Regioselective C?H Alkylation via Carboxylate-Directed Hydroarylation in Water

Article abstract of DOI:10.1002/chem.201800757

In the presence of catalytic [RuCl₂(p-cym)]₂ and using Li₃PO₄ as the base, benzoic acids react with olefins in water to afford the corresponding 2-alkylbenzoic acids in moderate to excellent yields. This C?H alkylation process is generally applicable to diversely substituted electron-rich and electron-deficient benzoic acids, along with α,β-unsaturated olefins including unprotected acrylic acid. The widely available carboxylate directing group can be removed or utilized for further derivatization. Mechanistic investigations revealed that the transformation proceeds via a ruthenacycle intermediate.

Full text of DOI:10.1002/chem.201800757

A Journal of
Accepted Article
Title: Regioselective C-H alkylation via carboxylate-directed
hydroarylation in Water
Authors: Guodong Zhang, Fan Jia, and Lukas J Goossen
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To be cited as: Chem. Eur. J. 10.1002/chem.201800757
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Chemistry - A European Journal
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COMMUNICATION
Regioselective C–H Alkylation via Carboxylate-Directed
Hydroarylation in Water
[a]
[a]
[a]
Guodong Zhang, Fan Jia, and Lukas J. Gooßen*
Dedication ((optional))
Abstract: In the presence of catalytic [Ru(p-cym)Cl
2 2
] and using
Established strategies for C-H hydroarylation of arenes
Li PO as the base, benzoic acids react with olefins in water to afford
3
4
the corresponding 2-alkylbenzoic acids in moderate to excellent yields.
This C–H alkylation process is generally applicable to diversely
substituted electron-rich and electron-deficient benzoic acids, along
with -unsaturated olefins including unprotected acrylic acid. The
widely available carboxylate directing group can be removed
tracelessly or utilized for further derivatization. Mechanistic
investigations revealed that the transformation proceeds via a
ruthenacycle intermediate.
cat. [M]
(
a)
organic solvent
DG = ketones, pyridines, amides, and imines
This work
Ru
H O
(b)
2
The aryl−alkyl motif is an important substructure in functional
materials,[
1 1]
natural products,
[2 2 ]
and pharmaceuticals.
[ 3 3]
Strategies for building such structures stand at the forefront of
modern organic synthesis.[ 4 ] Established methods to access
alkylarenes involve organometallic reagents[ 5 ] or pre-formed
alkylating agents.[6]
1
3
[Ru]L
H+
H+
Modern reaction development is aiming at the development of
catalytic C–H alkylations, ideally based on non-prefunctionalized
substrates and without stoichiometric organometallic regents.
Among them, directed hydroarylations of alkenes are particularly
advantageous due to their ideal atom-economy. In 1993, Murai
and co-workers[7] laid the foundation for this area with a Ru-
catalyzed C–H hydroarylation of olefins with aromatic ketones.
Similar reactions developed since all rely on comparably strong
directing groups in combination with Rh, Ir, Ru, Re, Co, Ni, Fe, or
other metal catalysts to achieve regioselectivity. These groups,
III
I
2
II
Scheme 1. Directed hydroarylations of functionalized (hetero)arenes.
[
8 ]
pyridines,[ 9 ] amides,[ 10 ] imines,[ 11 ] and
including ketones,
others,[ need to be installed in additional reaction steps and are
not easily removed from functionalized substrates (Scheme 1a).
Usually, organic solvents are used, but there are a few examples
of C-H functionalizations that proceed efficiently in water.[13]
In comparison, carboxylates have many advantages as
directing groups such as their wide availability, low cost, low
toxicity and broad range of follow-up reactions.[14] Their power as
directing groups in ortho-C–H functionalizations has been
12]
Hitherto, ortho-alkylations of benzoic acids remain rare, and
alkyl sources are so far limited to dihalogenoalkanes, epoxides,
alkyl trifluoroborates, or trimethylaluminium.[
15, 22]
Considering that
olefins are generally cheaper and more readily available than
other alkylating agents, the alkylation of benzoic acids with olefins
attracts increasing attention. However, undesired β-H elimination
of the alkylM species that is formed by migratory insertion of the
olefin into the CM bond, results predominately in the alkenylation
For -unsaturated carbonyl compounds, β-H
elimination seems less predominant, which has been attributed to
[
15]
Daugulis,[16] Larrosa,
[17]
[18]
documented by Yu,
Ackermann,
[ 23 ]
products.
Su,[19] ourselves,[20] and other groups.[21] The greatest hurdle to
the development of new C–H functionalization reactions using this
directing group is their intrinsically weak coordinating ability.
the formation of a stable ruthenium-oxa--allyl intermediate that
preferentially undergoes protonolysis.[
8a, 9a,b]
In contrast to the
carboxylate directed C-H hydroarylations of maleimides by
Baidya and Ackermann, no extrusion of carbon dioxide is
observed.[
24]
[
a]
G. Zhang, F. Jia, Prof. Dr. L. J. Gooßen
Evonic Chair of Organic Chemistry
Ruhr-Universität Bochum
Universitätsstr. 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
Based on these findings, we envisioned that ortho-alkylation
of benzoic acids (1) with ,-unsaturated olefins (2) would be
possible via a carboxylate-directed ortho-hydroarylation, leading
to 2-alkylbenzoic acids (3, Scheme 1b). The proposed
mechanism involves a ruthenacycle intermediate I, which would
coordinate to the olefin (intermediate II). 1,4-Conjugate addition
of the arylruthenium species to the double bond should then yield
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
10.1002/chem.201800757
COMMUNICATION
the ruthenium-oxa--allyl species III. Protonation of III would
release the alkylarene 3 and regenerate the ruthenium catalyst,
closing the catalytic cycle.
Using 2-toluic acid (1a) and methyl vinyl ketone (2a) as the
model reaction, we started our investigations with the catalyst
system previously developed for our Ru-catalyzed alkyne
hydroarylation (Table 1, see SI for details).[20c]
that the use of 1.0 equiv. of Li
3
PO
4
increased the yield to 85%
(entries 7-11). The product was obtained quantitatively when
using a slight excess of 2a (entries 12 and 13). In an air
atmosphere, the oxidative Heck-type product became
predominant (entry 14). Unprotected acrylic acid, which to our
knowledge has never before been utilized in C–H alkylations, also
gave a good product yield (entry 15). This could further be
improved by switching the base to CsF (0.5 equiv.) and increasing
the catalyst loading to 7.5 mol% (entries 16-18).
Table 1. Optimization of the ortho-alkylation reactions.[a]
Under optimized conditions, the directing ability of the
carboxylate was found to be superior to other typical directing
groups, such as ester, ketone, methylene carboxylate, amide,
acetamide, and even the strongly coordinating pyridine and
Daugulis amide groups, all inefficient for this transformation
(Scheme 2).
Cat. Ru, Base
Solvent
110 °C, 12 h
1a
2
3
Yield
(
Entry
Catalyst
R
Base (equiv.)
Solvent
%)[
b]
1
2
3
4
5
6
7
8
9
Ru(acac)
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OH
OH
OH
OH
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
(0.3)
(0.3)
(0.3)
(0.3)
(0.3)
(0.3)
tAmylOH/H
tAmylOH/H
2
2
2
O (9/1)
O (9/1)
O (9/1)
24
21
79
50
74
78
69
76
75
81
85
92
98
14
47
54
58
88
N. D.
N. D.
N. D.
N. D.
Ru(COD)Cl
2
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
(p-cym)]
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
tAmylOH/H
tAmylOH
N. D.
N. D.
trace
N. D.
toluene
Scheme 2. Comparison to alternative directing groups for ortho-alkylation.
Reaction conditions: 1’ (0.5 mmol), 2a (1.4 equiv.), [RuCl (p-cym)] (2 mol%),
Li PO (1.0 equiv.), H O (2 mL), 110 °C, 12 h, Ar atmosphere. N.D. = not
detected.
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
3
4
2
GuanCO
Na CO (0.3)
PO
3
(0.3)
2
3
The scope of the reaction was evaluated using the coupling
of a variety of aromatic and heteroaromatic carboxylic acids with
methyl vinyl ketone 2a (Scheme 3). Benzoic acids containing
electron-donating or -withdrawing groups in their ortho or meta
positions afforded the desired products in good to excellent yields
K
3
4
(0.3)
(0.3)
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
1
1
1
1
1
1
1
1
1
0
Li
Li
Li
Li
Li
Li
3
PO
3
PO
3
PO
3
PO
3
PO
3
PO
4
4
4
4
4
4
1
(
3aa-3oa).
For
meta-substituted
benzoic
acids,
the
2[c]
regioselectivity was high in favor of alkylation at the less hindered
ortho-position (3ka-3oa). The tolerance of acetamido,
methoxycarbonyl, and acetyl groups opens up opportunities for
further functionalization, because these are powerful directing
groups in combination with other metals.[ 25 ] Polysubstituted
benzoic acids and naphthylcarboxylic acids were also suitable
3[d]
4[e]
5[d,f]
6[d,f]
7[d,f]
8[d,g]
(
3pa-3va). Unsubstituted benzoic acid yielded mono- and di-
CsF (1.0)
CsF (0.5)
CsF (0.5)
alkylated products in close to 1:1 ratio (3wa and 3wa'). This
alkylation was also compatible with heteroaromatic carboxylic
acids, such as 2-thiophenecarboxylic acid and 1-methylindole-2-
carboxylic acid (3xa and 3ya). For the indole 1y, both 3ya and its
protodecarboxylated analog 3ya’ could be obtained depending on
the reaction temperature.
[
1
a] 1a (0.5 mmol), 2 (1.0 equiv.), [Ru] (4 mol%), base, degassed solvent (2 mL),
10 °C, 12 h, Ar atmosphere. [b] GC analysis as methyl esters using n-tetradecane
as the internal standard. [c] 2 (1.2 equiv.). [d] 2 (1.4 equiv.). [e] aerobic conditions.
f] [RuCl (p-cym)] (5 mol%), 24 h. [g] [RuCl (p-cym)] (7.5 mol%), 24 h. acac = further examined in combination with 2-methylbenzoic acid (1a).
The scope of -unsaturated carbonyl compounds was
[
2
2
2
2
3
acetoacetate; COD = 1,5-cyclooctadiene; p-cym = para-cymene; GuanCO =
Long-chain alkyl vinyl ketones displayed high reactivity (3ab and
ac). The hydroarylation of aryl vinyl ketones proceeded well
3ad-3ag), whereas 3- or 4-substituted vinyl ketones and cyclic
enones gave somewhat inferior yields (3ah-3aj). The
hydroarylation of -unsaturated amides was also efficient (3ak-
guanidine carbonate.
3
(
To our delight, the desired alkylation product was directly
detected (entry 1), and a switch to [RuCl (p-cym)] led to 79%
yield (entries 2-3). Several solvents were examined, among which
pure water gave an equivalent result to the tert-amyl alcohol/water
mixture used originally (entries 4-6). A screening of bases showed
2
2
3
al).
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Chemistry - A European Journal
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COMMUNICATION
The reaction is also applicable to a range of substituted
benzoates in combination with acrylic acid (Scheme 4). Both
electron-rich and -deficient substituents were tolerated.
source [Eq. (1)], and that protodecarboxylation was possible in a
one-pot process [Eq. (2)].
[
RuCl (p-cym)]2 (2 mol%)
2
Li PO4 (1.0 equiv.)
3
(1)
H O/2-propanol = 1/5
2
[
RuCl (p-cym)] , Li PO
2 2 3
4
110 °C, Ar, 24 h
R= Me, 4aa 72%
R= F, 4ea 47%
H O, 110 °C, Ar, 12 h
2
1
2
3
1
R1 = NHAc, 3ka 70%
1
2a
R
= Me,
= OMe, 3ba 90%
= OCF , 3ca 85%
3aa 92%
1
R1 = CO Me, 3la 69%
R
1) standard condition
2
1
1
= COMe, 3ma 57%[b]
(2)
R
R
3
2) Cu O, 1,10-Phen
2
1
R1 = CF ,
3na 83%
R
= Ph,
= F,
= Cl,
= Br,
= I,
3da 92%
3ea 76%
3fa 75%
3ga 71%
3ha 55%
3
NMP, 190 °C
1
R1 = Me,
R
3oa 81%
R = F, 5ea 66%
1
R
The reaction mechanism was investigated by deuteration
experiments and kinetic studies. In an H/D exchange experiment
in D O [Eq. (3)], complete deuteration in the ortho position
indicated reversible C–H bond cleavage. A deuterium-labelling
experiment revealed deuterium incorporation mostly in the α-
methylene position of the carbonyl group [Eq. (4)], which is
consistent with the proposed mechanism. High kinetic isotope
1
R
1
R
1
R
= CF3, 3ia 77%
2
R1 = NO2, 3ja 72%[a]
3pa 61%
3qa 90%
3ra 81%
3sa 51%
3ta 81%
3ua 79%
H D
effects (k /k = 3.5 and 3.8, respectively) were observed in
competition and parallel experiments [Eq. (5)], confirming that
C−H bond cleavage is rate-determining. The successful
conversion of preformed ortho-ruthenated toluate 6a supports the
intermediacy of a ruthenacycle [Eq. (6)].
mono, 3wa 31%
di, 3wa' 28%
3va 61%
3xa 66%[b]
3ya 91% 80 °C
>
99% D
[
RuCl (p-cym)]2 (2 mol%)
2
(
)4
Li PO4 (1.0 equiv.)
3
(3)
D O, 110 °C, Ar, 12 h
3ya' 66% 130 °C
3za 62% 80 °C
3ab 70%
3ac 61%
2
1a
(D)-1aa
R' = H,
R' = F,
R' = Cl,
3ad 65%
3ae 80%
3af 66%
13% D
28% D
[
RuCl (p-cym)]2 (2 mol%)
2
R' = OMe, 3ag 53%
3ah 51%
3ai 40% 130 °C[b]
3
Li PO4 (1.0 equiv.)
(4)
D O, 110 °C, Ar, 10 min
2
1a
2a
(D)-3aa
58% D
aj 52%[b,c]
3ak 66%[b,d]
3al 70%[b,d]
3
Scheme 3. Substrate scope for benzoic acids combined with -unsaturated
ketones / amides. Reaction conditions: 1 (0.5 mmol), 2 (1.4 equiv.), [RuCl (p-
cym)] (2 mol%), Li PO (1.0 equiv.), H O (2 mL), 110 °C, 12 h, Ar atmosphere;
isolated yields of the corresponding methyl esters after esterification. [a] Li PO
1a
standard condition
3aa
(5)
2
5
min
2
3
4
2
2a
3
4
(0.5 equiv.). [b] [RuCl
2 2
(p-cym)] (5 mol%). [c] 2 (1.0 equiv.). [d] 24 h.
intermolecular competition: kH/kD = 3.5
parallel experiments: kH/kD = 3.8
(
D )-3aa
6
(
D )-1a
7
[
RuCl (p-cym)] , CsF
2 2
(6)
H O, 110 °C, Ar, 24 h
H 2O, 110 °C
2
2a
1
2m
3
Ar, 12 h
3aa
6a
62% GC yield
R = Me, 3am 83%(78%)
R = CO Me, 3lm 61%
2
R = OCF , 3cm 87%
3
R = CF3,
3nm 84%
In summary, the carboxylate-directed hydroarylation of olefins
in the presence of [RuCl (p-cym)] provides a convenient and
R = Ph,
R = F,
3dm 90%
3em 75%
2
2
sustainable access to various 2-alkylbenzoic acids. This
transformation proceeds smoothly in water. It tolerates various
functional groups, including even standard directing groups,
which opens up opportunities for further functionalization. The
catalyst system is compatible with unprotected acrylic acid.
Potential follow-up reactions, including in situ-reduction of the
side-chain carbonyl group and ipso-substitution of the carboxylate,
further expand the synthetic potential of this transformation.
Scheme 4. Substrate scope for benzoic acids combined with acrylic acid.
Reaction conditions: 1 (0.5 mmol), 2m (1.4 equiv.), [RuCl (p-cymene)] (7.5
mol%), CsF (0.5 equiv.), H O (2 mL), 110 °C, 24 h, Ar atmosphere; isolated
2
2
2
yields of the corresponding methyl esters, and of the free acid in parentheses.
Further investigations revealed that the ketone could be
reduced in situ to hydroxyl group using isopropanol as the hydride
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Chemistry - A European Journal
10.1002/chem.201800757
COMMUNICATION
gradient) yielding the hydroarylation product 3 in the form of its methyl
ester.
Experimental Section
2 2
An oven-dried 20 mL vessel was charged with [RuCl (p-cym)] (6.40 mg,
0.01 mmol), lithium phosphate (57.9 mg, 0.50 mmol), and 1 (0.50 mmol).
2
Under exclusion of air, H O (2 mL) and 2 (0.70 mmol) were added via
Acknowledgements
syringe. The resulting mixture was stirred at 110 °C for 12 h. After this time
period, MeCN (3 mL), K CO (138 mg, 1.00 mmol), and MeI (358 mg, 2.50
2
3
We thank Umicore for the donation of chemicals, the CSC
mmol) were added and the mixture was stirred at 60 °C for 2.5 h. Brine (20
mL) was added and the resulting mixture was extracted with ethyl acetate
(
fellowships to G.Z. and F.J.) and the DFG (EXC 1069 “RESOLV”
(
3×20 mL). The combined organic layers were dried over MgSO
and the volatiles were removed under reduced pressure. The residue was
purified by column chromatography (SiO , ethyl acetate/cyclohexane
4
, filtered,
and SFB/TRR 88 “3MET”) for financial support.
2
Keywords: ruthenium • C–H alkylation • benzoic acids • olefins •
hydroarylation
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Guodong Zhang, Fan Jia, and Lukas J.
Gooßen*
Cat. Ru
Base
Cu
H O
- CO2
2
Page No. – Page No.
FG = NHAc, COMe, CO Me, NO , I, CF , etc.
43 examples; 40-92% yields
Regioselective C–H Alkylation of
Arenecarboxylates with Olefins in
Water
2
2
3
R , R = H or alkyl; R3 = alkyl, aryl, NR R or OH
1
2
4 5
Water serves as the solvent in a regioselective ortho-C–H alkylation of
arenecarboxylates with -unsaturated olefins catalyzed by ruthenium. A wide
range of arene substrates are converted efficiently, and the weakly basic medium
allows using even unprotected acrylic acid as an alkyl source.
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