Solvent Effects on the Selectivity of Palladium-Catalyzed Suzuki-Miyaura Couplings

Article abstract of DOI:10.1002/ijch.201900082

The use of polar solvents MeCN or dimethylformamide (DMF) was previously shown to induce a selectivity switch in the Pd/P^tBu₃-catalyzed Suzuki-Miyaura coupling of chloroaryl triflates. This phenomenon was attributed to the ability of polar solvents to stabilize anionic transition states for oxidative addition. However, we demonstrate that selectivity in this reaction does not trend with solvent dielectic constant. Unlike MeCN and DMF, water, alcohols, and several polar aprotic solvents such as MeNO₂, acetone, and propylene carbonate provide the same selectivity as nonpolar solvents. These results indicate that the role of solvent on the selectivity of Suzuki-Miyaura couplings may be more complex than previously envisioned. Furthermore, this observation has the potential for synthetic value as it greatly broadens the scope of solvents that can be used for chloride-selective cross coupling of chloroaryl triflates.

Full text of DOI:10.1002/ijch.201900082

Communication
DOI: 10.1002/ijch.201900082
Solvent Effects on the Selectivity of Palladium-Catalyzed
Suzuki-Miyaura Couplings
Emily K. Reeves,[a] Olivia R. Bauman,[a] Gunner B. Mitchem,[a] and Sharon R. Neufeldt*[a]
Abstract: The use of polar solvents MeCN or dimeth- alcohols, and several polar aprotic solvents such as MeNO2,
ylformamide (DMF) was previously shown to induce a acetone, and propylene carbonate provide the same selectiv-
selectivity switch in the Pd/PtBu3-catalyzed Suzuki-Miyaura ity as nonpolar solvents. These results indicate that the role
coupling of chloroaryl triflates. This phenomenon was of solvent on the selectivity of Suzuki-Miyaura couplings may
attributed to the ability of polar solvents to stabilize anionic be more complex than previously envisioned. Furthermore,
transition states for oxidative addition. However, we demon- this observation has the potential for synthetic value as it
strate that selectivity in this reaction does not trend with greatly broadens the scope of solvents that can be used for
solvent dielectic constant. Unlike MeCN and DMF, water, chloride-selective cross coupling of chloroaryl triflates.
Keywords: Chemoselectivity · Cross-coupling · DFT calculations · Palladium · Solvent effects
Solvents are known to strongly influence the outcome of
palladium-catalyzed cross-coupling reactions.[1] They can play
a role in activating precatalysts, stabilizing organometallic
reagents and catalysts, and modulating the reactivity of acids
and bases. In some cases, solvents can also influence the
selectivity of cross couplings. For example, the Pd-catalyzed
Suzuki-Miyaura (SM) cross coupling of chloroaryl triflate 1
with o-tolylboronic acid in the presence of PtBu3 leads to
product 3a in THF or toluene, but to product 3b in MeCN or
DMF (Scheme 1A).[2,3] DFT studies on this system indicate
that the active catalyst in nonpolar solvents is the mono-
phosphine species [Pd(PtBu3)].[4] In contrast, the active catalyst
in polar solvents was proposed to be an anionic heteroleptic
bisligated complex such as [Pd(PtBu3)F]À .[3,5] The observed
solvent-induced switch in selectivity was attributed to the
ability of polar solvents to stabilize charged palladium species.
However, herein we provide evidence that the role of polar
Scheme 1. Solvent effects on the selectivity of SM cross coupling of
chloroaryl triflates.
solvents in determining selectivity may be more complex than
previously thought. We demonstrate that selectivity for
reaction at triflate with the Pd/PtBu3 system does not trend
with solvent polarity, and is limited to a few coordinating
solvents such as MeCN, DMF, and N-methyl-2-pyrrolidone
(NMP). With many other polar solvents, the Pd/PtBu3-
catalyzed SM reaction of chloroaryl triflates gives the same
selectivity for reaction at chloride as observed in nonpolar
solvents (Scheme 1B).
might be beneficial to add water (our lab operates in a
particularly dry, high-altitude climate). Trace water not only
helps solvate inorganic salts,[9] but is also needed for efficient
transmetalation in the absence of a hydroxide base.[10,11]
However, because polar solvents were previously reported to
favor reaction at triflate using Pd/PtBu3, we were concerned
that added water could erode selectivity for reaction at
While trying to reproduce the reaction shown in Sche-
me 1A using THF, we initially obtained only trace yield of
cross coupled product (Table 1, entry 1). These results can be
rationalized in part by the problems associated with using Pd2
(dba)3: commercial sources of this Pd(0) precatalyst are
notoriously variable in purity.[6,7] The percent yield of product
3a was improved slightly by using Buchwald’s convenient air-
stable PtBu3 Pd G4[8] precatalyst instead of Pd2(dba)3/PtBu3
(entry 2). To increase yields further, we anticipated that it
[a] E. K. Reeves, O. R. Bauman, G. B. Mitchem, S. R. Neufeldt
Department of Chemistry and Biochemistry
Montana State University
PO Box 173400, Bozeman, MT 59717, USA
Fax: 406-994-5407
E-mail: sharon.neufeldt@montana.edu
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201900082
©
Isr. J. Chem. 2019, 59, 1–5
2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Effect of water on the selectivity of the Pd/PtBu3-catalyzed
SM coupling of 1.
Table 2. Cross-coupling selectivity in diverse nonpolar and polar
solvents.
ɛa
3a (%)b
3b (%)b
entry
THF (%)a
H2O (%)a
cat.b
3a (%)c
3b (%)c
entry
solvent
1
2
3
4
5
6
7
8
100
100
99.6
99.1
98.2
90
80
50
20
0
0
0
A
B
B
B
B
B
B
B
B
B
A
1
11
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1
1
2
3
4
5
6
7
8
dioxane
toluene
CHCl3
THF
CH2Cl2
PhCF3
iPrOH
acetone
EtOH
PhCN
CF3CH2OH
NMP
MeOH
CH3CN
CH3NO2
DMF
2.2
2.4
4.8
7.5
8.9
9.2
20.2
21.0
25.3
25.9
27.7
32.6
33.0
36.6
37.3
38.2
47.2
66.1
80.1
22
76
11
95
65
42
94
83
71
9
82
9
55
0
84
9
1
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
2
n.d.
62
1
37
2
81
2
45
61
11
n.d.
0.4
0.9
1.8
10
20
50
80
100
100
27
95 (52%)d
93
88
89
74
67
59
14
1
9
10
11
n.d.
n.d.
n.d.
9
10
11
12
13
14
15
16
17
18
19
0
aPercent of total solvent volume. Catalyst system A=Pd2(dba)3
(1.5 mol%), PtBu3 (3 mol%). Catalyst system B=PtBu3 Pd G4
(3 mol%). GC yields calibrated against undecane as an internal
standard. n.d.=not detected. Isolated yield.
b
c
d
DMSO
PC
H2O
71
59
chloride. Gratifyingly, small amounts of H2O greatly improved
conversion and were not detrimental to selectivity (entries 3–
5). The highest yield of 3a was obtained with 99.1% THF :
0.9% H2O (1 molar equiv. H2O relative to 1, entry 4). To our
surprise, the reaction also remained selective for coupling at
chloride with larger amounts of H2O, and even in neat H2O
(entries 5–10). These results are a counterexample to the prior
generalization that polar solvents favor reaction at triflate
using Pd/PtBu3. The Pd source is not a factor in this selectivity:
both Buchwald’s Pd G4 catalyst (entry 10) and Pd2(dba)3/P
tBu3 (entry 11) exclusively provide 3a in H2O.
We further explored the effect of other solvents on the
chemoselectivity of this transformation (Table 2). Consistent
with the previously described trends, nonpolar solvents give
high selectivity for cross coupling at chloride (3a, entries 1–
6), and some polar aprotic solvents (nitriles, amides, and
DMSO) effect the opposite selectivity for reaction at triflate
(3b, entries 10, 12, 14, 16, 17). However, protic solvents as
well as several polar aprotic solvents [acetone, MeNO2,
propylene carbonate (PC)] provide the same selectivity as
nonpolar solvents (entries 7–9, 11, 13, 15, 18, 19). It is clear
from these results that selectivity does not trend with solvent
dielectric constant.[12]
aDielectric constant of solvent from ref 12. GC yield. calibrated
against undecane as an internal standard.
b
cross couplings (Table 3). The meta- and ortho-chlorophenyl
triflates (4 and 5) undergo selective cross coupling at chloride
in MeOH to give products 4a and 5a. These products are
identical to those obtained in the nonpolar solvent THF.
However, the use of MeCN leads to selective cross coupling at
triflate to give 4b and 5b. Both electron-rich (2, 6, 9) and
electron-deficient (7, 8, 10) arylboronic acids react selectively
with 1 at either chloride (in alcohols or THF) or at triflate (in
MeCN).
The ability to selectively react at chloride in alcohol
solvents may be particularly valuable in cases where poor
conversion is obtained in nonpolar solvents. For example,
moderate yield of 9a is detected by GC with boronic acid 9 in
THF. The polar aprotic solvent MeCN leads to good
conversion, but this solvent favors reaction at triflate (9b).
i
However, the use of PrOH results in selective cross coupling
at chloride to give 9a in very good isolated yield compared to
the use of THF. Additionally, we have found that chloride-
selective cross couplings can be run at lower concentrations in
alcohols than in THF (eq 1). The ability to conduct reactions
at low concentration is valuable for small-scale high through-
put screening in which stock solutions of reagents must be
prepared.
To examine the generality of these solvent effects, we next
evaluated other substrate substitution patterns and arylboronic
acids. We chose to focus on THF, alcohols, and MeCN as
representative of nonpolar solvents that favor reaction at
chloride, polar solvents that favor reaction at chloride, and
polar solvents that favor reaction at triflate, respectively. The
divergent behavior of alcohol solvents and MeCN that we
observed in the coupling of 1 with 2 is maintained in other SM
©
Isr. J. Chem. 2019, 59, 1–5
2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 3. Generality of solvent trends to other chloroaryltriflates and arylboronic acids.
aGC yields calibrated against undecane as an internal standard. bSelectivity based on GC yields prior to purification. cWith 3 mol% PtBu3À Pd G4.
1
dProduct is ~82% pure by H NMR due to difficulties with isolation.
tally in water and MeOH, these results suggest that anionic
[Pd(PtBu3)X]À may not be the active catalyst in these polar
ð1Þ
solvents. Alternatively, the mechanism for oxidative addition
may be more complex than currently understood. We are
continuing to explore the relevance of solvent coordinating
ability on the selectivity of this transformation.
As described above, the selectivity for reaction at CÀ OTf
in some polar solvents has been attributed to stabilization of
an anionic transition state for oxidative addition.[3] In MeCN,
oxidative addition is proposed to involve [Pd(PtBu3)X]À (X=
anionic ligand such as fluoride or [ArB(OH)O]À ). Our own
DFT studies using an implicit solvent model (CPCM) are able
to reproduce prior results, that oxidative addition of 1 at [Pd(P
tBu3)F]À is favored at CÀ OTf over CÀ Cl in MeCN (Table 4;
TS11b is lower in energy than TS11a). However, DFT
predicts that [Pd(PtBu3)F]À should also favor reaction at
CÀ OTf in other solvents, including water and MeOH. This
result is consistent across several DFT methods including
those with dispersion (M06 L, M06, ωB97XD) and without
(B3LYP). Because reaction at CÀ Cl is observed experimen-
In summary, we have described that several polar solvents
give unexpected selectivity in the Pd/PtBu3-catalyzed Suzuki-
Miyaura cross coupling of chloroaryl triflates. We show that
water, alcohols, and some polar aprotic solvents including
acetone, MeNO2, and PC favor selective reaction at CÀ Cl.
However, in line with previous reports, some polar solvents
such as MeCN, DMF, and DMSO favor coupling at CÀ OTf.
Polar solvents were previously proposed to stabilize oxidative
addition transition states involving anionic palladium, leading
to preferential reaction at triflate. Our results suggest that
oxidative addition may not proceed through the same
mechanism in all polar solvents. Further studies to elucidate
©
Isr. J. Chem. 2019, 59, 1–5
2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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(CHE-1848090). O.R.B. thanks the NIH-NIGMS for support
through INBRE (P20GM103474). Calculations were per-
formed on Comet at SDSC through XSEDE (CHE-170089),
which is supported by NSF (ACI-1548562). NMR spectra
were recorded on an instrument purchased with support from
the NSF (NSF-MRI:DBI-1532078) and the Murdock Chari-
table Trust Foundation (2015066:MNL).
Table 4. Effect of solvent and DFT method on predicted relative
energies of anionic transition structures for oxidative addition at
chloride and triflate.
a
ΔΔG�
H2O
(TS11a–TS11b)
Methodb
MeCN
MeOH
THF
A
B
C
D
2.4
2.2
6.9
6.7
1.8
2.3
7.1
5.8
1.7
2.2
6.1
5.7
4.3
3.8
6.5
9.4
References
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aGibbs free energies in kcal molÀ 1. Optimized in indicated solvent.
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M06L/6-31 + G(d). B = CPCM-B3LYP/6-31 + G(d). C = CPCM-
ωB97XD/6-31 + G(d). D = CPCM-M06/6-311 + + G(2d,p)/SDD
(Pd)//CPCM-M06L/6-31+G(d).
b
the origin of divergent selectivity with different classes of
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Experimental Section
Representative Procedure. PtBu3À Pd G4 catalyst (1.8–
7.0 mg, 0.003–0.012 mmol, 0.75–3 mol%), KF (69.7 mg,
1.2 mmol, 3 equiv), and boronic acid (0.44–0.6 mmol, 1.1–
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solution, corresponding to 0.40 mmol, 1 equiv. of water). The
reaction mixture was immediately degassed by sparging with
N2 for 1 min. The vial was immediately sealed with a PTFE-
lined cap and the reaction was stirred at room temperature for
24 h. The reaction mixture was diluted with Et2O or acetone,
filtered through celite, concentrated, and purified by recrystal-
lization or flash column chromatography.
[10] For evidence supporting the involvement of
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hydroxide catalytic intermediate, see a) B. P. Carrow, J. F.
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and referenes therein, b) M. A. Ortuño, A. Lledós, F. Maseras, G.
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L. M. N. B. F. Santos, ChemCatChem 2014, 6, 1291.
[12] C. Wohlfarth “Permittivity (Dielectric Constant) of Liquids” in
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2005, Lide, D. R., ed., <http://www.hbcpnetbase.com>, CRC
Press, Boca Raton, FL, 2005.
Acknowledgement
Manuscript received: June 30, 2019
Revised manuscript received: August 11, 2019
Version of record online: ■■■, ■■■■
We are grateful to Montana State University for support. These
studies are based upon work supported by NSF CAREER
©
Isr. J. Chem. 2019, 59, 1–5
2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. K. Reeves, O. R. Bauman, G. B.
Mitchem, S. R. Neufeldt*
1 – 5
Solvent Effects on the Selectivity of
Palladium-Catalyzed Suzuki-
Miyaura Couplings