Functionalization of 4,6-dinitro-2-phenylindole at position 7

Article abstract of DOI:10.1007/s11172-008-0198-1

Transformation of the amino group in 7-amino-1-methyl-4,6-dinitro-2- phenylindole afforded a number of new 7-R-4,6-dinitroindoles and a first representative of a novel tricyclic heteroaromatic system of [1,2,5]oxadiazolo[4,3-g]indole.

Full text of DOI:10.1007/s11172-008-0198-1

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1539—1542, July, 2008
1539
Functionalization of 4,6ꢀdinitroꢀ2ꢀphenylindole at position 7
M. A. Bastrakov, A. M. Starosotnikov, A. Kh. Shakhnes, and S. A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: shevelev@ioc.ac.ru
Transformation of the amino group in 7ꢀaminoꢀ1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylindole afforded
a number of new 7ꢀRꢀ4,6ꢀdinitroindoles and a first representative of a novel tricyclic heteroaromatic
system of [1,2,5]oxadiazolo[4,3ꢀg]indole.
Key words: indoles, nitro compounds, amino group, diazotization, nucleophilic substitution.
The present work continues a series of investigations
into the functionalization and annulation of indoles of a
new type (2ꢀarylꢀ4,6ꢀdinitroindoles), which have become
accessible via transformations of 2,4,6ꢀtrinitrotoluene.1
Because indoles are very important as a basis for many
biologically active natural and synthetic compounds with
different spectra of action,2 creation of indole systems
with new combinations of substituents, as well as with
annulated heterocycles, is of current interest.
Previously,3 we functionalized 2ꢀarylꢀ4,6ꢀdinitroinꢀ
doles at position 3 and obtained various 4ꢀsubstituted
3ꢀRꢀ6ꢀnitroindoles via regiospecific nucleophilic substiꢀ
tution of the 4ꢀNO2 group. Further transformations gave
polycyclic periꢀannulated systems.
We studied diazotization of amine 2a (Ar = Ph) and
found that nitrosylsulfuric acid should be employed as
a nitrosating agent. Usually, this acid is used to obtain
diazonium salts from weakly basic amines (e.g., dinitroꢀ
anilines5). Treatment of a solution of diazonium salt 2a´
with a solution of cuprous chloride in HCl gave chloride
3 in 65% yield (Scheme 2).
Scheme 2
The goal of the present work was to study functionꢀ
alization of 2ꢀarylꢀ1ꢀmethylꢀ4,6ꢀdinitroindoles 1 at poꢀ
sition 7. Earlier,4 it was found that these compounds
can be aminated at position 7 with 1,1,1ꢀtrimethylꢀ
hydrazinium iodide (TMHI) in the presence of ButOK
under the conditions of vicarious nucleophilic substiꢀ
tution to give orthoꢀnitro amines 2 (Scheme 1). Transꢀ
formation of the 7ꢀNH2 group would make it possible to
use 2ꢀarylꢀ4,6ꢀdinitroindoles as a basis for the preparaꢀ
tion of new indole derivatives with potentially useful
biological activity.
Scheme 1
We studied reactions of chloride 3 with a number of
Sꢀ, Nꢀ, and Oꢀnucleophiles (Scheme 3). It turned out
that chloride 3 reacts with NaN3 in DMF even at room
temperature to give azide 5 in high yield (see Scheme 3).
A roomꢀtemperature reaction of chloride 3 with methyl
thioglycolate in MeOH in the presence of Et3N as a base
afforded the corresponding sulfide 6. More drastic conꢀ
ditions (60 °C) were required for a reaction with MeONa;
the expected methoxy derivative 4 was obtained (see
Scheme 3).
i. TMHI, ButOK, DMSO, 20 °C.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1508—1511, July, 2008.
1066ꢀ5285/08/5707ꢀ1539 © 2008 Springer Science+Business Media, Inc.

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Bastrakov et al.
Scheme 3
tion of sulfide 6 was unsuccessful (Scheme 5). To activate
the methylene unit, we oxidized compound 6 into the
corresponding sulfone 7. Nevertheless, treatment of the
latter with Et3N in methanol at 60 °C yielded no cyclizaꢀ
tion product (see Scheme 5).
Scheme 5
Thus, chloride 3 is similar to 1ꢀchloroꢀ2,4ꢀdiniꢀ
trobenzene in reactivity and substitution rate.6,7
It is known7 that an intermediate formed in reactions
of 1ꢀchloroꢀ2,4ꢀdinitroꢀ6ꢀXꢀbenzenes (X = Me, NO2,
etc.) with methyl thioglycolate in the presence of a small
excess of a base undergoes in situ cyclization into benꢀ
zothiazole Nꢀoxide through addition of an active methylꢀ
ene unit in the fragment SCH2CO2Me to the adjacent
NO2 group (Scheme 4).
Apparently, cyclization through an interaction of the
active methylene unit with the 6ꢀNO2 group in sulfide 6
or sulfone 7 is hindered by the lowered electrophilicity of
this group because of the strong πꢀabundant character of
the pyrrole fragment of indole, which is largely transꢀ
ferred to the benzene ring.8
Reflux of azide 5 in toluene resulted in its intramolecꢀ
ular cyclization into furoxan derivative 8 (Scheme 6).
Scheme 6
Scheme 4
Note that the literature data on the synthesis of indole
derivatives containing an annulated furoxan ring are lackꢀ
ing. It should be emphasized that tricyclic compound 8
can be of interest for biological investigations because of
a combination of indole2 and furoxan fragments, which
exhibit high and various biological activities. Furoxans
serve as a source of exogenous nitrogen oxide, a versatile
regulator of physiological processes.9 Nitrobenzofurꢀ
However, no cyclization product was obtained from
sulfide 6 under the substitution reaction conditions even
with an excess of Et3N. In addition, attempted cyclizaꢀ

Functionalization of 4,6ꢀdinitroꢀ2ꢀphenylindoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1541
oxans inhibit metabolism in lymphocytes.10 A known
alternative route to furoxans via oxidation of oꢀnitroꢀ
anilines11 failed in our case: furoxanoindole 8 was not
obtained from compound 2a under the action of sodium
hypochlorite or PhI(OAc)2.
The structures of all compounds obtained were conꢀ
firmed by NMR and IR spectroscopy (their IR spectra
show characteristic absorption bands of the main funcꢀ
tional groups: NO2, NH2, N3, etc.), mass spectrometry,
and elemental analysis.
To sum up, starting from 7ꢀaminoꢀ4,6ꢀdinitroindole
derivatives, we synthesized a number of new 7ꢀRꢀ4,6ꢀ
dinitroindoles and a first representative of a novel tricyꢀ
clic heteroaromatic system of [1,2,5]oxadiazolo[4,3ꢀg]ꢀ
indole.
with water, and dried in air to give compound 3 (2.2 g, 65%),
m.p. 195—200 °C. Found (%): C, 54.62; H, 3.31; Cl, 11.24;
N, 12.13. C15H10ClN3O4. Calculated (%): C, 54.31; H, 3.04;
Cl, 10.69; N, 12.67. 1H NMR, δ: 4.12 (s, 3 H, Me); 7.30 (s, 1 H,
H(3)); 7.55—7.79 (m, 5 H, Ph); 8.65 (s, 1 H, H(5)). IR, ν/cm–1
:
1612, 1560, 1516, 1484, 1464, 1344, 1300, 1272, 1172, 1148, 992,
892, 816, 768, 720, 700. MS, m/z: 331 [M]+.
7ꢀMethoxyꢀ1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindole (4).
Sodium methoxide (0.11 g, 2 mmol) was added to a solution of
chloride 3 (0.33 g, 1 mmol) in MeOH (15 mL). The reaction
mixture was stirred at 60 °C for 3 h, cooled, and poured into
acidified water. The precipitate that formed was filtered off, washed
with water, and dried in air to give compound 4 (0.26 g, 80%),
m.p. 173—176 °C. Found (%): C, 58.49; H, 4.12; N, 13.01.
C16H13N3O5. Calculated (%): C, 58.72; H, 4.00; N, 12.84.
1H NMR, δ: 4.03 (s, 3 H, Me); 4.15 (s, 3 H, OMe); 7.25 (s, 1 H,
H(3)); 7.55—7.80 (m, 5 H, Ph); 8.70 (s, 1 H, H(5)).
7ꢀAzidoꢀ1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindole (5). Sodiꢀ
um azide (0.25 g, 3.9 mmol) was added to a solution of chloride 3
(0.44 g, 1.3 mmol) in DMF (7 mL). The reaction mixture was
stirred at 20 °C for 24 h. The precipitate that formed was filtered off,
washed with water, and dried in air to give compound 5 (0.4 g,
88%), m.p. 158—160 °C. Found (%): C, 53.03; H, 2.58; N, 24.43.
C15H10N6O4. Calculated (%): C, 53.26; H, 2.98; N, 24.84.
1H NMR, δ: 4.12 (s, 3 H, Me); 7.27 (s, 1 H, H(3)); 7.55—7.80
(m, 5 H, Ph); 8.79 (s, 1 H, H(5)). IR, ν/cm–1: 2152, 1604, 1576,
1520, 1508, 1472, 1444, 1352, 1332, 1312, 1168, 1148, 1016, 904,
896, 824, 768, 756, 724, 696.
Experimental
1
H NMR spectra were recorded on a Bruker AMꢀ300 instruꢀ
ment in DMSOꢀd6. Chemical shifts are referenced to Me4Si.
IR spectra were recorded on a Specord Mꢀ80 instrument (KBr
pellets). Mass spectra were recorded on an MSꢀ30 Kratos instruꢀ
ment (EI, 70 eV). The course of the reactions was monitored and the
purity of the products was checked by TLC on Silufol UVꢀ254
plates. Reactions were carried out in dry DMF and DMSO. The
other solvents were not specially dried.
1ꢀMethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindole (1a). Potassium
tertꢀbutoxide (5.7 g, 51 mmol) was added to a solution of 4,6ꢀdinitroꢀ
2ꢀphenylindole1 (4.7 g, 17 mmol) in DMF (60 mL). The mixture
was stirred for 30 min. Then MeI (4.2 mL, 64 mmol) was added in
portions at 30—35 °C. The reaction mixture was stirred at 25—30 °C
for 2 h. The precipitate that formed was filtered off, washed with
water, and dried in air to give compound 1a (4.2 g, 85%),
m.p. 227—229 °C (cf. Ref. 2: m.p. 222—224 °C). Found (%):
C, 60.84; H, 3.62; N, 13.95. C15H11N3O4. Calculated (%): C,
Methyl 2ꢀ[(1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindolꢀ7ꢀyl)ꢀ
thio]acetate (6). A mixture of chloride 3 (0.33 g, 1 mmol), methyl
thioglycolate (0.18 mL, 2 mmol), and Et3N (0.3 mL, 2.2 mmol) in
MeOH (30 mL) was stirred at ~20 °C for 24 h. Then the solution
was poured into acidified water. The precipitate that formed was
filtered off, washed with water, and dried in air to give compound 6
(0.32 g, 80%), m.p. 127—130 °C. Found (%): C, 53.64; H, 3.93;
N, 10.61; S, 7.80. C18H15N3O6S. Calculated (%): C, 53.86; H, 3.77;
1
N, 10.47; S, 7.99. H NMR, δ: 3.95 (s, 3 H, Me); 4.10 (s, 2 H,
CH2); 4.15 (s, 3 H, Me); 7.25 (s, 1 H, H(3)); 7.37—7.75 (m, 5 H,
1
60.61; H, 3.73; N, 14.14. H NMR, δ: 4.01 (s, 3 H, Me); 7.31
(s, 1 H, H(3)); 7.57—7.84 (m, 5 H, Ph); 8.90 (s, 1 H, H(5)); 8.97
Ph); 9.06 (s, 1 H, H(5)).
(s, 1 H, H(7)).
Methyl 2ꢀ[(1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindolꢀ7ꢀyl)ꢀ
sulfonyl]acetate (7). A 30% solution of H2O2 (1.0 mL) was added
dropwise to a solution of sulfide 6 (0.3 g) in trifluoroacetic acid
(10 mL). The mixture was stirred at 20 °C for 1 h and poured into
water (50 mL). The precipitate that formed was filtered off, washed
with water, and dried in air to give compound 7 (0.28 g, 77%),
m.p. 119—121 °C. Found (%): C, 50.07; H, 3.22; N, 9.54; S, 7.59.
C18H15N3O8S. Calculated (%): C, 49.88; H, 3.49; N, 9.70; S, 7.40.
1H NMR, δ: 3.49 (s, 3 H, Me); 4.60 (s, 2 H, CH2); 4.15 (s, 3 H, Me);
7.37 (s, 1 H, H(3)); 7.57—7.85 (m, 5 H, Ph); 8.60 (s, 1 H, H(5)).
8ꢀMethylꢀ5ꢀnitroꢀ7ꢀphenylꢀ8Hꢀ[1,2,5]oxadiazolo[3,4ꢀg]inꢀ
dole 3ꢀoxide (8). A solution of azide 5 (0.395 g, 1.2 mmol) in
toluene (20 mL) was refluxed for 12 h. The major part of the solvent
was removed and the residue was diluted with hexane. The preꢀ
cipitate that formed was filtered off and dried in air to give comꢀ
pound 8 (0.19 g, 52%), m.p. 169—172 °C. Found (%): C, 57.95;
H, 3.31; N, 18.17. C15H10N4O4. Calculated (%): C, 58.07; H, 3.25;
7ꢀAminoꢀ1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindole (2a). Poꢀ
tassium tertꢀbutoxide (4.5 g, 40 mmol) was added to a solution of
indole 1a (6.0 g, 20 mmol) and TMHI (8.0 g, 40 mmol) in DMSO
(90 mL). The mixture was stirred at ~20 °C for 30 min, poured into
ice water, and acidified. The precipitate that formed was filtered off,
washed with CCl4, and recrystallized from pyridine to give comꢀ
pound 2a (5.5 g, 88%), m.p. >300 °C (cf. Ref. 2: m.p. >300 °C).
Found (%): C, 57.37; H, 3.98; N, 17.73. C15H12N4O4. Calculated
(%): C, 57.69; H, 3.87; N, 17.94. 1H NMR, δ: 4.03 (s, 3 H, Me);
7.13 (s, 1 H, H(3)); 7.51—7.68 (m, 5 H, Ph); 8.21 (s, 2 H, NH2);
8.79 (s, 1 H, H(5)). IR, ν/cm–1: 3500, 3348, 1576, 1496, 1452,
1320, 1244, 1044, 964, 772, 728, 700.
7ꢀChloroꢀ1ꢀmethylꢀ4,6ꢀdinitroꢀ2ꢀphenylꢀ1Hꢀindole (3).
Amine 2a (3.12 g, 10 mmol) was suspended in a mixture of AcOH
and CF3COOH (9 : 1) (100 mL). A solution of NaNO2 (2.1 g,
20 mmol) in H2SO4 (20 mL) was added dropwise at 5—15 °C to the
suspension. The resulting solution of the diazonium salt was stirred
for 30 min at the above temperature and poured at 0 °C into
a solution of CuCl (9.0 g, 60 mmol) in HCl (70 mL). The mixture
was stirred for 2 h, left in a refrigerator for ~14 h, and then poured
into ice water. The precipitate that formed was filtered off, washed
1
N, 18.06. H NMR, δ: 4.13 (s, 3 H, Me); 7.18 (s, 1 H, H(6));
7.51—7.61 (m, 3 H, Ph); 7.65—7.71 (d, 2 H, Ph, 3J = 8.2 Hz); 8.12
(s, 1 H, H(4)). IR, ν/cm–1: 3096, 1612, 1580, 1540, 1516, 1484,
1456, 1436, 1392, 1332, 1192, 1052, 1036, 1020, 1008, 932, 848,
824, 808, 772, 716, 664.

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Bastrakov et al.
7. V. Bertolasi, K. Dudova, P. Simunek, J. Cerny, V. Machacek,
J. Mol. Struct., 2003, 1—2, 33; K. Wagner, H. Heitzer, L. Oehlꢀ
mann, Chem. Ber., 1973, 106, 640.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00414).
8. A. F. Pozharskii, Teoreticheskie osnovy khimii geterotsiklov
[Theoretical Fundamentals of Heterocyclic Chemistry], Khimiya,
Moscow, 1985, 61 (in Russian).
9. V. G. Granik, S. Yu. Ryabova, N. B. Grigor´ev, Usp. Khim.,
1997, 66, 792 [Russ. Chem. Rev., 1997, 66 (Engl. Transl.)].
10. P. B. Ghosh, M. W. Whitehouse, J. Med. Chem., 1968, 11, 305.
11. L. I. Khmel´nitskii, S. S. Novikov, T. I. Godovikova, Khimiya
furoksanov: stroenie i sintez [The Chemistry of Furoxans: Strucꢀ
ture and Synthesis], Nauka, Moscow, 1996, 304 (in Russian).
References
1. V. V. Rozhkov, A. M. Kuvshinov, V. I. Gulevskaya, I. I. Cherꢀ
vin, S. A. Shevelev, Synthesis, 1999, 2065.
2. R. J. Sundberg, Indoles, Academic Press, SanꢀDiego, 1996;
Alkaloids: Chemical and Biological Perspectives, Ed. S. W.
Pelletier, 1983, Vol. 4, 211.
3. M. A. Bastrakov, A. M. Starosotnikov, V. V. Kachala, E. N.
Nesterova, S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2007,
1543 [Russ. Chem. Bull., Int. Ed., 2007, 56, 1603].
4. V. V. Rozhkov, A. M. Kuvshinov, S. A. Shevelev, Heterocycl.
Commun., 2000, 6, 525.
5. L. H. Welsh, J. Am. Chem. Soc., 1941, 63, 3276.
6. L. K. Dyall, Austr. J. Chem., 1986, 42, 89; F. B. Mallory, S. P.
Varimbi, J. Org. Chem., 1965, 28, 1656.
Received December 5, 2007;
in revised form March 21, 2008