Ring Expansion of Cyclic β-Amino Alcohols Induced by Diethylaminosulfur Trifluoride: Synthesis of Cyclic Amines with a Tertiary Fluorine at C3

Abstract

As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic β-fluoro amines was studied as well as the enantioselectivity of the process.

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

“…A DAST‐promoted azetidine‐to‐pyrrolidine transformation has also been described by the group of Cossy . In that regard, treatment of chiral azetidine 79 with 1.4 equiv.…”

“…In another study, the influence of a quaternary center in the α‐position with respect to the nitrogen atom has also been evaluated by employing cyclic amino alcohols 127 and 129 as substrates, resulting in complete regioselective ring‐transformation reactions in favor of piperidine formation (Scheme ) . Moreover, DAST‐induced ring expansion of β‐amino alcohols 129 proceeded with excellent enantioselectivity ( ee =98–99%).…”

“…As an extension of the DAST‐induced ring enlargement of prolinols with a quaternary center in the α‐position with respect to the nitrogen atom, the ring expansion of their higher homologues, 2‐(hydroxymethyl)piperazines/morpholines 182 , has also been investigated by Anxionnat et al . As exemplified in Scheme , six‐membered substrates 182 underwent a ring expansion to diazepanes/oxazepanes 185 without any trace of a six‐membered product.…”

Binap and Phosphoramidites as Privileged Chiral Ligands for the Metal‐Catalyzed Enantioselective 1,3‐Dipolar Cycloaddition of Azomethine Ylides

“…We envisaged that products 43 (a series of nitropiperidines that are potent farnesyltransferase inhibitors with promising antitumor activity)46 could be accessed through the enantiomerically enriched proline derivatives 40 by ring expansion of the cyclic β‐amino alcohol derivatives following the methodology developed by Cossy's group 47. Thus, crude nitroalcohol 44aa was obtained as an optically pure compound, in almost quantitative yield, after reduction with NaBH 4 /NaBH(AcO) 3 48.…”

Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines

“…To obtain piperidines 7, prolinols 5 were treated with diethylaminosulfur trifluoride (DAST; 1.4 equiv) in THF and the corresponding 5-fluoropiperidines 6 were obtained in good yields. [13] We have to point out that N-trityl prolinols 5 were exclusively converted to 6 and N-p-methoxybenzyl prolinols 5 were transformed to a mixture of piperidines 6 and pyrrolidines 6', which were then separated. Cleavage of the N-trityl protecting group (HCl in EtOH) and the N-PMB protecting group (Pd/C, HCOOH) in piperidines 6 led to 3-N-Boc-5-fluoropiperidines 7 ( Table 3).…”