Cyclization of keto esters

Of the possible monocyclic aromatic systems, only derivatives of the 1,3-oxathiolium system have been reported. The 2,5-diaryl derivatives may be obtained by the acid catalyzed cyclization of keto ester (109) as shown in Scheme 25. The compounds may be isolated and stored as the perchlorates (75H(3)217). The treatment of 2-alkoxy-l,3-oxathioles with perchloric acid also results in formation of the aromatic systems (74RTC99). 

McMurry, J. E., Miller, D. D. Titanium-induced cyclization of keto esters a new method of cycloalkanone synthesis. J. Am. Chem. Soc. 

The Chemistry of the Tetracyclic Diterpenoids.—The reaction of cnt-kaur-16-ene with thallium(lli) nitrate affords cnt-kaur-16-en-15j8-ol nitrate which undergoes a ready [3,3] sigmatropic rearrangement to cnt-kaur-15-en-17-ol nitrate. The reactions of phyllocladene and of labda-8(17)-en-13-ol with sodium azide and iodine chloride have been examined. ° The synthesis of 13-hydroxylated cnt-kaur-16-ene derivatives such as steviol using an acyloin-like cyclization of keto-esters has been developed. A detailed analysis was made of the products arising from the use of sodium in liquid ammonia in this reaction. 

CycUzation of -keto esters. Biogenetic-like cyclization of polyolefins (5, 627-628) has been extended to cyclization of -keto esters and used in an interesting synthesis of the tricyclic diterpene A < >-podocarpene-13-one (5). Thus treatment of (1), prepared in 61% yield from gcranyl bromide and methyl acetoacetate, with stannic chloride in CH2CI2 at 0 20° gave a single cyclic product (2) in 68% yield. This was converted into (5) by several steps as formulated. The intermediate (3) was also converted into a compound used for elaboration of ambreinolide and labdanoid systems. 

Regioselective F-C acylations of carboxylic anhydrides can be accompanied by other Lewis acid mediated reactions in tandem. Recently, a general method for the Lewis acid mediated intramolecular cyclization of keto ester alkyl substituted arenes to functionalized 1-indanones was reported by Pillion. Thus treatment of Meldrum s acid analogue 23 under a variety of... 

The intramolecular cyclization of keto esters has found comparatively little use in total steroid synthesis for the formation of rings C and D. 

Butenolides have been prepared by cyclization of keto esters (eq 14) or by elimination of H2O from a preformed hydroxy butenolide (eq 15). ... 

Fig (12) Transformation of keto ester (94) to (96) is described. Michael addition leads the formation of the adduct (97) which is subjected to cyclization, aromatization and hydrogenolysis to obtain the phenol (99). This on diazotization, methylation and reduction afforded the amino ether (100). Further diazotization, methanolysis and saponification produce ethyl (+)-camosic acid dimethylether (102). 

Cyclizations of hydroxy esters under basic conditions have been achieved." Aldol reactions of a-keto esters with aldehydes give unsaturated lactones." The photocatalytic addition of alcohols 17 to a,/f-unsaturated acids (e.g., 18) or esters is an example of a radical... 

A -Pyrimidinyl-iV-aryl guanidines have been cyclized with keto esters to give 1,3,5-triazine derivatives <05JGU303>. Trimolecular condensation of paraformaldehyde, primary amines and suitable isoxazolyl-iV-arylthioureas 31 using montmorillonite K-10 in diy media, under microwave irradiation afforded the corresponding isoxazolyl triazinethiones 32 <05JHC711>. 

The [3+4]cyclization of 4-oxoheptanal (5) with 3-substituted bis(trimethylsilyl) enol ethers of y3-diketones (4a) and of -keto esters (4b) is also regioselective but in the opposite sense (equation IV). 

A methodology leading to spiro p-methylene-y-butyro-lactonizations is a key step in the synthesis of several bak-kenolides. The crucial spiro intermediate was obtained by treatment of keto ester 173 with Mn(OAc)3 in ethanol and cleanly underwent 5-exo dig cyclization to provide a single lactone 174 in 68% yield (Scheme 25.81). 

Dieckmann cyclization (Section 21 2) An intra molecular analog of the Claisen condensation Cy die p keto esters in which the ring is five to seven membered may be formed by using this reaction... 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

In a number of cases the intermediate oxime has been isolated in the reaction of hydroxylamine and /3-keto esters. The reaction of ethyl acetoacetate with hydroxylamine generated an oxime which cyclized on base treatment (Scheme 144) (70MI41600). Likewise, treatment of an analogous amide with hydroxylamine generated a ring opened material which cyclized on treatment with HCl (Scheme 144) (67T831). The presence of a minor contaminant in the standard reaction of ethyl acetoacetate with hydroxylamine was discovered and identified as an isomeric isoxazolin-3-one. The mechanism of product formation has been discussed (70BSF2685). 

At the end of the nineteenth century, Claisen described the cyclization of P-keto esters with hydroxylamine to provide 3-hydroxyisoxazoles. Substituents Ri and R2 in the P-keto ester make it possible to introduce substituents in the 4- and 5-position of the heterocyclic ring. 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

Another improvement was reported by Leonard et al. in their preparation of a promising antimalarial, Endochin. The improvement was the alkylation of intermediate enamino-ester 28 by reaction with NaOEt followed by alkylation with an alkyl bromide, rather than forming 29 by reaction of 27 and a suitable P-keto-ester. This provided the important intermediate 29 required for cyclization to Endochin (30). Endochin was first reported by German scientists but was not publicly disclosed until the Department of Commerce made this information available after World War II.Leonard was able to improve upon the chemistry reported by Andersag and Salzer in 1940 and isolated Endochin in 40% overall yield from m-anisidine (27). 

The Conrad-Limpach reaction has been applied as a key step in the formation of pyrido[4,3-b]quinoline. Condensation of 3 different anilines 55 (R = H, Br, OMe) with keto-ester 56 provided the enamino-esters 57 in acceptable yields. Cyclization gave the desired quinolones 58 in good to moderate yield. ... 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

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. ... 

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