The construction of C N bonds of heteroaromatic compounds is a highly important transformation in synthetic chemistry since it can offer nitrogen-containing molecules of great interest in biological, pharmaceutical, and materials sciences. During the past decades, remarkable progresses have been made in the metal-facilitated C N bond-forming reactions such as hydroamination or oxidative amidation of double or triple bonds as well as the Buchwald–Hartwigtype cross couplings. Despite these significant advances, direct installation of amino groups or their surrogates on aryl or alkyl C H bonds is still challenging. To meet this demand, a new approach involving oxidative addition of amino or amido moieties into hydrocarbons has been extensively studied. 6] In particular, site-selective amination of preorganized arenes through catalytic C H bond activation was recently developed. An ortho-selective amination of naphthols through thermal cleavage of disubstituted hydrazines was also reported. Most recently, Mori and co-workers have reported an oxidative amination of azoles using copper salts at high temperature ( 140 8C). Herein, we describe an unprecedented silver-mediated C N bond formation of benzoxazoles by decarbonylative coupling with formamides. On the basis of mechanistic considerations, we have also developed a direct amination protocol with parent amines under very mild reaction conditions. In line with our recent efforts on metal-catalyzed C H bond functionalization, we wondered whether subjection of electron-rich heteroarenes to Pd/Ag-catalytic systems in the presence of formamides could provide amidated products (Scheme 1). To our surprise, when benzoxazole (1a) was treated with N,N-dimethylformamide (DMF) using the Pd(OAc)2/Ag2CO3 system in the presence of an acetic acid additive, 2-aminated benzoxazole 2a was obtained as a single product, albeit in moderate yield. In contrast, no amidated product 3a was observed under other reaction conditions examined. Subsequent studies revealed that the unexpected decarbonylative amination reaction also proceeded even in the absence of the palladium catalyst and with slightly higher yields. Encouraged by these preliminary result, we subsequently tried to optimize the decarbonylative amination conditions using benzoxazole (1a) in neat DMF (40 equiv), as shown in Table 1. Although no desired product was obtained in the absence of the silver salt or the acid additives (entries 1 and 2), addition of certain types of carboxylic acids promoted the transformation in the presence of silver salts (entries 3–8). Among various acids examined, p-anisic acid turned out to be most effective for the amination reaction (entry 8). Catalytic amounts of Ag2CO3 did not furnish the desired product (entry 9), thus indicating that the use of stoichiometric amounts of silver salts is essential for smooth conversion under these reaction conditions. In addition, other silver sources such as Ag2O, AgOAc, AgOTf (Tf = triflate), or AgF (entry 10) were less effective when compared to Ag2CO3. [13] Scheme 1. Decarbonylative amination of benzoxazole (1a).

Silver-Mediated Direct Amination of Benzoxazoles: Tuning the Amino Group Source from Formamides to Parent Amines

One-pot, three-component route to 2H-indazolo[2,1-b]phthalazine-triones

Silica sulfuric acid as an efficient and reusable heterogeneous catalyst have been used for the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives from the three-component condensation reaction of phthalhydrazide, dimedone, and aromatic aldehydes under solvent-free conditions in good to excellent yields and short reaction times.

Silica sulfuric acid as an efficient catalyst for the preparation of 2H-indazolo[2,1-b]phthalazine-triones

Chemical Reviews is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Review Advances in Solutionand Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries Jyoti P. Nandy, Michael Prakesch, Shahriar Khadem, P. Thirupathi Reddy, Utpal Sharma, and Prabhat Arya Chem. Rev., 2009, 109 (5), 1999-2060• Publication Date (Web): 27 February 2009 Downloaded from http://pubs.acs.org on May 13, 2009

Advances in Solution- and Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries

The ninth annual review provides listings of chemical libraries, solid-phase reagents and scavengers, linkers, and polymer-supported chiral ligands reported during the year 2005.

Comprehensive survey of combinatorial library synthesis: 2005.

Solid-Phase Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives via Selective, Reagent-Based Cyclization of Acyldithiocarbazate Resins

A general method is reported for the parallel solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives based on the cyclization of polymer-bound dithiocarbazate 3 with various electrophiles, such as 3-ethoxyacrylonitriles 8 and cyanocarboimidates 9. The polymer-bound dithiocarbazate 3, produced by nucleophilic reaction with carbon disulfide and Fmoc-hydrazine on the Merrifield resin, served as the key intermediate for subsequent heterocycle diversification. Further nucleophilic substitution on these polymer-bound 5-amino-1-dithiocarboxypyrazoles 4 and 1,2,4-triazoles 6 with various amines under thermal cleavage condition produced the desired 5-amino-1-(substituted thiocarbamoyl)pyrazoles 5 and 1,2,4-triazoles 7. The progress of reactions could be monitored as polymer-bound intermediates by ATR-FTIR spectroscopy on single bead. The final compounds, obtained in good four-step overall yields and high purities upon cleavage from the resins, were characterized by LC...

Solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives via dithiocarbazate linker.

Solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives

We report the solid-phase library construction of 2000 analogues of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran. The polymer-bound hydroxyalkoxychromanes 5, produced by nucleophilic reactions with various alcohols on epoxides generated in situ, served as key intermediates for subsequent diversification. Further reactions on these hydroxyalkoxychromanes 5 with various electrophiles, such as alkyl halides and acid halides, produced the desired 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran analogues 9, 10, and 11. The progress of reactions could be monitored as solid-bound intermediates by ATR-FTIR or HR-MAS-NMR spectroscopy. The final compounds, obtained in good yields and high purity upon cleavage from the resins, were characterized by LC/MS, HRMS, (1)H NMR, and (13)C NMR spectroscopy.

Construction of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran library by solid phase synthesis.

An efficient solid-phase methodology has been developed for the synthesis of 2-aminobenzoxazole derivatives. The key step in this procedure involves preparation of polymer-bound 2-mercaptobenzoxazole resins 3 by reaction of the Merrifield resin with 2-aminophenols and CS2 in the presence of DIC in MeCN. Oxidation of the resulting resins followed by treatment with amines gives the desired 2-aminobenzoxazole products 5. Further diversification can be introduced to the key resin 11, derived from the nitro group containing resin 3c. This process produces the corresponding amine, which upon reaction with acid chlorides and isocyanates can be used to generate various 6-functionalized 2-aminobenzoxazole analogues 13 and 15.

Jong Yeon Hwang

Papers

Solid-Phase Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives via Selective, Reagent-Based Cyclization of Acyldithiocarbazate Resins

Solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives via dithiocarbazate linker.

Solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives

Construction of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran library by solid phase synthesis.

Solid-phase synthesis of the 2-aminobenzoxazole library using thioether linkage as the safety-catch linker.