Polymer-supported thiobenzophenone: a self-indicating traceless 'catch and release' linker for the synthesis of isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2007.06.025

The use of a thiobenzophenone as a self-indicating linker in the polymer-supported synthesis of isothiocyanates via a traceless 'catch and release' strategy is reported. Isothiocyanates were furnished via 1,3-dipolar cycloaddition of nitrile oxides with the polymer-supported thiobenzophenone linker, followed by Lewis acid-assisted fragmentation of the resulting polymer-supported oxathiazole.

Full text of DOI:10.1016/j.tetlet.2007.06.025

Tetrahedron Letters 48 (2007) 5355–5358
Polymer-supported thiobenzophenone: a self-indicating traceless
‘catch and release’ linker for the synthesis of isothiocyanates
Brendan A. Burkett,* Jacqueline M. Kane-Barber, Robert J. O’Reilly and Lei Shi
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
Received 5 May 2007; revised 28 May 2007; accepted 7 June 2007
Available online 9 June 2007
Abstract—The use of a thiobenzophenone as a self-indicating linker in the polymer-supported synthesis of isothiocyanates via a
traceless ‘catch and release’ strategy is reported. Isothiocyanates were furnished via 1,3-dipolar cycloaddition of nitrile oxides with
the polymer-supported thiobenzophenone linker, followed by Lewis acid-assisted fragmentation of the resulting polymer-supported
oxathiazole.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The ability to monitor reactions performed on polymer-
supported substrates easily is arguably the most impor-
tant consideration when conducting a polymer-sup-
ported synthesis. Whilst a number of well-established
colorimetric tests are available to detect the appearance
or absence of certain functional groups,1–6 these tests are
limited in their application and usually result in destruc-
tion of precious polymer-supported substrates. IR spec-
troscopy is also widely applied for monitoring polymer-
supported reactions,1,7 but this technique is not without
limitations. The absence of strongly IR active functional
groups in a polymer-supported molecule renders IR
spectroscopy virtually useless due to the fact that key
vibrations of lesser intensity are often obscured by the
polystyrene backbone vibrations. Finally, whilst NMR
spectroscopy has also been used to monitor polymer-
supported reactions,1,8 the technique is highly dependent
on scale as well as access to suitable probes for success-
ful and routine implementation.
our preliminary results describing the use of a self-indi-
cating linker for the polymer-supported synthesis of
isothiocyanates (ITCs).
Our approach towards the synthesis of ITCs is based on
a traceless ‘catch and release’ methodology. Specifically,
we aim to ‘catch’ reactive nitrile oxides using polymer-
supported thiobenzophenone 1 via a 1,3-dipolar cyclo-
addition to afford the corresponding polymer-supported
1,4,2-oxathiazoles 2 (Scheme 1). ‘Release’ of ITCs would
then be conducted under thermal conditions via frag-
mentation of the 1,4,2-oxathiazole.
The self-indicating nature of this strategy is the result of
thiobenzophenone being intense blue in colour9 whereas
1,4,2-oxathiazoles are typically colourless. Monitoring
reactions involving the polymer-supported variant of
this species should therefore be easily achievable by sim-
ple visualisation of the polymer support.
Given these limitations, we recently became interested in
the development of highly coloured linkers designed to
play a pivotal role in the reactions being conducted on
the polymer support. We envisaged that any colour
change associated with reactions of such linkers would
enable us to monitor polymer-supported reactions with
the unaided eye and in real time. Herein, we present
Whilst the cycloaddition reactions of thioketones are well
documented,10 the fragmentation of 1,4,2-oxathiazoles
R
R
N
C
S
N
O
S
+
S
RCNO
Δ
O
Ph
Ph
3
Ph
1
2
Keywords: Self-indicating; Polymer-supported synthesis; Isothiocya-
nates; Catch and release.
"CATCH"
"RELEASE"
*
Corresponding author. Tel.: +64 4 463 5809; fax: +64 4 463 5237;
e-mail: Brendan.Burkett@vuw.ac.nz
Scheme 1. Proposed traceless ‘catch and release’ synthesis of ITCs.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.025

5356
B. A. Burkett et al. / Tetrahedron Letters 48 (2007) 5355–5358
has not been widely studied with only a few examples
appearing in the literature.11–14 High temperatures
(>200 ꢁC) are typically required in order to effect the frag-
mentation in all but a few systems, which has implications
in the development of a polymer-supported adaptation of
this reaction. Too high a temperature would result in deg-
radation of the polymer support, whilst too low a temper-
ature would render the system unsuitable for a successful
catch and release approach. Therefore, prior to investiga-
tion of the polymer-supported systems, preliminary solu-
tion phase studies were conducted to ascertain the
optimal conditions for the fragmentation of benzophe-
none-derived 1,4,2-oxathiazoles.
O
N
R
O
conditions
+
N
C S
Ph
Ph
S
R
Ph
Ph
Scheme 3. Fragmentation of 1,4,2-oxathiazoles 4 and 5.
investigation of various Lewis acids on the fragmenta-
tion reactions (Table 1, entries 4–9).
The effect of Lewis acid on the fragmentation was imme-
diately obvious with reactions performed in refluxing
xylenes or toluene showing a significant increase in the
conversion to products. In some cases, fragmentation
was shown to proceed with competing cycloreversion
as evidenced by the appearance of thiobenzophenone
in the reaction mixture (entries 4–6). Gratifyingly, zinc
chloride provided us with a consistently high conversion
to the corresponding ITCs, which were isolated in good
yields—far superior to those obtained from performing
the reaction neat under thermal conditions. Impor-
tantly, there was no evidence of cycloreversion taking
place under these conditions. We propose that the zinc
ion coordinates to the sulfur of the oxathiazole thereby
reducing the bond order of the C5–S bond. This would
then provide the impetus for formation of the ketone
fragment and concomitant migration of the C3-substitu-
ent. It is interesting to note that ‘harder’ Lewis acid
types led to some cycloreversion, which would be a re-
sult of co-ordination to harder Lewis base sites. Appli-
cation of the fragmentation conditions to oxathiazoles
5–6 showed similar trends with the best conversion
and yields being observed using zinc chloride in
acetonitrile.
Starting from readily accessible and inexpensive alde-
hydes and benzophenone, 1,4,2-oxathiazoles 4–6 were
synthesised from the in situ generation of nitrile oxides
from their corresponding hydroximoyl chlorides in the
presence of thiobenzophenone (Scheme 2). Interestingly,
p-nitrophenyl-derived 1,4,2-oxathiazole 7 could not be
isolated as it underwent easy cycloreversion at room
temperature as evidenced by the immediate return of
blue colouration upon standing. This cycloreversion
was further confirmed upon analysis of the reaction by
TLC.
With 1,4,2-oxathiazoles 4–6 in hand, fragmentation
studies were then pursued (Scheme 3). Oxathiazoles 4
and 5 were found to undergo fragmentation when
heated neat at 240 ꢁC for 2 h; however, 6 did not frag-
ment under these conditions.
It is likely that with higher temperatures 6 could be
forced to undergo fragmentation; however we did not
pursue this possibility and instead moved to an investi-
gation of solvent mediated systems.
Having determined the optimal conditions for fragmen-
tation of 1,4,2-oxathiazoles, we turned our attention to
the polymer-supported system (Scheme 4). Thus 2%
PS-DVB co-polymer was acylated with benzoyl chloride
in the presence of FeCl3 to afford polymer-supported
benzophenone. Successful reaction was evident from
the appearance of a strong absorbance for the carbonyl
Our initial studies involved an investigation of the
behaviour of 4 under a range of conditions (Table 1, en-
tries 1–9). It is evident from these results that the solvent
has a bearing on the efficiency of the fragmentation with
low conversion to ITCs observed in the case of refluxing
xylenes and toluene. Upon moving to acetonitrile (entry
3) the conversion to products improved dramatically.
This solvent effect prompted us to consider that an ionic
or asynchronous concerted mechanism may be in oper-
ation and we therefore turned our attention towards the
stretching vibration at 1657 cmÀ1
.
Estimation of the loading of the acylated polymer was
achieved using IR spectroscopy, which indicated a load-
ing of ꢀ2 mmol gÀ1. Subsequent treatment of this poly-
i) NH2OH.HCl,
NaOAc, EtOH
ii) NCS, DMF
NOH
Cl
RCHO
R
60-90%
N
R
NEt3, toluene,
0 oC
O
S
Ph
Ph
Lawesson's
reagent
R= Ph
4
5
6
7
86%
82%
O
S
R= p-methoxyphenyl
R=t-Bu
R= -nitrophenyl
77%
Ph
Ph
toluene,
reflux, 2 h
Ph
Ph
80%
p
not isolated
Scheme 2. Solution phase synthesis of 1,4,2-oxathiazoles.

B. A. Burkett et al. / Tetrahedron Letters 48 (2007) 5355–5358
Table 1. Isolated yield of ITCs as a function of fragmentation conditions
5357
Entry
R
Conditions
Yielda (%)
1
2
3
Ph
Ph
Ph
Xylenes, reflux, 24 h
Toluene, reflux, 24 h
Acetonitrile, reflux, 24 h
8
NR
30
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
Ph
Ph
AlCl3 (0.2 equiv) xylenes, reflux, 24 h
FeCl3 (0.2 equiv) xylenes, reflux, 24 h
LiCl (0.2 equiv) acetonitrile, reflux, 24 h
ZnCl2 (0.2 equiv), xylenes, reflux, 24 h
ZnCl2 (0.2 equiv), toluene, reflux, 24 h
ZnCl2 (0.2 equiv), acetonitrile, reflux, 12 h
Toluene, reflux, 24 h
60b
55b
30b
90
79
80
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
t-Bu
t-Bu
t-Bu
t-Bu
NRc
30
Acetonitrile, reflux, 12 h
ZnCl2 (0.2 equiv), toluene, reflux, 24 h
ZnCl2 (0.2 equiv), acetonitrile, reflux, 12 h
Toluene, reflux, 24 h
Acetonitrile, reflux, 12 h
ZnCl2 (0.2 equiv), toluene, reflux, 24 h
ZnCl2 (0.2 equiv), acetonitrile, reflux, 12 h
79d
78
NRc
25
75d
78
a Isolated yields. Spectroscopic analysis of the isolated compounds (1H and 13C NMR) was in concordance with those reported in the literature (see
Refs. 15–17).
b Cycloreversion noted.
c <5% conversion in refluxing xylenes.
d Similar results were obtained for the reaction conducted in refluxing xylene.
PhCOCl,
FeCl3
Lawesson's
reagent
S
O
Ph
NOH
Cl
Ph
CH2Cl2
toluene,
reflux
1
R
then, NEt3
N
R
S
O
conditions
O
+
C S
N
Ph
R
Ph
R= Ph
R= -methoxyphenyl
R= t-Bu
8
9
10
p
Figure 1. Polymer-supported benzophenone (left) and polymer-sup-
Scheme 4. Polymer-supported synthesis of ITCs.
ported thiobenzophenone (right) prepared as illustrated in Scheme 4.
particular, the thione absorbance at 1094 cmÀ1 is not a
reliable diagnostic peak for the success of the cycloaddi-
tion reaction. This further illustrates the value of the
self-indicating properties of the current system.
mer with Lawesson’s reagent afforded the thiobenzophe-
none polymer 1.18 The success of this reaction was
immediately evident from the change in colour of the re-
sin, which became intense blue (Fig. 1). Conversion to
the thione was also monitored by IR spectroscopy,
which revealed complete disappearance of the benzo-
phenone carbonyl stretch at 1657 cmÀ1 after 5 h. In
addition, the appearance of a less intense band associ-
ated with the presence of a thiocarbonyl was observed
Subsequent fragmentation of the polymer-supported
oxathiazoles 8–10 was then conducted under optimal
solution-phase conditions (Table 2).20
Our initial optimisation studies with oxathiazole 8 (Ta-
ble 2, entries 1–3) indicated that toluene was the solvent
at 1094 cmÀ1
.
The blue polymer beads were then swollen in a solution
of the desired hydroximoyl chloride in dichloromethane
at 0 ꢁC, prior to the addition of triethylamine.19 The
resulting 1,3-dipolar cycloaddition was easily monitored
by the gradual disappearance of the blue colour from
the beads without resorting to spectroscopic techniques.
It is noteworthy that observation of the key IR absorp-
tions for the polymer-supported oxathiazoles is prob-
lematic owing to the characteristic bands being
obscured by the polystyrene backbone vibrations. In
Table 2. Polymer-supported ‘catch and release’ synthesis of ITCs
Entry
R
Conditions
Yielda
(%)
1
2
3
4
5
Ph
Ph
Ph
ZnCl2 (0.2 equiv), xylenes, 24 h
ZnCl2 (0.2 equiv), toluene, 24 h
ZnCl2 (0.2 equiv), acetonitrile, 12 h 55
77
84
p-MeOC6H4 ZnCl2 (0.2 equiv), toluene, 24 h
t-Bu ZnCl2 (0.2 equiv), toluene, 24 h
82
60
a Isolated yield based on a loading of 2 mmol gÀ1 of benzophenone.

5358
B. A. Burkett et al. / Tetrahedron Letters 48 (2007) 5355–5358
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of choice when performing this strategy on a polymer-
supported system. We attribute this superior perfor-
mance to the greater swelling of the resin in toluene or
xylenes as compared to acetonitrile. Extending the opti-
mised conditions to 9 and 10 also gave rise to syntheti-
cally useful yields of the desired ITCs.
12. Katada, T.; Eguchi, S.; Sasaki, T. J. Chem. Soc., Perkin
Trans. 1 1984, 2641–2647.
13. Kandeel, K. A.; Youseff, A. S. A. Molecules 2001, 6, 510–
518.
Significantly, the cleaved products had a high degree of
purity with only small amounts of, as yet, uncharacter-
ised impurities evident in the H NMR spectra of the
1
14. Kim, J. N.; Ryu, E. K. Tetrahedron Lett. 1993, 34, 8283–
8284.
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crude cleavage mixtures. It is likely that these trace
impurities arise from the presence of byproducts from
Lawesson’s reagent that remain trapped in the polymer
support as in all cases, resonances attributed to p-OMe
protons were evident.
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In conclusion, we have demonstrated the viability of a
self-indicating linker for polymer-supported synthesis
via the first traceless ‘catch and release’ synthesis of
ITCs. This method is readily applicable to the synthesis
of small libraries of ITCs for preliminary biological
screening. This methodology is unique in that the syn-
thesis of the polymer-supported thione and the ‘catch-
ing’ of nitrile oxides can be conveniently and non-
destructively monitored by unaided visualisation of the
polymer support. Studies further investigating the scope
and limitations of this methodology are in progress and
will be reported in due course.
18. Polymer-supported benzophenone (2 mmol gÀ1
)
was
swelled in dry, degassed toluene (16 mL/g of resin) under
an inert atmosphere for 10 min and the resulting suspen-
sion was heated at reflux. Lawesson’s reagent (1.5 equiv)
was added in one portion and the polymer beads turned
blue within 5 min. Heating was continued for a further 5 h
after which time 10 mL of acetone was added to the
mixture. The resulting mixture was allowed to react for a
further hour before filtering the hot reaction mixture. The
resulting polymer-supported thione was filtered and
washed with dichloromethane (5 · 40 mL/g of polymer).
The blue thiobenzophenone polymer-support 1 was then
dried in vacuo and used immediately in the next step.
19. General procedure for 1,3-dipolar cycloaddition reactions
with 1. To a degassed suspension of polymer-supported
thione 1 (assuming a loading of 2 mmol gÀ1) in dichloro-
methane (20 mL/g) was added the appropriate hydroxi-
moyl chloride (1.1 equiv). The resulting mixture was
shaken gently under an inert atmosphere for 5 min
followed by the addition of triethylamine (1.1 equiv)
dropwise over a period of a few minutes. The reaction
was allowed to proceed for 2 h. Complete cycloaddition
was evident from the complete disappearance of the blue
colour from the polymer beads. The polymer support was
then filtered and washed with boiling toluene (2 · 40 mL/
g), acetone (2 · 40 mL/g), diethyl ether (2 · 40 mL/g) and
dichloromethane (2 · 100 mL/g). The resulting beads were
then dried in vacuo and stored under nitrogen.
20. General procedure for release of isothiocyanates from the
polymer-supported 1,4,2-oxathiazoles. A sample of poly-
mer-supported 1,4,2-oxathiazole 8–10 was swollen in dry
toluene under an inert atmosphere for 10 min after which
time 0.2 equiv (based on a loading of 2 mmol gÀ1) of zinc
chloride (anhydrous) was added. The reaction was allowed
to proceed under reflux for 24 h and the polymer was
filtered and washed with dichloromethane (2 · 10 mL/g).
The washings were collected and the solvent was removed
under reduced pressure. In all cases the resulting isothi-
ocyanates were isolated in good yield and were of high
purity.
Acknowledgements
The authors acknowledge Victoria University of Wel-
lington for the award of a faculty research grant.
R.J.O. is the recipient of a Curtis-Gordon research
scholarship. B.A.B. is grateful to the Maurice and Phyl-
lis Paykel Memorial Trust for the award of a travel
grant for travel associated with this work.
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