A facile and simple synthesis of novel 2-(substituted)-5-(1-methyl-1H- indazol-3-yl)-oxazole derivatives

Article abstract of DOI:10.1002/jhet.1089

Novel 2-(substituted)-5-(1-methyl-1H-indazol-3-yl)-oxazoles (13) were synthesized in moderate yields, from 1-methyl-1H-Indazole 3-carboxylic acid (1), by converting it into a variety of amides (12) and further its heterocyclization. The structures of all the compounds have been elucidated on the basis of IR, ¹H-NMR, and HRMS.

Full text of DOI:10.1002/jhet.1089

February 2013
A Facile and Simple Synthesis of Novel
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2‐(Substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐Oxazole Derivatives
c
b
E. Vishnu Vardhan Reddy,a,b J. Ramanatham, N. Devanna,
*
K. Srinivasa Reddy,a and D. Rajendera
aCustom Pharmaceutical Services, Dr Reddys Laboratories Limited, Miyapur, Hyderabad, India
bDepartment of Chemistry, JNT University, Ananthapur, Andhra Pradesh, India
cPfizer Pharmaceuticals India Pvt. Ltd, Turbhe, Navi Mumbai, India, 400705
*
E-mail: vishnuvardhanre@drreddys.com
Received May 3, 2011
DOI 10.1002/jhet.1089
Published online 7 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
Novel 2‐(substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐oxazoles (13) were synthesized in moderate
yields, from 1‐methyl‐1H‐Indazole 3‐carboxylic acid (1), by converting it into a variety of amides (12)
and further its heterocyclization. The structures of all the compounds have been elucidated on the basis
1
of IR, H‐NMR, and HRMS.
J. Heterocyclic Chem., 50, E221 (2013).
INTRODUCTION
bond which when present together, may have synergistic
effects leading to more biologically potent molecules.
Herein, in this article, the synthesis of hybrid molecules
possessing both indazole and oxazole in their core structure
are described.
Heterocyclic compounds play an important role in the
treatment of various diseases and recent analysis of
drugs in late development or on the market shows that
68% of them are heterocyclic compositions. Therefore, it
is not surprising that research in the field of synthesis
of heterocyclic compounds has gained special attention.
Indazole derivatives, which are bioisosteres of indoles,
are an important class of compounds in the medicinal
area [1]. Compounds containing the indazole skeleton
are known to show a variety of biological activities,
such as high binding affinity for estrogen receptor [2],
inhabitation of protein kinase C‐b [3], 5‐HT2, and 5‐HT3
receptor antagonist [4], human immunodeficiency virus
(HIV) protease inhibition [5], and anti‐tumor activity [6].
The oxazole heterocycle is a fundamental ring system
found in different compounds such as natural products,
pharmaceuticals, agrochemicals, peptidomimetics, and
polymers [7]. Naturally occurring oxazoles are usually
found with a 2,4‐substitution pattern [8], a consequence
of their biosynthetic assembly from serine residues.
However, 2,5‐substituted oxazole natural products are
also known [9].
RESULTS AND DISCUSSION
Based on our previous experience on facile and sim-
ple synthesis of novel 1‐methyl‐2‐(2‐substituted‐oxazol‐4‐
yl)‐1H‐benzimidazole derivatives [10], we attempted to
make 4‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐substituted oxazole
(9) starting from 1‐methyl‐1H‐indazole‐3‐carboxylic acid
(1) (Scheme 1). Acid chloride (5) was prepared in‐situ
from acid (1) and thionyl chloride in toluene medium
[11]. The obtained acid chloride (5) was reacted with
tetra‐methyl silane (TMS) diazomethane at room tempera-
ture for 16 h and the reaction mass was quenched with 48%
aq. HBr solution to get the corresponding mono‐bromo
compound (6). We developed an alternative, mild and flex-
ible strategy, owing to the safety challenges of the diazo
compounds, for the preparation of bromo compound, 6.
1‐Methyl‐1H‐ indazole‐3‐carboxylic methyl ester (3) was
reacted with the methyl magnesium bromide or iodide lead-
ing to the 3‐acetyl indazole derivative (4). 4 was alterna-
tively prepared from 1 by the coupling with N,O‐dimethyl
hydroxylamine hydrochloride, EDC hydrochloride, and
pyridine as base in THF at room temperature which furn-
ished the Weinreb amide (2). 2 when reacted with 5 mol
equivalents of methyl magnesium bromide or iodide gave
4 in a higher yield. Subsequently, bromination of 4 with
Recently, we reported a facile and simple synthesis of novel
1‐methyl‐2‐(2‐substituted‐oxazol‐4‐yl)‐1H‐benzimidazole
derivatives [10]. As a part of our continuous efforts to syn-
thesize new analogues of nitrogen heterocycles and study
their biological activities of these hybrid molecules, we
planned to synthesize hybrid molecules containing both
indazole and oxazole moieties bound together by a C─C
© 2013 HeteroCorporation

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Scheme 1. Reagent and conditions: (a) NH(OMe)Me.HCl, pyridine, EDC.HCl, THF, 0°C–RT; (b) MeMgI/Br, THF, 0–5°C, 1 h; (c) CuBr2, CHCl3,
ethyl acetate, 70–80°C, 16 h; (d) MeMgI/Br, THF, 0–5°C, 1 h; (e) SOCl2, toluene, 55–60°C, 3 h; (f) TMSCHN2, 48% HBr, RT, 16 h; (g) RCOOH,
TEA, acetone, RT, 30–60 min; (h) acetamide, BF3‐etherate, ethyl acetate, reflux, 48 h; (or) ammonium acetate, acetic acid, 100°C, 48 h.
copper (II) bromide in chloroform and ethyl acetate mixture
led to the corresponding mono‐bromo derivative (6) along
with small percentage of dibromo derivative (7). The bromo
derivative (6) was converted to corresponding ester (8) in
the presence of triethyl amine in acetone medium. Attempts
to convert the obtained ester (8) to the corresponding oxa-
zole (9) under Cornforth conditions [12] and BF3‐etherate
at different temperatures, different solvent media [13] were
unsuccessful. This could be because of the amide formation
with the carboxylate moiety displacing the heterocyclic alco-
holic group as seen in common for the esters.
prepare the corresponding nitrile derivative (10). As 10 was
unstable, it was immediately reduced with Pd/C under hydro-
gen atmosphere to the corresponding amine and was isolated
as its hydrochloride salt (11). The amine hydrochloride deriv-
ative (11) was converted to the corresponding amides (12)
with moderate to good yields by reacting with suitable acid
chlorides or acids based on its ease of use or commercial avail-
ability. Thus, the amides (12a–c) were synthesized by treating
the corresponding acid chloride in presence of TEA [14],
while the amides (12d–h) where synthesized by coupling
amine hydrochloride derivatives (11) with corresponding acids
in presence of EDC hydrochloride. The amides (12a–h) were
then converted to the corresponding oxazole (13a–h) by react-
ing with phosphorous oxychloride at elevated temperatures
under solvent free reaction conditions [15].
Eventually, we planned to synthesize 2‐(substituted)‐5‐
(1‐methyl‐1H‐indazol‐3‐yl)‐oxazole (13) instead of 4‐(1‐
methyl‐1H‐indazol‐3‐yl)‐2‐substitutedoxazole (9)(Scheme 2).
1‐Methyl‐3‐indazolyl chloride (5) was treated with CuCN to
Scheme 2. Reagent and conditions: (a) SOCl2, toluene, 55–60°C, 3 h; (b) CuCN, CH3CN, toluene, TBAI, 80–85°C, 12 h; (c) acetic acid, Pd/C,H2
50–55 psi, 8–10 h; (d) RCOCl, Et3N, DCM, RT, 3–4 h; or RCOOH, EDC.HCl, RT, 1–3 h; (e) POCl3, 50–60°C, 3–12 h.
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194.5, 142.0, 141.1, 126.7, 123.4, 122.8, 122.5, 109.1, 36.1,
26.6; ESI‐MS (m/z): 175 (M+1).
CONCLUSION
In conclusion, we have developed a simple, operationally
friendly process for the synthesis of 2‐(substituted)‐5‐(1‐
methyl‐1H‐indazol‐3‐yl)oxazole derivatives with moderate
to good yields. As a part of these studies, a number of 2‐
substituted oxazole derivatives have been synthesized and
biological evaluation of these molecules are under progress,
which will be reported in due course of time.
General procedure for 2‐bromo‐1‐(1‐methyl‐1H‐indazol‐
3‐yl)‐ethanone (6) from 4. To a solution of 1‐(1‐methyl‐1H‐
indazol‐3‐yl)‐ethanone (4) (1.0 g, 5.7 mmol) in a mixture of
chloroform (20 mL) and ethyl acetate (20 mL) was added
copper (II) bromide (2.3 g, 10.33 mmol) and stirred at 70–80°C
for 16 h. After completion of reaction, as monitored by TLC,
reaction mixture was cooled to room temperature and filtered
the solid. The filtrate was concentrated under reduced pressure.
Both monobromo (6) and dibromo (7) compounds were
separated by column chromatography on silica gel after eluting
with toluene/hexane (0.8 g, yield = 55%).
EXPERIMENTAL
Compound 6. Solid, m.p. 91–94°C; IR (KBr, v): 2925, 1663,
1471; H‐NMR (400 MHz, DMSO‐d6): δH 8.16 (d, J = 8.3 Hz,
1H), 7.83 (d, J = 8.4 Hz, 1H), 7.39–7.57 (m, 2H), 4.86 (s, 2H),
4.21 (s, 3H); ESI‐MS (m/z): 253.1 (M+1).
General methods. 1H‐NMR spectra were recorded in
DMSO‐d6 and CDCl3 on a Mercury plus Varian 400 MHz
spectrometers. Proton chemical shifts (δ) are relative to TMS
(δ 0.00) as internal standard and expressed in ppm. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet), and m
(multiplet). Coupling constants (J) are given in hertz. Melting
points were determined using a scientific open capillary melting
point apparatus and are uncorrected. Mass spectra were obtained
from Triple Quad 6410 Mass Spectrometer. Thin layer
chromatography was performed on silica gel plates (SRL 230–400
mesh). All the solvents used are commercially available and were
distilled before use.
1
Compound 7. Solid, m.p. 150–152°C; IR (KBr, v): 2939,
1682, 1470; 1H‐NMR (400 MHz, DMSO‐d6): δH 8.19 (dd,
J = 1.1 Hz, J = 8.0 Hz, 1H), 7.9 (d, J = 8.4, 1H), 7.57–7.59 (m,
1H), 7.54 (s, 1H), 7.45–7.49 (m, 1H), 4.25 (s, 3H); 13C‐NMR
(50 MHz, DMSO‐d6): ppm, 181.7, 141.3, 134.8, 127.5, 124.8,
122.8, 121.0, 111.4, 40.9, 36.8. ESI‐MS (m/z): 333 (M+1).
General procedure for synthesis of ester (8). A mixture of
2‐bromo‐1‐(1‐methyl‐1H‐indazol‐3‐yl)‐ethanone (6) (0.5g 1.0 mol),
corresponding carboxylic acid (1.0 mol), triethylamine (0.59 g,
5.92 mmol), and acetone (10 mL) were stirred at 25–35°C for
30–60 min. After completion of reaction, as monitored by TLC,
triethylamine hydro bromide was filtered and filtrate was distilled
off under vacuum. The residue was washed with water, and purified
by column chromatography on silica gel (EtOAc/hexane) to give
the pure title compound.
General procedure for 1‐methyl‐1H‐indazole‐3‐carboxylic
acid methoxy‐methyl‐amide (Weinreb amide) (2). To a solution of
1‐methyl‐1H‐indazole‐3‐carboxylic acid (1) (20 g, 0.0693 mol)
in THF (200 mL) was added N,O‐dimethylhydroxylamine
hydrochloride (12.2 g, 0.124 mol) at room temperature. The
mixture was cooled to 0°C and pyridine (20.2 mL, 0.249 mol) was
added. The reaction mixture was stirred initially for 1.5 h at 0°C
and then room temperature for 1 h. Pyridine (18.49 mL, 0.227 mol)
and 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride
(43.5 g, 0.227 mol) were successively added and the reaction
mixture was stirred overnight. After completion of the reaction,
water (500 mL) was added to the reaction mixture and extracted
with ethyl acetate. Organic layer was washed with water, dried over
a sodium sulfate and concentrated under vacuum to get viscous
liquid of 2. (20.0 g. Yield = 79.0%).
Compound 8a. Solid, m.p. 138–140°C; IR (KBr, v): 3265,
1
1714, 1683, 1282; H‐NMR (400 MHz, DMSO‐d6): δH 8.14 (d,
J = 7.8 Hz, 1H), 8.07 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.3 Hz,
1H), 7.72–7.74 (m, 1H), 7.55–7.61 (m, 3H), 7.38–7.42 (m, 1H),
5.74 (s, 2H), 4.23 (s, 3H); ESI‐MS (m/z): 295.2 (M+1).
Compound 8b. Solid, m.p. 127–129°C; IR (KBr, v): 3398,
1738, 1706,1616; 1H‐NMR (400 MHz, DMSO‐d6): δH 8.36
(d, J = 7.6 Hz, 1H), 8.3 (s, 1H), 8.12–8.15 (m, 2H), 7.87–7.88
(m, 2H), 7.40–7.57 (m, 2H), 5.80 (s, 2H), 4.24 (s, 3H); ESI‐MS
(m/z): 363.2 (M+1).
1
Compound 2. H‐NMR (400 MHz, DMSO‐d6): δH 8.0 (d,
J = 7.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.25–7.49 (m, 2H),
4.13 (s, 3H), 3.78 (s, 3H), 3.44 (s, 3H); electrospray ionisation‐
mass spectrometric (ESI‐MS) (m/z): 220.2 (M+1).
General procedure for 1‐methyl‐1H‐indazole‐3‐carbonyl
cyanide (10). A mixture of 1‐methyl‐1H‐indazole‐3‐carboxylic
acid (1) (10.0 g, 0.0565 mol), thionyl chloride (12.4 mL, 0.17 mol),
DMF (catalytic), and toluene (100 mL) was heated for 3 h at
55–60°C. Excess thionyl chloride was removed at 60°C under
vacuum and crude compound triturated with hexanes to afford
acid chloride 5.
To a well stirred mixture of copper (I) cyanide (4.98 g, 0.05
mol), toluene (24 mL) and acetonitrile (72 mL) was added 1‐
methyl‐1H‐indazole‐3‐carbonyl chloride (5) (8.0 g, 0.04 mol)
in toluene (24 mL) at room temperature under nitrogen atmo-
sphere. Tetra‐butyl ammonium iodide (3.0 g, 8.22 mmol) was
added to reaction mass and heated to 80–85°C for 12 h. Reaction
mass was diluted with toluene and filtered through celite. The
filtrate was evaporated under reduced pressure below 50°C
and material directly taken into for next step without any further
purification.
General procedure for 1‐(1‐methyl‐1H‐indazol‐3‐yl)
ethanone (4) from 2. To a stirred solution of 1‐methyl‐1H‐
indazole‐3‐carboxylic acid methoxy methyl amide (2) (10 g,
0.045 mol) in THF (100 mL) was added 1.5M solution of
methyl magnesium iodide in ether (152 mL, 0.22 mol) at 0–5°C
under nitrogen atmosphere and stirred for about 1 h at room
temperature. The reaction mass was quenched with saturated
aqueous NH4Cl solution and further extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over sodium sulfate and evaporated under reduced
pressure. The crude material was purified by column
chromatography on silica gel (EtOAc/hexane) to get the pure
title compound 4 (9.5 g, yield = 59.7%).
Compound 4. Solid, m.p. 91–93°C; IR (KBr, v): 2940,
1661, 1473, 1302; 1H NMR (400 MHz, CDCl3): δH 8.37
(d, J = 7.8 Hz, 1H), 7.43–7.44 (m, 2H), 7.31–7.34 (m, 1H),
4.15 (s, 3H), 2.71 (s, 3H). 13C‐NMR (5 MHz, CDCl3): ppm, δ
Compound (10). IR (KBr, v): 3445, 2942, 2223, 1741, 1651;
1H‐NMR (400 MHz, DMSO‐d6): δH 8.1 (d, J = 8.2 Hz, 1H),
7.95 (d, J = 8.6 Hz, 1H), 7.50–7.66 (m, 2H), 4.32 (s, 3H).
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General procedure for 2‐amino‐1‐(1‐methyl‐1H‐indazol‐
7.37–7.56 (m, 2H), 4.85 (d, J = 5.8 Hz, 2H), 4.23 (s, 3H);
HRMS (m/z): [M + H]+ calculated for [C17H14N3O2Cl2]+
362.0463. Found: 362.0448.
2‐(3,4‐dichlorophenyl)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)oxazole
(13a). Solid, m.p. 143–146°C; IR (KBr, v): 3115, 2939, 1594,
1494, 1474; 1H NMR (400 MHz, DMSO‐d6): δH 8.20 (d,
J = 8.3 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.3, 1H), 7.98 (s, 1H),
7.85(d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.32–7.55
(m, 2H), 4.15 (s, 3H); HRMS (m/z): [M + H]+ calculated for
[C17H12N3OCl2]+ 344.0357. Found: 344.0349.
3‐yl)‐ethanone hydrochloride (11). The 1‐methyl‐1H‐indazole‐3‐
carbonyl cyanide (10) (7.6 g, 0.041 mol) in acetic acid (500 mL)
was treated with hydrogen in presence of 10% Pd/C (0.76 g) at
50–55 psi for 8–10 h. The reaction mixture was filtered over
celite and the filtrate was concentrated under reduced pressure
at below 65°C. To the residue, 15% IPA‐HCl (100 mL) was
added and stirred for 30 min at 25–35°C. The solid obtained
was filtered, washed with IPA, and dried under reduced pressure at
50°C which offered a reddish brown color solid of 11 (5 g, yield
40% from acid (1)).
4‐fluoro‐N‐(2‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐oxoethyl)benzamide
(12b). Solid, m.p. 152–154°C; IR (KBr, v): 3500, 3305, 1683,
Compound (11). Solid, m.p. 272–275°C; 1H‐NMR (400
MHz, DMSO‐d6): 8.52 (bs, 2H), 8.18 (d, J = 8.3 Hz, 1H),
7.87 (d, J = 8.3 Hz, 1H), 7.42–7.59 (m, 2H), 4.52 (s, 2H),
4.23 (s, 3H); 13C‐NMR (50 MHz, DMSO‐d6): ppm, 188.1,
141.3, 138.9, 127.7, 124.8, 122.2, 122.38, 111.6, 44.6, 37.1;
high resolution mass spectrometry (HRMS) (m/z): [M + H]+
calcd for[C10H12N3O]+ 190.0980, found: 190.0988.
1
1644, 1503; H‐NMR (400 MHz, DMSO‐d6): δH 8.93 (t, J = 5.3
Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.99–8.02 (m, 2H), 7.83
(d, J = 8.5 Hz, 1H), 7.52–7.53 (m, 1H), 7.32–7.40 (m, 3H), 4.8
(d, J = 5.4 Hz, 2H), 4.23 (s, 3H); HRMS (m/z): [M + H]+
calculated for [C17H15N3O2F]+ 312.1148. Found: 312.1133.
2‐(4‐fluorophenyl)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)oxazole
(13b). Solid, m.p. 182–185°C; IR (KBr, v): 3120, 1595, 1495,
General procedure for N‐[2‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐
oxo‐ethyl]‐substituted amide from acid chloride (12a–c). To a
suspension of 2‐amino‐1‐(1‐methyl‐1H‐indazol‐3‐yl)‐ethanone
hydrochloride (11) (1.0 g, 4.4 mmol) in dichloromethane (10 mL)
was added triethylamine (1.34 g, 13.3 mmol) followed by
corresponding acid chloride (4.66 mmol) at 0–5°C and stirred for
appropriate time (see Table 1) at room temperature. After ensuring
the completion of reaction by TLC, the mixture was quenched with
water and extracted with dichloromethane. The organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure below 40°C. The crude compound on
trituration with diethyl ether gave as the title compounds (see Table 1).
General procedure for N‐[2‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐
oxo‐ethyl]‐substituted amide from acid (12d–h). To a
suspension of 2‐amino‐1‐(1‐methyl‐1H‐indazol‐3‐yl)‐ethanone
hydrochloride (11) (1.0 g, 4.4 mmol) in dichloromethane (10 mL)
was added corresponding acid (4.88 mmol) at 0–5°C. N‐Methyl
pyrrolidinone (1.34 g, 13.3 mmol) followed by 1‐(3‐dimethyl
amino propyl)‐3‐ethylcarbodiimide hydrochloride (1.0 g, 5.21 mmol)
were added to the above reaction mixture and stirred for
appropriate time (see Table 1) at room temperature. After
completion of the reaction, as confirmed by TLC, the mixture was
taken into water, extracted with dichloromethane and dried over
anhydrous sodium sulfate. The solvent was removed under
vacuum to afford the crude compound which on trituration with
diethyl ether gave the pure title compounds (see Table 1).
General procedure for 2‐(substituted)‐5‐(1‐methyl‐1H‐
indazol‐3‐yl)‐oxazoles (13a‐h). N‐[2‐(1‐Methyl‐1H‐indazol‐3‐yl)‐
2‐oxo‐ethyl]‐substituted amide (1.38 mmol) and phosphorous
oxychloride (5 mL) were stirred for appropriate time (see Table 2)
at 50–60°C under nitrogen atmosphere. After completion of the
reaction, as monitored by TLC, excess phosphorous oxychloride
was distilled off. Water was added to the residue and extracted
with dichloromethane (DCM). The organic layer was washed with
5% aqueous HCl solution followed by 5% NaHCO3 solution and
dried over anhydrous sodium sulfate. The solvent was removed
under vacuum and residue was purified by flash chromatography
using a 25:75 gradient of ethyl acetate/hexane to afford the pure
compounds (see Table 2).
1
1321; H‐NMR (400 MHz, DMSO‐d6): δH 8.14–8.19 (m, 3H),
7.92 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.50–7.54 (m, 1H),
7.43 (t, J = 8.8 Hz, 2H), 7.31–7.34 (m, 1H), 4.15 (s, 3H);
13C‐NMR (50 MHz, DMSO‐d6): ppm, δ159.5, 146.3, 140.9,
132.1, 128.8, 128.7, 127.2, 124.9, 123.7, 122.1, 120.8, 120.4,
116.9, 116.4, 110.6, 36.0; HRMS (m/z): [M + H]+ calculated
for [C17H13N3OF]+ 294.1043. Found: 294.1050.
N‐[2‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐oxo‐ethyl]‐benzamide
(12c). Solid, m.p. 148–151°C; IR (KBr, v): 3283, 3062, 1690,
1
1621, 1541; H‐NMR (400 MHz, DMSO‐d6): δH 8.8 (t, J = 5.8
Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.82–7.94 (m, 3H), 7.37–7.55
(m, 5H), 4.85 (d, J = 5.8 Hz, 2H), 4.23 (s, 3H); 13C‐NMR (50
MHz, DMSO‐d6): ppm, δ 190.7, 166.5, 140.7, 139.3, 133.9,
131.3, 128.3, 127.2, 126.9, 123.8, 121.8, 121.2, 110.7, 45.9,
36.4; HRMS (m/z): [M + H]+ calculated for [C17H16N3O2]+
294.1243. Found: 294.1240.
5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐phenyloxazole (13c). Solid,
1
m.p. 148–151°C; IR (KBr, v): 3118, 2926, 1722,1599; H‐NMR
(400 MHz, DMSO‐d6): δH 8.2 (d, J = 8.1 Hz, 1H), 8.11–8.14
(m, 2H), 7.93 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.31–7.63 (m,
5H), 4.16 (s, 3H); 13C‐NMR (50 MHz, DMSO‐d6): ppm, δ
159.9, 145.8, 140.5, 131.8, 130.6, 129.2, 126.8, 126.6, 125.9,
124.6, 121.6, 121.8, 120.5, 120.0, 110.3, 35.7; HRMS (m/z):
[M + H]+ calculated for [C17H14N3O]+ 276.1137. Found: 276.1139.
N‐[2‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐oxoethyl]‐4‐nitrobenzamide
(12d). Solid, m.p. 210–212°C; IR (KBr, v): 3323, 2947, 1693, 1635,
1
1595; H‐NMR (400 MHz, DMSO‐d6): δH 9.26 (t, J = 5.3 Hz,
1H), 8.37 (d, J = 8.8 Hz, 2H), 8.15–8.17 (m, 3H), 7.84 (d,
J = 8.8 Hz, 1H), 7.37–7.56 (m, 2H), 4.89 (d, J = 5.4 Hz,
2H), 4.2 (s, 3H); HRMS (m/z): [M + H]+ calculated for
[C17H15N4O4]+ 339.1093. Found: 339.1078.
5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐(4‐nitrophenyl)oxazole
(13d). Solid, m.p. 202–205°C; IR (KBr, v): 3114, 1734, 1605,
1
1593, 1333, 1314; H‐NMR (400 MHz, DMSO‐d6): δH 8.40–8.42
(m, 2H), 8.33–8.35 (m, 2H), 8.21 (d, J = 8.3, 1H), 8.06 (s, 1H), 7.7
(d, J = 8.8 Hz, 1H), 7.33–7.56 (m, 2H), 4.16 (s, 3H); HRMS (m/z):
[M + H]+ calculated for [C17H13N4O3]+ 321.0988. Found: 321.0994.
N‐(2‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐oxoethyl)‐3‐(trifluoromethyl)
benzamide (12e). Solid, m.p. 140–142°C; IR (KBr, v): 3421,
1678, 1661, 1512; 1H‐NMR (400 MHz, DMSO‐d6): δH 9.22
(t, J = 5.4 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J = 7.5 Hz, 1H),
8.17 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.1Hz 1H), 7.84 (d,
J = 8.6 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.37–7.56 (m, 2H),
Spectral data. 3,4‐dichloro‐N‐(2‐(1‐methyl‐1H‐indazol‐3‐
yl)‐2‐oxoethyl)benzamide (12a). Solid, m.p. 202–205°C; IR
1
(KBr, v): 3416, 3405, 1669, 1654, 1541; H‐NMR (400 MHz,
DMSO‐d6): δH 9.13 (t, J = 5.4 Hz, 1H), 8.15–8.17 (m, 2H),
7.92 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H), 7.80–7.90 (m, 2H),
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A Facile and Simple Synthesis of Novel
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2‐(Substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐oxazole Derivatives
Table 1
Preparation of amide (12) by reacting amine hydrochloride (11) with carboxylic acid or acid chloride.
Entry
a
Acid or acid chloride
Amide (12)
Yielda (%)
50
Time (h)
4
M.p. (°C)
202–205
b
56
4
152–154
c
64
56
3
3
148–151
210–212
d
e
50
1
140–142
f
45
52
1
1
161–163
146–149
g
h
43
1
188–190
aYields refer to isolated pure products characterized by IR, NMR, and HRMS.
4.90 (d, J = 5.3 Hz, 2H), 4.23 (s, 3H); 13C‐NMR (50 MHz, DMSO‐d6):
ppm, δ 190.6, 165.6, 140.9, 139.5, 134.9, 131.5, 130.0, 129.7,
129.1, 128.2, 127.2, 126.8, 124.1, 121.4, 110.9, 46.2, 36.6;
HRMS (m/z): [M + H]+ calculated for [C18H15N3O2F3]+
362.1116. Found: 362.1120.
5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐(3‐(trifluoromethyl)phenyl)
oxazole (13e). Solid, m.p. 171–173°C; IR (KBr, v): 3133, 2949,
1600, 1339, 1168, 1124; 1H‐NMR (500 MHz, DMSO‐d6) δH
8.41 (d, J = 7.6 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J = 8.2 Hz,
1H), 8.01 (s, 1H), 7.94–7.95 (m, 1H), 7.84–7.87 (m, 1H), 7.76
Journal of Heterocyclic Chemistry
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E226
E. V. V. Reddy, J. Ramanatham, N. Devanna, K. Srinivasa Reddy, and D. Rajender
Vol 50
Table 2
Preparation of 2‐(substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐oxazole derivatives (13) by reacting 12 with POCl3.
Entry
Amide (12)
Product (13)
Yielda (%)
69
Time (h)
12
M.p. (°C)
a
143–146
b
53
12
182–185
c
63
67
3
3
148–151
202–205
d
e
63
3
171–173
f
53
56
3
3
149–150
97–98
g
h
53
4
146–148
aYields refer to isolated pure products characterized by IR, NMR, and HRMS.
(d, J = 8.5 Hz, 1H), 7.33–7.55 (m, 2H), 4.16 (s, 3H); HRMS (m/
z): [M + H]+ calculated for [C18H13N3OF3]+ 344.1011. Found:
344.1009.
N‐(2‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐oxoethyl)thiophene‐2‐
carboxamide (12f). Solid, m.p. 161–163°C; IR (KBr, v): 3417,
3089, 1671, 1648, 1524; 1H‐NMR (400 MHz, DMSO‐d6):δH
8.92 (t, J = 5.9 Hz, 1H), 8.17 (d, J = 7.8, 1H), 7.79–7.88 (m,
3H), 7.37–7.55 (m, 2H), 7.19–7.21 (m, 1H), 4.82 (d, J = 5.8 Hz,
2H), 4.22 (s, 3H); 13C‐NMR (50 MHz, DMSO‐d6): ppm, δ
190.4, 161.4, 140.7, 139.3, 130.7, 128.3, 127.7, 126.8, 127.7,
126.8, 123.7, 121.8, 121.1, 110.6, 45.6, 36.3; HRMS (m/z):
[M + H]+ calculated for [C15H14N3O2S]+ 300.0807. Found:
300.0807.
5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐(thiophen‐2‐yl)oxazole (13f).
Solid, m.p. 149–150°C; IR (KBr, v): 3112, 2933, 1602, 1492,
1344, 1298, 1256; 1H‐NMR (400 MHz, DMSO‐d6): δH 8.15
Journal of Heterocyclic Chemistry
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February 2013
A Facile and Simple Synthesis of Novel
E227
2‐(Substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐oxazole Derivatives
(d, J = 7.9 Hz, 1H), 7.9 (s, 1H), 7.84–7.86 (m, 2H), 7.75 (d,
J = 8.8 Hz, 1H), 7.52 (t. J = 7.9 Hz, 1H), 7.27–7.34 (m, 2H),
4.15 (s, 3H); 13C‐NMR (50 MHz, DMSO‐d6): ppm, δ 156.2,
145.1, 140.4, 131.5, 129.6, 128.8, 128.4, 128.0, 126.7,
124.4, 121.6, 120.3, 119.9, 110.1, 40.7; HRMS (m/z): [M +
H]+ calculated for [C15H12N3OS]+ 282.0701. Found:
282.0714.
Acknowledgments. The authors thank Dr. Reddy’s Laboratories
Ltd for supporting this work. The authors also thank Dr. Vilas
Dahanukar, Dr. Suju Joseph, and Dr. Syam Kumar for their
constant help and encouragement. Cooperation extended by all
colleagues of analytical division is greatly acknowledged.
REFERENCES AND NOTES
2‐(3,4‐Difluorophenyl)‐N‐(2‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐
oxoethyl)acetamide (12g). Solid, m.p. 146–149°C; IR (KBr, v):
3304, 3074, 1690, 1636, 1549, 1519; 1H‐NMR (500 MHz,
DMSO‐d6): δH 8.49 (t, J = 5.4 Hz, 1H), 8.16 (d, J = 8.2 Hz,
1H), 7.81 (d, J = 8.5 Hz, 1H), 7.37–7.54 (m, 4H), 7.15–7.17
(m, 1H), 4.70 (d, J = 5.4 Hz, 2H), 4.19 (s, 3H), 3.59 (s, 2H);
13C‐NMR (50 MHz, DMSO‐d6): ppm, δ 190.6, 170.0, 140.7,
139.2, 133.9, 126.9, 125.9, 123.8, 121.8, 121.2, 118.1, 117.8,
117.2, 116.8, 110.7, 45.5, 36.4; HRMS (m/z): [M + H]+ calcd
for [C18H16N3O2F2]+ 344.1211. Found: 344.1200.
2‐(3,4‐Difluorobenzyl)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)oxazole
(13g). Solid, m.p. 97–98°C; IR (KBr, v): 3117, 3058, 1607,
1566, 1516; 1H‐NMR (500 MHz, DMSO‐d6): δH 8.0 (d,
J = 8.2 Hz, 1H), 7.69–7.71 (m, 2H), 7.41–7.51 (m, 3H),
7.23–7.28 (m, 2H), 4.30 (s, 2H), 4.09 (s, 3H); HRMS (m/
z): [M + H]+ calculated for [C18H14N3OF2]+ 326.1105.
Found: 326.1118.
[1] Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; deocariz,
C. O. Mini‐Rev Med Chem 2005, 5, 869.
[2] Angelis, M. D.; Stossi, F.; Carlson, K. A.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. J Med Chem 2005, 48, 1132.
[3] Zhang, H. C.; Derian, C. K.; McComsey, D. F.; White, K. B.;
Ye, H.; Hecker, L. R.; Li, J.; Addo, M. F.; Croll, D.; Eckardt, A. J.; Smith,
C. E.; Li Q.; Cheung, W. M.; Conway, B. R.; Emanuel, S.; Demarest,
K. T.; Andrade‐Gordon, P.; Damiano, B. P.; Maryanoff, B. E. J Med
Chem 2005, 48, 1725.
[4] May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin,
M. A.; Sharif, N. A. J Med Chem 2006, 49, 318.
[5] Han, W.; Pelletier, J. C.; Hodge C. N. Bioorg Med Chem Lett
1998, 8, 3615.
[6] Showalter, H. D. H.; Angelo, M. M.; Berman, E. M.;
Kanter, G. D.; Ortwine, D. F.; Ross‐Kesten, S. G.; Sercel, A. D.;
Turner, W. R.; Werbel, L. M.; Worth D. F.; Elslager, E. F.; Leopald, W. R.;
Shillis, J. L. J Med Chem 1988, 31, 1527.
[7] Palmer, D. C.; Taylor, E. C. The Chemistry of Heterocyclic
Compounds. Oxazoles: Synthesis, Reactions, and Spectroscopy, Parts
A & B; Wiley: New Jersey, 2004; p 60.
[8] Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.;
Walsh, C. T. Nat Prod Rep 1999, 16, 249.
[9] Fresneda, P. M.; Castaneda, M.; Blug, M.; Molina, P. Synlett,
2007, 324.
N‐(2‐(1‐methyl‐1H‐indazol‐3‐yl)‐2‐oxoethyl)cinnamamide
(12h). Solid, m.p. 188–190°C; IR (KBr, v): 3224, 1686,
1668,1649; 1H‐NMR (400 MHz, DMSO‐d6): δH 8.52 (t,
J = 5.9, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.8
Hz, 1H), 7.61 (d, J = 6.8 Hz, 2H), 7.52–7.55 (m, 6H),
6.86 (d, J = 15.7 Hz, 1H), 4.83 (d, J = 5.9 Hz, 2H), 4.2
[10] Vishnu, E.; Bhanu Prakash, P.; Sandip, K.; Ramanatham, J.;
Devanna, N. Synth Commun 2010, 40, 414.
(s, 3H); HRMS (m/z): [M
+
H]+ calculated for
[C19H18N3O2]+ 320.1399. Found: 320.1394.
[11] Bermudez, J.; Fake, C. S.; Joiner, G. I.; Joiner, K. A.;
King, F. D.; Miner, W. D. J Med Chem 1990, 33, 1924.
[12] Cornforth, J. W.; Cornforth, R. H. J Chem Soc 1953, 93.
[13] Pei, W.; Li, S.; Nie, X.; Li, Y.; Jian, P.; Bingzi, C.; Jie, W.;
Xiulin, Y. Synthesis 1998, 1298.
[14] Dalip, K.; Swapna, S.; Gautam, P.; Rao, V. S. Tetrahedron Lett
2008, 49, 867.
[15] Miyake, F.; Hashimoto, M.; Tonsiengsom, S.; Yakushijin, K.;
Horane, D. Tetrahedron 2010, 66, 4888.
(E)‐5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐2‐styryloxazole (13h).
Solid, m.p. 146–148°C; IR (KBr, v): 3121, 1602, 1520; 1H‐
NMR (400 MHz, DMSO‐d6) δH 8.18 (d, J = 8.2 Hz, 1H), 7.9
(s, 1H), 7.8 (d, J = 7.6 Hz, 2H), 7.5 (d, J = 8.2 Hz, 1H), 7.64
(d, J = 16.4 Hz, 1H), 7.27–7.54 (m, 6H), 4.15 (s, 3H); HRMS
(m/z): [M + H]+ calcd for [C19H16N3O]+ 302.1293. Found:
302.1294.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet