Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling

Abstract

An asymmetric Ni-catalyzed reductive cross-coupling has been developed to prepare enantioenriched allylic silanes. This enantioselective reductive alkenylation proceeds under mild conditions and exhibits good functional group tolerance. The chiral allylic silanes prepared here undergo a variety of stereospecific transformations, including intramolecular Hosomi-Sakurai reactions, to set vicinal stereogenic centers with excellent transfer of chirality.

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Organosilanes are valuable organic materials with applications in medicinal chemistry,¹ materials science,² and as reagents for organic synthesis.³ In particular, chiral allylic silanes are versatile synthetic reagents that engage in a variety of highly stereoselective reactions. For example, the Hosomi-Sakurai reaction⁴ is a powerful method for C–C bond formation that provides homoallylic alcohols with excellent transfer of chirality when enantioenriched allylic silanes are used.^5,6 Despite the utility of this and related transformations, the enantioselective preparation of chiral allylic silanes often requires multistep sequences, or the incorporation of specific functional groups to direct the formation of the C(sp³)-Si bond. Here we describe a Ni-catalyzed asymmetric reductive cross-coupling to directly prepare enantioenriched allylic silanes from simple, readily available building blocks (Figure 1). The resulting chiral allylic silanes undergo a variety of post-coupling transformations with high levels of chirality transfer.

Figure 1.

Synthesis of Chiral Allylic Silanes by Enantioselective Ni-Catalyzed Reductive Cross-Coupling

Chiral allylic silanes are most commonly prepared through diastereoselective or stereospecific transformations,⁷ which include the Claisen rearrangement of vinyl silanes,⁸ bis-silylation of allylic alcohols,⁹ silylene insertion of allylic ethers,¹⁰ and the alkenylation of 1,1-silaboronates.¹¹ In addition, several enantioselective transition metal-catalyzed reactions have been developed, including the hydrosilylation of dienes,¹² the silylboration of allenes¹³, the insertion of metal carbenoids into Si-H bonds,¹⁴ and conjugate addition¹⁵ and allylic substitution¹⁶ reactions. Asymmetric transition metal-catalyzed cross-coupling, in which the critical silicon-bearing C(sp³) stereogenic center is established in the C–C bond forming step, represents an alternative and highly modular approach to chiral allylic silanes. Indeed, the first synthesis of an enantioenriched chiral allylic silane was the Pd-catalyzed asymmetric cross-coupling between α-(trimethylsilyl)benzylmagnesium bromide and 1-bromo-1-propene reported by Kumada and coworkers in 1982.^5a However, this method employs Grignard reagents as coupling partners, which are not stable to long-term storage and decreases the functional group compatibility of the reaction. We envisioned that a Ni-catalyzed asymmetric reductive alkenylation would address this limitation,¹⁷ in that the required (chlorobenzyl)silanes are bench stable compounds and these reactions typically exhibit good functional group tolerance. Thus, a Ni-catalyzed reductive alkenylation could provide chiral allylic silanes that were not readily accessible by other methods.

Our investigations began with the coupling between (E)-1-(2-bromovinyl)-4-methoxybenzene (1) and (chloro(phenyl)methyl)trimethylsilane (2a) using chiral bis(oxazoline) ligand L1, which was optimal in our previously developed enantioselective reductive alkenylation reaction (Table 1).¹⁴ A screen of reaction parameters revealed that when the reaction is conducted at 5 °C with with N-methyl-2-pyrrolidone (NMP) as the solvent,¹⁸ allylic silane 3a was formed in low yield, but with high enantioselectivity (entry 1). We hypothesized that the presence of the bulky silyl group impeded the oxidative addition of 2a to the Ni catalyst. The addition of cobalt(II) phthalocyanine (CoPc), a cocatalyst that enables the Ni-catalyzed cross-coupling of benzyl mesylates by facilitating alkyl radical generation,¹⁹ doubled the yield of 3a (entry 3). The yield of 3a increased when excess vinyl bromide was used (entries 3–5); since the use of 2.0 equiv 1 proved most generally robust across a range of substrates, these conditions were used to evaluate the scope of the reaction (see Tables 2 and 3). A screen of other bis(oxazoline) ligands, e.g. L2 and L3, determined that L1 provided the highest enantioselectivity (entries 6–7). The use of isolated complex L1·NiCl₂ gave 3a in comparable yield to the in situ generated catalyst (entry 8). Control experiments confirmed that NiCl₂(dme), ligand, and Mn⁰ are required to form 3a.¹⁵ To demonstrate scalability, the cross-coupling was conducted on a 6.0 mmol scale, delivering 1.3 g of 3a in 74% yield and 97% ee.

Table 1.

Optimization of Allylic Silanes

entrya	ligand	equiv 1	additiveb	yield 4 (%)c	yield 3a (%)c	ee 3a (%)d
1	L1	1.0	none	26	20	96
2	L1	1.0	NaI	22	26	97
3	L1	1.0	CoPc	13	51	96
4	L1	1.5	CoPc	9	64	97
5	L1	2.0	CoPc	8	69	97
6	L2	2.0	CoPc	22	14	41
7	L3	2.0	CoPc	9	49	−90
8 e	L1	2.0	CoPc	9	70	97

^aReactions conducted under N₂ on 0.1 mmol scale for 48 h.

^bNaI = 0.5 equiv; CoPc = 5 mol %.

^cDetermined by ¹H NMR versus an internal standard.

^dDetermined by SFC using a chiral stationary phase.

^e10 mol % preformed (3R,8S)-L1·NiCl₂ complex used.

Table 2.

Chlorobenzyl Silane Scope^a

^aReactions conducted on 0.2 mmol scale under N₂. Isolated yields; ee is determined by SFC using a chiral stationary phase.

^bYield determined by ¹NMR versus an internal standard.

Table 3.

Vinyl Bromide Scope^a

^aReactions conducted on 0.2 mmol scale under N₂. Isolated yields are provided; ee is determined by SFC or HPLC using a chiral stationary phase.

^bYield determined by ¹NMR versus an internal standard.

With the optimized conditions in hand, the scope of the silane was investigated (Table 2). Whereas strained silacy-clobutane²⁰ 3b was prepared in good yield and excellent ee, the corresponding triethylsilane 3d was formed in poor yield, presumably due to the increased steric encumbrance at silicon. Substrates bearing either electron-withdrawing or electron-donating groups on the arene cross-coupled with universally high ee; however, in some cases the yield was diminished due to instability of the products (3e, 3g). The presence of an ortho substituent on the arene also decreased the yield of the cross-coupling product (3j).

The reaction tolerates a diverse array of functional groups on the alkenyl bromide partner (Table 3),²¹ including aryl boronates (6c), esters (6b, 6h), imides (6m), amides (6n), alkenyl silanes (6o), and alkyl halides (6f). For greasy substrates, m-methoxy silane 2h was used as the coupling partner to facilitate product purification (6o–6u). Alkyl-substituted alkenyl bromides performed comparably to styrenyl bromides; however, a limitation of the reaction is that Z-alkenes and tri- and tetra-substituted alkenyl bromides failed to react. By changing which enantiomer of L1 is employed, diastereomeric polyenes 6t and 6u were prepared, although the yield is decreased with the mismatched (3S,8R)-L1 catalyst. Finally, alkenyl bromides bearing furan (6q), thiophene (6r), pyridine (6k), pyrimidine (6l), and indole (6e) heterocycles could be cross-coupled, giving the corresponding allylic silanes in high ee. Functional groups that were not well tolerated include aldehydes and nitriles.²²

Although halide electrophiles were the primary focus of this study, oxygen-based electrophiles were also evaluated. We were pleased to find that mesylate 7 provided 3a in 45% yield and 92% ee; the lower yield was due to incomplete conversion of the starting material (Scheme 1a). Enol triflate 8 underwent cross-coupling to afford 6a in 57% yield, again with excellent enantioselectivity (Scheme 1b). Although the yields were modest, we note that these reactions were conducted under the conditions developed for the organic halides with minimal re-optimization.

Scheme 1.

Reactions of Oxygen-Based Electrophiles

This reductive cross-coupling provides rapid access to functionalized chiral allylic silanes that are useful in a variety of synthetic transformations.^23,24 For example, allylic silanes 6i and 6j, which contain pendant acetals, undergo stereospecific TiCl₄-mediated intramolecular cyclization to form the 5- and 6-membered rings 9 and 10, respectively (Scheme 2a). The observed absolute and relative stereochemistry is consistent with an anti-S_E’ mode of addition, which gives rise to the trans-substituted 5-membered ring and the cis-substituted 6-membered ring.^25,26,27 Either the 2,3-cis or 2,3-trans tetrahydrofurans can be prepared by Lewis-acid mediated cyclizations of alcohol 6g or chloride 6f, respectively; both proceed with excellent transfer of chirality (Scheme 2b).^5b,28 The utility of the method was further demonstrated in a concise enantioselective synthesis of (+)-tashiromine (Scheme 2c).²⁹ Sodium borohydride reduction of imide 6m provided aminal 13, which upon exposure to formic acidcyclized to form bicycle 14 in 93% yield as a 3.8:1 mixture of diastereomers.³⁰ The major diastereomer was isolated in 57% yield and 97% ee. Ozonolysis and reduction of the amide provided (+)-tashiromine.

Scheme 2.

Stereospecific Reactions of Chiral Allylic Silanes

In summary, a highly enantioselective cross-coupling reaction has been developed for the preparation of chiral allylic silanes. The reactions proceed under mild conditions and tolerate a variety of functional groups. The enantioenriched allylic silanes undergo several stereospecific transformations with high transfer of chirality, which we anticipate will prove useful in an array of synthetic contexts.