Chemistry 206 Advanced Organic Chemistry Handout-32B The Aza-Cope Rearrangement. Background and Application to Alkaloid Synthesis Mike calter Evans group seminar March 26. 1991 Review. Heimgartner, H. In"Iminium Salts in Organic Chemistry Bohme, H, Viehe, H, Eds. Wiley: New York, 1979; Part 2, pp655-732 Matthew d. shair Monday December 9. 2002
Chemistry 206 Advanced Organic Chemistry Handout–32B The Aza-Cope Rearrangement. Background and Application to Alkaloid Synthesis Matthew D. Shair Monday , December 9, 2002 Review: Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. Mike Calter Evans Group Seminar March 26, 1991
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Review The 3-aza-Cope Rearrangement Heimgartner, H In"Iminium Salts in Organic Chemistry". Bohme, H, Viehe, H, Eds. Wiley: New York, 1979; Part 2 pp655-732 First Neutral Case: Hill TL 1967. 1421 The 3-aza-Cope Rearrangement ■ Neutral variant M、入Me250°,Me Practically quantitative", no real 2 y Me 1hr Exothermic as written by -7-10kcal/mole First Cationic Case: Elkik Compt Rend. 1968, 267, 623 ■ Ammonium variant 80 No yields given Even more exothermic than the neutral version has st inium salt tronger p-Bond than imine does 2-aza- Cope Rearrangement OHC. In the simplest case, degenerate. Sterics or con- ing f a particul omer, will drive equilibrium to one side. As with Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169 H20 a 1-aza-Cope Rearrangement u e incorporating the imine into a strained ring or OHC. R R"\ 32B-0111/2493924AM
D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 Review: Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. The 3-aza-Cope Rearrangement: [3,3] Exothermic as written by ~7-10kcal/mole. ■ Ammonium Variant: [3,3] + + Even more exothermic than the neutral version, since enamine lacks resonance and iminium salt has stronger p-Bond than imine does. 1 2 3 1 2 3 ■ Neutral Variant: ■ 2-aza-Cope Rearrangement: 3 2 1 + [3,3] + 1 2 In the simplest case, degenerate. Sterics or conjugation, or selective trapping of a particular isomer, will drive equilibrium to one side. As with the 3-aza-Cope, the cationic version goes under much milder conditions. ■ 1-aza-Cope Rearrangement: 3 2 1 3 2 1 [3,3] The 3-aza-Cope rearrangement can be driven in reverse by judicious choice of substrates(i.e., incorporating the imine into a strained ring or by making R an acyl group). The 3-aza-Cope Rearrangement First Neutral Case: Hill TL 1967, 1421. 250oC, 1 hr "Practically quantitative", no real yields given. First Cationic Case: Elkik Compt. Rend. 1968, 267, 623. 80oC, 2-3 hr + + H2O No yields given. Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169. ∆ + H2O + + + -H2O N N R R N N R R R R N R N R N R N R N Me Me Me N Me Me Me Me N Me Me N Me Me Me Me Me OHC R' Me R OHC Me N R'' H R'' R R' N R'' R'' X R''' N R'' R'' R' R R''' R''' R OHC R''' R' N R'' R R' R'' 32B-01 11/24/93 9:24 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 N-Acyliminium lon Rearrangements: Hart JOC 1985, 50, 235 N-Acyliminium lon Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235 erved an unusual product while trapping mediates of N-acyliminium olefin 1)MeC(OEt)3. CF3CO2s TF Et3 SiH, Me' well-precedented reaction, 74%6 yield C3H, HCO2H NaBH4 C3H7 Expected product of nexpected, must be product iminium salt reduction. of 2-aza-Cope, followed by 3 and 4 substitution favors the rearrangement H2O,89% 1)BU3SnH 85%H0 astancine 2 is the sole product in 91% yield 32B-1011/24/9310:26AM
N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235. 1)MeC(OEt)3, H+, 145oC 2)OH- 3)SO2Cl 4)Curtius 5)TFA 52% + 81% NaBH4, MeOH, 83% + HCO2H + MeOH, H2O, 89% overall 1)H2, Pd/C 2)AcCl 90% HgO,I2 85% 1)Bu3SnH 2)LiAlH4 82% (-)-hastancine 2 is the sole product in 91% yield. N-Acyliminium Ion Rearrangements: Hart JOC 1985, 50, 235. Hart observed an unusual product while trapping the intermediates of N-acyliminium olefin cyclizations. TFA + No Et3SiH, normal, well-precedented reaction, 74% yield Et3SiH, 73% Expected product of iminium salt reduction. 3 : 5 + Unexpected, must be product of 2-aza-Cope, followed by reduction. 3 and 4 substitution favors the rearrangement. HCO2H + 3 4 cycln. + + 2-aza-Cope 1 2 D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 N OH O C3H7 C3H7 O N N O C3H7 CF3CO2 N O C3H7 C3H7 O N Me O N N O H O Me Me O Me N O A N O Me O Me Me HCO2 N Me Me Me Me OBn BnO Me OH NH2 O O O AcO N O O BnO OAc OAc BnO OH O N N OAc OBn O OAc O OBn N N OAc O Me Me HCO2 HO Me Me O OH N N OAc O Me Me HO N I O OAc N OH BnO BnO AcO AcO HO 32B-10 11/24/93 10:26 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 The 1-aza-Cope Rearrangement The 1-aza-Cope Rearrangement Fowler Joc1988,53,963: Fowler Joc1988,53,5998 Application to Aspidospermine Precursor The Basic Reaction 33] bomyl, the amide resonance energy should act s to favor the enamine product. 500°C, MeDco CO Me yield of l-aza-Cope product CO-Me 61% As you can see, not the greatest reaction, but it has been used to make an aspidospermine precursor aspidospermine 32B-1111/24/9310:30AM
4)ClCO2Me 33% The 1-aza-Cope Rearrangement aspidospermine t-BuOK 72% H2, Rh/C 81% 1-azaCope Application to Aspidospermine Precursor + MeAlCl2, 47% 1)NH2OH 2)BH3 3) FVT, 31% H+ As you can see, not the greatest reaction, but it has been used to make an aspidospermine precursor. Me OMe 61% Me CO2Me 33% Me Me 46% Me H 5% H H 0% R R' yield of 1-aza-Cope product The 1-aza-Cope Rearrangement Fowler JOC 1988, 53, 963; Fowler JOC 1988, 53, 5998 [3,3] The Basic Reaction In order to reverse the 3-aza-Cope rearrangement, Fowler put an acyl group on the imine nitrogen. Since the imine has negligible interaction with the carbonyl, the amide resonance energy should act to favor the enamine product. 500oC, FVT D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 O R O N N N MeO2CO CO2Me N MeO2CO CO2Me R' R R' R R N R' CO2Me N CO2Me R R' Et OMe O H Et MeOCHO N Cl O Cl MeO Et N OCO2Me O Cl Cl N O Et MeO OMe Et Cl O Cl O N Et O N O Et O Cl O N Et O N O Et O N Et N Ac MeO 32B-11 11/24/93 10:30 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 The 2-aza-Cope Rearrangement I First Reported Case: Horowitz JACS 1950, 72, 1518 Mechanism for Yohimbane Analog Formation C 2-aza-Cope Equilibrium between a and B driven towards b by conjugation of iminium double bond in B Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968. 101, 2938 2-aza-Cope, driven by Yohimbine Yohimbine Meoh HCHO. MeOH 个 32B-0211/2493927AM
+ 2-aza-Cope, driven by conjugation + HCHO, H+, -H2O Mechanism for Yohimbane Analog Formation: + MeOH .. 2-aza-Cope Yohimbane 15-Methoxy-isoyohimbane HCHO, MeOH, Cat. H+, 85% 1) POCl3 2)NaBH4, 20% Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B. B A H2O Yohimbine Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938. + PhCHO + + HCHO HCOOH 100oC, 2hr. ■ First Reported Case: Horowitz JACS 1950, 72, 1518. The 2-aza-Cope Rearrangement D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 Ph NH2 Ph N H N H Ph H N N H H NH O H2N N H N NH H N N H H OMe H N N H OH CO2Me H N NH H N N N H N N H H O N H H Me H H MeO N N H N N H H OMe 32B-02 11/24/93 9:27 AM