Baylis-Hillman reaction

The Baylis-Hillman reaction is an organic reaction of an aldehyde and an α,β-unsaturated electron-withdrawing group catalyzed by DABCO (1,4-diazabicyclo [2.2.2] octane) to give an allylic alcohol [Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972.] . This reaction is also known as the Morita–Baylis–Hillman reaction or MBH reaction [K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn.,1968, 41, 2815.] . It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony B. Baylis and the German chemist Melville E. D. Hillman.

In addition to DABCO, additional nucleophilic amines such as DMAP and DBU as well as phosphines have been found to successfully catalyze this reaction.

Reaction mechanism

The nucleophilic addition of DABCO 2 onto the α,β-unsaturated ketone 1 gives a charged zwitterionic intermediate 3, which will add to the electrophilic aldehyde producing the keto-alcohol 4. Elimination of the DABCO gives the desired allylic alcohol 5.

A simple relationship exists between pKa of the base (as its conjugate acids) and the reaction rate with quinuclidine even more effective than DABCO. Protic additives like methanol, triethanolamine, formamide, and water (molecule) also accelerate the reaction ["Correlation between pKa and Reactivity of Quinuclidine-Based Catalysts in the Baylis-Hillman Reaction: Discovery of Quinuclidine as Optimum Catalyst Leading to Substantial Enhancement of Scope" Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. (Article); 2003; 68(3); 692-700. DOI|10.1021/jo026671s ] .

An alternative mechanism, based on extensive rate data, has been proposed for some aldehydes. ["Baylis-Hillman Mechanism: A New Interpretation in Aprotic Solvents" Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T.; "Org. Lett.", 2005, "7(1)", 147-150. DOI|10.1021/ol047739o] ["A New Interpretation of the Baylis-Hillman Mechanism" Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. (Article); 2005; 70(10); 3980-3987. DOI|10.1021/jo050202j ] ["Synthetic potential of the tertiary-amine-catalysed reaction of activated vinyl carbanions with aldehydes" Drewes, S. E.; Roos, G. H. P.; "Tetrahedron" 1988, "44", 4653-4670. DOI|10.1016/S0040-4020(01)86168-8] . This mechanism (figure below) takes into account experimentally determined second order kinetics for the aldehyde and a substantial kinetic isotope effect for the enone alpha-proton. In it a second aldehyde molecule reacts to form a hemiacetal (4) and this step is followed by a rate-determining proton transfer step to intermediate 5.

In silico experiments confirm this mechanism ["Mechanism of the Morita-Baylis-Hillman Reaction: A Computational Investigation" Raphael Robiette, Varinder K Aggarwal, and Jeremy N. Harvey J. AM. CHEM. SOC. 2007, 129, 15513-15525 DOI|10.1021/ja0717865] and also explain how protic additives increase reaction rates by facilitating the proton transfer step.

A related reaction actually predating the Baylis-Hillman reaction utilising phosphines and not DABCO is the lesser known Rauhut-Currier reaction.

Scope

The MBH reaction in general is any reaction of electron deficient alkenes and sp² hybridized carbon electrophiles such as aldehydes, ketones and aldimines catalyzed by a nucleophile. Under special reaction conditions the reaction is also found to extend to alkyl halides as the electrophilic reagent ["Unprecedented reactivity in the Morita–Baylis–Hillman reaction; intramolecular -alkylation of enones using saturated alkyl halides" Marie E. Krafft, Kimberly A. Seibert, Thomas F. N. Haxell and Chitaru Hirosawa Chemical Communications, 2005, (46), 5772 - 5774 DOI: 10.1039/b512665g [http://www.rsc.org/publishing/journals/CC/article.asp?doi=b512665g Abstract] ] . In this variation amine nucleophiles are unsuitable and trialkyl phosphines are used instead. Under the given reaction conditions these phosphines do not react directly with the alkyl halide. The added base in the second step of this reaction promotes the elimination reaction to the enone.

In the aza-Baylis-Hillman reaction the electrophile is an imine. ["Enantioselective aza-Baylis-Hillman Reaction" Vasco D.B. Bonifacio, Org. Chem. Highlights, 2006, [http://www.organic-chemistry.org/Highlights/2006/30JanuaryA.shtm Full Article] ]

Limitations

The MBH reaction of phenyl vinyl ketone with benzaldehyde and DABCO in DMF is not limited to the monoadduct because the MBH adduct reacts with a second molecule of phenyl vinyl ketone in a nucleophilic conjugate addition ["Different Reaction Patterns in the Baylis-Hillman Reaction of Aryl Aldehydes with Phenyl Vinyl Ketone, Phenyl Acrylate and Phenyl Thioacrylate" Min Shi, Chao-Qun Li and Jian-Kang Jiang Molecules 2002, 7, 721-733 [http://www.mdpi.org/molecules/papers/71000721.pdf Full Article] ] .

References