The first report on the transition metal-free homocoupling of aryl halides in the presence of l-cysteine

Article abstract of DOI:10.1039/c8nj01518j

A green and efficient methodology for the coupling of aryl halides without the addition of a transition metal catalyst has been presented. The biaryl coupling of haloarenes can be promoted by l-cysteine and potassium hydroxide. This is the first report on the synthesis of symmetrical biaryls under transition metal-free conditions.

Full text of DOI:10.1039/c8nj01518j

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DOI: 10.1039/C8NJ01518J
New Journal of Chemistry
COMMUNICATION
The First Report on the Transition Metal-Free Homocoupling of
Aryl Halides in the presence of L-Cysteine
Received 00th January 20xx,
Accepted 00th January 20xx
Arash Ghorbani-Choghamarani* and Zahra Taherinia
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract Green and efficient methodology for coupling of aryl electron transfer route (potassium hydroxide in dimethyl sulfoxide
halides without the addition of transition metal catalyst has plays crucial role in the initiation process under transition metal-
free conditions). It should be noted that although the desired
been presented. Biaryl coupling of haloarenes can be promoted
product was synthesized from the reaction of iodobenzene in the
by L-cysteine and potassium hydroxide. This is the first report on
presence of other amino acids, no desired product was formed for
synthesis of symmetrical biaryls under transition metal-free
another aryl halide using amino acids. When the reaction was
conditions.
conducted in the presence of other L-cystine derivatives, such as N-
acetyl-L-cysteine and L-cysteine hydrochloride the desired product
Introduction
was not obtained (Table 1, entries 6 and 8) but by adding an excess
Many methods for the synthesis of symmetrical biaryls are based amount of base, the observed product was symmetrical aryl sulfides
on transition metal (TM) catalyzed cross coupling reactions (Table 1, entries 7 and 9). As it has been reported in the literatures,
1 2
between an aryl halide (Ar -X) and an organometallic reagent (Ar -
the oxidative coupling of thiols to disulfide bonds usually occurred
at a basic pH and the presence of an oxidizing agent such as
oxidized glutathione increases the rate of oxidative folding, whereas
the presence of denaturants such as urea or guanidine
1
-5
M), including the well-known Ullmann coupling reaction. They
offer remarkable effectiveness along with several drawbacks, for
example the reactions were conducted using expensive transition
metals with ligands such as phosphine and nitrogen-containing
heterocyclic carbene (NHC), usually even more expensive and
22
hydrochloride (Gdn.HCl) hampers the folding process . Raymond
6
-9
sometimes difficult to prepare. Also, transition metals are toxic.
reported the preparation of aromatic, S-substituted derivatives of
2
3
Moreover, special additives and co-catalysts are used for N-acetyl-L-cysteine using copper (1) iodide in dimethylformamide.
performance enhancement and selectivity of these kinds of
The ability of cysteine residues to undergo redox reaction can be
observed in different oxidation states in living systems, for example
Papanyan reported that the oxidation of L-cysteine can occur by
1
0-15
transformations
. Thus, studies on new cross-coupling reactions
that do not require a metal catalyst are attracting increasing
attention. Transition metal-free is one of the most widely accepted
green transformations for the formation of biaryls that can be
carried out in the presence of various bases, organo-catalysts and
2
4
dimethyl sulfoxide; during this process two electrons are released
2
5
but hot acidified solutions yield mainly cysteic acid.
It is also
1
6-21
various energy sources.
Herein, we have reported the synthesis known, that in some reactions, DMSO can serve as an oxidizer by
26
of symmetrical biaryls in the presence of potassium hydroxide and giving its oxygen atom. Besides, the DMSO solvent is widely used
L-cysteine through a homolytic aromatic substitution mechanism
in biology and medicine for drug delivery and as a cryoprotective
(
defined as the replacement of a leaving group X on an aromatic
27
agent . Also, Yuan et al. showed that this combination of KOH and
ring by an attacking radical species).
With so many reports involving heterocycles in electron transfer,
DMSO would be a medium for reaction between aryl halides with
various sulfur, oxygen and nitrogen containing compounds under
our attention was focused on amino acids as additive electron
transfer. For this purpose, various amino acids were examined such
as arginine, cysteine, hydroxyproline, and lysine; among them L-
cysteine exhibited the highest catalytic reactivity (Table 1, entry 5).
Since the reaction proceeds through radical intermediates, it is
expected that elemental sulfur will be present in L-cystine as an
2
8
transition metal-free conditions. However, to the best of our
knowledge this is the first report on the homocoupling of aryl
halides under transition metal-free conditions. According to these
reports, a test reaction was then performed in dimethyl sulfoxide as
solvent with various amino acids and KOH, using iodobenzene at
o
1
00 C. Among the various amino acids screened, L-cysteine was
most effective in the DMSO solvent (Table 1, entry 5). The control
experiment confirmed that the reaction did not occur in the
absence of L-cysteine. The effect of various bases (e.g., KOH,
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COMMUNICATION
Na CO , K CO , KF, Et
New Journal of Chemistry
2
3
2
3
3
N and NaOEt) with DMSO was also
18
19
20
L-
Cysteine
DMSO
DMSO
100
100
80
0.8
0.8
0.8
0.8
0.8
0.4
0.4
0.4
0.4
0.4
Na
2
CO
3
N.R
N.R
48
investigated and it was observed that the desired product was only
obtained in the presence of KOH. The reaction when conducted at
L-
Cysteine
NaOEt
KOH
KOH
KOH
o
8
0 C, the observed yield was very low. The ideal temperature for
the reaction was found to be 100 °C. Finally, the amount of L-
cysteine was also screened, and 0.8 mmol of L-cysteine was found
to be optimal value. A lower yield was observed and a longer
reaction time was required when the amount of L-cysteine was
decreased (Table 2, entries 24-26). Increasing the amount of L-
cysteine could increase the yield of biphenyl.
L-
Cysteine
DMSO
2
1
2
L-
Cysteine
DMSO:H
2
O
100
100
45
(2: 0.5)
2
L-
Cysteine
DMSO:H
(2: 0.1)
2
O
88
a
23
-
DMSO
DMSO
100
100
-
0.4
0.4
KOH
KOH
N.R
20
Table 1. Optimization for the Synthesis of symmetrical biaryl
24
25
26
L-
Cysteine
0.2
L-
Cysteine
DMSO
DMSO
100
100
0.4
0.6
0.4
0.4
KOH
KOH
65
78
L-
Cysteine
Entry
1
Amino acid
Solvent
Temp.
ºC)
100
Amino
acid(mmol)
0.8
0.8
Base
(g)
0.4
Base
Yield
(%)
65
70
b
(
Phenylalanine
DMSO
KOH
2
3
4
5
Arginine
Lysine
DMSO
DMSO
DMSO
DMSO
DMSO
100
0.4
KOH
KOH
KOH
KOH
KOH
a
Reaction conditions: 1 mmol of aryl iodide, 0.8 mmol of amino acid, 0.4 g KOH and
solvent (2 mL). Isolated yield.
observed product was symmetrical aryl sulfides
b
C and d
by adding an excess amount of base, (0.8 g) the
100
100
100
100
0.8
0.8
0.8
0.8
0.4
0.4
0.4
0.4
45
55
Hydroxyproline
L-Cysteine
To test our hypothesis, the role of sulfur in the homocoupling of
aryl halides, a series of structurally different substituted aromatic
thiols, aliphatic thiols, amines and benzoic acid was studied under
the same conditions (Table 2). It was observed that apart from L-
cysteine, thioglycolic acid, thiosalicylic acid, 2- mercaptoethanol and
aminothiophenol were also active for the reaction, giving the
corresponding biphenyl. Table 2 indicates that the oxidation of the
thiol occurs much faster than the carbon-sulfur coupling, but in the
case of amine and acid no desired product was formed.
80
c
6
N-Acetyl-L-
cysteine
N.R
7
8
N-Acetyl-L-
cysteine
DMSO
DMSO
DMSO
DMF
100
100
100
0.8
0.4
0.8
0.8
0.4
0.8
KOH
KOH
KOH
N.R
N.R
N.R
L-Cysteine
hydrochloride
a
Table 2. The effect of thiol, amine and acid in the synthesis of biaryl.
d
9
L-Cysteine
hydrochloride
10
11
12
13
14
15
16
17
L-Cysteine
L-Cysteine
L-Cysteine
L-Cysteine
L-Cysteine
L-Cysteine
L-Cysteine
L-Cysteine
100
100
100
100
100
100
100
100
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
KOH
KOH
KOH
KOH
-
N.R
N.R
N.R
N.R
N.R
N.R
N.R
N.R
2
H O
PEG
Toluene
DMSO
DMSO
DMSO
DMSO
3
Et N
KF
2 3
K CO
2
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New Journal of Chemistry
COMMUNICATION
We investigated the reactions using a variety of aryl iodides or
bromides as substrates under the optimized reaction conditions
Entry
1
Thiol/
Amine/Acid
Solvent
Product
Yield
(%)
b
DMSO
70
b
Time
h)
Yield
(%)
Mp (°C)
68-70
Entry
1
Ar-X
product
(
10
88
2
3
4
5
6
DMSO
DMSO
DMSO
DMSO
DMSO
60
14
70
68-70
2
3
30
42
24
50
68
170-174
oil
SH
2
4
0
4
5
6
NH2
1
82
80
oil
oil
NH
2
NH
2
-
-
N.R
N.R
9
2
4
4
55
45
122–123
122–123
7
8
7
DMSO
-
N.R
2
1
3
78
70
144-148
125-128
9
a
Reaction conditions: 1 mmol of aryl iodide, 0.8 mmol of thiol, amine or acid,
b
0
.4 g of KOH and DMSO: H
2
O (2: 0.1). Isolated yield
20
min)
1
1
1
0
1
2
(
40
55
50
70
125-128
31-33
(
min)
24
10
64-68
Br
1
3
N
and the results are summarized in Table 3. As presented in Table
, the C-C coupling reactions of a variety of aryl halides with
3
electron-donating and withdrawing groups were also
investigated under optimized conditions (Table 3), providing the
corresponding homocoupling of aryl halides in excellent yields.
It was observed that aryl halides with electron withdrawing
groups show greater activities compared to those having
electron-donating groups. Furthermore, it was found that
aromatic nitro compounds were reduced during the oxidative
process. However, its mechanism and the role of elemental
sulfur have not been thoroughly understood but our earlier
study indicated that reducing systems containing sulfur are used
to reduce aryl nitro compounds to anilines.29 Aryl halides
carrying an ortho substituent were also found to readily
participate in the reaction. For example, the reactions of 2-
iodotoluene provided good yields of the desired biaryl product
(
Table 3, entries 2 and 4), although the effect of steric hindrance
on the reaction was observed, the reaction of 1-bromo-4-
chlorobenzene as a dihalogenated aryl halide was also subjected
to investigate the selectivity of the method; the bromide showed
more reactivity (Table 3, entry 9). This selectivity provides the
remaining active halide site for further functionalization. This
protocol was also applied successfully for heteroaryl halides
such as 2-bromothiophene and 3-bromopyridine and the
corresponding symmetric products were obtained in the good
yields (Table 3, entries 12 and 13).
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COMMUNICATION
New Journal of Chemistry
O
O
H2N
OH
DMSO:H O
S
S
H N
OH
SH
2
2
KOH
a
HO
O
Table 3. Homocoupling of aryl halides in the presence of L-cysteine.
+
NH2
a
2e
Reaction conditions: 1 mmol of aryl halide, 0.8 mmol of L-cysteine, 0.4g of KOH,
o
b
2
temperature:100 C, 2 mL of DMSO: H O (2: 0.1). Isolated yield
electron transfer
F
At the moment, detailed mechanistic studies of the direct coupling
reaction of aryl halides in DMSO are unclear; and the proposed
routes are shown in Scheme 1.
-e
.-
Ar
Ar-X
It appears that the oxidation of L-cysteine thiol groups is a
dominant process and the formation is usually favored at a basic
E
KOH
.-
3
0
(
Ar-X)
pH 8 also β-elimination usually favored at a basic pH 10.6 (Scheme
31
.
Ar
2
), thus the second route does not occur. It is suggested that the
A
oxidation of L-cysteine in dimethyl sulfoxide is accompanied by
electron releasing. Consequently, the produced electrons at this
stage act as an efficient promoter for the next step. The electron
D
-
X
X
•
−
transferred to aryl halides affords an aryl radical anion (Ar–X) . This
•
−
subsequently fragments to an aryl radical Ar and the halide X . The
aryl radical is added to the aryl halide to give an aryl radical anion
•
−
X
.
(
Ar–X) , which is followed by the elimination of X to generate a
.-
Ar
Ar
radical intermediate, deprotonated with potassium hydroxide
followed by aromatization, thereby generating the biphenyl
product.
B
C
Ar-X
CONCLUSIONS
Scheme 1. Proposed mechanism for the synthesis of biaryls
In summary, this study has revealed a new efficient methodology
for the homocoupling of aryl halides with potassium hydroxide and
L-cysteine under transition metal-free conditions, which proceeds
through aryl radical intermediates.
O
O
H N
OH
SH
-
2
DMSO
KOH
KHN
OK
SK
In order to demonstrate Biaryl coupling of haloarenes can be
promoted by L-cysteine and potassium hydroxide under
transition metal-free, ICP analysis of the reaction components
O
KHN
OK + K2S
O
H
(including the solvent) carried out to determine the presence of
O
Pd, Cu, Ni, Co and results only show the presence of potassium.
KHN
HO
OK
KHN
OK
+
KOH
s
x
K2S
+
Scheme 2. Proposed mechanism for the synthesis of symmetrical aryl sulfide
AUTHOR INFORMATION
Corresponding Author
Arash Ghorbani-Choghamarani, Department of Chemistry, Ilam
University, P.O. Box 69315516, Ilam, Iran; Tel/Fax: +98 841
2
227022;
E-mail
address:
arashghch58@yahoo.comor
a.ghorbani@ilam.ac.ir
ACKNOWLEDGMENT
The authors would like to thank the research facilities of Ilam
University, Ilam, Iran, for the financial support of this research
project.
References
4
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