Ligand-Free Bioinspired Suzuki–Miyaura Coupling Reactions using Aryltrifluoroborates as Effective Partners in Deep Eutectic Solvents

Article abstract of DOI:10.1002/cssc.201801382

Pd-catalyzed Suzuki–Miyaura cross-coupling between (hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono- and bifunctional potassium aryltrifluoroborates proceeded efficiently and chemoselectively in air and under generally mild conditions; a catalyst loading as low as 1 mol % combined with Na₂CO₃ as a base in choline chloride/glycerol (1:2) deep eutectic solvent (DES) was used as a sustainable and environmentally responsible medium. The catalyst, base, and DES were easily and successfully recycled up to six times with an E-factor as low as 8.74. Valuable biaryls and terphenyl derivatives were furnished in yields of up to 98 %; over 50 reactions were compared and discussed. The methodology was applied for the synthesis of the nonsteroidal anti-inflammatory drugs Felbinac and Diflunisal.

Full text of DOI:10.1002/cssc.201801382

Accepted Article
Title: Ligand-free Bio-inspired Suzuki-Miyaura Couplings using
Aryltrifluoroborates as Effective Partners in Deep Eutectic
Solvents
Authors: Giuseppe Dilauro, Sergio Mata García, Donato Tagarelli,
Paola Vitale, Filippo M. Perna, and Vito Capriati
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10.1002/cssc.201801382
ChemSusChem
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Ligand-free Bio-inspired Suzuki–Miyaura Couplings using
Aryltrifluoroborates as Effective Partners in Deep Eutectic
Solvents
Giuseppe Dilauro,[a] Sergio Mata García,[b] Donato Tagarelli,[a] Paola Vitale,[a] Filippo M. Perna,*[a] and
Vito Capriati*[a]
Dedication ((optional))
Abstract: Pd-catalysed Suzuki–Miyaura cross-couplings between
(hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono-
and bifunctional potassium aryltrifluoroborates proceed efficiently
and chemoselectively in air and under generally mild conditions, with
a catalyst loading as low as 1 mol%, in the absence of additional
ligands, and employing Na2CO3 as base, and the deep eutectic
solvent (DES) choline chloride/glycerol (1:2) as a sustainable and
environmentally responsible medium. Catalyst, base and DES have
been easily and successfully recycled up to six times with an E-
factor as low as 8.74. Valuable biaryls and terphenyl derivatives
were furnished in yields of up to and above 98%; over 50 cases
have been compared and discussed. The methodology was also
applied to the synthesis of the non-steroidal anti-inflammatory drugs
Felbinac and Diflunisal.
overcome pitfalls experienced when poorly water-soluble and
poorly water-stable substrates and/or catalysts are used.[2] In the
absence of ligands and/or specific solid-supported palladium
catalysts, however, the coupling of the readily available and low-
cost aryl chlorides still poses challenges also in these
media.[2b,c,h,i] Significant eco-friendly enabling technologies
relying on microwaves, ultrasound, mechanochemistry, light,
and flow chemistry have also progressed impressively in recent
years.[3]
SM reactions are usually carried out utilising boronic acids
or boronate ester analogues. Disadvantages in the use of
organoboranes are (a) their propensity towards aerobic
oxidation, with decreased yields if the solvent is not degassed,
(b) dehydroboration and protodeboronation processes, which
imply the use of excess reagents to drive the reaction to
completion, and (c) Pd-catalysed homocoupling reactions.[4]
Arylboronic acids, jointly with aryl bromides and iodides, are still
the partners of choice in the reported examples of Pd-catalysed
SM couplings conducted either in biomass-derived solvents[5a–g]
or in ionic liquids (ILs).[5h] As for the former, with the exception of
ethyl lactate[5b] and glycerol derivatives,[5c] such couplings have
always been accomplished in the presence of soluble
phosphines and under harsh heating (100–120 °C). On the other
hand, cross-couplings with aryl chlorides have to date been
performed also in ILs but (a) in the presence of phosphine
ligands,[5i] (b) with the use of Pd nanoparticles stabilised by
tetraalkylammonium salts bearing long alkyl chains,[5j] or (c) by
employing hydroxyl-functionalised ILs.[5k] N-Methyliminodiacetic
acid (MIDA) boronates, developed and largely used by Burke,[6]
represent a more robust alternative to organoboranes to tackle
the above-mentioned critical issues.[7] Alternative nucleophilic
partners that, similarly to MIDA boronates, have proven largely
superior to boronic acids and esters in terms of physicochemical
properties, atom economy and scalability are potassium
organotrifluoroborates. These compounds are free-flowing
crystalline solids exhibiting excellent air and moisture stability,
and easy storability.[8a–d] Applications in SM coupling of a wide
Introduction
Among the wealth of transition-metal catalysed cross-coupling
reactions in the arsenal of chemical practitioners, the Suzuki–
Miyaura (SM) coupling has served over the last two decades as
one of the most versatile and powerful strategies for achieving
C–C bond formation because of the low toxicity and easy
availability of boron reagents, the usually mild reaction
conditions, and the tolerance of a wide range of functional
groups. These couplings are generally run under homogeneous
conditions with various ligands, typically in hazardous and toxic
volatile organic compounds (VOCs) (e.g., toluene, DMF),
thereby have a heavy environmental impact. Thus, intense
research efforts have been made to develop protocols of more
ecological relevance. These include the use of neat water,
usually with phase-transfer catalysts, water-soluble phosphines,
pseudo-halides as electrophilic partners, and harsh heating.[1]
Aqueous solvent systems have alternatively been investigated to
[a]
Dr. Giuseppe Dilauro, Dr. Donato Tagarelli, Dr. Paola Vitale, Dr.
Filippo M. Perna, Prof. Vito Capriati
range of (hetero)aryl-,[8e-h] alkenyl-,[8i,j]
organotrifluoroborates[8k] have been developed.
and alkynyl
Dipartimento di Farmacia–Scienze del Farmaco, Consorzio
C.I.N.M.P.I.S.
Università di Bari “Aldo Moro”
Recent pioneering work from several synthetic laboratories
worldwide has recognised the potential of the so-called ‘Deep
Eutectic Solvents’ (DESs) (also known in the literature as Low-
Melting Mixtures, LMMs) as superior green and bio-renewable
solvents. DESs are today generally referred to as combinations
of two or three safe and inexpensive components able to
engage in reciprocal hydrogen-bond interactions to form a
eutectic mixture with a melting point far below those of the
Via E. Orabona 4, I-70125 Bari, Italy
E-mail: filippo.perna@uniba.it; vito.capriati@uniba.it
Dr. Sergio Mata García
Departamento de Química Orgánica e Inorgánica e Istituto
Universitario de Química Organometálica “Enrique Moles”
Universidad de Oviedo
[b]
c/Julián Claveria 8, E-33006, Oviedo, Spain
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/cssc.201801382
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individual components, due to self-association. They are usually
formed by mixing and gently heating a quaternary ammonium
salt (e.g., choline chloride, ChCl) and a neutral hydrogen-bond
donor (HBD) [e.g., glycerol (Gly), urea, carbohydrates,
derivatives in good to excellent yields of up to and above 98%
even starting from challenging aryl chlorides as organic
electrophiles, (b) using up to 1 mol% Pd(OAc)2 as catalyst in
the absence of any additional ligand, (c) running reactions under
very mild reaction conditions; that is, under air and gently
warming (60 °C for aryl bromides and iodides), and (d) efficient
recycling of the DES, catalyst and base up to six times without
appreciable loss of activity (E-factor: 8.74). Examples also
include comparison with the performance of boronic acids as
reaction partners under optimised reaction conditions.
,
carboxylic acids] in
a specific molar ratio. DESs display
attractive advantages, such low price, non-flammability,
recyclability and low vapour pressure, and are believed to be
more biodegradable and less toxic than traditional ionic liquids
because of their environmentally friendly components.[9] The
solvent properties can also be tuned by simply changing the
nature and the molar ratio of the components.
The applications of DESs and other unconventional
solvents in the fields of metal-catalysed[5g,10] and metal-mediated
organic reactions,[11] have been experiencing an explosive
growth and development, particularly in recent years. As for SM
reactions, however, to the best of our knowledge, there are only
two reports: (i) Köning and co-workers documented the use of
LMMs based on sugar-urea-salt melts as solvents to promote
Pd-catalysed couplings between phenylboronic acid and aryl
bromides at 90 °C (Scheme 1a);[12a] (ii) Ramón, Alonso and co-
workers successfully cross-coupled phenylboronic acid with both
aryl bromides and iodides in a ChCl-based DES working with
structurally engineered phosphine ligands and PdCl2 at 100 °C
(Scheme 1b).[12b]
Results and Discussion
We set out to investigate the reaction between iodobenzene (1a)
(0.5 mmol) and phenylboronic acid (2a) (2 equiv.) in different
bio-based DESs and LMMs for the preparation of biphenyl (3aa)
using Pd(OAc)2 (10 mol%) as catalyst and Na2CO3 (2 equiv.) as
base (Table 1).
Table 1. Optimisation of the SM coupling in DESs between iodobenzene (1a)
and phenylboronic acid (2a) or phenyltrifluoroborate 2b.[a]
catalyst, base
+
I
X
solvent, time
60 °C
2a: X = B(OH)2
2b: X = BF3K
1a
3aa
Previous work:
König (2006) (ref. 12a)
Entry
Solvent
Catalyst (mol%) 2 (equiv.) Time
3aa yield
(h)
(%)[b]
NR[e]
NR[e]
52
(a)
B(OH)2
Br
Pd(OAc)2 (10 mol%)
1
PG/ChCl[c]
EG/ChCl[c]
LA/ChCl[c]
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
2[d]
24
24
24
24
24
24
24
24
24
24
1
Na2CO3
+
2
2[d]
R
R
90 °C, 6 h, in melt
3 examples: 78–97%
3
2[d]
Ramón, Alonso (2017) (ref. 12b)
4
D-fructose/urea[c] Pd(OAc)2 (10)
2[d]
40
B(OH)2
Hal
PdCl2 (x mol%)
(b)
ligand (3 x mol%)
+
urea/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[c]
Gly/ChCl[j]
Gly/ChCl[j]
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
2[d]
96
R
5
Gly/ChCl (2:1)
Na2CO3, 100 °C, 2 h
R
6
2[d]
>98[f]
75
Hal = Br, I
12 examples: 80–98%
7
1[g]
This work:
BF3K
Hal
(c)
Pd(OAc)2 (1 mol%)
8
1.5[h]
1.5[h]
1.5[h]
1.5[h]
1.5[h]
1.5[h]
1[g]
>98
84[i]
80
Na2CO3, under air
+
Het
Gly/ChCl (2:1)
60–100 °C, 5 h
R
R
9
R
R
>50 examples
up to >98% yield
10
11
12
13
14
15
Hal = Cl, Br, I; R = BF3K, alkyl, aryl, various functional groups
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (1)
63
Scheme 1. (a) SM coupling in melt; (b) ligand-based SM coupling with
PhB(OH)2 in DES; (c) ligand-free SM coupling with ArBF3K in DES.
5
>98
>98
>98
>98
5
Our efforts of late have focused on using water and DESs
to explore novel paradigms in organometallics,[10l,10p,11b–g,11j]
organocatalysis,[13] biocatalysis,[14] solar technology[15a] and
5
1[g]
5
photosynthesis [15b]
Herein, we wish to report a systematic
.
[a] Reaction conditions: 1.0 g DES per 0.5 mmol of 1a; DES: propylene glycol
(PG)/ChCl (3:1, mol mol–1); ethylene glycol (EG)/ChCl (3:1, mol mol–1); L-lactic
acid (LA)/ChCl (2:1, mol mol–1); D-fructose/urea (3:2, w/w); urea/ChCl (2:1,
mol mol–1); Gly/ChCl (2:1, mol mol–1). [b] The yields reported are for products
isolated and purified by column chromatography. [c] Substrate 2a. [d] 2 Equiv.
2a and Na2CO3. [e] NR = no reaction. [f] NR in the absence of Na2CO3 or
when using Et3N (2 equiv.). [g] 1 Equiv. 2a (or 2b) and Na2CO3. [h] 1.5 Equiv.
2a and Na2CO3. [i] T = 25 °C. [j] Substrate 2b.
study on the usefulness of DESs as sustainable reaction
media for ligand-free SM couplings between mono- and
bifunctional potassium aryltrifluoroborates and (hetero)aryl
halides (Scheme 1
procedure, the Gly ChCl (2:1) eutectic mixture proved to be
the most effective for (a) assem lying symmetrical and non-
symmetrical biaryl and, for the first time, also terphenyl
c). After extensive optimisation of the
/
b
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When the above mixture was heated at 60 °C for 24 h in DESs
formed between ChCl and ethylene glycol, propylene glycol or L-
lactic acid, as well as in a D-fructose/urea LMM, unsatisfactory
outcomes resulted, with yields of 3aa of up to 52% (Table 1,
entries 1–4). Upon changing the HBD to urea or Gly, 3aa could
be isolated in 96 or >98% yield, respectively (Table 1, entries
5,6). It was shown that in the absence of Na2CO3 or by replacing
it with weaker bases such as Et3N, no coupling took place (Table
1, entry 6). The amount of 2a could also be reduced up to 1.5
equiv. without affecting the final yield (Table 1, entries 7,8),
whereas the target product was formed in a lower yield by
running the reaction at room temperature (r.t.) (Table 1, entry 9).
Further screening of catalysts revealed that while PdCl2 (10
mol%) gave a reaction yield of 3aa of 80% (Table 1, entry 10),
other Pd salts [Pd(PPh3)4 (10 mol%), Pd/C (10 mol%)] as well as
different salts of transition metals [CuI (10 mol%), CuSO4 (10
mol%), FeCl2 (10 mol%), FeCl3 (10 mol%)] completely
suppressed the formation of the cross-coupling product in the
ChCl/Gly reaction medium. A reaction time of up to 5 h was also
enough to recover 3aa quantitatively (Table 1, entries 11,12).
Finally, to further improve this procedure, we also reduced the
catalyst loading, and were delighted to find that 3aa still formed
in quantitative yield with a loading of 5 mol%. (Table 1, entry 13).
Notably, upon replacing 2a with the corresponding potassium
phenyltrifluoroborate 2b, employed in a strict 1:1 stoichiometric
ratio with 1a, the effectiveness of such a cross-coupling was still
maintained (3aa: >98% yield) either with 5 mol% Pd(OAc)2 or
with a loading as low as 1 mol% (Table 1, entries 14,15).
Table 2. Synthesis of biaryls 3 via SM coupling between (hetero)aryl halides 1 and arylboronic acids 2a,2f or aryltrifluoroborates 2b–e in eutectic mixture
ChCl/Gly.[a]
2a: X = B(OH)2; R1,R2 = H
2b: X = BF3K; R1,R2 = H
Pd(OAc)2 (1 mol%)
R2
R1
R2
R1
2c: X = BF3K; R1 = H, R2 = 4-NO2
2d: X = BF3K; R1 = H, R2 = 4-MeO
2e: X = BF3K; R1 = 2-F, R2 = 4-F
2f: X = B(OH)2; R1 = 2-F, R2 = 4-F
X
Ar
Na2CO3 (1 or 1.5 equiv.)
Ar-Hal
Hal = Br, Cl, I
+
Gly/ChCl, 5 h, 60 °C
1
2
3
CO2Me
O2N
HO2C
NO2
CO2Et
3aa: (>98%, 2a, Cl)[b]
3ab: (90%, 2a, I)
(92%, 2b, I)
3ac: (80%, 2a, Br)
(86%, 2b, Br)
3ad: (70%, 2a, Br)
(>98%, 2b, Br)
3ae: (80%, 2a, Br)
(>98%, 2b, Br)
3af: (83%, 2a, I)
(93%, 2b, I)
(72%, 2b, Cl)[b]
(70%, 2b, Cl)[b]
S
S
OMe
N
N
3bj: (81%, 2b, Br) 3bk: (76%, 2b, I) 3bl: (61%, 2b, I)
3ag: (35%, 2a, Br, 12 h)
(>98%, 2b, Br) (60%, 2b, Cl)[b]
3ah: (NR, 2a, Br, 12 h)
3ai: (NR, 2a, Br, 12 h)
(76%, 2b, Br)
(75%, 2b, Br)
Cl
CO2H
O
O
CN
Cl
3bq: (70%, 2b, I)
3bn: (>98%, 2b, Br)
3bo: (91%, 2b, Br)
(81%, 2b, Cl)[b]
3bm: (97%, 2b, I)
3bp: (90%, 2b, Br)
3br: (92%, 2b, Br)
(82%, 2b, Cl)[b]
MeO
H2N
O
OH
3bu: (53%, 2b, Br)
O2N
O2N
3bs: (84%, 2b, I)
3bt: (58%, 2b, I)
3ac: (86%, 2c, I)
3co: (72%, 2d, Br)
O
MeO
Cl
O2N
Cl
MeO
3ag: (>98%, 2d, Br)
NC
MeO
3cq: (55%, 2c, I)
3do: (95%, 2d, Br)
3dq: (95%, 2d, I)
F
CO2H
OH
CO2H
F
CN
Felbinac
3bx: (95%, 2b, Cl)[b]
3ey: (>98%, 2e, I)
(52%, 2f, I)
Diflunisal
3bv: (90%, 2b, Cl)[b]
3bw: (92%, 2b, Cl)[b]
[a] Reaction conditions: (hetero)aryl halide (0.5 mmol), phenylboronic acid (2a,2f) (1.5 equiv.) or aryltrifluoroborate (2b–e) (1 equiv.), Na2CO3 (2a,2f: 1.5 equiv.;
2b–e: 1 equiv.), DES (Gly/ChCl, 2:1) (1.0 g), in air. The yields reported are for products isolated and purified by column chromatography. NR = no reaction. [b] T
= 100 °C.
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With satisfactory conditions found, we sought to capitalise
Diflunisal (3ey).[19] It is worh noting that 3ey was prepared in a
lower yield (52%) starting from arylboronic acid 2f (Table 2).
Some considerations are worth making at this point. As
has been pointed out in the introduction, the side reactions that
boronic acids are more susceptible to in SM coupling are
dehydroboration, protodeboronation, oxidation, and Pd-
catalysed homocoupling. Detailed mechanistic studies
performed by Lloyd-Jones and co-workers have demonstrated
that (a) organotrifluoroborates do not remain intact under basic,
protic conditions, and that their complete hydrolysis to the
on this by exploring the scope of the reaction with a variety of
(hetero)aryl halides (1) and arylboronic acids (2a,2f) (1.5 equiv.)
or aryltrifluoroborates (2b–e) (1 equiv.) (Table 2). With regard to
2a, the relatively higher yields (70–90%) of the desired coupled
products (3ab–3af) were obtained when both aryl iodides and
bromides bearing electron-withdrawing groups at the ortho-,
meta- and para-positions, such as nitro, carboxylic acid and
ester groups (1b–f), participated in the process (Table 2).
However, the presence of an electron-donating group (MeO) at
the para position (1g) dramatically hindered the coupling
reaction with 1a, and the expected product 3ag formed in 35%
yield only even after 12 h. Nitrogen heterocyclic substrates, such
as 5-bromo-1-methylindole (1h) and 3-bromopyridine (1i), did
not react either with 2a, and thus the formation of products
3ah,3ai did not occur (Table 2). Remarkably, upon switching to
potassium phenyltrifluoroborate 2b as the nucleophilic partner,
the yield range of products 3ab–3ag increased to 86–98%, and
even bromo heterocycles 1h,i could now be efficiently cross-
coupled to give the desired adducts 3ah,3ai in good yields (75–
76%, Table 2). Using electron-rich five-membered heterocycles,
such as 3-bromothiophene (1j) and 2-bromothiophene (1k), and
assorted aryl derivatives with ‘neutral’ substituents (1l), or with
electron-withdrawing (carboxylic, carbonyl, chloro, cyanomethyl)
(1m–r) or electron-donating (MeO) (1s) groups, 61–98% yields
of the expected products 3bj–3bs were obtained (Table 2).
Compounds 3bj and 3bk are important carbon scaffolds, since
several thiophene derivatives are known for their
electrochemical behaviour,[16] and are present in a variety of
pharmaceutical compounds and natural products.[17] Aryl halides
1t,u, with free amino and hydroxyl groups at the ortho- and para-
positions, also participated in the coupling process with salt 2b
to afford biphenyl derivatives 3bt,3bu, albeit in moderate yields
(53–58%) (Table 2). Aryltrifluoroborates containing electron-
deficient or electron-rich substituents (2c,d) proved to be
competent nucleophilic partners as well, and by reaction with 1a
and with aryl bromides and iodides functionalised with a formyl
corresponding boronic acids is
a
prerequisite for the
transmetalation reaction to take place;[20] (b) the superior
reaction
outcome
usually
observed
employing
organotrifluoroborates originates not from
a
more rapid
transmetalation step, rather from a suppression of side-product
formation.[21] Thus, organotrifluoroborates serve as stable
reservoirs for boronic acids, and the endogenous fluoride
liberated from the hydrolysis jointly with the slow release and the
low concentration of boronic acids formed from the potassium
salts are all important features contributing to the attenuation of
the above side reactions. This is also consistent with our
findings. Indeed, in all investigated cases depicted in Table 2,
the performance of aryltrifluoroborates proved to be always
superior to that of the corresponding arylboronic acids. Now, the
question is: if organotrifluoroborate hydrolysis is crucial for the
transmetalation step, how can this take place in DESs? An
important observation of our study is that no coupling occurs
starting from completely anhydrous eutectic mixtures.
Hydrophilic DESs have a tendency for water absorption closely
dependent on the duration time of exposure in open air. A recent
on-site quantitative Fourier transform infrared (FTIR)
spectroscopic analysis performed by our group of residual water
content in ChCl/Gly (1:2) eutectic mixture soon after its
preparation was consistent with up to 2.2 wt% (1.6 M).[15b] Thus,
most probably, the percentage of water incorporated in our
hydrophilic DES once prepared in air may be playing a role in
triggering the hydrolysis of organotrifluoroborates to the
corresponding boronic acids.
(1o) or with
a chloro (1q) group, delivered disubstituted
biphenyls 3ac, 3co, 3cq, 3ag, 3do, and 3dq in 55–98% yield
(Table 2).
To further explore the utility of this new protocol for Pd-
catalysed cross-couplings using eutectic mixtures, we
investigated the synthesis of functionalised terphenyl derivatives,
In consideration of their commercial availability, we also
made use of aryl chlorides for further investigation. Interestingly,
it was uncovered that biphenyl 3aa could be isolated in
quantitative yield by simply heating the reaction mixture from 60
to 100 °C, without adding any additional ligand, and without
increasing catalyst loading. Under these conditions, starting from
4-chloro- and 2-chlorobenzonitriles 1v and 1w, excellent yields
were obtained for the corresponding biphenyl derivatives 3bv
and 3bw (90–92%). 4-Acetyl-, 4-formyl-, 4-methoxy-, 2-nitro-
and 4-nitrophenyl chlorides proved to be good performers as
well, thereby giving rise to adducts 3ab, 3ac, 3ag, 3bn, and 3bo
in 70–82% yields (Table 2). Interestingly, using the combination
of 2-(4-chlorophenyl)acetic acid (1x) and phenyltrifluoroborate
which are interesting molecules displaying
a variety of
pharmaceutical and biological properties,[22] and are also
essential for material science applications.[23] As shown in Table
3, we discovered that one-pot double SM cross-coupling
reactions
of
bifunctional
dipotassium
phenylene-1,4-
bis(trifluoroborate)[24] (2g) with 1a, and with both electron-rich
(1g) and electron-deficient (1m,1v) aryl bromides and iodides,
proceeded uneventfully, thereby leading to conjugated
symmetrical triaryl derivatives 4ga, 4gg, 4gm and 4gv in 64–
97% yield. Of note, trihalogenated coupling module 1-bromo-2-
fluoro-4-iodobenzene (1z) cross-coupled with good reaction
efficiency as well as with 1b, affording fluorinated terphenyl 4bz
in 96% yield (Table 3).[25] Lastly, the challenging one-pot three-
component chemoselective assembly of two different aromatic
moieties to give unsymmetrical terphenyl derivatives was also
examined. Upon adding to a solution of p-bromonitrobenzene
2b
or
of
2-hydroxy-5-iodobenzoic
acid
(1y)
and
aryltrifluoroborate 2e as coupling partners, we straightforwardly
prepared in 96% and >98% yield, respectively, the analgesic,
non-steroidal anti-inflammatory drugs Felbinac (3bx)[18] and
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(1c) or p-bromoanisole (1g) in Gly/ChCl (2.1), first, p-
bromophenyltrifluoroborate 2h, and then phenyltrifluoroborate
2b, terphenyls 4hc and 4hg could be isolated in 68 and 70%
yield, respectively (Table 3).
Table 3. Synthesis of terphenyls 4 via SM coupling between aryl halides 1 and aryltrifluoroborates 2b,2g,h in eutectic mixture ChCl/Gly.[a]
Pd(OAc)2 (1 mol%)
2b: X = H
2g: X = BF3K
2h: X = Br
Na2CO3 (1 equiv.)
Hal = F, Br, I
Ar-Hal
+
X
BF3K
Gly/ChCl, 5 h, 60 °C
COOH
1
2
4
R2
R1
R3
OMe
CN
4ga: (97%, 2g, Br)
4gg: (77%, 2g, Br)
4gm: (80%, 2g, I)
4gv: (64%, 2g, Br)
MeO
NC
COOH
NO2
OMe
F
4bz: (96%, 2b, Br, I)[b]
4hc: (68%, 2b, 2h, Br)[c]
4hg: (70%, 2b, 2h, Br)[c]
[a] Reaction conditions: aryl halide (1) (0.5 mmol; 1.0 or 2.0 equiv.), aryltrifluoroborate (2b,2g,h) (1.0 equiv.) DES (Gly/ChCl, 2:1) (1.0 g), in air. The yields reported
are for products isolated and purified by column chromatography. [b] Phenyltrifluoroborate 2b (2.0 equiv.) was cross-coupled with 1-bromo-2-fluoro-4-iodobenzene
(1z). [c] Both phenyltrifluoroborate 2b (1.0 equiv.) and p-bromophenyltrifluoroborate 2h were cross-coupled with p-bromonitrobenzene (1c) or with p-bromoanisole
(1g) (see main text).
suggests a possible stabilising role played by DES components
The recycling of the catalyst was also realised by
exploiting the different solubility properties that Pd(OAc)2 proved
to exhibit in the DES employed and in other organic solvents.
The reference conditions were those set up for the reaction
between 1a (1.0 mmol) and 2b (1.0 equiv.) in 1.0 g DES and
with 5 mol% Pd(OAc)2 (Table 1, entry 14). Once the stirring was
stopped after 5 h reaction time, and the reaction mixture was
washed with 1 mL cyclopentyl methyl ether (CPME),[26] product
3aa could be recovered quantitatively (>98% yield) leaving the
catalyst in the eutectic mixture.[27]
(e.g., choline chloride) on the above PdNPs.[29]
Then, upon simply adding new, fresh reagents, the catalyst
(jointly with DES and base) could be successfully re-used for
further reaction runs. The catalyst remained active over six
cycles with a decrease in the final yield of 3aa up to 8%: 98%
(second run), 95% (third and fourth run), 94% (fifth run), and
92% (sixth run). (Figure 1a). Pd(OAc)2 is employed as a
heterogeneous catalyst precursor.[27] In ligandless SM coupling,
it is usually reduced in situ to form catalytically active Pd(0)
nanoparticles (NPs) whose nucleation is especially hard to
control kinetically.[28] Indeed, because of their high surface
energy, PdNPs tend to aggregate with each other into larger
particles. This often results in a marked reduction of their
catalytic activity, eventually leading to the deposition of Pd black.
A black precipitation of palladium was also observed during our
reactions. This might explain the progressive decrease of activity
detected during the recycling of the catalyst. However, the fact
that a good catalytic activity is still detected after 6 runs
Figure 1. Recycling of Pd(OAc)2, DES and Na2CO3 in the coupling reaction
between iodobenzene (1a) and phenyltrifluoroborate (2b) with (a) 5 mol%, or
(b) 1 mol% catalyst.
On the other hand, the recycling efficiency proved to be
lower when using 1 mol% Pd(OAc)2. In this case, the catalyst
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10.1002/cssc.201801382
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FULL PAPER
remained well active and could be efficiently recycled only over
four cycles (3aa: >98% yield first run; 94% yield fourth run)
(Figure 1b). The chemical yield of 3aa significantly dropped
down to 49% in the fifth and up to 46% yield in the sixth cycle
most probably because of the additional loss of palladium during
the work-up process. Indeed, we have experimentally
ascertained that no coupling occurs with a catalyst loading of
down to 0.1 mol%. The associated E-factors[30] for the two
recycling processes were 8.74 (5 mol% catalyst, 6 cycles) and
9.25 (1 mol% catalyst, 4 cycles) (see ESI for details).[31]
Acknowledgements
Interuniversities Consortium C.I.N.M.P.I.S., and the University of
Bari (code: capriati005057Prin15) are gratefully acknowledged
for supporting this work. The authors are also indebted to
Silvana Dambrosio for her contribution to the experimental work.
Keywords: deep eutectic solvents • Suzuki-Miyaura coupling •
aryltrifluoroborates • sustainable chemistry • catalysis
[1]
For recent reviews, see: a) A. Suzuki, Angew. Chem. 2011, 123, 6854–
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Conclusions
In summary, the environmentally friendly eutectic mixture
ChCl/Gly (1:2) turned out to be the most effective reaction
medium for carrying out Suzuki–Miyaura couplings
involving mono- and bifunctional aryltrifluoroborates as
nucleophilic partners in the absence of additional ligands,
and using to up to 1 mol% Pd(OAc)2 as catalyst, Na2CO3 as
base, and an efficient recycling sequence of catalyst, base
and DES with an E-factor as low as 8.74. The presented
protocol can be run in air and under gentle heating for
(hetero)aryl bromides and iodides (60 °C), and tolerates
many functional groups such as nitro, cyano, carboxylic
acids, esters, halides, carbonyl derivatives, alkoxy and free
hydroxy and amino functionalities. Valuable biaryl and
terphenyl derivatives (more than 50 cases compared and
discussed), which play a pivotal role in the pharmaceutical
industry, materials science and catalysis, have been
successfully synthesised in yields of up to and above 98%,
also starting from challenging aryl chlorides, by simply
increasing the temperature to 100 °C. The methodology
was applied to the synthesis of the non-steroidal anti-
inflammatory drugs Felbinac and Diflunisal. Efforts towards
reshaping other traditional cross-coupling methods
employing sustainable, nonconventional solvents are
underway and will be reported in due course.
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General procedure for Pd-catalysed Suzuki-Miyaura reactions for
the synthesis of biaryls
3 using aryltrifluoroborates 2b–e or
arylboronic acids 2a,2f and (hetero)aryl halides in Gly/ChCl.
To a suspension of potassium aryltrifluoborate (2b–e) (0.5 mmol) [for
arylboronic acids 2a,2f: 0.75 mmol] in 1.0 g of Gly/ChCl (2:1 mol mol-1),
(hetero)aryl halide (1a–y) (0.5 mmol), Na2CO3 (53 mg, 0.5 mmol), and
Pd(OAc)2 (1.1 mg, 0.005 mmol) were sequentially added. The reaction
mixture was stirred at 60 ºC (aryl chlorides: 100 °C) in air for 5 h until
complete consumption of the starting material (monitored by TLC), then
cooled to room temperature, and finally extracted with 1 mL of CPME.
The organic layer was filtered through a Celite pack and evaporated
under reduced pressure to afford the crude product. The latter was
purified by column chromatography on silica gel (hexane/EtOAc 5:1 ÷
4:1) to provide the desired biaryl 3 (see Table 2).
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10.1002/cssc.201801382
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[31] For the sake of comparison, the calculated E-factor values for the two
SM couplings reported in ref. 12a and 12b are 49.3 and 101.3,
respectively (see ESI for details).
[27] It is worth noting that the described protocol takes place under
heterogeneous conditions; indeed, the catalyst is neither soluble in the
employed eutectic mixture nor in the organic solvent used for recycling
(CPME).
[28] a) L. A. Adrio, B. N. Nguyen, G. Guilera, A. G. Livingston, K. K. Hii,
Catal. Sci. Technol. 2012, 2, 316–323; b) S. Özkar, R. G. Finke,
Langmuir 2016, 32, 3699–3716.
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10.1002/cssc.201801382
ChemSusChem
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Giuseppe Dilauro, Sergio Mata García,
Donato Tagarelli, Paola Vitale, Filippo
M. Perna,* Vito Capriati*
R
R
Pd(OAc)2, Na2CO3, 60–100 °C, 5 h
Het
R
Hal
+
X
BF3K
Gly/ChCl (2:1)
- up to >98% yield
- ligand-free synthesis
- over 50 examples
Het
R
or
Page No. – Page No.
- broad substrate scope
- recyclable medium
R
R
R
Ligand-free Bio-inspired Suzuki–
Miyaura Couplings using
X = H, F, Br, NO2, MeO, BF3K; Hal = Cl, Br, I
Aryltrifluoroborates as Effective
Partners in Deep Eutectic Solvents
Sustainable Suzuki-Miyaura coupling in DESs: Biaryl and terphenyl derivatives
have been successfully synthesized via a Pd-catalysed one-pot two- or three-
component assembly of mono- and bifunctional aryltrifluoroborates with (hetero)aryl
halides in environmentally responsible and recyclable deep eutectic solvents.
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