Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles

Article abstract of DOI:10.1002/ejoc.201500909

The first systematic study of the thermal rearrangement/fragmentation of 5,5-disubstituted 1,4,2-oxathiazoles into isothiocyanates is reported. Structure-activity relationships reveal that the choice of substituent at the 5-position of the 1,4,2-oxathiazoles is the predominant factor to influence the ease of fragmentation.

Full text of DOI:10.1002/ejoc.201500909

FULL PAPER
DOI: 10.1002/ejoc.201500909
Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
Russell J. Hewitt,*[a] Michelle Jui Hsien Ong,[a] Yi Wee Lim,[a] and Brendan A. Burkett*[a]
Keywords: Nitrogen heterocycles / Sulfur heterocycles / Oxygen heterocycles / Rearrangement / Substituent effects / Frag-
mentation / Structure–activity relationships
The first systematic study of the thermal rearrangement/frag-
mentation of 5,5-disubstituted 1,4,2-oxathiazoles into isothio-
cyanates is reported. Structure–activity relationships reveal
that the choice of substituent at the 5-position of the 1,4,2-
oxathiazoles is the predominant factor to influence the ease
of fragmentation.
tions, which makes the pairing of these two types of com-
pounds highly suitable for use as a click reaction. Although
click chemistry is typically associated with producing stable
linkages,[4] there are few examples of such linkages being
programmed to respond to a stimulus and release one or
more active compound.[5] We envisage that by exploiting
the thermal sensitivity of 1,4,2-oxathiazoles, the pairing of
nitrile oxides and thiocarbonyl compounds can offer at-
tractive possibilities to develop programmable click reac-
tions that can respond to different temperatures and release
functional molecules on demand.
Introduction
The 1,3-dipolar cycloaddition reaction between thio-
carbonyl-containing compounds 1 and nitrile oxides to gen-
erate 1,4,2-oxathiazoles was first reported by Huisgen and
Mack in 1961.[1] Although sporadic reports of the synthesis
of 1,4,2-oxathiazoles have appeared in the literature since
that time, there is limited interest in this class of compounds
because of their well-documented thermal sensitivity, which
results in fragmentation and rearrangement of the hetero-
cyclic core to give isothiocyanates (ITCs) 2 and a carbonyl-
containing counterpart (Scheme 1).[2]
A survey of the literature[2] from the time of Huisgen’s
pioneering work shows that the nature of the substituent at
the C-5 position of 1,4,2-oxathiazoles plays a dominant role
in determining the thermal sensitivity of these heterocycles,
and, in some cases, the reaction pathway.[6] In general, the
presence of electron-releasing substituents (N-, O-, and S-
substituents) at C-5 requires a lower temperature than a C-
substituted group (Ͼ180 °C) to effect fragmentation (Fig-
ure 1). The nature of the donor atom also has a significant
impact on the fragmentation temperature, as an N-substitu-
ent at C-5 sufficiently lowers the energy of activation barrier
for fragmentation to proceed at room temperature, whereas
O- and S-substitution require moderate heating (60–
120 °C). From our own work in this area, we have noted
that the substituent at C-3 also has a small influence on the
temperature sensitivity of 1,4,2-oxathiazoles, with aliphatic
C-3 substituents being more thermally sensitive than aryl
ones.[3c]
Scheme 1.
In recent years, efforts have been made to exploit the
thermal sensitivity of 1,4,2-oxathiazoles and thus increase
their synthetic utility by employing polymer-supported vari-
ants as synthetic equivalents of ITCs.[3] Although such
methods are useful in flow chemistry and small-scale prepa-
ration of ITCs, the general synthetic applicability of 1,4,2-
oxathiazoles remains limited.
Nevertheless, the cycloaddition between easily generated
nitrile oxides and thiocarbonyl-containing compounds pro-
ceeds with a high degree of selectivity under mild condi-
[a] Division of Organic Chemistry, Institute of Chemical and
Engineering Sciences, Agency for Science, Technology and
Research (A*STAR),
Figure 1. Summary of thermal responsiveness of previously re-
ported 1,4,2-oxathiazoles as a function of C-3 and C-5 substituents.
8 Biomedical Grove, #07-01 Neuros Building, Biopolis,
Singapore 166385
E-mail: brendan_burkett@ices.a-star.edu.sg
russell_hewitt@ices.a-star.edu.sg
To date, there has been only one study about the theoreti-
cal aspects of the fragmentation of 1,4,2-oxathiazoles,
which focused on the reactivity of 5,5-N-substitution rela-
http://www.ices.a-star.edu.sg
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500909.
Eur. J. Org. Chem. 2015, 6687–6700
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R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
FULL PAPER
tive to 5,5-C-substituted variants.[7] From this work, it was systems that are derived from five distinct classes of thio-
proposed that the increased thermal sensitivity of systems carbonyls 1, that is, thioketones (including thiobenzo-
with N-substituted systems results, in part, from a large phenones), O-thioesters, O,O-disubstituted thiocarbonates,
thermodynamic driving force associated with production of dithioesters, and trithiocarbonates (Scheme 3).
urea (vs. acetone for C-5 C-substituents). Additionally, it is
suggested that the donation of electron density to the C–S
σ* orbitals by the axial N-substituents results in the length-
ening and weakening of the C-5–S bond, which provides
kinetic assistance to the fragmentation process. Beyond this,
no experimental study has specifically addressed the reactiv-
ity of 1,4,2-oxathiazoles to corroborate and extend the cur-
rent level of understanding of these systems.
We have therefore undertaken the first systematic experi-
mental investigation of the thermal fragmentation of 1,4,2-
oxathiazoles to assess their potential as thermally program-
mable linkages for click chemistry. Given the well-known
propensity of 1,4,2-oxathiazoles derived from thiourea to
undergo fragmentation at low temperatures and our own
experience of attempting to isolate 2-amino-substituted
1,4,2-oxathiazoles from thioamides, we did not include
them as targets in our studies but instead focused on what
we consider isolable systems, which include C-, O, and S-
substituents at C-5 (i.e., 3–5, Figure 2).
Scheme 3. General routes to thiocarbonyl-containing di-
polarophiles 1 (THF = tetrahydrofuran, DCM = dichlorometh-
ane).
Thioketones were directly prepared by treatment of the
required ketone 10 with Lawesson’s reagent (LR). Thio-
benzophenones were typically prepared immediately prior
Figure 2. Oxathiazole classes studied.
to use, as a portion of the material oxidizes back into the
ketone, even with a minimal exposure to air. Other thio-
ketones with at least one alkyl group were much less
Results and Discussion
stable, and 1,4,2-oxathiazole formation was combined with
thionation as a one-pot procedure.
Synthesis of Oxathiazoles
Esters are generally less reactive towards Lawesson’s rea-
gent, yet they may be converted into thioesters by heating
at reflux in xylenes[9] or toluene in the case of volatile esters
such as ethyl propionate. In our hands, thionation of phenyl
benzoate was not observed, and hence the reaction of O-
phenyl chlorothioformate (12) and phenylmagnesium brom-
ide provided access to O-phenyl thiobenzoate. All O,O-di-
substituted thiocarbonates were prepared by reaction of
thiophosgene with an alcohol in the presence of base in
good to moderate isolated yields.
The requisite nitrile oxide precursors 6a–6c were synthe-
sized from aldoximes by following known literature pro-
cedures from readily available aldehydes as shown in
Scheme 2. The allyl hydroximidoyl chloride was prepared
by using an alternative route in which nitronate salt 9, syn-
thesized by the reaction of 4-bromobut-1-ene (7) with so-
dium nitrite followed by deprotonation, was used as the
allyl nitrile oxide precursor.[8]
Dithioesters were readily prepared from acyl chlorides
13 in a two-step procedure that involved reaction with the
appropriate thiol followed by treatment with Lawesson’s
reagent in refluxing toluene.[10] Diphenyl trithiocarbonate
was prepared analogously to the O,O-disubstituted thio-
carbonates by treating thiophosgene with thiophenol. Di-
benzyl and diethyl trithiocarbonates were prepared by a
milder route, that is, the reaction of the appropriate thiol
with carbon disulfide followed by alkylation, which fur-
nished the symmetrical trithiocarbonates in good yields and
Scheme 2. Synthesis of nitrile oxide precursors (NCS = N-chloro-
succinimide, DMF = N,N-dimethylformamide).
To adequately cover the scope of C-, O-, and S-substitu- purity.[11] The remaining targeted thiocarbonyl derivatives
ents at C-5 required for these studies, we focused only on were purchased from commercial sources.
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Eur. J. Org. Chem. 2015, 6687–6700

Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
Generally, the 1,3-dipolar cycloaddition reactions be- ponent (if possible) in the reaction mixture using the inte-
tween the nitrile oxides (generated in situ) and the thio- gration of the appropriate diagnostic signals in the 1H
carbonyl-containing compounds proceeded quantitatively NMR spectra over the duration of the experiment. A repre-
within minutes at room temperature. In most cases, purified sentative example of a typical experiment is shown in Fig-
oxathiazoles were obtained in good to high yields (50–90%) ures 3 and 4, which uses the moderately fast-fragmenting
and stored at low temperature. In cases where the thio- oxathiazole 3-phenyl-5,5-diphenoxy-1,4,2-oxathiazole (4g)
carbonyl compounds were unstable (e.g., aliphatic thio- in deuteroacetonitrile at 60 °C. This oxathiazole has a char-
ketones), the yields were much lower, and the dipolarophile acteristic peak at δ = 7.24 ppm, which was used to monitor
was best prepared immediately prior to use.
the proportion of fragmented material. To gain an under-
standing of the error that may be involved in our analysis,
Thermal Release Studies
Analysis of the fragmentation profiles of the 1,4,2-
oxathiazoles was not straightforward because these com-
pounds have a wide range of thermal sensitivities. Methods
such as GC and GC–MS could not be employed, as the
1,4,2-oxathiazoles will fragment in the injection port of the
instrument and make the ratios of the various breakdown
products impossible to determine. Liquid chromatography
(LC) was also unsuitable for our studies because of the po-
tential solvent effects and sample preparation times, which
introduce inaccuracies into the determination of product
1
ratios. Hence, H NMR spectroscopy was employed as the
method of choice to analyze the progress of fragmentation
over time.
As a result of the time-consuming nature of these studies,
variable temperature NMR analysis was impractical. There-
fore, each NMR tube was heated to a set temperature (se-
lected from 30, 60, 90, and 120 °C) for appropriate time
intervals prior to cooling to room temperature and re-
cording the spectra. For thermally insensitive 1,4,2-oxa-
thiazoles (e.g., 3a–3e, see Table 1), the samples were ana-
lyzed periodically for up to 182 days (i.e., 6 months). The
rate of disappearance of the oxathiazole along with the rate
of appearance of the ITC or carbonyl compound were mea-
Figure 3. Representative example of thermal release study con-
sured by determining the relative proportions of each com- ducted by 1H NMR spectroscopy of 4g in [D3]acetonitrile at 60 °C.
Table 1. Rate data for selected 1,4,2-oxathiazoles 3 heated at 60,[a] 90,[b] and 120 °C[b] (see Supporting Information for further examples).
60 °C
120 °C
Entry R1
R2
R3
3
k60 °C [s–1]
t1/2
k90 °C [s–1]
t1/290 °C k120 °C [s–1]
[days]
t1/2
[years]
[days]
1
2
3
4
5
6
7
8
Me
Et
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
n.d.[c]
n.d.
–
–
1.04ϫ10–7
6.53ϫ10–8
3.78ϫ10–7
9.40ϫ10–8
2.89ϫ10–7
5.12ϫ10–5
2.54ϫ10–6
8.51ϫ10–8
1.05ϫ10–6
9.37ϫ10–8
9.09ϫ10–7
1.08ϫ10–5
77
120
21
85
28
0.16
3.2
94
7.6
86
8.8
0.74
5.33ϫ10–6
2.10ϫ10–6
2.69ϫ10–5
3.62ϫ10–6
1.44ϫ10–5
1.43ϫ10–3
8.83ϫ10–5
3.20ϫ10–6
4.67ϫ10–5
n.d.
1.5
3.8
8.56ϫ10–9
4.00ϫ10–9[d]
7.37ϫ10–9[e]
2.36ϫ10–6
7.32ϫ10–8
4.53ϫ10–9
9.80ϫ10–9[f]
3.10ϫ10–9
1.15ϫ10–8
3.97ϫ10–7
2.6
5.5
3.0
3.4 d
110 d
4.8
2.2
7.1
1.9
20 d
0.30
2.2
0.56
0.0056
0.091
2.5
0.17
–
–
C6H4NMe2 Ph
C6H4OMe Ph
C6H4NO2 Ph
Ph
Ph
Ph
3g
3h
9
PhCH2CH2 3i
Me
allyl
10
11
12
3j
3k
3l
n.d.
n.d
C6H4OMe C6H4OMe Ph
–
[a] Recorded in [D3]acetonitrile. [b] Recorded in [D7]DMF. [c] Not determined: n.d. [d] In [D7]DMF, kfrag= 6.24ϫ10–9 s–1. [e] In [D7]-
DMF, kfrag = 8.42ϫ10–9 s–1. [f] In [D7]DMF, kfrag = 1.59ϫ10–8 s–1.
Eur. J. Org. Chem. 2015, 6687–6700
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R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
FULL PAPER
this experiment was repeated 10 times, which showed that cant solvent effects were in operation, which was confirmed
the rates of the 10 trials that were determined by using the to be the case. The kfrag values from these studies at 60,
NMR method were within 20% of the average. By using 90, and 120 °C are summarized in Table 1 along with the
this method, we expected that the faster fragmenting approximate half-lives at those temperatures. In general, the
oxathiazoles would have larger errors because of the differ- substitution of one or two alkyl groups at C-5 (Table 1, En-
ences in shimming times, whereas errors for slower frag- tries 1–4, compounds 3a–3d) did not have a pronounced ef-
menting systems were expected to be lower.
fect on the thermal sensitivity of these molecules relative to
the systems with two phenyl groups at C-5. In contrast, the
1,4,2-oxathiazoles derived from substituted thiobenzo-
phenones (i.e., 3e–3h) showed a much greater variation in
their thermal responsiveness. For example, a clear reduction
in the rate of fragmentation was observed in the case of 5-
(4-nitrophenyl)-3,5-diphenyl-1,4,2-oxathiazole (Table 1, En-
try 8, compound 3h) relative to 3e. The inclusion of elec-
tron-donating substituents on one of the C-5 aryl substitu-
ents [p-OMe (3g) and p-NMe2 (3f)] increased the thermal
sensitivity by orders of magnitude relative to 3e, although
in the latter case, the presence of the dimethylamino group
resulted in degradation of both the starting material and
products over the extended reaction times required at lower
temperatures. The inclusion of a second electron-donating
aryl substituent at C-5 (Table 1, Entry 12, compound 3l) re-
sulted in a further order of magnitude increase in the rate
of fragmentation, which shows that there is great flexibility
to program thermal responsiveness into these systems. The
1,4,2-oxathiazoles that have alkyl substituents larger than a
methyl group at the C-3 position (Table 1, Entries 9 and
11, compounds 3i and 3k) were at least three times more
susceptible to fragmentation at 60 °C than 3e.
Figure 4. Release curve of thermal fragmentation of 5,5-diphenoxy-
3-phenyl-1,4,2-oxathiazole by using spectra of 4g in Figure 3.
The proportion of oxathiazole observed by the NMR ex-
periments was recorded at each time point to the nearest
percent. The fragmentation rate constant (kfrag, s–1) was de-
termined directly from the reaction plot for this first-order
reaction by using MATLAB R2013a. For model compound
4g, the approximate kfrag value for the study in Figure 3 was
derived from Figure 4 and determined to be 2.82ϫ10–4 s–1,
which corresponds to a half-life of 0.68 h. All of the oxathi-
azoles gave an excellent linear fit as exemplified in Figure 4.
Athough this methodology was used for all of the release
studies of the stable oxathiazoles, the 5,5-dialkoxy-1,4,2-
oxathiazoles were unexpectedly too labile to be prepared
and isolated. Therefore, the formation of these compounds
was conducted in NMR tubes, and their fragmentations
were immediately monitored by recording spectra at several
times over the course of 20–30 min to estimate the rate con-
stants and half-lives. A more detailed discussion of this
analysis is supplied in the Supporting Information.
In all cases, there was a marked increase in the rate as
the temperature was increased by standard increments of
30 °C, which affords a rate increase by a factor of 20–100
and suggests half-lives of at least a century at 30 °C. The
fact that these molecules did not display typical Arrhenius
temperature dependence (i.e., an approximate doubling of
rate for every 10 °C increase in temperature) is interesting
and can be linked to the fact there are multiple atoms in-
volved along the fragmentation reaction coordinate.[12] For
those 1,4,2-oxathiazoles that were analyzed at three tem-
peratures in [D7]DMF, the Arrhenius plots (see Supporting
Information for examples) reveal approximate activation
energies of 135–145 kJmol–1. Given the significant rate in-
crease in moving from 3e to those 1,4,2-oxathiazoles with
C-5 aryl substituents that have electron-releasing groups, we
Thermal Responsiveness of 1,4,2-Oxathiazoles
used Hammett σ0 values to determine if a linear free en-
R
1. Oxathiazoles from Thioketones 3a–3l
ergy relationship exists by plotting them against the mea-
Thioketone-derived 1,4,2-oxathiazoles represent the most sured fragmentation rates of 1,4,2-oxathiazoles 3e–3h at 60,
stable of this class of compounds, and for all intents and 90, and 120 °C (Figure 5).
purposes are stable at room temperature. We therefore
It is encouraging that a linear free energy relationship
studied the fragmentation of a wide range of 1,4,2-oxathi- does appear to exist, and the temperature has little effect
azoles, which were derived from thioketones, at tempera- on the magnitude of the reaction constant (ρ), which can
tures ranging from 60 to 120 °C. Deuteroacetonitrile was be determined from the slope of the fitted curves. However,
used as the solvent for determining the fragmentation rates there does appear to be a nonlinear deviation in moving
at 60 °C, whereas [D7]DMF was the solvent of choice for from 3g to 3f, which would increase ρ, and this may have
higher temperatures. For reasons of practicality and cost, some mechanistic implications which will be discussed later.
we did not carry out all of the 60 °C release studies in [D7]- Nevertheless, the Hammett σ0R values provide a useful tool
DMF but monitored several representative 1,4,2-oxathi- to estimate the half-lives of C-5 aryl-substituted 1,4,2-
azoles in [D7]DMF at this temperature to ensure no signifi- oxathiazoles.
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Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
son between a second aryloxy or alkoxy substituent shows
a difference in rate of 103 s–1 at 30 °C (Table 2, Entries 4–7,
compounds 4d–4f vs. 4g). No rate data was obtained at
60 °C for these bis(alkoxy)-1,4,2-oxathiazoles, as the frag-
mentations would proceed too fast at this temperature. On
the basis of the fragmentation rates at 30 °C and by con-
sidering the typical rate increase for the other 1,4,2-oxathia-
zoles as the temperature was raised, the half-lives were pre-
dicted to be in the order of a few seconds at 60 °C. A similar
trend was seen with regard to C-3 substitution as that ob-
served with the thioketone-derived 1,4,2-oxathiazoles. The
C-3 alkyl substituents that are larger than a methyl group
displayed a higher thermal sensitivity than the C-3 aryl-
substituted derivatives (Table 2, Entries 8 and 10 vs. 7 and
9, compounds 4h and 4j vs. 4g and 4i).
In general, the 5-O-substituted series was slightly less
sensitive to temperature than the thioketone-derived tar-
gets, and their half-lives increased 10- to 50-fold per 30 °C
increment. Further release studies for 4g–4j at 40 and 50 °C
were performed, and the corresponding Arrhenius plots
were the generated (see Supporting Information for exam-
ples), which indicated approximate activation energies of
77–103 kJmol–1. However, these plots were decidedly less
linear than the C-5 substituted series.
Figure 5. Plot of logkfrag versus Hammett σ0 values[13] of 3e (Δ),
3f (᭺), 3g (ᮀ) and 3h (᭛) as a function of the para substituent at
60 °C (–––), 90 °C (–·–·–) and 120 °C (- - -).
R
2. 5-O-Substituted 1,4,2-Oxathiazoles 4a–4j
The results of the thermal release studies that were con-
ducted with thioester- and thiocarbonate-derived 1,4,2-ox-
athiazoles are shown in Table 2. As expected, the incorpora-
tion of an oxygen atom bonded at C-5 led to increased ther-
mal sensitivity of the 1,4,2-oxathiazoles relative to the thio-
ketone-derived systems, and compounds 4a and 4b frag-
3. S-Substituted 1,4,2-Oxathiazoles 5a–5m
The C-5 S-substituted 1,4,2-oxathiazoles were less ther-
mented readily at 30 °C. In the case of 4c, decomposition mally sensitive than the O-substituted series at all of the
into a nitrile was observed as a competing reaction path- examined temperatures (Table 3). For example, the half-life
way,[6b] and no efforts were made to determine the fragmen- of 5a at 30 °C (Table 3, Entry 1) was more than 200 times
tation rate at 30 °C. At elevated temperatures, however, the greater than that of corresponding thioester-derived 1,4,2-
presence of unconjugated alkoxy substituents at C-5 led to oxathiazole 4a (Table 2, Entry 1). Although thermally more
further increases in the thermal sensitivity relative to the stable in terms of ITC production, the dithioester-derived
aryloxy systems, and half lives of less than 1 h were noted 1,4,2-oxathiazoles that have a C-5 phenyl substituent (i.e.,
(Table 2, Entries 1–3, compounds 4a and 4b vs. 4c).
compounds 5b–5d, 5i, and 5j) displayed a higher propensity
The inclusion of a second alkoxy or phenoxy substituent to undergo an alternative fragmentation pathway in the
at C-5 led to further increases in reactivity, and a compari- presence of moisture to afford nitriles, similar to 4c.[6b]
Table 2. Rate data for selected 1,4,2-oxathiazoles 4 heated at 30,[a] 60,[a] and 90 °C.[b]
Entry R1
R2
R3
4
kfrag
[s–1] t1/2
[h] kfrag
[s–1]
t1/2
[h]
kfrag
[s–1]
t1/2
[h]
30 °C
30 °C
60 °C
60°C
90 °C
290 °C
1
2
3
4
5
6
7
8
9
10
Et
Ph
Ph
OEt
OEt
OPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
1.10ϫ10–5
2.29ϫ10–5
n.d.
17
8.4
–
0.097
0.020
0.081
29
7.2
34
4.2
6.13ϫ10–4
8.72ϫ10–4
1.90ϫ10–5
n.d.[c]
0.31
0.22
10
–
–
n.d.
n.d.
–
–
0.51
–
–
3.81ϫ10–4
n.d.[c]
OMe OMe
OEt OEt
OBn OBn
OPh OPh
OPh OPh
OPh OPh
OPh OPh
1.99ϫ10–3
9.82ϫ10–3
2.37ϫ10–3
6.75ϫ10–6
2.66ϫ10–5
5.67ϫ10–6
4.57ϫ10–5
n.d.[c]
n.d.[c]
n.d.[c]
–
n.d.[c]
–
4g
2.82ϫ10–4[d]
8.96ϫ10–4[e]
1.36ϫ10–4
8.00ϫ10–4
0.68
0.21
1.4
0.24
7.53ϫ10–3
1.34ϫ10–2
n.d.
0.026
0.014
–
PhCH2CH2 4h
Me
allyl
4i
4j
n.d.
–
[a] Recorded in [D3]acetonitrile. [b] Recorded in [D7]DMF. [c] Fragmentation of the 1,4,2-oxathiazole was too fast to be measured at this
temperature. [d] In [D7]DMF, kfrag = 5.09ϫ10–4 s–1. [e] In [D7]DMF, kfrag = 1.33ϫ10–3 s–1.
Eur. J. Org. Chem. 2015, 6687–6700
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FULL PAPER
Table 3. Rate data for selected 1,4,2-oxathiazoles 5 heated at 30,[a] 60,[a] and 90 °C.[b]
30°C
30 °C
60°C
60°C
90 °C
Entry
R1
R2
R3
5
kfrag
[s–1]
t1/2
[h]
kfrag
[s–1]
t1/2
[h] k90°C [s–1]
t1/2
[h]
1
2
3
4
5
6
7
8
Et
Ph
Ph
Ph
SMe
SEt
SBn
SPh
Ph
SEt
SEt
SBn
SPh
SMe
SEt
SBn
SPh
SEt
SPh
SEt
SBn
SPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
4.74ϫ10–8
n.d.
n.d.
4100
–
–
4.21ϫ10–6
3.27ϫ10–6
2.05ϫ10–6
2.29ϫ10–7
4.32ϫ10–4
9.30ϫ10–4
2.64ϫ10–4
2.12ϫ10–5[c]
7.12ϫ10–6
7.41ϫ10–7[d]
1.64ϫ10–3
4.75ϫ10–4
5.20ϫ10–5[e]
46
59
94
840
0.45
0.21
0.73
9.1
n.d.
–
1.6
–
38
–
–
1.24ϫ10–4
n.d.
n.d.
–
5.13ϫ10–6
n.d.
n.d.
1.28ϫ10–5
3.45ϫ10–5
5.69ϫ10–6
6.70ϫ10–7
n.d.
15
5.6
34
290
–
5g
5h
n.d.
–
5.17ϫ10–4
3.07ϫ10–4
1.34ϫ10–4[c]
n.d.
0.37
0.63
14
–
–
9
PhCH2CH2 5i
PhCH2CH2 5j
PhCH2CH2 5k
PhCH2CH2 5l
PhCH2CH2 5m
27
10
11
12
13
Ph
n.d.
–
260
0.12
0.41
3.7
SEt
SBn
SPh
6.91ϫ10–5
1.82ϫ10–5
1.22ϫ10–6
2.8
11
160
n.d.
9.76ϫ10–4
0.20
[a] Recorded in [D3]acetonitrile. [b] Recorded in [D7]DMF. [c] In [D7]DMF, kfrag = 2.22ϫ10–5 s–1. [d] Fragmentation into both the isothio-
cyanate and nitrile. See Supporting Information for method of rate constant determination. [e] In [D7]DMF, kfrag = 5.06ϫ10–5 s–1.
This side reaction made the determination of the lower S σ* orbital (Figure 6, structure A) results in the lengthen-
temperature fragmentation rates difficult to achieve, as the ing and weakening of the C-5–S bond relative to that of
alternative fragmentation pathway was temperature inde- the thioketone-derived 1,4,2-oxathiazoles.[7] An additional
pendent. At elevated temperatures, the kfrag values were interaction between the electron density of the equatorial
readily determined and indicated that the 1,4,2-oxathiazoles N-substituent and the endocyclic C-5–O σ* orbital was also
that have a single S-alkyl substituent at C-5 (Table 3, En- described, and this results in the lengthening the C-5–O
tries 1–3, compounds 5a–5c) displayed faster fragmentation bond (Figure 6, structure B) relative to the corresponding
rates than those with an S-aryl substituent (Table 3, En- bond in the thioacetone-derived 1,4,2-oxathiazole. Models
try 4, compound 5d) by up to an order of magnitude. As of systems with a single electron-releasing C-5 substituent
with the O-substituted series, the inclusion of an additional have not been done, but we propose that the substituent
S-alkyl substituent at C-5 led to a substantial increase in would reside in the axial position where it can interact with
the observed kfrag (Table 3, Entries 5–8, compounds 5e–5h) the C-5–S σ* orbital as described above (Figure 6, structure
and decreased the half-lives by approximately two orders of C). We also considered that, in the absence of an equatorial
magnitude at all of the temperatures investigated.
electron-releasing substituent at C-5, the contribution of
The effect of the C-3 substituent on the reactivity fol- electron density from the endocyclic oxygen atom to the
lowed a similar trend to those observed in the thioketone C-5–X σ* orbital (Figure 6, structure D) could also be an
and thioester series, as the C-3 alkylated 1,4,2-oxathiazoles important factor in determining the reactivity.
(Table 3, Entries 9–13, compounds 5i–5m,) displayed faster
fragmentation rates than the C-3 arylated derivatives. The
C-5 S-substituted series also exhibited a high degree of tem-
perature dependence with a 15- to 90-fold observed rate in-
crease per 30 °C increment. As no more than two tempera-
tures were studied in either [D3]acetonitrile or [D7]DMF,
Arrhenius plots were not possible. However, calculations
that use the rate constants in each solvent for both 5h and
5m (Table 3, Entries 8 and 13) give approximate activation
energies of 97–106 kJmol–1, which is similar to that of the
O-substituted 1,4,2-oxathiazoles.
Figure 6. Key anomeric interactions for monosubstituted 1,4,2-
oxathiazoles.
General Discussion
Reactivity Trends
Ab initio calculations performed by others on 5,5-di-
With these considerations in mind, we compared the ob-
amino-1,4,2-oxathiazole suggest that the overlap of the lone served rates for a selection of 1,4,2-oxathiazoles at 60 °C to
electron pairs of the axial C-5 N-substituent with the C-5– investigate if the major reactivity trends could be reconciled
6692
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Eur. J. Org. Chem. 2015, 6687–6700

Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
with these important interactions (Table 4). The effect of a C-5 N-substituent did not further increase the length of the
heteroatom as a substituent is immediately obvious by the C-5–S bond (Table 5, Entry 2) but showed an increase in
orders of magnitude difference in the kfrag values between the C-5–O bond length compared to that of the thioace-
the benchmark benzophenone-derived 1,4,2-oxathiazole 3e tone-derived 1,4,2-oxathiazole.
(Table 4, Entry 1) and those derived from O-alkyl and O-
aryl thioesters (Table 4, Entries 2 and 3) and dithioesters
Table 5. MP2/3-21G-calculated bond lengths as a function of C-5
(Table 4, Entries 4 and 5). These differences in kfrag trans-
late to large differences in the half-lives of these 1,4,2-
oxathiazoles, which range from years (Table 4, Entry 1) to
under 1 h (Table 4, Entry 2).
substitution.
Entry
R1
R2
C-5–S [Å]
C-5–O [Å]
Table 4. Rate data for selected 1,4,2-oxathiazoles heated in [D3]-
acetonitrile at 60 °C.[a]
1
2
3
4
5
6
7
NMe2
NMe2
OMe
OMe
SMe
SMe
Me
Me
NMe2
Me
OMe
Me
SMe
Me
2.033
2.021
1.963
1.946
1.920
1.921
1.927
1.487
1.516
1.456
1.462
1.478
1.474
1.499
Entry R1
R2
Compd. kfrag [s–1]
t1/2
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
OEt
OPh OPh
SEt
SPh
Ph
3e
4b
4c
5b
5d
4e
4g
5f
7.37ϫ10–9
8.72ϫ10–4
1.90ϫ10–5[b]
3.27ϫ10–6
2.29ϫ10–7[b]
0.3Ϯ0.1[c]
2.82ϫ10–4
9.30ϫ10–4
2.12ϫ10–5
3.0 years
0.22 h
10 h
OEt
OPh
SEt
SPh
OEt
The presence of an O-substituent in the axial position
led to a moderate increase in C–S bond length relative to
the thioacetone-derived systems, whereas an S-containing
substituent resulted in shorter C-5–S bond lengths, which
approximated those of the thioacetone-derived 1,4,2-oxathi-
azole. As expected, the C-5–O bond length of the 1,4,2-
oxathiazole core was shortest in the cases where the axial
substituent was most electronegative (Figure 6, Xaxial = O).
However, there was no evident correlation between the ob-
served reactivity and the C-5–O bond length (Table 5, En-
tries 1 and 3–6 vs. 7), hence, it appears that the interaction
described in Figure 6, structures A and C appear to be a
key determinant in the intrinsic thermal sensitivity of the
1,4,2-oxathiazoles.
59 h
840 h
2Ϯ1 s[c]
0.68 h
0.21 h
9.1 h
SEt
SPh
5m
[a] Although data was collected for up to three different tempera-
tures for each class of the 1,4,2-oxathiazoles investigated, a mean-
ingful comparison could only be achieved by observing their behav-
ior at 60 °C. [b] For 1,4,2-oxathiazoles 4c and 5d, a competing frag-
mentation pathway that afforded nitriles was observed in the pres-
ence of moisture. [c] The kfrag was unable to be determined at this
temperature as the fragmentation process proceeded too fast. Esti-
mates were determined by the extrapolation of data obtained at
30 °C.
On the basis of our analysis, we propose that a linear
free energy relationship between the Hammett σ0 values
R
The further acceleration of the rate of fragmentation and the relative rates of reaction measured across the three
upon substitution of a second electron-releasing substituent classes of examined oxathiazoles may exist. A plot of the
at C-5 was evident with the 1,4,2-oxathiazoles that were de- observed logkfrag against the literature σ0 values for the
R
rived from O,O-dialkyl and O,O-diphenyl thiocarbonates substituted 3,5-diphenyl-1,4,2-oxathiazole systems reveal an
(Table 4, Entries 6 and 7) and the alkyl and phenyl trithio- excellent correlation with a large negative value for the reac-
carbonates (Table 4, Entries 8 and 9), which exhibited much tion constant (ρ = –14.38, Figure 7). This prompted us to
shorter half-lives at these temperatures than the monosub- consider that, in addition to the reaction being promoted
stituted derivatives. In the case of Table 4, Entry 6, 1,4,2- by favorable orbital overlap, the rate-determining step may
oxathiazole 4e was only observed at 30 °C and had a half- involve the stabilization of a positive charge and, hence,
life of just over one minute, which implies a half-life of up support the notion of a stepwise or asynchronous mecha-
to a few seconds at 60 °C.
nism.
To investigate whether the substituent effects on the reac-
We also used the data from our studies and literature σ0
R
tivity would be manifested in the bond lengths and allow values to extrapolate the theoretical thermal sensitivity of
the determination of the most important orbital interac- 5-dimethylamino-5-phenyl-1,4,2-oxathiazole, which pre-
tions, we conducted ab initio calculations (MP2/3-21G)[14] dicted a half-life of less than 1 min at 60 °C. From this, we
on simplified systems and examined the calculated bond calculated a theoretical half-life of minutes at 30 °C and
lengths of the ground states (Table 5). It was noted that the were, therefore, confident that we could observe a 5-amino-
reactivity observed in our studies correlated to the degree substituted 1,4,2-oxathiazole for the first time. Unfortu-
of elongation of the C-5–S bond of the thioacetone-derived nately, no trace of 5-dimethylamino-5-phenyl-1,4,2-oxathi-
system (Table 5, Entry 7). The 1,4,2-oxathiazoles with a sin- azole at 30 °C was detected in our attempts, which implies
gle N-substituent at C-5 resulted in the longest calculated a fragmentation rate greater than that of 5,5-diethoxy-1,4,2-
length. As expected, the presence of an additional oxathiazole 4e (logk Ն –0.5).
Eur. J. Org. Chem. 2015, 6687–6700
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6693

R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
FULL PAPER
Figure 7. Plot of logkfrag versus Hammett σ0 values[12] as a func-
R
tion of the C-5 substituent (᭺). The logkfrag values were obtained
from experimental data. The predicted logkfrag value for 5-NMe2
(Δ, predicted kfrag = 0.012, t1/2 ≈ 48 sec).
Figure 8. Plot of logkfrag/k0 versus Hammet σ0 values[10] as a
function of the C-5 substituent at 60 °C [Group A (––––), Group B
(- - -)].
R
Mechanistic Implications
crossover, which would depend on the nature of the C-5
To better understand the mechanistic implications of our substituents. In this case, Group A compounds would frag-
studies, we classified 5-phenyl-1,4,2-oxathiazoles into two ment by undergoing route A, and Group B compounds
distinct groups: (1) those which bear C-5 heteroatom sub- would fragment by proceeding through route B. In reality,
stituents and can interact with the C-5–S σ* orbital to pro- it is difficult to delineate these two routes, and further calcu-
vide mesomeric stabilization to the carbocations (Group A) lations on these systems are required to corroborate our
and (2) those that do not (Group B). When plotted together experimental findings.
against Hammett σ0 values (by using 3e as the reference
R
compound of each group to define k0), the potential mech-
anistic impact of the C-5 substituent becomes clear (Fig-
ure 8).
The compounds that were classified into Group B (i.e.,
3c, 3d, 3f, 3g, and 3h) showed a moderate reaction constant
(ρ = –4.1), indicating that stabilization of positive charge is
an important consideration in the reaction mechanism. As
already described in the previous section, the strong nega-
tive correlation (ρ = –14.3), which was observed for com-
pounds classified into Group A (i.e., 4b, 4c, 5b, and 5d), is
strongly indicative that a formal positive charge is stabilized
in the rate-determining step.
Scheme 4. Two possible mechanistic pathways for the conversion
of 1,4,2-oxathiazoles into ITCs.
Through this analysis, we are able to provide the first
experimental evidence that supports the fragmentation
The Effect of C-3
process proceeding through
a
stepwise mechanism
From our studies, it is evident that in all classes of the
(Scheme 4).[7] The lengthening of the C-5–S bond by an 1,4,2-oxathiazoles studied, there is a general trend that 3-
axial electron-releasing substituent would lower the energy alkyl substituents lead to slightly faster fragmentation rates
of activation barrier to formation of INT (Scheme 4, than their 3-phenyl variants by up to a factor of five. The
Route A) and provide further mesomeric stabilization to exception is in the case of 3-methyl-1,4,2-oxathiazoles,
that intermediate. A second electron-donating substituent which are more stable than the 3-phenyl-1,4,2-oxathiazoles.
clearly offers additional stability to this intermediate. It can- Although the origin of this increase in reactivity for the
not be ruled out that the fragmentation of 1,4,2-oxathi- larger 3-alkyl-substituted oxathiazoles is unknown, it is
azoles into ITCs proceeds through a highly asynchronous likely that conformational hyperconjugative effects between
pathway (Scheme 4, Route B), in which the contributing alkyl side chains and the ring system are at play.[15] Given
factors described above would similarly stabilize the transi- that the C-3 substituent determines the structure of the ITC
tion state (TS). There is also the possibility of a mechanistic upon fragmentation, we consider this interaction to be of
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Eur. J. Org. Chem. 2015, 6687–6700

Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
as the spectra were obtained. Chemical shifts (δ) are reported in
parts per million relative to the chemical shift of tetramethylsilane
(δ = 0.00 ppm). The spectra were referenced to the residual chloro-
less importance in programming the temperature sensitivity
of 1,4,2-oxathiazoles for click chemistry applications.
1
form singlet (CHCl3, δ = 7.26 ppm) for H NMR or the center of
the chloroform triplet (CDCl3, δ = 77.00 ppm) for 13C NMR. In
Summary
CD2Cl2, the spectra were similarly referenced to the residual
1
dichloromethane signal (CHDCl2, δ = 5.32 ppm) for H NMR or
This investigation of the thermal sensitivity of 1,4,2-
oxathiazoles represents the most comprehensive study of
this class of compounds to date. The fragmentation half-
lives of the three classes of 1,4,2-oxathiazoles ranged from
seconds to centuries at 30 °C. These systems do not exhibit
typical Arrhenius behavior and have higher fragmentation
rates than expected at elevated temperatures, which is en-
couraging in the context of developing highly responsive
systems. Gratifyingly, there is a large degree of predictabil-
ity in the thermal responsiveness of these systems, which
allows click partners to be chosen on the basis of readily
the center of the dichloromethane multiplet (CD2Cl2,
δ =
53.84 ppm) for 13C NMR. The 1H NMR spectroscopic data are
reported in the order of chemical shift (δ), multiplicity [br. (broad),
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublets)], coupling constant (J), and relative integra-
tion (number of protons). The center of the multiplet is reported
for the chemical shifts of single protons. More complex multiplets
are reported as a range. The 13C NMR spectroscopic data are re-
ported by listing the chemical shifts (δ). Infrared spectra were re-
corded on a Perkin–Elmer Spectrum 100 FTIR spectrometer, and
the samples were run neat. Infrared data are recorded as key peak
in cm–1). High resolution mass spectra were ob-
available data in the form of Hammett σ0 parameters.
frequencies (ν
˜
max
R
tained on an Agilent LC-TOF instrument using an electrospray
ionization source in the positive mode. Benzyl dithiobenzoate and
dimethyl trithiocarbonate were purchased from Sigma–Aldrich. All
other reagents and solvents were of analytical quality and used as
received. Methods for the preparation of starting materials are in-
cluded in the Supporting Information.
On the basis of our own work involving 5,5-diphenoxy-
1,4,2-oxathiazoles,[3c] we envision that 5-alkoxy-1,4,2-
oxathiazoles hold promise as ideal candidates for program-
mable click reactions, as they would produce innocuous or
even volatile esters. In addition, we believe that being able
to produce ITCs at lower temperatures than those needed
for thioketone-derived systems would expand the scope of
possible applications. However, our studies indicate that the
greatest flexibility for the development of longterm, stable
programmable click linkers to release ITCs comes from
thiobenzophenone-derived 1,4,2-oxathiazoles. In these
cases, the thermal responsiveness of the system can be ade-
quately controlled by the choice of C-5 aryl substituent.
Thioketone-derived 1,4,2-oxathiazoles also do not suffer
from potential side reactions such as nitrile formation in
the presence of water. For shorter term click linkages, C-5
O- or S-substituted systems are more appropriate, as iso-
lable oxathiazoles exhibit half-lives that range from hours
to months at room temperature.
General Procedures for Oxathiazole Synthesis (3–5)
A – Synthesis of 1,4,2-Oxathiazoles: A solution of N-hydroxy-
imidoyl chloride (1.1 equiv.) and the thiocarbonyl compound
(1.0 equiv.) in dichloromethane (10 mL/mmol thiocarbonyl com-
pound) was cooled to 0 °C and then treated with triethylamine (ap-
proximately 1.1–3.0 equiv.). The resulting solution was then stirred
at room temperature for 1 to 2 h. The mixture was filtered through
a plug of silica, rinsing with dichloromethane (20 mL/mmol thio-
carbonyl compound), and the filtrate was then concentrated. Un-
less otherwise stated, the crude product was purified by column
chromatography to provide the corresponding oxathiazole.
B – Synthesis of 3-Allyl-1,4,2-oxathiazoles: A solution of sodium
but-3-en-1-ylideneazinate (1.1 equiv.) in diethyl ether (10 mL/mmol
thiocarbonyl compound) was cooled to –78 °C and then slowly
treated with hydrochloric acid (4 m in dioxane, 8 equiv.). The mix-
ture was stirred for 15 min, warmed to –40 °C, and then treated
with triethylamine until the color of the mixture changed from blue
to pale brown. The thiocarbonyl compound (1.0 equiv.) was added,
and the mixture was stirred at room temperature overnight. The
reaction was quenched by the addition of water (50 mL/mmol thio-
carbonyl compound). The aqueous and organic layers were sepa-
rated, and the aqueous layer was extracted with ethyl acetate (2ϫ
50 mL). The combined organic extracts were washed successively
with water and brine, dried, and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
or preparative TLC to provide the corresponding oxathiazole.
Conclusions
We have conducted the first systematic investigation of
the thermal reactivity of 1,4,2-oxathiazoles and have shown
that their behavior is atypical in response to temperature,
as fragmentation occurs at higher than expected rates at
elevated temperatures. This reactivity makes 1,4,2-oxathi-
azoles potentially useful as thermally responsive click link-
ers. Through this work, we have also provided the first ex-
perimental support for theoretical studies, which suggest
that two possible reaction pathways may exist for this frag-
mentation reaction.
C – 1,4,2-Oxathiazoles from Ketones: Lawesson’s reagent (approxi-
mately 0.75 equiv.) in degassed toluene (25 mL) was treated with
the selected ketone (approximately 5 mmol), and the resulting mix-
ture was heated at reflux for 2–4 h (3 d for acetone). The reaction
mixture was cooled to 0 °C and then treated with a solution of N-
hydroxyimidoyl chloride (1.1 equiv.) in dichloromethane (10 mL)
followed by triethylamine (ca. 1–3 equiv.). The reaction mixture
was then stirred at room temperature for 1 to 2 h and concentrated.
The residue was filtered through a plug of silica, rinsing with tolu-
ene. The filtrate was concentrated, and the crude product was puri-
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded with a Bruker NMR spectrometer operating at 400 and
100 MHz, respectively. CDCl3 was used as the NMR solvent, un-
less otherwise indicated, and the samples of the oxathiazoles were
typically filtered through potassium carbonate to minimize cleavage
Eur. J. Org. Chem. 2015, 6687–6700
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6695

R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
fied by column chromatography to provide the corresponding ox- 0.52 mmol) were employed in general procedure A. Chromato-
FULL PAPER
athiazole.
graphic purification (10–20% toluene in petroleum ether) provided
oxathiazole 3e (87 mg, 53%) as a white solid, m.p. 108–110 °C;
Thioketone-Derived Oxathiazoles
1
ref.[1] m.p. 110 °C. H NMR (400 MHz, CDCl3): δ = 7.71–7.67 (m,
5,5-Dimethyl-3-phenyl-1,4,2-oxathiazole (3a): Lawesson’s reagent
(2.08 g, 5.14 mmol) in degassed acetone (20 mL) was heated at re-
flux for 3 d. The reaction mixture was cooled to room temperature
and then treated with N-hydroxybenzimidoyl chloride (132 mg,
0.85 mmol) and triethylamine (0.2 mL, 1.4 mmol). The mixture was
stirred at room temperature for 1 h and then concentrated. The
residue was filtered through a plug of silica, rinsing with toluene.
The filtrate was concentrated. Chromatographic purification (50%
toluene in petroleum ether) of the crude product provided 3a
(13 mg, 8% from N-hydroxybenzimidoyl chloride) as a clear oil. 1H
NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 2 H), 7.46–7.38 (m, 3
H), 1.88 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.0,
2 H), 7.63–7.58 (m, 4 H), 7.45–7.31 (m, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.8, 141.3, 131.1, 128.73, 128.71, 128.21,
128.17, 128.0, 127.0, 108.6 ppm. IR: ν
= 1490, 1449, 1276, 980,
˜
max
962, 920, 758, 683 cm–1. HRMS (TOF): calcd. for C20H16NOS+ [M
+ H]+ 318.0947; found 318.0935.
5-(4-Dimethylaminophenyl)-3,5-diphenyl-1,4,2-oxathiazole (3f): N-
Hydroxybenzimidoyl chloride (80 mg, 0.51 mmol) and 4-dimethyl-
aminothiobenzophenone (111 mg, 0.46 mmol) were employed in
general procedure A. Chromatographic purification (0–4% ethyl
acetate in petroleum ether) provided oxathiazole 3f (53 mg, 32%)
1
as a yellow solid; m.p. 143–144 °C. H NMR (400 MHz, CDCl3):
δ = 7.69 (dd, J = 8.0, 1.5 Hz, 2 H), 7.64 (dd, J = 8.1, 1.4 Hz, 2 H),
7.44–7.30 (m, 8 H), 6.68 (d, J = 8.9 Hz, 2 H), 2.96 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 157.0, 150.7, 142.5, 130.8, 128.7,
128.62, 128.58, 128.4, 127.96, 127.93, 127.4, 126.9, 111.5, 109.2,
130.8, 128.9, 128.7, 127.8, 102.1, 29.2 ppm. IR: ν
= 1446, 1368,
˜
max
1276, 1175, 976, 899, 762, 690, 683 cm–1. HRMS (TOF): calcd. for
C10H12NOS+ [M + H]+ 194.0634; found 194.0633.
5,5-Diethyl-3-phenyl-1,4,2-oxathiazole (3b): By following general
procedure C, Lawesson’s reagent (1.60 g, 3.96 mmol) was treated
with 3-pentanone (446 mg, 5.18 mmol). The solution of the thio-
ketone was subsequently treated with a solution of N-hydroxy-
benzimidoyl chloride (0.49 g, 3.2 mmol) and triethylamine (2.0 mL,
14 mmol). Chromatographic purification (100% toluene) provided
oxathiazole 3b (96 mg, 8% from 3-pentanone) as a clear oil. 1H
NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 2 H), 7.45–7.36 (m, 3
H), 2.06 (q, J = 7.4 Hz, 4 H), 1.09 (t, J = 7.4 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.3, 130.6, 128.9, 128.6, 127.7,
40.3 ppm. IR: ν
= 1610, 1523, 1446, 1362, 1164, 963, 813 cm–1.
˜
max
HRMS (TOF): calcd. for C22H21N2OS+ [M + H]+ 361.1369; found
361.1361.
5-(4-Methoxyphenyl)-3,5-diphenyl-1,4,2-oxathiazole
(3g):
N-
Hydroxybenzimidoyl chloride (178 mg, 1.14 mmol) and 4-meth-
oxythiobenzophenone (223 mg, 0.98 mmol) were employed in gene-
ral procedure A. Chromatographic purification (7% ethyl acetate
in petroleum ether) provided oxathiazole 3g (272 mg, 80%) as a
white solid; m.p. 113–115 °C. 1H NMR (400 MHz, CDCl3): δ =
7.71–7.67 (m, 2 H), 7.63–7.59 (m, 2 H), 7.51 (dt, J = 9.0, 2.6 Hz,
2 H), 7.45–7.31 (m, 6 H), 6.88 (dt, J = 9.0, 2.6 Hz, 2 H), 3.81 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 156.9, 141.8,
132.9, 131.0, 128.8, 128.7, 128.6, 128.3, 128.1, 128.0, 126.9, 113.5,
110.9, 32.8, 9.3 ppm. IR: νmax = 1592, 1581, 1458, 1446, 1277, 978,
˜
932, 915, 761, 690 cm–1. HRMS (TOF): calcd. for C12H16NOS+ [M
+ H]+ 222.0947; found 222.0949.
5-Methyl-3,5-diphenyl-1,4,2-oxathiazole (3c): By following general
procedure C, Lawesson’s reagent (1.68 g, 4.15 mmol) was treated
with acetophenone (586 mg, 4.88 mmol). The solution of thioace-
tophenone was subsequently treated with a solution of N-hydroxy-
benzimidoyl chloride (346 mg, 2.22 mmol) and triethylamine
(0.5 mL, 3.6 mmol). Chromatographic purification (0–5% ethyl
acetate in petroleum ether) followed by recrystallization (petroleum
ether) provided oxathiazole 3c (156 mg, 13% from acetophenone)
108.6, 55.3 ppm. IR: ν
= 1611, 1512, 1446, 1307, 1258, 1180,
˜
max
1033, 980, 964, 921, 826 cm–1. HRMS (TOF): calcd. for C21H17
+
NO2SNa [M + Na]+ 370.0872; found 370.0872.
5-(4-Nitrophenyl)-3,5-diphenyl-1,4,2-oxathiazole (3h): N-Hydroxy-
benzimidoyl chloride (79 mg, 0.51 mmol) and 4-nitrothiobenzo-
phenone (111 mg, 0.46 mmol) were employed in general procedure
A. Chromatographic purification (0–3% ethyl acetate in petroleum
ether) provided oxathiazole 3h (104 mg, 63%) as a light yellow so-
1
as a white solid; m.p. 70–73 °C. H NMR (400 MHz, CDCl3): δ =
1
lid; m.p. 119–122 °C. H NMR (400 MHz, CDCl3): δ = 8.23 (dt, J
7.67 (dd, J = 8.2, 1.5 Hz, 2 H), 7.62 (dd, J = 7.2, 1.6 Hz, 2 H),
7.45–7.36 (m, 5 H), 7.32 (tt, J = 7.4, 1.7 Hz, 1 H), 2.20 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 156.9, 143.0, 140.0, 128.7, 128.5,
= 8.7, 2.2 Hz, 2 H), 7.80 (dt, J = 8.7, 2.3 Hz, 2 H), 7.69–7.66 (m,
2 H), 7.58–7.54 (m, 2 H), 7.48–7.36 (m, 6 H ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.8, 149.0, 148.0, 139.2, 131.5, 129.5,
128.41, 128.36, 127.9, 124.9, 104.5, 29.6 ppm. IR: ν
= 1491,
˜
max
1441, 1270, 1228, 979, 896, 759, 696, 684 cm–1. HRMS (TOF):
128.9, 128.6, 128.1, 127.7, 127.6, 127.1, 123.5, 107.3 ppm. IR: ν
˜
max
= 1607, 1522, 1447, 1349, 1275, 979, 851 cm–1. HRMS (TOF):
calcd. for C20H15N2O3S+ [M + H]+ 363.0798; found 363.0796.
calcd. for C15H14NOS+ [M + H]+ 256.0791; found 256.0800.
5-Ethyl-3,5-diphenyl-1,4,2-oxathiazole (3d): By following general
procedure C, Lawesson’s reagent (1.62 g, 4.01 mmol) was treated
with propiophenone (580 mg, 4.32 mmol). The solution of thio-
propiophenone was subsequently treated with a solution of N-
hydroxybenzimidoyl chloride (712 mg, 4.58 mmol) and triethyl-
amine (2.0 mL, 14 mmol). Chromatographic purification (100%
toluene) provided oxathiazole 3d (145 mg, 12% from propiophen-
3-Phenethyl-5,5-diphenyl-1,4,2-oxathiazole (3i): N-Hydroxy-3-phen-
ylpropanimidoyl chloride (205 mg, 1.11 mmol) and thiobenzo-
phenone (200 mg, 1.01 mmol) were employed in general procedure
A. Chromatographic purification (10–20% ethyl acetate in petro-
leum ether) provided oxathiazole 3i (257 mg, 74%) as a white solid;
1
m.p. 68–70 °C. H NMR (400 MHz, CDCl3): δ = 7.53–7.48 (m, 4
1
H), 7.37–7.31 (m, 6 H), 7.24–7.16 (m, 3 H), 7.10–7.08 (m, 2 H),
2.91–2.87 (m, 2 H), 2.83–2.78 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.2, 141.6, 139.7, 128.6, 128.5, 128.3, 128.1, 126.9,
one) as a clear oil; m.p. 33–35 °C. H NMR (400 MHz, CDCl3): δ
= 7.67–7.65 (m, 2 H), 7.56–7.54 (m, 2 H), 7.41–7.35 (m, 5 H), 7.32
(tt, J = 7.4, 1.8 Hz, 1 H), 2.50–2.33 (m, 2 H), 1.07 (t, J = 7.3 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.4, 142.9, 130.9,
128.7, 128.5, 128.24, 128.16, 127.9, 125.0, 108.8, 35.1, 9.7 ppm. IR:
126.4, 108.3, 33.6, 30.3 ppm. IR: ν
= 1573, 1494, 1448, 1204,
˜
max
965, 907 cm–1. HRMS (TOF): calcd. for C22H19NOSNa [M +
+
Na]+ 368.1080; found 368.1068.
ν
= 1593, 1446, 1275, 979, 915, 758, 690 cm–1. HRMS (TOF):
˜
max
calcd. for C16H16NOS+ [M + H]+ 270.0947; found 270.0957.
3-Methyl-5,5-diphenyl-1,4,2-oxathiazole (3j): N-Hydroxyacetimido-
yl chloride (655 mg, 7.0 mmol) and thiobenzophenone (1.03 mg,
5.20 mmol) were employed in general procedure A. Chromato-
3,5,5-Triphenyl-1,4,2-oxathiazole (3e): N-Hydroxybenzimidoyl
chloride (89 mg, 0.57 mmol) and thiobenzophenone (103 mg,
6696
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6687–6700

Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
graphic purification (2–5% diethyl ether in petroleum ether) pro-
155.2, 138.7, 131.0, 129.3, 128.9, 128.25, 128.22, 127.7, 126.6,
126.5, 60.3, 14.8 ppm. IR: ν = 1541, 1492, 1449, 1277, 1241,
vided oxathiazole 3j (0.57 g, 43% yield) as a white solid; m.p. 42–
˜
max
1
44 °C. H NMR (400 MHz, CDCl3): δ = 7.54–7.51 (m, 4 H), 7.38– 1092, 1074, 973, 759, 689 cm–1. HRMS (TOF): calcd. for
7.30 (m, 6 H), 2.17 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ C16H16NO2S+ [M + H]+ 286.0896; found 286.0891.
= 153.3, 141.6, 128.6, 128.1, 126.9, 108.7, 14.0 ppm. IR: ν
=
˜
max
5-Phenoxy-3,5-diphenyl-1,4,2-oxathiazole (4c): A solution of N-
hydroxybenzimidoyl chloride (91 mg, 0.59 mmol) and O-phenyl
thiobenzoate (88 mg, 0.41 mmol) in dichloromethane (4 mL) was
cooled 0 °C and then treated with triethylamine (64 μL,
0.46 mmol). The resulting mixture was stirred at room temperature
for 2 h. The mixture was diluted with water (20 mL) and then ex-
tracted with dichloromethane (2ϫ 10 mL). The combined extracts
were dried and filtered, and the filtrate was concentrated. The
crude product was purified by column chromatography (1% trieth-
ylamine, 3% ethyl acetate in petroleum ether) to provide oxathi-
1583, 1491, 1448, 1377, 1318, 1267, 1229, 1197, 1174 cm–1. HRMS
(TOF): calcd. for C15H14NOS+ [M
256.0798.
+
H]+ 256.0791; found
3-Allyl-5,5-diphenyl-1,4,2-oxathiazole (3k): By following general
procedure B, solution of sodium but-3-en-1-ylideneazinate
a
(63 mg, 0.51 mmol) in diethyl ether (12 mL) was treated with
hydrochloric acid (4 m in dioxane, 1 mL, 4 mmol). Thiobenzo-
phenone (94.5 mg, 0.48 mmol) was added. Purification by prepara-
tive TLC (10–30% chloroform in petroleum ether) provided oxathi-
1
1
azole 3k (33 mg, 22% yield) as a translucent semisolid. H NMR
azole 4c (75 mg, 55%) as a white solid; m.p. 88–89 °C. H NMR
(400 MHz, CDCl3): δ = 7.54–7.50 (m, 4 H), 7.38–7.30 (m, 6 H), (400 MHz, CD2Cl2): δ = 7.84–7.81 (m, 2 H), 7.50–7.45 (m, 5 H),
5.81 (ddt, J = 16.9, 10.1, 6.6 Hz, 1 H), 5.18 (dq, J = 9.8, 1.3 Hz, 1
7.45–7.41 (m, 1 H), 7.39–7.34 (m, 2 H), 7.25–7.23 (m, 4 H), 7.13–
H), 5.14 (m, 1 H), 3.25 (dt, J = 6.6, 1.4 Hz, 2 H) ppm. 13C NMR 7.07 (m, 1 H) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 156.4,
(100 MHz, CDCl3): δ = 156.4, 141.5, 131.3, 128.6, 128.1, 126.9, 153.5, 137.8, 131.5, 130.1, 129.3, 129.2, 128.9, 128.1, 128.0, 127.4,
119.1, 108.3, 32.7 ppm. IR: ν
= 1642, 1574, 1491, 1448, 1423,
127.2, 125.5, 123.3 ppm. IR: ν
= 1489, 1449, 1237, 1202, 1012,
˜
˜
max
max
1265, 1228, 1173 cm–1. HRMS (TOF): calcd. for C17H16NOS+ [M
+ H]+ 282.0947; found 282.0934.
979, 758, 690 cm–1. HRMS (TOF): calcd. for C20H15NO2SNa+ [M
+ Na]+ 356.0716; found 356.0727.
5,5-Bis(4-methoxyphenyl)-3-phenyl-1,4,2-oxathiazole (3l): Following 5,5-Dimethoxy-3-phenyl-1,4,2-oxathiazole (4d): A solution of N-
general procedure C, Lawesson’s reagent (331 mg, 0.81 mmol) was hydroxybenzimidoyl chloride (19 mg, 122 μmol) and a mixture of
treated with 4,4Ј-dimethoxybenzophenone (250 mg, 1.03 mmol). dimethyl thionocarbonate, dimethyl carbonate, and methanol
The solution of 4,4Ј-dimethoxythiobenzophenone was sub-
sequently treated with a solution of N-hydroxybenzimidoyl chloride
(7 mg, approximately 29 μmol thionocarbonate as judged by 1H
NMR analysis) were dissolved in deuterodichloromethane (1 mL),
(342 mg, 2.20 mmol) and triethylamine (0.48 mL, 2.86 mmol). and the resulting mixture was treated with triethylamine (30 μL,
1
Chromatographic purification (25% diethyl ether in petroleum
ether) provided oxathiazole 3l (110 mg, 28% yield) as a white vis-
220 μmol). A H NMR spectrum was immediately acquired. After
1
3 h, a H NMR spectrum showed the presence of phenyl isothio-
cous oil. 1H NMR (400 MHz, CDCl3): δ = 7.70–7.66 (m, 2 H), cyanate and dimethyl carbonate. H NMR (400 MHz, CD2Cl2): δ
1
7.54–7.49 (m, 4 H), 7.45–7.34 (m, 3 H), 6.90–6.85 (m, 4 H), 3.81
= 7.66–7.64 (m, 2 H), 3.54 (s, 6 H) ppm. Note: Because of the
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 157.0, transient nature of this species, all of the aromatic signals were not
133.4, 130.9, 128.7, 128.6, 128.4, 127.94, 113.4, 108.6, 55.3 ppm.
observed. Therefore, only signals clearly separate from those of
IR: ν
= 1608, 1540, 1509, 1463, 1445, 1305, 1274, 1253, 1173, other products are assigned.
˜
max
1033 cm–1. HRMS (TOF): calcd. for C22H20NO3S+ [M + H]+
5,5-Diethoxy-3-phenyl-1,4,2-oxathiazole (4e): A solution of N-
hydroxybenzimidoyl chloride (24 mg, 154 μmol) and diethyl thi-
onocarbonate (10 mg, 75 μmol) was dissolved in deuterodichloro-
methane (1 mL), and the mixture was then treated with triethyl-
amine (30 μL, 220 μmol). A 1H NMR spectrum was immediately
acquired. After 1 h, the 1H and 13C NMR spectra showed the pres-
ence of phenyl isothiocyanate and diethyl carbonate. 1H NMR
(400 MHz, CD2Cl2): δ = 7.66–7.63 (m, 2 H), 3.92–3.74 (m, 4 H),
1.28 (t, J = 7.1 Hz, 6 H) ppm. Note: Because of the transient nature
of this species, all of the aromatic signals were not observed. There-
fore, only signals clearly separate from those of other products are
assigned.
378.1158; found 378.1157.
Thioester-Derived Oxathiazoles
5-Ethoxy-5-ethyl-3-phenyl-1,4,2-oxathiazole (4a): A solution of N-
hydroxybenzimidoyl chloride (79 mg, 1.02 mmol) was added to a
solution of O-ethyl thiopropionate in toluene (10 mL, approxi-
mately 1.0 mmol). The resulting mixture was cooled to 0 °C, treated
with triethylamine (0.30 mL, 2.2 mmol), and then stirred at room
temperature for 1 h. The mixture was filtered through a plug of
silica, rinsing with dichloromethane (10 mL). The filtrate was then
concentrated. Chromatographic purification (5% ethyl acetate in
petroleum ether) provided oxathiazole 4a (99 mg, 82%) as an
1
orange oil. H NMR (400 MHz, CD2Cl2): δ = 7.70–7.67 (m, 2 H),
5,5-Dibenzyloxy-3-phenyl-1,4,2-oxathiazole (4f): A solution of N-
hydroxybenzimidoyl chloride (9 mg, 58 μmol) and dibenzyl thiono-
7.48–7.40 (m, 3 H), 3.67–3.48 (m, 2 H), 2.37–2.23 (m, 2 H), 1.21
(t, J = 7.0 Hz, 3 H), 1.14 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR carbonate (9 mg, 35 μmol) was dissolved in deuterodichloro-
(100 MHz, CD2Cl2): δ = 154.8, 131.2, 130.9, 129.2, 129.1, 127.9,
methane (1 mL), and the resulting mixture was treated with trieth-
ylamine (30 μL, 220 μmol). A H NMR spectrum was immediately
1
60.2, 34.5, 15.0, 10.4 ppm. IR: νmax = 2979, 1446, 1273, 1183, 1072,
˜
1057, 983, 949, 885, 761, 689 cm–1. HRMS (TOF): calcd. for
C12H16NO2S+ [M + H]+ 238.0896; found 238.0895.
acquired. After 2 h, the 1H and 13C NMR spectra showed the pres-
ence of phenyl isothiocyanate and dibenzyl carbonate. 1H NMR
(400 MHz, CD2Cl2): δ = 7.71–7.68 (m, 2 H), 4.93 (d, J = 11.4 Hz,
2 H), 4.86 (d, J = 11.4 Hz, 2 H) ppm. Note: Because of the tran-
sient nature of this species, all of the aromatic signals were not
observed. Therefore, only those signals clearly separate from those
of other products are assigned.
5-Ethoxy-3,5-diphenyl-1,4,2-oxathiazole (4b): N-Hydroxybenz-
imidoyl chloride (158 mg, 1.02 mmol) and O-ethyl thiobenzoate
(145 mg, 0.87 mmol) were employed in general procedure A. Chro-
matographic purification (7% ethyl acetate in petroleum ether) pro-
vided oxathiazole 4b (123 mg, 49%) as a clear oil. 1H NMR
(400 MHz, CDCl3): δ = 7.75–7.71 (m, 4 H), 7.48–7.37 (m, 6 H), 5,5-Diphenoxy-3-phenyl-1,4,2-oxathiazole (4g): N-Hydroxybenz-
3.83 (dq, J = 9.1, 7.1 Hz, 1 H), 3.70 (dq, J = 9.1, 7.0 Hz, 1 H), imidoyl chloride (74 mg, 0.47 mmol) and diphenyl thionocarbonate
1.34 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = (93 mg, 0.40 mmol) were employed in general procedure A.
Eur. J. Org. Chem. 2015, 6687–6700
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6697

R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
FULL PAPER
Chromatographic purification (10–20% toluene in petroleum ether)
provided oxathiazole 4g (120 mg, 85%) as a white solid, m.p. 74–
75 °C; ref.[1] m.p. 77–79 °C. 1H NMR (400 MHz, CDCl3): δ = 7.54–
7.5 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.7, 140.4,
131.2, 129.0, 128.8, 128.5, 127.84, 127.82, 125.8, 113.9, 26.6,
13.8 ppm. IR: ν
= 1447, 1275, 978, 760, 752, 689 cm–1. HRMS
˜
max
+
7.50 (m, 2 H), 7.42 (m, 1 H), 7.38–7.27 (m, 10 H), 7.18 (tt, J = 7.1, (TOF): calcd. for C16H16NOS2 [M + H]+ 302.0668; found
1.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.2, 152.5,
302.0661.
139.9, 131.3, 129.4, 128.8, 128.1, 127.3, 125.3, 121.6 ppm. IR: ν
˜
max
5-Benzylthio-3,5-diphenyl-1,4,2-oxathiazole (5c): A solution of N-
hydroxybenzimidoyl chloride (104 mg, 0.67 mmol) and benzyl
benzodithioate (0.1 mL, 0.48 mmol) in dichloromethane (5 mL)
were cooled 0 °C. The resulting mixture was treated with triethyl-
amine (75 μL, 0.54 mmol) and then stirred at room temperature for
2 h. The mixture was diluted with water (20 mL) and then extracted
with dichloromethane (2ϫ 10 mL). The combined extracts were
dried and filtered, and the filtrate was concentrated. The crude
product was purified by column chromatography (1% triethyl-
amine, 10% toluene in petroleum ether) to provide oxathiazole 5c
(55 mg, 31%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ =
7.78–7.75 (m, 2 H), 7.70–7.66 (m, 2 H), 7.49–7.34 (m, 6 H), 7.28–
7.25 (m, 4 H), 7.25–7.18 (m, 1 H), 4.07 (d, J = 12.2 Hz, 1 H), 3.93
(d, J = 12.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
157.8, 139.9, 136.0, 131.3, 129.22, 129.17, 128.8, 128.6, 128.5,
= 1588, 1487, 1191, 1061, 919, 761, 691 cm–1. HRMS (TOF): calcd.
for C20H15NO3SNa+ [M + Na]+ 372.0665; found 372.0662.
3-Phenethyl-5,5-diphenoxy-1,4,2-oxathiazole (4h): Oxathiazole 4h
was prepared as described in the literature.[3c] 1H NMR (400 MHz,
CDCl3): δ = 7.48–7.42 (m, 1 H), 7.36–7.29 (m, 4 H), 7.25–7.17
(m, 8 H), 7.07–7.04 (m, 2 H), 2.76–2.67 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.2, 152.5, 140.0, 139.3, 129.3, 128.6,
128.3, 126.6, 125.3, 121.7, 33.4, 31.0 ppm.
3-Methyl-5,5-diphenoxy-1,4,2-oxathiazole (4i): N-Hydroxyacetimi-
doyl chloride (116 mg, 1.24 mmol) and diphenyl thionocarbonate
(227 mg, 0.98 mmol) were employed in general procedure A.
Chromatographic purification (1–10% ethyl acetate in petroleum
ether) provided oxathiazole 4i (172 mg, 60%) as a white solid; m.p.
53–55 °C. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 4 H),
7.26–7.16 (m, 6 H), 2.08 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.3, 152.5, 140.2, 129.3, 125.3, 121.6, 14.8 ppm. IR:
127.9, 127.7, 127.2, 125.9, 113.8, 37.0 ppm. IR: ν
= 1494, 1447,
˜
max
1275, 978, 884, 760, 740, 693 cm–1. HRMS (TOF): calcd. for
C21H17NOS3Na+ [M + Na]+ 386.0644; found 386.0646.
ν
= 1590, 1489, 1456, 1432, 1379, 1291, 1192, 1163, 1066, 1000,
˜
max
907 cm–1. HRMS (TOF): calcd. for C15H14NO3S+ [M + H]+
3,5-Diphenyl-5-phenylthio-1,4,2-oxathiazole (5d): N-Hydroxybenz-
imidoyl chloride (147 mg, 0.94 mmol) and phenyl dithiobenzoate
(164 mg, 0.71 mmol) were employed in general procedure A.
Chromatographic purification (1% triethylamine, 33% toluene in
petroleum ether) provided oxathiazole 5d (130 mg, 52%) as a clear
oil. 1H NMR (400 MHz, CDCl3): δ = 7.60–7.55 (m, 4 H), 7.53–
7.49 (m, 2 H), 7.46–7.30 (m, 6 H), 7.29–7.19 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.1, 139.2, 136.5, 131.19, 131.18,
129.4, 128.9, 128.7, 128.5, 128.3, 127.8, 127.6, 126.1, 115.2 ppm.
288.0689; found 288.0684.
3-Allyl-5,5-diphenoxy-1,4,2-oxathiazole (4j): By following general
procedure B,
a solution of sodium but-3-en-1-ylideneazinate
(1.10 g, 8.90 mmol) in diethyl ether (60 mL) was treated with hydro-
chloric acid (4 m in dioxane, 18 mL, 72.0 mmol). Diphenyl thiono-
carbonate (330 mg, 1.43 mmol) was added. Chromatographic puri-
fication (10–30% chloroform in petroleum ether) provided oxathia-
zole 4j (100 mg, 22% yield) as a translucent semisolid. 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.31 (m, 4 H), 7.26–7.23 (m, 4 H),
7.20 (tt, J = 7.3, 1.3 Hz, 2 H), 5.62 (ddt, J = 16.9, 10.2, 6.6 Hz, 1
H), 5.08 (dq, J = 10.1, 1.2 Hz, 1 H), 5.03 (dq, J = 17.0, 10.2, 6.6 Hz,
1 H), 3.13 (dt, J = 6.6, 1.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.3, 152.5, 140.1, 130.8, 129.3, 125.3, 121.7, 119.3,
IR: ν
= 1447, 1275, 979, 884, 748, 688 cm–1. HRMS (TOF):
˜
max
calcd. for C20H16NOS2 [M + H]+ 350.0668; found 350.0681.
+
5,5-Bis(methylthio)-3-phenyl-1,4,2-oxathiazole (5e): N-Hydroxy-
benzimidoyl chloride (182 mg, 1.17 mmol) and dimethyl trithio-
carbonate (137 mg, 0.99 mmol) were employed in general pro-
cedure A. The crude product was dissolved (diethyl ether/petroleum
ether, approximately 1:1), and the solution was concentrated and
then cooled to induce crystallization and provide oxathiazole 5e
33.4 ppm. IR: ν
= 2252, 1782, 1591, 1489, 1232, 1191,
˜
max
1071 cm–1. HRMS (TOF): calcd. for C17H16NO3S+ [M + H]+
314.0845; found 314.0850.
(156 mg, 61%) as
a
white solid; m.p. 85–87 °C. 1H NMR
Dithioester-Derived Oxathiazoles
(400 MHz, CDCl3): δ = 7.66–7.63 (m, 2 H), 7.50–7.40 (m, 3 H),
2.41 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.7, 131.4,
5-Ethyl-5-ethylthio-3-phenyl-1,4,2-oxathiazole (5a): By following
general procedure A, a solution of N-hydroxybenzimidoyl chloride
(117 mg, 0.75 mmol) in dichloromethane (10 mL) was treated with
ethyl dithiopropionate in toluene (240 mg, approximately
0.45 mmol). Chromatographic purification (1% triethylamine, 5–
10% ethyl acetate in petroleum ether) provided oxathiazole 5a
(112 mg, 97%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ =
7.67–7.64 (m, 2 H), 7.50–7.41 (m, 3 H), 2.82 (t, J = 7.5 Hz, 2 H),
2.49–2.34 (m, 2 H), 1.28 (t, J = 7.5 Hz, 3 H), 1.20 (t, J = 7.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.4, 131.4, 129.3,
128.9, 127.7, 127.6, 117.0, 15.4 ppm. IR: ν
= 1442, 1273, 978,
˜
max
+
853, 763, 688, 679 cm–1. HRMS (TOF): calcd. for C10H12NOS3
[M + H]+ 258.0076; found 258.0069.
5,5-Bis(ethylthio)-3-phenyl-1,4,2-oxathiazole (5f): N-Hydroxybenz-
imidoyl chloride (160 mg, 1.03 mmol) and diethyl trithiocarbonate
(137 mg, 0.82 mmol) were employed in general procedure A.
Chromatographic purification (1% triethylamine, 25–50% toluene
in petroleum ether) provided oxathiazole 5f (58 mg, 25%) as a
1
translucent oil. H NMR (400 MHz, CDCl3): δ = 7.66–7.63 (m, 2
128.6, 128.0, 117.3, 35.7, 25.2, 14.2, 10.9 ppm. IR: ν
= 1446,
˜
H), 7.49–7.40 (m, 3 H), 3.04–2.91 (m, 4 H), 1.34 (t, J = 7.5 Hz, 6
max
1276, 978, 925, 761, 689 cm–1. HRMS (TOF): calcd. for
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 131.4, 128.9,
+
C12H16NOS2 [M + H]+ 254.0668; found 254.0669.
127.8, 127.7, 117.1, 27.4, 14.2 ppm. IR: ν
= 1446, 1274, 978,
˜
max
+
938, 862, 760, 688 cm–1. HRMS (TOF): calcd. for C12H16NOS3
[M + H]+ 286.0389; found 286.0387.
3,5-Diphenyl-5-ethylthio-1,4,2-oxathiazole (5b): N-Hydroxybenz-
imidoyl chloride (174 mg, 1.12 mmol) and ethyl dithiobenzoate
(192 mg, 1.05 mmol) were employed in general procedure A. Chro-
5,5-Bis(benzylthio)-3-phenyl-1,4,2-oxathiazole (5g): N-Hydroxy-
matographic purification (1% triethylamine, 5% ethyl acetate in benzimidoyl chloride (261 mg, 1.68 mmol) and dibenzyl trithio-
petroleum ether) provided oxathiazole 5b (194 mg, 61%) as a clear
carbonate (298 mg, 1.03 mmol) were employed in general pro-
cedure A. Recrystallization (diethyl ether/petroleum ether, 1:1) pro-
oil. 1H NMR (400 MHz, CDCl3): δ = 7.74–7.71 (m, 2 H), 7.69–
7.66 (m, 2 H), 7.48–7.33 (m, 6 H), 2.84–2.69 (m, 2 H), 1.26 (t, J = vided oxathiazole 5g (262 mg, 62%) as a white solid; m.p. 76–78 °C.
6698
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6687–6700

Investigations of the Thermal Responsiveness of 1,4,2-Oxathiazoles
1H NMR (400 MHz, CDCl3): δ = 7.66–7.63 (m, 2 H), 7.51–7.41 5,5-Bis(benzylthio)-3-phenethyl-1,4,2-oxathiazole (5l): N-Hydroxy-
(m, 3 H), 7.38–7.35 (m, 4 H), 7.32–7.28 (m, 4 H), 7.27–7.23 (m, 2
H), 4.24 (d, J = 12.3 Hz, 2 H), 4.19 (d, J = 12.3 Hz, 2 H) ppm. 13
NMR (100 MHz, CDCl3): δ = 159.3, 135.8, 131.5, 129.4, 128.9,
3-phenylpropanimidoyl chloride (128 mg, 0.45 mmol) and dibenzyl
trithiocarbonate (130 mg, 0.70 mmol) were employed in general
procedure A. Chromatographic purification (1% triethylamine, 5–
C
128.6, 127.8, 127.5, 127.4, 116.3, 37.7 ppm. IR: ν
= 1493, 1453,
10% ethyl acetate in petroleum ether) provided oxathiazole 5l
˜
max
1275, 978, 938, 865, 761, 706, 684 cm–1. HRMS (TOF): calcd. for (107 mg, 55%) as a translucent oil. H NMR (400 MHz, CDCl3):
1
+
C22H20NOS3 [M + H]+ 410.0702; found 410.0704.
δ = 7.34–7.19 (m, 15 H), 4.12 (d, J = 12.3 Hz, 2 H), 4.07 (d, J =
12.3 Hz, 2 H), 2.96–2.92 (m, 2 H), 2.87–2.83 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 160.1, 139.3, 135.9, 129.3, 128.62,
3-Phenyl-5,5-bis(phenylthio)-1,4,2-oxathiazole (5h): N-Hydroxy-
benzimidoyl chloride (171 mg, 1.10 mmol) and diphenyl trithio-
carbonate (262 mg, 1.00 mmol) were employed in general pro-
cedure A. Crystallization (10% toluene in petroleum ether) pro-
vided oxathiazole 5h (73 mg, 19%) as a white solid, m.p. 78–80 °C;
128.59, 128.4, 127.4, 126.7, 115.9, 37.5, 33.4, 30.3 ppm. IR: ν
=
˜
max
1495, 1454, 911, 845, 764, 738, 697 cm–1. HRMS (TOF): calcd. for
C24H24NOS3 [M + H]+ 438.1015; found 438.1015.
+
1
ref.[1] m.p. 82–83 °C. H NMR (400 MHz, CDCl3): δ = 7.69–7.65
3-Phenethyl-5,5-bis(phenylthio)-1,4,2-oxathiazole (5m): N-Hydroxy-
3-phenylpropanimidoyl chloride (243 mg, 1.32 mmol) and diphenyl
trithiocarbonate (260 mg, 0.99 mmol) were employed in general
procedure A. Chromatographic purification (33–50% toluene in pe-
troleum ether) provided oxathiazole 5m (222 mg, 55%) as a trans-
lucent oil. 1H NMR (400 MHz, CDCl3): δ = 7.65–7.61 (m, 4 H),
7.44–7.40 (m, 2 H), 7.39–7.34 (m, 4 H), 7.26–7.17 (m, 3 H), 7.04–
7.02 (m, 2 H), 2.62–2.58 (m, 2 H), 2.54–2.50 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.9, 139.4, 136.7, 130.8, 129.9,
(m, 4 H), 7.43–7.30 (m, 11 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 158.6, 136.6, 131.2, 130.7, 129.9, 128.8, 128.7, 127.6, 127.4,
119.1 ppm. IR: ν
= 1474, 1439, 1273, 862, 756, 748, 739, 703,
˜
max
687 cm–1. HRMS (TOF): calcd. for C20H16NOS3 [M + H]+
+
382.0389; found 382.0389.
3-Phenethyl-5-phenyl-5-ethylthio-1,4,2-oxathiazole (5i): N-Hydroxy-
3-phenylpropanimidoyl chloride (239 mg, 1.30 mmol) and ethyl di-
thiobenzoate (190 mg, 1.04 mmol) were employed in general pro-
cedure A. Chromatographic purification (1% triethylamine, 5%
ethyl acetate in petroleum ether) provided oxathiazole 5i (318 mg,
93%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ = 7.64–7.61
(m, 2 H), 7.41–7.25 (m, 5 H), 7.23–7.17 (m, 3 H), 2.96–2.90 (m, 2
H), 2.86–2.79 (m, 2 H), 2.72–2.57 (m, 2 H), 1.21 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3, 140.7, 139.5,
128.9, 128.6, 128.41, 128.37, 126.5, 125.7, 113.5, 33.5, 30.2, 26.4,
128.8, 128.5, 128.2, 126.5, 119.1, 33.3, 29.9 ppm. IR: ν
= 1472,
˜
max
1439, 1024, 925, 847, 748, 701, 690 cm–1. HRMS (TOF): calcd. for
C22H20NOS3 [M + H]+ 410.0702; found 410.0712.
+
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental procedures, H and 13C NMR spectra, determi-
nation of rate constants, and Arrhenius plots.
13.9 ppm. IR: ν
= 1496, 1447, 938, 869, 747, 696 cm–1. HRMS
˜
max
Acknowledgments
+
(TOF): calcd. for C22H20NOS2 [M + H]+ 330.0981; found
330.0967.
The authors acknowledge the technical assistance from Ms. Agnes
Lee. This work was supported by the Institute of Chemical and
3-Phenethyl-5-phenyl-5-phenylthio-1,4,2-oxathiazole (5j): 3-Phenyl-
propionaldehyde oxime (190 mg, 1.27 mmol) in DMF (5 mL) was Engineering Sciences, Agency for Science, Technology, and Re-
treated with N-chlorosuccinimide (209 mg, 1.57 mmol), and the re-
sulting mixture was heated at 40–50 °C for 2 h. The reaction mix-
ture was cooled to 0 °C and diluted with dichloromethane (10 mL).
The solution was then treated with triethylamine (0.25 mL,
1.8 mmol) and phenyl dithiobenzoate (160 mg, 0.69 mmol) and
then stirred at room temperature for 1 h. After diluting with water
(50 mL), the mixture was extracted with dichloromethane (2ϫ
20 mL). The combined organic extracts were dried and filtered, and
the filtrate was concentrated. The crude product was purified by
column chromatography (1% triethylamine, 10% ethyl acetate in
petroleum ether) to provide oxathiazole 5j (237 mg, 90%) as a clear
oil. 1H NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 4 H), 7.36–
7.25 (m, 8 H), 7.21 (tt, J = 7.3, 1.7 Hz, 2 H), 7.15–7.12 (m, 2 H),
2.79–2.59 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.2,
139.7, 139.5, 136.7, 131.4, 129.4, 128.8, 128.6, 128.5, 128.29,
search (A*STAR), Singapore (ICES/14-145A01).
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˜
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+
C22H20NOS2 [M + H]+ 378.0981; found 378.0983.
5,5-Bis(ethylthio)-3-phenethyl-1,4,2-oxathiazole (5k): N-Hydroxy-3-
phenylpropanimidoyl chloride (210 mg, 1.14 mmol) and diethyl tri-
thiocarbonate (113 mg, 0.68 mmol) were employed in general pro-
cedure A. Chromatographic purification (1% triethylamine, 33%
toluene in petroleum ether) provided oxathiazole 5k (48 mg, 23%)
as a translucent oil. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.20
(m, 5 H), 3.00–2.92 (m, 2 H), 2.90–2.82 (m, 6 H), 1.30 (t, J =
7.5 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7, 139.4,
128.6, 128.4, 126.6, 116.7, 33.4, 30.3, 27.2, 14.2 ppm. IR: ν
=
˜
max
1455, 1263, 908, 849, 780, 748, 699 cm–1. HRMS (TOF): calcd. for
C14H20NOS3 [M + H]+ 314.0702; found 314.0701.
+
Eur. J. Org. Chem. 2015, 6687–6700
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6699

R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett
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Published Online: September 14, 2015
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