Cycloacylation

The reacfion is affecfed by several factors, including fhe nafure of the cycloacylating functional group, the Lewis or protic acid, the nature and position of subsfifuenfs on fhe aromafic ring, and fhe size of fhe ring to be formed. In general, experimenfal conditions can be set up in order to efficiently synthesize cyclic aromatic and heteroaromatic ketones. 

Good yields of cyclic aryl ketones are achieved with arenes, provided they are not very electron deficient. For example, the cycloacylation of arylpropanoic acids can be performed in the presence of scandium triflate as Lewis acid to give indanones in good yields with electron-rich aromatic substrates, whereas lower yields are obtained with very electron-deficient ones. The reaction can also be performed in the presence of protic acid thus, 3-(3,5-dibromophenyl)propanoic acid is directly converted into 

The synthetic application to different arylalkanoic acids is reported in Table 2.4, showing that cyclic aryl ketones can be produced in high yields under very mild conditions. 

Intermediate 35 can be alternatively produced by aluminum-chloride-promoted reaction of the cyclic dichloride 34 that can be in turn produced by the same ring-chain isomerization of phthalic dichloride 32. This hypofhesis has been sfrongly supported by NMR studies showing that cyclic dichloride 34 is produced by treatment of phfhalic dichloride 32 with 

These studies allow the efficient synthesis of anfhraquinones under mild conditions, including anthracyclinones, by direcf ortho-bisacylafion of aromatic compounds with orf/io-phthaloyl dichlorides a few examples are reported in Table 2.6. Similarly, aromatic cycloalkanediones can be easily prepared by bis-acylation of aromafic compounds wifh different aliphatic diacyl chlorides.  

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Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

In all cases investigated, the cycloacylation reaction also occurred at the exocyclic nitrogen atoms. In order to obtain precursors for oligomeric/poly-meric heterofulvalenes the TAFs of type 85 were condensed with ortho es-... 

Intramolecular chain transfer, 20 220 Intramolecular cycloacylations, 72 177 Intramolecular self assembly, 20 482 Intramolecular stretching modes, 74 236 Intraoperative auto transfusion, 3 719 Intraparticle mass transfer, 75 729-730 Intrapellet Damkohler number, 25 294,... 

While examples of intermolecular electrophilic additions to 7t-deficient heterocycles are reported less frequently than with -excessive heterocycles, intramolecular electrophilic cyclization strategies can be used to access some heterocycles of interest. In some cases, different reaction conditions can afford isomeric heterocycles as exemplified in the cyclization of 1,2-diaryl ketols with 2-amino-pyrazoles. With hydrogen chloride in the reaction media, pyrrolo[2,3-c]pyrazoles (170) are obtained, whereas imidazo[l,2-6]pyrazoles (171) were obtained in the absence of hydrogen chloride (Scheme 29) <84JHC945>. Cycloacylation of the a-(thiazolylthio)acetic acid (172) was accomplished with phosphorus oxychloride to give thiazole (173) (Equation (50)) <56AC(R)275>. 

A new synthesis of 1,2-diazetines via simple cycloacylation reactions has been reported <02H1257>. 

Scheme 2.73. Synthesis of diterpenes via domino acylation/cycloalkylation and alkylation/ cycloacylation strategies.

The cycloacylation of benzamidines 1361 with oxalate-derived bisimidoyl chlorides 1360 provides 4/7-imidazoles... 

Cycloacylation of 3-hydroxy carboxylic acids can be accomplished with various dehydrating agents. For example (134) has been converted into the S-lactone acetal (135) with orthoformate. On heating,... 

Lactones are among the most abundant substructures in natural products." This fact had kindled enormous activity in the field of y-lactone synthesis." 7-Lactones have been prepared by direct cycloacylation of 7-hydroxy acids, eiAer as such or generated as transient intermediates, and by cycloalkyl ation, either of 7-halocarboxylates or of 3,7- or 7,S-unsaturated acids by additions to the double bond. 

Prior to our work, fluorenones had been synthesized by methods characterized by the limited accessibility of the starting substrate [28,30,32,33] (substrate being fluorene, biphenyl-1-carboxylic acid, benzophenone, fluoranthene, cyclohexene, phenanthrene or phenylpropionic acid derivatives), a lack of stereoselectivity [28,29,31,33] and poor yields. We therefore developed a simple methodology for synthesizing fluoren-9-ones via domino acylation-cycloalkylation/alkylation-cycloacylation (Chart-19). 

Our work on fluorenones and alkaloids was extended to design convenient, expeditious and stereocontrolled total synthesis of several naturally occuring diterpenoids [55] namely ( )-ferruginol (5), ( )-nimbidiol (6), ( )-nimbiol (7), ( )-totarol (8) and abietatriene (9) (Schemes 4-8) via a concerted mechanism of domino acylation-cycloalkylation/ alkylation-cycloacylation as the principal step to construct the basic carbocyclic framework required for the trans-fused... 

Scheme 7. Total synthesis of ( )-totarol (8) via domino alkylation-cycloacylation.

Aminobenzoic acid undergoes cycloacylation to give moderate yields of quinolin-2-ones. 

In situ production of triphenyl phosphonium anhydrides as triflate salts 25 (Scheme 2.14) is claimed to be the crucial step for the cycloacylation of arylalkanoic adds in the presence of triphenyl phosphine oxide and triflic anhydride. The reaction proceeds in satisfactory to high yields under mild conditions. Compounds 25 are commonly used directly in situ owing to their very hygroscopic nature and are produced by reaction... 

Table 2.4 Cycloacylation promoted by triphenyl phosphine oxide-triflic anhydride mixture...

Indane-l,3-diones 44 can be synthesized by a three-component sequential aluminum-chloride-promoted cross condensation-cycloacylation of various acyl chlorides (Scheme 2.20). Thus, the poorly stable acetoacetyl chloride 41, produced in situ by aluminum chloride-promoted self-condensation of acetyl chloride, reacts at the methylene active carbon with aromatic acyl chlorides 42, giving the reactive complexes 43 that... 

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