Routes to highly substituted thiophenol derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.07.039

Syntheses of highly substituted thiophenol derivatives that incorporate steric bulk into the ligand framework via ortho and para tert-butyl substituents are reported. S-Benzyl and trityl protection were investigated and the effects of substituents on the

Full text of DOI:10.1016/j.tetlet.2006.07.039

Tetrahedron Letters 47 (2006) 6541–6544
Routes to highly substituted thiophenol derivatives
Gary Nicholson, Jon D. Silversides and Stephen J. Archibald*
Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK
Received 5 June 2006; revised 28 June 2006; accepted 7 July 2006
Available online 28 July 2006
Abstract—Syntheses of highly substituted thiophenol derivatives that incorporate steric bulk into the ligand framework via ortho
and para tert-butyl substituents are reported. S-Benzyl and trityl protection were investigated and the effects of substituents on
the Newman–Kwart rearrangement of the thiocarbamate discussed. Single crystal X-ray structures are reported for three com-
pounds and demonstrate the role of hydrogen bonding in stabilising the thiophenol to oxidation.
ꢀ 2006 Elsevier Ltd. All rights reserved.
There is current interest in stabilising and characterising
radical species of biochemical significance.1–3 There are
very few examples in the literature of stabilised thiyl rad-
icals. Thiyl radicals (cysteine) may be intermediates in
the catalytic cycles of ribonucleotide reductases and
Ni–Fe hydrogenases.4,5 Small molecule mimics incorpo-
rating a metal bound phenylthiyl radical offer a more
complex synthetic challenge than the analogous phe-
noxyl radical species due to the potential for oxidation
to form disulfide bonds.
reactions and increase the lifetime of the radical species
to allow characterisation using a variety of spectroscopic
techniques.10
We aim to produce a variety of highly substituted func-
tionalised thiophenolates, 2, that may be incorporated
into chelate ligands. There are very few published routes
to highly substituted thiophenols. The route we initially
attempted was a Newman–Kwart rearrangement of
dimethylthiocarbamates. Brooker et al. and Schro¨der
and co-workers used dimethylthiocarbamates to incor-
porate the thiophenol into a chelate ligand framework,
providing rare examples of efficient SH protection
throughout the syntheses.11,12 The formyl substituted
phenol derivatives were converted into O-dimethylthio-
carbamates, 4, by reaction with DABCO and di-
methylthiocarbamoyl chloride followed by a Newman–
Kwart rearrangement to give the more thermodynami-
cally stable S-dimethylthiocarbamate, 5, using BF3ÆOEt2
in toluene at 85 ꢁC. Subsequent cleavage with KOH pro-
duces the thiophenol. These conditions were used in an
attempted synthesis of the O-2,4-di-tert-butyl-6-formyl-
phenyl dimethylthiocarbamate but the rearrangement
did not occur. The route was adapted to provide more
forcing conditions using vapour phase flash vacuum
pyrolysis (Scheme 1). This has been shown to effect the
rearrangement in sterically constrained systems.13 Com-
pound 3 was subjected to furnace temperatures ranging
from 200 to 500 ꢁC under an inert atmosphere but no
rearrangement was observed and only the starting mate-
rial was recovered. Both steric and electronic factors
contribute to the lowered reactivity.
R
R
OH
SH
1
2
The non-substituted phenylthiyl radical is estimated
to decay with head-to-head dimerisation at
9.6 · 109 MÀ1 sÀ1
.
S-Oxygenation can also occur as
6
an unwanted side reaction to form sulfoxy com-
pounds.7,8 A further problem can be the harsh condi-
tions which are often required for protection and
deprotection steps that can be incompatible with the re-
quired functional groups.9 Bulky (preferably tert-butyl)
substituents ortho and para to the phenol, 1, have been
shown to increase the lifetime of metal bound phenoxyl
radicals. Bulky substituents suppress radical coupling
Keywords: Radical; Thiophenol; Protecting group.
*
Wieghardt and co-workers have used a benzyl group
to protect the thiophenol in the synthesis of a highly
Corresponding author. Tel.: +44 1482465488; fax: +44
1482466410; e-mail: s.j.archibald@hull.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.039

6542
G. Nicholson et al. / Tetrahedron Letters 47 (2006) 6541–6544
R
R
O
R
R
O
S
S
NMe2
NMe2
.
.
BF3 OEt2
BF3 OEt2
O
O
R = t-Bu
R = H
3
x
4
Pyrolysis
R
R
S
O
NMe2
O
5
Scheme 1.
substituted derivative that has subsequently been incor-
porated into a triazacyclononane chelator framework.14
We exploited the para-methoxybenzyl protecting group
in the synthesis of novel substituted phenylthiol com-
pounds. 1,3-Di-tert-butyl-5-methylbenzene was used as
a starting material and the compounds were synthesised
via adaptations of the experimental procedures of Wieg-
hardt and co-workers and Shibata et al.14,15 The S-benz-
yl protected compound 8a16 was synthesised from
toluene-4-thiosulfonic acid S-(4-methoxybenzyl)ester
using a related procedure (Scheme 2). The methyl group
offers a potential site for further functionalisation of
thiophenolates while the sulfur is protected. The synthe-
sis of a benzylic bromide compound from 6 has previ-
ously been reported using NBS and the radical
initiator AIBN.14 Single crystals of 8a were grown by
evaporation of an n-hexane solution and X-ray crystallo-
graphic analysis confirmed the structural assignment
(Fig. 1).
perature, further BaMnO4 was added after 24 h. Precip-
itated solids were removed by filtration and washed with
CH2Cl2. Use of a 10-fold excess by mass of the reagent
over 24 h resulted in only a partially oxidised product.
The crude product was purified by column chromato-
graphy to give 8b in 53% yield.
The 4-methoxybenzyl S-protecting group can be re-
moved using mercury(II) acetate in DCM, then passing
hydrogen sulfide through the solution to produce solid
mercury(II) sulfide which is filtered off and the desired
product isolated. Compound 8a was subjected to this
cleavage reaction and the product isolated was the
expected 2-thio-2,4-di-tert-butyl-6-methyl thiophenol
derivative 9a.18 This was purified by column chromato-
graphy using n-hexane as an eluent to give 83% yield.
Again, single crystals were grown by slow evaporation
of the hexane solution in air. X-ray crystallographic
analysis revealed that air oxidation had occurred during
the crystallisation process resulting in formation of the
disulfide linked compound (Fig. 2). The Cambridge
Structural Database shows only four examples of
2,4,6-trisubstituted disulfide linked thiophenyl com-
pounds and none with the tert-butyl group.19 The S–S
Oxidation of the alcohol group in 7 to the aldehyde was
carried out using BaMnO4. Compound 8b17 was syn-
thesised over 48 h initially using a five-fold excess by
mass of BaMnO4 and stirring the reaction at room tem-
(i)
Br
6
(iii)
(iv)
R
R
R
S
SCPh3
SH
9a R=CH3
b R=COOCH3
10 R=CH3
OH
OMe
(ii)
S
8a R=CH3
b R=CHO
OMe
7
Scheme 2. Reagents and conditions: (i) n-BuLi, Et2O, 0 ꢁC, 10 min then rt, 3 h, Ar; toluene-4-thiosulfonic acid S-(4-methoxybenzyl) ester, Et2O,
À70 ꢁC, 1 h then À30 ꢁC, 4 h, Ar (65%) ; (ii) BaMnO4, CH2Cl2, rt, 48 h (53%); (iii) Hg(CH3CO2)2, 60 ꢁC, 6 h then H2S, 20 min, Ar (9a 83%, 9b 68%)
and (iv) trityl chloride, C6H6, 96 h, Ar (58%).

G. Nicholson et al. / Tetrahedron Letters 47 (2006) 6541–6544
6543
C15
C14
C11
C4
C18
C19
C8
C5
C6
C20
C10
O1
C3
C2
C7
C17
C12
C16
C9
C13
C12
C21
C1
C23
S1
C1
C7
C2
C4
C22
C11
C3
C6
S1
C14
C9
C8
C10
C13
C5
C15
Figure 1. ORTEP plot of the X-ray crystal structure of 8a.
O2
O1
C9
C16
C10
C8
C29
C26
C30
C21
C7
C2
C20
C19
Figure 3. ORTEP plot of the X-ray crystal structure of 9b.
C14
C3
S1
C16
C4
C6
C5
C28
S2
C11
C17
C22
C27
reports with highly substituted derivatives. It was
thought that the steric repulsion may be too great to
accommodate this protecting group. The conditions
given for unsubstituted thiophenol in the literature
suggest that the reaction with trityl chloride, performed
at reflux in benzene, is complete after 1 h. However, con-
siderably longer reaction times were required to protect
2,4-di-tert-butyl-6-methyl thiophenol. The reaction was
monitored by TLC and stopped after 96 h. Purification
was carried out using column chromatography with
hexane as an eluent to give 1018 in 58% yield. Despite
the reaction being carried out under an argon atmo-
sphere, a considerable amount of disulfide linked start-
ing material was also recovered. This protecting group
provides an option that may be useful due to the very
mild conditions for cleavage.
C12
C15
C25
C13
C24
C23
Figure 2. ORTEP plot of the X-ray crystal structure of the air
oxidation product from 9a.
˚
bond length of 2.059(1) A does not appear to be affected
by the steric bulk as it is similar to the overall average
for thiophenyl compounds of 2.052 A from 157 struc-
tures with S-coordinated compounds excluded.
˚
The cleavage of the benzyl group from 8b was attempted
under the same conditions employed for 8a. However,
the aldehyde product was not isolated and the product
identity was confirmed by X-ray crystallography
(Fig. 3). Crystals were grown by slow evaporation of
an n-hexane/CH2Cl2 solution in air. The product con-
tains a free thiol but the aldehyde has been transformed
to a methyl ester. This can be accounted for by the pres-
ence of a small amount of methanol required to solubi-
lise the mercury acetate, with the esterification catalysed
by mercury(II). The methyl ester substituted thiol 9b18
was isolated in 68% yield using gradient column chro-
matography with n-hexane/ CH2Cl2 as eluent. The X-
ray structural data give an insight into the stabilisation
of the thiophenol by formation of an intramolecular
H-bond (Fig. 3). The crystals were grown in air but
did not show oxidation to the disulfide linked com-
pound. The key difference is the presence of the ester
which forms an intramolecular H-bond with thiophenol,
thus inhibiting the oxidation process and disulfide bond
formation.
We have shown that the synthesis of some highly substi-
tuted thiophenolate functionalised derivatives is possible
using both benzylic and trityl protecting groups. How-
ever, such syntheses can be challenging due to slower
reaction times or no reaction via established routes for
unsubstituted thiophenols. Hydrogen bonding was dem-
onstrated to have an important role in stabilising the thio-
phenol to disulfide bond formation. These routes should
contribute to the synthesis of chelate systems for the
characterisation of metal bound thiyl radicals.
CCDC Nos. 296458, 296459 and 604270 contain the
supplementary crystallographic data for compounds
8a, 9a and 9b, respectively. These data can be obtained
free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgements
The applicability of a further S-protecting group to
highly substituted thiophenols that may be cleaved un-
der mild conditions was investigated. The trityl group
has been used to protect thiophenols but there are no
We thank the EPSRC National Mass Spectrometry
Service and the EPSRC (GR/R47547) and the Nuffield
foundation for funding. We wish to acknowledge the

6544
G. Nicholson et al. / Tetrahedron Letters 47 (2006) 6541–6544
1H, J = 2.3 Hz). 13C NMR (100 MHz, CDCl3): d 22.4,
31.3, 31.6 , 34.7, 37.6, 40.9, 55.2, 113.9, 121.9, 125.8, 129.5,
130.1, 130.6, 144.2, 150.6, 153.1, 158.8. MS (EI)m/z = 356
(M+).
use of the EPSRC’s Chemical Database Service at
Daresbury.
References and notes
17. 3,5-Di-tert-butyl-2-(4-methoxybenzylthio)benzaldehyde
8b. Barium manganate (15 g) was added to a stirred
solution of 7 (2.97 g, 8.03 mmol) in CH2Cl2 (50 mL). The
resulting suspension was stirred at room temperature for
48 h with further barium manganate (15 g) added after
24 h. The solids were separated by filtration of the reaction
mixture through a filter agent (Hyflo) and washed thor-
oughly with CH2Cl2. The combined CH2Cl2 washings
were dried over MgSO4 and concentrated in vacuo. The
pale green/yellow crude solid was purified by column
chromatography to yield a light yellow powder 8b. (Silica
gel 60, eluent: n-hexane/ Et2O 85/15 (v/v)). Rf: 0.38. Yield
1.58 g (53%). 1H NMR (400 MHz, CDCl3): d 1.33 (s, 9H),
1.55 (s, 9H), 3.77 (s, 2H), 3.78 (s, 3H), 6.78 (m, 2H), 7.03
(m, 2H), 7.71 (d, 1H, J = 2.2 Hz), 7.78 (d, 1H, J = 2.2 Hz),
10.72 (s, 1H). 13C NMR (100 MHz, CDCl3): d 31.1, 31.5,
35.1, 37.4, 45.2, 55.3, 114.0, 123.8, 128.4, 129.3, 130.2,
135.7, 139.9, 151.5, 153.7, 159.1, 194.3. HRMS (ESI) calcd
[M+H]+ for C23H31O2S: 371.2039; found 371.2039. IR
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