Synthesis of ketoximes under ultrasound irradiation

Li Xiaoliang, Li Jitai
(College of Chemistry and Environmental Science, Hebei University; Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding 071002, China)

Abstract The condensation of ketones with hydroxylamine hydrochloride results ketoximes in good yields in EtOH under ultrasound irradiation. Compared with conventional methods, the present procedure has several advantages such as mild conditions, simple reaction procedure, short reaction time and high yields.

Oximes are highly crystalline and extensively used for the characterization and purification of aldehydes and ketones. These compounds also have other applications such as the preparation of amides,[1] amines,[2] nitric oxide,[3] methylene dioximes[4] and nitriles.[5] Furthermore, oximes have served for the protection of carbonyl groups as exemplified in the synthesis of erythromycin derivatives and perhydrohistrionicotoxin.[6] Oximes may also be used as inhibitors of enzymes. For instances, some oximes are highly active tyrosinase inhibitors for skin lightening or antibrowning, because they may be able to complex the two copper atoms in the active site of tyrosinase;[7] the benzophenone oxime analogues may be used as inhibitor of secretory phospholipase A2 with anti-inflammatory activity;[8] pyridine carbaldoximes and alkyl pyridyl ketoximes act as strong non-competitive inhibitors of the enzymes.[9]
    The condensation of primary amine with RR’ C=O compound was first reported by Schiff in 1864 and since then a great number of these reactions were performed and reviewed. The experimental conditions depend mostly on the nature of the parent materials and basicity of the reaction medium. In organic chemistry, it is generally believed that reactions of RR’C=O and hydroxylamine at pH close to neutral occurred through nucleophilic attack of the nitrogen electron pair to the electrophilically activated C=O carbon, while in strongly basic media the attacking agent is most likely the anion N HOH or NHO .[10] Usually, the condensation of carbonyl compounds with hydroxylamine hydrochlorides needs longer reaction time and higher reaction temperature.[7, 11-15] Furthermore, because of the electronic and steric factors, ketones are less reactive to nucleophiles than aldehydes. Therefore, the synthesis of ketoximes is more difficult than the synthesis of aldoximes.
The chemical applications of ultrasound, “Sonochemistry”, have become an exciting new field of research during the past decade. Ultrasound has increasingly been used in organic synthesis in recent years. A large number of organic reactions can be carried out in higher yield, shorter reaction time and milder conditions under ultrasonic irradiation.[16] All of those stated above prompted us to study the synthesis of ketoximes in EtOH under ultrasound irradiation (Scheme 1).


Scheme 1

Liquid ketones were purified by distillation prior to use. Melting points were uncorrected. Sonication was performed in Shanghai Branson-CQX ultrasonic cleaner with a frequency of 25 kHz and a nominal power 250 W. The reaction flasks were located in the maximum energy area in the cleaner (Observation of the surface of the reaction solution during vertical adjustment of vessel depth will show the optimum position by the point at which maximum surface disturbance occurs), andthe addition or removal of water controlled the temperature of the water bath.
2.1 General procedure
The appropriate ketone (, 1 mmol) was dissolved in ethanol (5 mL). A solution of hydroxylamine hydrochloride (, 1.25 mmol, HO, 0.5 mL), anhydrous sodium acetate (1 mmol or 0 mmol) were added. The reaction mixture was irradiated in the water bath of the ultrasonic cleaner at 25-35 C for a period as indicated in Table 1. The mixture was filtered (without filtration, if no NaOAc added).The solvent was evaporated under reduced pressure. The residue was dissolved in CHCl, washed with water, and extracted with CHCl. The combined organic layers were dried over anhydrous MgSO, filtered, and evaporated to dryness under reduced pressure. The further purification was accomplished by recrystallization or by column chromatography on silica (200-300 mesh, eluted with petroleum ether or a mixture of petroleum ether and diethyl ether). The authenticity of the products was established by comparing their melting points with the data in the literatures.

Table 1Condensation of ketones with hydroxylamine hydrochloride under ultrasound irradiation

Entry Substrate / min Dehydration agent Isolated yield  /% m.p. / C (lit.)
  -ClCCOCH 150


96-98 (97.5-98) [15]






  -ONCCOCH 150


174-175 (174) [14]




  -ONCCOCH 180


129-131 (131-132) [17]




84-87 (87) [18]


  COC 180


139-142 (141-142) [13]



  COCH 120


54-57 (56-58) [19]



  cyclohexanone 20


85-86 (86-88) [20]



  cyclopentanone 180


53-56 (56.5) [21]



  CHCOCH 150


123-125(125) [21]



  camphor 180



113-116 (118) [21]
  anthrone 180


no reaction

Refluxed in ethanol without ultrasound.
The reaction temp. is 40-45

The results were summarized in Table 1. It can easily be seen that the condensation of ketones with hydroxylamine hydrochloride leads to ketoximes in good yields under ultrasound irradiation. For example, compound 3a was previously prepared in 93.5% yield in ethanol at reflux temperature for 5 h [15], whereas under ultrasonication, 3a was obtained in 94% at 20-30C within 150 min.
We also did experiments in the absence of ultrasound, the condensation of -chloroacetophenone and hydroxylamine hydrochloride in the presence of NaOH was refluxed in ethanol for 5 h to produce -chloroacetophenone oxime (3a) in 93% yield, the condensation of -nitroacetophenone and hydroxylamine hydrochloride was refluxed in ethanol for 150 min to give -nitroacetophenone oxime (3b) in 27% yield; 3d was obtained in 13% yield only in refluxed ethanol for 180 min. (Table 1). It is apparent that the ultrasound can accelerate the condensation reaction of ketones with hydroxylamine hydrochloride.
The reaction temperature has little effect on the reaction yield of -nitroacetophenone oxime (3b). Under ultrasonication, compound 3b was obtained in 92%at 20-30for 150 min, whereas at 40-45C, 3b was prepared in 94% for 150 min. In addition, the existence of dehydration agent can improve the yield. In the presence of NaOAc, acetophenone oxime was obtained not only in higher yield but also in shorter reaction time than that in the absence of NaOAc.
Steric factors also have a role to play in the reactivity of ketones. For example, the acetophenone oxime was prepared in 79% yield in EtOH for 120 min, while the benzophenone oxime was prepared in 17% yield in EtOH for 180 min, and no anthrone oxime was obtained.

In conclusion, we have found an efficient and convenient procedure for the preparation of ketoximes via the condensation of ketones with hydroxylamine hydrochloride under ultrasound irradiation. Compared with the reported, the main advantages of the present procedure are milder conditions, easier work-up, higher yields and shorter reaction period.

AcknowledgementsThe project was supported by Educational Ministry of China, Educational Department of Hebei Province (2001104) and Natural Science Foundation of Hebei Province (B2006000969), China.