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, MIT, 1985 (with Barry K. Sharpless)
Ph.D, Harvard, 1991 (with David A. Evans)
PDF, Caltech, 1993 (with Robert H. Grubbs)
•
•
•
•
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)
•
•
•
•
•
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
2
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
3
C-N bond Formation: Who needs it?
•
Process Chem •
•
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%)
N-Substitution
Alkylation/Arylation
8%
10%
36%
10%
7%
8%
17%
28%
57%
N-substitution
O-substitution
S-substitution
Other
20%
Alkylation with Alk-X
Reductive Alkylation
Arylation with Aryl
Amide Alkylation
Aniline alkylation
Heteroaryl Alkylati
(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.
4
C-N bond Formation: Who needs it?
Med Chem
•
•
N-Substitution
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).
4%3%
Alkylation/Arylation
29%
34%
3%
24%
29%
73%
N-substitution
O-substitution
Reductive Alkylation
N-Alkylation with Alk-X
N-Arylation with Aryl-X
Amide N-Alkylation
Heteroaryl N-Alkylation
S-substitution
(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.
5
C-N bond Formation: Who needs it?
1. SN2: 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: SNAr/ANRORC/SNR1.
For electron-deficient systems.
4. Buchwald-Hartwig Couplings
(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.
6
Transition-metal Mediated C-N bond formation
•
•
•
•
(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
•
•
•
(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.
Developed a tin-free
methodology utilizing a bulky
base.
Scope was limited to secondary
amines due to competing βhydride elimination.
Encouraged the development of
novel phosphine ligands to
improve the reaction generality.
7
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.
8
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.
9
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.
10
Development of the Ullmann Reaction
•
•
1901: Synthesis of biaryls
using stoichiometric Cu.
1903: Formation of C-N bond
using stoichiometric Cu.
11
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.
12
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, 7753. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(d) Monnier, F.; Taillefer, M. Angew. Chem. 2009, 48, 6954.
13
Proposed Mechanism
CuI-CuIII
CuI-CuII
Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 233.
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
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).
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.
14
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.
15
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.
16
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.
17
Preliminary Results
•
•
Reactivity parallels radical conditions;
I>Br>Cl.
18
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.
19
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!”
20
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.
21
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).
22
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.
23
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.
24
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.
25
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.
26
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
27
Scope
•
•
Good yields for a wide range of functional
groups.
Alkyl bromides, alkyl iodides and one example
of an alkyl chloride works.
28
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.
29
Scope
•
Lactam, 2-oxazalindinone, and α,β-unsaturated amide substrates also were suitable
30
Other Applications
Flow Chemistry
•
Developed flow conditions to produce 10.1 g of product
Med Chem
•
Synthesized opiod receptor agonist in 4 steps,
compared to 6 reported by an Eli Lilly patent.
31
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.
32
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.
33
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.
34
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
35