Diastereoselective Synthesis of and Mechanistic Understanding for the Formation of 2‐Piperidinones from Imines and Cyano‐Substituted Anhydrides

Abstract

2-Piperidinones are synthesized in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation. The pertinent transition structures have also been computed using quantum mechanics and reveal the key interactions controlling the stereochemical outcome of the reaction.

Trifluoroethanol Promoted Castagnoli–Cushman Cycloadditions of Imines with Homophthalic Anhydride

“…This could explain the increase in reaction kinetics (Scheme 2). This scenario is supported by computational studies on closely related reactions of imines with α-cyanosuccinic anhydride [5] and is consistent with the relatively high acidity of IVa (pK a = 8.15). Scheme 2.…”

“…[4+2] Cycloadditions of enolizable anhydrides (succinic IIa, glutaric IIb, or homophthalic IVa) and imines formed in situ or prepared in a separate step were discovered by Castagnoli and Cushman and have attracted considerable attention from chemists for the preparation of substituted γ, δ, and ε-lactams (Scheme 1a) [1][2][3]. Moreover, these cycloaddition reactions have seen wide applications in the synthesis of medicinal lead compounds piperidines and piperidinones derivatives [4,5], sting antagonist [6], and antimalarial [7] or anticancer agents [8][9][10]. In addition, lactams obtained by these reactions, and their reduced nitrogen heterocycle analogs are found to be key intermediates in the synthesis of biologically significant natural products such as 13-methyltetrahydroprotoberbines (i.e., (+)-thalictricavine, (+)-canadine, (+) and (−)cavidine [11][12][13], phenanthridine alkaloids and (−) and (+)-corynoline [14] possessing antitumor activity [15] (Figure 1).…”

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

“…The Castagnoli-Cushman reaction (CCR) between cyclic enolizable anhydrides (such as succinic (5) [9], glutaric (6) [10], and the corresponding oxygen (7) [11], sulfur (8) [11], and nitrogen analogs 9 [12], and homophthalic anhydride (10) [13,14]) and imines 11, 12 offers a route to substituted lactam molecules 13 and 14 [13][14][15][16][17][18][19]. Among them, the reactions of homophthalic anhydride (10) with Schiff bases 11 or cyclic imines 12 have been examined in detail (Scheme 1) [13,14,20,21].…”

“…The mechanism of the reaction is still under debate with two prevailing versions in the literature (Scheme 2) [16,17,[22][23][24]. The first reaction pathway includes the formation of an N-acyliminium ion 15, followed by a ring closure through an enolate ion 16.…”

Stereochemistry and reactivity of the HPA-imine Mannich intermediate

“…We find that chloroform, dichloromethane, ethyl acetate, and acetonitrile all work well as solvents, whereas DMF, tert -butyl methyl ether, and 2-butanol give lower yields. A series of benzalimines with differing R groups 21,26 was screened to evaluate the effect of the size of R and in some cases, the stereochemistry of the imine (Table 1). Thus, R was taken through a series from relatively small Me– ( 19 ) through n -Bu– ( 21 ), CF 3 CH 2 – ( 23 ), and i -Bu– ( 25 ), to relatively bulky t -Bu– ( 27 ).…”