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Carolyn L. Ladd Literature Meeting April 9, 2014

Carolyn L. Ladd Literature Meeting April 9, 2014. Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2014, 136 , 2162–2167. Author Profiles. B.S, University of Chicago, 1993 (with Gregory Hillhouse )

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Carolyn L. Ladd Literature Meeting April 9, 2014

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  1. Carolyn L. Ladd Literature Meeting April 9, 2014 Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc.2014,136, 2162–2167.

  2. Author Profiles • B.S, University of Chicago, 1993 (with Gregory Hillhouse ) • Marshall Scholar, University of Nottingham, (with James J. Turner) • Ph.D, MIT , 1998 (with Christopher C. Cummins) • PDF, Berkeley, 1993 (with T. Don Tilley) • B.S, MIT, 1985 (with Barry K. Sharpless) • Ph.D, Harvard, 1991 (with David A. Evans) • PDF, Caltech, 1993 (with Robert H. Grubbs) • Assistant Professor, MIT, 1993-1998 • Associate Professor, MIT, 1998-1999 • Professor, MIT, 1999-2007 • Fermenich Professor of Chemistry, MIT, 2007-2012 • Altair Professor of Chemistry, Caltech 2012-present • Assistant Professor, Caltech,1999-2004 • Associate Professor, Caltech, 2004-2006 • Professor, Caltech, 2006-2007 • W.M. Keck Professor of Energy, MIT, 2007-2010 • Brenn Professor of Chemistry, Caltech 2010-present

  3. Research Interests and Publications • Development of new reagents and methods for organic synthesis, with an emphasis on asymmetric catalysis; elucidation of reaction mechanisms • 203 publications; 95 JACS, 36 ACIE, 1 Science. • Multi-Electron Redox Reactions of Small Molecule Substrates Using Late First Row Transition Metals • Dicopper Cores as Multi-electron Redox Shuttles and Photochemical Reductants • Electrocatalytic Hydrogen Evolution at Positive Potentials • Zwitterionic Approach to Catalysis at Late Transition Metal Centers • 224 publications; 52 JACS, 11 ACIE, 1 Nature, 1 Science • Fu and Peters have collaborated on 5 other papers: 3 JACS, 1 ACIE, and 1 Science

  4. C-N bond Formation: Who needs it? • A survey of reactions used in Process Chem at GSK, Pfizer and Astra Zeneca. • Out of small molecule drugs (<550 MW), 90% contained nitrogen. • Heteroatom alkylation/arylation represented the largest class of reactions (19%) Process Chem • Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011,54, 3451. • (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,4, 2337.

  5. C-N bond Formation: Who needs it? • A survey of reactions used in Med Chem at GSK, Pfizer and Astra Zeneca from 2008 to 2011 • 23.1% included heteroatom alkylation/arylation (also largest class of reactions). Med Chem • Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011,54, 3451. • (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,4, 2337.

  6. C-N bond Formation: Who needs it? • SN2: Widely-used. Issues with overalkylation and poor reactivity for secondary alkyl halides. • Reductive alkylations: Can be one-pot or using preformed imine. • Need better methods for bulk amide reduction step. • Nucleophilic Aromatic Substition: SNAr/ANRORC/SNR1. • For electron-deficient systems. • Buchwald-Hartwig Couplings • Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011,54, 3451. • (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,4, 2337.

  7. Developed a tin-free methodology utilizing a bulky base. • Scope was limited to secondary amines due to competing β-hydride elimination. • Encouraged the development of novel phosphine ligands to improve the reaction generality. Transition-metal Mediated C-N bond formation (a) Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc.1996,118, 7215 (b) Driver, M.; Hartwig, J.J. Am. Chem. Soc.1996,118, 7217. • Early work by Migita in 1983. • Limited scope, but conditions are mild compared to other methods at the time. • Sn toxicity problematic. • Buchwald and Hartwig studied this reaction in detail. • Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett.1983, 927 • (b) Paul, F.; Patt, J.; Hartwig, J. Am. Chem. Soc.1994,116, 5969 • (c) Guram, A.; Buchwald, S.J. Am. Chem. Soc.1994,116, 7901

  8. Transition-metal Mediated C-N bond formation • Since 1994, vast amount of research devoted to extending the reaction generality. • Can now be applied to a vast array of systems. • Many variables to consider when designing a Pd-catalyzed amination reaction. (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 2, 27.

  9. Transition-metal Mediated C-N bond formation “Borrowing Hydrogen Strategy” (a) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766. (b) For a review on the borrowing hydrogen strategy, see: Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal.2007, 349, 1555.

  10. Transition-metal Mediated C-N bond formation Anti-Markovnikov (a) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013,135, 15746. (b) For a related methodology, see: Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. 2013,52, 10830. (c) For more on hydroamination, see: Reznichenko, A. L.; Nawara-Hultzsch, A. J.; Hultzsch, K. C. Topics in Current Chemistry (Springer), 2013, 343, 191–260. • Most methods require activated, electron deficient alkenes. • Issue with high activation energy resulting electrostatic repulsions between the amine lone pair and incoming electron-rich 𝜋-bond of the alkenes.

  11. Development of the Ullmann Reaction • 1903: Formation of C-N bond using stoichiometric Cu. • 1901: Synthesis of biaryls using stoichiometric Cu.

  12. Another Successful Collaboration! • 1905: Use of catalytic Cu to form aryl ethers. • 1906: Use of catalytic Cu for aryl amine synthesis • Harsh conditions gave room for much improvement and knowledge to be gained.

  13. Modern Improvements to Ullmann Reactions Shafir. A; Buchwald, S. J. Am. Chem. Soc. 2006, 128, 8742. Goodbrand. H; Hu, N. J. Org. Chem. 1999,64, 670. For more examples of modernized Ullman reactions/Cu-chemistry, see: (a) Lin, H.; Sun, D. Org. Prep. Proc. Int.2013, 45, 341. (b) Beletskaya, I. P.; Cheprakov, A. V. Organometallics2012, 31, 7753. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (d) Monnier, F.; Taillefer, M. Angew. Chem.2009,48, 6954.

  14. Proposed Mechanism CuI-CuIII CuI-CuII Yoshikai, N.; Nakamura, E. Chem. Rev.2012,112, 233. • Formation of Cu(I)-amide species. • Single electron transfer generates the aryl radical and Cu(II) species. • Aryl radical undergoes bond formation with the nucleophile, and in the process, Cu(II) is reduced to Cu(I). • Formation of Cu(I)-amide species. • Oxidative addition to generate Cu(III) intermediate • Reductive elimination to generate C-N product and regenerate Cu(I)-X For more mechanistic details, see: (a) J. W. Tye, Z. Weng, A. M. Johns, C. D. Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 2008,130, 9971. (b) R. Giri, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 15860. (c) G. O. Jones, P. Liu, K. N. Houk, S. L. Buchwald, J. Am. Chem. Soc.2010, 132, 6205. (d) H.-Z. Yu, Y.-Y. Jiang, Y. Fu, L. Liu, J. Am. Chem. Soc.2010,132, 18078. (e) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301.

  15. Project Origins: Exploiting Inorganic Chemistry… [Cu(PNP)]2 • Original purpose was to develop luminescent materials for use in OLED devices. • Designed an amido-bridged bimetallic copper system, which was an excellent luminophore, • Quantum yield: φ = 0.68 in cyclohexane, Lifetime: τ > 10 μs (unprecedented in Cu(I) complexes) (a) Harkins, S. B.; Peters, J. C. J. Am. Chem. Soc. 2005,127, 2030–2031.

  16. Project Origins: Exploiting Inorganic Chemistry… • Extended to designing easy to synthesize derivatives, including a novel example of a carbazolate Cu complex. • (Ph3P)2Cu(cbz) exhibited cyan emission at 461 nm and reported the highest quantum yield (0.24) and lifetimes (11.7) out of the other Cu complexes. a.) Lotito, K. J.; Peters, J. C. Chem. Commun. 2010, 46, 3690.

  17. Starting with a Bang! • Goal: Provide direct experimental evidence for a SET/radical process for Ullman C-N couplings. • Develop milder conditions for C-N bond formation using a photointiated process. Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J. C. Science 2012, 338, 647.

  18. Preliminary Results • Reactivity parallels radical conditions; • I>Br>Cl.

  19. Preliminary Results • Conducted cyclized experiment using a well-known radical probe. • Cyclization product obtained. • The lack of reactivity has been used previously to disprove a radical-based mechanism. • However could form via concerted oxidative addition, migratory insertion, and reductive elimination • Deuterium-labelling experiment supports radical mechanism. • If syn-insertion was in play, only 6d should form. • Checked to confirm SM does not isomerize.

  20. Preliminary Results • Competition experiment reveals preference for chlorobenzonitrile. • Indicative of SET-based mechanism as chlorobenzonitrile has a more favourable reduction potential compared to 1-bromonapthalene. • (-2.07 V vs. -2.17 V vs. SCE) “Ullmann C-N Coupling Is Possible with Photoinitiation!”

  21. Improving Reaction Generality • Can generate Cu-carbazolide complex in situ using CuI. • Scope extended to alkyl iodides, alkyl bromides. • Lithium plays an important role. Bissember, A. C.; Lundgren, R. J.; Creutz, S. E.; Peters, J. C.; Fu, G. C. Angew. Chem. 2013, 52, 5129.

  22. Improving Reaction Generality • Neopentyl iodide gives good conversion; a notorious poor electrophile in SN2 alkylation reactions. • Reaction is stereospecific; trans-product obtained in good dr. • Also a complementary method to SN2 (expect inversion).

  23. Improving Reaction Generality • Hypothesized that Li[Cu(carbazolide)2] is a reactive intermediate. • Synthesized Li complex and subjected to reaction conditions. • In the presence of light, the same yield is obtained, suggesting this Li-Cu-complex could be an intermediate.

  24. Improving Reaction Generality • Reaction extended to formation of C-S bond formation. • Demonstrated that other nucleophiles (i.e: thiols) could be utilized. • Reaction thought to proceed via a Cu(I)-thiolate complex. Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc.2013, 135, 9548–9552.

  25. Improving Reaction Generality • Reaction extended other nitrogen nucleophiles/ common pharmacophores • Wavelength of light important (254 nm vs. 350 nm for carbazoles). • Propensity for arylation parallels pKa of N-nucleophiles. Ziegler, D. T.; Choi, J.; Muñoz-Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2013,135, 13107.

  26. Photoinduced Amination! • Goal: Extend the methodology to non-aromatic nucleophiles (i.e: amides). Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc.2014,136, 2162–2167.

  27. Optimization • In parallel with previous papers, Li played an important role. • Higher wavelengths and 100 W Hg lamp gave trace yields. • Can use 36 W UVC air treatment lamp, instead of Luzchem Photoreactor. • Air and moisture tolerant. Honeywell 36 W UVC air treatment lamp Luzchem Photoreactor

  28. Scope • Good yields for a wide range of functional groups. • Alkyl bromides, alkyl iodides and one example of an alkyl chloride works.

  29. Scope • Aliphatic and aromatic amides both gave excellent conversions with good functional group tolerance. • Sterically-demanding amides worked well. • No overalkylation observed. • Alkyl iodides used due to poor solubility.

  30. Scope • Lactam, 2-oxazalindinone, and α,β-unsaturated amide substrates also were suitable

  31. Med Chem Other Applications Flow Chemistry • Synthesized opiod receptor agonist in 4 steps, compared to 6 reported by an Eli Lilly patent. • Developed flow conditions to produce 10.1 g of product

  32. Synthesis of Cu-Nu complex • Synthesized Cu(I)-oxazolindinyl tetramer and characterized by X-ray crystallography. • Utilized this Cu(I)-complex in the photo reaction, which gave comparable conversions to CuI. • Suggests Cu(I)-amidate might be a potential intermediate.

  33. Competition Experiments • Cyclization experiments generate endo:exo ratios in parallel with radical pathways. • Indicative of common radical intermediate. • Competition experiments between alkyl halides gave reactivity trends indicative of a radical pathway. • I>Br>Cl (a) For more details on radical cyclization, see: Hackmann, C.; Schäfer, H. J. Tetrahedron1993,49, 4559.

  34. Proposed Catalytic Cycle • Cu(I)-amidate complex undergoes photo excitation. • SET generates the alkyl radical which undergoes a C-N bond forming event. • Formation of product regenerates the Cu halide. • Admittedly intermediates are simplified, as anionic Cu species have been isolated and used as intermediates in these reactions.

  35. Concluding Remarks • Developed a photo induced process for alkylation of amides with unactivated secondary halides. • Applicable to a wide-range of substrates in varying sterics and electronics. • Mechanistic studies suggestive of radical pathway involving a Cu(I)-amidate complex. • More studies needed to fully elucidate this mechanistic pathway. • Goals include further expansion of the scope. • Pros: • A nice application of photochemistry. • Use of Cu over Pd (cost, toxicity) • Can be applied to flow chem. • Complementary method towards accessing alkylated amides. • No overalkylation. • Mild reaction conditions (rt) • Cons: • Use of alkylating agents (not ideal for late-stage functionalization) • Long reaction times (24 h) • Need for specialty glassware (i.e: quartz flasks) and equipment. MORAL:“It’s not what you look at that matters, it's what you see.” ― Henry David Thoreau

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