Synthesis of unprotected carboxy indazoles via Pd-catalyzed carbonylation

Article abstract of DOI:10.1080/00397911.2010.547970

The first published synthesis of unprotected carboxy indazoles from the corresponding bromoindazoles is described. This is achieved via Pd(II)-catalyzed carbonylation and is demonstrated to work on a variety of indazoles.

Full text of DOI:10.1080/00397911.2010.547970

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Synthesis of Unprotected Carboxy
Indazoles via Pd-Catalyzed Carbonylation
Philip Wainwright a , Remedios Perni a , Clare Vickers a , Steven B.
Coffey b , Leanne Buzon b , Kenneth DiRico b , Kendra L. Nelson b ,
Zhengrong Zhao b , Chris Limberakis b , Kevin D. Freeman-Cook b &
Jeffrey W. Corbett b
a Peakdale Molecular Ltd., Chapel-en-le-Frith , High Peak , United
Kingdom
b Pfizer Worldwide Research and Development , Groton ,
Connecticut , USA
Accepted author version posted online: 10 Nov 2011.Published
online: 26 Mar 2012.
To cite this article: Philip Wainwright , Remedios Perni , Clare Vickers , Steven B. Coffey , Leanne
Buzon , Kenneth DiRico , Kendra L. Nelson , Zhengrong Zhao , Chris Limberakis , Kevin D. Freeman-
Cook & Jeffrey W. Corbett (2012) Synthesis of Unprotected Carboxy Indazoles via Pd-Catalyzed
Carbonylation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:13, 1914-1921, DOI: 10.1080/00397911.2010.547970
To link to this article: http://dx.doi.org/10.1080/00397911.2010.547970
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Synthetic Communications1, 42: 1914–1921, 2012
Copyright # Peakdale Molecular Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.547970
SYNTHESIS OF UNPROTECTED CARBOXY INDAZOLES
VIA Pd-CATALYZED CARBONYLATION
Philip Wainwright,1 Remedios Perni,1 Clare Vickers,1
Steven B. Coffey,2 Leanne Buzon,2 Kenneth DiRico,2
Kendra L. Nelson,2 Zhengrong Zhao,2 Chris Limberakis,2
Kevin D. Freeman-Cook,2 and Jeffrey W. Corbett2
1Peakdale Molecular Ltd., Chapel-en-le-Frith, High Peak, United Kingdom
2Pfizer Worldwide Research and Development, Groton, Connecticut, USA
GRAPHICAL ABSTRACT
Abstract The first published synthesis of unprotected carboxy indazoles from the corre-
sponding bromoindazoles is described. This is achieved via Pd(II)-catalyzed carbonylation
and is demonstrated to work on a variety of indazoles.
Keywords Carbonylation; carboxylic acids; halides; indazoles; palladium
INTRODUCTION
The indazole heterocycle core has been of biological interest since the discovery
of HIV protease inhibitors, acetylcholinesterase inhibitors, serotonin receptor
antagonists, and aldol reductase inhibitors.[1,2] Halo indazoles have been prepared
in the literature either by the classic procedure of diazotization of toluidenes,[3,4]
nitrozation of their N-acetyl derivatives,[5,3] or more recently via condensation of
orthofluorobenzaldeydes with hydrazine.[6] However, relatively little has been pub-
lished on the conversion of the halides to the corresponding carboxy analogues.
Recently, Lin et al.[7] published the carbonylation of a N-Boc protected indazole
through ring lithiation followed by quenching of the resulting anion with carbon
dioxide. In contrast, we sought a method that avoided the use of a protecting group
on the indazole nitrogen and was reproducible on a range of scales and with a variety
of indazole substrates (Fig. 1).
Received November 29, 2010.
Address correspondence to Philip Wainwright, Peakdale Molecular Ltd., Chapel-en-le-Frith, High
Peak SK23 0PG, UK. E-mail: phil.wainwright@peakdale.co.uk
1914

SYNTHESIS OF UNPROTECTED CARBOXY INDAZOLES
1915
Figure 1. Indazole substrates.
Our initial trials were focused on organolithium chemistry where the dianion of
indazole 1 was generated. 5-Bromoindazole 1 was converted to the dianion by first
treatment with sodium hydride, and then metal-halogen exchange was achieved with
sec-butyllithium to deliver dianion 1a in situ. The resulting dianion was subsequently
quenched with carbon dioxide to deliver the carboxylic acid 2 in 53% yield (Scheme 1).
Despite our initial success, it was synthetically more appealing to avoid
pyrophoric reagents on a large scale. Hence, our investigations turned to a
palladium-catalyzed carbonylation approach. The carbonylation of aryl halides
was first introduced by Heck[8] via the use of palladium acetate and triphenylpho-
sphine; however, recently 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP)
was probed as a ligand, particularly for the carbonylation of halo pyridines.[9] The
authors discovered that use of BINAP over monodentate ligands significantly
increased the rate of reaction for halo pyridines. Based on these literature results,
we surmised that BINAP was a sensible starting point for our carbonlyation of halo
indazoles. A simple derivative 6-bromoindazole (3) was used to screen the reaction
conditions (Scheme 2).
Initial carbonylation conditions with PdCl2, BINAP, and NEt3 at 20 bar of CO
gave no reaction after 24 h at 100 ꢀC. However, by increasing the pressure to 40 bar,
50% conversion within 24 h and complete conversion within 48 h in a mixture of
acetonitrile and methanol were achieved. After chromatography, the corresponding
methyl ester was isolated in 90% yield (Scheme 2).
To explore the scope of this reaction, a series of 5- and 6-bromo-substituted
indazoles and 6-bromopyrazopyridine were selected (Table 1). Entries 2, 4, and 6
Scheme 1. (i) NaH, THF, rt; (ii) s-BuLi, ꢁ78 ꢀC; (iii) CO2 ꢁ78 ꢀC to rt; 53%.

1916
P. WAINWRIGHT ET AL.
Scheme 2. (i) PdCl2, BINAP, NEt3, MeOH=CH3CN, 40 bar CO, 100 ꢀC, 90%.
were prepared from the corresponding N-acetyl toluidenes,[3,5] and 1, 3, and 5 via the
fluoroaldehydes.[6] All carbonylations were done using PdCl2=BINAP in a
methanol=acetonitrile solvent mixture at 40 bar of carbon monoxide. Each reaction
Table 1. Carbonylation of bromoindazoles with PdCl2=BINAP
Entry
Bromoindazole
Product
Yielda (%)
1
81
2
3
66
90
4
85
5
6
92
19
Note. Conditions: PdCl2, BINAP, CO (40 bar), Et3N, MeOH=CH3CN.
aYields refer to isolated products.

SYNTHESIS OF UNPROTECTED CARBOXY INDAZOLES
1917
Scheme 3. (i) Pd(PPh3)2Cl2, NEt3, MeOH, 3 bar CO, 75 ꢀC, 40%.
was complete within 48 h, and the corresponding methyl esters were afforded in good
to excellent yields on a multigram scale, apart from entry 6, which gave a poor yield.
From this series of experiments, there appeared no firm evidence to connect the
reaction times to the structures of the halo indazoles.
It was not known how 6-chloro-5-bromoindazole would react under these reac-
tion conditions and whether there would be any selectivity for one halide over the
other. Based on liquid chromatography=mass spectrometry (LC=MS) results, the
palladium-catalyzed carbonylation showed no selectivity for either C5-Br or
C6-Cl. Thus, isomeric esters were detected as well as the diester. However, the
desired product was isolated in 19% yield after purification by chromatography.
All of the methyl esters in Table 1 were then hydrolyzed with sodium hydroxide
in methanol=water to afford their respective carboxylic acids in 90–100% yield.
Encouraged by these results, we examined additional palladium catalysts
including Pd(PPh3)2Cl2 and Pd(dppf)Cl2 (Schemes 3 and 4).
The conditions highlighted in Scheme 3 disappointingly did not provide as
good of a yield (40%) as that obtained with the PdCl2=BINAP catalytic system
(Table 1, entry 2, 66% yield). However, we were pleased that an excellent yield
was obtained using Pd(dppf)Cl2 (Scheme 4). Furthermore, Pd(dppf)Cl2 required
only the use of 3 bar of carbon monoxide rather than 40 bar for PdCl2=BINAP.
To further explore this success, two more indazoles were prepared via the corre-
sponding N-acetyl toluidenes[3,5] and treated under the Pd(dppf)Cl2-catalyzed carbo-
nylation conditions to deliver the corresponding methyl esters in good to excellent
yield (Table 2).
In summary, we developed a set of palladium-catalyzed carbonylation con-
ditions to convert unprotected bromoindazoles to their respective methyl esters.
These methyl esters were then hydrolyzed in a facile manner to their carboxylic acids.
These carbonylation conditions worked over a range of substituted indazoles and
were conducted on a multigram scale, demonstrating their potential generality and
scalability.
Scheme 4. (i) Pd(dppf)Cl2, NaOAc, MeOH=DMF, 3 bar CO, 70 ꢀC, 95%.

1918
P. WAINWRIGHT ET AL.
Table 2. Carbonylation of bromoindazoles with Pd(dppf)Cl2
Entry
Bromoindazole
Product
Yielda (%)
1
2
95
80
69
3
Note. Conditions: Pd(dppf)Cl2, CO (3 bar), NaOAc, MeOH=DMF.
aYields refer to isolated products.
EXPERIMENTAL
All purchased materials and reagents were used without further purification
1
unless noted. H NMR spectral data was recorded on an Jeol ECX 400-MHz spec-
trometer. Chemical shifts are expressed in parts per million (ppm). Splitting patterns
describe apparent multiplicities and are as designated as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or br s (broad singlet). LCMS were recorded
on a Waters 2795-ZQ instrument with a XBridge C18 2.1 ꢂ 30 mm, 5-mm column.
The eluent conditions for the LCMS were 5–95% acetonitrile over 3 min with 10%
10 mM ammonium carbonate as the aqueous phase. All carbonylation reactions
were carried out in a Parr series 4600 general purpose 1-L stainless steel bomb. Puri-
fication was performed by flash chromatography using Fluorochem silica gel
LC60A, 40–63 microns.
PdCl2 BINAP Method
A typical procedure for the PdCl2 BINAP method is given from entry 1 in
Table 1; however, all the entries were conducted in the same way.
Methyl-4-methoxy-1H-indazole-6-carboxylate:
Triethylamine
(48 mL,
343 mmol), BINAP (760 mg, 6.75 mmol), and PdCl2 (2.70 g, 15.4 mmol) were added
to a solution of the 6-bromo-4-methoxyindazole (13.95 g, 61.7 mmol) in methanol
(200 mL) and acetonitrile (100 mL). The mixture was then placed under an atmo-
sphere of carbon monoxide (40 bar) and stirred vigorously at 100 ꢀC for 18 h.

SYNTHESIS OF UNPROTECTED CARBOXY INDAZOLES
1919
The reaction mixture was cooled, opened to the atmosphere, and filtered through
celite, and the solvent was removed in vacuo to give a red=brown residue, which
was then subjected to column chromatography (10–30% ethyl acetate=hexane) to
give methyl 4-methoxy-1H-indazole-6-carboxylate as a pale yellow solid (10.25 g,
50 mmol, 81%).
LC rt 0.6 min, 92.15%; EIMS, m=z 207 (M þ 1); 1H NMR (CDCl3, 400 MHz,) d
3.96 (s, 3H), 4.01 (s, 3H), 7.15 (s, 1H), 7.86 (s, 1H), 8.18 (s, 1H).
Pd(dppf)Cl2 Method
A typical procedure for the Pd(dppf)Cl2 method is given from entry 1 in
Table 2; however, all the entries were conducted in the same way.
Methyl-3,7-dimethyl-1H-indazole-5-carboxylate: DMF (1.90 mL) was added
to a solution of 5-bromo-3-7-dimethylindazole (5.53 g, 24.6 mmol), Pd(dppf)Cl2
(2.88 g, 3.93 mmol), and sodium acetate (6.05 g, 73.7 mmol) in methanol (150 mL).
The mixture was degassed several times with nitrogen and then placed under an
atmosphere of carbon monoxide (3 bar) and stirred at 70 ꢀC for 18 h. The resulting
dark red solution was poured into water (100 ml), and the mixture was acidified with
10% citric acid. The mixture was then extracted with EtOAc (4 ꢂ 100 ml). The com-
bined organic layers were washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The crude product was then purified via flash
chromatography (silica gel) eluting with a gradient of hexanes to hexanes–EtOAc
(70:30) to deliver the methyl ester as an off-white solid (5.02 g, 24 mmol, 95%).
LC rt 1.77 min, 100%; APCI, m=z 205.2 (M þ 1); 1H NMR (400 MHz, CD3OD)
d 2.54 (s, 3 H), 2.57 (s, 3 H), 3.91 (s, 3 H), 7.77 (s, 1 H), 8.29 (s, 1 H).
Typical Procedure for the Hydrolysis of the Esters
4-Methoxy-1H-indazole-6-carboxylic acid: Sodium hydroxide (13.5 g,
250 mmol) was added to a solution of methyl 4-methoxy-1H-indazole-6-carboxylate
(10.25 g, 50 mmol) in methanol (250 mL) and water (250 mL) at 0 ꢀC, and the mixture
was allowed to warm to room temperature and stirred for 3 h. The methanol was
removed in vacuo, and the aqueous mixture was diluted to 300 mL, washed with
ethyl acetate (300 mL), and cooled to 0 ꢀC. HCl (2 M, 100 mL) was added until
pH 6 was reached. The precipitate that formed was then filtered, washed with water
(200 mL), and then dried in a vacuum oven (40 ꢀC over potassium hydroxide) for
48 h to give 4-methoxy-1H-indazole-6-carboxylic acid as an off-white solid (9.35 g,
48.7 mmol, 97%).
LC rt 0.52 min, 98.8%; EIMS, m=z 193 (M þ 1); 1H NMR (400 MHz, CDCl3) d
3.89 (s, 3H), 7.01 (s, 1H), 7.72 (s, 1H), 8.09 (s, 1H).
Selected Data
Data for all novel compounds detailed in Tables 1 and 2 are provided below.
The only exception is methyl 1H-indazole-5-carboxylate, whose analytical data
corresponded with that previously described in the literature.[10]

1920
P. WAINWRIGHT ET AL.
7-Methyl-1H-indazole-5-carboxylic acid. MS, APCI, m=z 177.2 (M þ 1);
1H NMR (400 MHz, CD3OD) 8.38 (s, 1 H), 8.18 (s, 1 H), 7.81 (s, 1 H), 2.59 (s, 3 H).
Methyl-7-methyl-1H-indazole-5-carboxylate. LC rt 1.81 min, 97.0%;
1
EIMS, m=z 191 (M þ 1); H NMR (400 MHz, CDCl3) d 8.33 (s, 1H), 8.15 (s, 1H),
7.76 (s, 1H), 3.92 (s, 3H), 2.56 (s, 3H).
Methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate. LC rt 0.47 min, 94.0%;
1
EIMS, m=z 178 (M þ 1); H NMR (400 MHz, CDCl3) d 10.56 (s, 1H), 9.23 (s, 1H),
8.35 (s, 1H), 8.40 (s, 1H), 4.01 (s, 3H).
Methyl-6-chloro-1H-indazole-5-carboxylate. LC rt 2.09 min; 92.0%;
1
EIMS, m=z 211 (M þ 1), H NMR (400 MHz, CDCl3) d 8.35 (s, 1H), 8.14 (s, 1H),
7.60 (s, 1H), 3.96 (s, 3H).
Methyl-3-ethyl-7-methyl-1H-indazole-5-carboxylate. LC rt 2.83 min,
1
100%; APCI, m=z 219.1 (M þ 1); H NMR (400 MHz, DMSO-d6) 13.07 (s, 1H),
8.24 (s, 1H), 7.69 (s, 1H), 3.85 (s, 3 H), 2.97 (q, J ¼ 7.6 Hz, 2H), 2.52 (s, 3H), 1.31
(t, J ¼ 7.6 Hz, 3H).
Methyl-7-ethyl-1H-indazole-5-carboxylate. LC rt 1.18 min, 100%; APCI,
1
m=z 205.2 (M þ 1); H NMR (400 MHz, CD3OD) 8.38 (d, J ¼ 1.6 Hz, 1H), 8.18 (s,
1H), 7.82 (s, 1H), 3.92 (s, 3H), 2.98 (q, J ¼ 7.3 Hz, 2H), 1.37 (t, J ¼ 7.3 Hz, 3H).
ACKNOWLEDGMENT
We gratefully acknowledge the help of Gemma Chew in compiling this paper.
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