Anthranoylhydrazones of aliphatic aldehydes and their cyclization to quinazolin-4-one derivatives

Article abstract of DOI:10.1007/s10593-009-0364-x

The isomeric transition of 2-aminobenzoylhydrazones of aliphatic aldehydes 2-H₂NC₆H₄CONHN=CHAlk (Alk = Me, Et, Pr, Bu) in chloroform-d₁ solution into the cyclic 1,2-dihydroquinazolin-4-one form has been studied.

Full text of DOI:10.1007/s10593-009-0364-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
ANTHRANOYLHYDRAZONES OF ALIPHATIC
ALDEHYDES AND THEIR CYCLIZATION TO
QUINAZOLIN-4-ONE DERIVATIVES
A. Yu. Ershov1*, N. A. Lovushkina1, I. V. Lagoda2, S. I. Yakimovich3,
I. V. Zerova3, V. V. Pakal'nis3, and V. V. Shamanin1
The isomeric transition of 2-aminobenzoylhydrazones of aliphatic aldehydes 2-H2NC6H4CONHN=CHAlk
(Alk = Me, Et, Pr, Bu) in chloroform-d1 solution into the cyclic 1,2-dihydroquinazolin-4-one form has
1
been studied. The structure of the obtained compounds was demonstrated by methods of H and
13C NMR spectroscopy.
Keywords: 2-aminobenzoylhydrazones, benzo-1,3,4-triazepines, 1,2-dihydroquinazolin-4(3H)-ones,
ring-chain tautomerism.
Condensation products of carbonyl compounds with N-methyl-N'-(2-aminobenzoyl)hydrazine and
N,N'-dimethyl-N'-(2-aminobenzoyl)hydrazine have a cyclic 1,3,4-triazepine structure [1-6]. On interacting
N-acyl-N'-(2-aminobenzoyl)hydrazine with carbonyl compounds derivatives of 1,2-dihydroquinazolin-4-one are
formed [7, 8]. The products of reaction of 2-aminobenzoylhydrazine unsubstituted at the hydrazine nitrogen
atom were assigned a linear structure [7-11]. The formation of possible cyclic forms as a result of intramolecular
attack by the nitrogen atom of the NH2 group at the C=N bond of the hydrazone fragment was not considered.
The aim of the present work was to study the structure of 2-aminobenzoylhydrazones of a series of
aliphatic aldehydes 2a-d, and also their inclination towards different variants of cyclization in solution leading
to the formation of ring forms.
Compounds 2a-d were obtained in 55-75% yield after briefly maintaining 2-aminobenzoylhydrazide
and the appropriate aldehyde in benzene at 25oC (see Table 1 and Experimental).
_______
* To whom correspondence should be addressed, e-mail: ershov@hq.macro.ru.
1Institute of Macromolecular Compounds, Russian Academy of Sciences, Saint Petersburg 199004, Russia.
2Scientific Research Test Center (Medical and Biological Protection) of the State Research Test Institute of
Military Medicine, Defence Ministry of Russian Federation, Saint Petersburg 195043, Russia; e-mail:
lagodai@peterst ar.ru.
3Saint Petersburg State University, Saint Petersburg 198504, Russia; e-mail: viktoriapakalnis@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1214-1219, August, 2009.
Original article submitted October 17, 2008.
0009-3122/09/4508-0965©2009 Springer Science+Business Media, Inc.
965

O
O
R
H
O
H
H
N
N
N
N
RCH=O
NH
NH2
H
NH2
NH2
N
R
H
1
B
2a–c A
O
O
O
NHCOPh
BzCl
(2a)
NH2
N
N
NHNH2
R
–HCl
N
H
Me
N
H
R
N
3
2a–d D
H
C
a R = Me, b R = Et, c R = Pr, d R = Bu
Judging by the change in 1H NMR spectra with time, compounds 2a-c in the crystalline state were found
to be in the linear hydrazone form A. In the 1H NMR spectra of compounds 2a-c taken directly after solution in
CDCl3 one set of resonance signals was observed corresponding to this form. In this a low field signal shows the
13
azomethine proton of appropriate multiplicity at 7.5 ppm (Table 2). In the C NMR spectra signals at 150 and
160 ppm, characteristic of carbon atoms at C=N and C=O bonds respectively (Table 3), correspond to the linear
form A. The position of these signals enables a conclusion to be made between the possible E,E'- and E,Z'-
conformational isomers of the linear form A in favor of the E,Z'-isomer. It is known that analogous signals of
the E,E'-conformer for acylhydrazones of aldehydes lie at 145 and 170 ppm respectively [12, 13]. The existence
of E,Z-configurational isomerism relative to the C=N bond was not considered by us, since aldoacylhydrazones
exist predominantly in the E-configuration relative to this bond [12-15].
1
Several hours after dissolving compounds 2a-c in CDCl3 signals appeared in the H NMR spectra
corresponding to the cyclic 1,3,4-triazepine form B. Typical features of this form, the content of which did not
exceed 10% for the compounds investigated, are a low-field signal for the NH group proton at 9.0 ppm and a
signal of appropriate multiplicity at 5.0 ppm (H-2) (Table 2). In the 13C NMR spectra the signal of the sp3-hybrid
atom at 70 (C-2) and the signal at 170 ppm (C-5) (Table 3) correspond to the triazepine form B.
TABLE 1. Physicochemical Characteristics of Compounds 2a-d
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
Form
mp, °C
С
H
N
2а
А
C9H11N3O
60.93
61.00
6.30
6.26
23.64
23.71
149-151
(150 [9])
55
D
А
D
А
D
D
C9H11N3O
C10H13N3O
C10H13N3O
C11H15N3O
C11H15N3O
C12H17N3O
61.07
61.00
62.78
62.81
62.87
62.81
64.42
64.37
64.31
64.37
65.80
65.73
6.22
6.26
6.79
6.85
6.91
6.85
7.31
7.37
7.44
7.37
7.75
7.81
23.78
23.71
22.06
21.97
21.89
21.97
20.54
20.47
20.56
20.47
19.21
19.16
Oil
140-143
Oil
98
75
98
60
99
65
2b
2c
2d
83-85
Oil
Oil
966

TABLE 2. 1H NMR Spectra of Compounds 2a-d
Com-
pound
Chemical shifts, δ, ppm (SSCC, J, Hz)*
2a
2b
2c
А (93%):
2.03 (3H, d, J = 5.4, СН3); 5.44 (2H, br. s, NH2); 6.58-7.36 (4H, m, Ar);
7.53 (1H, q, J = 5.4, HC=N); 9.34 (1H, br. s, NHCO)
B (7%):
1.35 (3H, d, J = 5.1, СН3); 4.51 (2H, br. s, 2NH); 5.18 (1H, q, J = 5.1, H-2);
8.96 (1H, br. s, NHCO)
D:
1.41 (3H, d, J = 6.2, СН3); 4.27 (2H, br. s, NH2); 4.38 (1H, br. s, NH);
4.92 (1H, q, J = 6.2, H-2); 6.52-7.76 (4H, m, Ar)
А (95%):
1.73 (3H, t, J = 5.4, СН3); 2.40 (2H, m, СН2); 5.45 (2H, br. s, NH2);
6.58-7.35 (4H, m, Ar); 7. 47 (1H, t, J = 5.0, HC=N); 9.06 (1H, br. s, NH)
B (5%):
0.93 (3H, t, J = 7.5, СН3); 2.26 (2H, m, СН2); 4.47 (2H, br. s, 2NH);
4.94 (1H, t, J = 5.3, H-2); 8.90 (1H, br. s, NHCO)
D:
0.95 (3H, t, J = 7.5, СН3); 1.88 (2Н, m, СН2); 4.42 (2H, br. s, NH2);
4.48 (1H, br. s, NH); 4.79 (1H, t, J = 5.5, H-2); 6.62-7.85 (4H, m, Ar)
А (92%):
0.91 (3H, t, J = 7.2, СН3); 1.50 (2H, m, СН2); 2.27 (2H, m, СН2);
5.42 (2H, br. s, NH2); 6.56-7.39 (4H, m, Ar); 7. 50 (1H, t, J = 4.8, HC=N);
9.64 (1H, br. s, NH)
B (8%):
0.88 (3H, t, J = 7.2, СН3); 1.57 (2H, m, СН2); 2.18 (2H, m, СН2);
4.35 (2H, br. s, 2NH); 4.97 (1H, t, J = 5.4, H-2); 9.01 (1H, br. s, NHCO)
D:
0.89 (3H, t, J = 7.3, СН3); 1.33 (2Н, m, СН2); 1.76 (2Н, m, СН2);
4.27 (2H, br. s, NH2); 4.38 (1H, br. s, NH); 4.92 (1H, q, J = 6.4, H-2);
6.52-7.76 (4H, m, Ar)
2d
D:
0.88 (3H, t, J = 7.2, СН3); 1.29 (4Н, m, 2СН2); 1.82 (2Н, m, СН2);
4.32 (2H, br. s, NH2); 4.53 (1H, br. s, NH); 4.80 (1H, t, J = 5.4, H-2);
6.51-7.82 (4H, m, Ar)
_______
*The spectrum of form A was taken 2 h after dissolving, and of form D
7 days after dissolving.
TABLE 3. 13C NMR Spectra of Compounds 2a-d
Com-
pound
Chemical shifts, δ, ppm*
Form
С=N or C-2
С=О
CH3
CH2
2а
2b
2c
A
D
A
D
A
B
D
D
152.1
69.2
165.4
164.1
165.8
163.8
165.6
170.1
163.6
163.6
20.1
19.7
10.6
8.7
150.5
73.9
26.7
25.5
151.8
71.9
13.5
13.5
13.5
13.7
19.8, 34.5
19.2, 35.1
72.6
17.6, 34.1
2d
72.8
22.2, 26.4, 32.1
_______
*Signals of C arom. lie in the range 114.4-145.3 ppm.
967

Seven days after dissolving compounds 2a-c in CDCl3 the shape of the 1H NMR spectra had undergone
significant changes. The proportions of linear form A and triazepine form B were significantly reduced, and an
additional set of resonance signals appeared in the spectra, belonging to a second cyclic form. Two broadened
singlet signal for the NH group protons located close to one another at 4.40-4.50 ppm, and a signal of
1
appropriate multiplicity at 4.80 ppm in the H NMR spectrum correspond to this form. The appearance of the
indicated signals is impossible to link with any conformational process of the triazepine form B, since the signal
1
of the amide H-4 proton at 9.00 ppm characteristic of the triazepine ring is absent from the H NMR spectra of
compounds 2a-c for the second cyclic form. The observed phenomenon may only be linked with the appearance
in solution of the 1,2-dihydroquinazoline form D, the formation of which is the result of opening the triazepine
ring accompanied by cleavage of the C–N(3) bond and a repeat attack by the nitrogen atom of the hydrazide
group at the C=N bond of the alkylidenimine fragment of the intermediate linear form C.
Later, 14 days after solution in CDCl3, judging by the spectral data, the quinazoline form D remains the
only form in solutions of compounds 2a-c and it may be isolated in the pure state by removing the solvent (see
Experimental). In other words, we have discovered and confirmed spectrally the recyclization of 2-amino-
benzoylhydrazone A → 1,2-dihydroquinazolin-4(3H)-one D proceeding with time.
For the condensation product of 2-aminobenzoic acid hydrazide with valeraldehyde 2d the process of
conversion into dihydroquinazoline begins directly after mixing the starting materials and is complete after
several hours. Consequently to isolate in the crystalline state or confirm spectrally trace amounts of linear
hydrazone A or the cyclic 1,3,4-triazepine B form were unsuccessful.
Additional confirmation of the 1,2-dihydroquinazoline structure D of compounds 2a-d is their
modification in N-benzoylation reactions (see Experimental). Compound 3, the product of reacting 2-methyl-
1,2-dihydroquinazolin-4(3H)-one 2a with benzoyl chloride, proved to be identical in its physicochemical and
spectral characteristics with that obtained by an alternative route, viz. by the interaction of N-benzoyl-N'-(2-
aminobenzoyl)hydrazine with acetaldehyde [8].
The final condensation products of aliphatic aldehydes with 2-aminobenzoylhydrazide therefore do not
have a linear 2-aminobenzoylhydrazone structure but a cyclic 1,2-dihydroquinazoline structure. It is interesting
to compare the structure of the condensation products of aliphatic aldehydes with aroylhydrazines containing
functional substituents (OH, SH, or NH2) in position 2 of the aromatic nucleus. Salicyloylhydrazones of
aldehydes are completely in the linear hydrazone form [16, 17], and the condensation products of aldehydes
with 2-mercaptobenzoic acid hydrazide have predominantly the cyclic 1,3,4-triazepine structure [12, 18]. In the
case of condensation products of aldehydes with 2-aminobenzoylhydrazide, the 2-aminobenzoylhydrazone
formed in the initial step in the course of time undergoes a cascade of conversions of the "ring opening – ring
closing" type, leading to the formation of 1,2-dihydroquinazoline derivatives in the concluding step of the
process.
EXPERIMENTAL
1
The H and 13C NMR spectra were obtained on a Bruker AV-400 spectrometer (400 and 100 MHz
respectively) in CDCl3, internal standard was TMS. The quantitative composition of the tautomeric forms was
1
determined by integration of the respective signals in the H NMR spectra. Error of measurements was ±1%. A
check on the progress of reactions and the purity of the obtained compounds was effected by TLC on Silufol
UV-254 plates in the system benzene–acetone, 4:1.
2-Aminobenzoylhydrazones of Aldehydes 2a-c (Form A). A mixture of 2-aminobenzoic acid
hydrazide 1 (1.51 g, 10 mmol) and the appropriate aldehyde (15 mmol) in benzene (50 ml) was maintained at
25oC for 2 h. The mixture was dried over Na2SO4, the solvent removed, and petroleum ether (50 ml) added to
968

the residue. The precipitated crystals were filtered off, washed with hexane, and dried. Under analogous
conditions the condensation of hydrazide 1 with valeraldehyde leads to the formation of 2-butyl-1,2-dihydro-
quinazolin-4(3H)-one 2d.
2-Alkyl-1,2-dihydroquinazolin-4(3H)-ones
2a-c
(Form
D).
The
appropriate
2-
aminobenzoylhydrazone 2a-c (5 mmol) in chloroform (10 ml) was maintained for 14 days. The solvent was
removed, and the 1,2-di-hydroquinazoline isolated as a viscous oily liquid in quantitative yield.
3-Benzoylamino-2-methyl-1,2-dihydroquinazolin-4(3H)-one (3). Benzoyl chloride (0.7 g, 50 mmol)
was added to a solution of 2-methyl-1,2-dihydroquinazolin-4(3H)-one 2a (0.85 g, 50 mmol) in chloroform
(10 ml) and triethylamine (0.75 ml) with cooling to 0oC. The mixture was maintained at 25oC for 2 h, washed
with water, the organic layer was dried over Na2SO4, filtered, the solvent was removed, and the residue
crystallized by adding petroleum ether. The precipitated crystals were filtered off, washed with hexane, dried,
and recrystallized from a mixture of water–ethanol, 4:1. Yield was 55%; mp 184-186oC (lit. mp 189-190oC [8]).
1H NMR spectrum, δ, ppm (J, Hz): 1.38 (3H, d, J = 5.6, CH3); 5.21 (1H, q, J = 5.6, H-2); 5.61 (1H, br. s, NH);
6.62-7.82 (9H, m, Ar); 10.23 (1H, br. s, NHCO). 13C NMR spectrum, δ, ppm: 19.0 (CH3); 68.1 (C-2);
114.9-146.7 (Ar); 163.8 (C-4); 166.2 (C=O). Found, %: C 68.27; H 5.43; N 14.86. C16H15N3O2. Calculated, %:
C 68.31; H 5.37; N 14.94.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
K. Pihlaja, M. F. Simeonov, and F. Fülöp, J. Org. Chem., 62, 5080 (1907).
F. Fülöp, M. F. Simeonov, and K. Pihlaja, Tetrahedron, 48, 531 (1992).
R. E. Valters, F. Fülöp, and D. Karbonits, Adv. Heterocycl. Chem., 64, 251 (1995).
O. Hromatka, M. Knollmüller, and F. Krenmüller, Monatsh. Chem., 100, 941 (1968).
L. Lázár and F. Fülöp, Eur. J. Org. Chem., 16, 3025 (2003).
M. Gál, E. Tihanyi, and P. Dvortsák, Acta Chim. Acad. Sci, Hung., 123, 55 (1986).
P. S. N. Reddy and P. P. Reddy, Indian J. Chem., 27B, 135 (1988).
G. A. Smirnov, E. P. Sizova, O. A. Lukyanov, I. V. Fedyanin, and M. Yu. Antipin, Izv. Akad. Nauk, Ser.
Khim., 2311 (2003).
9.
10.
11.
12.
G. Heller, J. Prakt. Chem., 131, 82 (1931).
K. Neuvonen, F. Fülöp, H. Neuvonen, M. Simeonov, and K. Pihlaja, J. Phys. Org. Chem., 10, 55 (1997).
P. Grammaticakis, Bull. Soc. Chim. Fr., 1242 (1957).
A. Yu. Ershov, I. V. Lagoda, M. V. Mokeev, S. I. Yakimovich, I. V. Zerova, V. V. Pakal'nis, and
V. V. Shamanin, Khim. Geterotsikl. Soedin., 460 (2008). [Chem. Heterocycl. Comp., 44, 356 (2008)].
K. N. Zelenin, S. V. Oleinik, V. V. Alekseev, and A. A. Potekhin, Zh. Obshch. Khim., 71, 1116 (2001).
Yu. P. Kitaev and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974), p. 381.
N. A. Parpiev, V. G. Yusupov, S. I. Yakimovich, and Kh. T. Sharipov, Acylhydrazones and Their
Complexes with Transition Metals [in Russian], Fen, Tashkent (1988), 164 pp.
A. V. Dolgarev, V. V. Lukachina, and O. I. Karpova, Zh. Anal. Khim., 29, 721 (1974).
S. A. Flegontov, Z. S. Titova, A. P. Stolyarov, B. I. Buzykin, and Yu. P. Kitaev, Izv. Akad. Nauk SSSR,
Ser. Khim., 1014 (1979).
13.
14.
15.
16.
17.
18.
A. Yu. Ershov, I. V. Lagoda, S. I. Yakimovich, V. V. Pakal'nis, and V. V. Shamanin, Zh. Org. Khim.,
43, 1742 (2007).
969