Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions

Abstract

Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents.

Xanthates as Thiol Surrogates for Nucleophilic Substitution with Aryl Halides

“…Thioesters 2 a , [28] 2 b , [29] 5 c , [30] 6 a , [8b] 6 b , [31] 7 n , [32] 8 , [7] 11 , [33] 12 , [34] as well as aminothieno,– [2,–3b] pyridines 15 a , [35] 15 b [19b] and 2‐Methoxy‐3‐nitropyridine 3 [36] have already been prepared in the literature by other methods.…”

The 2‐Pyridyl Problem: Challenging Nucleophiles in Cross‐Coupling Arylations

“…While pyridine-2-sulfinates are an excellent tool in forming medicinally relevant cross-coupled biaryl products,t hey are not without issue.B eing salts,t hey display purification and solubility issues in organic media, which can in turn limit their utility.I n2 018, the Willis group described allylsulfones acting as latent sulfinate reagents. [125] TheP dc atalyst has adual function;first, the sulfinate "unmasks" in situ through deallylation and then, the previously described desulfinative cross-coupling process follows (Scheme 27).…”

Recent Advances in the Synthesis of 2,2′-Bipyridines and Their Derivatives

“…The methodology was further extended to allylsulfones as replacements for sulfinates. 22 The synthesis of bipyridines via the Stille coupling was first accomplished in 1986. 23 Since then, this method has been regularly used for the construction of bipyridine scaffolds.…”