18 Important (and sometimes forgotten) organic transformations Original idea from Macmillan group presentation: http://www.princeton.edu/chemistry/macmillan/groupmeetings/BDH_important%20forgotten.pdf Other good sites: http://www.chem.ox.ac.uk/thirdyearcomputing/NOR-oxford.asp Nadia Fleary-Roberts 8/02/12 1 1 Sandmeyer reaction •Synthesis of aryl halides via diazoninum salts Advantages Limitations •Can access substitution patterns otherwise unachievable by direct substitution •Addition of hypophosphorous acid (H3PO2) can result in dediazonization (H-substitution) Mechanism Sandmeyer, T. Ber. 1884, 17, 1633-1635. 2 2 Echenmoser fragmentation •Formation of a ketone and an alkyne from the fragmentation of an epoxide using TsNHNH2 •Reaction starts with formation of tosylhydrazone A Eschenmoser et al, Helv. Chim. Acta 50, 708 (1967) 3 3 Fischer Indole synthesis •Requires acid catalysis and elevated temperatures Larock indole synthesis •The presence of alcohol groups in the alkyne seems to have a particularly strong directing effect •catalytic process involves arylpalladium formation, regioselective addition to the C-C triple bond of the alkyne, and subsequent intramolecular palladium displacement. Larock, R.; Yum, E.K. J. Am. Chem. Soc. 1991, 113, 6689 4 4 Vilsmeier-Haack reaction formylation of electron-rich arenes. •The formylating (Vilsmeir) reagent is formed in-situ from DMF •Followed by electrophilic aromatic substitution and hydrolysis Haack, A. Ber, 1927, 60, 119 5 5 Pummerer reaction •Rearrangement of an alkyl sulfoxide to an α-substituted sulfide •Common nucleophiles are carboxylates, amides, alkenes and phenols •Pummerer fragmentation occurs when the α- group eliminates instead R. Pummerer, Chem. Ber., 1909, 42, 2282; R. Pummerer, Chem. Ber., 1910, 43, 1401; Jérôme Lacour Chem Commun, 2006, 2786–2788, 6 6 Barton McCombie reaction •Deoxygenation of alcohols •Xanthate ester is formed first •Driving force is the formation of very stable S-Sn bonds •Tertiary alcohols are prone to elimination (Chugaev reaction) •Thionoformates may be used to derivatise and deoxygenate tertiary alcohols without competing elimination Barton, D. H. R; McCombie, S. W. 1975. J. Chem. Soc., Perkin Trans. 1, 16: 1574–1585 7 7 Prevost reaction •Synthesis of anti-diols from alkenes •neighbouring-group participation mechanism prevents the immediate nucleophilic substitution of iodine by a second equivalent of benzoate that would lead to a syn-substituted product. The Ag+ helps to make iodine a better leaving group •The Woodward modification can be used to make syn-diols Woodward modification •Reagents used are iodine and silver acetate in wet acetic acid 8 8 Baylis-Hillman reaction •Phosphines can also be used •DMAP and DBU are better in some cases •Other mechanism proposed: JOC, 2005, 70, 3980 9 dr: 64:36 Zhu, EJOC: 2003, 1133-1144 9 Ugi reaction •Multi-component reaction between a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid •Useful for forming compound libraries Mechanistic steps 1. Imine formation 2. Protonation of imine by acid 3. α-addition of carboxylate and imimium ion to the isocyanide 4. Intramolecular acyl transfer Ugi, I. ACIE. 1962. 1,8. 10 10 Zweifel Olefin synthesis •Synthesis of trans alkenes via hydroboration-cyanohalogenation •Hydroboration of an alkyne to form a vinyl borane which can then undergo reductive elimination •Hydroboration, alkyl migration and B-X elimination are all stereospecific Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem. Soc. 1972, 94, 6560-6571 11 11 Polonovski reaction •Rearrangement of a tertiary N-oxide activated by Ac2O to form an N,Ndisubstituted acetamide and an aldehyde •Other activating agents such as chloroformate esters, acid chlorides, iron salts and sulfur dioxide can be used. M. Polonovski, Bull. Soc. Chim. France 41, 1190 (1927). •The Polonovski-Potier modification uses TFAA Cave et al., Tetrahedron 23, 4681 (1967); 12 12 Wolff rearrangement/ArndtEistert reaction 13 13 Cannizzaro reaction •Only works with unenolizable aldehydes Clayden pg: 713 14 14 Kornblum oxidation •Oxidative cleavage of carbon-halogen bond •Reaction of a primary halide/triflate with DMSO to form an aldehyde •Modification involves treatment of the primary halide with silver tosylate followed by DMSO and the base. 15 15 Ponndorf (Meerwein-Verley) reduction •Reduction of ketones/aldehydes to alcohols •The reverse reaction is known as the Oppenauer oxidation 16 16 Seyferth-Gilbert Homologation •Base promoted homologation of aldehydes to alkynes •The Ohira-Bestmann modification allows the use of milder bases (K2CO3) Gilbert J. Org. Chem., 1982, 47, 1837-1845 Ohira, Synth. Commun., 1986, 19, 561. 17 17 Wolff-Kishner reduction •Reduction of aldehydes/ketones to alkanes •The hydrazone is formed first and then treated with base 18 Me3SiCl, LDA Pd(OAc)2, MeCN 25 °C, 60 h 18 Saegusa Oxidation •conversion of a silyl enol ether functional group into the corresponding α, β unsaturated enone •The oxidising agent palladium (II) acetate is used in stoichiometric amounts Y. Ito et al., J. Org. Chem. 43, 1011 (1978)