Palladium-Catalyzed Decarboxylation of Benzyl Fluorobenzoates

Article abstract of DOI:10.1055/s-0036-1588572

The decarboxylation of benzyl fluorobenzoates has been developed by using the palladium catalyst prepared in situ from Pd(η ³ -allyl)Cp and bulky monophosphine ligand XPhos. The catalytic reaction afforded a range of fluorinated diarylmethanes in good yields with broad functional-group compatibility. The substrates were readily synthesized by condensation of the corresponding benzoic acid with benzyl alcohol. Therefore, the transformation is formally regarded as a cross-coupling reaction between fluorine-containing benzoic acids and benzyl alcohols.

Full text of DOI:10.1055/s-0036-1588572

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© Georg Thieme Verlag Stuttgart · New York
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Palladium-Catalyzed Decarboxylation of Benzyl Fluorobenzoates
Yusuke Makida
0
0
0
0
0-
0
0
2
2-
9
9
9
4-
1
0
4
F
O
F
Yasutaka Matsumoto
Ryoichi Kuwano*
[Pd]-XPhos catalyst
CO2
PCy2
iPr
O
R2
R3
R2
R3
iPr
R1
R1
Department of Chemistry, Faculty of Science, Kyushu University,
744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
rkuwano@chem.kyushu-univ.jp
16 examples
up to 89% yield
XPhos
iPr
Published as part of the Cluster CO Activation
Received: 19.06.2017
Accepted after revision: 28.08.2017
Published online: 26.09.2017
mains in premature for the benzylic cross-couplings.3e,8 In
this context, we envisioned that the diarylmethanes are ef-
ficiently obtained from the corresponding benzyl benzoates
through the decarboxylation. The decarboxylation may pro-
ceed with the palladium catalysis through the pathway as
depicted in Scheme 1: (i) the oxidative addition of the ben-
zylic C–O bond to palladium(0) A, (ii) the decarboxylation of
the resulting palladium benzoate C to form arylbenzylpalla-
dium(II) D, (iii) the reductive elimination from D to produce
the desired diarylmethane.9 Herein, we successfully devel-
oped the palladium-catalyzed decarboxylative carbon–car-
bon bond formation of the benzyl esters. The catalytic reac-
tion proceeds without any additives other than the palladi-
um catalyst and emits carbon dioxide as the sole byproduct.
DOI: 10.1055/s-0036-1588572; Art ID: st-2017-s0493-c
Abstract The decarboxylation of benzyl fluorobenzoates has been de-
veloped by using the palladium catalyst prepared in situ from Pd(η3-al-
lyl)Cp and bulky monophosphine ligand XPhos. The catalytic reaction
afforded a range of fluorinated diarylmethanes in good yields with
broad functional-group compatibility. The substrates were readily syn-
thesized by condensation of the corresponding benzoic acid with ben-
zyl alcohol. Therefore, the transformation is formally regarded as a
cross-coupling reaction between fluorine-containing benzoic acids and
benzyl alcohols.
Key words decarboxylation, benzylation, palladium catalyst, diaryl-
methane, fluoroarene, C–O activation, benzyl palladium intermediate
O
Palladium-catalyzed cross-coupling reactions between
organometals and organo(pseudo)halides are currently one
of well-studied and reliable methods for carbon–carbon
bond formation.1 However, the catalytic transformation is
fate to generate a stoichiometric amount of metal salts as
byproducts. The salts may make a great impact on the envi-
ronment. For avoiding the generation of the inevitable me-
tallic byproduct, a new surrogate of the organometallic sub-
strate is highly attractive. Carboxylic acids are a strong can-
didate for the organometal alternative, because their
transition-metal salts eliminate carbon dioxide to give aryl-
metal species.2 This decarboxylative process can be equiva-
lent to the transmetalation in the classical cross-coupling
mechanisms. Tremendous efforts have been devoted to
achieving the cross-coupling reaction using carboxylic ac-
ids as the nucleophilic substrates.3
Ar1
Ar2
Ar1
O
Ar2
[Pd0]
A
O
Ar1
Ar2
[PdII]
O
[PdII]
Ar1
R
D
B
O
CO2
Ar2
[PdII]
Ar1
O
C
Scheme 1 Working hypothesis for the palladium-catalyzed
decarboxylation of benzyl benzoate
Diarylmethane is an important structural motif in or-
ganic chemistry, because the skeleton is often seen in many
useful compounds.4 The cross-coupling reaction of benzylic
esters with arylmetal compounds has been developed by
us5 and others.6,7 However, the use of carboxylic acids re-
To develop the decarboxylative carbon–carbon bond
formation, we chose benzyl 2,6-difluorobenzoate (1a) as
the model substrate for the following catalyst screening, be-
cause the ortho-fluorine atoms were known to facilitate the
decarboxylation of the metal benzoate (Table 1).10 First, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Y. Makida et al.
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decarboxylation of 1a was attempted using Pd(η3-allyl)Cp
and some bidentate bisphosphines, which were reported as
the useful ligands for the related catalytic alkylations with
benzylic carbonates (Table 1, entries 1–3).11 However, these
ligands did not allow the palladium catalyst to efficiently
provide the desired diarylmethane 2a. Use of the alkyl vari-
ants of DPPF is favorable for the decarboxylative reaction
(Table 1, entries 4 and 5). Furthermore, a series of bulky
monodentate dialkylarylphosphine ligands12 were evaluat-
ed to the palladium-catalyzed decarboxylation of 1a. The
palladium catalyst produced 2a in the highest yield when
XPhos was used as the spectator ligand with 2.4 molar
equivalents to palladium (Table 1, entry 6). Decrease in the
molar equivalent of the ligand caused the formation of
black precipitates during the reaction and led to the signifi-
cant low yield of 2a (Table 1, entry 7). Other biarylyldicyclo-
hexylphosphines, SPhos and DavePhos, are comparable to
XPhos (Table 1, entries 8 and 9). However, the palladium
catalyst bearing bulkier and/or more electron-donating li-
gand failed to selectively and efficiently promote the de-
sired reaction (Table 1, entries 10 and 11). The catalysis of
XPhos–palladium complex is scarcely affected by the sol-
vent (Table 1, entries 12–15). Toluene is the solvent of
choice for the present reaction. The palladium-catalyzed
decarboxylation was slightly improved by elevating tem-
perature (Table 1, entry 16). It is noteworthy that catalyst
loading can be reduced to 1 mol% without loss of the yield
of 2a (Table 1, entry 17).
Table 1 (continued)
Entry
Ligand (mol%)
Solvent
Conv. (%)b
Yield (%)b
7
8
XPhos (6)
toluene
toluene
toluene
toluene
toluene
DMF
57
60
16
63
54
4
SPhos (12)
9
DavePhos (12)
t-BuXPhos (12)
BrettPhos (12)
XPhos (12)
XPhos (12)
XPhos (12)
XPhos (12)
XPhos (12)
XPhos (2.4)
100
47
10
11
12
13
14
15
16c
17c,d
27
trace
54
50
69
61
75
80e
99
t-AmOH
CPME
100
100
100
100
100
1,4-dioxane
toluene
toluene
a Unless otherwise noted, all reactions were carried out with 0.20 mmol of
1a in 0.50 mL of solvent under N2 at 120 °C for 24 h.
b Determined by GC analysis.
c At 140 °C.
d The reaction was conducted on a 0.50 mmol scale with 1 mol% of Pd(η3-
allyl)Cp and 2.4 mol% of XPhos in 0.50 mL of toluene for 15 h.
e Yield of isolated product 2a.
Next, we attempted the reaction of various substituted
benzoates to investigate the substituent effect on the ben-
zoate moiety of 1 (Scheme 2). As with 1a, the substrates
1b–d, which have fluorine atoms on both ortho-carbons,
were transformed into the corresponding diarylmethanes
2b, 2c, and 2d in 70%, 89% and 82% yields, respectively. The
reaction of benzyl 2-fluoro-6-methoxybenzoate (1e) also
proceeded smoothly to afford diarylmethane 2e in 71%
yield. Meanwhile, benzyl 2-fluorobenzoate remained intact
under the reaction conditions. The XPhos–palladium cata-
lyst failed to transform the electron-deficient substrates
Table 1 Effect of Ligand and Solvent on the Decarboxylation of Benzyl
2,6-Difluorobenzoate (1a)a
5 mol% Pd(η3-allyl)Cp
6–12 mol% ligand
F
O
F
O
Ph
Ph
solvent, 120 °C, 24 h
F
O
F
3 mol% Pd(η3-allyl)Cp
7.2 mol% XPhos
F
F
1a
2a
O
Ph
Ph
R2
R2
PR2
toluene, 140 °C
F
R1
R1
1
2
Fe
O
F
PR2
Ph2P PPh2
DPPPent
Ph2P
PPh2
DPPF (R = Ph)
DiPrPF (R = iPr)
DCyPF (R = Cy)
Ph
Ph
2b
70% (3 h)
DPEphos
R1
2d
82% (6 h)
MeO
F
F
F
F
F
F
F
R1
R2
PR2
R3
XPhos (R = Cy, R1 = H, R2 = R3 = R4 = iPr)
F
F
Ph
Ph
SPhos (R = Cy, R1 = H, R2 = R3 = OMe, R4 = H)
DavePhos (R = Cy, R1 = H, R2 = NMe2, R3 = R4 = H)
tBuXPhos (R = tBu, R1 = H, R2 = R3 = R4 = iPr)
BrettPhos (R = Cy, R1 = OMe, R2 = R3 = R4 = iPr)
2c
2e
89% (9 h)
71% (6 h)
OMe
R4
F
NO2
F
F
Entry
Ligand (mol%)
Solvent
Conv. (%)b
Yield (%)b
F3C
Me
1
2
3
4
5
6
DPPPent (6)
DPEphos (6)
DPPF (6)
toluene
toluene
toluene
toluene
toluene
toluene
49
49
17
4
F
OMe
Cl
70
6
DiPrPF (6)
DCyPF (6)
XPhos (12)
88
37
61
74
OMe
Me
<5% conv.
Cl
100
100
Scheme 2 Substituent effects on benzoate moiety of 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Y. Makida et al.
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having no ortho-fluorine atoms into the diarylmethane
products. In addition, bis-ortho-substituted benzoates
without fluorine atoms also gave no decarboxylation prod-
ucts, while the corresponding metal benzoates are amena-
ble to the decarboxylation.10f,13 These results suggest that
the present palladium catalysis requires one ortho-fluorine
atom and the steric constraint on another ortho-position to
induce the decarboxylative carbon–carbon bond formation.
The scope of the benzyl moiety is summarized in Table 2.
The catalytic decarboxylation tolerated a broad spectrum of
functionalities (e.g., ether, ketone, ester, nitrile) and was
virtually unaffected by the electronic property of the
benzyl moiety. The benzyl esters 1 bearing an electron-do-
nating (Me and MeO) or electron-withdrawing group (CF3, Ac,
CO2Me, CN, and NO2) at the para position were converted
into the corresponding diarylmethanes 2 in good yields
(Table 1, entries 1–7). The reaction of meta-substituted
benzyl esters (1m, 1n, and 1o) also proceeded in compara-
ble yields to the para-substituted ones (Table 1, entries 8–
10). Moreover, sterically congested 1p was compatible with
the decarboxylative diarylmethane synthesis, but required
higher catalyst loading for the efficient production of 2p
(Table 1, entry 11).
In order to get a mechanistic insight into the current de-
carboxylative carbon–carbon bond formation, an equimolar
mixture of benzyl fluorobenzoates 1b and 1j was heated in
toluene in the presence of 2.5 mol% of XPhos–palladium
catalyst at 140°C for 1 h (Equation 1). Interestingly, the re-
action gave not only 2b (25%) and 2j (27%), but also the
crossover products 2q (37%) and 2a (26%). This observation
suggests that the (π-benzyl)palladium and benzoate anion
of intermediate B in Scheme 1 form a weak ion pair during
the course of the reaction. Moreover, the decarboxylation
from C to D might be relatively slow. As a result, the carbox-
ylate counter anion in the (π-benzyl)palladium B would be
scrambled rapidly, because the (σ-benzyl)palladium C is in
equilibrium with the ion pair B. The scrambling may cause
the formation of the equimolar mixture of four possible
products.
2.5 mol% Pd(η3-allyl)Cp
O
O
6 mol% XPhos
+
Ar1
O
Ph
Ar2
O
Ar3
toluene, 140 °C, 1 h
Ar2 = 2,6-F2C6H3
Ar3 = 4-CO2MeC6H4
1j (0.1 mmol)
Ar1 = 2,4,6-F3C6H2
1b (0.1 mmol)
Ar1
2b (25%)
Ph
Ar2 Ar3
2j (27%)
Ar1 Ar3
2q (37%)
Ar2
2a (26%)
Ph
+
+
+
Table 2 Decarboxylation of Benzyl Fluorobenzoates 1a
Equation 1 Crossover experiment using 1b and 1j
O
1 mol% Pd(η3-allyl)Cp
In summary, we have successfully developed the decar-
boxylation of benzyl fluorobenzoates by using XPhos–palla-
dium catalyst, which gives fluorinated diarylmethanes in
good yields with broad functional-group compatibility.14,15
The carbon–carbon bond formation is formally regarded as
the cross-coupling reaction between benzoic acids and
benzyl alcohols, because the benzoate substrates are readi-
ly prepared through the esterification. It is noteworthy that
the reaction generates only a nontoxic and easily removable
byproduct, carbon dioxide. However, the current decarbox-
ylation requires high reaction temperature and has severe
benzoate limitations at this moment. Investigations to re-
move these drawbacks are ongoing in our laboratory.
2.4 mol% XPhos
Ar
O
Ar
R
R
toluene, 140 °C
1
2
Ar = 2,6-F2C6H3
Entry
1
Time
(h)
2
Yield
(%)b
1
2
1f
14
6
2f R = Me
76
76
86
73
78
86
73
75
82
80
1g
1h
1i
2g R = OMe
2h R = CF3
2i R = Ac
F
3
3
4
9
F
R
R
5
1j
17
6
2j R = CO2Me
2k R = CN
2l R = NO2
2m R = Me
2n R = OMe
2o R = CF3
2f–2l
6c
7
1k
1l
4
Funding Information
8d
9
1m
1n
1o
3
F
F
This work was supported by Grant-in-Aid for Young Scientists (B)
6
(JSPS KAKENHI Grant Number JP17K14450).
)(
10
4
F
2m–2o
11e
1p
9
73
Acknowledgment
Me
We thank the Cooperative Research Program of ‘Network Joint Re-
search for Material and Devices’ for HRMS measurements.
F
2p
a Unless otherwise noted, all reactions were carried out with 0.50 mmol of 1
in 0.50 mL of toluene under N2 at 140 °C.
Supporting Information
b Yield of isolated product 2.
c 2 mol% of Pd(η3-allyl)Cp and 4.8 mol% of XPhos were used.
d 3 mol% of Pd(η3-allyl)Cp and 7.2 mol% of XPhos were used.
e 5 mol% of Pd(η3-allyl)Cp and 12 mol% of XPhos were used.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588572.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Y. Makida et al.
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References and Notes
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In a nitrogen-filled glove box, Pd(η3-allyl)Cp (1.1 mg, 5.0 μmol),
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Watson, M. P. J. Am. Chem. Soc. 2013, 135, 3307.
(15) 1-Benzyl-2,6-difluorobenzene (2a)
Yield 80%. 1H NMR (400 MHz, CDCl3, TMS): δ = 4.02 (s, 2 H), 6.87
(t, J = 7.6 Hz, 2 H), 7.10–7.22 (m, 2 H), 7.23–7.33 (m, 4 H). 13C
{1H} NMR (100 MHz, CDCl3): δ = 28.1 (t, J = 3 Hz), 111.2 (dd, J =
7, 19 Hz), 116.8 (t, J = 20 Hz), 126.3, 127.8 (t, J = 10 Hz), 128.4,
128.5, 139.2, 161.4 (dd, J = 9, 247 Hz). IR (neat): 3064, 3031,
2940, 1593, 1470, 1265, 1009 cm–1. Anal. Calcd for C13H10F2: C,
4.94; H, 76.46. Found: C, 4.92; H, 76.55.
(7) For reactions using electron-deficient arenes directly instead of
aryl metal compounds, see: (a) Tabuchi, S.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2014, 79, 5401. (b) Yang, G.; Jiang, X.; Liu,
Y.; Li, N.; Yin, G.; Yu, C. Asian J. Org. Chem. 2016, 5, 882.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D