Ni-Catalyzed Regioselective 1,2-Dialkylation of Alkenes Enabled by the Formation of Two C(sp³)−C(sp³) Bonds

Abstract

We disclose a Ni-catalyzed vicinal difunctionalization of alkenes with benzyl halides and alkylzinc reagents, which produces products with two new alkyl–alkyl bonds. This alkene dialkylation is effective in combining secondary benzyl halides and secondary alkylzinc reagents with internal alkenes, which furnishes products with three contiguous all-carbon secondary stereocenters. The products can be readily elaborated to access complex tetralene, benzosuberene, and bicyclodecene cores. The reaction also features as the most efficient alkene difunctionalization process to date with catalyst loadings down to 500 ppm and the catalytic turnover number (TON) and turnover frequency (TOF) registering up to 2 × 10³ and 165 h⁻¹ at rt, respectively.

Metal-catalyzed alkene dicarbofunctionalization is an emerging reaction built on promise to provide economical and speedy access to complex carbon skeletons.¹ This emergent reaction is engineered to seam together three carbon fragments at desired combinations to create complex branched carbon networks.² Over the years, its development has mostly been hindered by β-hydride (β-H) elimination from alkylmetal (β-H−C(sp³)−[M]) species, a key reaction intermediate generated during catalysis. Nevertheless, a significant progress has been made recently in difunctionalizing alkenes with Csp- and Csp²-hybridized coupling partners for diarylation,³ arylvinylation,⁴ arylalkynylation,⁵ and similar reactions⁶ (Scheme 1A–C). These reactions, still difficult to develop, intrinsically minimize the number of catalytically generated alkylmetal species prone to undergo β-H elimination. A few reports on alkene alkylarylation have also been disclosed (Scheme 1D), but these reactions mostly utilize tert-alkyl⁷ and perfluoroalkyl halides,⁸ and α-haloesters⁹ amenable to the formation of alkyl, difluoroalkyl, and α-alkoxycarbonylalkyl radicals.¹⁰ Reactions with these reagents bypass the generation of additional β-H−C(sp³)−[M] intermediates.¹¹

Scheme 1.

Most Common Regioselective Alkene 1,2-Dicarbofunctionalization Reactions

Catalytic alkene difunctionalization with two alkyl groups creates two new C(sp³)−C(sp³) bonds, which has the potential to offer a rapid and direct method to build branched molecules with saturated carbon linkages. However, the reaction with alkyl coupling partners poses more severe challenges than with C(sp)- and C(sp²)-coupling reagents due to the generation of multiple additional β-H−C(sp³)−[M] intermediates (Scheme 2). These extra alkylmetal species susceptible to β-H elimination open a plethora of possibilities for side reactions at different stages of catalysis. Therefore, intermolecular addition of two alkyl groups across an alkene remains one of the most challenging alkene difunctionalization reactions to develop to date, and the development of such reactions has remained exceptionally rare¹² mainly requiring vinylboron reagents as alkene sources.¹³ Regrettably, these reactions proceed with a limited scope largely for the addition of primary alkyl groups to terminal alkenes with no example for the coupling of secondary-secondary alkyl reagents with internal alkenes.¹⁴ Addition of secondary alkyl reagents to internal alkenes is a much desired combination to generate branched molecules with multiple contiguous stereocenters that are ubiquitously featured in complex bioactive chemicals.¹⁵ The fact that these reactions require a large excess of reactive coupling reagents (2–8 equiv each) along with high catalyst loadings (5–15 mol %) undoubtedly highlights the exceedingly difficult nature of the challenge that must be addressed. Herein, we describe a Ni-catalyzed process for regioselective 1,2-dialkylation of alkenes with benzyl halides and alkylzinc reagents, a reaction that proceeds at room temperature with the highest turnover number (TON) and turnover frequency (TOF) known to date in alkene difunctionalization reactions. The reaction combines internal alkenes with both coupling partners bearing secondary alkyl groups, generates two alkyl–alkyl [C(sp³)−C(sp³)] bonds simultaneously, and furnishes profusely branched products by creating up to three contiguous all-carbon secondary stereocenters.

Scheme 2.

Complications in Regioselective Alkene 1,2-Dialkylation by β-H Elimination

We initiated the development of the alkene 1,2-dialkylation reaction with the selection of 2-alkenylaldimine 1 as an alkene source along with benzyl bromide 3 and (2-(1,3-dioxan-2-yl)ethyl)zinc bromide as electrophilic and nucleophilic partners, respectively (Table 1). Examination of 1,2-dialkylation with Ni(cod)₂ by varying parameters like solvent, temperature, catalyst loading, and reaction time (entries 1–7) revealed that the reaction could be performed with a very low catalyst loading (0.050–0.10 mol %, 500–1000 ppm) at room temperature (rt) in THF, toluene, and dioxane (entries 1–4). The reaction proceeded most efficiently in toluene furnishing the expected product 4 in optimal yield (99%) with the catalytic turnover number (TON) and frequency (TOF) reaching up to 10³ and 165 h⁻¹ in 6 h (1000 ppm of Ni) (entry 3) and 2 × 10³ and 83 h⁻¹ in 24 h (500 ppm of Ni) (entry 4) at rt. The reaction can be scaled up (5 mmol) readily with a low catalyst loading at rt, and the product can be generated in excellent isolated yield (entry 3 parentheses; 1.6 g, 95%). Replacing Ni(cod)₂ with Ni(PPh₃)₄ generated the product 4 in reduced yield (entry 8). NiBr₂ and catalysts based on other metals such as Fe, Co, Cu, and Pd were ineffective (entries 9–10), and the reaction did not proceed in the absence of a transition metal catalyst (entry 11). Benzyl chloride was not effective at rt (entry 12), but at 60 °C the product 4 was formed in 60% yield (entry 13). The imine functional group remains critical for the success of the reaction since a control experiment performed with 2-vinylbenzaldehyde and styrene afforded no dialkylated product (entries 14 and 15).

Table 1.

Optimization of Reaction Conditions^a

^aReactions were conducted at 0.10 mmol scale with 1.1 equiv each of 2 and 3. The imine is hydrolyzed to an aldehyde during dilute acid workup.

^b1H NMR yields using pyrene as a standard. Isolated yield from a 5 mmol scale reaction in parentheses.

^c2 mol % of Co(OAc)₂, FeCl₂, Pd(OAc)₂, or CuI was used.

The optimized reaction conditions are broadly applicable for 1,2-dialkylation of a wide range of alkenes with various benzyl halides and alkylzinc reagents (Table 2). 2-Alkenylarenes containing both electron-donating (Me, OMe, and dioxolyl) and electron-withdrawing (F, CF₃, and Cl) functional groups on the aryl moiety were regioselectively dialkylated in excellent yields with benzyl bromide and (2-(1,3-dioxan-2-yl)ethyl)zinc bromide (8–16). The reaction conditions are also compatible with a wide range of substituted benzyl bromides including those that contain polyaromatic hydrocarbons (17–36). Functional groups such as Me, tBu, OMe, CF₃, Br, Cl, and OCF₃ (18–29) along with the traditionally challenging groups like SMe (28), COR (29), and ortho-Br (30) are well tolerated on benzyl bromides. The compatibility of the reaction with benzyl bromides borylated at both the ortho- and meta-positions (35 and 36) exemplify a remarkable synthetic orthogonality of the current alkene dialkylation method toward the nucleophilic arylboron and alkylzinc reagents. Likewise, the reaction protocol also displays a notable functional group compatibility on alkylzinc reagents with the tolerance of sensitive and metal-binding groups like ester (25–28 and 35), nitrile (24, 30, and 32), ortho-halogenated pyridine (33–34), alkene (31), and dioxanyl-protected aldehyde (8–16 and 21–23). These reactions can be conducted with 0.050 mol % (500 ppm) Ni(cod)₂, and the products are obtained in comparable yields in 24 h (8, 10–12, 18, 25, and 36).

Table 2.

Scope of Dialkylation with Alkenes, Benzyl Halides, and Alkylzinc Reagents^a

^aReactions were run at 0.50 mmol scale in 2.5 mL of toluene with 0.10 mol % Ni(cod)₂ unless specified otherwise. The percentage numbers are the yields of isolated products. Numbers in parentheses are isolated yields with 0.050 mol % (500 ppm) of Ni(cod)₂ in 24 h.

^b40 °C.

^c0.50 mol % Ni(cod)₂.

^d80 °C.

^e12 h.

^f60 °C.

^g0.20 mol % Ni(cod)₂.

^hDioxane.

ⁱ2.0 mol % Ni(cod)₂.

^j3 h.

^k1.0 mol % Ni(cod)₂.

^l100 °C.

^m120 °C.

ⁿ5.0 mol % Ni(cod)₂.

Alkene difunctionalization reactions are largely successful for terminal alkenes with C(sp²)-hybridized coupling partners.¹⁶ Internal alkenes are less polarized and more sterically hindered than terminal alkenes and, therefore, present a fundamental challenge for reactivity.¹⁷ Moreover, coupling of secondary carbons with internal alkenes, which requires bond formation between two sterically demanding secondary C(sp³) hybridized carbons involving secondary C(sp³)-alkylmetal intermediates, is even more challenging since the molecular assembly at the metal center becomes highly crowded and raises the activation barrier for the reaction. We are pleased to report that our current alkene dialkylation reaction can readily negotiate the fundamental issue of coupling secondary alkyl groups with internal alkenes (Table 2).¹⁸ The secondary benzyl bromides and secondary alkylzinc reagents bearing different functional groups can be sewn together with terminal and internal alkenes in different combinations. The reaction proceeded efficiently for the coupling of terminal alkenes with both the primary and secondary benzyl bromide derivatives and primary and secondary alkylzinc reagents (37–50). Products are formed in good to excellent yields (46–78%) with functionalized primary (37–39 and 51–54) and secondary benzyl bromides (40–50) including cyclic 1-tetrahydronaphthayl bromide (43) and more sterically congested α-isopropylbenzyl bromide (44 and 50). Cyclic and acyclic secondary alkylzinc reagents bearing cyclopropyl (37, 45, and 54), cyclobutyl (38, 39, and 46), cyclopentyl (47 and 55), cyclohexyl (48 and 56), adamantyl (49), and isopropyl (50) groups are excellent coupling partners, which afford the dialkylated products in 41–78% yields. The dialkylation reactions of terminal alkenes with the secondary benzyl bromides and both the primary and the secondary alkylzinc reagents generated 1,3-carbon-branched molecules bearing two skipped (1,3) all-carbon secondary stereocenters (40–50) with a varying degree of diastereoselectivity reaching up to a 10:1 ratio for cyclic benzyl bromide (43 and 47).

The reaction also proceeds efficiently for the coupling of internal alkenes with primary benzyl bromides and both primary and secondary alkylzinc reagents, which creates products branched at two adjacent carbons with stereocenters (51–54) in 70–85% yields. These products are formed as single diastereomers consistent with the syn-addition for migratory insertion. The syn-addition of alkyl reagents to alkenes was further confirmed by a single crystal X-ray crystallographic analysis of the single diastereoisomer of the product 52 derived from trans-alkene, which revealed the relative stereochemistry as (±)-(S,S). In addition, the product 51 was obtained as a single diastereomer from trans-alkene and as a mixture of two diastereomers in 5:1 ratio from a 5:1 trans/cis-alkene further supporting the migratory insertion pathway for syn-addition.¹⁹ Remarkably, internal alkenes could also be dialkylated in good yields with secondary benzyl bromides and secondary alkylzinc reagents (55–56), reactions that require proceeding with congested transition states for bond formation. The hemming of the internal alkenes with secondary benzyl bromides and secondary alkylzinc reagents constructed complex carbon skeletons branched at four adjacent carbons and comprised of three contiguous all-carbon secondary stereocenters. These products were also generated with high stereocontrol as a mixture of only two diastereoisomers in up to a 10:1 ratio.

The ability to manipulate products further offers unconventional and concise synthetic disconnection strategies for building complex molecules. In this regard, we show that the dialkylated imine products can be reduced in one pot with NaBH₄ to produce complex secondary benzylarylamines in 76–84% yields (Table 3). The reactions were conducted in dioxane rather than toluene to facilitate one-pot reduction without workup. We also demonstrate that alkylzinc reagents bearing appropriately placed aldehyde surrogate (2), ester (64a), and nitrile (64b) functional groups enable the incorporation of six- and seven-membered cyclic structures on arenes upon one-pot hydrolytic cyclization of their carbonyl side chains with the o-benzaldehyde group of the dialkylation products (Table 4). Such a synthetic strategy simplifies the construction of aldehyde, ester, and nitrile derivatives of 4-substituted tetralene (66–70) and 5-substituted benzosuberene (71) skeletons,²⁰ the cores of many natural products, and pharmaceutically important molecules. These structures are also featured in drugs designed to increase hydrophobicity and enhance efficacy.²¹ In addition, we showcase that the alkene dialkylation products can be readily elaborated to bicyclic structures rich in complexity with aryl and alkyl networks. For example, we demonstrate that the dialkylation of alkene 1 with ortho-bromobenzyl bromide in the presence of functionalized alkylzinc reagents, such as (2-(1,3-dioxan-2-yl)ethyl)zinc, followed by hydrolytic cyclization produces the tetralene carbaldehyde 72 in one pot (Table 4, bottom equation). The ortho-Br on the 4-phenethyl substituent of tetralene 72 is then utilized as a functional arm for a Pd-catalyzed Heck reaction to the intramolecular α,β-unsaturated aldehyde, which furnishes a substantially complex arene-studded bicyclo[4.2.2]decene scaffold (73).

Table 3.

Rapid Access to Benzylarylamine Derivatives

Table 4.

Rapid Access to Complex Tetralene, Benzosuberene, and Bicyclic Derivatives^a

^a3 N HCl (final concn) was used for cyclization for compounds 66–68 and 72. 1.5 equiv of NaOEt in EtOH (6 h) was used for cyclization for compounds 69 and 70. 1.5 equiv of KHMDS in THF (3 h) was used for cyclization for compound 71.

^b0.50 mol % Ni(cod)₂.

^c60 °C.

^d12 h.

^eDialkylation in toluene.

^f40 °C.

^g80 °C.

In summary, we report a Ni-catalyzed regioselective alkene dialkylation reaction with benzyl bromides and alkylzinc reagents that permits the rapid assembly of complex molecules through the formation of two alkyl–alkyl bonds. The reaction represents the most efficient alkene difunctionalization reaction to date with the catalytic TON and TOF at ~10³ and 165 h⁻¹ in 6 h (1000 ppm of Ni) and 2 × 10³ and 83 h⁻¹ in 24 h (500 ppm of Ni) at room temperature. The mild reaction condition offers high functional group compatibility and allows the coupling of secondary alkyl reagents with internal alkenes. The coupling of secondary alkyl reagents with internal alkenes enabled the construction of complex structures with three to four adjacent carbon-branching and both the skipped 1,3 and contiguous 1,2 and 1,2,3 all-carbon secondary stereocenters with a high fidelity of stereocontrol. Rapid elaboration of the dialkylated products to functionalized tetralene, benzosuberene, and bicyclodecene cores demonstrates the method’s application in speedy access to complex molecule potential for drug discovery.