Summary
In conclusion, we have demonstrated a simple, stoichio-
metric technique for the preparation of an array of 1,2-azoles
within an EOF-based microreactor, whereby excellent con-
versions were obtained in all cases.
combined extracts were dried (MgSO4) and concentrated in
vacuo, whereby purification by silica gel chromatography
(7-10% ethyl acetate in hexane) afforded the respective 1,2-
azole.
3,5-Dimethyl-1H-pyrazole (4):12 (0.48 g, 100%) as a pale
yellow solid; δH (400 MHz, CDCl3/TMS) 2.19 (6H, s, 2 ×
CH3), 5.75 (1H, s, CH), and 7.25 (1H, br s, NH); δC (100
MHz, CDCl3/TMS) 12.2 (2 × CH3), 104.0 (CH), and 144.4
(2 × CN); m/z (EI) 97 (M+ + 1, 100%) and 96 (5); GC-
MS retention time RT ) 7.35 min.
Experimental Section
Materials and Methods. All materials (analytical grade)
were purchased from Aldrich and were used without
purification. All NMR spectra were recorded as solutions in
deuteriochloroform (CDCl3) using tetramethylsilane (TMS)
as an internal standard. The spectra were recorded on a Joel
GX400 spectrometer and the chemical shifts given in parts
per million (ppm) with coupling constants in Hertz (Hz).
The following abbreviations are used to report NMR data:
s ) singlet, d ) doublet, t ) triplet, br s ) broad singlet, m
) multiplet, and C0 ) quaternary carbon. Gas chromatog-
raphy-mass spectrometry (GC-MS) was performed using
a Varian GC (CP-3800) coupled to a Varian MS (2000) with
a CP-Sil 8 (30 m) column (Phenomenex) and ultrahigh purity
helium (99.999%, Energas) carrier gas. Samples were
analysed using the following method: injector temperature
200 °C, helium flow rate 1 mL min-1, oven temperature 50
°C for 4 min and then ramped to 250 °C at 30 °C min-1,
with a 3.0 min filament delay.
Microreactor Methodology. The reactions described
herein were carried out using a three-channel microreactor,
as illustrated in Figure 1, with channel dimensions of 350
µm (wide) × 52 µm (deep) × 2.5 cm (long).10 To minimise
the effect of pressure gradients within the microchannels,
microporous silica frits were placed within the channels.11
To mobilise reagents by EOF, platinum electrodes (0.5 mm
o.d. × 2.5 cm) were placed within the reagent reservoirs
and voltages applied using a Paragon 3B high-voltage power
supply (HVPS) (capable of applying 0-1000 V to four pairs
of outputs) (Kingfield Electronics). Automation of the HVPS
using an in-house LabVIEW program enabled complex
sequences of voltages to be investigated. To enable the results
obtained to be applied to devices of different dimensions,
voltages are reported as applied fields (V cm-1), i.e. voltage/
channel length. To monitor the progress of the reaction,
experiments were conducted over a period of 20 min, after
which the product reservoir was analysed by GC-MS,
whereby comparison of the amount of product with respect
to residual starting material enabled the progression of the
reaction to be determined.
3-Methyl-5-phenyl-1H-pyrazole (5):13 (0.49 g, 100%)
as a pale yellow solid; δH (400 MHz, CDCl3/TMS) 2.35 (3H,
s, CH3), 6.36 (1H, s, CH), and 7.29-7.62 (5H, m, Ar) (NH
not observed); δC (100 MHz, CDCl3/TMS) 11.8 (CH3), 102.2
(CH), 125.7 (CH), 127.0 (2 × CH), 128.0 (CH), 128.6 (CH),
132.3 (C0), 143.2 (CNCH3), and 149.9 (CN); m/z (EI) 159
(M+ + 1, 75%), 158 (100), and 77 (5); GC-MS retention
time RT ) 10.43 min.
3-Phenyl-4,5,6,7-tetrahydro-2H-indazole (6):14 (0.49 g,
94%) as a pale yellow oil; δH (400 MHz, CDCl3/TMS) 1.85
(4H, m, 2 × CH2), 2.74 (2H, t, J 5.7, CH2), 2.86 (2H, t, J
5.7, CH2), 7.46 (3H, m, Ar), 7.80 (2H, m, Ar), and 12.14
(1H, br s, NH); δC (100 MHz, CDCl3/TMS) 21.4 (3 × CH2),
22.7 (CH2), 114.4 (C0), 127.5 (C0), 127.6 (2 × CH), 129.2
(2 × CH), 129.9 (CH), 142.4 (CN), and 145.4 (CN); m/z
(EI) 199 (M+ + 1, 100%), 198 (5), and 170 (10); GC-MS
retention time RT ) 12.71 min.
3,5-Diphenyl-1H-pyrazole (7):13 (0.42 g, 86%) as a pale
yellow solid; δH (400 MHz, CDCl3/TMS) 7.13 (1H, s, CH),
7.49 (6H, m, Ar), 7.96 (4H, m, Ar), and 9.96 (1H, br s, NH);
δC (100 MHz, CDCl3/TMS) 100.2 (CH), 126.0 (4 × CH),
127.6 (2 × C0), 128.6 (4 × CH), 129.3 (2 × CH), and 147.0
(2 × CN); m/z (EI) 221 (M+ + 1, 20%), 220 (100), and 77
(25); GC-MS retention time RT ) 14.98 min.
3,4-Dimethyl-5-phenyl-1H-pyrazole (8):15 (0.45 g, 93%)
as a pale yellow solid; δH (400 MHz, CDCl3/TMS) 2.13 (3H,
s, CH3), 2.25 (3H, s, CH3), 7.22 (3H, m, Ar), 7.32 (2H, m,
Ar), and 18.29 (1H, s, NH); δC (100 MHz, CDCl3/TMS)
10.9 (CH3), 31.4 (CH3), 127.4 (2 × CH), 127.9 (2 × CH),
128.7 (CH), 130.9 (C0), 141.9 (CNCH3), and 146.8 (CN);
m/z (EI) 173 (M+ + 1, 70%), 172 (100), and 77 (15); GC-
MS retention time RT ) 10.72 min.
5-Methyl-3-phenylisoxazole (11).16 Hydroxylamine hy-
drochloride 13 (0.21 g, 3.09 mmol) was dissolved in THF
(10 mL) and added dropwise to a stirred solution of
1-phenylbutane-1,3-dione 10 (0.50 g, 3.09 mmol) in THF
(10 mL). After stirring overnight, the reaction mixture was
concentrated in vacuo prior to the addition of water (50 mL),
and the reaction products were extracted into ethyl acetate
(3 × 50 mL). The combined organic extracts were dried
(MgSO4), concentrated in vacuo, and purified by silica gel
chromatography. Elution with 10% ethyl acetate in hexane
General Procedure for the Preparation of 1,2-Azoles
in Batch. A typical experimental procedure was as follows:
Hydrazine monohydrate 3 (1.1 equiv) in THF (2 mL mmol-1)
was added via a syringe to a stirred solution of 1,3-diketone
in THF (2 mL mmol-1) over a period of 30 min. After
stirring overnight, the reaction mixture was concentrated in
vacuo prior to the addition of water (50 mL), and the reaction
products were extracted into ethyl acetate (3 × 50 mL). The
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(13) Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis 1986, 409.
(14) Bunnelle, W. H.; Singam, P. R.; Narayanan, B. A.; Bradshaw, C. W.; Liou,
J. S. Synthesis 1997, 439.
(15) Tensmeyer, L. G.; Ainsworth, C. J. Org. Chem. 1996, 31, 1878.
(16) Werner, A.; Sanchez-Migallon, A.; Fruchier, A.; Elguero, J.; Fernandez-
Castano, C.; Foces-Foces, C. Tetrahedron 1995, 51, 4779.
(10) Broadwell, I.; Fletcher, P. D. I.; Haswell, S. J.; McCreedy, T.; Zhang, X.
Lab Chip 2001, 1, 66.
(11) Christensen, P. D.; Johnson, S. W. P.; McCreedy, T.; Skelton, V.; Wilson,
N. G. Anal. Chem. 1963, 35, 341.
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