N-杂环卡宾参与的芳香醛与卤代烃的亲核取代反应及其机理研究
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摘要
N-杂环卡宾(NHCs)是极性反转的有机催化反应中最常用的有机小分子催化剂之一。NHCs参与的各类反应中,以Stetter反应通常在不对称催化和天然产物、药物中间体合成中起到关键作用而倍受关注,但亲电试剂局限于以α,β-不饱和羰基化合物为代表的Michael受体。NHCs参与的亲核取代反应是NHCs在极性反转的应用中较新型的一类,目前有关的亲核取代反应的报道中底物往往缺乏多样性,或者反应仅限于分子内的亲核取代,或者反应实质上还是属于经典Stetter反应。在我们研究的NHC参与的亲核取代反应中以卤代烃代替Michael受体作为亲电试剂,在NHC参与下与芳香醛进行反应,不但拓宽了该类反应的底物范围和反应类型而且建立了方便合成各种含乙酮基结构单元的,包括α-芳基酮在内的各种酮类化合物的新方法,该类化合物是重要的医药、香精香料中间体或生物活性分子。我们在研究过程中,通过对N-杂环卡宾、碱、溶剂、反应温度和时间等一系列条件的筛选优化建立最佳反应体系,并在条件优化过程中探索可能的反应机理,以期在机理的理论指导下进一步优化本方法。
N-Heterocyclic Carbene(NHCs) is the most common and important organocatalyst in umpolung reaction. Among various kinds of reactions catalyzed by NHCs, Stetter reaction attracted a great deal of attention by playing an outstanding role in asymmetric catalysis and synthesis of natural products and drug intermediates, but the electrophilic reagents are limited toα,β-unsaturated carbonyl compounds as Michael acceptor. The research on N-Heterocyclic Carbene mediated nucleophilic substitution reaction is less common compared to others. Currently, according to the published reports, the substrates of nucleophilic substitution reaction were lack of diversity, or the reaction only proceeded intramolecularly, or the mechanism of reaction was the same as Stetter reaction. In the nucleophilic substitution reaction we studied, halogenated hydrocarbons were chosen as electrophilic reagents instead of Michael acceptor. The reaction of aromatic aldehydes and halogenated hydrocarbons mediated by NHCs generated various kinds of bioactive molecules or their intermediates containing building block ethnone, which not only widened the scope of nucleophilic subsititution reaction, but also can be applied to synthesize important intermediat of medicine, essence and perfume. After optimization of reaction conditions including catalysts, reaction temperature, solvents etc., we finally established the optimal reaction system. In addition, we also explored the mechanism of this reaction to seek guidance for further optimization.
N-Heterocyclic Carbene(NHCs) is the most common and important organocatalyst in umpolung reaction. Among various kinds of reactions catalyzed by NHCs, Stetter reaction attracted a great deal of attention by playing an outstanding role in asymmetric catalysis and synthesis of natural products and drug intermediates, but the electrophilic reagents are limited toα,β-unsaturated carbonyl compounds as Michael acceptor. The research on N-Heterocyclic Carbene mediated nucleophilic substitution reaction is less common compared to others. Currently, according to the published reports, the substrates of nucleophilic substitution reaction were lack of diversity, or the reaction only proceeded intramolecularly, or the mechanism of reaction was the same as Stetter reaction. In the nucleophilic substitution reaction we studied, halogenated hydrocarbons were chosen as electrophilic reagents instead of Michael acceptor. The reaction of aromatic aldehydes and halogenated hydrocarbons mediated by NHCs generated various kinds of bioactive molecules or their intermediates containing building block ethnone, which not only widened the scope of nucleophilic subsititution reaction, but also can be applied to synthesize important intermediat of medicine, essence and perfume. After optimization of reaction conditions including catalysts, reaction temperature, solvents etc., we finally established the optimal reaction system. In addition, we also explored the mechanism of this reaction to seek guidance for further optimization.
引文
[1]Mizuhara, S.; Handler, P. Mechanism of thiamine-catalyzed reactions. J. Am. Chem. Soc. 1954,76,571.
[2]Arduengo Ⅲ A. J.; Harlow R. L.; Kline M. A stable crystalline carbine. J. Am. Chem. Soc. 1991,113,361-363.
[3]Dixon, D. A.; Arduengo, A. J. Ⅲ. Electronic structure of a stable nucleophilic carbene. J. Phys. Chem.1991,95,4180.
[4]Cioslowski, J. Rigorous interpretation of electronic wave functions. Ⅳ. Origins of the unusual stability of the 1,3-dimethylimidazol-2-ylidene carbene. Int. J. Quantum Chem., Quantum Chem. Symp.1993,27,309.
[5]Heinemann, C; Muller, T.; Apeloig, Y.; Schwarz, H. On the Question of Stability, Conjugation, and "Aromaticity" in Imidazol-2-ylidenes and Their Silicon Analogs. J. Am.Chem. Soc.1996,118,2023.
[6]Boehme, C.; Frenking, G. Electronic Structure of Stable Carbenes, Silylenes, and Germylenes. J. Am. Chem. Soc.1996,118,2039.
[7]Bourissou, D.; Guerret O.; Bertrand G et al. Stable Carbenes. Chem. Rev.2000,100, 39-91.
[8]Jones, W. D. Diverse Chemical Applications of N-Heterocyclic Carbenes. J. Am. Chem. Soc.2009,131,15075-15077.
[9]Enders, D.; Niemeier, O.; Henseler A. Organocatalysis by N-Heterocyclic Carbenes. Chem. Rev.2007,107,5606-5655.
[10]Sun, X. Y.; Wu, J. N-Heterocyclic Carbene:a Versatile Organocatalyst. Chinese Journal of Organic Chemistry.2006,26,745-756.
[11]Corey, E. J.; Seebach, D. Carbanions of 1,3-dithianes. Reagents for C-C bond formation by nucleophilic displacement and carbonyl addition. Angew. Chem., Int. Ed. Engl.1965,4, 1075-77.
[12]Lapworth, A. Reactions, which arrange the addition of hydrogen cyanide at carbon compounds, [machine translation]. J. Chem. Soc.1903,83,995.
[13]Seebach, D. Reactivity umpolung methods. Angew. Chem.1979,91,259
[14]Breslow, R. Mechanism of thiamine action. Ⅳ. Evidence from studies on model systems. J. Am. Chem. Soc.1958,80,3719.
[15]Stetter, H.; Ramsch, R. Y; Kuhlmann, H. The preparative use of thiazolium salt-catalyzed acyloin and benzoin formation, I. Preparation of simple acyloins and benzoins. Synthesis,1976,733-735.
[16]Stetter, H.; Kuhlmann, H. The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org. React.1991,40,407.
[17]Sheehan, J.; Hunneman, D. H. Homogeneous asymmetric catalysis. J. Am. Chem. Soc. 1966,88,3666.
[18]Sheehan, J.; Hara, T. Asymmetric thiazolium salt catalysis of the benzoin condensation. J. Org. Chem.1974,39,1196.
[19]Enders, D.; Kallfass, U. An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew.Chem., Int. Ed.2002,41,1743.
[20]Stetter, H.; Dambkes, G. Preparative use of 1,3-thiazolium salt-catalyzed acyloin and benzoin formation. III. A new method for the preparation of substituted enol trimethylsilyl ethers of 1,2-cyclopentanedione. Synthesis.1980,309.
[21]Mattson, A. E.; Scheidt, K. A. Catalytic additions of acylsilanes to imines:An acyl anion strategy for the direct synthesis of.alpha.-amino ketones. Org. Lett.2004,6,4363.
[22]Stetter, H. Catalyzed Addition of Aldehydes to Activated Double Bonds-A New Synthetic Approach. Angew. Chem. Int. Ed.,1976,15,639.
[23]Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. The Thiazolium-Catalyzed Sila-Stetter Reaction:Conjugate Addition of Acylsilanes to Unsaturated Esters and Ketones. J. Am. Chem. Soc.2004,126,2314.
[24]Anjaiah, S.; Chandrasekhar, S.; Gree, R. Stetter Reaction in Room Temperature Ionic Liquids and Application to the Synthesis of Haloperidol. Adv. Synth. Catal,2004,346, 1329.
[25]Kerr, M, S.; Rovis, T. A Highly Enantioselective Catalytic Intramolecular Stetter Reation. J. Am. Chem. Soc.2002,124,10298.
[26]Kerr, M. S.; Rovis, T. Effect of the Michael Acceptor in the Asymmetric Intramolecular Stetter Reation. Synlett。,2003,1934.
[27]Javier Read de Alaniz; Rovis, T. Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed by Chiral Nucleophilic Triazolinylidene Carbenes. J. Org. Chem.(FeaturedArticle),2008,73,2033-2040.
[28]Cullen, S. C。; Rovis, T. Catalytic Asymmetric Stetter Reation Onto Vinylphosphine Oxides and Vinylphosphonates. Org. Lett.,2008,10,3141-3144.
[29]Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M.; Miyashita, A. Nucleophilic acylation of arylfluorides catalyzed by imidazolidenyl carbine. Chem. Commun.2003,1314-1315.
[30]Suzuki, Y.; Ota, S.; Fukuta, Y.; Ueda, Y.; Sato, M. N-Heterocyclic Carbene-Catalyzed Nucleophilic Aroylation of Fluorobenzenes.J. Org. Chem.2008,73,2420-2423.
[31]Scheidt, K. A. Direct Nucleophilic Acylation of Nitroalkenes Promoted by a Fluoride Anion/Thiourea Combination. J. Am. Chem. Soc.2006,128,4932-4933.
[32]Van de Water, R. W.; Pettus,T. R. R. o-Quinone methides:intermediates underdeveloped and underutilized in organic synthesis. Tetrahedron.2002,58,5367-5405.
[33]Mattson, A. E.; Scheidt, K. A. Nucleophilic Acylation of o-Quinone Methides:An Umpolung Strategy for the Synthesis of r-Aryl Ketones and Benzofurans. J. Am. Chem. Soc.2007,129,4508-4509.
[34]He, J.; Zheng J.; Liu, J.; She, X.; Pan X. F. N-Heterocyclic Carbene Catalyzed Nucleophilic Substitution Reaction for Construction of Benzopyrones and Benzofuranones. Org. Lett.2006,8,4637-4640.
[35]He, J.; Tang, S. C.; Pan, X. F. et al. N-Heterocyclic carbene catalyzed intramolecular nucleophilic addition of carbonyl anion equivalents to enol ethers. Tetrahedron.2008,64, 8797-8800.
[36]Sakai, T. T.; Krishna, N. R. Synthesis and properties of some novel anti-calmodulin drugs. Bioorg. Med. Chem.1999,7,1559-1565.
[37]Hinrichsen, P.; Vicuna, R. Possible initial steps in the catabolism of 1,2-diphenylethanone (deoxybenzoin) by Pseudomonas fluorescens DB-5. Appl. Environ. Microbiol.1993,59, 3477-3479.
[38]Battace, A.; Feuerstein, M.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Heck reactions of.alpha.-or.beta.-substituted enol ethers with aryl bromides catalyzed by a tetraphosphane/palladium complex-direct access to acetophenone or 1-arylpropanone derivatives. Eur. J. Org. Chem.2007,3122-3132.
[39]Zhang, L. J.; Huang, Y. Z.; Jiang, H. X.; Jun, D. M.; Liao, Y. Studies of the synthetic applications of element-organic compounds of 15th and 16th Groups.97. Pentaorganylstiborane.2. Reactions of pentaorganylstiboranes with acyl chlorides and ketones. J. Org. Chem.1992,57,774-777.
[40]Zhao, B.; Lu, X. Palladium(II)-catalyzed addition of arylboronic acid to nitriles. Tetrahedron Lett.2006,47,6765-6768.
[41]Churruca, F.; Martin, R. S.; Tellitu, I.; Dominguez, E. PCP-Bis(phosphinite) pincer complexes:new homogeneous catalysts for α-arylation of ketones. Tetrahedron Lett. 2006,47,3233-3237.
[42]Liu,Y. K.; Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding L. S. Unexpected Ring-Opening Reactions of Aziridines with Aldehydes Catalyzed by Nucleophilic Carbenes under Aerobic Conditions. Org. Lett.2006,8,1521-1524.
[43]Miyashita, A.; Matsuoka, Y.; Iwamoto, K.; Higashino, T. Formation of deoxybenzoins from 1,3-dimethyl-2-(a-benzyloxybenzyl)benzimidazolium iodides through rearrangement followed by expulsion of azolium ylide. Chem. Pharm. Bull.1994,42, 1960-1962.
[44]Arduengo III A. J.; Benac, B. L.; Burgess, E. M. 1,3-dimethylimidazole-2-thione. Organic Syntheses, Coll.1990,7,195.
[45]Lai, G.; Tan, P. Z.; Ghoshal, P. A One-Pot Method for the Efficient Conversion of Aryl-and Acyl-substituted Methyl Alcohols into Chlorides. Synthetic Communications.2003, 33, 1727-1732.
[46]Ram, R. N.; Singh, V. Palladium(II) chloride/EDTA-catalyzed biaryl homo-coupling of aryl halides in aqueous medium in the presence of ascorbic acid. Tetrahedron lett.2006, 47,7625-7628.
[47]Page, P. C. B.; Rassias, G. A.; Barros, D. New Organocatalysts for the Asymmetric Catalytic Epoxidation of Alkenes Mediated by Chiral Iminium Salts. Synlett.2002,4, 580-582.
[2]Arduengo Ⅲ A. J.; Harlow R. L.; Kline M. A stable crystalline carbine. J. Am. Chem. Soc. 1991,113,361-363.
[3]Dixon, D. A.; Arduengo, A. J. Ⅲ. Electronic structure of a stable nucleophilic carbene. J. Phys. Chem.1991,95,4180.
[4]Cioslowski, J. Rigorous interpretation of electronic wave functions. Ⅳ. Origins of the unusual stability of the 1,3-dimethylimidazol-2-ylidene carbene. Int. J. Quantum Chem., Quantum Chem. Symp.1993,27,309.
[5]Heinemann, C; Muller, T.; Apeloig, Y.; Schwarz, H. On the Question of Stability, Conjugation, and "Aromaticity" in Imidazol-2-ylidenes and Their Silicon Analogs. J. Am.Chem. Soc.1996,118,2023.
[6]Boehme, C.; Frenking, G. Electronic Structure of Stable Carbenes, Silylenes, and Germylenes. J. Am. Chem. Soc.1996,118,2039.
[7]Bourissou, D.; Guerret O.; Bertrand G et al. Stable Carbenes. Chem. Rev.2000,100, 39-91.
[8]Jones, W. D. Diverse Chemical Applications of N-Heterocyclic Carbenes. J. Am. Chem. Soc.2009,131,15075-15077.
[9]Enders, D.; Niemeier, O.; Henseler A. Organocatalysis by N-Heterocyclic Carbenes. Chem. Rev.2007,107,5606-5655.
[10]Sun, X. Y.; Wu, J. N-Heterocyclic Carbene:a Versatile Organocatalyst. Chinese Journal of Organic Chemistry.2006,26,745-756.
[11]Corey, E. J.; Seebach, D. Carbanions of 1,3-dithianes. Reagents for C-C bond formation by nucleophilic displacement and carbonyl addition. Angew. Chem., Int. Ed. Engl.1965,4, 1075-77.
[12]Lapworth, A. Reactions, which arrange the addition of hydrogen cyanide at carbon compounds, [machine translation]. J. Chem. Soc.1903,83,995.
[13]Seebach, D. Reactivity umpolung methods. Angew. Chem.1979,91,259
[14]Breslow, R. Mechanism of thiamine action. Ⅳ. Evidence from studies on model systems. J. Am. Chem. Soc.1958,80,3719.
[15]Stetter, H.; Ramsch, R. Y; Kuhlmann, H. The preparative use of thiazolium salt-catalyzed acyloin and benzoin formation, I. Preparation of simple acyloins and benzoins. Synthesis,1976,733-735.
[16]Stetter, H.; Kuhlmann, H. The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org. React.1991,40,407.
[17]Sheehan, J.; Hunneman, D. H. Homogeneous asymmetric catalysis. J. Am. Chem. Soc. 1966,88,3666.
[18]Sheehan, J.; Hara, T. Asymmetric thiazolium salt catalysis of the benzoin condensation. J. Org. Chem.1974,39,1196.
[19]Enders, D.; Kallfass, U. An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew.Chem., Int. Ed.2002,41,1743.
[20]Stetter, H.; Dambkes, G. Preparative use of 1,3-thiazolium salt-catalyzed acyloin and benzoin formation. III. A new method for the preparation of substituted enol trimethylsilyl ethers of 1,2-cyclopentanedione. Synthesis.1980,309.
[21]Mattson, A. E.; Scheidt, K. A. Catalytic additions of acylsilanes to imines:An acyl anion strategy for the direct synthesis of.alpha.-amino ketones. Org. Lett.2004,6,4363.
[22]Stetter, H. Catalyzed Addition of Aldehydes to Activated Double Bonds-A New Synthetic Approach. Angew. Chem. Int. Ed.,1976,15,639.
[23]Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. The Thiazolium-Catalyzed Sila-Stetter Reaction:Conjugate Addition of Acylsilanes to Unsaturated Esters and Ketones. J. Am. Chem. Soc.2004,126,2314.
[24]Anjaiah, S.; Chandrasekhar, S.; Gree, R. Stetter Reaction in Room Temperature Ionic Liquids and Application to the Synthesis of Haloperidol. Adv. Synth. Catal,2004,346, 1329.
[25]Kerr, M, S.; Rovis, T. A Highly Enantioselective Catalytic Intramolecular Stetter Reation. J. Am. Chem. Soc.2002,124,10298.
[26]Kerr, M. S.; Rovis, T. Effect of the Michael Acceptor in the Asymmetric Intramolecular Stetter Reation. Synlett。,2003,1934.
[27]Javier Read de Alaniz; Rovis, T. Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed by Chiral Nucleophilic Triazolinylidene Carbenes. J. Org. Chem.(FeaturedArticle),2008,73,2033-2040.
[28]Cullen, S. C。; Rovis, T. Catalytic Asymmetric Stetter Reation Onto Vinylphosphine Oxides and Vinylphosphonates. Org. Lett.,2008,10,3141-3144.
[29]Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M.; Miyashita, A. Nucleophilic acylation of arylfluorides catalyzed by imidazolidenyl carbine. Chem. Commun.2003,1314-1315.
[30]Suzuki, Y.; Ota, S.; Fukuta, Y.; Ueda, Y.; Sato, M. N-Heterocyclic Carbene-Catalyzed Nucleophilic Aroylation of Fluorobenzenes.J. Org. Chem.2008,73,2420-2423.
[31]Scheidt, K. A. Direct Nucleophilic Acylation of Nitroalkenes Promoted by a Fluoride Anion/Thiourea Combination. J. Am. Chem. Soc.2006,128,4932-4933.
[32]Van de Water, R. W.; Pettus,T. R. R. o-Quinone methides:intermediates underdeveloped and underutilized in organic synthesis. Tetrahedron.2002,58,5367-5405.
[33]Mattson, A. E.; Scheidt, K. A. Nucleophilic Acylation of o-Quinone Methides:An Umpolung Strategy for the Synthesis of r-Aryl Ketones and Benzofurans. J. Am. Chem. Soc.2007,129,4508-4509.
[34]He, J.; Zheng J.; Liu, J.; She, X.; Pan X. F. N-Heterocyclic Carbene Catalyzed Nucleophilic Substitution Reaction for Construction of Benzopyrones and Benzofuranones. Org. Lett.2006,8,4637-4640.
[35]He, J.; Tang, S. C.; Pan, X. F. et al. N-Heterocyclic carbene catalyzed intramolecular nucleophilic addition of carbonyl anion equivalents to enol ethers. Tetrahedron.2008,64, 8797-8800.
[36]Sakai, T. T.; Krishna, N. R. Synthesis and properties of some novel anti-calmodulin drugs. Bioorg. Med. Chem.1999,7,1559-1565.
[37]Hinrichsen, P.; Vicuna, R. Possible initial steps in the catabolism of 1,2-diphenylethanone (deoxybenzoin) by Pseudomonas fluorescens DB-5. Appl. Environ. Microbiol.1993,59, 3477-3479.
[38]Battace, A.; Feuerstein, M.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Heck reactions of.alpha.-or.beta.-substituted enol ethers with aryl bromides catalyzed by a tetraphosphane/palladium complex-direct access to acetophenone or 1-arylpropanone derivatives. Eur. J. Org. Chem.2007,3122-3132.
[39]Zhang, L. J.; Huang, Y. Z.; Jiang, H. X.; Jun, D. M.; Liao, Y. Studies of the synthetic applications of element-organic compounds of 15th and 16th Groups.97. Pentaorganylstiborane.2. Reactions of pentaorganylstiboranes with acyl chlorides and ketones. J. Org. Chem.1992,57,774-777.
[40]Zhao, B.; Lu, X. Palladium(II)-catalyzed addition of arylboronic acid to nitriles. Tetrahedron Lett.2006,47,6765-6768.
[41]Churruca, F.; Martin, R. S.; Tellitu, I.; Dominguez, E. PCP-Bis(phosphinite) pincer complexes:new homogeneous catalysts for α-arylation of ketones. Tetrahedron Lett. 2006,47,3233-3237.
[42]Liu,Y. K.; Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding L. S. Unexpected Ring-Opening Reactions of Aziridines with Aldehydes Catalyzed by Nucleophilic Carbenes under Aerobic Conditions. Org. Lett.2006,8,1521-1524.
[43]Miyashita, A.; Matsuoka, Y.; Iwamoto, K.; Higashino, T. Formation of deoxybenzoins from 1,3-dimethyl-2-(a-benzyloxybenzyl)benzimidazolium iodides through rearrangement followed by expulsion of azolium ylide. Chem. Pharm. Bull.1994,42, 1960-1962.
[44]Arduengo III A. J.; Benac, B. L.; Burgess, E. M. 1,3-dimethylimidazole-2-thione. Organic Syntheses, Coll.1990,7,195.
[45]Lai, G.; Tan, P. Z.; Ghoshal, P. A One-Pot Method for the Efficient Conversion of Aryl-and Acyl-substituted Methyl Alcohols into Chlorides. Synthetic Communications.2003, 33, 1727-1732.
[46]Ram, R. N.; Singh, V. Palladium(II) chloride/EDTA-catalyzed biaryl homo-coupling of aryl halides in aqueous medium in the presence of ascorbic acid. Tetrahedron lett.2006, 47,7625-7628.
[47]Page, P. C. B.; Rassias, G. A.; Barros, D. New Organocatalysts for the Asymmetric Catalytic Epoxidation of Alkenes Mediated by Chiral Iminium Salts. Synlett.2002,4, 580-582.