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Indium Mediated Allylations in Aqueous Media

Indium Mediated Allylations in Aqueous Media. Lauren Huffman Stahl Group 28 September 2006. Why Water?. Advantages Not flammable, toxic or explosive Cheapest solvent on the planet Highest heat capacity of all liquids (4.19 J/gC˚) Isolation of organics facile through extraction

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Indium Mediated Allylations in Aqueous Media

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  1. Indium Mediated Allylations in Aqueous Media Lauren Huffman Stahl Group 28 September 2006

  2. Why Water? Advantages • Not flammable, toxic or explosive • Cheapest solvent on the planet • Highest heat capacity of all liquids (4.19 J/gC˚) • Isolation of organics facile through extraction • Low volatility aids recycling Drawbacks: • Metals difficult to remove • Removing organics before disposal can also be difficult • High heat capacity = lots of energy for distillation Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.

  3. Water in Industry: Hydroformylation Rurchemie / Rhone-Poulenc hydroformylation oxo process (RCH/RP) Homogeneous process where water aids in: • Economic heat management • Avoiding complicated catalyst recycling • Product separation > 600,000 tons/year production Cornils, B.; Kuntz, E.G. Hydroformylation. In Aqueous-Phase Organometallic Catalysis; 2nd Ed; Cornils, B.; Herrmann, W.A., Eds.; Wiley-VCH: Weinheim 2004; pp 351-363.

  4. Water in Industry: Palladium Processes Wacker process • Biphasic process • Cu re-oxidizes Pd • O2 stoichiometric oxidant • Higher alkenes still being investigated Telomerization (Kuraray 1-octanol process) • Biphasic process • Ni catalyzed hydrogenation yields octanol Aqueous-Phase Organometallic Catalysis; Cornils, B.; Herrmann, W.A., Eds.; Wiley-VCH: Weinheim 2004; pp 481-487, pp 545-546.

  5. Water in Industry: Electrochemistry Synthesis of Adiponitrile (Monsanto) • Quaternary ammonium salts (QASs) essential for selectivity • Sodium phosphate-borate electrolyte Asahi’s Sebacic Acid Process • 92% yields, 85% to 90% current efficiency • 20% aqueous solution of monomethyl adipate neutralized by NaOH Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.

  6. Laboratory Scale Interest in Water Diels Alder - rate acceleration due to hydrophobic effect Olefin Metathesis - promising for bio-molecule synthesis Rideout, D.C.; Breslow, R.; J. Am. Chem. Soc. 1980, 102, 7816. Hong, S.H.; Grubbs, R.H.: J. Am. Chem. Soc.2006, 128, 3508-3509.

  7. Indium Mediated Reactions • Grignard and Barbier Allylations • Indium Facts • Indium in Organic Solvent • Stoichiometric Indium • Selectivity • Mechanism • Synthetic Applications • Catalytic Indium • Summary • Future Directions

  8. Barbier and Grignard • Grignard reaction pre-generates the RMgX compound • Barbier is the “one pot” equivalent, (Li and Mg) • Enolization and reduction side reactions occur • Proposed single electron transfer (SET) at metal surface to form organometallic intermediate http://nobelprize.org/nobel_prizes/chemistry/laureates/1912/ Molle, G.; Bauer, P., J. Am. Chem. Soc.1982, 104, 3481-3487. Smith, M. B.; March, J. Advanced Organic Chemistry; 5th Ed;Wiley: New York 2001; pp 1205-1209.

  9. Meet Indium • Discovered in 1863 • 63rd most abundant element • Canada produces the majority of the world’s supply • Named for the brightest line in its spectrum • 111In (t1/2 = 2.8d) used for -ray imaging • Used in dental work and low melting alloys • Electron Configuration: [Kr] 5s24d105p1 LANL Chemistry Division http://periodic.lanl.gov/elements/49.html (Accessed Sep 2006) Chandler, J.E.; Messer, H.H.; Ellender, G. J. Dent. Res. 1994, 73, 1554-1559. Cotton, F.A.; Wilkinson, G., Murillo, C.A.; Bochman, M. Advanced Inorganic Chemistry, 6th Ed. Wiley & Sons: New York, 1999; pp 175-207.

  10. In Mediated Allylations in Organic Solvent • First Allylation mediated by Indium • Allylation of aromatic and aliphatic aldehydes and ketones with allyl, crotyl and propargyl halides and phosphonates • Proposed a sesquiiodide intermediate based on the stoichiometry of the best conditions (2:3:2) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem.1988, 53, 1833-1835.

  11. In Mediated Allylations in Organic Solvent Ongoing field with success in selective imine allylation (2R,3S) 4,4,4,-Trifluoroisleucine synthesis Loh, T.P.; Ho, D.S.C.; Xu, K.C.; Sim, K.Y. Tetrahedron Lett.1997, 38, 865-868. Chen, Q.; Qiu, X.L.; Qing, F.L. J. Org. Chem.,2006, 71, 3762-3767.

  12. Why Indium in Water? • Does not form oxides readily in air • Not sensitive to boiling water or alkali • Low first ionization energy (5.79 eV) • Believed to be non-toxic Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media, Wiley & Sons: New York, 1997. http://www.webelements.com/webelements/elements/text/In/key.html

  13. Indium Mediated Allylations in Water Li, C.J; Chan, T.H. Tetrahedron Lett.1991, 48, 7017-7020.

  14. Regioselectivity Crotyl bromide and other substituted allyls give a rearranged () product Methyl (2-bromomethyl) acrylate and other 1,1 disubstituted alkenes do not rearrange Paquette, L.A.; Mitzel, T.M. J. Org. Chem. 1996, 61, 8799-8804. Li, C.J; Chan, T.H. Tetrahedron Lett.1991, 48, 7017-7020.

  15. Diastereoselectivity Non-chelating substrates follow Felkin-Ahn T.S. Chelating substrates follow a chelated T.S. Paquette, L.A.; Mitzel, T.M.; Issac, M.B.; Crasto, C.F.; Schomer, W.W. J. Org. Chem.1997, 62, 4293-4301.

  16. Diastereoselectivity: 1,2 Induction Paquette, L.A.; Lobben, P.C. J. Am. Chem. Soc. 1996, 118, 1917-1930.

  17. Diastereoselectivity: 1,3 Induction Paquette, L.A.; Mitzel, T.M. J. Am. Chem. Soc.1996,118, 1931-1937.

  18. Diastereoselectivity: 1,4 Induction Paquette, L.A.; Bennett, G.D.; Issac, M.B.; Chhatriwalla, A. J. Org. Chem. 1998, 63, 1836-1845.

  19. Diastereoselectivity: 1,4 Induction Sterics - of protecting group, R group and substituent on allylbromide - are defining factor Paquette, L.A.; Bennett, G.D.; Issac, M.B.; Chhatriwalla, A., J. Org. Chem. 1998, 63, 1836-1845.

  20. -product vs. -product  - homoallylic alcohols also useful building blocks Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.

  21. Spectroscopic Study of Product Selectivity • 1H NMR spectroscopy study • Spectra taken at 2, 4, and 24 hour intervals. • Reaction proceeded rapidly to product, which slowly converted to  product • Crossover experiment Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.

  22. Proposed Mechanism of Rearrangement Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.

  23. E - Z Isomerization Regioselectivity independent of initial double bond geometry - sterics may be determining factor Another route by which scrambling can occur Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc.2003, 125, 2958-2963. Li, C.J.; Chan, T.H. Tetrahedron1999, 55, 11149 - 11176.

  24. Selectivity Recap • 1,2 diastereoselectivity - Felkin-Ahn transition state trajectory if chelation not favored or possible • 1,3 diastereoselectivity - chelation increases selectivity and sometimes rate • 1,4 diastereoselectivity - chelation increases rate and erodes selectivity •  vs.  substitution -  substitution requires more time, a specific amount of water, and excess aldehyde to rearrange • E/Z isomerization - mostly dependent on sterics, not degree of substitution or conjugation with substituent

  25. Accepted Mechanisms for Grignard • Four membered transition state • Homogeneous SET • Heterogeneous SET Molle, G.; Bauer, P. J. Am. Chem. Soc.1982, 104, 3481-3487. Smith, M. B.; March, J. Advanced Organic Chemistry; 5th Ed;Wiley: New York 2001; pp 1205-1209.

  26. Aqueous Mg Barbier and Mechanism Barbier-Grignard allylation in water with Mg Also observed 1,5 hexadiene as a by-product and complete conversion of aldehyde. Li, C.J.; Zhang, W.C. J. Am. Chem. Soc.1998, 120, 9102-9103.

  27. Postulated Mechanism: SET Chan and Li postulate a radical anion, generated by single electron transfer (SET) is coordinated to the metal surface, and then a subsequent SET occurs This mechanism is like the mechanism for both the Barbier allylations Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.

  28. Organometallic Complex • A discrete organometallic complex is thought to form • Debate about whether an In(I) or In(III) complex • Proposed mechanism: Kim, E.; Gordon, D.M.; Schmid, W.; Whitesides, G.M. J. Org. Chem.1993, 58, 5500-5507. Chan, T.H.; Yang, Y.; J. Am. Chem. Soc.1999, 121, 3228-3229.

  29. NMR Spectroscopic Study • Allyl bromide with In in D2O studied by NMR spectroscopy • Resonance at 1.7ppm grew in quickly and disappeared overnight • Signal at a maximum (30 min), quenched with benzaldehyde and obtained 99% yield of homoallylic alcohol • Formed same species by reaction with allyl mercury with In in water - ruled out intermediates 3,4 and 5 • Allyl mercury with InBr3 did not form same complex by NMR - ruled out 2 as well Chan, T.H.; Yang, Y. J. Am. Chem. Soc.1999, 121, 3228-3229.

  30. Stereochemical Support Setting contiguous stereogenic centers in water - would be difficult to predict if there were no organo-indium intermediate. Issac, M.B.; Paquette, L. A.; J. Org. Chem. 1997, 62, 5333-5338.

  31. Radical Inhibition in THF Although run in THF, seems to support a non-radical pathway for allylation Radical inhibitor experiments Hayashi, N.; Honda, H.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett.2006, 8, 4553-4556.

  32. Most Likely Mechanism A discrete organometallic intermediate • Helps to explain selectivity • NMR spectroscopic evidence • Able to be generated separately and still affect allylation • Radical inhibitor does not affect allylation of carbonyl

  33. Synthetic Application: KDO Gao, J.; Härter, R.; Gordon, D.M.; Whitesides, G.M. J. Org. Chem. 1994, 59, 3714-3715.

  34. Synthetic Applications: KDN Chan, T.H.; Li, C.J.; J. Chem. Soc., Chem. Commun. 1992, 747-748.

  35. Synthetic Application: Neu5Ac analogs Edible bird’s nest Indium allylation easily scaled to >5 g with no loss of yield. Comparable to isolation from edible birds nests or chemo-enzymatic synthesis. Choi, S.K.; Lee, S.; Whitesides, G.M. J. Org. Chem. 1996, 61, 8739-8745.

  36. Synthetic Applications: (+) Cyclophellitol Hansen, F.G.; Bundgaard, E.; Madsen, R. J. Org. Chem.2005, 70, 10139-10142.

  37. Synthetic Application: -Lactams • Diastereofacial selectivity linked to amido substituent • Chiral auxiliary allows for high stereoselectivity - only two of four possible isomers are isolated • Anhydrous conditions lead to enolization side reactions • Route to highly functionalized, enantiomerically pure  lactams Paquette, L.A.; Rothhaar, R.R.; Issac, M.B.; Rogers, L.M.; Rogers, R.D. J. Org.Chem. 1998, 63, 5463-5472.

  38. Synthetic Applications: Carbocyclic Ring Expansion • Water found to be crucial for reaction to proceed • Prepared 7,8,9,10 and 14 membered rings this way Li, C.J.; Chen, D.L.; Lu, Y.Q.; Haberman, J.X.; Mague, J.T. J. Am.Chem. Soc. 1996,118,4216-4217.

  39. Catalysis with Indium: Stoichiometric Mn Need mild reductant (Mn) and oxophile (TMSCl) to complete catalytic cycle. Cannot rule out activation of Mn by In. Predictable stereochemistry Augé, J.; Lubin-Germain, N.; Marque, S.; Seghrouchni, L. J. Organomet. Chem.2003,679, 79-83.

  40. Catalysis with Indium: Stoichiometric Al Need stoichiometric aluminum as reductant, water is oxophile Araki, S.; Jin, S.J.; Idou, Y.; Butsugan, Y. Bull. Chem. Soc. Jpn.1992, 65, 1736-1738.

  41. Catalysis with Indium: Electrochemistry Can regenerate indium electrochemically • Uses an undivided cell • Reduction takes place at the sacrificial Al anode • Also get bis-allylation of methyl esters, in low conversion • Side reactions are problematic Hilt, G.; Smolko, K.I. Angew. Chem., Int. Ed.,2001, 40, 3399-3402.

  42. Summary Allylating with indium in water is advantageous: • Carbohydrates do not have to be protected • Reactive without many by-products • Selective and predictable reactions • Stereochemistry relative to another stereocenter can be set •  or  product can be had depending on conditions • E vs. Z is still a little hard to predict, but large groups favor E • Indium is able to be regenerated • Scalable • Water helps make separation of product from metal facile • Homoallylic alcohol product can be further functionalized or utilized with ease

  43. Next Steps • Further exploration of the intermediate indium complexes would be exciting - organometallic chemistry in water • Further kinetic study of the reaction will aid in understanding which indium species is used in allyation • Continue to couple aqueous RCM and this methodology to make a two step organometallic sequence in water

  44. Shannon Stahl Stahl Group Practice talk attendees Joe Binder Brian Popp Michelle Rogers Mike Konnick Chris Scarborough DOE Dr. Tetsuya Hamada Dr. Guosheng Liu Dr. Denis Kissounko Nattawan Decharin James Hrovat Acknowledgements

  45. Indium vs. Zinc and Tin • Tin • Requires heat or sonication • Reactive toward allyl halides but does not reduce aldehyde • Zinc • Requires sonication or heat • Poorer selectivity and yield in the same reactions as Sn or In • De-halogenation by-product seen • Indium • Reacts as well as tin, only at room temp without sonication • More reactive toward allyl halides, does not reduce aldehyde • No by-products observed Kim, E., Gordon, D.M., Schmid, W., Whitesides, G.M. J. Org. Chem. 1993, 58, 5500-5507

  46. Allenylation vs. propargylation • Allenyl is generally preferred product • Propargyl product favored when bromo-2-propyne used • NMR spectroscopy study shows intermediate depends on solvent and substitution Issac, M.B., Chan, T.H., J.Chem.Soc. Chem. Commun., 1995, 1003-1004 Miao, W., Chung, L.W., Wu, Y.-D., Chan, T.H. J.Am.Chem.Soc. 2004, 126, 13326-13334

  47. Total Synthesis of (+)-Goniofurone Yi, X.Y., Meng, Y., Hua, X.G., Li, C.J., J. Org. Chem. 1998,63, 7472-7480

  48. Other allylations Addition to cylopropene - solvent and protecting groups affect syn:anti ratio Cyclization of tethered haloenynes Araki, S., et.al. Chem. Eur. J. 2001, 7, 2784-2790 Goeta, A., Salter, M.M., Shah, H., Tetrahedron, 2006, 62, 3582-3599

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