32 8 Vol. 32 Iss. 8 2015 8 CHINESE JOURNAL OF APPLIED CHEMISTRY Aug. 2015 a a b* a a a a a 416000 b 410083 CuI /DTBP N- α- α- α- C H O664 A DOI 10. 11944 /j. issn. 1000-0518. 2015. 08. 150005 1000-0518 2015 08-0884-08 C C 1-2 - 3-10 AIBN 11 N- 4 α- N- Scheme 1 12 2012 13 / N- - Pd /Ag 14-15 / 120 α-c H - α- α- 16-17 Scheme 2 Scheme 1 Several representative pharmaceutical oxindoles 2015-01-06 2015-04-14 2015-05-06 21462017 JDZ201402 Tel /Fax 0743-8563911 E-mail stang@ jsu. edu. cn
8 885 α- Scheme 2 Synthesis of oxindoles bearing α-cyano quarterary carbon center 1 1. 1 AIBN 1 1- -1- AVANCE 400 MHz Bruker TMS GC-MS-QP2010 XT5A 1. 2 N- 5 1. 3 3 3a 87. 5 mg 0. 5 mmol N- 1a 2 ml 9. 6 mg 0. 05 mmol 244 mg 1. 0 mmol 1 1- -1-146 mg 1. 0 mmol 80 12 h TLC - 3a 3a mp 158 ~ 159 1 H NMR 400 MHz CDCl 3 δ 7. 32 ~ 7. 28 m 2H 7. 06 t J = 7. 6 Hz 1H 6. 87 d J = 8. 0 Hz 1H 3. 21 s 3H 2. 39 d J = 14. 4 Hz 1H 2. 14 d J = 14. 4Hz 1H 1. 64 ~ 1. 03 m. 10H 1. 31 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 8 143. 0 131. 3 128. 5 124. 6 122. 4 122. 1 108. 5 46. 7 46. 6 38. 1 37. 0 35. 0 27. 7 26. 4 24. 8 22. 8 22. 5 IR KBr σ /cm - 1 2231 1701 1614 1471 HRMS m /z ESI C 18 H 23 N 2 O M + H + 283. 1805 283. 1808 3b mp 145 ~ 146 1 H NMR 400 MHz CDCl 3 δ 7. 11 s 1H 7. 07 d J = 7. 6 Hz 1H 6. 74 d J = 8. 0 Hz 1H 3. 17 s 3H 2. 31 s 3H 2. 25 d J = 14. 8 Hz 1H 2 11 d J = 14. 8 Hz 1H 1. 28 ~ 1. 09 m 10H 1. 28 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 8 140. 6 131. 8 131. 2 128. 6 125. 5 122. 2 108. 1 46. 7 46. 5 38. 1 37. 0 34. 8 27. 8 26. 4 24. 8 22. 7 22. 5 21. 2 IR KBr σ /cm - 1 2233 1706 1617 1496 HRMS m /z ESI C 19 H 25 N 2 O M + H + 297. 1962 297. 1965 3c mp 150 ~ 151 1 H NMR 400 MHz CDCl 3 δ 7. 05 ~ 6. 97 m 2H 6. 81 ~ 6. 77 m 1H 3. 20 s 3H 2. 39 d 14. 8 Hz 1H 2. 19 d J = 14. 8 Hz 1H 1. 52 ~ 0. 99 m 10H 1. 31 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 4 159. 1 d J = 241 Hz 139. 0 133. 0 d J = 7. 8 Hz 121. 9 114. 6 112. 6 d J = 24. 5 Hz 108. 9 d J = 7. 1 Hz 47. 1 46. 6 38. 1 36. 9 35. 3 27. 6 26. 5 24. 5 22. 7 22. 5 IR KBr σ /cm - 1 2234 1713 1621
886 32 1451 HRMS m /z ESI C 18 H 22 FN 2 O M + H + 301. 1711 301. 1714 3d mp 140 ~ 141 1 H NMR 400 MHz CDCl 3 δ 8. 05 dd J = 8. 4 Hz 1. 6 Hz 1H 7. 90 s 1H 6. 90 d J = 8. 4 Hz 1H 4. 34 q J = 6. 8 Hz 2H 3. 25 s 3H 2. 32 d J = 14. 4 Hz 1H 2. 25 d J = 14. 4 Hz 1H 1. 61 ~ 0. 98 m 10H 1. 37 t J = 7. 2 Hz 3H 1. 35 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 9 166. 3 147. 2 131. 5 131. 1 125. 4 124. 6 121. 6 108. 0 60. 9 46. 7 46. 6 37. 9 36. 9 36. 1 27. 5 26. 6 24. 8 22. 7 22. 5 14. 3 IR KBr σ /cm - 1 2235 1726 1701 1612 1475 HRMS m /z ESI C 21 H 27 N 2 O 3 M + H + 355. 2017 355. 2019 3f mp 100 ~ 101 1 H NMR 400 MHz CDCl 3 δ 7. 40 ~ 7. 25 m 2H 7. 09 t J = 6. 0 Hz 1H 6. 90 d J = 6. 4 Hz 1H 3. 23 s 3H 2. 32 d J = 11. 6 Hz 1H 2. 16 d J = 11. 6 1H 1. 34 s 3H 1. 13 s 3H 1. 08 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 5 143. 1 130. 9 128. 6 124. 6 123. 9 122. 4 108. 5 47. 0 46. 5 30. 7 29. 6 27. 4 26. 8 26. 4 IR KBr σ /cm - 1 2234 1716 1610 1432 1378 1335 HRMS m /z ESI C 15 H 19 N 2 O M + H + 243. 1492 243. 1495 3g mp 80 ~ 81 1 H NMR 400 MHz CDCl 3 δ 7. 40 ~ 7. 20 m 7H 7. 05 t J = 7. 2 Hz 1H 6. 83 d J = 8. 0 Hz 2H 5. 12 d J = 15. 6 Hz 1H 4. 72 d J = 15. 6 Hz 1H 2. 36 d J = 14. 8 Hz 1H 2. 22 d J = 14. 4 Hz 1H 1. 40 s 3H 1. 19 s 3H 1. 03 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 7 142. 3 130. 8 128. 7 128. 5 127. 7 127. 6 124. 8 124. 1 122. 4 119. 9 109. 5 47. 0 46. 2 44. 1 30. 8 29. 7 28. 1 26. 3 MS IR KBr σ /cm - 1 2233 1701 1610 1432 1376 1332 HRMS m /z ESI C 21 H 23 N 2 O M + H + 319. 1805 319. 1801 3h mp 121 ~ 122 1 H NMR 400 MHz CDCl 3 δ 7. 50 ~ 7. 48 m 7H 7. 18 t J = 8. 0 Hz 1H 6. 96 d J = 8. 0 Hz 1H 3. 22 s 3H 2. 82 d J = 14. 4 Hz 1H 2. 49 d J = 14. 4 Hz 1H 1. 23 s 3H 1. 18 s 3H 13 C NMR 101 MHz CDCl 3 δ 177. 4 144. 1 140. 7 140. 4 129. 4 128. 0 127. 5 125. 4 124. 2 123. 8 122. 5 108. 9 54. 6 46. 6 30. 7 30. 2 29. 0 28. 7 IR KBr σ /cm - 1 2234 1713 1611 1470 1372 1341 HRMS m /z ESI C 17 H 21 N 2 O M + H + 269. 1649 269. 1653 301. 1547 301. 1546 3i 1 H NMR 400 MHz CDCl 3 δ 7. 37 m 2H 7. 07 t J = 7. 6 Hz 1H 6. 90 d J = 8. 4 Hz 1H 4. 34 d J = 10. 4 Hz 1H 4. 00 d J = 10. 8 Hz 1H 3. 24 s 3H 2. 28 s 2H 1. 90 s 3H 1. 17 s 3H 1. 10 s 3H 13 C NMR 101 MHz CDCl 3 δ 176. 3 170. 2 143. 9 129. 4 125. 9 123. 7 122. 5 108. 5 68. 5 50. 9 41. 6 30. 3 27. 8 26. 8 26. 5 20. 5 IR KBr σ /cm - 1 2234 1732 1710 1614 1491 1378 1340 HRMS m /z ESI C 17 H 21 N 2 O 3 M + H + 3j 1 H NMR 400 MHz CDCl 3 δ 7. 20 d J = 7. 2 Hz 1H 7. 13 d J = 7. 6 Hz 1H 7. 04 t J = 7. 6 Hz 1H 3. 85 ~ 3. 74 m 2H 2. 93 ~ 2. 79 m 2H 2. 38 d J = 14. 4 Hz 1H 2. 19 d J = 14. 4 Hz 1H 2. 11 ~ 2. 09 m 2H 1. 41 s 3H 1. 22 s 3H 1. 18 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 3 139. 8 130. 3 128. 1 124. 8 123. 3 122. 6 121. 4 49. 1 47. 2 31. 6 30. 4 27. 9 27. 7 25. 4 21. 9 IR KBr σ /cm - 1 2232 1710 1608 1473 1372 1341 HRMS m /z ESI C 17 H 21 N 2 O M + H + 269. 1649 269. 1653
8 887 3k mp 128 ~ 129 1 H NMR 400 MHz CDCl 3 δ 7. 31 ~ 7. 25 m 2H 6. 81 d J = 8. 0 Hz 1H 3. 21 s 3H 2. 32 d J = 14. 4 Hz 1H 2. 10 d J = 14. 4 Hz 1H 1. 34 s 3H 1. 15 s 3H 1. 10 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 0 141. 7 132. 7 127. 9 125. 0 123. 9 123. 6 109. 4 47. 2 46. 6 30. 5 29. 6 27. 3 27. 1 26. 5 IR KBr σ /cm - 1 2233 1715 1610 1432 1383 1345 HRMS m /z ESI C 15 H 18 ClN 2 O M + H + 277. 1103 277. 1106 3l mp 107 ~ 108 1 H NMR 400 MHz CDCl 3 δ 7. 10 ~ 7. 00 m 2H 6. 60 ~ 6. 71 m 1H 3. 21 s 3H 2. 32 d J = 14. 8 Hz 1H 2. 11 d J = 14. 8 Hz 1H 1. 34 s 3H 1. 16 s 3H 1. 10 s 3H 13 C NMR 101 MHz CDCl 3 δ 179. 2 159. 2 d J = 204. 4 Hz 139. 1 132. 6 123. 7 114. 8 d J = 23. 4Hz 112. 7 d J = 24. 5 Hz 109. 0 47. 4 46. 5 30. 6 29. 1 23. 3 26. 9 26. 5 IR KBr σ /cm - 1 2234 1718 1617 1435 1383 1335 HRMS m /z ESI C 15 H 18 FN 2 O M + H + 261. 1397 261. 1399 3m mp 114 ~ 115 1 H NMR 400 MHz CDCl 3 δ 7. 60 d J = 8. 4 Hz 1H 7. 52 s 1H 6. 96 d J = 8. 4 Hz 1H 3. 26 s 3H 2. 33 d J = 14. 8 Hz 1H 2. 15 d J = 14. 8 Hz 1H 1. 37 s 3H 1. 11 s 6H 13 C NMR 101 MHz CDCl 3 δ 179. 4 146. 1 131. 6 126. 3 q J = 3. 9 Hz 124. 0 q J = 32. 8 Hz 123. 4 121. 6 q J = 3. 5 Hz 120. 2 108. 3 47. 0 46. 5 30. 5 29. 5 27. 2 27. 1 26. 6 IR KBr σ /cm - 1 2235 1715 1624 1432 1385 1327 HRMS m /z ESI C 16 H 18 F 3 N 2 O M + H + 311. 1366 311. 1367 1. 4 4 3c 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 10 1 2 ml 0 0. 5 h 1 mol /L HCl 5 ml 5 min K 2 CO 3 Na 2 SO 4-4 105 mg 73% 4 1 H NMR 400 MHz CDCl 3 δ 6. 83 ~ 6. 73 m 2H 6. 41 dd J = 8. 0 Hz 4. 0 Hz 1H 3. 87 s 1H 2. 77 s 3H 2. 69 d J = 12. 8 Hz 1H 2. 58 d J = 12. 8 Hz 1H 1. 97 br 1H 1. 70 ~ 1. 50 m 10H 1. 39 s 3H 1. 17 ~ 1. 04 m 2H 13 C NMR 101 MHz CDCl 3 δ 157. 4 d J = 234. 4 Hz 146. 5 141. 4 113. 5 d J = 23. 4 Hz 110. 1 d J = 23. 7 Hz 107. 9 d J = 7. 1 Hz 87. 5 49. 1 45. 3 41. 4 38. 5 35. 9 32. 8 32. 1 27. 4 26. 9 22. 6 22. 3 HRMS m /z ESI C 18 H 26 FN 2 M + H + 289. 2075 289. 2079 2 2. 1 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%
888 32 70% 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 ~ 16 60 42% 1 entry 17 110 64% 1 entry 18 N- 1 0. 5 mmol a- 1 mmol CuI 0. 05mmol DTBP 1 mmol 80 12 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 76 10 CuI K 2 S 2 O 8 CH 3 CN 70 11 CuI PhI OAc 2 CH 3 CN 66 12 CuI PhI OTFA 2 CH 3 CN 62 13 CuI none CH 3 CN 14 14 CuI DTBP dioxane 90 15 CuI DTBP toluene 80 16 CuI DTBP DCE 78 17 c CuI DTBP CH 3 CN 42 18 d CuI DTBP CH 3 CN 64 a. Reaction conditions 1a 0. 5 mmol 2a 1 mmol oxidant 1 mmol metal 0. 05 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. 100. 2. 2 Scheme 3 1 1- -1-2a N- Me H F CO 2 Et N- 95% 3e
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 1 0. 5 mmol 2 1 mmol DTBP 1 mmol CuI 0. 05 mmol and CH 3 CN 2 ml at 80 for 12 h. a. run on 5 mmol scale 2. 3 3c 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
890 32 Scheme 5 Proposed mechanism for the formation of oxindoles 2. 4 3-10 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 1986 86 5 831-834. 2 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 2012 45 8 1278-1293. 3 Mai W Wang J Yang L et al. Progress in Synthesis of Oxindoles by Radical Addition-Cyclization J. Chinese J Org Chem 2014 14 10 1958-1965. 4 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 2014 58 4 684-688. 5 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 2014 50 5 554-556. 6 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 2013 4 6 2690-2694. 7 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 2014 2014 16 3395-3401. 8 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 2014 50 29 3865-3867. 9 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 2013 49 92 10817-10819. 10 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 2015 47 5 604-629.
8 891 11 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 2008 130 11 3304-3305. 12 Klein J Taylor R. Transition-Metal-Mediated Routes to 3 3-Disubstituted Oxindoles through Anilide Cyclisation J. Eur J Org Chem 2011 2011 34 6821-6841. 13 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 2011 50 52 12578-12581. 14 Li J Wang Z Wu N et al. Oxindoles J. Chem Commun 2014 50 95 15049-15051. 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 2015 13 2 361-364. 16 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 2007 9 17 3413-3416. 17 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 2014 2014 17 3656-3661. 18 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 2014 56 9 1293-1300. 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 416000 China b College of Chemistry and Chemical Engineering Central South University Changsha 410083 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 2015-01-06 Revised 2015-04-14 Accepted 2015-05-06 Supported by the National Natural Science Foundation of China NSFC No. 21462017 Key Laboratory of Hunan Forest Product and Chemical Industry Engineering No. JDZ201402 Research-Based Learning and Innovative Experiment Project of Jishou University Corresponding author TANG Shi associate professor Tel /Fax 0743-8563911 E-mail stang@ jsu. edu. cn Research interests transitionmetal catalysis and synthesis