Development of a palladium-catalyzed decarboxylative cross-coupling of (2-azaaryl)carboxylates with aryl halides
Graphical abstract
Introduction
The 2-substituted pyridine motif (Fig. 1), is present in a number of important small molecules,1 however 2-azaaryl nucleophiles typically used in cross-coupling reactions, such as organozincs, Grignards, organolithiums, organostannanes, and boronic acids, are notoriously unstable and difficult to prepare.2 While some modifications have been made to improve their synthetic viability, especially within the realm of boronic acid derivatives, these approaches are often inconvenient or produce toxic waste.3 The development of a decarboxylative method of generating these organometallic species (e.g., 2) in situ from (2-azaaryl)carboxylates (1) represents a desirable alternative to traditional aryl nucleophiles for the synthesis of 2-aryl pyridine structures (3). 2-(Azaaryl)carboxylates are generally inexpensive, are stable to both air and water, and represent a more ecologically friendly alternative to their organometallic counterparts.
Myers and co-workers reported the first practical decarboxylative cross-coupling in 2002,4 a palladium-catalyzed decarboxylative Heck-type olefination (Fig. 2). This work demonstrated that olefinated arenes are accessible from benzoic acids and olefins in the presence of catalytic palladium(II) triflate and silver carbonate. This represented an important advance as it provided an alternative to aryl halides and aryl pseudo-halides usually used in Heck reactions. A critical development within the field of decarboxylative cross-coupling was reported in 2006; Goossen and co-workers disclosed a catalytic decarboxylative cross-coupling reaction, utilizing a dual-catalyst system of copper and palladium. Mechanistically, this dual-catalyst approach likely proceeds through a decarboxylative cupration of the arylcarboxylate partner. The resulting aryl copper species subsequently undergoes transmetallation onto the palladium, which furnishes the coupled product through reductive elimination (Fig. 2).5 Unlike typical cross-couplings, which require stoichiometric aryl organometallic nucleophiles, decarboxylative couplings proceed through an in situ generation of the nucleophilic coupling partner. A variety of non-aryl carboxylates have proven to act as efficient coupling partners in decarboxylative cross-coupling reactions,6 including alkynes,7 α-keto acids,8 and 2-(2-azaaryl)acetates.9 While these represent great advances within the field, the robust coupling of a key class of molecules, namely 2-(azaaryl)carboxylates, has been elusive. Recently, during the course of our own work on this topic, Wu and co-workers reported on the palladium-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid (Fig. 2).10 In light this work, we sought to supplement their studies with our own findings.
Section snippets
Optimization of a decarboxylative cross-coupling of picolinic acid with bromobenzene
To develop a general cross-coupling methodology, we selected simple substrates for optimization studies, namely picolinic acid (8) and bromobenzene (9, Table 1). We began our investigations by applying conditions similar to those reported by Goossen with disappointing results (Table 1, entry 1). Using the same catalyst system we examined microwave irradiation and observed an increase in yield over heating in an oil bath (Table 1, entry 2). Similar results were disclosed by Goossen and Crabtree
Conclusion
Decarboxylative coupling is an attractive alternative to traditional cross-coupling reactions. The starting materials are stable and inexpensive while the byproducts of these reactions are less toxic and easier to dispose of than traditional organometallic reagents and boronic acids. 2-Metallated heteroarenes are particularly unstable, difficult to prepare and expensive. Herein we have reported an approach to circumvent the need to use these undesirable reagents. We have shown that
General
Spectral data for compounds 10, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 were consistent with previously reported data.10, 14, 15
A representative procedure for the decarboxylative cross-coupling of (2-azaaryl)carboxylates with aryl halides.
2-Phenyl pyridine (10)
74.9 mg (0.464 mmol) 13, 18.3 mg (0.0697 mmol) PPh3, 8.36 mg (0.0464 mmol) PdI2, and 6.6 mg (0.046 mmol) Cu2O were added to a flame-dried 2.0 mL microwave vial equipped with a spin vane. The vial was sealed, evacuated and back-filled with argon (three times).
Acknowledgements
The authors wish to thank NIH-NIGMS (R01GM080269) for financial support.
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