Practical synthesis of 3-carboxyindazoles

Article abstract of DOI:10.1080/00397910500214318

A clean, high-yielding synthetic route to methyl 5-(bromomethyl)-1- tritylindazole 3-carboxylate 1 was needed. A principal intermediate was 5-methyl-3-carboxyindazole 2. An analysis of a by-product found after executing Schad's 3-carboxyindazole synthesis led to undertaking this reaction with an inverse addition in the principal step. This simple modification gave 2 in excellent and reproducible yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500214318

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Practical Synthesis of
3‐Carboxyindazoles
Barry L. Johnson a & James D. Rodgers a
a Bristol‐Myers Squibb Co., Wallingford, Connecticut,
USA
Version of record first published: 22 Aug 2006.
To cite this article: Barry L. Johnson & James D. Rodgers (2005): Practical Synthesis
of 3‐Carboxyindazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:20, 2681-2684
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Synthetic Communicationsw, 35: 2681–2684, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500214318
Practical Synthesis of 3-Carboxyindazoles
Barry L. Johnson and James D. Rodgers
Bristol-Myers Squibb Co., Wallingford, Connecticut, USA
Abstract: A clean, high-yielding synthetic route to methyl 5-(bromomethyl)-1-tritylin-
dazole 3-carboxylate 1 was needed. A principal intermediate was 5-methyl-3-
carboxyindazole 2. An analysis of a by-product found after executing Schad’s
3-carboxyindazole synthesis led to undertaking this reaction with an inverse addition
in the principal step. This simple modification gave 2 in excellent and reproducible
yields.
Keywords: Carboxyindazole, indazole, indazole carboxylic acid, indazolone
A high-yielding synthesis of methyl 5-(bromomethyl)-1-tritylindazole-3-
carboxylate (1) was needed. It was a key intermediate employed to build a
subgroup of our HIV protease inhibitors.[1] A simple, efficient, scalable, and
reliable synthesis of the 3-carboxyindazole precursor 2 was necessary
(Scheme 1).
Philipp Schad reported an attractive one-pot synthesis of 3-carboxyinda-
zoles from isatins in 1893.[2] However, subsequent papers have reported low
and variable yields with laborious purifications upon repeating his
procedure.[3] In our hands, Schad’s methodology produced one major, and
hard to separate, contaminant identified as 5-methyl-3-indazolone 4. It
accounted for up to 35% of our isatin 3 consumption. Baiocchi et al.
reported isolating 3-indazolone by-products exclusively using Schad’s
reaction.[4] It was rationalized that an intramolecular cyclization of the azo
Received in the USA May 18, 2005
Address correspondence to Barry L. Johnson, Bristol-Myers Squibb Co., 5
Research Way, Wallingford, CT 06492, USA. Tel.: 203-677-7843; Fax: 203-677-
7702; E-mail: Barry.Johnson@BMS.com
2681

2682
B. L. Johnson and J. D. Rodgers
Scheme 1.
intermediate 6 gave the indazolone 4, by way of decarboxylation, in compe-
tition with the desired reduction of 6 to the hydrazine 7 (Scheme 2). Accord-
ingly, the formation of the by-product would increase with a slower addition
of the reducing agent to the reaction. Naturally, unequal addition rates could
account for the observed variability of the reaction.
This hypothesis was tested by using a less-vigorous reducing agent.
Enhanced indazolone formation was anticipated from a slower reduction of
6. Sodium sulfite was employed in place of tin chloride, giving an 81%
yield of 4 (Scheme 3). Only a trace of 2 was detected in the crude product.
This reaction is a novel, selective, high-yielding, one-step synthesis of 4
from isatin.
In the preparation of 2, the tin chloride mixtures had been added at slower
rates to the diazonium solutions for larger reactions because this step was very
exothermic and because it foamed excessively. Slower additions gave lower
yields of 2 contaminated with more of 4. Inverting this key step, by adding
the diazonium solution to the tin chloride mixture, would maintain a high
concentration of the reducing agent relative to the substrate for the duration
of the reaction, thereby promoting the quick reduction of 6. The formation
of 2 would then be less dependent on the diazonium addition rate.
In practice, the inverse addition reliably suppressed the formation of 4 and
rendered 2 in 80% to 90% yields (Scheme 4).
In conclusion, an analysis of a by-product found when repeating Shad’s
3-carboxyindazole synthesis led to inverting the addition of reactants in the
key step. A diazonium solution was added to a tin chloride mixture. This
Scheme 2.

Practical Synthesis of 3-Carboxyindazoles
2683
Scheme 3.
simple modification gave 5-methyl-3-carboxyindazole 2 in excellent and
reproducible yields.
EXPERIMENTAL
Typical Procedure for the Preparation of 5-Methyl-3-
carboxyindazole
A chilled (08C) aqueous solution of NaNO2 (2.2 g, 32 mmol, 10 mL of water)
was added to a chilled (08C) solution of commercially available 5-methylisa-
tin (5.1 g, 32 mmol) in aqueous NaOH (1.3 g, 32 mmol, 10 mL of water). The
combined solutions were added slowly to chilled (08C) aqueous H2SO4
(3.4 mL of conc. H2SO4, 64 mmol, 60 mL of water) by means of an addition
funnel with the tip below the surface of the acid solution. Ice was added to
the reaction to maintain 08C and ether was added to control foaming, as
needed. After stirring an additional 10 min, the diazonium solution was
.
added slowly to a chilled (08C) mixture of SnCl2 2(H2O) (18 g, 80 mmol)
in concentrated HCl (30 mL) by means of an addition funnel with the tip
below the surface of the tin chloride mixture. Ice was again added to the
reaction to maintain 08C and ether was added to control foaming, as
needed. After stirring an additional hour, the reaction was filtered. The
golden yellow powder was dissolved in aqueous NaOH, washed with ether,
precipitated with aqueous HCl, and crystallized from AcOH/H2O to give
4.8 g of 2 (86%) as very pale yellow needles, mp 340–3428C (lit.[3c]
1
3438C). H NMR (300 MHz, DMSO-d6) d 13.76 (bs, 1H), 7.87 (s, 1H), 7.55
(d, 1H, 8Hz), 7.27 (d, 1H, 8Hz), 2.44 (s, 3H).
Scheme 4.

2684
B. L. Johnson and J. D. Rodgers
Preparation of 5-Methylindazol-3-one
A chilled (08C) aqueous solution of NaNO2 (0.49 g, 7.0 mmol, 7.0 mL of
water) was added to a chilled (08C) solution of commercially available
5-methylisatin (1.0 g, 6.4 mmol) in aqueous NaOH (0.31 g, 7.7 mmol,
7.0 mL of water). The combined solutions were added slowly to chilled
(08C) aqueous H2SO4 (1.3 mL of conc. H2SO4, 24 mmol, 15 mL of water)
by means of an addition funnel with the tip below the surface of the acid
solution. Ice was added to the reaction to maintain 08C and ether was added
to control foaming, as needed. After stirring an additional 30 min, a chilled
(08C) aqueous solution of NaHSO3 (3.3 g, 32 mmol, 15 mL of water) was
added by means of an addition funnel with the tip below the surface of the
diazonium solution. The reaction was stirred at room temperature for 12 h.
The reaction was poured into water and the mixture was filtered. The
orange powder was washed with ether and crystallized from ethanol to give
0.80 g of 4 (84%) as creamy white plates, mp 243–2448C (lit.[5] 240–
1
2428C). H NMR (300 MHz, DMSO-d6) d 11.13 (bs, 1H), 7.39 (s, 1H), 7.15
(AB, 2H), 2.36 (s, 3H).
REFERENCES
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Cordova, B.; Bacheler, L.; Garber, S.; DeLucca, I.; Chang, C.-H. Synthesis and
biological activity of potent cyclic urea HIV protease inhibitors with an
improved resistance profile. 35th National Organic Chemistry Symposium, San
Antonio, TX, June 23, 1997, M108; (b) Rodgers, J. D.; Johnson, B. L.;
Wang, H.; Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B.; Bacheler, L.;
Garber, S.; DeLucca, I.; Chang, C.-H. Synthesis and biological activity of potent
cyclic urea HIV protease inhibitors with an improved resistance profile. 16th Inter-
national Congress of Heterocyclic Chemistry, Boseman, MT, August 11, 1997,
POI 108.
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