A new route to 3-phosphonylpyrazoles

Article abstract of DOI:10.1080/10426500903329278

The regioselective synthesis of 3-diethoxyphosphonopyrazoles has been accomplished through the addition of aryl or alkyl hydrazines to (3-ethoxyacryloyl)phosphonic acid diethyl ester. An example of hydrolysis of the pyrazolephosphonic ester to the corresponding acid is described. Copyright

Full text of DOI:10.1080/10426500903329278

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Phosphorus, Sulfur, and Silicon and the
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A New Route to 3-Phosphonylpyrazoles
Romuald Bartnik a & Dariusz Cal a
a Department of Organic and Applied Chemistry , University of Łódź
, Łódź, Poland
Published online: 25 Aug 2010.
To cite this article: Romuald Bartnik & Dariusz Cal (2010) A New Route to 3-Phosphonylpyrazoles,
Phosphorus, Sulfur, and Silicon and the Related Elements, 185:9, 1858-1861, DOI:
10.1080/10426500903329278
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Phosphorus, Sulfur, and Silicon, 185:1858–1861, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903329278
A NEW ROUTE TO 3-PHOSPHONYLPYRAZOLES
Romuald Bartnik and Dariusz Cal
Department of Organic and Applied Chemistry, University of Ło´dz´, Ło´dz´, Poland
The regioselective synthesis of 3-diethoxyphosphonopyrazoles has been accomplished
through the addition of aryl or alkyl hydrazines to (3-ethoxyacryloyl)phosphonic acid
diethyl ester. An example of hydrolysis of the pyrazolephosphonic ester to the corresponding
acid is described.
Keywords Aminophosphonic acids; cycloaddition reactions; phosphonylpyrazoles
INTRODUCTION
Organophosphorus compounds have found a wide range of applications in the areas of
biological, medicinal, and synthetic chemistry.1–3 Their biological activity is often enhanced
by their association with various heterocycles, which are themselves biologically active.4
Among the numerous methods developed to synthesise pyrazoles,5 the most often applied
protocols are the reaction of hydrazines with β-difunctional compounds, and the 1,3-
dipolar cycloaddition of diazocompounds or nitrileimines to alkenes and alkynes. By these
methods, several phosphonylpyrazoles have already been prepared.4,6,7 However, in most
cases, the synthesis involves multistep reaction sequences.8,9
In this article, we describe a regioselective synthesis of 1-substituted or unsubstituted
pyrazoles 2a–d bearing diethylphosphonic ester moiety at the 3-position. An example of
transformation of phosphonylpyrazole 2b into the corresponding phosphonic acid is also
reported.
RESULTS AND DISCUSSION
It has been reported that 1-benzoyl-2-ethoxyvinylphosphonic acid diethyl ester can
be cyclized with hydrazine hydrate to form 4-phosphonylpyrazole.10 In this article, we
report on a facile strategy for the synthesis of 3-phosphonylpyrazoles from a similar β-
ethoxyenone system. The starting 3-ethoxyprop-2-enoylphosphonic acid diethyl ester (1)
was synthesised by a two-step procedure as shown in Scheme 1. The Arbuzov reaction
of acetyl chloride and triethylphosphite gave acetylphosphonic acid diethyl ester,11 which
was then refluxed with triethyl orthoformate in acetic anhydride as solvent for 16 h. The
Received 3 August 2009; accepted 9 September 2009.
This research project was supported by the Faculty of Chemistry, University of Ło´dz´.
Address correspondence to Dariusz Cal, Department of Organic and Applied Chemistry, University of Ło´dz´,
Tamka 12, PL 90-403, Ło´dz´, Poland. E-mail: darekcal@uni.lodz.pl
1858

A NEW ROUTE TO 3-PHOSPHONYLPYRAZOLES
1859
O
O
P(OEt)3
HC(OEt)3
Ac2O
EtO CH CH CO PO(OEt)2
H3C Cl
H3C PO(OEt)2
1 (63%)
Scheme 1
pure product was separated by distillation at reduced pressure in 63% yield. A similar
3-ethoxyprop-2-enoylphosphonic acid dimethyl ester has been described in literature as a
product of Arbuzov reaction of 3-ethoxyprop-2-enoyl chloride with trimethylphohosphite.12
Finally we investigated the reaction of β-ethoxyenone 1 with four hydrazines
(Scheme 2). The reaction was carried out in dichloromethane as a solvent, and we ob-
served a mild heat evolution. In all cases, we obtained the 3-phosphonylpyrazoles 2a–d,
which were purified by column chromatography. The structures of compounds 2a–d were
confirmed by analytical and spectroscopic data. In the case of 2b–d they are in accordance
with literature,8,13,14 while products 2a,c are new.
O
CH2Cl2
a: R = Me
b: R = Ph
c: R = 4-MeC6H4
d: R = H
P(OEt)2
1
H2N NHR
+
N
N
R
2 a (30%)
b (35%)
c (41%)
d (26%)
Scheme 2
The pure pyrazolephosphonic acid 3 was obtained by refluxing 2b with 20% HCl
(aq.) solution for 10 h and subsequent treatment with propylene oxide (Scheme 3).
In summary, a new and simple method for the synthesis of 1-H or 1-substituted 3-
phosphonylpyrazoles has been developed, which is based on the reaction of easily available
3-ethoxyacryloylphosphonic acid diethyl ester and hydrazines.
EXPERIMENTAL
Melting points are uncorrected. NMR spectra were obtained with a Bruker DPX 250,
a Varian Gemini 200, and a Tesla BS 687 spectrometer operating at 250, 200, and 80 MHz
for 1H (TMS), at 63 and 50 MHz for 13C, and at 101 and 80 MHz for 31P (H3PO4), respec-
tively. MS-ESI spectra were recorded with a Bruker Esquire-LC instrument. The elemental
analyses were performed by the Laboratory of Microanalysis of the Centre of Molecular and
O
P(OH)2
1. HCl (aq), reflux
2 b
N
N
Ph
O
2.
Scheme 3

1860
R. BARTNIK AND D. CAL
Macromolecular Studies, Polish Academy of Science in Ło´dz´, Poland. Acetylphosphonic
acid diethyl ester was obtained according to the method described in literature.11
3-Ethoxyprop-2-enoylphosphonic Acid Diethyl Ester (1)
A solution of acetylphosphonic acid diethyl ester (18.0 g, 0.1 mol) and triethyl
orthoformate (30.0 g, 0.2 mol) in acetic anhydride (30.0 g) was refluxed for 16 h. Then the
solvent was evaporated, and the residue was fractionated under reduced pressure to yield
the pure product as a pale yellow oil (59.6 g, 63%), bp 118–150 ◦C/0.4 mm Hg. 1H NMR
(CDCl3, 80 MHz): δ 1.27–1.47 (m, 9H, CH3), 3.95–4.38 (m, 6H, CH2O), 5.98 (dd, 3JPH
14.9 Hz, 3JHH 12.5 Hz, 1H, CH), 8.26 (d, 3JHH 12.5 Hz, 1H, CH). 13C NMR (CDCl3,
3
2
50 MHz): δ 13.5 (CH3), 15.4 (d, JPC 5.7 Hz, CH3), 62.6 (d, JPC 6.9 Hz, CH2),
67.5 (CH2), 107.2 (d, 2JPC 68.1 Hz, C-2), 167.4 (d, 3JPC 2.8 Hz, C-3), 195.3 (d, 1JPC
173.7 Hz, C-1). 31P NMR (CDCl3, 80 MHz): δ
–2.3. Anal. Calcd. for C9H17O5P: C,
45.76; H, 7.25%. Found: C, 45.36; H, 7.38%.
3-Phosphonylpyrazoles 2a-d: General Procedure
To a solution of 1 (10.0 mmol) in CH2Cl2 (50 mL), substituted hydrazine or hydrazine
hydrate (10.5 mmol) was added and mild heat evolution was observed. The mixture was
stirred for 1 h, then the solvent was evaporated, and the products 2a–d were purified by
chromatography on SiO2 (hexane–ethyl acetate, gradient 50 to 100% ethyl acetate).
1-Methyl-1H-pyrazol-3-ylphosphonic acid diethyl ester (2a). Yellow oil
1
(0.65 g, 30%). H NMR (CDCl3, 80 MHz): δ
1.25–1.43 (m, 6H, CH3), 3.99 (s, 3H,
CH3), 4.04–4.37 (m, 4H, CH2), 6.69–6.74 (m, 1H, CH), 7.42–7.48 (m, 1H, CH). 13C NMR
(CDCl3, 50 MHz): δ
5.5 Hz, CH2), 111.4 (d, JPC 23.5 Hz, C-4), 130.7 (d, JPC 10.0 Hz, C-5), 140.8 (d,
1JPC 232.9 Hz, C-3). 31P NMR (CDCl3, 80 MHz): δ 9.9. Anal. Calcd. for C8H15N2O3P:
C, 44.04; H, 6.93%. Found: C, 43.82; H, 6.93%.
3
2
15.6 (d, JPC
6.4 Hz, CH3), 38.8 (CH3N), 61.8 (d, JPC
2
3
1-Phenyl-1H-pyrazol-3-ylphosphonic acid diethyl ester (2b). Yellow oil
1
3
(0.98 g, 35%). H NMR (CDCl3, 200 MHz): δ
1.38 (t, JHH
7.1 Hz, 6H, CH3),
4.17–4.32 (m, 4H, CH2), 6.91–6.92 (m, 1H, CH), 7.35–7.76 (m, 5H, C6H5), 7.99–8.01
3
(m, 1H, CH). 13C NMR (CDCl3, 50 MHz): δ
16.0 (d, JPC
6.6 Hz, CH3), 62.5 (d,
2
2JPC
5.5 Hz, CH2), 113.0 (d, JPC
23.2 Hz, C-4), 119.7 (CHarom), 127.4 (CHarom),
127.8 (d, 3JPC 9.4 Hz, C-5), 129.3 (CHarom), 139.4 (Carom), 143.1 (d, 1JPC 231.5 Hz,
C-3). 31P NMR (CDCl3, 80 MHz): δ 9.6. Anal. Calcd. for C13H17N2O3P: C, 55.71; H,
6.11%. Found: C, 55.60; H, 5.92%.
1-(4-Tolyl)-1H-pyrazol-3-ylphosphonic acid diethyl ester (2c). Yellow oil
1
3
(1.21 g, 41%). H NMR (CDCl3, 80 MHz): δ 1.36 (t, JHH 7.0 Hz, 6H, CH3), 2.38
(s, 3H, CH3), 4.05–4.41 (m, 4H, CH2), 6.86–6.90 (m, 1H, CH), 7.19–7.69 (m, 4H, C6H4),
7.92–7.98 (m, 1H, CH). 13C NMR (CDCl3, 50 MHz): δ 15.9 (d, 3JPC 6.5 Hz, CH3),
20.5 (CH3), 62.4 (d, 2JPC 5.6 Hz, CH2), 112.7 (d, 2JPC 23.2 Hz, C-4), 119.5 (CHarom),
3
127.6 (d, JPC
9.5 Hz, C-5), 129.6 (CHarom), 137.0 (Carom), 137.1 (Carom), 142.5 (d,
1JPC 231.3 Hz, C-3). 31P NMR (CDCl3, 80 MHz): δ 9.7. Anal. Calcd. for C14H19N2O3P:
C, 57.14; H, 6.51%. Found: C, 57.11; H, 6.65%.
1H-Pyrazol-3-ylphosphonic acid diethyl ester (2d). Colorless crystals (0.53
◦
◦
1
g, 26%), mp 64–66 C (lit.8,13 mp 63–64 C). H NMR (CDCl3, 80 MHz): δ
1.32 (t,
3JHH
7.1 Hz, 6H, CH3), 3.98–4.26 (m, 4H, CH2), 6.71–6.76 (m, 1H, CH), 7.85–7.91

A NEW ROUTE TO 3-PHOSPHONYLPYRAZOLES
1861
(m, 1H, CH). 13C NMR (CDCl3, 50 MHz): δ 15.8 (d, 3JPC 6.1 Hz, CH3), 62.2 (d, 2JPC
5.0 Hz, CH2), 110.2 (d, 2JPC 23.3 Hz, C-4), 131,0 (d, 3JPC 9.4 Hz, C-5), 139.2 (d,
1JPC
230.1 Hz, C-3). 31P NMR (CDCl3, 80 MHz): δ
10.3. ESI-MS (MeOH): 205
(30%, [M+H]+), 227 (100%, [M+Na]+).
1-Phenyl-1H-pyrazol-3-ylphosphonic Acid (3)
The ester 2b (1.40 g, 0.005 mol) was dissolved in HCl (aq.) solution (8 mol/L,
55 mL) and EtOH (5 mL) was added. The mixture was refluxed for 12 h, and then the
solvent was evaporated. The residue was dissolved in MeOH (10 mL), propylene oxide was
added, and the mixture was left for 10 h. Then the solvent was evaporated, and the residue
was crystallized from water to yield aminoacid 3 as colorless crystals (0.17 g, 15%), mp
159–160 ◦C. 1H NMR (CDCl3, 250 MHz): δ 6.57–6.58 (m, 1H, CH), 7.10–7.39 (m, 5H,
2
C6H5), 7.80–7.82 (m, 1H, CH). 13C NMR (D2O/NaOD, 63 MHz): δ 111.0 (d, JPC
20.7 Hz, C-4), 120.1 (CHarom), 127.4 (CHarom), 129.3 (CHarom), 129.4 (CHarom), 139.1
(Carom), 150.0 (d, 1JPC 212.0 Hz, C-3). 31P NMR (D2O/NaOD, 101 MHz): δ 4.9. Anal.
Calcd. for C8H9N2O3P: C, 48.23; H, 4.05%. Found: C, 48.11; H, 4.09%.
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