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
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 74
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 22
- -1 pyridine compound Chemical class 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 16
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000007306 functionalization reaction Methods 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 150000002466 imines Chemical class 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- 238000004440 column chromatography Methods 0.000 claims abstract description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002808 molecular sieve Substances 0.000 claims description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000004492 methyl ester group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 150000001299 aldehydes Chemical class 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 238000004821 distillation Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- HJKGBRPNSJADMB-UHFFFAOYSA-N 3-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CN=C1 HJKGBRPNSJADMB-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
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- 239000007787 solid Substances 0.000 description 8
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- XFRQMBFCAKTYIV-UHFFFAOYSA-N tert-butyl n-benzylidenecarbamate Chemical compound CC(C)(C)OC(=O)N=CC1=CC=CC=C1 XFRQMBFCAKTYIV-UHFFFAOYSA-N 0.000 description 5
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 4
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 4
- AWCQJXPOCRXHNK-UHFFFAOYSA-N 3-bromo-5-phenylpyridine Chemical compound BrC1=CN=CC(C=2C=CC=CC=2)=C1 AWCQJXPOCRXHNK-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000007336 electrophilic substitution reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- YLUZKERNKYNCLG-UHFFFAOYSA-N 2-methyl-3-phenylpyridine Chemical compound CC1=NC=CC=C1C1=CC=CC=C1 YLUZKERNKYNCLG-UHFFFAOYSA-N 0.000 description 2
- UUCLVSDUMKMBSM-UHFFFAOYSA-N 3-benzylpyridine Chemical compound C=1C=CN=CC=1CC1=CC=CC=C1 UUCLVSDUMKMBSM-UHFFFAOYSA-N 0.000 description 2
- FQQRGAUVWHBXDN-UHFFFAOYSA-N 3-chloro-5-phenylpyridine Chemical compound ClC1=CN=CC(C=2C=CC=CC=2)=C1 FQQRGAUVWHBXDN-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- NEBAPZLPZNLDPL-UHFFFAOYSA-N 3-[(4-nitrophenyl)methyl]-5-phenylpyridine Chemical compound [O-][N+](C1=CC=C(CC2=CC(C3=CC=CC=C3)=CN=C2)C=C1)=O NEBAPZLPZNLDPL-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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- 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
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- 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
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- 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
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- 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
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- 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
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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。
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