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

A 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.

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 amide-containing compounds, those found in conjunction with N-heterocycles exhibit diverse and marked pharmacological activities. In particular, the HIV-1 NNRTIs, dihydrofolate reductase (DHFR) inhibitors, and histone deacetylase (HDAC) inhibitors stand out. It is not surprising therefore that there are numerous papers in which amide bond formation has been described. 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 K2CO3, triethylamine or pyridine as the base. Another variant utilizes methylethylketone and CaCO3 while other references describe condensation promoted by triethylamine in acetic acid. Examples of aniline acylation in acetate buffer and aqueous K2CO3 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 or in a mixed solvent system. 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. 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. Surprisingly, there was no information in the literature for the preparation of 2-chloroacetanilides that utilized the silyl methodology. As a result, we have now employed this approach to synthesize a series of 2-chloroacetanilides, as shown in Scheme 1 , which were then used for the synthesis of the desired NNRTIs.

Scheme 1

Proposed pathway to 2-chloroacetanilides.

As shown in Scheme 1, the starting anilines were converted into N-trimethylsilyl derivatives by refluxing in excess HMDS to form the N-silylated intermediates, followed by treatment with chloroacetyl chloride in anhydrous 1,2-dichloroethane to produce target amides 1–5 in 82–98% yield (Table 1 ). Notably, this occurred without any of the tar-like by-products typically observed with these reactions.

Table 1

Physical properties of 2-chloroacetanilides

Compd	R	Rfa	Yield (%)	Mp (°C)
1	H	0.70	82	135–136.5
2	2-Me	0.60	86	111.5–113
3	4-Ме	0.67	87	163–165
4	3,4-Me2	0.71	97	110–112
5	3,5-Me2	0.73	98	143–145

Ethyl acetate/hexane 1:1.

The target 2-(1-benzyluracil-3-yl)-N-phenylacetamides 6–13 were then obtained in excellent to almost quantitative yields (78–96%, see Table 2 ) by alkylation of 1-benzyluracils 14 with the appropriate 2-chloroacetanilides 1–5 in the presence of a 1.5-fold molar excess of K2CO3 in DMF as shown in Scheme 2 .

Table 2

Physical properties of 2-(1-benzyluracil-3-yl)-N-phenylacetamides

Compd	R1	R	Rfa	Yield (%)	Mp (°C)
6	H	H	0.57	96	212–213
7	2,5-Me2	H	0.65	90	175–176.5
8	3,5-Ме2	H	0.61	84	248–250
9	4-tBu	Н	0.63	90	219–220
10	H	2-Me	0.48	84	201–202
11	H	4-Ме	0.59	83	221–222
12	H	3,4-Me2	0.56	78	222.5–224
13	H	3,5-Me2	0.64	87	214–215
15	—	—	0.71	90	197.5–198.5
16	—	—	0.78	96	125–127

Ethyl acetate/1,2-dichloroethane 1:1.

Scheme 2

Synthesis of target uracil derivatives.

In an analogous fashion, N-phenylacetamides 15 and 16 were synthesized starting with 1-benzylthymine and 1-(benzhydryl)uracil, respectively. It should be noted that all the compounds were obtained without suffering the intractable workups or side products the typical procedures have been associated with, thereby making this approach highly attractive to adaptation with other heterocyclic compounds.

Compounds 6–13, 15, and 16 were evaluated as inhibitors against a large set of DNA and RNA viruses. Disappointingly, none of them proved to be active against any of the strains tested including HIV-1, HIV-2, HSV-1, HSV-2, HCMV, VZV, Vaccinia virus, Para-influenza-3 virus, Reovirus-1, Sindbis virus, Vesicular stomatitis virus, Respiratory syncytial virus, Coxsackie virus B4 or Feline Corona Virus.20, 21

In summary, while the target NNRTIs synthesized proved inactive, a facile and high-yielding route to N-phenylacetamides was developed, which should prove useful for many synthetic applications employing heterocyclic amides.