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.

Abstracts

(A) Synthesis of Biologically Active Amides The reaction of 1 with various amine substrates was successful for the synthesis of biologically active compounds. Thus, imino-2H-chromen-3-carboxamide derivatives 4, inhibitors of β-secretase, were obtained in three steps starting from substituted anilines and pyrazole 1.[5] The reaction of spirocyclic amine 5 with a two-fold excess of 1 led to N-cyanoacetyl derivative 6, an inhibitor of Janus kinase 3.[6] [7]
(B) Synthesis of Oxadiazoles New 5-cyanomethyl-1,2,4-oxadiazoles 7 have been synthesized by the reaction of pyrazole 1 with arylamidoximes. The obtained compounds 7 are recognized as valuable building blocks for heterocyclic synthesis.[8] [9]
(С) Synthesis of Guareschi Imides Pyrazole 1 can be used as an active methylene compound capable of successfully replacing ethyl cyanoacetate in most cases. Thus, the Guareschi condensation could be vastly improved by replacing ethyl cyanoacetate with 1. The Guareschi imides as well as their sulfur and selenium analogues were obtained as triethylammonium salts 8 by a Michael-type addition of 1 to 2-cyanoacrylamides 9 followed by subsequent cyclocondensation.[10] [11] [12] [13] [14]
(D) O- and C-Cyanoacetylation While a number of papers have focused on the reactions of 1 with various N-nucleophiles, the reactions of cyanoacetylpyrazole with C- and O-nucleophiles have been neglected. The only examples of such reactions were reported by Swellem et al.[15] and Tverdokhlebov and co-workers.[16] Ternary condensation of 2-nitrobenzaldehyde with pyrazole 1 and ethylene glycol or glycerol gives 2-cyanoacrylates 10 in about 40% yield.[15] Despite the low yields, this approach is the method of choice in cases where the corresponding cyano­acetates are not readily available. The first examples of C-cyanoacetylation with 1 were reported a few years ago. The hetarylideneacetonitrile 11 reacts with 1 to give β-keto glutaronitrile 12. The latter upon treatment with HBr readily cyclizes to pyridine 13 in good yield.[16]
(E) Azo Coupling and Related Reactions As an active methylene compound, 1 readily reacts with diazonium salts to afford hydrazone products 14, which were found to be good starting materials for the synthesis of a variety of functionalized heterocycles.[17] In a similar manner, 1 gives dimethylaminomethylene derivative 15 upon treatment with DMF dimethyl acetal.[18]
(F) Functionalized Phosphorus Ylides The highly functionalized phosphorus ylides 16 are accessible in high yield by a three-component reaction of triphenylphosphine, dialkyl acetylene-dicarboxylates, and pyrazole 1.[19]

• 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