Synthesis and study of the mutagenic activity of di(indeno[2,1-b]indolyl)- and di(indeno[2,1-b]pyrrolyl)methanes and -dimethylsilanes

Article abstract of DOI:10.1023/A:1012745325790

Dihetaryldimethylsilanes and dihetarylmethanes containing indeno[2,1-b]indolyl and indeno[2,1-b]pyrrolyl fragments were synthesized. Their mutagenic activity was tested according to Ames with standard test strains Salmonella typhimurium TA 1537, TA 98, and TA 100.

Full text of DOI:10.1023/A:1012745325790

Russian Chemical Bulletin, International Edition, Vol. 50, No. 8, pp. 1439—1445, August, 2001
1439
Synthesis and study of the mutagenic activity
of di(indeno[2,1-b]indolyl)- and di(indeno[2,1-b]pyrrolyl)methanes
and -dimethylsilanes
I. E. Nifant´ev,a« I. A. Kashulin,a V. V. Bagrov,a S. K. Abilev,b and I. K. Lyubimovab
aM. V. Lomonosov Moscow State University, Department of Chemistry,
Leninskie Gory, 119899 Moscow, Russian Federation.
Fax: (095) 939 4523. E-mail: inif@org.chem.msu.ru
bN. I. Vavilov Institute of General Genetics, Russian Academy of Science,
3 ul. Gubkina, 119991 Moscow, Russian Federation.
Fax: (095) 132 8962
Dihetaryldimethylsilanes and dihetarylmethanes containing indeno[2,1-b]indolyl and
indeno[2,1-b]pyrrolyl fragments were synthesized. Their mutagenic activity was tested accord-
ing to Ames with standard test strains Salmonella typhimurium TA 1537, TA 98, and TA 100.
Key words: indeno[2,1-b]indole, indeno[2,1-b]pyrrole, Fisher reaction, Ames test.
It is known that polyaromatic fused systems can
exhibit mutagenic properties. The basic structural char-
acteristics responsible for the mutagenic activity of such
compounds are the planar structure and the polarity of
their molecules, which is determined by the type and
positions of substituents.1 The mutual effects of two
planar fragments of this type in the same molecule on
its total mutagenic activity (synergism) was not studied
hitherto.
To answer this question, indeno[2,1-b]indoles (1),
indeno[2,1-b]pyrroles (2), dihetaryldimethylsilanes 3—5,
and dihetarylmethanes 6 and 7 each containing two
fragments of the aforesaid types were synthesized and
tested for mutagenicity in the present work.
The choice of the model compounds was based on
the following reasoning. First, indenoindoles and
indenopyrroles are rather easily accessible. Second, when
treated with strong bases, these compounds give carban-
ions, which, in turn, react with various electrophiles to
yield CH2- and SiMe2-bridged bisderivatives. Third, as
indenoindole can be regarded as indenopyrrole fused
with an additional benzene ring, the comparison of
indenoindole and indenopyrrole derivatives makes it
possible to study the influence of the additional annelated
ring on the total mutagenic activity.
Earlier,2—4 HCl, PPA, and ZnCl2 were used as
cyclization agents. Our choice was H2SO4. As both
stages of the process occur in the same solvent, and
hydrazones 8a—c are formed in virtually quantitative
yields, compounds 1a—c may be synthesized by a one-
pot procedure.
Methylation of indenoindoles 1a—c under phase-
transfer catalysis with p-C16H33NMe3Br as a catalyst
(by analogy with indoles5) yielded N-methylindeno-
indoles 1d—f (see Scheme 1). Both MeI and more easily
available dimethyl sulfate were used as methylating
agents, though the latter provides partially resinified
products in somewhat lower yields.
Compound 1g containing trimethylsilyl group at the
nitrogen atom was obtained by treating an N-lithium-
indenoindole 1a with Me3SiCl in ether. The smooth
silylation of 1a occurs in the presence of tetramethyl-
ethylenediamine, which enhances the nucleophilic prop-
erties of the nitrogen atom via complexation with the
lithium atom (see Scheme 1).
Compound 1i (yield 52%) was obtained by treating a
lithium derivative of N-methyldihydroindenoindole 1d
with Me3SiCl in ether (see Scheme 1).
N-Phenylindenoindole 1h was synthesized by the
reaction of N,N-diphenylhydrazine with indan-2-one in
ethanol in the presence of H2SO4 (see Scheme 1).
Using a standard procedure, we failed to isolate
diphenylhydrazone 8d. Apparently, the rate of its cy-
clization is much higher than that for monophenyl-
hydrazones. Unlike other indenoindoles, compound 1h
crystallizes only slightly and can be isolated in the
individual form in low yield (41%) using column chro-
matography on silica gel.
Results and Discussion
At present, the most common and convenient method
for the synthesis of indeno[b]indoles is the acid-cata-
lyzed cyclization of indanone arylhydrazones (the Fisher
reaction).2 Following this approach, we prepared
indenoindoles 1a—c from hydrazones 8a—c (the latter
were synthesized by heating the corresponding hydra-
zines with indan-2-one in ethanol (Scheme 1).
The initial attempt to synthesize the framework of
indeno[2,1-b]pyrrole by condensation of indan-2-one
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1369—1375, August, 2001.
1066-5285/01/5008-1439 $25.00 ©ꢀ2001 Plenum Publishing Corporation

1440
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Nifant´ev et al.
Scheme 1
NH NH2
NH N
R
R
O
H2SO4
MeI
C6H6/NaOH
N
H
N
R
R
Me
8a—c
1a—c
1d—f
R = H (a), Me (b), But (c)
R = H (a, d); Me (b, e); But (c, f)
1. BuLi/TMEDA
1. BuLi
1a
1d
2. SiMe3Cl
2. SiMe3Cl
N
N
SiMe3
SiMe3
1g
Me
1i
NH2
N
O
H2SO4
N N
N
Ph
1h, 41%
8d
with oxime 9 (Scheme 2) according to the known
procedure6 gave no target indenopyrrole 2a. Instead,
the condensation of two aminoacetoacetate molecules
yielded compound 10. Because of this, an alterna-
tive approach, namely, the condensation of amino-
indanone hydrochloride with ethyl acetoacetate was used
(cf. Ref. 7). As in the case of indenoindoles, indeno-
pyrrole 2b was methylated at the nitrogen atom under
phase-transfer catalysis. Hydrolysis of ester 2c afforded
acid 2d, which was decarboxylated in diethylene glycol
to give indenopyrrole 2e (see Scheme 2).
Symmetrical dihetarylsilanes were obtained by the
action of SiMe2Cl2 on a lithium salt of indenoindole or
indenopyrrole in ether, by analogy with the known
procedure8 (Scheme 3). The yields of products 3 and 4
were 35—60%. Being insoluble in ether, they were easily
isolated by filtration as a mixture of racemic and
meso-forms in the ratio ∼1 : 1. The exception is com-
pound 3b, which is well soluble in ether; its pure
racemate was isolated by recrystallization from hexane
in 52% yield. The oily meso-form of 3b was not isolated.
The ratio of stereoisomers was determined by
1H NMR spectroscopy. Thus, the Si-bound methyl
groups in the meso-forms are diastereotopic giving two
singlets in the 1H NMR spectrum. The analogous groups
of the racemic form are equivalent, and their 1H NMR
spectrum shows one signal (s, 6 H).
Unsymmetrical dihetarylsilanes 5 were synthesized
by the action of the corresponding chloro(fluorenyl)di-
methylsilanes on the lithium salt of 5-methylinde-
no[2,1-b]indole (1d) in ether (see Scheme 3).
Dihetarylmethanes were obtained by the reactions of
indenoindoles and indenopyrroles with CH2O in DMF
in the presence of EtONa according to the known
procedure9 (Scheme 4). Products 6 and 7 are insoluble
in DMF and can easily be filtered off. One could assume
that derivatives 6 and 7 would also be obtained as
mixtures of racemic and meso-forms. Unexpectedly, it
turned out that only indenopyrrole 7 gives such a mix-
ture in the ratio ∼1 : 1, while indenoindole derivatives 6
are formed only as a racemate. To obtain an equimolar
mixture of racemic and meso-forms of compounds 6, the
racemic form 6 should be treated successively with a
solution of BuLi in hexane and with water. It was such a
mixture that was tested for mutagenic activity.
The ratio of diastereomers 6 and 7 was determined
1
from the H NMR spectra. An ABX2-type spin system
composed of the chemically nonequivalent CH2 protons
of the meso-form and the CH protons of the cyclopenta-
dienyl ring gives two different signals (both dt) in the
1H NMR spectrum; the CH protons manifest them-
selves by a doublet of doublets. The racemate is ob-
served as an AA´XX´ spin system, and the CH2 protons
(like the CH ones) give one signal (dd).

Bridged indenoindoles and indenopyrroles
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1441
Scheme 2
Scheme 3
R2
CO2Et
N
H
N
O
R1
R2
Zn
2a
+
Me
Me
1. BuLi
H
H
2
N
CO2Et
Si
H
N
2. SiMe2Cl2
OH
O
N
CO2Et
R1
N
9
R1
EtO2C
N
H
1d,f,h
R2
10
3a—c
O
O
1d
Me
H
1f
1h
Ph
H
3a
3b
Me
But
3c
Ph
H
OEt
NaOAc/AcOH
NH2•HCl
R1
R2
Me
But
Me
H
O
CO2Et
C6H6/NaOH
MeI
Me
Me
Me
Me
N
N
Me Me
Si
N
1. BuLi
2
2. SiMe2Cl2
H
H
H
Me
N
2b, 47%
Me
2e
4
CO2Et
NaOH
EtOH
R
R
N
Me
Me
Me
Si
1. BuLi
2c, 65%
1d
Me
2.
R
R
N
COOH
170—180 °C
Diethylene glycol
SiMe2Cl
N
5a,b
R = H (a), But (b)
Me
2d, 81%
The study of mutagenic activity. Mutagenic activity
was tested with standard histidine-dependent test strains
Salmonella typhimurium TA 1537 (hisC3076, rfa, uvrB),
TA 98 (hisD3052, rfa, uvrB), and TA 100 (hisG46, rfa,
uvrB) as indicators, which are able to revert to the
histidine dependence under the action of different-type
mutagens.10 The strains were tested according to the
N
Me
2e, 76%

1442
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Nifant´ev et al.
Scheme 4
Table 1. The number of his+-revertants induced by the com-
pounds under study in Salmonella typhimurium TA 98
R
Com-
pound
Dose*
0
50
100
250
500
1000
1a
1d
1g
1i
20
20
20
20
20
20
31
20
31
29
29
20
32
31
21
28
27
24
24
40
29
350
30
461
85
23
27
30
38
31
22
22
22
30
28
154
31
726
26
993
753
24
20
22
23
43
24
100
24
1097
27
799
1219
17
25
31
30
29
29
R
2
N
Me
NaOEt/DMF
H
H
CH2O
C
2å
3a
3b
3c
4
H
H
N
50
30
t.e.**
31
1572
30
t.e.**
1251
t.e.**
45
Me
Me
N
486
22
728
129
20
1d,e
5a
5b
6a
6b
7
R = H (d), Me (e)
19
36
28
R
36
28
38
27
42
29
32
6a,b
R = H (a), Me (b)
Note. Control: 2-nitrofluorene (5 µg per plate) induced
2313—2876 his+-revertants.
* The dose was measured in micrograms per plate.
** Toxic (bactericidal) effect.
Me
Me
Me
Me
N
N
H
H
circumstance is very important when the compound is
used as an inductor of mutations of microorganisms for
the purpose of selecting new lines, e.g., potential pro-
ducers for microbiological industry.
C
NaOEt/DMF
CH2O
2
H
H
Me
N
Thus, the mutagenic synergism was observed only in
the case of indenoindole-containing dihetarylsilanes.
The only exception is compound 3b. Apparently, the
presence of the bulky tert-butyl substituents prevents its
intercalation into the DNA molecule. The indenopyrrole
derivatives contain fused fragments whose length is in-
sufficient to be firmly retained in DNA and cause
mutations. This confirms a significant influence of the
number of fused rings in the molecules of the mutagen
of this type on its mutagenic properties.
Me
2e
7
standard procedure without metabolic activation of the
mammal liver with an S9 fraction.11
It was found that the compounds obtained show
mutagenic activity only with the strain Salmonella
typhimurium TA-98, i.e., they cause frameshift muta-
tions of the type –1 (deletion) in the D-gene of the
histidine operon. None of the compounds obtained
induced frameshift mutations of the type +1 (strain
TA 1537), and base mismatch mutations (strain TA 100).
The data on the mutagenicity of the compounds
synthesized with strain TA 98 are given in Table 1.
Compounds 1a,d,g,i, and 2e, dihetarylmethanes 6 and
7, and dihetarylsilanes 3b and 4 were not found to be
mutagens. Compound 6a in high doses inhibited bacte-
rial growth. The various mutagenic activity was exhib-
ited by compounds 3a, 3c, and 5. (Note that the lowest
activity was provided by compound 3a, which inhibited
bacterial growth in high doses, with toxic effect.) Com-
pounds 3c and 5a increased the rate of spontaneous
mutations ten times and more in the lowest experimen-
tal dose (50 µg per plate), but bacterial growth was
inhibited only by the latter in high doses. In low doses,
compound 5b is less active than 3c. Thus, compound 3c
can be regarded as frameshift mutagen possessing high
mutagenic activity in a broad range of doses (from low
to high), without inhibiting bacterial growth. The latter
Experimental
1
H and 13C NMR were recorded on a Varian VXR-400
instrument. p-C16H33NMe3Br was used as a phase-transfer
catalyst. Reactions were carried out in an atmosphere of argon.
Reagents were purchased from Lancaster Co. Diethyl ether
was dried according to the known procedure.12 SiMe2Cl2 and
TMSCl were distilled in an atmosphere of argon immediately
before use.
6H-Indeno[2,1-b]indole (1a)2. A mixture of indan-2-one
(30 g, 0.23 mol), PriOH (300 mL), freshly distilled phenylhy-
drazine (22.3 mL, 0.23 mol), and TsOH (1 g) was refluxed for
1 h and then cooled. The yellow precipitate that formed was
indan-2-one phenylhydrazone. A solution of conc. H2SO4
(16 mL) in 50 mL of PriOH was added, and the reaction
mixture was refluxed for 40 min, cooled, and poured into
800 mL of 2.5% NaOH. The precipitate that formed was
filtered off and washed with water and twice with PriOH to give
compound 1a (37.8 g, 80%) as colorless crystals, m.p. 205 °C.
1H NMR (CDCl3, 20 °C), δ: 3.70 (s, 2 H, CH2); 7.10 (t, 1 H,
J = 7.8 Hz); 7.21 (m, 2 H); 7.38 (m, 3 H); 7.65 (d, 1 H,

Bridged indenoindoles and indenopyrroles
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1443
J = 7.8 Hz); 7.87 (dd, 1 H, Ar, J1 = 5.6 Hz, J2 = 2.8 Hz); 8.30
(br.s, 1 H, NH).
indenoindole 1a (10.25 g, 0.05 mol) in 100 mL of anhydrous
Et2O. Stirring was continued at ∼20 °C for 30 min, and then
tetramethylethylenediamine (7.53 mL) was added. The reaction
mixture was stirred for an additional 1 h and cooled to –30 °C.
A solution of Me3SiCl (6.3 mL, 0.05 mol) in 10 mL of
anhydrous Et2O was added rapidly, and the reaction mixture
was refluxed with stirring for 3 h. After the addition of water
(30 mL), the organic phase was separated, washed with water,
and dried with Na2SO4. The solvent was removed, and the
residue was washed twice with light petroleum to give com-
pound 1g (7.35 g, 53%) as light yellow-green crystals, m.p.
141—143 °C. Found (%): C, 77.90; H, 6.93; N, 5.04.
C18H19NSi. Calculated (%): C, 77.93; H, 6.90; N, 5.05.
1H NMR (CDCl3, 20 °C), δ: 0.81 (s, 9 H, Si—Me); 3.83 (s,
2 H, CH2); 7.18 (t, 1 H, Ar, J = 7.7 Hz); 7.28 (t, 1 H, Ar,
J = 7.6 Hz); 7.33 (t, 1 H, Ar, J = 7.7 Hz); 7.42 (t, 1 H, Ar,
J = 7.6 Hz); 7.49 (d, 1 H, Ar, J = 7.6 Hz); 7.63 (d, 1 H, Ar,
J = 7.7 Hz); 7.73 (d, 1 H, Ar, J = 7.6 Hz); 7.96 (d, 1 H, Ar,
J = 7.7 Hz).
5-Phenyl-6H-indeno[2,1-b]indole (1h). A mixture of indan-
2-one (2.64 g, 0.02 mol), EtOH (50 mL), 1,1-diphenylhydrazine
(3.68 g, 0.02 mol), and conc. H2SO4 (1 mL) was refluxed for
1.5 h and then poured into 150 mL of water. The products were
extracted with CH2Cl2. The organic phases were combined,
dried with Na2SO4, and concentrated. The residue was
chromatographed on SiO2 in benzene—light petroleum (2 : 1).
The yellow oil obtained was dissolved in a minimum amount of
boiling hexane. The crystals that formed on cooling were
filtered off and washed with cold light petroleum. The yield of
compound 1h was 2.2 g (41%), colorless crystals, m.p.
129—130 °C. Found (%): C, 89.57; H, 5.43; N, 5.00. C21H15N.
Calculated (%): C, 89.65; H, 5.37; N, 4.98. 1H NMR (CDCl3,
20 °C), δ: 3.80 (s, 2 H, CH2); 7.14 (t, 1 H, Ar, J = 7.3 Hz);
7.22 (m, 3 H, Ar); 7.42 (m, 3 H, Ar); 7.57 (m, 4 H, Ar); 7.72
(d, 1 H, Ar, J = 7.3 Hz); 7.95 (d, 1 H, Ar, J = 7.3 Hz).
13C NMR (CDCl3, 20 °C), δ: 32.0 (CH2); 110.2, 188.6, 119.4,
120.9, 121.9, 122.4, 122.7, 122.9, 124.5, 124.7, 127.0, 127.1,
129.8, 138.4, 139.6, 141.3, 142.3, 148.8 (all Ar).
5-Methyl-6-(trimethylsilyl)-6H-indeno[2,1-b]indole (1i).
A 1.6 M solution of BuLi (6.25 mL, 0.01 mol) in n-hexane was
added dropwise with stirring and cooling by water and ice to a
suspension of indenoindole 1d (2.19 g, 0.01 mol) in 30 mL of
anhydrous Et2O. After the cooling was completed, the reaction
mixture was stirred at ∼20 °C for 30 min and then cooled again
to –30 °C. A solution of Me3SiCl (1.27 mL, 0.01 mol) in
10 mL of anhydrous Et2O was rapidly added, and the resulting
mixture was refluxed with stirring for 1 h. The precipitate of
LiCl that formed was filtered off, washed with Et2O, and the
filtrate was concentrated. The residue was recrystallized from
hexane—benzene to give compound 1i (1.52 g, 52%) as beige
crystals, m.p. 152—154 °C. Found (%): C, 78.24; H, 7.23;
N, 4.83. C19H21NSi. Calculated (%): C, 78.30; H, 7.26; N, 4.81.
1H NMR (CDCl3, 20 °C), δ: 0.00 (s, 9 H, Si—Me); 3.78 (s,
1 H, CH); 3.84 (s, 3 H, N—Me); 7.10 (t, 1 H, Ar, J = 6.8 Hz);
7.26 (d, 1 H, Ar, J = 6.8 Hz); 7.28 (d, 1 H, Ar, J = 6.8 Hz);
7.36 (m, 2 H, Ar); 7.43 (d, 1 H, Ar, J = 5.9 Hz); 7.73 (d, 1 H,
Ar, J = 5.9 Hz); 7.93 (dd, 1 H, Ar, J1 = 5.9 Hz, J2 = 2.1 Hz).
Ethyl 2-methyl-8H-indeno[2,1-b]pyrrole-3-carboxylate
(2b).7 Sodium acetate trihydrate (47.6 g, 0.35 mol) was added
in small portions to a mixture of 2-aminoindan-1-one hydro-
chloride (51.3 g, 0.28 mol) obtained according to the known
procedure14 and ethyl acetoacetate (38 mL, 0.3 mol) in 300 mL
of glacial AcOH. The reaction mixture was heated with stirring
at 50—60 °C for 5 h and left for 12 h. Then, it was poured into
1.5 L of water, and the precipitate that formed was filtered off
and washed with a solution of NaHCO3 and water. The yield of
2-Methyl-6H-indeno[2,1-b]indole (1b). Compound 1b was
obtained analogously from 1-(4-methylphenyl)hydrazine (12.2 g,
0.1 mol), indan-2-one (13.2 g, 0.1 mol), and TsOH (0.5 g) in
70 mL of PriOH. The yield of compound 1b was 19.3 g (88%),
light brown crystals, m.p. 206 °C. Found (%): C, 87.62;
H, 5.94; N, 6.44. C16H13N. Calculated (%): C, 87.63; H, 5.98;
N, 6.39. 1H NMR (CDCl3, 20 °C), δ: 2.54 (s, 3 H, Me); 3.70
(s, 2 H, CH2); 7.02 (d, 1 H, Ar, J = 7.8 Hz); 7.08 (t, 1 H, Ar,
J = 7.8 Hz); 7.23 (d, 1 H, Ar, J = 6.5 Hz); 7.33 (t, 1 H, Ar,
J = 7.8 Hz); 7.42 (d, 1 H, Ar, J = 6.5 Hz); 7.64 (m, 2 H, Ar);
8.02 (br.s, 1 H, NH).
2-tert-Butyl-6H-indeno[2,1-b]indole (1c)2. Compound 1c
was obtained analogously from 4-tert-butylphenylhydrazine
(21.5 g, 0.13 mol), indan-2-one (17.2 g, 0.13 mol), and TsOH
(0.5 g) in 80 mL of PriOH. The yield of compound 1c was
24.7 g (72%), light brown crystals, m.p. 182—183 °C. 1H NMR
(CDCl3, 20 °C), δ: 2.54 (s, 9 H, CMe3); 3.64 (s, 2 H, CH2);
7.12 (t, 1 H, Ar, J = 5.9 Hz); 7.25 (d, 1 H, Ar, J = 5.2 Hz);
7.31 (d, 1 H, Ar, J = 5.2 Hz); 7.38 (t, 1 H, Ar, J = 5.9 Hz);
7.45 (d, 1 H, Ar, J = 5.9 Hz); 7.71 (d, 1 H, Ar, J = 5.9 Hz);
7.88 (s, 1 H, Ar); 8.03 (br.s, 1 H, NH).
5-Methyl-6H-indeno[2,1-b]indole (1d)13. Benzene (80 mL),
indenoindole 1a (5 g, 0.022 mol), a phase-transfer catalyst
(0.2 g, 0.5 mmol), and MeI (1.6 mL, 0.025 mol) were added to
a solution of NaOH (40 g) in 40 mL of water. The reaction
mixture was heated with vigorous stirring at 40 °C for 8 h. The
organic phase was separated, washed with water, dried with
Na2SO4, and concentrated. The residue was recrystallized from
benzene—hexane (1 : 2) to give compound 1d (3.4 g, 70%) as
colorless crystals, m.p. 172 °C. 1H NMR (CDCl3, 20 °C),
δ: 3.66 (s, 2 H, CH2); 3.78 (s, 3 H, Me); 7.07 (t, 1 H, Ar,
J = 6.7 Hz) 7.22 (m, 2 H, Ar); 7.34 (m, 2 H, Ar); 7.42 (d, 1 H,
Ar, J = 6.7 Hz); 7.62 (d, 1 H, Ar, J = 6.9 Hz); 7.86 (dd, 1 H,
Ar, J1 = 6.9 Hz, J2 = 2.1 Hz).
2,5-Dimethyl-6H-indeno[2,1-b]indole (1e). Benzene
(100 mL), indenoindole 1b (19.3 g, 0.088 mol), a phase-
transfer catalyst (0.6 g, 1.6 mmol), and MeI (6.23 mL, 0.01 mol)
were added to a solution of NaOH (100 g) in 100 mL of water.
The reaction mixture was heated with vigorous stirring at 40 °C
for 1 h. After the reaction was completed, the precipitate that
formed was filtered off and washed with water and EtOH. The
yield of compound 1e was 18.0 g (88%), colorless crystals, m.p.
199—200 °C. Found (%): C, 87.45; H, 6.44; N, 6.11. C17H15N.
Calculated (%): C, 87.52; H, 6.48; N, 6.00. 1H NMR (CDCl3,
20 °C), δ: 2.56 (s, 3 H, Me); 3.62 (s, 2 H, CH2); 3.76 (s, 3 H,
N—Me); 7.09 (m, 2 H, Ar) 7.24 (d, 1 H, Ar, J = 6.3 Hz); 7.36
(t, 1 H, Ar, J = 6.3 Hz); 7.43 (d, 1 H, Ar, J = 5.6 Hz); 7.62 (m,
2 H, Ar). 13C NMR (CDCl3, 20 °C), δ: 21.6 (Me); 30.0 (CH2);
31.1 (N—Me); 109.3, 118.2, 119.3, 119.8, 121.9, 122.4, 122.4,
124.6, 127.0, 129.0, 139.7, 140.6, 142.0, 148.5 (all Ar).
2-tert-Butyl-5-methyl-6H-indeno[2,1-b]indole (1f). Com-
pound 1f was obtained as described for 1e from indenoindole
1c (26.0 g, 0.099 mol), a phase-transfer catalyst (0.6 g,
1.6 mmol), and MeI (9.3 mL, 0.15 mol). The yield of com-
pound 1f was 22.6 g (82%), colorless crystals, m.p. 208—209 °C.
Found (%): C, 87.23; H, 7.74; N, 5.03. C20H21N. Calcu-
lated (%): C, 87.22; H, 7.69; N, 5.09. 1H NMR (CDCl3,
20 °C), δ: 2.54 (s, 9 H, Me); 3.64 (s, 2 H, CH2); 3.85 (s, 3 H,
N—Me); 7.01 (t, 1 H, Ar, J = 6.1 Hz); 7.23 (t, 1 H, Ar,
J = 6.1 Hz); 7.32 (m, 2 H, Ar); 7.39 (d, 1 H, Ar, J = 6.1 Hz);
7.64 (d, 1 H, Ar, J = 6.1 Hz); 7.82 (d, 1 H, Ar, J = 1.5 Hz).
5-(Trimethylsilyl)-6H-indeno[2,1-b]indole (1g). A 2.18 M
solution of BuLi (22.9 mL) in n-hexane was added dropwise
with stirring and cooling by water and ice to a suspension of

1444
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Nifant´ev et al.
compound 2b was 31.8 g (47%), colorless crystals, m.p. 200 °C.
1H NMR (CDCl3, 20 °C), δ: 1.46 (t, 3 H, OCH2Me,
J = 7.8 Hz); 2.60 (s, 3 H, Me); 3.51 (s, 2 H, CH2); 4.42 (q,
2 H, OCH2Me, J = 7.8 Hz); 7.11, 7.30 (both t, each 1 H, Ar,
J = 7.4 Hz); 7.38, 8.02 (both d, each 1 H, Ar, J = 7.4 Hz); 8.40
(br.s, 1 H, NH). 13C NMR (acetone-d6, 20 °C), δ: 14.0 (Me);
15.1 (Me); 30.9 (CH2); 59.7 (OCH2); 107.0, 121.5, 123.6,
125.2, 127.2, 129.3, 137.9, 139.8, 140.9, 144.7 (all Ar);
166.0 (C=O).
Ethyl 1,2-dimethyl-8H-indeno[2,1-b]pyrrole-3-carboxylate
(2c). Compound 2c was obtained as described for 1e from
indenopyrrole 2b (15.9 g, 0.066 mol), a phase-transfer catalyst
(0.5 g, 1.4 mmol), and MeI (8.1 mL, 0.13 mol). The yield of
compound 2c was 11.0 g (65%), cream-colored crystals, m.p.
152 °C. Found (%): C, 75.35; H, 6.67; N, 5.43. C16H17NO2.
Calculated (%): C, 75.26; H, 6.71; N, 5.49. 1H NMR (CDCl3,
20 °C), δ: 1.46 (t, 3 H, OCH2Me, J = 7.9 Hz); 2.59 (s, 3 H,
Me); 3.46 (s, 3 H, N—Me); 3.51 (s, 2 H, CH2); 4.42 (q, 2 H,
OCH2Me, J = 7.9 Hz); 7.08 (t, 1 H, Ar, J = 7.5 Hz); 7.28 (t,
1 H, Ar, J = 7.5 Hz); 7.37 (d, 1 H, Ar, J = 7.5 Hz); 8.00 (d,
1 H, Ar, J = 7.5 Hz).
1,2-Dimethyl-8H-indeno[2,1-b]pyrrole-3-carboxylic acid
(2d). A mixture of ester 2c (14 g, 0.055 mol), EtOH (150 mL),
water (150 mL), and NaOH (130 g) was refluxed with stirring
for 6 h and then poured into 200 mL of water. The precipitate
of the salt that formed was filtered off and added to a solution
of HCl (70 mL) in 200 mL of water. The reaction mixture was
stirred for 30 min, and the precipitate that formed was filtered
off. The yield of acid 2d was 10.1 g (81%), m.p. 170—172 °C
(decomp.). Found (%): C, 73.92; H, 5.69; N, 6.24. C14H13NO2.
Calculated (%): C, 73.99; H, 5.77; N, 6.16. 1H NMR
(DMSO-d6, 20 °C), δ: 2.53 (s, 3 H, Me); 3.52 (s, 3 H,
N—Me); 3.56 (s, 2 H, CH2); 7.03 (t, 1 H, Ar, J = 7.7 Hz); 7.22
(t, 1 H, Ar, J = 7.7 Hz); 7.38 (d, 1 H, Ar, J = 7.7 Hz); 7.92 (d,
1 H, Ar, J = 7.7 Hz). 13C NMR (DMSO-d6, 20 °C),
δ: 11.4 (Me); 29.4 (CH2); 32.0 (N—CH2); 105.8, 120.4, 122.6,
124.6, 126.0, 126.4, 138.9, 139.5, 139.9, 143.2 (all Ar);
166.5 (C=O).
1,2-Dimethyl-8H-indeno[2,1-b]pyrrole (2e). A mixture of
acid 2d (20.7 g, 0.91 mol) and diethylene glycol (230 mL) was
heated to 170—200 °C until gas evolution ceased (∼50 min).
The reaction mixture was cooled with water and ice, and the
precipitate that formed was filtered off and washed with EtOH.
The yield of compound 2e was 12.8 g (76%), cream-colored
crystals, m.p. 180 °C. Found (%): C, 85.19; H, 7.23; N, 7.58.
C13H13N. Calculated (%): C, 85.21; H, 7.15; N, 7.64. 1H NMR
(CDCl3, 20 °C), δ: 2.14 (s, 3 H, Me); 3.33 (s, 2 H, CH2); 3.38
(s, 3 H, N—Me); 5.92 (s, 1 H, CH); 6.85 (m, 1 H, Ar) 7.12 (m,
1 H, Ar); 7.19 (m, 2 H, Ar). 13C NMR (CDCl3, 20 °C),
δ: 29.6 (Me); 29.9 (CH2); 31.6 (N—Me); 98.4, 117.7, 121.8,
124.5, 126.3, 126.5, 132.2, 139.8, 140.6, 142.9 (all Ar).
Dimethylbis(5-methyl-6H-indeno[2,1-b]indol-6-yl)silane
(3a). A 1.6 M solution of BuLi (100 mL, 0.16 mol) in n-hexane
was added dropwise with stirring and cooling by water and ice
to a suspension of indenoindole 1d (35.0 g, 0.16 mol) in
400 mL of anhydrous Et2O. After cooling was completed, the
reaction mixture was stirred at ∼20 °C for 30 min and then
cooled to –30 °C. A solution of SiMe2Cl2 (9.4 mL, 0.08 mol)
in 20 mL of anhydrous Et2O was added rapidly, and the
resulting solution was refluxed with stirring for 2 h. Then a
solution of NH4Cl (8.6 g, 0.16 mol) in 100 mL of water was
added; the precipitate that formed was filtered off and washed
with water and twice with Et2O to give a colorless crystalline
substance. The concentration of the filtrate afforded an addi-
tional 4.1 g. The yield of 3a was 24.6 g (62%), m.p. 226—228 °C.
Found (%): C, 82.44; H, 6.19; N, 5.60. C34H30N2Si. Calcu-
lated (%): C, 82.55; H, 6.11; N, 5.66. 1H NMR (CDCl3,
20 °C), δ: racemic form: 0.38 (s, 6 H, Si—Me); 3.45 (s, 6 H,
N—Me); 4.05 (s, 2 H, CH); 7.79—7.19 (m, 16 H, Ar);
meso-form: –0.40 (s, 3 H, Si—Me); 0.09 (s, 3 H, Si—Me); 3.75
(s, 6 H, N—Me); 3.80 (s, 2 H, CH); 8.05—7.16 (m, 16 H, Ar).
Bis(2-tert-butyl-5-methyl-6H-indeno[2,1-b]indol-6-yl)-1,1-
dimethylsilane (3b). A 2.24 M solution of BuLi (18.0 mL,
0.04 mol) in n-hexane was added dropwise with stirring and
cooling by water and ice to a suspension of indenoindole 1f
(11 g, 0.04 mol) in 200 mL of anhydrous Et2O. After cooling
was completed, the reaction mixture was stirred at ∼20 °C for
30 min and then cooled to –30 °C. A solution of SiMe2Cl2
(2.42 mL, 0.02 mol) in 20 mL of anhydrous Et2O was added
rapidly, and the resulting solution was refluxed for 1 h. Then a
solution of NH4Cl (2.13 g, 0.04 mol) in 40 mL of water was
added. The organic layer was separated, washed with water, and
concentrated. The residue was dissolved with heating in a
minimum amount of hexane and cooled. After ∼24 h, the
precipitate that formed was filtered off and washed with pen-
tane to give compound 3b (6.3 g, 52%) as colorless crystals,
m.p. 225—227 °C. Found (%): C, 82.99; H, 7.71; N, 5.56.
C42H46N2Si. Calculated (%): C, 83.12; H, 7.65; N, 4.62.
1H NMR (CDCl3, 20 °C), δ: racemic form: –0.42 (s, 6 H,
Si—Me); 1.45 (s, 18 H, CMe3); 3.55 (s, 6 H, N—Me); 4.18 (s,
2 H, CH); 7.20 (t, 2 H, Ar, J = 5.8 Hz); 7.27 (d, 2 H, Ar,
J = 5.8 Hz); 7.33 (dd, 2 H, Ar, J1 = 5.5 Hz, J2 = 1.9 Hz); 7.43
(t, 2 H, Ar, J = 5.8 Hz); 7.70 (d, 2 H, Ar, J = 5.5 Hz); 7.80 (d,
2 H, Ar, J = 5.8 Hz); 7.90 (d, 2 H, Ar, J = 1.9 Hz).
Dimethylbis(5-phenyl-6H-indeno[2,1-b]indol-6-yl)silane
(3c). Compound 3c was obtained as described for 3a from
indenoindole 1h (2.81 g, 0.01 mol), a 1.6 M solution of BuLi
(6.25 mL, 0.01 mol) in n-hexane, and SiMe2Cl2 (0.62 mL,
0.005 mol) in 40 mL of anhydrous Et2O. The yield of com-
pound 3c was 1.1 g (35%), light yellow crystals, m.p. 205 °C.
Found (%): C, 85.31; H, 5.48; N, 4.49. C44H34N2Si. Calcu-
lated (%): C, 85.40; H, 5.54; N, 4.53. 1H NMR (CDCl3,
20 °C), δ: racemic form: –1.01 (s, 6 H, Si—Me); 3.64 (s, 2 H,
CH); 7.92—7.09 (m, 26 H, Ar); meso-form: –0.98 (s, 3 H,
Si—Me); –0.96 (s, 3 H, Si—Me); 3.71 (s, 2 H, CH); 7.72—7.15
(m, 26 H, Ar).
Dimethylbis(1,2-dimethyl-8H-indeno[2,1-b]pyrrol-8-yl)si-
lane (4). Compound 4 was obtained as described for 3a from
indenopyrrole 2e (2.75 g, 0.015 mol), a 1.6 M solution of BuLi
(9.38 mL, 0.015 mol) in n-hexane, and SiMe2Cl2 (0.88 mL,
0.0075 mol) in 50 mL of anhydrous Et2O. The yield of com-
pound 4 was 1.74 g (55%), light gray crystals, m.p. 153—155 °C.
Found (%): C, 79.47; H, 7.08; N, 6.58. C28H30N2Si. Calcu-
lated (%): C, 79.57; H, 7.15; N, 6.63. 1H NMR (CDCl3,
20 °C), δ: racemic form: –0.05 (s, 6 H, Si—Me); 2.18 (s, 6 H,
Me); 3.21 (s, 2 H, CH); 3.41 (s, 6 H, N—Me); 6.02 (s, 2 H,
CH); 7.41—6.79 (m, 8 H, Ar); meso-form: –0.51 (s, 3 H,
Si—Me); –0.48 (s, 3 H, Si—Me); 2.16 (s, 6 H, Me); 3.12 (s,
2 H, CH); 3.37 (s, 6 H, N—Me); 5.98 (s, 2 H, CH); 7.24—6.64
(m, 8 H, Ar).
6-[9H-Fluoren-9-yl(dimethyl)silyl]-5-methyl-6H-inde-
no[2,1-b]indole (5a). Compound 5a was obtained as described
for 3a from indenoindole 1d (2.19 g, 0.01 mol), a 1.6 M
solution of BuLi (6.25 mL, 0.01 mol) in n-hexane, and
chloro(9H-fluoren-9-yl)dimethylsilane15 (2.6 g, 0.01 mol) in
30 mL of anhydrous Et2O. The yield of compound 5a was 2.6 g
(60%), light yellow crystals, m.p. 206—208 °C. Found (%):
C, 84.44; H, 6.19; N, 3.20. C31H27NSi. Calculated (%):
C, 84.31; H, 6.16; N, 3.17. 1H NMR (CDCl3, 20 °C), δ: –0.41
(s, 3 H, Si—Me); –0.35 (s, 3 H, Si—Me); 3.59 (s, 3 H,
N—Me); 3.98 (s, 1 H, CH); 4.30 (s, 1 H, CH); 7.86—7.16
(m, 16 H, Ar).

Bridged indenoindoles and indenopyrroles
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1445
6-[2,7-Di-tert-butyl-9H-fluoren-9-yl(dimethyl)silyl]-5-me-
thyl-6H-indeno[2,1-b]indole (5b). Compound 5b was obtained
as described for 3a from indenoindole 1d (0.65 g, 0.003 mol), a
1.6 M solution of BuLi (1.9 mL, 0.003 mol) in n-hexane, and
(2,7-di-tert-butyl-9H-fluoren-9-yl)chloro(dimethyl)silane15
(1.1 g, 0.003 mol) in 15 mL of anhydrous Et2O. The yield of
compound 5b was 1.13 g (68%), light yellow crystals, m.p.
192—194 °C. Found (%): C, 84.47; H, 7.89; N, 2.61.
C39H43NSi. Calculated (%): C, 84.57; H, 7.83; N, 2.53.
1H NMR (CDCl3, 20 °C), δ: –0.45 (s, 3 H, Si—Me); –0.29 (s,
3 H, Si—Me); 1.25 (s, 9 H, CMe3); 1.35 (s, 9 H, CMe3); 3.40
(s, 3 H, N—Me); 3.55 (s, 1 H, CH); 4.01 (s, 1 H, CH);
7.79—6.83 (m, 14 H, Ar).
and NH4Cl (1.28 g) in 47 mL of DMF. The yield of compound
7 was 2.6 g (59%), light yellow crystals, m.p. 132—134 °C
(decomp.). Found (%): C, 85.59; H, 6.86; N, 7.55. C27H26N2.
Calculated (%): C, 85.68; H, 6.92; N, 7.40. 1H NMR (CDCl3,
20 °C), δ: meso-form: 2.31 (s, 6 H, Me); 2.89 (dt, 1 H, CH2,
J1 = 15.9 Hz, J2 = 6.6 Hz); 2.89 (dt, 1 H, CH2, J1 = 15.9 Hz,
J2 = 3.9 Hz); 3.41 (s, 6 H, N—Me); 3.62 (dd, 2 H, CH,
J1 = 6.6 Hz, J2 = 3.9 Hz); 6.08 (s, 2 H, CH, pyrrole);
7.78—7.08 (m, 8 H, Ar); racemic form: 2.11 (m, 2 H, CH2);
2.22 (s, 6 H, Me); 3.32 (s, 6 H, N—Me); 4.26 (dd, 2 H, CH,
J1 = 8.3 Hz, J2 = 6.6 Hz); 6.05 (s, 2 H, CH, pyrrole);
7.78—7.08 (m, 8 H, Ar).
Bis(5-methyl-6H-indeno[2,1-b]indol-6-yl)methane (6a).
Indenoindole 1d (21.9 g, 0.1 mol) was heated with stirring in
200 mL of DMF at 60 °C for 5 min. Sodium ethoxide (3.4 g,
0.05 mol) was added, and stirring was continued for 30 min.
Then 37% aqueous CH2O (3.8 mL, 0.05 mol) was added, and
the reaction mixture was stirred at 60 °C for 2 h. Ammonium
chloride (5.0 g, 0.09 mol) was added, and the precipitate that
formed was filtered off and washed with DMF and Et2O. The
yield of compound 6a was 20.9 g (92%), colorless crystals,
m.p. 237 °C. Found (%): C, 87.89; H, 5.86; N, 6.25. C33H26N2.
Calculated (%): C, 87.96; H, 5.82; N, 6.22. 1H NMR (CDCl3,
20 °C), δ: 2.27 (dd, 2 H, CH2, J1 = 6.2 Hz, J2 = 8.8 Hz); 3.59
(s, 6 H, N—Me); 4.52 (dd, 2 H, CH, J1 = 6.2 Hz, J2 = 8.8 Hz);
7.16 (t, 2 H, Ar, J = 6.5 Hz); 7.24 (m, 6 H, Ar); 7.42 (t, 2 H,
Ar, J = 6.2 Hz); 7.68 (d, 2 H, Ar, J = 6.5 Hz); 7.88 (m, 4 H,
Ar). 13C NMR (CDCl3, 20 °C), δ: 31.2 (N—Me); 35.1 (CH2);
40.8 (CH); 109.8, 118.8, 118.9, 119.3, 120.2, 121.2, 121.7,
122.3, 124.8, 127.7, 139.8, 141.5, 146.4, 151.5 (all Ar).
Bis(2,5-dimethyl-6H-indeno[2,1-b]indol-6-yl)methane (6b).
Compound 6b was obtained analogously from indenoindole 1e
(9.32 g, 0.04 mol), NaOEt (1.36 g, 0.02 mol), 37% aqueous
CH2O (1.52 mL, 0.02 mol), and NH4Cl (2.5 g, 0.047 mol) in
80 mL of DMF. The yield of compound 6b was 8.9 g (93%),
colorless crystals, m.p. 267 °C. Found (%): C, 87.78; H, 6.29;
N, 5.93. C35H30N2. Calculated (%): C, 87.83; H, 6.32; N, 5.85.
1H NMR (CDCl3, 20 °C), δ: 2.34 (dd, 2 H, CH2, J1 = 8.1 Hz,
J2 = 6.9 Hz); 2.52 (s, 6 H, Me); 3.59 (s, 6 H, N—Me); 4.48
(dd, 2 H, CH, J1 = 8.1 Hz, J2 = 6.9 Hz); 7.05 (d, 2 H, Ar,
J = 6.8 Hz); 7.15 (m, 4 H, Ar); 7.42 (t, 2 H, Ar, J = 5.6 Hz);
7.64 (s, 2 H, Ar); 7.69 (d, 2 H, Ar, J = 5.6 Hz); 7.84 (d, 2 H,
Ar, J = 6.8 Hz). 13C NMR (CDCl3, 20 °C), δ: 21.4 (Me);
31.1 (N—Me); 35.2 (CH2); 40.8 (CH); 109.4, 115.3, 118.4,
118.7, 119.2, 121.9, 122.1, 122.6, 124.9, 128.7, 129.5, 140.1,
146.4, 151.6 (all Ar).
References
1. W. Vance and D. Levin, Environ. Mutagen, 1984, 6, 797.
2. D. Brown, P. Graupner, M. Sainsbury, and H. Shertzer,
Tetrahedron, 1991, 47, 4383.
3. G. Kempter, M. Schwalba, W. Stoss, and K. Walter, J. Prakt.
Chem., 1962, 18, 39.
4. Buu-Hoi and R. Royer, Bull. Soc. Chim. Fr., 1947, 14, 812.
5. G. N. Zhungietu, N. N. Suvorov, and A. N. Kost, in Novye
preparativnye sintezy v indol´nom ryadu [New Preparative
Syntheses in the Indole Series], Shtiintsa, Chisinau, 1983, 35
(in Russian).
6. D. M. Quizon-Colquit and T. D. Lash, J. Heterocycl.
Chem., 1993, 30, 477.
7. C. F. Charles and H. Adkins, J. Am. Chem. Soc., 1933,
55, 4169.
8. P. V. Ivchenko and I. E. Nifant´ev, Zh. Org. Khim., 1998,
34, 9 [Russ. J. Org. Chem., 1998, 34 (Engl. Transl.)].
9. L. Resconi, D. Balboni, G. Baruzzi, C. Fiori, and
S. Guidotti, Organometallics, 2000, 19, 420.
10. S. K. Abilev and G. G. Poroshenko, in Toksikologiya.
Uskorennye metody prognozirovaniya mutagennykh i blastomo-
gennykh svoistv khimicheskikh soedinenii [Toxycology, Accel-
erated Tests for the Mutagenic and Blastogenic Properties of
Chemical Compounds], VINITI, Moscow, 1986, 14, 174 (in
Russian).
11. D. M. Maron and B. N. Ames, Mutat. Res., 1983, 113, 173.
12. Organic Solvents. Physical Properties and Methods of Purifi-
cation, Ed. A. Weissberger, Interscience Publ., New
York—London, 1955.
13. J. Armit and R. Robinson, J. Chem. Soc., 1922, 121, 838.
14. S. Gabriel and R. Stelsner, Chem. Ber., 1896, 29, 2605.
15. K. Patsidis, H. G. Alt, W. Millius, and S. J. Palackal,
J. Organomet. Chem., 1996, 509, 63.
Bis(1,2-dimethyl-8H-indeno[2,1-b]pyrrol-8-yl)methane (7).
Compound 7 was obtained analogously over 5 h from
indenopyrrole 2e (4.3 g, 0.0235 mol), NaOEt (0.80 g,
0.01175 mol), 37% aqueous CH2O (0.88 mL, 0.01175 mol),
Received October 31, 2000;
in revised form April 3, 2001