Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

Abstract

Alkenes are ubiquitous in organic chemistry, yet many classes of alkenes remain challenging to access by current synthetic methodology. Herein, we report a copper hydride-catalyzed approach for the synthesis of Z-configured trisubstituted alkenes with high stereo- and regioselectivity via alkyne hydroalkylation. A DTBM-dppf-supported Cu catalyst was found to be optimal, providing a substantial increase in product yield compared to reactions conducted with dppf as the ligand. DFT calculations show that the DTBM substitution leads to the acceleration of alkyne hydrocupration through combined ground and transition state effects related to preventing catalyst dimerization and enhancing catalyst–substrate dispersion interactions, respectively. Alkyne hydroalkylation was successfully demonstrated with methyl and larger alkyl tosylate electrophiles to produce a variety of (hetero)aryl-substituted alkenes in moderate to high yields with complete selectivity for the Z stereochemically configured products. In the formation of the key C–C bond, computational studies revealed a direct S_N2 pathway for alkylation of the vinylcopper intermediate with in situ-formed alkyl iodides.

Highly substituted alkenes are widely utilized products and synthetic intermediates with applications across organic chemistry, and their preparation, especially in stereochemically enriched forms, remains an important goal. While classic reactions for alkene synthesis, such as the Wittig¹ and Julia-Kocienski² methods, are reliably used to prepare disubstituted alkenes, challenges associated with forming highly substituted (i.e., tri- and tetrasubstituted) alkenes using these methods limit their broad applicability. Efforts to enable the synthesis of highly substituted alkenes have resulted in the development of catalytic strategies based on olefin metathesis³ and cross-coupling.⁴ As an alternative approach, transition-metal catalysis has been applied to the synthesis of alkenes via the hydroalkylation of alkynes (Figure 1A). Notably, Lalic has made significant contributions to this area with the development of copper-catalyzed hydroalkylation reactions of terminal alkynes to produce E-configured disubstituted alkenes.⁵ In addition, MacMillan⁶ has utilized metallophotoredox conditions to effect the decarboxylative hydroalkylation of alkynes, and Lu and Fu⁷ have disclosed a regiodivergent ligand-controlled alkyne hydroalkylation process. In comparison to terminal alkynes, internal alkynes have been far less explored as substrates in hydroalkylation chemistry,^5–8 yet their use would provide access to valuable trisubstituted alkene products.⁹ While Ni-catalyzed E-selective hydroalkylation reactions of internal alkynes have been described by Lu,¹⁰ we sought to expand access to thermodynamically less stable Z alkene isomers via copper hydride catalysis (Figure 1B).¹¹ Olefin stereochemistry and substitution patterns are implicitly tied to important properties, including the behavior of functional bioactive molecules,^12a polymeric materials,^12b and substrates for asymmetric catalysis.¹³ This calls for methods for the preparation of all classes of alkenes, especially highly substituted Z alkenes, for which general high-yielding protocols have yet to be developed.^4b Several catalytic avenues toward Z alkenes have been pursued including alkyne semihydrogenation,¹⁴ olefin cross metathesis,¹⁵ and the contra-thermodynamic photoisomerization of E alkenes.¹⁶ However, these strategies are currently largely limited to the preparation of disubstituted alkenes and in some cases suffer from low E/Z selectivity. With these limitations in mind, we considered that the copper hydride-catalyzed hydroalkylation of alkynes could provide access to highly substituted Z-configured alkenes (Figure 1B).

Figure 1.

(A) Contemporary challenges in catalytic synthesis of trisubstituted alkenes, (B) copper-catalyzed hydroalkylation of internal alkynes, and (C) proposed catalytic cycle.

Previously, our laboratories have reported that highly enantioselective hydromethylation^17a and hydroallylation^17b of vinyl arenes could be enabled using copper hydride catalysis. Prompted by these reports, we envisioned that syn-hydrocupration of alkyne substrates would provide access to stereochemically defined vinylcopper intermediates, which could then react stereospecifically with a suitable alkyl electrophile (Figure 1C). As observed previously in our work on vinyl arene hydromethylation,^17a we anticipated that alkyl iodides formed in situ from the corresponding tosylates and metal iodide salt would constitute the active electrophiles. The stereospecific reaction of vinylcopper intermediates with alkyl iodides would provide access to Z-configured alkenes, with catalyst turnover achieved through salt metathesis with a metal alkoxide and subsequent reaction of the resulting copper alkoxide with a silane (Figure 1C).

Herein, we describe the successful implementation of copper hydride-catalyzed alkyne hydroalkylation, which was observed to proceed with complete Z selectivity and high regioselectivity¹⁸ to produce a variety of pharmaceutically relevant (hetero)aryl-substituted alkene products. Key to the success of the method was the use of a DTBM-dppf-supported copper catalyst (DTBM = 3,5-(t-Bu)₂-4-MeOC₆H₂; dppf = diphenylphosphino ferrocene), which density functional theory (DFT) calculations suggest accelerates alkyne hydrocupration through combined ground and transition state effects.

Based on the well-documented ability of methyl substituents to positively impact the pharmacokinetic properties of small-molecule drugs,¹⁹ we began by targeting the hydromethylation of alkynes. Optimization studies commenced with model alkyne 1a using methyl tosylate (MeOTs) as the electrophile (Figure 2A). With our previously reported conditions for vinyl arene hydromethylation^17a involving the use of DTBM-SEGPHOS ligand and copper iodide catalyst, the hydromethylation of 1a was observed to take place with high stereo- and regioselectivity to provide the desired product 2a and regioisomer 3a in low yields (25% and 2%, respectively), along with the 1,2-disubstituted alkene byproduct 4a (8% yield), presumably arising from protodemetalation of the vinylcopper intermediate (Figure 2A, entry 1). A survey of bisphosphine ligands revealed that the use of dppf (L3) led to the formation of 2a in increased yield (52%, entry 3), however, further improvement could not be achieved through extended reaction times, higher catalyst loadings, or the use of other reaction conditions (see Supporting Information for full details). Conducting the hydromethylation with L4 (entry 4), in which the four phenyl substituents of L3 were replaced with tert-butyl groups, led to nearly complete inhibition of reactivity, suggesting that this position on the ligand might be particularly important for reactivity, potentially offering a site for targeted ligand modification to enhance the performance of the reaction.

Figure 2.

(A) Optimization studies: ^aReactions were conducted with 0.10 mmol of 1a. Conversions, yields, and regioselectivity values were obtained from ¹H NMR analysis of crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal standard. ^bThe reaction was conducted with 1.5 equiv of MeI instead of MeOTs. ^cThe reaction was conducted with 3 mol % TBAI, and nd = not determined. (B) DFT studies of ligand effects on hydrocupration and catalyst dimerization. Bond distances are reported in Å.

In our previously reported CuH-catalyzed alkene hydroamination chemistry, modification of the phosphino-phenyl groups of the SEGPHOS ligand to DTBM-substituted arenes led to substantial increases in reactivity for all classes of alkene substrates examined.²⁰ Mechanistic analysis concluded that this effect could be attributed to acceleration of alkene hydrocupration through stabilizing dispersive interactions involving the alkene substrate and tert-butyl groups of the DTBM-substituted ligand.²¹ With these observations in mind, we replaced the phosphino-phenyl groups of dppf with DTBM-substituted arenes to form L5 (Figure 2A, bottom). The use of L5 under the standard reaction conditions led to the production of 2a in the highest yield (87%, entry 5) with excellent regioselectivity and complete stereoselectivity for the Z-configured alkene.^22,23

DFT calculations were conducted to provide insight into the difference in the performance of ligands L3 and L5 (Figure 2B). Calculations were performed at the M06/6–311+G(d,p)–SDD/SMD(THF)//B3LYP-D3/6–31G(d)–SDD level of theory to investigate the rate of hydrocupration, which was identified as the rate-determining step based on the computed reaction energy profiles (see Figures S1 and S2 in the SI). The alkyne hydrocupration with the DTBM-dppf (L5)-supported CuH requires a slightly lower activation barrier compared to that with the dppf (L3)-supported catalyst (ΔG^⧧ = 21.4 and 22.1 kcal/mol, respectively, with respect to the monomeric CuH). Energy decomposition analysis (EDA)²⁴ calculations revealed that the dominant stabilizing factor for the hydrocupration transition state is the attractive dispersion interactions (ΔE_disp) between the tert-butyl substituents of L5 and the alkyne substrate 1b, including C–H/π and C–H/C–H²¹ interactions with the aryl and alkyl substituents on the alkyne (Figure S4). Another important feature of the bulky tert-butyl groups of L5 is to destabilize the catalytically inactive CuH dimer, an off-cycle intermediate prior to hydrocupration (7, Figure 2B, bottom).²⁵ These calculations suggest that L5 accelerates the transformation through the combined effects of stabilizing the hydrocupration transition state through non-covalent dispersion interactions and increasing the concentration of active monomeric copper hydride catalyst (6).

The use of CuI was found to be critical to the performance of the reaction, with the use of CuOAc or CuBr leading to lower yield and increased formation of disubstituted alkene product 4a arising from protonation of the vinylcopper intermediate (Figure 2A, entries 6, 7). The dependence of yield and product selectivity on the identity of the copper anion implies a direct role for the anion in promoting the productive chemistry. Although MeOTs is a competent electrophile, its sluggish reactivity allows for the competing vinylcopper protonation to take place. These observations are consistent with the mechanistic proposal that methyl iodide (MeI) is formed in situ from the reaction of NaI and MeOTs and at least partially represents the active methylating reagent, as observed previously in our report on vinyl arene hydromethylation.^17a,26 Indeed, DFT calculations support that methylation occurs preferentially using MeI, whereas the alkylation with MeOTs requires a 12.4 kcal/mol higher barrier (see Figure S5 in the SI). While the use of MeI directly in the reaction was found to be unproductive (Figure 2A, entry 8), this is likely due to the competitive alkylation of the metal alkoxide base to form MeOTMS.²⁷ Conducting the reaction with catalytic (3 mol %) tetrabutyl ammonium iodide (TBAI) was found to provide a beneficial effect on yield and product selectivity when CuBr was used as the catalyst (Figure 2A, entry 9), further supporting MeI as the active electrophile. Finally, several mechanisms of vinylcopper alkylation by MeI were evaluated using DFT calculations. An oxidative addition/reductive elimination sequence (Figure 3A)^17a,28 requires an activation free energy of 19.6 kcal/mol. An outer-sphere dissociative single electron transfer (DET, Figure 3B)²⁹ pathway requires an activation free energy of >30 kcal/mol. However, a direct S_N2 reaction³⁰ involving the vinylcopper intermediate has a significantly lower computed barrier (ΔG^⧧ = 13.5 kcal/mol, Figure 3C). Here, the oxidative addition pathway is disfavored due to the steric bulk of the DTBM-dppf ligand, which has a wide computed bite angle of 107.2°. Instead, the methylation proceeds via the direct S_N2 pathway without forming a sterically more encumbered Cu(III) intermediate (see Figure S7 in the SI for intrinsic reaction coordinate (IRC) calculations that confirmed the concertedness of the computed S_N2 pathway).

Figure 3.

DFT calculations of alkylation mechanisms.

With optimized reaction conditions in hand, we explored the scope of the newly developed hydromethylation method (Figure 4, R = methyl). A diverse set of N-heteroaryl aryl alkyne substrates was found to efficiently undergo hydromethylation to form Z-configured alkene products in moderate to high yields with high regioselectivity favoring methylation at the α position. In all cases, complete selectivity for the Z-configured products was observed. The method was found to generate trisubstituted alkenes possessing various N-heterocycles, including quinoline (2c, 2i), pyrimidine (2d, 2g), indole (2e), pyridine (2h), and benzoxazole (2j). Notably, hydromethylation could be carried out successfully with d₃-methyl tosylate to form the deuteromethylated thiazole 2l in comparable yield (81%) to its CH₃ analog 2k (82%).

Figure 4.

Hydoalkylation reactions of alkynes. Reported yields correspond to the yield of isolated product, averaged over two runs. All reactions were conducted with 0.50 mmol of alkyne substrate and 0.75 mmol of alkyl tosylate substrate. Regioisomeric ratios (r.r.) were determined using ¹H NMR analysis of crude reaction mixtures. ^aConducted using conditions A. ^bConducted using conditions B. ^cConducted with 0.75 mmol (1.5 equiv) of BnBr as the electrophile.

This method was successfully extended to enable alkyne hydroalkylation with a variety of primary alkyl tosylates (Figure 4, R ≠ methyl). The addition of catalytic quantities (10 mol %) of exogenous iodide in the form of TBAI was found to exert a beneficial effect on the reaction yield, again supporting the hypothesis that alkyl iodides represent the kinetically active form of the electrophiles (see the Supporting Information for details). Copper-catalyzed hydroalkylation was carried out with a number of alkyl tosylate electrophiles to produce trisubstituted alkenes with complete selectivity for the Z-configured products. An alkyl chloride (2n), ester (2u), and acetal (2v) were well-tolerated, allowing for the generation of products possessing versatile functional handles. Hydroalkylation could be performed using more sterically encumbered β-branched electrophiles to produce products 2o and 2r in good yields. In addition, we found that the use of benzyl bromide as an electrophile led to productive hydrobenzylation, a reaction for which very few methods exist, to form product 2s in good yield.³¹ The hydroalkylation protocol was found to be amenable to preparative scale synthesis (Figure 5). Hydroalkylation of commercially available diphenylacetylene (8) with alkyl tosylate OTs-e was performed on gram scale (4.0 mmol with respect to 8) to afford the corresponding hydroalkylated product 2w in 61% yield.

Figure 5.

Application of the hydromethylation reaction to a preparative scale synthesis.

In summary, we have disclosed a highly stereo- and regioselective copper-hydride-catalyzed method for the synthesis of trisubstituted alkenes via alkyne hydroalkylation. The choice of the copper-supported ligand for this transformation was found to be critical, with DTBM-dppf proving optimal. DFT calculations reveal a direct role of the DTBM-substituted ligand in accelerating alkyne hydrocupration through combined effects of transition state stabilization via attractive dispersion interactions and ground state destabilization of inactive CuH dimers. The hydroalkylation protocol was found to exhibit a broad substrate scope, providing access to a variety of Z-configured trisubstituted alkene products bearing medicinally relevant heterocyclic cores. Our future efforts are directed toward applying the insights gained from this study to other alkyne hydrofunctionalization reactions.