The Stereochemical Course of Pd-Catalyzed Suzuki Reactions Using Primary Alkyltrifluoroborate Nucleophiles

Abstract

Using deuterium-labeled stereochemical probes, we show that primary alkyltrifluoroborate nucleophiles undergo transmetalation to palladium exclusively via a stereoretentive pathway and that the resulting stereospecificity is broadly independent of electronic and steric effects. This stands in stark contrast to the stereochemical course of transmetalation for secondary alkyltrifluoroborates, which varies between net stereoretention and net stereoinversion depending upon the electronic properties of the supporting phosphine ligand, the electronic properties of the aryl electrophile, and the steric properties of the alkylboron nucleophile. In this study, we additionally show that the stereochemical course of transmetalation for secondary alkylboron reagents can be under reagent steric control, while no such steric control exists for analogous primary alkylboron nucleophiles. The combined study reveals fundamental mechanistic differences between transmetalations of primary and secondary alkylboron reagents in Pd-catalyzed Suzuki reactions.

Graphical Abstract

Over recent decades, the emergence of Pd-catalyzed cross-coupling reactions has revolutionized our modern approach to organic synthesis. Oxidative addition, transmetalation, and reductive elimination constitute the fundamental steps in the standard catalytic cycle of cross-coupling reactions proceeding via a Pd(0)−Pd(II) redox couple.¹ Although oxidative addition and reductive elimination processes are mechanistically well understood, the prevailing mechanistic pathway of transmetalation can be less clear.^2,3 This is especially true for Suzuki cross-coupling reactions involving alkylboron nucleophiles.⁴ In principle, transmetalation of an alkylboron nucleophile can occur with retention (Figure 1a) or inversion (Figure 1b) of the absolute configuration. As such, the stereochemical outcome of Suzuki cross-coupling reactions involving enantioenriched alkylboron compounds is often difficult to predict.

Figure 1.

Putative mechanistic pathways for stereoretentive and stereoinvertive transmetalation of alkylboron nucleophiles.

The Biscoe/Sigman laboratories⁴ and the Burke laboratory⁵ have each reported approaches toward stereospecific Pd-catalyzed Suzuki reactions using unactivated enantioenriched secondary alkyltrifluoroborates (i.e., without α-heteroatom substitution, α-C(sp²) substitution, or remote coordinating groups).^6–9 Our study resulted in the development of a stereodivergent Suzuki process in which the preferred stereochemical course was intimately tied to the electronic properties of the supporting phosphine ligand (Figure 2a). In these cross-coupling reactions, the bulky electron-deficient ligand bis-CF₃PhXPhos¹⁰ (1) promoted a stereoretentive transmetalation pathway, whereas bulky electron-rich ligands P^tBu₃ and Pad₃ (2)¹¹ promoted a stereoinvertive transmetalation pathway. This study also revealed that the electronic properties of the aryl electrophile can bias the transmetalation pathway. In contrast to our observation, Molander and Dreher (Figure 2b) have shown that 2-methylcyclohexyltrifluoroborate (3) undergoes stereoretentive arylation using the bulky electron-rich ligand P^tBu₃.¹² These seemingly conflicting stereochemical outcomes suggest that the steric effects of 3 preclude transmetalation via the stereoinvertive pathway (see Figure 7 within for a model). Thus, steric properties can potentially override ligand properties in dictating the stereocontrol of transmetalation. Collectively, these results suggest that the electronic properties of the phosphine ligand and electrophilic coupling partner, as well as the steric properties of the alkylboron nucleophile, can independently bias the stereochemical outcome of B-alkyl Suzuki reactions. Hence, the factors influencing the prevailing pathway of alkylboron transmetalation are much more nuanced than were previously appreciated.

Figure 2.

Stereospecific Pd-catalyzed Suzuki cross-coupling reactions using unactivated nucleophiles: (a) ligand-controlled stereodivergent Suzuki reactions; (b) stereoretentive transmetalation of 3; (c) previous use of isotopically labeled alkyl-9-BBN nucleophiles as stereochemical probes; (d) investigation of the stereochemical course of alkylboron transmetalation described in this study.

Figure 7.

Models depicting (a) proposed sterically controlled transmetalation of 3, (b) hindered stereoinvertive transmetalation of 11, and (c) minimally hindered stereoinvertive transmetalation of 12.

Using the Whitesides protocol for probing the stereochemical course of organometallic reactions,^13,14 Woerpel¹⁵ and Soderquist¹⁶ conducted seminal mechanistic investigations of primary alkylboron transmetalation to palladium. In these studies, vicinally deuterated primary alkyl-9-BBN nucleophiles (syn-4 and anti-4) were employed in Suzuki cross-coupling reactions, with the vicinal J_H–H coupling constant being indicative of the stereochemistry of the resulting product (Figure 2c). The investigations showed that transmetalation of primary alkyl-9-BBN nucleophiles to palladium proceeds with retention of configuration for alkylboron nucleophile 4. Though these studies provided an important foundation on which to build our mechanistic understanding of alkylboron transmetalation, recent transmetalation studies using enantioenriched secondary alkyltrifluoroborate nucleophiles imply that primary alkylboron transmetalation might likewise proceed through competing mechanisms that are highly sensitive to ligand, electronic, and steric effects.^4,5,12 Additionally, because alkyl-9-BBN reagents exhibit nucleophilicity more comparable to that of alkylzinc reagents, it is unclear how the stereochemical course of their transmetalation relates to that of less reactive alkyltrifluoroborates, boronic acids, or boronic esters. Herein we report on the stereochemical course of transmetalation for Suzuki cross-coupling reactions involving primary alkyltrifluoroborate nucleophiles.¹⁷ Using vicinally deuterated alkyltrifluoroborate reagents as stereochemical probes, we have conducted studies to deconvolute potential stereochemical effects arising from electronic, steric, and ligand effects within the reaction components. Through careful evaluation of these effects, we have determined that, unlike the transmetalation of secondary alkyltrifluoroborates, the transmetalation of primary alkyltrifluoroborates proceeds preferentially via a stereoretentive pathway that is independent of electronic, steric, and ligand perturbations.

Starting from tert-butylacetylene, we successfully prepared the vicinally deuterated alkyltrifluoroborate compounds syn-6 and anti-6 as stereochemical probes of transmetalation to palladium (Figure 3). Unlike previously employed alkyl-9-BBN reagents,^15,16 alkylBPin compounds syn-5 and anti-5 are isolable and are easily characterized. An examination of the vicinal J_H–H coupling constants from their ²H-decoupled ¹H NMR spectra supports their stereochemical assignments (Figure 4a). Representative cross-coupling products syn-7c and anti-7c are shown in Figure 4b. As with syn-5 and anti-5, the relative stereochemistry of syn-7c and anti-7c is easily established using the vicinal J_H–H coupling constants from their ²H-decoupled ¹H NMR spectra. Because we sought to determine the dominant transmetalation mechanism while also investigating the possibility of competitive transmetalation pathways, it was important that we obtained clearly resolved quantifiable signals indicative of syn or anti stereochemistry. An 800 MHz NMR instrument was thus employed to ensure that trace impurities from the preparation of deuterated probes or from the coupling reactions could be clearly identified and not mistaken as products arising from a minor transmetalation pathway. Accordingly, because anti-5 showed greater isotopic purity in comparison to syn-5, the use of anti-5 and anti-6 as stereochemical probes enabled a clearer evaluation of the stereochemical course of transmetalation.

Figure 3.

Synthetic routes to deuterated stereochemical probes syn-6 and anti-6.

Figure 4.

²H-decoupled ¹H NMR (800 MHz) spectra showing vicinal J_H–H coupling constants for deuterium-labeled (a) alkyltrifluoroborates syn-5 and anti-5 (0.66–0.70 ppm range shown) and (b) cross-coupling products syn-7c and anti-7c (1.42–1.46 ppm range shown). Minor peaks appearing in (a) alongside syn-5 arise from isotopic impurities (e.g., t-BuCH₂CHD-BPin and/or t-BuCHDCH₂–BPin—see refs14 and 16).

Our discovery that the stereochemical course of transmetalation of secondary alkyltrifluoroborates to LPd(Ar)X complexes is dictated by the electronic properties of the supporting phosphine ligand (L) as well as by the electronic properties of the aryl unit (Ar) suggested that the mechanism of primary alkylboron transmetalation may likewise proceed via competing stereoretentive and stereoinvertive pathways depending on the specific components of the cross-coupling reaction.⁴ Accordingly, anti-6 was employed in cross-coupling reactions using bis-CF₃PhXPhos (1), which has been to shown to promote the stereoretentive transmetalation of secondary alkyltrifluoroborates, and using P^tBu₃, which has been shown to promote the stereoinvertive transmetalation of secondary alkyltrifluoroborates (Table 1). Because we have observed that the use of electron-rich aryl electrophiles can bias the transmetalation of secondary alkyltrifluoroborates toward the stereoinvertive pathway, reactions of primary alkyltrifluoroborates were conducted using electron-deficient, electron-neutral, and electron-rich electrophilic coupling partners. The use of electronically differentiated electrophiles thus enabled an assessment of the effect of subtle electronic changes on the net stereochemical course of transmetalation. For all such reactions of anti-6, only the stereoretentive transmetalation pathway was observed.¹⁸ The use of syn-6 also provided stereochemical data consistent with stereoretention, though the presence of isotopic impurities in syn-6 complicated its use as a mechanistic probe (see the Supporting Information for a complete study using syn-6). No stereochemical variance resulted when the phosphine ligand was changed from bis-CF₃PhXPhos (1) to P^tBu₃ or when the aryl electrophile was varied. To assess the possibility that transmetalation is influenced by the identity of the leaving group on the aryl electrophile, we also investigated the use of aryl bromides and triflates in analogous reactions. These reactions, likewise, resulted in exclusive formation of the cross-coupling products from stereoretentive alkylboron transmetalation. Finally, the direct use of the alkyl pinacol boronate probe anti-5 was employed to determine the preferred transmetalation pathway for pinacol boronate nucleophiles, which undergo slower transmetalation to palladium in comparison to their corresponding trifluoroborate and boronic acids.^3a Though cross-coupling conditions developed by our group for use with alkyltrifluoroborates failed for anti-5,¹⁹ reaction conditions developed by Liu, Marder, and Steel^17k specifically for use with primary alkyl pinacol boronates successfully generated the cross-coupling product anti-7c (Figure 5), again via a stereorententive transmetalation pathway. Together, these results suggest that, unlike transmetalation of unactivated secondary alkyltrifluoroborates, the transmetalation mechanism of unactivated primary alkylboron nucleophiles proceeds exclusively through a stereoretentive pathway that is insensitive to the electronic properties of both the phosphine ligand and aryl electrophile.²⁰

Table 1.

Pd-Catalyzed Suzuki Cross-Coupling Reactions of Vicinally Deuterated anti-6 Using the Electron-Rich Ligand P^tBu₃ and the Electron-Deficient Ligand 1

^aVicinal JH–H coupling constant of alkylBPin derivative 5.

^bCalibrated GC yields (average of two runs).

Figure 5.

Pd-catalyzed Suzuki cross-coupling reaction of vicinally deuterated pinacol boronate anti-5 using the conditions of ref 17k.

Though the data presented in Table 1 suggest that the mechanism of transmetalation of unactivated primary alkyltrifluoroborates is broadly independent of electronic effects, we were concerned that the steric properties of the tert-butyl substituent of anti-6 might override electronic effects from the phosphine ligand and aryl electrophile, resulting in a sterically controlled pathway of transmetalation. Indeed, the Whitesides protocol for stereochemical analysis using vicinal coupling constants requires the presence of such a bulky β substituent to bias conformational preference toward the anti conformer (Figure 2c). Additionally, a report from Molander and Dreher (Figure 2b) demonstrating stereoretentive transmetalation of trans-2-methylcylcohexyltrifluoroborate (3) using P^tBu₃ as the supporting phosphine contrasts with our observation that P^tBu₃ promotes stereoinvertive transmetalation of unhindered and unactivated secondary alkyltrifluoroborates (Figure 2a). To gain general insight into the potential steric effects on alkylboron transmetalation and the divergent stereochemical outcomes using P^tBu₃, we prepared a cis/trans (ca. 5/1) mixture of 4-tert-butylcyclohexyltrifluoroborate (9) for use as a probe of alkylboron transmetalation. Though 3 is capable of conformation equilibration through ring inversion, which complicates mechanistic and kinetic analysis, 9 strongly favors a conformation that places the tert-butyl group in the equatorial position, which greatly simplifies an assessment of the stereochemical course of transmetalation. Using P^tBu₃ as a ligand, Suzuki coupling of cis-9 occurs rapidly (half-life of approximately 10 min) and exclusively generates trans-10 with clean stereoinvertive transmetalation. In contrast, Suzuki coupling of trans-9 proceeds very slowly (half-life of approximately 2 h) and occurs with stereoretentive transmetalation, also generating trans-10 as the exclusive reaction product (Figure 6).²¹ These results are easily rationalized, as cis-9 freezes the boron group in an axial position from which the stereoinvertive S_E2 pathway of transmetalation is readily accessed, while trans-9 freezes the boron substituent in an equatorial position from which the stereoinvertive S_E2 pathway of transmetalation is hindered by axial repulsions (Figure 6, inset). Because trans-9 cannot undergo stereoinvertive transmetalation, the slow stereoretentive S_E2 pathway emerges as the only viable option. The comparative kinetics of these reactions, alongside the exclusive formation of trans-10 from both reactions, is consistent with sterically controlled transmetalation for trans-9. On the basis of these results, we propose that the stereoretentive Suzuki reaction of 3, which was demonstrated by Molander and Dreher using P^tBu₃, arises from steric control of the transmetalation pathway (Figure 7a). Stereoinvertive transmetalation of conformer 3a is impeded by axial repulsions, while stereoinvertive transmetalation of conformer 3b is impeded by its lower abundance at equilibrium as well as potential steric effects arising from the β-anti-methyl group. Thus, it is vital that potential steric effects also be considered when predicting or rationalizing the stereochemical course of alkylboron transmetalation.

Figure 6.

Relative reaction rates of cis-9 and trans-9 in Pd-catalyzed Suzuki reactions using P^tBu₃ as a ligand.

In order to minimize the potential steric effect on the stereochemistry of transmetalation using primary alkyltrifluoroborates, we redesigned our stereochemical probe. In our new approach, we employed a CH₂OSiPh₂^t Bu group as the bulky β substituent, which enables an assessment of syn and anti stereochemistry in the cross-coupling products, as shown by Woerpel (Figure 7b,c).¹⁵ However, following preparation of vicinally deuterated alkylBPin compound 13, the bulky silyl group was removed and replaced with a much smaller CH₂OMe (MOM) protecting group on the alkylboron probe (12) (Figure 8). Thus, the mechanism for stereoinvertive transmetalation of 12 should be significantly less sensitive in comparison to 11 to the steric properties of the β substituent (Figure 6b,c). Following the use of 12 in cross-coupling reactions, the bulky silyl group was reinstalled to enable differentiation of syn- and anti-14. When cross-coupling reactions were performed using 12, the stereoretentive pathway of transmetalation was again observed, independent of the ligand and the electronic properties of the aryl electrophile (Table 2).²² These results strongly suggest that the general stereochemical course of transmetalation for primary alkylboron nucleophiles proceeds via a stereoretentive mechanism and that the stereospecificity is not influenced by steric perturbations of the alkylboron nucleophile or by the electronic properties of the phosphine ligand and aryl electrophile. These results stand in stark contrast to the mechanism of transmetalation of secondary alkylboron nucleophiles, which is strongly influenced by subtle electronic and steric properties of the supporting ligand and coupling partners.

Figure 8.

Reaction sequence used to establish the stereospecificity of Pd-catalyzed Suzuki reactions using syn-12.

Table 2.

Pd-Catalyzed Suzuki Cross-Coupling Reactions of Vicinally Deuterated syn-12 Using the Electron-Rich Ligand P^tBu₃ and Electron-Deficient Ligand 1

^aIsolated yield over three steps (average of two runs).

In summary, we have shown that primary alkyltrifluoroborate nucleophiles undergo transmetalation to palladium exclusively via a stereoretentive pathway and that the resulting stereospecificity is broadly independent of electronic and steric effects. This contrasts with the pathway of transmetalation for secondary alkyltrifluoroborates, which varies between net stereoretention and net stereoinversion depending upon the electronic properties of the supporting phosphine ligands, the electronic properties of the aryl electrophile, and the steric properties of the alkyltrifluoroborate nucleophile. During these studies, sterically controlled transmetalation of secondary alkylboron nucleophiles was also demonstrated for the first time, which highlights the importance of considering steric effects in attempting to predict or rationalize the stereochemistry of secondary alkyl Suzuki reactions. The insensitivity of the stereochemical course of primary alkylboron transmetalation to electronic (ligand and substrate) and steric properties indicates that the mechanisms of transmetalation for primary and secondary alkylboron nucleophiles are mutually distinct and underscores the intrinsic complexity of alkylboron transmetalation. These mechanistic insights should help to guide the future design of new strategies for Pd-catalyzed B-alkyl Suzuki cross-coupling reactions involving primary and secondary alkylboron reagents.