Palladium-Catalyzed Synthesis of Indoles by Reductive N-Heteroannulation of 2-Nitrostyrenes

Article abstract of DOI:10.1021/jo970516+

A palladium-phosphine catalyzed reductive N-heteroannulation of 2-nitrostyrenes, in the presence of carbon monoxide, producing indoles has been developed. Indoles were obtained, in moderate to excellent yield, from substituted 2-nitrostyrenes having either electron-withdrawing (NO₂ and CO₂-Me) or electron-donating (Br, OH, Me, OMe, and OTf) substituents on the aromatic ring. Best results were obtained using palladium diacetate (6 mol percent) together with triphenylphosphine (24 mol percent) as the catalytic system, under 4 atm of carbon monoxide in acetonitrile at 70 °C. Other palladium(II) and palladium(0) complexes also catalyze the reaction.

Full text of DOI:10.1021/jo970516+

5838
J . Org. Chem. 1997, 62, 5838-5845
P a lla d iu m -Ca ta lyzed Syn th esis of In d oles by Red u ctive
N-Heter oa n n u la tion of 2-Nitr ostyr en es
Bjo¨rn C. So¨derberg* and J ames A. Shriver
Department of Chemistry, West Virginia University, P.O. Box 6045,
Morgantown, West Virginia 26506-6045
Received March 20, 1997X
A palladium-phosphine catalyzed reductive N-heteroannulation of 2-nitrostyrenes, in the presence
of carbon monoxide, producing indoles has been developed. Indoles were obtained, in moderate to
excellent yield, from substituted 2-nitrostyrenes having either electron-withdrawing (NO2 and CO2-
Me) or electron-donating (Br, OH, Me, OMe, and OTf) substituents on the aromatic ring. Best
results were obtained using palladium diacetate (6 mol %) together with triphenylphosphine (24
mol %) as the catalytic system, under 4 atm of carbon monoxide in acetonitrile at 70 °C. Other
palladium(II) and palladium(0) complexes also catalyze the reaction.
Sch em e 1
In tr od u ction
Since the first synthesis of indole by Bayer in 1866,1
more synthetic routes to indoles have probably been
published compared to any other heterocyclic, or car-
bocyclic, ring system.2 A number of named reactions can
be found in most heterocyclic chemistry textbooks, such
as the Fischer, Madelung, Bischler, Reissert, Nenitzescu,
and Leimgruber-Batcho indole syntheses, to name a few
of the more well-known methods. More recently, several
synthetic methods to highly substituted indole deriva-
tives, employing transition metal reagents, have been
developed.3 Especially noteworthy are the numerous
palladium-catalyzed routes employing, for example, 2-al-
kenylanilines, 2-alkynylanilines, 2-halo-N-alkenylanilines,
and 2-halo-N-allylanilines.4
Sch em e 2
on the aryl group.5 During this study, a number of
substituted 2-vinylanilines and their nitrobenzene pre-
cursors were required for the synthesis of the carbene
complexes. Upon an attempted methoxycarbonylation6
of 3-bromo-2-ethenylnitrobenzene (1), using a catalytic
amount of palladium diacetate and 1,3-bis(diphenylphos-
phino)propane, in the presence of triethylamine and
carbon monoxide (4 atm) in a methanol-DMF solvent
mixture, we were surprised to isolate 4-bromoindole (2)
in 63% yield as the sole product (Scheme 1).7 A few cases
of a similar reaction were first observed by Kasahara et
al. upon Heck reactions of 2-bromonitrobenzenes with
ethene in the presence of palladium diacetate. For
example, methyl indole-4-carboxylate was obtained by
reaction of methyl 2-bromo-3-nitrobenzoate with ethene
(Scheme 2).8 Recently, Watanabe et al. published a
related procedure employing 2-ethenyl-1-nitrobenzenes
as starting materials using a catalytic amount of PdCl2-
(MeCN)2 in the presence of carbon monoxide, tri-
phenylphosphine, and an excess of tin dichloride (Scheme
3).9 A few other reductive cyclization reactions, related
to those shown in Schemes 1 and 3, can be found in the
literature. Indoles, in addition to a number of side
We have recently described a novel synthesis of indoles
and quinolines, via a thermally induced intramolecular
cyclization of N-aryl amino substituted Fischer chromium
carbene complexes having a pendant vinyl substituent
* To whom correspondence should be addressed. Phone: (304) 293-
3435. Fax: (304) 293-4904. E-mail: bcs@wvnvm.wvnet.edu.
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
(1) Bayer, A. J ustus Lieb. Ann. Chem. 1866, 140, 295.
(2) For a recent review see, Gribble, G. W. Contemp. Org. Synth.
1994, 1, 1.
(3) For reviews, see: (a) Hegedus, L. S. Angew. Chem. Int. Ed. Engl.
1988, 27, 1113. (b) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Hetero-
cycles 1988, 27, 2225. (c) Rieke, R. D.; Hanson, M. V. Tetrahedron
1997, 53, 1925.
(4) For some examples not included in ref 3, see: (a) Iritani, K.;
Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1799. (b)
Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J . K. J . Org. Chem.
1988, 53, 1170. (c) Rudisill, D. E.; Stille, J . K. J . Org. Chem. 1989,
54, 5856. (d) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215. (e) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc.
1991, 113, 6689. (f) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron
Lett. 1992, 33, 3915. (g) Macor, J . E.; Blank, D. H.; Post, R. J .; Ryan,
K. Tetrahedron Lett. 1992, 33, 8011. (h) Cacchi, S.; Canicelli, V.;
Marinelli, F. J . Organomet. Chem. 1994, 475, 289. (i) Yang, C.-C.;
Sun, P.-J .; Fang, J .-M. J . Chem. Soc., Chem. Commun. 1994, 2629. (j)
Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H.
Tetrahedron 1994, 50, 11803. (k) Amatore, C.; Blart, E.; Genet, J .-P.;
J utand, A.; Lemair, Audoire, S.; Savignac, M. J . Org. Chem. 1995, 60,
6829. (l) Botta, M.; Summa, V.; Corelli, F.; DiPietro, G.; Lombardi, P.
Asymmetry 1996, 7, 1263. (m) Chen, C.-Y.; Lieberman, D. R.; Street,
L. J .; Guiblin, A. R.; Larsen, R. D.; Verhoeven, T. R. Synth. Commun.
1996, 26, 1977. (n) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.;
Peterson, K. P. J . Org. Chem. 1996, 61, 3584. (o) Latham, E. J .;
Stanforth, S. P. J . Chem. Soc., Chem. Commun. 1996, 2253. (p) Macor,
J . E.; Ogilvie, R. j.; Wythers, M. J . Tetrahedron Lett. 1996, 37, 4289.
(q) Ezquerra, J .; Pedregal, C.; Lamas, C.; Barluenga, J .; Perez, M.;
Garcia-Martin, M. A.; Gonzalez, J . M. J . Org. Chem. 1996, 61, 5804.
(r) Hodges, L. M.; Spera, M. L.; Moody, M. W.; Harman, W. D. J . Am.
Chem. Soc. 1996, 118, 7117. (s) Chen, C.-i.; Lieberman, D. R.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J . Org. Chem. 1997, 62, 2676.
(5) So¨derberg, B. C.; Helton, E. S.; Austin, L. R.; Odens, H. H. J .
Org. Chem. 1993, 58, 5589.
(6) For a recent example, see: Quirante, J .; Escolano, C.; Massot,
M.; Bonjoch, J . Tetrahedron 1997, 53, 1391.
(7) Presented in part at the 211th American Chemical Society
meeting, New Orleans, 1996, Abstract ORGN-86.
(8) Kasahara, A.; Izumi, T.; Murakami, S.; Miyamoto, K.; Hino, T.
J . Heterocycl. Chem. 1989, 26, 1405.
(9) (a) Akazome, M.; Kondo, T.; Watanabe, Y. Chem. Lett. 1992, 769.
(b) Akazome, M.; Kondo, T.; Watanabe, Y. J . Org. Chem. 1994, 59,
3375.
S0022-3263(97)00516-1 CCC: $14.00 © 1997 American Chemical Society

Palladium-Catalyzed Synthesis of Indoles
J . Org. Chem., Vol. 62, No. 17, 1997 5839
Sch em e 3
dropped significantly at 1 atm of carbon monoxide, and
a substantial amount of starting material was recovered
after 22 h (entry 6). An insignificant increase in yield,
compared to entry 6, could be realized when the reaction
was performed at 120 °C (entry 7). Neither methanol
nor triethylamine, used in our preliminary experiment,
is required for the reaction to proceed (entries 8 and 9).
In fact, the reaction rate appears to be somewhat faster
in the absence of triethylamine. In addition to the DMF-
methanol solvent mixture, the three solvents examineds
methanol, DMF, and acetonitrilesgave satisfactory yields
of 2. Since, the reactions performed in acetonitrile
appeared to be somewhat cleaner and easier to workup,
it was the solvent of choice (entry 14). A number of
different palladium reagents can be used as catalysts.
Palladium(II) salts, such as Pd(OAc)2, and PdCl2(MeCN)2,
and palladium(0) reagents, such as Pd(dba)2 and Pd/C
(10% Pd), all enter the catalytic cycle, forming 2 under
various reaction conditions (entries 15-20).
Methyl N-(3-bromo-2-ethenylphenyl)carbamate (3,
e17%) and methyl 2-ethenyl-3-nitrobenzoate (15, e11%),
the originally expected product, were the only side
products isolated from reaction of 1. Carbamates and
urea derivatives have previously been prepared by reduc-
tion of aromatic nitro compounds in methanol using a
palladium-phosphine catalyst at high carbon monoxide
pressure (40-80 atm).17 For obvious reasons, these two
products are observed only in the presence of methanol;
no additional or related side products have been isolated
using DMF or acetonitrile as the solvent in the absence
of methanol. A 17% yield of 3 was realized in the absence
of triethylamine. This may open a new palladium-
catalyzed route to carbamates. The highest yield of the
ester 15 was obtained using only 1 equiv of tri-
phenylphosphine to palladium, a side reaction that was
completely eliminated by employing 4 equiv of phosphine
(entries 10 and 11). Further reaction of 4-bromoindole
(2) to methyl 4-indolecarboxylate (32) was not observed.
This result is intriguing in that a palladium-catalyzed
carbomethoxylation of 2 under similar reaction condi-
tions, using PdBr2(PPh3)2 as the catalyst, has previously
been reported.18
products, have been prepared by reaction of 2-nitrosty-
renes with a catalytic amount of various metal carbon-
yls10 and palladium(II) salts11 at high pressure and
temperature. 2-Aryl-4-quinolinones can be obtained from
2-nitrochalcones via ruthenium(0)- or palladium(II)-
catalyzed reactions in the presence of carbon monoxide
(30 atm, 170 °C).12 In addition, syntheses of quinazo-
lines13 and 1-pyrroline derivatives14 have been reported
employing a variety of transition metal catalysts. Fi-
nally, McMurry type cyclizations of aromatic acylamido
carbonyl compounds forming indoles have been de-
scribed.15 Reductive cyclization can also be obtained in
the absence of a transition metal catalyst and carbon
monoxide. Sundberg has reported a reaction using excess
triethylphosphite as the reducing agent at elevated
temperatures.16
Compared to Watanabe’s procedure, our protocol pro-
ceeds at a substantially lower temperature and pressure
and does not require an added Lewis acid, such as tin
dichloride. It should also be noted that in the latter study
only substitution on the pendant alkene was examined.
Compared to previously reported palladium-catalyzed
routes to indoles employing aniline derivatives, this route
offers some one or more of the following advantages: (1)
no protection group strategies are required, (2) nitroben-
zenes are usually the precursors to the aniline deriva-
tives, thus eliminating additional synthetic steps, and (3)
no re-oxidant, such as 1,4-benzoquinone, is required.
Thus, the present method potentially offers a shorter,
milder, and more economical route to substituted indoles.
With this in mind, an in-depth study of this reductive
N-heteroannulation reaction was undertaken. Herein is
reported the scope and limitation of this method.
Resu lts a n d Discu ssion
For the present synthesis, the overall yield of 4-bro-
moindole (2) compares favorably to previously published
routes. For example, using the same starting material,
the overall yield of 4-bromoindole (2) following our
protocol (82%) is higher compared to the yield obtained
from a Leimgruber-Batcho reaction (70%)19 and substan-
tially higher compared to Hegedus’s palladium (II)-
catalyzed reaction20 (e50%). A fourth route to 4-bro-
moindole starting from 3-bromo-2-methylnitrobenzene
via 3-bromo-2-(2-hydroxyethenyl)nitrobenzene has been
published (e72%).21
The reaction conditions for the reaction of 1 forming 2
were studied in more detail, and the results thereof are
summarized in Table 1. Three of the reagents were
shown to be crucial for the formation of 2; only starting
material was recovered from reactions of 1 in the absence
of either phosphine, palladium catalyst, or carbon mon-
oxide (entries 2-4). A small decrease in yield was
observed when a somewhat higher carbon monoxide
pressure was employed (entry 5). In contrast, the yield
(10) Crotti, C.; Cenini, S.; Rindone, B.; Tollari, S.; Demartin, F. J .
Chem. Soc., Chem. Commun. 1986, 784.
(11) Tollari, S.; Cenini, S.; Crotti, C.; Giannella, E. J . Mol. Catal.
1994, 87, 203.
(12) (a) Annunziata, R.; Cenini, S.; Palmisano, G.; Tollari, S. Synth.
Commun. 1996, 26, 495. (b) Tollari, S.; Cenini, S.; Ragaini, F.; Cassar,
L. J . Chem. Soc., Chem. Commun. 1994, 1741. (c) Ragani, F.; Tollari,
S.; Cenini, S. J . Mol. Catal. 1993, 85, L1.
To determine the scope of the reaction and to evaluate
the influence of substituents on the alkene and the
aromatic ring, a number of substituted 2-nitrostyrenes
were prepared. The alkenyl group was introduced either
(13) Akazome, M.; Yamamoto, J .; Kondo, T.; Watanabe, Y. J .
Organomet. Chem. 1995, 494, 229.
(14) Watanabe, Y.; Yamamoto, J .; Akazome, M.; Kondo, T.; Mitsudo,
T.-a. J . Org. Chem. 1995, 60, 8328.
(15) (a) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; J anssen, E. J . Org.
Chem. 1994, 59, 5215. (b) Fu¨rstner, A.; Hupperts, A. J . Am. Chem.
Soc. 1994, 117, 4468.
(16) (a) Sundberg, R. J .; Yamazaki, T. Y. J . Org. Chem. 1967, 32,
290. (b) Sundberg, R. J . J . Org. Chem. 1965, 30, 3604. For a recent
example in synthesis, see: Cotterill, A. S.; Moody, C. J .; Roffey, J . R.
A. Tetrahedron 1995, 51, 7223.
(17) Wehman, P.; Dol, G. C.; Moorman, E. R.; Kamer, P. C. J .; van
Leeuwen, P. W. N. M.; Fraanje, J .; Goubitz, K. Organometallics 1994,
13, 4856 and references therein.
(18) Kasahara, A.; Izumi, T.; Ogata, H.; Goton, T.; Kohei, K.
Yamagata Daigaku Kiyo, Kogaku 1988, 20, 141. [Chem. Abstract 1989,
111, 80291u].
(19) Moyer, M. P.; Shiruba, J . F.; Rapoport, H. J . Org. Chem. 1986,
51, 5106.
(20) Harrington, P. J .; Hegedus, L. S. J . Org. Chem. 1984, 49, 2657.
(21) Tsuji, Y.; Kotachi, S.; Huh, K. T.; Watanabe, Y. J . Org. Chem.
1990, 55, 5106.

5840 J . Org. Chem., Vol. 62, No. 17, 1997
Ta ble 1. Rea ction Con d ition Stu d y
Soderberg and Shriver
yield (%)b,c
entrya
catalyst
phosphine
dpppd
solvent
base
atmosphere
2
3
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Pd(OAc)2
Pd(OAc)2
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF
DMF-MeOH
DMF-MeOH
DMF-MeOH
DMF
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
CO
CO
CO
Ar (3 atm)
63 (68)
f
tracee
trace
dppp
dppp
dppp
dppp
dppp
dppp
dppp
f
f
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd/C (10%)
Pd/C (10%)
Pd/C (10%)
CO (6 atm)
56 (58)
22 (69)
27 (53)h
59 (89)
76
76 (85)
86
76 (82)
80
3
CO (1 atm)
8
CO (1 atm)g
CO
CO
CO
CO
CO
CO
CO
CO
CO
17
i
PPh3
NEt3
NEt3
11
PPh3
PPh3
PPh3
PPh3
dppp
dppp
PPh3
dppp
dppp
PPh3
MeCN-MeOH
NEt3
MeCNj
84
DMF-MeOH
DMF-MeOH
MeCN
DMF-MeOH
DMF
NEt3
NEt3
49 (89)
82
47 (90)
45 (61)
56 (76)
56 (63)
trace
8
6
3
CO
NEt3
CO
trace
COk
CO
MeOH
a
All reactions were performed at 70 °C (oil bath temperature) for 22 h using 2 mmol of 1, 6 mol % catalyst, 6 mol % phosphine for dppp
b
or 24 mol % for PPh3 dissolved in 6 mL of DMF-MeOH (2:1) under 4 atm of CO, unless otherwise stated. Pure isolated compounds after
column chromatography. c Yield in parentheses is based on recovered starting material. dppp ) 1,3-bis(diphenylphosphino)propane.
d
e Trace <3% by 1H NMR of the crude reaction mixture. f Only starting material was observed by 1H NMR of the crude reaction mixture.
g
h
At 120 °C (oil bath temperature) for 22 h. A complex inseparable mixture of products containing some starting material and 13 was
i
j
k
also isolated. 6 mol % phosphine was used. Heated for 15 h. Heated for 48 h.
Ta ble 2. Cr oss-Cou p lin g of 2-Br om on itr oben zen es Ta ble 3. Styr en e Syn th esis via th e Wittig Rea ction
yield (%)b
Wittig salt
entrya
Y
R
yield (%)b
entrya
R
bromide
alkene
1
2
3
4
5
6
7
8
4-Me
H
H
H
H
Me
H
H
8 (78)
9 (89)
1
2
3
4
5
3-Br
1 (95)c
15 (92)
16 (99)
18 (100)
20 (91)
3-OMe
4-OMe
5-OMe
5-OMe
3-OH
3-CO2Me
4-CO2Me
6-CO2Me
3-NO2
99d
95
75
90
10 (61)
11 (96)
12 (79)c
13 (30)
17 (52)d
19 (81)d
55
55
79
5-CO2Me
4-Br
a
b
See Experimental Section for details. The yields for the
bromides and the Wittig salts are crude yields, and the yields for
the alkenes are for pure isolated compounds. c Overall yield for
three steps. A modification of the reaction reported in ref 20 (83%)
H
a
b
See Experimental Section for details. Isolated pure products.
c Tetrakis(triphenylphosphine)palladium(0) was used. 2-OTf was
d
d
was used. Yield for two steps.
used in place of 2-Br, and LiCl was added to the reaction mixture.
no reaction was observed from the related 2-bromo-3-
hydroxy-N-tosylaniline (entry 3).23,24
by a palladium-catalyzed cross coupling of 1-alkenyl tri-
n-butyltin derivatives with aryl bromides or triflates
(Stille coupling) or by Wittig olefination. Coupling reac-
tions22 of bromo-, carbomethoxy-, methoxy-, and methyl-
substituted 2-bromonitrobenzene with ethenyl- or 2-(1-
propenyl)tri-n-butyltin proceeded uneventfully, and the
corresponding 2-vinylnitrobenzene derivatives were ob-
tained in good to excellent yield (Table 2). Coupling of
3-hydroxy-2-bromonitrobenzene (entry 6) gave a low yield
of 2-ethenyl-3-hydroxynitrobenzene (13). Although low,
the yield is satisfactory since Stille et al. reported that
Several phosphonium salts were prepared from the
corresponding 2-methyl-1-nitrobenzenes via radical bro-
mination and reaction with triphenyl phosphine. Wittig
reactions of these benzylic phosphonium salts with
formaldehyde gave the expected alkenes in excellent yield
(Table 3).
Next, with a number of substituted 2-(1-alkenyl)-1-
nitrobenzenes in hand, we examined the cyclization
reaction using the optimized reaction conditions in Table
1 (entry 14). The results thereof are summarized in
Table 4. Indole (21) and 2-phenylindole (24) were
obtained in 87% and 100% yield, respectively (entries 1
and 4), yields substantially higher than those reported
(22) For a review on palladium-catalyzed cross-coupling reactions
using organotin reagents, see: (a) Stille, J . K. Angew. Chem. Int. Ed.
Engl. 1986, 25, 508. (b) Mitchell, T. N. Synthesis 1992, 803.
(23) The presence of an hydroxy group is in itself not detrimental
to the Stille reaction. (a) Echavarren, A. M.; Stille, J . K. J . Am. Chem.
Soc. 1987, 109, 5478. (b) Foote, K. M.; Hayes, C. J .; Pattenden, G.
Tetrahedron Lett. 1996, 37, 275.
(24) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J . K. J .
Org. Chem. 1988, 53, 1170.

Palladium-Catalyzed Synthesis of Indoles
J . Org. Chem., Vol. 62, No. 17, 1997 5841
Ta ble 4. F or m a tion of In d oles F r om 2-Nitr ostyr en es
a
b
For reaction conditions, see Experimental Section. Pure isolated compounds after column chromatography. c The second yield in
d
parentheses is the yield based on recovered starting material. Only starting material was isolated (89%).
by Watanabe et al., who employed the same starting
materials. The stereochemistry of the alkene does not
affect the outcome of a given reaction. For example, no
apparent rate or yield decrease was observed using a
mixture of cis- and trans-2-nitrostilbene compared to pure
trans-2-nitrostilbene (entries 2-4). In general, the reac-
tion appears to be independent of the substitution pattern
and electronic properties of the substituents on the
aromatic ring. Substrates containing either electron-
donating (entries 3-9) or electron-withdrawing (entries
10-13 and 16) groups react to give indoles in moderate
to excellent yields. The reaction is very clean and,
usually, only the expected indole was observed by 1H
NMR of the crude reaction mixtures. Reactions forming
4-substituted indoles are particularly successful, and
yields ranging from 84% to 100% were realized, regard-
nitro groups in 20 is reduced under the reaction condi-
tions. Reduction of an additional nitro group is often
observed using the Leimgruber-Batcho procedure.25,26
The synthetic sequence starting from methyl 2-methyl-
3-nitrobenzoate (Table 2, entry 2) represents, to our
knowledge, the best current alternative to methyl indole-
4-carboxylate (32).27 However, an exception is the reac-
tion of the triflate 14, where, in addition to the expected
product 4-[(trifluoromethyl)sulphonyl]indole (31), a fair
amount of starting material is recovered (entry 9). The
relatively low isolated yield of 6-methoxyindole (28) is
probably a reflection of the product’s rapid oligomeriza-
tion under the reaction conditions (entry 6). In this case,
upon chromatography of the crude reaction mixture, a
(25) By careful control of stoichiometry of the reducing agent
overreduction can be avoided: Somei, M.; Inoue, S.; Tokutake, S.;
Yamada, F.; Kaneko, C. Chem. Pharm. Bull. 1981, 29, 726.
(26) For a recent method to 4-nitroindoles, see: Bergman, J .; Sand,
P. Tetrahedron 1990, 46, 6085.
(27) (a) Ponticello, G. S.; Baldwin, J . J . J . Org. Chem. 1979, 44, 4003.
(b) Kozikowski, A. P.; Ishida, H.; Chen, Y. Y. J . Org. Chem. 1980, 45,
3350.
less of the electronic properties of the substrates.
A
hydroxy functionality in the 3-position of the substrate
does not interfere with the reaction, and 4-hydroxyindole
(30) can be isolated from 13 in almost quantitative yield
(entry 8). It is interesting to note that only one of the

5842 J . Org. Chem., Vol. 62, No. 17, 1997
Soderberg and Shriver
test) 13C NMR experiments are shown in parentheses, where,
relative to CDCl3, (-) denotes CH3 or CH and (+) denotes CH2
or C.
Sch em e 4
Tetrahydrofuran (THF), 1,4-dioxane, toluene, and diethyl
ether were distilled from sodium benzophenone ketyl prior to
use. Pyridine, hexanes, acetonitrile, and ethyl acetate were
distilled from calcium hydride. Chemicals prepared according
to literature procedures have been footnoted the first time they
are used; all other reagents were obtained from commercial
sources and used as received. Silica gel (200-400 mesh) was
used for flash chromatography. All reactions were performed
in oven-dried glassware. Solvents were removed on a rotary
evaporator at water aspirator pressure unless otherwise
stated. Elemental analyses were performed by Atlantic Mi-
crolab, Inc., Norcross, GA.
2-Eth en yl-4-m eth yln itr oben zen e (8).8 To a solution of
2-bromo-4-methylnitrobenzene29 (1.00 g, 4.61 mmol) and vi-
nyltri-n-butyltin (1.61 g, 5.07 mmol) in toluene (25 mL) was
added, under a positive flow of argon, bis(dibenzylideneac-
etone)palladium(0)30 (265 mg, 0.46 mmol) together with tri-
phenylphosphine (498 mg, 1.90 mmol). The solution was
heated at reflux (19 h) whereupon a red solution containing a
black precipitate was formed. The reaction mixture was cooled
to ambient temperature, and the solvent was removed to give
a black oil. The oil was dissolved in dichloromethane (50 mL),
washed with NH4OH (10%, aq, 3 × 30 mL), and dried (MgSO4).
Removal of solvent gave a yellow oil containing a smaller
amount of a black viscous oil. The crude product was purified
by chromatography (hexanes-EtOAc, 19:1) to give 8 (589 mg,
3.61 mmol, 78%) as a yellow oil.
2-Eth en yl-3-m eth oxyn itr oben zen e (9). A solution of
2-bromo-3-methoxynitrobenzene24 (928 mg, 4.00 mmol) and
vinyltri-n-butyltin (1.16 mL, 4.40 mmol) in toluene (30 mL)
was reacted with bis(dibenzylideneacetone)palladium(0) (115
mg, 0.20 mmol) and triphenylphosphine (210 mg, 0.80 mmol)
as described above (23.5 h). Extraction and purification by
chromatography (hexanes-EtOAc, 19:1) gave 9 (641 mg, 3.58
mmol, 89%) as yellow crystals: mp 42-43 °C; 1H NMR δ 7.83-
6.98 (m, 3H), 6.71 (dd, J ) 17.9 and 11.5, 1H), 5.68 (dd, J )
17.4 and 1.7 Hz, 1H), 5.52 (dd, J ) 11.5 and 1.7 Hz, 1H), 3.86
(s, 3H); 13C NMR δ 130.5 (s), 128.8 (d), 128.3 (d), 127.0 (s),
125.3 (s), 121.5 (t), 115.2 (d), 114.0 (d), 56.1 (q); IR (CH2Cl2)
2843, 1622, 1532, 1362, 1295, 1245, 1059 cm-1. Anal. Calcd
for C9H9NO2: C, 60.33; H, 5.06. Found: C, 60.55; H, 5.15.
2-Eth en yl-4-m eth oxyn itr oben zen e (10).8 A solution of
2-bromo-4-methoxynitrobenzene31 (1.16 g, 5.00 mmol) and
vinyltri-n-butyltin (1.45 mL, 5.50 mmol) in toluene (40 mL)
was reacted with bis(dibenzylideneacetone)palladium(0) (144
mg, 0.25 mmol) and triphenylphosphine (263 mg, 1.00 mmol)
as described above (46 h). Extraction and chromatography
(hexanes-EtOAc, 19:1) gave 790 mg of a mixture of 2-ethenyl-
4-methoxynitrobenzene and dibenzylideneacetone. The mix-
ture was dissolved in THF (20 mL), and NaBH4 (42 mg, 1.10
mmol) was added. After 20 h, the mixture was diluted with
water (25 mL) and extracted with dichloromethane (3 × 25
mL). The combined organic phases were dried (MgSO4) and
filtered. The solvents were removed, and the residue was
purified by chromatography (hexanes-EtOAc, 9:1) to give 10
(548 mg, 3.05 mmol, 61%) as faint yellow oil that crystallized
upon storage in a freezer (-20 °C).
number of highly colored bands with high polarity were
observed. The identity of these products has not been
established. We anticipated a reduction of oligomeriza-
tion in the presence of a 3-substituent on the formed
indole. Thus, we were pleased to isolate 6-methoxy-3-
methylindole (29) in 81% yield upon reaction of the
2-propenyl-substituted nitrobenzene 12 (entry 7).
One apparent difference between electron-donating
and electron-withdrawing substituents is that the latter
undergo cyclization at a somewhat slower rate. The
esters 33-35 (and the triflate 31) were isolated in fair
to good yield together with varying amounts of starting
material (entries 9 and 11-13). In the cases where
starting material was recovered, a prolonged reaction
time did not improve the chemical yield.
Although the mechanism for the reaction described
herein and that reported by Watanabe et al. is closely
related, it remains obscure. Based on a brief mechanistic
study, formation of an active transition metal nitrene
intermediate followed by an insertion reaction was sug-
gested.9 Since the reaction described by Izumi et al.
proceeds in the absence of CO, a different mechanism is
probably in operation. These authors tentatively sug-
gested a mechanism consisting of an initial reduction of
the nitro group to an amine, by an intermediately formed
palladium hydride species, followed by a more conven-
tional palladium(II)-catalyzed cyclization reaction pro-
ducing the indole. In our case, the close proximity of the
alkene to the nitro group was found to be crucial for the
reaction to occur. For example, trans-4-nitrostilbene28
was recovered unchanged, in quantitative yield, after 22
h (Scheme 4). This result is in sharp contrast to the
quantitative yield of 2-phenylindole obtained from trans-
2-nitrostilbene (Table 4, entry 4). It is plausible that
palladium coordinated to the double bond assists in the
reduction of the nitro group.
Finally, the only 2-nitrostyrene that did not undergo
the cyclization reaction was 19, which was recovered in
89% yield after 24 h (entry 14). No trace of the expected
product, 5-bromoindole (36), was observed even after
prolonged reaction time (5 days). We have presently no
explanation for the lack of reactivity of 19.
In conclusion, a relatively mild, palladium-catalyzed,
reductive N-heteroannulation of 2-nitrostyrenes forming
indoles in moderate to excellent yield has been developed.
Applications of this methodology toward a number of
naturally occurring indole alkaloids is presently under-
way in our laboratories.
2-Eth en yl-5-m eth oxyn itr oben zen e (11).8 A solution of
2-bromo-5-methoxynitrobenzene (2.32 g, 10.0 mmol) with
vinyltri-n-butyltin (3.49 g, 11.0 mmol) in toluene (75 mL) was
reacted with bis(dibenzylideneacetone)palladium(0) (288 mg,
0.50 mmol) and triphenylphosphine (525 mg, 2.00 mmol) as
described above (24 h). Extraction and chromatography
(hexanes-EtOAc, 9:1) gave 11 (1.72 g, 9.60 mmol, 96%) as a
pale yellow oil.
Exp er im en ta l Section
Gen er a l P r oced u r es. All NMR spectra were determined
in CDCl3 at 270 MHz (1H NMR) and 67.5 MHz (13C NMR)
unless otherwise stated. The chemical shifts are expressed
in δ values relative to Me4Si (0.00, 1H and 13C) or CDCl3 (7.26,
1H and 77.00, 13C) internal standards. Multiplicities observed
in off-resonance decoupled 13C NMR experiments are shown
in parentheses. 1H-1H coupling constants are reported as
calculated from spectra; thus, a slight difference between J a,b
and J b,a is usually obtained. Results of APT (attached proton
5-Meth oxy-2-p r op en -2-yln itr oben zen e (12). A similar
reaction of 2-bromo-5-methoxynitrobenzene (4.64 g, 20.0 mmol)
(29) Coffey, S. J . Chem. Soc. 1926, 3219.
(30) Takahashi, Y.; Ito, T.; Sakai, S.; Ishii, Y. J . Chem. Soc., Chem.
Commun. 1970, 1065.
(31) Hodgeson, H. H.; Moore, F. H. J . Chem. Soc. 1926, 155.
(28) Aun, C. E.; Clarkson, T. J .; Happer, D. A. R. J . Chem. Soc.
Perkin Trans. 2 1990, 645.

Palladium-Catalyzed Synthesis of Indoles
J . Org. Chem., Vol. 62, No. 17, 1997 5843
with propen-2-yltri-n-butyltin32 (6.62 g, 20.0 mmol) in toluene
(100 mL) in the presence of tetrakis(triphenylphosphine)-
palladium(0) (116 mg, 0.10 mmol) for 64 h gave, after extrac-
tion and chromatography (hexanes-EtOAc, 8:2), 12 (3.04 mg,
15.76 mmol, 79%) as a pale yellow oil: 1H NMR δ 7.37 (d, J )
2.8 Hz, 1H), 7.23 (d, J ) 8.5 Hz, 1H), 7.08 (dd, J ) 8.5 and 2.6
Hz, 1H), 5.14 (t, J ) 1.6 Hz, 1H), 4.90 (br s, 1H), 3.86 (s, 3H),
2.05 (s, 3H); 13C NMR δ 158.6 (+), 148.4 (+), 142.4 (+) 131.2
(-), 130.9 (+), 118.8 (-), 114.9 (+) 108.6 (-), 55.6 (-), 23.1
(-); IR (neat) 1529; 1353 cm-1. Anal. Calcd for C10H11NO3:
C, 62.17; H, 5.74. Found: C, 62.44; H, 5.74.
(+), 132.6 (-), 132.5 (-), 131.5 (-), 127.6 (-), 125.9 (-), 118.9
(+), 52.1 (+); IR (neat) 1730, 1531, 1292, 1264, 1124, 707 cm-1
.
Anal. Calcd for C10H9NO4: C, 57.97; H, 4.38. Found: C, 57.72;
H, 4.47.
Meth yl 3-Eth en yl-4-n itr oben zoa te (16).8 A solution of
methyl 3-methyl-4-nitrobenzoate34 (3.92 g, 20.0 mmol), diben-
zoyl peroxide (242 mg, 1.00 mmol), and N-bromosuccinimide
(3.92 g, 22.0 mmol) in carbon tetrachloride (55 mL) was heated
(90 °C, 22.5 h) and irradiated as described above. Solvent
removal followed by chromatography (hexanes-EtOAc, 49:1)
gave methyl 3-bromomethyl-4-nitrobenzoate (2.64 g, 9.61
mmol, 48%) as faint yellow crystals. Earlier fractions contain-
ing starting material, dibrominated product, and methyl
3-bromomethyl-4-nitrobenzoate were repurified by chroma-
tography (hexanes-EtOAc, 9:1), affording an additional amount
of product (400 mg, 1.45 mmol, 7%): mp 118-119 °C; 1H NMR
δ 8.23 (s, 1H), 8.12 (d, J ) 8.4 Hz, 1H), 8.05 (d, J ) 8.4 Hz,
1H), 4.82 (s, 2H), 3.97 (s, 3H); 13C NMR δ 164.5 (+), 150.5 (+),
134.7 (-), 132.5 (+), 132.3 (+), 129.1 (-), 127.7 (-), 53.0 (-),
2-Eth en yl-3-h yd r oxyn itr oben zen e (13). A solution of
2-bromo-3-hydroxynitrobenzene24 (2.18 g, 10.0 mmol) and
vinyltri-n-butyltin (3.49 g, 11.0 mmol) in toluene (75 mL) was
reacted with bis(dibenzylideneacetone)palladium(0) (288 mg,
0.50 mmol) and triphenylphosphine (525 mg, 2.00 mmol) as
described above (17 h). Extraction and chromatography
(hexanes-EtOAc, 9:1) gave 13 (0.51 g, 3.00 mmol, 30%) as
1
golden crystals: mp 62-64 °C; H NMR δ 7.50 (dd, J ) 7.9
22.7 (+); IR (neat) 1720, 1529 cm-1
. Anal. Calcd for C9H8-
BrNO4: C, 39.42; H, 2.94. Found: C, 39.57; H, 2.91.
and 1.4 Hz, 1H), 7.27 (t, J ) 8.1 Hz, 1H), 7.19 (dd, J ) 8.1 Hz
and 1.4 Hz, 1H), 6.84 (dd, J ) 18.2 and 11.7 Hz, 1H), 6.43 (br
s, 1H), 5.74 (dd, J ) 11.7 and 1.4 Hz, 1H), 5.63 (dd, J ) 18.0
and 1.2 Hz, 1H); 13C NMR δ 153.9 (+), 148.6 (+), 129.0 (-),
128.6 (-), 122.0 (+), 120.7 (-), 119.8 (+), 116.2 (-); IR (CH2-
Cl2) 3464, 1519, 1360, 1293, 925 cm-1. Anal. Calcd for C8H7-
NO3: C, 58.18; H, 4.27. Found: C, 58.28; H, 4.34.
Triphenylphosphine (2.10 g, 8.00 mmol) was reacted with
methyl 3-bromomethyl-4-nitrobenzoate (2.00 g, 7.27 mmol) in
chloroform (15 mL) as described above to give crude phospho-
nium salt (3.71 g, 6.90 mmol, e95%). The salt was used as
such without further purification. Spectral data of the crude
product: 1H NMR δ 8.35 (s, 1H), 8.07 (d, J ) 8.6 Hz, 1H),
7.93 (d, J ) 8.6 Hz, 1H), 7.85-7.55 (m, 15H), 6.17 (d, J ) 15.1
Hz, 2H), 3.83 (s, 3H).
A solution of the salt (3.00 g, 5.58 mmol) in dichloromethane
(70 mL) was reacted with triethylamine (726 µL, 29.99 mmol)
and methanal (g) as described above to give, after chromatog-
raphy (hexanes-EtOAc, 9:1), 16 (1.14 g, 5.50 mmol, 99%) as
pale yellow crystals.
Meth yl 2-eth en yl-3-n itr oben zoa te (15). Bromine (2.77
mL, 54.0 mmol) dissolved in carbon tetrachloride (20 mL) was
added over 30 min to a boiling solution of methyl 2-methyl-
3-nitrobenzoate27a (8.83 g, 45.0 mmol) and dibenzoyl peroxide
(543 mg, 2.25 mmol) in carbon tetrachloride (80 mL) under
irradiation using a 100 W lamp. After 20 h of heating and
irradiation,33 additional bromine (0.69 mL, 13.5 mmol) in
carbon tetrachloride (5 mL) and dibenzoyl peroxide (136 mg,
0.56 mmol) was added. After continued heating and irradia-
tion (29 h), the red solution was allowed to cool to ambient
temperature followed by solvent removal, affording crude
methyl 2-bromomethyl-3-nitrobenzoate (12.8 g) as pale brown
crystals. The crude product was used in the next reaction
without further purification. Spectral data of the crude
Meth yl 4-Eth en yl-3-n itr oben zoa te (17).8 To a solution
of 4-carbomethoxy-2-nitrophenyl trifluoromethanesulfonate4c
(1.98 g, 6.01 mmol) and vinyltri-n-butyltin (1.95 mL, 6.15
mmol) in dioxane (27 mL) was added, under a positive flow of
argon, bis(dibenzylideneacetone)palladium(0) (70 mg, 0.12
mmol), triphenylphosphine (126 mg, 0.48 mmol), and LiCl (848
mg, 20.00 mmol), together with a few crystals of 2,6-(1,1-
dimethylethyl)phenol. The solution was heated at reflux (20
h), whereupon a red solution containing a black precipitate
was formed. The reaction mixture was cooled to ambient
temperature, and the solvent was removed to give a black oil.
The oil was dissolved in dichloromethane (50 mL), washed with
NH4OH (10%, aq, 3 × 50 mL) and H2O (3 × 50 mL), and dried
(MgSO4). Removal of the solvent gave a brown oil that was
purified by chromatography using hexanes-EtOAc (9:1) as
eluent to give 17 (651 mg, 3.13 mmol, 52%) as yellow crystals.
Meth yl 3-Eth en yl-2-n itr oben zoa te (18).8 A solution of
methyl 3-methyl-2-nitrobenzoate34 (392 mg, 2.00 mmol), diben-
zoyl peroxide (24 mg, 0.10 mmol), and N-bromosuccinimide
(374 mg, 2.10 mmol) in carbon tetrachloride (4 mL) was heated
(90 °C, 23.5 h) and irradiated as described above. Solvent
removal followed by chromatography (hexanes-EtOAc, 19:1)
gave methyl 3-bromomethyl-2-nitrobenzoate (300 mg, 1.09
mmol, 55%) as faint yellow crystals:35 mp 90-90.5 °C; 1H NMR
δ 7.95 (d, J ) 7.7 Hz, 1H), 7.73 (d, J ) 7.7 Hz, 1H), 7.57 (t, J
) 7.6 Hz, 1H), 4.44 (s, 2H), 3.89 (s, 3H); 13C NMR δ 163.5 (+),
149.3 (+), 135.3 (-), 131.2 (-), 130.8 (-), 130.3 (+), 124.3 (+),
53.2 (-), 25.5 (+); IR (neat) 1727, 1535, 1289 cm-1. Anal. Calcd
for C9H8BrNO4: C, 39.44; H, 2.94. Found: C, 39.53; H, 2.97.
Triphenylphosphine (1.28 g, 4.86 mmol) was added to a
solution of methyl 3-bromomethyl-2-nitrobenzoate (1.24 g, 4.53
mmol) in chloroform (20 mL). The solution was heated at
reflux (15 min). After cooling to ambient temperature, dry
diethyl ether (150 mL) was added to precipitate the Wittig salt.
The slurry was filtered to give a white powder. The powder
was washed with dry diethyl ether (100 mL) and dried under
high-vacuum to give the crude phosphonium salt (1.96 g, 3.65
1
reaction mixture: mp 68-69 °C; H NMR δ 8.09 (dd, J ) 7.7
and 1.2 Hz, 1H), 7.94 (dd, J ) 8.1 and 1.2 Hz, 1H), 7.53 (t, J
) 8.1 Hz, 1H), 5.15 (s, 2H), 3.99 (s, 3H); 13C NMR δ 165.8 (+),
150.5 (+), 134.7 (-), 132.5 (+), 132.3 (+), 129.1 (-), 127.7 (-),
53.0 (-), 22.7 (+); IR (neat) 1722, 1530, 1271 cm-1. Anal. Calcd
for C9H8BrNO4: C, 39.44; H, 2.94. Found: C, 39.33; H, 2.94.
Triphenylphosphine (18.87 g, 49.5 mmol) was added to a
solution of methyl 2-bromomethyl-3-nitrobenzoate (12.40 g,
44.12 mmol) in chloroform (60 mL). The solution was heated
at reflux (1 h). After cooling to ambient temperature, dry
diethyl ether (200 mL) was added to precipitate the Wittig salt.
The slurry was cooled in a freezer (-20 °C) overnight followed
by filtration to give a white powder. The powder was washed
with dry diethyl ether (200 mL) and dried under high vacuum
to give the crude phosphonium salt (23.42 g, 43.58 mmol, 99%).
The salt was used as such without further purification.
Methanal (g) was bubbled through a purple solution of the
salt (1.00 g, 1.86 mmol) and triethylamine (514 µL, 4.00 mmol)
in dichloromethane (50 mL) at ambient temperature. Upon
addition of methanal, the purple color of the ylide slowly
changed to a pale brownish-yellow, which indicated the end
point of the reaction. The solvent was removed, affording a
yellowish-white crystalline residue. The crystalline mass,
containing product and triphenylphosphine oxide, was added
to a filter funnel and washed with hexanes (100 mL). The
solvent was removed from the filtrate to give the crude product.
Chromatography using hexanes-EtOAc (9:1) followed by
hexanes-EtOAc (8:2) as eluent gave 15 (354 mg, 1.71 mmol,
1
92%) as pale yellow crystals: mp 41-42 °C; H NMR δ 7.98
(dd, J ) 7.7 and 1.2 Hz, 1H), 7.92 (dd, J ) 8.3 and 1 Hz, 1H),
7.47 (t, J ) 7.9 Hz, 1H), 7.18 (dd, J ) 17.6 and 11.5 Hz, 1H),
5.43 (dd, J ) 10.4 and 0.8 Hz, 1H), 5.23 (dd, J ) 17.6 and 1.0
Hz, 1H), 3.89 (s, 3H); 13C NMR δ 166.1 (+), 149.8 (+), 133.3
(34) Somei, M.; Saida, Y.; Komura, N. Chem. Pharm. Bull. 1986,
34, 4116.
(32) Seyferth, D.; Vaugan, L. G. J . Organomet. Chem. 1963, 1, 138.
(35) Fractions containing an unseparable mixture of starting mate-
rial and dibrominated product were also isolated.
(33) The reaction was followed by 1H NMR.

5844 J . Org. Chem., Vol. 62, No. 17, 1997
Soderberg and Shriver
mmol, 75%). The salt was used as such without further
purification.
A solution of the salt (1.00 g, 1.88 mmol) in dichloromethane
(50 mL) was reacted with triethylamine (514 µL, 4.00 mmol)
and methanal (g) as described above. Removal of solvent and
purification by chromatography (hexanes-EtOAc, 9:1 followed
by hexanes-EtOAc, 8:2) gave 20 (354 mg, 1.71 mmol, 91%)
as pale yellow crystals: mp 82-83 °C; 1H NMR δ 8.05 (d, J )
8.1 Hz, 2H), 7.61 (t, J ) 8.1 Hz, 1H), 7.04 (dd, J ) 17.8 and
11.5 Hz, 1H), 5.53 (d, J ) 11.5 Hz, 1H), 5.34 (d, J ) 17.8 Hz,
1H); 13C NMR δ 150.1 (+), 128.8 (-), 128.6 (+), 128.0 (-), 127.2
Methanal (g) was bubbled through a purple solution of the
salt (1.96 g, 3.66 mmol) and triethylamine (2.73 mL, 19.6
mmol) in dichloromethane (70 mL) at ambient temperature.
The purple color was discharged within 5 min of addition of
the methanal. The solvent was removed to afford a yellowish-
white crystalline residue. The solvent was removed from the
filtrate to give the crude product. Chromatography using
hexanes-EtOAc (8:2) as eluent gave 18 (761 mg, 3.67 mmol,
100%) as pale yellow crystals.
(-), 121.3 (+); IR (neat), 1532, 1361 cm-1
. Anal. Calcd for
C8H6N2O4: C, 49.49; H, 3.12. Found: C, 49.57; H, 3.16.
In d ole (21).37 To an oven-dried, threaded ACE glass
pressure tube was added 2-nitrostyrene (4)38 (298 mg, 2.00
mmol), palladium diacetate (26 mg, 0.12 mmol), triphenylphos-
phine (124 mg, 0.48 mmol), and 4 mL of MeCN. The tube was
fitted with a pressure head, the solution was saturated with
CO (four cycles to 4 atm of CO), and the reaction mixture was
heated to 70 °C (oil bath temperature) under CO (4 atm) until
all starting material was consumed (15 h) as judged by TLC.
The reaction mixture was diluted with HCl (aq, 10%, 10 mL)
and extracted with Et2O (3 × 10 mL). The combined organic
phases were washed with HCl (aq, 10%, 10 mL) and dried
(MgSO4), and the solvent was removed to give the crude
product. The crude product was purified by chromatography
(hexanes-EtOAc, 9:1) to give 21 (203 mg, 1.75 mmol, 87%) as
white crystals.
5-Br om o-2-n itr oph en yl Tr iflu or om eth an esu lfon ate. To
a solution of 5-bromo-2-nitrophenol31 (5.77 g, 26.5 mmol) in
pyridine (25 mL), cooled in an ice-bath, was added trifluo-
romethanesulfonic acid anhydride (4.79 mL, 28.5 mmol) under
an argon atmosphere. The resulting orange reaction mixture
was stirred for 1 h, removed from the ice bath, and stirred an
additional 20.5 h at ambient temperature. H2O (50 mL) was
added, and the mixture was extracted with CH2Cl2 (4 × 50
mL). The combined organic phases were washed with H2O (4
× 30 mL), dried (MgSO4), filtered, and evaporated to afford a
brown oil. The crude product was purified by chromatography
(hexanes-EtOAc, 8:2) to give 5-bromo-2-nitrophenyl trifluo-
romethanesulfonate (5.89 g, 16.8 mmol, 63%) as a pale yellow
oil: 1H NMR δ 8.12 (d, J ) 8.7 Hz, 1H), 7.80 (d, J ) 8.7 Hz,
1H), 7.66 (s, 1H); 13C NMR δ 141.5 (-), 140.4 (-), 132.7 (+),
129.4 (-), 127.8 (+), 127.5 (+), 118.5 (q, J ) 1274 Hz, -); IR
2-Meth ylin d ole (22).39 A solution of 2-(1-propenyl)ni-
trobenzene (5)10 (326 mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12
mmol), and PPh3 (124 mg, 0.48 mmol) in MeCN (4 mL) was
heated (24 h) under CO (4 atm) as described above. Extraction
and chromatography (hexanes-EtOAc, 9:1) gave 22 (274 mg,
1.92 mmol, 96%) as faint yellow crystals.
(neat) 1593, 1537, 1434, 1347, 1215 cm-1
. Anal. Calcd for
C7H3NO5S: C, 24.02; H, 0.86. Found: C, 24.10; H, 0.94.
4-Br om o-2-eth en yln itr oben zen e (19).36 To a solution of
5-bromo-2-nitrophenyl trifluoromethanesulfonate (3.51 g, 10.0
mmol) and vinyltri-n-butyltin (2.93 mL, 11.0 mmol) in dioxane
(40 mL) was added, under a positive flow of nitrogen, bis-
(dibenzylideneacetone)palladium(0) (288 mg, 0.50 mmol), tri-
phenylphosphine (525 mg, 2.00 mmol), and LiCl (1.48 g, 30.0
mmol), together with a few crystals of 2,6-(1,1-dimethylethyl)-
phenol. The solution was heated at reflux (15.5 h), whereupon
2,3-Dim eth ylin d ole (23).40 A solution of 641 (161 mg, 0.91
mmol), Pd(OAc)2 (12 mg, 0.05 mmol), and PPh3 (57 mg, 0.22
mmol) in MeCN (2 mL) was heated (21.5 h) under CO (4 atm)
as described above. Extraction and chromatography (hex-
anes-EtOAc, 9:1) gave 23 (128 mg, 0.88 mmol, 97%) as white
crystals.
a
yellow-red solution containing a black precipitate was
2-P h en ylin d ole (24).42 A solution of trans-79b (182 mg,
0.81 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and PPh3 (52 mg,
0.20 mmol) in MeCN (4 mL) was heated (18.5 h) under CO (4
atm) as described above. Extraction and chromatography
(hexanes-EtOAc, 9:1) gave 24 (156 mg, 0.81 mmol, 100%) as
white crystals.
Similar reaction of a 1:1 mixture of cis- and trans-7 (225
mg, 1.00 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), and PPh3 (63
mg, 0.24 mmol) in MeCN (4 mL) was heaed (21 h) under CO
(4 atm) gave 24 (176 mg, 0.91 mmol, 91%).
formed. The reaction mixture was cooled to ambient temper-
ature, and the solvent was removed to give a black oil. The
oil was dissolved in dichloromethane (20 mL), washed with
NH4OH (10%, aq, 3 × 20 mL) and H2O (3 × 20 mL), and dried
(MgSO4). Removal of the solvent gave a two-phase residue
consisting of a black oil (bottom) and a yellow oil (top), which
was purified by two consecutive chromatographies using for
the first column hexanes-EtOAc (19:1) as eluent and for the
second column hexanes-EtOAc (49:1) to give 19 (1.85 g, 8.13
mmol, 81%) as yellow crystals.
5-Meth ylin d ole (25).43 A solution of 8 (152 mg, 0.93
mmol), Pd(OAc)2 (13 mg, 0.06 mmol), and PPh3 (62 mg, 0.24
mmol) in MeCN (4 mL) was heated (48 h) under CO (4 atm)
as described above. Additional Pd(OAc)2 (6 mg, 0.03 mmol)
and PPh3 (8 mg, 0.03 mmol) were added, and the mixture was
pressurized and heated (24 h). Extraction and chromatogra-
phy (hexanes-EtOAc, 9:1) gave 25 (62 mg, 0.47 mmol, 51%)
as faint yellow crystals.
2-Eth en yl-1,3-d in itr oben zen e (20). Bromine (1.23 mL,
24.0 mmol) was added, over a 2 min period, to a boiling
solution of 2-methyl-1,3-dinitrobenzene (1.82 g, 10.0 mmol) and
benzoyl peroxide (242 mg, 1.00 mmol) in carbon tetrachloride
(20 mL) under irradiation using a 100 W lamp. Under
constant heating and irradiation, the mixture was monitored
by TLC, and small increments of benzoyl peroxide and bromine
were added until all starting material was consumed. When
completed, the solution was allowed to cool to ambient tem-
perature followed by solvent removal. The crude product was
purified by chromatography (hexanes-EtOAc, 9:1) to give
2-bromomethyl-1,3-dinitrobenzene (2.07 g, 7.92 mmol, 79%)
4-Meth oxyin d ole (26).44 A solution of 9 (179 mg, 1.00
mmol), Pd(OAc)2 (13 mg, 0.06 mmol), and PPh3 (62 mg, 0.24
mmol) in MeCN (2 mL) was heated (20 h) under CO (4 atm)
as described above. Extraction and chromatography (hex-
anes-EtOAc, 9:1) gave 26 (131 mg, 0.89 mmol, 89%) as faint
yellow crystals.
1
as white crystals: mp 73-74 °C; H NMR δ 8.10 (d, J ) 8.1
Hz, 2H), 7.68 (t, J ) 8.2 Hz, 1H), 4.94 (s, 2H); 13C NMR δ 149.9
(+), 130.2 (-), 128.6 (-), 126.5 (+), 20.3 (+); IR (neat) 1530,
1355 cm-1. Anal. Calcd for C7H5BrN2O4: C, 32.21; H, 1.93.
Found: C, 32.46; H, 2.02.
(37) Aldrich Library of Spectra: 1H and 13C NMR spectra 3, 121 A,
FT-IR spectra 2,653 A.
Triphenylphosphine (2.02 g, 7.70 mmol) was reacted with
2-bromomethyl-1,3-dinitrobenzene (1.83 g, 7.00 mmol) in
chloroform (30 mL), as described above, to give a crude
phosphonium salt (3.71 g, 6.90 mmol, e90%) as a bright yellow
powder. The salt was used as such without further purifica-
tion. Spectral data of the crude product: 1H NMR δ 8.13 (d,
J ) 8.1 Hz, 2H), 7.91-7.57 (m, 16H), 5.77 (d, J ) 14.2 Hz,
2H).
(38) Haslinger, E.; Wolschann, P. Org. Magn. Reson. 1977, 9, 1.
(39) Aldrich Library of Spectra: 1H and 13C NMR spectra 3, 121 C,
FT-IR spectra 2,653 C.
(40) Aldrich Library of Spectra: 1H and 13C NMR spectra 3,124 A,
FT-IR spectra 2,655 B.
(41) Mochlov, S. S.; Kutateladze, T. G.; Fedotov, A. N. Zh. Org.
Khim. 1991, 27, 1343.
(42) Smith, A. B., III; Visnik, M.; Haseltine, J . N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957.
(43) Aldrich Library of Spectra: 1H and 13C NMR spectra 3,122 C,
FT-IR spectra 2,654 B.
(36) Oda, N.; Yoshida Y.; Nagai, S.; Ueda, T.; Sakakibara, J . Chem.
Pharm. Bull. 1987, 35, 1796.
(44) Aldrich Library of Spectra: 1H and 13C NMR spectra 3,127 C,
FT-IR spectra 2,657 C.

Palladium-Catalyzed Synthesis of Indoles
J . Org. Chem., Vol. 62, No. 17, 1997 5845
5-Meth oxyin d ole (27).8 A solution of 10 (358 mg, 2.00
mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124 mg, 0.48
mmol) in MeCN (4 mL) was heated (19 h) under CO (4 atm)
as described above. Extraction and chromatography (hex-
anes-EtOAc, 9:1) gave 27 (185 mg, 1.26 mmol, 63%) as faint
yellow crystals.
Meth yl In d ole-6-ca r boxyla te (34).8 A solution of 17 (414
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg, 0.48 mmol) in MeCN (4 mL) was heated (21 h) under CO
(4 atm) as described above. After this time, some starting
material remained (by TLC) and an additional amount of Pd-
(OAc)2 (26 mg, 0.12 mmol) and PPh3 (124 mg, 0.48 mmol) was
added. The mixture was heated for another 25 h to give, after
extraction and chromatography (hexanes:EtOAc, 9:1), 34 (274
mg, 1.57 mmol, 78%) as faint yellow crystals.
Meth yl In d ole-7-ca r boxyla te (35).8 A solution of 18 (414
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg, 0.48 mmol) in MeCN (4 mL) was heated (27 h) under CO
(4 atm) as described above. After this time, some starting
material remained (by TLC), and additional Pd(OAc)2 (26 mg,
0.12 mmol) and PPh3 (124 mg, 0.48 mmol) were added. The
mixture was heated for another 48 h, affording, after extraction
and chromatography (hexanes-EtOAc, 9:1), 35 (260 mg, 1.40
mmol, 71%) as faint yellow crystals and 6-carbomethoxy-2-
ethenylnitrobenzene (110 mg, 0.53 mmol, 27%).
6-Meth oxyin d ole (28).8 A solution of 11 (358 mg, 2.00
mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124 mg, 0.48
mmol) in MeCN (4 mL) was heated (21 h) under CO (4 atm)
as described above. Extraction and chromatography (hexanes:
EtOAc, 9:1) gave 28 (116 mg, 0.79 mmol, 40%) as faint yellow
crystals.
6-Meth oxy-3-m eth ylin d ole (29).45 A solution of 12 (386
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg 0.48 mmol) in MeCN (4 mL) was heated (24 h) under CO
(4 atm) as described above. Extraction and chromatography
(hexanes-EtOAc, 19:1) gave 29 (261 mg, 1.62 mmol, 81%) as
white crystals.
4-Hyd r oxyin d ole (30).46 A solution of 13 (207 mg, 1.25
mmol), Pd(OAc)2 (18 mg, 0.08 mmol), and PPh3 (84 mg, 0.32
mmol) in MeCN (4 mL) was heated overnight under CO (4
atm) as described above. Extraction and chromatography
(hexanes:EtOAc, 7:3) gave 30 (159 mg, 1.20 mmol, 96%) as
faint yellow-brown crystals.
4-Br om oin d ole (2).19 A solution of 3-bromo-2-ethenylni-
trobenzene (1)20 (456 mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12
mmol), and PPh3 (124 mg, 0.48 mmol) in MeCN (4 mL) was
heated (15 h) under CO (4 atm) as described above. Extraction
and chromatography (hexanes:EtOAc, 19:1) gave 2 (328 mg,
1.67 mmol, 84%) as faint yellow crystals.
4-[(Tr iflu or om eth yl)su lfon yl]in d ole (31). A solution of
2-ethenyl-3-nitrophenyl trifluoromethanesulfonate (14)24 (594
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg, 0.48 mmol) in MeCN (4 mL) was heated (48 h) under CO
(4 atm) as described above. Extraction and chromatography
using hexanes-EtOAc (9:1) followed by hexanes-EtOAc (8:
2) gave 2-ethenyl-3-nitrophenyl trifluoromethanesulfonate (230
mg, 0.77 mmol, 39%) followed by 31 (210 mg, 0.79 mmol, 40%),
the latter as a faint yellow oil: 1H NMR δ 8.39 (br s, 1H), 7.33
(d, J ) 7.9 Hz, 1H), 7.21-7.15 (m, 2H), 7.10 (d, J ) 7.9 Hz,
1H), 6.68 (s, 1H); 13C NMR δ 142.2 (+), 138.0 (+), 125.9 (-),
121.8 (-), 120.9 (+), 118.8 (q, J ) 318 Hz, +), 111.7 (-), 111.5
(-), 98.7 (-); IR (neat) 3447, 1414, 1210 cm-1. Anal. Calcd
for C9H6F3NO3: C, 40.76; H, 2.28. Found: C, 40.68; H, 2.35.
Meth yl In d ole-4-ca r boxyla te (32).47 A solution of 15 (414
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg, 0.48 mmol) in MeCN (4 mL) was heated (23 h) under CO
(4 atm) as described above. Extraction and chromatography
(hexanes-EtOAc, 9:1) gave 32 (350 mg, 2.00 mmol, 100%) as
faint yellow crystals.
4-Br om oin d ole (2) a n d Met h yl N-(3-Br om o-2-et h -
en ylp h en yl)ca r b a m a t e (3). A solution of 3-bromo-2-eth-
enylnitrobenzene (1) (456 mg, 2.00 mmol), Pd(OAc)2 (26 mg,
0.12 mmol), and dppp (50 mg, 0.12 mmol) in DMF (4 mL) and
MeOH (2 mL) was heated (22 h) under CO (4 atm) as described
above. Extraction and chromatography (hexanes:EtOAc,
19:1) gave, in order of elution, 3 (88 mg, 0.34 mmol, 17%) as
white crystals followed by 2 (297 mg, 1.52 mmol, 76%) as faint
yellow crystals. Analytical data for 3: mp 94-95 °C; 1H NMR
δ 8.08 (d, J ) 7.9 Hz, 1H), 7.35 (s, 1H), 7.28 (d, 8.1 Hz, 1H),
7.12 (t, J ) 8.2 Hz, 1H), 6.60 (dd, J ) 18.0 and 11.4 Hz, 1H),
5.73 (dd, J ) 11.3 and 1.2 Hz, 1H), 5.48 (dd, J ) 18.3 and 1.5
Hz, 1H), 3.76 (s, 3H); 13C NMR δ 153.7 (+), 136.3 (+), 133.4
(-), 129.0 (-), 128.2 (-), 126.9 (-), 123.3 (+), 122.3 (+), 118.0
(-), 52.4 (+); IR (neat) 3278, 1718, 1692 cm-1. Anal. Calcd
for C10H10BrNO2: C, 46.90; H, 3.94. Found: C, 46.64; H, 4.05.
4-Nitr oin d ole (37).48 A solution of 20 (388 mg, 2.00 mmol),
Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124 mg, 0.48 mmol)
in MeCN (4 mL) was heated overnight (26 h) under CO (4 atm)
as described above. Extraction and chromatography (hex-
anes-EtOAc, 9:1) gave 37 (310 mg, 1.78 mmol, 89%) as fine
yellow crystals.
Meth yl In d ole-5-ca r boxyla te (33).8 A solution of 16 (414
mg, 2.00 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), and PPh3 (124
mg, 0.48 mmol) in MeCN (4 mL) was heated (120 h) under
CO (4 atm) as described above. Extraction and chromatogra-
phy (hexanes:EtOAc, 9:1) gave methyl 3-ethenyl-4-nitroben-
zoate (180 mg, 0.87 mmol, 43%) followed by 33 (165 mg, 0.94
mmol, 47%), the latter as faint yellow crystals.
Ack n ow led gm en t. Startup funds from West Vir-
ginia University (BCS) and grants from the National
Science Foundation (Grant CHE-9203146) and the
National Institutes of Health (Grant R15 GM51030-02)
supporting this research are gratefully acknowledged.
5-Bromo-2-nitrophenyl trifluoromethanesulfonate was
prepared by Stacy R. Rector.
(45) Fleming, I.; Woolias, M. J . Chem. Soc., Perkin Trans. 1 1979,
827.
(46) Aldrich Library of Spectra: 1H and 13C NMR spectra 3,130 C,
FT-IR spectra 2,659 C.
(47) Watanabe, F.; Hamaguchi, F.; Ohki, S. Chem. Pharm. Bull.
1972, 20, 2123. See also ref 27a.
(48) Melhado, L. L.; Brodsky, J . L. J . Org. Chem. 1988, 53, 3852.
J O970516+