Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides

Abstract

Herein we would like to communicate that an unstabilized azomethine ylide generated from commercial trimethylamine N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in good yield with electron-rich and unpolarized olefins. A broad range of substituents on the alkenes are tolerated provided they are compatible with excess LDA. This demonstration of novel reaction scope should encourage others to try trimethylamine N-oxide as an azomethine ylide precursor in the synthesis of challenging 3,4-disubstituted pyrrolidines.Substituted pyrrolidines are common structural motifs present in a wide variety of natural products, 1 chiral ligands, 2 and biologically active compounds. 3 One of the most prevalent and reliable methods for the diastereoselective construction of 3,4-substituted architecture is the 1,3-dipolar cycloaddition reaction of an azomethine ylide and an appropriately substituted alkene. 4During the course of our research we became interested in constructing novel 3,4-disubstituted pyrrolidine ring systems. Since we did not require substitution on the 2-and 5-positions of the pyrrolidine ring, the azomethine ylide derived from the acid-catalyzed decomposition of commercial N-methoxymethyl-N-trimethylsilyl methyl phenyl methanamine (1) 5 was deemed a suitable choice (Scheme 1). Scheme 1 Acid-catalyzed [3+2]-cycloaddition reactionIn general, with compatible substrates, we found this wellprecedented chemistry to be operationally simple and scalable. In several cases we obtained multigram quantities of the corresponding N-benzyl pyrrolidine. A welldocumented drawback of this method is that this type of unstabilized azomethine ylide does not readily undergo cycloaddition with unactivated dipolarophiles. 6Pyrrolidines whose requisite alkenes were unreactive under the acid-catalyzed conditions required a different preparation. A survey of the chemical literature unearthed a little used, but powerful method wherein a reactive unstabilized azomethine ylide can be generated by treating trimethylamine N-oxide 4 with lithium diisopropylamide at low temperature. 7 Under these strongly basic conditions, ylide formation is thought to proceed by deoxygenation of the N-oxide. The resultant intermediate is extremely reactive and can be trapped by simple alkenes such as hex-1-ene, cyclopentene, styrene, and stilbene. 8 Scheme 2 Basic [3+2]-cycloaddition reactionHerein we would like to report that this cycloaddition reaction furnished targeted N-methyl pyrrolidines in yields ranging from good to excellent in nearly all cases examined. 9 A broad range of substituents on the alkenes were tolerated in this transformation provided that functionalities were compatible with excess LDA. Among the successful dipolarophiles were several examples of electronrich olefins including those that failed under the acid conditions (specifically products 8-10, Table 1). We found this reaction to be operationally straightforward with cycloadditions generally reaching completion in less than one hour.

Tetrahydropyrrolization of Resveratrol and Other Stilbenes Improves Inhibitory Effects on DNA Oxidation

“…Thus, another precursor was evaluated for cycloaddition with these stilbenes. (CH 3 ) 3 SiCH 2 Cl was heated in CH 3 NH 2 , followed by addition of HCHO and CH 3 OH to afford (CH 3 ) 3 SiCH 2 N(CH 3 )CH 2 OCH 3 (see Figure ) . After the hydroxy groups in 13 , 19 , 21 , and 23 were acetylated, these stilbenes reacted with (CH 3 ) 3 SiCH 2 N(CH 3 )CH 2 OCH 3 in the presence of CF 3 COOH to afford desired products, 14 , 20 , 22 , and 24 , respectively.…”

Recent Advances in Transformations Involving Electron‐Rich Alkenes: Functionalization, Cyclization, and Cross‐Metathesis Reactions

“…Later, Davoren [49] and Zhang [50] independently reported a [3+2] cycloaddition of electron‐rich olefins with azomethine ylides, which were formed from trimethylamine N ‐oxide and N ‐tosyl aziridines respectively, providing an efficient approach to construct diverse pyrrolidines. Due to the weak bond between the adjacent donor‐ and acceptor‐substituted carbons of the three‐membered ring, Werz and coworkers employed the donor‐acceptor (D−A) cyclopropanes in‐situ generated from electron‐rich alkenes 27‐1 and α ‐diazo‐ α ‐nitro ethyl acetate 27‐2 to construct cyclic nitronates 27‐3 in one pot through a cyclopropanation/ring‐enlargement process.…”

Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

“…16 While the trans-diastereoisomers (8-10) were inactive in both assay formats (IC 50 > 30µM and K d > 100 µM), we were encouraged to find that the cis-diastereoisomers, which were predicted to adopt a more favourable conformation to act as an isostere of 1, did show modest activity and reversibility against LSD1 by SPR ( workers. 22 This afforded the N-methyl products, which were deprotected by reaction with 1-chloroethyl chloroformate followed by refluxing in methanol. Amide coupling, followed by Boc-deprotection, afforded amines 21a-h, 22a-b and 22a-e.…”