Synthesis of tricyclic-2-aminoindoles by intramolecular 1,3-dipolar cycloaddition of 1-ω-azidoalkylindoles

Article abstract of DOI:10.1016/S0040-4039(01)01006-1

Thermolysis of the 1-ω-azidoalkylindoles 4, bearing an electron attracting substituent at C-3 (CHO, COMe, COOMe, CN) provides imidazo[1,2-a]indoles (5, n = 1), pyrimidino[1,2-a]indoles (5, n = 2), and 1,3-diazepino[1,2-a]indoles (5, n = 3).

Full text of DOI:10.1016/S0040-4039(01)01006-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5351–5353
Synthesis of tricyclic-2-aminoindoles by intramolecular
1,3-dipolar cycloaddition of 1-v-azidoalkylindoles
Marco A. de la Mora,a Erick Cuevas,a Joseph M. Muchowskib and Raymundo Cruz-Almanzaa,*
aInstituto de Qu´ımica, UNAM. Circuito Exterior, Ciudad Universitaria, Coyoaca´n 04510, Mexico, D.F.
bRoche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304-1320, USA
Received 9 May 2001; revised 11 June 2001; accepted 12 June 2001
Abstract—Thermolysis of the 1-v-azidoalkylindoles 4, bearing an electron attracting substituent at C-3 (CHO, COMe, COOMe,
CN) provides imidazo[1,2-a]indoles (5, n=1), pyrimidino[1,2-a]indoles (5, n=2), and 1,3-diazepino[1,2-a]indoles (5, n=3). © 2001
Elsevier Science Ltd. All rights reserved.
R3
2-Aminoindoles in which the nitrogen atoms are con-
nected by a polymethylene chain 1 are a relatively rare
R1
R2
class of compounds, some of which have recently been
patented as 5HT4-receptor antagonists.1 The pyrim-
idino[1,2-a]indole derivatives (1, n=2) are most expedi-
tiously synthesized by the remarkable phosphorous
oxychloride induced rearrangement of 1-phenyl-2-
acylpyrazolidines (Golubeva synthesis).2 They can also
be prepared from m-dinitrobenzene derivatives and 1,8-
diazabicyclo[5.4.0] undec-5-ene (DBU),3 and by alkyla-
tion of 2-chloro-3-acylindoles with 3-chloro-N,N-
dialkylaminopropane.4 The latter process also provides
imidazo[1,2-a]indoles (1, n=1) where the alkylation is
effected with 2-chloro-N,N-dimethylaminoethane.4 This
communication describes a simple three-step process
which provides easy access to congeners of 1 where
n=1–3.
N
N
n
1
N-Alkylation of the indoles 2 (Scheme 1) with the
appropriate 2-bromoalkyl chloride gave the chloro
compounds 3 (55–96%),5 which, on reaction with
sodium azide in DMSO, produced the azides 4 (80–
100%).6 These azido compounds were stable in toluene
at 100°C, but heating bromobenzene solutions thereof
at 180°C in a sealed metal reactor (4–12 h) did result in
product formation. For these azido compounds where
R is an electron attracting substituent, mixtures of the
tricyclic 2-aminoindoles 5 and the indoles 2 were pro-
duced (Table 1)7 in which the tricyclic compounds
R
R
R
c
a
NH
N
H
N
N
X
n
n
2
5
3, X = Cl
4, X = N3
b
Scheme 1. (a) BrCH2(CH2)nCl, NaH–DMF; (b) NaN3, DMSO; (c) PhBr, 180°C.
Keywords: cycloaddition; synthesis; pyrimidinol[1,2-a]indoles; imidazo[1,2-a]indoles.
* Corresponding author. Tel.: (52) 56 22 44 28; fax: (52) 56 16 22 17; e-mail: raymundo@servidor.unam.mx
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01006-1

5352
M. A. de la Mora et al. / Tetrahedron Letters 42 (2001) 5351–5353
Table 1. Thermolysis products of 1-v-azidoalkylindoles (4)
Products13
Entry
R
n
5
2
Yield (%)
Mp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
H
Me
1
1
1
2
3
1
2
2
2
0
0
80
75
20
CHO
CHO
CHO
COMe
COMe
CO2Me
CN
a
b
c
d
e
f
80
53
60
50
65
50
70
(188–190)
(165–166)
(137–139)
(196–197)
(185–188)
(186–187)
(196–197)
25a
20a
20a
25a
30a
23
g
a Unreacted starting material was recovered.
predominated in all cases. In contrast, when the sub-
stituent in 4 was hydrogen or methyl, no tricyclic
compounds were formed, and the indoles 2 were the
only products (entries 1 and 2).
The exclusive formation of nitrene-derived products
from the azido compounds 4 (R=H, Me) implies that
the activation energy for the cycloaddition process is
significantly greater than that for nitrene generation.
An electron attracting substituent at C-3 would be
expected15 to facilitate the cycloaddition process and
the results described herein suggest that in these cases
the two processes have similar activation energies.
We suggest that the formation of 5 proceeds by an
intramolecular 1,3-dipolar cycloaddition of the azido
moiety to the indole 2,3-double bond to produce an
intermediate triazoline 6. Loss of nitrogen from 6,
perhaps via an intermediate aziridine, would lead to the
observed tricyclic indoles. There is ample literature
precedent for processes of this type involving the
intramolecular cycloaddition of aliphatic azido func-
tions to activated double bonds.9 Dipolar cycloaddi-
tions to indoles both of the intramolecular10 and
intermolecular type,11,12 are very rare, however, and the
intramolecular azide cycloaddition described herein
does not appear to have been reported previously.
Our studies in this area are continuing.
Acknowledgements
Financial support from CONACyT (No. 27997E) is
gratefully acknowledged. The authors would also like
to thank R. Patin˜o, A. Pen˜a, J. Pe´rez and H. Rios for
the technical support.
R
N
N
H
References
N
N
1. Gaster, L. M.; Wyman, P. A. PCT Int. Apl. WO
93,18,036 1993; Chem. Abstr. 1994, 120, 134454.
2. (a) Kost, A. N.; Golubeva, G. A.; Portnov, Y. N. Dokl.
Akad. Nauk USSR 1971, 200, 342; Chem. Abstr. 1972, 76,
34047e; (b) Portnov, Y. N.; Golubeva, G. A.; Kost, A. N.
Khim. Geterotsikl. Soedin. 1972, 61; Chem. Abstr. 1972,
77, 448377; (c) Portnov, Y. N.; Golubeva, G. A.; Kost,
A. N.; Volkov, V. S. Khim. Geterotsikl. Soedin. 1973, 647;
Chem. Abstr. 1973, 79, 453269.
n
6
We propose that the formation of the indoles 2 from
the azido compound 4 is nitrene based and proceeds via
the imines derived by hydrogen migration.14 For exam-
ple, the four carbon derived imine 7, upon retroene
fragmentation, would give rise to an N-vinylindole
convertible into 2 on work-up.
3. Sutherland, J. K. Chem. Commun. 1997, 325.
4. Coppola, E. M.; Hardtmann, G. E. J. Heterocyclic Chem.
1979, 16, 769.
R
5. Typical procedure for the synthesis of 3. To a solution of
indole (1.17 g, 0.1 mol) in 10 mL of DMF was added
sodium hydride (0.253 g 0.11 mol 60% in mineral oil,
previously washed with hexane) under a nitrogen atmo-
sphere and the reaction mixture was stirred for 30 min at
room temperature before the dihalide was added. After 2
h of stirring the reaction mixture was quenched by drop-
wise addition of water, extracted with EtOAc and washed
with water and brine. The organic layer was dried over
N
H
NH
7

M. A. de la Mora et al. / Tetrahedron Letters 42 (2001) 5351–5353
5353
Na2SO4, filtered and concentrated in vacuo and the
residue purified by flash column chromatography on
silica gel, using hexane–EtOAc (8:2) as eluent.
6. Typical procedure for the synthesis of 4. To a solution of
alkylindole 3 (1 mmol) in DMSO (15 mL), sodium azide
(2 mmol) was added and the mixture was stirred
overnight at 60°C. The reaction mixture was quenched
with water, extracted with EtOAc and washed with a
sodium bicarbonate saturated solution and brine. The
product was purified by flash column chromatography.
7. The structures of the tricyclic compounds are supported
by NMR, IR and mass spectral data, and by a single
crystal X-ray structure for 5 (n=2) (R=CHO), a known
compound.8
2956, 2923, 1635, 1564, 1449, 1184, 1093; EI-MS m/z:
200 (M+, 85), 199 (100). 5c: 1H NMR (300 MHz, CDCl3):
l 2.04 (m, 4H, CH2-CH2), 3.44 (m, 2H, CH2-NH), 4.04
(m, 2H, CH2-N), 7.14 (m, 3H, ArH), 7.63 (d, 1H, J=4.5
ArH), 8.46 (br, 1H, NH), 9.90 (s, 1H, CH=0). 13C NMR
(75 MHz, CDCl3): l 184.4, 122.3, 121.1, 115.1, 109.2,
100.1, 52.3, 45.6, 29.8, 29.2, 23.8; IR (film) wmax (cm−1):
3300, 2922, 2852, 1624, 1344, 1202; ESI-MS m/z: 215.2
([MH]+, 100). Compound 5d: 1H NMR (300 MHz,
CDCl3): l 2.52 (s, 3H, CH3CO), 4.20 (m, 4H, CH2-CH2),
6.12 (br, 1H, NH), 7.07 (m, 2H, ArH), 7.14 (m, 1H,
ArH), 7.56 (d, 1H, J=7.0 Hz, ArH); 13C NMR (75 MHz,
CDCl3): l 193.2, 131.5, 130.0, 121.4, 120.4, 118.9, 108.4,
49.1 29.7, 28.7, 22.6; IR (film) wmax (cm−1): 3287, 2919,
2850, 1624, 1576; ESI-MS m/z: 201.2 ([MH]+, 100). Com-
8. Golubeva, G. A.; Svirdova, L. A.; Besidskii, E. A.;
Besidskaya, G. S. Khim. Geterotsikl. Soedin. 1990, 486;
Chem. Abstr. 1990, 113, 231305.
1
pound 5e: H NMR (300 MHz, CDCl3): l 2.22 (m, 2H,
CH2), 2.53 (s, 3H, CH3CO), 3.54 (m, 2H, CH2-NH) 3.97
(t, 2H, J=6.0 Hz, CH2-N), 7.07 (m, 2H, ArH), 7.15 (m,
1H, ArH), 7.53 (d, 1H, J=8.0 Hz, ArH), 8.40 (br, 1H
NH); 13C NMR (75 MHz, CDCl3): l 192.8, 132.8, 121.9,
120.1, 118.2, 107.6, 52.3, 39.3, 38.2, 29.2, 20.9; IR (film)
wmax (cm−1): 3303, 2937, 2860, 1624, 1584, 1479, 1255,
1170; ESI-MS m/z: 215.2 ([MH]+, 100). Compound 5f:
1H NMR (300 MHz, CDCl3): l 2.22 (qt, 2H, J=6.0,
CH2), 3.53 (m, 2H, CH2-NH), 3.87 (s, 3H, CH3O), 3.99
(t, 2H, J=6.0, CH2-N), 7.03 (m, 2H, ArH), 7.13 (m, 2H),
7.73 (m, 1H, NH). 13C NMR (75 MHz, CDCl3): l 188.5,
136.3, 121.7, 119.6, 118.8, 107.1, 50.4, 39.5, 37.6; IR
(film) wmax (cm−1): 3369, 2973, 2950, 1648, 1599, 1480,
1266, 1169, 1051; ESI-MS m/z: 231.1 ([MH]+, 100). Com-
9. See: Molander, G. A.; Hiersemann, M. Tetrahedron Lett.
1997, 38, 4347 and the list of references in Ref 10 of this
paper.
10. Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem.
1994, 59, 7072.
11. Caramella, P.; Corsico Coda, A.; Corsaro, A.; Del
Monte, D.; Marinone Albini, F. M. Tetrahedron 1982,
38, 173.
12. (a) Gribble, G. W.; Pelkey, E. T.; Switzer, F. L. Synlett.
1998, 1061; (b) Gribble, G. W.; Pelkey, E. T.; Simon, W.
M.; Trujillo, H. A. Tetrahedron 2000, 56, 10133.
1
13. Characterization of compounds 5a–e. Compound 5a: H
NMR (300 MHz, CDCl3): l 4.14 (m, 2H, CH2-NH), 4.20
(m, 2H, CH2-N), 6.02 (br, 1H, NH), 7.03–7.14 (m, 3H,
ArH), 7.62 (d, 1H, J=6 Hz, ArH), 9.82 (s, 1H, CH=O);
13C NMR (75 MHz, CDCl3): l 181.7, 122.1, 121.5, 116.8,
108.9, 50.0, 42.6, 30.1; IR (film) wmax (cm−1): 3246, 2921,
2889, 1607, 1138, 946; ESI-MS m/z: 187.1 ([MH]+, 100).
1
pound 5g: H NMR (300 MHz, CDCl3): l 2.23 (m, 2H,
CH2), 3.52 (m, 2H CH2-NH), 4.00 (t, 2H, J=6.0 CH2-N),
5.16 (br, 1H, NH) 7.05 (m, 2H, ArH), 7.13 (m, 1H, ArH),
7.39 (d, 1H, J=7.5, ArH); 13C NMR (75 MHz, CDCl3):
l 121.9, 120.2, 117.0, 107.8, 53.2, 39.9, 39.1, 31.0, 21.3;
IR (film) wmax: (cm−1): 3298, 2983, 2958, 2189, 1600, 1470;
EI-MS m/z: 197.0 (M+, 100).
1
Compound 5b: H NMR (300 MHz, CDCl3): l 2.23 (m,
2H, CH2), 3.54 (m, 2H, CH2-NH), 3.97 (t, 2H, J=6.0 Hz,
CH2-N), 7.01–7.15 (m, 3H, ArH), 7.59 (dd, 1H, J=6.5
Hz, J=1.5 Hz), 7.83 (br, 1H, NH), 9.81 (s, 1H, CH=0);
13C NMR (75 MHz, CDCl3): l 184.6, 138.5, 124.3, 123.1,
122.3, 110, 52.3, 48.2, 44.0; IR (film) wmax (cm−1): 3350,
14. Lewis, F. W.; Senders in Nitrenes; Lwowski, W. Ed.;
Interscience: New York, 1970; pp. 47–97.
15. Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
.