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聚焦微波促进下碳酸二甲酯作甲基化试剂合成甲基取代的2-巯基吡啶并[2,3-d]嘧啶酮

    聚焦微波促进下碳酸二甲酯作甲基化试剂合成甲基取代的2-巯基吡啶并[2,3-d]嘧啶酮
    王喜存,姚 轲,梁军灵,张 彰,权正军
    (西北师范大学 化学化工学院,甘肃省高分子材料重点实验室,甘肃 兰州 730070)
    摘 要:在聚焦微波辐射下,氧化镁和四丁基溴化铵存在时,以二甲基亚砜为共催化剂,碳酸二甲酯作甲基化试剂,实现了2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮的甲基化反应,并且可选择性地得到单甲基化和双甲基化的二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮衍生物.结果表明,该甲基化方法具有产率高、时间短等优点.使用无毒的碳酸二甲酯代替碘甲烷或硫酸二甲酯作为甲基化试剂,避免了强碱和有毒试剂的使用,符合绿色化学的要求.
    关键词:2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮;碳酸二甲酯;聚焦微波辐射;甲基化
    中图分类号:O 626.4    文献标识码:A    文章编号:1001-988Ⅹ(2012)05-0061-06
  
    碳酸二酯尤其是碳酸二甲酯(DMC)被认为是卤代甲烷或硫酸二甲酯的环境友好的替代试剂,在近年来得到了广泛的关注和应用[1-5].舒婷等[6]综述了碳酸二甲酯作甲基化试剂在碳、氧、氮和硫原子上进行甲基化反应的研究进展.本课题组曾报道了家用微波炉微波辐射下碳酸二甲酯为甲基化试剂对3,4-二氢嘧啶硫酮进行甲基化的反应研究[7],取得了理想的结果.吡啶并[2,3-d]嘧啶-4-酮类稠环化合物是一类具有良好生理活性的多氮稠合杂环化合物,具有抗肿瘤[8]、抗菌[9]、镇痛[10]、利尿[11]、CXCR3拮抗[12]等良好的生物活性.然而有关吡啶并[2,3-d]嘧啶-4-酮衍生物反应的研究较少[11-13],并且所需原料的制备较为繁琐,因此,寻找一种简洁、高效合成该类化合物的方法显得尤为重要.
    本研究小组以碳酸二甲酯为甲基化试剂,在聚焦微波辐射下,利用氧化镁(MgO)作碱,四丁基溴化铵(TBAB)存在下,DMSO为共催化剂,实现了2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮1的甲基化反应,选择性的合成了2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮2和3-甲基-2-甲硫 基-5,7-二 芳 基 吡 啶 并 [2,3-d]嘧 啶-4(3H)-酮3,合成过程见图1.
     
    1 实验部分
    1.1 仪器与试剂
    微波仪器用美国CEM公司微波合成系统;红外光谱用Digilab Merlin FT-IR 360光谱仪测定,KBr压片;核磁共振谱用Mercury plus-400核磁共振仪测定,DMSO为溶剂,Me4Si为内标;高分辨质谱用Bruker Daltonics APEXII 47eFT-ICR质谱仪测定.实验中所用的试剂和溶剂均为市售分析纯,未经进一步处理.2-氨基-3-甲酰氨基-4,6-二芳基吡啶参照文献[14]制备.
    1.2 实验步骤
    1.2.1 2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮(1)的制备 将1mmol 2-氨基-3-甲酰氨基-4,6-二芳基吡啶、2mmol CS2、3mmol KOH、2mL DMF加入到10mL的带磁搅拌子的密封管中,设定微波辐射功率为10 W,温度迅速从室温上升到155℃,持续辐射15min.TLC检测,反应结束后,将反应液冷却至室温,加入5mL水,析出大量固体,抽滤,用乙醇-DMF重结晶得化合物1.
    1.2.2 聚焦微波辐射合成2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮 (2)  将 1 mmol 1、1mmol DMC、1 mmol MgO、1 mmol TBAB和0.1mL DMSO加入到10mL的带磁搅拌子的密封管中.设定微波辐射功率为10 W,温度迅速从室温上升到180 ℃,持续辐射12min.TLC检测反应结束后,将反应液冷却至室温,加入乙醇和水,析出大量固体,抽滤,用乙醇-DMF重结晶得化合物2.
    1.2.3 聚焦微波辐射合成3-甲基-2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮(3) 将1mmol1、10mmol DMC、1mmol MgO、1mmol TBAB和0.1mL DMSO加入到10mL的带磁搅拌子的密封管中.设定微波辐射功率为10 W,温度迅速从室温上升到180 ℃,持续辐射12min.TLC检测反应结束后,将反应液冷却至室温,加入乙醇和水,析出大量固体,抽滤,用乙醇-DMF重结晶得化合物3.
    2 结果与讨论
    2.1 反应条件的探索
    探索了DMC的用量对甲基化产物1的影响,当反应物1和DMC的摩尔比为1∶1时,产物为单甲基化的2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮2;反应物1和DMC的摩尔比为1∶10时,产物为双甲基化的3-甲基-2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮3.以化合物3a的合 成 为 例, 在1 mmol 1a、10 mmol DMC、1mmol MgO、1mmol TBAB、0.1mL DMSO的条件下,考察不同反应时间和反应温度对3a产率的影响,结果见表1.由表1可见,随着反应温度的增大,反应产率逐渐提高,在180℃时反应8min,所得产物3a的产率最高,可达75%;但当温度升高至190 ℃时,3a的产率反而下降.同样,随着聚焦辐射时间的加长,产率逐渐提高,当在180℃辐射反应12min时,3a的产率最高(80%),再继续延长辐射时间,反应产率没有明显的变化.
    在此最佳反应条件下,合成了13个2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮(2a~2m)和13个3-甲基-2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮(3a~3m)(表2).由表2结果可以看出,芳环上无论带有供电子基团还是吸电子基团,无溶剂下应用聚焦微波反应可以较高产率的合成出相应的单甲基化产物和双甲基化产物.使用无毒的DMC取代了碘甲烷或硫酸二甲酯为甲基化试剂,同时,以DMC为反应溶剂,避免了有毒试剂溶剂的使用;聚焦微波技术大大缩短了反应时间.
    
    
      
    比较了聚焦微波辐射和传统加热对反应产率和反应时间的影响,结果见表3.从表3可以看出,在聚焦微波辐射条件下合成化合物2和3比传统加热快30倍左右,产率也明显提高.
    2.2 波谱分析
    所合成的化合物经IR、1 HNMR、13 CNMR和HRMS分析确证.在2a~2m的1 HNMR谱中,巯甲基碳上质子信号在δ3.59~3.69处呈现单峰,氮氢上质子信号在δ12.89~14.49处呈现宽峰;在3a~3m的1 HNMR谱中,巯甲基和氮甲基碳上质子信号分别在δ2.63~2.82和δ3.34~3.82处呈现单峰;在2a~2m的IR谱中,3 000~3 200cm-1范围内的吸收峰为—N—H的伸缩振动;在3a~3m的IR谱中,2 850~2 960cm-1范围内的吸收峰为—CH3的伸缩振动.对2a~2m和3a~3m的HRMS研究发现,可以确定目标化合物分子量.
    2.3 化合物的表征数据
    2a产率82%;1 HNMR(400MHz,DMSO-d6)δ:13.20(br,1H),8.24(d,J=6.4Hz,2H),7.65~7.43(m,9H),3.66(s,3H);IR(KBr)ν:3107,3051,2926,2892,1682,1597,1555,1496,1406,1177,766cm-1;HRMS(ESI)C20H16N3OS[M+H]+:346.0903(计算值),346.0900(实测值).
    2b产率85%;1 HNMR(400MHz,DMSO-d6)δ:13.14(br,1H),8.24(m,2H),7.66~7.49(m,8H),3.68(s,3H);IR(KBr)ν:3125,3047,2945,2899,2539,1676,1597,1555,1494,1176,772cm-1cm-1;HRMS(ESI)C20H15ClN3OS[M + H]+:380.0560(计算值),380.0564(实测值).
    2c产率90%;1 HNMR(400MHz,DMSO-d6)δ:13.09(br,1H),8.23(m,2H),7.61~7.23(m,8H),3.59(s,3H),2.38(s,3H);IR(KBr)ν:3122,3055,2910,1701,1601,1555,1170,776cm-1;HRMS(ESI)C21H18N3OS[M+H]+:360.1160(计算值),360.1166(实测值).
    2d产率80%;1 HNMR(400MHz,DMSO-d6)δ:14.49(br,1H),8.29(m,2H),7.80~6.91(m,8H),3.81(s,3H),3.68(s,3H);IR(KBr)ν:3120,3050,2900,2538,1676,1600,1492,1495,1176,778cm-1;HRMS(ESI)C21H18N3O2S[M+H]+:376.1047(计算值),376.1052(实测值).
    2e产率72%;1 HNMR(400MHz,DMSO-d6)δ:12.89(br,1H),8.09(m,2H),7.51~7.40(m,8H),3.65(s,3H);IR(KBr)ν:3291,3067,2917,1701,1668,1603,1557,1508,1410,1173,774cm-1;HRMS(ESI)C20H15FN3OS[M+H]+:364.0847(计算值),364.0846(实测值).
    2f产率85%;1 HNMR(400MHz,DMSO-d6)δ:13.16(br,1H),8.24(m,2H),7.70~6.81(m,8H),3.82(s,3H),3.61(s,3H);IR(KBr)ν:3163,3061,2930,2860,1669,1588,1548,1496,1364,1173,753cm-1;HRMS(ESI)C21H18N3O2S[M+ H]+:376.1047(计 算 值),376.1052(实 测值).
    2g产率78%;1 HNMR(400MHz,DMSO-d6)δ:13.27(br,1H),8.25(m,2H),7.68~7.42(m,8H),3.64(s,3H);IR(KBr)ν:3128,3063,2903,2541,1677,1595,1553,1492,1406,1176,772cm-1;HRMS(ESI)C20H15BrN3OS[M+H]+:424.3172(计算值),424.3176(实测值).
    2h产率84%;1 HNMR(400MHz,DMSO-d6)δ:13.15(br,1H),8.22(d,J=8.4Hz,2H),7.95~7.44(m,8H),3.60(s,3H);IR(KBr)ν:3192,3058,2911,2868,2541,1705,1647,1595,1566,1402,1185,765cm-1;HRMS(ESI)C20H15BrN3OS[M+ H]+:424.3172(计 算 值),424.3176(实 测值).
    2i产率95%;1 HNMR(400MHz,DMSO-d6)δ:13.18(br,1H),8.24(m,2H),7.65~7.33(m,7H),3.59(s,3H),2.40(s,3H);IR(KBr)ν:3156,3042,2911,2482,1590,1553,1510,1493,1152,812,712cm-1;HRMS(ESI)C21H17BrN3OS[M+ H]+:438.0290(计 算 值),438.0291(实 测值).
    2j产率90%;1 HNMR(400 MHz,DMSO-d6)δ:13.13(br,1H),8.23(d,J=7.0Hz,2H),7.81~7.47(m,7H),3.69(s,3H);IR(KBr)ν:3125,3047,2954,2899,2539,1631,1597,1574,1491,1012,824,667cm-1;HRMS(ESI)C20H14BrClN3OS[M+ H]+:457.9716(计 算 值),457.9718(实 测值).
    2k产率80%;1 HNMR(400MHz,DMSO-d6)δ:13.02(br,1H),8.16(d,J=7.0Hz,2H),7.73~7.43(m,7H),3.66(s,3H);IR(KBr)ν:3139,3067,2928,1701,1668,1634,1557,1509,1452,1173,774cm-1;HRMS(ESI)C20H14BrFN3OS[M+H]+:441.9903(计 算 值),441.9905(实 测值).
    2l产率93%;1 HNMR(400 MHz,DMSO-d6)δ:13.21(br,1H),8.24(d,J=7.0Hz,2H),7.82~7.43(m,7H),3.67(s,3H);IR(KBr)ν:3128,3060,2903,2545,1678,1595,1553,1492,1406,1176,778cm-1;HRMS(ESI)C20H14Br2N3OS[M+H]+:501.9147(计 算 值),501.9154(实 测值).
    2m产 率87%;1 HNMR(400 MHz,DMSO-d6)δ:13.82(br,1H),8.26(d,J=7.0 Hz,2H),7.88~7.18(m,7H),3.79(s,3H),3.66(s,3H);IR(KBr)ν:3165,3055,2948,2838,1701,1591,1555,1512,1169,829cm-1;HRMS(ESI)C21H17BrN3O2S[M+ H]+:454.0190(计 算 值),454.0194(实 测值).
    3a产率80%;1 HNMR(400MHz,DMSO-d6)δ:8.24(d,J=6.4Hz,2H),7.65~7.43(m,9H),3.44(s,3H),2.73(s,3H);IR(KBr)ν:3057,2922,1680,1559,1536,1496,1406,1177,766cm-1;HRMS(ESI)C21H18N3OS[M+H]+:360.1165(计算值),360.1159(实测值).
    3b产率88%;1 HNMR(400MHz,DMSO-d6)δ:8.24(m,2H),7.66~7.49(m,8H),3.42(s,3H),2.71(s,3H);IR(KBr)ν:3047,2926,2849,2539,1676,1597,1555,1494,1176,772 cm-1;HRMS(ESI)C21H17ClN3OS[M+H]+:394.0798(计算值),394.0794(实测值).
    3c产率95%;1 HNMR(400MHz,DMSO-d6)δ:8.23(m,2H),7.61~7.23(m,8H),3.45(s,3H),2.75(s,3H),2.38(s,3H);IR(KBr)ν:3055,2910,1701,1601,1555,1170,776 cm-1;HRMS(ESI)C22H20N3OS[M+H]+:374.1292(计算值),374.1291(实测值).
    3d产率80%;1 HNMR(400MHz,DMSO-d6)δ:8.29(m,2H),7.80~6.91(m,8H),3.81(s,3H),3.46(s,3H),2.78(s,3H);IR(KBr)ν:3050,2900,2538,1676,1600,1492,1495,1176,778cm-1;HRMS(ESI)C22H20N3O2S[M + H]+:390.1264(计算值),390.1269(实测值).
    3e产率74%;1 HNMR(400MHz,DMSO-d6)δ:8.09(m,2H),7.51~7.40(m,8H),3.34(s,3H),2.63(s,3H);IR(KBr)ν:3067,2917,1701,1668,1603,1557,1508,1410,1173,774 cm-1;HRMS(ESI)C21H17FN3OS[M+H]+:378.1022(计算值),378.1017(实测值).
    3f产率80%;1 HNMR(400MHz,DMSO-d6)δ:8.24(m,2H),7.70~6.81(m,8H),3.82(s,3H),3.42(s,3H),2.71(s,3H);IR(KBr)ν:3061,2930,2860,1669,1588,1548,1496,1364,1173,753cm-1;HRMS(ESI)C22H20N3O2S[M+H]+:390.1264(计算值),390.1269(实测值).
    3g产率83%;1 HNMR(400MHz,DMSO-d6)δ:8.25(m,2H),7.68~7.42(m,8H),3.44(s,3H),2.73(s,3H);IR(KBr)ν:3063,2903,2541,1677,1595,1553,1492,1406,1176,772 cm-1;HRMS(ESI)C21H17BrN3OS[M+H]+:438.0245(计算值),438.0248(实测值).
    3h产率78%;1 HNMR(400MHz,DMSO-d6)δ:8.22(d,J=8.4Hz,2H),7.95~7.44(m,8H),3.43(s,3H),2.72(s,3H);IR(KBr)ν:3058,2926,2868,2541,1705,1647,1595,1566,1402,1185,765cm-1;HRMS(ESI)C21H17BrN3OS[M+H]+:438.0245(计算值),438.0248(实测值).
    3i产率83%;1 HNMR(400MHz,DMSO-d6)δ:8.24(m,2H),7.65~7.33(m,7H),3.49(s,3H),2.82(s,3H),2.40(s,3H);IR(KBr)ν:3042,2911,2482,1590,1553,1510,1493,1152,812,712cm-1;HRMS(ESI)C22H19BrN3OS[M+H]+:452.0438(计算值),452.0437(实测值).
    3j产率95%;1 HNMR(400 MHz,DMSO-d6)δ:8.23(d,J=7.0Hz,2H),7.81~7.47(m,7H),3.53(s,3H),2.82(s,3H);IR(KBr)ν:3047,2926,2899,2539,1631,1597,1574,1491,1012,824,667cm-1;HRMS(ESI)C21H16BrClN3OS[M+H]+:471.9822(计算值),471.9817(实测值).
    3k产率90%;1 HNMR(400MHz,DMSO-d6)δ:8.16(d,J=7.0Hz,2H),7.73~7.43(m,7H),3.51(s,3H),2.80(s,3H);IR(KBr)ν:3067,2928,1701,1668,1634,1557,1509,1452,1173,774cm-1;HRMS(ESI)C21H16BrFN3OS[M+H]+:456.0165(计算值),456.0159(实测值).
    3l产率80%;1 HNMR(400 MHz,DMSO-d6)δ:8.24(d,J=7.0Hz,2H),7.82~7.43(m,7H),3.48(s,3H),2.80(s,3H);IR(KBr)ν:3060,2903,2545,1678,1595,1553,1492,1406,1176,778cm-1;HRMS(ESI)C21H16Br2N3OS[M+H]+:515.9336(计算值),:515.9338(实测值).
    3m产率:92%;1 HNMR(400 MHz,DMSO-d6)δ:8.26(d,J=7.0 Hz,2H),7.88~7.18(m,7H),3.79(s,3H),3.45(s,3H),2.70(s,3H);IR(KBr)ν:3055,2948,2838,1701,1591,1555,1512,1169,829cm-1;HRMS(ESI)C22H19BrN3O2S[M+H]+:468.0360(计算值),468.0364(实测值).
    3 结论
    在聚 焦 微 波 辐 射 条 件 下,MgO、TBAB和DMSO存在时,以DMC作甲基化试剂,实现了2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮的甲基化反应,快速合成了2-甲硫基-5,7-二芳基吡西啶并[2,3-d]嘧啶-4(3H)-酮和3-甲基-2-甲硫基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮.该甲基化方法适应于一系列2-巯基-5,7-二芳基吡啶并[2,3-d]嘧啶-4(3H)-酮的甲基化.使用无毒的DMC取代了卤代甲烷或硫酸二甲酯为甲基化试剂,在反应中,DMC既作为反应物参与反应,同时也是反应的溶剂,不需其他有机溶剂,对环境友好;聚焦微波辐射具有反应快、操作简便、产率高等特点.
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