C C AIBN. Scheme Pd /Ag. α- C H CHINESE JOURNAL OF APPLIED CHEMISTRY Aug b. CuI /DTBP N- O664

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1 32 8 Vol. 32 Iss CHINESE JOURNAL OF APPLIED CHEMISTRY Aug a a b* a a a a a b CuI /DTBP N- α- α- α- C H O664 A DOI /j. issn C C AIBN 11 N- 4 α- N- Scheme / N- - Pd /Ag / 120 α-c H - α- α Scheme 2 Scheme 1 Several representative pharmaceutical oxindoles JDZ Tel /Fax stang@ jsu. edu. cn

2 8 885 α- Scheme 2 Synthesis of oxindoles bearing α-cyano quarterary carbon center AIBN AVANCE 400 MHz Bruker TMS GC-MS-QP2010 XT5A 1. 2 N a mg 0. 5 mmol N- 1a 2 ml 9. 6 mg mmol 244 mg 1. 0 mmol mg 1. 0 mmol h TLC - 3a 3a mp 158 ~ H NMR 400 MHz CDCl 3 δ ~ m 2H t J = 7. 6 Hz 1H d J = 8. 0 Hz 1H s 3H d J = Hz 1H d J = 14. 4Hz 1H ~ m. 10H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 18 H 23 N 2 O M + H b mp 145 ~ H NMR 400 MHz CDCl 3 δ s 1H d J = 7. 6 Hz 1H d J = 8. 0 Hz 1H s 3H s 3H d J = Hz 1H 2 11 d J = Hz 1H ~ m 10H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 19 H 25 N 2 O M + H c mp 150 ~ H NMR 400 MHz CDCl 3 δ ~ m 2H ~ m 1H s 3H d Hz 1H d J = Hz 1H ~ m 10H s 3H 13 C NMR 101 MHz CDCl 3 δ d J = 241 Hz d J = 7. 8 Hz d J = Hz d J = 7. 1 Hz IR KBr σ /cm

3 HRMS m /z ESI C 18 H 22 FN 2 O M + H d mp 140 ~ H NMR 400 MHz CDCl 3 δ dd J = 8. 4 Hz 1. 6 Hz 1H s 1H d J = 8. 4 Hz 1H q J = 6. 8 Hz 2H s 3H d J = Hz 1H d J = Hz 1H ~ m 10H t J = 7. 2 Hz 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 21 H 27 N 2 O 3 M + H f mp 100 ~ H NMR 400 MHz CDCl 3 δ ~ m 2H t J = 6. 0 Hz 1H d J = 6. 4 Hz 1H s 3H d J = Hz 1H d J = H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 15 H 19 N 2 O M + H g mp 80 ~ 81 1 H NMR 400 MHz CDCl 3 δ ~ m 7H t J = 7. 2 Hz 1H d J = 8. 0 Hz 2H d J = Hz 1H d J = Hz 1H d J = Hz 1H d J = Hz 1H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ MS IR KBr σ /cm HRMS m /z ESI C 21 H 23 N 2 O M + H h mp 121 ~ H NMR 400 MHz CDCl 3 δ ~ m 7H t J = 8. 0 Hz 1H d J = 8. 0 Hz 1H s 3H d J = Hz 1H d J = Hz 1H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 17 H 21 N 2 O M + H i 1 H NMR 400 MHz CDCl 3 δ m 2H t J = 7. 6 Hz 1H d J = 8. 4 Hz 1H d J = Hz 1H d J = Hz 1H s 3H s 2H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 17 H 21 N 2 O 3 M + H + 3j 1 H NMR 400 MHz CDCl 3 δ d J = 7. 2 Hz 1H d J = 7. 6 Hz 1H t J = 7. 6 Hz 1H ~ m 2H ~ m 2H d J = Hz 1H d J = Hz 1H ~ m 2H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 17 H 21 N 2 O M + H

4 k mp 128 ~ H NMR 400 MHz CDCl 3 δ ~ m 2H d J = 8. 0 Hz 1H s 3H d J = Hz 1H d J = Hz 1H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ IR KBr σ /cm HRMS m /z ESI C 15 H 18 ClN 2 O M + H l mp 107 ~ H NMR 400 MHz CDCl 3 δ ~ m 2H ~ m 1H s 3H d J = Hz 1H d J = Hz 1H s 3H s 3H s 3H 13 C NMR 101 MHz CDCl 3 δ d J = Hz d J = 23. 4Hz d J = Hz IR KBr σ /cm HRMS m /z ESI C 15 H 18 FN 2 O M + H m mp 114 ~ H NMR 400 MHz CDCl 3 δ d J = 8. 4 Hz 1H s 1H d J = 8. 4 Hz 1H s 3H d J = Hz 1H d J = Hz 1H s 3H s 6H 13 C NMR 101 MHz CDCl 3 δ q J = 3. 9 Hz q J = Hz q J = 3. 5 Hz IR KBr σ /cm HRMS m /z ESI C 16 H 18 F 3 N 2 O M + H c 150 mg 0. 5 mmol LiAlH 4 76 mg 2. 0 mmol 10 ml N 2 1 h 0. 5 h THF /H 2 O ml h 1 mol /L HCl 5 ml 5 min K 2 CO 3 Na 2 SO mg 73% 4 1 H NMR 400 MHz CDCl 3 δ ~ m 2H dd J = 8. 0 Hz 4. 0 Hz 1H s 1H s 3H d J = Hz 1H d J = Hz 1H br 1H ~ m 10H s 3H ~ m 2H 13 C NMR 101 MHz CDCl 3 δ d J = Hz d J = Hz d J = Hz d J = 7. 1 Hz HRMS m /z ESI C 18 H 26 FN 2 M + H N- -N- 1a 1 1-2a 1 23% 3a 1 entry 1 92% 3a 1 entries 2 ~ 5 FeSO 4 7H 2 O Fe NH 4 2 SO 4 2 6H 2 O 65%

5 % 1 entries 6 ~ 8 DTBP TBHP DTBP 76% 1 entry 9 70% 1 entry 10 PhI OAc 2 PhI OTFA 2 DTBP 1 entries 11 ~ 12 14% 1 entry 13 90% 1 entry 14 1 entries 15 ~ % 1 entry % 1 entry 18 N mmol a- 1 mmol CuI 0. 05mmol DTBP 1 mmol h Table 1 1 Screening of optimal reaction conditions a Entry Metal Oxidant Solvent Yield /% b 1 none DTBP CH 3 CN 23 2 CuCl DTBP CH 3 CN 85 3 CuBr DTBP CH 3 CN 74 4 CuI DTBP CH 3 CN 92 5 CuCN DTBP CH 3 CN 87 6 FeSO 4 7H 2 O DTBP CH 3 CN 65 7 FeBr 2 DTBP CH 3 CN 75 8 Fe NH 4 2 SO 4 2 6H 2 O DTBP CH 3 CN 70 9 CuI TBHP CH 3 CN CuI K 2 S 2 O 8 CH 3 CN CuI PhI OAc 2 CH 3 CN CuI PhI OTFA 2 CH 3 CN CuI none CH 3 CN CuI DTBP dioxane CuI DTBP toluene CuI DTBP DCE c CuI DTBP CH 3 CN d CuI DTBP CH 3 CN 64 a. Reaction conditions 1a 0. 5 mmol 2a 1 mmol oxidant 1 mmol metal mmol solvent 2 ml at 80 for 12 h. DTBP = Di-tert-butyl peroxide TBHP = tert-butyl hydrogenoxide 70% aqueous solution DCE = 1 2-dichloroethane b. isolated yield c. 60 d Scheme a N- Me H F CO 2 Et N- 95% 3e

6 8 889 AIBN 2 2'- -2 2'- 81% 3f AIBN N- N 70% 3g CH 2 OAc 73% 66% 3h 3i 3j Scheme 3 Scope of N-arylacrylamide 1 Reaction conditions mmol 2 1 mmol DTBP 1 mmol CuI mmol and CH 3 CN 2 ml at 80 for 12 h. a. run on 5 mmol scale c LiALH 4 73% 4 4 Scheme 4 Scheme 4 Synthetic transformation of oxindole 3c Reagent and conditions a LiAlH 4 4 equiv THF 1 h then reflux 0. 5 h

7 Scheme 5 Proposed mechanism for the formation of oxindoles Scheme 5 1a A A N- B C C Cu Ⅰ t BuO-Cu Ⅱ t BuO 8 3a 3 CuI 5% DTBP 2 80 N- 1 Posner G H. Multicomponent One-pot Annulations Forming 3 to 6 Bonds J. Chem Rev Lu L Q Chen J R Xiao W J. Development of Cascade Reactions for the Concise Construction of Diverse Heterocyclic Architectures J. Acc Chem Res Mai W Wang J Yang L et al. Progress in Synthesis of Oxindoles by Radical Addition-Cyclization J. Chinese J Org Chem Tang S Zhou D Deng Y et al. Copper-catalyzed Meerwein Carboarylation of Alkenes with Anilines to Form 3-Benzyl-3- Alkyloxindole J. Sci China Chem Shen T Yuan Y Jiao N. Metal-Free Nitro-Carbocyclization of Activated Alkenes A Direct Approach to Synthesize Oxindoles by Cascade C N and C C Bond Formation J. Chem Commun Zhou M Song R Ouyang X et al. Metal-free Oxidative Tandem Coupling of Activated Alkenes with Carbonyl C Sp2 -H Bonds and Aryl C Sp2 -H Bonds using TBHP J. Chem Sci Ouyang X Song R Li J. Iron-Catalyzed Oxidative 1 2-Carboacylation of Activated Alkenes with Alcohols A Tandem Route to 3-2-Oxoethyl indolin-2-ones J. Eur J Org Chem Dai Q Yu J Jiang Y et al. The Carbomethylation of Arylacrylamides Leading to 3-Ethyl-3-Substituted Indolin-2-One by Cascade Radical Addition /Cyclization J. Chem Commun Zhou M Wang C Song R et al. Oxidative 1 2-Difunctionalization of Activated Alkenes with Benzylic C sp3 -H Bonds and Aryl C sp2 -H Bonds J. Chem Commun Chen J Yu X Xiao W. Tandem Radical Cyclization of N-Arylacrylamides An Emerging Platform for the Construction of 3 3-Disubstituted Oxindoles J. Synthesis

8 Yu W Sit W N Lai K et al. Palladium-Catalyzed Oxidative Ethoxycarbonylation of Aromatic C H Bond with Diethyl Azodicarboxylate J. J Am Chem Soc Klein J Taylor R. Transition-Metal-Mediated Routes to 3 3-Disubstituted Oxindoles through Anilide Cyclisation J. Eur J Org Chem Wu T Mu X Liu G S. Palladium-Catalyzed Oxidative Arylalkylation of Activated Alkenes Dual C H Bond Cleavage of an Arene and Acetonitrile J. Angew Chem Int Ed Li J Wang Z Wu N et al. Oxindoles J. Chem Commun Radical Cascade Cyanomethylation of Activated Alkenes to Construct Cyano Substituted 15 Pan C Zhang H Zhu C. Fe-promoted Radical Cyanomethylation / Arylation of Arylacrylamides to Access Oxindoles via Cleavage of the sp3c H of Acetonitrile and the sp2c H of the Phenyl Group J. Org Biomol Chem Tang S Yu Q Peng P et al. Palladium-catalyzed Carbonylative Annulation Reaction of 2-1-Alkynyl benzenamines Selective Synthesis of 3- Halomethylene indolin-2-ones J. Org Lett Tang S Zhou D Wang Y. Metal-Free Meerwein Carboarylation of Alkenes with Anilines A Straightforward Approach to 3-Benzyl-3-alkyloxindoles J. Eur J Org Chem Tang S Li S Zhou D et al. Stereoselective C sp 3 C sp 2 Negishi Coupling of 2-Amido-1-phenylpropyl zinc Compounds Through the Steric Control of β-amido Group J. Sci Chinese Chem Copper-catalyzed Cyanoalkylation of Alkenes to Form Cyano- containing Oxindoles LI Zhihao a TANG Shi a b* ZHOU Dong a DENG Youlin a LI Yuhua a LI Shuhua a a Key Laboratory of Hu'nan Forest Product and Chemical Industry Engineering Jishou University Zhangjiajie Hu'nan China b College of Chemistry and Chemical Engineering Central South University Changsha China Abstract A practical mild and highly efficient cyanoalkylation reaction of activated alkenes by copper catalysis has been developed. In the presence of CuI /DTBP Di-tert-butyl peroxide N-arylacrylamide undergoes radical cyclization smoothly and affords a series of pharmaceutically important oxindoles bearing an α-cyano quaternary carbon center. The protocol features broad substrate scope simplicity of operation and handling and inexpensive catalytic systems. In addition the synthetic application and possible mechanism process in the cyclization reaction were also demonstrated. Keywords α-cyano azo compounds cyano-containing oxindoles C H cyclization radical copper catalysis Received Revised Accepted Supported by the National Natural Science Foundation of China NSFC No Key Laboratory of Hunan Forest Product and Chemical Industry Engineering No. JDZ Research-Based Learning and Innovative Experiment Project of Jishou University Corresponding author TANG Shi associate professor Tel /Fax stang@ jsu. edu. cn Research interests transitionmetal catalysis and synthesis