氨甲酰基硅烷与醛、酮反应合成α-羟基酰胺及其衍生物的研究
摘要
本文合成了两种氨甲酰基硅烷，研究了其中一种与醛、酮反应制备α-羟基酰胺的方法。通过对反应产率、反应时间及反应温度的实验数据分析，探讨了醛、酮中不同取代基对反应活性的影响。
氨甲酰基硅烷21a能与各种醛进行反应，包括烷基醛，烯醛，芳香醛及杂环醛，得到了11种α-羟基酰胺。21a分别与正丁醛57、异丁醛58反应，合成了N,N-二甲基-α-羟基-戊酰胺69、N,N-二甲基-α-羟基-异戊酰胺70，结果表明：醛烃基的空间位阻对反应有很大的影响，烷基空间位阻越大，反应越困难，需要更长的反应时间；21a分别与对二甲氨基苯甲醛59、对甲氧基苯甲醛60、对甲基苯甲醛61、苯甲醛62、对氯苯甲醛63和对硝基苯甲醛64反应，得到N,N-二甲基-α-羟基-对甲氧基苯乙酰胺71、N,N-二甲基-α-羟基-对甲基苯乙酰胺72、N,N-二甲基-α-羟基-苯乙酰胺73、N,N-二甲基-α-羟基-对氯苯乙酰胺74和N,N-二甲基-α-羟基-对硝基苯乙酰胺75（其中59不反应），实验表明：芳环取代基为供电子基团时，醛羰基碳的电正性较弱，不利于和21a反应，当取代基为吸电子基团时，增强了醛羰基碳的亲电能力，有利于同21a的亲核加成反应，反应产率也随着吸电子能力的增强而增高；21a分别和丙烯醛65、苯乙烯基苯甲醛66反应合成了N,N-二甲基-α-羟基-3-丁烯酰胺76、N,N-二甲基-α-羟基-3-苯丁烯酰胺77，结果表明：两种烯醛都可与21a反应，得到1, 2-加成产物，没有得到1, 4-加成产物；21a分别和2-呋喃甲醛67、2-噻吩甲醛68反应生成了N,N-二甲基-α-羟基-2-呋喃乙酰胺78、N,N-二甲基-α-羟基-2-噻吩乙酰胺79，结果表明：两种杂环醛的活性都很高，二者比较，由于呋喃环氧原子的电负性比噻吩环硫原子的大，增加了羰基碳的正电性，利于亲核加成，体现在产率的增大。
氨甲酰基硅烷21a与烷基酮，烯酮，炔酮，芳香酮及杂环酮反应，除了开链烷基酮不发生反应，大部分得到了较好的结果，但与醛的反应相比，其活性明显降低，可能是：烷基具供电子效应和超共轭效应使得羰基碳正电性减弱，不利于亲核反应的发生，另外烷基空间位阻也较大，对加成反应有一定的影响；21a分别与环戊酮85、环己酮86、樟脑87发生反应，发现只有环己酮可发生反应，生成了1-三甲基硅氧基-1-N,N-二甲氨甲酰基环己烷108；21a分别与苯乙酮88、对溴苯乙酮89、二苯甲酮90、三苯甲基苯基甲酮91发生反应，只有90可发生反应，得到了N,N-二甲基-2,2-二苯基-2-三甲基硅氧基乙酰胺109；21a与甲基苯乙烯基甲酮93和5-甲基-1-苯基-2,5-己二烯-3-酮94的反应没有获得新物质，表明原因是受烷基影响；21a分别与对二甲氨基苯乙烯基苯基甲酮95、对甲氧基苯乙烯基苯基甲酮96、对甲基苯乙烯基苯基甲酮97、苯乙烯基苯基甲酮98、对氯苯乙烯基苯基甲酮99、对硝基苯乙烯基苯基甲酮100、苯乙炔基苯基甲酮101反应，除95不反应外，分别生成了N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对甲氧基苯基-3-丁烯酰胺110、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对甲基苯基-3-丁烯酰胺111、N,N-二甲基-2,4-二苯基-2-三甲基硅氧基-3-丁烯酰胺112、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对氯苯基-3-丁烯酰胺113、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对硝基苯基-3-丁烯酰胺114、N,N-二甲基-2,4-二苯基-2-三甲基硅氧基-3-丁炔酰胺115，结果表明：羰基两侧含有双键、三键及芳烃的酮都可反应，可能是这些基团有吸电子能力，使羰基碳正电性增加，反应容易发生，而苯炔酮碳碳三键电负性强于相应苯烯酮的双键，增强了羰基碳的亲电能力，有利于加成反应的进行，因而产率较高；21a与1,5-二苯基-2,4-戊二烯酮102、1,5-二苯基-1,4-戊二烯酮103反应生成了N,N-二甲基-2,6-二苯基-2-三甲基硅氧基-3,5-己二烯酰胺116、N,N-二甲基-2-二苯乙烯基-2-三甲基硅氧基-3-丁烯酰胺117，结果表明：共轭二烯酮也可与21a发生反应，发生1, 2-加成，不发生1, 4-加成；21a分别与甲基-2-呋喃乙烯基甲酮104、2-呋喃乙烯基苯基甲酮105、2-噻吩基苯基甲酮106、2-噻吩乙烯基苯基甲酮107反应发现：104和106不反应，而105和107可得到相应的化合物：N,N-二甲基-2-苯基-2-三甲基硅氧基-4-(2-呋喃基)-3-丁烯酰胺118、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-(2-噻吩基)-3-丁烯酰胺119，实验表明：104由于羰基连有烷基而不能反应，而106是由于噻吩环的给电性强而不反应。
用氨甲酰基硅烷与醛、酮反应得到的产物α-羟基酰胺作为一类重要的药物中间体，在生物医药和有机合成等领域有非常广泛的应用，本文从方法学的角度，为经济有效的合成该类化合物提供了一条实用可行的途径，具有十分重要的理论意义和潜在的实用价值。
In this paper, two kinds of carbamoylsilanes were synthesizedand one of which was applied to the reaction with aldehydes orketones obtainedα-hydroxyamides. Meanwhile, the differentsubstituents of aldehydes or ketones by the yield, reaction time aswell as reaction temperature on reactivity were investigatedsystematically.
While the Carbamylsilane 21a was used to react with all kindsof aldehydes, it’s found that alkyl, aryl, alkenyl and heteroarylaldehydes, most of them have high activity, and 11 kinds ofcorrespondingα-hydroxyamides were obtained. 21a reacted withbutyraldehyde 57, isobutyraldehyde 58 and synthesizedN,N-dimethyl-α-hydroxypentanamide 69,N,N-dimethyl-α-hydroxyisopentanamide 70. The results show that:the steric hindrance of the aldehyde substituent has a greatinfluence on the reaction results. The bigger the steric resistance,the reaction was more difficult, and longer reaction time wasneeded. 21a with p-dimethylaminobenzaldehyde 59,p-methoxybenzaldehyde 60, p-methylbenzaldehyde 61,benzaldehyde 62, p-chlorobenzaldehyde 63, p-formylnitrobenzene64 respectively obtainedN,N-dimethyl-α-hydroxy-p-methoxyphenethylamide 71, N,N-dimethyl-α-hydroxy-p-methylphenethylamide 72,N,N-dimethyl-α-hydroxy-phenylethylamide 73,N,N-dimethyl-α-hydroxy-p-chlorophenylacetamide 74 andN,N-dimethyl-α-hydroxy-p-nitrophenylacetamide 75 (59 had noreaction activity). Experimental data showed that: substituent ofthe aromatic ring for the electronic-donating group declined thecarbonylcarbon's electricity positive, which was not conducive tothe addition reaction, to the contrary the electron-withdrawingsubstituents decreased the electron density around the carbonylcarbon, which was in favor of the addition reaction, and the yieldincreased. 21a reacted with acrolein 65, cinnamaldehyde 66respectively, and N,N-dimethyl-α-hydroxy-3-buteneamide 76,N,N-dimethyl-α-hydroxy-3-benzenebuteneamide 77 were obtained.The results shown that: both of the two alkenyl aldehydes couldreact with carbamylsilane, occur only 1,2-addition, and no1,4-addition product was obtained. 21a reacted with 2-furaldehyde67, 2-thiophenaldehyde 68 respectively to obtainedN,N-dimethyl-α-hydroxy-2-furanacetamide 78,N,N-dimethyl-α-hydroxy-2-thiopheneacetylamide 79. The resultsshown that: the activity of the two heterocyclic aldehydes was high,however, due to the oxygen atom of the furan ring’selectronegativity was bigger than the sulfur atoms of thethiophene ring, it was conducive to nucleophilic addition, andreflected the increasing of the yield.
In addition, we also researched the carbamylsilane 24areaction with ketones, in which alkyl, aryl, alkenyl, heteroarylketones were so actively that most of the results were satisfied except open-chain alkyl ketones. But compared with the reactionof the aldehydes, its activity is significantly reduced. Wespeculated that the electron-donating ability andhyper-conjugation effect of the alkyl is so strong that results in thelower electropositive of the carbonyl carbon, which was notconducive the occurrence of nucleophilic reaction. Moreover, thesteric hindrance of the alkyl was larger and restricted theadditional reaction. 21a attempted to react with cyclopentanone85, cyclohexane 86, camphor 87 respectively, and it’s found thatonly cyclohexane can react to obtained1-trimethylsilyloxy-1-N,N-Dimethylaminoformylcyclohexane 108;21a tried to reacted with phenyl methyl ketone 88,p-bromoacetophenones89, benzophenone 90, triphenylmethylphenyl ketone 91 respectively, and it’s found that onlybenzophenone obtainedN,N-dimethyl-2,2-iphenyl-2-trimethylsiliconoxy-acetamide 109; 21acould’nt react with methyl styryl ketone 93 or 5-methyl-1-phenyl-2,5-hexadiene-3-ketone 94, and the influence of the alkylwas the possible reason. 21a reacted with p-dimethylamino styrylphenyl ketone95, methoxystyryl phenyl ketone96, methyl styrenephenyl ketone97, the styrene phenyl ketone98, chlorobenzene vinylphenyl ketone 99, nitrobenzene vinyl phenyl ketone100,phenylethynyl phenyl ketone101 respectively, exception of 95having no activity, and others obtainedN,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-methoxyphenyl)-3-buteneamide 110,N,N-dimethyl-2-phenyl-2-trimethylsiliconoxy-4-(p-tolyl)-3-buteneam ide 111,N,N-dimethyl-2,4-diphenyl-2-trimethylsilyloxy-3-buteneamide 112,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-chlorophenyl)-3-teneamide 113,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-nitrophenyl)-3-buteneamide 114,N,N-dimethyl-2,4-diphenyl-2-trimethylsilyloxy-3-butynamide 115.The results shown that: The ketones which both sides of thecarbonyl containing a double bond, triple bond, and aromatic canreact with 21a due to the electron-withdrawing ability of thesegroups can increase the electropositive of the carbonyl carbon andmade the reaction easy. While electronegativity of the benzyneketone carbon-carbon triple bond is stronger than thecorresponding benzene kenone’s carbon-carbon double bond,which enhanced the electrophilic ability of the carbonyl carbon,which was in favor of the addition reaction and the yield isincreased monotonically. 21a reacted with1,5-diphenyl-2,4-glutaricketene 102,1,5-diphenyl-1,4-glutaricketene 103 respectively to obtainedN,N-dimethyl-2,6-diphenyl-2-trimethylsilyloxyhex-3,5-dienamide116,N,N-dimethyl-2-diphenylvinyl-2-trimethylsiliconoxyhex-3-buteneamide 117. The results shown that: conjugated dienone can react with21a, and the reaction occurred only 1,2-addition, no 1,4-additionproduct was obtained. 21a reacted with methyl-2-furylvinylketone104, 2-furanvinylphenylketone 105, 2-thienylphenylketone 106,2-thiophenevinylphenylketone 108 respectively. We found that: 104 and 106 didn’t react with 21a, while the 105 and 107 got thecorresponding compounds:N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-furan(2-furyl)-3-buteneamide 118,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-thiophene(2-thienyl)-3-buteneamide 119. The experimental data shown that: 104 couldn’treact with 21a due to the influence of the carbonyl alkyl, while 106constrained by the stronger electron-donating ability of thethiophene ring.
The products,α-hydroxyamides obtained from the reaction ofcarbamoylsilane with aldehydes/ketones are considered as animportant class of drug intermediates, which are widely applicatedin biological medicine, organic synthesis and other fields. Thisarticle provides a practical way to synthesis these compoundseconomically and effectively from the angle of methodology, and itpossesses a very important theoretical significance and enjoys thevalue of potential application.
氨甲酰基硅烷21a能与各种醛进行反应，包括烷基醛，烯醛，芳香醛及杂环醛，得到了11种α-羟基酰胺。21a分别与正丁醛57、异丁醛58反应，合成了N,N-二甲基-α-羟基-戊酰胺69、N,N-二甲基-α-羟基-异戊酰胺70，结果表明：醛烃基的空间位阻对反应有很大的影响，烷基空间位阻越大，反应越困难，需要更长的反应时间；21a分别与对二甲氨基苯甲醛59、对甲氧基苯甲醛60、对甲基苯甲醛61、苯甲醛62、对氯苯甲醛63和对硝基苯甲醛64反应，得到N,N-二甲基-α-羟基-对甲氧基苯乙酰胺71、N,N-二甲基-α-羟基-对甲基苯乙酰胺72、N,N-二甲基-α-羟基-苯乙酰胺73、N,N-二甲基-α-羟基-对氯苯乙酰胺74和N,N-二甲基-α-羟基-对硝基苯乙酰胺75（其中59不反应），实验表明：芳环取代基为供电子基团时，醛羰基碳的电正性较弱，不利于和21a反应，当取代基为吸电子基团时，增强了醛羰基碳的亲电能力，有利于同21a的亲核加成反应，反应产率也随着吸电子能力的增强而增高；21a分别和丙烯醛65、苯乙烯基苯甲醛66反应合成了N,N-二甲基-α-羟基-3-丁烯酰胺76、N,N-二甲基-α-羟基-3-苯丁烯酰胺77，结果表明：两种烯醛都可与21a反应，得到1, 2-加成产物，没有得到1, 4-加成产物；21a分别和2-呋喃甲醛67、2-噻吩甲醛68反应生成了N,N-二甲基-α-羟基-2-呋喃乙酰胺78、N,N-二甲基-α-羟基-2-噻吩乙酰胺79，结果表明：两种杂环醛的活性都很高，二者比较，由于呋喃环氧原子的电负性比噻吩环硫原子的大，增加了羰基碳的正电性，利于亲核加成，体现在产率的增大。
氨甲酰基硅烷21a与烷基酮，烯酮，炔酮，芳香酮及杂环酮反应，除了开链烷基酮不发生反应，大部分得到了较好的结果，但与醛的反应相比，其活性明显降低，可能是：烷基具供电子效应和超共轭效应使得羰基碳正电性减弱，不利于亲核反应的发生，另外烷基空间位阻也较大，对加成反应有一定的影响；21a分别与环戊酮85、环己酮86、樟脑87发生反应，发现只有环己酮可发生反应，生成了1-三甲基硅氧基-1-N,N-二甲氨甲酰基环己烷108；21a分别与苯乙酮88、对溴苯乙酮89、二苯甲酮90、三苯甲基苯基甲酮91发生反应，只有90可发生反应，得到了N,N-二甲基-2,2-二苯基-2-三甲基硅氧基乙酰胺109；21a与甲基苯乙烯基甲酮93和5-甲基-1-苯基-2,5-己二烯-3-酮94的反应没有获得新物质，表明原因是受烷基影响；21a分别与对二甲氨基苯乙烯基苯基甲酮95、对甲氧基苯乙烯基苯基甲酮96、对甲基苯乙烯基苯基甲酮97、苯乙烯基苯基甲酮98、对氯苯乙烯基苯基甲酮99、对硝基苯乙烯基苯基甲酮100、苯乙炔基苯基甲酮101反应，除95不反应外，分别生成了N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对甲氧基苯基-3-丁烯酰胺110、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对甲基苯基-3-丁烯酰胺111、N,N-二甲基-2,4-二苯基-2-三甲基硅氧基-3-丁烯酰胺112、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对氯苯基-3-丁烯酰胺113、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-对硝基苯基-3-丁烯酰胺114、N,N-二甲基-2,4-二苯基-2-三甲基硅氧基-3-丁炔酰胺115，结果表明：羰基两侧含有双键、三键及芳烃的酮都可反应，可能是这些基团有吸电子能力，使羰基碳正电性增加，反应容易发生，而苯炔酮碳碳三键电负性强于相应苯烯酮的双键，增强了羰基碳的亲电能力，有利于加成反应的进行，因而产率较高；21a与1,5-二苯基-2,4-戊二烯酮102、1,5-二苯基-1,4-戊二烯酮103反应生成了N,N-二甲基-2,6-二苯基-2-三甲基硅氧基-3,5-己二烯酰胺116、N,N-二甲基-2-二苯乙烯基-2-三甲基硅氧基-3-丁烯酰胺117，结果表明：共轭二烯酮也可与21a发生反应，发生1, 2-加成，不发生1, 4-加成；21a分别与甲基-2-呋喃乙烯基甲酮104、2-呋喃乙烯基苯基甲酮105、2-噻吩基苯基甲酮106、2-噻吩乙烯基苯基甲酮107反应发现：104和106不反应，而105和107可得到相应的化合物：N,N-二甲基-2-苯基-2-三甲基硅氧基-4-(2-呋喃基)-3-丁烯酰胺118、N,N-二甲基-2-苯基-2-三甲基硅氧基-4-(2-噻吩基)-3-丁烯酰胺119，实验表明：104由于羰基连有烷基而不能反应，而106是由于噻吩环的给电性强而不反应。
用氨甲酰基硅烷与醛、酮反应得到的产物α-羟基酰胺作为一类重要的药物中间体，在生物医药和有机合成等领域有非常广泛的应用，本文从方法学的角度，为经济有效的合成该类化合物提供了一条实用可行的途径，具有十分重要的理论意义和潜在的实用价值。
In this paper, two kinds of carbamoylsilanes were synthesizedand one of which was applied to the reaction with aldehydes orketones obtainedα-hydroxyamides. Meanwhile, the differentsubstituents of aldehydes or ketones by the yield, reaction time aswell as reaction temperature on reactivity were investigatedsystematically.
While the Carbamylsilane 21a was used to react with all kindsof aldehydes, it’s found that alkyl, aryl, alkenyl and heteroarylaldehydes, most of them have high activity, and 11 kinds ofcorrespondingα-hydroxyamides were obtained. 21a reacted withbutyraldehyde 57, isobutyraldehyde 58 and synthesizedN,N-dimethyl-α-hydroxypentanamide 69,N,N-dimethyl-α-hydroxyisopentanamide 70. The results show that:the steric hindrance of the aldehyde substituent has a greatinfluence on the reaction results. The bigger the steric resistance,the reaction was more difficult, and longer reaction time wasneeded. 21a with p-dimethylaminobenzaldehyde 59,p-methoxybenzaldehyde 60, p-methylbenzaldehyde 61,benzaldehyde 62, p-chlorobenzaldehyde 63, p-formylnitrobenzene64 respectively obtainedN,N-dimethyl-α-hydroxy-p-methoxyphenethylamide 71, N,N-dimethyl-α-hydroxy-p-methylphenethylamide 72,N,N-dimethyl-α-hydroxy-phenylethylamide 73,N,N-dimethyl-α-hydroxy-p-chlorophenylacetamide 74 andN,N-dimethyl-α-hydroxy-p-nitrophenylacetamide 75 (59 had noreaction activity). Experimental data showed that: substituent ofthe aromatic ring for the electronic-donating group declined thecarbonylcarbon's electricity positive, which was not conducive tothe addition reaction, to the contrary the electron-withdrawingsubstituents decreased the electron density around the carbonylcarbon, which was in favor of the addition reaction, and the yieldincreased. 21a reacted with acrolein 65, cinnamaldehyde 66respectively, and N,N-dimethyl-α-hydroxy-3-buteneamide 76,N,N-dimethyl-α-hydroxy-3-benzenebuteneamide 77 were obtained.The results shown that: both of the two alkenyl aldehydes couldreact with carbamylsilane, occur only 1,2-addition, and no1,4-addition product was obtained. 21a reacted with 2-furaldehyde67, 2-thiophenaldehyde 68 respectively to obtainedN,N-dimethyl-α-hydroxy-2-furanacetamide 78,N,N-dimethyl-α-hydroxy-2-thiopheneacetylamide 79. The resultsshown that: the activity of the two heterocyclic aldehydes was high,however, due to the oxygen atom of the furan ring’selectronegativity was bigger than the sulfur atoms of thethiophene ring, it was conducive to nucleophilic addition, andreflected the increasing of the yield.
In addition, we also researched the carbamylsilane 24areaction with ketones, in which alkyl, aryl, alkenyl, heteroarylketones were so actively that most of the results were satisfied except open-chain alkyl ketones. But compared with the reactionof the aldehydes, its activity is significantly reduced. Wespeculated that the electron-donating ability andhyper-conjugation effect of the alkyl is so strong that results in thelower electropositive of the carbonyl carbon, which was notconducive the occurrence of nucleophilic reaction. Moreover, thesteric hindrance of the alkyl was larger and restricted theadditional reaction. 21a attempted to react with cyclopentanone85, cyclohexane 86, camphor 87 respectively, and it’s found thatonly cyclohexane can react to obtained1-trimethylsilyloxy-1-N,N-Dimethylaminoformylcyclohexane 108;21a tried to reacted with phenyl methyl ketone 88,p-bromoacetophenones89, benzophenone 90, triphenylmethylphenyl ketone 91 respectively, and it’s found that onlybenzophenone obtainedN,N-dimethyl-2,2-iphenyl-2-trimethylsiliconoxy-acetamide 109; 21acould’nt react with methyl styryl ketone 93 or 5-methyl-1-phenyl-2,5-hexadiene-3-ketone 94, and the influence of the alkylwas the possible reason. 21a reacted with p-dimethylamino styrylphenyl ketone95, methoxystyryl phenyl ketone96, methyl styrenephenyl ketone97, the styrene phenyl ketone98, chlorobenzene vinylphenyl ketone 99, nitrobenzene vinyl phenyl ketone100,phenylethynyl phenyl ketone101 respectively, exception of 95having no activity, and others obtainedN,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-methoxyphenyl)-3-buteneamide 110,N,N-dimethyl-2-phenyl-2-trimethylsiliconoxy-4-(p-tolyl)-3-buteneam ide 111,N,N-dimethyl-2,4-diphenyl-2-trimethylsilyloxy-3-buteneamide 112,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-chlorophenyl)-3-teneamide 113,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-(p-nitrophenyl)-3-buteneamide 114,N,N-dimethyl-2,4-diphenyl-2-trimethylsilyloxy-3-butynamide 115.The results shown that: The ketones which both sides of thecarbonyl containing a double bond, triple bond, and aromatic canreact with 21a due to the electron-withdrawing ability of thesegroups can increase the electropositive of the carbonyl carbon andmade the reaction easy. While electronegativity of the benzyneketone carbon-carbon triple bond is stronger than thecorresponding benzene kenone’s carbon-carbon double bond,which enhanced the electrophilic ability of the carbonyl carbon,which was in favor of the addition reaction and the yield isincreased monotonically. 21a reacted with1,5-diphenyl-2,4-glutaricketene 102,1,5-diphenyl-1,4-glutaricketene 103 respectively to obtainedN,N-dimethyl-2,6-diphenyl-2-trimethylsilyloxyhex-3,5-dienamide116,N,N-dimethyl-2-diphenylvinyl-2-trimethylsiliconoxyhex-3-buteneamide 117. The results shown that: conjugated dienone can react with21a, and the reaction occurred only 1,2-addition, no 1,4-additionproduct was obtained. 21a reacted with methyl-2-furylvinylketone104, 2-furanvinylphenylketone 105, 2-thienylphenylketone 106,2-thiophenevinylphenylketone 108 respectively. We found that: 104 and 106 didn’t react with 21a, while the 105 and 107 got thecorresponding compounds:N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-furan(2-furyl)-3-buteneamide 118,N,N-dimethyl-2-phenyl-2-trimethylsilyloxy-4-thiophene(2-thienyl)-3-buteneamide 119. The experimental data shown that: 104 couldn’treact with 21a due to the influence of the carbonyl alkyl, while 106constrained by the stronger electron-donating ability of thethiophene ring.
The products,α-hydroxyamides obtained from the reaction ofcarbamoylsilane with aldehydes/ketones are considered as animportant class of drug intermediates, which are widely applicatedin biological medicine, organic synthesis and other fields. Thisarticle provides a practical way to synthesis these compoundseconomically and effectively from the angle of methodology, and itpossesses a very important theoretical significance and enjoys thevalue of potential application.
引文
[1] G. J. D. Peddle, R. W. Walsingham. Carbamyfsilanes: a new class of organosilicon compound[J] Chem.Commun., 1969, 462-462.
[2] J. E. Baldwin, A. E. Derome, P. D. Riordan. Deoxygenation of isocyanates to isonitriles. A mechanisticstudy by nuclear magnetic resonance[J] Tetrahedron,1983, 39, 2989-2994.
[3] C. M. Lindsay, D. A. Widdowson. Organicsynthesis with carbon monoxide: the synthesis ofcarbamoylstannanes and aromatic carbamoylation[J] J. Chem. Soc. Perkin Trans. 1, 1988, 569-573.
[4] R. F. Cunico. On the metalation-silylation of 1, 3, 5-trioxane[J] Synth. Commun., 2000, 30, 433-436.
[5] A. Orita, K. Ohe, S. Murai. Reaction of lithium silylamides with carbon monoxide leading tocarbamoylsilanes[J] Organometallics, 1994, 13, 1533-1536.
[6] R. F. Cunico. Carbamoylsilanes from the in situ metalation–silylation of a formamide[J] J. TetrahedronLet., 2001, 42, 1423-1425.
[7] R. F. Cunico., J. X. Chen. On the preparation of Carbamoylsilanes[J] Synth. Commun., 2003, 33,1963-1968.
[8] R. F. Cunico. Aminooxycarbene behavior of a carbamoylsilane[J] J. Tetrahedron Let., 2001, 42,2931–2932.
[9] (a) Moss, R. A. Acc. Chem. Res. 1989, 22, 15; (b) Warkentin, J. InAdvances in Carbene Chemistry;Brinker, U. H., Ed.; JAI: Stamford, 1998; Vol. 2, pp. 245–295.
[10] R. F. Cunico, B. C. Maity. Direct carbamoylation of aryl halides[J] Org. Lett., 2002, 4, 4357-4359.
[11] R. F. Cunico.α-Siloxyamides from a carbamoylsilane and carbonyl compounds[J] J. Tetrahedron Let.,2002, 43, 355–358.
[12] J. X. Chen, R. F. Cunico.α-(Dimethylamino)amides from a carbamoylsilane and iminium salts[J] J.Tetrahedron Let., 2002, 43, 8585–8547.
[13] R. F. Cunico, B. C. Maity. Direct carbamoylation of alkenyl halides[J] Org. Lett., 2003, 5, 4947-4949.
[14] J. X. Chen, R. F. Cunico.α-Aminoamides from a carbamoylsilane and aldehyde imines[J] J.Tetrahedron Let., 2003, 44, 8025–8027.
[15] J. X. Chen, R. K. Pandey, R. F. Cunico. Diastereoselective formation ofα-aminoamides fromcarbamoylsilanes and aldehyde imines[J] Tetrahedron: Asymmetry, 2005, 16, 941-947.
[16] R. F. Cunico, A. R. Motta. Addition of carbamoylsilanes to electrophilically substituted alkenes.Preparation ofβ-functionalized tertiary amides[J] Org. Lett., 2005, 7, 771-774.
[17] J. X. Chen, X. S. Wen. Reaction of carbamoylsilane with nitrone and tautomerism of product[J] ActaChemica Sinca, 2009, 67, 1709-1711.
[18]J. X. Chen, R. F. Cunico. Synthesis ofα-ketoamides from a carbamoylsilane and acid chlorides[J] J.Org. Chem., 2004, 69, 5509-5511.
[19] R. F. Cunico, A. R. Motta. Structural and electronic effects on the reactivity of carbamoylsilanestowards acrylonitrile addition[J] J. Organometallic Chemistry, 2006, 691, 3109-3112.
[20] R. F. Cunico, R. K. Pandey. Palladium-catalyzed synthesis ofα-iminoamides from imidoyl chloridesand a carbamoylsilane[J] J. Org. Chem., 2005, 70, 5344-5346.
[21] R. F. Cunico, R. K. Pandey. Palladium-catalyzed Conversion of benzylic and allylic halides intoα-Arylandβ,γ-unsaturated tertiary amides by the use of a carbamoylsilane[J] J. Org. Chem., 2005, 70,9048-9050.
[22] G. Ehrhart, I. Hennig. Lindner, E.α-Hydroxycarbonsureamide[J] Arch. Pharm., 1960, 293, 210-225.
[23] A. Khalaj, E. J. Nahid. Direct determination of carbon hybridization in amorphous carbon films using13C n.m.r. spectroscopy[J] Chem. Soc. Chem. Commun., 1985, 1153-1154.
[24] G. R. Nakayama, E. G. Schultz. stereospecific antibody-catalyzed reduction of an .alpha.-keto amide[J]J. Am. Chem. Soc. 1992, 114, 780-781.
[25] A. Solladie-Cavallo, M. Benchegroin. Inexpensive reagents for the synthesis of amides from esters andfor regioselective opening of epoxides[J] J. Org. Chem., 1992, 57, 5831-5833.
[26] K. Matsumoto, S. Hashimoto, S. Otani. Direkte Aminolyse von nicht aktivierten Estern bei hohemDruck[J] Angew. Chem., 1986, 98, 569-571.
[27] J. M. Shin, Y. H. Kim. New facile synthesis ofα-hydroxyamides: Intermolecular and intramolecularcatalysis in the reaction ofα-hydroxycarboxylic acids with N-sulfinylamines[J] Tetrahedron Lett. 1986,27, 1921-1923.
[28] S. E. Kelly, T. G. LaCour. A One Pot Procedure for the Synthesis ofα-Hydroxyamides from theCorrespondingα-Hydroxyacids[J] Synth. Commun., 1992, 22, 859-861.
[29] D. E. Kiely, J. L. Naiva. Palladium catalysed intramolecular coupling of aryl and benzylic halides andrelated tandem cyclisations. A simple synthesis of hippadine[J] Tetrahedron Lett., 1991, 32,3859-3861.
[30] E. A. Davis, T. G. Ulatowski, M. S. Haque. Asymmetric oxidation of chiral enolates in the preparationof acyclic tertiary .alpha.-hydroxy amides in high optical purity[J] J. Org. Chem., 1987, 52,5288-5290.
[31] A. Khalaj, E. Nahid. Synthesis ofα- Hydroxy acid amides from Acetonides ofα- Hydroxy acids andAmines[J] Synthesis 1985, 1153-1155.
[32] A. M. Thompson, J. W. Blunt, M. H. G. Munro, N. B. Perry, L. K. Pannell. Chemistry of themycalamides, antiviral and antitumour compounds from a marine sponge. Part 3. Acyl, alkyl and silylderivatives[J] J. Chem. Soc. Perkin Trans. 1, 1992, 1335-1342, and references therein.
[33] S. Ahmad, A. Ashfaq, M. Alam, G. S. Bisacchi, P. Chen, P. T. Cheng, J. A. Greytok, M. A. Hermsmeier,P. F. Lin, K. A. Lis, Z. Merchant, T. Mitt, M. Skoog, S. H. Spergel, J. A. Tino, G. D. Vite, R. J.Colonno, R. Zahler, J. C. Barrish.α-hydroxyamide derived aminodiols as potent inhibitors of hivprotease[J] Bioorg. Med. Chem. Lett. 1995, 5, 1729-1734.
[34] P. Wipf, H. Kim. Total Synthesis of Cyclotheonamide A[J] J. Org. Chem., 1993, 58, 5592-5594.
[35] J. C. Menéndez, M. Villacampa, M. M. S llhuber. Synthesis and Stereochemical Study of (±)-(2R*,11bS*)-9,10-Dimethoxy-1,3,4,6,7,11b-hexahydrospiro[benzo[a]quinolizine-2,5’-oxazolidine]-2’,4’-dione[J] Heterocycles, 1991, 32, 469-474.
[36] J. Y. Lai, X. X. Shi, Y. S. Gong, L. X. Dai. Optically Active Tetrahydro-1,4-oxazine Derivatives[J] J.Org. Chem. 1993, 58, 4775-4777.
[37] C. Kashima, H. Kazuo. Synthesis and reaction of optically active morpholinones[J] J. Chem. Soc.Perkin Trans. 1, 1988, 1521-1526.
[38] B. Bánhidai, U. Sch llkopf. (Dimethylcarbamoy1)lithium from dimethylformamide and lithiumdiisopropylamide; synthesis ofα-hydroxy N, N-Dimethylcarboxyamides[J] Angew. Chem. internat.Edit., 1731, 12, 836-837.
[39] U. Sch llkopf , H. Beckhaus.α-Hydroxycarboxamides fromN,N-Bis(methoxymeth-yl)carbamoyllithium and carbonyl compounds[J] Angew. Chem. Int. Ed.Engl., 1976, 15, 293.
[40] T. Punniyamurthy, J. Iqbal. Polyaniline supported cobalt(II) salen catalysed synthesis ofpyrrolidine containingα-hydroxyamide core Structures as inhibitors for HIV proteases[J] TetrahedronLet., 1997, 38, 4463-4466.
[41] M. Adamczyk, J. Grote, S. Rege. Stereoselective pseudomonas cepacia lipase mediated synthesis ofα-hydroxyamides[J] Tetrahedron: Asymmetry, 1997, 8, 2509-2512.
[42] W. Szymanski, R. Ostaszewski. Chemoenzymatic synthesis of enantiomerically enrichedα-hydroxyamides[J] Journal of Molecular Catalysis B: Enzymatic, 2007, 47, 125-128.
[43]T. Kurz, K. Widyan. Microwave-assisted conversion of N-substituted oxazolidin-2,4-diones intoa-hydroxyamides[J] J. Tetrahedron, 2005, 61, 7247-7251.
[44] O. Merino, B. M. Santoyo, L. E. Montiel, H. A. Jiménez-Vázquez, L. G. Zepeda, J. Tamariz. Versatilesynthesis of quaternary 1,3-oxazolidine-2,4-diones and their use in the preparation ofα-hydroxyamides[J] Tetrahedron Let., 2010, 51, 3738-3742.
[45] J. S. Kumar, S. C. Jonnalagadd, V. R. Mereddy. An efficient boric acid-mediated preparation ofα-hydroxyamides[J] Tetrahedron Let., 2010, 51, 779-782.
[46] J. B. Conant, Neal Tuttle. Diacetone alcohol[J] Organic Synth, 1941, 1, 199-200.
[47] J. B. Conant, Neal Tuttle. Diacetone alcohol[J] Organic Synth, 1941, 1, 345-346.
[48] W. E. Bachmann. Benzopinacol[J] Organic Synth, 1943, 2, 71-72.
[49] W. E. Bachmann.β-Benzopinacolone[J] Organic Synth, 1943, 2, 73-74.
[50] G. J. Leuck, L.Cejka. 2-Furfuralacetone[J] Organic Synth, 1941, 1, 283-284.
[51] E. P. Kohler, H. M. Chadwell. Benzalacetophenone[J] Organic Synth, 1941, 1, 78-284.
[52] Charles. R. Conard, Morris. A. Dolliver. Dibenzalacetone[J] Organic Synth, 1943, 2, 167-168.
[53] Wesley Minnis. Phenyl thienyl ketone[J] Organic Synth, 1943, 2, 520-521.
[2] J. E. Baldwin, A. E. Derome, P. D. Riordan. Deoxygenation of isocyanates to isonitriles. A mechanisticstudy by nuclear magnetic resonance[J] Tetrahedron,1983, 39, 2989-2994.
[3] C. M. Lindsay, D. A. Widdowson. Organicsynthesis with carbon monoxide: the synthesis ofcarbamoylstannanes and aromatic carbamoylation[J] J. Chem. Soc. Perkin Trans. 1, 1988, 569-573.
[4] R. F. Cunico. On the metalation-silylation of 1, 3, 5-trioxane[J] Synth. Commun., 2000, 30, 433-436.
[5] A. Orita, K. Ohe, S. Murai. Reaction of lithium silylamides with carbon monoxide leading tocarbamoylsilanes[J] Organometallics, 1994, 13, 1533-1536.
[6] R. F. Cunico. Carbamoylsilanes from the in situ metalation–silylation of a formamide[J] J. TetrahedronLet., 2001, 42, 1423-1425.
[7] R. F. Cunico., J. X. Chen. On the preparation of Carbamoylsilanes[J] Synth. Commun., 2003, 33,1963-1968.
[8] R. F. Cunico. Aminooxycarbene behavior of a carbamoylsilane[J] J. Tetrahedron Let., 2001, 42,2931–2932.
[9] (a) Moss, R. A. Acc. Chem. Res. 1989, 22, 15; (b) Warkentin, J. InAdvances in Carbene Chemistry;Brinker, U. H., Ed.; JAI: Stamford, 1998; Vol. 2, pp. 245–295.
[10] R. F. Cunico, B. C. Maity. Direct carbamoylation of aryl halides[J] Org. Lett., 2002, 4, 4357-4359.
[11] R. F. Cunico.α-Siloxyamides from a carbamoylsilane and carbonyl compounds[J] J. Tetrahedron Let.,2002, 43, 355–358.
[12] J. X. Chen, R. F. Cunico.α-(Dimethylamino)amides from a carbamoylsilane and iminium salts[J] J.Tetrahedron Let., 2002, 43, 8585–8547.
[13] R. F. Cunico, B. C. Maity. Direct carbamoylation of alkenyl halides[J] Org. Lett., 2003, 5, 4947-4949.
[14] J. X. Chen, R. F. Cunico.α-Aminoamides from a carbamoylsilane and aldehyde imines[J] J.Tetrahedron Let., 2003, 44, 8025–8027.
[15] J. X. Chen, R. K. Pandey, R. F. Cunico. Diastereoselective formation ofα-aminoamides fromcarbamoylsilanes and aldehyde imines[J] Tetrahedron: Asymmetry, 2005, 16, 941-947.
[16] R. F. Cunico, A. R. Motta. Addition of carbamoylsilanes to electrophilically substituted alkenes.Preparation ofβ-functionalized tertiary amides[J] Org. Lett., 2005, 7, 771-774.
[17] J. X. Chen, X. S. Wen. Reaction of carbamoylsilane with nitrone and tautomerism of product[J] ActaChemica Sinca, 2009, 67, 1709-1711.
[18]J. X. Chen, R. F. Cunico. Synthesis ofα-ketoamides from a carbamoylsilane and acid chlorides[J] J.Org. Chem., 2004, 69, 5509-5511.
[19] R. F. Cunico, A. R. Motta. Structural and electronic effects on the reactivity of carbamoylsilanestowards acrylonitrile addition[J] J. Organometallic Chemistry, 2006, 691, 3109-3112.
[20] R. F. Cunico, R. K. Pandey. Palladium-catalyzed synthesis ofα-iminoamides from imidoyl chloridesand a carbamoylsilane[J] J. Org. Chem., 2005, 70, 5344-5346.
[21] R. F. Cunico, R. K. Pandey. Palladium-catalyzed Conversion of benzylic and allylic halides intoα-Arylandβ,γ-unsaturated tertiary amides by the use of a carbamoylsilane[J] J. Org. Chem., 2005, 70,9048-9050.
[22] G. Ehrhart, I. Hennig. Lindner, E.α-Hydroxycarbonsureamide[J] Arch. Pharm., 1960, 293, 210-225.
[23] A. Khalaj, E. J. Nahid. Direct determination of carbon hybridization in amorphous carbon films using13C n.m.r. spectroscopy[J] Chem. Soc. Chem. Commun., 1985, 1153-1154.
[24] G. R. Nakayama, E. G. Schultz. stereospecific antibody-catalyzed reduction of an .alpha.-keto amide[J]J. Am. Chem. Soc. 1992, 114, 780-781.
[25] A. Solladie-Cavallo, M. Benchegroin. Inexpensive reagents for the synthesis of amides from esters andfor regioselective opening of epoxides[J] J. Org. Chem., 1992, 57, 5831-5833.
[26] K. Matsumoto, S. Hashimoto, S. Otani. Direkte Aminolyse von nicht aktivierten Estern bei hohemDruck[J] Angew. Chem., 1986, 98, 569-571.
[27] J. M. Shin, Y. H. Kim. New facile synthesis ofα-hydroxyamides: Intermolecular and intramolecularcatalysis in the reaction ofα-hydroxycarboxylic acids with N-sulfinylamines[J] Tetrahedron Lett. 1986,27, 1921-1923.
[28] S. E. Kelly, T. G. LaCour. A One Pot Procedure for the Synthesis ofα-Hydroxyamides from theCorrespondingα-Hydroxyacids[J] Synth. Commun., 1992, 22, 859-861.
[29] D. E. Kiely, J. L. Naiva. Palladium catalysed intramolecular coupling of aryl and benzylic halides andrelated tandem cyclisations. A simple synthesis of hippadine[J] Tetrahedron Lett., 1991, 32,3859-3861.
[30] E. A. Davis, T. G. Ulatowski, M. S. Haque. Asymmetric oxidation of chiral enolates in the preparationof acyclic tertiary .alpha.-hydroxy amides in high optical purity[J] J. Org. Chem., 1987, 52,5288-5290.
[31] A. Khalaj, E. Nahid. Synthesis ofα- Hydroxy acid amides from Acetonides ofα- Hydroxy acids andAmines[J] Synthesis 1985, 1153-1155.
[32] A. M. Thompson, J. W. Blunt, M. H. G. Munro, N. B. Perry, L. K. Pannell. Chemistry of themycalamides, antiviral and antitumour compounds from a marine sponge. Part 3. Acyl, alkyl and silylderivatives[J] J. Chem. Soc. Perkin Trans. 1, 1992, 1335-1342, and references therein.
[33] S. Ahmad, A. Ashfaq, M. Alam, G. S. Bisacchi, P. Chen, P. T. Cheng, J. A. Greytok, M. A. Hermsmeier,P. F. Lin, K. A. Lis, Z. Merchant, T. Mitt, M. Skoog, S. H. Spergel, J. A. Tino, G. D. Vite, R. J.Colonno, R. Zahler, J. C. Barrish.α-hydroxyamide derived aminodiols as potent inhibitors of hivprotease[J] Bioorg. Med. Chem. Lett. 1995, 5, 1729-1734.
[34] P. Wipf, H. Kim. Total Synthesis of Cyclotheonamide A[J] J. Org. Chem., 1993, 58, 5592-5594.
[35] J. C. Menéndez, M. Villacampa, M. M. S llhuber. Synthesis and Stereochemical Study of (±)-(2R*,11bS*)-9,10-Dimethoxy-1,3,4,6,7,11b-hexahydrospiro[benzo[a]quinolizine-2,5’-oxazolidine]-2’,4’-dione[J] Heterocycles, 1991, 32, 469-474.
[36] J. Y. Lai, X. X. Shi, Y. S. Gong, L. X. Dai. Optically Active Tetrahydro-1,4-oxazine Derivatives[J] J.Org. Chem. 1993, 58, 4775-4777.
[37] C. Kashima, H. Kazuo. Synthesis and reaction of optically active morpholinones[J] J. Chem. Soc.Perkin Trans. 1, 1988, 1521-1526.
[38] B. Bánhidai, U. Sch llkopf. (Dimethylcarbamoy1)lithium from dimethylformamide and lithiumdiisopropylamide; synthesis ofα-hydroxy N, N-Dimethylcarboxyamides[J] Angew. Chem. internat.Edit., 1731, 12, 836-837.
[39] U. Sch llkopf , H. Beckhaus.α-Hydroxycarboxamides fromN,N-Bis(methoxymeth-yl)carbamoyllithium and carbonyl compounds[J] Angew. Chem. Int. Ed.Engl., 1976, 15, 293.
[40] T. Punniyamurthy, J. Iqbal. Polyaniline supported cobalt(II) salen catalysed synthesis ofpyrrolidine containingα-hydroxyamide core Structures as inhibitors for HIV proteases[J] TetrahedronLet., 1997, 38, 4463-4466.
[41] M. Adamczyk, J. Grote, S. Rege. Stereoselective pseudomonas cepacia lipase mediated synthesis ofα-hydroxyamides[J] Tetrahedron: Asymmetry, 1997, 8, 2509-2512.
[42] W. Szymanski, R. Ostaszewski. Chemoenzymatic synthesis of enantiomerically enrichedα-hydroxyamides[J] Journal of Molecular Catalysis B: Enzymatic, 2007, 47, 125-128.
[43]T. Kurz, K. Widyan. Microwave-assisted conversion of N-substituted oxazolidin-2,4-diones intoa-hydroxyamides[J] J. Tetrahedron, 2005, 61, 7247-7251.
[44] O. Merino, B. M. Santoyo, L. E. Montiel, H. A. Jiménez-Vázquez, L. G. Zepeda, J. Tamariz. Versatilesynthesis of quaternary 1,3-oxazolidine-2,4-diones and their use in the preparation ofα-hydroxyamides[J] Tetrahedron Let., 2010, 51, 3738-3742.
[45] J. S. Kumar, S. C. Jonnalagadd, V. R. Mereddy. An efficient boric acid-mediated preparation ofα-hydroxyamides[J] Tetrahedron Let., 2010, 51, 779-782.
[46] J. B. Conant, Neal Tuttle. Diacetone alcohol[J] Organic Synth, 1941, 1, 199-200.
[47] J. B. Conant, Neal Tuttle. Diacetone alcohol[J] Organic Synth, 1941, 1, 345-346.
[48] W. E. Bachmann. Benzopinacol[J] Organic Synth, 1943, 2, 71-72.
[49] W. E. Bachmann.β-Benzopinacolone[J] Organic Synth, 1943, 2, 73-74.
[50] G. J. Leuck, L.Cejka. 2-Furfuralacetone[J] Organic Synth, 1941, 1, 283-284.
[51] E. P. Kohler, H. M. Chadwell. Benzalacetophenone[J] Organic Synth, 1941, 1, 78-284.
[52] Charles. R. Conard, Morris. A. Dolliver. Dibenzalacetone[J] Organic Synth, 1943, 2, 167-168.
[53] Wesley Minnis. Phenyl thienyl ketone[J] Organic Synth, 1943, 2, 520-521.