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J. CHEM. SOC. PERKIN TRANS. 1 1991 953 Perkin Communications A New Sequence for the C-Alkylation of 4,5-Dihydroirnidazoles Raymond C. F. Jones," Simon C. Hirst and Ian Turner Chemistry Department, Nottingham University, Nottingham NG7 2RD, UK The C-alkylation of 1-benzyl-2-(ethoxycarbonylmethylene) -2,3,4,5-tetrahydroimidazole with halogeno- and dihalogeno-alkanes is described; subsequent removal of the ethoxycarbonyl group provides a new route to 2-alkyl-4,5-dihydroimidazoles. 183-Dihalogenoalkanes afford imidazo-[1,2-a]pyridines. An important part of our studies of the 4,5-dihydroimidazole (2- imidazoline) heterocycle, a moiety that occurs in a number of pharmacologically active molecules and is involved in bio- logical C -transfers as N ',N 'o-methenyltetrahydrofolate,2is the generation of nucleophilic reactivity at the a-carbon atom as in l.3We have previously indicated the value of the readily available and crystalline enamino ester 2 3b as a C-nucleophile in conjugate additions and annul at ion^,^ and now report the use of 2 in alkylation reactions as a substitute for lateral metallation of 1-benzyl-2-methyl-4,5-dihydroimidazole3a.3a 1 2 CH2Ph 4 a; R' = (CH2)4Me, F? = H b;R' = (CH2)3Me,I$= H c; R' = Et, R2= H d; R' = CH2Ph,R2 = H e; R' = (CH2)30SiMe2Bu',dL = H f; R' = R2= Et g; R' = R2 = CH2Ph h; R', R2 = -(CHZ)4-i; R', R2= -(CH2)s 6 Initial studies exploited the enamine character of 2 that we had observed in conjugate addition^.^" Treatment of the enamino ester 2 in ethanol with 1-iodopentane (Et3N, 1 rnol equiv., reflux 18 h) gave the C-alkylated product 4a-f in only 24% yield with substantial recovery of starting material, along with polar material presumed to be quaternised compounds, whereas heating 2 with 1-iodobutane in dimethylformamide (1 10 OC, 24 h) gave the alkylated dihydroimidazole 4b in 67% yield.$ A more generally useful procedure, however, involved stoichiometric deprotonation of 2 with sodium hydride [1 rnol t All new compounds gave spectral data (IR, UV, NMR, MS) in accord with the assigned structure, and satisfactory combustion analysis or accurate mass measurement.$ Use of dimethyl sulphoxide at 130"C led to an inseparable mixture. T We thank Rachel Lloyd and Jeffrey W.Hobbs for this experiment. Table 1 Synthesis of C-alkylated 4,5-dihydroimidazoles 4 using the NaH-THF protocol" Alkyl halide (mol equiv.) Dihydroimidazole 4 (yield %) EtI (1) 4c (71) PhCH,Br (1) 4d (74)Bu'Me,SiO(CH,),Br (1) 4e (36) EtI (2.2) 4f (84) PhCH,Br (2.2) 4g (79)Br(CH,),Br (1) 4b(67) Br(CH,),Br (1) 4i (35) a Typical experimental directions (for 4c). Sodium hydride (60% dispersion in oil; 0.04 g, 1 mmol) was added to a stirred solution of the tetrahydroimidazole 2 (0.246 g, 1 mmol) in dry THF (5 cm3) at 0°C under nitrogen. The mixture was stirred at 0 OC for 30 min and then at 20 OC for 1 h; iodoethane (0.156 g, 1 mmol) was then added dropwise. The solution was stirred overnight and then poured into saturated aq. NaHCO, (20 cm') and extracted with dichloromethane (3 x 25 cm3).The combined organic phases were dried and evaporated under reduced pressure, and the residue was chromatographed on silica, eluting with ethyl acetate-hexane-triethylamine (15:4:1 v/v/v), to afford 4c as a colourless oil. equiv., tetrahydrofuran (THF), 0 "C] before addition of the alkylating agent (1 mol equiv.) and either heating at reflux for 4 h or stirring at 20°C overnight.' Using this method with iodoethane, benzyl bromide and 3-(rerr-butyldimethyIsilyloxy)-1-bromopropane, the alkylated dihydroimidazoles 4c-e were obtained (see Table 1). All of the C-monoalkylation products 4a-e were found to exist as the imine tautomer illustrated, rather than the enamine tautomer seen in 2,3b as indicated by an absorption at approx.1735 cm-' in the IR spectrum (M, unconjugated ester) and an a-proton resonance in the 'H NMR spectrum (typically 6 3.7).k Use of 2 rnol equiv. each of sodium hydride and of the halogenoalkanes iodoethane or benzyl bromide afforded the C-dia

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