A regioselective route to 5-substituted pyrazole- and pyrazoline-3-phosphonic acids and esters

Article abstract of DOI:10.1016/j.tet.2007.04.027

The regioselective synthesis of 5-substituted-3-dimethoxyphosphono-pyrazoles and -2-pyrazolines has been accomplished through the 1,3-dipolar cycloaddition of a suitable nitrile imine to monosubstituted alkynes and alkenes. Examples of hydrolysis of the heterocyclic phosphonic esters to the corresponding acids are described.

Full text of DOI:10.1016/j.tet.2007.04.027

Tetrahedron 63 (2007) 5554–5560
A regioselective route to 5-substituted pyrazole- and
pyrazoline-3-phosphonic acids and esters
a
a
b
a
P. Conti,a, A. Pinto, L. Tamborini, V. Rizzo and C. De Micheli
*
aIstituto di Chimica Farmaceutica e Tossicologica ‘P. Pratesi’, Universitaꢀ degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy
bCISI, Universitaꢀ degli Studi di Milano, Via Fantoli 16/15, 20138 Milano, Italy
Received 1 February 2007; revised 15 March 2007; accepted 5 April 2007
Available online 14 April 2007
Abstract—The regioselective synthesis of 5-substituted-3-dimethoxyphosphono-pyrazoles and -2-pyrazolines has been accomplished
through the 1,3-dipolar cycloaddition of a suitable nitrile imine to monosubstituted alkynes and alkenes. Examples of hydrolysis of the
heterocyclic phosphonic esters to the corresponding acids are described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
3-hydroxyisoxazole, 3-hydroxythiadiazole, and phosphonate.
As an example, in the glutamatergic systems the replace-
ment of the distal carboxylate group with the phosphonate
moiety is responsible for a substantial increase in potency.
As a matter of fact, such a bioisosteric modification trans-
forms a weak NMDA antagonist such as (R)-2-amino-adipic
acid 1 into the quite potent (R)-2-amino-5-phosphonopenta-
noate 2 (Fig. 1).13 The same trend is observed on passing
from 4-carboxypropyl-piperazine-2-carboxylic acid 3 to
1,3,5-Trisubstituted pyrazoles are synthetic targets of utmost
importance in the pharmaceutical industry, since such a
heterocyclic moiety represents the core structure of numer-
ous drugs,1 including the widely prescribed Celebrex and
Viagra.2 Furthermore, recent reports indicate the pyrazole
chemotype as the structural motif of a number of highly
potent inhibitors of coagulation factor Xa.3 Among them,
Rivaroxaban4 and Apixaban5 were selected for clinical
development for the prevention and treatment of thrombotic
diseases. If we focus our attention on pyrazole- and 2-pyrazo-
line acids, we can find a huge number of derivatives with anti-
microbial,6 herbicide,7 hypoglycemic,8 and hypolipidemic9
activities. Furthermore, pyrazole 3-carboxylates were also
identified as selective antagonists of subtype 1 PGE2 recep-
tors (EP1).10 These compounds showed efficacy in numerous
preclinical model of pain, including allodynia, neuropathic
pain, and are expected to be devoid of the gastrointestinal ef-
fects associated with non-steroidal anti-inflammatory drugs
(NSAIDS)11 and the cardiovascular side effects typical of
COX-2 selective inhibitors.12
COOH
NH2
COOH
NH2
HOOC
HOOC
H2O3P
H2O3P
(R)-2
(R)-1
N
N
N
H
(R)-3
COOH
N
H
(R)-4
COOH
H2O3P
Me2O3P
Me2O3P
Bioisosterism is a common strategy applied in medicinal
chemistry to increase the potency and/or selectivity, as
well as to ameliorate the overall pharmacokinetic profile of
drugs. In particular, the carboxylate group can be fruitfully
replaced by an array of moieties characterized by similar
physico-chemical properties, e.g., hydroxamate, tetrazole,
N
N
N
R
R
Ph
N
N
N
5a: R = Ph
6a: R = Ph
7: pyrazole
8: 2-pyrazoline
5b: R = CO2Me
5c: R = C4H9
5d: R = C9H19
6b: R = CO2Me
6c: R = C4H9
6d: R = C9H19
* Corresponding author at present address: Istituto di Chimica Farma-
ꢀ
ceutica e Tossicologica ‘Pietro Pratesi’, Universita degli Studi di Milano,
Viale Abruzzi 42, 20131 Milano, Italy. Tel.: +39 02 50317570; fax: +39
02 50317574; e-mail: paola.conti@unimi.it
Figure 1. Structures of reference [(R)-1, (R)-2, (R)-3, and (R)-4] and target
compounds [5a–d, 6a–d, 7, and 8].
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.027

P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
5555
4-phosphonopropyl-piperazine-2-carboxylic acid (CPP) 4
(Fig. 1), which is a commonly used pharmacological tool
to characterize NMDA receptors.13
dehydrohalogenation of hydrazonoyl halides, such as 10,
by treatment with a base (Scheme 1). Therefore, we prepared
the phenylhydrazide of dimethyl formylphosphonate by
condensing phenylhydrazine with trimethyl phosphono-
formate under vacuum to remove methanol. As shown in
Scheme 1, intermediate 9 was transformed into hydrazonoyl
bromide 10 by treatment with a mixture of carbon tetrabro-
mide and triphenylphosphine.16 In parallel, we devised an
alternative route to hydrazonoyl bromide 10 through the
condensation of phenylhydrazine with dimethyl formyl-
phosphonate followed by treatment with N-bromo succin-
imide (NBS). Dimethyl formylphosphonate, obtained by
Swern oxidation of dimethyl (hydroxymethyl)phospho-
nate,17 was not characterized but directly condensed with
phenylhydrazine, since it is chemically unstable and at
ꢀ10 ꢁC undergoes decomposition to carbon monoxide and
dimethyl phosphite.18
In connection with our medicinal chemistry project aimed at
the discovery of new NMDA antagonists, we needed to
prepare a series of 3-phosphono-2-pyrazolines as well as
3-phosphono-pyrazoles. Among the numerous methods
developed to synthesize pyrazoles and 2-pyrazolines,14 the
most applied protocol is the reaction of hydrazines with
either 1,3-dicarbonyl compounds, a,b-ethynyl ketones, or
a,b-unsaturated ketones. We did not take into account this
methodology due to the uncertainty of the reaction out-
come, i.e., by using 1,3-dicarbonyl compounds a mixture
of regioisomers is usually formed, the difficulty in the prep-
aration of the substrates, and the limited possibility to gener-
ate a library of compounds. A valid synthetic alternative is
represented by the 1,3-dipolar cycloaddition of diazoalkanes
or nitrile imines with alkynes or alkenes. The advantage of
this procedure is that it is often highly regioselective and,
in addition, the 1,3-dipole can be reacted with an array of
unsaturated substrates to produce a number of different
heterocyclic entities.15
Nitrile imine 11, generated in situ by reacting hydrazonoyl
bromide 10 with sodium bicarbonate, was evaluated for its
reactivity toward representative alkynes 12a–d and alkenes
14a–d. All the cycloaddition reactions, reported in Scheme
2, were run under comparable conditions with a threefold
excess of dipolarophile. The reactions progressed until the
disappearance of the hydrazonoyl bromide. The outcome
of the reactions was carefully analyzed by LC–MS to evalu-
ate the ratio among the couple of regioisomers 5a–d/13a–d
and 6a–d/15a–d. The relative percentages of the two re-
gioisomers are reported in Table 1. Major isomers 5a–
d and 6a–d were fully characterized by spectroscopic and
analytical methods, whereas minor regioisomers 13a–
d and 15a–d were detected by HPLC and identified through
their MS spectrum.
Herein, we describe a highly regioselective synthesis of 5-
substituted 1-phenyl-pyrazoles 5a–d and 2-pyrazolines 6a–
d bearing at the 3-position the dimethyl phosphonic ester
moiety (Fig. 1). Examples of their transformation into the
corresponding phosphonic acids as well as the oxidation of
a 2-pyrazoline to the related pyrazole derivative are also
reported.
2. Results and discussion
The almost unidirectional behavior observed in the cyclo-
addition of nitrile imine 11 to monosubstituted alkynes
and alkenes parallels the results obtained with the thoroughly
studied diphenylnitrile imine.15 The regioselectivity of such
a 1,3-dipole has been explained on the basis of the Frontier
orbital theory where the dominant interaction involves the
Nitrile imines can be generated in a variety of ways, e.g., by
oxidation of aldehyde hydrazones, thermolysis of 2,5-disub-
stituted tetrazoles or oxadiazolin-5-ones, and photochemical
degradation of sydnones. Usually, the most practical and
scalable method is the in situ technique based on the
H
NH2
N
PO3Me2
HN
HN
HN
a
O
+
Me2O3P CO2Me
9
N
PO3Me2
c,d
Br
b
CHO
Me2O3P
Me2O3P CH2OH
10
PO3Me2
+ N
e
f
9
10
-
N
Ph
11
Scheme 1. (a) Neat, 40 ꢁC, 20 mbar, 2 h; (b) (COCl)2, DMSO, TEA, ꢀ60 ꢁC/CH2Cl2; (c) PhNHNH2, ꢀ40 ꢁC/CH2Cl2; (d) NBS/AcOEt, D; (e) CBr4, PPh3/
CH2Cl2; (f) NaHCO3/AcOEt.

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P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
Me2O3P
Me2O3P
R
N
N
a
R
N
N
R
10
12a: R = Ph
5a: R = Ph
13a: R = Ph
12b: R = CO2Me
12c: R = C4H9
12d: R = C9H19
5b: R = CO2Me
5c: R = C4H9
5d: R = C9H19
13b: R = CO2Me
13c: R = C4H9
13d: R = C9H19
Me2O3P
Me2O3P
R
N
N
N
R
N
a
10
R
14a: R = Ph
6a: R = Ph
15a: R = Ph
14b: R = CO2Me
14c: R = C4H9
14d: R = C9H19
6b: R = CO2Me
6c: R = C4H9
6d: R = C9H19
15b: R = CO2Me
15c: R = C4H9
15d: R = C9H19
H2O3P
N
b
Ph
Ph
N
5a
7
H2O3P
N
b
N
6a
8
c
5a
6a
Scheme 2. (a) NaHCO3/AcOEt, D; (b) TMSBr, CH2Cl2; (c) PDC, DMF.
LUMO of the 1,3-dipole and the HOMO of the
dipolarophile.19,20 According to the principle of the maxi-
mum overlap, the preferred isomer comes from the union of
the two sites of the reactants having the largest coefficients.
Since the dipolarophile HOMO of monosubstituted alkynes
and alkenes has the larger coefficient at the b carbon, regard-
less of the substitution pattern, and the nitrilium carbon is
the terminus endowed with the highest LUMO coefficient,
the formation of cycloadducts 5a–d and 6a–d as the major
regioisomers is fully accounted for.19
3. Experimental
3.1. Materials and methods
All reagents were purchased from Sigma. Dimethyl
(hydroxymethyl)phosphonate was prepared according to
a literature procedure.17 1H NMR (300 MHz), 13C NMR
(75.5 MHz), and 31P NMR (121.5 MHz) spectra were re-
corded with a Varian Mercury 300 spectrometer in CDCl3
or DMSO-d6 solution at 20 ꢁC. Chemical shifts (d) are ex-
pressed in parts per million and coupling constants (J) in
hertz. IR spectra were recorded with a Perkin–Elmer FTIR
spectrometer Paragon 1000 PC. TLC analyses were per-
formed on commercial silica gel 60 F254 aluminum sheets;
spots were visualized by spraying with a dilute alkaline
potassium permanganate solution. Melting points were
To check the applicability of the present methodology to the
synthesis of pyrazole- and 2-pyrazoline-3-phosphonic acids,
we treated the representative cycloadducts 5a and 6a with
a 10-fold excess of trimethylsilyl bromide; heterocyclic
phosphonic acids 7 and 8, respectively, were obtained in
quantitative yield.21 Finally, the conversion of 2-pyrazolines
into the corresponding pyrazole derivatives was proved to be
effective by reacting 6a with a 15-fold excess of pyridinium
dichromate (PDC) in DMF at room temperature to produce
pyrazole 5a in high yield.
€
determined on a model B 540 Buchi apparatus and are
uncorrected.
HPLC–MS analyses were carried out using an Agilent 1100
HPLC coupled with an ESI (+) Bruker Esquire 3000 ionic

P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
5557
Table 1. Regioisomeric ratio of the cycloaddition between nitrile imine 11 and dipolarophiles 12a–d and 14a–d
Dipolarophile
Products
Me2O3P
Regioisomeric ratioa
Yieldb (%)
Me2O3P
Ph
Ph
+
N
N
90:10
40
Ph
N
N
12a
Ph
5a
Ph
13a
Me2O3P
Me2O3P
CO2Me
+
MeOOC
N
N
78:22
95:5
81:19
97:3
97:3
98:2
34
18
12
30
20
20
CO2Me
N
Ph
5b
N
Ph
13b
12b
Me2O3P
Me2O3P
C4H9
+
C4H9
N
N
C4H9
N
Ph
5c
N
Ph
13c
12c
Me2O3P
N
Me2O3P
C9H19
C9H19
+
N
C9H19
N
Ph
5d
N
Ph
13d
12d
Me2O3P
Me2O3P
Ph
+
Ph
N
N
Ph
N
Ph
6a
N
14a
Ph
15a
Me2O3P
Me2O3P
CO2Me
+
MeO2C
N
N
CO2Me
N
Ph
6b
N
Ph
15b
14b
Me2O3P
Me2O3P
C4H9
+
C4H9
N
N
C4H9
N
Ph
6c
N
Ph
15c
14c
Me2O3P
N
Me2O3P
N
C9H19
+
C9H19
95:5
27
C9H19
N
Ph
6d
N
14d
Ph
15d
a
Determined by LC–MS analysis of the crude reaction mixture.
Yield of isolated product 5 or 6.
b
trap. The instrument was fitted with a Waters Atlantis col-
umn (4.6ꢂ50 mm, 3 mm). Analyses were carried out using
mobile phases A and B according to one of the following
methods:
Method3:t¼0, A:90%,B:10%;t¼6 min,A:10%, B:90%.
Method 4: t¼0, A: 40%, B: 60%; t¼10 min, A: 10%, B:
90%.
3.2. Dimethyl [(2-phenylhydrazino)carbonyl]-
phosphonate (9)
Phase A: H2O+0.1% TFA; phase B: acetonitrile+0.1%
TFA.
Method 1: t¼0, A: 80%, B: 20%; t¼10 min, A: 50%, B:
Trimethyl phosphonoformate (1 mL, 7.6 mmol) and phenyl-
hydrazine (0.75 mL, 7.6 mmol) were mixed in a round bot-
tom flask. The mixture was promptly stirred at 40 ꢁC under
reduced pressure (20 mbar). After 3 h, the crude material
50%.
Method 2: t¼0, A: 60%, B: 40%; t¼10 min, A: 0%, B:
100%.

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P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
was purified by flash chromatography (petroleum ether/
AcOEt 1:1) to obtain 9 (250 mg, 1.03 mmol, yield 14%) as
a white solid.
The reaction mixture was refluxed for 24 h and the progress
of the reaction was followed by TLC (AcOEt). Water (1 mL)
was added and the organic layer was separated and dried over
anhydrous Na2SO4. HPLC–MS analysis of the crude mate-
rial, obtained after evaporation of the solvent, showed the for-
mation of regioisomers 5 and 13 in the relative ratio reported
in Table 1. The crude material was purified by flash chroma-
tography on silica gel (petroleum ether/AcOEt 2:3) to give
pyrazole 5.
Phosphonate 9: crystallized from (i-Pr)2O as white prisms;
1
mp 142–144 ꢁC. Rf ¼0.4 (AcOEt). H NMR (CDCl3): d¼
3.87 (d, JH–P¼11.0, 3H), 3.88 (d, JH–P¼11.0, 3H), 6.42 (br
s, 1H), 6.86 (d, J¼7.7, 2H), 6.94 (t, J¼7.7, 1H), 7.25 (dd, J¼
7.7, 7.7, 2H), 9.5 (br s, 1H); 13C NMR (CDCl3): 55.1 (JC–P
¼
7.0), 114.3, 122.1, 129.5, 146.9, 164.5 (d, JC–P¼223.0); 31
P
NMR (CDCl3): 1.12; nmax (neat) 3251, 2958, 1676, 1659,
1602, 1498, 1248, 1036. Anal. Calcd for C9H13N2O4P: C,
44.27; H, 5.37; N, 11.47. Found: C, 44.63; H, 5.50; N, 11.09.
Pyrazole 5a: Rf ¼0.22 (petroleum ether/AcOEt 2:3); yellow
1
oil; H NMR (CDCl3): 3.90 (d, JH–P¼11.0, 6H), 6.97 (d,
JH–P¼1.5, 1H), 7.17–7.23 (m, 2H), 7.25–7.40 (m, 8H); 13C
NMR (CDCl3): 53.2 (d, JC–P¼6.0), 53.2 (d, JC–P¼6.0),
112.8 (d, JC–P¼23.0), 125.3, 128.1, 128.4, 128.5, 128.7,
129.1, 139.1, 141.2 (d, JC–P¼233.0), 144.0 (d, JC–P¼10.0);
31P NMR (CDCl3): 14.21; nmax (neat) 3470, 2953, 1498,
1256, 1031; HPLC retention time: 5.01 min (method 3).
Anal. Calcd for C17H17N2O3P: C, 62.19; H, 5.22; N, 8.53.
Found: C, 62.03; H, 5.31; N, 8.35.
3.3. Dimethyl [bromo(phenylhydrazono)methyl]-
phosphonate (10)
To a solution of 9 (3.0 g, 12 mmol) in CH2Cl2 (20 mL) a solu-
tion of CBr4 (6.0 g, 18 mmol) in CH2Cl2 (10 mL) was added
dropwise, followed by a solution of PPh3 (3.9 g, 15 mmol) in
CH2Cl2 (10 mL) at 0 ꢁC. The reaction mixture was stirred at
room temperature overnight. The solvent was removed under
reduced pressure and the crude material was purified by flash
chromatography (petroleum ether/AcOEt 1:1) to give 10
(2.6 g, 8.5 mmol, yield 70%) as a white solid.
Pyrazole 5b: Rf¼0.31 (petroleum ether/AcOEt 3:7); yellow
1
oil; H NMR (CDCl3): 3.82 (s, 3H), 3.88 (d, JH–P¼11.3,
6H), 7.40–7.55 (m, 6H); 13C NMR (CDCl3): 52.4, 53.4 (d,
JC–P¼6.0), 118.0 (d, JC–P¼24.0), 126.0, 128.7, 129.4, 132.0,
139.5, 141.4 (d, JC–P¼234.0), 158.8; 31P NMR (CDCl3):
12.19; nmax (neat) 3473, 2956, 1737, 1499, 1280, 1035;
HPLC retention time: 5.03 min (method 1). Anal. Calcd
for C13H15N2O5P: C, 50.33; H, 4.87; N, 9.03. Found: C,
50.04; H, 5.02; N, 8.90.
Hydrazonoyl bromide 10: crystallized from (i-Pr)2O as
white prisms; mp (dec) >108 ꢁC; Rf ¼0.6 (AcOEt); 1H
NMR (CDCl3): 3.92 (d, JH–P¼11.0, 6H), 7.05 (t, J¼7.7,
1H), 7.2 (d, J¼7.7, 2H), 7.32 (dd, J¼7.7, 7.7, 2H), 8.55
(br s, 1H); 13C NMR (CDCl3): 54.3 (JC–P¼6.0), 107.6 (d,
JC–P¼280.0), 114.1, 122.8, 129.3, 141.1; 31P NMR
(CDCl3): 5.78; nmax (neat) 3197, 2954, 1602, 1556, 1510,
1251, 1039. Anal. Calcd for C9H12BrN2O3P: C, 35.20; H,
3.94; N, 9.12. Found: C, 35.51; H, 4.05; N, 9.02.
Pyrazole 5c: Rf ¼0.29 (petroleum ether/AcOEt 3:7); yellow
1
oil; H NMR (CDCl3): 0.87 (t, J¼7.3, 3H), 1.20–1.40 (m,
2H), 1.55–1.65 (m, 2H), 2.63 (t, J¼7.7, 2H), 3.86 (d, JH–P
¼
11.4, 6H), 6.68 (s, 1H), 7.35–7.50 (m, 5H); 13C NMR
(CDCl3): 13.7, 22.2, 25.8, 30.6, 53.2 (d, JC–P¼6.0), 111.0
(d, JC–P¼24.0), 125.8, 128.8, 129.2, 132.0, 139.2, 140.6
(d, JC–P¼233.0), 145.4 (d, JC–P¼10.0); 31P NMR (CDCl3):
14.83; nmax (neat) 3431, 2954, 1500, 1255, 1031; HPLC
retention time: 3.08 min (method 2). Anal. Calcd for
C15H21N2O3P: C, 58.43; H, 6.87; N, 9.09. Found: C,
58.15; H, 6.95; N, 8.88.
3.4. Preparation of 10 from dimethyl (hydroxymethyl)-
phosphonate
To a solution of oxalyl chloride (0.48 mL, 5.5 mmol) in dry
CH2Cl2 (13 mL) cooled at ꢀ60 ꢁC, under N2, was added
DMSO (0.79 mL, 11 mmol). After 2 min, a solution of
dimethyl (hydroxymethyl)phosphonate17 (0.70 g, 5 mmol),
in dry CH2Cl2 (5 mL), was added slowly with stirring. After
15 min, TEA (3.5 mL, 25 mmol) was added dropwise. The
temperature was then let to rise at ꢀ40 ꢁC and stirred for
1 h. After that time phenylhydrazine (0.38 mL, 10 mmol)
was added and the mixture was let to warm to room tempera-
ture. Thesolventwasevaporatedundervacuum, andthecrude
material was purified by flash chromatography (petroleum
ether/AcOEt 1:1) to give the intermediate dimethyl [(phenyl-
hydrazono)methyl]phosphonate (0.24 g, 1.06 mmol), which
was directly submitted to bromination with NBS (0.21 g,
1.17 mmol) in AcOEt (5 mL) at reflux. After 1 h, the solvent
was evaporated under vacuum and the crude material was pu-
rified by flash chromatography (petroleum ether/AcOEt 1:1)
to give 10 (0.30 g, 0.98 mmol, overall yield 20%).
Pyrazole 5d: Rf ¼0.31 (petroleum ether/AcOEt 1:1); yellow
1
oil; H NMR (CDCl3): 0.86 (t, J¼7.0, 3H), 1.15–1.40 (m,
12H), 1.55–1.65 (m, 2H), 2.62 (t, J¼8.0, 2H), 3.85 (d, JH–P
¼
11.2, 6H), 6.70 (s, 1H), 7.40–7.60 (m, 5H); 13C NMR
(CDCl3): 14.4, 23.0, 26.4, 28.9, 29.4, 29.5, 29.7, 30.0,
32.2, 53.4 (d, JC–P¼6.3), 53.5 (d, JC–P¼6.3), 111.1 (d,
JC–P¼24.0), 125.9, 128.9, 129.3, 139.4, 140.9 (d,
JC–P¼233.0), 145.5 (d, JC–P¼9.7); 31P NMR (CDCl3):
14.96; nmax (neat) 3368, 2926, 1501, 1258, 1034; HPLC
retention time: 3.99 min (method 4). Anal. Calcd for
C20H31N2O3P: C, 63.47; H, 8.26; N, 7.40. Found: C,
63.15; H, 8.42; N, 7.37.
3.6. General procedure for the cycloaddition of 11 to
alkenes 14
3.5. General procedure for the cycloaddition of 11 to
alkynes 12
To a solution of alkene 14 (3 mmol) in AcOEt (5 mL) were
added 10 (0.31 g, 1 mmol) and NaHCO3 (0.34 g, 4 mmol).
The reaction mixture was refluxed for 24 h and the progress
of the reaction was followed by TLC (AcOEt). Water (1 mL)
To a solution of alkyne 12 (3 mmol) in AcOEt (5 mL) were
added 10 (0.31 g, 1 mmol) and NaHCO3 (0.34 g, 4 mmol).

P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
5559
was added and the organic layer was separated and dried
over anhydrous Na2SO4. HPLC–MS analysis of the crude
material, obtained after evaporation of the solvent, showed
the formation of regioisomers 6 and 15 in the relative ratio
reported in Table 1. The crude material was purified by flash
chromatography on silica gel (petroleum ether/AcOEt 2:3)
to give pyrazoline 6.
4). Anal. Calcd for C20H33N2O3P: C, 63.14; H, 8.74; N,
7.36. Found: C, 62.79; H, 9.03; N, 7.10.
3.7. Preparation of 1,5-diphenyl-1H-pyrazole-3-
phosphonic acid (7)
To a solution of 5a (164 mg, 0.5 mmol) in CH2Cl2 (3 mL)
was added bromotrimethylsilane (0.66 mL, 5 mmol). The
reaction mixture was then stirred at room temperature for
4 h. Methanol (2 mL) was added and the reaction mixture
was stirred for 1 h and then the solvent was evaporated under
vacuum to give 7 (150 mg, 0.5 mmol, yield 100%) as a white
powder.
Pyrazoline 6a: Rf ¼0.4 (petroleum ether/AcOEt 3:7); white
prisms from i-PrOH, mp (dec) >122 ꢁC; 1H NMR
(CDCl3): 3.00 (dd, J¼7.4, 18.0, 1H), 3.68 (dd, J¼13.0,
18.0, 1H), 3.88 (d, JH–P¼11.3, 3H), 3.90 (d, JH–P¼11.3,
3H), 5.30 (dd, J¼7.4, 13.0, 1H), 6.85 (t, J¼7.3, 1H), 7.04
(d, J¼8.4, 2H), 7.10–7.40 (m, 7H); 13C NMR (CDCl3):
45.0 (d, JC–P¼20.0), 53.2 (d, JC–P¼6.6), 53.3 (d, JC–P
¼
Phosphonic acid 7: white prisms from i-PrOH, mp (dec)
1
6.6), 64.0 (d, JC–P¼4.3), 114.0, 120.6, 125.4, 127.7, 128.7,
129.1, 136.8 (d, JC–P¼236.0), 140.9, 142.6; 31P NMR
(CDCl3): 13.43; nmax (neat) 3474, 2953, 1599, 1499, 1258,
1119; 1032; HPLC retention time: 9.61 min (method 1).
Anal. Calcd for C17H19N2O3P: C, 61.81; H, 5.80; N, 8.48.
Found: C, 61.58; H, 5.86; N, 8.40.
>210 ꢁC; H NMR (DMSO-d6): 6.82 (d, JH–P¼1.5, 1H),
7.18–7.48 (m, 10H); 13C NMR (DMSO-d6): 112.0 (d, JC–P
¼
22.0), 126.2, 129.0, 129.2, 129.3, 129.4, 129.9, 130.1, 140.1,
143.8 (d, JC–P¼9.2), 148.2 (d, JC–P¼221.0); 31P NMR
(DMSO-d6): 5.45; nmax (neat) 3245, 2972, 2290, 1596,
1499, 1132, 1001. Anal. Calcd for C15H13N2O3P: C,
60.00; H, 4.36; N, 9.33. Found: C, 59.74; H, 4.69; N, 9.09.
Pyrazoline 6b: Rf ¼0.18 (petroleum ether/AcOEt 2:3); yel-
1
low oil; H NMR (CDCl3): 3.27 (ddd, J¼1.5, 7.0, 18.0,
3.8. Preparation of 1,5-diphenyl-4,5-dihydro-1H-
pyrazole-3-phosphonic acid (8)
1H), 3.51 (ddd, J¼1.5, 13.2, 18.0, 1H), 3.73 (s, 3H), 3.85
(d, JH–P¼11.3, 3H), 3.86 (d, JH–P¼11.3, 3H), 4.83 (dd,
J¼7.0, 13.2, 1H), 6.95 (t, J¼7.3, 1H), 7.07 (d, J¼8.4, 2H),
Compound 6a was treated as described for 5a to give the
corresponding phosphonic acid 8 as a white powder in quan-
titative yield.
7.27 (dd, J¼7.3, 8.4, 2H); 13C NMR (CDCl3): 40.4 (d, JC–P
¼
22.0), 53.3, 53.8 (d, JC–P¼6.0), 53.9 (d, JC–P¼6.0), 61.5
(d, JC–P¼4.0), 113.8, 121.7, 129.5, 137.6 (d, JC–P¼203.0),
142.8, 170.9; 31P NMR (CDCl3): 12.15; nmax (neat)
3474, 2956, 1745, 1599, 1501, 1261, 1124, 1035; HPLC re-
tention time: 5.78 min (method 1). Anal. Calcd for
C13H17N2O5P: C, 50.00; H, 5.49; N, 8.97. Found: C,
49.75; H, 5.68; N, 8.70.
Phosphonic acid 8: white prisms from i-PrOH, mp (dec)
>160 ꢁC; 1H NMR (DMSO-d6): 2.78 (dd, J¼6.0, 17.5,
1H), 3.64 (dd, J¼12.6, 17.5, 1H), 5.40 (dd, J¼6.0, 12.6,
1H), 6.73 (t, J¼7.6, 1H), 6.92 (d, J¼7.6, 2H), 7.13 (t,
J¼7.6,7.6, 2H), 7.17–7.27 (m, 3H), 7.32 (t, J¼7.0, 7.0,
2H); 13C NMR (DMSO-d6): 46.1 (d, JC–P¼20.0), 63.1 (d,
JC–P¼4.5), 114.0, 120.1, 126.4, 128.1, 129.6, 129.6, 142.7,
144.1, 145.2 (d, JC–P¼220.0); 31P NMR (DMSO-d6): 4.84;
nmax (neat) 3296, 2974, 2297, 1599, 1499, 1120, 1031.
Anal. Calcd for C15H15N2O3P: C, 59.60; H, 5.00; N, 9.27.
Found: C, 59.62; H, 4.84; N, 8.97.
Pyrazoline 6c: Rf ¼0.29 (petroleum ether/AcOEt 2:3); yel-
1
low oil; H NMR (CDCl3): 0.88 (t, J¼7.0, 3H), 1.20–1.40
(m, 4H), 1.42–1.62 (m, 1H), 1.70–1.82 (m, 1H), 2.90 (ddd,
J¼1.4, 5.3, 17.3, 1H), 3.25 (ddd, J¼1.4, 12.0, 17.3, 1H),
3.85 (d, JH–P¼11.3, 3H), 3.86 (d, JH–P¼11.3, 3H), 4.41
(dddd, J¼2.7, 5.3, 8.5, 12.0, 1H), 6.92 (t, J¼7.5, 1H), 7.14
(d, J¼7.5, 2H), 7.27 (dd, J¼7.5, 7.5, 2H); 13C NMR
(CDCl3): 14.2, 22.7, 26.9, 31.6, 39.8 (d, JC–P¼20.0), 53.5
(d, JC–P¼3.5), 60.0 (d, JC–P¼4.6), 114.6, 121.0, 129.4,
137.2 (d, JC–P¼237.0), 142.7; 31P NMR (CDCl3): 14.18;
nmax (neat) 3470, 2955, 1599, 1499, 1258, 1124, 1033;
HPLC retention time: 4.06 min (method 2). Anal. Calcd
for C15H23N2O3P: C, 58.05; H, 7.47; N, 9.03. Found: C,
57.80; H, 7.72; N, 8.81.
3.9. Oxidation of dimethyl 1,5-diphenyl-4,5-dihydro-1H-
pyrazole-3-phosphonate (6a) to dimethyl 1,5-diphenyl-
1H-pyrazole-3-phosphonate (5a)
To a solution of 6a (165 mg, 0.5 mmol) in DMF (3 mL) was
added PDC (2.8 g, 7.5 mmol). The solution was stirred at
room temperature for 4 h. The reaction was followed by
TLC (petroleum ether/AcOEt 3:7). Water (6 mL) was then
added and the solution was extracted with AcOEt
(3ꢂ5 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The crude material was purified by
column chromatography on silica gel (petroleum ether/
AcOEt 2:3) to give 5a (131 mg, 0.4 mmol, 80% yield) as a
yellow oil.
Pyrazoline 6d: Rf ¼0.32 (petroleum ether/AcOEt 1:1); yel-
1
low oil; H NMR (CDCl3): 0.86 (t, J¼7.0, 3H), 1.15–1.30
(m, 14H), 1.40–1.60 (m, 1H), 1.65–1.80 (m, 1H), 2.87
(ddd, J¼1.4, 5.3, 17.3, 1H), 3.51 (ddd, J¼1.4, 12.0, 17.3,
1H), 3.82 (d, JH–P¼11.3, 3H), 3.83 (d, JH–P¼11.3, 3H),
4.38 (dddd, J¼2.4, 5.3, 8.5, 12.0, 1H), 6.90 (t, J¼7.5, 1H),
7.12 (d, J¼7.5, 2H), 7.26 (dd, J¼7.5, 7.5, 2H); 13C NMR
(CDCl3): 14.4, 23.0, 24.8, 29.6, 29.7, 29.8, 29.8, 32.0,
32.2, 39.9 (d, JC–P¼20.0), 53.5 (d, JC–P¼3.5), 60.2 (d, JC–P
¼
Acknowledgements
4.8), 114.6, 121.0, 129.3, 137.2 (d, JC–P¼237.0), 142.7; 31
P
NMR (CDCl3): 14.30; nmax (neat) 3399, 2926, 1599, 1499,
1259, 1124; 1033; HPLC retention time: 5.07 min (method
This work was financially supported by MIUR (PRIN 2005,
ꢀ
Rome) and Universita degli Studi di Milano (FIRST).

5560
P. Conti et al. / Tetrahedron 63 (2007) 5554–5560
9. Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J.
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