Palladium-catalyzed Suzuki-Miyaura reactions of potassium aryl- and heteroaryltrifluoroborates with aryl- and heteroaryl triflates

Article abstract of DOI:10.1055/s-2005-871544

The Suzuki-Miyaura cross-coupling of potassium aryl-and heteroaryltrifluoroborates with aryl- and heteroaryl triflates is reported. The catalyst system provides good to excellent yields using sterically hindered and electronically diverse coupling partners. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871544

CLUSTER
1763
Palladium-Catalyzed Suzuki–Miyaura Reactions of Potassium Aryl- and
Heteroaryltrifluoroborates with Aryl- and Heteroaryl Triflates
C
ross-Coupling of
a
Aryltrifluo
r
roborate
y
s with
A
ryl Triflate
A
s
. Molander,* Daniel E. Petrillo, Nicole R. Landzberg, John C. Rohanna, Betina Biolatto
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA
Fax +1(215)5737165; E-mail: gmolandr@sas.upenn.edu
Received 23 March 2005
conditions. Herein we report an expansion of this method
Abstract: The Suzuki–Miyaura cross-coupling of potassium aryl-
to the synthesis of biaryl- and heterobiaryl systems using
aryl triflates as electrophiles.
and heteroaryltrifluoroborates with aryl- and heteroaryl triflates is
reported. The catalyst system provides good to excellent yields us-
ing sterically hindered and electronically diverse coupling partners.
In a previous study of Suzuki–Miyaura couplings under
Key words: Suzuki–Miyaura, palladium, cross-coupling, biaryls, ligandless conditions that was optimized for aryl halide
electrophiles [0.5 mol% Pd(OAc)2, K2CO3. MeOH],6 only
aryltrifluoroborates, aryl triflates
electron-poor aryl triflates underwent coupling with po-
tassium aryltrifluoroborates. When these conditions (as
well as the ligand-assisted conditions7) were applied to the
The Suzuki–Miyaura reaction is one of the most effective
and reliable methods of forming biaryl compounds.1 Al-
though the synthesis of biaryls via cross-coupling proce-
dures can be carried out using a variety of organometallic
reagents, organoboron compounds possess several advan-
tages including their ease of preparation by a variety of
methods and low toxicity. Competent aryl electrophiles
for the Suzuki–Miyaura reaction include aryl halides (io-
dides, bromides, and chlorides) and trifluoromethane-
sulfonates (triflates). A wide variety of functionality is
tolerated in the coupling process using organoborons,
making the process amenable to complex molecule syn-
thesis.
coupling of electron rich p-methoxyphenyl triflate (1)
with potassium phenyltrifluoroborate (2), only traces of
product were seen. Because of the importance of aryl tri-
flates as substrates for biaryl coupling, targeted optimiza-
tion for these electrophiles was undertaken. A screen of
catalysts, ligands, bases, and solvents led to the combina-
tion of Pd(OAc)2, PCy3, Cs2CO3 and THF–H2O which
produced an 80% assay yield (GC) of product in the cou-
pling between phenyltrifluoroborate and p-methoxyphe-
nyl triflate. Further optimization of catalyst loading and
concentration led to a 92% isolated yield of 3 using 5
mol% Pd(OAc)2, 10 mol% PCy3, 3 equivalents of
Cs2CO3, and a total concentration of 0.2 M in THF–H2O
(10:1, Scheme 1).
Recently, organotrifluoroborates have been demonstrated
to be effective partners in the Suzuki–Miyaura reaction as
well as other carbon–carbon bond-forming reactions.2
These reagents offer many advantages over other orga-
noborons such as boronic acids, boronate esters and
trialkylboranes. The organotrifluoroborates are easily pre-
pared in large quantities and are indefinitely bench-stable.
In contrast to boronic acids, they are monomeric species,
making the determination of stoichiometry very reliable.
The trifluoroborates are more atom economical than
boronate esters, and the exclusive production of inorganic
by-products makes work up of their coupling reactions
more facile as well.
5% Pd(OAc)2
10% PCy3
Cs2CO3 (3 equiv)
TfO
OMe
BF3K
Ph
OMe
THF/H2O (10:1)
reflux, 20 h, 92%
3
1
2
Scheme 1
To test the generality of these conditions, various aryl
triflates were then coupled to potassium phenyltrifluoro-
borate (Table 1).
In 1996 Genêt reported the coupling of potassium aryl-
and alkenyltrifluoroborates with arenediazonium tetra-
fluoroborates.3 In 1999, Xia used diaryliodonium salts as
electrophiles under the same conditions.4 The coupling of
tetrabutylammonium aryltrifluoroborates with aryl io-
dides and bromides was first described by Batey in 2001.5
In 2002, we reported the palladium-catalyzed reaction of
aryl- and heteroaryl trifluoroborates with aryl- and
heteroaryl halides under ligandless6 and ligand-assisted7
Electron-rich (entry 1), electron-poor (entries 3 and 8),
and electronically neutral (entry 4) triflates all coupled in
good to excellent yields with potassium phenyltrifluoro-
borate. Sterically hindered (entry 5) and naphthyl triflates
(entries 2 and 6) coupled smoothly. Additionally, a het-
eroaryl triflate (entry 9) underwent the coupling reaction,
giving 8-phenylquinoline in good yield.
Interestingly, when the bromophenyl triflate (entry 7) was
used as the electrophile, coupling occurred at the bromide
rather than the triflate. However, when the chlorophenyl
triflate (entry 8) was subjected to the optimized condi-
tions, coupling occurred at the triflate. This is consistent
SYNLETT 2005, No. 11, pp 1763–1766
0
7
.0
7
.2
0
0
5
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871544; Art ID: Y00205ST
© Georg Thieme Verlag Stuttgart · New York

1764
G. A. Molander et al.
CLUSTER
4-Methoxybiphenyl9 – General Procedure A for Suzuki
with our previous observations for the cross-coupling of
potassium alkyltrifluoroborates with aryl electrophiles, in
which the order of reactivity is Br > OTf > Cl.8
Coupling of Potassium Aryltrifluoroborates with Aryl Triflates
Tricyclohexylphosphine (0.10 mmol, 0.028 g) was added to a dry,
2-neck 25 mL flask equipped with a stirbar, reflux condenser and
septum in a glove box. The flask was removed from the glove box
and placed under nitrogen gas. Potassium phenyltrifluoroborate10
(1.20 mmol, 0.221 g), Cs2CO3 (3.00 mmol, 0.975 g), and palladium
acetate (0.050 mmol, 0.011 g) were sequentially added to the flask.
After addition, the flask and condenser were evacuated and refilled
with nitrogen. 4-Methoxyphenyl triflate (1.00 mmol, 0.256 mL) and
THF–H2O (4.55 mL:0.45 mL) were then added to the flask. The
mixture was heated at reflux for 20 h at which point GC-MS indi-
cated consumption of the triflate. The resulting mixture was parti-
tioned between EtOAc (20 mL) and H2O (10 mL). The aqueous
layer was extracted with EtOAc (4 × 10 mL), and the organic layer
was then washed with brine. The organic layer was then dried with
MgSO4 and concentrated. The resulting product was purified by
flash chromatography (0.5% EtOAc–hexanes) to give 0.169 g
(92%) of 4-methoxybiphenyl. Product appearance: white solid; mp
87.5–88.5 °C; Rf = 0.37 (5% EtOAc–hexanes). 1H NMR (300 MHz,
CDCl3): d = 7.62 (t, J = 6.7 Hz, 4 H), 7.49 (t, J = 8.0 Hz, 2 H), 7.38
(t, J = 6.7 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 2 H), 3.91 (s, 3 H). 13C NMR
(75 MHz, CDCl3): d = 159.2, 140.9, 133.8, 128.8, 128.2, 126.8,
126.7, 114.3, 55.3.
Electronically diverse potassium aryltrifluoroborates
were then reacted under the optimized conditions
(Table 2).
Electron-rich (entry 2), electron-poor (entries 4 and 6),
and electronically neutral (entry 3) aryltrifluoroborates all
coupled, providing good to excellent yields of the desired
products. A heteroaryltrifluoroborate (entry 1) coupled to
1 in good yield as well.
In summary, potassium aryltrifluoroborates are readily
prepared, easily handled, and stable to indefinite storage.
Their outstanding physical properties and synthetic utility
as described herein, combined with the facile preparation
of aryl triflates from phenol derivatives, allows an impor-
tant new entry to a wide array of functionalized biaryls.
Table 1 Reaction of Potassium Phenyltrifluoroborate with Aryl
Triflatesa
4-(3-Thienyl)anisole11 – General Procedure B for Suzuki
Coupling of Aryltrifluoroborates with Aryl Triflates
Entry ArOTf
Product
Yield of
Product (%)
In a glove box, tricyclohexylphosphine (0.20 mmol, 0.056 g) was
added to a dry, 10 mL flask or 20 mL vial. The flask was removed
from the glove box and the phosphine was dissolved in THF (1 mL)
under nitrogen gas. Potassium 3-thienyltrifluoroborate (2.40 mmol,
0.456 g), Cs2CO3 (6.00 mmol, 1.95 g), and palladium acetate (0.10
mmol, 0.022 g) were sequentially added to a separate 25 mL, 2-neck
round-bottomed flask. After addition, the flask was evacuated and
refilled with nitrogen. 4-Methoxyphenyl triflate (2.00 mmol, 0.512
g), THF (8 mL), and H2O (0.9 mL) were added to the flask. The so-
lution of the phosphine was then added via double-ended needle to
the reaction vessel. The mixture was heated at reflux for 48 h at
which point GC-MS revealed consumption of starting material. The
resulting mixture was partitioned between EtOAc and H2O. The
aqueous layer was extracted with EtOAc (4 × 20 mL) and the organ-
ic layer was washed with brine, dried with MgSO4, and concentrat-
ed. The resulting product was purified by flash chromatography
(1.0% EtOAc–hexanes) to give 0.300 g (79%) of 4-thienylanisole.
Product appearance: yellow solid; mp 123–125 °C; Rf = 0.15 (1%
EtOAc–hexanes). 1H NMR (500 MHz, CDCl3): d = 7.54–7.52 (m,
2 H), 7.38–7.34 (m, 3 H), 6.95–6.93 (m, 2 H), 3.84 (s, 3 H). 13C
NMR (125 MHz, CDCl3): d = 159.0, 142.2, 128.9, 127.7, 126.4,
126.2, 119.1, 55.5.
1
92
86
TfO
OMe
Ph
OMe
2
OTf
Ph
3
65
94
83
TfO
NO2
Ph
Ph
NO2
4
TfO
5
Ph
TfO
6
92
Ph
OTf
7
43
82
81
1-Phenylnaphthalene12
TfO
Br
Cl
TfO
Ph
Ph
Cl
General procedure A was used, but the reaction was heated at reflux
for 22 h. Yield 86%. Product appearance: colorless oil. Rf = 0.33
(0.5% EtOAc–hexanes). 1H NMR (500 MHz, CDCl3): d = 8.29 (d,
J = 7.5 Hz, 1 H), 8.19 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H),
7.83–7.69 (m, 9 H). 13C NMR (125 MHz, CDCl3): d = 140.9, 140.4,
133.9, 131.8, 130.2, 128.8, 128.4, 128.3, 127.7, 127.3, 127.0, 126.1,
125.8, 125.5.
8
TfO
9
OTf
Ph
N
N
4-Nitrobiphenyl13
General procedure A was used, but the reaction was heated at reflux
for 4 h. Yield 65%. Product appearance: yellow solid; mp 107.5–
a Conditions: Pd(OAc)2 (5 mol%), PCy3 (10 mol%), Cs2CO3
(3 equiv), THF–H2O (10:1), reflux.
1
108.0 °C; Rf = 0.35 (5% EtOAc–hexanes). H NMR (500 MHz,
CDCl3): d = 8.29 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H),
7.64–7.62 (m, 1 H), 7.53–7.44 (m, 2 H). 13C NMR (125 MHz,
CDCl3): d = 147.6, 147.1, 138.8, 129.2, 129.0, 127.8, 127.4, 124.1.
Synlett 2005, No. 11, 1763–1766 © Thieme Stuttgart · New York

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Cross-Coupling of Aryltrifluoroborates with Aryl Triflates
1765
Table 2 Reaction of Potassium Aryltrifluoroborates with Aryl Triflatesa
Entry
1
ArBF3K
ArOTf
Product
Yield (%)
79
BF3K
OMe
TfO
OMe
S
S
2
3
4
76
66
59
MeO
OMe
TfO
TfO
TfO
OMe
OMe
OMe
MeO
BF3K
OMe
BF3K
F3C
OMe
F3C
BF3K
5
6
71
92
TfO
OMe
BF3K
OMe
CF3
OTf
F3C
BF3K
a Conditions: Pd(OAc)2 (5 mol%), PCy3 (10 mol%), Cs2CO3 (3 equiv), THF–H2O (10:1), reflux.
1
4-Methylbiphenyl12
°C; Rf = 0.34 (hexanes). H NMR (500 MHz, CDCl3): d = 7.57–
7.35 (m, 9 H). 13C NMR (125 MHz, CDCl3): d = 140.2, 139.8,
133.5, 129.1, 129.0, 128.5, 127.7, 127.1.
General procedure B was used, but the reaction was heated at reflux
for 22 h. Yield 94%. Product appearance: white solid; Rf = 0.32
(hexanes); mp 43.5–44.5 °C. 1H NMR (500 MHz, CDCl3): d = 7.63
(d, J = 8.2 Hz, 2 H), 7.55 (d, J = 7.7 Hz, 2 H), 7.47 (t, J = 7.7 Hz, 2
H), 7.37 (t, J = 7.7 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 2 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 141.3, 138.5, 137.2, 129.6, 128.8,
127.1, 127.1, 21.2.
8-Phenylquinoline18
General procedure B was used, but the mixture was heated for 24 h.
Yield 81%. Product appearance: brown oil; Rf = 0.16 (5% EtOAc–
hexanes). H NMR (500 MHz, CDCl3): d = 8.97 (dd, J = 4.2, 1.8
1
Hz, 1 H), 8.21 (dd, J = 8.2, 1.8 Hz, 1 H), 7.83 (dd, J = 8.0, 1.4 Hz,
1 H), 7.76–7.73 (m, 3 H), 7.61 (t, J = 7.3 Hz, 1 H), 7.53–7.50 (m, 2
H), 7.44–7.40 (m, 2 H). 13C NMR (125 MHz, CDCl3): d = 150.4,
146.2, 141.1, 139.7, 136.4, 130.4, 130.4, 128.9, 128.1, 127.7, 127.5,
126.4, 121.1.
2,6-Dimethylbiphenyl14
General procedure B was used, but the mixture was heated for 72 h.
Yield 83%. Product appearance: colorless oil; Rf = 0.33 (hexanes).
1H NMR (500 MHz, CDCl3): d = 7.49–7.12 (m, 8 H), 2.05 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 142.0, 141.2, 136.2, 129.2, 128.6,
127.4, 127.2, 126.7, 21.0.
4-4¢-Dimethoxybiphenyl19
General procedure A was used, but the reaction was heated at reflux
for 38 h. Yield 76%. Product appearance: off-white solid; mp 172–
173 °C; Rf = 0.27 (2.5% EtOAc–hexanes). H NMR (500 MHz,
CDCl3): d = 7.50 (d, J = 8.4 Hz, 4 H), 6.98 (d, J = 8.8 Hz, 4 H), 3.86
(s, 6 H). 13C NMR (125 MHz, CDCl3): d = 158.9, 133.6, 127.9,
114.3, 55.5.
2-Phenylnaphthalene15
General procedure A was used, but the reaction was heated at reflux
for 20 h. Yield 92%. Product appearance: white solid; mp 100–101
1
1
°C; Rf = 0.27 (5% EtOAc–hexanes). H NMR (500 MHz, CDCl3):
d = 8.1 (s, 1 H), 7.98–7.91 (m, 3 H), 7.84–7.77 (m, 3 H), 7.60–7.52
(m, 4 H), 7.47–7.43 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 141.3, 138.7, 133.8, 132.8, 129.0, 128.6, 128.3, 127.8, 127.6,
127.5, 126.4, 126.0, 125.9, 125.7.
4-Methoxy-4¢-methylbiphenyl20
General procedure A was used, but the reaction was heated at reflux
for 21 h. Yield 66%. Product appearance: white solid. Recrystalli-
zation from EtOH gave an analytical sample (42%); mp 107–108
°C; Rf = 0.32 (2.5% EtOAc–hexanes). 1H NMR (500 MHz, CDCl3):
d = 7.61 (d, J = 9.6 Hz, 2 H), 7.55 (d, J = 7.9 Hz, 2 H), 7.32 (d,
J = 7.7 Hz, 2 H), 7.06 (d, J = 9.0 Hz, 2 H), 3.91 (s, 3 H), 2.48 (s, 3
H). 13C NMR (125 MHz, CDCl3): d = 159.1, 138.1, 136.5, 133.9,
128.1, 126.7, 114.3, 55.5, 21.2.
4-Trifluoromethylsulfonyloxybiphenyl16
General procedure B was used, but the mixture was heated for 48 h.
Yield 43%. Product appearance: yellow solid; mp 57–61 °C.
Rf = 0.22 (1% EtOAc–hexanes). 1H NMR (500 MHz, CDCl3):
d = 7.69–7.34 (m, 9 H). 13C NMR (125 MHz, CDCl3): d = 149.1,
141.9, 139.5, 129.1, 129.0, 128.2, 127.4, 121.8, 118.9 (q,
JCF = 321.4 Hz).
4-Methoxy-4¢-(trifluoromethyl)biphenyl21
4-Chlorobiphenyl17
General procedure B was used, but the reaction was heated at reflux
for 24 h. Yield 82%. Product appearance: white solid; mp 76.0–76.5
General procedure B was used, but the mixture was heated for 40 h.
Yield 59%. Product appearance: white solid; mp 117–121 °C;
1
Rf = 0.14 (1% EtOAc–hexanes). H NMR (500 MHz, CDCl3): d =
Synlett 2005, No. 11, 1763–1766 © Thieme Stuttgart · New York

1766
G. A. Molander et al.
CLUSTER
7.68–7.64 (m, 4 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.00 (d, J = 8.8 Hz, 2
H), 3.86 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 160.0, 144.4,
132.3, 128.8 (q, JCF = 32.6 Hz), 128.5, 127.0, 125.8 (q, JCF = 3.8
Hz), 125.6 (q, JCF = 271.6 Hz), 114.6, 55.5.
References
(1) (a) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
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1995, 95, 2457.
1-(4-Methoxyphenyl)naphthalene21
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General procedure A was used, but the reaction was heated at reflux
for 3.5 h. Yield 71%. Product appearance: off-white solid; mp 113–
115 °C; Rf = 0.11 (1% EtOAc–hexanes). 1H NMR (500 MHz,
CDCl3): d = 8.00 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.90
(d, J = 8.4 Hz, 1 H), 7.59–7.45 (m, 6 H), 7.11–7.08 (m, 2 H), 3.94
(s, 3 H). 13C NMR (125 MHz, CDCl3): d = 159.1, 140.0, 134.0,
133.3, 132.0, 131.2, 128.4, 127.5, 127.0, 126.2, 126.0, 125.8, 125.5,
113.9, 55.4.
2-(4-Trifluoromethylphenyl)naphthalene
General procedure A was used, but the reaction was heated at reflux
for 24 h. Yield 92%. Product appearance: white solid; mp 127–129
°C; Rf = 0.35 (EtOAc–hexanes 1%). 1H NMR (500 MHz, CDCl3):
d = 8.08 (s, 1 H), 7.99–7.89 (m, 3 H), 7.85–7.77 (m, 5 H), 7.60–7.53
(m, 2 H). 13C NMR (125 MHz, CDCl3): d = 144.8, 137.2, 133.7,
133.1, 129.5 (q, JCF = 32.6 Hz), 128.9, 128.5, 127.8, 127.8, 126.7,
126.6, 126.5, 125.9 (q, JCF = 3.8 Hz), 125.3, 124.5 (q, JCF = 271.6
Hz). IR (KBr): 3062, 2368, 1926, 1617, 1595, 1503, 1436, 1408,
1339, 1114, 1076, 1009 cm–1. Anal. Calcd for C17H11F3: C, 74.99;
H, 4.07. Found: C, 75.04; H, 3.98.
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Acknowledgment
The authors wish to thank the NIH, Johnson & Johnson, Merck Re-
search Laboratories, and Amgen for their support of this program.
We thank Johnson-Matthey for the generous donation of palladium
catalysts used in this study.
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Synlett 2005, No. 11, 1763–1766 © Thieme Stuttgart · New York