Heterogeneous CuII-catalysed solvent-controlled selective N-arylation of cyclic amides and amines with bromo-iodoarenes

Article abstract of DOI:10.1002/chem.201302645

A selective N-arylation of cyclic amides and amines in DMF and water, respectively, catalysed by Cu^II/Al₂O₃ has been achieved. This protocol has been employed for the synthesis of a library of arenes bearing a cyclic amide and an amine moiety at two ends, including a few scaffolds of therapeutic importance. The mechanism has been established based on detailed electron paramagnetic resonance (EPR) spectroscopy, X-ray photoelectron spectroscopy (XPS), UV diffuse reflectance spectroscopy (DRS) and inductively coupled plasma-mass spectrometry (ICP-MS) studies of the catalyst at different stages of the reaction. The Cu^II/Al₂O ₃ catalyst was recovered and recycled for subsequent reactions. One over the other: A selective N-arylation of cyclic amides and amines in DMF and water, respectively, catalyzed by Cu^II/Al₂O₃ has been achieved (see scheme). This protocol has been employed for the synthesis of a library of arenes bearing cyclic amide and amine moieties at two ends including a few scaffolds of therapeutic importance. The mechanism has been established based on detailed spectroscopic studies (FG=functional group). Copyright

Full text of DOI:10.1002/chem.201302645

FULL PAPER
DOI: 10.1002/chem.201302645
Heterogeneous CuII-Catalysed Solvent-Controlled Selective N-Arylation of
Cyclic Amides and Amines with Bromo-iodoarenes
Debasish Kundu,[a] Sukalyan Bhadra,[a] Nirmalya Mukherjee,[a] Bojja Sreedhar,[b] and
Brindaban C. Ranu*[a]
Abstract: A selective N-arylation of
cyclic amides and amines in DMF and
water, respectively, catalysed by CuII/
Al2O3 has been achieved. This protocol
has been employed for the synthesis of
a library of arenes bearing a cyclic
amide and an amine moiety at two
ends, including a few scaffolds of thera-
peutic importance. The mechanism has
been established based on detailed
(EPR) spectroscopy, X-ray photoelec-
tron spectroscopy (XPS), UV diffuse
reflectance spectroscopy (DRS) and in-
ductively coupled plasma-mass spec-
trometry (ICP-MS) studies of the cata-
lyst at different stages of the reaction.
The CuII/Al2O3 catalyst was recovered
and recycled for subsequent reactions.
electron
paramagnetic
resonance
Keywords: amides · amines · bioac-
tive scaffolds · heterogeneous catal-
ysis · solvent-controlled selectivity
Introduction
ꢀ
The formation of C N bonds is one of the most important
reactions in chemical and pharmaceutical industries,[1] as
a majority of the pharmaceutically active molecules are de-
rived from heterocyclic units. In particular, N-arylation of
nitrogen heterocycles such as cyclic amides and amines by
aryl halides has received current attention as a series of
compounds containing both cyclic amides and amines at-
tached with an aromatic ring through a nitrogen centre are
found as structural motifs of biologically active molecules
and drugs as outlined in Figure 1.[2] Interestingly, no straight-
forward and efficient methodology was available for the syn-
thesis of these molecules. This prompted us to initiate an in-
vestigation to find a suitable protocol for an access to these
molecules.
The transition-metal-catalysed cross-coupling reaction is
one of the efficient tools for the N-arylation of heterocy-
cles.[3] These reactions are usually mediated by palladium,[4]
nickel,[5] copper[6] , more recently, iron[7] catalysts in pres-
ence of a ligand. However, copper and iron being less ex-
pensive and toxic, have received more attention. Although
N-arylation of a variety of cyclic amines such as imidazoles,
pyrazoles and indoles were studied extensively by these pro-
[a] D. Kundu, Dr. S. Bhadra, N. Mukherjee, Prof. Dr. B. C. Ranu
Department of Organic Chemistry
Indian Association for the Cultivation of Science
Jadavpur, Kolkata-700032 (India)
Figure 1. Potent molecules containing both cyclic amide and amine
moieties.
Fax : (+91)33-24732805
E-mail: ocbcr@iacs.res.in
[b] Dr. B. Sreedhar
Inorganic Chemistry Divison
Indian Institute of Chemical Technology
Hyderabad-500007 (India)
cedures, less active cyclic amides have not been addressed
adequately. In addition, we did not find a single report on
the selective N-arylation of a cyclic amide over an amine
and vice versa, which would be of much significance towards
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302645.
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Table 1. Standardisation of the amide coupling reaction.[a]
the synthesis of the molecules containing both cyclic amide
and amine moieties, as outlined in Figure 1.
A few years back, we have developed a unique Al2O3-sup-
ported CuII catalyst that has been successfully used for C S,
ꢀ
[8]
ꢀ
ꢀ
C Se and C Te cross-coupling reactions. We now report
here its application for N-arylation of cyclic amines and
Entry
Catalyst [mol%]
Solvent
Base
T [oC]
Yield [%][b]
ꢀ
amides involving C N bond formation. Significantly, we
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
5
5
2
5
5
0
5
NMP
DMSO
CH3CN
toluene
H2O
H2O
dioxane
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
KOH
K3PO4
K3PO4
K3PO4
K3PO4
none
110
110
110
110
110
110
110
reflux
110
110
110
110
110
110
80
90
53
72
0
0
0
have observed that cyclic amides underwent N-arylations by
aryl iodides in DMF, whereas amines were arylated margin-
ally under this condition. On the other hand, arylation of
amines proceeded efficiently in water by aryl iodide/bro-
mide, whereas amides remained inert. Based on this differ-
ential reactivity of iodo- and bromo-arenes, we have devel-
oped a simple protocol for the hitherto unreported synthesis
of arenes containing both cyclic amide and amine moieties
at two ends (Scheme 1), starting from bromo-iodobenzene.
38
traces
92
0
86
76
66
20
traces
0
9
10
11
12
13[c]
14[d]
15[c]
16
17
110
110
0
[a] Reaction conditions: iodobenzene (1.0 mmol), 2-pyrrolidinone
(1.2 mmol), 12 h, under an argon atmosphere. [b] Yields of the isolated
pure products. [c] 24 h. [d] CuSO4 was used as catalyst and basic alumina
(0.1 mmol) was used as additive.
when the reaction was performed in water at 1008C in the
presence of K3PO4 and 5 mol% of the catalyst (Table 2,
entry 10). Significantly in a sharp contrast, DMF, which
works most efficiently for the arylation of amides, did not
initiate the arylation reaction for the amine at all (Table 2,
entries 1–3 and 5). On the other hand, water, which was
Scheme 1. Solvent-selective differential N-arylations of cyclic amides and
amines. FG=functional group.
Results and Discussion
Table 2. Standardisation of the amine coupling reaction.[a]
To standardise the reaction conditions for the arylation of
cyclic amide a series of experiments for a representative re-
action of 2-pyrrolidinone and iodobenzene with variation of
the reaction parameters such as solvent, temperature, base,
catalyst loading and reaction time were performed. Among
DMF, N-methylpyrrolidone (NMP), DMSO, CH3CN, diox-
ane and water used for this reaction, DMF was found to be
the best solvent giving 92% yield at 1108C in presence of
K3PO4 and Cu/Al2O3 (5 mol%) (Table 1, entry 9).Water
failed to initiate the reaction (Table 1, entries 5 and 6). The
reaction did not proceed at all in the absence of a catalyst
and a base (Table 1, entries 16 and 17). Only marginal reac-
tion was observed by using CuSO4 and Al2O3 separately
(Table 1, entry 14). K3PO4 was found to be the most suitable
base among other bases tried.
For the optimisation of the reaction conditions for the ar-
ylation of amines, similar experiments for a representative
reaction of 1-(4-bromophenyl)pyrrolidin-2-one (3ha) (ob-
tained by arylation of pyrrolidinone) and morpholine were
carried out with variation of solvent, base, catalyst loading,
time and temperature. The results are summarised in
Table 2. It was revealed that the best yield was obtained
Entry
Catalyst [mol%]
Solvent
Base
T [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
5
5
5
2
0
5
DMF
DMF
DMF
NMP
DMF
DMSO
CH3CN
Toluene
THF
H2O
H2O
H2O
H2O
K2CO3
K3PO4
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
None
110
110
110
110
140
110
110
110
reflux
100
100
100
100
100
100
RT
0
traces
traces
traces
0
20
45
0
9
traces
86
78
traces
60
10
11
12
13
14
15
16
KOH
H2O
H2O
H2O
K3PO4
K3PO4
K3PO4
53
0
0
[a] Reaction conditions: 1-(4-bromophenyl)pyrrolidine-2-one (1.0 mmol),
morpholine (2.0 mmol), 12 h, under an argon atmosphere. [b] Yields of
the isolated pure products.
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CuII-Catalysed Solvent-Controlled Selective N-Arylation of Amides and Amines
FULL PAPER
Table 3. N-Arylations of cyclic amides.[a]
found to be inactive for the arylation of the amide, worked
successfully for the arylation of amines.
Thus, in a typical reaction procedure a mixture of a cyclic
amide and an aryl iodide was heated in DMF at 1108C in
the presence of K3PO4 and Cu/Al2O3 for a certain period of
time as required to complete the reaction (TLC) (procedur-
e A). On the other hand, arylation of an amine was per-
formed by using aryl iodide/bromide in water at 1008C
under similar conditions (procedure B).
A series of 5-, 6-, 7- and 8-membered cyclic amides under-
went reactions with several diversely substituted aryl and
heteroaryl iodides by procedure A to give the corresponding
N-arylated or heteroarylated amides. The results are sum-
marised in Table 3. Both electron-donating and electron-
withdrawing groups on the aryl iodide are compatible in this
procedure giving uniform yields. The reaction is highly che-
moselective being successful for the coupling of an amide
with an iodo-moiety leaving Br unaffected in the bromo-io-
dobenzene.
The heteroaryl iodides bearing thiophenyl (1e) and pyri-
dinyl (1 f) units also underwent facile reactions. Sterically
hindered iodides, such as 2-bromo-4-methyl-iodobenzne
(1k) and 2-bromoiodobenzene (1i), reacted with 5- and
6-membered cyclic amides (i.e., compounds 2a and 2c)
without any difficulty. The bridged cyclic amide 1g is also
equally reactive to form compound 3jg. The arylation of the
eight-membered cyclic amide 2 f is reported for the first
time.
Product
Yield
[%]
Product
Yield
[%]
92
89
90
80
86
81
83
92
93
90
80
90
We then turned our attention to the arylation of amines.
The N-(bromophenyl) cyclic amides, prepared earlier, were
then subjected to reaction with cyclic amines by following
procedure B to provide the corresponding products involv-
ing a coupling through a Br functionality. The results are re-
ported in Table 4. A variety of amines such as pyrrolidine
(4a), piperidine (4c), morpholine (4b), thiomorpholine (4d)
and 4-methyl piperidine (4e) have been used for this cou-
pling reaction. All the products were characterised by their
spectroscopic data. In addition, the X-ray structures of two
of these products (Table 4, 5kab and 5hfc) also confirmed
their identities (Figure 2).[9]
These products, the arenes bearing an amide and an
amine moiety at two ends, are of much potential as thera-
peutic agents. Several such compounds have been obtained
by this reaction. Product 5hab (Table 4) constitutes the core
unit of the 5-HT1B antagonist (a, Figure 1) and the hepati-
tis C virus replication inhibitor (b, Figure 1) and product
5jdb resembles linezolid (d, Figure 1). Product 5jab is a pre-
cursor to a drug against Alzheimer disease (c, Figure 1) and
product 5jba resembles the BACE-1 inhibitor (e, Figure 1)
and the products 5haa and 5laa resemble the compound
showing tremogenic activity (f, Figure 1).
82
88[b]
81[c]
85
80[c]
83[c]
80
84[d]
86[d]
85[e]
83[e]
82[e]
In general, both reactions are clean and high yielding.
The products are obtained in high purity. Thus, this protocol
provides an efficient synthesis of arenes containing a cyclic
amide on one end and a cyclic amine at the other for the
first time through a unique solvent-controlled sequential
N-arylation of cyclic amides and amines. The catalyst was
[a] Reaction conditions: iodoarene (1.0 mmol), amide (1.2 mmol), K3PO4
(1.5 mmol), DMF (3.0 mL), 1108C, 12 h, under an argon atmosphere.
[b] 13 h time is required. [c] 14 h time is required. [d] 15 h time is re-
quired. [e] 16 h time is required.
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B. C. Ranu et al.
Table 4. N-Arylations of cyclic amines.[a]
Product
Yield
[%]
Product
Yield
[%]
82
83
86
88
85
86
82
78
72[b]
78[c]
72[c]
74
76[c]
Figure 2. Top: ORTEP diagram of compound 5hfc. Bottom: ORTEP dia-
gram of compound 5kab.
84[d]
recycled for five times without any appreciable loss of activi-
ty (Figure 3).
Study of the mechanism: To understand this solvent-selec-
tive N-arylation of amides and amines a detailed investiga-
tion on the mechanism was undertaken. To check whether
the reaction is going through the heterogeneous or homoge-
neous catalysis pathway inductively coupled plasma (ICP)
MS studies of the catalyst at different stages of the reaction
were carried out. The fresh catalyst is found to contain
0.518 mmolgꢀ1 of copper whereas the recovered one from
the amide coupling after fourth cycle contains
0.502 mmolgꢀ1 of copper and that from the amine reaction
contains 0.496 mmolgꢀ1 of copper. These data indicate mar-
ginal loss of catalyst in the process, which might be due to
loss during handling. In another experiment for homogenei-
ty test, a coupling reaction of 2-pyrrolidinone and 4-methyl
iodobenzene was stopped at 3.5 h after 26% conversion
(NMR spectroscopy). The catalyst was separated and the re-
action mixture was allowed to run further. Even after 12 h
no formation of product was observed and the separated
88[d]
87[e]
85[e]
[a] Reaction conditions: bromoarene (1.0 mmol), amine (2.0 mmol),
K3PO4 (1.5 mmol), water (3 mL), 1008C, 12 h, 1 atm argon. [b] 14 h time
is required. [c] 15 h time is required. [d] 16 h time is required. [e] 18 h
time is required.
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CuII-Catalysed Solvent-Controlled Selective N-Arylation of Amides and Amines
FULL PAPER
Scheme 2. Coupling of styryl derivatives with retention of the stereoselec-
tivity.
Scheme 3. Expected behaviour of 1,4-diiodobenzene under a radical–
anion mechanistic pathway.
Figure 3. Top: Recyclability diagram of the catalyst in the amide cou-
pling. Bottom: Recyclability diagram of the catalyst in the amine cou-
pling.
mation of a mono-N-arylated product (Scheme 4). The reac-
tion through a radical anion intermediate would lead to the
disubstitution product in place of a monosubstituted one.[14]
Thus, a radical anion pathway for this reaction is unlikely.
catalyst was found to contain 0.514 mmolgꢀ1 of copper by
ICP-MS analysis. Thus, this study clearly establishes hetero-
geneous catalysis in this process.
As the reactions did not occur in the absence of catalyst
(Tables 1 and 2), uncatalysed pathways such as SNAr[10] or
[11]
S 1
RN
(thermal or photochemical) are unlikely. Thus, in
this copper-catalysed process three paths involving 1) radical
intermediates, 2) oxidative addition/reductive elimination
and 3) metal-assisted nucleophilic displacement, are consid-
ered.
Scheme 4. Behaviour of 1,4-diiodobenzene under standardised reaction
condition.
To check the possibility of a radical process we performed
the coupling reaction of 2-pyrrolidinone and 4-methyl iodo-
benzene in the presence of a nitroarene (electron acceptor)
and THF (radical scavenger)[12] and practically no effect was
observed. These results did not support the involvement of
radicals. In another experiment, the coupling of 2-pyrrolidi-
none and trans-4-chlorostyrenyl bromide led to the trans
product (Scheme 2) only (100%). This observation too does
not support the radical pathway as the involvement of vinyl
radials would provide mixture of stereoisomers undergoing
a rapid inversion of the configuration.[13]
If an oxidative addition–reductive elimination pathway is
considered, it would involve a CuII/CuIV transition, which is
unusual. The other possibility is initial reduction of CuII to
CuI[15] or Cu0 followed by oxidative addition involving a CuI/
CuIII[6e] or Cu0/CuII pathway. However, the EPR and XPS
studies of the catalyst at intermediate stage of the reaction
did not show the presence of any CuI or Cu0 species. Hence,
the oxidative addition–reductive elimination pathway is also
ruled out.
To find the involvement of a radical anion we have also
carried out the CuII-catalysed reaction of 2-pyrrolidinone (2
equivalents) and 1,4-diiodobenzene (1 equivalent) under the
same conditions (Scheme 3) and we have observed the for-
Next, we focussed our attention to a Cu-assisted nucleo-
philic displacement process.[16] Thus, a more detailed investi-
gation on the nature of the catalyst and reaction was under-
taken. The XPS study of the fresh catalyst at the Cu 2p
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B. C. Ranu et al.
level shows the 2p3/2 line at 934.556 with characteristic shake
up feature at 942.969 (Figure 4a),[17] which suggests the pres-
ence of the oxidation state +2 of copper. The X-band EPR
spectrum of the alumina-supported copper catalyst exhibits
a broad four-line hyperfine splitting for solid sample at 77 K
(Figure 4b).[18] The g values with gj j >g? >2.0023 indicate
that an unpaired electron resides in a dx2ꢀy2 orbital with the
copper centre in axial symmetry. The gj j, g? and Aj j values
of 2.318, 2.143 and 114.9ꢁ10ꢀ4 cmꢀ1 suggest a tetrahedrally
distorted copper(II) species with the presence of an in-plane
sigma bonding interaction. This fact is also supported by
a UV-DRS study, where we got an absorption peak for CuII
in the region of l=750 nm[19] (Figure 4c).
tion, we have performed a reaction of iodobenzene and bro-
mobenzene in presence of CuII/Al2O3 in DMF and water, re-
spectively, without any nucleophile and base at 100–1108C.
After 2 h the EPR spectrum of the catalyst, suspended in
DMF and water, shows similar kinds of X-bands as found in
the fresh catalyst (Figure 5). The EPR spectrum of the cata-
To conclude whether the copper centre is interacting with
the electrophile or nucleophile in the first stage of the reac-
Figure 5. EPR pattern of the catalyst with bromobenzene in water.
lyst at intermediate stages of the reaction with the amide
and amine in DMF and water, respectively, in the absence
of any electrophile, suggest a change in the coordination en-
vironment of the CuII centre (Figure 6a). The EPR spectral
pattern of the species generated upon treatment of the
copper catalyst with amine in water changed dramatically.
The EPR parameters (gk =2.229, g? =2.049 and Aj j =
171.1ꢁ10ꢀ4 cm-1) clearly suggest a change in the coordina-
tion environment resulting in a square-planar coordination
geometry at the copper(II) centre. On the other hand, the
EPR spectrum of catalyst after addition of amide in DMF
suggests a change in coordination geometry at the copper
centre with a tetrahedral distortion (gj j =2.298, g? =2.075
and Aj j =144.1ꢁ10ꢀ4 cmꢀ1). However, the extent of the tet-
rahedral distortion gets reduced in the latter stage. In both
cases, however, the nucleophiles get coordinated at the
metal centre with a concomitant change in the coordination
environment. The EPR parameters indicate the binding of
the amine through the nitrogen atom and of the amide
through the anionic oxygen atom, or the nitrogen atom or
through the N-C-O p cloud to the copper(II) centre. Bind-
ing or coordination of the amide, a bulky ligand, (Figure 7)
results in a tetrahedrally distorted copper(II) centre in order
to alleviate steric repulsion between the ligands. It was ob-
served that an increase in the ring size of the cyclic amide
led to a reduction of the rate of the reaction because of
steric strain.
The X-band EPR spectrum of the catalyst at the inter-
mediate stage of the amide and amine coupling in presence
of both an electrophile and a nucleophile under standar-
dised reaction conditions in DMF and water, respectively,
after 4 h shows similar types of results with that taken in ab-
sence of an electrophile (Figure 6b). In case of amide cou-
pling the catalyst suffers a tetrahedral distortion (gk =2.307,
Figure 4. a) XPS study of the fresh catalyst. b) X-band EPR spectrum of
the fresh catalyst. c) UV diffuse reflectance spectrum (DRS) of the fresh
catalyst.
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CuII-Catalysed Solvent-Controlled Selective N-Arylation of Amides and Amines
FULL PAPER
porting Information) with the characteristic shake up fea-
ture of copper(II). These facts indicate that copper is in the
oxidation state +2 at the intermediate stage of the reaction.
The UV-DRS spectrum of the amine intermediate shows
a strong N–Cu charge transfer (ligand-to-metal charge trans-
fer, LMCT)[20] band in the region of l=450–600 nm, which
indicates that copper is bound to the amine nitrogen atom.
In case of the amide intermediate, the spectral pattern is
quite similar to that of the fresh catalyst; however a weak
band is present in the region of l=450–550 nm (Figure 8).
Figure 8. Comparative UV-DRS study of (A) the fresh catalyst, (B) the
amide intermediate and (C) the amine intermediate.
Figure 6. a) X-band EPR pattern of the catalyst at the stage of (A) the
amine–Cu and (B) the amide–Cu intermediate in DMF and water, re-
spectively, without any electrophile. b) X-band EPR pattern of the cata-
lyst at the intermediate stage of (A) the amide-Cu and (B) the amine-Cu
in DMF and water, respectively, in the presence of iodobenzene as elec-
trophile.
In line with the EPR findings the UV-DRS study also sug-
gests that, in case of amine coupling, the amine is interacting
with copper directly through the nitrogen centre, but in case
of the amide the binding possibly occurs through the oxygen
centre, which could also be preferable due to hard–hard in-
teraction or the N-C-O p cloud.
After activation of the nucleophile by the Cu catalyst, the
aryl halide and the base come close to the metal centre and
a metal-assisted nucleophilic displacement leads to the for-
mation of the product. The catalyst is regenerated and takes
part in the next cycle. The regenerated catalysts from both
the amide and the amine coupling in DMF and water, re-
spectively, are characterised by EPR (see Figure S2 in the
Supporting Information) and XPS (see Figure S3a and b in
the Supporting Information). The X-band EPR spectrum of
Figure 7. Reactivity order of different cyclic amides with respect to iodo-
benzene.
the recycled catalyst in the amide coupling (gk =2.336, g?
=
2.066 and Ak =122.3ꢁ10ꢀ4 cmꢀ1) indicates that the CuII
centre remains in a tetrahedral environment with some
short tetragonal distortion with respect to the fresh catalyst.
This distortion is due to the presence of solvent in the coor-
dination environment of copper(II). The EPR parameters of
g? =2.063 and Aj j =137.64ꢁ10ꢀ4 cmꢀ1) and in case of amine
coupling in water the catalyst achieves a square-planner ge-
ometry (gk =2.230, g? =2.057 and Aj j =167.4ꢁ10ꢀ4 cmꢀ1).
This clearly suggests that the nucleophilic activation by the
metal centre is the first and key step in this reaction.
In case of the amide–copper intermediate the XPS shows
the Cu 2p3/2 and N 1s lines at 935.081 and 401.842 eV, re-
spectively, with the characteristic shake up feature of cop-
per(II) (see Figure S1a and b in the Supporting Informa-
tion). On the other hand, for the amine–copper intermediate
the XPS shows the Cu 2p3/2 and N 1s lines at 935.023 and
400.474 eV, respectively, (see Figure S1c and d in the Sup-
the recycled catalyst in the amine coupling (gk =2.338, g?
=
2.067 and Ak =127.2ꢁ10ꢀ4 cmꢀ1) show the similar result,
and in both cases the copper centre remains in the same co-
ordination environment, which is quite expected.
The XPS study of the regenerated catalyst in the amide
coupling in DMF and the amine coupling in water at the Cu
2p level shows the 2p3/2 lines at 934.006 and 934.355 eV, re-
spectively, with characteristic shake-up features at 943.494
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B. C. Ranu et al.
and 944.002 eV, respectively, after the fourth catalytic cycle.
This clearly shows that copper remains in the oxidation
state +2 after the reaction (See Figure S3a and b in the
Supporting Information).
To find a rationale for the selective N-arylation of the
amide in DMF over water, the X-band EPR spectrum of the
catalyst at the intermediate stage of amide coupling in water
was taken. This gives a similar result as that of the interac-
tion of the catalyst with water only without an amide or an
electrophile (Figure 9). This suggests that in water the metal
bromobenzene in water in the presence of 2-pyrrolidinone
was performed and 15% of phenol was obtained as product.
This indicates that in this case water is activated by the cata-
lyst over the amide. So, on the basis of above experiments
we have proposed the following mechanism (Schemes 5 and
6) in case of the amide and the amine coupling.
Scheme 6. Probable mechanism of the amine coupling.
Figure 9. Comparative EPR study of the catalyst in water in the presence
(A) and the absence (B) of a cyclic amide with base.
In the amide coupling, the copper catalyst activates the
amide through the oxygen centre or the N-C-O p-electron
cloud. The coordination of a bulky ligand like an amide re-
sults in a tetragonally distorted copper–amide intermediate.
Then, the iodoaryl electrophile comes close to the metal
centre and in the presence of a base, copper-assisted nucleo-
philic displacement takes place. The extent of the tetragonal
distortion is then reduced by the expulsion of the product
from the metal coordination environment, which leads to
a solvent-coordinated distorted tetrahedral catalyst. The cat-
alyst is then regenerated through the exclusion of the sol-
vent to take part in the next reaction cycle.
catalyst is not binding to the amide, which is the initial step
of the reaction (Scheme 5) and hence in water the amide
coupling did not occur. Moreover, the XPS spectrum of the
catalyst at the intermediate stage of the amide coupling in
water does not show any N 1s line, suggesting no Cu–amide
interaction is formed. To validate this finding, a reaction of
On the other hand, a cyclic amine is coordinated through
the nitrogen centre, which leads to a square-planar copper–
amine intermediate. The bromo- or iodoaryl electrophile in-
teracts with the metal centre and in the presence of a base,
nucleophilic displacement takes place. The catalyst attained
its original distorted tetrahedral geometry through the re-
lease of the product from its coordination environment.
The morphology of the Cu catalyst remained unaltered
before and after the reaction as revealed by SEM images
(see Figure S4a–c) and the XRD pattern (see Figure S5).
Conclusion
We have developed a convenient and efficient protocol for
the selective N-arylation of a cyclic amide and an amine in
DMF and water, respectively. We have outlined possible re-
Scheme 5. Probable mechanism of the amide coupling. Ar=aryl.
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CuII-Catalysed Solvent-Controlled Selective N-Arylation of Amides and Amines
FULL PAPER
(hexane/ethyl acetate 30:60) to provide the pure 1-(4-morpholinophenyl)-
pyrrolidin-2-one as white solid (212 mg, 86%),. M.p. 102–1048C;
action pathways for both reactions based on detailed EPR,
XPS, UV-DRS and ICP-MS analysis of the catalyst at differ-
ent stages of the reaction. A logical explanation for the pref-
erential reaction of the amide in DMF over water was also
provided. This strategy has been successfully employed for
the synthesis of several scaffolds of potent therapeutically
active arenes bearing cyclic amide and amine moieties at
two ends (Figure 1). To the best of our knowledge, we are
not aware of any report demonstrating such solvent-selec-
tive N-arylation of amides and amines and such an efficient
synthesis of the therapeutically important amide, amine-sub-
stituted arenes by a two-step procedure from readily avail-
able materials. The other attractive features of this proce-
dure are the simple operation, the recyclability of the cata-
lyst, high yields and the scope for versatile manipulations.
We believe this strategy will find useful applications in or-
ganic synthesis.
a
1H NMR (500 MHz, CDCl3): d=2.10–2.16 (m, 2H), 2.57 (t, J=8.0 Hz,
2H), 3.11 (t, J=5.0 Hz, 4H), 3.80–3.85 (m, 6H), 6.90 (d, J=9.0 Hz, 2H),
7.48 ppm (d, J=9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=18.0, 32.5,
49.2 (2C), 49.6, 66.9 (2C), 116.1 (2C), 121.6 (2C), 132.1, 148.5,
174.2 ppm; IR (KBr): n˜ =2975, 2842, 1679, 1515, 1226, 833 cmꢀ1; HRMS:
m/z calcd for C14 H19 N2O2: 247.1441 [M+H]+; found: 247.1442.
This procedure was followed for all the reactions listed in Table 4. All of
these compounds are new and were not reported earlier. They were char-
acterised properly by their spectroscopic and spectrometric data (IR,
1H NMR, 13C NMR spectroscopy and HRMS). All these data are provid-
ed in the Supporting Information.
Although these procedures were described with a 1 mmol scale, 10 mmol
scale reactions also provided uniform results.
Recyclability of the catalyst: After workup the residual catalyst was
washed with water (3 mL), EtOAc (3 mL) and acetone (4 mL). The solid
was then dried at 1008C for 8 h for further use. The catalyst was recycled
five times without appreciable loss of activity.
Preparation of the amide complex in DMF: A mixture of the Cu/Al2O3
catalyst (100 mg, 5 mol%) and 2-pyrrolidinone (102 mg, 1.2 mmol) in
DMF (3 mL) was heated at 1108C for 8 h. The mixture was cooled to
room temperature and the supernatant liquid was filtered off. The dirty
brownish solid residue was thoroughly washed with water (4 mL), ethyl
acetate (4 mL) and acetone (3 mL) and dried to get the intermediate A.
Experimental Section
IR spectra were taken as thin films for liquid compounds and as KBr pel-
lets for solids. NMR spectra were recorded at 300 and 500 MHz for
1H NMR spectra and at 75 and 125 MHz for 13C NMR spectra in CDCl3
solutions. XPS measurements were performed with a spectrometer fitted
with an EA125 hemispherical analyser and a monochromatised Al KR
(1486.6 eV) source. X-Band EPR measurements were carried out at
77 K. The Cu/Al2O3 catalyst was prepared following our procedure re-
ported earlier.[8a]
Preparation of the amine complex in water: A mixture of the Cu/Al2O3
catalyst (100 mg, 5 mol%) and morpholine (174 mg, 2 mmol) in water
(4 mL) was heated at 1008C for 8 h. The mixture was cooled to room
temperature and the supernatant liquid was filtered off. The orange solid
residue was thoroughly washed with water (4 mL), ethyl acetate (3 mL)
and acetone (3 mL) and dried to get the intermediate B.
Representative experimental procedure for the coupling of 2-pyrrolidi-
none and iodobenzene to 1-phenylpyrrolidin-2-one (Table 3, entry 1): In
a 10 mL round bottom flask, a mixture of iodobenzene (204 mg, 1 mmol),
2-pyrrolidinone (102 mg, 1.2 mmol), K3PO4 (425 mg, 2 mmol), Cu/Al2O3
(100 mg, 5 mol%) and DMF (3 mL) was heated at 1108C for 12 h (TLC)
in an oil bath. The reaction mixture was then allowed to cool down and
was extracted with EtOAc (3ꢁ20 mL). The extract was washed with
water (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4)
and evaporated to leave the crude product, which was purified by
column chromatography over silica gel (hexane/ethyl acetate 80:20) to
provide the pure 1-phenylpyrrolidin-2-one as a white solid (148 mg,
92%). M.p. 68–698C; 1H NMR (CDCl3, 500 MHz): d=2.11–2.17 (m,
2H), 2.58–2.61 (m, 2H), 3.83–3.86 (m, 2H), 7.13 (t, J=7.0 Hz, 1H), 7.34–
7.37 (m, 2H), 7.59–7.61 ppm (m, 2H); 13C NMR (CDCl3, 125 MHz): d=
18.1, 32.8, 48.9, 120.0 (2C), 124.6, 128.9 (2C), 139.5, 174.3 ppm; IR
(KBr): n˜ =3059, 2916, 2898, 1680, 1171 cmꢀ1; HRMS: m/z calcd for
C10H12NO: 162.0193 [M+H]+; found: 162.0194.
Acknowledgements
We gratefully acknowledge financial support from CSIR, New Delhi
(Grant no. 01ACTHNUGRTNEUNG(2365)/2010/EMR-II)) and DST, New Delhi for the J. C.
Bose Fellowship to B.C.R. (Grant no. SR/S2/JCB-11/2008). D.K., S.B.
and N.M. thank CSIR, New Delhi for their fellowships. We sincerely
thank Dr. T. K. Paine for helpful discussions. We also thank Prof. P. Das-
tidar and his group for their help to get X-ray structures of a couple of
compounds.
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This procedure was followed for all the reactions listed in Table 3. Many
of these compounds are not reported earlier and these unknown com-
pounds were characterised properly by their spectroscopic and spectro-
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Representative experimental procedure for the coupling of 1-(4-bromo-
phenyl)pyrrolidin-2-one and morpholine to 1-(4-morpholinophenyl)pyr-
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Received: July 8, 2013
Published online: && &&, 0000
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CuII-Catalysed Solvent-Controlled Selective N-Arylation of Amides and Amines
FULL PAPER
Catalysis
D. Kundu, S. Bhadra, N. Mukherjee,
B. Sreedhar, B. C. Ranu* .... &&&& — &&&&
Heterogeneous CuII-Catalysed
Solvent-Controlled Selective N-Aryla-
tion of Cyclic Amides and Amines
with Bromo-iodoarenes
One over the other: A selective N-ar-
ACHTUNGTRENNUNGylation of cyclic amides and amines in
DMF and water, respectively, catalyzed
by CuII/Al2O3 has been achieved (see
scheme). This protocol has been
of arenes bearing cyclic amide and
amine moieties at two ends including
a few scaffolds of therapeutic impor-
tance. The mechanism has been estab-
lished based on detailed spectroscopic
studies (FG=functional group).
employed for the synthesis of a library
Chem. Eur. J. 2013, 00, 0 – 0
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