Chemodivergent, multicomponent domino reactions in aqueous media: L-proline-catalyzed assembly of densely functionalized 4H-pyrano[2,3-c]pyrazoles and bispyrazolyl propanoates from simple, acyclic starting materials

Article abstract of DOI:10.1039/c3gc37128j

A library of 4H-pyrano[2,3-c]pyrazol-6-amines was synthesized in excellent yield employing an l-proline-catalyzed, on-water four-component domino reaction from hydrazines, β-dicarbonyl compounds, nitriles and dialkyl acetylenedicarboxylates that generates two rings by the creation of C-C (two), C-N, CN and C-O bonds and presumably involves a sequence of hydrazone formation, cyclocondensation, Michael, [1,3]-hydrogen shift, Michael addition and 6-exo-dig annulation steps. When alkyl propiolates were employed, a three-component reaction took place furnishing alkyl 3,3-bis(5-hydroxy-1H- pyrazol-4-yl)propanoates via a double Michael domino process.

Full text of DOI:10.1039/c3gc37128j

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PAPER
Chemodivergent, multicomponent domino reactions
in aqueous media: L-proline-catalyzed assembly of
densely functionalized 4H-pyrano[2,3-c]pyrazoles and
bispyrazolyl propanoates from simple, acyclic starting
materials†
Cite this: Green Chem., 2013, 15, 1292
Pitchaimani Prasanna,a Subbu Perumal*a and J. Carlos Menéndez*b
A library of 4H-pyrano[2,3-c]pyrazol-6-amines was synthesized in excellent yield employing an L-proline-
catalyzed, on-water four-component domino reaction from hydrazines, β-dicarbonyl compounds, nitriles
and dialkyl acetylenedicarboxylates that generates two rings by the creation of C–C (two), C–N, CvN and
C–O bonds and presumably involves a sequence of hydrazone formation, cyclocondensation, Michael,
[1,3]-hydrogen shift, Michael addition and 6-exo-dig annulation steps. When alkyl propiolates were
employed, a three-component reaction took place furnishing alkyl 3,3-bis(5-hydroxy-1H-pyrazol-4-yl)pro-
panoates via a double Michael domino process.
Received 28th December 2012,
Accepted 25th February 2013
DOI: 10.1039/c3gc37128j
www.rsc.org/greenchem
has also become one of the main challenges for organic syn-
thesis,3 and is also of great relevance to green chemistry
Introduction
One of the most important aspects of modern synthetic metho- because of the diminished generation of waste from organic
dology is the need to develop methods with a low environ- solvents and chromatographic stationary phases associated
mental impact. Taking into account that organic solvents are with a lower number of intermediate purification steps. In this
the main source of waste from synthetic work, the develop- context, multicomponent reactions (MCRs)4 have emerged as a
ment of methods with diminished use of organic solvents is of powerful tool to achieve synthetic efficiency, as they have
high priority. Water is the reaction medium used by nature in unique advantages such as convergence, operational simpli-
all biosynthetic routes, and has the advantage of being abun- city, facile automation, flexibility, and pot, atom and step
dantly available, non-hazardous, non-flammable, redox-stable economy (PASE),5 besides diminished waste generation. MCRs
and cheap. Consequently, water is close to being an ideal enable the expedient assembly of structurally complex mole-
green solvent, preferable to alternatives such as ionic liquids.1 cules and also furnish structurally diverse libraries of drug-like
In addition, water facilitates novel solvation and molecular molecules,6,7 thereby playing a pivotal role in lead identifi-
assembly processes leading to remarkable modes of reactivity cation and optimization processes in drug discovery pro-
and selectivity.2
grammes.8 Another approach to the generation of molecular
On the other hand, the development of synthetic methods diversity involves the use of chemodivergent reactions, which
able to yield molecular diversity and complexity from simple give differentiated products upon subtle changes in the reac-
and inexpensive starting materials via the generation of several tion conditions or in the structure of the starting materials
bonds in a single synthetic operation, ideally in a single step, and are thus of interest for the rapid preparation of structu-
rally diverse organic compounds. However, chemodivergent
multicomponent reactions are almost unknown in the litera-
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj
ture.9 Furthermore, the development of multicomponent reac-
University, India. E-mail: subbu_perum@rediffmail.com
tions in aqueous environments is a recent endeavour that has
received relatively little attention.10,11
bDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@farm.ucm.es;
Fax: +34 91 3941840; Tel: +34 91 3941822
The dihydropyrano[2,3-c]pyrazole scaffold represents an
interesting template in medicinal chemistry, and its derivatives
possess useful biological and pharmacological properties.12
The methods available for the synthesis of dihydropyrano-
†Electronic supplementary information (ESI) available: Copies of 1H- and
13C-NMR spectra of all compounds, 2D-NMR and HRMS spectra for selected
compounds and X-ray diffraction data for compounds 5g and 7a. CCDC 896612
and 894543. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3gc37128j
[2,3-c]pyrazoles include
a
two-component reaction of
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pyrazolones with aldehydes in the presence of tetrabutylam-
monium hydrogen sulfate in acetonitrile or xylene13 and three-
component reactions of (i) 1H-pyrazol-5(4H)-one, malononi-
trile and aldehydes,14 or substituted piperidin-4-ones.15 Four-
component reactions of unsubstituted hydrazines, β-keto
esters, malononitrile or ethyl cyanoacetate and aldehydes16 or
ketones are also known.17 However, these methods lack gener-
ality and do not allow the presence of functional groups at
certain positions such as C-4, thus restricting the possibility of
generating molecular diversity from the MCR products.
Fig. 1 Structure of compound 5a, synthesized during the optimization studies.
Table 1 Optimization of the synthesis of compound 5aa
In this context, in the present paper we describe work that
proves that the L-proline catalyzed multicomponent reaction in
water between phenylhydrazines, β-ketoesters and acetylene
mono- or dicarboxylates in the presence of activated nitriles
follows two chemodivergent pathways, depending on the struc-
ture of the acetylene component. The choice of acetylene-
derived esters as electrophiles was motivated by the highly
functionalized nature of the products arising from them,
which will facilitate their future use in diversity-oriented syn-
thesis. The present work forms a part of our ongoing research
programme on the development of novel multi-component
and domino reactions for the construction of biologically
important heterocyclic ring systems.10b,18 The choice of
L-proline as the catalyst was based on the fact that it is an eco-
friendly and abundantly available bifunctional organocatalyst
capable of playing multiple catalytic roles as an acid, base, or
nucleophile, forming enamine and iminium cations. Being
amphoteric and soluble in water, it also facilitates chemical
transformations in concert, similar to enzymatic catalysis, and
in fact L-proline has been described as “the smallest
Reaction
time (h)
Yield of 5ab
(%)
Entry
Additive
Solvent
1
2
3
4
5
6
7
8
Et3N
Water
Water
Water
Water
Water
Water
Water
Water
Water
EtOH
MeOH
CH3CN
DMF
6
5
5
6
6
7
7
6
3
5
6
8
6
5
8
10
12
7
10
10
78
73
71
68
63
59
54
64
97
66
64
56
62
73
0
Methylamine
Benzylamine
Pyrrolidine
Piperidine
DBU
DABCO
K2CO3
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
None
9
10
11
12
13
14
15
16
17
18
19
20
Nonec
Water
Water
Water
Water
Water
Water
PPTS
58
10
70
0d
0d
Et3N/CF3CO2H
Pyrrolidine/HCO2H
TsOH
CH3CO2H
enzyme”.19 The versatile catalytic ability of L-proline is a All reactions carried out with ethyl acetoacetate (1 mmol),
phenylhydrazine (1 mmol), diethyl acetylenedicarboxylate (1 mmol),
reflected in its applications in diverse organic transformations
malononitrile (1 mmol) and a catalyst (0.3 eq. for L-proline, 1 eq. for
such as aldol20 and Knoevenagel21 condensations, Michael
other additives) in solvents heated to reflux. b Yield of the isolated
addition,22 and some multicomponent reactions,23 among product. c This reaction was performed at 100 °C. d 3-Methyl-1-phenyl-
2-pyrazolin-5-one (intermediate I in Scheme 3) was obtained in these
cases (42% and 95% yield, respectively).
others.
Results and discussion
was sufficient to enable the reaction to go to completion in 3 h
affording an excellent yield of 97%, rendering the process cata-
lytic with respect to the base (Table 1, entry 9). When the same
reagents were mixed in other solvents such as ethanol (entry
10), methanol (entry 11), acetonitrile (entry 12) and N,N-
dimethylformamide (entry 13), as well as under solvent-free
conditions (entry 14), lower yields of the product were
observed. These observations led to the conclusion that water
is the solvent of choice for this proline-promoted transform-
ation, although a control experiment proved that water alone
cannot promote the reaction (entry 15). One clear advantage of
the L-proline–water combination was that it afforded products
that could be rendered very pure by simple recrystallization
from ethanol or by filtration through a pad of silica gel. In
order to provide additional data for the mechanistic discussion
(see below), we also examined the role of three equimolecular
base/acid combinations, which may be viewed as related to
proline in that the latter simultaneously contains carboxylic
We began our study with the optimization of the four-com-
ponent reaction in water between equimolecular amounts of
ethyl acetoacetate, phenylhydrazine, diethyl acetylenedicarboxy-
late and malononitrile. This reaction was initially carried out
in the presence of 1 eq. of triethylamine under reflux for 6 h,
and afforded ethyl 6-amino-5-cyano-4-(2-ethoxy-2-oxoethyl)-3-
methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-4-carboxylate
5a (Fig. 1).
This model reaction afforded compound 5a in 78% yield
(Table 1, entry 1). It was also investigated employing as bases
equimolecular amounts of other amines, including methyl-
amine (entry 2), benzylamine (entry 3), pyrrolidine (entry 4),
and piperidine (entry 5), with similar results in all cases. The
yield was slightly lower when DBU (entry 6) or DABCO (entry 7)
was employed, and did not improve upon use of potassium
carbonate (entry 8). Interestingly, when L-proline was used, the
reactivity was much improved, since 30 mol% of the additive
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Fig. 2 Selected 1H and 13C chemical shifts and summary of the HMBC experi-
ments performed on 5a.
a
series of 3-alkyl-1-aryl-1,4-dihydropyrano[2,3-c]pyrazol-6-
amines 5a–5i in excellent yield.
The structure of compounds 5 was established from one-
and two-dimensional NMR spectroscopic data, as illustrated in
Fig. 2 for compound 5a as a representative example. The 1H
NMR spectrum of 5a has a singlet at 2.30 ppm, ascribable to
methyl hydrogens at C-3. The diastereotopic 1′-CH2 hydrogens
appear as doublets at 3.10 and 3.20 ppm (J = 15.3 Hz). These
assignments are evident from the HMBCs of diastereotopic
proton, (H-1′) with (i) the carbonyl carbon at 169.2 ppm, (ii)
the quaternary carbon C-4 at 44.7 ppm and (iii) C-5 and C-3a
at 62.1 and 95.5 ppm respectively. The methyl hydrogens at
C-3 also show HMBCs with C-3 and C-3a at 145.7 and
95.5 ppm respectively. The NH2 protons appear as a singlet at
5.12 ppm, which shows HMBCs with C-6 and C-5 at 143.9 and
62.1 ppm respectively. Finally, the conclusions obtained by
NMR were confirmed by X-ray diffraction of a single crystal of
compound 5g (Fig. 3). Because of the chiral nature of L-Pro, we
wished to ascertain whether there was any enantiodifferentia-
tion in the formation of compounds 5. However, all of them
failed to show any measurable optical rotation, and analysis of
representative compounds 5a and 5f using a chiral HPLC
column showed them to be racemic. Not unexpectedly in view
of this lack of enantioselection, D-proline and racemic proline
in water under reflux for 3 h led to identical yields of racemic
5a (93% and 90%).
Scheme 1 Four-component synthesis of 4H-pyrano[2,3-c]pyrazole deriva-
tives 5.
and amino functions. An equimolecular mixture of pyridine
and toluenesulfonic acid (PPTS) gave 58% of compound 5a
(entry 16). While a mixture of triethylamine and trifluoroacetic
acid gave a poor result (entry 17), the pyrrolidine–formic acid
combination, which is more closely related to proline, afforded
a respectable 70% yield (entry 18), although a longer reaction
time (7 h) and one equivalent of this mixture were needed.
Purely acidic additives, such as toluenesulfonic acid and acetic
acid, did not afford compound 5a, but instead gave the pyrazo-
linone derivative arising from condensation between phenyl-
hydrazine and ethyl acetoacetate.
After determining the optimal conditions, the scope of the
reaction was further examined. As shown in Scheme 1 and
Table 2, the four-component reactions of ethyl acetoacetate
or ethyl 3-oxohexanoate 1 (1 mmol), phenylhydrazines 2
(1 mmol), dialkyl acetylenedicarboxylates 3 (1 mmol) and mal-
ononitrile or ethyl cyanoacetate 4 (1 mmol) in the presence of
L-proline (0.3 mmol) in water under reflux for 3–3.5 h afforded
During our studies on the scope of the reaction, we found
that replacement of dialkyl acetylenedicarboxylates 3 by ethyl
Table 2 One-pot, four-component synthesis of 3-alkyl-1-aryl-1,4-dihydropyr-
ano[2,3-c]pyrazol-6-amines 5a
Time Yieldb
Cmpd.
R
R1
R2
R3
(h)
(%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
CH3
CH3
CH3
CH3
C2H5 CN
CH3 CN
3.0
3.0
97
94 (87)
92
93 (86)
97
95
96
92 (83)
90 (85)
C2H5 CO2Et 3.5
CH3 CO2Et 3.5
C2H5 CN 3.0
CH3 CO2Et 3.5
CH2CH2CH3 CH3 CN 3.0
CO2Et 3.5
CN 3.5
2,5-(CH3)2 CH3
4-Cl
H
4-F
4-F
CH3
CH3
CH3
CH3
CH3
a All reactions carried out with ethyl acetoacetate (1 mmol),
phenylhydrazine (1 mmol), diethyl acetylenedicarboxylate (1 mmol),
malononitrile (1 mmol) and L-proline (0.3 eq.). b Yields after filtration
through a pad of silica gel; in brackets, yields after recrystallization
from ethanol.
Fig. 3 X-Ray diffraction study of compound 5g.
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Fig. 4 X-Ray diffraction structure of compound 7a.
β-ketoester 1 and phenylhydrazine 2, followed by a subsequent
cyclocondensation. A subsequent Michael addition of I to the
acetylenedicarboxylate 3 furnishes intermediate II, which iso-
merizes to III via a [1,3] hydrogen shift. The next step involves
a new Michael addition to the enone system in III, for which
two nucleophiles are available in the reaction medium, namely
a second molecule of I or the activated nitrile 4. Owing to
steric hindrance, in the case of R = CO2Et, III selectively reacts
with the less hindered nucleophile 4 and affords intermediate
IV, which upon annulation with a concomitant tautomeriza-
tion results in the formation of the observed final products 5.
On the other hand, for the case R = H the only observed reac-
tion involves the participation of I as the nucleophile, leading
to intermediate V and then to the observed product 7 by
tautomerism.
In many of these steps, including the initial reaction
between phenylhydrazine and the starting β-ketoester, the
L-proline zwitterion, which is the predominant species in
aqueous solution, can conceivably play dual catalytic roles,
acting as an acid and a base in concert, and this explains the
fact that the other bases investigated for this transformation
were less efficient than L-proline. The greater efficiency of
proline in comparison to the pyrrolidine–formic acid mixture
can be ascribed to entropic factors associated with the pres-
ence of acidic and basic functions in the same molecule.
The greater efficacy of water in this transformation com-
pared to other solvents investigated such as methanol,
ethanol, acetonitrile and DMF suggests that the reactions
described here belong to the “on-water” type,24 which is rather
uncommon for multicomponent reactions25 and involves
hydrogen bonding with the oxygen atom of water molecules
surrounding the suspended oily globules containing the reac-
tants. This type of mechanism also explains the fact that we
have observed some promotion of the reaction by potassium
carbonate (Table 1, entry 8), which is explained by the same
type of association with hydroxide anions present in the
aqueous phase, which are generated by hydrolysis of the car-
bonate anion, and which may assist both the formation of
pyrazolinone intermediate I by deprotonating phenylhydrazine
molecules and the annulation of IV that leads ultimately to the
formation of 5 (Scheme 3).
Scheme 2 Synthesis of 3,3-bis(1H-pyrazol-4-yl)propanoate derivatives 7.
propiolate led to the exclusive formation of ethyl 3,3-bis-
(5-hydroxy-3-alkyl-1-phenyl-1H-pyrazol-4-yl)propanoate 7a in
good yield, revealing that in this case the activated nitrile was
excluded from the multicomponent process. Indeed, the same
result was obtained when malononitrile was not added to the
reaction mixture. This observation led us to synthesize a small
library of compounds 7 from the pseudo-five component reac-
tions of ethyl acetoacetate or ethyl 3-oxohexanoate 1 (2 mmol),
phenylhydrazines 2 (2 mmol) and methyl propiolate or ethyl
propiolate 6 (1 mmol) in the presence of L-proline (30 mol%),
in water under reflux for 3–3.5 h (Scheme 2 and Table 3).
The structure of compounds 7 was confirmed by the X-ray
diffraction study of a single crystal of 7a (Fig. 4). It is interest-
ing to note that, against the behavior normally observed for
2-pyrazolin-5-ones, both pyrazole rings in 7a are in the lactim
tautomeric form, which is presumably stabilized by intramole-
cular hydrogen bonding.
A plausible mechanism for the formation of compounds 5
and 7 is depicted in Scheme 3. The first reaction, common to
both mechanisms, probably involves the generation of pyrazo-
lone I by the formation of a hydrazone from the starting
Table 3 Synthesis of alkyl 3,3-bis(5-hydroxy-3-alkyl-1-phenyl-1H-pyrazol-4-yl)-
propanoates 7a
Cmpd.
R
R1
R2
Time (h)
Yieldb (%)
5a
5b
5c
5d
5e
H
H
Cl
Cl
H
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
C2H5
CH3
3.0
3.0
3.5
3.5
3.0
95 (86)
96
94
91
96
CH2CH2CH3
a All reactions carried out with ethyl acetoacetate (1 mmol),
phenylhydrazine (1 mmol), diethyl acetylenedicarboxylate (1 mmol),
malononitrile (1 mmol) and L-proline (0.3 eq.). b Yields after filtration
through a pad of silica gel; in brackets, yields after recrystallization
from ethanol.
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Scheme 3 Mechanistic rationalization of the processes leading to compounds 5 and 7.
scale) and coupling constants are given in hertz. Silica gel-G
plates (Merck) were used for TLC analysis with a mixture of
Conclusions
In conclusion, the present work describes eco-friendly multi- petroleum ether (60–80 °C) and ethyl acetate as an eluent.
component protocols for the synthesis in excellent yields of Elemental analyses were performed on a Perkin Elmer 2400
3-alkyl-1-aryl-1,4-dihydropyrano[2,3-c]pyrazol-6-amines by the Series II Elemental CHNS analyzer. HRMS measurements were
creation of two rings and two C–C, one C–N, one CvN and performed by the CAI de Espectrometría de Masas, Universi-
one C–O bonds, or alkyl 3,3-bis(5-hydroxy-3-alkyl-1-phenyl-1H- dad Complutense, using an FTMS Bruker APEX QIV instru-
pyrazol-4-yl)propanoates by the generation of two rings and ment. Optical rotation values were measured using an
two C–C, two C–N and two CvN bonds, employing water as AUTOPOL-IV digital polarimeter (readability 0.001°). HPLC
the reaction medium and L-proline as the catalyst. This new analyses were performed on an SCL-10ATVP SHIMADZU
methodology is endowed with advantages such as short reac- instrument. Compounds 5a and 5f were analyzed using a
tion time, excellent yields and ease of operation. Our study chiral cell OD-H column using hexane/2-propanol as an
also discloses a subtle dependence of the product-selectivity of eluent.
the reactions on the nature of the alkyne component
employed, which renders these processes one of the rare cases
General procedure for the synthesis of 3-alkyl-1-aryl-1,4-
of chemodivergent multicomponent reactions performed in an
dihydropyrano[2,3-c]pyrazol-6-amines 5a–5i
aqueous reaction medium.
A mixture of ethyl acetoacetate or ethyl 3-oxohexanoate (1)
(1 mmol), phenylhydrazines (2) (1 mmol), dialkyl acetylene-
dicarboxylates (3) (1 mmol), malononitrile or ethyl cyanoace-
Experimental section
tate (4) (1 mmol) and L-proline (30 mol%) in water (5 mL) was
Melting points were measured in open capillary tubes and are heated under reflux for 3.0–3.5 h. After completion of the reac-
uncorrected. The 1H NMR, 13C NMR, H,H-COSY, C,H-COSY tion (TLC), the solid that separated was filtered, washed with
and HMBC spectra were recorded on a Bruker (Avance) water and purified by recrystallization from ethanol (com-
300 MHz NMR instrument using TMS as an internal standard pounds 5b, 5d, 5h, 5i) or by filtration through a pad of silica
and CDCl3 as solvent. Standard Bruker software was used gel using petroleum ether–ethyl acetate (7 : 3 v/v). Characteri-
throughout. Chemical shifts are given in parts per million (δ zation data for compounds 5 are given below.
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Ethyl 6-amino-5-cyano-4-(2-ethoxy-2-oxoethyl)-3-methyl-
Ethyl 6-amino-5-cyano-1-(2,5-dimethylphenyl)-4-(2-ethoxy-
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-4-carboxylate (5a)
2-oxoethyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-4-
carboxylate (5e)
Yield, 398 mg (97%) after silica gel filtration. Colorless solid,
1
mp 112–113 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.09 (t, J = Yield, 426 mg (97%) after silica gel filtration. Colorless solid,
7.1 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.11 (d, J = mp 152–153 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.13–1.17
1
15.3 Hz, 1H), 3.20 (d, J = 15.3 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), (m, 3H), 1.28–1.33 (m, 3H), 2.08 (s, 3H), 2.28 (s, 3H), 2.34 (s,
4.26 (q, J = 7.2 Hz, 2H), 5.13 (s, 2H, NH2), 7.28–7.31 (m, 1H), 3H), 3.08–3.24 (m, 2H), 4.02 (q, J = 6.8 Hz, 2H), 4.23–4.30 (m,
7.42 (t, J = 7.7 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H); 13C NMR 2H), 4.84 (s, 2H, NH2), 7.10–7.27 (m, 3H); 13C NMR (75 MHz,
(75 MHz, CDCl3, δ ppm): 13.7, 13.9, 14.0, 40.3, 44.7, 60.4, 62.1, CDCl3, δ ppm): 13.7, 14.0, 14.1, 16.8, 20.6, 40.3, 44.9, 60.4,
62.5, 95.5, 117.7, 121.3, 126.9, 129.2, 137.3, 144.0, 145.7, 159.8, 62.4, 94.0, 117.8, 128.0, 129.6, 130.2, 130.8, 132.3, 135.2, 136.6,
169.2, 170.8; Anal. Calcd for C21H22N4O5: C, 61.45; H, 5.40; N, 144.8, 145.3, 159.8, 169.2, 170.9. HRMS (ESI): Calcd for
13.65. Found: C, 61.56; H, 5.47; N, 13.56.
C23H26N4O5Na (M+ + Na): 461.18009. Found: 461.17954. Anal.
Calcd for C23H26N4O5: C, 63.00; H, 5.98; N, 12.78. Found: C,
63.08; H, 5.87; N, 12.90.
Methyl 6-amino-5-cyano-4-(2-methoxy-2-oxoethyl)-3-methyl-
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-4-carboxylate (5b)
5-Ethyl 4-methyl 6-amino-1-(4-chlorophenyl)-4-(2-methoxy-
2-oxoethyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-4,5-
dicarboxylate (5f)
Yield, 359 mg (94%) after silica gel filtration or 332 mg (87%)
after recrystallization from ethanol. Colorless solid, mp
1
198–199 °C. H NMR (300 MHz, CDCl3, δ ppm): 2.28 (s, 3H),
Yield, 441 mg (95%) after silica gel filtration. Colorless solid,
3.14 (d, J = 15.9 Hz, 1H), 3.23 (d, J = 15.9 Hz, 1H), 3.58 (s, 3H),
3.80 (s, 3H), 5.04 (s, 2H, NH2), 7.27–7.33 (m, 1H), 7.43 (t, J =
7.8 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3,
δ ppm): 13.6, 40.0, 44.7, 51.7, 53.3, 62.1, 95.5, 117.7, 121.5,
127.0, 129.2, 137.3, 144.0, 145.5, 159.8, 169.6, 171.3; Anal.
Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C,
59.59; H, 4.62; N, 14.76.
1
mp 219–220 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.26 (t, J =
7.1 Hz, 3H), 2.20 (s, 3H), 3.23 (d, J = 15.9 Hz, 1H), 3.31 (d, J =
15.9 Hz, 1H), 3.49 (s, 3H), 3.69 (s, 3H), 4.13–4.27 (m, 2H), 6.77
(s, 2H, NH2), 7.36–7.39 (m, 2H) 7.60–7.63 (m, 2H); 13C NMR
(75 MHz, CDCl3, δ ppm): 13.1, 14.2, 40.2, 44.1, 51.3, 52.6. 60.1,
78.3, 97.9, 122.2, 129.9, 132.1, 136.2, 144.2, 145.4, 160.6, 168.3,
171.1, 173.2. HRMS (ESI): Calcd for
C21H22ClN3O7Na
(M+ + Na): 486.10440 (35Cl) and 488.10145 (37Cl). Found:
486.10385 and 488.10090. Anal. Calcd for C21H22ClN3O7: C,
54.37; H, 4.78; N, 9.06. Found: C, 54.43; H, 4.69; N, 8.99.
Diethyl 6-amino-4-(2-ethoxy-2-oxoethyl)-3-methyl-1-phenyl-
1,4-dihydropyrano[2,3-c]pyrazole-4,5-dicarboxylate (5c)
Yield, 421 mg (92%) after silica gel filtration. Colorless solid,
1
mp 172–173 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.04 (t, J = Methyl 6-amino-5-cyano-4-(2-methoxy-2-oxoethyl)-1-phenyl-
7.1 Hz, 3H), 1.20–1.30 (m, 6H), 2.24 (s, 3H), 3.22 (d, J = 15.0 3-propyl-1,4-dihydropyrano[2,3-c]pyrazole-4-carboxylate (5g)
Hz, 1H), 3.30 (d, J = 15.0 Hz, 1H), 3.92 (q, J = 6.9 Hz, 2H),
Yield, 393 mg (96%) after silica gel filtration. Colorless solid,
mp 158–159 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.00 (t, J =
4.10–4.24 (m, 4H), 6.78 (s, 2H, NH2), 7.24–7.29 (m, 1H), 7.41 (t,
J = 7.7 Hz, 2H), 7.64 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3, δ ppm): 13.1, 13.9, 14.0, 14.1, 40.9, 44.4, 59.9, 61.4,
78.4, 97.7, 121.1, 126.5, 129.1, 137.6, 144.0, 145.2, 160.5, 168.5,
170.7, 172.7; Anal. Calcd for C23H27N3O7: C, 60.38; H, 5.95; N,
9.19. Found: C, 60.31; H, 6.05; N, 9.25.
1
7.4 Hz, 3H), 1.64–1.81 (m, 2H), 2.52–2.57 (m, 2H), 3.15 (d, J =
16.2 Hz, 1H), 3.23 (d, J = 15.9 Hz, 1H), 3.56 (s, 3H), 3.78 (s,
3H), 5.10 (s, 2H, NH2), 7.27–7.32 (m, 1H), 7.42 (t, J = 7.8 Hz,
2H), 7.62 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3, δ ppm):
13.9, 21.2, 29.7, 40.0, 44.6, 51.6, 53.2, 61.7, 95.2, 117.7, 121.4,
126.9, 129.1, 137.4, 143.9, 149.0, 160.0, 169.8, 171.6; Anal.
Calcd for C21H22N4O5: C, 61.45; H, 5.40; N, 13.65. Found: C,
61.35; H, 5.46; N, 13.57.
5-Ethyl 4-methyl 6-amino-4-(2-methoxy-2-oxoethyl)-3-methyl-
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-4,5-dicarboxylate (5d)
Yield, 399 mg (93%) after silica gel filtration or 369 mg (86%)
after recrystallization from ethanol. Colorless solid, mp
211–212 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.26 (t, J = 7.1
5-Ethyl 4-methyl 6-amino-1-(4-fluorophenyl)-4-(2-methoxy-
2-oxoethyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
4,5-dicarboxylate (5h)
1
Hz, 3H), 2.22 (s, 3H), 3.23 (d, J = 15.6 Hz, 1H), 3.31 (d, J =
15.6 Hz, 1H), 3.48 (s, 3H), 3.69 (s, 3H), 4.11–4.29 (m, 2H), 6.75 Yield, 412 mg (92%) after silica gel filtration or 371 mg (83%)
(s, 2H, NH2), 7.26–7.30 (m, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.65 (d, after recrystallization from ethanol. Colorless solid, mp
J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3, δ ppm): 13.1, 14.2, 97–98 °C. 1H NMR (300 MHz, CDCl3, δ ppm): 1.25 (t, J =
40.3, 44.2, 51.2, 52.5, 60.0, 78.2, 97.5, 121.3, 126.6, 129.1, 7.2 Hz, 3H), 2.19 (s, 3H), 3.22 (d, J = 16.2 Hz, 1H), 3.30 (d, J =
137.6, 144.1, 145.0, 160.7, 168.4, 171.1, 173.3. HRMS (ESI): 15.9 Hz, 1H), 3.48 (s, 3H), 3.68 (s, 3H), 4.09–4.27 (m, 2H), 6.78
Calcd for C21H23N3O7Na (M+
+
Na): 452.14337. Found: (s, 2H, NH2), 7.06–7.12 (m, 2H) 7.57–7.62 (m, 2H); 13C NMR
452.14282. Anal. Calcd for C21H23N3O7: C, 58.74; H, 5.40; N, (75 MHz, CDCl3, δ ppm): 13.0, 14.2, 40.3, 44.2, 51.2, 52.5, 60.0,
9.79. Found: C, 58.86; H, 5.48; N, 9.69.
78.2, 97.5, 115.8, 116.1, 123.0, 123.1, 133.8, 144.1, 145.0, 159.5,
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160.6, 162.8, 168.3, 171.1, 173.2; Anal. Calcd for C21H22FN3O7: Methyl 3,3-bis(1-(4-chlorophenyl)-5-hydroxy-3-methyl-
C, 56.37; H, 4.96; N, 9.39; Found: C, 56.28; H, 4.90; N, 9.46.
1H-pyrazol-4-yl)propanoate (7c)
Yield, 471 mg (94%) after silica gel filtration. Colorless solid,
mp 128–129 °C. 1H NMR (300 MHz, CDCl3, δ ppm): 2.26 (s,
6H), 3.12 (d, J = 7.8 Hz, 2H), 3.62 (s, 3H), 4.05 (t, J = 7.7 Hz,
1H), 7.26–7.32 (m, 4H), 7.56–7.59 (m, 4H); 13C NMR (75 MHz,
CDCl3, δ ppm): 11.6, 25.6, 36.3, 51.6, 106.0, 122.3, 129.0, 131.7,
135.6, 146.6, 158.1, 172.7. HRMS (ESI): Calcd for
C25H24Cl2N4O4Na (M+ + Na): 537.10723. Found: 537.10668.
Anal. Calcd for C24H22Cl2N4O4: Elemental Analysis: C, 57.49;
H, 4.42; N, 11.17. Found: C, 57.39; H, 4.36; N, 11.26.
Methyl 6-amino-5-cyano-1-(4-fluorophenyl)-4-(2-methoxy-
2-oxoethyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
4-carboxylate (5i)
Yield, 360 mg (90%) after silica gel filtration or 340 mg (85%)
after recrystallization from ethanol. Colorless solid, mp
1
214–215 °C. H NMR (300 MHz, CDCl3, δ ppm): 2.27 (s, 3H),
3.15 (d, J = 15.9 Hz, 1H), 3.23 (d, J = 16.2 Hz, 1H), 3.58 (s, 3H),
3.80 (s, 3H), 4.98 (s, 2H, NH2), 7.10–7.16 (m, 2H) 7.55–7.60 (m,
2H); 13C NMR (75 MHz, CDCl3, δ ppm): 12.7, 43.7, 50.7, 52.2,
57.7, 94.6, 114.9, 115.2, 117.7, 121.8, 121.9, 132.9, 143.4, 144.5,
158.4, 160.0, 161.6, 168.7, 170.9; Anal. Calcd for C19H17FN4O5:
C, 57.00; H, 4.28; N, 13.99. Found: C, 57.10; H, 4.36; N, 13.90.
Ethyl 3,3-bis(1-(4-chlorophenyl)-5-hydroxy-3-methyl-
1H-pyrazol-4-yl)propanoate (7d)
Yield, 469 mg (91%) after silica gel filtration. Colorless solid,
1
mp 125–126 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.15 (t, J =
6.9 Hz, 3H), 2.20 (s, 6H), 3.06 (d, J = 7.5 Hz, 2H), 3.99–4.06 (m,
3H), 7.25 (d, J = 8.4 Hz, 4H), 7.49 (d, J = 8.4 Hz, 4H); 13C NMR
(75 MHz, CDCl3, δ ppm): 11.5, 14.1, 25.6, 36.6, 60.5, 105.8,
122.3, 128.9, 131.7, 135.4, 146.5 158.0, 172.2; Anal. Calcd for
C25H24Cl2N4O4: C, 58.26; H, 4.69; N, 10.87. Found: C, 58.35; H,
4.63; N, 10.95.
General procedure for the synthesis of alkyl 3,3-bis(5-hydroxy-
3-alkyl-1-phenyl-1H-pyrazol-4-yl)propanoates 7a–7e
A mixture of ethyl acetoacetate or ethyl 3-oxohexanoate (1)
(2 mmol), phenylhydrazines (2) (2 mmol), methyl propiolate or
ethyl propiolate (6) (1 mmol), and L-proline (30 mol%) in water
was heated to reflux for 3.0–3.5 h. After completion of the reac-
tion (TLC), the solid that separated was filtered, washed with
water and purified by recrystallization from ethanol (com-
Methyl 3,3-bis(5-hydroxy-1-phenyl-3-propyl-1H-pyrazol-4-yl)-
propanoate (7e)
pound 7a) or by filtration through a pad of silica gel using pet- Yield, 469 mg (96%) after silica gel filtration. Colorless solid,
1
roleum ether–ethyl acetate (6 : 4 v/v). Characterization data for mp 154–155 °C. H NMR (300 MHz, CDCl3, δ ppm): 0.95 (t, J =
compounds 7 are given below.
7.4 Hz, 6H), 1.47–1.66 (m, 4H), 2.44 (t, J = 7.8 Hz, 4H), 3.05 (d,
J = 7.5 Hz, 2H), 3.56 (s, 3H), 4.00 (t, J = 7.7 Hz, 1H), 7.07–7.13
(m, 2H), 7.24–7.29 (m, 4H), 7.54 (d, J = 8.4 Hz, 4H); 13C NMR
(75 MHz, CDCl3, δ ppm): 14.0, 14.1, 22.3, 22.4, 25.6, 28.3, 36.8,
51.4, 51.5, 105.2, 121.4, 126.1, 128.7, 137.0, 150.1, 157.9, 172.6;
Anal. Calcd for C28H32N4O4: C, 68.83; H, 6.60; N, 11.47; Found:
C, 68.71; H, 6.67; N, 11.53.
Methyl 3,3-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
propanoate (7a)
Yield, 411 mg (95%) after silica gel filtration or 372 mg (86%)
after recrystallization from ethanol. Colorless solid, mp
1
201–202 °C. H NMR (300 MHz, CDCl3, δ ppm): 2.01 (s, 6H),
3.04 (d, J = 7.5 Hz, 2H), 3.56 (s, 3H), 3.86–3.88 (m, 1H), 7.08 (t,
J = 7.5 Hz, 2H), 7.24–7.30 (m, 4H), 7.55 (d, J = 7.5 Hz, 4H); 13C
NMR (75 MHz, CDCl3, δ ppm): 11.4, 25.4, 36.1, 51.5, 105.5,
Acknowledgements
121.4, 126.2, 128.8, 136.9, 146.0, 157.8, 172.8. HRMS (ESI): SP and JCM thank the Department of Science and Technology
Calcd for C24H24N4O4 (M+ + 1): 433.18856. Found: 433.18703. (India) and MICINN (Spain) for the Indo-Spanish collaborative
Anal. Calcd for C24H24N4O4 C, 66.65; H, 5.59; N, 12.96. Found: research project that has made this joint work possible (DST/
C, 66.77; H, 5.52; N, 12.90.
INT/SPAIN/P-11/09 and ACI2009-0956, respectively). SP also
gratefully acknowledges DST for funds under the IRHPA
program for the purchase of
spectrometer.
a high resolution NMR
Ethyl 3,3-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
propanoate (7b)
Yield, 426 mg (96%) after silica gel filtration. Colorless solid,
1
mp 165–166 °C. H NMR (300 MHz, CDCl3, δ ppm): 1.12 (t, J =
Notes and references
7.2 Hz, 3H), 2.03 (s, 6H), 3.04 (d, J = 7.8 Hz, 2H), 3.89 (t, J =
7.8 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 7.10 (t, J = 7.5 Hz, 2H),
7.26–7.31 (m, 5H), 7.57 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3, δ ppm): 11.5, 14.1, 25.7, 36.5, 60.3, 105.9, 121.3, 126.2,
128.9, 137.1, 146.2 158.0, 172.4. HRMS (ESI): Calcd for
C25H26N4O4Na (M+ + Na): 469.18518. Found: 469.18087. Anal.
Calcd for C25H26N4O4: C, 67.25; H, 5.87; N, 12.55. Found: C,
67.14; H, 5.96; N, 12.47.
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1298 | Green Chem., 2013, 15, 1292–1299
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Paper
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