A highly facile approach to the synthesis of novel 2-(3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-N-phenylacetamides

Abstract

a b s t r a c tA series of heterocyclic compounds were designed as potential nonnucleoside HIV reverse transcriptase inhibitors. Although the compounds ultimately proved inactive against HIV, during the course of the synthesis, a new and highly facile method to realize N-phenylacetamides was developed. Notably, the new route avoids the intractable workups and byproducts previously reported procedures have been associated with, thereby making this approach highly attractive to adaptation with other heterocyclics.Ó 2012 Elsevier Ltd. All rights reserved.As a part of our ongoing efforts to synthesize aryl and heteroaromatic nonnucleoside HIV reverse transcriptase inhibitors (NNRTIs), we sought to construct a new series of N-3 phenylacetamides for use in alkylating various uracils. The amide unit is one of the most important and widely occurring functional groups; it is present in many natural products and is a key feature of many important drugs. Among the more notable examples of amidecontaining compounds, those found in conjunction with N-heterocycles exhibit diverse and marked pharmacological activities. In particular, the HIV-1 NNRTIs, 1 dihydrofolate reductase (DHFR) inhibitors, 2 and histone deacetylase (HDAC) inhibitors stand out. 3 It is not surprising therefore that there are numerous papers in which amide bond formation has been described. 4 Despite the plethora of available routes, most are plagued with problems, in particular, low yields and difficult workups. As a result, a new and more facile route was sought.A preliminary search of the literature revealed several known methods for the formation of 2-chloroacetanilides. The most commonly used methodology involves condensation of chloroacetyl chloride with various anilines in aprotic solvents (e.g. ether, dioxane, chloroform, dichloromethane, ethyl acetate, or DMF) in the presence of anhydrous K 2 CO 3 , 5 triethylamine 6 or pyridine 7 as the base. Another variant utilizes methylethylketone and CaCO 3 8 while other references describe condensation promoted by triethylamine in acetic acid. 9 Examples of aniline acylation in acetate buffer 10 and aqueous K 2 CO 3 11 are also known, while another approach proposes the synthesis of 2-chloroacetanilides in base-free conditions. In the latter case, the reaction takes place in nonpolar solvent 12 or in a mixed solvent system. 13 Although there are many options available, it is important to note that most of these methods suffer from numerous side reactions arising from either N-quaternization of the organic base or hydrolysis, which lead to low yields and tedious work-up procedures. It has however, been shown that amide bond formation could be achieved by the cleavage of the silicon-nitrogen bonds in TMS-protected alkylamines and anilines by acid halides. 14 The absence of a base renders the silyl method very attractive for the synthesis of 2-chloroacetanilides, as this serves to bypass the problems with side reactions such as quaternization and hydrolysis that are common with the aforementioned routes. Surpri...

Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication

“…Synthesis of the starting uracil derivatives 1 was described previously 20 . 2-Chloro- N -(4-phenoxyphenyl)acetamides and their analogues 2 were prepared according to earlier published method 21 . Methylation of Z263 to obtain Z431 was performed as described 22 .…”

Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

“…The ring closing reactions were performed by stirring 6a-i with chlorotrimethylsilane (TMS-Cl) in THF for 30 min, followed by the addition of LiHMDS, and subsequent heating to 100 °C in a microwave reactor, which afforded the desired qA analogues 3a-i in moderate to good yields across the series ( Table 2 ). Increasing the nucleophilicity of an amino group by in situ silylation has previously been reported 36 37 38 , and was found to be essential here, as reactions performed without pre-stirring with TMS-Cl gave either no reaction or complex mixtures. A significant by-product observed in many of these reactions was the N -disilylated starting material, which unlike the monosilylated intermediate is unreactive and proved to be remarkably resistant to hydrolysis.…”

2-(2,4-Dioxy-1,2,3,4-Tetrahydropyrimidin-1-yl)-N-(4-Phenoxyphenyl)-Acetamides as a Novel Class of Cytomegalovirus Replication Inhibitors

“…2-Chloro-N-(4-phenoxyphenyl)acetamide ( 1 ) was synthesized as described previously [ 10 ]. The uracil derivatives substituted at N1 ( 12 )–( 19 ) were obtained by condensation of equimolar amounts of 2,4-bis- (trimethylsilyloxy)-pyrimidine and arylmethylchloride/ bromide as described in [ 8 ].…”