14 MARCH 2014
by
William Schulz Bechara
Charette/Collins Literature Meeting
April 8th, 2014
Controlling Site Selectivity in C-H Functionalization
Catalyst-based control
Substrate-based control
DG
Y
H
X
catalyst 1
R
H
"activated" (pKa)
proximity
catalyst 2
DG
H
remote
functionalization
a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
1
Directing Groups in Substrate-Based Control With Pd
Monodentate
Bidentate
Tridentate
O
N
N
Pd
Pd N
N N
Pd N
N
strong coordination
O
X
O
Pd
N
R'
R
N
O
N Pd
weak coordination
a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. c)
Colby, D. A.; Tsay, A.-S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. e) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. f) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013,
52, 11726. g) Shi Chem. Sci. 2013, 4, 3712.
2
Catalytic Manifolds in Pd-Catalyzed C-H Functionalization
Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
3
Jin-Quan Yu
 Education :
•
•
•
•
•
•
East China Normal University - Shanghai, China : 1982 - 1987
B.Sc. in Chemistry - Top 5% of national examination for admission to SIOC
Shanghai Institute of Organic Chemistry (SIOC) - Shanghai, China : 1987 - 1988
Coursework for M.Sc. degree
Guangzhou Institute of Chemistry - Guangzhou, China : 1988 - 1990
M.Sc. in Chemistry with S.D. Xiao
University of Cambridge - Cambridge, UK : 1994 - 1999
Ph.D. in Chemistry with Jonathan Spencer
University of Cambridge - Cambridge, UK : 1999 - 2003
Junior Research Fellow (JRF) of St. John's College
Harvard University - Cambridge, MA, USA : 2001 - 2002
Postdoctoral Fellow, supervisor: E.J. Corey
 Academic Positions :
•
•
•
O F
X
F
HN
CF3
H
F
F
20 (or 16) years of
academic studies!!
University of Cambridge - Cambridge, UK
Royal Society Research Fellow : 2003 - 2004
Brandeis University - Waltham, MA, USA
Assistant Professor of Chemistry : 2004 - 2007
Scripps Research Institute - La Jolla, CA, USA
Associate Professor of Chemistry : 2007 – 2010
Professor of Chemistry : 2010 – 2012
Frank and Bertha Hupp Professor of Chemistry : 2012 - present
4
Pd(0)-Catalyzed Intermolecular Arylation of C(sp3)-H Bonds
Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.
5
Pd(II)-Catalyzed Olefination of C(sp3)-H Bonds
Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680.
6
Key Features of the Weak Coordinating “N-ArF” DG Auxiliary
O F
X
F
HN
O F
X
Pd
CF3
F
N
Pd
O F
X
CF3
H
F
HN
CF3
R
F
F
Ln
Pd
F
Xm
Aryl, Hetaryl, Alkyl, Cyclopropane
F
F
F
= ArF
R = Aryl, Arene, CF3, NR2, OR, D, I, P(O)R2...
- Low pKa : Faster deprotonation. Lower pKa is instrumental for the presence of a larger population of the
reactive deprotonated amide.
- Weak coordination : EWG group coordinated to the N center pushes the hybridization toward a N(sp2) center
and weakens the coordination to the Pd center (relative to other N(sp3)).
- PES (potential energy surface/DFT studies) of the reaction is slightly flatter in presence of ArF compared to
fully H-substituted. Reductive elimination step is slightly more favorable.
- Weak coordination has been successfully exploited to control the reactivity and selectivity of Pd-cat.
C-H functionalization.
Figg, T. M.; Wasa, M.; Yu, J.-Q.; Musaev, D. G. J. Am. Chem. Soc. 2013, 135, 14206.
7
Synthesis of Unnatural Chiral a-Amino Acids
Can one apply the Pd(II)-catalyzed C-H activation
for the b-functionalization of Alanine based SM?
R12N
O
H
X
Pd
R12N
O
R2
X
8
Synthesis of Unnatural Chiral a-Amino Acids
NPth
H
N
N
R1
H
O
Pd(OAc)2 (10 mol %)
(BnO)2PO2H (30 mol %)
H
N
Ag2CO3 (0.8 equiv)
DCE/tBuOH, 50-90 °C, 24 h
N
R
N
NPth
H
N
H
O
NPth
H
N
O
SMe
N
Pd(OAc)2 (5-11 mol %)
NPth
H
N
R
O
H
O
R2
General Limitations
Pd(OAc)2 (10 mol %)
CuF2 (1.5 equiv)
DMPU (5 equiv)
Ar-I, AgOAc
PhH, 60 ˚C, 60-72 h
H
R1
I
acetone, 100 ˚C, 24 h
Ar-I (1.5 equiv)
H
NPth
Pd(OAc)2 (5-11 mol %)
Ar-I, AgOAc
PhH, 60 ˚C, 72-96 h
N
NPth
H
N
Ar
O
NPth
H
N
Ar
O
SMe
NPth
H
N
N
R
O
- Long reaction time
- Di-arylation
- Low yields
- Different N-Aux for monoor di-arylation
- Racemization
- Limited to electron-rich ArX
- No one-pot di-arylation with
2 different substituents
Ar
a) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906. b) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.J.; Shi, B.-F. Angew. Chem. Int. Ed. 2013, 52, 13588. c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, 5188.
9
Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds
 Substituted pyridine ligands can match the weak coordination of the amide auxiliary (CONHArF)
a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.
10
Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. *Gram-scale reaction.
11
Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. *Gram-scale reaction.
12
Determination of Enantiomeric Purity
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
13
Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds
 Better yields using electron-donating 2-alkoxylpyridines.
 The conformation of the lone pairs on the oxygen atom (in L10) is rigidified to
favor p-conjugation with the pyridine ring.
a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.
14
Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
15
Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
16
Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
17
Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
18
Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
19
Ligand-Enabled C(sp3)–H Arylation With Heteroaryl Iodides
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
20
Synthesis of N-Fmoc-Protected Unnatural Amino Acid
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
21
C(sp3)–H Olefination of Alanine Derivatives (PdII/Pd0)
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
22
Unnatural a–Amino Acid Elaboration
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
23
Crystallography of Primary C(sp3)–H Activation Intermediate
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
24
Crystallography of Secondary C(sp3)–H Activation Intermediate
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
25
Catalytic Reactivity of Intermediates A and B
- TFA is required for this
transformation, presumably to
facilitate the dissociation of
one of the pyridine ligands.
He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.
26
Intramolecular Kinetic Isotope Effect
27
Proposed Mechanism for Pd(II)/Pd(IV) Catalysis
CsF or AgCO3 help
scavenge the I from Pd
by forming clusters*
PhthN
Ar
Ligand
Exchange
O
NPhth
H
TFA
O
PdII(TFA)2 (10 mol%)
N ArF
2-MePyr (20 mol%) PhthN
CsF (2 equiv)
DCE, 100 ˚C
PdII
N
N
CMD
H
O F
F
HN
CF3
F
F
HN ArF
O
PhthN
O
PhthN
Ar
PdII
Ln
Pd
N Ar
F
PdII
N Ar
F
N
I
Reductive
Elimination
O
PhthN
PdIV
* M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.
Ar
Ln
N Ar
F
I
N
Intermediate A
X-Ray
Oxidative
Addition
28
Future Work
- These rare and valuable C(sp3)–H insertion intermediates (A and B)
provide a promising platform for further kinetic and computational
study of elementary steps in a well-defined manner.
29
Thank You
Questions?