Supramolecular Pd(II) complex of DPPF and dithiolate: An efficient catalyst for amino and phenoxycarbonylation using Co2(CO)8 as sustainable C1 source

Article abstract of DOI:10.1016/j.mcat.2019.110672

Highly active, efficient and robust “dppf ligated tetranuclear palladium dithiolate complex” was synthesized and applied as a catalyst for chemical fixation of carbon monoxide for the synthesis value added chemicals such as tertiary amide and aromatic esters. The synthesized catalyst was characterized using different analytical techniques such as elemental analysis, ¹H and ³¹P NMR spectroscopy. The use of Co₂(CO)₈ as a cheap, less toxic and low melting solid surrogate are additional advantages over the current protocol. The catalyst showed superior activity towards the Amino (10^?3 mol % catalyst) and Phenoxycarbonylation (10^-2 mol % catalyst) and high TON (10⁴ to 10³) and TOF (10³ to 10² h^-1). The Betol and Lintrin (active drug molecules) were synthesized under an optimized reaction condition. The scalability of the current protocol has been demonstrated up-to the gram level.

Full text of DOI:10.1016/j.mcat.2019.110672

MolecularCatalysisxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Supramolecular Pd(II) complex of DPPF and dithiolate: An efficient catalyst
for amino and phenoxycarbonylation using Co2(CO)8 as sustainable C1
source
Vinayak V. Gaikwada, Pravin A. Maneb, Sandip Deyb,c,**, Divya Patela,
Bhalchandra M. Bhanagea,*
a Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai, 400 019, Maharashtra, India
b Chemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
c Homi Bhabha National Institute, Training School Complex, Mumbai 400 094, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Highly active, efficient and robust “dppf ligated tetranuclear palladium dithiolate complex” was synthesized and
applied as a catalyst for chemical fixation of carbon monoxide for the synthesis value added chemicals such as
tertiary amide and aromatic esters. The synthesized catalyst was characterized using different analytical techniques
such as elemental analysis, 1H and 31P NMR spectroscopy. The use of Co2(CO)8 as a cheap, less toxic and low
melting solid surrogate are additional advantages over the current protocol. The catalyst showed superior activity
Carbonylation
Cobalt carbonyl
Amides
Esters
Pd-dithiolate
towards the Amino (10−3 mol % catalyst) and Phenoxycarbonylation (10-2 mol % catalyst) and high TON (104 to
-1
h
103) and TOF (103 to 102
). The Betol and Lintrin (active drug molecules) were synthesized under an optimized
reaction condition. The scalability of the current protocol has been demonstrated up-to the gram level.
Introduction
using lewis acids or strong bronsted acids (ii) alkylation of carboxylate
salt of alkali metal, alkaline earth metals, acylation of phenol with an
The development of efficient and robust methods for the synthesis of
aromatic amides and esters is extremely significant in synthetic organic
chemistry. Aromatic amides and esters are the most common and im-
portant structural scaffold and building blocks mainly found in organic
synthesis, pharmaceutically active drug molecules and also in natural
products (Fig. 1). They have been also found in agrochemicals, pep-
tides, polymers and biologically active molecules [1–5].
acyl halides or acid anhydrides has been widely studied [31–40]. Now-
a-days, the palladium-catalyzed carbonylative cross-coupling reactions
have emerged in the last few years as the most powerful C–C bond
forming processes for the synthesis of aromatic esters [41–50].
Nowadays, the palladacycles are important, popular and thoroughly
investigated class of organopalladium due to its accessible, thermal
stability, and high activity at lower catalyst loading. There are several
heteroatom containing (–N, –S, –P and –O) active precursors, which
have been used for various cross-coupling reactions [51–60]. Typically,
the higher TON and TOF were observed in non carbonylative ap-
proaches compared with carbonylative approaches. This is attributed to
the π acceptor character of carbon monoxide. Carbonylation of aryl
halides lies in the coordination of CO to the metal center; when bound
to the palladium, the π acceptor character of CO significantly reduces
the reactivity of the palladium towards oxidative insertion into the C–X
bond. Sometimes, the catalytic activity leads to decreases due to the
facile aggregation of palladium metal. Hence, to achieve the high TON
and TOF by reducing palladium concentration (ppm level) in carbo-
Conventionally, the aromatic amides have been synthesis by (i)
condensation of carboxylic acids or acyl chlorides with amines, (ii)
oxidative amidation of benzaldehydes, benzyl-amine, and benzyl alco-
hols with amines, (iii) trans-amidation of primary amides and the
aminolysis of acids or esters by coupling with secondary or tertiary
amines have been also reported [6–21]. However, the aminocarbony-
lation of aryl halides with amines has been a most potent and robust
tool in the synthetic chemistry. There are several reports available for
this reaction by homogeneous as well as heterogeneous palladium
systems for the synthesis of amides [22–30].
Likewise, traditionally the aromatic esters were synthesized from (i)
coupling between carboxylic acids with phenol/ alcohols/ alkyl halides
nylation is
a challenging task. Literature, survey shows that
⁎ Corresponding author.
⁎⁎ Corresponding author at: Chemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.
E-mail addresses: sandipdey2000@yahoo.com (S. Dey), bm.bhanage@ictmumbai.edu.in (B.M. Bhanage).
https://doi.org/10.1016/j.mcat.2019.110672
Received 10 September 2019; Received in revised form 5 October 2019; Accepted 14 October 2019
2468-8231/©2019ElsevierB.V.Allrightsreserved.
Pleasecitethisarticleas:VinayakV.Gaikwad,etal.,MolecularCatalysis,https://doi.org/10.1016/j.mcat.2019.110672

V.V. Gaikwad, et al.
MolecularCatalysisxxx(xxxx)xxxx
motivated from this results further optimization was carried out with
Pd(1) catalyst. To ensure the higher conversion, next we studied the
effect of various inorganic as well as organic bases on the model reac-
tion. It was observed that inorganic bases such as Na2CO3 and K3PO4
provided 73% and 82% conversion and good selectivity (Table 1, en-
tries 6 and 7), while organic bases DBU and NEt3 provided higher
conversion of iodobenzene (85% and 95%) with formation of pre-
dominant species of 3a (Table 1, entries 8 and 9). Hence, the base
study revealed that NEt3 is best based for this reaction. Solvents play a
crucial role in the reaction hence they were screened for the model
reaction. Non polar solvent like toluene (Table 1, entry 9) furnished
excellent conversion (95%) and selectivity (100%) while use of polar
solvents such as DMF (90%), THF (87%), and PEG-200 (60%) conver-
sion of iodobenzene was noted (Table 1, entries 10-12). Based on these
results toluene was selected for further studies. Subsequently, we stu-
died
Fig. 1. Representative examples of pharmaceutically active drug molecules.
the effect of various CO surrogates on the model reaction (Table 1,
entries 13 and 14). The n-formylsachharin (Table 1, entry 13) pro-
vided only 66% conversion with 88% selectivity and if we used phenyl
formate as a C1 source it gave 70% conversion and 78% selectivity
towards the product (Table 1, entry 14). Hence, we could conclude the
conversion and selectivity provided by Co2(CO)8 was higher than other
C1 sources and it choose as optimized C1 source for remaining opti-
mization. Next, varying the reaction temperature to 100 °C, 60 °C and it
was found that 80 °C to be the optimized reaction temperature (Table 1,
entry 15 and 16). Next, after time study we noticed that at 15 h didn’t
have any changes in conversion and selectivity, if on reducing the re-
action time to 10 h, the conversions as well as in selectivity were de-
creased (Table 1, entries 17 and 18). Hence, it was concluded at 12 h,
the reaction proceeded smoothly with higher conversion and se-
lectivity. However, in the absence of palladium catalyst reaction did not
proceed which conformed the importance of the catalyst (Table 1,
entry 19). Finally the optimized parameters are follows: 1a (0.5 mmol),
2a (0.7 mmol), Pd“1″ (10−1 mol %), NEt3 (1 mmol), Co2(CO)8
(0.3 mmol), toluene (4 mL), 80 °C for 12 h.
palladacycles have been seldom reports on the carbonylation to gen-
erate higher TON and TOF [61–63].
However, the cumbersome handling of CO gas hampered for its
further application in academic as well as industry. Hence, recently,
many researchers turned the attention towards the development of
surrogate chemistry for the synthesis of amides and esters [64–69].
They have used various solid as well as liquid CO surrogates although
all of these CO surrogates have their own merit still to develop such a
system which works at lower metal concentration and subsequently
generates high TON and TOF. Recently, our group reported dppf ligated
palladacycle for the carbonylative Suzuki-Miyaura reaction using
Co2(CO)8 as a C1 source to provide high TON (104 to 103) and TOF (102
-1
to 103 h ) [70]. To continue our research interest for developing the
surrogate chemistry for carbonylation reactions, further we explore this
work for the Amino and Phenoxycarbonylation reactions. The concept
of low catalyst loading at CO source still not been addressed for this
reaction.
We have recently developed the supramolecular Pd(II) dithiolate
Next, we investigated the effect of catalyst loading on the amino-
carbonylation reaction (Table 2). When decreasing the catalyst loading
from 1 mol % to 0.001 mol % (detail process as shown in ESI), we didn’t
notice any changes in the conversion and yield of the product (Table 2,
entries 1-4) with TON ranging from 9.5 × 101 to 9.3 × 104 and TOF
from 0.79 × 101 to 7.75 × 103 respectively. Further, decreasing the
catalyst loading to 0.0001 mol % the conversion and yield of the pro-
duct were lowered (Table 2, entry 5). It indicated that the catalyst
loading up to 0.001 mol % provided satisfactory conversion and yield of
the product below that it’s affected the reaction. To ensure maximum
conversion and yield, next to the same reaction (0.0001 mol %) was
proceeded by increasing reaction temperature to 120 °C, unfortunately,
it didn’t show any changes in the conversion and yield of the product
complexes
with
diphosphines
of
varied
bite
angles
[Pd2(P∩P)2(SC12H8S)]2(OTf)4 (P∩P: dppe (1,2-bis(diphenylphosphino)
ethane);
Xantphos
(9,9-dimethyl-4,5-bis(diphenylphosphino)xan-
thenes) and dppf (1,1′-bis(diphenylphosphino)ferrocene)). These com-
plexes are highly soluble, stable and robust catalysts and showed ex-
cellent activity in Suzuki [59,71], Heck [60] C–C coupling reactions,
and in carbonylative Suzuki-Miyaura reactions [63,70]. Next, we
decided to explore the Amino and Phenoxycarbonylation reactions
using Co2(CO)8 as C1 source employing the tetranuclear complex
[Pd2(dppf)2(SC12H8S)]2(OTf)4 (Pd(1)) as a catalyst which provided
high TON and TOF.
Results and discussion
(Table 2, entry 6). Although, TON and TOF amplified up-to (8.6 × 105)
-1
and (5.37 × 104 h ) respectively. Hence, finally we concluded that a
Initially the reaction optimization was carried out by carbonylative
coupling between iodobenzene (1a) and morpholine (2a) led to the
synthesis of amide as a model reaction. We tested various reaction
optimization parameters such as CO sources, time, temperature, bases,
and solvents on the model reaction and the outcomes were summarized
in Table 1. Initially, we investigated commercially available “Pd” pre-
cursors for the model reaction. Here, K2CO3 used as a base, and toluene
as a solvent along with Co2(CO)8 as C1 source and content were heated
at 80 °C for 12 h. The Pd(OAc)2, and PdCl2(PPh3)2 provided moderate
conversion of iodobenzene (55% and 60% respectively) and hetero-
geneous catalysts such as Pd/C, and Pd@GOIL (Palladium ion con-
taining ionic liquid immobilized onto graphene oxide) provided only
35% and 45% of conversion with medium selectivity (Table 1, entries
1-4). Next, the same reaction proceeded with the synthesized Pd (1),
and delightfully it was observed that higher conversion (78%) and se-
lectivity (95%) than other palladium precursors (Table 1, entry 5). By
minimum 0.001 mol % catalyst loading required for achieved max-
imum TON and TOF.
Next, we turned the attention towards the synthesis of various
amides under the optimized reaction condition. The simple iodo-
benzene, o-Me, p-Me and p-OMe iodobenzene were smoothly reacted
with morpholine and converted into amide 3a, 3b, 3c, and 3d respec-
tively, and producing the TON ranges from 8.8 × 104 to 9.3 × 104 and
TOF 7.3 × 103 to 7.5 × 103 h−1 (Table 3, entries 1-4). Further, we
screened the various cyclic amines with simple and substituted iodo-
benzene for the synthesis of tertiary amides. Initially, the o-iodo-
naphthalene was satisfactorily converted into 3i by coupled with die-
thylamine and provided catalytic TON 9.0 × 104 and TOF
7.5 × 103 h−1 (Table 3, entry 9). Next, the strong electron donating
moiety such as o-Me, and weakly donating moiety such as p-fluoro io-
dobenzene was proficiently converted into 3j and 3k by carbonylation
for the synthesis of amides. The results showed that the piperidine was
2

V.V. Gaikwad, et al.
MolecularCatalysisxxx(xxxx)xxxx
Table 1
Screening of optimal reaction condition for Aminocarbonylation.a
Entry No
Pd precursors
Base
Solvent
CO Source
Temp. (oC)
Time (h)
Conv.b
(%)
Select.b (%)
1
Pd(OAc)2
PdCl2(PPh3)2
Pd/C
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
DBU
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
n-formylsachharin
Phenyl Formate
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
80
80
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
15
10
12
55
60
35
45
78
73
82
85
95
90
87
60
66
70
96
76
95
88
–
60
78
44
85
95
93
96
99
100
95
90
90
88
78
100
100
98
95
–
2
3
4
Pd@GOIL
Pd(1)
5
6
Pd(1)
7
Pd(1)
8
Pd(1)
9
Pd(1)
Pd(1)
NEt3
10
11
12
13
14
15
16
17
18
19
NEt3
Pd(1)
NEt3
THF
Pd(1)
NEt3
PEG-200
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Pd(1)
NEt3
Pd(1)
NEt3
Pd(1)
NEt3
Pd(1)
NEt3
Pd(1)
NEt3
Pd(1)
NEt3
–
NEt3
a
b
Reaction condition: 1a (0.5 mmol), 2a (0.7 mmol), Pd (1) 10−1 mol%, base (1 mmol), CO source (0.3 mmol), solvent (4 mL).
Conversion and selectivity were calculated based on GC-GCMS.
with satisfactory yield and achieved catalytic TON 6.8 × 104 and TOF
5.6 × 103 h-1(Table 3, entry 14). Delightfully, it was observed that
aromatic amines such as benzyl amine also efficiently converted into 3o
by coupling with iodobenzene while they produced TON 7.3 × 104 and
TOF 6.0 × 103 h−1 (Table 3, entry 15).
Table 2
Effect of catalyst loading on the Aminocarbonylation reaction.a
We initiated the reaction optimization by carbonylative cross-cou-
pling between iodobenzene (4a) with phenol (5a) for the synthesis of
ester (6a) as a model reaction. Various parameters like base, time,
temperature were tested and summarized results are shown in Table 4.
Initially, the investigation was carried out by using various commer-
cially and synthesized palladium precursors such as PdCl2, Pd(OAc)2,
Pd@GOIL on the model reaction at 100 °C, for 15 h (Table 4, entries 1-
3). Here, we used NEt3 as a base and CO2(CO)8 as a C1 source in toluene
as a solvent. It was noted that conversion and selectivity were not more
than 77% and 93% respectively. Gratifyingly it was observed that the
excellent catalytic activity [conversion (96%) and selectivity (100%)]
than rest one when the same reaction proceeded with Pd(1). By
screening of palladium precursors, Pd(1) was found to be superior than
other (Table 4, entry 4). Since, base a vital for this reaction, organic
bases such as NEt3 (96%), DBU (87%) (Table 4, entries 4 and 5) and
inorganic bases such as K2CO3 (70%), and KOtBu (83%) were screened
but all were found to be inferior to NEt3 and gave lower conversion and
selectivity (Table 4, entries 6 and 7). Next, the series of solvents such
as toluene, 1, 4-dioxane and THF were screened for this reaction. As
shown in Table 4 reaction could not proceed smoothly in polar solvents
(1, 4-dioxane, and THF) (Table 4, entries 8 and 9) than non-polar
toluene. Excellent conversion (96%) and selectivity (100%) were
achieved using toluene hence it was used for further optimization.
Subsequently, we studied the effect of various CO surrogates including
gaseous CO for the model reaction. It was observed that CO (balloon)
provided excellent conversion and selectivity, while moderate conver-
sion and selectivity were found when n-formylsaccharin as a C1 source
(Table 4, entries 10 and 11). Since Co2(CO)8 would allow to use of the
C1 source for this reaction, and it was chosen as the choice of CO
surrogate (Table 4, entries 4). Further, increasing the reaction tem-
perature (120 °C) didn’t have a significant effect on conversion, while
Entry No
Pd 1 (mol%)
Conv.b
(%)
Yieldb (%)
TON
TOF(h−1
)
1
1
97
95
96
95
90
89
95
94
93
93
88
87
9.5 × 101
9.4 × 102
9.3 × 103
9.3 × 104
8.8 × 105
8.7 × 105
0.79 × 101
7.83 × 101
7.75 × 102
7.75 × 103
7.33 × 104
7.25 × 104
2
0.1
3
0.01
0.001
0.0001
0.0001
4
5
6c
a
Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol), NEt3 (1 mmol), CO
source (0.3 mmol), toluene (4 mL), 80 °C, 12 h.
b
Conversion and Yield were calculated based on GC-GCMS. c120 °C.
efficiently coupled with simple iodobenzene to form of 3e with TON
9.3 × 104 and TOF 7.7 × 103 h-1(Table 3, entry 5). Next, the pyrroli-
dine was successfully transformed into esters 3f, 3g and 3h by carbo-
nylative coupling with iodobenzene, o-bromo and o, p di-fluoro iodo-
benzene while generated TON ranges from 6.8 × 104 to 7.3 × 104 and
TOF 6.8 × 103 to 7.3 × 103 h−1 (Table 3, entries 6-8). Then we moved
towards the use of acyclic coupling with diethylamine as an amine
source (Table 3, entries 10 and 11). The reaction produced the cata-
lytic TON (8.2 × 104 and 8.3 × 104) and TOF (6.8 × 103 to
6.9 × 103 h-1) respectively. However, aryl iodide containing strong
electron withdrawing groups p-nitro and o-nitro also converted into
corresponding amides of 3l and 3m with good yield with corresponding
high TON 6.4 × 104 to 7.0 × 104 and TOF 6.4 × 103 to 5.8 × 103 h−1
(Table 3, entries 12 and 13). By motivation of the above results, next
we proceeded the reaction with longer chain amines, such as dibutyl
amine was carbonylative coupled with p-Me iodobenzene to produce 3n
3

V.V. Gaikwad, et al.
MolecularCatalysisxxx(xxxx)xxxx
Table 3
The substrate scope of palladium catalyzed Aminocarbonylation reaction.a
aReaction condition: 1a (0.5 mmol), 2a (0.7 mmol), NEt3 (1 mmol), Pd (1) 10−3 mol%, CO2(CO)8 (0.3 mmol), toluene (4 mL), 80 °C, 12 h. bYield was calculated
based on GC-GCMS. TOF (h-1).
only 77% conversion was found when temperature decreases to 80 °C
(Table 4, entries 12 and 13). Hence, it was confirmed that 100 °C
temperature is required for getting higher conversion and selectivity.
Further, there is no significant changes were noted when the reaction
proceeded at 18 h while decreases the reaction time to 12 h and 10 h led
to decreasing in conversion and selectivity (Table 4, entries 14-16).
Hence, the time study revealed that a minimum 15 h required to getting
maximum conversion and selectivity. Next, the reaction carried out
without catalyst and it proceeded to 0% conversion and selectivity and
which signifies the importance of the catalyst (Table 4, entry 17). Fi-
nally, optimized reaction parameters are follows: 4a (0.5 mmol), 5a
(0.7 mmol), Pd“1″ (10−1 mol %), NEt3 (1.5 mmol), toluene (4 mL) at
100 °C for 15 h.
4). Although, high TON 8.7 × 104 and TOF 5.80 × 103 h−1 was
achieved. Next, the same reaction by increasing the temperature to
120 °C for 15 h and it was noted that no temperature effect was ob-
served on conversion and yield of the product (Table 5, entry 5). The
TON 8.8 × 104 and TOF 5.86 × 103 h−1 were achieved. Hence, finally
we conclude that 0.001 mol % palladium concentration is sufficient for
maximum TON and TOF.
Optimized reaction condition in hand next we explored the syn-
thetic versatility of current protocol for the preparation of a wide
variety of aromatic esters. The outcomes revealed that the reaction was
progressed easily with a tolerance of a variety of functional groups and
the results are summarized in Table 6. Simple iodobenzene smoothly
coupled with phenol to provide the excellent yield of the 6a and gen-
erated TON 9.3 × 103 and TOF 6.20 × 102 h−1 (Table 6, entry 1). The
introduction of strong electron donating moiety such as methyl and
methoxy at para position of iodobenzene gave the satisfactory yield of
esters 6b and 6c and with corresponding TON ranging from 9.3 × 103
to 9.1 × 103 and TOF from 6.20 × 102 to 6.06 × 102 h−1 (Table 5,
entries 2 and 3). However, the electron rich moiety on both iodo-
benzene as well as phenol (p-OMe and p-Me) were tolerated and re-
sulted yield of ester 6d with TON values 8.8 × 103 and TOF
After, optimization next we turned the attention towards the de-
creasing the catalyst loading and its effects on phenoxycarbonylation
are summarized in Table 5. Delightfully, it was observed that conver-
sion and yield remain constant when the catalyst loading decreases
from 1 mol % to 0.01 mol %. While, the reaction generated catalytic
TON and TOF are 103 and 102 respectively (Table 5, entries 1-3).
Further, the conversion and yield were significantly decreased,
when palladium concentration lowered to 0.001 mol %, (Table 5, entry
4

V.V. Gaikwad, et al.
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Table 4
Screening of optimal reaction condition for Phenoxycarbonylation.a
Entry No
Pd precursors
Base
Solvent
CO Sources
Temp.oC
Time
(h)
Conv.b (%)
Select.b
(%)
1
PdCl2
Pd(OAc)2
Pd@GOIL
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
Pd(1)
–
NEt3
NEt3
NEt3
NEt3
DBU
K2CO3
KotBu
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1, 4-dioxane
THF
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
CO (balloon)
n-formylsaccharin
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
100
100
100
100
100
100
100
100
100
100
100
120
80
15
15
15
15
15
15
15
15
15
15
15
15
15
18
12
10
15
50
73
77
96
87
70
83
73
77
95
80
96
77
97
88
65
–
83
2
88
3
93
4
100
100
87
5
6
7
95
8
90
9
88
10
11
12
13
14
15
16
17
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
99
92
100
99
100
100
100
100
100
100
95
–
a
b
Reaction condition: 4a (0.5 mmol), 5a (0.7 mmol), Catalyst (1) 10−1 mol%, CO source (0.3 mmol), Base (1.5 mmol), Solvent (4 mL).
Conversion and selectivity were calculated by GC-GCMS.
ketone such as 6k was successfully synthesized by coupling with simple
iodobenzene with 2 4-difluoro phenol. The catalytic TON 7.0 × 103 and
TOF 4.66 × 102 h−1 were achieved (Table 6, entry 11). Finally, the
strong electron withdrawing moiety such as p-NO2 was tested with io-
dobenzene and it was observed that significant loss in the yield of 6 l
and while catalytic TON 5.0 × 103 and TOF 3.33 × 102 h−1 were
achieved (Table 6, entry 12).
Table 5
Effect of catalyst loading on the phenoxycarbonylation.a
The developed synthetic methodology was then attempted for the
gram-scale synthesis of amides. For this purpose next we carried out
reaction of iodobenzene (5 mmol) with morpholine (7 mmol) using
Entry No
Pd (mol%)
Conv.b (%)
Yieldb (%)
TON
TOF(h−1
)
1
1
96
96
95
90
89
95
93
93
87
88
9.5 × 101
9.3 × 102
9.3 × 103
8.7 × 104
8.8 × 104
0.63 × 101
6.20 × 101
6.20 × 102
5.80 × 103
5.86 × 103
triethylamine (10 mmol) as
a base and Co2(CO)8 as C1 source.
2
0.1
Gratifyingly, it was found that 65% yield of desired amine (Scheme 1).
Next, we have synthesized the pharmaceutically active drug mole-
cules under optimized reaction conditions. The active drugs such as
betol (69%) and lintrin (73%) were successfully synthesized by carbo-
nylative coupling between o-iodo phenol and iodobenzene with β-
naphthol with an excellent yield of the products (Scheme 2).
Based on previous reports [43,70] and experimental data herein we
have proposed a plausible reaction mechanism of the current protocol.
Initially, aryl iodide (A) undergoes oxidative addition (through the
breaking of weak C–I bond) to the palladium atom to the formation of
species (B). Other hand, at 80 °C the Co2(CO)8 release the CO (gas) and
it gets inserted between species (B) to the formation of active species
(C). Next, in the presence of base, amine undergoes transmetallation
with C to give species D. Subsequently, reductive elimination of species
D to the formation of the expected product of amide was observed
(Fig. 2).
3
4
0.01
0.001
0.001
5c
a
Reaction condition: 4a (0.5 mmol), 5a (0.7 mmol), NEt3 (1.5 mmol), CO
source (0.3 mmol), toluene (4 mL), 100 °C, 15 h.
b
c
Conversion and Yield were calculated based on GC-GCMS.
120 °C.
5.86 × 102 h-1 (Table 6, entry 4). Next, the electron withdrawing
functionalities such as p-CN and m-NO2 present on iodobenzene slightly
affected the reaction and converted esters 6e and 6f in good yield and
corresponding TON ranging from 8.0 × 103 to 8.4 × 103 and TOF
5.33 × 102 to 5.6 × 102 h-1 (Table 6, entries 5 and 6). Subsequently,
we investigated the coupling of substituted phenol with aryl iodides for
the synthesis of esters. The simple methyl substituted phenols such as o-
Me, p-Me and m-Me are smoothly carbonylatively coupled with iodo-
benzene and gets converted into esters 6 g, 6 h and 6i with excellent
yields. It was observed that the yield of ortho substituted phenol
slightly affected than the yield of meta and para substituted phenols
due to the sterically hindrance of o-Me group. However, they provided
TON ranging from 8.5 × 103 to 9.0 × 103 and TOF 5.66 × 102 to
6.0 × 102 h-1 (Table 6, entries 7-9). Further, the Guaiacol (ortho
methoxy phenol) was smoothly converted into ester 6j by carbonylative
coupling with iodobenzene with TON values 8.3 × 103 and TOF values
5.53 × 102 h-1 (Table 6, entry 10). Further, the halogenated biaryl
The similar reaction mechanism was observed in the
Phenoxycarbonylation, however at 100 °C cobalt carbonyl released the
CO and gets inserted to the formation of species C (Fig. 3).
Conclusion
In conclusion, we have first time established methodology for amino
and phenoxycarbonylation using Co2(CO)8 as C1 source instead of
gaseous CO with high TON and TOF. Use of Co2(CO)8 as less toxic and
inexpensive C1 source than other C1 precursors. Developed
5

V.V. Gaikwad, et al.
MolecularCatalysisxxx(xxxx)xxxx
Table 6
Substrate scope of Palladium catalyzed Phenoxycarbonylation reaction.a
aReaction condition: 4a (0.5 mmol), 5a (0.7 mmol), NEt3 (1.5 mmol), Pd(1) 10−2 mol%, CO source (0.3 mmol), toluene (4 mL), 100 °C, 15 h. b Yield was calculated
based on GC-GCMS. TOF(h-1).
Scheme 1. Palladium catalyzed gram scale synthesis of esters using Co2(CO)8
as a C1 source.
Fig. 2. Plausible reaction mechanism of the Aminocarbonylation reaction.
Scheme 2. Synthesis of active drug molecules by carbonylation using Co2(CO)8
as C1 source.
methodology does not require any external additive, ligands and co-
catalyst even at CO surrogate. The synthesis of amides and esters was
achieved at very low catalyst loading (10−3 mol %) for
Aminocarbonylation and (10-2 mol %) for Phenoxycarbonylation. The
generated TON ranges from 104 to 103 and TOF from 103 to 102 h-1. The
practical applicability of current protocol up-to gram level and also
tolerated of a wide variety of functional groups. The drug molecules
Betol and Lintrin were synthesized under the optimized reaction con-
dition. The synthesized catalyst was characterized using various ana-
lytical techniques such as CHNS, melting point, 1H NMR and 31P NMR,
Fig. 3. Plausible reaction mechanism of Phenoxycarbonylation reaction.
spectroscopy (see ESI).
6

V.V. Gaikwad, et al.
MolecularCatalysisxxx(xxxx)xxxx
Declaration of Competing Interest
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lab and this work is completely submitted in Molecular Catalysis.
Submission of an article implies that the work described has not been
published previously that it is not under consideration for publication
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