Cycloadditions of 1,1-disubstituted benzocyclobutenes obtained by C(sp 3)-H activation

Full text of DOI:10.1021/jo802471u

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

TABLE 1. Cycloaddition of 1,1-Disubstituted BCBs 2a-k and
N-Methylmaleimide (4a)a
SCHEME 2. Torquoselectivity of the Electrocyclic Ring
Opening of BCB 2a
of BCB 2a is expected to occur in favor of o-xylylene A1 due
to the dominant outward rotation of the methyl group. Inter-
mediate A1 would then undergo an endo-selective cycloaddition
with 4a to give diastereoisomer 5aa. In contrast, inward rotation
of the methyl group would provide o-xylylene B1, that would
furnish diastereoisomer 5ab and olefin 6 by cycloaddition with
4a and [1,5]-hydrogen shift, respectively.7b,8
The reactions of other 1,1-disubstituted BCBs 2b-k with
N-methylmaleimide 4a were next examined under the same
conditions (Table 1, entries 2-11). Cycloadducts 5b-k were
obtained in good to excellent yields as single diastereoisomers,
the configuration of which was determined by NOESY experi-
ments or X-ray diffraction analysis (see the Supporting Informa-
tion for crystallographic data for compounds 5e and 5h). All
cycloadducts 5aa and 5b-j have the same relative configuration,
which reflects a complete outward torquoselectivity for the alkyl
group. The reaction proved compatible with a variety of
substituents on the benzene and cyclobutene rings, regardless
of their electronic or steric properties. In particular, pyridocy-
clobutene 2f gave rise to the original fused heterocycle 5f in
63% yield (entry 6). In addition, diester 2k furnished the
corresponding cycloadduct 5k in excellent yield despite the
strong electron-withdrawing nature of the o-xylylene intermedi-
ate (entry 11).
Next, we examined the cycloaddition of BCBs with other
dienophiles. We found the reaction limited to activated dieno-
philes such as maleimides (4a,b), maleic anhydride (4c), and
tetracyanoethylene (4d) (Table 2). With less activated dieno-
philes,9 the formation of the [1,5]-hydrogen shift product (e.g.,
compound 6, Scheme 2) became predominant. In spite of this
limitation, good yields were achieved with dienophiles 4b-d
and the observed diastereoselectivity in favor of cycloadducts
5l-p was again total and in the same sense.
The cycloaddition of 1-monosubstituted BCB 2l, readily
accessible by C-H activation,3b was also examined for the
purpose of comparison with its 1,1-disubstituted counterparts
(Scheme 3). Reaction with dienophile 4b under the same
conditions as above furnished an inseparable mixture of
cycloadducts 5ra and 5rb in 1:8 ratio and 90% yield. This ratio
reflects the major outward torquoselectivity of the ester group
in accordance with previous work.5 Compared to disubstituted
analogue 2a (Table 2, entry 1), the torquoselectivity of the
a Conditions: BCB (1 equiv), N-methylmaleimide (2 equiv),
o-dichlorobenzene, microwave irradiation (Pmax ) 250 W), 180 °C,
10-20 min. b Synthesized as described in ref 3b. c Obtained in two
steps from 2a by hydrolysis and Curtius rearrangement; see the
Supporting Information (alloc ) allyloxycarbonyl).
6 (Scheme 2). It is known that high temperatures are required
for the electrocyclic ring-opening of BCBs such as 2a, that is
1,1-disubstituted and at the same time bears an electron-
withdrawing group on the cyclobutene ring.1,2 In accordance
to previous work by Houk and co-workers,5 the ring-opening
(8) Shishido, K.; Ito, M.; Shimada, S.; Fukumoto, K.; Kametani, T. Chem.
Lett. 1984, 13, 1943.
(9) For instance, benzoquinone, dimethyl acetylenedicarboxylate, phenyl vinyl
sulfone, and 2-cyclohexen-1-one.
J. Org. Chem. Vol. 74, No. 4, 2009 1775

TABLE 2. Cycloaddition of Various 1,1-Disubstituted BCBs and
Activated Dienophilesa
SCHEME 3. Cycloaddition of 1-Monosubstituted BCB 2l
observed in the cycloaddition step, which most probably reflects
the dominant outward torquoselectivity of alkyl groups in the
electrocyclic ring-opening step.
Experimental Section
Representative Cycloaddition Procedure. Compound 5aa. A
mixture of benzocyclobutene 2a (40.5 mg, 0.23 mmol) and
N-methylmaleimide 4a (51 mg, 0.46 mmol) in o-dichlorobenzene
(0.2 mL) was placed in a closed vessel and irradiated in a focused
microwave reactor for 15-20 min at 180 °C (Pmax ) 250 W). The
resulting mixture was directly purified by flash chromatography
(heptanes, then heptanes/AcOEt 8:2) to give compound 5aa as a
colorless oil (61.4 mg, 93%): 1H NMR (CDCl3, 300 MHz,) δ
7.33-7.26 (m, 2 H), 7.21 (ddd, J ) 7.0, 7.0, 2.0 Hz, 1 H), 7.09 (d,
J ) 7.0 Hz, 1 H), 3.82 (d, J ) 8.6 Hz, 1 H), 3.62 (s, 3 H), 3.43
(ddd, J ) 8.6, 8.6, 1.8 Hz, 1 H), 3.15 (dd, J ) 15.6, 1.8 Hz, 1 H),
2.72-2.64 (m, 4 H), 1.99 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ
179.1, 176.9, 175.3, 137.0, 134.0, 128.4, 128.1, 127.8, 125.5, 53.2,
48.9, 47.0, 40.2, 29.7, 24.8, 20.8; IR (film) ν 2985, 2992, 1724,
1696, 1432, 1247, 1106, 984, 768, 628 cm-1; HRMS (ESI) m/z
calcd for C16H17NO4Na (M + Na)+ 310.1055, found 310.1046.
a Conditions: BCB (1 equiv), dienophile (2 equiv), o-dichlorobenzene,
microwave irradiation (Pmax ) 250 W), 180 °C, 10-20 min.
Acknowledgment. This work was financially supported by
ICSN (fellowship to M.C.) and CNRS (ATIP grant to O.B.).
electrocyclic ring-opening of 2l is reversed, which further
illustrates the strongly dominant outward rotation of alkyl groups
observed for compounds 2a-j.
In conclusion, tricyclic molecules were synthesized in good
yields from 1,1-disubstituted benzocyclobutenes, that are now
easily accessible by C(sp3)-H activation, using a microwave-
enhanced [4 + 2] cycloaddition. A high diastereoselectivity was
Supporting Information Available: Full characterization of
all new compounds, detailed experimental procedures, copies
of NMR spectra for target compounds, and CIF files for 5e and
5h. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802471U
1776 J. Org. Chem. Vol. 74, No. 4, 2009