Pd-Catalyzed intermolecular C-H bond arylation reactions: Effect of bulkiness of carboxylate ligands

Article abstract of DOI:10.1039/d0cc01129k

A bulky carboxylic acid bearing one 1-adamantylmethyl and two methyl substituents at the α-position is demonstrated to work as an efficient carboxylate ligand source in Pd-catalyzed intermolecular C(sp²)-H bond arylation reactions. The reactions proceeded smoothly under mild conditions, taking advantage of the steric bulk of the carboxylate ligands.

Full text of DOI:10.1039/d0cc01129k

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DOI: 10.1039/D0CC01129K
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Pd-catalyzed intermolecular C–H bond arylation reactions: effect of
bulkiness of carboxylate ligands
Yutaka Tanji, Ryo Hamaguchi, Yasushi Tsuji and Tetsuaki Fujihara*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A bulky carboxylic acid bearing one 1-adamantylmethyl and two different steric congestion, we found the addition of a carboxylic acid
methyl substituents at the -position is demonstrated to work as with suitable steric bulk remarkably enhanced the catalytic activity
an efficient carboxylate ligand source in Pd-catalyzed and the desired reactions proceeded under milder conditions.
intermolecular C(sp2)–H bond arylation reactions. The reactions
The Pd-catalyzed intermolecular C(sp2)–H bond arylation reaction
proceeded smoothly under mild conditions, taking advantage of using 4-bromotoluene (2a) and benzene (3a) was selected as the
the steric bulk of the carboxylate ligands.
model reaction.3 In the present study, the reaction demonstrated in
Table 1 were performed at a lower temperature (70 °C) compared to
previous reports.3 The efficiency of carboxylic acids (1) as the
carboxylate ligand source was investigated by employing 30 mol% of
1 in the presence of a catalytic amount (3.0 mol%) of PdCl2 and
Rb2CO3 (1.5 equiv) in N,N-dimethylacetamide (DMA). First, various
carboxylic acids exhibiting different steric bulk were screened.
Conventional pivalic acid (1a) afforded a product 4aa in a low yield
of 11% (entry 1). Tri(cyclohexylmethyl)acetic acid (1b), which was the
most optimal for intramolecular C(sp2)–H arylation reactions,8 was
not good in intermolecular reaction (entry 2). When -mono- (1c and
1d) or -di- substituted (1e and 1f) carboxylic acids were utilized, 4aa
was not obtained at all (entries 3–6). Additionally, -trisubstituted
carboxylic acids such as 1-adamantancarboxylic acid (1g) were less
effective than 1a (entry 7). When one of the methyl groups in 1a was
replaced by a long alkyl chain (1h), 4aa was obtained in a low yield
(entry 8). A carboxylic acid containing a cyclohexylmethyl group at
the -position (1k) was more effective than compounds possessing
cyclohexyl (1i) or cyclohexylethyl groups (1j) at the same position to
The transition-metal-catalyzed carbon–hydrogen (C–H) bond
activation is one of the most straightforward organic
transformations.1 In particular, Pd catalysts are widely utilized in
such processes.2 Fagnou and Hartwig independently reported that
pivalic acid was an effective ligand source in the Pd-catalyzed
intermolecular C(sp2)–H arylation reactions.3 Nevertheless, the
methods require high reaction temperatures (120 °C and 110 °C,
respectively). Intermolecular C(sp2)–H arylation reactions of
electron-deficient arenes4 and electron-rich heteroarenes reported
by other groups5 are also carried out at high temperatures (in most
cases over 100 °C).
Carboxylates are known as common ligands in transition metal
complexes. In catalytic C–H bond activation reactions, carboxylate
ligands have proved to play a crucial role in the C–H bond cleavage
step via a concerted metalation deprotonation (CMD) pathway.6
However, little research is available on the steric effects of
carboxylate ligands using transition metal-catalyzed reactions as well
as on the development of new carboxylate ligands.7 We recently
found that a bulky carboxylic acid bearing three cyclohexylmethyl
substituents at the -position, namely tri(cyclohexylmethyl)acetic
acid, worked as an efficient ligand source in Pd-catalyzed
intramolecular C(sp2)–H and C(sp3)–H arylation reactions under very
mild reaction conditions including at room temperature.8
afford 4aa in moderate yield (entries 9–11). Thus, we subsequently
designed and synthesized modified carboxylic acids based on
the structure of 1k. When a cyclohexyl moiety of 1k was
replaced with a t-butyl group (1l), the yield of 4aa decreased
(entry 12). On the other hand, replacing the cyclohexyl group
with 1-adamantyl moiety (1m) was effective and afforded 4aa
in 72% yield (entry 13). From these results, 1m was determined
as the best carboxylate ligand source in the intermolecular
reaction. When the loading of 1m was reduced to 10 mol%, the
reaction proceeded well (73% yield).9 However, the reactions
using 7.5 mol% and 5.0 mol% of 1m afforded 4aa in 53% and
47% yields, respectively.
Herein, the steric effects of carboxylic acids on Pd-catalyzed
intermolecular C(sp2)–H bond arylation reactions were evaluated.
After designing and synthesizing a panel of carboxylic acids exhibiting
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan. E-mail: tfuji@scl.kyoto-u.ac.jp FAX: +81-
75-383-2514
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
The two key factors, which must be considered when elucidating
the role of the carboxylate ligands, are basicity and steric bulk.
Considering the basicity aspect, we have previously estimated the
pKa values of carboxylic acids using the maximum values of their
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molecular electrostatic potential (max MEP)9 via a density functional as mixtures of isomers under mild reaction conditVioienwsA.rt(icelenOtrnilienes
theory (DFT) method (B3LYP/6-311G++(2d,p)).10 Despite analogous 4 and 5). Utilizing 1,4-difluorobenzene (3DeO)I:a1s0.t1h03e9a/Dr0yCl Cso0u11r2c9eK,
pKa values of -trisubstituted carboxylic acids 1a, 1b and 1g–1m the reaction proceeded at 40 °C, affording the product (4be) in
(5.03–5.50),11 the efficiency of 1a, 1b and 1g–1m considerably a good yield (entry 6).
differed (Table S3)9. Thus, it can be concluded that it is the steric
effects rather than the electronic effects (basicity) of 1, which are tested in the intermolecular C(sp2)–H bond arylation reactions
Next, various aryl halides (2c–2k) and an aryl triflate (2l) were
responsible for the efficiency of the reaction.
using 1,4-difluorobenzene (3e) as the aryl source. Pleasingly, a
wide variety of functional groups were tolerant, and products
having methyl (4ce), trifluoromethyl (4de), methoxy (4ee), and
cyano (4fe) substituents at the p-position were successfully
obtained at 45 °C in high isolated yields (entries 7–10).
Furthermore, formyl and methoxycarbonyl groups at the o-
position were also tolerated, and the corresponding products
4ge and 4he were successfully obtained at 45°C in high yields
(entries 11 and 12). When these reactions were performed
using 1a at a higher temperature (80 °C), the yields of 4ge and
4he were considerably decreased to 53% and 65%, respectively,
Table 1 The effects of carboxylic acids as ligand sources on the Pd-catalyzed C-
H arylation reaction using 2a and 3a a
with full conversion of
using 1- or 2-bromonaphtharenes (2i and 2j) was achieved at
60 °C (entries 13 and 14). An electron-deficient aryl chloride (2k
2. Introduction of naphthyl moieties
)
as well as phenyl triflate (2l) were also employed and the
corresponding products 4ke and 4le were obtained at 60 °C and
50 °C, respectively (entries 15 and 16). When the reactions
shown in entries 5 and 12 were carried out using 1b, which was
determined as the most optimal carboxylate ligand source in
the intramolecular reactions,8 the products were obtained in 61
and 49 % yields, respectively. Thus, 1m proved to be the best
carboxylate ligand source in the intermolecular reactions in
terms of realizing milder reaction condition and wide functional
group tolerance.
In order to elucidate reaction mechanisms, the kinetic isotope
effect (KIE) was measured by comparing the initial rates of the
reactions using benzene (3a) and benzene-d6 at 90 °C (Scheme 1),9
affording kH/kD = 5.61, which is in agreement with the value reported
in the literature.13 Accordingly, the C–H bond cleavage must be
involved in the rate-determining step. Our preliminary DFT
calculation also revealed that the C–H bond cleavage is the rate-
determining step.9
a Conditions: 2a (0.20 mmol), PdCl2 (0.010 mmol, 5.0 mol %), carboxylic acid (1,
0.060 mmol, 30 mol %), Rb2CO3 (0.30 mmol, 1.5 equiv) in DMA (1.0 mL) and 3a
(1.0 mL) at 70 °C for 40 h. b Determined by GC analysis using an internal
standard method.
Scheme 1 Kinetic isotope effect using 3a and 3a-d6
With the optimal carboxylic acid 1m in hand, various
substrates were applied in the intermolecular C(sp2)–H bond
arylation reactions (Table 2). The reaction using 4-
bromotoluene
(
2a
)
and benzene
(
3a
)
afforded the
corresponding product 4aa in 62% isolated yield (entry 1).
When the sterically crowded 2-bromotoluene (2b) was utilized
as an aryl halide, the desired reaction proceeded smoothly to
afford the desired product (4ba) in good yield (entry 2).
Subsequently, various arenes (3b
intermolecular C(sp2)–H bond arylation reactions using 2-
bromobenzene 2b as the substrate. Applying 1,3-
–3e) were evaluated in the
(
)
bis(trifluoromethyl)benzene (3b) at 55 °C resulted in the
formation of 4bb (entry 3). Both chloro and fluoro substituents
were tolerated (3c and 3d), successfully affording 4bc and 4bd
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC01129K
Table 2 Scope of substratesa
aConditions: 2 (0.20 mmol), PdCl2 (0.010 mmol, 5.0 mol %), 1m (0.060 mmol, 30 mol %), Rb2CO3 (0.30 mmol, 1.5 equiv) in DMA (1.0 mL) and 3 (1.0 mL) for
40 h. bA mixture of three isomers (ortho : meta : para = 33:18:49). cA mixture of two isomers (ortho : para = 91:9).
We previously proposed that in intramolecular reactions, the substrate arenes to the Pd center in the intermolecular reactions.
steric effect of the bulky carboxylic acid (1b) used as a ligand source Overall, 1m exhibits suitable bulkiness for generating reactive
most likely generates active mononuclear Pd species, which mononuclear Pd species as well as for facilitating access of the
accelerates the rate-determining C–H bond cleavage step.8 When substrate to the Pd center.
carboxylic acids 1a, 1k, 1m and 1b were tested in the intramolecular
In summary, we found that a bulky carboxylic acid bearing a 1-
reactions using 5 in DMA at 70°C, the bulkiest carboxylic acid 1b was adamantylmethyl moiety and two methyl groups at the -position
the most effective, giving 6 in the highest yield (Scheme 2 (a)). On the (1m) acted as an efficient carboxylate ligand source in Pd-catalyzed
other hand, in the intermolecular C(sp2)–H bond arylation reaction, intermolecular C(sp2)–H bond arylation reactions. The desired
1b was not effective and carboxylic acid 1m proved to be the most reactions proceeded smoothly under very mild conditions. Studies to
optimal carboxylate ligand source (Scheme 2 (b)). We suspect that as extend the scope of 1m to a variety of C–H activation reactions and
a consequence of its bulkiness, 1b would prevent the access of the
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El-Salfiti, C. J. Whipp and K. Fagnou, TetrahedrVoienw, A2rt0ic0le9O,n6lin5e
,
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2 Comparison of steric effect of carboxylic acids between (a)
intramolecular- and (b) intermolecular C(sp2)–H bond arylation
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11 pKa values of 1a-l:
1a (5.03)12 1b (5.37), 1c (4.76),12 1d
This work was supported by JSPS KAKENHI Grant Number
17H03096 in Grant-in-Aid for Scientific Research (B) from MEXT,
Japan (Y. Tsuji). T. Fujihara acknowledged JSPS KAKENHI Grant
Number 18H04257 in Precisely Designed Catalysts with
Customized Scaffolding from MEXT, Japan. Y. Tanji is grateful to
a Research Fellowship from JSPS for Young Scientists.
(4.85),12 1e (4.84),12 1f (4.91), 1g (5.50), 1h (5.35), 1i (5.26), 1j
(5.35), 1k (5.39), 1l (5.11), 1m (5.40).
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Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1-3
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