Rearrangement Reactions Lecture Notes O O O O NH O SPh See slides for key review articles The Baeyer-Villager Oxidation/Rearrangement O O O O R O H O Mechanism: R1 O R O 1 RO3H O O R2 O O R R + R 2 2 R1 O O R O Criegee intermediate Alkyl group that migrates does so with retention of configuration More electron-rich (most substituted) alkyl group migrates in preference For a review, see: M. Renz, B. Meunier, Eur. J. Org. Chem. 1999, 737. The Baeyer-Villager Oxidation/Rearrangement O O O O R O H O Mechanism: R1 O R O 1 RO3H O O R2 O O R R + R 2 2 R1 O O R O Criegee intermediate Alkyl group that migrates does so with retention of configuration More electron-rich (most substituted) alkyl group migrates in preference For a review, see: M. Renz, B. Meunier, Eur. J. Org. Chem. 1999, 737. The Baeyer-Villager Oxidation/Rearrangement O CH3CO3H (88%) O 25 oC, 2 h O [Baeyer- O O O Villiger O oxidation] J. Meinwald and co-workers, J. Am. Chem. Soc. 1960, 82, 5235. R. Noyori and co-workers, J. Org. Chem. 1982, 47, 902. The Baeyer-Villager Oxidation/Rearrangement O CH3CO3H (88%) O 25 oC, 2 h O [Baeyer- O O O Villiger O oxidation] H O H TMSOOTMS O O BF3•OEt2 H (75-80%) H [Baeyer- Villiger oxidation] J. Meinwald and co-workers, J. Am. Chem. Soc. 1960, 82, 5235. R. Noyori and co-workers, J. Org. Chem. 1982, 47, 902. The Baeyer-Villager Oxidation/Rearrangement O OH N N [Nitrile oxide N O 1,3-dipolar Me Me aq. NaClO, cycloaddition] CH2Cl2, 25 °C (59%) Me OTBDPS OTBDPS OTBDPS Zn, AcOH, (66%) 25 °C, 4 h OTES O O OTMS Me 1. MeOH, O Me mCPBA, K CO AcOH, 25 °C Me 2 3 OH 2. TESCl; OH [Baeyer-Villiger MeO C TMSCl oxidation] 2 OTBDPS (74% overall) OTBDPS OTBDPS T. Fukuyama and co-workers, J. Am. Chem. Soc. 1999, 121, 3791. For a review, see Classics in Total Synthesis II, Chapter 18. The Baeyer-Villager Oxidation/Rearrangement MsCl, mCPBA LiAlH4 base (93%) (73%) (80%) [Baeyer- O OH O O Villiger O HO oxidation] O O O TFAA/ O O O H O TFA 2 2 H [Baeyer- (80%) O HO HO H Villiger H oxidation] HO O H farnesiferol C A. P. Marchand, V. S. Kumar, H. K. Hariprakasha, J. Org. Chem. 2001, 66, 2072. F. W. Demnitz, C. Philippini, R. A. Raphael, J. Org. Chem. 1995, 60, 5114. The Baeyer-Villager Oxidation/Rearrangement MsCl, mCPBA LiAlH4 base (93%) (73%) (80%) [Baeyer- O OH O O Villiger O HO oxidation] O O O TFAA/ O O O H O TFA 2 2 H [Baeyer- (80%) O HO HO H Villiger H oxidation] HO O H farnesiferol C A. P. Marchand, V. S. Kumar, H. K. Hariprakasha, J. Org. Chem. 2001, 66, 2072. F. W. Demnitz, C. Philippini, R. A. Raphael, J. Org. Chem. 1995, 60, 5114. The Beckmann Rearrangement OH OLVG N N H N H2O N O Versatile reaction to make lactams and amides Prepared starting from hydroxime, with many leaving groups possible Alkyl group that migrates does so with retention of configuration, and is always anti to the oxime leaving group E. Beckmann, Ber. Dtsch. Chem. Ges. 1886, 19, 988. The Beckmann Rearrangement conditions OH O NH N NH O POCl3, pyridine 98% 2% SOCl2, pyridine 90% 10% 20% aq. H2SO4 43% 57% HCl/Et2O 5% 95% Need to be careful about reaction conditions not isomerizing the oxime derivative to achieve appropriate regiocontrol in the rearrangement The Beckmann Rearrangement H2NOH•HCl MsCl, Et3N MeOH, Δ CH2Cl2, O (89%) N -25 oC, 1 h OH N OMs [Beckmann rearrangement] Note selectivity DIBAL-H in hydroxime formation (73% over N two steps) N O H H N. S. Mani, M. Wu, Tetrahedron: Asymmetry 2000, 11, 4687. The Beckmann Rearrangement HO TsO O N N H H H H2NOH•HCl TsCl, Et3N MeOH, CH Cl , OTIPS Δ OTIPS 2 2 OTIPS (81%) Δ, 3 h H H H MeO OMe MeO OMe MeO OMe [Beckmann rearrangement] (74%) O H H Note selectivity N N in hydroxime formation N OTIPS H H MeO ibogamine OMe J. D. White, Y. Choi, Org. Lett. 2000, 2, 2373. The Hofmann Rearrangement Br , O H O O 2 O 2 base C or ROH H NH2 or N OR R NH2 R NHBr [Hofmann N R R R rearrange- O ment] Mechanism: R group that migrates does so with retention of configuration, and is always anti to the leaving group on nitrogen A. W. Hofmann, Ber. 1881, 14, 2725; ibid. 1882, 15, 407, ibid. 1882, 15 762. The Hofmann Rearrangement OMe PMPO OMe OMe RO PMPO PMPO Br , RO RO 2 O NaNH2, NaOMe, O O NH3 MeOH O O O [Hofmann HO HO rearrange- N O ment] C H2N O O O (93%) OMe OMe PMPO HO RO O R = MOM O O MeO N O NH Me (+)-cepharamine O A. G. Schultz, A. Wang, J. Am. Chem. Soc. 1998, 120, 8259. The Curtius Rearrangement O O P H O O PhO N O 2 PhO 3 C or ROH H N NH2 or N OR R OH (DPPA) R N3 [Curtius R R R rearrange- O ment] Mechanism: R group that migrates does so with retention of configuration, and is always anti to the leaving group on nitrogen T. Curtius, Ber. 1890, 23, 3023. T. Curtius, J. Prakt. Chem. 1894, 50, 275. The Curtius Rearrangement OMe OMe OMe TBSO OTBS O O TBSO OTBS TBSO OTBS MeO OH O O piperidine, AcOH, DPPA, Et3N, N toluene, 25 °C, 18 h toluene, N O H HO N (92%) 70 °C, 2 h O OMe O OMe [Curtius -[N ] rearrangement] 2 OMe OMe OMe TBSO OTBS TBSO OTBS TBSO OTBS Rh[(COD)-(R,R)- + - DIPAMP] BF4 , BnOH, BnOH H H2 (3 atm) H 70 °C, 1 h BnO N BnO N (100%, 96% ee) (89%) N H C O [Asymmetric O O O OMe hydrogenation] O OMe O OMe E. J. Corey, D. Y. Gin, R. A. Kania, J. Am. Chem. Soc. 1996, 118, 9202. The Curtius Rearrangement O O OH C OH OBn DPPA, Et3N, N OBn HO toluene, Δ [Curtius rearrangement] OMe OMe (68%) O O O O HN OH HN OBn H2, Pd/C OMe OMe (-)-cytoxazone M. Carda, F. Gonzalez, R. Sanchez, J. A. Marco, Tetrahedron: Asymmetry 2002, 13, 1005. The Curtius Rearrangement O MeO DPPA, Et3N, N OMe H N OMe benzene, Δ; Br N N O Br N LiOH in H2N N THF/H O BnO BnO 2 H2N Me O HO2C Me H N Me (86%) MOMO 2 MOMO HO [Curtius rearrangement] MeO MeO MeO MeO MeO MeO streptonigrone O MeO2C N CO2Me DPPA, Et N, MeO2C N CO2Me 3 N CO2H benzene, Δ; H2N H2O/benzene H N Me O HO2C Me 2 Me Br (72%) Br HN [Curtius rearrangement] lavendamycin D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733. D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5789. The Curtius Rearrangement O MeO DPPA, Et3N, N OMe H N OMe benzene, Δ; Br N N O Br N LiOH in H2N N THF/H O BnO BnO 2 H2N Me O HO2C Me H N Me (86%) MOMO 2 MOMO HO [Curtius rearrangement] MeO MeO MeO MeO MeO MeO streptonigrone O MeO2C N CO2Me DPPA, Et N, MeO2C N CO2Me 3 N CO2H benzene, Δ; H2N H2O/benzene H N Me O HO2C Me 2 Me Br (72%) Br HN [Curtius rearrangement] lavendamycin D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733. D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5789. The Schmidt Reaction General name for three individual reactions 1) Conversion of ketones into amides N N N N O HN -H O 3 O HN 2 N R R R R R R H2O -N2 O R R HN N R R N H R O OH2 Most studied; similar to Beckmann rearrangement with similar migratory aptitude in the vast majority of cases K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Schmidt Reaction O NaN3, O Bn MeSO3H CO Et NH 2 (83%) Bn (>95% ee) CO2Et HO MeO MeO NaN3, H2O, OMe CF3CO2H OMe OMe Me Me o Me 25 C, 30 min, N 65 oC, 4 h NH Me O (88%) O analog of morphine O O O TiCl 4; N H O N 3 2 H H N N O (62%) O O (+)-sparteine G. Georg and co-workers, Bioorg. Med. Chem. Lett. 1991, 1, 125 A. G. Schultz and co-workers, J. Med. Chem. 1996, 39, 1956. B. T. Smith, J. A. Wendt, J. Aube, Org Lett. 2002, 4, 2577. The Schmidt Reaction O NaN3, O Bn MeSO3H CO Et NH 2 (83%) Bn (>95% ee) CO2Et HO MeO MeO NaN3, H2O, OMe CF3CO2H OMe OMe Me Me o Me 25 C, 30 min, N 65 oC, 4 h NH Me O (88%) O analog of morphine O O O TiCl 4; N H O N 3 2 H H N N O (62%) O O (+)-sparteine G. Georg and co-workers, Bioorg. Med. Chem. Lett. 1991, 1, 125 A. G. Schultz and co-workers, J. Med. Chem. 1996, 39, 1956. B. T. Smith, J. A. Wendt, J. Aube, Org Lett.