Palladium-catalyzed isobenzofuran generation under neutral conditions via oxidative addition to lactol methyl ether

Article abstract of DOI:10.1021/ol0265416

(matrix presented) A novel method for generation of isobenzofuran is developed from lactol methyl ether using palladium catalysts. This reaction can be carried out under neutral conditions and hence improves on the precedent methods under acidic or basic conditions and at high temperatures. Furthermore, this Pd-catalyzed isobenzofuran generation suggests the involvement of oxidative addition of Pd catalyst into benzylic or allylic methyl ethers.

Full text of DOI:10.1021/ol0265416

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3355-3357
Palladium-Catalyzed Isobenzofuran
Generation under Neutral Conditions via
Oxidative Addition to Lactol Methyl
Ether
Koichi Mikami* and Hirofumi Ohmura
Department of Applied Chemistry, Tokyo Institute of Technology, O-okayama,
Meguro-ku, Tokyo, 152-8552, Japan
kmikami@o.cc.titech.ac.jp
Received June 14, 2002 (Revised Manuscript Received August 23, 2002)
ABSTRACT
A novel method for generation of isobenzofuran is developed from lactol methyl ether using palladium catalysts. This reaction can be carried
out under neutral conditions and hence improves on the precedent methods under acidic or basic conditions and at high temperatures.
Furthermore, this Pd-catalyzed isobenzofuran generation suggests the involvement of oxidative addition of Pd catalyst into benzylic or allylic
methyl ethers.
Several excellent methods for isobenzofuran generation1,2
have been developed.3 However, these are still limited by
the reaction conditions (acidic or basic) or applicable
substrates. Therefore, new generation methods are desirable
especially under neutral conditions. Recently, we reported
the example of (2,5)-ene cyclization4 using an oxonium ion
intermediate as an enophile (Scheme 1).5-7 It is expected
base leading to isobenzofuran (Scheme 2). Herein we report
a novel method for isobenzofuran generation from lactol
methyl ether using palladium catalysts under neutral condi-
tions via oxidative addition to the methyl ether followed by
sequential8 deprotonation.
Scheme 2
Scheme 1
There is a pioneering work by Tsuji in which Pd(0)
catalysts undergo oxidative addition to allylic carbonate to
form the π-allylpalladium intermediate accompanied by
decarboxylation.9,10 The resultant alkoxide on Pd acts as a
that the R-proton of this oxonium intermediate is very acidic
and therefore may easily be abstracted in the presence of
(1) Reviews: (a) Haddadin, M. J. Heterocycles 1978, 9, 865. (b)
Friedrichsen, W. AdV. Heterocycl. Chem. 1980, 26, 135. (c) Wiersum, U.
E. Aldrichimica Acta 1981, 14, 53. (d) Rodrigo, R. Tetrahedron 1988, 44,
2093.
(2) (a) Fieser, L. F.; Haddadin, M. J. J. Am. Chem. Soc. 1964, 86, 2081;
(b) Can. J. Chem. 1965, 43, 1599.
10.1021/ol0265416 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

base to abstract hydrogen from an active methylene com-
pound to generate a carbanion that attacks π-allylpalladium
to form a carbon-carbon bond. We applied this reaction to
isobenzofuran generation using benzylic carbonate 1 as a
substrate (Scheme 3). First, alkyl palladium species 2 would
Scheme 5
Scheme 3
Pd(0) catalyst, no generation of isobenzofuran was observed
up to 100 °C. Generation of isobenzofuran was further
investigated using Pd(PPh3)4, Pd(OAc)2 + dppp, and Pd2-
(dba)3‚CHCl3 as Pd(0) species in several solvents (Table 1).
Table 1. Choice of Pd(0) Catalystsa
time
yield of 3
entry
Pd(0)
solvent
(days)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CH2Cl2
C6H6
CH3CN
THF
CH2Cl2
C6H6
CH3CN
CH3CNb
THF
CH2Cl2
C6H6
CH3CN
THF
1
1
4
1.5
1.5
20 h
1
3
20 h
1
2
2
nr
nr
17 (30)c
nr
nr
0d
30d
21 (45)e
0d
nr
0f
Pd(PPh3)4
be generated from 1. The alkoxide on Pd might act as a base
to abstract a benzylic proton to generate isobenzofuran that
could be trapped in situ by dimethyl acetylenedicarboxylate
(DMAD) affording the adduct 3.11
To prepare 1, lactone 4 was treated with DIBAL to give
lactol 5 followed by the addition of methyl chloroformate
(Scheme 4). As a result, lactol methyl ether 6 was obtained
(8 mol %)
Pd2(dba)3‚CHCl3
(4 mol %)
Pd(OAc)2 (4 mol %)
DPPP (8 mol %)
27g
<10 (<20)h
Scheme 4
2
a All reactions were carried out using a catalytic amount of palladium
complex in the presence of DMAD (3 equiv) under reflux at 0.4 M. b DPPP
(16 mol %) was added. c Based on recovery of starting material 6: 46%.
d All starting material 6 was consumed. e Based on recovery of starting
material 6: 54%. f Product was detected by TLC after 1 day. g Recovery
of starting material 6: 66%. h Based on recovery of starting material 6:
48%.
As a result, the desired DMAD adduct of isobenzofuran 3
was obtained in CH3CN with all Pd(0) species. Above all,
Pd2(dba)3‚CHCl3 was found to be the best in terms of
catalytic activity and the yield of 3 (entry 7).12 The addition
of phosphine ligand lowered the catalytic activity of Pd(0)
species and the yield of 3 (entry 8). The sterically bulky
phosphine ligand might interrupt the deprotonation by
methoxide. Therefore, further investigation was carried out
without phosphine ligand in various solvents.
presumably via 1 because of its lability (Supporting Informa-
tion). Methyl ether 6 was prepared separately by treatment
with sodium hydride followed by methyl iodide.
Interestingly, 6 was found to give isobenzofuran by
treatment with Pd(0) catalyst (Scheme 5). In the absence of
(3) (a) Pyrolysis at 650 °C: Wiersum, U. E.; Mijs, W. J. J. Chem. Soc.,
Chem. Commun. 1972, 347. (b) Acidic conditions: Plaumann, H. P.; Smith,
J. G.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1980, 354. (c) Basic
conditions: Tobia, D.; Rickborn, B. J. Org. Chem. 1986, 51, 3849. (d)
Use of diazo compound: Hamaguchi, M.; Ibata, T. Chem. Lett. 1976, 287.
(e) Basic and acidic conditions: Hayakawa, K.; Yamaguchi, Y.; Kanematsu,
K. Tetrahedron Lett. 1985, 26, 2689.
(4) (2,5)-Ene cyclization: (a) Ohmura, H.; Smyth, G. D.; Mikami, K. J.
Org. Chem. 1999, 64, 6056. (b) Ohmura, H.; Mikami, K. Tetrahedron Lett.
2001, 42, 6859.
(5) Review on l-(m,n) terminology: (a) Mikami, K.; Shimizu, M. Chem.
ReV. 1992, 92, 1021.
(6) Account on l-(m,n)-ene cyclizations: Sarkar, T. K. J. Indian Inst.
Sci. 1994, 74, 329.
(7) Recent examples of l-(m,n)-ene cyclization: (a) Loh, T.-P.; Hu, Q.-
Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett. 2001, 3, 2669. (b) Okano, T.;
Nakagawa, K.; Kubodera, N.; Ozono, K.; Isaka, A.; Osawa, A.; Terada,
M.; Mikami, K. Chem. Biol. 2000, 7, 173. (c) Mikami, K.; Osawa, A.;
Isaka, A.; Sawa, E.; Shimizu, M.; Terada, M.; Kubodera, N.; Nakagawa,
K.; Tsugawa, N.; Okano, T. Tetrahedron Lett. 1998, 39, 3359. (d) Noguchi,
M.; Mizukoshi, T.; Nishimura, S. Bull. Chem. Soc. Jpn. 1997, 70, 2201.
(8) Reviews on sequential reactions: (a) Nakai, T.; Mikami, K. Kagaku
no Ryoiki 1982, 36, 661; Chem. Abstr. 1982, 96, 16001. (b) Ziegler, F. E.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.,
Pergamon Press: Oxford, 1991; Vol. 5, p 875. (c) Ho, T.-L. Tandem
Organic Reactions; Wiley: New York, 1992. (d) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (e) Special issue on frontiers
in organic reaction sequence: Wender, P. A. Chem ReV. 1996, 96, 1.
(9) Reviews: (a) Tsuji, J. J. Synth. Org. Chem. Jpn. 1999, 57, 1036. (b)
Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (c) Tsuji, J. Tetrahedron
1986, 42, 4361.
(10) General reviews on Pd chemistry: (a) Tsuji, J. Palladium Reagents
and Catalysts, InnoVations in Organic Synthesis; Wiley & Sons: Chichester,
UK, 1995. (b) Trost, B. M. Tetrahedron 1977, 33, 2615.
(11) For the spectral data of 3, see: Sambaiah, T.; Huang, D.-J.; Cheng,
C.-H. J. Chem. Soc., Perkin Trans. 1 2000, 195.
(12) Adduct 3 was scarcely obtained without palladium complex.
3356
Org. Lett., Vol. 4, No. 20, 2002

The catalytic activity of Pd species turned out to depend
on the solvent employed (Table 2). The most suitable solvent
Scheme 6
Table 2. Effect of Solventa
entry
solvent
time
yield of 3 (%)
1
2
3
4
5
6
7
DMSO
15 min
45 min
1.5 h
2.5 h
13 h
71
65
53
68
52
46
0
DMSO
DMSO
DMA
DMA
DMF
7 h
7 h
1,4-dioxane
a All reactions were carried out using 4 mol % Pd2(dba)3‚CHCl3 in the
presence of DMAD (3 equiv) at 100 °C.
styrene 7 (X ) OMe), which has a structure similar to 6,
with Pd(PPh3)4 in the presence of dimethylmalonate, pro-
duced conjugate ester 9 (Scheme 6). These results support
the oxidative addition of Pd catalyst into allylic or benzylic
methyl ether.
In summary, a novel method of generating isobenzofuran
from lactol methyl ether using palladium catalysts has been
developed. This reaction can be carried out under neutral
conditions and, hence, is of greater advantage than the
precedent methods of isobenzofuran generation under acidic
or basic conditions and at high temperature.1-3 Furthermore,
this Pd-catalyzed isobenzofuran generation suggests the
involvement of oxidative addition of Pd catalyst into benzylic
or allylic methyl ether.
was DMSO, which gave 3 in 71% yield within 15 min (entry
1). However, prolonged reaction time resulted in a lower
yield, possibly because of decomposition of 3 (entries 2 and
3). The cycloadduct 3 was also obtained using DMA and
DMF in reasonably good yields (entries 4 and 6). We
speculate that the reason polar solvents such as DMSO,
DMA, and DMF are suitable for this reaction is that
coordinating solvents could stabilize the polarized palladium
intermediate. Moreover, dissociation of methoxide was
facilitated and the basicity of methoxide was increased in
polar solvents.
The results shown in Tables 1 and 2 imply that the
oxidative addition of Pd catalyst to benzylic methyl ether
does take place. In general, this type of oxidative addition
of Pd catalyst to methyl ether has been considered to be
difficult.13 However, there was a report that allylic methyl
ether with Pd(PPh3)4 in the presence of hydride gave a
demethylated reduction product as shown in our own product
10.14 This type of product was reported to be generated by
the oxidative addition of Pd to the methyl ether. In a similar
reaction with â-methoxymethyl styrene (7: X ) H), we
obtained the demethylated product, â-methyl styrene 10
(22%). Furthermore, treatment of â-(dimethoxymethyl)-
Supporting Information Available: Preparative methods,
spectral and analytical data, and experimental details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0265416
(13) Oxidative addition of Pd(0) species was reported in dioxane on
allylic phenyl ethers but not on methyl ether: Tsuji, J.; Yamakawa, T.;
Kaito, M.; Mandai, T. Tetrahedron Lett. 1978, 2075. Enantiospecific Pd-
(0)-catalyzed substitution of acetates and carbonates of 1-naphthyletha-
nols: Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235.
(14) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380.
Org. Lett., Vol. 4, No. 20, 2002
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