Iodides Heck reaction

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

Heck reactions can be carried out in the absence of phosphine ligands.141 These conditions usually involve Pd(OAc)2 as a catalyst, along with a base and a phase transfer salt such as tetra-n-butylammonium bromide. These conditions were originally applied to stereospecific coupling of vinyl iodides with ethyl acrylate and methyl vinyl ketone. 

The Heck reaction has been applied to synthesis of intermediates and in multistage syntheses. Some examples are given in Scheme 8.9. Entries 1 and 2 illustrate both the (3-regioselectivity and selectivity for aryl iodides over bromides. Entries 3 and 4 show conditions that proved favorable for cyclohexene. These examples also indicate preferential syn Pd-H elimination, since this accounts for formation of the 3-substituted cyclohexene as the major product. 

Palladium-catalyzed carbon-carbon cross-coupling reactions are among the best studied reactions in recent decades since their discovery [102, 127-130], These processes involve molecular Pd complexes, and also palladium salts and ligand-free approaches, where palladium(O) species act as catalytically active species [131-135]. For example, the Heck reaction with aryl iodides or bromides is promoted by a plethora of Pd(II) and Pd(0) sources [128, 130], At least in the case of ligand-free palladium sources, the involvement of soluble Pd NPs as a reservoir for catalytically active species seems very plausible [136-138], Noteworthy, it is generally accepted that the true catalyst in the reactions catalyzed by Pd(0) NPs is probably molecular zerovalent species detached from the NP surface that enter the main catalytic cycle and subsequently agglomerate as N Ps or even as bulk metal. 

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... 

The Balme group [82] also used the anion capture approach to develop a short entry to triquinanes as 6/1-150 forming a transient Pdn-complex in a Heck reaction of the vinyl iodide 6/1-149 (Scheme 6/1.39). The latter reacts with the carbanion ofa malonate moiety in the substrate however, the products of the normal Heck reaction are also formed. 

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

Suitably positioned vinyl halide can undergo Heck-type intramolecular coupling to generate dienes (equations 124 and 125)216,217. When one of the reacting partners in the Heck reaction is a diene, trienes are obtained (equation 126)218. Heck coupling of ally lie alcohols and alkenyl iodides has been employed for the synthesis of vitamin A and related compounds (equation 127)219,220. A similar double Heck reaction on a Cio-diiodide with a Cis-allylic alcohol leads to -carotene as a mixture of isomers (equation 128)209e. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

Intramolecular Heck reactions.6 Heck intramolecular coupling of alkenyl or aryl iodides substituted by 3-cycloalkenyl group is an attractive route to fused, spiro, and bridged polycyclic products. Coupling is achieved with a Pd-phosphine catalyst such as Pd[P(QH5),]4 in combination with a base, N(C2H5)3 or NaOAc. The coupling tends to produce a mixture of two isomeric alkenes, in which the newly formed bond is allylic or homoallylic to the ring juncture. 

We recently focused on processes involving the reductive Heck and Domino-Heck reactions [3] in a single synthetic operation by treating aryl iodides in conjimction with this work. 

Scheme 37.2 Domino-Heck reaction of compound 1 with phenylacetylene and aromatic iodides...

We continued our work with the reductive Heck and Domino-Heck reactions [1, 7J of new bicyclic compound (3) by treating it with different aryl- and hetaryl-iodides, as a result a series of new epibatidine analogues were synthesized, continuously separated and purificated by column chromatography on silica gel. Treatment of 3 with iodobenzene, 2-iodothiophene, 1-iodonapthalene and 2-chloro-5-iodopy-ridine under reductive Heck conditions gave new compounds 4a-d and 5b, 5d as exo-regioisomers after chromatographic separations. The reactions with iodobenzene and 1-iodonapthalene gave only 5-exo- products. The use of trimethylsily-lacetylene under Domino-Heck conditions provided alkynic bicyclic systems 6e andf. 

The suitability of the polymer-Hnker conjugate was examined for a variety of transformations, in particular Pd°-catalyzed reactions. For instance, the polymer-bound aryl iodide (63) was transformed quantitatively in a Heck reaction to a cinnamic acid ester (64) and to biphenyl (66) in a Suzuki reaction. It gave an alkyne (65) in a Sonogashira reaction (Scheme 10.12). 

Halogen atoms. The introduction of side-chains on 9-trifluoromethyl-paullone 409 can be accomplished applying a Stille coupling (Scheme 86, Section 5.2.1.1 (2005EJM655)). Similarly, a Heck reaction of iodo 409 with terminal alkenes under standard conditions affords 2-substituted paullones 413 exclusively as E-isomers. The reaction of terminal alkynes with 409 in the presence of cuprous iodide and a palladium catalyst in triethylamine furnishes the 2-alkynyl-paullones 412 (2000BMCL567). 

In experiments with a supported palladium catalyst, Pd/C, satisfactory yields were obtained without the use of phosphine ligands for the Heck reactions of aryl iodide with acrylonitrile, styrene, and methyl methacrylate in the ionic liquid [BMIM]PF6 (259). The addition of triethylamine improved the yields. The Pd/C remained in the ionic liquid only. The ionic liquid containing Pd/C can be reused as... 

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