Arylation strategy

Sanford and co-workers reported on an alternative procedure for the same reaction. Their arylation strategy occurs under milder conditions (acetic acid at 25°C) with unprotected hetaroaryls (Scheme 7.12, pathway b) [61], Instead of following a conventional Pd(0)/Pd(II) catalytic cycle, the authors proposed a Pd(II)/Pd(IV) catalytic cycle that used complex 29 and a diaryUodonium salt. 

Pandey, G., Karthikeyan, M., and Mumgan, A. (1998) New intramolecular a-arylation strategy of ketones by the reaction of silyl enol ethers to photosensitized electron transfer generated arene radical cations construction of benzannulated and benzospiroannulated compounds. Journal of Organic Chemistry, 63, 2867-2872. 

Lautens has applied the direct arylation strategy to enable the coupling of a variety of heteroaromatics as the terminal step of the Catellani reaction sequence. A variety of /V-bromoalkyl nitrogen heterocycles including indoles [77-79], azaindoles [78], pyrroles [78, 80], pyrazoles [80, 81], and indazoles [81] have successfully undergone an ortfto-alkylation/direct arylation reaction to afford a wide variety of heterocyclic products in good to excellent yields (Scheme 33). The reaction conditions... 

Scheme 1 Indole C2- and C3-arylation strategies traditional versus C-H activation.

Ma and coworkers recently utilized a double arylation strategy for an efficient synthesis of benzofuran-3-carboxylates 69 (Scheme 9.24) [125]. In the first step of this domino reaction, the Cu( I)-catalyzed chemoselective C-arylation of (3-ketoesters 67 vtith ortho-bromoiodobenzenes 66 provided the key o-bromoaryl-substituted eno-lates 68. These reactive intermediates vide supra) readily underwent the second Cu (I)-catalyzed intramolecular O-arylation, furnishing the desired benzofurans 69. The reaction tolerates a variety of substituents on both coupling partners 66 and 67, allowing for the preparation of tri- and tetra-substituted frameworks in good yields. 

Buchwald et al. expanded this methodology to access unsymmettically substituted urea derivatives with a broad substrate scope. The approach rehes on the sequential amidation of benzyl-protected urea. Functionalized unsymmetrical urea derivatives were obtained exercising an arylation/deprotection/arylation strategy. The potential of this strategy was confirmed by the short synthesis of two complex pharmaceutical target molecules (Scheme 13.82) [128]. 

The groups of Wen and Nachtsheim developed one-pot syntheses of carbazoles from cyclic diaryliodonium salts and amines using copper- and palladium-catalyzed reaction conditions, respectively. This double arylation strategy made... 

Recently, many groups have utilized the boronic acid arylation strategy in the synthesis of many biologically important molecules. The protocol developed by Evans remains the method of choice for many of these applications. 

Baran successfully employed a regioselective substrate-controlled sequential arylation strategy via Pd-mediated C—H functionalization toward the construction of the piperarborenine cyclobutane containing family of alkaloids (Scheme 3.31). At the time of publication this was the first example of sp hybridized arylation of the cyclobutane ring. Cw-disubstituted cyclobutane 36 underwent a regio- and completely diastereoselective sp C—H arylation with the listed aryl iodide to afford advanced intermediate 37. Epimerization of the resident amide followed by a successive sp C—H arylation afforded tetra-substituted cyclobutane 39. 

Once we realized that the substrate-directed arylation strategy could promote a rapid increase in the structural complexity of the allylic acetates, we decided to apply it in the total synthesis of biologically active kavalactones, represented by compound 18 in Scheme 7. The key step would be the stereoselective arylation of the substrate 19, which would lead us directly to the core skeleton of these natural products. 

A.M. Hyde, S.L. Buchwald, Synthesis of 5,5-Disubstituted butenolides based on a Pd-catalyzed y-arylation strategy, Org. Lett. 11 (2009) 2663-2666. 

In addition to carbazoles, pyrrole ring-containing PAHs such as 7/f-indolo[2,3-clquinoline 9,1 l//-indolo[3,2-c]isoquinoline 11, 9/7-pyrrolo[2,3- 4,5-c ]dipyridine 13a, 9/7-pyrido[2,3- ]indole 13b, benzo[a]pyrrolo[3,4-c]carbazole-l,3-(2//,8//)-dione 15, and 6//-indolo[3,2-fe]benzo[fe]thiophene 17 were accessible by intramolecular direct arylation strategy (Scheme 22.4) [10]. The cyclization of 3-(2-bromophenylamino)quinoline 8 and 4-(2-bromophenylamino)isoquinoline 10 was catalyzed by Pd(PPh3)2Cl2 in the presence of NaOAc in DMA and reached to... 

Scheme 16.11 An early contribution for the synthesis of a pyrrole-containing natural product by using an intramolecular C-H arylation strategy.

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Harrwig and Bnchwidd have developed a new methodology for aryladon of amines or phenols with aryl halides and palladium catiilysts This reacdon provides a very useful strategy for the preparadon of various heterocyclic compounds such as phenazines, as shown in Scheme... 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

By using a cocatalyst of Pd-Cu, aryl-alkenyl halides couple efficiently widi alkynes to generate die disubstituted alkynes (Scheme 9.6).8 This coupling reaction has been applied to die synthesis of polyphenyleneethynylenes by Yamamoto et al. in 1984 (Scheme 9.7).9a Due to the ready availability of diacetylenes and the mild coupling condition, this strategy has been widely used for die preparation of many poly(aryleneethynylene)s.9... 

For example, the sensitive imidoyl chloride moiety at the C-3 position of the pyrazinone scaffold is known to vmdergo Stille reactions with a variety of tetraaryltin reagents, generating the corresponding 3-substituted pyrazi-nones (Scheme 10) [26]. Furthermore, the transition-metal-catalyzed stannyl-ation at the C-3 position is also documented in the hterature, in view of cross-couphng with a variety of alkyl and (hetero)aryl hahdes [26]. However, this strategy is completely restricted to the C-3 position, while the Cl atom of C-5 position was found to be inert under these conditions. 

In a related strategy, ethynylphosphines (81) have been prepared with a view to synthesising polyphosphacyclopolyyne materials such as (82) (Scheme 24) [70]. Interaction between the phosphorus lone pairs and the organic 71-systems is supported by the fact that the phosphorus atoms of mono- and di-silyl-capped analogues of bis(arylphosphine) derivative (81) exhibit an unusually low inversion barrier (65 kj mol versus 130-140 kj mol for classical alkyl-or aryl-phosphines). Indeed, the rings (82) exhibit values of at ca. 300 nm, consistent with this assumption. 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

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