Identification of a Surprising Boronic Acid Homocoupling Process in Suzuki-Miyaura Cross-Coupling Reactions Utilizing a Hindered Fluorinated Arene

Article abstract of DOI:10.1055/s-0040-1707266

The Suzuki-Miyaura cross-coupling reaction of 2-bromo-1,3-bis(trifluoromethyl)benzene with arylboronic acids was evaluated and determined to suffer from the formation of large amounts of boronic acid homocoupling products in conjunction with dehalogenation. Homocoupling product formation in this process likely occurs through a rare protonolysis/second transmetalation event rather than by the well-established mechanism requiring the involvement of O ₂. The scope of this boronic acid homocoupling reaction was investigated and shown to predominate with electron-deficient arylboronic acids. Finally, a good yield of cross-coupling products could be obtained by employing dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (SPhos) as the ligand.

Full text of DOI:10.1055/s-0040-1707266

SYNLETT0936-52141437-2096
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
cluster
A
The Power of Transition Metals: An Unen-
S. L. Gargaro et al.
Cluster
Synlett
Identification of a Surprising Boronic Acid Homocoupling Process
in Suzuki–Miyaura Cross-Coupling Reactions Utilizing a Hindered
Fluorinated Arene
Samantha L. Gargaroa
Bre’Shon Dunsona,b
Joshua D. Siebera 16-5097
(dppf)PdCl2
Na2CO3
O2-free!
Pd(OAc)2
SPhos
Na2CO3
H
R'
R'
Br
F3C
CF3
F3C
CF3
+
F3C
CF3
R'
R'
R'
a Department of Chemistry, Virginia Commonwealth University,
1001 West Main Street, Richmond, VA 23284-3028, USA
jdsieber@vcu.edu
cross-coupling
homocoupling
B(OH)2
B(OH)2
b Thomas Jefferson High School, 4100 W Grace Street, Richmond,
VA 23230, USA
F3C
LnPd
R'
Dedicated to Professor Barry Trost in honor of his 80th birthday.
LnPd
CF3
Published as part of the Cluster The Power of Transition Metals: An
Unending Well-Spring of New Reactivity
R'
R'
ArB(OH)2
2nd transmetalation
Corresponding Author
JDeoMesphaauilratjdmDse.ieSnbiteeobrfe@rCvhceum.edisutry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-3028, USA
Received: 16.07.2020
Accepted after revision: 03.08.2020
Published online: 27.08.2020
by the presence of O2 in the reaction mixture. As a result,
rigorous exclusion of O2 is required to avoid this unwanted
reaction pathway.
DOI: 10.1055/s-0040-1707266; Art ID: st-2020-k0400-c
Organofluorine compounds are used extensively in the
pharmaceutical industry and in medicinal chemistry due to
the unique properties of the C–F bond, which can increase
lipophilicity and provide high metabolic stability.7 There-
Abstract The Suzuki–Miyaura cross-coupling reaction of 2-bromo-
1,3-bis(trifluoromethyl)benzene with arylboronic acids was evaluated
and determined to suffer from the formation of large amounts of bo-
ronic acid homocoupling products in conjunction with dehalogenation.
Homocoupling product formation in this process likely occurs through a
rare protonolysis/second transmetalation event rather than by the well-
established mechanism requiring the involvement of O2. The scope of
this boronic acid homocoupling reaction was investigated and shown to
predominate with electron-deficient arylboronic acids. Finally, a good
yield of cross-coupling products could be obtained by employing dicy-
clohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (SPhos) as the ligand.
Suzuki–Miyaura cross-coupling and oxidative boronic acid homocoupling:
X
B(OH)2
R
R'
cat. LnPd(0)
base
R
R
+
R'
solvent
H2O
R
1
2
3
cross-coupling (CC)
Key words palladium catalysis, Suzuki–Miyaura reaction, cross-cou-
pling, arylboronic acids, bromobistrifluoromethylbenzene
R'
R'
cat. LnPd(0)
base
Via:
O
L2Pd
O2
O
5
4
The Suzuki–Miyaura (SM) cross-coupling (CC) reaction
(Scheme 1) represents one of the most powerful and widely
used methods for the construction of biaryl compounds in
both academic and industrial settings.1 Research develop-
ments in this area over the last 50 years have led to a de-
tailed understanding of the reaction mechanism that has
permitted the identification of highly robust and efficient
Pd catalysts2 capable of operating at low catalyst loadings,
making the reaction amenable to large-scale syntheses.3
However, in addition to the desired CC product 3, side-reac-
tions prevalent in the SM CC reaction include dehalogena-
tion of the aryl halide 1, protodeboronation of the boronic
acid 2,4,5 and homocoupling (HC).5 These undesirable path-
ways must be suppressed to achieve high yields of the de-
sired CC product. With regard to oxidative HC of boronic
acid 2, detailed mechanistic investigations6 have implicated
the formation of 4 through a Pd–peroxo species 5 generated
homocoupling (HC)
This work:
Boronic acid homocoupling through a rare second transmetalation event
Br
H
cat. LnPd(0)
base
O2-free!
EWG
EWG
F3C
CF3
F3C
CF3
+
B(OH)2
6
8
9
7
homocoupling (HC)
EWG
F3C
LnPd
7
9
EWG
EWG
LnPd
CF3
second
EWG
transmetalation
through
protonolysis
10
11
Scheme 1 Suzuki–Miyaura cross-coupling and competitive boronic
acid homocoupling
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. L. Gargaro et al.
Cluster
Synlett
fore, the synthesis of fluorinated biaryls by using the SM CC
reaction is a practical way to access new potentially useful
therapeutics. As a result, we recently became interested in
employing the fluorinated arene 6 in SM CC reactions
(Scheme 1). Surprisingly, large amounts of the boronic acid
HC product 8, along with the dehalogenation product 9,
were obtained when employing electron-deficient arylbo-
ronic acids 7 although rigorous exclusion of O2 was carried
out. This result appears to have occurred through a rare sec-
ond transmetalation (TM) event8 facilitated by protonolysis
of the 2,6-bis(trifluoromethyl)phenyl moiety of complex
10. Here, we report our findings in support of this proposed
pathway that, to the best of our knowledge, represent the
first evidence of a second TM process in SM CC.
Initial investigation into the SM CC reaction of 6 was
carried out by using the arylboronic acid 2a while varying
the phosphine ligand (Table 1). Surprisingly, the use of the
commonly employed catalyst (dppf)PdCl2 led to substantial
amounts of the HC product 14a (Table 1, entry 1). Rigorous
exclusion of oxygen by setting up the reaction in an argon-
filled glovebox with degassed solvent led to no improve-
ment. Upon completion of the ligand survey shown in Table
1, we determined that Buchwald’s 2-dicyclohexylphosphi-
no-2′,6′-dimethoxybiphenyl (SPhos) ligand9 afforded high
yields of the CC product 13a (entry 14). However, an inter-
esting trend was observed: regardless of the phosphine em-
ployed, the amount of HC product 14a formed was similar
to the amount of dehalogenated product 9 (entries 1–14).
This observation implied that the formation of the boronic
acid HC product 14a and the dehalogenation product 9
were mechanistically related and not a result of O2 in the
system. Additionally, a control experiment employing (dp-
pf)PdCl2 as catalyst in the absence of 6 afforded only trace
amounts of 14a, further excluding the role of O2.
The reaction scope in relation to the effect of the struc-
ture of the boronic acid on the efficiency of HC versus CC in
this unique HC reaction was next investigated by employing
electronically and sterically differentiated boronic acids 2
with (dppf)PdCl2 as the catalyst (Scheme 2).10 In general,
electron-deficient boronic acids 2a–g afforded HC products
in preference to CC products. When (4-fluorophenyl)boron-
ic acid (2h) was employed, equal amounts of HC and CC
products were obtained; however, when the 3-fluorophe-
nyl derivative 2i was used, the amount of the HC product
increased. This result highlights an important electronic ef-
fect whereby the electron-donating ability of the 4-fluoro
substituent, by resonance, decreases the amount of HC
formed, whereas a 3-fluoro substituent is purely electron-
withdrawing, as the resonance effect is removed at this po-
sition. Additionally, when an electron-donating substituent
(2j–k) or a simple phenyl group (2n) was used, the CC prod-
uct predominated. Finally, ortho-substitution was either
not tolerated (2c) or afforded the HC product (2l), and pro-
Table 1 Catalyst Evaluation for the CC of 6 and 2aa
CHO
OHC
B(OH)2
CHO
2a
CF3
H
Pd(OAc)2 (3 mol%)
ligand (6 mol%)
Br
F3C
CF3
+
+
Na2CO3 (2.0 equiv)
1,4-dioxane/H2O
90 °C, 2 h
F3C
CF3
CF3
6
CHO
13a
14a
9
Entry
Ligand
Yield (%)
13ab
14a
9b
1
2
dppfd
17
56
5
78
15
60
14
61
9
65
10
71
12
64
7
PPh3
3
P(o-Tol)3
P(C6F5)3
PCy3
4
<5
<5
44
<5
8
5
6
P(t-Bu)3
PBu3
7
67
42
9
60
38
5
8
dppme
dppef
9
<5
2
10
11
12
13
14
dpppg
dppbh
Xantphosi
XPhosj
SPhos
6
2
6
6
2
82
20
93
7
7
68
10
62
6
a Reaction conditions: arene 6 (0.325 mmol), 2a (0.650 mmol), Na2CO3
(0.650 mmol), Pd(OAc)2 (3 mol%), ligand (6 mol%), 1,4-dioxane (0.7 mL),
H2O (0.25 mL).
b Determined by 19F NMR spectroscopic analysis of the unpurified reaction
mixture with PhCF3 as standard.
c Determined by 1H NMR spectroscopic analysis of the unpurified reaction
mixture with dimethyl fumarate as standard.
d (dppf)PdCl2·CH2Cl2 (3 mol%).
e CH2(PPh2)2 (3 mol%).
f Ph2P(CH2)2PPh2 (3 mol%).
g Ph2P(CH2)3PPh2 (3 mol%).
h Ph2P(CH2)4PPh2 (3 mol%).
i 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (3 mol%).
j 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
tection of the formyl group in 2a as a 1,3-dioxolane (2m)
led to a reduction in the amount of HC product.
To further elucidate a possible anaerobic mechanism to
account for the formation of the dehalogenation product 9
and boronic acid HC in this system, stoichiometric studies
using (Cy3P)2Pd(0) (15), as outlined in Scheme 3, were per-
formed, because use of PCy3 as a ligand afforded a high HC
selectivity (Table 1, entry 5). The reaction of aryl bromide 6
with 15 under the typical CC reaction conditions, but in the
absence of a boronic acid, led to the oxidative addition com-
plex 16, with the formation of only traces of the dehaloge-
nated product 9, as determined by 19F NMR spectroscopy
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
S. L. Gargaro et al.
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(97:3 ratio of 16 to 9). However, when the reaction was re-
peated in the presence of arylboronic acid 2a, full conver-
sion of the aryl bromide 6 into the dehalogenated product 9
was observed by 19F NMR spectroscopy in only five min-
utes, affording a 75% NMR yield of 14a, with only traces of
the CC product 13a. No other fluorine-containing com-
pounds were detected by 19F NMR spectroscopy. Repeating
the reaction with the aryl pinacol boronate ester 2o also re-
sulted in complete conversion of the aryl bromide 6 into 9
within five minutes, with trace amounts of the CC product,
but gave a reduced NMR yield of the HC product (49%), and
unreacted 2o was also detected by 1H NMR spectroscopy of
the crude mixture.
Br
F3C
CF3
Na2CO3
(Cy P) Pd(0)
+
3
2
F3C
CF3
+
9
1,4-dioxane
H2O, 90 °C
90 min
15
Cy3P Pd PCy3
(1.0 equiv)
6
Br
16
(1.0 equiv)
19F NMR: 97
:
3
CHO
CHO
BR2
6
(1.0 equiv)
Na2CO3
(Cy3P)2Pd(0)
+
9
+
1,4-dioxane
H2O, 90 °C
5 min
sole product
by 19F NMR
15
F3C
CF3
(1.0 equiv)
CHO
(2 equiv)
2a: R = OH
2o: R = pin
CHO
14a
75% (R = OH)
13a
<5%
CF3
49% (R = pin)
Br
Scheme 3 Stoichiometric studies employing (Cy3P)2Pd
B(OH)2
R'
CF3
R'
R'
R'
6
(dppf)PdCl2•CH2Cl2 (3 mol%)
+
inates when reductive elimination is slow. However, such a
pathway is not possible in the SM reaction because trans-
metalation between Pd and arylboron derivatives is
known12 to require a Pd–O–B interaction. Therefore Pd does
not undergo direct aryl–aryl exchange with boronic acids.
As a result, a protonolysis of the more sterically hindered
2,6-bis(trifluoromethyl)phenyl group of 18 to generate 9
directly and to provide a possible competent intermediate
(19 or 20)12 for a second TM with 2 to lead to HC product
14a via 21 seems to be required. This is surprising because
Pd–C bonds are relatively inert to protonolysis.11 This path-
way appears to be unique to this system with its 2,6-bis(tri-
fluoromethyl) substitution; moreover, it requires a boro-
nate derivative because formation of 9 was minimal in the
absence of a boronic acid, whereas it was rapidly generated
in the presence of boron derivatives 2 (Scheme 3). There-
fore, 18 might be subjected to direct protonolysis by the bo-
ronic acid to afford 20,12d or protonolysis might simply be
facilitated by the presence of the second aryl group of com-
plex 18 introduced after the first TM. The latter seems more
likely because both the boronic acid 2a and the boronate
ester 2o induced rapid dehalogenation of 6 (Scheme 3). Ad-
ditionally, it is well appreciated that the rate of transmeta-
lation of aryl pinacol boronates is lower than that of the
corresponding boronic acid in SM CC reactions.12d There-
fore, the use of boronate 2o instead of boronic acid 2a
should provide a reduced rate of HC formation in the stoi-
chiometric reactions in Scheme 3 if a second TM occurs.
The presence of unreacted boronate 2o and the reduced
yield of 14a when boronate 2o is used instead of boronic
acid 2a is fully consistent with this argument.13
F3C
CF3
Na2CO3 (2.0 equiv)
1,4-dioxane/H2O
90 °C, 2 h
2
13
14
CHO
OHC
OHC
B(OH)2
B(OH)2
B(OH)2
2a
2b
2c
78% HC
16% CC
59% HC
17% CC
<5% HC
0% CC
MeO2C
B(OH)2 F3C
B(OH)2 O2N
B(OH)2
2d
2e
2f
62% HC
26% CC
53% HC
15% CC
28% HC
6% CC
F
NC
B(OH)2
F
B(OH)2
B(OH)2
2g
2h
2i
72% HC
18% CC
31% HC
35% CC
47% HC
18% CC
MeO
OMe
MeO
B(OH)2
B(OH)2
B(OH)2
2j
2k
2l
31% HC
47% CC
9% HC
60% CC
70% HC
0% CC
O
B(OH)2
B(OH)2
O
2m
35% HC
33% CC
2n
22% HC
57% CC
Scheme 2 Boronic acid homocoupling reaction scope employing 610
A possible mechanism to account for the results ob-
tained is consistent with a second TM pathway8 that pre-
sumably requires a Pd–C protonolysis11 event to permit TM
of the arylboronic acid (Scheme 4). For example, the HC of
the organometallic coupling partner in Negishi8a or Kuma-
da8b coupling reactions is well established to occur through
this second TM by a direct aryl–aryl exchange that predom-
According to the proposal outlined in Scheme 4, the ra-
tio of CC to HC products should be dictated by the rate of
reductive elimination of 18 relative to the outlined HC path-
way. For cases where reductive elimination of 18 is slow, HC
products should predominate.8 The results obtained from
an investigation of the reaction of 6 with various boronic
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
S. L. Gargaro et al.
Cluster
Synlett
protonolysis of the 2,6-bis(trifluoromethyl)aryl group war-
rants further investigation and is probably not facilitated by
retro-concerted metalation–deprotonation10 enabled by
F3C
L2Pd
F3C
1
st TM
L2Pd(0)
2
13a
(CC)
6
CF3
L2Pd
CF3
base
H2O
–
Br
17
the presence of HCO3 , as control experiments in which
NaOH or KF was used as the base in the reactions shown in
Scheme 2 afforded no improvements in CC selectivity.15
High selectivities toward boronic acid HC with aryl bromide
coupling partners other than 6 have not been identified. For
example, preliminary studies with perfluorinated bromo-
benzene and boronic acid 2a, 2-bromo-1,3-dimethoxyben-
zene and boronic acid 2l, or 2-bromo-1,3,5-triisopropyl-
benzene and boronic acid 2l all afforded the CC product as
the major product.
Finally, successful CC with arene 6 was achieved by us-
ing a Pd catalyst derived from SPhos9 (Table 1, entry 14). As
a result, the substrate scope of the CC reaction of 6 with
specifically electron-deficient arylboronic acids was further
evaluated (Scheme 5).16 In general, good yields of CC prod-
ucts were obtained except when employing arylboronic ac-
ids with ortho-substituents (2c and 2l).
protonolysis
slow
base
H2O
CHO
18
protonolysis
fast
2, base/H2O
H
F3C
CF3
OH
HO
O
Na
B
p-CHO-Ph
OH
9
L2Pd
L2Pd
or
CHO
CHO
CHO
19
20
2b
2nd TM
14a
(HC)
L2Pd
21
21
14a
(HC)
CHO
CF3
Scheme 4 Possible mechanism for HC formation in the absence of O2
Br
through a protonolysis/second transmetalation pathway
CF3
R'
R'
R'
6
B(OH)2
R'
acids and (dppf)PdCl2 as catalyst (Scheme 2) further sup-
port this proposal. Because of the high electron-withdraw-
ing ability of the CF3 groups, reductive elimination from
complex 18 to afford the CC product should be slow when
electron-deficient boronic acids are employed (e.g., 2a–g or
2i), due to the polarity mismatch of forming a C–C bond be-
tween two electropositive carbon atoms. Additionally, the
steric effect of the two ortho CF3 groups in the 2,6-disubsti-
tuted compound inhibits CC. As a result, the protonoly-
sis/second TM can compete, leading to preferential boronic
acid HC. In contrast, electron-rich boronic acids (e.g., 2h, 2j,
or 2k) should show an increased rate of reductive elimina-
tion from the analogous unsymmetrical LnP(Ar)Ar′ complex
of 18 by minimizing this polarity mismatch, leading to in-
creased amounts of CC products, as observed (Scheme 2).
On the other hand, an electron-rich sterically hindered bo-
ronic acid (2l) presumably favors HC on steric grounds. Fi-
nally, the increase in selectivity for CC when Xantphos or
SPhos was used as ligand (Table 1, entries 12 and 14) can be
rationalized in terms of an increased rate of reductive elim-
ination of 18 due to the large bite angle and the steric hin-
derance associated with these two ligands, respectively.14
Overall, the formation of HC byproducts in the SM CC
reaction of fluorinated arene 6 appears to be due its unique
properties resulting from the high electron-withdrawing
ability of the two CF3 groups and from the steric effect of
their 2,6-disubstitution pattern, which together lead to sur-
prisingly easy protonolysis, facilitating a second TM. This
problem is exacerbated when electron-deficient arylboron-
ic acids are employed as coupling partners in the reaction.
The unique ability of intermediates such as 18 to undergo
Pd(OAc)2 (3 mol%)
SPhos (6 mol%)
F3C
CF3
+
Na2CO3 (2.0 equiv)
1,4-dioxane/H2O
90 °C, 2 h
2
13
14
CHO
OHC
OHC
B(OH)2
B(OH)2
B(OH)2
2a
6% HC
81% CC
2b
2c
22% HC
67% CC
21% HC
0% CC
MeO2C
B(OH)2 F3C
B(OH)2 O2N
B(OH)2
2d
11% HC
57% CC
2e
2f
18% HC
81% CC
5% HC
91% CC
OMe
B(OH)2
NC
B(OH)2
2g
2l
10% HC
83% CC
50% HC
<5% CC
Scheme 5 CC reaction of aryl halide 6 with electron-deficient aryl
boronic acids with SPhos as ligand14
In conclusion, a novel mechanism for boronic acid HC in
SM CC reactions was discovered that occurs under anaero-
bic conditions. This HC pathway is unique to the 2,6-bis(tri-
fluoromethyl)phenyl substitution pattern of aryl halide 6,
which presumably reduces the rate of reductive elimination
leading to CC when employing an electron-deficient boron-
ic acid; this permits a surprisingly facile protonolysis to
compete, enabling a second TM. Because of the significance
of the SM CC reaction and of organofluorine compounds,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
S. L. Gargaro et al.
Cluster
Synlett
the findings described here provide a valuable guide to fu-
ture developments of SM CC reactions employing fluorinat-
ed arenes as coupling partners. Additionally, these results
point to an alternative operable mechanism for boronic
acid HC in SM CC reactions where the rate of reductive
elimination might be slow (e.g., asymmetric CC of tri- or
tetrasubstituted biaryls).17
(6) (a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J.
Am. Chem. Soc. 2006, 128, 6829. (b) Moreno-Mañas, M.; Pérez,
M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346. (c) Aramendia, M.
A.; Lafont, F. J. Org. Chem. 1999, 64, 3592. (d) Yoshida, H.;
Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003, 44,
1541. (e) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42,
4087.
(7) (a) Dolbier, W. R. J. Fluorine Chem. 2005, 126, 157. (b) Müller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) O’Hagan, D.
Chem. Soc. Rev. 2008, 37, 308. (d) Purser, S.; Moor, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(e) Yale, H. L. J. Med. Pharm. Chem. 1959, 1, 121.
Funding Information
Startup funding was provided by the Virginia Commonwealth Univer-
sity and the Bill and Melinda Gates Foundation (The Medicines for All
Institute, grant number OPP1176590)BliandMelindGatesFudation(OP17659)0VngriaComonwetlahUnversity)(
(8) (a) Liu, Q.; Lan, Y.; Liu, J.; Li, G.; Wu, Y.-D.; Lei, A. J. Am. Chem.
Soc. 2009, 131, 10201. (b) Wang, J.; Meng, G.; Xie, K.; Li, L.; Sun,
H.; Huang, Z. ACS Catal. 2017, 7, 7421.
(9) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2004, 43, 1871.
Acknowledgment
(10) Biphenyl-4,4′-dicarbaldehyde (14a); Typical HC Procedure
A crimp-cap vial equipped with magnetic stirrer bar was
charged with (dppf)PdCl2·CH2Cl2 (8.2 mg, 0.010 mmol), (4-
formylphenyl)boronic acid (2a; 97.9 mg, 0.653 mmol), Na2CO3
(69.2 mg, 0.653 mmol), and 2-bromo-1,3-bis(trifluoro-
methyl)benzene (6; 95.7 mg, 0.327 mmol). The vial was sealed
with a crimp-cap septum and filled with Ar by using three
vacuum–purge cycles. Degassed (Ar sparge) 1,4-dioxane (0.70
mL) and H2O (0.25 mL) were added, and the vial was immersed
in an oil bath at 90 °C for 2 h, then cooled to r.t. H2O was added
and the mixture was extracted with CH2Cl2 (2 × 4 mL). The com-
bined organics were mixed with PhCF3 (60.0 L, 0.488 mmol) as
an added standard, and an aliquot was diluted in CDCl3 for
quantitative 19F NMR spectroscopy. The organics were then
dried (Na2SO4) and concentrated in vacuo. Purification by flash
chromatography [silica gel, hexanes–EtOAc (0–25%)] gave a
white solid; yield: 53.2 mg (77%); mp 141–143 °C; Rf = 0.26 (25%
EtOAc–hexanes).
B.D. thanks the American Chemical Society for a summer research fel-
lowship as a part of the ACS Project SEED Program. We thank Dr. Jo-
seph Turner (VCU) for assistance in collecting HRMS data.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707266. SuprtigInfrmatioSnuprtigInfrmation
References and Notes
(1) For reviews, see: (a) Suzuki, A. J. Organomet. Chem. 1999, 576,
147. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(c) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64,
3047. (d) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
1H NMR (600 MHz, CDCl3):  = 10.09 (s, 2 H), 8.00 (d, J = 8.0 Hz,
4 H), 7.80 (d, J = 8.0 Hz, 4 H). 13C NMR (CDCl3, 150 MHz):  =
191.7, 145.5, 135.9, 130.4, 128.0. HRMS (DART): m/z [M + H]+
calcd for C14H11O2: 211.0759; found: 211.0788.
(2) (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
(b) Christmann, U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366.
(c) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062. (d) Lundgren,
R. J.; Stradiotto, M. Chem. Eur. J. 2012, 18, 9758. (e) Miura, M.
Angew. Chem. Int. Ed. 2004, 43, 2201. (f) Martin, R.; Buchwald, S.
L. Acc. Chem. Res. 2008, 41, 1461. (g) DeAngelis, A. J.; Gildner, P.
G.; Chow, R.; Colacot, T. J. J. Org. Chem. 2015, 80, 6794.
(h) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073. (i) Yang, Y.; Oldenhuis, N. J.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2013, 52, 615. (j) Bruno, N. C.; Tudge, M. T.;
Buchwald, S. L. Chem. Sci. 2013, 4, 916. (k) Li, H.; Johansson
Seechurn, C. C. C.; Colacot, T. J. ACS Catal. 2012, 2, 1147.
(l) Gildner, P. G.; Colacot, T. J. Organometallics 2015, 34, 5497.
(3) (a) Dumrath, A.; Lubbe, C.; Beller, M. In Palladium-Catalyzed
Coupling Reactions: Practical Aspects and Future Developments;
Molnar, A., Ed.; Wiley-VCH: Weinheim, 2013, 445. (b) Torborg,
C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027. (c) Budarin, V.;
Shuttleworth, P. S.; Clark, J. H.; Luque, R. Curr. Org. Synth. 2010,
7, 614.
(11) O’Duill, M. L.; Engle, K. M. Synthesis 2018, 50, 4699.
(12) (a) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116.
(b) Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329.
(c) Thomas, A. A.; Wang, H.; Zahrt, A. F.; Denmark, S. E. J. Am.
Chem. Soc. 2017, 139, 3805. (d) Thomas, A. A.; Zahrt, A. F.;
Delaney, C. P.; Denmark, S. E. J. Am. Chem. Soc. 2018, 140, 4401.
(e) Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2013,
52, 7362. (f) Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J.
2011, 17, 2492. (g) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque,
G. ChemCatChem 2014, 6, 3132. (h) Sicre, C.; Braga, A. A. C.;
Maseras, F.; Cid, M. M. Tetrahedron 2008, 64, 7437. (i) Braga, A.
A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem. Soc.
2005, 127, 9298. (j) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.;
Lledós, A.; Maseras, F. J. Organomet. Chem. 2006, 691, 4459.
(k) Braga, A. A.; Ujaque, G.; Maseras, F. Organometallics 2006,
25, 3647. (l) Miyaura, N. J. Organomet. Chem. 2002, 653, 54.
(13) The results obtained are also consistent with the formation of
HC product 14a from 21 through a bimetallic-catalyst-exchange
mechanism where aryl–aryl exchange between two molecules
of 18 occurs to generate 21 along with a symmetrical Pd
complex bearing two 2,6-bis(trifluoromethyl)phenyl fragments
(4) (a) Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.;
Lloyd-Jones, G. C. J. Am. Chem. Soc. 2017, 139, 13156. (b) Cox, P.
A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am. Chem.
Soc. 2016, 138, 9145.
(5) Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J. Chem. 2010, 50, 664.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
S. L. Gargaro et al.
Cluster
Synlett
that would need to undergo protonolysis to form 9 and reenter
the catalytic cycle. For an example of bimetallic exchange, see:
Wang D., Izawa Y., Stahl S. S.; J. Am. Chem. Soc.; 2014, 136: 9914
(14) Other strategies to facilitate reductive elimination using elec-
tron-deficient fluorinated styrenes as additives have been
reported. It is possible that coordination of electron-deficient
arene 9 to the Pd-intermediates involved in these processes
might play a role in the observed reaction outcomes. For exam-
ples, see: (a) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998,
120, 11186. (b) Giovannini, R.; Stüdemann, T.; Devasagayaraj,
A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
(c) Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew.
Chem. Int. Ed. 1998, 37, 2387.
were then dried (Na2SO4) and concentrated in vacuo. Purifica-
tion by flash chromatography [silica gel, hexanes–EtOAc (0–
25%)] gave a yellow oil; yield: 84.6 mg (85%); Rf = 0.59 (25%
EtOAc–hexanes).
1H NMR (600 MHz, CDCl3):  = 10.09 (s, 1 H), 7.99 (d, J = 8.0 Hz,
2 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.45 (d, J =
8.0 Hz, 2 H). 13C NMR (150 MHz, CDCl3):  = 191.8, 140.3, 138.7,
136.1, 130.9 (q, J = 30.0 Hz), 130.8, 129.4 (q, J = 5.0 Hz),
128.5, 128.2, 123.1 (q, J = 275.0 Hz). 19F NMR (565 MHz, CDCl3):
 = –57.5. HRMS (DART): m/z [M + H]+ calcd for C15H9F6O:
319.0558; found: 319.0578.
(17) (a) Patel, N. D.; Sieber, J. D.; Tcyrulnikov, S.; Simmons, B. J.;
Rivalti, D.; Duvvuri, K.; Zhang, Y.; Gao, D. A.; Fandrick, K. R.;
Haddad, N.; Lao, K. S.; Mangunuru, H. P. R.; Biswas, S.; Qu, B.;
Grinberg, N.; Pennino, S.; Lee, H.; Song, J. J.; Gupton B, F.; Garg,
N. K.; Kozlowski, M. C.; Senanayake, C. H. ACS Catal. 2018, 8,
10190. (b) Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
12051. (c) Shen, X.; Jones, G. O.; Watson, D. A.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278.
(d) Cammidge, A. N.; Crépy, K. V. L. Chem. Commun. 2000, 1723.
(e) Cammidge, A. N.; Crépy, K. V. L. Tetrahedron 2004, 60, 4377.
(f) Bermejo, A.; Ros, A.; Fernández, R.; Lassaletta, J. M. J. Am.
Chem. Soc. 2008, 130, 15798. (g) Uozumi, Y.; Matsuura, T.;
Arakawa, T.; Yamada, Y. M. Angew. Chem. Int. Ed. 2009, 48, 2708.
(h) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025. (i) Genov,
M.; Almorín, A.; Espinet, P. Chem. Eur. J. 2006, 12, 9346.
(j) Mešková, M.; Putala, M. Tetrahedron: Asymmetry 2013, 24,
894.
(15) See the Supporting Information.
(16) 2′,6′-Bis(trifluoromethyl)biphenyl-4-carbaldehyde
(13a):
Typical CC Procedure
A crimp-cap vial equipped with magnetic stirrer bar was
charged with Pd(OAc)2 (2.2 mg, 0.010 mmol), SPhos (8.3 mg,
0.020 mmol), (4-formylphenyl)boronic acid (2a; 97.9 mg, 0.653
mmol), Na2CO3 (69.2 mg, 0.653 mmol), and 2-bromo-1,3-
bis(trifluoromethyl)benzene (6; 95.7 mg, 0.327 mmol). The vial
was sealed with a crimp-cap septum and filled with Ar by using
three vacuum–purge cycles. Degassed (Ar sparge) 1,4-dioxane
(0.70 mL) and H2O (0.25 mL) were added, and the vial was
immersed in an oil bath at 90 °C for 2 h, then cooled to r.t. H2O
was added, and the mixture was extracted with CH2Cl2 (2 × 4
mL). The combined organics were mixed with PhCF3 (60.0 L,
0.488 mmol) as an added standard, and an aliquot was diluted
in CDCl3 for quantitative 19F NMR spectroscopy. The organics
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F