Carbonylative Tertiary Amide Synthesis from Aryl Iodides and Tertiary Amines via Oxidant-Free C?N Bond Cleavage Catalyzed by Palladium(II) Chloride in Polyethylene Glycol/Water

Article abstract of DOI:10.1002/adsc.201700317

In this work, we have described the carbonylative synthesis of amides from aryl iodides and tertiary amines as an aminal source via oxidant-free C(sp³)?N bond cleavage using in situ formation of palladium(0) nanoparticles from palladium(II) chloride in polyethylene glycol 400/water. Notably, these reactions were performed under base-free, ligand-free conditions and do not require any oxidant for the C?N bond cleavage. The developed protocol offers the selective N-dealkylation of tertiary amines in a polyethylene glycol/water solvent system. Numerous symmetrical and unsymmetrical aliphatic, alicyclic, benzyl, as well as aromatic tertiary amines with aryl iodides were well tolerated and afforded the desired products in good yields. Furthermore, the in situ generation of palladium(0) nanoparticles in the polyethylene glycol 400 was confirmed by TEM, FEG-SEM, EDS and XRD techniques, which strongly indicate that the palladium nanoparticles are highly active species and the reaction proceeds through the classical palladium(0)/palladium(II) pathway. Additionally, the syntheses can be easily scaled up and the catalytic system can be recycled up to five times without loss of its catalytic activity and selectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700317

Title: Carbonylative Tertiary Amide Synthesis from Aryl Iodides and
Tertiary Amines via Oxidant-Free C-N Bond Cleavage Catalyzed
by Palladium(II) Chloride in Polyethylene Glycol/Water
Authors: Bhalchandra Bhanage and Rajendra S Mane
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Carbonylative Tertiary Amide Synthesis from Aryl Iodides and
Tertiary Amines via Oxidant-Free C-N Bond Cleavage
Catalyzed by Palladium(II) Chloride in Polyethylene
Glycol/Water
Rajendra S. Manea and Bhalchandra M. Bhanagea*
a
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai – 400019, India
Fax: (+91)-22-33611020; e-mail: bm.bhanage@gmail.com or bm.bhanage@ictmumbai.edu.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. In this work, we have described the carbonylative Further, the in situ generation of palladium(0) nanoparticles
synthesis of amides from aryl iodides and tertiary amines as in the polyethylene glycol-400 was confirmed by TEM,
an aminal source via oxidant-free Csp3-N bond cleavage FEG-SEM, EDS and XRD techniques, which strongly
using in situ formation of palladium(0) nanoparticles from indicate that the palladium nanoparticles are highly active
palladium(II) chloride in polyethylene glycol-400/water. species and the reaction proceeds through the classical
Notably, these reactions were performed under base-free, palladium(0)/palladium(II) pathway. Additionally, the
ligand-free conditions and do not require any oxidant for the syntheses can be easily scaled up and the catalytic system
C-N bond cleavage. The developed protocol offers can be recycled up to five times without loss of its catalytic
selectively N-dealkylation of tertiary amines in polyethylene activity and selectivity.
glycol/water solvent system. A series of symmetrical and
unsymmetrical aliphatic, alicyclic, benzyl, as well as
aromatic tertiary amines with aryl iodides were well
tolerated and afforded the desired products in good yields.
Keywords: palladium; carbonylation; oxidant free; C-N
bond cleavage; tertiary amides; PEG-400
recyclable noble transition metals. In 1974, Heck et
al. first reported transition-metal catalyzed three
component coupling reactions of aryl halides, CO and
alcohols or amines.[9] However, carbonylation
reactions represent straightforward, efficient and
most powerful alternative approach for the
construction of carbonyl containing compounds.[10,11]
Carbon monoxide is an inexpensive and readily
available C1 source and it is also valued because of
its simplicity and atom economy.
Over past two decades, palladium-catalyzed
carbonylation of aryl halides using primary or
secondary amines for the access of secondary or
tertiary amides has been extensively studied.[12] These
reactions are usually limited to primary and
secondary amines along with requirements of excess
base, ligand and uses organic solvents under harsh
conditions. Recently, Jiao and co-workers reported
Pd/Cu/O2 catalyzed carbonylative synthesis of tertiary
amides from organoboronic acids and secondary
amines.[13] Murahashi and Huang group demonstrated
palladium catalyzed direct carbonylation of
allylamines via C–N bond cleavage.[14] However,
activation of Csp3-N bond of inert tertiary amines
still remains a great challenge despite its usefulness
in the field of organic synthesis. Thus, a vast array of
C-N bond formation reactions using tertiary amines
Introduction
Amide chemistry is vital in synthetic organic
chemistry since C-N bond functionalization is
ubiquitous in peptides, polymers, natural products,
agrochemicals, advanced material synthesis. It is also
important in biologically as well as pharmaceutically
active compounds.[1] Beyond conventional methods
for construction of amides,[2] several alternative
methodologies have been reported. Transition metal
and metal free catalyzed oxidative amidation of
aldehydes with amines and formamides have been
widely studied using Cu, Pd, Rh and Ru complexes.[3]
Direct amide synthesis from oxidative coupling of
benzyl alcohols with amines using Fe, Cu, Ru, Rh
and Ag based catalytic systems have also been well
documented.[4] Alternative strategies including
hydroamidation of alkynes,[5] transamidation,[6]
aminolysis of esters,[7,15h,i] and amidation of thioacids
with azides[8] have been demonstrated for access of
such amides. Despite their excellent potential utility,
these reported strategies still exhibit some drawbacks
such as poor atom economy, need of explosive
oxidants (such as hydrogen peroxide or TBHP etc.),
use of highly hazardous reagents, limited amide
coupling reagents and use of expensive as well as non
1
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
as an amine reservoir have attracted tremendous
attention in synthetic chemistry.[15] Up to now, only a
few examples are reported for C-N bond cleavage of
tertiary amines.[16] Deng and co-workers reported
PdCl2(PhCN)2 catalyzed carbonylation of
To the best of our knowledge, oxidant free Csp3-N
bond cleavage of inert tertiary amines as an aminal
source in this transformation is unprecedented.
Therefore, to develop an efficient, base free and
ligand free direct carbonylative synthesis of amides
via oxidant free C-N bond cleavage of tertiary amines
with aryl iodides using PdCl2/PEG-400/H2O as a
reusable media is highly desirable. Herein, we wish
to address in situ generated Pd(0) nanoparticle
catalyzed carbonylative amide synthesis directly from
aryl iodides and various tertiary amines as an aminal
source via Csp3-N bond cleavage in PEG-400
without using any oxidant (Scheme 1).
Scheme 1. Oxidants free N-dealkylative carbonylation of
tertiary amines with aryl iodides.
Results and Discussion
aryl iodides via C-N bond activation of tertiary
In our initial investigation, we focused on the N-
dealkylative carbonylation of the NBu3 (2a) with
iodobenzene (1a) under oxidant free conditions using
PEG-400 as an environmentally benign solvent. Only
28% yield of 3aa was obtained under combined
reaction conditions of 5 mol% PdCl2 in a 8 mL
degassed PEG-400 at 80 °C for 8 h at atmospheric
pressure of CO (Table 1, entry 1). However, the C-N
bond is inert in organic chemistry. Therefore, the
activation of Csp3-N bond is usually difficult and
oxidants such as Cu, O2, air and per-acids are
generally required. In all probability, we thought that
the requirement of hydrolysis of Pd-iminium ion step
in reaction mechanism may be responsible for this
selectivity switch to dealkylation of tertiary
amines.[15h,18] It is interesting to note that 84% of 3aa
was obtained, when we used few drops H2O with
PEG-400 as reaction media without any oxidants
(Copper species, TBHP, air and O2), which is greener
and abundant (Table 1, entry 2). This
environmentally benign catalytic system features low
toxicity, potential reusability, and good applicability
in process chemistry. Further, we noticed an in situ
formation of Pd nanoparticles after first experiment
without any additional reducing agents. Presence of
these in situ generated nanoparticles was confirmed
by SEM, EDS and TEM techniques (Figure 2).
Interestingly, when we carried out the reaction with 8
mL of PEG/H2O (7:1), selectively 85% yield of 3aa
was observed instead of hydroxycarbonylated product
(Table 1, entry 3). Then, we examined various
palladium pre-catalysts and the results are
summarized in (Table 1, entries 3-6). Among these,
PdCl2 and PdCl2(PPh3)2 were found active catalysts
for the synthesis of tertiary amides in PEG-400/H2O.
Then, the PdCl2 was chosen for the further
optimization study which doesn’t need a co-catalyst,
base and phosphine ligand. Next, the effect of various
PEG such as PEG-200 and PEG-600 was investigated
and had found no significant effect on the yield of
3aa (Table 1 entries 7-8). Then, we studied the effect
of solvents including polar as well as non-polar
organic solvents (Table 1, entries 9-12). In addition,
we utilized [bmim]PF6 and [bmim]BF4 as an ionic
liquid. Interestingly instead of the desired product the
amines using CuO as an oxidant.[17] Meanwhile, we
demonstrated
Pd/C-catalyzed
N-dealkylative
carbonylation of tertiary amines with aryl iodides
using molecular oxygen (O2) as a terminal oxidant.[18]
Although these reactions afford efficient access to
tertiary amides, their applications are limited by
necessity of 3 equiv of CuO for C-N bond cleavage
which makes the work-up tedious. Moreover, the
mixture of CO/O2 is explosive under certain
conditions and uses organic solvents with harsh
reaction conditions. The Csp3-N bond is very strong
in organic molecules and literature study reveals that
cleavage of Csp3-N bond is usually difficult and
requires oxidants such as Cu, O2, air and per-
acids.[15,16] Further, various organic solvents are
extensively engaged in organic syntheses and have
been a cause of a major concern due to their
associated environmental hazards.
Thus development of simple, cost effective
catalytic systems for the organic transformation is
becoming an area of growing importance in organic
transformations. Recently, researchers tend to utilize
ionic liquids (ILs) and polyethylene glycols (PEGs)
as greener and safer reaction media to avoid use of
environmentally hazardous organic solvents.[19,20]
PEGs, in contrast to common organic media, have
gained fabulous interest because of their non-toxic,
thermally
stable,
neutral,
bio-degradable,
environmentally-friendly and potentially reusable
properties. Further, PEG has an ability to coordinate
with many metal centers to form stable complexes. It
has also been reported that reduction of Pd(II) to
Pd(0) NPs takes place in presence of CO[21a] and PEG.
PEG not only enables the reduction but also well
disperses the generated Pd nanoparticles resulting in
their stabilization.[21h,i] In this context, PEGs have
been effectively exploited as environmentally benign
and recyclable media to C-C cross-coupling
reactions.[20,21] Han and co-workers demonstrated in
situ generated Ni and Pd nanoparticles in PEG-400
without any ligand/additive for the carbonylative
Suzuki coupling and aminocarbonylation reactions.[22]
Our group and Cai group have reported Pd-catalyzed
carbonylative Sonogashira coupling reaction for the
synthesis of alkynyl ketones using PEG solvent.[23]
2
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.[a]
T
[°C]
80
80
80
80
80
80
80
80
80
80
80
80
80
80
120
100
60
Rt
Entry
[Pd]
Solvent
Time [h]
Yield [%][b]
1[c]
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[e]
PdCl2
PdCl2
PdCl2
PEG-400
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-200/H2O
PEG-600/H2O
THF/H2O
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
28
84
85
54
87
45
82
86
21
Trace
Trace
10
-
Pd(OAc)2
PdCl2(PPh3)2
Pd/C
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Nano-Pd
Dioxane/H2O
Toluene/H2O
MeCN/H2O
[bmim]PF6/H2O
[bmim]BF4/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
PEG-400/H2O
-
86
85
68
17
83
67
24
16
8
80
80
[a]
Reaction conditions: Iodobenzene (1.0 mmol), Bu3N (1.5 mmol), [Pd] (5 mol%), PEG-400 (7 mL), H2O (1 mL) under
1atm CO at 80 °C for 8 h. rt = Room temperature (28 oC).
[b] GC/GCMS yield.
[c] Reaction was performed in inert condition using degassed PEG-400.
[d] Few drops of H2O.
[e] Prepared Pd NPs.
94% yield of benzoic acid was obtained (Table 1,
entries 13-14). However, when we used organic
solvents as well as ionic liquids, it was observed that
tertiary amine acts as a base and gives the
hydroxycarbonylated product. Increasing the reaction
temperature to 120 °C, did not show any significant
effect on the yield, while with decreasing the
temperature yield of 3aa decreased markedly (Table
1, entries 15-18). Also, we carried out the reaction at
room temperature for 24 h, unfortunately 17% yield
of 3aa was observed (Table 1, entry 18). When the
reaction time was prolonged 8 h to 16 h there was no
significant effect on the reaction yield (Table 1, entry
19). Moreover, ex situ generated palladium
nanoparticles were also prepared (see ESI) and then
directly used for the model reaction under the
optimized conditions to give 67% yield of 3aa (Table
1, entry 20). These consequences specify that the in
situ generated Pd nanoparticles are highly active
catalytic species than the ex situ Pd nanoparticles.
amines to amides that could be synthesized under the
developed protocol. At first, we evaluated different
aryl iodides bearing electron-rich and electron-
deficient substituent’s on the phenyl ring that could
be employed efficiently (Table 2). Aryl iodide
containing electron-rich substituents such as, -Me and
-OMe at the ortho or para position in 2a were well
tolerated and desired amides 3ba-3ea were obtained
in good yields. Likewise, 1-iodo and 2- iodo-
naphthalene were also smoothly coupled under the
developed conditions to give the tertiary amides 3fa
and 3ga in 93% and 91% yields respectively.
Electron-deficient substituents such as, para-cyano,
para-bromo and para-fluoro on the aryl iodide were
also well tolerated, furnishing the corresponding
products 3ha-3ja in good to excellent yields. Further,
we carried out the reaction of bromobenzene and
chlorobenzene under the optimized conditions which
failed to give desired product 3aa. Disappointingly,
heterocyclic substrates did not produce the
Having established optimized conditions in hand, corresponding amides 3ka and 3la. It can be
we investigated the scope of the reaction for a range
of aryl iodides with oxidant free N-dealkylative
carbonylation of aliphatic as well as aromatic tertiary
speculated that the Pd(0) might be blocked or
chelated with nitrogen of the pyridine ring.
Interestingly, double-carbonylated product 3ma could
3
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
Table 2. Scope of carbonylation of aryl iodides with NBu3
Table 3. Scope of carbonylation of iodobenzene with C-N
as amine source.[a]
bond cleavage of various tertiary amines.[a]
[a]
Reaction conditions: PhI (1.0 mmol), R1R2NR3 (1.5
[a]
Reaction conditions: ArI (1.0 mmol), Bu3N (1.5 mmol),
mmol), PdCl2 (5 mol%), 8 mL of PEG-400/H2O (7:1)
under 1 atm CO at 80 °C for 8 h.
[b] Isolated yield.
PdCl2 (5 mol%), 8 ml of PEG-400/H2O (7:1) under 1 atm
CO at 80 °C for 8 h. Isolated yield.
[b] The reaction was scaled up to 5 mmol of 1d.
with
different
alkyl
groups
like
N,N-
be successfully accomplished in high yield. Further,
to extend the robustness of the highly efficient
catalytic system, we performed a scaled up reaction.
Delightfully, reaction of 4-iodoanisole could be easily
achieved on gram scale, affording 3da in 77% yield.
After evaluating the scope of the aryl iodide
coupling partner, we tested a wide range of
symmetrical, unsymmetrical aliphatic as well as
alicyclic and aromatic tertiary amine derivatives to
demonstrate the generality of the protocol (Table 3).
Remarkably, N-dealkylative carbonylation of tertiary
amine derivatives could be converted to amide
products with 1a in good to excellent yield under the
standard conditions without any oxidant. It was
found that symmetrical trialkylamines were well
tolerated under the optimized conditions providing
corresponding amides 3ab, 3ac and 3ae-3ag in good
to excellent yields. Notably, when tertiary amines
diisopropylethylamine was employed and provides
3ada and 3adb. Importantly, tribenzyl amine (Bn3N)
efficiently reacted and resulted in a satisfactory yield
of amide 3ah, while N,N-dibenzyl-N-methyl amine
furnished two different amides, 3ah and 3ai. When,
we used triphenylamine (Ph3N) as an aminal source
the target product was not obtained. Compared to
previously reported protocols, arylamines, such as
N,N-dimethylaniline and N,N-diethylaniline were
proven to be useful substrates under an optimized
conditions and accomplished good yield of desired
products 3ak and 3al. Delightfully, alicyclic and
heteroalicyclic tertiary amines, such as 1-ethyl or 1-
methylpiperidine,
4-ethymorpholine,
and
1-
methylpyrrolidine well furnished corresponding
amides 3am-3ao in good yields.
In order to exhibit the efficiency of this protocol,
4
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
recyclability and reusability of developed catalytic
system were examined in 4-iodoanisole with Bu3N as
a substrate (Figure 1). After initial experimentation,
the reaction mixture was extracted with diethyl ether
(4 × 10 mL) and solidified PdCl2/PEG-400/H2O was
subjected to a second run by charging with the same
substrates (4-iodoanisole and Bu3N) under 1 atm of
CO without any oxidant. We have noticed that this
transformation is more rapid after the first recycle run
and becomes high yielding due to in situ Pd NPs
generation. We were gratified to observe that this
catalytic system could be reused up to five times
without any loss of catalytic activity and selectivity.
However, the leaching experiments revealed that only
0.1% total amount of Pd was leached out during the
recyclability study.
It was also noticed that there is an in situ formation
of Pd nanoparticles from PdCl2 in the presence
reducing nature of gaseous CO and PEG 400. PEG-
400 acts as a reductant and also stabilizes the in situ
generated Pd(0) nanoparticles as well.[21a,h,i,22] The
catalytic activity of the in situ and ex situ attribute to
formation of palladium nanoparticles were confirmed
by TEM, FEG-SEM, EDS and XRD as shown in
Figure 2 and ESI. The TEM analysis revealed that the
slight change in particle size of the in situ generated
palladium nanoparticles in PEG-400 after 1st and 5th
recycle run ranges from 20-50 nm (Figures 2a, 2b and
2c and ESI). FEG-SEM exhibits the rough
morphology and EDS confirmed the in situ formation
Pd NPs after 1st and 5th recycle run (Figure 2c and 2f
and ESI). The X-ray diffraction pattern also
confirmed that the formations of Pd NPs after 1st
recycle run. Moreover, the ex situ generated
palladium nanoparticles were prepared and
Figure 1. Reusability study of PdCl2/PEG-400/H2O.
characterized by FEG-SEM and EDS techniques (ESI,
Figure S3).
To gain deeper insight into the mechanism we
performed a series of experiments to establish for the C-N
bond cleavage of tertiary amines (Scheme 2). First, the
reaction of PhI and Bu3N as an aminal source under the
same reaction conditions, afforded the amide product 3aa
in 85% yield, while in absence of water under N2
atmosphere only 28% of amide product was obtained. This
result strongly suggests that Pd-iminium ion intermediate
may be generated in reaction and it can
Figure 2. Characterization of in situ formed Pd NPs in PEG-400 after 1st and 5th recycle run. (a) and (b) shows the TEM
images and (c) shows the FEG-SEM image of in situ formed Pd NPs of 1st recycle run. (d) and (e) shows the TEM images
and (f) shows the FEG-SEM image of in situ formed Pd NPs of 5th recycle run.
5
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
Pd(0) followed by CO insertion leads to formation of
acyl intermediate A. Then, the lone pair of tertiary
amines coordinates with palladium of A to form B
followed by elimination of HI, this was then
transformed into the Pd-iminium ion intermediate C.
Further, the C can be easily hydrolyzed to afford D,
and leads to aldehyde and H2 as by-product. Finally,
the reductive elimination of D delivers the amide 3
and regenerates Pd(0) NPs as an active catalytic
species and the catalytic cycle is continued.
Conclusion
In summary, we described a simple, cost effective
and eco-friendly catalytic system for the direct
synthesis of amides via oxidant free N-
dealkylation/carbonylation of diverse tertiary amines
with aryl iodides. Notably, these reactions were
catalyzed by in situ generated Pd(0) NPs in PEG-
400/H2O under the base free, ligand free conditions
at atmospheric pressure of carbon monoxide.
Importantly, the presence of H2O effectively
influences the Csp3-N bond cleavage of tertiary
amines in PEG-400 making the developed protocol
green and highly efficient. Also, the selectivity of
amide formation from tertiary amines is different
from those with conventional solvents and ionic
liquid media. A series of tertiary amines as well as
aryl iodides were well tolerated affording desired
products in good to excellent yield. Furthermore, this
catalytic system could be easily scaled up and reused
up to five consecutive cycles and shows significant
recyclability. The TEM, FEG-SEM, EDS and XRD
techniques confirmed in situ formation of Pd(0)
nanoparticles in the PEG-400/H2O and strongly
indicate that palladium nanoparticles are catalytically
active species and the reaction proceeds through the
classical Pd(0)/Pd(II) pathway.
Scheme 2. Some control experiments.
be easily hydrolyzed to secondary amine with
aldehydes and H2 as by-product.[15k,m] Also we
observed the formation of aldehyde along with
formamide due to presence of excess tertiary amine,
the same was confirmed by GC-MS. Further, we
carried out the reaction in water under the same
conditions, the hydroxycarbonylated product was
obtained in 94% yield. Typically, the tertiary amines
employed as a base in many organic transformations
and it is well documented. Notably, the combination
of PdCl2/PEG-400 and H2O offers selectively N-
dealkylation of tertiary amines to secondary amines.
PEG has the ability to coordinate with metal centers
to form stable complexes and it provides the positive
effect on catalyst activity and stability.
On the basis of our results and literature,[12,15h,i,k]
we proposed a possible reaction mechanism as shown
in Scheme 3. Initially, the Pd(II) reduces to Pd(0)
NPs as an active species in the presence of CO and
PEG-400.[21a,h,i] Thus, oxidative addition of ArI to
Experimental Section
General Information
All the reactions were performed in inert conditions under
the nitrogen atmosphere by using 100 mL stainless steel
reactor. The solvents were purchased from commercial
suppliers and used without further purification. The
prepared and in situ generated Pd NPs were characterized
by X-ray diffract meter (Shimadzu XRD-6100 using
CuKα-1.54 Å) with a scanning rate 2θ per min and 2 theta
(θ) angle ranging from 20 θ to 90 θ with current 30 mA
and voltage 40 kW, Field emission gun scanning electron
microscopy (FEG-SEM) analysis was done by Tescan
MIRA 3 model with secondary electron (SE) detector
between 10.0 kV to 20.0 kV. The energy dispersive X-ray
spectrum (EDS) was recorded by using an Oxford
instrument (model 51-ADD0007). The Transmission
Electron Microscope (TEM) analysis was recorded by
using PHILIPS instruments (model: CM 200) with
operating voltages was the 20-200 kV and resolution was
2.4 Å. Reaction monitor by using Perkin Elmer Clarus 400
gas chromatography equipped with flame ionization
detector with a capillary column (Elite-1, 30 m × 0.32 mm
× 0.25 μm). GC-MS-QP 2010 instrument (Rtx-17, 30 m ×
25 mm ID, film thickness (df) = 0.25 µm, was used for the
Scheme 3. Possible reaction mechanism.
6
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10.1002/adsc.201700317
Advanced Synthesis & Catalysis
mass analysis of the products. Products were purified by
[2] See ref 1a and following reviews on non-traditional
strategies for amide synthesis, see: a) R. Garcia-
Alvarez, P. Crochet, V. Cadierno, Green Chem. 2013,
15, 46-66; b) C. L. Allen, J. M. J. Williams, Chem. Soc.
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J. Org. Chem. 2009, 1144-1147; d) E. Valeur, M.
Bradley, Chem. Soc. Rev. 2009, 38, 606-631.
1
column chromatography on silica (100-200 mesh). The H
NMR spectrum was recorded on the Agilent (400 MHz
spectrometer) in CDCl3 using tetramethylsilane (TMS) as
an internal standard. The 13C NMR spectrum was recorded
on the Agilent (101 MHz spectrometer) in CDCl3. The
chemical shift values are reported in parts per million (δ)
relative to tetramethylsilane as an internal standard. The J
(coupling constant) values were described in Hz. Splitting
patterns of proton are depicted as s (singlet), d (doublet), t
(triplet) and m (multiplet). The products were confirmed
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Wan, Angew. Chem. Int., Ed. 2012, 51, 3231-3235; h)
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1
by the comparison of their GC, GC-MS, H and 13C NMR
spectra with those of authentic data.
Typical experimental procedure for oxidant free N-
dealkylative carbonylation of tertiary amines with aryl
iodides
Aryl iodides (1 mmol), Bu3N (1.5 mmol), PdCl2 (5 mol%)
in a 8 mL of PEG-400/H2O (7:1) were placed in 100 mL
stainless steel autoclave. Then, the reactor was closed,
purged three times with nitrogen, pressurized with 1 atm of
CO, and heated at 80 °C for 8 h. After the completion of
the reaction, the reactor was cooled to room temperature,
and the remaining CO gas was vented carefully, and the
reactor was opened. The reaction mixture was extracted
with diethyl ether (4 × 10 mL) and then washed with
saturated aqueous NaCl solution (15 mL). The organic
phases were combined, and the volatile components were
evaporated in a rotary evaporator. The crude product was
purified by column chromatography (silica gel, 100−200
mesh; petroleum ether/ethyl acetate) to afford the desired
purified product.
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Scale up study
4-Iodoanisole (5 mmol, 1.170 g), Bu3N (7.0 mmol, 1.3 g),
PdCl2 (15 mol%) in 8 mL PEG-400/H2O (7:1) were added
to a 100 mL stainless steel autoclave. The autoclave was
closed and flushed with nitrogen three times and then
pressurized with CO to 1 bar (~15 psi) at ambient
temperature. The reaction mixture was stirred with a
mechanical stirrer (550 rpm) at 80 °C for 10-12 h. After
cooling to room temperature, the pressure was carefully
released. The reaction mixture was extracted with diethyl
ether (4 × 10 mL) and then washed with saturated aqueous
NaCl solution (10-20 mL). The organic phases were
combined, and the volatile components were evaporated by
rotary evaporation to obtain the crude product which was
subjected to GC-MS analysis.
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Procedure for recycling of PdCl2/PEG-400/H2O catalyst
After initial experimentation, the reaction mixture was
extracted with diethyl ether (4 × 10 mL) and the solidified
PdCl2/PEG-400/H2O was subjected to a second run by
charging with the same substrates (4-iodoanisole and
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Acknowledgements
R.S.M gratefully acknowledges to Council of Scientific &
Industrial Research (CSIR), New Delhi, India for the award
Senior Research Fellowship (SRF).
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8
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FULL PAPER
Carbonylative Tertiary Amide Synthesis from Aryl
Iodides and Tertiary Amines via Oxidant-Free C-N
Bond Cleavage Catalyzed by Palladium(II)
Chloride in Polyethylene Glycol/Water
Adv. Synth. Catal. Year, Volume, Page – Page
Rajendra S. Manea and Bhalchandra M. Bhanagea*
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