Palladium-Catalyzed ortho-C-H Methylation of Benzoic Acids

Article abstract of DOI:10.1021/acs.joc.9b01204

A palladium-catalyzed methylation of C-H bonds of benzoic acids with di-tert-butyl peroxide as the methylating reagent under an external oxidant and ligand-free conditions has been achieved. The reaction is found to be directed by a weakly coordinating carboxyl group, offering a facile route for the synthesis of highly functionalized ortho-methyl benzoic acids.

Full text of DOI:10.1021/acs.joc.9b01204

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Note
Palladium-Catalyzed Ortho- C-H Methylation of Benzoic Acids
Weiwei Lv, Si Wen, Jing Liu, and Guolin Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01204 • Publication Date (Web): 27 Jun 2019
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Palladium-Catalyzed Ortho- C−H Methylation of Benzoic Acids
Weiwei Lv, Si Wen, Jing Liu, Guolin Cheng*
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College of Materials Science & Engineering, Huaqiao University, Xiamen 361021, China
Pd(OAc)2 (10 mol %)
KOAc (2 equiv)
HFIP, air, 80 °C, 24 h
R
R
CO2H
CO2H
Me
+
tBu tBu
O O
oxidant and ligand-free
low-cost methylating reagent
carboxyl group as directing group
18 examples, up to 79% yield
ABSTRACT: A palladium-catalyzed methylation of C–H bonds of benzoic acids with di-tert-butyl peroxide as the methylating
reagent under external oxidant and ligand-free conditions has been achieved. The reaction is found to be directed by a weakly
coordinating carboxyl group, offering a facile route for the synthesis of highly functionalized ortho-methyl benzoic acids.
The methyl group as the smallest alkyl group plays a very
important role in biologically active molecules.1 The introduction
of a methyl group increases the hydrophobic character of organic
compounds, thus can modulate the biological activity and physical
property of a pharmacologically active molecule, which is the so-
called “magic methyl” effect. For example, the replacement of
C−H by C−Me can significantly improve the IC50 value of a drug
candidate.2
Initially, we began the studies with 3-methylbenzoic acid 1a
and DTBP 2a to explore the reaction conditions. After
systematic screening of the reaction conditions, the optimal
conditions were achieved to be: Pd(OAc)2 (10 mol %), KOAc
(2 equiv) in HFIP under air at 80 °C to yield the desired
Scheme 1. Palladium-Catalyzed Ortho- C−H Methylation
of Benzoic Acid Derivatives.
The transition metal-catalyzed C−H methylation reactions
are the most straightforward methods to installation of a
methyl group.3 Recently, a variety of monodentate and
bidentatethe directing groups were developed to achieve
ortho-methylation of benzamide derivatives using Mn,4 Fe,5
Co,6 Ni,7 and Pd8 as catalysts (Scheme 1a). However, the
requirement of installation and removal of an external
directing group has hampered the use of simple benzoic acids,
thus reducing their synthetic utility.9 The examples of
methylation of benzoic acids are extremely limited to only two
reports until date. The Pd-catalyzed methylation of simple
benzoic acids pioneered by Yu use MeB(OH)2 and Ag2CO3 as
the methylating reagent and oxidant, respectively (Scheme
1b).10 In 2016, Nakamura described a tridentate phosphine
a) Transition metal-catalyzed ortho-methylation of benzamide derivatives
O
O
Me
Me
O
O
Me
Me
Me
N
N
N
N
NBn
N
H
H
H
H
N
N
N
Me
Me
Me
Me
Co/AlMe3
Ni/(PhMe3N)I
Co/dicumyl peroxide
Fe/MeMgBr
Mn/MeMgBr
b) Pd-catalyzed ortho-methylation of benzoic acids
Pd(OAc)2 (10 mol %)
Me
Me
BQ (0.5 equiv)
Ag2CO3 (1 equiv)
CO2H
Me
CO2H
MeB(OH)2
3 equiv
+
K2HPO4 1.5 equiv
tBuOH, 120 °C, 3 h
50%
c) Fe-catalyzed ortho-methylation of benzoic acids
NMe2
ligand
4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-
AlMe3 (2 equiv)
Fe(acac)3 (10 mol %)
Ligand (10 mol %)
Ph
CO2H
Ph
CO2H
Me
N,N-dimethylaniline enabled Fe-catalyzed methylation of
simple benzoic acids under oxidative conditions (Scheme
1c).11 Despite the significant progress offered by the
aforementioned methods, there are still certain limitations,
including the requirement of external oxidant and
sophisticated ligand. In 2008, li and coworkers reported the
first example of palladium-catalyzed ortho-C−H methylation
of 2-phenyl pyridines with dicumyl peroxide as methylating
reagent (Scheme 1d).12a Inspired by Li’s work, herein, we
reported a Pd-catalyzed ortho-methylation of benzoic acids
using commercial available and low-cost di-tert-butyl
peroxide (DTBP) as both the methylating reagent and
hydrogen acceptor under external oxidant and ligand-free
conditions (Scheme 1e).13
PPh2
P
2,3-DCB (300 mol %)
THF/DME/toluene
70 °C, 24 h
1a
PPh2
73%
Ligand
d) Pd-catalyzed ortho-methylation of 2-phenyl pyridines with DTBP as methylating reagent
N
N
Pd
oxidant and ligand-free
tBu
O O
tBu
+
Me
Me
72% (mono:di = 3:1)
e) This work: Pd-catalyzed ortho-methylation of benzoic acids with DTBP as methylating reagent
R
R
CO2H
CO2H
Me
Pd
tBu
O O
tBu
+
oxidant and ligand-free
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The Journal of Organic Chemistry
methylation product 3a in 79% yield (Table 1, entry 1, see SI reaction of 1a and 2a was complete within 24 h, generating the
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for details). Under other conditions, no desired product or only
low yields were observed. No desired product 3a was formed
in the absence of either the base or Pd catalyst (entries 2, 3).
Replacing KOAc with NaOAc decreased the yield to 15%
(entry 4). The use of Ac-Gly-OH as ligand afforded a lower
yield (entry 5). Interestingly, other solvents, such as tAmylOH
and toluene, inhibited the reaction completely (entries 6, 7).
Dicumyl peroxide 2b also gave the methylation product in 23%
yield. (entry 8). However, no reaction was observed when tert-
butyl hydroperoxide 2c instead of 2a was used (entry 9). Only
trace of 3a was detected when tert-butyl peroxybenzoate 2d
was used (entry 10).
desired
Scheme 2. Scope of Benzoic acidsa
Pd(OAc)2 (10mol%)
KOAc (2 equiv)
HFIP, air, 80 °C, 24 h
R
R
CO2H
CO2H
Me
tBu
O O
tBu
+
3a s
1a-r
2a,
-
2.0 equiv
Me
Me
9
I
CO2H
Me
CO2H
Me
CO2H
F3C
CO2H
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Me
30%
Me
, 48%
Me
Me
, 54%
Me
3a
, 79%
3b
3c
3d,
Table 1. Role of Select Parametersa
Me
Me
Me
CO2H
Me
CO2H
CO2H
CO2H
Me
Pd(OAc)2 (10mol%)
KOAc (2 equiv)
HFIP, air, 80 °C, 24 h
Cl
Me
Br
Me
Me
CO2H
Me
CO2H
Me
F
+
tBu
O
O
tBu
3g
3h
, 45%
CO2H
, 47%
, 32%
3f
, 67%
3e
, 75%
1a
3a
2a,
2 equiv
MeO
Me
Me
Br
CO2H
Me
Me
F
CO2H
Me
MeO
MeO
CO2H
Me
O
tBu
O
O
Me
Ph
O
O
Ph
tBu
O OH
Ph
2d
3i
3j
2c
, 33%
, 60%
3k
3l
, 58%
2b
CO2H
Cl
CO2H
Me
Br
CO2H
Cl
Cl
CO2H
Me
yield (%)b
Me
entry
deviation from standard conditions
Me
Me
Me
, 46%
1
2
3
4
5
6
7
8
9
10
none
79
0
2-Me : 8-Me = 10:1
3p 3p`
3n
3o
, 28%
/
, 40%
Me
3m
3q
, 52%
no KOAc
Me
CO2H
Me
CO2H
Me
CO2H
Me
CO2H
no Pd(OAc)2
0
+
+
F
F
NaOAc instead of KOAc
Ac-Gly-OH (10 mol %) as ligand
tAmylOH instead of HFIP
toluene instead of HFIP
2b instead of 2a
15
63
0
F3C
F3C
Me
3e
3s
3r
77%, mono/di = 1:1.2
56%, mono/di = 1:1.2
0
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2
(10 mol%), KOAc (0.6 mmol) in HFIP (0.8 mL) at 80 °C under
air atmosphere for 24 h.
23
0
2c instead of 2a
products (3a) in 54% yield (Scheme 3a). The reaction of 1j
and 2a was carried out under standard conditions for 24 h,
giving the desired products (3a) in 34% yield, and 1j could be
recovered in 60% yield (Scheme 3b).
2d instead of 2a
trace
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2
(10 mol%), KOAc (0.6 mmol) in HFIP (0.8 mL) at 80 °C under
air atmosphere for 24 h. bIsolated yields. HFIP = 1,1,1,3,3,3-
hexafluoro-2-propanol.
To gain insight into the mechanism of this reaction, a
radical trapping experiment was implemented. It was observed
that the addition of 2 equiv of 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) inhibited the reaction completely. This result
suggested that a radical process might be involved in this
transformation (Scheme 3c). The putative palladacycle A was
independently prepared9c and resubmitted to the reaction
conditions with or without 1 equiv KOAc. The desired product
3a was not detected, which indicated that it is unlikely for
palladacycle A to serve as an intermediate in this methylation
reaction (Scheme 3d). We also performed kinetic isotope
effects study. The competition reaction between benzoic acid
1t and deuterated benzoic acid 1t-d5 was managed in one-pot.
After reacting 24 h, a mixture of 3t and 3t-d4 was obtained in
23% total yield and 1.86:1 ratio. The observation of KIE effect
demonstrated that the C−H cleavage step is not obvious
participated in the rate-determining step (Scheme 3e).
Next, the generality of this Pd-catalyzed methylation
reaction was examined under the optimized reaction
conditions (Scheme 2). In all tested cases, the desired
methylation reaction proceeded smoothly. In general, the
reaction process can be extended to various meta-, ortho-,
para-, as well as disubstituted benzoic acids, thus giving the
corresponding methyl substituted benzoic acids (3a−s) in
28−79% yields. Various valuable functional groups were
tolerated, including trifluoromethyl, fluoro, chloro, bromo,
iodo, and methoxyl. For meta-substituted benzoic acids, the
C−H methylation occurred regioselectively at the sterically
less hindered position (3a, 3b, 3h−o). Importantly, 1-
naphthoic acid was found to be an applicable substrate,
providing the desired 2-methyl (3p) and 8-methyl (3p`)
products in 40% combined yield. The reactions of para-
substituted benzoic acids resulted in 1:1.2 mixtures of mono-
and dimethylated products (3q/3e; 3r/3s).
On the basis of these results and the literature reports,12 we
proposed a catalytic cycle in Scheme 4. Initially, PdII complex
B is formed through coordination of benzoic acid 1a with
Pd(OAc)2. Then B is oxidized by tert-butoxy radical,
To demonstrate the utility of this chemistry, the C−H
methylation reactions were conducted on a gram-scale. The
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generated from the peroxide 2a, through a single-electron
approach for the synthesis of methyl substituted benzoic acids
with efficient. This approach is compatible with a wide
spectrum of readily available functionalized benzoic acids.
transfer (SET) process giving the PdIV species C. Next, β -
1
2
methyl
3
Scheme 3. Gram-Scale Reaction and Control Experiments
4
5
6
7
8
9
a) 10 mmol scale reaction
Pd(OAc)2 (10 mol %)
KOAc (2 equiv)
EXPERIMENTAL SECTION
General Information. All the solvents were used without
further purification. The other commercial chemicals were
used without further purification. All reactions were
performed under an inert atmosphere of nitrogen in flame-
dried glassware, unless otherwise stated. Analytical thin layer
chromatography was performed on 0.25 mm silica gel 60-
F254. Visualization was carried out with UV light and Vogel’s
permanganate. Preparative TLC was performed on 1.0 mm
silica gel. 1H NMR spectra were recorded on Bruker DRX-500
instrument (500 MHz). 13C NMR spectra were recorded on
Bruker DRX-500 instrument (126 MHz) were fully decoupled
by broad band proton decoupling. High-resolution mass
spectra (HRMS) were recorded on an Agilent 1290 Mass
spectrometer using ESI-TOF (electrospray ionization-time of
flight). NMR spectra were recorded in CDCl3. 1H NMR
spectra were referenced to residual CHCl3 at 7.26 ppm, and
13C NMR spectra were referenced to the central peak of CDCl3
at 77.0 ppm. Chemical shifts (δ) are reported in ppm, and
coupling constants (J) are in Hertz (Hz). Multiplicities are
reported using the following abbreviations: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet.
Me
CO2H
Me
CO2H
HFIP, air, 80 °C, 24 h
tBu
O O
tBu
+
Me
2a,
2 equiv
1a,
10 mmol, 1.36 g
3a
, 0.812 g, 54%
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b) 5 mmol scale reaction
Pd(OAc)2 (10 mol %)
KOAc (2 equiv)
HFIP, air, 80 °C, 24 h
Me
CO2H
Me
Br
CO2H
tBu
O O
tBu
+
Br
Me
2a,
2 equiv
1j,
5 mmol, 1.075 g
3j
, 0.391 g, 34%
c)
Pd(OAc)2 (10 mol %)
KOAc (2 equiv)
HFIP, air, 80 °C, 24 h
Me
CO2H
Me
CO2H
Me
+
tBu tBu
O O
TEMPO (2 equiv)
2a,
2 equiv
1a,
5 mmol
3a
, 0%
d)
OK
Me
Me
CO2H
Me
HFIP, air, 80 °C, 24 h
O
tBu
O
O
tBu
+
with or without
KOAc (1 equivt)
Pd
AcO
2a,
2 equiv
2
3a
Procedure for Preparation of 3.
, 0%
A
A dried 10 mL Schlenk tube was charged with 1 (40.8 mg, 0.3
mmol), 2a (87.6 mg, 0.6 mmol), Pd(OAc)2 (6.8 mg, 10 mol %),
KOAc (58.8 mg, 0.6 mmol) in HFIP (0.8 mL) under air. This
mixture was heated to 80 °C in a heating plate for 24 h. Upon
completion, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and filtered through a
pad of celite. The filtrate was concentrated under vacuum, and
the resulting residue was purified by preparative thin layer
chromatography (PTLC) with ethyl acetate: hexane:AcOH
(1:4:0.03) to give the corresponding products 3.
e)
Pd(OAc)2 (10 mol %)
KOAc (2 equiv)
D
H/D
H
D
D
CO2H
D/H
D/H
CO2H
Me
H
H
CO2H
HFIP, air, 80 °C, 24 h
+
DTBP (2 equiv)
D
H
D
H/D
H
3t 3t
23% total yield
/
-d4 = 1.86,
1t
1t
-d5
1t 1t-
/
d5 = 1 : 1
elimination of C gives PdIV species D, followed by ortho-
C−H activation to deliver intermediate E. Finally, reductive
elimination of E giving the methylation product 3a and
regenerating Pd(OAc)2. However, the pd0/PdII catalytic cycle
could not be ruled out.12a
2,5-dimethylbenzoic acid (3a)14 (35.5 mg, 79%) as white
1
solid. H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.32 – 7.27
(m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 2.65 (s, 3H), 2.40 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 173.7, 138.2, 135.4, 133.7,
132.0, 131.8, 128.1, 21.6, 20.7.
Scheme 4. Proposed Catalytic Cycle
Me
CO2H
Me
CO2H
+
KOAc
2-methyl-5-(trifluoromethyl)benzoic acid (3b) (33 mg, 54%)
Me
1a
3a
HOAc
KO
1
Pd(OAc)2
as white solid. H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H),
HOAc
OK
7.70 (dd, J = 8.1, 1.9 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 2.73 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.8, 145.4, 132.6,
129.3 (q, J = 3.5 Hz), 128.9 (q, J = 28.1 Hz), 128.7 (q, J = 5.1
Hz), 128.6 (q, J = 4.2 Hz), 123.7 (q, J = 272.0 Hz), 22.1;
OAc
PdII OAc
Me
Me
OAc
O
O
PdIV
E
L
OAc
Me
B
L
-
HRMS (ESI-TOF) m/z: calcd for C9H6F3O2 : 203.0325 (M -
tBuOH
Me
O
tBu
80 o
H)-, found: 203.0320.
C
2,6-dimethylbenzoic acid (3c)10 (21.6 mg, 48%) as white
solid. 1H NMR (500 MHz, CDCl3) δ 7.28 – 7.23 (m, 1H), 7.10
(d, J = 7.6 Hz, 2H), 2.48 (s, 6H); 13C{1H} NMR (126 MHz,
CDCl3) δ 175.7, 135.6, 132.4, 129.9, 127.9, 20.1.
3-iodo-2,6-dimethylbenzoic acid (3d)15 (24.8 mg, 30%) as
OK
O
tBu
O
O
tBu
OK
OAc
OAc
OAc
PdIV
OAc
Me
2
PdIV
Me
O
OtBu
O
L
OtBu
D
L
OtBu
C
1
white solid. H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 8.1,
1.4 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 2.49 (s, 3H), 2.34 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.3, 140.2, 137.1,
134.9, 134.0, 129.4, 98.6, 26.0, 19.5.
CONCLUSION
In conclusion, we have developed a palladium-catalyzed
C−H ortho-methylation reaction of benzoic acids with DTBP
as the methylating reagent. This methodology provides a utility
4-fluoro-2,6-dimethylbenzoic acid (3e) (37.8 mg, 75%) as
white solid. 1H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 9.3 Hz,
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2H), 2.44 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.7,
163.0 (d, J = 249.6 Hz), 139.2 (d, J = 8.9 Hz), 128.2 (d, J =
2.9 Hz), 114.8 (d, J = 21.5 Hz), 20.5 (d, J = 1.5 Hz) ; HRMS
2-methyl-1-naphthoic acid (3p)14 and 8-methyl-1-naphthoic
1
acid (3p`)19 (24.8 mg, 40%) as white solid. H NMR (500
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 8.4, 2.0
Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.51 – 7.47 (m, 1H), 7.37 (d,
J = 8.4 Hz, 1H), 2.67 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 175.6, 173.4, 134.5, 134.4, 133.8, 132.4, 131.7,
130.3, 130.3, 130.0, 128.9, 128.7, 128.5, 128.1, 127.8, 127.7,
127.2, 127.2, 126.3, 125.5, 124.7, 123.9, 22.2, 20.6.
-
(ESI-TOF) m/z: calcd for C9H8FO2 : 167.0514 (M - H)-, found:
167.0510.
4-chloro-2,6-dimethylbenzoic acid (3f) (37 mg, 67%) as
1
white solid. H NMR (500 MHz, CDCl3) δ 7.08 (s, 2H), 2.42
(s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.1, 137.9,
135.6, 127.9, 127.8, 20.2; HRMS (ESI-TOF) m/z: calcd for
4-fluoro-2-methylbenzoic acid (3q)20 (12.8 mg, 25%) as
-
C9H8ClO2 : 183.0218 (M - H)-, found: 183.0218.
1
white solid. H NMR (500 MHz, CDCl3) δ 8.15 – 8.08 (m,
9
4-bromo-2,6-dimethylbenzoic acid (3g)16 (30.8 mg, 45%) as
1H), 7.02 – 6.93 (m, 2H), 2.67 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 171.9, 165.2 (d, J = 254.4 Hz), 145.1 (d, J =
9.2 Hz), 134.4 (d, J = 9.6 Hz), 124.3 (d, J = 2.9 Hz), 118.7 (d,
J = 21.4 Hz), 113.0 (d, J = 21.4 Hz), 22.4.
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1
white solid. H NMR (500 MHz, CDCl3) δ 7.25 (s, 2H), 2.41
(s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.9, 138.0,
131.1, 130.8, 124.1, 20.1.
2,4,5-trimethylbenzoic acid (3h)17 (23.1 mg, 47%) as white
solid. 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.04 (s, 1H),
2.59 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 173.3, 142.4, 138.8, 134.0, 133.3, 132.7,
125.5, 21.6, 19.8, 19.1.
4-fluoro-2,6-dimethylbenzoic acid (3e) (17.4 mg, 31%) as
white solid.
2-methyl-4-(trifluoromethyl)benzoic acid (3r)21 (23.8 mg,
1
35%) as white solid. H NMR (500 MHz, CDCl3) δ 8.17 (d, J
= 8.5 Hz, 1H), 7.60 – 7.51 (m, 2H), 2.72 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 172.3, 142.1, 134.3 (q, J = 32.5
Hz), 132.0, 131.5, 128.7 (q, J = 3.8 Hz), 123.5 (q, J = 272.8
Hz), 122.73 (q, J = 3.7 Hz), 22.04.
4-fluoro-2,5-dimethylbenzoic acid (3i) (16.6 mg, 33%) as
white solid. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.1 Hz,
1H), 6.91 (d, J = 10.4 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J = 1.7
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 172.2, 163.8 (d,
J = 253.4 Hz), 142.1 (d, J = 9.1 Hz), 135.5 (d, J = 7.1 Hz),
123.9 (d, J = 2.9 Hz), 122.4 (d, J = 17.6 Hz), 118.3 (d, J =
22.5 Hz), 21.9, 14.0 (d, J = 3.0 Hz); HRMS (ESI-TOF) m/z:
2,6-dimethyl-4-(trifluoromethyl)benzoic acid (3s)22 (29.9
mg, 42%) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.31 (s,
2H), 2.43 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.9,
153.6, 136.4 (q, J = 3.7 Hz ), 136.0, 131.5 (q, J = 32.0 Hz), 125.8
(q, J = 272.7 Hz), 124.5 (q, J = 3.8 Hz), 19.9.
-
calcd for C9H8FO2 : 167.0514 (M - H)-, found: 167.0515.
4-bromo-2,5-dimethylbenzoic acid (3j) (41 mg, 60%) as
Procedure for Preparation of A.
1
white solid. H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.14
3-Methylbenzoic acid 1a (68 mg, 0.5 mmol) was treated with
KOH (16 mg, 0.4 mmol) in water (0.5 mL) at room
temperature for 1 h. Then solvent was removed in a rotary
evaporator, and the white solid was washed with CH2Cl2 (1.0
mL × 3) and dried under vacuum at 100 °C to get potassium
m-toluate (50 mg, 57% yield). Palladium acetate (56 mg, 0.25
mmol) was added to a suspension of potassium m-toluate (43.5
mg, 0.25 mmol) in 1,4-dioxane (3.0 mL), then the mixture was
heated at reflux temperature in a heating plate for 2 h. The
reaction mixture was filtered, and the residue was washed with
CH2Cl2 (3 mL × 3) and dried under vacuum to get the
(s, 1H), 2.57 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 171.8, 143.4, 140.5, 135.3, 134.3, 127.2, 121.7, 22.9,
-
21.6; HRMS (ESI-TOF) m/z: calcd for C9H8BrO2 : 226.9713
(M - H)-, found: 226.9717.
5-methoxy-2,4-dimethylbenzoic acid (3k) (31.3 mg, 58%) as
1
white solid. H NMR (500 MHz, CDCl3) δ 7.52 (s, 1H), 7.03
(s, 1H), 3.86 (s, 3H), 2.56 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 173.2, 155.5, 134.3, 133.7, 132.7, 126.0,
112.3, 55.5, 21.2, 16.2; HRMS (ESI-TOF) m/z: calcd for
+
C9H12O3 : 180.0786 (M)+, found: 180.0784.
1
4,5-dimethoxy-2-methylbenzoic acid (3l)14 (18.8 mg, 32%)
palladacycle A (43.2 mg, 51% yield). H NMR (500 MHz,
1
DMSO – d6) δ 7.46 (d, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.88 (d,
J = 7.9 Hz, 1H), 2.21 (s, 3H), 1.76 (s, 3H); 13C{1H} NMR (126
MHz, DMSO – d6) δ 178.2, 175.9, 143.1, 143.0, 133.5, 131.5,
131.0, 129.5, 25.2, 20.9.
as white solid. H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H),
6.72 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 2.63 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 172.7, 152.6, 146.5, 136.4, 119.7,
114.2, 114.0, 56.0, 55.9, 22.1.
5-chloro-2,4-dimethylbenzoic acid (3m)18 (28.7 mg, 52%) as
Gram-Scale reaction experiment
1
white solid. H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.11
A dried 50 mL Schlenk tube was charged with 1j (1.075g, 5
mmol), 2a (1.46 mg, 10 mmol), Pd(OAc)2 (113 mg, 10 mol %),
KOAc (0.98 g, 10 mmol) in HFIP (15 mL) under air. This
mixture was heated to 80 °C in an oil bath for 24 h. Upon
completion, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and filtered through a
pad of celite. The filtrate was concentrated under vacuum, and
the resulting residue was purified by flash chromatography on
silica gel with ethyl acetate: hexane:AcOH (1:8:0.03) to give
the corresponding products 3j (0.387g, 34%) and 1j (0.644g,
60%).
(s, 1H), 2.56 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 172.1, 141.2, 139.5, 134.3, 131.8, 131.6, 127.6, 21.4,
20.1.
5-bromo-2,4-dimethylbenzoic acid (3n) (31.5 mg, 46%) as
1
white solid. H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.14
(s, 1H), 2.57 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 171.8, 143.4, 140.5, 135.3, 134.3, 127.2, 121.7, 22.9,
+
21.6; HRMS (ESI-TOF) m/z: calcd for C9H12O3 : 180.0786
(M)+, found: 180.0784.
4,5-dichloro-2-methylbenzoic acid (3o) (17.1 mg, 28%) as
1
One-pot competition experiment
white solid. H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.36
(s, 1H), 2.58 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
A dried 10 mL Schlenk tube was charged with Benzoic acid
1t (12.2 mg, 0.1 mmol), deuterated benzoic acid 1t-d5 (12.7
mg, 0.1 mmol), 2a (58.4 mg, 0.4 mmol), Pd(OAc)2 (4.5 mg,
10 mol %), KOAc (39.3 mg, 0.4 mmol) in HFIP (0.5 mL)
171.3, 141.0, 137.1, 133.5, 133.1, 130.0, 128.1, 21.4; HRMS
-
(ESI-TOF) m/z: calcd for C9H8BrO2 : 227.9713 (M - H)-,
found: 227.9714.
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The Journal of Organic Chemistry
Directed C–H Bond Activation. Eur. J. Org. Chem. 2017, 3041-3048. (f)
under air. This mixture was heated to 80 °C in a heating plate
for 24 h. Upon completion, the reaction mixture was cooled to
room temperature, diluted with ethyl acetate, and filtered
through a pad of celite. The filtrate was concentrated under
vacuum, and the resulting residue was purified by preparative
thin layer chromatography (PTLC) with ethyl acetate:
hexane:AcOH (1:4:0.03) to give a mixture of 3t and 3t-d4 in
23% combined yield. The ratio of 3t/3t-d4 was determined to
be 1.86 by the 1H NMR spectrum of the mixture.
Wang, X.; Niu, S.; Xu, L.; Zhang, C.; Meng, L.; Zhang, X.; Ma, D. Pd-
Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for
Synthesis of (S)-N-Boc-2,6-dimethyltyrosine and Its Analogues. Org.
Lett. 2017, 19, 246-249. (g) Chen, X.-Y.; Sorensen, E. J. Pd-Catalyzed,
ortho C–H Methylation and Fluorination of Benzaldehydes Using
Orthanilic Acids as Transient Directing Groups. J. Am. Chem. Soc.
2018, 140, 2789-2792. (h) Sun, Q.; Yoshikai, N. Cobalt-Catalyzed
Directed ortho-Methylation of Arenes with Methyl Tosylate. Org. Chem.
Front. 2018, 5, 2214-2218. (i) Li, Z.-L.; Wu, P.-Y.; Cai, C. Cobalt
catalyzed regioselective C–H methylation/acetoxylation of anilides: new
routes for C–C and C–O bond formation. Org. Chem. Front. 2019, DOI:
10.1039/c9qo00411d.
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ACS Publications website.
(4) Sato, T.; Yoshida, T.; Al Mamari, H. H.; Ilies, L.; Nakamura, E.
Manganese-Catalyzed Directed Methylation of C(sp2)–H Bonds at
25 °C with High Catalytic Turnover. Org. Lett. 2017, 19, 5458-5461.
(5) Graczyk, K.; Haven, T.; Ackermann, L. Iron-Catalyzed C(sp2)–H and
C(sp3)–H Methylations of Amides and Anilides. Chem-Eur. J. 2015, 21,
8812-8815.
(6) (a) Li, Q.; Li, Y.; Hu, W.; Hu, R.; Li, G.; Lu, H. Cobalt-Catalyzed C(sp2)–
H Methylation by using Dicumyl Peroxide as both the Methylating
Reagent and Hydrogen Acceptor. Chem-Eur. J. 2016, 22, 12286-12289.
(b) Xu, K.; Tan, Z.; Zhang, H.; Zhang, S. Cobalt-Catalyzed
Monoselective ortho-C–H Ethylation of Carboxamides with
Triethylaluminum. Synthesis 2017, 49, 3931-3936.
1H and 13C NMR spectra of new compounds.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
glcheng@hqu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(7)
(a) Kubo, T.; Chatani, N. Dicumyl Peroxide as a Methylating Reagent
in the Ni-Catalyzed Methylation of Ortho C–H Bonds in Aromatic
Amides. Org. Lett. 2016, 18, 1698-1701. (b) Uemura, T.; Yamaguchi,
M.; Chatani, N. Phenyltrimethylammonium Salts as Methylation
Reagents in the Nickel-Catalyzed Methylation of C–H Bonds. Angew.
Chem. Int. Ed. 2016, 55, 3162-3165.
This work was supported by the NSF of China (21672075), the
Program for New Century Excellent Talents in Fujian Province
University, and Postgraduates’ Innovative Fund in Scientific
Research of Huaqiao University.
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