A New Approach to 5-Functionalized 1,2-Dihydropyrimidin-2-ones/imines via Base-Induced Chloroform Elimination from 4-Trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones /imines †

: A novel four-step methodology for the synthesis of 5-acyl-and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones has been developed. The reaction of readily available N -[(1-acetoxy-2,2,2-trichloro)ethyl]-ureas with Na-enolates of 1,3-diketones, β -oxoesters, or α -arylsulfonylketones followed by heterocyclization–dehydration of the oxoalkylureas formed gave 5-acyl- or 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones. The latter, in the presence of strong bases, eliminates CHCl 3 to give the target compounds. The above methodology was also used in the synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines starting from N -[(1-acetoxy-2,2,2-trichloro)ethyl]- N ′ -guanidine.


Results and Discussion
In our previous experience, α-tosyl-substituted N-alkylureas proved very useful starting materials for the preparation of various 5-functionalized 1,2,3,4-tetrahydropyrimidin-2-ones by ureidoalkylation of α-functionalized ketones [37][38][39][40][41].However, the synthesis of tosyl derivative 3 bearing a trichloromethyl group failed (Scheme 2), while acetoxy derivatives 4 and 5 [42] were conveniently prepared by treatment of the readily available 2 [43] with Ac2O in pyridine and Ac2O in the presence of H2SO4, respectively.Based on the ability of the acetoxy group to serve as a good leaving group in various reactions of ureidoalkylation [44][45][46][47][48][49], we hypothesized that compounds 4 and 5 might also be used in the synthesis of compounds 7 under the conditions similar to those applicable for ureidoalkylation of α-substituted ketones with α-tosyl-substituted N-alkylureas [37][38][39][40][41]. Sodium enolates of 1,3-dicarbonyl compounds 6a,b and β-oxoesters 6c,d generated in situ by treating the corresponding CH-acids with an equivalent amount of NaH reacted with urea 4 for 2.7-4.3 h at room temperature to give the products of acetoxy group substitution, N-oxoalkylureas 7a-d, in 70-95% yield (Scheme 3, Table 1).Anhydrous MeCN was used as a solvent for preparation of compounds 7a,c-d; however, for compound 7b anhydrous THF was used because the solubility of the enolate of 6b in MeCN was very low and the resulting extremely dense suspension hampered the completion of reaction of NaH with 6b.
IR-, 1 H-, and 13 C-NMR spectra indicated that compounds 7a-f only existed in acyclic form both in solid state and in DMSO-d6 solution.Their cyclic isomers 8a-f (Scheme 3) were not detected by any spectroscopic methods.
Compounds 7c,d,f were formed as mixtures of two diastereomers (Table 1).The diastereoselectivity of the product formation depended on the structures of both reagents and was higher with 5 than with 4 (entry 3 vs.entry 8) and with 6d than with 6c (entry 3 vs.entry 4).The reaction time did not affect the ratio of diastereomers (entry 5 vs. entry 6).The use of a greater excess of a nucleophile slightly reduced the stereoselectivity (entry 5 vs. entry 4), which indicated that these reactions were controlled by both kinetic and thermodynamic factors.
Sodium enolates of ketones bearing the arylsulfonyl group at the α-position generated in situ by treating the corresponding CH-acids 9a-d with an equivalent amount of NaH reacted with ureas 4 and 5 (MeCN or THF, rt, 4-9 h) to give products of nucleophilic substitution of the acetoxy group, sulfones 10a-e, in a 76-90% yield (Scheme 4, Table 2).Reactions of 9a-d with 4 and 5 proceeded with high diastereoselectivity to give sulfones 10a-e in 70-94% diastereomeric excesses (Table 2).The polarity of the solvent had a slight effect on diastereoselectivity (Entry 1 vs. Entry 2; Entry 6 vs. Entry 7).N-Acyl-substituted urea 5 reacted with enolate of 9b with higher diastereoselectivity compared with urea 4 (Entry 3 vs.Entry 4).
Based on the values of vicinal couplings of protons in the NH-CH-CH moiety, we have concluded that the minor diastereomers of 10a-e in DMSO-d6 solution exist in a conformation with an anti-anti orientation of the named protons ( 3 JNH,CH = 10.1-10.8Hz, 3 JCH,CH = 8.8-9.0Hz), while the orientation of the protons for major diastereomers is anti for NH-CH and gauche for СH-CH moieties ( 3 JNH,CH = 9.5-9.6Hz, 3 JCH,CH = 1.5-1.8Hz).
In contrast to the smooth conversion of 7a into 12a in MeCN, refluxing 7a in EtOH, MeOH, or toluene in the presence of TsOH led to the formation of 12a plus the product of its deacetylation, pyrimidine 13 (entries 2-6).Presumably, 13 was obtained as a result of the acid-promoted deacylation of 7a followed by heterocyclization and dehydration of the intermediate formed.The data listed in Table 3 indicates that the formation of 13 was favored in more polar solvents (entry 4 vs. entry 6), at higher reaction temperature (entry 2 vs. entry 3), and in protic solvents (entry 1 vs. entry 5).The amount of catalyst had no appreciable effect on the ratio of 12a to 13 (entry 3 vs.entry 4 vs. entry 5).
Formation of compounds 14a,b from 10a,b proceeds via heterocyclization of intermediate hydroxypyrimidines 11a,b followed by dehydration.In case of N-acetylureas 10c-e, the first step is N-deacylation into corresponding ureas 10b,f,g followed by cyclization into hydroxypyrimidines 11b,f,g and fast dehydration into tetrahydropyrimidines 14b-d.The data presented in Table 4 shows that the result of the reaction depends on the structure of the starting compounds and reaction conditions.The rate of pyrimidine 14 formation increases with increasing reaction temperature (Entry 7 vs.Entry 8) and quantity of TsOH (Entry 3 vs.Entry 4; Entry 6 vs. Entry 7).N-deacylation of 10c-e proceeds much faster than subsequent transformation of obtained 10b,f,g into в 14b-d (Entry 2 vs. Entry 4; Entries 3, 6, and 7).Benzoyl-containing ureas 10a-c react significantly slower comparing with acetyl-containing ureas 10d,e (Entries 1, 2, and 4 vs.Entries 5 and 8).Apparently, cyclization of N-deacylated ureas 10a,b,f,g into the corresponding hydroxypyrimidines (11), which is affected by electrophilicity of carbonyl group and steric bulk of R 1 , is the rate-determining step of compounds 14a-d formation.Thus, under optimal conditions, reflux of 10a-e in BuOH in the presence of 2-4 equiv of TsOH led to the smooth formation of pyrimidines 14a-d in 63-93% yields.
Finally, aromatization of tetrahydropyrimidines 12a-d by NaH (1.2-1.25 equiv) in an aprotic solvent at room temperature led to formation of the corresponding 5-acyl-1,2-dihydropyrimidin-2-ones 15a-d in good yields (Scheme 7).The reaction proceeded best in THF (for 15a,c,d) and, for 15b, in DME while the more polar MeCN failed to give satisfactory yields even with a prolonged reaction time (24 h) and a greater excess of NaH (up to 1.5 equiv).
Analogously, treatment of tetrahydropyrimidines 14a-d with strong bases in aprotic solvents resulted in the formation of the corresponding 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 16a-d (Scheme 7).Target pyrimidines (16a-d) were obtained by the reaction of 14a-d (rt, MeCN, 1.2-3.3h) with NaH (1.1 equiv) in 80-98% yields.The rate of elimination decreased with a decrease in the base strength.When compound 14d was treated with DBU (2.1 equiv) in MeCN, aromatization was completed in five days and led to the formation of 16d in 96% yield.Reaction of 14с with sodium malonate in MeCN did not proceed at rt and was complete only after reflux for 1 h, resulting in 16c in 85% yield.Compound 14d being treated with NaH (1.1 equiv) in THF (rt, 2 h) gave compound 16d in 90% yield.

Table 1 . Reaction of ureas 4 and 5 with sodium enolates of 6a-d a . Entry Starting Material Solvent Reaction Time, h Molar Ratio (4/6 or 5/6) Product Diastereomeric Ratio b
a At room temperature.b Established by 1 H NMR data of crude product.c All yields refer to isolated material homogeneous spectroscopically and by thin-layer chromatography (TLC).

Table 2 .
Reaction of ureas 4 and 5 with sodium enolates of 9a-d at rt.
a Boiling in the presence of TsOH.b Based on 1 H NMR spectrum of crude product.

Table 4 .
Transformation of 10a-e into 14a-d a .

Molar ratio of Products, 14:10 b
Reflux in alcohols in the presence of TsOH.b According to 1 H NMR data.