Solid-phase synthesis of indolecarboxylates using palladium-catalyzed reactions

Article abstract of DOI:10.1021/jo0340307

Polymer-supported, palladium-catalyzed cyclization reactions effectively synthesized indolecarboxylates. Palladium-catalyzed carbon - carbon bond-forming reactions of immobilized enaminoesters followed by transesterification yielded indole 2- or 3-carboxylates with various functional groups on the benzene ring. Indolecarboxylates were efficiently cyclized via an intramolecular palladium-catalyzed amination reaction of immobilized N-substituted dehydrohalophenylalanines, and immobilized N-acetyl-dehydroalanines were efficiently converted into indolecarboxylates via tandem Heck-amination reactions.

Full text of DOI:10.1021/jo0340307

Solid -P h a se Syn th esis of In d oleca r boxyla tes Usin g
P a lla d iu m -Ca ta lyzed Rea ction s
Kazuo Yamazaki,*,† Yosuke Nakamura, and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Aoba-ku, Sendai 980-8578, J apan
ykondo@mail.pharm.tohoku.ac.jp; kazuo.yamazaki@ssp.co.jp
Received J anuary 9, 2003
Polymer-supported, palladium-catalyzed cyclization reactions effectively synthesized indolecar-
boxylates. Palladium-catalyzed carbon-carbon bond-forming reactions of immobilized enaminoesters
followed by transesterification yielded indole 2- or 3-carboxylates with various functional groups
on the benzene ring. Indolecarboxylates were efficiently cyclized via an intramolecular palladium-
catalyzed amination reaction of immobilized N-substituted dehydrohalophenylalanines, and
immobilized N-acetyl-dehydroalanines were efficiently converted into indolecarboxylates via tandem
Heck-amination reactions.
In tr od u ction
to improve solid-phase methodologies for synthesizing
diverse heterocyclic compounds. Therefore, we have
examined novel methods for obtaining several immobi-
lized intermediates and palladium-catalyzed cyclizations.
This paper reports the results of the solid-phase synthesis
of indoles and related heterocyclic compounds4 (Figure
1). While the manuscript was being prepared, two
alternative solid-phase syntheses of 2,3-disubstituted
indoles using a modified Madelung indole synthesis and
a modified Bischler indole synthesis have appeared in
the literature.3r,s High diversity at the C-2 or the C-3
positions can be introduced using the typical building
blocks and one of these methods.
A major aspect of solid-phase chemistry is synthesizing
heterocyclic compounds from various methods.1 In par-
ticular, low molecular weight heterocyclic compounds are
used in pharmaceutical lead compounds because they are
highly functionalizable scaffolds, and indoles have re-
ceived a lot of attention in solution- and solid-phase
chemistry.2,3 The reported solid-phase indole syntheses
can be classified into several categories by reaction type.
These methods provide indoles with a variety of substi-
tuted patterns, and indoles that have substituents at the
C-2 and C-3 positions are critical to biological activity.
Fischer indolization of immobilized ketones with phenyl-
hydrazines should ensure diversity at the C-2 and the
C-3 positions, as well as on the benzene ring. However,
this reaction has limitations: such electron-deficient
para-substituted hydrazines cannot cyclize, and meta-
substituted phenylhydrazines usually yield a mixture of
4- and 6-substituted indoles.3a In addition, under strongly
acidic conditions, an acid-stable linker3a,l is required.
Palladium-catalyzed coupling reactions have the poten-
tial to completely control the substitution position on the
benzene ring, which seems to be adequate since combi-
natorial chemistry has recently moved from using mix-
ture libraries to single compounds. Although several
solid-phase indole syntheses using palladium-catalyzed
reactions are reported, more research is expected in order
(3) (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37,
4869-4872. (b) Yun, W.; Mohan, R. Tetrahedron Lett. 1996, 37, 7189-
7192. (c) Hughes, I. Tetrahedron Lett. 1996, 37, 7595-7598. (d) Zhang,
H.-C.; Maryanoff, B. E. J . Org. Chem. 1997, 62, 1804-1809. (e)
Fagnola, H. C.; Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.;
Mongelli, N.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307-2310. (f)
Zhang, H.-C.; Brumfield, K. K.; Maryanoff, B. E. Tetrahedron Lett.
1997, 38, 2439-2442. (g) Collini, M. D.; Ellingboe, J . W. Tetrahedron
Lett. 1997, 38, 7963-7966. (h) Zhang, H.-C.; Brumfield, K. K.;
J aroskova, L.; Maryanoff, B. E. Tetrahedron Lett. 1998, 39, 4449-4452.
(i) Smith, A. L.; Stevenson, G. I.; Swain, C. J .; Castro, J . L. Tetrahedron
Lett. 1998, 39, 8317-8320. (j) Stephensen, H.; Zaragoza, F. Tetrahedron
Lett. 1999, 40, 5799-5802. (k) Ketcha, D. M.; Wilson, L. J .; Portlock,
D. E. Tetrahedron Lett. 2000, 41, 6253-6257. (l) Yang, L. Tetrahedron
Lett. 2000, 41, 6981-6984. (m) Zhang, H.-C.; Ye, H.; Moretto, A. F.;
Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89-92. (n) Zhang,
H.-C.; Ye, H.; White, K. B.; Maryanoff, B. E. Tetrahedron Lett. 2001,
42, 4751-4754. (o) Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schultz, P. G.
Org. Lett. 2001, 3, 3827-3830. (p) Macleod, C.; Hartley, R. C.;
Hamprecht, W. Org. Lett. 2002, 4, 75-78. (q) Willoughby, C. A.;
Hutchins, S. M.; Rosauer, K. G.; Dhar, M. J .; Chapman, K. T.; Chicchi,
G. G.; Sadowski, S.; Weinberg, D. H.; Patel, S.; Malkowitz, L.; Salvo,
J . D.; Pacholok, S. G.; Cheng, K. Bioorg. Med. Chem. Lett. 2002, 12,
93-96. (r) Wacker, D. A.; Kasireddy, P. Tetrahedron Lett. 2002, 43,
5189-5191. (s) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J .;
J anda, K. D. J . Comb. Chem. 2003, 5, 188-196.
* Address correspondence to this author. Fax: +81-22-217-6804.
† On leave from Central Research Laboratories, SSP Co., Ltd.,
Narita, J apan.
(1) (a) Krchnˇa´k, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61-91.
(b) Dolle, R. E. J . Comb. Chem. 2002, 4, 369-418. (c) Franze´n, R. J . J .
Comb. Chem. 2000, 2, 195-214. (d) Bunin, B. A. The Combinatorial
Index; Academic Press: San Diego, 1998. (e) Czarnik, A. W.; DeWitt,
S. H. A Practical Guide to Combinatorial Chemistry; American
Chemical Society: Washington, DC, 1997. (f) Wilson, S. R., Czarnik,
A. W., Eds. In Combinatorial Chemistry; J ohn Wiley & Sons: New
York, 1997.
(4) Portion of this work has been previously communicated: (a)
Yamazaki, K.; Kondo, Y. J . Comb. Chem. 2002, 4, 191-192. (b)
Yamazaki, K.; Kondo, Y. Chem. Commun. 2002, 210-211. (c) Yamaza-
ki, K.; Nakamura, Y.; Kondo, Y. J . Chem. Soc., Perkin Trans. 1 2002,
2137-2138.
(2) For recent review of indole synthesis, see: Gribble, G. W. J .
Chem. Soc., Perkin Trans. 1, 2000, 1045-1075 and references therein.
10.1021/jo0340307 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/01/2003
J . Org. Chem. 2003, 68, 6011-6019
6011

Yamazaki et al.
TABLE 1. Im m obilized â-(2-Ha lop h en yl)a m in o-
Su bstitu ted r,â-Un sa tu r a ted Ester s
loading
4
X
R1
R2
method
(mmol/g)
a
b
c
d
e
f
g
h
i
I
H
H
4-Me
5-CF3
H
Me
Me
Me
Me
H
H
H
H
H
A
A
A
A
B
B
B
B
B
B
0.78
0.86
0.93
0.77
0.98
1.06
0.68
0.81
0.82
0.88
Br
Br
Br
I
Br
Br
Br
Br
Br
H
4-Me
4-CF3
5-NO2
5-CF3
j
H
of 2a and 2b were determined from the yield of 3-alkyl-
3-pyrazolin-5-one, which was cleaved and isolated from
the resin by treatment with 5% hydrazine in EtOH.
Although azeotropic water had to be removed, acid-
catalyzed condensation of resin 2a with 2-iodoaniline in
benzene proceeded smoothly to yield the corresponding
immobilized enaminoester, 4a . The strong peak at 1611
cm-1, which is the absorption of the double bond in the
enaminoester, indicated the formation of resin 4a . Im-
mobilized enaminoesters, 4b-d , were obtained with
reasonable loading according to a similar procedure.
Unfortunately, a lower conversion was obtained when
resin 2b was used under acid-catalyzed conditions. The
lower conversion is probably due to the lower reactivity
of the sterically hindered carbonyl group.
F IGURE 1.
SCHEME 1a
An alternate procedure for producing the unsubstituted
enaminoesters 4e-j (R1 ) H) was investigated. Many
oxidative transformations have been achieved using a
palladium(II) catalyst in the presence of oxidizing agents
in solution.9 However, a palladium(II)-chloride-catalyzed
oxidative amination reaction between REM (regenerat-
able Michael linker) resin 310 and haloanilines has not
been reported. To prepare a halophenylamino-substituted
REM resin, initially a palladium-catalyzed oxidative
amination was performed by agitating REM resin 3, 2
equiv of 2-iodoaniline, 20 mol % PdCl2(CH3CN)2, 2 equiv
of 1,4-benzoquinone, and a large excess of LiCl in THF
at room temperature for 24 h. Resin 4e exhibited a strong
IR peak at 1623 cm-1, which is typical of enaminoesters,
but there was also a weak peak at 1723 cm-1 (REM
resin), which indicted that resin 3 was not completely
converted into 4e. When the reaction was conducted at
50 °C for 24 h, the FT-IR spectrum indicated that the
reaction went to completion. Analyzing the nitrogen on
the polymer bead gave estimations of the loading of 4a -j
(Table 1). Under these conditions, both electron-donating
and electron-withdrawing substituted anilines could be
used.
a
(a) tert-Butyl acetoacetate (10 equiv), toluene, 100 °C, 4 h; (b)
5-acyl-Meldrum’s acid adduct (5 equiv), THF, reflux, 5 h; (c)
2-haloanilines (1.5 equiv), p-TsOH (2 mol %), benzene, reflux, 4
h, Dean Stark apparatus; (d) acryloyl chloride (8.6 equiv), DIEA
(8.6 equiv), THF, rt, 5 h; (e) PdCl2(CH3CN)2 (20 mol %), 1,4-
benzoquinone (2 equiv), LiCl (20 equiv), 2-haloanilines (2.0 equiv),
THF, 50 °C, 24 h.
Resu lts a n d Discu ssion
P r ep a r a tion of Im m obilized â-(2-Ha lop h en yl)-
a m in o-Su bstitu ted r,â-Un sa tu r a ted Ester s (Sch em e
1). Previously, indole-3-carboxylates were synthesized in
solution via an intramolecular palladium-catalyzed cy-
clization of â-(2-halophenyl)amino-substituted R,â-un-
saturated esters,5 and we first applied this methodology
to solid-phase indole synthesis. In solution, the most
straightforward method for synthesizing â-enaminoesters
is to condense an amine with a â-ketoester. Immobilized
â-ketoesters 2a and 2b were prepared according to a
literature procedure.6-8 The reactions were followed by
P r ep a r a tion of Im m obilized r-(2-Ha lop h en yl)-
a m in o-Su bstitu ted r,â-Un sa tu r a ted Ester s. Acid-
catalyzed condensation was reexamined to prepare im-
mobilized R-enaminoesters (Scheme 2). Thus, condensation
of hydroxymethyl polystyrene resin with pyruvic acid was
monitoring the ketone (1717 cm-1) and ester (1742 cm-1
ATR FT-IR peaks. After washing and drying, the loading
)
(5) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
1990, 215-219.
(9) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Books; Sausalito, CA, 1999. (b)
Bozell, J . J .; Hegedus, L. S. J . Org. Chem. 1981, 46, 2561-2563. (c)
Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H. Bull. Chem. Soc.
J pn. 1986, 59, 927-928.
(10) Brown, A. R.; Rees, D. C.; Rankovic, Z.; Morphy, J . R. J . Am.
Chem. Soc. 1997, 119, 3288-3295.
(6) Tietze, L. F.; Steinmetz, A. Synlett 1996, 667-668.
(7) Tietze, L. F.; Steinmetz, A. Balkenhohl, F. Bioorg. Med. Chem.
Lett. 1997, 7, 1303.
(8) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org. Chem. 1978, 43,
2087-2088.
6012 J . Org. Chem., Vol. 68, No. 15, 2003

Solid-Phase Synthesis of Indolecarboxylates
TABLE 2. Im m obilized r-(2-Ha lop h en yl)a m in o-
Su bstitu ted r,â-Un sa tu r a ted Ester s
SCHEME 2
loading
6
X
R1
R2
(mmol/g)a
a
I
Br
I
Br
I
I
H
H
H
H
H
H
H
Ph
Ph
1.00
1.04
0.94
0.90
0.93
0.98
1.10
0.92
1.06
0.93
0.89
0.75
0.42
b
c
d
e
f
g
h
i
4-MeOC6H4
2-pyridyl
2-thienyl
cyclohexyl
n-pentyl
Ph
Ph
Ph
Ph
Ph
SCHEME 3a
I
Br
Br
Br
Br
Br
Br
4-Me
5-OMe
4-CF3
5-CF3
5-NO2
4,6-diF
j
k
l
m
Ph
a
Loading values of 6a -m were estimated by elemental analysis
of nitrogen on the polymer beads.
acetate showed characteristic absorptions at 2124 and
1702 cm-1, which indicated diazo and ester functions,
respectively. The loading of resin 8, which was estimated
by nitrogen elemental analysis of the polymer beads, was
1.1-1.2 mmol/g. On the basis of the loading of 1, the
measured values indicated a smooth and reasonable
transformation. Next, a rhodium-catalyzed insertion
reaction with haloanilines was investigated. Treating 8
with 2-iodoaniline in the presence of rhodium acetate (5
mol %) in toluene at 80 °C for 40 h yielded 9a , the N-H
insertion product. Resin 9a shows an absorption peak at
1737 cm-1. During the reaction, the characteristic diazo
absorption peak completely disappeared, which is con-
sistent with the elemental analysis of polymer 9a and
suggested a high conversion yield. A catalytic amount of
phenol was used as an additive to improve the reactivity
of 2-iodoaniline, since a previous report suggested an
additive effect of phenol12c and the rate was vastly
accelerated. However, adding phenol was not necessary
for 2-bromoaniline derivatives because the reaction was
completed within 24 h for both the electron-donating and
the electron-withdrawing groups on the benzene ring
with high loading (0.85-1.04 mmol/g). The subsequent
solid-phase Horner-Emmons reactions14,15 of 9a -g with
aromatic and aliphatic aldehydes (3 equiv) using DBU16
(3 equiv) as a base proceeded smoothly, and a broad range
of aldehydes were applicable to the reaction, as shown
in Table 2. The reaction was monitored by the dis-
appearance of the peak at 1737 cm-1 and the new
a
(a) Diethylphosphonoacetic acid (3 equiv), 2,6-dichlorobenzoyl
chloride (3 equiv), pyridine (6 equiv), DMF, rt, 16 h; (b)
p-C12H25PhSO2N3 (3 equiv), DBU (3 equiv), toluene, rt, 4 h; (c) 5
mol % Rh2(OAc)4, 2-haloanilines (5 equiv), toluene, 80 °C; (d)
R2CHO (3 equiv), DBU (3 equiv), THF, rt, 12 h.
conducted in standard DIC-coupling conditions followed
by several acid-catalyzed condensation of immobilized
R-keto-ester 5 with 2-iodoaniline. However, the reactions
were unsuccessful and only gave the starting polymer 5.
Various alternatives for preparing R-enaminoesters
were considered, and a rhodium-catalyzed N-H insertion
reaction on immobilized R-diazophosphonoacetate with
aniline, followed by the Horner-Emmons reaction, was
attempted. Recently, carbene and carbenoid species
insertion reactions have been widely used in organic
chemistry.11 Moody and co-workers reported the N-H
insertion reaction of rhodium carbenoids, which ef-
fectively functionalized amides, carbamates, and anilines.12
Although rhodium carbenoid insertion reactions are
already used to construct several heterocyclic compounds
and cyclopropane derivatives in solid-phase chemistry,13
N-H insertion reaction of R-diazophosphonoacetate on
a polymer support has not been reported. Immobilized
diethylphosphonoacetate was prepared by reaction of a
hydroxymethyl polystyrene resin with diethylphos-
phonoacetic acid according to the mixed anhydride
method14 (Scheme 3). When resin 7 was formed, the FT-
IR spectrum displayed a strong peak at 1735 cm-1. Diazo
transfer to resin 7 was achieved by treating 7 with
p-dodecylbenzenesulfonyl azide using DBU as the base
in toluene. The resulting immobilized R-diazophosphono-
absorption of 6a at 1702 cm-1
.
Solid -P h a se Syn th esis of In d oleca r boxyla tes Us-
in g P a lla d iu m -Ca ta lyzed In tr a m olecu la r Cou p lin g
(Ta ble 3). The palladium-catalyzed cyclization was
investigated using immobilized enaminoester, 4. Resin
4a was heated at 110 °C for 15 h in the presence of 15
mol % Pd(OAc)2 and triethylamine in DMF. Then trans-
esterification of the immobilized indole carboxylate using
MeONa in MeOH-THF at 60 °C resulted in a 27% yield
of methyl indole 3-carboxylate, 10a , based on the loading
of 4a after SiO2 column chromatography. Adding P(2-
Tol)3 to the reaction mixture increased the isolated yield
from 27 to 63%. For aryl-bromide substrate, 4b, Pd2(dba)3‚
(11) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(12) (a) Aller, E.; Buck, R. T.; Drysdale, M. J .; Ferris, L.; Haigh, D.;
Moody, C. J .; Pearson, N. D.; Sanghera, J . B. J . Chem. Soc., Perkin
Trans. 1 1996, 2879-2884. (b) Ferris, L.; Haigh, D.; Moody, C. J . J .
Chem. Soc., Perkin Trans. 1 1996, 2885-2888. (c) Haigh, D. Tetra-
hedron 1994, 50, 3177-3194. (d) Moody, C, J .; Ferris, L.; Haigh, D.;
Swann, E. Chem. Commun. 1997, 2391-2392.
(13) (a) Clapham, B.; Spanka, C.; J anda, K. D. Org. Lett. 2001, 3,
2173-2176. (b) Iso, Y.; Shindo, H.; Hamana, H. Tetrahedron 2000, 56,
5353-5361. (c) Gowravaram, M. R.; Gallop, M. A. Tetrahedron Lett.
1997, 38, 6973-6976. (d) Whitehouse, D. L.; Nelson, K. H.; Savinov,
S. N.; Austin, D. J . Tetrahedron Lett. 1997, 38, 7139-7142. (e) Cano,
M.; Camps, F.; J oglar, J . Tetrahedron Lett. 1998, 39, 9819-9822.
(14) Salvino, J . M.; Kiesow, T. J .; Darnbrough, S.; Labaudiniere, R.
J . Comb. Chem. 1999, 1, 134-139.
(15) Wipf, P.; Henninger, T. C. J . Org. Chem. 1997, 62, 1586-1587.
(16) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.
Mangold, R.; Meyer, R. Riedl, B. Synthesis 1992, 487.
J . Org. Chem, Vol. 68, No. 15, 2003 6013

Yamazaki et al.
TABLE 3. P a lla d iu m -Ca ta lyzed In tr a m olecu la r
Cycliza tion Rea ction s
TABLE 4. P a lla d iu m -Ca ta lyzed In tr a m olecu la r
Cycliza tion Rea ction s
Pd
catalys
purity yield
6
X
11
R1
R2
purity (%)a yield (%)b
4
X
10
R1
R2
ligand
(%)a
(%)b
a
I
Br
I
Br
I
I
a
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
Ph
Ph
70
82
52
65
55
nd
nd
88
nd
nd
nd
nd
69
48
52
40
54
31
72
60
62
a
a
b
b
c
d
e
e
f
I
I
a
a
a
a
b
c
d
d
d
e
f
H
H
H
H
Me Pd(OAc)2 none
91
90
93
92
93
93
83
87
90
nd
nd
90
82
27
63
35
53
43
32
74
78
69
57
65
39
66
b
c
d
e
f
g
h
i
Me Pd(OAc)2 P(2-Tol)3
Me Pd(OAc)2 P(2-Tol)3
Me Pd2(dba)3 P(2-Tol)3
Me Pd2(dba)3 P(2-Tol)3
4-MeOC6H4
2-pyridyl
2-thienyl
cyclohexyl
n-pentyl
Ph
Br
Br
Br
Br
I
5-Me
6-CF3 Me Pd2(dba)3 P(2-Tol)3
I
H
H
H
H
H
H
H
H
H
H
Pd2(dba)3 none
Br
Br
Br
Br
Br
Br
5-Me
I
Pd2(dba)3 P(2-Tol)3
Pd2(dba)3 P(2-Tol)3
Pd2(dba)3 P(2-Tol)3
Pd2(dba)3 P(2-Tol)3
Pd2(dba)3 P(2-Tol)3
Pd2(dba)3 P(2-Tol)3
6-OMe
5-CF3
6-CF3
6-NO2
Ph
Ph
Ph
Ph
25, 67c
56
62
60
40
Br
Br
Br
Br
Br
j
k
l
g
h
i
5-Me
5-CF3
6-NO2
6-CF3
j
k
l
g
h
m
5,7-diF Ph
j
a
Purity determined by HPLC at 254 nm of crude product.
Isolated yields (>95% pure as judged by NMR and HPLC
analysis) of 11 after SiO2 column chromatography were based on
the loading of 6a -m . c Pd2(dba)3‚CHCl3 (7.5 mol %), 30 mol %
t-Bu3PHBF4, and 3 equiv of Cy2NMe were used.
a
Purity determined by HPLC at 254 nm of crude product.
Isolated yields (>95% pure as judged by NMR and HPLC
analysis) of 10 after SiO2 column chromatography were based on
the loading of 4a -j.
b
b
TABLE 5. Rh od iu m -Ca ta lyzed In ser tion a n d
CHCl3 worked better than Pd(OAc)2. Table 3 summarizes
the optimized conditions for 4c-j. Under optimum condi-
tions, 2-unsubstituted 3-indolecarboxylates generally
produced better results than 2-methyl 3-indolecarbox-
ylates. The main reason for the lower yield of 2-methyl
3-indolecarboxylates is probably the lower stability of the
immobilized enaminoesters under the coupling condi-
tions. In a preliminary study in solution, benzyl â-(2-
iodophenyl) amino-R-methyl acrylate was completely
decomposed into 2-iodoaniline and benzyl acetoacetate
in CDCl3. However, the purity of the 2-methyl 3-indole-
carboxylates was very high (>90% by HPLC analysis).
In a similar fashion, the palladium-catalyzed reactions
for the polymers, 6a -m , also yielded the 3-substituted
indole 2-carboxylates, 11a -l, and Table 4 summarizes
the yields. After heating the p-methoxy-substituted resin
6i for 40 h, the corresponding indolecarboxylate, 11h , and
a considerable amount of uncyclized enamine were
obtained. The reaction was significantly improved by
replacing P(2-Tol)3 with t-Bu3PHBF4,17 and 11h was
obtained in 67% yield.
In tr a m olecu la r Hor n er -Em m on s Rea ction on a
P olym er Su p p or t. R-Diazophosphonates in solution are
versatile building blocks,11,12,18 and we have extended this
chemistry to include polymer-supported reactions. Treat-
ing 8 with 2-substituted anilines or 2-substituted benzoic
acid in the presence of rhodium acetate (5 mol %) in
toluene at 80 °C yielded the N-H or O-H insertion
products. The FT-IR spectrum indicated that the diazo
function was completely consumed, although using 2′-
aminobenzophenone required a longer reaction time. The
intramolecular Horner-Emmons reaction and subse-
In tr a m olecu la r Hor n er -Em m on s Rea ction sa
compd
X
R1
purity (%)b
yield (%)c
11a
11m
12a
12b
12c
N
N
COO
COO
COO
Ph
Me
Ph
Me
H
84
95
87
76
42
75
87
27
21
15
a
Reaction conditions: (a) Rh2(OAc)4 (5 mol %), toluene, 80 °C,
12-42 h; (b) DBU (5 equiv), THF, rt, 12 h; (c) MeONa (5 equiv),
MeOH, THF, rt, 8 h, for indoles; (d) DBU (3 equiv), CH2Cl2, rt, 12
b
h. (e) Et3N, MeOH, THF, 70 °C, 15 h, for isocoumarins. Purity
determined by HPLC at 254 nm of the crude product. c Isolated
yield.
quent cleavage yielded indolecarboxylates and isocou-
marins (Table 5). For the isocoumarins, after cleaving,
the reduced methylene compound from the R-diazophos-
phonate was detected in the crude product. The side
reaction caused the low yield of the O-H insertion
reaction.
In tr a m olecu la r P a lla d iu m -Ca ta lyzed Am in a tion
Rea ction on
a P olym er Su p p or t. Intramolecular
(17) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
(18) Recently, some applications for aniline insertion to indole
synthesis were reported. (a) Moody, C. J .; Swann, E. Synlett 1998, 135-
136. (b) Brown, J . A. Tetrahedron Lett. 2000, 41, 1623. (c) Nakamura,
Y.; Ukita, T. Org. Lett. 2002, 4, 2317-2320.
animation reactions have synthesized a wide variety of
nitrogen-containing heterocyclic compounds.18b,19-20 To
date, intramolecular amination in solid-phase reactions
6014 J . Org. Chem., Vol. 68, No. 15, 2003

Solid-Phase Synthesis of Indolecarboxylates
SCHEME 4a
TABLE 6. In tr a m olecu la r P a lla d iu m -Ca ta lyzed
Am in a tion of N-Cbz-Deh yd r op h en yla la n in ea
yield
solvent (%)
entry
X
“Pd”
ligand
base
1
2
Br
Br
Br
PdCl2(dppf)b none
KOAc
Cs2CO3 toluene 40
Cy2NMe toluene 98
Cy2NMe toluene
Cy2NMe DMF
DMF
0
Pd2(dba)3
Pd2(dba)3
t-Bu3Pc
a
(a) 2-Acetoamideacrylic acid (5 equiv), 40% DEAD in toluene
3
t-Bu3P
t-Bu3P
t-Bu3P
(5 equiv), PPh3 (5 equiv), THF, rt, 24 h; (b) 1-bromo-2-iodobenzene
(3 equiv), 7.5 mol % Pd2(dba)3‚CHCl3, Et3N (15 equiv), DMF, 100
°C, 24 h; (c) R2NH2 (3-10 equiv), 5-10 mol % Rh2(OAc)4, toluene,
100 °C, 7-20 h; (d) ArCHO (3 equiv), DBU (3 equiv), THF, rt,
3-12 h.
4d
5
OTf Pd2(dba)3
OTf Pd2(dba)3
OTf Pd2(dba)3
0
53
87
6e
t-Bu3PHBF4 Cy2NMe DMF
a
b
Catalyst loading was not minimized. PdCl2(dppf) (6 mol %)
and 3.3 equiv of KOAc were used at 90 °C. c Stock solution of
t-Bu3P (0.5 M) in toluene was used. Pd2(dba)3‚CHCl3 (5 mol %),
20 mol % t-Bu3P, and 1.2 equiv of base were used for entries 2-5.
could have general applications since phenolic intermedi-
ates are readily available and easily converted to aryl
triflates.24 Therefore, the amination reaction with an aryl
triflate substrate was examined.25 However, intra-
molecular amination of aryl triflate substrate, 13b, under
the same reaction conditions was unsuccessful (entry 4).
Adding LiCl and using Cs2CO3 were also ineffective, but
changing the solvent to DMF or THF improved the
results. Although the cyclization reaction was slower than
with the aryl bromide substrates, S-O cleavage of the
triflate was not observed under these reaction conditions.
On the basis of the above results, solid-phase, intra-
molecular palladium-catalyzed amination reactions were
investigated. The substrates for the amination reaction,
17a -f, were prepared by one of two methods, shown in
Scheme 4.
13b was recovered in 80% after 12 h. e Pd2(dba)3‚CHCl3 (3 mol
%), 12 mol % t-Bu3PHBF4 and 1.2 equiv of Cy2NMe were used at
100 °C for 13 h.
d
is unprecedented in the literature, although a few pal-
ladium-catalyzed amination reactions have been applied
to the solid-phase synthesis of arylamines using im-
mobilized aryl halides.21 Therefore, we applied these
methodologies to create diverse libraries using solid-
phase combinatorial approaches by examining the cy-
clization reaction on a polymer support. In solution,
Brown demonstrated that the intramolecular palladium-
catalyzed annulation of dehydrohalophenylalanine can
produce N-substituted 2-indolecarboxylate derivatives in
excellent yields.18b However, using these reported condi-
tions on a polymer support did not successfully cyclize
the aryl bromide substrates. Thus, the catalytic system
for the transformation was improved and evaluated for
general use. Phosphine ligands were screened for the
cyclization of 13a in solution, and t-Bu3P22 gave the best
results, as shown in Table 6. Other phosphine ligands
such as P(2-Tol)3, P(2-furyl)3, and 2-(di-tert-butylphos-
phino)biphenyl yielded unidentified products. Using
Cy2NMe23 instead of Cs2CO3 as a base dramatically
improved the yield, and the reaction was completed
within 15 min (entry 3). If this reaction could convert
aryl triflate substrates into indoles, then this method
In method A, a Heck reaction of immobilized N-acetyl-
dehydroalanine 1526 with 3 equiv of 1-bromo-2-iodoben-
zene was performed under the Heck coupling conditions
for the REM resin.27
In method B, a rhodium-catalyzed insertion reaction
of immobilized R-diazophosphonoacetate with benzyl-
carbamate or substituted anilines yielding the immobi-
lized N-substituted-R-phosphonylglycine, 16, which was
used in a Horner-Emmons reaction. Table 7 summarizes
the loading of 17a -f. The values indicate that the
transformation progresses smoothly and reasonably.
Palladium-catalyzed intramolecular amination was
performed using reaction conditions similar to the solu-
tion-phase procedure. Thus, immobilized N-acetyl- or
N-Cbz-dehydrobromophenylalanine, 17a -f, were heated
at 80 °C for 12 h in the presence of a palladium catalyst,
a ligand, and a base in toluene, which was followed by
the transesterification of immobilized indolecarboxylate
using MeONa in MeOH-THF. Table 8 summarizes the
(19) For recent reviews of amination reaction, see: (a) Wolfe, J . P.;
Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805-818. (b) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999,
576, 125-146. (c) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37,
2046-2067.
(20) (a) Wolfe, J . P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron
1996, 52, 7525-7546. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999,
1, 35-37. (c) Aoki, K.; Peat, A. J .; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 3068-3073. (d) Brain, C. T.; Brunton, S. A. Tetrahedron
Lett. 2002, 43, 1893-1895. (e) Deboves, H. J . C.; Hunter, C.; J ackson,
R. F. W. J . Chem. Soc., Perkin Trans. 1 2002, 733-736.
(21) (a) Ward, Y.; Farina, V. Tetrahedron Lett. 1996, 37, 6993-6996.
(b) Willoughby, C. A.; Chapman, K. T. Tetrahedron Lett. 1996, 37,
7181-7184. (c) Saha, A. K.; Liu, L.; Marichal, P.; Odds, F. Bioorg. Med.
Chem. Lett. 2000, 10, 2735-2739. (d) Saha, A. K.; Liu, L.; Simoneaux,
R. L. J . Comb. Chem. 2001, 3, 181-188.
(22) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y.
Tetrahedron Lett. 1998, 39, 2367-2370. (c) Watanabe, M.; Yamamoto,
T.; Nishiyama, M. Angew. Chem., Int. Ed. 2000, 39, 2501-2504.
(23) (a) Gu¨rtler, C.; Buchwald, S. L. Chem. Eur. J . 1999, 5, 3107-
3112. (b) Littke, A. F.; Fu, G. C. J . Am. Chem. Soc. 2001, 123, 6989.
(24) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109,
5478-5486.
(25) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1264-
1267. (b) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S.
L. J . Org. Chem. 2000, 65, 1158-1174. (c) Louie, J .; Driver, M. S.;
Hamann, B. C.; Hartwig, J . F. J . Org. Chem. 1997, 62, 1268-1273.
(26) (a) Barbaste, M.; Rolland-Fulcrand, V.; Roumestant, M.-L.;
Viallefont, P.; Martinez, J . Tetrahedron Lett. 1998, 39, 6287-6290.
(b) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J . Tetrahedron Lett.
1999, 40, 4535-4538.
(27) Kondo, Y.; Inamoto, K.; Sakamoto, T. J . Comb. Chem. 2000, 2,
232-233.
J . Org. Chem, Vol. 68, No. 15, 2003 6015

Yamazaki et al.
TABLE 7. Im m obilized r-Am in o-Su bstitu ted
r,â-Un sa tu r a ted Ester s
TABLE 9. P a lla d iu m -Ca ta lyzed Ta n d em C,N-Ar yla tion a
loading
17
X
R1
R2
(mmol/g)a
a
b
c
d
e
f
Br
Br
OTf
OTf
Br
H
H
H
OMe
H
Ac
0.51
0.79
0.90
1.13
0.84
0.79
Cbz
Cbz
Cbz
2-MeC6H4
4-CF3C6H4
Br
H
a
Loading value of 17a was determined from the yields after
cleavage using Et3N/MeOH at 50 °C. The loading values of 17b-f
were estimated by elemental analysis of nitrogen on the polymer
beads.
19
R1
R2
X
18
R1
R2
yield (%)b
a
b
c
d
e
H
H
H
Me
OMe
H
H
H
Me
H
I
Br
OTf
Br
Br
a
a
a
e
f
H
H
H
Me
OMe
H
H
H
H
Me
H
46
78
41
82
39
31
TABLE 8. In tr a m olecu la r P a lla d iu m -Ca ta lyzed
Am in a tion of Im m obilized N-Su bstitu ted
Deh yd r obr om op h en yla la n in e
b
OMe
a
A 0.5 M stock solution of t-Bu3P in toluene was used for 19a ,b,
and t-Bu3PHBF4 was used for 19c-e. DME was used for 19c.
b
Isolated yield of 18 after SiO2 column chromatography based on
the loading of 15.
addition of palladium catalyst and ligand was required.
In our approach, the initial step is Heck coupling followed
by an amination reaction to yield the indoles.
Initially, the immobilized N-acetyl-dehydroalanine, 15,
with excess 1-bromo-2-iodobenzene, 19a , resulted in a
mixture of Heck coupling compounds and a small amount
of the cyclization product, 18a . After careful optimization,
it was determined that reducing the amount of 19a
significantly improved the isolated yield of 18a , which
increased to 46%. Further optimization by replacing 19a
with 1,2-dibromobenzene, 19b, at 100 °C led to indole-
carboxylate in good yields after transesterification. A
similar result was obtained when a symmetric dibromo
derivative, 19d , was used, and additional palladium
catalyst or ligand was not required to complete the
reaction. However, a problematic result was obtained
when the asymmetrical dibromo derivative, 19e, was
used and the reaction of resin 15 with 19e yielded a
mixture of 5-methoxy-2-indolecarboxylate, 18f, and
6-methoxy-2-indolecarboxylate, 18b. The overall yield for
18b and 18f was acceptable, but the reaction was not
selective. The low selectivity for the tandem C,N-aryl-
ation of asymmetrical substrates suggests that, at this
point, this methodology may be limited to symmetric
substrates.
As an extension of the Heck reaction on the im-
mobilized dehydroalanate, the synthesis of isoquinolines29
and related compounds were examined (Table 10). The
Heck reactions of immobilized N-acetyl-dehydroalanine
with 2-bromobenzaldehyde or methyl 2-bromobenzoate
followed by a transesterification resulted in the isoquino-
line-3-carboxylates, 20 or 21, in moderate yields. Em-
ploying the above method afforded thieno[2,3-c]pyridines,
22 and 23, in moderate yields. Naphthyridine synthesis
was tried using bromopyridinecarbaldehydes under the
same reaction conditions; however, no successful result
has been obtained at this moment.
17
X
18
R1
R2
yield (%)a
a
b
c
d
e
f
Br
Br
OTf
OTf
Br
a
a
a
b
c
d
H
H
H
OMe
H
H
H
H
H
99
62
48
43
44
48
2-MeC6H4
4-CF3C6H4
Br
H
a
Isolated yield of 18a -d after SiO2 column chromatography
based on the loading of 17a -f.
yield of methyl 2-indolecarboxylates, 18a -d . Under
optimal reaction conditions, good results for aryl bromide
substrates were obtained. Aryl triflate substrates were
also used, but the reaction conditions need to be further
modified. N-Aryl indoles, 18c and 18d , were also obtained
in moderate yields.
P a lla d iu m -Ca ta lyzed Ta n d em C,N-Ar yla tion of
Im m obilized En a m in e. We investigated an indole one-
pot synthesis on a polymer support using optimal reac-
tion conditions, and the Pd2(dba)3/t-Bu3P/Cy2NMe was
quite similar to the Heck reaction reported by Fu et al.23b
(Table 9). Palladium-catalyzed one-pot syntheses with
good yields have been reported such as a palladium-
catalyzed annulation reaction between o-iodoanilines and
cyclic ketones28a and palladium-catalyzed tandem ami-
nation-Heck reactions between 1,2-dibromobenzene and
an enaminone.28b In the latter case, the initial step was
the amination reaction followed by a Heck-type cycliza-
tion to yield 2,3-disubstituted indoles, but a second
(28) For palladium-catalyzed one-pot indole syntheses in solution,
see: (a) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J . J . Org. Chem. 1997, 62, 2676-2677. (b) Edmondson, S.
D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2, 1109-1112.
(29) Most recently, similar solution-phase chemistry for isoquinoline-
3-carboxylates was reported. Chattopadhyay, S. K.; Maity, S.; Pal, B.
K.; Panja, S. Tetrahedron Lett. 2002, 43, 5079-5081.
6016 J . Org. Chem., Vol. 68, No. 15, 2003

Solid-Phase Synthesis of Indolecarboxylates
TABLE 10. Heck Rea ction of Im m obilized
Deh yd r oa la n a te 15
P r oced u r e for th e P r ep a r a tion of Im m obilized â-Keto
Ester (2a ).6 A mixture of hydroxymethyl polystyrene resin (7.5
g, 9.3 mmol), tert-butyl acetoacetate (10.8 g, 93 mmol), and
toluene (75 mL) was heated at 100 °C for 4 h. After cooling,
the resin was washed with toluene (50 mL × 3), THF (50 mL
× 5), and MeOH (50 mL × 3) and the resin was dried under
reduced pressure at 40 °C. The loading was determined from
the isolated yield of 3-methyl-3-pyrazolin-5-one cleaved from
resin by the treatment with 5% hydrazine in EtOH as 1.12
mmol/g.
Gen er a l P r oced u r e for th e P r ep a r a tion of Im m obi-
lized â-(2-H a lop h en yl)a m in o-Su b st it u t ed r,â-Un sa t u -
r a ted Ester (4). A mixture of immobilized â-keto ester 2a (1
g, 1.12 mmol), 2-haloaniline (1.5 equiv), p-toluenesulfonic acid
hydrate (2%), and benzene (10 mL) was refluxed for 4 h using
a Dean Stark apparatus. After cooling, the resin was washed
with toluene (10 mL × 3), H2O (10 mL × 3), THF (10 mL ×
3), and MeOH (10 mL × 3), and the resin was dried under
reduced pressure at 40 °C. The loading of resin 4 was
estimated by elemental analysis for nitrogen.
Gen er a l P r oced u r e for th e P r ep a r a tion of Im m obi-
lized â-(2-H a lop h en yl)a m in o-Su b st it u t ed r,â-Un sa t u -
r a ted Ester (4) fr om REM Resin . A mixture of REM resin
3 (1 g, 1.39 mmol), PdCl2(CH3CN)2, (72 mg, 0.278 mmol), LiCl
(1.18 g, 27.8 mmol), 1,4-benzoquinone (300 mg, 2.78 mmol),
and THF (10 mL) was stirred at room temperature. After 10
min, 2-haloaniline (2 equiv) was added, and then the mixture
was stirred for 24 h at 50 °C. The resin was filtered and
washed with THF (10 mL × 3), 5% NaHCO3 (10 mL × 3), H2O
(10 mL × 3), DMF (10 mL × 3), THF (5 mL × 3), and MeOH
(5 mL × 3), and the resin was dried under reduced pressure
at 40 °C. The loading of resin 4 was estimated by elemental
analysis for nitrogen.
Con clu sion s
P r ocedu r e for th e P r epar ation of Im m obilized r-Diazo-
p h osp h on oa ceta te (8). A mixture of hydroxymethyl poly-
styrene resin 1 (11 g, 13.64 mmol) and DMF (110 mL) was
stirred at room temperature. After 20 min, diethylphosphono-
acetic acid (6.58 mL, 40.93 mmol), pyridine (6.6 mL, 81.84
mmol), and 2,6-dichlorobenzoyl chloride (5.86 mL, 40.92 mmol)
were added consecutively, and then the mixture was stirred
for 15 h at room temperature. The resin was filtered and
washed with DMF (100 mL × 4), THF (100 mL × 2), CH2Cl2
(100 mL × 2), and MeOH (100 mL × 2), and the resin was
dried under reduced pressure at 40 °C to give 13.5 g of resin
7. A mixture of resin 7 (6 g, 6.06 mmol), p-dodecylbenzene-
sulfonyl azide (6.4 g, 18.18 mmol), and toluene (60 mL) was
stirred at room temperature. DBU (2.72 mL, 18.18 mmol) was
added at room temperature and the mixture continued to stir
for 4 h. The resin was filtered and washed with toluene (60
mL × 3), DMF (60 mL × 3), THF (60 mL × 3), CH2Cl2 (60 mL
× 3), and MeOH (60 mL × 3), and the resin was dried under
reduced pressure at 40 °C to give 6.1 g of resin 8. The loading
of resin 8 was estimated by elemental analysis for nitrogen
as 1.1 mmol/g (N, 3.08%).
In summary, new methods for solid-phase indole
syntheses were demonstrated. Palladium catalysts on a
solid support oxidatively formed enaminoesters. En-
aminoesters were also prepared in a solid-phase, rhodium-
catalyzed N-H insertion into immobilized carbenoids,
which were generated from the immobilized R-diazo-
phosphonoacetate followed by a Horner-Emmons reac-
tion. Intramolecular palladium-catalyzed cyclization of
the R- or â-(2-halophenyl)amino-substituted R,â-unsatu-
rated esters was effective in the solid-phase synthesis of
indole 2- and 3-carboxylates with various functional
groups on the benzene ring. Moreover, the intramolecular
palladium-catalyzed amination route was a useful strat-
egy and the palladium-catalyzed tandem C,N-arylation
also provided a new one-pot method for solid-phase indole
synthesis.
Exp er im en ta l Section
Gen er a l Com m en ts. All reactions were carried out under
an argon atmosphere. Tetrahydrofuran was distilled from
sodium benzophenone ketyl under an argon atmosphere. Other
dry solvents and reagents were purchased from commercial
sources and used without further purification. Hydroxymethyl
polystyrene resin (1% divinylbenzene) was used. Aryl triflate
substrates,24 3,4-dibromoanisole30 and 3-bromothiophene-2-
carbaldehyde31 were prepared according to a literature pro-
cedure. The overlapped quaternary carbon in 13C NMR was
confirmed by the J EOL QUAT32 method. Melting points (mp)
are uncorrected.
Gen er a l P r oced u r e for th e Rh od iu m -Ca ta lyzed In ser -
tion Rea ction . A mixture of resin 8 (1.5 g, 1.8 mmol),
2-haloaniline (5 equiv), Rh2(OAc)4 (5 mol %), and toluene (15
mL) was heated at 80 °C for 12-40 h. The resin was filtered
and washed with toluene (15 mL × 3), DMF (15 mL × 3), THF
(15 mL × 3), CH2Cl2 (15 mL × 3), and MeOH (15 mL × 3),
and the resin was dried under reduced pressure at 40 °C. The
loading of 9 was estimated by elemental analysis for nitrogen.
Gen er a l P r oced u r e for th e Hor n er -Em m on s Rea c-
tion . DBU (0.11 mL, 0.75 mmol) was added to a suspension
of resin 9 (0.25 mmol) in THF (3 mL) and the mixture agitated
for 5 min; aldehyde (3 equiv) was added and the mixture
agitated for 12 h at room temperature. The resin was washed
with THF (3 mL × 3), DMF (3 mL × 3), THF (3 mL × 3),
CH2Cl2 (3 mL × 3), and MeOH (3 mL × 3), and the resin was
dried under reduced pressure. The loading of 6 was estimated
by elemental analysis for nitrogen.
(30) Andersh, B.; Murphy, D. L.; Olson, R. J . Synth. Commun. 2000,
30, 2091-2098.
(31) Fuller, L. S.; Iddon, B.; Smith, K. A. J . Chem. Soc., Perkin
Trans. 1 1997, 3465-3470.
(32) Bendall, M. R.; Pegg, D. T.; Doddrell, D. M.; J ohns, S. R.;
Willing, R. I. J . Chem. Soc., Chem. Commun. 1982, 1138-1140.
J . Org. Chem, Vol. 68, No. 15, 2003 6017

Yamazaki et al.
P alladiu m -Catalyzed Cyclization of Resin 4 an d Cleav-
a ge fr om Resin Usin g Na OMe. A mixture of resin 4b (0.39
g, 0.33 mmol), Pd2(dba)3‚CHCl3 (23 mg, 0.025 mmol), P(o-Tol)3
(30 mg, 0.1 mmol), Et3N (0.69 mL, 4.95 mmol), and DMF (3
mL) was heated at 110 °C for 15 h. The resin was washed with
DMF (5 mL × 3), DMF/H2O 1:1 (5 mL × 3), DMF (5 mL × 3),
THF (5 mL × 3), and MeOH (5 mL × 3), and the resin was
dried under reduced pressure at 40 °C. A mixture of the above
resin and NaOMe (107 mg, 1.98 mmol) in THF (3 mL) and
MeOH (1.5 mL) was agitated at 60 °C for 12 h. The resin was
separated by filtration and washed with ethyl acetate; the
filtrate was washed with saturated aqueous NH4Cl, water, and
brine, dried over Na2SO4, and evaporated to afford the crude
product. The crude product was purified by chromatography
on silica gel using hexane/ethyl acetate (4:1) to afford 33 mg
(53%) of 10a .
3.95 (3H, s), 7.10-7.18 (1H, m), 7.29-7.40 (2H, m), 7.67 (1H,
d, J ) 8.0 Hz), 8.71 (1H, brs). 13C NMR (CDCl3) δ (ppm): 9.93
(CH3), 51.70 (CH3), 111.63 (CH), 119.95 (CH), 120.39 (C),
120.81 (CH), 123.19 (C), 125.66 (CH), 128.51 (C), 135.90 (C),
163.06 (C). IR ν (cm-1): 3308, 1676, 1254. MS m/z: 189 (M+).
HRMS: calcd for C11H11NO2, 189.0790; found, 189.0747.
Meth yl N-Ben zyloxycar bon yl-2-in dolecar boxylate (14).
To a solution of 13a (195 mg, 0.5 mmol) and Pd2(dba)3‚CHCl3
(23 mg, 0.025 mmol) in toluene (3 mL) was added 0.5 M toluene
solution of tri-tert-butylphosphine (0.2 mL, 0.1 mmol) and N,N-
dicyclohexyl-N-methylamine (0.13 mL, 0.6 mmol) at room
temperature. The whole mixture was stirred for 30 min at 80
°C and then poured into water. The organic phase was
separated, and the aqueous phase was extracted with EtOAc
(two times). The combined extracts were washed with water
(two times) and brine, dried over Na2SO4, and evaporated to
afford the crude product. The crude material was purified by
chromatography on silica gel using diethyl ether/hexane (5:1)
to afford 152 mg (98%) of 14 as a colorless viscous oil. 1H NMR
(CDCl3) δ (ppm): 3.73 (3H, s), 5.42 (2H, s), 7.14 (1H, s), 7.26-
7.46 (7H, m), 7.61 (1H, d, J ) 8.5 Hz), 8.09 (1H, d, J ) 8.5
Hz). 13C NMR (CDCl3) δ (ppm): 52.32 (CH3), 69.66 (CH2),
115.05 (CH), 115.71 (CH), 122.27 (CH), 123.66 (CH), 127.10
(CH), 127.63 (C), 128.71 (2CH), 128.77 (2CH), 128.82 (CH),
130.32 (C), 134.45 (C), 137.62 (C), 150.69 (C), 162.22 (C). IR ν
(cm-1): 1727, 1202. MS m/z: 309 (M+). HRMS: calcd for
Meth yl 2-Meth yl-3-in d oleca r boxyla te (10a ).33 Mp 164-
165 °C (diethyl ether-hexane) (lit. 162-163 °C). 1H NMR
(CDCl3) δ (ppm): 2.75 (3H, s), 3.94 (3H, s), 7.18-7.35 (3H,
m), 8.05-8.12 (1H, m), 8.36 (1H, brs). 13C NMR (CDCl3) δ
(ppm): 14.18 (CH3), 50.78 (CH3), 104.47 (C), 110.49 (CH),
121.24 (CH), 121.70 (CH), 122.35 (CH), 127.09 (C), 134.46 (C),
144.01 (C), 166.54 (C). IR ν (cm-1): 3265, 1663, 1198. MS (EI)
m/z: 189 (M+). HRMS: calcd for C11H11NO2, 189.0790; found,
189.0775.
P alladiu m -Catalyzed Cyclization of Resin 6 an d Cleav-
a ge fr om Resin Usin g Na OMe. A mixture of resin 6a (0.23
g, 0.23 mmol), Pd2(dba)3‚CHCl3 (16 mg, 0.0173 mmol), P(o-
Tol)3 (21 mg, 0.069 mmol), Et3N (0.48 mL, 3.45 mmol), and
DMF (2 mL) was heated at 110 °C for 12 h. The resin was
washed with DMF (3 mL × 3), DMF/H2O 1:1 (3 mL × 3), DMF
(3 mL × 3), THF (3 mL × 3), and MeOH (3 mL × 3), and the
resin was dried under reduced pressure at 40 °C. A mixture
of the above resin and NaOMe (75 mg, 1.38 mmol) in THF (2
mL) and MeOH (1 mL) was agitated at room temperature for
6 h. The resin was separated by filtration and washed with
ethyl acetate; the filtrate was washed with saturated aqueous
NH4Cl, water, and brine, dried over Na2SO4, and evaporated
to afford the crude product. The crude product was purified
by chromatography on silica gel using hexane/ethyl acetate
(6:1) to afford 28 mg (48%) of 11a .
C
18H15NO4, 309.1001; found, 309.1033.
Im m obilized N-Acetyl-d eh yd r oa la n in e (15).26 To a mix-
ture of hydroxymethyl polystyrene resin (4.8 g, 7 mmol),
2-acetamidoacrylic acid (4.52 g, 35 mmol), and triphenylphos-
phine (9.2 g, 35 mmol) in THF (72 mL) was added dropwise
at room temperature a 40% solution of diethyl azodicarboxylate
(16 mL, 35 mmol) in toluene. The mixture was gently stirred
for 24 h at room temperature. The resin was collected by
filtration and washed with THF (three times), CH2Cl2 (three
times), MeOH (three times), CH2Cl2 (three times), and MeOH
(three times), and the resin was dried under reduced pressure
at 40 °C. The loading was determined from the isolated yield
of methyl 2-acetamidoacrylate cleaved from the resin by the
treatment with 10% triethylamine in MeOH at 50 °C for 8 h
as 0.95 mmol/g. IR ν (cm-1): 3398, 1717, 1696.
Meth yl 3-P h en yl-2-in d oleca r boxyla te (11a ).34 Mp 137-
Meth yl 2-Aceta m id oa cr yla te.36 Mp 47-49 °C (lit. 49-51
1
139 °C (MeOH) (lit. 138-139 °C). H NMR (CDCl3) δ (ppm):
1
°C). H NMR (CDCl3) δ (ppm): 2.13 (3H, s), 3.85 (3H, s), 5.88
3.82 (3H, s), 7.12-7.19 (1H, m), 7.33-7.50 (5H, m), 7.54-7.59
(2H, m), 7.64 (1H, d, J ) 8.3 Hz), 9.00 (1H, brs). 13C NMR
(CDCl3) δ (ppm): 51.81 (CH3), 111.70 (CH), 120.94 (CH),
121.82 (CH), 122.38 (C), 124.43 (C), 125.93 (CH), 127.28 (CH),
127.89 (2CH, C), 130.56 (2CH), 133.37 (C), 135.73 (C), 162.40
(C). IR ν (cm-1): 3323, 1669, 1251. MS m/z: 251 (M+). HRMS:
calcd for C16H13NO2, 251.0946; found, 251.0966. Anal. Calcd
for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.37; H,
5.37; N, 5.64.
(1H, s), 6.60 (1H, s), 7.73 (1H, brs), 7.95 (1H, s), 8.00 (1H, d,
J ) 8.0 Hz). IR ν (cm-1): 3361, 1706, 1673, 1507. MS m/z: 143
(M+). HRMS: calcd for C6H9NO3, 143.0582; found, 143.0544.
Im m obilized r-Aceta m id o-â-(2-br om op h en yl)-a cr yla te
(17a ). To a mixture of immobilized 2-acetamidoacrylate 15 (2
g, 1.9 mmol), Pd2(dba)3‚CHCl3 (130 mg, 0.14 mmol), and
triethylamine (4 mL, 28.5 mmol) in DMF (18 mL) was added
1-bromo-2-iodobenzene (0.74 mL, 5.7 mmol) at room temper-
ature. The whole mixture was gently stirred for 24 h at 100
°C. The resin was collected by filtration and washed with DMF
(three times), DMF/H2O 1:1 (three times), THF (three times),
and MeOH (three times), and the resin was dried under
reduced pressure at 40 °C. The loading was determined from
the isolated yield of methyl-R-acetamido-â-(2-bromophenyl)-
acrylate cleaved from the resin by the treatment with 10%
triethylamine in MeOH at 50 °C for 12 h as 0.51 mmol/g. IR
ν (cm-1): 3024, 2921, 1700, 1684, 1239.
Meth yl r-Aceta m id o-â-(2-br om op h en yl)-a cr yla te.37 Mp
138-139 °C (diethyl ether) (lit. 142-144 °C). 1H NMR (CDCl3)
δ (ppm): 2.04 (3H, brs), 3.88 (3H, s), 7.02 (1H, brs), 7.18-
7.44 (4H, m), 7.62 (1H, d, J ) 8.0 Hz). IR ν (cm-1): 3147, 3000,
1719, 1654. MS m/z: 297 (M+). HRMS: calcd for C12H12BrNO3,
297.0001; found, 296.9959.
In tr a m olecu la r Hor n er -Em m on s Rea ction . DBU (0.22
mL, 1.47 mmol) was added to a suspension of resin 12b (525
mg, 0.49 mmol) in THF (5 mL), and the mixture was agitated
for 12 h at room temperature. The resin was washed with THF
(5 mL × 3), DMF (5 mL × 3), THF (5 mL × 3), CH2Cl2 (5 mL
× 3), and MeOH (5 mL × 3), and the resin was dried under
reduced pressure. A mixture of the above resin and NaOMe
(159 mg, 2.94 mmol) in THF (4 mL) and MeOH (2 mL) was
agitated at room temperature for 8 h. The resin was separated
by filtration and washed with ethyl acetate; filtrate was
washed with saturated aqueous NH4Cl, water, and brine, dried
over Na2SO4, and evaporated to afford the crude product. The
crude product was purified by chromatography on silica gel
using hexane/ethyl acetate (4:1) to afford 81 mg (87%) of
methyl 3-methyl-2-indolecarboxylate35 11m . Mp 147-148 °C
1
(MeOH) (lit. 148 °C). H NMR (CDCl3) δ (ppm): 2.61 (3H, s),
(36) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.;
Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm.
Bull. 1994, 42, 832-838.
(37) Wagaw. S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 8451-8458.
(33) Kaneko, C.; Naito, T.; Hashiba, M.; Fujii, H.; Somei, M. Chem.
Pharm. Bull. 1979, 27, 1813-1819.
(34) Sohda, T.; Yamazaki, I.; Kawamura, N. EP 449196, 1991.
(35) Elvidge, J . A.; Spring, F. S. J . Chem. Soc. 1949, S135-140.
6018 J . Org. Chem., Vol. 68, No. 15, 2003

Solid-Phase Synthesis of Indolecarboxylates
Im m obilized r-N-Cbz-â-(2-br om op h en yl)-a cr yla te 17b.
A mixture of immobilized R-diazophosphonoacetate 8 (1.0 g,
1.1 mmol), benzyl carbamate (831 mg, 5.5 mmol), Rh2(OAc)4
(23 mg, 0.055 mmol), and toluene (10 mL) was heated at 100
°C for 7 h. The resin was collected by filtration and washed
with toluene (three times), DMF (three times), THF (three
times), CH2Cl2 (three times), and MeOH (three times) and the
resin was dried under reduced pressure at 40 °C. The loading
of 16 was estimated by elemental analysis for nitrogen as 0.87
mmol/g (N, 1.22%).
DBU (0.49 mL, 3.3 mmol) was added to the above resin 16
in THF (10 mL), and the mixture was agitated for 5 min. Then,
2-bromobenzaldehyde (0.39 mL, 3.3 mmol) was added, and the
mixture was again agitated for 12 h at room temperature. The
resin was collected by filtration and washed with THF (three
times), DMF (three times), THF (three times), CH2Cl2 (three
times), and MeOH (three times), and the resin was dried under
reduced pressure at 40 °C. The loading of 17b was estimated
by elemental analysis for nitrogen as 0.79 mmol/g (N, 1.1%).
IR ν (cm-1): 3021, 2919, 1719.
mL) and MeOH (1.5 mL) was agitated at room temperature
for 16 h. The resin was separated by filtration and washed
with ethyl acetate; the filtrate was washed with saturated
aqueous NH4Cl, water, and brine, dried over Na2SO4, and
evaporated to afford the crude product. The crude product was
purified by chromatography on silica gel using hexane/ethyl
acetate (4:1) to afford 39 mg (78%) of 18a as a colorless solid.
Meth yl 3-Isoqu in olin eca r boxyla te (20).39 A mixture of
resin 15 (500 mg, 0.475 mmol), 2-bromobenzaldehyde (0.17
mL, 1.425 mmol), Pd2(dba)3‚CHCl3 (33 mg, 0.036 mmol), tri-
tert-butylphosphonium tetrafluoroborate (41 mg, 0.143 mmol),
and N,N-dicyclohexyl-N-methylamine (0.31 mL, 1.43 mmol)
in toluene (4 mL) was heated at 100 °C for 18 h. The resin
was collected by filtration and washed with DMF (three times),
DMF/H2O 1:1 (three times), DMF (three times), THF (three
times), and MeOH (three times), and the resin was dried under
reduced pressure at 40 °C. A mixture of the above resin and
NaOMe (26 mg, 0.475 mmol) in THF (4 mL) and MeOH (2
mL) was agitated at room temperature for 7 h. The resin was
separated by filtration and washed with ethyl acetate, and the
filtrate was washed with saturated aqueous NH4Cl, water, and
brine, dried over Na2SO4, and evaporated to afford the crude
product. The crude product was purified by chromatography
on silica gel using hexane/ethyl acetate (1:1) to afford 50 mg
(56%) of 20 as a colorless solid. Mp 77-79 °C (diethyl ether-
Meth yl 2-In d oleca r boxyla te 18a Usin g Resin 17a .38 To
a mixture of resin 17a (400 mg, 0.2 mmol), Pd2(dba)3‚CHCl3
(19 mg, 0.02 mmol), and N,N-dicyclohexyl-N-methylamine
(0.13 mL, 0.6 mmol) in toluene (4 mL) was added 0.5 M toluene
solution of tri-tert-butylphosphine (0.16 mL, 0.08 mmol), and
the mixture was then heated at 80 °C for 12 h. The resin was
collected by filtration and washed with DMF (three times),
DMF/H2O 1:1 (three times), DMF (three times), THF (three
times), and MeOH (three times), and the resin was dried under
reduced pressure at 40 °C. A mixture of the above resin and
NaOMe (11 mg, 0.2 mmol) in THF (4 mL) and MeOH (2 mL)
was agitated at room temperature for 12 h. The resin was
separated by filtration and washed with ethyl acetate, and the
filtrate was washed with saturated aqueous NH4Cl, water, and
brine, dried over Na2SO4, and evaporated to afford the crude
product. The crude product was purified by chromatography
on silica gel using hexane/ethyl acetate (4:1) to afford 36 mg
(99%) of 18a as a colorless solid. Mp 150-151 °C (ethyl
1
hexane) (lit. 70-71 °C). H NMR (CDCl3) δ (ppm): 4.08 (3H,
s), 7.73-7.85 (2H, m), 7.99 (1H, d, J ) 7.7 Hz), 8.08 (1H, d, J
) 7.7 Hz), 8.62 (1H, s), 9.35 (1H, s). IR ν (cm-1): 1723, 1437,
1291, 1094. MS m/z: 187 (M+). HRMS: calcd for C11H9NO2,
187.0633; found, 187.0592.
Meth yl 3-Isoqu in olon eca r boxyla te40 (21). A mixture of
resin 15 (500 mg, 0.475 mmol), methyl 2-bromobenzoate (1.425
mmol), Pd2(dba)3‚CHCl3 (33 mg, 0.036 mmol), tri-tert-butyl-
phosphonium tetrafluoroborate (41 mg, 0.143 mmol), and N,N-
dicyclohexyl- N-methylamine (0.31 mL, 1.425 mmol) in toluene
(4 mL) was heated at 100 °C for 24 h. The resin was collected
by filtration and washed with DMF (three times), DMF/H2O
1:1 (three times), DMF (three times), THF (three times), and
MeOH (three times), and the resin was dried under reduced
pressure at 40 °C. A mixture of the above resin and NaOMe
(26 mg, 0.475 mmol) in THF (4 mL) and MeOH (2 mL) was
agitated at room temperature for 6 h. The resin was separated
by filtration and washed with ethyl acetate, and the filtrate
was washed with saturated aqueous NH4Cl, water, and brine,
dried over Na2SO4, and evaporated to afford the crude product.
The crude product was purified by chromatography on silica
gel using hexane/ethyl acetate (1:1) to afford 58 mg (60%) of
21 as a colorless solid. Mp 160-162 °C (ethyl acetate-hexane)
(lit. 158-159.5 °C). 1H NMR (CDCl3) δ (ppm): 4.00 (3H, s),
7.38 (1H, s), 7.61-7.77 (3H, m), 8.47 (1H, d, J ) 8.0 Hz), 9.17
(1H, brs). IR ν (cm-1): 3166, 3056, 2954, 1725, 1656. MS m/z:
203 (M+). HRMS: calcd for C11H9O3N, 203.0582; found,
203.0607.
1
acetate-hexane) (lit. 148-150 °C). H NMR (CDCl3) δ (ppm):
3.95 (3H, s), 7.14-7.45 (4H, m), 7.70 (1H, d, J ) 8.0 Hz), 8.89
(1H, brs). IR ν (cm-1): 3330, 1696, 1684. MS m/z: 175 (M+).
HRMS: calcd for C10H9NO2, 175.0633; found, 175.0609.
Meth yl 2-In d oleca r boxyla te 18a Usin g Resin 17c. To
a mixture of resin 17c (300 mg, 0.27 mmol), Pd2(dba)3‚CHCl3
(51 mg, 0.055 mmol), tri-tert-butylphosphonium tetrafluoro-
borate (64 mg, 0.22 mmol), and N,N-dicyclohexyl-N-methyl-
amine (0.24 mL, 1.1 mmol) in DME (2.8 mL) was heated at
100 °C for 38 h. The resin was collected by filtration and
washed with DMF (three times), DMF/H2O 1:1 (three times),
DMF (three times), THF (three times), and MeOH (three
times), and the resin was dried under reduced pressure at 40
°C. A mixture of the above resin and NaOMe (30 mg, 0.55
mmol) in THF (4 mL) and MeOH (2 mL) was agitated at room
temperature for 12 h. The resin was separated by filtration
and washed with ethyl acetate, and the filtrate was washed
with saturated aqueous NH4Cl, water, and brine, dried over
Na2SO4, and evaporated to afford the crude product. The crude
product was purified by chromatography on silica gel using
hexane/ethyl acetate (4:1) to afford 20 mg (48%) of 18a as a
colorless solid.
Ta n d em P r oced u r e for Meth yl 2-In d oleca r boxyla te
18a on a P olym er Su p p or t. To a mixture of resin 15 (300
mg, 0.285 mmol), 1,2-dibromobenzene (0.051 mL, 0.428 mmol),
Pd2(dba)3‚CHCl3 (39 mg, 0.043 mmol), and N,N-dicyclohexyl-
N-methylamine (0.18 mL, 0.855 mmol) in toluene (3 mL) was
added 0.5 M toluene solution of tri-tert-butylphosphine (0.34
mL, 0.17 mmol), and the mixture was then heated at 100 °C
for 24 h. The resin was collected by filtration and washed with
DMF (three times), DMF/H2O 1:1 (three times), DMF (three
times), THF (three times), and MeOH (three times), and the
resin was dried under reduced pressure at 40 °C. A mixture
of the above resin and NaOMe (15 mg, 0.285 mmol) in THF (3
Ack n ow led gm en t. This work was partly supported
by the Grant-in Aid for Scientific Research (No.
12557198) from the Ministry of Education, Science,
Sports and Culture, J apan. We thank Mr. Kinichi Mogi
of Central Research Laboratories at SSP Co., Ltd., for
detailed 13C and 19F NMR measurements.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0340307
(38) Hamel, P.; Zajact, N.; Atkinson, J . G.; Girard, Y. Tetrahedron
Lett. 1993, 34, 2059-2062.
(39) Cain, M.; Weber, R. W.; Guzman, F.; Cook, J . M.; Barker, S.
A.; Rice, K. C.; Crawley, J . N.; Paul, S. M.; Skolnick, P. J . Med. Chem.
1982, 25, 1081-1091.
(40) Nunami, K.; Suzuki, M.; Yoneda, N. J . Org. Chem. 1979, 44,
1887-1888.
J . Org. Chem, Vol. 68, No. 15, 2003 6019