Cascade regioselective synthesis of pyrazoles from nitroallylic acetates and N-tosyl hydrazine

Article abstract of DOI:10.1016/j.tet.2013.12.046

A simple, practical, and regioselective synthetic protocol for the formation of pyrazoles was developed. Unlike all other previously reported reactions of nitroallylic acetates, this process was initiated by a S _N2 reaction at the electrophilic γ site. A plausible mechanism for the cascade S_N2-Michael synthesis is proposed.

Full text of DOI:10.1016/j.tet.2013.12.046

Tetrahedron 70 (2014) 795e799
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cascade regioselective synthesis of pyrazoles from nitroallylic
acetates and N-tosyl hydrazine
,
Nana Shao a, Tong Chen a, Taotao Zhang a b, Huajian Zhu a, Qunxiong Zheng b,
,
Hongbin Zou a
*
a Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
b College of Food Science, Zhejiang Gongshang University, Hangzhou 310035, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 October 2013
Received in revised form 4 December 2013
Accepted 17 December 2013
Available online 22 December 2013
A simple, practical, and regioselective synthetic protocol for the formation of pyrazoles was developed.
Unlike all other previously reported reactions of nitroallylic acetates, this process was initiated by a SN2
reaction at the electrophilic
proposed.
g
site. A plausible mechanism for the cascade SN2-Michael synthesis is
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
Nitroallylic acetates
N-Tosyl hydrazine
SN2 reaction
Michael addition
1. Introduction
Due to the important applications of pyrazoles, significant effort
has been put forth in developing approaches for their synthesis.5
Among the many methodologies now available, cyclo-
condensation of 1,3-dielectrophilic compounds with hydrazines
play a prominent role6 of which 1,3-dicarbonyl compounds are the
most prevalent synthons.6eei 1,3-Dipolar cycloaddition is also
widely used for the synthesis of pyrazoles, using diverse 1,3-
dipoles, such as nitrilimines,7aec diazoalkanes,7d,e and azomethine
imines.7f,g Recently, progress has been made in the synthesis of
pyrazoles through the use of transition metal-catalyzed reactions.8
Despite significant advances in pyrazole synthesis, efficient and
regioselective preparation of pyrazoles from readily available
building blocks continues to be actively pursued.
Pyrazoles represent an important class of heterocyclic com-
pounds that possess a wide range of pharmaceutical activities,1
such as inhibitors of cyclooxygenase-2,1a protein kinase,1b brain
cannabinoid receptor,1c NS5B polymerase,1d metabotropic
glutamate-5 receptor,1e and antimicrobial activities.1f In fact, some
compounds with pyrazole motif are successfully commercialized
agents, such as Celecoxib (nonsteroidal anti-inflammatory drug),2a
Fipronil (insecticide),2b and Sildenafil (anti-erectile dysfunction
drug)2c (Fig. 1). Moreover, some pyrazoles are widely used in ag-
rochemical industries3 as well as useful building blocks in the field
of materials chemistry.4
Nitroallylic acetates, derived from MoritaeBayliseHillman re-
action of nitroethylene and aldehydes, are highly reactive synthetic
Michael acceptors with four potential electrophilic sites (a, b, g, d,
Scheme 1).9 All four electrophilic sites are highly reactive and fre-
quently used as efficient synthons to construct diversified func-
tional organic molecules (I-AeI-I) as shown in Scheme 1.9 Up to
now, reactions of nitroallylic acetates were normally initiated by
Michael addition at the electrophilic
a
site (I, Scheme 1).9 Very
recently, we reported the synthesis of 1,3,5-trisubstituted pyrazoles
(I-H, Scheme 1) through cascade double Michael-elimination re-
actions in which the first Michael addition between phenyl-
hydrazine and nitroallylic acetates also occurred at the electrophilic
Fig. 1. Drugs containing pyrazole motif.
* Corresponding author. Tel./fax: þ86 571 8820 8835; e-mail address: zouhb@zju.
a
site.9j Herein, for the first time, we report a regioselective
edu.cn (H. Zou).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.046

796
N. Shao et al. / Tetrahedron 70 (2014) 795e799
approach to the 3,5-disubstituted pyrazoles (4h as an example,
Scheme 1) with cascade SN2 (electrophilic site)-Michael (elec-
After the first SN2 reaction, we tried to increase the reaction
temperature and no further reaction occurred (entry 2, Table 1).
Interestingly, addition of Na2CO3 initiated the reaction in situ to
form pyrazole 4a (entry 3, Table 1). Reaction temperature is also
crucial for the synthesis of pyrazole since no reaction was ob-
served when it was stirred at room temperature in the presence of
Na2CO3 (entry 4). The preformation of the intermediate 3 was
found to be very necessary (entries 3 and 5). Intrigued by the
above results, we conducted a solvent and base screen using this
protocol (unless otherwise specified entry 3) and monitored by
HPLC analysis. The results are summarized in Table 1. Methanol
was found to be the most favorable solvent for this cascade re-
action (entries 5e8) and Na2CO3 was selected as the best base
under this reaction condition, which substantially increased the
yield (entries 5 and 9e12).
g
trophilic
a
site) reactions of nitroallylic acetates and N-tosyl
hydrazine.
Using the optimized reaction condition, we investigated the
scope of this unique one-pot pyrazole formation reaction and the
results are summarized in Table 2. The pyrazole structures (4aer)
were established by HRMS, 1H and 13C NMR spectroscopic analysis
and further confirmed by X-ray diffraction study of 4h (Fig. 2).11 As
presented in Table 2, the reaction can tolerate various nitroallylic
acetates with either aromatic or aliphatic substituents. Both
electron-donating and -withdrawing groups on the phenyl ring
afforded the desired product with good isolated yields. The nitro-
allylic acetates with electron withdrawing substituents on phenyl
ring showed high isolated yields of pyrazoles 4 (entries 2e6 and
11). Further analysis of the results indicates that the efficiency of
the para halide substituted phenyl ring (entries 2e4) ranks as
Scheme 1. New case of nitroallylic acetates reactions.
2. Results and discussion
FiCliBr. Among them, 4-fluoro phenyl substituted nitroallylic ace-
tate afforded 4b with an excellent isolated yield of 96% (entry 2).
Our initially initial experiments were performed with nitro-
allylic acetate 1a and N-tosyl hydrazine10 2 under different condi-
tions (Table 1). Two solvents employed in the literature,9b,d THF and
methanol, were tested first at room temperature. Methanol was
found to be much more efficient for the transformation. We were
pleased to note the formation of a sole product, which was further
purified and determined to be the reaction intermediate 3 (Table 1,
3h of Scheme 1 as an example). Unexpectedly, the HMBC analysis of
3h (Scheme 1) indicated that this process in our case was initiated
Table 2
Pyrazoles from nitroallylic acetates and N-tosyl hydrazines
Entry
R
Product
Yielda (%)
for the first time by a SN2 reaction at the electrophilic site
Scheme 1), which might due to the ‘hard’ nucleophilic nature of the
nitrogen atom in tosyl hydrazine.
g (II,
1
2
3
4
5
6
7
8
Ph
4-FePh
4-ClePh
4-BrePh
2-BrePh
3-BrePh
4-CH3ePh
4-OCH3ePh
4-N(CH3)2ePh
4-OAcePh
3-CF3vPh
2-Furyl
1-Naphthyl
3-Cyclohexenyl
Propyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
79
96
87
80
83
84
74
70
72
77
82
69
80
70
70
81
87
61
Table 1
Screening of reaction conditionsa
9
10
11
12
13
14
15
16
17
18
Entry
Base
Solvent
T (ꢀC)
Yieldb (%)
Isopropyl
Cyclopropyl
Cyclohexyl
1
d
MeOH
MeOH
MeOH
MeOH
MeOH
THF
CH3CN
DMF
MeOH
MeOH
MeOH
MeOH
25
65
65
25
65
65
81
80
65
65
65
65
0
0
49
0
79
66
60
41
71
19
37
11
2
d
3c
4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DABCO
DBU
a
Isolated yield.
5
6
7
8
9
10
11
12
Et3N
a
Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol) in solvent (1 mL) were stirred
at room temperature for 30 min. Then base (0.1 mmol) was added and the mixture
was stirred for 2 h.
b
Isolated yield of 4a. The most successful entry is highlighted in bold.
c
Reaction was directly stirred at 65 ꢀC.
Fig. 2. Crystal structure of 4h.

N. Shao et al. / Tetrahedron 70 (2014) 795e799
797
Based on these experimental results, we proposed the cascade
SN2-Michael reaction mechanism as shown in Scheme 2. In the
was purified by flash column chromatography (petroleum ether/
EtOAc) on silica gel to afford the desired pyrazole 4.
absence of base, the electrophilic
g site of the nitroallylic acetate
was attacked by the electron-rich nucleophilic nitrogen of N-tosyl
hydrazine 2 to afford the intermediate 3. The intermediate 3h, as an
example, was isolated and its structure was confirmed by NMR.
4.2.1. Ethyl 3-phenyl-1H-pyrazole-5-carboxylate (4a). White solid.
Mp: 107e108 ꢀC; 1H NMR (500 MHz, CDCl3):
d 7.72 (2H, d,
J¼7.0 Hz), 7.39 (2H, t, J¼7.5 Hz), 7.33 (1H, t, J¼7.5 Hz), 7.03 (1H, s),
Then the Michael addition at the electrophilic
a site of 3 was ini-
4.26 (2H, q, J¼7.0 Hz), 1.27 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz,
tiated by addition of base to the reaction mixture and an increase of
the reaction temperature to 65 ꢀC. Subsequent elimination and
aromatization of the intermediate provided the product 4.
CDCl3): d 161.1, 148.4, 140.2, 130.4, 129.0, 128.7, 125.8, 105.4, 61.0,
14.2; HRMS calcd for C12H13N2O2þHþ: 217.0977, found: 217.0980.
4.2.2. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate
(4b). White solid. Mp: 145e146 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.72 (2H, dd, J¼8.5, 5.5 Hz), 7.09 (2H, t, J¼8.5 Hz), 6.99 (1H, s), 4.30
(2H, q, J¼7.0 Hz), 1.31 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
162.9 (d, J¼247 Hz), 160.5, 127.5 (d, J¼8 Hz), 127.1, 115.9 (d,
J¼22 Hz), 105.2, 61.3, 14.2; HRMS calcd for C12H12FN2O2þHþ:
235.0883, found: 235.0887.
4.2.3. Ethyl 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylate
(4c). White solid. Mp: 146e147 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.68 (2H, d, J¼8.5 Hz), 7.36 (2H, d, J¼8.0 Hz), 7.01 (1H, s), 4.31 (2H,
q, J¼7.0 Hz), 1.32 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
Scheme 2. Proposed mechanism.
d
160.4, 134.4, 129.7, 129.1, 126.9, 105.4, 61.4, 14.2; HRMS calcd for
C
12H12ClN2O2þHþ: 251.0587, found: 251.0591.
3. Conclusions
4.2.4. Ethyl 3-(4-bromophenyl)-1H-pyrazole-5-carboxylate
In summary, starting from the nitroallylic acetates 1 and N-tosyl
hydrazine 2, a novel regioselective synthetic approach of 3,5-
disubstituted pyrazoles has been described. This synthetic pro-
tocol appears to be useful and convenient due to the readily
available starting materials, operational simplicity, mild conditions,
and high isolated yields. Notably, the reactions of nitroallylic ace-
tates were initiated for the first time by the SN2 reaction at an
(4d). White solid. Mp: 145e147 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.64 (2H, d, J¼8.4 Hz), 7.54 (2H, d, J¼8.4 Hz), 7.07 (1H, s), 4.37 (2H,
q, J¼6.8 Hz), 1.37 (3H, t, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3):
d
160.1, 132.0, 130.3, 127.2, 122.5, 105.6, 61.5, 14.2; HRMS calcd for
C
12H12BrN2O2þHþ: 295.0082, found: 295.0088.
4.2.5. Ethyl 3-(2-bromophenyl)-1H-pyrazole-5-carboxylate
(4e). Light yellow oil; 1H NMR (500 MHz, CDCl3):
7.67 (1H, d,
electrophilic
g site. The results herein provide insights to the re-
d
activity of nitroallylic acetates with bifunctional nucleophiles.
Further investigation on transformation of nitroallylic acetates to
a wider range of valuable heterocycles is underway.
J¼8.0 Hz), 7.61 (1H, dd, J¼8.0,1.5 Hz), 7.37 (1H, t, J¼7.5 Hz), 7.24 (1H,
td, J¼7.5, 1.5 Hz), 7.23 (1H, s), 4.41 (2H, q, J¼7.0 Hz), 1.40 (3H, t,
J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 160.8, 133.8, 131.7, 131.0,
130.0, 127.7, 121.8, 109.3, 61.4, 14.3; HRMS calcd for
C
12H12BrN2O2þHþ: 295.0082, found: 295.0088.
4. Experimental section
4.1. General
4.2.6. Ethyl 3-(3-bromophenyl)-1H-pyrazole-5-carboxylate
(4f). Brown oil; 1H NMR (500 MHz, CDCl3):
7.98 (1H, s), 7.71
d
(1H, d, J¼8.0 Hz), 7.47 (1H, d, J¼8.0 Hz), 7.28 (1H, t, J¼8.0 Hz), 7.10
Purifications of reaction products were carried out by chroma-
tography using silica gel (200e300 mesh). Melting points were
(1H, s), 4.39 (2H, q, J¼7.0 Hz), 1.38 (3H, t, J¼7.0 Hz); 13C NMR
€
(125 MHz, CDCl3):
d 160.1, 133.5, 131.4, 130.4, 128.7, 124.2, 123.0,
recorded on a BUCHI B-540 melting point apparatus. NMR spectra
105.9, 61.6, 14.2; HRMS calcd for C12H12BrN2O2þHþ: 295.0082,
were mostly recorded for 1H NMR at 500 MHz and for 13C NMR at
125 MHz while some of them were recorded for 1H NMR at
400 MHz and for 13C NMR at 100 MHz. For 1H NMR, tetrame-
found: 295.0087.
4.2.7. Ethyl
3-(p-tolyl)-1H-pyrazole-5-carboxylate
(4g). White
7.62 (2H, d,
thylsilane (TMS) served as internal standard (d). The spectral data
solid. Mp: 145e146 ꢀC; 1H NMR (500 MHz, CDCl3):
d
presented here are reported as follows: chemical shift, integration,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), and coupling constant(s) in Hertz. For 13C NMR TMS
J¼8.0 Hz), 7.22 (2H, d, J¼8.0 Hz), 7.05 (1H, s), 4.36 (2H, q, J¼7.0 Hz),
2.38 (3H, s), 1.36 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
160.8, 138.6, 129.6, 127.9, 125.6, 105.2, 61.2, 29.7, 21.3, 14.2; HRMS
(
d
¼0) or CDCl3 ( ¼77.26) was used as internal standard and spectra
d
calcd For C13H15N2O2þHþ: 231.1134, found: 231.1141.
were obtained with complete proton decoupling. HRMS were ob-
tained using ESI ionization. The starting material nitroallylic ace-
tates 1 were prepared according to the known methods.12,13
4.2.8. Ethyl 3-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate
(4h). White solid. Mp: 152e153 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.62 (2H, d, J¼8.5 Hz), 6.93 (1H, s), 6.91 (2H, d, J¼8.5 Hz), 4.25 (2H,
4.2. General procedure for the synthesis of 3,5-disubstituted
pyrazoles 4
q, J¼7.0 Hz), 3.82 (3H, s), 1.26 (3H, t, J¼7.5 Hz); 13C NMR (125 MHz,
CDCl3):
d 161.1, 159.9, 148.0, 140.3, 127.0, 122.9, 114.3, 104.5, 61.1,
55.3, 14.1; HRMS calcd for C13H15N2O3þHþ: 247.1083, found:
A mixture of 4-methylbenzenesulfonylhydrazide (2, 1.0 equiv)
and nitroallylic acetate (1, 1.0 equiv) was dissolved in CH3OH (1 mL)
and stirred at room temperature for 30 min. Then Na2CO3
(0.1 mmol) was added and the mixture was refluxed at 65 ꢀC for 2 h.
The reaction mixture was concentrated in vacuum and the crude
247.1090.
4.2.9. Ethyl 3-(4-(dimethylamino)phenyl)-1H-pyrazole-5-
carboxylate (4i). Brown oil; 1H NMR (400 MHz, CDCl3):
d
7.57
(2H, d, J¼8.8 Hz), 6.95 (1H, s), 6.76 (2H, d, J¼8.8 Hz), 4.36 (2H, q,

798
N. Shao et al. / Tetrahedron 70 (2014) 795e799
J¼7.2 Hz), 2.99 (6H, s), 1.36 (3H, t, J¼7.2 Hz); 13C NMR (100 MHz,
104.3, 61.0, 14.3, 8.0, 7.5; HRMS calcd for C9H13N2O2þHþ: 181.0977,
CDCl3):
d
161.5, 150.4, 148.4, 140.9, 126.7, 118.6, 112.7, 104.1, 61.1,
found: 181.0969.
40.6, 14.3; HRMS calcd for C14H18N3O2þHþ: 260.1399, found:
260.1407.
4.2.18. Ethyl 3-cyclohexyl-1H-pyrazole-5-carboxylate (4r). White
solid. Mp: 99e101 ꢀC; 1H NMR (400 MHz, CDCl3):
d 6.60 (1H, s), 4.36
4.2.10. Ethyl 3-(4-acetoxyphenyl)-1H-pyrazole-5-carboxylate
(2H, q, J¼7.2 Hz), 2.74e2.64 (1H, m), 2.04e1.95 (2H, m), 1.85e1.76
(4j). Light yellow solid. Mp: 144e145 ꢀC; 1H NMR (400 MHz,
(2H, m), 1.76e1.67 (1H, m), 1.48e1.33 (4H, m), 1.37 (3H, t, J¼7.2 Hz),
CDCl3):
d
7.76 (2H, d, J¼7.6 Hz), 7.14 (2H, d, J¼7.6 Hz), 7.07 (1H, s),
1.30e1.21 (1H, m); 13C NMR (100 MHz, CDCl3):
d 161.7, 104.9, 60.9,
4.39 (2H, q, J¼7.2 Hz), 2.32 (3H, s), 1.38 (3H, t, J¼7.2 Hz); 13C NMR
35.8, 32.7, 26.0, 25.8, 14.3; HRMS calcd for C12H19N2O2þHþ:
(100 MHz, CDCl3):
d
169.4, 160.3, 150.8, 149.6, 138.3, 129.0, 126.9,
223.1447, found: 223.1486.
122.1, 105.6, 61.4, 21.1, 14.2; HRMS calcd for C14H15N2O4þHþ:
275.1032, found: 275.1027.
Acknowledgements
4.2.11. Ethyl 3-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-
carboxylate (4k). White solid. Mp: 114e116 ꢀC; 1H NMR
This work was supported by the National Natural Science
Foundation of China (21272207), Natural Science Foundation of
Zhejiang Province (LY12H30006), and Zhejiang Qianjiang Talent
Plan (2011R10023). We thank Yongping Yu and Sunliang Cui
(Zhejiang University, China) for valuable discussions and Marc A.
Giulianotti (Torrey Pines Institute for Molecular Studies, USA) for
critical reading of the manuscript.
(500 MHz, CDCl3):
d
8.08 (1H, s), 8.00 (1H, d, J¼8.0 Hz), 7.60 (1H, d,
J¼7.5 Hz), 7.55 (1H, t, J¼8.0 Hz), 7.18 (1H, s), 4.42 (2H, q, J¼7.0 Hz),
1.40 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 159.9, 150.2,
136.9, 132.6, 131.3 (q, J¼32 Hz), 129.4, 128.9, 125.0 (q, J¼4 Hz), 124.0
(d, J¼271 Hz), 122.5 (q, J¼4 Hz), 105.9, 61.7, 14.2; HRMS calcd for
C
13H12F3N2O2þHþ: 285.0851, found: 285.0848.
Supplementary data
4.2.12. Ethyl 3-(furan-2-yl)-1H-pyrazole-5-carboxylate (4l). Brown
oil; 1H NMR (400 MHz, CDCl3):
7.48 (1H, d, J¼1.6 Hz), 7.03 (1H, s),
Copies of 1H and 13C NMR spectra for all products. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2013.12.046. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
d
6.74 (1H, d, J¼3.2 Hz), 6.50 (1H, dd, J¼3.2, 1.6 Hz), 4.41 (2H, q,
J¼7.2 Hz), 1.41 (3H, t, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d 160.2,
142.6, 129.5, 128.0, 122.2, 111.6, 107.2, 105.0, 61.5, 14.3; HRMS
calcd for C11H10N2O3þHþ: 207.0770, found: 207.0777.
4.2.13. Ethyl 3-(naphthalen-1-yl)-1H-pyrazole-5-carboxylate
References and notes
(4m). Yellow oil; 1H NMR (500 MHz, CDCl3):
d 8.18 (1H, d,
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€
Arnsmann, M.; Totzke, F.; Ehlert, J. E.; Kubbutat, M. H.; Schachtele, C.;
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Buckingham, S. D.; Sattelle, D. B. Br. J. Pharmacol. 1995, 115, 909e912; (c) Boolell,
M.; Allen, M. J.; Ballard, S. A.; Gepi-Attee, S.; Muirhead, G. J.; Naylor, A. M.;
Osterloh, I. H.; Gingell, C. Int. J. Impotence Res. 1996, 8, 47e52.
4.2.14. Ethyl 3-(cyclohex-3-en-1-yl)-1H-pyrazole-5-carboxylate
(4n). White solid. Mp: 77e78 ꢀC; 1H NMR (400 MHz, CDCl3):
d
6.63 (1H, s), 5.74 (2H, m), 4.37 (2H, q, J¼7.2 Hz), 3.06e2.99 (1H,
m), 2.45e2.35 (1H, m), 2.23e2.10 (3H, m), 2.07e2.00 (1H, m),
1.78e1.67 (1H, m),1.38 (3H, t, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
161.5, 127.2, 125.6, 105.3, 61.0, 31.8, 31.0, 28.4, 24.6, 14.3; HRMS
calcd for C12H17N2O2þHþ: 221.1290, found: 221.1293.
4.2.15. Ethyl 3-propyl-1H-pyrazole-5-carboxylate (4o). Yellow oil;
1H NMR (400 MHz, CDCl3):
d
6.60 (1H, s), 4.36 (2H, q, J¼7.2 Hz), 2.66
(2H, t, J¼7.6 Hz), 1.67 (2H, m), 1.37 (3H, t, J¼7.2 Hz), 0.96 (3H, t,
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3):
d 161.6, 148.5, 140.8, 106.5,
3. Romagnoli, C.; Andreotti, E.; Mares, D. J. Agric. Food Chem. 2007, 55,
10331e10338.
60.9, 28.3, 22.4, 14.3, 13.6; HRMS calcd for C9H15N2O2þHþ:
ꢀ
4. (a) Cavero, E.; Uriel, S.; Romero, P.; Serrano, J. L.; Gimenez, R. J. Am. Chem. Soc.
2007, 129, 11608e11618; (b) Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.;
Twamley, B.; Shreeve, J. M. Org. Lett. 2007, 9, 3841e3844.
183.1134, found: 183.1140.
5. For excellent reviews and some latest articles on the synthetic methodologies,
see: (a) Fustero, S.; Simon-Fuentes, A.; Sanz-Cervera, J. F. Org. Prep. Proced. Int.
4.2.16. Ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (4p). Light yel-
ꢀ
low oil; 1H NMR (400 MHz, CDCl3):
d
6.62 (1H, s), 4.37 (2H, t,
ꢀ
ꢀ
ꢀ
2009, 41, 253e290; (b) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-
Fuentes, A. Chem. Rev. 2011, 111, 6984e7034; (c) Zou, H.; Zhu, H.; Shao, J.; Wu, J.;
Chen, W.; Glulianotti, M. A.; Yu, Y. Tetrahedron 2011, 67, 4887e4891; (d) Janin,
Y. L. Chem. Rev. 2012, 112, 3924e3958; (e) Zhang, T.; Bao, W. J. Org. Chem. 2013,
78, 1317e1322; (f) Xu, X.; Zavalij, P. Y.; Hu, W.; Doyle, M. P. J. Org. Chem. 2013, 78,
1583e1588.
J¼7.2 Hz), 3.03 (1H, m), 1.37 (3H, t, J¼7.2 Hz), 1.29 (6H, d, J¼6.8 Hz);
13C NMR (100 MHz, CDCl3):
d 160.5, 153.8, 139.5, 103.8, 60.0, 25.5,
21.4, 13.3; HRMS calcd for C9H15N2O2þHþ: 183.1134, found:
183.1139.
6. For selected examples, see: (a) Persson, T.; Nielsen, J. Org. Lett. 2006, 8,
3219e3222; (b) Duncan, N. C.; Garner, C. M.; Nguyen, T.; Hung, F.; Klausmeyer,
K. Tetrahedron Lett. 2008, 49, 5766e5769; (c) Prakash, O.; Sharma, D.; Kamal, R.;
Kumar, R.; Nair, R. R. Tetrahedron 2009, 65, 10175e10181; (d) Gerstenberger, B.
S.; Rauckhorst, M. R.; Starr, J. T. Org. Lett. 2009, 11, 2097e2100; (e) Singh, S. K.;
Reddy, M. S.; Shivaramakrishna, S.; Kavitha, D.; Vasudev, R.; Babu, J. M.; Siva-
lakshmidevi, A.; Rao, Y. K. Tetrahedron Lett. 2004, 45, 7679e7682; (f) Patel, M.
4.2.17. Ethyl 3-cyclopropyl-1H-pyrazole-5-carboxylate (4q). White
solid. Mp: 102e103 ꢀC; 1H NMR (400 MHz, CDCl3):
d
6.44 (1H, s),
4.35 (2H, q, J¼7.2 Hz), 1.89 (1H, m), 1.35 (3H, t, J¼7.2 Hz), 0.90 (2H,
m), 0.67 (2H, m); 13C NMR (100 MHz, CDCl3):
161.4, 151.4, 140.2,
d

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V.; Bell, R.; Majest, S.; Henry, R.; Kolasa, T. J. Org. Chem. 2004, 69, 7058e7065;
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Micheli, C. D. Tetrahedron 2007, 63, 5554e5560; (b) Donohue, S. R.; Halldin, C.;
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