Convergent and Stereoselective Method for the Synthesis of Acyclic α-Chloroenamides

Abstract

A direct, stereocontrolled synthesis of acyclic α-chloroenamides is presented. Our methodology showed good yields and substrate scope. Mechanistic insights are provided that account for the high levels of stereoselectivity reported. Subsequent synthetic manipulation of the α-chloroenamides provides direct entry to polyfunctionalized acyclic enamides, compounds of wide use in organic chemistry and the pharmaceutical industry.

α-Haloenamides: Synthesis and Subsequent Transformations

“…In most cases, coupling reactions conducted with α-chloro-, α-bromo-, and α-iodoenamides gave trisubstituted or tetrasubstituted enamides with good to excellent yields with retention of the initial geometry of the double bond. 6 9 10 16 18 , 31 32 33 34 35 36 , 38 Isomerization of the double bond during these processes have been reported by Sahoo­, 20 Hammond and Xu, 13 and Tang. 5 They described the coupling reactions of ( E )-α-haloenamide to give a mixture of ( E )- and ( Z )-enamides due to partial isomerization that probably occurs during the palladium-catalyzed transformations.…”

“…35 Scheme 44 -Halo eneformamides 44-A,B from caprolactam using the Vilsmeier-Haack reaction Wang, Collier, and co-workers, in 2020, the use of the Vilsmeier-Haack reaction the synthesis of varacyclic -chloro eneformamides from -substituted secondary acetamides (Scheme 45). 36 The reaction was found to be quite general in scope with respect to the acid component of the amide. Electronrich and electron-deficient aryl-and heteroaryl-acetamides were well tolerated to give (Z)--chloro eneformamides This document was downloaded for personal use only.…”

“…Wang, Collier and co-workers recently generalized the use of Vilsmeier-Haack reaction to the synthesis of various acyclic αchloro eneformamides from α-substituted secondary acetamides (Scheme 45). 36 Scheme 45 Use of Vilsmeier-Haack reaction in the synthesis of various acyclic α-chloro eneformamides from secondary acetamides.…”

“…Furthermore, α-bromo eneformamides were less reactive, highlighting the uniqueness of the more stable α-chloro eneformamides as coupling partners. Wang and Collier 36 showed that Heck reaction of α-chloro eneformamide 52A with 4-fluorostyrene gave the desired enamide in good yield and high stereochemical fidelity (Scheme 52 , eq. 2).…”

“…All rights reserved. Synthesis 2023, 55,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]…”