Journal of the American Chemical Society
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the ability to chelate and stabilize cationic π-allyl Pd interme-
ACKNOWLEDGEMENTS:
1
2
3
4
5
6
7
8
diates electrophilically activated towards functionalization.
Figure 4. Proposed mechanism and mechanistic studies
a. Proposed mechanism
Financial support NIGMS MIRA (R35 GM122525). We thank W.
Liu, Dr. S. Ammann for preliminary ligand studies; Dr. J. Clark, Dr. J.
Griffin for checking experimental procedure; Dr. L. Zhu for NMR
data analysis, and Johnson Matthey for Pd(OAc)2.
H
OH
OAc
R
(SOX)PdII
X
HO
C–H Cleavage
Reoxidation
REFERENCES:
O
AcOH
(1). Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
(2) Roughley, S. D. J. Med. Chem. 2011, 54, 3451
O
+
2HX
II(SOX)
X
9
Pd
(SOX)Pd0
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
Functionalization
(3) Copper: (a) Miki, Y.; Hirano, K.; Satoh, T.; Masahiro Misura. An-
gew. Chem. Int. Ed. 2013, 52, 10830. (b) Zhu, S.; Niljianskul, N.; Buch-
wald, S. L. J. Am. Chem. Soc. 2013, 135, 15746. Other metals: (c) Sevov,
C. S.; Zhou, J-R.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 3200. (d)
Yang, X-H.; Dong. V. M. J. Am. Chem. Soc. 2017, 139, 1774. organocat-
alytic: (e) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F.
D. Nature 2011, 470, 245. (f) Margrey, K. A.; Nicewicz, D. A. Acc.
Chem. Res. 2016, 49, 1997. (g) Musacchio, A. J.; Lainhart B. C.; Naguib,
S. G.; Sherwood, T. C.; Knowles, R. R. Science 2017, 355, 727.
(4) (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129,
7274. (b) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
(c) Liu, G-S.; Yin, G-Y.; Wu, L. Angew. Chem. Int. Ed. 2008, 47, 4733.
(d) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009,
131, 11701. (e) Liron, F.; Oble, J.; Lorion, M. M.; Poli, G. Eur. J. Org.
Chem. 2014, 5863.
X
= AcO
RTfNH
= (±)-MeO-SOX
SOX
R
(L-5)
R
N
+
X
RTfNH2
+ HX
Tf
b. kinetic isotope effect (KIE)
X
standard
conditions
X
Y
TfHN
Ph
+
n-C7H15
N
Ph
n-C7H15
Tf
58 (X=Y=H), 58-d2 (X=Y=D)
59 (X=H, Y=D)
Intermolecular KIE (parallel rates): kH/kD = 2.4 ± 0.1
Intramolecular competition:
kH/kD = 4.0 ± 0.1
c. Effect of N-triflyl amine on standard Pd(II)/bis-sulfoxide C—H amination
O
O
(10 mol%)
Cy
Equiv. (b) Yield (60)
Cy
(1.0 eq)
S
S
Ph
Ph
0
1.0
84%
32%
Pd(OAc)2
DIPEA, BQ
TfNH(CH2)2Ph (b)
NTsCO2Me
+
TsNHCHO2Me
(2.0 eq)
60
(No N-triflyl amine 1 observed)
d. Stoichiometric Pd π-allyl study to evaluate functionalization
O
O
PdCl/2
(±)-MeO-SOX
S
S
Ph
Ph
+
AgOAc
L-5
(Bis-SO)
n-C7H15
-
PdOAc/2
AcO
Pd(SOX)
+ Bis-SO
(5) (a) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009,
5061. (b) Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc.
2011, 133, 17207. (c) Paradine, S. M.; Griffin, J. R. Zhao, J-Z, Petronico,
A. L. Miller, S. M.; White, M. C. Nat. Chem. 2015, 7, 987.
(6) Kondo, H.; Yu, F.; Yamaguchi, J.; Liu, G-H.; Itami, K. Org. Lett.
2014, 16, 4212.
complexationa
no complexationa
n-C7H15
n-C7H15
(1H NMR)
(1H NMR)
A
TfHN
“mock catalytic”
Ph
n-C7H15
66%; >20:1 E/Z , L/B a, b
a See supporting information. b Yield comparable to catalytic reaction.
N
Ph
61
not detected
Tf
61
(7) Ammann, S. E.; Liu, W.; White, M. C. Angew. Chem. Int. Ed. 2016,
55, 9571.
The (±)-MeO-SOX ligand/Pd(OAc)2 catalyzed intermo-
lecular allylic C—H amination showcases the ability of C—H
functionalizations to serve as cross-coupling methods that
simultaneously introduce new functionality while joining two
complex fragments. Mechanistic studies indicate that the SOX
ligand is effective at promoting functionalizations with π-allyl
Pd electrophiles by stabilizing a cationic intermediate. This is
analogous to the role of phosphine ligands in Pd(0)-catalyzed
allylic substitutions and suggests that the SOX framework may
provide an oxidatively stable ligand platform for C—H oxida-
tion that controls functionalization.
(8) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14, 3839.
(9) (a) Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547. (b) Chen,
K. & Baran, P. S. Nature 2009, 459, 824-828. (c) Chen, M. C.; White, M.
C. Science. 2007, 318, 783. (d) Gormisky, P. E.; White, M. C. J. Am.
Chem. Soc. 2013, 135, 14052. (e) Huang, X-Y.; Bergsten, T. M.; Groves,
J. T. J. Am. Chem. Soc. 2015, 137, 5300. (f) Karimov, R.R., Sharma, A. &
Hartwig, J. F. ACS, Cent. Sci. 2016, 2, 715. (g) Czaplyski, W. L.; Na, C.
G.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 13854.
(10) Howell, J. M.; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White, M. C.
J. Am. Chem. Soc. 2015, 137, 14590.
(11) (a) Eignerová, B.; Sedlák, D.; Dračínský, M.; Bartůněk, P.; Kotora,
M. J. Med. Chem. 2010, 53, 6947. (b) 3-vinyl pyridine is in steroidal
drug ZYTIGA (abiraterone acetate).
(12) González, M. A. Eur. J. Med. Chem. 2014, 87, 834.
(13) (a) Han, S-Y.; Kitahata, N.; Saito, T.; Kobayashi, M.; Shinozaki, K.;
Yoshida, S. Asami, T. Bioorg. Med. Chem. Lett. 2004, 14, 3033. (b)
Prediger, P.; Barbosa, L. F.; Génisson, Y.; Correia, C. R. D. J. Org. Chem.
2011, 76, 7737.
ASSOCIATED CONTENT
Supporting Information. The Supporting information is availa-
ble free of charge on the ACS Publications website at DOI XXX.
Experimental details, characterization data, spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
(14) Hayes, S. T.; Assaf, G.; Checksfield, G.; Cheung, C.; Critcher, D.;
Harris, L.; Howard, R.; Mathew, S.; Regius, C.; Scotney, G. Org. Process
Res. Dev. 2011, 15, 1305.
(15) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51,
3066.
*mcwhite7@illinois.edu
ORCID
M. Christina White: 0000-0002-9563-2523
Notes
The authors declare no competing financial interest
(16) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970.
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