D.A. Evans Ambiphilic Functional Groups-3: Hydrazone-Based Transformations Chem 206 http:/www.courses.fasharvardedu/-chem206/ Relevant Background Reading Hutchins, R O (1991). Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming Chemistry 206 Oxford, Pergamon Press. 8: 327 shapiro, R H (1976). Alkenes from Tosylhydrazones. Org. React (N.Y. )23 dvanced Organic Chemistry Addlington, R. M. and A. G. M. Barrett (1983). " Recent Applications of the Lecture Number 28 Shapiro Reaction. ACC. Chem. Res 16: 55 Chamberlin, and Bloom Lithioalkenes from arylsulphonyl-hydraz Ambiphilic Functional Groups-3 Org. React (N.Y. )39: 1 Hydrazone-Based Transformations Bergbreiter, and Momongan(1991). Hydrazone Anions" Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 2 Wolff-Kischner eduction Cume Question, November, 2000 Wharton Rearrangement Sorensen and coworkers recently reported the synthesis of (-)-hispidospermidin(Sorens I Eschenmoser-Tanabe Fragmentation ACS. 2000, 122, 9556). The Shapiro Reaction, along with meth a Reduction of Tosyl Hydrazones: The Alkene Walk Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 Tosyl Hydrazone- Based Fragment Coupling The sh Bamford-Stevens reaction Reading Assignment for this Week: (-hispidospermidin Shapiro Reaction: Chamberlin, and Bloom. "Lithioalkenes from HCL,CH3CN,75% Intermediate n-BuLi(2.05equv) Intermediate arylsulphonyl-hydrazones. Org. Reactions 1990, 39: 1.(handout Wolff-Kishner Related Reactions: Hutchins, (1991).Reduction of C=X to MgBr2,78°c CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic then add 2 Synthesis. Trost and Fleming. OXford, Pergamon Press. 8: 327. (in library) Matthew d shair Monda November 25. 2002
http://www.courses.fas.harvard.edu/~chem206/ 1 1 Me H O Me 2 O O Me Me Ph Me Me O Me Me MeO O Me Me Ph Me HO 3 Me HN R O Me H Me H H D. A. Evans Chem 206 Matthew D. Shair Monday, November 25, 2002 Reading Assignment for this Week: Ambiphilic Functional Groups–3: Hydrazone-Based Transformations Relevant Background Reading Chemistry 206 Advanced Organic Chemistry Lecture Number 28 Ambiphilic Functional Groups–3 Hydrazone-Based Transformations ■ Wolff-Kischner Reduction ■ Wharton Rearrangement ■ Eschenmoser-Tanabe Fragmentation ■ Reduction of Tosyl Hydrazones: "The Alkene Walk" ■ Tosyl Hydrazone-Based Fragment Coupling ■ The Shapiro Reaction ■ Bamford-Stevens Reaction Hutchins, R. O. (1991). "Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 8: 327. Shapiro, R. H. (1976). “Alkenes from Tosylhydrazones.” Org. React. (N.Y.) 23: 405. Addlington, R. M. and A. G. M. Barrett (1983). “Recent Applications of the Shapiro Reaction.” Acc. Chem. Res. 16: 55. Chamberlin, and Bloom (1990). “Lithioalkenes from arylsulphonyl-hydrazones.” Org. React. (N.Y.) 39: 1. Bergbreiter, and Momongan (1991). "Hydrazone Anions". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 2: 503. Cume Question, November, 2000 Sorensen and coworkers recently reported the synthesis of (–)-hispidospermidin (Sorensen JACS. 2000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 and 2 (eq 1). (eq 1) (–)-hispidospermidin 2,4,6-triisoproylbenzenesulfonyl hydrazine, HCl, CH3CN, 75% Intermediate A MgBr2 , -78 °C then add 2 55% Intermediate B Shapiro Reaction: Chamberlin, and Bloom. “Lithioalkenes from n-BuLi (2.05 equiv) arylsulphonyl-hydrazones.” Org. Reactions 1990, 39: 1. (handout) Wolff-Kishner & Related Reactions: Hutchins, (1991). "Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 8: 327. (in library)
D. A Evans, N. Finney Hydrazone Transformations- 1 Chem 206 Hydrazone Anions: A useful Reversed Polarity Equivalent R Me?N 1.03:2DMs A-C(+) A-C(+) R=H or alkyl nBu0cuN界rbu,N Lassaletta. J-M. et al. Tet Lett. 1992. 33 3691 J E. Baldwin, et al. JcS Chem. Comm. 1983. 1040 HcHO Wolff-Kishner Reduction Procedures Pr 1. n-BuLi NaoCH2 CH2O (HOCH2CH2)20 HoP 2. H/H2O reflux and then heat to210℃c larton D. H. R, Ives, D. A J, and Thomas B. R. J. chem. Soc. 1955. 2056. 1. n-BuLi.-78°c OCH3 For particulary hindered ketones: anhydrous hydrazine or formation of hydrazone under acid catalysis(hydrazine hydrazine dihydrochloride), then basi er these forcing conditions, saponification, epimerization, and methyl ether A-C avage can occur Mechanism R2C=N-NH R2C=N-NH R2C--NNH hydrolysis Me RnR→、一B9H J E. Baldwin. et al. JCS Chem. Comm. 1984. 1095 A-C(- RO-H
R2C N N H (RDS)* –N2 R2C H R2C H H tBu N N iPr H H A C(+) N N:– R H R O iPr HO Ph H THF R H N N:– R H i N Pr N tBu i N Pr N tBu LiO H Ph H PhCHO R H N N: R A C(–) tBu N N iPr H Me2N N CH2 A C(–) CH3CO2 Me Me Me O O R Me H H H R N R' O O CH2Cl2 Me H N NH tBu O Me OCH3 O OCH3 Me Me O O OCH3 Me Me N N H tBu O OCH3 Me Me N N tBu H H + , H2O A C(–) A C(+) R2C N NH2 R2C N NH A C(–) A C(–) OH OH RO–H RO–H Me2N N R NO2 R' H O R' NO2 R H H H Me R Me Me Me HO R2C N NH H RO A C(+) Hydrazone Transformations-1 Chem 206 Hydrazone Anions: A useful Reversed Polarity Equivalent ✔✔ (+) (–) (–) n-BuLi, 0°C 2. H+ /H2O 95% 1. n-BuLi J. E. Baldwin, et al. JCS Chem. Comm. 1983, 1040. 1. n-BuLi, -78°C J. E. Baldwin, et al. JCS Chem. Comm. 1984, 1095. 58% Lassaletta, J-M, et al.Tet. Lett. 1992, 33, 3691. (40-92%) R=alkyl or aryl R'=H or alkyl + 1. O3 ; 2. DMS For particulary hindered ketones: anhydrous hydrazine or formation of hydrazone under acid catalysis (hydrazine/hydrazine dihydrochloride), then basify. Under these forcing conditions, saponification, epimerization, and methyl ether cleavage can occur. Barton, D. H. R., Ives, D. A. J., and Thomas, B. R. J. Chem. Soc. 1955, 2056. N2H4, NaOCH2CH2OCH2CH2OH, (HOCH2CH2 )2O Wolff-Kishner Reduction Procedures reflux and then heat to 210°C + Mechanism D. A. Evans, N. Finney RT, ca. 24h hydrolysis
D. A. Evans, N. Finney Hydrazone Transformations-2 Chem 206 The Wharton Rearrangement 1. LAH Me W-K 2HH20 CHO CO2CH3 L H. Zalkow, NN. Girotra J.Org. Chem. 1964, 29, 1299 Elimination of (-Lea oups This example illustrates the 2 possible modes for the decomposition of A. BrcH2、Me BrcH2、Me H Kishner CHOH.△ Me a A-C(+) adical -B D.H. Gusyafson, W. F. Erman J. Org. Chem. 1965, 30, 1665 G. Stork et al. JACS 1977. 99. 7067 Some procedural improvements ca.40%,32pa KDA, Ko Bu, etc M Kupchan JACS 1967, 89, 6327 For stable hydrazones, strongly basic conditions favor the ionic pathway C Dupuy, J. L Luche Tetrahedron Lett. 1989, 44, 3437
Me Me O O CO2CH3 O O O Me O O Me O Me BrCH2 Me Me H N N H Br Me -B Me Me CHO –N2 –HBr BrCH2 Me NNH Me W-K –N2 Me Me CH2 O O Me O O Me H A C(–) Me Me Me Me Me OH Me Me Me Me Me O Me O Me Me Me Me O O N2H4 CH3OH, D R R R NNH R O O N Me Me Me Me H N H A C(+) NH2NH2 •H2O N2H4 Me Me Me Me OH :B OH H R R R R OH Me Me Me Me –N2 Me Me Me Me OH N NH OH Me Me Me Me A Hydrazone Transformations-2 Chem 206 L. H. Zalkow, N. N. Girotra J. Org. Chem. 1964, 29, 1299. 1. LAH 2. H+ /H2O 3. CrO3 Elimination of -Leaving Groups D. H. Gusyafson, W. F. Erman J. Org. Chem. 1965, 30, 1665. N2H4, H+ WolffKishner WolffKishner S. M. Kupchan JACS 1967, 89, 6327. ca. 40%, 3:2 b:a 76% Some procedural improvements: G. Stork et al. JACS 1977, 99, 7067. 20% For stable hydrazones, strongly basic conditions favor the ionic pathway. –N2, H• • This example illustrates the 2 possible modes for the decomposition of A. 30% The Wharton Rearrangement C. Dupuy, J. L. Luche Tetrahedron Lett. 1989, 44, 3437. KDA, KOtBu, etc. D. A. Evans, N. Finney radical pathway polar pathway
D. A. Evans, N Finney Hydrazone Transformations-3 Chem 206 Tosylhydrazones- Better Than Hydrazones R|clH NaOAC3H20 =NNHTs+ N一NH Tosylhydrazones are isolable, stable, and easily prepared The presence of the tosyl leaving group strongly biases the system towards polar reaction pathways under hydridic reducing conditions R Ts CHO NHTS LAH (XS) R-C-N一 C-N-NH THF,△ G W. Kabalka, et al. J. Org. Chem. 1975, 40, 1834 Another Interesting Leaving Group H/H2O Ph LAH OI L. Caglioti, M. Magi Tetrahedron 1963, 19, 1127 -stilbene Further refinements Very mild reduction with NaBH3CN under slightly acidic conditions(pH 4-5) No reduction in the absence of acid; carbonyl, nitro, nitrile FGs unaffected Aromatic, sterically hindered carbonyls very poor substrates A R. Chamberlin, et al. Tetrahedron Lett. 1991, 32, 1691 laBH3 CN, CH3 COz NHTS R.O. Hutchins et al. JA
TsNHNH2 LAH (xs) THF, D THF, D CHO N NHTs H N N Ts H CH3 H N NHTs H N N – H R C R NNHTs Me H – Me N N Ph Ph OR B RO NH Ts C N H R R OAc O BH O R–H R C R H N NH Ph Ph N N R Me Me R C R H N B NH Ts RO OR –N2 C H H R R NaOAc•3H2O Ph Ph N N R Me Me N N R Hydrazone Transformations-3 Chem 206 – – L. Caglioti, M. Magi Tetrahedron 1963, 19, 1127. –Ts– H + /H2O Tosylhydrazones – Better Than Hydrazones Tosylhydrazones are isolable, stable, and easily prepared. The presence of the tosyl leaving group strongly biases the system towards polar reaction pathways under hydridic reducing conditions. Further Refinements Very mild reduction with NaBH3CN under slightly acidic conditions (pH 4-5). No reduction in the absence of acid; carbonyl, nitro, nitrile FGs unaffected. Aromatic, sterically hindered carbonyls very poor substrates. NaBH3CN, CH3CO2H 94% R. O. Hutchins, et al. JACS 1973, 95, 3662. 59% G. W. Kabalka, et al. J. Org. Chem. 1975, 40, 1834. – + -stilbene LAH A. R. Chamberlin, et al. Tetrahedron Lett. 1991, 32, 1691. Another Interesting Leaving Group D. A. Evans, N. Finney
D. A. Evans Hydrazone Transformations-4 Chem 206 The Eschenmoser-Tanabe Fragmentation Tosylhydrazone Reductions: The Alkene Walk TsNHNH2, ACOH N NNHTS base H C. Djerassi, et al. JACS 1976, 98, 2275 A Eschenmoser. et al. Helv. Chem. Acta 1967. 50. 708. This has been developed into a reliable reduction N A Eschenmoser, et al. Hel. Chem. Acta 1967. 50. 2108 16 cases reported: Hutchins, et al. JOC 1975, 40, 92
N N H NaBD3CN Me TsNHN N N H H Ts NaBH3CN N N H Ts H H - + CH3 O O O H N N Ts CH3 O O CH3 Ph N NH2 O Ph N N H CH3 –N2 CH3 N O N Ph H N O CH3 N H Ts H CH3 O Ph CH2 H3C CHO D O S O Ar Me NNHTs Me Me Me Me O Me O Me Me H D Me H Me Me Me Me Hydrazone Transformations-4 Chem 206 + + + 94% HOAc Et2O, 0°C A. Eschenmoser, et al. Helv. Chem. Acta 1967, 50, 708. TsNHNH2, AcOH + The Eschenmoser–Tanabe Fragmentation CH2Cl2, RT A. Eschenmoser, et al. Helv. Chem. Acta 1967, 50, 2108. : + 68% D. A. Evans Tosylhydrazone Reductions: The Alkene Walk C. Djerassi, et al. JACS 1976, 98, 2275. 16 cases reported: Hutchins, et al. JOC 1975, 40, 923 84% 81% This has been developed into a reliable reduction base