Acidic heterocycles, arylation

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

Various aryl, alkenyl and even alkylborane reagents of different reactivity can be used for coupling with aryl, alkenyl, alkynyl and some alkyl halides, offering very useful synthetic methods. The cross-coupling of aryl and heteroarylboronic acids with aryl and heterocyclic halides and triflates provide useful synthetic routes to various aromatic and heteroaromatic derivatives. Sometimes, the reaction proceeds in the... 

In Table 15.12 are reported the planar acidic heterocycles and aryl derivatives that are commonly used as carboxylic acid bioisosters. The most used is the tetrazole ring which has found wide application in different therapeutic helds spanning from type 2 diabetes to hepatitis C virus... 

Two sets of conditions have been developed for electron-rich heterocycle arylation [94, 95], Most acidic heterocycles such as benzoxazole or benzothiazole may be arylated by employing fBuOLi base, aryl iodide, and DMF solvent (Scheme 23). These reactions proceed at 140 °C in minutes. For less acidic imidazole, 1,2,4-triazole, and caffeine derivatives a stronger fBuOK base is required, and the reaction proceeds by a benzyne-type mechanism. Formation of regioisomer mixtures was observed if substituted aryl halides were used in combination with fBuOK (Scheme 23). 

A further improvement was the development of ligands 5 and 6, the use of which allowed for the synthesis of tetra-ortho-substituted biaryls, as well as the use of heterocyclic aryl chlorides and heteroarylboronic acids and esters (Equation 2.22) [40]... 

SCHEME 7.1 Copper-catalyzed arylation of acidic heterocycles. 

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. 

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. 

Xominaga, Y, Castle, L.W, and Castle, R.N., Photocyclization of 2-(naphth-l-yl)-3-(thien-2-yl)propenoic acid and the total assignment of the H-1- and C-13-NMR spectra of the product,/. Heterocycl. Chem., 33, 1017, 1996 Sasaki, K., Satoh, Y, Hirota, X., Nakayama, X., Xominaga, Y, and Castle, R.N., Syntheses of thiopyrone and pyrone derivatives by photocyclization reaction of 3-aryl-2-([l]benzothien-3-yl)propenoic acids, /. Heterocycl. Chem., 37, 959, 2000. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

Phenyl radicals can be generated by the thermal decomposition of lead tctrabcnzoate, phenyl iodosobenzoate, and diphenyliodonium hydroxide,- - and by the electrolysis of benzoic acid.- These methods have been employed in the arylation of aromatic compounds, including heterocycles. A method of promise which has not been applied to the arylation of heterocycles is the formation of aryl radicals by the photolysis of aromatic iodides at 2537... 

The simple ring opening of tetrahydro-1,3-oxazine derivatives is not the only possible reaction of these heterocyclic compounds catalyzed by mineral acids. An interesting rearrangement of 6-aryl-6-alkyltetrahydro-l,3-oxazines when warmed with concentrated hydrochloric acid was found by Schmiedle and Mansfield ... 

Substrates can be 1,2-diketones with aryl groups as well as some aliphatic substituents, cyclic and heterocyclic diketones. However the benzilic acid rearrangement is of limited preparative importance. 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles ... 

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