Versatile synthesis of 4-methylidenepyrazolidin-3-ones using a Horner-Wadsworth-Emmons approach

Article abstract of DOI:10.1055/s-0033-1340071

A new, versatile method for the synthesis of, so far unknown, variously substituted 4-methylidenepyrazolidin-3-ones as potential cytotoxic agents is described. Target compounds were synthesized from the corresponding 4-diethoxyphosphorylpyrazolidin-3-ones which were used as Horner-Wadsworth- Emmons -reagents for the olefination of formaldehyde. 4-Phosphorylpyrazolidin-3- ones were, in turn, obtained starting from the sodium salt of ethyl 2-diethoxyphosphoryl-3-hydroxy-2-propenoate, ethyl 2-acyl-2- diethoxyphosphorylacetates, or 3-methoxy-2-diethoxyphosphorylacrylate and monosubstituted or 1,2-disubstituted hydrazines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340071

LETTER
▌105
lVetteerrsatile Synthesis of 4-Methylidenepyrazolidin-3-ones Using a Horner–
Wadsworth–Emmons Approach
Synthesis of 4-Methylidenepyrazolidin-3-ones
Jakub Modranka, Rafał Jakubowski, Tomasz Janecki*
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
Fax +48(42)6365530; E-mail: tjanecki@p.lodz.pl
Received: 25.08.2013; Accepted after revision: 01.10.2013
dene-γ- and δ-lactones, as well as α-methylidene-γ-lac-
tams, by applying Horner–Wadsworth–Emmons
Abstract: A new, versatile method for the synthesis of, so far un-
known, variously substituted 4-methylidenepyrazolidin-3-ones as
potential cytotoxic agents is described. Target compounds were
synthesized from the corresponding 4-diethoxyphosphorylpyrazoli-
a
approach to the construction of the exo-alkylidene
bond.2b,4 Many of the compounds obtained in our labora-
din-3-ones which were used as Horner–Wadsworth–Emmons tory turned out to be highly potent against several cancer
reagents for the olefination of formaldehyde. 4-Phosphorylpyr-
azolidin-3-ones were, in turn, obtained starting from the sodium salt
of ethyl 2-diethoxyphosphoryl-3-hydroxy-2-propenoate, ethyl 2-
most or all available therapeutic classes of antimicrobial
acyl-2-diethoxyphosphorylacetates, or 3-methoxy-2-diethoxyphos-
phorylacrylate and monosubstituted or 1,2-disubstituted hydra-
cell lines as well as against nosocomial and community-
associated staphylococci (MRSA) which are resistant to
drugs.5 Recently, we envisaged that introduction of an ad-
ditional heteroatom to the lactone or lactam ring might be
beneficial for biological activity. Consequently, a series
of 4-methylideneisoxazolidin-5-ones 6 (Figure 2) con-
taining an additional nitrogen atom in the lactone ring, has
been synthesized in our laboratory and, to our satisfaction,
certain isoxazolidinones 6 proved to be very potent
against HL-60, NALM-6, MCF-7, and MDA-MB-231
cancer cells.6 The most active compounds have been sub-
jected to extended biological studies which have shed
light on their mode of action at the molecular level.7
zines.
Key words: alkylation, antitumor agents, heterocycles, lactams,
Michael addition, olefination
Carbo- and heterocycles containing an exo-methylidene
moiety conjugated with a carbonyl group constitute a
large class of natural and synthetic compounds which dis-
play a broad spectrum of biological properties, ranging
from cytotoxic/anticancer, allergenic, anti-inflammatory,
and cardiovascular to antibacterial, antifungal, and phyto-
toxic activities. These classes of compounds include α-
methylidenecyclopentanones 1,1 and α-alkylidene-γ- and
δ-lactones 2 and 3 as well as α-alkylidene-γ- and δ-lac-
tams 4 and 5 (Figure 1)2 It is believed that the Michael ac-
ceptor functionality, which is present in all these
compounds, can effectively react with various bionucleo-
philes and therefore is crucial for their biological activi-
ties.3
R2
R2
N
R1
O
N
R1
N
R3
7
O
O
6
Figure 2
Encouraged by these results we decided to develop the
synthesis of, so far unknown, 4-methylidenepyrazolidin-
3-ones 7 which have an additional nitrogen atom in the
lactam ring. Although it is well established that α-alkyli-
dene-γ-lactams usually display lower cytotoxic activity
than α-alkylidene-γ-lactones,5a–c on the other hand, these
species are considered as particularly promising because
the γ-lactam moiety can help to mitigate the biological
toxicity often observed for γ-lactones.8 Therefore, synthe-
sis of α-methylidene-γ-lactams with potentially enhanced
cytotoxicity profile seemed an attractive goal. In this pa-
per we describe our preliminary results concerning a con-
venient and versatile Horner–Wadsworth–Emmons
approach to variously substituted 4-methylidenepyrazoli-
R1
R2
R1
R2
R
O
O
O
O
O
1
2
3
R1
R2
R2
R1
O
N
R3
5
O
N
R3
4
Figure 1
In a search for new, biologically promising analogues we din-3-ones 7.
have developed syntheses of several classes of α-alkyli-
Synthesis of 2-aryl-1-methyl-4-methylidenepyrazolidin-
3-ones 14a–e substituted with various aryl groups in posi-
tion 2 was accomplished as shown in Scheme 1. 1-Aryl-4-
diethoxyphosphoryl-1H-pyrazol-5-ols 11a–e were pre-
pared by adapting the literature procedure described for
SYNLETT 2014, 25, 0105–0109
Advanced online publication: 21.11.2013
DOI: 10.1055/s-0033-1340071; Art ID: ST-2013-D0818-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

106
J. Modranka et al.
LETTER
O
O
O
O
P(OEt)2
P(OEt)2
(EtO)2P
COOEt
(EtO)2P
COOEt
ONa
b
a
c
+
ArNHNH2 × HCl
N
N
Me
O
OH
N
N
NHNHAr
Ar
Ar
8
9a–e
10a–e
11a–e
12a–e
O
P(OEt)2
O
e
d
N
Me
O
N
N
N
Me
Ar
Ar
13a–e
14a–e
Scheme 1 Reagents and conditions: (a) H2O, reflux, 10 min; (b) K2CO3 (1.1 equiv), H2O, reflux, 10 min; (c) Me2SO4 (1.2 equiv), DCE, 80 °C,
18 h; (d) L-Selectride (1.25 equiv), THF, –78 °C, 1 h, then r.t., 18 h; (e) (CH2O)n (5 equiv), NaH (1.2 equiv), THF, r.t., 2 h.
the corresponding 4-dimethoxyphosphorylpyrazol-5-ols.9 12 to provide access to Horner–Wadsworth–Emmons re-
The sodium salt of ethyl 2-diethoxyphosphoryl-3-hy- agents 13. Standard hydrogenation of 12a in the presence
droxy-2-propenoate 8 was treated with arylhydrazine hy- of palladium or platinum catalysts gave only starting ma-
drochlorides 9a–e followed by addition of potassium terial. However, application of L-Selectride as a reducing
carbonate (Table 1). This one-pot, two-step reaction obvi- agent furnished the expected pyrazolidinones 13a–e in
ously proceeds via an addition–elimination sequence to good yields (Table 1).11 Finally, reaction of 13a–e with
give substitution products 10a–e followed by intramolec- paraformaldehyde in the presence of sodium hydride gave
ular cyclization. Pyrazoles 11a–e obtained in this fashion the targeted 4-methylidenepyrazolidin-3-ones 14a–e in
were next N-methylated with dimethyl sulfate to give 2- good to excellent yields (Table 1).12
aryl-1-methyl-4-diethoxyphosphorylpyrazol-3-ones 12a–
To gain access to 5-substituted 2-aryl-1-methyl-4-methy-
lidenepyrazolidin-3-ones 19a–g we decided to prepare
substituted 1-aryl-4-diethoxyphosphoryl-1H-pyrazol-5-
ols 16a–g from various ethyl 2-acyl-2-diethoxyphosphor-
e in satisfactory yields (Table 1).10 Unfortunately, all at-
tempts to introduce various substituents into position 5 of
the pyrazolone ring, by executing Michael addition of
Grignard reagents to 12, failed. Therefore, we decided to
ylacetates 15a–g and arylhydrazine hydrochlorides by ap-
perform the reduction of the double bond in pyrazolones
plying a modified literature procedure13 (Scheme 2,
Table 1 Preparation of 1-Aryl-4-diethoxyphosphoryl-1H-pyrazol-5-ols 11a–e, 2-Aryl-4-diethoxyphosphoryl-1-methyl-1,2-dihydro-3H-pyr-
azol-3-ones 12a–e, 2-Aryl-4-diethoxyphosphoryl-1-methylpyrazolidin-3-ones 13a–e, and 2-Aryl-1-methyl-4-methylidenepyrazolidin-3-ones
14a–e
Entry
Compd
Ar
Yield of 11 (%)a Yield of 12 (%)a Yield of 13 (%)a
Yield of 14 (%)a
1
2
3
4
5
a
b
c
Ph
79
86
87
85
81
54
72
67
46
63
86
77
82
80
79
91
68
68
84
61
2-MeC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
d
e
a Yield of purified, isolated products based on 8, 11, 12, or 13, respectively.
O
O
O
O
R
P(OEt)2
P(OEt)2
R
R
P(OEt)2
R
(EtO)2P
COOEt
O
d
e
a or b
c
N
Me
O
N
N
N
N
O
O
Me
Me
N
N
OH
R
N
Ar
Ar
Ar
Ar
15a–g
16a–g
17a–g
18a–g
19a–g
Scheme 2 Reagents and conditions: (a) 1. H2NNHAr·HCl, H2O, reflux, 2 h; 2. K2CO3 (2 equiv), reflux, 2 h, then r.t., 18 h; (b) H2NNHPh,
AcOH (2 equiv), H2O, reflux, 3 h; (c) CF3SO3Me (2 equiv), DCE, 80 °C, 2 h; (d) L-Selectride (1.25 equiv), THF, –78 °C, 1 h, then r.t., 18 h;
(e) (CH2O)n (5 equiv), NaH (1.2 equiv), THF, r.t., 2 h.
Synlett 2014, 25, 105–109
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4-Methylidenepyrazolidin-3-ones
107
procedure a). This procedure worked well for alkyl-sub- placement of 8 by 3-methoxy-2-diethoxyphosphoryl-
stituted acetates 15a–e (R = Alk) but aryl-substituted ace- acrylate (20)15 proved to be successful. When acrylate 20
tates 15f,g (R = Ar) gave low yield of the expected and 1,2-diphenylhydrazine (21) were heated in refluxing
pyrazoles. Pleasingly, heating aryl-substituted acetates toluene for 80 hours the expected 4-diethoxyphosphoryl-
15f,g and phenylhydrazine with acetic acid in water (pro- 1,2-diphenyl-1,2-dihydro-3H-pyrazol-3-one (22) was ob-
cedure b) furnished 1,3-diarylpyrazolols 16f,g in good tained in 83% yield (Scheme 3). In the next step we exam-
yields (Table 2).14 N-Methylation of pyrazolols 16a–g10 ined the addition of Grignard reagents to pyrazolone 22.
using methyl triflate followed by reduction of 2-aryl-1- Unfortunately, all attempts to perform the addition of
methylpyrazol-3-ones 17a–g11 with L-Selectride gave methylmagnesium chloride to 22 under standard condi-
Horner–Wadsworth–Emmons reagents 18a–g, which tions (0 °C to r.t., THF or Et2O as solvent, addition of CuI)
were obtained as single isomers or mixtures of trans and failed. However, performing this reaction in boiling THF
cis diastereoisomers in the ratio shown in Table 2. Due to for two hours with 1.2 equivalents of MeMgCl gave, after
highly basic conditions employed during the reduction purification by column chromatography, the expected
one could expect thermodynamic control within the reac- 5-methyl-4-diethoxyphosphoryl-1,2-diphenylpyrazolidin-
tion and the preferential formation of the trans isomers. 3-one (23a) in a reasonable 52% yield. Applying these op-
Unfortunately, resonances for the H-4 and H-5 protons in timized conditions we performed the reaction of several
the 1H NMR spectra of pyrazolidiones 18 were not suffi- Grignard reagents with pyrazolone 22 and obtained the
ciently resolved to determine JH4–H5 coupling constants expected adducts 23b–e, usually as mixtures of trans and
and to confirm the assumed trans configuration of these cis isomers (Table 3).16 Contrary to pyrazolidinones 18, in
1
compounds. In view of the planned transformation of pyr- the H NMR spectra of 23 all signals were resolved and
azolidinones 18 into methylidenepyrazolidinones 19 no JH4–H5 coupling constants could be easily determined. For
efforts were undertaken to separate the diastereoisomers. example, for the major and minor diastereoisomer of 23a
In the final step, pyrazolidinones 18a–g were used for the JH4–H5 coupling constants were 2.8 Hz and 6.7 Hz, respec-
olefination with formaldehyde to provide final 5-substi- tively, confirming the trans configuration of the latter if
tuted pyrazolidinones 19a–g in good yields (Table 2).12
pseudoaxial positions of phosphoryl and methyl groups
are assumed. To unequivocally confirm the trans config-
uration of the major isomer of pyrazolidinone 23a, a NOE
experiment was performed, showing 13% enhancement in
the signal of the H-4 proton when protons of the methyl
group in position 5 were irradiated. Because of similar
coupling constant patterns in all major isomers of pyr-
Having accomplished the synthesis of 3-methylidene-1-
methyl-2-arylpyrazolidin-3-ones 14a–e and 19a–g we
turned our attention to the reaction of the sodium salt of 3-
hydroxy-2-propenoate 8 with disubstituted hydrazines.
To our disappointment the reaction of 8 with 1,2-diphe-
nylhydrazine hydrochloride did not occur. Pleasingly, re-
Table 2 Preparation of 1-Aryl-4-diethoxyphosphoryl-1H-pyrazol-5-ols 16a–g, 2-Aryl-4-diethoxyphosphoryl-1-methylpyrazol-3-ones 17a–g,
2-Aryl-4-diethoxyphosphoryl-1-methypyrazolidin-3-ones 18a–g, and 2-Aryl-1-methyl-4-methylidenepyrazolidin-3-ones 19a–g
Entry
Compd
R
Ar
Yield of 16
Yield of 17
Yield of 18
Yield of 19
(%)a
(%)a
(%)a (trans/cis ratio)
(%)a
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
Ph
86
64
41
72
72
75
72
61
60
51
57
75
65
61
75 (85:15)
75 (90:10)
41 (65:35)
88 (90:10)
70 (90:10)
84 (100:0)
51 (100:0)
72
61
70
58
79
63
85
Et
Ph
i-Pr
Ph
n-Bu
Ph
Et
3-ClC6H4
Ph
Ph
Ph
g
4-MeOC6H4
a Yield of purified, isolated products based on 15, 16, 17, or 18, respectively.
O
O
O
R
N
R
P(OEt)2
P(OEt)2
(EtO)2P
COOEt
OMe
a
b
c
+
PhNHNHPh
Ph
O
N
N
N
Ph
O
Ph
O
N
N
Ph
Ph
Ph
20
21
22 83%
23a–e
24a–e
Scheme 3 Reagents and conditions: (a) toluene, reflux, 80 h; (b) RMgX (1.2 equiv), THF, reflux, 2 h; (c) NaH (1.2 equiv), (CH2O)n (5 equiv),
THF, r.t., 2 h.
© Georg Thieme Verlag Stuttgart · New York
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108
J. Modranka et al.
LETTER
(b) Albrecht, A.; Koszuk, J. F.; Modranka, J.; Różalski, M.;
Krajewska, U.; Janecka, A.; Studzian, K.; Janecki, T.
Bioorg. Med. Chem. 2008, 16, 4872. (c) Albrecht, A.;
Albrecht, Ł.; Różalski, M.; Krajewska, U.; Janecka, A.;
Studzian, K.; Janecki, T. New J. Chem. 2010, 34, 750.
(d) Modranka, J.; Albrecht, A.; Jakubowski, R.; Krawczyk,
H.; Różalski, M.; Krajewska, U.; Janecka, A.; Wyrębska, A.;
Różalska, B.; Janecki, T. Bioorg. Med. Chem. 2012, 20,
5017.
Table 3 Synthesis of 4-Diethoxyphosphoryl-1,2-diphenylpyrazoli-
din-3-ones 23a–e and 4-Methylidene-1,2-diphenylpyrazolidin-3-
ones 24a–e
Entry Compd RMgX
Yield of 23
Yield of 24
(%)a (trans/cis ratio) (%)a
1
2
3
4
5
a
b
c
MeMgCl
EtMgCl
52 (85:15)
42 (90:10)
56 (95:5)
87
92
92
85
89
(6) Janecki, T.; Wąsek, T.; Różalski, M.; Krajewska, U.;
Studzian, K.; Janecka, A. Bioorg. Med. Chem. Lett. 2006,
16, 1430.
(7) (a) Różalski, M.; Krajewska, U.; Panczyk, M.; Mirowski,
M.; Różalska, B.; Wąsek, T.; Janecki, T. Eur. J. Med. Chem.
2007, 248. (b) Wyrębska, A.; Gach, K.; Szemraj, J.;
Szewczyk, K.; Hrabec, E.; Koszuk, J.; Janecki, T.; Janecka,
A. Chem. Biol. Drug Des. 2012, 79, 112. (c) Wyrębska, A.;
Szymański, J.; Gach, K.; Piekielna, J.; Koszuk, J.; Janecki,
T.; Janecka, A. Mol. Biol. Rep. 2013, 40, 1655.
(8) (a) Belaud, C.; Roussakis, C.; Letourneux, Y.; Alami, N. E.;
Villiéras, J. Synth. Commun. 1985, 15, 1233. (b) Elford, T.
G.; Hall, D. G. Tetrahedron Lett. 2008, 49, 6995.
(9) Miller, P. C.; Molyneaux, J. M. Org. Prep. Proced. Int.
1999, 31, 295.
(10) General Procedure for the N-Methylation: Synthesis of
2-Aryl-4-diethoxyphosphoryl-1-methyl-1,2-dihydro-3H-
pyrazol-3-ones 12a–e and 2-Aryl-4-diethoxyphosphoryl-
1-methyl-1,2-dihydro-3H-pyrazol-3-ones 17a–g
A solution of the corresponding pyrazolol 11a–e (5 mmol)
and (MeO)2SO2 (0.57 mL, 6 mmol) in DCE (50 mL) was
heated at 80 °C for 18 h. The solvent was evaporated, and the
crude product was purified by column chromatography
(eluent: EtOAc–MeOH, 9:1). With the pyrazolols 16a–g the
reaction was performed with CF3SO3Me (1.64 g, 10 mmol)
at 80 °C for 2 h.
n-BuMgCl
vinylMgBr
PhMgBr
d
e
83 (90:10)
35 (100:0)
a Yield of purified, isolated product based on 22 or 23, respectively.
azolidinones 23a–e, we construe that all major isomers
have the trans configuration. Phosphorylated pyrazoli-
dinones 23a–e were next used as Horner–Wadsworth–
Emmons reagents for the olefination with formaldehyde
to furnish the targeted 4-methylidene-1,2-diphenylpyr-
azolidin-3-ones 24a–e in excellent yields (Table 3).12
In summary, as a part of an ongoing program in our labo-
ratory focused on the application of Horner–Wadsworth–
Emmons approaches in the synthesis of biologically im-
portant 2-alkylidene-1-oxoheterocyles, we have devel-
oped a simple, effective, and general methodology for the
synthesis of novel 4-methylidenepyrazolidin-3-ones. As
disclosed, three complementary methods enable the intro-
duction of various alkyl or aryl substituents at positions 1,
2, and/or 5 on the pyrazolidinone ring and open access to
a new class of α-alkylidene-γ-lactams with potential cyto-
toxic activity. Further studies to extend the presented
methodology and to test the obtained compounds for their
cytotoxic activity are under way.
Diethyl [1-Methyl-3-oxo-2-(p-tolyl)-2,3-dihydro-1H-
pyrazol-4-yl]phosphonate (12c)
Pale-yellow oil. IR (film): 3035, 1655, 1509, 1258, 1029,
758, 542 cm–1. 1H NMR (250 MHz, CDCl3): δ = 1.25 [t, 3JH–
H = 7.1 Hz, 6 H, (CH3CH2O)2P(O)], 2.28 (s, 3 H, CH3), 3.27
(s, 3 H, CH3), 4.06–4.14 [m, 4 H, (CH3CH2O)2P(O)], 7.09 (d,
3JH–H = 8.2 Hz, 2 H, 2 × HAr), 7.18 (d, 3JH–H = 8.2 Hz, 2 H,
2 × HAr), 7.84 (d, 3JH–P = 4.4 Hz, 1 H, H-5). 13C NMR (62.9
MHz, CDCl3): δ = 16.0 [d, 3JC–P = 6.9 Hz, (CH3CH2O)2P(O)],
20.8 (s, CH3), 36.9 (s, CH3), 62.0 [d, 2JC–P = 5.6 Hz,
(CH3CH2O)2P(O)], 93.8 (d, 1JC–P = 222.2 Hz, C-4), 126.3 (s,
2 × CAr), 129.8 (s, 2 × CAr), 130.0 (s, CAr), 138.6 (s, CAr),
147.1 (d, 2JC–P = 18.8 Hz, C5), 162.9 (d, 2JC–P = 14.0 Hz,
C3). 31P NMR (101 MHz, CDCl3): δ = 12.51. Anal. Calcd
for C15H21N2O4P: C, 55.55; H, 6.53. Found: C, 55.42; H,
6.60.
Acknowledgement
This work was financed by the Ministry of Science and Higher Edu-
cation (Project No. N N204 005736).
References and Notes
(1) Balczewski, P.; Mikolajczyk, M. Org. Lett. 2000, 2, 1153.
(2) (a) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew.
Chem. Int. Ed. 2009, 48, 9426. (b) Albrecht, A.; Albrecht,
Ł.; Janecki, T. Eur. J. Org. Chem. 2011, 2747.
(11) General Procedure for L-Selectride Reduction:
Synthesis of 2-Aryl-4-diethoxyphosphoryl-1-
methylpyrazolidin-3-ones 13a–e and 2-Aryl-4-
diethoxyphosphoryl-1-methylpyrazolidin-3-ones 18a–g
To a cooled (–78 °C) solution of the corresponding
pyrazolone 12a–e or 17a–g (1 mmol) in THF (15 mL) was
added dropwise a THF solution of L-Selectride (1.25 mmol)
under an argon atmosphere, and the mixture was stirred at
this temperature for 1 h. Then, the mixture was allowed to
slowly warm to r.t. and was stirred at r.t. overnight. The
reaction mixture was concentrated to half the initial volume
and quenched with 10% aq NH4Cl. After extraction with
CH2Cl2 (3 × 15 mL), the combined organic layers were
washed with brine and dried over MgSO4. After filtration
and evaporation, the crude product was purified by column
chromatography (eluent: EtOAc–MeOH, 9:1).
(3) (a) Zhang, S.; Won, Y.-K.; Ong, C. N.; Shen, H. M. Curr.
Med. Chem. – Anti-Cancer Agents 2005, 5, 239. (b) Zhang,
S.; Ong, C. N.; Shen, H. M. Cancer Lett. 2004, 208, 143.
(c) Heilmann, J.; Wasescha, M. R.; Smidt, T. J. Bioorg. Med.
Chem. 2001, 9, 2189. (d) Knight, D. W. Nat. Prod. Rep.
1995, 12, 271.
(4) Janecki, T. In Targets in Heterocyclic Systems:
Organophosphorus Reagents as a Versatile Tool in the
Synthesis of α-Alkylidene-γ-butyrolactones and α-
Alkylidene-γ-butyrolactams; Vol. 10; Attanasi, O. A.;
Spinelli, D., Eds.; Italian Society of Chemistry: Rome, 2006,
301.
(5) (a) Janecki, T.; Błaszczyk, E.; Studzian, K.; Janecka, A.;
Krajewska, U.; Różalski, M. J. Med. Chem. 2005, 48, 3516.
Synlett 2014, 25, 105–109
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diethyl [1-Methyl-3-oxo-2-(p-tolyl)pyrazolidin-4-
Synthesis of 4-Methylidenepyrazolidin-3-ones
109
(14) General Procedure for the Synthesis of 1-Aryl-4-
diethoxyphosphoryl-1H-pyrazol-5-ols 16f,g
yl]phosphonate (13c)
Pale-yellow oil. IR (film): 2982, 1689, 1614, 1508, 1354
1248, 1018, 963 cm–1. 1H NMR (250 MHz, DMSO-d6):
δ = 1.24 [t, 3JH–H = 7.0 Hz, 3 H, (CH3CH2O)P(O)], 1.27 [t,
3JH–H = 7.0 Hz, 3 H, (CH3CH2O)P(O)], 2.25 (s, 3 H, CH3),
2.57 (s, 3 H, CH3), 3.56 (dd, 3JH–H = 9.2 Hz, 3JH–P = 14.5 Hz,
2 H, 2 × H-5), 3.84 (dt, 3JH–H = 9.2 Hz, 2JH–P = 21.5 Hz, 1 H,
H-4), 4.05–4.20 [m, 4 H, (CH3CH2O)2P(O)], 7.13–7.20 (m,
2 H, 2 × HAr), 7.48–7.55 (m, 2 H, 2 × HAr). 13C NMR
(62.9 MHz, DMSO-d6): δ = 15.5 [d, 3JC–P = 5.6 Hz,
(CH3CH2O)2P(O)], 19.8 (s, CH3), 40.4 (d, 1JC–P = 146.9 Hz,
C-4), 42.9 (s, CH3), 51.7 (d, 2JC–P = 1.8 Hz, C-5), 61.5 [d,
2JC–P = 6.7 Hz, (CH3CH2O)P(O)], 61.9 [d, 2JC–P = 6.4 Hz,
(CH3CH2O)P(O)], 119.7 (s, 2 × CAr), 128.7 (s, 2 × CAr),
133.7 (s, CAr), 134.1 (s, CAr), 164.9 (d, 2JC–P = 2.3 Hz, C-
3). 31P NMR (101 MHz, DMSO-d6): δ = 23.13. Anal. Calcd
for C15H23N2O4P: C, 55.21; H, 7.10. Found: C, 55.11; H,
7.23.
A mixture of ethyl 2-aroyl-2-diethoxyphosphorylacetate
15f,g (10 mmol), phenylhydrazine (11 mmol), and AcOH
(0.6 g, 20 mmol) was refluxed in H2O (50 mL) for 3 h. The
reaction mixture was cooled and extracted with EtOAc
(2 × 30 mL). The organic extracts were washed with brine,
dried over Na2SO4, and concentrated. The crude product was
purified by column chromatography (eluent: EtOAc–
hexane, 1:1).
(15) Janecki, T.; Albrecht, A.; Koszuk, J. K.; Modranka, J.;
Słowak, D. Tetrahedron Lett. 2010, 51, 2274.
(16) General Procedure for the Synthesis of 4-Diethoxy-
phosphoryl-1,2-diphenylpyrazolidin-3-ones 23a–e
To a solution of the 4-diethoxyphosphoryl-1,2-diphenyl-
pyrazol-3-one 22 (2 mmol) in THF (15 mL) a solution of the
corresponding Grignard reagent (2.4 mmol) was added
dropwise, under an argon atmosphere at r.t., and the resulting
mixture was refluxed for 2 h. After this time the reaction
mixture was quenched with H2O (5 mL), acidified to pH ca.
3 with 10% aq HCl solution, and extracted with CH2Cl2
(3 × 10 mL). The organic extracts were dried over MgSO4,
filtered, and the solvent was evaporated. The crude product
was purified by column chromatography (eluent: CHCl3–
MeOH, 98:2).
(12) General Procedure for Methylidenation: Synthesis of 2-
Aryl-1-methyl-4-methylidenepyrazolidin-3-ones 14a–e,
2-Aryl-1-methyl-4-methylidenepyrazolidin-3-ones 19a–
g, and 4-Methylidene-1,2-diphenylpyrazolidin-3-ones
24a–e
To a solution of the corresponding pyrazolidinone 13a–e,
18a–g, or 23a–e (0.5 mmol) in THF (5 mL), NaH (14 mg,
0.6 mmol) was added, and the resulting mixture was stirred
at r.t. for 30 min. Then, paraformaldehyde (75 mg, 2.5
mmol) was added in one portion. After 2 h the reaction
mixture was quenched with brine (5 mL), the solvent was
evaporated, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The organic extracts were dried over
MgSO4, filtered, and the solvent was evaporated. The crude
product was purified by column chromatography (eluent:
CH2Cl2).
1-Methyl-4-methylene-2-(p-tolyl)pyrazolidin-3-one (14c)
Pale-yellow oil. IR (film): 2960, 2858, 1693, 1662, 1492,
1348, 822 cm–1. 1H NMR (250 MHz, CDCl3): δ = 2.32 (s, 3
H, CH3), 2.56 (s, 3 H, CH3), 3.52–3.88 (m, 1 H, 1 × H-5),
4.06–4.40 (m, 1 H, 1 × H-5), 5.49–5.51 (m, 1 H, HCH=),
6.14–6.16 (m, 1 H, HCH=), 7.15–7.20 (m, 2 H, 2 × HAr),
7.70–7.79 (m, 2 H, 2 × HAr). 13C NMR (62.9 MHz, CDCl3):
δ = 19.5 (s, CH3), 45.9 (s, CH3), 55.8 (s, C-5), 117.9 (s,
CH2=), 119.3 (s, 2 × CAr), 127.9 (s, 2 × CAr), 134.3 (s,
CAr), 134.8 (s, CAr), 139.2 (s, C-4), 165.2 (s, C-3). Anal.
Calcd for C12H14N2O: C, 71.26; H, 6.98. Found: C, 71.09; H,
7.12.
4-Diethoxyphosphoryl-1,2,5-triphenylpyrazolidin-3-one
(23e)
Pale-yellow oil. IR (film): 2981, 1703, 1593, 1489, 1391,
1250, 1014, 964 cm–1. 1H NMR (250 MHz, CDCl3): δ = 1.07
[t, 3JH–H = 7.1 Hz, 3 H, (CH3CH2O)P(O)], 1.30 [t, 3JH–H = 7.0
Hz, 3 H, (CH3CH2O)P(O)], 3.30 (dd, 2JH–P = 23.4 Hz, 3JH–
H = 3.0 Hz, 1 H, H-4), 3.67–3.84 [m, 1 H, (CH3CHO)P(O)],
3.91–4.04 [m, 1 H, (CH3CHO)P(O)], 4.08–4.22 [m, 2 H,
(CH3CH2O)P(O)], 5.39 (dd, 3JH–P = 19.1 Hz, 3JH–H = 3.0 Hz,
1 H, H-5), 6.81–6.98 (m, 4 H, 4 × HAr), 7.10–7.24 (m, 3 H,
3 × HAr), 7.31–7.43 (m, 4 H, 4 × HAr), 7.50–7.53 (m, 2 H,
2 × HAr), 7.83–7.87 (m, 2 H, 2 × HAr). 13C NMR (62.9
MHz, CDCl3): δ = 15.9 [d, 3JC–P = 5.4 Hz, (CH3CH2O)P(O)],
16.1 [d, 3JC–P = 6.1 Hz, (CH3CH2O)P(O)], 46.7 (d, 1JC–
P = 137.2 Hz, C-4), 62.9 [d, 2JC–P = 6.9 Hz, (CH3CH2O)P(O)],
63.3 [d, 2JC–P = 6.6 Hz, (CH3CH2O)P(O)], 68.6 (d, 2JC–
P = 0.9 Hz, C-5), 117.4 (s, 2 × CAr), 118.9 (s, 2 × CAr),
123.1 (s, CAr), 125.0 (s, CAr), 125.2 (s, 2 × CAr), 128.1 (s,
CAr), 128.7 (s, 2 × CAr), 128.9 (s, 2 × CAr), 129.1 (s,
2 × CAr), 137.7 (s, CAr), 142.1 (d, 3JC–P = 12.1 Hz, CAr),
149.4 (s, CAr), 164.6 (d, 2JC–P = 5.7 Hz, C-3). 31P NMR (101
MHz, CDCl3): δ = 19.60. Anal. Calcd for C25H27N2O4P: C,
66.66; H, 6.04. Found: 66.49; H, 5.97.
(13) Miller, P. C.; Curtis, J. M.; Molyneaux, J. M.; Owen, T. J.
US 6,297,194 B1, 2001.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 105–109

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