Mendeleev Communications Electronic Version, Issue 2, 2002 1 Alkylation of malonic and acetoacetic esters in an ionic liquid Galina V. Kryshtal, Galina M. Zhdankina and Sergei G. Zlotin* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: zlotin@ioc.ac.ru 10.1070/MC2002v012n02ABEH001563 1-Butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) has been used as a recyclable medium in the alkylation of malonic and acetoacetic esters with alkyl, benzyl and prenyl halides.The alkylation of malonic and acetoacetic esters is widely used for the synthesis of polyfunctional compounds.1(a)–(c) Classical alkylation procedures,1(a)–(c) alkylations in dipolar aprotic solvents2( a),(b) and under phase-transfer catalysis conditions3(a)–(f) are often complicated by using flammable organic solvents and difficulties in their regeneration, as well as in the regeneration of phase-transfer catalysts and in the isolation of reaction products.These problems can be solved by performing reactions in organic ionic liquids, which are of interest as an alternative to common organic solvents.4(a),(b) These melts, of which 1,3-dialkylimidazolium tetrafluoroborates and hexafluorophosphates containing poorly coordinating ion pairs have received most attention,5(a)–(c) are good solvents for both organic and inorganic compounds. They are moisture stable, not flammable and, what is very important, can be easily recovered and reused.4(a),(b) Due to the ionic nature, they can serve as polar solvents and phasetransfer catalysts simultaneously.Many applications of these melts in C–C coupling reactions, for instance, in the Friedel–Crafts,6 Diels–Alder,7(a)–(c) Wittig,8 Horner–Emmons,9 Knoevenagel10 and Heck11(a)–(c) have been reported. To the best of our knowledge, there is only one example of the C-alkylation of carbanions in ionic liquids, the base-promoted cycloalkylation of phenylacetonitrile with 1,4- dibromobutane in 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]).12 It is unclear whether the reaction can be used for the monoalkylation of phenylacetonitrile.12 There is no information on the base-promoted alkylation of ambident carbanions in ionic liquids; only Pd2(dba)3-catalysed C-allylation of dimethylmalonate with (E)-1,3-diphenyl-3-acetoxyprop- 1-ene was published.13 Here, we report the first example of the base-promoted alkylation of malonic 1 and acetoacetic 2 esters in an ionic liquid.We found that malonic ester 1 regioselectively reacts with alkyl, benzyl and prenyl halides 3a–f (1:3 ratio £ 1.5) in [bmim][PF6] in the presence of K2CO3 to afford monosubstituted malonates 4a–f in 53–80% yield.The reactions were carried out at 85–130 °C for 5–20 h (until starting compound 1 disappeared; TLC monitoring). Two substituents can be introduced into diethyl malonate 1 if an excess of an alkylating agent is used. Indeed, the reaction of 1 with 2.5 equiv. of benzyl chloride 3e under the same conditions afforded dibenzyl derivative 5 (yield 64%) as the only isolated product (Table 1).The K2CO3-promoted reactions of the ambident anion of acetoacetic ester 2, with 3a,d,e in [bmim][PF6] proceeded in a less selective manner to give, along with C-alkylation products 6a,d,e, vinyl ethers 7a,d,e. The ratio 6:7 varied from 88:12 to 60:40 depending on the alkylating agent. The fraction of O-alkylation products 7a,d,e in [bmim][PF6] was generally higher than those obtained under classical1(a),(b) and phase-transfer catalysis14,15 conditions (Table 2).This fact may be explained by a higher polarity of [bmim][PF6] than that of the most commonly used organic solvents16 and, consequently, by a higher likelihood of the SN1 mechanism of alkylation in the ionic liquid. Unlike 3e, more reactive benzyl bromide 3e' reacted with 2 in [bmim][PF6] under milder conditions to afford C-alkylation product 6e (yield 50%), which, according to 1H NMR spectra, was not contaminated with ether 7 (there are no vinyl protons in the d range 4.8–5.2 ppm).This difference in the behaviour of 3e and 3e' is not unexpected because less electrone-withdrawing leaving groups (particularly, Br compared to Cl) usually reduce the portion of O-alkylation.17(a),(b) The reaction of 2 with prenyl chloride 3f in [bmim][PF6] gave only C-alkylation product 6f, which was also obtained under classical1(a),(b) and phase-transfer catalysis14,15 conditions (Table 2).Tables 1 and 2 indicate that the yields of compounds 4–7 obtained in [bmim][PF6], as well as under the classical and phasetransfer catalysis conditions, are similar.Reactions in ionic liquids are preferable besause of the simplicity of product isolation and solvent regeneration.9,18 Compounds 4–7 can be isolated by evaporation at a reduced pressure (2 torr) from their solutions in the non-volatile ionic liquid.5(c) This procedure is technologically attractive but inconvenient in small-scale preparations (~10 mmol) owing to the irregularity of boiling of the reaction mixture.In laboratory conditions, it seems reasonable to use the extraction of alkylation products with diethyl ether (which is immiscible with [bmim][PF6]) followed by distillation. The ionic liquid was recovered by filtration from inorganic salts followed by the removal of volatile impurities at 40–60° (2 torr). In all cases, Table 1 K2CO3-Promoted alkylation of diethylmalonate in [bmim][PF6].Compound R Hal t/h T/°C Yield of 4a–f, 5 (%)a aYield of distilled compounds. b1:3:EtONa = 1:2:2.1(a) c1:3:NaOHaq:PTC = 1:1:2:1, CH2Cl2, 40 °C, 1 h.3(e),(f) d1:3:K2CO3:BTEA-Cl = 1:1.5:1.5:0.1, DMF, 50–65 °C, 6–9 h.2(b) e1:3:NaOHaq:BTEA-Cl = 1:1:2:0.1, 40–45 °C, 2 h.2(a) Reported yield of 4a–f, 5 (%) EtONa/EtOH (1:3:EtONa = 1:1:1) Phase-transfer catalysis (PTC) 4a Bu Br 12 85–90 80 80–901(a) 85c 4b Pri Br 20 85–90 54 65-801(a) 45c 4c cyclopentyl Br 15 120–130 57 701(a) 21d 4d Ami Br 15 110–120 70 801(a) 72d 4e PhCH2 Cl 5 120–130 72 51–571(b) 70e 4f (Me)2C=CHCH2 Cl 5 90–95 53 501(a) 46e 5 PhCH2 Cl 7 120–130 64 84b — RCH(COOEt)2 CH2(COOEt)2 (PhCH2)2C(COOEt)2 i ii Reagents: i, 1,5 equiv.RHal (3a–f), 2 equiv.K2CO3, 6 equiv. [bmim][PF6]; ii, 2.5 equiv. PhCH2Cl (3e), 2 equiv. K2CO3, 6 equiv. [bmim][PF6]. 4a–f 1 5Mendeleev Communications Electronic Version, Issue 2, 2002 2 we were able to recover 97–98% of the starting [bmim][PF6]. The recovered melt can be reused several times either in the same alkylation reaction (Table 3, items 2 and 3) or in the alkylation of another carbanion (Table 3, item 5) without a decrease in the yield and purity of compounds 4, 6, 7.† As a result, we have developed a recyclable procedure for the alkylation of malonic and acetoacetic esters, which is a good alternative to classical and phase-transfer catalysis methods.References 1 (a) A. C. Cope, H. L. Holmes and H. O. House, Organic Reactions, New York, 1957, vol. 9, p. 107; (b) H. Henecka, in Houben-Weyl, 1952, 8, 600; (c) S. Banetty, R. Romagnoli, C. De Risi, G. Spalluto and V. Zanirato, Chem. Rev., 1995, 95, 1065. 2 (a) A. Jonczyk, M. Ludwikow and M. Makosza, Rocz. Chem., 1973, 47, 89; (b) N. N. Sukhanov, L. N. Trappel, V. P. Chetverikov and L. A. Yanovskaya, Zh. Org. Khim., 1985, 21, 2503 [J. Org. Chem. USSR (Engl. Transl.), 1985, 21, 2341]. 3 (a) E. V. Dehmlow and S. S. Dehmlow, Phase-Transfer Catalysis, 3rd edn., Verlag Chemie, Weinheim, 1993; (b) C. M. Starks, C. L. Liotta and M. Halpern, Phase-Transfer Catalysis, Fundamentals, Applications and Industrial Perspectives, Chapman & Hall, London, 1994; (c) M. Makosza and M. Fedorynski, Adv. Catal., 1987, 35, 375; (d) M. Fedorynski, K. Wojciechowski, Z. Matacz and M.Makosza, J. Org. Chem., 1978, 43, 4682; (e) A. Brandstrom and U. Junggren, Acta Chem. Scand., 1969, 23, 2204; (f) A. Brandstrom and U. Junggren, Acta Chem. Scand., 1969, 23, 3585. 4 (a) M. J. Earle and K. R. Seddon, Pure Appl. Chem., 2000, 72, 1391, and references therein; (b) T. Welton, Chem. Rev., 1999, 99, 2071. 5 (a) P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. de Souza and J.Dupont, Polyhedron, 1996, 15, 1217; (b) S. Chun, S. V. Dzyuba and R. A. Bartsch, Anal. Chem., 2001, 73, 3737; (c) R. Hagiwara and Y. Ito, J. Fluorine Chem., 2000, 105, 221. 6 C. J. Adams, M. J. Earle, G. Roberts and K. R. Seddon, Chem. Commun., 1998, 2097, and references therein. 7 (a) C. W. Lee, Tetrahedron Lett., 1999, 40, 2461; (b) M. J. Earle, P. B. McCormac and K.R. Seddon, Green Chem., 1999, 1, 23; (c) T. Fisher, A. Sethi, T. Welton and J. Woolf, Tetrahedron Lett., 1999, 40, 793. 8 V. le Boulaire and R. Gree, Chem. Commun., 2000, 2195. 9 T. Kitazume and G. Tanaka, J. Fluorine Chem., 2000, 106, 211. 10 D. W. Morrison, D. C. Forbes and J. H. Davis, Tetrahedron Lett., 2001, 42, 6053. 11 (a) A. J. Carmichael, M. J. Earle, J. D. Holbrey, P. B.McCormac and K. R. Seddon, Org. Lett., 1999, 1, 997; (b) W. Chen, L. Xu, C. Chatterton and J. Xiao, Chem. Commun., 1999, 1247; (c) L. Xu, W. Chen, J. Ross and J. Xiao, Org. Lett., 2001, 3, 295. 12 C. Wheeler, K. N.West, C. L. Liotta and C. A. Eckert, Chem. Commun., 2001, 887. 13 S. Toma, B. Gotov, I. Kmentova and E. Solcaniova, Green Chem., 2000, 2, 149. 14 P. Tundo, P. Venturello and E.Angeletti, J. Chem. Soc., Perkin Trans. 1, 1987, 2159. 15 H. D. Durst and L. Liebeskind, J. Org. Chem., 1974, 39, 3271. 16 S. N. V. K. Aki, J. F. Brennecke and A. Samanta, Chem. Commun., 2001, 413. 17 (a) A. L. Kurts, N. K. Genkina, A. Macias, I. P. Beletskaya and O. A. Reutov, Tetrahedron, 1971, 54, 4777; (b) O. A. Reutov, I. P. Beletskaya and A. L. Kurts, Ambident Anions, Consultants Bureau, New York, 1983. 18 S. V. Dzyuba and R. A. Bartsch, J. Heterocycl. Chem., 2001, 38, 265. † General procedure. To a vigorously stirred solution of 1 or 2 (10 mmol) in [bmim][PF6] (60 mmol) prepared according to known method5(b) were added successively 3a–f (10–25 mmol) and K2CO3 (20 mmol). The reaction mixture was stirred for 5–20 h at 65–130 °C (reaction conditions are given in Tables 1 and 2), cooled to 20 °C and extracted with Et2O (4×20 ml).The combined ether extracts were dried over anhydrous MgSO4. The solvent was evaporated, and products 4–7 were distilled. Boiling points, n20 D and 1H NMR spectra of compounds 4–7 were in accordance with reported data. Reaction conditions were not optimised. The remaining ionic liquid was filtered from inorganic salts and kept at 40–60 °C (2 torr) for 2 h to afford 58.8 mmol (98%) of [bmim][PF6].The 1H NMR spectrum of thus recovered melt was identical to that of freshly prepared [bmim][PF6].5(b) Table 2 K2CO3-Promoted alkylation of acetoacetic ester in [bmim][PF6]. Compound R Hal t/h T/°C Yield of 6 + 7 (%)a (Ratio 6:7)b aYield of distilled compounds. b6:7 ratio was determied from 1H NMR spectra.c2:3:K2CO3:Carbowax 6000 = 1:1.5:2.5:0.05, GLC conditions.14 d2:3:NaH: Aliquat 336 = 2:1:2:0.1, PhH, 80 °C, 8 h.15 Reported yield of 6+7 (%) (Ratio 6:7) EtONa/EtOH (2:3:EtONa = 1:1:1) Phase-transfer catalysis 6a + 7a Bu Br 12 115–120 51 (88:12) 651(b) (>99:1) 52c (75:25) 6d + 7d Ami Br 12 115–120 75 (60:40) 701(a) (>99:1) — 6e + 7e PhCH2 Cl 12 120–125 52 (80:20) 551(b) (>99:1) 72d (>99:1) 6e PhCH2 Br 12 65–70 50 (>99:1) — — 6f (Me)2C=CHCH2 Cl 6 90–95 66 (>99:1) 471(a) (>99:1) 30d (>99:1) EtOOCCH2COMe EtOOCCHCOMe + EtOOCCH=C–Me i Reagents: i, 1–1.5 equiv. RHal (3a,d,e,e',f), 2 equiv. K2CO3, 6 equiv. [bmim][PF6]. R OR 2 6a, d,e,f 7a, d,e Table 3 K2CO3-Promoted alkylation of malonic and acetoacetic esters 1 and 2 in recovered [bmim][PF6]. Item no. Cycle no. Starting compound RHal Product Yield of 4a, 4d, 6d+7d (%) Recovered [bmim][PF6] (%) 1 1 1 BuBr 4a 80 98 2 2 1 BuBr 4a 78 98 3 3 1 BuBr 4a 79 97 4 1 1 AmiBr 4d 70 98 5 2 2 AmiBr 6d + 7d (60:40) 75 98 Received: 25th January 2002; Com. 02/1889