环丙基甲基酮的合成新方法

苯并咪唑盐;grignard试剂;环丙基甲基酮;合成     

环二酮的新合成方法

以二苯并咪唑盐和双Grignard试剂为原料 ,合成了 4种环二酮 .报道了二苯并咪唑盐与双Grignard试剂的加成水解反应 ,并提出了一种可以用于制备多种环二酮的重要合成方法     

环丙基甲基酮的合成研究进展

环丙基甲基酮是合成环丙氟哌酸类广谱抗菌药物和抗艾滋特效药依法韦仑的重要中间体,在医药、化工及农林等领域均有广泛应用。环丙基甲基酮的合成方法大致分为4类,分别以酮类、酯类、醇类及呋喃有机物为原料,在一定条件下生成环丙基甲基酮粗品,经萃取及精馏得到环丙基甲基酮纯品。本文综述了环丙基甲基酮的合成研究进展。     

新型含有苯并咪唑取代基的多取代吡啶类化合物及其配合物的合成与表征

以苯并咪唑查尔酮、吡啶盐在醋酸氨和冰醋酸中的混合物为原料,在微波作用下合成了一系列未见文献报道的多取代吡啶类化合物,并研究了具有代表性的化合物与金属离子的配位反应.通过IR,UV,1HNMR,13CNMR等方法进行了表征,并用单晶X-ray衍射法测定了一个配合物的单晶分子结构.     

苯并咪唑盐与胺类化合物的加成-水解反应研究

四氢叶酸辅酶在生物体内的生物合成过程中的作用是转移不同氧化态的一碳单元.本课题组曾首次提出并报道了苯并咪唑盐作为四氢叶酸辅酶的模型化合物,并研究了该模型化合物与多种格利雅试剂和丙二酸二乙酯碳负离子等反应,实现了一碳单元的转移反应,为许多醛、酮和β-羰基酸等有机化合物提供了仿生合成新方法[1,2].本文对苯并咪唑盐与亲核试剂胺类化合物的加成-水解反应进行了研究,提出了苯并咪唑盐的另一种新反应,为一些酰胺类化合物提供了一种未见文献报道的重要仿生合成新方法.     

2，4-共轭不饱和酮、酯、腈的合成

前文我们报道了溴化对-苯基苯甲酰甲基二丁基碲、溴化对-溴苯甲酰甲基二丁基碲和溴化间-硝基苯甲酰甲基二丁基碲等碲盐与醛、酮缩合成α,β-不饱和酮的反应。为了进一步研究碲盐反应性能,扩大它在有机合成中应用范围,我们在前期工作基础上,由碲盐和(E)-α,β-不饱和醛合成了2,4-共轭不饱和酮、酯、腈,这是一种未见文献报道的新合成方     

二十四种作为麝香酮及类似大环酮重要中间体的长链二酮的仿生合成

烷基取代的大环酮（例如,名贵香料麝香酮）是珍贵的香料,天然来源稀少,它的人工合成一直是有机合成中的一个研究热点和难点。在本文中,受四氢叶酸辅酶的一碳单元转移反应的启发,作者以双苯并咪唑盐作为四氢叶酸辅酶模型,利用格利雅试剂与双苯并咪唑盐的加成-水解反应,成功合成了二十四种作为麝香酮及类似大环酮重要前体的长链二酮,同时,提供了一种麝香酮及类似大环酮的仿生合成新方法。     

O-甲基-α-羟基烃基膦酸酯单金属盐的合成

以KF-Al2O3为催化剂,通过亚膦酸二甲酯与各种酮加成反应,生成一系列α-羟基烃基膦酸酯,它们再与不同的碱金属盐作用合成了12个未见文献报道的O-甲基-α-羟基烃基膦酸酯单金属盐。通过^1H NMR,IR和元素分析确证了它们的结构。     

从苯并咪唑盐制备酮的新合成方法研究

报道取代苯并咪唑盐与Grignard试剂作用制备酮的一种新的合成方法,讨论了反应机理及不同的Grignard试剂对酮收率的影响。     

2,3-二取代-5-羟基苯并呋喃衍生物的合成

用1,4-环己二酮与联二酮的缩合反应首次合成了4个未见文献报道的标题化合物,结构经IR,1H NMR,MS和元素分析等测试确证,并对反应条件进行了初步探讨.结果表明,以LiCl作为催化剂,用1,3-二甲基-2-咪唑啉酮(DMI)为溶剂,于200℃反应1 h时收率最高.     

Formation of unsaturated bicyclic γ-butyrolactone by oxidative dimerization of 2-methyl-2-ethynylcyclopropanecarboxylic acid

Conclusions The oxidative dimerization of a mixture of the trans and cis isomers of 2-methyl-2-ethynylcyclopropanecarboxylic acid in the presence of CuCl and NH₄Cl gives, along with bis(trans-1-methyl-2-carboxyl-1-cyclopropyl)diacetylene (53% yield), also the corresponding dilactone, and specifically bi(1-methyl-4-oxo-3-oxabicyclo[3.1.0]-2-hexalidene)methyl (14% yield), which is probably formed via the intramolecular cyclization of the intermediately formed bis(cis-1-methyl-2-carboxy-1-cyclopropyl) diacetylene.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1164–1166, May, 1981.     

Tricyclo[2.1.0.01,3]pentane

The reaction of 1,1-dibromo-2,3-bis(chloromethyl)cyclopropane with methyllithium leads initially to ring closure to 1-bromo-2-chloromethylbicyclo[1.1.0]butane. Further reaction leads to an unstable compound which reacts with phenylthiol to give 2-vinyl-1-cyclopropyl phenyl sulfide and undergoes thermal rearrangement at ∼ -50°C to give cyclopentadiene. Strong evidence is presented which suggests that tricyclo[2.1.0.01,3]pentane may be the intermediate.     

Design and synthesis of 5-cyclopropyl substituted cyclic acylguanidine compounds as BACE1 inhibitors

By taking compound 1 as a lead, a series of 5-cyclopropyl substituted cyclic acylguanidine compounds were designed and synthesized as BACE1 inhibitors, compound 4d exhibited 84-fold improved inhibition efficiency than lead compound 1. The diphenyl fragment at the P3 position and the substituents at the second phenyl ring were essential for the compounds to achieve improved inhibition efficiency. This SAR studies provides new insights into the design and synthesis of more promising BACE1 inhibitors for the potential treatment of AD.     

Coupling of two diazotized 3‐aminothieno[3,4‐c]coumarins with aromatic amines

The coupling reactions of two diazotized 3‐aminothieno[3,4‐c]coumarins were investigated. Compounds 1a , 1b both react with sodium nitrite in concentrated sulphuric acid at 0–5°C to give the diazotized intermediates 2 and 3 , the latter resulting from the acid ‐catalyzed hydrolysis of the lactonic ring of 2 . The in situ formed diazonium salts react with aromatic amines ( 4 ) to afford a series of arylazothiophenes dyes in the form of their ammonium sulfate salts. With diazotized aniline, besides the normally expected phenylazothiophene 10 from the reaction with compound 1a , the corresponding product of acid hydrolysis 11 was also isolated. In at least one of the cases, the thienyl diazonium salt 2 undergoes a Gomberg–Bachmann arylation reaction with p‐nitroaniline to give the 2‐arylthiophene 9 . The direct hydrolysis of compounds 1a , 1b by concentrated sulphuric acid and subsequent oxidative dimerization of the primary product of acid hydrolysis led to compound 12 . J. Heterocyclic Chem., (2011).     

Dense compounds of C,H, N,and O atoms: Nitramine derivatives of diimino- and dioxodecahydro-1 h,5h-diimidazo-[4,5-b:4′,5′-e]pyrazine

Guanidine condensed with 1,4-diformyl-2,3,5,6-tetrahydroxypiperazine 1 to give 2,6-diiminodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 3 isolated as the tetrahydrochloride salt. nitric acid (100%) at −40°C converted the bisguanidine 3 to 2,6-dinitrimino-4,8-dinitrodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]- pyrazine 8 isolated as a dihydrate, whereas nitration by nitronium tetrafluoroborate at 0° to 25°C afforded 2,6-diimino-4,8-dinitrodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 9 isolate as the monohydrated bistetrafluoroborate salt, and treatmetn with nitric acid (100%) and acetic anhydride or phosphorus pentoxide converted the bisguanidine 3 to 2,6-dioxo-1,3,4,5,7,8-hexanitrodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 4 , also obtained from the tetra N-nitro compound 8 · 2 H₂O and from the dinitramine 9 · 2 BHF₄ · H₂O after similar treatment. The cis-syn-cis- configuration of the tricyclic bisurea 4 and bisguanidine 9 was confirmed by X-ray crys-tallographic analysis. Nitrosation by nitrous acid or by dinitrogen tetroxide converted the bisguanidine 3 to a hydrated 2,6-dinitrosimino-4,8-dinitrosodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-]pyrazine 10 · 2.5 H₂O, whereas treatment with nitrosonium tetrafluo-roborate afforded the bistetrafluoroborate salt of 4,8-dinitroso derivative 11 · 2 BHF 4 . The nitrosamines 10 and 11 were converted to the tetranitro compound 8 · 2 H₂O on treatment with nitric acid (100%) at −40°C. Treatmnt with fluoroboric acid etherate in acetonitrile converted nitroimino groups in compound 8 · 2 H₂O and nitrosimino groups in compound 10 · 2.5 H₂O to imino groups in compounds 9 · 2 BHF₂ · H₂O and 11 · 2 HBF₄ respectively.     

Tris(oxalato)phosphorus acid and its lithium salt

The conversion of three equivalents of anhydrous oxalic acid with phosphorus pentachloride yields tris(oxalato)phosphorus acid 1, which crystallizes from diethyl ether solutions as protonated diethyl ether complex [(Et2O)2H](+)[P(C2O3)3)]-. The superacidic compound can be used as catalyst for Friedel-Crafts-type reactions. Upon neutralization with lithium hydride, the lithium salt Li[P(C2O3)3] 2 is obtained, which is highly soluble in aprotic solvents and which exhibits a wide voltage window. Thus, the lithium compound is a promising candidate as electrolyte for high performance non-aqueous batteries.     

Umlagerung von Vinyl-Cyclopropan-Carbaminalen

Rearrangement of Vinyl-Cyclopropane-Carbaminals Both (c-2, t-3-diphenyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 4 ) and its (t-2, t-3)-isomer 10 underwent a thermal rearrangement to (E)-N-2-benzylidene-1-indanyl-pyrrolidine ( 5 ). Under the conditions of the rearrangement, 5 was partially converted into 2-benzyl-1-indanone ( 6 ) in a base catalysed reaction. The structures of 5 and 6 were derived from spectroscopic data and from degradation reactions.- N,N′-(t-2-Vinyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 11 ) rearranged thermally to N-(2-methylidene-3-cyclopenten-1-yl)pyrrolidine ( 12 ), the structure of which was established from spectroscopic evidence and from a hydrogenation to N-(2-methylcyclopentyl)pyrrolidine ( 13 , cis/trans mixture 3:2). The aminal 4 was reduced with formic acid to give N-(c-2, t-3-diphenyl-r-1-cyclopropyl)methyl-pyrrolidine ( 14 ). If perdeuterio formic acid was used, the mixture product 14-d/14-d ₂ was obtained which contained exactly one deuterium atom in its methylene group and about half a deuterium atom on C(1). This labeling pattern is mechanistically explained with the existence of a fast equilibrium between the iminium ion 19 and the enamine 18 , so that 18 and 19 are considered to be plausible reactive intermediates in the above mentioned thermal rearrangement. - Based on this, several mechanisms for the rearrangements 4 → 5, 10 → 5 and 11 → 12 were considered: A Pictet-Spengler- or Mannich-type reaction, which starts from the iminium ion 23 and is followed by a cyclopropylmethyl-homoallylic rearrangement and by deprotonation (path a, Scheme 5), was judged to be improbable because the postulated intermediates could lead more easily to other stable products than the observed ones. If the reaction is formulated as a [3,3]-sigmatropic shift occurring on exclusively the (E)-isomer 5 suggests a concerted process whose steric course is predominantly controlled by strain factors. Alternatively, the reaction could be formulated via a dipolar ( 27 ) or a diradical ( 26 ) species derived from the enamine 22 (paths c and d, Scheme 5); attempts to trap such species by a number of agents were unsuccessful. - The previously unknown aminals 10 and 11 were synthesized by standard methods.     

Synthesis of 2-dichloromethyl-2-methyl [2-14C]-1,3-dioxolane

The labelled compound was prepared by chlorination of [2-¹⁴C]acetone obtained from the barium salt of [1-¹⁴C]acetic acid by pyrolysis. The reaction product 1,1-dichloro [2-¹⁴C]acetone was converted to 2-dichloromethyl-2-methyl [2-¹⁴C]-1,3-dioxolane by condensation with ethylene glycol in the presence of thionyl chloride. Radiochemical yield: 62% based on [1-¹⁴C]acetic acid.     

Umwandlung von 6-Methylen-tricyclo[3.2.1.02,7]oct-3-en-8-onen in Polymethyltropyliumsalze

When dissolved in trifluoroacetic or fluorosulfonic acid, 6-methylene-tricyclo[3.2.1.0^2,7]oct-3-ene-8-one derivatives of type 2 (;scheme 1); give polymethyltropylium salts in moderate to good yields by CO-extrusion. These tropylium salts can be isolated pure as hexachloroplatinates. Thus the tricyclic compound 6 gives 1,2,4-trimethyltropylium trifluoroacetate 19 in trifluoroacetic acid (;scheme 3);. This salt in CDCl₃ is in equilibrium with its covalent cycloheptatriene (;tropilidene); form 20 , the ratio of the two forms being 1.5–2.1/1. The tropylium salt 19 is reduced by lithium aluminium hydride to a mixture of 1,2,4-trimethylcycloheptatrienes, isomeric with respect to the double bonds, which on hydride abstraction with trityl-tetrafluoroborate gives again the 1,2,4-trimethyltropylium salt 19 (;scheme 3);. From the trimethyl-substituted tricyclic compounds 7 and 8 , in trifluoroacetic acid, are obtained respectively the 1,2,4,6- and 1,2,3,4-tetramethyltropylium ions (; 22 and 24 ); (;schemes 4 and 5);. In this way the 1,2,3,5,6-pentamethyl-tropylium ion (; 26 ); was obtained from 9 (;scheme 6);. With the higher substituted tropylium trifluoroacetates in CDCl₃ the equilibrium tropylium trifluoroacetate ? trifluoroacetoxycycloheptatrienes lies well to the left. The hexamethylated tricyclic compound 10 gives a small quantity of heptamethyltropylium trifluoroacetate (; 27 ); and as the main product the C(;3);-protonated species 28 (;scheme 7);, which when treated with aqueous sodium hydrogencarbonate yielded unchanged educt 10 . - The heptamethyltropylium ion (; 27 ); was, apart from polymeric species, the only product from the treatment of starting material 10 with fluorosulfonic acid (;50%);; its salts have as yet not been isolated in their pure form, however. The mechanism for the rearrangement of the tricyclic compounds of type 2 into tropylium salts is presented for compound 6 in scheme 8: The first step is the protonation at C(;9);. Ring opening of the cyclopropane of the tertiary carbenium ion 29 gives the allylic ion 30 , which then yields the aromatic tropylium salt 19 by carbon monoxide extrusion in a linear cheletropic reaction. The smooth conversion with strong acids of the easily accessible tricyclic compounds of type 2 to the corresponding polymethylated tropylium salts, presents a new and useful method for the synthesis of the latter compounds.     

Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors

We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound.