Thiol-ene/oxidation tandem reaction under visible light photocatalysis: Synthesis of alkyl sulfoxides

Article abstract of DOI:10.1039/c7cc05672a

The photocatalyzed synthesis of sulfoxides from alkenes and thiols has been carried out using Eosin Y. This is a metal-free method which uses a low catalyst loading, atmospheric oxygen as the oxidant, and visible light conditions (green light). A mechanism has been proposed that is consistent with the experimental results.

Full text of DOI:10.1039/c7cc05672a

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Thiol–ene/oxidation tandem reaction under
visible light photocatalysis: synthesis of alkyl
sulfoxides†
Cite this: Chem. Commun., 2017,
53, 10463
Received 21st July 2017,
Accepted 4th September 2017
a
a
Andrea Guerrero-Corella,
Enrique Ming,a Alberto Fraile
Ana Marıa Martinez-Gualda,
Fereshteh Ahmadi,a
´
ab
ab
*
and Jose Aleman
*
´
´
DOI: 10.1039/c7cc05672a
rsc.li/chemcomm
The photocatalyzed synthesis of sulfoxides from alkenes and thiols
has been carried out using Eosin Y. This is a metal-free method
which uses a low catalyst loading, atmospheric oxygen as the
oxidant, and visible light conditions (green light). A mechanism
has been proposed that is consistent with the experimental results.
The radical addition of thiols to olefins was described by
Posner in 1905,1 and has since emerged as one of the most
direct methods for the construction of carbon–sulfur bonds.
The thiol–ene reaction has attracted much scientific attention
in recent years,2 particularly in the fields of polymers, materials
and drug design. In the latter case, there are a wide variety of
sulfur-containing pharmaceuticals and natural products e.g.
zantac and romidepsin.3 In addition, this has increased its
Scheme 1 Previous reactions and tandem reaction of this work.
importance as ligands and chiral auxiliaries in synthetic the reaction occurs in synergistic cycles.8 In this case bromotri-
chemistry.4 The thiol–ene coupling fulfills the requirements chloromethane is reduced by initiation, generating the trichloro-
of the ‘click-chemistry’ concept5 due to the atom economy, methyl radical, which promotes the addition and propagation
efficiency and regioselectivity of the process. In this reaction, reactions.8 More recently, semiconductor metal oxides (TiO2)9
the anti-Markovnikov radical addition of the S–H bond occurs and phenylglyoxylic acid10 have also been employed in the thiol–ene
to an alkene (eqn (a), Scheme 1). This reaction can be initiated addition. All of these methods are exclusively used for the synthesis
by thermal activation, using a radical initiator or by direct of thioethers by thiol–ene reaction.
irradiation with UV light. However, this procedure often results
On the other hand, the sulfinyl group can be found in several
in a low yield due to uncontrollable radical routes and the natural and pharmaceutical products such as esomeprazole, alliin
formation of different by-products. In the last years, visible light and armodafinil. In addition, the sulfinyl group has been used as a
photoredox catalysis has emerged as a new powerful tool for the chiral auxiliary11 or in many other reactions such as the Pummerer
construction of organic molecules, using LEDs and domestic and Mislow–Evans rearrangements.12 The most traditional way for
light bulbs which are cheaper and easier to handle than UV the synthesis of sulfoxides is the oxidation of sulfur derivatives.13
reactors.6 In 2012, Yoon’s group demonstrated that thiol–ene This oxidation is typically carried out using peroxides or peracids.
reactions can occur by photo-redox using ruthenium catalysts However, the over-oxidation to sulfones and the safety aspects
with visible light.7 Two years later, Stephenson et al. proposed related to their use (m-CPBA, peracetic acid) are the main
a mechanism in which a catalytic initiation and propagation of drawbacks associated with industrial processes. The oxidation
of sulfides using atmospheric oxygen has proved to be a safer
alternative (eqn (b), Scheme 1). This has been achieved using
a
different photocatalysts.14 Rose Bengal,14a tetra-O-acetyl-riboflavin,14b
or the platinum complex developed by our group,14c have showed to
be good alternatives for this oxidation. Consequently, for the
synthesis of alkylsulfoxide derivatives, a two-step process with
´
´
´
Departamento de Quımica Organica (Modulo 1), Facultad de Ciencias,
´
Universidad Autonoma de Madrid, 28049, Madrid, Spain.
E-mail: jose.aleman@uam.es; Web: www.uam.es/jose.aleman
b Institute for Advanced Research in Chemical Sciences (IAdChem),
´
Universidad Autonoma de Madrid, 28049, Madrid, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc05672a two different catalytic systems is necessary. Therefore, two
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Table 1 Screening reaction conditions for the addition of 2a to 1a in the
presence of oxygena
consecutive reactions are required as well as the isolation and
the purification of the intermediates.15
Tandem reactions are considered to be a good alternative to
economize the number of steps in the synthesis of products, by
avoiding intermediate purification processes.16 Even though in
the field of organocatalysis and metal-catalyzed reactions,
tandem reactions have been widely developed, the number of
publications relating to tandem processes in the photocatalytic
field are scarce.17 Therefore, we considered whether it would be
possible to carry out the tandem thiol–ene reaction and direct
oxidation to sulfoxides, using a single photocatalyst and visible
light (eqn (c), Scheme 1). However, in order to make both
catalytic cycles (thiol–ene and oxidation) compatible, certain
requirements must be met: (i) the formation of disulfides in the
presence of oxygen should be avoided;18 (ii) the oxidation of the
double bond with oxygen species should be eliminated (aldehyde
formation)19 and (iii) the over-oxidation to sulfone must be
controlled.13 In this work, we have developed the thiol–ene/
oxidation tandem reaction, starting from alkenes. In addition, a
plausible mechanism based on different mechanistic proofs is
presented.
With the previous hypothesis, we started the screening reaction
conditions by the addition of thiol 2a to styrene 1a in the presence
of different photocatalysts using CH2Cl2 as solvent in an open-air
vial (Table 1). Different light irradiation was chosen dependent on
the absorption of the photocatalysts. Different iridium catalysts
(3a–3d) enabled us to obtain as the major product the desired
compound 4a, but they always resulted in a certain amount of
the sulfur compound 5a and aldehyde 6a (entries 1–4). Other
photocatalysts such as 3e, rhodamine 3f, led to a mixture of
products, and Rose Bengal 3g did not evolve to the final
oxidation after 36 hours. However, the inexpensive Eosin Y
produced a full conversion in a very selective manner and
yielded sulfoxide 4a (entry 8) exclusively. Other solvents or lower
catalyst loading also led to the final product 4a, but with a lower
selectivity (entries 10–13). The absence of Eosin Y did not afford
any conversion (entry 14) in DCM or other solvents and blue
light (see ESI† for details). With the best conditions ascertained
(entry 8), we continued with different thiols (Scheme 2) and
different double bonds (Schemes 3 and 4).
Entry
Photocatalyst
Light
Solvent
Ratio (4a : 5a : 6a)b
1
2
3
4
5
6
7
8
3a (2.5)
3b (2.5)
3c (2.5)
3d (2.5)
3e (2.5)
3f (2.5)
3g (2.5)
3h (2.5)
3h (2.5)
3h (2.5)
3h (2.5)
3h (2.5)
3h (1.0)
No catalyst
Blue
Blue
White
White
Blue
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
Toluene
MECN
DMF
DCM
DCM
59 : 32 : 8
63 : 23 : 15
Decomposition
85 : 14 : 1
45 : 45 : 10
45 : 40 : 15
16 : 83 : 1
Blue
Green
Green
Green
Green
Green
Green
Green
Green
99 : 0 : 1 (81%)c
98 : 0 : 2
9
10
11
12
13
14
88 : 0 : 12
84 : 0 : 16
Complex mixture
30 : 69 : 1
No reaction
a
Reactions were performed in 0.1 mmol scale of 1a in 0.360 mL of the
indicated solvent after 36 h. Determined by 1H-NMR. Isolated yield
b
c
after flash chromatography.
The reaction of phenyl derivatives, containing electron-
donating groups, allowed the final products 4b and 4c with
lower yield than the benzyl group (4a) due to the formation of
different byproducts, whereas the electron-withdrawing groups
(EWGs) achieved a better yield (4d) (Scheme 2). The alkyl thiols
were also compatible with the tandem reaction (4e), even in the
case of the bulkiest of them (4f). Different EWGs and electron-
Scheme 2 Reactions of styrene 1a with different thiols 2.
donating groups (EDGs) at the double bond were tolerated from moderate to good yields with a-methyl (4l), a-phenyl (4m)
under these reaction conditions (Scheme 3). The use of a and b-methyl (4n) substituents. The reaction with oct-1-ene did
methoxy group or CF3 at the phenyl derivative produced 4g not work.
and 4h in good yields. Interestingly, the presence of those groups
The importance of the nitrogen atom in the pharmaceutical
sensitive to radical conditions, such as the nitro group (1i) or industry is reflected by the large number of products containing
the bromine atom (1j), allowed the synthesis of sulfoxides nitrogen with biological activity.20 Therefore, the inclusion of a
4i and 4j in good yields. However, the presence of a bulkier nitrogen atom in these styrene derivatives would increase the
substituent such as the naphthyl group (1k) gave a moderate broad spectrum of this methodology. We started using ortho-
yield. The reaction also worked with trisubstituted double bonds vinylamino substituted derivatives 7. After some trials with
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Scheme 6 Reactions of ene-addition and oxidation of compounds 1j and 11j.
of the tandem reaction (thiol–ene reaction and oxidation) were
taking place. In the absence of oxygen the thiol–ene reaction
was stopped and no oxidized product 4j was observed, giving
the sulfur product 11j in good yield (eqn (a), Scheme 6). In
addition, when product 11j was placed under the same reaction
conditions in the presence of oxygen, the oxidation gave the
sulfoxide 4j in good yield. Then, Stern–Volmer fluorescence
quenching studies with thiol 2b and the alkene 1j were carried
out (see ESI†).21 This experiment makes possible to determine
if a reaction between the excited state of the EY* and one or
more substrates occur. The fluorescence of EY* was quenched
in the presence of the thiol (see ESI†). Therefore, the photo-
oxidation of the thiol by EY is thermodynamically favorable and
it should be the first step in our reaction.
Scheme 3 Reactions of different double bonds 1 with thiol 2b.
Once the first stage of the reaction had been determined, the
next study consisted of measuring the quantum yield in the
addition of thiols to the double bond.21,22 This indicates
the relationship between the absorbed photons and the emitted
photons. If the result is larger than one this means that a chain
propagation mechanism is taking place because each mole of
photons absorbed gives rise to more than one mole of product.
On the other hand, if the result is less than one, this means that
it is a light dependent process, although a chain propagation
process cannot be eliminated. The quantum yield measured for
Scheme 4 Sulfoxidation of vinyl-amino derivatives 7.
different protecting groups (see ESI†), we found that the use of this thiol–ene reaction was 5.8, pointing to a chain propagation
the Boc group was the most appropriate. The use of 7a in mechanism.22
optimal reaction conditions resulted in the synthesis of the
For the second reaction, the oxidation step, two mechanisms
amino-sulfoxide derivative 8a in a good yield after 20 hours are proposed for the oxidation of the sulfur atom. The first
(Scheme 4). The bromo substituent (8b) and other benzyl consists of a process of energy transfer to form singlet oxygen,
derivatives (8c, 8d and 8e) were also tolerated but with a slightly and the second involves the transfer of an electron to form the
lower isolated yields. The use of an aromatic group (Tol, 7f) superoxide radical anion.23 The discrimination between these
worked with a 52% yield. As example of the potential of this two pathways can be demonstrated by indirect studies to determine
methodology, we carried out one transformation to yield seven- which is the predominant one (see Table SI-2 in ESI†). The addition
1
membered rings (Scheme 5). Compound 8a was placed under of DABCO, which acts as quencher of O2,23,24 almost completely
Pummerer reaction conditions, in which the more acidic inhibits the oxidation reaction (conversion = 14%). Interestingly,
benzylic position was prone to be functionalized, giving the benzoquinone, which acts as scavenger of the superoxide radical
cyclized product (9) with 71% yield.
anion,23 did not significantly change the final conversion (87%),
In order to propose a plausible mechanism for the reaction, indicating that the formation of this radical derivative is not taking
different studies were carried out. Firstly, we performed two place. The iodine test25 did not produce the blue dark colour
independent reactions to ensure that the two individual steps indicative of the formation of peroxide radical species. It is well
known that oxidations via singlet oxygen can be accelerated
using deuterated solvents,26 and this was observed when the
reaction was performed in MeOH (conversion = 60%, 3 h) and in
CD3OD (conversion = 95%, 3 h, see the kinetic profile in ESI†).
The quantum yield was also calculated for this process. We
found a F = 0.003, showing that it is a light dependent process
(see ESI,†).27 To confirm this hypothesis the reaction was
Scheme 5 Pummerer reaction over the sulfoxide 8a.
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ESI†). The results indicated that the product formation only
occurred during the periods of visible light irradiation, therefore
the process is light dependent. These mechanistic proofs point
to the following proposal (Fig. 1). Firstly, the EY is excited when
irradiated with green light from the ground state to the triplet
excited state (E = 1.91 eV).6c,28 The photoexcited catalyst (EY*,
E1/2 = +0.83 V vs. SCE (saturated calomel electrode)6c,28) oxidises
the thiol I, which acts as a donor via a hydrogen atom transfer
process (HAT)29 (E1/2 = +0.45 V vs. SCE),30 generating a thiyl
radical II. Then, alkene III reacts with the thiyl radical to form IV.
This latter radical (IV) can be reduced by the oxidized EY to
yield the final thioether V, recovering the initial photocatalyst
(EY). A mechanism of chain propagation is also possible according
to the quantum yield (F = 5.8) which was measured for this
reaction (eqn (a), Scheme 6). Therefore, in this propagation
mechanism, the radical IV can be reduced via a HAT process29
by an electron and a proton from the thiol I to form V (right,
Fig. 1). In fact, we have used a deuterated thiol (TolSD) which has
been incorporated to the final product D-V (R = o-Br–C6H4) in an
anti-Markovnikov manner (Fig. 1 and ESI†). In the second
oxidation cycle the Eosin Y is excited to the triplet state, and
by means of an energy transfer mechanism, results in the
formation of singlet oxygen31 which can react with the thioether
V to give the final sulfoxide 4. This mechanism is possible
because the activation energy of singlet oxygen is 0.95 eV,31a,32
which indicates that the energy transfer of the excited EY
(1.91 eV6c,28) is thermodynamically flexible.
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In conclusion, the first photo-catalyzed synthesis of sulfoxides
from alkenes and thiols was carried out using Eosin Y, which has
been shown to be the best catalyst.
Spanish Government (CTQ2015-64561-R) and the ERC Council
(ERC-CG, contract number: 647550) are acknowledged.
¨
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Conflicts of interest
There are no conflicts to declare.
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10466 | Chem. Commun., 2017, 53, 10463--10466
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