(R1 = R2 = H)

[20428-58-4, 55440-71-6]  · C2H2LiN  · Lithioacetonitrile  · (MW 46.99) (R1 = Me, R2 = H)

[59263-57-9]  · C3H4LiN  · 2-Lithiopropionitrile  · (MW 61.01) (R1 = R2 = Me)

[55440-70-5, 50654-53-0]  · C4H6LiN  · 2-Lithioisobutyronitrile  · (MW 75.04)

(C2 carbanion for nucleophilic cyanomethylation of alkyl halides, epoxides, carbonyl electrophiles, a,b-enals (1,2-addition), a,b-enones (1,2- or 1,4-addition), heteroelectrophiles, C=N double bonds, and diene and arene transition metal complexes; cyanomethylenation of aldehydes and ketones1)

Preparative Methods: addition of Acetonitrile to n-Butyllithium in Et2O and warming to 25 °C provides lithioacetonitrile as a white solid in 81% yield; this material is insol hexane, octane, Et2O, THF, and DME but is sol DMSO.2a Lithioacetonitrile can also be prepared from lithium dialkylamides in THF; this material is sol THF even at low temperatures.

Handling, Storage, and Precautions: should be handled in a fume hood.


The alkylation of lithioacetonitrile and related metalated derivatives with alkyl halides or sulfonates2b-5 and with epoxides6-8 proceeds in good yield (eq 1).2b An interesting example involves the alkylation with spiro[4.2]hepta-1,3-diene in which cyclopentadienyl anion functions as the leaving group.9 The regioselective ring opening of epoxides with lithioacetonitrile finds application in the synthesis of g-hydroxy nitriles.6-8 The addition of Copper(I) Iodide to lithioacetonitrile gives a (cyanomethyl)cuprate that reacts efficiently with primary allylic bromides (eq 2).10

Addition to C=O Bonds.

The addition of lithioacetonitrile to diaryl, alkyl aryl, and alkyl ketones11 as well as aryl11-13 and aliphatic aldehydes13b provides the expected b-hydroxy nitriles (eq 3). The dehydration of these intermediates, typically using 85% Phosphoric Acid,11 provides substituted acrylonitriles. Bis(addition) products are observed under some conditions.14 The addition of lithioacetonitrile15a or 2-lithiopropionitrile15b to cyclohexanones gives b-hydroxy nitriles principally with axial selectivity for the cyanomethyl or 1-cyanoethyl groups, respectively (eq 3). Organomanganese or organocerium reagents derived from lithioacetonitrile using Mn(OCO-t-Bu)2 and Cerium(III) Chloride, respectively, undergo selective carbonyl addition reactions.16

The addition of nitrile-stabilized anions to carbonyl electrophiles other than aldehydes and ketones affords several potentially useful products. The addition of 2-lithiopropionitrile to a trimethylsilyl ketone proceeds with migration of a silyl group from carbon to oxygen and cyanide elimination to give a trimethylsilyl enol ether (eq 4).17 Lithioacetonitrile adds to N-methoxycarbonyl-protected succinimides to give g-hydroxy lactams in modest yield.18 The reaction of nitrile-stabilized anions with N,N-di-t-butyldiaziridone leads to an acyclic hydrazide derivative with lithioacetonitrile and a pyrazolinone with 2-lithiopropionitrile.19 The addition of 2-lithiopropionitrile to a g-lactone gives an intermediate a-cyano ketone that cascades to a substituted tetrahydrofuran.20

Michael Addition.

The addition of nitrile-stabilized carbanions to a,b-unsaturated aldehydes favors 1,2-addition.21,22 In an interesting variant of this process, the reaction of tricarbonyl(sorbaldehyde)iron with lithioacetonitrile initially gives a cis/trans mixture of acrylonitriles (eq 5). Migration of the Fe(CO)3 group, reduction of the nitrile, and reiteration of the addition process furnishes the next higher homolog in the series (eq 5).23

Kinetically controlled 1,2-addition to a,b-unsaturated ketones occurs at -25 to -30 °C and dehydration leads to cyano-substituted dienes.24 Higher temperatures lead to the thermodynamic 1,4-addition product. The axial selectivity noted in 1,2-additions to cyclohexanones15a increases for the addition of nitrile-stabilized carbanions to cyclohexenones15b,c and reaches very high levels (136:1) in the reaction of 2-lithiopropionitrile with pulegone.15b The 1,2-additions of lithioacetonitrile and 2-lithiopropionitrile to a-oxoketene dithioacetals and cycloaromatization of the intermediate b-hydroxy nitriles with phosphoric acid provides access to substituted pyridines.25 The reaction of lithioacetonitrile with an a,b-unsaturated ester leads to both 1,2- and 1,4-addition products (for a solution to this problem, see Trimethylsilylacetonitrile).26 The 1,4-addition of lithioacetonitrile to other Michael acceptors, such as a,b-unsaturated sulfones27,28 and vinyl sulfonium salts,29 proceeds as expected.

Reactions with Heteroelectrophiles.

Trapping nitrile-stabilized carbanions with a variety of electrophiles provides access to sulfur-,30 phosphorus-,31 or silicon-substituted nitriles.32

Additions to C=N Double Bonds.

The addition of lithioacetonitrile to nitrones33 and 2-aza-1,3-butadienes34 furnishes hydroxylamines and, following hydrolysis in the latter case, b-amino nitriles (eq 6), respectively.

Addition to h4-Diene, h5-Dienyl, and h6-Arene Metal Complexes.35

The addition of nitrile-stabilized anions to diene and dienyl transition metal complexes provides access to various cyano-substituted alkenes, ketones, or dienes. The addition of nitrile-stabilized anions to substituted (h4-1,3-butadiene)tricarbonyliron complexes furnishes cyano-substituted alkenes36 as, for example, in the synthesis of 2,2,3,4-tetramethyl-4-pentenenitrile (eq 7).36b

Trapping the intermediate iron complexes with carbon monoxide leads, in the case of most acylic 1,3-dienes, to cyclopentanones (eq 8),37 or trapping with carbon monoxide followed by an alkylation gives g,d-unsaturated ketones.38 The addition of 2-lithiobutyronitrile to tricarbonyl(h5-dienyl)manganese complexes and a subsequent oxidation provides 1,3-dienes (eq 9).39 The addition of nitrile-stabilized carbanions to various arene-transition metal complexes affords substituted arenes35a,b or 1,3-cyclohexadienes35b,40 (see (h6-Benzene)tricarbonylchromium). In the case of a methoxy-substituted arene, the addition of 3-lithiobutyronitrile to (h6-anisole)tricarbonylchromium(0) and the further acid-catalyzed hydrolysis of the intermediate 1-methoxy-1,3-cyclohexadiene provides a substituted cyclohexenone.40e

Related Reagents.

Acetonitrile; Cyanoacetic Acid; Ethyl Cyanoacetate; Ethyl Lithioacetate; Pentacarbonyliron; Tricarbonyl(cyclohexadienyl)iron Tetrafluoroborate; Tricarbonyl(pentadienyl)iron Tetrafluoroborate.

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David Watt & Miroslaw Golinski

University of Kentucky, Lexington, KY, USA

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