Palladium(II)-catalyzed ortho alkylation of benzoic acids with alkyl halides

Full text of DOI:10.1002/anie.200902262

Angewandte
Chemie
DOI: 10.1002/anie.200902262
C–H Activation
Palladium(II)-Catalyzed ortho Alkylation of Benzoic Acids with Alkyl
Halides**
Yang-Hui Zhang, Bing-Feng Shi, and Jin-Quan Yu*
0
À
The Pd -initiated arylation of C H bonds with aryl halides
was among the earliest examples of Pd-catalyzed C–H
activation/arylation chemistry.[1–6] A single pioneering exam-
0
À
ple of the Pd -catalyzed alkylation of aryl C H bonds using a
tethered alkyl chloride was also developed by Buchwald and
Hennessy for the highly efficient synthesis of oxindoles.[7a]
Scheme 1. Pd-catalyzed alkylation of aryl C–H Bonds.
Two examples of intra- and intermolecular alkylation of
heterocycles have also been reported by Chang et al.[7b] and
Hoarau et al.[7c] recently. In these reactions, no added oxidants
other than the aryl halides or alkyl halides themselves are
needed, which affords this C–H functionalization process a
practical advantage. During the past five years, PdII-catalyzed
arylation using Ar2IX as the stoichiometric oxidant through a
PdII/PdIV catalytic cycle has undergone major advances.[8,9]
Especially noteworthy is the broad range of arylation
reactions using ArI/AgOAc.[10] To our knowledge, the PdII-
each cycle must be converted to Pd(OAc)2 by reaction with
AgOAc. Knowing that Pd–Cl or Pd–Br species would be
generated when alkyl chlorides or bromides were used as the
alkylating reagents, we began our screening efforts using 1,2-
dichloroethane as the alkylating reagent with the aim of
discovering conditions that would promote the displacement
of chloride from the Pd–Cl species by a benzoate anion to
close the catalytic cycle. We were pleased to find that the
presence of K2HPO4 alone is sufficient for the catalytic
alkylation to proceed (Table 1, entry 1). As anticipated, the
initially formed alkylation product underwent an SN2 reaction
to give the corresponding lactone 1. A control experiment
showed that the Pd catalyst is essential (Table 1, entry 2). The
major competing side reaction is the SN2 reaction between the
substrate and 1,2-dichloroethane. Since methylbenzoate is not
reactive, we investigated the effect of the base on the SN2
reaction. For instance, the use of K2CO3 and Cs2CO3 resulted
in predominant formation of the SN2 product (Table 1,
entries 5 and 9). The use of K2HPO4 is decisively superior
to Na2HPO4 with the latter giving only a negligible amount of
the desired product. This catalytic reaction can be performed
under either air or argon, although the latter gives a slightly
lower yield (Table 1, entry 3). The minor effect of O2 suggests
À
catalyzed intermolecular alkylation of C H bonds with alkyl
halides[11,12] remains an unsolved problem, except for a single
example of methylation of acetanilide with MeI.[13,14] In
addition, a large excess of AgOAc is required to scavenge the
iodide from Pd–I species in this case. Herein we report a
sequential monoselective alkylation/lactonization reaction of
benzoic acids with 1,2-dichloroethane, dichloromethane, and
dibromomethane (Scheme 1). Alkylation with 1-chloropen-
tane was also found to proceed, albeit in lower yield. The use
of alkyl chlorides instead of iodides allows the catalytic cycle
to be closed in the presence of an inexpensive base without
using stoichiometric amounts of Ag+ salts.
We recently established that the k2 coordination of a
cation with a carboxylate group forces the PdII center to
À
chelate in the proximity of the ortho C H bonds (for benzoic
À
acid and phenyl acetic acid substrates) and b C H bonds (for
Table 1: Influence of the base on the alkylation reaction.
aliphatic acids), a geometry that is essential for facile C–H
bond cleavage.[15] The broad utility of carboxylate groups
prompted us to develop a potentially useful catalytic system
À
for the alkylation of C H bonds in these substrates.
Although alkyl iodide is a more reactive oxidant for alkyl–
palladium species, the subsequently formed Pd–I species in
Entry
Base (equiv)
1 [%][a]
2 [%][a]
3 [%][a]
Remaining
substrate [%][a]
1
K2HPO4 (3)
K2HPO4 (3)
K2HPO4 (3)
KHCO3 (2)
K2CO3 (3)
82
0
10
16
16
23
58
34
<2
0
4
33
8
<1
<1
2
0
0
5
0
16
0
35
5
2[b]
3[c]
4
[*] Dr. Y.-H. Zhang, Dr. B.-F. Shi, Prof. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2409
67
40
32
34
17
3
5
6
7
8
K3PO4 (3)
0
E-mail: yu200@scripps.edu
Na2CO3 (2)
Na2HPO4 (3)
Cs2CO3 (2)
74
97
0
[**] We thank The Scripps Research Institute, the U.S. National
Institutes of Health (NIGMS, 1 R01 GM084019-01A1), Amgen, and
Lilly for financial support, and the A. P. Sloan Foundation for a
fellowship (J.-Q.Y.).
9
0
90
[a] Yield was determined by 1H NMR analysis of the crude product using
CH2Br2 as the internal standard. [b] No Pd(OAc)2 was used. [c] The
reaction was carried out under an atmosphere of argon.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902262.
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that a small amount of Pd0 may form through side reactions
albeit in only 26% yield owing to significant formation of the
SN2 product (Table 2, entry 9).
and that O2 could reoxidize the Pd0 back into the catalytic
cycle.
To further expand the scope of this alkylation reaction, we
tested dichloromethane and dibromomethane as the alkylat-
ing reagents. Although dichloromethane only worked well
with a few substrates (Table 3, entry 2), the use of dibromo-
methane substantially improved the reaction yields and
expanded the substrate scope. Electron-withdrawing halo
and trifluoromethyl groups were well tolerated (Table 3,
entries 4–8 and 11). Keto and ester groups were also
compatible, though these substrates gave lower yields
(Table 3, entries 12 and 13). Most importantly, the alkylation
protocols with both dichloroethane and dibromomethane
exhibit exclusive monoselectivity at the less hindered ortho
position, partly because of rapid lactone formation. The
catalyst loading can be reduced to 5 mol% (Table 3, entry 2).
From the viewpoint of synthetic applications, d-benzolac-
tones (Table 2) can be readily converted into coumarins under
dehydrogenative oxidations.[16] Although alkylation with
dibromomethane introduces only one carbon unit into the
arene, the excellent reactivity of the new benzylic carbon
allows for versatile chain extension using a broad range of
nucleophiles to afford valuable building blocks for synthesis
(Scheme 2).[17]
This optimized protocol was then tested with other
substrates. Although alkylation of closely related benzoic
acids (Table 2, entry 2) under identical conditions gave the
desired products in comparable yields, further variation in
Table 2: Alkylation with 1,2-dichloroethane or pentyl chloride.[a]
Entry Substrate
Base
(equiv)
T [8C] Product
Yield
[%][b]
K2HPO4
(3.0)
81
1
2
3
115
115
115
34[c]
K2HPO4
(3.0)
80
55
K2HPO4
(3.0)
To gain insight into the reaction mechanism and catalytic
cycle, further experimental studies were performed. The
observation that 2 and 4 were unreactive to both Pd(OAc)2 or
PdBr2 (Scheme 3) speaks against a mechanism in which
KHCO3
(2.5)
4
5
6
7
8
140
140
140
140
140
51
42
45
67
75
KHCO3
(2.5)
Na2CO3
(3.0)
KHCO3
(2.5)
Na2CO3
(3.0)
Scheme 2. Building blocks derived from benzolactones. Nucleophiles
used and literature references are listed under each product.
Phth=phthaloyl.
K2HPO4
(3.0)
9[d]
115
26
[a] Unless otherwise noted, the reaction was carried out on a 0.5 mmol
scale in 2.0 mL of 1,2-dichloroethane. [b] Yield of isolated product.
[c] 10 mol% PdCl2. [d] n-Pentyl chloride (2.0 mL) was used instead of 1,2-
dichloroethane.
substitution on the arene resulted in a significant decrease in
the yields. In most cases the SN2 reaction was predominant
because of the increase in nucleophilicity of the carboxylate
or an increase in the acidity of the parent carboxylic acid. We
were pleased to find that careful selection of the base restored
reactivity with a wider range of benzoic acids. For instance,
alkylation of benzoic acids proceeded to a noticeable extent
when various carbonates were used (Table 2, entries 4–8).
The alkylation of electron-deficient arenes afforded syntheti-
cally useful yields when KHCO3 (entry 7) or Na2CO3 (entry 8,
Table 2) was used. Of particular mechanistic importance, it
was found that alkylation with 1-chloropentane was feasible,
Scheme 3. Preliminary mechanistic studies.
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Table 3: Alkylation with dibromomethane.[a]
nucleophilic substitution occurs
first, followed by C–H activation
initiated by oxidative addition to
the intramolecular halide.[8] This
finding combined with data from
kinetic isotope effect studies also do
not support a Friedel–Crafts-type
reaction mediated by the PdII cata-
lyst or by trace quantities of HCl
Entry Substrate
Product
Yield%[d]
Entry Substrate
Product
Yield%[d]
1[b]
81
9[c]
62
generated
(Scheme 3).
Finally,
from
PdII
salts
intermediate
6,
2[b,e]
92 83[f] 68 g] 80 h] 10[b]
90
71
obtained by ortho C–H insertion
with o-toluic acid,[15] was used to
test the reactivity of such arylpalla-
dium species with alkyl halides. We
found that treatment of 6 with
dibromomethane afforded the
anticipated lactone as the major
product [Eq. (1)].
Although the oxidation of the
arylpalladium(II) intermediate by
MeI to PdIV was previously pro-
posed (intermediate 8),[14] in light of
previous discoveries that arylpalla-
dium species react with electro-
philes such as aldehydes and
ketones,[18] direct s-bond metathe-
sis[8] between the aryl–Pd bond and
the alkyl halide cannot be ruled out
(intermediate 9) [Eq. (2)]. In both
cases, Pd–halide species are formed.
Although alkylation using 10 mol%
PdCl2 and PdBr2 gave the desired
product in yields of 34% and 68%,
respectively, the formation of palla-
dium benzoate in situ could still be
responsible for the catalytic C–H
activation reactivity.
3[b]
62
81
11[b]
4[c]
12[c]
47
5[c]
6[c]
7[c]
75
59
81
13[c]
55
87
7
14[b]
8[c]
72
15[b]
68
In summary, we have developed
a PdII-catalyzed alkylation of aryl
À
C H bonds with alkyl chlorides
[a] Unless otherwise noted, the reaction was carried out on a 0.5 mmol scale in 2.0 mL of
dibromomethane. [b] 3.0 equiv K2HPO4, 1408C. [c] 2.5 equiv KHCO3, 1408C. [d] Yield of isolated
product. [e] 1158C. [f] Dichloromethane (2.0 mL) was used instead of dibromomethane. [g] 10 mol%
PdBr2. [h] 5 mol% Pd(OAc)2.
without using Ag+ salts as the
iodide scavengers. This reaction
provides a new synthetic method
for benzolactones.
Received: April 28, 2009
Published online: July 9, 2009
Keywords: alkylation · benzoic acid · benzolactones ·
.
À
C H activation
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À
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