Palladium-catalyzed sequential alkylation-alkenylation reactions. Application to the synthesis of 2-substituted-4-benzoxepines and 2,5-disubstituted-4-benzoxepines

Article abstract of DOI:10.1021/jo025730z

The synthesis of 2-substituted-4-benzoxepines and 2,5-disubstituted-4-benzoxepines from aryl iodides and bromoenoates is described. This methodology is based on a palladium-catalyzed aromatic substitution followed by an intramolecular Heck sequence. Under

Full text of DOI:10.1021/jo025730z

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J . Org. Chem. 2002, 67, 3972-3974
P a lla d iu m -Ca ta lyzed Sequ en tia l
Alk yla tion -Alk en yla tion Rea ction s.
Ap p lica tion to th e Syn th esis of
-Su bstitu ted -4-Ben zoxep in es a n d
,5-Disu bstitu ted -4-Ben zoxep in es
2
2
Mark Lautens,* J ean-Fran c¸ ois Paquin, and
Sandrine Piguel†
Davenport Laboratories, Chemistry Department, University
of Toronto, Toronto, Ontario, Canada M5S 3H6
F igu r e 1.
Sch em e 1
mlautens@chem.utoronto.ca
Received March 18, 2002
Abstr a ct: The synthesis of 2-substituted-4-benzoxepines
and 2,5-disubstituted-4-benzoxepines from aryl iodides and
bromoenoates is described. This methodology is based on a
palladium-catalyzed aromatic substitution followed by an
intramolecular Heck sequence. Under the reaction conditions
(Pd(OAc)2 (10 mol %), tri-2-furylphosphine (20 mol %),
norbornene (2 equiv), Cs2CO3 (2 equiv), CH3CN, 85 °C),
moderate to excellent yields of benzoxepines bearing numer-
ous substituents (Me, F, Cl, etc.) are obtained.
Ta ble 1. F or m a tion of 2-Disu bstitu ted -4-ben zoxep in es
fr om Or th o-Su bstitu ted Ar yl Iod id esa
1
In recent times, seven-membered-ring oxacycles and
particularly benzoxepine derivatives have received in-
creasing interest because of their occurrence in natural
2
2b,3,4
products , their biological activities,
and their use as
natural herbicides.5
yield (%)b
entry
R
aryl iodide
product
We recently reported a new methodology for the
formation of fused aromatic rings from the reaction of
aryl iodides and bromoenoates under palladium catalysis
1
2
3
4
5
Me
CH2OMe
CH OTBS
OMe
7
8
9
10
11
12
13
14
15
16
85
23
53
75
0
2
in which two carbon-carbon bonds are formed in a one-
pot process.6
,7
CO2Me
We now report an extension of this
a
methodology for the synthesis of 2-substituted-4-benzoxe-
pines 1a and 2,5-disubstituted-4-benzoxepines 1b from
aryl iodides 2 and bromoenoates 3 (Figure 1).
4 equiv of the bromoenoate were used, but it was later found
that 2 equiv could be used without affecting the yield. Isolated
yield.
b
To test the feasibility of the reaction, iodobenzene 4
was reacted with the oxygenated difunctional acceptor
reaction probably occurs through the same mechanism
described previously for the formation of six- and seven-
membered carbocycles.6
We then examined aryl iodides bearing an ortho
substituent (Table 1), blocking the second alkylation. The
use of different ortho substituents gave the benzoxepine
derivatives in moderate to good yield. With R ) Me (entry
8
5
2
under our modified Catellani conditions: Pd(OAc) (10
,7,10
9
mol %), trifurylphosphine (20 mol %), norbornene (2
equiv), Cs CO (2 equiv), CH CN, 85 °C (Scheme 1). The
2
3
3
desired bicyclic compound 6 was obtained in modest yield
indicating that the reaction was indeed possible. The
†
Present address: Laboratoire de Synth e` se et Electrosynth e` se
Organique (SESO), Universit e´ de Rennes 1, 35042 Rennes, France.
(8) Compound 5 was obtained in three steps from di(ethyleneglycol).
For synthesis details, see Supporting Information.
(
1) Hoberg, J . O. Tetrahedron 1998, 54, 12631-12670.
(
2) For recent examples, see: (a) Mac ´ı as, F. A.; Varela, R. M.; Torres,
A.; Molinillon, J . M. G. Tetrahedron Lett. 1999, 40, 4725-4728 and
references therein. (b) Wijnberg, J . B. P. A.; van Veldhuizen, A.; Swarts,
H. J .; Frankland, J . C.; Field, J . A. Tetrahedron Lett. 1999, 40, 5767-
5
770 and references therein. (c) Asakawa, Y.; Hashimoto, T.; Takikawa,
K.; Tori, M.; Ogawa, S. Phytochemistry 1991, 30, 235-251. (d) Meri c¸ li,
F.; Meri c¸ li, A. H.; Becker, H.; Ulubelen, A. Phytochemistry 1996, 42,
1
257-1258.
(
3) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G. Pure Appl.
Chem. 1999, 71, 2039-2046.
4) Kaupmann, W.; Ohlendorf, H. W.; Wolf, K. U. Eur. J . Med. Chem.
985, 20, 207-212.
5) Vyvyan, J . R.; Looper, R. E. Tetrahedron Lett. 2000, 41, 1151-
154.
(
(9) For a review on the use of trifurylphosphine (TFP) in catalysis,
see: Anderson, N. G.; Keay, B. A. Chem. Rev. 2001, 101, 997-1030.
(10) (a) Catellani, M.; Frignagni, F.; Rangoni, A. Angew. Chem. 1997,
109, 142-145 and references therein.; Angew. Chem., Int. Ed. Engl.
1997, 36, 119-122 and references therein. (b) Catellani, M.; Fagnola,
M. C. Angew. Chem. 1994, 106, 2559-2560; Angew. Chem., Int. Ed.
Engl. 1994, 33, 2421-2422. (c) Catellani, M.; Cugini, F. Tetrahedron
1999, 55, 6595-6602.
1
1
1
(
(
6) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
046. For the first report of Pd-catalyzed ortho-alkylation, see ref 10.
(
7) Lautens, M.; Paquin, J .-F.; Piguel, S.; Dahlmann, M. J . Org.
Chem. 2001, 66, 8127-8134.
1
0.1021/jo025730z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3973
Sch em e 2. Syn th esis of
,5-Disu bstitu ted -4-ben zoxep in es
Ta ble 2. F or m a tion of 2-Su bstitu ted -4-ben zoxep in es
fr om P olysu bstitu ted Ar yl Iod id esa
2
1
), the desired product 12 was isolated in 85% yield.
Changing from a methyl ether (entry 2) to a TBS benzyl
ether (entry 3) improved the yield from 20 to 41%. This
lack of reactivity might be explained by a complexation
between the oxygen atom and the palladium center,
which inhibits the subsequent steps in the catalytic cycle.
We suppose that this phenomenon is minimized in the
case of R ) CH
of the silyl group. Interestingly, when R ) OMe (entry
), the desired benzoxepine 15 was obtained in 75%,
2
OTBS (entry 3) because of the steric bulk
4
2
whereas the use of 11 (R ) CO Me) gave no desired
product.11 These results correlated with our previous
findings on the reactivity of fused aromatic seven-
7
membered rings.
We then studied the functional group tolerance on the
aryl iodides (Table 2). Chlorine or fluorine substituents
are well tolerated since the desired benzoxepines 21 and
a
2 equiv of bromoenoates were used. b Isolated yield.
pines from aryl iodides and bromoenoates under pal-
ladium catalysis in which two carbon-carbon bonds are
formed in one pot. The bicyclic compounds are obtained
in moderate to excellent yields under relatively mild
conditions, and substitution is tolerated on both the aryl
iodides and the bromoenoate. Application of this meth-
odology to the synthesis of more complex bicyclic com-
pounds as well as bioactive molecules is in progress in
our laboratory and will be reported in due course.
2
3 were isolated in 84 and 78% yields, respectively. The
presence of an amide (entry 2) did not adversely affect
the reaction since 22 was obtained in 80% yield. The
reaction also proceeds in the presence of a basic nitrogen
since 5-iodoquinoline (20) reacted to give 24 in 72% yield.
It is important to note that the majority of the products
allow for further functionalization.
Benzoxepine 21 was a crystalline solid allowing X-ray
crystallography12 to confirm the (E)-geometry of the
exocyclic double bond as previously indicated by NOE
experiments.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Natural Sciences and Engineer-
We then explored the effect of a substituent adjacent
to one of the reactive groups on the difunctional acceptor
(
13) Compound 26 was synthesized in four steps from ethyl (S)-
(
-)-lactate. For synthesis details, see Supporting Information.
(
Scheme 2). The bromoenoate 26 bearing a methyl
1
3
substituent was synthesized and submitted to the
reaction conditions. 1-Iodonaphthalene (25) gave the
desired 2,4-disubstituted-4-benzoxepine 27 in 72%. When
2
2
6 was reacted with the aryl iodide 28, the benzoxepine
9 was obtained in 55% yield indicating the lower
reactivity of 28. These results illustrate that R-branching
on the alkyl bromide is well tolerated.
In conclusion, we described the synthesis of 2-substi-
tuted-4-benzoxepines and 2,5-disubstituted-4-benzoxe-
(
11) No side products were isolated since only unreacted 5 along
with baseline material were detectable by TLC after workup.
12) See Supporting Information for details.
(

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974 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
ing Research Council (NSERC) of Canada, the Ontario
Research and Development Challenge Fund (ORDCF),
and the University of Toronto. J .-F.P. acknowledges
NSERC and the Fonds pour la Formation de Chercheurs
et l’Aide a` la Recherche (FCAR) for PGS scholarships,
and S.P. thanks the Fondation Bettencourt-Schueller
for a postdoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure for the formation of benzoxepines, details for the
synthesis of aryl iodides and difunctional acceptors, as well
as spectroscopic data for the new benzoxepines. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O025730Z