Practical Organocatalytic Synthesis of Functionalized Non‐C₂‐Symmetrical Atropisomeric Biaryls

Abstract

An organic acid catalyzed direct arylation of aromatic C(sp2)H bonds in phenols and naphthols for the preparation of 1,1′‐linked functionalized biaryls was developed. The products are non‐C2‐symmetrical, atropoisomeric, and represent previously untapped chemical space. Overall this transformation is operationally simple, does not require an external oxidant, is readily scaled up (up to 98 mmol), and the structurally diverse 2,2′‐dihydroxy biaryl (i.e., BINOL‐type), as well as 2‐amino‐2′‐hydroxy products (i.e., NOBIN‐type) are formed with complete regioselectivity. Density‐functional calculations suggest that the quinone and imino‐quinone monoacetal coupling partners are exclusively arylated at their α‐position by an asynchronous [3,3]‐sigmatropic rearrangement of a mixed acetal species which is formed in situ under the reaction conditions.

Practical and Scalable Kinetic Resolution of BINOLs Mediated by a Chiral Counterion

“…[3] However,t his strategy is not always feasible for non-C 2 -symmetric derivatives. [4] One approach to this problem that may extend across aw ide range of substrates is kinetic resolution (KR)-the achievement of resolution by virtue of unequal rates of reaction. [5,6] This is av aluable technique for obtaining extremely high levels of enantioenrichment in unreacted substrate through high selectivity factors (s)a nd control of conversion.…”

Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives

“…Development of our catalytic atroposelective direct arylation approach to non- C 2 -symmetric BINOL derivatives (A, 6b B) and a recent report by Tan and co-workers (C). 5k …”

“…As part of an ongoing program in the Kürti group to develop new and practical transition-metal-free direct arylation methods for the preparation of highly functionalized symmetrical and unsymmetrical biaryls, 6a,5h,6b we recently successfully exploited quinone and iminoquinone monoacetals as arylating agents to access both BINOL- and NOBIN-type functionalized biaryls that are atropoisomeric but non- C 2 -symmetric from phenols and naphthols under organocatalytic conditions ( 1 + 2 → 5 ; Figure 2A). 6b We also briefly explored the possibility of using chiral BINOL-derived phosphoric acids as catalysts to obtain the biaryl products in an enantiomerically enriched form.…”

“…6b We also briefly explored the possibility of using chiral BINOL-derived phosphoric acids as catalysts to obtain the biaryl products in an enantiomerically enriched form. Unfortunately, although moderate to good isolated yields were achieved, the level of enantioinduction was very poor (3–10% enantiomeric excess, ee ), which we partially attributed to interference by the MeOH liberated during the formation of the mixed-acetal intermediate ( 1 + 2 → 3 ; Figure 2A); 6b addition of 3 Å molecular sieves (MS) did not improve the ee . We observed similar interference by proton donors (i.e., H 2 O) during the catalytic synthesis of BINAM derivatives; 5h in that case the addition of 4 Å MS was advantageous.…”

“…On the basis of these findings, 6b we decided to redesign the quinone monoacetal coupling partner in a way that avoids the generation of a proton source (i.e., MeOH), thereby removing this potentially detrimental factor from the catalytic cycle. 7 We selected readily available N -sulfonyl-protected iminoquinones as substrates, as these were expected to undergo acid-catalyzed in situ aminal formation 8 and subsequent [3,3]-rearrangement/rearomatization (Figure 2B).…”