Pd(II)-catalyzed para-selective C-H arylation of monosubstituted arenes

Article abstract of DOI:10.1021/ja206572w

Pd-catalyzed highly para-selective C-H arylation of monosubstituted arenes (including toluene) is developed for the first time using an F⁺ reagent as a bystanding oxidant. This finding provides a new retrosynthetic disconnection for para-substituted biaryl synthesis via C-H/C-H cross-coupling.

Full text of DOI:10.1021/ja206572w

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pubs.acs.org/JACS
Pd(II)-Catalyzed para-Selective CÀH Arylation of Monosubstituted
Arenes
Xisheng Wang, Dasheng Leow, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: Pd-catalyzed highly para-selective CÀH ar-
ylation of monosubstituted arenes (including toluene) is
developed for the first time using an F+ reagent as a
bystanding oxidant. This finding provides a new retrosyn-
thetic disconnection for para-substituted biaryl synthesis via
CÀH/CÀH cross-coupling.
he electrophilic palladation of arenes observed in the 1960s
mainly involves either highly reactive electron-rich arenes or
T
excess benzene to promote palladation through high molarity.1
Extensive efforts to exploit directed ortho-palladation to develop
synthetically useful reactions have shown encouraging progress
during the past decade.2 Recently, mono-N-protected amino acid
ligands have been demonstrated to enhance reactivity3 and to
control regio-3a and stereoselectivity.4 From the viewpoint of
synthetic applications, the next fundamental challenge in this
field is to achieve meta- and para-selectivity with representative
monosubstituted arene substrates.5,6 Herein, we report the first
example of highly para-selective arylation of monosubstituted
arenes via a CÀH/CÀH coupling. This provides a unique route
for accessing para-substituted biaryls, a structural motif found
in antagonist drug molecules such as Losartan and Valsartan
(Figure 1).7 The combination of an acidic amide directing group
for the first CÀH activation step and a bystanding F+ oxidant for
the second CÀH activation step is crucial for high para-selectivity.
Reactions that directly couple two aryl CÀH bonds8 have
witnessed a recent resurgence in interest, owing to the prospect
of achieving predominant cross-coupling by increasing the
reactivity of one of the two arenes. This has been achieved by
either using an electron-rich arene9 or appending a directing
group10 onto one of the arenes to suppress undesired CÀH/
CÀH homocoupling. Among numerous seminal contributions,
recent reports by the Dong group using amide directing groups
have shown the most encouraging substrate scope, including
broadly useful benzoic acid and phenylacetic acid carbogenic
skeletons, albeit only those containing electron-neutral and -rich
arenes.10g A common problem in these reactions is the formation
of an intractable mixture of regioisomers when a simple mono-
substituted arene is used as the coupling partner, which com-
promises their synthetic utility. Although sterically less hindered
CÀH bonds were often preferentially activated with 1,2-disub-
stituted arene substrates, synthetically useful regioselectivity was
achieved only with anisole by Buchwald10d (o/m/p = 1/2/12)
and Dong10g (o/m/p = 1/1.4/8.6) when monosubstituted arenes
were used.
Figure 1. A new disconnection for para-substituted biaryl synthesis.
We recently employed F+ reagents as bystanding oxidants
to promote selective CÀN and CÀO reductive elimination
from Pd(IV) in a number of CÀH functionalization reactions.11
Michael and co-workers observed that a [Pd(II)-alkyl] interme-
diate generated from the carboamination of olefins reacted with
toluene in the presence of N-fluorobenzenesulfonimide (NFSI)
to give mainly para-alkylated toluene compounds as the isolated
products in 45À90% yields.12 In our previous fluorination of
benzyltriflamide with F+,13a a small amount of ortho-arylation
product (<10%) was also formed when toluene was used as the
solvent. In this case, toluene was activated with moderate
selectivity (o/m/p = 1/4/12) (eq 1).
Guided by these observations, we began to search for a suitable
combination of directing group and reaction conditions that
would allow highly para-selective arylation of toluene. Since the
acidic amide as a carboxylic acid mimic derived from 4-trifluoro-
methyl-2,3,5,6-tetrafluoroaniline (ArNH2) has demonstrated
superior reactivity for CÀH activation,14 we focused on amide
1a and screened oxidants and additives known to promote CÀH
activation (Table 1). We found that the use of the F+ reagent
1-fluoro-2,4,6-trimethylpyridinium triflate (NFTMPT) and 2
equiv of DMF as an additive promoted the arylation of toluene
to give the desired product in 70% yield with a para/meta ratio
of 13/1 (entry 14). No ortho-arylation was observed. Intri-
guingly, replacing NFTMPT with the previously reported oxi-
dant K2S2O810g gave the arylated products with poor selectivity
(para/meta, 1.7/1; entry 13). Considering the result shown in
Received: June 11, 2011
Published: August 11, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja206572w J. Am. Chem. Soc. 2011, 133, 13864–13867
|

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COMMUNICATION
Table 1. Pd(II)-Catalyzed Oxidative CÀH/CÀH Cross-
Table 3. Scope of Benzamidesa,b,c
Coupling: Survey of Oxidantsa,
oxidant
(equiv)
yieldb
(%)
oxidant
(equiv)
yieldb
(%)
entry
entry
1
2
3
AgOAc (3.0)
Cu(OAc)2 (1.5)
AgOAc/CuCl2
(1.5/1.5)
0
0
0
8
9
(PhCOO)2
NCS (1.5)
0
0d
10 Phl(OAc)2 (1.5) 0e
4
5
6
7
PhCO3t-Bu (1.5)
oxone (3.0)
0
0
0
0
11 Phl(TFA)2 (1.5)
12 Phl(OPiv)2 (1.5)
13c K2S2O8 (3.0)
0
0
Ce(SO4)2 (2.0)
75 (1.7/1)f
(t-BuO)2 (1.5)
14 NFTMPT (1.5) 70 (13/1)f
a Unless otherwise noted, the reaction conditions were as follows: amide
1a (0.2 mmol), Pd(OAc)2 (10 mol %), oxidant (1.5 equiv), DMF
(2.0 equiv), toluene (2 mL), 100 °C, 24 h. b Isolated yield. c CF3COOH
(5 equiv) was added. d Chlorinated product was formed in 40% GC yield.
a Unless otherwise noted, the reaction conditions were as follows:
amide 1 (0.2 mmol), Pd(OAc)2 (10 mol %), oxidant (1.5 equiv),
DMF (2.0 equiv), toluene (2 mL), 70 °C, 48 h. b Isolated yields are
given. c Regioselectivity determined by GC analysis (para/meta, no ortho-
product was observed) is shown in parentheses. d 90 °C, 24 h. e 80 °C,
36 h. f 100 °C, 24 h. g 15 mol % Pd(OAc)2.
f
e Acetoxylated product was formed in 45% GC yield. Regioselectivity
determined by GC analysis (para/meta) is shown in parentheses.
Table 2. Survey of F+ Oxidantsa,b,c
corresponding biaryl products with excellent para-selectivity
with respect to toluene (2bÀe). A number of halogenated
benzamides also reacted with toluene with similarly high regios-
electivity to give the biaryl products in good yields (2fÀi). The
chloro and bromo substituents are useful handles for further
synthetic elaboration. Of special importance, benzamides con-
taining electron-withdrawing groups including trifluoromethyl,
ketone, and cyano groups are also compatible with this cat-
alytic system (2jÀm). Notably, previously reported CÀH/CÀH
coupling reactions were typically low-yielding with electron-
deficient substrates, except for highly reactive pentafluoroben-
zene,10 which illustrates the efficiency of this acidic amide direc-
ting group in CÀH/CÀH coupling reactions.
High levels of para-selectivity were consistently observed with
other substituted arenes containing alkyl, methoxy, and halo
groups (Table 4). The compatibility of halides with the reaction
conditions allows for additional synthetic elaboration through
venerable Pd(0)-catalyzed cross-coupling and BuchwaldÀHartwig
amination reactions. The amide products could be readily con-
verted to carboxylic acids as useful intermediates for the synthesis of
drug molecules such as Losartan and Valsartan (treatingwith TFA/
H2O (4/1) at 90 °C; see Supporting Information).
The exceedingly high para-selectivity observed for such
CÀH/CÀH coupling reactions could have significant mechan-
istic implications. Since the first CÀH activation step involving
this acidic amide directing group is relatively well under-
stood,14 we focused on the second CÀH activation step.
By comparing the initial reaction rate of toluene to that of
toluene-d8, kH/kD was determined to be 1.0 (Figure 2), which
is consistent with an electrophilic palladation mechanism if
we consider the first CÀH activation step to be a relatively
fast step.
a Unless otherwise noted, the reaction conditions were as follows:
amide 1a (0.2 mmol), Pd(OAc)2 (10 mol %), oxidant (1.5 equiv),
DMF (2.0 equiv), toluene (2 mL), 100 °C, 24 h. b Isolated yields
are given. c Regioselectivity determined by GC analysis (para/meta) is
shown in parentheses.
eq 1, these experimental observations suggest that both the
directing group and the F+ reagent are crucial for obtaining high
para-selectivity.
With the insight that F+ reagents are crucial for para-selectivity,
we next tested various F+ sources. In all cases, uniformly high
para-selectivity was observed, and NFSI gave the highest yield
(Table 2).
Under these optimized conditions, an array of synthetically
useful benzamides was reacted with toluene (Table 3). Benza-
mides containing no substituent and those substituted with
electron-donating groups were arylated smoothly to give the
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Journal of the American Chemical Society
COMMUNICATION
Table 4. Scope of Monosubstituted Arenesa,b,c
potentially lead to practical new tools for the synthesis of para-
substituted biaryls.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization of all new compounds; complete ref 7b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS, 1 R01 GM084019-02),
Amgen, Eli Lilly, and Novartis for financial support. We thank
A*STAR for a postdoctoral fellowship (D.L.).
a Unlessotherwisenoted, thereaction conditionswereasfollows: amide1a
(0.2 mmol), Pd(OAc)2 (10 mol %), NFSI (1.5 equiv), DMF (2.0 equiv),
c
arene (2 mL), 70 °C, 48 h. b Isolated yields are given. Regioselectivity
determined by GC analysis (para/meta, no ortho-product was observed) is
shown in parentheses. d 100 °C, 24 h.
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