Steric effect of carboxylic acid ligands on Pd-catalyzed C-H activation reactions

Article abstract of DOI:10.1016/j.catcom.2016.06.003

Various carboxylic acids with different substitution patterns were used as ligands in intra- and intermolecular Pd-catalyzed C-H activation reactions to investigate steric effect of the ligands. Bulky carboxylic acids suppress deactivation of Pd catalysts

Full text of DOI:10.1016/j.catcom.2016.06.003

Steric effect of carboxylic acid ligands on Pd-catalyzed C–H activation
reactions
Tetsuaki Fujihara, Atsushi Yoshida, Motoi Satou, Yutaka Tanji, Jun Terao,
Yasushi Tsuji
PII:
DOI:
Reference:
S1566-7367(16)30194-7
doi: 10.1016/j.catcom.2016.06.003
CATCOM 4676
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
23 April 2016
1 June 2016
2 June 2016
Please cite this article as: Tetsuaki Fujihara, Atsushi Yoshida, Motoi Satou, Yutaka Tanji,
Jun Terao, Yasushi Tsuji, Steric effect of carboxylic acid ligands on Pd-catalyzed C–H
activation reactions, Catalysis Communications (2016), doi: 10.1016/j.catcom.2016.06.003
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ACCEPTED MANUSCRIPT
Catalysis Communications
Steric effect of carboxylic acid ligands on Pd-catalyzed C–H
activation reactions
Tetsuaki Fujihara,* Atsushi Yoshida, Motoi Satou, Yutaka Tanji, Jun Terao and
Yasushi Tsuji*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto
University, Kyoto 615-8510, Japan.
TEL: +81-75-383-2515, FAX: +81-75-383-2514.
E-mail: tfuji@scl.kyoto-u.ac.jp and ytsuji@scl.kyoto-u.ac.jp
Abstract
Various carboxylic acids with different substitution patterns were used as ligands in intra- and
intermolecular Pd-catalyzed C–H activation reactions to investigate steric effect of the ligands.
Bulky carboxylic acids suppress deactivation of Pd catalysts.
Key Word
Carboxylic Acid, C–H Activation, Homogeneous Catalysis, Palladium
1

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1. Introduction
Transition-metal-catalyzed carbon-hydrogen (C–H) bond activation reaction is one of the
most straightforward methods in organic transformations [1-7]. Among them, Pd catalysis is
widely utilized [8-14]. In these cases, carboxylic acids, typically pivalic acid, play an
important role as the ligand in C–H bond activation step via concerted metalation
deprotonation (CMD) mechanism [15-17]. Fagnou reported that the Pd-catalyzed
3
intramolecular C(sp )–H bond arylation reactions proceeded efficiently with pivalic acid as
the ligand (Scheme 1a) [18]. In the reaction, acetic acid was not so effective. Fagnou also
reported that pivalic acid was more effective ligand than acetic acid in the Pd-catalyzed
2
intermolecular C(sp )–H arylation with aryl bromides (Scheme 1b) [19]. Therefore, it is
interesting to see how steric effect of the carboxylic acids (carboxylates) influences the C-H
bond activation reactions. Recently, Thompson investigated the effect of various carboxylic
acids on the Pd-catalyzed direct arylation polymerization with 3-hexylthiophene [20].
However, it is still unclear how the nature of carboxylic acid ligands affects the C–H bond
activation reactions.
3
Scheme 1. Pd-catalyzed C
–
H bond activations: (a) Intramolecular C(sp )
–H arylation. (b)
2
Intermolecular C(sp )
–H arylation.
In the present study, a series of primary (1a–c), secondary (1d–1h), and tertiary (1i–1o)
-substituted carboxylic acids (Scheme 2) were evaluated as a ligand in the Pd-catalyzed intra-
and intermolecular C–H bond activation reactions shown in Schemes 1a and 1b.
2

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Scheme 2. Primary, secondary, and tertiary -substituted carboxylic acids used in this study.
2. Experimental
2.1 General procedure
All the manipulations were performed under argon atmosphere using standard
Schlenk-type glasswares and a dual-manifold Schlenk line. THF and toluene were dried and
purified before use by usual methods [21]. Mesitylene, N,N-dimethylacetoamide (DMA),
p-bromobenzene, and benzene were purified by distillation under reduced pressure and stored
under Ar atmosphere [22]. Unless otherwise noted, materials obtained from commercial
1
suppliers were used as received. H NMR spectra were measured with a Bruker AVANCE-500
1
spectrometer or a JEOL ECX-400P spectrometer. The H NMR chemical shifts are reported
relative to tetramethylsilane (TMS, 0.00 ppm). The GC analysis was carried out using a
Shimadzu GC-17A instrument equipped with a capillary column (CBP-5, 0.25 mm i.d.  25
m). The column chromatography was carried out using silica gel (Kanto N60, spherical,
neutral, 63-210 m). The TLC analyses were performed using commercial glass plates
containing a 0.25-mm layer of Merck Silica gel 60F254. Carboxylic acids 1a–j, 1n and 1o
3

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were purchased and used as received. Carboxylic acids 1k–m and 1p were prepared according
to a modified literature method [23,24]. 1q was a new compound and prepared as shown
below.
2.2 Synthesis of 1q
A freshly prepared lithium diisopropyl amide (LDA) solution (11 mmol) in THF was
added to a solution of acetonitrile (0.52 mL, 10 mmol) in THF (5.0 mL) at 0 °C and stirred for
5 min. Then, 1-bromododecane (2.4 mL, 10 mmol) was slowly added and the reaction mixture
was stirred at room temperature for 40 min. Then, the sequential addition of the LDA solution
11 mmol) and 1-bromododecane (2.4 mL, 10 mmol) was repeated for three times. The
2
(
resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched
by adding 1 M HCl aq., and the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO , and concentrated under reduced pressure. The product
4
was purified by silica gel column chromatography (EtOAc / hexane = 1 / 40, R = 0.19),
f
affording 2,2-didodecyltetradecanenitrile (3.7 g, 6.8 mmol) in 68% yield. The nitrile was added
to 75% sulfuric acid (15 mL), and the reaction mixture was stirred at 100 °C for 23 h. After
cooling to room temperature, NaNO (1.9 mg, 27 mmol) was added and the reaction mixture
2
was stirred for 20 min. The mixture was diluted with water (30 mL) and extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO , and concentrated under reduced
4
pressure. The product was purified by column chromatography on silica gel (EtOAc / hexane =
1
1
/ 15, R = 0.10), giving 1q (3.0 g, 5.2 mmol) in 77 % yield as white solid. H NMR (400 MHz,
f
13
CDCl ):  11.00 (brs, 1H), 1.56–1.40 (m, 6H), 1.38–1.08 (m, 60H), 0.88 (t, J = 6.8 Hz, 9H). C
3
NMR (100 MHz, CDCl ):  183.38, 48.80, 34.33, 31.93, 30.14, 29.70, 29.66, 29.49, 29.37,
3
23.83, 22.70, 14.11 (two peaks were overlapped). IR (neat): 2918.3, 2848.9, 1699.3, 1465.9,
-1
-
7
23.3 cm . ESI-HRMS: Calcd. for C H O ([M–H] ), 563.5773. Found, 563.5776.
38
75
2
2.3 Catalytic reaction
3
2
.3.1 Pd-catalyzed intramolecular C(sp )–H arylation reaction
To a 10-mL Schlenk flask equipped with a reflux condenser was added Rb CO (0.20 g,
2
3
0.87 mmol) and dried with a heating-gun under vacuum. The flask was backfilled with argon.
Then, Pd(OAc) (6.5 mg, 0.029 mmol, 5.0 mol%), PCy ·HBF (21 mg, 0.058 mmol, 10 mol%),
2
3
4
carboxylic acid (1, added here if it is a solid, 0.17 mmol, 30 mol%), and
-bromo-N-cyclohexyl-N-methylbenzamide (2, 0.17 g, 0.58 mmol) were added to the flask. The
2
flask was evacuated and backfilled with argon three times. Then, mesitylene (2.9 mL) and
4

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carboxylic acid (1, added here if it is a liquid , 0.17 mmol, 30 mol%) was added to the flask.
The resulting reaction mixture was stirred at 150 °C for 16 h. After cooling to room temperature,
the reaction mixture was analyzed by GC, and the yield of 2-cyclohexylisoindolin-1-one 3 was
determined using tetradecane (50 L) as an internal standard.
2
2
.3.2 Pd-catalyzed intermolecular C(sp )–H arylation reaction
To a 10-mL Schlenk flask equipped with a reflux condenser was added Rb CO (0.20 g,
2
3
0.87 mmol) and carboxylic acid (1, added here if it is a solid, 0.060 mmol, 30 mol%), and dried
with a heating-gun under vacuum. The flask was backfilled with argon three times. Then,
Pd(OAc) (0.0060 mmol, 3.0 mol% as a stock solution in DMA, 1.2 mL) and carboxylic acid (1,
2
added here if it is a liquid, 0.060 mmol, 30 mol%) was added. The mixture was stirred at room
temperature for 30 min. Then, 4-bromotoluene (4, 25 L, 0.20 mmol) and benzene (1.0 mL)
were added to the mixture, and the resulting reaction mixture was stirred at 90 °C for 20 h.
After cooling to room temperature, the reaction mixture was analyzed by GC, and the yield of
compound 5 was determined using tetradecane (50 L) as an internal standard.
3. Results and Discussion
First, we carried out the intramolecular Pd-catalyzed C–H activation shown in Scheme 1a
as a model reaction. Thus, the reaction of 2-bromo-N-cyclohexyl-N-methylbenzamide (2) to
-cyclohexylisoindolin-1-one (3) was carried out using 30 mol% of carboxylic acid 1 in the
presence of a catalytic amount (5.0 mol%) of Pd(OAc) /PCy ·HBF in mesitylene at 150 °C
2
2
3
4
(
Table 1). When acetic acid (1a) was used as the ligand, 3 was obtained in only 26% yield
entry 1), as reported in the original report [4]. Other primary -substituted carboxylic acids
(
afforded 3 in moderate yields (entries 2 and 3). The use of secondary -substituted carboxylic
acids such as 2-methylpropionic acid (1d) and 2-ethylhexanoic acid (1e) improved the yields
of 3 to 80% and 79%, respectively (entries 4 and 5), whereas 1f, 1g, and 1h with a
cyclopropyl, cyclopentyl, and cyclohexyl group, respectively, were not efficient (entries 6–8).
Pivalic acid (1i), which was the best carboxylic acid ligand in the previous report [4], was
more effective, producing 3 in 74% yield (entry 9). Gratifyingly, the yield of 3 significantly
increased by elongating one of the methyl substituents of 1i to ethyl (1j: 80%), n-pentyl (1k:
8
8%) and n-dodecyl (1l: 91%) groups, respectively (entries 10–12). However, the use of 1m
bearing a cyclohexylmethyl substituent decreased the yield of 3 to 55% (entry 13). Other
carboxylic acids (1n and 1o) bearing alicyclic systems showed good catalytic activity (entries
5

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1
4 and 15). Thus, the bulkiness of the carboxylic acid ligands (1) affected the yield of 3 and
the ligands with longer primary alkyl chains showed high catalytic activity.
Because the carboxylic acid bearing a longer n-alkyl chain (1l) was a promising ligand
(
entry 12, Table 1), carboxylic acid ligands bearing three n-pentyl (1p) and n-dodecyl chains
1q) were synthesized (Scheme 2). When 1i, 1p and 1q were used as the carboxylate ligand
(
under the same reaction conditions as shown in Table 1 (reaction time: 16 h), 3 was obtained
in 74% (entry 9, Table 1), 52%, and 59% yields, respectively. When the reaction time was
prolonged to 40 h, the yields of 3 increased to 88% and 88% with 1p and 1q, respectively,
whereas 1i afforded the same yield (Scheme 3). Importantly, upon reducing the amount of the
carboxylic acid from 30 mol% to 10 mol%, 1i was inefficient, affording 3 in only 8% yield
after 40 h. In the reaction, Pd black was generated in the reaction mixture after 16 h,
indicating the catalyst decomposed under the reaction conditions. In sharp contrast, with 1p
and 1q, the catalytic activity was maintained even under the low carboxylic acid loadings and
the product was obtained in 88% and 92% yields, respectively. When the reaction was carried
out using 10 mol% of 1l, the product was also obtained in 87% yield. Thus, the longer alkyl
chains prevent the aggregation of Pd species because of their bulkiness. We have already
reported the suppression of Pd black formation using bulky pyridine ligands [25,26].
3
Scheme 3. Pd-catalyzed intramolecular C(sp )
–H bond arylation of 2 under low carboxylic
acid loading.
2
Next, the Pd-catalyzed C(sp )–H arylation of benzene with 4-bromotoluene (4) was
carried out. In the original report [19], Fagnou used both pivalic acid (1i) and basic phosphine
6

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as ligands in DMA at 120 °C. Later, Hartwig reported that the reaction proceeded with only 1i
as the ligand (without any phosphine) at 110 °C [27]. Therefore, in the present study, the
catalytic reaction was performed without phosphines. The reaction was carried out employing
various carboxylic acids (1a–o) as carboxylate ligands in the presence of a catalytic amount of
Pd(OAc) in a mixture of benzene and DMA at a lower temperature (90 °C) than the
2
Hartwig’s conditions [27]. The results are shown in Table 2. Using primary and secondary

-substituted carboxylic acids (1a–1h) as the ligands, the reactions virtually did not proceed
entries 1–8). When pivalic acid (1i) was used [19,27], 4-phenyltoluene (5) was obtained in
7% yield (entry 9). By replacing one of the methyl groups of 1i to an ethyl group (1j), the
(
4
reaction smoothly proceeded affording 5 in 71% yield (entry 10). Similarly, n-pentyl (1k) and
n-dodecyl (1l) substituted carboxylic acids furnished 5 in 63% and 52%, respectively (entries
1
0–12). Furthermore, 1m bearing cyclohexylmethyl and two methyl substituents at the
-position was most effective ligand in this particular reaction and provided 5 in 72% yield
entry 13). All the other more bulky carboxylic acid ligands (1n, 1o, 1p, and 1q) were

(
inefficient and the yields of 5 were quite low. Thus, the bulkiness of these carboxylic acid
ligands significantly affects the catalytic activity. Regarding carboxylato palladium
complexes, a palladium trimer was afforded with 1a as the ligand [28]. A bulky 1i also
afforded a similar palladium trimer [29]. In contrast, more bulky carboxylic acid ligands may
suppress the aggregation of the Pd center and maintain an active Pd catalyst species by steric
effect.
4
. Conclusion
Various carboxylic acids were evaluated in the intra- and intermolecular Pd-catalyzed C–H
activation reactions. In the intramolecular reaction of
-bromo-N-cyclohexyl-N-methylbenzamide, a bulky carboxylic acid bearing three long alkyl
2
chains at the -position suppressed the deactivation of Pd catalysts. In the intermolecular direct
C–H arylation of an aryl bromide with benzene, the reaction proceeded smoothly when a bulky
carboxylic acid bearing a cyclohexylmethyl group at the -position was used. Further studies on
mechanism and substrate scope are underway.
References
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Table 1.
3
a
Effect of carboxylic acids on the Pd-catalyzed intramolecular C(sp )
–H bond arylation of 2.
b
Entry
Carboxylic acid (1)
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
26
57
59
80
79
23
58
39
74
80
88
91
55
82
65
1g
1h
1i
1
0
1
2
3
4
5
1j
1
1
1
1
1
1k
1l
1m
1n
1o
a
Reaction conditions: 2-bromo-N-cyclohexyl-N-methylbenzamide (2, 0.58 mmol),
Pd(OAc) (0.029 mmol, 5.0 mol%), PCy ·HBF (0.058 mmol, 10 mol%), carboxylic
2
3
4
acid (1, 0.17 mmol, 30 mol%), Rb CO (0.87 mmol, 1.5 equiv) in mesitylene (2.9 mL)
2
3
at 150 °C for 16 h.
b
Determined by GC analysis using an internal standard method.
1
0

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Table 2.
Effect of carboxylic acids on the Pd-catalyzed C(sp )
2
a
–H bond arylation with 4.
b
Entry
Carboxylic acid (1)
Yield of 5 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
0
0
0
0
1
0
1g
1h
1i
2
1
47
71
63
52
72
0
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
1j
1k
1l
1m
1n
1o
1p
1q
5
11
4
a
Reaction conditions: 4-bromotoluene (4, 0.20 mmol), Pd(OAc) (0.0060 mmol,
2
3
.0 mol%), carboxylic acid (1, 0.060 mmol, 30 mol%), K CO (0.50 mmol, 2.5
2
3
equiv) in DMA (1.2 mL) and benzene (1.0 mL) at 90 °C for 20 h.
b
Determined by GC analysis using an internal standard method.
11

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Graphical abstract
1
2

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Reserach Highlights
Steric effect of carboxylic acid ligands on Pd-catalyzed C–H activation reactions
Tetsuaki Fujihara,* Atsushi Yoshida, Motoi Satou, Yutaka Tanji, Jun Terao, and Yasushi
Tsuji*
Various carboxylic acids were used as ligands Pd-catalyzed C–H activation reactions.
A carboxylic acid bearing three long alkyl chains suppress the deactivation.
A carboxylic acid bearing a cyclohexylmethyl group was efficient in C-H arylation.
1
3