One-Pot Microwave-Assisted Synthesis of a Benzopyrano[2,3-c]pyrazol-3(2H)-one Library Alexander V. Borisov,* ,† Nikolay Yu. Gorobets, ‡,§ Sergey A. Yermolayev, ‡ Irina O. Zhuravel’, † Sergiy M. Kovalenko, † and Sergey M. Desenko ‡ National UniVersity of Pharmacy, Pushkinska str. 53, 61002 KharkiV, Ukraine, and Department of Chemistry of Heterocyclic Compounds, SSI “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Lenin AVe 60, 61001 KharkiV, Ukraine ReceiVed May 31, 2007 Modern methodology applies the reactivity of 2-iminocou- marine (2-imino-2H-chromene) derivatives in reaction with different nucleophiles 1 and electrophiles 2 for construction of heterocyclic systems containing the coumarine (benzopyrane, 2H-chromen-2-one) moiety. The products of these reactions are used as bioactive compounds 3 or luminescent dyes 4 for different needs. In continuation of our works 2 on utilization of the 2-iminocoumarine reactivity for the synthesis of diverse benzopyranes fused with nitrogen containing het- erocycles, here, we present a facile one-pot microwave- assisted protocol for fast generation of a benzopyrano[2,3- c]pyrazol-3(2H)-one library. Initially the simplest benzopyrano[2,3-c]pyrazol-3(2H)-one was isolated from a complex reaction mixture by O’Callaghan. 5 Afterwards, some other synthetic methods for this compound and its 3-thioanalogue were published. 6 Thus, a reaction of substituted 1H-pyrazol-5(4H)-ones with 4-di- alkylaminosalicylic aldehydes was proposed for the synthesis of 7-dialkylaminobenzopyrano[2,3-c]pyrazol-3(2H)-ones sub- stituted in the pyrazolone ring. 7 However, all the published reactions cannot be used for fast generation of the desired benzopyrano[2,3-c]pyrazol-3(2H)-one combinatorial library. They are limited by low overall yield and restricted diversity of the final products. In our previous work, 8 a representative of the compounds 4{12,10} was isolated as a side product of acetylation of hydrazonocoumarine 3{12,10} in the medium of acetic anhydride under reflux conditions during 15 min (Scheme 1). The same compound 4{12,10} was also obtained as the only product from the hydrazone 3{12,10} in refluxing DMF during 36 h. Addition of 2.0 equiv of the acetic anhydride to the reaction mixture was shown to decrease the reaction time to 6 h without formation of the diacetilated product 5 (Scheme 1). Thus, the presence of the acetic anhydride assisted the desamination of the hydrazone 3{12,10} into the benzopyrano[2,3-c]pyrazol-3(2H)-one 4{12,10}. Due to the long reaction time (6–36 h), the reaction described above (Scheme 1) can not be carried out in high- throughput format for fast generation of a combinatorial library. To improve this method, we applied the technology of microwave-assisted organic synthesis. This technology is now widely used for fast generation of combinatorial libraries in automated and parallel synthesis. 9 Initially, we chose the starting unsubstituted hydrazone 3{1,3} to find the optimal conditions for the desamination process. We varied the DMF–acetic anhydride ratio, reaction time, and temperature under microwave irradiation and established that the optimal conditions are 2.5 equiv of the Ac 2 O in 1 mL of DMF, 200 °C, and 10 min and the maximal HPLC yield of the desired product 4{1,3} is only 66%. However, the HPLC analysis of the final reaction mixture indicated also a formation of several by-products that could be caused by side acetylation reactions. Moreover, the presence of the acetic anhydride makes it impossible to apply starting compounds containing reactive substituents such as OH or COOH groups (e.g., building blocks 1{7}, {10}, {11}, and 2{6}). The possibility to introduce these substituents into the final molecule is important regarding future diversification of the benzopy- rano[2,3-c]pyrazol-3(2H)-one scaffold. Thus, we switch over to a search for such reaction conditions that could exclude the acetic anhydride. Applying acetic acid as a reaction medium under microwave irradiation at 190 °C for 5 min led to a full conversion of the starting hydrazone 3{1,3} into the desired benzopyrano[2,3-c]pyrazol- 3(2H)-one 4{1,3} (Scheme 2) with a small level of byprod- ucts in the final reaction mixture. Moreover, we have succeeded in carrying out this transformation in one pot starting from the 2-iminocoumarine-3-carboxamide 1{1} and the phenyl hydrazine under the same conditions. Thus, in the final protocol, we applied 1.50 mmol of the starting 2-iminocoumarin-3-carboxamide 1 and 5% excess of the hydrazine 2 in 4.5 mL of the acetic acid under microwave irradiation at 190 °C for 5 min. The compounds 4{7,3} and 2{2,6} containing OH and COOH groups correspondingly were also synthesized in larger scale in 19 mL of the acetic acid using 6.0 mmol of the parent iminocoumarins 1, the * Corresponding author. E-mail: borisov@onet.com.ua. † National University of Pharmacy. ‡ SSI “Institute for Single Crystals” of National Academy of Sciences of Ukraine. § E-mail: gorobets@isc.kharkov.com. Fax: +38(057)3409343. Table 1. Representative Library Members (Isolated Yields and Purity) entry R 1 R 2 isolated yield (%) purity (HPLC, %) 4{1,3} H H 72 98 4{1,7} H 4-NO 2 -Ph 85 90 4{1,9} H 4-OMe-Ph 70 94 4{1,10} H 4-Br-Ph 74 95 4{2,3} 8-OMe H 80 98 4{2,6} 8-OMe 4-COOH-Ph 79, 87a 99 4{2,2} 8-OMe Bn 52 98 4{3,3} 8-OEt H 61 >99 4{5,2} 6-Cl Bn 65 97 4{5,1} 6-Cl t-Bu 49 89 4{7,3} 7-OH H 42, 43a >99 4{10,3} 6-t-Bu-8-OH H 52 98 a Scale-up protocol. J. Comb. Chem. 2007, 9, 909–911 909 10.1021/cc700090c CCC: $37.00  2007 American Chemical Society Published on Web 08/30/2007