Synthesis of indoles via palladium[0]-mediated ullmann cross-coupling of o-halonitroarenes with α-halo-enones or -enals

Article abstract of DOI:10.1021/ol034745w

(Matrix presented) Palladium[0]-mediated Ullmann cross-coupling of o-halonitrobenzene (1) and various related nitroarenes with a range of α-halo-enones (e.g., 2) or -enals readily affords the expected α-arylenones, e.g., 3, or -enals, which are converted into the corresponding indoles, e.g., 4, on reaction with dihydrogen in the presence of Pd on C.

Full text of DOI:10.1021/ol034745w

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2497-2500
Synthesis of Indoles via
Palladium[0]-Mediated Ullmann
Cross-Coupling of o-Halonitroarenes
with r-Halo-enones or -enals
Martin G. Banwell,* Brian D. Kelly, Okanya J. Kokas, and David W. Lupton
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received May 5, 2003
ABSTRACT
Palladium[0]-mediated Ullmann cross-coupling of o-halonitrobenzene (1) and various related nitroarenes with a range of r-halo-enones (e.g.,
2) or -enals readily affords the expected r-arylenones, e.g., 3, or -enals, which are converted into the corresponding indoles, e.g., 4, on
reaction with dihydrogen in the presence of Pd on C.
The indole moiety represents a key substructure associated
with many biologically active natural products and medicinal
entities.1 Various methods1,2 have been developed for the
construction of this ring system. The most well-known and
venerable is the Fischer indole synthesis2 wherein an
arylhydrazine is condensed with a enolizable ketone to give,
after loss of ammonia, the corresponding 2,3-disubstituted
heterocycle. While being an enormously important procedure,
this approach suffers from a number of drawbacks, not the
least being the rather harsh reaction conditions required to
effect [3,3]-sigmatropic rearrangement of the initially pro-
duced hydrazone and the lack of regiocontrol available when
employing ketones that can exist in more than one enolic
form. These difficulties have been addressed by Rawal and
co-workers3 through the coupling of o-nitrophenylphenyl-
iodonium fluoride (NPIF) with various trimethylsilyl enol
ethers followed by TiCl3-induced reductive cyclization of
the resulting R-(o-nitrophenyl)ketone to give 2,3-disubstituted
indoles. The NPIF employed in such conversions is produced
over two steps from the corresponding o-iodonitroarene,
while the TMS-enol ether can be generated through 1,4-
reduction/enolate trapping of the relevant enone or enoliza-
tion of the appropriate ketone under conditions of kinetic or
thermodynamic control followed by trapping with chlorot-
rimethylsilane. In recent and related work, Scott and So¨der-
berg have reported4 that the products of Stille cross-coupling
of o-(tri-n-butylstannyl)nitrobenzene with various R-iodocy-
cloalkenones engage in a novel metal-catalyzed reductive
N-heteroannulation in the presence of 6 atm of CO to give
1,2-dihydro-4(3H)-carbazolones. In Shibasaki’s recently
communicated5 synthesis of (-)-strychnine, the indole
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996.
(b) Joule, J. A. Indole and its DeriVatiVes. In Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations; Thomas, E. J., Ed.; Georg
Thieme Verlag: Stuttgart, 2000; Category 2, Vol. 10, Chapter 10.13. (c)
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(2) (a) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience:
New York, 1982. (b) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
(3) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org. Lett.
1999, 1, 673.
(4) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron Lett. 2002, 43, 1621.
10.1021/ol034745w CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003

Table 1. Optimization of Conditions for Coupling Reaction 1 + 2 f 3
entry
halide 1 (mmol)
halide 2 (mmol)
catalysta,b (equiv of Cu)c
solvent
temp (°C)/time (h)
% yieldd (of 3)
1
2
3
4
5
6
7
8
9
10
11
12
13
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) I (1.0)
X ) Br (1.0)
X ) I (5.0)
X ) Br (1.0)
X ) I (1.0)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) I (0.5)
X ) Br (0.5)
X ) Br (0.5)
X ) I (0.5)
X ) I (0.5)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
B (10)
C (10)
D (10)
B (10)
B (10)
B (10)
B (5)
DMSO
DMSO
DMSO
DMF
NMP
DME
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
90/1
70/1
80
74
83
58
67
no rxn
91
85
89
88
72
88
87e
50/21
70/5
70/30
70/30
50/1
50/3
50/4
70/2
70/6
70/1.5
70/1
a Catalysts: A ) Pd(PPh3)4; B ) Pd2(dba)3; C ) PdCl2(dppf); D ) Pd(OAc)2. b Catalyst loadings of 6 mol % were used in these optimization studies.
c Equiv with respect to 2. d Yield calculations based on quantities of 2 employed. e Yield of homocoupling product 5 was 51%.
residue is assembled via Stille cross-coupling of an R-iodo-
cyclohexenone with o-(tri-n-methylstannyl)nitrobenzene and
then reductive cyclization of the coupling product with zinc
in methanolic aqueous ammonium chloride. In an especially
important development, Buchwald and co-workers have
demonstrated6 that methyl and certain other enolizable
ketones can couple with o-chloro- or o-bromonitrobenzenes
in the presence of Pd2(dba)3 and phenolic additives to give
R-(o-nitroaryl)ketones that undergo reductive cyclization to
the corresponding indoles on exposure to TiCl3/NH4OAc. It
is against this background that we now report a comple-
mentary and operationally simple two-step indole synthesis
that employs readily available starting materials and reagents,
avoids the need for using stannanes or hypervalent iodine-
containing species, and still addresses the deficiencies
associated with, inter alia, the Fischer indole synthesis (vide
supra).
of Pd on C then affords the target indole, e.g., 4. The requisite
R-halo-enones or -enals are readily obtained by halogenation
of the corresponding enone or enal according to the simple
and highly effective procedures reported by Johnson9a and
Smith.9b
Preliminary studies were focused on optimization of the
coupling reaction 1 + 2 f 310 and involved efforts to identify
the most effective solvent, catalyst, temperature, stoichiom-
etry, etc. The results of such studies are summarized in Table
1 and reveal that DMSO is the best solvent and that reaction
temperatures of 50-70 °C are required. A range of palladium
catalysts can be employed, including Pd(OAc)2, which is
presumably reduced to an active Pd[0] species by the copper
powder. Not surprisingly, efficient and rapid reactions are
observed with the iodinated versions of coupling partners 1
and 2, although their brominated counterparts can also be
employed, either together (see entry 10) or individually (see
entries 11 and 12). In contrast, neither o-chloronitrobenzene
(1, X ) Cl) nor o-nitrophenyl triflate (1, X ) OTf) could
be induced to couple with 2 (X ) I) under any of the
conditions defined in Table 1. In the optimization experi-
ments, ca. 5-10 equiv (with respect to 2) of copper powder
were employed and the chromatographically separable by-
product 5,8 arising from homocoupling of 1, was always
observed. This unwanted process could be suppressed,
although generally not completely eliminated, by reducing
the amount of iodoarene employed and/or by slow addition
of compound 1 to the reaction mixture. Bearing such
The essential aspects of our approach are shown in Scheme
1 with the pivotal step involving a palladium[0]-mediated
Scheme 1
(5) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 14546.
(6) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 15168.
(7) Shimizu, N.; Kitamura, T.; Watanabe, K.; Yamaguchi, T.; Shigyo,
H.; Ohta, T. Tetrahedron Lett. 1993, 34, 3421.
(8) Banwell, M. G.; Smith, J. A. Org. Biomol. Chem. 2003, 1, 296.
(9) (a) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(b) Smith, A. B.; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J. Org. Chem.
1982, 47, 1855 (see also: Ramanarayanan, G. V.; Shukla, V. G.; Akamanchi,
K. G. Synlett 2002, 2059).
(10) Compound 3 has previously been obtained via mutlistep reaction
sequences: (i) ref 4. (ii) Sole´, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996,
52, 4013.
Ullmann cross-coupling reaction7,8 of an o-iodo- or o-
bromonitrobenzene, e.g., 1, with an R-halo-R,â-unsaturated
ketone, e.g., 2, or aldehyde. Reduction of the ensuing
coupling product, e.g., 3, with dihydrogen in the presence
2498
Org. Lett., Vol. 5, No. 14, 2003

outcomes in mind, the optimal conditions, in terms of a
favorable time/yield ratio, for effecting this Ullmann-type
coupling were considered to involve those shown in entry
13 and employing 5 equiv of copper at 70 °C for 1 h. The
predominance of the cross-coupling product in these reactions
is consistent with the mechanistic proposals advanced by
Shimizu et al.7
applied to cycloheptenone 94 produced, via intermediate 10,4
the hexahydrocyclohept[b]indole 1113 in an efficient manner.
Cross-coupling of the enantiomerically pure R-iodocyclo-
pentenone 1214 with o-iodonitrobenzene afforded product 13,
which underwent reductive cyclization to give the indole 14.
Exploitation of the readily available R-halocinnamaldehyde
15 (X ) I or Br)15 in an analogous sequence leading, via
16, to compound 1716 demonstrates that this methodology
can be applied to the preparation of non-annulated indoles.
The application of more highly substituted o-halonitroben-
zenes to the synthesis of indoles is highlighted in entries
5-7 of Table 2. Thus, coupling of 2,4-dinitrobromobenzene
18 with iodoenone 2 (X ) I) afforded the expected product
19, which upon reductive cyclization gave the especially air-
Conversion of coupling product 3 into the annulated indole
4 was best effected by reduction of the former compound
with dihydrogen (at 1 atm) in the presence of 10% Pd on C.
The spectral data derived from the carbazole 411 so obtained
proved to be identical, in all respects, with those of an
authentic sample. Conversion 3 f 4 proceeded in essentially
1
quantitative yield, as judged by H NMR analysis of the
sensitive 7-amino-substituted tetrahydrocarbazole 20.17
A
crude reaction mixture, but attempts to rigorously purify this
slightly air- and light-sensitive product by flash chromatog-
raphy resulted in some decomposition. As a consequence,
only a ca. 60% yield of analytically pure 4 was finally
obtained. Nevertheless, this reductive cyclisation procedure
proved to be perfectly adequate in carrying forward related
coupling products to the target indoles (vide infra).
The reaction conditions established above for the first step
of the two-step conversion shown in Scheme 1 were applied
to a range of other coupling partners, with the products then
being reduced to the corresponding indoles. The relevant
structures are shown below and outcomes of these reaction
sequences presented in Table 2. Thus, the lower homologue
related sequence employing the methoxy-substituted arene
21 affords, via intermediate 22,4 the analogous methoxylated
system 23.18 Interestingly, the dibromonitrobenzene 24
engages in a regioselective cross-coupling reaction with
compound 2 (X ) I) to give compound 25, the structure of
which follows from its reductive cyclization, with ac-
companying debromination, to compound 4.
Table 2. Indole Synthesis via an Ullmann Coupling/Reductive
Cyclization Sequence
cross-
% yield of
nitro-
arene
enone/
enal
coupling
%
2,2′-dinitro-
%
entry
producta yield biphenyl indole yield
1
2
3
4
5
6
7
8
9
1 (X ) I)
1 (X ) I)
6
9
7
10
13
16
16
19
22
25
26b
30
30
33
75
66
68
67
50
82
80
71
77
64
64
75
46c
55c
48c
54c
52
8
11
14
17
17
20
23
4
28
31
31
34
90
72
90
88
88
80
97
90
77g
92
92
88
1 (X ) I)) 12
1 (X ) I) 15 (X ) I)
1 (X ) Br) 15 (X ) Br)
18
21
24
2 (X ) I)
2 (X ) I)
2 (X ) I)
46d
56e
56f
10
11
12
1 (X ) I) 29
1 (X ) Br) 29 (X ) Br)
1 (X ) I) 32
45c
47c
53c
a Reaction conditions defined in entry 13, Table 1, were employed for
the Ullmann couplings listed here. b Product obtained via Suzuki-Miyaura
cross-coupling of compound 25 with 1,3-benzodioxol-5-ylboronic acid.
c Yield of compound 5. d Yield of 2,2′,4,4′-tetranitrobiphenyl (see Supporting
Information for spectral data). e Yield of 2,2′-dimethoxy-4,4′-dinitrobiphen-
yl.7 f Yield of 4,4′-dibromo-2,2′-dinitrobiphenyl (see: Yamoto, T.; Hideshi-
ma, C.; Suehiro, K.; Tashiro, M.; Surya Prakash, G. K.; Olah, G. A. J.
Org. Chem. 1991, 56, 6248). g Yield after an extended reaction time (see
text and Supporting Information).
The bromo-substituent of compound 25 can be exploited in
cross-coupling reactions prior to implementing the reductive
cyclization process. Thus, Suzuki-Miyaura reaction of this
arene with 1,3-benzodioxol-5-ylboronic acid19 afforded prod-
(13) Anderson, A. G., Jr.; Richards, H. F.; Haddock, R. D. Org. Prep.
Proced. Int. 1989, 21, 649.
(14) Banwell, M.; Hockless, D.; Jarrott, B.; Kelly, B.; Knill, A.;
Longmore, R.; Simpson, G. J. Chem. Soc., Perkin Trans. 1 2000, 3555.
(15) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach,
D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58.
of 2 (X ) I), viz. compound 6,9 coupled with compound 1
(X ) I) and the resulting product, 7,4 was then converted
into the corresponding indole, 8,12 using the reductive
cyclization procedure defined above. An analogous sequence
(16) Stuetz, P.; Stadler, P. A. Org. Synth. 1977, 56, 8.
(17) Kuehne, M. E. J. Am. Chem. Soc. 1962, 84, 837.
(18) Wender, P. A.; White, A. W. Tetrahedron 1983, 39, 3767.
(19) Banwell, M. G.; Cowden, C. J. Aust. J. Chem. 1994, 47, 2235.
(11) Adam, G.; Andrieux, J.; Plat, M. Tetrahedron, 1985, 41, 399.
(12) Miyata, O.; Kimura, Y.; Naito, T. Synthesis 2001, 1635.
Org. Lett., Vol. 5, No. 14, 2003
2499

uct 26, which engaged in the expected reductive cyclization
reaction to give indole 28, although if the usual reaction time
(0.75 h) was used then this was accompanied by roughly
equal amounts of compound 27. However, simply running
the reaction overnight led to complete and efficient conver-
sion into the indole.
protocol. The similarly successful conversion of the R-io-
docrotonaldehyde 32, via nitroarene 33, into 3-ethylindole
(34)22 serves to further emphasize the utility of the present
work, which provides an exceptionally simple means of
gaining access to a wide range of derivatives of the title
heterocycle.
Acknowledgment. We thank the Australian Research
Council for providing a postdoctoral Fellowship to B.D.K..
Supporting Information Available: Preparation and
characterization of compounds 3, 4, 7, 8, 10, 11, 13, 14, 16,
17, 19, 20, 22, 23, 25-28, and 30-34 and 1H NMR spectra
of compounds 4, 7, 8, 10, 11, 13, 14, 16, 19, 20, 22, 23,
25-28, and 30-34. This material is available free of charge
via the Internet at http://pubs.acs.org.
The successful conversion of readily available halo-enone
29 (X ) I,9a X ) Br20), via coupling product 30, into indole
3121 highlights the capacity to employ open-chain R-halo-
enones in the present cross-coupling/reductive cyclization
OL034745W
(20) Park, K. P.; Ha, H.-J.; Williard, P. G. J. Org. Chem. 1991, 56, 6725.
(21) (a) Dave, V.; Warnhoff, E. Can. J. Chem. 1976, 54, 1015. (b) Satoh,
T.; Kaneko, Y.; Sakata, K.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1986,
59, 457.
(22) (a) Kubo, A.; Nakai, T. Synthesis 1980, 365. (b) Amat, M.; Hadida,
S.; Sathyanarayana, S.; Bosch, J. Org. Synth. 1996, 74, 248.
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Org. Lett., Vol. 5, No. 14, 2003