Synthesis and Reactivity of 3,4-Dimethyl-4H-1,3,4-thiadiazines

Article abstract of DOI:10.1055/s-2003-43342

3,4-Dimethyl-4H-1,3,4-thiadiazines, novel 8π heterocyclic systems, were prepared by cyclization of α-haloketones with 1,2,4- trialkylthiosemicarbazides. The desulfurization of the products afforded 5-imino-1,2-dimethylpyrazoles by valence isomerization in

Full text of DOI:10.1055/s-2003-43342

2392
LETTER
Synthesis and Reactivity of 3,4-Dimethyl-4H-1,3,4-thiadiazines
S
ynthesis and Reactivity
o
of 3,4-Dim
e
thyl-
4
H
-1,3,4-t
-
hiadiaz
i
D
nes iethard Pfeiffer,* Erich Dilk, Harald Roßberg, Peter Langer*
Institut für Chemie und Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
E-mail: peter.langer@uni-greifswald.de
Received 25 July 2003
H
Abstract: 3,4-Dimethyl-4H-1,3,4-thiadiazines, novel 8p hetero-
N
N
S
N
S
N
N
cyclic systems, were prepared by cyclization of a-haloketones with
1,2,4-trialkylthiosemicarbazides. The desulfurization of the prod-
ucts afforded 5-imino-1,2-dimethylpyrazoles by valence isomeriza-
tion into thia-s-homopyrazoles.
N
S
2H-1,3,4
6H-1,3,4
4H-1,3,4
Key words: cyclizations, heterocycles, sulfur, synthetic methodol-
ogy, valence isomerization
Figure 1
the methyl group attached to nitrogen atom N4, the prod-
ucts reside in the 4H-tautomeric form. The isolation of
an open-chained intermediate showed that the reaction
proceeded by regioselective attack of the sulfur atom of
the thiosemicarbazide onto the bromide and subsequent
cyclization by attack of the hydrazide onto the carbonyl
group. The structure of thiadiazines 3a–g was elucidated
by spectroscopy and was independently confirmed by
desulfurization experiments (vide infra).
1,3,4-Thiadiazines are of considerable pharmacological
relevance and represent versatile synthetic building
blocks.1 In this context, the desulfurization represents an
important feature.2 Most 1,3,4-thiadiazines reside in their
6H-tautomeric form, due to the relative instability of the
8p-electron system of the 4H-isomer.3 The synthesis of
3,4-unsubstituted 4H-1,3,4-thiadiazines has been claimed
in the early 1950s,4a but the structures were later shown to
be thiazole rather than thiadiazine isomers.4b,c A number
of 4-aryl-4H-1,3,4-thiadiazines were successfully pre-
pared.4b–h Due to the substitution of the nitrogen atom N4,
these compounds reside in the 4H-tautomeric form. The
synthesis of bicyclic derivatives, stabilized by annulation,
has also been reported.5 In an early publication of 1927,
the structure of a number of 3-aryl-1,3,4-thiadiazines
were drawn in the 4H-tautomeric form.6 However, no
spectroscopic evidence was provided. In fact, we and oth-
ers have shown that simple 3-alkyl-1,3,4-thiadiazines re-
side as 6H-tautomers.7 In contrast, the 4H-tautomeric
form is stabilized by the presence of an acetyl or ester
group at carbon C6, due to the conjugation of the double
bond with the carbonyl group.8 Herein, we wish to report
the synthesis of 3,4-dimethyl-4H-1,3,4-thiadiazines. In
contrast to 3-methyl-6H-1,3,4-thiadiazines (Figure 1), we
have found that the desulfurization proceeded very
rapidly and allowed a facile synthesis of pharmacological-
ly relevant 5-imino-1,2-dimethylpyrazoles. 4H-1,3,4-
Thiadiazines (Figure 1) represent interesting building
blocks which should have a variety of synthetic and
pharmacological applications.
Me
N
Me
N
R1
O
Me
R1
Me
H
N
EtOH
N
+
R2
reflux
1 h
Br
S
N
H
S
N
R2
2a–d
1a,b
3a–g
Scheme 1 Synthesis of 2-imino-3,4-dialkyl-2,3-dihydro-4H-1,3,4-
thiadiazines 3a–g
Table 1 Products and Yields
3
R1
R2
[%]a
70b
79b
83b
59b
82b
78c
76c
Mp (°C)
160–161
186–187
190–192
164–166
123–125
131–133
155–157
A
B
C
D
E
F
C6H5
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
4-BrC6H4
4-ClC6H4
C6H5
4-MeC6H4
4-BrC6H4
4-ClC6H4
G
Our starting point was the preparation of the 1,2,4-tri-
alkylthiosemicarbazides 1a,b by reaction of the corre-
sponding isothiocyanates with N,N¢-dimethylhydrazine.9a
The cyclization of 1a,b with a-haloketones 2a–d afforded
the 2-imino-3,4-dimethyl-2,3-dihydro-4H-1,3,4-thiadia-
zines 3a–g in good yields (Scheme 1, Table 1).10 Due to
a Yields of isolated products.
b Hydrobromide.
c Free base.
Treatment of 4H-1,3,4-thiadiazine 3a with HBr acid
(48%) or HCl acid (concd) afforded the novel 5-imino-
1,2-dimethylpyrazole 4 in 40% and 30% yield, respective-
ly (Scheme 2).11,12 The yield was increased to 53% by use
SYNLETT 2003, No. 15, pp 2392–2394
0
1
.1
2
.2
0
0
3
Advanced online publication: 21.11.2003
DOI: 10.1055/s-2003-43342; Art ID: D18903ST.pdf
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis and Reactivity of 3,4-Dimethyl-4H-1,3,4-thiadiazines
2393
of glacial HOAc. The desulfurization proceeded very rap-
idly and precipitation of considerable amounts of sulfur
was observed already after stirring for a few minutes. A
possible mechanism, based on work of Schmidt,3 is
depicted in Scheme 2: Protonation of the amidine moiety
afforded intermediate A and its mesomeric structure B.
An 8p valence isomerization afforded the thia-s-homo-
pyrazole C; extrusion of sulfur gave the protonated pyra-
zole D which afforded the product 5a by deprotonation.
The product was isolated as a hydrobromide when hydro-
bromide acid was used. It was shown by NMR that the hy-
drobromide exists as a protonated amidine (structure D).
Me
N
Me
N
Me
R
O
R
Me
H
N
EtOH
N
+
tBu
Se
N
H
reflux
1 h
Br
Se NtBu
2a,c
E
5
+ H+
Me
Me
N
N
+
R
N
Me
N
Me
R
H
_
N
Se
H+
Se
_
NtBu
tBu
F
Me
6a,b
Me
Ph
N
Me
N
conditions
Me
Ph
N
Scheme 3 Cyclization of selenosemicarbazide 5 with -phenacyl-
bromides 2a,c (6a: R = C6H5, 54%, 6b: R = 4¢-ClC6H4, 62%)
N
_
S
S
N
N
Me
Me
4
Protonation of the amidine moiety and an acid catalyzed
prototropic shift afforded the 8p system G which under-
went a valence isomerization to give the thia-s-homo-
pyrazole H. Desulfurization and deprotonation afforded
the final product.
3a
+ H+
_
H+
Me
N
Me
Ph
N
Me
Me
+
Ph
N
N
AcOH
reflux, 40 h
Ph
N
Me
NR
N
Me
Ph
N
+
N
N
H
S
N H
S
_
Me
S
Me
Me
NHR
D
A
8a,b
7a,b
_
S
_
H+
+ H+
_
S
Me
+
+
N
Ph
N
N
Me
Ph
N
Me
H
N
H
N
+
+
N
Ph
Me
Ph
Me
H
H
N
N
S
N
S
H
H
Me
Me
N
R
S
N
R
S
C
B
G
H
Scheme 2 Desulfurization of 3a. Reaction conditions: Reflux, 1 h,
HBr (48%), HCl (concd) or glacial HOAc, 30–53% yield
Scheme 4 Desulfurization of 7a,b (8a: R = Me, 41%, 8b: i-Pr, 81%)
The synthesis and desulfurization of a 4H-1,3,4-selenadi-
azine was next studied (Scheme 3). The reaction of sele-
nosemicarbazide 59b with a-phenacylbromides 2a and 2c
directly afforded the 5-imino-1,2-dimethylpyrazoles 6a
and 6b in 54% and 62% yield, respectively. The reaction
proceeded by formation of the 4H-1,3,4-selenadiazine E
which underwent a valence isomerization into the selena-
s-homopyrazole F. The latter underwent a rapid extrusion
of selenium.
The results outline above can be explained as follows: the
extrusion of sulfur from thiadiazines 3 and 7 proceeded by
a valence isomerization and required the formation of a
thermodynamically unfavourable 8p electron intermedi-
ate. The rapid desulfurization of 4H-1,3,4-thiadiazines 3
can be explained by the fact that the 8p intermediate B is
readily available by simple protonation of the amidine
moiety; the C(5)=C(6) double bond was already present in
the starting material. In contrast, the desulfurization of the
6H-1,3,4-thiadiazines 7 required the formation of the
C(5)=C(6) double bond (intermediate G). In case of the
selena-analogous system, the 4H-1,3,4-selenadiazine was
detected only in the form of intermediate F.
We have earlier reported that the desulfurization of the 6-
unsubstituted 3-methyl-6H-1,3,4-thiadiazine 7a was stud-
ied (Scheme 4).7a This experiment is included herein for
reasons of comparison. Treatment of 7a and of novel 7b
with glacial HOAc afforded the pyrazoles 8a and 8b in
41% and 81% yield. In contrast to the rapid desulfuriza-
tion of 4H-1,3,4-thiadiazines 3, a much longer reaction
time (40 h) was required to achieve a complete desulfur-
ization. A possible mechanism is depicted in Scheme 4:
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
Synlett 2003, No. 15, 2392–2394 © Thieme Stuttgart · New York

2394
W.-D. Pfeiffer et al.
LETTER
820 (m), 970 (m), 1030 (m), 1170 (m), 1311 (s), 1410 (m),
1460 (s), 1499 (s), 1610 (s), 2995 (m), 3110 (m), 3225 (s)
cm–1. 1H NMR (300 MHz, DMSO-d6): d =3.22 (br s, 1 H,
NH+), 3.36 (d, 3 H, NHMe+), 3.75 (s, 3 H, NMe) 4.18 (s, 3
References
(1) Reviews: (a) Pfeiffer, W.-D. In Methoden der organischen
Chemie (Houben-Weyl), Volume E9; Thieme: Stuttgart,
1997, 489. (b) Beyer, H. Z. Chem. 1969, 9, 361.
H, NMe), 6.26 (s, 1 H, 6-H), 7.32–7.66 (m, 5 H, ArH). 13
C
(2) (a) Schmidt, R. R.; Huth, H. Tetrahedron Lett. 1975, 33.
(b) Pfeiffer, W.-D.; Bulka, E. Synthesis 1977, 196.
(c) Pfeiffer, W.-D.; Bulka, E. Synthesis 1977, 485.
(d) Pfeiffer, W.-D.; Miethchen, R.; Bulka, E. Z. Chem. 1978,
27, 296. (e) Pfeiffer, W.-D.; Geisler, K.; Roßberg, H.;
Bulka, E. Z. Chem. 1982, 22, 137.
NMR (75 MHz, DMSO-d6): d = 30.14 (NMe), 32.52 (NMe),
43.99 (NMe), 121.78 (6-C), 124.38 (CH, Ar), 128.65 (CH,
Ar), 129.90 (CH, Ar), 130.92 (Ar), 150.58 (5-C), 152.50 (2-
C). MS (EI, 70 eV): m/z = 234 (17) [M+], 233 (11), 231 (9),
220 (31), 218 (43), 202 (23), 201 (29), 187 (48), 186 (16),
118 (23), 96 (92), 94 (100). Anal. Calcd for C12H16N3BrS
(314.25): C, 45.87; H, 5.13; N, 13.37. Found: C, 45.79; H,
4.56; N, 13.08. All products gave satisfactory spectroscopic
and analytical data.
(3) For a review of 8p heterocycles, see: Schmidt, R. R. Angew.
Chem. 1975, 87, 603.
(4) (a) Sato, T.; Ohta, M. J. Pharm. Soc. Jpn. 1955, 75, 1535;
Chem. Abstr. 1956, 50, 10727. (b) For true 4-aryl-4H-1,3,4-
thiadiazines, see: Schildknecht, H.; Enzmann, F.; Gessner,
K.; Penzien, K.; Römer, F.; Volkert, O. Angew. Chem. 1966,
78, 841. (c) Ege, G. Angew. Chem. 1967, 79, 618.
(d) Campaigne, E.; Selby, T. P. J. Heterocycl. Chem. 1978,
15, 401. (e) See also: Mathes, R. A. J. Org. Chem. 1952, 17,
877. (f) Sandström, J. Ark. Kemi 1955, 6, 487.
(g) Giammanco, G. Atti Accad. Sci. Lett. Arti Palermo Parte
1 1964, 23, 139; Chem. Abstr. 1965, 62, 10425b. (h) Saad,
H. A. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 175, 65.
(5) (a) Ismail, I. M.; Jacobi, R. Indian J. Chem. Sect. B 1978,
16B, 307. (b) Gakhar, H. K.; Gupta, S. C.; Kumar, N. Indian
J. Chem. Sect. B 1981, 20, 14. (c) Udupi, R. H.; Kulkarni,
V. M.; Purushottamachar, P.; Srinivasalu, N. J. Indian
Chem. Soc. 2002, 79, 381.
(6) (a) Bose, R.; Ray-Chaudhury, G. J. Indian Chem. Soc. 1927,
4, 259. (b) See also: Entenmann, G. Synthesis 1973, 225.
(7) (a) Pfeiffer, W.-D.; Dilk, E.; Bulka, E. Z. Chem. 1982, 22,
173. (b) See also: Pfeiffer, W.-D.; Lachmann, K.; Epperlein,
U. Pharmazie 1994, 49, 401.
(8) Tanabe, Y.; Mori, K.; Nishii, Y. Heterocycles 1996, 43, 141.
(9) (a) Jensen, K. A. Acta Chem. Scand. 1968, 22, 1.
(b) Jensen, K. A.; Felbert, G.; Pedersen, C. T.; Svanholm, U.
Acta Chem. 1966, 20, 278.
(10) Typical Procedure for the Synthesis of 2-Alkylamino-
3,4-dimethyl-5-aryl-2,3-dihydro-4H-1,3,4-thiadiazines
(3). An EtOH solution (20 mL) of 1,2-dimethyl-4-iso-
propylthiosemicarbazide (1a) (1.47 g, 10.0 mmol) or of
1,2,4-trimethylthiosemicarbazide (1b) (1.19 g 10.0 mmol)
and of the corresponding phenacyl bromide 2 (10.0 mmol)
was refluxed for 1 h. After cooling to 20 °C, Et2O was added
to give a colourless precipitate. The latter was isolated by
filtration and recrystallized from EtOH–Et2O with addition
of HBr. 3a: Yield: 2.20 g (70%); colourless lamella (EtOH–
Et2O); mp 160–161 °C. IR (KBr): 705 (m), 712 (m), 781 (m),
(11) 1,2-Dimethyl-3-phenyl-5-methyliminopyrazoline-
hydrate hydrobromide (4). Method A: A solution of 3a
(3.14 g, 10.0 mmol) in HBr acid (15 mL, 48%) was refluxed
for 1 h. After refluxing for 4–5 min sulfur started to
precipiate. The solvent was evaporated under reduced
pressure. The residue was recrystallized from EtOH–Et2O to
give 4 as colourless lamella (1.20 g, 40%), mp 168 °C. The
compound crystallized as a hydrate and hydrobromide. The
water could not be completely removed in vacuo over P4O10
(140 °C). Method B: A solution of 3a (3.14 g, 10.0 mmol) in
HCl acid (15 mL, concentrated) was refluxed for 1 h. The
work up was carried out as described for method A. Yield:
0.90 g, 30%. Method C: A solution of 3a (3.14 g, 10.0 mmol)
in glacial HOAc (10 mL) was refluxed 1 h. The mixture was
poured into Et2O (150 mL). A colourless precipitate was
formed. The latter was filtered off and recrystallized from
EtOH–Et2O to give 4 as a colourless solid (1.60 g, 53%). IR
(KBr): 780 (s), 805 (m), 812 (m), 924 (w), 989 (w), 1045
(m), 1082 (m), 1203 (w), 1295 (m) 1302 (m), 1430 (s), 1480
(s), 1496 (m), 1542 (m), 1645 (s), 2920 (m), 2951 (m), 3098
(s), 3225 (s) cm–1. 1H NMR (300 MHz, CDCl3): d = 1.78 (br
s, 1 H, NH+), 2.99–3.01 (d, 3 H, NHMe+), 3.71–3.78 (d, 3 H,
NHMe+), 4.24 (s, 3 H, NMe), 5.74 (s, 1 H, 4-H), 7.45–7.59
(s, 5 H, ArH), 8.40 (br s, 1 H, NH+). 13C NMR (75 MHz,
CDCl3): d = 30.31 (NMe), 34.74 (NMe), 35.11 (NMe), 89.53
(CH, Hetar), 126.89 (CH, Ar), 128.8 (CH, Ar), 129.49 (CH,
Ar), 131.34 (Ar), 152.10 (3-C), 153.72 (5-C). MS (EI, 70
eV): m/z = 234 (4) [M+], 219 (4), 201 (11), 188 (100), 172
(10), 145 (16), 102 (48). Anal. Calcd for C12H18N3O
(300.20): C, 48.01; H, 6.04; N, 13.98. Found: C, 48.20; H,
6.20; N, 13.98.
(12) For a related derivative, see: Plescia, S.; Daidone, G. J.
Heterocycl. Chem. 1983, 20, 1153.
Synlett 2003, No. 15, 2392–2394 © Thieme Stuttgart · New York