Arylation Processes

The novel synthesis of chromanocoumarans illustrated in Scheme 159 constitutes a modification of the Heck arylation process (cf. Eq. 14 in Section IV,B,1) in which arylation of a 2H-chroman is followed by intramolecular nucleophilic displacement of the palladium moiety.235... 

In the search for more economical, tailored CH arylation processes, cheaper transition metals were employed for... 

Another useful method for effecting the ring closure of the bromo- and iodoaryl enaminones 166 (Z = Br, I) featured an intramolecular electrophilic arylation process involving benzyne intermediates (127). For example, treatment of 166 (Z = Br, I) with lithium diethylamide at room temperature afforded the pyrrolophenanthridone 169. When 169 was treated with oxygen in aqueous ethanol containing potassium hydroxide, the vinylogous imide 168 was produced... 

Although introduced separately, transmetalation (catalytic Cycle 2) and cyclopal-ladation (catalytic Cycle 1) were found to be competitive processes under given arylation reaction conditions. Because 6 is ineffective in catalyzing the desired transformation, any condition that favors its formation (fast C-H bond activation before transmetalation) would inhibit the arylation process. Thus, substrates that form stable five membered cyclopalladated complexes will fail to undergo the arylation reaction (see Section 1.4.3). 

The enolate anions of 2-acetylthiophene and 2-acetylfuran have been arylated under photochemical conditions in the presence of t-BuOK and good electron donors such as acetone enolate (entrainment reaction) to give the corresponding benzyl 2-thienyl and 2-furanyl ketones respectively. Use of FeBr2 as initiator in a dark reaction gives good yields of the substitution products without the need for added nucleophiles, and it is suggested that these arylation processes occur by an SrnI mechanism. 

The second step of the arylation process involves a coupling reaction between two of the ligands linked to the bismuth atom. Various mechanistic pathways were considered to be possible. Study of the relative migratory aptitudes of aryl groups indicated that the C-phenylation reaction with either a phenol or a p-dicarbonyl does not follow an ionic pathway. Although these migratory aptitudes were of the same order as a free-radical type, the relative ratios are more consistent with a non-synchronous concerted mechanism.26... 

Over the past decade, significant advances have been made in the transition-metal-catalyzed aryl-aryl bond formation through C-H activation (for reviews see [23-32]). In this direct arylation reaction one of the preactivated reaction partners is replaced by a simple arene. This direct arylation process is not only just of academic interest but also attractive for industrial applications, since only one preactivated reaction partner is needed. Obviously, the cost of the reaction will be reduced by... 

No rationale is provided for the particular catalytic efficiency of the [Rh(CO)2Cl]2 for this transformation, or for the suppression of catalytic activity in the presence of ligands that improve the reactivity in closely related reactions [176], Nevertheless, this reaction is likely to share a common mechanism with other heterocyle arylation processes that include heterocycle coordination, C-H insertion and tautomerization to the rhodium(I) NHC complex, oxidative addition to the bromoarene, and reductive elimination of the arylated heterocycle (Scheme 20). 

The general reaction mechanism has been shown to involve typical steps for cross-coupling [98, 113]. Oxidative addition of an aryl halide generates a Pd(II) species that undergoes transmetalation to form a Pd(II)-thiolate. C-S reductive elimination provides the aryl sulfide and regenerates the Pd(0) catalyst. More recently, Hartwig reported a detailed mechanistic analysis of the Pd/Josiphos system derived from different Pd precursors. The dominant Pd species were found to be off the catalytic cycle, which accounted for differences in rates between stoichiometric and catalytic reactions [114]. Thioketones are also effective thiolate nucleophiles for C-S bond formation. The reaction involves tandem Pd-catalyzed thioenolate alkylation, followed by 5-arylation (8) [102]. Presumably, the arylation process proceeds by a similar mechanism to related Pd-catalyzed transformations. 

Combination of the oxidative addition of aryl halide with olefin insertion followed by -hydrogen elimination provides a useful olefin arylation process catalyzed by a palladium complex (Mizoroki-Heck reaction) [63-65]. The essential part of the catalytic cycle is shown in Scheme 1.23. 

From a mechanistic point of view, the authors proposed a tandem orf/zo-alkylation/direct C2-arylation process (Scheme 10), where the initial Pd(II)-aryl species undergoes norbomene-assisted ortho-alkylation via a... 

Regioselective (site-selective) functionalization of unsaturated haloge-nated nitrogen, oxygen, and sulfur heterocycles by Pd-catalyzed cross-couplings and direct arylation processes 07CSR1036. 

In a substrate-dependent, palladium-catalyzed domino N-benzylation/ intramolecular direct arylation process, tosylamides 133 and 2-bromobenzyl bromides 134 reacted to form dibenzo-l,2-thiazepine dioxides 135 exclusively, or gave mixtures that also contained 6,7-dihydro-5H-dibenzo[c,e] azepines 136 (14JOC10899). 

Hallberg s group deliberately introduced y6-amino tethers for the /3-selective arylation of vinyl ethers. They further extended this system to chiral substrates for diastereoselec-tive arylation processes. Similar to their systems, Badone introduced /3-phosphino tethers for the /3-selective arylation of vinyl ethers. Tamaru has reported carbamate directing... 

The base and the solvent for the direct coupling reactions are important. Because the net direct arylation process liberates acid as a byproduct, base is typically required. Often, inorganic bases such as KjCOj, CSjCOj, KOAc, KO Bu, and CsOPiv are used. Tlie yields and rates depend on the identity of the base, and some data imply that the base participates in the reaction more intimately than simply to quench released acid. In some systems the base may be involved in the formation of the penultimate diarylpalladium(ll) species. As discussed in Section 19.9.2, this process is believed to occur via either an Sj3 or a concerted process involving metalation and deprotonation (Scheme 19.16). Of the above carboxylate bases, Cs COj and CsOPiv have proven to be the most effective and most commonly employed, due to their higher solubility in organic solvents than the other bases listed. 

Thus, direct arylation reactions are becoming a useful synthetic tool. However, one must be able to control the regioselective in a more general fashion. In addition, catalysts are needed that enable high yielding, direct arylation processes at lower temperatures. 

A number of interesting one-pot or two-pot sequences of PdNegishi coupling followed by intramolecular C—N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield. 

Figure 4.2 (a) Generic description of C-H activation arylation processes, (b) C -H activation via chelate-assisted C-H activation, (c) The distinction between direct arylation and dehydrogenative cross-coupling. 

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