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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.

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Presentation on theme: "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."— Presentation transcript:

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

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

4 C-N bond Formation: Who needs it? 4 (a)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. Process Chem A survey of reactions used in Process Chem at GSK, Pfizer and Astra Zeneca. A survey of reactions used in Process Chem at GSK, Pfizer and Astra Zeneca. Out of small molecule drugs (<550 MW), 90% contained nitrogen. Out of small molecule drugs (<550 MW), 90% contained nitrogen. Heteroatom alkylation/arylation represented the largest class of reactions (19%) Heteroatom alkylation/arylation represented the largest class of reactions (19%)

5 C-N bond Formation: Who needs it? 5 (a)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. Med Chem A survey of reactions used in Med Chem at GSK, Pfizer and Astra Zeneca from 2008 to 2011 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). 23.1% included heteroatom alkylation/arylation (also largest class of reactions).

6 C-N bond Formation: Who needs it? 6 (a)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. 1.S N 2: Widely-used. Issues with overalkylation and poor reactivity for secondary alkyl halides. 2.Reductive alkylations: Can be one-pot or using preformed imine. Need better methods for bulk amide reduction step. 3.Nucleophilic Aromatic Substition: S N Ar/ANRORC/S NR 1. For electron-deficient systems. 4.Buchwald-Hartwig Couplings

7 Transition-metal Mediated C-N bond formation 7 Early work by Migita in 1983. Early work by Migita in 1983. Limited scope, but conditions are mild compared to other methods at the time. Limited scope, but conditions are mild compared to other methods at the time. Sn toxicity problematic. Sn toxicity problematic. Buchwald and Hartwig studied this reaction in detail. Buchwald and Hartwig studied this reaction in detail. (a)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 Developed a tin-free methodology utilizing a bulky base. Developed a tin-free methodology utilizing a bulky base. Scope was limited to secondary amines due to competing β- hydride elimination. Scope was limited to secondary amines due to competing β- hydride elimination. Encouraged the development of novel phosphine ligands to improve the reaction generality. Encouraged the development of novel phosphine ligands to improve the reaction generality. (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.

8 Transition-metal Mediated C-N bond formation 8 Since 1994, vast amount of research devoted to extending the reaction generality. Since 1994, vast amount of research devoted to extending the reaction generality. Can now be applied to a vast array of systems. Can now be applied to a vast array of systems. Many variables to consider when designing a Pd-catalyzed amination reaction. 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 9 “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 10 Most methods require activated, electron deficient alkenes. Most methods require activated, electron deficient alkenes. Issue with high activation energy resulting electrostatic repulsions between the amine lone pair and incoming electron-rich -bond of the alkenes. Issue with high activation energy resulting electrostatic repulsions between the amine lone pair and incoming electron-rich -bond of the alkenes. (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. Anti-Markovnikov

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

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

13 Modern Improvements to Ullmann Reactions 13 Goodbrand. H; Hu, N. J. Org. Chem. 1999,64, 670. Shafir. A; Buchwald, S. J. Am. Chem. Soc. 2006, 128, 8742. 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. Organometallics 2012, 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 14 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. 1.Formation of Cu(I)-amide species. 2.Oxidative addition to generate Cu(III) intermediate 3.Reductive elimination to generate C-N product and regenerate Cu(I)-X Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 233. Cu I -Cu III Cu I -Cu II 1.Formation of Cu(I)-amide species. 2.Single electron transfer generates the aryl radical and Cu(II) species. 3.Aryl radical undergoes bond formation with the nucleophile, and in the process, Cu(II) is reduced to Cu(I).

15 Project Origins: Exploiting Inorganic Chemistry… 15 [Cu(PNP)] 2 Original purpose was to develop luminescent materials for use in OLED devices. Original purpose was to develop luminescent materials for use in OLED devices. Designed an amido-bridged bimetallic copper system, which was an excellent luminophore, 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) 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… 16 Extended to designing easy to synthesize derivatives, including a novel example of a carbazolate Cu complex. Extended to designing easy to synthesize derivatives, including a novel example of a carbazolate Cu complex. (Ph 3 P) 2 Cu(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. (Ph 3 P) 2 Cu(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! 17 Goal: Provide direct experimental evidence for a SET/radical process for Ullman C-N couplings. 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. 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 18 Reactivity parallels radical conditions; Reactivity parallels radical conditions; I>Br>Cl. I>Br>Cl.

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

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

21 Improving Reaction Generality 21 Can generate Cu-carbazolide complex in situ using CuI. Can generate Cu-carbazolide complex in situ using CuI. Scope extended to alkyl iodides, alkyl bromides. Scope extended to alkyl iodides, alkyl bromides. Lithium plays an important role. 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 22 Neopentyl iodide gives good conversion; a notorious poor electrophile in S N 2 alkylation reactions. Neopentyl iodide gives good conversion; a notorious poor electrophile in S N 2 alkylation reactions. Reaction is stereospecific; trans-product obtained in good dr. Reaction is stereospecific; trans-product obtained in good dr. Also a complementary method to S N 2 (expect inversion). Also a complementary method to S N 2 (expect inversion).

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

24 Improving Reaction Generality 24 Reaction extended to formation of C-S bond formation. Reaction extended to formation of C-S bond formation. Demonstrated that other nucleophiles (i.e: thiols) could be utilized. Demonstrated that other nucleophiles (i.e: thiols) could be utilized. Reaction thought to proceed via a Cu(I)-thiolate complex. 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 25 Reaction extended other nitrogen nucleophiles/ common pharmacophores Reaction extended other nitrogen nucleophiles/ common pharmacophores Wavelength of light important (254 nm vs. 350 nm for carbazoles). Wavelength of light important (254 nm vs. 350 nm for carbazoles). Propensity for arylation parallels pKa of N-nucleophiles. 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! 26 Goal: Extend the methodology to non-aromatic nucleophiles (i.e: amides). 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 OptimizationOptimization 27 In parallel with previous papers, Li played an important role. In parallel with previous papers, Li played an important role. Higher wavelengths and 100 W Hg lamp gave trace yields. Higher wavelengths and 100 W Hg lamp gave trace yields. Can use 36 W UVC air treatment lamp, instead of Luzchem Photoreactor. Can use 36 W UVC air treatment lamp, instead of Luzchem Photoreactor. Air and moisture tolerant. Air and moisture tolerant. Honeywell 36 W UVC air treatment lamp Honeywell 36 W UVC air treatment lamp Luzchem Photoreactor

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

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

30 ScopeScope 30 Lactam, 2-oxazalindinone, and α,β-unsaturated amide substrates also were suitable Lactam, 2-oxazalindinone, and α,β-unsaturated amide substrates also were suitable

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

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

33 Competition Experiments 33 Competition experiments between alkyl halides gave reactivity trends indicative of a radical pathway. Competition experiments between alkyl halides gave reactivity trends indicative of a radical pathway. I>Br>Cl I>Br>Cl Cyclization experiments generate endo:exo ratios in parallel with radical pathways. Cyclization experiments generate endo:exo ratios in parallel with radical pathways. Indicative of common radical intermediate. Indicative of common radical intermediate. (a) For more details on radical cyclization, see: Hackmann, C.; Schäfer, H. J. Tetrahedron 1993, 49, 4559.

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

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


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