Chemistry of aminophenols. Part 2: A general and efficient synthesis of indoles possessing a nitrogen substituent at the C4, C5, C6, and C7 positions

Article abstract of DOI:10.1016/S0040-4039(02)01851-8

A general and efficient synthesis of indoles possessing a nitrogen substituent at the C4, C5, C6, and C7 positions has been developed. Starting from commercially available nitro 2-aminophenols, 5-, 6-, and 7-arenesulfamoylindoles were synthesized via a ba

Full text of DOI:10.1016/S0040-4039(02)01851-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7699–7702
Chemistry of aminophenols. Part 2: A general and efficient
synthesis of indoles possessing a nitrogen substituent at the C4,
C5, C6, and C7 positions
Wei-Min Dai,* Li-Ping Sun and Dian-Shun Guo
Combinatorial Chemistry Laboratory, The Biotechnology Research Institute and Department of Chemistry,
The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
Received 10 June 2002; revised 22 August 2002; accepted 30 August 2002
Abstract—A general and efficient synthesis of indoles possessing a nitrogen substituent at the C4, C5, C6, and C7 positions has
been developed. Starting from commercially available nitro 2-aminophenols, 5-, 6-, and 7-arenesulfamoylindoles were synthesized
via a base-promoted ring closure of 2-alkynylanilides, reduction of the nitro group, and sulfonylation. C4 nitrogen substituted
indoles were synthesized from 2-chloro-1,3-dinitrobenzene via cyclization of 2-alkynyl-1,3-diaminobenzene as the key step. © 2002
Elsevier Science Ltd. All rights reserved.
Indoles possessing nitrogen substituents on the ring
skeleton are often found to exhibit biological activity.
As illustrated in Scheme 1, the C4 nitrogen substituted
indole, SDZ-216525 1, is a 5-HT7 selective agonist.1
Delavirdine 2 is one of the non-nucleoside reverse
transcriptase inhibitors (NNRTIs) approved for HIV
therapy.2 Zafirlukast is an LTD4 antagonist effective
against exercise-induced asthma, in antigen-induced
bronchospasm, and for protection in cold-air challenge
studies.3 Another C5 nitrogen substituted indole,
LY334370, is a selective 5-HT1F receptor agonist.4 It
was reported to be a potent inhibitor of neurogenic
dural inflammation and was tested for treatment of
migraine although it was suspended from phase III
clinical trials due to non-mechanism based liver toxic-
ity. The C7 nitrogen substituted indole, ER-35744,
E7070 3, was reported to be in phase I clinical trials for
anticancer activity and is thought to affect the progres-
sion of the cell cycle in the G1 phase with inhibition of
expression of cyclin E and phosphorylation of cdk2.5 In
connection with our study on diversity-oriented synthe-
sis of bioactive heterocycles from readily available com-
mercial reagents,6 we undertook a general and efficient
synthesis of indoles possessing a nitrogen substituent at
the C4, C5, C6, and C7 positions.
Three commercially available nitro 2-aminophenols, i.e.
2-amino-5-nitrophenol 4a, 2-amino-4-nitrophenol 4b,
and 2-amino-3-nitrophenol 4c, were used in our synthe-
sis of C5, C6, and C7 nitrogen substituted indoles 10a–c
(Scheme 2).7 Selective protection of the amino group in
4a,b was carried out by treatment with an acyl chloride,
for example, butyryl chloride, in the presence of pyri-
dine in refluxing THF to give 5a,b in 86% and 97%
Scheme 1. Selected examples of bioactive nitrogen substituted indoles.
Keywords: coupling reactions; indoles; phenols; triflates.
* Corresponding author. Fax: +852 2358 1594; e-mail: chdai@ust.hk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01851-8

7700
W.-M. Dai et al. / Tetrahedron Letters 43 (2002) 7699–7702
yield, respectively. Under the heating conditions, the
undesired O-acylation products gradually rearranged to
the N-acylation product and only the anilides 5a,b were
obtained.8 Acylation of 4c did not work well using
pyridine as the base, therefore, 5c was obtained from 4c
using NaH and butyryl chloride (rt, 24 h) in 60% yield.
The triflates 6a–c, prepared from 5a,b (NaH, Tf2O, 80%
and 87%) and 5c (Et3N, Tf2O, 94%), underwent a facile
cross-coupling reaction with 1-alkynes catalyzed by 10
mol% Pd(PPh3)4 and 30 mol% CuI in the presence of
an additive, nBu4NI (150 mol%),6 in Et3N/MeCN
(1:5).9 To evaluate the reactivity of alkyl and aryl
1-alkynes with the triflates, 1-pentyne and phenyl-
acetylene were used in the cross-coupling reactions,
which were complete within 0.5–1 h to provide 7a–c in
excellent yields (Table 1, entries 1–4, 7, and 8).
(R=Ph), three arenesulfonyl chlorides were used to
form 10b-1, 10b-2, and 10b-3, respectively, in 70–80%
yields (Table 1, entries 4–6). The C7 arenesulfamoylin-
dole 10c was synthesized similarly in 73% yield (Table
1, entry 8).
Scheme 3 illustrates the synthesis of C4 nitrogen substi-
tuted indoles starting from 2-chloro-1,3-dinitrobenzene
11.7 The key step is the cross-coupling of 11 with
1-alkynes, which must be conducted using a suitable
catalytic system. Although the nitro groups in 11 may
activate the CꢀCl bond, the steric repulsion makes the
cross-coupling difficult. Compound 11 failed to form
cross-coupled products with 1-alkynes when PPh3 was
used. Recently, Buchwald and Fu reported a modified
catalyst system for the Sonogashira reaction of aryl
bromides at room temperature, where a bulky phos-
phine, PtBu3, was used together with Pd(PhCN)2Cl2.11
We tried the cross-coupling reaction of 11 with 1-pen-
tyne using 10 mol% Pd(PhCN)2Cl2, 20 mol% PtBu3, 20
mol% CuI, and 150 mol% nBu4NI6 in Et3N/MeCN
(1:5). The reaction was complete at room temperature
after 1 h giving 12 (R=nPr) in 93% yield. However,
phenylacetylene failed to couple with 11 at room tem-
perature. Compound 12 (R=Ph) was obtained in 60%
yield by carrying out the reaction at 80°C in Et3N/
DMF (1:5). Reduction of the nitro groups in 12 was
attempted under different sets of conditions. For exam-
ple, 12 (R=nPr) was reduced to 13 (R=nPr) in 51%
yield by Fe+HCl (0.5%) in 50% EtOH (reflux, 4 h).
We carried out the ring closure reaction within the
t
2-alkynylanilides 7a–c using 1.2 equiv. of BuOK in
NMP at 60–70°C.6,10 It was found that the nitro group
survived the basic conditions without significant decom-
position. The nitro indoles 8a–c were isolated in 72–
86% yields (Table 1). Reduction of the nitro group in
8a–c (R=Ph) over Pd/C in EtOH with hydrogen fur-
nished the amino indoles 9a–c (R=Ph, 85–96% yields),
which were converted into the arenesulfamoylindoles
10a–c (Scheme 2 and Table 1, entries 2, 4–6, and 8).
For the C5 substituted indoles, the product 10a was
obtained in 84% yield. To demonstrate the generality of
the sulfonamide formation, for the C6 amino indole 9b
Scheme 2. Synthesis of 5-, 6-, and 7-arenesulfamoylindoles from nitro 2-aminophenols.
Scheme 3. Synthesis of 4-arenesulfamoylindoles from 2-chloro-1,3-dinitrobenzene.

W.-M. Dai et al. / Tetrahedron Letters 43 (2002) 7699–7702
7701
Table 1. Structures and chemical yields of cross-coupling products and nitrogen substituted indoles
When SnCl2·H2O (10 equiv.) was used as the reductant
in hot EtOH (65°C, 0.5 h),12 the substrate was con-
sumed but the desired product was not detected. By
changing the solvent to DMF/CH2Cl2 (1:1), 12 was
reduced to 13 by SnCl2·H2O (60 equiv., rt, 4 h) in 66%
(R=nPr) and 80% (R=Ph) yields, respectively. Ring
closure of 13 was examined under two different condi-
tions. Treatment of 13 with CuI13 in DMF (100°C, 2 h)
afforded the product 9d in 42% (R=nPr) and 10%
yields (R=Ph). Alternatively, high yields were obtained
t
via the BuOK-mediated ring closure in NMP at 80°C
for 5 h (9d: R=Ph, 90%) and 8 h (9d: R=nPr, 75%).10
Finally, treatment of the C4 amino indoles 9d with
3-(trifluoromethyl)benzenesulfonyl chloride in pyridine

7702
W.-M. Dai et al. / Tetrahedron Letters 43 (2002) 7699–7702
furnished the C4 arenesulfamoylindoles 10d-1 and 10d-
2 in 75–83% yields (Scheme 3 and Table 1, entries 9 and
10).
Rep. Med. Chem.; Bristol, J. A., Ed.; Academic Press:
San Diego, 1997; Vol. 32, p. 92; (b) Galatsis, P. In Ann.
Rep. Med. Chem.; Bristol, J. A., Ed.; Academic Press:
San Diego, 1997; Vol. 32, p. 321.
In summary, we have developed a general synthesis of
indoles possessing a nitrogen substituent at the C4, C5,
C6, and C7 positions from the commercially available
nitro 2-aminophenols 4a–c and 2-chloro-1,3-dinitroben-
zene 11. Introduction of diversity at the C2 position can
be achieved by using commercially available 1-alkynes.
Our synthesis is of interest for the generation of indole
libraries. Work toward this goal is currently in progress
in our laboratory.
4. Robichaud, A. J.; Largent, B. L. In Ann. Rep. Med.
Chem.; Doherty, A. M., Ed.; Academic Press: San Diego,
2000; Vol. 35, p. 13.
5. Li, Q.; Sham, H. L.; Rosenberg, S. H. In Ann. Rep. Med.
Chem.; Doherty, A. M., Ed.; Academic Press: San Diego,
1999; Vol. 34, pp. 145–146.
6. Dai, W.-M.; Guo, D.-S.; Sun, L.-P. Tetrahedron Lett.
2001, 42, 5275–5278.
7. All new compounds are fully characterized by IR, 1H
NMR, 13C NMR and MS.
8. Dai, W.-M.; Cheung, Y. K.; Tang, K. W.; Choi, P. Y.;
Chung, S. L. Tetrahedron 1995, 51, 12263–12276.
9. Dai, W.-M.; Wu, J. Tetrahedron 1997, 53, 9107–9114.
10. Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 2488–2490.
11. Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G.
C. Org. Lett. 2000, 2, 1729–1731.
12. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25,
839–842.
Acknowledgements
This work is supported by the Innovation and Technol-
ogy Fund (ITS/119/00) from the Innovation and Tech-
nology Commission of the Hong Kong Special
Administration Region, China. We also thank HKUST
for providing a Post Doctoral Fellowship Matching
Fund to D.-S. Guo.
13. (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28,
2163; (b) Castro, C. E.; Gauhan, E. J.; Owsley, D. C. J.
Org. Chem. 1966, 31, 4071–4078; (c) Villemin, D.;
Goussu, D. Heterocycles 1989, 29, 1255–1261; (d)
Kumar, V.; Dority, A. A.; Bacon, E. R.; Singh, B.;
Lesher, G. Y. J. Org. Chem. 1992, 57, 6995–6998; (e)
Katritzky, A. R.; Li, J.; Stevens, C. V. J. Org. Chem.
1995, 60, 3401–3404; (f) Ezquerra, J.; Pedregal, C.;
Lamas, C.; Barluenga, J.; Pe´rez, M.; Garc´ıa-Mart´ın, M.
A.; Gonza´lez, J. M. J. Org. Chem. 1996, 61, 5804–5812;
(g) Soloducho, J. Tetrahedron Lett. 1999, 40, 2429–2430.
References
1. (a) Schoeffter, P.; Floyd, J. R.; Stoll, A.; Siegl, H.; Seiler,
M. P.; Hoyer, D. Eur. J. Pharmacol. 1993, 244, 251–257;
(b) Rea, M. A.; Barrera, J.; Glass, J. D.; Gannon, R. L.
Neuroreport 1995, 6, 1417–1420.
2. Molla, A.; Kohlbrenner, W. E. In Ann. Rep. Med. Chem.;
Bristol, J. A., Ed.; Academic Press: San Diego, 1997; Vol.
32, p. 131.
3. (a) Bell, R. L.; Summers, J. B.; Harris, R. R. In Ann.