Direct stereoselective α-arylation of unmodified enals using an organocatalytic cross-coupling-like reaction

Abstract

Cross-coupling reactions typically rely on the use of transition metal catalysis. However, although achieving this process using metal-free organocatalysts is highly challenging, it could offer unique opportunities to discover novel bond-forming strategies in organic synthesis. Here we report a new amine catalysed direct stereoselective C-H α -arylation reaction of unmodifi ed enals with bromoarenes. The power of this process, which involves an unprecedented iminiumMichael-alkylation-enamine-retro-Michael cascade sequence, has been demonstrated in the context of direct α -functionalization reactions of simple, unmodifi ed enals with 4-bromophenols, 1-bromo-2-naphthol and 3-bromoindoles under mild reaction conditions. Notably, the process can be used for highly stereoselective syntheses of non-readily accessible E isomers, which normally require the use of transition metal-promoted cross-couplings and functionalized enals. The results of these studies signifi cantly expand the scope of aminocatalysis.

Synthetic journey towards transition metal-free arylations

“…Transition-metal-free arylations Song et al [40] subsequently reported the direct stereo-selective a-arylation of enals via TMF conditions. After an intensive investigation, they provided a simple and efficient protocol showing simple, easy and metal-free synthesis of arylated products via organo-catalyst mediation (Scheme 21).…”

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

“…On the basis of the above resultsa nd our previous study on the organocatalytic coupling of prefunctionalized para-bromophenols and enals through Michael addition/dearomatization/ cyclopropanation/enamination/ retro-Michael cascade process, [15] we proposed as imilarc atalytic cycle for the process. The pathway involves an in situ bromination-Friedel-Crafts alkylation dearomatization/cyclopropanation/enamination/retro-Michael (ring opening) cascade sequence (Scheme 3).…”

“…By considering the lack of organocatalytic methods for parafunctionalization of 1-naphthols, and inspired by our earlier study of organocatalytic coupling of prefunctionalized parabromophenols and enals through aM ichael addition/S N 2-substitution/retro-Michael cascade sequence (Scheme 2), [15] we envisioned that prefunctionalized 4-bromo-1-naphthols might direct the installation of the enals into the para-position of the structures. However,w ef ound that the process presents daunting challenges in our exploratory investigation.…”

“…With the proposal and issues in mind, we explored am odel reactiono f1 -naphthol (1a)w ith trans-cinnamaldehyde (2a)i n CH 3 CN in the presence of an amine catalyst and PHBP as abrominationr eagent. Diphenylprolinol TMS ether A,w hichw as used in our earlier study [15] involving the coupling of para-bromophenols with enals and simple secondary amines B-D (Table 1).…”

Direct Transformation of Simple Enals to 3,4‐Disubstituted Benzaldehydes under Mild Reaction Conditions via an Organocatalytic Regio‐ and Chemoselective Dimerization Cascade

“…Recently, we developed an organocatalytic stereoselective cross-coupling-like a-arylation reaction of aromatic a,b-unsaturated aldehydes with 4-bromophenols and 3-bromoindoles (Scheme 1 a). [7] However, when an aliphatic crotonaldehyde was subjected to the reaction conditions, an unexpected 4-methyl benzaldehyde was obtained (Scheme 1 b). This serendipitous discovery prompted us to investigate this interesting "side reaction".…”