Ascorbate mediated copper catalyzed reductive cross-coupling of disulfides with aryl iodides

Article abstract of DOI:10.1039/c002725a

The concept of using ascorbic acid as a mediator/ reducing agent in a Cu(i) catalyzed process is introduced and further demonstrated on a cross-coupling reaction of aryl iodides with disulfides.

Full text of DOI:10.1039/c002725a

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Ascorbate mediated copper catalyzed reductive cross–coupling
of disulfides with aryl iodidesw
Marek Martinek, Michal Korf and Jiri Srogl*
Received 8th February 2010, Accepted 13th April 2010
First published as an Advance Article on the web 12th May 2010
DOI: 10.1039/c002725a
The concept of using ascorbic acid as a mediator/ reducing
agent in a Cu(I) catalyzed process is introduced and further
demonstrated on a cross–coupling reaction of aryl iodides with
disulfides.
temperatures together with a stoichiometric amount of highly
reactive metals in the latter case rendered the method rather
harsh and consequently unfit for a variety of functional
groups.
Addressing those issues while seeking a mild replacement
for the reducing agents traditionally used in reductive coupling
protocols, we proposed ascorbic acid or its salts to be viable
substitutes for its general availability and chemical tolerance.
The reducing ability of ascorbic acid, particularly when
coupled with the Cu catalyst is well known.8 Equally well
documented is the involvement of Cu complexes in coupling
chemistry of arylhalides and thiols.6b–d,9 Linking both of the
reactivity patterns, we have followed on the proposal and
centered our investigation on the development of a new mild,
synthetically useful protocol.
One of the foremost examples of modern synthetic method is
the chemistry that helps connect two often highly functionalized
entities, while forming a new bond between two atoms of
respective subunits in the process. The presence of a transition
metal, which facilitates chemistry through consequent oxidative
addition/reductive elimination steps, is often required.1 In this
scenario, the reaction partners must possess respective,
formally electrophilic and nucleophilic properties in order to
keep the catalyst in the reduced form and thus maintain its
activity. Although far less used, the opposite circumstances, in
which both of the coupling partners show the electrophilic
attributes, have been recently the center of intensive research.2
Setting aside the selectivity issues ensuing inevitably from the
presence of two moieties belonging to the same reactivity
bracket, the rising challenge in such a reductive cross–coupling
to keep the catalyst in an active reduced form has been met by
employing a variety of reducing reagents. Unlike a working
line of oxidants used in organic synthesis, which is virtually
limitless, the selection of reducing agents is, despite great
progress in the last few decades, somehow narrow.3 Complex
hydrides of aluminium, boron, tin and silicon commonly
added to supplement a variety of traditional reducing agents,
alkali metals, Mg, Zn, Mn etc. cannot fully remedy the
situation due to their high reactivity and toxicity, accompanied
by, in some cases, rather prohibitive cost.
In order to map the reactivity of disulfides with aryl iodides
in the presence of copper, disulfide 1 was treated with aryl
iodide 2 and an equimolar amount of Cu(I)3-methylsalicilate.
The experiment resulted in an exclusive formation of
cross–coupling product 3h in high yield. (Scheme 1) When
disulfide was omitted from the reaction mixture in the control
experiment, Ullmann homocoupling product 4 was formed
quantitatively, fully in accordance with the published
account.10
Validating the concept by reducing the amount of the Cu
catalyst, the same experiment was carried out with 5% of
the CuMeSal and 1.5 equivalents of sodium ascorbate. This,
again, led to an exclusive formation of the desired thioether 3
(Scheme 2).
Looking for the best reaction conditions, a series of solvents
was examined (THF, AcOH, DMF, H2O). The best results
were obtained when water with a catalytic amount of BrijR
micellar catalyst was used as the reaction media. The
superiority of the latter condition can be reasoned by solubility
factors (sodium ascorbate) and the issues connected to the
product isolation.
Trying to amend the situation above, we want to present
a mild and selective reductive cross–coupling reaction of
disulfides with aryl iodides, which leads to thioethers as the
desired reaction product. There are a great number of methods
for the preparation of thioethers in the toolbox of the modern
organic chemist.4 The number is justified by the importance of
this functionality in various areas of chemistry.5 The methods
for thioether preparation have been traditionally based on
chemistry utilizing a high nucleophilicity of thiolate moieties in
non–catalyzed or transition metal catalyzed coupling reactions
with organic halides.6z The method employing disulfides as the
source of a thioorganic group has also been introduced,
employing Mg and Zn as the reducing agents.7y Elevated
To demonstrate the synthetic scope, various reaction
partnersz were examined under the reaction conditions with
the results depicted below (Table 1).
Institute of Organic Chemistry and Biochemistry, Academy of
´
Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Praha 6,
Czech Republic. E-mail: jsrogl@uochb.cas.cz
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c002725a
Scheme 1 Cu(I) mediated transformation of aryl iodide.
Chem. Commun., 2010, 46, 4387–4389 | 4387
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Scheme 2 Cu (I) catalyzed, ascorbic acid mediated cross–coupling
reaction of aryl iodides with disulfides.
There are multiple possibilities of how to view the reaction
from the mechanistic standpoint. The first possible path is
based on the extensively discussed oxidative addition of Cu(I)
into the carbon iodine bond of the aryl halides in the first
step,9b the alternative way is based on prior reductive
generation of Cu(I)thiolate, which further reacts with
aryliodide. In order to distinguish between the two routes
p-tolyldisulfide and 2-formanilidedisulfide respectively were
treated in separate experiments with sodium ascorbate in the
presence of catalytic Cu. Neither experiment led to any
significant amount of the reduction product. When, in the
complementary set of experiments, the disulfides were omitted
from the reaction mixture, various amounts of dehalogenated
product were formed. As a result, we tentatively propose the
Scheme 3 Tentative mechanism of Cu catalyzed, ascorbate mediated
reaction.
mechanism involving the formation of oraganocopper species
in the first step, which further interact, after the reduction by
ascorbate, with the present disulfide moiety, forming the
desired thioether (Scheme 3).8
Overall, we presented here the concept of using a mild and
environmentally benign reducing agent, sodium ascorbate, to
keep the catalyst in the metal catalyzed reaction in its reduced,
active form. The concept has been illustrated on the reductive
Table 1 Investigation of the reaction scope
Entry
Disulfide 1 R=
Aryliodide 2
Thioether 3
Yield
83%
a
p-Tolyl
2-Nitrophenyl
b
c
2-Aminophenyl
Benzyl
2-Nitrophenyl
2-Nitrophenyl
71%
64%
d
e
p-Tolyl
2-(3-Methoxy)pyridne
2-Nitrophenyl
70%
51%
4-Nitrophenyl
f
Benzyl
2-(Carboxymethyl)phenyl
2-Nitrophenyl
39%
65%
66%
g
h
2-Phenylcaronyl
p-Tolyl
2-(Carboxymethyl)phenyl
i
2-Formanilide
2-Nitrophenyl
89%
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cross–coupling of aryl iodides with disulfides leading to synthe-
tically desirable products in good to excellent yields. To
demonstrate the chemical tolerance of the reaction conditions,
substrates containing easily reducible groups have been selected.
The work was supported by the Czech Academy of Sciences
(Z40550506, M200550907) and GACR (203/08/1318).
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Notes and references
z Complementary protocols have also been published which utilize
disulfides11a or their equivalent11b as the substrates for a metal
catalyzed cross–coupling reaction with arylboronic acid. While
the void of detrimentally high nucleophilicity of thiolates can be
considered preferable, arylhalides are, compared with organoboron
compounds, the reagent of choice due to their general availability.
y Thiolate intermediates can be the likely reaction culprits under those
conditions.
z In an attempt to keep the focus on the conceptual part of the
study—ascorbate as the mild alternative to the traditionally used
coupling reductive mediators—substrates were deliberately selected a)
which possess easily reducible groups and/or b) whose reactivity
record in Cu(I) catalyzed reaction under Ullman conditions is well
known. There has been no intention, however, to map all the synthetic
aspects of the reaction for a fear of venturing into the area discussed
elsewhere. The corresponding aryl bromides did not show under the
reaction conditions any reactivity.
9 (a) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428;
(b) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
42, 5400–5449.
10 S. Zhang, D. Zhang and L. S. Liebeskind, J. Org. Chem., 1997, 62,
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11 (a) N. Taniguchi, Synlett, 2006, 1351–1354; (b) C. Savarin, J. Srogl
and L. S. Liebeskind, Org. Lett., 2002, 4, 4309–4312.
8 Pre-coordination of disulfides to the Cu catalyst seems to be a
fundamental part of the cross–coupling mechanism as no traces of
the Ullman or reduction products have been detected when disulfides
were present in even the ‘‘Cu stoichiometric’’ reaction mixture.
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This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4387–4389 | 4389