Lateral lithiation and substitution of N' -(2-methylphenyl)- N,N -dimethylurea

Lithiation of N' -(2-methylphenyl)- N , N -dimethylurea with three molar equivalents of tert -butyl- lithium at  40 to  30  C takes place on the nitrogen and on the methyl group at position 2 of the phenyl group. The lithium intermediate thus obtained reacts with a variety of electrophiles to give the corresponding side-chain substituted derivatives in high yields


Introduction
Lateral lithiation, followed by reactions with electrophiles, provides a convenient route for the production of substituted aromatics and heterocycles.Such lateral lithiation requires a group that stabilizes an organolithium either by coordination or by delocalizing a negative charge. 1,2 Various heteroatom-based stabilizing groups, located at an ortho-position, have been used successfully for lateral lithiations. 3-16 In the course of our own studies of lithiation reactions 17 we have synthesized various substituted aromatics and heterocycles via efficient lateral lithiation procedures. 18-22For example, we have successfully laterally lithiated and substituted N'-(2-methylbenzyl)-N,N-dimethylurea (1) with tert-butyllithium (t-BuLi; 2.2 equiv.) at 78 C in tetrahydrofuran (THF) to produce the corresponding substituted derivatives 2 in high yields (Scheme 1). 21   . 21  Recently, we have shown that lithiation of N'- (2-(2-methylphenyl)ethyl)-N,N-dimethylurea (3) with n-butyllithium (n-BuLi; 3.0 equiv.) at 0 C in THF, rather than taking place on the methyl group, takes place on the CH 2 next to the 2-methylphenyl ring (α-lithiation), giving substituted derivatives 4 in excellent yields following in-situ reaction with electrophiles (Scheme 2). 22    22   There are no previous reports of lithiation and substitution of N'-(2-methylphenyl)-N,Ndimethylurea.We now report that lithiation of this compound takes place on the methyl group at position 2 to provide substituted derivatives that might have pharmacological activities and would be difficult to prepare by other means.

Results and Discussion
N'-(2-Methylphenyl)-N,N-dimethylurea (6) was synthesized in 99% yield after crystallization, based on a literature procedure for analogous compounds, 21,22 from reaction of 2-toluidine (5) with dimethylcarbamoyl chloride (DMCC) under reflux for 2 h in dichloromethane (DCM) in the presence of triethylamine (TEA) (Scheme 3).The spectroscopic data for 6 were consistent with those reported for the product of reaction of 2-tolyl isocyanate with dimethylamine hydrochloride. 23  DMCC, DCM TEA, reflux, 2 h Initially the reaction of 6 with n-BuLi (2.5 equiv.) was carried out in anhydrous THF at -78 C under a nitrogen atmosphere.Initial addition of n-BuLi provided a pale yellow solution, presumably because of formation of the monolithium reagent 7 (Scheme 4), until approximately one equivalent had been added, then gave a deep yellow solution as the remaining n-BuLi was added, presumably because of formation of a dilithium reagent.The mixture was stirred at -78 °C for 2 h.Benzophenone (1.2 equiv.) was added, the mixture was stirred for another 2 h at -78 C and the reaction was then quenched by the addition of aqueous ammonium chloride (NH 4 Cl) solution.The 1 H NMR spectrum of the product mixture showed that N'-(2-(2-hydroxy-2,2diphenylethyl)phenyl)-N,N-dimethylurea (9) was produced, but in only ca.7% yield (Table 1; Entry 1), along with residual 6 (ca.90%).This implied that the expected laterally lithiated reagent 8 was produced in-situ (Scheme 4), although in low yield.Use of t-BuLi as the lithiating agent under similar reaction conditions provided no product and only starting material 6 was quantitatively recovered (Table 1; Entry 2).Raising the temperature of lithiation to -20 C improved the yield of product 9 to 17% (n-BuLi) and 31% (t-BuLi), respectively (Table 1; Entries 3 and 4), although there was still much residual 6.However, the NMR spectra of the product mixtures showed the presence of traces of a side-product.Raising the temperature of lithiation to 0 C failed to provide any of the substituted product 9 (Table 1; Entries 5 and 6), but the side-product became significant, so it was purified by column chromatography (silica; EtOAc) and then identified as 10 (16% yield with n-BuLi and 39% with t-BuLi).Production of 10 involves incorporation of two additional carbon atoms and Clayden has shown that conditions similar to those used in these reactions result in significant formation of acetaldehyde enolate by organolithium-induced decomposition of THF. 24Assuming the enolate to be the source of the additional carbon atoms, the mechanism shown in Scheme 5 is suggested for the formation of 10, while recognizing that the intermediate organolithium species might be in equilibrium with other tautomeric forms or with species having different levels of lithiation.

Entry
RLi (mol equiv)  In order to avoid formation of the side product and to maximize the yield of 9 further reactions were conducted with t-BuLi at lower temperature.The results indicated that the highest yield of 9 was obtained by use of t-BuLi (3.3 equiv.) in the presence of tetramethylethylenediamine (TMEDA; 1.1 equiv.) at -40 to -30 C (Table 1; Entry 8), which gave 9 in 93% yield after crystallization, while use of t-BuLi without TMEDA under similar conditions produced 9 in 51% yield along with unreacted 6 (Table 1; Entry 7).
Production of 9 in high yield implied that dilithium intermediate 8 had been formed efficiently.It was therefore interesting to see if reactions of 8 with other electrophiles would be useful, making the reaction general.Therefore, reactions of 8, prepared in-situ from compound 6, with other electrophiles (cyclohexanone, acetophenone, 2-butanone, benzaldehyde and iodomethane) were carried out.Each reaction was conducted under identical conditions and then quenched by the addition of aqueous NH 4 Cl.Afterwards, the crude products were crystallized (Et 2 O-hexane, 1:2 by volume) to give the corresponding substituted derivatives 1115 (Scheme 6) in high yields (Table 2).As can be seen from Table 2, the process is successful with various electrophiles.The 1 H NMR spectra of compounds 1214 showed that the signals of the two protons of the CH 2 group appeared separately, verifying that they are diastereotopic.

Conclusions
A simple, efficient and general procedure that allows lateral lithiation and substitution of N'-(2methylphenyl)-N,N-dimethylurea has been demonstrated to provide high yields of various derivatives substituted on the 2-methyl group.

8 Scheme 5 .
Scheme 5. A possible mechanism for formation of 10.