Liu et al.
o-silylaryl triflate (0.72 mmol) and the diazo compound (0.3 mmol)
in MeCN (4 mL) was added CsF (1.2 mmol) in one portion. The
reaction mixture was stirred at room temperature for 24 h. The
resultant solution was diluted with brine (20 mL) and extracted
with ethyl acetate (20 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel to afford the
desired product.
6, we obtained the N-arylated indazole 4aa in a 45% yield (Table
4, entry 17). Obviously, this cycloaddition reaction is ac-
companied with a loss of the phosphonate group, as well as
further arylation by the benzyne. Although we are not sure at
what stage the phosphonate group is lost, we have been able to
increase the yield by adding more benzyne precursor 1a to the
reaction to be consistent with the apparent stoichiometry. Thus,
running the same reaction with 2.4 equiv of 1a resulted in an
improved yield of 55%. We also studied the cycloaddition of
diphenyldiazomethane 1o,16 which does not have any carbonyl
groups on the diazo carbon. This compound reacted uneventfully
to furnish the desired, unrearranged product in an 87% yield
(Table 4, entry 18).
Ethyl 1-phenyl-1H-indazole-3-carboxylate (4aa): white solid;
1
mp 112-113 °C (lit.18 mp 112-114 °C); H NMR (400 MHz,
CDCl3) δ 8.29 (dd, J ) 8.0, 0.8 Hz, 1 H), 7.66-7.73 (m, 3 H),
7.32-7.54 (m, 5 H), 4.54 (q, J ) 7.2 Hz, 2 H), 1.48 (t, J ) 7.2
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 162.8, 140.4, 139.4,
137.2, 129.7, 128.2, 127.8, 124.6, 124.1, 123.8, 122.7, 111.1, 61.4,
14.7; IR (CDCl3) 3058, 3045, 2978, 2934, 2897, 1725, 1593, 1478
cm-1; HRMS (EI) calcd for C16H14N2O2 266.1055, found 266.1060.
General Procedure for Synthesis of the Indazoles from
Disubstituted Diazo Compounds. To a solution of the o-silylaryl
triflate (0.35 mmol) and the diazo compound (0.3 mmol) in MeCN
(4 mL) was added CsF (0.6 mmol) in one portion. The reaction
mixture was stirred at room temperature for 24 h. The resultant
solution was diluted with brine (20 mL) and extracted with ethyl
acetate (20 mL). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel to afford the desired
product.
Conclusions
In summary, an efficient route to a variety of indazoles and
their derivatives has been developed. It involves the reaction
of a variety of diazo compounds with o-silylaryl triflates in the
presence of CsF or TBAF to afford the corresponding [3+2]
cycloadducts in good to excellent yields. Diazo compounds
bearing a hydrogen undergo tautomerization to the correspond-
ing 1H-indazoles. Use of an excess of the aryne precursor
affords excellent yields of N-aryl-1H-indazoles. Diazo com-
pounds with carbonyl groups attached to the diazo carbon
undergo acyl migration to form the corresponding 1-acyl
indazoles. This methodology provides a useful new route to
indazoles, which should find application in the construction of
molecules with interesting biological properties and pharma-
ceutical potential.
Ethyl 3-phenyl-3H-indazole-3-carboxylate (5ka): white solid;
1
mp 58-59 °C; H NMR (300 MHz, CDCl3) δ 8.15-8.18 (m, 1
H), 7.86-7.89 (m, 1 H), 7.59-7.63 (m, 2 H), 7.35-7.38 (m, 3 H),
7.48-7.51 (m, 2 H), 4.20-4.27 (m, 2 H), 1.23 (t, J ) 7.2 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 166.7, 157.5, 137.7, 132.9, 130.4,
130.0, 128.9, 128.8, 127.3, 124.8, 122.1, 101.1, 62.7, 13.8; IR
(CDCl3) 3016, 2926, 2856, 1734, 1641 cm-1; LRMS (EI) 210-
(21), 180(38), 165(100), 152(51), 139(28), 115(27), 89(41), 82-
(46); HRMS (EI) calcd for C16H14N2O2 266.1055, found 266.1060.
Ethyl 3-phenyl-1H-indazole-1-carboxylate (6ka): white solid;
mp 76-79 °C (some impurities present); 1H NMR (300 MHz,
CDCl3) δ 8.30 (d, J ) 8.5 Hz, 1 H), 7.80-7.95 (m, 3 H), 7.38-
7.58 (m, 5 H), 4.61 (q, J ) 7.0 Hz, 2 H), 1.53 (t, J ) 7.1 Hz, 3 H);
13C NMR (75 MHz, CDCl3) δ 150.9, 150.6, 141.2, 131.6, 129.4,
129.1, 128.8 ,128.3, 124.3, 124.2, 121.4, 114.8, 64.3, 14.5; LRMS
(EI) 266(100), 194(47), 165(16); HRMS (EI) calcd for C16H14N2O2
266.1055, found 266.1060.
Experimental Section
General Procedure for Synthesis of the indazoles from
Monosubstituted Diazo Compounds. To a solution of the o-
silylaryl triflate (0.3 mmol) and the diazo compound (0.45 mmol)
in THF (4 mL) at -78 °C was slowly added TBAF (0.36 mmol)
with stirring. The reaction mixture was allowed to gradually warm
up to room temperature and then stirred for an additional 10 h.
The resultant solution was diluted with brine (20 mL) and extracted
with diethyl ether (20 mL). The combined organic layers were dried
over Na2SO4 or MgSO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel to
afford the desired 1H-indazole product.
Acknowledgment. We are grateful to the National Institutes
of Health and Kansas University Center of Excellence in
Chemical Methodologies and Library Development (P50
GM069663) for their generous financial support. We also thank
Dr. Arkady Ellern for the X-ray analysis of compound 6da.
Ethyl 1H-indazole-3-carboxylate (3aa): white solid; mp 132-
1
134 °C (lit.17 mp 130 °C); H NMR (300 MHz, CDCl3) δ 12.88
(br s, 1 H), 8.21 (d, J ) 7.8 Hz, 1 H), 7.83 (d, J ) 8.4 Hz, 1 H),
7.47 (m, 1 H), 7.33 (m, 1 H), 4.57 (q, J ) 7.2 Hz, 2 H), 1.47 (t, J
) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.2, 141.5, 136.3,
127.2, 123.2, 122.3, 121.7, 111.5, 61.1, 14.4; HRMS (EI) calcd
for C10H10N2O2 190.0742, found 190.0748.
Supporting Information Available: Characterization of the
1
final products, including full H and 13C NMR spectra, and the
X-ray structure of compound 6da, including a CIF file and
crystallographic data. This material is available free of charge via
General Procedure for Synthesis of the N-Aryl Indazoles
from Monosubstituted Diazo Compounds. To a solution of the
JO702062N
(17) Schmidt, A.; Merkel, L.; Eisfeld, W. Eur. J. Org. Chem. 2005, 2124.
(18) Dalla Croce, P. Synthesis 1984, 982.
226 J. Org. Chem., Vol. 73, No. 1, 2008