Acetone Hydrazone1

(1; R1 = R2 = H)

[5281-20-9]  · C3H8N2  · Acetone Hydrazone  · (MW 72.11) (2; R1 = H, R2 = Ph)

[103-02-6]  · C9H12N2  · Acetone Phenylhydrazone  · (MW 148.21) (3; R1 = R2 = Me)

[13483-31-3]  · C5H12N2  · Acetone Dimethylhydrazone  · (MW 100.17)

(metalated dimethylhydrazones as anion equivalents are especially useful for regioselective alkylations1,2 and as precursors of unsymmetrical ketone hydrazones;1,3 gem-dimethyl synthons in cycloaddition reactions4)

Physical Data: (1) n22D 1.4607, colorless liquid, bp 124-125 °C; (2) mp 42 °C, rhombic crystals, bp 163 °C/50 mm Hg; (3) light yellow liquid, bp 94-95.5 °C (92-94 °C5).

Solubility: sol alcohol, ether, THF, CH2Cl2.

Analysis of Reagent Purity: (1) nitrogen evolution upon treatment with glacial acetic acid; acetone azine is a common impurity; (2, 3) IR or NMR spectroscopy.

Preparative Methods: (1) is best prepared by either of two methods: from the acetone azine7 or by an exchange reaction between Hydrazine and (3) in the presence of glacial acetic acid.6,8 Both methods give nearly quantitative yields of (1), but the latter method produces hydrazone without azine contamination. The general method for the preparation of phenylhydrazones can be applied to the synthesis of (2).1a,9 Equimolar amounts of Acetone and Phenylhydrazine are refluxed gently in aqueous ethanol with catalytic amounts of glacial acetic acid. The phenylhydrazone separates out upon cooling and can be recrystallized from aqueous ethanol. The synthesis of (2) by reaction of acetone, ammonia, and aniline in the presence of water has also been reported.9b The dimethylhydrazone can be prepared in very high yield by a general procedure for ketones using anhydrous N,N-Dimethylhydrazine.6,8 Hydrazines should be handled with care because of their toxicity. Caution! Anhydrous hydrazine is also highly reactive with oxidizing agents; the syntheses should be carried out behind a protective screen, in a fume hood.

Handling, Storage, and Precautions: (1) usually prepared just before use; unstable in the pure liquid state; disproportionates slowly to hydrazine and acetone azine at rt. Use in a fume hood. It is claimed that simple hydrazones can be stored indefinitely with minimal deterioration in the absence of moisture in the solid state at low temperature.6 Azine formation is rapid in the presence of moisture. Regeneration of old samples is accomplished by heating the hydrazone at 100 °C for 12-16 h before distillation.7 Hydrazones (2) and (3) are relatively stable and can be stored for long periods of time without deterioration.

Hydrazone Oxidations.

The reactions of ketone hydrazones depend largely on the degree and kind of substitution on the N-amino group. Hydrazone (1) (R1 = R2 = H) is most prone to oxidation. Oxidation of (1) in the presence of Mercury(II) Oxide or Silver(I) Oxide and KOH serves as the easiest route to 2-Diazopropane.10 The latter undergoes 1,3-cycloaddition reactions with electrophilic C=C bonds to form substituted pyrazoles,11 vinylic and epoxy quinones,12 and pyrazolines.13 With Diphenylacetylene a pyrazole is formed that can be subsequently photolyzed to a conjugated alkynylcyclopropane.14 Thus (1), being a precursor of 2-diazopropane, serves as a potential source of gem-dimethyl groups in cycloaddition reactions.

Oxidative denitrogenation has also been accomplished by a variety of electrophilic reagents. With HgO/Mercury(II) Acetate, (1) forms an acetoxy adduct that yields 4-acetoxy-4-methylvaleronitrile upon reaction with Acrylonitrile.15 In general, simple ketone hydrazones react with excess Benzeneselenenyl Bromide in the presence of a hindered guanidine base to afford phenyl vinyl selenide16 or with excess Iodine in triethylamine-THF to afford vinyl iodides.17 1-Alkenyl cobalt complexes are formed in the presence of a Co-dioxygen complex. Subsequent reduction by Sodium Borohydride produces propene from (1) and cis alkenes from higher aliphatic ketone hydrazones.18

Phenylhydrazone (2) couples to form a C-N dimer as the oxidation product when treated with Potassium Permanganate in acetone. Upon heating, the dimer gives a vicinal bis(azo)alkane (eq 1).19

Oxidation of (3) generally leads to C=N bond cleavage and has been utilized most successfully to regenerate acetone and other ketones from their dialkylhydrazones. Oxidizing agents that are commonly used for this purpose include Ozone at low temperature,20a Sodium Perborate, Sodium Periodate, and H5IO6.20 With Selenium(IV) Oxide, however, oxidation leads to a-carbonylation in high yield.21


1,3-Dipolar cycloaddition reactions involving hydrazones offer a very versatile means of synthesizing five-membered heterocyclic rings. Cycloadditions between (1) and nitrile oxides form oxadiazolines in modest yields.22 Cyclocondensation of benzoylhydrazinoacrylate from (1) affords aminoquinolonecarboxylates.23 An alternative to the Piloty-Robinson pyrrole synthesis has been used by Baldwin24 to prepare pyrroles from any enolizable aldehyde or ketone via azines synthesized from the corresponding hydrazones. The reaction is shown for (1) (eq 2).

The Fischer indole synthesis provides an efficient route for the synthesis of indoles and related compounds from phenylhydrazones. Heating (2) in the presence of Zinc Chloride, Formic Acid/H2SO4, formic acid/HCl, or modified alumina catalysts provides 2-methylindole in modest to high yields. Indole formation is favored when anhydrous acid catalysts are used at high temperature to promote formation of the ene-hydrazine intermediate (eq 3).25,26 In addition, b-lactams27 and triazolinones28 have also been synthesized from (2). Some cyclic diaza compounds containing other heteroatoms have been prepared from phenylhydrazones. Cycloaddition with thiocyanates or Carbon Disulfide leads to the formation of substituted thiadiazolidines (eq 4).29 Treating (2) with Phosphorus(III) Chloride or AsCl3 results in the formation of diazaphosphole and diazaarsole in modest yields (eq 5).30

With (3) and other ketone dimethylhydrazones, formation of heterocycles occurs via annulation reactions of their condensation or alkylation products. The strategy involves either a Michael-type addition or 1,2-addition of the azaallyl anion of (3) to carbonyl compounds or esters followed by a ring closure step to afford dihydropyridines31 and substituted pyridines.32 1-Pyrrolines have also been prepared in good yield by alkylation of the anion of (3) with o-iodo azide followed by treatment with Triphenylphosphine (eq 6).33

Metalation and Anion Formation.

Hydrazones react with strong bases to deprotonate the amide NH as well as the a-carbon. Deprotonation usually occurs on the less substituted a-position. The anions thus formed are not isolated, but are used immediately in synthesis. N-Deprotonation proceeds smoothly and almost exclusively with equimolar amounts of NaH,29,34,35 NaNH2 or KNH2 in liquid ammonia,36 LDA at 0 °C, KDA, n-BuLi, or t-BuLi at -78 °C.37-39 Anions generated by hydride deprotonations of (2) have been used in N-alkylation reactions with alkyl halides34 and in a cycloaddition reaction with phenyl isothiocyanate (eq 4).29 Alternatively, equilibrium deprotonations using 50% aqueous NaOH with a phase-transfer catalyst or NaOH in DMF may be used to generate the azaanion in the presence of alkyl halides.34,40 The lithium anion of (2) can undergo N-sulfonation and is also used in the synthesis of siladiazacyclopentenes (eq 7).41,42

Carbanions from (3) and N-deprotonated (1) and (2) are most commonly generated by reaction with an alkyllithium reagent at -78 °C or LDA at 0 °C using THF or THF/HMPA as solvents. KDA can also be used and has been preferred by some workers due to a more rapid reaction rate and a wider range of hydrazone substrates.39 The azaallyl lithium and potassium reagents thus generated have limited thermal stability due to side reactions arising from addition to the sp2 carbon.43 Transmetalation of the azaallyl lithium anion of (3) with either CuI-Me2S39,44 or CuI-i-Pr2S38 provides a route to the formation of the corresponding homocuprate derivative. The mixed cuprate is obtained if CuI thiophenoxide is used.38b


Dimethylhydrazone (3) serves as a presursor of unsymmetrical ketone hydrazones via a-alkylation reactions involving allyl and alkyl halides, dihalides, tosylates, and epoxides. Compounds (4)-(10) are examples of compounds prepared from (3) and the appropriate alkylating agent. Most of the alkylation products serve as intermediates in the asymmetric synthesis of a wide variety of natural products, e.g. exogonol,45 rutamycin antibiotics,46 insect pheromones,5a,47 lycopodium alkaloids,48 homotropanes,49 pyrenophorin,50 zingeron,51 and the jasmonoids.52 The use of (3) is preferred over acetone in these reactions because the latter tends to undergo self-aldol condensation in the presence of base rather than C-alkylation. Alkylation occurs at the less substituted carbon of unsymmetrical derivatives of (3)36 unless there is an anion stabilizing group present. A study by Rapoport showed a 50:1 preference for the monoalkylation product.49a Other functional groups are not usually affected during alkylation or carbonyl regeneration. However, partial debenzylation or hydrolysis of the THP ether upon prolonged heating has been observed in Cu-catalyzed hydrolysis.49

Alkylation also provides a method for synthesis of isotopically labeled hydrazones.53 Use of allyl bromide and 4-bromo-1-butene furnishes unsaturated dimethylhydrazones that can be cleaved by ozonolysis to produce 1,4- and 1,5-keto aldehydes in good yields. These compounds are used in annulation reactions to produce medium-sized rings.54

Condensation Reactions.

Anions of (1) may undergo condensation reactions with carbonyl compounds and nitriles. Aldol-type condensations using trianions of simple hydrazones have been reported.19 The monolithium salt of (1) adds to acetonitrile and t-butyl chloride to yield an amidrazone which can then be cyclized to a triazoline (eq 8).55

Phenylhydrazone (2) adds to acetyl isocyanate to give aryl-substituted triazolinones upon elimination of acetone (eq 9).54 The azaallyl lithium reagent from (3) undergoes aldol-like reactions with carbonyl compounds to give high yields of b-hydroxyhydrazones. The strategy described by Corey and Enders37 entails generation of the anion by BuLi, addition of the aldehyde or ketone to yield the b-hydroxy hydrazone, and oxidative cleavage using NaIO4 in methanol at pH 7 to regenerate the carbonyl compound. This approach has been applied to the synthesis of compounds (11)-(15) (yields are shown). Periodate does not affect the b-hydroxy groups in these compounds. Ester hydrazone (18) was used as an intermediate in the synthesis of a-pyrones (2H-pyran-2-ones).56

A stereoselective aldol-type synthesis of (+)-S-[6]-gingerol (60% ee) was achieved via a chiral a-sulfinylhydrazone from an unsymmetrical ketone hydrazone derived from (3) (eq 10).57,58 This synthesis complements Ender's synthesis of (-)-R-[6]-gingerol (36% ee) via SAMP-hydrazone.51

In the presence of a,b-unsaturated ketones, mixed and homocuprates of (3) undergo conjugate addition to form 1,5-ketohydrazones (16)-(18).37,38 Heathcock used the homocuprate to prepare a synthesis intermediate of lycopodine. However, Sakurai's method using methallyltrimethylsilane provided higher yields (90%) of the same compound.47

An alternative route to b-keto hydrazones involves a Claisen-type condensation of (3) with N-methoxy-N-methylbenzamide (eq 11)59a and a variety of acylating agents.59b With carbon disulfide, lithium dimethylhydrazonoalkanedithioate is the initial product from which alkyl dithiolates can be prepared in good yields by reaction with various alkyl iodides.60 The azaallyl potassium from (3) undergoes conjugate addition to vinyl sulfones. The adduct serves as an intermediate in annulation reactions for seven-membered rings.61

Removal of the hydrazone group is often one of the steps in these reactions. Bergbreiter1c gives a comprehensive list of oxidative and hydrolytic regeneration schemes for ketone and aldehyde hydrazones.

Other Reactions.

Wolf-Kishner reduction of (1) to propane occurs in the presence of strong alkali at high temperature. Hydrogenation of (2) using Pd/C catalyst affords isopropylamine.62 Heating (2) in base results in its isomerization to methylphenyldiimide.63 With difluoramine, N-fluoroketimine is produced in a vigorous reaction.64 N-Acylation of (3) in the presence of various acid chlorides produces ene-hydrazides in high yields.65

Related Reagents.

Acetoacetic Acid; Acetone; Acetone Cyclohexylimine; 2-Diazopropane; N,N-Dimethylhydrazine; Ethyl Acetoacetate; Hydrazine; Phenylhydrazine; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.

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Milagros Momongan Peralta

University of the Philippines at Los Banos, Laguna, Philippines

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