Expedient synthesis of indoles from N-Boc arylhydrazines

Article abstract of DOI:10.1016/j.tetlet.2004.01.011

The readily available N-Boc arylhydrazines undergo efficient Fischer cyclizations to provide the indoles in good yields, when reacted with enolizable ketones.

Full text of DOI:10.1016/j.tetlet.2004.01.011

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1857–1859
Expedient synthesis of indoles from N-Boc arylhydrazines
Young-Kwan Lim and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, 17 Haengdang-Dong, Sungdong-Gu, Seoul 133-791, South Korea
Received 29 November 2003; revised 27 December 2003; accepted 6 January 2004
Abstract—The readily available N-Boc arylhydrazines undergo efficient Fischer cyclizations to provide the indoles in good yields,
when reacted with enolizable ketones.
Ó 2004 Elsevier Ltd. All rights reserved.
Indoles have a wide spectrum of physiological activities.1
While the classical Fischer indole synthesis still remains
powerful in the synthesis of indoles, the requisite use of
poorly available arylhydrazines limits the scope. Due to
their pharmaceutical importance as well as high abun-
dance in nature, many synthetic alternatives have
appeared in the literature. Some of the notable recent
advances include transition metal catalyzed cyclizations
of o-alkenylanilines and annulations of o-haloanilines
with nucleophiles.2 Attempts to overcome the limitation,
while retaining its merits have also been reported.
Readily prepared from commercially available benzo-
phenone hydrazone through the coupling with aryl
bromides, N-aryl benzophenone hydrazone was shown
to be an effective surrogate to the less appealing aryl-
hydrazine in the Fischer cycle (Scheme 1).3
byproduct needs to be chromatographically removed.
Herein, we present the use of N-Boc arylhydrazines in
the Fischer indole cyclization, as an efficient and prac-
tical alternative to N-aryl benzophenone hydrazones,
providing indoles with no inevitable organic byproduct
(Scheme 2). The starting N-Boc arylhydrazines can be
Scheme 2. N-Boc arylhydrazines in the Fischer cycle.
Table 1. Indoles from arylhydrazides and 2-butanone
Despite the usefulness, however, it may not be readily
applicable to large scale synthesis as the benzophenone
Entry
Arylhydrazide
Time Indole
(h)
Yield
(%)
1
2
1a (R ¼ H)
1
1
1
1
1
1
1
1
1
1
2a (R ¼ H)
72
94
75
23
87a
92
69
1b (R ¼ p-Me)
1c (R ¼ p-OMe)
1d (R ¼ o-OMe)
1e (R ¼ m-OMe)
1f (R ¼ p-t-Bu)
1g (R ¼ p-Ph)
2b (R ¼ 4-Me)
2c (R ¼ 4-OMe)
2d (R ¼ 6-OMe)
2e (R ¼ OMe)
2f (R ¼ 4-t-Bu)
2g (R ¼ 4-Ph)
3
4
5
6
Scheme 1. N-Aryl benzophenone hydrazone in the Fischer cycle.
7
8
1h (R ¼ p-n-hexyl)
1i (R ¼ p-COPh)
1j (R ¼ p-CO2Et)
2h (R ¼ 4-n-hexyl) 79
9
10
2i (R ¼ 4-COPh)
2j (R ¼ 4-CO2Et)
58b
60b
Keywords: Indoles; Fischer indole synthesis; N-Boc arylhydrazines.
* Corresponding author. Tel.: +82-2-22900936; fax: +82-2-22990762;
e-mail: ccho@hanyang.ac.kr
a 1:1 Mixture of 2,3,4-trimethyl- and 2,3,5-trimethyl-1H-indole.
b Heated in toluene at 80 °C.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.011

1858
Y.-K. Lim, C.-G. Cho / Tetrahedron Letters 45 (2004) 1857–1859
readily prepared from various types of aryl or heteroaryl
halides according to the literature methods, securing
structural diversity in the arylhydrazine part.4
the ortho-position (entry 4) gave only marginal yield,
while the one with substituent at the meta-position
provided a 1:1 mixture of two regioisomeric indoles
(entry 5). The Fischer cyclizations with other enolizable
ketones also proceeded to the corresponding indoles
within an hour in good to excellent yields in most cases
(Table 2).
Table 1 summarizes the results on the cyclizations of
various substituted N-Boc arylhydrazines with 2-buta-
none.5
Evidently, the Boc protecting group is removed in situ
prior to the subsequent Fischer cyclization to the cor-
responding indoles. The hydrazide with substituent at
In addition to the cyclizations with enolizable ketones,
N-Boc arylhydrazines can be directly coupled with var-
ious vinyl halides to generate the coupling products,
Table 2. The indole synthesis with other ketones
Entry
Hydrazide
Ketone
Indole
Yield (%)
89
1
R ¼ H
2
R ¼ Me
90
3
4
5
R ¼ OMe
R ¼ n-Hex
R ¼ OMe
53
78
90
57a
90
O
6
7
R ¼ n-Hex
R ¼ n-Hex
8
R ¼ Ph
83
74
54
9
R ¼ t-Bu
R ¼ t-Bu
10
a Heated in THF under reflux.

Y.-K. Lim, C.-G. Cho / Tetrahedron Letters 45 (2004) 1857–1859
1859
Acknowledgements
This work was supported by Nuclear R&D Program
of the Ministry of Science and Technology (MOST).
LYG thanks the financial support from the BK 21
Program.
References and notes
1. For some of the recent reviews on indole, see: (a) Katritzky,
A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chem-
istry; Oxford: Pergamon, 2000, Chapter 4; (b) Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry;
Oxford: Pergamon, 2000, Chapter 3.
Scheme 3. Coupling followed by the Fischer cyclization.
2. (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27,
1113; (b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org.
Chem. 1998, 63, 7652; (c) Roesch, K. R.; Larock, R. C. Org.
Lett. 1999, 1, 1551; (d) Hiroya, K.; Itoh, S.; Ozawa, M.;
Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43,
1277; (e) Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahe-
dron Lett. 2004, 45, 35.
which undergo facile Fischer cyclizations to the corre-
sponding indoles when heated in the presence of an acid
(Scheme 3). The intermediate coupling products need
not be isolated, but can be directly subjected to the
Fischer cyclization condition to the indole.
3. Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 10251.
4. (a) Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron
Lett. 1999, 40, 3543; (b) Wolter, M.; Klapars, A.; Buch-
wald, S. L. Org. Lett. 2001, 3, 3803; (c) Arterburn, J. B.;
Rao, K. V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3,
1351.
5. Representative procedure: A mixture of N-Boc phenyl
hydrazine (1a, 50 mg, 0.24 mmol), cyclohexanone (35 mg,
0.36 mmol), TsOH monohydrate (274 mg, 1.44 mmol) in
3 mL of EtOH was heated under reflux for 1 h. The reaction
mixture was then concentrated and filtered through a plug
of silica gel to give 37 mg of 3 in 89% yield.
In summary, we have found that N-Boc arylhydrazines
readily undergo cyclization reactions to indoles when
heated with enolizable ketones in the presence of an
acid. Unlike the cases with N-aryl benzophenone
hydrazones, the reactions with N-Boc arylhydrazines do
not give organic byproducts need to be removed chro-
matographically. In this new synthesis, the product in-
dole can be isolated from the reaction mixture in an
essentially pure form with a simple water workup,
suitable for a large scale preparation.