Carboxylic acid derivatives, intramolecular

Carboxylic acids and their anhydrides acy late a variety of benzene derivatives, fused ring systems, and heterocyclic compounds. An improved procedure for the preparation of l,4-difluoroanthracene-9,10-dione involves reacting phthalic anhydride and 1,4-difluorobenzene to prepare an intermediate carboxylic acid [35] Intramolecular acylation in polyphosphonc acid completes the synthesis (equahon 24). 

Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to l-(phenylthio)nitroalkene predominantly as the m-isomer (9.1 1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50... 

A pyran ring is formed in the intramolecular Diels-Alder cycloaddition of alkene-tethered enantiopure (lS,2R)-l,2-dihydroxycyclohexa-3,5-diene-l-carboxylic acid derivatives (derived from the biodihydroxylation of benzoic acid). For the three cases illustrated in Scheme 6.246, Mihovilovic and colleagues found that moderate to high yields of the desired cycloadducts could be obtained by exposing a solution of the precursor to microwave irradiation at 135-210 °C for extended periods of time... 

The halogenated derivatives of six membered heterocycles, like their carbacyclic analogues, usually participate readily in coupling reactions that involve the incorporation of an olefin or carbon monoxide. The insertion of carbon monoxide commonly leads to the formation of either a carboxylic acid derivative or a ketone, depending on the nature of the other reactants present. Intermolecular and intramolecular variants of the insertion route are equally popular, and are frequently utilized in the functionalization of heterocycles or the formation of annelated ring systems. 

An interesting variant of electrophilic cleavage is intramolecular attack at the linking carboxylic acid derivative by a substrate-bound electrophile (Figure 3.23). This cleavage strategy generally produces lactones. 

Figure 3.23. Intramolecular electrophilic cleavage of carboxylic acid derivatives from polymeric supports. X leaving group Y NR, O.

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

C-Alkylation of 1,1-enediamines takes place readily when they are treated with electrophilic olefins including a,/ -unsaturated aldehydes, ketones and carboxylic acid derivatives. Primary and secondary 1,1-enediamines usually lead to fused heterocyclic products due to the simultaneous intramolecular cyclocondensation between the amino and the carbonyl groups of the initially formed adducts. 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

Uenoyama et al. also envisaged combining TEMPO-based radical cycUza-tions with carbonylations in order to yield precursors of the tetralone framework [131]. Surprisingly, treatment of 140 at 130 °C under a CO atmosphere directly yielded a cycUzed carboxylic acid. This was shown to arise from intermediate 141 by an unknown mechanism. The free carboxylic acid derivative could be further cycUzed into tricycUc ketone 142 using Otera s intramolecular Eriedel-Crafts procedure. 

General acid-catalyzed hydrolysis of carboxylic acid derivatives has been observed mostly in intramolecular catalysis. In phthalic acid derivatives the mechanism changes from general acid to nucleophilic... 

C. Intramolecular Cyclization of 4-Aminocyclohexane-carboxylic acid Derivatives... 

Yoshikawa, N., Tan, L., Yasuda, N., et al. (2004) Enantioselective syntheses of bicyclo[3.1.0]hexane carboxylic acid derivatives by intramolecular cyclopropanation. Tetrahedron Letters, 45, 7261-7264. 

Intramolecular cyclization is a useful method for the preparation of lactones and cyclic ethers [34], The most common examples are iodolactonization and iodoetherification, the former using a carboxylic acid derivative as the nucleophile and the latter relying on a hydroxy group. Thus, butyrolactones are available from Y, -unsaturated carboxylic acid derivatives [1,35,36], while unsaturated alcohols lead to cyclic ethers [37-40], Lactones are also available from a wide variety of nucleophiles such as carbonates [41], orthoesters [42], or carbamates [43,44], which can all be used in place of a carboxylate anion [44,45],... 

Carboxylic acid derivatives 279 of the pyrrolonaphthyridine series - potential preparations for treatment of degenerative, ischemic and autoimmune diseases -have been synthesized using intramolecular cyclization of ethyl (3-et-hoxycarbonylnaphthyridin-4-ylamino)acetates 280 induced by potassium tert-but-oxide in a toluene BuOII mixture (1994EUP587473). 

---