Expeditious solid-phase synthesis of pyrazoledicarboxylic acid derivatives by functionalization of resin-bound cyanoformate

Article abstract of DOI:10.1002/ejoc.200500381

Esterification of the Wang resin 5 with the monoamide of oxalic acid (oxamic acid, 7) followed by dehydration of the amide function furnishes the resin-bound cyanoformate 9, which can be elaborated by zinc-catalyzed reaction with β-keto esters. The obtained enamino keto diesters 10a-d react with hydrazines affording, after removal from the solid support, fully substituted pyrazoledicarboxylic acids 12a-n. Optimization of the above sequence and the solid-phase synthesis of a small test-library of 1,5-disubstituted pyrazole-3,4-dicarboxylic acid derivatives are described. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500381

FULL PAPER
Expeditious Solid-Phase Synthesis of Pyrazoledicarboxylic Acid Derivatives by
Functionalization of Resin-Bound Cyanoformate
Carlo F. Morelli,*[a] Alberto Saladino,[a] Giovanna Speranza,[a] and Paolo Manitto[a]
Keywords: Solid-phase synthesis / Nitrogen heterocycles / Pyrazoledicarboxylic acids / Resin-bound cyanoformate
Esterification of the Wang resin 5 with the monoamide of ox-
alic acid (oxamic acid, 7) followed by dehydration of the
amide function furnishes the resin-bound cyanoformate 9,
which can be elaborated by zinc-catalyzed reaction with β-
keto esters. The obtained enamino keto diesters 10a–d react
with hydrazines affording, after removal from the solid sup-
port, fully substituted pyrazoledicarboxylic acids 12a–n. Op-
timization of the above sequence and the solid-phase synthe-
sis of a small test-library of 1,5-disubstituted pyrazole-3,4-
dicarboxylic acid derivatives are described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
In recent years a new route to pyrazole, isoxazole and
pyrimidine derivatives has been described,[7] in which the
key step is the metal-catalyzed reaction between a β-keto
ester 1 and an alkyl cyanoformate 2.[8] The resulting inter-
mediate, the enamino keto diester 3, affords pyrazoledicar-
boxylic acids 4 by treatment with substituted hydrazines
(Scheme 1). Usually one of the two possible regioisomeric
pyrazoledicarboxylic acids, that corresponding to 4 in
Scheme 1, is obtained as preponderant or as the only reac-
tion product.[7,9]
Introduction
Solid-phase organic synthesis, in conjunction with com-
binatorial strategies, represents a powerful tool for the rapid
preparation of a large number of compounds.[1] In addition,
the solid phase synthetic methods greatly speed up the
achievement of a synthetic plan by simplifying the workup
procedure after every synthetic step.[2,3]
Heterocyclic structures have received special attention in
combinatorial chemistry.[4] They can be synthesized from
easily available precursors to obtain a high degree of chemi-
cal diversity simply changing the subsitutents linked to a
common heteroaromatic core.
The pyrazole nucleus is an especially interesting target
due to the broad spectrum of biological activities of a
number of its derivatives.[5] The solid-phase synthesis of li-
braries of tri- and tetrasubstituted pyrazole derivatives has
attracted much attention, with the development of various
synthetic strategies.[6]
A valuable solid-phase synthetic plan usually takes ad-
vantage of the use of readily available building blocks. Thus,
the most widely used strategy to construct the pyrazole ring
is the ring-forming reaction of a suitable electrophilic pre-
cursor, such as 3, grafted to a polymeric support, with com-
mercially available substituted hydrazines. Up to date the
precursors used have been 1,3-dicarbonyl com-
pounds[6g,6h,6m,6n] or their synthetic equivalents,[6b] en-
ones[6c,6d,6i] or enoates,[6d] α,β-unsaturated carbonyl deriva-
tives,[6j] and nitriles.[6k,6l] However, the solid-phase construc-
tion of a properly substituted precursor usually involves
carbon–carbon bond-forming reactions which are not a
minor task when carried out on solid phase.
Scheme 1. Synthesis of pyrazoledicarboxylic acid derivatives.
Due to the accessibility of the starting materials and the
mild reaction conditions required, we have been persuaded
that this approach could well be suited for the solid-phase
synthesis of fully substituted and functionalized pyrazole-
dicarboxylic acid derivatives. The presence of two carboxylic
[a] Dipartimento di Chimica Organica e Industriale, Università
degli Studi di Milano,
21 Via Venezian, 20133 Milano, Italy
Fax: +39-02-50314072
E-mail: carlo.morelli@unimi.it
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DOI: 10.1002/ejoc.200500381
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C. F. Morelli, A. Saladino, G. Speranza, P. Manitto
FULL PAPER
functions could also allow the choice of two possible ways of our knowledge, polymer-supported cyanoformates were
to graft the starting material to the polymeric support.
In this paper we describe the validation of the mentioned
not known in the literature.
In a preliminary test, we used the monoamide of oxalic
approach for the solid-phase synthesis of pyrazoledicarbox- acid (oxamic acid) 7, which was loaded onto the Wang resin
ylic acid derivatives.
5 following the mixed anhydride method.[11] The amide
functional group of intermediate 8 was then dehydrated[12]
to give the resin-bound cyanoformate 9 (Scheme 3). All
these steps were checked by FT-IR. In particular, the dehy-
dration step showed the disappearance of the amide bond
signals at 1714 and 1697 cm–1 and the appearance of a
sharp peak of a carbon–nitrogen triple bond at 2244 cm–1.
Subsequent functionalization of 9 was accomplished using
a 20-fold excess of methyl acetoacetate in dichloromethane
solution in the presence of 5 mol% zinc acetylacetonate at
room temperature for 24 hours affording 10a. Reaction of
10a with two equivalents of phenylhydrazine (room tem-
perature, 12 hours) and removal of the product 11a from
the solid support with trifluoroacetic acid in dichlorometh-
ane gave the pyrazole acid 12a in 70% overall yield. The
pyrazole acid 12a was finally esterified with thionyl chloride
and ethanol to give the diester 13, which was found to be
identical in all respects to that previously described in the
literature (Scheme 3).[7]
Results and Discussion
A polystyrenic resin containing 2% divinylbenzene as re-
ticulating agent and functionalized with a benzyloxybenzyl
linker (Wang resin, 5) seemed to be suited for our purpose.
This kind of resin has a good chemical stability, a high
loading capacity (up to 1.5–2.0 mmol/g), good swelling
properties in apolar solvents and the linked product can be
removed from the solid support by treatment with a solu-
tion of trifluoroacetic acid in dichloromethane.
It is well known that the reactions of the Wang resin
5 with appropriate compounds give a resin-bound β-keto
ester.[6i,10] So, methyl acetoacetate was allowed to react with
that resin in N-methyl-2-pyrrolidone in the presence of
DMAP,[6i] as a first attempt. The resulting polymer-bound
β-keto ester 6 was subjected to metal-catalyzed function-
alization with ethyl cyanoformate (10–100 equiv.) in the
presence of 2–10 mol% of zinc acetylacetonate, under vari-
ous experimental conditions. In all experiments, no appreci-
able amounts of the expected product were observed
(Scheme 2). A plausible explanation could be that in the
solid-phase reaction, differently from the liquid-phase ap-
proach, the starting dicarbonyl compound and the reaction
product, both being bound to the solid support, cannot act
as complexing agents able to ensure the mobility of the
catalytic zinc within the reaction medium. Thus, the cata-
lytic cycle is inhibited by sequestering the catalyst. On the
base of these findings, our strategy was adapted to the use
of resin-bound cyanoformate in order to have the complex-
ing β-keto ester in solution, ensuring the exchange of the
catalytically active zinc between the reaction product and
the free β-keto ester reagent.
The metal-catalyzed formation of the intermediate en-
amino keto diester 10a was then optimized with respect to
the excess of β-keto ester required, the amount of the cata-
lyst, and the reaction times.
Intermediate 10a showed a complex FT-IR spectrum. A
broad band between 1682 and 1745 cm–1 accounted for the
conjugate system of two ester groups, and a ketone linked
to the central ethylene unit. Therefore, the zinc-catalyzed
reaction between the resin-bound cyanoformate 9 and
methyl acetoacetate (1) was considered to be complete after
the disappearance of the carbon–nitrogen triple-bond peak
of the starting material 9 at 2244 cm–1. The amount of the
catalyst was determined by carrying out the reaction in the
presence of 0.5, 1 and 2 mol% of zinc acetylacetonate, using
20 equiv. of β-keto ester. The short reaction times found for
experiments carried out with 1 and 2 mol% zinc acetylace-
tonate (5 and 2 hours, respectively), prompted us to test
whether a lower excess of the β-keto ester could be used.
Indeed, we found that treatment of 9 with a 10-fold excess
of methyl acetoacetate in the presence of 1 mol% zinc ace-
tylacetonate gave complete reaction after 16 hours (FT-IR
monitor).
Resin-bound enamino keto diester 10a was then allowed
to react with 2 equiv. of phenylhydrazine in dichlorometh-
ane at room temperature for 3 and 20 hours. The obtained
products were cleaved from the resin and their yield and
purity were checked by 1H NMR spectroscopy. Interest-
ingly, better yields of a purer product were obtained with
the shorter reaction time.
Scheme 2. First approach to the synthesis of resin-bound enamino
keto diesters of type 3.
Since the transesterification reaction between the Wang
To explore the breadth of applicability of such an opti-
resin and an alkyl cyanoformate could be accompanied by mized synthetic sequence, we performed the synthesis of a
polymer-bound carbonate ester formation, because of the test library of representative pyrazole derivatives. The start-
leaving group ability of the cyano group, we decided to pre- ing building blocks were selected on the basis of their elec-
pare the polymer-bound cyanoformate by modifying a pre- tronic and steric requirements and are listed in Table 1. All
cursor previously grafted to the solid support. To the best the required β-keto esters 14a–c were synthesized as ethyl
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Pyrazoledicarboxylic Acid Derivatives from Resin-Bound Cyanoformate
FULL PAPER
Scheme 3. Solid-phase synthesis of pyrazoledicarboxylic acid derivatives 12. See Table 1 for R1, R2 and R3. Reagents and conditions: i:
2,6-dichlorobenzoyl chloride, pyridine, Wang resin (5), DMF, 0 °C; ii: TFAA, pyridine, dichloromethane, 0 °C; iii: R1COCH2COOR2 (1
or 14a–c), Zn(acac)2, CH2Cl2, room temp.; iv: R3NHNH2, CH2Cl2, room temp.; v: TFA/CH2Cl2 (3:1 vol/vol), room temp.; vi: SOCl2
followed by EtOH, 0 °C, then reflux.
esters starting from commercially available nitriles by Blaise
reaction with ethyl bromoacetate in the presence of zinc
dust, followed by hydrolysis of the intermediate enamino
ester (Scheme 4).[13]
Table 1. R1, R2 and R3 residues for the test-library of the pyrazoles
12a–r. See Scheme 3 for the synthetic plan.
R1
R2
R3
Yield[a] [%]
Scheme 4. Synthesis of the β-keto esters 14.
12
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Me
p-MeOC6H4
p-ClC6H4
tBu
Ph
Me
p-MeOC6H4
p-ClC6H4
tBu
Ph
Me
p-MeOC6H4
p-ClC6H4
tBu
82
72
81
40
70
55
80
63
61
58
63
74
50
35
–
nitrogen triple-bond signal of 9 in the FT-IR spectra was no
longer detectable in all cases. The subsequent ring-forming
reactions of intermediates 10a–d (see Table 1 for hydrazine
residues) occurred in the presence of two equivalents of the
appropriate hydrazine at room temperature for 3.5 hours.
Two equivalents of triethylamine were added to the reaction
mixtures in the case of hydrazines in the form of their hy-
drochloride salts.
Cleavage of the resulting products 11a–n from the solid
support was accomplished with two consecutive treatments
with trifluoroacetic acid in dichloromethane at room tem-
perature for 30 min.
Ph
CH2CHMe2
CH2CHMe2
CH2CHMe2
CH2CHMe2
CH2CHMe2
tBu
Ph
Me
tBu
–
–
–
tBu
tBu
Pyrazoles 12a–n were obtained in moderate to good
chemical yields in all cases (Table 1). Considering what
mentioned above,[7,9] we found that all the synthesized com-
[a] Isolated yields of compounds 12. All compounds gave satisfac-
tory elemental analyses.
pounds consisted of only one regioisomer, as revealed by
The zinc-catalyzed reactions of methyl acetoacetate (1) inspection of their H and 13C spectra. However, when the
and the keto esters 14a–c with the resin-bound cyanofor- bulky tert-butyl group was linked as substituent at the ke-
mate 9 were carried out in dichloromethane at room tem- tonic carbonyl carbon (Entries p–r of Table 1), no appreci-
perature with 10 equivalents of the dicarbonyl compounds able amounts of the expected products were observed. To
and 1 mol% Zn(acac)2 for 16 hours to give the compounds gain further insight on this point, ring-forming reactions of
10a–d (Scheme 3 and Table 1). After this time the carbon– enamino keto diester 15 with various hydrazines were tested
1
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C. F. Morelli, A. Saladino, G. Speranza, P. Manitto
FULL PAPER
respectively with a Bruker AVANCE 400 Spectrometer using a
Xwin-NMR software package; at 300.133 and 75.47 MHz with a
Bruker AC 300 (Bruker, Karlsruhe, Germany), equipped with an
ASPECT 3000 data system. Chemical shifts (δ) are given in ppm
and were referenced to the signals of CDCl3 (δH, 7.26 and δC
77.00 ppm). 13C NMR signals multiplicities were based on APT
spectra. FT-IR spectra were recorded with a Perkin–Elmer 1725 X
spectrometer by triturating ca. 5 mg of resin with few drops of nu-
jol. APCI mass spectra were recorded with a Termo Finnigan LCQ
Advantage mass spectrometer. Wang resin (loading capacity
in liquid phase. Compound 15 was prepared from 14b and
ethyl cyanoformate and was found to be present as an equi-
librium mixture of geometric stereoisomers (Scheme 5) (cf.
ref.[8a]). Reactions of compound 15 with methyl and phenyl-
hydrazine gave intractable mixtures of rather unstable com-
pounds. Treatment of enamino keto diester 15 with the ste-
rically demanding tert-butylhydrazine resulted in no reac-
tion at all. In this case, over 90% starting compound 15
was recovered unchanged even after 24 hours reaction time.
Thus, steric hindrance of the substituent at the ketonic car- 1.21 mmol g–1, as specified by the supplier) was from Aldrich.
Resin-bound cyanoformate 9 was prepared on 2.0 or 4.0 resin
grams scale using standard glassware. Parallel synthesis of pyrazole
derivatives was carried out by use of 12 mL fritted tubes by means
of a home-modified Ika-vibrax-VXR orbital shaker. All reagents
were of commercial quality. Ethyl 3-oxo-3-phenylpropanoate
(14a),[14] ethyl 4,4-dimethyl-3-oxo-pentanoate (14b),[15] and ethyl 5-
methyl-3-oxohexanoate (14c)[16] were prepared according to the lit-
erature.[13] Solvents were dried by standard methods prior to use.
bonyl carbon appears to be critical for the reaction, while
the steric hindrance of the hydrazine is of minor impor-
tance. Steric bulkiness of the hydrazine substituent becomes
critical only when a voluminous group is also present in the
ketonic counterpart (see 12o in Table 1).
Synthesis of the Resin-Bound Cyanoformate 9: To a solution of ox-
amic acid (862 mg, 9.68 mmol) in dry DMF (30 mL), cooled to
0 °C, pyridine was added (0.93 mL, 11.62 mmol) followed, after
5 min, by 2,6-dichlorobenzoyl chloride (2.10 mL, 14.52 mmol). Af-
ter 5 min, the Wang resin was added (4.00 g, 4.84 mmol), and the
suspension was stirred at 0 °C for 2 h. The resin was collected by
filtration and washed consecutively with dry DMF (2×20 mL), Ac-
OEt (3×20 mL) and dichloromethane (3×20 mL) and dried under
reduced pressure. FT-IR (nujol mull): ν = 1737, 1714, 1697 cm–1.
˜
The resin obtained as described above was suspended in dry dichlo-
romethane (40 mL) and the mixture was cooled to 0 °C. Pyridine
was then added (1.90 mL, 24.20 mmol) and the suspension was
stirred for 5 min. Trifluoroacetic anhydride (0.82 mL, 5.81 mmol)
was added dropwise over 5 min and the resulting suspension was
stirred at 0 °C for additional 30 min. The resin was collected by
filtration, washed with dichloromethane (3×20 mL) and dried un-
der reduced pressure. FT-IR (nujol mull): ν = 2244, 1746 cm–1.
˜
Scheme 5. Synthesis of compound 15.
General Procedure for the Synthesis of the Polymer-Bound Enamino
Keto Diesters 10a–d: Polymer-bound cyanoformate obtained as de-
scribed above (1.0 g, ca 1.2 mmol) was suspended in CH2Cl2
(10 mL) in a 12-mL fritted tube. The appropriate β-keto ester
(10 equiv.) and Zn(acac)2 (32 mg, 0.12 mmol) were then added. The
mixture was shaken at room temperature for 16 h, the liquid phase
was removed by filtration, the resin was washed with DMF
(10 mL), AcOEt (2×10 mL) and CH2Cl2 (2×10 mL) and dried un-
der reduced pressure.
Conclusions
A test-library of fully substituted pyrazoledicarboxylic
acid derivatives was synthesized by addition of commer-
cially available hydrazines to the easily prepared intermedi-
ates arising from the zinc-catalyzed reaction of the resin-
bound cyanoformate with β-keto esters. The yields were sat-
isfactory and the purity of the compounds obtained after
General Procedure for the Synthesis of the Polymer-Bound Pyrazole
Derivatives 11a–n: Resin-bound enamino keto diester of type 10
minimal workup, was generally high enough to avoid fur- (0.75 mmol) was suspended in CH2Cl2 (8 mL) in a 12-mL fritted
tube. The appropriate hydrazine was then added (1.50 mmol). In
the case of hydrazine hydrochlorides triethylamine (1.50 mmol) was
also added. The mixture was shaken at room temperature for 3.5 h
and filtered. The resin was washed with DMF (2×10 mL), AcOEt
(2×10 mL) and CH2Cl2 (2×10 mL) and dried under reduced pres-
sure.
ther purification. The very mild experimental conditions
and the high reproducibility of the reaction times make our
approach potentially suitable for automation and for appli-
cation to combinatorial synthetic strategies.
General Procedure for the Cleavage of the Pyrazoledicarboxylic
Acids from the Solid Support 12a–n: Resin-bound pyrazole deriva-
tive of type 11 (0.75 mmol) was shaken with a mixture of trifluoro-
acetic acid and CH2Cl2 (3:1 v/v, 8 mL) in a 12-mL fritted tube at
room temperature for 1 h. The resin was filtered off and the liquid
phase was collected. The procedure was repeated in order to ensure
complete cleavage of the product from the solid support. The com-
bined liquid phases were evaporated under reduced pressure; the
Experimental Section
General Remarks: TLC was performed on silica gel F254 precoated
aluminum sheets (0.2 mm layer, Merck, Darmstadt, Germany);
components were detected by spraying a ceric sulfate ammonium
molybdate solution, followed by heating to ca 150 °C. Silica gel
(Merck, 40–63 µm) was used for flash chromatography (FC). 1H
and 13C NMR spectra were recorded at 400.132 and 100.613 MHz,
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Pyrazoledicarboxylic Acid Derivatives from Resin-Bound Cyanoformate
FULL PAPER
residue was taken up in ethyl acetate (10 mL) and washed with
water (2×8 mL); the organic layer was extracted with half-satu-
rated solution of NaHCO3 (2×5 mL), the combined aqueous layers
were acidified with concentrated HCl at pH ca 1 and extracted
with AcOEt (3×8 mL). The combined organic layers were dried
(Na2SO4) and evaporated under reduced pressure to give pyrazole
derivatives 12a–n.
ppm. MS-APCI: m/z = 337 [MH+], 291 [M – EtOH], 180 [M –
EtOH – 111].
4-(Ethoxycarbonyl)-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic
Acid (12g): Obtained from 10b and methylhydrazine in 80% overall
1
yield. H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H,
CH2CH3), 3.80 (s, 3 H, N-CH3), 4.16 (q, J = 7.2 Hz, 2 H,
CH2CH3), 7.32–7.34 (m, 2 H, aromatic H), 7.52–7.55 (m, 3 H, aro-
matic H) ppm. 13C NMR (400 MHz, CDCl3): δ = 13.51 (CH2CH3),
38.64 (N–CH3), 63.14 (CH2CH3), 111.44 (pyrazole C4), 128.78,
129.05, 129.82, 130.58 (aromatic C), 143.53 (pyrazole C3), 149.34
(pyrazole C5), 161.85 (COO), 167.37 (COO) ppm. MS-APCI:
m/z = 275 [MH+], 229 [M – EtOH], 118 [M – EtOH – 111].
4-(Methoxycarbonyl)-5-methyl-1-phenyl-1H-pyrazole-3-carboxylic
Acid (12a): Obtained from 10a and phenylhydrazine in 82% overall
1
yield. H NMR (400 MHz, CDCl3): δ = 2.56 (s, 3 H, Me), 4.05 (s,
3 H, OMe), 7.41–7.46 (m, 2 H, aromatic H), 7.50–7.52 (m, 3 H,
aromatic H) ppm. 13C NMR (400 MHz, CDCl3): δ = 13.53 (Me),
53.61 (OMe), 110.47 (pyrazole C4), 126.19, 129.29, 129.89, 137.66
(aromatic C), 144.27 (pyrazole C3), 146.47 (pyrazole C5), 160.17
(COO), 168.17 (COO) ppm. MS-APCI: m/z = 261 [MH+], 229 [M –
MeOH].
4-(Ethoxycarbonyl)-1-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-3-
carboxylic Acid (12h): Obtained from 10b and (4-methoxyphenyl)
hydrazine hydrochloride in 63% overall yield. 1H NMR (400 MHz,
CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3 H, CH2CH3), 3.78 (s, 3 H,
OCH3), 4.20 (q, J = 7.2 Hz, 2 H, CH2CH3), 6.77–6.79 (m, 2 H,
aromatic H), 7.15–7.17 (m, 2 H, aromatic H), 7.22–7.25 (m, 2 H,
aromatic H), 7.35–7.49 (m, 3 H, aromatic H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 13.23 (CH2CH3), 55.46 (O–CH3), 62.72
(CH2CH3), 110.21 (pyrazole C4), 113.97, 127.00, 128.19, 128.48,
129.61, 130.21, 131.15 (aromatic C), 144.04 (pyrazole C3), 148.28
(pyrazole C5), 159.73 (aromatic C), 160.63 (COO), 166.85 (COO)
ppm. MS-APCI: m/z = 367 [MH+], 321 [M – EtOH], 210 [M –
EtOH – 111].
4-(Methoxycarbonyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic Acid
(12b): Obtained from 10a and methylhydrazine in 72 % overall
1
yield. H NMR (400 MHz, CDCl3): δ = 2.58 (s, 3 H, Me), 3.93 (s,
3 H, NMe), 4.02 (s, 3 H, OMe) ppm. 13C NMR (400 MHz, CDCl3):
δ = 12.64 (Me), 38.07 (NMe), 53.90 (OMe), 110.30 (pyrazole C4),
143.47 (pyrazole C3), 146.21 (pyrazole C5), 161.00 (COO), 168.45
(COO) ppm. MS-APCI: m/z = 199 [MH+], 181 [M – H2O], 167
[M – MeOH].
4-(Methoxycarbonyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-
carboxylic Acid (12c): Obtained from 10a and (4-methoxyphenyl)-
hydrazine hydrochloride in 81% overall yield. 1H NMR (300 MHz,
1-(4-Chlorophenyl)-4-(ethoxycarbonyl)-5-phenyl-1H-pyrazole-3-
carboxylic Acid (12i): Obtained from 10b and 4-chlorophenylhydra-
zine hydrochloride in 61 % overall yield. 1H NMR (400 MHz,
CDCl3): δ = 2.49 (s, 3 H, Me), 3.83 (s, 3 H, OMe), 4.00 (s, 3 H, CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3 H, CH2CH3), 4.21 (q, J = 7.2 Hz,
OMe), 6.95 (m, 2 H, aromatic H), 7.29 (m, 2 H, aromatic H) ppm.
2 H, CH2CH3), 7.19–7.29 (m, 6 H, aromatic H), 7.39–7.42 (m, 3
13C NMR (300 MHz, CDCl3): δ = 13.52 (Me), 53.60 (OMe), 55.64 H, aromatic H) ppm. 13C NMR (400 MHz, CDCl3): δ = 13.62
(OMe), 110.67 (pyrazole C4), 114.43, 127.49, 130.47 (aromatic C), (CH2CH3), 63.24 (CH2CH3), 112.00 (pyrazole C4), 127.22, 127.98,
143.94 (pyrazole C3), 146.62 (pyrazole C5), 160.31 (COO or aro-
matic C), 160.32 (COO or aromatic C), 168.21 (COO) ppm. MS-
APCI: m/z = 291 [MH+], 259 [M – MeOH].
128.82, 129.55, 130.35, 130.55, 135.43, 137.07 (aromatic C), 145.01
(pyrazole C3), 148.71 (pyrazole C5), 160.51 (COO), 167.26 (COO)
ppm. MS-APCI: m/z = 371 [MH+], 325 [M – EtOH], 214 [M –
EtOH – 111].
1-(4-Chlorophenyl)-4-(methoxycarbonyl)-5-methyl-1H-pyrazole-3-
carboxylic Acid (12d): Obtained from 10a and 4-chlorophenylhy-
drazine hydrochloride in 40% overall yield. 1H NMR (400 MHz,
CDCl3): δ = 2.55 (s, 3 H, Me), 4.05 (s, 3 H, OMe), 7.38–7.41 (m,
2 H, aromatic H), 7.47–7.50 (m, 2 H, aromatic H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 13.49 (Me), 53.70 (OMe), 110.71 (pyrazole
C4), 127.46, 129.63, 135.98, 136.08 (aromatic C), 144.40 (pyrazole
C3 or C5), 146.59 (pyrazole C3 or C5), 160.07 (COO), 168.01
(COO) ppm. MS-APCI: m/z = 295 [MH+], 277 [M – H2O], 263
[M – MeOH].
1-tert-Butyl-4-(ethoxycarbonyl)-5-phenyl-1H-pyrazole-3-carboxylic
Acid (12j): Obtained from 10b and tert-butylhydrazine hydrochlo-
ride in 58% overall yield. H NMR (400 MHz, CDCl3): δ = 0.73
1
(t, J = 7.2 Hz, 3 H, CH2CH3), 1.47 (s, 9 H, tBu), 3.99 (q, J =
7.2 Hz, 2 H, CH2CH3), 7.27–7.28 (m, 2 H, aromatic H), 7.39–7.42
(m, 3 H, aromatic H) ppm. 13C NMR (400 MHz, CDCl3): δ =
13.31 (CH2CH3), 31.72 [C(CH3)3], 62.59 (CH2CH3), 63.46 (CMe3),
112.95 (pyrazole C4), 128.33, 129.85, 130.65, 131.77 (aromatic C),
141.84 (pyrazole C3), 148.53 (pyrazole C5), 161.46 (COO), 167.71
(COO) ppm. MS-APCI: m/z = 317 [MH+], 260 [MH+ – isopro-
pylidene].
1-tert-Butyl-4-(methoxycarbonyl)-5-methyl-1H-pyrazole-3-carbo-
xylic Acid (12e): Obtained from 10a and tert-butylhydrazine hydro-
chloride in 70% overall yield. 1H NMR (400 MHz, CDCl3): δ =
1.72 (s, 9 H, tBu), 2.58 (s, 3 H, Me), 4.01 (s, 3 H, OMe) ppm. 13C
NMR (400 MHz, CDCl3): δ = 14.95 (Me), 30.24 (CMe3), 53.83
(OMe), 63.70 (CMe3), 112.02 (pyrazole C4), 141.43 (pyrazole C3),
145.81 (pyrazole C5), 162.21 (COO), 168.87 (COO) ppm. MS-
APCI: m/z = 241 [MH+], 184 [MH+ – isopropylidene].
4-(Ethoxycarbonyl)-5-isobutyl-1-phenyl-1H-pyrazole-3-carboxylic
Acid (12k): Obtained from 10c and phenylhydrazine in 63% overall
1
yield. H NMR (300 MHz, CDCl3): δ = 0.72 = [d, J = 6.8 Hz, 6
H, CH2CH(CH3)2], 1.44 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.80 [m, 1
H, CH2CH(CH3)2], 2.86 [d, J = 7.0 Hz, 2 H, CH2CH(CH3)2], 4.48
(q, J = 7.2 Hz, 2 H, CH2CH3), 7.35–7.37 (m, 2 H, aromatic H),
7.45–7.49 (m, 3 H, aromatic H) ppm. 13C NMR (300 MHz,
CDCl3): δ = 14.03 (CH2CH3), 22.23 [CH2CH(CH3)2], 29.36
[CH2CH(CH3)2], 34.57 [CH2CH(CH3)2], 63.14 (CH2CH3), 109.90
(pyrazole C4), 126.91, 129.39, 130.01, 138.07 (aromatic C), 144.42
(pyrazole C3), 150.25 (pyrazole C5), 165.59 (COO), 167.70 (COO)
4-(Ethoxycarbonyl)-1,5-diphenyl-1H-pyrazole-3-carboxylic Acid
(12f): Obtained from 10b and phenylhydrazine in 55% overall yield.
1H NMR (400 MHz, CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3 H,
CH2CH3), 4.20 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.23–7.52 (m, 10
H, aromatic H) ppm. 13C NMR (400 MHz, CDCl3): δ = 13.63
(CH2CH3), 63.14 (CH2CH3), 112.34 (pyrazole C4), 126.12, 128.61,
129.29, 129.40, 130.11, 130.62, 134.15, 138.57 (aromatic C), 144.68
(pyrazole C3), 148.67 (pyrazole C5), 160.96 (COO), 167.35 (COO)
ppm. MS-APCI: m/z = 317 [MH+], 271 [M+ – EtOH], 253 [M+
EtOH – H2O].
–
4-(Ethoxycarbonyl)-5-isobutyl-1-methyl-1H-pyrazole-3-carboxylic
Acid (12l): Obtained from 10c and methylhydrazine in 74% overall
Eur. J. Org. Chem. 2005, 4621–4627
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. F. Morelli, A. Saladino, G. Speranza, P. Manitto
FULL PAPER
yield. H NMR (400 MHz, CDCl3): δ = 0.97 [d, J = 6.8 Hz, 6 H,
1
Acknowledgments
CH2CH(CH3)2], 1.45 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.00 [m, 1 H,
CH2CH(CH3)2], 2.85 [d, J = 7.6 Hz, 2 H, CH2CH(CH3)2], 3.94 (s,
3 H, N–CH3), 4.46 (q, 2 H, J = 7.2 Hz, CH2CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 14.37 (CH2CH3), 22.68 [CH2CH(CH3)2],
29.67 [CH2CH(CH3)2], 34.91 [CH2CH(CH3)2], 38.35 (N–CH3),
63.40 (CH2CH3), 110.36 (pyrazole C4), 143.82 (pyrazole C3),
149.67 (pyrazole C5), 161.18 (COO), 167.94 (COO) ppm. MS-
APCI: m/z = 255 [MH+], 209 [M+ – EtOH], 191 [M+ – EtOH –
H2O].
Authors thank MIUR for financial support. A postgraduate fel-
lowship from Consorzio COMBIGEN (to A.S.) is gratefully ac-
knowledged.
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4-(Ethoxycarbonyl)-5-isobutyl-1-(4-methoxyphenyl)-1H-pyrazole-3-
carboxylic Acid (12m): Obtained from 10c and (4-methoxyphenyl)-
hydrazine hydrochloride in 50% overall yield. 1H NMR (400 MHz,
CDCl3): δ = 0.77 [d, J = 6.6 Hz, 6 H, CH2CH(CH3)2], 1.48 (t, J =
7.2 Hz, 3 H, CH2CH3), 1.85 [m, 1 H, CH2CH(CH3)2], 2.85 [d, J =
7.2 Hz, 2 H, CH2CH(CH3)2], 3.89 (s, 3 H, OMe), 4.51 (q, J =
7.2 Hz, 2 H, CH2CH3), 7.00 (m, 2 H, aromatic H), 7.30 (m, 2 H,
aromatic H) ppm. 13C NMR (400 MHz, CDCl3): δ = 14.41
(CH2CH3), 22.57 [CH2CH(CH3)2], 29.66 [CH2CH(CH3)2], 34.99
[CH2CH(CH3)2], 55.01 (OMe), 63.42 (CH2CH3), 110.54 (pyrazole
C4), 114.74, 128.58, 131.31 (aromatic C), 144.65 (pyrazole C3),
150.75 (pyrazole C5), 160.89 (aromatic C or COO), 160.91 (aro-
matic C or COO), 168.10 (COO) ppm. MS-APCI: m/z = 347
[MH+], 301 [M+ – EtOH], 283 [M+ – EtOH – H2O].
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[5]
1-(4-Chlorophenyl)-4-(ethoxycarbonyl)-5-isobutyl-1H-pyrazole-3-
carboxylic Acid (12n): Obtained from 10c and 4-chlorophenylhy-
drazine hydrochloride in 35% overall yield. 1H NMR (300 MHz,
CDCl3): δ = 0.72 [d, J = 6.4 Hz, 6 H, CH2CH(CH3)2], 1.44 (t, J =
7.2 Hz, 3 H, CH2CH3), 1.80 [m, 1 H, CH2CH(CH3)2], 2.83 [d, J =
7.2 Hz, 2 H, CH2CH(CH3)2], 4.48 (q, J = 7.2 Hz, 2 H, CH2CH3),
7.31 (m, 2 H, aromatic H), 7.46 (m, 2 H, aromatic H) ppm. 13C
NMR (300 MHz, CDCl3 ): δ = 13. 97 (CH2 CH3 ), 22.18
[CH2CH(CH3)2], 29.40 [CH2CH(CH3)2], 34.53 [CH2CH(CH3)2],
63.25 (CH2CH3), 110.32 (pyrazole C4), 128.18, 129.65, 136.50,
138.07 (aromatic C), 145.40 (pyrazole C3), 150.36 (pyrazole C5),
160.53 (COO), 167.18 (COO) ppm. MS-APCI: m/z = 351 [MH+],
305 [M+ – EtOH], 287 [M+ – EtOH – H2O].
Synthesis of Diethyl 2-Amino-3-(2,2-dimethylpropanoyl)-2-butene-
dioate (15): To a solution of ethyl 4,4-dimethyl-3-oxo-pentanoate
(14b) (1.11 g, 6.45 mmol) and ethyl cyanoformate (2) (0.70 mL,
7.10 mmol) in dry dichloromethane (1.5 mL), zinc acetylacetonate
(34 mg, 0.13 mmol) was added, and the mixture was stirred at room
temperature for 1.5 h. The mixture was diluted with ethyl acetate
(10 mL) and filtered through celite. The filtrate was evaporated un-
der reduced pressure and the residue was chromatographed (silica
gel, ethyl acetate/hexane, 2:8) to give the title compound. White
powder, 1.57 g, 90% yield. 1H NMR (300 MHz, CDCl3): two in-
separable geometric isomers were present in solution (see ref.[8a]).
Major isomer (85%) showed resonances at δ = 1.21 (s, 9 H, CMe3),
1.28 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.35 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.20 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.32 (q, J = 7.1 Hz,
2 H, CH2CH3), 6.75 (br. s, 2 H, NH2) ppm. The minor isomer
(15 %) showed distinguishable resonances at δ = 1.22 (s, 9 H,
CMe3), 7.75 (br. s, 2 H, NH2) ppm. 13C NMR (300 MHz, CDCl3):
two inseparable geometric isomers were present in solution. Major
isomer showed resonances at δ = 13.71 (CH2CH3), 13.99
(CH2CH3), 28.31 (CMe3), 45.29 (CMe3), 60.19 (CH2CH3), 62.71
(CH2CH3), 104.48 (C3), 145.77 (C2), 162.64 (COO), 167.32 (COO),
210.29 (CO) ppm. The minor isomer showed distinguishable reso-
nances at δ = 27.25 (CMe3), 43.77 (CMe3), 60.60 (CH2CH3), 63.03
(CH2CH3) ppm. C13H21NO5 (271.14): calcd. C 57.55, H 7.80, N
5.16; found C 57.81, H 8.00, N 4.97.
[6]
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4626
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pyrazoledicarboxylic Acid Derivatives from Resin-Bound Cyanoformate
FULL PAPER
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Received: May 26, 2005
Published Online: September 12, 2005
Eur. J. Org. Chem. 2005, 4621–4627
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4627