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DOI: 10.1055/s-0029-1218559
An Efficient and Regioselective Difluoromethylation of 3-Iodoindazole with Chlorodifluoromethane
Publikationsverlauf
Publikationsdatum:
09. Dezember 2009 (online)
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Abstract
A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane is described. The reaction was extensively optimized with regard to combinations of base, solvent, addition order as well as stoichiometry. A key reaction parameter was the generation of a 2-M stock solution of the gaseous reagent chlorodifluoromethane in acetonitrile. This allowed control of the quantity of carbene generated in the reaction mixture, providing good N1-regioselectivity between the two reactive indazole nitrogens. Upon optimization of this protocol 1-difluoromethyl-3-iodoindazole was synthesized on a preparative scale providing 14.2 grams of product in 59% yield.
Key words
alkylations - fluorinated carbenes - indazoles - chlorodifluoromethane - regioselectivity
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References and Notes
All reactions were run under normal
atmosphere. ¹H NMR and ¹9F
NMR spectra were run on a Varian Inova 400 spectrometer. ¹³C
NMR spectra were run at 100 MHz on the same spectrometer. Structure
determination of isomers 3-5 was determined by 2D NMR on a Varion
Inova 500 instrument equipped with cryoprobe, gHSQC, gHMBC. All chemical
shifts are reported as δ relative to trimethylsilane. GC-MS
ratios were determined using a Hewlett Packard 6870 series GC system
with a 5973 mass selective detector. LCMS was run on a Hewlett Packard
Series 1100 instrument. Purification was done using a Biotage version 2.0
with a Biotage 40M silica column. All solvents and reagents were
obtained and used without further purification from commercial sources.
3-Iodoindazole (2): Indazole 2 was synthesized in accordance with Rault¹0 using
indazole (10.0 g, 85.0 mmol, Aldrich), DMF (150 mL), KOH (14.2 g,
254.0 mmol), and iodine (43.0 g, 169.0 mmol) to produce 2 (21.0 g, 82.2 mmol, 97%) as
a yellow solid; mp 142-144 ˚C. ¹H
NMR (400 MHz, DMSO-d
6): δ = 7.52
(1 H, d, J = 8.0 Hz), 7.36-7.44
(2 H, m), 7.16 (1 H, d, J = 8.0
Hz). ¹³C NMR (100 MHz, DMSO-d
6): δ = 140.42,
127.23, 126.79, 121.24, 120.40, 110.53, 93.50. ESI-MS: m/z = 245 [M+ + H].
HRMS: m/z
[M + H] calcd
for C7H6N2I: 244.9576; found: 244.957.
CHClF
2
Solution in MeCN: To a flame-dried round-bottom flask
equipped with a stir bar were added anhyd MeCN (60 mL) and the flask
was capped with a septum. The flask was then weighed and recorded.
CHClF2 (Synquest Labs Inc.) was vigorously bubbled through
the solution using a Teflon needle for 15 min with constant stirring
at 25 ˚C. The flask was weighed again and the molarity
was calculated by mass of solution.
1-(Difluoromethyl)-3-iodo-1
H
-indazole (3):
Indazole 2 (20.0 g, 82.0 mmol) in MeCN
(320 mL) was cooled to 0 ˚C and KOH (8 N, 20 mL) was added
slowly over 10 min. After stirring at 0 ˚C for 30 min,
CHClF2 in MeCN (44 mL, 1.9 M, 82.0 mmol) was added by
addition funnel over 15 min. The reaction mixture was allowed to
warm to 25 ˚C and was stirred overnight. NH4Cl
(sat. aq; 100 mL) was then added and the organics were extracted
with EtOAc (3 × 100 mL), dried with MgSO4 and
concentrated. Purification by chromatography (silica gel; 0-5% EtOAc-hexane)
produced 3 as an off-white solid (14.16
g, 48.16 mmol, 59%); mp 86-89 ˚C. ¹H
NMR (400 MHz, DMSO-d
6): δ = 8.22
(1 H, t, J = 58.0 Hz), 7.86
(1 H, d, J = 8.4 Hz), 7.69 (1
H, dd, J = 8.0 Hz), 7.59 (1
H, d, J = 8.2 Hz), 7.44 (1 H,
t, J = 7.5 Hz). ¹³C
NMR (100 MHz, DMSO-d
6): δ = 138.08,
129.70, 129.14, 124.00, 121.86, 110.76, 110.60, 101.46. ESI-MS: m/z = 294.1 [M+ + H].
HRMS: m/z [M + H] calcd
for C8H6N2F2I: 294.9544; found:
294.9557.
2-(Difluoromethyl)-3-iodo-2
H
-indazole (4):
isolated as an off-white solid (35 mg, 0.11 mmol, 4%);
mp 89-92 ˚C. ¹H NMR (500 MHz,
DMSO-d
6): δ = 8.19
(1 H, t, J = 57.2 Hz), 7.70
(1 H, d, J = 8.1 Hz), 7.50 (1
H, d, J = 8.6 Hz), 7.59 (1 H,
dd, J = 6.5 Hz), 7.21 (1 H,
t, J = 6.6 Hz). ¹³C
NMR (500 MHz, DMSO-d
6): δ = 149.09,
129.05, 127.80, 124.25, 121.22, 118.44, 112.21, 77.88. ¹9F
NMR (400 MHz, DMSO-d
6): δ = -37.69, -31.52,
28.38. ESI-MS: m/z = 294.1 [M+ + H].
HRMS: m/z [M + H] calcd
for C8H6N2F2I: 294.9544; found:
294.9558.
2-(Difluoromethyl)-2
H
-indazole (5):
isolated as a colorless oil (14 mg, 0.08 mmol, 1%). ¹H
NMR (500 MHz, DMSO-d
6): δ = 8.89
(1 H, s), 8.16 (1 H, t), 7.79 (1 H, d, J = 8.0
Hz), 7.71 (1 H, d, J = 8.0 Hz),
7.39 (1 H, t, J = 8.0 Hz), 7.16
(1 H, t, J = 8.0 Hz). ¹³C
NMR (400 MHz, DMSO-d
6): δ = 149.7, 128.10,
123.11, 123.04, 121.55, 121.15, 117.92, 111.06. ESI-MS: m/z = 168.2 [M+ + H].
HRMS: m/z [M + H] calcd for
C8H7N2F2: 169.0577;
found: 169.0580.