Markovic Tim, Murray Philip R D, Rocke Benjamin N, Shavnya Andre, Blakemore David C, Willis Michael C
Department of Chemistry, Chemistry Research Laboratory , University of Oxford , Mansfield Road , Oxford OX1 3TA , U.K.
Medicine Design , Pfizer Inc. , Eastern Point Road , Groton , Connecticut 06340 , United States.
J Am Chem Soc. 2018 Nov 21;140(46):15916-15923. doi: 10.1021/jacs.8b09595. Epub 2018 Nov 9.
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.
杂环亚磺酸盐是钯催化的与芳基卤化物和杂芳基卤化物偶联反应中的有效试剂，常常能高产率地得到目标联芳基化合物。然而，复杂杂环亚磺酸盐的制备和纯化可能存在问题。此外，亚磺酸盐官能团不耐受大多数合成转化反应，使得这些试剂不适用于多步合成。在此，我们表明杂环烯丙基砜可作为潜在的亚磺酸盐试剂，当用Pd(0)催化剂和芳基卤化物处理时，会发生脱烯丙基反应，随后进行高效的脱亚磺酰基交叉偶联反应。通过几种互补的路线可以方便地制备多种烯丙基杂芳基砜，并证明它们是与各种芳基和杂芳基卤化物有效的偶联伙伴。我们证明烯丙基砜官能团能够耐受一系列标准的合成转化反应，包括正交的C-和N-偶联反应，从而实现多步合成。烯丙基砜成功地与多种具有药用价值的底物偶联，证明了它们在苛刻的交叉偶联转化反应中的适用性。此外，使用烯丙基杂芳基砜偶联伙伴制备了药物克唑替尼和依托考昔，进一步证明了这些新试剂的实用性。
