Steric control of site selectivity in the Pd-catalyzed C-H acetoxylation of simple arenes

Article abstract of DOI:10.1021/ol4024248

This report describes the use of an oxidant and a ligand to control site selectivity in the Pd(OAc)₂-catalyzed C-H acetoxylation of simple arenes. The use of MesI(OAc)₂ as the terminal oxidant in combination with acridine as the ligand results in primarily sterically controlled selectivity. In contrast, with Pd(OAc)₂ as the catalyst and PhI(OAc)₂ as the oxidant, electronic effects dominate the selectivity of arene C-H acetoxylation.

Full text of DOI:10.1021/ol4024248

ORGANIC
LETTERS
2013
Vol. 15, No. 21
5428–5431
Steric Control of Site Selectivity in the
Pd-Catalyzed CÀH Acetoxylation
of Simple Arenes
Amanda K. Cook, Marion H. Emmert,† and Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 North University Avenue,
Ann Arbor, Michigan 48109-1055, United States
mssanfor@umich.edu
Received August 22, 2013
ABSTRACT
This report describes the use of an oxidant and a ligand to control site selectivity in the Pd(OAc)2-catalyzed CÀH acetoxylation of simple arenes.
The use of MesI(OAc)2 as the terminal oxidant in combination with acridine as the ligand results in primarily sterically controlled selectivity.
In contrast, with Pd(OAc)2 as the catalyst and PhI(OAc)2 as the oxidant, electronic effects dominate the selectivity of arene CÀH acetoxylation.
The ability to oxidatively transform carbonÀhydrogen
bonds into carbonÀheteroatom bonds is highly desirable
for the late-stage derivatization of complex molecules.
Such transformations have the potential to greatly expe-
dite the discovery and optimization of biologically active
molecules including pharmaceuticals and agrochemicals.1
However, the full potential of this strategy has not yet been
realized, inlarge part duetothe difficulty ofcontrolling site
selectivity.2 For example, while many advances have been
made in Pd-catalyzed ligand-directed CÀH oxidation,1À3
analogous nonchelate assisted transformations remain
relatively poorly developed.1À4 For example, the Pd-
catalyzed CÀH oxygenation of simple arenes is typically
characterized by the formation of complex mixtures of
isomers.4,5 In many of these systems, the selectivity is
governed by electronic factors, with CÀH oxidation oc-
curring preferentially at the more electron rich site(s) in the
substrate.4À6
We recently reported that pyridine dramatically accele-
rates the Pd(OAc)2-catalyzed CÀH acetoxylation of sim-
ple arenes.7À9 Pyridine is believed to serve as a ligand for
Pd during this process, and the ratio of pyridine:Pd was
found to be critical to high activity (an approximately 1:1
ratio was optimal). We hypothesized that, in addition to
accelerating the rate of CÀH acetoxylation, the ancillary
ligand could also be used to influence the site selectivity of
† Current address: Worcester Polytechnic Institute.
(1) (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (b)
Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem.;Eur. J. 2010, 16, 2654. (c) Stokes, B. J.; Driver, T. G. Eur. J. Org.
Chem. 2011, 4071. (d) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed.
2011, 50, 3362. (e) Chen, D. Y.-K.; Yuon, S. W. Chem.;Eur. J. 2012, 18,
9452. (f) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 8960. (g) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013,
5, 369.
(2) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(3) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412.
(4) Alonso, D. A.; Najera, C.; Pastor, I. M.; Yus, M. Chem.;Eur. J.
2010, 16, 5274.
(6) Throughout this manuscript, discussions of selectivity governed
by electronic factors refer to selectivity similar to that observed in
electrophilic aromatic substitution reactions.
(7) (a) Gary, J. B.; Cook, A. K.; Sanford, M. S. ACS Catal. 2013, 3,
700. (b) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew.
Chem., Int. Ed. 2011, 50, 9409.
(8) For similar effects of pyridine in oxidative CÀH olefination, see:
Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760.
(9) For the use of substituted pyridine ligands in the meta-selective
CÀH olefination of electron-deficient arenes, see: (a) Zhang, Y. H.; Shi,
B. F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072. (b) Zhang, S.; Shi, L.;
Ding, Y. J. Am. Chem. Soc. 2011, 133, 20218.
(5) (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem. 1996,
€
108, 35. (b) Eberson, L.; Jonsson, L. Liebigs Ann. Chem. 1977, 233.
€
(c) Eberson, L.; Jonsson, L. J. Chem. Soc., Chem. Commun. 1974, 885.
€
(d) Eberson, L.; Jonsson, L. Acta Chem. Scand. B 1976, 30, 361. (e)
€
Eberson, L.; Jonsson, L. Acta Chem. Scand. B 1974, 28, 771. (f) Eberson,
L.; Gomez-Gonzales, L. J. Chem. Soc., Chem. Commun. 1971, 263.
(g) Henry, P. M. J. Org. Chem. 1971, 36, 1886.
r
10.1021/ol4024248
Published on Web 10/14/2013
2013 American Chemical Society

the reaction. Such ligand-modulated selectivity would
provide opportunities for accessing different isomeric pro-
ducts by simply changing the catalyst structure.2 Herein we
report the realization of this strategy in the development of
pyridine-based ligands that impart sterically controlled
selectivity10,11 in Pd-catalyzed CÀH acetoxylation.
Table 1. Effect of Pyridine Ligands on Site Selectivity and Yield
for the CÀH Acetoxylation of 1,2-Dichlorobenzenea
Our initial studies probed the effect of a series of
pyridine-based ligands on the selectivity of the CÀH ac-
etoxylation of 1,2-dichlorobenzene (1) with MesI(OAc)2.12
Pyridine and its derivatives are highly attractive ligands for
this chemistry, because: (1) they are generally not suscep-
tible to oxidation by hypervalent iodine reagents, (2) they
are known to increase the rate of CÀH acetoxylation,7b
and (3) they possess highly modular structures. The test
substrate 1 was selected because it has two inequivalent
arene CÀH bonds that are electronically similar, but
sterically dissimilar.6 Furthermore, electron-deficient
arenes such as 1 are traditionally difficult to functionalize
via Pd-catalyzed CÀH acetoxylation.5,7b,13
yield
(%)
selectivity
entry
ligand
none
(1A:1B)
1
2
19
28
76
84
82
77
55
71
59
78
29:71
27:73
11:89
8:82
7:93
7:93
6:94
6:94
6:94
5:95
In the absence of added ligand, the Pd(OAc)2-catalyzed
reaction of 1 with MesI(OAc)2 proceeded in low yield
(19%) after 16h at 100 °C (Table 1, entry 1). Acetoxylation
at the less sterically hindered 4-position was weakly pre-
ferred under these ligand-free conditions (1A:1B = 29:71).
A similar yield and selectivity wereobtainedinthe presence
of 2 mol % of 2,6-di-tert-butylpyridine (entry 2), suggest-
ing that the very sterically hindered nitrogen atom does not
bind to the Pd center. In contrast, other pyridine derivatives,
including lutidine, picoline, quinoline, 3-fluoropyridine,
2-methylquinoline, pyridine, 4-methoxypyridine, and acri-
dine (entries 3À10), all afforded large increases in yield
and enhancements in selectivity for acetoxylation at the
sterically less hindered 4-position.14 Under these conditions,
the best selectivity was obtained with acridine as the ligand
(1A:1B = 5:95, entry 8).15
We next evaluated the influence of the acridine:Pd
ratio on the reaction yield and site selectivity. As shown
in Table 2, the addition of up to 6 mol % of acridine
(3 equiv relative to Pd) led to further enhancements in
selectivity (1A:1B = 2:98) with minimal deleterious effect
on the overall reaction yield (entry 4). Further increases in
acridine loading resulted in even better selectivity (>1:99
at 20 mol % acridine, entry 7); however, the product yield
was significantly lower under these conditions. Notably,
2,6-tBu2-py
2,6-lutidine
2-picoline
quinoline
2-Me-quinoline
3-F-py
3
4
5
6
7
8
pyridine
9
4-OMe-py
acridine
10
a Yield and selectivity were determined by GC using a calibration
curve based on PhCl as a standard.
the results with acridine stand in striking contrast to the
effects observed upon increasing the loading of pyridine.
As shown in entries 8À11 (Table 2), increasing the pyridine
loading to 6 mol % led to a precipitous drop-off in yield.
Overall, an acridine:Pd ratio of 3:1 provided the best
balance of yield and selectivity and was thus used in all
further experiments exploring the substrate scope.
Further studies revealed that the site selectivity of
Pd(OAc)2/acridine catalyzed CÀH acetoxylation is sub-
stantially influenced by the nature of the oxidant.7b,12 For
instance, a significant erosion in selectivity is observed
when MesI(OAc)2 is replaced with PhI(OAc)2. With 2 mol
% of acridine and 2 mol % of Pd(OAc)2, the 1A:1B ratio
was 5:95 with MesI(OAc)2 and 19:81 with PhI(OAc)2
as the oxidant. These results implicate a synergistic effect
between the hypervalent iodine oxidant and the ligand.16
We next optimized the catalyst loading using tri-
fluorotoluene (2). This was selected because it is a challen-
ging substrate that typically shows low reactivity in Pd-
catalyzed CÀH oxidations.7b,8,9 Thus, we anticipated that
the trends observed in this system should be transferrable
to a wide variety of other substrates. Varying the catalyst
loading from 6 to 0.2 mol % Pd(OAc)2 while keeping the
(10) For a recent example of Pd-catalyzed CÀH amination where
selectivity is dictated by substrate sterics, see: Shrestha, R.; Mukherjee,
P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135,
8480.
(11) For a review on sterically controlled selectivity in CÀH boryla-
tion reactions, see: Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(12) For preliminary studies of the influence of MesI(OAc)2 [versus
PhI(OAc)2] on the site selectivity of CÀH aectoxyation with the
Pd(OAc)2/pyridine catalyst system, see ref 7b.
(13) Emmert, M. H.; Gary, J. B.; Villalobos, J. M.; Sanford, M. S.
Angew. Chem., Int. Ed. 2010, 49, 5884.
(14) Pyridine, 4-methoxypyridine, and 3-fluoropyridine afforded
identical selectivity, suggesting that there is minimal ligand electronic
effect on this reaction.
(15) A recent report by Hartwig and co-workers demonstrated
sterically controlled selectivity in Pd-catalyzed CÀH aminations of
simple arenes (see ref 10). However, the supporting ligand had no effect
on the site selectivity of the reaction in this system.
(16) Similar effects were seen with pyridine as the ligand. For
example, with 2 mol % Pd(OAc)2 and 2 mol % pyridine, the selectivity
(1A:1B) using substrate 1 was 19:81 with PhI(OAc)2 and 6:94 with
MesI(OAc)2. See Supporting Information Table S1B for more details.
Org. Lett., Vol. 15, No. 21, 2013
5429

Table 2. Optimization of Pd(OAc)2/Acridine-Catalyzed CÀH
Table 4. Pd(OAc)2/Acridine-Catalyzed CÀH Acetoxylation of
Acetoxylation of 1,2-Dichlorobenzene
Tri- and Disubstituted Arenesa
ligand
loading
(mol %)
yielda
(%)
selectivityb
entry
ligand
(1A: 1B)
1
acridine
acridine
acridine
acridine
acridine
acridine
acridine
pyridine
pyridine
pyridine
pyridine
1
79
78
78
76
68
66
29
62
71
56
3
10:90
5:95
5:95
2:98
1:99
1:99
>1:99
9:91
6:94
7:93
2
2
3
3
4
6
5
8
6
10
20
1
7
8
9
2
10
11
3
b
6
À
a Yield and selectivity were determined by GC using a calibration
curve based on PhCl as a standard. b The yield was too low for accurate
determination of the selectivity.
Table 3. Optimization of Catalyst Loadinga
entry
mol % Pd
yield (%)
TON
1b
2b
3c
4b
5d
6e
6
21
30
35
36
44
38
3.5
7.4
18
4
2
1
36
0.5
0.2
88
188
a Yields determined by GC using a calibration curve based on PhCl
as a standard. In all cases, the o:m:p selectivity was 1:76:23. Reactions
were generally stopped upon observation of Pd black, as our previous
studies7,8 have shown that this is indicative of the reaction cessation.
b 22 h. c 21 h. d 49 h. e 120 h.
a Yields and selectivities in columns 2 and 3 were determined by
calibrated GC using PhCl or PhCH2C(CH3)3 as a standard. Conditions
A: 0.5 mol % Pd(OAc)2, 1 equiv of PhI(OAc)2. Conditions B: 0.5 mol %
Pd(OAc)2, 1.5 mol % acridine, 1 equiv of MesI(OAc)2.
acridine:Pd ratio constant at 3:1 revealed that the reaction
yield is highest at 0.5 mol % Pd (44% yield, corresponding
to a TON of 88; Table 3, entry 5). As such, this catalyst
loading was selected for subsequent experiments.17
With these optimized conditions in hand, we next
explored the CÀH acetoxylation of a variety of mono-,
di-, and trisubstituted arene substrates (Tables 4 and 5).
For each substrate we compared the ligand-free conditions
with PhI(OAc)2 as the oxidant (conditions A) to the con-
ditions with acridine as the ligand and MesI(OAc)2 as the
oxidant (conditions B).18 In general, conditions A provided
modest yields and poor site selectivities. With a few excep-
tions, the selectivity under conditions A was dominated by
(18) Reactions were also run using no ligand and MesI(OAc)2 (see
Supporting Information, Table S8 for details), and the resulting selec-
tivities are intermediate between those observed in conditions A and
conditions B.
(17) Similar trends of ligand sterics, metal-to-ligand ratio, and cata-
lyst loading were observed for all of the other substrates examined in
these studies (see Supporting Information, Tables S4ÀS7 for details).
5430
Org. Lett., Vol. 15, No. 21, 2013

Pd/acridine system, and the major product is the B-isomer
(8A:8B = 39:61, conditions B of Table 4).
Table 5. Pd(OAc)2/Acridine-Catalyzed CÀH Acetoxylation of
Although the product ratios using Pd/acridine/
MesI(OAc)2 typically reflect a preference for acetoxylation
at the least hindered site, this catalyst system does
not effectively distinguish between the meta- and para-
positions of monosubstituted arenes. For example, ortho-
acetoxylation of anisole (14) and chlorobenzene (16) was
dramatically suppressed under conditions B, but a nearly
1:1 ratio of meta and para substituted products was formed
(Table 5).
Monosubstituted Arenesa
In conclusion, this report demonstrates the use of acri-
dine as an ancillary ligand to control site selectivity in the
Pd(OAc)2-catalyzed CÀH acetoxylation of simple arenes.
In combination with MesI(OAc)2 as the terminal oxidant,
the Pd(OAc)2/acridine system overrides the substrate elec-
tronic bias that dominates the site selectivity observed
using ligand-free Pd(OAc)2 as the catalyst and PhI(OAc)2
as the oxidant. Instead, the site selectivity of acetoxylation
using the Pd(OAc)2/acridine/MesI(OAc)2 system is pri-
marily dictated by sterics for a variety of different sub-
strates. Overall, catalyst-controlled selectivity through the
use of ancillary ligands provides exciting new prospects for
the field of Pd-catalyzed CÀH oxidation.
a Yields and selectivities in columns 2 and 3 were determined by
calibrated GC using PhCl or PhCH2C(CH3)3 as a standard. Conditions
A: 0.5 mol % Pd(OAc)2, 1 equiv of PhI(OAc)2. Conditions B: 0.5 mol %
Pd(OAc)2, 1.5 mol % acridine, 1 equiv of MesI(OAc)2.
Acknowledgment. ThisworkwassupportedbytheNSF
under the CCI Center for Enabling New Technologies
through Catalysis (CENTC) Phase II Renewal, CHE-
1205189. We thank Professors Karen Goldberg
(University of Washington), Bill Jones (University of
Rochester), Mike Heinekey (University of Washington),
Elon Ison (NCSU), and Tom Cundari (University of
North Texas) for valuable discussions and input. A.K.C.
thanks the Rackham Graduate School for a predoctoral
fellowship.
electronic factors,6 with preferential functionalization at
the most electron-rich sites in the molecule. In contrast,
conditions B generally provided higher product yields.
Furthermore, the selectivity was typically enhanced in
favor of acetoxylation at the least sterically hindered
CÀH bond. In many cases (e.g., 4À8 and 12), a reversal
in the favored isomer was observed upon moving from
conditions A to conditions B. For example, the CÀH
bond at the A-position of 8 is electronically activated,
and acetoxylation is favored at this site in the absence
of acridine (8A:8B = 81:19, conditions A of Table 4).
In contrast, this electronic bias is overridden with the
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 21, 2013
5431