Synthesis of 1H-indazoles by reductive cyclization of o-nitro-ketoximes

Article abstract of DOI:10.3987/com-03-9926

ortho-Nitro-ketoximes are converted to 1H-indazoles upon reaction with carbon monoxide with [Cp*Fe(CO)₂]₂ as catalyst.

Full text of DOI:10.3987/com-03-9926

HETEROCYCLES, Vol. 63, No. 2, 2004, pp. 373 - 382
Received, 29th September, 2003, Accepted, 2nd December, 2003, Published online, 8th December, 2003
SYNTHESIS
OF
1H-INDAZOLES
BY
REDUCTIVE
CYCLIZATION OF o-NITRO-KETOXIMES
David K. O’Dell and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, University of Oklahoma,
Norman, OK. 73019, U.S.A.
Abstract – ortho-Nitro-ketoximes are converted to 1H-indazoles upon
reaction with carbon monoxide with [Cp*Fe(CO)2]2 as catalyst.
INTRODUCTION
Indazoles are important compounds as evidenced by their preponderance in the chemical patent literature
as kinase inhibitors1 and their use as anti-cancer2 and anti-spermatogenic agents.3 Indazoles were
originally prepared by Fischer,4 and many syntheses have since been reported.5 The most widely used
methods involve the diazotization of 2-alkylanilines and the cyclization of ortho-substituted hydrazones.
The former usually requires acidic conditions and works best with electron deficient aromatic substrates
while the latter employs hydrazine, a basic reducing agent, and has a similar electronic character. We
have been investigating the synthesis of nitrogen heterocycles in our laboratory by the reductive
cyclization of ortho-substituted nitroaromatics with CO catalyzed by Group 8 metal carbonyl
complexes.6 These reactions, which proceed under neutral, chemoselective conditions, have provided
new routes to indoles6a and quinolines6b (Scheme 1).
Scheme 1
R
Z
n
N
OR'
CO
[CpFe(CO) ]
CO
[Cp*Fe(CO) ]
H
R
R
R
2 2
+
2 2
Z
n
Z
n
R'=H
NO
2
R'=COCH
N
3
Z
n
N
H
O

Although the reductions of o-nitrobenzylanilines7 and o-nitroimines8 provide a route to 2-arylindazoles,
to our knowledge, the conversion of o-nitroketoximes to 1H-indazoles has not been reported. Von
Auwers prepared indazoles from benzaldoxime acetates bearing o-tosyl-9 or o-acyl-amino groups.10
Others have shown that sydnones with pendant oxime units cyclize under acidic conditions to give 1H-
indazoles11 and that o-azidobenzaldoximes give 2-hydroxyindazoles upon boiling in alkali.12 These
conditions are not suitable for substrates bearing acid/base sensitive groups.
The ability of metal carbonyl/CO systems to deoxygenate RNO1,2 compounds,13 as well as N-O bonds in
isoxazoles14 and other heterocycles15 has been established. We were intrigued by an early report by Alper
.
on the formation of ketones from ketoximes with Fe(CO)5/BF3 Et2O16 in which it was suggested that the
keto-oxygen originated from the oxime oxygen. Others have since reported similar behavior.17 We
wondered about possible reductive transformations of substrates bearing both oxime and nitro groups,
anticipating the discovery of new cyclization pathways. Accordingly, we have investigated the behavior
of o-nitro-ketoximes with the CO/Fp*2 reductive system and report herein their novel conversion to 1H-
indazoles.
RESULTS AND DISCUSSION
When 2-nitroacetophenone oxime (1a) was heated with 10 mol% of pentamethylcyclopentadienyl
dicarbonyl iron(II) dimer [Cp*Fe(CO)2]2 in dioxane under 50 atm CO, two main products were isolated:
3-methyl–1H-indazole (2a, 59 % yield) and 2-aminoacetophenone (3a, 15 %), identified
spectroscopically and by comparison with authentic samples (eq. 1). Small amounts of other
unidentified products and some tar were also produced. Reactions conducted at lower temperatures and
pressures were extremely sluggish. Attempts to suppress the formation of ketone 3a by the addition of
drying agents (4Å molecular sieves, MgO, BaO) to the reactions were unsuccessful; no change in the
2a/3a ratio was found. This suggests that the ketone byproduct is not the result of oxime hydrolysis but
may derive from O-transfer from the oxime or nitro functions.
R
O
NOH
R
X1
X2
X1
X2
50 atm CO
X1
X2
R
N
N
+
(1)
10 mol%
[Cp*Fe(CO)2]2
dioxane
NO2
NH2
H
2
3
1
150oC
We have used this method to prepare several other 1H-indazoles as shown in Table 1. Substrates were
chosen bearing both electron-donating (ED) and electron-withdrawing (EW) substituents. The 4',5'-

dimethoxy-2'-nitroacetophenone oxime (1c) gave the highest yield (2c, 85%). While substitution of the
R group of the oxime had little effect for alkyl or aryl groups, trifluoromethyl substitution gave a poorer
yield (2b, 40%). The higher yield with the substrate bearing ED groups is somewhat surprising given
that more electron rich species should be harder to reduce. Indazoles with electron donating groups are
more difficult to prepare by previous methods and therefore our route is complimentary.18 The geometry
of the oxime has little or no effect on the rate or the outcome of the cyclization, as suggested by the fact
that the reactions of E-1c and E/Z-1c gave nearly identical product mixtures during the same reaction
time.
Table 1. Synthesis of 1H-indazoles from o-nitroketoximes
1
R
X1
X2
Yield (%) 2 Yield (%) 3a Time(h)
a
b
Me
CF3
Me
H
H
H
59
40b
85
52
56
46
72
15
--
H
--
c
d
e
OMe
H
OMe
H
68
75
75
17
--
Ph
H
p-MeO-C6H4
H
a) Compound 3 was detected by GCMS in all cases, but due to separation difficulties was not always
isolated. b) Yield based on recovered starting material.
Although the mechanism of this transformation is not yet known, it formally involves the removal of
three oxygen atoms from the o-nitro-ketoxime. Although both the nitro- and oxime-functions are
deoxygenated, presumably by O-transfer to coordinated CO ( CO2), the order of these steps and the
nature of the intermediate which undergoes N-N bond formation are uncertain. Transition metal
carbonyls are known to react with oximes to form imine and imine oxide complexes, which might be
intermediates.19 The imine (free or coordinated) or a derived iminyl radical20 could then N-couple with
the nearby nitroso group21 (free or coordinated) to form the nitrogen-nitrogen bond (with subsequent
deoxygenation). Efforts are currently underway to elucidate the mechanistic details of this remarkable
transformation.

EXPERIMENTAL
All reactants and reagents were purchased from US suppliers unless otherwise noted. NMR spectra were
recorded on Varian Mercury 300 or Gemini 400 spectrometers using residual solvent protons as
references for all 13C and 1H spectra and CFCl3 asan internal standard for 19F NMR. TLC was performed
on glass-backed plates (Sorbtech) and visualized with UV light. Flash chromatography was carried out
on Kieselgel 60 (Merck). Elemental analysis was performed by Midwest Microlabs (Indianapolis, IN).
The configuration of the oximes was determined by comparison of the 13C NMR resonances of the methyl
groups of the two isomers.22 The following compounds were prepared by reported procedures:
[Cp*Fe(CO)2]223 (1a),24 4',5'-dimethoxy-2'-nitroacetophenone,25 2-nitrobenzhydryl26 and MnO2.27
2,2,2-Trifluoro-2'-nitroacetophenone oxime (1b). Applying the method of Knochel,28
phenylmagnesium chloride (13.2 mL, 2.0M in THF) was added to a solution of 1-iodo-2-nitrobenzene
(6.0 g, 24.0 mmol) in THF (40 mL) at –40oC. After 5 min trifluoroacetic anhydride (4.23 mL, 30.0
o
mmol) was added dropwise. The mixture was stirred for 1 h at –40 C, quenched with saturated NH4Cl
(60 mL), and extracted with ether (4 x 30 mL). The ether extracts were combined and dried over MgSO4,
concentrated and then chromatographed on SiO2 (1:4 ether/hexane), giving 2.34 g (45 %) of 2,2,2-
1
trifluoro-2'-nitroacetophenone.28 (Rf = 0.3). H NMR (300 MHz, acetone-d6) 7.83 (d, J = 6.6 Hz, 1H),
8.05- 8.12 (m, 2 H), 8.45 (d, J = 7.2 Hz, 1 H), 13C NMR (75.45 MHz, acetone-d6) 116.0 (q, 1JCF = 302 Hz),
2
125.0, 129.8, 129.9, 133.9, 136.2, 184.3 (q, JCF = 39 Hz).
The 2,2,2-trifluoro-2'-nitroacetophenone (800 mg, 3.65 mmol) was then refluxed in ethanol (10 mL) and
pyridine (20 mL) with hydroxylamine hydrochloride (650 mg, 9.0 mmol) for 91 h. Solvent was removed
in vacuo and the residue chromatographed on SiO2 (1:5 ether/hexanes) to give 445 mg (52 %) of 1b as a
1
single isomer of undetermined stereochemistry. Rf = 0.35, mp 83-90 oC; H NMR (300 MHz acetone-d6)
7.59 (1H, d, J = 7.2 Hz), 7.85 (1H, dt, J = 7.6 Hz, J = 1.5 Hz), 7.95 (1H, dt, J = 7.5 Hz, J = 1.5 Hz), 8.29
(1H, dd, J = 8.4 Hz, J = 0.9Hz), 12.02 (1H, br s); C NMR (75.45 MHz, acetone-d6) 121.3 (q, 1JCF = 272
13
2
19
Hz), 125.5, 130.7, 132.4, 135.1, 144.9 (q, JCF = 34 Hz), 148.7; F NMR (282.35 MHz CDCl3) -67.24.
MS(EI) 186 (100), 167 (8), 138 (21), 63 (4). Exact Mass (ESI) calcd for C8H5N2O3F3Na (M+ Na)
257.0151, found 257.0157.
4',5'-Dimethoxy-2'-nitroacetophenone oxime (1c). To a solution of 4',5'-dimethoxy-2'-
nitroacetophenone25 (600 mg, 2.67 mmol) in pyridine (5 mL) and ethanol (10 mL) was added
hydroxylamine hydrochloride (1.0 g, excess). The mixture was refluxed for 7 h and solvent was removed
in vacuo. The residue was dissolved in CHCl3 (30 mL) and washed with 2M HCl (3 x 20 mL).
CHCl3 was removed in vacuo to give 1c as a light yellow solid. Recrystallization from a minimal

amount of hot ethanol gave 150 mg of yellow crystals that were the pure E isomer, mp 171-172 oC. The
supernatant liquid gave 470 mg of a mixture of isomers whose ratio was determined to be 5:3 (E:Z) by
1H NMR, for a total yield of 620 mg (98 %, 72% E, 28% Z) MS(EI) 241 (18), 209 (100), 194 (25), 180
1
(10), 164 (24), 150 (46); E isomer IR (KBr) 3448, 2965, 2556, 1524, 1319 H NMR (300 MHz, acetone-
d6) 2.12 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.99 (s, 1 H), 7.57 (s, 1 H), 10.30 (s, 1 H); 13C NMR (75.45
MHz, acetone-d6) 15.4, 56.5, 56.7, 108.2, 112.9, 128.6, 141.3, 149.6, 153.7, 154.2. Anal. Calcd for
1
C10H12N2O5: C 50.00, H 5.03, N 11.66. Found C 49.72, H 5.01, N 11.39. Z isomer: H NMR (300 MHz,
acetone-d6) 2.18 (s, 3H), 3.97 (s, 3 H), 3.98 (s, 3 H), 6.89 (s, 1 H), 7.63 (s, 1 H), 9.69 (s, 1 H); 13C NMR
(75.45 MHz, acetone-d6) 21.0, 56.5, 56.7, 107.8, 110.8, 126.4, 140.4, 149.2, 151.9, 154.4.
2-Nitrobenzophenone oxime (1d). A solution of 2-nitrobenzhydryl (723 mg, 3.2 mmol) in CH2Cl2 (15
28
mL) was refluxed with 1.6 g of MnO2 for 20 h. The solution was filtered through Celite to give 674
o
o
mg (93%) of 2-nitrobenzophenone as yellow solid. mp 104-106 C, lit.,29 mp 105-106 C. The 2-
nitrobenzophenone (650 mg, 2.86 mmol) was refluxed in pyridine/ethanol (1:2 / 20 mL) for 30 h.
Solvent was removed in vacuo and the residue was dissolved in ether and washed with 2M HCl (2 x 20
mL). The ether extract was concentrated and chromatographed on SiO2 with CHCl3/MeOH (35:1) to give
510 mg (2.10 mmol, 73%) of 1d as a white solid along with 140 mg of recovered starting material. mp
117-121oC, lit.,22 mp 122-123oC.
(4-Methoxyphenyl)(2-nitrophenyl)methanone oxime (1e). Applying the method of Knochel,27
phenylmagnesium chloride (4.4 mL, 2.0 M in THF) was added to a solution of 1-iodo-2-nitrobenzene
o
(2.0 g, 8.0 mmol) in THF (40 mL) at –40 C. After 5 min p-anisaldehyde (1.2 mL, 10.0 mmol) was
o
added dropwise over 5 minutes. The mixture was stirred for 1 h at –40 C, quenched with saturated
NH4Cl (60 mL), and extracted with ether (4 x 30 mL). The ether extracts were combined and dried over
MgSO4, concentrated, and then chromatographed on SiO2 (35% ether/hexane), giving 1.64 g (79%) of (4-
1
methoxyphenyl)(2-nitrophenyl)methanol30 as a yellow oil. Rf = 0.28. H NMR (400 MHz, acetone-d6)
3.75 (s, 3H), 5.14 (s, 1H), 6.41 (s, 1H), 6.86 (d, J = 6.6 Hz, 2H), 7.24 (d, J = 6.6 Hz, 2 H), 7.51 (t, J = 6.3
Hz, 1 H), 7.73 (t, J = 5.7 Hz, 1 H), 7.87 (dd, J = 6.0 Hz, J = 0.9 Hz, 1 H), 7.95 (d, J = 6.0 Hz). 13C NMR
(100.57 MHz, acetone-d6) 55.5, 70.7, 114.4, 124.9, 129.0, 129.3, 129.6, 133.8, 136.2, 140.4, 149.4, 160.0.
The resulting (4-methoxyphenyl)(2-nitrophenyl)methanol (1.64 g, 6.33 mmol) and 1.23 g of MnO222
were heated to reflux in CH2Cl2 (35 mL). After 23 h the reaction was only 40% complete (1H NMR) so
the mixture was then refluxed for 24 h more with an additional 3.0 g of MnO2. The mixture was filtered
through Celite and evaporated to give an orange solid that was dissolved in a minimal amount of hot

o
ether and recrystallized at 0 C to give 1.41 g (87 %) of (4-methoxyphenyl)(2-nitrophenyl)methanone as
1
rose-colored crystals. mp 106-107oC, lit.,31 mp 86-90oC; H NMR (300 MHz, CD3OD) 3.87 (s, 3H), 7.01
(d, J = 9.0 Hz, 2H), 7.51 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.72 (d, J = 9.0 Hz), 7.76 (dd, J = 8.1 Hz, J =
13
1.5 Hz, 1H), 7.85 (dt, J = 7.5 Hz, J = 1.2 Hz), 8.24 (dd, J = 8.1 Hz, J =1.2 Hz, 1 H); C NMR (100.57
MHz, CD3OD) 56.3, 115.3, 125.8, 130.2, 130.3, 132.0, 133.1, 135.5, 137.6, 148.4, 166.1, 194.4.
To a solution of (4-methoxyphenyl)(2-nitrophenyl)methanone (1.31 g, 5.06 mmol) in pyridine/ethanol
(20 mL 1:1) was added 2.0 g of hydroxylamine hydrochloride. The mixture was refluxed for 40 h.
Solvent was removed in vacuo and the residue was dissolved in ether and washed with 2M HCl (2 x 20
mL). The ether extract was dried with MgSO4 to give 1.31 g (95 %) of a yellow solid that was the oxime
o
1
1e, mp 142-148 C. The ratio of E/Z isomers was determined by H NMR spectroscopy to be 5:1.
Recrystallization from ethanol gave the pure E-isomer. IR (KBr) 3228, 1607, 1529, 1262, 1H NMR (300
MHz, acetone-d6), 3.82 (s, 3H), 6.92 (d, J = 9.0 Hz, 2H), 7.36 (dd, J = 7.5 Hz, J = 1.5 Hz, 1 H), 7.44 (d, J
= 9.0Hz, 2H), 7.74 (dt, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.86 (dt, J = 7.5 Hz, J = 1.2 Hz, 1H), 10.43 (s, 1H),
8.20 (dd, J = 8.1Hz, J = 1.2Hz, 1H); 13C NMR (100.57 MHz, acetone-d6) 55.0, 114.0, 124.2, 128.1, 128.4,
129.8, 130.0, 130.7, 133.9, 148.8, 153.2, 161.0 MS (EI) 272 (M+, 53), 242 (8), 225 (27), 211 (15), 196
(22), 182 (100), 167 (53), 154 (85), 139 (19), 77 (24), 63 (21). Anal. Calcd for C14H12N2O4: C 61.76, H
4.44, N 10.29. Found: C 61.74, H 4.46, N 10.12. Z-isomer (oil), 1H NMR (300 MHz, acetone-d6) 3.90 (s,
3H), 10.83 (s, 1H).
3-Methyl-1H-indazole (2a). In a glass-lined, stainless steel Parr reaction vessel 2-nitro-acetophenone
oxime (1a, 200 mg, 1.11 mmol) and [Cp*Fe(CO)2]2 (54 mg, 0.11 mmol) were combined with dry
dioxane (40 mL). The vessel was flushed three times with CO and charged to 50 atm (Caution: FUME
o
HOOD!). The mixture was heated at 150 C for 46 h. The vessel was cooled to room temperature and
the pressure was discharged (FUME HOOD!). The resulting brown solution was concentrated by rotary
evaporation and then chromatographed on silica gel with a gradient elution of ether/hexanes (1:1 to 4:1)
o
o
giving 86 mg of 2a (59%) as a light brown solid, mp.110-114 C, lit.,32 110-112 C; Rf (1:1
ether/hexanes) = 0.29. Also isolated was 2-amino-acetophenone 22 mg (15%) which was
spectroscopically identical to a commercial sample.
3-Trifluoromethyl-1H-indazole (2b). In the manner described for 2a, 300 mg (1.28 mmol) of the
oxime (1b) was combined with [Cp*Fe(CO)2]2 (60 mg, 0.13 mmol) in dioxane (60 mL) and charged to 50
o
atm with CO. After heating at 150 C for 72 h, cooling, and solvent evaporation, the mixture was
purified by preparative TLC with (30% EtOAc/hexanes) to give the indazole (2b) that was slightly

contaminated with a product of the same Rf, along with 72 mg (0.31 mmol) of recovered 1b. Indazole
(2b) was purified by preparative TLC, eluting with CHCl3/MeOH (30:1) to give 72 mg (30 %) of 2b. Rf
(CHCl3/MeOH) = 0.54, mp 73-78oC, lit.,33 mp 104oC. Sublimation of this material at 100 oC (0.1 mm Hg)
o
1
gave a white powder, mp 94-97 C. H NMR (300 MHz, acetone-d6) 7.35 (t, J = 7.2 Hz), 7.52 (t, J = 6.0
Hz, 1 H), 7.75 (d, J = 8.4 H, 1H), 7.85 (d, J= 8.0 Hz), 13.2 (br s, 1 H). 13C NMR (75.45 MHz, acetone-d6)
1
2
111.9, 119.9, 120.2, 123.4 (q, JCF = 268 Hz), 123.7, 128.3, 135.2 (q, JCF = 38 Hz), 142.1. 19F NMR
(282.35 MHz CDCl3) -61.67; MS (EI) 186 (100), 167 (8), 138 (20), 63 (4).
5,6-Dimethoxy-3-methyl-1H-indazole (2c). As above, 240 mg (1.00 mmol) of the oxime (1c) and 49
o
mg (0.10 mmol) of [Cp*Fe(CO)2]2 in dioxane (60 mL) was heated at 150 C for 68 h. After cooling and
solvent evaporation chromatography of the residue on silca gel with ethyl acetate/hexanes (4:1) gave 163
mg (0.85 mmol, 85%) of 2c as a yellow solid that could be recrystallized from cold ether to give light
brown crystals. Rf = 0.30; mp 163-167 oC lit.,18 mp 164 oC; 1H NMR (400 MHz, acetone-d6) 2.45 (s, 3 H),
13
3.84 (s, 3 H), 3.85 (s, 3H), 6.96 (s, 1 H), 7.10 (s, 1H), 11.54 (br s, 1 H). C NMR (100.57 MHz, acetone-
d6) 12.1, 56.1, 56.4, 92.5, 101.1, 116.5, 138.0, 141.8, 146.8, 152.0; MS(EI) 192 (100), 177 (64), 149 (24),
134 (17), 108 (22), 80 (13).
3-Phenyl-1H-indazole (2d). The oxime (1e) (294 mg, 1.21 mmol) with [Cp*Fe(CO)2]2 (60 mg, 0.12
o
mmol) was heated at 150 C under 50 atm CO in dioxane (70 mL) for 75 h. After concentration,
chromatography of the residue on silica gel with 30% ethyl acetate/hexanes gave 3-phenylindazole (2d,
0.63 mmol, 52 %). Rf = 0.30. mp 102-108 oC, lit.,32 mp 107-108 °C; the 13C NMR spectra was identical to
that described in the literature.35 Also recovered was 2-aminobenzophenone, 40 mg (17%), identical
spectroscopically to an authentic sample.
3-(4-Methoxyphenyl)-1H-indazole35 (2e). The oxime (1e) (305 mg, 1.12 mmol) together with
[Cp*Fe(CO)2]2 (55 mg, 0.11 mmol) was heated at 150 oC under 50 atm. CO in dioxane (70 mL) for 75 h.
After concentration, chromatography of the residue on silica gel with CHCl3/methanol (30:1) gave 2e that
was slightly impure. Preparative TLC of this mixture with CH2Cl2/acetone (95:5) gave 140 mg of 2e
(56 %) as a yellow gum. Rf (CH2Cl2/acetone) = 0.43; 1H NMR (300 MHz, CD3CN) 3.92 (s, 3H), 7.16 (d,
J = 9.0 Hz, 2H), 7.30 (dt, J = 6.5 Hz, J = 0.9Hz, 1H), 7.50 (dt, J = 7.8Hz, J = 1.2Hz), 7.66 (d, J = 9.0 Hz,
1H), 8.02 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 8.1Hz, 1H), 11.62 (br s, 1 H). MS (EI) 224 (100), 209 (62),
181 (30), 152 (20).

ACKNOWLEDGMENTS
We are thankful for financial support provided by the National Science Foundation and for an O.U.
Alumni Fellowship (to D.K.O.).
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