Nickel‐Catalyzed Negishi Cross‐Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature

Abstract

In recent years, significant progress has been made in the development of metal-catalyzed cross-couplings of alkyl electrophiles.[1] A number of substantial challenges have not yet been met, including the coupling of sterically demanding partners. For example, we are not aware of reports of palladium- or nickel-catalyzed cross-couplings of secondary alkyl electrophiles with secondary organometallic nucleophiles.[2] Recognizing the importance of overcoming this limitation, we have recently turned our attention to addressing this deficiency. Due in part to the ease of synthesis and functional-group compatibility of alkylzinc reagents, we chose to focus our efforts on Negishi reactions.[3, 4, 5] In this communication, we describe the first nickel-based catalysts that achieve cross-couplings of secondary nucleophiles with secondary electrophiles [Eq. (1)]. (1) As part of our initial investigation, we explored the Negishi reaction illustrated in Table 1.[6] Unfortunately, none of the methods that have previously been reported for cross-couplings of secondary alkyl electrophiles with primary alkylzinc reagents furnishes the desired product in substantial yield (<20%).[7,8] By optimizing the various reaction parameters, we were able to develop a catalyst system that achieves this Negishi cross-coupling with good efficiency at room temperature (89% yield; Table 1, entry 1).[9] In the absence of NiCl2•glyme or terpyridine, essentially no carbon–carbon bond formation occurs (entries 2 or 3). If the bulky TIPS substituent is replaced with a smaller silyl or alkyl group, the yield of the cross-coupling decreases, due to the formation of a substantial amount of homocoupled electrophile (entries 4 and 5).[10] The other ligands, both bidentate and tridentate, that we have examined, are less useful than terpyridine (entries 6–8), as are solvents other than DMA (entries 9–11). Table 1 Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles: Effect of reaction parameters. Our optimized method (NiCl2•glyme/terpyridine/DMA) can be applied to cross-couplings of a range of secondary propargylic bromides with secondary alkylzincs (Table 2). Esters, olefins (no E/Z isomerization), ethers, and carbamates are compatible with the reaction conditions.[11] Table 2 Room-temperature Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles. Although our primary objective was to develop a method for secondary–secondary cross-couplings, we were also interested in exploring the versatility of this catalyst. We have determined that, without modification, NiCl2•glyme/terpyridine/DMA can also be applied to Negishi reactions of less-hindered coupling partners, e.g., primary alkylzinc reagents with secondary/primary propargylic bromides (Table 3). Cross-couplings proceed in very good yield in the presence of an unactivated primary alkyl chloride, an ether, and an ester.[12] Table 3 Negishi reactions of primary nucleophiles with secondary and primary propargylic electrophiles. If the alkyl group of the organozinc reagent is more hindered than cyclohexyl or isopropyl, the efficiency of NiCl2•glyme/terpyridine/DMA diminishes significantly (e.g., for entry 1 of Table 4: 20% yield). However, by replacing terpyridine with a related ligand, 2,6-bis(N-pyrazolyl)pyridine, and switching to THF as the solvent, the desired Negishi cross-coupling can be achieved in good yield (entry 1 of Table 4: 86% yield).[13,14] Functional groups such as alkynes, unactivated alkyl chlorides, and ethers are tolerated by this method (Table 4).[15] Table 4 Room-temperature Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles. We have determined that our coupling conditions can be employed not only for propargylic bromides, but also for propargylic chlorides (also at room temperature; [Eq. (2) and Eq. (3)]. (2) (3) We have applied our method for secondary-secondary cross-couplings to the formal total synthesis of α-cembra-2,7,11-triene-4,6-diol (Scheme 1), a cembranoid diterpene with antitumor activity that has been synthesized by Marshall[16] and by Thomas.[17] We envisioned that the isopropyl substituent could be installed by a Negishi reaction of propargylic bromide 1, which can be generated from farnesyl acetate; indeed, using our Ni/terpyridine method, we were able to achieve the desired cross-coupling in 61% yield on a gram-scale. In preliminary studies, we have converted coupling product 2 into 14-membered macrocycle 3, which served as an intermediate in the Thomas synthesis of α-cembra-2,7,11-triene-4,6-diol.[17,18] Scheme 1 Application of a secondary-secondary Negishi cross-coupling in a formal total synthesis of α-2,7,11-cembranetriene-4,6-diol. In conclusion, we have developed the first method for secondary–secondary cross-couplings with a Group X catalyst, specifically a nickel-based system for coupling propargylic halides with alkylzinc reagents that proceeds under mild conditions (room temperature and no basic activators). Future efforts will focus on further expanding the scope of cross-coupling reactions of alkyl electrophiles.