Synthesis of Bis-heteroaryls Using Grignard Reagents and Pyridylsulfonium Salts

Abstract

Herein are reported ligand-coupling reactions of Grignard reagents with pyridylsulfonium salts. The method has wide functional group tolerance and enables the formation of bis-heterocycle linkages, including 2,4′-, 2,3′-, and 2,2′-bipyridines, as well as pyridines linked to pyrimidines, pyrazines, isoxazoles, and benzothiophenes. The methodology was successfully applied to the synthesis of the natural products caerulomycin A and E.

Sulfur(IV) in Transition-Metal-Free Cross-Couplings for Biaryl Synthesis

“…McGarrigle, Duong, et al have applied ligand coupling chemistry in natural product synthesis to access caerulomycin E 139 and caerulomycin A 140 (Scheme 33). 96 The first step of this synthesis involved a ligand coupling reaction between the pyridyl sulfonium salt 136 and Grignard reagent 137 to access the bipyridine 138. Further manipulations then provided access to the caerulomycin natural products 139 and 140.…”

“…Another important contribution came from the McGarrigle group, who developed sulfonium salts 120 as reagents for the synthesis of 2-heteroarylpyridines 122 (Scheme ). , This work largely built on the pioneering studies by Oae and Furukawa (Scheme ), but importantly provided a reliable and robust method for the synthesis of heterobiaryls 122 from either Grignard or organolithium reagents 121 . During these studies, they also developed an efficient method for the synthesis of sulfonium salts 120 by arylation of sulfides with diaryliodonium salts.…”

First total synthesis of caerulomycin K: a case study on selective, multiple C–H functionalizations of pyridines

“…[6][7][8][9][10][11] For instance, taking caerulomycin E as the prototype of this type of bioactive compounds, different routes have been designed to decorate the core pyridine ring with common substituents such as a carbonyl group (ortho-aldehyde), an alkoxide (para-MeO), and an aromatic ring (ortho-pyridine). [12][13][14][15][16][17][18][19][20][21] Yet, the installation of these functionalities via C-H activation is not straightforward since it requires several functional group interconversions (Scheme 1B).…”

“…18,19 The insertion of an ortho-pyridine group is usually more rapid but requires the use of Grignard reagents or prefunctionalized 2-bromopyridines. 15,16 Finally, the insertion of the carbonyl group is achieved by oxidation of a methyl group whose installation has been obtained only with a halogen (Cl or Br) already placed in ortho-position. 18,21 Given the recent advancements in selective C-H functionalizations of pyridines, 4,5 it would be expected that alternative strategies should now allow a faster synthesis of caerulomycins.…”

Accessing unsymmetrical Ru(ii) bipyridine complexes: a versatile synthetic mechanism for fine tuning photophysical properties

“…The McGarrigle group recently disclosed a sulfur-mediated ligand-coupling methodology for the preparation of unsymmetrical bipyridines, including biologically active targets (Scheme 1). [22][23][24][25][26] In this process, a pyridyllithium or Grignard reagent is reacted with a pyridylsulfonium salt, to give a trigonal bipyramidal sulfurane intermediate, which on collapse yields the desired bipyridine. This methodology permits the modular and selective introduction of functionality to either side of an unsymmetrical bipyridine ligand, i.e., from both the organometallic reagent and the pyridylsulfonium salt.…”