UV promoted phenanthridine syntheses from oxime carbonate derived iminyl radicals

Article abstract of DOI:10.1039/c1cc12720a

Oxime carbonates were found to be excellent precursors for the clean and direct generation of iminyl radicals under UV irradiation. Suitably functionalised iminyls underwent cyclisations yielding various phenanthridines and also substituted quinolines and

Full text of DOI:10.1039/c1cc12720a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 7974–7976
www.rsc.org/chemcomm
COMMUNICATION
UV promoted phenanthridine syntheses from oxime carbonate derived
iminyl radicalsw
Roy T. McBurney,* Alexandra M. Z. Slawin, Laura A. Smart, Yanping Yu and
John C. Walton*
Received 9th May 2011, Accepted 3rd June 2011
DOI: 10.1039/c1cc12720a
Oxime carbonates were found to be excellent precursors for the
clean and direct generation of iminyl radicals under UV irradiation.
Suitably functionalised iminyls underwent cyclisations yielding
various phenanthridines and also substituted quinolines and
isoquinolines. EPR and X-ray analyses of oxime carbonates
provided insight into the mechanism.
on 40-methoxybiphenyl-2-carbaldehyde O-ethoxycarbonyl oxime
1a (Scheme 1a). UV reactions were carried out in deaerated
benzotrifluoride solutions with 1 equiv. wt/wt of 4-methoxy-
acetophenone (MAP) as a photosensitiser. UV irradiation was
supplied by an unfiltered 400 W medium pressure Hg lamp
situated 6–8 cm from quartz tubes containing the oxime
carbonates. After irradiation for 3 h 6-methoxyphenanthridine
2 was isolated in a low 30% yield, also obtained was nitrile 3 in
a comparable yield (27%). In addition, an aldehyde produced
by hydrolysis of the corresponding imine (generated by the
iminyl radical undergoing hydrogen abstraction) was observed.
We reasoned that a resonance stabilised oxygen centred
radical might improve the efficacy of this reaction, thus
O-phenoxycarbonyl oxime derivative 1b was synthesised and
tested. Whilst the yield of phenanthridine 2 improved (40%),
the yield of nitrile 3 also increased (41%) and aldehyde
by-product was still observed. We postulated that nitrile 3
is produced by a competing pericyclic mechanism, where a
degree of pre-organisation is required such that an intramolecular
hydrogen bond is formed (Scheme 1b). In order to disrupt the
H-bonding, to favour production of phenanthridine over
nitrile, a brief set of solvent screening reactions was under-
taken employing acetonitrile, N,N-dimethylformamide and
tert-butanol (t-BuOH) (see ESIw). Pleasingly, performing the
UV photolysis reaction on 1b in t-BuOH resulted in a greater
yield of phenanthridine 2 (75%) with only 20% of nitrile 3
isolated. Although the reaction selectivity had been altered to
Our group has long been interested in the clean and direct
generation, and subsequent synthetic use, of organic radicals.1
Iminyl radical cyclisations to form various N-heterocyclic
products have been well investigated.2,3 Whilst most methods
use the toxic and explosive stalwarts of radical chemistry, i.e.
tin hydrides, AIBN, peroxides, etc., some reports are of
‘‘greener’’ alternatives.4 Methods to generate iminyl radicals
can be neutral and mild,2,3 attracting those seeking to develop
‘clean’ synthetic procedures. We reported the direct generation
of iminyl radicals via microwave irradiation of oxime ethers5
and UV irradiation of oxime esters,6 oxime oxalate amides7
and dioxime oxalates.8 Also of note are thermal routes
for iminyl radicals through cascade processes9,10 and from
iminoxyperacetates en route to benzoisothiazoles.11 Herein, we
report the use of oxime carbonates for radical mediated
synthesis of N-heterocycles, where the only by-products
produced are innocuous.
Surprisingly, despite possessing weak N–O bonds similar to
those of other oxime esters, oxime carbonates have not yet
been used as precursors for the generation of iminyl radicals.
Our synthetic route to the oxime carbonates (see ESIw) was
relatively inexpensive. A second advantage of oxime carbonates
is their long-term stability cf. dioxime oxalates which readily
decomposed.8 Previous studies demonstrated that UV promoted
cyclisations proceeded best when oxime-derived radical precursors
possessed an aryl group adjacent to the CQN bond.8
Therefore, initial exploratory UV cyclisations were performed
School of Chemistry, University of St. Andrews, EastChem,
St. Andrews, Fife, KY16 9ST, UK.
E-mail: roy.mcburney@st-andrews.ac.uk, jcw@st-andrews.ac.uk;
Fax: +44 (0)1334 463808; Tel: +44 (0)1334 463864
w Electronic supplementary information (ESI) available: General
methods, characterising data for oxime carbonates and N-heterocyclic
products including 1H & 13C NMR spectra. CCDC 824855–824858.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc12720a
Scheme 1 (a) UV photolysis of carbaldehyde oxime carbonate
derivatives; (b) proposed intramolecular mechanism of nitrile formation.
c
7974 Chem. Commun., 2011, 47, 7974–7976
This journal is The Royal Society of Chemistry 2011

View Article Online
Scheme 2 Phenanthridine preparations from UV photolyses of
acetophenone O-ethoxycarbonyl oxime derivatives at RT.
favour our desired phenanthridine product (B4 : 1), the electro-
cyclic mechanism was still in play. To avert nitrile production,
we chose to replace the iminyl hydrogen with a methyl
group, thus blocking the electrocyclic pathway. Incorporation
of a methyl group adjacent to the CQN bond was achieved
by starting the synthesis of oxime carbonate 4a from
20-bromoacetophenone and phenyl boronic acid. UV photo-
lysis of 4a (R1 = H) under our reaction conditions, 1 equiv. of
MAP, PhCF3 as solvent, 3 h UV irradiation at ambient
temperature, gave 6-methylphenanthridine 5a in 60% yield
(Scheme 2).12
Scheme 3 (a) and (b) UV photolysis of heterocyclic O-ethoxycarbonyl
oxime derivatives, and (c) synthesis of trispheridine.
A set of substituted biphenyl O-ethoxycarbonyl oxime
derivatives 4b–f was prepared to probe the toleration of the
process for substituents in the para position of the aromatic
ring on to which the iminyl radical cyclised. Under our
standard photolysis conditions, we isolated 3-substituted
6-methylphenanthridines 5b–f in good to quantitative yields
(52%–99%, Scheme 2) irrespective of the electron-withdrawing
or -releasing character of the substituent. Para-nitro substituted
oxime carbonate 4d gave rise to a welcome surprise after UV
irradiation. Crystals suitable for X-ray crystallographic analysis
had grown from a nucleation site on the wall of the quartz
tube closest to the UV source! 1H NMR and X-ray analysis of
the crystals confirmed the structure as that of 5d (see ESIw).
Filtration of the crude reaction mixture gave 5d in quantitative
yield, which is probably a result of a kinetic effect arising from
the crystallisation of 5d out of the reaction solution. The yield
of 3-methoxy-6-methyl-phenanthridine (5e) was also high
(90%) so we further examined this reaction to see if shorter
UV irradiation times resulted in better yields. Sadly, after 1 h
irradiation just 56% of 5e was isolated. Interestingly, in the
absence of MAP, UV irradiation for 3 h produced 5e in 74%
yield. We attribute these high yields to the structural similarity
of 4e to MAP, facilitating effective harvesting of UV light
without the need for a photosensitiser.
were observed for both isoquinolines 9a (65%) and 9b
(67%). To complete our synthetic exploration we turned
to the pharmacologically active alkaloid trispheridine. An
O-phenoxycarbonyl oxime was synthesised as our earlier
results had demonstrated that aldehyde-O-phenoxy-carbonates
gave better yields than aldehyde-O-ethoxy-carbonates.
Precursor 10 was subjected to UV irradiation in t-BuOH, to
disrupt any preorganised H-bonding that would favour nitrile
formation, and produced trispheridine 11 in 49% yield.
Extended UV irradiation times (5 h) led to photo-degradation
of the natural product, reducing the yield to only 22%.
Here, our oxime carbonates were stable over a period Z 1
year. Indeed, a year-old neat sample of oxime carbonate 4f
had developed crystals suitable for X-ray crystallographic
analysis which revealed two independent molecules within
the asymmetric unit (Fig. 1a).13 Furthermore, 1b and 10 also
crystallised out from neat samples (Fig. 1b and 1c).13 The
oxime carbonate units were found to be close to planar and in
extended all-trans conformations;14 as observed previously for
dioxime oxalates.8
We studied all of the oxime carbonates by 9 GHz EPR
spectroscopy. Deaerated samples of the each oxime carbonate
plus 1 equiv. wt/wt of MAP in PhBu-t were photolysed
directly in the resonant cavity by a 500 W unfiltered Hg lamp.
The spectrum (Fig. 2a) obtained from 1b showed an iminyl
radical (1 : 1 : 1 triplets at either wing) with EPR parameters
[g-factor = 2.0029, a(1H) = 80.00, a(1N) = 9.91 G] similar to
those reported for other iminyls.15,16
To expand the scope of our methodology we synthesised
O-ethoxycarbonyl oximes based on furan and thiophene
derivatives, Scheme 3a. The para-methoxy substituent was
retained due to the high yields achieved for the synthesis of
5e. Under our standard conditions furanyl oxime carbonate 6a
and thiophenyl oxime carbonate 6b gave quinolines 7a and 7b
in 71% and 62% yields respectively. The ground state iminyl
SOMO and the attacked aromatic ring orbital, in the radicals
derived from 6a,b, will be further apart than in the radicals
derived from 4a–f, because of the larger angles associated with
5-membered rings (721) compared to 6-membered rings (601).
However, our results demonstrate that this did not significantly
affect the yields of cyclised heterocycles 7a,b.
The spectrum in the central region [g = 2.0049, a(2H) =
2.02, a(2H) = 6.85, a(1H) = 9.87 G] was clearly that of the
phenoxyl radical.17 Similar iminyl radical spectra were observed
for all our oxime carbonates.18 In our proposed mechanism
(Scheme 4) the weak N–O bond homolytically cleaves to
generate the iminyl radical 12, as observed in the EPR spectra,
plus acyloxyl radical 13. The EPR spectrum from 1b showed
equal amounts of 12 and PhOꢀ (49.7% : 50.3%) and hence
dissociation of 13 to CO2 and phenoxyl (ethoxyl for other
precursors) must have been essentially instantaneous even at
240 K. An intramolecular ring closure of iminyl radical 12
Benzo[b]furan (8a) and benzo[b]thiophene (8b) oxime
carbonates were next investigated, Scheme 3b. Comparable yields
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7974–7976 7975

View Article Online
including phenanthridines, furo- and thieno-quinolines,
benzofuro- and benzothieno-isoquinolines by our mild radical-
mediated procedure. The only by-products, CO2 and either
ethanol or phenol, are innocuous and easily removed. The
process is evidently an attractive strategy for the development
of target-oriented heterocycle syntheses.
We thank the EPSRC & EastChem for funding and the
EPSRC National Mass Spectrometry Service, Swansea.
Notes and references
1 J. C. Walton and A. Studer, Acc. Chem. Res., 2005, 38, 794;
A. Studer, S. Amrein, F. Schleth, T. Schulte and J. C. Walton,
J. Am. Chem. Soc., 2003, 125, 5726.
2 A. G. Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543.
3 W. R. Bowman, C. F. Bridge, P. Brookes, M. O. Cloonan and
D. C. Leach, J. Chem. Soc., Perkin Trans. 1, 2002, 58;
W. R. Bowman, M. O. Cloonan, A. J. Fletcher and T. Stein,
Org. Biomol. Chem., 2005, 3, 1460.
Fig. 1 The X-ray crystal structures13 of oxime carbonates (a) 4f
(showing just one of the two independent molecules present in the
asymmetric unit), (b) 1b, and (c) 10.
4 J. Boivin, E. Fouquet and S. Z. Zard, Tetrahedron Lett., 1991, 32,
4299–4302; P. A. Baguley and J. C. Walton, Angew. Chem., 1998,
110, 3272–3283, Angew. Chem., Int. Ed. Engl., 1998, 37, 3072–3082;
A. Studer and S. Amrein, Synthesis, 2002, 835.
5 J. A. Blake, D. A. Pratt, S. Lin, J. C. Walton, P. Mulder and
K. U. Ingold, J. Org. Chem., 2004, 69, 3112; F. Portella-Cubillo,
J. S. Scott and J. C. Walton, Chem. Commun., 2007, 4041;
F. Portella-Cubillo, J. S. Scott and J. C. Walton, J. Org. Chem.,
2008, 73, 5558; F. Portella-Cubillo, J. S. Scott and J. C. Walton,
J. Org. Chem., 2009, 74, 4934.
6 A. J. McCarroll and J. C. Walton, J. Chem. Soc., Perkin Trans. 2,
2000, 2399; Acyloximes have also been investigated: R. Alonso,
P. J. Campos, B. Garcı
8, 3521; R. Alonso, A. Caballero, P. J. Campos and
M. A. Rodrıguez, Tetrahedron, 2010, 66, 8828.
7 E. M. Scanlan and J. C. Walton, Helv. Chim. Acta, 2006, 89, 2133;
E. M. Scanlan and J. C. Walton, Chem. Commun., 2002, 2086.
8 F. Portella-Cubillo, E. M. Scanlan, J. S. Scott and J. C. Walton,
Chem. Commun., 2008, 4189; F. Portella-Cubillo, J. Lymer,
E. M. Scanlan, J. S. Scott and J. C. Walton, Tetrahedron, 2008,
64, 11908.
a and M. A. Rodrıguez, Org. Lett., 2006,
´ ´
Fig. 2 (a) EPR spectrum from UV irradiation of 1b in PhBu-t at
240 K; (b) computer simulated spectrum for both iminyl and phenoxyl
radicals.
´
onto the phenyl acceptor produces a cyclohexadienyl radical
14 that undergoes H-atom transfer to an ethoxyl radical (or to
phenoxyl) thus yielding the aromatic phenanthridine product
and ethanol (or phenol).
9 D. Nanni, P. Pareschi, C. Rizzoli, P. Sgarabotto and A. Tundo,
Tetrahedron, 1995, 33, 9045.
Our investigations demonstrated that oxime carbonates are
convenient and clean radical precursors. Benefiting from a
cheap and facile synthesis from a large variety of carbonyl
compounds, oxime carbonates also possess long shelf lives.
They can be transformed into a variety of N-heterocycles
10 D. Nanni, in Radicals in Organic Synthesis, ed. P. Renaud and
M. P. Sibi, Wiley, Weinheim, 2001, vol. 2, pp. 44–61.
11 R. Leardini, H. McNab, M. Minozzi and D. Nanni, J. Chem. Soc.,
Perkin Trans. 1, 2001, 1072.
12 The cyclisations did not take place under thermal conditions (MW,
150 1C, 30 min) although nitrile formation from 1a,b was efficient.
13 The crystal data and experimental details of the structural
refinement for 1b, 4f, 5d and 10 are provided in the ESIw. CCDC
824855, 824856, 824857 and 824858 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
14 The N–O bond lengths for 4f were 1.425(9) A and 1.431(10) A.
Replacing the iminyl methyl group with an H-atom did not
appreciably affect the N–O bond lengths as shown by the crystal
structures of 1b at 1.4473(17) A and 10 at 1.451(2) A. The dihedral
angle about the iminyl CQN bond was close to planar in each of
the molecular structures: 4f (ꢁ175.7(8)1 and 177.5(8)1); 1b
(178.4(1)1); 10 (179.6(2)1).
15 A. R. Forrester and F. A. Neugebauer, in Landolt-Bornstein,
¨
Magnetic Properties of Free Radicals, ed. H. Fischer and
F. A. Neugebauer, Springer-Verlag, Berlin, 1979, vol. 9c1,
pp. 115–121.
16 Note that the unequal heights of the outer and inner lines of each
1 : 1 : 1 triplet are the result of anisotropy from ineffficient
molecular tumbling at 240 K.
17 S. A. Weiner, J. Am. Chem. Soc., 1972, 94, 581.
18 Alkoxyl radicals are EPR ‘silent’ in solution so, as expected, EtOꢀ
radicals were not detected from the O-ethoxy-carbonates.
Scheme 4 Postulated radical mechanism for the formation of
substituted phenanthridines.
c
7976 Chem. Commun., 2011, 47, 7974–7976
This journal is The Royal Society of Chemistry 2011