Organometallic cross-coupling reactions

Reactions that form carbon–carbon bonds are of supreme importance in synthetic chemistry. Palladium catalyzed cross-coupling reactions have become a significant part of drug discovery. Heck, Suzuki, and Stille coupling reactions are easily performed with microwave synthesis instrumentation. It was first suggested that microwave irradiation could enhance Suzuki and Stille cross-coupling reactions in June 1988 by Mills and co-workers at Glaxo in London, England.184,185 Wali et al. performed the first Heck reaction in a multi-mode cavity in 1995.186 He reacted iodobenzene with 1-decene (Scheme 33) and was able to get a complete reaction in approximately ten minutes compared to 14 hours with conventional methods.

Scheme 33

The second microwave work in palladium chemistry was done by Villemin and co-workers in France and presented in 1995 at a conference in Spain.187 His palladium catalyzed Heck reaction (Scheme 34) was the first reported work in a single-mode cavity. Like Wali, his work yielded results in about 10 minutes, using only 140 W of power.

Scheme 34

More recently, Larhed and Hallberg, from the University of Upsalla in Sweden, have also explored palladium-coupling Heck reactions (Scheme 35), as well as Suzuki (Scheme 36) and Stille couplings (Scheme 37).188,189 Their work, which has been quite extensive, again shows the major advantages in using microwave energy — rapid reaction times and increased yields.13,188-201

Scheme 35

Scheme 36

Scheme 37

Other research groups have been working in the areas of heteroaromatic synthesis and aqueous or solvent-free conditions via transition metal cross-coupling reactions.99,117,202-207 Villemin and co-workers have executed Suzuki reactions in both water and solvent free conditions (Scheme 38).206,207 Alternatively, Combs et al. have performed Suzuki-like reactions using a copper catalyst (Scheme 39).204

Scheme 38

Scheme 39

Another area that has been recently explored is microwave-assisted Negishi cross-coupling reactions. The majority of the reactions discussed previously utilize aryl triflates, bromides, and iodides. Aryl and vinyl chlorides, unfortunately, have been quite unsuccessful in coupling reactions. The carbon–chlorine bond has a much larger bond dissociation energy than the others, which makes it harder to break. The Negishi cross-coupling reaction employs organozinc reagents, and it is a powerful solution to this dilemma. It opens up the use of an entire family of chlorides that are inexpensive and commercially available. With conventional heating, the Negishi reaction can require hours of heating for completion. Scheme 40 shows a reaction with an aryl bromide, which was complete in one minute and in a 90% yield.208 The ease of cross-coupling between aryl chloride derivatives and organozinc halides is exhibited in Scheme 41.18

Scheme 40

Scheme 41

Instruments

Discover 2.0

Microwave Synthesizer

13. Larhed, M.; Hallberg, A. “Microwave-assisted high-speed chemistry: a new technique in drug discovery.” Drug Discovery Today 2001, 6, pp. 406-16.

18. a) Internal Communication, CEM Corporation, Matthews, NC. b) This reaction was performed on a CEM Discover System. This microwave system is equipped with “hot keys”, which allow the user to change parameter values “on-the-fly”. One of these hot keys is for simultaneous controlled cooling. Once the reaction has reached its programmed temperature, the cooling option can be turned on with the hot key. This will ensure a constant, high power level. Use of the power hot key can then allow the user to increase the power level in small increments in order to maximize the amount of microwave energy being delivered to the reaction.

99. Kabalka, G.W.; Pagni, R.M.; Wang, L.; Namboodiri, V. “Microwave-assisted, solventless Suzuki coupling reactions on palladium-doped alumina.” Green Chem. 2000, 2, pp. 120-22 and Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5) 2001, E0029 (www.mdpi.net).

117. Wang, C.; Li, G.S.; Li, J.C.; Feng, S.; Li, X.L. “Synthesis of 5-alkylene barbituric acid in solventless system under microwave irradiation.” Chin. J. Org. Chem. 2001, 21, pp. 310-12.

184. Mills, K.; United States Patent No. 4933461, “Preparation of a piperidinylcyclopentylheptenoic acid derivative.” 1990.

185. Collington, E.W.; Finch, H.; Hayes, R.; Mills, K.; Woodings, D.F.; United States Patent No. 5039673, “Aminocyclopentyl ethers and their preparation and pharmaceutical formulation.” 1991.

186. a) Wali, A.; Pillai, S.M.; Satish, S. “Heterogeneous Pd catalysts and microwave irradiation in Heck arylation.” Research Centre, Indian Petrochemicals Corporation Ltd. 1995, IPCL Communication No. 294. b) Wali, A.; Pillai, S.M.; Satish, S. “Heterogeneous Pd catalysts and microwave irradiation in Heck arylation.” React. Kinet. Catal. Lett. 1997, I, pp. 189-94 [Received on October 17, 1995].

187. Villemin, D.; Jaffres, P.A.; Nechab B., ENSI de Caen, ISMRA, Caen, France, presented at the University of Saragosse, Spain, 1995.

188. Larhed, M.; Hallberg, A. “Microwave-promoted palladium-catalyzed coupling reactions.” J. Org. Chem. 1996, 61, pp. 9582-84.

189. Larhed, M.; Lindeberg, G.; Hallberg, A. “Rapid microwave-assisted Suzuki coupling on solid-phase.” Tetrahedron Lett. 1996, 37, pp. 8219-22.

190. Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D.P.; Hallberg, A. “Rapid fluourous Stille coupling reactions conducted under microwave irradiation.” J. Org. Chem. 1997, 62, pp. 5583-87.

191. Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. “Rapid microwave-induced palladium-catalyzed asymmetric allylic alkylation.” J. Org. Chem. 1999, 64, pp. 1082-83.

192. Olofsson, K.; Kim, S.Y.; Larhed, M.; Curran, D.P.; Hallberg, A. “High-speed, highly fluorous organic reactions.” J. Org. Chem. 1999, 64, pp. 4539-41.

193. Kaiser, N.F.K.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. “Microwave-mediated palladium-catalyzed asymmetric allylic alkylation; an example of highly selective fast chemistry.” J. Organomet. Chem. 2000, 603, pp. 2-5.

194. Bremberg, U.; Lutsenko, S.; Kaiser, N.F.; Larhed, M.; Hallberg, A.; Mobert, C. “Rapid and stereoselective C-C, C-O, C-N and C-S couplings via microwave accelerated palladium-catalyzed allylic substitutions.” Synthesis 2000, 7, pp. 1004-08.

195. Kaiser, N.F.K.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. “Fast, convenient, and efficient molybdenum-catalyzed asymmetric allylic alkylation under non-inert conditions: an example of microwave-promoted fast chemistry.” Angew. Chem., Int. Ed. Eng. 2000, 39, pp. 3596-98.

196. Vallin, K.S.A.; Larhed, M.; Johansson, K.; Hallberg, A. “Highly selective palladium-catalyzed synthesis of protected α,β-unsaturated methyl ketones and 2-alkoxy-1,3-butadienes. High-speed chemistry by microwave flash heating.” J. Org. Chem. 2000, 65, pp. 4537-42.

197. Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. “Regioselective palladium-catalyzed synthesis of β-arylated primary allylamine equivalents by an efficient Pd-N coordination.” J. Org. Chem. 2001, 66, pp. 544-49.

198. Vallin, K.S.A.; Larhed, M.; Hallberg, A. “Aqueous DMF-potassium carbonate as a substitute for thallium and silver additives in the palladium-catalyzed conversion of aryl bromides to acetyl arenes.” J. Org. Chem. 2001, 66, pp. 4340-43.

199. Garg, N.; Larhed, M.; Hallberg, A. “Heck arylation of 1,2-cyclohexanedione and 2-ethoxy-2-cyclohexenone.” J. Org. Chem. 1998, 63, pp. 4158-62.

200. Olofsson, K.; Larhed, M.; Hallberg, A. “Highly regioselective palladium-catalyzed internal arylation of allyltrimethylsilane with aryl triflates.” J. Org. Chem. 1998, 63, pp. 5076-79.

201. Moberg, C.; Bremberg, U.; Hallman, K.; Svensson, M.; Norrby, P.O.; Hallberg, A.; Larhed, M.; Csoregh, I. “Selectivity and reactivity in asymmetric allylic alkylation.” Pure Appl. Chem. 1999, 71, pp. 1477-83.

202. Qabaja, G.; Jones, G.B. “An intramolecular arylation route to the kinafluorenones.” Tetrahedron Lett. 2000, 41, pp. 5317-20.

203. Diaz-Ortiz, A.; Prieto, P.; Vazquez, E. “Heck reactions under microwave irradiation in solvent-free conditions.” Synlett. 1997, pp. 269-70.

204. Combs, A.P.; Saubern, S.; Rafalski, M.; Lam, P.Y.S. “Solid supported aryl/heteroaryl C-N cross-coupling reactions.” Tetrahedron Lett. 1999, 40, pp. 1623-26.

205. Blettner, C.G.; Konig, W.A.; Stenzel, W.; Schotten, T. “Microwave-assisted aqueous Suzuki cross-coupling reactions.” J. Org. Chem. 1999, 64, pp. 3885-90.

206. Villemin, D.; Gomez-Escalonilla, M.J.; Saint-Clair, J.F. “Palladium-catalysed phenylation of heteroaromatics in water or methylformamide under microwave irradiation.” Tetrahedron Lett. 2001, 42, pp. 635-37.

207. Villemin, D.; Caillot, F. “Microwave mediated palladium-catalysed reactions on potassium fluoride/alumina without use of solvent.” Tetrahedron Lett. 2001, 42, pp. 639-42.

208. Ohberg, L.; Westman, J. “One-pot three-step solution phase syntheses of thiohydantoins using microwave heating.” Synlett. 2001, 12, pp. 1893-96.