Heterocycles from Morita-Baylis-Hillman adducts: Synthesis of 5-oxopyrazolidines, arylidene-5-oxopyrazolidines, and oxo-2,5-dihydro-pyrazols

Article abstract of DOI:10.1016/j.tet.2012.10.057

Starting from Morita-Baylis-Hillman (MBH) adducts, an approach for the synthesis of oxopyrazolidines, arylidene-oxopyrazolidines, and oxo-2,5-dihydropyrazoles is described. The method is based on a tandem process involving a Michael addition of amino-guan

Full text of DOI:10.1016/j.tet.2012.10.057

Tetrahedron 69 (2013) 826e832
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heterocycles from MoritaeBayliseHillman adducts: synthesis
of 5-oxopyrazolidines, arylidene-5-oxopyrazolidines, and
oxo-2,5-dihydro-pyrazols
a
a
a
b
a,
*
ꢀ
ꢀ
Jose Tiago M. Correia , Manoel T. Rodrigues, Jr. , Hugo Santos , Claudio F. Tormena , Fernando Coelho
a Laboratory of Synthesis of Natural Products and Drugs, University of Campinas, Institute of Chemistry, 13083-970 Campinas, SP, Brazil
b Laboratory of Physical Organic Chemistry, University of Campinas, Institute of Chemistry, 13083-970 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 August 2012
Received in revised form 19 October 2012
Accepted 19 October 2012
Available online 29 October 2012
Starting from MoritaeBayliseHillman (MBH) adducts, an approach for the synthesis of oxopyrazolidines,
arylidene-oxopyrazolidines, and oxo-2,5-dihydropyrazoles is described. The method is based on a tan-
dem process involving a Michael addition of amino-guanidine into silylated and acetylated MBH adducts,
followed by intramolecular cyclization. The use of acetylated MBH adducts led also to the synthesis of
unusual pyrazoles, which is facilitated by an unexpected base-mediated equilibrium.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
MoritaeBayliseHillman
Pyrazolones
Pyrazolidines
Michael reaction
Heterocycles
1. Introduction
Heterocycles form the most basic building blocks of life playing
also a key role in several segments of the chemical industry. They are
also important monomers for polymers and moieties of biologically
active compounds, such as agrochemicals and drugs.1 A large amount
of additives and modifiers used in different segments of chemical
industry, such as cosmetics, reprographic, plastics, and information
storage are also heterocyclic in their constitution.1c Owing to the vast
commercial and biological relevance of heterocycles in organic
chemistry, many methodologies are available for their preparation.1a,b
Pyrazolones and pyrazolidinones are common heterocycles with
a great diversity of biological properties.2 For instance, they exhibited
analgesic, antibacterial, and antifungal activities (1 and 2, Fig. 1),3 as
well as anti-tumoral activity4 and anti-ischemic effect.5 Recently,
pyrazolones 3 and 4 (Fig. 1) were identified as HIV-integrase in-
hibitors, which constitutes a new class of antiretroviral agents.6
The synthetic utility and biological activity of pyrazolidinones
have also raised interest on these compounds in the last decade.7
They have been used as templates in enantioselective Diel-
seAlder,8 Michael,9 and click reactions.10 Pyrazolidinones are also
present in some bicyclic antibiotics developed by Eli Lilly (Fig. 1,
compounds 5, 6, and 7) some years ago.11
* Corresponding author. Tel.: þ55 19 3521 3085; fax: þ55 19 3521 3023; e-mail
Fig. 1. Some representative examples of biologically active pyrazolones and
pyrazolidinones.
address: coelho@iqm.unicamp.br (F. Coelho).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.057

J.T.M. Correia et al. / Tetrahedron 69 (2013) 826e832
827
The presence of both pyrazolone and pyrazolidinone units in
many molecules of pharmaceutical interest has also led to the de-
velopment of a great variety of methods for their preparation.
The most classic approach to prepare pyrazolones is via the
of two stereogenic centers and form a new five-membered ring in
a single step (Scheme 1, part B).
We therefore disclose herein a new, simple, and direct approach
to the synthesis of pyrazolones and pyrazolidinones from MBH
adducts. Our methodology uses a one-pot two step sequence in-
volving a Michael addition of amino-guanidine, followed by intra-
molecular cyclization.
reaction between a b-ketoester, a b-cyanoester or a,b-unsaturated
esters and hydrazine or hydrazine derivatives (alkyl, aryl or het-
erocyclic).12 Recently, Ma et al.13 reported on a one-pot synthesis of
arylidene-pyrazolones by treatment of a mixture of ethyl acetoa-
cetate, electrodeficient phenyl-hydrazines and electron poor aro-
matic aldehydes in the presence of microwaves. Alternatively,
palladium can be used as catalyst for the preparation of pyr-
azolones from 1,2-diaza-1,3-butadienes.14 Organocatalyzed meth-
odologies for the synthesis of pyrazolones have also been reported
recently.15
Most methods for the preparation of pyrazolidinones rely on
[3þ2] cycloadditions using dipoles, such as diazoalkanes,16 nitrile
imines,17 azomethine18 or hydrazones.19 Metal-catalyzed amina-
tion of allenes is also used as an alternative methodology to obtain
pyrazolidinones or pyrazolidines.20 Recently, oxo-ketenes were
used as substrate for [1,3]dipolar cycloaddition with hydrazones.21
2. Results and discussion
The investigation was initiated by preparing some MBH adducts
according to a method we described some years ago.29 The adducts
were then silylated in the presence of TBSOTf/NEt3 to provide the
corresponding silyl ethers in good to excellent overall yields (Table 1).
The silylated compounds were then diluted in MeOH and
treated, under reflux, with aminoguanidine carbonate in the pres-
ence of triethylamine to give the substituted pyrazolidinones in
good yields and diastereoselectivity varying from 2:1 to 7:1 after
3 h (Table 2).
Addition of substituted hydrazines to
a,b-unsaturated esters has
Table 1
MBH reaction and silylation
also been used as approach to prepare pyrazolidinones.19
The MoritaeBayliseHillman (MBH) reaction22,23 is a versatile
chemical transformation that provides small poly-functionalized
molecules, which can be used as Michael acceptors in the prepa-
ration of a great diversity of molecules.24
Recently, Kim et al.25 and McLaughlin et al.26 have in-
dependently investigated the chemical behavior of MBH adducts as
substrates for a reaction with amidine. These reactions gave the
respective substituted pyrimidines or 2,5-substituted pyrimidine
carboxylate as main products in good yields (Scheme 1).
Entry
Aldehyde
MBH, yield (%)a,b
Silylation (%)b
1
2
3
4
5
6
9
R¼4-NO2Ph (7)
14, 97
15, 87
16, 91
17, 87
18, 77
19, 72
20, 73
21, 97
22, 94
R¼2-FePh (8)
R¼3-ClePh (9)
23, >99
24, >99
25, >99
26, >99
27, >99
KIM's
A
R¼4-ClePh (10)
R¼4-tBuePh (11)
R¼4-MeO-Ph (12)
R¼3,4-OCH2OePh (13)
MCLAUGHLIN's
WORK
WORK
Substituted
pyrimidines
NH
Cl
R
H N
R
R
O
X
N
O
I
O
H N
NH
OAc
MBH
R
= CH or Ph
N
N
N
X
a
H
R
R
The reactions were carried out using an excess of methyl acrylate (as solvent)
and 0.65 equiv of DABCO at room temperature or in the presence of ultrasound
radiation.
EWG
X
R
oxidation
R
R
R
COX
O
b
X= OMe or OH
R= alkyl or aryl
EWG = CO Me, COMe, CN
Yields refer to isolated and purified products.
X= OH or Me or NH
Substituted pyrimidines
Table 2
O
NH
NH
Michael addition reaction with amino-guanidine
B
THIS WORK
R
N
N
OTBS
O
H
NH
OR
O
NH
NH
Arylidene-pyrazolidinones
R
= TBS
R
R
= Ac
N
NH
N
H N
+
or
R
O
N
H
H
O
NH
R = alkyl or aryl
amino-guanidine
Pyrazolidinones
R
N
NH
N
H
Entry
Silylated adduct
Yield (%)a
syn: anti ratiob, c
Pyrazolones
1
2
3
4
5
6
9
21, R¼4-NO2
22, R¼2-F
28a/b, 83
29a/b, 81
30a/b, 78
31a/b, 88
32a/b, 83
33a/b, 81
34a/b, 83
2:1
7:1
5:1
4:1
3:1
5:1
2:1
Scheme 1. Kim’s and McLaughlin’s syntheses of substituted pyrimidines and our ap-
proach to the synthesis of pyrazolones and pyrazolidinones both from Mor-
itaeBayliseHillman adducts.
23, R¼3-Cl
24, R¼4-Cl
25, R¼4-tBu
26, R¼4-MeO
27, R¼3,4-OCH2e
These results associated with our interest in preparing some
pyrazolones and pyrazolidinones for biological screening against
some strains of human cancer cells stimulated us to investigate the
chemical behavior of amino-guanidine in the presence of silylated
and acetylated MBH adducts. Curiously, guanidine has already been
used as catalyst for the MBH reaction,27 but this bis-nucleophile or
their derivatives have never been investigated as reagent in a Mi-
chael addition with MBH adducts.
We have already demonstrated the influence of the silylated
protecting groups in the diastereoselectivity of the Michael addi-
tion reaction on MBH adducts.28 If this behavior is also observed
here, it would be possible to control the relative stereochemistries
a
Yields refer to isolated and purified products.
b
c
Determined by 1H NMR of the crude reaction mixture.
The relative stereochemistry was determined by measuring the coupling con-
stant of the duplet attributed to the carbinolic hydrogen.
A wide range of MBH adducts are well tolerated, allowing the
synthesis ofasetofsubstitutedpyrazolidinonesina tandem sequence.
Forallreactions,diastereoselectivity favoredthe syn diastereoisomers.
These results are in accordance with previous observations made by
us28 and confirmed elsewhere.30 Unfortunately, all chromatographic
attempts to separate the diastereoisomers failed.

828
J.T.M. Correia et al. / Tetrahedron 69 (2013) 826e832
Further, a dichloromethane solution of the MBH adducts was
were formed, as unique products in moderate yields (Table 4 entries
1 and 8).
treated with acetyl chloride in the presence of a catalytic amount of
DMAP at 0 ꢀC to afford the acetylated derivatives in good yields
(Table 3).
However, when the aromatic ring was substituted by electron-
donating groups or replaced by aliphatic substituents the aryli-
dene pyrazolidinones were the only formed products, even after
48 h of reflux (Table 4, entries 3e7 and 9e10). Searching to change
the product distribution toward the pyrazoles, we have increased
the amount of triethylamine (from 3 to 20 equiv), however no
change was observed.
Table 3
Acetylation of the MBH adducts
The only exception was observed for 39 (Table 4, entry 2). In this
particular case, after 12 h an arylidene pyrazolidinone was obtained
as the only product. When the reaction was refluxed for 12 h more,
however, 39 was completely converted to a pyrazolone in 56% yield
(Table 4, entry 2).
Based on Table 4, thermodynamic control is likely and guided by
the influence of the substituents attached to the aromatic ring. The
pyrazolidinones are the sole products formed from the reaction
between the acetylated adduct and amino-guanidine and we as-
sume that the interconversion barriers between the pyr-
azolidinones and the pyrazolones are low.
If this hypothesis is correct, the presence of electron-donating
groups or even the absence of substituents should contribute to
stabilize much more the formation of pyrazolidinones than of
pyrazolones, even after a long period of heating. But the presence of
electron-withdrawing groups should destabilize the formation of
pyrazolidinones, favoring pyrazolones (Scheme 2).
Entry
MBH adduct
Acetylated MBH, yield (%)a
1
2
3
4
5
6
7
8
7, R¼4-NO2ePh
8, R¼2-FePh
38, 93
39, 62
40, 92
41, 75
42, 81
43, 95
44, 75
45, 85
46, 70
47, 74
48, 70
9, R¼3-ClePh
10, R¼4-ClePh
11, R¼4-tBuePh
12, R¼4-MeOePh
13, R¼3,4-OCH2OePh
35, R¼4-MeO2SePh
36, R¼Ph
9
10
11
37, R¼cyclohexyl
38, R¼3-NO2ePh
a
Yields refer to isolated and purified products.
The experimental protocol used with the silylated adducts was
repeated to provide either arylidene pyrazolidinones31 or pyr-
azolones with the exception that MeOH was replaced by acetoni-
trile (Table 4).
Table 4
Scheme 2. Thermodynamic control as hypothesis to explain the pyrazolidinone/pyr-
azole ratio.
Synthesis of arylidene pyrazolidinones and pyrazolones from acetylated MB
Substituted
pyrazolones
Arylidene-
NH
NH2
pyrazolidinones
H2CO3
H2N
We decided therefore to compare the relative stability of our
pyrazolidinones and pyrazolones via theoretical calculations at the
B3LYP/cc-pVDZ level (Table 5). To our surprise, calculations
N
H
O
O
OAc
NH
NH
NH2
CO2Me
+
R
R
R
N
N
NH2
Et3N, (3. equiv.)
CH3CN, reflux
N
H
N
H
revealed that the
DE differences for all cases varied from 8.7 to
58-63
9.7 kcal molꢁ1 in favor of the pyrazolones. Most probably, this
stability can be rationalized if the pyrazolone unity displays some
aromatic character.
49-57
38-48, R = alkyl or aryl
acetylated MBH adducts
Entry
Acetyl-MBH
Time (h)
Pyrazolidinones (%)a
Pyrazolones (%)a
Table 5
1
2
38
39
12
12
24
12
12
12
12
12
48
12
12
12
12
24
d
58, 53
Geometries and energies of theoretical and experimental compounds calculated at
B3LYP/cc-pVDZ level
49, 30
d
59, 56
60, 5
61, 8
3
4
5
6
7
40
41
42
43
44
50, 53b,d
51, 58c,d
52, 45
53, 65
54, 76
54, 86
d
a
(R)
Epyrazolidinone (a.u.)
Epyrazolone (a.u)
D )
E (kcal molꢁ1
4-MeO
H
4-NO2
ꢁ832.7053991 (53)
ꢁ718.492495 (55)
ꢁ922.5184813b
ꢁ832.7193084b
ꢁ718.5074739b
ꢁ922.5339952 (58)
8.7
9.4
9.7
a
D
E¼(jEpyrazolidinejꢁjEpyrazolej)$627.5095.
8
9
10
11
45
46
47
48
62, 59
d
b
These compounds are not part of this work, they are used only for calculations.
55, 65
56, 70
57, 27
d
d
63, 27
63, 42
The data obtained from theoretical calculations failed to confirm
the thermodynamic control hypothesis. Therefore, we moved our
attention toward the interconversion barriers between the
regioisomers. This interconversion should be mediated by basic
catalysis, through the abstraction of the hydrogen at C3 to form a p-
allyl system, which in turn is protonated at the benzylic position to
generate the corresponding pyrazolone (Scheme 3).
a
Yields refer to isolated and purified products.
This compound was obtained as an inseparable mixture of pyrazolidinone/
b
pyrazolone (12:1).
c
The same regioisomeric mixture was obtained in this case, however with a
different pyrazolidinone/pyrazolone ratio (7:1).
d
Yields were determined by NMR analysis.
Apparently the acidity of the hydrogen at C3 is the determinant
factor for the interconversion between the heterocycles. A new
analysis of the data reported in Table 4 reveals that the acidity of
hydrogen at C3 has a direct relationship with the nature of the
substituents. That is, electron-withdrawing substituents increase
In this reaction, we observe net influence of the substituent at-
tached to the aromatic ring into the ratio of products. Curiously after
12 h, in some acetylated adducts where the aromatic ring was
substituted with an electron-withdrawing group, the pyrazolones

J.T.M. Correia et al. / Tetrahedron 69 (2013) 826e832
829
Pyrazolones
Pyrazolidinones
more efficient when the substituents can act by resonance (ortho-
or para-positionsdTable 4, entries 1, 2, and 8). Electron-
withdrawing groups acting by inductive effects are weaker and
consequently less effective to stabilize the negative charge (Table
4, entries 3, 4, and 11). This stabilization became less likely
when electron-donating substituents are present on the aromatic
rings and is unfeasible without the presence of an aromatic ring.
These difficulties can be however compensated by the presence of
a polar protic solvent, which can probably stabilize the charge by
solvation.
H
NEt
O
O
O
O
NH
NH
R
NH
NH
NH
NH
NH
NH
R
R
R
N
N
N
N
N
H
H
N
N
H
N
H
H
NEt
Scheme 3. Proposed mechanism for the base-mediated interconversion pyr-
azolidinones/pyrazolones.
the relative acidity of the hydrogen at C3 leading to lower energy of
activation for this abstraction.
Curiously, when the reactions were performed in the presence
of K2CO3 in MeOH we only observed the formation of a complex
mixture of products.
Pyrazolidinones 53, 54, and 55 (Table 4) were also treated with
K2CO3 in the presence of MeOH. This protocol has been used by Kim
et al.25 to form pyrimidines from MBH adducts, and seems appro-
priate since the pyrazolidinones are more soluble in MeOH than in
CH3CN. Indeed, all pyrazolidinones were quantitatively converted
to the corresponding pyrazolones after 8 h of heating (Scheme 4). It
is worth noting that we have treated the pyrazolidinone 55 with
Et3N in CH3CN in order to obtain pyrazolone 66, however after 72 h
of reflux no double bond isomerization has been detected in the
isolated product.
3. Conclusions
Efficient and direct preparation of pyrazolidin-5-ones and pyr-
azol-5-ones from the reaction between silylated and acetylated
MBH adducts with aminoguanidine is described. Diaster-
eoselectivities varying from 2:1 to 7:1 were obtained when sily-
lated adducts were treated with aminoguanidine. When acetylated
adducts are used as substrate, arylidene pyrazolidin-5-ones are
prepared in moderate to good yields.
K CO , MeOH,
reflux, 8h
O
O
NH
NH
N
The pyrazolidin-5-ones can be directly converted to pyrazol-5-
ones with selectivity being related to the acidity of hydrogen at-
N
NH
NH
>99%
N
N
R
H
R
H
tached to a carbon in a CeN
s bond. We have also demonstrated the
64, R = 4-OMe
65, R = 3,4-OCH O-
66, R = H
53, R = 4-OMe
54, R = 3,4-OCH O-
55, R = H
favoring of polar aprotic solvents for this interconversion.
This seems to be the first report on the use of amino-
guanidine as nucleophile in a Michael reaction with MBH ad-
ducts. The new heterocycles synthesized in this work are cur-
rently under biological evaluation and the results will be reported
in due course.
Scheme 4. Converting pyrazolidinones into pyrazolones.
As the basicity of triethylamine is comparable to that of K2CO3
(pKb 3.67 against pKb 3.29, respectively), these results indicate that
the conjugate base of these compounds is more stabilized by
a protic polar solvent as MeOH than by an aprotic polar solvent,
such as CH3CN. This stabilization should contribute to increase the
acidity of C3-H, independently of the substituents attached to the
aromatic ring. Based on these experimental observations, the se-
lectivity of this reaction seems to be only governed by the in-
terconversion barriers between pyrazolidinones and pyrazolones
(Scheme 5).
4. Experimental section
4.1. General
The reaction progress was monitored by thin layer chromatog-
raphy on silica gel (aluminum foils) and spotted under UV light
(254 nm), followed by staining with ethanolic 25% phosphomo-
lybdic solution or aqueous KMnO4. Purifications were carried out
by column chromatography on silica gel (70e230 or
230e400 mesh).1H NMR spectra were recorded at 250 MHz,
500 MHz or 600 MHz and the 13C NMR spectra at 62.5 MHz,
125 MHz or 150 MHz, in CDCl3, MeOD or DMSO-d6 at room tem-
A
O
NH
N
O
N
H
NH
N
O
O
O
NH
NH
NH
NH
perature. Chemical shifts (d) were reported in parts per million and
N
N
N
N
O N
H
O N
the coupling constants (J) in Hertz (Hz). Signal multiplicity was
assigned as singlet (s), doublet (d), double doublet (dd), triplet (t),
double triplet (dt), multiplet (m) and broad (br). The high resolu-
tion mass spectra were recorded using a Q-TOF Micromass equip-
ment (Waters, UK). Spectral data for known compounds (silylated
and acetylated MoritaeBayliseHillman adducts) are available in
the Supplementary data. The compounds are named according to
IUPAC rules using the program MarvinSketch version 5.9.3.
H
H
O
56
B
NH
NH
probably formed in
the reaction medium
N
O
N
N
O
H
BH
B
O
N
O
O
NH
NH
NH
NH
NH
NH
N
N
N
H
N
H
N
H
MeO
MeO
MeO
H
59
52
stabilized by the protic
polar solvent
B
4.2. General procedure for the preparation of silylated pyr-
azolidin-5-ones
Scheme 5. Stabilizing charges after deprotonation.
To a mixture of silylated MBH adduct (1.00 mmol) in methanol
(20 mL) was added Et3N (0.7 mL) and aminoguanidine bicarbonate
(1.05 mmol). The resulting solution was stirred under reflux for 3 h.
After, the solvent was removed and the crude residue was purified
by silica gel flash chromatography (CHCl3:MeOH) to afford 28e34
in 78e88% yield.
Canonic forms can help to explain the increasing of the hy-
drogen (C3) acidity when electron-withdrawing groups are pres-
ent on the aromatic unity (Scheme 5, part A). The negative charge
of the
p-allylic system can be promptly stabilized by delocalization
through the electron poor aromatic ring. This delocalization is

830
J.T.M. Correia et al. / Tetrahedron 69 (2013) 826e832
4.2.1. 4-{[(tert-Butyldimethylsilyl)oxy](4-nitrophenyl)methyl}-5-
oxopyrazolidine-1-carboximidamide (28a/b). Yield: 83%; yellow
tinged solid. nmax (KBr) 3411, 2955, 1667, 1615 cmꢁ1 dH (250 MHz,
MeOD) (minor regioisomer) ꢁ0.03 (3H, s), 0.18 (3H, s), 0.98 (9H, s),
3.01e3.08 (1H, m), 3.47 (1H, dd, J 12.6, 5.6 Hz), 3.70 (1H, dd, J 12.5,
6.8 Hz), 5.44 (1H, d, J 5.0 Hz), 7.70 (2H, d, J 8.6 Hz, aromatics), 8.23
(2H, d, J 8.6 Hz, aromatics); (major regioisomer) ꢁ0.04 (3H, s), 0.16
(3H, s), 0.95 (9H, s), 2.82e2.90 (1H, m), 3.32 (1H, m), 3.78 (1H, dd, J
11.8, 10.4 Hz), 5.70 (1H, d, J 2.7 Hz), 7.71 (2H, d, J 8.6 Hz), 8.30 (2H, d,
J 8.6 Hz); dC (62.5 MHz, MeOD) ꢁ4.9, ꢁ4.5, 19.2, 26.4, 26.6, 51.0,
52.3, 74.0, 124.1, 124.6, 128.6, 128.6, 148.9, 149.1, 149.9, 152.1, 162.6,
163.3, 178.4; HRMS (ESI): [MþH]þ, found 394.1934. C17H28N5O4Si
requires 394.1911.
white solid. nmax (KBr) 3345, 2954, 1664, 1487 cmꢁ1 dH (250 MHz,
MeOD) ꢁ0.07 (3H, s), 0.11 (3H, s), 0.92 (9H, s), 2.70e2.77 (1H, m),
3.33e3.41 (1H, m), 3.78 (1H, dd, J 12.0, 9.2 Hz), 5.46 (1H, d, J 2.4 Hz)
5.99 (2H, s), 6.78e6.92 (3H, m); dC (62.5 MHz, MeOD) ꢁ4.5, 18.4,
26.3, 48.2, 49.9, 71.8, 101.3, 106.6, 108.3, 119.1, 137.9, 146.4, 147.4,
161.7, 174.7; HRMS (ESI): [MþH]þ, found 393.1962. C18H29N4O4Si
requires 393.1958.
4.3. General procedure for the preparation of pyrazolidin-5-
ones (49e57) and pyrazol-5-ones (58e63)
To a solution of the acetylated MoritaeBayliseHillman adduct
(1 mmol) in acetonitrile (30 mL) was added the guanidine car-
bonate (0.83 mmol) and triethylamine (5 mmol). The resulting
yellow suspension was stirred, under reflux, for 12 h. After this time
a precipitate is formed. The reaction was cooled to room temper-
ature the reaction was filtered and the filtrate was washed suc-
cessively with acetonitrile to provide the corresponding
pyrazolidin-5-ones and pyrazol-5-ones.
4.2.2. 4-{[(tert-Butyldimethylsilyl)oxy](2-fluorophenyl)methyl}-5-
oxopyrazolidine-1-carboximidamide (29a/b). Yield: 81%; white
solid. nmax (KBr) 3411, 2955, 1667, 1615 cmꢁ1 dH (250 MHz, MeOD)
ꢁ0.11 (3H, s), 0.10 (3H, s), 0.90 (9H, s), 2.80e2.88 (1H, m), 3.33e3.38
(1H, m), 3.79 (1H, dd, J 12.0, 9.4 Hz), 5.84 (1H, d, J 2.3 Hz), 7.03e7.11
(1H, m), 7.18e7.23 (1H, m), 7.28e7.35 (1H, m), 7.56 (1H, td, 7.4,
1.5 Hz); dC (62.5 MHz, MeOD) ꢁ4.8, ꢁ4.6, 19.2, 26.6, 49.4, 68.3, 116.4
(d, J 21.6 Hz), 125.2 (d, J 3.4 Hz), 129.7 (d, J 4.4 Hz), 130.4 (d, J 7.8 Hz),
131.2 (d, J 13.8 Hz), 1.60.5 (d, J 244.9 Hz), 163.2, 178.3; HRMS (ESI):
[MþH]þ, found 367.1960. C17H27FN4O2Si requires 394.1966.
4.3.1. (4E)-4-[(2-Fluorophenyl)methylidene]-5-oxopyrazolidine-1-
carboximidamide (49). Yield: 30%; yellow tinged solid; mp
227e229 ꢀC; nmax (KBr) 3404, 3294, 3207, 3065, 1682, 1588, 1482,
1452, 1360, 1305, 1224 cmꢁ1 dH (250 MHz, DMSO-d6) 4.39 (2H, d, J
0.5 Hz), 4.82 (2H, s), 6.76 (2H, br s), 7.24e7.48 (5H, m); dC
(62.5 MHz, DMSO-d6) 52.5, 52.5, 115.5, 115.8, 112.7, 123, 123.7,
123.7, 124.5, 124.5, 130.4, 130.5, 130.7, 157.9, 161.2, 161.8, 168.4;
HRMS (ESI): [MþH]þ, found 235.1004. C11H11FN4O requires
235.0995.
4.2.3. 4-{[(tert-Butyldimethylsilyl)oxy](3-chlorophenyl)methyl}-5-
oxopyrazolidine-1-carboximidamide (30a/b). Yield: 78%; white
solid. nmax (KBr) 3453, 2954, 1638, 1586, 1491 cmꢁ1 dH (250 MHz,
MeOD) ꢁ0.08 (3H, s), 0.11 (3H, s), 0.92 (9H, s), 2.75e2.83 (1H, m),
3.32 (1H, m), 3.76 (1H, dd, J 11.9, 9.5 Hz), 5.53 (1H, d, J 2.2 Hz),
7.31e7.37 (m, 3H), 7.45 (1H, s); dC (62.5 MHz, MeOD) ꢁ4.7, ꢁ4.6,
18.4, 26.2, 48.2, 49.6, 71.4, 124.8, 126, 127.3, 130.4, 133.3, 146.7, 162.1,
174.4; HRMS (ESI): [MþH]þ, found 383.1701. C17H27ClN4O2Si re-
quires 383.1670.
4.3.2. (4E)-4-[(3-Chlorophenyl)methylidene]-5-oxopyrazolidine-1-
carboximidamide (50). Yield: 58%; yellow tinged solid; nmax (KBr)
3417, 3291, 1661, 1573, 1484, 1414, 1372, 727 cmꢁ1 dH (250 MHz,
DMSO-d6) (major regioisomer) 4.51 (2H, d, J 2.5 Hz), 4.85 (2H, s),
6.76 (2H, br s), 7.23e7.43 (5H, m); dC (62.5 MHz, DMSO-d6) (major
regioisomer) 52.5 (d, J 2.8 Hz), 115.7 (d, J 21.4 Hz), 122.8 (d, J
13.8 Hz), 123.7 (d, J 3.7 Hz), 124.5 (d, J 3.3 Hz), 130.4 (d, J 2.4 Hz),
130.5, 130.7, 159.8 (d, J 247.0 Hz), 161.2, 168.4; HRMS (ESI): [MþH]þ,
found 251.0718. C11H11ClN4O requires 251.0700.
4.2.4. 4-{[(tert-Butyldimethylsilyl)oxy](4-chlorophenyl)methyl}-5-
oxopyrazolidine-1-carboximidamide (31a/b). Yield: 88%; white
solid. nmax (KBr) 3454, 3325, 2954, 1641, 1590, 1494 cmꢁ1 dH
(250 MHz, MeOD) ꢁ0.12 (3H, s), 0.09 (3H, s), 0.90 (9H, s), 2.74 (1H,
dt, J 8.2, 2.5 Hz), 3.33 (1H, m), 3.72 (1H, dd, J 12.1, 8.2 Hz), 5.48 (1H,
d, J 2.7 Hz), 7.31e7.41 (4H, m); dC (62.5 MHz, MeOD) ꢁ4.6, ꢁ4.1, 17.6,
25, 49.7, 72.5, 127.4, 127.9, 132.7, 141.6, 161.6, 177.3; HRMS (ESI):
[MþH]þ, found 383.1611. C17H27ClN4O2Si requires 383.1670.
4.3.3. (4E)-4-[(4-Chlorophenyl)methylidene]-5-oxopyrazolidine-1-
carboximidamide (51). Yield: 66%; yellow tinged solid; nmax (KBr)
3397, 1691, 1638, 1585, 1492, 1366, 1097, 816 cmꢁ1 dH (250 MHz,
DMSO-d6) (major regioisomer) 4.50 (2H, d, J 2.5 Hz), 4.83 (2H, s),
6.76 (2H, br s), 7.34e7.38 (3H, m), 7.50 (2H, d, J 8.5 Hz); dC
(62.5 MHz, DMSO-d6) (mixture of regioisomers) 32.7, 52.6, 116.9,
128, 128.6, 128.9, 130.1, 130.4, 130.5, 131.2, 132.9, 134.1, 139.5, 141.4,
156.2, 161, 168.5, 169.1; HRMS (ESI): [MþH]þ, found 251.0602.
C11H11ClN4O requires 251.0700.
4.2.5. 4-{[(tert-Butyldimethylsilyl)oxy](4-tert-butylphenyl)methyl}-
5-oxopyrazolidine-1-carboximidamide (32a/b). Yield: 83%; white
solid. nmax (KBr) 3454, 2956, 1663, 1610, 1485 cmꢁ1 dH (250 MHz,
MeOD) ꢁ0.12 (3H, s), 0.08 (3H, s), 0.90 (9H, s), 1.31 (9H, s),
2.70e2.90 (1H, m), 3.36e3.45 (1H, m), 3.59e3.80 (1H, m), 5.17 (1H,
d, J 5.1 Hz, minor diastereoisomer), 5.50 (1H, d, J 2.2 Hz, major di-
astereoisomer), 7.29e7.41 (4H, m); dC (62.5 MHz, MeOD) ꢁ4.6,
ꢁ4.4, 19.2, 26.5, 32, 35.5, 51.5, 52.6, 74.5, 126.3, 127.1, 141.2, 151.6,
163.1, 179.3; HRMS (ESI): [MþH]þ, found 405.2700. C21H37N4O2Si
requires 405.2686.
4.3.4. (4E)-4-[(4-tert-Butylphenyl)methylidene]-5-oxopyrazolidine-
1-carboximidamide (52). Yield: 45%; yellow tinged solid; mp
210e211.8 ꢀC; nmax (KBr) 3394, 2959, 1678, 1589, 1493, 1357, 1308,
566 cmꢁ1 dH (250 MHz, DMSO-d6) 1.31 (9H, s), 4.52 (2H, d, J 2.5 Hz),
4.83 (2H, s), 6.73 (2H, br s), 7.27 (2H, d, J 8.5 Hz), 7.39 (1H, s), 7.47
(2H, d, J 8.3 Hz); dC (62.5 MHz, DMSO-d6) 31, 34.4, 52.8, 125.4, 127.5,
129.4, 131.2, 132.4, 151, 160.9, 168.9; HRMS (ESI): [MþH]þ, found
273.1698. C15H20N4O requires 273.1715.
4.2.6. 4-{[(tert-Butyldimethylsilyl)oxy](4-methoxyphenyl)methyl}-5-
oxopyrazolidine-1-carboximidamide (33a/b). Yield: 81%; white
solid. nmax (KBr) 3397, 2959, 1611, 1483 cmꢁ1 dH (250 MHz, MeOD)
ꢁ0.07 (3H, s), 0.12 (3H, s), 0.94 (9H, s), 2.73e2.80 (1H, m), 3.39e3.47
(1H, m), 3.76e3.81 (1H, m), 5.50 (1H, d, J 2.3 Hz), 6.92 (2H, d, J 8.5 Hz),
7.33 (2H, d, J 8.5 Hz); dC (62.5 MHz, MeOD) ꢁ4.3, ꢁ4.9,17.3, 24.9, 47.5,
49.5, 54.3, 72, 112.9, 126.3, 134, 158.3, 160.7, 176.8; HRMS (ESI):
[MþH]þ, found 379.2141. C18H30N4O3Si requires 379.2165.
4.3.5. (4E)-4-[(4-Methoxyphenyl)methylidene]-5-oxopyrazolidine-1-
carboximidamide (53). Yield: 65%; yellow tinged solid; mp
214.2e215.4 ꢀC; nmax (KBr) 3465, 3179, 3087, 3046,1658,1646,1608,
1570,1548,1456,1359,1230 cmꢁ1 dH (250 MHz, DMSO-d6) 3.81 (3H,
s), 4.51 (2H, d, J 2.4 Hz), 4.83 (2H, s), 6.71 (2H, br s), 7.02 (2H, d, J
8.7 Hz), 7.39 (2H, d, J 9.2 Hz), 7.37 (1H, t, J 2.4 Hz); dC (62.5 MHz,
4.2.7. 4-{2H-1,3-Benzodioxol-5-yl[(tert-butyldimethylsilyl)oxy]
methyl}-5-oxopyrazolidine-1-carboximidamide (34a/b). Yield: 83%;

J.T.M. Correia et al. / Tetrahedron 69 (2013) 826e832
831
DMSO-d6) 53, 55.3, 114.1, 126, 127.7, 131.2, 131.2, 159.3, 160.9, 169;
HRMS (ESI): [MþH]þ, found 247.1209. C12H14N4O2 requires 247.1195.
116.1, 126.8, 129.5, 138.4, 141.9, 147, 156.3, 169.2; HRMS (ESI):
[MþH]þ, found 295.0889. C12H14N4O3S requires 295.0865.
4.3.6. (4E)-4-(2H-1,3-Benzodioxol-5-ylmethylidene)-5-oxopyrazolid-
ine-1-carboximidamide (54). Yield: 76% (after 12 h) and 86% (after
48 h); yellow tinged solid; mp 234e235.7 ꢀC; nmax (KBr) 3433, 3314,
3014, 1657, 1642, 1578, 1504, 1488, 1341 cmꢁ1 dH (250 MHz, DMSO-d6)
(data for the hydrochloride) 4.79 (2H, s), 5.41 (2H, s), 6.13 (2H, s), 7.07
(3H, m), 7.68 (1H, s), 8.46 (2H, s),11.66 (1H, br s); dC (62.5 MHz, DMSO-
d6) 52.2, 101.9, 108.8, 110, 119.2, 126.4, 127.4, 138.5, 147.9, 149.1, 153.4,
160.4; HRMS (ESI): [MþH]þ, found 261.0980. C12H13N4O3 requires
261.0988.
4.3.13. 4-[(3-Nitrophenyl)methyl]-5-oxo-2,5-dihydro-1H-pyrazole-
1-carboximidamide (63). Yield: 42%; yellowish solid; mp
240.6e242.9 ꢀC; nmax (KBr) 3334, 3092, 1673, 1520, 1455, 1344, 819,
736, 668 cmꢁ1 dH (250 MHz, DMSO-d6) 3.61 (2H, s), 5.73 (2H, s), 6.81
(2H, brs), 7.30 (1H, s), 7.56 (1H, t, J 7.8 Hz), 7.74 (1H, d, J 7.5 Hz), 8.04
(1H, d, J 6.9 and 8.0 Hz), 8.11 (1H, s); dC (62.5 MHz, DMSO-d6) 32.7,
116.2,121.3,123.4,129.7,135.9,143.1,148.1,156.7,169.7,169.8; HRMS
(ESI): [MþH]þ, found 262.0933. C12H14N4O3S requires 262.0940.
4.4. General procedure for the isomerization of pyrazolidin-
5-ones 53, 54, and 55 to pyrazol-5-ones 64, 65, and 66
4.3.7. (4E)-5-Oxo-4-(phenylmethylidene)pyrazolidine-1-carboximi-
damide (55). Yield: 65%; yellow tinged solid; mp 205e207.5 ꢀC;
nmax (KBr) 3398, 3294, 3209, 3165, 3056, 1681, 1626, 1584, 1490,
1370, 770 cmꢁ1 dH (250 MHz, DMSO-d6) 4.52 (2H, d, J 2.6 Hz), 4.87
(2H, s), 6.67 (1H, br s), 7.06 (2H, br s), 7.32e7.40 (4H, m), 7.46 (2H, t, J
7.5 Hz); dC (62.5 MHz, DMSO-d6) 52.8, 128.2, 128.3, 128.6, 129.5,
131.4, 135.2, 161, 168.7; HRMS (ESI): [MþH]þ, found 217.1039.
C12H14N4O2 requires 271.1089.
To a suspension of 52 or 54 (0.5 mmol) in methanol (10 mL) was
added K2CO3 (1.0 mmol). The resulting mixture was stirred under
reflux for 8 h. After this period we observed the complete disso-
lution of the reagents into the solvent. Then, the solvent was re-
moved under reduced pressure and the residue was washed with
distilled water (2ꢂ5 mL) and dried under vacuum to provide the
pyrazol-5-ones as unique products.
4.3.8. (4E)-4-(Cyclohexylmethylidene)-5-oxopyrazolidine-1-
carboximidamide (56). Yield: 70%; white solid; mp 215e216.5 ꢀC;
nmax (KBr) 3436, 3273, 2921, 2850, 1660, 1635, 1583, 1477,
1377 cmꢁ1 dH (250 MHz, DMSO-d6) 1.17e1.37 (5H, m), 1.57e1.72
(5H, m), 2.05e2.17 (1H, m), 4.20 (2H, d, J 2.5 Hz), 4.78 (2H br s), 6.26
(1H, dd, J 7.5, 2.5 Hz); dC (62.5 MHz, DMSO-d6) 25.6, 25.8, 31.9, 36.6,
51.6, 125.9, 140, 161.5, 169; HRMS (ESI): [MþH]þ, found 223.1580.
C11H19N4O requires 223.1559.
4.4.1. 4-[(4-Methoxyphenyl)methyl]-5-oxo-2,5-dihydro-1H-pyr-
azole-1-carboximidamide (64). Yield: >99%; white solid; mp
205.5e207.5 ꢀC. nmax (KBr) 3420, 3295, 1679, 1648 cmꢁ1 dH
(500 MHz, DMSO-d6) 3.38 (2H, s), 3.71 (3H, s), 5.69 (2H, s), 6.72 (2H,
br s), 6.83 (2H, d, J 8.6 Hz), 6.90 (2H, s), 7.14 (2H, d, J 8.6 Hz); dC
(62.5 MHz, DMSO-d6) 32.1, 55, 113.6, 117.9, 129.8, 132, 140.9 156,
157.5, 169.3; HRMS (ESI): [MþH]þ, found 247.1215. C12H14N4O2 re-
quires 247.1195.
4.3.9. (4E)-4-[(3-Nitrophenyl)methylidene]-5-oxopyrazolidine-1-
carboximidamide (57). Yield: 27%; yellow solid. dH (250 MHz,
DMSO-d6, mixture of regioisomers) 3.61 (2H, s), 4.56 (2H, s). 4.89
(2H, s), 5.73 (2H, s), 6.79e7.10 (4H, m), 7.50 (1H, s), 7.49e7.59 (2H,
m), 7.73e7.82 (3H, m), 8.12 (4H, m); dC (62.5 MHz, DMSO-d6) 32.6,
52.4, 116, 120.9, 122.8, 123, 123.4, 129, 129.4, 130.1, 130.7, 135.6,
135.9, 136.9, 141.9, 143.2, 147.6, 147.9, 156.3, 160.9, 168.1, 169.1;
HRMS (ESI): [MþH]þ, found 262.0933. C11H11N5O3 requires
262.0940.
4.4.2. 4-(2H-1,3-Benzodioxol-5-ylmethyl)-5-oxo-2,5-dihydro-1H-
pyrazole-1-carboximidamide (65). Yield: >99%; white solid. nmax
(KBr) 3431, 3299, 1682, 1649 cmꢁ1 dH (250 MHz, DMSO-d6) 3.38
(2H, s), 5.75 (2H, s), 5.94 (2H, s), 6.68e6.71 (1H, m), 6.78e6.81 (1H,
m), 6.90 (2H, s), 6.93 (1H, br s), 7.03 (1H, s); dC (62.5 MHz, DMSO-d6)
32.5, 100.6, 107.9, 109.2, 117.5, 117.9, 121.6, 133.9, 141.4, 145.3, 147,
155.9, 168.9; HRMS (ESI): [MþH]þ, found 261.0979. C12H14N4O2
requires 261.0982.
4.3.10. 4-[(4-Nitrophenyl)methyl]-5-oxo-2,5-dihydro-1H-pyrazole-
1-carboximidamide (58). Yield: 53%; yellowish solid; mp
263e265 ꢀC; nmax (KBr) 3422, 3350, 3281, 3072, 1679, 1651, 1584,
1511, 1457, 1346, 1110 cmꢁ1 dH (250 MHz, DMSO-d6) 3.62 (2H, s),
5.68 (2H, s). 6.66 (2H, s), 7.22 (1H, s), 7.72 (2H, d, J 8.5 Hz), 8.12 (2H,
d, J 8.8 Hz); dC (62.5 MHz, DMSO-d6) 32.8, 115.8, 123.2, 129.7, 142,
145.8, 149.2, 156.3, 169.1; HRMS (ESI): [MþH]þ, found 262.0971.
C11H11N5O3 requires 262.0940.
4.4.3. 4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazole-1-carboximidamide
(66). Yield: >99%; white solid; mp 230.9e231.2 ꢀC. nmax (KBr)
3425, 3295, 1679, 1650, 1613, 1590, 1508, 1475 cmꢁ1 dH (600 MHz,
DMSO-d6) 3.46 (2H, s), 5.71 (2H, s), 6.75 (2H, br s), 6.98 (1H, s),
7.16e7.19 (1H, m), 7.21e7.28 (4H, m); dC (150 MHz, DMSO-d6) 33.4,
117.8, 126.3, 128.6, 129.2, 140.8, 141.6, 156.6, 169.7; HRMS (ESI):
[MþH]þ, found 217.1081. C11H13N4O requires 217.1089.
Acknowledgements
4.3.11. 4-[(2-Fluorophenyl)methyl]-5-oxo-2,5-dihydro-1H-pyrazole-
1-carboximidamide (59). Yield: 53%; yellowish solid; mp
250.8e251.5 ꢀC; nmax (KBr) 3427, 3292, 3204, 3083,1682, 1651,1613,
1591, 1515, 1488, 1227 cmꢁ1 dH (250 MHz, DMSO-d6) 3.48 (2H, s),
5.70 (2H, s), 6.75 (2H, s), 6.87 (1H, s), 7.08e7.22 (4H, m); dC
(62.5 MHz, DMSO-d6) 26.0 (d, J 3.2 Hz), 115.0 (d, J 21.9 Hz), 115.6,
124.1 (d, J 3.3 Hz), 126.5 (d, J 15.6 Hz), 128.0 (d, J 7.9 Hz), 131.2 (d, J
4.6 Hz), 141.1, 156.1, 160.4 (d, J 243.5 Hz); 169.0; HRMS (ESI):
[MþH]þ, found 235.0987. C11H11FN4O requires 235.0995.
Authors thank Fapesp, CNPq, and CAPES for fellowships (J.T.M.C.,
M.T.R. Jr., H.S.) and research fellowship (C.F.T. and F.C.). Authors also
thank these agencies for financial support.
Supplementary data
Supplementary data with all spectroscopic data of pyrazolidin-5-
ones and pyrazol-5-ones are available. Supplementary data related to
this article can be found at http://dx.doi.org/10.1016/j.tet.2012.10.057.
4.3.12. 4-[(4-Methanesulfonylphenyl)methyl]-5-oxo-2,5-dihydro-
1H-pyrazole-1-carboximidamide (62). Yield: 59%; yellowish solid;
mp 250.5e252.5 ꢀC; nmax (KBr) 3421, 3348, 3017, 2912, 1673, 1638,
1593, 1501, 1463, 1298, 1148 cmꢁ1 dH (250 MHz, DMSO-d6) 3.15 (3H,
s), 3.59 (2H, s), 5.67 (2H, s), 6.63 (2H, s), 7.18 (1H, s), 7.51 (2H, d, J
8.3 Hz), 7.81 (2H, d, J 8.3 Hz); dC (62.5 MHz, DMSO-d6) 32.9, 43.7,
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ꢀ
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