Heck arylations, oxidative

Oxidative Heck arylation of enamides with arylboronic acids, using oxygen gas as a reoxidant for Pd(0) and 2,9-dimethyl-1,10-phenanthroline as a chelating regiocontrolling ligand, yielded a (= internally) arylated reaction product as the major compound with a very good a//3 selectivity [92]. Microwave irradiation with prepressurized sealed vials proved useful in reducing the reaction time (Scheme 82). 

Another example involves dioxygen-promoted regioselective oxidative Heck aryla-tions of electron-rich alkenes with arylboronic acids (Scheme 4.12c). For this, two types of microwave reactors have been used. In a single-mode instrument (1 mmol run 25 mL vessel), the Heck arylation was performed by first pre-pressurizing the... 

Popp BV, Stahl SS (2007) Palladium-Catalyzed Oxidation Reactions Comparison of Benzo-quinone and Molecular Oxygen as Stoichiometric Oxidants. 22 149-189 Prashad M (2004) Palladium-Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical Ingredients. 6 181-204 Prestipino C, see Zecchina A (2005) 16 1-35 Pretraszuk C, see Marciniec B (2004) 11 197-248... 

Heck arylation of AMrenzyloxycarbonyl-l, 2,3,6-tctrahydropyridinc 247 with aryldiazonium salts results in formation of a mixture of unstable ct-hydroxy carbamates, which can be isolated, after oxidation, as the stable lactam derivatives. Arylation occurs preferentially at the 5-position to give lactam 248 and tetrahydropyridine 249 with 4-aryl lactam 250 being formed to a lesser extent (Equation 23) <2002TL741>. 

Eberlin also studied the Heck reaction of aryltellurides [45] and Svennebring [19] reported the identification of three types of cationic, catalytic intermediates (Fig. 4A-C) in the microwave-assisted, phosphine-containing Heck arylation of electron rich olefins. In the latter case the authors support a Pd(0)/Pd(II) cycle as opposed to a Pd(II)/Pd(IV) cycle based on ESI-MS evidence for reduction of the palladium(II) precatalyst to Pd(0) by the ligand, and oxidative addition of the aryl substrate to a Pd(0) species. None of the expected Pd-bound olefin intermediates were observed however, this is often the case either because the olefin-bound species is neutral or because OA (oxidative addition) is the turnover-limiting step and the subsequent steps occur too quickly to be observed by the sampling method (in this case sampling included quenching and dilution of samples from a reaction vessel). 

Fig. 19. Cationic intermediates in the oxidative Heck arylation of l-vinyl-2-pyrrolidinone by p-tolylboronic acid observed by ESI(+)-MS 18. ...

One of the most important transformations catalysed by palladium is the Heck reaction. Oxidative addition of palladium(O) into an unsaturated halide (or tri-flate), followed by reaction with an alkene, leads to overall substitution of a vinylic (or allylic) hydrogen atom with the unsaturated group. For example, formation of cinnamic acid derivatives from aromatic halides and acrylic acid or acrylate esters is possible (1.209). Unsaturated iodides react faster than the corresponding bromides and do not require a phosphine ligand. With an aryl bromide, the ligand tri-o-tolylphosphine is effective (1.210). The addition of a metal halide or tetra-alkylammonium halide can promote the Heck reaction. Acceleration of the coupling can also be achieved in the presence of silver(I) or thallium(I) salts, or by using electron-rich phosphines such as tri-tert-butylphosphine. ... 

Aryl halides are frequently prepared from the corresponding aryldiazonium salts by diazotation procedures. However, diazonium salts can be subjected directly to very mild Heck arylation conditions, which deliver coupled products (entry 19). Preferably, the reaction is executed in nonaqueous solvents such as acetonitrile, acetone, or methylene chloride with sodium acetate as base and with palladiumbis(dibenzylideneacetone) as catalyst. Alternatively, a combination of the amine and f-butyl nitrite, in a mixture of acetic acid and monochloroacetic acid, can provide the desired product directly, which makes the isolation of a diazonium salt unnecessary (entry 20). " It is also possible to use aromatic acid anhydrides as oxidative addition precursors (entry 21). Clearly, anhydrides are very interesting starting materials for a number of Heck reactions due to price and absence of halide salt formation. 

Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of a-olefins and organoborane compounds in good yields and with excellent regio-and stereoselectivities (Figure 6). Unlike other Heck arylation methods, no Pd-H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions. 

Andappan, M.M.S, Nilsson, R, von Schenck, H. and Larhed, M. (2004) Dioxygen-promoted regioselective oxidative Heck arylations of electron-rich olefins with arylboronic acids. J. Org. Chem., 69, 5212-8. 

A tentative mechanism for the Mizoroki-Heck arylation of carboxylic esters is shown in Scheme 7.11 [29]. The initial step of the catalytic cycle is the oxidative addition of the C(0)—O bond of carboxylic ester 47 to palladium catalyst 1, forming acylpaUadium complex 50 (1 50). Ligand exchange of alkoxide for halide (50—>... 

The directed C—H bond activation of arenes is an established technique for the regioselective functionaHzahon of (het)arenes (see Chapters 9 and 10), and was also appUed to the regioselective oxidative Mizoroki-Heck arylation of anilides (181 183 Scheme 7.44) [117]. 

Recent examples s. F. Fringuelli et al., Gazz. Chim. ItaL 779, 249 (1989) (Baeyer-Villiger oxidation) Synth. Meth. 27, 1H44 (Heck arylation) N.A. Bumagin et al., Izv. Akad. Nauk SSSR Ser. Khim. 1989, 2394 (boronic acid coupling) S.R. Wilson, M.E. Guazzaroni, J. Org. Chem. 54, 3087-91 (1989) (Luche reaction). 

SCHEME 3.20 Oxidative Heck arylation of terminal alkenes. 

While aryl halides are the substrates of choice for the neutral Heck arylations of allylamine derivatives, aryl triflates are the most used for the catimiic mode. However, as oxidative addition of Pd(0) to aryl triflates is usually slower than that with aryl bromides and iodides, bidentate ligands are commonly used to increase the stability and nucleophilicity of the Pd(0) catalyst, thus preventing the formation of Pd black (an inactive form of Pd(0)). 

Here is another approach whose biomimetic nature is more apparent than the carbanion and free radical routes we just examined. Overman (UC Irvine) anticipated that 82 could be taken to morphine through a series of standard transformations. This olefin was to be prepared from 83 via an interesting palladium-mediated reaction (a variation of the Heck arylation). Substrate 83 can clearly be recognized as an isoquinoline that is more highly reduced than in reticiiline (31), the natural substrate used in morphine biosynthesis. In essence, the oxidation states of the two aromatic rings that nature couples have been purposely differentiated. 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

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