Heck-Mizoroki reaction allylation

Coupling reactions that are included in this chapter are the Heck-Mizoroki reaction, the Suzuki-Miyaiu-a reaction, the Sonogashira reaction, the Kumada-Corriu reaction, the Negishi reaction, allylic substitution and arylation via CH-activation. 

The Pd(0)-catalyzed reactions of Ar-X and B-H (or B-Y) can be expressed by the following general equations, which involve no oxidation. The Mizoroki-Heck reaction, allylation of nucleophiles, and cross-couplings are typical reactions of this type. They are treated in Chapters 3-8. 

Since the early reports by Mizoroki, Heck and others, allylic alcohols 1 have been elusive substrates in the Mizoroki-Heck reaction (Figure 7.4) [5], When an insertion of ArPdX to C=C results in an organopalladium intermediate with palladium on the j8-carbon of allylic alcohol, which is often the case, there are hydrogen atoms available at the a- (Ha) and y-carbon (H ) in the subsequent 8-elimination step (Figure 7.4). It has been known from the early days that the treatment of allylic alcohol (1) with iodobenzene under typical... 

Shibasaki and coworkers [40] also demonstrated the use of soft carbanionic nucleophiles, initially sodium dimethyl malonate, in cascade asymmetric Mizoroki-Heck cyclization- j -allyl trapping sequences. This conversion succeeds with various soft carbanionic nucleophiles to provide functionalized bicyclo[3.3.0]octane derivatives 55 in excellent yields (72-92%) and up to 94% ee (Scheme 16.13). The enantioselectivity of these Mizoroki-Heck reactions is significantly diminished in the absence of NaBr a speculative rationale to account for the effect of the NaBr additive has been advanced [40]. 

Allylic esters act as effective conpling partners (Scheme 22.28). Electron-rich substituents on the aromatic moiety of the carboxylic acids provide the expected Mizoroki-Heck products in high yields. On the other hand, 2,6-diflnoro-, 2,4,6-triflnoro-, and perfluorobenzoic acids afford only very low yields of the Mizoroki-Heck prodncts. Substituted allylic esters react efficiently in this ARCIS reaction [17]. 

Related reactions, that have been catalysed by NHC/Pd systems, are the intramolecular Mizoroki-Heck using catalysts formed in situ from imidazolium salts and a Pd(0) source [69], and the arylation of allylic alcohols by a benzothiazole-Pd complex [70,71] (Scheme 6.14). 

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]. 

There are a host of palladium-catalyzed C-C coupling reactions that have been developed since the mid-1960s, but only a couple of specific examples will be covered here (cf. Ref 14, 14a). Tsuji discovered Pd-catalyzed tr-allyl and carbon nucleophile coupling reactions in 1965.Mizoroki and Heck " separately developed vinylic coupling reactions (Equation (16)) in the early 1970s, and this is commonly referred to as a Heck reaction or coupling. 

By far most the popular class of the allylic substrates in the Mizoroki-Heck reaction has been allylic alcohols, partly due to their ubiquitousness, but also due to the possibility of testing and developing catalytic systems for regiocontrol, as this coupling often results in mixtures of isomers. Reactions under Jeffery conditions are known to result in terminal insertions (Figure 3.24) [79], and similar reactions with vinylic triflates instead of halides are also well known (Figure 3.25) [80]. 

Figure 3.25 Terminal selectivity in the Mizoroki-Heck reaction with a vinylic triflate and an allylic alcohol.

Of course, syntheses of annulated aromatic compounds via classic Mizoroki-Heck reaction of aryl (pseudo)halides are prevalent a selection of substrates with open-chain allyl moieties is depicted in Scheme 5.4. Simple aryl iodide 19a was cyclized in high yield (90%), but in a 60 40 mixture of exocyclic and endocyclic double-bond isomers (19a -> 20a) [21]. A structural modification, conjugation with an ester group, a recurrent motif in Mizoroki-Heck chemistry, allowed for preparation of isomerically pure 20b in 74% yield (19b 20b) [22]. In the second example, reaction of pyridine 21 leads to an intermediate... 

There are more examples of 5-exo-cyclizatzion via intramolecular Mizoroki-Heck reaction than of any other compound class, among which substructure A (Figure 6.3) with an allyl side chain constitutes the most widespread substrate. 

Another often encountered substructure for intramolecular 5- xo-Mizoroki-Heck reactions is allyl side chain containing vinyl halide D (Figure 6.3) [73, 74], Based on this substrate structure, a series of 3-substituted pyrrolo[2,3-b]quinoxalines have been prepared via intramolecular Mizoroki-Heck reaction under Jeffery s ligand-free conditions in moderate to excellent yields (Scheme 6.25) [75]. 

Allylic alcohols and amines are typical substrates that bear directing heteroatoms within the main substrate structure. Under suitable conditions, oxygen and nitrogen atoms in allylic alcohols and amines participate in the Mizoroki-Heck reaction through O—Pd or N—Pd coordination, bringing about some chelation effect in the outcome of reactions. 

Jeffery has reported an alternative additive-based solution to yield Hy-abstracted products. Mizoroki-Heck reaction of allylic alcohols with aryl or alkenyl hahdes in the presence of silver salts (AgOAc or Ag2C03) results in selective Hy -abstraction [7]. Similar hydroxy-coordination to the cationic organopalladium intermediates are believed to be involved in this system. In this regard, the use of hypervalent iodonium salts is also effective for generating cationic palladium species [8]. 

Figure 7.8 Directed Mizoroki-Heck reaction of allylic amines.

One distinguishes palladium(0)- and palladium(ll)-catalysed reactions. The most common palladium(O) transformations are the Mizoroki-Heck and the cross-coupling transformations such as the Suzuki-Miyaura, the Stille and the Sonogashira reactions, which allow the arylation or alkenylation of C=C double bonds, boronic acid derivates, stan-nanes and alkynes respectively [2]. Another important palladium(O) transformation is the nucleophilic substitution of usually allylic acetates or carbonates known as the Tsuji-Trost reaction [3]. The most versatile palladium(ll)-catalysed transformation is the Wacker oxidation, which is industrially used for the synthesis of acetaldehyde from ethylene [4]. It should be noted that many of these palladium-catalysed transformations can also be performed in an enantioselective way [5]. 

A combination of a Mizoroki-Heck reaction with an intramolecular aldol condensation is observed on treatment of aromatic aldehydes or ketones such as 184 with allylic alcohols 185 as described by Dyker and coworkers [102]. The palladium-catalysed reaction led to 187 via 186 in 55% yield (Scheme 8.48). 

Allylic Substitution (Tsuji-Trost)/Mizoroki-Heck Reaction... 

The palladium(0)-catalysed nucleophilic substitution of allylic acetates, carbonates or halides, also known as the Tsuji-Trost reaction, is a powerful procedure for the formation of C—C, C—O and C—N bonds. One of the early impressive examples, where this transformation had been combined with a pallada-ene reaction, was developed by Oppolzer and Gaudin [126], Although, in general, the Tsuji-Trost reaction can be combined with other palladium-catalysed transformations, there are only a few examples where it is combined with a Mizoroki-Heck transformation. 

In their enantioselective total synthesis of the alkaloid cephalotaxine (246), Tietze and Schirok [127] used a combination of a Tsuji-Trost and a Mizoroki-Heck reaction (Scheme 8.62). It was necessary to adjust the reactivity of the two palladium-catalysed transformations to allow a controlled process. Reaction of 243a using Pd(PPh3)4 as catalyst led to 244, which furnished 245 in a second palladium-catalysed reaction. In this process, the nucleophilic substitution of the allylic acetate is faster than the oxidative addition of the arylbromide moiety in 243a however, if one uses the iodide 243b, then the yield drops dramatically due to an increased rate of the oxidative addition. 

A combination of a Tsuji-Trost and a Mizoroki-Heck reaction was also used by Poli and coworkers [130] for the synthesis of the aza analogues 254 of the antimicotic podophyl-lotoxin (249a) and the cytotoxic etoposide (249b) (Scheme 8.64) [131]. For the synthesis of 254, compound 250, obtained from piperonal and the amide 251 containing an allyl acetate moiety, was transformed into 252, which served as the starting material for the... 

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