Pd/C in Propylene Carbonate: A Sustainable Catalyst–Solvent System for the Carbonylative Suzuki–Miyaura Cross-Coupling Using N-Formylsaccharin as a CO Surrogate

Article abstract of DOI:10.1002/ejoc.201700543

This work documents the first Pd/C-catalyzed carbonylative Suzuki–Miyaura cross-coupling of aryl iodides with N-formylsaccharin as a CO surrogate. In contrast to previous reaction protocols, which make use of toxic and hazardous solvents, the reaction could be advantageously performed in propylene carbonate as an environmentally benign and sustainable polar aprotic solvent. A range of biaryl ketones, including (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone, an antineoplastic belonging to the phenstatin family, could be synthesized under cocatalyst-free, additive-free and ligand-free conditions. The Pd/C could be recycled up to five times under CO surrogacy with only a marginal decrease in catalytic activity. The reaction could also be scaled up to gram-scale syntheses.

Full text of DOI:10.1002/ejoc.201700543

A Journal of
Accepted Article
Title: Pd/C in Propylene Carbonate: A Sustainable Catalyst-Solvent
System for the Carbonylative Suzuki-Miyaura Cross-Coupling
using N-Formylsaccharin as a CO Surrogate
Authors: Prashant Gautam, Rashi Gupta, and Bhalchandra Mahadeo
Bhanage
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700543
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700543
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European Journal of Organic Chemistry
10.1002/ejoc.201700543
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Pd/C in Propylene Carbonate: A Sustainable Catalyst-Solvent
System for the Carbonylative Suzuki-Miyaura Cross-Coupling
using N-Formylsaccharin as a CO Surrogate
Prashant Gautam, Rashi Gupta and Bhalchandra M. Bhanage*[a]
Abstract: This work documents the first Pd/C catalyzed
carbonylative Suzuki-Miyaura cross-coupling of aryl iodides using N-
formylsaccharin as a CO surrogate. As compared to previous
reaction protocols which make use of toxic and hazardous solvents,
the reaction could be advantageously carried out in propylene
carbonate as an environmentally benign and sustainable polar
aprotic solvent. A range of biaryl ketones could be synthesized
under co-catalyst free, additive free and ligand free conditions
including (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone, an
antineoplastic belonging to the phenstatin family. Pd/C could be
recycled up to five times under CO surrogacy with only a marginal
decrease in catalytic activity. The reaction could also be scaled up to
gram scale synthesis.
with poor atom economy. The inability to regioselectively access
ortho or para isomers, their separation and accessing biaryl
ketones with meta substitution and electron-withdrawing groups
are added disadvantages of the Friedel-Crafts acylation.
In the early 1990’s, Suzuki documented the palladium
catalyzed three component carbonylative cross-coupling
between aryl halide and aryl boronic acid utilizing carbon
monoxide as the C1 source leading to the synthesis of biaryl
ketones.[3] As compared to other carbonylative cross-coupling
reactions, which make use of organometallic reagents as
nucleophilic coupling partners, the carbonylative Suzuki-Miyaura
cross-coupling is preferred because aryl boronic acids are air,
moisture and thermally stable, easy to handle and non-toxic
(
Scheme 1).
Introduction
The synthesis of biaryl ketones is imperative as they
represent key structural building blocks present in
Scheme 1. Comparison between Friedel-Crafts acylation and carbonylative
pharmaceuticals,
agrochemicals,
photosensitizers
and
Suzuki-Miyaura cross-coupling.
sunscreen agents.[ (Figure 1).
1]
Although the carbonylative Suzuki-Miyaura cross-coupling is
well documented through different homogeneous and
heterogeneous catalytic protocols, the usage of gaseous CO
impedes the application of carbonylation reactions in academic
laboratories and at the industrial scale. This is primarily due to
the fact that CO is an odourless, colourless and inflammable
toxic gas whose inhalation can have lethal consequences. The
requirement to transport and store gaseous CO in cylinders and
the need to handle specialized high pressure reactors for
carrying out carbonylation reactions pose serious safety
concerns and further limit their use. CO surrogates- molecules
which release gaseous CO under appropriate conditions-
address the aforementioned limitations.
Figure 1. Representative examples of molecules containing the biaryl ketone
functionality.
Over the last decade, various synthetic methodologies and
improvised reaction protocols have been adopted for carrying
Biaryl ketones are conventionally synthesized by the Friedel-
Crafts acylation.[2] The reaction which is carried out by
incorporating stoichiometric amounts of Lewis acid suffers from
poor compatibility with functional groups. The reaction is also
accompanied by generation of large amounts of waste coupled
out carbonylation reactions using CO surrogates.[
4]
The
synthesis of biaryl ketones through the palladium catalyzed
carbonylative Suzuki-Miyaura cross-coupling has been achieved
incorporating
various
CO
surrogates.
Molybdenum
hexacarbonyl,[ formic acid,[6] N,N-dimethylformamide
5]
[7]
and
chloroform[8] have been applied as CO surrogates through in situ
CO generation. Skrydstrup and co-workers reported the
carbonylative Suzuki-Miyaura cross-coupling through ex situ CO
[
a]
P. Gautam, R. Gupta, Prof. Dr. B.M. Bhanage
Department of Chemistry,
Institute of Chemical Technology,
N.P. Marg, Matunga-400019, Mumbai, India
E-mail: bm.bhanage@gmail.com; bm.bhanage@ictmumbai.edu.in;
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
generation using a two-chamber system and 9-methyl-fluorene-
[9]
9
-carbonyl chloride (COgen) as a CO surrogate. They also
documented the reaction under base free conditions.[
10]
N-formylsaccharin, initially used for formylation of
amines[11] was applied for the first time as a CO surrogate by
Manabe and co-workers for the palladium catalyzed reductive
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European Journal of Organic Chemistry
10.1002/ejoc.201700543
FULL PAPER
carbonylation of aryl halides.[12] The same group also
documented the fluorocarbonylation of aryl halides and
subsequent synthesis of carboxylic acid derivatives under
palladium catalysis using N-formylsaccharin.[13] Fleischer and
co-workers
reported
the
palladium
catalyzed
alkoxycarbonylation of alkenes for the synthesis of aliphatic
esters using N-formylsaccharin.[14]
Figure 2. Structures of ethylene carbonate (1) and propylene carbonate (2).
The carbonylative Suzuki-Miyaura cross-coupling using
CO surrogates, to the best of our knowledge, has only been
carried out under homogeneous catalytic protocols. Even though,
advantageously, aryl bromides could be used as inexpensive
coupling partners, the reaction protocols suffer from the use of
either toxic metal (molybdenum) carbonyl as the CO surrogate,
requirement of a specialized two-chamber system, use of
phosphine ligands, toxic anhydride and excess amount of
hydroxide base. Moreover, the carbonylative Suzuki-Miyaura
cross-coupling under CO surrogacy has been carried out mostly
in hydrocarbon solvents[5-6,8-10] (anisole and toluene) and N,N-
dimethylformamide (N,N-DMF).[7] Further, reactions making use
of N-formylsaccharin as the CO surrogate have been carried out
in N,N-DMF[12,13] and dichloromethane (DCM).[14] Although, the
carbonylative cross-coupling could be effectively carried out and
N-formylsaccharin underwent ready decarbonylation, the
aforementioned amide, chlorinated and hydrocarbon solvents
are considered toxic and unsustainable. It is extremely important
to consider the impact and consequence of reaction solvents on
health safety and environment in contemporary chemistry.
Under REACH[15] (Registration, Evaluation, Authorization and
restriction of CHemicals)- a regulation passed by the European
Union, the utilization and consumption of solvents will be
carefully scrutinized and restricted. Hence it is imperative to find
alternative sustainable solvents for chemical transformations.
Organic cyclic carbonates have gained importance as
benign polar aprotic solvents in chemical synthesis.[16] This is
attributed to the fact that they are odourless, non-toxic, bio-
degradable and possess low vapour pressure. They can also be
synthesized from inexpensive and renewable feedstocks at the
industrial scale.[17] Amongst organic cyclic carbonates, ethylene
and propylene carbonate (Figure 2) are widely used as
solvents in different reactions and they have been rated good to
excellent, thus showing no points of concern across all criteria
by the GlaxoSmithKline (GSK) solvent selection guide.[
Furthermore, when compared to amide (N,N-DMF), chlorinated
18]
(
DCM) and hydrocarbon solvents (anisole and toluene), ethylene
and propylene carbonate have higher boiling points (low vapour
pressure) which thus results in lower atmospheric emissions and
also makes them convenient to handle and safe to store.
Advantageously, since organic cyclic carbonates are comprised
entirely of only carbon, hydrogen and oxygen, oxides of nitrogen
and sulfur are not produced or emitted on their combustion or
incineration. Ethylene carbonate is a solid at room temperature
and is difficult to use as a solvent, but propylene carbonate
being a liquid is a convenient and sustainable alternative to N,N-
DMF and DCM. In spite of these advantages, the application of
cyclic carbonates as solvents for carbonylation reactions is less
documented.[19]
As mentioned earlier, carbonylative Suzuki-Miyaura cross-
coupling under CO surrogacy has only been carried out through
homogeneous catalytic protocols, with catalyst product
separation and the inability to recycle palladium being the major
disadvantages. Palladium on activated carbon (Pd/C) is an
inexpensive and commercially available heterogeneous catalyst
which addresses the disadvantages associated with
[20]
homogeneous catalysis. Moreover, Pd/C has only been rarely
reported as heterogeneous palladium precursor in
a
[
21]
carbonylation reactions carried out using CO surrogates. We
recently reported the Pd/C catalyzed phenoxycarbonylation of
aryl iodides using N-formylsaccharin as a CO surrogate in
propylene carbonate.[22]
Scheme 2. Comparison of previous reaction protocols with current protocol.
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European Journal of Organic Chemistry
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Taking into consideration our sustained interest in Pd/C
catalyzed carbonylation reactions,[23] we herein report the first
Pd/C catalyzed carbonylative Suzuki-Miyaura cross-coupling
using N-formylsaccharin as a CO surrogate in propylene
carbonate as an environmentally benign and sustainable
solvent (Scheme 2).
Results and Discussion
We started the reaction optimization by monitoring the
carbonylative cross-coupling between iodobenzene 3a and
phenylboronic acid 4a thus leading to the synthesis of
benzophenone 5a (Table 1). We initially applied Pd(OAc)
2
and PdCl
DMF
2
as homogeneous palladium precursors in N,N-
as
the
solvent
at
100
°C.
Table 1. Optimization of reaction parameters.[a]
Amount
of NFS
Selectivity[c]
Selectivity[c]
Time
h)
Temperature
(°C)
Conversion[c]
(%)
Entry
Pd source[b] (mol%)
Base
Solvent
5a
(%)
6a
(%)
(
(mmol)
Effect of palladium source
1
2
3
Pd(OAc)
PdCl (3 mol%)
Pd/C (5 mol%)
2
(3 mol%)
Na
2
Na
2
Na
2
CO
CO
CO
3
3
3
0.5
0.5
0.5
N,N-DMF
N,N-DMF
N,N-DMF
24
24
24
100
100
100
72
65
70
58
51
65
42
49
35
2
Effect of solvent
4
5
6
7
8
9
Pd/C (5 mol%)
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
0.5
0.5
0.5
0.5
0.5
0.5
1,4-Dioxane
Toluene
24
24
24
24
24
24
100
100
100
100
100
100
43
77
92
72
64
98
81
11
57
52
44
75
19
89
43
48
56
25
Pd/C (5 mol%)
Pd/C (5 mol%)
Pd/C (5 mol%)
Pd/C (5 mol%)
Pd/C (5 mol%)
N,N-DMF:Dioxane (1:1)
N,N-DMF:Dioxane (3:1)
N,N-DMF:Dioxane (1:3)
Propylene carbonate
Effect of base
1
0
1
Pd/C (5 mol%)
Pd/C (5 mol%)
K
2
CO
3
0.5
0.5
Propylene carbonate
Propylene carbonate
24
24
100
100
91
84
48
23
52
77
1
Et
3
N
Effect of time
12
13
14
15
Pd/C (5 mol%)
Pd/C (5 mol%)
Pd/C (5 mol%)
Pd/C (5 mol%)
Na
2
2
2
2
CO
3
3
3
3
0.5
0.5
0.5
0.5
Propylene carbonate
Propylene carbonate
Propylene carbonate
Propylene carbonate
18
12
8
100
100
100
100
89
69
52
39
76
71
70
74
24
29
30
26
Na
Na
Na
CO
CO
CO
6
Effect of temperature
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European Journal of Organic Chemistry
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1
6
7
Pd/C (5 mol%)
Pd/C (5 mol%)
Na
2
CO
3
3
0.5
0.5
Propylene carbonate
Propylene carbonate
24
24
80
70
85
68
79
84
21
16
1
Na
2
CO
Effect of N-formylsaccharin concentration
1
8
9
Pd/C (5 mol%)
Pd/C (5 mol%)
Na
2
CO
3
3
0.4
0.6
Propylene carbonate
Propylene carbonate
24
24
100
100
78
98
64
77
36
23
1
Na
2
CO
[
a] Reaction conditions: iodobenzene (0.25 mmol), phenylboronic acid (0.375 mmol), base (0.75 mmol), solvent (2 mL). [b] 10% Pd/C. [c] Conversion and
selectivity were based on iodobenzene and determined using GC technique based on external standard method and confirmed using GC-MS.
The reaction proceeded with 72% and 65% conversion with
8% and 51% selectivity respectively towards 5a in 24 h.
Table 1, entries 1 and 2). However, on changing the
palladium precursor to heterogeneous Pd/C, we obtained
similar conversion as Pd(OAc) with slightly better selectivity
towards 5a (Table 1, entry 3). Next, we focused our attention
on solvent screening. We observed that when the reaction
was carried out in 1,4-dioxane, the conversion dropped to
Na
formylsaccharin and for driving the carbonylative cross-
coupling while other bases (K CO and Et N) gave inferior
2
CO
3
is the most suited for decarbonylation of N-
5
(
2
3
3
conversion and selectivity (Table 1, entries 10 and 11). The
time and temperature optimization revealed that maximum
conversion is obtained at 24 h and at 100 °C. Decrease in
time from 24 h to 6 h results in a decrease in conversion from
98% to 39%. Similarly, decrease in reaction temperature from
100 °C to 70 °C results in a decrease in conversion from 98%
to 68% but with an increase in selectivity from 75% to 84%
(Table 1 entries 12-17). Subsequently, the effect of the
concentration of N-formylsaccharin on conversion showed
that, the maximum conversion is effected using 0.5 mmol of
N-formylsaccharin. Decreasing the amount of surrogate to 0.4
mmol brings down the conversion to 78%. However,
increasing the amount of surrogate to 0.6 mmol does not
have any profound effect on the conversion (Table 1, entries
18 and 19).
2
43% while the selectivity towards 5a increased to 81% (Table
1, entry 4). Hence, we carried out the subsequent reactions in
a mixture of N,N-DMF and 1,4-dioxane in different ratios. We
observed that when the reaction was carried out in a 1:1
mixture of N,N-DMF and 1,4-dioxane, the reaction proceeded
with 92% conversion and 57% selectivity towards 5a (Table 1,
entries 6-8) In non-polar solvent (toluene), the reaction
proceeded predominantly with non-carbonylative Suzuki-
Miyaura cross-coupling (Table 1, entry 5). The carbonylative
Suzuki-Miyaura cross-coupling of aryl halides is known to
lead to the formation of the corresponding aryl carboxylic
acids in polar aprotic solvents.[3a] However, delightfully, using
Pd/C as the palladium precursor in propylene carbonate
resulted in a 98% conversion with a 75% selectivity towards
Having established the optimized reaction conditions,
we turned our attention to the scope of different biaryl
ketones that could be synthesized through the developed
protocol (Table 2).
5a (Table 1, entry 9). The base screening study showed that
Table 2. Scope of the Pd/C catalyzed carbonylative Suzuki-Miyaura cross-coupling using N-formylsaccahrin.[a]
1.
2.
3.
4.
5.
[
b]
C: 84%
[b]S: 77%
C: 91%
S: 75%
C: 100%
S: 59%
C: 100%
S: 78%
C: 87%
S: 63%
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European Journal of Organic Chemistry
10.1002/ejoc.201700543
FULL PAPER
6.
7.
8.
9.
10.
C: 100%
S: 60%
C: 79%
S: 70%
C: 100%
S: 50%
C: 99%
S: 54%
C: 93%
S: 74%
11.
12.
13.
14.
15.
C: 85%
S: 58%
C: 89%
S: 43%
C: 97%
S: 50%
C: 99%
S: 55%
C: 97%
S: 71%
16.
17.
18.
19.
20.
C:84
S:73%
C: 100%
S: 66%
C: 100%
S: 45%
C:100%
S:50%
C:92%
S:64%
[
a] Reaction conditions: 3 (0.25 mmol), 4 (0.375 mmol), Na
2
CO
3
(0.75 mmol), N-formylsaccharin (0.5 mmol), 10% Pd/C (5 mol%), propylene carbonate (2 mL) at
1
00 °C for 24 h. [b] All compounds are known compounds. Conversion and selectivity were based on aryl iodide and determined using GC technique based on
1
13
external standard method and were confirmed using GC-MS, H and C NMR.
Electron-donating substituents, para-methoxy and para-
methyl present on the aryl iodide could be smoothly coupled
with phenylboronic acid to give the corresponding biaryl
synthesized with high conversion of the corresponding aryl
iodide and selectivity of 50% and 43% respectively (Table 2,
entries 11 and 12). Fluorine containing biaryl ketones, 5n, 5o
and 5p and unsymmetrical ketones 5q, 5r and 5s, bearing a
combination of electron-donating and electron-withdrawing
substituents were synthesized with high conversion and
selectivity ranging from 50% to 73% (Table 2, entries 13-18).
Polyaromatic naphthyl ketone 5t and heteroaryl thiophene
ketone 5u were obtained with conversion/selectivity of
100%/66% and 100%/45% respectively (Table 2, entries 19
and 20). The carbonylative Suzuki-Miyaura cross-coupling of
4-bromoanisole and 4-chloroanisole under the optimized
conditions did not yield the corresponding biaryl ketones. The
aryl halides did not undergo any conversion and were
recovered as such.
ketones 5b and 5c through
8
2
a
conversion/selectivity of
4%/77% and 91%/75% respectively (Table 2, entries 1 and
). Electron-withdrawing substituents present on aryl iodide
are known to undergo non-carbonylative Suzuki-Miyaura
cross-coupling.[24] However, strong electron-withdrawing
substituents, meta-fluoro, para-cyano, meta-nitro and para-
nitro present on the aryl iodide could be transformed to the
corresponding ketones 5d, 5e, 5f and 5g with
conversion/selectivity of 87%/63%, 100%/59%, 100%/78%
and 100%/60% respectively (Table 2, entries 3-6).
Arylboronic acid bearing meta-methoxy group was coupled to
give ketone 5h with conversion/selectivity 79%70% (Table 2,
entry 7). Para- fluoro, and -chloro substituted arylboronic
acids gave the corresponding ketones 5i and 5j with high
conversion and selectivity of 50% and 54% respectively
In order to demonstrate the practical applicability of the
developed protocol, we carried out the synthesis of (4-
methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone 5v, an
antineoplastic. It is a cytotoxic compound belonging to the
(
Table 2 entries 8 and 9). Ketone 5k containing an ester
functionality could be synthesized from the corresponding
arylboronic acid in 93% conversion and 74% selectivity
phenstatin family which causes cell apoptosis by inhibiting
cells.[
25]
The
tubulin polymerization in
cancerous
(
Table 2, entry 10). Biaryl ketone, 5l and 5m, bearing an
carbonylative Suzuki-Miyaura cross-coupling of 5-iodo-1,2,3-
ortho-phenoxy and methylenedioxy functionality were
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European Journal of Organic Chemistry
10.1002/ejoc.201700543
FULL PAPER
trimethoxybenzene with 4-methoxyphenylboronic acid
afforded 5v in 60% yield (Scheme 3).
and it was found that the palladium content was less than 0.1
ppm thus indicating negligible palladium leaching. Thus, the
marginal decrease in conversion may be attributed to
handling loss.
Next, the application of the developed protocol at the
gram scale was evaluated. Delightfully, the reaction between
iodobenzene 3a and phenylboronic acid 4a could be carried
out at the gram scale thus resulting in the synthesis of
benzophenone 5a in 68% yield (Scheme 4).
Scheme 3. Carbonylative synthesis of (4-methoxyphenyl)(3,4,5-
trimethoxyphenyl)methanone (5v).
The inability to recycle expensive palladium and
catalyst-product separation are some of the drawbacks
associated with homogeneous catalytic protocols. Recycling
expensive palladium will reduce the overall cost of the
process and render the process economically viable and
sustainable. Hence, we turned our attention to check the
recyclability of Pd/C under CO surrogacy. In order to carry out
the recyclability study, the reaction between iodobenzene 3a
and phenylboronic acid 4a leading to the synthesis of
benzophenone 5a was chosen as the model reaction. After
the fresh run, the reaction mixture was subjected to
centrifugation at 10,000 rpm for 15 min. Pd/C was then
separated from the reaction mixture, washed with ethyl
acetate to remove traces of the product and dried overnight at
Scheme 4. Gram scale Pd/C catalyzed carbonylative Suzuki-Miyaura
cross-coupling using N-formylsaccharin.
The mechanism for the Pd/C catalyzed carbonylative Suzuki-
Miyaura cross-coupling using N-formylsaccharin as the CO
surrogate is shown in Scheme 5.
100 °C. The dried and reactivated Pd/C was applied for the
subsequent run by charging with fresh substrates (3a and 4a),
N-formylsaccharin, sodium carbonate and propylene
carbonate. It was worth noting that, Pd/C could be
successfully recycled up to five times with only a marginal
decrease in conversion with selectivity remaining almost
constant throughout (Figure 3).
Scheme 5. Proposed mechanism for the Pd/C catalyzed carbonylative
Suzuki-Miyaura cross-coupling using N-formylsaccharin.
The aryl iodide 3a undergoes oxidative addition to the Pd0
centre resulting in the formation of the aryl palladium
intermediate A. In the presence of Na
2
CO
3
,
N-
formylsaccharin undergoes decarbonylation and the released
CO coordinates with the aryl palladium species followed by
CO insertion to give the acyl palladium intermediate B.
Figure 3. Recyclability study of Pd/C catalyzed carbonylative Suzuki-
Miyaura cross-coupling using N-formylsaccharin.
II
Arylboronic acid 4a undergoes transmetallation with the Pd
centre in the presence of Na
2
CO
3
to give C. This
subsequently undergoes reductive elimination to give the
biaryl ketone product 5a with the simultaneous regeneration
of Pd for the next catalytic cycle.
After the fifth recycle, the reaction mixture separated from
Pd/C by centrifugation was subjected to ICP-AES analysis
0
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European Journal of Organic Chemistry
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Conclusions
To a 15 mL pressure tube, 5-iodo-1,2,3-trimethoxybenzene (0.25
mmol), 4-methoxyphenylboronic acid (0.375 mmol), Na CO (0.75
2 3
mmol), N-formylsaccharin (0.5 mmol), and 10% Pd/C (5 mol%, 13.3
mg) were added. Subsequently, 2 mL of propylene carbonate was
added to the reaction mixture. The reaction mixture was stirred at
In conclusion, we have established the first Pd/C catalyzed
carbonylative Suzuki-Miyaura cross-coupling using N-
formylsaccharin as a CO surrogate in propylene carbonate as
an environmentally benign and sustainable polar aprotic
solvent. Notably, the developed protocol does not require the
need to handle gaseous CO and a high pressure reactor.
Advantageously, using Pd/C as a commercially available,
recyclable heterogeneous catalyst, the reaction could be
carried out under co-catalyst free, additive free and ligand
free conditions using N-formylsaccharin as an air-stable and
100 °C for 24 h. After completion of the reaction, the reaction mixture
was centrifuged for 15 min at 10,000 rpm. Pd/C was separated from
the reaction mixture and washed with 2 mL ethyl acetate to remove
the traces of the product. The combined reaction mixture was
evaporated by rotary evaporation to obtain the crude product which
was purified by column chromatography (silica gel, 100−200 mesh
size), with petroleum ether−ethyl acetate as the eluent to afford 60%
of 5z as the pure product
safe CO source.
synthesized as part of the substrate scope including (4-
methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone, an
antineoplastic. The Pd/C catalyst could be recycled up to five
times under CO surrogacy with a marginal loss in catalytic
activity and could be scaled up to gram scale synthesis. Thus,
the combination of Pd/C, gaseous CO free condition and
propylene carbonate represent a green and sustainable
methodology for the synthesis of biaryl ketones.
A range of biaryl ketones could be
Scale up experiment
To
a
100 mL pressure tube, iodobenzene (5 mmol, 1.02 g),
CO (15 mmol, 1.6 g),
phenylboronic acid (7.5 mmol, 0.91 g), Na
2
3
N-formylsaccharin (10 mmol, 2.11 g), and 10% Pd/C (5 mol%, 260
mg) were added. Subsequently, 10 mL of propylene carbonate was
added to the reaction mixture. The reaction mixture was stirred at
100 °C for 24 h. After completion of the reaction, the reaction mixture
was centrifuged for 15 min at 10,000 rpm. Pd/C was separated from
the reaction mixture and washed with (2 × 5 mL) ethyl acetate to
remove the traces of the product. The combined mixture was
subjected to column chromatography (silica gel, 100–200 mesh size)
with petroleum ether–ethyl acetate as the eluent to afford
benzophenone (0.62 g, 68% yield) as the pure product.
Experimental Section
General
Recyclability study
All chemicals and solvents were purchased from different commercial
sources
and
were
used
as
received
without further
To
a
15 mL pressure tube, iodobenzene (0.25 mmol),
CO (0.75 mmol),
purification. The progress of the reaction was monitored by GC-MS. A
GC-MS-QP 2010 instrument (Rtx-17, 30
ID, film thickness (df) 0.25 µm) (column flow
phenylboronic acid (0.375 mmol), Na
2
3
m
×
2
25 mm
mL min ,
N-formylsaccharin (0.5 mmol), and 10% Pd/C (5 mol%) were added.
Subsequently, 2 mL of propylene carbonate was added to the
reaction mixture. The reaction mixture was stirred at 100 °C for 24 h.
After completion of the reaction, the reaction mixture was centrifuged
for 15 min at 10,000 rpm. Pd/C was separated from the reaction
mixture and washed with 2 mL ethyl acetate to remove the traces of
the product and dried at 100 °C overnight. The dried Pd/C was
applied for the next run after charging with fresh substrates, N-
formylsaccharin, sodium carbonate and propylene carbonate. The
product yields were calculated by subjecting the reaction mixture at
each cycle to GC-MS analysis.
-
1
=
-1
100 °C to 240 °C at 10 °C min rise) was used for the mass
analysis of the products. The products were purified by column
chromatography on 100–200 mesh silica gel. The 1H NMR spectra
was recorded on 400 MHz spectrometer in CDCl
spectra was recorded on 100 MHz spectrometer in CDCl
chemical shifts were reported in parts per million (δ) relative to
tetramethylsilane (TMS) as an internal standard and J (coupling
constant) values were reported in hertz. The splitting patterns of
protons are described as s (singlet), d (doublet), dd (doublet of
doublets), t (triplet) and m (multiplet).
.The 13C NMR
. The
3
3
Typical procedure for Pd/C catalyzed carbonylative Suzuki-
Acknowledgements
Miyaura cross-coupling using N-formylsaccharin as
a CO
surrogate
P. G. is thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, Government of India, for
providing a Senior Research Fellowship (SRF).
To a 15 mL pressure tube, aryl iodide (0.25 mmol), phenylboronic
acid (0.375 mmol), Na CO (0.75 mmol), N-formylsaccharin
0.5 mmol), and 10% Pd/C (5 mol%, 13.3 mg) were added.
2
3
(
Subsequently, 2 mL of propylene carbonate was added to the
reaction mixture. The reaction mixture was stirred at 100 °C for 24 h.
After completion of the reaction, the reaction mixture was centrifuged
for 15 min at 10,000 rpm. Pd/C was separated from the reaction
mixture and washed with 2 mL ethyl acetate to remove the traces of
the product. The combined reaction mixture was subjected to GC-MS
analysis to determine the conversion and selectivity.
Keywords: Carbonylation • Palladium • Ketones •
Heterogeneous catalysis • Sustainable chemistry
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Entry for the Table of Contents
Commercially available and recyclable Pd/C catalyzes the
carbonylative Suzuki-Miyaura cross-coupling using N-
formylsaccharin as an air stable and safe CO surrogate. The
reaction could be carried out in propylene carbonate as an
environmentally benign and sustainable solvent under
additive free, co-catalyst free and ligand free conditions.
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