CN113527188B - 一种制备间位官能团化的吡啶化合物的方法 - Google Patents
一种制备间位官能团化的吡啶化合物的方法 Download PDFInfo
- Publication number
- CN113527188B CN113527188B CN202111093323.6A CN202111093323A CN113527188B CN 113527188 B CN113527188 B CN 113527188B CN 202111093323 A CN202111093323 A CN 202111093323A CN 113527188 B CN113527188 B CN 113527188B
- Authority
- CN
- China
- Prior art keywords
- reaction
- pyridine
- meta
- ester group
- catalyst
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明提供了一种制备间位官能团化的吡啶化合物的方法,包括:S1,制备1,4‑二氢吡啶:在充满氮气的手套箱中,向反应瓶中依次加入催化剂、溶剂、频那醇硼烷和吡啶,搅拌,在40~110℃,反应5~12小时,得到1,4‑二氢吡啶;S2,催化吡啶间位官能团化:向上述反应瓶中加入亚胺、醛、酮或卤代试剂,在氮气氛围中搅拌至反应结束;减压蒸馏除去溶剂,柱层析分离得到间位官能团化的吡啶,反应温度为40~110℃,反应时间为5~24小时。该方法无需使用过渡金属催化剂,其反应条件温和、选择性好、官能团兼容性广。
Description
技术领域
本发明涉及化学合成领域,特别是涉及一种制备间位官能团化的吡啶化合物的方法。
背景技术
吡啶结构的化合物广泛存在于天然产物和药物分子中,直接的吡啶C-H键官能团化是合成和修饰吡啶类化合物最直接高效的方法。由于吡啶自身的缺电子性,其邻位和对位对于亲核取代反应具有较高活性。含吡啶骨架的药物分子的间位官能团化,一方面可以丰富药物分子的多样性,另一方面可以提高药物分子的生物活性,因此具有巨大的应用潜力。但是,由于间位的亲电取代反应活性较低,因此吡啶间位的官能团化存在一定挑战。
目前有两种策略可以实现吡啶间位的官能团化,其一是在高温条件下,吡啶的亲电取代反应。(S. M. McElvain, M. A. Goese. J. Am. Chem. Soc. 1943, 65, 2227; K.Murakami, S. Yamada, T. Kaneda, K. Itami. Chem. Rev.2017, 117, 9302.):
其二是采用过渡金属催化碳氢键活化的策略。(M. Ye, G.-L. Gao, A. J. F.Edmunds, P. A. Worthington, J. A. Morris, J.-Q. Yu. J. Am. Chem. Soc. 2011,133, 19090; M. Ye, G.-L. Gao, J.-Q. Yu. J. Am. Chem. Soc.2011, 133, 6964; I.A. I. Mkhalid, D. N. Coventry, D. Albesa-Jove, A. S. Batsanov, J. A. K.Howard, R. N. Perutz, T. B. Marder. Angew. Chem. Int. Ed.2006, 45, 489; J. M.Murphy, X. Liao, J. F. Hartwig. J. Am. Chem. Soc. 2007, 129, 15434; M. A.Larsen, J. F. Hartwig. J. Am. Chem. Soc. 2014, 136, 4287; C. Cheng, J. F.Hartwig. J. Am. Chem. Soc. 2015, 137, 592.):
但上述这些方法的局限性比较大,比如在上述亲电取代反应中,反应需要的温度高达300 ℃,且适用的亲电试剂很少,而在碳氢键活化的策略中,一般需要大大过量的吡啶,而且通常得到吡啶邻位、对位和间位取代的混合物,难以分离纯化。
通过三芳基硼催化吡啶的硼氢化反应,可以得到1,4-二氢吡啶,再发生转移氢化反应,就能够实现吡啶的还原。(Z.-Y. Liu, Z.-H. Wen, X.-C. Wang. Angew. Chem. Int. Ed.2017, 56, 5817; J.-J. Tian, Z.-Y. Yang, X.-S. Liang, N. Liu, C.-Y.Hu, X.-S. Tu, X. Li, X.-C. Wang. Angew. Chem. Int. Ed.2020, 59, 18452.) 然而利用吡啶的硼氢化反应中得到的1,4-二氢吡啶来实现吡啶官能团化则一直没有报道。
发明内容
本发明的目的是提供一种制备间位官能团化的吡啶化合物的方法,该方法反应条件温和、区域选择性高、无需使用贵金属催化剂且官能团兼容性较好。
为此,本发明的技术方案如下:
一种制备间位官能团化的吡啶化合物的方法,包括以下步骤:
S1,制备1,4-二氢吡啶:
在充满氮气的手套箱中,向反应瓶中依次加入催化剂、溶剂、频那醇硼烷和吡啶,搅拌,使其充分反应,得到1,4-二氢吡啶,其反应式如下:
其中:
所述催化剂为三芳基硼,其与吡啶的摩尔比为(10~15):100,其结构式为:B(R1)3,其中,R1为五氟苯基、3,5-二(三氟甲基)取代的苯基或2,4,6-三氟取代的苯基;
所述频那醇硼烷与吡啶的当量比为1.5:1;
所述溶剂为四氢呋喃、1,2-二氯乙烷或芳香溶剂;
反应温度为 40~110 ℃,反应时间为5~12 小时;
S2,催化吡啶间位官能团化:
向上述反应瓶中加入亚胺、醛、酮、氯代试剂或溴代试剂,在氮气氛围中搅拌至反应结束;减压蒸馏除去溶剂,柱层析分离后分别得到间位氨甲基、苄基、羟甲基、氯或溴取代的吡啶化合物,其反应式分别如下:
其中,反应温度为 40~110 ℃,反应时间为5~24 小时;
在上述吡啶、1,4-二氢吡啶和间位氨甲基、羟甲基、苄基、氯或溴取代的吡啶化合物的结构式中,R2为烯基、芳基、烷基、卤素、酯基或杂芳基取代基;R3为烷基;R4为叔丁氧羰基或苄氧羰基;R5为芳基、烷基或杂芳基取代基;R6为芳基;R7为酯基;R8为酯基或三氟甲基;R9为氯或溴。
优选的是,在步骤S1的反应物中还加入4Å分子筛,所述4Å分子筛与吡啶的投料比为50 mg/0.2 mmol。
当所述R2为卤素时,所述卤素为氟、氯或碘;
当所述R2为杂芳基时,所述杂芳基为呋喃基、噻吩基或吡啶基。
优选的是,所述R3为甲基。
当所述R5为杂芳基时,所述杂芳基为呋喃基、噻吩基或吡啶基。
优选的是,所述R6为间硝基或间三氟甲基取代的苯基。
优选的是,所述R7为甲酯基或乙酯基。
当所述R8为酯基时,所述酯基为甲酯基或乙酯基。
本发明以三芳基硼为催化剂,通过制备1,4-二氢吡啶和催化吡啶间位官能团化两步串联反应,实现了吡啶间位官能团化反应,合成了一系列间位取代的吡啶产物。
与现有技术相比,本发明具有以下有益效果:
1. 本发明反应条件温和,最低反应温度仅需40℃;
2. 本发明中,吡啶原料仅需1当量,原子的利用率高,避免了资源的浪费;
3. 本发明单一地得到了间位取代的吡啶化合物,区域选择性高;
4. 本发明的吡啶底物适用范围广,单取代和多取代的吡啶、吡啶的衍生物等均可;官能团兼容性强,可以是芳基、烷基、卤素、烯基、杂芳基等;
5. 本发明采用硼催化剂替代过渡金属,降低了生产成本,减少了环境污染;
6. 本发明适用于含吡啶结构药物分子的后期官能团化修饰,可应用于药物研发和生产。
具体实施方式
下面结合具体实施例对本发明的方法进行详细说明。
以下实施例的反应式中,LA为催化剂;HBpin为频那醇硼烷;MS为分子筛;THF为四氢呋喃;equiv为当量。
实施例1
一种制备3-(1-苯基N-Boc甲氨基)-5-苯基吡啶的方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)13.0 mg(0.02 mmol, 10.0 mol %)、4Å分子筛50 mg、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol, 1.5 equiv)和3-苯基吡啶(1a)31.0 mg(0.2 mmol, 1.0 equiv)依次加入到8 mL反应小瓶中,在80℃下反应5小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA为B(3,5-(CF3)2C6H3)3,结构式如下:
S2,体系冷却至室温,将82.0 mg(0.4 mmol,2.0 equiv)苯甲醛N-Boc亚胺(2a)加入到上述反应小瓶中,在80℃下反应14小时,反应式如下:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-(1-苯基N-Boc甲氨基)-5-苯基吡啶 (tert-butyl (phenyl(5-phenylpyridin-3-yl)methyl)carbamate)(3a),其为白色固体,收率为80%。
产物表征如下:
1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0Hz, 1H), 7.73 (s, 1H), 7.52 – 7.50 (m, 2H), 7.45 – 7.42 (m, 2H), 7.39 – 7.37(m, 1H), 7.35 – 7.25 (m, 5H), 6.01 (s, 1H), 5.57 (s, 1H), 1.44 (s, 9H). 13CNMR (101 MHz, CDCl3) δ 155.2, 147.6, 147.3, 141.0, 137.8, 137.7, 136.5,133.2, 129.2, 129.1, 128.3, 128.0, 127.5, 127.3, 80.3, 56.8, 28.5. HRMS-ESI:m/z calculated for C23H24N2O2Na+ (M+Na)+ 383.1730, found 383.1733.
实施例2
一种制备3-(1-苯基N-Boc甲氨基)-5-苄基吡啶的方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)B(3,5-(CF3)2C6H3)3 13.0 mg(0.02mmol, 10.0 mol %)、4Å分子筛(50 mg)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和3-苄基吡啶(1b)33.8 mg(0.2 mmol, 1.0 equiv)依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例1相同,为B(3,5-(CF3)2C6H3)3;
S2,体系冷却至室温,苯甲醛N-Boc亚胺(2a)82.0 mg(0.4 mmol, 2.0 equiv)加入到反应小瓶中,在80 ℃下反应24小时,反应式如下:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化,得到产物3-(1-苯基N-Boc甲氨基)-5-苄基吡啶(tert-butyl ((5-benzylpyridin- 3-yl)(phenyl)methyl)carbamate)(3b),其为白色固体,收率为72%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.34 – 8.33 (m, 2H), 7.36 (s, 1H), 7.32 –7.25 (m, 5H), 7.21 – 7.17 (m, 3H), 7.13 – 7.11 (m, 2H), 5.89 (s, 1H), 5.42(s, 1H), 3.93 (s, 2H), 1.41 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 155.1, 149.2,146.8, 141.0, 139.7, 137.6, 136.3, 135.2, 129.0, 128.9, 128.8, 127.9, 127.5,126.6, 80.2, 56.7, 39.1, 28.4. HRMS-ESI: m/z calculated for C24H27N2O2 + (M+H)+375.2067, found 375.2069.
实施例3
一种3-(1-苯基N-Boc甲氨基)-5-苯基-6-甲基吡啶的制备方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)13.0 mg(0.02 mmol,10.0 mol %)、4Å分子筛(50 mg)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和2-甲基-3-苯基吡啶(1c)33.8 mg(0.2 mmol,1.0 equiv)依次加入到8 mL反应小瓶中,在40 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例1相同,为B(3,5-(CF3)2C6H3)3;
S2,体系冷却至室温,苯甲醛N-Boc亚胺(2a)82.0 mg(0.4 mmol,2.0 equiv)加入到反应小瓶中,在40 ℃下反应24小时,反应式如下:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-(1-苯基N-Boc甲氨基)-5-苯基-6-甲基吡啶(tert-butyl ((6-methyl-5- phenylpyridin-3-yl)(phenyl)methyl)carbamate) (3c),其为白色固体,收率为66%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 1.9 Hz, 1H), 7.44 – 7.25 (m,11H), 5.95 (s, 1H), 5.19 (s, 1H), 2.49 (s, 3H), 1.44 (s, 9H). 13C NMR (101MHz, CDCl3) δ 155.1, 155.1, 146.9, 141.2, 139.9, 136.9, 136.1, 135.2, 129.2,129.1, 128.6, 128.0, 127.7, 127.5, 80.4, 56.6, 28.5, 23.2. HRMS-ESI: m/zcalculated for C24H27N2O2 + (M+H)+ 375.2067, found 375.2063.
实施例4
一种3-(1-环己基N-Boc甲氨基)-5-苯基吡啶的合成方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)13.0 mg(0.02 mmol,10.0 mol %)、4Å分子筛(50 mg)、1 mL 四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)、3-苯基吡啶(1a)31.0 mg(0.2 mmol,1.0 equiv)依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例1相同,为B(3,5-(CF3)2C6H3)3;
S2,体系冷却至室温,环己基甲醛N-Boc亚胺(2b)84.4 mg(0.4 mmol,2.0 equiv)加入到反应小瓶中,在80 ℃下反应24小时,反应式如下:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-(1-环己基N-Boc甲氨基)-5-苯基吡啶 (tert-butyl (cyclohexyl(5-phenylpyridin-3-yl)methyl)carbamate) (3d),其为白色固体,收率为55%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 7.69(t, J = 2.0 Hz, 1H), 7.59 – 7.57 (m, 2H), 7.50 – 7.46 (m, 2H), 7.43 – 7.39(m, 1H), 5.06 (d, J = 8.2 Hz, 1H), 4.54 (s, 1H), 1.90 – 1.49 (m, 5H), 1.42(s, 9H), 1.26 – 0.96 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 155.6, 147.6, 147.1,138.0, 136.4, 133.1, 129.2, 128.3, 127.4, 79.9, 58.2, 43.4, 30.2, 29.2, 28.5,26.3, 26.2, 26.1. HRMS-ESI: m/z calculated for C23H31N2O2 + (M+H)+ 367.2380,found 367.2383.
实施例5
一种3-(4-硝基苄基)-5-苯基吡啶的合成方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)13.0 mg(0.02 mmol,10.0 mol %)、4Å分子筛(50 mg)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和3-苯基吡啶(1a)31.0 mg(0.2 mmol,1.0 equiv)依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例1相同,为B(3,5-(CF3)2C6H3)3;
S2,体系冷却至室温,4-硝基苯甲醛(2c)60.4 mg(0.4 mmol,2.0 equiv)加入到反应小瓶中,在80 ℃下反应24小时,反应式如下:
4-硝基苯甲醛(2c)的结构式为:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-(4-硝基苄基)-5-苯基吡啶 (3-(4-Nitrobenzyl)-5-phenylpyridine)(3e),其为白色固体,收率为51%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 8.7Hz, 2H), 7.63 (s, 1H), 7.55 – 7.53 (m, 2H), 7.49 – 7.45 (m, 2H), 7.42 – 7.38(m, 3H), 4.16 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 148.9, 147.5, 147.1, 147.0,137.6, 137.0, 134.9, 134.8, 129.9, 129.3, 128.5, 127.3, 124.2, 39.0.HRMS-ESI:m/z calculated for C18H15N2O2 +(M+H)+ 291.1128, found 291.1127.
实施例6
一种2-羟基-2-(5-苯基-3吡啶基)丙二酸二乙酯的合成方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)13.0 mg(0.02 mmol,10.0 mol %)、4Å分子筛(50 mg)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和3-苯基吡啶(1a)31.0 mg(0.2 mmol,1.0 equiv)依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例1相同,为B(3,5-(CF3)2C6H3)3。
S2,体系冷却至室温,酮基丙二酸二乙酯(2d)69.6 mg(0.4 mmol,2.0 equiv)加入到反应小瓶中,在80 ℃下反应24小时,反应式如下:
酮基丙二酸二乙酯(2d)的结构式为:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物2-羟基-2-(5-苯基-3吡啶基)丙二酸二乙酯(diethyl 2-hydroxy-2-(5-phenylpyridin-3-yl)malonate)(3f),其为白色固体,收率为58%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 2.1Hz, 1H), 8.23 (t, J = 2.1 Hz, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.4Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 4.65 (s, 1H), 4.34 (qq, J = 10.7, 7.1 Hz,4H), 1.32 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 169.4, 148.1, 147.3,137.7, 136.1, 133.2, 132.0, 129.3, 128.4, 127.4, 78.9, 63.6, 14.1. HRMS-ESI:m/z calculated for C18H20NO5 + (M+H)+ 330.1336, found 330.1333.
实施例7
一种3-氯-5-苯基吡啶的合成方法,包括以下步骤:
S1,在充满氮气的手套箱中,催化剂(LA)13.0 mg(0.02 mmol,10.0 mol %)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和3-苯基吡啶 (1a)31.0 mg(0.2mmol,1.0 equiv)依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA为B(2,4,6-F3C6H3)3,结构式如下:
S2,体系冷却至室温,N-氯代邻磺酰苯酰亚胺(2e)87.0 mg(0.4 mmol,2.0 equiv)加入到反应小瓶中,在40 ℃下反应12小时,反应式如下:
N-氯代邻磺酰苯酰亚胺(2e)的结构式为:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-氯-5-苯基吡啶 (3-chloro-5-phenylpyridine)(3g),其为白色固体,收率为82%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.56 (s, 1H), 7.86 (t, J = 2.0Hz, 1H), 7.60–7.53 (m, 2H), 7.52–7.40 (m, 3H). 13C NMR (101 MHz, CDCl3) δ147.4, 146.2, 138.0, 136.5, 134.2, 132.3, 129.4, 128.8, 127.3. HRMS-ESI: m/zcalculated for C11H9ClN(M+H)+ 190.0418, found 190.0417.
实施例8
一种3-溴-5-苯基吡啶的合成方法,包括以下步骤:
S1,在充满氮气的手套箱中,将催化剂(LA)8.0 mg(0.02 mmol,10.0 mol %)、1 mL四氢呋喃、频那醇硼烷38.4 mg(0.3 mmol,1.5 equiv)和3-苯基吡啶(1a)31.0 mg(0.2mmol,1.0 equiv) 依次加入到8 mL反应小瓶中,在80 ℃下反应12小时,得到1,4-二氢吡啶,反应式如下:
其中,催化剂LA与实施例7相同,为B(2,4,6-F3C6H3)3。
S2,体系冷却至室温,将N-溴代邻磺酰苯酰亚胺(2f)104.0 mg(0.4 mmol,2.0equiv) 加入到反应小瓶中,在40 ℃下反应12小时,反应式如下:
N-溴代邻磺酰苯酰亚胺(2f)的结构式如下:
反应完成后,旋蒸除去溶剂,残余物通过硅胶柱层析分离纯化得到产物3-溴-5-苯基吡啶的合成(3-bromo -5-phenylpyridine)(3h),其为白色固体,收率为62%。
产物表征:
1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0Hz, 1H), 8.01 (t, J = 2.1 Hz, 1H), 7.56–7.53 (m, 2H), 7.50–7.46 (m, 2H),7.45–7.41 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 149.5, 146.5, 138.4, 137.0,136.4, 129.4, 128.9, 127.3, 121.1. HRMS-ESI: m/z calculated for C11H9BrN+(M+H)+233.9913, found 233.9913.
Claims (10)
1.一种制备间位官能团化的吡啶化合物的方法,包括以下步骤:
S1,制备1,4-二氢吡啶:
在充满氮气的手套箱中,向反应瓶中依次加入催化剂、溶剂、频那醇硼烷和吡啶,搅拌,使其充分反应,得到1,4-二氢吡啶,其反应式如下:
其中:
所述催化剂为三芳基硼,其与吡啶的摩尔比为(10~15):100,其结构式为:B(R1)3,其中,R1为五氟苯基、3,5-二(三氟甲基)取代的苯基或2,4,6-三氟取代的苯基;
所述频那醇硼烷与吡啶的当量比为1.5:1;
所述溶剂为四氢呋喃、1,2-二氯乙烷或芳香溶剂;
反应温度为 40~110 ℃,反应时间为5~12 小时;
S2,催化吡啶间位官能团化:
向上述反应瓶中加入亚胺、醛、酮、氯代试剂或溴代试剂,在氮气氛围中搅拌至反应结束;减压蒸馏除去溶剂,柱层析分离后分别得到间位氨甲基、苄基、羟甲基、氯或溴取代的吡啶化合物,其反应式分别如下:
其中,反应温度为 40~110 ℃,反应时间为5~24 小时;
在上述吡啶、1,4-二氢吡啶和间位氨甲基、羟甲基、苄基、氯或溴取代的吡啶化合物的结构式中,R2为烯基、芳基、烷基、卤素、酯基或杂芳基取代基;R3为烷基;R4为叔丁氧羰基或苄氧羰基;R5为芳基、烷基或杂芳基取代基;R6为芳基;R7为酯基;R8为酯基或三氟甲基。
2.根据权利要求 1所述的方法,其特征在于:在步骤S1的反应物中还加入4Å分子筛,所述4Å分子筛与吡啶的投料比为50 mg/0.2 mmol。
4.根据权利要求1所述的方法,其特征在于: 所述R2为卤素时,所述卤素为氟、氯或碘。
5.根据权利要求1所述的方法,其特征在于:所述R2为杂芳基时,所述杂芳基为呋喃基、噻吩基或吡啶基。
6.根据权利要求1或2所述的方法,其特征在于:所述R3为甲基。
7.根据权利要求1或2所述的方法,其特征在于:所述 R5为杂芳基时,所述杂芳基为呋喃基、噻吩基或吡啶基。
8.根据权利要求1或2所述的方法,其特征在于:所述R6为间硝基或间三氟甲基取代的苯基。
9.根据权利要求1或2所述的方法,其特征在于:所述R7为甲酯基或乙酯基。
10.根据权利要求1或2所述的方法,其特征在于:所述R8为酯基时,所述酯基为甲酯基或乙酯基。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111093323.6A CN113527188B (zh) | 2021-09-17 | 2021-09-17 | 一种制备间位官能团化的吡啶化合物的方法 |
PCT/CN2021/124108 WO2023039975A1 (zh) | 2021-09-17 | 2021-10-15 | 一种制备间位官能团化的吡啶化合物的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111093323.6A CN113527188B (zh) | 2021-09-17 | 2021-09-17 | 一种制备间位官能团化的吡啶化合物的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113527188A CN113527188A (zh) | 2021-10-22 |
CN113527188B true CN113527188B (zh) | 2021-11-26 |
Family
ID=78092824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111093323.6A Active CN113527188B (zh) | 2021-09-17 | 2021-09-17 | 一种制备间位官能团化的吡啶化合物的方法 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113527188B (zh) |
WO (1) | WO2023039975A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116003312A (zh) * | 2022-05-12 | 2023-04-25 | 南开大学 | 一种制备间位三氟甲硫基、二氟甲硫基或三氟甲基取代的吡啶化合物的方法 |
CN116396211A (zh) * | 2023-04-18 | 2023-07-07 | 南开大学 | 一种制备间位手性烯丙基取代的吡啶化合物的方法 |
-
2021
- 2021-09-17 CN CN202111093323.6A patent/CN113527188B/zh active Active
- 2021-10-15 WO PCT/CN2021/124108 patent/WO2023039975A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023039975A1 (zh) | 2023-03-23 |
CN113527188A (zh) | 2021-10-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113527188B (zh) | 一种制备间位官能团化的吡啶化合物的方法 | |
CN108299423B (zh) | 一种二氢吡咯并2-氨基喹啉类化合物的合成方法 | |
García Ruano et al. | Enantioselective Generation of Benzylic Stereocenters Mediated by a Remote Sulfoxide | |
US20040106818A1 (en) | Process for the preparation of cyclohexanol derivatives | |
CN111848675B (zh) | 四氢喹啉骨架手性膦-氮配体及其制备方法和应用 | |
CN109096174B (zh) | 一种n-烃基-2,5-未取代的[60]富勒烯吡咯烷衍生物的合成方法 | |
CN111793016B (zh) | 一种拉罗替尼中间体的制备方法以及中间体化合物 | |
CN114478351B (zh) | 一种合成α-烷基取代吲哚-3-甲醛类化合物的方法 | |
CN114989063B (zh) | 一种β-卤代吡咯类化合物的合成方法 | |
JP6028606B2 (ja) | アミン化合物の製造方法 | |
CN103748065B (zh) | 2-烯基胺化合物的制造方法 | |
CN111233827B (zh) | 一种2,5-二取代硒吩类化合物及其合成方法 | |
WO2011118625A1 (ja) | 光学活性なn-モノアルキル-3-ヒドロキシ-3-アリールプロピルアミン化合物の製造方法 | |
US9272966B2 (en) | Method for preparing optically active 1-bromo-1[3,5-bis(trifluoromethyl)phenyl]ethane | |
JP2017002002A (ja) | 含フッ素有機化合物及びこれとグリニャール試薬によるビアリール化合物の製造方法 | |
CN115490728B (zh) | 一种烯丙基膦衍生物的合成方法 | |
JP4807549B2 (ja) | シロキサン類,シラノール類及びシラン類,並びにその製造方法 | |
JP6868890B2 (ja) | 環上に置換基を有する含窒素環状化合物の製造方法 | |
CN117209457A (zh) | 一种α-手性脒化合物的合成 | |
JP4635251B2 (ja) | 有機ビスマス化合物およびその製法 | |
WO2004106314A1 (ja) | オキセタン環含有ビフェニル化合物の製造方法 | |
JP2017206485A (ja) | 光学活性な1,3−ジアミン誘導体およびその製造方法 | |
JP2946678B2 (ja) | キラルなフェロセン誘導体 | |
CN114478611A (zh) | 四乙烯硅烷的合成方法 | |
CN117820139A (zh) | 一种2-叔丁基胺基苯甲醛类衍生物的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |