Synthesis of 4,5,6-trichloropyrimidine-2-carbonitrile from 4,6-dichloro-2-(methylthio)pyrimidine

A route to 4,5,6-trichloropyrimidine-2-carbonitrile was developed starting from 4,6-dichloro-2-(methylthio)- pyrimidine. The latter was converted to 4,6-bis(benzyloxy)-5-chloropyrimidine-2-carbonitrile in four steps giving an overall yield of 67%. The steps involved nucleophilic displacement of the 4,6-chlorides by benzyloxide, followed by oxidation of the sulfide group to sulfone, its displacement by cyanide and chlorination at the pyrimidine C5 position with NCS. 4,6-Bis(benzyloxy)-5-chloropyrimidine-2-carbonitrile was finally converted into 4,5,6-trichloropyrimidine-2-carbonitrile in a moderate (30%) yield in a two-step procedure.


AUTHOR(S)
chlorine-substituted C4/6 carbons, as well as via modification of the C2 nitrile group.However, the chemistry of the trichloropyrimidine 1 has remained unexplored due to its low yielding synthesis.To date, the known chemistry of trichloropyrimidine 1 is limited only to the nucleophilic displacement of the C4 chloride by DABCO to give piperazine 5, 8 and its involvement in the formation of the fused thiazole 6 from the degradation of tetrachlorothiadiazine 3 (Scheme 2). 9Scheme 2. Reactions of 4,5,6-trichloropyrimidine-2-carbonitrile (1) and structure of 2,4,6-trichloropyrimidine-5-carbonitrile (7).
Directly comparable is the isomeric 2,4,6-trichloropyrimidine-5-carbonitrile (7) (Scheme 2), which was prepared as far back as 1964, 10 and has since been extensively used as a precursor to dyes, 10 herbicides, 11 antithrombotics, 12 and inhibitors of phosphoinositide 3-kinases (PI3Ks). 13o investigate the chemistry of trichloropyrimidine-2-carbonitrile (1) further, we required access to larger quantities, and pursued various independent syntheses.An alternative route to pyrimidine 1 to the ones described above started from the dichloropyrimidine 8 that was easily prepared from thiobarbituric acid. 14ichloropyrimidine 8 was converted into the dimethoxypyrimidine 9 by nucleophilic displacement by methoxide (Scheme 3).Subsequently, oxidation of the thioether group and substitution by cyanide gave pyrimidine 11.The latter was chlorinated at the C5 position using NCS to give chloropyrimidine 12, but the subsequent hydrolysis of the methyl ethers failed, thereby halting the synthesis of trichloropyrimidine 1. 15 In light of the hurdles encountered during the above synthesis we chose the more labile benzyl ether protecting group that could be more readily deprotected to afford the dihydroxypyrimidine 13.Herein, we report a successful synthesis of pyrimidine 1 starting from 8 in an overall yield of 20%.

Results and Discussion
Our independent synthesis began from the known 4,6-dichloro-2-(methylthio)pyrimidine (8) that was prepared in two steps and 92% overall yield from thiobarbituric acid. 14Thiobarbituric acid is a valid starting material for this route due to its good availability, low cost and the high yield of its transformation to dichloropyrimidine 8. 15 The displacement of the C4 and C6 chlorides by benzyloxy groups proceeded smoothly to give dibenzyloxypyrimidine 14 in 86% yield (Scheme 4).While dibenzyloxypyrimidine 14 has already been reported in the literature starting from 2,4,6-trichloropyrimidine, 16 this new synthesis provides an alternative route from more readily available thiobarbituric acid.The chlorination of cyanopyrimidine 16 occurred upon treatment with NCS (3 equiv) in AcOH, at ca. 118 °C, to give 5-chloropyrimidine 17 in an excellent (95%) yield (Scheme 6).With 5-chloropyrimidine 17 in hand, we then investigated the deprotection of its benzyl ethers.Initially, we attempted the deprotection by hydrogenation using H 2 (2.6 bar), Pd/C (10 mol%), in MeOH/THF (2:1) in a Parr shaker, which led to complete consumption of the starting material after 2 h and isolation of an intractable baseline the identity of which could not be resolved by NMR or IR spectroscopy, which showed the absence of a ν(C≡N) stretching frequency.Weak or absent ν(C≡N) stretching frequencies can be an inherent feature of the compound structure, and their absence cannot be used to definitively aid a structure determination. 17A milder reductive approach was also attempted using HCO 2 NH 4 (6 equiv), Pd/C (10 mol%) as the reductant, in MeOH, at 65 °C, that led to a consumption of the starting material after 48 h and isolation of a complex mixture of products. 18he use of TMSI in MeCN, at ca. 82 °C also degraded the starting material, tentatively to acyclic sideproducts. 19Two oxidative debenzylation methods were also attempted, the first one using KMnO 4 (10 equiv), FeCl 3 (6 equiv), in acetone, at ca. 20 °C, 20 and the second using CrO 3 (4 equiv), in AcOH, at 20-80 °C. 21nfortunately, both methods failed, with the first giving only recovered starting material after 24 h, while the second gave a complex mixture of products.
Nevertheless, two following deprotection methods gave limited success.Refluxing a neat TFA solution of pyrimidine 17 led to a consumption of the starting material after 2 h, but gave a complex mixture of products that could not be purified by column chromatography (product was unstable 2D-TLC) or recrystallization.A similar result was observed with BBr 3 (4 equiv), in DCM, at ca. -5 °C which led to a consumption of the starting material after 10 min.NMR studies of the crude mixtures obtained from the above reactions tentatively revealed the presence of crude dihydroxypyrimidine 13.Therefore we attempted to telescope the last two steps of the conversion, and treated the crude product from each debenzylation with PCl 5 (10 equiv) in POCl 3 , at 106 °C, for 2 h (Scheme 6).This approach successfully gave the trichloropyrimidine 1, although in low yields (19 and 30%, respectively).Scheme 6. Preparation of the trichloropyrimidinecarbonitrile 1.

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Although this study has only yielded a small overall yield of the desired trichloropyrimidine 1, it has provided access to three new polyfunctionalized pyrimidines that can be of use in the further investigation of the chemistry and properties of pyrimidines.Efforts to improve the overall yield of the trichloropyrimidine 1 remain in progress.

Experimental Section
General.All chemicals were commercially available except those whose synthesis is described.Anhydrous Na 2 SO 4 was used for drying organic extracts and all volatiles were removed under reduced pressure.Acetonitrile (MeCN), tetrahydrofuran (THF) and dichloromethane (DCM) were distilled over CaH 2 before use.Reactions were protected from moisture with CaCl 2 tubes or an Ar atmosphere.All reaction mixtures and column eluents were monitored by TLC using commercial glass backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F 254 ).The plates were observed under UV light at 254 and 365 nm.The technique of dry flash chromatography was used throughout for all non-TLC scale chromatographic separations using Merck Silica Gel 60 (less than 0.063 mm). 22Melting points were determined using a PolyTherm-A, Wagner & Munz, Koefler -Hotstage Microscope apparatus.Solvents used for recrystallization are indicated after the melting point.UV spectra were obtained using a Perkin-Elmer Lambda-25 UV/vis spectrophotometer and inflections are identified by the abbreviation "inf".IR spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with Pike Miracle Ge ATR accessory and strong, medium and weak peaks are represented by s, m and w, respectively. 1H and 13 C NMR spectra were recorded on a Bruker Avance 300 (at 300 and 75 MHz, respectively), or a 500 machine (at 500 and 125 MHz, respectively).Deuterated solvents were used for homonuclear lock and the signals are referenced to the deuterated solvent peaks.APT NMR studies were used for the assignment of the 13 C peaks as CH 3 , CH 2 , CH, and Cq (quaternary).APCI + mass spectra were recorded on a Model 6110 Quadrupole MSD, Agilent Technologies.The elemental analysis was run by the London Metropolitan University Elemental Analysis Service.4,6-Dichloro-2-(methylthio)pyrimidine (8) was prepared according to literature procedure. 14