Alkylation Mizoroki-Heck

The above approach of an intermolecular ortho-alkylation followed by an intermolecular Mizoroki-Heck coupling was later extended to heteroaryl iodides by Lautens [48], Using a Pd(OAc)2/triarylphosphine catalyst system, 3-iodothiophene, -benzothiophene, and -indole were transformed to the o/t/zo-alkylation/Mizoroki-Heck coupling products in good to excellent yields (Scheme 17). Unfortunately, 2-iodoheteroaryls were found to be poor substrates for the reaction. 

Scheme 17 Polysubstituted heteroaryls synthesized via ortho-alkylation/Mizoroki-Heck coupling...

Scheme 18 Ortho-alkylation/Mizoroki-Heck/aza-Michael reaction...

Scheme 19 Polycyclic heterocycles synthesized via intramolecular o/t/jo-alkylation/Mizoroki— Heck coupling...

Scheme 23 Synthesis of chromans via ortho-alkylation/Mizoroki-Heck reaction...

Also the titanocene (r2 -C5H5)2TiCl216 has proved to be an excellent catalyst for a number of various alkylation reactions of alkenes and dienes such as re-gioselective double alkylation, Mizoroki-Heck type alkylation, carbosilylation, carbomagnesation, and double silylation [16]. Of special interest are the first... 

A similar situation prevails in other C-C and C-N coupling reactions since they also contain a PdL key intermediate. It is therefore no surprise that mixed NHC/phosphane ligand systems have been employed for the Mizoroki-Heck, Suzuki-Miyaura and StiUe reactions [238,255-258]. In all these cases, the incorporation of a phosphane ligand instead of the second NHC ligand improves the activity of the catalytic reaction. Similar results are reported for the allylic alkylation of dimethylmalonate using mixed NHC/phosphane palladium catalysts [252]. 

Alkenyl, Alkynyl, Aryl and Heteroaryl Acids. Treatment of readily accessible (E)- and (Z)-alkyl and aryl substituted vinyl boronates (196) with triethyl phosphite in the presence of lead diacetate results in their stereospecific transformation into (E)- and (Z)-vinylphosphonates (197) (Scheme 53). ° Palladium acetate catalysed Mizoroki-Heck reaction of arylboronic acids (198) with diethyl vinylphosphonates (199) is an effective synthetic approach to... 

The first example of an o/t/20-alkylation/Mizoroki-IIcck coupling was reported by Catellani [4] in 1997. Using the PNP dimer as a catalyst in the presence of an aryl halide, norbomene, an alkyl iodide, a terminal olefin and a base at room temperature, 1,2,3-trisubstituted benzenes (Scheme 16), were synthesized through alkylation of a palladacycle of type 35, followed by Mizoroki-Heck coupling with an arylpalladium(II) species of type 36. Although the synthetic scope of the reaction was limited, the importance of the report reveals an unprecedented catalytic transformation where two aryl C-H bonds are converted to sp2-sp3 C-C bonds followed by a standard Mizoroki-Heck coupling. The 1,2,3-trisubstitution pattern generated in the products would be very difficult to obtain via conventional methods. 

While the PNP dimer was an efficient catalyst for the ort/toalkylation/ Mizoroki-Heck reaction, the practicality of the transformation is lessened by the fact that the PNP dimer is not commercially available, and can be quite difficult to prepare. Thus, Catellani adapted the reaction conditions to include commercially available and air-stable Pd(OAc)2 as the catalyst source [46], Under these conditions, the ortho-u kylation/Mizoroki-I Ieck coupling of aryl iodides containing a pre-existing ortho substituent could be carried out. The reaction required higher temperatures, and the addition of KOAc to promote the carbopalladation of norbomene [47] and encourage the o/t/zo-alkylation pathway vs a direct Mizoroki-Heck coupling. 

Efforts have been made to explain the high rate acceleration of Mizoroki-Heck reactions in ionic liquids. The formation of the dialkylimidazol-2-ylidene palladium complex under conditions similar to those employed for the Mizoroki-Heck reaction has been studied. The C2-H proton of the imidazolium cation exhibits high acidity and can be deprotonated to form a carbene species, behaving as a good ligand for transition metals. Therefore, in the presence of a palladium salt and a base, [bmim][Br] formed the dimeric carbene complex 89, which further evolved to the monomeric c/x-90 and trans-9Q complexes. Each of these exists as an anti and a syn rotamer owing to the sterically demanding (V-alkyl substituents (Scheme 35 only the anti-90 rotamers are represented). 

Scheme 1,36 Mechanism of the Mizoroki-Heck reaction when the catalytic precursor is Pd(OAc)2 associated with dppp (i) when X = X = I, R = Ph, 0- -Bu (the formation of HPdS(dppp)+ may be by-passed if the base is strong enough to deprotonate the agostic H in the a-alkyl-PdS(dppp) complexes, see Scheme 1.37) (ii) when acetate is used as base with X = i,X= OAc, R = Ph, 0- -Bu, C02Me.

The reaction was successfully applied to both electron-rich and electron-poor 4-nitrophenyl carboxylates among them, the conversion of the electron-deficient esters was found to be faster and more efficient. Many functional groups are tolerated on both the side of the carboxylic ester (halo, keto, formyl, ester, cyano, nitro and protected amino groups, heterocyclic and a,-unsaturated carboxylic esters) and of the alkene (electron-rich alkyl-substituted alkenes, electron-poor acrylate derivatives, trimethylvinylsilane as an ethylene surrogate). The cinnamate derivatives could become particularly useful substrates, since the availability of the synthetically equivalent vinyl halides is rather limited. In analogy to conventional Mizoroki-Heck chemistry, linear (Zi)-substituted alkenes are predominantly but not exclusively obtained. Selected examples are shown in Table 4.1. 

Beside 4-nitrophenyl esters, other activated esters and amides (e.g. of pentafluorophenol, imidazole and meanwhile even 3-chlorophenol) have been shown to be viable substrates. However, substantial additional progress in catalyst development is required to extend the scope of the reaction further to carboxylic acid alkyl esters, which can be regenerated by in situ esterification. This is strictly required, as a two-step process is not likely to be able to compete with the standard Mizoroki-Heck reaction from a purely economical standpoint. 

The same group [44] also developed a double Mizoroki-Heck reaction which was then terminated by a formal Friedel-Crafts alkylation to give 70 from 69 involving an... 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

The use of pyridine (31) as additive allowed for more selective and efficient nickel-catalysed arylations of styrenes (Scheme 10.10) [32, 33]. Aryl and alkyl bromides gave good yields of isolated products. With respect to the latter, secondary alkyl bromides proved superior to primary ones. However, use of methyl acrylate (1) as substrate yielded predominantly products originating from conjugate additions, rather than Mizoroki-Heck-type reactions. 

An organometallic reaction which shows a close similarity to the Mizoroki-Heck reaction is the cobalt-catalysed [46] reaction between alkenes and organic halides. The use of [CoCKPPhsls] (59) as catalyst for intermolecular arylations of methyl acrylate (1) and styrene (2) was reported by Iyer [47] (Scheme 10.20). The para-substituted aryl iodides could be employed with this homogeneous catalyst, but the more sterically hindered ortho-substituted iodoarenes failed to undergo the desired substitution reaction. Aryl bromides and chlorides, as well as alkyl-substituted halides, proved unreactive under these reaction conditions. 

A more efficient and more generahy applicable cobalt-catalysed Mizoroki-Heck-type reaction with aliphatic halides was elegantly developed by Oshima and coworkers. A catalytic system comprising C0CI2 (62), l,6-bis(diphenylphosphino)hexane (dpph 73)) and Mc3 SiCH2MgCl (74) allowed for intermolecular subshtution reactions of alkenes with primary, secondary and tertiary alkyl hahdes (Scheme 10.25) [51, 53]. The protocol was subsequently applied to a cobalt-catalysed synthesis of homocinnamyl alcohols starting from epoxides and styrene (2) [54]. 

The catalytic system proved not only applicable to alkyl hahdes, but also allowed for the intramolecular conversion of aryl halides. Interestingly, the corresponding Mizoroki-Heck-type cyclization products were formed selectively, without traces of reduced side-products (Scheme 10.27) [55]. Therefore, a radical reaction via a single electron-transfer process was generally disregarded for cobalt-catalysed Mizoroki-Heck-type reactions of aromatic hahdes. Instead, a mechanism based on oxidative addition to yield an aryl-cobalt complex was suggested [51]. 

Scheme 10.25 Cobalt-catalysed intermolecular Mizoroki-Heck-type reaction with alkyl halides.

Microwave irradiation was applied to the synthesis of base-stable ionic liquids [210]. For example, N-alkyl-AA -dimethylethanolamine salts were prepared and used in several reactions, for instance Mizoroki-Heck reaction, polymerization or condensation reactions, with good yield (95%). 

These advances in the construction of 3-alkyl-3-aryloxindoles by catalytic asymmetric Mizoroki-Heck cyclizations laid the groundwork for the total synthesis of various members of the cyclotryptamine family of alkaloids (Figure 16.5). Three quite different strategies for exploiting asymmetric Mizoroki-Heck cyclizations to assemble structurally complex target structures were exemplified in these syntheses [70],... 

The insertion of olefins into metal-alkyl linkages is the cornerstone of the preparation of polyolefins and a-olefins, and the insertions of olefins into metal-aryl bonds is one step of a common class of palladium-catalyzed coupling reactions (the Mizoroki-Heck reaction). The insertions of olefins into early-metal-alkyl bonds is part of the so-called Cos-see mechanism of Ziegler-Natta olefin polymerization and of Cramer s mechanism for olefin dimerization. The following sections present examples of these insertion reactions and information on the mechanisms of this type of C-C bond formation. 

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