1,2-Diborylsilanes: Catalytic Enantioselective Synthesis and Site-Selective Cross-Coupling

Abstract

A Pt-catalyzed enantioselective hydrosilylation of (Z)-1,2-diborylethylene provides a 1,2-diboryl-1-silylalkane that can be used in catalytic cross-coupling reactions. Depending on the catalyst employed and the cross-coupling reaction conditions, the coupling can occur at either α or β relative to the silane center.

Graphical Abstract

Due to their high reactivity and their ability to undergo stereospecific transformations, chiral organometallic compounds are valuable reagents in modern organic chemistry.¹ Amongst these species, structures bearing two or more organometallic groups can be employed to address complexity-generating synthesis via sequential chemoselective transformations.² As alternatives to reactive organometallic reagents such as organolithium compounds³ or Grignard reagents, organoboron and organosilicon reagents have attracted attention in recent years due to their configurational stability, low-toxicity, and versatility.⁴ These compounds can undergo an array of C–C and C–heteroatom bond formation via transition metal catalyzed cross-coupling reactions such as the Suzuki–Miyaura⁵ and Hiyama–Denmark reactions.⁶ While significant effort has been directed towards the preparation and utilization of motifs bearing multiple boronic esters such as diboryl⁷ and triborylalkanes⁸, due to challenges in the stereoselective synthesis of requisite reagents, the utility of dimetallic reagents bearing silanes is less explored. Considering the polyfunctionalization that might emanate from silylborylalkanes⁹, we initiated studies on a modular route to these materials along with a study of their transformations.

Often employed as carbanion precursors or masked alcohols, organosilanes possess unique electronic properties. Despite the large size of silanes, the elongated Si–C bond distance reduces steric hindrance¹⁰ while still offering electronic modulation of reactivity due to the α¹¹ and β¹² silicon effect. These unique properties offer useful reactivity to silylboronate intermediates, especially geminal borylsilylalkanes.¹³ It was hypothesized that a chiral trifunctional diborylsilylalkane might allow sequential functionalization thereby affording useful routes to enantiomerically-enriched building blocks. Pioneering investigations by Yun showed that these reagents could be prepared by enantioselective Cu-catalyzed double borylation of silylacetylenes (Figure 1a).¹⁴ As an alternate route, the Chen group accessed α-silyl-β-boryl-allylboronates by diboration of allenylsilanes (Figure 1b).¹⁵ Whereas these two studies examined oxidation and allylation of diborylsilylalkanes, studies in cross-coupling have not been undertaken. Addressing related compounds, regioselective coupling of enantiomerically-enriched vicinal bis(boronates) with either palladium catalysts,¹⁶ or copper catalysts (Figure 1c)¹⁷ have been described. These processes occur by transmetalation at the less hindered primary boronate, followed by coupling with the electrophile. In this connection, our interest in examining 1,2-diborylsilanes (1, Figure 1d), compounds that contain the structural features of both vicinal bis(boronates) and α-boryl silanes, derives from fundamental questions about whether the boronate or the silyl group participates in transmetalation preferentially, whether the site-selectivity of coupling depends on the nature of the catalyst, and whether steric effects or electronic effects dictate regioselectivity of coupling.¹¹ In this report we show that coupling of electrophiles can be controlled by the catalyst and offers a route for the rapid synthesis of diverse molecules based on the simple diborylsilane skeleton.

Figure 1.

(a) Catalytic enantioselective preparation of 1,2-diborylsilanes from alkynes. (b) Enantioselective diboration of allenylsilanes. (c) Catalytic coupling reactions involving vicinal bis(boronates). (d) This work: complementary site-selective couplings of 1,2-diboryl-1-silylalkanes

Expecting that 1,2-diboryl-1-silylalkanes might be useful chiral building blocks, we initiated studies on the development of a method to prepare these compounds in a catalytic asymmetric fashion. Strategies involving enantioselective diboration¹⁸ of vinylsilanes¹⁹ were examined first and as depicted in Figure 2A (entries 1–4, see Supporting Information for additional data) either provided modest yield or modest selectivity. We suspect that the diminished selectivity relative to reactions of 1-alkenes and styrenes²⁰ results from an elongated C–Si bond that results in lessened catalyst substrate interaction. As an alternative method, Pt-catalyzed hydrosilylation of diboryl ethylene was examined and was found to occur with good efficiency (entries 5–13).²¹ The requisite (Z)-diborylethylene (2) could be accessed in quantitative yield from Zr-mediated reduction of diborylacetylene.²² Examination of a collection of taddol-derived phosphoramidite ligands revealed L6 (Figure 2B, entries 11, 12) to be highly effective, providing quantitative yield and 94:6 er when the reaction was conducted in THF solvent. Other taddol-derived ligands were also surveyed and gave moderate reactivity and enantioselectivity (Figure 2B, entries 5–10). Of note, because (Z)-2 is symmetrically substituted, its reaction doesn’t suffer from regiochemical concerns and, in a quadrant diagram analysis²³(Figure 2C), the two prochiral faces of the alkene are well distinguished. The use of the (Z)-diborylethylene was crucial to obtain a high level of enantioselectivity, as the analogous (E)-diborylalkene reacted with diminished selectivity despite furnishing the same enantiomer of product (entry 13). Quadrant diagram analysis (Figure 2C) suggests that steric bulk from the catalyst ensemble may extend from quadrant a into quadrant b thereby enhancing selectivity for the cis alkene but diminishing selectivity for the trans alkene. In addition to Me₂PhSiH, Me₂PMPSiH, Me₂BnSiH and Et₃SiH also showed high reactivity and modest to good enantioselectivity (entries 14–16, Figure 2B).

Figure 2. Development of a Catalytic Enantioselective Synthesis of Silyldiboronates.

A. Diboration of vinyl silanes. B. Hydrosilation of 1,2-diborylethylene. C. Analysis of selectivity with cis versus trans substrates. ^aYields are of isolated material after purification by column chromatography. Reactions were carried out with 0.20 mmol of substrate and 1 mL of solvent. ^bReaction carried out using (E)- diborylalkene.

With a route to chiral enantiomerically-enriched 1,2-diboryl organosilanes established, we initiated studies on the reactivity of these species. Initial studies focused on the copper-catalyzed reaction of racemic 1,2-diborylsilanes, which were readily prepared by diboration of commercially available dimethylphenylvinylsilane.^24,25 Similar to previous studies on copper-catalyzed coupling of vicinal diboronates¹⁷, CuCN was initially employed as catalyst for coupling reactions with allyl bromide serving as the electrophile. In contrast to reactions with 1,2-diborylalkanes, when the 1,2-diborylsilane 1a was used as the substrate, the reaction occurred at the more substituted carbon and produced allylation product 3a as a single regioisomer (Figure 3). We considered that the reversal of regioselectivity might arise as a result of α silicon effect: during transmetalation, the incipient σ_C–Cu may be stabilized by donation into the adjacent σ*_C–Si.²⁶ To probe the role of the vicinal diboronate motif, experiments with α-boryl silane 4 and β-boryl silanes 5 and 6 were also conducted. These reactions did not provide any product and returned the substrate unchanged thereby indicating the activating effect of the 1,2-diboryl motif in facilitating the reaction of substrates 1a and 1e.

Figure 3. Copper-catalyzed coupling of allyl bromide with diborylsilanes (1).

Reaction of other borylsilanes (4–6) do not provide product.

With coupling conditions identified, we briefly examined the impact of reaction conditions and found CuCN●2 LiCl consistently provided the highest yields. The scope of the coupling was then examined with different classes of electrophiles (Figure 4). As noted in previous studies,¹⁷ Cu complexes are known to engage a broad array of electrophiles. In addition to allyl bromide, electrophiles bearing other leaving groups such as allyl chloride, allyl iodide and allyl phosphate reacted with a similar level of efficiency (7). Functionalized allyl electrophiles were also found to be effective coupling partners. Aromatic, aliphatic, and halogenated substituents were well-tolerated and their presence did not alter the course of the reaction (products 8–12). Of note, the 2-silyl-4-alkenol products of this reaction sequence have been employed by others in stereoselective electrophile-induced cyclization.^27,28 Coupling reactions with trichloropropene gave the dichloroalkene 12 as product, which could be transformed into an ester functional group in one step.²⁹ In addition, S_N2’ coupling to substituted primary propargylic bromides afforded substituted terminal allenes (13–18) bearing different functional groups. These homoallenylsilanes are valuable synthetic intermediates and can undergo further chemoselective transformation.^30,31,32 Base-sensitive functional groups such as an alkyl bromide and an alkenyl silane survived the reaction intact. While most propargylic bromides gave rise to S_N2’ product, triisopropylsilyl (TIPS) protected propargyl bromide gave S_N2 product (19) only, presumably due to increased steric demand. Copper-catalyzed coupling with functionalized alkynyl bromides provided access to propargylic silanes 20–26, which were previously prepared via Cu-catalyzed 1,4-addition conjugate of silicon nucleophiles to alkyne-containing enones,³³ or alkynyl carbene insertion into Si−H bonds.³⁴ Apart from aryl- and alkyl-substituted alkynes, alkenyl substituents were also incorporated in the product. Lastly, with access to enantiomerically enriched substrate 1 from enantioselective hydrosilylation, we examined the stereospecificity of coupling reactions. The products of coupling to allyl (R-7, Figure 4), propargyl (R-15) and alkynyl (R-23) electrophiles occurred with near-perfect stereospecificity delivering chiral silane products. For compounds 20 and 7, the overall process was determined to occur with retention of configuration at carbon by correlation of both the starting material and the product with compounds of known configuration.

Figure 4. Scope of the Cu-catalyzed cross-coupling of α-boryl silylboronates and organic electrophiles.

Yields are of isolated material after purification by column chromatography.

With the knowledge that cooperative Pd/Cu co-catalysis might allow coupling of aromatic electrophiles,^{35 , 36} we envisioned that the alkyl−Cu intermediate derived from diborylsilanes 1 might undergo Pd-catalyzed cross-coupling. Probing this strategy, 5 mol% of Pd(OAc)₂/Ruphos and an aryl bromide were introduced into the copper-catalyzed coupling reactions (Figure 5). After purification of the reaction mixture, the corresponding coupling products were obtained in synthetically useful yield for several substrates. In general, electron-rich aromatic electrophiles were effective coupling partners regardless of their steric encumbrance. When alkenyl electrophiles were engaged in the reaction, the process delivered allylsilanes (33, 34), which are versatile reagents in organic synthesis.^37,38 Lastly, similar to the examples in Figure 3, when enantiomerically-enriched substrate was employed in the reaction, this co-catalyzed coupling occurred with useful levels of enantiospecificity (91% es for 27, 86% es for 28) and comparison of the product configuration to the substrate configuration showed the reaction occurred with net retention of configuration at carbon.

Figure 5. Scope of the Cu/Pd synergistic catalyzed cross-coupling of α-boryl silylboronates and organic electrophiles.

Yields are of isolated material after purification by column chromatography. ^aP(i-Pr)₃(6 mol%) was used instead of Ruphos.

While the Cu-catalyzed cross-coupling reaction with LiOMe as the activator resulted in regioselective coupling α to the silyl group, coupling at the site β to the silicon group could be effected with alternate activation conditions. As depicted in Figure 6, when the diborylsilane 1 was subjected to Pd-catalyzed cross-coupling reaction in the absence of copper cyanide, efficient cross-coupling with the primary boronic ester was observed.¹⁶ We suspect the small size and linear nature of CuCN allow it to transmetalate at the more hindered secondary boronate and benefit from the a-silicon effect, whereas the dramatically increased steric demand of a four-coordinate ligand-bearing palladium center prohibits transmetalation at the more encumbered site thereby resulting in the observed product. As expected, the configuration at the pre-existing stereocenter is essentially unperturbed during the coupling and it is notable that this cross-coupling could be extended to a series of other electrophilic substrates to furnish 36–41. The geminal silylboronates that arise from this reaction are known to be useful building blocks in the construction of allylsilanes, aminosilanes, amino alcohol derivative.^{21, 39}

Figure 6. Direct Pd-catalyzed cross-coupling of a β-silyl boronate with C(sp²) bromide electrophiles.

Yields are of isolated material after purification by column chromatography.

A last feature that was probed with respect to synthesis utility, was the possibility of conducting single flask hydrosilation/coupling sequences in such a way that the intermediate diborylsilane need not be isolated (Figure 7). Thus, starting from the (Z)-diborylethylene, Pt-catalyzed hydrosilylation and in situ Cu-catalyzed cross-coupling with allyl bromide furnished vicinal silylboronate (S)-7 in good yield and enantioselectivity. Similarly, Pt-catalyzed hydrosilylation followed by in situ Pd-catalyzed cross-coupling with bromobenzene afforded geminal silylboronate (R)-35 in good yield and enantioselectivity.

Figure 7.

Single-flask sequential catalytic hydrosilylation/Cu-catalyzed allylation of 1,2-bis(boryl)ethylene and single-flask sequential catalytic hydrosilylation/Pd-catalyzed cross-coupling.

In summary, we have demonstrated the regiodivergent transformation of 1,2-diborylsilanes by transition-metal catalyzed stereospecific reactions to afford functionalized organosilane products. The requisite reagents could be prepared with high level of enantiomeric purity by Pt-catalyzed enantioselective hydrosilylation. This method offers a synthetic route to useful silicon-containing building blocks in an efficient fashion.