Synthesis of new 1-substituted 4-(2-phenylquinazolin-4-yl)-and 4-(2-phenylquinazolin-4-ylidene) thiosemicarbazides

Article abstract of DOI:10.1007/s10593-009-0191-0

Two new 1-substituted 4-(2-phenylquinazolin-4-yl)-and 4-(2- phenylquinazolin-4-ylidene) thio-semicarbazides were formed by a multistep domino reaction of imidoyl isothiocyanate derivative with 1,1-di-R-hydrazine in acetone solution. Application of hydrazine hydrate under the same reaction conditions afforded 4-(2-phenylquinazolin-4(3H)-ylidene)-2-(propen-2-yl)-1- (propan-2-ylidene) thio-semicarbazide via a six-step triple-component domino reaction.

Full text of DOI:10.1007/s10593-009-0191-0

Chemistry of Heterocyclic Compounds, Vol. 44, No. 11, 2008
SYNTHESIS OF NEW 1-SUBSTITUTED
4-(2-PHENYLQUINAZOLIN-4-YL)- AND
4-(2-PHENYLQUINAZOLIN-4-YLIDENE)
THIOSEMICARBAZIDES
W. Fathalla1 and P. Pazdera2
Two new 1-substituted 4-(2-phenylquinazolin-4-yl)- and 4-(2-phenylquinazolin-4-ylidene) thio-
semicarbazides were formed by a multistep domino reaction of imidoyl isothiocyanate derivative with
1,1-di-R-hydrazine in acetone solution. Application of hydrazine hydrate under the same reaction
conditions afforded 4-(2-phenylquinazolin-4(3H)-ylidene)-2-(propen-2-yl)-1-(propan-2-ylidene) thio-
semicarbazide via a six-step triple-component domino reaction.
Keywords: quinazoline, thiosemicarbazide, domino reaction, hydrogen bond interaction.
Finding a new methodologies for the synthesis of a family of biologically potent compounds by
employing building blocks with multifunctional groups is a key target for drug development. Thioureas and
thiosemicarbazides appear to be ideal candidates for the development of such processes since they are the core
structural fragments in the families of compounds known to display biological activities, e.g. pyrazole [1], 1,2,4-
triazoles [1–5], 1,3,4-oxadiazoles [3, 4], 1,3,4-thiadiazoles [1, 4, 5], 1,3-thiazoles [6], 1,2,4-triazepine [7], 1,3,4-
thiadiazine [8], 1,3,4-thiadiazepine [9, 10], etc. The reported synthetic routes for thioureas and
thiosemicarbazides were usually addition of amines and hydrazines to isothiocyanates [11].
Recently we described the domino syntheses of 3,3-disubstituted 1-(2-phenyl-3H-quinazolin-4-ylidene)-
thioureas [12] and 3-N-substituted 1-N-(2-phenylquinazolin-4-yl)thioureas [13–15] by a simple reaction of the
in situ generated N-(2-cyanophenyl)benzimidoyl isothiocyanate with secondary and primary amines,
respectively.
Herein we report an efficient synthesis of 1-substituted 4-(2-phenyl- quinazolin-4-yl)- and 4-(2-phenyl-
quinazolin-4-ylidene) thiosemicarbazides by a simple reaction of N-(2-cyanophenyl)benzimidoyl isothiocyanate
(1) with hydrazines. Thus, the reactions of imidoyl isothiocyanate 1 with 1,1-dimethyl-hydrazine (2), 1,1-di-
phenylhydrazine (3), or hydrazine hydrate in acetone gave three different interesting products: 1,1-dimethyl-
4-(2-phenylquinazolin-4-yl) thiosemicarbazide (4), 1,1-diphenyl-4-(2-phenylquinazolin-4(3H)-ylidene) thiosemi-
carbazide (5), or 4-(2-phenylquinazolin-4(3H)-ylidene)-2-(propen-2-yl)-1-(propan-2-ylidene) thiosemicarbazide
(6), respectively (Scheme 1).
__________________________________________________________________________________________
1Department of Mathematics and Physical Sciences, Faculty of Engineering Suez Canal University,
2
Port-Said, Egypt;e-mail: walid399@yahoo.com. Centre for Syntheses at Sustainable Conditions and Their
Management, Faculty of Science, Masaryk University, Brno, Czech Republic. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 11, pp. 1688-1693, November, 2008. Original article submitted August 1,
2007; revision submitted September 3, 2008.
1374
0009-3122/08/4411-1374©2008 Springer Science+Business Media, Inc.

Scheme 1
S
Me
N
H
CN
N
N
N
H
Me
Me2NNH2
NCS
2
N
N
Me2CO, 25°C, 24h
1
4
Ph2NNH2
Me2CO,
25°C, 24h
H2NNH
2 · H2O
3
Me2CO, 25°C,
24h
H
N
N
N
N
S
S
N
N
H
H
N
N
N
N
5
6
The sophistic approach to the synthesis of all three thiosemicarbazides 4, 5, and 6 is shown in Scheme 2
[12–15]. The reaction between hydrazine and acetone to form dimethylketazine (N,N'-diisopropylidene-
hydrazine) is well known [16, 17]. This azine reacts further with an additional molar equivalent of hydrazine
hydrate or hydrolyzed under acidic conditions to give hydrazone intermediate 7 (Scheme 3) [18, 19]. Hydrazone
7 was proved to be a key intermediate for dimethylketazine formation [17, 18].
The reaction is assumed to proceed via three- to six-step domino reactions as follows (Scheme 2).
Scheme 2
NH
S
CN
N
CN
N
S
H
N
NCS
N
NHR
H2NR
NHR
N
NMe ,
2 R =
3 R =
2
NPh2,
1
7 R = N
A
B
R
R
S
HN
N
N
R
N
S
HN
S
N
H
H
N
H
Me2CO
N
N
N
N
N
4
5
6
(end product for R= NMe2)
(end product for R= NPh2)
)
(
end product
R= N
1375

The hydrazines with a free NH2 group (1,1-di-R-hydrazine 2 or 3 and the in situ generated hydrazone 7)
add to the isothiocyanate function of compound 1 to give the thiosemicarbazide intermediates A, which in the
next step cyclize by the intramolecular addition of NH to the cyano group to give 4-imino- quinazoline
intermediates B. Dimroth rearrangement furnishes the isolated product 4 (R = NMe2). A further tautomerization
of compound 4 to compound 5 was observed for R = NPh2. Compound 5 (R = N=CMe2) subsequently
condenses with an additional acetone molecule in the free active NH group to finally form thiosemicarbazide 6.
This method has the advantage of a domino reaction with an overall moderate yield at room
temperature.
Scheme 3
N
N
O
NH2NH2
+
+
O
NH2
N
7
1
The structure assignment of thiosemicarbazides 4–6 is based on elemental analysis, H, 13C NMR
spectral data, and on the correlation with fully analyzed references for N-(2-phenylquinazolin-4(3H)-
ylidene)pyrrolidine-1-carbothioamide [12] and 1-benzyl-3-(2-phenylquinazolin-4-yl)thiourea [13] (Fig. 1).
S
4.01
3.87
151
4.98
N
183
179
8.88
H
N
N
N
S
N
N
156
12.31
H
N
16.5
H
N
158
155
Fig. 1. Selected 1H and 13C NMR spectral data of N-(2-phenylquinazolin-4(3H)-ylidene)pyrrolidine-
1-carbothioamide [12] and 1-benzyl-3-(2-phenylquinazolin-4-yl)thiourea [13].
The 1H NMR spectrum of compound 4 exhibits two signals exchangeable by deuterium oxide at δ 12.98
and 8.77 ppm corresponding to 1-NH and 3-NH of the thiosemicarbazide moiety, respectively. We might
conclude that an intramolecular hydrogen bond interaction of the type N–H···N=C participates in the
stabilization of this structure and the consequent formation of a single tautomer [13-15, 20]. The 13C NMR
spectrum of compound 4 reveals carbon signals at δ 178.20, 158.79, 155.75, and 47.14 ppm assigned to C=S,
C-2, C-4, and CH3, respectively.
At the same time, both thiosemicarbazides 5 and 6 exhibit a single exchangeable signal at ~ δ 16.72 ppm
corresponding to one NH group. This implies that the NH group participates in an intramolecular hydrogen bond
interaction of the type N–H···S=C [12], and the consequent formation of the most stable product 5. According to
our previous results [13–15] the structure of compound 4 might be expected when imidoyl isothiocyanate 1
reacts with 1,1-diphenylhydrazine 3. The structure of compound 4 was hampered probably because the N–
H···N=C system in the expected compound 4 moves the two phenyl groups closer to the quinazoline ring making
this compound more strained, as shown in Scheme 1. On the other hand, the long bond C=S and the exocyclic
phenyl groups as well as better conjugation make the structure 5 more favorable. The 13C NMR spectrum of
compound 5 gave a signal at δ 188 ppm assigned to the C=S group participating in hydrogen
1376

bond interaction and extended conjugation. Both the 1H NMR and 13C NMR data were in good agreement with
the results reported for the reference compound 1,1-diphenyl-3-(2-phenyl-3H-quinazolin-4-ylidene)thiourea [12]
prepared by the reaction of diphenylamine and imidoyl isothiocyanate. The 13C NMR spectrum of
thiosemicarbazide 6 gave signals at 181.91, 155.85, 149.34, 67.45, 55.52, 27.96, and 17.05 ppm assigned to
C=S, C-2, C-4, C=CH2, C=CH2, CH2=CCH3, and CH3, respectively, which gave clear evidence for the
participation of two acetone molecules in the reaction.
Thus, the reaction of N-(2-cyanophenyl)benzimidoyl isothiocyanate 1 with hydrazines 2, 3, and 7
afforded thiosemicarbazides 4, 5, and 6, respectively, in a three- to six-step domino reaction.
EXPERIMENTAL
The solvents were purified and dried in the usual way. The boiling range of the petroleum ether used
was 40–60°C. Thin layer chromatography (TLC): silica gel 60 F254 plastic plates (E. Merck, layer thickness
0.2 mm) detected by UV-absorption. Melting points were measured on a Boetius Rapido PHMK 79/2106
1
(Wägetechnik) instrument. Elemental analyses were carried out with an Erba 1102 instrument. The H and 13C
NMR spectra were recorded at 300 and 75.5 MHz, respectively (DRX 300 Avance Bruker) in CDCl3 solution
with tetramethylsilane as an internal standard.
The starting compound 1 was prepared according to the method described in [12-15].
1-Substituted 4-(2-phenylquinazolin-4-yl) and 4-(2-phenylquinazolin-4-ylidene) thiosemicarbazides
(General Method). To a solution of imidoyl isothiocyanate 1 (1.32 g, 5 mmol) [12-15] in acetone (10 ml) a
hydrazine derivative (5-10 mmol) was added. The reaction mixture was stirred at room temperature (25°C) for
24 h. The solvent was evaporated under reduced pressure and the residue was crystallized from ethanol.
1,1-Dimethyl-4-(2-phenylquinazolin-4-yl) thiosemicarbazide (4). From compound 1 and 1,1-dimethyl-
1
hydrazine (2) (0.4 ml). White crystals (0.89 g, 56%); mp 147-148°C. H NMR spectrum, δ, ppm: 12.98 (1H, s,
N–H···N=C); 8.77 (1H, s, NH); 8.45-8.32 (2H, m, ArH); 8.04-8.01 (1H, m, ArH); 7.9–7.89 (2H, m, ArH);
7.64-7.54 (4H, m, ArH); 2.91 (6H, s, CH3). 13C NMR spectrum, δ, ppm: 178.20 (C=S); 158.79 (C=N, C-2); 155.75
(C=N, C-4); 151.54 (C q); 137.64 (C q); 134.71 (CH Ar); 131.24 (CH Ar); 129.83 (CH Ar); 129.01 (CH Ar);
128.29 (CH Ar); 127.96 (CH Ar); 120.74 (CH Ar); 112.57 (C q); 47.41 (CH3). Found, %: C 63.08; H 5.26;
N 21.61; S 9.88. C17H17N5S. Calculated, %: C 63.13; H 5.30; N 21.65; S 9.91.
1,1-Diphenyl-4-(2-phenylquinazolin-4(3H)-ylidene) thiosemicarbazide (5). From compound 1 and
1
1,1-diphenylhydrazine 4 (0.7 ml). White crystals (1.4 g, 64 %); mp 166-167°C. H NMR spectrum, δ, ppm (J,
13
Hz): 16.75 (1H, s, N–H···S=C); 8.32 (2H, d, J = 7.9, ArH); 7.82-7.32 (18H, m, ArH, NH). C NMR spectrum,
δ, ppm: 188.32 (N–H···S=C); 155.85 (C=N, C-2); 149.34 (C=N, C-4); 148.54 (C q); 134.90 (CH Ar); 132.67 (C q);
132.08 (CH Ar); 129.35 (CH Ar); 129.22 (CH Ar); 128.15 (CH Ar); 127.61 (CH Ar); 127.53 (CH Ar); 126.11
(CH Ar); 121.43 (C q). Found: C 72.31; H 4.65; N 15.64; S 7.08. C27H21N5S. Calculated, %: C 72.46; H 4.73;
N 15.65; S 7.16.
4-(2-Phenylquinazolin-4(3H)-ylidene)-2-(propen-2-yl)-1-(propan-2-ylidene) thiosemicarbazide (6).
From compound 1 and hydrazine hydrate (85%, 0.5 ml, 10 mmol). Yellow powder (0.63 g, 34 %), mp
1
162-163°C. H NMR spectrum, δ, ppm: 16.72 (1H, s, N–H···S=C); 8.36-8.24 (3H, m, ArH); 7.78-7.64 (2H, m,
ArH); 7.49-7.31 (4H, m, ArH); 2.89 (2H, s, CH2); 2.13 (3H, s, CH3); 1.80 (6H, s, 2CH3). 13C NMR spectrum, δ,
ppm: 181.91 (N–H···S=C); 155.56 (C=N, C-2); 149.98 (C=N, C-4); 149.40 (C q); 134.61 (CH Ar); 132.76 (C q);
131.97 (CH Ar); 129.32 (CH Ar); 128.60 (CH Ar); 127.67 (CH Ar); 127.30 (CH Ar); 125.41 (CH Ar); 121.73
(C q); 67.45 (C=CH2); 55.52 (C=CH2); 27.96 (2CH3); 17.05 (CH3). Found, %: C 66.95; H 5.51; N 18.43; S 8.48.
C21H21N5S. Calculated, %: C 67.17; H 5.64; N 18.65; S 8.54.
1377

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