Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes

Abstract

SummarySensitised photolyses of ethoxycarbonyl oximes of aromatic and heteroaromatic ketones yielded iminyl radicals, which were characterised by EPR spectroscopy. Iminyls with suitably placed arene or heteroarene acceptors underwent cyclisations yielding phenanthridine-type products from ortho-additions. For benzofuran and benzothiophene acceptors, spiro-cyclisation predominated at low temperatures, but thermodynamic control ensured ortho-products, benzofuro- or benzothieno-isoquinolines, formed at higher temperatures. Estimates by steady-state kinetic EPR established that iminyl radical cyclisations onto aromatics took place about an order of magnitude more slowly than prototypical C-centred radicals. The cyclisation energetics were investigated by DFT computations, which gave insights into factors influencing the two cyclisation modes.

Functionalised Oximes: Emergent Precursors for Carbon-, Nitrogen- and Oxygen-Centred Radicals

“… a Data from reference [31] except as indicated otherwise; all in hydrocarbon solution. Arrhenius A -factors assumed to be log( A c /s −1 ) = 10.0; b Data from references [31,32]; c Data from reference [33]. …”

“…In general, iminyls with aromatic acceptors such as 20 cyclised in 6-endo mode with production of 6-member rings (see, however, Section 2.7). Kinetic data is sparse but implies that the rate constants for iminyl ring closures onto aromatics are also about an order of magnitude less than those of C -centred analogues [33].…”

“…In preparative photolyses with 54a and 54b at ambient temperature (~330 K) exclusively, the benzofuro[3,2- c ]isoquinoline and benzo[4,5]thieno[3,2- c ]isoquinoline products derived from the endo -radicals 57a and 57b were isolated in good yields [78]. Curiously, EPR spectra taken during photolyses of 54a and 54b in solution at 230 K showed solely the spiro -radicals 56a and 56b [33]. The structures and energies of the iminyl and cyclised radicals were computed by DFT at the B3LYP/6-311+G(2d,p) level of theory with the Gaussian 09 package [79].…”

Synthetic Strategies for 5- and 6-Membered Ring Azaheterocycles Facilitated by Iminyl Radicals

“…This rule holds good for cyclisations onto a wide range of aromatic acceptors including benzene, naphthalene, furan, thiophene, indole, pyridine and analogous moieties. As would be expected for less-favoured 6-endo processes, the rate constants for these iminyl ring closures are significantly smaller than for 5-exo cyclisations [75]. Never-the-less practicable preparative protocols have been established for many mono- and poly-cyclic heterocycles.…”

“…For the preparation of aza-arenes commercial ethyl chloroformate ( 50 , R 2 = Et) was found to be very convenient because the main by-product (EtOH) is volatile and easily separated. UV photolyses of appropriately functionalised oxime carbonates, with MAP as additive, enabled phenanthridines 53 , methylfuro- and methylthieno-[2,3- c ]quinolines 54 to be prepared as well as the 5-methylbenzofuro- and 5-methylbenzo[4,5]thieno-[3,2- c ]isoquinolines 55 in generally good yields [75,77].…”