Richter cyclization and co-cyclization reactions of triazene-masked diazonium ions Annelies Goeminne, Peter J. Scammells, Shane M. Devine, Bernard L. Flynn ⇑ Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville Vic. 3052, Australia article info Article history: Received 25 August 2010 Revised 6 October 2010 Accepted 22 October 2010 Available online 30 October 2010 Keywords: Richter reaction Triazenes Cinnolines Domino reaction abstract The conventional Richter cyclization involves diazotization of 2-alkynylanilines with HX (aq) (X = Br or Cl) and NaNO 2 , followed by spontaneous ring closure to give a mixture of 4-halocinnoline and 4-cinnoli- none products. The different products result from competing attack of X À and H 2 O, respectively, upon an intermediate 2-alkynylphenyl diazonium ion during the cyclization step. In order to improve the chemoselectivity of this reaction, we have utilized triazenes as masked diazonium ions. These can be unmasked using MeSO 3 H in anhydrous solvents and the resultant 2-alkynylphenyl diazonium ion cyclized chemoselectively by the incorporation of a specifically added nucleophile. This process has been extended to tethered nucleophiles, leading to a Richter induced co-cyclization process to give ring-fused cinnolines. Ó 2010 Elsevier Ltd. All rights reserved. Cinnolines are a valuable heterocyclic class from which a number of biologically active compounds have been identified, including anti-cancer, fungicidal, antibacterial, and anxiolytic com- pounds, among others. 1 The first cinnolines were prepared by von Richter over 125 years ago by diazotization of 2-alkynylanilines 1 and heating to form cinnolinones 4 as the major product (Scheme 1). 2 Although it was the first reported method for the synthesis of cinnolines, it was subsequently superseded by the related Bor- sche–Herbert and Widman–Stoermer reactions as the preferred methods of preparing these heterocycles, due to the greater ease with which the starting materials could be accessed and the in- creased generality of the reactions. 1,3 However, with the emer- gence of efficient palladium-mediated coupling methods for accessing 2-alkynylanilines 1 (e.g., Sonogashira coupling) the syn- thetic potential of the Richter reaction has been enhanced signifi- cantly. 4,5 Recent studies into the mechanism of the Richter reaction have revealed that the initially formed diazonium ion 2 cyclizes to 3 and 4 at room temperature upon competitive nucleo- philic attack of the halide and water (Nu = X À or H 2 O), respectively (2 solid arrows). 1a,6,7 Heating this mixture, as initially performed by Richter, hydrolyzes 3 into 4. Depending on the nature of substit- uents R 1/2 , cyclization can be redirected through the a-carbon of the alkyne to give indazoles 6 and 7 (2 dashed arrows), instead of cinnolines. 6,7 When R 1 in 2 is a C5 electron-withdrawing group (i.e., EWG para to the alkyne) or R 2 is an electron-donating group, the alkyne becomes polarized so as to favor cyclization through the a-carbon and attack of the nucleophile at the b-carbon to give products 6/7. While diazoniums 2, used in most studies to date, have gener- ally been formed from the treatment of 2-alkynylanilines 1 with HBr (aq) or HCl (aq) and NaNO 2 , they can also be formed by the reaction of (2-alkynylphenyl)triazenes 5 with HBr (aq) or HCl (aq) (Scheme 1). 5 While only a few examples of the use of triazenes 5 in the Richter reaction exist, similar chemoselectivity issues have been reported, where selective formation of either 3 or 4 is compli- cated by the competitive formation of the other (see also below). 5a While hydrolysis of 3 can be used to gain selective access to cinn- olinones 4, albeit under forcing conditions, chemoselective access to 3 is more difficult. In this respect, Fedenock and coworkers have utilized high concentrations of chloride ions during the Richter reaction of 2-alkynylanilines 1 to favor formation of 3 (X = Cl). 7 However, we have found this to be problematic, particularly for the selective formation of bromides 3 (X = Br). In many cases the cinnolinone 4 still prevails and/or brominated by-products are formed, which is known to be an issue for diazotizations involving HBr. 4c We anticipated that triazenes 5 might prove more useful substrates for highly selective formation of variously substituted cinnolines by using an acid that has a non-nucleophilic conjugate base (e.g., MeSO 3 H) to form a stable diazonium 2-MeSO 3 À that can then be treated with a nucleophile to afford variously substi- tuted cinnolinones 3/4/8 (Scheme 2). In order to form 4-halocinn- olines 3 selectively, 2-MeSO 3 À could be formed in an anhydrous solvent and a tetraalkylammonium halide added to induce cycliza- tion to 3, avoiding competitive formation of 4. Alternatively, selective formation of cinnolinone 4 could be achieved by using MeSO 3 H in an aqueous solvent, favoring direct attack of 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.10.122 ⇑ Corresponding author. E-mail address: bernard.flynn@pharm.monash.edu.au (B.L. Flynn). Tetrahedron Letters 51 (2010) 6882–6885 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet