Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines

Abstract

A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.

Development of a Continuous Flow Synthesis of 2-Substituted Azetines and 3-Substituted Azetidines by Using a Common Synthetic Precursor

“…On the other hand, such a relatively unexplored motif continues to stimulate organic chemists’ creativity . Our research group is involved in developing synthetic tactics involving metalated (i.e., lithiated) azetidines as useful intermediates for creating molecular diversity. , In addition, we became interested in the use of flow technology as a tool for taming, controlling, and using highly reactive organometallic intermediates . The benefits of flow microreactor technology as a pivotal synthetic “toolbox” for enabling new and previously inaccessible reactivity patterns or for controlling safety concerns of old-fashioned chemistry are nowadays well-documented. , Furthermore, flow technology holds the potential to be a green technology addressing the quest for sustainability coming from modern society .…”

Synthesis and strain-release reactions of 1-azabicyclo[1.1.0]butanes: an update

“…In parallel with this innovation, organic chemists devoted their efforts to the development of efficient methods for the construction and functionalization of the azetidine ring. [5][6][7][8][9][10] The strategies that allow for the preparation of azetidines generally involve cycloaddition, cyclization, ring-expansion, and ring-contraction transformations. 11 Aside from these general methods, the exploitation of azabycliclo[1.1.0]butanes (ABBs) represents an innovative approach and recently enabled the access to an unexplored chemical space.…”