Mechanistic insights into a copper-disulfide interaction in oxidation of imines by disulfides

Article abstract of DOI:10.1039/b904403e

The concept of using disulfides as an oxidant for Cu(i) is introduced as part of a Cu-catalyzed process leading to the formation of benzothiazole from an iminodisulfide under an inert atmosphere.

Full text of DOI:10.1039/b904403e

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Mechanistic insights into a copper–disulfide interaction in oxidation
of imines by disulfidesw
a
b
a
Jiri Srogl,*a Jakub Hy
vl, Agnes Revesz and Detlef Schroder*
´
´
´ ´ ¨
Received (in Cambridge, UK) 4th March 2009, Accepted 3rd April 2009
First published as an Advance Article on the web 5th May 2009
DOI: 10.1039/b904403e
The concept of using disulfides as an oxidant for Cu(I) is
introduced as part of a Cu-catalyzed process leading to the
formation of benzothiazole from an iminodisulfide under an inert
atmosphere.
using acetic acid as a solvent. Under these conditions,
the starting material was converted to a 1 : 1 mixture of
2-arylbenzothiazole 2a and 2,3-dihydro-2-arylbenzothiazole
3a (R = 2-chloro-4-nitrophenyl) (Scheme 1).
In the copper-catalyzed addition of disulfides to styrenes, a
mechanism involving in situ generated cationic sulfur species
attacking electron-rich substrates in an electrophilic fashion
was proposed.3a The other plausible mechanism involving the
oxidative addition of Cu(I) into the S–S bond of disulfide, as
the first step of the catalytic cycle, is indirectly supported by
similarities of other transition metals (Rh, Ru),8 but would
involve generally less favorable Cu(III) intermediates.9 To gain
some further insight into the mechanism, we set up
the following experiment. With an intramolecular pathway
unlikely due to bond constraints, we wanted to rule out an
intermolecular addition–elimination mechanism, consistent
with sulfur-centered cationic route,3a and trap the proposed
electrophilic sulfur species by an established nucleophile.
Thus, the mixture of the iminodisulfide 1a (R = 2-chloro-4-
nitrophenyl) and styrene was treated under the same conditions.
The experiment led to a 1 : 1 mixture of 2a and 3a,
while styrene remained intact, and no other products
were observed. This observation strongly suggests that no
free sulfur-electrophiles are formed as intermediates which
could react with external nucleophiles. An option for an
alternative route is a Cu(I) oxidative addition into the
disulfidic S–S bond with subsequent hydrogen transfer leading
to overall disproportionation of the disulfide 1 into 2 and 3.
In order to lend further evidence to this mechanistic
proposal, the unimolecular behavior of the isolated Cu(I)
complex (1)Cu+ in the gas phase was investigated by mass
spectrometry. Specifically, a diluted mixture of the reactant 1b
(R = Ph) and the catalyst in methanol was probed via
electrospray ionization (ESI).10 Under mild conditions of
ionization, the reactant complex (1b)Cu+ is observed as a
major cationic species,11 whose assignment is confirmed by
the characteristic isotope pattern (see inset in Fig. 1).
Collision-induced dissociation (CID) of mass-selected
(1b)Cu+ is associated with loss of neutral 2b, concomitant
with an ionic species (m/z 276), which formally corresponds to
the product complex (3b)Cu+ (Fig. 1).
Copper-catalyzed oxidations have been at the center of
chemists’ interest for several decades. Coupled with
molecular oxygen in an aerobic media1 or with peroxides in
anaerobic systems,2 copper-catalyzed oxidations have become
cornerstones of analytical, biological, and organic chemistry.
While the oxidations have been generally accepted as a
valuable tool, the nature of the reaction intermediates and
the reaction mechanisms have, despite great efforts, often
remained obscure, primarily due to the complexity of the
multi-component processes involved. However, oxygen-based
electron acceptors are not the only viable substrate for
copper-catalyzed oxidations. Following examples of biological
chemistry, copper–disulfide interactions have recently attracted
growing attention.3 This interest was found to be fully justified
when a product of an oxidative addition of copper into a
disulfide bond was isolated and characterized, endorsing thus
the capability of disulfide as a copper oxidant.4 Based on
this concept, we wanted to explore the oxidative process
without the complications associated with highly reactive
oxygen-centered reagents (stoichiometric requirements, side
reactions, etc.).5 The forseeable advantages are the accurate
analytical accessibility of all the reaction components,
i.e. reduced and oxidized forms, in a closed system which
should enable to accurately map the entire process.
Here we want to demonstrate our findings pertaining
to the intramolecular oxidation of imines featuring a tethered
disulfide function. The importance of ligands for the
stabilization of high-valent copper species has been discussed
and demonstrated in the literature.6 In line with those findings,
we based our model compounds on the 2,20-anilinedisulfide
platform, which accommodates the concept of ‘‘non-innocent’’
ligands.7
In our study, one equivalent of the imine disulfide 1a
(R = 2-chloro-4-nitrophenyl) was treated with a catalytic
amount of copper(I) 3-methylsalicylate under inert atmosphere
a Institute of Organic Chemistry and Biochemistry, Academy of
´
Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Praha 6.
E-mail: jsrogl@uochb.cas.cz, detlef.schroeder@uochb.cas.cz;
Fax: +420 220183578; Tel: +420 739680642
b
´
Department of General and Inorganic Chemistry, Eotvos Lorand
University, Pazmany Peter setany 1/a, 1117 Budapest, Hungary
¨
¨
´
´
´
´ ´
w Electronic supplementary information (ESI) available: Details of the
preparative kinetic and mass spectrometric experiments, and NMR
data of all new compounds. See DOI: 10.1039/b904403e
Scheme 1 Cu(I)-catalyzed transformation of imine disulfide.
Chem. Commun., 2009, 3463–3465 | 3463
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likely, directly to the product 2 concomitant either the product
complex (3)Cu+ or that of the corresponding Cu+ thiol
moiety, where the latter easily forms the dihydrobenzothiazole
3 under the reaction conditions; note that the added acid may
serve to return Cu(I) back to the catalytic cycle. An alternative
to the proposed mechanism may be the reaction pathway
involving a multi-centered transition state,16 i.e. simultaneous
cleavage of the S–S bond resulting in formation of a new C–S
bond, and accompanied by hydrogen migration. This scenario
would thus circumvent the oxidative addition of copper to
the disulfide. Indirect evidence for the involvement of an
intermediate Cu–H bond is also provided by the loss of neutral
CuH from (3b)Cu+ (Fig. 1).
Fig. 1 CID spectrum of mass-selected (1b)Cu+ (m/z 487 for the 63Cu
isotope) showing the highly preferential loss of neutral 2a to formally
afford (3b)Cu+ (m/z 276). The protonated benzothiazole [2bꢁH]+
(m/z 212) arises from consecutive loss of neutral CuH from
(3b)Cu+. The signals at m/z 294 and 308 are due to subsequent
addition of water and methanol, respectively, present as residuals
from the spray solvent in the background of the mass spectrometer.
The inset shows the measured and calculated isotope pattern of the
(1b)Cu+ precursor ion.
In conclusion, we present a concise mechanism of the
interaction between Cu(I) and a disulfide moiety involved in
a useful chemical transformation and thus introduce the
concept of using disulfides as an oxidant for Cu(I). The key
intermediate of the suggested mechanism does not contradict
the involvement of Cu(III) species. Supported by the chemical
experiments and corroborated by the gas-phase data, the
present results thus provide vital insight into the origin of this
increasingly important interaction.
The apparent threshold of this fragmentation of about
2 eV12 is qualitatively consistent with a reaction in the
condensed phase occurring at ambient conditions.13 Thus,
The work was supported by the Czech Academy of Sciences
(Z40550506), and the grant agencies GAAV (KJB400550704),
GACR (203/08/1318), and HNSF (OTKA 60679).
the gas-phase experiments demonstrate
a purely intra-
molecular reaction of a mononuclear copper species as a viable
scenario for the overall reaction. To further support these
conclusions, also the Cu(I) complex of the derivative 1a
(R = 2-chloro-5-nitrophenyl) and a specifically deuterated
isotopolog, [D2]-1a, were investigated by means of ESI MS.
Again, loss of the neutral thiazole is observed as the by far
predominating fragmentation of mass-selected (1a)Cu+, and
for ([D2]-1a)Cu+ the deuterium label is completely left in the
ionic product, as expected.
Notes and references
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Further insight into the reaction mechanism was
obtained by kinetic investigations. A primary isotope effect
(kH/kD = 2.3) was observed when H(D)-iminodisulfides were
treated with Cu(I) under the reaction conditions, indicating
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Scheme
2 Tentative mechanism of the Cu(I)-catalyzed imine
oxidation.
mass spectrometer; for
a description of the apparatus, see:
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