Palladium-catalyzed intramolecular C-O bond formation

Article abstract of DOI:10.1021/ja012046d

A number of oxygen heterocycles were synthesized using the palladium-catalyzed intramolecular etherification of aryl halides by employing di-tert-butylphosphinobiaryl ligands. The reaction proceeds under mild conditions using weak bases such as Cs₂CO₃ or K₃PO₄. A variety of functional groups are tolerated in the reaction, and enantioenriched alcohols can be coupled without erosion of optical purity. The mildness of the reaction conditions allows for the use of polyfunctionalized substrates. This method was used as the key step in the synthesis of MKC-242, an antidepressant currently in clinical trials. The synthesis of MKC-242 was achieved in 40% overall yield from commercially available sesamol and acrylonitrile.

Full text of DOI:10.1021/ja012046d

12202
J. Am. Chem. Soc. 2001, 123, 12202-12206
Palladium-Catalyzed Intramolecular C-O Bond Formation
Shin-itsu Kuwabe, Karen E. Torraca, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed August 24, 2001
Abstract: A number of oxygen heterocycles were synthesized using the palladium-catalyzed intramolecular
etherification of aryl halides by employing di-tert-butylphosphinobiaryl ligands. The reaction proceeds under
mild conditions using weak bases such as Cs2CO3 or K3PO4. A variety of functional groups are tolerated in
the reaction, and enantioenriched alcohols can be coupled without erosion of optical purity. The mildness of
the reaction conditions allows for the use of polyfunctionalized substrates. This method was used as the key
step in the synthesis of MKC-242, an antidepressant currently in clinical trials. The synthesis of MKC-242
was achieved in 40% overall yield from commercially available sesamol and acrylonitrile.
Introduction
ol, using 2-aminopyridine as ligand to provide, respectively,
dihydrobenzofuran or chromane.6a These reports, in combina-
tion, had a substrate scope that was limited to the three halo
alcohols described.
Aryl ethers and oxygen heterocycles are common structures
in many pharmaceutically and agriculturally important com-
pounds.1,2 Traditional methods for the preparation of these
compounds include the Williamson ether synthesis,3 direct
nucleophilic substitution reactions,4 and Ullman-type couplings
of alkoxides with aryl halides.5,6,7 Each of these reactions,
however, typically requires either highly reactive aryl halides,
an excess of the alkoxide, or harsh conditions.
A promising transformation used to construct these hetero-
cycles involves the intramolecular Cu-catalyzed C-O bond
formation between aryl halides and alcohols. Zhu has reported
the efficient copper-catalyzed conversion of 2′-chlorophenethyl
alcohol to furnish dihydrobenzofuran.7 Similarly, Fagan and
Hauptman have described the copper-catalyzed cyclization of
2′-bromophenethyl alcohol and 3-(2′-bromophenyl)-propan-1-
The intramolecular8 Pd-catalyzed C-O bond formation is a
potentially attractive means to assemble oxygen heterocycles.
In the first report in this area, we disclosed that p-tol-BINAP
or DPPF could be used as supporting ligands for such C-O
bond forming processes.9 However, the method, in general,
worked well only for tertiary alcohols. Cyclizations of secondary
alcohols proceeded in low to moderate yields (32-66%) because
of competitive formation of the reduced aldehyde B. This arises
because of â-hydride elimination from palladacycle A being
competitive with or faster than reductive elimination to form
the desired product. Hartwig subsequently reported that using
di-tert-butylphosphinopentaphenylcyclopentadienylferrocenyl as
a ligand was effective for the cyclization of substrates bearing
tertiary alcohols, but application of these conditions to primary
and secondary alcohol substrates afforded the cyclized product
in only moderate yields, presumably because of competitive
â-hydride elimination.8h
(1) For recent reports involving 1,4-benzodioxane derivatives, see: (a)
Czompa, A.; Dinya, Z.; Antus, S.; Varga, Z. Arch. Pharm. (Weinheim, Ger.)
2000, 333, 175. (b) Gu, W. X.; Jing, X. B.; Pan, X. F.; Chan, A. S. C.;
Yang, T. K. Tetrahedron Lett. 2000, 41, 6079. (c) Ward, R. S. Nat. Prod.
Rep. 1999, 16, 75. (d) Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Chiarini,
A.; Gotti, R.; Leonardi, A.; Minarini, A.; Poggesi, E.; Recanatini, M.; Rosini,
M.; Tumiatti, V.; Melchiorre, C. J. Med. Chem. 1999, 42, 4214.
(2) For recent reports involving 1,4-benzoxazine derivatives, see: (a)
Matsumoto, Y.; Uchida, W.; Nakahara, H.; Yanagisawa, I.; Shibanuma,
T.; Nohira, H. Chem. Pharm. Bull. 2000, 48, 428. (b) Kuroita, T.;
Marubayashi, N.; Sano, M.; Kanzaki, K.; Inaba, K.; Kawakita, T. Chem.
Pharm. Bull. 1996, 44, 2051. (c) Largeron, M.; Lockhart, B.; Pfeiffer, B.;
Fleury, M. J. Med. Chem. 1999, 42, 5043. (d) Buon, C.; Chacun-Lefevre,
L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56, 605. (e)
Bourlot, A.; Sa´nchez, I.; Dureng, G.; Guillaumet, G.; Massingham, R.;
Monteil, A.; Winslow, E.; Pujol, M. D.; Me´rour, J. J. Med. Chem. 1998,
41, 3142.
(3) For a review, see: Feuer, H.; Hooz, J. In Chemistry of the Ether
Linkage; Patai, S., Ed.; Wiley Interscience: New York, 1967; p 445.
(4) For a review, see: Paradisi, C. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p
423.
(5) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
(6) (a) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043. (b) Keegstra, M. A.; Peters, T. H. A.;
Brandsma, L. Tetrahedron 1992, 48, 3633. (c) Bates, R. B.; Janda, K. D.
J. Org. Chem. 1982, 47, 4374.
Recent studies in our group have focused on extending the
scope and utility of the intramolecular C-O bond forming
reaction, and we have reported our initial findings as a
Communication.10 Herein, we report in full the results of this
investigation as well as the application of this methodology in
the synthesis of MKC-242, a benzodioxane antidepressant.
Results and Discussion
Initial studies focused on the development of a new ligand
for palladium that would accelerate the desired reductive
(8) For Pd-catalyzed intermolecular C-O bond formation, see: (a) Mann,
G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109. (b) Palucki, M.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395. (c) Mann,
G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. (d) Mann, G.; Hartwig, J.
F. Tetrahedron Lett. 1997, 38, 8005. (e) Mann, G.; Incarvito, C.; Rheingold,
A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224. (f) Aranyos, A.;
Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 4369. (g) Watanabe, M.; Nishiyama, M.; Koie,
Y. Tetrahedron Lett. 1999, 40, 8837. (h) Shelby, Q.; Kataoka, N.; Mann,
G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718. (i) Parrish, C. A.;
Buchwald, S. L. J. Org. Chem. 2001, 66, 2498.
(7) (a) Zhu, J.; Price, B. A.; Zhao, S. X.; Skonezny, P. M. Tetrahedron
Lett. 2000, 41, 4011. (b) Aalten, H. L.; van Koten, G.; Grove, D. M.;
Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron
1989, 45, 5556. (c) Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc. C 1969,
312. (d) Castro, C. E.; Havlin, R.; Honwad, V. K.; Malte, A.; Moje, S. J.
Am. Chem. Soc. 1969, 91, 6464.
(9) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333.
(10) Torraca, K. E.; Kuwabe, S.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 12907.
10.1021/ja012046d CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/08/2001

Intramolecular C-O Bond Formation
J. Am. Chem. Soc., Vol. 123, No. 49, 2001 12203
Scheme 1
elimination of intermediate A relative to â-hydride elimination
(Scheme 1).11 We have recently shown that bulky, electron-
rich o-biaryl phosphines are effective in a variety of Pd-catalyzed
cross-coupling reactions including amine arylation,12 enolate
arylation,13 and Suzuki couplings.14 After screening these and
related ligands in the cyclization of 2-bromophenethyl alcohol,
it was found that choice of ligand is key to the formation of the
desired product in high yield.
Figure 1. Bulky dialkylphosphinobiaryl ligands.
Table 1. Ligand Effects in the Pd-Catalyzed Etherificationa
entry
L
yield (%)
The Pd complexes prepared from ligands 1 and 3 (Figure 1)
display high catalytic activity to form 5-methyl chroman with
minimal reduction (Table 1). Typically, these transformations
required 24 h for complete cyclization. It is believed that such
bulky ligands possessing the di-tert-butylphosphino moiety
facilitate reductive elimination to release the steric strain of the
palladium (II) aryl-alkoxide intermediate. Steric bulk has been
shown to accelerate reductive elimination in other processes.15
As shown in Table 2, five-, six-, and seven-membered rings
can be formed in good yield with no observed reduced byproduct
being formed using this method. Primary as well as secondary
alcohol substrates were efficiently cyclized. In general, primary
alcohols were more reactive, and the desired transformation
could be effected at slightly lower temperatures (24 h).
Substrates bearing an electron-donating methoxy group para
to the bromide are often difficult substrates for these palladium-
catalyzed reactions; however, cyclization proceeded in good
yield without formation of the reduced arene (entry 7). Both
aryl chlorides and bromides could be cyclized using the 1/Pd-
(OAc)2 catalyst system, although the reactions of aryl bromides
proceeded more rapidly and cleanly than those of the corre-
sponding aryl chlorides. Binaphthyl ligand 1 proved to be most
generally useful in these cyclizations, although, in some
instances, commercially available phosphine 4 could be used
to attain the desired products in comparable yields (entries 1,
3, 4, 7, 8). Ligand 4 proved to be ineffective in reactions
involving aryl chlorides. It should be noted that dicyclohexyl-
substituted ligand 7, one of the most useful phosphines for the
Pd-catalyzed amination, is ineffective for C-O bond forma-
tion.12
1
2
3
4
1
3
4
7
81
81
51
<5
a Reaction conditions: 2 mol % Pd(OAc)2, 2.5 mol % L, 1.5 equiv
of Cs2CO3, toluene, 70 °C, 24 h.
Table 2. Palladium-Catalyzed Synthesis of Cyclic Aryl Ethersa
a Reaction conditions: 2-3 mol % Pd(OAc)2, 1.5 equiv of Cs2CO3,
2.5-3.5 mol % 1 in toluene. Yields in parentheses were obtained using
4 and were carried out at 80 °C. b Yields refer to average isolated yields
of two separate experiments.
Application of this method for the formation of heterocycles
containing multiple heteroatoms is important because those
(11) (a) Koo, K.; Hillhouse, G. L.; Rheingold, A. L. Organometallics
1995, 14, 456. (b) Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119,
8135.
(12) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
1999, 38, 2413. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158 and references therein. (d)
Fox, J. M.; Buchwald, S. L. Unpublished results.
(13) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J.
M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897. (c) Moradi, W. A.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7996 and references therein.
(14) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 9550. (b) Yin, J.; Buchwald, S. L. J. Am. Chem
Soc. 2000, 122, 12051 and references therein.
(15) (a) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem.
Soc. 1996, 118, 3626. (b) Jones, W. D.; Kuykendall, V. L. Inorg. Chem.
1991, 30, 2615.
structures are widely found in nature and biologically active
compounds.1,2 While the construction of benzodioxanes and
benzoxazines via palladium catalysis proved successful, the
efficient coupling of these substrates proved to be highly ligand
dependent (Table 3). The use of a mild base such as Cs2CO3 in
these reactions allows for the use of an ester-containing aryl
bromide (entry 3). Notably, the presence of an unprotected
aniline NH does not inhibit the desired C-O bond formation,
and no amination side products were observed (entry 4). A
sulfur-containing substrate which would form 2,3-dihydro-
benzo[1,4]oxathiine cyclized only in trace amounts; the analo-
gous sulfoxide and sulfone were also poor substrates for this
transformation. Typically, these transformations require 21-
27 h to proceed to completion.

12204 J. Am. Chem. Soc., Vol. 123, No. 49, 2001
Kuwabe et al.
Table 5. Cyclization of Optically Active Naphthalene-Derived
Table 3. Palladium-Catalyzed Synthesis of Benzodioxanes and
Benzoxazinesa
Substratesa
ee
Pd
T (°C), yield
ee
entry (%)a precursor
L
base
t (h)
(%)
(%)b
1
96
96
96
90
90
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
5
5
1
1
2
t-BuONa 50, 48
24
39
71
82
83
2b
3c
4d
5c
Cs2CO3
K3PO4
K3PO4
K3PO4
70, 96
70, 72
50, 72
70, 72
93
99
99
a Reaction conditions: 1 mol % Pd2(dba)3, 2.5 mol % L, 1.3 equiv
of t-BuONa in toluene. b Reaction run with 1.5 equiv of Cs2CO3.
c Reaction run with 3 mol % Pd(OAc)2, 3.5 mol % L, 1.5 equiv of
K3PO4.
a Reaction Conditions: 2 mol % Pd(OAc)2, 1.5 equiv of Cs2CO3,
1.2 equiv of L, in toluene. b Yields refer to average isolated yields of
two separate experiments.
Table 6. Pd-Catalyzed Synthesis of an Optically Active
Benzoxazapinea
Table 4. Palladium-Catalyzed Synthesis of an Optically Active
Benzodioxanea
T (°C),
t (h)
yield
(%)
ee
(%)
entry
Pd precursor
L
base
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1
1
1
2
5
5
1
6
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Cs2CO3
50, 20
50, 20
70, 16
50, 16
50, 20
50, 16
70, 64
70, 64
82
94
86
95
95
58
98
80
98
99
85
94
92
2b
3b
4b
5b
6c
7d
8d
ee
Pd
T (°C), yield
ee
entry (%)a precursor
L
base
t (h)
(%)
(%)b
1c
2c
3c
4d
5d
6d
7e
96
96
96
90
90
90
90
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1
3
5
1
5
5
5
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa 50, 24
t-BuONa 50, 20
t-BuOK
Cs2CO3
70, 48
70, 48
70, 20
66
48
80
89
95
33
93
94
83
95
90
90
78e
82e
Cs2CO3
a Reaction conditions: 3 mol % Pd(OAc)2, 3.5 mol % L, 1.3 equiv
of t-BuONa in toluene. b Reaction run with 1.5 mol % Pd2(dba)3.
c Reaction run with 1.0 mol % Pd2(dba)3 and 2.5 mol % L. d Reaction
run with 1.5 equiv of Cs2CO3. e 8-14% reduced arene was observed.
50, 20
70, 40
90
a Enantiomeric excess of starting material. b Enantiomeric excess of
product. c Reaction run with 3 mol % Pd(OAc)2, 3.5 mol % L, and 1.5
equiv of Cs2CO3 in toluene. d Reaction run with 1 mol % Pd2(dba)3, 2
mol % L, and 1.3 equiv of base. e Reaction run with 1 mol % Pd2(dba)3,
2 mol % L, and 1.5 equiv of Cs2CO3.
diminished enantiomeric purity (entry 1). This problem was
alleviated by changing the Pd source to Pd2(dba)3 (entry 2).
Cyclizations that employed Cs2CO3 as base were plagued with
arene reduction as a side reaction (entries 7 and 8). A catalyst
derived from Pd2(dba)3 and ligand 5 with NaOt-Bu as base
provided the best results; the use of temperatures higher than
50 °C or catalyst loadings less than 3 mol % Pd led to the
formation of the desired product with decreased enantiomeric
excess (entries 3, 6). The racemization presumably occurs via
reversible â-hydride elimination analogous to the situation that
was observed in related Pd-catalyzed C-N bond forming
processes (Scheme 2).16
The analogous aryl chlorides were also prepared, and their
cyclization reactions were studied (Table 7). The yields were
comparable to those realized using the corresponding aryl
bromides. Partial racemization (1-10% ee), unfortunately, could
not be suppressed in the cases examined. In these reactions,
K3PO4 proved to be the base of choice; reaction times were on
the order of 40-60 h. In the case of the amine-substituted aryl
chloride (entry 5), the addition of 2,6-dimethylphenol resulted
in improved yields while preserving enantiomeric purity in the
product. At this point, the role of the phenol is unclear; the
phenol may act as a catalytic base or may also serve as a
transient ligand for palladium. Analogous additive effects have
been observed in Pd-catalyzed C-N bond-forming reactions.8a,17
We next turned our attention toward the cyclization of
optically active alcohols to the corresponding ethers to determine
whether these substrates reacted with conservation of enantio-
meric purity. As shown in Table 4, aryl bromides bearing a
secondary alcohol were cyclized without erosion of optical
purity using ligands 1 or 5. Both Pd(OAc)2 and Pd2(dba)3 were
suitable palladium sources, although Pd2(dba)3 was preferable,
particularly when NaOt-Bu was employed. Both Cs2CO3 and
NaOt-Bu could function as the bases for this transformation.
With NaOt-Bu, the reactions could be effected at a lower
temperature (Table 4).
Surprisingly, the conditions that were successful with the
2-bromophenol-derived substrates were not applicable to the
corresponding naphthalene compounds (Table 5). The combina-
tion of 5/Pd2dba3 and either Cs2CO3 or NaOt-Bu as base resulted
in low yields of the desired heterocycle (entries 1, 2). In this
case, the combination of Pd(OAc)2 and K3PO4 afforded better
results. A catalyst derived from ligand 1 yielded the cyclized
product with a slight loss of enantiomeric excess (entry 3);
however, lowering the temperature (entry 4) or using ligand 2
(entry 5) led to a suppression of racemization.
The cyclization of the analogous aniline derivatives constitutes
an efficient route to benzoxazines; our efforts to optimize such
a transformation are summarized in Table 6. Using 1/Pd(OAc)2
as the precatalyst resulted in formation of the product with
(16) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451.
(17) Harris, M. C.; Buchwald, S. L. Unpublished results.

Intramolecular C-O Bond Formation
J. Am. Chem. Soc., Vol. 123, No. 49, 2001 12205
Table 8. Pd-Catalyzed Cyclization of Functionalized Substratesa
Scheme 2
Table 7. Cyclization of Optically Active Aryl Chloridesa
entry
X
L
T (°C), t (h)
yield (%)
ee (%)
1
2
O
O
O
NCH3
NCH3
1
6
6
5
5
70, 96
50, 96
23, 96
70, 64
70, 44
92
94
88
71
95
90
92
93
98
99
3
4b
5c
a Reaction conditions: 3 mol % Pd (OAc)2, 2.5 mol % L, 1.5 equiv
of K3PO4 in toluene. b Reaction run with 5 mol % Pd(OAc)2 and 6
mol % L. c Reaction run with 5 mol % Pd(OAc)2, 6 mol % L, and 2
mol % 2,6-dimethylphenol.
a Reaction conditions: 3 mol % Pd (OAc)2, 2.5 mol % L, 1.5 equiv
of K3PO4 in toluene.
We next focused on the cyclization of aryl bromides in which
the hydroxyl-bearing chain possessed additional functional
groups (Table 8). Generally, 44-72 h was required to achieve
complete cyclization under these conditions. The presence of
ester groups was well tolerated under these reaction conditions
(entries 1, 2, 7). Additionally, 1,2-diols were cleanly converted
to the corresponding hydroxymethyl benzodioxanes without the
need to protect the primary hydroxyl group. In no case was
any of the seven-membered ring isomer observed (entries 3, 4,
5). Although 1,2-amino alcohols are poor substrates, the
corresponding amide was cyclized in good yield without loss
of optical purity (entry 6). Again, 1 is the most general ligand
for these reactions, while 4 is effective in certain cases (entries
2, 4). Remarkably, an R-hydroxy ester was efficiently cyclized
in good yield and without stereochemical erosion despite the
relative sensitivity of the product toward base-mediated epimer-
ization (entry 7). Whether the resistance of the product toward
base-mediated epimerization is due to development of allylic
strain or unwanted dipole-dipole interactions upon deprotona-
tion is unknown.
mannitol.19 These synthetic methods typically require a relatively
large number of synthetic steps, however. Alternatively, resolu-
tions of racemic 2-substituted benzodioxanes by recrystallizaton
of diastereomeric derivatives or enzymatic resolution have been
reported.20,21 These methods are unattractive because 50% of
the compound must be discarded, and additional transformations
are necessary to recycle the undesired enantiomer.
Our approach to the synthesis of benzodioxanes is relatively
straightforward. In the case of MKC-242, epoxide 10 would be
utilized as a chiral building block. This material can be easily
prepared from racemic epichlorohydrin and 2-bromophenol
using the chiral oligomeric (salen)-Co catalyst developed by
Jacobsen.22 The benzodioxane ring can then be constructed from
aryl halide 11 via a Pd-catalyzed cyclization.
Our synthesis began with the addition of sesamol to acrylo-
nitrile. Previously, a 30% yield was reported for this reaction
using Triton B as base.23 Using a catalytic amount (1 mol %)
of Cs2CO3 improved the yield dramatically, presumably because
of decreased decomposition of product 8 under these conditions.
Synthesis of MKC-242
To highlight the methodology described above, we undertook
the synthesis of MKC-242, an antidepressant developed by
Mitsubishi Chemical Co. that is currently in Phase II clinical
trials.18 The key feature of our synthesis involves the construc-
tion of the benzodioxane ring system from compound 11 via a
Pd-catalyzed cyclization (Scheme 3).
The preparation of enantiomerically pure 2-substituted ben-
zodioxanes typically involves the reaction of catechol and an
optically active tosyl ester of glycerol acetonide prepared from
(19) (a) Valoti, E.; Pallavicini, M.; Villa, L.; Pezzeta, D. J. Org. Chem.
2001, 66, 1018. (b) Nelson, W. L.; Wennerstrom, J. E. J. Med. Chem. 1977,
20, 880.
(20) Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Chiarini, A.; Gotti, R.;
Leonardi, A.; Minarini, A.; Poggesi, E.; Recanatini, M.; Rosini, M.; Tumiatti,
V.; Melchiorre, C. J. Med. Chem. 1999, 42, 4214.
(21) Mauleon, D.; Lobato, C.; Carganico, G. J. Heterocycl. Chem. 1994,
31, 57.
(22) Chiral epoxide 10 was kindly provided by Mr. Joseph M. Ready
and Professor Eric N. Jacobsen (Harvard University). See: Ready, J. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.
(23) Devakumar, C.; Saxena, V. S.; Mukerjee, S. K. Agric. Biol. Chem.
1985, 49, 725.
(18) Iwata, H.; Baba, A.; Matsuda, T.; Egawa, M.; Tobe, A.; Saito, K.
Eur. Pat. Appl. EP446921 A2, 1991.

12206 J. Am. Chem. Soc., Vol. 123, No. 49, 2001
Kuwabe et al.
Scheme 3
and practicality of the intramolecular Pd-catalyzed C-O bond
forming process in the preparation of medicinally interesting
substances.
Conclusion
We have developed a palladium-catalyzed method for the
efficient cyclization of halo alcohols. This improved catalyst
system is effective in coupling primary and secondary alcohol
substrates, and reactions involving aryl bromides bearing
stereogenic centers at the carbinol carbon can be effected without
racemization via reversible â-hydride elimination. The analogous
aryl chloride substrates can also be efficiently cyclized with
this catalyst; however, small amounts of epimerization (1-10%)
may be observed. The mild reaction conditions required for this
C-O bond-forming process allow for the presence of a variety
of functional groups including alcohols, esters, and amides. The
utility of this Pd-catalyzed etherification was highlighted as the
key step in the synthesis of antidepressant MKC-242.
a Acrylonitrile, Cs2CO3, THF. b BH3-THF, THF. c N,O-Bis(tri-
methylsilyl)acetamide, THF. d (S)-2-(2-Bromo-phenoxy) methyloxirane
(10), THF. e Ac2O, Et3N, THF. f 3 M aq NaOH, MeOH. g Pd(OAc)2,
5, K3PO4, toluene. h n-BuOH, 3 M HCl. i 1.1 M HCl-EtOH, EtOAc.
General Procedures for the Intramolecular C-O Bond
Formation
Borane reduction of nitrile 8 was carried out to afford amine 9,
General Procedure A. An oven-dried 15 mL resealable Schlenk
tube was charged with Pd(OAc)2 (3.4 mg, 15 µmol, 2 mol %), 1 (7.5
mg, 18.8 µmol, 2.5 mol %), and Cs2CO3 (365 mg, 1.12 mmol, 1.5
equiv). The Schlenk tube was evacuated and back-filled with argon
and fitted with a rubber septum. Aryl halide (0.75 mmol) and toluene
(1.5 mL) were added via syringe. The resealable Schlenk tube was
then sealed under argon and placed in a preheated oil bath until the
aryl halide had been consumed as judged by GC analysis. The reaction
mixture was cooled to room temperature, diluted with pentane (2 mL),
and filtered through a pad of Celite. The resulting solution was purified
by flash chromatography on silica gel with an eluent of 99:1 hexanes/
ethyl acetate.
General Procedure B. An oven-dried 15 mL resealable Schlenk
tube was charged with Pd(OAc)2 (3.4 mg, 15 µmol, 3 mol %), 1 (17.5
µmol, 3.5 mol %), and K3PO4 (159 mg, 0.75 mmol, 1.5 equiv). The
Schlenk tube was evacuated and back-filled with argon and fitted with
a rubber septum. Aryl halide (0.5 mmol) and toluene (1.0 mL) were
added via syringe. The Schlenk tube was then sealed with a Teflon
screwcap under argon and placed on a preheated oil bath until the aryl
halide had been consumed as judged by GC analysis. The reaction
mixture was cooled to room temperature and diluted with Et2O (5 mL).
Water (5 mL) was added, and the layers were separated. The aqueous
layer was extracted with Et2O (2 × 5 mL). The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo. The crude material was purified by silica gel chromatography.
which was utilized in the next step without further purification.24
Although there are many examples of epoxide opening
reactions with amines, an excess of amine is typically employed
to suppress amine dialkylation. Several epoxide opening reac-
tions have been reported in which a slight excess of amine was
used in the presence of Lewis acids such as MgBr2‚OEt2 or
Y(OTf)3.25,26 In these cases, sterically hindered amines, such as
tert-butylamine, or secondary amines were good substrates for
this selective transformation. However, these conditions were
unsuccessful, presumably because amine 9 is relatively unhin-
dered. Eventually, we found that by using a silyl-protected
amine, as reported by Atkins, epoxide opening could be
successfully carried out with N,O-bis(trimethylsilyl)acetamide
as the silylating reagent at room temperature in THF.27 After
treatment of the reaction mixture with acetic anhydride and
subsequent desilylation with methanolic NaOH, the desired
amide 11 was obtained in a one-pot procedure from primary
amine 9 in 84% yield (based on 10).
Palladium-catalyzed C-O bond formation of 11 was per-
formed according to our optimized conditions. Using Pd(OAc)2
and 2, desired product was isolated in 94% yield. Cyclizations
using ligands 1 and 4 were also successful, giving 90 and 83%
yields of the desired heterocycle, respectively. With all three
ligands, no diminution of optical purity relative to the substrate
was observed. Acetamide 12 was hydrolyzed with HCl in
n-BuOH (84% yield), and treatment with HCl in ethanol
afforded MKC-242. MKC-242 was synthesized from com-
mercially available starting materials such as sesamol and
acrylonitrile in ∼40% overall yield. The synthesis required nine
steps which were carried out in six reaction vessels. The
preparation of MKC-242, thus, demonstrates the potential utility
Acknowledgment. We gratefully acknowledge the National
Institutes of Health (GM 58160) for financial support of this
work. We also thank Pfizer and Merck for additional unrestricted
funds. S.K. thanks Ono Pharmaceutical Co. for support, and
K.E.T. thanks the NIH for a postdoctoral fellowship (GM
20346). We are grateful to Professor Eric N. Jacobsen and Mr.
Joseph M. Ready (Harvard University) for providing a valuable
sample of (S)-2-(2-bromophenoxy) methyloxirane (10) and for
helpful discussions. We thank Dr. Alexander Muci for assistance
in preparing this manuscript.
(24) (a) Brown, H. C.; Choi, Y. M.; Narashimhan, S. Synthesis 1981,
605. Other reducing reagents such as LiAlH4 or CoCl2-NaBH4 proved less
effective. See: (b) Nagarajan, S.; Ganem, B. J. Org. Chem. 1986, 51, 4856.
(25) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.
(26) Chini, M.; Crotti, P.; Favero, L.; Macchina, F.; Pineschi, M.
Tetrahedron Lett. 1994, 35, 433.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds (37
pages, PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) Atkins, R. K.; Frazier, J.; Moore, L. L. Tetrahedron Lett. 1986, 27,
2451.
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