Organic Process Research & Development
ARTICLE
analogues without investing any further time in reaction optim-
isation.
1-Methyl-6-(methyloxy)-1H-indazole (1f): yield 65% as a
pale-pink solid. 1H NMR (400 MHz, CDCl3): δ = 7.88
(1H, s), 7.58 (1H, d, J = 8.8), 6.81 (1H, dd, J = 8.8, 2.0), 6.72
(1H, bs), 4.03 (3H, s), 3.91 (3H, s).
’ CONCLUSION
6-Bromo-1-methyl-1H-indazole (1g): yield 49% as a brown
1
Here we have presented a versatile route to enable the rapid
and safe syntheses of a range of N-methylated indazoles and
analogues, both known and novel. Although we recognise that,
in most cases, the yields are somewhat moderate, these semi-
optimised “fit for purpose” conditions facilitated rapid synthesis
and scale-up as required without the need for any further optimisa-
tion. Furthermore, this approach represents a safe, practical, and
scalable method of performing high-temperature reactions involv-
ing hydrazine, which would otherwise be potentially hazardous in
batch mode.
solid. H NMR (400 MHz, CDCl3): δ = 7.95 (1H, bs), 7.60
(2H, m), 7.26 (1H, m), 4.05 (3H, s).
1,6-Dimethyl-1H-indazole (1h): yield 44% as an orange solid.
1H NMR (400 MHz, CDCl3): δ = 7.92 (1H, s), 7.61 (1H, d,
J = 8.0), 7.18 (1H bs), 6.99 (1H, d, J = 8.3), 4.05 (3H, s), 2.52
(3H, s).
1,3-Dimethyl-1H-indazole (1i): yield 57% as an orange solid.
1H NMR (400 MHz, CDCl3): δ = 7.66 (1H, d, J = 8.3), 7.37
(2H, m), 7.14 (1H, m) 4.01 (3H, s), 2.58 (3H, s).
1-Methyl-1H-pyrazolo[3,4-b]pyridine (1j): yield 73% as a
1
yellow solid. H NMR (400 MHz, CDCl3): δ = 8.55 (1H, dd,
J = 4.5, 1.5), 8.06 (1H, dd, J = 8.1, 1.5), 8.00 (1H, s), 7.11 (1H, dd,
J = 8.1, 4.5), 4.17 (3H, s).
’ EXPERIMENTAL SECTION
All reagents and solvents were of analytical grade and were
used without further purification. NMR spectra were recorded
on a Bruker Avance Ultrashield 400 using tetramethylsilane
(TMS) as an internal standard. LC/MS analyses were carried
out on an Agilent Series 1100 HPLC coupled to a Waters Micro-
mass ZQ mass spectrometer. Chromatography was performed
using IST Isolute Flash Si cartidges.
5-Nitro-1-(phenylmethyl)-1H-indazole (1k): yield 18% as a
brown solid. H NMR (400 MHz, CDCl3): δ = 8.79 (1H, d,
J = 2.0), 8.30 (1H, s), 8.27 (1H, dd, J = 9.2, 2.1), 7.44 (1H, d,
J = 9.3), 7.23-7.41 (5H, m), 5.69 (2H, s).
1
Synthesis of 3-Aminoindazoles. General procedure A
was followed, with the temperature of the flow reactor set to
150 °C.
Flow Reactor Setup. A Vapourtec R4þ was used in all flow
reactions, and a 10-mL stainless steel reactor was used to perform
the optimisation and small-scale reactions. The entire system
was first flushed with DMA and the temperature allowed to
stabilise before manually injecting the reagents (2 mL of each)
via the Rheodyne valves. DMA was used as the system solvent.
The large-scale reactions were carried out using 4 ꢀ 10 mL
PFA reactors linked together in series. The collected reactions
were then either analysed by LC/MS or worked up as below.
General Procedure A. Synthesis of Indazoles. Solution
A = benzaldehyde (1.0 mmol) þ DMA (2 mL); solution
B = methylhydrazine (1.2 mmol) þ DIPEA (1.05 mmol) +
DMA (2 mL). Solutions injected 1:1 (v/v) and driven through the
system (10-mL stainless steel reactor, set to either 150 or 250 °C,
using a 250-psi backpressure regulator at the reactor output) at a
total flow rate of 0.334 mL/min using DMA as the system solvent.
The collected reactions were concentrated under reduced pressure,
and the residue was purified by flash column chromatography
(20 g silica, 0-100% EtOAc in cyclohexane) to give the desired
indazole.
6-Nitro-1H-indazol-3-amine (2a): yield 54% as an orange
1
solid. H NMR (400 MHz, DMSO): δ = 12.11 (1H, bs), 8.12
(1H, d, J = 1.8), 7.91 (1H, d, J = 8.8), 7.72 (1H, dd, J = 8.8, 2.0),
5.70 (2H, bs).
1H-Indazol-3-amine (2b): yield 38% as an off-white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.58 (1H, d, J = 8.3), 7.35 (2H,
m), 7.09 (1H, t, J = 7.3), 3.78 (3H, bs).
5-(Methyloxy)-1H-indazol-3-amine (2c): yield 29% as a
1
pale-pink solid. H NMR (400 MHz, MeOD): δ = 7.20 (1H,
d, J = 9.0), 7.12 (1H, d, J = 2.3), 6.99 (1H, dd, J = 9.0, 2.3), 3.82
3H, s).
6-Bromo-1H-indazol-3-amine (2d): yield 49% as a pale-pink
solid. 1H NMR (400 MHz, MeOD): δ = 7.59 (1H, d, J = 8.5),
7.47 (1H, d, J = 1.3), 7.09 (1H, dd, J = 8.5, 1.5).
6-Methyl-1H-indazol-3-amine (2e): yield 64% as a white,
crystalline solid. 1H NMR (400 MHz, DMSO): δ = 11.16 (1H,
s), 7.53 (1H, d, J = 8.3), 6.98 (1H, s), 6.72 (1H, dd, J = 8.3), 5.21
(2H, s), 2.36 (3H, s).
1-Methyl-6-nitro-1H-indazol-3-amine (2g): yield 63% as a
red solid. 1H NMR (400 MHz, CDCl3): δ = 8.19 (1H, d, J = 1.5),
7.87 (1H, dd, J = 8.9, 1.9), 7.64 (1H, d, J = 8.8), 4.15 (2H, bs),
3.96 (3H, s).
1
5-Nitro-1H-indazole (1a): yield: 69% as a yellow solid. H
NMR (400 MHz, CDCl3): δ = 8.79 (1H, d, J = 1.8), 8.33 (2H, m),
7.60 (1H, d, J = 9.0). No NH observed.
1-Methyl-1H-indazol-3-amine (2h): yield 43% as a white
solid. 1H NMR (400 MHz, CDCl3): δ = 7.54 (1H, d, J = 8.0),
7.35 (1H, m), 7.22 (1H, d, J = 8.5), 7.02 (1H, t, J = 7.4), 4.04 (2H,
bs), 3.86 (3H, s).
6-Bromo-1-methyl-1H-indazol-3-amine (2j): yield 62% as a
yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.39 (2H, m),
7.11 (1H, m), 4.03 (2H, bs), 3.81 (3H, s).
1,6-Dimethyl-1H-indazol-3-amine (2k): yield 25% as a white
solid. 1H NMR (400 MHz, CDCl3): δ = 7.41 (1H, d, J = 8.3),
6.99 (1H, s), 6.85 (1H, d, J = 8.3), 4.04 (2H, bs), 3.81 (3H, s),
2.48 (3H, s).
6-(Methyloxy)-1H-indazole (1b): yield 18% as a yellow solid.
1H NMR (400 MHz, CDCl3): δ = 9.9 (1H, bs), 7.98 (1H, s),
7.62 (1H, d, J = 8.8), 6.88 (1H, bs), 6.85 (1H, dd, J = 8.8, 2.3),
3.88 (3H, s).
6-Bromo-1H-indazole (1c): yield 28% as an off-white solid.
1H NMR (400 MHz, CDCl3): δ = 8.07 (1H, s), 7.70 (1H, s),
7.64 (1H, d, J = 8.5), 7.29 (1H, dd, J = 8.5, 1.3).
1-Methyl-5-nitro-1H-indazole (1d): yield 71% as a yellow
solid. 1H NMR (400 MHz, CDCl3): δ = 8.74 (1H, d, J = 2.0), 8.30
(1H, dd, J = 9.3, 2.0), 8.21 (1H, s), 7.47 (1H, d, J = 9.3), 4.16
(3H, s).
1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-amine (2l): yield
1
1-Methyl-1H-indazole (1e): yield 41% as a pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 8.00 (1H, s), 7.74 (1H, d,
J = 8.0), 7.41 (2H, m), 7.16 (1H, m), 4.10 (3H, s).
57% as a yellow solid. H NMR (400 MHz, CDCl3): δ = 8.44
(1H, dd, J = 4.8, 1.5), 7.88 (1H, dd, J = 7.8, 1.5), 6.93 (1H, dd,
J = 7.9, 4.7), 3.97 (2H, bs), 3.92 (3H, s).
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dx.doi.org/10.1021/op100288t |Org. Process Res. Dev. 2011, 15, 565–569