Heteroaryl chlorides

Besides sulfonamides, chiral sulfoximines have also been used in C - N bond formation under microwave irradiation [103]. The only heteroaryl chloride used in the study—namely, 2-chloropyridine—gave the desired M-(pyridin-2-yl)sulfoximine at a yield of 43% (Scheme 101). Interestingly,... 

A mild and efficient a-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described <06OL1447>. Treatment of 2-chloro-benzo[//Jthiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[c(jthiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed a-arylation reactions. First, heteroaryl chlorides... 

The dealkylative functionalization of tertiary amines 23 with electron deficient heteroaryl chlorides including triazinyl chloride 24 has been published <06TL2229>. Efficient and practical reaction conditions were determinated for a range of substrates. 

There is certain similarity in the order of reactivities between SnAt displacement reactions and oxidative additions in palladium chemistry. Therefore, the ease with which the oxidative addition occurs for these heteroaryl chlorides has a comparable trend. Even a- and y-chloroheterocycles are sufficiently activated for Pd-catalyzed reactions, whereas chlorobenzene requires sterically hindered, electron-rich phosphine ligands. 

The implications of these discoveries in heterocyclic chemistry reside on the Suzuki coupling of non-activated heteroaryl chlorides. Extensions of these methods to the Suzuki couplings using inexpensive heteroaryl chlorides will be an important development. 

Normally, the oxidative addition of an aryl chloride to Pd(0) is reluctant to take place. But such a process is greatly accelerated in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(/-Bu)3 or tricyclohexylphosphine]. In late 1990s, Reetz [76] and Fu [77] successfully conducted intermolecular Heck reactions using arylchlorides as substrates, as exemplified by the conversion of p-chloroanisole to adduct 77 [77], The applications of this discovery will surely be reflected on future Heck reactions of non-activated heteroaryl chlorides. 

The reaction of aryl electrophiles with organomagnesium compounds is known as Kumada or Kumada-Tamao-Corriu reaction. The most common leaving groups in the electrophile are halogen atoms and, among them, chlorine is the most wanted due to the good availability and the low price of aryl or heteroaryl chlorides. Unfortunately, the oxidative addition of a metal center to an aryl chloride is a difficult reaction and many efforts have been made to overcome existing limitations. 

TABLE 6. Cross-coupling between alkyl Grignard reagents and aryl or heteroaryl chlorides, triflates, and tosylates... 

Furstner and coworkers also reported various examples of coupling with nitrogen heteroaryl chlorides (Table 7). In all cases, at least two equivalents of phenylmagnesium bromide are required and the yield never rises above 71%. 

Potassium hydroxide in DMSO has proved a useful reagent to promote the reaction of activated aryl and heteroaryl chlorides with long chain primary alcohols, to form the corresponding ethers (equation 16).157 The procedure failed with secondary alcohols. 

Reaction of 9-chloroacridine with aryl sulfonyl hydrazides results in aminodechlo-rination to give the corresponding A-acridinylbenzenesulfonyl hydrazides kinetic studies in methanol and DMSO have been reported.44 Reaction of electron-deficient heteroaryl chlorides with tertiary amines may proceed by quaternization and dealkylation, as shown in Scheme 3. These reactions occur under mild conditions, e.g. acetonitrile solvent at room temperature, and in THF may be accelerated by the addition of lithium chloride.45... 

Although aryl chlorides are not usually reactive enough to couple efficiently with alkyl-coppers, heteroaryl chlorides often couple quite well. For example, the most efficient way of alkylating chlorinated phenanthrolines and quinolines, and both 2- and 3-substitued pyridines involves the use of Grignard reagents and copper salts (equation 51)73. 

Senanayake also demonstrated that the amination reaction could be effected with several related heteroaryl chlorides [34, 87]. The coupling of piperidine with several heteroarene substrates proceeded in good yield, Eq. (161). 

Rouden described the amination of the heteroaryl chloride below with several primary amines using the BINAP/Pd-catalyst, Eq. (163)[130].The resulting products were new ligands for serotoninergic receptors. 

Under solvent-free conditions, imidazole and benzimidazole were efficiently arylated by aryl/heteroaryl chloride or bromide, catalyzed by copper(l) bromide in the presence of 2-aminon,6-dihydroxypyrimidine 220 as a ligand and TBAF as a base <2006JOC8324>. Even sterically crowded 2-methylimidazole and 2-methylbenzimidazole were efficiently arylated with high yields. However, arylation of 2-phenylimidazole with 2-chloropyrimidine gave only a trace of product while arylation of 2-methylimidazole with the same aryl chloride afforded the product in quantitative yield. 

When treated with TBAF in DMF, 2-bromobenzimidazole was converted into 2-fluorobenzimidazole (24% yield) <2001JBS417>. TBAF in DMSO was found to be very efficient in converting electron-deficient aryl and heteroaryl chlorides, including 2-chlorobenzimidazole 252, into their fluoro analogues, even at room temperature, in high yields (Scheme 63) <2006AGE2720>. 

It is important to notice that certain A -heteroaromatic chlorides are much more readily carbonylated, due to the reduction of electron density in the aromatic ring and stronger polarization of the C-Cl bond. An overview of the alkoxycarbonyl-ation of A-heteroaryl chloride has been published recently [50b]. 

A plausible mechanism for the above reaction involves oxidative addition of the heteroaryl chloride to Pd(0) to provide Pd(II) intermediate 75, which subsequently inserts into benzoxazole to form the arylpalladium(II) complex 76. P-Hydride elimination of 76 would afford 11 with concomitant regeneration of Pd(0) for the next catalytic cycle. 

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