Malonic ring closure with

Ring closure with malonic acid 2,4-dichlorophenyl esters... 

Ring closures with malonic acid esters... 

Knoevenagel condensation of malonic acid with heptaldehyde [111-71-7] followed by ring closure, gives the fragrance y-nonanoic lactone [104-61-0] (6) (14). Beside organic synthesis, malonic acid can also be used as electrolyte additive for anodization of aluminum [7429-90-5] (15), or as additive in adhesive compositions (16). 

A variant of the free-radical addition method has been used for ring closure. For example, treatment of 75 with the free-radical initiator hexamethylditin gave a mixture of cis- and tmns-76, with a small amount of cis- and trans-11 (total yield 83%). The reaction has been performed with a-iodo esters, ketones, and malonates. 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

Table 20 Ring closures to [1,2,4]triazolo[1,5-a]pyrimidines by reaction of 3-amino[1,2,4]triazoles with /3-oxo ketones, esters, nitriles, or malonic acid derivatives...

V-(3-trifluoromethylphenyl)aminomethylenemalonate (749, R = 3-CF3) proved unsuccessful in boiling phosphoryl chloride. The thermal cycliza-tion of ZV-ethyl-N-arylaminomethylenemalonates (749) and their ring closure in acetic acid, in acetic anhydride with zinc chloride, or in a melt of aluminium chloride were likewise unsuccessful (71JHC357). The corresponding quinoline was not obtained in a one-pot version when N-ethylani-line and EMME were reacted in polyphosphoric acid. Table V shows the yields of quinoline-3-carboxylic acid derivatives obtained from /V-ethyl-N-phenyl- and iV-ethyl-7V-(3,4-methylenedioxyphenyl)aminomethylene-malonates (749, R = H and 3,4-0CH20) under various acidic cyclization conditions. 

The reaction of 2-amino-5,7-dimethyl-1,8-naphthyridine and EMME in boiling Dowtherm A for 45 min gave the pyrido[l,2-o]-1,8-naphthyridine derivative (1602) in 40% yield. The same product (1602) was obtained in 44% yield in the reaction of N-( 1,8-naphthyridin-2-yl)aminomethylene-malonate (1603) and EMME in boiling Dowtherm A for 1 hr. The thermal ring closure of 1603 was unsuccessful. An ethanolic suspension of 1603 was treated with concentrated aqueous ammonium hydroxide at reflux for 24 hr to give 2-aminopyrido[ 1,2-a]-1,8-naphthyridine (1604) in quantitative yield (80FES1052). 

An appendix systematically lists references to reactions of dialkylalkoxy-malonates with amines, including not only the common aliphatic and aromatic amines, but also a very wide variety of heterocyclic amines classified according to ring system. The appendix also provides systematic references to the different ring systems obtained by ring closure of the dialkylaminomethylenemalonates. The appendix should be used in conjunction with the subject index a separate subject index is provided for this monograph volume. 

Solution studies of malonate complexes include the unusual observation that [(H20)sCr(Hmal)]2+ has considerable kinetic stability.924 The mechanism of ring closure has been the subject of detailed study.925 The methylenic protons of [Cr(mal)3]3- undergo bromination when a suspension of the potassium salt is treated with bromine in ether (2 h). Legg and co-workers927 have recently used a number of malonate complexes to demonstrate that the 2H NMR spectra are both readily observed and useful for solving structural problems. The resolution that may be obtained by this method may be appreciated by the fact that in the complex [Cr(mal-d2)2(bipy)]2 the geminal protons of the malonate are clearly resolved. 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

The synthesis of the 4,5,6,7-tetrahydrotetrazolo[l,5-a]pyrimidine ring started by reacting 5-aminotetrazole with diethyl bromomalonate to afford diethyl(tetrazol-5-ylamino)malonate (633), whose chloroacetylation led to the formation of 634 rather than 636. Treatment with triethylamine induced ring closure of the chloroacetyl derivative to afford the tetrazolo[l,5-ajpyrimidine 635 rather than the isomer 637 (93ACH683) (Scheme 128). 

Urban et al. effected the ring closure of 2-aminopyridines and diethyl malo-nate in ethanolic sodium ethoxide. 2-Amino-4-chloropyridine and diethyl 2-methoxyethyl malonate gave only the noncyclized product (68), which was then transformed in a separate reaction with N,N -dicyclohexylcarbodiimide in dimethylformamide at room temperature to the pyrido[l,2-a]pyrimidine (69).112 Besides diethyl malonates, the active esters107 108 1 13 117 and malonyl dichlorides52,118119 have also been used as reaction partners of 2-aminopyridines. 

By contrast, 3-hydrazino-l,2,4-thiadiazoles (163), which are prepared by ring closure methods, are very sensitive to acids and undergo elimination of sulfur with formation of 5-arylamino-l,2,4-triazoles (164) as indicated in Scheme 61 (63JCS4566). The mechanism of this conversion is not known but presumably involves the attack of a hard nucleophile at the 5-position followed by ring opening, loss of sulfur and recyclization as has been observed with the quaternary salts (77JCS(P1)1791) (see Schemes 22, 23, and 24). Hydrazine (163) reacts with aldehydes to produce hydrazones (165) and with dimethyl malonate to yield pyrazoles (166). Diazonium salts of type (153) have been prepared by the methods... 

An efficient procedure for the preparation of 2,3,4-trisubstituted furans in three steps was reported. Thus, the reaction of hydroxyacrylonitrile sodium salts with chloromalonate gave rise to malonate ester intermediates, ring closure of which afforded 3-amino-4-arylfuran-2-carboxylates in 15-40% yields <02S753>. 

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