Nitriles, condensation with malonate

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Catalytic reduction of the nitrile 79 in the presence of semicarbazide affords initially the semicarbazone of 80. Hydrolysis-interchange, for example in the presence of pyruvic acid, gives the aldehyde 80. Condensation with the half ester of malonic acid leads to the acrylic ester 81 the double bond is then removed by means of catalytic reduction (82). Base catalyzed reaction of the... 

Pyridines having a 3-nitroso substituent in combination with a 2-amino group can be condensed with methylene-active compounds such as malonic esters, / -oxo esters, ketones, or nitriles.18... 

Kozmin s synthesis of the side chain was more efficient than Leighton s method (Scheme 60). Oxazole 285 was synthesized by Rh-catalyzed condensation of alkynyl nitrile 283 with diazo malonate 284 using the Helquist protocol [116]. Lindlar reduction of alkyne, reduction by Super-H, and bromi-nation afforded bromide 216, which was employed for the alkylation of metalloenamine to afford the aldehyde 200. Subsequent (Z)-olefination and saponification furnished the side chain subunit 269. 

Malonic acid derivatives, 634 Malononitrile, 603 dimer, 602, 632 Malonyl chloride, condensation with nitriles, 637 Maltol, conversion to 3-hy-droxy-2-methyl-4-pyridone, 649... 

The nitrile group is one of the most reactive electron withdrawing groups in the active methylene component, and with two nitriles, malononitrile is very reactive and condenses with almost all aldehydes and many ketones under mild conditions.Even sterically hindered ketones such as pinacolone condense with malononitrile in 48% yield using P-alanine as a catalyst. Formation of the bis-adduct is less of a problem with malononitrile than with malonic esters. 

The nitrile in cyanoacetic acid and cyanoacetic esters makes them more reactive than the corresponding malonic acid or esters. As with malonic acid, cyanoacetic acid can condense to give the alkylidine cyanoacetic acid or the decarboxylated a,P-unsaturated nitriles. Cyanoacetic acid reacts in a similar fashion as malonic acid, and often gives mixtures of the a,P and P,y-... 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

It was suggested73 that the most probable mechanism of this reaction is an initial aldol condensation of the starting ketone leading to the a,/ -unsaturated ketone 100 or to the /Miydroxyketone 101 which serve as precursors to the tertiary carbenium ions 102, which reacts in turn with nitriles by an acid-catalyzed Ritter reaction to give 103 (equation 36). This suggestion is confirmed by the results of a cross-reaction experiment of benzaldehyde and diethyl malonate with acetonitrile to give 14 (equation 37). 

The synthesis of one of the agents begins with nucleophilic aromatic displacement of bromine by cyanide in the highly fluorinated compound 78. Acid hydrolysis of the nitrile (79), followed by esterification of the newly formed acid, affords ester 80. Base-catalyzed condensation of the intermediate with diethyl malonate leads to the tricarbonyl derivative 81. 

SnCU-promoted addition of malonates and bromomalonates to simple nitriles (not electron-deficient) gives a,/8-dehydro-/3-amino acid derivatives (Eq. 44) [74]. SnCU is the Lewis acid of choice for the condensation of aroyl chlorides with sodium isocyanate, affording aroyl isocyanates in 70-85 % yields [75]. Non-aromatic acyl chlorides react under more variable reaction conditions. 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

Amino-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehydes have been treated with activated methylene compounds such as malonic acid derivatives, fi-oxo esters, or -nitriles. The Knoevenagel condensation between the aldehyde function and the activated methylene group to build up the side chain is followed by cyclization. 

Pyrido[2,3-(7]pyrimidincs 23, unsubstituted in the 2,4-positions, have been synthesized by condensation of ethyl 4-aminopyrimidine-5-carboxylate with several esters, phenylacetonitrile, phenylacetamide, or malonic ester chloride.173 In the first step, the 4-amino group reacts with the ester, nitrile, or acid chloride function of the cyclization partner, ring closure then being effected by a Dieckmann-type cyclization. 

Reactions of 1,3,5-triazine (1) with amidines, amidine salts or nitriles which have acidic a-methylcne groups are of great preparative value. The base-catalyzed reactions produce 5-substituted pyrimidin-4-amines 3 (R3 = NH2) in good yield. The corresponding imidate or thioamidate hydrochlorides yield 4-alkoxy- and 4-(alkylsulfanyl)pyrimidines, respectively.24 Some other malonic acid derivatives react in a similar manner as shown below. In these cases, a sodium alkoxide is needed as condensing agent.18,25... 

Condensation of 2,3-0-isopropylidene-o-glyceraldehyde with, for example, malonic, acetoacetic, and cyanoacetic acids gave unsaturated products (8) that could be converted into the 2-ulose (9) and the nitrile (10). o-Erythrose has been... 

The syntheses of chiral C2-symmetric methylene-bis(oxazolines) and bi-oxazolines of type 6 and 8 are summarized in Schemes 10 and 11 [25]. Using the well-established three-step sequence - amide formation, conversion to the bis(2-chloroalkyl)amide, and subsequent base-induced cyclization [26] - various derivatives were prepared in good overall yields. Alternatively, these ligands may be synthesized in one step from the corresponding amino alcohols and readily available bis-imidates derived from malonate or oxalate [25, 27] or, as described by Masamune et al [28], by amide formation with diethyl malonate and subsequent reaction with dimethyltin dichloride, or by metal-catalyzed condensation of amino alcohols with nitriles [29]. 

If two equivalents of the 2-halo-carbonyl compound (or 2-halo-nitrile) are utilised to react with an enolate/carbon disulfide adduct, double S-alkylation and then double ring closure produce thieno[2,3-h]thiophenes [129] Scheme 82 shows how this works. Taking this idea further, if a malonate is used as the 1,3-dicarbonyl component, 3,4-dihydroxythieno[2,3-h]thiophenes are the final result (Scheme 83) [130], the ring closure steps then having the character of Claisen condensations. If malononitrile is used instead of a 1,3-dicarbonyl compound, the product is a 3,4-diaminothieno[2,3-6]thiophene - product 60 in Scheme 84 is the result of using chloroacetonitrile in the alkylation step [131]. 

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