CN106117154A - 一种邻芳氧基‑1,4‑二芳基‑1,2,3‑三氮唑衍生物及其制备方法和应用 - Google Patents
一种邻芳氧基‑1,4‑二芳基‑1,2,3‑三氮唑衍生物及其制备方法和应用 Download PDFInfo
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- CN106117154A CN106117154A CN201610495103.9A CN201610495103A CN106117154A CN 106117154 A CN106117154 A CN 106117154A CN 201610495103 A CN201610495103 A CN 201610495103A CN 106117154 A CN106117154 A CN 106117154A
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- diaryl
- adjacent
- triazole
- aryloxy group
- triazole derivatives
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- 125000004104 aryloxy group Chemical group 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 diaryl 1,2,3 triazole derivatives Chemical class 0.000 title abstract description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 150000003624 transition metals Chemical group 0.000 claims abstract description 5
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000605 extraction Methods 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- 235000011009 potassium phosphates Nutrition 0.000 claims description 15
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 13
- 230000006837 decompression Effects 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 12
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical class C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- YXPUNWKYPJPPFC-UHFFFAOYSA-N COC1=C(C(=CC=C1)OC)C1=CC=CC=C1.P Chemical group COC1=C(C(=CC=C1)OC)C1=CC=CC=C1.P YXPUNWKYPJPPFC-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
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- 238000000926 separation method Methods 0.000 claims description 2
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- 125000000524 functional group Chemical group 0.000 abstract description 5
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 abstract description 3
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- CPYAKBMFQCYAHX-UHFFFAOYSA-N 1-(2-bromophenyl)-4-phenyltriazole Chemical compound BrC1=CC=CC=C1N1N=NC(C=2C=CC=CC=2)=C1 CPYAKBMFQCYAHX-UHFFFAOYSA-N 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 4
- 150000002931 p-cresols Chemical class 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- HKAQEAXHZNPVEZ-UHFFFAOYSA-N 1-(2-phenoxyphenyl)-4-phenyltriazole Chemical compound O(C1=CC=CC=C1)C1=C(C=CC=C1)N1N=NC(=C1)C1=CC=CC=C1 HKAQEAXHZNPVEZ-UHFFFAOYSA-N 0.000 description 3
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 3
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- 235000002639 sodium chloride Nutrition 0.000 description 3
- FODHQUPOYMTEOT-UHFFFAOYSA-N 1-(2,4-dibromophenyl)-4-(2-methylphenyl)triazole Chemical compound BrC1=C(C=CC(=C1)Br)N1N=NC(=C1)C1=C(C=CC=C1)C FODHQUPOYMTEOT-UHFFFAOYSA-N 0.000 description 2
- DTBAYPQJFDEVGR-UHFFFAOYSA-N 1-(2,5-dibromophenyl)-4-(2-methylphenyl)triazole Chemical compound CC1=CC=CC=C1C2=CN(N=N2)C3=C(C=CC(=C3)Br)Br DTBAYPQJFDEVGR-UHFFFAOYSA-N 0.000 description 2
- PPTXBUKAVDAUNC-UHFFFAOYSA-N 1-[5-bromo-2-(4-methoxyphenyl)phenyl]-4-(2-methylphenyl)triazole Chemical class COC1=CC=C(C=C1)C1=C(C=C(C=C1)Br)N1N=NC(=C1)C1=C(C=CC=C1)C PPTXBUKAVDAUNC-UHFFFAOYSA-N 0.000 description 2
- JHODODBNOMARQV-UHFFFAOYSA-N 4-bromo-5-phenyl-2h-triazole Chemical compound N1=NNC(C=2C=CC=CC=2)=C1Br JHODODBNOMARQV-UHFFFAOYSA-N 0.000 description 2
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- ODSQGCFBRXCLKM-UHFFFAOYSA-N C1=CSC(C2=C(C(C=CC=C3)=C3OC3=CC=CC=C3)NN=N2)=C1 Chemical class C1=CSC(C2=C(C(C=CC=C3)=C3OC3=CC=CC=C3)NN=N2)=C1 ODSQGCFBRXCLKM-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- YUWJNNCIAAHVIH-UHFFFAOYSA-N 1-(2-bromophenyl)-4-thiophen-2-yltriazole Chemical compound C1=CC=C(C(=C1)N2C=C(N=N2)C3=CC=CS3)Br YUWJNNCIAAHVIH-UHFFFAOYSA-N 0.000 description 1
- JIMJNJLOPIPUEI-UHFFFAOYSA-N 1-[4-bromo-2-(4-methoxyphenyl)phenyl]-4-(2-methylphenyl)triazole Chemical class COC1=CC=C(C=C1)C1=C(C=CC(=C1)Br)N1N=NC(=C1)C1=C(C=CC=C1)C JIMJNJLOPIPUEI-UHFFFAOYSA-N 0.000 description 1
- WJQOZHYUIDYNHM-UHFFFAOYSA-N 2-tert-Butylphenol Chemical compound CC(C)(C)C1=CC=CC=C1O WJQOZHYUIDYNHM-UHFFFAOYSA-N 0.000 description 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RPMOVVBYQKVHPP-UHFFFAOYSA-N C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.C(CCCCC)[P] Chemical group C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.C(CCCCC)[P] RPMOVVBYQKVHPP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0213—Complexes without C-metal linkages
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开一种邻芳氧基‑1,4‑二芳基‑1,2,3‑三氮唑衍生物及其制备方法和应用,属于药物及有机合成技术领域;本发明以邻溴‑1,4‑二芳基‑1,2,3‑三氮唑和酚为原料,在“过渡金属/磷配体”体系催化下发生选择性碳‑氧偶联反应,克服空间位阻,选择性生成邻芳氧基‑1,4‑二芳基‑1,2,3‑三氮唑衍生物;所合成的化合物同时含有1,2,3‑三唑环及醚结构单元,两官能团处于邻位,可作为过渡金属配体应用于催化反应,亦为药物的合成与修饰提供了一种新方法和新目标。
Description
技术领域
本发明涉及一种邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物及其制备方法和应用,属于药物及有机合成技术领域。
背景技术
三氮唑类化合物在医药、农药及材料等领域已广泛应用,一直以来备受化学家们的重视。尤其在Sharpless发现有机叠氮与末端炔的点击反应之后,1,2,3-三氮唑类化合物的合成近些年发展尤为迅速,并广泛应用于抗菌、杀菌、免疫及治疗肿瘤、关节炎、软骨病等方面(Kantheti S., Narayan R., Raju K. V. S. N. RSC Adv., 2015, 5, 3687;Schulze B., Schubert U. S. Chem. S℃. Rev., 2014, 43, 2522; Bromidge S. M.,Arban R., Bertani B., Bison S., et al. Med. Chem., 2010, 53, 5827.),同时还作为过渡金属配体应用于有机合成领域(Chen Y., Yan W., Akhmedov N., et al. Org. Lett., 2010,12(2), pp 344–347; Yan W., Ye X., Akhmedov N., et al.Org. Lett.,2012, 14(9), 2358.)。
该类化合物的合成方法主要有两类:方法一是通过炔与叠氮类化合物发生环加成反应,两者在亚铜催化下选择性得到1,4-二取代-1,2,3-三氮唑衍生物,而在钌或季胺碱催化下得则到1,5-二取代-1,2,3-三氮唑衍生物(Chen, Z., Yan, Q., Liu, Z., Zhang, Y.Chem. Eur. J., 2014, 20, 17635; Bai, H., Cai, Z., Wang, S., Ji S. Org. Lett.2015, 17, 2898. Smith, C., Greaney, M. Org. Lett.2013, 15, 4826; Wang,Y., Xie, Y., Qu, H., et al. J. Org. Chem.2014, 79, 4463.)。方法二是直接对1,2,3-三氮唑衍生物进行修饰,目前主要集中在2-单取代-1,2,3-三氮唑及4-苄基-1-芳基-1,2,3-三氮唑衍生物的邻位官能团化,包括烯基化、酰氧基化、烷氧基化等(Liu W., Li Y.,Xu, B., Kuang,C. Org. Lett., 2013, 15, 2342; He, P. Tian, Q., Kuang, C. Org. Biomol. Chem., 2015, 13, 7146; Zhao S., Yu R., Chen W., Liu M., Wu H., Org. Lett., 2015, 17, 2828.),而邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物目前无法获得。
发明内容
本发明的目的在于提供一种邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物其结构式为以下两种中的一种:
其中,R1 = H、 3-Br、4-Br中的任意一种; R2 = H、Me、Cl、 t Bu中的任意一种; R3 = H、F、OMe、Me、Br中的任意一种; R4 为2-吡啶基、2-噻吩基中的任意一种。
本发明的另一目的在于提供所述邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,具体包括以下步骤:
(1)按邻溴-1,4-二芳基-1,2,3-三氮唑、酚、催化剂、配体、碱、溶剂的摩尔比为1:(1~3):(0.01~0.2):(0.02~0.4):(1~5):(10~100)的比例,依次将邻溴-1,4-二芳基-1,2,3-三氮唑、酚、催化剂、配体、碱、溶剂加入到反应器中,在70℃-150℃下反应5~60小时即生成混合产物;
(2)用乙酸乙酯萃取混合产物,合并萃取液,洗涤干燥后减压蒸馏得粗产品,再分离提纯即得邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物产品。
优选的,本发明所述催化剂为Pd2(dba)3、CuI、CuBr、CuCl中的一种。
优选的,本发明所述配体为2-双环己基膦-2',6'-二甲氧基联苯(S-Phos)、2-二环己基磷-2,4,6-三异丙基联苯(X-Phos)中的一种。
优选的,本发明所述碱为磷酸钾、碳酸铯、碳酸钾、碳酸钠中的一种。
优选的,本发明所述溶剂为甲苯、DMF、DMSO中的一种。
本发明所述1,4-二芳基-1,2,3-三氮唑为1-邻溴苯基-4-苯基-1,2,3-三氮唑、1-邻溴苯基-4-(对甲苯基)-1,2,3-三氮唑、1-邻溴苯基-4-(邻氟苯基)-1,2,3-三氮唑、1-邻溴苯基-4-(2-吡啶基)-1,2,3-三氮唑、1-邻溴苯基-4-(邻噻吩基)-1,2,3-三氮唑、1-邻溴苯基-4-(邻甲氧苯基)-1,2,3-三氮唑、1-邻溴苯基-4-(间溴苯基)-1,2,3-三氮唑、1-(2,4-二溴苯基-4-(对甲苯基)-1,2,3-三氮唑、1-(2,5-二溴苯基-4-(邻甲苯基)-1,2,3-三氮唑中的一种。
所述酚为邻甲苯酚、间甲苯酚、对甲苯分、间氯苯酚、对氯苯酚、邻叔丁基苯酚中的一种。
本发明所述邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物同时含有1,2,3-三唑环及醚官能团结构单元,两官能团处于邻位,可作为过渡金属配体应用于催化反应,亦为药物合成与修饰提供了一种新方法和新目标。
本发明的有益效果为:以易得的邻溴-1,4-二芳基-1,2,3-三氮唑和酚为起始原料,通过碳-氧偶联反应选择性地获得邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物,所合成的化合物同时含有1,2,3-三唑环及醚官能团结构单元,两官能团处于邻位,可作为过渡金属配体应用于催化反应,亦为药物的合成与修饰提供了新方法和新目标。
具体实施方式
下面结合实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容。
实施例1
1-(2-苯氧苯基)-4-苯基-1,2,3-三氮唑(3a)的合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、对甲苯酚(2a)、碘化亚铜、X-Phos、磷酸钾、甲苯的摩尔比为1:1:0.01:0.01:1:10的比例,依次将1mmol 1-(2-苯氧苯基)-4-苯基-1,2,3-三氮唑、1mmol对甲苯酚、0.01mmolCuI、0.01mmol X-Phos、1mmol磷酸钾、10mmol甲苯加入到反应器中,在70℃反应60小时。
(2)所得混合产物用40mL水稀释,再以100mmol乙酸乙酯萃取混合产物2次,合并萃取液,洗涤干燥后减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:1(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得191mg产品1-(2-苯氧苯基)-4-苯基-1,2,3-三氮唑3a,收率为61%,反应方程式如下:
产物核磁共振谱表征数据如下:1H NMR (400 MHz, CDCl3) δ = 8.38 (s, 1H), 7.99(dd, J = 7.9, 1.6 Hz, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.85 (s, 1H), 7.45 (s,1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.38 – 7.36 (m, 1H), 7.35 (s, 1H), 7.34 –7.31 (m, 1H), 7.30 – 7.25 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.10 – 6.98 (m,3H). 13C NMR (101 MHz, CDCl3) δ = 155.8, 148.5, 147.6, 130.4, 130.0, 129.9,128.8, 128.4, 128.1, 125.8, 125.6, 124.2, 124.2, 121.3, 119.6, 118.8。
实施例2
1-(2-间甲苯氧苯基)- 4-苯基-1,2,3-三氮唑(3b)的合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、间甲苯酚(2b)、溴化亚铜、X-Phos、磷酸钾、甲苯的摩尔比为1:1.2:0.02:0.02:1.5:20的比例,依次将1mmol1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、1.2 mmol间甲苯酚(2b)、0.02 mmol溴化亚铜、0.02 mmol X-Phos、1.5mmol磷酸钾、20 mmol甲苯加入到反应器中,在80℃下反应40小时即生成混合产物;
(2)所得混合产物用40mL水稀释,再以乙酸乙酯150萃取混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:5(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得252mg产品1-(2-间甲苯氧苯基)- 4-苯基-1,2,3-三氮唑3b,收率为77%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H NMR (400 MHz, CDCl3) δ = 8.39 (s, 1H), 7.99(dd, J = 8.0, 1.7 Hz, 1H), 7.89 – 7.83 (m, 2H), 7.42 (dd, J = 8.0, 6.8 Hz,2H), 7.39 – 7.29 (m, 2H), 7.29 – 7.20 (m, 2H), 7.05 (dd, J = 8.3, 1.3 Hz,1H), 6.96 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 7.6 Hz, 2H), 2.32 (s, 3H). 13C NMR(126 MHz, CDCl3) δ = 155.8, 148.6, 140.4, 130.4, 129.8, 129.7, 129.6, 128.8,128.1, 126.4, 126.3, 125.7, 125.1, 124.0, 121.3, 119.6, 119.5, 115.9, 21.3。
实施例3
1-(2-对甲苯氧苯基)-4-苯基-1,2,3-三氮唑(3c)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、对甲苯酚(2c)、氯化亚铜、X-Phos、碳酸铯、甲苯的摩尔比为1:1.6:0.05:0.05:2:30的比例,依次将1mmol 1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、1.6mmol对甲苯酚(2c)、0.05mmol氯化亚铜、0.05 mmol X-Phos、2 mmol磷酸钾、30 mmol甲苯加入到反应器中,在90℃下反应15小时即生成混合产物;
(2)所得混合产物用40mL水稀释,再以乙酸乙酯200萃取步骤混合产物2次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:8(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得298m g产品1-(2-对甲苯氧苯基)-4-苯基-1,2,3-三氮唑合成3c,收率为91%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.49 (s, 1H),8.05 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H),7.42 (dd, J = 6.1, 4.8 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 8.0Hz, 2H), 7.09 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H). 13CNMR (101 MHz, CDCl3) δ = 153.3, 148.9, 147.4, 134.0, 130.4, 130.3, 129.8,128.7, 128.0, 125.7, 125.3, 125.2, 123.7, 121.3, 118.9, 118.7, 20.6。
实施例4
1-(2-对氯苯氧苯基)-4-苯基-1,2,3-三氮唑(3d)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、对氯苯酚(2d)、Pd2(dba)3、X-Phos、磷酸钾、甲苯的摩尔比为1:1.8:0.08:0.15:2.5:40的比例,依次将1mmol 1-邻溴苯基-4-苯基-1,2,3-三氮唑(1a)、1.8mmol对氯苯酚(2d)、0.08mmolPd2(dba)3、0.15mmol X-Phos、2.5mmol磷酸钾、40mmol甲苯加入到反应器中,在100℃下反应20小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯250萃取步骤混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:10(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得202mg产品1-(2-对氯苯氧苯基)-4-苯基-1,2,3-三氮唑3d,收率为58%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.24 (s, 1H), 7.87(dd, J = 8.0, 1.5 Hz, 1H), 7.77 (d, J = 7.3 Hz, 2H), 7.33 (ddd, J = 7.5, 6.6,2.6 Hz, 3H), 7.28 – 7.16 (m, 4H), 6.97 (dd, J = 8.2, 1.1 Hz, 1H), 6.89 – 6.83(m, 2H). 13C NMR (101 MHz, CDCl3) δ = 154.4, 148.2, 130.2, 130.2, 130.0,129.9, 129.4, 128.8, 128.5, 128.2, 125.8, 124.6, 121.2, 119.9, 119.7, 116.8。
实施例5
1-(2-对甲苯氧苯基)-4-邻甲氧苯基-1,2,3-三氮唑(3e)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-邻甲氧苯基-1,2,3-三氮唑(1b)、对甲苯酚(2c)、碘化亚铜、X-Phos、磷酸钾、甲苯的摩尔比为1:2:0.1:0.18:3:50的比例,依次将1mmol 1-邻溴苯基-4-邻甲氧苯基-1,2,3-三氮唑(1b)、2 mmol对甲苯酚(2c)、0.1 mmol碘化亚铜、0.18 mmol X-Phos、3 mmol磷酸钾、50mmol甲苯加入到反应器中,在110℃下反应25小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯300萃取步骤混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:12(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得328mg产品1-(2-对甲苯氧苯基)-4-邻甲氧苯基-1,2,3-三氮唑3e,收率为92%,反应方程式如下:
;
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.67 (s, 1H),8.48 – 8.39 (m, 1H), 8.06 – 7.95 (m, 1H), 7.45 – 7.37 (m, 1H), 7.32 (dt, J =14.0, 4.2 Hz, 2H), 7.22 – 7.06 (m, 4H), 6.96 (dd, J = 11.8, 8.6 Hz, 3H), 3.85(s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 155.6, 153.8, 148.6,142.8, 133.4, 130.3, 129.7, 129.5, 128.8, 127.5, 125.5, 124.7, 123.9, 120.8,119.7, 119.1, 118.2, 110.7, 55.1, 20.5。
实施例6
1-(2-对甲氧苯基-5-溴苯基)-4-邻甲苯基-1,2,3-三氮唑(3f)合成,具体包括以下步骤:
(1)按1-(2,5-二溴苯基)-4-邻甲苯基-1,2,3-三氮唑(1c)、对甲苯酚(2c)、碘化亚铜、S-Phos、磷酸钾、甲苯的摩尔比为1:2.2:0.12:0.2:3.5:60的比例,依次将1mmol 1-(2,5-二溴苯基)-4-邻甲苯基-1,2,3-三氮唑(1c)、2.2mmol对甲苯酚(2c)、0.12mmol碘化亚铜、0.2mmol S-Phos、3.5mmol磷酸钾、60mmol甲苯加入到反应器中,在120℃下反应60小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯350mmol萃取步骤混合产物2次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1: 20(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得189mg产品1-(2-对甲氧苯基-5-溴苯基)-4-邻甲苯基-1,2,3-三氮唑3f,收率为45%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.34 (s, 1H), 8.25(d, J = 2.3 Hz, 1H), 7.88 – 7.76 (m, 1H), 7.50 (dd, J = 8.8, 2.3 Hz, 1H),7.36 – 7.26 (m, 3H), 7.19 (d, J = 8.4 Hz, 2H), 6.95 (dd, J = 11.4, 8.7 Hz,3H), 2.47 (s, 3H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 153.0, 147.7,147.0, 135.6, 134.3, 132.5, 130.7, 129.4, 129.1, 128.9, 128.2, 128.0, 126.0,123.3, 120.7, 118.5, 116.0, 21.2, 20.6。
实施例7
1-(2-对甲氧苯基-4-溴苯基)-4-邻甲苯基-1,2,3-三氮唑(3g)合成,具体包括以下步骤:
(1)按1-(2,4-二溴苯基)-4-邻甲苯基-1,2,3-三氮唑(1d)、对甲苯酚(2c)、碘化亚铜、X-Phos、磷酸钾、甲苯的摩尔比为1:2.4:0.15:0.1:4:70的比例,依次将1mmol 1-(2,4-二溴苯基)-4-邻甲苯基-1,2,3-三氮唑(1d)、2.4mmol对甲苯酚(2c)、0.15mmol碘化亚铜、0.1mmol XS-Phos、4mmol磷酸钾、70mmol甲苯加入到反应器中,在130℃下反应35小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯400mmol萃取步骤混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1: 8(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得214mg产品1-(2-对甲氧苯基-4-溴苯基)-4-邻甲苯基-1,2,3-三氮唑3g,收率为51%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.40 (s, 1H),7.90 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.39 (dd, J = 8.6, 1.8Hz, 1H), 7.30 – 7.20 (m, 4H), 7.13 (d, J = 1.7 Hz, 1H), 6.98 (d, J = 8.4 Hz,2H), 2.40 (d, J = 7.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ = 152.4, 149.7,147.7, 138.0, 134.9, 130.7, 129.4, 127.3, 126.9, 126.6, 126.3, 125.7, 122.7,121.4, 120.7, 119.4, 21.2, 20.7。
实施例8
1-对甲苯氧苯基-4-间溴苯基-1,2,3-三氮唑(3h)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-间溴苯基-1,2,3-三氮唑(1e)、对甲苯酚(2c)、碘化亚铜、X-Phos、磷酸钾、甲苯的摩尔比为1:2.6:0.18:0.08:4.5:80的比例,依次将1mmol 1-邻溴苯基-4-间溴苯基-1,2,3-三氮唑(1e)、2.6 mmol对甲苯酚(2c)、0.18 mmol碘化亚铜、0.08 mmol X-Phos、4.5 mmol磷酸钾、80 mmol甲苯的摩尔比为加入到反应器中,在140℃下反应20小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯450mL萃取混合产物5次,合并萃取液,洗涤干燥后减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:8(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得288mg产品1-对甲苯氧苯基-4-间溴苯基-1,2,3-三氮唑3h,收率为71%,反应方程式如下:
产物核磁共振谱表征数据如下:1H-NMR (400 MHz, CDCl3) δ = 8.34 (s, 1H), 7.94(t, J = 1.6 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.73 (d, J = 7.8 Hz,1H), 7.38 (d, J = 7.9 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.25 – 7.14 (m, 2H), 7.09(d, J = 8.3 Hz, 2H), 6.93 (dd, J = 8.3, 0.9 Hz, 1H), 6.86 (d, J = 8.5 Hz,2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 153.2, 149.1, 146.1, 134.3,132.5, 131.0, 130.5, 130.3, 130.0, 128.7, 127.8, 125.4, 124.3, 123.7, 122.9,121.7, 119.2, 118.8, 20.7。
实施例9
1-(2-对甲苯氧苯基-4-(2-吡啶基)-1,2,3-三氮唑(3i)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-(2-吡啶基)-1,2,3-三氮唑(1f)、对甲苯酚(2c)、碘化亚铜、X-Phos、磷酸钾、DMSO的摩尔比为1:2.8:0.2:0.12:5:90的比例,依次将1mmol1-邻溴苯基-4-(2-吡啶基)-1,2,3-三氮唑(1f)、2.8 mmol对甲苯酚(2c)、0.2 mmol碘化亚铜、0.12 mmolX-Phos、5 mmol磷酸钾、90 mmol DMSO加入到反应器中,在150℃下反应5小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯500萃取混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:8(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得207mg产品1-(2-对甲苯氧苯基-4-(2-吡啶基)-1,2,3-三氮唑3i,收率为63%,反应方程式如下:
产物核磁共振谱表征数据如下:1H-NMR (400 MHz, CDCl3) δ = 8.70 (s, 1H), 8.47(d, J = 4.2 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.85 (dd, J = 7.9, 1.4 Hz,1H), 7.66 (td, J = 7.8, 1.5 Hz, 1H), 7.29 – 7.19 (m, 1H), 7.17 – 7.06 (m,2H), 7.03 (d, J = 8.3 Hz, 2H), 6.84 (dd, J = 16.5, 8.4 Hz, 3H), 2.20 (s, 3H).13C NMR (101 MHz, CDCl3) δ = 153.0, 150.1, 149.5, 149.2, 147.9, 136.7, 134.1,130.4, 129.9, 127.7, 125.4, 123.7, 123.3, 122.7, 120.3, 119.4, 118.3, 20.6。
实施例10
1-(2-对甲苯氧苯基-4-(2-噻吩基)-1,2,3-三氮唑(3j)合成,具体包括以下步骤:
(1)按1-邻溴苯基-4-(2-噻吩基)-1,2,3-三氮唑(1g)、对甲苯酚(2c)、碘化亚铜、X-Phos、碳酸钠、DMF的摩尔比为1:3:0.05:0.1:2:100的比例,依次将1mmol1-邻溴苯基-4-(2-噻吩基)-1,2,3-三氮唑(1g)、3 mmol对甲苯酚(2c)、0.05 mmol碘化亚铜、0.1 mmol X-Phos、2 mmol碳酸钠、100 mmol DMF加入到反应器中,在120℃下反应55小时即生成混合产物。
(2)所得混合产物用40mL水稀释,再以乙酸乙酯600 mL萃取混合产物3次,合并萃取液,洗涤干燥后,减压蒸馏去溶剂得粗产品,再以乙酸乙酯/石油醚1:8(体积比)为淋洗液进行柱层析(400目硅胶)提纯即得220mg产品1-(2-对甲苯氧苯基-4-(2-吡啶基)-1,2,3-三氮唑3i,收率为66%,反应方程式如下:
产物核磁共振谱表征数据如下: 1H-NMR (400 MHz, CDCl3) δ = 8.35 (s, 1H), 7.98(d, J = 7.8 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.32(d, J = 4.7 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.12 –7.07 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 2.36 (s,3H). 13C NMR (101 MHz, CDCl3) δ = 149.0, 142.5, 134.1, 132.5, 130.4, 129.9,129.7, 127.5, 125.4, 125.0, 124.3, 123.6, 120.8, 119.0, 118.8, 115.2, 20.6。
实施例11
产品3a作为配体,应用于叠氮-炔的环加成反应,具体包括以下步骤:
(1)将1mmol邻甲苯基叠氮4a、1.1mmol对甲基苯乙炔5a、0.05mmol碘化亚铜、0.1mmol产品1-(2-苯氧苯基)-4-苯基-1,2,3-三氮唑3a、20mmol二甲基亚砜加入到25mL圆底烧瓶中,在室温下磁力搅拌1小时即反应完全。
(2)所得混合产物用40mL水稀释,再以100mmol乙酸乙酯分3次萃取,萃取液合并后再依次用水和饱和食盐水各10mL洗涤,然后用2g无水硫酸钠干燥,通过旋转蒸发仪蒸去溶剂即得粗产品,再以乙酸乙酯/石油醚1:10(体积比)为淋洗液对所得粗产品进行柱层析(400目的硅胶)分离提纯即得217mg产品1-邻甲苯基-4-对甲苯基-1,2,3-三氮唑6a,收率为87%,反应方程式如下:
;
产物核磁共振谱表征数据如下:1H-NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.81(d, J = 8.1 Hz, 2H), 7.45 – 7.39 (m, 2H), 7.39 – 7.33 (m, 2H), 7.27 (d, J =8.5 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H);13C-NMR (100 MHz, CDCl3) δ 147.7,138.2, 136.6, 133.8, 131.5, 129.8, 129.6, 127.5, 126.8, 126.0, 125.7, 120.8,21.3, 17.9。
实施例12
产品3i作为配体,应用于叠氮-炔的环加成反应,具体包括以下步骤:
(1)将1mmol邻甲苯基叠氮4a、1.1mmol对氯苯乙炔5b、0.05mmol碘化亚铜、0.1mmol产品1-(2-苯氧苯基)-4-(2-吡啶基)-1,2,3-三氮唑3i、20mmol二甲基亚砜加入到25mL圆底烧瓶中,在室温下磁力搅拌1小时即反应完全。
(2)所得混合产物用40mL水稀释,再以100mmol乙酸乙酯分3次萃取,萃取液合并后再依次用水和饱和食盐水各10mL洗涤,然后用2g无水硫酸钠干燥,通过旋转蒸发仪蒸去溶剂即得粗产品,再以乙酸乙酯/石油醚1:10(体积比)为淋洗液对所得粗产品进行柱层析(400目的硅胶)分离提纯即得251mg产品1-邻甲苯基-4-对甲苯基-1,2,3-三氮唑6b,收率为93%,反应方程式如下:
;
产物核磁共振谱表征数据如下:1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 –7.86 (m, 1H), 7.86 – 7.84 (m, 1H), 7.46 – 7.42 (m, 3H), 7.42 – 7.34 (m, 3H),2.28 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 146.6, 136.4, 134.1, 133.8, 131.6,130.0, 129.2, 128.9, 127.1, 126.9, 126.0, 121.2, 17.9。
实施例13
产品3j作为配体,应用于叠氮-炔的环加成反应,具体包括以下步骤:
(1)将1mmol间乙酰苯基叠氮4b、1.1mmol苯乙炔5c、0.05mmol碘化亚铜、0.1mmol产品1-(2-苯氧苯基)-4-苯基-1,2,3-三氮唑3j、20mmol二甲基亚砜加入到25mL圆底烧瓶中,在室温下磁力搅拌1小时即反应完全。
(2)所得混合产物用40mL水稀释,再以100mmol乙酸乙酯分3次萃取,萃取液合并后再依次用水和饱和食盐水各10mL洗涤,然后用2g无水硫酸钠干燥,通过旋转蒸发仪蒸去溶剂即得粗产品,再以乙酸乙酯/石油醚1:10(体积比)为淋洗液对所得粗产品进行柱层析(400目的硅胶)分离提纯即得190mg产品1-邻甲苯基-4-对甲苯基-1,2,3-三氮唑6c,收率为72%,反应方程式如下:
;
产物核磁共振谱表征数据如下: 1H-NMR (300 MHz, CDCl3) δ 8.38 – 8.32 (m, 1H),8.30 (s, 1H), 8.15 – 8.06 (m, 1H), 8.05 – 8.00 (m, 1H), 7.95 – 7.88 (m, 2H),7.68 (t, J = 7.9 Hz, 1H), 7.47 (dd, J = 8.1, 6.6 Hz, 2H), 7.40 (d, J = 7.3Hz, 1H), 2.70 (s, 3H)。
Claims (7)
1.一种邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物,其特征在于,其结构式为以下两种中的一种:
其中,R1 = H、 3-Br、4-Br中的任意一种; R2 = H、Me、Cl、 t Bu中的任意一种; R3 = H、F、OMe、Me、Br中的任意一种; R4 为2-吡啶基、2-噻吩基中的任意一种。
2.权利要求1所述邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,其特征在于,具体包括以下步骤:
(1)按邻溴-1,4-二芳基-1,2,3-三氮唑、酚、催化剂、配体、碱、溶剂的摩尔比为1:(1~3):(0.01~0.2):(0.02~0.4):(1~5):(10~100)的比例,依次将邻溴-1,4-二芳基-1,2,3-三氮唑、酚、催化剂、配体、碱、溶剂加入到反应器中,在70℃-150℃下反应5~60小时即生成混合产物;
(2)用乙酸乙酯萃取混合产物,合并萃取液,洗涤干燥后减压蒸馏得粗产品,再分离提纯即得邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物产品。
3.根据权利要求2所述的邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,其特征在于:所述催化剂为Pd2(dba)3、CuI、CuBr、CuCl中的一种。
4.根据权利要求2所述的邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,其特征在于:所述配体为2-双环己基膦-2',6'-二甲氧基联苯(S-Phos)、2-二环己基磷-2,4,6-三异丙基联苯(X-Phos)中的一种。
5.根据权利要求2所述的邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,其特征在于:所述碱为磷酸钾、碳酸铯、碳酸钾、碳酸钠中的一种。
6.根据权利要求2所述的邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物的制备方法,其特征在于:所述溶剂为甲苯、DMF、DMSO中的一种。
7.权利要求1~6任意一项所述的邻芳氧基-1,4-二芳基-1,2,3-三氮唑衍生物作为过渡金属配体应用于催化反应。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110396068A (zh) * | 2019-07-22 | 2019-11-01 | 昆明理工大学 | 4-邻烷氧芳基-1,2,3-三唑衍生物及合成方法和应用 |
CN110423239A (zh) * | 2019-08-23 | 2019-11-08 | 昆明理工大学 | 1,3-噁嗪并1,2,3-三氮唑类衍生物及其合成方法与应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130310569A1 (en) * | 2012-05-21 | 2013-11-21 | Hunaid Nulwala | Triazolide based ionic liquids |
CN104903309A (zh) * | 2013-01-07 | 2015-09-09 | 埃斯蒂文博士实验室股份有限公司 | 用于治疗σ受体相关疾病和病症的1,2,3-三唑-4-胺衍生物 |
WO2015193915A1 (en) * | 2014-06-20 | 2015-12-23 | Council Of Scientific & Industrial Research | Novel 1,2,3 triazole antifungal agents and preparation thereof |
-
2016
- 2016-06-30 CN CN201610495103.9A patent/CN106117154B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130310569A1 (en) * | 2012-05-21 | 2013-11-21 | Hunaid Nulwala | Triazolide based ionic liquids |
CN104903309A (zh) * | 2013-01-07 | 2015-09-09 | 埃斯蒂文博士实验室股份有限公司 | 用于治疗σ受体相关疾病和病症的1,2,3-三唑-4-胺衍生物 |
WO2015193915A1 (en) * | 2014-06-20 | 2015-12-23 | Council Of Scientific & Industrial Research | Novel 1,2,3 triazole antifungal agents and preparation thereof |
Non-Patent Citations (2)
Title |
---|
HONG-JIE CHEN,等: "Possible intermediates of Cu(phen)-catalyzed C–O cross-coupling of phenol with an aryl bromide by in situ ESI-MS and EPR studies", 《DALTON TRANSACTIONS》 * |
黄莉娜: "过渡金属催化的1,4-二取代-1,2,3- 三氮唑与α-烷基酮的合成", 《西北师范大学硕士学位论文》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110396068A (zh) * | 2019-07-22 | 2019-11-01 | 昆明理工大学 | 4-邻烷氧芳基-1,2,3-三唑衍生物及合成方法和应用 |
CN110396068B (zh) * | 2019-07-22 | 2023-01-20 | 昆明理工大学 | 4-邻烷氧芳基-1,2,3-三唑衍生物及合成方法和应用 |
CN110423239A (zh) * | 2019-08-23 | 2019-11-08 | 昆明理工大学 | 1,3-噁嗪并1,2,3-三氮唑类衍生物及其合成方法与应用 |
CN110423239B (zh) * | 2019-08-23 | 2021-10-26 | 昆明理工大学 | 1,3-噁嗪并1,2,3-三氮唑类衍生物及其合成方法与应用 |
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