Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

Article abstract of DOI:10.1002/chem.201602844

A palladium(II)-catalyzed C?H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline-based hemiacetal scaffold that can direct the selective C?H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.

Full text of DOI:10.1002/chem.201602844

A Journal of
Accepted Article
Title: Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with a Rea-
dily Attachable and Cleavable Molecular Scaffold
Authors: Qiankun Li; Brian J Knight; Eric M. Ferreira
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To be cited as: Chem. Eur. J. 10.1002/chem.201602844
Link to VoR: http://dx.doi.org/10.1002/chem.201602844
Supported by

Chemistry - A European Journal
10.1002/chem.201602844
COMMUNICATION
Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with
a Readily Attachable and Cleavable Molecular Scaffold
[a]
[a]
[a]
Qiankun Li, Brian J. Knight, and Eric M. Ferreira*
Abstract:
A
palladium(II)-catalyzed C–H arylation process of
novel
demonstrated the capacity of this scaffold to induce oxidative
alcohols has been developed. The strategy utilizes
a
olefinations of benzylic, homo-, and bishomobenzylic alcohols.
Herein, we disclose the expansion of this strategic concept
toward arylation, requiring the development of a new molecular
quinoline-based hemiacetal scaffold that can direct the selective C–
H bond functionalization. This reaction provides a useful method to
construct biaryl compounds of benzyl alcohols in good to excellent
scaffold based on
a quinoline-incorporated acetal (QuA -
yields. The new molecular scaffold can be readily attached, removed, Quinolinyl Acetal, Figure 1). We demonstrate its utility in ortho-
and recovered.
selective C–H arylations of benzylic and homobenzylic alcohols.
Of note, we highlight this scaffold has similar features to our
earlier report in terms of attachability and cleavability, as well as
show that this method can incorporate ortho-substituted arene
coupling partners, illustrating complementarity to the earlier
Transition metal (TM)-catalyzed selective C–H functionalization
represents a versatile approach to construct the core structures
in both natural products and pharmaceuticals. Arylation via a
C–H functionalization strategy can present a complementary
[
1]
[11b]
report.
0
[2]
approach to Pd -catalyzed cross couplings for biaryl synthesis.
A commonly employed strategy to achieve highly selective
activations is to use substrates possessing a Lewis basic
functional group that can coordinate the metal and direct the
precise reaction of the otherwise unreactive C–H bond.
Representative example substrate classes include pyridines,
[
1c,3]
oxazolines, and amides,
among several others. Easily
attached and removed functional groups that can bestow the
necessary Lewis basicity may allow this approach to be adapted
to less commonly employed substrate classes. Alcohols are one
such substrate family; these have been comparatively infrequent
in C–H functionalization chemistry, likely due to their
susceptibility toward oxidation and their relatively weaker
[
4]
coordination ability. In 2010, Yu and co-workers disclosed a
II
series of reports on Pd -catalyzed hydroxyl-directed C–H
[
5]
Figure 1. Pd(II)-catalyzed PyA/QuA-assisted C–H functionalization.
functionalization; tertiary alcohols were necessary to achieve
high yields, however. In contrast, primary and secondary
[
6]
alcohols tended to afford products in notably diminished yields.
In preliminary attempts to expand our scaffold-directed
chemistry to arylation, we first investigated the PyA scaffold-
attached benzylic alcohol (3) as the substrate. The scaffold was
readily attached from the parent alcohol (1) using hemiacetal 2
An alternative approach relating to those cases involves
alcohol “scaffolding,” using species that can be directly attached
to and later removed from the alcohol functional group.
[
7]
[8]
[9]
[10]
Transformations reported by Hartwig, Yu, Tan, Dong,
[
12]
[
11]
[12]
under dehydrative conditions (Scheme 1).
When the acetal
Zhao, and us demonstrated the feasibility of this concept in
was treated under ligand-accelerated Pd-catalyzed C–H
arylation conditions developed by Yu and coworkers [PhBPin (3
C–H functionalization. Specifically, a recent report from Zhao
[
11b]
and coworkers
demonstrated the Pd-catalyzed ortho-
equiv), Pd(OAc)
equiv), CsF (2 equiv) in HFIP],
2
(10 mol %), Ac-Gly-OH (20 mol %), Ag
2
CO
3
(1
selective arylation to construct biaryls, using oximes as the
surrogate species. As part of a program directed toward
designing novel molecular directing groups for C–H
[
14]
the desired product was
observed in 11% yield (NMR), with 83% yield of unreacted
starting material. Although we were encouraged by the proof-of-
principle reactivity, the low yield demanded further attention.
After a series of optimizations (see the Supporting Information
for full details), 45% yield of arylated product could be obtained,
as a 42:3 mixture of the ortho-monoarylated species (5) and a
further diarylated species (6). This latter species presumably
arises via a subsequent directed arylation of product 5 at the
ortho position of the initially installed arene. A 38% yield of the
[
12,13]
functionalization,
we recently described the development of
a practical scaffold for catalytic C–H functionalization (PyA -
Pyridyl Acetal, Figure 1), which is readily attachable to alcohols,
[
12]
cleavable, and recoverable in excellent yields.
We had
[
a]
Dr. Q. Li, Dr. B. J. Knight, and Prof. Dr. E. M. Ferreira
Department of Chemistry, University of Georgia
Athens, GA 30602 (USA)
recovered starting material was also observed.
We
E-mail: emferr@uga.edu
hypothesized that this overall arylation process was somewhat
hampered by the pairing of boronate species with the strongly
Lewis basic pyridyl scaffold. Thus, we believed we needed to
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201602844
COMMUNICATION
1
. R3SiCl (1.2 equiv)
imidazole (3 equiv)
DMF, 23 °C
explore structural changes to our scaffold system in order to
improve reactivity.
TBAF (1 equiv)
THF, 23 °C
OH
Me
OSiR3
CHO
92% yield from 7
N
2. SeO2 (1.25 equiv)
,4-dioxane, reflux
N
using TBDPSCl
1
7
8
(82% yield using TBSCl)
(
known, ref 11a)
BzCl (1.1 equiv)
Et3N (1.1 equiv)
O
O
N
CH Cl , 0 ® 23 °C
N
2
2
OH
OBz
9
1% yield
9
10
1
. TFA (10 mol %)
DCE, 80 °C
Me
Me
O
OH
OQuA
N
2 3
2. K CO (2 equiv)
OBz
MeOH/DCE, 23 °C
1
10
94% yield
11
QuA :
O
N
Scheme 2. Quinolinyl-Acetal (QuA) synthesis and scaffold attachment.
To our delight, when the QuA-attached benzyl alcohol 11
was subjected to the reaction, a significantly improved arylation
(
69/4% mono/di) was achieved (Table 1, entry 1), with an
additional 24% of recovered starting material (rsm). Using 4
equiv of PhBPin gave a slightly improved reaction (entry 2).
After reevaluating bases, 2 equiv of K
75/14% mono/di with 6% rsm, entry 5). Aryltrifluoroborates
were also reactive, albeit with lower activity than PhBPin (entry
2 3
CO gave the best yield
(
8
). Using benzoquinone or water has been shown in specific
Scheme 1. Preliminary C–H arylation based on pyridyl acetal (PyA).
[
19]
cases to facilitate transmetalation and/or reductive elimination;
unfortunately these additives did not improve the yield for this
transformation (entries 9, 10). When amino acid based ligands
were analyzed, N-acetylisoleucine (Ac-Ile-OH) was optimal, with
Toward this idea, we reasoned that a more tempered
coordinating group may lead to improved reactivity. Quinolines
have been widely used as directing groups for TM-catalyzed C–
[20]
a much improved mono- to diarylation ratio (entry 14).
The
[
15]
ligand Ac-tLeu-OH afforded an even better mono/di ratio, but
lower yields overall (entry 15). Presumably, more bulky ligands
can suppress the formation of the diarylated product, but they
also lead to lower yields. Ultimately we chose entry 14 in Table
H functionalizations,
so we pursued an analogous scaffold
based on this heterocycle. The synthesis of the scaffold is
[
16]
illustrated in Scheme 2. From known quinoline alcohol 7,
a
silylation/oxidation/desilylation sequence afforded hemiacetal 9
in excellent yield. TBSCl could be used instead of TBDPSCl for
this sequence, although the yield of hemiacetal 9 in that case
1
as the optimized conditions for further studies, providing the
optimal balance of high reactivity and monoarylation selectivity.
[
17]
was slightly diminished.
Although we had used the
Table 1. C–H arylation optimization with QuA-attached alcohol 11.
hemiacetal functional group to attach the PyA moiety (e.g.,
Scheme 1), for the quinoline-based compound we observed an
acetal dimerization that complicated purification. Ultimately, we
found that benzoylation of hemiacetal 9 proceeded smoothly,
and benzoate 10 could be readily attached to o-methyl benzyl
alcohol under acidic conditions (TFA/DCE) to afford the
Pd(OAc)2 (10 mol %)
Ligand (20 mol %)
Ag2CO3 (2 equiv)
Base (2 equiv)
Me
Me
Me
OQuA
OQuA
OQuA
PhBPin
HFIP (0.05 M), air
90 °C, 6 h
H
Ph
11
4a
(4 equiv)
12a
13a
[
18]
]
[a]
Quinolinyl-Acetal (QuA)-attached alcohol in 94% yield.
Entry
Base
Ligand
% Yield
12a / 13a / rsm)
(
[
b]
1
2
3
4
5
6
7
Na
Na
Na
2
2
3
CO
3
3
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
69 / 4 / 24
71 / 6 / 17
71 / 8 / 17
75 / 11 / 7
75 / 14 / 6
50 / 2 / 24
75 / 12 / 9
CO
PO
4
KHCO
3
K
K
2
CO
3
3
PO
4
Cs
2
CO
3

Chemistry - A European Journal
10.1002/chem.201602844
COMMUNICATION
[
c]
d]
[
ortho-substituted arenes, good yields of the biaryls were formed.
For cases that were unsubstituted at the ortho position, both
mono- and ortho-diarylated products were observed.
8
9
1
1
1
1
1
1
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Val-OH
Ac-Ala-OH
Ac-Leu-OH
Ac-Ile-OH
57 / 2 / 39
18 / 0 / 76
74 / 12 / 9
77 / 8 / 8
[
e]
0
1
2
3
4
5
Pd(OAc)2 (10 mol %)
R
Ac-Ile-OH (20 mol %)
R
Ag2CO3 (2 equiv)
OQuA
Me
Me
K2CO3 (2 equiv)
OQuA
70 / 6 / 16
75 / 8 / 10
84 / 5 / 7
BPin
H
HFIP (0.05 M), 90 °C
1
4
(R = CF3)
(R = OMe)
(R = NO2)
Me
Me
15, 77% yield (R = CF3)
16
4
b (4 equiv)
18
17, 88% yield (R = OMe)
19, 62% yield (R = NO2)
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
Ac-tLeu-OH
76 / 1 / 17
Me
Me
OQuA
BPin
Me
OQuA
HFIP (0.05 M), 90 °C
[
a] NMR yield with 1-octene as the standard. [b] 3 equiv of PhBPin used. [c]
PhBF K used instead of PhBPin. [d] 0.5 equiv benzoquinone was added. [e] 2
equiv H O was added.
H
3
20
4b (4 equiv)
Me
2
21, 67% yield
Pd(OAc)2 (10 mol %)
Table 1. C–H arylation optimization with QuA-attached alcohol 11.
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
OQuA
Me
Ar
R
H
OQuA
The substrate scope was next explored (Table 2). We first
tested the scope of arylboronic pinacol esters. Variously
substituted Ar-BPins (with both electron-donating and electron-
OQuA
BPin HFIP (0.05 M), 90 °C
R
Ar
o-monoarylation
23, 69% yield (33/36 mono/di, R = H)
25, 63% yield (26/37 mono/di, R = OMe)
22 (R = H)
4 (R = OMe)
R
Ar
o,o'-diarylation
2
Me
4
b (4 equiv)
3 2
withdrawing substituted groups, such as OMe, CF , CO Me)
were tolerated, affording the corresponding products in good to
excellent yields (entries 2-7). Moreover, 2-naphthylboronic acid
pinacol ester was also tolerated, giving the corresponding
monoarylated product in 76% yield (entry 8). Most notably,
arylboronic pinacol esters that were ortho-substituted were
participatory in this reaction manifold, and the corresponding
arylated products were isolated in good yields (entries 9, 10).
Ortho-substituted aryl species were reported to be unreactive in
Scheme 3. Examination of benzylic alcohol scope.
In the aforementioned alkenylation process, we observed
that our scaffold could be successfully extended to systems
beyond primary benzylic alcohols. For arylation, this extension
was also achievable, although the results in these cases were
somewhat more modest (Scheme 4). A substrate derived from
a homobenzylic alcohol could be coupled in this transformation,
as product 27 was afforded in 83% yield.
originating from a bishomobenzylic alcohol, however, showed
low reactivity, with only 11% yield of the arylated species
[
11b]
Zhao’s oxime-based system,
demonstrating that our method
has some complementarity to this prior art.
[
21]
A compound
Table 2. C–H arylation - Variation of aryl boronate.
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
produced, and 77% yield of the recovered starting material.
secondary alcohol-based substrate was also reactive, with only
mono-arylation observed.
A
Me
Me
Me
OQuA
OQuA
ArBPin
OQuA
HFIP (0.05 M), 90 °C
R
H
11
Ar
2a-j
4a-j
4 equiv)
Ar
13a-j
1
(
Pd(OAc)2 (10 mol %)
o-monoarylation (MA) o,a -diarylation (DA)
Me
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
Yield (%)[a]
MA DA rsm
Yield (%)[a]
MA DA rsm
Me
Me
OQuA
Me
Me
Entry
ArBPin
Entry
ArBPin
OQuA
BPin
1
2
BPin
82
84
7
0
6
6
7
MeO2C
F3C
BPin 80 (4) (16)
4f
HFIP (0.05 M), 90 °C
H
4a
Me
26
4b (4 equiv)
Me
27, 83% yield
BPin
71
7
(9)
BPin
(3)
4g
Me
4b
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
Me
BPin
8
9
76
0
(8)
Me
Me
Me
OQuA
Me
MeO
BPin
4h
3
4
76 (9) (5)
OQuA
4c
BPin
MeO
BPin
4i
69
63
0
0
(4)
H
HFIP (0.05 M), 90 °C
72 (4)
6
BPin
Me
Me
28
4b (4 equiv)
4d
29, 11% yield (NMR)
77% yield rsm (NMR)
10
BPin
(14)
Me
BPin
5
71
6
(5)
4j
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
4e
OMe
Me
[a] Yields are as isolated mixtures of MA/DA/rsm components. Yields in parentheses are NMR
Me
Me
Me
OQuA
OQuA
Me
yields based on integration of the crude product mixture. These components were removed in
purification.
BPin
HFIP (0.05 M), 90 °C
H
Me
A range of scaffold-attached benzylic alcohol substrates
were also evaluated (Scheme 3). The QuA scaffold was
attached to these alcohols and those in Scheme 4 in 77-96%
yield using the same conditions as described in Scheme 4. For
30
4b (4 equiv)
31, 65% yield (NMR)
1
4% yield rsm (NMR)
Scheme 4. Arylation of non-primary benzylic alcohol-based substrates.

Chemistry - A European Journal
10.1002/chem.201602844
COMMUNICATION
A significant attribute of our acetal-based scaffold is the ease
of both attachment and cleavage,. A sequential procedure, with
arylation followed by immediate direct scaffold cleavage was
performed (Scheme 5). The two steps, with only one purification,
afforded the biaryl alcohol in 89% yield. Furthermore, the methyl
acetal-derived scaffold (33) was isolated in 86% yield,
highlighting its recoverability. Although the benzoate derived
precursor was generally preferable for attachment, this
recovered acetal compound (33) could be readily reused
using our scaffolding strategy in C–H functionalization are
currently underway and will be reported in due course.
Experimental Section
Typical C–H arylation procedure: A suspension of acetal 11 (29.6 mg,
0.102 mmol), PhBPin (4a, 81.0 mg, 0.397 mmol), Pd(OAc)
0.0103 mmol), N-acetylisoleucine (3.4 mg, 0.0197 mmol), Ag
mg, 0.207 mmol), and CO (29.0 mg, 0.210 mmol) in
2
(2.3 mg,
2
CO (57.0
3
K
2
3
(
Scheme 5). Much like in our olefination studies, a telescoping
hexafluoroisopropanol (2.00 mL) in a 2-dram vial with a PTFE-lined cap
was heated at 90 °C and stirred for 6 h. The reaction was cooled to
ambient temperature and filtered through a short pad of silica gel, eluting
with diethyl ether (50 mL). The filtrate was concentrated by rotary
evaporation, and the resulting residue was purified by flash column
chromatography (10:1:1 hexanes/EtOAc/CH Cl eluent) to afford
procedure using our quinolinyl scaffold could be executed.
Benzylic alcohol 1 was converted to the arylated alcohol (32) in
59% yield (89% yield brsm) without any intermediate
purifications. The iterative procedure was higher yielding than
the telescoping process (84% vs. 59%); the initial attachment
afforded small amounts of quinoline-based impurities that
2
2
arylation products 12a/13a (35.6 mg, 89% yield (82:7 mono/di) + 6%
recovered 11, R = 0.40 in 5:1:1 hexanes/EtOAc/CH Cl ) as a light yellow
oil. 12a: H NMR (400 MHz, CDCl )  8.17 (d, J = 8.5 Hz, 1 H), 8.03 (s, 1
H), 7.83 (d, J = 8.2 Hz, 1 H), 7.76-7.68 (m, 1 H), 7.61-7.53 (m, 1 H), 7.52-
hampered the
arylation
reactivity when telescoped.
f
2
2
1
3
Nevertheless, the overall telescoping procedure can indeed be
executed, and arylated alcohol 32 was obtained in reasonable
yield.
7
1
1
.41 (m, 4 H), 7.41-7.34 (m, 1 H), 7.25-7.17 (m, 2 H), 7.14 (dd, J = 7.2,
.3 Hz, 1 H), 6.22 (s, 1 H), 5.34 (d, J = 13.2 Hz, 1 H), 5.20 (d, J = 13.2 Hz,
13
H), 4.90 (d, J = 9.8 Hz, 1 H), 4.68 (d, J = 9.8 Hz, 1 H), 2.59 (s, 3 H);
)  159.7, 148.8, 143.9, 141.6, 139.5, 132.7, 130.7,
130.1, 129.8, 129.5, 128.9, 128.3, 128.1, 128.07, 128.04, 127.98, 127.2,
C
Arylation/Cleavage Procedure
NMR (100 MHz, CDCl
3
4b (4 equiv)
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K2CO3 (2 equiv)
-1
Me
104.1, 70.2, 66.0, 19.9; IR (film) 1503, 1067, 1007, 910, 760 cm ; HRMS
+
+
Me
OH
Me
(ESI+) m/z calc’d for (M +H) [C25
H
2
21NO + H] : 368.1645, found
HCl(g)
Me
O
OQuA
368.1646.
HFIP (0.05 M), 90 °C
14.5 h
filter & concentrate
MeOH
23 °C
22.5 h
N
H
OMe
32
33
86% yield
11
8
9% yield
Me
Me
5
ÅMS (0.5 g/mL)
Acknowledgements
O
OH
OQuA
N
toluene, 140 °C
4 h
3% yield
OMe
2
The University of Georgia is acknowledged for support of this
research. Q. L. was supported by the NSF and EPA through the
Network for Sustainable Molecular Design and Synthesis
program (NSF-CHE-1339674).
1
33
11
8
Telescoping Procedure
4b (4 equiv)
Pd(OAc)2 (10 mol %)
Ac-Ile-OH (20 mol %)
Ag2CO3 (2 equiv)
K CO (2 equiv)
QuAOBz (1.3 equiv)
TFA (10 mol %)
DCE, 80 °C, 8 h
Me
HCl(g)
2
3
OH
then K2CO3 (2 equiv)
MeOH/DCE (1:1)
23 °C, 15 h
HFIP (0.05 M), 90 °C
MeOH, 23 °C
9 h
Keywords: C–H functionalization • Arylation • C-C coupling •
Palladium • Quinoline acetal
H
15 h
2
1
filter & concentrate
aqueous workup
Me
[
1]
For select reviews, see: a) K. Godula, D. Sames, Science 2006, 312,
67-72; b) X. Chen, K. M. Engle, D. -H. Wang, J. -Q. Yu, Angew. Chem.
2009, 121, 5196-5217; Angew. Chem. Int. Ed. 2009, 48, 5094-5115; c)
T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147-1169; d) L.
McMurray, F. O'Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885-
OH
Me
O
N
OMe
Me
2
33
73% yield
3
5
9% yield (89% brsm)
(based on QuAOBz)
1898; e) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem., Int.
Ed. 2012, 51, 8960-9009.
Scheme 5. Sequential procedure, recovery, and telescoping.
[2]
For select reviews covering biaryl synthesis via C–H functionalization,
see: a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174-238; b) S. Pascual, P. de Mendoza, A. M. Echavarren, Org. Biomol.
In conclusion, we have developed a modified molecular
scaffold that enables a practical strategy for the C-H arylation of
benzylic and homobenzylic alcohols. The derivatization of the
scaffold to incorporate a quinolinyl moiety proved pivotal to
temper the Lewis basicity and enable boronic ester compatibility.
The new scaffold is readily synthesized in just two steps from
Chem. 2007, 5, 2727-2734; c) G. P. McGlacken, L. M. Bateman, Chem.
Soc. Rev. 2009, 38, 2447-2464; d) J. A. Ashenhurst, Chem. Soc. Rev.
2010, 39, 540-548; e) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215-1292; f) I. Hussain, T. Singh, Adv. Synth. Catal. 2014, 356, 1661-
1696.
[3]
For select reviews, see: a) P. B. Arockiam, C. Bruneau, P. H. Dixneuf,
Chem. Rev. 2012, 112, 5879-5918; b) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624-655.
[
22]
known starting materials.
The scaffold is readily attached and
removed, and the biaryl compounds can be accessed in good to
excellent yields. A range of both alcohol and boronic ester
coupling partners could be tolerated, and an overall telescoping
procedure is feasible with this technology. Further investigations
[4]
For a review on C–H functionalization strategies for alcohol-based
substrates, see, F. Mo, J. R. Tabor, G. Dong, Chem. Lett. 2014, 43,
2
64-271.
a) Y. Lu, D. -H. Wang, K. M. Engle, J. -Q. Yu, J. Am. Chem. Soc. 2010,
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[5]
1

Chemistry - A European Journal
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Soc. 2010, 132, 12203-12205; c) Y. Lu, D. Leow, X. Wang, K. M. Engle,
J. -Q. Yu, Chem. Sci. 2011, 2, 967-971.
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[6]
For other examples of metal-catalyzed C–H functionalizations based on
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acetoacetate in 3 steps. See SI for details.
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[17] See the Supporting Information for details.
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2 3
[18] The K CO /MeOH process as the final step of attachment was used to
[
[
9]
S. Lee, H. Lee, K. L. Tan, J. Am. Chem. Soc., 2013, 135,18778-18781.
convert residual benzoate 10 to hemiacetal, aiding in the purification.
[19] a) X. Chen, C. E. Goodhue, J. -Q. Yu, J. Am. Chem. Soc. 2006, 128,
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[
[
[
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1
1
[21] Biaryl compound 27 could be isolated in only ~92% purity, together with
an unidentified byproduct.
2
[22] The aldehyde product from step 2 in the sequence in Scheme 2 (8,
Yu, J. Am. Chem. Soc. 2013, 135, 18056-18059; c) G. Yang, P.
Lindovska, D. Zhu, J. Kim, P. Wang, R. -Y. Tang, M. Movassaghi, J. -Q.
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3
SiR = TBDPS) is known. See ref 11a.

Chemistry - A European Journal
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Entry for the Table of Contents (Please choose one layout)
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Qiankun Li, Brian J. Knight, and Eric M.
Ferreira*
Page No. – Page No.
Palladium(II)-Catalyzed ortho-
Arylation of Aromatic Alcohols with a
Readily Attachable and Cleavable
Molecular Scaffold
II
Catalytic (QuA)rylation. A Pd -catalyzed C–H arylation process of alcohols has
been developed. The strategy utilizes a novel quinoline-based hemiacetal scaffold
that can direct the selective C–H bond functionalization. This reaction provides a
useful method to construct biaryl compounds of benzyl alcohols in good to excellent
yields. The new molecular scaffold can be readily attached, removed, and
recovered.