Lithiation and Substitution of N′-(ω-Phenylalkyl)-N,N-dimethylureas

Abstract

Lithiation of N′-phenethyl-N,N-dimethylurea with three equivalents of tert-butyllithium in anhydrous tetrahydrofuran at -78°C takes place on the nitrogen and on the side-chain of the CH 2 next to the phenyl ring (α-lithiation). The 2-lithio isomer can be obtained via bromine-lithium exchange of N′-2-(2-bromophenyl)ethyl-N,N-dimethylurea using methyllithium followed by tertbutyllithium in tetrahydrofuran at -78°C. The lithium reagents thus obtained react with various electrophiles to give the corresponding substituted derivatives in excellent yields. Lithiation of N′-(3-phenylpropyl)-N,N-dimethylurea takes place on the α-CH 2 with tert-butyllithium at 0 °C. On the other hand, lithiation of N′-(4-phenylbutyl)-N,N-dimethylurea with tert-butyllithium at 0 °C takes place on one of the methyl groups of the urea unit.Key words: N′-phenethyl-N,N-dimethylurea, side-chain lithiation, bromine-lithium exchange, electrophile, synthesis Many aromatic compounds undergo lithiation ortho to a functional group, [2][3][4] and the organolithium reagents in such reactions are useful intermediates for the synthesis of ortho-disubstituted aromatics. Moreover, ortho-lithiation has been applied to various heterocycles to produce the corresponding substituted derivatives. 6For example, we have developed several efficient lithiation procedures for preparation of various substituted aromatics and heteroaromatics that might be difficult to prepare by other means. 7As part of such studies we have successfully lithiated and substituted various N-(substituted benzyl)pivalamides and N′-(substituted benzyl)-N,Ndimethylureas selectively using n-butyllithium or tert-butyllithium in tetrahydrofuran. [8][9][10] Such processes have been applied for the production of substituted isoindoline and isoquinoline derivatives. 11-13As part of such studies we became interested in directed lithiation of N′-phenethyl-N,N-dimethylureas. Lithiation of N-phenethylpivalamide derivatives have been reported by Schlosser. 14,15 For example, lithiation of N-phenethylpivalamide itself took place on the side chain (α-lithiation) with three equivalents of tert-butyllithium in tetrahydrofuran at -75 °C. Reaction of the dilithium reagent thus obtained with carbon dioxide, the only electrophile tried, gave the corresponding acid in 72% yield. 14 However, there are no reports of lithiation and substitution of N′-phenethyl-N,N-dimethylureas, and pivalamide and dimethylurea derivatives do not always behave in an identical manner towards lithiation 9 and the urea derivatives are more generally useful for synthesis.We now report the successful lithiation and substitution of N′-phenethyl-N,N-dimethylureas using a simple, general and efficient α-lithiation procedure using tert-butyllithium. We also report a procedure for ring-substitution by Br-Li exchange with methyllithium followed by tert-butyllithium in tetrahydrofuran at -78°C.The first tasks were to synthesise N′-phenethyl-N,N-dimethylurea (2) 16 and to try to find conditions under which its lithiation could ...

Crystal structure of 1,1-dimethyl-3-(4-methylphenyl)urea, C10H14N2O

“…Many convenient processes have been reported for the production of substituted ureas [6][7][8][9][10][11]. Aromatic ureas can be substituted efficiently via lithiation chemistry [12][13][14][15][16].…”

Crystal structure of 1,1-dimethyl-3-(4-methoxyphenyl)urea, C10H14N2O2

“…Various efficient procedures for the synthesis of aromatic ureas are known [6][7][8][9][10][11]. Aromatic ureas can be easily modified via treatment with lithium reagents followed by reactions with electrophiles, a methodology we have used in the last few years [12][13][14][15][16]. The asymmetric unit contains one molecule of C 10 H14N 2 O 2 .…”

Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives

“…We now report that lithiation can be controlled to give either ring or side-chain substitution, depending on the protocol used. 3-Substituted pyridines 4-6 were synthesized, based on a literature procedure for analogous compounds, 9,10 ride, di-tert-butyl dicarbonate or dimethylcarbamoyl chloride, respectively (Scheme 2). Initially, N-(pyridin-3-ylmethyl)pivalamide (4) was treated with n-butyllithium (2.2 equiv) in anhydrous tetrahydrofuran at -78°C for two hours to form first the monolithium compound 7 (Scheme 3) and then perhaps one or more dilithium species.…”

“…[3][4][5] In our own studies 6 we have investigated selective lithiation of various benzyl-and phenylethylamine derivatives and shown that the site of lithiation depends on any substituent groups, the nature of the lithium reagent, and the reaction conditions. [7][8][9][10][11][12] We have applied such processes in the preparation of substituted heterocycles. [13][14][15] Heterocyclic compounds are of great importance since they represent the core unit of numerous important products.…”