Alkylation of pyrimido[5′,4′:5,6]pyrido[3,2-b]indol-4-one derivatives

Article abstract of DOI:10.1007/s11172-008-0234-1

Alkylation of 11-benzyl-3,11-dihydro-4H-pyrimido[5′,4′:5,6] pyrido[3,2-b]indol-4-one with methyl iodide and methyl bromoacetate in DMF gave 3-alkylpyrimidopyridoindolones as the corresponding salts. The reaction in acetone in the presence of K₂CO₃ yielded 3,6-disubstitution products. Alkylation with DMF dimethyl acetal gave a mixture of the 3- and 6-alkylpyrimidopyridoindol-4-one bases. The structure of 4-oxo-4,6-dihydro-3H-pyrimido-[5′,4′:5,6]pyrido[3,2-b]indol-11-ium chloride (3b) was proved by X-ray diffraction analysis.

Full text of DOI:10.1007/s11172-008-0234-1

Russian Chemical Bulletin, International Edition, Vol. 57, No. 8, pp. 1765—1772, August, 2008
1765
Alkylation of pyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀone derivatives
N. S. Masterova,a L. M. Alekseeva,a A. S. Shashkov,b V. A. Tafeenko,c S. Yu. Ryabova,a and V. G. Granika
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117003 Moscow, Russian Federation.
Fax: +7 (499) 611 1548. Eꢀmail: syuryabova@yandex.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3654. Eꢀmail: viktor@struct.chem.msu.ru
Alkylation of 11ꢀbenzylꢀ3,11ꢀdihydroꢀ4Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀone
with methyl iodide and methyl bromoacetate in DMF gave 3ꢀalkylpyrimidopyridoindolones
as the corresponding salts. The reaction in acetone in the presence of K2CO3 yielded
3,6ꢀdisubstitution products. Alkylation with DMF dimethyl acetal gave a mixture of the 3ꢀ and
6ꢀalkylpyrimidopyridoindolꢀ4ꢀone bases. The structure of 4ꢀoxoꢀ4,6ꢀdihydroꢀ3Hꢀpyrimidoꢀ
[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium chloride (3b) was proved by Xꢀray diffraction analysis.
Key words: 11ꢀbenzylꢀ3,11ꢀdihydroꢀ4Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀone, Xꢀray
diffraction analysis, alkylation, 3ꢀ and 6ꢀmonoalkylpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀones,
3,6ꢀdialkylpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀones, halides.
Earlier,1 it was found that 2ꢀ(2ꢀcyanopropꢀ2ꢀenylidene)ꢀ
indolinꢀ3ꢀones 1a—c containing primary and secondary
amino groups in position 3 of the side chain react with
DMF diethyl acetal to give derivatives 2a—c of the novel
heterocyclic system 4,11ꢀdihydroꢀ1Hꢀpyrimido[5´,4´:5,6]ꢀ
pyrido[3,2ꢀb]indolꢀ4ꢀone (Scheme 1). The mechanism
of formation of these compounds was proposed and conꢀ
firmed.
The structure of compounds 2a—c combines the
δꢀcarboline and pyrimidine fragments. Some δꢀcarboline
derivatives were found to exhibit antitumor, antimuscarine,
antibacterial, and antiviral activities.2—5 And such known
Scheme 1
R = Me (a), CH2Ph (b), C6H4—OMeꢀ4 (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1731—1738, August, 2008.
1066ꢀ5285/08/5708ꢀ1765 © 2008 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Masterova et al.
drugs as, e.g., the bactericides sulfamonomethoxine and
sulfadimethoxine, the soporific cyclobarbital, and the
antitumor drug 6ꢀmercaptopurine are pyrimidine derivaꢀ
tives.6 Combination of the above fragments in a molecule
can impart new biological properties to the resulting
compounds. That is why here we studied alkylation of
11ꢀbenzylꢀ4,11ꢀdihydroꢀ1Hꢀpyrimido[5´,4´:5,6]pyridoꢀ
[3,2ꢀb]indolꢀ4ꢀone (2b) with various alkylating agents to
obtain more soluble (than 2a—c) compounds for pharꢀ
macological investigations.
Note that the structure of 4,11ꢀdihydroꢀ1Hꢀpyrimidoꢀ
pyridoindolꢀ4ꢀone was assigned to compounds 2 from
their IR spectra,1 although they can exist as tautomers
2A and 2B.
Compounds 2 were not examined by Xꢀray diffraction
analysis because their crystals were unsuitable for this
technique.
C(22B)
c
C(21B)
C(20B)
b
C(23B)
C(24B)
a
C(14B)
C(15B)
C(12B)
C(19B)
C(13B)
C(16B)
C(18B)
N(1B)
Cl(1B)
O(6A)
N(5A)
N(3B)
C(2B)
C(8B)
C(9B)
N(10B)
C(6A)
C(4B)
C(6B)
C(7A)
C(8A)
C(7B)
C(4A)
N(3A)
C(2A)
C(18A)
C(9A)
N(10A)
N(1A)
N(5B)
O(6B)
Cl(1A)
C(12A)
C(11A)
C(15A)
C(14A)
C(17A)
C(16A)
C(19A)
C(24A)
C(23A)
C(13A)
C(20A)
C(21A)
Hydrochloride 2b•HCl (3b), which is substantially
more soluble than free base 2b, was recrystallized from
methanol and its single crystals were studied by Xꢀray
diffraction analysis.
C(22A)
The independent part of the unit cell comprises two
molecules 3b (Fig. 1) and 3.5 molecules of water.
Selected geometrical parameters of hydrochloride 3b are
given in Table 1. The poor quality of its crystals precluded
location of the H atoms of solvate water molecules;
however, the short distances (less than the sum of the
van der Waals radii) between the atoms (Table 2) point to
the water atoms probably involved in hydrogen bonding.
According to Xꢀray diffraction data, chloride 3b exists
in the crystal as a quasiꢀcentrosymmetric dimer. The
planes of its tetracycles are above each other (if viewed
along the normal) and are spaced at, on average, 3.35 Å.
Fig. 1. General view of two crystallographically independent
molecules in chloride 3bA. Solvate water molecules are omitted
because they mask the positions of the atoms in the solvated
molecules.
In the crystal, the chloride anions Cl(lA) and Cl(lB) link
the organic cations (A and B, respectively) to form chains
along the crystallographic axis a by means of the hydrogen
bonds N(10A,B)—H(10A,B)...Cl(1A,B) and C(4A,B)—
H(4A,B)...Cl(1A,B) (Fig. 2). The chains of molecules A
and B are united through the hydrogen bonds N(5A)—
H(5A)...O(6B) (1 – x, 0.5 + y, 1.5 – z) and a complex
Table 1. Bond lengths (d) and angles (ω) in structure 3b
Bond
d/Å
Bond
d/Å
Parameter
Value
Angle
ω/deg
N(1A)—C(17A) 1.357(8)
N(1A)—C(2A) 1.377(7)
N(1A)—C(18A) 1.470(7)
N(10A)—C(11A) 1.377(8)
N(1B)—C(2B) 1.353(8)
N(1B)—C(17B) 1.355(8)
N(1B)—C(18B) 1.478(7)
Bond
d/Å
C(9A)—N(10A)—C(11A) 108.8(6)
C(2B)—N(1B)—C(17B) 119.7(6)
C(2B)—N(1B)—C(18B) 120.0(6)
С(17B)—N(1B)—C(18B) 120.3(6)
C(4B)—N(3B)—C(2B) 116.5(7)
C(4B)—N(5B)—C(6B) 122.3(6)
C(11B)—N(10B)—C(9B) 110.4(6)
C(9B)—N(10B)
N(10B)—C(11B)
Angle
C(17A)—N(1A)—C(2A) 120.5(6)
C(17A)—N(1A)—C(18A) 119.1(6)
C(2A)—N(1A)—C(18A) 120.4(6)
C(4A)—N(3A)—C(2A) 113.4(7)
C(4A)—N(5A)—C(6A) 121.2(7)
1.379(8)
1.361(8)
ω/deg
C(2A)—N(3A)
N(3A)—C(4A)
C(4A)—N(5A)
N(5A)—C(6A)
C(6A)—O(6A)
1.370(9)
1.272(8)
1.361(9)
1.390(9)
1.233(9)
C(2B)—N(3B)
N(3B)—C(4B)
C(4B)—N(5B)
N(5B)—C(6B)
C(6B)—O(6B)
1.354(8)
1.280(8)
1.361(8)
1.399(8)
1.217(7)
C(9A)—N(10A) 1.374(8)

Alkylpyrimidopyrido[3,2ꢀb]indolꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1767
Table 2. Parameters of the hydrogen bonds in structure 3b and the shortest distances around the O(1), O(2), O(3), and O(4) atoms of
the solvate water molecules that suggest possible hydrogen bonding (the H atoms in the solvate water molecules were not located)*
D—Н....А
Distance
D...А/Å
Angle
D—Н...А/deg
Distance
D...А
d/Å
Distance
D...А
d/Å
N(10A)—H(10A)...Cl(1A)
N(10B)—H(10B)...Cl(1B)
N(5A)—H(5A)...O(6B)a
C(4B)—H(4B)...Cl(1B)b
C(4A)—H(4A)...Cl(1A)c
3.156(7)
3.189(7)
2.738(7)
3.621(9)
3.99(1)
172
153
161
166
173
O(1)...O(3)
O(1)...O(2)d
O(1)...Cl(1A)
O(3)...Cl(1A)
O(3)...O(4)e
3.348(9)
2.759(8)
3.293(7)
3.010(6)
2.80(1)
O(3)...N(5B)
O(4)...C(l1B)
O(4)...O(2)
O(4)...O(2)f
2.744(9)
3.21(1)
3.48(1)
3.20(1)
* Symmetry operation codes: a (1 – x, 0.5 + y, 1.5 – z); b (1 + x, y, z); c (–1 + x, y, z); d (1 – x, 0.5 + y, 1.5 – z); e (x, 0.5 – y, –0.5 + z);
f (1 – x, –y, 2 – z).
system of hydrogen bonds involving water molecules (see
Table 2). In addition, Xꢀray diffraction data provide
convincing evidence that compounds 3 (as well as 2)
exist in the crystal as tautomer 3A (2A); i.e., they are
4,11ꢀdihydroꢀ3Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ
4ꢀone derivatives.
Alkylation of tetracyclic compound 2bA with methyl
iodide and methyl bromoacetate was carried out under
different conditions. For instance, reactions of compound
2bA with alkyl halides in DMF in the absence of bases
could be expected to occur at the indole N atom because
of a considerable energy gain resulting from the formation
of the aromatic indole system. This assumption was supꢀ
ported by the high basicity of Nꢀmethylꢀδꢀcarboline 4
(pKa = 10.77).7
Me
N
Me
N
+
+
H
N
N
H
4
However, moderate heating (40—50 °C) of compound
2bA with methyl iodide or methyl bromoacetate in DMF
Cl(1B)ii
Cl(1B)
N(10B)
Cl(1B)iii
H(4A)ii
Cl(1A)
Cl(1A)ii
H(10A)
Cl(1A)iii
N(5A)
O(6B)i
c
a
b
Cl
N
C
H
O
Fig. 2. Fragment of the molecular packing in the crystal structure 3bA. Hydrogen bonds between the atoms of adjacent molecules are
indicated with dashed lines.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Masterova et al.
Scheme 2
PhH2C
PhH2C
N
N
N
H
N H
N
N
O
O
N
N δ
+
2bA
H
H
R
X
–
N
N δ
i
N
N
O
N
N
O
PhH2C
PhH2C
2bA
N
N
PhH2C
X–
PhH2C
N
N
+
N
R
N
Me
N
N
NaOH
äëÿ 5a
for
O
O
ii
N
N
H
5a,b
6a
R = Me, X = I (a); R = CH2COOMe, X = Br (b)
Reagents and conditions: i. 2bA, DMF, MeI, 40—50 °C, 14 h; 2bA, DMF, BrCH2COMe, 50 °C, 0.5 h, 20 °C, 64 h; ii. MeOH, 4 N NaOH.
gave alkylation products only at the pyrimidine NH group:
11ꢀbenzylꢀ3ꢀmethylꢀ and 11ꢀbenzylꢀ3ꢀmethoxycarbonylꢀ
methylꢀ4,11ꢀdihydroꢀ3Hꢀpyrimido[5´,4´:5,6]pyridoꢀ
[3,2ꢀb]indolꢀ4ꢀones (iodide 5a and bromide 5b, respecꢀ
tively). Apparently, this unexpected outcome can be
explained by the sufficiently high acidity of the pyrimidine
NH group (pKa = 8.59 for pyrimidinꢀ4ꢀone8) and the
presence of the highly basic N atom in position 6 (see
above).
and the sufficiently acid N(3)H atom. As the result, a
significant partial negative charge on the pyrimidine
N(3) atom favors alkylation at this position and a partial
positive charge on the N(6) atom hinders N(6)—C
bonding (Scheme 2).
Treatment of iodide 5a with NaOH in aqueous
methanol gave free base 6a.
Alkylation of tetracyclic compound 2bA with methyl
iodide, methyl bromoacetate, or dimethyl sulfate in
acetone in the presence of K2CO3 occurred at both the
pyrimidine and indole N atoms to give dialkyl derivatives
7a—c as the corresponding salts. The first step of the
The alkylation of compound 2bA is probably preceded
by the formation of the strong intermolecular hydrogen
bond N(3)H...N(6)= between the highly basic N(6) atom
Scheme 3
PhH2C
X–
PhH2C
X–
PhH2C
X–
N
N
N
+
+
+
N
R
N
R
N R
N
N
N
K2CO3
RX
RX
2bA
K2CO3
O
O
O
N
N
N
–
K+
H
R
5a—c
7a—c
R = Me, X = I (a); R = CH2COOMe, X = Br (b); R = Me, X = [MeSO4]– (c)

Alkylpyrimidopyrido[3,2ꢀb]indolꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1769
reaction involves the formation of monoalkyl derivatives
5a—c; in this case, K2CO3 (rather than compound 2bA)
seems to act as an acceptor of the N(3)H proton. Then,
K2CO3 abstracts the proton from the indole N atom of
compounds 5a—c, which gives rise to an integer negative
charge on it and favors secondary alkylation (Scheme 3).
Replacement of K2CO3 by NaOH in the methylation
of compound 2bA with methyl iodide in acetone does not
affect the final outcome of the reaction. We isolated 3,6ꢀ
dimethyl derivative 7a as an iodide salt in 18% yield.
Interestingly, the final product in the alkylation with
methyl bromoacetate under similar conditions was
3ꢀmonoalkyl derivative 5b (as bromide) identical in
physicochemical characteristics with the compound
synthesized according to Scheme 2. An increase in either
the reaction time or the excess of methyl bromoacetate
did not lead to a dialkylation product. Apparently, NaOH
(which is a stronger base than K2CO3) promotes a rapid
transformation of bromide 5b into base 6b incapable of
producing an anion. In addition, one can assume that the
alkali reacts with methyl bromoacetate more rapidly than
does with compound 5b, methyl bromoacetate undergoes
hydrolysis of the ester group and replacement of the Br
atom by the hydroxy group, and, consequently, the reacꢀ
tion does not proceed any further.
HMBC, and NOESY spectra of compound 5a and comꢀ
pared them with analogous spectra of 3,6ꢀdimethylꢀ
pyrimidopyridoindolium iodide 7a. The HMBC spectrum
1
shows correlation peaks of the H NMR signals for two
methyl groups (δ 3.67 and 4.26) in compound 7a with the
signals for the C(2) (δ 153.6) and C(4) atoms (δ 159.6)
and with the signals for the C(5a) (δ 134.2) and C(6a)
atoms (δ 145.5), respectively. The NOESY spectrum of
compound 7a exhibits a correlation peak of the lowꢀfield
N(6)Me group with the H(5) (δ 9.66) and H(7) atoms
(δ 8.03) and a correlation peak of the highꢀfield N(3)Me
group with the singlet for the H(2) atom (δ 8.94). According
to our signal assignment, the methyl group with the signal
at δ 3.67 should be in position 3 of monomethyl indolium
iodide 5a. Indeed, the HMBC spectrum of compound 5a
shows a correlation peak of the signal for the methyl group
(δ 3.67) with the signals for the C(2) (δ 153.5) and C(4)
atoms (δ 159.6) and the NOESY spectrum shows a correꢀ
lation peak of the same signal with the signal for the H(2)
atom (δ 8.95). Structure 5b was determined from the
NOEDIFF data: when the signal for the methylene group
(δ 5.06) is saturated, the intensity of the singlet for the
H(2) atom (δ 8.96) changes by 10%.
It is known that amide acetals can serve as alkylating
agents.9—11 Substrates containing both Nꢀ and Oꢀalkylaꢀ
tion centers yield mixtures of Nꢀ and Oꢀalkylation products,
the Oꢀalkylation usually being dominant.
For unambiguous determination of the structures
of monoalkyl derivatives 5a,b, we recorded the HSQC,
Scheme 4
PhH2C
PhH2C
(MeO)2CHNMe2
N
N
N
H
N
N
N
+
–MeOH
O
O
N
N
Me2N
OMe
–
+
H
OMe
2bA
2bC
PhH2C
PhH2C
N
N
N–
O
N
O
N
N
N
N–
D
E
PhH2C
PhH2C
N
N
N
NH
O
HCl/EtOAc
MeOH
Cl–
N
N+
6a
+
O
N
N
Me
Me
8

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Masterova et al.
Table 3. Yields, elemental analysis data, and physicochemical and spectroscopic characteristics of the compounds obtained
Comꢀ Yield
pound (%)
M.p./°Сa
М
Found__
Calculated
Molecular
formula
IR,
max/cm–1
MS,
m/z
(%)
ν
(CO)
1689
С
Н
N
—
I
5а
53
240—244
(Pri : H2O,
2 : 1)
468
53.88 3.61
53.86 3.66
26.99
27.10
C21H17IN4O
341 [M – HI + H]+,
250 [M – HI + H – 91]+
5b
6a
7а
43 (A)
41 (B)
59 (A)
11.5 (B)
68 (A)
240—242
(MeOH)
244—246
488
340
482
56.55 4.71 11.46
56.57 4.13 11.47
73.61 5.241 16.12
74.10 4.74 16.46
—
—
C23H19BrN4O3• 1755,
399 [M – HBr + H]+,
797 [2 (M – HBr) + H]+
341 [M + H]+,
•0.5 H2Ob
1707
1685
C21H16N4O
681 [2 M + H]+
250—252
54.68 4.10
54.78 3.97
—
26.29
26.31
С22H19IN4O
1691
355 [M – HI + H]+
18 (B) (H2O : MeCN,
2 : 1)
194—198
(H2O)
250—254
(Pri : H2O,
2 : 1)
240—244
(MeOH)
7b
7c
55
45
551
466
56.88 5.30 10.40
56.63 4.80 10.16
59.22 4.93 12.06
59.22 4.75 12.01
—
—
C26H23BrN4O5
C23H22N4O5S
1681,
1749
1689
471 [M – HBr + H]+,
379 [M – HBr + H – 92]+
355 [M – HMeSO4 + H]+,
264 [M – HMeSO4 +
+ H – 91]+
8
9
13.5
57
340
385
73.56 4.95 16.33
74.10 4.74 16.46
—
—
C21H16N4O
1627
1712
341 [M + H]+,
363 [M + Na]+,
681 [2 M + H]+,
703 [2 M + Na]+
>330
(MeOH)
64.80 5.53 14.43
65.37 4.70 14.52
C21H17ClN4O•
•0.5 H2O
341 [M – HCl + H]+,
363 [M – HCl + Na]+,
681 [2 (M – HCl) + H]+,
703 [2 (M – HCl) + Na]+
a The solvent for recrystallization is given in parentheses. b Found (%): H2O, 1.38. Calculated (%): H2O, 1.84. c Found (%): S, 6.85.
Calculated (%): S, 6.87.
However, a reaction of compound 2bA with DMF
dimethyl acetal gave a mixture of two monomethyl
derivatives (at the N(3) and N(6) atoms): 11ꢀbenzylꢀ
3ꢀmethylꢀ4,11ꢀdihydroꢀ3Hꢀpyrimido[5´,4´:5,6]pyridoꢀ
[3,2ꢀb]indolꢀ4ꢀone (6a) and 11ꢀbenzylꢀ6ꢀmethylꢀ6,11ꢀ
dihydroꢀ4Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀone
(8). These products were separated by column chromaꢀ
tography. The formation of a mixture of monomethyl
derivatives can be explained by the existence of another
tautomer 2bC (apart from the aforementioned tautomers
2b, 2bA and 2bB of the starting reagent). In this case, the
alkylating agent is an ambident cation; this cation and the
alkoxy anion are in equilibrium with the amide acetal.
The alkylation proceeds through anions D and E formed
by means of abstraction of the NH protons by the alkoxy
anion. Note that when treated with HCl in methanol,
compound 8 is transformed into chloride 9 because of the
formation of the thermodynamically favorable aromatic
indole system (Scheme 4).
two signals resonate (NOE up to 10%): the doublet at
δ 7.78 (H(7)) and the singlet at δ 9.37 (H(5)). We tried to
obtain an Oꢀalkyl derivative in a reaction with triethylꢀ
oxonium fluoroborate tending toward Oꢀalkylation.12
However, Et3O+BF4 did not react with compound 2bA
–
under these conditions at all, probably because the latter
is virtually insoluble in nonpolar solvents (chloroform,
dichloromethane, dichloroethane, etc.) usually employed
for such reactions.
Experimental
IR spectra were recorded on an FSMꢀ1201 instrument
(Nujol). Mass spectra were recorded on a Waters ZQꢀ2000 mass
spectrometer (electrospray ionization, direct inlet probe).
spectra were recorded on Bruker DRXꢀ500 and Bruker ACꢀ300
spectrometers. The course of the reactions was monitored and
the purity of the products was checked by TLC on Merck 60
F254 plates in chloroform—methanol (10 : 1) and ethyl acetate—
PriOH—ammonia (5 : 3 : 1). Spots were visualized under UV
light. The yields, melting points, elemental analysis data, and
mass and IR spectra of the compounds obtained are given in
Table 3.
1H NMR
Compound 6a obtained according to Scheme 4 was
identical in all physicochemical characteristics with the
compound synthesized from iodide 5b. The Nꢀalkylation
is confirmed by the NOEDIFF spectrum of compound 8:
when the signal for the methyl group (δ 4.19) is saturated,
Single crystals of salt 3b were obtained by crystallization
from methanol. Xꢀray diffraction analysis was carried out on

Alkylpyrimidopyrido[3,2ꢀb]indolꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1771
Table 4. Crystallographic parameters and a summary of data
collection for structure 3b
113.9 (C(7)); 115.1 (C(4a)); 122.2 (C(9)); 124.4 (C(10)); 125.3
(C(5)); 126.0, 128.0, 129.0, 133.0 (Ph); 133.4 (C(5a)); 133.6
(C(8)); 135.6 (C(10b)); 144.9 (C(6a)); 147.0 (C(11a)); 153.5
(C(2)); 159.6 (C(4)).
Parameter
Value
11ꢀBenzylꢀ3ꢀ(2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ
3Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium bromide (5b).
Method A. Methyl bromoacetate (0.13 mL, 1.38 mmol)
was added to a suspension of pyrimidopyridoindole 2bA (0.3 g,
0.92 mmol) in DMF (7 mL). After 30ꢀmin stirring at 50 °C,
another portion of methyl bromoacetate (0.13 mL) was added,
which caused a new precipitate to form. The suspension was left
for 64 h. The precipitate was filtered off, washed with DMF and
acetone, and dried to give compound 5b (0.19 g). 1H NMR
(DMSOꢀd6), δ: 3.77 (s, 3 H, OMe); 5.06 (s, 2 H, CH2COOMe);
6.76 (s, 2 H, CH2Ph); 7.23—7.34 (m, 5 H, CH2Ph); 7.42 (t,
1 H, H(9), Jo = 8.2 Hz); 7.92 (m, 2 H, H(7), H(8)); 8.24 (d, 1 H,
H(10), Jo = 8.2 Hz); 8.96 (s, 1 H, H(2)); 9.40 (s, 1 H, H(5));
13.30 (br.s, 1 H, N(6)H).
Molecular formula
Molecular mass
Crystal system
Space group
Unit cell parameters
a/Å
b/Å
2(C20H15H4OCl)•3.5H2O
783
Monoclinic
P21/с
12.596(13)
20.568(2)
15.350(7)
3635.3(2)
3635.3(2)
4
1.448
2θ < 61
5254
c/Å
β/deg
V/Å3
Z
ρ
calc/g cm–3
Scan range/deg
Number of measured reflections
Method B. Potassium hydroxide (0.07 g, 1.22 mmol) and
methyl bromoacetate (0.14 mL, 1.53 mmol) were added to a
suspension of pyrimidopyridoindole 2bA (0.2 g, 0.61 mmol) in
anhydrous acetone (7 mL). The suspension was refluxed with
stirring for 2 h and then for an additional 14 h with another
portion of methyl bromoacetate (0.14 mL). The precipitate was
filtered off, washed with acetone, water, and again acetone, and
dried to give compound 5b (0.12 g). A mixture of the samples
obtained according to methods A and B did not depress the
melting point.
Number of reflections with I > 2σ
Number of parameters refined
Rint
R
Rw
1737
488
0.04
0.061
0.12
an Enraf Nonius CADꢀ4 diffractometer (graphite monochroꢀ
mator, λ = 1.54061 Å (Cu, Kα ), ωꢀscan mode). Selected crysꢀ
tallographic parameters and a 1summary of data collection for
structure 3b are given in Table 4. Selected geometrical paramꢀ
eters of chloride 3b are given in Table 1. The structure was
solved by the direct method. The coordinates and thermal
parameters of the nonꢀhydrogen atoms were refined in the fullꢀ
matrix anisotropic approximation. The hydrogen atoms were
located geometrically and refined in the rider model. The
H atoms of solvate water molecules were not located from
difference electronꢀdensity maps because of the poor quality
of crystals and probably because of alternative ways of hydrogen
bonding in the crystal with participation of water molecules (see
Table 2). All calculations were performed with the SHELX97
program package.13 The drawings were made with the
DIAMOND program.14
11ꢀBenzylꢀ3ꢀmethylꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ3Hꢀpyrimidoꢀ
[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium iodide (5a). Methyl iodide
(1 mL) was added to a suspension of pyrimidopyridoindole 2bA
(0.3 g, 0.92 mmol) in DMF (7 mL). The reaction mixture was
stirred at 40 °C for 14 h. The resulting solution gradually settled
to give a new precipitate. The suspension was stirred at 20 °C for
14 h and the precipitate was filtered off, washed with DMF,
ethyl acetate, and acetone. The yield of compound 5a was 0.1 g.
The mother liquor was stirred with another portion of MeI
(0.3 mL) at 40 °C for 9 days, MeI (0.3 mL) being added every
next day. The solution was concentrated by half in vacuo and
triturated with acetone (1 mL). The precipitate was filtered off
and washed with DMF and acetone. An additional crop of
11ꢀBenzylꢀ3ꢀmethylꢀ4,11ꢀdihydroꢀ3Hꢀpyrimido[5´,4´:5,6]ꢀ
pyrido[3,2ꢀb]indolꢀ4ꢀone (6a). Method A. A suspension of comꢀ
pound 5a (0.17 g, 0.36 mmol) in methanol (30 ml) was brought
to boiling. The resulting solution was cooled to room temperaꢀ
ture and alkalified with 4 N NaOH (7 mL) to pH 10—11. The
red precipitate that formed was filtered off, washed with water
and isopropyl alcohol, and dried to give compound 6a (0.1 g).
Method B. A suspension of pyrimidopyridoindole 2bA
(0.5 g) in DMF dimethyl acetal (6 mL) was refluxed with
stirring for 5.5 h. On cooling, the precipitate that formed was
filtered off and washed with PriOH and ethyl acetate to give
a mixture (0.15 g) of compound 6a and 11ꢀbenzylꢀ6ꢀmethylꢀ
6,11ꢀdihydroꢀ4Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ4ꢀone
(8). The mixture was separated by column chromatography on
SiO2 with chloroform—methanol (10 : 1), chloroform—methaꢀ
nol (10 : 2), and methanol as eluents. The yields of compounds
6a and 8 were 0.06 and 0.07 g, respectively. A mixture of
compounds 6a obtained according to methods A and B did not
depress the melting point.
1
A mixture of compounds 6a (methods A and B): H NMR
(DMSOꢀd6 + CCl4), δ: 3.61 (s, 3 H, N(3)Me); 6.63 (s, 2 H,
CH2Ph); 6.95 (t, 1 H, H(9), Jo = 8.2 Hz); 7.09—7.26 (m, 5 H,
CH2Ph); 7.44 (t, 1 H, H(8), Jo = 8.2 Hz); 7.68 (d, 1 H, H(7),
Jo = 8.2 Hz); 8.00 (d, 1 H, H(10), Jo = 8.2 Hz); 8.64 (s, 1 H,
H(2)); 8.97 (s, 1 H, H(5)).
Compound 8: 1H NMR (DMSOꢀd6 + CCl4), δ: 4.19 (s,
N(6)Me); 6.62 (s, 2 H, CH2Ph); 7.10—7.29 (m, 6 H, H(9),
CH2Ph); 7.71 (t, 1 H, H(8), Jo = 8.2 Hz); 7.78 (d, 1 H, H(7),
Jo = 8.2 Hz); 8.10 (d, 1 H, H(10), Jo = 8.2 Hz); 8.35 (s, 1 H,
H(2)); 9.37 (s, 1 H, H(5)).
1
compound 5a was 0.13 g (its total yield was 0.26 g). H NMR
(DMSOꢀd6), δ: 3.67 (s, 3 H, N(3)Me); 6.75 (s, 2 H, CH2Ph);
7.22—7.34 (m, 5 H, CH2Ph); 7.40 (t, 1 H, H(9), Jo = 8.2 Hz);
7.86 (t, 1 H, H(8), Jo = 8.2 Hz); 7.92 (d, 1 H, H(7), Jo = 8.2 Hz);
8.25 (d, 1 H, H(10), Jo = 8.2 Hz); 8.95 (s, 1 H, H(2)); 9.38 (s,
1 H, H(5)); 13.13 (br.s, 1 H, N(6)H). 13C NMR (DMSOꢀd6), δ:
34.4 N(3)Me); 52.3 (CH2Ph); 112.1 (C(7)); 112.9 (C(10a));
11ꢀBenzylꢀ3,6ꢀdimethylꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ3Hꢀpyrimidoꢀ
[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium iodide (7a). Method A.
Potassium carbonate (0.43 g, 3.1 mmol) and methyl iodide

1772
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Masterova et al.
(1 mL) were added to a suspension of pyrimidopyridoindole 2Ab
(1 g, 3.1 mmol) in anhydrous acetone (30 mL). The reaction
mixture was refluxed with stirring for 6 h. The precipitate was
filtered off hot, washed with acetone, water, methanol, and
again acetone, and dried. The yield of compound 7a was 1.01 g.
1H NMR (DMSOꢀd6), δ: 3.67 (s, 3 H, N(3)Me); 4.26 (s, 3 H,
N(6)Me); 6.77 (s, 2 H, CH2Ph); 7.20—7.33 (m, 5 H, CH2Ph);
7.45 (t, 1 H, H(9), Jo = 8.2 Hz); 7.94 (t, 1 H, H(8), Jo = 8.2 Hz);
8.03 (d, 1 H, H(7), Jo = 8.2 Hz); 8.28 (d, 1 H, H(10), Jo = 8.2 Hz);
8.94 (s, 1 H, H(2)); 9.66 (s, 1 H, H(5)). 13C NMR (DMSOꢀd6),
δ: 30.3 (N(6)Me); 34.4 (N(3)Me); 52.3 (CH2Ph); 112.1 (C(7));
112.6 (C(10a)); 115.1 (C(4a)); 122.4 (C(9)); 124.3 (C(5)); 124.6
(C(10)); 126.0, 128.0, 129.0, 133.3 (Ph); 133.7 (C(8)); 134.2
(C(5a)); 135.1 (C(10b)); 145.5 (C(6a)); 146.9 (C(11a)); 153.6
(C(2)); 159.6 (C(4)).
8.31 (d, 1 H, H(10), Jo = 8.2 Hz); 8.94 (s, 1 H, H(2)); 9.71
(s, 1 H, H(5)).
11ꢀBenzylꢀ6ꢀmethylꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ3Hꢀpyrimido[5´,4´:5,6]ꢀ
pyrido[3,2ꢀb]indolꢀ11ꢀium chloride (9). A saturated solution of
HCl in ethyl acetate (0.1 mL) was added to a suspension of
compound 8 (0.08 g, 0.26 mmol) in methanol (4 mL). The
reaction mixture was brought to boiling. The resulting solution
was filtered, cooled, and triturated. The precipitate that formed
was filtered off and washed with methanol and acetone. The
yield of chloride 9 was 0.05 g. 1H NMR (DMSOꢀd6 + CCl4), δ:
4.27 (s, N(6)Me); 6.79 (s, 2 H, CH2Ph); 7.20—7.29 (m, 5 H,
CH2Ph); 7.42 (t, 1 H, H(9), Jo = 8.2 Hz); 7.92 (t, 1 H, H(8),
Jo = 8.2 Hz); 8.01 (d, 1 H, H(7), Jo = 8.2 Hz); 8.29 (d, 1 H,
H(10), Jo = 8.2 Hz); 8.67 (s, 1 H, H(2)); 9.68 (s, 1 H, H(5));
13.75 (br.s, 1 H, N(3)H).
Method B. Compound 7a was obtained analogously from
pyrimidopyridoindole 2bA (0.3 g, 0.92 mmol), methyl iodide
(1 mL), and KOH (0.01 g, 1.84 mmol) in anhydrous acetone
(10 mL). The yield was 0.08 g. A mixture of compounds 7a
obtained according to methods A and B did not depress the
melting point.
References
1. S. Yu. Ryabova, L. M. Alekseeva, N. S. Masterova, V. G.
Granik, Izv. Akad. Nauk, Ser. Khim., 2007, 1529 [Russ. Chem.
Bull., Int. Ed., 2007, 56, 1588].
11ꢀBenzylꢀ3,6ꢀbis(2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ
3Hꢀpyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium bromide (7b).
Method A. Potassium carbonate (0.13 g, 0.92 mmol) and methyl
bromoacetate (0.2 mL, 2.3 mmol) were added to a suspension
of pyrimidopyridoindole 2bA (0.3 g, 0.92 mmol) in anhydrous
acetone (10 mL). The reaction mixture was refluxed with stirꢀ
ring for 2 h and another portion of methyl bromoacetate (0.2 mL)
was added. The suspension was kept at 20 °C for 64 h. The
precipitate that formed was filtered off, washed with acetone,
water, and again acetone, and dried. The yield of compound 7b
was 0.28 g. 1H NMR (DMSOꢀd6 + CCl4), δ: 3.77, 3.80 (both s,
3 H each, OMe, OMe); 5.09, 5.89 (both s, 2 H each, CH2COOMe,
CH2COOMe); 6.83 (s, 2 H, CH2Ph); 7.23—7.33 (m, 5 H, CH2Ph);
7.46 (t, 1 H, H(9), Jo = 8.2 Hz); 7.94 (t, 1 H, H(8), Jo = 8.2 Hz);
8.00 (d, 1 H, H(7), Jo = 8.2 Hz); 8.31 (d, 1 H, H(10), Jo = 8.2 Hz);
9.03 (s, 1 H, H(2)); 9.86 (s, 1 H, H(5)).
2. N. N. Suvorov, V. A. Chernov, V. S. Velezheva, Yu. A.
Ershova, V. V. Simakov, V. P. Sevodin, Khim.ꢀFarm. Zh.,
1981, No. 9, 27 [Pharm. Chem. J., 1981, 15 (Engl. Transl.)].
3. E. Aszel, R. Rocca, P. Grellier, M. Labaeid, F. Frappier,
F. Gueritte, C. Gaspard, F. Marsais, A. Godard, G. Queguiner,
J. Med. Chem., 2001, 44, 949.
4. Jpn Pat. 76 136 698; Chem. Abstrs., 1977, 87, 5937s.
5. V. G. Granik, in Izbrannye metody sinteza i modifikatsii
geterotsiklov [Selected Methods for the Synthesis and Modification of
Heterocycles], Ed. V. G. Kartsev, IBS PRESS, Moscow, 2006,
Vol. 5, p. 7 (in Russian).
6. M. D. Mashkovskii, Lekarstva XX veka [Drugs of the XX Century],
Novaya Volna, Moscow, 1998 (in Russian).
7. R. A. Abramovitch, K. A. N. Adams, A. D. Notation, Can. J.
Chem., 1960, 38, 2152.
8. A. Albert, J. N. Phillips, J. Chem. Soc., 1956, 1294.
9. L. T. Guss, L. V. Ershov, V. G. Granik, Khim. Geterotsikl.
Soedin., 1990, 215 [Chem. Heterocycl. Compd., 1990, 26 (Engl.
Transl.)].
10. L. T. Guss, L. V. Ershov, V. G. Granik, Khim. Geterotsikl.
Soedin., 1987, 1969 [Chem. Heterocycl. Compd., 1987, 23
(Engl. Transl.)].
Method B. Compound 7b was obtained analogously from
pyrimidopyridoindole 2bA (0.2 g, 0.61 mmol), methyl bromoꢀ
acetate (0.14 mL, 1.53 mmol), and KOH (0.07 g, 1.23 mmol) in
anhydrous acetone (7 mL). The yield was 0.12 g. A mixture of
compounds 7b obtained according to methods A and B did not
depress the melting point.
11ꢀBenzylꢀ3,6ꢀdimethylꢀ4ꢀoxoꢀ4,6ꢀdihydroꢀ3Hꢀpyrimidoꢀ
[5´,4´:5,6]pyrido[3,2ꢀb]indolꢀ11ꢀium methyl sulfate (7c). Potasꢀ
sium carbonate (0.08 g, 0.61 mmol) and dimethyl sulfate (0.09 mL,
0.92 mmol) were added to a suspension of pyrimidopyridoindole
2bA (0.2 g, 0.61 mmol) in anhydrous acetone (10 mL). The
reaction mixture was refluxed with stirring for 5 h and then
for an additional 1 h with another portion of dimethyl sulfate
(0.09 mL). The suspension was cooled and the precipitate that
formed was filtered off, washed with acetone, water, and
again acetone, and dried. The yield of compound 7c was 0.13 g.
1H NMR (DMSOꢀd6 + CCl4), δ: 3.37 (s, 3 H, [MeSO4]–); 3.71
(s, 3 H, N(3)Me); 4.28 (s, 3 H, N(6)Me); 6.80 (s, 2 H, CH2Ph);
7.20—7.29 (m, 5 H, CH2Ph); 7.43 (t, 1 H, H(9), Jo = 8.2 Hz);
7.93 (t, 1 H, H(8), Jo = 8.2 Hz); 8.00 (d, 1 H, H(7), Jo = 8.2 Hz);
11. A. K. Shanazarov, Ph.D. (Chem.) Thesis, VNIKhFI, Moscow,
1988, 184 pp. (in Russian).
12. V. G. Granik, B. M. Pyatin, R. G. Glushkov, Usp. Khim.,
1971, 40, 1593 [Russ. Chem. Rev., 1971, 40 (Engl. Transl.)].
13. G. M. Sheldrick, SHELXL97, SHELXS97, 1997, University
of Göttingen, Germany.
14. K. Brandenburg, DIAMOND, 2000, Release 2.1d, Crystal
Impact GbR, Bonn, Germany.
Received January 25, 2008;
in revised form March 4, 2008