Ring Expansion of 2‐(α‐Hydroxyalkyl)azetidines: A Synthetic Route to Functionalized Pyrrolidines

Abstract

A series of 2‐(α‐hydroxyalkyl)azetidines synthesized from enantiomerically pure β‐amino alcohols and presenting various patterns both on the four‐membered ring and on the adjacent hydroxy group were treated with either thionyl chloride or methanesulfonyl chloride in the presence of triethylamine. The thus‐prepared 2‐(α‐chloro‐ or α‐methanesulfonyloxyalkyl)azetidines were shown to rearrange stereospecifically into 3‐(chloro‐ or methanesulfonyloxy)pyrrolidines. When this rearrangement is conducted in the presence of an added nucleophile (NaN3, KCN, KOH, or NaOAc), the produced pyrrolidine incorporates the added nucleophile at C‐3 stereospecifically. The relative configuration of the substituents in the formed pyrrolidines is consistent with a mechanism involving the formation of an intermediate bicyclic aziridinium ion, which is opened regioselectively at the bridgehead carbon atom. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A nitrilase-mediated entry to 4-carboxymethyl-β-lactams from chemically prepared 4-(cyanomethyl)azetidin-2-ones

“…of triethylamine, providing mesylated b-lactams 8a,b in high yields. 48 In an analogous manner, stirring of 4-hydroxymethyl-b-lactams 7a-c in the presence of tosyl chloride, triethylamine and DMAP under reux conditions for nearly two days, afforded 4-tosyloxymethyl-b-lactams 9a-c in 60-67% yield. The expected nal step in this synthetic pathway consisted of the nucleophilic substitution of both sulfonyloxy leaving groups by a cyanide anion to give rise to 4-cyanomethylb-lactams 11a-c.…”

Ring Expansions of Nonactivated Aziridines and Azetidines

“…In our group, having devised a method for the stereocontrolled preparation of α-(hydroxymethyl)azetidines, we studied the behavior of a set of primary, secondary, and tertiary azetidinic alcohols involved in this ring expansion after transformation of the hydroxyl group into a leaving group (chloride or mesylate). This reaction [134,135] was found to occur in a stereospecific way and was general when primary and secondary alcohols were involved, as shown with several examples showing structures 292-299 in Scheme 74. However, it failed to produce any rearranged product in the case of tertiary alcohols.…”

Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

“…In this report evidence of a dissociative isomerisation mechanism is revealed, which corroborates hypotheses of Couty and others in the area (see later). 24,25 Paulmier, Outurquin and co-workers reported selenium induced cyclisation of homoallyl amines to azetidines and pyrrolidines. 26,27 Bott et al reported a one carbon ring expansion of azetidines via ammonium ylide shifts.…”

“…26,27 Bott et al reported a one carbon ring expansion of azetidines via ammonium ylide shifts. 28 Couty and coworkers have studied a number of ring enlargement reactions that deliver pyrrolidines from azetidines, such as fluoride, 29 chloride 25 and bromide derivatives, 30 alkene derivatives 31 and hydroxy derivatives. 25 Van Brabandt et al also utilised ring expanded chloride and bromide bearing azetidines.…”

“…28 Couty and coworkers have studied a number of ring enlargement reactions that deliver pyrrolidines from azetidines, such as fluoride, 29 chloride 25 and bromide derivatives, 30 alkene derivatives 31 and hydroxy derivatives. 25 Van Brabandt et al also utilised ring expanded chloride and bromide bearing azetidines. 32 Amongst this catalogue of work Couty and coworkers reported a computational study where ring expansion of 2-(chloromethyl)-1-isopropylazetidine was discussed, 24 and noted that a polar solvent (DMSO) reduced the barrier to isomerisation and the reaction proceeds via two transition states through a strained intermediate, Scheme 7. It is also important to point out that a five ( pyrrolidine) to six ( piperidine) membered ring expansion reaction that exploits the nucleophilic displacement of a beta iodide by Davies et al supports an ion pair aziridinium salt hypothesis Using the knowledge that the isomerisation of 2,4-cis-azetidines 2 to 2,4-cis-pyrrolidines 3 is facile and our knowledge that nucleophilicly displacing iodine from azetidine products delivers stable amino azetidines we chose to run a similar protocol for generation of trans-pyrrolidine (whilst never observed it was speculated that iodopyrrolidines might be prone to polymerisation via N-quaternisation or other side reactions so reaction of the iodide directly was deemed appropriate).…”