A Novel Palladium-Catalyzed Intramolecular Redox Reaction

Article abstract of DOI:10.1021/ol015813m

matrix presented A new type of palladium-catalyzed redox reaction is described, forming enones from 2-(2-bromobenzyl)-ketones with an overall loss of HBr. The scope and limitations of the reaction are demonstrated by a series of cyclic and acyclic substra

Full text of DOI:10.1021/ol015813m

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1495-1497
A Novel Palladium-Catalyzed
Intramolecular Redox Reaction
Klemens Ho1genauer and Johann Mulzer*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
johann.mulzer@uniVie.ac.at
Received March 8, 2001
ABSTRACT
A new type of palladium-catalyzed redox reaction is described, forming enones from 2-(2-bromobenzyl)-ketones with an overall loss of HBr.
The scope and limitations of the reaction are demonstrated by a series of cyclic and acyclic substrates. The mechanism most probably
involves the formation of an intramolecular arylpalladium enolate and is related to the oxidation of silyl enol ethers with palladium acetate.
Palladium has found widespread use in modern organic
synthesis because of the important carbon-carbon bond
forming reactions catalyzed by Pd(0) complexes, as well as
the unique oxidative properties of Pd(II) salts.1 The reaction
of a silyl enol ether with palladium acetate developed by
Ito2 is one of the most convenient methods of forming R,â-
unsaturated ketones.3 However, stoichiometric quantities of
the reagent are usually required. A catalytic variant of this
reaction using Pd(0) and diallycarbonate via a π-allyl
palladium enolate4 has not found widespread application.
However, the reaction of 1 with a catalytic amount of the
Herrmann-Beller palladacycle 36 resulted in the unexpected
formation of dienone 2 as the main product.
To test the generality of this yet unprecedented overall
dehydrobromination reaction, we prepared cyclic and acyclic
2-(2-bromobenzyl)-ketones as model compounds. In the
course of the following palladium-catalyzed reactions, the
conditions were optimized. A catalyst load of 5 mol %
proved to give the best yields. Other bases, such as NaOAc
or KOAc, and alternative solvent systems (omitting water
In the course of our program to develop a new synthetic
strategy toward the molecular skeleton of the Lycopodium
alkaloid huperzine A,5 we planned an intramolecular Heck
cyclization of aryl bromide 1 as a key step (Scheme 1).
Scheme 1
(1) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester, 1995.
(2) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(3) For a review of forming R,â-unsaturated ketones, see: Buckle, D.
R.; Pinto, I. L. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 7, p 119. An efficient method using
IBX has recently been developed: Nicolaou, K. C.; Zhong, Y.-L.; Baran,
P. S. J. Am. Chem. Soc. 2000, 122, 7596.
(4) (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 5635.
(b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 5639. (c)
Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J. Tetrahedron
1986, 42, 2971.
(5) Kozikowski, A. P.; Tu¨ckmantel, W. Acc. Chem. Res. 1999, 32, 641.
(6) (a) Herrmann, W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 1844. (b) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C.-P. J.
Organomet. Chem. 1999, 576, 23.
10.1021/ol015813m CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/05/2001

and/or acetonitrile) resulted in less satisfactory results. In
addition, the temperature also proved to be critical. To
maintain a reflux temperature of at least 130 °C, the
proportions of both water and acetonitrile were kept fairly
low. The results for the reaction of the cyclopentanone and
cyclohexanone derivatives 4a-c with Pd(0) are summarized
in Table 1. Indeed, all substrates gave the corresponding
Scheme 2a
Table 1. Synthesis of Cyclic Enonesa
a (a) Same reaction conditions as in Table 1.
compound
n
R
product(s) (yield)
4a
4b
4c
1
2
2
H
H
6a (72%)
6b (57%)
5c (23%), 6c (73%)
To elucidate the mechanism of the redox reaction, we
performed control experiments with 2-(4-bromobenzyl)-
ketone 12 and 2-(3-bromobenzyl)-ketone 13 (Table 2). None
-O(CH2)2O-
a (a) Reagents and conditions: 5 mol % 3, 2 equiv of n-Bu4NOAc, DMF/
CH3CN/H2O ) 5/1/1, 130 °C, 16 h
enones, although the reaction of 2-(2-bromobenzyl)-cyclo-
hexanone (4b) additionally gave a range of unidentified
byproducts. Blocking C4 of the cyclohexanone with a cyclic
ketal (4c) resulted in better yields of the corresponding enone
6c. In this particular case, the fully conjugated enone 5c was
also formed to a considerable extent. The position and
geometry of the double bond in structures 5 and 6 were
unambiguously assigned by NOE experiments.7 These results
are particularly interesting, as substrates 4a and 4b have been
reported to give a palladium-catalyzed intramolecular R-
arylation using PdCl2(Ph3P)2 and CsCO3 in THF.8
Table 2. Control Experiments with 2-(4-bromobenzyl)-ketone
12 and 2-(3-Bromobenzyl)-ketone 13
Subjecting the acyclic bromoketone 7 to the same reaction
conditions resulted in the formation of the dimeric structures
10 and 11 as inseparable diastereomeric mixtures. We assume
that the expected enones 8 and 9 are initially formed but
undergo additional palladium-catalyzed reactions with the
oxidative addition complex of 7 and a Pd(0) species. In
particular, this complex could insert into the highly reactive
double bond of enone 8 via a Heck reaction to form 10,
whereas 11 might be formed by an intermolecular R-arylation8b
of the fully conjugated enone 9 (Scheme 2). Performing the
reaction under high dilution did not avoid the dimerization.
entry
bromide
methoda
product(s) (yield)
1
2
3
12
12
13
A
B
A
14a (66%), 15 (8%)
14b (60%)b
14a (55%), 16 (30%)
a Method A: 5 mol % 3, 2 equiv of n-Bu4NOAc, DMF/CH3CN/H2O )
5/1/1, 130 °C, 72 h. Method B: 5 mol % 3, 2 equiv of n-Bu4NOAc, d7-
DMF/CH3CN/H2O ) 5/1/1, 130 °C, 72 h. b Only main product isolated.
of these reactions resulted in the formation of the corre-
sponding enones. After extended reaction times (72 h), the
dehalogenated aryl ketone 14a was isolated as the main
product in both cases (entries 1 and 3). The nature of the
reducing agent became clear when we used deuterated DMF
as part of the solvent mixture (entry 2), resulting in the
formation of aryl deuteride 14b. We concluded that DMF is
slowly hydrolyzed under the basic, aqueous conditions and
the formate thus formed acts as the active hydrogen donor.9
The aryl homocoupling products 15 and 16 were also found
in both control experiments.10
(7) The aromatic ortho protons of 5 showed NOE contacts to the olefinic
proton and to the endocyclic allylic protons. In 6, the aromatic ortho protons
only showed NOE contacts to the benzylic protons, which themselves
showed an NOE contact to the olefinic proton.
(8) (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581.
(b) For comprehensive intermolecular examples, see: Fox, J. M.; Huang,
X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360.
(9) Triethylammonium formate has been used as a reducing agent for
aryl triflates: Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541.
(10) (a) A similar palladium-catalyzed aryl homocoupling using 3 has
recently been published: Hennings, D. D.; Iwama, T.; Rawal, V. H. Org.
Lett. 1999, 1, 1205. (b) For other examples, see: de Meijere, A.; Bra¨se, S.
J. Organomet. Chem. 1999, 576, 88.
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Org. Lett., Vol. 3, No. 10, 2001

species. Subsequent deprotonation would furnish enolate B,
which could displace the bromine at palladium in a nucleo-
philic manner to give an oxo-π-allyl palladium complex.11
This palladium enolate can be formulated using the tauto-
meric structures C, D, and E. The redox step would then
form the palladium-containing enone F. Depending on the
substitution pattern of the ketone, a benzylic proton can also
undergo the elimination. Finally, reductive elimination leads
to the enone G.
Scheme 3
In summary, we have discovered a new type of a
palladium-catalyzed redox reaction. Elucidation of the mech-
anism revealed that the reaction proceeds intramolecularly
and forms enones from 2-(2-bromobenzyl)-ketones with an
overall loss of HBr. Further studies are underway to apply
the reaction in a more general manner.
Acknowledgment. We thank Prof. Dirk Trauner for help-
ful discussions and the Jubila¨umsfonds der O¨ sterreichischen
Nationalbank for funding.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The failure to apply the palladium-catalyzed reaction
intermolecularly using cyclohexanone and 2 equiv of bromo-
benzene additionally confirmed the proposed mechanism
given in Scheme 3. Thus, the first step would involve an
oxidative addition of the aryl bromine of ketone A to a Pd(0)
OL015813M
(11) For a similar complex, see ref 2.
Org. Lett., Vol. 3, No. 10, 2001
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