Pyridone coupling reactions

Halogen-substituted 2-pyridones are key intermediates for further metal-catalyzed coupling reactions and the halogenation of these scaffolds has already been described in previous sections. In the following section, a variety of C - C and C - N cross-coupling reactions under microwave-assisted conditions are described with some illustrative examples. 

Furo[2,3- ]pyridines can be synthesized from alkynylpyridones and iodonium sources (Scheme 31) <20060L1113>. Iodine proved to be much more effective at promoting the iodocyclization reaction than other iodonium sources (ICl, A -iodosuccinimide (NIS)). The pyridinium triiodide salt, 104, can be converted into the corresponding pyridinone by treatment with an external source of iodide. In a variation of the reaction, a one-pot synthesis of the furopyridine derivatives 105 can be achieved, with overall yields of 79-92%, by treatment with iodine followed by sodium iodide without isolation of the triiodide salt. Another similar one-pot synthesis involves 3-iodo-2-pyridones, terminal alkynes, and organic halides in a series of two palladium cross-coupling reactions (Equation 45) <20030L2441>. This reaction could also be carried out in a two-step sequence, but the overall reaction yields were typically improved for the one-pot method. 

Fu, J.-M., Chen, Y., and Castelhano, A.L., Synthesis of functionalized pyridones via palladium catalyzed cross coupling reactions, Synlett, 1408, 1998. 

Interest in copper-catalyzed coupling reactions has resurged due to the economic attractiveness of copper. Two different groups described the use of copper as a catalyst for efficient arylation reactions. Cristau and Taillefer detailed a mild copper-catalyzed N- and C-arylation with aryl bromides and iodides with various substrates <04CEJ5607>. One reaction examined was A -arylation of 2-pyridones. Li et al. has explored the copper-catalyzed coupling reaction of 2-pyridones 27 with aromatic halides 28 based on Buchwald s protocol to prepare N-aryl-2-pyridones 29 <04TL4257> as shown in Scheme 12. 

Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethyl-amine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi-nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for NIO-vinylation. The boronic acids can be replaced with siloxanes or starmanes. The mild condition of this reaction is an advantage over Buchwald-Hartwig s Pd-catalyzed cross-coupling. The Chan-Lam C-X bond cross-coupling reaction is complementary to Suzuki-Miyaura s C-C bond cross-coupling reaction. 

The triflate leaving group was introduced to coupling reactions as an alterative to halogens. They are particularly useful when there is no simple way to prepare the required halide partner. Aryl triflates can be prepared from phenols and pyridyl triflates can be prepared from pyridones. This transformation is usually achieved using triflic anhydride and an amine base. The coupling of a triflate 2.191, derived from quinolone 2.190, with stannane 2.192 was used in a short synthesis of dubamine 2.193 (Scheme 2.66). 

Oxidation of iV-aminopyridinium tosylates (70) with aqueous bromine yields, as expected, the tetrazenes (71). " However, if R = Me or Bu , pyridinio-pyridinium salts (72) are obtained, albeit in low yields. During the so-far unsuccessful search for a better oxidizing agent for this unusual coupling reaction, it has been found that -aminopyridinium salts (70), with lead tetra-acetate in acetic acid, yield l-(acetamido)-2-pyridones (73). A similar oxidation prevails for the quinolinium and isoquinolinium analogues. 

Thiocarbonyl Transfer. While virtually all uses of TCDI involve a thiocarbonyl transfer reaction, this section covers those uses of the thiocarbonyl transfer that do not lead to radical chemistry or alkene syntheses. TCDI has been used for the simple placement of a thiocarbonyl group between two nucleophilic atoms of one or two molecules. An alcohol which has been converted to an imidazolide is a reactive functionality for coupling reactions, for sigmatropic rearrangements, and for elimination (eq 8). The TCDI alternative l,r-thiocarbonyl-2,2 -pyridone seems to be an excellent thiocarbonyl transfer agent. 

The Boekelheide reaction has been applied to the synthesis of non-natural products with the preparation of quaterpyridines serving as an example. The sequence began with the 2,4-linked bipyridyl-N-oxide 25. Execution under the typical reaction conditions produced the expected bis-pyridone 26. Treatment with POCI3 afforded the corresponding dichloride that was submitted to a palladium-catalyzed coupling with 2-stannyl pyridine to produce the desired quaterpyridine 27. 

Pyridones can also be converted to 2-chloropyridines by exchanging the carbonyl functionality using phosphoroxychloride (POCI3) [72]. A combination of N-halosuccinimides and triphenylphosphine has also been applied to introduce halogens in this position [73]. The carbonyl functionality in 2-pyridones makes these systems reactive towards nucleophiles as well, which add in 1,4-reactions with displacement of halides [74]. The use of transition metal mediated couplings like Heck, and Suzuki have also been successfully applied on halogenated 2-pyridones (d. Scheme 10) [36,75]. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Quinolone (122), 2-pyridone (123), kojic acid (124) and 4-hydroxycoumarin (125) couple with diazonium salts (to form azo compounds, e.g. 126) and undergo Mannich reactions (e.g. with HCHO + HNMe2 to form -CH2NMe2 derivatives) at the positions indicated. Chromones undergo the Mannich reaction to give, for example, (127). 

Pd-mediated coupling of 50 could, in principle, terminate via p-elimination of either the C8 or C12 hydrogens. However, only the latter was observed. In our case, pentacycle 46 has only the C8 hydrogen available, and the normal course of the Heck reaction would be expected to produce pyridone 58 (Scheme 30). If p-elimination proved slow, an added hydride source might capture the palladium a-complex and provide the desired formal conjugate addition product 51. 

Pyridines, pyridones, and pyrones containing an amino or hydroxy group also undergo diazo coupling, nitrosation, and Mannich reactions, as do their benzenoid analogues, phenol or aniline. Such reactions take place under conditions of relatively low acidity where less of the compound is in the form of an unreactive cation. 

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