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. 2018 Apr 25;140(16):5599-5606.
doi: 10.1021/jacs.8b02142. Epub 2018 Apr 13.

Second-Generation Palladium Catalyst System for Transannular C-H Functionalization of Azabicycloalkanes

Pablo J Cabrera  1 , Melissa Lee  1 , Melanie S Sanford  1
Affiliations

Second-Generation Palladium Catalyst System for Transannular C-H Functionalization of Azabicycloalkanes

Pablo J Cabrera et al. J Am Chem Soc. .

Abstract

This article describes the development of a second-generation catalyst system for the transannular C-H functionalization of alicyclic amines. Pyridine- and quinoline-carboxylate ligands are shown to be highly effective for increasing the reaction rate, yield, and scope of Pd-catalyzed transannular C-H arylation reactions of azabicyclo[3.1.0]hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C-H arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are shown to promote both transannular C-H arylation and transannular C-H dehydrogenation on a homotropane substrate.

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Figures

Figure 1
Figure 1
Examples of bioactive alicyclic amines.
Figure 2
Figure 2
Initial rate for reaction of S1 with PhI in the presence of 5 mol % L9 (red curve) and absence of ligand (blue curve). Conditions red curve: S1 (0.03 mmol, 1 equiv, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), L9 (0.006 M), t-amylOH (0.25 mL), 100 °C. Conditions blue curve: S1 (0.03 mmol, 1 equiv, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-amylOH (0.25 mL), 100 °C.
Figure 3
Figure 3
Full reaction profile for the reaction of S1 with PhI in of 5 mol % L9 (red curve) and absence of ligand (blue curve). Conditions red curve: S1 (0.03 mmol, 1 equiv, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), L9 (0.006 M), t-amylOH (0.25 mL), 100 °C. Conditions blue curve: S1 (0.03 mmol, 1 equiv, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-amylOH (0.25 mL), 100 °C.
Figure 4
Figure 4
Catalyst recovery by addition of quinalidic acid after 4 hours. Conditions: S1 (0.03 mmol, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-AmylOH (0.25 mL), 100 °C, 4 h. Then, add L9 (0.006 M) and heat to 100 °C.
Scheme 1
Scheme 1
(a) Linear synthesis of epibatidine; (b) Late stage C–H functionalization approach to substituted 7-azanorbornanes.
Scheme 2
Scheme 2
First-generation Pd-catalyzed method for transannular C–H arylation of alicyclic amines.
Scheme 3
Scheme 3
Ligand-enabled C–H arylation of tropane, homotropane, and 7-azanorbornane derivatives
Scheme 4
Scheme 4
Two Possible Roles for L8/L9 in C–H Arylation of S1.
Scheme 5
Scheme 5
Kinetic Isotope Effect for S1 and S1-d5 with and without L9.a aConditions: S1 or S1-d5 (0.03 mmol, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-amylOH (0.25 mL), 100 °C, with and without L9 (0.006 M).
Scheme 6
Scheme 6
Catalytic activity of precipitate (I) for C–H arylation of S1 with and without L9 Conditions A: S1 (0.03 mmol), Pd(OAc)2 (0.003 mmol), CsOPiv (0.09 mmol), PhI (0.09 mmol), t-amylOH (0.25 mL), 100 °C, 90 min. Conditions B: Centrifuge and decant supernatant. Conditions C/D: S1 (0.03 mmol), precipitate (I), CsOPiv (0.09 mmol), with or without L9 (0.0015 mmol), 4-iodoanisole (0.09 mmol), t-amylOH (0.25 mL), 100 °C, 18 h.
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