Towards a sustainable synthesis of amides: chemoselective palladium-catalysed aminocarbonylation of aryl iodides in deep eutectic solvents

Article abstract of DOI:10.1039/c8cc03858a

A palladium-catalysed aminocarbonylation of (hetero)aryl iodides has, for the first time, been accomplished in deep eutectic solvents as environmentally benign and recyclable media, under mild conditions. The reactions proceeded with a good substrate scope, and a variety of amides have been synthesized in yields up to 98%.

Full text of DOI:10.1039/c8cc03858a

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Towards a Sustainable Synthesis of Amides: Chemoselective
Palladium-catalysed Aminocarbonylation of Aryl Iodides in Deep
Eutectic Solvents
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
Francesco Messa, Serena Perrone, Martina Capua, Francesco Tolomeo, Luigino Troisi, Vito
,
b
,a
DOI: 10.1039/x0xx00000x
Capriati* and Antonio Salomone*
www.rsc.org/
Palladium-catalysed aminocarbonylation of (hetero)aryl iodides so-called Deep Eutectic Solvents (DESs) (also known in the
has, for the first time, been accomplished in deep eutectic literature as Low Melting Mixtures, LMMs) have become to
solvents as environmentally benign and recyclable media, under emerge as a new, unconventional class of reaction media in
mild conditions. The reactions proceed with good substrate scope, green synthesis. DESs are combinations of two or three safe,
and a variety of amides have been synthesized in yields up to 98%. inexpensive, and nature-inspired components able to engage
in reciprocal hydrogen bond interactions to form an eutectic
Transition-metal-catalysed carbonylation reactions have
become a cornerstone of modern organic synthesis, whether it
is in academia or in industry, for the one-pot synthesis of a
variety of carbonyl-containing functionalities such as carboxylic
acids, esters, ketones, aldehydes, amides, and thus for the
preparation of high value-added organic molecules useful for
mixture with a melting point much lower than that of either of
the individual components. Compared to conventional VOCs,
DESs show high thermal stability, non-flammability and
practically no vapour pressure, therefore low volatility. Typical
DES components [e.g., choline chloride (ChCl), urea, glycerol
(Gly), natural carboxylic acids, amino acids and carbohydrates,
1
our daily life. A common feature of all Pd-catalysed
polyalcohols] come from renewable sources. Thus, their
biodegradability is extraordinarily high, and their toxicity is
non-existent or very low. DESs also display high tunable
solvent properties by simply changing the nature and the
carbonylation of halogenated or triflate aromatic
hydrocarbons, however, is the use of toxic, volatile organic
compounds (VOCs) (e.g., toluene, 1-butanol, DMF, dioxane),
and heating the mixture at a temperature of or higher than
6
molar ratio of the components.
1
a,2
1
00 °C.
been introduced only for ionic liquids,
assisted homogeneous and heterogeneous processes.
Milder temperatures (60–100 °C) have recently
From the perspective of green chemistry, although the
application of these neoteric solvents in several fields of
sciences has experienced an exponential growth particularly in
3
a,b
and for microwave-
3
c
6
Increasingly, stringent environmental legislation and
urgent action to address the climate crisis have generated a
4
pressing need for cleaner methods of chemical production. In
the last years, Pd-catalysed reactions in DESs have received
7
much less attention. Building on recent findings in Pd-
8
catalysis, and as part of our ongoing efforts to develop
particular, the progressive replacement of extensively used
conventional and hazardous VOCs in favour of safe,
environmentally responsible and bio-renewable solvents is
environmentally benign synthetic and catalytic protocols using
9
a multiple bond-forming approach or unconventional reaction
1
0
media, herein, we disclose a sustainable, chemoselective
route to amides by exploiting the direct carbonylation reaction
of (hetero)aryl iodides in DESs. Notable features of our report
include: (i) phosphine-free and mild conditions, (ii) absence of
VOCs, (iii) easy isolation of products, and (iv) efficient recycling
of both DES and catalyst.
holding
a key interest, and has become a topic of
5
interdisciplinary research. Such a replacement also minimises
the emission of effluents in the chemical industry, and
contributes to bridge the divide between industrial
applications and the fundamental chemistry. Accordingly, the
Our investigation started with 1-chloro-3-iodobenzene (1.0
mmol) (1a) and EtOH (6.0 mmol) (2a) as model substrates to
synthesize ethyl 3-chlorobenzoate 3aa under a pressure of CO
(Table 1). When the reaction was run in THF (5 mL) using
Pd(PPh ) (5 mol%) as catalyst, NEt (3.0 mmol) as base, under
3
4
3
a CO atmosphere (27 atm) for 12 h and gently heating at 60 °C,
aa was isolated in 50% yield, with the remaining mass
3
balance being starting material only (Table 1, entry 1). When
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–1
performed in the eutectic mixture Gly/ChCl (2:1 mol mol ), (86–95%) (Table 2). The direct carbonylation of 1e in the
under the same experimental conditions, such coupling proved presence of a secondary amine (4b) was less favourable and
less effective (3aa: 35% yield; Table 1, entry 2). Upon switching furnished product 5eb in 57% yield (Table 2). Despite the lower
–1
to LMM L-lactic acid/D-glucose (5:1 mol mol ), no coupling yield, however, the sustainable preparation of compounds of
was observed (Table 1, entry 3). The product 3aa was obtained the type of 5eb, which are nicotinamide derivatives, appears
–
in moderate yield (58%) by employing urea/ChCl (2:1 mol mol
1
very interesting since these carbon scaffolds are known for
)
as eutectic mixture and NEt
3
(3.0 mmol) as base (Table 1, their important pharmacological activities such as
1
entry 4). Further screening of catalysts/bases to boost the cytotoxicity, the inhibition of succinate dehydrogenase, and
2
13
+
+
14
transformation revealed a negligible dependence on both the of gastric H /K -ATPase. When an aryl iodide bearing a nitro
Pd-source and the nature of base, the yields of 3aa being in group (1f) and amine 4a were jointly submitted to this
the range of 45 to 56% (Table 1, entries 5–8). On the other carbonylative protocol, coupling product 5fa was delivered in
hand, a lower pressure of CO (10 atm) almost completely 58% yield, however, with the reduction of the nitro group to
1
5
suppressed the formation of the coupling product (3aa: <5%; amino group.
Table 1, entry 9). By performing ethoxycarbonylation or
Table 1. Alkoxycarbonylation and aminocarbonylation of aryl iodides 1 in
various solvents.
(
benzyloxy)-carbonylation (2b: BnOH) with CO (27 atm) at 60
C in urea/ChCl of variously substituted aryl iodides 1b , or of
electron-deficient heteroaromatic rings (e.g., 3-iodopyridine,
), unsatisfactory outcomes resulted, with yields of the
expected adducts 3ba 3cb 3db, and 3ea of up to 41% (Table
, entries 10–13). However, despite the low isolated yields of
a
°
–d
O
I
1e
Pd source, CO
Nu
+
NuH
or
,
,
base, solvent
60 °C, 12 h
R1
X
1
2
4
1
X
3 or 5aa
R
1
Nu = OEt, OBn, NHBu
esters, it was noted that starting substrate 1a was completely
consumed in all the above alkoxycarbonylation reactions. We
questioned at this point whether DES components themselves,
in competition with alcohols, might trigger alternative
acylation processes. Thus, we focused on the use of more
nucleophilic species, such as amines. To our delight, the
b
1
Entry Solvent
Pd
source
R
NuH
3 or 5aa
c
yield (%)
d
e
f
1
2
3
4
5
6
7
8
9
THF
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
)
)
)
)
4
4
4
4
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1b: 4-Ac
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2a: EtOH
2b: BnOH
2b: BnOH
2a: EtOH
3aa: 50
e
g
e
f
Gly/ChCl
LMM
3aa: 35
g,h
NR
reaction of 1a (1.0 mmol) with n-BuNH
a pressure of CO (27 atm) for 12 h, at 60 °C and using Pd(OAc)
5 mol%) as catalyst and K CO (3.0 mmol) as base,
2
(6.0 mmol) (4a) under
f
urea/ChCl Pd(PPh
urea/ChCl Pd/C
urea/ChCl Pd(PPh3)4
3aa: 58
e
f
2
3aa: 45
e
h
(
2
3
3aa: 55
e
h
straightforwardly led to the desired aminocarbonylated
product 5aa in high yield (93–98%) either in a Gly/ChCl or in a
urea/ChCl eutectic mixture (Table 1, entries 14,15). By
changing the solvent to pure glycerol, however, the yield of
urea/ChCl
urea/ChCl
urea/ChCl
urea/ChCl
urea/ChCl
urea/ChCl
urea/ChCl
Gly/ChCl
urea/ChCl
Gly
Pd/C
3aa: 52
e
f
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
3aa: 56
e
f,i
3aa: <5
e,j
h
1
0
1
2
3
4
5
6
7
3ba: 25
e
h
1
1
1
1
1
1
1
Pd(OAc)
2
1c: H
3cb: 28
5aa dropped down to 27%, most probably because of the high
e
h
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
1d: CO
2
ET
3db: 41
viscosity of the medium (Table 1, entry 16). The use of DMF or
water (heterogeneous conditions) as reaction media was also
k
h
1e: H
3ea: 21
e
h,l
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
1a: 3-Cl
4a: BuNH
4a: BuNH
4a: BuNH
2
5aa: 93
1
1
less satisfactory (5aa: 46–75% yield; Table 1, entries 17,18).
e
e
e
e
h
2
5aa: 98
To examine the scope and limitations of the reaction,
various functionalised (hetero)aryl iodides and different
primary and secondary amines were tested (Table 2). The
carbonylative coupling between 1a and piperidine (4b) or 2-
aminopyridine (4c) took place smoothly, either in a ChCl/urea
h
Pd(OAc)
Pd(OAc)
Pd(OAc)2
2
2
5aa: 27
h
DMF
2
4a: BuNH
2
5aa: 46
h
18
2
H O
4a: BuNH2
5aa: 75
a
Reaction conditions: (hetero)aryl iodide (1.0 mmol), alcohol or n-BuNH
6.0 mmol), base (3.0 mmol), Pd source (5 mol% in Pd; Pd/C: 1 mol% in Pd),
CO (27 atm), DES or LMM (2 g), 60 °C, 12 h. All reactions were run in
2
(
(1:2) (DES A) or in a ChCl/Gly (1:2) (DES B) eutectic mixture,
b
–1
and provided the desired products 5ab and 5ac in 92–96% duplicate. Gly/ChCl (2:1 mol mol ); LMM: L-lactic acid/D-glucose (5:1 mol
yields (Table 2). The direct carbonylation of an acyl-containing mol ); urea/ChCl (2:1 mol mol ). Calculated by H-NMR analysis of the
–
1
–1
c
1
crude reaction mixture using an internal standard technique (NMR internal
aryl iodide (1b) with 4a gave the expected adduct 5ba in up to
d
e
f
g
standard: dimethylsulfone). 5 mL. X = CH. Base = NEt . NR = no reaction.
3
51% yield (DES A); an inspection of the crude (GC-MS analysis)
h
I
j
k
l
Base = K
2 3 3
CO . Reaction performed under 10 atm CO. Ac = CH CO. X = N.
revealed the formation of an imine as a by-product. The
aminocarbonylation reaction was less efficient in the absence
The yield of 5aa dropped down to 15% when using NaOAc as the base.
of an electron-withdrawing group on the phenyl ring. Indeed, Such a concomitant reductive carbonylation of aromatic nitro
the coupling of 1c with 4a, under a carbon monoxide pressure, compounds is very attractive as it paves the way for the
provided 5ca in 60% vs. 93% yield, as in the case of 5aa (Tables synthesis of amino-substituted benzamides, which are not
1,2). On the other hand, an electron-deficient nitrogen easy to be straightforwardly prepared. Remarkably, the
heterocycle, such as 3-iodopyridine (1e), proved to be a carbonylation of 1-bromo-3-iodobenzene (1g), run in the
competent partner, and underwent aminocarbonylation with presence of either a primary amine (4a) or a secondary amine
assorted N-nucleophiles [4a
,
4c, and aniline (4d)] delivering
(
4b), led to the chemoselective reaction of the aryl iodide
the corresponding adducts 5ea
,
5ec and 5ed in excellent yields functionality to provide 5ga (75% yield) or 5gb (70% yield),
2
| J. Name., 2012, 00, 1-3
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respectively, leaving the bromide unreacted, and thus donating group (MeO) in the starting aryl iodide (1i) was
available for further functionalisation (Table 2). The use of the detrimental to the reaction outcome as the yields of amides
benzaldehyde derivative 1h was also tolerated, and furnished produced in the coupling with 4a and 4b were poor (5ia: 15%;
1
6
the valuable formyl-fluorobenzamide 5ha (61% yield) by 5id: 42%) (Table 2).
carbonylative coupling with 4a. The presence of an electron-
a
Table 2 Synthesis of amides 5 via aminocarbonylation of (hetero)aryl iodides 1 in deep eutectic solvents.
1
1
1
1
1
1
1
1
a
: X = CH; R1 = H, R2 = 3-Cl
: X = CH; R1 = H, R2 = 4-CH
b
3
CO
HN
Pd(OAc)
2
O
4
a
: n-BuNH
2
4b:
1
2
c
e
: X = CH; R , R = H
I
R4
R4
CO (27 atm)
X
H
1
2
R2
X
N
: X = N; R , R = H
+
N
R2
f
: X = CH; R1 = H, R2 = 4-NO
2
R3
DES, K CO3
2
R3
R1
: X = CH; R1 = H, R2 = 3-Br
: X = CH; R1 = 4-F, R2 = 3-CHO
4c:
4d:
1
4
R1
5
g
60 °C, 12 h
N
NH
2
NH2
h
DES A: ChCl/urea (1:2); DES B: ChCl/Gly (1:2)
i
: X = CH; R1 = H, R2 = 4-MeO
O
O
O
O
Cl
Cl
N
N
H
N
N
H
N
H
3
H C
5
ab: 94% (DES A); 96% (DES B) 5ac: 95% (DES A); 92% (DES B)
5ba: 51% (DES A); 35% (DES B)
5ca: 60% (DES B)
O
O
O
O
O
O
N
H
N
N
H
N
N
H
N
H
N
N
N
H
N
2
H N
5
ea: 95% (DES B)
5eb: 57% (DES B)
5ec: 86% (DES B)
5ed: 95% (DES B)
5fa: 58% (DES B)
O
O
O
O
O
O
Br
Br
N
H
3
N
N
H
3
N
H
3
N
H
F
MeO
MeO
5
ga: 75% (DES B)b
5gb: 70% (DES B)b
5ha: 61% (DES B)
5ia: 15% (DES B)
5id: 42% (DES B)
a
2 3 2
Reaction conditions: (hetero)aryl iodide (1.0 mmol), amine (6.0 mmol), K CO (3.0 mmol), Pd(OAc) (5 mol %), CO (27 atm), DES (2.0 g), 60 °C, 12 h. The
b
yields reported are for products isolated and purified by column chromatography. Reaction time: 3 h.
Both the Pd-catalyst and DES could be easily recycled. The
aminocarbonylation of iodoarene 1a with amine 4a in
ChCl/urea (1.2) was chosen as a model reaction, since it
provided almost quantitative yield of the corresponding
coupling product 5aa (Table 1, entry 15). Upon completion of
the first coupling, in-flask extraction with AcOEt afforded
product 5aa (98% yield, Figure 1, number of recycles = 0), but
leaving the active palladium species in the eutectic mixture.
The DES phase was then dried under vacuum until constant
weight. Then, upon simply adding new, fresh reagents (1a
, 4a,
and K CO ), the catalyst and DES could be successfully re-used
2
3
for further reactions. As shown in Figure 1, the catalyst
remained active over 5 cycles, albeit with a drop in the
chemical yield of 5aa of up to 34%. The recycling efficiency was
improved by using the less viscous ChCl/Gly (1:2) eutectic
mixture and Pd/C (1 mol%) as the catalyst, in the presence of
Figure 1 Recycling of Pd(OAc)
2
(5 mol%) or Pd/C (1 mol%) and DES in the
(4a).
coupling reaction between 1-chloro-3-iodobenzene (1a) and n-BuNH
2
The proposed protocol (a) does not require additional
ligands, (b) is highly chemoselective towards the aryl carbon-
iodine bond cleavage, (c) tolerates various functional groups
1
7
K
2
CO
3
.
In this case, the chemical yield of 5aa dropped down
to only 14% in the fourth and up to 24% in the fifth cycle.
In summary, Pd-catalysed aminocarbonylation of
(with the exception of nitro group which is in-situ reduced to a
valuable amino group), (d) proceeds with good reaction
efficiency especially starting from electron-deficient
(hetero)aryl iodides can be performed under remarkably mild
conditions (60 °C) using biodegradable eutectic mixtures as
environmentally responsible reaction media in place of toxic
and hazardous VOCs.
(hetero)aryl iodides, and (e) allows an effective recycling of
both DES and catalyst. Efforts towards clarifying the “active”
role played by DES components in promoting carbonylation
reactions, and in tuning the activity of the Pd-catalyst, will
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surely help to expand even more the substrate scope with
respect to other nucleophiles.
Green Chem., 2006, 8, 1051; (c) F. Ilgen and B. König, Green
Chem., 2009, 11, 848; (d) X. Zhao, X. Liu and M. Lu, Appl.
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Consortium C.I.N.M.P.I.S., the University of Bari, and the
University of Salento for supporting this work.
2
014, 16, 3876; (f) X. Marset, A. Khoshnood, L. Sotorríos, E.
Gjmez-Bengoa, D. A. Alonso and D. J. Ramón, ChemCatChem.,
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Conflicts of Interest
There are no conflicts to declare.
5
7
, 3363; (c) S. Perrone, A. Salomone, A. Caroli, A. Falcicchio,
C. Citti, G. Cannazza and L. Troisi, Eur. J. Org. Chem., 2014,
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M. Capua, S. Perrone, F. M. Perna, P. Vitale, L. Troisi, A.
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(
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