A novel, selective free-radical carbamoylation of heteroaromatic bases by
Ce(IV) oxidation of formamide, catalysed by N-hydroxyphthalimide
Francesco Minisci,*a Francesco Recupero,a Carlo Punta,a Cristian Gambarotti,a Fabrizio Antonietti,a
Francesca Fontanab and Gian Franco Pedullic
a Dipartimento di Chimica, Materiali e Ingegneria Chimica BG. NattaB, Politecnico di Milano, via
Mancinelli 7, I-20131 Milano, Italy. E-mail: francesco.minisci@polimi.it; Fax: +39 02 2399 3080;
Tel: +39 02 2399 3030
b Dipartimento di Ingegneria, Università di Bergamo, viale Marconi 5, I-24044 Dalmine BG, Italy.
E-mail: fontana@unibg.it; Fax: +39 035 562779; Tel: +39 035 277322
c
Dipartimento di Chimica Organica A.Mangini, Università di Bologna, via S. Donato 15, I-40127 Bologna
BO, Italy. E-mail: pedulli@kaiser.alma.unibo.it; Tel: +39 051 243218
Received (in Cambridge, UK) 27th June 2002, Accepted 18th September 2002
First published as an Advance Article on the web 8th October 2002
The Ce(IV)-NHPI system was used to generate a carbamoyl
radical by oxidation of formamide; this nucleophilic radical
has been successfully used in the carbamoylation of hetero-
aromatic bases.
Thus we have considered the possibility of trapping the
·CONH2 radical generated in eqn. (1) by protonated hetero-
aromatic bases.
On the basis of the enthalpic evaluation eqn. (1) can be
considered an equilibrium process, which, however, could be
shifted to the right by the fast reaction of the ·CONH2 radical
with either oxygen or a heteroaromatic base.
Actually, when the aerobic oxidation of formamide, cata-
lysed by NHPI and Co(II) salt, was carried out in the presence of
protonated quinoxaline the selective carbamoylation of the
heteroaromatic base took place [eqn. (2)].
The substitution of protonated heteroaromatic bases by nucleo-
philic carbon-centred radicals is one of the main general
reactions of this class of aromatic compounds as a result of the
large variety of successful radical sources, the high regio- and
chemoselectivity and the simple experimental conditions. It
reproduces most of the Friedel–Crafts aromatic substitutions,
but with opposite reactivity and selectivity, due to the high
sensitivity to polar effects. Absolute rate constants in the range
105–108 M21 s21 at rt make the most reactive bases effective
traps for nucleophilic carbon-centred radicals. Practically all the
s-type carbonyl radicals (acyl, carbamoyl and alkoxycarbonyl)
and the alkyl p-type radicals without electron-withdrawing
groups directly attached to the radical centre are suitable for
these substitutions.1
Recently, we have shown that hydrogen abstraction from C–
H and Si–H bonds by the phthalimido-N-oxyl (PINO) radical is
strongly affected by polar and enthalpic effects in the selective
aerobic oxidation of alcohols,2 amines,3 amides4 and silanes,5
catalysed by N-hydroxyphthalimide (NHPI). The PINO radical
was generated by hydrogen abstraction from NHPI by peroxyl
and alkoxyl radical intermediates of the aerobic oxidations.
We have also evaluated the bond dissociation energy of the
O–H bond in NHPI (88.1 kcal mol21) and the absolute rate
constants for hydrogen abstraction from NHPI by the peroxyl
radical (7.4 3 103 M21 s21 at rt, the rate being much higher
with alkoxy radical for obvious enthalpic reasons) and from the
benzylic C–H bond of cumene by the PINO radical (6.1 M21
s21 at rt).4–6 The PINO radical is much more reactive than the
TEMPO radical in hydrogen abstraction for both enthalpic and
polar reasons. The effect is, in our opinion, similar to the one
observed for acylperoxyl radicals, R–C(NO)OO·, compared to
alkylperoxyl radicals, R–OO·.4,7 The BDE value for the C–H
bond in H–CONH2 is about 94 kcal mol21;8 these thermochem-
ical and kinetic data would suggest that hydrogen abstraction
from formamide by PINO [eqn. (1)] could be a selective
process.
(2)
The selectivity was complete, but the conversion was
moderate (18%) by using air at atmospheric pressure as the
oxidant in order to keep the oxygen concentration low, meaning
that the reaction of the carbamoyl radical was faster with
oxygen than with quinoxaline. The conversions were even
lower ( < 10%) with less reactive heteroaromatic bases (pyr-
idine and quinoline derivatives). The process shows a modest
synthetic interest and, from a mechanistic standpoint, it proves
the intermediate formation of the carbamoyl radical. We next
considered the possibility of generating the PINO radical by a
different oxidant, in the absence of O2.
Cerium(IV) ammonium nitrate (CAN) proved to be partic-
ularly effective for this purpose [eqn. (3)].
> N–OH + Ce(IV) ? > N–O· + Ce(III) + H+
(3)
When the oxidation of formamide by CAN, catalysed by
NHPI, was carried out in the presence of protonated hetero-
aromatic bases in the absence of O2, the selective carbamoyla-
tion of the heterocyclic compounds took place. In the absence of
NHPI no reaction occurs, clearly showing that the ·CONH2
radical is formed according to eqns. (3) and (1). CAN has a
twofold function: it generates the PINO radical [eqns. (3)] and
it determines the aromatisation of the radical adduct between
the heteroaromatic base and ·CONH2 [eqns. (4) and (5)], so that
the overall stoichiometry requires 2 mol of CAN per mol of
heterocyclic compound.
(4)
(1)
2496
CHEM. COMMUN., 2002, 2496–2497
This journal is © The Royal Society of Chemistry 2002
Minisci, Francesco
