Efficient Preparation of [1‐¹⁵N]‐3‐Cyano‐4‐methyl‐1H‐pyrrole by a Wittig‐Based Strategy

Abstract

3‐Cyano‐4‐methyl‐1H‐pyrrole (1) was prepared by a new Wittig procedure from simple, commercially available starting materials in four steps with an overall yield of 39 %. Similarly, [1‐15N]‐3‐cyano‐4‐methyl‐1H‐pyrrole (1a) was prepared starting from [15N]‐phthalimide. In this synthesis, Wittig coupling was used to form the central C–C bond of intermediate 6, which has nitrile and methyl substituents. Upon deprotection and cyclization pyrrole 1 is obtained directly in one pot. This scheme also allows stable isotope incorporation at any position or a combination of positions. 3‐Cyano‐4‐methyl‐1H‐pyrrole was converted into the novel 1‐benzyl‐3‐cyano‐4‐methylpyrrole and the novel 4‐methyl‐1H‐pyrrole‐3‐aldehyde. It is clear that this novel Wittig procedure has a wide scope that will allow the easy preparation of many new pyrrole systems.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Structure–Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer

“…22 Treatment of 15 with refluxing hydrazine removed the phthaloyl protecting group, and subsequent cyclization in the same pot gave the tetramic acid 16. 23 Deprotonation of 16 with n-butyllithium followed by reaction with the p-nitrophenylester of Boc-D-leucine 17 24 gave the desired N-acylated tetramate 18. Removal of the Boc protecting group in 18 with TFA followed by reaction with propionic acid anhydride in pyridine gave NCSTD (10).…”

“…Homologation of acid chloride 13 with the dianion of monoethylmalonate gave the desired β-ketoester 14 , which was methylated using trimethyl orthoformate and a catalytic amount of H 2 SO 4 in MeOH to give enol ether 15 . Treatment of 15 with refluxing hydrazine removed the phthaloyl protecting group, and subsequent cyclization in the same pot gave the tetramic acid 16 . Deprotonation of 16 with n -butyllithium followed by reaction with the p -nitrophenylester of Boc- d -leucine 17 gave the desired N -acylated tetramate 18 .…”

“…The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with hexanes/ EtOAc (5:1 → 3:1) to afford primary alcohol (S)-22 ( (23). To a stirred solution of (S)-22 (3.13 g, 9.00 mmol) in DMF (10 mL) at 0 °C were added tertbutyldiphenylsilyl chloride (3.7 mL, 14.2 mmol) and imidazole (2.97 g, 43.6 mmol).…”

The Role of the Chromophore in the Biological Photoreceptor Phytochrome: An Approach Using Chemically Synthesized Tetrapyrroles

“…Several improvements of this fairly laborious synthetic route have been presented, preferentially aiming at reducing the number of starting materials. In recent years, important contributions have been made by the groups of Inomata and Jacobi, who published detailed overviews of their work. , Quite innovative synthetic approaches for strongly modified tetrapyrroles were introduced by Inomata (see below), also aimed at reducing the number of building blocks, , and Dawadi and Lugtenburg introduced an extended Knoevenagel- and a Wittig-type reaction for the generation of pyrroles. , …”

“…35,36 Quite innovative synthetic approaches for strongly modified tetrapyrroles were introduced by Inomata (see below), also aimed at reducing the number of building blocks, 35,37 and Dawadi and Lugtenburg introduced an extended Knoevenagel-and a Wittig-type reaction for the generation of pyrroles. 38,39 Building an open-chain tetrapyrrole by convergent synthesis requires all pyrrole compounds with their correct substitution pattern, as well as activation of the pyrroles at selected positions. Whereas rings B, C, and D are synthesized relatively readily and are also fairly inert during the reaction pathway, ring A demands special care, in particular considering the ethylidene substituent at position C3, essential for covalent attachment to the protein.…”