Unusual course of the reaction of Lawesson's reagent with β-phosphoryl-β'-carbethoxyhydrazones: First synthesis of 5-mercapto-3-(methylthiophosphoryl) pyrazoles

Article abstract of DOI:10.2174/157017812801264764

It is well known that Lawesson's reagent (LR) reacts with hydrazone derivatives at 80 °C to yield 3-thioxo-1,2,3-diazaphospholine derivatives. We show, in the present investigation, that the reaction of LR with β-phosphoryl-β'-carbethoxyhydrazones under the same conditions, took an entirely different course and gave a new type of pyrazole derivatives, the 5-mercapto-3-(methylthiophosphoryl)pyrazoles.

Full text of DOI:10.2174/157017812801264764

320
Letters in Organic Chemistry, 2012, 9, 320-324
Unusual Course of the Reaction of Lawesson’s Reagent with β-Phosphoryl-
β’-carbethoxyhydrazones: First Synthesis of 5-Mercapto-3-(methylthio-
phosphoryl)pyrazoles
Emna Chebil and Soufiane Touil*
Laboratory of Heteroatom Organic Chemistry, Department of Chemistry, Faculty of Sciences of Bizerta, University of
Carthage, 7021-Jarzouna, Tunisia
Received January 19, 2012: Revised April 04, 2012: Accepted April 12, 2012
Abstract: It is well known that Lawesson’s reagent (LR) reacts with hydrazone derivatives at 80 °C to yield 3-thioxo-
1,2,3-diazaphospholine derivatives. We show, in the present investigation, that the reaction of LR with β-
phosphoryl-β’-carbethoxyhydrazones under the same conditions, took an entirely different course and gave a new type of
pyrazole derivatives, the 5-mercapto-3-(methylthiophosphoryl)pyrazoles.
Keywords: Hydrazones, Lawesson’s reagent, mercaptopyrazoles, pyrazoles, thiophosphorylpyrazoles.
INTRODUCTION
It is worth noting that pyrazole derivatives are an
important class of compounds in medicinal chemistry with a
wide range of biological properties including anticancer [9,
10], antimicrobial [11, 12], antiviral [13] and anti-
inflammatory [14, 15] activities. Some of these compounds
are also known for their applications in agrochemistry as
herbicide [16] fungicide [17] and insecticide [18] agents.
The use of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiaphos-
phetane-2,4-disulfide [Lawesson’s reagent (LR)] in
heterocyclic synthesis has been well documented [1-4]. One
of its important applications involves the synthesis of 1,2,3-
diazaphospholine derivatives by reaction with hydrazones
S
S
S
S
Ar
S
Ar
P
P
P
2
LR:
S
Ar
S
R2
H
S
P
Ar
P
Ar
S
- H2S
S
R1
R2
R1
R2
C
CH
CH
R2
R1
CH
C
R1
C
N
P
SH
Ar
N
N
N
NH
Ph
NHPh
NHPh
NHPh
Scheme 1. Synthesis of diazaphospholine derivatives by reaction of LR with hydrazones.
[5] (Scheme 1). In this area, we have previously shown that
phosphoryl- and esterhydrazones react with LR to give 3-
Experimentally [19], hydrazones 2 were easily obtained
from the reaction of β-keto-δ-carbethoxyphosphonates and
phosphineoxides 1 [20] with phenylhydrazine in ethanol at 0
°C (Scheme 2). The reaction times range from 2 to 4 h
depending on the nature of the substrate. The isolated yield
of the reaction is about 90% (Table 1).
thioxo-1,2,3-diazaphospholine
derivatives
bearing
a
phosphoryl or an ester group [6-8]. We report, in the present
investigation, the extension of this reaction to β-phosphoryl-
β’-carbethoxyhydrazones 2. Our initial objective was to
study the effect of the phosphoryl and ester groups on the
course of the reaction, and to access new 1,2,3-
diazaphospholine derivatives. Contrary to our expectation,
the reaction took an entirely different course and gave the
novel 5-mercapto-3-(methylthiophosphoryl)pyrazoles 3.
Compounds 2 were characterized on the basis of their IR,
NMR (1H, 31P, 13C) and mass spectral data [21], which
indicate that they are obtained as a mixture of Z and E
isomers. Their relative proportions were estimated from the
31P NMR spectra where a singlet for each isomer is present
(Table 1).
*Address correspondence to this author at the Laboratory of Heteroatom
Organic Chemistry, Department of Chemistry, Faculty of Sciences of
Bizerta, University of Carthage, 7021-Jarzouna, Tunisia; Tel:
(+216)72590906; Fax: (+216)72590566; E-mail: soufiane.touil@fsb.rnu.tn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

First Synthesis of 5-Mercapto-3-(methylthiophosphoryl)pyrazoles
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
321
O
O
NH2-NHPh
EtOH, 0 °C
CO2Et
R2P
R2P
CO2Et
H2O
+
O
N
1
NHPh
2
Scheme 2. Synthesis of β-phosphoryl-β’-carbethoxyhydrazones 2.
Table 1. Synthesis of β-phosphoryl-β’-carbethoxyhydrazones 2
Reaction
time (h)b
Entry
R or R2P
Product
Yielda (%)
δ 31P (Z)c,d
δ 31P (E)
% Ze
% Ee
1
2
3
Ph
EtO
MeO
O
2a
2b
2c
96
83
91
2
2
3
31.5
25.2
23.7
29.9
24.1
21.0
79
60
72
21
40
28
4
P
2d
2e
88
87
4
4
-14.7
4.1
-7.6
-2.3
67
59
33
41
O
O
P
5
O
aIsolated yield.
bThe progress of the reactions was monitored by TLC.
c121.5 MHz, CDCl3.
dδ in ppm.
eDetermined from the 31P NMR spectra.
The Z and E configurations were attributed on the basis
of the 13C chemical shift values for the CH2-P carbon.
Indeed, according to some literature data [22-25] concerning
the stereochemistry of hydrazones, the carbon adjacent to the
C=N double bond resonates at higher field when it is in syn
position to the NHPh group.
Lawesson’s reagent. Thus, treatment of compounds 2 with
an equimolar amount of LR, performed in toluene, at 80 °C,
for 5-8 h, afforded the novel 5-mercapto-3-(methylthio-
phosphoryl)pyrazoles 3 [26] rather than the expected 1,2,3-
diazaphospholine derivatives A or B (Scheme 3). This can be
attributed to the poor nucleophilicity of the carbons at the α
and α’ positions relative to the C=N double bond, because of
the conjugation with the phosphoryl and ester groups [8].
This poor nucleophilicity would render the α and α’ carbons
With these hydrazone derivatives in hand, we next
focused our efforts to investigate their behaviour towards
O
R2P
CO2Et
LR
S
S
P
R2P
O
P
or
CO2Et
Ar
Toluene, 80 °C
Ar
N
N
N
N
O
R2P
Ph
Ph
A
B
CO2Et
N
NHPh
S
2
SH
R2P
LR
N
N
Toluene, 80 °C
Ph
3
S
Ar
P
S
P
Ar:
,
OMe
LR:
S
Ar
S
Scheme 3. Synthesis of 5-mercapto-3-(methylthiophosphoryl)pyrazoles 3.

322 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Chebil and Touil
poor nucleophilicity
poor nucleophilicity
!
!'
OEt
OEt
OEt
R2P
O
R2P
R2P
NH
NHPh
O
N
O
NH
NHPh
O
O
O
NHPh
2
LR
X
X
LR
O
CO2Et
R2P
S
S
P
R2P
O
P
CO2Et
Ar
Ar
Ph
N
N
N
N
Ph
B
A
Scheme 4. Loss of reactivity of the α and α’ carbons because of the conjugation with the ester and phosphoryl groups.
S
S
S
S
S
Ar
S
Ar
P
P
P
2
LR:
Ar
S
S
O
S
Ar
P
OEt
OEt
R2P
R2P
N
O
N
O
2
NHPh
NHPh
S
S
S
S
S
O
S
SH
Ar
P
R2P
R2P
R2P
Tautomerization
N
N
N
N
N
N
Ph
Ph
Ph
3
Scheme 5. Reaction mechanism for the synthesis of pyrazoles 3.
unable to initiate cyclization to give the diazaphospholine
derivatives A and B (Scheme 4).
700 and 2500 cm-1 corresponding respectively to the P=S
and S-H vibrators. The 1H NMR spectrum of each compound
3 showed, in particular, a doublet at 3.6-3.9 ppm, ascribable
to the CH2-P=S protons. Such a doublet is characteristic of
A plausible mechanism for the formation of compounds
3 is depicted in scheme 5. It is believed that the reaction
begins with a thionation of the phosphoryl group followed
by an intramolecular cyclization. The obtained pyrazolone
intermediate undergoes a second thionation with LR to lead,
after tautomerization, to the aromatic pyrazole derivative 3.
This mechanism can be confirmed by some literature data [3]
which indicate that LR thionates readily the phosphoryl,
ketone, amide and ester functions, and that the relative
reactivity order of these functional groups toward LR is as
follows: phosphoryles > amides > ketones > esters.
2
the coupling with phosphorus with a JPH coupling constant
of about 15 Hz. We also observed a singlet (in some cases a
4
doublet with a small JPH coupling constant) towards 6 ppm
assignable to the pyrazolic CH. The S-H proton resonates as
a broad singlet at 8-9 ppm. The 31P NMR shift recorded for
compounds 3 was δ = 40-80 ppm which is consistent with
the thiophosphoryl chemical shift values. The 13C NMR
spectra display the characteristic signals of all carbons and
particularly those corresponding to the pyrazole ring. Of
particular note is the CH2-P=S carbon which resonates as a
doublet (1JCP = 53.6-143.4 Hz) around 30 ppm. Structure of
compounds 3 was supported additionally by the mass spectra
which showed the correct molecular ion peaks.
The formation of compounds 3 was confirmed by IR,
NMR (1H, 31P, 13C) and mass spectral data [27]. The IR
spectra revealed the presence of absorption bands towards

First Synthesis of 5-Mercapto-3-(methylthiophosphoryl)pyrazoles
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
323
Table 2. Synthesis of 5-mercapto-3-(methylthiophosphoryl)pyrazoles 3
Entry
R or R2P
Product
Yielda (%)
Reaction time (h)b
δ 31P (ppm)c
1
2
3
Ph
EtO
MeO
O
3a
3b
3c
89
79
84
7
8
6
40.7
71.2
79.9
4
P
3d
3e
75
81
7
5
43.9
46.8
O
O
P
5
O
aIsolated yield.
bThe progress of the reactions was monitored by TLC.
c121.5 MHz, CDCl3.
[8]
[9]
Chebil, E.; Touil, S. Reaction of Lawesson's reagent with ester
hydrazones: synthesis of novel 3-thioxo-1,2,3-diazaphospholine
derivatives. J. Sulfur Chem., 2011, 32, 297-302.
Lv, P.-C.; Li, H.-Q.; Sun, J.; Zhou, Y.; Zhu, H.-L. Synthesis and
biological evaluation of pyrazole derivatives containing thiourea
skeleton as anticancer agents. Bioorg. Med. Chem., 2010, 18, 4606-
4614.
Lin, R.; Chiu, G.; Yu, Y.; Connolly, P. J.; Li, S.; Lu, Y.; Adams,
M.; Fuentes-Pesquera, A.R.; Emanuel, S.L.; Greenberger, L.M.
Design, synthesis and evaluation of 3,4-disubstituted pyrazole
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Sridhar, R.; Perumal, P.J.; Etti, S.; Shanmugam, G.; Ponnuswamy,
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Bondock, S.; Fadaly, W.; Metwally, M.A. Synthesis and
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El-Sabbagh, O.I.; Baraka, M.M.; Ibrahim, S.M.; Pannecouque, P.;
Andrei, G.; Snoeck, R.; Balzarini, J.; Rashad, A.A. Synthesis and
antiviral activity of new pyrazole and thiazole derivatives. Eur. J.
Med. Chem., 2009, 44, 3746-3753.
Bekhit, A.A.; Ashour, H.M.A.; Abdel Ghany, Y.S.; Bekhit,
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thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-
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456-463.
In conclusion, we have shown in the present
investigation, that the introduction of electron-withdrawing
phosphoryl and ester groups at the β and β’ positions relative
to the hydrazone function, significantly changes the
reactivity towards Lawesson’s reagent and provides the
novel 5-mercapto-3-(methylthiophosphoryl)pyrazoles rather
than the expected 1,2,3-diazaphospholine derivatives.
[10]
CONFLICT OF INTEREST
[11]
[12]
[13]
[14]
Declared none.
ACKNOWLEDGEMENTS
We thank the Tunisian Ministry of Higher Education and
Scientific Research for financial support.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
web site along with the published article.
REFERENCES AND NOTES
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Action du réactif de Lawesson sur les hydrazones β-phosphonatées:
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diazaphospholines. Phosphorus, Sulfur Silicon Relat. Elem., 1995,
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[5]
[6]
General procedure for the synthesis of β-phosphoryl-β’-
carbethoxyhydrazones 2. To a mixture of phenylhydrazine (0.02
mol) in absolute ethanol (20 mL), cooled at 0 °C, was added
dropwise with stirring, a solution of ketoesterphosphonate 1 (0.02
mol) in absolute ethanol (10 mL). Stirring at 0 °C was continued
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réactif de Lawesson sur les hydrazones γ-phosphonatées: Synthèse
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324 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Chebil and Touil
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[24]
[25]
[26]
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Spectral data of compound 2a (Table 1, entry 1). White solid; mp =
1
3
178-180 °C; H NMR (300 MHz, CDCl3): δ = 1.15 (t, 3H, JHH
=
6.0 Hz, CH3-CH2-O, Z); 1.16 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O, E);
Ben Akacha, A.; Barkallah, S.; Zantour, H. 13C NMR and 31P NMR
spectral assignment of new β-phosphonylated hydrazones. Magn.
Reson. Chem., 1999, 37, 916-920.
4
2
2.78 (d, 2H, JPH = 3.0 Hz, CH2-C=O, Z); 3.44 (d, 2H, JPH = 15.0
4
Hz, CH2-P=O, E); 3.53 (d, 2H, JPH = 3.0 Hz, CH2-C=O, E); 3.60
(d, 2H, JPH = 15.0 Hz, CH2-P=O, Z); 4.01 (q, 2H, JHH = 6.0 Hz,
CH3-CH2-O, Z); 4.06 (q, 2H, JHH = 6.0 Hz, CH3-CH2-O, E); 6.76-
2
3
General procedure for the synthesis of 5-mercapto-3-
(methylthiophosphoryl)pyrazoles 3. A mixture of hydrazone 2 (0.01
mol), LR (0.01 mol) and dry toluene (30 mL) was heated at 80 °C
with stirring for 5-8 h (Table 2). The reaction mixture was then
concentrated in vacuo. The residue obtained was chromatographed
on a silica gel column using a mixture of Et2O and hexane (9:1) as
eluent.
3
7.80 (m, 15H, arom-H); 8.23 (br s, 1H, N-H, E); 9.89 (br s, 1H, N-
H, Z); 13C NMR (75.5 MHz, CDCl3): δ = 14.1 (s, CH3-CH2-O, Z);
18.4 (s, CH3-CH2-O, E); 34.3 (d, 1JCP = 64.9 Hz, CH2-P, Z); 40.0 (d,
1JCP = 66.4 Hz, CH2-P, E); 43.2 (s, CH2-C=O, E); 43.7 (s, CH2-
C=O, Z); 61.0 (s, CH3-CH2-O, Z); 61.7 (s, CH3-CH2-O, E); 145.1
(s, C=N, E); 146.2 (s, C=N, Z); 168.7 (s, C=O, E); 170.3 (s, C=O,
Z); phenyl carbons: δ = 113.2, 113.7, 118.9, 120.0, 121.9, 125.2,
125.9, 128.5, 128.6, 128.7, 128.9, 129.0, 129.1, 130.5, 130.6,
[27]
Spectral data of compound 3a (Table 2, entry 1). White solid; mp =
1
2
152-153 °C; H NMR (300 MHz, CDCl3): δ = 3.91 (d, 2H, JPH
=
4
15.0 Hz, CH2-P); 6.50 (d, 1H, JPH = 2.2 Hz, CH=C-S); 7.06-7.83
130.8, 130.9, 131.0, 131.9, 132.2, 134.4, 134.6; IR (neat): νP=O
=
(m, 15H, arom-H); 8.07 (br s, 1H, S-H); 13C NMR (75.5 MHz,
1233 cm-1; νC=N = 1601 cm-1; νC=O = 1732 cm-1; νNH = 3311 cm-1; EI-
HRMS: calculated for C24H25N2O3P, 420.1603 (M+); found:
420.1607.
CDCl3): δ = 34.7 (d, JCP = 53.6 Hz, CH2-P); 116.5 (d, JCP = 2.3
Hz, CH=C-S); 138.8 (s, C-S); 144.0 (d, JCP = 6.0 Hz, C=N);
1
3
2
phenyl carbons: 125.58, 128.15, 128.50, 128.66, 128.71, 131.54,
[22]
Naulet, N.; Filleux, H. L.; Martin, G. J.; Pornet, J. Etude par RMN
du carbone des systèmes C=N: imines, phénylhydrazones,
131.58, 131.62, 131.67, 131.74, 132.80, 133.64; IR (neat): νP=S
= 698 cm-1; νS-H
=
2551 cm-1; EI-HRMS: calculated for
C22H19N2PS2, 406.0727 (M+); found: 406.0725.