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• 含有2-甲基-1-取代苯基-2-丙胺的结构单元存在于许多生物活性分子中, 例如, 用于治疗抑郁症的胃饥饿素受体拮抗剂ghrelin receptor antagonists^[1]、用于治疗胃肠道和心血管疾病的钙敏感受体抑制剂CaSR antagonists^[2]、用于治疗肥胖症的β₃肾上腺素受体激动剂LY377604^{[3, 4]}以及长效β₂肾上腺素受体激动剂BI167107(图 1)^[5~7].

  图 1

  

  图 1.  含2-甲基-1-取代苯基-2-丙胺结构单元的生物活性化合物

  Figure 1.  Several biological active compounds which contain 2-methyl-1-substituted-phenyl-2-propylamine subunits

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  2009年, Hoenke等^{[6, 7]}利用2-甲基苯丙烯同氰化钠进行Ritter反应^[8~10]合成了2-甲基-1-取代苯基-2-丙胺类化合物.但是, 氰化钠是剧毒品, 尤其是在酸性条件下, 所生成的氢氰酸是致命的.他们也尝试了芳基乙酸酯与甲基格氏试剂反应, 所生成的2-甲基-1-取代苯基-2-丙醇同乙腈在浓硫酸条件下进行Ritter反应.不过, Ritter反应的产率不高, 浓硫酸腐蚀性比较大.另外, 有些芳基乙酸酯, 例如2-甲基苯基乙酸酯, 价格昂贵, 市场上不易购买.

  2013年, 王江波等^[11]以2-甲基苯甲醛为原料, 经过Wittig反应、Ritter反应和高温水解反应, 以16%的总产率合成了2-甲基-1-(2-甲基苯基)-2-丙胺.其中, Ritter反应的产率只有30%.

  2015年, Ling等^[12]以碘代烷为原料, 在二异丙基氨基锂(LDA)作用下与异丁酸乙酯发生烷基化反应, 接着, 经过水解成酸, Curtius重排以及酸处理, 合成了2-甲基-1-(2-甲基苯基)-2-丙胺及其它含有2-甲基-2-丙胺单元的化合物.该方法比较直接, 不过, 碘代烷不是很稳定, 而且很多碘代烷市场上没有销售.

  上述文献合成方法存在所用试剂有毒、环境不友好、原料价格昂贵且不易购买以及产率不高等诸多局限性.鉴于2-甲基-1-取代苯基-2-丙胺类化合物是许多药物中间体的重要组成部分, 因此, 寻找一条经济实用的路线来合成该类化合物具有现实意义.为了克服上述缺陷, 我们以廉价易得的2-甲基氯化苄为原料, 来合成2-甲基-1-(2-甲基苯基)-2-丙胺(1a) (Scheme 1).

  图式 1

  

  图式 1.  2-甲基-1-(2-甲基苯基)-2-丙胺(1a)的合成路线

  Scheme 1.  Synthesis of 2-methyl-1-(2-methyl phenyl)-2-propyl- amine (1a)

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  1.   结果与讨论

  首先, 在LDA存在下, 2-甲基氯化苄和异丁腈在－78 ℃下反应^[13], 得到2-甲基-1-(2-甲基苯基)-2-丁腈(3a), 产率为89%;接着, 在氢氧化钾作用下加热水解8 h, 生成2-甲基-1-(2-甲基苯基)-2-丁酸(4a), 产率高达92%.接下来, 羧酸4a在叠氮磷酸二苯酯(DPPA)、三乙胺以及苄醇的作用下发生Curtius重排^[14~17], 最终以71%的产率得到了化合物5a.值得一提的是, 我们分离得到了Curtius重排中间体2-甲基-1-(2-甲基苯基)-2-丙基-异氰酸酯, 其结构经¹H NMR, ¹³C NMR和HRMS确认^[18].最后一步, 使用钯碳催化加氢^[19]脱去化合物5的Cbz保护基, 生成目标产物2-甲基-1-(2-甲基苯基)-2-丙胺(1a), 产率为57%.

  在顺利合成化合物1a的基础上, 我们对该路线的普适性进行了探索(表 1).选择苯环上为给电子基团(例如甲基和甲氧基以)及吸电子基团(例如氟原子和氯原子)的苄氯进行反应.研究结果表明, 该合成路线可以得到多种2-甲基-1-取代苯基-2-丙胺类化合物1b~1i, 总产率21%~46%.当取代苯环变为位阻较大的萘环时, 也能以较好的总产率(52%)得到2-甲基-1-萘基-2-丙胺(1j).

  表 1

  

  表 1  2-甲基-1-取代苯基-2-丙胺类化合物1的合成

  Table 1.  Synthesis of 2-methyl-1-substituted-phenyl-2-propyl- amines 1

  下载: 导出CSV

  a Overall yield for the 4 steps of reaction from the corresponding benzyl chlorides and 1-(chloromethyl)- naphthalene, respectively.

  该路线同样适用于合成二取代的2-甲基-1-取代苯基-2-丙胺类化合物(Scheme 2).间二苄氯6在碱作用下, 和异丁腈发生烷基化反应生成化合物7, 产率为81%;接着以乙二醇作溶剂, 在氢氧化钾的作用下水解, 生成羧酸8, 产率为74%;随之发生Curtius重排, 以88%产率得到化合物9.最后, 9经过钯碳催化氢化, 生成目标产物10, 产率为45%.

  图式 2

  

  图式 2.  1, 1'-(1, 3-亚苯基)双(2-甲基丙-2-胺)的合成路线

  Scheme 2.  Synthetic route for 1, 1'-(1, 3-phenylene)-bis(2- methyl-propan-2-amine)

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  2.   结论

  发展了一条简便路线用于合成2-甲基-1-取代苯基- 2-丙胺类化合物, 以廉价易得的氯化苄为原料, 经过四步反应, 以较好的产率得到了2-甲基-1-取代苯基-2-丙胺衍生物1a~1i和2-甲基-1-萘基-2-丙胺(1j), 还有双取代衍生物1, 1'-(1, 3-亚苯基)-双(2-甲基丙-2-胺)(10).该合成方法操作简单, 原料廉价易得, 避免了使用有毒试剂, 可以很方便地用于合成含有此结构单元且具有重要生物活性的新颖化合物.

  3.   实验部分

  3.1   仪器与试剂

  数显加热磁力搅拌器, 型号为IKA C-MAG HS 7; NMR用Bruker (300 MHz和400 MHz)型核磁共振仪测定(CDCl₃, DMSO-d₆作溶剂, TMS为内标); HRMS用Thermo Orbitrap Elite测定; 熔点用SGW X-4B显微熔点仪测定.柱层析用160~200目硅胶购自青岛海洋化工厂, 薄层色谱(TLC)分析使用HSGF-254薄层色谱板(烟台江友硅胶开发有限公司).试剂和溶剂均为分析纯.

  3.2   实验方法

  3.2.1   2-甲基-1-取代苯基-2-丁腈(3)的合成

  在氮气保护下, 取二异丙胺(3.97g, 39.2 mmol, 1.1 equiv.)溶于四氢呋喃(25 mL)中, 降温至－78 ℃, 滴加正丁基锂(15.75 mL, 39.4 mmol, 1.1 equiv.), 搅拌30 min后, 在此温度下, 将异丁腈(2.75 g, 39.8 mmol, 1.1 equiv.)逐滴滴加到反应液中, 搅拌1 h, 再加入取代芳基甲基氯(35.4 mmol)搅拌30 min后移至室温.向反应液中加稀盐酸(20 mL)淬灭反应, 所得混合物用乙酸乙酯(80 mL×3)萃取, 合并有机相, 有机相依次用水(30 mL×2)和饱和食盐水(30 mL)洗涤, 无水硫酸钠干燥.粗产物经过柱层析纯化[(V(石油醚):V(乙酸乙酯)＝20:1]得化合物3.

  2-甲基-1-(2-甲基苯基)-2-丁腈(3a):产率89%, 无色透明液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.30~7.16 (m, 4H), 2.88 (s, 2H), 2.38 (s, 3H), 1.40 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 137.56, 134.74, 131.58, 131.33, 127.89, 126.42, 125.57, 42.92, 34.43, 27.38, 20.79; HRMS (ESI, positive) calcd for C₁₂H₁₅NNa [M+Na]⁺ 196.1097, found 196.1094.

  2-甲基-1-(3-甲基苯基)-2-丁腈(3b):产率84%, 白色固体. m.p. 40~42 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.25~7.20 (m, 1H), 7.11~7.05 (m, 3H), 2.77 (s, 2H), 2.35 (s, 3H), 1.34 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 136.92, 134.56, 129.93, 127.20, 127.02, 126.23, 123.80, 45.54, 32.42, 25.50, 20.38; HRMS (ESI, positive) calcd for C₁₂H₁₅NNa [M+Na]⁺ 196.1097, found 196.1102.

  2-甲基-1-(4-甲基苯基)-2-丁腈(3c):产率91%, 无色透明液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.15 (s, 4H), 2.77 (s, 2H), 2.34 (s, 3H), 1.33 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 137.50, 133.16, 130.64, 129.61, 125.42, 46.83, 34.11, 27.01, 21.62; HRMS (ESI, positive) calcd for C₁₂H₁₅NNa [M+Na]⁺ 196.1097, found 196.1093.

  2-甲基-1-(2-氯苯基)-2-丁腈(3d):产率87%, 白色晶体. m.p. 32~33 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.50~7.46 (m, 1H), 7.41~7.40 (d, J＝1.6 Hz, 1H), 7.30~7.20 (m, 2H), 3.05 (s, 2H), 1.61 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 135.03, 133.87, 132.18, 129.87, 128.86, 127.04, 124.78, 42.16, 34.30, 26.58; HRMS (ESI, positive) calcd for C₁₁H₁₂ClNNa [M+Na]⁺ 216.0550, found 216.0555.

  2-甲基-1-(3-氯苯基)-2-丁腈的合成(3e):产率96%, 白色晶体. m.p. 43~44 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.35~7.25 (m, 4H), 2.85 (s, 2H), 1.43 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 137.58, 134.13, 130.18, 129.67, 128.32, 127.58, 124.31, 46.14, 33.34, 26.45; HRMS (ESI, positive) calcd for C₁₁H₁₂ClNNa [M+Na]⁺ 216.0550, found 216.0556.

  2-甲基-1-(4-氯苯基)-2-丁腈(3f):产率74%, 白色晶体. m.p. 43~44 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.26~7.23 (m, 4H), 2.86 (s, 2H), 1.20 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 134.23, 133.47, 131.58, 128.67, 124.53, 46.03, 33.57, 26.52; HRMS (ESI, positive) calcd for C₁₁H₁₂ClNNa [M+Na]⁺ 216.0550, found 216.0564.

  2-甲基-1-(2-氯苯基)-2-丁腈(3g):产率76%, 无色透明液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.38~7.35 (m, 1H), 7.28~7.25 (m, 1H), 7.15~7.04 (m, 2H), 2.89 (s, 2H), 1.38 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.62, 132.92, 129.88, 129.85, 125.11, 124.74, 116.05, 39.40, 34.28, 26.86; HRMS (ESI, positive) calcd for C₁₁H₁₂FNNa [M+Na]⁺ 200.0846, found 200.0851.

  得到2-甲基-1-(4-氟苯基)-2-丁腈(3h):产率97%, 无色透明液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.26~7.21 (m, 2H), 7.05~7.00 (m, 2H), 2.79 (s, 2H), 1.35 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 163.79, 160.54, 131.68, 131.57, 124.49, 115.36, 115.07, 45.75, 33.52, 33.50, 26.33; HRMS (ESI, positive) calcd for C₁₁H₁₂FNNa [M+Na]⁺ 200.0846, found 200.0863.

  2-甲基-1-(4-甲氧基苯基)-2-丁腈(3i):产率87%, 白色固体. m.p. 46~48 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.20~7.17 (d, J＝12.0 Hz, 2H), 6.88~6.86 (d, J＝8.0 Hz, 2H), 3.80 (s, 3H), 2.75 (s, 2H), 1.33 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.82, 131.15, 127.71, 124.82, 113.69, 55.17, 45.78, 33.62, 26.31; HRMS (ESI, positive) calcd for C₁₂H₁₅NONa [M+Na]⁺ 212.1046, found 212.1051.

  得到2-甲基-1-萘基-2-丁腈(3j):产率97%, 白色固体. m.p. 33~35 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.85~7.78 (m, 1H), 7.54~7.50 (m, 2H), 7.49~7.43 (m, 4H), 3.32 (s, 2H), 1.39 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 134.52, 133.22, 132.63, 129.63, 129.53, 128.77, 126.59, 126.24, 125.90, 125.69, 124.64, 42.09, 34.97, 27.69; HRMS (ESI, positive) calcd for C₁₅H₁₅NNa [M+Na]⁺ 232.1097, found 232.1099.

  3.2.2   2-甲基-1-取代苯基-2-丁酸(4)的合成

  取化合物3 (23.7 mmol)加到50 mL单口烧瓶中, 再加入KOH (4.0 g, 71.5 mmol, 3 equiv.)和乙二醇(30 mL), 然后, 在170 ℃下加热回流8 h, TLC检测反应完成.冷却至室温, 向反应液中加入10%盐酸溶液调节pH＝1.所得混合物用乙酸乙酯(50 mL×3)萃取, 合并有机相, 有机相依次用水(20 mL×2)和饱和食盐水(20 mL)洗涤, 无水硫酸钠干燥.粗产物经过柱层析纯化[V(二氯甲烷):V(甲醇)＝200:1], 得化合物4.

  2-甲基-1-(2-甲基苯基)-2-丁酸(4a):产率93%, 白色固体. m.p. 42~44 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.17~7.12 (m, 4H), 2.97 (s, 2H), 2.33 (s, 3H), 1.24 (d, J＝9.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 184.79, 137.09, 135.96, 130.64, 130.50, 126.54, 125.54, 43.96, 41.96, 24.64, 20.25; HRMS (ESI, negative) calcd for C₁₂H₁₅O₂ [M－H]^－ 191.1080, found 191.1078.

  2-甲基-1-(3-甲基苯基)-2-丁酸(4b):产率60%, 白色固体. m.p. 32~33 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.23~6.95 (m, 4H), 2.85 (s, 2H), 2.31 (s, 3H), 1.20 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.83, 138.09, 138.02, 131.65, 128.50, 127.86, 46.39, 43.98, 25.24, 21.99; HRMS (ESI, negative) calcd for C₁₂H₁₅O₂ [M－H]^－ 191.1078, found 191.1079.

  2-甲基-1-(4-甲基苯基)-2-丁酸(4c):产率87%, 白色固体. m.p. 46~48 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.14~7.04 (m, 4H), 2.85 (s, 2H), 2.32 (s, 3H), 1.20 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.98, 136.58, 135.00, 130.69, 129.32, 46.07, 44.02, 25.20, 21.61; HRMS (ESI, negative) calcd for C₁₂H₁₅O₂ [M－H]^－ 191.1078, found 191.1080.

  2-甲基-1-(2-氯苯基)-2-丁酸(4d):产率94%, 淡黄色固体. m.p. 54~55 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.38~7.36 (m, 1H), 7.27~7.24 (m, 1H), 7.20~7.15 (m, 2H), 3.14 (s, 2H), 1.25 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 184.61, 135.78, 135.35, 131.95, 129.84, 128.11, 126.63, 44.15, 41.58, 24.70; HRMS (ESI, negative) calcd for C₁₁H₁₃Cl₂O₂ [M+Cl]^－ 247.0298, 249.0269; found 247.0300, 249.0268.

  2-甲基-1-(3-氯苯基)-2-丁酸(4e):产率86%, 白色固体. m.p. 52~53 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.21~7.02 (m, 4H), 2.86 (s, 2H), 1.21 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 183.98, 139.54, 133.82, 130.25, 129.29, 128.38, 126.79, 45.36, 43.37, 24.65; HRMS (ESI, negative) calcd for C₁₁H₁₂ClO₂ [M－H]^－ 211.0531, 213.0502; found 211.0531, 213.0503.

  2-甲基-1-(4-氯苯基)-2-丁酸(4f):产率73%, 白色固体. m.p. 79~81 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.20~7.17 (m, 2H), 7.05~7.02 (m, 2H), 2.80 (s, 2H), 1.14 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 184.16, 136.09, 132.64, 131.92, 131.40, 128.65, 128.04, 45.24, 43.55, 24.74; HRMS (ESI, negative) calcd for C₁₁H₁₂ClO₂ [M－H]^－ 211.0531, 213.0502; found 211.0536, 213.0506.

  2-甲基-1-(2-氟苯基)-2-丁酸(4g):产率88%, 黄褐色固体. m.p. 26~27 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.24~7.18 (m, 2H), 7.08~7.00 (m, 2H), 2.96 (s, 2H), 1.22 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.70, 163.48, 133.06, 129.15, 125.41, 124.44, 116.06, 44.19, 38.84, 25.12; HRMS (ESI, negative) calcd for C₁₁H₁₂FO₂ [M－H]^－ 195.0827, found 195.0832.

  2-甲基-1-(4-氟苯基)-2-丁酸(4h):产率83%, 淡褐色固体. m.p. 33~35 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.14~7.10 (m, 2H), 6.97~6.93 (t, J＝8.7 Hz, 2H), 2.85 (s, 2H), 1.19 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.61, 163.16, 160.73, 133.34, 133.31, 131.78, 131.70, 115.11, 114.90, 45.13, 43.61, 24.74; HRMS (ESI, negative) calcd for C₁₁H₁₃FClO₂ [M+Cl]^－ 231.0594, found 231.0597.

  2-甲基-1-(4-甲氧基苯基)-2-丁酸(4i):产率70%, 白色固体. m.p. 54~56 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.10~7.07 (d, J＝11.6 Hz, 2H), 6.83~6.80 (d, J＝11.6, 2H), 3.78 (s, 3H), 2.83 (s, 2H), 1.19 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.63, 158.41, 131.31, 129.72, 113.56, 55.30, 45.16, 43.66, 24.71; HRMS (ESI, negative) calcd for C₁₂H₁₅O₃ [M－H]^－ 207.1027, found 207.1026.

  2-甲基-1-萘基-2-丁酸(4j):产率93%, 白色固体. m.p. 95~96 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.50~7.34 (m, 4H), 3.43 (s, 2H), 1.24 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 184.58, 134.00, 133.91, 133.13, 128.79, 128.49, 127.46, 125.68, 125.38, 125.16, 124.50, 44.13, 40.77, 25.10; HRMS (ESI, negative) calcd for C₁₅H₁₅O₂ [M－H]^－ 227.1078, found 227.1075.

  3.2.3   2-甲基-1-取代苯基-2-丙基-氨基甲酸苄基酯(5)的合成

  氮气保护下, 取化合物4 (5.2 mmol), 三乙胺(0.58 g, 5.7 mmol, 1.1 equiv.)和无水甲苯(40 mL), 加到100 mL三口烧瓶中, 然后滴加叠氮磷酸二苯酯(1.5 g, 5.5 mmol, 1.05 equiv.), 在室温下搅拌1 h后, 将温度升至85 ℃, 加热回流2 h.再向三口烧瓶中加入BnOH (1.1 g, 10.4 mmol, 2.0 equiv.), 继续搅拌回流20 h, TLC检测反应完成.冷却至室温后, 减压蒸去溶剂, 剩余物溶于乙酸乙酯(80 mL), 分别用5% HCl溶液、水、饱和碳酸氢钠溶液以及饱和食盐水洗涤两次.干燥浓缩, 粗产物经过柱层析纯化[(V(石油醚):V(乙酸乙酯)＝20:1]得化合物5.

  2-甲基-1-(2-甲基苯基)-2-丙基-氨基甲酸苄基酯(5a):产率71%, 无色油状液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.38~6.99 (m, 9H), 5.09 (s, 2H), 3.03 (d, J＝4.4 Hz, 2H), 2.32 (d, J＝10.9 Hz, 3H), 1.31 (d, J＝10.4 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 137.17, 136.17, 131.42, 130.45, 128.50, 128.16, 128.05, 126.37, 125.41, 65.90, 54.30, 27.36, 20.25; HRMS (ESI, positive) calcd for C₁₉H₂₃NO₂Na [M+Na]⁺ 320.1621, found 320.1618.

  2-甲基-1-(3-甲基苯基)-2-丙基-氨基甲酸苄基酯(5b):产率78%, 无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.37~7.32 (m, 5H), 7.14~6.85 (m, 4H), 5.19 (s, 2H), 2.93 (s, 2H), 2.33 (s, 3H), 1.32 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 155.34, 138.24, 138.02, 137.42, 131.87, 129.08, 128.73, 128.61, 128.41, 128.12, 127.62, 66.59, 53.72, 45.71, 27.98, 21.95; HRMS (ESI, positive) calcd for C₁₉H₂₃NO₂ [M+H]⁺ 298.1802, found 298.1803.

  2-甲基-1-(4-甲基苯基)-2-丙基-氨基甲酸苄基酯(5c):产率65%, 无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.38~7.32 (m, 5H), 7.04~6.93 (m, 4H), 5.09 (s, 2H), 4.54 (s, 1H), 2.92 (s, 2H), 2.31 (s, 3H), 1.28 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 137.46, 136.39, 135.19, 130.96, 129.27, 129.08, 128.74, 128.61, 66.59, 53.76, 45.40, 27.90, 21.60; HRMS (ESI, positive) calcd for C₁₉H₂₃NO₂ [M+H]⁺ 298.1802, found 298.1797.

  2-甲基-1-(2-氯苯基)-2-丙基-氨基甲酸苄基酯(5d):产率74%, 无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.39~7.36 (m, 5H), 7.17~7.14 (m, 2H), 6.97~6.94 (m, 2H), 5.09 (s, 2H), 1.27 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 136.86, 136.40, 132.33, 131.87, 131.81, 128.69, 128.44, 128.39, 128.31, 128.20, 66.24, 53.22, 44.21, 27.54, 27.20; HRMS (ESI, positive) calcd for C₁₈H₂₁ClNO₂ [M+H]⁺ 318.1255, found 318.1256.

  2-甲基-1-(3-氯苯基)-2-丙基-氨基甲酸苄基酯(5e):产率66%, 无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.33~7.32 (m, 5H), 7.24~6.91 (m, 4H), 5.10 (s, 2H), 4.53 (s, 1H), 2.97 (s, 2H), 1.30 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 140.57, 137.34, 134.41, 131.11, 130.07, 129.86, 129.32, 129.25, 128.87, 128.80, 127.49, 127.19, 66.68, 53.76, 45.06, 28.14; HRMS (ESI, positive) calcd for C₁₈H₂₁ClNO₂ [M+H]⁺ 318.1255, found 318.1251.

  2-甲基-1-(4-氯苯基)-2-丙基-氨基甲酸苄基酯(5f):产率73%, 无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.39~7.36 (m, 5H), 7.17~7.14 (m, 2H), 6.97~6.94 (m, 2H), 5.09 (s, 2H), 2.95 (s, 2H), 1.27 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 136.39, 132.33, 131.87, 131.81, 128.69, 128.44, 128.39, 128.31, 128.20, 66.24, 53.22, 44.21, 27.54; HRMS (ESI, positive) calcd for C₁₈H₂₁ClNO₂ [M+H]⁺ 318.1255, found 318.1248.

  2-甲基-1-(2-氟苯基)-2-丙基-氨基甲酸苄基酯(5g):产率65%, 淡黄色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.31~7.29 (m, 5H), 7.22~7.03 (m, 1H), 7.02~6.94 (m, 3H), 5.10 (s, 2H), 4.63 (s, 1H), 3.04 (s, 2H), 1.31 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 163.77, 155.41, 133.48, 133.52, 129.19, 128.91, 128.86, 128.80, 128.74, 125.54, 124.40, 115.99, 115.68, 66.72, 54.34, 38.73, 27.88; HRMS (ESI, positive) calcd for C₁₈H₂₁FNO₂ [M+H]⁺ 302.1551, found 302.1551.

  2-甲基-1-(4-氟苯基)-2-丙基-氨基甲酸苄基酯(5h):产率71%, 无色油状液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.38~6.99 (m, 9H), 5.09 (s, 2H), 3.03 (d, J＝4.4 Hz, 2H), 2.32 (d, J＝10.9 Hz, 3H), 1.31 (d, J＝10.4 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 137.17, 136.17, 131.42, 130.45, 128.50, 128.16, 128.05, 126.37, 125.41, 65.90, 54.30, 27.36, 20.25; HRMS (ESI, positive) calcd for C₁₉H₂₃NO₂Na [M+Na]⁺ 320.1621, found 320.1618.

  2-甲基-1-(4-甲氧基苯基)-2-丙基-氨基甲酸苄基酯(5i):产率59%, 无色油状液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.42~7.41 (m, 5H), 7.02~7.00 (d, J＝8.6 Hz, 2H), 6.80~6.77 (d, J＝8.6 Hz, 2H), 5.13 (s, 2H), 4.57 (s, 1H), 3.80 (s, 3H), 2.94 (s, 2H), 1.31 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.19, 154.80, 136.93, 131.44, 129.85, 128.55, 128.27, 128.09, 113.42, 66.01, 55.20, 53.27, 44.28, 27.32; HRMS (ESI, positive) calcd for C₁₉H₂₄NO₃ [M+H]⁺ 314.1751, found 314.1747.

  2-甲基-1-萘基-2-丙基-氨基甲酸苄基酯(5j):产率70%, 无色液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.81~7.71 (m, 2H), 7.45~7.21 (m, 10H), 5.10 (s, 2H), 3.51 (s, 2H), 1.33 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 137.45, 135.03, 134.54, 133.93, 129.69, 129.34, 129.22, 128.88, 128.77, 127.87, 126.36, 126.01, 125.76, 125.44, 41.00, 28.57; HRMS (ESI, positive) calcd for C₂₂H₂₃NO₂Na [M+Na]⁺ 356.1621, found 356.1619.

  3.2.4   2-甲基-1-取代苯基-2-丙胺(1)的合成

  取化合物5 (3.6 mmol)于50 mL单口烧瓶中, 加入MeOH (20 mL)溶解, 再加入10% Pd/C (220 mg), 接着在氢气环境下, 室温搅拌过夜, TLC检测反应完成.滤除催化剂后, 浓缩滤液, 粗产物经过柱层析纯化[V(二氯甲烷):V(甲醇)＝30:1]得化合物1

  2-甲基-1-(2-甲基苯基)-2-丙胺(1a):产率57%, 无色液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.23~7.13 (m, 4H), 3.17 (s, 2H), 2.39 (s, 3H), 2.05 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ: 130.36, 129.58, 125.35, 124.38, 76.50, 76.08, 75.66, 50.47, 45.50, 29.46, 19.54; HRMS (ESI, positive) calcd for C₁₁H₁₈N [M+H]⁺ 164.1434, found 164.1434.

  2-甲基-1-(3-甲基苯基)-2-丙胺(1b):产率63%, 无色液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.20~6.97 (m, 4H), 2.64 (s, 2H), 2.34 (s, 3H), 1.75 (s, 2H), 1.13 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 138.87, 138.16, 131.92, 128.54, 128.16, 127.67, 51.50, 50.83, 30.85, 22.08; HRMS (ESI, positive) calcd for C₁₁H₁₈N [M+H]⁺ 164.1434, found 164.1434.

  2-甲基-1-(4-甲基苯基)-2-丙胺(1c):产率68%, 无色液体. ¹H NMR (300 MHz, CDCl₃) δ: 7.12~7.05 (m, 4H), 2.61 (s, 2H), 2.33 (s, 3H), 1.08 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 135.65, 135.23, 130.26, 128.62, 50.59, 49.92, 30.22, 20.94; HRMS (ESI, positive) calcd for C₁₁H₁₈N [M+H]⁺ 164.1434, found 164.1434.

  2-甲基-1-(2-氯苯基)-2-丙胺(1d):产率75%, 淡黄色固体. m.p. 193~194 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.34~7.27 (m, 3H), 7.25~7.23 (m, 1H), 3.11 (s, 2H), 1.45 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 134.93, 130.80, 128.59, 127.38, 55.97, 46.29, 25.21; HRMS (ESI, positive) calcd for C₁₀H₁₅ClN [M+H]⁺ 184.0888, 186.0858; found 184.0889, 186.0861.

  2-甲基-1-(3-氯苯基)-2-丙胺(1e):产率75%, 淡黄色固体. m.p. 195~197 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.33~7.24 (m, 5H), 3.09 (s, 2H), 1.45 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 135.25, 131.16, 128.98, 127.79, 56.27, 46.75, 25.63; HRMS (ESI, positive) calcd for C₁₀H₁₅ClN [M+H]⁺ 184.0888, found 184.0887.

  2-甲基-1-(4-氯苯基)-2-丙胺(1f):产率63%, 淡黄色固体. m.p. 199~200 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.33~7.28 (m, 3H), 7.24 (s, 1H), 3.09 (s, 2H), 1.46 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 134.93, 130.80, 128.59, 127.38, 55.92, 46.31, 25.21; HRMS (ESI, positive) calcd for C₁₀H₁₅ClN [M+H]⁺184.0891, 186.0858; found 184.0887, 186.0858.

  2-甲基-1-(2-氟苯基)-2-丙胺(1g):产率48%, 淡黄色透明液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.24~7.02 (m, 4H), 2.72 (s, 2H), 1.48 (s, 2H), 1.14 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.38, 133.43, 128.83, 126.17, 124.31, 116.13, 51.33, 44.27, 30.78; HRMS (ESI, positive) calcd for C₁₀H₁₅FN [M+H]⁺ 168.1183, found 168.1187.

  2-甲基-1-(4-氟苯基)-2-丙胺(1h):产率65%, 淡黄色透明液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.16~7.12 (m, 2H), 7.00~6.96 (t, J＝8.7 Hz, 2H), 2.63 (s, 2H), 1.50 (s, 2H), 1.11 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.91, 160.49, 134.09, 134.05, 131.81, 131.73, 114.89, 114.68, 50.06, 30.18; HRMS (ESI, positive) calcd for C₁₀H₁₅FN [M+H]⁺ 168.1186, found 168.1187.

  2-甲基-1-(4-甲氧基苯基)-2-丙胺(1i):产率92%, 无色液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.11~7.09 (d, J＝8.6 Hz, 2H), 6.85~6.83 (d, J＝8.6 Hz, 2H), 3.79 (s, 3H), 2.60 (s, 2H), 1.40 (s, 2H), 1.10 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.24, 131.42, 130.59, 113.48, 55.28, 50.21, 50.12, 30.31; HRMS (ESI, positive) calcd for C₁₁H₁₈NO [M+H]⁺ 180.1383, found 180.1379.

  2-甲基-1-萘基-2-丙胺(1j):产率84%, 无色液体. ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (d, J＝8.0 Hz, 1H), 7.84 (d, J＝8.0 Hz, 1H), 7.54 (d, J＝8.0 Hz, 1H), 7.50~7.40 (m, 3H), 7.35 (d, J＝8.0 Hz, 1H), 3.18 (s, 2H), 1.18 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 135.03, 134.02, 133.19, 129.01, 128.75, 127.16, 125.62, 125.38, 125.14, 125.08, 51.30, 46.11, 31.17; HRMS (ESI, positive) calcd for C₁₄H₁₈N [M+H]⁺ 200.1434, found 200.1438.

  3.2.5   3, 3'-(1, 3-亚苯基)-双(2, 2-二甲基丙腈)(7)的合成

  在氮气保护下, 取二异丙胺(3.0 g, 29.6 mmol, 2.6 equiv.)溶于四氢呋喃(15 mL)中, 降温至－78 ℃, 滴加正丁基锂(11.5 mL, 28.8 mmol, 2.5 equiv.).搅拌30 min后, 在此温度下, 将异丁腈(2.5 mL, 28.3 mmol, 2.5 equiv.)逐滴滴加到反应中, 搅拌1 h, 再加入间二氯苄6 (11.4 mmol), 搅拌1 h后停止反应.向混合液加稀盐酸淬灭反应, 用乙酸乙酯(60 mL×3)萃取, 合并有机相, 有机相依次用水(20 mL×2)和饱和食盐水(20 mL)洗涤, 无水硫酸钠干燥.粗产物经过柱层析纯化[V(石油醚):V(乙酸乙酯)＝25:1], 得到7 (2.23 g, 产率81%), 白色固体. m.p. 63~65 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.32~7.30 (m, 1H), 7.24~7.18 (m, 3H), 2.82 (s, 4H), 1.36 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ: 135.78, 132.05, 129.13, 128.35, 124.61, 46.42, 33.50, 26.47; HRMS (ESI, positive) calcd for C₁₆H₂₀N₂Na [M+Na]⁺ 263.1519, found 263.1516.

  3.2.6   3, 3'-(1, 3-亚苯基)-双(2, 2-二甲基丙酸)(8)的合成

  取7 (9.3 mmol)加到50 mL单口烧瓶中, 再加入KOH (2.6 g, 46.4 mmol, 5.0 equiv.)和乙二醇(20 mL), 在185 ℃下加热回流12 h.停止反应后, 向反应液中加入稀盐酸调节pH＝1, 所得混合物用乙酸乙酯(60 mL×3)萃取, 有机相依次用水(20 mL×2)和饱和食盐水(20 mL)洗涤, 无水硫酸钠干燥.粗产物经过柱层析纯化[V(二氯甲烷):V(甲醇)＝150:1]得到8 (1.8 g, 产率74%), 白色固体. m.p. 119~120 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.18 (t, J＝9.0 Hz, 1H), 7.03~6.99 (m, 3H), 2.85 (s, 4H), 1.17 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ: 185.02, 137.98, 132.41, 129.36, 128.28, 46.57, 44.16, 25.18; HRMS (ESI, negative) calcd for C₁₆H₂₁O₄ [M－H]^－ 277.1445, found 277.1440.

  3.2.7   (1, 3-亚苯基-双(2-甲基丙烷-1, 2-二基))二氨基甲酸二苄酯(9)的合成

  在氮气保护下, 取8 (3.6 mmol), 三乙胺(800 mg, 7.9 mmol, 2.2 equiv.)和无水甲苯(30 mL), 加到50 mL三口烧瓶中, 然后滴加DPPA (2.1 g, 7.6 mmol, 2.1 equiv.), 在室温下搅拌1 h.将温度升至90 ℃, 加热回流2 h后, 向三口烧瓶中加入BnOH (1.6 g, 14.4 mmol, 4.0 equiv.), 搅拌回流24 h.停止反应后, 将反应液浓缩, 剩余物溶入乙酸乙酯(40 mL), 分别用5% HCl溶液、水、饱和碳酸氢钠溶液以及饱和食盐水洗涤.干燥浓缩后, 粗产物经过柱层析纯化[V(石油醚):V(乙酸乙酯)＝20:1], 得到9 (1.58 g, 产率89%), 无色透明液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.37~7.29 (m, 10H), 7.10~7.06 (m, 1H), 6.92~6.90 (m, 2H), 6.84 (s, 1H), 5.08 (s, 4H), 2.90 (s, 4H), 1.25 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 141.53, 138.00, 133.46, 130.13, 129.19, 128.91, 128.75, 128.27, 127.63, 127.00, 65.95, 53.82, 27.95; HRMS (ESI, positive) calcd. for C₃₀H₃₆N₂O₄Na [M+Na]⁺ 511.2567, found 511.2563.

  3.2.8   1, 1'-(1, 3-亚苯基)-双(2-甲基丙-2-胺)(10)的合成

  称取9 (3.27 mmol)于50 mL单口烧瓶中, 加入MeOH (20 mL)溶解, 再加入10% Pd/C (320 mg), 然后, 在氢气环境和室温下搅拌过夜.滤除催化剂后, 浓缩滤液, 粗产物经过柱层析纯化[V(二氯甲烷):V(甲醇)＝30:1]得到10 (320 mg, 产率45%), 无色液体. ¹H NMR (400 MHz, CDCl₃) δ: 7.28~7.22 (m, 1H), 7.08~7.04 (t, J＝7.6 Hz, 3H), 2.67 (s, 4H), 1.14 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 138.33, 133.38, 128.99, 128.23, 51.06, 50.97, 30.48; HRMS (ESI, positive) calcd. for C₁₄H₂₅N₂ [M+H]⁺ 221.2012, found 221.2017.

  辅助材料(Supporting Information)  化合物化合物3a~3j, 4a~4j, 5a~5j, 1a~1j, 7~10的¹H NMR, ¹³C NMR以及HRMR数据.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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  图 1  含2-甲基-1-取代苯基-2-丙胺结构单元的生物活性化合物

  Figure 1  Several biological active compounds which contain 2-methyl-1-substituted-phenyl-2-propylamine subunits

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  图式 1  2-甲基-1-(2-甲基苯基)-2-丙胺(1a)的合成路线

  Scheme 1  Synthesis of 2-methyl-1-(2-methyl phenyl)-2-propyl- amine (1a)

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  图式 2  1, 1'-(1, 3-亚苯基)双(2-甲基丙-2-胺)的合成路线

  Scheme 2  Synthetic route for 1, 1'-(1, 3-phenylene)-bis(2- methyl-propan-2-amine)

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  表 1  2-甲基-1-取代苯基-2-丙胺类化合物1的合成

  Table 1.  Synthesis of 2-methyl-1-substituted-phenyl-2-propyl- amines 1

  a Overall yield for the 4 steps of reaction from the corresponding benzyl chlorides and 1-(chloromethyl)- naphthalene, respectively.

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