Intramolecular acylation reaction

Stereoselective Acylations. Intramolecular Ftiedel-Crafts acylation reaction of A/-ataLkyl a-amino acid detivatives gives cycHc ketones with high enantioselectivity (100). This methodology has been used for the enantiospeciftc syntheses of tylophorine [482-20-2] and cryptopleutine [87302-53-2] the ptincipal representatives of phenanthroiadolizidine and phenanthroquiaolizidine alkaloids (qv) (101). 

Interesting results have been obtained in intramolecular acylation reactions involving pyrrole and thiophene derivatives. A muscone synthesis involves selective intramolecular acylation at a vacant a-position (Scheme 18) (80JOC1906). In attempts to prepare 5,5-fused systems via intramolecular acylation reactions on to a jS-position of a thiophene or a pyrrole, in some cases ipso substitution occurs with the result that rearranged products are formed (Scheme 19) (82TH30200). 

The Reforrnatsku reaction of a-halogenated carboxylic esters with silylated cyanohydrins combined with an intramolecular acylation reaction gives fluorinated derivatives of tetronic acid [28] (equation 17) It is noteworthy to mention that this particular reaction sequence only proceeds with ultrasonic irradiation A very... 

Each of the compounds indicated undergoes an intramolecular Friedel-Crafts acylation reaction to yield a cyclic ketone. Write the structure of the expected product in each case. 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

It has been suggested that the kinetic preference for formation of (3,y-unsaturated ketones results from an intramolecular deprotonation, as shown in the mechanism above.51 The carbonyl-ene and alkene acylation reactions have several similarities. Both reactions occur most effectively in intramolecular circumstances and provide a useful method for ring closure. Although both reactions appear to occur through highly polarized TSs, there is a strong tendency toward specificity in the proton abstraction step. This specificity and other similarities in the reaction are consistent with a cyclic formulation of the mechanism. 

The acylation reaction has been most synthetically useful in intramolecular reactions. The following examples are illustrative. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

An alternative route to anthraquinone, which involves Friedel-Crafts acylation, is illustrated in Scheme 4.3. This route uses benzene and phthalic anhydride as starting materials. In the presence of aluminium(m) chloride, a Lewis acid catalyst, these compounds react to form 2-benzoyl-benzene-1-carboxylic acid, 74. The intermediate 74 is then heated with concentrated sulfuric acid under which conditions cyclisation to anthraquinone 52 takes place. Both stages of this reaction sequence involve Friedel-Crafts acylation reactions. In the first stage the reaction is inter-molecular, while the second step in which cyclisation takes place, involves an intramolecular reaction. In contrast to the oxidation route, the Friedel-Crafts route offers considerable versatility. A range of substituted... 

Fig. 2.30. Intramolecular acylation reactions with carbene-derived vinylketene complexes. Table 2.20. Preparation of five-membered rings by cyclization of vinylketene complexes.

Intramolecular acylation reactions with ketene complexes, generated, for instance, by thermolysis or photolysis of carbene complexes, can also be used for the preparation of six-membered rings. Illustrative examples are shown in Table 2.23. 

Further methods for preparing seven-membered rings with the aid of heteroatom-substituted carbene complexes include the intramolecular acylation reactions with ketene complexes discussed in Section I.2.6.2. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

In this section, we will focus on intramolecular functionalization. Such reactions normally achieve selectivity on the basis of proximity of the reacting centers. In acylic molecules, intramolecular functionalization normally involves hydrogen-atom abstraction via a six-membered cyclic transition state. The net result is introduction of functionality at... 

The electron-rich thiophene ring system can be annelated by intramolecular Friedel-Crafts acylation reactions to give fused thiophenes <99IJC648, 99JMC2774>. The synthesis of a thiophene isostere of ninhydrin involved an intramolecular Friedel-Crafts acylation <99SL1450>. Specifically, treatment of thiophene 86 with thionyl chloride followed by aluminum chloride gave annelated thiophene 87. The synthesis of isothianinhydrin 88 was then accomplished in six steps from 87. 

Ring closure by an intramolecular acylation reaction followed by a halogenation-dehydrohalogenation sequence (equation 70) may account for the isolation of the... 

On HY, phenylacetate dissociates into phenol and ketene (reaction a). Ortho-hydroxyacetophenone is produced partly by the Fries rearrangement of phenylacetate (intramolecular reaction, reaction b) and by trans-acylation (reaction c) while para-hydroxyacetophenone is exclusively the result of trans-acylation (reaction d). Phenylacetate can also disproportionate into phenol and acetoxyacetophenones (reaction e). Para-acetoxyacetophenone can also be formed through transesterification between para-hydroxyacetophenone and phenylacetate (reaction f).The formation of secondary products like 2-methylchromone and 4-methylcoumarine is consecutive to the formation of... 

The acylation is thought to occur as shown in Scheme 3. The ir-allyl intermediate (5) was isolated in 86% yield and characterized by X-ray analysis.13 The NMR spectrum and crystal structure of (5) indicate that only the anti-al y structure is formed no other positional isomers were detected. The iron atom in (5) obtains a closed-shell electron configuration by intramolecular o-donation of a lone pair of electrons from the acyl oxygen atom, which is confirmed by a lowering the acyl CO bond order (vco 1637 cm-1).12 There is no direct evidence for formation of (4) its intermediacy has been suggested primarily based on the endo stereochemistry of the acylation reaction (see below). 

Alkylation or acylation reactions of dihydroazines can proceed as intramolecular processes and follow with heterocyclizations [308, 310] (Scheme 3.98). 

The cyclization phase of the process is an intramolecular Friedel-Crafts acylation reaction. It requires conversion of the carboxylic acid to the acyl chloride (thionyl chloride is a suitable reagent) followed by treatment with aluminum chloride. 

Intramolecular Friedel-Crafts acylation reactions that produce five-membered or six-membered rings occur readily. Cyclization must take place at the position ortho to the reacting side chain. 

All these products of cyclization would contain two fused five-membered rings mutually fused to a benzene nucleus. This structure, formula XLVIII, represents a highly strained system. On the other hand, thp basic polycyclic structures represented by formulas XLIX through LIT can be formed by the intramolecular acylation reaction.10 3[Pg.124]

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Finally, the intramolecular version of the Friedel-Crafts acylation reaction has proved to be very valuable in the construction of polycyclic compounds, as illustrated in the following equation ... 

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