Ethoxymethylenemalononitrile

Jéssica Venância Faria was born in 1985 in Rio de Janeiro, Brazil. She obtained her Chemistry degree from the Universidade Federal Fluminense in 2010. She is currently working toward her M.Sc. in Chemistry under the supervision of Dr. Alice Maria Rolim ­Bernardino and Dr. Maurício Silva dos Santos. Her research interests focus on the synthesis of pyrazolyl and tetrazolyl derivatives with potential antileishmanial activity.

Introduction

Ethoxymethylenemalononitrile (3) is an orange solid with a melting point of 64–66 °C. It is a functionalized malono­nitrile widely used to synthesize pyrazoles,[ ¹ ] pyrimidines[ ² ] as well as a variety of fused heterocyclic systems, like pyrazolooxazines,[ ³ ] pyrazolopyrimidines[ ⁴ ] and benzodiazepines.[ ⁵ ] It is an inexpensive reagent, but can be prepared in 94% yield by the reaction of 1,1′,1′′-[methanetriyltris(oxy)]triethane (1) and malononitrile (2) under reflux in the presence of acetic anhydride for four hours.[ ³ ]

Scheme 1 Synthesis of ethoxymethylenemalononitrile (3)

Abstracts

(A) A simple reaction of o-phenylenediamine (4) with ethoxymethylenemalononitrile at room temperature formed 2-[(2-aminophenylamino)methylene]malononitrile (5). Then an intramolecular cyclization of 5 happened under microwave conditions to generate the benzimidazole ring in quantitative yield by elimination of ­malononitrile.[ 6 ]
(B) This reaction proceeds via attack of hydroxytropone 7 onto the electrophilic alkene to form a Michael-type adduct and subsequent loss of ethanol to give the potassium salt of [(8-hydroxy-1,3-dimethyl-4-oxo-4H-cyclohepta[c]furan-7-yl)methylene]malononitrile (8).[ 7 ]
(C) The reaction between 3-methoxypropionitrile (12), t-butyl bromoacetate (13) and ethoxymethylenemalononitrile allowed the synthesis of t-butyl 6-amino-5-cyano-2-(2-methoxyethyl)nicotinate (14).[ 2 ]
(D) According to Zaki and co-workers,[ 8 ] two different products can be obtained by the reaction between derivatives 9 and ethoxymethylenemalononitrile, depending on the reaction conditions. At low temperature, a nucleophilic substitution provides the enaminone derivative N′-(2,2-dicyanovinyl)hexanohydrazide (10a). Under reflux conditions using DBU as a catalyst, the reaction mixture allows the cyclization to the seven-membered 1,2-diazepine rings 11a–d.
(E) Bruno et al.[ 9 ] reported the synthesis of 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide (18) by condensation of hydrazine 15 with ethoxymethylenemalononitrile (3) to give 16, followed by an alkaline hydrolysis providing 17 and subsequent cyclization to give the fused pyrazoloimidazole 18, which exhibits potent anti-inflammatory properties.
(F) The condensation of 4-hydrazino-8-(trifluoromethyl)quinoline (19) with ethoxymethylenemalononitrile afforded intermediate 20 that reacted with formamide to provide fused pyrazolopyrimidine 21, a potential antimicrobial agent.[ 10 ]

• References

• 1 Santos MS, Oliveira ML. V, Bernardino AM. R, Leo RM, Amaral VF, Carvalho FT, Leon LL, Canto-Cavalheiro MM. Bioorg. Med. Chem. Lett. 2011; 21: 7451
• 2 Chen Y, Zhao X, Deng J, Li Q. Acta Cryst. 2012; E68: o1375
• 3 Li JR, Zhang LJ, Chen JN, Yang XQ, Wang LJ, Zhao XF, Qiu JX. Chin. Chem. Lett 2007; 18: 636
• 4 Gomha SM, Hassaneen HM. E. Molecules 2011; 16: 6549
• 5 Zivec M, Sova M, Brunskole M, Lenarsic R, Rizner TL, Gobec S. J. Enzym. Inhib. Med. Chem. 2007; 22: 29
• 6 Marinho ER, Proença FP. ARKIVOC 2009; 14: 346
• 7 Arsenyeva MY, Arsenyev VG. Chem. Heterocycl. Compd. 2008; 44: 1328
• 8 Zaki ME. A, Yousef EA. A, Hassanien AZ. A. Heteroatom Chem. 2007; 18: 259
• 9 Bruno O, Brullo C, Bondavalli F, Ranise A, Schenone S, Falzarano MS, Varani K, Spisani S. Bioorg. Med. Chem. Lett. 2007; 17: 3696
• 10 Holla BS, Mahalinga M, Karthikeyan MS, Akberali PM, Shetty NS. Bioorg. Med. Chem. 2006; 14: 2040