碱催化的3-芳基硫代-7-氮杂吲哚衍生物的绿色制备工艺研究
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摘要
研究了一种高效、绿色、经济的硫醚取代的7-氮杂吲哚衍生物的合成工艺,考察了溶剂的种类、反应温度、碱的种类和用量及苯硫酚取代基对反应的影响。研究发现,在50%的CsOAc的催化作用下,苯硫酚和7-氮杂吲哚在DMSO中120℃条件下反应6 h,可以得到高达83%的分离产率;同时,在最优的催化条件下,进行放大量实验,结果表明该制备工艺具有很好的适用性和稳定性。该工艺具有产率高、操作简单、在空气中就可以实现、底物适应性强等优点。
Developing a cheap,green and sustainable method to synthesis sulfonyl 7-azaindole.The influence of solvent,reaction temperature,base,loading and phenylthiophenol substituents on reaction were investigated.It was found that the 7-azaindole and thiophenol were sulfonated with the use of 50% catalytic amount of CsOAc in DMSO at 120 ℃ for 6 h,83% yield was isolated.In addition,we examined different thiophenol derivatives and did scale-up reaction under the optimized reaction conditions without reactivity decreased.The protocol here has proven to be simply manipulation,realization under air and broad functional group tolerance.
Developing a cheap,green and sustainable method to synthesis sulfonyl 7-azaindole.The influence of solvent,reaction temperature,base,loading and phenylthiophenol substituents on reaction were investigated.It was found that the 7-azaindole and thiophenol were sulfonated with the use of 50% catalytic amount of CsOAc in DMSO at 120 ℃ for 6 h,83% yield was isolated.In addition,we examined different thiophenol derivatives and did scale-up reaction under the optimized reaction conditions without reactivity decreased.The protocol here has proven to be simply manipulation,realization under air and broad functional group tolerance.
引文
[1]Unangst P C,Connor T D,Stabler S R,et al.Novel indolecarboxamidotetrazoles as potential antiallergy agents[J].Journal of Medicinal Chemistry,1989,32(6):1360-1366.
[2]Funk C D.Leukotriene modifiers as potential therapeutics for cardiovascular disease[J].Nature Reviews Drug Discovery,2005,4(8):664-672.
[3]Ragno Q,Coluccia A,Regina G L,et al.Design,molecular modeling,synthesis,and anti-HIV-1 activity of new indolyl aryl sulfones.Novel derivatives of the indole-2-carboxamide[J].Journal of Medicinal Chemistry,2006,49(11):3172-3184.
[4]Regina G L,Edler M C,Brancale A,et al.Arylthioindole inhibitors of tubulin polymerization.3.Biological evaluation,structure-activity relationships and molecular modeling studies[J].Journal of Medicinal Chemistry,2007,50(12):2865-2874.
[5]Coluccia A,Passacantilli S,Famiglini V,et al.New inhibitors of indoleamine 2,3-dioxygenase 1:Molecular modeling studies,synthesis,and biological evaluation[J].Journal of Medicinal Chemistry,2016,59(21):9760-9773.
[6]Liao H,Yang Y,Li W,et al.Cu I-catalyzed regioselective sulfenylation of indoles with disulfides[J].Current Organic Chemistry,2017,21(24):2509-2513.
[7]Porter J,Lumb S,Franklin R J,et al.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase[J].Bioorganic&Medicinal Chemistry Letters,2009(10):2780-2784.
[8]Visor G C,Ibrahim P N,Spevak W,et al.Solid forms of sulfonamides and amino acids:WO,2010129570 A1[P].2010-11-11.
[9]Sang P,Chen Z,Zou J,et al.K2CO3promoted direct sulfenylation of indoles:a facile approach towards 3-sulfenylindoles[J].Green Chemistry,2013,15(8):2096-2100.
[10]Zhang J,Buell J,Chan K,et al.Heterocyclic compounds and uses thereof:WO,2014145051A1[P].2014-09-18.
[11]Bharathan I T,Blackburn C,Ciavarri J P,et al.Heteroaryls and uses thereof:WO,2015108861A1[P].2015-07-23.
[12]Zhang H,Bao X,Song Y,et al.Iodine-catalysed versatile sulfenylation of indoles with thiophenols:controllable synthesis of mono-and bis-arylthioindoles[J].Tetrahedron,2015,71(47):8885-8891.
[13]Liu Y,Zhang Y,Hu C,et al.Synthesis of 3-sulfenylated indoles by a simple Na OH promoted sulfenylation reaction[J].RSC Advances,2014,4(67):35528-35530.
[14]Bernotas R C,Lenicek S E,Antane S A,et al.1-(Aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands:WO,2003101990 A1[P].2003-12-11.
[15]Bernotas R C,Lenicek S E,Elokdah H M,et al.1-Heterocyclylalkyl-3-sulfonylazaindole or-azaindazole derivatives as 5-hydroxytryptamine-6 ligands:WO 2004009600 A1[P].2004-01-24.
[16]Bernotas R C,Lenicek S,Antane S,et al.Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists[J].Bioorganic&Medicinal Chemistry,2009,17(14):5153-5163.
[17]Liu C,Fan J,Wu M,et al.Metal free mono-and 2,3-bissulfenylation of indoles in water with sodium sulfinates as a sulfur source[J].Chinese Journal of Chemistry,2018,36(9):819-825.
[18]Wu Z,Li Y C,Ding W Z,et al.Copper-catalyzed regioselective sulfenylation of indoles with arylsulfonyl chlorides[J].Asian Journal of Organic Chemistry,2016,5(5):625-628.
[19]Yang Y,Zhang S,Tang L,et al.Catalyst-free thiolation of indoles with sulfonyl hydrazides for the synthesis of 3-sulfenylindoles in water[J].Green Chemistry,2016,18(9):2609-2613.
[20]Wang F X,Zhou S D,Wang C,et al.N-Hydroxy sulfonamides as new sulfenylating agents for the functionalization of aromatic compounds[J].Organic&Biomolecular Chemistry,2017,15(25):5284-5288.
[21]Qi H,Zhang T,Wan K,et al.Catalytic synthesis of 3-thioindoles using bunte salts as sulfur sources under metalfree conditions[J].The Journal of Organic Chemistry,2016,81(10):4262-4368.
[22]罗美明,齐鸿.一种3-吲哚硫醚的制备方法:CN,201510978857.5[P].2016-03-23.
[2]Funk C D.Leukotriene modifiers as potential therapeutics for cardiovascular disease[J].Nature Reviews Drug Discovery,2005,4(8):664-672.
[3]Ragno Q,Coluccia A,Regina G L,et al.Design,molecular modeling,synthesis,and anti-HIV-1 activity of new indolyl aryl sulfones.Novel derivatives of the indole-2-carboxamide[J].Journal of Medicinal Chemistry,2006,49(11):3172-3184.
[4]Regina G L,Edler M C,Brancale A,et al.Arylthioindole inhibitors of tubulin polymerization.3.Biological evaluation,structure-activity relationships and molecular modeling studies[J].Journal of Medicinal Chemistry,2007,50(12):2865-2874.
[5]Coluccia A,Passacantilli S,Famiglini V,et al.New inhibitors of indoleamine 2,3-dioxygenase 1:Molecular modeling studies,synthesis,and biological evaluation[J].Journal of Medicinal Chemistry,2016,59(21):9760-9773.
[6]Liao H,Yang Y,Li W,et al.Cu I-catalyzed regioselective sulfenylation of indoles with disulfides[J].Current Organic Chemistry,2017,21(24):2509-2513.
[7]Porter J,Lumb S,Franklin R J,et al.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase[J].Bioorganic&Medicinal Chemistry Letters,2009(10):2780-2784.
[8]Visor G C,Ibrahim P N,Spevak W,et al.Solid forms of sulfonamides and amino acids:WO,2010129570 A1[P].2010-11-11.
[9]Sang P,Chen Z,Zou J,et al.K2CO3promoted direct sulfenylation of indoles:a facile approach towards 3-sulfenylindoles[J].Green Chemistry,2013,15(8):2096-2100.
[10]Zhang J,Buell J,Chan K,et al.Heterocyclic compounds and uses thereof:WO,2014145051A1[P].2014-09-18.
[11]Bharathan I T,Blackburn C,Ciavarri J P,et al.Heteroaryls and uses thereof:WO,2015108861A1[P].2015-07-23.
[12]Zhang H,Bao X,Song Y,et al.Iodine-catalysed versatile sulfenylation of indoles with thiophenols:controllable synthesis of mono-and bis-arylthioindoles[J].Tetrahedron,2015,71(47):8885-8891.
[13]Liu Y,Zhang Y,Hu C,et al.Synthesis of 3-sulfenylated indoles by a simple Na OH promoted sulfenylation reaction[J].RSC Advances,2014,4(67):35528-35530.
[14]Bernotas R C,Lenicek S E,Antane S A,et al.1-(Aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands:WO,2003101990 A1[P].2003-12-11.
[15]Bernotas R C,Lenicek S E,Elokdah H M,et al.1-Heterocyclylalkyl-3-sulfonylazaindole or-azaindazole derivatives as 5-hydroxytryptamine-6 ligands:WO 2004009600 A1[P].2004-01-24.
[16]Bernotas R C,Lenicek S,Antane S,et al.Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists[J].Bioorganic&Medicinal Chemistry,2009,17(14):5153-5163.
[17]Liu C,Fan J,Wu M,et al.Metal free mono-and 2,3-bissulfenylation of indoles in water with sodium sulfinates as a sulfur source[J].Chinese Journal of Chemistry,2018,36(9):819-825.
[18]Wu Z,Li Y C,Ding W Z,et al.Copper-catalyzed regioselective sulfenylation of indoles with arylsulfonyl chlorides[J].Asian Journal of Organic Chemistry,2016,5(5):625-628.
[19]Yang Y,Zhang S,Tang L,et al.Catalyst-free thiolation of indoles with sulfonyl hydrazides for the synthesis of 3-sulfenylindoles in water[J].Green Chemistry,2016,18(9):2609-2613.
[20]Wang F X,Zhou S D,Wang C,et al.N-Hydroxy sulfonamides as new sulfenylating agents for the functionalization of aromatic compounds[J].Organic&Biomolecular Chemistry,2017,15(25):5284-5288.
[21]Qi H,Zhang T,Wan K,et al.Catalytic synthesis of 3-thioindoles using bunte salts as sulfur sources under metalfree conditions[J].The Journal of Organic Chemistry,2016,81(10):4262-4368.
[22]罗美明,齐鸿.一种3-吲哚硫醚的制备方法:CN,201510978857.5[P].2016-03-23.