0, 127. 93, 127. 85, 127. 6, 12 1.7(q, J = 39. 3Hz), 120. 3 (q, J = 268. 7Hz), 116. 4(q, J = 2. 0Hz), 115. 3,65. 8,51.7,21.6 ; 19F NMR(376MHz,CDC13) δ-59· 11 ;HRMS(Q-T0F,m/z)calcd for C27H26F3N204S[M+NH 4]+531. 15 60, found 531. 1588.
[0019] Methyl
[0020] 4-(phenyl (tosyl) methyl)- 5- (m-tolyl) -2-(trifluoromethyl) -lH-py rrole-3-ca;r boxylate(2b):white solid ;mp 214-215 O;1!! M1R(400MHz,CDC13) δ 8. 89 (s, 1H), 7. 48 (d, J = 8. 2Hz, 2H) , 7. 28 (d, J = 7. 5Hz, 2H), 7. 12 (t, J = 9. 3Hz, 5H), 7. 03 (t, J = 7. 5Hz, 2H), 6. 95 - 6. 85 (m, 1H), 6. 62 (d, J = 8. 5Hz, 2H), 3. 73 (s ,3H),2. 36 (s, 3H),2. 19 (s, 3H) ;13C NMR(100MHz, CDC13) δ 163. 9, 144. 2, 137. 5, 136. 1,135 .6, 133. 2, 131. 2, 130. 1, 129. 9, 129. 8, 129. 3, 129. 0, 127. 9, 127. 8, 127. 6, 121. 54 (q, J = 39. 3Hz), 127. 51, 120. 3 (q, J = 268. 5Hz), 116. 4 (q, J = 2. 0Hz), 115. 1, 65. 8, 51. 7, 21. 6, 21 ? 3 ;19F NMR(376MHz, CDC13) δ -59. 08 ;HRMS(Q-T0F,m/z)calcd for C2SH25F3N04S[M+H]+528. 1 451, found 528. 1453.
[0021] Methyl
[0022] 4-(phenyl (tosyl) methyl)- 5-(p-tolyl)-2 -(trifluoromethyl) - lH-py rrole-3-ca;r boxylate(2c):white solid ;mp 233-234 O;1!! M1R(400MHz,CDC13) δ 8. 74 (s, 1H), 7. 51 (d, J = 8. 2Hz, 2H), 7. 27 (d, J = 7. 5Hz, 2H), 7. 12 (dd, J = 14. 8, 7. 7Hz, 3H), 7. 03 (t, J = 6. 9Hz, 4H), 6. 92 (d, J = 8. 0Hz, 2H), 6. 67 (s, 1H), 3. 76 (s, 3H ),2. 36 (s, 6H) (2CH3) ;13C NMR (100MHz, CDC13) δ 163. 9, 144. 2, 139. 3, 136. 2, 135. 4, 133. 3, 130. 6, 129. 9, 129. 3, 129. 0, 128. 7, 127. 9, 127. 6, 127. 4, 121. 6 (q, J = 39. 4Hz), 120. 4 (q, J =268. 4Hz), 116. 4(q, J = 2. 3Hz), 115. 3, 65. 9, 51. 7, 21. 7, 21. 5 ;19F NMR(376MHz, CDC13) δ-59. 16 ;HRMS(Q-T0F,m/z)calcd for C28H25F3N04S [M+H]+528. 1451, found 528. 1459.
[0023] Methyl
[0024] 5- (2-methoxyphenyl)~4~(phenyl(tosyl)methyl)~2~(trifluoromethyl)-1 H-pyr ΓοΙθΙ?ΒΛοχγΙα?θΟ?Ι):1!! NMR(400MHz,CDCl3)Sl0.29(s,lH),7.53(dd,J = 7. 7, 1. 5Hz, 1H), 7. 37 (d, J = 8. 3Hz, 2H), 7. 35 - 7. 26 (m, 2H), 7. 24 - 7. 19 (m, 2H), 7. 16 (d, J =8. 1Hz, 2H), 7. 02 (td, J = 7. 6, 0. 9Hz, 1H), 6. 80 - 6. 73 (m, 3H), 5. 84 (s, 1H) ,3.63( s, 3H), 3. 53(s, 3H), 2. 40(s, 3H) ;13C 匪R(100MHz, CDC13) δ 163. 1,157. 0, 145. 1,135 .1, 132. 3, 130. 9, 130. 3, 130. 1, 129. 53, 129. 51, 128. 7, 127. 6, 127. 5, 123. 4(q, J = 38. 2Hz), 123. 2, 121. 5, 120. 4 (q, J = 268. 7Hz), 120. 3, 114. 7 (q, J = 2. 2Hz), 111. 7, 60. 3, 5 5. 6, 51. 6, 21. 7 ;19F NMR(376MHz, CDC13) δ -59. 24.
[0025] Methyl
[0026] 4- (phenyl (tosyl) methyl) ~2~ (trifluoromethyl) -5- (2~ (trifluoromethyl) phenyl)-lH-pyrrole-3-
[0027] carboxylate (2e) : white solid ;mp 198-199 °C NMR (400MHz, CDC13) δ 9. 07 (s, 1H) , 8. 13 - 7. 47 (m, 5H) , 7. 41 (d, J = 5. 8Hz , 1H) , 7. 1 5 (d, J = 8. 1Hz, 2H), 6. 93(d, J = 20. 3Hz, 4H), 6. 81 (t, J = 7. 2Hz, 2H), 3. 82 (s, 3H), 2. 33 (s, 3H); 13CNMR(100MHz,CDC13)S164.0,144.3,135.8,131.1,130.5,130.3,130.0,129.93,129. 90, 129. 4, 129. 1, 128. 0, 127. 6, 127. 5, 125. 9, 125. 8, 123. 2 (q, J = 274. 8Hz), 122. 1 (q, J =39. 4Hz), 120. 2(q, J = 268. 6Hz), 116. 3, Π 6. 2 (q, J = 1. 2Hz), 65. 5, 51. 7, 21. 6 ;19F NMR (376MHz, CDC13) δ-59.37 ;HRMS(Q-T0F,m/z) calcd for C2SH25F6N204S[M+NH 4]+599. 1434, found 599.1454.
[0028] Methyl
[0029] 5- (2-fluorophenyl)~4~(phenyl (tosyl)methyl)~2~(trifluoromethyl)-1H -pyrro le-3-carboxylate(2f):white solid ;mp 218-219 O;1!! NMR(400MHz,CDC13) δ 8. 85 (s, 1H), 7. 35 (d, J = 8. 2Hz, 2H), 7. 17 - 7. 11 (m, 1H), 7. 07 - 7. 03 (m, 2H), 6. 99 - 6. 89 (m, 4H), 6. 98 - 6. 90 (m, 3H), 6. 67 (t, J = 9. 0Hz, 1H), 6. 60 (s, 1H), 3. 55 (s, 3H), 2. 1 7(s,3H);13C NMR(100MHz,CDCl3)Sl63.6,161.0(d,J = 249.1Hz), 144. 4,135.9, 134.1 ,132. 9, 131. 6(d, J = 8. 2Hz), 129. 6, 129. 3, 129. 1, 128. 5, 127. 9, 127. 6, 123. 6 (d, J = 3. 6Hz), 122. 5 (q, J = 39. 2Hz), 120. 2 (q, J = 268. 6Hz), 117. 5, 116. 2 (q, J = 2. 1Hz), 115 ? 3, 115. 1,65.2,51.6,21.7 ;19F NMR(376MHz,CDC13) δ-59. 39,-112. 29 ;HRMS(Q-T0F,m/z) calcd for C27H25F4N204S [M+NHj+549. 1466, found 549. 1487.
[0030] Methyl
[0031] 5- (4-f luorophenyl) ~4~ (phenyl (tosyl) methyl) ~2~ (trif luoromethyl) -lH-pyr ro le-3-carboxylate (2g) : white solid ;:Η NMR(400MHz, CDC13) δ 8. 83 (s, 1H), 7. 54 (d, J =8. 2Hz, 2H), 7. 18 (t, J = 8. 2Hz, 4H), 7. 11 - 6. 96 (m, 5H), 6. 92 - 6. 85 (m, 2H), 6. 81 (s, 1H), 3. 77 (s, 3H), 2. 37 (s, 3H) ;13CNMR (100MHz, CDC13) δ 163. 8, 163. 4 (d, J = 249. 4Hz), 144. 4, 136. 0, 134. 1, 133. 1, 133. 0, 129. 7, 129. 4, 129. 1, 127. 9, 127. 6, 12 6. 4(d, J = 3. 4Hz), 121. 8(q, J =