Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model

Abstract

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

Figure 1. Pyridine-containing drugs, pyridyne isomers, and previous examples of pyridynes

a, Common pharmaceutical drugs containing the pyridine scaffold. b, The structure of the 2,3-pyridyne (1) and energy-minimized structure of the 3,4-pyridyne (2) obtained using B3LYP/6-31G* calculations. The lack of unsymmetrical aryne distortion is responsible for the poor regioselectivity in reactions of 2. c, Snieckus’ use of a C2 amide to direct attack to C4 of pyridyne 4. d, Caubère’s use of a C2-oxygen substituent in the dehydrohalogenation approach to pyridyne 7. e, Guitián’s examination of halide effects on pyridyne cycloadditions. TES, triethylsilyl; Tf, trifluoromethansulfonyl; TBAF, tetra-N-buylammonium fluoride; THF, tetrahydrofuran; TMS, trimethylsilyl.

Figure 2. Design of 3,4-pyridynes with controllable regioselectivity

a, Effect of substituents at either C2 or C5 on the distorion of 3,4-pyridyne. Inductively withdrawing substituents at C2 lead to a flattening at C4, while inductively withdrawing substituents at C5 lead to a flattening at C3. b, Selection of pyridyne targets based on retrosynthetic analysis. c, Geometry-optimized structures of pyridynes 13 and 16 using B3LYP/6-31G* calculations and their predicted site of attack based on the calculated angles.

Figure 3. Synthesis of silyltriflates 20, 22, and 25

a, preparation of 3,4-pyridyne precursor 20. b, preparation of 5-bromo-3,4-pyridyne precursor 22. c, preparation of 2-sulfamoyl-3,4-pyridyne precursor 25. i-PrNCO, isopropyl isocyanate; TMEDA, N,N,N,N-tetramethylethane-1,2-diamine; TBS, tert-butyldimethylsilyl; LDA, lithium diisopropylamide; Pd/C, palladium on carbon.

Figure 4. Competition between sterics and electronics in transition states for nitrone cycloadditions

a, TS1 shows the steric interaction between the C5 bromide and the large phenyl group of the nitrone, whereas this interaction is not present in TS2. However, the major product suggests that TS1 is favored due to electronic effects. b, TS4 shows the steric interaction between the C2 sulfamate and the phenyl group on the nitrone, however, the product arising from this transition state is favored over the competing sterically favorable pathway, TS3.

Figure 5. Derivatization of adducts 26 and 30

a, Pd-catalyzed amination, reduction, and Suzuki-coupling of pyridyl bromide 26. b, Ni-catalyzed amination, reduction, and Kumada-coupling of pyridyl sulfamate 30. BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Ni(cod)₂, bis(cyclooctadiene)nickel (0); SIPr·HCl, N,N′-(2,6-Diisopropylphenyl)dihydroimidazolium chloride; TMDSO, tetramethyldisiloxane; NiClCpIMes, (η⁵-C₅H₅)NiCl(1,3-dimesitylimidazol-2-ylidene).