Expanding the scope of the Cu assisted Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.088

Recent advances in the development of the copper facilitated Suzuki-Miyaura reaction are described. Improvements include expansion of substrate scope to include aryl chlorides and polyhalo aryl boronates. It was found that use of S-Phos and X-Phos could a

Full text of DOI:10.1016/j.tetlet.2011.07.088

Tetrahedron Letters 52 (2011) 5055–5059
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expanding the scope of the Cu assisted Suzuki–Miyaura reaction
⇑
Brendan M. Crowley , Craig M. Potteiger, James Z. Deng, Christopher K. Prier, Daniel V. Paone,
Christopher S. Burgey
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Recent advances in the development of the copper facilitated Suzuki–Miyaura reaction are described.
Improvements include expansion of substrate scope to include aryl chlorides and polyhalo aryl boro-
nates. It was found that use of S-Phos and X-Phos could accomplish the coupling of 2-pyridyl boronates
to aryl chlorides and bromides in shorter reaction times and in higher yield than previously described
with DPPF.
Received 19 July 2011
Accepted 20 July 2011
Available online 27 July 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Suzuki–Miyaura
2-Pyridyl boronates
Copper assisted reaction
S-Phos
Organometallic
The Suzuki–Miyaura coupling1 is a powerful method for the
synthesis of biaryl bonds. Numerous variants,2 optimizations, and
applications3 have been disclosed in the literature. The robust nat-
ure of this reaction has led to its widespread use in the pharmaceu-
tical industry.4 Despite the advancements in this area, there are
still challenging cases, such as 2-pyridyl5 and polyfluoro-boro-
nates.6 Each of these substitution patterns represents desirable
structural motifs for SAR studies in a medicinal chemistry program.
In a prior work,7 we disclosed a new protocol utilizing the addi-
tion of Cu salts to an optimized set of Suzuki–Miyaura conditions
enabling the coupling of aryl bromides to 2-pyridylpinacolboro-
nates. In addition to the significantly improved yields versus the
copper-free reactions, advantages of this protocol include the com-
mercial availability and relative stability of the 2-pyridylpinacol-
boronates versus the corresponding boronic acids, the tolerance
of the reaction to ambient moisture,8 and the low cost of copper(I)
chloride.
Since then we have explored an expansion of the utility of that
methodology, including investigation of additional aryl halides and
boronates as coupling partners and modified conditions that would
allow couplings to proceed at lower temperatures and in shorter
reaction times. From our initial work, we had hypothesized
(Fig. 1) that the higher yields with copper versus those without
was due to the transmetallation from boron to copper (C) being
faster than the competing proto-deboronation (B) and that the
subsequent transmetallation to palladium (D) was faster than that
from boron to palladium (A) in the copper free case. It seemed pos-
sible, then, that use of copper(I) chloride could improve the overall
rate of the reaction in the general Suzuki–Miyaura reaction as well.
This rate enhancement would be particularly useful for certain
polyfluoroarylboronates, such as the 2,6- and 2,4,6-isomers, which
are similarly prone to deboronation under typical Suzuki–Miyaura
conditions.6
Our first set of experiments involved simply applying our dis-
closed protocol to non-pyridyl boronates, Table 1.
Significantly improved yields were observed in the 2,6-difluoro-,
2,6-dichloro-, and 2-methanesulfonylphenyl cases (entries 1, 3, and
4), though the absolute yield in these latter two cases was poor
to fair. Notably, no improvement in the yield was observed in the
N
X
LnPd0
oxidative
addition
reductive
elimination
LnPdII
PdIILn
N
X
transmetallation
OR
RO
A
B
H
D
N
N
N
CuX
CuLn
B
C
CuX
⇑
Corresponding author.
E-mail address: brendan_crowley@merck.com (B.M. Crowley).
Figure 1. Possible mechanism.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.088

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B. M. Crowley et al. / Tetrahedron Letters 52 (2011) 5055–5059
Table 1
Expansion of the scope of Cu assisted Suzuki-Miyaura reaction with DPPF
Cs2CO3 (2 eq), CuCl (1 eq)
Ph
Ph
ArB(OR)2
2 eq.
+
dppf (10 mol%), Pd(OAc)2 (5 mol%)
DMF (0.1 M), 100 °C
Br
Ar
Yield
Entry
ArB(OR)2
Time (H)
w/Cu (%)
w/o Cu (%)
0
1
2
3
4
2
30
40
23
71
F
F
B(pin)2
25
25
37
26
0
B(OH)2
Cl
Cl
B(OH)2
0
SO2Me
B(OH)2
Table 2
First generation ligand/condition optimization
Ph
Ph
N
Cs2CO3 (2 or 4 eq), CuCl (1 eq)
+
O
B
O
N
ligand (10 mol%), Pd(OAc)2 (5 mol%)
DMF (0.1 M), 100 °C, 2 h
Cl
2 eq.
Entry
Ligand
Modification
Yield (%)
1
2
3
4
5
dppf
2 equiv Cs2CO3
2 equiv Cs2CO3
4 equiv Cs2CO3
4 equiv Cs2CO3
4 equiv Cs2CO3
4 equiv K3PO4
DME
2 mol % Pd; 8 mol % ligand
20 mol % ligand
1 equiv boronate
5
67
81
89
89
44
47
31
95
S-Phos
S-Phos
X-Phos
Brett-Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
6
7a
8a
9a
10a
11a
58
0; 0
w/o Cu; w/o Pd
a
4 equiv Cs2CO3.
2,6-dimethylphenylboronic acid9 case, suggesting that the
improvement in the yield is not due to steric considerations but
rather an electronic effect.
Next we undertook a small ligand screen and additional reac-
tion optimization10 to further expand the utility of the method.
The first generation results of these studies, Table 2, showed that
by using a suitably electron rich ligand, such as S-Phos or X-Phos,
we could expand the scope to include aryl chlorides, increasing
the yield from 5% to 67% by switching from dppf to S-Phos (entries
1 and 2).11
The yields were also increased by doubling the amount of base
to 4 equiv (entry 3). Since both S-Phos and X-Phos gave similar
yields (entries 4 and 5) but have quite different retention times
on silica gel chromatography, the choice of ligand can be made
based on the expected polarity of the product, thus simplifying
purification. Switching to the more electron rich ligand BrettPhos
led to similar results (entry 5), which may be of utility with less
reactive aryl halides.
dium = 4:1), however, led to an increase in the yield (entry 9).
Notably, this reaction was complete by LC/MS analysis in
15–30 min.12 While 2 equiv of the boronate coupling partner is
superior, reasonable yields were obtained with a single equivalent,
which may be important for the cases in which availability of the
desired boronate is limited. Control reactions without copper or
palladium showed no productive coupling.
In efforts to lower the reaction temperature, Table 3, the re-
cently disclosed Buchwald precatalysts13 were explored (entry 3).
No reaction was seen at 23 °C and heating to 75 °C was required
to achieve good conversions. This suggests that the limiting step
is either the transmetallation of the aryl boronate to the corre-
sponding aryl cuprate or the subsequent transmetallation to palla-
dium. While the yields were modestly lower at this temperature,
this result was comparable to the S-Phos/Pd(OAc)2 combination
(entry 4) at 75 °C.
Good yields were also achieved with water-soluble versions of
S-Phos and X-Phos14 (entries 5 and 6). Upon washing the crude
organics from these reactions with 15% aqueous sodium hydroxide,
ca. 50–75% of the ligand could be removed, thus making the reac-
tion potentially more amenable to library or large scale syntheses.
Reducing the ligand and palladium loading or switching the
base or solvent reduced the yields, in line with our previous obser-
vations (entries 6–8). Doubling the amount of S-Phos (ligand/palla-

B. M. Crowley et al. / Tetrahedron Letters 52 (2011) 5055–5059
5057
Table 3
Second generation ligand/condition optimization
Ph
Ph
N
Cs2CO3 (4 eq), CuCl (1 eq)
+
O
N
B
O
ligand (20 mol%), Pd(OAc)2 (5 mol%)
Cl
DMF (0.1 M), 100 °C, 2 h
2 eq.
Entry
Ligand
S-Phos
X-Phos
S-Phos precatalyst
S-Phos
Modification
Yield (%)
1
2
3
4
5
6
—
—
75 °C
75 °C
—
95
95
70
74
88
88
Water sol S-Phos
Water sol X-Phos
—
P(cy)2
OMe
P(cy)2
iPr
Cl
Pd
MeO
iPr
N
H
H
P(cy)2
OMe
OSO3Na
MeO
OSO3Na
water sol. S-Phos
water sol. X-Phos
S-Phos precatalyst
Table 4
Application of optimized conditions to various aryl boronates
Ph
Ph
Cs2CO3 (4 eq), CuCl (1 eq)
R
+
B(OR)2
S-Phos (20 mol%), Pd(OAc)2 (5 mol%)
DMF (0.1 M), 100 °C, 2 h
Cl
R
2 eq.
Entry
1
Aryl boronate
Yield w/Cu (%)
Yield w/o Cu (%)
F
91a
63
B(pin)2
F
F
F
F
2
3
85
47
10c
B(pin)2
F
F
F
10
B(pin)2
F
SO2Me
4
5
6
7
8
9
79a
60
99
73
55
75
0
32
60
0
B(pin)2
N
N
B(pin)2
N
B(pin)2
B(pin)2
N
NC
50
72
B(pin)2
B(pin)2
OMe
10
11
88
74
0
B(OH)2
OMe
Cl
13b
B(OH)2
Cl
a
b
c
10 mol % S-Phos, 48 h.
By LC.
48% With boronic acid.

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B. M. Crowley et al. / Tetrahedron Letters 52 (2011) 5055–5059
Table 5
Application of optimized conditions to various aryl halides
N
Cs2CO3 (4 eq), CuCl (1 eq)
R
+
R
O
N
B
O
S-Phos (20 mol%), Pd(OAc)2 (5 mol%)
DMF (0.1 M), 100 °C, 2 h
X
X
Y
2 eq.
Entry
1
Aryl halide
Yield w/Cu (%)
58
Yield w/o Cu (%)
0
Br
Cl
2
3
4
5
45
45
88
54
0
0
0
0
Ph
N
Cl
MeO
MeO
Br
Cl
Cl
6
71
50
0
0
N
H
H2N
N
7a
Cl
a
X-Phos, 20 mol %.
With an optimized set of conditions in hand, we next looked at
the scope of the reaction with regard to the boronate coupling
partner, Table 4.15
following a short ligand screen and optimization of reaction
parameters that identified electron-rich phosphine ligands such
as S-Phos and X-Phos as superior ligands for the reaction.
Significant increases in the yield were seen in most cases,
though reasonable, albeit lower, yields were obtained in some
cases without copper. Both electron donating and electron with-
drawing substituents were tolerated.
Notably higher yields were obtained in the challenging polyflu-
orinated aryl boronate cases (entries 1–3), with particularly dra-
matic yield increases observed for the 2,4,6-trifluorophenyl and
2,3,5,6-tetrafluorophenyl couplings. Highly hindered substrates,
such as the 2-methanesulfonylphenyl boronate (entry 4), also
showed significant improvement with the addition of copper(I)
chloride, in this case achieving a 79% yield compared to no conver-
sion without copper(I) chloride.
Acknowledgment
We thank John Lim for the in lab mentorship of C. Prier.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.088.
References and Notes
In addition, other heteroaryl boronate couplings (entries 5–7)
showed improved yields with the addition of copper(I) chloride
and, in the cases of entries 5 and 6, were accomplished in higher
yields than those observed under the original conditions (dppf).
Yields slightly improved or were similar in the 2,6-dimethoxy-
phenyl cases (entry 10) and in the simple boronate cases (entries
8 and 9).
While the conversion in the 2,6-dichlorophenyl case (entry 11)
was quite low, it did show improvement versus the copper(I) chlo-
ride-free case, which showed no productive coupling.
1. Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3427; Suzuki
reviews: (a) Miyaura, N.; Suzuki, A. Chem. Res. 1995, 95, 2457–2483; (b)
Miyaura, N. J. Organomet. Chem. 2002, 653, 54–57; Wolfe, J. P.; Nakhla, J. S. The
Suzuki Reaction In Name Reactions for Homologations 1; Li, J. J., Ed.; John Wiley
& Sons: Hoboken, NJ, 2009; Vol. 1, pp 163–184.
2. Selected reviews: Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240–9261; Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17–27.
3. Selected review: McGlacken, G. P.; Fairlamb, Ian J. S. Eur. J. Org. Chem. 2009, 24,
4011–4029.
4. Selected review: Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027–3043.
5. For Suzuki reactions with heterocyclic boronates, see: (a) Campeau, L.-C.;
Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058–1068; (b) Billingsley, K.; Buchwald, S.
L. J. Am. Chem. Soc. 2007, 129, 3358–3366; (c) Bouillon, A.; Lancelot, J.-C.;
Sopkova de Oliveira Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003,
59, 10043–10049.
6. Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073–14075.
7. Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman, S.
A.; Stauffer, S.; Burgey, C. S. Org. Lett. 2009, 11, 345–347.
8. Reagent grade DMF was used for this work.
9. In general, yields were similar between boronic acids and esters of the same
aryl group.
10. In addition to the modifications of the reaction parameters, we made some
minor changes to the work-up protocol for the reaction, such as switching to a
saturated aqueous ammonium chloride wash to improve removal of Cu salts
and DMF.
11. For 2-pyridylboronates, the pinacol ester is preferable to the corresponding
boronic acid due to stability, though the acid does undergo productive
coupling, albeit in much lower yields (23%).
The next set of experiments, Table 5,16 examined variations of
the aryl halide. Improved yields versus the original conditions were
seen with the 2,6-dimethyl substituted substrates (entry 1, 10% in
the original work, 58% in this work) and 4-bromoanisole (entry 4,
46% in the original work and 88% in this work). Similar results were
seen with some aryl and heteroaryl chlorides (entries 6 and 717).
The copper facilitated Suzuki–Miyaura reaction is a powerful
technique for the coupling of 2-pyridylboronates with aryl halides.
The present work expands the scope of the reaction to aryl chlo-
rides as well as to polyhalo, simple, and hindered arylboronates.
Couplings proceed in shorter reaction times18 and in higher yields
than previously described. These improvements were achieved

B. M. Crowley et al. / Tetrahedron Letters 52 (2011) 5055–5059
5059
12. In our original work, the corresponding reaction with 4-bromobiphenyl
proceeded in 88% yield under the conditions listed in that paper.
16. For entry 7, isolation of the product of this reaction was hampered by its water
solubility, so the conversion is somewhat higher than what the yield would
indicate.
13. Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686–6687.
14. Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173–6177.
15. For simple aryl boronates, such as entries 8 and 9, we recognize that there are
other optimized conditions in the literature to achieve similar or higher yields,
but our intent is to show that this is a general method for a range of substrates
that can achieve good yields in most cases.
17. X-Phos was used to simplify purification.
18. While our original work listed the standard reaction time as 18 h, some of the
reactions listed therein as well as most of the reactions described here went to
completion in <1 h, as determined by the LC/MS analysis of each reaction at 15,
30, 60, and 120 min intervals.