Reactions of quinazoline alkaloids and their derivatives with electrophilic reagents

Article abstract of DOI:10.1007/s10600-008-9106-z

Nitration of deoxypeganine (DOP), deoxyvasicinone (DOV), 2,3-tetramethylene-, 2,3-pentamethylene-, and 3,4-dihydroquinazol-4-ones and their 1,2-dihydro derivatives was studied. It was shown that the reaction pathway changed depending on the presence of a carbonyl on C-4 and an N=C bond in these compounds. Only the H atom on C-6 was subject to nitration if both functional groups were present, for example DOV and its homologs. Substitution of the H atom of either the 6-position (DOP, 1,2-dihydro-DOV, and their homologs) or the 6- and 8-positions simultaneously (DOP and its homologs) was enhanced if one of these functional groups was missing depending on the substrate:nitrating agent ratio. The bromination and nitration reactions of 1,2-dihydro-DOV and its analogs in a 1:2 ratio were accompanied by oxidation of the N¹H-CH bond with formation of 6,8-dibromo- and 6,8-nitro-DOV and their homologs. The difference in the behavior of these compounds was due to the different nucleophilicity of the benzene rings in them. The reaction of 1,2-dihydro-DOV and its homologs with isocyanates and p-nitro- and p-methylbenzoic acid chlorides was studied. 6-Nitro- and 6,8-dinitro-DOP and 6,8-dibromo- and 6,8-dinitro-DOV and their homologs and 6-bromo- and 6-nitro-1,2,3,4-tetrahydro-2,3-polymethylenequinazol-4-ones and their 1-alkyl(aryl)-carbamoyl and p-nitro(methyl)-benzoyl derivatives were synthesized. The molecular structures of 1-ethyl-and 1-(o-chlorophenyl)- carbamoyl-1,2-dihydrodeoxyvasicinones and 6,8-dinitro-2,3pentamethylene-3,4- dihydroquinazol-4-one were established.

Full text of DOI:10.1007/s10600-008-9106-z

Chemistry of Natural Compounds, Vol. 44, No. 4, 2008
REACTIONS OF QUINAZOLINE ALKALOIDS AND THEIR
DERIVATIVES WITH ELECTROPHILIC REAGENTS
Z. U. Samarov,* Z. M. Khakimova, R. Okmanov,
B. Tashkhodzhaev, and Kh. M. Shakhidoyatov
UDC 547.944/945 547.856.1
Nitration of deoxypeganine (DOP), deoxyvasicinone (DOV), 2,3-tetramethylene-, 2,3-pentamethylene-, and
3,4-dihydroquinazol-4-ones and their 1,2-dihydro derivatives was studied. It was shown that the reaction
pathway changed depending on the presence of a carbonyl on C-4 and an N=C bond in these compounds.
Only the H atom on C-6 was subject to nitration if both functional groups were present, for example DOV
and its homologs. Substitution of the H atom of either the 6-position (DOP, 1,2-dihydro-DOV, and their
homologs) or the 6- and 8-positions simultaneously (DOP and its homologs) was enhanced if one of these
functional groups was missing depending on the substrate:nitrating agent ratio. The bromination and
nitration reactions of 1,2-dihydro-DOV and its analogs in a 1:2 ratio were accompanied by oxidation of the
1
N H–CH bond with formation of 6,8-dibromo- and 6,8-nitro-DOV and their homologs. The difference in the
behavior of these compounds was due to the different nucleophilicity of the benzene rings in them. The
p
p
reaction of 1,2-dihydro-DOV and its homologs with isocyanates and -nitro- and -methylbenzoic acid
chlorides was studied. 6-Nitro- and 6,8-dinitro-DOP and 6,8-dibromo- and 6,8-dinitro-DOV and
their homologs and 6-bromo- and 6-nitro-1,2,3,4-tetrahydro-2,3-polymethylenequinazol-4-ones and their
p
1-alkyl(aryl)-carbamoyl and -nitro(methyl)-benzoyl derivatives were synthesized. The molecular structures
o
of 1-ethyl- and 1-( -chlorophenyl)-carbamoyl-1,2-dihydrodeoxyvasicinones and 6,8-dinitro-2,3-
pentamethylene-3,4-dihydroquinazol-4-one were established.
Key words: deoxypeganine, deoxyvasicinone, 2,3-tetramethylene-, 2,3-pentamethylene-3,4-dihydroquinazol-4-ones,
1,2,3,4-tetrahydro-2,3-polymethylenequinazol-4-ones, isocyanates, electrophilicsubstitution, alkaloids, x-raydiffraction analysis,
carbamoylation, acylation.
The alkaloids deoxyvasicinone (1) and deoxypeganine (2) were isolated from the plant
[1, 2];
[3].
M. makrosciadia
Peganum harmala
and
2,3-tetramethylene-3,4-dihydroquinazol-4-one (3) and -quinazoline (4), from
Mackinlaya subulata
These alkaloids and their seven-membered ring synthetic homolog 5 have been synthesized. A simple and convenient
preparation method has been developed [4, 5].
O
N
N
(CH )
2 n
(CH )
2 n
N
N
1, 3, 5
1: n = 1;3: n = 2;5: n = 3
2, 4
2: n = 1;4: n = 2
We have previously studied the reaction of 1 with various electrophilic reagents (nitration, sulfochlorination,
bromination with potassium bromate and conc. H SO ) to give 6-substituted 1 [4-6].
2
4
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan,
Tashkent, fax (99871) 120 64 75, e-mail: Zarif1980@rambler.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp.
387-393, July-August, 2008. Original article submitted May 5, 2008.
0009-3130/08/4404-0480 ©2008 Springer Science+Business Media, Inc.
480

In continuation of our research on the search for biologically active compounds among tricyclic quinazolone alkaloids
and on the introduction of a second electrophilic substituent in the 8-position to produce 6,8-disubstituted 1, we reacted 1 with
an excess of a nitrating mixture under various conditions, in contrast with the literature [4]. However, we produced only
6-nitrodeoxyvasicinone (6) despite using a 1:2 ratio of 1:nitrating mixture and increasing the reaction temperature to 0-5°C.
In contrast with this, nitration of 2 followed various pathways and depended on the ratio of reagents. Thus, using a 1:1 ratio
of 2:nitrating mixture formed 6-nitrodeoxypeganine (7); using a 1:2 ratio of reagents, 6,8-dinitrodeoxypeganine (8).
O N
2
N
O
N
X
N
N
N
1 : 1
1: 2
O N
2
7
X = H
N
X = O
N
2
O N
2
N
6
1, 2
1: X = O;2: X = H
2
NO
2
8
Such a difference in the behavior of 1 and 2 in the nitration reaction is explained by the relatively low nucleophilicity
of the benzene ring in 1 after introducing one nitro group. Thus, 6 contains such electronegative groups as NO , C=O, and
2
C=N, which withdraw electrons from the benzene ring and create a deficiency of electron density in it. Without the
carbonyl on C-4, i.e., in 7, the nucleophilicityofthe aromatic ring is relativelyhigher than in 6 [6]. Therefore, the intermediate
6-nitrodeoxypeganine (7) undergoes a second electrophilic substitution by the nitrating agent at the 8-position and forms 8.
It can be assumed that the lack of a N=C double bond increases the nucleophilicity of the benzene ring compared
with 6. In order to confirm this hypothesis, we reduced the N=C bond in 1 with sodium borohydride [7, 8] to give
1,2-dihydrodeoxyvasicinone (9) and its homologs 10 and 11.
O
O
N
N
(CH )
2 n
NaBH
(CH )
2 n
+
4
N
N
H
1, 3, 5
9 - 11
1: n = 1; 3: n = 2; 5: n = 3
9: n = 1; 10: n = 2; 11: n = 3
A study of the nitration of 9 showed, as hypothesized, 6-nitro-1,2-dihydrodeoxyvasicinone (12) was formed with a 1:1
ratio of 9:nitrating agent. Using a 1:2 ratio of reagents led to the formation of 6,8-dinitrodeoxyvasicinone (18) instead of the
expected 6,8-dinitro-1,2-dihydrodeoxyvasicinone (15).
Nitration of 2,3-tetramethylene- and 2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-ones (10, 11) occurred
analogously to produce 6,8-dinitro-2,3-tetramethylene- and 2,3-pentamethylene-3,4-dihydroquinazol-4-ones (19, 20),
respectively.
O
O
O
O
X
X
X
N
N
N
N
(CH )
(CH )
2 n
n
(CH )n
2
2
(CH )
2 n
N
H
N
H
N
N
H
X
X
12 - 14, 21 - 23
9 - 11
15 - 17, 24 - 26
18 - 20, 27 - 29
12 - 20: X = NO2; 21 - 29: X = Br
12, 15, 18, 21, 24, 27: n = 1; 13, 16, 19, 22, 25, 28: n = 2; 14, 17, 20, 23, 26, 29: n = 3
481

O 2
C 4 A
C 8 A
C 1 2
C 11
C 1 0
N 3
C 2
C 5
C 8
N 4
C 4
N 1
O 3
C 1 3
C 6
C 7
C 9
N 5
O 5
O 4
Fig. 1. Molecular structure of 20.
Thus, we developed a method for preparing 6,8-dinitrodeoxyvasicinone and its six- and seven-membered ring
homologs, which are difficultly available by other methods.
It seemed interesting to investigate the behavior of 9-11 in bromination reactions because they might behave similarly
as for nitration.
Bromination of 9 in 70% acetic acid formed 6-bromo-1,2-dihydrodeoxyvasicinone (21, 9:bromine ratio 1:1). Using
a 1:2 ratio of reagents gave 6,8-dibromodeoxyvasicinone (27), i.e., bromination of 9 occurred anlaogously to nitration with
simultaneous oxidation of the NH–CH bond toan N=C bond. According tothe literature, bromination ofDOV (1) with bromine
in acetic acid occurred exclusively at the α-C atom [4-6]. Electrophilic substitution of the H atoms in the 6- or 8-positions did
not occur although it is known that the hydrochloride of 2 reacted with N-bromosuccinimide (NBS) in dry CHCl to give a
3
mixture of6-bromopeganol (6-bromo-4-hydroxy-2) and 8-bromo-DOV in a 1:1.7 ratio. The main product was 6-bromopeganol
[9]. We showed recently that bromination of 2 with NBS in CHCl and subsequent treatment with NaOH (10%) gave a mixture
3
of peganol (4-hydroxy-2) and 6-bromopeganol, which formed mixed crystals upon crystallization [10, 11].
Bromination of2,3-tetramethylene-and2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-ones(10and11) bybromine
in a 1:1 ratiogave monobromo-2,3-tetramethylene- and -pentamethylene-1,2,3,4-tetrahydroquinazol-4-ones (22 and 23). A 1:2
ratio of reagents formed, like for bromination of 1,2-DOV, 6,8-dibromo-2,3-tetramethylene- and -pentamethylene-3,4-
dihydroquinazol-4-ones (28 and 29).
The structures of 6,8-dinitro-2,3-polymethylene-3,4-dihydroquinazol-4-ones 18-20 were confirmed by spectral data
and for 20, also by an x-ray diffraction analysis. Figure 1 shows the molecular structure of 20. It can be seen that the
quinazolone core with the adjoining atoms and the nitro group in the C6-position are planar within 0.037 Å. The seven-
membered heterocycle adopted the chair conformation. The planar nitro group in the C8-position is situated practically
perpendicular (73.3°) to the plane of the aromatic ring. This is unusual in conjugated systems. An analogous placement of the
nitrogroupwasobservedin thestructureof2-(3′,5′-dinitro-2′-methoxyphenyl)-6,8-dinitroquinazolin-4-one[12]. Themolecules
in the crystal are located at Van-der-Waals distances from each other.
It is known that 9 reacts with acid chlorides, adds to phenylacetylene, and is alkylated by allylchloride [7, 8, 13]. The
analog of 9 with a six-membered ring instead of the five-membered one, the 1,2-dihydro derivative of the alkaloid
2,3-tetramethylene-3,4-dihydroquinazol-4-one, is also acylated and carbamoylated upon reaction with acid chlorides
and isocyanates [14]. Herein we report on an investigation of the reaction of 9 and its homolog 11 with p-nitro- and
p-methylbenzoylchlorides and isocyanates.
A study of the acylation of 9 and 11 by p-nitrobenzoylchloride and p-toluylchloride showed that the reaction occurs
in CHCl solution at the N-1 nitrogen and gives 1-p-nitrobenzoyl- and 1-p-methylbenzoyl-1,2-dihydrodeoxyvasicinones and
3
their homologs (30-33).
O
O
O
N
N
RNCO
N
RCOCl
(CH )
2 n
(CH )
2 n
(CH )
2 n
N
N
N
H
COR
CONHR
30 - 33
9, 11
34 - 42
9: n = 1; 11: n = 3
p
p
o
o
30, 32: R = -NO2-C6H4; 31, 33, 37, 42: R = -CH3-C6H4; 34, 39: R = -NO2-C6H4; 35, 40: R = -Cl-C6H4
m
36, 41: R = -Cl-C6H4; 38: R = C2H5 30, 31, 34 - 38: n = 1; 32, 33, 39 - 42: n = 3
482

O 1
C 11
C 2
C 1 0
N 3
C 4 A
C 8
C 4
C 5
C 7
C 6
C 9
N 1
C 8 A
O 2
C 1 2
N 1 3
C l 1
C 1 5
C 1 4
C 1 9
C 1 6
C 1 7
C 1 8
38
35
Fig. 2. Molecular structures of 35 and 38.
Compounds 9 and 11 reacted with isocyanates to form the corresponding quinazoline ureas (34-42). We used the
isocyanates o-nitro-, o- and m-chloro-, and p-methylphenylisocyanates and ethylisocyanate. The reaction occurred smoothly
with heating of a 1:2 mixture of the reagents in benzene solution without a catalyst.
The structures of 34-42 were established by spectral properties and for 35 and 38, also by x-ray diffraction analyses.
The crystal structures of 35 and 38 showed that the crystals were racemic. Both crystals had antipodes related by a
center of symmetry that formed dimers through intermolecular H-bonds between the quinazolone carbonyl O atom and the
aminoacetyl NH group with N13...O1, 2.88; N13–H...O1, 1.94 Å; 160.9°. These values for 35 were 2.86 and 2.03 Å and 175.2°,
respectively.
Figure 2 shows the molecular structures of 35 and 38. The quinazolone benzene ring (including N1 and C4) was planar
within 0.008 Å. Atoms C2 and N3 in the six-membered ring in 35 and 38 deviated from the plane of the remaining four atoms
by -0.76 and 0.28 Å and -0.74 and 0.26 Å, respectively. These values indicated that the six-membered ring adopted an
intermediate conformation between a chair and half-chair. The five-membered rings in 35 and 38 adopted the envelope
conformation with C9 deviating from the plane of the remaining four atoms by 0.55 and 0.57 Å, respectively. The aminoacyl
group (including N1 and C14) in 35 and 38 were planar within 0.024 and 0.009 Å and was twisted relative to the mean-square
plane of the quinazolone benzene ring (including N1 and C4) by57.2 and 63.3°, respectively. The o-chlorophenyl group in 35
is twisted relative to the plane of the amino group by 63.3°.
The methyl group in 38 was disordered. This moiety was found in two positions with different occupancies (degree
of occupying positions in the unit cell) of 0.7 and 0.3. This was evident in the large thermal parameters of C15 and the
anomalous shortening of the length of the C14–C15 single bond [distances of 1.331(8) and 1.393(8) Å, respectively] compared
with the normal value (1.54 Å).
A comparison of equivalent bonds in 35 and 38 showed that they differed significantly in the aminoacetyl group. The
C12–N13 amide bond length in 35 [1.358(4) Å] was longer whereas the N1–C12 bond [1.407(4) Å] was shorter than that
observed in 38 [1.294(3) and 1.421(2) Å, respectively]. This indicated that the π-electron system of –C(O)–NH bonds was
conjugated with the analogous system of the chloro-substituted benzene ring, which is impossible in 38.
483

TABLE 1. Principal Crystallographic Parameters and X-ray Structure Properties for 20, 35, and 38
Structure
Molecular formula
20
35
38
C13H12N4O5
304.27
C18H16N3O2Cl
341.79
C14H17N3O2
259.31
MW
System
Space group
Monoclinic
P21/c
Monoclinic
P21/n
Triclinic
P-1
Z
4
4
2
a, Å
6.383 (3)
22.556 (11)
9.310 (5)
89.99 (4)
92.16 (4)
90.00 (4)
1339.6 (11)
1.508
11.701 (6)
11.103 (4)
12.730 (5)
90
110.93 (3)
90
1544.7 (12)
1.470
0.45×0.35×0.15
1.71≤θ≤25.0°
0.264
8.138 (1)
8.414 (2)
10.966 (2)
82.82 (3)
70.73 (3)
64.93 (3)
641.9 (2)
1.342
b, Å
c, Å
α
β
γ
V, Å3
Dx, g/cm3
Crystal size, mm
0.60×0.50×0.25
1.96≤θ≤58.0°
1.012
0.70×0.60×0.20
1.97≤θ≤26.0°
0.092
θ-Scanning range
μ
1
exp, mm−
Number of reflections
Number of reflections with I>2σ (I)
1857
1710
2714
1829
2290
1896
R1 (I>2σ (I) and total)
WR2
0.04 (0.043)
0.11 (0.112)
1.09
0.07 (0.111)
0.10 (0.120)
1.17
0.05 (0.062)
0.12 (0.135)
1.10
S
3
3
3
Difference electron-density peaks
0.17 and -0.19 eÅ−
0.26 and -0.23 eÅ−
0.22 and -0.32 eÅ−
EXPERIMENTAL
IRspectra in mineral oil were recorded on aPerkin—Elmer Model2000 Fourier-IRspectrometer. PMRspectra in TFA
+
and CDCl were recorded on a UNITY 400 plus spectrometer (Varian). Mass spectra were obtained in a MS 25-RF (Kratos)
3
instrument with direct sample introduction into the ion source, ionizing electron energy 70 eV, ion source temperature 250°C,
and sample introduction temperature 200°C. The course of reactions and the purity of products were monitored by TLC on
Silufol UV-254 plates using benzene:acetone (5:2) and UV light developer.
X-ray Diffraction Analyses. Unit-cell constants of crystals of 20, 35, and 38 were determined and refined on a Stoe
Stadi-4 diffractometer (T = 298 K, graphite monochromator). Intensities of reflections were measured on the same
diffractometer by ω/2θ-scanning using Cu (20) and Mo (35 and 38) Kα-radiation. Absorption corrections for 20 were applied
by ψ-scanning and were not applied for the other structures. Table 1 lists the principal parameters of the x-ray diffraction
analyses and the calculations. The structures were solved by direct methods using the SHELXS-97 programs. Structures were
refined using the SHELXL-97 program. All nonhydrogen atoms were refined bya full-matrix anisotropic least-squares method
2
(over ). Positions of H atoms were found geometrically and refined with fixed isotropic thermal parameters
= n
,
U
eq
F
U
iso
where n = 1.5 for methyls and 1.2 for others and
are the equivalent isotropic thermal parameters of the corresponding C
U
eq
atoms. The positions of the NH H atoms in 35 and 38 were found in difference electron-density syntheses and refined
isotropically. Data from the x-raydiffraction analyses were deposited as CIF-files in the Cambridge Crystallographic Database
[CCDC-685459 (20), 685460 (35), 685461 (38)].
Deoxyvasicinone(1), deoxypeganine(2), and2,3-tetramethylene-3,4-dihydroquinazol-4-one(5)werepreparedasbefore
[3]. 1,2-Dihydrodeoxyvasicinone(9), 2,3-tetramethylene- (10), and2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-ones(11)
were synthesized by the literature method [7].
Elemental analyses for newly synthesized compounds agreed with those calculated.
6-Nitrodeoxypeganine (7). Compound 2 (0.33 g, 2 mmol) was dissolved with stirring and cooled to -5°C in conc.
H SO (3 mL), stirred vigorously, treated in portions with a nitrating mixture consisting of HNO (0.09 mL, 2.1 mmol, d = 1.5)
2
4
3
and H SO (0.2 mL, d = 1.84) at a rate such that the temperature remained below 0°C, stirred at this temperature for 30 min,
2
4
484

at 5-10°C for 1 h, at 20°C for 1 h, poured into ice, and basicified with ammonia solution until the pH was 8-9. The resulting
solid was filtered off, washed with water, and dried. Yield of 7, 0.33 g (82%), mp 187-189°C, R 0.46 (Al O , CHCl :ether,
f
2
3
3
1:1). IR spectrum (ν, cm−1): 1620 (C=N), 1508 (NO ).
2
PMR spectrum (CDCl , δ, ppm, J/Hz): 6.80 (1H, d, J = 8.0, H-8), 7.78 (1H, d, J
= 12, J = 2, H-7), 8.70 (1H,
meta
3
ortho
d, J
= 2.5, H-5), 2.80 (2H, t, α-CH ), 2.10 (2H, m, β-CH ), 3.63 (2H, t, γ-CH ), 4.55 (2H, s, H -4).
meta
2 2 2 2
+
+
+
+
Mass spectrum (m/z, %): 262 (100) [M] , 215 (25) [M - 47] , 182 (12) [M - 80] , 169 (54) [M - 93] , 149 (10) [M -
+
+
113] , 103 (9) [M - 159] .
6,8-Dinitrodeoxypeganine (8) was prepared analogously as above from 2 (0.5 g, 3 mmol) and a nitrating mixture
consisting of HNO (0.25 mL, d = 1.5) and H SO (0.36 mL, d = 1.84) to afford 8. Yield 0.56 g (76%), mp 214-216°C, R 0.46
f
3
2
4
(Al O , CHCl :ether, 1:1). IR spectrum (ν, cm−1): 1625 (C=N), 1520 (NO ).
2
3
3
2
PMR spectrum (CDCl , δ, ppm, J/Hz): 8.68 (1H, d, J
= 2.5, H-5), 7.98 (1H, d, J
= 2, H-7), 2.98 (2H, t, α-CH ),
3
meta
meta 2
2.10 (2H, m, β-CH ), 3.63 (2H, t, γ-CH ), 4.73 (2H, s, H -4).
2
2
2
+
Mass spectrum (m/z, %): 217 (100) [M] , 201, 187, 170 (57), 158, 149.
6-Nitro-1,2-dihydrodeoxyvasicinone (12). Compound 9 (0.541 g, 2.87 mmol) was dissolved with stirring and cooled
to 0°C in conc. H SO (21 mL), stirred vigorously, treated in portions with a nitrating mixture (0.25 mL HNO , d = 1.34;
2
4
3
0.3 mL H SO , d = 1.84) at such a rate that the temperature remained at 0-2°C, stirred for 1 h at 5-10°C, and poured onto ice.
2
4
The solid was filtered off, washed with water, and dried. Recrystallization afforded 12, 0.54 g (80%), mp 210°C (methanol),
R 0.49 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1630 (C=N), 1522 (NO ), 1645 (C=O).
f
2
6-Nitro-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (13). Compound10(0.58g, 2.87mmol)wasdissolved
with stirring and cooled to 0°C in conc. H SO (21 mL), stirred vigorously, treated in portions with a nitrating mixture
2
4
(0.25 mL HNO , d = 1.34; 0.3 mL H SO , d = 1.84) at such a rate that the temperature remained at 0-2°C, stirred for 1 h at
3
2
4
5-10°C, and poured onto ice. The solid was filtered off, washed with water, and dried. Recrystallization afforded 13, 0.55 g
(78%), mp 224-226°C (methanol), R 0.56 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1630 (C=N), 1522 (NO ),
f
2
1645 (C=O).
6-Nitro-2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (14) was prepared analogously as above from 11
(0.62 g, 2.87 mmol), conc. H SO (21 mL), and HNO (0.25 mL, d = 1.34) and H SO (0.3 mL, d = 1.84) to afford 14
2
4
3
2
4
(0.61 g, 82%), mp 175-177°C (methanol), R 0.55 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1630 (C=N), 1522
f
(NO ), 1640 (C=O).
2
Reaction of 9 and Nitrating Mixture. Synthesis of 6,8-Dinitrodeoxyvasicinone (18). Compound 9 (0.6 g,
3.91 mmol) was dissolved with stirring and cooled to 0°C in conc. H SO (21 mL), stirred vigorously, treated in portions with
2
4
a nitrating mixture (0.56 mL HNO , d = 1.34; H SO , 0.3 mL, d = 1.84) at a rate such that the temperature remained below
3
2
4
2°C, stirred at room temperature for 1 h, and poured onto ice. The resulting precipitate was filtered off, washed with water, and
dried. Recrystallization afforded 18 (0.8 g, 90%), mp 216-218°C (methanol), R 0.69 (Silufol, benzene:acetone, 5:2).
f
IR spectrum (ν, cm−1): 1628 (C=N), 1640 (C=O), 1526 (NO ).
2
PMR spectrum (CDCl , δ, ppm, J/Hz): 9.23 (1H, d, J
= 2.7, H-5), 8.77 (1H, d, J
= 2.7, H-7), 3.23 (2H, t,
3
meta
meta
α-CH ), 2.25 (2H, m, β-CH ), 4.22 (2H, t, γ-CH ).
2
2
2
Nitration of 2,3-Tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (1:2 10:nitrating mixture ratio). Synthesis
of 6,8-Dinitro-2,3-tetramethylene-3,4-dihydroquinazol-4-one (19). Compound 10 (0.79 g, 3.91 mmol) was dissolved with
stirring and cooled to 0°C in conc. H SO (21 mL), stirred vigorously, treated in portions with a nitrating mixture (0.56 mL
2
4
HNO , d = 1.34; 0.3 mL H SO , d = 1.84) at such a rate that the temperature remained below 2°C, stirred for 1 h at 5-10°C,
3
2
4
and poured onto ice. The resulting precipitate was filtered off, washed with water, and dried. Recrystallization afforded 19
(0.97 g, 85%), mp 220-222°C (methanol), R 0.7 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1628 (C=N), 1526
f
(NO ), 1635 (C=O).
2
Reaction of 2,3-Pentamethylene-1,2,3,4-tetrahydroquinazol-4-one with Nitrating Mixture. Synthesis of
6,8-Dinitro-2,3-pentamethylene-3,4-dihydroquinazol-4-one (20). Compound 20 was prepared analogously as above from
11 (0.85 g, 3.91 mmol), conc. H SO (21 mL), and nitrating mixture (0.56 mL HNO , d = 1.34; 0.3 mL H SO , d = 1.84),
2
4
3
2
4
1.1 g (90%), mp 239-241°C (methanol), R 0.75 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1628 (C=N), 1526
f
(NO ), 1645 (C=O).
2
+
Mass spectrum (m/z, %): 304 (38) [M] , 55 (88), 43 (100). Table 1 and Fig. 1 list the principal crystallographic
parameters and characteristics of the x-ray diffraction analysis.
485

6-Bromo-1,2-dihydrodeoxyvasicinone(21). Compound9(1g, 5.32mmol)wasdissolvedin aceticacid(20mL, 70%),
stirred vigorously, treated in portions with bromine (0.3 mL, d = 3.1), stirred for 3 h at 5-10°C, and poured onto ice. The
resulting precipitate was filtered off, washed with water, and dried. Recrystallization afforded 21 (0.51 g, 36%), mp 218-220°C
(acetone). IR spectrum (ν, cm−1): 1645 (C=O), 1628 (C=N), 855 (Br).
Reactionof1,2-DihydrodeoxyvasicinonewithBromine(1:2ratio). Synthesisof6,8-Dibromodeoxyvasicinone(27).
A solution of 9 (1 g, 5.32 mmol) in acetic acid (20 mL, 70%) was stirred vigorously, treated dropwise over 30 min with bromine
(0.55 mL, d = 3.1), stirred for 2 h at 5-10°C, and poured onto ice. The resulting precipitate was filtered off, washed with water,
and dried to afford 27 (1.6 g, 87%), mp 255-257°C (acetone). IR spectrum (ν, cm−1): 1643 (C=O), 1628 (C=N), 850 (Br).
PMR spectrum (TFA, δ, ppm, J/Hz): 8.10 (1H, d, J
= 2.04, H-5), 7.95 (1H, d, J
= 2.04, H-7), 3.38 (2H, t,
meta
meta
α-CH ), 2.20 (2H, m, β-CH ), 4.10 (2H, t, γ-CH ).
2
2
2
+
+
Mass spectrum (m/z, %): 346 (30) [M] , 344 (100), 77 (51) [M] .
6-Bromo-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (22). Compound10(1.1 g, 5.32mmol)andbromine
(0.3 mL, d = 3.1) in acetic acid (20 mL, 70%) analogously as above afforded 22 (0.6 g, 40%), mp 214-216°C (acetone), R 0.52
f
(Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1645 (C=O), 1626 (C=N), 855 (Br).
Conversion of 2,3-Tetramethylene-1,2,3,4-tetrahydroquinazol-4-one into 6,8-Dibromo-2,3-tetramethylene-3,4-
dihydroquinazol-4-one (28). Compound 10 (1.1 g, 5.32 mmol) and bromine (0.55 mL, d = 3.1) in acetic acid (20 mL, 70%)
analogously as above afforded 28 (1.7 g, 85%), mp 217-218°C (acetone), R 0.75 (Silufol, benzene:acetone, 5:2). IR spectrum
f
(ν, cm−1): 1643 (C=O), 1628 (C=N), 850 (Br).
6-Bromo-2,3-pentamethylene-1,2,3,4-dihydroquinazol-4-one (23). Compound11 (1.15 g, 5.32 mmol)andbromine
(0.3 mL, d = 3.1) in acetic acid (20 mL, 70%) analogously as above afforded 23 (0.6 g, 38%), mp 245-247°C (acetone), R 0.72
f
(Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1640 (C=O), 1624 (C=N), 850 (Br).
Reaction of 2,3-Pentamethylene-1,2,3,4-tetrahydroquinazol-4-one with Bromine (1:2 ratio). Synthesis of 6,8-
Dibromo-2,3-pentamethylene-3,4-dihydroquinazol-4-one (29). Compound 11 (1.15 g, 5.32 mmol) and bromine (0.55 mL,
d = 3.1) in acetic acid (20 mL, 70%) analogouslyas above afforded 29 (1.75 g, 87%), mp 166-168°C (acetone), R 0.83 (Silufol,
f
benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1643 (C=O), 1628 (C=N), 850 (Br).
+
Mass spectrum (m/z, %): 372 (100) [M] , 318 (72), 343 (62).
1-(p-Nitrobenzoyl)-1,2-dihydrodeoxyvasicinone (30). A solution of9 (1 g, 4.9 mmol) in CHCl (50 mL) was treated
3
with 4-nitrobenzoylchloride (1.36 g, 7.35 mmol), heated on a water bath at 50-60°C with sitrring for 2 h, and treated with
aqueous NaOH (10%). The organic layer was separated, washed with water (3×), and dried over MgSO . The CHCl was
4
3
distilled off. Recrystallization afforded 30 (1.15 g, 70%), mp 158°C (hexane), R 0.7 (Silufol, benzene:acetone, 5:2).
f
IR spectrum (ν, cm−1): 1651 (C=O), 1351-1333 (NO ).
2
1-(p-Methylbenzoyl)-1,2-dihydrodeoxyvasicinone (31). A solution of 9 (1 g, 4.9 mmol) in CHCl (50 mL) was
3
treated with toluylchloride (0.2 mL, 7.35 mmol), refluxed for 3 h, and treated with aqueous NaOH (10%). The organic layer
was separated, washed with water (3×), and dried over Na SO . The solvent was distilled off. Recrystallization afforded 31
2
4
(1.15 g, 70%), mp 146°C (hexane), R 0.6 (Silufol, benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1651 (C=O), 1351-1333
f
(NO ).
2
1-(p-Nitrobenzoyl)-2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (32). A solution of 11 (1.1 g, 5 mmol)
in absolute benzene (30 mL) was treated with 4-nitrobenzoylchloride (1.36 g, 7.35 mmol), refluxed on a water bath with stirring
for 4 h, and treated with aqueous NaOH (10%). The organic layer was separated, washed with water (3×), and dried over
Na SO . The solvent was distilled off. Recrystallization afforded 32 (1.48 g, 80%), mp 149-151°C (hexane), R 0.8 (Silufol,
f
2
4
benzene:acetone, 5:2). IR spectrum (ν, cm−1): 1651 (C=O), 1351-1333 (NO ).
2
1-(p-Methylbenzoyl)-2,3-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (33). Compound 11 (1.1 g, 5 mmol)
was dissolved in CHCl (30 mL), treated with toluylchloride (0.2 mL, 7.35 mmol), heated on a water bath at 60-70°C for 2 h,
3
and worked up analogously as above to afford 33 (1.2 g, 70%), mp 139°C (hexane), R 0.65 (Silufol, benzene:acetone, 5:2).
f
IR spectrum (ν, cm−1): 1651 (C=O), 1351-1333 (NO ).
2
1-(o-Chlorophenylcarbamoyl)-1,2-dihydrodeoxyvasicinone (35). A solution of 9 (0.225 g, 1.2 mmol) in benzene
(25 mL) was treated with o-chlorophenylisocyanate (0.37 g, 2.5 mmol), refluxed on a water bath for 3 h, and left for 1 d. The
resulting precipitate was filtered off to afford 35 (0.17 g, 41%), mp 210°C (alcohol), R 0.48 (Silufol, benzene:acetone, 5:2).
f
IR spectrum (ν, cm−1): 1644 (C=O), 739 (Cl). Table 1 and Fig. 2 list the principal crystallographic parameters and the
characteristics of the x-ray diffraction analysis.
486

1-(o-Nitrophenylcarbamoyl)-1,2-dihydrodeoxyvasicinone(34)waspreparedanalogouslyfrom 9(0.225g, 1.2mmol)
and o-nitrophenylisocyanate (0.4 g, 2.5 mmol) to afford 34 (0.31 g, 73%), mp 205°C (benzene), R 0.57 (Silufol,
f
benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1643 (C=O), 1362 (NO ).
2
1-(m-Chlorophenylcarbamoyl)-1,2-dihydrodeoxyvasicinone (36) was prepared analogously as above from 9
(0.225 g, 1.2 mmol) and m-chlorophenylisocyanate (0.37 g, 2.5 mmol) to afford 36 (0.2 g, 48%), mp 258-259°C (alcohol),
R 0.48 (Silufol, benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1697 (C=O), 777 (Cl).
f
1-(p-Methylphenylcarbamoyl)-1,2-dihydrodeoxyvasicinone (37) was prepared analogously as above from 9
(0.225 g, 1.2 mmol) and p-tolylisocyanate (0.34 g, 2.5 mmol) to afford 37 (0.27 g, 70%), mp 253°C (alcohol), R 0.61 (Silufol,
f
benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1645 (C=O).
+
Mass spectrum (m/z, %): 321 (2.8) [M] , 187 (76), 133 (96), 132 (100), 146 (73), 160 (47), 104 (50).
1-(Ethylcarbamoyl)-1,2-dihydrodeoxyvasicinone(38)was prepared analogouslyas above from 9(0.225g, 1.2mmol)
and ethylisocyanate (0.177 g, 2.5 mmol) to afford 38 (0.186 g, 60%), mp 208°C (alcohol), R 0.49 (Silufol, benzene:acetone,
f
5:2), IR spectrum (ν, cm−1): 1645 (C=O). Table 1 and Fig. 2 list the principal crystallographic parameters and characteristics
of the x-ray diffraction analysis.
1-(o-Nitrophenylcarbamoyl)-3,4-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (39)waspreparedanalogously
as above from 11 (0.257 g, 1.2 mmol) and o-nitrophenylisocyanate (0.4 g, 2.5 mmol) to afford 39 (0.31 g, 68%), mp 210-212°C
(benzene), R 0.85 (Silufol, benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1626 (C=O), 1362 (NO ).
f
2
+
Mass spectrum (m/z, %): 380 (2.4) [M] , 216 (56), 187 (60), 173 (100), 160 (68).
1-(o-Chlorophenylcarbamoyl)-3,4-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (40). A mixture of 11
(0.257 g, 1.2 mmol) and o-chlorophenylisocyanate (0.37 g, 2.5 mmol) in aboslute benzene (20 mL) was heated for 2 h and
worked up analogously as above to afford 40 (0.21 g, 48%), mp 248°C (alcohol), R 0.74 (Silufol, benzene:acetone, 5:2),
f
IR spectrum (ν, cm−1): 1644 (C=O), 739 (Cl).
1-(m-Chlorophenylcarbamoyl)-3,4-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (41) was prepared
analogously as above from 11 (0.257 g, 1.2 mmol) and m-chlorophenylisocyanate (0.37 g, 2.5 mmol) to afford 41 (0.215 g,
49%), mp 255°C (alcohol), R 0.69 (Silufol, benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1697 (C=O), 777 (Cl).
f
1-(p-Methylphenylcarbamoyl)-3,4-pentamethylene-1,2,3,4-tetrahydroquinazol-4-one (42)waspreparedanalogously
as above from 11 (0.257 g, 1.2 mmol) and p-tolylisocyanate (0.34 g, 2.5 mmol) to afford 42 (0.25 g, 60%), mp 242°C (alcohol),
R 0.65 (Silufol, benzene:acetone, 5:2), IR spectrum (ν, cm−1): 1645 (C=O).
f
ACKNOWLEDGMENT
The work was supported financially by Basic Research of TsNT of the Republic of Uzbekistan (Project No. FA-FZ-
T047).
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