Synthesis of heterocycles based on products of anion arylation of unsaturated compounds. 5. Reaction of 2-aryl-1,4-benzoquinones with thiourea

Article abstract of DOI:10.1023/A:1012420128922

2-Aryl-1,4-benzoquinones, that can be obtained by arylation of quinone by arenediazonium salts, regioselectively react with thiourea in acid medium to form 7-aryl-5-hydroxy-1,3-benzoxathiol-2-ones. In the presence of excess arylquinones at room temperature, 2-amino-6-hydroxybenzothiazoles are formed in the same reaction.

Full text of DOI:10.1023/A:1012420128922

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
SYNTHESIS OF HETEROCYCLES
BASED ON PRODUCTS OF ANION
ARYLATION OF UNSATURATED
COMPOUNDS. 5.* REACTION OF 2-ARYL-
1,4-BENZOQUINONES WITH THIOUREA
N. D. Obushak, V. S. Matiichuk, and R. L. Martyak
2-Aryl-1,4-benzoquinones, that can be obtained by arylation of quinone by arenediazonium salts,
regioselectively react with thiourea in acid medium to form 7-aryl-5-hydroxy-1,3-benzoxathiol-2-ones.
In the presence of excess arylquinones at room temperature, 2-amino-6-hydroxybenzothiazoles are
formed in the same reaction.
Keywords: 2-aryl-1,4-benzoquinones, thiourea.
The products of haloarylation [1-4] and thiocyanatoarylation [5] of unsaturated compounds of
arenediazonium salts are convenient reagents for synthesis of heterocycles. One variant of the Meerwein
reaction (haloarylation or arylation of unsaturated compounds) is the reaction of quinones with arenediazonium
salts, as a result of which generally monoaryl-substituted quinones are obtained [6, 7].
In this work, we have studied the possibility of synthesis of heterocycles based on the arylation products
of p-benzoquinone 1a-h. We know that quinones add to compounds with thiol groups, and using polyfunctional
reagents in this reaction makes it possible to obtain different condensed heterocycles as a result of subsequent
intramolecular cyclocondensations [8, 9]. When quinones react with thiourea, thiuronium salts are obtained for
which the direction of further cyclization depends on the reaction conditions [10, 11]. We have established that
arylquinones 1a-h react with thiourea in acid medium to form 7-aryl-5-hydroxy-1,3-benzoxathiol-2-ones 4a-h
(Table 1).
In the course of the reaction, at an intermediate stage S-(3-aryl-2,5-dihydroxyphenyl)thiuronium
chlorides 2a-h*2 and 7-aryl-5-hydroxy-2-imino-1,3-benzoxathioles 3a-h [10] are formed. The latter are rapidly
hydrolyzed under the reaction conditions to form compounds 4a-h, and we did not isolate them in pure form.
The structure of the end products of the reaction is due to the regiodirective nature of the addition of thiourea to
p-benzoquinone.
_______
* For Communication 4, see [1].
*2 The salts 2a-h can be isolated in pure form. The characteristics of compounds 2f,h are presented in the
Experimental section.
__________________________________________________________________________________________
Lvov Ivan Franko State University, Lvov 290602, Ukraine; e-mail: obushak@is.lviv.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 986-992, July, 2001. Original article submitted January 22,
1999; revision submitted January 26, 2000.
0009-3122/01/3707-0909$25.00©2001 Plenum Publishing Corporation
909

O
O
S
O
O
R1
–
+
H2N
NH2
, HCl
R1C6H4N2 Cl , AcONa
1a–h
+
O
H
R1
S
SH
+
H2N
NH2
H2N
NH
O
OH
R1
R1
S
NH2
R1
–
+
NH2 Cl
O
S
O
S
.
NH HCl
O
OH
HO
HO
2a–h
3a–h
4a–h
1–4 a R1 = H, b R1 = 3-Me, c R1 = 4-Me, d R1 = 4-MeO, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 4-Cl, h R1 = 4-NO2
Theoretically, in addition to compounds 4a-h it is possible that isomers of type 5, 6 can be formed. However,
we found that the reaction occurs regioselectively: the thiourea adds in the meta position relative to the aromatic
1
substituent (compounds 2a-h). We draw such a conclusion based on the H NMR spectroscopy data (Table 2).
1
In the H NMR spectra of these compounds, we observe two doublets from the aromatic protons ortho to the
TABLE 1. Characteristics of 7-Aryl-5-hydroxy-1,3-benzoxathiol-2-ones
Found, %
——————
Com-
pound
Empirical
formula
mp, °С
Yeild, %
Calculated, %
С
Н
S
4a*
4b
4c
C13H8O3S
63.74
63.92
3.19
3.30
13.11
13.13
176-177
153-154
91
51
50
93
70
70
72
81
C14H10O3S
C14H10O3S
C14H10O4S
C13H7ClO3S
C13H7ClO3S
C13H7ClO3S
C13H7NO5S
64.91
3.82
12.30
65.10
3.90
12.41
64.95
65.10
3.87
3.90
12.48
12.41
170-171
61.27
3.53
11.67
165-166
4d
4e
61.30
3.68
11.69
55.90
56.02
2.48
2.53
11.39
11.50
167-168.5
204-205
55.85
2.42
11.37
4f
56.02
2.53
11.50
56.10
56.02
2.46
2.53
11.56
11.50
175-176
4g
4h
54.11
2.40
10.99
>300 (dec.)
53.98
2.44
11.08
_______
* The constants for the substance are consistent with literature data in [10].
910

1
TABLE 2. H NMR Spectra for 7-Aryl-5-hydroxy-1,3-benoxathiol-2-ones,
, ppm
δ
Com-
Ме or
4-Н, 1Н, d 6-Н, 1Н, d
J46
Нarom in RC6H4
ОН, 1Н, s
pound ОМе, 3Н, s
—
2.38
2.36
3.82
—
—
—
6.87
6.85
6.84
6.84
6.72
6.88
6.96
7.15
7.14
7.13
7.09
7.21
7.18
7.25
2.5
2.7
2.4
2.4
2.1
1.0
2.1
7.48 (3Н, m*); 7.61 d (2Н)
7.24 (1Н, m*); 7.39 (3Н, m*)
7.30 (2Н, d); 7.50 (2Н, d)
7.06 (2Н, d); 7.56 (2Н, d)
7.46 (3Н, m*); 7.59 (1Н, d)
7.53 (3Н, m*); 7.67 (1Н, s)
7.90 (2Н, d); 8.34 (2Н, d)
9.94
9.86
9.89
9.81
9.90
9.89
10.05
4a
4b
4c
4d
4e
4f
4h
_______
* Centers of multiplets are indicated.
hydroxy group (4-H, 6-H), with characteristic long-range spin–spin coupling constants (J46). The signals that
were typical for the isomers 5, 6 are missing in the spectra. Only when using 2-(4-nitrophenyl)-1,4-
benzoquinone do we observe formation of isomers 4 and 5 in ~ 5:1 ratio.
O
1
O
R
O
S
S
HO
O
R1
HO
5
6
We also attempted to synthesize compounds 4 by reaction of arylquinones with thiocyanic acid (such an
approach to synthesis of similar compounds is described in [12]). However, this process is complicated by side
reactions, which makes it difficult to isolate the target products 4a-h.
OH
OH
R1
R1
NCS
+
KSCN, HCl
H
1a–h
4a–h
O
S
NH
HO
Compounds 4a-h are rather easily acylated by acid chlorides in benzene in the presence of bases. The
characteristics of 5-aroyloxy-7-aryl-1,3-benzoxathiol-2-ones 7a-s are given in Table 3, and the 1H NMR spectral
data are given in Table 4.
911

R1
O
4a–h
+
O
S
R2
O
Cl
O
O
R2
7a–s
Cl
7 R1 = H, R2 = H (a), 4-NO2 (b); R1 = H, instead of R2C6H4 –
(c),
S
R1 = 3-Me, R2 = 2-Cl (d), 4-Cl (e); R1 = 4-Me, R2 = H (f), 2-Cl (g), 4-Cl (h);
R1 = 4-OMe, R2 = H (i), 2 -Cl (j), 4-Cl (k); R1 = 2-Cl, R2 = H (l), 2-Cl (m),
4-Cl (n), 4-Br (o); R1 = 4-Cl, R2 = H (p), 2-Cl (q), 4-Cl (r), 4-Br (s)
TABLE 3. Characteristics of 5-Aroyloxy-7-aryl-1,3-benzoxathiol-2-ones
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
C20H12O4S
68.72
68.95
3.40
3.47
97-98
51
55
65
59
57
67
50
50
76
49
53
60
55
71
56
61
52
48
57
7a
7b
7c
7d
7e
7f
C20H11NO6S
C22H11ClO4S2
C21H13ClO4S
C21H13ClO4S
C21H14O4S
61.20
2.85
190-191
181-182
102-103
134-135
135-136
123-124
163-164
154-155
176-177
174-175
138-139
134-135
141-142
168-169
141-142
152-153
178-179
181-182
61.07
2.82
60.09
60.20
2.47
2.53
63.28
3.25
63.56
3.30
63.62
63.56
3.27
3.30
69.41
3.88
69.60
3.89
C21H13ClO4S
C21H13ClO4S
C21H14O5S
63.32
63.56
3.18
3.30
7g
7h
7i
63.53
3.25
63.56
3.30
66.36
66.65
3.72
3.73
C21H13ClO5S
C21H13ClO5S
C20H11ClO4S
C20H10Cl2O4S
C20H10Cl2O4S
C20H10BrClO4S
C20H11ClO4S
C20H10Cl2O4S
C20H10Cl2O4S
C20H10BrClO4S
60.89
3.12
7j
61.10
3.17
61.14
61.10
3.08
3.17
7k
7l
62.60
2.77
62.75
2.90
57.33
57.57
2.34
2.42
7m
7n
7o
7p
7q
7r
7s
57.67
2.50
57.57
2.42
51.84
52.03
2.23
2.18
62.61
2.85
62.75
2.90
57.38
57.57
2.37
2.42
57.69
2.47
57.57
2.42
51.90
52.03
2.11
2.18
912

The thiuronium salts 2a-h can be oxidized by arylquinones 1a-h [11]. Therefore, if we use an excess of
compounds 1a-h in the reaction with thiourea and we carry out the reaction in the presence of a mineral acid at
room temperature, then 2-amino-4-aryl-6-hydroxybenzothiazoles 11a-h are formed rather than compounds 4a-h.
The most probable mechanism for such a reaction includes intermediates 9, 10a-h [11].
OH
R1
O
R1
S
NH2
1a–h
2a–h
+
+
–
+
NH2 Cl
OH
8a–h
O
9a–h
R1
R1
+ 8a–h/ – 1a–h
NaHCO3
N
N
–
+
O
N H2Cl
S
HO
NH2
S
11a–h
10a–h
1
The aminothiazoles 11a-h were not isolated in pure form; they were identified using H NMR
spectroscopy and chromatographic mass spectroscopy. In this case, fairly small amounts of the isomers and
products of side reactions were also formed, which we did not study more closely.
1
TABLE 4. H NMR Spectra of 5-Aroyloxy-7-aryl-1,3-benzoxathiol-2-ones
7a-s, , ppm*
δ
Com-
pound
1
4-Н, 1Н,
6-Н, 1Н, d*2
R1C6H4
4
R2C6H4
5
d*2
2
3
7.46
7.78
7.44-7.65 (5Н, m)
7.69-7.77 (3H, m);
7a
8.16 (2Н, d; о-Н)
7.61
7.58
7.83
7.84
7.50 (3Н, m); 7.71 (2Н, d)
8.39 (2Н, d); 8.44 (2Н, d)
7.70 (4Н, m)
7b
7c
7.50 (3Н, m)
8.03 (1Н, d); 8.19 (1Н, d)
7.39
7.38
7.39
7.36
7.46
7.38
7.35
7.70
7.68
7.69
7.64
7.71
7.65
7.64
2.44 (3Н, s, СН3); 7.25 (1Н, d); 7.52-7.66 (3Н, m);
7d
7e
7g
7h
7i
7.37-7.50 (3Н, m) 8.10 (1Н, d, о-Н)
2.44 (3Н, s, СН3), 7.24 (1Н, d); 7.62 (2Н, d), 8.16 (2Н, d)
7.39-7.50 (3Н, m)
2.43 (3Н, s,СН3); 7.32 (2Н, d); 7.50-7.65 (3Н, m);
7.58 (2Н, d)
8.10 (1Н, d, o-Н)
2.41 (3Н, s, СН3); 7.30 (2Н, d); 7.61 (2Н, d); 8.15 (2Н, d)
7.57 (2Н, d)
3.81 (3Н, s, СН3О)
7.59-7.80 (3Н, m);
8.14 (2Н, d, o-Н)
7.07 (2Н, d); 7.65 (2Н, d)
3.85 (3Н, s, СН3О);
7.50-7.65 (3Н, m);
7j
7.05 (2Н, d); 7.63 (2Н, d)
8.10 (1Н, d, o-Н)
3.83 (3Н, СН3О); 7.03 (2Н, d); 7.61 (2Н, d); 8.15 (2Н, d)
7k
7.60 (2Н, d)
913

TABLE 4 (continued)
1
2
3
4
5
7.23
7.77
7.59 (3Н, m)
7.71 (1Н, t);
8.15 (2Н, d, o-Н)
7.45–7.68 (7Н, m)
7l
7.48 (3Н, m)
7.27
7.82
7m
8.09 (1Н, d, o-Н)
7.24
7.24
7.41
7.79
7.80
7.70
7.49 (3Н, m); 7.57 (1Н, d)
7.49 (3Н, m); 7.59 (1Н, m)
7.52 (2Н, d); 7.72 (2Н, d)
7.61 (2Н, d); 8.15 (2Н, d)
7n
7o
7p
7.77 (2Н, d); 8.07 (2Н, d)
7.60 (2Н, m); 7.70 (1Н, m);
8.16 (2Н, d, o-Н)
7.44
7.74
7.53 (2Н, d); 7.72 (2Н, d)
7.50-7.67 (3Н, m);
7q
8.10 (1Н, d, o-Н)
7.43
7.41
7.71
7.70
7.52 (2Н, d); 7.72 (2Н, d)
7.52 (2Н, d); 7.72 (2Н, d)
7.62 (2Н, d); 8.15 (2Н, d)
7.78 (2Н, d); 8.08 (2Н, d)
7r
7s
_______
* In the case of narrow multiplets, their centers are given.
*2 J46 ~ 2-2.5 Hz.
EXPERIMENTAL
The 1H NMR spectra of compounds 4a-f,h, 7e, 11a-h were taken on a Varian VXR-300; the spectra for
compounds 7a-d, f-s were taken on a Bruker WM-250 in DMSO-d6, internal standard HMDS. The mass spectra
were taken on a Finnigan MAT INKOS-50 chromatographic mass spectrometer.
The 2-aryl-1,4-benzoquinones 1a-h were obtained by a procedure close to that described in [13] in the
following yields: 1a, 070%; 1b, 84%; 1c, 85%; 1d, 62%; 1e, 82%; 1f, 85%; 1g, 75%, 1h, 91%. The constants
for these substances agree with literature data [13,14].
5-Hydroxy-7-phenyl-1,3-benzoxathiol-2-one (4a). A solution of 2-phenyl-1,4-benzoquinone (3.7 g,
0.02 mol) in acetic acid (20 ml) was added to a solution of thiourea (2.3 g, 0.03 mol) in 2 N hydrochloric acid
(40 ml). The mixture was heated for 1 h and then cooled; the precipitate formed was filtered off and crystallized
from aqueous alcohol. Compounds 4b-h were obtained similarly.
When the reaction mixture was held without heating, a precipitate of thiuronium salt 2a-h was formed.
The compounds 2e,h were isolated and characterized.
S-[3-(3-Chlorophenyl)-2,5-dihydroxyphenyl]thiuronium Chloride (2f). Yield 72%; mp 133-134°C.
1H NMR spectrum, , ppm: 6.91 (2H, d, Hdihydroxyphenyl); 7.30-7.57 (4H, m, Harom); 8.62 (2H, br. s, NH2); 8.90 (1H,
δ
+
s, OH); 9.35 (2H, br. s, NH2 ; 9.40 (1H, s, OH). Found, %: C 46.92; H 3.60; N 8.52. C13H12Cl2N2O2S.
Calculated, %: C 47.14; H 3.65; N 8.46.
S-[2,5-Dihydroxyphenyl-3-(4-nitrophenyl)]thiuronium Chloride (2h). Yield 74%; mp 210-212°C.
Found, %: C 45.80; H 3.49; N 12.11. C13H12ClN3O4S. Calculated, %: C 45.68; H 3.54; N 12.29.
Reaction of 2-Aryl-1,4-benzoquinones 1a-h with HSCN. A mixture of arylquinone 1a-h (0.01 mol),
KSCN (1.45 g), 2 N hydrochloric acid (20 ml), and acetic acid (15 ml) were heated for 1.5 h. The precipitate
formed was filtered off. The presence of compounds 4a-h in the precipitate was established by TLC and
1H NMR spectroscopy.
7-Aryl-5-aroyloxy-1,3-benzoxathiol-2-ones (7a-s) (Table 3). N-methylmorpholine (1.01 g, 0.01 mol)
and the corresponding acid chloride (0.01 mol) were added to a solution of compound 4a-h (0.01 mol) in
benzene (30 ml). The mixture was heated for 1 h, the precipitate of N-methylmorpholinium chloride was filtered
off, the filtrate was evaporated down to formation of a precipitate of compounds 7a-s, which were crystallized
from an acetone–alcohol or DMF–alcohol mixture.
914

2-Amino-4-aryl-6-hydroxybenzothiazoles (11a-h). A solution of arylquinone 1a-h (13.4 mmol) in
ethanol (20-30 ml) was added to a mixture of thiourea (0.51 g, 6.7 mmol) and concentrated hydrochloric acid in
ethanol (15 ml). The mixture was held for 24 h at room temperature, then the ethanol was evaporated off, water
was added to the residue and it was heated until the hydrochlorides of amines 11a-h were dissolved. The
mixture was filtered and NaHCO3 was added to the filtrate. A precipitate formed that, judging from the 1H NMR
spectra and the mass spectra, consisted mainly of 2-amino-4-aryl-6-hydroxybenzothiazoles.
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915