Cyclization carboxylic acids

The electrochemical reduction of 3-nitrophthalic acid at controlled potentials gave 2,1-benzisoxazole-3-carboxylic acid. Cyclization is presumed to proceed via an intermediate oxime (67AHC(8)277). Treating 5-iodoanthranilic acid with acetic anhydride gave 3-acetoxy-5-iodo-2,l-benzisoxazole (596) (65JMC550). 

Both anilides and thioanilides of cyclohexanone-2-carboxylic acid cyclize satisfactorily under acid conditions thus, 7,8,9,10-tetrahydro-phenanthridone (154a) and the corresponding tetrahydrophenanthri-dine thione (154b) and its 2-methyl derivative (154c) have been obtained by the action of sulfuric acid on (153ar-c), respectively.182... 

Similarly, AT-allylthioamides derived from carboxylic acids cyclize to 2-thiazoline derivatives by the action of the bromine-dioxane complex <93PJCI043>. The Mitsunobu reaction can be eflSciently used for preparing 4-carboxy-2-thiazolines from -hydroxy-a-amino acids <92TL2807). Diethyl-... 

Pentahydroxypentylpyrazoles, e.a.. diphenyl-derivative (47), have been prepared by condensation of D-galactose phenylhydrazones with various j9-nitrostyrenes, and were converted to pyrazole-3-carboxylic acids. Cyclization (by use of ACaO) of per-Q-... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

The synthesis of 9H-benzo[2,l-e]thiazolo-[2,3-c]-as-triazine (401) was achieved by oxydative cyclization of 2-imino-3-(o-aminophenyl)-4-phenyl-4-thiazoline (718, 719). This latter reacts also with paraformaldehyde in hot toluene yielding 3-phenyl-9H.10H-benzo[l,2-/]thiazolo-[2,3-d][l,3,5]triazepine (402) (720). This heterocyclic sytem is also formed when carboxylic acids replace paraformaldehyde (Scheme 230) (721). 

There is also the possibility of removing the 2-oxo group by ring cleavage and subsequent recyclization. Lumazine can be hydrolyzed by strong alkali to 2-aminopyrazine-3-carboxylic acid (153) which is converted first into the amide (154) and then cyclized by ethyl orthoformate into pteridine-4-one (155 equation 47) (51JCS474). 

The intermediacy of an aci-nitro compound has been proposed for the sulfuric acid cyclization of o-nitrophenylacetic acid to yield a mixture of 2,1-benzisoxazole and 2,1-benzisoxazole-3-carboxylic acid. The acid does not decarboxylate under the reaction conditions. The proposed aci-nitro intermediate cyclized to an A/ -hydroxy compound which decomposed to the products (Scheme 179) (70JCS(C)2660). 

The salts of -halo acids cyclize in ionizing media to oxetan-2-ones, as do -diazonium carboxylates (64HC(19-2)787). Thietanes are obtained analogously (Section... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Imidazole-4-carboxylic acid, 5-amino-cyclization, 5, 583 decarboxylation, 5, 434—435 ethyl ester diazotization, 5, 414 synthesis, 5, 477... 

During electrochemical fluorination retention of important functional groups or atoms in molecules is essential. Acyl fluorides and chlorides, but not carboxylic acids and anhydrides (which decarboxylate), survive perfluorination to the perfluorinated acid fluorides, albeit with some cyclization in longer chain (>C4) species [73]. Electrochemical fluorination of acetyl fluoride produces perfluoro-acetyl fluoride in 36-45% yields [85]. Electrochemical fluorination of octanoyl chloride results in perfluorinated cyclic ethers as well as perfluorinated octanoyl fluonde. Cyclization decreases as initial substrate concentration increases and has been linked to hydrogen-bonded onium polycations [73]. Cyclization is a common phenomenon involving longer (>C4) and branched chains. a-Alkyl-substituted carboxylic acid chlorides, fluorides, and methyl esters produce both the perfluorinated cyclic five- and six-membered ring ethers as well as the perfluorinated acid... 

On treatment with DAST, 4-kelo carboxylic acids undergo cyclization to form Y-fluorolactones almost quntitatively [192] (equations 98 and 99)... 

The Reissert procedure involves base-catalyzed condensation of an o-nitrotoluene derivative 1 with an ethyl oxalate (2) which is followed by reductive cyclization to an indole-2-carboxylic acid derivative 4, as illustrated below . ... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

A formal Pictet-Spengler condensation to give 2,3-dihydro-lH-2-benzazepine-3-carboxylic acid 36 was achieved in quantitative yield via a sigmatropic rearrangement of ci5-2,3-methanophenylalanine 35 in the presence of paraformaldehyde and hydrochloric acid at room temperature. It is interesting to note that homophenylalanine 38 did not cyclize to give 37, even under vigorous reaction conditions. 

However, for the preparation of derivatives which contain a functional group directly attached to position 6, the application of the foregoing cyclization method is considerably limited by the availability or existence of the required derivatives of -keto acids and may also be affected by differences in their reactivity. Cyclization of thiosemicarbazones was, therefore, used for these substances only in the case of the 6-carboxylic acid (see also Section II,B,2,a). Of the other derivatives known, the 6-acetic acid ester should be mentioned. Recently some further derivatives of dioxotriazine-6-carboxylic acid were reported. ... 

In general, a hydroxamic acid function results from the condensation of a hydroxylamine group with a carboxylic acid derivative. If these two groups are positioned suitably in the same molecule, spontaneous cyclization can occur. The most usual technique involves... 

Polycyclic derivatives have been prepared by straightforward amide formation. The tetracyclic amide 166 was obtained by reductive cyclization of 3-o-nitrophenylindole-2-carboxylic acid (165).22 When l-(2 -ethoxycarbonylskatyl)isoquinoline (167) was heated the pentacyclic j8-carboline derivative 168 was formed. If,... 

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