untitled European Journal of Chemistry 6 (2) (2015) 219‐224 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.2.219‐224.1223 European Journal of Chemistry Journal webpage: www.eurjchem.com Utility of 2‐cyano‐N‐(2‐hydroxyethyl) acetamide in heterocyclic synthesis Moustafa Ahmed Gouda 1,2,*, Meshal Abdulrahim Sabah 2, Waled Khaled Aljuhani 2, Ahmed Saleh El‐Gahani 2, Snad Abd El‐Karem El‐Enazi 2, Salem Atalleh Al Enizi 2 and Majed Musallam Al‐Balawi 2 1 Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt 2 Department of Chemistry, Faculty of Science and Arts, Taibah University, Ulla, 41411, Kingdom of Saudi Arabia * Corresponding author at: Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt. Tel.: +2.050.6432235. Fax: +2.050.2246781. E‐mail address: dr_mostafa_chem@yahoo.com (M.A. Gouda). REVIEW INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.2.219‐224.1223 Received: 19 November 2014 Received in revised form: 28 December 2014 Accepted: 03 January 2015 Published online: 30 June 2015 Printed: 30 June 2015 This review presents a systematic and comprehensive survey of the method of preparation and the chemical reactivity of 2‐cyano‐N‐(2‐hydroxyethyl) acetamide. The target compounds are important intermediates for the synthesis of a variety of synthetically useful and novel heterocyclic systems. KEYWORDS Reactivity Synthesis Ethanolamine Cyanoacetylation Fused heterocycles 2‐Cyano‐N‐(2‐hydroxyethyl) acetamide Cite this: Eur. J. Chem. 2015, 6(2), 219‐224 1. Introduction Cyanoacetamides are polyfunctional compounds posses‐ sing both electrophilic and nucleophilic properties. Typical nucleophilic position at NH and CH2. On the other hand, cyano acetamides possesses electrophilic positions, especially at the carbon of the cyano. These chemical properties have been used to design different heterocyclic moiety with difrerent ring sizes such as pyrole [1], thiophene [2], pyrazole [3], thiazole [4], thiadiazole [5], pyridine [6], pyridine [7], coumarin [8]. Moreover, cyanoacetamides and their related heterocyclic derivatives have generated great attention due to their interesting biological, therapeutic value and pharma‐ ceutical activities e.g. as herbicidal [9], anti‐inflammatory [10], anti‐tumor [11], and analgesic properties [12]. Furthermore, 2‐cyano‐N‐(2‐hydroxyethyl)acetamide is a highly reactive compound. It is extensively utilized as reactant or reaction intermediate since the cyano function of this compound are suitably situated to enable reaction with common mono or bidentate to form a variety of heterocyclic compounds. Moreover, the active hydrogen on N and O atoms of this compound can take part in a variety of condensation and substitution reactions. There is no review summarizing the literature on the synthesis and chemistry of 2‐cyano‐N‐(2‐ hydroxyethyl) acetamide. 2. Synthesis The synthesis of 2‐cyano‐N‐(2‐hydroxyethyl)acetamide (3) may be carried out in several ways. The most versatile and economical method involves the treatment of ethanolamine (1) with (ethyl) methylcyanoacetate (2) using different reaction conditions to yield 2‐cyano‐N‐(2‐hydroxyethyl) acetamide (3). The following are some of the methods that have been used to synthesis of 2‐cyano‐N‐(2‐hydroxyethyl) acetamide (3). 2.1. Solvent‐free methods The solvent‐free reaction of ethanolamine with (ethyl) methylcyanoacetate constitutes one of the most widely used methods for the preparation of 2‐cyano‐N‐(2‐hydroxy ethyl) acetamide (3). Thus, stirring of methylcyanoacetate with an ethanol amine at room temperature for 2 h afforded cyano acetanilide (3) [13]. Moreover fusion of ethanolamine with 220 Gouda et al. / European Journal of Chemistry 6 (2) (2015) 219‐224 methylcyanoacetate at 100‐120 °C [14] or 95‐150 °C [15] afforded cyanoacetanilide derivative 3 (Scheme 1). Scheme 1 2.2. Using different solvent The reaction of ethanolamine (1) with ethyl (methyl) cyanoacetate (2) in boiling ethanol or methanol afforded 2‐ cyano‐N‐(2‐hydroxyethyl) acetamide (3) (Scheme 1) [16‐20]. Furthermore reaction of cyanoacetylchloride (4) with ethanol amine (1) in dichloromethane containing triethylamine as a basic catalyst afforded 2‐cyano‐N‐(2‐hydroxyethyl)‐acetamide (3) (Scheme 2) [21]. Scheme 2 2.3. Reactivity 2‐Cyano‐N‐(2‐hydroxyethyl)acetamide have polyfunctions, possessing both electrophilic and nucleophilic properties. Typical nucleophilic positions are NH, OH and C‐2. These chemical properties have been used to design different heterocyclic moiety with different ring sizes such as pyrrole, thiophene, oxazole, triazole, pyridine, quinolone, coumarin and diazepinone. On the other hand, 2‐cyano‐N‐(2‐hydroxyethyl) acetamide possesses electrophilic positions, especially at C‐3, C‐1 of 2‐cyano‐N‐(2‐hydroxyethyl)acetamide. Figure 1. Reactivity of 2‐cyano‐N‐(2‐hydroxyethyl)acetamide (3). 2.4. Synthesis of five membered rings An efficient one‐pot, two‐step solution‐phase synthetic method was developed to synthesize 2‐amino‐indole‐3‐ carboxamide (7) from 2‐halonitrobenzene (5) and cyano acetamide (3). In this sequence, first, intermediate 2‐cyano‐2‐ (2‐nitrophenyl)acetamide (6) was generated under basic condition via nucleophilic aromatic substitution reaction; after direct addition of hydrochloric acid solution, FeCl3, and Zn powder, indole (7) was generated via reduction/cyclization process (Scheme 3) [22]. Gewald reaction of t‐butyl 4‐methyl‐1‐oxopentan‐3‐yl carbamate (8) with cyanoacetamide (1) in ethanol in presence of sulfur and triethylamine afforded the corresponding thiophene 9 (Scheme 4) [23]. Furthermore cyanoacetamide 3 reacted with butanal (10) and sulfur in DMF in presence of DEA under Gewald reaction condition in to give the corresponding 2‐aminothiophene (11) (Scheme 5) [21]. Cyanoacetamide (3) reacted with oxime derivative 12 in sodium ethanolate in ethanol to give the corresponding 5‐ aminooxazole (13). Furthermore isoxazoles 15 having a heterocycle at the omega‐position of the side chain of compound 15 was prepared via heating of compound 13 with SOCl2 in pyridine/CHCl3, followed by heating the chloro derivative 14 in xylene containing sodium. Reduction of compound 14 with LiAlH4 in MeOH afforded the oxazolone derivative 16 (Scheme 6) [24]. 3 HO HN CN O Sodium hydride DMF 1 HCl / FeCl3 2 NaH/ Zn / DMF 5 6 7 N OO F N OO CN O H N N H O N H OH NH2 OH Scheme 3 Scheme 4 Scheme 5 Triazoles 20 are synthesized by reaction of azides 17 with cyanoacetamide (3) in methanolate followed by reaction of the formed triazole 18 with SOCl2 in pyridine/CHCl3 to give the chloroderivative 19 which cyclized in methanol containing sodium and sodium iodide to give the corresponding oxazoles 20 (Scheme 7) [20]. 2.5. Synthesis of six membered rings Knoevenagel condensation of cyanoacetamide (3) with 2, 4‐dihydroxybenzaldehyde 21 in ethanol and piperidine afforded the corresponding iminocoumarin (22) which condensed with p‐methoxyaniline (23) to give the correspond‐ ding p‐methoxyphenyliminocoumarin (24) (Scheme 8) [25]. Furthermore Knoevenagel condensation of cyanamide 3 with 4‐bromo (3‐methoxy)‐2‐hydroxbenzaldehyde (25) in H2O in presence of sodium carbonate afforded the correspond‐ ding iminocoumarin (26), which hydrolyzed with HCl to give coumarin 27 (Scheme 9) [26]. Whereas, Knoevenagel condensation of cyanamide 3 with 2‐hydroxbenzaldehyde (28) in ethanol in presence of piper‐ Gouda et al. / European Journal of Chemistry 6 (2) (2015) 219‐224 221 dine afforded the corresponding arylidine (29) (Scheme 10) [19]. NC NH OH O + N Cl HO O N H2N O NH HO Na R R SOCl2 Pyridine CHCl3 O N H2N O NH Cl HN NH N O O Xylene Na R R LiAlH4 THF O N O NH H2N R MeOH 3 12 13 14 15 16 Scheme 6 Scheme 7 Scheme 8 Condensation of 2‐amino‐5‐chlorobenzaldehyde (30) with cyanoacetamide (3) in sodium hydroxide in ethanol afforded the aminoquinolone derivative 31 (Scheme 11) [13]. Scheme 9 Scheme 10 Scheme 11 6‐Chloro‐1, 2‐dihydro‐4‐hydroxy‐N‐(2‐hydroxyethyl)‐2‐ imino‐1‐methyl‐3‐quinolinecarbox‐amide (33) was prepared via condensation of 6‐chloro‐1,2‐dihydro‐4‐hydroxy‐N‐(2‐ hydroxy‐ethyl)‐2‐imino‐1‐methyl‐3‐quinoline‐ carboxamide (32) with 2‐cyano‐N‐(2‐hydroxyethyl)‐acetamide (3) in ethanol containing sodium (Scheme 12) [27]. Scheme 12 222 Gouda et al. / European Journal of Chemistry 6 (2) (2015) 219‐224 Cyanoacetamide 3 reacted with oxime derivative 34 in sodium ethanolate in ethanol to give the corresponding 2‐ aminobenzo[5,6]quinoxaline (35). Heating of compound 35 with SOCl2 followed by heating the chloro derivative (36) in DMF containing sodium carbonate afforded the corresponding diazepin‐12‐on derivative (37) (Scheme 13) [28]. Scheme 13 Furthermore, 2‐cyano‐N‐(2,2‐dimethoxyethyl)‐acetamide (38) which obtained from ethyl cyanoacetate and amino acetaldehyde di‐methylacetal [29] reacted with dimethylform‐ (acet)amide dimethylacetals 39а and 39b to give 3‐dimethyl amino‐N‐(2,2‐dimethoxyethyl)‐ 2‐cyanoacryl(croton) amides 40 and 40b. Condensation of compound 40а and 40b with hydrazine hydrate (41а) or alkylhydrazines 41b‐41e in pyridine give amides 42a‐42g (Scheme 14) [30]. 38 HN CN O + 39 R2NHNH2 41 R1 N Me Me H3CO H3CO O N H R1 40 N N R1 NH O R OMe OMe 42 OCH3 OCH3 N CH3 H3C CN OCH3 OCH3 39a, 40a, R1=H 39b, 40b, R1=Me 41a; R2=H 41b; R2=PhCH2 41c; R2=Me 41d; R2=CH2CH2OH 41e; R2=CH2CH2CN 42a; R1=H, R2=Me 42b; R1=H, R2=CH2CH2OH 42c; R1=H, R2=PhCH2 42d; R1=Me, R2=H 42e; R1=Me, R2=PhCH2 42f; R1=Me, R2=CH2CH2OH 42g; R1=Me, R2=CH2CH2CN Scheme 14 Amide 42a was converted into the corresponding pyrazolodiazepines (43) and (44) after boiling in water in the presence of hydrochloric acid (Scheme 15) [30]. Scheme 15 Stirring of amides 42 in formic acid followed by addition of thiophenols (45) afforded 7‐R‐sulfanyl derivatives 46 (Scheme 16) [30]. Scheme 16 Reaction of 4,6‐diamino‐2‐substituted 5‐nitrosopyrimi‐ dines (47) with N‐substituted cyanoacetamide (3) in refluxing ethanol containing catalytic amounts of sodium afforded the 2‐ (4,7‐diamino‐2‐phenylpteridin‐6‐ylamino)ethanol (Scheme 17) [31]. Scheme 17 Heating of cyanoacetamide 3 with ethylacetoacetate (49) in KOH/EtOH afforded 3‐cyano‐1‐(hydroxyethyl)‐6‐hydroxy‐ 4‐methylpyrid‐2(1H)‐one (50). Cyclodehydration of com‐ pound 50 via heating in o‐dichlorobenzene afforded 6‐cyano‐ 2, 3‐dihydro‐7‐methyloxazolo[3, 2‐a]pyrid‐5(H)‐one (51). Hydrolysis of compound 51 with sulfuric acid, afforded the carboxamide (52) (Scheme 18) [32]. Scheme 18 Furthermore condensation of compound 51 with alkoxides (53), carbanion of di‐Et malonate (54) and sodium azide afforded the corresponding pyridines 55‐57 (Scheme 19) [18]. Gouda et al. / European Journal of Chemistry 6 (2) (2015) 219‐224 223 Scheme 19 2.6. Miscellaneous reaction 2.6.1. Reaction with aldehyde 3‐(4‐Amino‐5‐(4‐phenoxyphenyl)‐7H‐pyrrolo[2, 3‐d]pyri midin7‐yl)benzaldehyde (58) reacted with 2‐cyano‐N‐(2‐ hydroxyethyl)acetamide (3) in presence of in piperidinium acetate to give the corresponding (E)‐3‐(3‐(4‐amino‐5‐(4‐ phenoxyphenyl)‐7H‐pyrrolo[2,3‐d]pyrimidin‐7‐yl)phenyl)‐2‐ cyano‐N‐(2‐hydroxyethyl) acrylamide (59) (Scheme 20) [33]. NC N H OH O + Piperidinium acetate 3 58 59 N N N O O H NH2 N N N O H NH2 CN O NH HO 2-Propanol Scheme 20 Furthermore, treatment of N,N‐(disubstituted amino) benzaldehyd (60) with 2‐cyano‐N‐(2‐hydroxyethyl)acetamide (3) in isopropyl alcohol in presence of sodium acetate gave the acrylamide (61) (Scheme 21) [15]. Scheme 21 Stirring of 4‐(dibenzylamino)benzaldehyd (62) with 2‐ cyano‐N‐(2‐hydrox‐yethyl) acetamide (3) in methanol in presence of in piperidinium acetate gave the acrylamide (63) (Scheme 22) [15]. Scheme 22 Moreover, heating of 4‐N,N‐dimethylaminobenzaldehyde (64) with acetamide (3) in sodium methylate in methanol afforded the corresponding arylidene (65) (Scheme 23) [15]. Scheme 23 Refluxing of cyanamide 3 with 4‐piperdinylbenzaldehyde derivative (66) in methanol gave the corresponding acrylo nitrile (67) (Scheme 24) [15]. 3HO NH CN O + 67 H CN O N H OH OH N N Sodium methylate Methanol 66 S OO S O O Scheme 24 Piperidine was condensed with 1,1,3,3‐tetramethoxy propane (68) and 2‐cyano‐N‐(2‐hydroxyethyl)acetamide (3) in acetic acid, to afford the corresponding enamine 69 (Scheme 25) [32]. Scheme 25 Eight hydroxyl functionalized donoreacceptor polyene chromophores (72a‐f) were synthesized via Knoevenagel condensation reaction of aromatic polyenals (70) with 2‐ cyanoacetamide derivatives (71) (Scheme 26) [34]. 224 Gouda et al. / European Journal of Chemistry 6 (2) (2015) 219‐224 Scheme 26 2.6.2. Reaction with ketones 2‐Cyano‐2‐cyclohexylidene‐N‐(2‐hydroxyethyl)acetamide (74) was prepared via Knoevenagel condensation of 2‐cyano‐ N‐(2‐hydroxyethyl)‐acetamide (3) with cyclohexanone (73) in acetic acid and ammonium acetate in toluene under reflux Dean‐Stark (Scheme 27) [16]. + Ammmonium acetate Toluene 3 73 74 O N H NC OH O CN O N H OH Scheme 27 Furthermore acetamide 77 was prepared via condensation of 2‐cyano‐N‐(2‐hydroxyethyl)‐acetamide (3) with, cyclo hexenone derivative 75 in dimethylsulfate in presence of 1,8‐ diazabicyclo[5.4.0]undec‐7‐ene (76) (Scheme 28) [32]. + 3 O N H NC OH O CN O NH OH Dimethyl sulfate 75 77 76HN N N HN Scheme 28 3. Conclusion The objective of the present study was to shows a systematic and comprehensive survey of the method of preparation and the chemical reactivity of 2‐cyano‐N‐(2‐ hydroxyethyl)acetamide. The target compounds are important intermediate for the synthesis of a variety of synthetically useful and novel heterocyclic systems. Acknowledgement To Dr. Mohamed Aboseid and Dr. Amr El‐Demerdash Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt, he is greatly acknowledged. This review is dedicated to the spirit and soul of my dearest Father. References [1]. Elgemeie, G. H.; Elghandour, A. H.; Elzanate, A. M.; Ahmed, S. A. J. Chem. Soc. Perkin Trans I 1997, 21, 3285‐3290 [2]. Milad, R. M.; Zaki, H. S.; Ibrahim, S. A. J. Chem. Res. (S) 1992, 5, 154‐ 155. [3]. Kim, C. K.; Zielinski, P. A.; Maggiulli, A. C. J. Org. Chem. 1984, 49, 5247‐ 5250. [4]. Elgemeie, G. H.; Elzanaty, A. M.; Elghandour, A. H.; Ahmed, S. A. Synth. Commun. 2006, 36, 825‐834. [5]. Dankova, E. F.; Bakulev, V. A.; Grishakov, A. N.; Mokrushin, V. S. Izv. Akad. Nauk. SSSR. Ser. Khim. 1988, 5, 1126‐1128 [6]. Hawes, E. M.; Gorecki, D. K. J.; Gedir, G. G. J. Med. Chem, 1977, 20, 838‐ 841. [7]. Mijin, D.; Marinkovic, A. Synth. Commun. 2006, 36, 193‐198. [8]. Zhuravel, I.; Kovalenko, M. S.; Ivachtchenko, V. A.; Balakin, K. V.; Kazmirchuk, V. V. Bioorg. Med. Chem. 2005, 15, 5483‐5487. [9]. Geissler, A. E.; Huppatz, J. L.; Phillips, J. N. Pesticide Sci. 1980, 11, 432‐ 438. [10]. Roifman, C. M.; Aviv, G.; Alexander, L. PCT. Int. Appl. WO Patent, 2000, 0055, 128; Chem. Abstr. 2000, 133, 237695h. [11]. Fahmy, H. T. Y.; Rostom, S. A. F.; Bekhit, A. A. Archiv der Pharm. 2002, 335, 213‐322. [12]. Ismail, M. M. F.; Ammar, Y. A.; El‐Zahaby, H. S. A.; Eisa, S. I.; Barakat, S. E. Arch. Pharm. Life Sci. 2007, 340, 476‐482. [13]. Doemling, A.; Wang, K.; Herdtweck, E. ACS Comb. Sci. 2012, 14, 316‐ 322. [14]. Horecker, B. L.; Kornberg, A. J. Biol. Chem. 1948, 175, 385‐390. [15]. Pearson, J. C.; Weaver, M. A.; Fleischer, J. C.; King, G. A. US 2006/115516. [16]. Gillen, K. J.; Jamieson, C.; Maclean, J. K. F.; Moir, E. M.; Rankovic, Z. Patent; N. V. Organon, 2008, WO2008/3452. [17]. Osdene, T. S.; Santilli, A. A.; McCardle, L. E.; Rosenthale, M. E. J. Med. Chem. 1967, 10, 165‐171. [18]. Tilak, B. D.; Ayyangar, N. R.; Rao, U. S. Indian J. Chem. B 1984, 23, 18‐ 23. [19]. Manidhar, D. M.; Rao, K. U. M.; Reddy, N. B.; Sundar, C. S.; Reddy, C. S. J. Korean. Chem. Soc. 2012, 56, 459‐463. [20]. Ivanov, E. I.; Kalayanov, G. D.; Yaroshchenko, I. M. Zh. Org. Khim. 1989, 25, 1975‐1975. [21]. Rideau, E.; Smith, T. K.; Stewart, G.; Westwood, N. J.; Zhou, L.; Rideau, E.; Smith, T. K. A. J. Med. Chem. 2013, 56, 796‐806. [22]. Doemling, A.; Wang, K.; Herdtweck, E. ACS Comb. Sci. 2011, 13, 140‐ 146. [23]. Doemling, A.; Kim, D.; Wang, K. J. Comb. Chem. 2010, 12, 111‐118 [24]. Dannhardt, G.; Dominiak, P.; Laufer, S. Arch. Pharm. 1991, 324, 141‐ 148. [25]. Endo, S.; Hu, D.; Suyama, M.; Matsunaga, T.; Sugimoto, K.; Matsuya, Y.; El‐Kabbani, O.; Kuwata, K.; Hara, A.; Kitade, Y.; Toyooka, N. Bioorg. Med. Chem. 2013, 21, 6378‐6384. [26]. Areias, F.; Costa, M.; Castro, M.; Brea, J.; Gregori‐Puigjane, E.; Proenca, M. F.; Mestres, J.; Loza, M. I. Eur. J. Med. Chem. 2012, 54, 303‐310. [27]. Santilli, A. A. Patent; American Home Products Corporation, 1981, US4266050. [28]. Santilli, A. A.; Osdene, T. S. J. Org. Chem. 1964, 29, 2066‐2068 [29]. Wang, K.; Kim, D.; Domling, A. J. Comb. Chem. 2010, 12, 111‐118. [30]. Bol’but, A. V.; Kemskii, S. V.; Vovk, M. V. Russ. J. Org. Chem. 2014, 50, 685‐690 [31]. Santilli, A.; McCardle, L. E.; Rosenthale, M. E.; Osdene, T. S. J. Med. Chem. 1967, 10, 165‐171. [32]. Winkler, B.; Hueglin, D.; Eichin, K.; Ehrsam, L.; Marat, X.; Richard, H.; Kienzle, I. M.; Schroede, U. PCT Int. Appl. , WO, 2013, 2013011480 A1 20130124, 10, 165. [33]. Taunton, T.J. W.; Maglathlin, Jr. R.; Serafimova, I.; Cohen, M. S.; Miller, R.; Paavilainen, V.; McFarland, J.; Krishnan, S. US, US20130035325 A1. [34]. Tuuttila, T.; Lipsonen, J.; Huuskonen, J.; Rissanen, K. Dyes Pigments 2008, 77, 357‐362.