Ni(I)-Catalyzed β,δ-Vinylarylation of γ,δ-Alkenyl α-Cyanocarboxylic Esters via Contraction of Transient Nickellacycles

Abstract

We disclose a transmetalation-initiated Ni(I)-catalyzed regioselective β,δ-vinylarylation of γ,δ-alkenyl α-cyanocarboxylic esters with vinyl triflates and arylzinc reagents. This reaction proceeds via contraction of six-membered nickellacycles to five-membered nickellacycles to form carbon–carbon bonds at the nonclassical homovicinal sites, and it provides expeditious access to a wide range of complex aliphatic α-cyanoesters, α-cyanocarboxylic acids, dicarboxylic acids, dicarboxylic acid monoamides, monocarboxylic acids, nitriles, and spirolactones. Control, deuterium labeling, and crossover experiments indicate that (i) the nickellacycle contraction occurs by β-H elimination, followed by hydronickellation on transiently formed alkenes, and (ii) the Ni species are stabilized as Ni-enolates.

Graphical Abstract

Catalytic dicarbofunctionalization of unactivated alkenes¹ is an emerging synthetic method that holds great promise to furnish a modular, convergent, and expedient route to generate complex molecules rapidly from readily available starting materials.² In a classical approach, this process harnesses the potential of two reactive vicinal C(sp²) sites in alkenes to create new bonds.³ Therefore, the known examples of reactions difunctionalize alkenes at the vicinal⁴ and geminal⁵ sites by intercepting alkylmetal intermediates, either at their initial formation (1) or after their rearrangement (2) by a β-H elimination/M–H reinsertion process (see Scheme 1).⁶

Scheme 1.

Classical Alkene Difunctionalization at Vicinal and Geminal Sites

Recently, we⁷ and Zhao⁸ introduced a metallacycle contraction process to difunctionalize unactivated alkenes with ArX and ArZnX or ArB(OH)₂ at nonclassical homovicinal sites (see Scheme 2A). This alkene difunctionalization reaction created two new carbon–carbon (C–C) bonds at the vinylic C(sp²) and allylic C(sp³) carbons. In this process, an initially formed six-membered nickellacycle underwent coordination-assisted ring contraction to a five-membered nickellacycle. The use of strong coordinating groups, such as imine and pyrimidine, remained crucial to trigger metallacycle contraction and stabilize the five-membered nickellacycle prior to its interception by organometallic reagents to furnish difunctionalized products.

Scheme 2.

Nonclassical Alkene Difunctionalization at Homovicinal Sites by Metallacycle Contraction Process: (A) Previous Work and (B) This Work

To expand the scope of alkene difunctionalization by the metallacycle contraction process, we envisioned to use functional groups directly for coordination to generate metallacycles (see Scheme 2B). The use of a functional group will eliminate the necessity to install a removable or nonremovable coordinating group that is currently in practice for coordination-assisted alkene difunctionalization reactions.⁹ We hypothesized that the initially generated fluxional six-membered metallacycle (3) would have a high propensity to undergo ring contraction to a five-membered metallacycle (4) via β-H elimination/M–H reinsertion,¹⁰ which is a process modulated by the weakly coordinating nature of the functional group. Based on this idea, we herein report the first example of β,δ-vinylarylation of unactivated γ,δ-alkenes in α-cyanocarboxylic esters with vinyl triflates and arylzinc reagents. The reaction proceeds with complete regioselectivity with the addition of the aryl group to the distal alkenyl carbon (δ-position) and the vinyl group to the allylic carbon (β-position) via a transmetalation-initiated Ni(I)/Ni(III) catalytic cycle.

We began our studies for vinylarylation of γ,δ-alkenyl carboxylic esters with cyclohexenyl triflate and diphenylzinc in the presence of Ni catalysts (see Table 1). Examination of various ester derivatives (Table 1, entries 1–4) with varied reaction parameters revealed that 5 mol % NiCl₂ promoted β,δ-vinylarylation of γ,δ-alkenyl α-cyanocarboxylic ester 8 in THF at 80 °C and afforded the β-cyclohexenyl-δ-phenyl-α-cyanocarboxylic ester 9 in 38% yield (Table 1, entry 4). The addition of 4-phenylpyridine as a base increased the product yield to 52% (Table 1, entry 5).

Table 1.

Optimization of Reaction Conditions^a

entry	R	additives	deviation in reaction conditions	yields of 9b (%)
1	H (5)	none	none	0
2	Ph (6)	none	none	0
3	CO2Et (7)	none	none	0
4	CN (8)	none	none	38
5	CN	1.5 equiv of 4-PhPy	none	52
6	CN	1.5 equiv of 4-PhPy and KPF6	none	78 (72)
7	CN	10 mol % CuI instead of KPF6	none	62
8	CN	1.5 equiv of 4-PhPy and KPF6	no NiCl2	0
9	CN	1.5 equiv of 4-PhPy and KPF6	Ni(cod)2 instead of NiCl2	17
10	CN	1.5 equiv of 4-PhPy and KPF6	Ni(PPh3)4 instead of NiCl2	8
11	CN	1.5 equiv of 4-PhPy and KPF6	Pd(OAc)2 instead of NiCl2	6
12	CN	1.5 equiv of 4-PhPy and KPF6	Co, Fe, or Cu-cat. instead of NiCl2	0c
13	CN	1.5 equiv of 4-PhPy and KPF6	dioxane instead of THF	74
14	CN	1.5 equiv of 4-PhPy and KPF6	NMP or toluene instead of THF	40–52
15	CN	1.5 equiv of 4-PhPy and KPF6	MeCN, DMF, or DMSO instead of THF	13–25

^a0.1 mmol scale reactions in 0.5 mL solvent.

^b1H NMR yields using pyrene as an internal standard. Value in parentheses is the isolated yield (diastereomeric ratio (dr) = 1:09) from 0.5 mmol, and the dr was determined by ¹H NMR of a crude reaction mixture.

^cCoCl₂, FeCl₂, or CuI.

The presence of both the cyano and ester groups is crucial for the success of the reaction. We hypothesize that their presence will not only facilitate the ready generation of enolates but also shift the equilibrium of the bidentate arrangement toward the alkene-bound species, which will position the Ni catalyst to react with the alkene (see Scheme 3). The requirement for the formation of a tightly bound γ,δ-alkenyl-Ni-enolate for reactivity is also consistent with our further experiment with a δ,ε-alkenyl cyanoester, a substrate bearing alkene one more carbon away, which did not furnish any difunctionalized product (Scheme 3). We believe that the distal δ,ε-alkene was likely unable to generate the required alkene-bound Ni-enolate for reaction.

Scheme 3.

Analysis of Substrate Backbones for Reactivity

Similar enolization can be expected with the malonate substrates (7). However, malonates function as a good bidentate anionic ligand in much the same way as acetylacetonate (acac) does. This conformational arrangement will prevent the Ni catalyst to access alkenes for further reaction. In addition, substrates with less acidic α-H, such as ethyl α-phenyl-4-pentenoate (6) (pK_a ~22), could not function as a substrate, because of their inability to enolize in the presence of a pyridine base.

The need for vinyl triflates as electrophiles also indicated a potential involvement of cationic Ni species in the reaction.^4c,11 Upon examination of a variety of noncoordinating counteranions that could increase the concentration of cationic Ni-species, we found that the addition of 1.5 equiv of KPF₆ increased the yield of the product to 78% (Table 1, entry 6). Other sources of noncoordinating counteranions, such as NaPF₆, TBAPF₆ and KBARF produced the product in lower yields (see the Supporting Information for data), indicating a crucial role played by KPF₆. KPF₆ can be replaced with 10 mol % CuI, although the product was formed in slightly lower yield (Table 1, entry 7). No product was observed in the absence of NiCl₂ (Table 1, entry 8). Ni(0) and other metal-based catalysts (Pd, Co, Fe, or Cu) either did not form the product or generated the product in low yields (Table 1, entries 8–12). The reaction also furnishes the product 9 in a comparable yield in dioxane (Table 1, entry 13). The product 9 was formed only in low to moderate yields in other common solvents such as toluene, MeCN, NMP, DMF, and DMSO (Table 1, entries 14 and 15). Note that the current reaction produces products with γ,δ-alkenes, which are analogous to the starting γ,δ-alkenyl cyanoesters. However, attempts to further difunctionalize the product 9 were unsuccessful, because the resultant γ,δ-alkene is trisubstituted and sterically less accessible.

With the optimized reaction condition in hand, we examined the scope of β,δ-vinylarylation of γ,δ-alkenyl α-cyanocarboxylic esters with various vinyl triflates and arylzinc reagents (see Table 2).¹² The reaction of γ,δ-alkenyl α-cyanocarboxylic ester 8 proceeds well with various arylzinc reagents and alkenyl triflates, such as cyclopentenyl triflate, cyclohexenyl triflate, and 4-tert-butylcyclohexenyl triflate, which affords the corresponding β,δ-vinylarylated products 10–20 in good yields.¹³ The reaction can also be conducted with acyclic alkenyl triflate derived from ketones (21 and 22). However, acyclic alkenyl triflates derived from aldehydes, such as (E)-1-hexenyl triflate, did not form any difunctionalized product. The reaction also furnishes products 23–27 in good yields with α-cyanocarboxylic esters containing internal γ,δ-alkenes, such as ethyl 2-(2-butenyl)-2-cyanoacetate and ethyl 2-(5-phenyl-2-pentenyl)-2-cyanoacetate. Moreover, we have expanded substrate scope by using heterocyclic triflates, which afford the corresponding β,δ-vinylheteroarylated products (28–30) in good yields.¹⁴

Table 2.

Scope with Alkenes, Vinyl Triflates, and Arylzinc Reagents^a

^aIsolated from 0.5 mmol. 1.2 equiv each of Ar₂Zn and vinyl triflate used. dr was determined by ¹H NMR of a crude reaction mixture.

^b100 °C.

^c4-FC₆H₄ZnI was used.

^d1:0.6 E/Z mixture based on decarboxylated nitrile product is identical with starting vinyl triflate (see the Supporting Information).

^eThe dr value was determined by ¹H NMR of isolated products.

The current reaction also provides an expedient route to access a wide variety of β,δ-vinylarylated aliphatic nitriles (31–39), β,δ-vinylarylated aliphatic carboxylic acids (40–42) and complex spirolactones (43–45) (see Table 3). Cyclohexdienyl triflates derived from steroids can also be used as coupling partners (39), which demonstrates the potential application of the current method in the functionalization of complex molecules. These products are readily accessible after selective one-pot hydrolysis of the β,δ-vinylarylated products without purification under mildly basic and acidic reaction conditions. The β,δ-vinylarylated aliphatic nitriles are formed after the crude reaction mixture is subjected to hydrolysis with 3 equiv of aqueous NaOH. The presence of 4-PhPy in the reaction mixture triggers protodecarboxylation of in-situ-generated α-cyanocarboxylic acids, leading to the formation of the aliphatic nitrile products. The β,δ-vinylarylated crude reaction mixture can be hydrolyzed further to aliphatic carboxylic acids upon treatment with 8 equiv of NaOH in the presence of 6 equiv of pyridine at 120 °C for 15 h. The additional pyridine enables protodecarboxylation of in-situ-generated aliphatic dicarboxylic acids. The proximity of the alkene substituent to the in-situ-generated carboxyl group also facilitates lactonization upon promotion of cyclization by pyridinium hydrochloride (Py·HCl) under acidic conditions.

Table 3.

Expeditious Access to Complex Aliphatic Nitrile, Carboxylic Acid, and Spirolactone Derivatives^a

^aIsolated from 0.5 mmol. 1.2 equiv each of Ar₂Zn and vinyl triflate used; dr was determined by ¹H NMR of a crude reaction mixture.

^b1 equiv of pyridine added.

^c48 h.

Moreover, the β,δ-vinylaryl-α-cyanocarboxylic esters can also be selectively hydrolyzed under basic conditions to afford α-cyanocarboxylic acid, dicarboxylic acid and dicarboxylic acid monoamide derivatives (see Scheme 4). These progressively hydrolyzed products 46–48 are selectively generated with increased equivalents of NaOH and reaction times at 110 °C. The ability to provide access to seven different complex molecular architectures (Table 3 and Scheme 4) with one synthetic protocol demonstrates the broad scope and significance of the new β,δ-vinylarylation reaction.

Scheme 4.

Selective Hydrolysis^a

^aIsolated from 0.3 mmol; dr was determined by ¹H NMR of a crude reaction mixture.

Based on the regioselectivity and diastereoselectivity of the reaction, and the nature of the substrates and reagents, we propose a Ni^I/Ni^III catalytic cycle involving neutral and anionic Ni-enolate intermediates (see Scheme 5). Based on literature reports,¹⁵ we postulate that, in the presence of Ar₂Zn, 4-PhPy, and KPF₆, NiCl₂ is first reduced to a substrate/4-PhPy-bound cationic Ni(I) species 49, which transmetalates with Ar₂Zn reagents.¹⁶ The neutral transmetalation intermediate (50) then inserts the bound alkene to generate a six-membered anionic Ni(I)-enolate metallacycle 51.¹⁷ The formation of the Ni-enolate 51 would generate a protonated pyridine (PyH⁺), which could potentially quench Ar₂Zn reagents. However, we note that PyH⁺ is only formed in a very small concentration (1.0 equiv to Ni catalyst, 0.010 M) and its reaction with Ar₂Zn could be kinetically much slower than the difunctionalization reaction.¹⁸

Scheme 5.

Proposed Catalytic Cycle

The fluxional metallacycle 51 then undergoes ring contraction by endocyclic β-H elimination/Ni–H reinsertion to form a stable five-membered anionic Ni(I)-enolate metallacycle 53. Oxidative addition of vinyl triflate to this species followed by reductive elimination generates the β,δ-vinylarylated product 56. The resultant substrate/4-PhPy-bound neutral Ni(I) species 55 remains in equilibrium with the cationic Ni(I) species 49 to prime the Ni(I) intermediate for subsequent transmetalation.¹⁷ We note that the generation of Py (4-phenylpyridine) in this step is a consequence of the use of PyH⁺ as a proton source rather than a need to regenerate Py for the catalytic cycle, since Py is used in excess (1.5 equiv) in the reaction.

We provide evidence for the role of the acidic α-H and the metallacycle contraction process by control, deuterium-labeling, and crossover experiments (see Schemes 6–8). The reaction of γ,δ-alkenyl α-cyano-α-methylcarboxylic ester 57 lacking an α-H with Ph₂Zn and cyclohexenyl triflate under the standard condition did not generate the expected product 58 (see Scheme 6). This experiment indicates that the acidic α-H is required, likely for the stabilization of Ni-species as Ni-enolates, such as 51–55. The presence of Ni-enolate intermediates is also consistent with the observed lack of diastereoselectivity, which can arise from unselective facial recognition during α-protonation of a product Ni(I)-enolate generated after reductive elimination from the Ni(III)-enolate species 54.

Scheme 6.

Requirement for an α-Proton

Scheme 8.

Crossover Experiment

We also subjected a β-dideuterium-labeled γ,δ-alkenyl α-cyanocarboxylic ester (8-d₂) (98% D) to our standard reaction condition for β,δ-vinylarylation (see Scheme 7). Analysis of the β,δ-vinylaryl product 9-d₂ revealed that one of the β-deuteriums migrated quantitatively (98% D) to the γ-position. We also conducted a crossover experiment between the γ,δ-alkenyl α-cyanocarboxylic ester 8 and the styryl α-cyanocarboxylic ester 59 (see Scheme 8), which is a potential intermediate of the β-H elimination process. Analysis of the products disclosed that the product 9, which could arise from the styryl α-cyanocarboxylic ester 59, was not formed. Only the product 12, generated from γ,δ-alkenyl α-cyanocarboxylic ester 8, was produced in 64% yield. These results from the deuterium-labeling and crossover experiments indicate that the metallacycle contraction process proceeds via weak coordination-assisted endocyclic β-H elimination and regio-reversed hydronickellation steps wherein the Ni–H species generated in situ remains bound to the transient alkene product during ring contraction.

Scheme 7.

Deuterium Labeling Experiment

In summary, we have developed a new Ni-catalyzed β,δ-vinylarylation of γ,δ-alkenyl α-cyanocarboxylic esters with vinyl triflates and arylzinc reagents in which nonclassical homovicinal positions are functionalized. This new method provides expeditious access to a wide variety of β,δ-vinylarylated aliphatic α-cyanocarboxylic ester, α-cyanocarboxylic acid, nitrile, monocarboxylic acid, dicarboxylic acid, dicarboxylic acid, monoamide, and spirolactone derivatives. Mechanistic studies indicate that the reaction proceeds via the contraction of six-membered nickellacycles to five-membered nickellacycles modulated by a weakly coordinating functional group and involves neutral and anionic Ni-enolate intermediates in a transmetalation-initiated Ni(I)/Ni(III) catalytic cycle.