Quinoline allylic alkylation

Pyridine and related aromatic (quinoline, quinazoline) P,N derivatives (11, 12) have been created for Rh-catalyzed hydroboration-oxidation [44] or -amination [45]. Other pyridine-related auxiliaries have been synthesized for Pd-assisted allylic alkylation [46] in test conditions furnishing the substitution product in up to 93 % ee. The QUIPHOS ligand 13 has been tested in Pd-assisted allylic amination (up to 94 % ee) [47], allylic alkylation of -ketoesters (up to 95 % ee) [48], and Cu-catalyzed Diels-Alder reaction between an acryloyl derivative and cyclopentadiene [49]. 

SCHEME 13.45. Pd-Catalyzed asymmetric allylic alkylation in the synthesis of the bioactive quinoline 173. 

The Claisen rearrangement of allyl ethers in the quinoline series is thus seen to be unusually fast, affording high yields of products. In no case has migration of the allyl side-chain to the benzenoid ring been observed. Migrations to the nitrogen atom and to the alkyl side-chain proceed by concurrent rather than consecutive paths. 

Chloro- and 3-bromo-quinolines and 2- and 4-chIoroisoquinoIines undergo Ni-catalyzed coupling with primary alkyl, allyl and cyclohexyl Grignard reagents selective monoalkylation in 4,5-dichloroiso-quinoline may be noted (equations 147-150). 44... 

Alkylation of the sodium salt of 152 with allyl bromide in DMSO afforded the 3-S-allyl 160 (R = H), which underwent a thio-Claisen rearrangement in the presence of p-toluenesulfonic acid to give 2-allyl-3-mercapto 161 (R = H) that cyclized partially during purification to hexahydrothiophene 162 (R = H). Alternatively, acetylation of 161 (R = H) gave 163, which cyclized on heating in quinoline to afford 162 (R = H). Similarly, 2-butenyl 160 (R = Me) gave 161 (R = Me) but the... 

The anion of the isoquinoline Reissert compound (26) has also been alkylated with a wide variety of other alkyl halides.519-35 38 48-62-66,90 93 The alkylation product from 26 and allyl chloride undergoes isomerization to 38 on base-catalyzed hydrolysis.90 The phthalazine Reissert compound (3) has also been alkylated, in the presence of sodium hydride, with methyl iodide39 and with benzyl halides40 to give, after hydrolysis, 1-substituted phthalazines. A phthalazine analog of 34 (n = 3) has been prepared.1511 An additional example of the alkylation of the quinoline Reissert compound in the 4-position has appeared.943... 

O Donnell reported the asymmetric alkylation of the Schiff base of tert-h xty glycinate using TV-benzylcinchonium chloride (Scheme 3.26b, [151]). This process, which works for methyl, primary alkyl, allyl, and benzyl halides (Table 3.11), is noteworthy because the substrate is acyclic and because monoalkylation is achieved without racemization under the reaction conditions. The observed chirality sense may be rationalized by assuming an jE fO)-enolate and Jt-stacking of the benzophenone rings of the enolate above the quinoline ring on the catalyst, and approach of the electrophile as before. 

Malonic acid labeled with carbon-14 at C2 or at Cl,3 and the corresponding mono- and diesters have become important and highly versatile building blocks for the synthesis of a broad range of labeled compounds, such a,/3-unsaturated acids and esters, cycloalkanes, 8-keto esters, a-amino acids, phenols, dihydropyridines/pyridines, pyrimidines and quinolines. In addition, they are widely used as acetic acid synthons ( CH2COOR CHCOOR) for the extension of carbon chains of alkyl, allyl and benzyl halides as well as of saturated and a,)8-unsaturated carbonyl compounds. This Section discusses aU malonates, wherever labeled, and unlabeled malonates used with carbon-14-labeled reaction partners. However, it is the [2- " C]malonates that have been most often used in radiochemical synthesis. 

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