Malonates reaction with amines

Diethyl malonate blocked diisocyanates cross-fink polyols at 120°C for 30 min. The reaction with alcohols does not srield urethanes, rather transesterification occurs (134), and reaction with amines srields amides, not ureas. Storage-stable coatings can be formulated by using monofimctional alcohol in the solvent (135). Clear coats for automobiles that have both excellent environmental etch and abrasion resistance have been formulated with a combination of a hydroxy-functional acrylic resin, malonic ester blocked HDI and IPDI trimers, and an ME resin (136). 

Preparation of Isocyanates. Isocyanates are prepared by rearrang-ii azides in inert solvents such as ethers, chloroform, benzene and its homologs, malonic ester, mid ligroin. If the isocyanate is to be isolated, the solvent is removed by distillation, or, if the isocyanate is the lower boiling, it is distilled directly. In this operation, a safety shield is advisable to guard against a possible explosion of yet undecomposed azide. Isocyanates can be converted to sym-ureas by reaction with water, to urethans by reaction with alcohols, to os-ureas by reaction with amines, or to acylamines by reaction with anhydrous acids or acid anhydrides, or they can be hydrolyzed directly to amines. Acylamines can also be obtained. from isocyanates by reaction with Grignard re-... 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

Allylation under basic conditions. Allylation can be carried out under basic conditions with allylic acetates and phosphates, and under neutral conditions with carbonates and vinyloxiranes. The allylations under neutral conditions are treated separately in Section 2.2.2.1 from those under basic conditions. However, in some cases, allylations of the same substrates are carried out under both basic and neutral conditions to give similar results. These reactions are treated together in this section for convenience. Allylic acetates are widely used for Pd-catalyzed allylation in the presence of bases tertiary amines or NaH are commonly used[6,7,4l]. As a base, basic alumina or ICF on alumina is conveniently used, because it is easy to remove by filtration after the reaction[42]. Allyl phosphates are more reactive than acetates. The allylation with 40 proceeds stepwise. At first allylic phosphate reacts with malonate and then allylic acetate reacts with amine to give 41(43]. 

Like butadiene, allene undergoes dimerization and addition of nucleophiles to give 1-substituted 3-methyl-2-methylene-3-butenyl compounds. Dimerization-hydration of allene is catalyzed by Pd(0) in the presence of CO2 to give 3-methyl-2-methylene-3-buten-l-ol (1). An addition reaction with. MleOH proceeds without CO2 to give 2-methyl-4-methoxy-3-inethylene-1-butene (2)[1]. Similarly, piperidine reacts with allene to give the dimeric amine 3, and the reaction of malonate affords 4 in good yields. Pd(0) coordinated by maleic anhydride (MA) IS used as a catalyst[2]. 

Tlie bifunctional sulfenyl chloride 213 was obtained by chlorination of 144 in good yield, although excessive chlorination led to the saturated compound 214 (94CB533). A series of compounds 215-220 were obtained from 213 by reactions with secondary amines ferf-butyl methyl ketone hexane-2,4-dione 2,6-dimethylcyclohexanone diethyl malonate and acetylacetone, respectively. 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

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. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

Reaction XXXm. (b) Condensation of Malonic Adds with Aldehydes or some Ketones under the influence of Primary or Secondary Amines. (B., 35,1143.)—This is an example of the activating effect of two 1 3 oxy groups on a methylene group between them. In the presence of primary or secondary amines—e.g., ethylamine, di-ethylamine, piperidine— malonic acid condenses with aldehydes and some ketones to give unsaturated dicarboxylic acids. It is probable that the amine reacts first with the aldehyde, water being eliminated. 

Alternatively, the remaining sulfate ester of 70 may serve as a leaving group for a second nucleophilic displacement reaction. When this displacement is by an intramolecular nucleophile, a new ring is formed, as was first shown in the synthesis of a cyclopropane with malonate as the nucleophile [68] and of aziridines with amines as the nucleophiles [76]. The concept is further illustrated in the double displacement on (/J,/ )-stilbenediol cyclic sulfate (72) by benzamidine (73) to produce the chiral imidazoline 74 [79]. Conversion of the imidazoline (74) to (.V,.S )-stilbenediaminc 75 demonstrates an alternative route to optically active 1,2-diamines. Acylation of 75 with chloroacetyl chloride forms a bisamide, which, after reduction with diborane, is cyclized to the enantiomerically pure trans-2,3-diphenyl- 1,4-diazabicy-clo[2.2.2]octane (76) [81],... 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Several approaches to the synthesis of morphinans start with cyclohexanone intermediates leading to octahydroisoquinolines such as 3 by way of a route similar to that exploited by Grewe (Scheme 3.1). Amination of 2-hydroxymethylenecyclohexanone (6) followed by reaction with malonic ester afforded the hexahydroisoquinoline, 7, that was decarboxylated and converted on a commercial scale to 5,6,7,8-tetrahydroisoquinoline(9) via the 3-chloro intermediate. 

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