Morita-Baylis-Hillman adducts as building blocks of heterocycles: a simple approach to 4-substituted pyrazolones, and mechanism investigation via ESI-MS(/MS)

Article abstract of DOI:10.1007/s00706-015-1427-6

Abstract We describe herein an efficient approach for the preparation of 4-substituted 2,3-dihydro-1H-pyrazol-3-ones starting from Morita-Baylis-Hillman adducts. These heterocycles were obtained in two or three steps as single isomers with moderate to goo

Full text of DOI:10.1007/s00706-015-1427-6

Monatsh Chem (2015) 146:1557–1570
DOI 10.1007/s00706-015-1427-6
ORIGINAL PAPER
Morita–Baylis–Hillman adducts as building blocks
of heterocycles: a simple approach to 4-substituted pyrazolones,
and mechanism investigation via ESI–MS(/MS)
•
Rosimeire C. Barcelos Lucas A. Zeoly Manoel T. Rodrigues Jr.
•
•
•
Bruno R. V. Ferreira Marcos N. Eberlin Fernando Coelho
•
Received: 29 December 2014 / Accepted: 15 January 2015 / Published online: 10 February 2015
Ó Springer-Verlag Wien 2015
Introduction
Abstract We describe herein an efficient approach for
the preparation of 4-substituted 2,3-dihydro-1H-pyrazol-3-
Heterocycles are one of the most important classes of
ones starting from Morita–Baylis–Hillman adducts. These
heterocycles were obtained in two or three steps as single
isomers with moderate to good overall yields. One efficient
and alternative methodology for the synthesis of a-methyl-
b-ketoesters is also reported (up to 91 % yield). Addi-
tionally, the mechanism of formation of pyrazolones was
investigated employing ESI–MS/MS reaction monitoring.
Graphical abstract
compounds in nature and are present in almost all
biologically active molecules [1]. Among them, the pyra-
zolone core has been gaining increasing attention due to its
applications, representing a versatile template for combi-
natorial and medicinal chemistry [2–7].
A wide variety of patents featuring different syntheses
of pyrazolones and applications for it have also appeared,
which demonstrates the strong economical potential of this
nucleus [8–10]. Their anticancer [11–14] and antimicrobial
[15–17] properties have also been studied. Pyrazolones
have traditionally been used due to their analgesic, anti-
pyretic, and anti-inflammatory activities [18–22]. For ex-
ample, dipyrone, phenazone, propyphenazone, and
ampyrone, drugs in current use, show some or all of these
properties (Fig. 1). Recently, Simon et al. [23] have re-
ported a new class of pyrazolones and isoxazol-5-ones that
inhibit Sirtuin, which can potentially be used in the treat-
ment of lymphomas (Fig. 2).
Keywords Morita–Baylis–Hillman Á Pyrazolones Á
b-Ketoesters Á Heterocycles
Classically, 4-substituted pyrazolones have been syn-
thesized from 1,3-dicarbonyl compounds, where b-
ketoesters are combined with hydrazines to obtain simple
rings, which are then functionalized. One of the ways by
which this functionalization can be achieved is using
Mannich or Michael chemistry to introduce the required
substituent at position 4 (Scheme 1), but this strategy adds
an additional step to the synthesis. Furthermore, dialky-
lated products can be obtained when Michael addition is
used [24–26].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1427-6) contains supplementary
material, which is available to authorized users.
R. C. Barcelos Á L. A. Zeoly Á M. T. Rodrigues Jr. Á
F. Coelho (&)
Laboratory of Synthesis of Natural Products and Drugs,
University of Campinas, PO Box 6154, Campinas,
SP 13083-970, Brazil
An alternative to eliminate these drawbacks would be to
obtain the pyrazolones starting from substituted b-keto-
esters. 1,3-Ketoesters substituted in the a position can be
prepared by different approaches. One of them would be
e-mail: coelho@iqm.unicamp.br
B. R. V. Ferreira Á M. N. Eberlin
Laboratory ThoMSon of Mass Spectrometry, University of
Campinas, PO Box 6154, Campinas, SP 13083-970, Brazil
123

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R. C. Barcelos et al.
via the alkylation of ketoesters, which can be done using a
base and an alkylating agent. Dialkylation and the need of
protecting groups for free amines and alcohols, however,
are serious disadvantages. A Knoevenagel reaction could
be used to overcome the problem of poly-alkylation, but it
would also introduce an additional reduction step. Another
approach would be to rely on Claisen chemistry, providing
that one of the esters is nonenolizable, but this would re-
quire the use of a strong base and sometimes the presence
of a Lewis acid, both making the reaction moisture and, in
some cases, air sensitive. The Reformatsky reaction would
be another alternative to obtain b-ketoesters; however, one
more step would be necessary, consisting in the oxidation
of the hydroxyl group primarily obtained. Another modern
synthesis of 1,3-ketoesters employs alkyl diazoacetates, but
it has a limited scope in varying substituents in the a po-
sition (Scheme 2) [27–37].
Based on the importance of this nucleus, and to over-
come the drawbacks described above, we describe herein
an efficient and alternative methodology to prepare b-ke-
toesters, which employ transformations on the allylic
portion of the Morita–Baylis–Hillman (MBH) adducts to
furnish pyrazolones in 1–2 steps, in good to excellent
yields (70–96 %). These transformations employ either
oxidation with IBX followed by a novel chemoselective
reduction using the borane dimethyl sulfide complex of the
double bond to give the a-methyl-substituted b-ketoesters
in two steps, or a Heck reaction, which in a single step
furnishes different substituted ketoesters. Using these two
protocols, substituted 2,3-dihydro-1H-pyrazol-3-ones were
synthesized in good overall yields (up to 70 %), in two or
three steps starting from the MBH adducts (Scheme 3).
Results and discussion
The synthesis of the pyrazolone derivatives was accom-
plished in three or four steps starting from the commercial
aldehydes, depending on the strategy employed to prepare
b-ketoesters. The first step of both approaches consisted of
an MBH reaction [38–45]. A series of MBH adducts (2a–
2j) was prepared in good yields (70–96 %) from different
aldehydes (1a–1j), containing aromatic, heterocyclic, or
aliphatic substituents (Scheme 4; Table 1).
Fig. 1 Some biologically active pyrazolones
Next, we attempted the synthesis of 2-methylated
b-ketoesters from MBH adducts in two steps. The hydroxyl
groups in 2a–2g and 2j were oxidized using IBX [46], and
then the conjugated double bond was reduced using the
borane dimethyl sulfide complex (Scheme 5; Table 2).
Fig. 2 Two pyrazolones with pronounced anti-lymphoma activity
Scheme 1
123

Morita–Baylis–Hillman adducts
1559
Scheme 2
Scheme 3
oxides [52–54]. Thus, the usage of the borane dimethyl
sulfide complex to reduce the double bonds of oxidized
MBH adducts represents a new and chemoselective
methodology to reduce this type of system.
Scheme 4
The yields for the two-step synthesis of b-ketoesters 3a–
3g and 3j varied from 70 to 91 %. The a-methylene-b-
ketoesters that are produced as intermediates do not need to
be purified. Simple filtration for IBA (2-iodosobenzoic
acid) removal, followed by solvent removal, furnishes the
intermediates with enough purity to proceed with the
reduction.
Boranes have already been used in combination with si-
lanes as reducing agents for some particular type of double
bonds [47–51]; however, the only example where the bo-
rane dimethyl sulfide complex was used to reduce
electronically poor double bonds was reported some years
ago for cyclic vinylphosphine oxides or dihydrophosphole
The main limitation reported for the synthesis of b-ke-
toesters occurs for the preparation of a-substituted
123

1560
R. C. Barcelos et al.
Table 1 Preparation of MBH
adducts 2a–2j
Entry
Substrates
Yields 2/%a,b,c
1
2
1a, R1 = 3,4,5-MeOC6H2; R2 = Me
1b, R1 = 4-MeOC6H4; R2 = Me
1c, R1 = Piperonyl; R2 = Me
1d, R1 = 4-BrC6H4; R2 = Me
1e, R1 = 4-O2NC6H4; R2 = Me
1f, R1 = C6H5; R2 = Me
1g, R1 = 2-Thienyl; R2 = Me
1h, R1 = Ethyl; R2 = Me
1i, R1 = 4-ClC6H4; R2 = Me
1j, R1 = 4-MeOC6H4; R2 = Et
2a (75)
2b (70)
2c (85)
2d (85)
2e (96)
2f (74)
2g (90)
2h (85)
2i (85)
2j (81)
3
4
a
Yields refer to isolated and
purified compounds
5
6
b
Spectroscopic data are
compatible for the proposed
structures
7
8
c
9
Spectroscopic data of all
MBH adducts are described in
our previous work [38, 39, 46]
10
Scheme 5
Table 2 Preparation of b-
ketoesters 3a–3g and 3j
Entry
Substrates
Yields 3/%a,b
1
2
3
4
5
6
7
8
2a, R1 = 3,4,5-CH3OC6H2; R2 = Me
2b, R1 = 4-CH3OC6H4; R2 = Me
2c, R1 = Piperonyl; R2 = Me
2d, R1 = 4-BrC6H4; R2 = Me
2e, R1 = 4-NO2C6H4; R2 = Me
2f, R1 = C6H5; R2 = Me
3a (71)
3b (91)
3c (70)
3d (91)
3e (65)
3f (80)
3g (83)
3j (90)
a
Yields refer to isolated and
purified compounds
2g, R1 = 2-Thienyl; R2 = Me
2j, R1 = 4-CH3OC6H4; R2 = Et
b
All spectroscopic data are
compatible with the proposed
structures
substrates. Here, we prepared the 2-methylated b-ke-
toesters observing no issues regarding dialkylation. Our
protocol avoids the use of strong bases and acylating
reagents and leads to both, yields and scope, comparable or
even better than those reported in literature [27, 29, 32, 33,
55–60]. This was clearly shown for compound 3b, where
different methodologies and their respective yields are
presented (Scheme 6) [27, 29, 33, 55–57].
intermediate boron enolate [63] which, after work-up with
methanol, furnishes the desired a-methyl-b-ketoester.
The last step in the synthesis of 4-methylpyrazolones
was the cyclization of the b-ketoesters 3a–3g and 3j with
hydrazine hydrate, a classical procedure that furnished
4-methyl-2,3-dihydro-1H-pyrazol-3-ones 4a–4h with
yields ranging from 50 to 95 % (Scheme 8; Table 3). Note
that even substituted hydrazines can be used (Table 3,
entry 6) to give higher substituted pyrazolones.
Note that we used boranes for what seems to be an
unusual task: as a selective reducing agent for (activated)
double bonds. Boranes are normally used for hydrobora-
tion–oxidation of double bonds or reduction of carbonyls
[61, 62]. But we have noted that, rather than reducing the
carbonyl group of oxidized MBH adducts, the borane
dimethyl sulfide complex reduces the double bond in a
fully selective fashion. Our mechanistic proposal for this
chemoselective reduction (Scheme 7) invokes an
To increase the structural diversity of the pyrazolones,
we have employed MBH adducts in an intermolecular
Heck reaction with different aryl iodides to obtain b-ke-
toesters with substituents other than methyl in the a-
position. Adducts 2b, 2c, and 2e–2i were used as substrates
for this reaction (Scheme 9; Table 4) [39, 64], and this
approach allowed the synthesis of b-ketoesters 5a–5h in a
single step with very good yields (70–96 %, Table 4),
123

Morita–Baylis–Hillman adducts
1561
Scheme 6
Scheme 7
To confirm that our approach was a useful alternative to
the preparation of b-ketoesters, we show different
methodologies to synthesize compound 5e (Scheme 10).
We can observe that our yield was similar or even better
than those reported in literature [27, 65, 66, 68–74].
Finally, substrates 5a–5h were submitted to the same
conditions of cyclization employing hydrazine hydrate,
leading to the synthesis of 4-(4-hydroxybenzyl)-2,3-dihy-
dro-1H-pyrazol-3-ones 6a–6h with good yields (60–92 %,
Table 4).
Scheme 8
enabling structural diversification. Our yields were similar
or even better than those reported in literature [28, 65–75].
The synthesis of a-functionalized b-ketoesters by other
methodologies, such as alkylation or via Knoevenagel,
would require protection group chemistry for the free
amines and phenols or the use of large quantities of base,
adding at least two additional steps to the synthesis (pro-
tection/deprotection).
Mechanistic study employing mass spectrometry
In 1987, Katrizky and co-workers [76] reported a 13C NMR
mechanistical study of the pyrazolone ring formation by
the reaction of b-ketoesters with hydrazines. Analyzing the
123

1562
R. C. Barcelos et al.
Table 3 Synthesis of
4-methylpyrazolones 4a–4h
Entry
Substrates
Yields 4/%a,b
1
2
3
4
5
6
7
8
9
3a, R1 = 3,4,5-CH3OC6H2; R2 = Me; R = H
3b, R1 = 4-CH3OC6H4; R2 = Me; R = H
3c, R1 = Piperonyl; R2 = Me; R = H
3d, R1 = 4-BrC6H4; R2 = Me; R = H
3e, R1 = 4-NO2C6H4; R2 = Me; R = H
3e, R1 = 4-NO2C6H4; R2 = Me; R = Ph
3f, R1 = C6H5; R2 = Me; R = H
4a (65)
4b (74)
4c (65)
4d (70)
4e (95)
4f (50)
4 g (78)
4 h (64)
4b (76)
a
Yields refer to isolated and
purified compounds
b
3g, R1 = 2-Thienyl; R2 = Me; R = H
3j, R1 = 4-CH3OC6H4; R2 = Et; R = H
All spectroscopic data are
compatible with the proposed
structures
Scheme 9
Table 4 Synthesis of
4-arylated b-ketoesters 5a–5h
and 4-arylated pyrazolones 6a–
6h
Entry
Substrates
Ar
Yields/%a
5
6
1
2
3
4
5
6
7
8
2b, R = 4-MeOC6H4
2c, R = Piperonyl
2e, R = 4-NO2C6H4
2e, R = 4-NO2C6H4
2f, R = C6H5
C6H5
5a (86)
5b (77)
5c (96)
5d (76)
5e (78)
5f (80)
5g (70)
5h (75)
6a (69)
6b (80)
6c (73)
6d (75)
6e (76)
6f (60)
6g (92)
6h (70)
C8H7N
4-HOC6H4
C6H5
C6H5
2g, R = 2-Thienyl
2h, R = C2H5
4-HOC6H4
4-HOC6H4
C6H5
a
Yields refer to isolated and
purified products
2i, R = 4-ClC6H4
spectra, peaks were assigned to the starting materials, in-
termediates, and products, but correct assignment of
intermediates was not possible when substituted b-ke-
toesters were employed. Based on these 13C NMR, a
reaction mechanism via a hydrazide rather than a hydra-
zone intermediate was proposed (Scheme 11).
via ESI–MS, and efficient ‘‘fishing’’ of multiple inter-
mediates and products directly from the reaction solution
have been attained [83–88].
ESI(?)-MS(/MS) monitoring was therefore performed,
first for a reaction solution containing 3j (0.42 mmol),
hydrazine hydrate (1.3 equiv.), AcOH (10 mol %), and
5.0 cm3 methanol as the solvent under reflux. Aliquots
(0.5 mm3) were diluted in methanol with a trace amount of
formic acid, and directly subjected to ESI(?) in 1-h in-
tervals up to 24 h. Figure 3 shows typical ESI(?)-MS of
the reaction solution (t = 0 min and t = 3 h) as well as
ESI–MS/MS of a key intercepted intermediate.
Due to the cationic nature of the intermediates pro-
posed for pyrazolone formation from MBH adducts,
which should favor ESI(?) ‘‘fishing’’, this reaction seems
ideal to ESI(?)-MS(/MS) monitoring [77–81]. This
technique has offered an exceptional tool for mechanistic
studies, providing proper and continuous [82] snapshots
of the ionic composition of reaction solutions. The
method is also able to gently transfer reaction interme-
diates to the gas phase with great speed and sensitivity for
proper MS and MS/MS characterization. Organic reac-
tions or metal catalysis has been extensively investigated
At t = 0 min (Fig. 3a), ESI(?)-MS detected 7a of m/
z = 237, a ion that corresponds to the protonated MBH
adduct [3j ? H]?, as well as 7b of m/z = 269 and 7c of m/
z = 504, corresponding to [3j ? hydrazine ? H]? and
[3j ? 3j ? hydrazine ? H]?.
123

Morita–Baylis–Hillman adducts
1563
Scheme 10
Scheme 11
At t = 3 h, the reaction has progressed far enough that
other key reaction intermediates could then be properly
detected and characterized (Fig. 3b), such as 7d
(m/z = 205), 7e (m/z = 251), 7f (m/z = 441), and 7g
(m/z = 495). Note that 7d corresponds in fact to the pro-
tonated final product [4b ? H]?. Note also that 7e results
from dehydration of 7b. ESI–MS/MS data firmly cor-
roborate the proposed structures, as illustrated that for 7e in
Fig. 3c. The reaction mechanism we propose (Scheme 12)
is therefore corroborated by the species intercepted and
characterized via ESI (?)-MS(/MS) monitoring.
bonds. The b-ketoesters synthesized were also proved to be
useful in the direct preparation of 4-substituted pyra-
zolones. Since both methods are applicable to different
esters, their use in the synthesis of pharmaceutically im-
portant pyrazolones can be anticipated. Compounds similar
to those described as sirtuin inhibitors (Fig. 1) could also
be prepared using our protocols. Studies of the biological
potential of the novel pyrazolones described herein are
underway. By ESI–MS monitoring experiments new in-
sights into the mechanism of formation of pyrazolones
from b-ketoesters were also provided.
In conclusion, the two methodologies presented herein
for b-ketoester preparation are both simple, fast, and could
be successfully applied to a large diversity of MBH
adducts. The reduction of the double bond employing bo-
rane proved to be very chemoselective, and provided an
alternative method to reduce highly activated double
Experimental
Aldehydes used as substrates for the reactions are com-
mercial and were purchased. The other chemicals were
123

1564
R. C. Barcelos et al.
Fig. 3 ESI(?)-MS of the
reaction solution containing 3j
and hydrazine a at t = 0 min,
b at t = 3 h, c ESI(?)-MS/MS
of 7e of m/z = 251
123

Morita–Baylis–Hillman adducts
1565
Scheme 12
used as purchased unless otherwise noticed. Acetonitrile
was distilled from calcium hydride immediately prior to
use. IBX was prepared according to Martin’s procedure
[89]. Reaction progress was monitored by thin-layer chro-
matography on silica gel (aluminum foils) and spotted
under UV light (254 nm), followed by staining with
ethanolic 25 % phosphomolybdic solution, aqueous
KMnO4 or sulfuric vanillin. Purification by column chro-
matography was carried out with silica gel (70–230 or
230–400 Mesh). 1H NMR spectra were measured at
250 MHz and the 13C NMR spectra at 62.5 MHz, in CDCl3,
MeOD, TFA-d or DMSO-d6 at room temperature. Chemical
shifts (d) were reported in ppm and the coupling constants
(J) in Hertz (Hz). Signal multiplicity was assigned as singlet
(s), doublet (d), double doublet (dd), triplet (t), quartet (q),
multiplet (m), and broad (br). The IR spectra were obtained
by means of the FT-IR spectrophotometer NicoletTM
iSTM5 with the frequencies expressed in cm-1. The ESI–
MS(/MS) data were acquired using a high-resolution QT of
mass spectrometer (Manchester, UK) with a resolution of
5,000 and less than 50.0 ppm accuracy in TOF mass
analyzer. The mechanistic study was performed on an LTQ
FT Ultra equipment (Thermo Scientific). Melting points
were obtained using an Electrothermal equipment model
9100 and the values are corrected.
DABCO (0.65 equiv.) was sonicated using an ultrasonic
cleaner UNIQUE model GA 1000 (1,000 W, 25 kHz) for
16–120 h at room temperature. The reaction mixture was
then diluted with 50 cm3 dichloromethane. The organic
solution was washed with 2 9 10 cm3 water and 10 cm3
brine, concentrated under reduced pressure, and dried over
MgSO4. After filtration and solvent removal, the residue
was purified by column chromatography (gradient elution
acetate:n-hexane 10:90 to 40:60 v/v). All data obtained for
the adducts prepared are in agreement with literature [38].
General procedure for the preparation
of the a-methyl-b-ketoesters 3a–3g and 3j
To a stirred solution of a MBH adduct (1.0 mmol) in
acetonitrile (final concentration: 0.14 mol/dm3), 420 mg
o-iodoxybenzoic acid (IBX, 1.5 equivalents) was added.
The resulting mixture was then stirred at 70 °C and the
progression of the reaction was monitored by TLC. At the
end, the mixture was cooled to room temperature, filtered,
and the solvent was removed under reduced pressure. After
that, under a nitrogen atmosphere, the oxidized MBH ad-
duct was dissolved in 10 cm3 THF, borane in dimethyl
sulfide (2 mol/dm3 in THF, 1.0 equivalent) was added to
the mixture, and the resulting solution was stirred. The
reaction was monitored by TLC. After reaction completion,
2 cm3 methanol was added, the inert atmosphere was re-
moved, and the solvent evaporated under reduced pressure.
The crude product was purified by silica gel flash column
chromatography (gradient elution acetate:n-hexane 5:95 to
30:70 v/v) to give the corresponding b-ketoesters 3a–3g
General procedure for the preparation
of Morita–Baylis–Hillman adducts 2a–2i
A
mixture of the aliphatic or aromatic aldehydes
(18–20 mmol), methyl or ethyl acrylate (2.5 equiv.), and
123

1566
R. C. Barcelos et al.
Methyl 2-methyl-3-oxo-3-phenylpropanoate
(3f, C11H12O3)
and 3j. The yields were calculated for the two-step
procedure.
ꢀ
Yield: 80 %; pale-yellow oil; IR (ATR): m = 3,065, 2,993,
2,953, 1,741, 1,686, 1,597, 1,449, 1,220, 1,199, 949,
Methyl 2-methyl-3-oxo-3-(3,4,5-trimethoxyphenyl)-
propanoate (3a, C14H18O6)
Yield: 71 %; white solid; m.p.: 61–63 °C; IR (ATR):
735 cm-1 1H NMR (250 MHz, CDCl3): d = 1.35 (d,
;
J = 7.1 Hz, 3H), 3.52 (s, 3H), 4.31 (q, J = 7.1 Hz, 1H),
7.27–7.38 (m, 2H), 7.39–7.48 (m, 1H), 7.80–7.90 (m, 2H)
ppm; 13C NMR (62.5 MHz, CDCl3): d = 13.7, 47.8, 52.2,
128.4 (2C), 128.6 (2C), 133.4, 135.6, 171.1, 195.7 ppm.
-1
ꢀ
m = 3,058, 2,943, 2,840, 1,739, 1,680, 1,583, 1,128 cm
;
1H NMR (250 MHz, CDCl3): d = 1.47 (d, J = 7.1 Hz,
3H), 3.67 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 4.33 (q,
J = 7.1 Hz, 1H), 7.22 (s, 2H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 14.1, 48.3, 52.7, 56.5 (2 OCH3), 61.1, 106.4
(2C), 131.0, 143.2, 153.4 (2C), 171.6, 194.5 ppm; HRMS
(ESI?): m/z calcd. for C14H19O6 283.1182 ([M?H]?),
found 283.1133.
Methyl 2-methyl-3-oxo-3-(thiophen-2-yl)propanoate
(3g, C9H10O3S)
ꢀ
Yield: 83 %; yellow oil; IR (ATR): m = 1,740, 1,663,
1,413, 1,240, 1,266, 1,059, 861 cm-1; 1H NMR (250 MHz,
CDCl3): d = 1.38 (d, J = 7.0 Hz, 3H), 3.57 (s, 3H), 4.18
(q, J = 7.0 Hz, 1H), 7.04–7.11 (m, 1H), 7.59 (d,
J = 4.7 Hz, 1H), 7.69 (d, J = 3.7 Hz, 1H) ppm; 13C
NMR (62.5 MHz, CDCl3): d = 13.9, 49.1, 52.4, 128.4,
133.0, 134.9, 142.9, 170.7, 188.5 ppm.
Methyl 3-(4-methoxyphenyl)-2-methyl-3-oxopropanoate
(3b, C12H14O4)
ꢀ
Yield: 91 %; colorless oil; IR (ATR): m = 3,057, 2,954,
2,843, 1,741, 1,677, 1,601, 1,264, 1,171, 1,029, 844 cm-1
;
1H NMR (250 MHz, CDCl3): d = 1.37 (d, J = 7.0 Hz,
3H), 3.57 (s, 3H), 3.75 (s, 3H), 4.29 (q, J = 7.0 Hz, 1H),
6.84 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H) ppm;
13C NMR (62.5 MHz, CDCl3): d = 13.9, 47.6, 52.3, 55.4,
113.9 (2C), 128.6, 130.9 (2C), 163.9, 171.4, 194.3 ppm.
Ethyl 3-(4-methoxyphenyl)-2-methyl-3-oxopropanoate
(3j, C13H16O4)
ꢀ
Yield: 90 %; colorless oil; IR (ATR): m = 3,050, 2,952,
2,840, 1,741, 1,675, 1,598, 1,260, 1,174, 1,032, 840 cm-1
;
1H NMR (250 MHz, CDCl3): d = 1.17 (t, J = 7.2 Hz, 3H),
1.46 (d, J = 7.2 Hz, 3H), 3.86 (s, 3H), 4.13 (q, J = 7.2 Hz,
1H), 4.32 (q, J = 7.2 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H),
7.96 (d, J = 8.9 Hz, 2H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 13.8, 13.9, 48.1, 55.5, 61.3, 114.1 (2C), 128.9,
130.9 (2C), 164.0, 171.2, 194.5 ppm.
Methyl 3-(2H-1,3-benzodioxol-5-yl)-2-methyl-3-
oxopropanoate (3c, C12H12O5)
ꢀ
Yield: 70 %; yellow oil; IR (ATR): m = 2,992, 2,953,
2,905, 1,739, 1,676, 1,441, 1,248, 1,037, 736 cm-1; H
1
NMR (250 MHz, CDCl3): d = 1.36 (d, J = 7.1 Hz, 3H),
3.58 (s, 3H), 4.24 (q, J = 7.1 Hz, 1H), 5.94 (s, 2H), 6.75
(d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.48 (dd,
J = 8.2, 1.6 Hz, 1H) ppm; 13C NMR (62.5 MHz, CDCl3):
d = 14.0, 47.7, 52.4, 102.0, 107.9, 108.2, 125.0, 130.5,
148.4, 152.2, 171.3, 193.9 ppm.
General procedure for the preparation of the Heck
adducts 5a–5h
In a 10-cm3 round-bottom flask, aryl iodide (1.1 mmol),
Morita–Baylis–Hillman adduct (1 mmol), 0.32 cm3 trieth-
ylamine (2.3 mmol), palladacycle A (0.5 mol %), and
2–3 cm3 DMF were mixed. The mixture was stirred at
110 °C in air and the reaction progress was analyzed by
TLC. The crude reaction mixture was extracted with 15 cm3
water and 3 9 15 cm3 ethyl acetate. The organic phase was
dried over Na2SO4 and evaporated to yield the crude product
of the corresponding a-benzyl-b-ketoesters 5a–5h.
Methyl 3-(4-bromophenyl)-2-methyl-3-oxopropanoate
(3d, C11H11BrO3)
ꢀ
Yield: 91 %; pale-yellow oil; IR (ATR): m = 2,993, 2,952,
1,742, 1,687, 1,585, 1,397, 1,217, 1,198, 1,071, 940 cm-1
;
1H NMR (250 MHz, CDCl3): d = 1.43 (d, J = 7.1 Hz,
3H), 3.63 (s, 3H), 4.30 (q, J = 7.1 Hz, 1H), 7.56 (d,
J = 8.6 Hz, 2H), 7.78 (d, J = 8.6 Hz, 2H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 13.8, 48.2, 52.7, 128.9, 130.2
(2C), 132.2 (2C), 134.7, 171.1, 194.9 ppm.
Methyl 2-benzyl-3-(4-methoxyphenyl)-3-oxopropanoate
Methyl 2-methyl-3-(4-nitrophenyl)-3-oxopropanoate
(3e, C11H11NO5)
(5a, C18H18O4)
ꢀ
Yield: 86 %; yellow oil; IR (ATR): m = 3,058, 3,022,
2,949, 1,740, 1,679, 1,612, 1,227 cm-1 1H NMR
;
Yield: 65 %; yellow solid; m.p.: 66–68 °C; IR (ATR):
ꢀ
m = 2,994, 2,956, 1,744, 1,698, 1,528, 1,347, 1,223, 856,
(250 MHz, CDCl3): d = 3.31 (dd, J = 7.2, 4.1 Hz, 2H),
3.61 (s, 3H), 3.81 (s, 3H), 4.62 (t, J = 7.2 Hz, 1H), 6.86 (d,
J = 8.9 Hz, 2H), 7.14–7.23 (m, 5H), 7.93 (d, J = 8.9 Hz,
2H) ppm; 13C NMR (62.5 MHz, CDCl3): d = 35.0, 52.5,
55.5, 55.6, 114.0 (2C), 126.7, 128.6 (2C), 128.9 (2C),
129.1, 131.1 (2C), 138.6, 164.0, 170.0, 192.8 ppm.
704 cm-1 1H NMR (250 MHz, CDCl3): d = 1.47 (d,
;
J = 7.0 Hz, 3H), 3.64 (s, 3H), 4.38 (q, J = 7.0 Hz, 1H),
8.08 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H) ppm;
13C NMR (62.5 MHz, CDCl3): d = 13.5, 48.5, 52.7, 124.0
(2C), 129.6 (2C), 140.4, 150.5, 170.6, 194.5 ppm.
123

Morita–Baylis–Hillman adducts
1567
Methyl 3-(2H-1,3-benzodioxol-5-yl)-2-(1H-indol-5-
1H), 7.71 (d, J = 3.8 Hz, 1H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 34.3, 52.9, 57.7, 115.7 (2C), 128.6, 129.9,
130.2 (2C), 133.6, 135.5, 143.4, 154.9, 169.9, 187.6 ppm.
ylmethyl)-3-oxopropanoate (5b, C20H17NO5)
ꢀ
Yield: 77 %; brown oil; IR (ATR): m = 3,400, 2,953,
2,911, 1,734, 1,670, 1,604, 1,506, 1,442, 1,251,
Methyl 2-[(4-hydroxyphenyl)methyl]-3-oxopentanoate
1
1,037 cm-1; H NMR (250 MHz, CDCl3): d = 3.42 (dd,
(5g, C13H16O)
J = 7.4, 4.7 Hz, 2H), 3.64 (s, 3H), 4.64 (t, J = 7.4 Hz,
1H), 6.00 (s, 2H), 6.47 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H),
7.06 (d, J = 7.8 Hz, 1H), 7.13–7.16 (m, 1H), 7.24–7.28
(m, 1H), 7.43–7.51 (m, 2H), 7.57 (dd, J = 8.2, 1.5 Hz,
1H), 8.2 (br s, 1H) ppm; 13C NMR (62.5 MHz, CDCl3):
d = 35.4, 52.6, 56.7, 102.4, 102.5, 108.1, 108.5, 111.3,
120.8, 123.2, 124.7, 125.4, 128.3, 129.8, 131.2, 134.9,
148.5, 152.4, 170.3, 193.1 ppm; HRMS (ESI?): m/z calcd.
for C20H18NO5 352.1185 ([M?H]?), found 352.1217.
ꢀ
Yield: 70 %; colorless oil; IR (ATR): m = 3,413, 1,728,
1
1,709, 1,516, 1,438, 1,266, 1,217, 1,171, 838 cm-1; H
NMR (250 MHz, CDCl3): d = 0.97 (t, J = 7.0 Hz, 3H),
2.21–2.62 (m, 2H), 3.07 (d, J = 7.6 Hz, 2H), 3.66 (s, 3H),
3.74 (t, J = 7.6 Hz, 1H), 5.00 (br s, 1H), 6.70 (d,
J = 8.2 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H) ppm; 13C
NMR (62.5 MHz, CDCl3): d = 7.7, 33.7, 36.5, 52.7, 60.6,
115.7 (2C), 130.2 (2C), 130.3, 154.6, 170.0, 205.9 ppm.
Methyl 2-benzyl-3-(4-chlorophenyl)-3-oxopropanoate
Methyl 2-[(4-hydroxyphenyl)methyl]-3-(4-nitrophenyl)-3-
(5h, C17H15ClO3)
oxopropanoate (5c, C17H15NO6)
ꢀ
Yield: 75 %; colorless viscous oil; IR (ATR): m = 1,738,
ꢀ
Yield: 96 %; orange oil; IR (ATR): m = 3,443, 1,737,
1,693, 1,605, 1,527, 1,527, 1,438, 1,347, 1,320, 1,231,
1,681, 1,589, 1,274, 1,233, 1,091, 831 cm-1 1H NMR
;
(250 MHz, CDCl3): d = 3.31 (dd, J = 7.4, 1.7 Hz, 2H),
3.63 (s, 3H), 4.59 (t, J = 7.4 Hz, 1H), 7.16–7.24 (m, 5H),
7.38 (d, J = 6.8 Hz, 2H), 7.86 (d, J = 6.8 Hz, 2H) ppm;
13C NMR (62.5 MHz, CDCl3): d = 34.9, 52.8, 56.0, 126.9,
128.7 (2C), 129.0 (2C), 129.2 (2C), 130.2 (2C), 134.6,
138.3, 140.3, 169.6, 193.4 ppm.
736 cm-1 1H NMR (250 MHz, CDCl3): d = 3.26 (d,
;
J = 7.3 Hz, 2H), 3.64 (s, 3H), 4.57 (t, J = 7.3 Hz, 1H),
4.98 (s, 1H), 6.69 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz,
2H), 8.02 (d, J = 8.8 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H)
ppm; 13C NMR (62.5 MHz, CDCl3): d = 34.1, 53.1, 56.9,
115.8 (2C), 124.1 (2C), 129.8 (2C), 129.9, 130.3 (2C),
140.9, 150.7, 154.7, 169.3, 193.7 ppm.
General procedure for the preparation
Methyl 2-benzyl-3-(4-nitrophenyl)-3-oxopropanoate
of the pyrazolones 4a–4h and 6a–6h
(5d, C17H15NO5)
Yield: 76 %; yellow oil; IR (ATR): m = 1,741, 1,694, 1,256,
To a stirred solution of the b-ketoester (1.0 mmol) in 3 cm3
methanol, a catalytic amount of acetic acid (0.1 mmol) was
added. The mixture was allowed to stir for 10 min, and
hydrazine hydrate (5.0 mmol) or phenyl hydrazine hy-
drochloride was added, and the reaction was heated to
reflux and kept stirring for 12 h. After that, the solvent was
evaporated and the crude material was purified using flash
column chromatography (CH2Cl2:MeOH—90:10 v/v) to
yield the corresponding 2,3-dihydro-1H-pyrazol-3-ones
4a–4h and 6a–6h.
ꢀ
1
1,346, 1,229, 863, 852 cm-1; H NMR (250 MHz, CDCl3):
d = 3.35 (d, J = 7.4 Hz, 2H), 3.67 (s, 3H), 4.64 (t,
J = 7.4 Hz, 1H), 7.16–7.29 (m, 5H), 8.04 (d, J = 8.7 Hz,
2H), 8.26 (d, J = 8.7 Hz, 2H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 34.7, 52.7, 56.2, 123.8 (2C), 126.8, 128.6 (2C),
128.8(2C), 129.6(2C), 137.7, 140.6, 150.3, 169.0, 193.5 ppm.
Methyl 2-benzyl-3-oxo-3-phenylpropanoate
(5e, C17H16O3)
ꢀ
Yield: 78 %; yellow oil; IR (ATR): m = 3,062, 3,029,
1
2,953, 1,739, 1,686, 1,597, 1,448, 1,267, 948 cm-1; H
4-Methyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-
pyrazol-3-one (4a, C13H16N2O4)
NMR (250 MHz, CDCl3): d = 3.32 (dd, J = 7.4, 2.5 Hz,
2H), 3.58 (s, 3H), 4.67 (t, J = 7.4 Hz, 1H), 7.10–7.22 (m,
5H), 7.35–7.43 (m, 2H), 7.48–7.55 (m, 1H), 7.89–7.98 (m,
2H) ppm; 13C NMR (62.5 MHz, CDCl3): d = 34.9, 52.5,
55.9, 126.7, 128.6 (2C), 128.7 (2C), 128.8 (2C), 128.9
(2C), 133.6, 136.1, 138.4, 169.7, 194.5 ppm.
Yield: 65 %; white solid; m.p.: 110–112 °C; IR (ATR):
mꢀ = 3,054, 2,926, 2,853, 1,590, 1,508, 1,415, 1,265,
1,127 cm-1 1H NMR (250 MHz, MeOH-d4): d = 2.07
;
(s, 3H), 3.80 (s, 3H), 3.88 (s, 6H), 6.82 (s, 2H) ppm; 13C
NMR (62.5 MHz, MeOH-d4): d = 7.8, 56.9 (2C), 61.3,
98.7, 105.9 (2C), 128.2, 139.5, 144.4, 154.9 (2C),
163.1 ppm; HRMS (ESI?): m/z calcd. for C13H17N2O4
265.1188 ([M?H]?), found 265.1177.
Methyl 2-[(4-hydroxyphenyl)methyl]-3-oxo-3-(thien-2-yl)-
propanoate (5f, C15H14O4S)
ꢀ
Yield: 80 %; yellow oil; IR (ATR): m = 3,410, 1,736, 1,657,
1,519, 1,412, 1,242, 733 cm-1 1H NMR (250 MHz,
;
5-(4-Methoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrazol-3-
one (4b, C11H12N2O2)
CDCl3): d = 3.23 (dd, J = 7.2, 2.1 Hz, 2H), 3.63 (s, 3H),
4.42 (t, J = 7.2 Hz, 1H), 5.99 (br s, 1H), 6.68 (d,
J = 8.2 Hz, 2H), 6.98–7.12 (m, 3H), 7.64 (d, J = 4.8 Hz,
Yield: 74 %; yellow solid; m.p.: 178–180 °C; IR (ATR):
ꢀ
m = 3,251, 3,054, 2,964, 2,841, 1,682, 1,610, 1,517, 1,265,
123

1568
R. C. Barcelos et al.
838 cm-1; 1H NMR (250 MHz, TFA-d): d = 2.00 (s, 3H),
3.84 (s, 3H), 7.02 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz,
2H) ppm; 13C NMR (62.5 MHz, TFA-d): d = 7.2, 57.7,
102.3, 117.6 (2C), 122.0, 131.9 (2C), 150.5, 158.4,
163.4 ppm; HRMS (ESI?): m/z calcd. for C11H13N2O2
205.0977 ([M?H]?), found 205.1021.
4-Methyl-5-phenyl-2,3-dihydro-1H-pyrazol-3-one
(4g, C10H10N2O)
Yield: 78 %; white solid; m.p.: 203–205 °C; IR (ATR):
mꢀ = 3,270, 2,923, 2,854, 1,730, 1,598, 1,507, 1,159,
1
766 cm-1; H NMR (250 MHz, DMSO-d6): d = 1.99 (s,
3H), 3.35 (br s, 1H), 7.28–7.38 (m, 1H), 7.40–7.49 (m, 2H),
7.50–7.58 (m, 2H) ppm; 13C NMR (62.5 MHz, DMSO-d6):
d = 7.6, 95.9, 126.3 (2C), 127.4, 128.7 (2C), 131.1, 139.5,
160.2 ppm; HRMS (ESI?): m/z calcd. for C10H11N2O
175.0871 ([M?H]?), found 175.0822.
5-(2H-1,3-Benzodioxol-5-yl)-4-methyl-2,3-dihydro-1H-
pyrazol-3-one (4c, C11H10N2O3)
Yield: 65 %; white solid; m.p.: 126–128 °C; IR (ATR):
ꢀ
m = 3,224, 2,981, 2,905, 1,712, 1,610, 1,505, 1,457, 1,236,
1,195, 1,038, 816 cm-1 1H NMR (250 MHz, TFA-d):
d = 2.18 (s, 3H), 6.07 (s, 2H), 6.90–7.23 (m, 3H) ppm; 13
4-Methyl-5-(thien-2-yl)-2,3-dihydro-1H-pyrazol-3-one
;
(4h, C8H8N2OS)
Yield: 64 %; brown solid; m.p.: [172.5 °C (dec.); IR
C
NMR (62.5 MHz, TFA-d): d = 6.7, 101.9, 103.9, 109.8,
111.3, 121.7, 125.0, 150.1, 150.6, 152.3, 158.0 ppm;
HRMS (ESI?): m/z calcd. for C11H11N2O3 219.0770
([M?H]?), found 219.0746.
-1
;
ꢀ
(ATR): m = 3,162, 1,665, 1,513, 1,413, 1,258, 1,132 cm
1H NMR (250 MHz, DMSO-d6): d = 2.00 (s, 3H),
7.08–7.17 (m, 1H), 7.28–7.35 (m, 1H), 7.48–7.57 (m,
1H), 10.82 (br s, 1H) ppm; 13C NMR (62.5 MHz, DMSO-
d6): d = 7.6, 95.8, 124.0, 125.4, 127.7, 133.2, 135.5,
159.3 ppm; HRMS (ESI?): m/z calcd. for C8H9N2OS
181.0436 ([M?H]?), found 181.0438.
5-(4-Bromophenyl)-4-methyl-2,3-dihydro-1H-pyrazol-3-
one (4d, C10H19BrN2O)
Yield: 70 %; white solid; m.p.: 127–129 °C; IR (ATR):
ꢀ
m = 2,926, 2,711, 1,667, 1,610, 1,443, 1,209, 1,187, 1,187,
1,137, 1,008, 830 cm-1 1H NMR (250 MHz, TFA-d):
;
4-Benzyl-5-(4-methoxyphenyl)-2,3-dihydro-1H-pyrazol-3-
one (6a, C17H16N2O2)
d = 2.07 (s, 3H), 7.35 (d, J = 7.9 Hz, 2H), 7.62 (d,
J = 7.9 Hz, 2H) ppm; 13C NMR (62.5 MHz, TFA-d):
d = 6.8, 102.7, 126.8, 128.5, 131.1 (2C), 134.9 (2C),
149.4, 158.2 ppm; HRMS (ESI?): m/z calcd. for
C10H10BrN2O 252.9977 ([M?H]?), found 252.9948.
Yield: 69 %; white solid; m.p.: 202–204 °C; IR (ATR):
ꢀ
m = 3,435, 1,663, 1,618, 1,513, 1,453, 1,293, 1,251,
1,111 cm-1 1H NMR (250 MHz, DMSO-d6): d = 3.73
;
(s, 3H), 3.81 (s, 2H), 6.96 (d, J = 8.6 Hz, 2H), 7.07–7.29
(m, 5H), 7.40 (d, J = 8.6 Hz, 2H), 10.94 (br s, 1H) ppm;
13C NMR (62.5 MHz, DMSO-d6): d = 27.6, 55.2, 99.0,
114.3 (2C), 123.3, 125.7, 127.9 (2C), 127.9 (2C), 128.3
(2C), 140.2, 141.6, 159.0, 160.8 ppm; HRMS (ESI?): m/z
calcd. for C17H17N2O2 281.1290 ([M?H]?), found
281.1282.
4-Methyl-5-(4-nitrophenyl)-2,3-dihydro-1H-pyrazol-3-one
(4e, C10H9N3O3)
Yield: 95 %; yellow solid; m.p.: [255.4 °C (dec.); IR
ꢀ
(ATR): m = 3,364, 1,599, 1,507, 1,350, 1,335, 1,145,
852 cm-1 1H NMR (250 MHz, TFA-d): d = 2.12 (s,
;
3H), 7.76 (d, J = 8.5 Hz, 2H), 8.39 (d, J = 8.5 Hz, 2H)
ppm; 13C NMR (62.5 MHz, TFA-d): d = 6.9, 104.3,
126.8 (2C), 131.6 (2C), 135.1, 147.4, 151.3, 158.5 ppm;
HRMS (ESI?): m/z calcd. for C10H10N3O3 220.0722
([M?H]?), found 220.0737.
5-(2H-1,3-Benzodioxol-5-yl)-4-(1H-indol-5-ylmethyl)-2,3-
dihydro-1H-pyrazol-3-one (6b, C19H15N3O3)
ꢀ
Yield: 80 %; brown oil; IR (ATR): m = 3,420, 2,255,
1
2,128, 1,662, 1,506, 1,455, 1,293, 1,235, 1,152 cm-1; H
NMR (250 MHz, DMSO-d6): d = 3.89 (s, 2H), 5.89 (s,
2H), 6.33 (s, 1H), 6.91–7.02 (m, 4H), 7.26–7.33 (m, 3H)
ppm; 13C NMR (62.5 MHz, DMSO-d6): d = 27.6, 100.1,
100.8, 101.2, 106.9, 108.6, 111.2, 118.6, 120.3, 121.7,
125.0, 125.3, 127.9, 131.7, 134.5, 140.1, 146.9, 147.6,
160.7 ppm; HRMS (ESI?): m/z calcd. for C19H16N3O3
334.1192 ([M?H]?), found 334.1182.
4-Methyl-5-(4-nitrophenyl)-2-phenyl-2,3-dihydro-1H-
pyrazol-3-one (4f, C16H13N3O3)
Yield: 50 %; yellow solid; m.p.: 167–169 °C; IR (ATR):
ꢀ
m = 3,014, 1,621, 1,558, 1,512, 1,457, 1,340, 1,275,
1,105, 859 cm-1 1H NMR (250 MHz, DMSO-d6):
;
d = 2.17 (s, 3H), 7.25–7.37 (m, 1H), 7.49 (t,
J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.99 (d,
J = 8.8 Hz, 2H), 8.27 (d, J = 8.8 Hz, 2H), 10.99 (br s,
1H) ppm; 13C NMR (62.5 MHz, DMSO-d6): d = 5.4,
93.5, 118.6, 120.8 (2C), 123.2, 124.4, 125.9 (2C), 135.6,
137.8, 143.3, 143.4, 147.8 ppm; HRMS (ESI?): m/z
calcd. for C16H14N3O3 296.1035 ([M?H]?), found
296.1059.
4-[(4-Hydroxyphenyl)methyl]-5-(4-nitrophenyl)-2,3-
dihydro-1H-pyrazol-3-one (6c, C16H13N3O4)
Yield: 73 %; yellow solid; m.p.: [285.4 °C (dec.); IR
ꢀ
(ATR): m = 3,437, 3,307, 1,599, 1,589, 1,541, 1,514,
1,505, 1,330, 1,209, 857 cm-1
;
1H NMR (250 MHz,
TFA-d): d = 3.93 (s, 2H), 6.87 (d, J = 8.5 Hz, 2H), 7.06
123

Morita–Baylis–Hillman adducts
1569
(d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 8.37 (d,
J = 8.8 Hz, 2H) ppm; 13C NMR (62.5 MHz, TFA-d):
d = 27.7, 107.6, 118.0 (2C), 126.5 (2C), 131.3 (2C), 131.8
(2C), 133.5, 134.8, 147.9, 151.3, 154.6, 158.6 ppm; HRMS
(ESI?): m/z calcd. for C16H14N3O4 312.0984 ([M?H]?),
found 312.0991.
4-Benzyl-5-(4-chlorophenyl)-2,3-dihydro-1H-pyrazol-3-
one (6h, C16H13ClN2O)
Yield: 70 %; white solid; m.p.: 188–190 °C; IR (ATR):
mꢀ = 1,702, 1,613, 1,516, 1,229, 1,090, 836 cm-1; 1H NMR
(250 MHz, MeOH-d4): d = 3.83 (s, 2H), 7.08–7.24 (m,
5H), 7.30–7.37 (m, 4H) ppm; 13C NMR (62.5 MHz,
MeOH-d4): d = 28.7, 102.4, 127.0, 129.2 (2C), 129.5
(2C), 129.9 (2C), 130.0 (2C), 130.8, 135.5, 142.5, 143.4,
162.7 ppm; HRMS (ESI?): m/z calcd. for C16H14ClN2O
285.0795 ([M?H]?), found 285.0787.
4-Benzyl-5-(4-nitrophenyl)-2,3-dihydro-1H-pyrazol-3-one
(6d, C16H13N3O3)
Yield: 75 %; yellow solid; m.p.: [199.4 °C (dec.); IR
ꢀ
(ATR): m = 3,394, 1,600, 1,513, 1,347, 1,210, 1,110,
855 cm-1 1H NMR (250 MHz, TFA-d): d = 3.86 (s,
;
Acknowledgments The authors thank the Sa˜o Paulo Research
Foundation (FAPESP) and the Brazilian Council for Scientific and
Technological Development (CNPq) for financial support. We also
thank FAPESP for a post-doctoral fellowship to RCB (process
FAPESP 2012/24783-1) and CNPq for fellowships to MTRJr and
LAZ.
2H), 6.94–7.21 (m, 5H), 7.58 (d, J = 7.7 Hz, 2H), 8.23 (d,
J = 7.7 Hz, 2H) ppm; 13C NMR (62.5 MHz, TFA-d):
d = 28.6, 107.6, 126.6 (2C), 129.3, 129.8 (2C), 131.1 (2C),
131.9 (2C), 134.8, 139.4, 148.0, 151.3, 158.7 ppm; HRMS
(ESI?): m/z calcd. for C16H14N3O3 296.1035 ([M?H]?),
found 296.0969.
References
4-Benzyl-5-phenyl-2,3-dihydro-1H-pyrazol-3-one
(6e, C16H14N2O)
1. Baumanan M, Baxendale IR, Ley SV, Nikbin N (2011) Beilstein
J Org Chem 7:442
2. Varvounis G, Fiamegos Y, Pilidis G (2008) Adv Heterocycl
Chem 95:27
Yield: 76 %; white solid; m.p.: [183.5 °C (dec.); IR
ꢀ
(ATR): m = 3,060, 3,027, 2,924, 1,589, 1,513, 1,451,
1,211, 1,114, 808 cm-1 1H NMR (250 MHz, TFA-d):
;
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d = 3.81 (s, 2H), 6.92–7.19 (m, 5H), 7.24–7.46 (m, 5H)
ppm; 13C NMR (62.5 MHz, DMSO-d6): d = 27.6, 99.5,
125.6, 126.4 (2C), 127.8, 127.8 (2C), 128.2 (2C), 128.8
(2C), 130.8, 140.2, 141.4, 160.6 ppm; HRMS (ESI?): m/z
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251.1159.
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Yield: 60 %; yellow solid; m.p.: [240.4 °C (dec.); IR
ꢀ
(ATR): m = 3,100, 2,915, 2,848, 1,616, 1,591, 1,511,
1,436, 1,240, 711 cm-1 1H NMR (250 MHz, TFA-d):
;
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d = 4.03 (s, 2H), 6.90 (d, J = 8.4 Hz, 2H), 7.09–7.21 (m,
3H), 7.46 (d, J = 4.0 Hz, 1H), 7.61 (d, J = 4.0 Hz, 1H)
ppm; 13C NMR (62.5 MHz, TFA-d): d = 28.0, 105.5,
117.9 (2C), 127.5, 130.3, 131.4 (2C), 132.1, 132.4, 133.6,
145.1, 154.4, 158.5 ppm; HRMS (ESI?): m/z calcd. for
C14H13N2O2S 273.0698 ([M?H]?), found 273.0694.
5-Ethyl-4-[(4-hydroxyphenyl)methyl]-2,3-dihydro-1H-
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Yield: 92 %; colorless viscous oil; IR (ATR): m = 1,700,
1,587, 1,514, 1,431, 1,382, 1,250, 827 cm-1 1H NMR
;
(250 MHz, TFA-d): d = 1.16 (td, J = 7.6, 1.2 Hz, 3H),
2.64 (q, J = 7.6 Hz, 2H), 3.74 (s, 2H), 6.86 (d, J = 7.8 Hz,
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TFA-d): d = 12.7, 20.6, 27.7, 105.8, 118.2 (2C), 131.7
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219.1163.
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