Malononitrile1

[109-77-3]  · C3H2N2  · Malononitrile  · (MW 66.07)

(active methylene reagent useful for condensation reactions, for preparing synthetic intermediates, and for the synthesis of heterocycles)

Alternate Names: propanedinitrile; dicyanomethane; malonic (acid) dinitrile; propiodinitrile; methylene cyanide; cyanoacetic acid nitrile; malonitrile; malodinitrile; malonodinitrile.

Physical Data: mp 32-34 °C; bp 218-219 °C; d 1.191 g cm-3; pKa 11.

Solubility: sol acetone, benzene, ethanol, ether, water.

Form Supplied in: white crystals; available commercially.

Preparative Methods: prepared from cyanoacetamide.2,3 The high temperature, continuous, one-step process for the synthesis of malononitrile by Lonza Inc. permits commercial-scale production of high purity reagent.

Purification: crystallization.4

Handling, Storage, and Precautions: caution: highly toxic irritant and should be stored in a well-ventilated fume hood. Over time, colorless malononitrile becomes dark and eliminates hydrogen cyanide. Inhalation should be avoided. Persons who suffer from a poor sense of smell, heart condition, or blood circulation problems should not be exposed to malononitrile. Above 100 °C, malononitrile may decompose spontaneously.

Introduction.

Fatiadi1b in his comprehensive review stated that malononitrile has become the keystone for synthesis of unique heterocyclic systems, fungicides, pharmaceuticals, pesticides, charge-transfer salts that conduct electricity, and solvatochromic dyes. Malononitrile is easily converted to derivatives, including dimers and trimers, which are also valuable in synthesis.1

Condensation Reactions with Aldehydes and Ketones.

Malononitrile undergoes the Knoevenagel condensation with aldehydes and ketones. Effective catalysts for the condensation include glycine5 and b-alanine.5,6 Benzaldehyde condenses with malononitrile in the presence of a catalytic amount of glycine to give benzalmalononitrile, which is valuable in heterocyclic synthesis, in quantitative yield (eq 1).5 The condensation of 1,4-cyclohexanedione with malononitrile proceeds almost quantitatively to 1,4-bis(dicyanomethylene)cyclohexane under catalysis by b-alanine (eq 2).7 1,4-Bis(dicyanomethylene)cyclohexane is used to prepare the quinomethane electron acceptor 7,7,8,8-tetracyanoquinonedimethane (TCNQ).7 In general, the Knoevenagel condensation of malononitrile with ketones8 or esters9 is efficiently catalyzed by weak bases (b-alanine, ammonium acetate) while stronger bases (KF, KOAc, NaOAc) promote telomerization of malononitrile.8 Dimethylformamide (DMF) is a useful solvent for a wide variety of Knoevenagel reactions.10 Dialkylidenemalononitriles having cyclic and terpenoid groups are potential cytostatic and pesticidal agents that may be useful in regulating insect juvenile hormone activity.11,12

2,3-Butanedione reacts with malononitrile to produce 4,5-dimethyl-5-hydroxy-2-oxo-3-pyrroline-3-carbonitrile (1), 1,5-dimethyl-3,7-dioxo-2,6-diaza-cis-bicyclo[3.3.0]octane-4,8-dicarbonitrile (2), 3-imino-1,5,9,11-tetramethyl-7-oxo-2,10-dioxa-6-azatetracyclo[6.3.0.04,11.05,9]undecane-4,8-dicarbonitrile (3) (eq 3), and the isomeric bislactam 1,5-dimethyl-3,7-dioxo-2,8-diaza-cis-bicyclo[3.3.0]octane-4,6-dicarbonitrile (4) (eq 4).13,14 Benzil reacts with malononitrile to give the Knoevenagel product (5) or the g-lactam (6) (4-cyano-2,3-diphenyl-5-oxo-3-pyrrolin-2-ylmalononitrile) (eq 5).15-17

2-Acetylcyclohexanones react with malononitrile to give a mixture of products including polyhydrobenzo[c]pyridines (isoquinolines) and tetrahydronaphthalenes (eq 6).18-20 The reaction with 2-acetylcyclopentanone proceeds similarly. Enolizable aliphatic and aromatic 1,4-diketones (e.g. 2,5-hexanedione) react with malononitrile in benzene in the presence of ammonium acetate or piperidinium acetate to give an array of products including double Knoevenagel adducts, cyclopentadiene derivatives, and 1-pyrindine derivatives (eq 7).21-23

Condensation Reactions with Esters.

Ethyl pyruvate condenses with malononitrile to yield ethyl 2-dicyanomethylenepropanoate (eq 8), a useful dienophile in the Diels-Alder reaction and in natural products synthesis.9,24 Ethoxycarbonyl-1-cyclohexanone reacts with malononitrile to give the Knoevenagel condensation product, which rearranges to the tetrahydroisoquinoline (eq 9).18-20,25,26

Reactions with a,b-Unsaturated Carbonyl Compounds.

The Knoevenagel reaction of aliphatic methyl ketones with malononitrile produces 6-alkyl-2,4-diamino-3,5-dicyanopyridines in moderate yield.27 The Michael reaction between aliphatic a,b-unsaturated ketones and malononitrile gives 2-amino-3-cyano-4,6-dialkylpyridines.27 Conjugated aromatic ketones react with malononitrile in the presence of ammonium acetate to give 2-amino-4,6-diarylnicotinonitriles.28 The Michael addition of malononitrile to a-acetylcinnamamides and chiral a-acylacrylates to form 2-amino-4H-pyrans and polyfunctionalized carbocycles,29,30 and the first asymmetric synthesis of polyfunctionalized 4H-pyrans via Michael addition of malononitrile to 2-acyl acrylates, have been reported.31 Polyfunctionalized 4H-pyrans are a common structural unit in a number of natural products.

Reaction with Allene.

Malononitrile reacts with allene in the presence of catalytic Pd0 complexes, such as (Maleic anhydride)bis(triphenylphosphine)palladium, to afford a 2-(1,1-dicyanoethyl)-3-methyl-1,3-butadiene (eq 10).32

Reaction with Tetracyanoethylene.

Tetramethylammonium 1,1,2,3,3-pentacyanopropenide, which is useful for preparation of pentacyanopropenide salts of other metals and quaternary ammonium cations by metathesis, is prepared from malononitrile and tetracyanoethylene (eq 11).33

Reactions with Alkyl- and Cycloalkylureas.

Malononitrile condenses with heptylurea and ethyl triorthoformate to form the 3-heptylureidomethylenemalononitrile, which is a precursor to 3-heptyl-5-cyanocytosine (eq 12).34 The reaction is effective for preparing 3-alkyl- and 3-cycloalkyl-5-cyanocytosines, but not for 3- and 5-cyanocytosines from arylureas.

Reactions with Carbon Disulfide and/or Sulfur.

Malononitrile reacts with carbon disulfide in aqueous ammonia to yield 4,6-diamino-3,5-dicyano-2H-1-thiapyran-2-thione (eq 13).35 Malononitrile reacts with carbon disulfide and sulfur in the presence of secondary or tertiary amines to give 4-cyano-5-amino-1,2-dithiole-3-thione.36 2-Amino-3-cyano-4,5-dialkylthiophenes are obtained from malononitrile, ketones, and sulfur.37 Cholestan-3-one reacts with malononitrile and sulfur in ethanol containing morpholine to produce cholestanothiophene (2-aminocholest-2-eno[3,2-b]thiophene-4-carbonitrile) (eq 14).38

Other Applications.

Malononitrile forms synthetically useful dimers and trimers1 and can be alkylated under a variety of experimental conditions.39,40 Ethyl orthoformate reacts with malononitrile to form Ethoxymethylenemalonitrile.41 Malononitrile reacts with 2,3-bis(phenylsulfonyl)-1,3-butadiene via a novel 4H-annulation to yield 1-sulfonyl-4,4-dicyanocyclopentene.42 Cholest-1-en-3b-yl esters undergo allylic alkylation with malononitrile in the presence of a palladium catalyst.43 Malononitrile may be used to prepare adenine,44,45 aminopyrroles,46 aminocyanopyrroles,47 diaminopyrimidines,48 and many other heterocycles.1 Malononitrile is converted to aminomalononitrile (aminopropanedinitrile) which is useful in the synthesis of heterocycles including pyrazines,49,50 C-nucleosides,51,52 dicyanoazomethine ylides,53 substituted 2-aza-1,3-butadienes,54 piperazines,55 and thiazoles.56 Malononitrile is also an important precursor for dicyanocarbene57 and for dibromodicyanomethane, which is useful in the synthesis of tetracyanocyclopropanes.58-61


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Fillmore Freeman

University of California, Irvine, CA, USA



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