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

Summary Sensitised 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.


General experimental section
All reagents and solvents were purchased from either Sigma Aldrich or Alfa Aesar and used without further purification. Toluene and tetrahydrofuran were distilled over sodium, and dichloromethane was distilled over calcium hydride. Benzaldehyde oxime and acetophenone oxime were prepared according to the literature procedure [1], as was N-benzylpent-4-en-1amine [2]. Column chromatography was carried out using Silica 60A (particle size 40-63 µm, Silicycle, Canada) as the stationary phase, and TLC was performed on precoated silica gel plates (0.20 mm thick, Sil G UV 254 , Macherey-Nagel, Germany) and observed under UV light. 1 H and 13 C NMR spectra were recorded on Bruker AV III 500, Bruker AV II 400 and Bruker AV 300 instruments. Chemical shifts are reported in parts per million (ppm) from low to high frequency and referenced to the residual solvent resonance. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, q = quartet, m = multiplet, b = broad. Melting points (mp) were determined using a Sanyo Gallenkamp apparatus and are reported uncorrected. Mass spectrometry was carried out at the EPSRC National Mass Spectrometry Service Centre, Swansea, UK.

Synthesis and experimental section
Oxime carbonates 1a-f, and 2a,b were prepared as described previously [1].

UV cyclisation of oxime carbonate derivatives general procedure
A quartz tube was charged with oxime carbonate (1.0 equiv), 4-methoxyacetophenone (MAP) (1 equiv wt/wt) and benzotrifluoride (3 mL). The reaction mixture was degassed by bubbling Ar through the solution for 15 min. The solution was irradiated with UV light (400 W medium pressure Hg lamp) for 3 h. The solvent was removed under reduced pressure and the crude residue purified by column chromatography (CH 2 Cl 2 /EtOAc 9:1 as eluent).

EPR spectroscopy
EPR spectra were obtained at 9.5 GHz with 100 kHz modulation employing a Bruker EMX 10/12 spectrometer fitted with a rectangular ER4122 SP resonant cavity and a Bruker ER4122-SHQE X band cavity on EMX and EMX Micro consoles in Manchester. Stock solutions of each oxime carbonate (2 to 15 mg) and MAP (1 equiv wt/wt) in tertbutylbenzene or benzene (0.5 mL) were prepared and sonicated where necessary. An aliquot (0.2 mL), to which any additional reactant had been added, was placed in a 4 mm o.d. quartz tube and deaerated by bubbling nitrogen for 15 min. Photolysis in the resonant cavity was by S8 unfiltered light from a 500 W super pressure mercury arc lamp or, in the Manchester experiments, the light source was a Luxtel CL300BUV lamp. Solutions in cyclopropane were prepared on a vacuum line by distilling in the cyclopropane, degassing with three freeze-pump-thaw cycles and finally flame sealing the tubes. In all cases where spectra were obtained, hfs were assigned with the aid of computer simulations using the Bruker SimFonia and NIEHS Winsim2002 software packages. For kinetic measurements, precursor samples were used mainly in "single shot" experiments, i.e., new samples were prepared for each temperature and each concentration to minimise sample-depletion effects. EPR signals were digitally filtered and double integrated by using the Bruker WinEPR software and radical concentrations were calculated by reference to the double integral of the signal from a known concentration of the stable radical DPPH [1  10 −3 M in PhMe], run under identical conditions, as described previously. The majority of EPR spectra were recorded with 2.0 mW power, 0.8 G pp modulation intensity, and a gain of ca. 10 6 .

Computational methods
Radical ground-state calculations were carried out by using the Gaussian 09 program package [4]. Becke's three-parameter hybrid exchange potential (B3) was used with the LYP correlation functional, B3LYP. This method has previously described the chemistry of iminyl radicals accurately. The standard split-valence 6-31+G(d) basis set was initially employed and then the computations were extended to the UB3LYP/6-311+D(2d,p) level. Geometries were fully optimised for all model compounds. Optimised structures were characterised as minima or saddle points by frequency calculations. The experimental kinetic and spectroscopic data was all obtained in the nonpolar hydrocarbon solvents tert-butylbenzene or cyclopropane. Solvent effects, particularly differences in solvation between the neutral reactants and neutral transition states, are therefore expected to be minimal. In view of this, no attempt was made to computationally model the effect of the solvent.