Bis(pentafluorophenyl) disulfide as a hydrogen abstractor and an electron acceptor from the resulting radical intermediate

Article abstract of DOI:10.1016/j.tetlet.2003.10.211

The pentafluorobenzenethiyl radical is an efficient hydrogen abstractor from an activated methylene or methine group and bis(pentafluorophenyl) disulfide is an efficient electron acceptor from the resulting radical intermediate. Thus benzyl-OTBS ether was easily converted into the corresponding pinacol, and 2-phenyl-1,3-dioxanes are converted into the monobenzoates of diols.

Full text of DOI:10.1016/j.tetlet.2003.10.211

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 17–19
Bis(pentafluorophenyl) disulfide as a hydrogen abstractor and an
electron acceptor from the resulting radical intermediate
Masaru Tada,* Emi Katayama, Naoto Sakurai and Keita Murofushi
Department of Chemistry, School of Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
Received 16 October 2003; revised 30 October 2003; accepted 31 October 2003
Abstract—The pentafluorobenzenethiyl radical is an efficient hydrogen abstractor from an activated methylene or methine group
and bis(pentafluorophenyl) disulfide is an efficient electron acceptor from the resulting radical intermediate. Thus benzyl-OTBS
ether was easily converted into the corresponding pinacol, and 2-phenyl-1,3-dioxanes are converted into the monobenzoates of
diols.
Ó 2003 Elsevier Ltd. All rights reserved.
1/2(2RS)2
3R* (*= , +, -)
1R + 2RSH
The hydrogen transfer between a thiol and a carbon
radical is reversible and the equilibrium is shifted more
to the thiyl radical (Scheme 1).1 In biological system,
nucleic acids and proteins are often damaged by other
toxic species generating the free radicals of these bio-
molecules. The damage, however, is repaired by the thiol
of another biomolecule such as glutathione and the
cysteine residue of proteins.2 This repair process is based
on the favorable equilibrium of the hydrogen transfer
1RH + 2RS
Scheme 1.
this property must stimulate the hydrogen transfer from
an alkyl group to the thiyl radical. Schaefer III et al.
described in recent paper5 that ‘‘perfluororinated aro-
matics will be very effective electron acceptor and may
be useful in the invention of new materials and new
reactions’’. An alkyl radical has a rather low oxidation
potential and the perfluorinated aromatics have a posi-
tive electron affinity in contrast to the negative electron
affinity for common aromatics.5 Furthermore, the
disulfides containing electronegative substituents have a
rather low reduction potential compared to dialkyl
disulfides.6 Thus bis(pentafluorophenyl) disulfide
(BPFD) must be an efficient electron acceptor from a
carbon radical to produce a carbo-cation. These situa-
tions prompted us to test the hydrogen abstraction of
benzyl-OTBS ether (PhCH2O-SiMet2Bu) (1) by thiyl
radicals including the PFBT radical and the results are
shown in Scheme 2 and Table 1.
1
from sulfur to carbon (Scheme 1, RÅ ¼ Ôdamaged bio-
moleculeÕ).3 On the other hand, the chemical transfor-
mation of an organic molecule (1RH) by a thiyl radical
(2RSÅ) involves the unfavorable hydrogen transfer from
carbon to sulfur.
This unfavorable hydrogen abstraction by the thiyl
radical becomes more efficient upon removal of the
carbon radical. Furthermore, the rate of hydrogen
transfer is affected by the polarity factor of both the
hydrogen donor and acceptor.4 Thiyl radicals are elec-
trophilic and alkyl radicals are nucleophilic based on the
polarity concept of free radical.4b
The pentafluorobenzenethiyl (PFBT) radical must be
strongly electrophilic with a low reduction potential and
The photolyses of dimethyl and bis(2-phenylethyl)
disulfides in the presence of 2 mol equivalents of benzyl-
TBS ether (1) gave pinacol 3 as a mixture of diastereo-
mers7 but diphenyl disulfide produced no product
(Scheme 2 and Table 1).8 On the other hand, the
Keywords: Thiyl radical; Pentafluorobenzenethiyl radical; H abstrac-
tion; Electron transfer.
* Corresponding author. Fax: +81-3-5286-3237; e-mail: mtada@
waseda.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.211

18
M. Tada et al. / Tetrahedron Letters 45 (2004) 17–19
R1
Ph
H
H
R1
R2
+
(RS)2
O
O
TBSO
(1)
(2)
(RS)2
+
Ph
R2
hν (350 nm)
benzene
24h
(2)
(6, 9)
Ph
Ph
Ph
OH
benzene
(H2O)
hν (350 nm)
+
+
RSH
24h
TBSO
OTBS
H
TBSO
(3)
(5)
(4)
(PhCHO)(4')
R1
R1
R1
R1
R2
R2
R2
R2
H
HO
PhCO
Scheme 2.
+
PhCO
O
O
(8,11)
(7,10)
Table 1. Photolyses of disulfides (2) in the presence of benzyl-OTBS
ether
6,7,8 : R1=H, R2=Me 9,10,11: R1=Me,R2=H
Disulfide (2)
Product yield (%)
4+40
Scheme 4.
3
(MeS)2
62.6
46.5
0.0
0.0
0.0
(PhCH2CH2S)2
(PhS)2
(C6F5S)2
0.0
44.2
5.9
Table 2. Photolyses of disulfides (2) in the presence of 1-phenyl-1,3-
dioxane
Disulfide
(2)
Substrate Irradiation
time (h)
Product yield (%)
photolysis of BPFD gave mostly benzaldehyde (40) and
its congener 49 together with a small amount of pinacol 3.
The former (40) must be derived from the latter (4) under
the reaction conditions and the work up procedure.
Diphenyl disulfide showed no reactivity most probably
due to the unfavorable equilibrium (Scheme 1) as
reported by Fujisawa et al.7 The equilibrium is over-
weighed the right side due to the low S–H bond energy.
The reaction scheme for the reaction with BPFD is
summarized in Scheme 3. The reaction is triggered by
the thiyl radical generated by photolysis of the disulfide
and the following chain process produces the oxidation
product. However, this chain reaction must be inefficient
due to the rapid annihilation of the thiyl radical by
disulfide formation.
(MeS)2
(PhS)2
6
6
6
9
9
9
24
24
3
7 (trace)
7 (0.0)
7 (0.0)
8 (70.1)
8 (12.5)
8 (64.5)
11 (4.1)
11 (5.4)
11 (36.0)
(C6F5S)2
(MeS)2
(PhS)2
24
24
3
10 (93.5)
10 (4.1)
10 (3.5)
(C6F5S)2
8,11 an oxidation product, without the formation of an
ester 7, the isomerization product (Scheme 4 and Table
2). When 2-phenyl-4,4-dimethyl-1,3-dioxane (9)12 was
used as the substrate,8 both the isomerization product
1011 and the oxidation product 1111 were obtained
(Table 2). A similar mechanism must be operating as in
the case of the benzyl-TBS ether, but the intermediate
carbon radical seems to be more easily oxidized.
Next, 2-phenyl-5,5-dimethyl-1,3-dioxane (6)10 was sub-
jected to a reaction with the thiyl radicals.8 The thiyl
radicals from disulfides 2 gave only the benzoate ester
To understand the origin of oxygen in the product 8, the
reactions were conducted under different conditions.
The reaction solution was thoroughly degassed by
repeated thaw–freeze cycling under vacuum but no
distinct change was observed in the results. On the other
hand, the addition of a small amount of water to the
reaction solution increased the formation rate of the
product 8. These results indicate that the hydroxyl
groups in the products 8 and 11 are derived from the
moisture in the reaction solution and not from the dis-
solved oxygen.
hν
1/2(C F S)
6
5
2
C F S
6 5
+ PhCH OTBS
C F SH + PhCHOTBS
6 5
C F S
2
6
5
PhCHOTBS + (C F S)
PhCHOTBS + C F S-SC F
6 5
6
5
2
6
5
+
PhCHOTBS + H O
2
PhCH(OH)OTBS + H
-
C F S-SC F
C F S
+
C F S
6
5
6
5
In general, the reactions are clean and the reaction
solutions contain the products, the thiols from the
disulfide, and the intact starting materials. Small
amount of diphenyl sulfide was formed by direct pho-
tolysis of the disulfide. All the reactions were stopped
before complete consumption of the starting materials
for the evaluation of the relative reactivity, and the
6
5
6
5
-
-
C F SH
+
OH
C F S
6
+ H O
2
6
5
5
hν
PhCH OTBS + (C F S) + H O
2C F SH + PhCH(OH)OTBS
6 5
2
6
5
2
2
Scheme 3.

M. Tada et al. / Tetrahedron Letters 45 (2004) 17–19
19
R1 R1
H
Acknowledgements
R1
R2
R1
R2
[H]
This study was supported by Waseda University
through an Annual Project Program, 2001A-097 and
2002B-019.
PhCO
PhCO
O
O
R2
R2
(a)
(b)
R1
R1
R2
O
O
Ph
R2
R1
References and Notes
R1
R1
R2
R1
O
O
H2O
HO
PhCO
R2
R2
12: R1=H, R2=Me
13: R1=Me,R2=H
1. Schoeneich, C.; Bonifacic, M.; Asmus, K. D. Free Radical
Res. Commun. 1989, 6, 393–405.
Ph
R2
O
2. Schoneich, C.; Bonifacic, M.; Dillinger, U.; Asmus, K.-D.
In Sulfur-Centered Reaction Intermediates in Chemistry
and Biology. NATO ASI Series A, Chatgilialoglu, C.,
Asmus, K.-D., Eds.; Plenum: New York and London,
1990; Vol. 197, pp 367–376.
Scheme 5.
3. Wardman, P. In S-centered Radicals; Alfassi, Z. B., Ed.;
John-Wiley & Sons: Chichester, 1999; pp 289–309.
4. (a) Tronche, C.; Martinez, F. N.; Horner, J. H.;
Newcomb, M.; Senn, M.; Giese, B. Tetrahedran Lett.
1996, 37, 5845–5848; (b) Roberts, B. P. Chem. Soc. Rev.
1999, 28, 25–35.
product yields can be improved by prolonged irradia-
tion.
Compared to the benzyl-TBS ether radical, the 2-phe-
nyl-1,3-dioxanyl radicals, 12 and 13, are more suscepti-
ble to the electron transfer to the disulfide, which
produces the oxidation products 8 and 11 from the
substrates 6 and 9, respectively, even by using dimethyl
or diphenyl disulfides. It is noteworthy that 2-phenyl-
4,4-dimethyldioxane (9) produced an isomerization
product in spite of no isomerization product from
2-phenyl-5,5-dimethyldioxane (6). This result is
accounted for by the competitive process between the
skeletal rearrangement (route a) and the electron
transfer (route b) of the intermediate radical (Scheme 5).
The ring opening of the dioxanyl radical intermediate 13
from 9 is favorable due to the formation of a tertiary
radical13 and prevails over electron transfer when the
electron acceptor is dimethyl disulfide. Diphenyl disul-
fide is not active both in the initial hydrogen abstraction
and also electron transfer, which results in the low yields
of products 10 and 11. The PFBT radical is an efficient
hydrogen abstractor and BPFD is a good electron
acceptor that predominantly gives the oxidation product
11. The electron transfer is considered to take place
between the carbon radical and the disulfide since it has
been known that no electron transfer occurs between an
allyl silyl ether and the PFBT radical14 derived from the
corresponding thiol. However, we cannot eliminate the
possible electron transfer between the intermediate car-
bon radical, 12 and 13, and the thiyl radical from the
present experimental results.
5. Xie, Y.; Schaefer, H. F., III, Cotton, F. A. Chem.
Commun. 2003, 102–103.
6. Antonello, S.; Benassi, R.; Gavioli, G.; Taddei, F.;
Maran, F. J. Am. Chem. Soc. 2002, 124, 7529–7538.
7. Fujisawa, H.; Hayakawa, Y.; Sasaki, Y.; Mukaiyama, T.
Chem. Lett. 2001, 23, 632–633, Pinacol 3 is a mixture of
diastereomers.
8. The photolyses were carried out in the following manner.
One of the disulfides (0.05 mol/L) and the substrate 1, 6, or
9 (0.10 mol/L) in benzene were placed in a Pyrex reaction
tube and degassed by bubbling argon while in an ultra-
sonic bath. The mixture was irradiated by a Rayonet
photoreactor equipped with 350nm lamps. For the quan-
titative determination of the products, an aliquot of the
reaction mixture was subjected to 1H NMR measurement
using an internal standard. For product identification, the
condensed residue of the reaction mixture was separated
by TLC plate (SiO2) and GPC (gel permeation chroma-
tography) on JAIGEL-1H eluted by 1,2-dichloroethne.
9. The hemiacetal 4 quantitatively gave the benzaldehyde
oxime. 4: 1H NMR (400 MHz) d )0.08 (3H, s), )0.04 (3H,
s), 0.84 (9H, s), 6.17 (1H, s), 7.26–7.31 (3H, m), 7.34–7.36
(2H, m).
10. Pals, G. C. G.; Keshavaraja, A.; Saravanan, K.; Kumar,
P. J. Chem. Res (S) 1996, 426–427.
11. Products 8, 10, and 11, colorless oils, were identified by
comparison to the authentic samples prepared from
benzoyl chloride and the corresponding diols. 8: 1H
NMR (400 MHz) d 1.02 (6H, s), 2.33 (1H, br s, OH), 3.39
(2H, s), 4.19 (2H, s), 7.45 (2H, dd, J ¼ 7:4 and 5.1), 7.58
(1H, tt, J ¼ 7:4 and 1.5), 8.04 (2H, dd, J ¼ 5:1 and 1.5).
10: 1H NMR (400 MHz) d 0.98 (6H, d, J ¼ 6:8), 1.45 (2H,
q, J ¼ 6:8), 1.80(1H, nonet, J ¼ 6:8), 4.35 (2H, t,
J ¼ 6:8), 7.42 (2H, dd, J ¼ 7:6 and 7.4), 7.55 (1H, t,
J ¼ 7:4), 8.04 (2H, d, J ¼ 7:6). 11: 1H NMR (400 MHz) d
1.32 (6H, s), 1.96 (2H, t, J ¼ 6:8), 4.25 (2H, t, J ¼ 6:8),
7.44 (2H, t, J ¼ 7:5), 7.55 (1H, t, J ¼ 7:5), 8.04 (2H, d,
J ¼ 7:5).
In contrast, the ring cleavage isomerization of the
intermediate 12 is slow due to the formation of the less
stable primary alkyl radical, and the electron transfer to
disulfides prevails to produce the product 8 even with
dimethyl disulfide.
As described above, the PFBT radical acts as an efficient
hydrogen abstractor due to its electrophilic nature, and
BPFD acts as an oxidizing agent. These reactions of
BPFD are expected to work similarly for the hydroxyl-
ation of alkanes activated by the adjacent group such as
hydroxyl, ether, or double bond.
12. Fielding, A. J.; Franchi, P.; Roberts, B. P.; Smits, T. M.
J. Chem. Soc., Perkin. Trans. 2 2002, 155–163.
13. Roberts, B. P.; Smits, T. M. Tetrahedran Lett. 2001, 42,
3663–3666.
14. Fielding, A. J.; Roberts, B. P. Tetrahedran Lett. 2001, 42,
4061–4064.