Robust and Scalable Approach to 1,3‐Disubstituted Pyridylcyclobutanes

Abstract

An approach to all isomeric 3‐pyridylcyclobutane‐derived building blocks, i.e. ketones, alcohols and amines, is described. Synthesis of the title compounds relied on the five‐step reaction sequence including alkylation of isomeric pyridyl acetonitriles with 1,3‐dibromo‐2,2‐dimethoxypropane. Hydrolysis, decarboxylation and removal of the ketal moiety led to the key 3‐pyridylcyclobutanones (obtained on up to 120 g scale in a single run), which were transformed into the corresponding alcohols and amines with high diastereoselectivity. The title cyclobutanone derivatives were used to synthesize three isomeric nicotine analogues, as well as for parallel synthesis of a small lead‐like compound library via reductive amination.

Synthesis of Fused Pyridine Carboxylates by Reaction of β-Alkoxyvinyl Glyoxylates with Amino Heterocycles

“…17,[40][41][42][43] To the best of our knowledge, synthetic utility of alkoxyvinyl glyoxylates for the construction of fused pyridines was not demonstrated to date. In continuation of our work in the field of pyridine chemistry, [44][45][46][47][48][49][50] we have now aimed at the study of the low-molecular-weight alkoxyvinyl glyoxylates 11a-c as CCC bis-electrophiles in the reactions with common NCC binucleophiles 9 (Scheme 1).…”

Multigram Synthesis of α‐ and γ‐((Hetera)cyclo)alkylpyridines through α‐Arylation of (Hetero)aliphatic Nitriles

“…The known approaches to the construction of cycloalkylpyridine scaffolds include both ring size-specific reactions (i. e. various cycloadditions), [6][7][8][9][10][11][12] and general methods, including metal-catalysed couplings of alkyl and hetaryl halogenides, [13][14][15][16][17][18][19][20][21] double alkylations of the CH 2 unit in pyridylacetic acid derivatives, [22][23][24][25] and radical reactions [26][27][28][29] (Figure 2, A). Being one of the oldest and most studied transformation in the aromatic series, [30] S N Ar reactions of 2-or 4-halopyridines can be considered a convenient site-specific method for the synthesis of substituted pyridines.…”

Diastereoselective Synthesis of a cis-1,3-Disubstituted Cyclobutane Carboxylic Acid Scaffold for TAK-828F, a Potent Retinoic Acid Receptor-Related Orphan Receptor (ROR)-γt Inverse Agonist

“…The key synthetic challenge in the above route was the diastereoselective reduction of 12 . Although the cis -selective reduction of cyclobutylidene Meldrum’s acid derivatives has no precedent, cis -selective reduction of 3-mono-substituted cyclobutanones to 3-mono-substituted cyclobutanols with NaBH 4 has been reported (Scheme a). , Furthermore, the reduction of alkylidene Meldrum’s acid derivatives with NaBH 4 has been reported, even with highly congested substrates (Scheme b) . Accordingly, the cis -selective reduction of 12 with NaBH 4 was envisaged to be feasible (Scheme c).…”