Microwave-assisted synthesis of pyrazoles by 1,3-dipolar cycloaddition of diazo compounds to acetylene derivatives

Article abstract of DOI:10.3987/COM-06-10803

Microwave-assisted preparation of a wide range of 5-ethoxycarbonylpyrazoles and 3-pyrazoles by 1,3-dipolar cycloaddition of diazo compound to acetylenes is described. All reactions were carried out using high throughput sequential technique.{A figure is p

Full text of DOI:10.3987/COM-06-10803

HETEROCYCLES, Vol. 68, No. 9, 2006
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HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1961 - 1967. © The Japan Institute of Heterocyclic Chemistry
Received, 7th June, 2006, Accepted, 14th July, 2006, Published online, 18th July, 2006. COM-06-10803
MICROWAVE-ASSISTED SYNTHESIS OF PYRAZOLES BY
1,3-DIPOLAR CYCLOADDITION OF DIAZO COMPOUNDS TO
ACETYLENE DERIVATIVES
Irena Zrinski, Marina Juribasic, and Mirjana Eckert-Maksic*
Division of Organic Chemistry and Biochemistry, Rudjer Boskovic Institute,
P.O.B. 180, HR-10002 Zagreb, Croatia; *Corresponding author. Tel.:+385 1 4680
197 fax:+385 1 4680 195; e-mail:mmaksic@emma.irb.hr
Abstract
–
Microwave-assisted preparation of
a
wide range of
5-ethoxycarbonylpyrazoles and 3-pyrazoles by 1,3-dipolar cycloaddition of diazo
compound to acetylenes is described. All reactions were carried out using high
throughput sequential technique.
INTRODUCTION
Pyrazole derivatives have been subject of broad interest due to their wide application in pharmaceutical and
agrochemical industry.1 The most widely used method of their synthesis has been the reaction between
1,3-dicarbonyl compounds and hydrazines.2,3 Its usage is, however, somewhat limited due to the harsh
reaction conditions or the multistep sequences usually required to access the starting materials. Another
popular method involves 1,3-dipolar cycloaddition of diazo compounds or some other 1,3-dipoles to the
triple bond.2,4 These reactions lead to formation of 3H-pyrazoles that can be isolated when di-substituted
diazomethanes are employed. In case of the parent diazomethane and monosubstituted diazomethanes
unstable 3H-pyrazoles are formed, which subsequently undergo 1,5-sigmatropic shift yielding pyrazoles as
the final product.2 In last few years, several new approaches to synthesis of pyrazoles derivatives, including
the microwave-assisted synthesis by Vilsmeier cyclization of hydrazones5a and pyrazole libraries obtained
by imine cycloaddition to the polymer-supported vinylsulfone5b have been developed.5
Herewith, we report on preparation of some substituted pyrazoles by 1,3-dipolar cycloaddition of diazo
compounds (1) and (2) to variety of acetylene derivatives assisted by controlled microwave (MW) heating
in a high-throughput fashion (Scheme 1 and Table 1). To the best of our knowledge the effect of microwave
heating on reactivity of ethyl diazoacetate (1) has been reported only towards alkenes, while reactivity of
acetylene derivatives has not been explored so far.6 We were particularly interested in exploring possibility

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HETEROCYCLES, Vol. 68, No. 9, 2006
of obtaining derivatives of pyrazoles of type (5) by replacing diazomethane with more stable trimethylsilyl
derivative.7 Given the high tendency of the TMS for migration, we anticipated that the TMS group will
undergo 1,5-shift more easily than H-atom giving rise to formation of 1-trimethylsilyl-derivative of 58
followed by hydrolytic cleavage of the N-Si bond to pyrazole (5).9
R1
R2
R2
R1
1,5-H shift
H
+
N
N
N
+
N
EtO2C
N
EtO2C
N
R
MW
10-45 min, 120 -140 C
H
3
H
4
°
R1
R2
R1
R2
1 R = CO2Et
2 R = SiMe3
1,5-Me3Si shift, H2O
N
H
N
H
5
Scheme 1
RESULTS AND DISCUSSION
We first explored reactivity of 1 towards a series of acetylene derivatives as summarized in Table 1(Entries
1 – 11). The reaction was carried out using neat reaction conditions. All the alkynes reacted smoothly with
ethyl diazoacetate to give the target pyrazole product in good to high yields with high regioselectivity with
one notable exception provided by 3-hexyne, which failed to give the desired product even in trace amount
(Entry 9). Instead, at higher temperature (140 °C) decomposition of the reaction mixture was observed. In
the case of reactions of 1 and mono(n-alkyl) substituted acetylenes, a mixture containing two regioisomeric
products (3) and (4) were formed, with the former product being predominant (Entries 1 and 3). In all other
cases the 3(5)-ethoxycarbonylpyrazoles (3) were the only products formed.
We next investigated reactivity of (trimethylsilyl)diazomethane (2) using the same acetylenic derivatives as
in the first set of experiments (Table 1, Entries 12 – 19). These reactions were carried out by irradiating a
mixture of 2.0 M solution of (trimethylsilyl)diazomethane (2) in hexane and acetylene derivatives. As
expected, in each case except with 3-hexyne (Entry 17), the only product formed was the corresponding
derivative of 3-pyrazole (5). This conclusion was corroborated by carrying out GC-MS analysis of the
reaction products obtained by reacting phenylacetylene and 2 immediately after completion of reaction and
after keeping it in an open vessel during night. In case of the former experiment the GC-MS analysis
exhibited only one signal with molecular ion mass of 216 dalton (which corresponds to the
3-(phenyl)-1-trimethylsilyl-pyrazole), whereas in the latter presence of a new signal with molecular ion

HETEROCYCLES, Vol. 68, No. 9, 2006
1963
mass of 144 dalton (which corresponds to the hydrolyzed product (5)) was observed.10 Based on 1H NMR
analysis the structure of the 3-(phenyl)-1-trimethylsilyl-pyrazole could be unequivocally assigned to the
isomer with the TMS group at the nitrogen atom.10
Table 1. 1,3-Dipolar cycloaddition reaction of diazo compounds (1), (2) and mono(di)-substituted
acetylenes
Entry
1a
R1
H
R2
n-Bu
n-Bu
n-Hex
CMe3
SiMe3
SiMe3
Ph
Reaction condition
MW, 140 °C, 30 min
∆, 48 h
Ratio of isomers (3) : (4)c Yield (%)d
9.1: 0.9
60e
38e
65
58
95
67
97e
81e
-
2a
H
8.7 : 1.3
3a
4a
H
MW, 140 °C, 30 min
MW, 140 °C, 45 min
MW, 120 °C, 15 min
∆, 48 h
8.5 : 1.5
H
1 : 0
5a
6a
H
1 : 0
H
1 : 0
7a
H
MW, 120 °C, 10 min
∆, 24 h
1 : 0
8a
H
Ph
1 : 0
9a
Et
Et
MW, 140 °C, 20 min
MW, 140 °C, 20 min
MW, 140 °C, 20 min
-
10a
11a
SiMe3
Ph
SiMe3
Ph
-
98e
96e
-
products (5)
12b
13b
14b
15b
16b
17b
18b
19b
H
H
n-Bu
n-Hex
CMe3
SiMe3
Ph
MW, 140 °C, 30 min
MW, 140 °C, 30 min
MW, 140 °C, 45 min
MW, 120 °C, 15 min
MW, 120 °C, 10 min
MW, 140 °C, 20 min
MW, 140 °C, 45 min
-
-
-
-
-
-
-
-
58e
60
H
55e
97e
96e
-
H
H
Et
Et
SiMe3
SiMe3
55e, f
61e, f
Ph
Ph
MW, 140 °C, 45 min
b
c
aReaction with ethyl diazoacetate (1). Reaction with (trimethylsilyl)diazomethane (2). The ratio of the
1
d
regioisomeric products was determined by H NMR analysis of crude reaction mixture. Isolated yields.
eNMR data were identical to those reported previously in literature. fThe product (5) was accompanied by
small amount of the starting acetylene derivative.

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HETEROCYCLES, Vol. 68, No. 9, 2006
Closer analysis of the results in Table 1 shows that all MW reactions, irrespective of the diazo compound
employed, were accomplished within 10 – 45 minutes. Another point worth of noting is that reactions of
acetylenes substituted with one electron-withdrawing group (Me3Si, Ph) (Entries 5, 7, 15 and 16) proceeded
at lower temperature and with higher yields than those substituted with one electron-accepting group
(Entries 1, 3, 4 and 12 - 14). We note in passing that the above mentioned trends are consistent with changes
in HOMO-LUMO energy gaps between diazocarbonyl compounds and employed alkynes calculated using
DFT method.11 Furthermore, the rate of reactions was found to be dependent on steric effects, as evidenced
by comparing reactions of mono- and di-substituted acetylenes.4
Finally, it is of some interest to compare results described above with those obtained by conventional
synthesis.2,12 For this purpose we have carried out several reactions using ethyldiazoacetate as a starting
dipole under conventional heating (Table 1, Entries 2, 6 and 8). In each case the reaction time was
considerably longer and work up more difficult than in MW syntheses. The same holds for comparison of
the present results with those obtained by alternative methods, e.g. with diazomethane as the starting
compound being typical example.2,12 In addition, as mentioned above, both ethyl diazoacetate (1) and
trimethylsilyl-substituted diazomethane (2) used in this work are more stable and less toxic and thus safer
for practical use than diazomethane itself.7
To summarize, we have prepared a variety of pyrazoles of type (3), (4) and (5) in a high-throughput fashion
using microwave assisted 1,3-dipolar cycloaddition of substituted diazo compounds and corresponding
mono- and di-substituted acetylene derivatives. This opens a simple route to a wide range of
polyfunctionalized pyrazoles in a short reaction times, offering at the same time efficient way of generating
a library of pyrazoles starting from various diazo compounds and acetylene derivatives. Finally, it should
be emphasized that the synthesis of 5-ethoxycarbonylpyrazoles (3) and (4) presents one of few examples of
intermolecular 1,3-dipolar cycloaddition of electron-deficient diazocarbonyl compounds with alkynes
described in literature so far.2,5g,13 This is of considerable importance since 3(5)-alkoxycarbonyl pyrazoles
and their derivatives have been often used as precursors to a variety of five- and six-membered heterocyclic
compounds.5,14
EXPERIMENTAL
Microwave Irradiation Experiments. All microwave irradiation experiments were carried out using
CEM Discover® LabMateTH/ExplorerPLS® monomode reactor in a high-throughtput sequential fashion.
All experiments were performed in sealed microwave process vials with MW power from 150 - 250 W
depending on MW absorbing capability of reaction mixture. Reaction time under MW conditions

HETEROCYCLES, Vol. 68, No. 9, 2006
1965
corresponds to actual reaction time at given temperature without ramp time needed to reach desired
temperature (see Table 1).
The crude products were purified by radial chromatography using Harrison Research 7924T Chromatotron
and Merck silica gel 60 PF254 containing CaSO4. GC analyses were carried out on Varian 3300 gas
1
chromatograph. Infrared spectra (IR) were recorded on Perkin-Elmer FT 2000 infrared spectrometer. H
and 13C NMR spectra were measured on a Bruker AV-300. Chemical shifts are reported in parts per million
(δ/ppm) downfield from tetramethylsilane using the residual solvent signal as an internal standard. GC–MS
analyses were measured on Hewlett-Packard 5890 Series II gas chromatograph. Elemental analyses of new
compounds (Table 1, Entries 3 and 13) were carried out using a PerkinElmer 2400 Series II CHNS/O
analyser.
(a) Synthesis of 5-ethoxycarbonyl pyrazoles (3) and (4). General procedure: A mixture of diazo
compound (1) (1 mmol) and acetylene (10 mmol) in 5 mL (large) microwave process vial was irradiated in
the MW reactor with magnetic stirring for 10 – 45 min at 120 – 140 °C (see Table 1). The excess of
acetylene was recovered by distillation under reduced pressure (10 mmHg/25 °C). The reaction mixture
was treated with CH2Cl2 and than concentrated in vacuo. In reactions giving less than 95 % purity (GC) of
product after CH2Cl2 evaporation the residue was further purified by radial chromatography on SiO2
(eluent: petrol ether and AcOEt).
3-n-Hexyl-5-ethoxycarbonyl-1H-pyrazole (Entry 3): 1H NMR (300 MHz, CDCl3), δ/ppm: 0.81-0.85 (m,
3H), 1.25-1.34 (m, 9H), 1.57-1.62 (m, 2H), 2.66-2.77 (t, J=7.6 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H), 6.55 (s, 1H).
13C NMR (300 MHz, CDCl3), δ/ppm: 14.0, 14.2, 22.5, 26.8, 28.7, 29.1, 31.5, 60.8, 106.1, 141.6, 147.9,
162.0. IR (CHCl3), υ/cm-1: 1719, 3443. Anal. Calcd for C12H20N2O2: C 64.26, H 8.99, N 12.49. Found: C
64.0, H 9.04, N 12.64.
3-t-Butyl-5-ethoxycarbonyl-1H-pyrazole (Entry 4):15 1H NMR (300 MHz, CDCl3), δ/ppm: 1.24-1.39 (m,
12 H), 4.34 (q, J=7.1 Hz, 2H), 6.61 (s, 1H). 13C NMR (300 MHz, CDCl3), δ/ppm: 14.2, 30.14, 31.3, 60.77,
104.24, 141.0, 156.90, 161.92.
3-Trimethylsilyl-5-ethoxycarbonyl-1H-pyrazole (Entry 5):12a 1H NMR (300 MHz, CDCl3), δ/ppm: 0.22
(s, 9H), 1.17-1.21 (t, 3H, J = 7.18 Hz), 4.27 (q, 2H, J = 7.05 Hz), 6.87 (s, 1H), 12.94 (br. s. NH). 13C NMR
(300 MHz, CDCl3), δ/ppm: -1.74 (q), 13.79 (q), 60.37 (t), 114.98 (d), 143.47 (s), 144.35 (s), 162.74 (s).
(b) Synthesis of 3-pyrazoles (5). General procedure: A mixture of 2 M solution of diazo compounds (2)
(1 mL, 2 mmol) and acetylenes (2 mmol) in 5 mL (large) microwave process vial was irradiated in the
MW reactor with magnetic stirring for 10 – 45 min at 120 – 140 °C (see Table 1). Reaction mixture was
diluted wiht CH2Cl2 and than concentrated in vacuo. In reactions giving less than 95 % purity (GC) of
products after CH2Cl2 evaporation the residue was further purified by radial chromatography on silica gel
(eluent: petrol ether and AcOEt).

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HETEROCYCLES, Vol. 68, No. 9, 2006
1
3-n-Hexyl-1H-pyrazole (Entry 13): H NMR (300 MHz, CDCl3), δ/ppm: 0.92-0.97 (t, 3H, J=7.1 Hz),
1.20-1.30 (m, 6H), 1.60-1.65 (m, 2H), 2.69-2.73 (t, J=7.6 Hz, 2H), 6.1 (d, J=1.3, 1H), 7.51 (d, J=1.7 Hz,
1H). 13C NMR (300 MHz, CDCl3), δ/ppm: 13.82, 22.5, 26.4, 28.7, 29.1, 32.0, 103.30, 135.10, 147.81. Anal.
Calcd for C9H16N2: C 71.01, H 10.60, N 18.40. Found: C 71.16, H 10.49, N 18.54.
ACKNOWLEDGEMENTS
This work was supported by Ministry of Science and Technology of the Republic of Croatia (Project No.
0098056). We thank Mr. Sc. Z. Marinić for help in running NMR spectra.
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