Azetidines: New Tools for the Synthesis of Nitrogen Heterocycles

Abstract

Compared to other nitrogen heterocycles such as aziridines, pyrrolidines, or piperidines, the chemistry of azetidines is much less developed, probably because of their limited availability. In this account, recent synthetic routes to these strained heterocycles starting from readily available enantiomerically pure starting compounds will be detailed. The ring strain in these heterocycles makes them excellent candidates for nucleophilic ring-opening or ring-expansion reactions yielding higher ring systems or highly substituted acyclic amines. These useful transformations will be described in the second section of this account.

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

“…[36] In addition, the fact that benzylic lithiation, which leads to a-1 a-Li (Scheme 10), was never observed, even when the lithiation reaction was executed at high temperature (Table 1, entry 21), strengthens the hypothesis that conformer A (Scheme 10) could be responsible for the observed reactivity. [37] Assuming the directing ability of the azetidine ring, we explored the possibility of further functionalization of the aromatic group. A careful look at the X-ray structures of monofunctionalized azetidines 2 k, 2 o and 2 w (Figure 1), reveal a peculiar arrangement of the aryl group linked to the C2 carbon atom of the azetidine ring.…”

Synthesis of 1,3-Disubstituted Azetidines via a Tandem Ring-Opening Ring-Closing Procedure

“…1 Table 2 To a solution of {2-[(tert-butyldimethylsilyloxy)methyl]oxiran-2-yl}methyl 4-methylbenzenesulfonate (1, 100 mg, 0.27 mmol) in EtOH (2.7 mL, 0.1 M) was added the corresponding amine (3 equiv, Table 2). The solution was heated at reflux for 8 h and allowed to cool slowly to r.t.…”

“…13 Having identified that the major products formed from the reaction of 1 with primary amines were the symmetrical azetidines (presumably via route b), we sought to discover if the reaction pathways would change if secondary amines were used instead, not least because the analogous reaction product 21 (Scheme 2) would be an azetidinium ion which is potentially capable of further reaction in situ. 1 It was also possible that a number of other scenarios could occur; either the synthetically useful tertiary amines 18 or 20 would be isolated, unlike before, where the increased steric bulk of the amines would restrict subsequent reaction, or, if the amine was not found to be too sterically demanding, then a double addition product 19 may be isolated, the result of the attack of a second equivalent of amine with either 18 or 21 (Scheme 2). Under the same reaction conditions to those used with the primary amines, we subjected 1 to a series of secondary (Table 2).…”

Azacycloalkanes from epoxides and aziridines

“…The azetidine 2 derivatives are also used in the treatment of the central nervous system distortions like Alzheimer, Parkinson diseases, painful syndrome, schizophrenia, depressions due to the involvement of the nicotinic acetylcholine receptor (nAChRs) [38]. Azetidine ring is far less strained than that of aziridine therefore the azetidines are less reactive [39,40], yet many among them are valuable initial compounds in the syntheses of various azaheterocycles [41,42].…”

“…Actually, the opening of the azetidinium ions to form epoxides occurred under the action of acetate and alkoxide anions [214]. Tri-and tetraazasubstituted epoxides were successfully obtained by reactions of the azetidinium ions and carbonyl compounds (aldehydes and ketones) [215].…”