Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and Pd Catalysis

Abstract

Detailed in this Communication is the enantioselective synthesis of 1,1-diarylalkanes, a structure found in a range of pharmaceutical drug agents and natural products, through the employment of copper(I) hydride and palladium catalysis. Judicious choice of ligand for both Cu and Pd enabled this hydroarylation protocol to work for an extensive array of aryl bromides and styrenes, including β-substituted vinylarenes and six-membered heterocycles, under relatively mild conditions.

Palladium-catalyzed cross coupling has proven to be a successful and reliable method for carbon–carbon bond construction. Among the many substrate classes employed in this field, stoichiometric organometallic reagents (e.g., Mg, Zn, Sn reagents) are traditionally used as coupling partners in Pd chemistry due to their propensity for facile transmetalation, and much successful work has been realized with the use of these reagents to generate functionalized arenes.¹ Drawbacks associated with the use of stoichiometric organometallic reagents, including their possible sensitivity toward air/water, promiscuity toward undesired pathways of reactivity, and necessity to preform them before their use in cross coupling, have inspired methods avoiding their intermediacy.²

Recent advances in Cu chemistry have demonstrated that nucleophilic alkylcopper(I) species can be generated catalytically via olefin insertion and successfully intercepted with a range of electrophiles.^3,4 As an alternative to stoichiometric organometallic reagents, we questioned whether an Cu(I) alkyl intermediate of this nature could be generated catalytically and exploited in a Pd-catalyzed cross-coupling process to yield the corresponding sp²–sp³ cross-coupled product (Scheme 1). Importantly, we sought a chiral CuH catalyst that would effect an enantioselective olefin hydrocupration to form a stereodefined Cu(I) intermediate, which would undergo transmetalation with Pd with high stereospecificity, ultimately leading to an enantioenriched coupling product. Using this approach, we anticipated that a suitable combination of Cu and Pd catalysts would allow for the enantioselective coupling of styrenes with aryl bromides to form 1,1-diarylalkanes, a biologically active structure common in both pharmaceuticals and natural products.⁵

Scheme 1. (A) Enantioselective Access to 1,1-Diarylalkanes via Pd and Cu Catalysis; (B) Proposed Catalytic Cycle for Enantioselective Hydroarylation of Styrenes.

Enantioenriched 1,1-diarylalkanes have previously been prepared through the stereospecific cross coupling of enantioenriched benzylic electrophiles.^6,7 A nickel-catalyzed stereoconvergent coupling of racemic benzylic alcohols with arylzinc reagents has also been reported.⁸ Methods that employ prochiral substrates include asymmetric hydrogenation of 1,1-diarylalkenes⁹ and conjugate addition of arylmetal nucleophiles to cinnamaldehyde derivatives.¹⁰ Our approach represents a highly modular alternative for the enantioselective synthesis of this class of compounds. Moreover, aryl bromides and vinylarenes are widely available reagents or feedstock chemicals and are therefore nearly ideal coupling partners.¹¹

Pioneering efforts by several researchers have demonstrated the synergistic potential of Cu and Pd catalysis.¹² More recently, Nakao¹³ and Brown¹⁴ have both reported the diastereoselective borylarylation of styrene derivatives using both Cu and Pd in catalytic quantities, while Liao¹⁵ demonstrated the enantioselective boroallylation of vinylarenes using a similar system. At the outset of this project, the use of CuH and Pd catalysis in a cooperative manner for hydrofunctionalization was unknown. However, a report detailing the Pd/Cu-catalyzed hydroarylation of styrenes to furnish racemic 1,1-diaryl alkanes was recently published.¹⁶

Scheme 1B details our proposed dual catalytic cycle for enabling the described transformation. Formation of active CuH catalyst I would occur through the use of a Cu(I) or Cu(II) salt, chiral ligand, and silane. Enantioselective hydrocupration of olefin II would form stereodefined Cu(I) benzylic intermediate III.^17,18 In the second catalytic cycle, ligated Pd(0) IV would oxidatively add to the aryl bromide V to form complex VI. As the key step in this process, the dual catalytic cycle converges via a stereospecific transmetalation of organocopper III with Pd species VI to form chiral Pd(II) alkyl complex VII.¹⁹ Stereoretentive reductive elimination furnishes enantioenriched 1,1-diarylalkane VIII and regenerates Pd(0) species IV. Considering previous reports with CuH catalysis, we reasoned that salt metathesis of Cu(I) halide IX with base would be required to regenerate CuH catalyst I.²⁰ We believed that the success of our strategy was predicated on three issues: (i) competitive reduction of aryl halide V via a metal hydride species would need to be suppressed; (ii) choice in ligand would enable productive reactivity of each metal species while not deactivating the other; (iii) the rate of each metal cycle would need to be matched so as to avoid unproductive side reactions.

The optimization of an enantioselective hydroarylation process for styrene and 4-bromoanisole is detailed in Table 1. Examination of several silanes (entries 1–5) indicated that methyldiphenylsilane (MePh₂SiH) was the optimal silane tested when combined with sodium trimethylsilanolate (NaOTMS), providing a moderate yield and high level of enantioselectivity for the desired product (entry 4, 58% yield, 83% ee). NaOTMS was a uniquely effective base for this chemistry and little to no product was observed with LiOTMS and KOTMS.²¹ Testing several biarylphosphine ligands (entries 4, 6, and 7) showed that a modest increase in yield was observed when using BrettPhos as a secondary ligand (entry 6, 66% yield, 85% ee). Employing [Pd(cinnamyl)Cl]₂ as the source of Pd for this reaction resulted in improved reactivity while not significantly affecting the enantioselectivity of the process (entry 10, 75% yield, 88% ee). A range of Cu(I) and Cu(II) salts were examined, and a slight improvement was observed using CuOAc as the source of Cu (entry 11, 84% yield, 90% ee). Evaluation of a variety of chiral bisphosphines demonstrated that DTBM-SEGPHOS was an excellent ligand for this transformation with many other ligands giving significantly lower yield and enantioselectivity of the desired product.²²

Table 1. Optimization of the Pd/Cu-Catalyzed Enantioselective Hydroarylation of Styrene^a.

^aYields determined by GC analysis of the crude reaction mixture using tetradecane as an internal standard; enantioselectivity of the purified product was determined by chiral HPLC; ND = not determined.

^bCu(OAc)₂ used as the Cu source.

^cCuOAc used as the Cu source.

With the optimized conditions in hand, we turned toward examining the substrate scope of the aryl bromide coupling partners (Table 2).²³ Electron-rich aryl bromides (2a and 2n) worked well in this reaction, while 4-bromobenzonitrile and aryl bromides with acidic protons were not compatible with the reactions conditions. A range of functional groups, including ethers (such as 2a, 2h, 2i, 2k, and 2n), an ester (2c), a thioether (2d), an amine (2h), a carbamate (2l), an aryl chloride (2l), and an amide (2l), were all tolerated in this protocol. Employing ortho-substituted aryl bromides as viable substrates required a slightly higher reaction temperature and longer reaction times to provide the product (3n) in good yield and high enantiopurity. Importantly, a variety of brominated heterocycles, such as pyridines (e.g., 2b and 2m), quinolines (2f and 2t), a pyrimidine (2h), a pyridazine (2i), and an azaindole (2j), were competent coupling partners. In addition, a five-membered brominated heterocycle was effective (2o). Certain aryl bromides, such as 4-bromoisoquinoline (2e) and 5-bromo-1-methylindole (2g), resulted in moderate yields but poor to modest enantioselectivities (76% yield, 27% ee and 68% yield, 56% ee, respectively).²⁴ Characterization of 3i via X-ray crystallography revealed the absolute configuration of the stereocenter. This data, combined with the sense of stereoinduction observed with our method for CuH-catalyzed hydroamination of styrenes,^3d suggests that the proposed Cu-to-Pd transmetalation step occurs with retention of configuration (see Supporting Information for details).^25,26

Table 2. Scope of Aryl Bromide Coupling Partners^a.

^aAll yields represent the average of isolated yields from two runs performed with 1 mmol of styrene; enantioselectivity determined by chiral SFC.

^bAverage of isolated yields from three runs.

The scope of arylalkene coupling partners was then evaluated with a selection of aryl bromides (Table 3). Ortho-substituted styrenes were well tolerated in this chemistry (1m and 1n). Electron-rich arylalkenes productively coupled with good levels of yield and enantioselectivity (for example entry 1o, 66% yield, 93% ee), while an electron-deficient styrene (entry 1p) produced a much lower level of yield and stereoselectivity (23% yield, 61% ee). This might be indicative of the configurational stability of the RCu intermediate. Finally, β-substituted styrenes can be utilized in this transformation, affording good yields and reasonable levels of enantioselectivity (1s and 1t). Due to a more challenging hydrocupration step, a lower Pd catalyst loading (1 mol% Pd) was required for β-substituted styrenes, presumably to slow down competitive reduction of the aryl bromide and match the rate of the two productive catalytic cycles. In addition, a slightly elevated reaction temperature and use of dimethylphenylsilane (Me₂PhSiH) as the reductant was required to achieve good results with this class of olefins.

Table 3. Scope of Styrene Coupling Partners with Various Heteroaryl and Aryl Bromides^a.

^aAll yields represent the average of isolated yields from two runs performed with 1 mmol of alkene; enantioselectivity determined by chiral SFC.

^b2 equiv of Me₂PhSiH used as the silane; reaction run at 45 °C.

^cReaction run for 40 h.

^d0.5 mol% of [Pd(cinnamyl)Cl]₂ used with 1.1 mol% BrettPhos L3 and 2 equiv of Me₂PhSiH used as the silane; reaction run at 45 °C.

In conclusion, we report the enantioselective Pd/Cu-catalyzed hydroarylation of styrenes to form 1,1-diarylalkanes, a valuable structure in medicinal chemistry. This procedure performs well for a variety of aryl bromides, including six-membered heterocycles, to form the respective products in generally good yields and with high levels of enantioselectivity. A range of vinylarenes, including ortho- and β-substituted styrenes, were also productively coupled in this hydroarylation reaction. Extending this chemistry to other substrates classes is currently being explored in our laboratory.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b04566.

• Crystallographic data for 3i (CIF)

• Experimental procedures and characterization data for all compounds (PDF)

The authors declare the following competing financial interest(s): MIT has obtained patents for some of the ligands that are described in this Communication from which S.L.B. and former/current co-workers receive royalty payments.