An efficient and regioselective difluoromethylation of 3-iodoindazole with chlorodifluoromethane

Synlett

Volumn , Issue 2, 2010, Pages 219-222

  Pelc, Matthew ^a   Huang, Wei ^a   Trujillo, John ^a   Baldus, John ^a   Turner, Steve ^a   Kleine, Pete ^a   Yang, Shengtian ^a   Thorarensen, Atli ^a  

^a PFIZER INC   (United States)

Author keywords

Alkylations; Chlorodifluoromethane; Fluorinated carbenes; Indazoles; Regioselectivity

Indexed keywords

1 (DIFLUOROMETHYL) 3 IODO 1H INDAZOLE; 2 (DIFLUOROMETHYL) 2H INDAZOLE; 2 (DIFLUOROMETHYL) 3 IODO 2H INDAZOLE; 3 IODOINDAZOLE; ACETONITRILE; CHLORODIFLUOROMETHANE; INDAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; MASS FRAGMENTOGRAPHY; STOICHIOMETRY;

EID: 75749155801     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1218559     Document Type: Article

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19. 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 35 was determined by 2D NMR on a Varion Inova 500 instrument equipped with cryoprobe, gHSQC, gHMBC. All chemical shifts are reported as d relative to trimethylsilane. GCMS 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 142144 C. 1H NMR (400 MHz, DMSO-d6): d = 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-d6): d = 140.42, 127.23, 126.79, 121.24, 120.40, 110.53, 93.50. ESIMS: m/z = 245 [M+ + H]. HRMS: m/z [M + H] calcd for C7H6N2I: 244.9576; found: 244.957. CHClF2 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-1H-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; 05% EtOAchexane) produced 3 as an off-white solid (14.16 g, 48.16 mmol, 59%); mp 86 89 C. 1H NMR (400 MHz, DMSO-d6): d = 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-d6): d = 138.08, 129.70, 129.14, 124.00, 121.86, 110.76, 110.60, 101.46. ESIMS: m/z = 294.1 [M+ + H]. HRMS: m/z [M + H] calcd for C8H6N2F2I: 294.9544; found: 294.9557. 2-(Difluoromethyl)-3-iodo-2H-indazole (4): isolated as an off-white solid (35 mg, 0.11 mmol, 4%); mp 8992 C. 1H NMR (500 MHz, DMSO-d6): d = 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-d6): d = 149.09, 129.05, 127.80, 124.25, 121.22, 118.44, 112.21, 77.88. 19F NMR (400 MHz, DMSOd6): d = 37.69, 31.52, 28.38. ESIMS: m/z = 294.1 [M+ + H]. HRMS: m/z [M + H] calcd for C8H6N2F2I: 294.9544; found: 294.9558. 2-(Difluoromethyl)-2H-indazole (5): isolated as a colorless oil (14 mg, 0.08 mmol, 1%). 1H NMR (500 MHz, DMSOd6): d = 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-d6): d = 149.7, 128.10, 123.11, 123.04, 121.55, 121.15, 117.92, 111.06. ESIMS: m/z = 168.2 [M+ + H]. HRMS: m/z [M + H] calcd for C8H7N2F2: 169.0577; found: 169.0580.
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