A Theoretical and Experimental Study on Acid-Catalyzed Isomerization of 1-Acylaziridines to the Oxazolines. Reexamination of a Possible S_Ni Mechanism by Using ab Initio Molecular Orbital Calculations

Abstract

The S(N)i mechanism, which was previously proposed for the isomerization of 1-acylaziridines to the oxazolines, was reexamined theoretically by performing molecular orbital (MO) calculations of 1-formylaziridine and its derivatives as model compounds and experimentally by using 1(R)-[alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl]-2(S)-methylaziridine (5). At the MP2/6-31G//RHF/6-31G level, the activation energy was estimated to be 38.9 kcal mol(-1) for the S(N)i mechanism in which N-protonated 1-formylaziridine 8a(NH(+)) isomerizes to the N-protonated oxazoline 9a(NH(+)). Intrinsic reaction coordinate calculations showed that this reaction proceeds with retention of the ring carbon configuration. Methyl substitution in the aziridine ring reduces the activation energy by 10 kcal mol(-1). The ring closure of N-(2-chloroethyl)formamide (10a) to the oxazoline, which is a model reaction of the rate-determining step for the addition-elimination mechanism, was estimated to have an activation energy of 45.4 kcal mol(-1). The results of these MO calculations are consistent with the observation that the isomerization of the acylaziridine 5 to the oxazoline 6 is facilitated in the presence of weak nucleophiles such as with BF(3).OEt(2) while the formation of 6 is very slow in the presence of stronger nucleophiles such as p-toluenesulfonate. Both theoretical and experimental results suggest that the S(N)i mechanism explains well the isomerization of (R,S)-5 to the oxazoline with BF(3).OEt(2) in refluxing benzene.

The Ring Expansions of Glyceraldehyde-Derived Aziridine-2-carboxylates to Oxazolines Take Place with an Uncommon Regiochemistry

“…[3] Moreover, it is to be assumed that the regioselectivity is driven by the stability of the carbocationic intermediate or carbocationic-like transition state. [7,8] For this reason, it was to have been anticipated that the ring expansion of both of the aziridines was likely to take place in favour of the C-3 positions, which seem more capable of stabilizing the incipient positive charge (Scheme 1). This observed regioselectivity might be caused by the operation of a neighbouring-group effect, [6] as suggested by a study of the Lewis acid·9 complex that we carried out using semiempirical computations.…”

“…Indeed, the aziridine N atom is pyramidalized by ring strain, making it more prone to complexation than the nitrogen atom of planar amides. [7,8,29] We performed PM3 semiempirical energy minimization [24] of a conformation set generated by a Monte Carlo procedure. [25] In a similar way, we calculated the more stable PM3 conformation of uncomplexed 9.…”

“…In this complex, however, there are only small or even no changes in the aziridine interatomic distances relative to those in 9. [30] This situation reflects only slight aziridine activation towards ring opening, and in addition the complexation reduces the benzoyl O nucleophilicity, [7,8,29] and so is generally considered not to be productive in the rearrangement to oxazoline. [7,8] The next most stable MgBr 2 ·9 structure, 9.3 kcal/mol higher in energy, shows Mg chelating both N and dioxolanic O-4Ј (Scheme 7).…”

“…The aziridine interatomic distances are lengthened with respect to 9, and this bond weakening can activate ring expansion. [7,8] In this structural and conformational situation, the dioxolanic O-1Ј is forced to point towards C-2, allowing the possibility that in the course of ring expansion to trans-oxazoline-5-carboxylate 10, the C-2 carbocationic transition state might be stabilized by an O-1Ј lone pair (Scheme 7). This stabilization does not appear to be possible for the alternative (not observed experimentally) ring expansion to the oxazoline-4-carboxylate by way of an aziridine C-3 carbocation.…”

“…Scheme 7 Because of the impossibility of obtaining energy minima with BF 3 we substituted it with BH 3 and performed AM1 semiempirical computations for the complex BH 3 ·9. We considered both N-and O-boron coordination, [7,8,29] minimizing geometries furnished by the Monte Carlo procedure. [24,25] We also calculated the preferred AM1 conformation of uncomplexed 9.…”