Suzuki-Miyaura cross coupling is not an informative reaction to demonstrate the performance of new solvents

Article abstract of DOI:10.3762/bjoc.16.89

The development and study of new solvents has become important due to a proliferation of regulations preventing or limiting the use of many conventional solvents. In this work, the suitability of the Suzuki-Miyaura reaction to demonstrate the usefulness of new solvents was evaluated, including CyreneTM, dimethyl isosorbide, ethyl lactate, 2-methyltetrahydrofuran (2-MeTHF), propylene carbonate, and γ-valerolactone (GVL). It was found that the cross coupling is often unaffected by the choice of solvent, and therefore the Suzuki-Miyaura reaction provides limited information regarding the usefulness of any particular solvent for organic synthesis.

Full text of DOI:10.3762/bjoc.16.89

Suzuki–Miyaura cross coupling is not an informative reaction
to demonstrate the performance of new solvents
James Sherwood
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1001–1005.
Green Chemistry Centre of Excellence, Department of Chemistry,
University of York, Heslington, YO10 5DD, UK
doi:10.3762/bjoc.16.89
Received: 03 March 2020
Accepted: 04 May 2020
Published: 13 May 2020
Email:
James Sherwood - james.sherwood@york.ac.uk
This article is part of the thematic issue "Green chemistry II".
Guest Editor: L. Vaccaro
Keywords:
cross coupling; green solvents; palladium; solvent selection; Suzuki
reaction
© 2020 Sherwood; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The development and study of new solvents has become important due to a proliferation of regulations preventing or limiting the
use of many conventional solvents. In this work, the suitability of the Suzuki–Miyaura reaction to demonstrate the usefulness of
new solvents was evaluated, including Cyrene™, dimethyl isosorbide, ethyl lactate, 2-methyltetrahydrofuran (2-MeTHF), propy-
lene carbonate, and γ-valerolactone (GVL). It was found that the cross coupling is often unaffected by the choice of solvent, and
therefore the Suzuki–Miyaura reaction provides limited information regarding the usefulness of any particular solvent for organic
synthesis.
Findings
The objective of this work was to reveal if there is a relation- lytic intermediates, the rate determining step, and stereochemis-
ship between the productivity of Suzuki–Miyaura cross try (where applicable) of Suzuki–Miyaura cross couplings [8].
couplings and the properties of the solvent, and whether this Despite this, the reaction is generally tolerant of a wide range of
could be used to justify solvent selection. The choice of solvent solvents (often an ether or amide solvent is used, and water is a
is one variable that dictates reaction rate, selectivity, equilibria, common co-solvent). This calls into question the benefits of
solubility, and ultimately product yield. If there is an observ- using Suzuki–Miyaura cross coupling as a test of new solvents,
able change in reaction performance correlating to one or more regardless of how vital the reaction is.
solvent properties (often polarity), then it is possible to identify
and implement an optimum solvent. Suzuki–Miyaura cross cou- Three variations of the Suzuki–Miyaura cross-coupling protocol
pling is the premier method of palladium catalysed carbon–car- were performed. Each case study is a transformation of phenyl-
bon bond formation, making it an obvious case study to vali- boronic acid (1.2 molar equivalents) under different conditions
date the performance of novel solvents [1-7]. The polarity of the (see Scheme 1), but all using 1 part water to 3 parts organic sol-
solvent is known to determine the structure and activity of cata- vent (by volume) and 0.6 mmol (1 equivalent) of an aryl bro-
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Beilstein J. Org. Chem. 2020, 16, 1001–1005.
mide. The solvent screening included twelve solvents. The Figure S4). The results are summarised in Table 1. No evi-
following eminent green and bio-based solvents were included dence of significant hydrodehalogenation or other unintended
in the study to assess their ability to substitute conventional sol- reactions was observed throughout unless noted subsequently.
vents: Cyrene™ [3], and its alcohol equivalent levoglucosanol
[9], ethyl lactate [10], 2-methyltetrahydrofuran (2-MeTHF) The first case study was adapted from that developed by
[11], γ-valerolactone (GVL) [12], dimethyl isosorbide (DMI) Watson and co-workers [3,6]. The desired coupling is of
[6], and propylene carbonate [7]. This study compares solvents 4-bromotoluene to produce 4-phenyltoluene, assisted by the
under the same conditions to offer a fair comparison. Addition- inclusion of the bis(diphenylphosphino)ferrocene ligand and
al solvents were included to ensure a range of polarities were 3 equivalents of base (Scheme 1a). In this work the proportion
investigated (see Supporting Information File 1). In each case of water added is less than that previously optimised for reac-
study, conversion to the desired product was measured by tions in Cyrene™ [3], and more than that previously optimised
1H NMR spectroscopy (see Supporting Information File 1, for reactions in DMI [6]. In case study 1, the majority of sol-
Scheme 1: (a) Case study 1, reaction of 4-bromotoluene; (b) case study 2, reaction of 4-bromophenylacetic acid; (c) case study 3, reaction of
4’-bromoacetophenone.
Table 1: Conversions in three Suzuki–Miyaura reactions.a
solvent
greenness ranking
case study 1
case study 2
case study 3
NMP
hazardous (reprotoxicity)
problematic (health and safety issues)
recommended
85%
94%
92%
81%
76%
98%
100%
92%
100%
100%
81%
2%
100%
42%
30%
100%
28%
73%
5%
toluene
butanone
2-propanol
ethyl acetate
ethyl lactate
Cyrene™
levoglucosanol
DMI
recommended
recommended
problematic (causes serious eye damage) 75%
problematic (low volatility)
lacking data (low volatility)
problematic (low volatility)
problematic (low volatility)
problematic (low volatility)
problematic (health and safety issues)
83%
77%
96%
81%
87%
79%
64%
63%
100%
98%
100%
82%
74%
98%
36%
16%
propylene carbonate
GVL
2-MeTHF
aGreenness ranking is taken from the CHEM21 solvent selection guide.
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Beilstein J. Org. Chem. 2020, 16, 1001–1005.
vents resulted in conversion to the product in the range of reaction temperature, and the choice and quantity of catalyst
75–85% after 1 hour. The highest conversion of 96% was ob- and base.
tained in DMI, but overall it is fair to conclude the reaction
quickly reaches good conversions with little apparent influence Given the broad choice of solvents available, what is left to
from the solvent.
decide is the most benign solvent that should be preferred for
conducting Suzuki–Miyaura reactions. Table 1 lists the green-
The second case study transformed 4-bromophenylacetic acid ness rating from the CHEM21 solvent selection guide (except
into felbinac, a nonsteroidal anti-inflammatory drug for levoglucosanol which lacks the necessary data) [15]. The
(Scheme 1b) [13]. Here, palladium acetate without an auxiliary ‘recommended’ solvent with a high performance across the
ligand was used for a pre-catalyst and the base changed to three case studies is IPA, known as a robust solvent for
potassium carbonate. Reaction conditions of 20 hours at 65 °C Suzuki–Miyaura type cross couplings [16-18]. However, it is
were decided after observing 11% conversion after 2 hours and also worth noting that the ‘problematic’ designation of
33% after 20 hours in NMP at room temperature. The majority Cyrene™, DMI, propylene carbonate, and GVL is due to their
of solvents provided conversions in excess of 90%. In the case high boiling points placing a high energy demand on recovery
of Cyrene™, its instability towards inorganic bases is presum- by distillation. If recovery has been considered and deemed
ably the reason for the very low conversion (2%). During one infeasible, then propylene carbonate in particular should also be
run the reaction mixture did solidify, as has been reported previ- considered given its superior hazard profile compared to IPA.
ously for various chemistries in Cyrene™ under basic condi- However, caution is advised in the presence of nucleophilic
tions [14].
reagents, as this has previously been reported to cause ring
opening of propylene carbonate during Suzuki–Miyaura cross
The third case study was a coupling of 4-bromoacetophenone couplings [7]. In this work no decomposition of propylene
(Scheme 1c) using the same pre-catalyst and base as in case carbonate was identified. Using only water as a solvent is also
study 2. In this example the reaction proceeds at room tempera- appealing from a green chemistry perspective if the water can
ture, but now the conversion to the product varies considerably be reused. To this end, micellar chemistry is appropriate for
between solvents. Reactions in N-methyl-2-pyrrolidone (NMP) cross couplings [19]. Residual water also assists ‘solvent-free’
and 2-propanol (IPA) resulted in complete conversion, and the methods [20].
product could be isolated by crystallisation from diethyl ether.
Propylene carbonate also provided excellent conversion to the In summary, the Suzuki–Miyaura reaction is a fantastically
product (98%). The alcohol functionalised solvents outper- versatile and industrially important reaction [21,22], and excels
formed their aprotic analogues, while Cyrene™, GVL, and in a variety of reaction media. On the evidence of this study, it
2-MeTHF were poor solvents. Replacing potassium carbonate can be concluded that the Suzuki–Miyaura reaction is not an
with triethylamine, the conversion in Cyrene™ rose slightly to informative case study for solvent effects and cannot reliably
10%. Despite the variation between experiments no discernible validate the benefits of one particular solvent. This is because
correlation between any solvent properties and the observed catalysts and conditions can be chosen to promote high conver-
conversions was found.
sions regardless of the properties of the solvent. Additionally,
the diverse properties of high performance solvents across
The results achieved in DMI across the three case studies typify Suzuki–Miyaura reactions means it is hard to discern what are
the lack of an obvious solvent effect. In one instance DMI is the the requisite qualities of the reaction medium (if any) that
best performing solvent (case study 1), then the worst aside encourage the desired cross coupling. Specific mechanistic
from the reactive Cyrene™ (case study 2), and then somewhere studies whereby the rate limiting step or mechanism changes
in between (case study 3). To demonstrate that not even case according to the solvent remain a valid pursuit, as does
study 3 is robust enough to definitively establish a measure- measuring the palladium contamination in products [23]. How-
ment of solvent performance in Suzuki–Miyaura cross ever, the works of Watson [24], Denmark [25], and others
couplings, a short optimisation study was conducted to improve [26,27], have already elucidated many of the key fundamental
the conversion to 4-phenylacetophenone in 2-MeTHF (origi- principles of boron and palladium speciation and the role of the
nally 16%). Reducing the water content to an 18:1 v/v ratio and base in the Suzuki–Miyaura reaction.
increasing the excess of base to 3 equivalents and catalyst to
5 mol % was found to be beneficial, as was a higher reaction For researchers developing safer solvents, the Mizoroki–Heck
temperature of 65 °C. These conditions produced a conversion reaction is a more suitable cross-coupling methodology to
of 79% after 4 hours in 2-MeTHF. This is an indication of the demonstrate solvent performance [28]. The reaction kinetics of
weak influence of the solvent compared to the impact of the Mizoroki–Heck reactions have a strong dependence on the
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Beilstein J. Org. Chem. 2020, 16, 1001–1005.
4. Wolfson, A.; Dlugy, C. Chem. Pap. 2007, 61, 228–232.
dipolarity of the reaction medium, and the rate determining step
can be controlled by the equivalents of ligand added, thereby
eliminating one variable [8]. Reprotoxic solvents such as N,N-
dimethylformamide (DMF) are routinely used in the
Mizoroki–Heck reaction and hence there is also a motivation to
investigate safer alternative solvents that the Suzuki–Miyaura
reaction lacks.
doi:10.2478/s11696-007-0026-3
5. Lei, P.; Ling, Y.; An, J.; Nolan, S. P.; Szostak, M. Adv. Synth. Catal.
2019, 361, 5654–5660. doi:10.1002/adsc.201901188
6. Wilson, K. L.; Murray, J.; Sneddon, H. F.; Jamieson, C.;
Watson, A. J. B. Synlett 2018, 29, 2293–2297.
doi:10.1055/s-0037-1611054
7. Czompa, A.; Pásztor, B. L.; Sahar, J. A.; Mucsi, Z.; Bogdán, D.;
Ludányi, K.; Varga, Z.; Mándity, I. M. RSC Adv. 2019, 9, 37818–37824.
doi:10.1039/c9ra07044c
If researchers are still compelled to study the utility of solvents
in the Suzuki–Miyaura reaction, I encourage future studies to be
directed at challenging substrates that correspond to commer-
cially important products (e.g., enantiopure pharmaceuticals,
polymeric materials) and if a substrate screening should follow,
the protocol established by Collins and Glorius is effective [29].
For the development of new catalysts, it is preferable to work
with a benign solvent such as aqueous IPA from the outset [30].
This is because late-stage solvent screens rarely reveal a superi-
or solvent due to the catalyst having already been optimised to
work in the original solvent, which may have been chosen only
for ease of removal (e.g., the volatile but suspected carcinogen
dichloromethane) or the high solubility of organic and inorgan-
ic reagents (e.g., the reprotoxic DMF).
8. Sherwood, J.; Clark, J. H.; Fairlamb, I. J. S.; Slattery, J. M.
Green Chem. 2019, 21, 2164–2213. doi:10.1039/c9gc00617f
9. Sherwood, J.; Granelli, J.; McElroy, C. R.; Clark, J. H. Molecules 2019,
24, 2209. doi:10.3390/molecules24122209
10.Wan, J.-P.; Wang, C.; Zhou, R.; Liu, Y. RSC Adv. 2012, 2, 8789–8792.
doi:10.1039/c2ra21632a
11.Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15,
3950–3953. doi:10.1021/ol401727y
12.Petricci, E.; Risi, C.; Ferlin, F.; Lanari, D.; Vaccaro, L. Sci. Rep. 2018,
8, 10571. doi:10.1038/s41598-018-28458-y
13.Del Zotto, A.; Amoroso, F.; Baratta, W.; Rigo, P. Eur. J. Org. Chem.
2009, 110–116. doi:10.1002/ejoc.200800874
14.Wilson, K. L.; Kennedy, A. R.; Murray, J.; Greatrex, B.; Jamieson, C.;
Watson, A. J. B. Beilstein J. Org. Chem. 2016, 12, 2005–2011.
doi:10.3762/bjoc.12.187
15.Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.;
Abou-Shehada, S.; Dunn, P. J. Green Chem. 2016, 18, 288–296.
doi:10.1039/c5gc01008j
16.Navarro, O.; Oonishi, Y.; Kelly, R. A.; Stevens, E. D.; Briel, O.;
Nolan, S. P. J. Organomet. Chem. 2004, 689, 3722–3727.
doi:10.1016/j.jorganchem.2004.04.001
Supporting Information
Supporting Information File 1
17.Camp, J. E.; Dunsford, J. J.; Cannons, E. P.; Restorick, W. J.;
Gadzhieva, A.; Fay, M. W.; Smith, R. J. ACS Sustainable Chem. Eng.
2014, 2, 500–505. doi:10.1021/sc400410v
Synthetic procedures and calculation of reaction
conversions and solvent polarity data.
18.Stewart, G. W.; Maligres, P. E.; Baxter, C. A.; Junker, E. M.;
Krska, S. W.; Scott, J. P. Tetrahedron 2016, 72, 3701–3706.
doi:10.1016/j.tet.2016.02.030
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-89-S1.pdf]
19.Isley, N. A.; Gallou, F.; Lipshutz, B. H. J. Am. Chem. Soc. 2013, 135,
17707–17710. doi:10.1021/ja409663q
20.Bernhardt, F.; Trotzki, R.; Szuppa, T.; Stolle, A.; Ondruschka, B.
Beilstein J. Org. Chem. 2010, 6, No. 7. doi:10.3762/bjoc.6.7
21.Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062–5085.
doi:10.1002/anie.201107017
Funding
This research was funded by the Bio-Based Industries Joint
Undertaking (JU) under the European Union's Horizon 2020
research and innovation programme (agreement No 745450).
The publication reflects only the author’s view and the JU is not
responsible for any use that may be made of the information it
contains.
22.Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177–2250.
doi:10.1021/cr100346g
23.Strappaveccia, G.; Ismalaj, E.; Petrucci, C.; Lanari, D.; Marrocchi, A.;
Drees, M.; Facchetti, A.; Vaccaro, L. Green Chem. 2015, 17, 365–372.
doi:10.1039/c4gc01677g
ORCID® iDs
James Sherwood - https://orcid.org/0000-0001-5431-2032
24.Molloy, J. J.; Seath, C. P.; West, M. J.; McLaughlin, C.;
Fazakerley, N. J.; Kennedy, A. R.; Nelson, D. J.; Watson, A. J. B.
J. Am. Chem. Soc. 2018, 140, 126–130. doi:10.1021/jacs.7b11180
25.Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329–332.
doi:10.1126/science.aad6981
References
1. Sarmah, M.; Mondal, M.; Bora, U. ChemistrySelect 2017, 2,
26.Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2013, 52,
7362–7370. doi:10.1002/anie.201301737
5180–5188. doi:10.1002/slct.201700580
2. Sherwood, J.; Parker, H. L.; Moonen, K.; Farmer, T. J.; Hunt, A. J.
Green Chem. 2016, 18, 3990–3996. doi:10.1039/c6gc00932h
3. Wilson, K. L.; Murray, J.; Jamieson, C.; Watson, A. J. B. Synlett 2018,
29, 650–654. doi:10.1055/s-0036-1589143
27.Amatore, C.; Le Duc, G.; Jutand, A. Chem. – Eur. J. 2013, 19,
10082–10093. doi:10.1002/chem.201300177
1004

Beilstein J. Org. Chem. 2020, 16, 1001–1005.
28.Parker, H. L.; Sherwood, J.; Hunt, A. J.; Clark, J. H.
ACS Sustainable Chem. Eng. 2014, 2, 1739–1742.
doi:10.1021/sc5002287
29.Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597–601.
doi:10.1038/nchem.1669
30.Dyson, P. J.; Jessop, P. G. Catal. Sci. Technol. 2016, 6, 3302–3316.
doi:10.1039/c5cy02197a
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