1-Cyanoacetyl-3,5-dimethylpyrazole

Introduction

1-Cyanoacetyl-3,5-dimethylpyrazole (1) is a white crystalline solid with a melting point of 118–121 °C,[1] stable at room temperature in air. In the 1950s, Ried and Meyer[1] were the first to describe it as a mild cyanoacetylating reagent, being more reactive than ethyl cyanoacetate. Pyrazole 1 is a cheap, handy, and non-toxic reagent that proved to be superior to cyanoacetyl chloride and cyanoacetyl azide in terms of stability and convenience. It is commercially available and can be prepared in about 90% yield by condensation of acetylacetone (2) with cyanoacetohydrazide (3) in aqueous hydrochloric acid (Scheme [1]).[2]

Scheme 1 Preparation of 1-cyanoacetyl-3,5-dimethylpyrazole

The first and most common application of 1-cyanoacetyl-3,5-dimethylpyrazole (1) is the synthesis of N-substituted cyanoacetamides, which are known as versatile building blocks for heterocyclic synthesis.[3] [4] 1 readily reacts with various N-nucleophiles (amines, hydrazines, hydrazides, semicarbazides) in an inert solvent (ether, benzene, toluene, dioxane) under mild conditions.

Scheme 2 Synthesis of s-substituted cyanoacetamides

The N-cyanoacetylation products can be isolated from the reaction mixture in crystalline form, while the 3,5-dimethylpyrazole by-product remains in the mother liquor. The yields are usually high and sometimes nearly quantitative.

• References

• 1 Ried W, Meyer A. Chem. Ber. 1957; 90: 2841
• 2 Gorobets NY, Yousefi BH, Belaj F, Kappe CO. Tetrahedron 2004; 60: 8633
• 3 Fadda AA, Bondock S, Rabie R, Etman HA. Turk. J. Chem. 2008; 32: 259
• 4 Dyachenko VD, Tkachiov RP, Bityukova OS. Russ. J. Org. Chem. 2008; 44: 1565
• 5 Edraki N, Firuzi O, Foroumadi A, Miri R, Madadkar-Sobhani A, Khoshneviszadeh M, Shafiee A. Bioorg. Med. Chem. 2013; 21: 2396
• 6 Noji S, Shiozaki M, Miura T, Hara Y, Yamanaka H, Maeda K, Hori A, Inoue M, Hase Y. WO Pat. Appl. 2011013785, 2011
• 7 Noji S, Shiozaki M, Miura T, Hara Y, Yamanaka H, Maeda K, Hori A, Inoue M, Hase Y. US Pat. 2011136778, 2011
• 8 Borisov AV, Detistov АS, Pukhovaya VI, Zhuravel’ IO, Kovalenko SM. J. Comb. Chem. 2009; 11: 1023
• 9 Zhuravel’ IO, Kovalenko SM, Zaremba OV, Detistov АS, Kovalenko SS, Chernykh VP. Synth. Commun. 2008; 38: 3778
• 10 Chigorina EA, Dotsenko VV, Krivokolysko SG. Chem. Heterocycl. Compd. 2011; 47: 913
• 11 Chigorina EA. Chem. Heterocycl. Compd. 2013; 49: 574
• 12 Dotsenko VV, Krivokolysko SG, Litvinov VP. Monatsh. Chem. 2007; 138: 607
• 13 Dotsenko VV, Krivokolysko SG, Litvinov VP. Russ. Chem. Bull., Int. Ed. 2007; 56: 2482
• 14 Frolov KA, Dotsenko VV, Krivokolysko SG, Litvinov VP. Chem. Heterocycl. Compd. 2012; 48: 442
• 15 Swellem RH, Chabaka LM, Nawwar GA. M. Egypt. J. Chem. 2007; 50: 135
• 16 Denisenko AV, Tverdokhlebov AV, Tolmachev AA, Volovenko YM, Shishkina SV, Shishkin OV. Synthesis 2011; 251
• 17 El Rady EA. Heterocycl. Commun. 2012; 18: 215
• 18 Abdel-Megid M. Chem. Heterocycl. Compd. 2010; 46: 316
• 19 Anary-Abbasinejad M, Hassanabadi A, Esmikhani N. J. Chem. Res. 2010; 34: 508