The kinetics of the oxidative additions of haloheteroarenes HetX (X=I, Br, Cl) to [Pd(0) (PPh3 )2 ] (generated from [Pd(0) (PPh3 )4 ]) have been investigated in THF and DMF and the rate constants have been determined. In contrast to the generally accepted concerted mechanism, Hammett plots obtained for substituted 2-halopyridines and solvent effects reveal a reaction mechanism dependent on the halide X of HetX: an unprecedented SN Ar-type mechanism for X=Br or Cl and a classical concerted mechanism for X=I. These results are supported by DFT studies.
Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp(3) C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
Halide anions can increase or decrease the transmetallation rate of the Stille reaction through in situ halide metathesis. Although the influence of the halogen present in oxidative addition complexes on the transmetallation rate with organostannanes was already known, the application of in situ halide metathesis to accelerate cross-coupling reactions with organometallic reagents is not described in the literature yet. In addition a second unprecedented role of halides was discovered. Halide anions stabilize the [Pd(0)(L)(2)] catalyst in Stille reactions, by means of [Pd(0)X(L)(2)](-) formation (X=Cl, I), hereby preventing its leaching from the catalytic cycle. Both arene (iodobenzene) and azaheteroarene (2-halopyridine, halopyrazine, 2-halopyrimidine) substrates were used.
Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded 4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the first examples of cine substitution in which the anionic σ(H)-adduct is quenched by electrophiles (other than a proton) before elimination takes place. Insight into the reaction mechanism led to the direct transformation of 2-benzylpyridazin-3(2H)-one (7) and 2-benzyl-6-chloropyridazin-3(2H)-one (9) into the corresponding C-4 alkyl and aryl derivatives (when Br(2) was used as the electrophile).
An auto-tandem Pd-catalyzed process consisting of an intramolecular direct arylation and an intermolecular Buchwald-Hartwig reaction for C-ring amino-substituted 1-methyl-1H-α-carboline synthesis has been developed. A mechanistic study of the direct arylation reaction revealed a rate effect of the inorganic base on the C-H activation step ("base effect"). The amines, reagents in the tandem protocol, appear to have a similar effect on the direct arylation.
Oxidative alkylamination of electron-deficient (hetero)aromatic compounds, via the nucleophilic substitution of hydrogen, is a methodology that has made significant progress since the introduction of AgPy(2)MnO(4) as oxidant. This oxidant generally gives good conversions and yields, whereas the use of KMnO(4) only sometimes works equally well. In order to rationalize this, the reaction mechanism of oxidative alkylamination has been studied. 3-Nitropyridine (1), 1,3-dinitrobenzene (2), and quinazoline (3) were chosen as model substrates and n-butylamine and pyrrolidine as model alkylamines. The rate-limiting step of the mechanism for these substrate/alkylamine combinations was determined. With the use of (1)H NMR spectroscopy thermodynamic properties of sigma(Eta)-adduct formation were deduced and the effect of additives on the adduct formation was investigated. The fundamental insights resulting from these studies led to the identification of a cheap additive (tetrabutylammonium chloride), which in combination with the standard and cheap oxidant KMnO(4) generally gave excellent yields, similar to the ones previously obtained with more expensive AgPy(2)MnO(4).
The site‐selectivity of Pd‐catalyzed reactions of 2,3‐dihalopyridines [2,3‐dichloropyridine (1), 2,3‐dibromopyridine (3) and2‐chloro‐3‐iodopyridine (2)] has been studied by computing the oxidative addition process using DFT calculations. The activating effect of the azine nitrogen atom on C(2) and C(3) has been obtained by comparison with the corresponding dihalobenzene [1,2‐dichlorobenzene (4), 1,2‐dibromobenzene (5) and 1‐chloro‐2‐iodobenzene (6)]. The performed calculations involve the use of Pd(PPh3)2, Pd(BINAP) and Pd(XANTPHOS) as catalysts. The formation of pre‐reactive complexes proved to be a very important factor in the determination of the activation energy values. A comparison with the simplified systems Pd(PPH3)2, Pd(H‐BINAP) and Pd(H‐XANTPHOS) revealed that care has to be taken when simplified catalyst systems are used for the simulation of the oxidative addition process.
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