SCHEME 1. Overall Synthetic Strategy
Cycloadditions of 1,1-Disubstituted
Benzocyclobutenes Obtained by C(sp3)-H
Activation
Manon Chaumontet,† Pascal Retailleau,† and
Olivier Baudoin*,‡
Institut de Chimie des Substances Naturelles, CNRS UPR2301,
AVenue de la Terrasse, 91198 Gif-sur-YVette, France, and
UniVersite´ Lyon 1, CNRS UMR5246, Institut de Chimie et
Biochimie Mole´culaires et Supramole´culaires, 43 BouleVard du
11 NoVembre 1918, 69622 Villeurbanne, France
oliVier.baudoin@uniV-lyon1.fr
ReceiVed NoVember 05, 2008
of available BCBs as substrates for pericyclic reactions.4 In this
paper, we report on [4 + 2] cycloadditions performed from such
BCBs under microwave irradiation.
Our overall synthetic strategy is highlighted in Scheme 1.
Substituted BCBs 2 obtained from aryl bromides 1 by C-H
activation could generate o-xylylene isomers A and B upon
thermolysis, the ratio of which defines the torquoselectivity of
the cyclobutene ring-opening. Trapping of A and/or B with an
appropriate dienophile (4) should lead to the formation of
cycloadducts 5. The torquoselectivity of the electrocyclic ring-
opening of benzocyclobutenes has been studied computationally
by Houk5 and Santelli,6 who showed that it is mainly governed
by electronic effects. In the case of 1,1-disubstituted BCBs (R2
and R3 * H), synergistic or antagonist effects of these
substituents can thus be anticipated. Since intermolecular
cycloadditions of o-xylylenes under normal electronic demand
are known to occur mainly with endo selectivity, the relative
configuration of cycloadducts 5 is expected to reflect the
torquoselectivity of the electrocyclic ring-opening of BCBs 2.
In contrast to 1-monosubstituted BCBs, very little work has been
published on intermolecular cycloadditions from 1,1-disubsti-
tuted BCBs.5,7 Since the latter are now easily accessible from
aryl bromides 1 by our C-H activation method,3b we decided
to study the outcome of their intermolecular cycloaddition with
various dienophiles.
We first examined the reaction of BCB 2a (Table 1, entry 1)
with N-methylmaleimide (4a). After a short optimization, it was
found that heating a mixture of 2a and 4a in o-dichlorobenzene
under microwave irradiation at 180 °C for 10 min furnished
cycloadduct 5aa in high yield as a single diastereoisomer (Table
1, entry 1). Microwave heating proved superior to conventional
heating in the same solvent and at the same temperature, since
in the latter case 5aa was obtained after 3 h in 79% yield,
together with traces of the other diastereoisomer 5ab and styrene
An efficient synthesis of polycyclic molecules has been
performed by a sequence involving palladium-catalyzed
C-H activation and [4 + 2] cycloaddition. The intermediate
benzocyclobutenes underwent a microwave-enhanced elec-
trocyclic ring-opening/cycloaddition process with complete
torquoselectivity and diastereoselectivity.
Benzocyclobutenes (BCBs) are important intermediates in
organic synthesis that have been widely used in [4 + 2]
cycloadditions and other pericyclic reactions for the construction
of polycyclic molecules.1 Indeed, the thermolysis of a BCB
generates a very reactive o-xylylene by electrocyclic ring-
opening, and this intermediate can be trapped in situ by an
internal or external dienophile to give the corresponding
cycloadduct. This sequence has been widely applied in natural
product synthesis in the past three decades.2 In spite of their
recognized synthetic interest, BCBs are only accessible by a
few methods that show limited compatibility with substituents
on the aromatic and cyclobutene rings. We recently described
the synthesis of functionalized BCBs by the palladium-catalyzed
C-H activation of benzylic methyl groups.3 This method shows
an unprecedented chemoselectivity and thus extends the array
(4) For our work on electrocyclizations, see: Chaumontet, M.; Piccardi, R.;
Baudoin, O. Angew. Chem., Int. Ed. 2009, 48, 179–182.
(5) Jefford, C. W.; Bernardinelli, G.; Wang, Y.; Spellmeyer, D. C.; Buda,
A.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1157.
(6) Mariet, N.; Pellissier, H.; Parrain, J.-L.; Santelli, M. Tetrahedron 2004,
60, 2829.
(7) (a) Arnold, B. J.; Sammes, P. G.; Wallace, T. W J. Chem. Soc., Perkin
Trans. 1 1974, 415. (b) Kametani, T.; Tsubuki, M.; Shiratori, Y.; Kato, Y.;
Nemoto, H.; Ihara, M.; Fukumoto, K.; Satoh, F.; Inoue, H J. Org. Chem. 1977,
42, 2672. (c) Matsuya, Y.; Ohsawa, N.; Nemoto, H J. Am. Chem. Soc. 2006,
128, 412.
† Institut de Chimie des Substances Naturelles.
‡ Universite´ Lyon 1.
(1) (a) Mehta, G.; Kotha, S. Tetrahedron 2001, 57, 625. (b) Sadana, A. K.;
Saini, R. K.; Billups, W. E. Chem. ReV. 2003, 103, 1539.
(2) (a) Oppolzer, W. Synthesis 1978, 793. (b) Charlton, J. L.; Alauddin, M. M.
Tetrahedron 1987, 43, 2873. (c) Nemoto, H.; Fukumoto, K. Tetrahedron 1998,
54, 5425.
(3) (a) Baudoin, O.; Herrbach, A.; Gue´ritte, F. Angew. Chem., Int. Ed. 2003,
42, 5736. (b) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J.-L.;
Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.
1774 J. Org. Chem. 2009, 74, 1774–1776
10.1021/jo802471u CCC: $40.75 2009 American Chemical Society
Published on Web 01/05/2009