A Diverted Aerobic Heck Reaction Enables Selective 1,3-Diene and 1,3,5-Triene Synthesis through C–C Bond Scission

Abstract

Substituted 1,3-dienes are valuable synthetic intermediates used in myriad catalytic transformations, yet modern catalytic methods for their preparation in a highly modular fashion using simple precursors are relatively few. We report here an aerobic boron Heck reaction with cyclobutene that forms exclusively linear 1-aryl-1,3-dienes using (hetero)arylboronic acids, or 1,3,5-trienes using alkenylboronic acids, rather than typical Heck products (i.e., substituted cyclobutenes). Experimental and computational mechanistic data support a pericyclic mechanism for C−C bond cleavage that enables the cycloalkene to circumvent established limitations associated with diene reagents in Heck-type reactions.

Dienedioic acid as a useful diene building block via directed Heck-decarboxylate coupling

“…16). Meanwhile, methyl sorbate (1-16) bearing similar steric and electronic properties as those of sorbic acid, afforded no ɑand β-selective products (5)(6)(7)(8)(9)(10)(11)(12)(13)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Instead, the δ-selective product 5-15 was observed by H-NMR, in consistent with Heck's discovery 42 (Fig.…”

“…Heteroarenes are frequently encountered in medicinal chemistry, and it is important to develop novel access to their functionalization. Therefore, several heteroaryl bromides were selected and tested in this reaction, including benzofuran (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), benzothiophene (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), pyridine (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(1...…”

“…Of note, pyridine (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and isoquinoline bearing Lewis basic nitrogen can be well tolerated, although they could coordinate to palladium. However, 2-bromopyridine failed to afford the desired coupling product (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Solvent effects in palladium catalysed cross-coupling reactions

“…328 For example, the coupling of boron compounds is successful in the production of bio-active compounds, 329 and for aerobic boron-Heck reactions. 330 An attempt to use 2-MeTHF in the Buchwald-Hartwig reaction was less productive than the conventional (and less dipolar) toluene and 1,4-dioxane, 246 but is suitable in combination with N,N-dimethyl octanamide for the synthesis of Imatinib, as described in Section 3.1.5. At present the number of examples where 2-MeTHF is being applied in C-C and C-N coupling reactions is fairly low, 331,332,333 but the benefits of a water-immiscible alternative to THF should be valued more highly.…”

Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes

“…As yet another contribution to the oxidative Heck vinylation reaction, McAlpine and co-workers reported the coupling of arylboronic acids and cyclobutene to form terminal linear 1,3-dienes in near quantitative yield and total E stereoselectivity ( Scheme 21 ) [ 96 ].…”