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,
Associate Professor, MIT,
Professor, MIT,
Fermenich Professor of Chemistry, MIT,
Altair Professor of Chemistry, Caltech 2012-present
Assistant Professor, Caltech,
Associate Professor, Caltech,
Professor, Caltech,
W.M. Keck Professor of Energy, MIT,
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. Transition-metal Mediated C-N bond formation
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
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.
(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
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”
Catalyst removes hydrogen, to “activate the alcohol”, then returns it to generate the amine
(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,
(b) For a related methodology, see: Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem , 52,
(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
1901: Synthesis of biaryls using stoichiometric Cu.
1903: Formation of C-N bond 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
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, (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
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
Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 233.
CuI-CuIII
CuI-CuII
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).
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, (b) R. Giri, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, (c) G. O. Jones, P. Liu, K. N. Houk, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, (d) H.-Z. Yu, Y.-Y. Jiang, Y. Fu, L. Liu, J. Am. Chem. Soc. 2010,132,
(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 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 , 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,

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 Air and moisture tolerant. Honeywell 36 W UVC
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.
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. Other Applications Flow Chemistry Med Chem
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
Competition experiments between alkyl halides gave reactivity trends indicative of a radical pathway.
I>Br>Cl
Cyclization experiments generate endo:exo ratios in parallel with radical pathways.
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
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