Chemical modification of the alkaloid 2,3-tetramethylene-3,4- dihydroquinazol-4-one

Article abstract of DOI:10.1007/s10600-007-0157-3

The 1,2-dihydro derivative of 2,3-tetramethylene-3,4-dihydroquinazol-4-one was produced by reduction and characterized using NMR spectra. 1-Acyl-1,2,3,4-tetrahydroquinazol-4-ones and ureas were synthesized by acylation of 2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one with acid chlorides and arylisocyanates, respectively. The molecular structures of 1-acetyl-and-m- chlorophenylaminocarbonyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-ones were established using x-ray structure analyses.

Full text of DOI:10.1007/s10600-007-0157-3

Chemistry of Natural Compounds, Vol. 43, No. 4, 2007
CHEMICAL MODIFICATION OF THE ALKALOID
2,3-TETRAMETHYLENE-3,4-DIHYDROQUINAZOL-4-ONE
Kh. M. Shakhidoyatov, Z. U. Samarov, N. I. Mukarramov,
M. G. Levkovich, N. D. Abdullaev, B. Tashkhodzhaev,
Yasser Barakat, and B. A. Urakov
UDC 547.944/945 547.856.1
The 1,2-dihydro derivative of 2,3-tetramethylene-3,4-dihydroquinazol-4-one was produced by reduction and
characterized using NMR spectra. 1-Acyl-1,2,3,4-tetrahydroquinazol-4-ones and ureas were synthesized by
acylation of 2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one with acid chlorides and arylisocyanates,
m
respectively. The molecular structuresof1-acetyl-and- -chlorophenylaminocarbonyl-2,3-tetramethylene-
1,2,3,4-tetrahydroquinazol-4-ones were established using x-ray structure analyses.
13
Key words: 2,3-tetramethylene-2,3-dihydro(1,2,3,4-tetrahydro)quinazol-4-one, alkaloids, PMR and C NMR
spectroscopy, XSA, acylation, reduction, nucleophilic substitution.
The chemistry of 2,3-tetramethylene-3,4-dihydroquinazol-4-one (6,7,8,9-tetrahydropyrido[2,1- ]quinazolin-11-one)
b
(1) and quinazoline (2) alkaloids is little studied. These compounds are isolated from the plants
Philipson
Mackinlaya subulata
and
(Araliaceae) and are six-membered analogs of the alkaloids deoxyvasicinone and deoxypeganine [1, 2].
M. makrosciadia
Mutual transformations of 1 into 2 by reduction with zinc in acidic medium or oxidation of 2 into 1 are known [1-3].
O
5
5
4
4
3
N
3
N
11
11
7
7
N
N
9
9
1
1
1
2
Alkaloids 1 and 2 have been synthesized. A simple and convenient preparation of them has been developed [3, 4].
The presence of N1 and N3, the activated N1=C2 double bond of the α-methylene, the carbonyl, and the benzene ring
make it possible to perform reactions at N1, C=O, α-CH , and the aromatic ring [2, 4, 5].
2
Although reactions of these functional groups have been well investigated [4, 5], little attention has been paid to the
reactivity of the N=C bond.
Herein we report the reduction of the N=C bond of 1, the elucidation of the structural features of the resulting
13
2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one using PMR and C NMR spectroscopy, and the study of its chemical
transformations.
Reduction of 1 and deoxyvasicinone by NaBH formed their 1,2-dihydro derivatives 2,3-tetramethylene-1,2,3,4-
4
tetrahydroquinazol-4-one (3) and 1,2-dihydrodeoxyvasicinone (4).
O
N
(CH )
2 n
N
H
3, 4
3: n = 2; 4: n = 1
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan,
Tashkent, fax (99871) 120 64 75. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 364-370, July-August, 2007.
Original article submitted April 23, 2007.
0009-3130/07/4304-0441 ©2007 Springer Science+Business Media, Inc.
441

TABLE 1. NMR Spectra of 3, CD3OD, H0 = 400 MHz, 0 = TMS
1H chemical shifts,
13C chemical
shifts, ppm
Atom
ppm
J/Hz*
2
4
4a
5
6
7
4.77
3.02 (He-9), 10.37 (Ha-9)
70.19
166.49
114.75
128.95
118.63
134.92
114.93
148.68
34.26
7.68
6.67
7.23
6.61
7.85 (H-6), 1.57 (H-7), 0.51 (H-8)
7.85 (H-5), 7.20 (H-7), 1.07 (H-8)
1.57 (H-5), 7.20 (H-6), 8.16 (H-8)
0.51 (H-5), 1.07 (H-6), 8.16 (H-7)
8
8a
9e
9a
10e
10a
11e
11a
12e
12a
1.92
1.77
1.74
1.55
1.87
1.47
4.50
2.65
3.02 (H-2), 12.49 (Ha-9), 3.26 (He-10), 2.80 (Ha-10), 1.48 (He-11)
10.37 (H-2), 12.49 (He-9), 3.58 (He-10), 12.70 (Ha-10)
3.26 (He-9), 3.58 (Ha-9), 12.65 (Ha-10), 1.63 (He-11), 3.20 (Ha-11), 1.95 (He-12)
2.80 (He-9), 12.70 (Ha-9), 12.65 (He-10), 3.20 (He-11), 12.70 (Ha-11)
1.48 (He-9), 1.63 (He-10), 3.20 (Ha-10), 12.70 (Ha-11), 2.04 (He-12), 3.58 (Ha-12)
3.20 (He-10), 12.70 (Ha-10), 12.70 (He-11), 4.40 (He-12), 12.61 (Ha-12)
1.95 (He-10), 2.04 (He-11), 4.40 (Ha-11), 13.48 (Ha-12)
23.36
25.45
13.48
3.58 (He-11), 12.61 (Ha-11), 13.48 (He-12)
______
*The coupling partner is indicated in parentheses next to the SSCC.
H 12e
J12 a
H 12a
J11a
J11e
J10 a
J12 e
J11a
J11e
H 2
J9a
J9e
H 11e
H 9e
H 10e
H 11e
H 10a
H 9a
2.7
2.6
2.5
2.4
2.3
2.2
2.1
2.0
1.9
1.8
1.7
1.6
1.5
ppm
4.8
4.7
4.6
4.5
Fig. 1. Proton resonances of the cyclohexane ring in the PMR spectrum of 3.
The PMR spectrum of 3 in CD OD exhibited several characteristic groups of resonances. The aromatic protons
3
appeared as a typical four-spin system for an o-substituted benzene ring.
Table 1 and Fig. 1 show the PMR spectrum of 3.
All SSCC were clearlyvisible in the resonances of aromatic protons. Chemical shifts of aromatic protons of 3 showed
a slight weak-field shift compared with those of its five-membered analog 1,2-dihydrodeoxyvasicinone (4). Protons H-6 and
H-8 underwent the greatest shifts (0.12 and 0.13 ppm, respectively). Therefore, these protons were sensitive to the electronic
state of the molecule in general and to the conformation of the cyclopentane and cyclohexane rings, with the first factor perhaps
3
being dominant. The resonance of H-2 was a doublet of doublets at 4.77 ppm with J = 3.02 and 10.37 Hz with two vicinal
SSCC to H -9 and H -9, respectively.
e
a
Of the four cycloalkane methylenes, only protons H-12 exhibited isolated and non-overlapping multiplets for H -12
e
at 4.50 and H -12 at 2.65 ppm.
a
442

J = 1 .4 8 H z
C 1 0
H 9 e
1
2
8
C 9
1 0
9
3
H 11 e
C 11
4
1 2
5
11
C 1 2
H 1 2 e
C 1 0
H 1 0 e
C 11
J = 1 .9 5 H z
Fig. 2. Two W-fragments in the structure of 3.
The resonance of equatorial proton H -12 was split into 10 lines due to coupling with four protons; J = 13.48,
2
e
3
4
4
J = 4.40, 2.04 Hz, and J = 1.95 Hz. The observation of SSCC J = 1.95 Hz between H -12 and H -10 indicated that the
e
e
planar fragment consisting of H -12, C12, C11, C10, and H -10 was conformationally rigid with a W-configuration. Axial
e
e
2
3
proton H -12 formed a typical multiplet with three SSCC J = 13.48 and J = 12.61 and 3.58 Hz with H -12, H -11, and H -11,
a
e
a
e
respectively.
The remaining six methylene protons on C9, C10, and C11 formed three groups of2Hoverlapping multiplets. A series
of differential double resonance experiments and calculation of resonance structures using the integration program LAME for
calculating PMR spectra managed to reproduce the spectral properties of all coupled protons (Table 1).
4
Through-space spin—spin coupling through four bonds J = 1.48 Hz was observed for H -9 and H -11. Therefore, two
e
e
W-shaped couplings were formed in the saturated ring. This fact and the clearly resolved SSCC structure confirmed that this
cyclohexane ring had a relatively stable chair conformation. Furthermore, the SSCC of H-2 with two H-9 protons agreed well
3
3
with trans-axial ( J
= 10.37 Hz) and gauche ( J
= 3.02 Hz) couplings between them (Fig. 2).
H -9
H -9
a
e
13
The C NMR spectrum of 3 in CD OD showed 12 resonances, 7 in the aromatic region and 5 in the cyclohexane
3
region. Table 1 gives the resonance assignments. Their properties were consistent with the proposed structure ofthe compound.
Comparison of the spectral properties of 3 and 4 showed that resonances of the methylenes situated in the α-position
to N-3 (H-12 in 3 and H-11 in 4) underwent the greatest changes. In 3, the difference in chemical shifts for the protons of this
geminal pair was 1.85 ppm. The reason for this was the more distinct axial and equatorial orientation of H -12 and H -12
a
e
relative to the carbonyl and the unshared pair of the N atom than in 4. In 4, this difference in chemical shifts was 0.1 ppm.
For all remaining geminal pairs in both 3 (Table 1) and 4 [6], the shift was less than 0.4 ppm.
Acylation of 2-aryl-3H-(benzyl, aryl)-1,2,3,4-tetrahydroquinazol-4-ones by acetic or trifluoroacetic anhydrides and
adamantylcarboxylic and acetic acid chlorides is known to give the N-1 acyl derivatives [7]. Acylation of other simple
1,2,3,4-tetrahydroquinazol-4-oneshasnotbeen reported. Ithasbeen reportedthatacylationof1,2,3,4-tetrahydroquinazol-4-one
by chloroacetylchloride in acetone in the presence of K CO formed the 1-chloroacetyl derivative [8]. Acylation of1,2-dihydro-
2
3
deoxyvasicinone (4) with acetic anhydride and benzoylchloride also occurred at N-1 [9].
Weinvestigatedacylation of3with aceticanhydride, benzoylchloride,4-nitrobenzoylchloride, andchloroacetylchloride.
Acylation with acetic anhydride occurred without a catalyst if an excess of the anhydride was used and formed 1-acetyl-2,3-
tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (5).
O
O
N
N
RCOX
N
N
H
COR
5 - 7
3
X = CH3COO, Cl
p
5: R = CH3; 6: R = C6H5; 7: -NO2-C6H4
443

TABLE 2. Bond Lengths (r, Å) and Angles (ω, deg) in 5 and 16
Bond
r5
R16
Angle
ω5
ω16
O(1)-C(4)
O(2)-C(13)
N(1)-C(13)
N(1)-C(8a)
N(1)-C(2)
1.229 (3)
1.215 (3)
1.375 (3)
1.422 (3)
1.456 (3)
1.355 (3)
1.461 (3)
1.469 (3)
1.515 (3)
1.479 (3)
1.391 (3)
1.393 (3)
1.370 (4)
1.376 (4)
1.383 (4)
1.380 (3)
1.520 (3)
1.520 (4)
1.515 (4)
1.241 (3)
1.219 (3)
1.396 (3)
1.422 (3)
1.465 (3)
1.343 (3)
1.473 (3)
1.464 (3)
1.520 (4)
1.491 (4)
1.391 (4)
1.403 (4)
1.378 (4)
1.378 (5)
1.387 (4)
1.391 (4)
1.536 (4)
1.527 (4)
1.522 (4)
1.498 (4)
1.362 (3)
1.390 (3)
1.396 (4)
1.411 (3)
1.376 (4)
1.382 (4)
1.375 (4)
1.378 (4)
1.748 (3)
C(13)-N(1)-C(8a)
C(13)-N(1)-C(2)
C(8a)-N(1)-C(2)
C(4)-N(3)-C(12)
C(4)-N(3)-C(2)
124.58 (19)
118.65 (18)
116.25 (17)
119.9 (2)
123.34 (19)
112.52 (19)
109.86 (17)
115.21 (19)
109.46 (18)
122.4 (2)
121.7 (2)
115.9 (2)
119.0 (2)
119.7 (2)
121.2 (2)
120.7 (3)
119.5 (2)
121.1 (3)
119.1 (2)
120.4 (2)
122.6 (2)
117.0 (2)
109.6 (2)
111.4 (2)
111.2 (2)
109.2 (2)
120.3 (2)
120.4 (2)
119.2 (2)
127.1 (2)
114.7 (2)
118.1 (2)
121.1 (2)
123.8 (2)
112.2 (2)
110.9 (2)
115.6 (2)
109.0 (2)
122.3 (3)
121.7 (2)
116.0 (2)
119.5 (3)
119.0 (2)
121.5 (2)
120.9 (3)
119.3 (3)
121.1 (3)
119.7 (3)
119.3 (2)
123.4 (2)
117.2 (2)
108.5 (3)
111.8 (2)
111.8 (3)
109.2 (3)
N(3)-C(4)
C(12)-N(3)-C(2)
N(1)-C(2)-N(3)
N(3)-C(12)
N(3)-C(2)
N(1)-C(2)-C(9)
C(2)-C(9)
N(3)-C(2)-C(9)
C(4)-C(4a)
C(4a)-C(5)
C(4a)-C(8a)
C(5)-C(6)
O(1)-C(4)-N(3)
O(1)-C(4)-C(4a)
N(3)-C(4)-C(4a)
C(5)-C(4a)-C(8a)
C(5)-C(4a)-C(4)
C(8a)-C(4a)-C(4)
C(6)-C(5)-C(4a)
C(5)-C(6)-C(7)
C(6)-C(7)
C(7)-C(8)
C(8)-C(8a)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
C(13)-C(14)
C(13)-N(14)
C(14)-C(19)
C(14)-C(15)
C(14)-N(14)
C(15)-C(16)
C(16)-C(17)
C(17)-C(18)
C(18)-C(19)
C(18)-C1(1)
C(8)-C(7)-C(6)
C(8a)-C(8)-C(7)
C(8)-C(8a)-C(4a)
C(8)-C(8a)-N(1)
C(4a)-C(8a)-N(1)
C(10)-C(9)-C(2)
C(9)-C(10)-C(11)
C(12)-C(11)-C(10)
N(3)-C(12)-C(11)
O(2)-C(13)-N(1)
O(2)-C(13)-C(14)
N(1)-C(13)-C(14)
O(2)-C(13)-N(14)
O(2)-C(13)-N(1)
N(14)-C(13)-N(1)
C(19)-C(14)-C(15)
C(19)-C(14)-N(14)
C(15)-C(14)-N(14)
C(16)-C(15)-C(14)
C(15)-C(16)-C(17)
C(18)-C(17)-C(16)
C(17)-C(18)-C(19)
C(17)-C(18)-C1(1)
C(19)-C(18)-C1(1)
C(18)-C(19)-C(14)
C(13)-N(14)-C(14)
123.9 (2)
120.0 (2)
116.1 (2)
119.4 (2)
122.9 (2)
117.7 (2)
120.0 (3)
121.3 (3)
117.9 (3)
122.6 (3)
119.3 (2)
118.1 (2)
118.9 (3)
124.9 (2)
444

TABLE 3. Chemical Shifts in PMR Spectra of 6, 7, and 17 (DMSO, HMDS = 0, ppm, J/Hz)
Compound
Compound
Atom
Atom
6
7
17
6
7
17
2
5.66
7.85
5.67
7.88
5.66
7.84
12a
NH
CH3
2.87
2.29
2.86
9.00
2.19
5
6
7.16
7.20
7.10
7
7.16
7.20
7.40
-COC6H5
5H, 7.35
8
6.63
6.72
7.29
-COC6H4NO2-p
-CONHC6H4CH3-p
2H, 7.63, 2H, 8.14
9-11
12e
1.10-1.90
5.48
1.10-1.90
4.52
1.10-1.90
4.48
2H, 7.02, 2H, 7.28
TABLE 4. Spin-Spin Coupling Constants for Protons of 6, 7, and 17
Atom
SSCC, Hz
Atom
SSCC, Hz
1.0 (H-6), 8.0 (H-7)
2
5
6
7
9.4 (H-9)
8
8.0 (H-6), 1.8 (H-7)
12e
12a
13.0 (H-12a), 4.0 (H-11e), 3.0 (H-11a)
13.0 (H-12e), 11.5 (H-11a), 3.5 (H-11e)
8.0 (H-5), 7.5 (H-7), 1.0 (H-8)
1.8 (H-5), 7.5 (H-6), 8.0 (H-8)
______
The coupling partner is indicated in parentheses next to the SSCC.
The structure of 5 was established by an x-ray structure analysis (XSA) in addition to IR and PMR spectra. Figure 3
andTable2givethemolecular structure of5 and its experimentallydetermined geometric parameters (bondlengthsandangles),
respectively. Figure 3 shows that the aromatic ring, like in other quinazolines, is planar (within ±0.014 Å) whereas the
cyclohexane ring adopts an ideal chair conformation. This is consistent with the conformation proposed on the basis ofthe PMR
data for 3. The pyrimidine ring with the acetyl group is slightly distorted and has the twist—boat conformation (a two-fold
symmetry axis passes through the middle of the C4–C4a and N1–C2 bonds). The planar acetyl group (±0.006 Å) is slightly
rotated (16.3°) relative to the plane of the N1 bonds (±0.022 Å). This indicates that the π-electrons of the carbonyl may be
2
conjugated with the unshared pair on N1 with
-hybridization (like in amides).
sp
We showed that acylation of 3 by benzoylchloride in CHCl occurred at N1 and gave 1-benzoyl-2,3-tetramethylene-
3
1,2,3,4-tetrahydroquinazol-4-one (6). Under similar conditions, 3 was acylated by 4-nitrobenzoylchloride to give
1-(4-nitrobenzoyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (7).
The structures of 5-7 were confirmed by spectral methods. Thus, the IR spectrum of 5 contained an absorption band
for carbonyl at 1646 cm−1; of 6, at 1647 cm−1.
The PMR spectra of 6, 7, and the product from reaction of 3 and 4-tolylisocyanate (17, see below) were typical of
quinazolones. Of the aromatic protons, H-5 was particularly noteworthy because of its weak-field shift and appearance at
7.85 ppm. In 6 and 7, the aromatic protons formed a symmetric structure that could be recognized as AB C. The chemical
2
shifts of H-6 and H-7 were the same whereas that of H-8 was almost a mirror reflection of the H-5 resonance relative to the
combined resonance of H-6 and H-7. In general, these resonances gave a typical symmetric structure with doublets (J ≈ 8.0 Hz)
at the edges and a 2H triplet in the middle. In 17, H-6 and H-8 formed an asymmetric structure that was more typical of 3 near
7.2 ppm. For 6, the aromatic protons of the benzene ring formed a single slightly broadened singlet at 7.35 ppm. In 7 and 17,
the aromatic ring of the substituent appeared as two characteristic 2H doublets with an -constant of about 8.0 Hz. The most
o
significant difference in the spectra of 6, 7, and 17 from that of 3 was the weak-field shift of H-8 (by 0.5 ppm) due to the effect
of the acyl group on N1.
The cyclohexane part of the spectra of 6, 7, and 17 showed three isolated resonances (H-2, H -12, and H -12) and a
e
a
common 6H multiplet at 1.10-1.90 ppm (Table 3).
Table 4 gives the indirect SSCC for all three compounds and shows that they are rather well repeated.
445

We recently showed that the Cl of 1-chloroacetyl-1,2-dihydrodeoxyvasicinone is labile and susceptible to nucleophilic
substitution [6]. This compound was prepared by chloroacetylation of 4. We decided to study the reaction of 3 with
chloroacetylchloride in order to expand this reaction to 2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one derivatives.
Acylation in benzenesolution in thepresenceofEt Ntobind released HCl produced 1-chloroacetyl-2,3-tetramethylene-
3
1,2,3,4-tetrahydroquinazol-4-one (8).
O
O
O
N
N
N
ClCOCH Cl
RR NH
1
2
N
N
N
H
COCH Cl
COCH NRR
2 1
2
3
9 - 12
8
9: R = R1 = CH3; 10: R = R1 = C2H5; 11: R + R1 = (CH2)2O(CH2)2; 12: R + R1 = (CH2)5
Nucleophilic sustitution of the Cl in 8 was studied using its reaction with aliphatic and heterocyclic amines. This
reaction went smoothly to form 1-dimethyl-, -diethylamino-, -morpholino-, and -piperidinoacetyl-2,3-tetramethylene-1,2,3,4-
tetrahydroquinazol-4-ones (9-12) in good yields.
The possible substitution of Cl by other nucleophilic reagents was studied by reacting 1-chloroacetyl-2,3-
tetramethylene-1,2,3,4-tetrahydroquinazol-4-onewith metal alkoxides, phenoxide, cyanide, selenide, and anionsofcompounds
with an activated methylene (acetoacetic, cyanacetic, and malonic esters and acetylacetone). However, like for 1-chloroacetyl-
1,2-dihydrodeoxyvasicinone [6], this produced 2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one. Because reactions with
nucleophilic reagents can involve the Cl (substitution) or the amide (transamidation or cleavage of acetyl), the reaction for these
nucleophilic reagents occurred with cleavage of the chloroacetyl and formation of 3.
Next we investigated the reaction of 3 with isocyanates and isothiocyanates.
Compound 3 reacted with isocyanates and isothiocyanates to form the corresponding quinazoline ureas and thioureas
(13-17).
O
O
N
N
+ RNCX
N
N
H
CXNHR
3
13 - 17
13: R = C6H5, X = S; 14: R = o-NO2-C6H4, X = O
15: R = o-Cl-C6H4, X = O; 16: R = m-Cl-C6H4, X = O
17: R = p-CH3-C6H4, X = O
We used 2-nitro-, 2-, 3-chlorophenyl-, and 4-tolylisocyanates and phenylisothiocyanate as the isocyanates and
isothiocyanate. Compound 3 reacted with phenylisothiocyanate to form the corresponding thiourea 13.
The reaction proceeded smoothly with heating of a 1:2 ratio of reagents in benzene without a catalyst. The ability to
perform this reaction without catalyst, in particular Et N that is often used for these purposes, was indicative of the rather high
3
basicity of the N atom in 3.
The structures of 13-17 were confirmed by IR and PMR spectra. The IR spectra of 14-17 had absorption bands at
1681-1648, 1628-1647, and 3434-3390 cm −1. The absorption band of the 4-carbonyl in 13 appeared at 1694 cm −1; of NH,
at 3185 cm −1
.
The structures of 13-17 were established using 16 as an example by x-ray structure analysis (XSA). Figure 4 and
Table 5 give the molecular structure of 16 projected along the N1 bond (the same projection as in Fig. 4) and the experimentally
determined geometric parameters, respectively.
446

TABLE 5. Crystallographic and X-ray Structure Data for 5 and 16
Structure
Molecular formula
5
16
C14H16N2O2
244.29
C19H18N3O2Cl
355.81
MW/g·mol
System
Space group
Monoclinic
P21/n
Triclinic
P-1
Z
a,
b,
c,
α
4
2
12.512 (3)
7.4160 (15)
13.919 (3)
90
104.55 (3)
90
9.229 (2)
9.334 (2)
11.787 (2)
111.93 (3)
91.75 (3)
111.35 (3)
860.8 (3)
1.373
β
γ
3
V,
1250.1 (4)
1.298
ρ, g/cm3
Crystal size, mm
0.70×0.55×0.25
2.0≤θ≤25.0°
0.088
0.85×0.20×0.20
1.9≤θ≤25.0°
0.240
2θ scan range
1
µ
exp, cm−
Number of reflections
2200
3028
Number of reflections with I > 2σ(I)
1635
2204
R1 (I>2σ (I) and total)
wR2
S
0.0485 (0.0759)
0.1056 (0.1255)
1.005
0.0520 (0.0810)
0.0974 (0.1129)
1.144
3
3
−
Electron density difference peaks
0.16 and -0.15 e.
0.19 and -0.21 e.
O 1
C 11
C 10
C 12
C 11
C 4
N 3
C 5
C 6
C 4a
C 8a
C 9
O 1
C 2
C 1 2
C 1 0
C 7
C 8
N 1
C 5
C 4
C 9
N 3
C 4 a
C 13
C 6
C 2
O 2
C 8 a
C 7
N 1
N 14
C 8
C 14
C 15
C 1 3
C 1 4
C 19
C 18
O 2
C 16
C l 1
C 17
Fig. 3. Molecular structure and atomic numbering of 5.
Fig. 4. Molecular structure and atomic numbering of 16.
The conformation of the quinazoline ring and the location of the carbonyl relative to this ring in 16 are identical to
those observed in 5. The planar aminoacyl group (±0.042 Å) is rotated by 18.1° relative to the plane of the N1 bonds
(±0.003 Å) whereas the 2-chlorobenzene ring (±0.008 Å) is rotated relative to the plane of the aminoacyl group by 25.9°.
Comparison of equivalent bond lengths and angles in 16 and 5 (Table 2) did not reveal significant differences in their values
with the exception of the bond angles of N1, which was probably due to steric differences in the substituents on it.
447

EXPERIMENTAL
IR spectra were recorded on a Model 2000 Fourier IR spectrometer (Perkin—Elmer) in pressed KBr disks. Mass
spectra were recorded in MX-1310 and MS25,30RS spectrometers (Kratos) at ionizing potential 70 eV, source temperatures
250 and 210°C, direct injection of probe temperature 120°C, and accelerating potential 4 kV. NMR spectra were recorded on
1
13
a UNITY-400+ spectrometer at operating frequency 400 MHz for H and 100 MHz for C. Samples were prepared in CD OD
3
and DMSO-d with TMS (0 ppm) internal standard. Spectra were recorded at room temperature.
6
X-ray Structure Analysis. Unit-cell constants of crystals of 5 and 16 were determined and refined on a Stoe Stadi-4
diffractometer (T = 300 K, graphite monochromator). Table 5 gives the main parameters of the XSA and the calculations. A
three-dimensional set of reflections was obtained on the same diffractometer by ω/2θ-scanning using MoKα-radiation.
Absorption corrections were not applied.
The structures of 5 and 16 were solved by direct methods using the SHELXS-97 programs and refined using the
2
SHELXL-97 programs. All nonhydrogen atoms were refined by full-matrix anisotropic least-squares methods (over F ).
Positions of H atoms were found geometrically and refined using fixed isotropic thermal parameters U = nU , where n = 1.5
iso
eq
for methyls and 1.2 for others and U is the equivalent isotropic thermal parameter of the corresponding C atoms. Methyl H
eq
atoms in 5 were found in a difference electron density synthesis.
Data from the XSA were deposited as CIF files in the Cambridge Crystallographic Data Centre (CCDC 635629 and
635630).
2,3-Tetramethylene-3,4-dihydroquinazol-4-one (1) was prepared by the literature method [4].
2,3-Tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (3). A solution of 1 (1 g, 5 mmol) in alcohol (20 mL) was
treated with NaBH (1 g, 26 mmol) and heated on a water bath for 6 h. Solvent was distilled off. The solid was treated with
4
water until it dissolved and was extracted with CHCl (3 × 100 mL). The organic layer was dried over anhydrous Na SO . The
3
2
4
CHCl was distilled off. The solid was recrystallized to afford 3 (0.89 g, 89%), mp 135°C (water), R 0.65 (Silufol,
f
3
benzene:acetone, 5:2). IR spectrum (ν, cm −1): 1629 (CO).
1-Acetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (5). Compound 3 (1 g, 4.9 mmol) was dissolved in
acetic anhydride (10 mL), heated on a water bath for 3 h, treated with water, neutralized with aqueous NaHCO (20%), and
3
extracted with CHCl (3 × 50 mL). The CHCl was distilled off. The solid was recrystallized to afford 5 (1.06 g, 87%),
3
3
mp 130°C (hexane), R 0.68 (Silufol, benzene:acetone, 5:2). IR spectrum (ν, cm −1): 1672 (CO). Mass spectrum (m/z, %): 244
f
+
+
+
(20) [M] , 201 (45) [M - 1] , 200 (100) [M - 2] , 185 (25), 173 (25), 160 (23), 147 (19), 146 (40), 119 (30).
1-Benzoyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (6). A solution of 3 (1 g, 4.9 mmol) in CHCl
3
(50 mL) was treated with benzoylchloride (1 mL, 9 mmol), heated and stirred on a water bath for 3 h, and treated with aqueous
NaOH (10%). The organic layer was separated, washed with water (3 times), and dried over MgSO . The CHCl was distilled
4
3
off. The solid was recrystallized to afford 6 (1.14 g, 78%), mp 181°C (Et O), R 0.68 (Silufol, benzene:acetone, 5:2).
f
2
IR spectrum (ν, cm −1): 1647 (CO).
1-(4-Nitrobenzoyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (7) was prepared analogously as above
from 3 (1 g, 4.9 mmol) and 4-nitrobenzoylchloride (1.67 g, 9 mmol) to afford 7 (1.35 g, 80%), mp 184°C, R 0.77 (Silufol,
f
benzene:acetone, 5:2). IR spectrum (ν, cm −1): 1647 (CO).
1-Chloroacetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (8). Asolution of3(2.4g, 12mmol)andEt N
3
(1.2 mL, 8.6 mmol) in benzene (30 mL) was stirred, treated dropwise with chloroacetylchloride (1.81 mL, 24 mmol) in benzene
(5 mL), and heated on a water bath for 3 h. The resulting precipitate was filtered off. Solvent was distilled off. The solid was
washed with water, dried, and recrystallized from hexane to afford 8 (2.6 g, 79%), mp 158-160°C, R 0.73 (Silufol,
f
+
+
CHCl :CH OH, 10:1). IR spectrum (ν, cm −1): 1645 (CO). Mass spectrum (m/z, %): 278/280 (8) [M] , 277/279 (5) [M - 1] ,
3
3
244 (22), 243 (60), 201 (26), 200 (13), 174 (25), 160 (100), 119 (23).
1-Dimethylaminoacetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one(9). Amixtureof7(0.4g, 1.4mmol)
in alcohol (10 mL) and aqueous dimethylamine (0.5 mL, 8.4 mmol, 33%) was heated on a water bath for 4 h, cooled, diluted
with water, and extracted with CHCl (3×). The extract was dried over Na SO . Solvent was distilled off. The solid was
3
2
4
reprecipitated from hexane to afford 9 (0.3 g, 70%), R 0.73 (Silufol, CHCl :CH OH, 10:1). IRspectrum (ν, cm −1): 1645 (CO),
f
3
+
3
+
+
2995 (CH ). Mass spectrum (m/z, %): 287 (22) [M] , 286 (10) [M - 1] , 285 (13) [M - 2] , 243 (21), 229 (7), 228 (13), 202
Ar
(100), 201 (23), 200 (19), 175 (89), 161 (48), 119 (26).
448

1-Diethylaminoacetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (10). Amixtureof7(0.4g, 1.4mmol)
and diethylamine (0.44 mL, 4.2 mmol) in benzene (10 mL) was boiled on a water bath for 3.5 h, cooled, and washed with water
(3×). The organic layer was dried over Na SO . Solvent was distilled off. The solid was reprecipitated from hexane to afford
2
4
10 (0.32 g, 72%), R 0.64 (Silufol, CHCl :CH OH, 10:1). IR spectrum (ν, cm −1): 1645 (CO), 2995 (CH ).
f
3
3
Ar
1-Morpholinoacetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (11) was prepared analogously to that
above from 7 (0.4 g, 1.4 mmol) and morpholine (0.34 mL, 4.2 mmol) to afford 11 (0.35 g, 73%), mp 135-137°C (hexane),
R 0.62 (Silufol, CHCl :CH OH, 10:1). IR spectrum (ν, cm −1): 1615 (CO), 2995 (CH ). Mass spectrum (m/z, %): 329 (15)
f
3
+
3
Ar
+
+
[M] , 328 (4) [M - 1] , 327 (6) [M - 2] , 299 (70), 259 (81), 243 (55), 229 (19), 201 (83), 200 (75), 199 (64), 174 (71), 160
(100), 119 (42).
1-Piperidinoacetyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (12) was prepared analogously from 7
(0.4 g, 1.4 mmol) and piperidine (0.37 mL, 4.2 mmol) to afford 12 (0.35 g, 70%) as an oil, R 0.53 (Silufol, CHCl :CH OH,
f
3
3
+
+
+
5:1). Mass spectrum (m/z, %): 327 (18) [M] , 326 (22) [M - 1] , 325 (17) [M - 2] , 243 (48), 229 (9), 228 (17), 202 (89), 201
(83), 200 (75), 160 (100).
1-(2-Chlorophenylaminocarbonyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (15). A solution of 3
(0.25 g, 1.2 mmol) in benzene (25 mL) was treated with o-chlorophenylisocyanate (0.37 g, 2.5 mmol), boiled on a water bath
for 3 h, and left for 1 d. The resulting precipitate was filtered off to afford 15 (0.29 g, 68%), mp 214°C (alcohol), R 0.67
f
(Silufol, benzene:acetone, 5:2). Compounds 13, 14, 16, and 17 were prepared analogously.
1-Phenylaminothiocarbonyl-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (13) was prepared from
3 (0.25 g, 1.2 mmol) and phenylisothiocyanate (0.33 g, 2.5 mmol). Yield 0.12 g (29%), mp 212-214°C (acetone), R 0.68
f
(Silufol, benzene:acetone, 5:2).
1-(2-Nitrophenylaminocarbonyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (14) was prepared from
3 (0.25 g, 1.2 mmol) and o-nitrophenylisocyanate (0.4 g, 2.5 mmol). Yield 0.32 g (71%), mp 195°C (benzene), R 0.68 (Silufol,
f
benzene:acetone, 5:2).
1-(3-Chlorophenylaminocarbonyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (16)wasprepared from
3 (0.25 g, 1.2 mmol) and m-chlorophenylisocyanate (0.37 g, 2.5 mmol). Yield 0.31 g (70%), mp 245°C (alcohol), R 0.68
f
(Silufol, benzene:acetone, 5:2).
1-(4-Tolylaminocarbonyl)-2,3-tetramethylene-1,2,3,4-tetrahydroquinazol-4-one (17) was prepared from 3
(0.25 g, 1.2 mmol) and p-tolylisocyanate (0.34 g, 2.5 mmol). Yield 0.25 g (60%), mp 273°C (alcohol), R 0.68 (Silufol,
f
+
+
+
benzene:acetone, 5:2). Mass spectrum (m/z, %): 335 (14) [M] , 252 (15) [M - 1] , 202 (50) [M - 2] , 201 (100), 185 (19), 174
(30), 173 (50), 147 (33), 146 (58).
ACKNOWLEDGMENT
The work was supported financially by GNTP-10 (State Science and Technology Program).
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1.
2.
3.
J. S. Fitzgerald, S. R. Johns, J. A. Lamberton, and A. H. Redcliefe, Aust. J. Chem., 151 (1966).
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4.
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7.
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9.
Yu. V. Kozhevnikov, O. E. Sattarova, V. S. Zalestov, et al., Khim.-farm. Zh., No. 11, 69 (1982).
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