Formation of new heterocycles by intramolecular cyclization reactions of alkynethiolates with nitrogen nucleophiles

Article abstract of DOI:10.1016/S0040-4039(01)02326-7

1,2,3-Thiadiazole-4-carbohydrazides undergo base-catalyzed ring cleavage with liberation of nitrogen and recyclization to 5-thiopyrazolones, 6-thiomethylidene-1,3,4-oxadiazin-5-ones or 5-thio-7H-pyrazolo[5,1-b][1,3]thiazine-2,7-diones.

Full text of DOI:10.1016/S0040-4039(01)02326-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1015–1017
Formation of new heterocycles by intramolecular cyclization
reactions of alkynethiolates with nitrogen nucleophiles
Ahmed Hameurlaine, Michael A. Abramov and Wim Dehaen*
University of Leuven, Celestijnenlaan 200F, Leuven 3001, Belgium
Received 5 October 2001; revised 5 December 2001; accepted 6 December 2001
Abstract—1,2,3-Thiadiazole-4-carbohydrazides undergo base-catalyzed ring cleavage with liberation of nitrogen and recyclization
to 5-thiopyrazolones, 6-thiomethylidene-1,3,4-oxadiazin-5-ones or 5-thio-7H-pyrazolo[5,1-b][1,3]thiazine-2,7-diones. © 2002 Pub-
lished by Elsevier Science Ltd.
1,2,3-Thiadiazoles and 1,2,3-selenadiazoles, that are
unsubstituted at the 5-position are usually easily
cleaved with liberation of nitrogen and formation of
alkynethiolates1 and alkyneselenolates2 by the action of
relatively weak bases, such as alkoxides or hydroxide.
The resulting acetylenic thiolates and selenolates have
been widely used in organic synthesis for the synthesis
of the corresponding sulfides and selenides, in cycload-
dition reactions leading to new heterocycles or, after
protonation, as a source of reactive thioketenes and
seleno-ketenes.3
When we carried out the base-catalyzed (1 equiv. of
t-BuOK) ring cleavage of 3 and 4 followed by alkyla-
tion, either the expected 5-alkylthiopyrazolone deriva-
tives 6a,b and 7a–c (with 1 equiv. of alkylating agent)
or the pyrazoles 8a,b and 9a (with 2 equiv. of alkylating
agent) were isolated. The same reaction conditions
applied to hydrazide 2 gave no product. To obtain
N
N
R
S
base; RX
R
S
O
We recently reported a synthesis of benzofuran-2-thio-
lates which used the base-catalyzed decomposition of
4-(2-hydroxyaryl)-1,2,3-thiadiazoles.4,5 The thiadiazole
ring is transferred by base into a thioketene function,
which cyclizes with the ortho-hydroxy group to form
the thiolate, which can be alkylated to afford the
corresponding sulfides (Scheme 1). The same reaction,
applied to 1,2,3-selenadiazoles, afforded the selenides.5,6
R
OH
Scheme 1.
Table 1. 1,2,3-Thiadiazole-4-carbohydrazides 2–5, 10
O
O
Cl
HN
N
RNHNH2
N
N
R
N
R'
N
We decided to apply this methodology for the forma-
tion of nitrogen heterocycles. In order to have an entry
to 1,2,3- thiadiazoles, and hence alkynethiolates, having
a nucleophilic nitrogen atom, the reaction of 1,2,3-thia-
diazole-4-carbonyl chloride 18 with a number of
hydrazines was used and 1,2,3-thiadiazole-4-carbohy-
drazides 2–4 were obtained in 60–75% overall yield.
Phenyl hydrazine, on treatment with an excess of the
acid chloride 1 gave the diacylated hydrazide 5 (Table
1).
S
S
1
2-5
Product
R
R%
Yield (%)
2
3
4
5
Ph
PhCO
Ts
H
H
H
75
74
60
Ph
1,2,3-Thiadiazole-4-carbonyl 70a
10
Ts
Me
35b
a To prepare hydrazide 5 an excess of 1,2,3-thiadiazole-4-carbonyl
chloride has been used.
* Corresponding author. Tel.: ++32 16 32 74 39; fax: ++32 16 32 79
90; e-mail: wim.dehaen@chem.kuleuven.ac.be
b By alkylation of 4.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02326-7

1016
A. Hameurlaine et al. / Tetrahedron Letters 43 (2002) 1015–1017
compounds 6–9 it is necessary to carry out the base-cat-
alyzed ring cleavage of 3 and 4 about 18 h previous to
the addition of alkylating agent.9 Yields are between
20–35% after chromatography. The balance of the reac-
tion is formed by polar, unidentified products (Table 2).
In the case when the alkylating agent (methyl iodide)
was present in situ in the decomposition reaction mix-
ture of 4 a complicated mixture of reaction products
was obtained, including 7a, 9a and the N-methylated
hydrazide 10 (Table 1). Without alkylating agent, none
of the expected pyrazolethione could be isolated after
neutralization of the reaction mixture.
cyclization to a pyrazolone-5-thiolate anion. This thio-
late is easy alkylated, forming either pyrazoles 6 and
7
or on subsequent alkylation with
a
second
O
O
HN
HN
R
N
HC
R
N
C
H
S
S
O
O
R'X
R'X
base
The pyrazoles 6–9 apparently result from a multistep
process involving the cleavage of the thiadiazole ring
with formation of the alkynethiolate (Scheme 2). Fast
intramolecular proton shift gives the reactive thio-
ketene, which undergoes intramolecular nucleophilic
HN
N
7a-c
8a,b, 9a
S
S
N
R
N
R'
R
Scheme 2.
Table 2. Ring cleavagea of hydrazides of 2–5 with t-BuOK in DMSO at 20°C followed by alkylation
O
HN
NH
N
R
N
S
2-5
2eq t-BuOK, DMSO
1eq t-BuOK, DMSO
2eq R'X
2eq R'X
R'X
O
O
R'
O
O
S
S
R'
R'
S
N
N
O
HN
N
N
N
R'
O
R'
S
S
S
N
N
R
N
N
R'
R'
R'
Ph
O
COPh
Ts
Ph
11a,b
8a,b
6a,b, 7a-c
9a
15a-c
Product
Substrate
R%X
R
Yield (%)
–
6a
6b
7a
7b
7c
8a
8b
2
3
3
4
4
4
3
3
4
3
3
5
5
5
MeI
MeI
Ph
0
20
25
30
35
34
20
35
23
40
51
30
20
25
PhCO
PhCO
Ts
Ts
Ts
PhCO
PhCO
Ts
PhCO
PhCO
C16H33Br
MeI
C16H33Br
PhCH2Cl
MeI
C16H33Br
MeI
MeI
PhCH2Cl
MeI
9a
11a
11b
15a
15b
15c
1,2,3-Thiadiazole-4-carbonyl
1,2,3-Thiadiazole-4-carbonyl
1,2,3-Thiadiazole-4-carbonyl
C16H33Br
PhCH2Cl
a The ring cleavage of hydrazides in other systems (t-BuOK–DMF, t-BuOK–MeCN, t-BuOK–THF, NaH–DMF, NaH–MeCN, NaH–THF at
20°C as well as BuLi or t-BuLi in THF at −78°C) gave no results or the yields of compounds 6–9 were very poor. The balance of these reactions
is formed by unidentified products.

A. Hameurlaine et al. / Tetrahedron Letters 43 (2002) 1015–1017
1017
S
equivalent of methyl iodide, the dialkylated pyrazoles
S
8a,b and 9a. 13C NMR spectroscopic analysis showed
that O-alkylation occurred in the case of benzoyl
derivative 3. The 13C NMR signals for methyl or meth-
ylene groups of 8a and 8b are at 56 and 65 ppm,
respectively. However, we were surprised to see that the
tosyl derivative 9a was N-alkylated (13C NMR signal
for methyl at 36 ppm).
O
S
O
N
O
H+
N
S
Ph
O
NH
Ph
N
N
S
Ph
N
O
O
S
16
17
18
When the ring cleavage of hydrazides 3–5 was carried
out in the presence of 2 equiv. or more of t-BuOK, the
cyclization takes another course. Thus, the decomposi-
tion of benzoyl hydrazide 3 followed by alkylation
results in 1,3,4-oxadiazin-5-one derivatives 11a,b. On
the other hand, the tosylhydrazide 4 under the same
conditions yields benzyltolylsulfinate7 as the only iden-
tifiable decomposition product (Table 2).
Scheme 4.
Acknowledgements
We thank the University, the Ministerie voor Weten-
schapsbeleid and the FWO Vlaanderen for their contin-
uing support.
In the case of the benzoyl hydrazide 3, we can rational-
ize the product obtained by the intermediacy of the
alkynethiolate dianion 12, which does not cyclize, but
rather is monoalkylated to the alkynesulfide 13, which
undergoes cyclization to the six-membered ring by
attack of the imidate anion on the alkynesulfide, rather
than the formation of the alternative seven-membered
ring (Scheme 3). The resulting anion 14 is then alky-
lated on nitrogen (13C NMR methyl or methylene
signals for 11a,b at 36 and 52 ppm). We were not able
to isolate monoalkylated oxadiazine derivatives from
this reaction.
References
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Finally, 1,2,3-thiadiazole-4-carbohydrazide 5, after
cleavage of two 1,2,3-thiadiazole rings, recyclization
and alkylation gives the novel fused 7H-pyrazolo[5,1-
b][1,3]thiazine-2,7-diones 15a–c (Table 2). Here we can
assume that the bis(alkynethiolate) 16 is formed first,
which then cyclizes, similar to Scheme 2, to the pyra-
zole-5-thiolate 17. This can undergo a second cycliza-
tion with the formation of a thiazine-6-thiolate 18,
which finally is alkylated to give the products 15a–c
(Scheme 4).
6. Petrov, M. L.; Abramov, M. A.; Dehaen, W.; Toppet, S.
Tetrahedron Lett. 1999, 40, 3903.
7. Maiti, A. K.; Bhattacharyya, P. Tetrahedron 1994, 50, 3.
8. Pain, D. L.; Slack, R. J. Chem. Soc. 1965, 5166.
9. 1-Tosyl-5-(1-hexadecylthio)pyrazol-3-one 7b. To a solu-
tion of hydrazide 4 (1 mmol) in DMSO (5 mL) a solution
of t-BuOK (1 mmol) in DMSO (5 mL) was added and the
reaction mixture was stirred at room temperature for 18 h.
1-Bromohexadecane (1 mmol) was added and after stirring
for 6 h, the solvent was evaporated under reduced pressure
at 40°C. Dichloromethane was added to the residue, the
organic layer was washed twice with water, dried, evapo-
rated, and the reaction product was purified by silica gel
column chromatograpy. Yield of 7b: 30%, mp 116–118°C.
1H NMR (CDCl3, l, ppm): 0.88 (t, 3H, CH3), 1.26 (s,
24H, (CH2)12), 1.40 (txd, 2H, SCH2CH2CH2), 1.68 (txd,
2H, SCH2CH2), 2.42 (s, 3H, CH3), 2.87 (t, 2H, SCH2),
5.65 (s, 1H, CHhet), 7.26 (d, 2H m-CHarom.), 7.85 (d, 2H,
o-CHarom.), and 11.31 (br s, 1H, NHhet). 13C NMR
(CDCl3, l, ppm): 14.5, 22.1 (CH3 tosyl), 23.0, 28.5, 29.2,
29.4, 29.5, 29.8, 30.0, 32.3, 34.4 (CH2S), 99.3 (C4het), 128.5,
130.2, 133.7, 146.0, 148.7 and 166.1 (C5het and Ch3et). MS
495. Found: C, 62.9; H, 8.3; N, 6.0. C26H42N2O3S2. M 495.
Calcd: C, 63.1; H, 8.6; N, 5.7%.
O
O
S
S
HN
N
HN
N
R'X
R'
O
O
Ph
Ph
13
12
O
R'
N
S
11a,b
N
O
Ph
14
Scheme 3.