Modification of the Pictet-Spengler reaction in the synthesis of fused 2,3-benzodiazocines

Article abstract of DOI:10.1007/s10593-011-0867-0

A new strategy for the synthesis of the eight-membered heterocyclic skeleton of tetrahydro-quinazolino[3,2-c][2,3]benzodiazocin-15-ones, based on the Pictet-Spengler reaction of 3-amino-2-[2-(3,4-dimethoxyphenyl)ethyl] quinazolin-4(3H)-one with carbonyl c

Full text of DOI:10.1007/s10593-011-0867-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
MODIFICATION OF THE PICTET–SPENGLER REACTION
IN THE SYNTHESIS OF FUSED 2,3-BENZODIAZOCINES
A. S. Tolkunov1*, V. N. Baumer2, G. V. Palamarchuk2,
O. V. Shishkin2,3, A.V. Mazepa4, S. V. Tolkunov1, and S. L. Bogza1
A new strategy for the synthesis of the eight-membered heterocyclic skeleton of tetrahydro-
quinazolino[3,2-c][2,3]benzodiazocin-15-ones, based on the Pictet–Spengler reaction of 3-amino-2-[2-
(3,4-dimethoxyphenyl)ethyl]quinazolin-4(3H)-one with carbonyl compounds in acidic media, is
proposed.
Keywords: 3-amino-2-[2-(3,4-dimethoxyphenyl)ethyl]quinazolin-4(3H)-one,
fused diazocines,
hydrochloric acid, tetrahydroquinazolino[3,2-c][2,3]benzodiazocin-15-ones, trifluoroacetic acid,
cyclization, Pictet–Spengler reaction.
2,3-Benzodiazocines are homologs of 2,3-benzodiazepines. Methods used for preparation of
benzodiazepines have been well-developed [1], while benzodiazocines are still not readily available. Only a few
examples for the synthesis of benzodiazocines have been described in the literature, by intramolecular
aziridation of the double bond in 3-aminoquinazolone under the action of lead tetraacetate [2-6], and also by
cyclization of ortho-phenylenedicarbonyl compounds by the action of hydrazine hydrobromide [7-9].
Recently, we reported the synthesis of heteroannellated 2,3-benzodiazepines using the Pictet–Spengler
reaction from 3-amino-2-(3,4-dimethoxybenzyl)quinazolin-4(3H)-one and carbonyl compounds in hydrochloric
or trifluoroacetic acids [10,11]. This method was also used for the synthesis of benzothienodiazepines [12].
With the aim of determining the limits of application of the Pictet–Spengler reaction, we investigated
the possibility of obtaining the eight-membered heterocyclic skeleton of 9,10-dimethoxy-6,7,12,13-tetrahydro-
15H-quinazolino[3,2-c][2,3]benzodiazocin-15-ones 2 by the reaction of 3-amino-2-[2-(3,4-dimethoxyphenyl)-
ethyl]quinazolin-4(3H)-one (1) with carbonyl compounds in acidic media.
_______
*To whom correspondence should be addressed, e-mail: s_tolkunov@yahoo.com.
1L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine.
2Research Branch for the Chemistry of Functional Materials, Institute for Single Crystals of the National Academy
of Sciences of Ukraine, 60 Lenin Ave., Kharkiv 61001, Ukraine; e-mail: shishkin@xray.isc.kharkov.com.
3V. N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv 61077, Ukraine.
4A. V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, 86 Lustdorfskaya
Road, Odessa 65080, Ukraine; e-mail: almazepa@rambler.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1223-1231, August, 2011.
Original article submitted November 10, 2010.
1006
0009-3122/11/4708-1006©2011 Springer Science+Business Media, Inc.

We showed previously that in the synthesis of benzodiazepines the best yields were obtained using
hydrochloric acid as the cyclizing agent [10, 11]. While studying the reaction of formation of diazocines 2a-f,
we discovered that compound 1 in hydrochloric acid reacts well only with paraformaldehyde. The
corresponding diazocine 2a was isolated as the hydrochloride in 87% yield. Reaction with benzaldehydes and
4-pyridinecarboxaldehyde in hydrochloric acid gave low yields of diazocines 2b-d, while isatin and ninhydrin
did not react at all. In trifluoroacetic acid, amine 1 interacts with benzaldehydes, isatin, and ninhydrin, forming
the corresponding 12-substituted benzodiazocines 2b,c,e,f in 35-70% yield (Table 1). However, the reaction
with 4-pyridinecarboxaldehyde in trifluoroacetic acid stopped at the stage of formation of azomethine 3.
Aliphatic aldehydes and pyruvic acid ethyl ester did not react at all.
R
O
H
N
OMe
OMe
+
RCHO, H
N
N
2a–d
O
O
H
N
NH2
N
O
N
O
O
N
N
OMe
OMe
N
H
OMe
N
H
1
CF3CO2H
OMe
4-PyCHO
CF3CO2H
2e
O
OH
OH
O
N
N
O
O
N
N
O
O
CF3CO2H
N
H
OMe
OMe
N
N
OMe
3
OMe
2f
2 a R = H, b R = 4-МеС6Н4, c R = 4-ClС6Н4, d R = 4-Py
It was discovered that under identical conditions the formation of diazocines occurred significantly
more slowly than diazepines. For example, completion of the reaction of compound 1 with aromatic aldehydes
in trifluoroacetic acid required no less than 48 h, while diazepines were usually formed in 6-8 h [10, 11].
On heating amine 1 with benzaldehydes in CF3COOH for 24 h, up to 50% Schiff’s base was present in
the reaction mixture, which is possibly connected with spatial factors (with the large distance from the
azomethine carbon atom to the C(6) atom of the veratrole ring). It is also possible that the low yields of
compounds 2b-d in hydrochloric acid are due to the competing reaction of hydrolysis of the Schiff’s base. On
carrying out the cyclization in hydrochloric acid diazocines 2b-d were isolated in 10-15% yields.
To confirm the structure of compounds obtained, mass spectra with ionization by electron impact were
recorded (Table 2). As it should be seen from the data given, the molecular ion peaks of compounds 2b and 2c
were of low intensity, which reduces the reliability of identifying them. Consequently, to confirm their
structure, mass spectra were recorded using ionization by fast atom bombardment (FAB) in which [M+H]+ ion
peaks of maximum intensity were observed. Irrespective of the method of ionization, the mass spectra of
compounds 2b and 2c were characterized by identical fragment ions. On the basis of the spectra of metastable
ions (B/E and B2/E linked scanning), two main mutually competing directions for the fragmentation A and B
can be distinguished.
1007

TABLE 1. Characteristics of Compounds Synthesized 1-3
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
Cl
—
N
1
С18Н19N3O3
66.58
66.45
5.76
5.89
12.95
12.91
137
63
2a
2b
2c
2d
2e
2f
C19H19N3O3·HCl
C26H25N3O3
60.96
61.04
5.42
5.39
9.39
9.48
11.39
11.24
229
87*
40*2
35*2
10*
65*2
70*2
73.18
73.05
5.96
5.89
—
9.79
9.83
155–156
187–189
208–209
319–320
C25H22ClN3O3
C24H22N4O3
67.21
67.04
5.12
4.95
7.95
7.91
9.21
9.38
69.67
69.55
5.56
5.35
—
—
—
13.63
13.52
C26H22N4O4
68.90
68.71
5.02
4.88
12.38
12.33
C27H21N3O5
69.33
69.37
4.58
4.53
8.89
8.99
270
(decomp.)
3
C24H22N4O3
69.51
69.55
5.47
5.35
—
13.56
13.52
134–135
90
_______
*Cyclizing agent hydrochloric acid.
*2Cyclizing agent trifluoroacetic acid.
R
O
R
+
O
N
.
.
H
N
H
N
OMe
OMe
OMe
N
N
N
OMe
N
– OH
A
B
R
+
O
.
R
H
OMe
OMe
N
OMe
OMe
N+
OMe
OMe
N
+
R
N
N
H
ФB
ФA
Direction A, as is evident from the presented scheme, is connected with the elimination of a hydroxyl
radical by the molecular ions and the formation of ions ФA [M-17]+. Since such a fragment is absent from the
molecules of the compounds being analyzed, it may be assumed that its formation is the result of migration of a
hydrogen atom to the carbonyl group. It is probable that the source of such hydrogen atoms is the NH group of
the neighboring eight-membered ring.
The second factor determining the stability of the molecular ions of compounds 2a-d is the intensity of
the fragmentation in direction B, which leads to the formation of ions ФB with a mass of 176+R. As is seen from
the scheme, this is connected with the decomposition of the eight-membered ring, the ease of proceeding of
which depends on the character of the substituent R. It is evident that electron-donating substituents must
facilitate the stabilization of the cations formed, meaning, to increase the probability of their formation. Such a
proposal is in agreement with the observed change in intensity of the peak of ions ФB in the mass spectra of
compounds 2a-d.
1008

TABLE 2. Mass Spectra of Compounds 2a-f
Com-
pound
m/z (Irel %)
2а
337 [М]+ (34), 322 (21), 321 (30), 320 (100), 306 (22), 305 (57), 277 (10), 191 (2),
186 (11), 177 (19), 176 (18), 161 (13), 160 (17), 77 (13)
2b
427 [М]+ (1), 411 (21), 410 (74), 395 (14), 268 (24), 267 (100), 252 (25)
2с
447 [М]+ (2), 432 (35), 431 (36), 430 (100), 418 (11), 417 (17), 416 (31), 415 (29),
289 (34), 288 (36), 287 (94), 272 (26), 165 (13), 160 (14), 151 (18), 139 (19), 111 ( 11)
2d
2e
2f
414 [М]+ (55), 397 (100), 382 (40), 336 (12), 267 (10), 254 (88), 239 (24), 160 (11),
151 (11)
454 [М]+ (100), 426 (13), 395 (18), 295 (10), 294 (47), 281 (19), 280 (68), 279 (24),
216 (11), 57 (12), 55 (10)
467 [М]+ (58), 334 (14), 320 (27), 308 (25), 307 (11), 293 (20), 132 (16), 105 (20),
104 (100), 76 (18)
2b*
428 [M + H]+ (100), 427 (10), 426 (12), 411 (17), 410 (52), 268 (12), 267 (39)
2с*
448 [M + H]+ (100), 447 (12), 446 (11), 432 (21), 431 (15), 430 (46), 289 (19), 288 ( 11),
287 (28)
_______
*FAB spectra.
For compound 2a, the observed direction of decomposition is brought about to an insignificant extent
by the absence of the stabilizing effect of a substituent on the stability of the resulting fragments. The result of
this is the relatively low intensity of the ФB ion peak (19%). The dominant direction of decomposition in this
case is direction A (intensity of the peak of ions ФA is 100%). Introduction of aromatic fragments as substituent
R significantly increases the probability of carrying out decomposition by direction B, but the relative intensity
of ion peaks ФB is in good agreement with the electron-donating properties of substituent R. As follows from
the data of Table 2 the ratio of intensities of ion peaks ФB and ФA for compound 2b is 1.36, while for
compound 2c this value is 0.94, and for compound 2d 0.88.
Introduction of an isatin fragment almost entirely suppressed the direction of decomposition connected
with elimination of a hydroxyl radical and increased the stability of molecules towards electron impact. Low-
intensity ion peaks were observed in the mass spectrum, formed as a result of the sequential elimination of a
molecule of CO (m/z 426) and a methoxyl radical (m/z 395). The dominant direction of decomposition in this
case was accompanied by cleavage of the eight-membered ring with the formation of fragment ions of m/z 294
and 280, which probably have the structure shown in the following scheme.
+
+
.
H
.
H
N
N
O
N
O
N
O
N
O
N
N
N
OMe
OMe
OMe
OMe
N
OMe
OMe
O
+
m/z 454 [M]+
m/z 280
N
OMe
OMe
O
m/z 294
Me
1009

The direction of decomposition observed for compound 2f is accompanied by complete elimination of
the ninhydrin fragment and the formation of an ion of m/z 104, the peak of which was the maximum in the
spectrum.
+
.
O
O
O
+
N
.
OMe
OMe
H
N
O
N
m/z 104
m/z 467 [M]+
According to the data of X-ray diffraction study the eight-membered heterocycle has a twist-boat
conformation (Fig. 1) The C(6)–C(7) and C(12)–N(13) bonds lying in the base of boat are twisted relative to
one another by -20.2o. The C(5A), C(7), C(11), and N(14) atoms deviate from the mean square plane made
through the atoms of the base by 1.17, 0.98, 1.10, and 0.99 Å respectively. The significant bend of this ring
causes the formation of strong intramolecular shortened contacts: C(5A)…C(11A) 3.16 Å (sum of the van der
Waals radii [13] 3.42 Å), N(14)…C(7A) 3.09 (3.21), N(13)…C(7) 2.80 (3.21), N(13)…H(7B) 2.53 Å (2.66 Å).
The N(13) atom has a pyramidal configuration (sum of valence angles centered on the atom was 335o).
The methoxy groups lay in the plane of the C(7A)–C(11A) benzene ring (the C(11)–C(10)–O(3)–C(17) and
C(8)–C(9)–O(2)–C(16) torsion angles were -0.9(3)o and 9.6(3)o respectively), in spite of shortened contacts
H(8)…H(16C) 2.29 (2.32) and H(11)…H(17B) 2.27 Å (2.32 Å).
Fig. 1. Structure of the compound 2a molecule according to X-ray structural analysis.
In the crystal the 2a molecule is disordered in two orientations differing in the direction of the carbonyl
group with populations 82:18%. This leads to the appearance of intermolecular shortened contacts C(2)…H(13')
(2.5-x, 0.5+y, -0.5-z) 2.67, C(3)…H(13') (2.5-x, 0.5+y, -0.5-z) 2.76, C(3)…H(6'B') (2.5-x, 0.5+y, -0.5-z) 2.74 Å (sum of
van der Waals radii [13] 2.87 Å); H(16C)…H(6'A') (-1+x, y, z) 2.13 Å (sum of van der Waals radii [13] 2.32 Å).
1010

The X-ray structural investigation of 2a hydrochloride (Fig. 2) showed that salt formation led to the
disappearance of disordering in the crystal. Protonation of the N(5) atom of the pyrimidine ring therefore
occurs, which appears to be linked with chloride anion by a strong hydrogen bond N(5)–H(5)…Cl(1) (H…Cl
1.92 Å, N–H…Cl 171o).
Fig. 2. Structure of compound 2a hydrochloride according to data of X-ray structural analysis.
Salt formation has a weak influence on the conformation of the molecule. The twisting of bonds lying
in the base of the boat conformation of the eight-membered ring is somewhat less than in the neutral molecule
(-16.4o), but the deviation of the atoms from the mean square plane through the atoms of the base was somewhat
greater (deviation of atoms C(5A), C(7), C(11), and N(14) were 1.19, 1.05, 1.15, and 1.06 Å respectively).
Some increase was also observed in the pyramidality of the N(13) atom. The sum of the valence angles
centered on the atom in the hydrochloride was 328o.
We have therefore shown that the Pictet–Spengler reaction may be used successfully not only for
obtaining fused benzodiazepines [10, 11], but also for the previously unknown 9,10-dimethoxy-12-R-6,7,12,13-
tetrahydro-15H-quinazolino[3,2-c][2,3]benzodiazocine-15-ones.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker Avance II 400 (at 400 MHz) in DMSO-d6 solution,
internal standard was TMS. Electron ionization mass spectra were recorded on a MX 1321 mass spectrometer at
an ionizing voltage of 70 eV, temperature of ionization chamber 220oC using direct insertion of sample. The
spectra of metastable ions were recorded on a VG7070 mass spectrometer under the same conditions. The FAB
spectra were recorded on the VG7070 mass spectrometer. Desorption of ions from sample solutions in
p-nitrobenzyl alcohol was effected with a pulse of argon atoms with an energy of 8 keV.
Crystals of compound 2a were monoclinic, C19H19N3O3, at 293 K, a 9.826(1) Å, b = 13.633(1) Å,
c = 12.199(1) Å, β = 99.09(1)o, V = 1613.5(2) Å3, Mr = 337.37, Z = 4, space group P21/n, dcalc = 1.389 g/cm3,
μ(MoKα) = 0.096 mm-1, F(000) = 712. Parameters of the unit cell and the intensities of 9072 reflections (2655
independent, Rint = 0.052) were measured on a Xcalibur-3 diffractometer (MoKα radiation, CCD-detector,
graphite monochromator, ω-scanning, 2θmax = 50o).
1011

TABLE 3. 1H NMR Spectra of Compounds Synthesized
Com-
pound
Chemical shifts, , ppm (J, Hz)
1
3.06 (2H, m, ArСН2); 3.24 (2H, m, HetarСН2); 3.76 (3Н, s) and
3.78 (3Н, s, 3',4'-ОСН3); 5.64 (2H, s, NH2); 6.77 (1H, d, J5',6' = 8.0, Н-5');
6.81 (1H, d. d, J6',5' = 8.0, J6',2' =1.6, Н-6'); 6.85 (1H, d, J2',6' = 1.6, Н-2');
7.42 (1Н, t, J = 8.0, Н-6); 7.60 (1Н, d, J = 8.0, Н-8); 7.71 (1Н, t, J = 8.0, Н-7);
8.13 (1Н, d, J = 8.0, Н-5)
2a
2b
3.55 (2Н, m, 7-СН2); 3.69 (2Н, m, 6-СН2); 3.60 (3H, s) and 3.73 (3H, s, 9,10-OCH3);
4.30 (1Н, br. s, NH in exchange with Н2О); 4.41 (2Н, s, 12-CH2); 6.50 (1Н, s, Н-8);
6.78 (1Н, s, Н-11); 7.50 (1Н, t, J = 8.0, Н-2); 7.72-7.83 (2Н, m, H-3,4);
8.20 (1Н, d, J = 8.0, Н-1)
2.34 (3Н, s, СН3); 2.74 (1Н, m) and 3.53 (1Н, m, 7-СН2); 3.10 (1Н, m) and
3.95 (1Н, m, 6-СН2); 3.61 (3H, s) and 3.75 (3H, s, 9,10-OCH3);
5.74 (1Н, d, J = 3.2, 12-CН); 6.53 (1Н, s, Н-8); 6.65 (1Н, d, J = 3.2, NH);
6.71 (1Н, s, Н-11); 7.13 (2Н, d, J = 8.0, Н-3',5'); 7.28 (2Н, d, J = 8.0, Н-2',6');
7.38 (1Н, t, J = 8.0, Н-2); 7.43 (1Н, d, J = 8.0, Н-4); 7.65 (1Н, t, J = 8.0, Н-3);
8.10 (1Н, d, J = 8.0, Н-1)
2c
2.73 (1Н, m) and 3.55 (1Н, m, 7-СН2); 3.09 (1Н, m) and 3.81 (1Н, m, 6-СН2);
2d
2.71 (1Н, m) and 3.59 (1Н, m, 7-СН2); 3.04 (1Н, m) and 3.75 (1Н, m, 6-СН2);
3.66 (3H, s) and 3.74 (3H, s, 9,10-OCH3); 5.85 (1Н, d, J = 3.2, 12-CН);
6.69 (1Н, s, Н-8); 6.71 (1Н, s, Н-11); 7.24 (1Н, d, J = 3.2, NH);
7.37 (1Н, t, J = 8.0, Н-2); 7.41 (2Н, d, J = 4.8, Н-3',5'); 7.44 (1Н, d, J = 8.0, Н-4);
7.65 (1Н, t, J = 8.0, Н-3); 8.09 (1Н, d, J = 8.0, Н-1); 8.49 (2Н, d, J = 4.8, Н-2',6')
2e
2.96 (1H, m) and 3.57 (1H, m, 7-СН2); 3.31 (1H, m) and 4.73 (1H, m, 6-СН2);
3.55 (3H, s) and 3.83 (3H, s, 9,10-OCH3); 6.11 (1H, s, H-8); 6.70 (1H, s, H-11);
6.84 (1H, s, NH); 6.94 (1H, t, J = 7.6, H-6'); 7.00 (1H, d, J = 7.6, H-4');
7.25 (1H, t, J = 7.6, H-5'); 7.29 (1H, d, J = 7.6, H-7'); 7.38 (1Н, t, J = 8.0, Н-2);
7.47 (1Н, d, J = 8.0, Н-4); 7.68 (1Н, t, J = 8.0, Н-3); 8.00 (1Н, d, J = 8.0, Н-1);
10.76 (1H, s, NH)
2f
3
2.92 (1H, m) and 3.55 (1H, m, 7-СН2); 3.22 (1H, m) and 4.65 (1H, m, 6-СН2);
3.45 (3H, s) and 3.82 (3H, s, 9,10-OCH3); 5.97 (1H, s, H-8); 6.91 (1H, s, H-11);
7.40 (1Н, t, J = 8.0, Н-2); 7.46 (1Н, d, J = 8.0, Н-4); 7.69 (1Н, t, J = 8.0, Н-3);
8.01 (1Н, d, J = 8.0, Н-1); 8.03–8.15 (5H, m, H-4',5',6',7' + NH)
3.04 (2H, m, ArСН2); 3.20 (2H, m, HetarСН2); 3.66 (3H, s) and
3.75 (3Н, s, 3',4'-ОСН3); 6.66–6.73 (3H, m, H-2',5',6'); 7.50 (1Н, t, J = 8.0, Н-6);
7.67 (1Н, d, J = 8.0, Н-8); 7.80 (1Н, t, J = 8.0, Н-7); 7.81 (2H, d, J = 5.2, H-3",5");
8.20 (1Н, d, J = 8.0, Н-5); 8.75 (2H, d, J = 5.2, H-2",6"); 9.10 (1H, s, CH=N)
Crystals of compound 2a hydrochloride were monoclinic, C19H20ClN3O3, at 293 K, a = 9.131(1),
b = 14.817(4), c = 13.633(3) Å, β = 95.65(2)°, V = 1835.5(6) Å3, Mr = 373.83, Z = 4, space group P21/n,
d
calc = 1.353 g/cm3, μ(MoKα) = 0.232 mm-1, F(000) = 784. Parameters of the unit cell and intensities of 12268
reflections (3181 independent, Rint = 0.074) were measured on a Xcalibur-3 diffractometer (MoKα radiation,
CCD detector, graphite monochromator, ω-scanning, 2θmax = 50o).
The structures were solved by the direct method using the SHELXTL package [14]. The positions of
hydrogen atoms were located from an electron density difference maps and were refined using "rider" model
with Uiso = nUeq of the non-hydrogen atom linked with the given hydrogen (n = 1.5 for methyl groups and
n = 1.2 for the remaining hydrogen atoms). Structures were refined against F2 by the full-matrix least-squares
method in an anisotropic approximation for non-hydrogen atoms to wR2 = 0.167 for 2655 reflections
(R1 = 0.068 at 1461 reflections with F > 4σ(F), S = 0.934) for compound 2a, and to wR2 = 0.057 for 3166
reflections (R1 = 0.043 for 1284 reflections with F > 4σ(F), S = 0.934) for 2a hydrochloride. The atomic
coordinates, geometric parameters of the molecules, and crytallographic data are deposited in the Cambridge
Crystallographic Data Center as CCDC 784407 (2a) and CCDC 791211 (2a hydrochloride).
3-Amino-[2-(3,4-dimethoxyphenyl)ethyl]quinazolin-4(3H)-one (1) was obtained by the cyclization of
methyl 2-[2-(3,4-dimethoxyphenyl)ethylcarboxamido]benzoate with hydrazine hydrate by the procedure of
[15, 16].
1012

9,10-Dimethoxy-6,7,12,13-tetrahydro-15H-quinazolino[3,2-c][2,3]benzodiazocin-15-one
Hydro-
chloride (2a). Paraformaldehyde (1 mmol) and conc. HCl (4 ml) were added to a solution of amine 1 (1 mmol)
in dioxane (1-2 ml). The mixture was heated at 80oC for 4 h, cooled, water (5 ml) was added, and the mixture
was maintained at -10oC. The precipitate of 2a hydrochloride was filtered off and washed with acetone. Crystals
for X-ray structural analysis were obtained by crystallization from 90% aqueous 2-propanol.
9,10-Dimethoxy-12-(4-pyridyl)-6,7,12,13-tetrahydro-15H-quinazolino[3,2-c][2,3]benzodiazocin-
15-one (2d). 4-Pyridinecarboxaldehyde (1 mmol) and conc. HCl (4 ml) were added to a solution of amine 1
(1 mmol) in dioxane (1-2 ml). The mixture was heated at 80oC for 4 h, cooled, diluted with water, and unreacted
starting amine was filtered off. The filtrate was neutralized with 10% aqueous ammonia solution to a weakly
alkaline reaction. The mixture was left for 1 h, then the precipitated crystals were filtered off and washed with
water. The product was crystallized from a DMF–acetonitrile mixture.
9,10-Dimethoxy-12-R-6,7,12,13-tetrahydro-15H-quinazolino[3,2-c][2,3]ones 2b,c,e,f (General
Method). A mixture of amine 1 (2 mmol) and the corresponding carbonyl compound (2 mmol) in trifluoroacetic
acid (5 ml) was boiled for 48 h. The reaction mixture was cooled, diluted with water and neutralized with 10%
aqueous ammonia solution to weakly alkaline reaction. The reaction mixture was left for 1 h, then crystals were
filtered off, washed with water, and crystallized from a DMF–acetonitrile mixture.
Under these conditions the interaction of amine 1 with 4-formylpyridine leads to 2-[2-(3,4-dimethoxy-
phenyl)ethyl]-3-[(E)-1-(4-pyridyl)methylideneamino]quinazolin-4(3H)-one 3.
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