http://www.courses.fas.harvard.edu/~chem206/ 1 1 Me OH Me 2 O O Me Me Ph Me Me O Me Me MeO O Me MePh Me HO 3 MeHN R O Me H Me H H Chem 206D. A. Evans 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 a73 Wolff-Kischner Reduction a73 Wharton Rearrangement a73 Eschenmoser-Tanabe Fragmentation a73 Reduction of Tosyl Hydrazones: "The Alkene Walk" a73 Tosyl Hydrazone-Based Fragment Coupling a73 The Shapiro Reaction a73 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) (–)-hispidospermidin2,4,6-triisoproylbenzene- sulfonyl hydrazine, HCl, CH3CN, 75% IntermediateA MgBr2, -78 °C then add 255% IntermediateB n-BuLi (2.05 equiv)Shapiro Reaction: Chamberlin, and Bloom. “Lithioalkenes from 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) R2C N N H(RDS)* –N2 R 2C H R2C H H tBu N N iPr H H A C(+) N N:– HR R O iPr HO PhH THF R H N N:– R H iPrN N tBu iPrN 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 RMe H HH R N R' O O CH2Cl2 Me H N NH tBu O OCH3Me O OCH3 Me Me O O OCH3 Me Me N N H tBu O OCH3 Me Me N N tBu H H+, H2OA C(–) A C(+) R2C N NH2 N NHR2C 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 MeMe HO N NHR2C H RO A C(+) Chem 206Hydrazone Transformations-1 Hydrazone Anions: A useful Reversed Polarity Equivalent a20a20 (+) (–) (–) 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 arylR'=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,NaOCH 2CH2OCH2CH2OH,(HOCH 2CH2)2O Wolff-Kishner Reduction Procedures reflux and then heat to 210°C + Mechanism D. A. Evans, N. Finney RT, ca. 24h hydrolysis Me Me O O CO2CH3 O O O OMe 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(–) MeMe Me Me Me OH MeMe Me Me Me O Me O Me Me Me Me OO N2H4 CH3OH, ? R R R NNH R O O N Me Me MeMe HN H A C(+) NH2NH2?H2O N2H4 Me Me Me Me OH :B OH H RRRR OH Me Me MeMe –N2 Me Me Me Me OH N NH OH Me Me MeMe A Chem 206Hydrazone Transformations-2 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+ Wolff-Kishner Wolff-Kishner S. M. Kupchan JACS 1967, 89, 6327. ca. 40%, 3:2 β:α 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 radicalpathway polarpathway TsNHNH2 LAH (xs) THF, ?THF, ? 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 NC H R R OAc O BH O R–H R C R H N NH Ph Ph NN MeR Me R C R H N B NH Ts RO OR –N2 C H H R R NaOAc?3H2O Ph Ph NN MeR Me N N R Chem 206Hydrazone Transformations-3 – – 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 NNH NaBD3CN Me TsNHN N HNH Ts NaBH3CN NNH Ts H H- + CH3 O O O H N TsN CH3 O O CH3 Ph N NH2 O PhN N H CH3 –N2 CH3 N O N Ph H NO CH3 N H TsH CH3 O Ph CH2 H3C CHO ? O S O Ar Me NNHTs Me Me Me Me O Me O Me Me H D Me H Me Me Me Me Chem 206Hydrazone Transformations-4 + + + 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 O H H MeO AcO Me O CO2Et N H H MeO AcO Me H N Ts H –HSO2Ts –OAc [H] AcO MeO H H Me H CO2Et H N H H MeO AcO Me N H RCH2 OH NO2 SO2–NHNH2 OH OH OMe MeO Bu OH Me N O OH EtO2CN NCO2Et Ph3P, –30 °C a71 RCH2 H RCH2 N S O O Ar NH2 Bu H Me N O Me OMe MeO RCH2 RCH2 N N–H Ina71 a71 Me S O O– Ar Chem 206Hydrazone Transformations-5 Sulfonylhydrazone Reductions: Alcohol Deoxygenation ~0 °C 80% 86% 86% The intervention of radicals has been implicated (again): 10 cases reported: A. Myers, et al. JACS 1997, 119, 8572. D. A. Evans, N. Finney Compactin, Wendler, N. L., et al. Tet. Lett. 1982, 23, 5501. 1. NH2NHTs, THF, 25°C Alkene Walk: Syntheses 1. NH2NHTs, THF, 25°C 2. CB 3. NaOAc?3H2O (60%) Topiramate, Maryanoff, B. E., et al. Tet. Lett. 1992, 33, 5009. The stereochemical course of the hydrazone reduction may be stereospecifically transferred via the 1, 3-rearrangement (Mitsunobo Reaction)Org Rxns Volume 29 2. Catecholborane3. NaOAc?3H 2O R H N N TBS Ts R H O R' Li R R' LiN N TBS Ts R R' R R' N NH O CHO O O O OMe Me Me Me R' Li AcOH CF3CH2OH A RO Ph Me MeRO Me N NHSO2AR H Ph Me LI HEt Li H Me Li Me H Me CHO Me H Me H Et Li H Me CHO Me H Me Me Li Me H Bu Bu OHHO OHHO Me Me MeO OMe MeO OMe Me ROBu Bu Me Me I OMeMeO Bu MeO OMe Me RO BuNN TBS Ts O O O O OMe Me Me Me NN SO2Ar TBS Me Li Me H RLi Me Me H Me H Et CH3 O O O O OMe Me Me Me H Me Et Me Me H Me H Me Et O O O O OMe Me Me Me H Et Me O O O O OMe Me Me Me N Me Me H N H D. A. Evans, N. Finney Chem 206Hydrazone Transformations-5 Tosylhydrazone-Based Fragment Coupling TBS = t-BuMe2Si– –78 °C –78 → rt The monoalkyl azene A decomposes via a radical pathway 95% 16 cases reported: A. G. Myers etal. JACS, 1998, 120, 8891. 50:50 79% <5:95 1) H2NNHTs 2) Et3N, TBSOTf 3) RLi Ratio Z:E 81% Yield Stereoselective Construction of Trisubstituted Olefins (Z) 4) AcOH, F3CCH2OH (as above) 82%, >20:1 90%, ca. 2:1 (as above) (E) Cylindrocyclophane-F t-BuLi (1.8 eq.)ether, -78 °C (73%) A Complex Application: A. Smith etal. JACS 1999, 121, 7423 A. G. Myers, P. J. Kukkola JACS, 1990, 112, 8208. nBuLi nBuLi nBuLi R R’ N NHTs R R’ BuLi Me O Me Me Me Me Me O Me Me O Me HMe Me H O O N NHTs N N Li SO2Ar N N Li Li MeO NNHTs Me H Me C5H11 NTrisHN O OMeMe Me CO2Et O S O O NR H Li S NR O O Me Me Me SO2 Me Me Me N N Li SO2Ar Li THF BuLi EtO2C Me Me Me O OMeMe O H Me MeH Me O C5H11 Li Li C5H11 H Me MeO CO2EtMe Me C5H11 LiGeneral Reviews:Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.3 . Shapiro, Organic Reactions 1976, Vol 23, pp 405-507. Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.6. the Triisopropylsulfonyl (Trisyl) group is used (Roberts Tet. Let. 1981, 22, 4895). Trisyl = (5 %)(95 %) 1. TsNHNH2 2. LDA via trianion via dianion 2. LDA 1. TsNHNH2 2. K2CO3, ? 1. TsNHNH2 Bond J. Org. Chem. 1978, 43, 154. In THF solution regiochemical ratios generally reflect the starting hydrazone geometries Grieco J. Org. Chem. 1977, 42, 1717. Nemoto et. al. JCS, Perkin Trans. 1 1985, 927. 80 % nBuLi, THF 65 % 2. LDA 1. TsNHNH2 Deprotonation of the monoanion occurs predominantly at the kinetically more acidic site giving after elimination the less substituted alkene product. (100 %) 1. TsNHNH2 2. MeLi, Et2O (2 %)(98 %) +2. MeLi, Et 2O 1. TsNHNH2Regiochemistry –TsLi Mechanism: + N2 2. Quench 1. Strong Base Chem 206D. A. Evans The Shapiro Reaction-1 (E):(Z) = 4:1 TMEDA/hexane + 4 : 1 Side Reaction ClN NHTris C6H13 OHR’R SiMe3 C6H13 R’ R O Me3SiCl RCH2Br Li Cl Br+ C6H13 Li CH2R C6H13 C6H13 Br CO2 Me2NCHO C6H13 CO2H CHO C6H13 N N Me HPh TBS Ts O O Me Me H H O O O O O O N N(TBS)Ts Li H Me Et N H H N Ts TBS Ph C4H9 Me Me MeMe NNHTris Me HO Me MeMe HO Me Me Me Me Me Me OH MeOH HO Me Me Me MeMe Me Me Me Me NNHTs OMeMe SMe Me OMe O CO2Me H NH2N Ph H CO2Me N OMeMe N Ph H CO2Me OMeMe BuLi -N2 RCHO H H Me Me O O N N Me C4H9Ph H H O O O O O Et Me H HO Li Me Me Me C4H9 Ph Me Myers, J. Am. Chem. Soc. 1990, 112, 8208 >20:1 (E):(Z) 81 % + 2. HOAc (E):(Z) = 12:1 -"TsTBS"1. nBuLi Aphidicolin van Tamelen J. Am. Chem. Soc. 1983, 105, 142. 82 % 2. nBuLi, TMEDA 1. TsNHNH2, TsOH Applications The Shapiro Reaction-2D. A. Evans Chem 206 Trapping of the intermediate alkenyllithium TMEDA/hexane 75 % loroxanthin Baütikofer Helv. Chim. Acta. 1983, 66, 1148 BusLi TMEDA/hexane-78°C 0°C 82 % Bloom Tet Lett. 1984, 25, 4901 Carbonyl Transposition 1. 2.1 equiv. nBuLi 2. MeSSMe TMEDA/THF 2 eq. HgCl2 82 % Nakai Chem. Lett. 1980, 1099 Shapiro alternatives 2.7 eq. LDA 0°C THF - styrene (Juvabione) Evans J. Am. Chem. Soc. 1980, 102, 774 3. 1 3quiv BuLiwarm Me HO Br Me N NHEtO 2C Me O Me N NEtO 2C HBr H Me N NEtO 2C H H Me N NHEtO 2C 1 1 Me OH Me Me Me O H2N N SO2Ar H Me Me N N SO2ArH Me Me Li 2 O OMe MePh MeMe O N N Me Me N N SLi Li Ar O O Me Me MeO OMe MePh Me HO Me Me N N Li 3 MeHN R O Me H Me HH S Ar O O Me Me Li Me H Br H O H2N–NHCO2Et Me Me MgBr Br H3O+ Me Me MeO OMe MePh Me HO 2 O OMe MePh MeO Me Mg XX 3 The Shapiro Reaction-ApplicationsD. A. Evans Chem 206 A Recent Aplication of the Shapiro Reaction 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) (–)-hispidospermidin2,4,6-triisoproylbenzene- sulfonyl hydrazine, HCl, CH3CN, 75% Intermediate A MgBr2, -78 °C then add 255% IntermediateB n-BuLi (2.05 equiv) n-BuLi (2.05 equiv) Part A (8 points). Provide a mechanism for the Shapiro Reaction of 1 to intermediate B in the space below. Feel free to use a simplified analog of 1 such as 2,2-dimethylcyclopentanone to answer this question. Part B (7 points). Provide a mechanism for the transformation of intermediate B to the illustrated product 3. Use 3-dimensional representations to illustrate the stereochemical aspects of this individual step. MgBr2, -78 °C then add 2 Front (Re) face of C=Oblocked by Aryl moiety Back(Si) face of C=Oattacked by Nu (eq 1) Mattox-Kendall Dehydrohalogenation (Paquette, Reagents, Vol 5, p 3509) AOAc, heat Problem: The syn relationship between Br and H renders the direct dehydrohalogenation with base unfavorable (relative to other potential reactions. Solution; proceed via the hydrazone. AOAc, heat tautomerization MeMe Me N NHTs MeMe Me N NHTs MeMe Me Me Me CH2NaOMe, diglyme 55% ca. 180 °C 45% CH3Li, Et2O, 0 °C quantitative CH3 NNHTs R R' N NHTs R R' N NTs R'R CH3 NNHTs CH3 ? CH3 CH3 CH3 R R' N N CH3 R R' N NNHX N N Ph BnTMS Ha Hb R'R MeMe Me TMS Bn TMS Bn R Ha R' Hb Ha Hb R'R D. A. Evans Chem 206 base – products – +: R. H. Shapiro Org. React. 1976, 23, 405. : An Alternate Decomposition Pathway for Tosyl Hydrazones Bamford-Stevens vs. Shapiro NaOCH3, NMP, ? 63% 27% 4% trace 2 eq. BuLi, 0 °C 98% The Bamford-Stevens Reaction 1,2 Ha 1,2 Hb 66% (4:1 E:Z) T. K. Sarkar, et al. JCS Chem. Comm. 1992, 1184. PhCH3, 145°C Directed Bamford-Stevens PhCH3, 145°C Rh2(OAc)4 66% (14:86 E:Z)