(1H-Tetrazol-5-yl)-Allenes: Building Blocks for Tetrazolyl Heterocycles

Abstract

(1H-Tetrazol-5-yl)-allenes have been prepared for the first time, and their reactivity toward aziridines explored. Reaction of a (1-benzyl-1H-tetrazol-5-yl)-phosphonium chloride and acyl chlorides in the presence of triethylamine afforded the target allenes via Wittig reaction of the in situ generated phosphorus ylide and ketenes. 1-(1-Benzyl-1H-tetrazol-5-yl)propa-1,2-diene and 3-methyl-, 3-ethyl- and 3-benzyl derivatives undergo microwave-induced formal [3 + 2] cycloaddition with cis-N-benzyl-2-benzoyl-3-phenylaziridine, through C-N bond cleavage, to give selectively tetrasubstituted pyrroles. In contrast, with (1H-tetrazol-5-yl)-allenes bearing bulkier substituents at C-3, such as i-propyl or a tert-butyl, 4-methylenepyrrolidines were obtained exclusively via [3 + 2] cycloaddition of the in situ generated azomethine ylide. The latter allenes also gave 4-methylenepyrrolidines on reacting with cis-2-benzoyl-N-cyclohexyl-3-phenylaziridine, whereas with the other allenes, pyrroles were obtained as major products together with the formation of 4-methylenepyrrolidines. All the studied (1H-tetrazol-5-yl)-allenes reacted with N-benzyl-cis-3-phenylaziridine-2-carboxylate to give the corresponding 4-methylenepyrrolidines exclusively.

Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

“…13 These compounds have proven to be versatile building blocks for several transformations giving rise to an array of cyclic and acyclic nitrogen-containing compounds. 14 On the other hand, we reported the synthesis of (1H-tetrazol-5yl)-allenes, 15 tetrazolyl-tryptamines and 2-halo-2-(tetrazol-5yl)-2H-azirines and the use of these compounds for the construction of tetrazolyl-heterocycles, namely 3-tetrazolyl-βcarbolines with anti-cancer activity. [15][16][17][18] Building blocks bearing a tetrazolyl substituent are a particularly interesting synthetic tool to explore carboxylic acid/tetrazole bioisosterism as a way to find new molecules with enhanced biological activity.…”

“…14 On the other hand, we reported the synthesis of (1H-tetrazol-5yl)-allenes, 15 tetrazolyl-tryptamines and 2-halo-2-(tetrazol-5yl)-2H-azirines and the use of these compounds for the construction of tetrazolyl-heterocycles, namely 3-tetrazolyl-βcarbolines with anti-cancer activity. [15][16][17][18] Building blocks bearing a tetrazolyl substituent are a particularly interesting synthetic tool to explore carboxylic acid/tetrazole bioisosterism as a way to find new molecules with enhanced biological activity. In this context, we have selected 2-(tetrazol-5yl)-2H-azirines as our target molecules due not only to their interesting chemical features but also considering that these heterocycles are bioisosters of relevant 2H-azirine-2carboxylates.…”

“…The observed molecular conformation in the crystal maximizes the ππ interaction between the electron clouds of the phenyl rings and effects. As the molecules lacks any strong H-bonding donor, the only significant intermolecular interactions spotted in the crystal structure involve C-H groups acting as donors (D) and N or O atoms as acceptors (A), namely C(15)-H(15)...N(5) i , i = 1-x,1-y,1-z (D…A = 3.435(4) Å) and C(22)-H(22) ...O(17) ii , ii = 2-x,-1/2+y,3/2-z (D…A=3.466(3) Å). In addition, the two short intramolecular contacts C(9)-H(9A)...N(1) (D…A = 3.102(3) Å) and C(15)-H(15) ...N(8) (2.861(3) Å) deserve to be remarked.…”

Synthesis of Allenes by 1,2-Elimination

“…Pinho e Melo and co-workers recently disclosed a one-pot method for olefination of acid chlorides with tetrazole containing phosphonium salt 49 (Scheme 12b). [31] This process requires two equivalents of triethylamine. The first deprotonates the phosphonium salt to form an ylide and the second generates a ketene in situ.…”

Current Trends towards the Synthesis of Bioactive Heterocycles and Natural Products Using 1,3-Dipolar Cycloadditions (1,3-DC) with Azomethine Ylides

“…197, X = OEt), allene substitution was not important and pyrrolidines 201 were obtained exclusively in excellent diastereoisomeric ratios and high chemical yields (Scheme 58). 87 Important chromenopyrrole derivatives 203 and 205 were prepared by the generation of azomethine ylides from aziridines 202 and 204 bearing terminal alkyne/allene groups, respectively. The stereoselective intramolecular 1,3-DC took place in refluxing toluene giving only one stereoisomer in good chemical yields.…”