Copper‐Catalyzed One‐Pot Synthesis of 2‐Alkylidene‐1,2,3,4‐ tetrahydropyrimidines

Abstract

A one-pot synthesis of N-sulfonyl-2-alkylidene-1,2,3,4-tetrahydropyrimidines via a highly selective and copper-catalyzed multicomponent reaction of sulfonyl azides, terminal alkynes and a,b-unsaturated imines has been developed. The a,b-unsaturated imine substrates could be generated from amines and a,b-unsaturated aldehydes in a one-pot process. The procedure is concise, general and efficient.Keywords: ketenimines; multicomponent reactions; tandem reaction; tetrahydropyrimidines Ketenimines are nitrogen-containing heterocumulenes, which can participate in a variety of organic reactions, [1] such as nucleophilic addition reactions, [2] radical addition reactions, [3] [2 + 2] and [4 + 2] cycloaddition reactions [4] and sigmatropic rearrangements.[5]Previously, we [6] and several other groups [7] developed the Cu-catalyzed three-component reactions of sulfonyl azides with terminal alkynes and a number of nucleophiles. The reactions involve a copper-catalyzed azide-alkyne cycloaddtion (CuAAC) and the generation of a ketenimine intermediate. Phosphoryl azides could also serve as a high-yielding type of azide to participate in the reaction.[8] These multicomponent reactions are versatile with regard to the substrate scope and the synthetic applicability. On the basis of these results, we anticipated that the ketenimine intermediate A (Scheme 1), which was in situ generated from terminal alkyne 1a and sulfonyl azide 2a, could react with a,b-unsaturated imine 3a through a nucleophilic cyclization to give tetrahydropyrimidine 4aaa and/or azetidin-2-imine 5aaa, respectively. Since the formation of azetidin-2-imines via the reaction of the ketenimine intermediate with imines has been reported by Whiting and Fokin, [7e] we systematically optimized the reaction leading to the six-membered product and investigated the applicability of this method to a variety of terminal alkynes, sulfonyl azides and a,b-unsaturated imines. Herein, we report the details of this work.Exhaustive studies of the reaction conditions for the synthesis of 4aaa from terminal alkyne 1a, sulfonyl azide 2a and a,b-unsaturated imine 3a showed that CuCl (Table 1, entry 1), CuBr (Table 1, entry 2), and CuI (Table 1, entries 3-14) could catalyze the reaction to result in a mixture of the six-membered product 4aaa and the four-membered product 5aaa, Scheme 1. Copper-catalyzed three-component reaction of alkyne 1a, sulfonyl azide 2a and imine 3a.

Copper(I)‐Catalyzed [3+2] Cycloaddition/Ring‐Opening Rearrangement/[4+2] Cycloaddition/Aromatization Cascade: An Unprecedented Chemo‐ and Stereoselective Three Component Coupling of Sulfonyl Azide, Alkyne and N‐Arylidenepyridin‐2‐ amine to Pyrido[1,2‐a]pyrimidin‐4‐imine

“…In the present study, we have utilized a 1,3‐diazadiene skeleton, namely, N ‐arylidenepyridin‐2‐amine for a facile [4+2] cycloaddition with N ‐sulfonylketenimine, generated in situ from the copper(I)‐catalyzed [3+2] cycloaddition of sulfonyl azides and terminal alkynes. To our surprise, the cycloaddition proceeds exclusively across the CC double bond of N ‐sulfonylketenimine and subsequent aromatization leading to pyrido[1,2‐ a ]pyrimidin‐4‐imines (Scheme ), in contrast to the previous report14d with α,β‐unsaturated imine. The presence of two electron‐rich nitrogen atoms in diazadiene (Scheme and Scheme ) increases the electron density and hence the reactivity of diene component towards Diels–Alder reactions.…”

Syntheses of N-sulfonyl-N,N-disubstituted amidines via a three-component free-radical coupling reaction of tertiary amines and arenesulfonyl azides with terminal alkynes

“…According to Chang [16][17][18][19][20][21][22][23][24][25][26][27] and Wang [28][29][30][31][32][33], arenesulfonyl azide 1 can react with the alkyne 2 to form the ketenimine species B in the There are possibly two competitive reaction routes for the formation of compound 4 (Scheme 4): the reaction between the intermediate B and hydrogen radical and the one between B and the free radical D. Therefore, a quantum chemical calculation has been performed. With DFT method implemented in Gaussian 09 package [48] under B3LYP/6-31+g** level, the reactants, products, possible intermediates and transition state geometries along the proposed reaction routes are optimized, and the reaction potential energy profiles are plotted in Figure 2.…”

“…Among various MCRs recently developed [2][3][4][5], the CuIcatalyzed MCRs of sulfonyl azides and alkynes with a third component, like amines, water, alcohol, imines, salicylaldehyde, aziridine or nitroolefin have attracted increasing research interests lately [6][7][8][9][10][11][12][13][14][15]. For example, Chang's [16][17][18][19][20][21][22][23][24][25][26][27] and Wang's [28][29][30][31][32][33] groups have applied these CuI-catalyzed MCRs on terminal alkynes respectively for the efficient generation of N-sulfonylamidines, amides, Nsulfonylazetidin-2-imines, iminocoumarins, 5-arylidene-2-imino-3-pyrrolines, and γ-nitro imidates. Our group has also applied this reaction for the efficient generation of benzoxazoline-amidines and 4-arylsulfonylimino-4,5-dihydrofurans by reacting sulfonyl azides and alkynes with Schiff bases or -ketoesters [34,35].…”

Chemistry in Confinement: Copper and Palladium Catalyzed Ecofriendly Organic Transformations within Porous Frameworks

“…The cycloaddition proceeded with reversal of chemoselectivity involving addition across the C=C double bond of N‐sulfonylketenimine and subsequent aromatization leads to pyrido[1,2‐α]pyrimidin‐4‐imines (3) (Scheme ), in contrast to the work reported by Lu et. al., with α,β‐unsaturated imines. The presence of two electron‐rich nitrogen atoms in diazadiene increases the electron density and hence the reactivity of diene component towards Diels‐Alder reactions.…”