Alkylation of heteroarenes

Scheme 19.31 Nickel/copper-catalyzed direct alkylation of heteroarenes.

The scope of the intermolecular alkylation of heteroarenes has been expanded to include pharmaceutically important pyridines and quinoHnes (Scheme 19.89) [131]. The reactions were performed at high concentration (0.8 M) with catalyst loadings as low as 1 mol%. Substitution ortho to the heterocyclic nitrogen was required for efficient alkylation at the other ortho position. In addition, increasing the bulk of this ortho substituent from methyl to isopropyl led to an increase in both the alkylation rate and the isolated yield of the alkylated product In that prospect silyl groups were found to be suitable temporary blocking groups. 

Scheme 19.97 Mechanism of the nickel-catalyzed alkylation of heteroarenes.

Ackermann has recently described the direct alkylation of heteroarenes (ben-zoxazoles and benzthiazoles) with unactivated primary alkyl halides, using a user-friendly, nitrogen and phosphorus ligand-free catalytic system derived from inexpensive [(diglyme)NiBr2]. Cul was found to be required as a cocatalyst and Nal was beneficial when using alkyl chlorides and bromides. However, the authors noted that the one secondary alkyl halide studied, 2-bromohexane, did not couple in an acceptable yield (Scheme 5.30). ... 

SCHEME 5.29 Nickel-catalyzed alkylation of heteroarenes with alkyl halides. 

One impressive strategy for a-C(sp )-H functionalization of alcohols was developed in 2015 still from MacMillan s group. Indeed, instead of expected a-C-H heteroarylation of alcohols, unprecedented alkylation of heteroarenes was... 

Scheme 3.21 Visible-light-mediated alkylation of heteroarenes with alcohols [69]...

The palladium-catalyzed hydroxy-alkylation of heteroarenes, which does not require the use of stoichiometric acid for activation of the heterocycle [6] ... 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

Beside the Friedel-Crafts-type alkylation of arenes, the direct functionalization of 2,4-pentanediones is of great interest in Lewis acid catalysis. Although Pd-catalyzed Tsuji-Trost type allylations of 1,3-diketones are known, direct benzylation procedures catalyzed by Lewis acids are less explored [40-43]. Based on the previously described Friedel-Crafts alkylation of arenes and heteroarenes, the Rueping group developed a Bi(OTf)3-catalyzed benzylation of 2,4-pentanediones. Alcohols such as benzyl, allyl or cinnamyl alcohols were used as the electrophilic component to yield important 2-alkylated 1,3-dicarbonyl compounds. Initially, different Bi(III) salts were screened. In contrast... 

This overview impressively demonstrates that Bi(III) salts are not only versatile Lewis acid catalysts for the activation of cr-donors, including benzyl and propargyl alcohols, but also efficient catalysts for the activation of Ji-donors such as styrenes or alkynes. In recent years, various environmentally benign bismuth-catalyzed methods have been developed for the alkylation of arenes, heteroarenes,... 

Arenes and heteroarenes which are particularly easy to metalate are tricarbo-nyl( 76-arene)chromium complexes [380, 381], ferrocenes [13, 382, 383], thiophenes [157, 158, 181, 370, 384], furans [370, 385], and most azoles [386-389]. Meta-lated oxazoles, indoles, or furans can, however, be unstable and undergo ring-opening reactions [179, 181, 388]. Pyridines and other six-membered, nitrogen-containing heterocycles can also be lithiated [59, 370, 390-398] or magnesiated [399], but because nucleophilic organometallic compounds readily add to electron-deficient heteroarenes, dimerization can occur, and alkylations of such metalated heteroarenes often require careful optimization of the reaction conditions [368, 400, 401] (Schemes 5.42 and 5.69). 

Only one example of an attachment of heteroarenes by addition/elimination strategy has been devised [77, 111]. Although arenes are more or less resistant toward addition, heteroaromatic systems such as isoquinolines 118 are prone to addition of nucleophiles. Subsequent reaction with addition of electrophiles furnishes the so-called Reissert compounds 120. These are stable compounds which can, for example, be alkylated. In solid-phase synthesis the electrophile chosen was a polymer-based acid chloride. Detachment can be achieved by simple addition of hydroxide ions (Scheme 6.1.30). 

Radical precursors with a five-membered heteroarene for ring D of the important anticancer and antiviral alkaloids (Camptothecin, Mappicine, Nothapodytine B, and Nothapodytine A), l-(2-halo-3-phenylprop-2-en-l-yl]-l//-pyrrole-2-carbonitriles 163, ( )/(Z) mixture, were synthesized in high yields (87-96%) by alkylation of l//-pyrrole-2-carbonitrile with the cinnamyl bromides 162 using KOH in DME (Equation 30) <2002J(P1)58>. 

M A K O S Z A Vicarious rwcleoptuHc substttutlon Synthesis of alkyl substituted heterocydes by vicarious nucleophffic substitution ol hydrogen in heteroarenes, mtrodenvatives of heteroarenes. 

Owing to its Lewis acidity, zinc complex 106 lends itself to schemes for alkylation of electron-rich arenes and heteroarenes such as pyrroles by way of conjugate addition. An even more valuable method is the 3-component condensation that unites indole with a nitroalkene and an aldehyde. Three contiguous stereocenters are established in a controlled manner and in an absolute sense by conducting the reaction in the presence of CuOTf, 126, and hexafluoroisopropanol. ... 

The Minisci reaction has successfully been applied for the alkylation of various heteroarenes, i. e. lepidine, pyrazine, quinoline and quinoxaline [2e, 2g, 10]. Organic compounds such as alkanes, alkenes, carboxylic acids, esters, amides, amines, alcohols, ethers, aldehydes, ketones, halides etc. have been successfully used as radical precursors in the Minisci reaction. A good overview of the different methods which have been applied to generate the alkyl radicals in these processes is summarized in [10b]. 

Furthermore, iminyl radicals, which are supposed to be intermediates in the annulations discussed above (see 32), have been directly generated from the corresponding oximes [56] or hydrazones [57] and applied in the intramolecular homolytic aromatic substitution. The intramolecular radical alkylation of arenes [58] and heteroarenes [59-62] was investigated by various research groups. As for the aryl radicals, the alkyl radicals used in these reactions are generally generated from the... 

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