Stereoselective Cyclopropanation of 1,1-Diborylalkenes via Palladium-Catalyzed (Trimethylsilyl)diazomethane Insertion.

Palladium catalyzes the cyclopropanation of 2-substituted 1,1-diborylalkenes with (trimethylsilyl)diazomethane. The relative stereoselectivity is controlled via a carbene insertion sequence generating an exclusive anti conformation between the R and SiMe3 substituents. Mixed 1,1-diborylalkenes also contributed to the formation of stereoselective B, B, Si-cyclopropanes. Orthogonal activation with NaOtBu gives protodeborylation preferentially on the boron moiety syn to the aryl group. Further oxidation gives access to polyfunctional cyclopropyl alcohols with controlled enantioselectivity when chiral boryl motifs are involved.

Polyborylated carbon frameworks act as valuable building blocks to be transformed into biologically active substances and functional organic materials.[1] In particular, gem-bis(boryl)cyclopropanes represent an important structural motif to be sequentially functionalized into target cyclopropane frameworks involved in the pharmaceutical industry.[2] An early approach to synthesizing gem-bis(boryl)cyclopropane was developed on the basis of the efficient reactivity between 1,1-dibromocyclopropanes and bis(pinacolato)diboron (B2pin2) at low temperatures.[3] The protocol implied the in situ formation of cyclopropylidene lithium carbenoids that interact with B2pin2 to form the boronate intermediate that evolves, through 1,2-migration, toward the corresponding 1,1-diborylated cyclopropane. The relative syn or anti conformation of the substituents is fixed along the 1,1-dibromocyclopropane formation by choosing the appropriate Z- or E-alkene, respectively (Scheme ).[3]

Scheme 1

Synthetic Approaches to 1,1-Diborylcyclopropanes via (a) Cyclopropylidene Lithium Carbenoids, (b) Cu-Catalyzed Borylative Intramolecular Cyclization, and (c) Pd-Catalyzed TMSDM Insertion on 1,1-Diborylalkenes

With the aim of contributing to the modulated construction of polyfunctionalized gem-bis(boryl)cyclopropanes, we describe here a direct cyclopropanation process via palladium-catalyzed addition of (trimethylsilyl)diazomethane (TMSDM) to 2-substituted 1,1-diborylalkenes (Scheme c). The relative stereoselectivity can be controlled throughout the carbene insertion step, showing an exclusive anti conformation of the vicinal R and SiMe3 substituents on the new B, B, Si-cyclopropanes. This methodology avoids the use of brominated cyclopropanes[3,4] and seems to be highly tolerant of the nature of the substituents on the alkene. To the best of our knowledge, only one precedent has reported the preparation of anti-B, Si bifunctional cyclopropanes, through copper-catalyzed intramolecular borylative cyclization of γ-silylated allylic carbonates with B2pin2 (Scheme b).[5] We have also explored the orthogonal functionalization of the tetrasubstituted carbon atom as a key connective unit for selective B activation. In the presence of NaOBu, the Bpin moiety syn to R suffers protodeborylation, suggesting that SiMe3 might protect the syn boryl unit. Subsequent oxidation gives access to the stereoselective syn-2-(trimethylsilyl)cyclopropan-1-ols (Scheme b). Our method contributes to the preparation of stereoselective gem-bis(boryl)cyclopropanes containing different boryl moieties, as an alternative to the reported method based on the diastereotopic pinacolboryl desymmetrization via trifluorination.[6]

The preparation of 1,1-bis(pinacolboryl)alkenes[7] can be performed by alkylidene-type lithium carbenoids that react with B2pin2.[8] However, to avoid the use of halogenated reagents in our new synthetic strategy, we faced the condensation of tris(boryl)methane with aldehydes followed by B–O elimination (Scheme , method A). Matteson originally described that tris(boryl)methide ions could be formed by treatment of tetra(boryl)methane with methyllithium to eventually react with formaldehyde and benzaldehyde to undergo the expected condensation.[9] Here, we have adapted the boron-Wittig reaction[10] synthesizing tris(pinacolboryl)methane (1) that forms in situ the corresponding salt Li[C(Bpin)3], after treatment with LiTMP. The organolithium Li[C(Bpin)3] reacts with a variety of aldehydes to perform the condensation/B–O elimination, with the subsequent formation of the trisubstituted gem-diborylalkenes. Scheme shows that benzyl, alkyl, and aryl aldehydes can be efficiently transformed into 2-substituted 1,1-diborylalkenes 2a, 2c, 2f, and 2h through method A.

Scheme 2

Synthesis of 2-Substituted 1,1-Diborylalkenes through Condensation of Lithium Tris(pinacolboryl)methide and Aldehydes (Method A), Copper-Catalyzed Dehydrogenative Borylation/Hydroboration of Alkynes (Method B), and Transborylation Reaction (Method C)

We also developed an alternative method B to generate 2-substituted 1,1-diborylalkenes from accessible alkynes via copper-catalyzed dehydrogenative borylation/hydroboration with pinacolborane (HBpin) (Scheme , method B). Recently, Marder and co-workers described a related protocol for preparing triborylalkanes from alkynes,[11] whereas Miura, Murakami, and co-workers developed a cobalt(II)-catalyzed 1,1-diboration of alkynes with B2pin2 to gain access to 1,1-diborylalkenes.[12] 2-Naphthyl-substituted gem-diborylalkene 2g has been prepared by a boryl-Heck reaction reported previously.[13]

We next explored the preparation of valuable mixed 1,1-diborylalkenes, which have been prepared only via hydroboration of alkynyl boronic esters[14,15] or Co-catalyzed 1,1-diboration of terminal alkynes with nonsymmetrical diboron reagents.[16] Here, we adapted the protocol for the B–C(sp2)–B/B′–B′ cross metathesis reaction based on our recently developed transborylation sequence.[17] Consequently, 2-substituted 1,1-bis(pinacolboryl)alkenes reacted with bis(hexylene glycolato) diboron (B2hex2) or bis(neopenthyl glycolato) diboron (B2neo2), in MeOH at 90 °C, to generate the mixed 2-aryl 1,1-diborylalkenes 3a–3f (Scheme , method C). The transborylation took place stereoselectively on the less sterically hindered position, as we unambiguously proved by one-dimensional (1D) NMR NOE experiments. Similarly, the transborylation between 1,1-bis(pinacolboryl)alkenes and bis(+)-pinanediolato diboron (B2pai2) or (4S,4′S,5S,5′S)-4,4′,5,5′-tetraphenyl-2,2′-bi(1,3,2-dioxaborolane) (S,S)-B2(O-CHPh-CHPh-O)2 was conducted to isolate the chiral mixed 2-aryl 1,1-diborylalkenes 3g–3j (Scheme , method C).

For the cyclopropanation of 1,1-diborylalkenes, we became inspired by the previous studies of Carboni and co-workers concerned with the palladium-catalyzed addition of diazomethanes to 1-alkenylboronates.[18] We selected (trimethylsilyl)diazomethane (TMSDM), as the carbene source, to be added on the 2-substituted 1,1-diborylalkenes with the aim of generating polyfunctionalized B, B, Si-cyclopropanes. To the best of our knowledge, cyclopropanation with TMSDM was achieved only through copper-catalyzed addition to vinylarenes.[19] The proof of concept was conducted on 1,1-diborylalkene 2a in the presence of Pd(OAc)2 (15 mol %) and TMSDM, in hexane at rt. To our delight, the reaction was completed in 16 h with total control of the stereoselectivity, placing the trimethylsilyl and benzyl groups with anti conformation in the new product 4 (Scheme a). A similar reaction outcome was observed for cyclopropanation of 2-aryl-substituted 1,1-diborylalkenes 2b–2g independent of the electron rich or electron poor aryl substituents involved. The diastereoisomer with anti conformation between the SiMe3 and the aryl groups were also exclusively formed in products 5–10 (Scheme a). The suggested model for the diastereoselectivity observed on the Pd-catalyzed cyclopropanation of 2-aryl 1,1-diborylalkenes with TMSDM might involve migratory insertion of Pd=CH-TMS into the trisubstituted alkenes (Scheme b). The observed preferred anti diastereoselection contrasts with the favored syn diastereoselection in the synthesis of 1-boryl 2,3-disubstituted cyclopropanes through cyclopropanation of alkenylboronates with ethyl diazoacetate in the presence of catalytic amounts of a copper(I) complex.[20]

Scheme 3

Pd-Catalyzed Stereoselective Cyclopropanation of 2-Substituted 1,1-Diborylakenes with (Trimethylsilyl)diazomethane [(a) substrate scope and (b) suggested mechanistic model]

Surprisingly, when 2-aryl-substituted 1,1-diborylalkene 2f reacted with TMSDM, in the presence of Pd(OAc)2, the cyclopropanation did not occur and (E)-vinyl silane product A was isolated instead (Scheme ). The formation of this product could be explained by the oxidative addition of Ar–Br to Pd, followed by a double-palladium carbene migratory insertion process (Scheme ). Similar direct olefination of aryl/alkyl halides with (trimethylsilyl)methylene was observed by Chen and Xu to occur via carbene migratory insertion in the presence of palladium complexes.[21] The cyclopropanation of 2-cyclohexyl 1,1-diborylalkene (2h), 2-cyclohexenyl 1,1-diborylalkene (2i), and 2-(3-thiophenyl) 1,1-diborylalkene (2j) did not progress toward the desired product, suggesting an inhibited migratory insertion of the alkene into the Pd=CH-TMS intermediate, as a consequence of the lower electrophilic character of C2.

Scheme 4

Pd-Catalyzed Olefination of the 2-Br Aryl Group with (Trimethylsilyl)diazomethane

The Pd-catalyzed cyclopropanation of the mixed 1,1-(BpinBhex)alkenes 3a–3d with TMSDM resulted in high stereoselectivity, providing one exclusive conformer in which the Bhex moiety appears syn to the SiMe3 group, whereas the Bpin fragment is placed syn to the aryl group, for compounds 11–14 (Scheme ). The diastereoselection has been unambiguously determined by 1D NMR NOE experiments, and in product 11, we have been able to isolate the two isomers with regard to the Me conformation on the Bhex group.[22] Interestingly, when we conducted the Pd-catalyzed cyclopropanation of the mixed chiral 1,1-BpinB* alkenes 3g–3j with TMSDM [B* = Bpai = (+)-pinanediolboryl or (S,S)-B2(O-CHPh-CHPh-O)2], the corresponding B*, Bpin, Si-cyclopropanes 15–18 were isolated as unique isomers, in contrast to the reported Pd-catalyzed cyclopropanation of alkenylmonoboronates, containing Bpai motifs, using CH2N2 as the carbene source, providing a modest diastereselection of ≤63:37.[23] It is worth mentioning, for comparison, that Masarwa and co-workers suggested a complementary diastereoselective model for the desymmetrization of gem-diborylcyclopropanes via nucleophilic “trifluorination” of the Bpin group, taking place on the less sterically hindered face of the cyclopropane (Scheme b).[6]

Scheme 5

Stereoselective Pd-Catalyzed Cyclopropanation of Mixed 1,1-Diborylakenes with TMSDM and Comparison with Desymmetrization Pathways

Taking advantage of the stereoselective formation of the B, B, Si-cyclopropanes prepared in this work, we next conducted the orthogonal functionalization of the gem-bis(boryl)cyclopropanes. When we applied the protodeborylation protocol with NaOBu (3 equiv) at 60 °C on B, B, Si-cyclopropane 7, we observed a preferred activation of the Bpin unit syn to the aryl group to form 19a in 86% yield, instead of the activation of the Bpin unit syn to the SiMe3, which generates 19b in 14% yield (Scheme a). A similar preferred reaction outcome was observed for the protodeborylation of B, B, Si-cyclopropanes 9 and 10, toward products 20a and 21a, respectively (Scheme a). The steric hindrance associated with the SiMe3 group might justify the selective protodeborylation. This hypothesis is in contrast to the selective alkoxide-assisted protodeborylation of gem-BpinBdan-cyclohexanes, based on the different electronic properties of the boryl moieties and the enhanced stabilization of the carbanion p-type electron density into the π-channel of Bdan units (Scheme b).[24] The resulting syn-B, Si bifunctional cyclopropanes are complementary to the anti-B, Si bifunctional cyclopropanes synthesized by Sawamura and Ito through the copper-catalyzed intramolecular borylative cyclization of γ-silylated allylic carbonates with B2pin2 (Scheme b).[5] Subsequent oxidation of 19a, 20a, and 21a produced the corresponding (aryl)-3-(trimethylsilyl)cyclopropan-1-ol (22–24) in quantitative yields (Scheme a).

Scheme 6

Site-Selective Protodeborylation of gem-Bis(boryl)cyclopropanes and gem-Bis(boryl)cyclohexanes

B*, B, Si-cyclopropanes 15–18, containing the chiral boryl units B* = (+)-pinanediolboryl (Bpai) or (S,S)-B2(O-CHPh-CHPh-O)2, also reacted with NaOBu (3 equiv) at 60 °C to protodeborylate exclusively the Bpin unit (Scheme ). The X-ray single-crystal diffraction analysis of compound 25 projected the absolute configuration of the three new stereocenters formed on the major enantiomer (Figure ). The enantiomeric ratio was determined from the corresponding alcohol derivatives, after oxidation of B*, Si-cyclopropanes 25–28 with NaBO3, in comparison with racemic samples 22 and 24. The enantiomeric ratio seems to be slightly higher when B* = (+)-pinanediolboryl (Bpai) is involved rather than (S,S)-B2(O-CHPh-CHPh-O)2, independent of the aryl group present in the compounds (Scheme ). This is presumably a result of an efficient asymmetric induction during the palladium insertion of TMSDM into chiral mixed 2-aryl 1,1-diborylalkenes 3g and 3h versus 3i and 3j.

Scheme 7

Enantioenriched Synthesis of B*, Si-Cyclopropane Compounds

Figure 1

X-ray single-crystal diffraction analysis of the major enantiomer of compound 25. Thermal ellipsoids draw at the 50% level.

In conclusion, we have described a palladium-catalyzed cyclopropanation of 2-substituted 1,1-diborylalkenes with (trimethylsilyl)diazomethane. The relative stereoselectivity is controlled via a carbene insertion sequence generating an exclusive anti conformation between R and SiMe3 substituents and an enantiomeric ratio of ≤10:90 when B* = (+)-pinanediolboryl (Bpai) is involved. The new B, B, Si-cyclopropanes can be activated by NaOBu, via protodeborylation preferentially on the boron moiety syn to the aryl group. Further oxidation enabled the formation of polyfunctional cyclopropyl alcohols with controlled stereoselectivity and enantioselectivity.