Catalytic direct acetoxylation of indoles

Article abstract of DOI:10.1021/jo901321b

(Chemical Equation Presented) 3-Acetoxyindole-2-carboxylates could be readily synthesized in a Pd(OAc)₂- or PtCl₂-catalyzed direct C-3 acetoxylation of indole-2-carboxylates using PhI(OAc)₂ as a terminal oxidant.

Full text of DOI:10.1021/jo901321b

pubs.acs.org/joc
from 3-bromoindoles by a lithiation-boronation-oxidation
Catalytic Direct Acetoxylation of Indoles
reaction sequence (route B)4,5 or from 3-formylindole-2-car-
boxylates by a Baeyer-Villiger oxidation (route C).6 Recently,
a Pd-catalyzed alkoxylation of 3-bromoindoles has also been
reported.1b In all cases, the syntheses are multiple-step pro-
cesses and require suitably substituted starting materials.
Another efficient approach to 3-hydroxy- and 3-alkoxyin-
dole-2-carboxylates makes use of a Rh(II)-catalyzed inser-
tion of 3-diazoindole into OH and OR bonds.7 However,
this method is restricted to N-unsubstituted indole-2-carboxy-
lates. Furthermore, the poor stability of diazoindoles com-
promises the utility of this transformation. Finally, 3-acyloxy-
indole-2-carboxylic acid esters could also be accessed in
poor yields (<30%) from the corresponding 1-hydroxyin-
doles.8
Ilga Mutule,† Edgars Suna,*,† Kristofer Olofsson,‡,§ and
Benjamin Pelcman‡
†Latvian Institute of Organic Synthesis, Aizkraukles 21,
LV-1006, Riga, Latvia, and ‡Orexo AB, Box 303, SE-751 05,
Uppsala, Sweden. §Present address: Medical Products
Agency, Box 26, SE-751 03 Uppsala, Sweden.
edgars@osi.lv
Received June 20, 2009
3-Acetoxyindole-2-carboxylates could be readily synthe-
sized in a Pd(OAc)2- or PtCl2-catalyzed direct C-3 acet-
oxylation of indole-2-carboxylates using PhI(OAc)2 as a
terminal oxidant.
FIGURE 1. Synthetic approaches toward 3-hydroxyindole-2-car-
boxylates.
Substituted 3-oxyindoles are common scaffolds in medicinal
chemistry. Thus, 3-aryloxy- and 3-alkoxyindoles have been
employed in the development of COX-2 inhibitors,1a used as
Mcl-1 inhibitors in the design of novel antitumor agents1b and
synthesized for the treatment of respiratory disorders.1c,d Spe-
cifically, 3-hydroxyindole-2-carboxylates have been used as
key synthetic building blocks in the development of potent
PPARγ (peroxisome proliferator-activated receptor γ) modu-
lators.2
3-Hydroxyindole-2-carboxylic acid esters are traditionally
synthesized by Dieckmann cyclization of N-substituted an-
thranilic esters (Figure 1, route A).3 However, this approach
suffers from moderate yields and is limited by the lack of
availability of properly substituted anthranilates. Alterna-
tively, 3-alkoxyindole-2-carboxylic esters have been prepared
The most straightforward access to 3-hydroxyindole-2-car-
boxylates is a direct regioselective oxidation of the heterocycle.
Notably, there are only scattered reports on the C-3 oxidation
of the indole nucleus, and only a few of them provided 3-
hydroxyindoles in synthetically useful yields. Thus, oxidation
of ethyl N-methylindole-2-carboxylate with Pb(OAc)4 furn-
ished the corresponding 3-acetoxy derivative in 25% yield,
while the N-unsubstituted analogue gave a dimer under the
reaction conditions.9 The use of benzoyl peroxide as an
oxidant afforded N-methyl-3-benzyloxyindoles in moderate
50-56% yield.10 Alternatively, Mg monoperoxyphthalate
was employed in the oxidation of N-phenylsulfonylindole to
the corresponding indol-3-one (60% yield, single example).5
N-Substituted 3-acyloxyindoles were also formed as minor
(1) (a) Campbell, J. A.; Bordunov, V.; Broka, C. A.; Browner, M. F.;
Kress, J. M.; Mirzadegan, T.; Ramesha, C.; Sanpablo, B. F.; Stabler, R.;
Takahara, P.; Villasenor, A.; Walker, K. A. M.; Wang, J.-H.; Welch, M.;
Weller, P. Bioorg. Med. Chem. Lett. 2004, 14, 4741. (b) Bruncko, M.; Song, X.;
Ding, H.; Tao, Z.; Kunzer, A. R. WO 130970 A1, 2008; Chem. Abstr. 2008, 149,
493528. (c) Modulators of CRTh2: Bonnert, R. V.; Cook, A. R.; Luker, T. J.;
Mohammed, R. T.; Thom, S. WO 019171 A1, 2005; Chem. Abstr. 2005, 142,
280051. (d) MCP-1 antagonists: Kettle, J. G.; Faull, A. W. U.S. Patent 6,833,387
2004; Chem. Abstr. 2000, 133, 150463.
(4) Unangst, P. C.; Connor, D. T.; Miller, S. R. J. Heterocycl. Chem.
1996, 33, 1627.
(5) Gribble, G. W.; Conway, S. C. Heterocycles 1990, 30, 627.
(6) (a) Hickman, Z. L.; Sturino, C. F.; Lachance, N. Tetrahedron Lett.
2000, 41, 8217. (b) Bourlot, A. S.; Desarbre, E.; Merour, J.-Y. Synthesis 1994,
411.
(7) Kettle, J. G.; Faull, A. W.; Fillery, S. M.; Flynn, A. P.; Hoyle, M. A.;
Hudson, A. P. Tetrahedron Lett. 2000, 41, 6905.
(8) (a) Nagayoshi, T.; Saeki, S.; Hamana, M. Chem. Pharm. Bull. 1984,
32, 3678. (b) Somei, M. Heterocycles 1999, 50, 1157.
(9) Sukari, M. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1983,
2219.
(2) (a) Dropinski, J. F.; Akiyama, T.; Einstein, M.; Habulihaz, B.;
Doebber, T.; Berger, J. P.; Meinke, P. T.; Shi, G. Q. Bioorg. Med. Chem.
Lett. 2005, 15, 5035.
(3) Unangst, P. C.; Connor, D. T.; Stabler, S. R.; Weikert, R. J.
J. Heterocycl. Chem. 1987, 24, 811.
(10) (a) Kanaoka, Y.; Aiura, M.; Hariya, S. J. Org. Chem. 1971, 36, 458.
(b) Colonna, M.; Greci, L.; Poloni, M. Tetrahedron Lett. 1981, 22, 1143.
DOI: 10.1021/jo901321b
r
Published on Web 08/18/2009
J. Org. Chem. 2009, 74, 7195–7198 7195
2009 American Chemical Society

Mutule et al.
JOCNote
products in the synthesis of 2,3-diacetyloxyindoles by oxida-
tion of indoles in carboxylic acid media with N-iodosuccini-
mide.11 Clearly, an improved method for the direct regio-
selective oxidation of indoles would be of value.
TABLE 1. Evaluation of the Acetoxylation Conditionsa
We envisaged that the most suitable way toward 3-oxyin-
doles would be a Pd(II)-catalyzed C-H activation-oxidation
strategy. This concept was pioneered by Henry12 and
Eberson13 in the early 1970s and later developed by Sanford14
into a regioselective heteroatom-directed acetoxylation of
arenes. This synthetic approach is based on an electrophilic
metalation of an arene with a Pd(II) species, oxidation of the
resulting σ-aryl-Pd(II) intermediate, and reductive elimina-
tion of an acetyloxyarene from the Pd(IV) complex.15 Indoles,
owing to their electron-rich character, readily undergo
metalation with electrophilic transition-metal salts,16 usually
Pd(II) complexes, affording C-3-17 or C-2-cyclopalladated18
intermediates. It has been suggested that the C-3 position
is the preferred site for electrophilic palladation and that
the isomeric C-2 palladium complexes form by a 1,2-migra-
tion of Pd(II) species.19 The formation of the C-2 indo-
lyl-Pd species is not possible in the case of N-substituted
indole-2-carboxylates. However, electron-withdrawing C-2
ester moieties may decrease the electrophilicity of the C-3
position, rendering the indole less reactive toward palla-
dation.19a
N-Methyl-5-bromoindole-2-carboxylic acid ester 1a was
chosen to test the feasibility of the C-H activation-oxida-
tion in indoles using Pd(II) salts. We were delighted to find
that the acetoxylated product 2a was readily formed in 75%
yield (Table 1, entry 1) under the conditions developed by
Crabtree.20
In the absence of Pd(OAc)2, acetoxyindole 2a was formed
in negligible amounts (<5%) (Table 1, entry 2) ruling out the
scenario of direct C-3 oxidation of indole by PhI(OAc)2.21
Notably, PtCl2 turned out to be a superior catalyst to
Pd(OAc)2 as 3-acetoxyindole 2a was formed in 91%
yield (entry 4). However, the product 2a, was contaminated
GC yieldb (%)
1a 2a
entry catalyst (mol %)
oxidant (equiv)
PhI(OAc)2 (1.3)
PhI(OAc)2 (1.3)
PhI(OAc)2 (1.3)
PhI(OAc)2 (1.3)
PhI(OAc)2 (1.3)
K2S2O8 (2.0)
Oxone (1.0)
m-CPBA (2.0)
t-BuOOH (2.0)
Cu(OAc)2 (2.0)
Mg peroxyphthalate (2.0)
1
2
3
Pd(OAc)2 (5)
none
PdCl2 (5)
9
75
95
23
<1
20
99
<1
57
<5
59c
91c
30d
0
4
PtCl2 (5)
5
6
7
8
9
10
11
Pt(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
5d
0
77
99
20
0
0
18d
aReactions were run in a sealed vessel single-mode microwave reactor
using 0.5 mmol of indole 1a in 2.0 mL of AcOH. bCalibrated GC yields
(C11H24 as an internal standard). cAccompanied with ∼5% of 3-chloro-
2a. dAccompanied by a mixture of unidentified oxidation products.
with the corresponding 3-Cl-2a (<5% GC yield). Evidently,
the C-Cl bond was formed in a competing (Cl vs OAc)
product-forming reductive elimination from a Pt(III) {or
23
Pt(IV)} complex.22 Surprisingly, Pt(OAc)2 was consi-
derably less efficient than PtCl2 (entry 5 vs entry 4). Thus,
indole 2a was formed in only 30% yield (entry 5) together
with large amounts (ca. 50%) of unidentified side pro-
ducts. In contrast, PdCl2 was inferior to Pd(OAc)2 (entry 3
vs entry 1).
Various alternative oxidants were also examined.24 K2S2-
O8, m-CPBA, t-BuOOH, and Cu(OAc)2 were totally ineffi-
cient (0% conversion; entries 6, 8-10), while the use of
Oxone resulted in an inseparable mixture of oxidation
products (entry 7). High conversion (80%) was observed in
the case of Mg peroxyphthalate (entry 11), but the desired 2a
was formed in poor yield (18%).
The optimal conditions from entry 1 and entry 4 (Table 1)
were subsequently employed to test the scope of the method
(see Table 2). Although microwave dielectric heating was
employed during evaluation of the acetoxylation conditions,
the conventional oil bath heating afforded the acetoxylated
indoles 2 in comparable yields (entries 2, 3, 5, 17, and 21,
Table 2). Consequently, both heating modes could be used
with comparable efficiency.
(11) Kwon, S.; Kuroki, N. Chem. Lett. 1980, 237.
(12) Henri, P. M. J. Org. Chem. 1971, 36, 1886.
(13) Eberson, L.; Gomez-Gonzales, L. Chem. Comm. 1971, 263.
(14) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300. (b) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149.
(15) Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142.
(16) Selected reviews on a direct functionalization of heterocycles:
(a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (b) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(17) Selected examples of electrophilic C-3 metalation of indoles with
Pd(II) complexes: (a) Itahara, T.; Kawasaki, K.; Ouseto, F. Synthesis 1983,
236. (b) Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc., Perkin Trans. 1
1983, 1361. (c) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1,
2097. (d) Ma, S.; Yu, S. Tetrahedron Lett. 2004, 45, 8419. (e) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005,
44, 3125. (f) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (g) Zhang, Z.;
Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48,
2415. (h) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529.
(18) Selected examples of electrophilic C-2 metalation of indoles with
Pd(II) complexes: (a) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
(b) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 4972. (c) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem.
Soc. 2007, 129, 12072. (d) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem.
2007, 72, 1476. (e) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130,
2926.
The Pd(II)-catalyzed oxidation was found to be sensi-
tive to the electronic nature of the substituents on both
the pyrrole and the benzene rings of the indole hetero-
cycle. Thus, electron-releasing substituents on the indole
benzene ring facilitated the oxidation (entries 5-6, Table 2),
presumably by increasing the electrophilicity of the C-3
(22) Dimeric Pt(III)-Pt(III) complexes form upon oxidation of Pt(II)
complex by PhI(OAc)2 in AcOH; in alcoholic solvents, however, monomeric
Pt(IV) complexes dominate: Dick, A. R.; Kampf, J. W.; Sanford, M. S.
Organometallics 2005, 24, 482.
(23) Prepared from PtCl2 and AgOAc as described in: Basato, M.; Biffis,
A.; Martinati, G.; Tubaro, C.; Venzo, A.; Ganis, P.; Benetollo, F. Inorg.
Chim. Acta 2003, 355, 399.
(19) (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (b) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854.
(c) Reference 17e.
(20) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996, 108, 35.
(21) Phenyliodine(III) bis-trifluoroacetate (PIFA) has been employed for
direct 3-arylthiolation of 2-substituted indoles: Campbell, J. A.; Broka, C. A.
Gong, L.; Walker, K. A. M.; Wang, J.-H. Tetrahedron Lett. 2004, 45, 4073.
(24) Desai, L. V.; Malik, H. A.; D.; Sanford, M. S. Org. Lett. 2006, 8,
1141.
7196 J. Org. Chem. Vol. 74, No. 18, 2009

Mutule et al.
JOCNote
TABLE 2. Scope of the Direct 3-Acetoxylation of Indoles
entry
indole 1
R1
R2
R3
catalysta
PhI(OAc)2 (equiv)
time (h)
conv (%)
yield of 2b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
CO2Et
Me
Me
5-Br
A
B
A
B
1.3
1.3
2.0
1.3
1.3
1.3
2.0
2.5
2.5
1.5
1.3
2.0
1.3
2.5
2.0
1.3
1.3
1.3
1.3
2.0
1.3
1.3
2
1
3
1
2
0.5
16
16
16
16
2
18
2
16
17
2
99
99
99
99
99
99
99
50
48
95
51
99
34
65
99
99
99
0
77c
78 (82c)
80 (71c)
85c
b
CO2Et
5-I
c
d
e
f
CO2Et
CO2Me
CO2Et
CO2Et
Me
Me
Me
Me
5-OMe
6-OMe
5-NO2
6-CN
A
A
A
A
B
A
A
A
A
A
A
A
B
75 (71c)
67c
63
32
21
66
44
60
27
g
h
CO2Et
CO2Et
4-Me-C6H4
3-Cl-C6H4
5-Br
5-Br
i
CO2Et
4-O2N-C6H4
5-Br
48
60
j
k
CO2Et
CO2Et
PhCH2
H
5-Br
5-Br
51c
1
2
2
2
2
2
67 (67c)
l
CO2Et
PhSO2
5-Br
A
B
A
A
A
0
m
n
o
CH3
CH2OAc
Ph
PhSO2
Me
H
H
5-Br
H
99
99
99
52c
76 (73c)
0c,d
aCatalyst A: Pd(OAc)2. Catalyst B: PtCl2. bYields refer to isolated products 2a-n. cMicrowave irradiation in a single-mode reactor was employed.
dUnidentified mixture of products was formed.
position.19a On the contrary, electron-withdrawing groups
substantially attenuated the reactivity (entries 7-9). Nota-
bly, the acetoxylation was found to be even more sensitive to
the electronic nature of the substituents on the pyrrole ring.
Thus, the time required to reach >95% conversion increased
from 1-2 h to 16-18 h by switching the N-methyl group
to the more electron-withdrawing N-aryl substituents
(entry 1 vs entries 10,12), with N-(4-nitrophenyl)indole 1i
being the least reactive in the series (entry 14). The introduc-
tion of the strongly electron-withdrawing N-phenylsulfonyl
moiety renders the indole 1l completely unreactive (entries
18-19). Replacing the C-2 ester moiety with a methyl group
(1m) re-established the reactivity of the indole (entry 20).
Surprisingly, the N-benzyl-substituted indole 1j required
prolonged heating (17 h) to reach 99% conversion (entry
15 vs entry 1).
Importantly, none of the side-chain oxidation products
were observed under the conditions employed (entries 20 and
21). As anticipated, neither bromo nor iodo substituents on
the indole were affected under the conditions of the Pd(II)/
Pd(IV) catalytic cycle (entries 1, 3, 10-16, 21)25 or in the
presence of PtCl2 (entries 2, 4, 17). Acetoxylation of the
N-unsubstituted indole 1k was possible (entries 16 and 17).
In the case of Pd(OAc)2, the product 2k was isolated in 51%
yield (entry 16), accompanied by the dimeric side product 3
(∼7% isolated yield).26 Improvement of yields (up to 67%)
and cleaner reactions were achieved by replacing Pd(OAc)2
with PtCl2 (entry 17). Interestingly, 2-phenylindole 1o afforded
a complex mixture of unidentified products under the
acetoxylation conditions (entry 22).
The lack of reactivity in the case of the electron-deficient
indole 1l (entry 18) is consistent with the electrophilic C-3
palladation mechanism for the oxidation. Furthermore,
none of the 2-acetoxylation products were observed when
2-unsubstituted 3-methylindole 4 was subjected to the Pd-
(II)-catalyzed oxidation conditions. These results reinforce
the view that the formation of the σ-indolyl-Pd(II) complex
occurs solely at the C-3 position.
The outcome of the 3-acetoxylation is heavily dependent
on the amount of the PhI(OAc)2 used. Thus, 1.3 equiv of the
oxidant was sufficient to bring about the O-acetoxylation of
electron-rich indoles (entries 1, 2, 4-6, and 21) in 67-85%
yield. In contrast, the oxidation of electron-deficient indoles
1e,f,h,i in the presence of 1.3 equiv of the oxidant stalled
after ca. 2 h. Furthermore, the formation of Pd-black was
observed, suggesting undesired reductive elimination of the
products from the transient σ-indolyl-Pd(II) species, which
inhibits the catalytic cycle. We speculate that reductive elim-
(25) (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44,
4046. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 3382.
(26) The structure of the bis-indole 3 was determined by X-ray analysis.
J. Org. Chem. Vol. 74, No. 18, 2009 7197

Mutule et al.
JOCNote
SCHEME 1. Acetoxylation of 2,3-Unsubstituted Indole
with PhI(OAc)2 as the terminal oxidant. The oxidation could
be catalyzed both by Pd(OAc)2 and PtCl2. The C-H activa-
tion/oxidation occurs most probably at the C-3 position as
none of the 2-acetoxylation products was observed in the case
of 2-unsubstituted 3-methylindole. The yields of the acetox-
ylation products are dependent on the electronic character of
the substrate. Electron rich indoles readily undergo acetoxyla-
tion, while electron-deficient analogues require increased
amounts of PhI(OAc)2 (up to 2.5 equiv) and prolonged
reaction times to achieve synthetically useful yields. Further
studies to expand the application of the Pd(II)- and Pt(II)-
catalyzed C-H activation-oxidation sequence toward the
synthesis of 3-alkoxyindoles and 3-aryloxyindoles are ongoing
in our laboratory.
ination is faster for Pd(II) complexes of the electronically
deficient indoles 1e,f,h,i,l as compared to the electronically
sufficient analogues 1a-d,k,n. This assumption is based
on kinetic studies of a C-O bond-forming reductive elim-
ination from a square planar aryl(alkoxo)Pd(II) complex.27
The reductive elimination there was shown to be faster for
aryl ligands possessing resonance-stabilizing substituents
on the palladium-bound aryl group. We reasoned that the
undesired reductive elimination from a σ-indolyl-Pd(II)
complex could be circumvented by expediting the competi-
tive oxidation of the transient Pd(II) complex to Pd(IV)
species. Indeed, increasing the PhI(OAc)2 load to 2.0-
2.5 equiv improved the conversion (entries 12 and 14 vs 11
and 13, respectively) and afforded reasonable yields (entries
3, 7-10, 15, and 20).
Both PtCl2 and Pd(OAc)2 could be employed in the C-H
activation-oxidation of indoles. Usually, the use of PtCl2
gave higher or comparable yields and cleaner reactions
(entry 2 vs 1, 4 vs ,3 and 17 vs 16). However, 3-Cl-indoles
were always formed in <5% yields when PtCl2 was used as
the catalyst. Pd(OAc)2 was somewhat less efficient, although
this is compensated by the lower cost of the catalyst.28
Finally, the Pd(OAc)2-catalyzed oxidation of the 2,3-un-
substituted indole 5 was examined. As anticipated, a com-
plex mixture of products was formed (Scheme 1). Among the
major products isolated were the desired 3-acetoxyindole 6a
(34% yield), 2,3-diacetoxylated indole 6b (5% yield), and
indoxyl 6c (13% yield).29 The remaining material consisted
of a number of unidentified minor side products. The
formation of the C-2-oxidized side products 6b,c evidently
occurs via the C-3 to C-2 migration of the transient σ-indolyl-
Pd(II) complex, followed by repeated electrophilic C-3 pal-
ladation of the intermediate C-2 acetoxyindole.
Experimental Section
Representative Procedure for Acetoxylation of Indoles Using
PtCl2. Ethyl 3-(acetyloxy)-5-bromo-1-methyl-1H-indole-2-car-
boxylate (Table 2, Entry 2). A Biotage microwave vial (2.0-
5.0 mL size) equipped with a Teflon-coated stirring bar was
charged with indole (0.5 mmol), PtCl2 (5 mol %, 0.025 mmol,
6.7 mg), and 1.3-2.0 equiv of PhI(OAc)2, and glacial acetic acid
(2.0 mL) was added. The vial was closed using an aluminum
open-top seal with PTFE-faced septum and heated in an oil bath
at 100 °C for 1 h. After being cooled, the solution was diluted
with EtOAc (50 mL), washed with water (2 ꢀ 25 mL) and brine,
and dried over Na2SO4. Volatiles were removed (rotary
evaporator), and purification of the crude product by column
chromatography (40 mL silica gel, column i.d. 30 mm) using
gradient elution from 4% EtOAc/petroleum ether to 15%
EtOAc/petroleum ether afforded the desired product (132 mg;
78% yield); analytical TLC on silica gel, 2:5 EtOAc/petroleum
ether Rf = 0.50. Pure material was obtained by crystallization
from EtOAc/petroleum ether: mp 138-141 °C; colorless parall-
elepipeds; IR (film, cm-1) 1767 (CdO), 1701 (CdO); 1H NMR
(400 MHz, CDCl3, ppm) δ 7.65 (1H, d, J = 1.8 Hz), 7.41 (1H,
dd, J = 9.0, 1.8 Hz), 7.23 (1H, d, J = 9.0 Hz, overlapped with
CHCl3), 4.34 (2H, q, J = 7.0 Hz), 4.00 (3H, s), 2.38 (3H, s), 1.37
(3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3, ppm) δ 169.0,
160.7, 135.0, 133.1, 128.9, 121.4, 120.9, 118.8, 114.0, 112.0, 60.9,
32.0, 20.6, 14.3; GC-MS m/z (relative intensity, ion) 341 (81Br,
6, Mþ), 339 (79Br, 6, Mþ), 299 (81Br, 76), 297 (79Br, 76), 253
(81Br, 100), 251(79Br, 100) 225 (81Br, 24), 223 (79Br, 24), 197
(81Br, 27) 195 (79Br, 27). Anal. Calcd for C14H14BrNO4: C,
49.43; H, 4.15; N, 4.12. Found: C, 49.71; H, 3.91; N, 4.02.
Acknowledgment. This work was supported by the Lat-
vian Science Council (Grant No. LZP-09.1325). We thank
S. Andrejevs, E. Elksnis, and V. Jakjans for confirming some
of the acetoxylation results. We also thank Dr. S. Belyakov
for X-ray crystallographic analysis.
In summary, we have developed a convenient method
for the direct C-3 acetoxylation of indole-2-carboxylates
Supporting Information Available: General experimental
procedures for acetoxylation of indoles; full characterization
data and copies of 1H and 13C NMR spectra for all compounds;
X-ray crystallographic data (CIF) for 3 and 6c. This material is
available free of charge via the Internet at http://pubs.acs.org.
(27) Widenhoefer, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
6504.
(28) Pd(OAc)2, 98%: 92.30 euros/g; PtCl2, 98% 166.00 euros/g (Aldrich
Catalogue).
(29) The structure of 6c was proven by X-ray analysis.
7198 J. Org. Chem. Vol. 74, No. 18, 2009