Microwave-assisted preparations of dihydropyrroles from alkenone O-phenyl oximes

Article abstract of DOI:10.1039/b712582h

Microwave irradiation of alkenone O-phenyl oximes produces iminyl radicals that ring close to yield dihydropyrrole derivatives; pyrroles and pyridines can be obtained from related precursors. The Royal Society of Chemistry.

Full text of DOI:10.1039/b712582h

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COMMUNICATION
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Microwave-assisted preparations of dihydropyrroles from alkenone
O-phenyl oximes
Fernando Portela-Cubillo,a Jackie S. Scottb and John C. Walton*a
Received (in Cambridge, UK) 15th August 2007, Accepted 30th August 2007
First published as an Advance Article on the web 11th September 2007
DOI: 10.1039/b712582h
main initial reaction would be scission of the N–O bond yielding
butenyl-iminyl 3 together with the phenoxyl radical in equal
proportions. Scission of the weak N–O bond is favoured because
of the resonance stabilisation of the released phenoxyl radical.
5-exo-Ring closure of the iminyl radicals was expected to produce
3,4-dihydro[2H]pyrrolomethyl radicals 4 that would yield the
corresponding substituted dihydropyrrole on hydrogen abstraction
from solvent. The phenoxyl radicals were expected to abstract
hydrogen from the solvent giving phenol as the main by-product.
Compound 2a was chosen for detailed study to enable optimum
reaction conditions to be established. Solutions of 2a in toluene as
the H-atom donor were irradiated in a Biotage Initiator microwave
reactor (nominally 300 MHz). Experiments were carried out at
different concentrations, temperatures and irradiation times with
various proportions of the ionic liquid 1-ethyl-3-methyl-
1H-imidazol-3-ium hexafluorophosphate (emimPF6). Reaction
efficiency depended critically on temperature and time of
irradiation. Optimum conditions were found to involve irradiation
at 160 uC for 15 min with one equivalent of ionic liquid. 1H NMR
analysis of the total product mixture from 2a under these
conditions showed a very clean reaction with nearly quantitative
production of both 5a and phenol.17 The isolated product yields,
obtained from reactions of 2a–2d under these optimised condi-
tions, are shown in Scheme 1. As expected, in each case a 50 : 50
mixture of the two enantiomers was obtained. With toluene as the
H-atom donor, premature reduction of iminyl radicals, yielding
the corresponding uncyclised imines, was not observed for butenyl-
iminyl radicals. These results indicated that the method is an
Microwave irradiation of alkenone O-phenyl oximes produces
iminyl radicals that ring close to yield dihydropyrrole deriva-
tives; pyrroles and pyridines can be obtained from related
precursors.
Numerous bioactive alkaloids contain dihydropyrrole or related
rings.1a,b Interest in preparing them from iminyl radicals has
spiralled because radical ring closure conditions can be neutral and
mild.2 Iminyl radical precursors used with tin hydrides include
N-alkenyl-S-arylthiohydroxylamines3
and
N-benzotriazolyl-
imines.4 Oxime esters release iminyl radicals on treatment with
transition metals.3,5 Direct or sensitised photolyses of
O-carboxymethyl oxime esters of N-hydroxypyridine-2-thione,6
of ketoxime xanthates,7 of acyl oximes8,9 and of O-(4-cyanophe-
nyl) oximes10 also yield iminyl radicals. Thermal methods are
advantageous for synthetic work in terms of simplicity and ease of
scale-up. Scarcely any clean precursors suitable for thermal release
of iminyls are known. However, quinoline derivatives were
obtained by heating suitably functionalised O-2,4-dinitrophenyl
oximes with sodium hydride.11 Several types of heterocycles were
obtained in cascade processes involving iminyl formation from
ring closure of imidoyl radicals onto cyanoalkyl groups.12,13
Thermolyses of O-phenyl oxime ethers were shown recently to
release simple dialkyl- and diaryl-iminyl radicals.14 Furthermore,
the N–O bond dissociation enthalpies [BDE (R2CLN–OPh) =
140 kJ mol21 for R = Me or Ph] were found to actually be lower
than the O–O BDEs of dialkyl peroxides (159–167 kJ mol21).14
However, it proved difficult to develop conventional sealed tube
type thermolyses of O-phenyl oxime ethers for preparative work;
reaction times had to be long, the products were not cleanly
formed and yields were disappointingly low. In view of this, we
decided to investigate the reactions of O-phenyl oxime ethers
promoted by microwaves. The starting O-phenyl oxime ethers can
be prepared in good yields by condensation of ketones with the
commercially available O-phenylhydroxylamine hydrochloride in
the presence of pyridine.14 5-exo-Cyclisations of pent-4-en-1-iminyl
radicals are comparatively fast and are thought be only about a
factor of five slower than the archetype hex-5-enyl radical
cyclisations.2,15 We investigated iminyl radical generation and
cyclisation using the set of functionalised O-phenyl oxime ethers
2a–2d prepared from the corresponding pent-4-enyl ketones 1a–1d
(Scheme 1).16 We anticipated that under microwave irradiation the
aUniversity of St. Andrews, School of Chemistry, EaStChem, St.
Andrews, Fife, UK KY16 9ST. E-mail: jcw@st-and.ac.uk;
Fax: +44 (0)1334 463808; Tel: +44 (0)1334 463864
bGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex, UK CM19 5AW. E-mail: Jackie.S.Scott@gsk.com
Scheme 1 Preparation and microwave-assisted reactions of alkenone
O-phenyl oximes.
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Chem. Commun., 2007, 4041–4043 | 4041

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efficient way of preparing 3,4-dihydro[2H]pyrroles functionalised
with alkyl or aryl groups adjacent to the CLN bond.
The O-phenyl oxime of 1-phenylhex-5-en-1-one (i.e. 2c with the
chain lengthened by one methylene unit) was next examined as a
model compound for 6-exo ring closures, possibly giving access to
tetrahydropyridines. Microwave irradiation of this compound in
toluene, followed by the usual work-up, gave phenol and
1-phenylhex-5-en-1-one, together with several minor components.
The 1-phenylhex-5-en-1-one is almost certainly produced from
hydrolysis of the corresponding imine during work-up. It appears,
therefore, that the main reaction is simply H-atom abstraction by
the intermediate iminyl radical from the solvent and 6-exo-
cyclisation is too slow to compete.
The O-phenyl oxime of cyclohexylhex-5-yn-2-one, i.e. 6, was
chosen as a model compound to probe the effectiveness of the
alkyne group as an acceptor for iminyl radical cyclisations.
Compound 6 was prepared by ruthenium catalysed conjugate
addition of ethynylcyclohexane to methyl vinyl ketone using the
method of Kim and co-workers.18 Microwave irradiation of 6 in
toluene at 160 uC for 30 min gave, not the expected methylene-
dihydropyrrole 7, but the corresponding pyrrole 8 (Scheme 2). The
driving force for this rearrangement is evidently aromatisation of
the ring.
The use of aromatic rings as iminyl radical acceptors was next
examined. Ring closure onto an aromatic ring produces a
cyclohexadienyl type radical that can regain aromaticity by
transfer of a hydrogen atom. Non-H-atom donor solvents were
therefore required to facilitate this oxidative process. Microwave
irradiation of 2-oxo-2-phenylacetaldehyde oxime 9, in t-butylben-
zene as solvent, gave a 66% isolated yield of 3H-indol-3-one (10).
6-Membered ring heterocycles could also be prepared from
appropriate precursors. Thus, with t-butanol as solvent, and in
the absence of ionic liquid, useful yields of hexahydroacridine 12
and phenanthridine 14 were obtained from oxime ethers 11 and 13,
respectively (Scheme 3). The ZrCl4 catalysed reaction19 of indole
with methyl vinyl ketone yielded 4-(1H-indol-3-yl)butan-2-one
from which O-phenyl oxime ether 15 was obtained. Interestingly,
microwave irradiation of 15 in t-butanol afforded pyridoindole
derivative 16 in which both the acceptor ring and the pyridyl ring
had become aromatic. 6-endo-Cyclisation was probably favoured
in this example because this closure mode generates a resonance
stabilised benzyl type radical.
Scheme 3 Iminyl radical ring closures onto aromatic rings.
investigated. Microwave irradiation of this oxime ether with ten
equivalents of methyl acrylate in t-butanol at 160 uC gave mainly
phenol and polymer. Similar reactions were carried out with excess
phenylacetylene and with diphenylacetylene as acceptors but in
both cases only intractable mixtures were produced.
In conclusion, we have found that the weak N–O bonds of
O-phenyl oxime ethers readily cleave on irradiation by micro-
waves, releasing iminyl radicals together with resonance-stabilised
phenoxyl radicals. Butenyl-iminyl radicals cyclise to dihydropyr-
roles, butynyl-iminyl radicals produce pyrroles and 3-arylalkyl-
iminyls yield aromatic heterocycles. The phenol by-product is
easily removed by chromatography. The process amounts to a
convenient and rapid two step synthesis of heterocycles from
unsaturated carbonyl compounds.
Finally, intermolecular addition of 1-phenylethaniminyl radi-
cals, derived from PhC(Me)LNOPh, to olefins and alkynes was
We thank GSK and EaStChem for financial support and
Dr M. C. Clarke for loaning the microwave reactor.
Notes and references
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10 T. Mikami and K. Narasaka, Chem. Lett., 2000, 29, 338.
Scheme 2 i; [RuCl2(p-cymene)]2, pyrrolidine, 60 uC, 12 h, 58%. ii;
PhONH2?HCl, pyridine, 76%. iii; PhMe, emimPF6, MW, 160 uC, 30 min.
4042 | Chem. Commun., 2007, 4041–4043
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(5–20 cm3). The vessel was sealed and subjected to microwave
irradiation for 15 min at 160 uC. After cooling, the ionic liquid was
filtered off and the toluene was evaporated under reduced pressure. The
1H NMR spectrum of the crude mixture showed phenol and 5a in equal
proportions as essentially the only products. The residue was purified
by flash column chromatography (10% EtOAc, hexane) to give methyl
3-(2-methyl-3,4-dihydro-2H-pyrrol-5-yl)propanoate 5a as a red oil
1
(0.25 g, 78%). H NMR (400 MHz, CDCl3), d 1.15 (d, J = 6.67 Hz.,
15 M.-H. Le Tadic-Biadatti, A.-C. Callier-Dublanchet, J. H. Horner,
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J. Am. Chem. Soc., 1997, 119, 4569.
16 In each case the O-phenyl oxime ether was obtained as a mixture of
E- and Z-isomers.
17 Typical procedure: preparation of 5a. 1-Ethyl-3-methylimidazolium
hexafluorophosphate (0.5 g, 2.0 mmol) was added to a solution of 2a
(0.50 g, 1.91 mmol) in toluene (15 cm3) and placed in a microwave vessel
3H, CH3), 1.33 (m, 1H, CH2), 2.02 (m, 1H, CH2), 2.39 (m, 1H, CH2),
2.47 (m, 1H, CH2), 2.53 (m, 2H, CH2), 2.60 (m, 2H, CH2), 3.61 (s, 3H,
CH3), 3.97 (sextet, J = 6.67 Hz, 1H, CH); 13C NMR (100 MHz,
CDCl3), d 22.1, 28.5, 30.8, 38.0 (62), 51.8, 67.9, 173.5, 174.9; IR
n
max/cm21 2958.8, 1735.2, 1644.7, 1435.6, 1169.1; m/z (CI) 170, [100%,
(M + H)+], [Found (M + H)+, 170.1181, C9H16NO2 requires 170.1186].
18 S. Chang, Y. Na, E. Choi and S. Kim, Org. Lett., 2001, 3, 2089.
19 V. Kumar, S. Kaur and S. Kumar, Tetrahedron Lett., 2006, 47,
7001.
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