An efficient base-mediated intramolecular condensation of 2-(disubstituted amino)-benzonitriles to 3-aminoindoles

Article abstract of DOI:10.1016/j.tetlet.2008.12.052

A concise and versatile method for the preparation of 3-aminoindoles from 2-(disubstituted amino)-benzonitriles is described, and in situ functionalizations were illustrated.

Full text of DOI:10.1016/j.tetlet.2008.12.052

Tetrahedron Letters 50 (2009) 1029–1031
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Tetrahedron Letters
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An efficient base-mediated intramolecular condensation of 2-(disubstituted
amino)-benzonitriles to 3-aminoindoles
*
Churl Min Seong , Chul Min Park, Jinil Choi, No Sang Park
Center for Medicinal Chemistry, Drug Discovery Division, Korea Research Institute of Chemical Technology, 100 Chang-dong, Yuseong-gu, Daejeon 305-606, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and versatile method for the preparation of 3-aminoindoles from 2-(disubstituted amino)-ben-
zonitriles is described, and in situ functionalizations were illustrated.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 November 2008
Revised 9 December 2008
Accepted 12 December 2008
Available online 16 December 2008
Keywords:
3-Aminoindoles
Disubstituted amino-benzonitriles
Base-mediated cyclization
In situ acetylation
The indole nucleus is one of the most ubiquitous scaffolds found
in natural products, pharmaceuticals, functional materials, and
agrochemicals.1 The structural diversity and biological importance
of indoles have made them attractive targets for synthesis over
years.2 3-Substituted indoles, in particular, are important building
blocks for the synthesis of various biologically active molecules.
Consequently, there is a continuing interest in the development
of improved methods for the synthesis of these molecules.3 The
synthesis of the indoles from nonindolic starting materials has re-
ceived considerable attention, and numerous approaches were
developed. The most versatile and widely applied reaction is the
Fischer indole synthesis starting from phenylhydrazine with ke-
tones or aldehydes.4
amino)-benzonitriles in the presence of either sodium hydride or
potassium t-butoxide as a base.
The 2-(disubstituted amino)-benzonitriles (3a–d) were readily
prepared by reductive amination of 1-aminobenzonitrile 1 with
benzaldehyde using NaBH4, followed by alkylation with the appro-
priate bromides (or iodides) in the presence of NaH. 2-(Benzyl-
phenyl-amino)-benzonitrile 3e was readily prepared from the cor-
responding benzoic acid via the benzamide by
a literature
procedure.9,10
First we investigated the optimal combination between the
base and the solvent for the cyclization of 2-(disubstituted ami-
no)-benzonitriles 3 (Table 1). We were delighted to find that the
treatment of precursors 3d with NaH as a base in DMF at 80 °C pro-
duces 3-amino-2-phenylindoles 4d (entry 5). We also found that t-
BuOK serves as an attractive alternative to NaH (entry 7) when the
reaction was carried out in benzene under reflux. The disubstituted
amino-benzonitrile 3d was converted cleanly within 1 h to 5d after
subsequent treatment of Ac2O. In contrast, neither K2CO3 nor
Cs2CO3 was effective in any solvent we used (DMF, THF, and ben-
zene). NaH was only effective in aprotic polar solvent such as
DMF. Presumably, the solubility of a base in the solvents used plays
an important role to mediate the cyclization.
Next, as shown in Table 2, we were conducted the base-medi-
ated intramolecular condensation of various precursors 3 with
NaH as a base in DMF at 80 °C produces 3-amino-2-phenyl-indoles
4. After isolation, the free amino indoles 4 slowly decomposed to
unidentified compounds at ambient temperature. Due to lack of
stability of the intermediates 4, they were directly converted to
3-Aminoindoles are unique intermediates in the substituted in-
dole synthesis, and have been produced by hydrolysis of the corre-
sponding isocyanates,5 by reduction of the salts of
isonitrosoindoles obtained from indoles,6 or by the Fischer cycliza-
tion of the phenylhydrazines of
x
-(N-acylamino)acetophenones.7
The 3-aminoindole formation by cyclization under basic conditions
also remains challenging.8 In connection with these studies, we
envisioned that the reaction between acidic CH2 of N-benzylic
group in ortho-position and nitrile would lead to the formation of
3-aminoindoles in a single step (Scheme 1). In this Letter, we wish
to report a new facile and efficient method for the synthesis of 3-
amino-2-phenylindoles by direct cyclization of 2-(disubstituted
* Corresponding author. Tel.: +82 42 860 7134; fax: +82 42 861 1291.
E-mail address: cmsung@krict.re.kr (C.M. Seong).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.052

1030
C. M. Seong et al. / Tetrahedron Letters 50 (2009) 1029–1031
CN
CN
CN
a
b
N
H
N
R
NH2
1
2
3a~e
O
Me
NH
d
e
N
R
NH2
5a~e (major & minor rotomers)
c
N
R
Me
Me
N
4a~e
N
R
6
Scheme 1. Reagents and conditions: (a) PhCHO, NaBH3CN/AcOH, 0–25 °C; (b) R-Br or R-I, NaH/DMF, 25 °C; (c) NaH/DMF, 80 °C, 30 min; (d) Ac2O, 0–25 °C; (e) MeI, NaH/DMF,
25 °C.
the acylated amino indoles 5 (entries 1–5; 85–90%) by addition of
Ac2O. The acylated products 5 were identified as an inseparable
mixture of rotamer 5. The ratio of rotamers 5 was determined by
1H NMR spectra. Similarly, intermediate 1-benzyl-3-aminoindole
4d reacts with excess iodomethane in the presence of NaH in
DMF at 25 °C afforded 3-dimethylaminoindole 6 as the sole alkyl-
ated product in 62% yield.11
A mechanistic rationalization for this reaction sequence is illus-
trated in Scheme 2. We envisioned deprotonation of a disubsti-
tuted amino-benzonitrile 3 could be facilitated by the base at
elevated temperature to generate anionic species A. Facile intra-
molecular condensation led to intermediate 1,2-dihydro-indol-3-
Table 2
The base-mediated cyclization of disubstituted amino-benzonitriles 3 via Scheme 111
Entry
R
Benzonitrile
Product
Yielda(%)
Ratiob
1
2
3
4
5
6
Me
Et
n-Pro
Bn
Ph
Bn
3a
3b
3c
3d
3e
3d
5a
5b
5c
5d
5e
6
85
80
86
87
90
62
1.4
1.3
1.2
1.3
1.5
—
a
Overall yield from compound 3.
Major to minor rotamer ratio.
b
Table 1
The cyclization of 3d under various reaction conditions
Me
NH
O
NH2
CN
N
base
Ac2O, Et3N
CH2Cl2
N
N
3d
4d
5d
Entry
Reaction conditions
Time
Isolated products
Yielda (%)
Ratiob
1
2
3
4
5
6
7
8
K2CO3/DMF, 80 °C
NaH/THF, reflux
NaH/benzene, reflux
NaH/DMF, rt
2 days
1 day
1 day
3dc
3d
3d
3d
—
—
—
—
87
<5
73
—
—
—
—
—
1.34
—
1.32
—
1 day
NaH/DMF, 80 °C
40 min
30 min
40 min
1 day
5d
t-BuOK/DMF, 80 °C
t-BuOK/benzene, reflux
t-BuOK/THF, reflux
Unknown Pd+ 5d
5d
3d
a
Overall yield of 5d from compound 3d.
Major to minor rotomer ratio.
Starting material 3d was recovered.
b
c
d
5d was obtained in low yield (<5%), along with several unidentified compounds presumably due to decomposition under reaction conditions.

C. M. Seong et al. / Tetrahedron Letters 50 (2009) 1029–1031
1031
_
Base:H
N
C
N
NH
_
Base:
3
N
R
N
R
N
R
H
Base:
A
B
C
_
H:Base
Ac O, Et N
NH
2
3
NH
2
5
CH Cl
2
2
N
N
R
R
D
4
Scheme 2. A plausible mechanism for the cyclization of a disubstituted amino-benzonitrile 3.
6. (a) Hiremath, S. P.; Kaddargi, S. S.; Mruthyunjayaswamy, B. H. M.; Purohit, M. G.
Indian J. Chem., Sect. B 1980, 19B, 767; (b) Yarosh, A. V.; Velezheva, V. S.; Kozik,
T. A.; Suvorov, N. N. Khim. Geterotsikl. Soedin. 1977, 11, 481.
7. Przheval’skii, N. M.; Skvortsova, N. S.; Magedov, I. V. Chem. Heterocycl. Compd.
2002, 38, 1055.
8. (a) Radl, S.; Hezky, P.; Urbankova, J.; Vachal, P.; Krejci, I. Collect. Czech. Chem.
Commun. 2000, 65(2), 280; (b) Santagati, A.; Longmore, J.; Guccione, S.; Langer,
T.; Tonnel, E.; Modica, M.; Santagati, M.; Scolaro, L. M.; Russo, F. Eur. J. Med.
Chem. 1997, 32(12), 973; (c) Couture, A.; Deniau, E.; Gimbert, Y.; Grandclaudon,
P. Tetrahedron 1993, 49, 1431.
ylideneamine. Tautomerization of intermediate C to the 1H-indol-
3-ylamine 4 and subsequent acylation by Ac2O afforded acetylated
amino indoles 5. The cyclization of the amino-benzonitriles 3 toler-
ates with a wide variety substituents such as methyl, ethyl, propyl,
benzyl, and phenyl, and hence represents a potential general meth-
od for the synthesis of 3-(N-acylamino)-2-phenylindoles. More-
over, the cyclization featuring mild reaction conditions, short
reaction time, easy workup, and good yields would make it attrac-
tive for the synthesis of 3-amino indole derivatives.
In summary, the base-mediated intramolecular condensation of
2-(disubstituted amino)-benzonitriles has proved to be a useful
and highly efficient process for the synthesis of potentially valu-
able 3-aminoindoles under mild conditions.
9. Juby, P. F.; Hudyma, T. W.; Brown, M. J. Med. Chem. 1968, 11, 111.
10. Bergman, J.; Brynolf, A.; Vuorinen, E. Tetrahedron 1986, 42, 3689.
11. General procedure for the preparation of 1-substituted-N-(2-phenyl-1H-indol-3-
yl)acetamides 5: Disubstituted amino-benzonitrile 3 (1.0 mmol) was added to a
mixture of 60% NaH (1.3 mmol, 60% (w/w) in mineral oil) in DMF (5.0 mL) at
room temperature and was stirred at 80 °C for 40 min. Acetic anhydride
(1.2 mmol) was added at 0 °C and the reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was poured into water (40 mL),
extracted with CH2Cl2 (50 mL), dried, concentrated, and purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:3) to give an
inseparable mixture of two amide rotamers 5. Spectral data for selected
products:N-1-Benzyl-2-phenyl-1H-indol-3-yl)acetamide (5d): bright yellow
solid (ratio of two amide rotamers = 1:1.3); 87% yield; mp 170–174 °C; 1H
NMR (200 MHz, CDCl3) (major rotamer) d 2.18 (s, 3H, COCH3), 5.31 (s, 2H,
PhCH2), 6.77 (br s, 1H, NH), 6.93–7.04 (m, 2H, ArH), 7.16–7.42 (m, 11H, ArH),
7.55–7.62 (m, 1H, ArH) (minor rotamer) d 1.83 (s, 3H, COCH3), 5.25 (s, 2H,
PhCH2), 6.72 (br s, 1H, NH), 6.93–7.04 (m, 2H, ArH), 7.16–7.42 (m, 11H, ArH),
7.55–7.62 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3) (major rotamer) d 23.3, 47.8,
110.7, 111.1, 119.0, 120.5, 122.7, 124.9, 126.0, 127.2, 128.5, 128.7, 128.8, 129.4,
130.1, 137.3, 137.5, 137.9, 170.5 (minor rotamer) d 20.3, 47.8, 110.9, 112.1,
117.8, 121.0, 123.1, 125.8, 126.0, 127.5, 128.2, 128.7, 129.0, 129.7, 130.0, 135.4,
135.7, 136.0, 174.4; MS (EI) m/e (relative intensity): 340 (M+, 100), 297 (29),
207 (67); HRMS (EI): m/e [M]+ calcd for C23H20N2O1: 340.1576; found:
340.1572.(1-Benzyl-2-phenyl-1H-indol-3-yl)dimethylamine (6): Benzonitrile 3d
(300 mg, 1.00 mmol) was added to a mixture of 60% NaH (50 mg, 1.3 mmol) in
DMF (5.0 mL) at room temperature and was stirred at 80 °C for 1 h. After the
starting benzonitrile 3d was disappeared, the additional amount of 60% NaH
Acknowledgments
We thank Korea Tomorrow and Globalization (KT&G) Co., Ltd.
for financial support. We also wish to thank Dr. You-Hui Lee for
helpful discussions.
References and notes
1. (a) Lim, K.-H.; Hiraku, O.; Komiyama, K.; Koyano, T.; Hayashi, M.; Kam, T.-S. J.
Nat. Prod. 2007, 70, 1302; (b) Sundberg, R. J. Indoles; Academic Press: London,
1996; (c) Brown, R. K. In Indoles; Houlihan, W. J., Ed.; Wiley-Interscience: New
York, 1972; (d) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
2. (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970; (b)
Sundberg, R. J. In Best Synthetic Methods, Indoles; Academic Press: New York,
1996; pp 7–11; (c) Joule, J. A. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Thomas, E. J., Ed.; George Thieme Verlag: Stuttgart,
Germany, 2000. Category 2, Vol. 10, Chapter 10.13; (d) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550; (e) Austin, J. F.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172; (f) Srivastava, N.; Banik,
B. K. J. Org. Chem. 2003, 68, 2109.
3. (a) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6, 79; (b)
Hong, K. B.; Lee, C. W.; Yum, E. K. Tetrahedron Lett. 2004, 45, 693; (c) Kohling, P.;
Schmidt, A. M.; Eilbracht, P. Org. Lett. 2003, 5, 3213.
4. (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621; (b)
Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607; (c) Katritzky, A. R.; Rachwal,
S.; Bayyuk, S. Org. Prep. Proced. Int. 1991, 23, 357; (d) Robinson, B. The Fischer
Indole Synthesis; John Wiley & Sons: Chichester, 1982.
(50 mg, 1.3 mmol) and an iodomethane (140 lL, 2.20 mmol) were added to the
reaction mixture. After stirring at room temperature for 2 h, the reaction was
quenched by the addition of 0.1 N HCl aqueous solution (50 mL). The resulting
mixture was extracted with CH2Cl2 (50 mL Â 3), washed with water
(50 mL Â 3), and dried over anhydrous Na2SO4. The organic phase was
concentrated under reduced pressure. Purification of the residues was done
by a flash column chromatography on silica gel (ethyl acetate/n-hexane = 1:10)
to afford a yellow solid 6 (202 mg, 62%): mp 96–98 °C; 1H NMR (200 MHz,
CDCl3) d 2.82 (s, 6H, N(CH3)2), 5.12 (s, 2H, PhCH2), 6.91–7.01 (m, 2H, ArH),
7.11–7.23 (m, 6H, ArH), 7.25–7.35 (m, 5H, ArH), 7.82 (m, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d 45.8, 47.2, 110.4, 119.0, 119.6, 121.8, 124.5, 126.1, 127.0,
128.0, 128.1, 128.4, 128.5, 131.0, 132.2, 133.2, 135.5, 138.4; MS (EI) m/e
(relative intensity): 326 (M+,71), 235 (100), 219 (57), 91 (15); HRMS (EI): m/e
[M]+ calcd for C23H22N2: 326.1783; found: 326.1774.
5. Suvorov, N. N.; Velezheva, V. S.; Yarosh, A. V.; Erofeev, Y. V.; Kozik, T. N. Khim.
Geterotsikl. Soedin. 1975, 8, 1099.