Double Heck arylation

In a recent article by Botella and Najera, controlled mono- and double-Heck arylations in water catalyzed by an oxime-derived palladacycle were described [22], When the reaction was carried out under microwave irradiation at 120 °C in the presence of dicyclohexylmethylamine with only 0.01 mol% of palladium catalyst (palladium acetate or palladacycle), monoarylation took place in only 10 min with a very high turnover frequency (TOF) of > 40000 (Scheme 6.3). As regards diarylation, 1 mol% of the palladacycle catalyst and 2 equivalents of iodobenzene had to be utilized to obtain moderate to good yields of diarylated product. Whereas microwave heating at 120 °C provided a 31% yield after 10 min, a 66% isolated yield of product was obtained by heating the reaction mixture under reflux for 13 h at 100 °C. Here, the... 

Scheme 6.3 Mono- and double-Heck arylations in water using oxime-derived palladacycles.

Scheme 6.5 Double-Heck arylations of chelating alkenes with aryl bromides.

Scheme 9 Double Heck arylation with an ionic liquid as solvent...

Herrmann s palladacycle = [trans-di(p-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium (II)] Scheme 3.2. Microwave-assisted double-Heck arylations of vinyl ethers. 

The same group [38] also developed a double Heck reaction which was then terminated by a Friedel-Crafts alkylation to give 6/1-54 from 6/1-53 (Scheme 6/1.12) this involved an attack of an alkylpalladium(II) intermediate on an aryl or heteroaryl moiety. Noteworthy is the finding that the formal Friedel-Crafts alkylation occurs on both electron-rich and electron-poor heteroaromatic rings, as well as on substituted phenyl rings. Single Heck/Friedel-Crafts alkylation combinations have also been performed. 

To date, only double Heck reactions have been described, but triple Heck reactions are also possible [39]. Reaction of the alkynyl aryl iodide 6/1-55 with norbor-nene in the presence of Pd(OAc)2, triphenylphosphane and triethylamine as base led to the cyclopropanated norbornene derivate 6/1-59 as a single diastereomer in 40% yield (Scheme 6/1.13). It can be assumed that the alkenyl Pd-species 6/1-56 is first formed stereoselectively, and this undergoes a Heck reaction with norbornene... 

Using a different catalytic system, the Larhed group was able to perform regio-selective microwave-promoted chelation-controlled double-/3-arylations of terminal alkenes (Scheme 6.5) [24]. In this Heck approach, the authors used vinyl ethers as chelating alkenes and aryl bromides as coupling partners, employing Herrmann s... 

The Meerwein arylation is at least formally related to the atom transfer method because a net introduction of an aromatic ring and a chlorine across a double bond is accomplished (Scheme 62). Facile elimination of HC1 provides an efficient route to the kinds of substituted styrenes that are frequently prepared by Heck arylations. Standard protocol calls for the generation of an arene diazonium chloride in situ, followed by addition of an alkene (often electron deficient because aryl radicals are nucleophilic) and a catalytic quantity of copper(II) chloride. It is usually suggested that the copper salt operates in a catalytic redox cycle, reducing the diazonium salt to the aryl radical as Cu1 and trapping the adduct radical as Cu11. 

The palladacycle 29 is either prone to reductive elimination, furnishing the minor by-product 26, or to an oxidative addition of an alkyl iodide, giving rise to an octahedral Pd(IV) species 30. Reductive elimination places the alkyl substituent in the ortho position and another CH activation furnishes the palladacycle 31. Again, an octahedral Pd(IV) intermediate 32 is obtained after an oxidative addition of an alkyl iodide. As before, reductive elimination occurs and gives an alkyl-Pd intermediate 33 that sets the stage for a jd-elimination and expulsion of norbornene. Now, the resulting ortho, ortho double alkylated aryl Pd intermediate 34 reacts with the terminal olefin and finally concludes the sequence with a Heck vinylation to give the final product 27. 

TABLE 12. Double Heck 1,1-Arylation of Acrylates and Related Compounds... 

Figure 7.17 Stereochemical rationale for double MIzoroki-Heck arylation of vinyl 2-pyrlmldyl sulfide.

By merging this one-pot double Mizoroki-Heck arylation with the subsequent a-lithiation/cross-coupling and sulfur-based cross-coupling, a programmed and diversity-oriented synthesis of tetrasubstituted olefins 50 can be realized (Figure 7.16) [25]. Moreover, by using this one-pot double Mizoroki-Heck arylation as a key step, CDP840 (a selective phosphodiesterase-4 inhibitor) can be synthesized very rapidly [26]. 

Sonesson, C., Larhed, M., Nyquist, C. and Hallberg, A. (1996) Regiochemical control and suppression of double bond isomerisation in the Heck arylation of l-(methoxycarbonyl)-2,5-dihydropyrrole. J. Org. Chem., 61, 4756-63. 

Choudary, B.M., Lakshmi Kantam, M., Mahender Reddy, N. and Gupta, N.M. (2002) Layered-double-hydroxide-supported Pd(TPPTS)2Cl2 anew heterogeneous catalyst for Heck arylation of olefins. Catal. Lett., 82, 79-83. 

Ackermann employed a different reaction order to meld 1,2-dihaloaryls together with anilines to access a series of carbazoles, including murrayafoline A (Scheme 2, equations 1 and 2) [23]. Jean and colleagues reported a tandem Suzuki/aryl-Heck protocol to prepare functionalized carbazoles and glycosinine (equation 3) [24]. Larock and Liu synthesized a series of carbazoles and the alkaloid muko-nine via an aryl-Heck reaction, which featured an aryne mediated preparation of the requisite diaryl amines [25]. Willis and coworkers reported an indole synthesis involving Heck arylation followed by double bond isomerization (equation 4) [26]. Urabe and colleagues described a similar aryl-Heck indolization from p-bromo-Al-aryl enamines giving 2-alkylindoles [27]. 

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