Acylates electrophilic attack

Other reports of (jj -allyl)Fe(CO)3R complexes are much more scattered and much less systematic. At least three general types of reactions have been observed in more than one case. First, the reaction of (diene)Fe(CO)3 complexes with electrophilic alkenes gives aUyhron complexes in two different ways. If the diene in question is acylic, electrophilic attack at C-1 of the diene gives compounds of type (158) (equation 33). In the case of substituted rj -cycloheptatriene-or azepine-Fe(CO)3 complexes, reaction... 

Because the position of electrophilic attack on an aromatic nng is controlled by the direct ing effects of substituents already present the preparation of disubstituted aromatic com pounds requires that careful thought be given to the order of introduction of the two groups Compare the independent preparations of m bromoacetophenone and p bromoace tophenone from benzene Both syntheses require a Friedel-Crafts acylation step and a bromination step but the major product is determined by the order m which the two steps are carried out When the meta directing acetyl group is introduced first the final product IS m bromoacetophenone... 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Acylations were often carried out with diaziridines. Twofold acylation is normally observed when two NH groups are present. Most acylations were performed with benzoyl chloride, acetyl chloride or phenyl isocyanate (B-67MI50800). Ring opening reactions during acylation, foreseeable for intermediates of electrophilic attack on nitrogen, were observed only seldom, provided mild conditions were used. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Friedel-Crafts acylation involves electrophilic attack by acyl cation (CHsCO ) on the ring, and the ring s electronic character should indicate its susceptibility to attack. Compare electrostatic potential maps of ferrocene and acetylferrocene. Which molecule contains the most electron-rich ring Which acylation reaction should be faster Does an acetyl substituent enhance or diminish ring reactivity What should be the major product when ferrocene is combined with one equivalent of acetic anhydride ... 

Selective electrophilic attack has also been demonstrated, for example, during nitration,48 chlorination,37-49 bromination,32 acylation and formylation.32k... 

Organomercury reagents do not react with ketones or aldehydes but Lewis acids cause reaction with acyl chlorides.187 With alkenyl mercury compounds, the reaction probably proceeds by electrophilic attack on the double bond with the regiochemistry being directed by the stabilization of the (3-carbocation by the mercury.188... 

Intermodular Alkylation by Carbocations. The formation of carbon-carbon bonds by electrophilic attack on the ir system is a very important reaction in aromatic chemistry, with both Friedel-Crafts alkylation and acylation following this pattern. These reactions are discussed in Chapter 11. There also are useful reactions in which carbon-carbon bond formation results from electrophilic attack by a carbocation on an alkene. The reaction of a carbocation with an alkene to form a new carbon-carbon bond is both kinetically accessible and thermodynamically favorable. 

Mononuclear acyl Co carbonyl complexes ROC(0)Co(CO)4 result from reaction of Co2(CO)8 with RO-.77 These also form via the carbonylation of the alkyl precursor. The ROC(0)Co(CO)4 species undergo a range of reactions, including CO ligand substitution (by phosphines, for example), decarbonylation to the alkyl species, isomerization, and reactions of the coordinated acyl group involving either nucleophilic attack at the C or electrophilic attack at the O atom. 

Acylation of the tryptamine-based /3-enamino esters 458 with acryloyl chloride and its derivatives results in acylation of the enamine nitrogen and formation of the pyridiniminium ion intermediate 459. Electrophilic attack at C-3 of the indole and rearrangement of the spiro intermediate gives the indoloquinolizines 460 (Scheme 102) <2003TL6527>. 

Electrophilic attack at carbon is a well-documented reaction which occurs regioselectively at the C-3 position. It was illustrated by numerous examples, including nitrations, halogenations, acylations, and Mannich reactions in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249>. Table 1 reports some additional recent examples. It should be noted that all these synthetic transformations were carried out in the field of medicinal chemistry. 

Electrophilic attack at carbon occurs regioselectively at the C-l position, although the reaction shown in Scheme 34 might interfere to give small amounts of C-3-substituted product. This was illustrated by some examples in CHEC(1984). Additional recent examples include acylations under Friedel-Crafts conditions <1998H(48)1015, 2001CPB799>. 

In systems with two oxo moieties, electrophilic attack occurs at the nitrogen of the cyclic amide. As an illustration, triazidiridine dione 32 was converted in good yield to the salt 16 upon treatment with Mel and followed by ion exchange (Equation 4) <2005H(65)1629>. Similar reactivity was observed with substrate 33, but in this case a 3/1 mixture of O-acylated and iV-acylated products 34 and 35 was obtained (Equation 5) <1997J(P1)2223>. 

Friedel-Crafts acylation of a pyrazolo[l,5- ][l,3,5]triazine derivative 137 was published by Raboisson et al. <2002TL9501> and the transformation is shown in Scheme 20. The electrophilic attack of various acyl chlorides took place in position 3 to yield the new ketones 138 in moderate to excellent yields. 

If, on the other hand, it is assumed that the initial electrophilic attack is reversible and that addition can occur above or below the plane defined by the alkenes, two diastereomeric cations woidd be formed, perhaps in approximately equal concentration. Due to the proximity of the chiral acyl group, the probability of achieving the transition states (approximately represented by 146 and 147) would be unequal and a function of the difference in sizes of groups R and R (146 and 147). 

For 9-acylations, however, it is usually unnecessary to preform an anion. Direct electrophilic attack at carbazole nitrogen can occur (see Section II,A,4) followed by loss of the N-proton to produce iV-acylcarbazoles conveniently. 

In addition to those methods described in CHEC(1984) and CHEC-II(1996) (primarily alkylation and acylation reactions), Vicentini <1996T7179> has shown that 5-methylimidazo[4,5-f]pyrazole 28 can undergo electrophilic attack on nitrogen by hydroxylamine 0-sulfonic acid to yield the 4-amino species 29 (Equation 1). 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

Among isolable metal homoenolates only zinc homoenolates cyclize to cyclo-propanes under suitable conditions. Whereas acylation of zinc alkyls makes a straightforward ketone synthesis [32], that of a zinc homoenolate is more complex. Treatment of a purified zinc homoenolate in CDC13 with acid chloride at room temperature gives O-acylation product, instead of the expected 4-keto ester, as the single product (Eq. (22) [33]). The reaction probably proceeds by initial electrophilic attack of acyl cation on the carbonyl oxygen. A C-acylation leading to a 4-keto ester can, however, be accomplished in a polar solvent Eq. (44)-... 

The protonation studies are of interest in another connection. If protonation of metallocenes can be considered to be a simple form of electrophilic attack, it is possible that other types of electrophilic substitution reactions may proceed through initial coordination of the electrophile with the central metal atom (14, 93). The mechanism of acylation of metallocenes may therefore be more complex than might be expected by analogy to similar reactions of benzenoid compounds. Clearly more studies are needed along these lines, better to define specific metal effects on the properties and reactions of these remarkable compounds. 

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