Carboxylic acid derivatives, intramolecular cyclization reactions

Intramolecular Cyclization Reactions of Carboxylic Acid Derivatives... 

Intramolecular cyclization of unsaturated carboxylic acid derivatives using strong electrophiles is one of the most effective and common approaches to y-lactones. Not to mention, reactions of the unsaturated carboxylic acids with halonium sources such as X2 and NXS, the so-called halolactonization, produce the synthetically useful halolactones [4], N-Halosuccinimide (NXS) reaction is also commonly utilized for the construction of y-lactone structures. These days, development of effective catalysts, especially for enantioselective cyclization of unsaturated carboxylic acids including halolactonization reaction, is a hot topic in synthetic organic chemistry. 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Cyclizations of the type (156) - (151) include the conversion of (a) carboxylic acids (218 X = O, S) into diones (219) (34% yield) under acidic conditions <74MI 715-01) (b) pyridine derivative (220) into the pyrano[3,2-c]pyridine (221) (72% yield) via an intramolecular Grignard reaction <82JCS(P1)93> and (c) a 1 1 mixture of diastereoisomers (222) into a 1 1 mixture of diastereoisomeric pyranopyrans (223) via a HSnBu3-mediated free radical cyclization <93LA629>. The diethyl ethoxymethylenemalonate (EMME) synthesis of 3-ethoxycarbonyl-4-naphthyridone derivatives has been discussed in CHEC-I <84CHEC-i(2)58i>. 

Reaction of enaminones and carboxylic acids is mainly interesting as a route for cyclization of suitable substituted enaminoketones to N-heterocycles45. In this way iV-cyclohexenylglycines can cyclize to indoxyl derivatives (equation 30). By a similar intramolecular acylation at the / -carbon of enaminones, fused indoles or pyrrole derivatives are obtained46-48. 

Starting from 1-methyl-17/-pyrrole-2-carboxylic acid, the tricyclic fused quinolin-4-one and naphthyridin-4-one derivatives 441 were prepared, in only three steps, by an intramolecular Heck cyclization of derivative 440 (Scheme 94) <2005EJ02091>. This reaction was performed in DMA as solvent, with potassium acetate as base and Pd(PPh3)4 as catalyst. The use of microwave irradiation, in some cases, gives better yields of cyclized products. 

Decarboxylation of alkanoic acids means of LTA in benzene as solvent is hindered by die formation of all lbenzenes as by-products. This side reaction is especially pronounced widi radicals derived from primary acids or odier acids from which the radical is not easily oxidized LTA. In some cases, such as that of apocamphane-l-carboxylic acid (equation 54), good yields of alkylbenzene can be obtained. Intramolecular versions of this reaction in which the radical cyclizes onto an aromatic nucleus at the appropriate position in the chain have also been observed. 

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