Acetone Cyclohexylimine

[6407-36-9]  · C9H17N  · Acetone Cyclohexylimine  · (MW 139.24)

(acetonyl equivalent via lithiation and reaction with electrophiles;1 mild directed aldol condensation;2 Pd-catalyzed a-arylation of ketones3)

Alternate Name: N-(2-propylidene)cyclohexylamine.

Physical Data: bp 180.6 °C,4 70-72 °C/16 mmHg,5 30 °C/1.8 mmHg;6 n20D 1.4671.

Solubility: sol most organic solvents.

Form Supplied in: colorless liquid; not commercially available.

Analysis of Reagent Purity: GC; 1H NMR; IR (presence of ketone by hydrolysis).

Preparative Methods: condensation of Acetone with cyclohexylamine with or without various solvents (eq 1).4-7 The removal of water is performed afterwards with solid Sodium Hydroxide.4

Handling, Storage, and Precautions: very sensitive to hydrolysis; storage in closed vessels under inert atmosphere in the refrigerator. It is recommended to prepare the reagent freshly before each preparation. After some weeks of storage, purification by distillation is recommended. Use in a fume hood.

Introduction.

Acetone cyclohexylimine is the most frequently used acetone imine. Some attention will be given to the N-isopropyl analog, while lower alkyl derivatives, e.g. acetone methylimine, are too labile for general use.

Introduction of Acetonyl Group.

In general, most enolates have to be kept and reacted at -78 °C or lower in order to obtain useful results, as otherwise self-condensation reactions and nonselective reactions take place. This disadvantage can be circumvented by working with imines instead of ketones.2,8 Imines derived from acetone and methylamine or ethylamine are difficult to handle, while the relatively stable N-cyclohexylimine derived from acetone offers no problems in handling.2 One inconvenience is certainly the more complex NMR spectra of the reaction products. Since the desired end-products are usually carbonyl compounds, formed by acidic hydrolysis of these imines, the N-cyclohexyl group is only a temporary disadvantage. The most common use of acetone cyclohexylimine is their conversion into their nucleophilic lithiated salts, i.e. 1-azaallylic anions (metalloenamines), which are much more stable than enolates and which do not suffer from proton transfer during further reactions with electrophiles. Acetone cyclohexylimine is readily deprotonated by Lithium Diethylamide (mostly in benzene-HMPA),1 Lithium Diisopropylamide (in ether or THF),2 or n-Butyllithium (in THF) (eq 2).9 Less frequently used deprotonating agents are Potassium-Graphite10 or Potassium on Alumina.11

The deprotonation is usually followed by the reaction with an electrophile (E+), affording the a-substituted ketimine (eq 2). Lithiation of imines has syn selectivity (eq 3; the formula represents a gross structure, not indicating the definitive position of the Li counterion).12,13

Lithiated acetone cyclohexylimine reacts smoothly with alkyl and allyl halides to form the a-alkylated or a-allylated imines, which are readily hydrolyzed by aqueous acid to afford the corresponding acetonylated compounds (eq 4).1 Higher analogs, e.g. 2-butanone N-cyclohexylimine, after deprotonation, react regiospecifically with electrophiles at the methyl group.1 Double alkylations of acetone cyclohexylimine at the a- and a-position and subsequent hydrolysis into a,a-dialkylated acetones have been reported (eq 5).1 In a similar way, o-halo ketones (eq 6),1,14 g,d-unsaturated-g-halo ketones (eq 7),1a 1,4-diones (eq 7),1a g,d-unsaturated-d-halo ketones,1b and 1,5-diones1b are accessible.

1-Azaallylic anions have been utilized for the synthesis of dihydrojasmone (eq 8),1a,29 geranylacetone,15 cis-jasmone,29 and other functionalized 2-alkanones.16 Similar a-alkylations have been performed with aldimines.17-19

The use of potassium-graphite (C8K) in THF10 or highly dispersed potassium on alumina in THF11 at room temperature is an alternative method for the lithiation of acetone cyclohexylimine, but the alkylated acetones are obtained in moderate to low yields (eqs 9 and 10). Better yields of acetonylation products are obtained by lithiation of acetone N-isopropylamine with Lithium in THF in the presence of graphite30 or phenanthrene31 as hydrogen acceptor, followed by reaction of the lithio salt with electrophiles, e.g. iodobutane, to afford a-monoalkylated acetones after acidic hydrolysis.

Directed Aldol Condensation.

Lithiated acetone cyclohexylimine reacts with benzophenone to afford the corresponding isolable b-hydroxy ketimine, which undergoes hydrolysis and dehydration on treatment with aqueous sulfuric acid, while the ketol is obtained under milder hydrolytic conditions using silica gel and water (eq 11).20 Similar condensations of lithiated acetone cyclohexylimine with benzonitrile or ethyl chloroformate afforded a b-amino-a,b-unsaturated imine21 or an enamino ester,2 respectively (eqs 12 and 13).

Palladium-Catalyzed Arylation.

Condensation of acetone cyclohexylimine with bromobenzene in the presence of sodium t-butoxide, Palladium(II) Acetylacetonate, and tris(N-cyclohexyl-N-methylamino)phosphine in THF is reported to afford phenylacetone after hydrolysis (eq 14).3

Reactions of 1-Azaallyl Anions with Michael Acceptors.

Lithiated acetone cyclohexylimine reacts with a-methylthiovinyl sulfoxides to give the Michael adducts, which are suitable precursors for g-keto aldehydes (eq 15).22

Lithiation of acetone cyclohexylimine and further treatment with Copper(I) Iodide produces a copper azaallyl species which undergoes Michael addition to 2-methyl-2-cyclopentenone, the resulting adduct being trapped by Chlorotrimethylsilane (eq 16).9 However, it has been reported that lithiated acetone cyclohexylimine condensed with 2,6,6-trimethyl-2-cyclohexenone to give the 1,2-adduct (eq 17).23 Lithiated acetone cyclohexylamine gives a 9,10-adduct with acridine (eq 18).21

Lithiated acetone isopropylimine adds to the double bond of a-(N-methyl-N-phenylamino)acrylonitrile to give the Michael adduct, which is alkylated and ring closed to afford 2,5-dimethyl-1-isopropylpyrrole (eq 19).38

The reaction of acetone cyclohexylamine with Methyl Acrylate without added base has been investigated in detail. Several reactions take place depending on the concentrations; in particular, C-alkylation but no N-alkylation products are observed (eq 20).24 The lack of N-alkylation contradicts a previous report which stated that only N-alkylation took place.25,26

Direct condensation of excess acetone N-isopropylimine with Methyl Vinyl Ketone is a suitable method for the synthesis of 3-methyl-2-cyclohexenone via subsequent Michael addition, intramolecular aldol condensation, and hydrolysis (eq 21).32

Miscellaneous.

Oxidation of acetone cyclohexylimine with m-Chloroperbenzoic Acid gives 2-cyclohexyl-3,3-dimethyloxaziridine (eq 22),6 while the condensation with pyridinium iodides in DMSO affords indoles.27 Complete exchange of all six a-hydrogens of acetone cyclohexylimine has been accomplished through photolysis (125 W mercury lamp) in acetone-d6.28 Acetone N-isopropylimine reacts with nitroso-arenes through an ene reaction to form nitrones via intermediate hydroxylamines and aminyl oxides.33 Carbonyl diisocyanate condenses with acetone N-isopropylimine in ether to give the labile [1,3,5]triazino[2,1-b]-1,3,5-oxadiazine-4,8-dione, which is hydrolyzed into hexahydro-N,3-diisopropyl-2,2-dimethyl-4,6-dioxo-1,3,5-triazine-1-carboxamide (eq 23).34

Heating acetone N-isopropylimine with Triethylborane at 100 °C for 7 days produced diethyl-substituted vinylaminoboranes (eq 24).35

The Ni-ligand catalyzed reaction of acetone N-isopropylimine with 1,3-butadiene generated unsaturated amines (eq 25).36,37

Lithiated acetone cyclohexylamine condenses with chloro- or Bromoacetone to afford 1-cyclohexyl-2,4-dimethylpyrrole (eq 26).39 The same imine is converted into 1-cyclohexyl-3,3-dimethyldiaziridine by reaction with Chloramine (eq 27).5

Related Reagents.

Acetaldehyde N-t-Butylimine; Acetone Hydrazone; Diketene; N,N-Dimethylhydrazine; Ethyl Acetoacetate; 2-Methoxypropene; Methyl Dilithioacetoacetate; Propionaldehyde t-Butylimine; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


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Norbert De Kimpe

University of Gent, Belgium



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