Supported palladium catalyzed aminocarbonylation of aryl iodides employing bench-stable CO and NH3surrogates

Article abstract of DOI:10.1039/d0ob01445a

A simple, efficient and phosphine free protocol for carbonylative synthesis of primary aromatic amides under polystyrene supported palladium (Pd?PS) nanoparticle (NP) catalyzed conditions has been demonstrated. Herein, instead of using two toxic and difficult to handle gases simultaneously, we have employed the solid, economical, bench stable oxalic acid as the CO source and ammonium carbamate as the NH₃source in a single pot reaction. For the first time, we have applied two non-gaseous surrogates simultaneously under heterogeneous catalyst (Pd?PS) conditions for the synthesis of primary amides using an easy to handle double-vial (DV) system. The developed strategy showed a good functional group tolerance towards a wide range of aryl iodides and afforded primary aromatic amides in good yields. The Pd?PS catalyst was easy to separate and can be recycled up to four consecutive runs with small loss in catalytic activity. We have successfully extended the scope of the methodology to the synthesis of isoindole-1,3-diones from 1,2-dihalobenzene, 2-halobenzoates and 2-halobenzoic acid following double and single carbonylative cyclization approaches.

Full text of DOI:10.1039/d0ob01445a

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DOI: 10.1039/D0OB01445A
ARTICLE
Supported palladium catalyzed aminocarbonylation of aryl iodides
employing bench-stable CO and NH3 surrogates
Shaifali,a, b Sheetal,a, b Rohit Bains,a, b Ajay Kumar,a,b Shankar Ram,a,b Pralay Das* a, b
Received 00th January 20xx,
Accepted 00th January 20xx
A simple, efficient and phosphine free protocol for carbonylative synthesis of primary aromatic amides under polystyrene
supported palladium (Pd@PS) nanoparticles (NPs) catalyzed conditions has been demonstrated. Herein, instead of using
two toxic and difficult to handle gases simultaneously, we have employed solid, economic, bench stable oxalic acid as CO
source and ammonium carbamate as NH3 source in a single pot reaction. For the first time, we have applied two non-gaseous
surrogates simultaneously under heterogeneous catalyst (Pd@PS) conditions for synthesis of primary amides using easy to
handle Double-Vial (DV) system. The developed strategy displayed wide range of functional group tolerance of aryl iodides
and delivered good yields of primary aromatic amides. The Pd@PS catalyst was found to be easy to separate and can be
recycled up to four consecutive run with small loss in catalytic activity. We have successfully extended the scope of the
methodology for the synthesis of isoindole-1,3-diones from 1,2-dihalobenzene, 2-halobenzoates and 2-halobenzoic acid
following double and single carbonylative cyclization approaches.
DOI: 10.1039/x0xx00000x
could eradicate the problem associated with direct use of two
gases in a single vessel.
Moreover, phthalimides or isoindoline-1,3-dione derivatives
Introduction
Over the years, amide functionality has gained a key importance
in pharmaceutical industry due to its wide occurrence in
plethora of biologically active potent molecules.1 Owing to their
diverse importance, various protocols have been developed till
now for synthesis of amide moieties.2 In this context,
carbonylation chemistry offers a straightforward technique for
accessing amides using amines as nucleophiles in presence of
carbon monoxide (CO) as an indispensable C1 source. Although,
carbonylation chemistry is very well explored for synthesis of
secondary and tertiary amides,3 however, in case of primary
amides this methodology is still a formidable challenge. The
poor nucleophilicity and difficulty in handling of ammonia gas
could possibly explain the could possibly explain the challenges
associated with synthesis of primary amides through
carbonylation reaction. Furthermore, development of
recyclable catalytic system and environmental benign protocol
is highly desirable for the synthesis of primary amides to
overcome the deficiencies associated with homogeneous
catalytic system such as non-recyclable catalyst, difficulty in
product separation, air/moisture sensitive phosphine ligands
etc. The direct utilization of two gases explicitly, CO and NH3
further add to complexity to the reaction protocol. Hence,
utilization of bench stable and sustainable CO and NH3 sources
are important class of pharmaceutically active molecules.4
Although, there are various reports of N-substituted
phthalimides synthesis via double carbonylation under
heterogeneous conditions.5 However, to the best of our
knowledge, unsubstituted phthalimides synthesis using
ammonia or ammonia surrogate through similar protocol is still
underexplored.
After the initial work been carried out by Beller and co-
workers,6 chemists have employed several ammonia sources in
palladium catalyzed carbonylations such as HMDS,7
formamides,8 N-tert butyl amine9 titanium nitrogen complex,10
NH4Cl,1a ammonium carbamate11 and aq. NH3,12 to get rid of
ammonia gas. But, use of flammable HMDS, high reaction
temperature, multistep reaction procedure, non-recyclable
catalytic system, use of bulky and air/ moisture sensitive
phosphine ligands and high pressure of CO gas were the major
limiting factor of aforementioned protocols for general
laboratory practices. In this regard, Bhanage and co-workers
has contributed significantly to this field.13 To circumvent the
issues of recyclability of costly catalyst, they developed Pd/C
catalyzed protocol for synthesis of primary amides using
ammonium carbamate as ammonia source.14 However,
limitations of this protocol such as low substrate scope, high
catalyst loading and high CO pressure, encouraged us to work
in this direction for its further sustainable development.
Moreover, to avoid the use of toxic CO gas, the work of
Skrydstrup and co-workers is worth mentioning where they
synthesized primary amides in presence of homogeneous
palladium/ligand catalyst and 9-fluorenylcarbonyl chloride as ex
situ CO source.15 However, implementation
a. Natural Product Chemistry and Process Development, CSIR-Institute of Hiamalyan
Bioresource Technology, Palampur,176061, HP (India). E-mail: pdas@ihbt.res.in
b. Academy of Scientific & Innovative Research, New Delhi 112005 (India)
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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of sophisticated apparatus, expensive phosphine ligands, and observation led us to investigate the more additivVeieswtAhratictlecOonulinlde
DOI: 10.1039/D0OB01445A
requirement of additives for decomposition of CO source were help in aminocarbonylation of aryl halides. According to
the major challenges associated with this methodology. literature survey, it was found that DMAP and imidazole are
Alternatively, expensive metal carbonyls in combination with known to be powerful Lewis bases and acylating agents as
ammonia sources have also been employed for palladium well.21,17 Delightfully, we got 45% yield of 3a on utilizing 0.50
catalyzed aminocarbonylation such as Mo(CO)6 and equiv. of imidazole (Table 1, entry 6) under our reaction
hydroxylamine,16 and Co2(CO)8 in combination with NH4Cl for conditions. On increasing the catalyst loading from 2 to 3 mol%
the synthesis of primary amides.17 Recently, Liu et al. Pd in Pd@PS, the aminocarbonylated product 3a was formed in
demonstrated
ligand
bite
angle
dependent 57% yield (Table 1, entry 7). Furthermore, on increasing the
PdCl2(CH3CN)2/Xanthphos catalyzed synthesis of primary equivalency of imidazole to 0.75 equiv., resulted in 72% yield,
amides where NH4HCO3 played dual role of base and ammonia while more increment in imidazole quantity led to unidentified
source.18 Furthermore, NH4HCO3 as ammonia source and formic side products, thus lowering in yield of the product (Table 1,
acid as CO source have been utilized by Wu and co-workers for entries 8 and 9). No reaction was observed in absence of Pd@PS
synthesis of primary aromatic amides under homogeneous and which clearly reflected the role of the catalyst (Table 1, entry
non-recyclable Pd(OAc)2/PPh3 catalyzed conditions.19
10). On altering the equivalency of base from 2 to 2.5, the yield
In continuation of previous advancements of our group in the of 4-methylbenzamide (3a) increased to 75%, while no product
field of polystyrene supported transition metal NPs as catalyst was detected in absence of base (Table 1, entry 11-12).
and its application in carbonylation reactions using oxalic acid
as C1 source.20 Herein, we have developed a phosphine free,
Table 1. Optimization of reaction conditions
O
Pd@PS catalyzed aminocarbonylation of aryl halides utilizing
Catalyst, Base
O
I
Additive
NH2
bench stable and sustainable ammonium carbamate as
ammonia source and oxalic acid as CO surrogate. We prepared
Pd@PS nano-catalyst according to our previously established
protocol through reduction deposition technique. First time,
we have applied this combination for vast primary amides
synthesis using an easy to handle double-vial (DV) single screw
cap system. The same strategy was also successfully extended
to rarely followed isoindoline-1,3-diones or phthalimides
synthesis.
+
ONH4
CO
(ex situ
+
H2N
Solvent, 130 oC, 12 h
from oxalic acid)
1a
2
3a
Yield (%)a
Solvent
S.No.
Additive (equiv.)
Base (equiv.)
Catalyst (mol%)
Pd@PS (2)
Pd@PS (2)
Pd@PS (3)
Pd@PS (2)
K2CO3 (2)
NEt3 (2)
-
DMF
DMF
DMF
DMF
nd
nd
nd
nd
1
2
3
4
-
-
NEt3 (2)
KI (1)
DABCO (2)
Pd@PS (2)
DMAP (1)
DMF
32
45
5
6
NEt3 (2)
NEt3 (2)
Pd@PS (2)
Pd@PS (3)
Imidazole (0.50)
DMF
DMF
DMF
DMF
Imidazole (0.50)
Imidazole (0.75)
Imidazole (1)
57
72
65
7
8
NEt3 (2)
NEt3 (2)
NEt3 (2)
NEt3 (2)
Pd@PS (3)
Pd@PS (3)
Results and discussion
9
10
-
Imidazole (0.75)
nr
DMF
Under this development, we have employed a double-vial (DV)
system to carry out the aminocarbonylation of aryl iodides
which contains an inner vial and an outer vial sealed with PTFE
faced cap. We began our study with 4-iodotoluene (1equiv.),
ammonium carbamate as ammonia source (4 equiv.) and K2CO3
(2 equiv.) in DMF (inner vial) and oxalic acid in DMF (outer vial)
as ex situ CO source. Unfortunately, we have not succeeded for
the synthesis of aminocarbonylated product 3a. Instead, we got
4-methyl benzoic acid as major product under applied reaction
conditions (Table 1, entry 1). However, the use of organic base
i.e., NEt3 (2 equiv.) didn’t procure the desired product 3a (Table
1, entry 2). To our dismay, with increasing the catalyst loading
we have not noticed the desired product formation (Table 1,
entry 3). Furthermore, we have also checked the reactions
conditions using DABCO (2 equiv.) as base and KI (1 equiv.) as
additive. But, these reaction conditions found to be unable to
give the desired product (Table 1, entry 4). This may be
attributed to the poor nucleophilicity of ammonia that restrict
its nucleophilic addition during the course of the reaction cycle.
Hence, additives are required that can form active palladium
acyl intermediates to promote aminocarbonylation of ammonia
under heterogeneous reaction conditions.21 Keeping this point
in view, we used DMAP (1 equiv.) as an additive to get desired
product 3a. Fortunately, addition of DMAP resulted in the 32%
yield of 4-methylbenzamide (3a) (Table 1, entry 5). This
NEt3 (2.5)
-
11
12
13
14
15
16
17
18
Pd@PS (3)
Imidazole (0.75)
75
DMF
Pd@PS (3)
Pd@PS (3)
Imidazole (1)
nd
nd
DMF
DMF
K2CO3 (2.5)
Cs2CO3 (2.5)
KtOBu (2.5)
Imidazole (0.75)
Pd@PS (3)
Pd@PS (3)
Imidazole (0.75)
Imidazole (0.75)
DMF
DMF
Traces
26
nd
45
Pd@PS (3)
Pd@PS (3)
Imidazole (0.75)
Imidazole (0.75)
DMF
DMF
DBU (2.5)
DiPEA
62
NEt3 (2.5)
Imidazole (0.75)
DMA
NMP
Pd@PS (3)
Pd@PS (3)
30
Imidazole (0.75)
Imidazole (0.75)
Imidazole (0.75)
19
20
21
NEt3 (2.5)
Xylene
Traces
Pd@PS (3)
Pd@PS (3)
NEt3 (2.5)
NEt3 (2.5)
Traces
Anisole
nd
29
22
Pd@PS (3)
Pd@PS (3)
NEt3 (2.5)
NEt3 (2.5)
Imidazole (0.75)
Imidazole (0.75)
PEG-400
23b
DMF
DMF
DMF
24c
25d
Pd/C (3)
NEt3 (2.5)
NEt3 (2.5)
45
54
Imidazole (0.75)
Imidazole (0.75)
Pd(OAc)2 (3)
Reaction conditions: aryl iodides (1equiv.), ammonium carbamate (4 equiv.),
Pd@PS (0.03 equiv.) Imidazole (0.75 equiv.), NEt3 (2.5 equiv.), DMF (2 mL) in inner
vial; CO surrogate in solvent (0.2 mL) in outer vial stirred at 130 oC for 12 h. (a)
isolated yield, (b) reaction temperature 120 oC, (c) 5 wt% of Pd/C (d) PPh3 (6 mol%)
Encouraged by these results, we also scrutinized different
organic and inorganic bases such as K2CO3, Cs2CO3, KOtBu, DBU
and DIPEA to get good yield of the desired product 3a (Table 1,
entries 13-17). Among these, NEt3 base was found to be the
most suitable base for aminocarbonylation of aryl iodides and
2 | J. Name., 2012, 00, 1-3
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ammonium carbamate. In addition, we have also tested After the screening of CO sources, thereafter, wVeieswhAirftticeledOnoliuner
DOI: 10.1039/D0OB01445A
different polar and non-polar solvents, and DMF was found to focus towards screening of ammonia surrogates such as
be best (Table 1, entries 18-22). Furthermore, we have also NH4HCO3, (NH4)2CO3, NH4Cl, NH4OAc, HCOONH4 and aq. NH3 for
checked the reaction at 120 oC and lower yield of the standard reaction under optimized reaction conditions as
aminocarbonylated product i.e., 29% was obtained (Table 1, shown in Table 3. We found that NH4HCO3 and (NH4)2CO3 gave
entry 23). This could be due to partial decomposition of oxalic the product 3a in 50 and 40% yield respectively, while
acid at this temperature. Intriguingly, we also screened other aminocarbonylated product was not detected in case of NH4Cl
catalysts under optimized reaction conditions. But, none of the and HCOONH4 (Table 3, entries 1-4). In case of ammonium
catalyst was found to be as effective as Pd@PS nanocatalyst acetate as ammonia surrogate the final product 3a obtained in
(Table 1, entries 24-25). Hence, aryl iodide (1 equiv.), 20% yield (Table 3, entry 5). Furthermore, on utilizing aqueous
ammonium carbamate (4 equiv.), Pd@PS (0.03 equiv. Pd), NEt3
(2.5 equiv.) in DMF (2 mL) (inner vial) and oxalic acid (6 equiv.)
Table 3. Optimization of NH3 sources
CO
in 0.3 mL DMF (outer vial) was the best optimized reaction
conditions for aminocarbonylation of aryl iodides.
(ex situ from Oxalic acid)
Pd@PS, NEt3
Imidazole
DMF, 130 oC, 12 h
O
I
NH2
Ammonia
source
+
Furthermore, we have also checked different CO sources,
equivalency of CO surrogate, solvents, and compatibility of
various other CO surrogates under optimized reaction
conditions, results summarized in Table 2. When we decreased
the equivalency of CO surrogate to 4 equiv. the desired product
3a was found in 40% yield (Table 2, entry 1). It was found that 6
equiv. of oxalic acid in DMF was suitable for aminocarbonylation
of aryl iodides (Table 2, entry 2). Further, we
1a
3a
2
Ammonia
Yield(%)a
S.No.
surrogate (equiv.)
NH4HCO3 (4)
(NH4)2CO3 (4)
NH4Cl (4 )
1
2
3
4
5
50
40
Traces
Traces
20
HCOONH4 (4)
CH3COONH4 (4)
Aq. NH3
6
7
30
53
Table 2. Screening of ammonia sources
NH2COONH4 (3)
CO
NH2COONH4 (4)
8
75
(ex situ CO source)
O
Pd@PS
O
I
NEt3, Imidazole
NH2
Reaction conditions: aryl iodides (1equiv.), ammonium sources (4 equiv.), Pd@PS
(0.03 equiv.) Imidazole (0.75 equiv.), NEt3 (2.5 equiv.), DMF (2 mL) in inner vial; CO
surrogate in solvent (0.3 mL) in outer vial stirred at 130 oC for 12 h. (a) Isolated
yield
+
H2N
ONH4
DMF, 130 oC, 12 h
1a
2
3a
Yield %a
CO surrogate (equiv.) External solvent
S.No.
(COOH)2 (4 )
(COOH)2 (6)
(COOH)2 (6)
1
2
3
DMF
DMF
DMA
40
75
55
30
ammonia as ammonia source we got 30% of product 3a, in
addition to 4-methylbenzoic acid and 4,4'-dimethyl-1,1'-
biphenyl as side products (Table 3, entry 6). Among all these,
ammonium carbamate was found to be best for
aminocarbonylation of aryl iodides. Next, we also studied the
loading of ammonia surrogate and 4 eq. of ammonium
carbamate found to be optimum to deliver 75% yield of the
product.
(COOH)2 (6)
(COOH)2 (6)
4
5
NMP
Toluene
DMF
Traces
nd
6
-
7
N-formyl saccharin (6)
DMF
74
8
9
Formic acid (6)
DMF
DMF
Traces
Traces
Paraformaldehyde (6)
With the suitable reaction conditions in hand, we endeavoured
to explore the transformation of different aryl iodides to
corresponding primary amides. We have scrutinized wide array
of aryl iodides for aminocarbonylation, results summarized in
Table 4. During the course of the reaction, it was found that
electronic and steric effect of differently substituted aryl iodides
influenced the reaction dramatically. Firstly, the carbonylation
of iodobenzene afforded the benzamide (3b) in 65% yield. Aryl
iodides bearing electron donating groups such as 3-me, 2-ethyl,
4-tert butyl, 1,5-dimethyl and 1,4-dimethyl substituents
resulted in moderate to good yields of the corresponding
amides (Table 4, 3c-g). In contrast, methoxy group at para-,
meta- and ortho- positions successfully delivered the
aminocarbonylated products (3h-j) in 61-77% yields. Further,
we have checked the halogen substituted aryl iodides for
aminocarbonylation. In case of fluoro substituted aryl iodides,
the reaction of 4-fluoroiodobenzene was found to be sluggish
to deliver the desired product, whereas, 3- and 2-fluoro
Reaction conditions: aryl iodides (1equiv.), ammonium carbamate (4 equiv.),
Pd@PS (0.03 equiv.) Imidazole (0.75 equiv.), NEt3 (2.5 equiv.), DMF (2 mL) in inner
vial; CO surrogate in solvent (0.2 mL) in outer vial stirred at 130 oC for 12 h. (a)
Isolated yield
have investigated combination of various solvents with oxalic
acid such as DMA, NMP and toluene (Table 2, entries 3-5). In
similar lines with our previous reports, oxalic acid in DMF was
found to be suitable combination for aminocarbonylation. We
havn’t observed amniocarbonylated product in absence of
oxalic (Table 2, entry 6). The other CO surrogates were also
tested under given reaction conditions such as N-formyl
saccharin, formic acid and paraformaldehyde (Table 2, entries
7-9). To our surprise, 6 equiv. of N-formyl saccharin in DMF was
found to be equally compatible for aminocarbonylation under
developed reaction conditions and gave 3a in 74% yield.
However, being economic, easy availability and low waste
generation, we opted for oxalic acid as CO source for this
transformation.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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substituted iodobenzene delivered the desired products (3k reactions. Intriguingly, we got isoindoline-1,3-dione (4a) via
View Article Online
and
tandem double carbonylation of oD-dOihI:a10lo.1b0e39n/zDe0nOeBs014a4n5dA
cyclization resulted in 90 and 60% yield respectively (Table 5,
Table 4. Substrate scope for synthesis of primary amides
Table 5. synthesis of isoindoline-1,3-dione
Outer Vial
(COOH)2
DMF
CO
(Oxalic acid as ex situ source)
Inner Vial
CO
O
C
O
Pd@PS, NEt3
Imidazole
Pd@PS
O
NEt3/Imidazole
I
NH2
4a
1aa-d
R
+
H2
N
ONH4
H N
2
+
ONH4
DMF, 130 o
12 h
C
DMF, 130 o
C
R
1a
2
3a-z
(
)
12 h
O
O
O
O
O
S.No.
1
Substrate
I
Product
Yield(%)
90
NH2
NH2
NH2
NH2
NH2
O
C2H5
NH
3a
, 75%
3e
3b
3c
3d
, 53%
O
, 65%
, 52%
, 45%
I
O
O
O
O
O
O
1aa
4a
4a
NH2
H3CO
NH2
NH2
OCH3
NH2
NH2
I
H3CO
2
NH
60
82
3f
3g
3h
3i
3j
, 54%
, 63%
, 61%
, 77%
, 65%
O
Br
O
O
O
O
O
1ab
O
NH2
F
NH2
NH2
NH2
NH2
I
F
Cl
Cl
, 74%
3
4
F
3m
NH
COOMe
3k
3l
3n
, 76%
3o
, 51%
, 82%
, 56%
O
O
1ac
1ad
O
O
4a
4a
O
O
O
O
NH2
I
NH2
NH2
NH2
NH2
Cl
NH
75
H3COC
O2N
OH
NC
Cl
COOH
3p
3q
3r
3s
3t
, 49%
, 80%
NH2
, 65%
O
, 57%
, 72%
O
O
O
O
S
NH2
NH2
NH2
NH2
[a] Reaction conditions: aryl iodides (1 equiv.), ammonium carbamate (4 equiv.),
Pd@PS (0.03 equiv. of Pd), imidazole (0.75 equiv.), NEt3 (2.5 equiv.), DMF (2 mL) in
inner vial; oxalic acid (6 equiv.) in DMF (0.2 mL) in outer vial stirred at 130 oC for 12
h.
Ph
3w
, 49%
3u
3v
3x
3y
, 66%
, 60%
, 55%
, 42%
[a] Reaction conditions: aryl iodides (1equiv.), ammonium carbamate (4 equiv.),
Pd@PS (0.03 equiv. of Pd), imidazole (0.75 equiv.), NEt3 (2.5 equiv.), DMF (2 mL) in
inner vial; Oxalic acid (6 equiv.) in DMF (0.2 mL) in outer vial stirred at 130 oC for
12 h
entries 1 and 2). Furthermore, we have also attempted methyl-
2-iodobenzoate (1ac) and 2-iodobenzoic acid (1ad) as
substrates for aminocarbonylation and obtained 4a in 82 and
75% yields (Table 5, entries 3 and 4) through carbonylative
cyclization.
3l) in 51 and 82% yields respectively. Intriguingly, 3-fluoro-4-
methyliodobenzene also obtained the substituted benzamide
3m in moderate yield 56%. Encouraged by these results, 4-Cl, 2-
Cl, 3,4- dichloro were also attempted and gave comparably
good yields of the corresponding products (3n-p), while in case
of 3-Cl aryl iodide, the aminocarbonylated product was formed
in traces. Unfortunately, the reaction of 4-NH2 and 4-OH
substituted analogues were found to be unreactive under the
optimized reaction conditions. Whereas, in case of 2-
iodoaniline, we got N, N-diphenyl urea (ESI, 3a’) as major
product. To our surprise, we got 80% yield of product 3q when
2-OH substituted aryl iodide was subjected for
aminocarbonylation. To our delight, aminocarbonylations of the
electron withdrawing groups i.e., 4-COCH3, 4-NO2, 4-CN and 4-
Ph performed smoothly to obtain desired amides 3r-u in good
yields i.e., 57-72%. Prompted by above results, 1-
iodonapthalene, 2-iodonapthalene and 2-iodofluorene were
also attempted to get aminocarbonylated products 3v-x in
moderate yields. Moreover, we also subjected heterocyclic aryl
iodides and obtained desired amide (3y) in 66% yield in case of
2-iodothiophene.
After completion of the reaction, the mixture was quenched
with water and then the organic layer was extracted using ethyl
acetate as extracting solvent. Further, the Pd@PS catalyst was
filtered from the reaction mixture and washed with acetone,
and then finally dried under reduced pressure. The resulting
Pd@PS catalyst was reused for the next catalytic cycle. It was
observed that the recycled Pd@PS catalyst displayed good
catalytic activity and can be reused and recycled up to five runs
with small amount of loss in catalytic activity. Further, after 4th
cycle, Pd@PS catalyst was analysed through TEM at 200 nm and
500 nm (Figure 2a and d). The average particle size distribution
of Fig. 2a showed between 6-12 nm (Figure 2b). The deposition
of Palladium was also detected by SEM-EDX analysis (Figure 2c).
In an another image in Fig. 2d, after 4th cycle, more aggregated
Palladium particles were noticed at 500 nm. Although,
according to our previously reported protocols, the maximum
average particle size of freshly prepared catalyst was found to
be in between 2-4 nm.20a,d Thus, increase in average size of
particles due to aggregation might be the reason for decrease
in the catalytic activity of the recycled Pd@PS catalyst, which is
also in concordance with our earlier reports.20a,d
Further to explore the scope of aryl iodide, we have also
subjected 1,2-diiodo-benzene (1aa) and 1-bromo-2-
iodobenzene (1ab) for aminocaronylation under optimized
To investigate and support the role of imidazole as additive in
4 | J. Name., 2012, 00, 1-3
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Scheme 1: Control experiments
the catalytic cycle, we have carried out a set of control
experiments as shown in Scheme 1. As we have also mentioned
View Article Online
DOI: 10.1039/D0OB01445A
attacked by ammonia. After exhaustive literature survey, we
have also found the intermediate 5 mediated conversion of aryl
carboxylic acid into corresponding amide.22 Hence, we have
attempted the reaction of benzoic acid (6) under optimized
reaction conditions (Scheme 1, entry b). But, we got complex
reaction mixture which led us to conclusion that benzoic acid (6)
didn’t contribute to formation of product 3a. Furthermore, we
have also carried out reaction in absence of ammonium
carbamate under optimized reaction, but we didn’t get
intermediate 5 during the course of the reaction (Scheme 1,
entry c). This might be due to instability of acyl imidazole under
present reaction conditions.23 We have also checked the fate of
carbon dioxide produced due to decomposition of oxalic acid
and ammonium carbamate. For this, we have carried out the
standard reaction in the presence of CO2 (dry ice) and didn’t
obtained the product 3a (Scheme 1, entry d). This observation
clearly indicates that CO2 formed due to decomposition of oxalic
acid and ammonium carbamate does not contribute in
formation of 3a.
Figure 1. Recyclability Experiment.
An insight into reaction mechanism was carried out, and
plausible reaction pathway was proposed based upon the
literature reports and control experiments, illustrated in Figure
3. The path of catalytic cycle from intermediate (I) to (IV) is well
supported in literature.20 Initially, Pd@PS catalyst (I) underwent
oxidative addition into C-X bond of aryl halide to produce
intermediate (II). Simultaneously, in outer vial, oxalic acid in
DMF under heating conditions got decomposed into CO, CO2
and H2O.24 This ex situ generated CO further participated in
catalytic cycle to procure intermediate (III). The intermediate
Figure 2. (a) TEM image recorded at 200 nm; (b) Particle size distribution calculated from
TEM image of (a); (c) SEM-EDX spectra of recycled Pd@PS catalyst; (d) TEM image
recorded at 500 nm.
in Table 1 that in the absence of imidazole, we ended up the
reaction with 4-methylbenzoic acid as major product. This
observation indicated the low nucleophilicity of ammonia and
weak electrophilicity of palladium acyl intermediate (Figure 1.,
IV) towards ammonia to give the desired product 3a. Inspired
by literature reports,21 and keeping observations of Table 1 in
our mind, we think (1H-imidazol-1-yl) (p-tolyl)methanone (5)
could be the intermediate for this transformation. In this
context to decipher the role of imidazole, we have also carried
out the reaction of (1H-imidazol-1-yl) (p-tolyl)methanone (5)
under our experimental conditions and got 85% yield of
aminocarbonylated product 3a (Scheme 1, entry a). This
observation led us to conclude that imidazole act as acylating
agent and help in generating the electrophilic centre to be
(III)
through migratory insertion of aryl group gave
intermediate (IV). The role of imidazole as acylating agent is well
documented in literature25 and also supported with the help of
control experiments. Hence, with the aid of base, imidazole
reacted with intermediate (IV) and converted into intermediate
(1H-imidazol-1-yl)(p-tolyl)methanone (4) with subsequent
regeneration of Pd@PS catalyst. During the course of the
reaction, ammonia was generated via decomposition of
ammonium carbamate under heating and basic conditions. This
ammonia further reacted with intermediate (4) to produce
product 3a and imidazole.
O
O
N+Et3HI-
O
O
NEt3 (2.5 equiv.),
NH2
N
O
Ar
I
N
+
(a)
Pd0
H2N
ONH4
2
(4 equiv.)
DMF (2 mL), 130 oC,
12 h
Ar
N
Ar
NH2
N
3a,
85%
5
(1 equiv.)
COOH
3a
I
( )
4
Ar
O
Satandard reaction
Pd
Complex reaction
mixture
I
+
H2N
ONH4
(b)
(c)
CO
2 + 2NH3
Conditions
CO
N
II
(
)
Base
6
(1 equiv.)
2
(4 equiv.)
O
C
(ex situ from oxalic acid)
N
H
CO
O
Pd
O
Ar
NEt3
Ar
Pd CO
I
I
I
H2N
(COOH)2
CO +CO2+H2O
Outer Vial
ONH4
Absence of
ammonium
carbamate
Standard reaction
OH
5
+
+
2
IV
(
)
Conditions
Not detected
40%
III
)
(
CO from oxalic acid
1a (1
)
equiv.
Polystyrene resin
Figure 3: Plausible mechanism
O
Pd@PS (3 mol%)
Imidazole (0,75 equiv.)
O
I
NH2
(d)
+
H2N
ONH4
NEt3 (2.5 equiv.)
DMF, 130 oC, 12 h
CO2 (Dry Ice)
1a (1
)
2 (4 equiv.)
equiv.
Conclusions
3a,
Not deteded
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
A simple, phosphine ligand free heterogeneous Pd@PS NPs
catalyzed methodology has been developed for
Notes and references
View Article Online
DOI: 10.1039/D0OB01445A
1
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utilized under Pd@PS conditions. Furthermore, the DV-set up
used for aminocarbonylation is economic, easy to handle and
decreases the complexity to carry out the reaction in presence
of two gases simultaneously. The present protocol tolerated
wide range of functional groups and delivered moderate to
good yields of primary amides and isoindole-1,3-diones.
Moreover, the prepared Pd@PS catalyst recovered by simple
filtration and can be recycled up to four consecutive cycles with
small loss in catalytic activity.
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2
3
4
5
6
Experimental
In a double vial system (inner vial is of 2mL and another which
is outer is of 5mL), 4-methyl iodobenzene (0.229 mmol, 50 mg),
ammonium carbamate (0.917 mmol, 69.7mg), Pd@PS (0.0069
mmol, 70 mg), TEA (0.573 mmol, 79.7 µl), imidazole (0.172
mmol, 13 mg) and DMF (1.5 mL) were added in inner vial (2 mL)
while the outer vial was charged with oxalic acid (1.37 mmol,
123.8 mg) and DMF (0.3 mL). After completion of the addition,
the inner vial containing contents was placed carefully inside
outer vial (5 mL) having oxalic acid. Further, the 5 mL reaction
vessel tighten with the solid PTFE faced solid cap and Teflon
tape. The system was further stirred in oil bath heated at 130 oC
for the required time. The reaction progress was monitored by
TLC and after the completion of the reaction, the inner vial was
removed. The contents of the inner vial in a separatory funnel.
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with ethyl acetate. The combined organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
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chromatography using hexane:ethyl acetate (60:40) as elutent,
afforded 3a as white solid (23 mg, 75%).
7
8
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1H (600MHz, DMSO-d6), (δ ppm) 2.34 (s, 3H), 2.34 (s, 3H), 7.245
(d, J = 7.98 Hz, 2H), 7.28 (brs, 1H), 7.775 (d, J = 8.1 Hz, 2H), 7.90
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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Authors are grateful to Director CSIR-IHBT for providing
necessary facilities during the course of the work. The authors
thank CSIR project MLP0203 for financial support. Shaifali,
Sheetal, R.B. thank UGC and CSIR, New Delhi for awarding
fellowship.
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View Article Online
DOI: 10.1039/D0OB01445A
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DOI: 10.1039/D0OB01445A
TOC Graphic
An efficient and phosphine free synthesis of primary amides and phthalimides via
aminocarbonylation and carbonylative cyclization has been demonstrated using bench stable
CO and NH3 surrogates under recyclable Pd@PS catalyzed conditions.