One-pot synthesis of 2-substituted indoles from 2-aminobenzyl phosphonium salts. A formal total synthesis of arcyriacyanin A

Article abstract of DOI:10.1021/ol801034x

(Chemical Equation Presented) The reaction of (2-aminobenzyl) triphenylphosphonium bromide with aromatic aldehydes or α,β- unsaturated aldehydes under microwave-assisted conditions constitutes a new synthesis of 2-substituted indoles in high yields (81-97%) in a one-pot reaction. The adduct from indole-4-carboxaldehyde was an advanced intermediate in the synthesis of arcyriacyanin A.

Full text of DOI:10.1021/ol801034x

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3061-3063
One-Pot Synthesis of 2-Substituted
Indoles from 2-Aminobenzyl
Phosphonium Salts. A Formal Total
Synthesis of Arcyriacyanin A
George A. Kraus* and Haitao Guo
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
gakraus@iastate.edu
Received May 5, 2008
ABSTRACT
The reaction of (2-aminobenzyl) triphenylphosphonium bromide with aromatic aldehydes or r,ꢀ-unsaturated aldehydes under microwave-
assisted conditions constitutes a new synthesis of 2-substituted indoles in high yields (81-97%) in a one-pot reaction. The adduct from
indole-4-carboxaldehyde was an advanced intermediate in the synthesis of arcyriacyanin A.
Many 2-aryl and 2-vinylindoles are key subunits of a variety
of biologically active molecules.1 The 2-vinylindole moiety
can function as a heterocyclic diene for stereocontrolled
annulation of the indole skeleton.4c The traditional methods
include Fischer indole synthesis, Batcho-Leimgruber syn-
thesis from o-nitrotoluenes, Gassman synthesis from N-
haloanilines, reductive cyclization of o-nitrobenzyl ketones,
and Madelung cyclization of N-acyl-o-toluidines.2 Transition-
metal-catalyzed reactions, using palladium or copper, for the
direct arylation of indoles and related heterocycles have been
widely reported.3 The Wittig cyclizations of N-acylated
2-aminobenzyl phosphonium salts also provide versatile
syntheses of quinolines and 2-aryl or vinylindoles.4 Despite
the fact that these reactions are synthetically useful, they
suffer from several disadvantages: (i) high temperatures and
long times (above 125 °C and 12 h), (ii) expensive transition-
metal catalysts, (iii) multistep and moderate yields as well
as high sensitivity to moisture. We report herein a new
approach that can successfully afford 2-aryl or vinylindoles
in high yields in one pot under very mild conditions.
In an approach to the indoloquinoline alkaloids, we
condensed commercially available phosphonium salt 1 with
isatin 2 to form imine 3 under the conditions shown in
Scheme 1. Treatment of imine 3 with potassium tert-butoxide
in either THF or toluene provided adduct 5 in around 21%
yield.
(3) (a) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
1990, 215. (b) Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah, V.;
Thorntorn-Pett, M. Tetrahedron 1998, 54, 2595. (c) Larock, R. C.; Yum,
E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (d) Battistuzzi, G.;
Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671. (e) Sezen, B.; Sames,
D. J. Am. Chem. Soc. 2003, 125, 5274. (f) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 9578. (g) Lane, B. S.; Sames, D. Org. Lett.
2004, 6, 2897. (h) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 10250. (i) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc.
2005, 127, 8050. (j) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148. (k) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (l) Deprez, N. R.;
Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972.
(4) (a) Le Corre, M.; Hercouet, A.; Le Stanc, Y.; Le Baron, H.
Tetrahedron 1985, 41, 5313. (b) Mahboobi, S.; Bernauer, K. HelV. Chim.
Acta 1988, 71, 2034. (c) Eitel, M.; Pindur, U. Synth. 1989, 5, 364. (d)
Kuehler, T. C.; Swanson, M.; Christenson, B.; Klintenberg, A.; Lamm, B.;
Faegerhag, J.; Gatti, R.; Oelwegaard-Halvarsson, M.; Shcherbuchin, V.;
Elebring, T.; Sjoestroem, J. J. Med. Chem. 2002, 45, 4282. (e) Tao, M.;
Park, C. H.; Bihovsky, R.; Wells, G. J.; Husten, J.; Ator, M. A.; Hudkins,
R. L. Bioorg. Med. Chem. Lett. 2006, 16, 938.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa,
M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (c) Cacchi, S.; Fabrizi, G.
Chem. ReV. 2005, 105, 2873. (d) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005,
105, 2873.
(2) Indoles; Sundberg, R. J., Ed.; Academic: London, 1996.
10.1021/ol801034x CCC: $40.75
Published on Web 06/24/2008
2008 American Chemical Society

or toluene with a catalytic amount of acetic acid with a low
yield. Application of microwave energy as a nonconventional
activation source in organic syntheses is increasing rapidly,
and its benefits have been well documented.9 Microwave-
assisted organic synthesis has proven to be a valuable tool
to increase efficiency in the synthesis of heterocyclic
compounds.10 This prompted us to synthesize the 2-unsub-
stituted indoles under the microwave conditions. The results
presented in Table 1 show that under microwave-assisted
Scheme 1
Table 1. Reation of 1 with Isatin to Generate Compound 5a
Although we had expected the product to be compound
4, an intermediate in the synthesis of cryptolepine,5 our
proton, and carbon NMR spectra did not match the published
spectra.6 After considering its mass spectrum (which showed
the mass of 4 plus an oxygen atom) and the 13C NMR (which
showed a resonance at 99 ppm as the most downfield
resonance), we tentatively assigned structure 5. Compound
5 had been reported,7 and its major mass spec fragmentation
patterns were identical to those in our adduct.
We reasoned that if a spiro compound such as 5 had
formed such an intermediate might be employed in a general
synthesis of 2-substituted indoles. Since these compounds
are intermediates for the synthesis of indole natural products,
a one-pot synthesis from commercially available starting
materials would be useful. The strategy for the formation of
2-substituted indoles 9 from 1 via 7 and 8 is illustrated in
Scheme 2.
entry
solvent
temperature (°C)
time (h)
yieldb (%)
1
methanol
toluene
methanol
65
111
80
12
12
10 min
25
21
87
2
3c
a Reaction conditions: phosphonium salt 1 (1 mmol), isatin (1 mmol),
AcOH (0.4 mmol), solvent (2 mL). b Isolated yield. c Microwave assisted
conditions the reaction proceeds very efficiently within a few
minutes, and the yield also increased from 21% to 87%.
When phosphonium salt 1 was allowed to react with
benzaldehyde to form the imine and then potassium tert-
butoxide was added, 2-phenylindole (8) was formed as the
only product in 95% yield. In view of this promising result,
several aromatic and R,ꢀ-unsaturated aldehydes were reacted
with 1. The results of these experiments are collected in Table
2.
Scheme 2
As the results in Table 2 indicate, a wide range of
functionalized aldehydes react effectively with phosphonium
salt 1, including a variety of electron-donating and electron-
withdrawing substituents, such as aromatic ethers, halides,
nitro and aryl groups (entries 2, 3, 4, and 5), and also
heterocyclic aldehydes (entries 6 and 7). In addition, the
reactions with R,ꢀ-unsaturated aldehydes (entries 8 and 9)
also proceed very smoothly and gave high yields under these
conditions. Unfortunately, the alkyl aldehydes such as
isobutyraldehyde did not form the imine intermediates with
phosphonium salt 1 under the same microwave conditions.
Adduct 11 is an advanced intermediate in the synthesis of
the natural product arcyriacyanin A (12).
(9) (a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225. (b) Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985.
(10) (a) Kaddar, H.; Hamelin, J.; Benhaoua, H. J. Chem. Res. 1999,
718. (b) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95.
It is notable that our initial studies used the traditional
methods8 to form an imine by boiling overnight in methanol
(5) (a) Cimanga, K.; DeBruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger,
C. A. J. Nat. Prod. 1997, 60, 688. (b) Dassonviville, L.; Bonjean, K.; De
Pauw-Gillet, M. C.; Colson, P.; Houssier, C.; Quetin-Leclercq, J.; Angenot,
L.; Bailly, C. Biochemistry 1999, 38, 7719.
(11) (ai) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S J. Am.
Chem. Soc. 2006, 128, 4972. (aii) Bedford, R. B.; Betham, M. J. Org. Chem.
2006, 71, 9403. (bi) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007,
9, 2795. (bii) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
(c) Le Corre, M.; Hercouet, A.; Le Stanc, Y.; Le Baron, H. Tetrahedron
1985, 41, 5313. (d) Huffman, J. W. J. Org. Chem. 1962, 27, 503. (e) Arcadi,
A.; Bianchi, G.; Marinelli, F. Synth. 2004, 4, 610.
(6) (a) Paulo, A.; Gomes, E. T.; Houghton, P. J J. Nat. Prod 1995, 58,
1485. (b) Dutta, B.; Some, S.; Ray, J. K. Tetrahedron Lett. 2005, 47, 377.
(7) Kikumoto, R.; Kobayashi, T. Tetrahedron 1966, 22, 3337.
(8) Rajopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1987, 24, 1637.
3062
Org. Lett., Vol. 10, No. 14, 2008

Scheme 3
Table 2. Reaction of 1 with Aldehydes to Generate 2-Aryl and
2-Vinyl Indolesa
in Scheme 3,12 the synthesis of compound 11 constitutes a
formal two-step total synthesis of 12 from commercially
available starting materials.
In conclusion, we have established a new method for the
preparation of 2-aryl and 2-vinyl indoles from commercially
available starting materials. These reactions proceed under
very mild conditions (often at room temperature) and
remarkably short times (less than 2 h) in one pot with high
yields (81-97%). The adduct from indole-4-carboxaldehyde
was an advanced intermediate in the synthesis of arcyri-
acyanin A, which can be synthesized in two steps in 35%
overall yield.
Acknowledgment. We thank the Iowa State University
Department of Chemistry for support of this work.
Supporting Information Available: Detailed synthetic
1
procedures, characterization data, and H NMR, 13C NMR,
and HRMS spectra of these synthesized compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reaction conditions: (i) phosphonium salt 1 (1 mmol), aldehydes (1
mmol), AcOH (0.4 mmol), methanol (2 mL); (ii) t-BuOK (1.6 mmol), THF
(2 mL). b Isolated yield.
OL801034X
(12) (a) Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem.-Eur.
J. 1997, 1, 70. (b) Murase, M.; Watanabe, K.; Kurihara, T.; Tobinaga, S.
Chem. Pharm. Bull. 1998, 46, 889.
Arcyriacyanin A, a pigment of the slime mold of Arcyria
obVelata Onsberg, is an effective inhibitor of protein kinase
C and protein tyrosine kinase.13 Since compound 11 has been
transformed into 12 with 3,4-dibromomaleimide as shown
(13) (a) Gill, M.; Steglich, W. Progr. Chem. Org. Nat. Prod. 1987, 51,
216. (b) Steglich, W. Pure Appl. Chem. 1989, 61, 281. (c) Gribble, G. W.;
Berthel, S. J. Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1993; p 365.
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