A series of Pd-N-heterocyclic carbene (Pd-NHC) complexes with various NHC, halide and pyridine ligands (PEPPSI (pyridine, enhanced, precatalyst, preparation, stabilisation and initiation) precatalysts) were prepared, and the effects of these ligands on catalyst activation and performance were studied in the Kumada-Tamao-Corriu (KTC), Negishi, and Suzuki-Miyaura cross-coupling reactions. The lowered reactivity of more hindered 2,6-dimethylpyridyl complex 4 in the Negishi and KTC reactions is consistent with slow reductive dimerisation of the organometallic reaction partner during precatalyst activation. Comparative rate studies of complexes 1, 4 and 5 in the KTC and Suzuki-Miyaura reactions verify that 4 activated more slowly than the others. A potential on/off mechanism of pyridine coordination to NHC-Pd(0) is also plausible, in which the more basic pyridine stays bound for longer.

An additives study for the alkyl-alkyl Negishi reaction using an NHC-Pd catalyst revealed that bromide salts promote coupling while the cation is mechanistically benign. A double titration revealed that the cross-coupling begins at a 1 : 1 ratio of LiBr : (n)BuZnBr, suggesting that a higher-order zincate, presumably Li(m)Zn((n)Bu)Br(3)((2-m)-), is the active transmetalating agent.

Negishi cross-coupling reactions were analyzed in solution by mass spectrometry and NMR spectroscopy to identify both the effect of LiBr as an additive as well as the purpose of 3-dimethyl-2-imidazolidinone (DMI) as a co-solvent. The results suggest that the main role of DMI is to facilitate a higher order bromozincate formation during the addition of LiBr.

Tetrahydro-4H-thiopyran-4-one was prepared in >75% yield by treatment of dimethyl 3,3¢-thiobispropanoate with NaOMe (generated in situ) in THF solution and decarboxylation of the resulting methyl tetrahydro-4-oxo-2H-thiopyran-3-carboxylate in refluxing 10% aqueous H 2 SO 4 . Reaction of tetrahydro-4H-thiopyran-4-one with Me 3 SiCl and Et 3 N in CHCl 3 gave the corresponding trimethylsilyl enol ether in near quantitative yield. The prepared reagents are useful for the synthesis of thiopyran-containing compounds.Cyclic sulfides are an important class of compounds with numerous applications in many areas of chemistry. 1 In particular, thiopyran-derived scaffolds have been exploited in diverse ways. 2 The synthesis of such targets often involves the elaboration of simple thiopyran-containing reagents such as 2-4. 3 Of these, only tetrahydro-4H-thiopyran-4-one (3) is commercially available, albeit at a significant cost. 4 We have been investigating aldol reactions of 3 for the rapid assembly of stereochemically diverse polypropionate synthons and required large amounts of 2 and 3 for this purpose. 5 Herein we report simple and costefficient procedures for the preparation of 2, 3, and 4 (Scheme 1).Several methods for the synthesis of 3 are known, 3,6-9 most commonly by the decarboxylation of 2. 7-9 The bketo ester 2 is also a versatile reagent for synthesis of thiopyran-containing compounds and numerous reports on its preparation by Dieckmann cyclization of 1 10 or an analogous diester have been published. 7,8,11 Most of these methods involve the use of NaOMe or NaH in various modifications of Fehnel and Carmack's improvement of the original procedure by Bennet and Scorah. 7 Compared to the Fehnel and Carmack protocol (2 equiv of 'alcoholfree' NaOMe in refluxing diethyl ether; 64% yield of 2 on 1.4 mol scale), the modified procedures typically describe reactions on much smaller scale (<0.1 mol) and the reported yields vary widely (13-81%; most around 75%). The importance of the quality of the NaOMe used has been noted 9a and it is likely that the diester 1 is susceptible to hydrolysis by small amounts of NaOH. It is known that the reaction is accompanied by some cleavage of the sulfide linkage in 1, especially at higher temperatures, resulting in the formation of methyl 3-methoxypropionate, methyl 3-mercaptopropionate, and hydrogen sulfide. 9a Our experiments indicate that 2 readily decomposes under basic conditions in protic solution, perhaps contributing to the high variation in the reported yields.We previously reported a simplified procedure for the conversion of 1 into 2 (2 equiv of NaOMe in Et 2 O-THF; 93 ± 5% on 0.5 mol scale). 5b Subsequently, we optimized several reaction parameters and have now developed a very robust, scalable, and cost-effective procedure. The amount of NaOMe used can be reduced to 1.3 equivalents 12 and its quality is easily controlled with in situ generation by addition of anhydrous methanol to a suspension of Na metal in THF. Addition of 1 to the resulting NaOMe/THF mixture results in...

The phosphine ligand mediated palladium catalyzed alkoxycarbonylation of alkenes was investigated with the objective of attaining good linear selectivity for the ester. The effect of various parameters such as solvents, additives, palladium precursors, CO pressures, and alkenes of various structural complexities were examined. The results revealed the importance of using a Lewis acid such as SnCl2 or Ti(O(i)Pr)4 in combination with a monodentate ligand such CYTOP 292 or P(p-anisyl)3 to enhance the regioselectivity for the linear isomers in the range of 70-96%.