3-methylthio-pyrano[4,3-c]pyrazol-4(2H)-ones from 3-(bis-methylthio)methylene-2H-pyran-2,4-diones and hydrazines

Article abstract of DOI:10.1002/hc.10158

A useful synthesis of 3-methylthio-6-methyl-pyrano[4,3-c]pyrazol-4(2H)-ones via 3-(bis-methylthio)methylene -5,6-dihydro-6-alkyl(aryl)-2H-pyran-2,4-dione with hydrazine as well as methyl and phenyl hydrazines was described. The mechanism of formation was also discussed. It is a useful intermediate in the synthesis of a variety of important heterocyclic molecules.

Full text of DOI:10.1002/hc.10158

Heteroatom Chemistry
Volume 14, Number 4, 2003
3-Methylthio-pyrano[4,3-c]pyrazol-4(2H)-
ones from 3-(Bis-methylthio)methylene-2H-
pyran-2,4-diones and Hydrazines
Yu-Xin Li,2 You-Ming Wang,1 Xiao-Ping Yang,2 Su-Hua Wang,1
and Zheng-Ming Li1
1State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
2Department of Chemistry, Xiangtan Normal University, Xiangtan, Hunan Province 411201,
People’s Republic of China
Received 13 December 2002; revised 10 February 2003
5,6-dihydro-6-alkyl(aryl)-2H-pyran-2,4-diones have
ABSTRACT: A useful synthesis of 3-methylthio-6-
interesting fungicidal, tobacco virucidal activities
methyl-pyrano[4,3-c]pyrazol-4(2H)-ones via 3-(bis-
[8–9].
methylthio)methylene-5,6-dihydro-6-alkyl(aryl)-
As part of our program aimed at developing a
2H-pyran-2,4-dione with hydrazine as well as methyl
new class of pesticides, we have been interested in
and phenyl hydrazines is described and the mechanism
synthesizing nitrogen heterocyclic compounds such
ꢀ
C
of the formation is discussed. 2003 Wiley Periodicals,
as isothiazoles and pyrazoles because nitrogen het-
Inc. Heteroatom Chem 14:342–344, 2003; Published on-
erocycles play an important role among useful her-
line in Wiley InterScience (www.interscience.wiley.com).
bicides [10]. Combining ꢀ-keto-ꢁ-valerolactone and
DOI 10.1002/hc.10158
pyrazole, we expect to find better lead compounds
of herbicides. With these considerations in mind, we
synthesized substituted pyrano[4,3-c]pyrazol-4(2H)-
ones.
INTRODUCTION
Being a structural subunit in numerous natural
bioactivited products, pyrone exhibits a broad range
RESULTS AND DISCUSSION
of biological activity [1]. In addition, it is a use-
ful intermediate in the synthesis of a variety of
important heterocyclic molecules, which exhibit
antimicrobial, antifungal, antiviral, or phytotoxic ac-
tivity [2–4]. It is reported that ꢀ-keto-ꢁ-valerolactone
derivatives inhibit the activity of HIV proteases [5–7].
Recently we have reported that 3-anilinomethylene-
6-Methyl-5,6-dihydro-2H-pyran-2,4-dione (1a) was
prepared from dehydroacetic acid in two steps
[8]. 6-Methyl-6-benzyl and 6-methyl-6-piperonyl-5,6-
dihydro-2H-pyran-2,4-dione (1b,c) were prepared
as described [8]. It is generally believed that
6-alkyl(aryl)-5,6-dihydro-2H-pyran-2,4-diones react
with carbon disulfide and methyl iodide to give low
yields of 3-(bis-methylthio)methylene-5,6-dihydro-
6-alkyl(aryl)-2H-pyran-2,4-diones (38%) [11]. We
found that 1a–c react with carbon disulfide in the
presence of weak base such as anhydrous potassium
carbonate and methyl iodide to give compounds
Correspondence to: You Ming Wang; e-mail: youmingwang@
hotmail.com.
Contract grant number: NNSFC 29832050.
2003 Wiley Periodicals, Inc.
c
ꢀ
342

3-Methylthio-pyrano[4,3-c]pyrazol-4(2H)-ones from 3-(Bis-methylthio)methylene-2H-pyran-2,4-diones and Hydrazines 343
O
O
SK
O
O
SCH
3
O
O
SCH
K CO
2
3
CH I
SK
3
3
1
1
1
+
CS
2
R
R
R
DMF
H C
H C
O
O
H C
3
O
3
3
1a R1=H;
2a-c
1b R1=PhCH2 ;
O
CH2
1c R1 =
O
SCHEME 1
2a–c in reasonable yield (70%) (Scheme 1). Butyl
bromide and phenyl iodide did not give analogous
compounds.
3-Methylthio-6-methyl-pyrano[4,3-c]pyrazol-
4(2H)-ones 4a–h were synthesized by the process
described in Scheme 2. Generally, the reactions
proceeded quickly with excellent yields as shown
in Table 1. However, for the coupling reaction with
phenylhydrazine at room temperature, 3 h were
needed (monitored by TLC).
Interestingly, although the reaction of 1c with
2,4-dinitrophenylhydrazine failed to gain a com-
pound 4, we successfully separated an oily sub-
stance. 1H NMR (CDCl3): 1.49 (s, 3H, CH3), 2.54
(s, 2H, CH2), 2.84 (s, 6H, 2CH3), 2.94 (dd, 2H, J =
6.8 Hz, CH2), 5.92 (s, 2H, CH2), 6.70 (m, 3H), 7.92
(m, 3H), 11.68 (s, 1H, NH), and (EI) m/z = 546) of the
compound show it is an uncyclized product 3 (R1 =
piperonyl, R2 = 2,4-dinitrophenyl). The results indi-
cated that the formation of the transition state 3 is
reasonable.
6-Methyl-5,6-dihydro-3-(bis-methylthio)-
methylene-2H-pyran-2,4-diones 2a–c
2a: Compound 1a (1.28 g, 0.01 mol) was dissolved in
20 ml DMF. With constant agitation, 3.18 g (0.03 mol)
of potassium carbonate anhydrous was added in por-
tions to the mixture, which was agitated for 0.5 h
at room temperature. The mixture was cooled to
0◦C and 0.76 g (0.01 mol) carbon disulfide was
added dropwise. After the addition, the reaction mix-
ture was agitated for 0.5 h at 0◦C, and then 2.84 g
(0.02 mol) methyl iodide was added dropwise at
0◦C. The brown suspension was agitated for 4 h.
The suspension was poured into 200 ml ice-cooled
water and extracted with 100 ml dichloromethane
twice. The organic phase was separated and dried
over magnesium sulfate. After the filtration, the sol-
vent was evaporated in a vacuum. The crude prod-
uct was purified with silicon gel column using ethyl
acetate/petroleum ether (v/v, 1:3) as eluent and 2a
was obtained. Yield: 70.0%. mp 148–149◦C. 1H NMR
(CDCl3): 1.40 (d, 3H, J = 6.8, CH3), 2.56 (m, 2H,
CH2), 3.70 (s, 6H, SCH3), 4.45 (m, 1H, CH).
EXPERIMENTAL
2b: Following the above method and using 2.18 g
1b, 2.07 g 2b was obtained. Yield: 64.3%. mp 112–
Melting points were conducted on a Yanaco MP-500
micromelting point apparatus. 1H NMR spectra were
recorded in CDCl3 as solvent on AC-200 instrument,
using TMS as internal standard. Elemental analy-
ses were performed on MF-3 automatic elemental
analyzer.
1
113◦C. H NMR (CDCl3): 1.40 (s, 3H, CH3), 2.53 (s,
6H, SCH3), 2.64 (s, 2H, CH2), 2.97 (dd, 2H, J = 6.8,
CH2), 7.23 (m, 5H).
2c: Following the above method and using
2.62 g 1c, 2.49 g 2c was obtained. Yield: 68.2%. mp
2
NHR
O
SCH
3
N
O
SCH
3
1
NH2NHR2
-H2O
R
SCH
N
SCH
-CH3SH
3
3
2
1
1
H C
N R
3
R
R
O
H C
O
O
H C
O
3
3
SCH
3
O
2a-c
3
4a-h
SCHEME 2

344 Li et al.
TABLE 1 Data and Elemental Analyses of Compounds 4
Elemental Analysis (Calcd)
H
R1
R2
Yield (%)
mp (◦C)
C
N
4a
4b
4c
4d
4e
4f
H
H
CH3
Ph
H
CH3
Ph
H
98.1
94.3
68.7
63.2
73.5
88.3
80.2
85.6
102–103
167–169
145–146
oil
140–141
165–166
140–141
169–170
50.90 (50.94)
61.20 (61.30)
62.55 (62.50)
63.60 (63.58)
69.08 (69.23)
57.90 (57.83)
58.79 (58.96)
64.75 (64.70)
5.72 (5.66)
5.12 (5.11)
5.54 (5.56)
6.02 (5.96)
5.54 (5.49)
5.06 (4.82)
5.19 (5.20)
4.93 (4.90)
13.20 (13.20)
10.18 (10.22)
10.00 (9.72)
9.20 (9.27)
7.69 (7.69)
8.32 (8.43)
7.90 (8.09)
6.82 (6.86)
PhCH2
PhCH2
PhCH2
CH2O2C6H3CH2
CH2O2C6H3CH2
CH2O2C6H3CH2
4g
4h
CH3
Ph
129–131◦C. 1H NMR (CDCl3): 1.39 (s, 3H, CH3), 2.53
(s, 6H, SCH3), 2.64 (s, 2H, CH2), 2.93 (dd, 2H, J = 6.8,
CH2), 5.91 (s, 2H, CH2), 6.70 (m, 3H).
2.56 (s, 3H, SCH3), 2.90 (s, 2H, CH2), 3.09 (dd, 2H,
J = 8.2, CH2), 5.90 (s, 2H, CH2), 6.65 (m, 3H), 8.38
(bs, 1H, NH).
4g: Following the above method and using 1.83 g
2c and 0.28 g methylhydrazine, 1.38 g 4g was ob-
tained. H NMR (CDCl3): 1.43 (s, 3H, CH3), 2.52 (s,
3-Methylthio-6-methyl-5,6-dihydro-2H-
pyrano[4,3-c]pyrazole-4(2H)-ones 4a–h
1
3H, SCH3), 2.85 (s, 2H, CH2), 2.89 (dd, 2H, J = 8.0,
CH2), 3.72 (s, 3H, NCH3), 5.89 (s, 2H, CH2), 6.63 (m,
3H).
4h: Following the above method and using 1.83 g
2c and 0.65 g phenylhydrazine, 1.73 g 4h was ob-
tained. 1H NMR (CDCl3): 1.46 (s, 3H, CH3), 2.59
(s, 3H, SCH3), 2.88 (s, 2H, CH2), 2.97 (dd, 2H,
J = 8.2, CH2), 5.88 (s, 2H, CH2), 6.61 (m, 3H), 7.45
(m, 5H).
4a: Methylhydrazine (0.28 g, 0.006 mol) was added
dropwise to a mixture of 1.16 g (0.005 mol) 2a in
30 ml ethanol. After agitation for 1 h at room tem-
perature, the solvent was evaporated in vacuum and
gave 1.03 g 4a, which was purified with silicon gel
column using ethyl acetate/petroleum ether (1:2) as
eluent. 1H NMR (CDCl3): 1.49 (d, 3H, J = 6.4, CH3),
2.57 (s, 3H, SCH3), 2.85 (m, 2H, CH2), 3.87 (s, 3H,
NCH3), 4.70 (m, 1H, CH).
4b: Following the above method and using 1.16 g
2a and 0.65 g phenylhydrazine, 1.3 g 4b was ob-
tained. 1H NMR (CDCl3): 1.53 (d, 3H, J = 6.2, CH3),
2.61 (s, 3H, SCH3), 2.97 (m, 2H, CH2), 4.65 (m, 1H),
7.44 (m, 5H).
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4c: Following the above method and using 1.61 g
2b and 0.3 g 85% hydrazine hydrate solution, 0.97 g
4c was obtained. 1H NMR (CDCl3): 1.48 (s, 3H, CH3),
2.68 (s, 3H, SCH3), 2.94 (s, 2H, CH2), 3.08 (dd, 2H,
J = 7.0, CH2), 7.20 (m, 5H), 8.18 (bs, 1H, NH).
4d: Following the above method and using 1.61 g
2b and 0.28 g methylhydrazine, 0.95 g 4d was ob-
1
tained. H NMR (CDCl3): 1.43 (s, 3H, CH3), 2.62 (s,
3H, SCH3), 2.86 (s, 2H, CH2), 3.02 (dd, 2H, J = 5.6,
CH2), 3.92 (s, 3H, NCH3), 7.24 (m, 5H).
4e: Following the above method and using 1.61 g
2b and 0.65 g phenylhydrazine, 1.32 g 4e was ob-
1
tained. H NMR (CDCl3): 1.46 (s, 3H, CH3), 2.59 (s,
3H, SCH3), 2.95 (s, 2H, CH2), 3.03 (dd, 2H, J = 8.0,
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4f: Following the above method and using 1.83 g
2c and 0.3 g 85% hydrazine hydrate solution, 1.46 g
4f was obtained. 1H NMR (CDCl3): 1.51 (s, 3H, CH3),
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