Carboxylative cyclization

Cyclization-carboxylation. Cyclization of o-haloarylalkenes is induced by (cyclam)NiBr2. Under a carbon dioxide atmosphere, carboxylation occurs. However, yields in most cases are not impressive. 

Scheme 5.11 Nickel-mediated carboxylative cyclization of enynes (adapted from [52])...

Scheme 5.21 Carboxylative cyclization of bis-1,3-dienes (adapted from [99])...

Variation of the electronic and steric nature of the ruthenium catalysts allow the complementary carboxylative cyclization of 1,6-diynes (Scheme 36) [150]. Lee and coworkers described how a variety of carboxylic acids condense with 1,6-terminal diynes in the presence of catalytic amounts of [Ru(p-cymene)Cl2l2. P(4-F-C6H5)3 and 4-dimethylaminopyridine to give cyclohexylidene enol carboxylates with exclusive ( )-selectivity. The proposed mechanism involves the initial formation of a ruthenium vinylidene species I followed by intramolecular cyclization induced by the nucleophilic attack of the carboxylate anion to afford a vinylmthenium species II. Final protonolysis furnished the product and turns the catalyst over. 

Scheme 36 Ru-catalyzed carboxylative cyclization of 1,6-diynes to cyclohexylidene enol carboxylates...

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 synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

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]. 

COi is another molecule which reacts with conjugated dienes[10,95,96], COt undergoes cyclization with butadiene to give the five- and six-membered lactones 101. 102. and 103, accompanied by the carboxylic esters 104 and 105[97.98], Alkylphosphines such as tricyclohcxyl- and triisopropylphosphine are recommended as ligands. MeCN is a good solvent[99],... 

Tandem cyclization and 3-carboxylation has been done with o-(methanesulf-onamido)phenylacetylenes by conducting the reaction in methanol under a CO atmosphere[10]. 

A special application of the Japp-Klingemann/Eischer sequence is in the preparation of tryptamines from piperidone-3-carboxylate salts, a method which was originally developed by Abramovitch and Shapiro[2]. When the piperidone is subjected to Japp-Klingemann coupling under mildly alkaline conditions decarboxylation occurs and a 3-hydrazonopiperidin-2-one is isolated. Fischer cyclization then gives 1-oxotetrahydro-p-carbolines which can be hydrolysed and decarboxylated to afford the desired tryptamine. 

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). 

A series of glycol bis(aUyl phthalates) and bis(aUyl succinates) and their properties are reported in reference 88. In homopolymerizations, cyclization increases in the order diaUyl aliphatic carboxylates < glycol bis(allyl succinates) < glycol bis(allyl phthalates). Copolymerizations with small amounts of DAP can give thermo set moldings of improved impact (89). 

An intramolecular Diels-Alder cyclization produces excellent yields of 2-aminoquinoline-3-carboxylate esters (57). Equally fine yields of the requited carbodiimides have been reported, making this an attractive route to an unusual substitution type. 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

There are few examples of [5 + 1] cyclizations from pyrimidine intermediates. Two of these involve the chloropropionic ester (194), which gives the 5,6,7,8-tetrahydro-7-one (195) with ammonia (59JCS1849), and the cyclization of a 4-ethynylpyrimidine-5-carboxylate with ammonia to give a pyrido[4,3-. In a recent patent, 5-ethoxycarbonylpyrimidin-4-yl-j8 -alanine derivatives are cyclized with ammonia to pipemidic acid analogues (80GEP2903850). One-carbon pyrimidine [5 +1] syntheses are included in Section 2.15.5.5.1 above. 

The only example from a pyridazine intermediate is of the Dieckmann-type used so widely in the pyridopyrimidine field (Section 2.15.5.4.2). The 3-carboxyalkylamino-4-ester (365) is cyclized by strong base to give the pyrido[2,3-c]pyridazine-6-carboxylate (366) (77JAP(K)7733695). 

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). 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

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). 

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