Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds

Abstract

The stereospecific cross-coupling of secondary boronic esters with sp2 electrophiles (Suzuki–Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel–Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C–C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp2)–C(sp3) and an adjacent C–B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Alkynyl Moiety for Triggering 1,2‐Metallate Shifts: Enantiospecific sp2–sp3 Coupling of Boronic Esters with p‐Arylacetylenes

“…At this point, we decided to optimize the reaction conditions to maximize the formation of either 4 a or 4 b , initially focusing on the maximally functionalized boron‐incorporated product 4 b . We had previously observed such products when coupling electron‐rich aromatics with boronic esters and found that i PrOH/MeCN gave the best ratio 3b. We therefore carried out a brief solvent study (entries 2–5) and again found that i PrOH/MeCN was optimal here too, giving the highest ratio, leading to a 76 % yield of 4 b (entry 4).…”

Enantiospecific Trifluoromethyl‐Radical‐Induced Three‐Component Coupling of Boronic Esters with Furans

“…The reaction involves initial formation of aryl boronate I through Li–B exchange of an aryl lithium and an alkylboronic ester 6. Subsequent addition of an electrophilic halogenating agent (NBS= N ‐bromosuccinimide) to I forms oxocarbenium II (structure drawn for clarity although a concerted mechanism has been proposed),3b which promotes a 1,2‐metallate rearrangement giving the neutral boronic ester III . Finally, rearomatization‐driven elimination of the halide and the boronic ester group generates the substituted aryl product.…”

“…Species VII undergoes a 1,2‐metallate rearrangement to give boronic ester VIII . It is likely that oxidation of intermediate VI leads directly to boronic ester VIII but species VII is drawn for clarification 3b. Under oxidative conditions (K 2 CO 3 , I 2 ), rearomatization occurs to form the final three‐component‐coupled products with complete enantiospecificity.…”

Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

“…furan, thiophene, indole, and benzofuran) and electron‐rich aromatics, provided they were substituted with donor groups at the meta ‐position. The meta donor group and the electron‐rich boronate worked synergistically to promote an electrophilic reaction on the aromatic ring 5a,5b. Positioning the donor group in the para ‐position pushes electron density onto the sp 3 carbon atom of the boronate complex, resulting in a selective reaction via an S E 2 pathway, rather than an S E Ar pathway (e.g.…”

“…Positioning the donor group in the para ‐position pushes electron density onto the sp 3 carbon atom of the boronate complex, resulting in a selective reaction via an S E 2 pathway, rather than an S E Ar pathway (e.g. Scheme 1 c, left‐hand side) 5b, 7…”