18 Important ( and sometimes forgotten) organic transformations

1. 18Important (and sometimes forgotten) organic transformations Original idea from Macmillan group presentation: http://www.princeton.edu/chemistry/macmillan/group-meetings/BDH_important%20forgotten.pdf Other good sites: http://www.chem.ox.ac.uk/thirdyearcomputing/NOR-oxford.asp Nadia Fleary-Roberts 8/02/12

2. 1

3. Sandmeyer reaction 1 • Synthesis of aryl halides via diazoninum salts • Advantages • Can access substitution patterns otherwise unachievable by direct substitution • Limitations • Addition of hypophosphorous acid • (H3PO2) can result in dediazonization • (H-substitution) Mechanism Sandmeyer, T. Ber. 1884, 17, 1633-1635.

4. 2

5. 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)

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7. 3 Fischer Indole synthesis • Requires acid catalysis and elevated temperatures

8. 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

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10. 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

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12. Pummerer reaction 5 • 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,

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14. Barton McCombie reaction 6 • 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

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16. Prevost reaction 7 • 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

17. Woodward modification • Reagents used are iodine and silver acetate in wet acetic acid

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19. 8 Baylis-Hillman reaction • Phosphines can also be used • DMAP and DBU are better in some cases • Other mechanism proposed: JOC, 2005, 70, 3980

20. 9 dr: 64:36 Zhu, EJOC: 2003, 1133-1144

21. Ugi reaction 9 • Multi-component reaction between a ketone or aldehyde, an amine, an isocyanide • and a carboxylic acid • Useful for forming compound libraries Mechanistic steps Imine formation Protonation of imine by acid α-addition of carboxylate and imimium ion to the isocyanide Intramolecular acyl transfer Ugi, I. ACIE. 1962. 1,8.

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23. Zweifel Olefin synthesis 10 • 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

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25. Polonovski reaction 11 • Rearrangement of a tertiary N-oxide activated by Ac2O to form an N,N-disubstituted 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).

26. The Polonovski-Potier modification uses TFAA Cave et al., Tetrahedron 23, 4681 (1967);

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28. 12 Wolff rearrangement/Arndt-Eistert reaction

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30. 13 Cannizzaro reaction • Only works with unenolizable aldehydes Clayden pg: 713

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32. Kornblum oxidation 14 • 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.

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34. 15 Ponndorf (Meerwein-Verley) reduction • Reduction of ketones/aldehydes to alcohols • The reverse reaction is known as the Oppenauer oxidation

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36. Seyferth-Gilbert Homologation 16 • 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.

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38. 17 Wolff-Kishner reduction • Reduction of aldehydes/ketones to alkanes • The hydrazone is formed first and then treated with base

39. 18 Me3SiCl, LDA Pd(OAc)2, MeCN 25 °C, 60 h

40. 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)