Substituted heteroarenes

There is a limited number of examples of preparations involving the reaction of stannyl-alkali metal compounds with a substituted heteroarene, for example, Equations (58)-(60).88,197,198 Some of these reactions (e g Equation (58)) occur only with photoirradiation, showing that they involve SRN1 processes, but others may be straightforward nucleophilic heteroaromatic substitutions. 

The iodoalkane (1 mmol) and an excess of the heteroarene (5-15 mmol), Na2S203 (0.16 g), 2-methyloxirane (0.3 g), and TBA-Br (32 mg, 0.1 mmol) are added to MeOCMe3 (2 ml) in a Pyrex tube. The mixture is degassed under Ar at 0°C and photol-ysed for 36-48 h with a medium pressure Hanovia lamp. Et20 (10 ml) is added to the mixture and the organic phase is separated, washed well with H20, dried (MgS04), and evaporated to yield the substituted heteroarene. 

A number of aza-aromatic A-oxides, such as pyridine, quinoline, and pyrimidine A-oxides, were converted into the corresponding a-imidazolyl-substituted heteroarenes in good yields on treatment with sulfuryl diimidazole in nonpolar solvents at elevated temperatures (Scheme 19) [45]. 

SYNTHESIS OF SF5-SUBSTITUTED AROMATIC HETEROCYCLES FROM SF5CL (SF5BR) APPLICATION OF SF5-SUBSTITUTED ALKENES AND SF5-SUBSTITUTED ALKYNES TO THE SYNTHESIS OF SF5-SUBSTITUTED HETEROARENES... 

Keywords Heteroarenes, a,p-unsaturated ketones, methanol, PdCla, room temperature. Direct conjugate addition, C-H activation, substituted heteroarenes... 

To a mixture of PdCl2 (0.025 mol, 4.4 mg) and a,p-unsaturated ketone (2 0.5 mmol) in methanol (2.0 ml), heteroarene (1 1 mmol) was added. The resultant mixture was stirred at room temperature for 24 h the solvent was then removed under vacuum. The residue was purified by flash chromatography on silica gel (eluent petroleum ether/ethyl acetate =10 1 to 20 1, v/v) to afford the substituted heteroarene 3. AU the products were characterized by spectral studies. 

Keywords Electron-deficient heteroarenes, triazenes, silver nitrate, potassium persulfate, trifluoroacetic acid, dichloromethane-water (3 5), room temperature, open-flask C-H functionalization, C-arylation, substituted heteroarenes... 

The authors have proposed a plausible mechanism for the trifluoromethylation reaction (Scheme 13.31). They assumed that a SET reduction ofCF3S02Cl224 by the photoexcited catalyst gives the oxidatively active catalyst and a CF3SO2CI radical anion 227, which rapidly collapses to generate the CF3 radical by the release of SO2 and chloride. The CFg radical then adds to a heteroarene to form the radical 228. Single-electron oxidation and subsequent deprotonation of the resulting cation 229 furnishes the trrfluoromethyl-substituted heteroarene products. 

This protocol recently rose in appeal by the observation of Gau et al. that 4 mol% of cheap [NiCl2(PPh3)2] catalyzes such aryl-alkyne couplings with an even higher efficiency [146]. Moreover, various benzyl bromides as well as bromomethyl-substituted heteroarenes were alkynylated in yields exceeding 90% when diethyl ether was used as the solvent. These nickel-catalyzed benzyl-alkynyl couplings... 

A large variety of chloride or sulfonate-substituted heteroarenes can be subjected to iron-catalyzed cross-coupling. This holds true for pyridines, pyrimidines, triazines, quinolines, isoquinolines, carbazoles, purines, pyridazines, pyrazines, quinoxalines, quinazolines, uracils, thiophenes, and benzothiazoles. In the pyridine system the presence of leaving groups of different reactivity has been demonstrated to allow for sequential introduction of different alkyl groups (Scheme 4—220). ... 

M A K O S Z A Vicarious nucleoptiiHc substitution Synthesis of akyl substituted hetsrocydss by vicai1ous nucleophilic substitution ol hydrogen in heteroarenes, nitrodenvatives ol heleroarenes. 

These effects can occur when the active site at which a measurable phenomenon occurs is in close proximity to the substituent. Among the many systems exhibiting direct steric effects are ortho-substituted benzenes, 1, cis-substituted ethylenes, 2, and the ortho- (1,2-, 2,1- and 2,3-) and peri- (1,8-) substituted naphthalenes, 3, 4, 5 and 6, respectively. Other examples are d.v-1,2-disubstiUited cyclopropanes, c/ s-2,3-disubstituted norbornanes and ci.s-2,3-disubstituted [2.2.2]-bicyclooctanes, 7, 8 and 9, respectively. Some systems generally do not show steric effects. Vicinally substituted systems such as disubstituted methanes, 10, and 1,1-disubstituted ethenes, 11, are examples, 2,3-Disubstituted heteroarenes with five-membered rings such as thiophenes and selenophenes... 

The formation of six-membered or larger rings by intramolecular C-H bond insertion normally requires the attacked position to be especially activated towards electrophilic attack [1157,1158]. Electron-rich arenes or heteroarenes [1159-1162] and donor-substituted methylene groups can react intramolecularly with electrophilic carbene complexes to yield six- or seven-membered rings. Representative examples are given in Table 4.8. 

The [Ir(OMe)(COD)]2/dtbpy catalytic system borylates indole selectively at the 2-position (Scheme 6). Smith and coworkers reported that borylation of N-unprotected 2-substituted indoles exclusively occurs at 7-position (Scheme 6) [85, 86]. It has been suggested that nitrogen interaction with the iridium center or possibly the empty p-orbital of boron in a boryl ligand induces the observed regioselectivity. Borylation of other heteroarenes have been reported using the same or similar Ir(I) and bipyridine combination [85, 87-90]. 

The silylation of heteroarenes was also reported [96]. Silylation of thiophene or furan with 11 occurs selectively at the ot-position in the presence of [Ir(COD) (OMe)]2/2-ferf-butyl-l,10-phenanthroline (tbphen, 17). Silylation of pyrrole or indole under the same conditions was unsuccessful presumably due to the presence of the acidic N-H bond. Accordingly, N-substituted pyrrole and indole undergo silylation with 11, to selectively give 3-substituted products (Scheme 7). 

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

Some heteroarylamines have been prepared by aromatic nucleophilic substitution of suitable support-bound arylating agents with amines (Table 3.27). This technique has been successfully employed in the synthesis of 2-(alkylamino)pyrimidines [507,508], 2-(arylamino)pyrimidines [509], aminopurines [510-512], and 1,3,5-triazines [513]. When the heteroarene is bound to the support as a thioether, nucleophilic clea-... 

The alkylation reaction is limited to nitro-substituted arenes and heteroarenes and is highly chemoselec-tive nucleophilic displacement of activated halogens, including fluorine, was not observed. The regio-selectivity is determined by the bulkiness of the silicon reagent. With unhindered silyl derivatives a strong preference for ortho addition was observed, as in the example of equation (6). With bulkier reagents attack took place exclusively at the para position (Scheme 1). The success of this reaction, which could not be reproduced with alkali enolates, was attributed at least in part to the essentially nonbasic reaction conditions under which side processes due to base-induced reactions of nitroarenes can be effectively eliminated.12... 

One of the most common examples of an electrophilic aromatic substitution is Friedel-Crafts alkylation [40], These days, many important industrial processes are based on this type of Friedel-Crafts-chemistry [41]. The manufacture of high-octane gasoline, ethylbenzene, synthetic rubber, plastics and detergent alkylates are examples. Moreover, the Friedel-Crafts alkylation is among the most fundamental and convenient processes for C—C bond formation on arenes, especially for the synthesis of fine chemicals and agrochemicals containing functionalized arenes and heteroarenes. 

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