A versatile and efficient synthesis of substituted 1H-indazoles

Article abstract of DOI:10.1055/s-1999-3431

A facile synthesis of substituted 1H-indazole 4 from aryl mesylate 3 is described. The reaction, which proceeds through the intermediate hydrazone, was general with regard to the substituents on the arene and was applicable to several hydrazines. It was a

Full text of DOI:10.1055/s-1999-3431

588
PAPER
A Versatile and Efficient Synthesis of Substituted 1H-Indazoles
Stéphane Caron,* Enrique Vazquez
Process Research and Development, Central Research Division, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA
Fax +1(860)441-3630, E-mail: stephane_caron@groton.pfizer.com
Received 1 September 1998; revised 21 October 1998
Dedicated to Professor Robert H. Burnell on the occasion of his retirement from Laval University
Our goal was to develop a two-step, one-pot sequence in
Abstract: A facile synthesis of substituted 1H-indazole 4 from aryl
which the hydrazone would be generated and cyclized to
the desired 3-substituted-1H-indazole in a single opera-
mesylate 3 is described. The reaction, which proceeds through the
intermediate hydrazone, was general with regard to the substituents
on the arene and was applicable to several hydrazines. It was also
tion. We reasoned that the use of a better leaving group
discovered that with p-methoxyphenylhydrazine, the indazole for- than NO2–, HO–, or RO– could allow for the cyclization of
mation was more rapid than the competitive Fischer indole synthe-
sis.
an arylhydrazone at a practical temperature. Since several
o-ketophenols were commercially available, we selected
Key words: 1H-indazole, phenol, mesylate, hydrazine, hydrazone
mesylates derived from phenols as the leaving group of
choice. We also developed a one-pot acylation–Fries rear-
rangement sequence which provided access to an aryl ke-
tone in a single step from a phenol. For example, 3-
bromophenol (1) was treated with aluminum trichloride
and one equivalent of propionyl chloride in dichloroet-
hane at room temperature. Once the acylation was com-
pleted, the reaction mixture was heated to reflux, a
temperature at which the Fries rearrangement occurs. The
desired propiophenone 2d18 was isolated in 79% yield af-
ter crystallization and none of the para regioisomer was
detected.
Throughout the years, indazoles have proven to be a reli-
able pharmacophore. Several indazoles have recently
demonstrated significant levels of activity as HIV pro-
tease inhibitors,1,2 serotonin 5-HT1a, 5-HT2,3 and 5-HT3
receptor antagonists,4,5 acetylcholinesterase inhibitors,6
and aldol reductase inhibitors.7 However, a general proce-
dure for the formation of substituted 1H-indazoles from
easily accessible starting materials remains desirable.
1H-Indazoles have been prepared in a variety of ways.8
Recent reports include methods such as reduction of a
protected hydrazide with zinc,9 cyclization of an arylazo
sulfide under basic conditions,10 radical cyclization of an
azo ether,11 or diazotization of a toluidine derivative fol-
lowed by cyclization.12 Unfortunately, most of the current
syntheses suffer from several drawbacks such as expen-
sive reagents or starting materials and concerns regarding
the safety associated with the handling of certain interme-
diates or reagents.
The general sequence for our indazole synthesis is pre-
sented in Scheme 1. Reaction between phenol 2 and meth-
anesulfonyl chloride under standard conditions provides
the desired mesylate 3 in high yield. Mesylate 3 was then
treated with a hydrazine in a Dean–Stark apparatus. In the
cases where the hydrazine is used as a free base, ammoni-
um acetate is employed as an additive (Method A), while
sodium acetate is selected if the hydrazine is purchased as
one of its salts (Method B). This provides a slightly acidic
medium in which the conversion of the ketone to the hy-
drazone is rapid. We found that it is imperative to remove
the water generated in the hydrazone formation to avoid
hydrolysis of the mesylate to the corresponding phenol,
which does not undergo cyclization under the reaction
conditions.
One of the methods for the preparation of 1H-indazoles
which has received little attention is the cyclization of an
arylhydrazone possessing a leaving group in the ortho po-
sition. As early as 1889, Meyer observed that the phenyl-
hydrazone of ethyl 2,4-dinitrophenylglyoxalate would
cyclize under basic conditions at 270 °C to provide an in-
dazole.13 Pummerer also demonstrated the cyclization of
a phenylhydrazone on an aryl ether at a temperature ex-
ceeding 200 °C.14 The in situ hydrazone formation and cy-
clization of 2,2’,4,4'-tetrahydroxybenzophenone with
hydrazine, methyl hydrazine, and phenylhydrazine at a
similar temperature has also been reported to generate an
indazole derivative.15 However, the elevated temperatures
which are required for the indazole formation to occur
makes this approach impractical. The use of a fluorine as
a leaving group in the reaction of a benzophenone with a
hydrazine is known to provide an indazole in ethanol at re-
flux,16 while the generation of 5-cyanoindazoles was re-
cently reported to proceed from o-fluorohydrazones at
250 °C.17
Although the conversion of the mesylate to the desired
1H-indazoles 4 could be achieved in toluene, the reaction
did not progress at a practical rate. However, the reactions
were completed after several hours in refluxing xylenes as
the solvent. In all cases, we observed that the ketone rap-
idly converts to a mixture of hydrazones. While direct cy-
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A Versatile and Efficient Synthesis of Substituted 1H-Indazoles
589
clization of the (Z)-hydrazones is facile, the (E)-
hydrazones first require isomerization to the (Z)-hy-
drazones followed by nucleophilic aromatic substitution
of the mesylate to ultimately provide the 1H-indazoles 4.
Scheme 1
This indazole synthesis is quite general and proceeds in
acceptable yields (Table). One very interesting case is the
cyclization of mesylate 3d with 4-methoxyphenylhydra-
zine hydrochloride (entry 7). The indazole formation
proved to be somewhat more rapid than the competing
Fischer indole synthesis19 and a 2.7:1 ratio of the indazole
was generated over the undesired indole. Both pathways
require the generation of hydrazone 5, which can directly
cyclize and yield indazole 4g or isomerize to enehydra-
zine 6 for the Fischer indole synthesis to proceed (Scheme
2). The electronic properties of the arylhydrazine are very
important in this example since the reaction stopped at the
hydrazone stage and did not proceed to either the indazole
or indole when using phenylhydrazine.
Scheme 2
This indazole synthesis can be operated on alkylhydra-
zines (entries 1–5, 8–9) as well as benzylhydrazines (entry
6). We found that the hydrazine must be substituted since
all the cyclizations attempted using hydrazine itself, either
as an aqueous solution or as its hydrochloride, failed to
provide the desired indazole. The reaction can be carried
out with a variety of electron-rich or electron-deficient
arenes with several different substitution patterns.
ance to a large number of functional groups and its
minimal number of steps.
Unless otherwise noted, starting materials were obtained from com-
mercial suppliers and used without further purification. Butylhydra-
zine and 4-methoxyphenylhydrazine were purchased as the
hydrochloride, and benzylhydrazine as the dihydrochloride. Cyclo-
hexylhydrazine was prepared according to a known procedure.20
Silica gel chromatography was carried out with J.T.Baker 40 mm sil-
ica gel according to Still’s procedure.21 TLC was performed with
EM Separations Technology silica gel F254, HPLC was performed
with a Hewlett Packard Series 1100 using a Puresil C18 column (4.6
× 150 mm) and 50:50 or 80:20 MeCN/H2O mobile phase. Mps
An operationally simple and general synthesis of 3-substi-
tuted 1H-indazole has been developed. The reaction se-
quence utilized inexpensive starting materials and
reagents. This method allows for rapid access of other-
wise difficult compounds to prepare because of its toler-
Table 1 Formation of 1H-Indazoles
Entry
R1
R2 a
Yield (%) (3)
R3 (Method)b
Time
Yield (%) (4)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Et
Et
Et
Et
Ph
Me
3-MeO
5-MeO
5,6-(CH)4
5-Br
5-Br
5-Br
5-Br
4-Cl
4-Cl-6-NO2
94 (3a)
98 (3b)
87 (3c)
81 (3d)
Me (A)
Bu (B)
Me (A)
Me (A)
C6H11 (A)
Bn (B)
4-MeOC6H4 (B)
Me (A)
2 d
3 d
18 h
18 h
40 h
2 d
11 d
3 d
3 d
61 (4a)
45 (4b)
91 (4c)
75 (4d)
76 (4e)
41 (4f)
41c (4g)
63 (4h)
44 (4i)
85 (3h)
81 (3i)
Bu (B)
a For clarity, position 1 is at the mesylate and position 2 at the acyl group for all compounds.
b Method A: 3 (1.0 equiv), R3NHNH2 (2.0 equiv), NH4OAc (2.5 equiv), xylenes (6 vol), 135ºC.
Method B: 3 (1.0 equiv), R3NHNH2 (1.4-1.5 equiv), NaOAc (3.0 equiv), xylenes (6 vol), 135ºC
c 15% of 7 resulting from a Fischer indole synthesis was isolated.
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590
S. Caron, E. Vazquez
PAPER
were measured in open capillary tubes and are uncorrected. 1H (400
MHz) and 13C NMR were measured in CDCl3 unless otherwise in-
dicated. IR spectra were recorded as thin films on NaCl plates un-
less otherwise indicated.
1H NMR (400 MHz, CDCl3): d = 2.66 (s, 3H), 3.32 (s, 3H), 7.55–
7.62 (m, 2H), 7.66 (d, 1H, J = 8.7 Hz), 7.79 (d, 1H, J = 8.5 Hz), 7.83
(d, 1H, J = 7.7 Hz), 8.30 (dd, 1H, J = 8.1, 0.8 Hz).
13C NMR (100 MHz, CDCl3): d = 29.93, 39.29, 123.74, 124.63,
127.31, 127.66, 127.91,128.52, 130.02, 136.04, 142.32, 199.22.
1-(4-Bromo-2-hydroxyphenyl)propan-1-one (2d)
IR (KBr): n = 3075, 3034, 3022, 2942, 1676, 1336, 1177 cm–1.
(Note: HCl is generated in this reaction, it was performed in a well
ventilated area using an aq NaOH scrubber to neutralize the acid).
To a solution of 3-bromophenol (1) (20.0 g, 116 mmol) in dichloro-
ethane (100 mL) was added AlCl3 (23.1 g in three portions, 173.2
mmol) followed by propionyl chloride (10.0 mL, 115.1 mmol). The
mixture was heated to reflux for 2 h, cooled to r.t., and the mixture
was poured slowly into a beaker containing ice (100 mL) and 2 N
HCl (100 mL). The contents of the beaker were transferred to a sep-
aratory funnel and extracted with dichloroethane (100 mL). The or-
ganic extracts were dried (MgSO4), filtered, and concentrated to a
crude solid. MeOH/H2O (60:40, 25 mL) was added, the solid was
triturated, filtered, and dried overnight under vacuum to yield the
desired product (20.7 g, 78%) as a low melting solid; mp 49–52 °C.
Anal. calcd for C13H12O4S: C, 59.08; H, 4.58. Found: C, 59.11; H,
4.54.
5-Bromo-2-propionylphenyl Methanesulfonate (3d)
Yield: 81%; mp 61–62 °C (EtOH/H2O).
1H NMR (400 MHz, CDCl3): d = 1.17 (t, 3H, J = 7.3 Hz), 2.90 (q,
2H, J = 7.3 Hz), 3.24 (s, 3H), 7.51–7.56 (m, 2H), 7.59 (d, 1H, J =
1.3 Hz).
13C NMR (100 MHz, CDCl3): d = 8.04, 35.45, 38.51, 128.18,
127.08, 130.60, 130.69, 131.82, 146.15, 200.30.
IR (KBr): n = 3049, 2940, 1691, 1590, 1343, 959, 886 cm–1.
Anal. calcd for C10H12BrO4S: C, 39.10; H, 3.61. Found: C, 38.90;
H, 3.70.
1H NMR (400 MHz, CDCl3): d = 1.23 (t, 3H, J = 7.3 Hz), 2.99 (q,
2H, J = 7.3 Hz), 7.02 (dd, 1H, J = 8.5, 2.1 Hz), 7.17 (d, 1H, J = 2.1
Hz), 7.60 (d, 1H, J = 8.5 Hz), 12.42 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 8.05, 31.65, 118.06, 121.62,
122.36, 130.41, 130.73, 162.77, 206.54.
2-Benzoyl-4-chlorophenyl Methanesulfonate (3h)
Yield: 85% (filtered through a pad of silica gel and washed with
30% EtOAc/hexane); mp 82–83 °C.
1H NMR (400 MHz, CDCl3): d = 2.96 (s, 3H), 7.44–7.55 (m, 5H),
7.63 (t, 1H, J = 7.4 Hz), 7.78 (d, 2H, J = 7.7 Hz).
13C NMR (100 MHz, CDCl3): d = 38.06, 124.93, 128.71, 130.11,
132.09, 132.75, 133.98, 136.38, 144.59, 192.58.
IR (KBr): n = 2943, 1643, 1601, 1197, 956, 877 cm–1.
Anal. calcd for C9H9BrO2: C, 47.19; H, 3.96. Found: C, 47.05; H,
4.05.
IR (KBr): n = 3001, 1660, 1593, 1468, 1353, 1271 cm–1.
General Procedure for Mesylate Formation
To a solution of the phenol (1.0 equiv) in CH2Cl2 (5 vol) was added
Et3N (2.0 equiv). The resulting solution was cooled to 0 °C and
MsCl (1.0–1.3 equiv) was added dropwise. The reaction was stirred
(30 min to 2 h), poured into 1 N HCl and the layers were separated.
The aqueous layer was extracted with CH2Cl2, the organic layers
were combined, dried (MgSO4), filtered, and concentrated to give
the crude product 3, which was purified by the method indicated.
Anal. calcd for C14H11ClO4S: C, 54.11; H, 3.57. Found: C, 54.09; H,
3.41.
2-Acetyl-4-chloro-6-nitrophenyl Methanesulfonate (3i)
Yield: 81%; mp 93–94 °C (EtOH).
1H NMR (400 MHz, CDCl3): d = 2.66 (s, 3H), 3.36 (s, 3H), 7.85 (d,
1H, J = 2.7 Hz), 8.08 (d, 1H, J = 2.7 Hz).
2-Acetyl-3-methoxyphenyl Methanesulfonate (3a)
Yield: 94% (filtered through a pad of silica gel and washed with
50% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): d = 2.52 (s, 3H), 3.14 (s, 3H), 3.85 (s,
3H), 6.88 (d, 1H, J = 8.5 Hz), 7.05 (d, 1H, J = 8.3 Hz), 7.36 (t, 1H,
J = 8.3 Hz).
13C NMR (100 MHz, CDCl3): d = 30.11, 39.58, 128.32, 133.81,
135.97, 138.40, 144.39, 195.38.
IR (KBr): n = 3091, 1709, 1552, 1358, 1175, 819 cm–1.
Anal. calcd for C9H8ClNO6S: C, 36.81; H, 2.75; N, 4.77. Found: C,
36.68; H, 2.46; N, 4.55.
13C NMR (100 MHz, CDCl3): d = 32.21, 37.95, 56.11, 109.84,
General Procedure for Indazole Formation
115.23, 124.96, 131.07, 145.29, 157.27, 200.44.
Method A (using hydrazine free base): The mesylate (1.0 equiv) was
combined with the hydrazine (2.0 equiv) and NH4OAc (2.5 equiv)
in xylenes (6 vol). The mixture was heated to 135 °C in a Dean–
Stark apparatus until its HPLC analysis showed total disappearance
of the hydrazones. The reaction was cooled to r.t., poured into 1 N
HCl and extracted with toluene. The organic extracts were concen-
trated to a low volume under reduced pressure to afford the crude
indazole 4 which was purified by the method indicated.
IR: n = 3020, 1702, 1604, 1075, 817 cm–1.
Anal. calcd for C10H12O5S: C, 49.17; H, 4.95. Found: C, 49.20; H,
4.82.
2-Acetyl-6-methoxyphenyl Methanesulfonate (3b)
Yield: 98% (purified by flash chromatography 40% EtOAc/hex-
ane); mp 57–59 °C.
1H NMR (400 MHz, CDCl3): d = 2.56 (s, 3H), 3.25 (s, 3H), 3.85 (s,
3H), 6.86 (dd, 1H, J = 8.7, 2.5 Hz), 6.91 (d, 1H, J = 2.5 Hz), 7.76
(d, 1H, J = 8.7 Hz).
13C NMR (100 MHz, CDCl3): d = 29.70, 38.42, 55.84, 109.32,
112.74, 124.58, 132.24, 148.13, 163.37, 195.93.
Method B (using the salt of the hydrazine): The mesylate (1.0 equiv)
was combined with the salt of the hydrazine (1.4–1.5 equiv ) and
NaOAc (3.0 equiv) in xylenes (6 vol). The mixture was heated to
135 °C in a Dean–Stark apparatus until its HPLC analysis showed
complete disappearance of the hydrazones. The reaction was cooled
to r.t., poured into 1 N HCl and extracted with toluene. The organic
extracts were concentrated to a low volume under reduced pressure
to afford the crude indazole 4 which was purified by the method in-
dicated.
IR (KBr): n = 3019, 2940, 1684, 1608, 1357, 1259, 1122, 815 cm–1.
Anal. calcd for C10H12O5S: C, 49.17; H, 4.95. Found: C, 48.80; H,
4.88.
4-Methoxy-1,3-dimethyl-1H-indazole (4a)
Yield: 61% (purified by flash chromatography 20% EtOAc/hex-
ane); mp 87–89 °C.
2-Acetylnaphthalen-1-yl Methanesulfonate (3c)
Yield: 87% (purified by chromatography 25% EtOAc/hexane); mp
81–82 °C.
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A Versatile and Efficient Synthesis of Substituted 1H-Indazoles
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1H NMR (400 MHz, CDCl3): d = 2.65 (s, 3H), 3.91 (s, 3H), 3.92 (s,
3H), 6.37 (d, 1H, J = 7.7 Hz), 6.84 (d, 1H, J = 8.5 Hz), 7.22 (t, 1H,
J = 8.1 Hz).
1H NMR (400 MHz, CDCl3): d = 1.39 (t, 3H, J = 7.7 Hz), 2.96 (q,
2H, J = 7.7 Hz), 5.48 (s, 2H), 7.14–7.23 (m, 3H), 7.26–7.31 (m, 3H),
7.42 (s, 1H), 7.54 (d, 1H, J = 8.5 Hz).
13C NMR (100 MHz, CDCl3): d = 14.09, 35.18, 55.21, 98.56,
13C NMR (100 MHz, CDCl3): d = 13.70, 20.37, 52.68, 112.12,
120.77, 121.69, 121.83, 123.34, 126.97, 127.76, 128.75, 136.74,
141.37, 147.60.
101.55, 114.30, 127.59, 141.20, 143.01, 155.26.
IR (KBr): n = 2934, 1614, 1586, 1510, 1373, 1269, 1073, 777 cm–1.
IR: n = 3064, 3031, 2970, 2934, 2875, 1606, 1504, 1497, 1454,
1236, 1048, 831, 701 cm–1.
Anal. calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C,
68.31; H, 6.69; N, 15.84.
Anal. calcd for C16H15BrN2: C, 60.97; H, 4.80; N, 8.89. Found: C,
61.21; H, 4.92; N, 8.73.
1-Butyl-6-methoxy-3-methyl-1H-indazole (4b)
Yield: 45% (purified by chromatography 20% EtOAc/hexane).
6-Bromo-3-ethyl-1-(4-methoxyphenyl)-1H-indazole (4g)
Yield: 41% (purified by flash chromatography 20% EtOAc/hex-
ane).
1H NMR (400 MHz, CDCl3): d = 1.43 (t, 3H, J = 7.7 Hz), 3.00 (q,
2H, J = 7.7 Hz), 3.86 (s, 3H), 7.03 (d, 2H, J = 8.9 Hz), 7.25 (dd, 1H,
J = 8.5, 1.5 Hz), 7.53 (d, 2H, J = 9.1 Hz), 7.58 (d, 1H, J = 8.5 Hz),
7.73 (d, 1H, J = 1.5 Hz).
13C NMR (100 MHz, CDCl3): d = 13.53, 20.34, 55.61, 113.02,
114.70, 121.33, 121.70, 122.45, 123.93, 124.50, 132.90, 140.67,
148.83, 158.42.
1H NMR (400 MHz, CDCl3): d = 0.93 (t, 3H, J = 7.5 Hz), 1.29–1.39
(m, 2H), 1.85 (quint, 2H, J = 7.5 Hz), 2.50 (s, 3H), 3.87 (s, 3H), 4.21
(t, 2H, J = 7.3 Hz), 6.64 (s, 1H), 6.73 (d, 1H, J = 8.7 Hz), 7.46 (d,
1H, J = 8.7 Hz).
13C NMR (100 MHz, CDCl3): d = 11.75, 13.65, 20.08, 31.85, 48.11,
55.41, 90.05, 111.18, 118.08, 121.10, 141.03, 141.35, 159.26.
IR: n = 2958, 2932, 1625, 1511, 1243, 1227, 810 cm–1.
Anal. calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C,
71.13; H, 8.32; N, 12.60.
1,3-Dimethyl-1H-benzo[g]indazole (4c)
Yield: 91% (purified by flash chromatography 20% EtOAc/hex-
ane); mp 79–81 °C.
1H NMR (400 MHz, CDCl3): d = 2.58 (s, 3H), 4.43 (s, 3H), 7.42 (d,
1H, J = 8.7 Hz), 7.51–7.60 (m, 3H), 7.93 (d, 1H, J = 7.7 Hz), 8.39
(d, 1H, J = 8.1 Hz).
13C NMR (100 MHz, CDCl3): d = 11.58, 40.12, 118.61, 120.32,
121.36, 121.52, 121.79, 125.76, 125.88, 129.05, 133.15, 136.49,
141.05.
IR (KBr): n = 3009, 1753, 1491, 1474, 1131, 808, 749 cm–1.
IR: n = 2970, 2934, 1604, 1519, 1461, 1442, 1300, 1250, 1050,
1035, 945, 832 cm–1.
Anal. calcd for C16H15BrN2O: C, 58.02; H, 4.56; N, 8.46. Found: C,
58.39; H, 4.69; N, 8.13.
5-Bromo-2-(5-methoxy-3-methyl-1H-indol-2-yl)phenyl Meth-
anesulfonate (7)
Yield: 15% (purified by flash chromatography 20% EtOAc/hex-
ane); mp 148–149 °C.
1H NMR (400 MHz, CDCl3): d = 2.30 (s, 3H), 2.68 (s, 3H), 3.88 (s,
3H), 6.90 (d, 1H, J = 8.9 Hz), 7.01 (s, 1H), 7.27 (d, 1H, J = 8.7 Hz),
7.40 (d, 1H, J = 8.3 Hz), 7.66 (s, 1H), 8.36 (bs, 1H).
13C NMR (100 MHz, CDCl3): d = 9.55, 37.85, 55.91, 100.76,
110.93, 111.83, 113.53, 122.08, 125.69, 127.59, 128.63, 129.07,
130.93, 131.15, 132.87, 146.40, 154.22.
Anal. calcd for C13H12N2: C, 79.56; H, 6.16; N, 14.27. Found: C,
79.66; H, 6.02; N, 14.44.
6-Bromo-1-methyl-3-ethyl-1H-indazole (4d)
Yield: 75% (purified by flash chromatography 20% EtOAc/hex-
ane).
1H NMR (400 MHz, CDCl3): d = 1.35 (t, 3H, J = 7.7 Hz), 2.94 (q,
2H, J = 7.7 Hz), 3.95 (s, 3H), 7.18 (dd, 1H, J = 8.5, 1.5 Hz), 7.50 (d,
1H, J = 0.8 Hz), 7.52 (dd, 1H, J = 8.5, 0.6 Hz).
13C NMR (100 MHz, CDCl3): d = 13.66, 20.29, 35.21, 111.82,
120.61, 121.35, 121.60, 123.05, 141.68, 147.08.
IR: n = 2970, 2935, 1609, 1506, 1458, 1223, 1047, 819, 805 cm–1.
IR: n = 3440, 1367, 1220, 1170, 1157, 806 cm–1.
Anal. calcd for C17H16BrNO4S: C, 49.77; H, 3.93; N, 3.41. Found:
C, 50.12; H, 4.18; N, 3.37.
5-Chloro-1-methyl-3-phenyl-1H-indazole (4h)
Yield: 63% (purified by flash chromatography 10% EtOAc/hex-
ane).
1H NMR (400 MHz, CDCl3): d = 4.09 (s, 3H), 7.30–7.41 (m, 3H),
7.50 (t, 2H, J = 7.5 Hz), 7.88 (d, 2H, J = 7.5 Hz), 7.96 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 35.74, 110.28, 120.56,
122.38,126.73, 126.84, 127.27, 128.07, 128.89, 133.04, 139.91,
143.28.
IR: n = 3062, 2937, 1489, 1459, 1276, 822, 774 cm–1.
Anal. calcd for C10H11BrN2: C, 50.23; H, 4.64; N, 11.72. Found: C,
50.14; H, 4.57; N, 11.46.
6-Bromo-1-cyclohexyl-3-ethyl-1H-indazole (4e)
Yield: 76%. (purified by flash chromatography 10% EtOAc/hex-
ane).
1H NMR (400 MHz, CDCl3): d = 1.35 (t, 3H, J = 7.7 Hz), 1.39–2.06
(m, 10H), 2.95 (q, 2H, J = 7.7 Hz), 4.21–4.28 (m, 1H), 7.15 (d, 1H,
J = 8.5 Hz), 7.51 (d, 1H, J = 8.5 Hz), 7.56 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 13.95, 20.50, 25.35, 25.84, 32.44,
58.15, 112.01, 120.10, 121.37, 121.65, 122.82, 140.37, 146.60.
IR: n = 2934, 2855, 1606, 1502, 1451, 1048, 951, 834 cm–1.
Anal. calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54. Found: C,
69.04; H, 4.27; N, 11.39.
1-Butyl-5-chloro-3-methyl-7-nitro-1H-indazole (4i)
Yield: 44% (purified by chromatography 10% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3H, J = 7.5 Hz), 1.20–1.29
(m, 2H), 1.68 (quint, 2H, J = 7.5 Hz), 2.54 (s, 3H), 4.48 (t, 2H, J =
7.5 Hz), 7.86 (s, 1H), 8.03 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 11.5, 13.63, 19.78, 32.64, 52.68,
123.91, 124.65, 126.22, 129.31, 129.58, 134.89, 142.21.
Anal. calcd for C15H19BrN2: C, 58.64; H, 6.23; N, 9.12. Found: C,
58.82; H, 6.20; N, 9.01.
1-Benzyl-6-bromo-3-ethyl-1H-indazole (4f)
IR: n = 2955, 1781, 1534, 1300, 880 cm–1.
Yield: 41% (purified by flash chromatography 20% EtOAc/hex-
ane).
Anal. calcd for C12H14ClN3O2: C, 53.84; H, 5.27; N, 15.70. Found:
C, 54.00; H, 5.14; N, 15.63.
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PAPER
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Synthesis 1999, No. 4, 588–592 ISSN 0039-7881 © Thieme Stuttgart · New York