Regioselective Rapid Analogue Syntheses of 1-Methyl-3,5-diarylpyrazoles via Palladium-catalysed Coupling to 3(5)-Pyrazolyl Nonaflates

Abstract

Regioselective rapid analogue syntheses of 1-methyl-3,5-diarylpyrazoles were developed, based on Pd-catalysed couplings to 1-methyl-3(5)-arylpyrazole nonaflates, which offered an advantage in hydrolytic stability over the corresponding triflates. The new bifunctional reagent 1-methyl-3-bromo-pyrazol-5-yl nonaflate underwent highly chemoselective Pd-catalysed couplings to the nonaflate, followed by Suzuki couplings to the bromide, allowing sequential, regioselective introduction of the two aryl substituents.

regioselectivity - chemoselectivity - palladium - cross-coupling - heterocycles

References

<A NAME="RD28703ST-1">1</A>

New address: I. Collins, CRUK Centre for Cancer Therapeutics, The Institute for Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, U.K.

For reviews of the synthesis and biological activity of N-alkyl pyrazoles see:

<A NAME="RD28703ST-2A">2a</A> Elguero J. Comprehensive Heterocyclic Chemistry   Vol. 5:  Potts KT. Pergamon; Oxford: 1984.  p.167 

<A NAME="RD28703ST-2B">2b</A> Elguero J. Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.1 

For examples of Pd-catalysed cross-coupling to N-alkyl- or N-benzyl-3(5)-halopyrazoles see:

<A NAME="RD28703ST-3A">3a</A> Tretyakov EV. Knight DW. Vasilevsky SF. J. Chem. Soc., Perkin Trans. 1  1999,  3713 

<A NAME="RD28703ST-3B">3b</A> Paulson AS. Eskildsen J. Vedso P. Begtrup M. J. Org. Chem.  2002,  67:  3904 

<A NAME="RD28703ST-3C">3c</A> Cottineau B. Chenault J. Synlett  2002,  769 

<A NAME="RD28703ST-3D">3d</A> Balle T. Andersen K. Vedso P. Synthesis  2002,  1509 

<A NAME="RD28703ST-3E">3e</A> Eskildsen J. Ostergaard N. Vedso P. Begtrup M. Tetrahedron  2002,  58:  7635 

For examples of Pd-catalysed cross-coupling to N-aryl-3(5)-halopyrazoles see:

<A NAME="RD28703ST-4A">4a</A> Wang X.-J. Tan J. Grozinger K. Tetrahedron Lett.  2000,  41:  4713 

<A NAME="RD28703ST-4B">4b</A> Organ MG. Mayer S. J. Comb. Chem.  2003,  5:  118 

<A NAME="RD28703ST-5">5</A> Regan J. Breitfelder S. Crillo P. Gilmore T. Graham AG. Hickey E. Klaus B. Madwed J. Moriak M. Moss N. Pargellis C. Pav S. Proto A. Swinamer A. Tong L. Torcellini C. J. Med. Chem.  2002,  45:  2994 

<A NAME="RD28703ST-6">6</A> For a review see: Varvounis G. Fiamegos Y. Pilidis G. Adv. Het. Chem.  2001,  80:  73 

<A NAME="RD28703ST-7A">7a</A> Hamper BC. Kurtzweil ML. Beck P. J. Org. Chem.  1992,  57:  5680 

<A NAME="RD28703ST-7B">7b</A> Sucrow W. Slopianka M. Vetter HJ. Chem. Ber.  1978,  111:  791 

<A NAME="RD28703ST-8">8</A> Hendrickson JB. Hussoin MS. Synthesis  1989,  217 

<A NAME="RD28703ST-9">9</A> Morris J. Wishka DG. Synthesis  1994,  43 

<A NAME="RD28703ST-10">10</A> Rottlander M. Knochel P. J. Org. Chem.  1998,  63:  203 

<A NAME="RD28703ST-11">11</A> Renold P. Madero E. Maetke T. J. Chromatogr., A  2001,  908:  143 

<A NAME="RD28703ST-12A">12a</A> Collins I. J. Chem. Soc., Perkin Trans. 1  2000,  2845 

<A NAME="RD28703ST-12B">12b</A> Collins I. J. Chem. Soc., Perkin Trans. 1  2002,  1921 

<A NAME="RD28703ST-13">13</A> Boschi PM, and Gozzo AL. inventors; US Pat. Appl.  4256902.  ; Chem. Abstr. 1981, 95, 7281

<A NAME="RD28703ST-14A">14a</A> Rappe C. Arkiv Kemi  1964,  21:  503 

<A NAME="RD28703ST-14B">14b</A> Kim H. Hoffman HMR. Eur. J. Org. Chem.  2000,  2195 

<A NAME="RD28703ST-15">15</A> Rappe C. Andersson K. Arkiv Kemi  1965,  24:  303 

<A NAME="RD28703ST-16">16</A> Coates RM. Stack DP. Synthesis  1984,  434 

<A NAME="RD28703ST-17A">17a</A> Prepared by a modification of the method described by: Zinner G. Gebhardt U. Arch. Pharm.  1971,  304:  706 

<A NAME="RD28703ST-17B">17b</A>

A solution of MeNHNH₂ (26 mL) in (EtO)₂CO (60 mL) was refluxed under N₂ for 46 h. The solution was distilled at 1 atm to remove EtOH, then at 10 mmHg through a vigreux column, collecting the fraction boiling at 60-80 °C. Chromatography, eluting with MeOH-CH₂Cl₂ (3:97 then 5:95) gave ethyl 2-methyl-hydrazinecarboxylate (13.5 g, 85% pure by NMR) then ethyl 3-methylhydrazine-carboxylate (21.3 g, 93% pure by NMR).

<A NAME="RD28703ST-18">18</A> Bishop BC. Brands KMJ. Gibb AD. Kennedy DJ. Synthesis  2004,  43