Cyclization of thiohydrazonate esters and azo-hydrazone tautomerism of 2-arylhydrazono-3-oxo-1,4-benzothiazines

Article abstract of DOI:10.1002/jhet.5570400202

Reaction of ethyl arylhydrazonochloroacetates (1) with 2-aminothiophenol (2) in ethanol in the presence of triethylamine yielded the respective ethyl thiohydrazonate esters (3). Similarly, methyl arylhydrazonochloroacetates (6) gave the corresponding meth

Full text of DOI:10.1002/jhet.5570400202

Mar-Apr 2003
207
Cyclization of Thiohydrazonate Esters and Azo-Hydrazone
Tautomerism of 2-Arylhydrazono-3-oxo-1,4-benzothiazines
Ahmad S. Shawali and Said Elsheikh
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Cyril Párkányi
Department of Chemistry and Biochemistry, Florida Atlantic University,
777 Glades Road, P.O. Box 3091, Boca Raton, FL 33431-0991
Received February 26, 2001
Received revised February 18, 2003
Reaction of ethyl arylhydrazonochloroacetates (1) with 2-aminothiophenol (2) in ethanol in the presence
of triethylamine yielded the respective ethyl thiohydrazonate esters (3). Similarly, methyl arylhydra-
zonochloroacetates (6) gave the corresponding methyl thiohydrazonate esters (7). Treatment of both 3 and 7
with hydrogen chloride in ethanol afforded the respective 1,4-benzothiazine derivatives 4. Identical products
(4) were obtained by refluxing 1 or 6 in ethanol in the presence of triethylamine. The structure of 4 was
confirmed by their alternate synthesis starting with diethyl chloromalonate in ethanol in the presence of
triethylamine which yielded the intermediate 1,4-benzothiazine derivatives 8. The subsequent coupling of 8
with diazotized anilines in ethanol in the presence of potassium hydroxide afforded 4.
J. Heterocyclic Chem., 40, 207 (2003).
Within the framework of our interest in regioselectivity
ined. Because only the hydrazone form A can exist with a
15
in cyclization reactions of α-oxohydrazonoyl halides with
1,2-aminothiols [1-4] and azo-hydrazone tautomerism of
arylazo derivatives of heterocyclic compounds [5-8], we
wish to report the results of our study of the reactions of
2-aminothiophenol (2) with a series of ethyl N-arylhydra-
zono-2-chloroacetates (1) and elucidation of the tautomeric
structures of the respective products. At present, there are
two contradicting reports in the literature concerning the
structure of the products of such reactions. It has been
hydrogen attached to the N, a splitting of the proton res-
15
onance as well as of the N resonance would be a conclu-
sive proof of the existence of the hydrazone form. Finally,
the electronic absorption spectra of the compounds under
study were investigated in organic solvents of different
polarities.
Results and Discussion.
The reaction of 2-aminothiophenol (2) with each of
the ethyl arylhydrazonochloroacetates 1a-1i in ethanol
in the presence of triethylamine gives ethyl thiohydra-
zonate esters 3. Similarly, the use of methyl arylhydra-
zonochloroacetates 6 instead of 1 in this reaction
afforded the respective methyl thiohydrazonate esters 7
(Scheme 2). Treatment of either 3 or 7 with hydrogen
chloride in ethanol yielded the respective 1,4-benzoth-
iazine derivatives 4 (Method A). Reaction of 2 with
either 1 or 6 in ethanol in the presence of triethylamine
under reflux yielded 1,4-benzothiazine derivatives 4
directly (Method B). The identity of the latter products
was confirmed by their alternate synthesis. The reaction
of diethyl chloromalonate with 2 in ethanol, in the pres-
ence of triethylamine under reflux afforded 1,4-benzoth-
iazine derivative 8. Coupling of the latter with the appro-
priate diazotized anilines in ethanol in the presence of
potassium hydroxide yielded the respective products 4,
via the Japp-Klingemann reaction [11] (method C). The
products 4 prepared by the latter method proved identi-
cal in all respects with those obtained by either of the
other two methods (Method A and Method B; Scheme
2). Thus, these results exclude structure 5 previously
assigned to the product isolated from the reaction of 2
with 1b [10].
reported that the reaction of 2 with 1 (X = 4-NO ) afforded
2
2,3-dioxo-1,4-benzothiazine-2-(4-nitrophenylhydrazone)
4i via elimination of ethanol from the initially formed thio-
hydrazonate ester 3 [9]. However, it was also claimed [10]
that a similar reaction of 2 with 1 (X = 4-Me) yielded a
product that was assigned the structure of 2-ethoxycar-
bonyl-4-(4-methylphenyl)-1,3,4-benzothiadiazine 5,
obtained by elimination of ammonia from the intermediate
3 (Scheme 1). The latter assignment seems ambiguous,
because it involves nucleophilic aliphatic displacement of
an amino group from an aromatic amine residue.
This significant difference between the reaction prod-
ucts 4i and 5 prompted us to re-examine the reactions of 2
with a series of hydrazonoyl chlorides (1a-1i) and to study
the effect of the ring substituent upon the regioselectivity
in the cyclization reaction of thiohydrazonate esters of
type 3 (Scheme 2). Also, we have investigated the synthe-
sis of the title compounds 4 by other methods starting from
2 to confirm their structures (Scheme 2). Furthermore, as
the title compounds can have more than one tautomeric
structure (Chart 1), it was of interest to elucidate their tau-
15
tomeric structure. For this purpose, the N isotopomer of
4d (4d') was prepared as a typical example of the title
1
15
compounds, and its H and N nmr spectra were exam-

208
A. S. Shawali, S. Elsheikh and C. Párkányi
Vol. 40
Scheme 1
can be assigned to the resonances of carbon atoms in
COOEt and C=N-N groups (Table 2). Furthermore, mass
spectrum of 3d contains a characteristic peak at m/e 124
assignable to 2-aminothiophenol (2) (Table 1). This is sim-
ilar to the fragmentation of other aryl and heteroaryl thio-
hydrazonates whose mass spectra are characterized by the
loss of the corresponding arenethiol and heteroarylthiol
from their molecular ions, respectively [12].
Table 1
Infrared and Mass Spectra of the Products 3, 8, and 9f
-1
Compound. Infrared spectrum, ν (cm ) (KBr)
No.
Mass spectrum, m/z (rel. intensity, %)
3b
3219, 3165, 1655
329 (13, M ), 208 (28), 122 (73), 106 (100), 91 (29),
+
77 (87), 65 (30), 53 (41)
3306, 3149, 1699
315 (16, M ), 208 (69), 180 (11), 162 (31), 124 (29),
3d
+
92 (100), 80 (51), 77 (17), 65 (91)
3g
3h
8
3348, 3258, 1707
—
3244, 3186, 1701, 1676
—
3314, 3200, 1728, 1674
+
237 (46, M ), 208 (93), 180 (11), 136 (18), 124 (30),
108 (76), 92 (100), 80 (52), 77 (23), 65 (97)
3200, 1641
318 (33, M ), 303 (28), 178 (64), 150 (40), 136 (76),
9f
+
111 (100), 90 (33), 75 (69), 64 (38), 50 (44)
Table 2
1
13
H and C nmr Spectra of the Products 3, 8, and 9f
1
Compound
No.
H nmr spectrum (δ, ppm, Me SO-d )
2 6
13
C nmr spectrum (δ, ppm, Me SO-d )
2
6
3b
3d
3g
1.22 (t, 3H), 2.26 (s, 3H), 4.17 (q, 2H), 5.61 (s, 2H), 6.56-
7.36 (m, 8H), 10.47 (s, 1H)
14.1, 20.3, 61.1, 114.0, 114.5, 115.3, 116.9, 125.8, 126.2,
129.6, 130.1, 135.3, 140.5, 149.9, 162.9
1.36 (t, 3H), 4.32 (q, 2H), 4.58 (s, 2H), 6.67-7.40 (m, 8H),
9.46 (s, 1H)
14.1, 61.9, 111.3, 112.1, 115.0, 117.3, 122.3, 124.4, 129.2,
130.3, 135.5, 142.8, 149.5, 162.8
1.28 (t, 3H), 4.50 (q, 2H), 6.63 (s, 2H), 7.05-7.94 (m, 8H),
10.23 (s, 1H)
13.9, 60.9, 107.5, 116.9, 114.3, 116.9, 124.8, 127.6, 129.3,
130.2, 133.8, 143.0, 148.5, 161.6
3h
8
1.01 (t, 3H), 1.36 (t, 3H), 4.12 (q, 2H), 4.44 (q, 2H),
6.50 (s, 2H), 6.86-7.96 (m, 8H), 10.21 (s, 1H)
2.0 (t, 3H), 4.01 (q, 2H), 4.51 (s, 1H), 7.24-7.59 (m, 4H),
10.33 (s, 1H)
The thiohydrazonate esters 3 (and 7) were identified by
—
1
13
their ir, H and C nmr, and mass spectra (Tables 1 and 2).
For example, their ir spectra (Table 1) revealed the pres-
9f
3.59 (s, 3H), 6.96-7.35 (m, 8H), 8.05 (s, 1H)
—
-1
ence of two NH bands in the 3149-3348 cm region and a
-1
1
C=O band in the 1655-1707 cm region. The H nmr
spectrum of 3d shows two singlet signals at δ 9.46 and
The structure of the previously synthesized 1,4-benzoth-
4.58 ppm assignable to the NH and NH protons, respec-
tively (Table 2). The C nmr spectrum of 3d shows
characteristic signals at δ 163, 62, 14, and 150 ppm that
iazine derivative 8 [13-16] was readily identified on the
basis of its ir, H and C nmr, and mass spectra (Tables 1
and 2) and its elemental analysis (Table 3). Its ir spectrum
2
13
1
13

Mar-Apr 2003
Cyclization of Thiohydrazonate Esters and Azo-Hydrazone Tautomerism
209
Table 4 (continued)
3304, 3209, 1653
-1
contains two C=O bands at 1674 and 1728 cm and an NH
'
-1
band at 3200-3314 cm , in agreement with the literature
4f
6.95-7.39 (m, 8H), 10.06 (s, 1H), 11.16 (s, 1H)
—
3290, 3190, 1672
7.11-8.17 (m, 8H), 10.36 (s, 1H), 11.23 (s, 1H)
107.9, 113.7, 115.3, 117.1, 120.1, 123.1, 125.8, 127.4,
130.4, 133.9, 148.6, 154.5
[14]. In addition to the aromatic proton multiplet at δ 7.24-
7.59 ppm, its H nmr spectrum exhibits the following char-
acteristic signals: δ 2.0 (t, 3H), 4.01 (q, 2H), 4.51 (s, 1H),
and 10.33 ppm (s, 1H) (Table 2).
1
4g
4h
4i
3517, 3445, 1685, 1655
1.32 (t, 3H), 4.28 (q, 2H), 7.10-7.93 (m, 8H), 10.30 (s, 1H),
11.21 (s, 1H)
—
3277, 3190, 1678
7.10-8.25 (m, 8H), 10.67 (s, 1H), 11.31 (s, 1H)
—
Table 3
Synthesized Compounds 3, 8, and 9f
Compound Yield MP (°C) Mol. formula Analysis, calcd. (found), %
No.
3b
3d
3g
3h
3i
(%)
[a]
(mol. wt.)
C
H
N
70
200-1
(i)
108
(i)
160-2
(ii)
208
(i)
137 [b]
(i)
144 [c]
(i)
200
(i)
C
H
N O S
61.98
(61.4)
60.93
(60.7)
53.32
(53.0)
58.89
(58.6)
53.32
(53.0)
55.68
(55.5)
5.81 12.75
(5.5) (12.3)
5.43 13.32
(5.3) (13.0)
4.47 15.54
(4.2) (15.1)
5.46 10.84
(5.2) (10.5)
4.47 15.54
(4.2) (15.2)
-1
17 19
3 2
[a] See footnote [c] in Table 6. [b] Lit. gives 3220, 1650 cm (nujol)
[1a]; 1650 cm (nujol) [9]. [c] Lit. gives 9.64 (1H), 10.8 (1H) ppm
(329.4)
-1
65
70
75
60
90
45
C H N O S
16 17 3 2
(Me SO-d ) [9].
2
6
(315.4)
C H N O S
16 16 4 4
(360.4)
C H N O S
19 21 3 4
(387.4)
C H N O S
16 16 4 4
(360.4)
Table 5
Electronic Absorption Spectra of Compounds 4a-4i and 9f
8
C
H
NO S
4.67
5.90
11 11
3
(237.2)
(4.4) (5.7)
3.80 13.22
(3.6) (12.9)
9f
C
H
ClN OS 56.69
15 12
3
Compound
No.
λ
, nm (log ε) (dioxane)
max
(317.8)
(56.3)
[a] Solvent: i - EtOH, ii - HCONMe -EtOH. [b] Lit. mp 137 °C [9].
[c] Lit. mp 141-145 °C [14], 142-144 °C [13], 147.5 °C [15].
2
4a
4b
4c
4d [a]
4d’
4e
4f
4g
4h
4i
297 (4.54), 363 (4.81)
290 (4.62), 360 (4.85)
287 (4.58), 356 (4.92)
286 (4.44), 357 (4.67) [b]
284 (4.09), 354 (4.42) [c]
292 (4.69), 354 (4.97)
292 (4.76), 353 (4.92)
285 (4.70), 349 (5.10)
299 (4.74), 358 (5.08)
276 (4.63), 393 (5.21)
288 (4.48), 351 (4.80)
Table 4
1
13
Infrared and H and C nmr Spectra of the Products 4a-4i
-1
Compound Infrared spectrum, ν (cm ) (KBr)
1
No.
H nmr spectrum (δ, ppm, Me SO-d )
2
6
9f
13
C nmr spectrum (δ, ppm, Me SO-d )
2
6
[a] See footnote [c] in Table 6. [b] λ
(log ε) of 4d in additional sol-
max
4a
3300, 3225, 1654
vents: EtOH, 286 (4.54), 366 (4.76); MeCN, 282 (4.60), 356 (4.86);
CHCl , 286 (4.43), 361 (4.70); Me SO, 288 (3.97), 362 (4.26). [c] λ
max
3.73 (s, 3H), 6.89-7.36 (m, 8H), 9.73 (s, 1H), 10.98 (s, 1H)
55.2, 114.0, 114.3, 115.2, 116.9, 122.9, 125.7, 127.2, 129.4,
134.3, 138.1, 154.2, 155.4
3
2
(log ε) of 4d’ in additional solvents: EtOH, 285 (4.22), 363 (4.46);
MeCN, 282 (4.05), 356 (4.40); CHCl , 286 (4.03), 357 (4.37); Me SO,
287 (4.09), 363 (4.41).
3
2
4b
3296, 3211, 1653
2.25 (s, 3H), 7.07-7.37 (m, 8H), 9.80 (s, 1H), 11.03 (s, 1H)
20.3, 114.0, 114.3, 116.9, 120.3, 122.9, 125.7, 127.2, 129.4,
129.9, 134.3, 142.1, 155.3
3300, 3217, 1653
2.31 (s, 3H), 6.74-7.37 (m, 8H), 9.80 (s, 1H), 11.05 (s, 1H)
—
The structures of the final products 4a-4i were confirmed
4c
by their alternate syntheses outlined in Scheme 2, their ir,
1
13
uv, H and C nmr, and mass spectra (Tables 4 and 5), ele-
mental analyses (Table 6), and their reactions. For exam-
ple, the products 4 were recovered unchanged after treat-
4d [a]
3300, 3217, 1653 [b]
6.93-7.38 (m, 9H), 9.88 (s, 1H), 11.06 (s, 1H) [c]
114.0, 114.2, 117.0, 121.2, 123.0, 125.8, 127.3, 129.0,
134.2, 144.2, 155.2
3300, 3217, 1653
6.91-7.35 (m, 9H), 9.86 (d, J = 93.8, 1H), 10.97 (s, 1H)
—
ment with hydrogen peroxide. This finding excludes the
isomeric structure 10 [1a]. Structure 5, previously assigned
to the product formed from 1b and 2 [10], was rejected
4d’
4e
because the ir spectrum of the isolated products showed an
3304, 3213, 1655
-1
amide band near 1653 cm and two NH bands near 3217
7.05-7.38 (m, 8H), 10.10 (s, 1H), 11.11 (s, 1H)
114.0, 115.5, 117.1, 122.3, 123.0, 124.7, 125.8, 127.4,
128.9, 134.1, 143.4, 154.9
-1
and 3300 cm . Furthermore, with the exception of 4h, the
1
13
H and C nmr spectra of the isolated products, 4a-4g and

210
A. S. Shawali, S. Elsheikh and C. Párkányi
Vol. 40
Table 6
Synthesized Compounds 4a-4i
Compound
No.
Method
[a]
Yield
(%)
MP (°C)
[b]
Mol. formula
(mol. wt.)
Analysis, calcd. (found), %
C
H
N
4a
4b
B
A, B, C
B
74
80
70
75
85
85
90
85
90
240-1
(i)
C
H
N O S
60.18
(60.1)
4.37
(4.2)
14.03
(13.8)
15 13
3 2
(299.3)
232-3
(ii)
C
H
N OS
63.58
(63.3)
4.62
(4.5)
14.82
(14.5)
15 13
3
(283.3)
4c
249-50
(i)
C
H
N OS
63.58
(63.4)
4.62
(4.3)
14.82
(14.6)
15 13
3
(283.3)
4d [c]
4e
A, B, C
B
288 [d]
(iii)
C
H
N OS
62.43
4.11
(62.2)
15.60
(4.1) (15.3)
14 11
3
(269.3)
301-2
(iii)
C
H
ClN OS
55.35
(55.0)
3.31
(3.1)
13.83
(13.5)
14 10
3
(303.7)
4f
B
256-7
(iii)
C
H
ClN OS
55.35
3.31
(55.1)
13.83
(3.1) (13.4)
14 10
3
(303.7)
4g
A, B, C
A, B
A, B
268-9
(iii)
C
H
N O S
53.49
(53.2)
3.20
(2.9)
17.82
(17.4)
14 10
4 3
(314.3)
4h
244
(iii)
C
H
N O S
59.81
4.42
(59.5)
12.33
(4.1) (11.9)
17 15
3 3
(341.3)
4i
303-4
(i)
C
H
N O S
53.49
(53.3)
3.20
(3.1)
17.82
(17.5)
14 10
4 3
(314.3)
[a] See the text. [b] Solvent: i - HCONMe -EtOH; ii - EtOH; iii - HCONMe . [c] This compound was reported in one of our previous papers [1a] where
2
2
it was erroneously listed as 7b while the correct structure is 10b (Z = S, Ar = Ph). These two latter numbers refer to the numbering in ref. [1a]. [d] Lit. mp
288 °C (dec.) (HCONMe ) [1a]; 277 °C (EtOH) [9].
2
in heterocyclic compounds [17] and a paper devoted to the
tautomerism of 2-arylhydrazono-1,4,-benzothiazine deriv-
atives with a side chain containing a carboxy group or an
ester group in position 3 [18] are available.
As shown in Table 5, the electronic absorption spectra of
the products 4a-4i in dioxane reveal two bands in the
regions 276-297 nm and 354-393 nm. This indicates that
the compounds under study, 4a-4i, exist in solution pre-
dominantly as the hydrazone form A, because the absorp-
tion pattern is similar to that of typical hydrazones [8,19].
Furthermore, the spectra of the unsubstituted derivative 4d
in different solvents were found to exhibit little if any sol-
vent dependence (Table 5). The observed small shifts of
4i, revealed the absence of signals characteristic of the OEt
group.
We then turned our attention to the elucidation of the
tautomeric form of the products 4, because, in principle,
these compounds can exist in three possible tautomeric
forms, A-C (Chart 1). To cast some light on the actual
tautomeric form(s), we investigated their electronic
absorption spectra and compared them with those of azo
compounds and hydrazones. A review on the tautomerism
λ
of 4d in different solvents are due to solvent-solute
max
interactions. Supporting evidence for this observation is
the finding that the electronic absorption spectra of aryl-
hydrazones obtained from reactions of quinones with N-
methyl-N-phenylhydrazine, unlike the spectra of o- and p-
hydroxyazo compounds, are basically independent of sol-
vent polarity [8,19].
The assignment of the tautomeric form A to the products
4a-4i was further supported by the similarity of their elec-
tronic absorption spectra with that of 2-[N-methyl-(3-

Mar-Apr 2003
Cyclization of Thiohydrazonate Esters and Azo-Hydrazone Tautomerism
211
chlorophenyl)hydrazono]-3-oxo-1,4-benzothiazine 9f. The
latter compound was prepared in this work by treatment of
the product 4f with methyl iodide in ethanol in the pres-
ence of sodium ethoxide (Scheme 2). Its structure was con-
15
Furthermore, the presence of only one N-induced dou-
blet in the spectrum of the labeled 4d' indicates that only
the E-isomer of the hydrazone form is present in the sol-
vents used.
1
sistent with its spectra (ir, H nmr, and mass) and elemen-
Thus, on the basis of the above data, it is not unrea-
sonable to conclude that the compounds under study,
4a-4i, exist predominantly in the hydrazono tautomeric
structure A.
1
tal analysis. The H nmr spectrum contains a N-Me proton
signal at δ = 3.59 ppm. While this chemical shift is similar
to that reported for N-methyl-N-phenylhydrazones (δ =
3.80 ppm) [5a], it is different from that of N-methyl cyclic
amides (δ = 3.18-3.23 ppm) [20] and 4-methyl-1,4-ben-
zothiazine (δ = 3.13 ppm) [21]. Also, its electronic absorp-
tion spectrum in dioxane exhibits two absorption bands at
EXPERIMENTAL
All melting points were determined on a Gallenkamp appara-
tus and are uncorrected. The infrared (ir) spectra (potassium bro-
mide discs) were obtained on a Pye-Unicam infrared spectrome-
ter. The H, C, and N nmr spectra were recorded in chloro-
form-d and dimethyl-d sulfoxide on a Varian Gemini 300 MHz
instrument. Mass spectra were measured on a GCMS-QP 100EX
spectrometer (ionizing potential 70 eV). Electronic absorption
spectra were recorded in dioxane (and other solvents) on a
Shimadzu uv-visible 3101 PC spectrophotometer. Elemental
analyses were carried out by the Microanalytical Laboratory of
the University of Cairo, Giza, Egypt. N-Aniline (95% isotopic
purity) was purchased from Merck & Co., Inc., Rahway, NJ,
USA.
Ethyl 2-arylhydrazono-2-chloroacetates 1a-1i [23] and methyl
2-phenylhydrazono-2-chloroacetate 6d [9] were prepared by
direct coupling of arene diazonium chlorides with ethyl 2-chloro-
3-oxobutanoate and methyl chloroacetate, respectively, as previ-
ously described. The labeled compound 1d' was prepared by dia-
zotization of N-aniline followed by coupling with ethyl 2-
chloro-3-oxobutanoate. The physical constants of 1d' are identi-
cal with those of the unlabeled compound 1d [23].
λ
288 and 351 nm (Table 5) found in the spectra of typ-
max
ical hydrazones [19].
1
The H nmr spectra of the compounds under study, 4a-4i
1
13
15
(Table 4) provide additional evidence that they exist in the
6
hydrazone form A rather than the azo forms B and C
1
(Chart 1). For example, the H nmr spectrum of each of the
compounds 4a-4i in deuterated dimethyl sulfoxide exhibits
two singlets near δ 9.8 and 11.0-11.3 ppm due to the -
NHCO- and =NNH- protons, respectively. This conclusion
is substantiated by the literature data [20,22].
15
Finally, an unambiguous proof of the tautomeric form A
1
15
for 4a-4i is provided by the H nmr spectrum of the N-
isotopomer 4d' taken as a typical example of a compound
in the series under study. The latter compound was pre-
pared in this work by two different methods. In the first
15
method, N-aniline was diazotized in the usual way and
15
the resulting diazonium salt was coupled with ethyl 2-
15
chloro-3-oxobutanoate to give the N-isotopomer 1d'.
Reaction of 1d' with 2-aminothiophenol (2) in ethanol in
the presence of triethylamine under reflux afforded 4d'
Preparation of Alkyl 2-Arylhydrazono-2-[(2-aminophenyl)thio]-
acetates 3 and 7.
15
(Method B). Alternatively, diazotized N-aniline was
coupled with 8 to give 4d' (Method C). It should be
pointed out that there is no possibility of diazonium scram-
bling during diazotization or coupling reactions [22].
General Procedure.
To a solution of ethyl 2-chloro-2-arylhydrazonoacetate 1 (10
mmol) in ethanol or acetonitrile (30 mL), 2-aminothiophenol
(1.25 g, 10 mmol) and triethylamine (1.4 mL, 1.01 g, 10 mmol)
were added. The reaction mixture was stirred for 24 h at room
temperature and the solvent was evaporated. Water was added to
the residue and the organic product was extracted into chloroform.
The chloroform extract was collected, dried over anhydrous
sodium sulfate, and filtered. The solvent was then evaporated and
the remaining solid residue was collected and crystallized from
ethanol to afford the respective thiohydrazonate esters 3.
When the above procedure was repeated using methyl
2-chloro-2-phenyl-hydrazonoacetate 6d instead of 1, the thiohy-
drazonate ester 7d was obtained. The synthesized esters 3b, 3d,
3g-3i, together with 8 and 9f, and their physical constants are
listed in Table 3.
1
15
The H nmr spectra of N-derivative of ethyl phenylhy-
drazonochloroacetate 1d' in deuterated dimethyl sulfoxide
showed a doublet at δ 10.58 ppm with J = 97 Hz and in
deuterated chloroform a doublet at δ 8.37 ppm with J = 94
Hz, respectively. These observations substantiate the
above conclusion that no diazonium scrambling occurred
and they are consistent with the assigned hydrazone struc-
15
ture 1d'. Also, in deuterated chloroform, the N nmr spec-
trum of 1d' contains a doublet centered at δ 149.8 ppm
with J = 93.6 Hz.
1
15
The H nmr spectrum of the N-derivative 4d' in
deuterated dimethyl sulfoxide contains a doublet centered
at δ 9.86 ppm with J = 93.8 Hz. This indicates that the
Preparation of Ethyl 2,3-Dihydro-3-oxo-4H-1,4-benzothiazine-
2-carboxylate (8).
15
hydrazone proton is attached to the N atom. Because the
N-H signal separation is so large [22] and because the
area of the N-H proton signal relative to the aromatic
15
To a solution of 2-aminothiophenol (2, 12.5 g, 0.1 mol) in
absolute ethanol (100 mL), diethyl chloromalonate (19.0 g, 0.1
mol) and then triethylamine (19.2 mL, 14.0 g, 0.1 mol) were
added. The mixture was stirred for 24 h at room temperature and
15
protons was in a 1:9 ratio, compound 4d' must exist
entirely in the hydrazone form A under these conditions.

212
A. S. Shawali, S. Elsheikh and C. Párkányi
Vol. 40
then the solvent was evaporated. The residue was dissolved in
chloroform and the resulting solution was extracted three times
with water. The chloroform layer was separated, dried over anhy-
drous sodium sulfate, and filtered. The solvent was distilled off,
the remaining solid was collected and crystallized from ethanol
to give the pure benzothiazine derivative 8 (90% yield). The
physical constants of 8 are shown in Table 3.
Methylation of 4f.
To an ethanolic solution of sodium ethoxide, prepared by dis-
solving sodium metal (0.12 g, 5 g-atom) in absolute ethanol (30
mL), compound 4f (1.5 g, 3 mmol) was added with stirring.
Methyl iodide (0.7 g, 5 mmol) was added to the resulting solu-
tion, the mixture was refluxed on a water bath for 1 h, and then
left in a refrigerator for 24 h. The precipitated solid was collected
by filtration, washed with water, dried, and crystallized from
ethanol to afford 9f (Tables 1-3).
Preparation of 2,3-Dihydro-2-arylhydrazono-4H-1,4-benzoth-
iazin-3-ones (4) [9].
Method A.
REFERENCES AND NOTES
The appropriate thiohydrazonate ester 3 (0.01 mol) was added
to ethanol (30 mL, already saturated with hydrogen chloride)
with stirring. The solution was stirred for 3 h at room temperature
and the solvent was evaporated. Water was added to the residue
and the mixture was neutralized with a solution of sodium bicar-
bonate. The aqueous solution was extracted with chloroform
three times and the extracts were collected, dried over anhydrous
sodium sulfate, and filtered. The solvent was distilled off from
the filtrate and the remaining solid residue was collected and
crystallized from the appropriate solvent to give the respective
benzothiazine derivative 4. Information about these products and
their physical constants are summarized in Table 6.
[1a] C. Párkányi, A. O. Abdelhamid and A. S. Shawali,
J. Heterocyclic Chem., 21, 521 (1984); [b] A. O. Abdelhamid, H. M.
Hassaneen, A. S. Shawali and C. Párkányi, J. Heterocyclic Chem., 20,
639 (1983).
[2] M. A. Abdallah, M. A. N. Mosselhi, I. M. Abbas, A. A. Fahmi
and A. S. Shawali, J. Chem. Res. (S), 370 (1995).
[3] M. A. N. Mosselhi, M. A. Abdallah, S. M. Riyadh, A. E.
Harhash and A. S. Shawali, J. Prakt. Chem., 340, 160 (1994).
[4] M. A. Abdallah, M. A. N. Mosselhi, S. M. Riyadh, A. E.
Harhash and A. S. Shawali, J. Chem. Res. (S), 700, (M), 3038 (1998).
[5a] S. A. Khattab, A. S. Shawali and A. M. Farag, J. Chem. Eng.
Data, 22, 104 (1974); [b] C. Párkányi and A. S. Shawali, J. Heterocyclic
Chem., 17, 897 (1980).
Method B.
[6a] A. S. Shawali, H. M. Hassaneen and M. A. Hanna,
Heterocycles, 15, 697 (1981); [b] A. S. Shawali, A. O. Abdelhamid, N. F.
Ahmed, and C. Párkányi, Heterocycles, 19, 2331 (1982).
[7a] B. E. Elanadouli, A. O. Abdelhamid and A. S. Shawali, J.
Heterocyclic Chem., 21, 1087 (1984); [b] A. S. Shawali, S. S. Alkaabi
and M. A. Abdallah, Arch. Pharm. Res., 14, 237 (1991).
[8] A. S. Shawali, N. M. S. Harb and K. O. Badahdah, J.
Heterocyclic Chem., 22, 1397 (1985).
To a mixture of equimolar amounts of 1 and 2-aminothiophe-
nol (2) (5 mmol each) in ethanol (50 mL), triethylamine (0.96
mL, 0.7 g, 5 mmol) was added with stirring. The mixture was
refluxed for 6 h and then cooled. The precipitated solid material
was collected by filtration, washed with water, and crystallized
from the appropriate solvent (Table 6) to afford the respective
benzothiazine derivatives 4. The physical constants of the com-
pounds obtained by this method are shown in Table 6.
When the same procedure was repeated using the labeled com-
pound 1d' instead of 1d, the labeled product 4d' was obtained in
73% yield (mp 288 °C), with no depression of the mp when
mixed with the unlabeled derivative 4d.
[9] N. Almirante and L. Forti, J. Heterocyclic Chem., 20, 1523
(1983).
[10] M. K. A. Ibrahim, M. S. El-Gharib, A. M. Farag and A. H.
Elghandour, Indian J. Chem., Sect. B, 27B, 836 (1988).
[11] R. R. Philips, Organic Reactions, 10, 143 (1959).
[12a] A. S. Shawali and H. M. Hassaneen, Bull. Chem. Soc. Jpn.,
50, 2827 (1977); [b] A. J. Elliott, M. S. Gibson, M. M. Kayser and G. A.
Pawelchak, Can. J. Chem., 51, 4115 (1973).
Method C.
To a stirred solution of 8 (1.9 g, 0.01 mol) in ethanol (30 mL),
a solution of sodium hydroxide (0.6 g, 0.015 mol) in water (10
mL) was gradually added with stirring. The solution was stirred
for an additional 1 h and then chilled in an ice bath at 0-5 °C. A
cold solution of the appropriate benzenediazonium chloride was
prepared in the usual fashion by diazotization of the respective
aniline derivative (0.01 mol) in 6 M hydrochloric acid (4 mL)
with a solution of 1 M sodium nitrite (10 mL). Then the cold
solution of the diazonium salt was added to a stirred cold solution
of 8 described above. When the addition of the diazonium salt
was completed (20 min), the mixture was stirred for 2 h and then
left in a refrigerator for 24 h. The precipitated solid was collected
by filtration, washed with water, and crystallized from the appro-
priate solvent to give 4 identical in all respects with the products
obtained by methods A and B (Table 6).
[13] G. D. Searle & Co. (M. Zimmermann), U.S. Pat. 2841582
(1956); Chem. Abstr., 56, 3496 (1962).
[14] P. Baudet and C. Otten, Helv. Chim. Acta, 53, 1683 (1970).
[15] W. Ried and G. Sell, Liebigs Ann. Chem., 1917 (1980).
[16] H. Tawada, Y. Sugiyama, H. Ikeda, Y. Yamamoto and
K. Meguro, Chem. Pharm. Bull., 38, 1238 (1990); Chem. Abstr., 113,
132112z (1990).
[17] A. R. Katritzky, M. Karelson and P. A. Harris, Heterocycles,
32, 329 (1991).
[18] P. Frohberg, U. Baumeister, D. Stroehl and H. Danz,
Heterocycles, 45, 1183 (1997).
[19] R. Jones, A. J. Ryan, S. Sternhell and S. E. Wright,
Tetrahedron, 19, 1497 (1963).
[20] G. E. Wright, J. Heterocyclic Chem., 20, 1037 (1983).
[21] N. E. MacKenzie, R. H. Thompson and C. W. Greenhalgh,
J. Chem. Soc., Perkin Trans. 1, 2923 (1980).
15
Coupling of 8 with diazotized N-aniline under the same con-
15
ditions gave 4d' - the N- isotopomer of 4d, identical in all
[22] G. J. Lestina and T. H. Regan, J. Org. Chem., 34, 1685 (1969).
[23] A. S. Shawali and H. A. Albar, Can. J. Chem., 64, 871 (1986).
respects with that obtained by method A.