Regioselectivity of electrophilic attack on 4-methyl-1-thioxo-1,2,4,5- tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one. Part 1: Reactions at the sulfur atom

Article abstract of DOI:10.3390/60600557

The regioselectivity of the model compound 4-methyl-1-thioxo-1,2,4,5- tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one (3) towards different electrophiles was studied. Compound 3 reacts with alkyl and aryl halides to give the corresponding S-substituted derivatives. The reaction of the model thioamide with acyl halides proceeds by the formation of kinetically controlled S-acyl derivatives followed by a transacylation reaction to give the N ²-acyl derivatives as thermodynamically controlled products. Theoretical DFT computational studies supported the explanation of these results. The synthesized compounds were characterized by FTIR, ¹H-NMR, ¹³C-NMR, and mass spectroscopy.

Full text of DOI:10.3390/60600557

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Molecules 2001, 6, 557-573
molecules
ISSN 1420-3049
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Regioselectivity of Electrophilic Attack on 4-Methyl-1-thioxo-
1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one.
Part 1: Reactions at the Sulfur Atom
Walid Fathalla1, Michal Čajan1,2 and Pavel Pazdera* 1
1 Department of Organic Chemistry, Faculty of Science, Masaryk University, Brno, Czech
Republic. Tel.: +420 5 41129305, Fax: +420 5 41211214.
2
National Center for Biomolecular Research, Faculty of Science, Masaryk University, Brno,
Czech Republic.
*Author to whom correspondence should be addressed; E-mail: pazdera@chemi.muni.cz
Received: 16 July 2000; in revised form 21 May 2001 / Accepted: 23 May 2001 / Published: 31
May 2001
Abstract: The regioselectivity of the model compound 4-methyl-1-thioxo-
1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one (3) towards different
electrophiles was studied. Compound 3 reacts with alkyl and aryl halides to give
the corresponding S-substituted derivatives. The reaction of the model thioamide
with acyl halides proceeds by the formation of kinetically controlled S-acyl
derivatives followed by a transacylation reaction to give the N2-acyl derivatives as
thermodynamically controlled products. Theoretical DFT computational studies
supported the explanation of these results. The synthesized compounds were
characterized by FTIR, 1H-NMR, 13C-NMR, and mass spectroscopy.
Keywords: Cyclic thioamides, regioselective reactions, 4-methyl-1-thioxo-
1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one, DFT computational
studies.

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Molecules 2001, 6
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Introduction
The thioamide group is an interesting system for heterocyclic chemists because it can be used
as a useful synthetic building bloc, and its regioselectivity towards different electrophiles gives the
group of the great importance. The literature data show that in most cases of nucleophilic
substitution of an alkyl halide on a thioamide system sulfur atom attack is favored [1], while very
few examples are known where attack on the nitrogen atom is preferred [2]. The reaction of acyl
halides with thioamides gave the N-acyl derivatives [3,4], while aromatic nucleophilic substitution
of nitro aryl halides took place on the sulfur atom [5].
Results and Discussion
In this paper we report the results of a study of the regioselectivity of reactions of various
electrophilic reagents (alkyl, acyl and activated aryl halides) with the thioamide moiety of the
model compound 4-methyl-1-thioxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one (3).
The theoretical DFT studies of the anion formed by deprotonation of 3 (Figures 1a-b; results are
summarized in Tables 1 – 3) show that the anionic form is completely planar thus conferring
aromaticity to the whole system. On the other hand, the C(1) - N(2) bond order value would
suggest its double bond character, as could be expected for form 3a. However, the C(1) - S(11)
bond order value is even larger, which indicates the delocalization of negative charge between the
sulfur and nitrogen atoms. A residual bond order determined between the H(17) and S(11) atoms
show the weak H-bond character of the interaction between them.
The results of the theoretical DFT studies gave a larger value for the HOMO coefficient c2 on
sulfur than the same on N(2). Finally, the partial charge distributed on the sulfur atom is slightly
higher than that on the nitrogen atom [6]. These results indicate that electrophilic attack on the
sulfur atom might be preferred, in disagreement with literature data mentioned above.
These facts led us to focus our interest on controlled reactions involving only one of these two
forms and to examine reaction of these two structural forms with different electrophiles. The
problems faced are the elucidation of product structure if the reaction takes place either at the
nitrogen or the sulfur atoms, or on both, the secondly, to give a satisfactory explanation to account
for such a behavior.
18
13
12
N
19
20
O
C
14
5
9a
5a
4 3a
6
3
N
15
N
1
2
N
7
10
9
8
S
16
17
11
Figure 1a. Numbering of the model compound 3 - anion.

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Molecules 2001, 6
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Figure1b. HOMO graphical representation of the anion form of 3.
Table 1. The molecular orbital coefficient values of the anion form of 3.
HOMO
atom orbital coefficient c
LUMO
atom orbital coefficient c
c2
c2
N2
C3a
N3
N4
C9
C9a
C5a
C6
C5
8C
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
1s
-0.2781
0.1886
0.1441
-0.1039
0.0326
-0.0014
0.0300
0.0333
-0.0552
-0.0322
0.0715
0.0000
-0.0000
-0.2070
0.5352
0.0740
0.0355 C3a
0.0207
0.0108
0.0010
0
N2
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
2pz
1s
-0.0812
0.0239
0.0300
-0.1971
-0.1562
-0.2029
0.2396
-0.2304
0.2674
0.2948
-0.2179
-0.0000
-0.0000
-0.0078
0.0230
0.0066
0.0005
0.0009
0.0388
0.0244
0.0411
0.0574
0.0531
0.0715
0.0869
0.0475
0
N3
N4
C9
C9a
0.0009 C5a
0.0011
0.0030
0.0010
C6
C5
8C
O13
H17
0.0051 O13
0
0
H17
2s
2pz
3pz
2s
2pz
3pz
0
0
S11
0.0428 S11
0.2864
0.0005
Table 2. The partial charge values of selected atoms in the anion form of 3.
Mulliken
0.2998
-0.3620
-0.4398
0.7242
ESP
Mulliken
0.5793
0.0077
-0.1357
-0.1481
0.3345
ESP
Mulliken
10N -0.6558
ESP
1C
2N
3N
3aC
4N
0.2615
-0.3966
-0.4141
0.5434
-0.2757
5C
5aC
7C
8C
9aC
0.5440
0.0651
-0.2638
-0.0242 13O -0.5631
0.1136 17H 0.1947
-0.0286
-0.6419
-0.1919
-0.5354
0.1385
11S
12C
-0.4943
-0.3134
-0.5512

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Table 3. Bond orders of selected bonds in the anion form of 3.
S11-H17
C9a-N10
C5a-C5
C5-O13
0.1326
1.0707
1.1157
1.8372
N4-C3a
C3a-N10
C3a-N3
N2-N3
1.0977
1.2015
1.8301
1.0744
C5-N4
C1-N2
C1-N10
C1-S11
1.1996
1.6805
0.9445
2.0511
Compound 3 was prepared by a series of reactions starting from the easily available 3-methyl-
2-sulfanyl-3,4-dihydro-4-quinazolinone 1 [7]. Hydrazinolysis of this starting quinazoline afforded
the hydrazine derivative 2 that subsequently reacts with carbon disulfide to give the desired product
3 [8].
The triazoloquinazoline derivative displays an interesting tautomeric equilibrium between the
1
thiol (3a) and thione (3b) forms. This was proven by H-NMR spectroscopy ((CD3)2SO), which
shows a mixture of these two forms in a ratio of about 1:1 thiol 3a to thione 3b forms.
O
O
a
N
CH3
SH
N
CH3
N
N
NHNH2
1
2
b
O
O
N
N
CH3
N
N
CH3
N
N
N
N
HS
S
H
3b
3a
a: NH2NH2, butanol, 118°C, 18h.
b: CS2, ethanol, KOH, 70°C, 6h.
Scheme 1. Synthesis of the model compound 3