Synthesis of 2-thio derivatives of 4-phenyl-9H-pyrimido[4,5-b]indole

Article abstract of DOI:10.1007/s11172-006-0379-8

The reaction of 3-benzylidene-2-ethoxyindolenine tetrafluoroborate with thiourea gives a mixture of 4-phenylpyrimido[4,5-b]indole-2(1H)-thione, its 3,4-dihydro derivative, and the corresponding disulfide, the product ratio depending on the reaction condit

Full text of DOI:10.1007/s11172-006-0379-8

Russian Chemical Bulletin, International Edition, Vol. 55, No. 6, pp. 1071—1076, June, 2006
1071
Synthesis of 2ꢀthio derivatives of 4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole*
V. P. Borovik, V. G. Vasil´ev, and O. P. Shkurkoꢀ
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Eꢀmail: oshk@nioch.nsc.ru
The reaction of 3ꢀbenzylideneꢀ2ꢀethoxyindolenine tetrafluoroborate with thiourea gives a
mixture of 4ꢀphenylpyrimido[4,5ꢀb]indoleꢀ2(1H )ꢀthione, its 3,4ꢀdihydro derivative, and the
corresponding disulfide, the product ratio depending on the reaction conditions. A number of
transformations of the resulting compounds, in particular, those giving 2ꢀalkylthio pyrimidoꢀ
indole derivatives are described.
Key words: 4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indoleꢀ2(1H )ꢀthione, 2ꢀalkylthio derivatives of
4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole, alkylation, oxidation, nucleophilic substitution, desulfuꢀ
rization.
The functional derivatives of pyrimido[4,5ꢀb]indole,
in particular, synthetically most available 2ꢀ and 4ꢀaminoꢀ
substituted derivatives, possess a broad spectrum of bioꢀ
logical activities and present interest as a base for the
development of new medicines.1—3 The corresponding
thio derivatives may also attract attention as biologically
active substances, since compounds possessing antioxiꢀ
dant, antihypoxic, and hepatoprotector activities have
been found in the series of related heterocyclic systems,
1,2,4ꢀtriazino[5,6ꢀb]ꢀ and ꢀ[6,5ꢀb]indoles.4—6 In order to
extend the range of functional derivatives of 4ꢀphenylꢀ
pyrimido[4,5ꢀb]indole and to study their properties, we
attempted to synthesize its 2ꢀthio derivatives.
Previously, we carried out the reaction of 3ꢀbenꢀ
zylideneꢀ2ꢀethoxyindolenine tetrafluoroborate (1) with
thiourea, which yielded a product identified as 4ꢀphenylꢀ
pyrimido[4,5ꢀb]indoleꢀ2,4(1H )ꢀthione (2)7 (Scheme 1).
A repeated detailed study of the reaction showed that this
product is actually a mixture of thione 2, its 3,4ꢀdihydro
derivative 3, and disulfide 4. Similar analytical and specꢀ
troscopic characteristics of compounds 2—4, their poor
solubility in most organic solvents, similar chromatoꢀ
graphic behaviors of thiones 2 and 3, and easy transforꢀ
mation into disulfide 4 make separation and identificaꢀ
tion of these compounds a difficult task. The presence of
both thiones in the mixture can be detected by mass specꢀ
trometry, whereas disulfide 4 is not detected due to its
very low volatility. All three components of the mixture
can be observed by HPLC with mass selective detection
(HPLCꢀMSD). In addition, the presence of disulfide 4
can be determined by TLC.
The intermediate formation of dihydro pyrimidoindole
derivatives similar to compound 3 in the cycloconꢀ
densation of tetrafluoroborate 1 with amidines and guaniꢀ
dine has been proved previously.8 Here the proof for the
structure of compound 3 was based on chemical transforꢀ
mations and spectroscopic data. In addition to the intense
molecular ion peak with m/z 279 (88%), its mass specꢀ
trum exhibits a line with m/z 202 (100%), indicating a
typical easy elimination of the phenyl radical from the
sp3ꢀhybridized C(4) atom of the molecular ion.8 The
13C NMR spectrum of compound 3 exhibits a signal for
1
C(4) at δ 56.18, while the H NMR spectrum contains a
doublet for H(4) at δ 5.85 with J = 2.5 Hz due to spin—spin
coupling with the proton of the neighboring N(3)H group.
On selective decoupling of the signal at δ 9.11, the
H(4) proton signal becomes a singlet, while the signal for
the N(3)H group shows a clearꢀcut doublet structure with
the same coupling constant under suppression of the lowꢀ
estꢀfield signal of the N(1)H group at δ 11.07. In addition,
the lastꢀmentioned signal exhibits the NOE; its intensity
increases by 10% on application of an additional freꢀ
quency onto the signal of the neighboring indole N(9)H
group at δ 10.46. All NH groups undergo H—D exchange,
the lowest exchange rate being typical of the N(3)H group.
The signals for the aromatic protons of the indole fragꢀ
ment in compound 3 were assigned using double homoꢀ
nuclear resonance and published data. In particular, the
doublet at δ 7.30 was assigned to the H(5) proton based
on known data for indole,9,10 pyrido[2,3ꢀb]indolꢀ2(1H )ꢀ
one,11 and benzopyrimido[4,5ꢀb]indoleꢀ2,4(1H,3H )ꢀ
dione12 derivatives.
The aromatic proton signals in the 1H NMR spectrum
of thione 2 were also assigned using double resonance.
When comparing the spectral patterns for compounds 2
* Dedicated to the memory of Academician V. A. Koptyug on
the occasion of the 75th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1032—1037, June, 2006.
1066ꢀ5285/06/5506ꢀ1071 © 2006 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Borovik et al.
Scheme 1
Alk = Me (a), Et (b)
and 3, note the downfield shifts of the H(6), H(7), and
H(8) proton signals in thione 2 by 0.2—0.4 ppm under the
action of the annulated pyrimidine ring; conversely, the
H(5) proton signal shifts upfield by 0.1 ppm. Apparently,
the latter fact may be attributed to the influence of the
neighboring phenyl group, which is rotated, due to steric
requirements, in such a way that H(5) gets into its diaꢀ
magnetic shielding area. The position of the N(9)H signal
in the lowꢀfield part in the spectrum of thione 2 falls in
the range typical of substituted pyrimidoindoles,12—16
while an lowerꢀfield position of the N(1)H signal (δ 13.46)
is analogous to those of the NH group in quinazolinꢀ2ꢀ
and quinazolinꢀ4ꢀthiones (δ ~14)17.
are formed. The lastꢀmentioned compound could have
formed by stepwise oxidation—dehydrogenation of thione
3 in the presence of atmospheric oxygen during workup of
the reaction mixture and product isolation.
A change in the product isolation procedure (see Exꢀ
perimental) with respect to that described previously7 reꢀ
sulted in the preparation of pyrimidoindoleꢀ2ꢀthione 2 in
a satisfactory yield. It is also noteworthy that our attempts
to synthesize thione 2 by heating 2ꢀchloroꢀ4ꢀphenylꢀ
pyrimido[4,5ꢀb]indole (5) with thiourea or with its soꢀ
dium salt in boiling ethanol or in DMSO at 120 °C were
unsuccessful, unlike the behavior of chloropyrimidines in
these reactions.18
We found that the ratio of compounds 2—4 in the
products depends on the reaction conditions. Thus, an
increase in the reaction time (6, 12, 24 h) or blowing air
through the reaction mixture results in a substantial inꢀ
crease in the amount of disulfide 4, which was detected
by TLC. When the reaction is carried out under argon,
a mixture of thiones 2 and 3 and traces of disulfide 4
Easyꢀtoꢀoxidize derivative 3 has not been isolated in a
pure form. However, when the condensation of salt 1
with thiourea was carried out under argon, we were able
to obtain a product consisting of compound 3 and thione 2
impurity (~15%).
A similar formation of mixtures of dihydroꢀ and
tetrahydropyrimidines in the reactions of chalcones with

2ꢀThioꢀsubstituted 4ꢀphenylpyrimido[4,5ꢀb]indoles Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1073
thiourea is well known;19 so is the ease of oxidation of
4,6ꢀdiphenylpyrimidineꢀ2(1H )ꢀthione with atmospheric
oxygen to the corresponding disulfide.20 Previously, we
showed that the reactions of salt 1 with amidines and
guanidines carried out under similar conditions afford
2ꢀsubstituted pyrimidoꢀ and dihydropyrimido[4,5ꢀb]inꢀ
doles; the ease of dehydrogenation of the products deꢀ
pends on both the reaction temperature and the donorꢀ
acceptor properties of the substituents in the pyrimidine
ring. The electronꢀdonating substituents promote, while
the electronꢀwithdrawing substituents hamper dehydroꢀ
genation of the pyrimidine ring.8
Disulfide 4 was isolated in 5—10% yield by recrystalliꢀ
zation from DMF of the product mixture formed upon
the reaction of salt 1 and thiourea with access of air.
Compound 4 was also prepared in a high yield upon oxiꢀ
dation of a mixture of thiones 2 and 3 with sodium nitrite
in acetic acid. The reductive desulfurization of disulfide 4
with Raney nickel led to 4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]inꢀ
dole (6) in a good yield. Previously,13 we isolated this
compound as a minor product upon the reaction of
2ꢀchloropyrimidoindole 5 with hydrazine hydrate and
upon hydrogenation of the corresponding 2ꢀnitramino
derivative.
The alkylation of thione 2 with methyl iodide and
ethyl bromoacetate gave 2ꢀmethylthioꢀ4ꢀphenylpyrimidoꢀ
indole 7а and ethyl Sꢀ(4ꢀphenylpyrimidoindolyl)thioꢀ
glycolate 8 in good yields. An alternative method, i.e., the
reaction of salt 1 with Sꢀmethylꢀ and Sꢀethylisothioureas,
respectively, gave 2ꢀalkylthio derivatives 7а,b in moderꢀ
ate yields, while ethylthioglycolate 8 was prepared by nuꢀ
cleophilic displacement of the chlorine atom in 2ꢀchloroꢀ
pyrimidoindole 5 on treatment with ethyl thioglycolate.
This reaction proceeds with difficulty, its completion reꢀ
quiring heating in DMSO for many hours. The retardaꢀ
tion of nucleophilic substitution in the pyrimidoindole
series (in relation to chloro and nitramino derivatives)13
with respect to the pyrimidine analogs attests to substanꢀ
tial deactivating effect of the electronꢀreleasing pyrrole
fragment on the reactivity of the pyrimidoindole molꢀ
ecule. This conclusion is also confirmed by data on the
mobility of the MeSO2 group (see below).
We carried out methylation of dihydro derivative 3
(with a thione 2 impurity, see Experimental). The posꢀ
sibility of dehydrogenation of the dihydropyrimidine
fragment was taken into account.8 As expected, this
gave 2ꢀmethylthiopyrimidoindole 7а; however, a slight
amount of 9ꢀmethylꢀ2ꢀmethylthio derivative 9 was isoꢀ
lated as hydroiodide. Apparently, N,Sꢀdialkylation of
dihydro derivative 3 followed by dehydrogenation also
takes place. We demonstrated the possibility of alkylation
at the indole nitrogen atom by conducting the reaction of
the sodium salt of compound 6 with MeI (by analogy
with Ref. 4), which gave 9ꢀmethylꢀ4ꢀphenylpyrimidoꢀ
indole 10.
The oxidation of 2ꢀmethylthiopyrimidoindole 7а with
30% H2O2 in acetic acid gave 2ꢀmethylsulfonyl derivative
11 in a good yield; a spectral feature of this product is a
hypsochromic shift (17 nm) of the longꢀwavelength abꢀ
sorption band in the UV spectrum with respect to that in
the spectrum of starting compound 7а. A similar change
in the UV spectra was noted for a structurally related
heterocyclic system, 1,2,4ꢀtriazino[5,6ꢀb]indole.21
In the reaction of compound 11 with morpholine
(DMSO, 120 °C), the nucleophilic displacement of the
MeSO2 group to give 2ꢀmorpholinoꢀ4ꢀphenylpyrimidoꢀ
indole 12 proceeds with difficulty and not to completion;
longer reaction times and higher temperatures result only
in resinification of the reaction mixture. A similar outꢀ
come was attained in the reaction of derivative 11 with
piperidine and benzylamine, which indicates a lower moꢀ
bility of the MeSO2 group located in the annulated pyriꢀ
midine ring compared to that in a nonannulated ring.22
Thus, we demonstrated that the reaction of 3ꢀbenꢀ
zylideneꢀ2ꢀethoxyindolenine tetrafluoroborate (1) with
thiourea yields pyrimidoindoleꢀ2ꢀthione 2, its dihydro
derivative 3, and disulfide 4. The product ratio depends
on the reaction conditions. The transformation routes of
thione 2 into some Sꢀsubstituted pyrimidoindoles are preꢀ
sented. A substantial decrease in the nucleofugal properꢀ
ties of the chlorine atom and the methylsulfonyl group in
position 2 of pyrimidoindole with respect to that for the
same substituents in a nonannulated pyrimidine ring is
noted.
Experimental
IR spectra were recorded for KBr pellets on a Specord Mꢀ80
spectrophotometer; UV spectra of solutions in ethanol were meaꢀ
sured on an HP 8453 spectrophotometer. 1H and 13C NMR
spectra were recorded on a Bruker AM 400 (400 MHz) in
DMSOꢀd6 using the residual signals of the solvent at δ 2.50 (1H)
and 39.50 (13C) with respect to Me4Si as internal standards.
Mass spectra were recorded on a Finnigan MATꢀ8200 mass
spectrometer (EI, 70 eV). The reactions were monitored and the
purity of compounds was checked by TLC on Silufol UVꢀ254
plates with UV detection.
The molecular mass of compound 4 was determined by an
Agilent mass selective detector (model 1946с) connected to an
Agilent 1100 series LC/MSD liquid chromatograph. The ions
were generated in the mass detector by electrostatic spraying of a
0.05% solution of a sample of disulfide 4 in DMF at an atmoꢀ
spheric pressure (APIꢀES).
Reaction of 3ꢀbenzylideneꢀ2ꢀethoxyindolenine tetrafluoroꢀ
borate (1) with thiourea. A. Thiourea (0.76 g, 10 mmol) was
dissolved in a solution of sodium ethoxide prepared from sodium
(0.64 g, 28 mmol) and anhydrous ethanol (35 mL). Tetraꢀ
fluoroborate 1 (3.0 g, 9 mmol) was added in small portions with
stirring at 15—20 °C, the mixture was heated to boiling, kept for
6 h at a constant temperature, cooled, and neutralized by AcOH.
The precipitate was filtered off, suspended in water (200 mL),
filtered off again, and dried to give 0.87 g of (35%) 4ꢀphenylꢀ9Hꢀ

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Borovik et al.
pyrimido[4,5ꢀb]indoleꢀ2(1H )ꢀthione (2), m.p. 325—329 °C (from
DMF). The compound is hygroscopic. Found (%): C, 66.85;
H, 3.75; N, 14.98; S, 11.15. C16H11N3S•0.5H2O. Calcuꢀ
lated (%): C, 67.12; H, 4.22; N, 14.68; S, 11.20. MS,
m/z (Irel (%)): 278 [M + 1]+ (21), 277 [M]+ (86), 276 [M – 1]+
(100). Highꢀresolution MS, found: m/z 277.0666 [M]+.
137.34 (Ci); 138.37 (C(8а)); 157.17 (C(9a)); 159.28 (C(4));
163.56 (C(2)).
4ꢀPhenylꢀ9Hꢀpyrimido[4,5ꢀb]indole (6). Raney nickel (11 g)
was added to a solution of the hydrate of disulfide 4 (0.75 g,
1.3 mmol) in DMF (80 mL), and the mixture was stirred for 2 h
at 100—110 °C. The catalyst was separated and washed with hot
DMF (20 mL), the combined DMF solutions were concenꢀ
trated in vacuo and poured into water (100 mL). The precipitate
was filtered off, washed with water, and dried in vacuo over
P2O5. Yield 0.50 g (75%), m.p. 224—226 °C (from benzene).
Found (%): C, 78.77; H, 4.61; N, 17.04. C16H11N3. Calcuꢀ
lated (%): C, 78.35; H, 4.52; N, 17.13. MS, m/z (Irel (%)):
1
C16H11N3S. Calculated: M = 277.0674. H NMR, δ: 7.07 (td,
1 H, H(6), 3J = 7.9 Hz, 4J < 1 Hz); 7.18 (d, 1 H, H(5), 3J =
7.9 Hz); 7.37—7.44 (m, ABꢀpart of an ABХꢀsystem, 2 H, H(7),
H(8)); 7.63—7.71 (m, 3 H, Ph); 7.77 (d, 2 H, Ph, 3J = 8.0 Hz);
12.22 (br.s, 1 H, N(9)H); 13.46 (br.s, 1 H, N(1)H). 13C NMR,
δ: 104.25; 112.05; 119.80; 120.42; 121.53; 127.52; 128.69; 129.02;
130.39; 131.24; 139.84; 151.34; 158.15; 178.79 (C(2)=S).
Keeping of the initial alcohol filtrate at 5 °C gave additionꢀ
ally 0.75 g of a product with m.p. 317—321 °C, representing a
mixture of compounds 2—4, according to MS and TLC data
(benzene—acetone, 4 : 1). Recrystallization of this mixture from
DMF gave 0.25 g (10%) of disulfide 4, identical to that prepared
by oxidation of a mixture of 2 and 3 (see below).
245 [M]+ (50), 244 [M – 1]+ (100), 122 (14). UV,
1
λ
max/nm (logε): 252 (4.36), 303 (3.94). The H and 13C NMR
data were reported previously.13
9ꢀMethylꢀ4ꢀphenylpyrimido[4,5ꢀb]indole (10). Pyrimidoꢀ
indole 6 (0.10 g, 0.4 mmol) was added to a solution of sodium
ethoxide prepared from sodium (0.019 g, 0.8 mmol) and anꢀ
hydrous ethanol (10 mL), the mixture was stirred for 10 min and
concentrated to dryness in vacuo at 35 °C. The resulting sodium
salt of pyrimidoindole 6 was dissolved in dry DMSO (10 mL),
and MeI (0.17 g, 1.2 mmol) was added. The mixture was heated
for 3 h at 100 °C, an additional portion of MeI (0.11 g, 0.8 mmol)
was added, and the mixture was heated for additional 5 h, cooled,
and poured into water (100 mL). The resulting precipitate was
separated, washed with water on the filter, and dried. The prodꢀ
uct (0.086 g) dissolved in benzene, passed through a SiO2/Al2O3
layer, and the eluate was concentrated to dryness to give 0.051 g
(48%) of compound 10, m.p. 160—163 °C (from hexane—benꢀ
zene, 5 : 1). Found (%): C, 78.29; H, 5.21; N, 15.93. C17H13N3.
Calculated (%): C, 78.74; H, 5.05; N, 16.21. MS, m/z (Irel (%)):
259 [M]+ (63), 258 [M – 1]+ (100), 243 (13). UV,
B. The reaction was carried out in a similar way but under
argon; the product was isolated in air to give 1.6 g (64%) of a
compound with m.p. 315—320 °C; according to 1H NMR data,
this was a mixture of 4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indoleꢀ
2(1H )ꢀthione (2) (15%) and 4ꢀphenylꢀ3,4ꢀdihydroꢀ9Hꢀpyriꢀ
mido[4,5ꢀb]indoleꢀ2(1H)ꢀthione (3) (85%). According to TLC
data, the mixture also contained traces of disulfide 4. MS (mixꢀ
ture), m/z (Irel (%)): 279 ([M]+ (3)) (88), 278 ([M – 1]+ (3))
(27), 277 ([M]+ (2)) (21), 276 ([M – 1]+ (2)) (25), 219 (33), 218
(14), 203 (16), 202 ([M – Ph]+ (3)) (100), 148 (9), 110 (12),
109 (13).
4ꢀPhenylꢀ3,4ꢀdihydroꢀ9Hꢀpyrimido[4,5ꢀb]indoleꢀ2(1H )ꢀ
thione (3). Highꢀresolution MS, found: m/z 279.0839.
1
C16H13N3S. Calculated: M = 279.0831. H NMR, δ: 5.85 (d,
λ
max/nm (logε): 254 (4.40), 302 (4.01). 1H NMR, δ: 3.96 (s, 3 H,
NMe); 7.25 (td, 1 H, H(6), 3J = 7.7 Hz, 4J = 0.8 Hz); 7.61 (td,
1 H, H(4), 3J = 2.5 Hz); 6.83 (ddd, 1 H, H(7), 3J = 7.7 Hz, 3J =
7.4 Hz, 4J = 1.0 Hz); 6.90 (ddd, 1 H, H(6), 3J = 7.8 Hz, 3J =
3
4
1 H, H(7), J = 7.7 Hz, J = 0.7 Hz); 7.63—7.68 (m, 3 H, Ph);
7.76 (d, 1 H, H(8), 3J = 8.0 Hz); 7.83 (d, 1 H, H(5), 3J =
7.7 Hz); 7.90—7.93 (m, 2 H, Ph); 9.04 (s, 1 H, H(2)). 13C NMR,
δ: 27.60 (Me); 110.08 (C(4а)); 110.33 (C(8)); 118.11 (C(4b));
120.98 (C(6)); 121.83 (C(5)); 127.67 (C(7)); 128.57 (Cm); 128.65
(Co); 129.92 (Cp); 138.03 (Ci); 139.66 (C(8а)); 154.00 (C(2));
155.36 (C(9a)); 158.74 (C(4)).
4
3
7.4 Hz, J = 1.3 Hz); 6.95 (d, 1 H, H(8), J = 7.7 Hz); 7.30 (d,
1 H, H(5), 3J = 7.8 Hz); 7.32—7.36 (m, 5 H, Ph); 9.11 (br.s,
1 H, N(3)H); 10.46 (br.s, 1 H, N(9)H); 11.07 (br.s, 1 H, N(1)H).
13C NMR, δ: 56.18 (C(4)); 89.73; 111.37; 116.13; 119.38;
119.40; 126.62; 127.33; 128.29; 128.62; 131.64; 133.49; 144.07;
173.16 (C(2)=S).
Bis(4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indolꢀ2ꢀyl) disulfide (4).
A solution of NaNO2 (1.0 g, 14.5 mmol) in water (6 mL) was
added dropwise with stirring at 80 °C to a suspension of a mixꢀ
ture of 2 and 3 (see above) (1 g, 3.6 mmol) in AсOH (70 mL).
The reaction mixture was stirred for 5 h at this temperature and
cooled, the precipitate was separated and suspended in water,
and the suspension was washed with 10% NH4OH. The precipiꢀ
tate was filtered off, washed with water, and dried in vacuo
over P2O5. Yield 0.81 g (82%), m.p. 327—329 °C (from a
DMF—DMSO mixture, 15 : 1). The compound is hygroscopic.
Found (%): C, 66.92; H, 3.97; N, 14.94; S, 10.71. C32H20N6S2•
•H2O. Calculated (%): C, 67.34; H, 3.89; N, 14.73; S, 11.24.
Found: M = 552.1. C32H20N6S2. Calculated: M = 552.1.
1H NMR, δ: 7.18 (ddd, 1 H, H(6), 3J = 8.0 Hz, 3J = 6.0 Hz, 4J =
2.5 Hz); 7.45—7.49 (m, ABꢀpart of an ABXꢀsystem, 2 H, H(7),
H(8)); 7.59—7.64 (m, 3 H, Ph); 7.76 (d, 1 H, H(5), 3J = 8.0 Hz);
7.85—7.88 (m, 2 H, Ph); 12.64 (br.s, 1 H, NH). 13C NMR, δ:
108.41 (C(4а)); 111.89 (C(8)); 118.52 (C(4b)); 120.91 (C(6));
121.55 (C(5)); 127.39 (C(7)); 128.56 (Cm, Co); 130.20 (Cp);
2ꢀMethylthioꢀ4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole (7a).
A. Ground Sꢀmethylisothiourea sulfate (6.0 g, 22 mmol) was
added to a solution of sodium methoxide (1.2 g, 22 mmol) in
anhydrous THF (50 mL), and the mixture was stirred for 15 min.
The resulting mixture was slowly added to a stirred suspension of
tetrafluoroborate 1 (3.3 g, 10 mmol) in anhydrous THF (60 mL),
and after 30 min, a solution of sodium methoxide (0.43 g,
8 mmol) in methanol (15 mL) was added. The mixture was
stirred for 3 h at ~20 °C, refluxed for 3 h, and sodium methoxide
(0.43 g, 8 mmol) was added. The mixture was refluxed for addiꢀ
tional 3 h and left for ~14 h. The precipitate was filtered off, and
the filtrate was concentrated in vacuo, treated with water
(100 mL), and extracted with chloroform (5×60 mL). The exꢀ
tract was dried over MgSO4, concentrated in vacuo, and the
residue was treated with methanol (3 mL), squeezed on the
filter, washed with methanol (2×0.5 mL), and dried on the filter.
Keeping methanol filtrates in a refrigerator gave an additional
amount of compound 7а. The total yield was 0.82 g (28%), m.p.
~270 °C. A sample for analysis was recrystallized from ethyl

2ꢀThioꢀsubstituted 4ꢀphenylpyrimido[4,5ꢀb]indoles Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1075
cellosolve with some ethanol added and dried in vacuo at 100 °C,
m.p. 276—278 °C. Found (%): C, 70.04; H, 4.65; N, 14.31;
S, 10.85. C17H13N3S. Calculated (%): C, 70.08; H, 4.50;
N, 14.42; S, 11.00. MS, m/z (Irel (%)): 291 [M]+ (100), 290
[M – 1]+ (35), 245 (31), 244 [M – SMe]+ (43), 219 (10). UV,
for analysis was recrystallized from methyl cellosolve and dried
in vacuo over P2O5, m.p. 253—255 °C. Found (%): C, 68.70;
H, 5.43; N, 11.98; S, 9.18. C18H15N3S•0.5C4H10O2. Calꢀ
culated (%): C, 68.54; H, 5.75; N, 11.99; S, 9.15. MS,
m/z (Irel (%)): 305 [M]+ (100), 290 [M – Me]+ (36), 276
[M – Et]+ (24), 245 (38), 244 [M – SEt]+ (67), 219 (18).
1H NMR, δ: 1.40 (t, 3 H, Me, 3J = 7.2 Hz); 3.22 (q, 2 H, CH2,
3J = 7.2 Hz); 7.14 (td, 1 H, H(6), 3J = 8.0 Hz, 4J = 1.0 Hz); 7.44
(td, 1 H, H(7), 3J = 8.0 Hz, 4J = 1.0 Hz); 7.51 (d, 1 H, H(8),
3J = 8.0 Hz); 7.61—7.66 (m, 3 H, Ph); 7.70 (d, 1 H, H(5), 3J =
8.0 Hz); 7.88—7.91 (m, 2 H, Ph); 12.37 (br.s, 1 H, N(9)H).
Ethyl Sꢀ(4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indolꢀ2ꢀyl)thioꢀ
glycolate (8). A. Thione 2 (1.0 g, 3.6 mmol) was added with
stirring to a solution of sodium (0.09 g, 3.8 mmol) in anhydrous
ethanol (15 mL), and the mixture was concentrated to dryness
in vacuo at 35 °C. The residue was dissolved in dry DMF (25 mL),
ethyl bromoacetate (0.63 g, 3.8 mmol) was added, and the mixꢀ
ture was heated for 0.5 h at 100 °C. Then the reaction mixture
was cooled and poured into water (250 mL), and the precipitate
was separated, washed on the filter with water, and dried. The
product was formed in a quantitative yield, m.p. 209—222 °C.
After recrystallization from ethanol, the yield of compound 8
was 0.87 g (70%), m.p. 228—230 °C. Found (%): C, 66.34;
H, 4.72; N, 11.68; S, 8.70. C20H17N3O2S. Calculated (%):
C, 66.09; H, 4.71; N, 11.56; S, 8.82. MS, m/z (Irel (%)): 363 [M]+
λ
max/nm (logε): 268 (4.53), 329 (4.07). 1H NMR, δ: 2.63 (s, 3 H,
3
3
SMe); 7.16 (t, 1 H, H(6), J = 7.9 Hz); 7.46 (t, 1 H, H(7), J =
7.9 Hz); 7.52 (d, 1 H, H(8), J = 7.9 Hz); 7.62—7.68 (m, 3 H,
Ph); 7.71 (d, 1 H, H(5), J = 7.9 Hz); 7.89—7.92 (m, 2 H, Ph);
3
3
12.35 (br.s, 1 H, N(9)H).
B. Thione 2 (1.0 g, 3.6 mmol), and, after 15 min, MeI
(2.52 g, 18 mmol) were added with stirring to a solution of
sodium ethoxide prepared from sodium (0.09 g, 3.9 mmol) and
anhydrous ethanol (25 mL). The resulting suspension was heated
for 2 h at 80 °C and cooled, and the precipitate was separated,
washed with ethanol, and dried. The yield of compound 7a was
0.63 g (60%), m.p. 276—278 °C. The product was identical to
that obtained by method A.
C. Compound 3 (2.0 g, 7.2 mmol) containing thione 2
(~15%, see above) and MeI (5.0 g, 35 mmol) were added with
stirring to a solution of sodium ethoxide prepared from sodium
(0.17 g, 7.5 mmol) and anhydrous ethanol (40 mL). The suspenꢀ
sion was heated for 2 h at 80 °C and cooled, the precipitate was
separated, washed with ethanol, and dried to give 0.51 g of
compound 7a. Longꢀterm keeping of the alcohol filtrate in a
refrigerator, separation of the precipitate, and recrystallization
from ethyl cellosolve gave additionally 0.31 g of compound 7а.
The total yield of compound 7a was 39%, m.p. 275—277 °C.
Longꢀterm keeping of the ethyl cellosolve mother solution
in a refrigerator gave 0.21 g (3%) 9ꢀmethylꢀ2ꢀmethylthioꢀ4ꢀpheꢀ
nylꢀ9Hꢀpyrimido[4,5ꢀb]indole hydroiodide (9), m.p. 215—220 °C;
273—277 °C (from ethanol). Found (%): C, 50.14; H, 3.80;
I, 29.48; N, 9.48; S, 7.06. C18H15N3S•HI. Calculated (%):
C, 49.89; H, 3.72; I, 29.29; N, 9.70; S, 7.40.
(26), 291 (32), 290 [M – CO2Et]+ (100), 244 (27). IR, ν/cm–1
:
1
1236 (C—OEt); 1736 (C=O); 3400 (N—H). H NMR, δ: 1.15
(t, 3 H, Me, 3J = 7.2 Hz); 4.07 (q, 2 H, CH2, 3J = 7.2 Hz); 7.16
(t, 1 H, H(6), 3J = 8.0 Hz); 7.46 (t, 1 H, H(7), 3J = 8.0 Hz); 7.53
(d, 1 H, H(8), 3J = 8.0 Hz); 7.73 (d, 1 H, H(5), 3J = 8.0 Hz);
7.62—7.67 (m, 3 H, Ph); 7.87—7.92 (m, 2 H, Ph); 12.33 (br.s,
1 H, N(9)H).
B. Ethyl thioglycolate (0.34 g, 2.8 mmol) was added with
stirring to a solution of sodium (0.07 g, 3 mmol) in anhydrous
ethanol (2 mL) and the mixture was concentrated to dryness
in vacuo. The residue was dissolved in dry DMSO (4 mL),
2ꢀchloroꢀ4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole (5) (0.70 g,
2.5 mmol) was added,13 and the mixture was heated for 40 h at
120 °C. After cooling, ethyl acetate (50 mL) аnd then chloroꢀ
form (100 mL) were added to dissolve the product. The organic
extract was washed several times with water, and the remaining
product was extracted from the collected aqueous solutions with
chloroform. The combined organic extracts (~250 mL) were
dried over MgSO4 and concentrated in vacuo to dryness. The
residue was transferred onto a filter, washed with a minimum
quantity of 50% aqueous ethanol, and recrystallized from ethaꢀ
nol to give 0.78 g (86%) of compound 8, m.p. 225—228 °C. The
product was identical to the compound prepared by method A.
2ꢀMethylsulfonylꢀ4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole (11).
A 30% solution of H2O2 (10 mL, 87 mmol) was added with
stirring at 60 °C to a solution of 2ꢀmethylthiopyrimidoindole 7а
(2.54 g, 8.7 mmol) in AсOH (430 mL). The mixture was stirred
for 6 h at this temperature and concentrated in vacuo to 60 mL,
and the precipitate that formed was separated, washed with 10%
NH4OH and water, and dried. Yield 2.04 g (72%), m.p.
283—285 °C (from ethanol). Found (%): C, 63.10; H, 4.02;
N, 12.90; S, 9.72. C17H13N3O2S. Calculated (%): C, 63.15;
H, 4.05; N, 13.00; S, 9.90. MS, m/z (Irel (%)): 323 [M]+ (80),
260 (32), 244 [M – SO2Me]+ (100), 190 (28). IR, ν/cm–1: 1311,
1130 (SO2Me); 3400 (N—H). UV, λmax/nm (logε): 259 (4.50),
312 (4.06). 1H NMR, δ: 3.48 (s, 3 H, Me); 7.29 (ddd, 1 H, H(6),
Treatment of hydroiodide 9 (0.1 g, 0.23 mmol) with
10% NH4OH (8 mL) gave 0.07 g of 9ꢀmethylꢀ2ꢀmethylthioꢀ4ꢀ
phenylꢀ9Hꢀpyrimido[4,5ꢀb]indole (9), m.p. 220—223 °C (from
ethanol). Found (%): C, 70.56; H, 4.98; N, 13.67; S, 10.16.
C18H15N3S. Calculated (%): C, 70.80; H, 4.95; N, 13.76;
S, 10.48. MS, m/z (Irel (%)): 305 [M]+ (100), 259 (31), 258
1
[M – SMe]+ (19), 231 (14). H NMR, δ: 2.78 (s, 3 H, SMe);
4.11 (s, 3 H, NMe); 7.10 (td, 1 H, H(6), 3J = 8.0 Hz, 4J =
0.8 Hz); 7.42 (td, 1 H, H(7), 3J = 8.0 Hz, 4J = 1.0 Hz); 7.63 (d,
1 H, H(8), 3J = 8.0 Hz); 7.64—7.69 (m, 3 H, Ph); 7.80 (d, 1 H,
3
H(5), J = 8.0 Hz); 8.01—8.04 (m, 2 H, Ph).
2ꢀEthylthioꢀ4ꢀphenylꢀ9Hꢀpyrimido[4,5ꢀb]indole
(7b).
Ground Sꢀethylisothiourea hydrobromide (1.02 g, 5.5 mmol)
was added with stirring to a solution of sodium methoxide (0.3 g,
5.5 mmol) in anhydrous THF (15 mL), and the mixture was
stirred for 20 min. Tetrafluoroborate 1 (1.7 g, 5 mmol) in anꢀ
hydrous THF (30 mL) was slowly added with stirring to the
resulting suspension. After 1 h, more sodium methoxide (0.22 g,
4 mmol) in a THF (5 mL) and methanol (3 mL) mixture was
added, and the reaction mixture was stirred for 2 h at ~20 °C,
refluxed for 2 h, and concentrated in vacuo. The residue was
treated with water (10 mL) and extracted with chloroform
(5×60 mL), and the extract was washed with water and dried
over MgSO4. After the extract was concentrated in vacuo, the
residue was treated with methanol (5 mL), and the precipitate
was filtered off, washed with methanol (2×0.5 mL), and dried
on the filter. Yield 0.44 g (29%), m.p. 246—248 °C. The sample

1076
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Borovik et al.
3J = 8.0 Hz, 3J = 7.4 Hz, 4J = 1.0 Hz); 7.63 (td, 1 H, H(7), 3J =
110 [Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk,
1977, Issue 6 (Engl. Transl.)].
9. T. J. Batterham, NMR Spectra of Simple Heterocycles, Wileyꢀ
Interscience, New York, 1973, 250.
4
7.4 Hz, J = 1.0 Hz); 7.68—7.72 (m, 4 H, H(8) + Ph); 7.90 (d,
3
1 H, H(5), J = 8.0 Hz); 7.98—8.01 (m, 2 H, Ph); 13.10 (br.s,
1 H, N(9)H).
Reaction of 2ꢀmethylsulfonylpyrimidoindole 11 with morphoꢀ
line. A solution of sulfone 11 (0.2 g, 0.6 mmol) and morpholine
(0.16 g, 1.8 mmol) in dry DMSO (18 mL) was heated for 6 h at
120 °C, cooled, and poured into water (150 mL), and the preꢀ
cipitate was separated, washed with water, and dried over P2O5
to give 0.18 g of a mixture of 2ꢀmorpholinoꢀ4ꢀphenylꢀ9Hꢀ
pyrimido[4,5ꢀb]indole (12)13 and starting sulfone 11 in ~1 : 1
ratio (1H NMR data and TLC (benzene—acetone, 4 : 1)).
1H NMR (compound 12), δ: 3.70—3.73 (m, 4 H, NCH2);
3.81—3.85 (m, 4 H, OCH2); 7.04 (td, 1 H, H(6), 3J = 7.7 Hz,
4J = 1.1 Hz); 7.29 (td, 1 H, H(7), 3J = 7.7 Hz, 4J = 1.1 Hz); 7.39
(d, 1 H, H(8), 3J = 7.7 Hz); 7.56 (d, 1 H, H(5), 3J = 7.7 Hz);
7.58—7.63 (m, 3 H, Ph); 7.86—7.89 (m, 2 H, Ph); 11.79 (br.s,
1 H, N(9)H).
10. B. Hoefgen, M. Decker, P. Mohr, A. M. Schramm, S. A. F.
Rostom, H. ElꢀSubbagh, P. M. Schweikert, D. R. Rudolf,
M. U. Kassack, and J. Lehmann, J. Med. Chem., 2006,
49, 760.
11. J.ꢀP. Buisson, E. Bisagni, C. Monneret, P. Demerseman,
C. Leon, and N. Platzer, J. Heterocycl. Chem., 1996, 33, 973.
12. E. K. Panisheva, M. L. Alekseeva, and V. G. Granik,
Khim.ꢀFarm. Zh., 2004, 38, Issue 3, 29 [Pharm. Chem. J.,
2004, 38, Issue 3 (Engl. Transl.)].
13. V. P. Borovik and O. P. Shkurko, Izv. Akad. Nauk. Ser.
Khim., 2002, 1974 [Russ. Chem. Bull., Int. Ed., 2002,
51, 2129].
14. V. P. Borovik, M. M. Shakirov, and O. P. Shkurko, Khim.
Geterotsikl. Soedin., 2003, 1531 [Chem. Heterocycl. Compd.,
2003, 39, 1348 (Engl. Transl.)].
15. Y.ꢀM. Zhang, T. Razler, and P. F. Jackson, Tetrahedron
Lett., 2002, 43, 8235.
References
16. B. Dotzauer and R. Troschütz, Synlett, 2004, 1039.
17. T. Nishio, M. Fujisawa, and Y. Omote, J. Chem. Soc., Perkin
Trans. 1, 1987, 2523.
18. M. P. V. Boarland and J. F. W. McOmie, J. Chem. Soc.,
1951, 1218.
19. S. K. Naik, R. K. Benera, and A. Nayak, Ind. J. Chem., Sect.
B, 1982, 21, 1124.
20. F. G. Baddar, F. H. AlꢀHajjar, and N. R. ElꢀRayyes,
J. Heterocycl. Chem., 1976, 13, 257.
21. I. S. Ioffe, A. B. Tomchin, and E. N. Zhukova, Zh. Obshch.
Khim., 1969, 39, 2111 [J. Gen. Chem. USSR, 1969, 39 (Engl.
Transl.)].
22. Z. Budesinsky and J. Vavrina, Collect. Czech. Chem. Commun.,
1972, 37, 1721.
1. PCT Int. Appl. 93 20078; Chem. Abstrs, 1994, 121, 134139.
2. PCT Int. Appl. 98 42708; Chem. Abstrs, 1998, 129, 290145.
3. PCT Int. Appl. 00 66585; Chem. Abstrs, 2000, 133, 350241.
4. A. B. Tomchin, O. Yu. Uryupov, T. I. Zhukova, T. A.
Kuznetsova, M. V. Kostycheva, and A. V. Smirnov,
Khim.ꢀFarm. Zh., 1997, 31, Issue 3, 19 [Pharm. Chem. J.,
1997, 31, Issue 3 (Engl. Transl.)].
5. A. B. Tomchin and A. V. Kropotov, Khim.ꢀFarm. Zh., 1998,
32, Issue 1, 22 [Pharm. Chem. J., 1998, 32, Issue 1 (Engl.
Transl.)].
6. S. V. Okovityi, Biomeditsin. Khim. [Biomed. Chem.], 2004,
50, 293 (in Russian).
7. V. P. Borovik, L. S. Filatova, and V. P. Mamaev, Izv. Sib.
Otd. Akad. Nauk SSSR. Ser. Khim. Nauk, 1975, No. 3, 137
[Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1975,
Issue 3 (Engl. Transl.)].
8. V. P. Borovik, L. Yu. Ivanovskaya, and V. P. Mamaev, Izv.
Sib. Otd. Akad. Nauk SSSR. Ser. Khim. Nauk, 1977, No. 6,
Received February 22 , 2006;
in revised form May 10, 2006