N-Phenyltriazolinedione as an initiator in the radical addition of thiophenol to alkenes

Article abstract of DOI:10.1016/j.tetlet.2008.08.067

N-Phenyltriazolinedione is found to be an efficient initiator in the radical (anti-Markovnikov) addition of thiophenol to 2-methyl-2-butene. A second, minor, product (an alcohol, from oxygen addition) was also obtained, and a possible mechanistic scheme is proposed.

Full text of DOI:10.1016/j.tetlet.2008.08.067

Tetrahedron Letters 49 (2008) 6324–6326
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Phenyltriazolinedione as an initiator in the radical addition
of thiophenol to alkenes
*
Georgia Nicolaou, Yiannis Elemes
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Phenyltriazolinedione is found to be an efficient initiator in the radical (anti-Markovnikov) addition of
thiophenol to 2-methyl-2-butene. A second, minor, product (an alcohol, from oxygen addition) was also
obtained, and a possible mechanistic scheme is proposed.
Received 10 July 2008
Revised 14 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thiols
Triazolinediones
Urazoles
Radicals and radical reactions
Thiol addition to alkenes is a well-known reaction1 that takes
place at room temperature, upon heating,2 or under UV irradiation3
in a radical mode, shows an anti-Markovnikov regioselectivity,1,4
and finds many synthetic applications.5 Initiators are also used in
the reaction, and 2,20-azobis(1-methylpropionitrile), AIBN, is one
of the most frequently chosen ones.6 The action of AIBN as initiator
is, in the most simplified way, as shown in Scheme 1.
Δ or hv
N
N
2
CN
+
+ N2
PhS
CN
NC
AIBN
CN
initiation step
PhSH
CN
PhS
+ PhS
propagation step
Initial homolytic decomposition of AIBN liberates a N2 mole-
cule, and gives rise to two isobutyronitrile carbon-centered radical,
that abstract two hydrogen atoms from two molecules of thiophe-
nol and thus create two reactive thiophenoxy radicals, PhSÅ, during
the initiation step of the reaction. This adds to the double bond of
an alkene in an anti-Markovnikov mode and produces a carbon-
centered radical in the propagation step. Finally, this radical
abstracts a hydrogen atom from a thiophenol molecule in the
PhS
PhS
+
PhSH
+ PhS
H
termination step
PhSSPh
2 PhS
Scheme 1. AIBN as an initiator in the radical addition of thiophenol to alkenes.
termination step, reproducing
a thiophenoxy radical which
continues the propagation step. A combination of two thiophenoxy
radicals also contributes to the termination step.
here on PhTAD acting as an initiator in the radical addition of
thiophenol to 2-methyl-2-butene. To our knowledge this is a new
aspect of TAD reactivity.
4-Substituted-1,2,4-triazoline-3,5-diones, TADs, are compounds
of high reactivity toward cycloadditions7 and ene reactions.8 They
are prepared via an oxidation reaction from their precursor uraz-
oles,9 and their chemistry attracts research interest from both
the synthetic10 and mechanistic11 points of view. Recently, we
reported on the ability of 4-phenyl-1,2,4-triazoline-3,5-dione,
PhTAD, to dimerize thiols to disulfides in excellent yields, Scheme
2.12 Since TADs are cyclic diazo compounds, we decided to test
PhTAD as an initiator in radical additions to alkenes. We report
Ph
Ph
N
N
O
O
+
neat
O
O
PhSH
PhSSPh
+
N
N
N
N
or dry PhMe
H
H
PhTAD
PhTADH2
* Corresponding author. Tel.: +30 2651 0 98432; fax: +30 2651 098799.
E-mail address: yelemes@cc.uoi.gr (Y. Elemes).
Scheme 2. Reduction of PTAD to the parent urazole and oxidation of PhSH to the
diphenyl-disulfide.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.067

G. Nicolaou, Y. Elemes / Tetrahedron Letters 49 (2008) 6324–6326
6325
Solid PhTAD (2% molar ratio with regard to the alkene) was
Ph
N
Ph
N
added at room temperature to a freshly prepared solution of 2-
methyl-2-butene and PhSH in dry PhMe. After 10 min of stirring,
the addition product phenyl alkyl sulfide 1 and diphenyl disulfide,
Ph2S2, were detected by TLC and by GC MS. This was verified also
by 1H NMR spectroscopy of the crude reaction mixture after
removal of the excess PhSH and phenylurazole by washing the
solution with cold 1 N NaOH or KOH solution, and removal of the
solvent. The ene addition product, between PhTAD and the alkene,
was also formed in appreciable amounts.
O
O
+
O
O
initiation step
2 PhSH
+
2
PhS
N
N
N
N
H
H
PhS
propagation step PhS
+
PhS
PhS
+
PhSH
+ PhS
H
1
termination step
We then studied the reaction with respect to the molar ratio of
the reagents, reaction temperature and time, and solvent quantity.
The best conditions found were a temperature of ꢀ30 °C, with a
molar ratio of alkene:PhTAD:PhSH equal to 50:1:50, in an equal
volume solution of PhSH and dry PhMe, Scheme 3. Under the
above-mentioned conditions, the best molar ratio of [sulfide
1]:[Ph2S2] was found to be equal to unity, and no ene product
was detected. When the reaction was performed under the
above-mentioned experimental conditions in the absence of
PhTAD, only diphenyldisulfide was detected as the product by
TLC, GC MS, and 1H NMR.
PhSSPh
2 PhS
Scheme 4. A possible mechanistic scheme for the radical addition of PhSH to
2-methyl-2-butene, with PhTAD as initiator.
molar ratio of PhTAD is increased, the concentration of thiophen-
oxy radicals is high enough to give more dimerization product, as
was found experimentally. Furthermore, PhTAD could be recycled
from the resulting N-phenylurazole, isolated by filtration from
the reaction mixture, via known oxidation reactions.9
Formation of compound 2, is in accordance with a radical reac-
tion sequence, since it could be produced by trapping of the car-
bon-centered radical by traces of O2 in the reagents or solvent,
resulting in a peroxide intermediate 3, which could then decom-
pose to the final hydroxy-sulfide 2, Scheme 5.
Preparative TLC (n-hexane or pentane/EtOAc 30:1 v/v) afforded
sulfide 1 in 5% yield and hydroxy-sulfide 2 in 0.7% yield, with
regard to the starting alkene (i.e., molar ratio [1]/[2] ꢁ 7:1), which
were characterized by NMR spectroscopy and HRMS.13
Since all of the above reactions were performed in scattered
light (lights in the vicinity were turned off during the experi-
ments), we also ran the reaction in the dark. It is known that light
itself promotes the addition of thiophenol to alkenes.1 We found
that in the dark, at room temperature, and for the same reaction
time (75 min), the formation of the disulfide diminished dramati-
cally, the molar ratio [sulfide 1]:[Ph2S2] rose to 3:1, and the molar
ratio [1]/[2] was ꢁ15:1, as was judged from the 1H NMR of the
crude mixture. Again, in the absence of PhTAD no products 1 or 2
were detected except for diphenyl disulfide during the above-men-
tioned period of time. We decided to take advantage of this time
window to increase, if possible, the isolated yield of product 1.
Under the above-mentioned conditions, we ran the reaction by
changing the quantity of PhTAD and isolated the product 1 by pre-
parative TLC (with n-hexane as eluent). An almost linear increase
of the % yield of the isolated product 1 on going from 5% yield with
50:1:50 molar ratio to 14% yield with 50:2:50, and 21% with
50:5:50 molar ratio of alkene:PhTAD:PhSH was found.14 By further
increasing the quantity of PhTAD a plateau was encountered for
the % yield of product 1. By changing the molar ratio from
50:9:50 to 50:25:50, the yield was close to 16%. All isolated yields
are quoted with regard to the starting alkene. In addition, higher
concentrations of diphenyl disulfide were observed in these exper-
iments. In all the experiments the molar ratio [1]/[2] remained
almost unchanged, revealing a different formation pathway for
product 2.
Hydroxy-sulfides with similar structures have been reported to
be formed as secondary products during thiol radical addition to
alkenes under continuous flow of O2.15 Thus, we decided to test
the above reaction in the presence of pure oxygen. We ran the
reaction in the dark, at room temperature with the same molar
ratio of reactants and solvent quantity, and bubbling with pure
O2 for 75 min. After the usual work-up, the 1H NMR spectrum of
the crude reaction mixture showed the presence of an additional
quartet centered at 3.66 ppm (the corresponding quartet for
sulfide 1 resonates at 3.22 ppm, whereas that of hydroxy-sulfide
2 appears at 3.25 ppm). Upon addition of triphenylphosphine to
the NMR tube, the above quartet vanished and hydroxy-sulfide 2
was then evident. We interpret this result as evidence for the for-
mation of hydroperoxide 3, in higher quantities in the presence of
oxygen, and that in the presence of PPh3 it is reduced to the hydro-
xy-sulfide 2.
A comment should be made at this point with respect to the
smoother reactivity (low temperatures, dark conditions) of PhTAD
with regard to AIBN (higher temperatures, irradiation), as a radical
initiator. Despite the fact that PhTAD is a cis-locked azo-com-
pound, its action has some major differences on bond dissociation
energy grounds. In the case of PhTAD: a weak N@N double bond
has to open homolytically together with two, overall, weak S–H
bonds, Scheme 4. This energy demand is satisfied by the formation
of two N–H bonds in the urazole molecule. With AIBN, two strong
C–N bonds have to break (high energy demand) and a weak triple
N„N bond is the energy gain, Scheme 1. We are of the opinion that
such energy differences give PhTAD the opportunity to act as an
initiator in an easier way with regard to AIBN.
Taking together the above findings, we propose the following
mechanistic scheme for the studied reaction, Scheme 4.
According to the above scheme, PhTAD abstracts two hydrogen
atoms from two molecules of PhSH, giving rise to the formation of
the parent urazole and two thiophenoxy radicals in the initiation
step. The process then continues as discussed above (Scheme 1).
In the light of the above proposed mechanistic scheme, when the
O2
PhS
PhS
OO
PhS
PhS
PhS
+
+
PhSH
OO
OOH
PhS
PhS
PhSH/cat. PhTAD
dry PhMe, -30 oC, 75 min
3
+
PhS
H
OH
1
2
OH
2
Scheme 3. Addition of PhSH to 2-methyl-2-butene with PhTAD as an initiator in
catalytic quantities.
Scheme 5. Possible pathway for the formation of hydroxy-sulfide 2.

6326
G. Nicolaou, Y. Elemes / Tetrahedron Letters 49 (2008) 6324–6326
Org. Chem. 2002, 67, 8666–8668; (m) Hajipour, A. R.; Mallakpour, S. E.; Adibi, H.
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Sulfur Lett. 2002, 25, 155–160; (n) Akdag, A.; Webb, T.; Worley, S. D. Tetrahedron
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found to act as an initiator in the radical addition of thiophenol
to 2-methyl-2-butene. PhTAD could be recycled from the reaction
by oxidation of the urazole formed. The reaction was found to work
under conditions where no addition product was observed in the
absence of PhTAD. A hydroxy-sulfide was also isolated in minor
amounts, testifying to the radical nature of the addition reaction.
Further studies on clarification of the mechanistic profile of the
reaction are underway.
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Acknowledgments
The financial support from the Research Committee of the Uni-
versity of Ioannina, Dakaris II Program No.: 1216, is gratefully
acknowledged. We thank the NMR Center of the University of
Ioannina, Dr. V. Sakkas from the Laboratory of Industrial and Envi-
ronmental Chemistry, University of Ioannina for GC MS spectra,
and the Mass Spectrometry Facility, at The School of Pharmacy,
University of London for HRMS spectra.
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