Nucleophilic vinylic substitution in bicyclic methyleneaziridines: SNVπ or SNVσ?

A stereoselective synthesis of the monodeuterated methyleneaziridine shown allowed the stereochemical course of formal SNV-mode ring-opening with copper-based organometallics to be assigned.


Introduction
In 2010 both we 1 and Blakey 2 reported the first examples of intramolecular allene aziridination with sulfamate substrates, with the major products being derived in most cases via 2-amidoallylcation intermediates. 3 Our group followed this up with the first report 4 of analogous reactions of carbamate substrates 1 (Scheme 1) and, in that work, somewhat unstable bicyclic 1,3-oxazolidin-2-one methyleneaziridines 2 were obtained following Lebel's modification 5 of the Du Bois protocol 6 for Rh(II)-nitrenoid generation. Soon afterwards, Schomaker's group took on the area and developed it extensively, optimising the conditions for generating the methyleneaziridines, engineering the substrates for synthetic tractability (non-terminal allenes, formation of 1,3-oxazinan-2-ones), and elaborating the products into a variety of hydroxy/amino stereotriads and -tetrads and rearranged heterocycles. 7 In our original publication we noted that the methyleneaziridines were constrained by the ring-fusion such that only the exocyclic aziridine C-N bond is electronically activated in the ground state through hyperconjugation with the carbamate carbonyl p-system. This suggested the possibility of effecting direct substitution/ ring-opening at the sp 2 -carbon, in contrast to the prevailing reactivity of unconstrained methyleneaziridines in which ring-opening occurs preferentially at the sp 3 -carbon. 8 At the time, the only sp 2 -C-N bondcleaving processes involved either transition metal-mediated processes 9 or stepwise radical addition/b-scission. 10 In the event, treatment of methyleneaziridine 2 (R = i-Pr) with lithium diphenylcuprate, or various Grignard reagents in the presence of CuI, led to moderate to good yields of the products 3 of nucleophilic vinylic substitution (S N V). 11 That publication concluded with an intention to clarify the stereochemical details of the S N V reaction; the current paper describes studies to that end.

Results and discussion
A stereochemically defined monodeuterated analogue 4 (Scheme 2) of methyleneaziridine 2 (R = i-Pr) was targeted that would allow the stereochemistry of the S N V process to be probed without presenting any steric or electronic bias compared with the original methyleneaziridine. At the outset of this study, a dissociative mechanism for the substitution reaction was ruled out on the basis of the aprotic, low-temperature conditions for the process and the relative instability of a vinylic cation. An out-of-plane (relative to the cleaving C-N bond) stepwise p-addition/elimination process, proceeding via a short-lived formal carbanion located on the terminal methylene carbon, or an equivalent concerted mechanism, would proceed with retention of configuration (S N V p pathway, -5). An in-plane concerted process, akin to an S N 2 reaction in aliphatic substrates, would lead to inversion of configuration (S N V s pathway, -6). The operation of either of these reaction modes would then be revealed in the relative disposition of the newlyformed C-C bond and the adjacent H/D atoms, as shown.
In the absence of any literature precedent for the synthesis of a stereodefined terminally monodeuterated buta-2,3dienol, 12 a synthesis of methyleneaziridine 4 was proposed based upon diastereoselective coordinated delivery of hydride 13 to deuterated alkynyl epoxide 7 (Scheme 3) and the known stereochemical course of the intramolecular aziridination. Following this proposal, trans-2-ethynyl-3-isopropyloxirane 14 was stirred with an excess of D 2 O under basic conditions 15 to yield the deuterated alkyne 7 (94% deuterium incorporation). Alkyne 7 was treated with DIBAL in dichloromethane as a non-coordinating solvent that would support epoxide chelation with the aluminium centre, and allene 8 was isolated apparently as one predominant stereoisomer, 16 depicted as that expected, and confirmed retrospectively from the NMR data for methyleneaziridine 4. A slightly modified variant of Lebel's protocol for nitrenoid formation afforded consistent yields (B25%) of methyleneaziridine 4 from N-tosyloxy carbamate 9; lower yields were obtained from carbamate 10 with a range of Rh(II) catalysts including Rh 2 (OAc) 4 , Rh 2 (esp) 2 , 17 and Rh 2 (TPA) 4 . 18 The stereochemistry in methyleneaziridine 4 was confirmed by comparisons with the NMR data for non-deuterated methyleneaziridine 2, 4 and the NOE correlations shown in Fig. 1. In the 1 H NMR spectrum of methyleneaziridine 4, the adjacent methine protons at d 1.81 and 4.35 show 3 J HH = 9.5 Hz, indicating a dominating trans-antiperiplanar disposition that places one of the diastereotopic methyls more regularly in close proximity to the CHN and =CHD protons, as seen in the NOE spectra. A simple dihedral drive calculation supports this view (ESI †). 19 Two variants of the S N V reaction were carried out, both of which converted methyleneaziridine 4 into products with reasonable overall efficiency (Scheme 4). In the first, addition of lithium dimethylcuprate gave a 77% isolated yield of 4-isopropenyl oxazolidinone 11, in which the methyl group was found (see below) to be cis-to the deuterium atom. In the second, a copper-catalysed Grignard reaction with vinylmagnesium bromide gave 4-(buta-1,3-dien-2-yl) oxazolidine 12 as the major product, again with the new C-C bond formed cis-to the deuterium atom. The azirine 13 was also isolated in this work; its formation may be explained by competing addition at the carbonyl followed by 1,4-vinylation of the so-formed a,b-unsaturated ester. 20 A combination of NMR experiments, including NOE ( Fig. 2) provided support for the stereochemical assignments in S N V products 11 and 12. Notably, in 11 no NOE correlation was observed between the vinyl methyl protons andQCHD; similarly, in compound 12, there were no significant correlations between the vinyl protons and QCHD.
An invertive S N V s reaction appears to be stereoelectronically accessible in methyleneaziridines 2 and 4, and the microscopic reverse of such a process is supported in the NaNH 2 -mediated formation of simple methyleneaziridines from 2-bromoallylic amines. 21 Despite this, our results clearly rule out the S N V s mode of ring-opening, the stereochemical outcome being consistent with a (retentive) S N V p mode of reaction. Setting aside the extent of the involvement of the metal counterions in this process, at one simplistic mechanistic extreme, as the delivery of the methyl or vinyl ligand to the methylene group initiates and charge begins to build on the terminal carbon, the sp 2 -C-N bond weakens, with progression along this pathway  constituting an overall concerted process (cf. Scheme 2). At the other end of the spectrum, an initial carbocupration reaction from the exposed face of the methylene group would generate a short-lived organocopper intermediate that rapidly fragments following rotation via the lower energy pathway 11c to place the C-Cu and C-N bonds antiperiplanar to one another. Alternatively, a cross-coupling mechanism may be considered 22 in which formal-Cu(I) insertion into the activated sp 2 -C-N bond (-14, Scheme 5) and reductive elimination/ligand coupling (-15) would deliver the same stereochemical outcome; further research would be necessary to evaluate the viability and implications of such a mechanistic pathway.

Conclusions
To the best of our knowledge, the direct nucleophilic sp 2 C-N bond cleavage reactions that we reported in 2010 remain the only examples in methyleneaziridine chemistry. In this work, we have demonstrated that the substitution is stereoretentive, ruling out an S N V s pathway, but the detailed mechanism of these reactions remains open to speculation and further work is intended to close this particular chapter of methyleneaziridine reactivity. 23

General information
All solvents for anhydrous reactions were obtained dry from Grubbs solvent dispenser units after being passed through an activated alumina column under argon. THF was additionally distilled from sodium/benzophenone ketyl under argon. Commercially available reagents were used as supplied unless otherwise specified. Triethylamine was distilled from CaH 2 and stored over KOH pellets under argon. 'Petrol' refers to the fraction of light petroleum ether boiling between 30 and 40 1C; 'ether' refers to diethyl ether. All reactions were carried out in oven-dried glassware and under an atmosphere of argon unless otherwise specified. Thin layer chromatography (TLC) was carried out using Merck aluminium backed DC60 F254 0.2 mm precoated plates. Spots were then visualised by the quenching of ultraviolet light fluorescence (l max 254 nm) and then stained and heated with either anisaldehyde or KMnO 4 solutions as appropriate. Retention factors (R f ) are reported along with the solvent system used in parentheses. Flash column chromatography was performed using Merck 60 silica gel (particle size 40-63 mm) and the solvent system used is reported in parentheses. Infrared spectra were recorded using a Bruker Tensor 27 FT-IR fitted with a diamond ATR module. Absorption maxima (n max ) are reported in wavenumbers (cm À1 ) and are described as strong (s), medium (m), weak (w) or broad (br). Proton ( 1 H) and carbon-13 ( 13 C) spectra were recorded on Bruker AVIII HD 500, AVII 500, or AVIII HD 400 spectrometers. Chemical shifts (d H