Cross acyl electrophile

There are six discrete combinations for Pd-catalyzed cross-coupling between homoallyl-, homopropargyl-, or homobenzyhnetals and alkenyl or aryl electrophiles (Scheme 4). In addition to these processes, those involving alkyl, allyl, benzyl, propargyl, alkynyl, and acyl electrophiles are conceivable, and some have indeed been observed. However, these reactions are discussed in other pertinent sections. 

For reviews of the Pd-catalyzed acylation and other cross-coupling reactions with a-hetero-substituted organic electrophiles, see ... 

Dihydropyrroles have recently become readily available by ring-closing metathesis. For this purpose, N-acylated or N-sulfonylated bis(allyl)amines are treated with catalytic amounts of a ruthenium carbene complex, whereupon cyclization to the dihydropyrrole occurs (Entries 6 and 7, Table 15.3 [30,31]). Catalysis by carbene complexes is most efficient in aprotic, non-nucleophilic solvents, and can also be conducted on hydrophobic supports such as cross-linked polystyrene. Free amines or other soft nucleophiles might, however, compete with the alkene for electrophilic attack by the catalyst, and should therefore be avoided. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Accordingly, crossed Claisen condensations occur without any problems if the acylating agent is a better electrophile than the other, nondeprotonated ester. This is the case, for example, if the acylating agent is an oxalic ester (with an electronically activated carboxyl carbon) or a formic ester (the least sterically hindered carboxyl carbon). 

This mechanistic sequence (Sch. 4) wherein the triplet excited enone adds to the alkene, either via an exciplex intermediate or directly, to afford triplet 1,4-biradicals, which (after undergoing intersystem crossing) either cyclize to product(s) or revert to ground state reactants, is confirmed by both semi-empirical and ab-initio calculations [21-24], The origin of regioselectivity is supposed to stem from the primary binding step, the enone triplet being considered as a (nucleophilic) alkyl radical at C(3) linked to an (electrophilic) ot-acyl radical at C(2) [25], Thus additions of C(2) to the less substituted terminus of electron rich alkenes and of C(3) to the least substituted terminus of electron deficient alkenes should occur preferentially [26],... 

However, the azepine yield was low when a 5-OMe substituent was present, and no azepine was formed from the 5-N02 compound. This is possibly due to a rapid singlet-triplet crossing in the nitro compound the triplet nitrene then gives the corresponding azo compound.258 With the acyl group in meta or para position with respect to the nitrene, the azepine yields were lower. It was concluded that a reasonably electrophilic singlet nitrene is essential for azepine formation.258... 

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

Reactions of Pyrroles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104). Electrophilic substitution of pyrrole with MeaC or Me FC in the gas phase occurs mainly at the j3-position, as does nitration and Friedel-Crafts acylation of l-phenylsulphonylpyrrole2 Pyrrole-2,5-dialdehyde has been prepared by Vilsmeier-Haack formylation of the ester (105), followed by hydrolysis. A similar method has been used to convert the di-acetal (106) into pyrrole-2,3,5-tricarbaldehyde. AT-Benzoyl-pyrrole reacts with benzene in the presence of palladium(II) acetate to yield a mixture of l-benzoyl-2,5-diphenylpyrrole, the bipyrrolyl (107), and compound (108). Treating lithiated A-methylpyrrole with nickel(II) chloride results in the polypyrrolyls (109 = 0-4). 2-Aryl-1-methylpyrroles are obtained by cross-coupling of l-methylpyrrol-2-ylmagnesium bromide with aryl halides in the presence of palladium(0)-phosphine complexes. ... 

Good crossed aldol condensations require one component to enolize and act as a nucleophile and the other not to enolize and to act as the electrophile. Here follows a list of carbonyl substituents that prevent enolization and therefore force a carbonyl compound to take the role of the electrophilic partner. They are arranged roughly in order of reactivity with the most reactive towards nucleophilic attack by an enolate at the top. You do, of course, need two substituents to block enolization so typical compounds also appear in the list. Note that the last two entries—esters and amides—do not normally do aldol reactions with enolates, but they do react as acylating agents for enolates, as you will see later in this chapter. 

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