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Abstract Palladium‐catalyzed aryl amination and Heck arylation reactions are complementary transformations, generally requiring a suitable catalyst combination and a base. With substrates containing both an amino group and a vinyl moiety, control of C─N versus C─C reactivity can lead to regiodivergent functionalizations. With this focus, reactions of silyl‐protected 8‐vinyl 2'‐deoxyadenosine and adenosine with aryl bromides and iodides have been studied. Pd(OAc)2, Pd2(dba)3, and preformed dichloro[1,1′‐bis(di‐t‐butylphosphino)ferrocene]palladium (II) (Pd‐118) were evaluated as metal sources. Ligands tested were Xantphos, DPEphos, BIPHEP, and DPPF, with Cs2CO3and K3PO4as bases. In toluene as solvent, the Pd(OAc)2/Xantphos/Cs2CO3combination was uniquely capable of predominantN6arylation. Aryl bromides and iodides gave comparable product yields. Replacement of Cs2CO3with K3PO4redirected arylation from the nitrogen atom to the vinyl carbon atom, and all other catalyst, ligand, and base combinations gave Cvinylarylation as well. Simply switching from Pd(OAc)2to Pd2(dba)3resulted in loss of theN6‐selectivity and Cvinylarylation was favored. Based upon these results, using two structurally similar catalytic systems sequential CvinylandN6arylations of the nucleosides were accomplished. Some of the products were converted to other novel nucleoside analogues. Because some compounds were fluorescent, their photophysical properties were assessed experimentally and computationally.
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Umpolung Synthesis of Pyridyl Ethers by Bi V ‐Mediated O‐Arylation of Pyridones
Abstract We report that O‐selective arylation of 2‐ and 4‐pyridones with arylboronic acids is affected by a modular, bismacycle‐based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on SNAr or cross‐coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5‐membered transition state. The kinetically‐controlled regioselectivity for O‐arylation—which is reversed relative to previous BiV‐mediated pyridone arylations—is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.
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- Award ID(s):
- 1955876
- PAR ID:
- 10380602
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 61
- Issue:
- 51
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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