Hindered aryl deprotonation

Deprotonation of ethers is another route to the a-alkoxy anions, but this pathway is often precluded by a kinetic barrier. Unless the a-carbon is benzylic [175], surmounting this barrier usually requires conditions that are not favorable to the survival of the anion [164]. Notable exceptions are the hindered aryl esters studied by Beak [176], Figure 3.13a, and the carbamates studied by Hoppe [177], shown in Figure 3.13b. In both cases, ec-butyllithium is required for deprotonation, and the carbonyls which direct the metalation by a complex-induced proximity effect [178] must be shielded from the base by large alkyl groups. Once formed, the organo-lithiums are chelated and stabilized by the heteroatom-induced dipole [179]. 

They found that the expected products 13 are indeed formed, but are accompanied by an unexpected compound (14). The yield of 13 was reasonably good for 2,6-dimethylphenyl- and mesityllithium, whereas it was extremely low for 9-anthryllithium and the limit was exceeded for supermesityllithium since only supermesitylene was recovered after hydrolysis. Compound 14 (characterised by X-ray diffraction) was obtained exclusively as the isomer depicted in Scheme 4.5. Its formation can be explained by deprotonation of the benzylic proton of the ephedrine moiety by the aryllithium and subsequent elimination. This reaction is usually slow compared to the nucleophilic attack of the aryl group to the P atom, but when this attack is sterically hindered, the deprotonation-elimination reaction becomes competitive or even prevalent. With l-lithio-8-methoxynaphtha-lene, a mixture of products was also obtained (Scheme 4.6). 

Deprotonation of 3-fluorotoluene 53 with n-BuLi-KOr-Bu or, better, r-BuLi-KOr-Bu follows the selectivity expected with these superbases and leads to metallation at the least hindered position ortho to the fluoro substituent. Trapping the metallated intermediate 54 with dimethylfluoroboronate gave, after hydrolysis, a boronic acid whose Suzuki arylation provided the biaryl 55. These four steps may be carried out in a single pot, giving 55 in 79% overall yield from 53. 

The binding of a phosphinous acid to palladium can provide a phosphorus-bound adduct, which may be deprotonated to yield an electron-rich, anionic palladium-phosphine complex suitable as a catalyst for coupling processes. Li has recently demonstrated the viability of this strategy, establishing that catalytic systems consisting of [Pd2(dba)3] and (t-Bu)2P(0)H,as well as [Pd2(dba)3], (t-Bu)2PCl and H2O, effect Suzuki reactions of hindered and electron-rich aryl chlorides (Equation 2.30) [51, 52]. 

Alternatively, a SchifTs base (53), obtained from condensation of 2-aminobenzonitrile 49 and an aryl or heteroaryl methyl ketone 52, was deprotonated with LDA, and the resulting carbanion underwent cyclization to form a 4-aminoquinoline product 54 in high yield. It is interesting that when this reaction was carried out with the ethyl ketone analog of 52 it did not produce the analogous quinoline product. Instead, it was determined that rather than undergoing deprotonation, the more sterically hindered ethyl ketone derivative underwent an addition reaction with LDA to form 55. ... 

The coupling of various oxazoles with aryl iodides proceeds under Irgandless conditions, employing Pd(OAc)2 as the catalyst and Cul as the additive (eq 166). In case of the oxazole, it was necessary to use the aryl iodide as the limiting reagent to obtain synthetically useful yields (23 versus 74%). Moreover, two complementary C-2 C-5 arylations were developed for oxazoles. On the one hand, it was demonstrated that in nonpolar solvents, such as toluene, in the presence of a phosphine, such as RuPhos, selectivities >100 1 were obtained for arylation at the C-2 position (eq 167). On the other hand, polar solvents and hindered phosphines led to predominantly C-5 arylation (eq 167). It was hypothesized that, for the C-5 arylation, a CMD-type mechanism is operative, while a deprotonation pathway is the more likely explanation for the C-2 arylation. A general, paUadium-catalyzed, sequential arylation of ethyl oxazole-4-carboxylates at the C-2 and C-5 positions with a variety of aryl halides has also been reported. 

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