In Tandem Auto‐Sustainable Enantioselective Heck‐Matsuda Reactions Directly from Anilines

Abstract

An in tandem enantioselective Heck-Matsuda (HM) reaction of cyclic and acyclic olefins directly from anilines is described. The method relies on a process involving the progressive in situ diazotization of the starting anilines followed by a palladium-catalyzed Heck-Matsuda arylation using chiral N,N-ligands. This intermolecular enantioselective HM arylation strategy was applied to the desymmetrization of three distinct unactivated olefins as proof of concept. The method demonstrates broad substrate scope furnishing the Heck adducts in good to excellent enantiomeric ratios of up to 99:1, high diastereoselectivities (cyclopenten-3-ol with > 20:1 dr), and good overall yields of up to 82% over 2 or 3 steps.

In Tandem Enantioselective Intramolecular Heck-Matsuda Reactions directly from anilines

“…After these initial tests, we then examined the one-pot Heck Matsuda reaction based on our previous report of the intermolecular enantioselective Heck-Matsuda using the unsaturated aniline 1b. [18] In agreement with our previous results, the Heck-Matsuda reaction conducted without external acid demonstrated the viability of the intramolecular Heck-Matsuda reaction from the starting aniline, furnishing the desired tricyclic Heck product 2a, however, in only 28% yield in an excellent 97:3 er (Table 2, Entry 1). Since some acidic conditions are essential for the critical in situ formation of the aryldiazonium salt, we hypothesized that the addition of an external acid could provide the necessary conditions to form the aryldiazonium salt and start the sequential processes.…”

“…[17] Recently, we have reported an in tandem enantioselective Heck-Matsuda arylation of nonactivated cyclopentenes, and 1,4-butendiol which can be carried out in almost neutral conditions (Scheme 1b). [18] The endogenous acid produced in situ during the Heck reaction was capable of driving the diazotization of the aniline sequentially.…”

In Tandem Enantioselective Intramolecular Heck‐Matsuda Reactions directly from Anilines

“…After these initial tests, we then examined the combined diazotization‐Heck‐Matsuda arylation starting with the unsaturated aniline 3 a using conditions previously reported by us for the intermolecular enantioselective Heck‐Matsuda reaction [18] …”

“…After these initial tests, we then examined the combined diazotization-Heck-Matsuda arylation starting with the unsaturated aniline 3 a using conditions previously reported by us for the intermolecular enantioselective Heck-Matsuda reaction. [18] Gratifyingly, the Heck-Matsuda reaction conducted without external acid demonstrated the viability of the strategy starting with the aniline, furnishing the desired tricyclic Heck product 2 a, however, in only 28% yield in an excellent 97:3 er (Table 2, Entry 1). Since some acidic conditions are essential for the critical in situ formation of the aryldiazonium salt, we hypothesized that the addition of an external acid could provide the necessary conditions to form the aryldiazonium salt and start the sequential processes.…”

“…[17] Recently, we have reported an in-tandem enantioselective Heck-Matsuda arylation of non-activated cyclopentenes, and 1,4-butendiol which can be carried out in almost neutral conditions (Scheme 1b). [18] The endogenous acid produced in situ during the Heck reaction was capable of driving the diazotization of the aniline sequentially.…”