Synthesis, oxidation and dehydrogenation of cyclic N,O- and N,S-acetals. Part 1. Transformation of N,S-acetals: 3-acyl-1,3,4-thiadiazolines

Article abstract of DOI:10.3987/COM-04-10137

Aldehyde and ketone thiosemicarbazones are synthesized and cyclized into 3-acyl-1,3,4-thiadiazolines under acylating conditions. Reactions of the 2-monosubstituted heterocycles with oxidizing and dehydrogenating agents (KMnO₄ or for the first time with CAN, DDQ, IBDA) lead to the formation of thiadiazoles. CAN oxidation of 2,2-disubstituted 3-acyl-1,3,4-thiadiazolines regenerates the parent ketones efficiently.

Full text of DOI:10.3987/COM-04-10137

HETEROCYCLES, Vol. 63, No. 10, 2004, pp. 2243 - 2267
Received, 2nd June, 2004, Accepted, 2nd September, 2004, Published online, 7th September, 2004
SYNTHESIS, OXIDATION AND DEHYDROGENATION OF CYCLIC N,O-
AND N,S-ACETALS. PART 1. TRANSFORMATION OF N,S-ACETALS: 3-
ACYL-1,3,4-THIADIAZOLINES
László Somogyi
Department of Organic Chemistry, University of Debrecen, P.O. Box 20, H−4010
Debrecen, Hungary (Fax: + 36 (52) 453−836), somoladeszerv@freemail.hu.
Abstract – Aldehyde and ketone thiosemicarbazones are synthesized and cyclized
into 3-acyl-1,3,4-thiadiazolines under acylating conditions. Reactions of the 2-
monosubstituted heterocycles with oxidizing and dehydrogenating agents (KMnO4
or for the first time with CAN, DDQ, IBDA) lead to the formation of thiadiazoles.
CAN oxidation of 2,2-disubstituted 3-acyl-1,3,4-thiadiazolines regenerates the
parent ketones efficiently.
INTRODUCTION
The formation of cyclic N,O- and N,S-acetals can be formally described by addition of an OH or SH
group, located in the carbonyl or amino portion of the open-chain molecule, to the C=N bond (Scheme 1).
The structure of the cyclic compound formed in this way, and the state of the equilibrium are determined
by the electronic, steric and thermodynamic properties of the molecules and the nucleophilicity of the
heteroatoms X and Y, respectively.
The ring-chain tautomerism1 is a very important phenomenon from chemical and biological point of view
[glycosylamines, sugar-amino acid condensates, etc.; e.g. to D-galactose thiosemicarbazone an open-chain
hydrazone (B, Scheme 1) and a pyranose (A) structure,2 respectively, to the D-glucose derivative a
glucosylamine structure (A),3 to the ligand of a 1:1 complex of D-glucose thiosemicarbazone with CuCl2,
however, a 2-amino-5-(D-gluco-pentahydroxy)pentyl-1,3,4-thiadiazol-5-ine structure (C)4 have been
attributed]. The cyclic or open-chain isomers can be stabilized chemically, e.g. by acetylation,5 whereby
modifying solubility, biological absorption (membrane and barrier permeability) and activity. Chemical
as well as microbial or enzymic deacetylation6a-e (phase 1 metabolism) can lead to (re)cyclization or to
regeneration of the original isomerizable compound and the parent acid hydrazide6f–h respectively.

HX
N
HX
NH
R
X
R
R
C
C
C
Y
NH
YH
YH
C
B
A
Scheme 1
Dehydrogenation of aldehyde cyclic N,O- or N,S-acetals, the latter is a spontaneous process occasionally,
seems to be a versatile and promising alternative route for the synthesis of various 2-substituted 1,3-
azoles and 1,3-azines, respectively. – It should also be noted, however, that some dehydrogenation
products, e.g. 1,3,4-oxadiazoles7 and 1,3,4-thiadiazoles8 undergo recyclization with intra- or
intermolecular nucleophiles.
The chemistry of 1,3,4-thiadiazol(in)es1b,c,e,g,9a,10 as biologically active9b,c,11,12 and/or complex -
forming11p,13 substances is well documented and has been enormously extended if only in view of late
~15 years, as well. 2,5-Disubstituted 1,3,4-thiadiazoles have been synthesized by cyclization of N,N´-
di(thio)acylhydrazines,14 by condensing thioacid hydrazides with trichloromethanes,15 carboxylic acids,16
iminoesters,17 or (iso)nitriles16d,18 (eventually, however, under vigorous conditions), moreover by treating
aldehyde thioacylhydrazones (including thiosemicarbazones) with FeCl3,13a,19a–w K3[Fe(CN)6],19g,20
MnO2,21 Br2/AcOH,22 or DDQ.23 On the other hand, DDQ cyclizes 4-substituted thiosemicarbazides into
5-substituted
imino-∆3-2,1,3,4-oxathiadiazolines
and
-2,2-dioxo-∆3-1,2,3,4-dithiadiazolines,24
N-benzylidene-2-hydroxyanilines into 2-substituted phenylbenzoxazoles,25 and cleaves tosylhydrazones
or oximes to the parent carbonyl compounds.26 In addition, 2,5-disubstituted 1,3,4-thiadiazoles have been
prepared, in an uncommon reaction, by treating aldehyde thiosemicarbazones with
NaOAc/NaBr/AcOH,27 as well as by transforming 1,3,4-oxadiazoles with thiourea7d and 1,2,4,5-tetrazines
with sulfur,28 respectively. Of the various 1,3,4-thiadiazole syntheses, for this once, mostly the
dehydrocyclization reactions will be considered.
Thioacylhydrazines react with carbonyl compounds to give immediately the corresponding 1,3,4-
thiadiazolines11d,29 or sometimes their prototrops forms.11d,29g Thiosemicarbazones undergo similar
cyclization, mainly in acid medium to form an equilibrium mixture of the open-chain and prototrop cyclic
entities.11b,e,19m,30 Some aldehyde thiobenzoylhydrazones exist as ∆2-thiadiazolines also in solution and
are spontaneously dehydrogenated by prolonged heating,29c,31 or by oxygen at room temperature,19c,x,29d to
afford 1,3,4-thiadiazoles. With respect to the ring-chain tautomerism and the prototropy mentioned above,
stabilization of the cyclic form is suitable. Under acylating conditions thioacylhydrazones, including
thiosemicarbazones, undergo transformation to 5-substituted 3-acyl-1,3,4-thiadiazolines1i,14c,32 instead of

l,33
N,S-diacyl-thiosemicarbazones as have been suggested previously.13a,19
3-acylthiadiazolines by treating with H2O2,19 l,33c,d FeCl3,32a,d or KMnO4
Dehydrogenation of the
has been reported to afford
21,32d
1,3,4-thiadiazoles.
As an extension of our previous works with spiro[tetrahydroquinoline-4,2´-[1,3,4]thiadiazoline] (11a)34 and
spiro[flavan-4,2´-[1,3,4]oxa(thia)diazolines] (11b,c)32h the analogous thioflavan spirocompounds (11d,e)
have been synthesized35 and, for obtaining the corresponding thioflaven analogs subjected to
transformation with CAN capable36 of dehydrogenating thioflavanone to thioflavone. When treating 11e
with CAN, however, thioflavone formed with degradation of the thiadiazoline moiety.35 Owing to these
difficulties, the oxidation and dehydrogenation reactions of 1-thiobenzopyran37 and diazoline rings,
respectively, have been separately investigated. In this paper the works aimed at the transformation of
1,3,4-thiadiazolines by oxidizing and dehydrogenating agents are presented.
R
N
X
NAc
Q
Ph
11
Q
X
R
NAc
O
S
S
NHAc
NHAc
Me
R1
NR2R3
11a
11b
11c
11d
11e
O
O
O
S
S
S
R1= Me, Ph; R2= H, Ph; R3= Ac
RESULTS AND DISCUSSION
The electronic structure and chemical reactivity of a C=N bond is influenced by the electronic properties
of the substituents (see e.g. ref. 38). Thus, thiosemicarbazones of various benzaldehydes diversely
substituted as regards the position, number, bulk, electronic properties, and reactivity of the substituents
(1, see also Table 1) were prepared and, under acetylating conditions (Ac2O, Ac2O/pyridine,
Ac2O/ZnCl2), cyclized into 3-acetyl[1,3,4]thiadiazolines (2, Table 2). These compounds are substrates for
subsequent reactions with various types of oxidants and dehydrogenating agents of diverse mechanisms
of action (see Table 3). For explorating such cyclization reactions, some additional aldehyde and ketone
thiosemicarbazones (6) were prepared and converted into thiadiazolines (7) (see Tables 6,7). The
structure of the products was supported by 1H- and 13C NMR spectral data (see Tables 4,5,8).

R6
C
R7
R7
N
N
S
H
NH
N
S
NAc
S
N
H
O
C
C
R5
R4
R1
R2
R5
R1 R5
R1
R2
R5
R4
R1
R2
R4
R2 R4
R3
R3
R3
R3
1
2
3
4
R1
H
R2
R3
Cl
R4
H
H
H
H
H
H
R5
H
R6
R7
H
H
H
H
NH2
NH2
NH2
NHPh
NH2
NH2
NH2
NH2
NHAc
NHAc
NHAc
NAcPh
NHAc
NHAc
NHAc
NHAc
a
b
c
H
NO2
H
H
C1
C1
C1
H
Cl
Cl
Cl
H
H
d
e
NO2
Cl
H
Cl
f
H
OMe
H
OMe
OMe
OMe
H
g
h
OMe
H
OMe
AcHN
N
S
C
R2
R2
R1
H
S
NAc
C
N
N
NH2
O
R1
R1
R2
5
6
7
R1
R2
Me
Me
Me
Me
Me
H
4-ClC6H4
4-BrC6H4
2-pyridyl
a
b
c
d
e
f
2,4-(HO)2C6H3
2,4-(AcO)2C6H3
Indol-3-yl
1-(Ac)indol-3-yl
H
g
The acetylating agents used (and others e.g. AcCl/Me2NPh, Ac2O/Et3N) are reported, however, also to
transform2,32h,39,40 thiosemicarbazones into acylhydrazones and diacylhydrazones or N-triacetyl-
enehydrazines. On this subject, especially the Ac2O/ZnCl2 couple is capable of producing transformations
of various types. This agent is known to acetylate thiosemicarbazones at position 4,39 and to cyclize
(thio)acylhydrazones into 3-acetyl[1,3,4]oxa(thia)diazolines.41

Table 1. Preparation and properties of thiosemicarbazones (1)
Producto
Reactiono
Solvento
Reactiono
temp. [°C]a
(time [h]) o
Workupb
Yield [%]o
crudec
(pure)c
80o
o
o
o
o
components o
(mL) o
o
o
(mmol) o
o
o
1ao
1bo
4a (40) o
TSC (42)
AcOHo
(30)
100o
(3)
Ao
Ao
4b (20) o
TSC (30)
AcOHo
(20)
100o
(2)
90o
1co
4c (10) o
TSC (10.5)
MeOHf
(20)
bp o
(1.5)
A o
99.5 o
o
o
o
o
o
1dh
4d (10) o
EtOAco
(8)
bpo
Ao
95.5o
96.4 o
o
o
o
o
o
PTSC (10)
(1.5)
1eo
4ei (20) o
TSC (23)
AcOH o
(20)
100 o
Aj
o
o
o
o
(2)
1fo
4f (60) o
MeOHl
(75) o
bp o
A o
85 o
o
o
o
o
o
o
TSC (63)
(3.5) o
o
1go
4g (20) o
TSC (21)
MeOHo
(35)
bp o
(6)
A o
97 o
o
o
o
o
1ho
4h (20) o
TSC (21)
MeOHo
(40)
bp o
(2.5)
A o
96 o
(94)
o
o o
o
o
o
Table 1. Preparation and properties of thiosemicarbazones (1) (continued)
Producto
Mp [°C] o
(solvent)
Lit. mp [°C]o o
(solvent)
Formulao
(mol. mass)
Analysis
found (calcd)
H
C
N
1ao
215d
243d
220e
(aq.EtOH)
C8H8N3ClS o
(213.7)
o
1bo
255e
(95% EtOH)
C8H8N4O2S o
(224.2)
o
o
o
1co
237d
236−237g
(EtOH)
C8H7N3Cl2S o
(248.1)
o
1dh
208–209d
C14H11N3Cl2S o
(324.2)
52.07 o
(51.86)
3.49 o
(3.42)
13.08h
(12.96)
o
o
o
o
1eo
229−230d
234−235 (MeOH)
C8H6N4O2Cl2S o
(293.1)
33.28 o
(32.78)
2.51 o
(2.06)
18.93k
(19.11)
o
o
1fo
214−215d,m
194−195 o
C8H7N3Cl2S o
38.94 o
2.86 o
16.87 o
o
o
o
oo
o
o
o
216 (MeOH)oo
(EtOH)n
(248.1) o
(38.72) o
(2.84) o
(16.94) o
o
o
o
1go
206−207d
209−210 (EtOH)
216−217p
(DMF/EtOH)
C11H15N3O3S o
49.33 o
(49.05)
5.60 o
(5.61)
15.70q
(15.60)
o
o
o
o
o
(269.3)
1ho
160−162 o
(DMF/H2O)
C11H15N3O3So
(269.3)
49.22 o
(49.05)
5.71 o
(5.61)
15.68r
(15.60)
o
o
o

a
b
TSC = thiosemicarbazide, PTSC = 4-phenyl-3-thiosemicarbazide. Bath if not bp. For general operations of processing the
c
d
e
reaction mixtures see EXPERIMENTAL. Without workup of the mother liquors. Crude product. Corrected, ref. 53.
Containing 0.5 mL AcOH. Ref. 54. h Cl 21.98 (21.87), S 10.05 (9.89). The same product was obtained in 71% yield when
f
g
treating 2,6-dichlorobenzaldehyde hydrazone (1mmol) with PhNCS (1.1 mmol) in boiling EtOAc (2 mL) for 1.5 h; mp
i
j
k
206−208 °C (from pyridine with addition of water). Ref. 55. Previously water (10 mL) was added. Cl 24.04 (24.19), S
l
m
n
o
11.01 (10.94). Containing 3 mL AcOH. TLC [PhH/EtOAc (1:2)] homogeneous. Ref. 19b. Containing 1 mL AcOH.
p Ref. 56; ref. 57 : mp 215−216 °C. q S 11.87 (11.91). r S 11.66 (11.91).
By heating above the melting point, 5-acetamido-3-acetyl-2-(4-nitrophenyl)-1,3,4-thiadiazoline (2b) was
dehydrogenated to thiadiazole (3b) in 88% yield (see EXPERIMENTAL). Hitherto thermolysis of 2,5-
disubstituted 3-nitroso-1,3,4-thiadiazolines19m and of a spiro-∆3-1,3,4-thiadiazoline with C―O bond
cleavage to give a 2-substituted 1,3,4-thiadiazole have been reported.42 Also dehydrogenation of ketone
cyclic N,S-acetals with concomitant reductive C―C bond cleavage resulting in the formation of
benzothiazole43 and 1,3,4-thiadiazole19d,44 derivatives, respectively, has been observed perviously.
Moreover, when treating a carbohydrate aldehyde thiosemicarbazone with Ac2O/pyridine, in addition to
the expected formation of the corresponding 2-substituted 5-acetamido-3-acetyl-1,3,4-thiadiazoline the
Table 2. Preparation and properties of 1,3,4-thiadiazolines (2)
Producto
Substrateo
Agentso
Reaction oo
temp. [°C]a
(time [h]) o
Workupb
Yield[%o]o
crudeo
o
o
o
(mmol) o
(mmol) o
(pure)c
2a oo
2b o o
2c oo
1ao
Ac2Oo
(233)
bpo
(2)
C, D, Ao
90e
o
o
o
o
(20)
1bo
Ac2Oo
(53)
bpo
Bo
98f
o
o
o
o
(9)
(0.5)
1co
Ac2Oo
(530)
bpo
(1)
Ao
95o
o
o
o
o
(40)
1co
Ac2O (106) o
ZnCl2 (11)
55o
Ao
95o
o
o
o
o
(4) o
(5) o
2do
1do
Ac2O (106)o
pyl (124)
23o
Bo
97o
o
o
o
o
o
(6)o
(24) o
(80) o
2eo
2fo
1eo
Ac2Oo
(1060)
bpo
Ao
96o
o
o
o
o
(63)
(0.75)
(88)
1fo
Ac2O
(212)
bpo
Ao
85o
o
o
o
o
(16)
(2)
(70)
2go
2ho
1go
Ac2Oo
(159)
bpo
C, Eo
99o
o
o
o
o
(22)
(0.5)
(86)
1ho
Ac2Oo
(27)
bpo
(2)
Bo
69o
o
o
o
o
(1.9)
(27)

Table 2. Preparation and properties of 1,3,4-thiadiazolines (2) (continued)
Producto
Mp [°C] o
(solvent)
Lit. mp [°C]oo
(solvent)
Formulao
(mol. mass)
Analysis
found (calcd)
H
C
N
2ao
247d
(EtOH)
229−233e
(EtOH)
C12H12N3O2ClSoo
(297.8)
o
o
o
g
2bo
227do
230 (EtOH)
210−211f
(EtOH)
C12H12N4O4So
46.89
(46.74)
3.92
18.16
o
o
(3.92)
(18.17)
(308.3)
o
o
i
2co
203do
236−237
C12H11N3O2Cl2So
(332.2)
43.88
3.54
12.34
o
o
(43.38)
(3.34)
(12.65)
(DMSO/H2O) h
235−236d
203−204
(DMSO/H2O) h
o
o
j
2do
183o
C18H15N3O2Cl2So
(408.3)
53.12
3.70
10.34
o
o
(52.95)
(3.70)
(10.29)
(EtOAc/heptane)
o
o
k
2eo
266−267d
271−272 (Ac2O)
C12H10N4O4Cl2S
(377.2) o
38.42
2.70
14.90
o
o
o
o
o
(38.21)
(2.67)
(14.85)
o
o
m
2fo
202−204d
203
C12H11N3O2Cl2So
(332.2)
43.56
3.40
12.68
o
(43.38)
(3.34)
(12.65)
(EtOHl/heptane)
o
o
p
2go
164d,n
C15H19N3O5So
(353.4) o
51.03
5.63
12.18
o
166−167 (MEK) o
(50.98)
(5.42)
(11.89)
o
o
o
o
q
2ho
218−219o
C15H19N3O5So
(353.4) o
51.15
5.50
12.07
o
o
o
o
o
(CHCl3/EtOAc)
(50.98)
(5.42)
(11.89)
a
b
c
Bath if not bp. For general operation of processing the reaction mixtures see EXPERIMENTAL. Without workup of the
mother liquors. Crude product. e Ref. 32a, d, yield 68%. Ref. 32a, d , yield 57%. g S 10.67 (10.40). From hot DMSO
solution with addition of water. When recrystallized from AcOH/H2O or DMF/H2O 2c contains some AcOH and DMF,
recpectively, as a solvate. i Cl 21.05 (21.35), S 9.73 (9.65); before the analysis 2c was kept at 100 °C/0.1 Torr over P4O10. EI-
d
f
h
MS: m/z (%) [M+·] 333 (8) and 331 (11), [2,6−Cl2C6H3−C≡S+] 189 (6). Cl 17.37 (17.37), S 7.88 (7.85). Cl 18.93 (18.80),
S 8.65 (8.50). l Anhydrous. m Cl 21.28 (21.35), S 9.86 (9.65). n When workup (A) was done (yield 81%). o 2-butanone (methyl
ethyl ketone). p S 9.39 (9.07); EI-MS: m/z (%) [M+·] 353 (21). q EI-MS: m/z (%) [M+·] 353 (22).
j
k
dehydrogenated analog thiadiazole was also formed.19w For the pyrolysis of aldehyde thiosemicarbazones
to give, among others, 5-substituted 2-amino-1,3,4-thiadiazoles45 a free radical mechanism has been
suggested.46
Besides the oxidant KMnO4 used21,32d previously for the dehydrogenation of 2,5-disubstituted 3-acyl-
1,3,4-thiadiazolines, also the one-electron acceptor CAN was efficiently applied for such transformations
now for the first time. This method is more ready and, with more simple processing, often affords almost
pure crude products in better yields in comparsion with the KMnO4 oxidation (see Table 3). Also the
dehydrogenation power of the charge-transfer complex forming DDQ and the hypervalent iodine oxidant
IBDA were tested and found to be effective (transformations 2b→3b an d 2a→3a, Table 3).

It should be noted, however, that while IBDA has been reported47 to transform aldehyde acylhydrazones
into 1,3,4- oxadiazoles at room temperature within 2 minutes,47a it dehydrogenated 5-acetamido-3-acetyl-
1,3,4-thiadiazoline (2a) into thiadiazole (3a), devoid of a deprotonable N-iminoamide or an intermediary
endocyclic secondary amine moiety, much more slowly. The transformation of the 5-acetamido (2) entities
can be suggested to start with loss of the AcNH proton and then the electron rich heterocycle joins with
the endocyclic nitrogen to the hypervalent iodine reaction centre. In consonance with this mechanistic
hypothesis, while a treatment with IBDA in methanol solution dehydrogenated 5-acetamido thiadiazoline
(2c) at room temperature almost completely [TLC, CHCl3/MeOH (95:5)] during 3 days, under the same
conditions the 5-acetanilido analog (2d) resisted transformation [TLC, CHCl3/MeOH (95:5)] after 4 days,
Table 3. Preparation and properties of thiadiazoles (3)a
Producto
Substrateo
(mmol)
Agento
(mmol)
Solvento
(mL)
Reaction oo
temp. [°C]
Workupd
Yield[%]o
crude
o o
o
o
o
o
(time [h]b,c
)
(pure)
3ao
2ao
(0.5)
KMnO4
(1.85)
AcOH(10) o
H2O (3)
< 20o
F, C, Eo
70o
o
o
o
o
o
o
o
(1.5; 3)
2ao
(0.5)
CANh
MeCN(10) o
H2O (1)
23o
G, Ao
94.5o
o
o
o
o
o
(0.967) o
(0.33; 0.75) o
2ao
(0.5)
IBDAi
(0.55)
MeOH (15) o
23o
Ao
93o
o
o
o
o
o
o
(2; 36)
3bo
2bo
KMnO4
AcOH (20) o
H2O (3)
< 20o
F, G, Ao
G, A o
81o
o
o
o
o
o
o
o
(2) o
(5) o
(1; 1.5) o
2b o
CAN o
MeCN (10)o
H2O (3)
23 o
98.5 o
(1) o
(2.08) o
(0.15; 0.1) o
2bo
(0.5)
DDQo
(0.6)
PhH (5) o
bpo
(6)
A, Ko
85o
o
o
o
o
o
3co
2co
KMnO4
(2.5)
AcOH (10) o
oH2O (3) o
< 20o
F, G, Ao
G, A o
77.5o
o
o
o o
o
o
o
o
(1) o
(1.5; 1) o
2c o
CAN o
(1.7) o
MeCN (10)o
H2O (1)
23 o
84 o
(1) o
(0.13; 0.5) o
3d o
2d o
CAN o
MeCN (30)o
H2O (1.5)
23 o
G, A o
97 o
(1.5) o
(2.63) o
(0.2; 0.33) o
(88) o
3eo
2e o
KMnO4
AcOH (12) o
H2O (2)
< 20o
F, G, Ao
84o
o
o
o
o
o
o
o
(1) o
(2.5) o
(1.2; 1.5) o
3go
2go
KMnO4
AcOH (15) o
H2O (3)
< 20o
F, G, Ao
G, A o
35o
o
o
o
o
o
o
o
(2) o
(5) o
(1; 2) o
(31) o
2g o
CAN o
MeCN (5) o
H2O (1.5)
23 o
64 o
(1) o
(2.03) o
(0.6; 0.17) o
(52) o

Table 3. Preparation and properties of thiadiazoles (3)a (continued)
Producto o
Mp [°C] o
(solvent)
Lit. mp [°C] o
(solvent)
Formula o
(mol. mass)
Analysis
found (calcd)
H
C
N
3ao
330e,f
322−324o
o
(EtOH) g
331e,f
C10H8N3OClSo
(253.7) o o
47.31o
3.18o
16.65o
o
o
o
o
335(CHCl3) f
(47.34) o o
(3.18) o o
(16.56) o o
333e,f
3bo
>360e
C10H8N4O3S o
(264.3)
45.19o
(45.45)
3.00o
(3.05)
20.89j
(21.20)
o
o
o
>360 (DMSO/H2O)
>360e
>370e
3co
258−259e
260 (EtOH)
C10H7N3OCl2So
(288.2)
42.02o
(41.68)
2.74o
(2.45)
14.67k
(14.58)
o
o
o
258e
259 (CHCl3/EtOAc)
3d o
208e
C16H11N3OCl2So
(364.3) o
52.66o
2.95o
11.42l
o
o
208(CHCl3/EtOAc)
(52.75) o
(3.04) o
(11.54) o
3eo
298e
298 (DMF/H2O)
C10H6N4O3Cl2So
(333.2)
35.90o
(36.05)
1.90o
(1.82)
16.88o
(16.82)
o
o
o
o
3go
253−254e
255 (AcOH/H2O)
251m
(EtOH)
C13H15N3O4S o
(309.3)
50.87o
(50.47)
5.09o
(4.89)
13.54n
(13.58)
o
o
o
255 o
(AcOH/H2O)
a
b
For general method of preparation see EXPERIMENTAL. Input. c Additional reaction time. d For general operations of
processing the reaction mixtures see EXPERIMENTAL. Crude product. Volatile near the melting point. Ref. 58. h Ceric
e
f
g
i
l
ammonium nitrate. Iodobenzene diacetate: PhI(OAc)2. j S 12.50 (12.13). k Cl 24.44 (24.61), S 11.50 (11.13). Cl 19.56
(19.47), S 9.08 (8.80). m Ref. 59. n S 10.69 (10.37). o 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.
and only scarcely traces of the thiadiazole (3d) could be detected. Similary to the dehydrogenations 2→3,
treatment of the 2-monosubstituted fused ∆4-thiadiazoline (8) with KMnO4, or more advantageously with
CAN, led to the formation of the thiadiazolylbenzoic acid derivative (9) (see
EXPERIMENTAL). However, treatment of the dialdehyde derivative bithiadiazoline 10a with KMnO4,
CAN or PhI(OAc)2 (IBDA) did not afford the corresponding 5,5´-diacetamido-2,2´-bi[1,3,4]thiadiazole as
expected, but instead 2-acetamido[1,3,4]thiadiazole via cleavage of the C(2)―C(2´) bond. Although
CAN oxidation of 2,2´-disubstituted 3-acetyl[1,3,4]thiadiazolines was found35 to regenerate the carbonyl
group of the parent ketone (see also INTRODUCTION), treatment of the 1,2- keto aldehyde derivative

Table 4. Characteristic 1H NMR spectral dataa of thiosemicarbazones (1),
thiadiazolines (2), and thiadiazoles (3)
Compound
δ [ppm]
S–CH(Ar)–N
NH/OH
CH=N
CH3
1a oo
8.02b
8.11b
8.32o
1bo
o
1co
11.77o
8.42o
7.46o
12.19o
11.86o
8.47o
7.62o
1do
1eo
8.43o
8.30o
1go
11.84o
8.39o
8.11o
3.96c
3.81
o
o
o
8.25o
1ho
11.32o
8.41o
3.96o
3.94c
8.14o
7.26o
o
2ao
6.82b
6.98b
o
2bo
11.86o
2.27o
2.08o
2.14o
2.07o
o
o
o
2co
2do
12.50o
7.30o
7.37d
7.53o
6.81o
1.92o
1.75o
2.29o
2.23o
2.20o
2.05o
3.89c,e
3.78e
2.37o
2.18o
3.76f
o
2eo
2fo
12.06o
11.81o
2go
12.19o
6.92o
o
o
o
2ho
11.59o
7.05o
o
o
o
3ao
3bo
3co
12.69o
12.84o
12.90o
2.22o
2.25o
2.37o
g2.13
2.36o
4.03c,e
3.87e
2.35o
g2.68h
3do
o
3eo
12.93o
3go
o
a 200 MHz, for solutions in [DMSO-d6] if not otherwise stated before the
columns. b Ref. 32a, for 2b δ = 6.95. c 6 H. d Presumably; superimposed
on the signals of aromatic hydrogens. e OMe. f 9 H; 3 MeO. g For solutions in
CDCl3. h 360 MHz.
bithiadiazoline (10b) with CAN did not provide 5-acetamido-2-acetyl[1,3,4]thiadiazole but 5-acetamido-2-
methyl[1,3,4]thiadiazole likewise with C(2)―C(2´) bond cleavage (see EXPERIMENTAL).

CAN oxidation has been reported to transform thiocarboxamides into their oxygen analogs48a,b and/or into
1,2,4-thiadiazoles.48a Quite recently C―C bond cleavages of radical cations, obtained by photolysis of C-
4 analog cyclic N,S-acetals 2-substituted benzothiazolines, have been thoroughly investigated.48c
AcHN
AcHN
N
N
R
AcHN
S
N
NHAc
S
N
S
N
S
N
O
COOH
OMe
N
N
Ac
Ac
OMe
10a R=H, 10b R=Me
OMe
OMe
9
8
Table 5. Characteristic 50 MHz 13C NMR spectral data of
thiadiazolines (2) for solutions in [DMSO-d6]
Compound
δ [ppm]
S–C(R7)=N
C=O
S–C(Ar)H–N
CH3
2c
2d
2f
169.56
167.43
170.38
168.87
169.40
167.55
63.34
65.66
64.68
22.35
21.62
23.26
21.23
22.40
21.67
148.07
145.82
Table 6. Preparation and properties of thiosemicarbazones (6)
Yield[%]o
crudec
Producto
Reactiono
Solvento
Reactiono
Workupb
o
o
o
o
componentso
(mL) o
temp. [°C]a
(pure)c
(mmol) o
(time [h]) o
6ao
5a (30) o
TSC (60)
EtOHd,e
(200)
bpo
C, Ho
99.5o
(69)
o
o
o
o
o
(22)
6bo
5b (30) o
TSC (60)
EtOHd,e
(200)
bpo
I, Co
~ 100o
(76)
o
o
o
o
o
(20)
6co
5c (60) o
TSC (72)
H2Oj
(500)
bpo
(3)
Ak
98o
o
o
o
o
(92)
6do
5d (30) o
TSC (60)
EtOHd,e
(300)
bpo
C, Jo
90o
o
o
o
o
o
(44)
6fo
5f (10) o
TSC (15)
MeOHq
(25)
bpo
(4)
Ao
95o
o
o
o
o
o
(71)

Table 6. Preparation and properties of thiosemicarbazones (6) (continued)
Mp [°C] o
(solvent)
Lit. mp [°C] o
(solvent)
Formulao
Analysiso
found (calcd)
H
Product
(mol. mass)
C
N
6ao
190f
198 (EtOH)
202g
(EtOH)
C9H10N3ClSo
(227.7)
47.34o
4.27o
18.63ho
(18.45)
o
o
(47.47)
(4.43)
6bo
195f
204i
C9H10N3BrSo
(272.2) o
39.58o
3.65o
15.52o
(aq. H2O)
(39.71) o
(3.70) o
(15.44) o
199−200 (80% EtOH)
6co
6do
161m
C8H10N4So
(194.3) o
49.92o
5.36o
28.94n
161−162f
o
(EtOH) o
(49.46) o
(5.19) o
(28.84) o
162 (H2O) l
220f
221 (EtOH)
222o
(EtOH)
C9H11N3O2So
(225.3)
48.29o
(47.98)
5.08o
(4.92)
18.97p
(18.65)
o
6fo
221f
C10H10N4So
(218.3) o
55.36o
4.65o
25.76o
226−227s
o
221 (MEE/H2O)r
(55.02) o
(4.62) o
(25.67) o
(50% EtOH) o
TSC = thiosemicarbazide. a Bath if not bp. b For general operations of processing the reaction mixtures see EXPERIMENTAL.
c Without workup of the mother liquors. d Commercial anhydrous. e In the presence of cc. HCl (1.5 mL). f Crude product. g Ref.
60; 86 °C (sic!; EtOH), ref. 61. h Cl 15.90 (15.57), S 14.25 (14.08). i Ref. 60; 201−202 °C (MeOH), ref. 1g; 202−203 °C (corr.,
40–60% EtOH), ref. 53. j To a hot solution of TSC in water containing 4.8 mL AcOH was added 5c. k The mother liquor was
l
concentrated and the residue was crystallized from water. The product was dried at 100 °C/0.1 Torr over P4O10. m Ref. 62;
n
o
158−160 °C (EtOH), ref. 63; 158−160 °C (MeOH), ref. 64; 195 °C (H2O), ref. 65. S 16.95 (16.51). Ref. 66; 212−215 °C
(corr.; 40–60% EtOH), ref. 53. p S 14.41 (14.23). q Containing 0.5 mL AcOH. r 2-Methoxyethyl ether with addition of water to
the hot solution. s Ref. 67; 230−232 °C (MeOH), ref. 68; 265 °C, ref. 57; 208 °C (MeOH or EtOH), ref. 69.
Table 7. Preparation and properties of thiadiazolines (7)
Producto
Substrateo
Agentso
Reactiono
temp. [°C]a
(time [h]) o
Workupb
Yield[%]o
crudeo
(mmol) o
(mmol) o
(pure)c
7ao
7bo
7co
7eo
7go
6ao
Ac2O (212) o
pyd (247)
100o
C, Do
C, Eo
C, Do
C, Eo
C, Eo
93o
(15) o
(5) o
(70) o
6bo
Ac2O (424) o
pyd (247)
100o
(5) o
100o
(30) o
(84) o
6co
Ac2O (530) o
pyd (124)
100o
81o
(25) o
(5.5) o
(75) o
6do
Ac2O (1060) o
pyd (927)
100o
(83) o
(67) o
(5.5) o
6fo
Ac2O (318) o
pyd (247)
100o
(4) o
91o
(18) o
(58) o

Table 7. Preparation and properties of thiadiazolines (7) (continued)
Producto
Mp [°C] o
(solvent)
Formulao
Analysiso
found (calcd)
H
(mol. mass)
C
N
13.45f
(13.48)
7ao
214–216e
220–221
C13H14N3O2ClSo
(311.8)
49.94o
4.58o
(50.08)
(4.53)
(CHCl3/EtOAc)
7bo
7co
7eo
7go
218–219o
C13H14N3O2BrSo
(356.2) o
43.63oo
4.05o
11.76g
(CHCl3/EtOAc)
(43.83) o
(3.96) o
(11.79) o
219e
C12H14N4O2So
(278.3) o
52.06oo
5.09o
20.11i
220 (ME/H2O)h
(51.78) o
(5.07) o
(20.13) o
189o
C17H19N3O6So
(393.4) o
51.96oo
5.09o
10.42j
(CHCl3/EtOAc)
(51.90) o
(4.87) o
(10.68) o
C16H16N4O3So
(344.4) o
55.65o
4.82o
16.37l
165−166o
(55.80) o
(4.68) o
(16.27) o
(EtOH)k
a Bath if not bp. b For general operations of processing the reaction mixtures see EXPERIMENTAL. c Without workup of the
mother liquors. d Anhydrous. e Crude product. f Cl 11.73 (11.37), S 10.58 (10.28). g Br 23.13 (22.43), S 9.20 (9.00).
h 2-Methoxyethanol, with adition of water. i S 11.53 (11.52). j S 8.24 (8.15). k Commercial anhydrous. l The product was dried at
100 °C/0.1 Torr over P4O10; S 9.62 (9.31); EI-MS: m/z (%) [M+·] 344 (3), 302 (5). Treatment with boiling Ac2O for 4 h has been
reported (ref. 70) to transform 6f into 7f [C14H14N4O2S (302.3), the diacetyl analog of 7g, with free indole NH].
Table 8. Characteristic 200 MHz 1H- and 50 MHz 13C NMR spectral dataa
of thiadiazolines (7)
δ [ppm]
1H
13C
C-2b
Compound
NH
CH3
C=O
CH3
7ao
c10.93
2.33o
c169.19
78.24o
79.11o
79.67o
26.25o
o
o
o
o
o
o
o
2.24o
2.05o
168.06o
23.29o
22.21o
7bo
10.29o
e11.67
10.88o
2.33o
2.30o
1.84o
169.25d
26.57o
23.64o
22.49o
o
o
o
7co
7eo
2.30o
2.20o
2.02o
2.30o
2.24o
2.22o
2.18o
1.76o
e169.30
167.99o
25.87o
23.37o
22.31o
27.95o
23.15o
22.23o
20.86o
20.75o
22.61d
21.96o
o
o
o
170.00o
168.89o
168.35o
168.02o
75.60o
7gf
e11.11
2.15o
2.09o
2.06o
e169.25d
167.12o
60.88o
o
o
a For solutions in CDCl3 if not otherwise stated before the first column.
b C-2 of the thiadiazoline ring. c For solution in CDCl3 + [DMSO-d6]. d 2 C.
e For solution in [DMSO-d6]. f The signal of S−CHR−N is superimposed on
those of the indole hydrogens at δ = 7.49−6.97.

EXPERIMENTAL
Melting points (uncorrected): Kofler block. Solutions were concentrated under reduced pressure in a
rotary evaporator (< 50 °C, bath). TLC: Kieselgel 60 F254 (Merck, Alurolle). IR (KBr disks): Perkin-
1
13
Elmer 16 PC-FT and Perkin-Elmer 283 B spectrophotometers. 200 MHz H- and 50 MHz C NMR:
1
13
Bruker WP 200 SY, 360 MHz H- and 90 MHz C NMR: Bruker AM 360 spectrometers; for recording
the 13C spectra, J-echo techniques were used. MS: VG-7035 GC/MS/DS instrument (ion current 0.1 mA,
direct insertion technique, 70 eV).
General Operations of Processing the Reaction Mixtures (see Tables 1−3,6,7) (A) The product was
filtered off in the cold. (B) The cold reaction mixture was poured into ice and water. (C) The reaction
mixture was concentrated. (D) The cold residue was triturated with a small amount of anhydrous EtOH
and kept at room temperature for 0.5−1 h, then hexane was added. (E) The cold residue was triturated
with ice/water. (F) Under ice/water cooling, to the stirred reaction mixture was added 30% H2O2 in small
portions until discoloration was complete. (G) The mixture was diluted with 2−3-fold volume of water.
(H) To about a quarter. (I) The hot solution was filtered. (J) The residue was extracted with water on a
steam bath to remove unreacted thiosemicarbazide. (K) The solid was stirred with aq. NaHCO3 to leave
the crude product undissolved.
General Procedure for KMnO4 Oxidation (see Table 3) With a slight modification of the literature
method32d,7l to a stirred and cooled suspension of the finely powdered substrate in 99% AcOH were added
finely powdered KMnO4 in small portions, and water in 3–4 portions. For processing the reactions
mixtures see the indications in Table 3 and the General Operations (see above).
General Procedure for CAN Oxidation (see Table 3)
To a stirred suspension/solution of the powdered substrate in MeCN were added CAN in small portions
(the proper time intervals being indicated by the change of color) and water in 3–4 portions. For
processing the reaction mixtures see the indications in Table 3 and the General Operations (above).
Thermal Dehydrogenation of 3-Acetylthiadiazoline (2b) to Thiadiazole (3b). Thiadiazoline (2b)
(1.3290 g, 4.31 mmol; mp 228.5 °C) was kept at 245−260 °C (bath) for 30 min (after temporary sparkling
the melt resolidified; loss of weight 0.3000 g, i.e. 69.6 mg/mmol). The cold residue was triturated with 2-
PrOH to give crude (1.0013 g, 87.9%) or recrystallized 3b (0.4578 g, 40.2%), mp > 365 °C (from DMSO).
The product kept at 100 °C/0.5 Torr over P4O10 for 8 h was identical in all respects [mp, TLC, IR(KBr)
and 1H NMR (DMSO-d6) spectrum] with that obtained by KMnO4, CAN or DDQ dehydrogenations (see
Table 3).

6-(5-Acetamido-1,3,4-thiadiazol-2-yl)-2,3-dimethoxybenzoic Acid (9).
Procedure A. To a stirred suspension of the finely powdered thiadiazoline lactam49 (8) (9.219 g, 30 mmol)
in AcOH (225 mL) was added powdered KMnO4 (11.850 g, 75 mmol) in small portions during 25 min at
15−16 °C. The mixture was stirred for 10 min then H2O (37 mL) was added in portions during 20 min.
The mixture was stirred at 11−13 °C for an additional 100 min, then under further cooling ~30% H2O2
(~5.5 mL) was added in small portions until the decomposition of the excess KMnO4 was complete and
the colorless solution was concentrated. The solid residue was extracted with aq. NaHCO3 (3.60 g, ~43
mmol in 50 mL H2O) at 50−55 °C and filtered. The filtrate was acidified with concd HCl to Congo Red
and kept at 5 °C for 2−3 h to obtain crude (2.672 g, 27.5%) or recrystallized 9 (2.115 g, 21.8%), mp
269 °C (from AcOH). Anal. Calcd for C13H13N3O5S: C 48.29; H 4.05; N 13.00; S 9.92. Found: C 48.26;
1
H 4.24; N 12.98; S 10.00. IR (cm–1): 3161, 2938, 2786, 1730, 1702, 1596, 1552. H NMR (200 MHz,
DMSO-d6): δ 12.61 (s, 1 H, exchangeable with D2O, NH), 7.55 and 7.23 (each d, 1 H, J = 8 Hz, 2 H,
H–Ar), 3.91 and 3.78 (each s, 3 H; 2 MeO), 2.21 (s, 3 H, Ac).
Procedure B. To a stirred suspension of the powdered thiadiazoline lactam49 (8) (0.0768 g, 0.25 mmol) in
MeCN (4 mL) were added water (0.8 mL) and CAN (0.291 g, 0.531 mmol) in small portions during 30
min at rt. The mixture was concentrated and the residue triturated with water to furnish crude (0.0652 g,
80.7%) or recrystallized 9 (0.040 g, 49.5%), mp 265−267 °C (from AcOH with addition of water),
identical [TLC, 20 mL CHCl3/MeOH (7:3) + 6 drops of AcOH, as well as IR(KBr) spectrum] with the
product obtained in procedure A.
5,5´-Diacetamido-3,3´-diacetyl-2,2´-bi[1,3,4]thiadiazoline
(10a).
A
mixture
of
glyoxal
bis(thiosemicarbazone)50 (10.00 g, 48.95 mmol), Ac2O (50 mL) and anhydrous pyridine (20 mL) was
boiled with stirring for 1 h and then cooled to give a crude product (12.39 g, 68%), mp > 365 °C . The
mother liquor was poured into ice/water to afford a second crop (1.300 g, 7.1%). For analysis a sample
(2.00 g) was recrystallized from DMF (23 mL) with addition of warm water (50 mL) to give the pure title
compound (1.665 g). Anal. Calcd for C12H16N6O4S2: C 38.70; H 4.33; N 22.57. Found: C 38.82; H 4.40;
1
N 22.62. H NMR (100 MHz at 330 K, DMSO-d6) HMDSO as the internal standard: δ 11.73 (br s, 1 H,
exchangeable with CD3COOD, NH), 6.47 and 6.32 (2 s, ¾ and ¼ H, S−CHR−N), 2.28 (s, 3 H, Ac), 2.22
(s, 3 H, Ac).
Oxidative Transformation of the Bithiadiazoline (10a) into 2-Acetamido[1,3,4]thiadiazole.
Procedure A. To a stirred suspension of powdered 10a (0.372 g, 1 mmol, 2 “mmol” of the heteroring) in
AcOH (20 mL) were added powdered KMnO4 (0.790 g, 5 mmol) and water (1 + 1 mL) at rt during 1 h.
The reaction mixture was stirred for an additional 2 h then processed (see General Procedure as well as
General Operations C, E, G) to give crude (0.090 g, 62.8%) or recrystallized (0.055 g, 38.4%)

2-acetamido[1,3,4]thiadiazole, mp 269 °C (from water), ref. 51: 268 °C (from water), ref. 19i: mp
1
267−268 °C (from AcOH). H NMR (DMSO-d6): δ 12.26 (s, 1 H, NH), 9.27 (s, 1 H, 5-H), 2.31 (s, 3 H,
Ac).
Procedure B. To a stirred mixture of powdered 10a (0.9311 g, 2.5 mmol, 5 “mmol” of the heteroring) in
MeCN (60 mL) and water (12 mL) was added CAN (6.439 g, 11.51 mmol, 98%) during 30 min at rt. The
reaction mixture was saturated with Na2SO4 and thoroughly extracted with CHCl3. The CHCl3 solution
was washed with aq. NaHCO3 and water, dried (MgSO4) and then concentrated. The residue was
crystallized from EtOAc to give crude (0.2161 g, 60.4%) or recrystallized (0.1273 g, 39.1%) 2-
acetamido[1,3,4]thiadiazole, mp 272 °C (from EtOAc; near the mp it volatilizes). MS: m/z [M+·] 143(28),
[M+· − Me] 128(7), [M+· − N2: 2-acetamidothiirene] 115(30), [M+· − CH2CO: 2-aminothiadiazole]
101(100), [M+·− CH2CO − HCN: 3-aminothiazirene] 74(28), [M+· − CH2CO − H2NCN: thiazirene] 59(9),
[HC≡S+]
2-(acyl)amino[1,3,4]thiadiazoles.
45(45),
in
accordance
with
the
known52
fragmentation
pattern
of
Procedure C. To a stirred suspension of powdered 10a (1.117 g, 3 mmol, 6 “mmol” of the heteroring) in
MeOH (160 mL) was added powdered IBDA (2.241 g, 6.818 mmol, 98%) at rt during 10 min. The
mixture was stirred for 5 d (the oxidant was consumed: KI/starch paper), filtered and concentrated. The
residue was extracted with CHCl3 (~350 mL) and the solution washed with aq. NaHCO3 and water, dried
(MgSO4), treated with fuller’s earth and charcoal, and then concentrated. The residue was boiled in
EtOAc (30 mL) to give the TLC-homogeneous pure title thiadiazole (0.3595 g, 83.7%, calcd for 3 mmol),
mp 272−273 °C.
Degradation of 5,5´-Diacetamido-3,3´-diacetyl-2´-methyl-2,2´-bi[1,3,4]thiadiazoline (10b) to
2-Acetamido-5-methyl-1,3,4-thiadiazole. To a stirred suspension of the powdered bithiadiazoline (10b)41f
(0.773 g, 2 mmol, 4 “mmol” of the heteroring) in MeCN (50 mL) and water (10 mL) was added CAN
(4.984 g, 8.91 mmol, 98%) during 30 min. The mixture was neutralized with NaHCO3 and concentrated.
The residue was extracted several times with hot CHCl3. The combined CHCl3 solution was washed with
water, dried (MgSO4) and then concentrated. The residue was crystallized from EtOAc to give
homogeneous [TLC, CHCl3/MeOH (95:5)] 2-acetamido-5-methyl-1,3,4-thiadiazole (0.131 g, 41.7%), mp
294−296 °C, ref. 44c: 293 °C (from aq. NaOH with addition of HCl), ref. 51: 292 °C (from water). IR
(cm–1): 3170, 3040, 2914, 2796, 1696, 1570. MS: m/z [M+·] 157(18), [M+· − Me] 142(15), [M+· −
CH2=CO] 115(85), [2-aminothiadiazole?] 101(8), [M+· − CH2=CO − MeCN = 3-aminothiazirene] 74(45),
[thiazirene and/or Me−C≡S+] 59(25); 56(22), [Me−C≡O+] 43(100), in accordance with the known52
fragmentation pattern of 2-amino-1,3,4-thiadiazoles. C5H7N3OS (157.2).

ACKNOWLEDGEMENTS
The author thanks Mrs. Katalin Tréfás for the microanalyses and recording the IR spectra, Mme. Sára
Balla and Mrs. Éva Józsa for recording the NMR spectra, and Zoltán Dinya, D. Sc. for the MS
measurements. Grants from the Hungarian Scientific Research Fund (OTKA T025016 and T037201) for
this work are also gratefully acknowledged.
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