-Annulation of Azaoxyallyl Cations and Thiocarbonyls for the Assembly of Thiazolidin-4-ones

Article abstract of DOI:10.1021/acs.orglett.9b01933

A base-promoted, efficient [3 + 2] annulation between azaoxyallyl cations and thiocarbonyls is reported for flexible access to highly functionalized thiazolidin-4-one derivatives in good to excellent yields. An intriguing feature of this method is the met

Full text of DOI:10.1021/acs.orglett.9b01933

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[3 + 2]-Annulation of Azaoxyallyl Cations and Thiocarbonyls for the
Assembly of Thiazolidin-4-ones
Vandana Jaiswal,† Biplab Mondal,† Kuldeep Singh,† Dinabandhu Das,‡ and Jaideep Saha*,†
†Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research (CBMR), SGPGIMS Campus, Raebareli Road,
Lucknow 226014, Uttar Pradesh, India
‡School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India
S
* Supporting Information
ABSTRACT: A base-promoted, efficient [3 + 2] annulation
between azaoxyallyl cations and thiocarbonyls is reported for
flexible access to highly functionalized thiazolidin-4-one
derivatives in good to excellent yields. An intriguing feature
of this method is the metal or Lewis acid free late-stage entry
of distinct set of functional groups at C2 of thiazolidin-4-ones
via substitution of a latent amino functional group. Overall, this
approach constitutes a general platform for convenient access
to this medicinally important scaffold.
Scheme 1. Previous Reports and Our Approach
zaoxyallyl cation, a transiently formed reactive species, has
Abeen recognized as an important synthon for the
construction of important nitrogen-containing heterocycles.1−3
Formation of this species was first speculated during the
hydrolysis study of α-lactams in 1968.2 However, its existence
remained experimentally elusive until 2011 when Jeffrey et al.
demonstrated its trapping with cyclic dienes via a [3 + 4]
cycloaddition reaction.1b Since then, an expedited develop-
ment of different [3 + m] cycloadditions with azaoxyallyl
cation have appeared in the literature from the groups of both
Jeffrey and others (Scheme 1a).1−3 Notably, a major portion of
these developments is pillared on the use of different carbonyl
compounds such as aldehydes, ketones, enals, etc.
While carbonyls are the widely used feedstock functional
groups in organic synthesis, their heavier analogues, such as
thiocarbonyls, are markedly underrepresented in the context.
This can be corroborated with difficulties in handling these
compounds for their highly reactive nature, which often leads
to side reactions and oligomerization. Notwithstanding the
obstacles, thiocarbonyls have been employed for the synthesis
of various heterocycles via development of [2 + 1],4 [2 + 2],5
and [4 + 2]6 cycloadditions, in conjunction to some scarcely
reported [3 + 2]7 annulations (Scheme 1a).
Among the sulfur-containing heterocycles, thiazolidin-4-one
derivatives are of particular significance as they are featured in
many medicinally relevant compounds exhibiting wide range of
biological activities,8 such as anticancer, antimicrobial, antiviral,
antimycobacterial, anti-inflammatory, antipsychotic, etc. De-
spite the apparent importance of this scaffold, access to the
diversely functionalized variants have not been a straightfor-
ward task. The most common strategy for the preparation of
this heterocycle involves condensation of aldehyde, amine, and
mercaptoacetic acid at high temperature or under microwave
conditions.8b−d Apart from the use of elevated temperature,
this approach has limitations such as unavailability of suitably
functionalized α-mono- or disubstituted mercaptoacetic acid
derivatives and the incompatibility to use ketones that
combinedly impede the accessibility of thiazolidin-4-one
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01933
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
possessing varied substituents at C2 and C5 position (Scheme
1b).
Scheme 2. Scope for the Reaction of Thioketones with α-
Halo Hydroxamates
a,b
Prompted by the serious paucity of available means to
explore the chemical space around this privileged structure, we
were interested in developing an efficient and versatile strategy
for ready access to densely functionalized thiazolidin-4-ones.
We envisaged that compatibly engaging the in situ generated
azaoxyallyl cation with thiocarbonyls in [3 + 2] fashion could
constitute a promising approach for their assembly. Herein, we
report a successful realization of this strategy (Scheme 1c).
Additionally, the potential of a latent amino functional group at
C2 of the synthesized thiazolidin-4-ones was exploited for
making late-stage entries of very distinct classes of functional
groups, which clearly would be a highly challenging task if
pursued with the pre-existing methods. Thus, the present
strategy as a whole offers a unified platform for the synthesis of
this particular thioheterocycle, and we expect these scaffolds to
find useful applications in medicinal chemistry.
At the outset of our studies, we first checked the feasibility of
the anticipated [3 + 2] annulation with α-bromo hydroxamate
1a and thiobenzophenone 2a as model substrates, and the
screening results are summarized in Table 1. Considering the
a
Table 1. Optimization Studies
b
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
K2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
Et3N
DBU
pyridine
DIPA
DIPEA
DIPEA
DIPEA
DIPEA
HFIP
HFIP
CH3CN
CH2Cl2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
0.5
61
70
26
15
40
30
38
20
20
80
45
42
30
a
Reaction conditions: 1 (1.0 equiv), 2 (1.0 equiv), DIPEA (2.0
b
c
equiv), HFIP (0.4 M). Yields of the isolated products. Isolated as
diastereomeric mixture; relative configuration of major diastereomer
is shown.
different substituents on the aromatic ring of diaryl thioketones
were evaluated. In fact, the presence of both electron-donating
and electron-withdrawing groups at the ortho, meta, and para
positions smoothly afforded the desired products in good to
excellent yields (3ab−3ah). Larger aromatic rings could be
easily accommodated into the products (3ai−3aj) as well.
Next, we evaluated a thiochalcone derivative 2k in the reaction.
This class of compounds have high propensity for dimerization
and mostly participated as a 4π heterodiene system9 in the
reported cycloaddition reactions. In our case, exclusive [3 + 2]
cycloadduct (3ak) was obtained through the CS unit.
Thiophene- and furan-containing substrates also furnished the
desired products in excellent yields (3al−3am). Interestingly,
in former two examples, remarkable chemoselectivity of
thiocarbonyl moiety was observed, despite the fact that the
rest of the groups (such as alkene or furan) are also known to
react with the azaoxyallyl cation.1b,10 Aliphatic thiocarbonyls
were also used successfully in the process (3an, 3ao).
Importantly, the ability to use various α-aryl-substituted
chlorohydroxamates in the reaction opened up the possibility
to access various C5 aryl- and naphthyl-substituted (3ba−3fa,
3cl, 3cm, 3dl) products. The later compounds were obtained
as a mixture of diastereomers. Mono-α-substituted halohy-
droxamates were less efficient compared to the former
examples. The presence of a single methyl group at the α-
position afforded 3ga in 30% yield. Interestingly, monochloro-
substituted halohydroxamate 1h afforded 3ha (28%) in
c
d
a
Reaction conditions: 1a (1.0 equiv), 2a (1.0 equiv), base (2.0 equiv),
b
solvent (0.4 M), reaction time (0.5−1.0 h). Yields of the isolated
c
d
products. Reaction performed at 0 °C. Reaction concentration was
0.1 M.
stabilization of the putative azaoxyallyl cation by fluorinated
solvents,1b first we chose hexafluoro-2-propanol (HFIP) for
the reaction. Pleasingly, inorganic bases such as K2CO3 and
Na2CO3 both furnished the desired product in good yields in
HFIP (entries 1 and 2). Use of other solvents and Cs2CO3 as
base were found to be inferior (entries 3−5). Next, different
organic bases were screened in the reaction. Use of Et3N,
DBU, pyridine, and DIPA afforded moderate to low yields of
the product (entries 6−9). Gratifyingly, DIPEA provided the
best result and afforded 3aa in 80% yield (entry 10).
Performing this reaction at 0 °C or at a lower concentration
or in TFE had detrimental effects (entries 11−13).
With the optimized conditions in hand, we next proceeded
to explore the generality of the transformation with different
thioketones (Scheme 2). First, electronic and steric effects of
B
DOI: 10.1021/acs.orglett.9b01933
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Letter
reaction with 2a. This can be explained on the basis of a
secondary reaction that occurred via the displacement of the α-
chloride by thiobenzophenone on the initially formed product.
The ensuing carbocation was then captured with the HFIP
addition.
Interestingly, compound 6 was also obtained when 1a was
subjected to reaction with another thioamide 4b (Scheme 4).
Scheme 4. Plausible Mechanism of Solvolysis of 2-
Aminothiazolidin-4-ones by HFIP
With the notion of incorporating an amino substituent at the
C2 position of thiazolidin-4-ones, thioamides were chosen next
as another thiocarbonyl variant. We began the reaction with 1a
and N,N-diethylthiobenzamide (4a) under the optimized
conditions (i.e., with DIPEA in HFIP), which, however, was
unsuccessful for delivery of the desired product (vide infra).
After some additional screening, gratifyingly, the desired
product 5aa was obtained with Na2CO3 in acetonitrile at 80
°C. In fact, this condition suitably worked for a range of other
N,N-dialkylthiobenzamides (5ab−5ad). Secondary N-aryl
thioamides were compatible in the process (5ae), whereas
tertiary N-aryl thioamide proved futile (5af) (Scheme 3).
This clearly indicated that both of the reactions proceeded via
a common intermediate. We speculated that 2-amino-4-
thiazolidinones (e.g., 5aa and 5ab) would have formed first
in each case and subsequently were converted to 6 through
rapid solvolysis by HFIP (via a putative intermediate, 5′), as
the later is a highly ionizing solvent with strong hydrogen-bond
donor ability.11 This proposition was further supported by a
control experiment; when 5aa was stirred separately in HFIP at
room temperature, it was immediately converted to compound
Scheme 3. Scope for the Reaction of Thioamides with α-
Halo Hydroxamates
a
1
6 (90%). H NMR monitoring of this reaction revealed the
rapid and quantitative conversion of 5aa to 6, with the release
of Et2NH in the reaction mixture (see Figure S4).
Intrigued by the above observation, we envisioned the
possibility of further synthetic elaboration of 5aa or similar
compounds through incorporation of diverse set of functional
groups at C2, essentially under Bronsted acid but metal free
conditions (Scheme 5). In this context, we first investigated the
reaction of 5aa with a carbon nucleophile such as indole using
HFIP as solvent. To our delight, the C3 addition of indole
occurred smoothly at room temperature and furnished
compound 7 in excellent yield (92%). Use of 5ab instead of
5aa worked with similar efficiency and afforded 7 in 90% yield.
a
Reaction conditions: 1 (2.0 equiv), 4 (1.0 equiv), base (4.0 equiv).
Scheme 5. C-2 Modifications of 2-Aminothiazolidin-4-ones
b
Isolated yields are given. 64% yield for 1.0 g scale reaction with 4a.
Various electron-donating and electron-withdrawing sub-
stituents on the aromatic ring of benzamides were tolerated
(5ag−5ak). Substrates containing a heterocyclic nucleus (5al,
5am) were used successfully, and indole-2-thione furnished
spirocyclic compound 5an. α-Aryl-substituted chlorohydrox-
amate also reacted with thioamide and furnished 5db. X-ray
structural analysis of 5am revealed the axial conformational
preference of the pyrrolidine moiety. Compounds 5aj, 5ak, and
5db were obtained as mixture of diastereomers.8b It is
important to note that the reaction did not proceed when α-
haloamide was used in the reaction instead of α-halohydrox-
amate.
Curiously, when the reaction of α-bromohydroxamate 1a
and thioamide 4a was performed in DIPEA/HFIP, both of the
starting materials were consumed within 30 min and led to the
formation of a new compound that differed from the expected
2-aminothiazolidin-4-one product (5aa). The new compound
was later characterized to be an HFIP addition product 6
1
(76%) as supported by H/13C/19F NMR and MS analysis.
C
DOI: 10.1021/acs.orglett.9b01933
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Letter
A one-pot transformation of 1a, 4a, and indole was also viable,
albeit in lower yield (50%). Other indole derivatives and
pyrrole also reacted efficiently under the conditions, affording
8−10 in high yields. The reaction scope can be extended to
different active methylene compounds, such as pyrazolone
derivative and malononitrile (11 and 12).
Experimental procedures and characterization data for
all compounds and crystal data for 3am and 5am (PDF)
Accession Codes
CCDC 1918619−1918620 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Use of heteroatom nucleophiles ranging from aromatic
amines and alcohols to aliphatic variants was successful (5ae,
13−16). Importantly, since the reaction of 5aa with aniline or
nBuNH2 was viable, this indicated the possibility of a strain-
driven solvolysis event of the 3° amino moiety on 5aa (or 5ab)
by HFIP, which apparently was absent for related compounds
possessing 2° amino groups (e.g., 5ea and 13). Quite
remarkably, the strategy also allowed us to introduce a peroxy
group at C2 using TBHP (17), with no trace of oxidation of
sulfur moiety in the resulting product. Importantly, access to
such α-heteroatom-substituted peroxy compounds is highly
important in both synthetic methodologies and biological
contexts.12 We next used thiol, which added at C2 in similar
fashion to give 18 in 80% yield. Reaction with TBAF afforded
the hydrolyzed ring-opened product 19.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jaideep.saha@cbmr.res.in, jdsaha2000@gmail.com.
ORCID
Dinabandhu Das: 0000-0003-0143-7821
Jaideep Saha: 0000-0002-1505-5130
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
To demonstrate the utility of the synthesized compounds,
we performed the deprotection of the benzyloxy group on a
representative compound 3aa using Mo(CO)6, which led to
compound 20 (85%) with a free NH group via selective N−O
bond cleavage (Scheme 6). N-Alkylation of 20 with 1,4-
dibromobutane delivered 21, which could serve as a potential
intermediate for the preparation of analogues of a known
antipsychotic agent.8c
■
J.S. thanks SERB, New Delhi, for funding (ECR/2016/
001474). V.J. and B.M. thank UGC and CSIR, New Delhi,
for fellowships. K.S. thanks SERB, DST (PDF/2017/000097).
J.S. thanks the Director of CBMR for research facilities. D.D.
thanks DST-FIST for X-ray facility at SPS, JNU.
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In summary, we have developed a new approach for efficient
synthesis of highly functionalized thiazolidin-4-ones utilizing
an azaoxyallyl cation intermediate and thiocarbonyls. This is
another rare example of reactive thiocarbonyls participating in
the [3 + 2] annulation as a two-atom unit. Furthermore, the
C2 amino group in the 2-aminothiazolidin-4-ones displayed a
high degree of lability in HFIP, which opened up the
opportunity to use it as the latent reactive group for late-
stage modifications and enabled the introduction of a very
wide range of functional groups at the C2 position.
Importantly, this chemistry worked efficiently without the
need of any Lewis acids or metal catalysts. For the current [3 +
2] annulation, the prerequisite N-benzyloxy group was cleaved
easily to free the NH group, which was amenable to
subsequent functionalizations. More details of the mechanistic
studies on SN1-type solvolysis of 2-aminothiazolidin-4-ones
possessing the tertiary amino group in HFIP medium and
further applications are currently underway in our laboratory.
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.9b01933.
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DOI: 10.1021/acs.orglett.9b01933
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