Synthesis of Pyrazoles from 1,3-Diols via Hydrogen Transfer Catalysis
Synthesis of Pyrazoles from 1,3-Diols via Hydrogen Transfer Catalysis Daniel C. Schmitt,* Alexandria P. Taylor, Andrew C. Flick, and Robert E. Kyne, Jr. Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States
Supporting Information
Table of Contents
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General Information ...................................................................................................................................... 2 Experimental Procedures and Spectroscopic Data for Scheme 1 ................................................................. 3 Experimental Procedures and Spectroscopic Data for Scheme 2 ............................................................... 26 Experimental Procedures and Spectroscopic Data for Table 2 ................................................................... 37
1
General Information: All reagents were obtained from commercial suppliers and used without further purification, unless otherwise noted. All solvents used were purchased anhydrous and transferred by nitrogen-purged syringe. All reactions were conducted with oven-dried glassware under an atmosphere of nitrogen. Silica gel chromatography was performed using medium pressure Biotage or ISCO systems employing columns pre-packaged by various commercial vendors including Biotage and ISCO. 1H and 13C NMR characterization data were collected at 300 K on a Bruker AS-400 spectrometer operating at 400 and 100 MHz (respectively) with chemical shifts reported in parts per million relative to CHCl3 (1H NMR: 7.26 ppm; 13C NMR: 77.0 ppm). IR spectra were recorded on a Nicolet Avatar 360 FTIR spectrometer and only partial data are provided. High resolution mass spectroscopy (HRMS) was performed on an Agilent (6220) LC-MS TOF using a Xbridge C18 2.5 µm 2.0 X 5.0 mm at 60 °C; ammonium formate: water as mobile phase A1 and 50:50 methanol: acetonitrile as mobile phase B1.
2
Diols 1a-1g
Diols 1b, 1e, and 1f are available from commercial vendors. Diols 1a, 1c, and 1d are described in prior literature. Synthesis of 1a: Mirilashvili, S. et al. Eur. J. Org. Chem. 2010, 24, 4671-4686. Synthesis of 1c and 1d: Rios-Lombardia, N. et al. J. Org. Chem. 2009, 74, 2571-2574.
2-((2-(4-bromophenyl)-1,3-dioxolan-2-yl)methyl)propane-1,3-diol (1g)
Diol 1g was available from Pfizer’s chemical inventory as a white solid. 1
H NMR (400 MHz, CD3OD): δ 7.51 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.04 (m, 2H), 3.75 (m, 2H), 3.58 (m, 4H), 1.89-1.79 (m, 3H) ppm. 13
C NMR (100 MHz, CD3OD): δ 142.3, 131.1, 127.3, 122.4, 109.9, 64.8, 62.6, 38.3, 37.4 ppm.
HRMS (ESI+) Calcd. for C13H17BrO4 (M+Na): 339.0202, Found: 339.0200. FTIR (neat): 3368, 2888, 1589, 1481, 1393, 1195, 1069, 1038, 1011, 995, 826, 591 cm-1. MP 95 °C
3
4
Hydrazines 2a-2h
Hydrazines 2a-2f are available from commercial vendors. Hydrazines 2g and 2h (HCl salts) are described in prior literature. They were neutralized prior to use. Synthesis of 2g: Lowrie, H. S. J. Med. Chem. 1966, 9, 670-4. Synthesis of 2h: Argyle, C. S.; Goadby, S. C.; Mason, K. G.; Reed, R. A.; Smith, M. A.; Stern, E. S. J. Chem. Soc. C 1967, 21, 2156-70. 4-hydrazinyl-3-phenylcinnoline (2g)
4-hydrazinyl-3-phenylcinnoline hydrochloride (J. Med. Chem. 1966, 9, 670-4) (690 mg, 2.53 mmol) was dissolved in methylene chloride (8.4 mL). Aqueous NaOH (6 M solution, 0.84 mL, 5.06 mmol) was added. The solution was stirred at room temperature for 10 min. The phases were separated and the organic phase was dried over MgSO4, filtered, and concentrated to provide the freebase as a brown solid (210 mg, 35% yield). 1
H NMR (400 MHz, CD3OD): δ 8.26-8.22 (m, 1H), 7.75-7.65 (m, 2H), 7.40-7.30 (m, 4H), 7.14-7.10 (m, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 149.9, 131.3, 130.3, 129.8, 129.4, 129.1, 128.6, 128.2, 127.3, 126.9, 126.5, 118.8 ppm. HRMS (ESI) Calcd. for C14H12N4 (M+H): 237.1135, Found: 237.1136. FTIR (neat): 3253, 1606, 1498, 1469, 1440, 1363, 1326, 1261, 1212, 1070, 1022 cm-1. MP 143 °C
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6
Synthesis of Pyrazoles from 1,3-Diols: General Procedure: To an oven-dried round bottom flask containing a stir bar was added RuH2(CO)(PPh3)3 (0.03 equiv, 0.015 mmol), Xantphos (0.03 equiv, 0.015 mmol), diol (1.00 equiv, 0.50 mmol), and hydrazine (1.00 equiv, 0.50 mmol). The flask was fitted with a reflux condenser, placed under vacuum for five minutes, and backfilled with N2. The vacuum / backfill process was repeated two more times, then toluene (1.00 mL, 0.5 M) was added. Crotonitrile (2.2 equiv, 1.1 mmol) and acetic acid (0.15 equiv, 0.075 mmol) were added. The flask was submerged in an oil bath pre-heated to 120 °C and stirred under N2 atmosphere. After 24 h, the flask was cooled to 23 °C. The solution was concentrated in vacuo and purified by flash column chromatography using the solvent system indicated.
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4-isopropyl-1-phenyl-1H-pyrazole (3a)
According to the general procedure, diol 1a (1.00 g, 8.46 mmol) and phenylhydrazine (0.86 mL, 8.46 mmol) were reacted to provide pyrazole 3a as a yellow oil (1.32 g, 84%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.62-7.58 (m, 3H), 7.51 (s, 1H), 7.35 (virtual triplet, J = 8.0 Hz, 2H), 7.17 (virtual triplet, J = 8.0 Hz, 1H), 2.84 (septet, J = 8.0 Hz, 1H), 1.20 (d, J = 8.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.4, 139.5, 131.2, 129.3, 125.9, 123.3, 118.8, 24.4, 23.8 ppm.
HRMS (ESI) Calcd. for C12H15N2 (M+H): 187.123, Found: 187.1228. FTIR (neat): 2960, 1600, 1503, 1395, 953, 754, 672 cm-1. MP N.A.
8
9
4-isopropyl-1-(o-tolyl)-1H-pyrazole (3b)
According to the general procedure, 2-isopropylpropanediol (59 mg, 0.50 mmol) was reacted to provide the pyrazole 3b as a brown oil (57 mg, 60%) after column chromatography on silica gel (0-10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ ppm 7.50 (s, 1 H), 7.30 (s, 1H), 7.18-7.23 (m, 4 H), 2.86 (septet, J = 6.6 Hz 1 H), 2.19 (s, 3 H), 1.20 (d, J = 6.6 Hz, 6 H) ppm. 13
C NMR (101 MHz, CDCl3): δ 138.5, 133.4, 131.2, 129.7, 127.9, 127.1, 126.4, 125.9, 76.7, 24.3, 23.8, 18.1 ppm. LRMS (ESI) Calcd. for C13H16N2: (M+H): 201.13, Found: 201.10. FTIR (CH2Cl2): 2964, 1599, 1478, 1325, 1128, 1043, 795 cm-1.
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11
4-isopropyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3c)
According to the general procedure, diol 1a (59.1 mg, 0.50 mmol) and 4(trifluoromethyl)phenylhydrazine (88.1 mg, 0.50 mmol) were reacted to provide pyrazole 3c as a brown oil (98 mg, 77%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 2.94 (septet, J = 8.0 Hz, 1H), 1.29 (d, J = 8.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 142.7, 140.6, 132.1, 127.7 (q, J = 32 Hz), 126.6 (q, J = 4.0 Hz), 124.0 (q, J = 270 Hz), 123.3, 118.3, 24.4, 23.7 ppm. 19
F NMR decoupled (400 MHz, CDCl3): δ -62.2 ppm.
HRMS (ESI) Calcd. for C13H14F3N2 (M+H): 255.1104, Found: 255.1100. FTIR (neat): 2965, 1617, 1399, 1321, 1108, 949, 841 cm-1. MP N.A.
12
13
14
4-isopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole (3d)
According to the general procedure, 2-isopropylpropanediol (59 mg, 0.50 mmol) was reacted to provide the pyrazole 3d as a brown oil (92 mg, 72%) after column chromatography on silica gel (0-20% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.96 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.587.50 (m, 2H), 2.94 (septet, J = 7.0 Hz, 1H), 1.29 (d, J = 6.6 Hz, 6H). 13
C NMR (101 MHz, CDCl3): δ 138.5, 133.4, 131.2, 129.7, 127.9, 127.1, 126.4, 125.9, 76.7, 24.3, 23.8, 18.1 ppm. 19
F NMR decoupled (400 MHz, CDCl3): δ -62.8 ppm.
HRMS (ESI) Calcd. for C13H13N2F3 (M+H): 255.1104, Found: 255.1100. FTIR (CH2Cl2): 2960, 1592, 1501, 1463, 1152, 958, 761 cm-1.
15
16
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1-(4-iodophenyl)-4-isopropyl-1H-pyrazole (3e)
According to the general procedure, diol 1a (59.1 mg, 0.50 mmol) and 4-iodophenylhydrazine (117 mg, 0.50 mmol) were reacted to provide pyrazole 3e as a yellow oil (96 mg, 62%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 2.91 (septet, J = 8.0 Hz, 1H), 1.28 (d, J = 4.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.0 (2C), 138.2, 131.7, 123.1, 120.4, 89.8, 24.4, 23.7 ppm.
HRMS (ESI) Calcd. for C12H14IN2 (M+H): 313.0196, Found: 313.0205. FTIR (neat): 2960, 1493, 1392, 997, 822, 731 cm-1. MP N.A.
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3-(4-isopropyl-1H-pyrazol-1-yl)-N,N-dimethylaniline (3f)
According to the general procedure, diol 1a (22 mg, 0.19 mmol) was reacted to provide pyrazole 3f as an orange solid (21 mg, 50%) after column chromatography on silica gel (0%, 10% MeOH/CH2Cl2). 1
H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.54 (s, 1H), 7.26-7.22 (m, 1H), 7.08 (s, br, 1H), 6.92-6.88 (m, 1H), 6.61 (s, br, 1H), 3.00 (s, 6H), 2.89 (m, 1H), 1.25 (d, J = 7.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 141.4, 139.1, 130.8, 129.7, 123.9, 123.7, 110.4, 103.2, 103.4, 40.7, 24.4, 23.9 ppm. HRMS (ESI+) Calcd. for C15H19N2 (M+H): 230.1652, Found: 230.1653. FTIR (neat): 2960, 1609, 1581, 1507, 1393, 946 cm-1.
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21
4-(4-isopropyl-1H-pyrazol-1-yl)-3-phenylcinnoline (3g)
According to the general procedure, diol 1a (27 mg, 0.23 mmol) was reacted with hydrazine 2g (60 mg, 0.23 mmol) to provide pyrazole 3g as a yellow oil (41 mg, 57%) after column chromatography on silica gel (10%, 30% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.90 (t, J = 7.0 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.44-7.37 (m, 5H), 6.99 (s, 1H), 2.83 (septet, J = 7.0 Hz, 1H), 1.15 (d, J = 7.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 151.1, 149.9, 140.7, 135.1, 132.3, 131.9, 131.6, 130.6, 129.9, 129.2 (2 peaks), 129.0, 128.5, 123.4, 123.1, 24.2, 23.7 ppm. HRMS (ESI) Calcd. for C20H18N4 (M+H): 315.1604, Found: 315.1612. FTIR (neat): 3057, 2960, 1566, 1501, 1489, 1443, 1390, 1323, 1189, 1130 cm-1.
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3-(4-isopropyl-1H-pyrazol-1-yl)-3-methyltetrahydrothiophene 1,1-dioxide (3h)
Hydrazine HCl salt 2h was stirred with 2 equiv. NaOH (aq) in CH2Cl2, dried over Na2SO4, filtered, and concentrated to provide the hydrazine freebase. Then, according to the general procedure, 2isopropylpropanediol (43 mg, 0.36 mmol) was reacted to provide pyrazole 3h as a white solid (69 mg, 79%) after column chromatography on silica gel (1-4% MeOH/DCM). 1
H NMR (400 MHz, CDCl3): δ ppm 7.42 (s, 1 H), 7.32 (s, 1 H), 4.04 (d, J=14.0 Hz, 1 H), 3.20 - 3.39 (m, 3 H), 2.99 – 2.92 (m, 1 H), 2.85 (septet, J=6.6 Hz, 1 H), 2.38 - 2.55 (m, 1 H), 1.83 (s, 3 H), 1.22 (d, J=6.6 Hz, 6 H) ppm. 13
C NMR (101 MHz, CDCl3): δ 138.1, 130.2, 122.7, 63.7, 61.9, 51.3, 36.1, 27.7, 24.3, 23.8 ppm.
HRMS (ESI) Calcd. for C11H18N2O2S: (M+H): 243.1162, Found: 243.1157. FTIR (CH2Cl2): 2961, 1391, 1307, 1152, 979 cm-1. MP: 71-73 oC
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1-phenyl-4-propyl-1H-pyrazole (3i)
According to the general procedure, diol 1b (59.1 mg, 0.50 mmol) and phenylhydrazine (54.1 mg, 0.50 mmol) were reacted to provide pyrazole 3i as a colorless oil (58 mg, 62%) after column chromatography on silica gel (1 to 4% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.62-7.57 (m, 3H), 7.47 (s, 1H), 7.34 (virtual triplet, J = 8.0 Hz, 2H), 7.16 (virtual triplet, J = 8.0 Hz, 1H), 2.43 (t, J = 8.0 Hz, 2H), 1.63-1.51 (m, 2H), 0.90 (t, J = 8.0 Hz, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 145.0, 140.3, 129.3, 125.9, 124.7, 123.8, 118.7, 26.3, 23.9, 13.8 ppm.
HRMS (ESI) Calcd. for C12H15N2 (M+H): 187.1230, Found: 187.1231. FTIR (neat): 2959, 2869, 1600, 1503, 1396, 953, 754, 689 cm-1. MP N.A.
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4-cyclohexyl-1-phenyl-1H-pyrazole (3j)
According to the general procedure, diol 1c (79 mg, 0.50 mmol) was reacted to provide pyrazole 3j as a yellow oil (74 mg, 65%) after column chromatography on silica gel (0%, 7% EtOAc/heptane). 1
H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 2.69-2.52 (m, 1H), 2.10-1.93 (m, 2H), 1.90-1.68 (m, 3H), 1.53-1.21 (m, 5H) ppm. 13
C NMR (100 MHz, CD3OD): δ 141.6, 140.5, 131.7, 130.5, 127.4, 125.8, 120.1, 35.6, 35.4, 27.5, 27.2 ppm. LRMS (ESI+) Calcd. for C15H19N2 (M+H): 227.15, Found: 227.2. FTIR (neat): 2921, 2850, 1600, 1502, 1447, 1400, 1046, 984, 953, 794, 752, 659 cm-1.
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1-phenyl-4-(p-tolyl)-1H-pyrazole (3k)
According to the general procedure, diol 1d (83 mg, 0.50 mmol) was reacted to provide pyrazole 3k as a yellow solid (48 mg, 41%) after column chromatography on silica gel (0%, 3% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.50-7.46 (m, 4H), 7.31 (virtual triplet, J = 7.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 2.39 (s, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.1, 138.7, 136.6, 129.6, 129.4, 129.1, 126.4, 125.6, 124.9, 123.0, 119.0, 21.1 ppm. HRMS (ESI) Calcd. for C16H14N2 (M+H): 235.1230, Found: 235.1235. FTIR (neat): 2912, 1598, 1570, 1497, 1462, 1408, 1365, 1306, 1259, 1199, 1111, 1072 cm-1. MP 112 °C
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4-(2-phenoxyethyl)-1-phenyl-1H-pyrazole (3m)
According to the general procedure, diol 1f (98.1 mg, 0.50 mmol) and phenylhydrazine (54.1 mg, 0.50 mmol) were reacted to provide pyrazole 3m as an off white solid (64.3 mg, 49%) after column chromatography on silica gel (0 to 20% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.65-7.53 (m, 3H), 7.35 (t, J = 8.0 Hz, 2 H), 7.25-7.14 (m, 3H), 6.91-6.82 (m, 3H), 4.08 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 158.7, 141.2, 140.2, 129.5, 129.4, 126.2, 125.6, 120.8, 119.8, 118.9, 114.6, 68.0, 24.6 ppm. HRMS (ESI) Calcd. for C17H17N2O (M+H): 265.1335, Found: 265.1334. FTIR (neat): 2928, 1598, 1497, 1240, 1036, 953, 752, 689 cm-1. MP 60 °C
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4-((2-(4-bromophenyl)-1,3-dioxolan-2-yl)methyl)-1-phenyl-1H-pyrazole (3n)
According to the general procedure, diol 1g (159 mg, 0.50 mmol) was reacted to provide pyrazole 3n as an orange solid (81 mg, 42%) after column chromatography on silica gel (5%, 15% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.47-7.40 (m, 5H), 7.30 (d, J = 8.2 Hz, 2H), 7.25 (virtual triplet, J = 7.4 Hz, 1H), 3.98-3.90 (m, 2H), 3.81-3.72 (m, 2H), 3.08 (s, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 142.4, 141.3, 140.1, 131.1, 129.3, 127.9, 126.6, 126.0, 122.1, 118.7, 116.8, 109.1, 64.9, 36.0 ppm. HRMS (ESI) Calcd. for C19H17BrN2O2 (M+H): 385.0546, Found: 385.0547. FTIR (neat): 1598, 1502, 1396, 1215, 1176, 1070, 1039 cm-1. MP 109 °C
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1-(4-iodophenyl)-3-methyl-1H-pyrazole (10) I
N N
To an oven dried round bottom flask with a stirbar was added 4-iodo-phenylhydrazine (117 mg, 0.50 mmol), Xantphos (8.7 mg, 0.015 mmol), and RuH2CO(PPh3)3 (13.8 mg, 0.015 mmol). The flask was fitted with a reflux condenser and the system was placed under vacuum for 5 minutes and refilled with nitrogen. The vacuum / refill sequence was repeated two more times. Toluene (1.00 mL) was added, followed by 4-hydroxybutan-2-one (44 mg, 0.50 mmol), crotonitrile (45 µL, 0.55 mmol), and AcOH (4.3 µL, 0.075 mmol). The flask was submerged in an oil bath (preheated to 120 °C) and stirred at reflux under nitrogen atmosphere for 27 h. The reaction was cooled to room temperature and concentrated in vacuo. Column chromatography on silica gel (0%, 2% EtOAc/heptane) provided the title compound as a white solid (87 mg, 61% yield). Regiochemistry was determined by 1D NOE experiments. 1
H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H), 6.26 (d, J = 2.0 Hz, 1H), 2.37 (s, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 151.0, 139.9, 138.3, 127.1, 120.4, 108.0, 89.7, 13.7 ppm.
HRMS (ESI) Calcd. for C10H9IN2 (M+H): 284.9883, Found: 284.9882. FTIR (neat): 1588, 1537, 1499, 1464, 1415, 1375, 1254, 1224, 1044 cm-1. MP 92 °C
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38
Determination of regioselectivity: I
N N
39
7-(hydroxymethyl)-1,4-dioxaspiro[4.5]decan-8-one (11)
Ketone 11 was available from Pfizer’s chemical inventory. It was likely prepared according to the literature procedure: Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H., Angew. Chem. Ind. Ed. 2004, 43, 1983-1986.
2-phenyl-2,4,6,7-tetrahydrospiro[indazole-5,2'-[1,3]dioxolane] (12)
To an oven dried round bottom flask with a stirbar was added hydroxy ketone 11 (80% pure, 116 mg, 0.50 mmol), Xantphos (8.7 mg, 0.015 mmol), and RuH2CO(PPh3)3 (13.8 mg, 0.015 mmol). The flask was fitted with a reflux condenser and the system was placed under vacuum for 5 minutes and refilled with nitrogen. The vacuum / refill sequence was repeated two more times. Toluene (1.00 mL) was added, followed by phenylhydrazine (49 µL, 0.50 mmol), crotonitrile (90 µL, 1.10 mmol), and AcOH (4.3 µL, 0.075 mmol). The flask was submerged in an oil bath (preheated to 120 °C) and stirred at reflux under nitrogen atmosphere for 24 h. The reaction was cooled to room temperature and concentrated in vacuo. Column chromatography on silica gel (3%, 30% EtOAc/heptane) provided the title compound as a yellow oil (72 mg, 56% yield). Regiochemistry was determined by 1D NOE experiments. 1
H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1 H), 4.05 (s, 4H), 3.00 (t, J = 6.6 Hz, 2H), 2.88 (s, 2H), 2.05 (t, J = 6.6 Hz, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 149.4, 140.2, 129.3, 126.0, 124.6, 118.9, 116.4, 108.7, 64.7, 31.8, 31.5, 21.4 ppm.
HRMS (ESI) Calcd. for C15H16N2O2 (M+H): 257.1285, Found: 257.1291. FTIR (neat): 2947, 1598, 1574, 1504, 1462, 1413, 1379, 1306, 1252, 1214, 1108, 1059 cm-1.
40
41
Determination of regioselectivity:
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Supporting Information
Table of Contents
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General Information ...................................................................................................................................... 2 Experimental Procedures and Spectroscopic Data for Scheme 1 ................................................................. 3 Experimental Procedures and Spectroscopic Data for Scheme 2 ............................................................... 26 Experimental Procedures and Spectroscopic Data for Table 2 ................................................................... 37
1
General Information: All reagents were obtained from commercial suppliers and used without further purification, unless otherwise noted. All solvents used were purchased anhydrous and transferred by nitrogen-purged syringe. All reactions were conducted with oven-dried glassware under an atmosphere of nitrogen. Silica gel chromatography was performed using medium pressure Biotage or ISCO systems employing columns pre-packaged by various commercial vendors including Biotage and ISCO. 1H and 13C NMR characterization data were collected at 300 K on a Bruker AS-400 spectrometer operating at 400 and 100 MHz (respectively) with chemical shifts reported in parts per million relative to CHCl3 (1H NMR: 7.26 ppm; 13C NMR: 77.0 ppm). IR spectra were recorded on a Nicolet Avatar 360 FTIR spectrometer and only partial data are provided. High resolution mass spectroscopy (HRMS) was performed on an Agilent (6220) LC-MS TOF using a Xbridge C18 2.5 µm 2.0 X 5.0 mm at 60 °C; ammonium formate: water as mobile phase A1 and 50:50 methanol: acetonitrile as mobile phase B1.
2
Diols 1a-1g
Diols 1b, 1e, and 1f are available from commercial vendors. Diols 1a, 1c, and 1d are described in prior literature. Synthesis of 1a: Mirilashvili, S. et al. Eur. J. Org. Chem. 2010, 24, 4671-4686. Synthesis of 1c and 1d: Rios-Lombardia, N. et al. J. Org. Chem. 2009, 74, 2571-2574.
2-((2-(4-bromophenyl)-1,3-dioxolan-2-yl)methyl)propane-1,3-diol (1g)
Diol 1g was available from Pfizer’s chemical inventory as a white solid. 1
H NMR (400 MHz, CD3OD): δ 7.51 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.04 (m, 2H), 3.75 (m, 2H), 3.58 (m, 4H), 1.89-1.79 (m, 3H) ppm. 13
C NMR (100 MHz, CD3OD): δ 142.3, 131.1, 127.3, 122.4, 109.9, 64.8, 62.6, 38.3, 37.4 ppm.
HRMS (ESI+) Calcd. for C13H17BrO4 (M+Na): 339.0202, Found: 339.0200. FTIR (neat): 3368, 2888, 1589, 1481, 1393, 1195, 1069, 1038, 1011, 995, 826, 591 cm-1. MP 95 °C
3
4
Hydrazines 2a-2h
Hydrazines 2a-2f are available from commercial vendors. Hydrazines 2g and 2h (HCl salts) are described in prior literature. They were neutralized prior to use. Synthesis of 2g: Lowrie, H. S. J. Med. Chem. 1966, 9, 670-4. Synthesis of 2h: Argyle, C. S.; Goadby, S. C.; Mason, K. G.; Reed, R. A.; Smith, M. A.; Stern, E. S. J. Chem. Soc. C 1967, 21, 2156-70. 4-hydrazinyl-3-phenylcinnoline (2g)
4-hydrazinyl-3-phenylcinnoline hydrochloride (J. Med. Chem. 1966, 9, 670-4) (690 mg, 2.53 mmol) was dissolved in methylene chloride (8.4 mL). Aqueous NaOH (6 M solution, 0.84 mL, 5.06 mmol) was added. The solution was stirred at room temperature for 10 min. The phases were separated and the organic phase was dried over MgSO4, filtered, and concentrated to provide the freebase as a brown solid (210 mg, 35% yield). 1
H NMR (400 MHz, CD3OD): δ 8.26-8.22 (m, 1H), 7.75-7.65 (m, 2H), 7.40-7.30 (m, 4H), 7.14-7.10 (m, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 149.9, 131.3, 130.3, 129.8, 129.4, 129.1, 128.6, 128.2, 127.3, 126.9, 126.5, 118.8 ppm. HRMS (ESI) Calcd. for C14H12N4 (M+H): 237.1135, Found: 237.1136. FTIR (neat): 3253, 1606, 1498, 1469, 1440, 1363, 1326, 1261, 1212, 1070, 1022 cm-1. MP 143 °C
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6
Synthesis of Pyrazoles from 1,3-Diols: General Procedure: To an oven-dried round bottom flask containing a stir bar was added RuH2(CO)(PPh3)3 (0.03 equiv, 0.015 mmol), Xantphos (0.03 equiv, 0.015 mmol), diol (1.00 equiv, 0.50 mmol), and hydrazine (1.00 equiv, 0.50 mmol). The flask was fitted with a reflux condenser, placed under vacuum for five minutes, and backfilled with N2. The vacuum / backfill process was repeated two more times, then toluene (1.00 mL, 0.5 M) was added. Crotonitrile (2.2 equiv, 1.1 mmol) and acetic acid (0.15 equiv, 0.075 mmol) were added. The flask was submerged in an oil bath pre-heated to 120 °C and stirred under N2 atmosphere. After 24 h, the flask was cooled to 23 °C. The solution was concentrated in vacuo and purified by flash column chromatography using the solvent system indicated.
7
4-isopropyl-1-phenyl-1H-pyrazole (3a)
According to the general procedure, diol 1a (1.00 g, 8.46 mmol) and phenylhydrazine (0.86 mL, 8.46 mmol) were reacted to provide pyrazole 3a as a yellow oil (1.32 g, 84%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.62-7.58 (m, 3H), 7.51 (s, 1H), 7.35 (virtual triplet, J = 8.0 Hz, 2H), 7.17 (virtual triplet, J = 8.0 Hz, 1H), 2.84 (septet, J = 8.0 Hz, 1H), 1.20 (d, J = 8.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.4, 139.5, 131.2, 129.3, 125.9, 123.3, 118.8, 24.4, 23.8 ppm.
HRMS (ESI) Calcd. for C12H15N2 (M+H): 187.123, Found: 187.1228. FTIR (neat): 2960, 1600, 1503, 1395, 953, 754, 672 cm-1. MP N.A.
8
9
4-isopropyl-1-(o-tolyl)-1H-pyrazole (3b)
According to the general procedure, 2-isopropylpropanediol (59 mg, 0.50 mmol) was reacted to provide the pyrazole 3b as a brown oil (57 mg, 60%) after column chromatography on silica gel (0-10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ ppm 7.50 (s, 1 H), 7.30 (s, 1H), 7.18-7.23 (m, 4 H), 2.86 (septet, J = 6.6 Hz 1 H), 2.19 (s, 3 H), 1.20 (d, J = 6.6 Hz, 6 H) ppm. 13
C NMR (101 MHz, CDCl3): δ 138.5, 133.4, 131.2, 129.7, 127.9, 127.1, 126.4, 125.9, 76.7, 24.3, 23.8, 18.1 ppm. LRMS (ESI) Calcd. for C13H16N2: (M+H): 201.13, Found: 201.10. FTIR (CH2Cl2): 2964, 1599, 1478, 1325, 1128, 1043, 795 cm-1.
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11
4-isopropyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3c)
According to the general procedure, diol 1a (59.1 mg, 0.50 mmol) and 4(trifluoromethyl)phenylhydrazine (88.1 mg, 0.50 mmol) were reacted to provide pyrazole 3c as a brown oil (98 mg, 77%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 2.94 (septet, J = 8.0 Hz, 1H), 1.29 (d, J = 8.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 142.7, 140.6, 132.1, 127.7 (q, J = 32 Hz), 126.6 (q, J = 4.0 Hz), 124.0 (q, J = 270 Hz), 123.3, 118.3, 24.4, 23.7 ppm. 19
F NMR decoupled (400 MHz, CDCl3): δ -62.2 ppm.
HRMS (ESI) Calcd. for C13H14F3N2 (M+H): 255.1104, Found: 255.1100. FTIR (neat): 2965, 1617, 1399, 1321, 1108, 949, 841 cm-1. MP N.A.
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13
14
4-isopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole (3d)
According to the general procedure, 2-isopropylpropanediol (59 mg, 0.50 mmol) was reacted to provide the pyrazole 3d as a brown oil (92 mg, 72%) after column chromatography on silica gel (0-20% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.96 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.587.50 (m, 2H), 2.94 (septet, J = 7.0 Hz, 1H), 1.29 (d, J = 6.6 Hz, 6H). 13
C NMR (101 MHz, CDCl3): δ 138.5, 133.4, 131.2, 129.7, 127.9, 127.1, 126.4, 125.9, 76.7, 24.3, 23.8, 18.1 ppm. 19
F NMR decoupled (400 MHz, CDCl3): δ -62.8 ppm.
HRMS (ESI) Calcd. for C13H13N2F3 (M+H): 255.1104, Found: 255.1100. FTIR (CH2Cl2): 2960, 1592, 1501, 1463, 1152, 958, 761 cm-1.
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16
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1-(4-iodophenyl)-4-isopropyl-1H-pyrazole (3e)
According to the general procedure, diol 1a (59.1 mg, 0.50 mmol) and 4-iodophenylhydrazine (117 mg, 0.50 mmol) were reacted to provide pyrazole 3e as a yellow oil (96 mg, 62%) after column chromatography on silica gel (0 to 10% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 2.91 (septet, J = 8.0 Hz, 1H), 1.28 (d, J = 4.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.0 (2C), 138.2, 131.7, 123.1, 120.4, 89.8, 24.4, 23.7 ppm.
HRMS (ESI) Calcd. for C12H14IN2 (M+H): 313.0196, Found: 313.0205. FTIR (neat): 2960, 1493, 1392, 997, 822, 731 cm-1. MP N.A.
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19
3-(4-isopropyl-1H-pyrazol-1-yl)-N,N-dimethylaniline (3f)
According to the general procedure, diol 1a (22 mg, 0.19 mmol) was reacted to provide pyrazole 3f as an orange solid (21 mg, 50%) after column chromatography on silica gel (0%, 10% MeOH/CH2Cl2). 1
H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.54 (s, 1H), 7.26-7.22 (m, 1H), 7.08 (s, br, 1H), 6.92-6.88 (m, 1H), 6.61 (s, br, 1H), 3.00 (s, 6H), 2.89 (m, 1H), 1.25 (d, J = 7.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 141.4, 139.1, 130.8, 129.7, 123.9, 123.7, 110.4, 103.2, 103.4, 40.7, 24.4, 23.9 ppm. HRMS (ESI+) Calcd. for C15H19N2 (M+H): 230.1652, Found: 230.1653. FTIR (neat): 2960, 1609, 1581, 1507, 1393, 946 cm-1.
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4-(4-isopropyl-1H-pyrazol-1-yl)-3-phenylcinnoline (3g)
According to the general procedure, diol 1a (27 mg, 0.23 mmol) was reacted with hydrazine 2g (60 mg, 0.23 mmol) to provide pyrazole 3g as a yellow oil (41 mg, 57%) after column chromatography on silica gel (10%, 30% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.90 (t, J = 7.0 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.44-7.37 (m, 5H), 6.99 (s, 1H), 2.83 (septet, J = 7.0 Hz, 1H), 1.15 (d, J = 7.0 Hz, 6H) ppm. 13
C NMR (100 MHz, CDCl3): δ 151.1, 149.9, 140.7, 135.1, 132.3, 131.9, 131.6, 130.6, 129.9, 129.2 (2 peaks), 129.0, 128.5, 123.4, 123.1, 24.2, 23.7 ppm. HRMS (ESI) Calcd. for C20H18N4 (M+H): 315.1604, Found: 315.1612. FTIR (neat): 3057, 2960, 1566, 1501, 1489, 1443, 1390, 1323, 1189, 1130 cm-1.
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3-(4-isopropyl-1H-pyrazol-1-yl)-3-methyltetrahydrothiophene 1,1-dioxide (3h)
Hydrazine HCl salt 2h was stirred with 2 equiv. NaOH (aq) in CH2Cl2, dried over Na2SO4, filtered, and concentrated to provide the hydrazine freebase. Then, according to the general procedure, 2isopropylpropanediol (43 mg, 0.36 mmol) was reacted to provide pyrazole 3h as a white solid (69 mg, 79%) after column chromatography on silica gel (1-4% MeOH/DCM). 1
H NMR (400 MHz, CDCl3): δ ppm 7.42 (s, 1 H), 7.32 (s, 1 H), 4.04 (d, J=14.0 Hz, 1 H), 3.20 - 3.39 (m, 3 H), 2.99 – 2.92 (m, 1 H), 2.85 (septet, J=6.6 Hz, 1 H), 2.38 - 2.55 (m, 1 H), 1.83 (s, 3 H), 1.22 (d, J=6.6 Hz, 6 H) ppm. 13
C NMR (101 MHz, CDCl3): δ 138.1, 130.2, 122.7, 63.7, 61.9, 51.3, 36.1, 27.7, 24.3, 23.8 ppm.
HRMS (ESI) Calcd. for C11H18N2O2S: (M+H): 243.1162, Found: 243.1157. FTIR (CH2Cl2): 2961, 1391, 1307, 1152, 979 cm-1. MP: 71-73 oC
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1-phenyl-4-propyl-1H-pyrazole (3i)
According to the general procedure, diol 1b (59.1 mg, 0.50 mmol) and phenylhydrazine (54.1 mg, 0.50 mmol) were reacted to provide pyrazole 3i as a colorless oil (58 mg, 62%) after column chromatography on silica gel (1 to 4% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.62-7.57 (m, 3H), 7.47 (s, 1H), 7.34 (virtual triplet, J = 8.0 Hz, 2H), 7.16 (virtual triplet, J = 8.0 Hz, 1H), 2.43 (t, J = 8.0 Hz, 2H), 1.63-1.51 (m, 2H), 0.90 (t, J = 8.0 Hz, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 145.0, 140.3, 129.3, 125.9, 124.7, 123.8, 118.7, 26.3, 23.9, 13.8 ppm.
HRMS (ESI) Calcd. for C12H15N2 (M+H): 187.1230, Found: 187.1231. FTIR (neat): 2959, 2869, 1600, 1503, 1396, 953, 754, 689 cm-1. MP N.A.
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4-cyclohexyl-1-phenyl-1H-pyrazole (3j)
According to the general procedure, diol 1c (79 mg, 0.50 mmol) was reacted to provide pyrazole 3j as a yellow oil (74 mg, 65%) after column chromatography on silica gel (0%, 7% EtOAc/heptane). 1
H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 2.69-2.52 (m, 1H), 2.10-1.93 (m, 2H), 1.90-1.68 (m, 3H), 1.53-1.21 (m, 5H) ppm. 13
C NMR (100 MHz, CD3OD): δ 141.6, 140.5, 131.7, 130.5, 127.4, 125.8, 120.1, 35.6, 35.4, 27.5, 27.2 ppm. LRMS (ESI+) Calcd. for C15H19N2 (M+H): 227.15, Found: 227.2. FTIR (neat): 2921, 2850, 1600, 1502, 1447, 1400, 1046, 984, 953, 794, 752, 659 cm-1.
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1-phenyl-4-(p-tolyl)-1H-pyrazole (3k)
According to the general procedure, diol 1d (83 mg, 0.50 mmol) was reacted to provide pyrazole 3k as a yellow solid (48 mg, 41%) after column chromatography on silica gel (0%, 3% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.50-7.46 (m, 4H), 7.31 (virtual triplet, J = 7.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 2.39 (s, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 140.1, 138.7, 136.6, 129.6, 129.4, 129.1, 126.4, 125.6, 124.9, 123.0, 119.0, 21.1 ppm. HRMS (ESI) Calcd. for C16H14N2 (M+H): 235.1230, Found: 235.1235. FTIR (neat): 2912, 1598, 1570, 1497, 1462, 1408, 1365, 1306, 1259, 1199, 1111, 1072 cm-1. MP 112 °C
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4-(2-phenoxyethyl)-1-phenyl-1H-pyrazole (3m)
According to the general procedure, diol 1f (98.1 mg, 0.50 mmol) and phenylhydrazine (54.1 mg, 0.50 mmol) were reacted to provide pyrazole 3m as an off white solid (64.3 mg, 49%) after column chromatography on silica gel (0 to 20% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.65-7.53 (m, 3H), 7.35 (t, J = 8.0 Hz, 2 H), 7.25-7.14 (m, 3H), 6.91-6.82 (m, 3H), 4.08 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 158.7, 141.2, 140.2, 129.5, 129.4, 126.2, 125.6, 120.8, 119.8, 118.9, 114.6, 68.0, 24.6 ppm. HRMS (ESI) Calcd. for C17H17N2O (M+H): 265.1335, Found: 265.1334. FTIR (neat): 2928, 1598, 1497, 1240, 1036, 953, 752, 689 cm-1. MP 60 °C
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4-((2-(4-bromophenyl)-1,3-dioxolan-2-yl)methyl)-1-phenyl-1H-pyrazole (3n)
According to the general procedure, diol 1g (159 mg, 0.50 mmol) was reacted to provide pyrazole 3n as an orange solid (81 mg, 42%) after column chromatography on silica gel (5%, 15% EtOAc/heptane). 1
H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.47-7.40 (m, 5H), 7.30 (d, J = 8.2 Hz, 2H), 7.25 (virtual triplet, J = 7.4 Hz, 1H), 3.98-3.90 (m, 2H), 3.81-3.72 (m, 2H), 3.08 (s, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 142.4, 141.3, 140.1, 131.1, 129.3, 127.9, 126.6, 126.0, 122.1, 118.7, 116.8, 109.1, 64.9, 36.0 ppm. HRMS (ESI) Calcd. for C19H17BrN2O2 (M+H): 385.0546, Found: 385.0547. FTIR (neat): 1598, 1502, 1396, 1215, 1176, 1070, 1039 cm-1. MP 109 °C
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1-(4-iodophenyl)-3-methyl-1H-pyrazole (10) I
N N
To an oven dried round bottom flask with a stirbar was added 4-iodo-phenylhydrazine (117 mg, 0.50 mmol), Xantphos (8.7 mg, 0.015 mmol), and RuH2CO(PPh3)3 (13.8 mg, 0.015 mmol). The flask was fitted with a reflux condenser and the system was placed under vacuum for 5 minutes and refilled with nitrogen. The vacuum / refill sequence was repeated two more times. Toluene (1.00 mL) was added, followed by 4-hydroxybutan-2-one (44 mg, 0.50 mmol), crotonitrile (45 µL, 0.55 mmol), and AcOH (4.3 µL, 0.075 mmol). The flask was submerged in an oil bath (preheated to 120 °C) and stirred at reflux under nitrogen atmosphere for 27 h. The reaction was cooled to room temperature and concentrated in vacuo. Column chromatography on silica gel (0%, 2% EtOAc/heptane) provided the title compound as a white solid (87 mg, 61% yield). Regiochemistry was determined by 1D NOE experiments. 1
H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H), 6.26 (d, J = 2.0 Hz, 1H), 2.37 (s, 3H) ppm. 13
C NMR (100 MHz, CDCl3): δ 151.0, 139.9, 138.3, 127.1, 120.4, 108.0, 89.7, 13.7 ppm.
HRMS (ESI) Calcd. for C10H9IN2 (M+H): 284.9883, Found: 284.9882. FTIR (neat): 1588, 1537, 1499, 1464, 1415, 1375, 1254, 1224, 1044 cm-1. MP 92 °C
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38
Determination of regioselectivity: I
N N
39
7-(hydroxymethyl)-1,4-dioxaspiro[4.5]decan-8-one (11)
Ketone 11 was available from Pfizer’s chemical inventory. It was likely prepared according to the literature procedure: Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H., Angew. Chem. Ind. Ed. 2004, 43, 1983-1986.
2-phenyl-2,4,6,7-tetrahydrospiro[indazole-5,2'-[1,3]dioxolane] (12)
To an oven dried round bottom flask with a stirbar was added hydroxy ketone 11 (80% pure, 116 mg, 0.50 mmol), Xantphos (8.7 mg, 0.015 mmol), and RuH2CO(PPh3)3 (13.8 mg, 0.015 mmol). The flask was fitted with a reflux condenser and the system was placed under vacuum for 5 minutes and refilled with nitrogen. The vacuum / refill sequence was repeated two more times. Toluene (1.00 mL) was added, followed by phenylhydrazine (49 µL, 0.50 mmol), crotonitrile (90 µL, 1.10 mmol), and AcOH (4.3 µL, 0.075 mmol). The flask was submerged in an oil bath (preheated to 120 °C) and stirred at reflux under nitrogen atmosphere for 24 h. The reaction was cooled to room temperature and concentrated in vacuo. Column chromatography on silica gel (3%, 30% EtOAc/heptane) provided the title compound as a yellow oil (72 mg, 56% yield). Regiochemistry was determined by 1D NOE experiments. 1
H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1 H), 4.05 (s, 4H), 3.00 (t, J = 6.6 Hz, 2H), 2.88 (s, 2H), 2.05 (t, J = 6.6 Hz, 2H) ppm. 13
C NMR (100 MHz, CDCl3): δ 149.4, 140.2, 129.3, 126.0, 124.6, 118.9, 116.4, 108.7, 64.7, 31.8, 31.5, 21.4 ppm.
HRMS (ESI) Calcd. for C15H16N2O2 (M+H): 257.1285, Found: 257.1291. FTIR (neat): 2947, 1598, 1574, 1504, 1462, 1413, 1379, 1306, 1252, 1214, 1108, 1059 cm-1.
40
41
Determination of regioselectivity:
42
