Synthesis of 1,4,2-Oxathiazoles via Oxidative Cyclization of Thiohydroximic Acids

Article abstract of DOI:10.1021/acs.orglett.5b02256

An oxidative formation of 1,4,2-oxathiazoles from readily available thiohydroximic acids is reported. A variety of alkyl, aryl, and heteroaryl substituents are well tolerated for both the thiohydroximic acid and activating fragments, and the reaction has been demonstrated on gram-scale. This reaction represents the only method currently available to prepare a diverse set of oxathiazoles and expands the chemistry of C-H oxidation via appended N-OH functional groups. Finally, we also demonstrate the rapid preparation of a 1,4,2-oxathiazole analog of an anticancer lead molecule.

Full text of DOI:10.1021/acs.orglett.5b02256

Letter
pubs.acs.org/OrgLett
Synthesis of 1,4,2-Oxathiazoles via Oxidative Cyclization of
Thiohydroximic Acids
Berenice C. Lemercier and Joshua G. Pierce*
́
́
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
S
* Supporting Information
ABSTRACT: An oxidative formation of 1,4,2-oxathiazoles
from readily available thiohydroximic acids is reported. A
variety of alkyl, aryl, and heteroaryl substituents are well
tolerated for both the thiohydroximic acid and activating
fragments, and the reaction has been demonstrated on gram-
scale. This reaction represents the only method currently
available to prepare a diverse set of oxathiazoles and expands the chemistry of C−H oxidation via appended N−OH functional
groups. Finally, we also demonstrate the rapid preparation of a 1,4,2-oxathiazole analog of an anticancer lead molecule.
itrogen containing heterocycles are prevalent in a
majority of pharmaceutical compounds;1 therefore, new
efforts to investigate the use of thiohydroximic acids as building
blocks for synthesis,7 we discovered that they could be oxidized
to access 5H-1,4,2-oxathiazoles (Scheme 1, eq 4). Prior work by
Praly et al. reported the formation of 5,5′-spiroglucosyl-1,4,2-
oxathiazoles via free-radical cyclization of S-glucosyl-thiohy-
droximic acids (Scheme 1, eq 2).8 Chiba and co-workers
described the oxidative cyclization of amidoximes via oxime
radicals to afford 1,2,4-oxadiazoles (Scheme 1, eq 3).9 Despite
these efforts, there remains no general method to access 1,4,2-
oxathiazoles from readily available starting materials; therefore,
we explored the oxidation of readily available thiohydroximic
acids to access 1,4,2-oxathiazoles.
N
ways to access existing and novel nitrogen heterocycles are
always needed to expand the medicinal chemists’ toolbox. 1,4,2-
Oxathiazoles are 5-membered ring heterocycles containing
three different heteroatoms that have been very scarcely
reported in the literature.2 Current approaches to their
synthesis rely on [3 + 2] cycloaddition between a nitrile
oxide and a thiocarbonyl (Scheme 1, eq 1), analogous to the
Scheme 1. Strategies for the Preparation of 1,4,2-
Oxathiazoles
Thiohydroximic acid derivatives were easily prepared on
scale in one step via alkylation of the corresponding
thiohydroxamic acids7a or in a two-step, one-pot process
from the corresponding oximes via an improved procedure
from our previously published method. Both methods provided
a variety of thiohydroximic acids from commercially available
aldehydes. We began our optimization studies with the S-benzyl
thiohydroximic acid 1a (Table 1).10 Upon heating at 100 °C in
1,4-dioxane with CuII as the oxidant, we obtained the desired
1,4,2-oxathiazole 2a in 32% yield (entry 1) and confirmed its
structure via X-ray analysis (see Figure S1). We then screened
various solvents and temperatures, and the reaction yield was
improved to 46% in DMF at 150 °C (entries 2−4). Employing
CuI oxidants did not improve the yield of 2a (Table S1);
however, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
provided the desired product in 71% yield (entry 5). Solvents
were screened again with DDQ (see Table S1) as the oxidant,
and DMF remained the best solvent under anhydrous reaction
conditions. In an effort to further optimize the process, we
explored the use of additives. The addition of triethylamine
decomposed the starting material (entry 6), while camphor-
sulfonic acid (CSA) and pyridinium p-toluenesulfonate (PPTS)
preparation of their oxygen and nitrogen counterparts.2,3 Due
to the instability of thioaldehydes and thioketones, there are
almost no 5-alkyl-1,4,2-oxathiazoles reported in the literature,4
yet these heterocycles could be of great utility for medicinal
chemists as a new scaffold for SAR. Indeed, closely related
heterocycles such as 1,2,4-oxadiazoles, thiazoles, and isoxazoles
are privileged scaffolds for drug discovery.1,3,5 Moreover, 1,4,2-
oxathiazoles have been shown to be useful isothiocyanate
(ITC) precursors upon thermal decomposition.6 As part of our
Received: August 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02256
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
conditions
2a (%)
1
Cu(OAc)2·H2O, 1,4-dioxane, 30 min
Cu(OAc)2·H2O, toluene, 25 min
Cu(OAc)2·H2O, DMSO, 15 min
Cu(OAc)2·H2O, DMF, 20 min
32
28
34
46
71
d
2
3
4
c
5
DDQ, DMF, 15 min
c
6
DDQ, DMF, Et3N (1 equiv), 10 min
c
7
DDQ, DMF, CSA (1 equiv), 1 h
71
71
83
71
82
e
c
8
DDQ, DMF, PPTS (1 equiv), 15 min
c
9
DDQ, DMF, p-TsOH·H2O (1 equiv), 15 min
c
10
11
12
13
DDQ, DMF, p-TsOH·H2O (10 mol %), 5 min
c
DDQ, DMF, p-TsOH·H2O (50 mol %), 20 min
c
DMF, p-TsOH·H2O (1 equiv), 23 h
c
DMF, 23 h
e
c
a
b
Performed on 50 mg scale at 0.05 M. Isolated product yield. Flame-
dried and flushed with N2 reaction vessel. Starting material
decomposition. No reaction.
d
e
left the yield unchanged (entries 7 and 8). Employing p-
toluenesulfonic acid (p-TsOH) as an additive improved the
yield of 2a to 83%, even in substoichiometric quantities (entries
9−11). Control reactions demonstrated the necessity of the
oxidant for production of 2a (entries 12 and 13).
With these optimized conditions in hand, we explored the
substrate scope of the C−H activating group α to the sulfur
(R2, 1a−q, Figure 1). Aromatic activating groups gave
moderate to high yields with the exception of the pyridine
substrate, which provided decomposition (2a−e). Ether (2f),
ester (2g) and simple alkyl (2h) groups were not successful,
due to either their lack of reactivity or instability. In contrast,
the more activating cyclopropyl group gave a moderate yield of
product 2i. This result encouraged us to try an oxirane
substituent, but it decomposed without providing the desired
product 2j. We then screened various alkene-activating groups
(2l−n), and most produced a low yield of 1,4,2-oxathiazole
with the exception of the cinnamyl group that gave 68% yield of
2k. Because most alkene activating groups gave slower reaction
times, we propose that the low yields obtained are due to the
insufficient activation of the starting material rather than the
lack of stabilization of the intermediate. The prolonged reaction
times likely facilitate the decomposition of the 1,4,2-oxathiazole
products, which would explain the low yields. Finally, we
explored alkynes as the activating group; however, this
functionality was not stable to the reaction and provided no
product 2q (Figure 1).
Figure 1. Substrate scope of 1,4,2-oxathiazole formation. Performed
on 100 mg scale at 0.05 M: (b) decomposition of starting material; (c)
no reaction; (d) no p-TsOH was used.
order to investigate the reaction mechanism (Figure 2, eq 1).
Indeed, the oxidative cyclization could be triggered by two
distinct mechanisms: (1) the oxidation of the oxime to an
iminoxyl radical followed by a 1,5-hydrogen atom abstraction of
the activated C−H bond9,11 or (2) the direct oxidation of the
Variation of the thiohydroximic acid substituent was then
explored (R1, 1r−z). Aromatic (2r) and substituted aromatic
(2s) substrates gave high yields of 1,4,2-oxathiazoles, while
heteroaromatic substrates did not perform as well (2t−v).
Cinnamyl thiohydroximic acid and alkyl thiohydroximic acids
were well tolerated and provided moderate to high yields of
1,4,2-oxathiazoles (2w, 2x, and 2y). Finally, the reactive ester
functional group smoothly underwent cyclization and provided
2z in 68% yield, which provides a useful handle for further
functionalization.
During the evaluation of the substrate scope, we performed
the reaction with O-methyl S-benzyl thiohydroximic acid 3 in
Figure 2. Mechanistic study (1), proposed mechanism (2), and radical
clock reaction (3).
B
DOI: 10.1021/acs.orglett.5b02256
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Organic Letters
Letter
activated benzylic position α to the sulfur followed by the
nucleophilic attack by the oxime.12 To explore the potential
mechanisms, we subjected 3 to our reaction conditions to
evaluate the ability of DDQ to oxidize the benzylic position in
the absence of an N−OH moiety. After prolonged reaction
times, we observed no 1,4,2-oxathiazole product 2a as well as
no thiohydroxamic acid 4 as would be expected if a
thiocarbenium ion was formed (3 was reisolated in >75%
recovery). Therefore, we propose that the reaction proceeds via
a 1,5-hydrogen atom shift between the C−H α to the sulfur and
the iminoxyl radical (Figure 2, eq 2). Iminoxyl radicals are
known to be relatively stable radicals that undergo this type of
hydrogen shift producing more reactive carbon radicals in a
reversible manner.9,11 Moreover, sulfur is known to stabilize α-
radicals and carbocations.13 Interestingly, thiohydroximic acid
1i containing the well-known cyclopropyl radical clock gave the
unopened cyclopropyl product 2i and not 5 as would be
expected if a radical was formed α to the sulfur (Figure 2, eq 3).
This result could be rationalized by the possibility that the
radical is oxidized by DDQ faster than the rearrangement can
occur or that the sulfur sufficiently stabilizes the radical/
carbocation to prevent the opening of the cyclopropyl group.14
We also evaluated the scalability of the oxidative cyclization
(Figure 3, eq 1). We performed the reaction with S-benzyl
Scheme 2. Functionalization of 1,4,2-Oxathiazole 2k
available thiohydroximic acids. The method provides access to
currently unavailable 1,4,2-oxathiazoles bearing a wide range of
functional groups in up to 82% yield and is amenable to gram
scale synthesis. Importantly, this method represents the only
practical way to access these heterocycles that could be of great
utility for medicinal chemists as new scaffolds for SAR studies
of their related nitrogen and oxygen containing heterocycles.
Our initial studies show the potential of our method for analog
synthesis and building block preparation, and further efforts in
these areas will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02256.
Experimental procedures, characterization of products,
1H and 13C NMR spectra (PDF)
Crystallographic information for 2a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jgpierce@ncsu.edu.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Figure 3. Scale-up of the oxidative cyclization (1) and 1,2,4-oxadiazole
analog formation (2).
Notes
The authors declare no competing financial interest.
thiohydroximic acid 1a on 1 g scale and at 0.1 M concentration.
We were pleased to obtain 2a in 72% yield, highlighting the
practicality of this method for building block synthesis. In order
to demonstrate the utility of our method for analog synthesis,
we applied it to the synthesis of the 1,4,2-oxathiazole analog 8
of a 1,2,4-oxadiazole anticancer lead compound 6 (Figure 3).15
Gratifyingly, subjection of 7 to our optimized conditions
provided analog 6 in 71% yield (Figure 3, eq 2).
Finally, we evaluated the further functionalization of our
1,4,2-oxathiazole products (Scheme 2). 1,4,2-Oxathiazole 2k
could be converted to the corresponding alcohol 11 very
efficiently in three steps and 68% yield, highlighting the
versatility of our products and their utility as building blocks for
synthesis. Indeed, in our hands 1,4,2-oxathiazoles are stable to
acidic reaction conditions, aqueous basic workup, silica gel
chromatography, hydrogenation conditions, and oxidative
reaction conditions.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (Grant CHE-1454845) and Donors
of the American Chemical Society Petroleum Research Fund
for funding. Mass spectrometry data were obtained at the
NCSU Mass Spectroscopy Facility. We thank Dr. Roger
Sommer (NCSU) for X-ray crystallographic analysis of 2a.
Patrick Parker (NCSU) is acknowledged for characterization of
compounds 1f, 1k, 1l, and 1o−1q.
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C
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