Palladium catalyzed addition of arylboronic acid or indole to nitriles: Synthesis of aryl ketones

Article abstract of DOI:10.1016/j.tetlet.2014.11.009

Aryl ketones can be synthesized conveniently by a palladium catalyzed addition of arylboronic acid to nitriles in aqueous triflic acid. This catalytic system was extended to the addition of unprotected indoles to nitriles under a slightly modified condition to produce 3-acyl indoles in good yields.

Full text of DOI:10.1016/j.tetlet.2014.11.009

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Accepted Manuscript
Palladium catalyzed addition of arylboronic acid or indole to nitriles: Synthesis
of aryl ketones
Tuluma Das, Amarnath Chakraborty, Amitabha Sarkar
PII:
S0040-4039(14)01882-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.009
TETL 45393
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 October 2014
3 November 2014
3 November 2014
Please cite this article as: Das, T., Chakraborty, A., Sarkar, A., Palladium catalyzed addition of arylboronic acid or
indole to nitriles: Synthesis of aryl ketones, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.11.009
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Graphical Abstract.

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Palladium catalyzed addition of arylboronic acid or indole to nitriles: Synthesis of aryl
ketones
Tuluma Das, Amarnath Chakraborty, Amitabha Sarkar*
Department of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700032, India
ocas@iacs.res.in, Fax: +91 33 2473 2805; Tel: +91 33 2473 4971.
Abstract. Aryl ketones can be synthesized conveniently by a palladium catalyzed addition of
arylboronic acid to nitriles in aqueous triflic acid. This catalytic system was extended to the
addition of unprotected indoles to nitriles under a slightly modified condition to produce 3-
acyl indoles in good yield.
Keywords: Palladium, Pyrazolylpyridine, Addition reaction, Aryl ketone, 3-Acyl-indole
Aryl ketones are important building blocks for bioactive compounds1 and natural
products.2 Conventional synthetic methods for aryl ketones involve Friedel-Craft acylation,3
oxidation of secondary alcohols4 and reaction of nitrile with Grignard5 or organolithium
reagents.6 Discovery of catalytic transformation, especially transition metal catalyzed C-C
bond formation have largely replaced such stoichiometric reactions for the commercial
production of important molecules. For instance, transition metal catalyzed addition of aryl
boronic acid to nitriles emerged as an improvement over the traditional method of synthesis
of aryl ketones because of wider functional group tolerance and ease of handling.7 In the first
example of addition reaction of boronic acid to nitriles Larock utilized a Pd(II) catalyst.7h Lu
et al. later expanded the scope of the reaction.7f,g Miura7e used sodium tetraphenylboron as

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the organoboron reagent and Murakami7d described an analogous Rh catalyzed addition
reaction of boronic acid to nitriles.
Our ongoing research seeks to explore pyrazole tethered donors as effective ligands8
in metal catalyzed reactions. In this context, the ligand L1 was identified as a non-
phosphorus, inexpensive ligand9 that can coordinate with palladium and catalyze an addition
reaction of arylboronic acid to aryl aldehydes.10 Extending the reaction to nitriles instead of
aldehydes, we expected, we would have a general synthesis of aryl ketones. We report herein
the successful outcome of this reaction and our fruitful attempt to extend this chemistry to
achieve convenient synthesis of 3-acylindoles.
. Initially we chose 4-methoxybenzonitrile and phenylboronic acid as reaction
partners to optimize the reaction. When the reaction was performed in dioxane and water at
80 °C no product was obtained. An equivalent amount of Sc(OTf)3 as additive was necessary
(Table 1, compare entry 2 with 3) to obtain high yield of the addition product. In presence of
trifluoroacetic acid (TFA) or triflic acid the reactivity was greatly enhanced compared to
HOAc allowing the reaction to be performed at 60 °C. Triflic acid afforded slightly better
yield than TFA (Table 1, compare entry 12 with 11). Omission of additive left no impact on
product yield (Table 1, entry 14). Also, the reaction did not proceed in absence of the ligand;
the reaction mixture immediately turned black indicating precipitation of palladium black
(Table 1, entry 15). Significantly, L1 ensured less time and lower temperature than the
precedents.7 An important advantage is the use of aqueous medium without an organic
solvent.
a
Table S1. Optimization of addition of arylboronic acid to nitrile