A facile and practical copper diacetate mediated, ligand free C-N cross coupling of trivalent organobismuth compounds with amines and N-heteroarenes

Article abstract of DOI:10.1039/c6ra00395h

In present work, an efficient Cu(OAc)₂·H₂O catalyzed protocol in the absence of any additional ligand has been developed for the N-arylation of amines and nitrogen containing heterocycles using trivalent organobismuth reagents under mild conditions. This protocol tolerates a variety of functional groups on amines and the organobismuth reagent with a high degree of chemoselectivity.

Full text of DOI:10.1039/c6ra00395h

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A facile and practical copper diacetate mediated, ligand free C-N cross
coupling of trivalent organobismuth compounds with amines and
N-Heteroarenes
B. D. Jadhav and S.K. Pardeshi*
Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune),
Ganeshkhind, Pune-411007(INDIA)
*
Corresponding author. Tel.:+91 020 25601225 Extn. 514; Fax: +91 020 25691728
E-mail: skpar@chem.unipune.ac.in (S.K.Pardeshi)
Abstract
In present work, efficient Cu (OAc) .H Ocatalyzed protocol in absence of any additional
2
2
ligand has been developed for the N-arylation of amines and nitrogen containing heterocycles
using trivalent organobismuth reagents under mild conditions. This protocol tolerates variety of
functional groups on amines and the organobismuth reagent with high degree of
chemoselectivity.
Key words:
Organobismuth, N-Arylation, heterocycles, chemoselectivity
1

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Introduction
The N-aryl nitrogen heterocycles such as arylpyrroles, arylpyrazoles, arylimidazoles,
aryltriazoles, arylindoles, arylcarbazoles, diarylamines etc. are unique building blocks in
1
bioactive natural products and pharmaceutically interesting compounds. As a more efficient
and facile method for N-arylation, the transition-metal-catalyzed coupling of aryl halides and
2
amines is powerful method in both academic and industrial laboratories. However, current
methods have some potential limitations because these reactions are environmental unfriendly as
they require stoichiometric amounts of copper or copper salts, which produce significant
amounts of wastes, high reaction temperatures and also uses expensive transition-metal catalysts
3
4
5
6
such as palladium and rhodium . There are few reports where low cost nickel and cobalt
complexes were used as catalyst but their selectivity was not good. Thus screening inexpensive
and environmental benign metal catalysts for the arylation reaction still remains a great
challenge. In recent years, Buchwald and Hartwig initiated the use of inexpensive copper
catalysts bearing various ligands that have provided a highly economical and efficient method
7
for the N-arylation of nitrogen-containing heterocycles with aryl halides. The ligands employed
8
9
10
in the Cu-catalyzed reactions includes beta-diketones , 1, 2-diamines , phenanthrolines ,
1
1
12
13
14
bipyridines , amino acids , phosphines and others. These chelating ligands play an
important role in controlling the concentration of active catalytic species, but they may
1
5
contaminate the final products. Therefore use of ligand-free catalysts seems to be a good
alternative to avoid the inconvenience of ligand removal from reaction mixtures.
It is noted that simple inorganic copper (II) salts without extra ligands for catalyzing such
1
8
coupling reactions is of limited scope. There are few reports on the amination of aryl halides
with amines promoted by copper (II) salts without using organic ligands, they often required
18a, b
18c
large amounts of Cu (OAc) 2
or copper oxide nanoparticles , which raised the cost of the
reaction. Choudary and coworkers reported an efficient catalytic N-arylation reaction using the
1
8d
copper (II) apatite as the catalyst but require high catalyst loading. To this end, the
development of a simple, easily available, economical copper catalyst with a low catalyst loading
in the absence of any additional ligands for such coupling reactions would be highly demanding.
1
9
As a carbon source, we focused on the low toxic organobismuth compounds for use in
copper-mediated C-N bond formation with amines and imides. N- phenylation of aliphatic and
aromatic amines by Ph Bi under copper salt catalysis giving moderate yield of mono or
3
2

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2
0
diphenylated amines under mild conditions was reported by Barton et a1. Good yields of mono
and diphenylated derivatives was achieved in presence of metallic copper at room temperature
2
1
but substrate scope is limited. In another study Finet et al. used triphenylbismuth diacetate as
aryl source which reacts with various N-H containing heteroarenes in the presence of a catalytic
amount of copper diacetate to afford moderate yields of the N-phenyl heteroarenes. Indoles are
2
2
C or N-phenylated by triphenylbismuth bis-trifluoroacetate under copper catalyst. Combes and
3
2
3
Finet reported reaction of triarylbismuthanes with iodobenzene diacetate in DCM under mild,
neutral conditions to afford triarylbismuth diacetates, which can be isolated in good yields. The
reagents can also be directly used in a one-pot copper catalyzed N-arylatlon of anilines to give
near quantitative yields of the corresponding diarylamines. Various hydrazine derivatives were
studied with respect to arylation by triarylbismuthane and triarylbismuth diacetate reagents with
24
emphasis on scope and limitations by Tsubrik et al. Among these reagents, a few contained
bulky substituents in their aromatic rings and substrates spanned a range from simple hydrazides
to triply protected hydrazines. Organobismuth derivatives of pyrocatechol fragment for arylation
2
5
of piperazines using copper acetate as catalyst in DCM was reported by Vassileva et al. which
was used to synthesize Eltoptazine [l-(2,3-dihydro- 1,4-benzodioxine-5-yl)-piperazine] a
potential anxiolytic and antidepressant drug. Recently copper-catalyzed coupling reaction
between alkynyl (triaryl) bismuthonium salts and five-membered imides was reported by Sueda
2
6
et al. which was utilized to synthesize 4-Amino-1, 2, 3-triazole. In above cases they combined
the corresponding trivalent and in few cases pentavalent organobismuth compounds with a
27
stoichiometric amount of copper salt. Recently Petiot et al. used copper catalyzed N-arylation
of azoles and diazoles using functionalized organobismuth (III) reagents. In addition they
extended this protocol to N-arylate protected tryptophan derivatives promoted by a
substoichiometric amount of copper acetate.
In this paper, we report a simple reagent system consisting of the easily accessible
organonobismuth (III) reagents and copper diacetate which catalyzes the N-arylation of various
amines and N-heteroarenes in absence of any ligand. Optimization of reaction parameters such as
amount of catalyst, role of bases, role of solvents, role of oxygen and mole ratio of
organobismuth (III) reagents is also studied.
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Results and discussion
Usually pentavalent organobismuth species are prepared from their corresponding
trivalent analogues, our main goals is to develop conditions that would operate directly with
trivalent organobismuthanes. Another objective is to develop a protocol that would allow the use
of substoichiometric amounts of catalyst and tolerate a wide diversity of functional groups on
both coupling partners. With these goals in mind we initiated our investigation by examining the
conditions under which coupling reaction of imidazole and triphenyl bismuthine proceed
efficiently (Scheme 1).
N
Ph Bi (mmol)
3
N
N
Cu catalyst (mmol)
NH
Cs CO ( mmol)
2
3
THF, atmosphere
temp.°C,12h
(1l)
(3l)
Scheme 1 Optimization of reaction conditions for the N-phenylation of imidazole 1with
triphenylbismuthine
Screening of catalyst
Copper salts appear to be the most effective in coupling with poorly nucleophilic nitrogen
sources such as amides and imides In determining the effect of the copper salt for C-N cross
.
coupling, both copper (I) and copper (II) salts were tested with imidazole (1.2mmol) and
triphenyl bismuthine (1.0 mmol) as model substrates (Scheme1). Results from screening
experiment are summarized in Table 1.
4

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Table 1 Influence of various copper salts on N-arylation of imidazole with
a
triphenyl bismuthine in THF at 80°C
b
Entry
Cu salt
1.5 mmol)
Reaction time
(h)
Yield
(
(%)
Trace
55
1
2
3
4
5
6
7
8
CuSO4
Cu powder
Cu (OAc) 2
CuI
12 h
12 h
12 h
85
12 h
45
CuBr
12 h
35
CuCl
12 h
25
CuO
12 h
15
--
12 h
None
a
Reaction conditions: Triphenyl bismuthine (1 mmol), imidazole (1.2 mmol),
Cs CO (2 mmol)
Isolated yields
2
3
b
Among the tested copper salts, Cu (OAc) was found to be the best catalyst, which
2
afforded 85% yield of 1-phenyl imidazole(3l) in presence of Cs CO as base for 12 h at 80°C
2
3
(Table 1, entry 3 ). Cu powder and CuI giving 3l in moderate yields (Table 1, entry 2 and 4), but
Cu powder catalyst require acetic acid as non aqueous reaction medium. In case of CuSO and
4
CuO, poor yield of 3l was obtained (Table 1, entry 1 and 7). CuBr, and CuCl catalyst are more
efficient than CuSO and CuO produced 35 % and 25 % yields of 3l (Table 1, entry 5 and 6). It is
4
interesting to note that in CuBr catalysis cleavage of CAr-Bi bonds resulted in self coupling of
triphenyl bismuthine giving isolated biphenyl in 45% yield along with 35% yield of N-phenyl
imidazole using column chromatographic separation. Since CuBr and CuCl are more expensive
and oxidizes very readily, so their use in C-N cross coupling is avoided. Hence the most
efficient, inexpensive, and air-stable Cu (OAc) was selected as the catalyst for all further
2
reactions. It has been found that 1.5mmol copper acetate catalyst under optimized reaction
conditions provide excellent yields. Controlled experiment conducted in the absence of catalyst
indicate no desired C-N cross coupled product (Table 1, entry 8) the only detected and separated
products were unreacted starting material and small amount of biphenyl formed due to self
5

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coupling of organobismuthine ,which is known reactivity of organobismuthine under metal
catalysis.
Screening of bases
The efficiency of arylation with the Ar Bi / Cu (OAc) system is highly dependent on
3
2
2
0
basicity of amine as shown by Barton . To select the appropriate base for N-arylation reaction,
we carried out (Scheme1) in presence of various bases under optimized reaction conditions. The
results are summarized in Table 2.
Table 2 Effect of different bases on N-arylation of imidazole with triphenyl bismuthine in
a
THF , at 80°C
b
Entry
Base
Reaction time
h)
Yield
(
(%)
1
2
KOH
12h
12h
12h
12h
12h
12h
12h
12h
12h
68
K CO
2
75
3
3
K PO
3
25
4
4
CsF
20
5
Cs CO
85
2
3
6
NaOH
KF
35
7
45
8
TEA
--
65
9
No reaction
a
Reaction conditions: catalyst (1.5mmol), Triphenyl bismuthine (1 mmol),
Imidazole (1.2 mmol), Base (2 mmol),
b
Isolated yields
The study shows that, the reaction proceeds smoothly in presence of Cs CO which gives
2
3
8
5% yield of N-phenyl imidazole (Table 2, entry 5). Other bases namely K PO , CsF and NaOH
3 4
afforded low yields of 3l (Table 2, entries 3, 4, 6). KOH and K CO are other better choices in C-
2
3
N cross coupling which gives excellent yields (Table 2, entries 1 and 2). In case of TEA,
6

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moderate yield of C-N cross coupled product was obtained (Table 2, entry 8).The coupling
reaction does not proceed in the absence of base (Table 2, entry 9).
Screening of Solvents
It is well known fact that the choice of solvent significantly influences the C-N cross
coupling reaction. To study the effect of different solvents in our system, we performed
(
Scheme1) using Cs CO as base and Cu (OAc) as catalyst. Typical solvent effects are
2 3 2
summarized in Table 3.
a
Table 3 Influence of solvent in N-arylation of imidazole with triphenyl bismuthine
b
Entry
Solvent
T (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
DMF
120
120
120
80
40
35
55
10
65
85
45
60
70
0
DMSO
C H CH
3
c
c
6
5
MeCN
DCM
THF
80
80
THF
50
THF
60
THF
70
1
0
1
H O
2
100
80
1
MeOH
0
a
Reaction conditions: Catalyst (1.5 mmol), Triphenyl bismuthine (1 mmol),
Imidazole (1.2 mmol), Cs CO (2 mmol), 12 h
2
3
b
c
Isolated yields
Catalyst loading (2 mmol)
As seen from Table 3, the reaction proceeds in both non-polar and polar solvent with
significant variation in yield. C H CH and DCM which are non polar solvents favored the
6
5
3
formation of 3l and gives moderate yield (Table 3, entry3 and 5) but require high catalyst loading
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(
2mmol).THF gave the best results with Cs CO as base at 80°C (Table 3, entry 6) with 0.5mmol
2 3
copper catalyst. In case of MeCN, very poor yield of N-phenyl imidazole(3l) was obtained at
0°C (Table 3, entry 4).With increase in polarity of solvents, the cleavage of the CAr-Bi bond
8
was found to be enhanced, and in DMF (Table 3, entry 1) the predominant product was the homo
coupled biphenyl along with 3l .When reactions were conducted with optimal solvent, THF at
70°C, 60°C and 50°Cdecrease in yield of N-phenyl imidazole was noticed (Table 3, entries 7, 8
and 9). In H O and MeOH under reflux (Table 3, entry10 and 11), no C-N cross coupling was
2
observed instead white suspension got accumulated on the inner walls of the reaction flask
suggesting the decomposition of triphenyl bismuthine to bismuth hydroxide.
It is worth mentioning that, the reaction temperature, 110-130 °C which was proved to be
necessary for other Cu-catalyzed N-arylations of amines and N-heterocycles with aryl halides,
our catalytic system reduce reaction temperature to 80°C.
Effect of Oxygen, Air and inert atmosphere
An inert atmosphere was not essential requirement during the reaction, but protection
from atmospheric moisture is needed. Beneficial effect of oxygen on O-arylation of phenols
2
8
using trivalent organobismuthanes was investigated by Crifar et al. To check the effect of
oxygen on N-arylation, we tested the model reaction (Scheme1) under different reaction
atmosphere. Results from the reaction atmosphere are presented in Table 4.
8

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Table 4 Effect of oxygen, air and N atmosphere on the N-phenylation of imidazole 1
2
a
using triphenyl bismuthine at 80°C
b
Entry Ph Bi
Cu (OAc) 2
(mmol)
Atm.
Yield
(%)
3
(mmol)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
0.7
0.33
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.0
1.5
0.5
0.1
Air
O2
90
85
70
81
50
70
N2
Air
Air
Air
Air
Air
Air
c
65
55
30
a
Reaction conditions: Triphenyl bismuthine, imidazole (1.2 mmol),Cs CO (2 mmol)
2
3
in 5mLTHF
b
c
Isolated yields
Reaction was conducted in 50 mL flask
On reacting 1.0 mmol of triphenylbismuth with imidazole (1l) in the presence of 1.5
mmol of copper acetate and 2.0 mmol of Cs CO under air atmosphere, we obtained 3l in 90 %
2
3
yield (Table 4, entry 1). When the reaction was carried out under same stoichiometric ratio but in
the pure O atmosphere, 85% yield was noticed (Table 4, entry 2). To validate the importance of
2
oxygen, we performed the reaction under nitrogen atmosphere and noticed a drop in the yield of
3
l (Table 4, entry 3) thereby suggesting the role of air/O during catalytic cycle under Cu-acetate.
2
In addition when the reaction was carried out in a two neck round bottom flask of 50 mL
capacity wherein more space existed due to which the yield was depressed, thus reflecting effect
of molecular oxygen on reaction (Table 4, entry 7).The detail explanation is given in discussion
part of mechanism. When 0.5mmol of copper acetate was used, it has been found that the yield
9

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was further decreased up to 55 % (Table 4, entry 8). However, further reduction in the catalyst
loading was not tolerated where merely 30% yield of desired product was obtained (Table 4,
entry 9).
To evaluate the transferability of second aryl group from the triphenylbismuthane ,we
performed the reaction using 0.7 mmol and observed a significant drop in yield of N-phenyl
imidazole(Table 4 , entry 4).This clearly indicates only one aryl group can be transferred from
triarylbismuthane. Further reduction in mole ratio of triphenylbismuthine (0.33mmol) delivers
only 50 % yield of product (Table 4, entry 5) which also supports above observation. This
2
7,28
phenomenon is well known in copper catalysis involving organobismuth reagents.
From
above results it has been concluded that, the yield of N-phenylated product was dependent upon
the amount of Cu (OAc)2.
Hence the optimum conditions for cross-coupling reactions in THF consist of the
combination of Cu (OAc) (1.5mmol) and Cs CO (2.0 mmol) at 80°C for 12 h without
2
2
3
protection of air. The reactions were monitored by TLC as well as by the color change from the
initial deep blue to turquoise green, with the simultaneous precipitation of grayish Cu (I) salt.
After optimizing the reaction conditions, the reaction scope was extended with
electronically different anilines and triphenyl bismuthine (Scheme 2).
NH2
NH
Bi
R
+
Conditionsa
R
1
3a-n
2
a
Scheme 2: N-Arylation of Amines (1a-f), Amides (1g-h), Sulphonamine (1k), Imidazole (1l)
and Indole (1m) using triphenylbismuthane (2a)
We chose several nitrogenated compounds possessing various functional groups for our
study. Typical results are summarized in Table 5.
1
0

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a
Table 5 N-Arylation of amines with triphenyl bismuthine
b
Entry
1
Amine R (1)
(1a)
N-arylated product (3)
Yield (%)
H
3a
78
70
65
65
88
86
45
32
2
3
4
5
6
7
8
p-Br (1b)
p-Cl (1c)
3b
3c
3d
3e
3f
p-NO2 (1d)
p-OCH (1e)
3
p-CH3 (1f)
C H CO (1g)
6
5
3g
3h
CH CO (1h)
3
9
N
H
3i
--
(
1i)
Ph
Ph
N
H
1
0
1
3j
--
(1j)
O
S
1
3k
40
O
(1k)
N
N H
1
2
3l
80
75
(
1l)
c
13
(1l)
3m
14
N
3n
75
H
(1m)
a
Conditions: Amine (1.0 mmol), Ph Bi (1.2 mmol), Cu (OAc)
3
2
(
1.5mmol), Cs CO (2.0mmol), THF (5 mL), 80°C, 12h
2 3
b
c
Isolated yields.
Reaction was carried out by p-tolylbismuthine(2d).
1
1

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As illustrated in Table 5, aniline was monoarylated successfully using triphenyl
bismuthine (Table 5, entry1). Aromatic amines bearing either electron donating groups (Table 5,
Entry 6) or electron withdrawing groups (Table 5, entries 4 and 5) gave corresponding
unsymmetrical diarylamines in good yield. Notably, halo substituent on the aryl amine remained
unaffected under these reaction conditions. Thus, reaction of p-bromoanilline with triphenyl
bismuthine gives desired secondary amine in good yield (Table 5, entry 2). Imidazole and Indole
was cross-coupled with triphenyl bismuthine affording excellent yields of corresponding N-
phenyl derivatives (Table 5, entries 12 and 14). Imidazole on coupling with p-tolylbismuthine
provides 75% yield of 1-p-tolyl-1H-imidazole thereby suggesting the effect of methyl
c
substituent on cross coupling yield (Table 5, entry13 ).
The few reported methods to arylate amides and imides using the organobismuth
alone, or in the presence of copper, either failed completely or gave very unsatisfactory yields.
Almost all of these reactions require the use of high temperatures, very basic conditions, and
long reaction time. For amide substrates such as benzamide and acetamide the N-phenyaltion
under present reaction conditions produces low yields (45 % and 32%) of N-Arylated products
(Table 5, entries 7 and 8). p-toluenesulfonamide afforded the corresponding N-arylated product
in 40% yield (Table 5, entry11). Attempts with both aliphatic and aromatic secondary amines
(Table 5, entries 9 and 10) were unsuccessful.
The catalytic activity of this protocol under optimized condition was evaluated with
electronically different substituted bismuthines and pthalimide as per Scheme 3.
R
O
N H
O
Conditionsa
Bi
+
N
R
R
O
R
O
4
2
a-g
5a-g
Scheme 3: Steric and electronic effects of functionalized organobismuthanes (2a-g) on the N-
arylation of 4
The results are summarized in Table 5.
1
2

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a
Table 6 The N-arylation of pthalimide (4) with functionalized organobismuthanes
b
Entry
Triaryl bismuthane (2)
N-arylated product (5) Yield (%)
R
1
2
3
4
5
6
7
H
(2a)
(2b)
(2c)
(2d)
5a
5b
5c
5d
5e
5f
93
65
70
87
95
65
45
o-Me
m-Me
p-Me
p-OMe (2e)
p-Br
p-Cl
(2f)
(2g)
5g
a
Conditions: Pthalimide (1.0 mmol), Ar Bi (1.2 mmol), Cu (OAc) (1.5mmol),
3
2
Cs CO (2.0mmol), THF (5 mL), 80°C, 12h
Isolated yields.
2
3
b
It has been observed from Table 6 that, in copper-catalyzed reactions, the steric hindrance
of the organobismuth reagent plays a significant role, probably at the stage of the
transmetallation from bismuth to copper. When this transfer is very easy (by coordination of the
copper species with an amine), the steric effect induces less important consequences. Most of
bismuthines allows the arylation of the pthalimide heterocycle under mild and normal practical
conditions with good yields. The reaction activities of bromo and chloro bismuthines are
however less (Table 6, entry 6 and 7), when substituted with electron withdrawing group,
particularly methoxy, reacts well with pthalimide giving 95% yield of 5e (Table 6, entry 5).
Electron donating group at para- position favour the formation of cross coupled product over
ortho and meta substitution (Table 6, entries 2, 3 and 4) affording excellent yields. In the case of
ortho-tolylbismuthine, the influence of sterically hindered methyl substituent on aryl group gives
diacetate during reaction course which was clearly seen by its moderate yield (Table 6, entry 2).
1
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It is important to note that, present protocol tolerate thermally sensitive functional groups
in the substrate along with high levels of chemo selectivity, avoiding the occurrence of other
competitive coupling reactions such as O-arylation and aryl amidation.
Possible Mechanism of N-Phenylation
The mechanism of the present N-arylation reaction with triarylbismuthane is not clear at
present. We consider similar mechanisms for the N-arylation with pentavalent bismuth
2
0
compounds proposed by Barton et al. , reaction with arylboronic acids proposed by Collman et
29a,b
30
al
and the S-arylation with arylsilanes as proposed by Luo et al. , which may be relevant to
the N-arylation demonstrated here. Possible mechanism of the reaction between
triarylbismuthanes and amine in the formation of diaryl amines is depicted in Scheme 4.
I
Cu OAc ,nRNH
2
c
Ph Bi(OAc)
c
3
2
d
mRNH2 + Cu(OAc)2
I
Ph Bi
b
III
3
II
CuIII
Ph
X
I
Cu(OAc) , mRNH2
Cu X
OAc
2
e
a
IV
mRNH2
RNH-Ph
f
Scheme 4: Possible Mechanism of N-Phenylation of amine
In the step I catalyst activation takes place in the presence of aromatic amine and
generates copper diacetate amine complex (a).This complex in step II undergoes oxidative
I
addition with trivalent organobismuth reagent Ar Bi (b) which leads to the formation of Cu
3
complex(c) and pentavalent organobismuth diacetate Ar Bi(OAc) (d) as key intermediate. In
3
2
Step III ligand coupling takes place between (c) and (d) where phenyl copper (III) species (e) get
I
formed. This Species in step IV phenylate amine to afford N-arylated product (f) and Cu X and
catalytic cycle was continued.
1
4

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Oxygen is a highly atom-economical, environmentally benign, and abundant oxidant,
3
1
which makes it ideal in many ways. The chemistry of copper in combination with molecular
oxygen, increases exponentially since oxygen can act as either a sink for electrons (oxidase
activity) or a source of oxygen atoms that are incorporated into the product (oxygenase activity)
3
2
or both . The oxidation of copper with oxygen is a facile process allowing catalytic turnover in
III
net oxidative processes and ready access to the higher Cu oxidation state, which facilitates a
I
variety of transformations including two-electron reductive elimination to Cu . Molecular oxygen
does not generate toxic byproducts, which get either reduced to water, occasionally via H O or
2
2
get incorporated into the target structure. Such oxidations using oxygen or air (21% oxygen)
have been employed safely in numerous commodity chemical continuous and batch processes.
As discussed previously an inert atmosphere was not essential, when the reaction was
3
2
carried out in the pure O atmosphere or in a two neck round bottom flask of 50 mL capacity,
2
lower yields of desired product was noticed (Table 4, entries 2and 7).These results hints that
molecular oxygen plays a critical role in a copper catalyzed reaction and suggest the catalytically
active species to be Cu (I), which was formed in situ by oxidizing triarylbismuthine with O from
2
air during the reaction. The formation of Cu (I) species was supported by the observation of
characteristic pale green colour of solution. A sequential color changes observed during the N-
arylation reaction indicate that the oxidation of organobismuth (III) compound with subsequent
Cu (II) to Cu (I) should be a complex process. The presence of a suitable amount of air in the
round bottom flask is crucial to the formation of Bi (V) intermediate. An excess amount of air (or
oxygen) is unfavorable to the reaction since the Cu (I) species was further oxidized to less active
Cu (II) species, as evidenced by the distinctive blue colored copper amine complex.
It is important to note here that ,we were able to isolate in situ formed intermediate
1
(
d) under our reaction condition and characterized it as Ar Bi (OAc) by HNMR and IR
3
2
spectroscopy. This signifies the conversion of +3 oxidation state of bismuth to +5 state under
copper catalyst in inert solvent. As byproduct during catalytic cycle were presumably H O and
2
2
CH COOH which exerts oxidizing action and get enhanced in the presence of added inorganic
3
bases. This might be the reason for in situ oxidation triphenylbismuthine to Ar Bi (OAc) .
3
2
There are reports where tris (2-methoxyphenyl) bismuth is oxidized to the corresponding
33
diacetate in relatively good yields by iodobenzene diacetate under neutral conditions, Oxidation
3
4
of the trivalent bismuth compound was done by reaction with sodium perborate in acetic acid,
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DOI: 10.1039/C6RA00395H
which led to the diacetate in 63% yield. On the other hand copper diacetate increases the rate of
3
5
decomposition of triarylbismuth diacetate.
It is interesting to note that, addition of catalytic amount of copper to intermediate (d)
allows high yield and selective phenylation of pthalimide thereby suggesting the role of copper
catalyst in N-phenylation. Attempts to isolate bismuth containing byproducts were unsuccessful
due to their labile nature but small amount of biaryl were detected together with N-arylated
product due to reactivity of triarylbismuthines.The presence of aryl radical species in the course
of N-arylation reaction with triarylbismuthane and in situ generated pentavalent
organobismuthane [Ar Bi (OAc) ] was over ruled which is in agreement with the Barton’s
3
2
procedure.
In N-Arylation of a different group of N-H containing compounds with triarylbismuth
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6
and cupric acetate, tertiary amine such as triethylamine or pyridine act as promoter. They play
important role in increasing the solubility of the substrate thereby allowing the reaction to
proceed at low temperature and in good yields. We are employing Cs CO as optimized base in
2
3
presence of air atmosphere it also shows enhancement in the solubility of substrate thereby
follows similar function as promoter. A base promoter has a remarkable effect in these arylation
reactions where product formation in its absence in the case of imidazole is indicative (Table 2,
entry 9) and thereby significantly improves the yield in the phenylation of 4-nitroaniline.
In the present study, key mechanistic features of N-arylation reaction were elucidated
such as the identity of the catalyst inactive state and isolation of intermediate. In addition
principles that motivate the ability of copper that tends to undergo one-electron redox changes, to
mediate a two-electron oxidative coupling reaction with a four-electron oxidant (O ) was
2
identified.
Conclusions
We have successfully developed a highly efficient, simple, low temperature and easily
accessible protocol to N-arylate nitrogenated compounds like amines, amides, sulfonamides and
imides with organobismuth (III) compounds. The present coupling reaction gave moderate to
excellent yields of N-substituted pthalimide in comparison with earlier reports. Methodology
may be prominently suitable for synthesis of biologically active N-aryl heterocycles under
copper diacetate catalysis.
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Experimental
General
All reactions and manipulations were conducted under an air atmosphere. Organobismuth
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7a, b
(
III) compounds (2a-g) were synthesized by literature procedures.
Copper acetate and
heteroarenes were purchased from commercial sources and used without further purification.
Solvents were distilled before use. IR spectra were recorded on a Shimadzu 8400 FT-IR
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13
spectrometer. H NMR and C NMR spectra were measured on a Varian-300MHz spectrometer
with CDCl as the solvent and tetra methyl silane (TMS) as the internal standard. GCMS data
3
were collected on a Shimadzu Gas chromatograph mass spectrometer QP5050. The reactions
were monitored by TLC, and visualized with UV light followed by development in iodine
chamber.Preparative column chromatography was carried out on a column 10cm x l.5cm with
silica gel 60/120 mesh size. GCMS /CHNS analysis of few representative compounds is
provided in characterization section.
General catalytic procedure for the N-arylation of nitrogen containing heterocycles with
Organobismuth (III) reagents
To a solution of Cu (OAc) .H O (1.5 mmol) in THF (5 mL) were added organobismuth
2
2
(
(
III) compound (1.2 mmol), amine or nitrogen-containing heterocycle (1.0 mmol), and Cs CO3
2
2.0 mmol) under air atmosphere. The mixture was stirred at 80°C for 12 h. After cooling to
ambient temperature, the mixture was partitioned between water and ethyl acetate. The organic
layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na SO , and concentrated in vacuum. The
2
4
residue was purified by column chromatography on silica gel.
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Acknowledgments
B.D.J is grateful to the University Grant Commission, New Delhi for awarding Teacher
Fellowship under F.I.P. during the XI plan.
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Graphical Abstract
A facile and practical copper diacetate mediated, ligand free C-N cross
coupling of trivalent organobismuth compounds with amines and
N-Heteroarenes
B. D. Jadhav and S.K. Pardeshi*
Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune),
Ganeshkhind, Pune-411007(INDIA)
*
Corresponding author. Tel.:+91 020 25601225 Extn. 514; Fax: +91 020 25691728
E-mail: skpar@chem.unipune.ac.in (S.K.Pardeshi)
1