1542817-68-4

Upstream product

• 100306-33-0 (1R)-3-chloro-1-phenylpropanol 
• 1610980-30-7 (+)-(R)-(1,3-dichloropropyl)benzene 
• 74-89-5 methylamine 
• 14155-36-3 (+/-)-(1,3-dichloropropyl)benzene 
• 18776-12-0 3-chloro-1-phenyl-propan-1-ol 
• 936-59-4 3-chloropropiophenone 

Downstream Products

• 1542817-52-6 (2R)-2-(3,3-diphenyl-1,3-dihydroisobenzofuran-1-yl)-N-methylethanamine 
• 1542817-31-1 (S)-(2-(1-methylazetidin-2-yl)phenyl)diphenylmethanol 

Relevant academic research and scientific papers

Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization

The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.

Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.

Regioselective functionalization of 2-arylazetidines: Evaluating the ortho-directing ability of the azetidinyl ring and the α-directing ability of the N-substituent

The regioselective lithiation-functionalization of 2-arylazetidines has been explored. The nature of the N-substituent is mainly responsible for a regioselectivity switch. ortho-Lithiation occurred, using hexyllithium as a greener base, in N-alkylazetidines, while α-benzylic lithiation has been observed with N-Boc azetidines.