A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones

Article abstract of DOI:10.1021/ol036113f

(Equation presented) A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.

Full text of DOI:10.1021/ol036113f

ORGANIC
LETTERS
2004
Vol. 6, No. 1
79-82
A General Synthesis of Substituted
Indoles from Cyclic Enol Ethers and
Enol Lactones
Kevin R. Campos,* Jacqueline C. S. Woo, Sandra Lee, and Richard D. Tillyer
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
keVin_campos@merck.com
Received October 29, 2003
ABSTRACT
A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines
and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives.
This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This
method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.
The prevalence of indoles in natural products and biologically
active compounds has led to a continued strong interest in
the practical synthesis of the indole nucleus.1 Among the
diverse and creative approaches that have been discovered,2
the Fischer indole reaction remains the benchmark to which
other methods are compared.3 Despite being quite versatile,
the Fischer indole reaction with aldehydes often suffers from
low yields and involves a two-step process (i.e., hydrazone
formation, [3 + 3] rearrangement).4 We herein wish to report
a convenient and practical one-pot synthesis of 3-substituted
indoles from commercially available cyclic enol ethers and
enol lactones and the extension of this procedure to the
regioselective synthesis of 2,3-disubstituted indoles (eq 1).
This methodology is highlighted in the synthesis of several
structurally diverse pharmaceutical agents, including the
commercial drugs sumitriptan and indomethacin.
(1) (a) Ihara, M.; Fukumoto, K. Nat. Prod. Rep. 1995, 277. (b) Saxton,
J. E. Nat. Prod. Rep. 1994, 493. (c) Saxton, J. E. Indoles; Wiley-
Interscience: New York, 1983.
(2) For a review of recent developments in the synthesis of indoles, see:
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1. 2000, 1045-1075 and
references therein.
(3) (a) Gribble, G. W. Contemp. Org. Synth. 1994, 1, 1. (b) Hughes, D.
L. Org. Prep. Proc. Int. 1993, 25, 607-632. (c) Robinson, B. The Fischer
Indole Synthesis; Wiley-Interscience: New York, 1982.
In our pursuit of an efficient synthesis of tryptophol
homologs, we were intrigued with the possibility of using
dihydropyran as an aldehyde equivalent in the Fischer indole
reaction.5 We suspected that suitable conditions could be
(4) (a) Zepeda, L. G.; Morales-Rios, M. S.; Joseph,-Nathan, P. Synth.
Commun. 1992, 22, 3243-3256. (b) Shono, T.; Matsumura, Y.; Tsubata,
K. J. Org. Chem. 1984, 49, 3711-3716. (c) Fischer, G. W. J. Heterocycl.
Chem. 1995, 32, 1557-1561. (d) Pete, B.; Bitter, I.; Szantay, C. J.; Schon,
I.; Toke, L. Heterocycles 1998, 48, 1139-1149.
(5) This method has been attempted, resulting in low yields as a two-
step process. (a) White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc.
1994, 116, 1831-1838. (b) McKittrick, B.; Failli, A.; Steffan, R. J.; Soll,
R. M.; Hughes, R.; Schmid, J.; Asselin, A. A.; Shaw, C. C.; Noureldin, R.;
Gavin, G. J. Heterocycl. Chem. 1990, 27, 2151-2163.
10.1021/ol036113f CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/12/2003

developed that would not only generate the hydrazone from
the aryl hydrazine and dihydropyran in situ but also catalyze
the [3 + 3] rearrangement in the same pot.
Table 1. Synthesis of 3-Substituted Indoles from Dihydropyran
We chose 4% aqueous sulfuric acid as the solvent because
of its documented success in promoting the Fisher indole
reaction involving the in situ hydrolysis of an aldehyde
protected as its dimethyl acetal.6 When dihydropyran was
added to a solution of phenylhydrazine hydrochloride in 4%
aqueous sulfuric acid at 100 °C, indole 2a was obtained in
50% isolated yield. The major byproduct of the reaction was
triol 1, resulting from further reaction of 2a with dihydro-
pyran (eq 2).
We suspected that 1 was produced due to the high
concentration of dihydropyran relative to indole product
during the reaction; however, slow addition of dihydropyran
did not decrease the level of 1 (49%).7 After considerable
study, it was discovered that addition of a cosolvent to the
reaction significantly improved the reaction profile, produc-
ing less than 5% of byproduct 1.8 Of the solvents investi-
gated, acetonitrile (MeCN) and N,N-dimethylacetamide
(DMAc) were optimal, affording indole 2a in 85 and 90%
yields, respectively.9
The generality of the process was demonstrated with a
wide variety of functionalized hydrazines bearing ortho,
meta, and para substituents (Table 1).10 In the case of m-tolyl
hydrazine, a 1:1 mixture of regioisomeric indoles (2c:2d)
was obtained. Aryl hydrazines bearing more than one
substituent led to the formation of substituted indoles such
as 2k in good yield.
The utility of this method was highlighted in the synthesis
of Glaxo’s antimigraine drug, sumitriptan (Scheme 1).
Despite the documented difficulty of Fischer indole reactions
with hydrazine 3 due to the instability of the product under
(6) (a) Chen, C.-Y.; Senanyake, C. H.; Bill, T. J.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738-3741. (b)
Klaver, W. H.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989,
111, 2588-2595.
(7) Excess hydrazine (2 equiv) slightly reduced the amount of 1 (40%).
(8) Importance of the cosolvent is due to the homogenization of the
reaction mixture. In purely aqueous systems, the product and dihydrofuran
are insoluble, creating a highly concentrated “organic layer” that leads to
increased formation of 1.
a All reactions were run in 4% H2SO4/DMAc (20 mL/g substrate) at
100 °C unless otherwise noted. All reported yields are after isolation by
chromatography. b Reaction was run in 4% H2SO4/MeCN (20 mL/g) at
reflux. c Reaction was run at 55 °C.
(9) Performing the reaction at 100 °C was optimal. Lower temperatures
gave significantly lower yields of 2a (50 °C, 33% yield; 25 °C, 18% yield).
However, in the case of more electron-rich hydrazines such as p-
methoxyphenylhydrazine, lower temperatures (55 °C) were needed to
prevent the formation of the methoxy-substituted analogue of 1.
(10) Typical Procedure. To a solution of phenylhydrazine-HCl (1 g,
6.92 mmol) in 4% H2SO4 (aq) (10 mL) and DMAc (10 mL) at 100 °C was
added dihydrofuran (630 uL, 6.92 mmol) dropwise over 2 min. The reaction
was aged for 2 h and then cooled to room temperature, extracted with
isopropyl acetate, and washed with water three times. The crude material
was purified by flash chromatography.
acidic conditions,11 the one-pot reaction could be ac-
complished to cleanly afford the desired hydroxyindole 4.
Activation of the hydroxyl group as the mesylate followed
by displacement in the presence of excess dimethylamine
according to previously disclosed methodology11b afforded
sumitriptan in three steps and 45% overall yield (unopti-
mized) from dihydropyran.
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Org. Lett., Vol. 6, No. 1, 2004

Scheme 1. Synthesis of Sumitriptan
Table 2. Fischer Indole Reaction of Phenylhydrazine with
Cyclic Enol Ethers and Enol Lactonesa
To expand the scope of the methodology, the reaction of
phenylhydrazine with other cyclic enol ethers was investi-
gated (Table 2). For example, reaction of phenylhydrazine
with dihydrofuran (5) afforded tryptophol 6 in 72% yield.
Interestingly, reaction of 1-methyldihydrofuran (7) afforded
the 2,3-disubstituted indole 8 in 83% isolated yield as a single
regioisomer.12
Enol lactones also readily participate in this reaction. For
example, reaction of enol lactone 11 with phenylhydrazine
produced 2-methyl indole propionic acid 12 in 75% yield
as a single regioisomer (Table 2, entry 4).13 In contrast, when
the procedure was attempted on angelicalactone (13), the
cyclic acyl hydrazone 14 was the only observed product.14
This side reaction could be circumvented by installation of
an N-benzyl substituent on the hydrazine. Subjection of
N-benzyl phenylhydrazine to the same conditions cleanly
afforded N-benzyl-2-methylindole acetic acid (16) in 70%
yield.
This efficient approach to N-protected indole acetic acids
prompted us to apply the method to the synthesis of Merck’s
antiinflammatory drug, indomethacin.15 Coupling of N-acyl
hydrazine 1716 with angelicalactone under standard condi-
(11) Highest yield obtained in a Fischer indole with 3 was 63%. (a)
Albinson, F. D.; MacKinnon, J. W. M.; Crookes, D. L. U.S. Patent 5103020,
1992. (b) Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R.; Smith, P. R.;
Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil, J. K.;
Wang, S. J. Org. Chem. 1997, 62, 9192-9202. Much lower yields (20-
30%) have been reported in most other cases. (c) Dowles, M. D.; Coates,
I. H. U.S. Patent 4816470, 1989. (d) Oxford, A. W. U.S. Patent 5037845.
(12) Reported difficulty of achieving regioselective Fischer indole
cyclizations on unsymmetrical ketones makes this result particularly
noteworthy. Zhao, D.; Hughes, D. L.; Bender, D. R.; DeMarco, A. M.;
Reider, P. J. J. Org. Chem. 1991, 56, 3001 and references therein.
(13) Structures containing this nucleus have been reported to be human
neurokinin-1 receptor antagonists and serve as potential therapeutic agents
for emesis, anxiety, and depression. Copper, L. C.; Chicchi, G. G.; Dinnell,
K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison,
D.; Shaw, D. E.; Tsao, K.-L.; Watt, A. P.; Williams, A. R.; Swain, C. J.
Bioorg. Med. Chem Lett. 2001, 1233-1236. Dinnell, K.; Chicchi, G. G.;
Dhar, M. J.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Ridgill, M.
P.; Rycroft, W.; Tsao, K.-L.; Williams, A. R.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2001, 1237-1240.
(14) This is a commonly observed intermediate when the N-acylhydra-
zone forms a six-membered heterocycle. Gouault, N.; Cupif, J. F.; Picard,
S.; Lecat, A.; David, M. J. Pharm. Pharmacol. 2001, 53, 981-985.
(15) Shen, T. Y.; et al. J. Am. Chem. Soc. 1963, 85, 8-489. Shen, T. Y.
U.S. Patent 3161654.
(16) This hydrazine could be made in one step according to literature
precedent in 90% yield from commercially available starting materials.
Karady, S.; Ly, M. G.; Pines, S. H.; Chemerda, J. M.; Sletzinger, M.
Synthesis 1973, 50-51.
a All reactions were run in 4% H2SO4/DMAc (20 mL/g substrate) at
100 °C. All reported yields are after isolation by chromatography. b N-benzyl
phenylhydrazine was used in this coupling instead of phenylhydrazine.
c Reaction was run in 4% H2SO4/MeCN (20 mL/g substrate) at reflux.
tions delivered indomethacin (18) along with a significant
amount of deacylated product. We discovered that reduction
of the amount of water in the reaction suppressed the
deacylation reaction. When the reaction was run with a
minimal amount of water, using 1 equiv of sulfuric acid,
indomethacin was produced in 65% yield (Scheme 2). This
procedure represents a one-step approach to the regioselective
synthesis of indomethacin from readily available starting
materials.
In conclusion, a general, one-pot method for the synthesis
of highly functionalized indoles from commercially available
cyclic enol ethers and enol lactones has been demonstrated.
The procedure is general with respect to both the aryl
hydrazine and the enol ether that are used. The method was
Org. Lett., Vol. 6, No. 1, 2004
81

synthesis of two commercial drugs: sumitriptan and in-
domethacin. We are currently investigating the application
of this methodology to the preparation of highly function-
alized indoles. The results of our findings will be reported
in due course.
Scheme 2. Synthesis of Indomethacin
Acknowledgment. We would like to thank Dr. Jeff
Kuethe and Dr. Cheng-yi Chen (Merck & Co.) for valuable
comments and discussions.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
especially useful for the regioselective synthesis of 2,3-
disubstituted indoles. Cyclic enol lactones could be used in
this coupling to afford substituted indole propionic acids and
indole acetic acid derivatives in an efficient manner. The
utility of this method was highlighted in the efficient
OL036113F
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Org. Lett., Vol. 6, No. 1, 2004