Synthesis of oximes is an important reaction in organic chemistry, because these versatile oximes are used for protection, purification, and characterization of carbonyl compounds. Nitriles, amides via Beckmann rearrangement, nitro compounds, nitrones, amines, and azaheterocycles can be synthesised from oximes. They also find applications for selective α-activation. In inorganic chemistry, oximes act as a versatile ligand.
Several procedures for the preparation of oximes exist, but, most of them have not addressed the green chemistry issue. They are associated with generation of pollutants, requirement of high reaction temperature, low yields, lack of a generalized procedure, etc. Hence, there is a demand for developing an efficient, convenient, and non-polluting or less polluting alternative method for the preparation of oximes. In this context, bismuth compounds are very useful as they are cheap in general, commercially available, air stable crystalline solids, safe, and non-toxic, hence easy to handle.
Results
Carbonyl compounds (aliphatic, heterocyclic, and aromatic) were converted into the corresponding oximes in excellent yields by simply grinding the reactants at room temperature without using any solvent in the presence of Bi2O3. Most importantly, this method minimizes waste disposal problems, provides a simple yet efficient example of unconventional methodology and requires short time.
Conclusions
We have developed a novel, quick, environmentally safe, and clean synthesis of aldoximes and ketoximes under solvent-free grinding condition.
Conversion of carbonyl functionalities into oximes is an important reaction in organic chemistry. Oximes are highly crystalline compounds that find applications not only for protection, but also for purification and characterization of carbonyl compounds [1, 2].Conversions into nitriles [3], nitro compounds [4, 5], nitrones [6], amines [7], and synthesis of azaheterocycles [8] are some of the synthetic applications of oximes. They are also useful for selective α-activation [9] and are extensively used as intermediates for the preparation of amides by the Beckmann rearrangement [10, 11] and fungicides and herbicides [12]. In inorganic chemistry, oximes act as a versatile ligand.
Classically, oximes are prepared [2] by refluxing an alcoholic solution of a carbonyl compound with hydroxylamine hydrochloride and pyridine. The method has multiple drawbacks such as low yields, long reaction time, toxicity of pyridine, and effluent pollution caused by the use of organic solvent. In recent times, solvent-free reactions have drawn considerable attention and popularity [13, 14], not only from an environmental point of view, but also for synthetic advantages in terms of yield, selectivity, and simplicity of the reaction procedure. Since chemical industry deals with larger quantity of materials, these factors are particularly very important therein. Over the years, many reagents and catalysts have been developed for the synthesis of oximes. Basic aluminia [15], CaO [16], and TiO2/(SO42-) [17] coupled with microwave irradiation under solvent-free condition have been claimed to be efficient methods for the preparation of oximes. Hashem Sharghi and Hosseini [18] described a solventless reaction protocol for synthesizing aldoximes from corresponding aldehydes using ZnO as catalyst at 80°C. Interestingly, they obtained Beckmann rearrangement product at higher temperatures (140-170°C). More recently, conversion of carbonyl compounds to oximes in aqueous biphasic medium and ionic liquid/water biphasic system [19, 20] has been reported. However, problems of generation of polluting HCl, high reaction temperature, occasionally low yields, and lack of a generalized procedure covering all types of aldehydes and ketones still present. Consequently, there is a demand for developing an efficient, convenient, and non-polluting or less polluting alternative method for the preparation of oximes. In this context, because of the rich chemistry of bismuth compounds [21–25], we became interested therein. Bismuth compounds are generally cheap, commercially available, air stable crystalline solids, safe, and non-toxic, hence easy to handle. Their Lewis acidity is also well known [26, 27]. Most bismuth(III) compounds have an LD50 value which is comparable to or even less than that of NaCl [28].
In continuation to our interest in protection and deprotection chemistry [29, 30], we have developed a novel, quick, environmentally safe, and clean synthesis of aldoximes and ketoximes under grinding condition (Scheme 1) utilizing pestle and mortar under solvent-free condition. The method makes use of local heat generated by simply grinding the reactants and catalyzed by cheap and commercially available Bi2O3 for driving the chemical reaction at room temperature. The work up is easy and furnished the oximes in excellent yields. Most importantly, this method minimizes waste disposal problems and provides a simple yet efficient example of unconventional methodology, which is equally effective for all types of aldehydes and ketones. Earlier reports [15, 31] of similar type restricted their utility in carbonyl compounds (alicyclic and aliphatic) and aromatic aldehydes only and aromatic ketoximes were not obtained. In those reports, for ketoxime synthesis, microwave irradiation or addition of some other additives was necessary. In this regard, our method is superior, quite general, and versatile.
Scheme 1
Synthesis of aldoximes and ketoximes.
2. Results and discussion
In the present solvent-free method, the effectiveness of Bi2O3 in oxime synthesis (see Scheme 1) under grinding condition is demonstrated using a broad spectrum of aldehydes and ketones with hydroxylamine hydrochloride in the absence of a base or any other additives. To search for the best reaction condition for oximation using easily available bismuth compounds, a set of reactions have been carried out using p- chlorobenzaldehyde and hydroxylamine hydrochloride as substrates under various reaction conditions at constant catalyst (Bi2O3 and BiOCl) loading (50 mol% with respect to substrate). Figure 1 summarizes the results, which clearly shows that the Bi2O3 under solvent-free grinding condition is the most effective.
Figure 1
Effect of reaction conditions in yields.
After surveying a series of reaction conditions, the optimized results are summarized in Table 1. Aromatic, aliphatic, heterocyclic, and α,β-unsaturated aldehydes were converted to the corresponding oximes in almost quantitative yields within very short time (1.5-3 min, entries 1a-k, Table 1). Cinnamaldehyde (entry 1j, Table 1) was smoothly converted to cinnamaldehyde oxime without any rearrangement of α,β-double bond. For ketones (acyclic and cyclic), however, reactions were comparatively difficult and took a little longer time (5.5-20 min, entries 1l-q, Table 1). It was interesting to note that the less reactive benzophenone also condensed with hydroxylamine hydrochloride in 60% yield only that too requiring longer time, i.e., 20 min (entry 1q, Table 1). 5α-Pregn-16-en-3α-ol-20-one acetate oxime (entry 1l, Table 1) was obtained in 88% yield within 6 min. The unreacted materials were recovered from the reaction mixture. No observable difference in reactivity exerted by -NO2 group at m- or p-position was noticed (entries 1b and c, Table 1), being yields and reaction times were almost same. Entities such as chloro, nitro, hydroxyl were found to be inert to the reaction condition. The products were identified by their spectral (1H NMR,13C NMR, IR spectra) data, physical data (melting point, elemental analysis), and comparison with authentic ones. IR spectra supported this observation as no peak was observed around 2200 cm-1 characteristic of the -C≡N group. However, appearance of peaks around 3200-3450 and 1600-1680 cm-1 are indicative of -OH and >C = N- groups, respectively. In1H NMR spectra, the -OH signal of oximes appeared within δ = 8.0-10.00 ppm as a broad singlet (characteristic signal) that was exchangeable with D2O. It was very appealing that in these reactions neither the dehydration product, nitriles, nor the amides, via Beckmann rearrangement were observed. The reaction was very clean and no other product was observed.
Table 1
Preparation of aldoximes and ketoximes 2a
Entry
Substrate 1
Product 2
Time (min)
Isolated yield (%)
Mp/°C (Lit.)
a
1.5
95
-(35)b
b
2
96
105 (107)b
c
2
96
130 (133)b
d
2
95
120 (122)b
e
2
>98
75 (80)b
f
3
95
74 (72)b
g
2.5
98
128 (132)b
h
2
95
72 (-)c
i
2
>98
128 (132-136)b
j
2
>98
135 (139)b
k
6
88
197 (195.5-198)b
l
3
96
-(52)b
m
5.5
92
-(57)b
n
6
95
86 (91)b
o
7
>98
56 (59)b
p
6.5
>98
86 (88)b
q
20
60
140 (144)b
aAll compounds were characterized on the basis of IR,1H and13C NMR spectral data, Mass spectrometry data and mp.
b(i) Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (2008) Vogel's textbook of practical organic chemistry, 5th edn. Pearson Education, Dorling Kindersley (India). (ii) Alfa-Aesar Research Chemicals, Metals and Materials catalogue, 2008-2009.
cNot found in the literature.
To evaluate the synergy between rate, yield, and Bi2O3 loading in this reaction, several experiments were carried out. In a pilot experiment, the reaction was found to proceed poorly in the absence of Bi2O3. As far as Bi2O3 loading is concerned, 60 mol% of the catalyst with respect to the substrate was the optimum one (Table 2). An increase in Bi2O3 loading did not improve the yield as well as no change in reaction time was observed. However, a decrease in Bi2O3 loading appreciably decreased the rate and yield of the reaction.
Table 2
Optimization of catalyst loading in preparation of 2b
Entry
Catalyst loading (mol%)
Time
Yield (%)
1
No
2 h
15
2
20
30 min
48
3
30
30 min
57
4
40
30 min
70
5
50
15 min
90
6
60
2 min
96
7
70
2 mins
96
We have also checked the reusability of the catalyst using the recovered Bi2O3 from the reaction. It is observed that recovered catalyst could be satisfactorily used for the second run, whereas, third run of the recovered catalyst leads to poor yield and longer reaction time (Table 3). The surface areas of the fresh as well as the recovered catalyst after the third run in the reaction were determined in a surface area and pore size analyzer and found to be 5.21 and 37.106 m2/g, respectively. The average particle diameters of the fresh as well as the recovered catalyst after the third run in the reaction were calculated out from these measured surface areas and were found to be 129.396 and 18.168 nm, respectively. The increase in granularity of the catalyst after reuse is obvious since it was grounded. However, the decrease in efficiency of the catalyst after the third run might be due to the loss of active sites of the catalyst.
Table 3
Reusability of Bi2O3 in the preparation of 2b using 60 mol% of the catalyst
Entry
Run number
Time
Yield (%)
1
1
2
96
2
2
8
87
3
3
20
52
3. Conclusions
To the best of our knowledge, Bi2O3 has never been used in the synthesis of oximes earlier. In conclusion, the reported procedure is an interesting, extremely simple, suitable, fast, efficient, and novel method for the preparation of oximes. The methodology also offers chemical, economical, and environmental advantages. On the other hand, Bi2O3 is remarkably easier to use, non-hazardous, inexpensive and work under mild neutral conditions [32, 33].
4. Experimental
Melting points were determined on a Büchi 504 apparatus and were uncorrected. IR spectra were recorded in KBr pallets on a Nicolet (Impact 410) FT-IR spectrophotometer.1H NMR and13C NMR spectra were recorded on a JNM ECS 400 MHz FT-NMR (JEOL) spectrophotometer with TMS as the internal standard. Mass spectra were recorded on a Waters Q-TOF Premier & Aquity UPLC spectrometer. Surface area of the catalyst before and after use in the reaction was measured using surface area & pore size analyzer (NOVA 1000e, Quanta chrome Instruments). All the chemicals were used as-received.
5. Methods
5.1. Typical procedure for the formation of oxime 2
A mixture of aldehyde/ketone 1 (1 mmol), hydroxylamine hydrochloride (1.2 mmol), and Bi2O3 (0.6 mmol) was grounded in a mortar with a pestle for the required period of time. On completion of the reaction as monitored by TLC, ethyl acetate (2 × 10 mL) was added to the reaction mixture and filtered to separate the Bi2O3. The filtrate was concentrated down to approx. 6 mL, then added water to it when product precipitated out from the solution. The precipitate was filtered out and dried in high vacuum to furnish the pure oxime 2 in 60-98% yield.
Abbreviations
IR:
infrared
LD50
:
lethal dose that kills half (50%) of the animals tested
NMR:
nuclear magnetic resonance.
Declarations
Acknowledgements
The authors are very grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for financial support to the project CSIR (01(2147)/07/EMR-II).
Authors’ Affiliations
(1)
Department of Chemical Sciences, Central University
(2)
Chembiotek
(3)
TCG Lifesciences Ltd.
References
Sandier SR, Karo W: Organic functional group preparations. 2nd edition. Academic Press: San Diego; 1989:431–476.Google Scholar
Greene TW, Wuts PGM: Protective groups in organic synthesis. 3rd edition. Wiley: Toronto; 1999:355–358.View ArticleGoogle Scholar
Dewan SK, Singh R, Kumar A: One pot synthesis of nitriles from aldehydes and hydroxylamine hydrochloride using sodium sulphate (anhyd) and sodium bicarbonate in dry media under microwave irradiation. Arkivoc 2006, (ii):41–44.Google Scholar
Dave PR, Forshar F: Facile preparation of 3,7-diazabicyclo[3.3.0]octane and 3,7,10-triheterocyclic[3.3.3]propellane ring systems from 1,5-diazacyclooctane-3,7-derivatives.J Org Chem 1996,61(25):8897–8903. 10.1021/jo9614755View ArticleGoogle Scholar
Ballistreni FP, Barbuzzi E, Tomaselli GA, Toscano RM: Useful oxidation procedure of oximes to nitro compounds with Benz-Mo in acetonitrile.Synletters 1996, 11: 1093–1094.Google Scholar
Smith PAS, Gloyer SE: Oxidation of dibenzylhydroxylamines to nitrones. Effects of structure and oxidizing agent on composition of the products.J Org Chem 1975,40(17):2508–2512. 10.1021/jo00905a019View ArticleGoogle Scholar
Negi S, Matsukura M, Mizuno M, Miyake K, Minami N: Synthesis of (2R)-1-(4-Chloro-2-pyridyl)-2-(2-pyridyl)ethylamine: a selective oxime reduction and crystallization-induced asymmetric transformation.Synthesis 1996, 8: 991–996.View ArticleGoogle Scholar
Narasaka K: Synthesis of azaheterocycles from oxime derivatives.Pure Appl Chem 2003,75(1):19–28. 10.1351/pac200375010019View ArticleGoogle Scholar
Whitesell JK, Whitesell MA: Alkylation of ketones and aldehydes via their nitrogen derivatives.Synthesis 1983, 7: 517–536.View ArticleGoogle Scholar
Ramalingan C, Park Y-T: Mercury-catalyzed rearrangement of ketoximes into amides and lactams in acetonitrile.J Org Chem 2007, 72: 4536–4538. 10.1021/jo070297kView ArticleGoogle Scholar
Furuya Y, Ishihara K, Yamamoto H: Cyanuric chloride as a mild and active Beckmann rearrangement catalyst.J Am Chem Soc 2005, 127: 11240–11241. 10.1021/ja053441xView ArticleGoogle Scholar
Song BA, Liu XH, Yang S, Hu DY, Jin LH, Zhang YT: Recent advance in synthesis and biological activity of oxime derivatives.Chin J Org Chem 2005,25(5):507–525.Google Scholar
Metzger JO: Solvent-free organic syntheses.Angew Chem Int Ed 1998, 37: 2975–2978. 10.1002/(SICI)1521-3773(19981116)37:21<2975::AID-ANIE2975>3.0.CO;2-AView ArticleGoogle Scholar
Kad GL, Bhandari M, Kaur J, Rathee R, Singh J: Solventless preparation of oximes in the solid state and via microwave irradiation.Green Chem 2001, 3: 275–277. 10.1039/b107356gView ArticleGoogle Scholar
Sharjhi H, Sarvari MH: A mild and versatile method for the preparation of oximes by use of calcium oxide.J Chem Res (S) 2000, 1: 24–25.View ArticleGoogle Scholar
Guo JJ, Jin TS, Zhang SL, Li TS: TiO2/SO42-: an efficient and convenient catalyst for preparation of aromatic oximes.Green Chem 2001, 3: 193–195. 10.1039/b102067fView ArticleGoogle Scholar
Sharghi H, Hosseini M: Solvent-free and one-step Beckmann rearrangement of ketones and aldehydes by Zinc oxide.Synthesis 2002, 8: 1057–1059.View ArticleGoogle Scholar
Sloboda-Rozner D, Neumann R: Aqueous biphasic catalysis with polyoxometalates: oximation of ketones and aldehydes with aqueous ammonia and hydrogen peroxide.Green Chem 2006, 8: 679–681. 10.1039/b604837dView ArticleGoogle Scholar
Luo HM, Li YQ, Zheng WJ: A novel ionic liquid/water biphasic system for the preparation of oximes.Chin Chem Lett 2005,16(7):906–908.Google Scholar
Leonard NM, Wieland LC, Mohan RS: Applications of bismuth(III) compounds in organic synthesis.Tetrahedron 2002, 58: 8373–8397. 10.1016/S0040-4020(02)01000-1View ArticleGoogle Scholar
Gaspard-Iloughmane H, Le Roux C: Bismuth(III) triflate in organic synthesis.Eur J Org Chem 2004, 12: 2517–2532.View ArticleGoogle Scholar
Aggen DH, Arnold JN, Hayes PD, Smoter NJ, Mohan RS: Bismuth compounds in organic synthesis. Bismuth nitrate catalyzed chemoselective synthesis of acylals from aromatic aldehydes.Tetrahedron 2004, 60: 3675–3679. 10.1016/j.tet.2004.02.046View ArticleGoogle Scholar
Iglesias L, Aguilar C, Bandyopadhyay D, Banik BK: A new Bismuth nitrate-catalysed electrophilic substitution of Indoles with carbonyl compounds under solevnt-free conditions.Synth Commun 2010, 40: 3678–3682. 10.1080/00397910903531631View ArticleGoogle Scholar
Salvador JAR, Ppinto RMA, Silvestre SM: Recent advances of bismuth(III) salts in organic chemistry: application to the synthesis of heterocycles of pharmaceutical interest.Curr Org Synth 2009, 6: 426–470. 10.2174/157017909789108701View ArticleGoogle Scholar
Salvador JAR, Ppinto RMA, Silvestre SM: Recent advances of bismuth(III) salts in organic chemistry: application to the synthesis of aliphatics, alicyclics, aromatics, amino acids and peptides, terpenes and steroids of pharmaceutical interest.Mini Rev Org Chem 2009, 6: 241–274. 10.2174/157019309789371587View ArticleGoogle Scholar
Das S, Bora R, Devi RR, Thakur AJ: Molecular iodine in protection and deprotection chemistry.Synletters 2008, 18: 2741–2762.Google Scholar
Saikia L, Das S, Thakur AJ: Deprotection chemistry mediated by ZrOCl2.8H2O: an efficient, mild and green method for the conversion of oximes to carbonyl compounds in aqueous acetone.Synth Commun 2011, 41: 1071–1076. 10.1080/00397911003797783View ArticleGoogle Scholar
Damljanovic I, Vukicevic M, Vukicevic RD: A simple synthesis of oximes.Monatsh Chem 2006, 137: 301–305. 10.1007/s00706-005-0427-3View ArticleGoogle Scholar
Irwing-Sax N, Bewis RJ: Dangerous properties of industrial materials. Van Nostrand Reinhold, New York; 1989:283–284.Google Scholar
Reglinski J, Norman NC, (eds): Chemistry of arsenic, antimony and bismuth. Blackie Academic and Professional, New York; 1998:403–440.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
