D. A. Evans Cycloaddition Reactions: Part-1 Chem 206 Other Reading material http://www.courses.fas.harvardedu/-chem206/ [2+2] Cycloaddition Reactions Tidwell, T. T. Ketenes, John Wiley and Sons, 1995 Chemistry 206 Ghosez, L; Marchand-Brynaert, J. Comprehensive Organic Synthesis, Vol 5, Pergamon, 1991, p. 85-122 Advanced Organic Chemistry The Diels-Alder Cycloaddition Reactions Diels-Alder Reactions". Evans. D. A: Johnson J. s In Lecture number 15 Comprehensive Asymmetric Catalysis, Jacobsen, E N; Pfaltz, A and yamamoto, h ed oringer Verlag: Heidelberg, 1999: Vol ll.1178-1235(pdf Cycloaddition Reactions-1 ■ Problems of the Day I Introduction to Cycloaddition Reactions Propose a mechanism for this transformation I(2+2] Cycloaddition Reactions The Diels- Alder reaction EtN(Pr)2 Reading Assignment for week Carey Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions MacMillan, JACS 1999. 121 9726 Carey Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal eliminations Predict the stereochemical outcome of this reaction Fleming: Chapter 4 2 LDA, TMSCI oH O Thermal Pericyclic Reactions Wednesday Matthew d. shair October 23 2002 Kut,JOc1985,50,1840
http://www.courses.fas.harvard.edu/~chem206/ O N Me Cl Me O TiCl4 Me O OH O Me O N O Me Me OH O Me OTMS Me D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 23, 2002 ■ Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Cycloaddition Reactions: Part–1 Chemistry 206 Advanced Organic Chemistry Lecture Number 15 Cycloaddition Reactions-1 ■ Introduction to Cycloaddition Reactions ■ [2+2] Cycloaddition Reactions ■ The Diels-Alder Reaction ■ Other Reading Material: Fleming: Chapter 4 Thermal Pericyclic Reactions ■ Problems of the Day: [2+2] Cycloaddiltion Reactions The Diels-Alder Cycloaddition Reactions EtN(iPr)2 Propose a mechanism for this transformation MacMillan, JACS 1999, 121, 9726 Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations Tidwell, T. T. Ketenes, John Wiley and Sons, 1995. Ghosez, L.; Marchand-Brynaert, J. Comprehensive Organic Synthesis, Vol. 5, Pergamon, 1991, p. 85-122. "Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf) 2 LDA, TMSCl ❉ ❉ Kurth, JOC 1985, 50, 1840 Predict the stereochemical outcome of this reaction
D A. Evans Johnson Eschenmoser Claisen Rearrangements Chem 206 Johnson Orthoester Claisen Eschenmoser- Claisen Lead paper. Johnson, Faulkner, Peterson, JACS 1970, 92, 741 Eschenmoser. A. Helv. Chem. Acta 1964. 47 2425: He/v. Chim Acta 1969. 52. 1030 EtCo2H(cat) Me-C-oEt Eto oEt Et2N OMe I Compare the two variants CH3CH2 H(cat) Eto2C CH3C(NMe2)(OMe)2 38°c M 60% Hg(OAc)2.EVE High yield, E:Z= 99:1 98°c CH2=C(OMe)NEI2) Me2N OHC 98%(EZ=86:14) Xylene,140°C,14h The Saucy Marbet Alternative a Synthesis of Amide Acetals NMe, EtOH Me NMe2 94% 125°C C3H5 diastereoselection 6. 1 oEt Me evenson Tet Let. 1991. 32 4199 OL Saucy, Marbet, He/v. Chim. Acta 1967, 50, 2091, 2095 Me2(oBn) CMez(oBn Welch, JACS 1987
Et O Et Et OEt Me NMe2 N Me OMe C3H5 R N O Me Me BF4 - + + + OH Me C OEt OEt OEt EtO OEt Me O OH OEt O O OEt Me S Me OH Me EtO2C Me O Me Me Me OHC Me Et2N OMe O O Me H NMe2 Et OH Et Me CO2Me OH Me Me OH Me Me Me NMe2 O Me Me O Me OH Me Me Me Me OMe Et2N OMe Me OLi CMe2(OBn) O N Me Me Me OLi N Et OMe CMe2 (OBn) O Me Me Me Me Me O Me Me Me CHO Me Me Me Me OMe Me OEt H3PO4 D CH3C(OEt)3 CH3C(NMe2)(OMe)2 CH2=C(OMe)(NEt2) Et2O EtOH NaOEt CO2Me Me O Me2N Me O NEt2 NEt2 O Me NMe2 EtO OEt Et Me NMe2 O H ■ Reactions to ponder: 60% 94% 125oC 125oC H3PO4 or TsOH The Saucy Marbet Alternative Saucy, Marbet, Helv. Chim. Acta 1967, 50, 2091,2095 EtCO2H (cat) + Predict the major diastereomer Welch, JACS 1987, 109, 6716 Stevenson, Tet. Let. 1991, 32, 4199 diastereoselection 6:1 Predict the major diastereomer ■ Compare the two variants: 92% (E:Z = 98:2) 98% (E:Z = 86:14) 60% 138oC 98oC Hg(OAc)2 , EVE CH3CH2CO2H (cat) ■ Lead paper: Johnson, Faulkner, Peterson, JACS 1970, 92, 741 Johnson Orthoester Claisen D. A. Evans Johnson & Eschenmoser Claisen Rearrangements Chem 206 ■ Synthesis of Amide Acetals Eschenmoser-Claisen Eschenmoser, A. Helv. Chem. Acta 1964, 47, 2425; Helv. Chim.Acta 1969, 52, 1030. Xylene, 150oC Xylene, 110oC High yield, E:Z = 99:1 Faulkner and Peterson Xylene, 140oC, 14h 70%
D. A. Evans reland Enolate Claisen Rearrangement Chem 206 Ireland-Enolate Claisen Substituted enolates afford an additional stereocenter a Reviews Pereira. Aldrichimica Acta 1993. 26.17-29 Ireland. Aldrichimica Acta 1988. 21 59-69 Ireland, R. E: Mueller, R. H: Willard, A. K.J. Am. Chem. Soc. 1976. 98, 2868 OTBS OTBS conditions(E)-( z control 12(320c)=35h LDA. TBSCI LDA, TBSCI 94: 6 kinetic 7 93 thermo Enolization: Amide bases R2 Stereoelectronic Requirements: The a-CH bond must be able to erlap withπ*C-O OTB key study: Ireland, JOC 1991, 56, 650 and earlier cited papers 兀*C-0 Hc\hb R Double Claisen Rearrangements are also possible Paterson, Tet Lett 1991, 32, 7601 avored 日 LDA TMSC LM-Nr, disfavored 1,2 1, 5 syn relationship via The Ireland model 976,98,286 a、(地地了8y 981.22,4119 more recent study. 0c1991,56,650
Me R2 R1 OTBS O O OTBS R2 R1 Me O O R2 R1 Me O Et OEt N R R H H R Li O Me N R R H Me R Li O H ✽ ✽ ✽ O O Me O OTMS R O Me Hc Hb Ha R C O Hc Hb R O – OLi R Me R Me OLi OH O O Me Me OH OH Me Me Me Me Me Me O RO OR Me Me O O Me H OTBS H H R1 O R2 R2 H O R1 H OTBS Me H Me Me O O Me Me O Me Me O O R2 R1 OTBS O Me Me O OTBS R2 R1 OTBS OTBS Me O Me O O Me Me Me Me Ireland-Enolate Claisen Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868 LDA Me3SiCl t1/2 (32oC) = 3.5 h 66% ■ Reviews Pereira, Aldrichimica Acta 1993, 26, 17-29 (Ireland-Claisen) Ireland, Aldrichimica Acta 1988, 21, 59-69 (Claisen-related) D. A. Evans Ireland Enolate Claisen Rearrangement Chem 206 ■ Enolization: Amide Bases LM–NR2 ‡ (E) Geometry (Z) Geometry The Ireland Model (JACS 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650 Substituted enolates afford an additional stereocenter LDA, TBSCl LDA, TBSCl DMPU ✽ (E) (Z) conditions (E):(Z) LDA, TBSCl LDA, TBSCl DMPU 94:6 7:93 key study: Ireland, JOC 1991, 56, 650 and earlier cited papers Stereoelectronic Requirements: The a-C-H bond must be able to overlap with p* C–O – Ha + base p* C–O Paterson, Tet Lett 1991, 32, 7601 LDA, TMSCl Et3N 20-60 °C 1,2 syn aldol relation permuted into 1,5 syn relationship via Claisen rearrangement 63% yield (diastereoselection 86%) Double Claisen Rearrangements are also possible ‡ ‡ favored disfavored control kinetic thermo
D. A. Evans Cycloaddition Reactions-1 Chem 206 Why does maleic anhydride react easily with 1, 3-butadiene, but not with ■ Consider2+2] cycloaddition: Photochemical activation[π2s+π2s] ethylene? So what are the rules"? dThe related reaction of 2 ethylenes is nonconcerted: [2+ 2] cycloaddition HOMO 区一叹 a We also know that the photochemical variant is concerted The frontier orbitals of the reacting species must have the proper symmetries [2+2] Cycloaddition-Examples Nomenclature uprafacial Dy Quadricyclane Dauben, Tet. 1961, 15, 197 Using this nomenclature the Diels-Alder reaction is a T4s+ I2S ■ Consider2+2 I cycloaddition: Thermal activation【π2s+π2S] Schafer, AC 1967. 79. 54 Dewarbenzene-Derivative Prismane-Der akan抛 bonding t2 bonding [π2S+π2a" allowed π2s+π2]" forbidden must be antarafical for indicated stereochem L1967.4357.4723
X C C C C C C C C C C C C C C C C C C C C C C C C C C C C O O O O O O X Y Y X C C H Me Me Me Me Me Me Me Me Me Me Me Me HOMO X Y O O O D. A. Evans Cycloaddition Reactions-1 Chem 206 Why does maleic anhydride react easily with 1,3-butadiene, but not with ethylene? So what are the "rules"? [4+2] [2+2] p* p concerted ✻ bonding bonding + energy ✻ + light ✻ p p* new HOMO light ■ Consider [2 + 2] cycloaddition: Photochemical activation [ p2s + p2s] bonding ■ Consider [2 + 2] cycloaddition: Thermal activation [ p2s + p2s] The frontier orbitals of the reacting species must have the proper symmetries heat ■ The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition LUMO · · ■ We also know that the photochemical variant is concerted ■ Nomenclature p2s p2a Using this nomenclature, the Diels-Alder reaction is a p4s + p2s cycloaddition p2s p2s antibonding [ p2s + p2s] "forbidden" p2s p2a [ p2s + p2a] "allowed" bonding bonding suprafacial antarafacial [p 2 s + p 2 a] must be antarafical for indicated stereochem TL 1967, 4357, 4723. [2+2] Cycloaddition - Examples hn [p 2 s + p 2 s ] hn [p 2 s + p 2 s ] Quadricyclane Prismane-Der. Dauben, Tet. 1961, 15, 197. Schäfer, AC 1967, 79, 54. Dewarbenzene-Derivative
D. A. Evans Cycloaddition Reactions-2 Chem 206 Summary of Ketene Cycloadditions 人 c=0 Br Zn PhC=C=O R cH2c CH2 C=0 FMO Analysis Ketene Preparation HOMO sc=o Staudinger Reaction(very gener X=CL Ts AcO. DCC. etc.. (CH3 CO)20 H2C=C=0 ACOH RCH2CO2Ar -,O C=0
H2C C O Ph2C C O H C O O ZnBr2 Zn O O D O Ph Br O Ph Br O O O H O R R' O O R R' R' R O R R' R' R O (CH3CO)2O R X O R' C O R R' D H2C C O AcOH OH R O OAr C O R -ArO H2O C O R R' N O R R' Z Y O X R R' X Y Y X O R' R O R' R O 1 R 2 R 3 C O R 1 R 2 R 3 or D R R' O N2 or D C O R R' R O H D -CH2CH2 C O R H HOMO O H H O D R3N RCH2CO2Ar O O R R' D. A. Evans Cycloaddition Reactions-2 Chem 206 Ketene Preparation Staudinger Reaction (very general) X = Cl, Ts, AcO, DCC, etc... + _ _ _ _ _ _ or Alkene Imine R = -CH=CH2 1,3-Dipole Carbonyl Summary of Ketene Cycloadditions 550 °C hn hn [p 2 sp 2 a ] LUMO FMO Analysis