Microwave assisted one pot conversion of aromatic aldehydes to nitriles European Journal of Chemistry 9 (3) (2018) 269-274 European Journal of Chemistry View Journal Online View Article Online Microwave assisted one pot conversion of aromatic aldehydes to nitriles Yousef Mohammad Hijji *,1, Rajeesha Rajan 1, Hani Darwish Tabba 1, Imad Ali Abu-Yousef 2, Said Mansour 3 and Hamdi Ben Yahia 3 1 Department of Chemistry and Earth Sciences, Qatar University, 2713, Doha, Qatar yousef.hijji@qu.edu.qa (Y.M.H.), rajeesha.rajan@qu.edu.qa (R.R.), tabbah@qu.edu.qa (H.D.T.) 2 Department of Biology, Chemistry and Environmental Sciences, American University of Sharjah, 26666, Sharjah, United Arab Emirates iabuyousef@aus.edu (I.A.A.Y.) 3 Qatar Environment and Energy Research Institute, Hamad Bin Khalifa University, Qatar Foundation, 34110 Doha, Qatar smansour@hbku.edu.qa (S.M.), hyahia@hbku.edu.qa (H.B.Y.) * Corresponding author at: Department of Chemistry and Earth Sciences, Qatar University, 2713, Doha, Qatar. Tel: +974.44036548 Fax: +974.44034501 e-mail: yousef.hijji@qu.edu.qa (Y.M. Hijji). 10.5155/eurjchem.9.3.269-274.1751 Received: 31 May 2018 Received in revised form: 18 July 2018 Accepted: 28 July 2018 Published online: 30 September 2018 Printed: 30 September 2018 Nitriles are versatile organic precursors in organic synthesis and have numerous applications. An efficient microwave assisted method for conversion of aromatic aldehydes to the corresponding nitriles is reported. Aldehydes are readily converted to oxime followed by acetylation and acetic acid elimination to provide nitriles in good yields within minutes. The method proved to be efficient for the synthesis of aromatic and heterocyclic nitriles. The reaction proceeds smoothly by microwave at 150 °C for 5 minutes. The obtained products are isolated simply by filtration or extraction. Aldoxime Aldehyde Aryl nitrile Microwave Elimination Hydroxylamine Cite this: Eur. J. Chem. 2018, 9(3), 269-274 Journal website: www.eurjchem.com 1. Introduction The importance of nitriles arises from its use for the synthesis of a variety of important functionalities such as amines, amides, aldehydes, carboxylic acids, esters and keto- nes. Those are considered the scaffolds for agro-chemicals, dyes, pharmaceuticals, and functional materials. Nitriles are abundant in nature, for example in phytochemicals, bitter almond and cassava. Nitrile-containing pharmaceuticals have diverse medicinal indications. Furthermore, several substitu- ted benzonitriles have been developed as selective inhibitors for various enzymes related to chronic diseases. Few demonstrative examples are shown in Figure 1. Finrozole (1) is an aromatase and aldosterone inhibitor. Letrozole (2) is a Food and Drug Administration (FDA) approved drug used as aldosterone inhibitor for the treatment of breast cancer. Milrinone (3) is a meta-substituted benzonitrile and a phos- phordiesterase inhibitor used for heart failure. Vildagliptin (4) is an aminonitrile used as antidiabetic drug. Entacapone (5) is a vinylic nitrile prescribed for Parkinson’s disease. Bosutinib (6), having the core of 3-cyanoquinoline, was recently FDA approved as an anti-cancer drug. Febuxostat (7) is a xanthine oxidase inhibitor; used as uric acid reducer [1]. 2-Amino- oxazole-5-phenyl-3-cyanoindole (8) is an inosine monophos- phate dehydrogenase inhibitor [2]. These factors have promp- ted to us the importance of developing a fast, low cost, facile and feasible method for the synthesis of aromatic nitriles. Sandmeyer and Rosenmund-Von Braun developed the early methods to convert aromatic amines and halides to nitrile using CuCN as cyanating agent. Later, several other methods and reagents have been employed for conversion of aldehydes to nitrile via their aldoximes [3-17]. Recently, oxo- ammonium salts [18], hydroxylamine-o-sulphonic acid [19], and o-(diphenyl phosphinyl)hydroxylamine / toluene [20], were reported. In addition, Fe3O4 nanoparticles [21] and active silver nanoparticles [22] were used as catalyst. More recently, Cu catalyzed cyanation, [23] and Fe catalyzed dehydration of aldoximes [24] were used for nitrile formation. However, the drawbacks of these methods include harsh reaction condi- tions, use of toxic and corrosive reagents such as metal cyani- des, expensive, exotic or commercially unavailable reagents. ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2018 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.9.3.269-274.1751 http://dx.doi.org/10.5155/eurjchem.9.3.269-274.1751 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.3.269-274.1751&domain=pdf&date_stamp=2018-09-30 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.9.3.269-274.1751 mailto:yousef.hijji@qu.edu.qa mailto:rajeesha.rajan@qu.edu.qa mailto:tabbah@qu.edu.qa mailto:iabuyousef@aus.edu mailto:smansour@hbku.edu.qa mailto:hyahia@hbku.edu.qa mailto:yousef.hijji@qu.edu.qa http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.3.269-274.1751&domain=pdf&date_stamp=2018-09-30� 270 Hijji et al. / European Journal of Chemistry 9 (3) (2018) 269-274 Letrozole (2) N NC N N Vildagliptin (4) Milrinone (3) N H N O CN CN O NEt2 NO2 HO HO Entacapone (5) Bosutinib (6) Finrozole (1) CN N H N H O N NC 2-Aminooxazole-5-phenyl-cyanoindole (8) Febuxostat (7) N OH FNC N N H N HO N O NC N OCH3NC O NH Cl H3CO Cl O CNS NHO O N N Figure 1. Structures of selected arylonitriles containing drugs used for various ailments. In these reactions organic solvents are used, and long reaction times that have shown to generate multiple products in low yields. They involve tedious work-up procedures to isolate and purify the nitrile. Thus, considerable efforts are directed towards developing efficient methods for the conversion of aldehydes to nitriles, or dehydration of amides and aldoximes to nitriles. Recently, the microwave (MW) irradiation technique has been utilized as a powerful tool for the various organic trans- formations [25]. The main attained benefits are the significant enhancements of the reaction rates, yields, selectivity, and that the reaction can be done under heterogeneous conditions. These reactions resulted in almost complete conversion. In particular, microwave irradiation proved to be highly effective in promoting the condensation reactions [26-31]. Microwave was applied in nitrile formation with dehydrating agents such as peroxymonosulfate / alumina, sodium hydrogen sulphate / SiO2, or HY-Zeolite, anhydrous Na2SO4 and anhydrous NaHCO3 [32]. Most of these procedures employed a conventional kitchen microwave oven, in which temperature and pressure cannot be controlled, unlike the case of using standardized microwave reactor. In practice, the MW induced methods utilizing solid supports resulted in low reproducibility due to the heterogeneous nature of the reaction conditions. Further- more, among the conventional or MW irradiation, only few methods are available to produce nitriles from aldehydes without the use of inorganic salts or solid supports. Acetic anhydride, which is a common and cheap dehydrating agent reported in the conversion of aldoximes to nitrile. However, the reaction time was more than 10 hours and used excessive amount of reagents [33]. The acid-sensitive functional groups such as ester were partly cleaved. In some instances, the hydration of nitriles to the corresponding primary amides was also observed [34]. Herein, we are reporting an improved microwave assisted and environmentally friendly way for the synthesis of substituted aryl nitriles, which are still in high demand. 2. Experimental 2.1. Instrumentation The reactions were carried out in a Biotage Initiator system (Biotage Sweden). The identity of the products is determined by FT-IR Perkin Elmer Spectrum BX Spectrometer and Bruker FTIR Spectrometer ALPHA (ATR for liquid samples). The 1H and 13C NMR spectra were recorded on a Bruker AVANCE-400 spectrometer (Bruker BioSpin, Billerica, MA) operating at 400 and 100 MHz, respectively, using DMSO- d6 as a solvent. 2.2. General procedure for the conversion of aromatic aldehydes to nitriles The process is optimized using m-nitro benzaldehyde (m- NBA) as the model substrate. In this procedure, m-NBA (1 mmol) and hydroxylamine hydrochloride (1.5 mmol) were placed in a 10 mL microwave vial. To this mixture was added, pyridine (1 mmol), followed by Ac2O (1.5 mmol). This mixture was stirred and well capped. The vial was placed in the microwave chamber. The reaction was kept under constant stirring using a magnetic stirrer at T = 150 °C for 5 minutes. The reaction progress and completion were monitored by TLC (eluent EtOAc:hexane, 1:4, v:v) and FT-IR Spectrometer. After completion of the reaction, cold water was added to the reaction mixture. The solid products were precipitated. The solids were dissolved in a minimal quantity of ether and dried over anhydrous Na2SO4 and kept for crystallization to give a yellow or off white crystals (~80% yield). In the case of liquid products, upon addition of cold water, liquids separated out as a layer. This was extracted with ether, and the ether extract is then washed with brine solution 2-3 times, and then dried over anhydrous Na2SO4. 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.269-274.1751 Hijji et al. / European Journal of Chemistry 9 (3) (2018) 269-274 271 Table 1. The temperature and time optimization for conversion of m-NBA to m-nitrobenzonitrile. Aldehyde Time (mins) Temperature (°C) Reaction completion m-NBA 5.0 50 Incomplete 5.0 100 Incomplete 5.0 120 Incomplete 0.5 150 Incomplete 3.0 180 Completed 5.0 150 Completed Scheme 1. Conversion of aldehydes to nitriles in a single-pot (R = –H, -NO2, -OCH3, -CH3, -OH, -Cl, -Br). Finally, the solvent was removed under vacuum using Heidolph Rotary Evaporator (Laborota 4000). All products were characterized by melting points, FT-IR, 1H NMR, and 13C NMR. 3. Results and discussions 3.1. Optimisation of reaction condition in microwave reactor The reaction is studied initially from room temperature (RT) to 180 °C as shown in Table 1. At 180 °C the reaction reaches complete conversion as monitored by FT-IR analysis. It was observed that the reaction is exothermic as indicated by the sudden rise in temperature from the set temperature when the samples were microwaved from 50 °C onwards. m-NBA is reported to take long reaction time [19] while here it took 10 minutes for completion. Other aldehydes took only 5 minutes. For generalization, in our method, aromatic aldehydes (Entries 1-16) were successfully converted to the corresponding nitriles along with formamides in cases of (Entries 1, 2, 3, 7, 8, and 12) under the optimized conditions as mentioned as general procedure under Scheme 1. 3.1.1. The products properties melting point, IR stretch and the ratio of nitrile to formamide The reaction conditions and yields of the products are presented in Table 2. The NMR data clearly demonstrate the formation of the corresponding formamides obtained via Beckmann rearrangement to the extent of 25% conversion along with the nitrile as shown in Scheme 1. The nitrile is formed by acetic acid elimination reaction. The melting point, IR vibrational data and percent yields, as well as the ratio of nitrile to formamides as calculated from the 1H NMR data are also given in Table 2. This method is applied to a range of aldehydes, o-, m-, and p-substituted aromatic monoaldehydes, dialdehydes, and heterocyclic aldehydes towards the corresponding nitriles in good yields. One advantage of this method over the conventional reaction is that in the case of o-, m-, p-substituted hydroxyl group the esterification of the hydroxyl group under acidic and basic conditions are preserved to give the o-, m-, and p-hydroxyl benzonitrile (Entries 9 and 10). The present method probably proceeds via initial formation of o-acetylaldoxime intermediates, formed in situ followed by acetic acid elimination under the influence of MW irradiation [35]. The detailed mechanism is depicted in Scheme 2. The conventional method was tried for conversion of m- NBA to the nitrile in a two-step process. Firstly, the oxime of m-NBA is synthesized, followed by adding pyridine (1 mmol) and stirring at room temperature for 30 minutes. The reaction progress was monitored by TLC, eluted with ethyl acetate:hexane (1:4, v:v) and FT-IR spectrometer. A white solid formed in the reaction mixture. The precipitate was filtered off, and washed with diethyl ether to remove excess starting materials. Secondly, the solid was converted to nitrile by adding acetic anhydride (1.5 mmol) and toluene (2 mL) as solvent in which the mixture is refluxed for 24 hours. The nitrile was not formed under these conditions as evidenced by FT-IR spectrometer. This shows the advantage of using MW over the conventional procedure. 3.2. Synthesis of heterocyclic aromatic nitriles In the case of furfuraldehyde, an aromatic heterocyclic aldehyde, the reaction was performed under similar conditions, but a new product was obtained instead of the expected nitrile. This challenge was taken and done according to the following two steps: 3.2.1. Synthesis of furan aldoxime To furfuraldehyde (1 mmol) without further purification, NH2OH.HCl (1.5 mmol) were added followed by pyridine (1 mmol) and stirred for 3 hours at room temperature until the NH2OH.HCl is completely solubilized. The reaction mixture was then quenched in water where the furfuraldoxime precipi- tated. The solid was filtered off, and recrystallized from diethyl ether to give white needle like crystals (Yield = 74%). The product was characterised and confirmed by FT-IR spectro- meter (which showed two peaks at 3166 and 1634 cm-1), 1H NMR and 13C NMR, as well as, melting point. The product was divided into three portions and used for synthesising furanonitrile under different thermal conditions. 3.2.2. Synthesis of furonitrile To furanaldoxime (2.07 mmol), was added acetic anhydride (3.10 mmol) and the mixture was stirred for 3 hours at room temperature until the reaction mixture turned brown. The reaction mixture was then quenched in water where the separated out liquid was extracted with diethyl ether and washed with water to remove excess acetic acid. The ethereal solution was dried by flushing through anhydrous Na2SO4 and finally evaporated under vacuum resulting in a brown liquid (Yield: ~90%). The procedure was repeated under MW conditions as shown in Table 3. The presence of the nitrile was confirmed by FT-IR spectrometer at 2231 cm-1, along with oxime acetate as an intermediate which was confirmed by FT-IR peak at 1769 cm-1 for oxime ester. The structure was further confirmed by 1H- and 13C-NMR (given as supplementary material Figure 19, 20a, 20b and 20c). 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.269-274.1751 272 Hijji et al. / European Journal of Chemistry 9 (3) (2018) 269-274 Table 2. Aldehydes converted to nitriles under solvent free MW irradiation at T = 150 °C for 5 minutes. Entry Aldehyde Nitrile Melting point (°C) CN stretch (ν, cm-1) Yield (%) and Nitrile: Amide ratio 1 CHO O2N CN O2N 114-116 [22] 2237 (2235) [13] 80 (95:5) 2 CHO H3CO CN H3CO - 2229 82 (90:10) 3 CHO H3CO CN H3CO 20-25 2231 89 (78:22) 4 CHOH3CO CNH3CO 53-55 [22] 2219 (2227) [13] 86 * 5 CHO Br CN Br 36-38 2232 83 * 6 CHOBr CNBr 111-113 2225 72 * 7 CHO Cl CN Cl Mixture 2231 (2214) [36] 94 (75:25) 8 CHOCl CNCl Mixture 2225 (2226) [37] 58 (90:10) 9 CHO HO CN HO 76-83 2231 (2226) [22] 61 * 10 CHOHO CNHO 109-112 2234 55 * 11 CHO CN - 2230 (2225) [13] 62 (Impure) 12 CHO CN Mixture 2222 (2213) [38] 85 (75:25) 13 CHO CN 165-170 2212 31 * 14 OHC CHO NC CN 216-221 [22] 2232 (2232) [22] 74 * 15 N CHO N CN Mixture 2242 40 (Impure) 16 N H CHO N H CN 173-176 2224 76 * * Nitrile only. The reaction under MW at T = 150 °C for 5 minutes, resulted in the formation of the oxime acetate (FT-IR: 1760 and 1721 cm-1) rather than the nitrile, showing that the elimination did not take place. This means the thermal stability of oxime ester renders it from elimination to give nitrile. The formation of o-acetyl ester is also confirmed via benzoyl chloride reaction with furfuraldoxime, to give pale white needle like crystals of o-benzoyl ester. The structure was determined by 1H NMR, single crystal X-ray diffraction, showing 50% probability displacement ellipsoids (Figure 2). In addition, FT-IR spectrum shows the presence of a strong peak at 1736 cm-1 along with sharp peaks in the range 3139 to 2863 cm-1 corresponding to aromatic and aliphatic C-H stretching vibration, respectively. Similar reaction conversion of aldehyde to nitrile through the oxime ester formation using o-benzoyl hydroxylamine has been reported [39]. 3.2.3. Synthesis of o-benzoyl ester of furfuraldoxime Benzoyl chloride (1 mmol) was added slowly (drop-wise) to furfuraldoxime (1 mmol). Since the reaction was vigorous and exothermic, the temperature was maintained at 0 °C in ice bath and stirred for 30 minutes. The reaction mixture was quenched using ice-water, then extracted with ethyl acetate. The organic layer was separated and then washed with NaOH (1 M) solution to remove any remaining benzoic acid and HCl by-products. 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.269-274.1751 Hijji et al. / European Journal of Chemistry 9 (3) (2018) 269-274 273 Table 3. Reaction conditions for MW-initiated synthesis of furanaldoxime acetate. Time (Minutes) Temperature (°C) Yield (%) 10 100 60 5 150 55 Step 1: Formation of aldoxime O H + NH2OH. HCl N OH Intermediate formation of oxime ester N OH O O O + N O OH N O O H Step 2: Direct elimination to nitrile N O OH CN + OH O N O O H Heat Base Step 2: Beckmann rearrangement N OH N N H H O HO Scheme 2. Schematic representation of the reactions mechanisms. Figure 2. View of the molecular structure of 2-furanaldehyde oxime benzoate [40]. Ethyl acetate solution was dried over anhydrous Na2SO4 and evaporated under vacuum to get light brown solid recrystallized from ethanol:ethyl acetate binary solvents to give overall product; Yield: 50%, m.p.: 137-139 °C. 4. Conclusions We have developed an environmentally benign MW- initiated method for direct synthesis of aryl nitriles from aromatic aldehydes using hydroxylamine hydrochloride and acetic anhydride. The method is simple and efficient which makes it an attractive alternative synthetic methodology towards different classes of aromatic, heterocyclic nitriles. Acknowledgments This report was made possible by award NPRP-7-495-1- 094 from Qatar National Research Fund (a member of The Qatar Foundation). The statements made herein are solely the responsibility of the authors. We would like to thank Mr. Ziad Sara from The American University of Sharjah, Sharjah, United Arab Emirates for recording the NMR spectra. Supporting information Electronic supplementary information (ESI) available: Full experimental and characterization data. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.269-274.1751 274 Hijji et al. / European Journal of Chemistry 9 (3) (2018) 269-274 Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. Funding Qatar Foundation http://dx.doi.org/10.13039/100007458 ORCID Yousef Mohammad Hijji http://orcid.org/0000-0002-4116-1746 Rajeesha Rajan http://orcid.org/0000-0002-8798-8992 Hani Darwish Tabba http://orcid.org/0000-0002-5313-6951 Imad Ali Abu-Yousef http://orcid.org/0000-0002-5176-3599 Said Mansour http://orcid.org/0000-0001-8700-2874 Hamdi Ben Yahia http://orcid.org/0000-0001-6577-9498 References [1]. Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53(22), 7902-7917. [2]. Murali Dhar, T. G.; Shen, Z.; Gu, H. H.; Chen, P.; Norris, D.; Watterson, S. H.; Ballentine, S. K.; Fleener, C. A.; Rouleau, K. A.; Barrish, J. C.; Townsend, R.; Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg. Med. Chem. Lett. 2003, 13(20), 3557-3560. [3]. Arote, N. D.; Bhalerao, D. S.; Akamanchi, K. G. Tetrahedron Lett. 2007, 48(21), 3651-3653. [4]. Bajpai, A. R.; Deshpande, A. B.; Samant, S. D. Synth. Commun. 2000, 30(15), 2785-2791. [5]. 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RSC Advan. 2014, 4(27), 13782- 13787. [39]. An, X. D.; Yu, S. Organic Lett. 2015, 17(20), 5064-5067. [40]. Hijji, Y. M.; Rajan, R.; Mansour, S.; Ben-Yahia, H. Acta Crystallog. E 2017, 73(9), 1326-1328. Copyright © 2018 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.269-274.1751 http://dx.doi.org/10.13039/100007458 http://orcid.org/0000-0002-4116-1746 http://orcid.org/0000-0002-8798-8992 http://orcid.org/0000-0002-5313-6951 http://orcid.org/0000-0002-5176-3599 http://orcid.org/0000-0001-8700-2874 http://orcid.org/0000-0001-6577-9498 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. General procedure for the conversion of aromatic aldehydes to nitriles 3. Results and discussions 3.1. Optimisation of reaction condition in microwave reactor 3.1.1. The products properties melting point, IR stretch and the ratio of nitrile to formamide 3.2. Synthesis of heterocyclic aromatic nitriles 3.2.1. Synthesis of furan aldoxime 3.2.2. Synthesis of furonitrile 3.2.3. Synthesis of o-benzoyl ester of furfuraldoxime 4. Conclusions Acknowledgments Supporting information Disclosure statement Funding ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: