Nickel-catalyzed couplings and cyclizations involving allenes, aldehydes, and organozincs
Fully intermolecular and partially intramolecular examples reported.
Introduction
Homoallylic alcohols are versatile building blocks typically prepared by the addition of allylmetals to aldehydes,1 the addition of vinyl organometallics to epoxides,2 or carbonyl ene reactions.3 In addition to these well-established methods, an alternate preparative method for homoallylic alcohol synthesis involves the coupling of aldehydes and allenes. The earliest reports of allene/aldehyde cyclizations, in reports from Pattenden and Crandall, involved single electron transfer pathways.4 Those studies demonstrated that carbonyl-derived radical anions undergo efficient cyclizations with allenes to generate allylic or homoallylic alcohols depending on the substrate structure and tether length. Studies from Grigg developed complementary allene/aldehyde couplings by involving a third aryl iodide component in a novel palladium-catalyzed procedure.5 In order to expand the scope of allene/aldehyde addition reactions, we envisioned that the nickel-catalyzed coupling of allenes, aldehydes, and organozincs would afford a useful entry to homoallylic alcohols, and our group, concurrently with Kang, recently reported the first examples of nickel-catalyzed reductive and alkylative cyclizations of allenyl aldehydes (Eq. 1).6 Additional approaches to nickel- and palladium-catalyzed aldehyde/allene couplings have recently appeared,7, 8 and other attractive nickel-catalyzed approaches to homoallylic alcohols have been reported.9, 10, 11
Exocyclizations of allenyl aldehydes may potentially proceed with selectivity toward either the proximal or distal π-system of the allene to generate the two constitutional isomers 1 or 2 (Scheme 1). Additions to the proximal π-system could be complicated by unselective formation of the trisubstituted alkene or of the two stereogenic centers, whereas addition to the distal π-system could be complicated by unselective formation of the two stereogenic centers. The corresponding intermolecular couplings are inherently more complex than cyclizations since they may proceed to generate four different constitutional isomers 3–6 depending on the allene orientation (Scheme 1). Further complexities in the intermolecular couplings would result from lack of stereocontrol in the formation of trisubstituted alkenes or of the two stereogenic centers. Despite these potential hurdles, we set out to gain an understanding of the scope and efficiency of nickel-catalyzed additions of aldehydes and allenes. We describe in this paper, a more complete report of our previously communicated studies of nickel-catalyzed allenyl aldehyde cyclizations and provide the first examples of the corresponding fully intermolecular alkylative couplings of aldehydes, allenes, and organozincs.
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Results
Our studies began with an examination of cyclizations of allenyl aldehydes that possess monosubstituted allenes in the presence of simple diorganozincs (Table 1, entries 1–5). Both heterocyclic (entries 1–3)12 and carbocyclic (entries 4–5) frameworks could be prepared, and organozincs that either lacked (entries 1 and 4) or possessed (entries 2, 3, and 5) β-hydrogens were tolerated. Commercial organozincs could be directly used, or the organozinc may be prepared in situ by transmetalation of an
Discussion
The mechanism of the alkylative cyclizations could proceed by several potential pathways. The mechanism that we and others have generally favored in three-component nickel-catalyzed reductive couplings centers around the formation of nickel metallacycles, and an in-depth discussion of this general mechanism was provided in a recent combined experimental/computational study from our group in collaboration with Schlegel.15 In analogy to this commonly invoked mechanistic pathway, the allenyl
Conclusion
A procedure for the intramolecular and intermolecular coupling of allenes, aldehydes, and organozincs has been developed. In all instances, addition of a terminal position of the allene to the aldehyde is the preferred mode of addition, and the organozinc substituent is introduced at the central carbon of the allene. The reaction scope of cyclizations includes monosubstituted and 1,3-disubstituted allenes, and the scope in intermolecular examples includes monosubstituted, 1,1-disubstituted,
General
All reagents were used as received unless otherwise noted. Tetrahydrofuran (THF) and diethyl ether were freshly distilled from sodium/benzophenone ketyl or purified by filtration on an Innovative Technologies solvent purification system. All organolithium reagents were freshly titrated with 2,5-dimethoxybenzyl alcohol. Zinc chloride was dried at 150 °C at 0.1 mmHg overnight, thoroughly grounded by mortar and pestle in an inert atmosphere glove box, then dried again overnight at 150 °C at 0.1 mmHg
Acknowledgements
We thank the National Institutes of Health (GM 57014) for support of this research. We thank Dr. K. K. D. Amarasinghe for helpful suggestions and for important exploratory work.
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