Intramolecular acyl substitution

The first step of the Stobbe condensation is the deprotonation of the succinate at the a-carbon to afford an ester enolate that in situ undergoes an aldol reaction with the carbonyl compound to form a 3-alkoxy ester intermediate. The following intramolecular acyl substitution gives rise to a y-lactone intermediate which undergoes ring-opening and concomittant double bond formation upon deprotonation by the alkoxide ion. Under certain conditions the lactone intermediate can be isolated. 

A completely different approach initially involves the addition of the carbanion of ethyl 2-cyanoacetate 142 in the presence of base to the imine group of 2-naphthylsulfonyl hydrazone 147 followed by cyclization and oxidation to pyrazol-3-one 150 (02NN469) (Scheme 34). The reaction requires heating in ethanol with triethylamine and it is suggested that intermediate 148 is first produced, and then undergoes an intramolecular acyl substitution resulting in the unstable pyrazol-3-one 149. The latter is prone to oxidation by molecular oxygen and is converted to stable pyrazol-3-one 150. 

Less vigorous conditions than those described above converted diethyl (ethoxymethylene)malonate 205 and (3,4-dimethylphenyl)hydra-zine monohydrochloride 206 into pyrazol-3-one 208 (01JMC3730, 04H2537) (Scheme 46). The reaction took place in ethanol or methanol containing aqueous potassium carbonate via conjugate substitution of ethoxide ion, intramolecular acyl substitution and tautomerization of intermediate pyrazol-3-one 207. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

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). 

Intramolecular acylation of suitably 1-substituted 1,2,3,4-tetra-hydro-/8-carbolines has been studied. It has been stated that... 

THF) at room temperature (Scheme 18) (95T8605). The proposed mechanism for this conversion involves the abstraction of H3 by basic attack of NaH to give an enolate anion, which, via ring opening, affords the 2(5//)-furanone 61 by a straightforward intramolecular nucleophilic acyl substitution (Scheme 18) (95T8605). 

The. synthesis starts with the Stobbe condensation of diethylsuccinate and 3,4-dichloroben-zophenone (13). The product (14) is hydrolyzed and decarboxylated to a cis-trans mixture of olefins (15). This last is reduced using a Pd/C catalyst and then undergoes unidirectional Friedel-Crafts intramolecular acylation into the more reactive ring to produce substituted tetralone 16. 

The following reaction involves a hydrolysis followed by an intramolecular nucleophilic acyl substitution reaction. Write both steps, and show their mechanisms. 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

Fused octahydrocycl[3.2.2]azines of the type 392 are obtained by tandem cycloadditions of pyridinium phenacylide with iV-substituted maleimides <1989JOC420>, and other types of fused octahydrocyclazines, viz. 394, result from the attempted preparation of the enamines 393, since these are unstable and undergo intramolecular acylation <1999T1763> (Scheme 114). 

In 1984, we demonstrated that A-alkoxy-A-acyl nitrenium ions 15 could be generated by the reaction of A-alkoxy-A-chloroamides 14 with Lewis acids such as Ag + and Zn2+ and used these to form heterocycles by intramolecular aromatic substitution reactions (Scheme 2).90 In this manner, several novel A-acyl-3,4-dihydro-2,l-benzoxazines 16a and A-acyl-4,5-dihydro-( I //,3//)-2,1-benzoxazepines 16b were made. Subsequent work91,92 and that of Kikugawa93 96 produced numerous syntheses involving alkoxynitrenium ions including formation of natural products.97 99... 

Intramolecular Nucleophilic Acyl Substitution (INAS) Mediated by 1... 

Intermolecular nucleophilic acyl substitution is a fundamental carbon—carbon bondforming reaction. In spite of its high synthetic potential, however, its intramolecular version, that is, intramolecular nucleophilic acyl substitution (INAS) is rather rare because of the intrinsic difficulties involved in carrying it out. One difficulty associated with the INAS reaction is that a reactive nucleophilic species must be generated in the presence of carbonyl functionality, and at the same time this nucleophile is expected to react only with... 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

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. 

Intramolecular acylations of substituted thiophenes have been used for over 20 years as an entrance into thiophenophanes (63T1851), and the procedure has recently been extended... 

Intramolecular acylation of thiophenes has been thoroughly examined and shown to provide a reasonable route to substituted cycloalkanones on desulfurization of the bicyclic products (53BSF62, 73BSF343). A variety of five-, six- and seven-membered ring systems have been constructed, e.g. (285) — (287). 

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