Unsaturated Nitriles: Optimized Coupling of the Chloroprene Grignard Reagent 1 with ω-Bromonitriles Fraser F. Fleming* and Tao Jiang Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282 Received July 9, 1997 The Diels-Alder reaction is one of the most powerful reactions in organic synthesis. 2 Efficient access to Diels- Alder precursors has stimulated several expedient diene syntheses for both type I and type II Diels-Alder reactions. 3 A particularly efficient synthesis of dienes for type II 4 intramolecular Diels-Alder (IMDA) reactions 5 relies on coupling electrophiles with 1-methylene-2- propenylmagnesium chloride (2) 6 -the so-called chloro- prene Grignard reagent. 1 In connection with our interest in unsaturated nitriles, 7 we envisaged an efficient entry into type II IMDA precursors by coupling 2 with ω-bromonitriles 1 (eq 1). This coupling reaction is known to tolerate electrophiles containing ester and nitrile groups but has only once been used to assemble dienes containing these functionalities. 8 Our initial attempts to couple 1e (n ) 5) and 2 with Li 2 CuCl 4 were not encouraging. The coupling product 3e was obtained in low yield along with a significant amount of the elimination product, 6-heptenenitrile. We exam- ined several copper catalysts and found that Cu I Br gave the highest yield of 3e, although a considerable amount of 6-heptenenitrile was also obtained. Formation of 6-heptenenitrile requires a base that can conceptually arise by a reaction between the bromonitrile and the fine dispersion of magnesium metal that is present in the chloroprene Grignard solution. These magnesium par- ticulates are easily removed from the chloroprene Grig- nard solution by centrifuging 9 which provides a clear solution of 2 that cleanly couples with 1e in the presence of Cu I Br (71%, Table I). This optimized procedure is quite general, providing a range of unsaturated nitriles in good yield. The synthesis of 3a is particularly striking since the proximal nitrile group increases the likelihood of elimination, 10 and yet the yield of the unsaturated nitrile 3a is excellent (98%) on a 2-g scale! The reaction is noteworthy in affording good yields without competitive addition to the nitrile group and conceptually shortens routes to precursors for type II IMDA reactions. For example, hydrolysis 11 or reduction 12 of 3d would afford 4 13 and 5, 4a respectively, in two steps rather than the previously required six-step sequence. In conclusion, the coupling of 2 with ω-bromonitriles affords good yields of unsaturated nitriles that are not directly available by other chloroprene-based coupling procedures. 14 Experimental Section General experimental details can be found in ref 7b. 1 H NMR spectra were recorded at 300 MHz, while 13 C NMR spectra were recorded at 75 MHz. Solutions of 2 in THF were prepared using ZnI 2 as the initiator rather than ZnCl2 as described. 6 General Procedure. A THF solution of 2 (0.3-0.4 M, 1.1 equiv) was slowly added to a cold (0 °C) THF solution containing Cu I Br (10 mol %) and the bromonitrile (1.0 equiv). After the addition the solution was allowed to warm to room temperature and then stirred for a further 16 h. The resultant mixture was opened to the atmosphere, and saturated, aqueous NH 4Cl was added. Once the resultant solution became blue, the mixture was extracted with EtOAc and the combined extracts were dried and then concentrated. 4-Methylene-5-hexenenitrile (3a). The general procedure was employed with 54 mL of a THF solution of 2 (0.45 M, 24.3 mmol), Cu I Br (344 mg, 1.67 mmol), and 3-bromopropanenitrile (1) Shea, K. J.; Pham, P. Q. Tetrahedron Lett. 1983, 24, 1003. (2) Oppolzer, W. In Comprehensive Organic Synthesis; Fleming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 315-399. (3) Fringuelli, F.; Aldo Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley: New York, 1990. (4) For leading references, see: (a) Gwaltney, S. L., II; Sakata, S. T.; Shea, K. J. J. Org. Chem. 1996, 61, 7438. (b) Winkler, J. D.; Holland, J. M.; Peters, D. A. J. Org. Chem. 1996, 61, 9074. (c) Park, T. K.; Kim, I. J.; Danishefsky, S. J.; de Gala, S. Tetrahedron Lett. 1995, 36, 1019. (d) Rubenstein, S. M.; Williams, R. M. J. Org. Chem. 1995, 60, 7215. (e) Bonnert, R. V.; Jenkins, P. R. J. Chem. Soc., Perkin Trans. I 1989, 413. (5) (a) Roush, W. R. In Comprehensive Organic Synthesis; Fleming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 513-550. (b) Craig, D. Chem. Soc. Rev. 1987, 16, 187. (c) Fallis, A. G. Can. J. Chem. 1984, 62, 183. (6) Nunomoto, S.; Yamashita, Y. J. Org. Chem. 1979, 44, 4788. (7) (a) Fleming, F. F.; Pak, J. J. J. Org. Chem. 1995, 60, 4299. (b) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J. Org. Chem. 1997, 62, 1305. (c) Fleming, F. F.; Huang, A.; Sharief, V. A.; Pu, Y. J. Org. Chem. 1997, 62, 3036. (8) The reported yield for coupling 2 with 1b (n ) 2) is 45%; see: Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J. Org. Chem. 1983, 48, 1912. (9) Large volumes of 2 (g1 L) suitable for coupling are conveniently prepared by allowing the magnesium to settle out from a tall, thin container over a period of 3-4 days. The Grignard reagent is stable at room temperature for several weeks. 1 (10) Stirling, C. J. M. Acc. Chem. Res. 1979, 12, 198. (11) Balicki, R.; Kaczmarek, L. Synth. Commun. 1993, 23, 3149. (12) Barrett, A. G. M. In Comprehensive Organic Synthesis; Fleming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 251-254. (13) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc. 1993, 115, 2248. (14) 2-Lithio- and 2-(tri-n-butylstannyl)-1,3-butadiene are not di- rectly available from chloroprene but must be prepared via 2: Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. Chem. Soc. Jpn. 1985, 58, 1942. Table 1. Coupling of Chloroprene Grignard 2 with ω-Bromonitriles 1 entry bromonitrile series (n) unsaturated nitrile yield (%) 1 1a 1 3a 98 2 1b 2 3b 76 3 1c 3 3c 74 4 1d 4 3d 73 5 1e 5 3e 71 (1) 7890 J. Org. Chem. 1997, 62, 7890-7891 S0022-3263(97)01240-1 CCC: $14.00 © 1997 American Chemical Society