2-Bromo-6-isocyanopyridine as a Universal Convertible Isocyanide for Multicomponent Chemistry

Abstract

The development of 2-isocyanopyridines as novel convertible isocyanides for multicomponent chemistry is reported. Comparison of 12 representatives of this class revealed 2-bromo-6-isocyanopyridine as the optimal reagent in terms of stability and synthetic efficiency. It combines sufficient nucleophilicity with good leaving group capacity of the resulting amide moiety under both basic and acidic conditions. To demonstrate the practical utility of this reagent, an efficient two-step synthesis of the potent opioid carfentanil is presented.

Isocyanide 2.0

“…Synthesis of pyridine-and pyrimidine-containing isocyanides such as I-65 to I-69 at very low temperatures (−78 to −40°C) has been reported in the literature. 50 Due to the reported instability, the isolated isocyanides were immediately used in further reactions. 50 In contrast, our methodology enabled the synthesis of these isocyanides with regular ice bath cooling and isolation at room temperature and NMR analysis (ESI †).…”

“…50 Due to the reported instability, the isolated isocyanides were immediately used in further reactions. 50 In contrast, our methodology enabled the synthesis of these isocyanides with regular ice bath cooling and isolation at room temperature and NMR analysis (ESI †). 2-Isocyanopyridine (I-69, 30%) and 3-(isocyanomethyl)pyridine (I-64, 60%) were isolated in good yields.…”

“…A noteworthy exception is 2-bromo-6-isocyanopyridine which was reported recently as a stable universal convertible isocyanide amongst many similar heterocyclic but unstable relatives. 50 Thus, we decided to proceed to the synthesis of some MCR-derived compounds with the in situ formation of such isocyanides. By participating in a classical Ugi 4-component reaction and an Ugitetrazole reaction, respectively, 2-pyrimidine isocyanide was Quantitative conversion and product formation were observed by TLC, but the compound was difficult to isolate by this method due to its high volatility.…”

Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications

“…This reaction sequence was used to prepare the potent opioid carfentanil 4 via acidic methanolysis of Ugi product 3 to give carfentanil 4 in near-quantitative yield (98%) (Scheme 3). 20 Carfentanil 4 is an opioid analgesic belong to the fentanyl class, which is $100 000 times more potent than morphine. 20 (À)-Viridic acid is a tetrapeptide generated by many fungi of the Penicillium group, 21 which was rst isolated from P. viridicatum.…”

Efficient Diastereoselective Three‐Component Synthesis of Pipecolic Amides

“…Recently, we developed 2-bromo-6-isocyanopyridine (7) as a universal convertible isocyanide for selective post-transformations of Ugi and Passerini products under mild acidic or alkaline conditions. [30] Piperideine 5a was obtained from commercial 16 by the NCS-mediated chlorination followed by HCl elimination described in Scheme 3. For the NO 2 -protected quinolyl sulfonamide 8a (PG = NO 2 ) we initially envisioned to use (like Cossy and Belotti) N ω -nitro-l-arginine as the functionalized carboxylic acid input for the U-3CR.…”