Electron-poor heterocyclic acids

Direct perfluoroalkylatwn of electron poor aromatic and heterocyclic systems with perfluorocarboxylic acids is mediated by xenon difluonde [165] (equation 142)... 

Polyamino acids are easy to prepare by nucleophUe-initiated polymerisation of amino acid JV-carboxyanhydrides. Polymers such as poly-(L)-leucine act as robust catalysts for the epoxi-dation of a wide range of electron-poor alkenes, such as y-substituted a,Ji-unsaturated ketones. The optically active epoxides so formed may be transformed into heterocyclic compounds, polyhydroxylated materials and biologically active compounds such as dUtiazem and taxol side chain. 

Milstein et al. found that Pd complexes with chelating alkylphosphines such as bis(diisopropylphosphino)butane (dippb) efficiently catalyze the olefmation of aryl chlorides with styrenes in the presence of elemental zinc [29]. Unfortunately, these electron-rich phosphines are apparently incompatible with electron-poor olefins such as acrylic acid derivatives. The latter were successfully coupled with activated chloroarenes by Herrmann et al., who used palladacycles or Pd-catalysts with heterocyclic carbenes [30]. 

The reaction proved to be quite flexible both electron-rich and electron-poor substituted benzanilides worked well, as did heteroaroyl anilides, saturated heterocycle anilides, and alkyl anihdes. The presence of competitive acidic a-hydrogens or of a,P-unsaturated acyl residues did not lead to good results. For greater diversity, the cyano group of the original aniline could be efficiently replaced by a tert-butyl ester or a dimethylamide. Cleavage from the resin was performed with GH2Gl2/TFA/triethylsilane (94 5 1, v/v/v). The product (603) was then dried in vacuo at 40 °C. 

The [2+2] cycloaddition is the main method for the synthesis of cyclobutanes and 4-membered ring heterocycles. The thermal reaction between two alkenes is not a synchronous, pericyclic process, which is symmetry forbidden, but is a two-step, Lewis acid-catalysed procedure involving a Michael reaction between an electron-rich alkene and an electron-poor partner followed by cyclisation (Figure 8.7). 

Aromatic Chlorination. Many aromatic and heteroaromatic chlorinations using NCS are catalyzed by acetic acid. Ferric chloride and ammonium nitrite have also been used to catalyze the chlorination of various heterocycles with NCS. Although NCS has been used for halogenation of electron-rich aromatics, the halogenation of electron-poor aromatic systems with NCS has been difficult to achieve. However, the chlorination of various deactivated aromatic systems can be achieved when NCS is acid catalyzed with boron trifiuoride monohydrate. The reaction is impressive in that even the deactivated 1-fiuoro-2-nitrobenzene is chlorinated to afford 4-chloro-l-fiuoro-2-nitrobenzene in 81% yield after 18 h at 100 °C (eq 24). ... 

In another example of pyridine activation of C—H bonds, 8-amino-quinoline and picolinic acids promote Cu-catalyzed fluorination of y-sp C-H bonds (Scheme 43) (13JA9342).The arenes can be mono- or difluo-rinated. The reaction proceeds well for both electron-rich and electron-poor arenes it also works for heterocycles such as indoles and pyridines.The reaction does not affect key functional groups such as nitro, nitriles, and carboxylates. 

Direct formation of N-oxides of amino-aza-heterocycles can be troublesome. Welcome, therefore, is a report that m-chloroperbenzoic acid in acetone can be used as oxidizing agent without the need to protect the amino-function. " 2-Aminopyridine AT-oxide (71%), 2-aminopyrimidine N-oxide (68%), and 1-aminoisoquinoline A"-oxide (66%) are amongst the examples cited. An alternative method of synthesizing O-aryl-oxypyridinium salts has been proposed " and is illustrated in Scheme 12. The unsymmetrical diaryliodonium tetrafluoro-borate (56) suffers preferential attack at the electron-poor aryl ring, and the yields of W-aryloxy-pyridinium (57) are good when X = N02-... 

Electron-deficient as well as electron-rich aryl boronic acids proved to be competent partners in the reaction, but electron-deficient boronic acids required higher temperatures. Boronic acids containing aryl halides (I, Cl) were also competent partners, providing a functional handle for further elaboration. Both primary and secondary amines have been utilised as coupling partners. A limitation of this chemistry is the inability to use nitrogen-based heterocycles due to either protodeboronation or the instability of the electron-poor sulfonyl chloride intermediate. Buchwald and coworkers later found that pyridylzinc reagents could be coupled with 2,4,6-trichlorophenyl chlorosulfate (TCPC) to access pyridine sulfonates without a transition metal catalyst." The pyridine sulfonates were subsequently treated with amines to generate sulfonamides. 

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