si one-pot synthesis of 1-alkylindazoles - for obc one-pot synthesis of 1-alkyl-1h-indazoles from...

One-pot Synthesis of 1-Alkyl-1H-indazoles

from 1,1-Dialkylhydrazones via Aryne Annulation

Nataliya A. Markina, Anton V. Dubrovskiy, and Richard C. Larock*

Department of Chemistry, Iowa State University, Ames, IA, 50011, USA

larock@iastate.edu

Supporting Information

Table of contents

General procedure for the synthesis of N,N-dialkylhydrazones S2

Fluorohydrazone 7a’ S5

Characterization data for indazoles prepared

via NCS chlorination S6

General procedure for the preparation of 2-acetyl-1-methylindazolines S12

Characterization data for indazoles prepared

via anion trap/deprotection S14

Procedure for the preparation of 1-benzyl-3-phenyl-1H-indazole S16

Copies of 1H and 13C NMR spectra (19F NMR data for 7a’) S17-S80

NOE data for compound 15l S81-S82

Copies of GC/MS spectra for crude 7a’ and 15a S83-84

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

General procedure for the preparation of hydrazones 6

The starting hydrazones were prepared according to the procedure described in our recent

communication.1 The characterization of hydrazones 6a-6c, 6g, 6h, 6j-6m, 6p and 6r can

be found therein.

(E)-Methyl 4-[(2,2-dimethylhydrazono)methyl]benzoate2 (6d)

Compound 6d was obtained as a colorless solid in a 96% yield: M. P. 65-66 °C; 1H NMR

(400 MHz, CDCl3) δ 2.97 (s, 6H), 3.85 (s, 3H), 7.09 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.94

(d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 42.55, 51.93, 124.99, 128.02, 129.63,

129.83, 141.55, 167.00; MS (EI) m/z (%) 206 (M+, 97%), 163 (59%), 130 (100%), 102

(46%), 76 (23%), 44 (21%). IR (CH2Cl2, cm-1) 2953 (w), 1716 (s), 1581 (m), 1550 (m).

(E)-4-[(2,2-dimethylhydrazono)methyl]benzonitrile2 (6e)

Compound 6e was obtained as a colorless solid in a 92% yield: M. P. 141-143 °C; 1H NMR

(300 MHz, CDCl3) δ 3.04 (s, 6H), 7.05 (s, 1H), 7.50-7.61 (m, 4H); 13C NMR (75 MHz,

CDCl3) δ 42.63, 109.38, 119.58, 125.51, 128.06, 132.37, 141.75. MS (EI) m/z (%) 173 (M+,

100%), 158 (24%), 128 (67%), 42 (21%); IR (CH2Cl2, cm-1) 2866 (w), 2223 (s), 1576 (s),

1545 (s), 1054 (s).

1 A. V. Dubrovskiy, R. C. Larock, Org. Lett. 2011, 13, 4136. 2 M. Giurg, J. Mlochowski, A. Ambrozak, Polish J. Chem. 2002, 76, 1713.

4-Ethynylbenzaldehyde dimethylhydrazone (6f)

Compound 6f was obtained as a light yellow solid in a 94% yield: M. P. 79-80 °C; 1H

NMR (300 MHz, CDCl3) δ 3.00 (s, 6H), 3.10 (s, 1H), 7.16 (s, 1H), 7.40-7.47 (m, 2H),

7.47-7.53 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 42.90, 77.63, 84.26, 120.52, 125.42,

131.07, 132.50, 137.68; MS (EI) m/z (%) 172 (M+, 100%); HRMS (ESI) calcd for [M+H]+

C11H13N2 173.1073, found 172.1000; IR (CH2Cl2, cm-1) 3295 (s), 2863 (w), 2105 (w), 1578

(s), 1546 (m), 1040 (s).

Thiophene-2-carbaldehyde dimethylhydrazone3 (6i)

Compound 6i was obtained as a green liquid in a 99% yield: 1H NMR (400 MHz, CDCl3) δ

2.94 (s, 6H), 6.94-7.02 (m, 2H), 7.13 (d, J = 4.9 Hz, 1H), 7.42 (s, 1H); 13C NMR (75 MHz,

CDCl3) δ 43.04, 124.25, 124.72, 127.19, 128.00, 142.83; MS (EI) m/z (%) 154 (M+, 100%),

109 (27%); IR (neat, cm-1) 3084 (doublet, w), 2854 (m), 1570 (m), 1034 (m), 699 (m).

(E)-N-Benzylidenepiperidin-1-amine4 (6n)

Compound 6n was obtained as a colorless solid in a 72% yield: M. P. 69-70 °C; 1H NMR

(400 MHz, CDCl3) δ 1.57 (ddt, J = 11.7, 8.4, 4.8 Hz, 2H), 1.78 (p, J = 5.9 Hz, 4H), 3.10-

3.30 (m, 4H), 7.28 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.57 (s, 1H), 7.59-7.71 (m,

2H); 13C NMR (75 MHz, CDCl3) δ 24.12, 25.16, 51.99, 125.89, 127.65, 128.38, 134.26,

3 D. Perdicchia, E. Licandro, S. Maiorana, C. Baldoli, C. Giannini, Tetrahedron 2003, 59, 7733. 4 H. Bohme, S. Ebel, Chem. Ber. 1965, 98, 1819.

136.74; MS (EI) m/z (%) 188 (M+, 100%), 131 (22%), 103 (26%), 77 (18%); IR (CH2Cl2,

cm-1) 2939 (m), 2856 (m), 1592 (m), 1565 (m), 1363 (m), 1087 (m), 992 (m).

Dihydrocinnamaldehyde dimethylhydrazone5 (6o)

Compound 6o was obtained as a light yellow liquid in a 74% yield: 1H NMR (400 MHz,

CDCl3) δ 2.56 (q, J = 7.2, 6.6 Hz, 2H), 2.73 (s, 6H), 2.82 (t, J = 7.8 Hz, 2H), 6.67 (d, J =

5.5 Hz, 1H), 7.20 (dd, J = 12.4, 6.5 Hz, 3H), 7.29 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz,

CDCl3) δ 34.31, 34.96, 43.51, 126.07, 128.53, 128.61, 138.31, 141.61; MS (EI) m/z (%)

176 (M+, 15%), 91 (30%), 85 (100%), 44 (19%); IR (neat, cm-1) 3061 (w), 2952 (s), 2852

(s), 1603 (m), 1496 (s), 1029 (s), 699 (s).

2,4,6-Trimethoxybenzaldehyde dimethylhydrazone (6q)

Compound 6q was obtained as a light brown liquid in a 94% yield: 1H NMR (400 MHz,

CDCl3) δ 2.87 (s, 6H), 3.76 (s, 3H), 3.83 (d, J = 5.1 Hz, 6H), 6.42 (s, 1H), 7.37 (s, 1H),

7.53 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 43.11, 55.94, 56.15, 56.55, 97.34, 107.51,

117.37, 129.41, 143.51, 149.36, 151.23; MS (EI) m/z (%) 238 (M+, 81%), 193 (93%), 179

(100%), 164 (25%), 151 (34%), 121 (23%), 44 (49%); HRMS (ESI) calcd for [M+H]+

C12H19N2O3 239.139, found 238.1317; IR (neat, cm-1) 3005 (w), 2941 (m), 2839 (m), 1676

(w), 1592 (s), 1468 (m), 1126 (s).

5 S. Denmark, J. P. Edwards, T. weber, D. W. Piotrowski, Tetrahedron Asymmetry 2010, 21, 1278

(E)-Ethyl 2-(2,2-dimethylhydrazono)acetate6 (6s)

Compound 6s was obtained as a yellow liquid in a 69% yield: 1H NMR (400 MHz, CDCl3)

δ 1.28 (t, J = 7.1 Hz, 3H), 3.09 (s, 6H), 4.22 (q, J = 7.1 Hz, 2H), 6.35 (s, 1H); 13C NMR (75

MHz, CDCl3) δ 14.42, 42.50, 60.15, 117.37, 165.08; MS (EI) m/z (%) 144 (M+, 77%), 99

(34%), 71 (45%), 44 (100%); IR (neat, cm-1) 2981 (m), 1720 (s), 1545 (s), 1273 (s), 1184

(s), 1083 (s), 837 (m).

Benzaldehyde dibenzylhydrazone7 (6t)

Compound 6t was obtained as a colorless solid in an 85% yield: M. P. 84-86 °C; 1H NMR

(400 MHz, CDCl3) δ 4.57 (s, 4H), 6.61-7.49 (m, 14H), 7.55 (d, J = 7.3 Hz, 2H); 13C NMR

(100 MHz, CDCl3) δ 58.09, 125.73, 127.36, 127.82, 128.58, 128.72, 128.73, 131.98,

137.10, 137.76; MS (EI) m/z (%) 300 (M+, 47%), 181 (14%), 166 (13%), 103 (15%), 91

(100%); IR (CH2Cl2, cm-1) 3086 (w), 3029 (m), 2845 (w), 1589 (s), 1562 (s), 1494 (s),

1452 (s), 1129 (m).

Data for the crude N',N'-dimethylbenzohydrazonoyl fluoride (7a’)

6 T. Hoffman, Helv. Chim. Acta 1997, 80, 1843. 7 P. N. Anderson, J. T. Sharp, J. Chem. Soc. Perkin Trans. 1 1984, 2855.

1H NMR (400 MHz, CD3CN) δ 2.83 (s, 6H), 7.44 (m, 3H), 7.73 (d, J = 7.9 Hz, 2H)

(succinimide peak: δ 2.60); 19F NMR (400 MHz, CD3CN) δ -66.6; MS (EI) m/z (%) 166

(M+, 100%), 103 (20%), 77 (19%), 42 (21%); HRMS (ESI) calcd for [M+H]+ C9H12FN2

167.0907, found 167.0975.

Characterization data for indazoles 15 prepared via NCS-chlorination.

1-Methyl-3-(naphthalen-2-yl)-1H-indazole (15b)

Product 15b was isolated as a yellow oil in a 76% yield: 1H NMR (400 MHz, CDCl3) δ

4.19 (s, 3H), 7.27 (ddd, J = 7.7, 5.2, 2.0 Hz, 1H), 7.46 (d, J = 5.2 Hz, 2H), 7.53 (td, J = 5.2,

4.6, 2.1 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.98 (t, J = 7.9 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H),

8.44 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 35.81, 109.47, 121.25, 121.61, 121.95, 125.67,

126.19, 126.45, 126.52, 127.94, 128.42, 128.65, 131.37, 133.14, 133.82, 141.69, 143.73;

MS (EI) m/z (%) 258 (M+, 100%); HRMS (EI) calcd for [M+H]+ C15H15N2O 259.123,

found 259.1234; IR (CH2Cl2, cm-1) 2937 (m), 1615 (s), 1494 (m).

3-(4-Methoxyphenyl)-1-methyl-1H-indazole (15c)

Product 15c was isolated as a yellow oil in a 72% yield: 1H NMR (400 MHz, CDCl3) δ

3.88 (s, 3H), 4.11 (s, 3H), 7.05 (dd, J = 9.0, 2.2 Hz, 2H), 7.20 (ddd, J = 7.9, 5.5, 2.3 Hz,

1H), 7.41 (d, J = 5.4 Hz, 2H), 7.90 (dd, J = 9.0, 2.2 Hz, 2H), 7.99 (d, J = 8.2 Hz, 1H); 13C

NMR (100 MHz, CDCl3) δ 35.66, 55.53, 109.29, 114.42, 120.83, 121.52, 121.64, 126.38,

126.50, 128.74, 141.53, 143.73, 159.55; MS (EI) m/z (%) 238 (M+, 100%), 223 (61%), 195

(22%); HRMS (EI) calcd for [M+H]+ C15H15N2O 239.1179, found 239.1179; IR (CH2Cl2,

cm-1) 3007 (w), 2938 (m), 2838 (m), 1614 (s), 1530 (s), 1035 (s).

Methyl 4-(1-methyl-1H-indazol-3-yl)benzoate (15d)

Product 15d was isolated as a yellow solid in a 59% yield: M. P. 117-121 °C; 1H NMR

(400 MHz, CDCl3) δ 3.95 (s, 3H), 4.14 (s, 3H), 7.25 (dt, J = 8.1, 4.2 Hz, 1H), 7.44 (d, J =

3.5 Hz, 2H), 8.04 (dd, J = 11.3, 8.5 Hz, 3H), 8.16 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz,

CDCl3) δ 35.91, 52.34, 109.61, 121.29, 121.65, 121.82, 126.63, 127.12, 129.24, 130.30,

138.38, 141.68, 142.57, 167.17; MS (EI) m/z (%) 266 (M+, 100%), 235 (61%), 208 (12%),

192 (13%); HRMS (EI) calcd for [M+H]+ C16H15N2O2 267.1128, found 267.1133; IR

(CH2Cl2, cm-1) 2951 (m), 1720 (s), 1611 (s), 1114 (s).

4-(1-Methyl-1H-indazol-3-yl)benzonitrile (15e)

Product 15e was isolated as a light yellow solid in a 45% yield: M. P. 144-147 °C; 1H

NMR (400 MHz, CDCl3) δ 4.15 (s, 3H), 7.25-7.30 (m, 1H), 7.46 (d, J = 3.6 Hz, 2H), 7.74-

7.79 (m, 2H), 7.99 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz,

CDCl3) δ 36.02, 109.82, 111.08, 119.26, 120.96, 121.68, 122.02, 126.81, 127.63, 132.79,

132.96, 138.50, 141.61, 141.76 (the latter peak possibly appears due to the conformational

restriction at the C-3 carbon of the indazole); MS (EI) m/z (%) 233 (M+, 100%); HRMS

(EI) calcd for [M+H]+ C15H12N3 234.1026, found 234.1025; IR (CH2Cl2, cm-1) 2941 (w),

2228 (s), 1610 (s).

3-(4-Ethynylphenyl)-1-methyl-1H-indazole (15f)

Product 15f was isolated as a yellow solid in a 67% yield: M. P. 106-108 °C; 1H NMR (400

MHz, CDCl3) δ 3.16 (s, 1H), 4.13 (s, 3H), 7.18-7.28 (m, 1H), 7.43 (s, 2H), 7.63 (d, J = 8.2

Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ

35.84, 78.04, 83.91, 109.53, 115.50, 121.33, 121.42, 121.70, 126.57, 127.20, 132.76,

134.36, 141.63, 142.87; MS (EI) m/z (%) 232 (M+, 100%); HRMS (EI) calcd for [M+H]+

C16H13N2 233.1073, found 233.1078; IR (CH2Cl2, cm-1) 3296 (s), 2940 (w), 2107 (w), 1615

(m), 1493 (m).

3-(2-Bromophenyl)-1-methyl-1H-indazole (15g)

Product 15g was isolated as a yellow oil in a 65% yield: 1H NMR (400 MHz, CDCl3) δ

4.15 (s, 3H), 7.18 (ddd, J = 7.8, 5.6, 2.1 Hz, 1H), 7.30 (td, J = 7.7, 1.7 Hz, 1H), 7.38-7.48

(m, 3H), 7.55 (dd, J = 7.6, 1.7 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.72-7.77 (m, 1H); 13C

NMR (100 MHz, CDCl3) δ 35.86, 109.31, 120.76, 122.13, 122.66, 123.54, 126.49, 127.47,

129.91, 132.61, 133.46, 134.54, 140.78, 143.93; MS (EI) m/z (%) 288 ([M+2]+, 90%), 286

(M+, 100%), 206 (15%); HRMS (EI) calcd for [M+H]+ C14H12 BrN2 287.0178, found

287.0183; IR (CH2Cl2, cm-1) 2939 (m), 1617 (m), 1495 (m), 1027 (m).

(E)-1-Methyl-3-styryl-1H-indazole (15h)

Product 15h was isolated as a light brown solid in a 32% yield: M. P. 72-75 °C; 1H NMR

(400 MHz, CDCl3) δ 4.09 (s, 3H), 7.24 (s, 2H), 7.40 (dd, J = 9.5, 6.6 Hz, 3H), 7.43-7.54 (m,

2H), 7.60 (d, J = 7.4 Hz, 2H), 8.02 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ

35.76, 109.43, 120.19, 121.13, 121.20, 122.21, 126.64, 126.68, 127.91, 128.93, 130.45,

137.61, 141.46, 142.29; MS (EI) m/z (%) 234 (M+, 90%), 233 ([M-H]+, 100%), 218 (48%);

HRMS (EI) calcd for [M+H]+ C16H15N2 235.1230, found 235.123; IR (CH2Cl2, cm-1) 3082

(w), 2937 (m), 1614 (m), 1493 (m), 962 (s).

1-Methyl-3-(thiophen-2-yl)-1H-indazole (15i)

Product 15i was isolated as a yellow-green oil in a 60% yield: 1H NMR (300 MHz, CDCl3)

δ 4.10 (s, 3H), 7.17 (dd, J = 4.9, 3.7 Hz, 2H), 7.20-7.26 (m, 2H), 7.33-7.37 (m, 2H), 7.38-

7.46 (m, 3H), 7.63 (d, J = 3.6 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz,

CDCl3) δ 35.75, 109.44, 121.29, 121.32, 124.46, 124.94, 126.77, 127.82, 136.23, 138.98,

141.48; MS (EI) m/z (%) 214 (M+, 100%), 199 (25%); HRMS (EI) calcd for [M+H]+

C12H11N2S 215.0637, found 215.0640; IR (CH2Cl2, cm-1) 3397 (m), 2948 (m), 2842 (m),

2798 (m), 1595 (m), 1494 (m).

1-Methyl-3-phenyl-1H-benzo[f]indazole (15j)

Product 15j was isolated as a yellow solid in a 63% yield: M. P. 137-139 °C; 1H NMR (400

MHz, CDCl3) δ 4.20 (s, 3H), 7.33-7.39 (m, 1H), 7.46 (q, J = 6.6 Hz, 2H), 7.58 (t, J = 7.6

Hz, 2H), 7.78 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 7.3 Hz,

2H), 8.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 35.87, 104.18, 120.32, 123.15, 123.52,

126.22, 127.60, 127.77, 128.19, 129.09, 129.45, 132.57, 133.71, 140.52, 143.73; MS (EI)

m/z (%) 258 (M+, 100%); HRMS (EI) calcd for [M+H]+ C18H14N2 259.1230, found

259.1224.

5,6-Dimethoxy-1-methyl-3-phenyl-1H-indazole (15k)

Product 15k was isolated as a yellow solid in a 62% yield: M. P. 128-130 °C; 1H NMR

(400 MHz, CDCl3) δ 3.95 (s, 3H), 3.99 (s, 3H), 4.06 (s, 3H), 6.74 (s, 1H), 7.28 (s, 1H), 7.37

(t, J = 7.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.89 (d, J = 7.3 Hz, 2H); 13C NMR (100 MHz,

CDCl3) δ 35.84, 56.25, 56.46, 90.65, 100.77, 114.67, 127.29, 127.73, 128.97, 134.08,

137.28, 143.19, 146.53, 150.82; MS (EI) m/z (%) 268 (M+, 100%), 253 (62%), 210

(17%);HRMS (EI) calcd for [M+H]+ C16H17N2O2 269. 1285, found 269.1290; IR (CH2Cl2,

cm-1) 3008 (w), 2937 (m), 2832 (m), 1713 (s), 1630 (s), 1206 (s).

4-Methoxy-1-methyl-3-phenyl-1H-indazole (15l)

Product 15l was isolated as a yellow solid in a 64% yield: M. P. 96-97 °C; 1H NMR (400

MHz, CDCl3) δ 3.90 (s, 3H), 4.09 (s, 3H), 6.52 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H),

7.31-7.42 (m, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,

CDCl3) δ 35.86, 55.39, 99.92, 101.98, 112.91, 127.71, 127.78, 127.96, 129.70, 134.15,

143.57, 144.55, 154.72; MS (EI) m/z (%) 238 (M+, 100%), 223 (18%), 208 (20%);HRMS

(EI) calcd for [M+H]+ C15H15N2O 239.1179, found 239.1179; IR (CH2Cl2, cm-1) 2937 (m),

2840 (w), 1614 (s), 1584 (s), 1507 (s), 1358 (s), 1182 (m).

1-[2-(2-(3-Phenyl-1H-indazol-1-yl)ethoxy)ethyl]pyrrolidine-2,5-dione (15m)

Product 15m was isolated as a colorless oil in a 60% yield: 1H NMR (300 MHz, CDCl3) δ

2.39 (s, 4H), 3.53-3.60 (m, 2H), 3.60-3.66 (m, 2H), 3.95 (t, J = 5.2 Hz, 2H), 4.56 (t, J = 5.3

Hz, 2H), 7.16-7.25 (m, 1H), 7.38-7.46 (m, 2H), 7.46-7.56 (m, 3H), 7.95 (d, J = 8.0 Hz, 2H),

7.99 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 28.09, 38.19, 49.22, 67.23, 69.82,

110.21, 121.20, 121.26, 121.71, 126.51, 127.70, 128.10, 129.02, 133.83, 142.00, 144.36,

177.20; MS (EI) m/z (%) 363 (M+, 30%), 220 (28%), 207 (100%), 194 (32%), 77 (16%);

HRMS (EI) calcd for [M+H]+ C21H22N3O3 364.1656, found 364.1664; IR (CH2Cl2, cm-1)

2944 (m), 2873 (m), 2798 (m), 1776 (m), 1704 (s), 1399 (m), 1123 (s).

1-[5-(3-Phenyl-1H-indazol-1-yl)pentyl]pyrrolidine-2,5-dione (15n)

Product 15n was isolated as an orange oil in a 60% yield: 1H NMR (400 MHz, CDCl3) δ

1.35 (m, 2H), 1.62 (m, 2H), 1.99 (m, 2H), 2.62 (s, 4H), 3.48 (t, J = 7.3 Hz, 2H), 4.42 (t, J =

7.1 Hz, 2H), 7.20 (t, J = 7.0 Hz, 1H), 7.39 (dd, J = 14.4, 6.7 Hz, 3H), 7.50 (t, J = 7.6 Hz,

24.27, 27.41, 28.28, 29.55, 38.66, 48.75, 109.40, 121.05, 121.54, 121.77, 126.34, 127.61,

127.93, 128.94, 133.90, 141.06, 143.86, 177.35; MS (EI) m/z (%) 361 (M+, 100%), 249

(53%), 194 (48%), 77 (29%); HRMS (EI) calcd for [M+H]+ C22H24N3O2 362.1863, found

362.1870; IR (CH2Cl2, cm-1) 2937 (m), 2862 (m), 1773 (m), 1693 (s), 1491 (s), 1351 (s).

General procedure for the preparation of 2-acetyl-1-methylindazoles 17

[1-(1-Methyl-3-phenyl-1H-indazol-2(3H)-yl)ethanone (17a) as an example].

To a mixture of benzaldehyde dimethylhydrazone 6a (37 mg, 0.25 mmol), CsF (114 mg,

0.75 mmol, 3 equiv), acetic anhydride (51 mg, 0.50 mmol, 2 equiv) and 5 mL of

acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl triflate (84 mg, 0.28 mmol, 1.1 equiv)

was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65

°C. Then the reaction mixture was poured into 25 ml of water in a separatory funnel. After

shaking the layers, the organic fraction was separated and the aqueous layer was extracted

with dichloromethane (2 ! 10 ml). All organic fractions were combined and concentrated

under reduced pressure. The residue was purified by flash chromatography on silica gel

using hexanes/EtOAc as the eluent to afford the N-acetylated product 17a. Product 17a was

isolated as a light brown amorphous solid in an 83% yield as an inseparable mixture of

diastereomers (ratio ~5:1): major diastereomer 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H),

3.05 (s, 3H), 6.45 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.19-7.28 (m,

2H), 7.31 (t, J = 6.5 Hz, 3H), 7.37 (d, J = 6.9 Hz, 3H); minor diastereomer (selected peaks)

1H NMR (400 MHz, CDCl3) δ 1.96 (s, 0.67H), 3.36 (s, 0.61H) 6.06 (s, 0.19H) 6.94 (s,

0.5H); 13C NMR (100 MHz, CDCl3) (all of the peaks listed for the mixture of

diastereomers) δ 21.45, 22.85, 45.71, 48.55, 64.20, 64.23, 67.97, 112.73, 113.82, 115.41,

123.27, 124.08, 124.19, 126.37, 127.75, 127.84, 128.65, 129.01, 129.32, 130.76, 142.02,

150.43, 173.66; MS (EI) m/z (%) 252 (M+, 14%), 209 (100%), 194 (15%); HRMS (EI)

calcd for [M+H]+ C16H17N2O 253.1335, found 253.1332; IR (CH2Cl2, cm-1) 2921 (m), 1666

(s), 1610 (m), 1483 (m), 1381 (s).

1-[1-Methyl-3-phenethyl-1H-indazol-2(3H)-yl]ethanone (17o)

Product 17o was isolated as a light yellow amorphous solid in a 95% yield: 1H NMR (400

MHz, CDCl3) δ 2.03 (dd, J = 12.0, 6.5 Hz, 1H), 2.09-2.23 (m, 1H), 2.29 (s, 3H), 2.75 (d, J

= 14.6 Hz, 1H), 2.88 (td, J = 12.7, 6.1 Hz, 1H), 3.09 (s, 3H), 5.45 (t, J = 5.6 Hz, 1H), 6.94

(d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.15-7.24 (m, 4H), 7.28 (t, J = 7.2 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 21.44, 32.48, 41.10, 48.61, 61.70, 113.78, 117.52, 122.95,

123.80, 125.97, 128.33, 128.47, 132.41, 141.87, 150.05, 174.45; MS (EI) m/z (%) 280 (M+,

14%), 237 (85%), 175 (24%), 145 (71%), 133 (100%), 104 (33%), 77 (22%); HRMS (EI)

calcd for [M+H]+ C18H21N2O 281.1648, found 281.1656; IR (CH2Cl2, cm-1) 2920 (w), 2863

(w), 1660 (s), 1610 (w), 1385 (s).

Characterization data for indazoles 15 obtained via methods A and B.

3-Mesityl-1-methyl-1H-indazole1 (15p)

Product 15p was isolated as a red amorphous solid in a 91% yield (method A): 1H NMR

(400 MHz, CDCl3) δ 2.08 (s, 6H), 2.38 (s, 3H), 4.15 (s, 3H), 7.00 (s, 2H), 7.12 (t, J = 7.2

Hz, 1H), 7.38-7.49 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 20.56, 21.37, 35.65, 109.12,

120.33, 121.30, 123.53, 126.25, 128.32, 129.14, 137.90, 138.31, 140.76, 143.93; MS (EI)

m/z (%) 250 (M+, 73%), 249 ([M-H]+, 100%), 235 (13%), 219 (11%); HRMS (EI) calcd for

[M+H]+ C17H19N2 251.1543, found 251.1549; IR (CH2Cl2, cm-1) 3004 (m), 2921 (s), 2858

(m), 1614 (s), 1492 (s), 1337 (s).

1-Methyl-3-(2,4,6-trimethoxyphenyl)-1H-indazole (15q)

Product 15q was isolated as a yellow solid in a 76% yield (method A): M. P. 164-166 °C;

1H NMR (400 MHz, CDCl3) δ 3.71 (s, 6H), 3.89 (s, 3H), 4.13 (s, 3H), 6.27 (s, 2H), 7.08 (t,

J = 7.2 Hz, 1H), 7.33-7.42 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)

δ 35.70, 55.55, 56.08, 90.95, 109.02, 119.91, 121.85, 124.45, 125.88, 138.24, 140.71,

157.27, 160.12, 161.79; MS (EI) m/z (%) 298 (M+, 100%), 297 ([M-H]+, 39%), 267 (16%);

HRMS (EI) calcd for [M+H]+ C17H19N2O3 299.1390, found 299.1399; IR (CH2Cl2, cm-1)

3009 (w), 2940 (m), 2839 (m), 1615 (s), 1587 (s), 1337 (s), 1127 (s).

1-Methyl-3-(pyridin-3-yl)-1H-indazole (15r)

Product 15r was isolated as an orange amorphous solid in a 29% yield (method A): 1H

NMR (400 MHz, CDCl3) δ 4.07 (s, 3H), 7.18 (dt, J = 8.1, 4.0 Hz, 1H), 7.34 (dd, J = 7.9,

4.9 Hz, 1H), 7.37 (d, J = 3.6 Hz, 2H), 7.91 (d, J = 8.2 Hz, 1H), 8.17 (dt, J = 7.9, 1.8 Hz,

1H), 8.55 (dd, J = 4.7, 1.3 Hz, 1H), 9.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 35.89,

109.63, 121.02, 121.67, 121.72, 123.90, 126.75, 129.98, 134.54, 140.76, 141.62, 148.55,

148.99; MS (EI) m/z (%) 209 (M+, 100%), 208 ([M-H]+, 33%), 181 (10%); HRMS (ESI)

calcd for [M+H]+ C13H12N3 210.1026, found 210.1029; IR (CH2Cl2, cm-1) 3392 (w, broad),

2939 (m), 1618 (s), 1496 (s), 1153 (s).

(E)-Ethyl 2-(acetylimino)-2-[2-(dimethylamino)phenyl]acetate (20)

Product 20 was isolated as an orange amorphous solid in a 54% yield (method A): 1H NMR

(400 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 2.36 (s, 3H), 2.66 (s, 6H), 4.22 (q, J = 7.1 Hz,

2H), 7.09-7.21 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H); 13C NMR (75

MHz, CDCl3) δ 14.26, 25.12, 45.00, 62.08, 119.80, 124.15, 130.18, 130.37, 132.72, 154.07,

157.34, 163.42, 185.62.; MS (EI) m/z (%) 262 (M+, 11%), 203 (82%), 189 (29%), 175

(19%), 158 (84%), 147 (100%), 131 (31%), 43 (26%); HRMS (ESI) calcd for [M+H]+

C14H19N2O3 263.1390, found 263.1397; IR (CH2Cl2, cm-1) 2942 (m), 2867 (m), 2835 (m).

2792 (m), 1736 (s), 1708 (s), 1652 (s), 1595 (s), 1490 (s).

Procedure for the preparation of 1-benzyl-3-phenyl-1H-indazole8(15t).

To a mixture of benzaldehyde dibenzylhydrazone 6t (75 mg, 0.25 mmol), CsF (151 mg,

1.00 mmol, 4 equiv), and 5 mL of acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl

triflate (149 mg, 0.50 mmol, 2.0 equiv) was added. The vial was capped and the reaction

mixture was allowed to stir for 10 h at 65 °C. Then the reaction mixture was poured into 25

ml of water in a separatory funnel. After shaking the layers, the organic fraction was

separated and the aqueous layer was extracted with dichloromethane (2 ! 10 ml). All

organic fractions were combined and concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford

15t as a yellow amorphous solid in a 51% yield: 1H NMR (400 MHz, CDCl3) δ 5.68 (s, 2H),

7.16-7.34 (m, 6H), 7.37 (d, J = 4.1 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz,

53.29, 109.83, 121.29, 121.61, 122.30, 126.56, 127.33, 127.72, 127.88, 128.07, 128.88,

128.98, 133.86, 137.07, 141.26, 144.36; MS (EI) m/z (%) 284 (M+, 100%), 91 (79%);

HRMS (ESI) calcd for [M+H]+ C20H16N2 285.1386, found 285.1394; IR (CH2Cl2, cm-1)

2927 (m), 2854 (w), 1614 (s), 1493 (s), 1350 (s).

8 V. Collot, P. Dallemagne, P. R. Bovy, S. Rault, Tetrahedron 1999, 55, 6917.

��

� ��

��

� ��

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� ��

��

� ��

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

� �

��

si one-pot synthesis of 1-alkylindazoles - for obc one-pot synthesis of 1-alkyl-1h-indazoles from...

Documents

melting pot

3 ghz sica: breakdown measurement in ctf alexey dubrovskiy...

regioselective ethoxycarbonylation of indoles and indazoles...

australian indian aboriginal vietnamesechinese italian...

pot economy and one-pot synthesis - rsc publishing home

indazoles in drug discovery - pharmablock

pot-in-pot planter combining...

[ application ] - apr. 17, 2020 acura - yellow speed ·...

the pot-in-pot (pnp) production system

the pot kiln · the pot kiln country inn & game restaurant...

dispositivo pot-in-pot: estudio de variables y

pot growing

conditions of resuming and completing privatization in...

garden pot

scientific abstract dubrovskiy, v.p. - dubrovskiy,...

powerpoint presentation orange_sunstanding ngi.pdfm m m m m...

case ukraine driving forces for the unwanted reforms: can...

alessi, pot alessi, pot · alessi, pot alessi, pot...

the empty pot leveled book n the empty pot

case ukraine investment environment in ukraine vladimir...