Heterocycles pivalic acid

Intramolecular Direct Arylation of Heterocycles. Pivalic acid can promote a Pd-catalyzed intramolecular C-H activation process to furnish interesting pyrazolo[5,l-a]isoindoles (eq 22). ... 

Startg. alcohol heated 1 hr. at 138° with 7 equivalents ethyl orthoacetate in the presence of a catalytic amount of propionic acid with removal of the resulting alcohol by distillation product. Y 92%. - This rearrangement is highly geo-selective, giving trans-trisuhst carbon-carbon double bonds. F. e. s. W.S. Johnson et al.. Am. Soc. 92, 741 (1970) s. a. C. A. Henrick, F. Schaub, and J. B. Siddall, ibid. 94, 5374 (1972) N-heterocyclics with pivalic acid as catalyst s. F. E. Ziegler and G. B. Bennett, ibid. 93, 5930 (1971). 

The C-2 selective oxidative C-H coupling of unactivated pyridines with heterocycles was achieved in the presence of Pd(OAc)2, phenanthroline as the ligand, a silver oxidant, and pivalic acid (eq 145). Moderate to good yields were obtained when heteroarenes, such as thiophenes, indoles, furans, indazoles, or xanthines, were coupled to p3uidine (or p3razine, quinoline, pyrimidine). Virtually no homo-coupling or other regioselective (C-3 or C-4) products were observed in the reaction. 

A broadly applicable system for the arylation of various heterocycles with aryl bromides involves the employment of pivalic acid, along with Pd(OAc)2 and PCys (eq 160). It is h)q)othesized that the reaction involves a concerted metalation-deprotonation pathway. Other five-membered heterocycles react at the highlighted C-H position (eq 160). The same group also introduced electron-deficient fluoroarylphosphines for the direct functionalization of heteroarenes with aryl iodides. In the former report, low yields were obtained with 2-bromDpyridine or aryl halides bearing substituents such as nitro or cyano. A microwave-assisted protocol was instead developed that could overcome these limitations. ... 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

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