基于α-烯酰基二硫缩烯酮的多组分反应研究
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摘要
官能化二硫缩烯酮是一类重要的有机合成中间体。自从1910年由Kelber首次合成出α-苯甲酰基二甲硫缩烯酮以来,经过近百年的发展已经成为有机合成化学的研究热点之一。官能团的多样性这一结构特点和烷硫基的空间电子效应赋予了该类化合物化学反应的多样性。利用该中间体可以合成许多具有特殊结构的化合物,广泛地应用于有机合成和天然产物的合成中。
碳碳键形成和官能团的转化反应是构建有机分子骨架最重要、最基本的反应。多组分化学反应具有操作简便、资源利用率高以及高原子经济性等特点,是一类重要的有机化学反应,在新药设计与合成、组合化学和天然产物合成中具有广泛的应用。结合碳碳键形成反应和多组分反应研究的重要性,本论文拟以α-烯酰基基二硫缩烯酮为研究对象,着重研究了这类化合物和各种醛及活泼亚甲基类化合物的三组分反应.
我的研究工作主要有以下几方面:
1.研究α-烯酰基二硫缩烯酮、甲醛和活泼亚甲基化合物一锅煮反应形成多取代环己酮类化合物的可行性。
2.依次变换各种α-烯酰基基二硫缩烯酮、醛类化合物及各种活泼亚甲基化合物。
3.多取代环己酮合成不对称芳基化合物的应用研究。
4.摸索最佳反应条件。
5.研究反应机理。
本文合成了36个未见文献报道的新化合物,并对其进行了IR、~1H-NMR、~(13)C-NMR等数据表征。
Functionalized ketenedithioacetals are a kind of versatile intermediates in organic synthesis. Since Kelber first synthesized in 1910,α-oxo ketene-(S,S)-acetals chemistry has become a hot spot in organic chemistry research through the development of about one hundred years. It can be used in many reactions for their functional group multiplicity and special stereoelectronic effect from the alkylthio functionalities. It can construct many compounds with special structures and can be applied in organic synthesis and the composition of natural products.
The carbon-carbon bond formation and the functional group transformations are most fundamental reactions for the construction of a molecular framework and hence represent a forefront of research in organic chemistry. Multicomponent reactions (MCRs) have been refined in recent years into powerful and useful tool in synthetic chemistry and attract increasing attention due to the fact that complex molecules and drugs can be prepared from cheap and easily available starting materials. This reaction covers simple operation, high resource utilization and high atom economy, etc. And it can be applied in the design, synthesis of new drugs, and compounds with special structures.
In connection with the importance of carbon-carbon bond formation and multicomponent reactions, we will investigate the three components reaction ofα-alkenoyl ketene S,S-acetals, different aldehydes and active methylene compounds.
My research includes the following five aspects:
1、Explore the possibility of the three component reaction of readily availableα-alkenoyl ketene S,S-acetals with aldehydes and active methylene compounds to give various polyfunctionalized cyclohexanones.
2、Variation of theα-Alkenoyl Ketene S,S-acetals, aldehydes and active methylene compounds in sequence.
3、Application of polyfunctionalized cyclohexanones in the synthesis of unsymmetrical biaryls.
4、Explore the optimization of the reaction conditions.
5、Study the possible mechanism.
Thirty-six new compounds were synthesized and characterized by IR, Mass and NMR (~1H, ~(13)C) spectrum in this thesis.
碳碳键形成和官能团的转化反应是构建有机分子骨架最重要、最基本的反应。多组分化学反应具有操作简便、资源利用率高以及高原子经济性等特点,是一类重要的有机化学反应,在新药设计与合成、组合化学和天然产物合成中具有广泛的应用。结合碳碳键形成反应和多组分反应研究的重要性,本论文拟以α-烯酰基基二硫缩烯酮为研究对象,着重研究了这类化合物和各种醛及活泼亚甲基类化合物的三组分反应.
我的研究工作主要有以下几方面:
1.研究α-烯酰基二硫缩烯酮、甲醛和活泼亚甲基化合物一锅煮反应形成多取代环己酮类化合物的可行性。
2.依次变换各种α-烯酰基基二硫缩烯酮、醛类化合物及各种活泼亚甲基化合物。
3.多取代环己酮合成不对称芳基化合物的应用研究。
4.摸索最佳反应条件。
5.研究反应机理。
本文合成了36个未见文献报道的新化合物,并对其进行了IR、~1H-NMR、~(13)C-NMR等数据表征。
Functionalized ketenedithioacetals are a kind of versatile intermediates in organic synthesis. Since Kelber first synthesized in 1910,α-oxo ketene-(S,S)-acetals chemistry has become a hot spot in organic chemistry research through the development of about one hundred years. It can be used in many reactions for their functional group multiplicity and special stereoelectronic effect from the alkylthio functionalities. It can construct many compounds with special structures and can be applied in organic synthesis and the composition of natural products.
The carbon-carbon bond formation and the functional group transformations are most fundamental reactions for the construction of a molecular framework and hence represent a forefront of research in organic chemistry. Multicomponent reactions (MCRs) have been refined in recent years into powerful and useful tool in synthetic chemistry and attract increasing attention due to the fact that complex molecules and drugs can be prepared from cheap and easily available starting materials. This reaction covers simple operation, high resource utilization and high atom economy, etc. And it can be applied in the design, synthesis of new drugs, and compounds with special structures.
In connection with the importance of carbon-carbon bond formation and multicomponent reactions, we will investigate the three components reaction ofα-alkenoyl ketene S,S-acetals, different aldehydes and active methylene compounds.
My research includes the following five aspects:
1、Explore the possibility of the three component reaction of readily availableα-alkenoyl ketene S,S-acetals with aldehydes and active methylene compounds to give various polyfunctionalized cyclohexanones.
2、Variation of theα-Alkenoyl Ketene S,S-acetals, aldehydes and active methylene compounds in sequence.
3、Application of polyfunctionalized cyclohexanones in the synthesis of unsymmetrical biaryls.
4、Explore the optimization of the reaction conditions.
5、Study the possible mechanism.
Thirty-six new compounds were synthesized and characterized by IR, Mass and NMR (~1H, ~(13)C) spectrum in this thesis.
引文
[1] C. Kelber;über die Einwirkung von Schwefelkohlenstoff und ?tzkali auf Acetophenon. [J]. Chem. Ber. 1910, 43, 1252.
[2] R. K. Dieter;α-Oxo ketene dithioactetals and related compounds: Versatile three carbon synthons. [J]. Tetrahedron 1986, 42, 3029 - 3096.
[3] H. Junjappa, H. Ila, C. V. Asokan;α-Oxo ketene- S , S - , N , S - and N , N - acetals: Versatile intermediates in organic synthesis. [J]. Tetrahedron 1990, 46, 5423– 5506.
[4] a: M. Kolb; Umpolung of the reactivity of carbonyl compounds through sulfur– containing ketene dithioacetals in organic synthesis: Recent developments reagents. [J]. Sythesis 1997, 357 - 368. b: M. Kolb; [J]. Synthesis 1990, 171– 190.
[5] M. Yakoyama, T. Imamoto; Organic reactions of carbon disulfide. [J]. Synthesis 1984 , 797– 799 .
[6] (a) Li J, Liu Q, Zhao M,et al. Synthesis of Triphenyltin 2-(1,2-Ethylenedithio)- Methylene-3-Oxo-5 -Aryl-4-Pentenoate [J]. Chinese Chem. Lett., 1998 (9): 21-22; (b) Xie Z, Fang Q, Hu Y, et al. Condensation Reaction ofα- Aroyl-α-acetyl Ketene Cyclic Dithioacetals with Aromatic Aldehydes [J]. Chinese Chem. Lett., 1999 (10): 5-6; (c)艾林,肖幼萍,刘群, et al.α,α-二乙酰基二苄硫缩烯酮的碱催化脱乙酰基反应及缩合反应机理研究[J].高等学校化学学报, 2004 (25): 877-879.
[7] Thuiller A, Vialle J. Bull. Soc. Chim. Fr., 1962, 2182-2186.
[8] Asokan C V, Ila H, Junjappa H. Polarized Ketenedithioacetals.51.A Novel Route to Stilbenes via Cationic Cycloaromatization [J]. Synthesis-Stuttgart, 1987 (3): 284-285.
[9] Purkayastha M L, Ila H, Junjappa H. 5-Alkylthioisoxazoles and 3-Alkylthioisoxazoles from Acylketene Dithioacetals [J]. Synthesis, 1989 (1): 20-24.
[10] (a) Bi X, Dong D, Liu Q, et al. [5 + 1] Annulation: A Synthetic Strategy for Highly Substituted Phenols and Cyclohexenones [J]. J. Am. Chem. Soc., 2005, 127: 4578-4579; (b) Dong D, Bi X, Liu Q, et al. [5C + 1N] Annulation: a novel synthetic strategy for functionalized 2,3-dihydro-4-pyridones [J]. Chem. Commun., 2005, 3580–3582; (c) Bi X, Dong D, Li Y, et al. [5C + 1S] Annulation: A Facile and Efficient Synthetic Route toward Functionalized 2,3-Dihydrothiopyran-4–ones [J]. J. Org. Chem., 2005, 70: 10886-10889; (d) Zhao L, Liang F, Bi X, et al. Efficient Synthesis of Highly Functionalized Dihydropyrido[2,3-d]pyrimidines by a Double Annulation Strategy fromα-Alkenoyl-α-carbamoyl Ketene-(S,S)-acetals [J]. J. Org. Chem., 2006, 71: 1094-1098.
[11] Zhang Q, Sun S, Hu J, et al. BF3·Et2O-Catalyzed Direct Carbon-Carbon Bond Formation of r-EWG Ketene-(S,S)-Acetals and Alcohols and Synthesis of Unsymmetrical Biaryls [J]. J. Org. Chem., 2007, 72: 139-143.
[12] Hu J, Zhang Q, Yuan H, et al. Temperature-Controlled Synthesis of Substituted Pyridine Derivativesvia the [5C+1N] Annulation of 1,1-Bisalkylthio-1,4-pentanedienes and Ammonium Acetate [J]. J. Org. Chem., 2008, 73: 2442-2445.
[13] Wang M, Xu X, Liu Q, et al. Iododecarboxylation of alpha-carboxylate, alpha-cinnamoyl ketene cyclic dithioacetals [J]. Synthetic Commun., 2002, 32 (22): 3437-3443.
[14] (a) Yin Y, Wang M, Liu Q, et al. A C–C bond formation reaction at the a-carbon atom of -oxo ketene dithioacetals via the Baylis–Hillman type reaction [J]. Tetrahedron Lett. 2005, 46(25), 4399-4402; (b) Sun S, Zhang Q, Liu Q, et al. One-pot synthesis of aza-Morita–Baylis–Hillman adducts fromα-oxo ketene-S,S-acetals, arylaldehydes and nitriles [J]. Tetrahedron Lett. 2005, 46 (37): 6271–6274.
[15] Shaoguang Sun, Mang Wang,* Jianglei Hu, et al. Studies on the Pummerer-Type Reaction ofα-oxo Ketene Dithioacetals with Furfural and its Applications, in preparation.
[16] Anabha E R, Asokan C V. A Convenient Preparation of 2-Aroyl-3,3-bis(alkylsulfanyl)- acrylaldehydes and Their Application in the Synthesis of 5-Aroyl-2-oxo-1,2-dihydro -2-pyridinecarbonitriles [J]. Synthesis, 2006 (1), 151–155.
[17] Prakash Rao S, Sivakumar S. Condensation ofα-Aroylketene Dithioacetals and 2-Hydroxyarylaldehydes Results in Facile Synthesis of a Combinatorial Library of 3-Aroylcoumarins# [J], J. Org. Chem., 2006, 71 (23): 8715-8723.
[18] Yuan H, Wang M, Liu Y, et al. Copper(Ⅱ)-Catalyzed C-CBpnd-Forming Reactions of alpha-Electron- Withdrawing Group-Substituted Ketene S,S-Acetals with Carbonyl Compounds and a Facile Synthesis of Coumarins[J]. Adv. Synth. Catal .2009, 351, 112-116.
[19] Fu Z, Wang M, Ma Y, et al. Synthesis of Functionalized Allylic Sulfoxides and Their Use in the Construction of 2,3,4-Trisubstituted Furans via a [3+2] Annulation[J]. J. Org. Chem., 2008, 73, 7625-7630.
[20] Patra, P.; Sriram, V.; Iia, H.; Junjappa, H. Lewis Acid Induced Tandem Carbocationic RingOpening and cyclizations ofα-[Bis(methylthio)methylene]ethyl-2-styrylcyclopropyl Ketones and Carbinols: Novel Approach to Bicyclo3.3.0]octane and Cyclopent[a]indene frameworks [J] Tetrahedron 1998, 54, 531-540.
[21] Nandi, S.; Syam Kumar, U.; Iia, H.; Junjappa, H. Domino Carbocationic Cyclization of Functionalized Cyclopropyl Ketones: Facile One-Pot Access to Peri- and Angularly fused Polycyclic Aromatic and heteroaromatic Frameworks [J] J. Org. Chem. 2002, 67, 4916-4923. 1731-1734.
[22] BienayméH, Hulme C, Oddon G, et al. Chem. Eur. J., 2000, 6, 3321-3329.
[23] Poli G, Giambastiani G, Heumann A. Tetrahedron, 2000, 56, 5959-5989.
[24] Trost B M. Science, 1991, 254, 1471-1477.
[25] Johnson W S. Angew Chem Int Ed, 1976, 15, 9-17.
[26] BienayméH,Bouzid K. Angew Chem Int Ed Engl, 1998, 37, 2234-2237.
[27] Blackburn C, Guan B, Fleming P, et al. Tetrahedron Lett, 1998, 39, 3636-3638.
[28] Groebke K, Weber L, Mehlin F. Synlett, 1998, 661-663.
[29] Sun X, Janvier P, Zhao G, et al. Org Lett, 2001, 3, 877-880.
[30] Janvier P, Sun X, BienayméH, et al.J Am Chem Soc, 2002, 124, 2560-2567.
[31] Shiraishi H, Ma R, Suzuki I, et al. Org Lett, 2000, 2, 4245-4247.
[32] Grieco P A, Bahsas A. Tetrahedron Lett, 1988, 29, 5855-5858.
[33] Tietze L F, Evers H, Hippe T, et al. Eur J Org Chem, 2001, 1631-1634.
[34] Tietze L F, Modi A. Med Res Rev, 2000, 20, 304-322.
[2] R. K. Dieter;α-Oxo ketene dithioactetals and related compounds: Versatile three carbon synthons. [J]. Tetrahedron 1986, 42, 3029 - 3096.
[3] H. Junjappa, H. Ila, C. V. Asokan;α-Oxo ketene- S , S - , N , S - and N , N - acetals: Versatile intermediates in organic synthesis. [J]. Tetrahedron 1990, 46, 5423– 5506.
[4] a: M. Kolb; Umpolung of the reactivity of carbonyl compounds through sulfur– containing ketene dithioacetals in organic synthesis: Recent developments reagents. [J]. Sythesis 1997, 357 - 368. b: M. Kolb; [J]. Synthesis 1990, 171– 190.
[5] M. Yakoyama, T. Imamoto; Organic reactions of carbon disulfide. [J]. Synthesis 1984 , 797– 799 .
[6] (a) Li J, Liu Q, Zhao M,et al. Synthesis of Triphenyltin 2-(1,2-Ethylenedithio)- Methylene-3-Oxo-5 -Aryl-4-Pentenoate [J]. Chinese Chem. Lett., 1998 (9): 21-22; (b) Xie Z, Fang Q, Hu Y, et al. Condensation Reaction ofα- Aroyl-α-acetyl Ketene Cyclic Dithioacetals with Aromatic Aldehydes [J]. Chinese Chem. Lett., 1999 (10): 5-6; (c)艾林,肖幼萍,刘群, et al.α,α-二乙酰基二苄硫缩烯酮的碱催化脱乙酰基反应及缩合反应机理研究[J].高等学校化学学报, 2004 (25): 877-879.
[7] Thuiller A, Vialle J. Bull. Soc. Chim. Fr., 1962, 2182-2186.
[8] Asokan C V, Ila H, Junjappa H. Polarized Ketenedithioacetals.51.A Novel Route to Stilbenes via Cationic Cycloaromatization [J]. Synthesis-Stuttgart, 1987 (3): 284-285.
[9] Purkayastha M L, Ila H, Junjappa H. 5-Alkylthioisoxazoles and 3-Alkylthioisoxazoles from Acylketene Dithioacetals [J]. Synthesis, 1989 (1): 20-24.
[10] (a) Bi X, Dong D, Liu Q, et al. [5 + 1] Annulation: A Synthetic Strategy for Highly Substituted Phenols and Cyclohexenones [J]. J. Am. Chem. Soc., 2005, 127: 4578-4579; (b) Dong D, Bi X, Liu Q, et al. [5C + 1N] Annulation: a novel synthetic strategy for functionalized 2,3-dihydro-4-pyridones [J]. Chem. Commun., 2005, 3580–3582; (c) Bi X, Dong D, Li Y, et al. [5C + 1S] Annulation: A Facile and Efficient Synthetic Route toward Functionalized 2,3-Dihydrothiopyran-4–ones [J]. J. Org. Chem., 2005, 70: 10886-10889; (d) Zhao L, Liang F, Bi X, et al. Efficient Synthesis of Highly Functionalized Dihydropyrido[2,3-d]pyrimidines by a Double Annulation Strategy fromα-Alkenoyl-α-carbamoyl Ketene-(S,S)-acetals [J]. J. Org. Chem., 2006, 71: 1094-1098.
[11] Zhang Q, Sun S, Hu J, et al. BF3·Et2O-Catalyzed Direct Carbon-Carbon Bond Formation of r-EWG Ketene-(S,S)-Acetals and Alcohols and Synthesis of Unsymmetrical Biaryls [J]. J. Org. Chem., 2007, 72: 139-143.
[12] Hu J, Zhang Q, Yuan H, et al. Temperature-Controlled Synthesis of Substituted Pyridine Derivativesvia the [5C+1N] Annulation of 1,1-Bisalkylthio-1,4-pentanedienes and Ammonium Acetate [J]. J. Org. Chem., 2008, 73: 2442-2445.
[13] Wang M, Xu X, Liu Q, et al. Iododecarboxylation of alpha-carboxylate, alpha-cinnamoyl ketene cyclic dithioacetals [J]. Synthetic Commun., 2002, 32 (22): 3437-3443.
[14] (a) Yin Y, Wang M, Liu Q, et al. A C–C bond formation reaction at the a-carbon atom of -oxo ketene dithioacetals via the Baylis–Hillman type reaction [J]. Tetrahedron Lett. 2005, 46(25), 4399-4402; (b) Sun S, Zhang Q, Liu Q, et al. One-pot synthesis of aza-Morita–Baylis–Hillman adducts fromα-oxo ketene-S,S-acetals, arylaldehydes and nitriles [J]. Tetrahedron Lett. 2005, 46 (37): 6271–6274.
[15] Shaoguang Sun, Mang Wang,* Jianglei Hu, et al. Studies on the Pummerer-Type Reaction ofα-oxo Ketene Dithioacetals with Furfural and its Applications, in preparation.
[16] Anabha E R, Asokan C V. A Convenient Preparation of 2-Aroyl-3,3-bis(alkylsulfanyl)- acrylaldehydes and Their Application in the Synthesis of 5-Aroyl-2-oxo-1,2-dihydro -2-pyridinecarbonitriles [J]. Synthesis, 2006 (1), 151–155.
[17] Prakash Rao S, Sivakumar S. Condensation ofα-Aroylketene Dithioacetals and 2-Hydroxyarylaldehydes Results in Facile Synthesis of a Combinatorial Library of 3-Aroylcoumarins# [J], J. Org. Chem., 2006, 71 (23): 8715-8723.
[18] Yuan H, Wang M, Liu Y, et al. Copper(Ⅱ)-Catalyzed C-CBpnd-Forming Reactions of alpha-Electron- Withdrawing Group-Substituted Ketene S,S-Acetals with Carbonyl Compounds and a Facile Synthesis of Coumarins[J]. Adv. Synth. Catal .2009, 351, 112-116.
[19] Fu Z, Wang M, Ma Y, et al. Synthesis of Functionalized Allylic Sulfoxides and Their Use in the Construction of 2,3,4-Trisubstituted Furans via a [3+2] Annulation[J]. J. Org. Chem., 2008, 73, 7625-7630.
[20] Patra, P.; Sriram, V.; Iia, H.; Junjappa, H. Lewis Acid Induced Tandem Carbocationic RingOpening and cyclizations ofα-[Bis(methylthio)methylene]ethyl-2-styrylcyclopropyl Ketones and Carbinols: Novel Approach to Bicyclo3.3.0]octane and Cyclopent[a]indene frameworks [J] Tetrahedron 1998, 54, 531-540.
[21] Nandi, S.; Syam Kumar, U.; Iia, H.; Junjappa, H. Domino Carbocationic Cyclization of Functionalized Cyclopropyl Ketones: Facile One-Pot Access to Peri- and Angularly fused Polycyclic Aromatic and heteroaromatic Frameworks [J] J. Org. Chem. 2002, 67, 4916-4923. 1731-1734.
[22] BienayméH, Hulme C, Oddon G, et al. Chem. Eur. J., 2000, 6, 3321-3329.
[23] Poli G, Giambastiani G, Heumann A. Tetrahedron, 2000, 56, 5959-5989.
[24] Trost B M. Science, 1991, 254, 1471-1477.
[25] Johnson W S. Angew Chem Int Ed, 1976, 15, 9-17.
[26] BienayméH,Bouzid K. Angew Chem Int Ed Engl, 1998, 37, 2234-2237.
[27] Blackburn C, Guan B, Fleming P, et al. Tetrahedron Lett, 1998, 39, 3636-3638.
[28] Groebke K, Weber L, Mehlin F. Synlett, 1998, 661-663.
[29] Sun X, Janvier P, Zhao G, et al. Org Lett, 2001, 3, 877-880.
[30] Janvier P, Sun X, BienayméH, et al.J Am Chem Soc, 2002, 124, 2560-2567.
[31] Shiraishi H, Ma R, Suzuki I, et al. Org Lett, 2000, 2, 4245-4247.
[32] Grieco P A, Bahsas A. Tetrahedron Lett, 1988, 29, 5855-5858.
[33] Tietze L F, Evers H, Hippe T, et al. Eur J Org Chem, 2001, 1631-1634.
[34] Tietze L F, Modi A. Med Res Rev, 2000, 20, 304-322.
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