Switching regioselectivity of β-ketothioamides by means of iodine catalysis: Synthesis of thiazolylidenes and 1,4-dithiines

Article abstract of DOI:10.1002/chem.201304497

An efficient I₂-catalyzed synthesis of thiazolylidenes and 1,4-dithiines from β-ketothioamides (KTAs) has been developed by only controlling the amount of I₂ that triggers different cascade reaction sequences by means of [3+2] or [3+3] cyclocondensation in a one-step process. A possible mechanistic proposal for these transformations is presented.

Full text of DOI:10.1002/chem.201304497

DOI: 10.1002/chem.201304497
Full Paper
&
Regioselectivity
Switching Regioselectivity of b-Ketothioamides by Means of
Iodine Catalysis: Synthesis of Thiazolylidenes and 1,4-Dithiines
Li-Rong Wen,* Lian-Bin Men, Tao He, Guo-Jing Ji, and Ming Li*[a]
Abstract: An efficient I2-catalyzed synthesis of thiazolyli-
denes and 1,4-dithiines from b-ketothioamides (KTAs) has
been developed by only controlling the amount of I2 that
triggers different cascade reaction sequences by means of
[3+2] or [3+3] cyclocondensation in a one-step process. A
possible mechanistic proposal for these transformations is
presented.
Introduction
Some thiazolylidenes with general structures I and II have
been reported as the basis for cannabinoid receptor ligands.[1]
Also, 2-acylmethylidene-3-methyl thiazolines III are known to
possess anti-inflammatory and analgesic properties (Figure 1).[2]
Scheme 1. Two modes of KTAs to form thiazolylidenes and 1,4-dithiines.
Bogdanowicz-Szwed and co-workers have presented
a method for the synthesis of thiazolylidenes by self-condensa-
tion reaction of KTAs in the presence of piperidine in boiling
ethanol; however, there are some unreasonable expressions in
their proposed mechanism.[7] Owing to the highly polarized
push–pull (HS and RNH)/(C=O) interaction on the C=C bond,
the electron density on the a-carbon atom of one intermediate
as a nucleophilic center is increased, whereas the mercapto of
another intermediate is also a nucleophilic center, so they
could not connect directly in common cases. Therefore re-eval-
uation of this reaction mechanism is necessary. We think that
this reaction needs an oxidant to promote this transformation
efficiently.
Figure 1. Selected biologically active thiazolylidenes.
Owing to their biological and pharmacological importance, ex-
ploring and improving the synthetic methods of thiazolylidene
derivatives is very significant.
b-Ketothioamides (KTAs) have emerged as powerful syn-
thons in the construction of heterocycles.[3] Recent work has
been performed on the reactivities of nucleophilic N and C
atom sites of KTAs with dielectrophilic groups in multicompo-
nent reactions (MCRs).[4,5]
In continuation of our research interests in the application
of KTAs,[4] herein we report an efficient synthesis of thiazolyli-
denes and 1,4-dithiines by self-condensation reactions of KTAs
controlled by I2 at room temperature.
Molecular iodine has been used extensively in organic syn-
thesis, and many of the iodine-mediated reactions featured
mild reaction conditions, good selectivity, and short reaction
times.[6] However, the studies of KTAs on the reactivities of S
and N atoms by mode A in Scheme 1 to form thiazolylidenes,
and C and S atoms by mode B in Scheme 1 to form 1,4-di-
thiines in the presence of I2 have not been disclosed thus far.
Results and Discussion
To justify our assumption, we employed iodine (0.5 equiv) as
the oxidant to promote the self-condensation reaction of 3-
oxo-N-phenylpropanethioamide (1a) in ethanol at room tem-
perature for 3 h (Table 1, entry 1). The reaction led to the for-
mation of a mixture of two major oxidation products, (E)-2-(5-
benzoyl-3-phenyl-4-(phenylamino)thiazol-2(3H)-ylidene)-1-phe-
nylethanone (2a) in a yield of 32% and (2E,2’E)-2,2’-(4-phenyl-
1,2-dithiolane-3,5-diylidene)bis(1-phenylethanone) (4a)[8] in
a yield of 51% (Scheme 2). The structure of 4a was unequivo-
cally established by X-ray single-crystal diffraction analysis (Fig-
ure S1 in the Supporting Information).
[a] Prof. L.-R. Wen, L.-B. Men, T. He, G.-J. Ji, Prof. M. Li
State Key Laboratory Base of Eco-Chemical Engineering
College of Chemistry and Molecular Engineering
Qingdao University of Science and Technology
Qingdao 266042 (P.R. China)
E-mail: wenlirong@qust.edu.cn
liming928@qust.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304497.
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The more extensive scope of substrates was investigated to
test the generality of this reaction under the optimized condi-
tions (Table 2).
Table 1. Optimization of reaction conditions for the synthesis of 2a.[a]
Entry Oxidant [(equiv)] Base [(equiv)] Solvent T [8C] t [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
CAN (1.0)
I2 (0.25)
I2 (0.75)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
–
EtOH
EtOH
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
50
78
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
32
57
74
43
40
65
73
65
33
66
70
50
57
69
65
Et3N (1.0)
DABCO (1.0) EtOH
K2CO3 (1.0)
NaOH (1.0)
DABCO (0.75) EtOH
DABCO (1.25) EtOH
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0) MeCN
DABCO (1.0) CH2Cl2
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
EtOH
EtOH
EtOH
EtOH
EtOH
THF
EtOH
EtOH
[a] 0.5 mmol of 1a, performed in 1 mL solvent. [b] Yield of isolated prod-
uct.
Scheme 2. Iodine-catalyzed reaction of 1a.
To improve the regioselectivity of this oxidation reaction, the
reaction conditions were optimized with various bases, oxi-
dants, and solvents at different temperatures. The results are
listed in Table 1.
Initially, the reaction of 1a was carried out in the presence
of Et3N, 1,4-diazabicyclo[2.2.2]octane (DABCO), K2CO3, and
NaOH, respectively (Table 1, entries 2–5), and DABCO gave the
highest yield of 74%. The yield of 2a was not further improved
by increasing or decreasing the amount of DABCO (Table 1, en-
tries 6 and 7). Another oxidant, ceric ammonium nitrate (CAN),
was also investigated in the presence of DABCO (1 equiv), and
the result showed that CAN results in a lower yield than I2
(Table 1, entry 8). Then the amount of I2 was further examined
(Table 1, entries 9 and 10). It was found that 0.5 equivalents of
I2 are necessary for this oxidation reaction, but increased
amounts of I2 could not further improve the yield of 2a. Next,
different solvents such as CH3CN, CH2Cl2, and THF were also
tested in the presence of DABCO (1 equiv) and I2 (0.5 equiv).
Unfortunately, they could not afford higher yields than in EtOH
(Table 1, entries 11–13). Finally, the reaction temperature was
raised to improve the yield of 2a, but we did not obtain better
results (Table 1, entries 14 and 15). Therefore the optimum re-
action conditions for 2a were I2 (0.5 equiv) as catalyst, DABCO
(1 equiv) as base, and EtOH as solvent at room temperature
(Table 1, entry 4).
Figure 2. ORTEP drawings of compounds 2a (top) and 3e (bottom).
Scheme 3. Study of the reactions of KTAs with aromatic amines in the pres-
ence of 1 equivalent of I2.
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As can be seen from Table 2, when KTAs that bear
various electronically different substituents on the N-
phenyl ring or phenyl ring linked to the carbonyl
were employed as substrates, the reactions smoothly
provided the corresponding products in good yields.
Among them, 1a–c all gave the higher yields than
the counterparts reported in literature[7] (Table 2, en-
tries 1–3), which suggested that the self-condensa-
tion reaction of KTAs could be promoted by I2 as oxi-
dant under milder conditions. Notably, the position
of the substituent on the N-phenyl ring has almost
no influence on the reaction yield (Table 2, entries 3–
5), whereas the position of the substituent on the
phenyl ring linked to the carbonyl has a clear effect
on the yield (Table 2, entries 7–9). For example, rela-
tive to 1g and 1h, compound 1i with an ortho-Cl
group provided a lower yield of 55%, and the reac-
tion time was longer.
Table 2. Variation of KTA substrates for the synthesis of thiazolylidenes 2.[a]
Entry
Substrate 1
Product 2
t
Yield
[h] [%][b]
74
3
1
1a
2a
(62)[7b]
83
3
2
1b
2b
(57)[7b]
Next, we tried the possibility of applying this cata-
lytic system in the reaction of two different KTAs by
employing 1k and 1g in a ratio of 1:1. As expected,
not only homocoupling thiazolylidene products 2k
and 2g were obtained in 22 and 21% yields, respec-
tively, but also two cross-coupling products 2kg and
2gk were observed in a total yield of 37% (evaluated
76
2.5
3
1c
2c
(43)[7b]
1
by H NMR spectroscopy; also see the Supporting In-
formation).
Unfortunately, when a KTA with alkyl amine, such
as
N-cyclohexyl-3-oxo-3-phenylpropanethioamide
(1o), was employed under the above conditions, the
reaction afforded a complex mixture without the de-
sired thiazolylidene product 2o. Interestingly, when
the amount of I2 was increased to 1 equivalent, only
a homocoupling product 1,4-dithiine 3a was ob-
tained in a good yield of 82% (Table 3, entry 1). This
observation is truly rare and very interesting.
4
5
1d
2d
3
3
73
76
1e
2e
Functionalized 1,4-dithiines are of interest because
they represent an important class of heterocycles.
Many of them exhibit useful biological activities such
as fungicides, antibacterials, anthelmintics, antimicro-
bials, and nonpeptide antagonists of the human Gal-
anin hGAL-1 receptors.[9] In addition, polycyclic 1,4-di-
thiine derivatives are useful as pigments and func-
tional materials for electro-optical applications.[10] Al-
though 1,4-dithiines have been known for more than
100 years, a careful search of the literature shows
that there have been no reports on the synthetic ap-
plication of KTAs to construct 1,4-dithiines.[11]
6
1 f
2 f
2.5 79
To justify that this observation was not an excep-
tion, the reactions of more KTAs with alkyl amine
were investigated. The results are shown in Table 3.
As can be seen from Table 3, in all cases the reactions
proceeded smoothly to provide the corresponding
1,4-dithiines in good yields of 77–88% within 3 h. Un-
fortunately, when R=aryl, the reactions led to the
formation of a mixture of two major products 2 and
3 under the same conditions (Scheme 3 above).
7
1g
2g
3
81
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It is noteworthy that a KTA with an ortho-Cl group
on the phenyl ring linked to the carbonyl, which pro-
vided the lower yield in the synthesis of thiazolyli-
denes (Table 2, entries 7–9), gave higher yield in the
synthesis of 1,4-dithiines than KTAs with meta- and
para-Cl atoms (Table 3, entries 5–7). There is no ra-
tional explanation for this observation.
Table 2. (Continued)
Entry
Substrate 1
Product 2
t
Yield
[h] [%][b]
The structures of all new compounds 2 and 3 were
unequivocally established by spectroscopic methods
(IR, 1H and 13C NMR) and HRMS, and unequivocally
established by the X-ray single-crystal diffraction
analysis of compounds 2a and 3e (Figure 2).
8
1h
2h
3
83
55
On the basis of the above experimental results, we
present a plausible reaction mechanism that is out-
lined in Scheme 4. Firstly, KTAs 1 are mediated by
DABCO to deprotonate, thus forming intermediate A,
which reacts with I2 to generate intermediate B.[12]
When R=aryl and the amount of I2 is 0.5 equivalents,
intermediate A reacts with B by means of nucleophil-
ic substitution to give intermediate C. Finally, C un-
dergoes an intramolecular cyclization reaction to give
D, which loses a molecule of H2S to lead to the for-
mation of the thiazolylidenes 2. Clearly, the present
reaction mechanism is very different from that re-
ported in the literature.[7a] Whereas R=alkyl and the
amount of I2 is 1 equivalent, two molecules of B react
with each other through a nucleophilic substitution
to give intermediate E, which generates 1,4-dithiines
3 easily by means of tautomerization.
9
1i
2i 15
10
1j
1k
1l
2j
2k
2l
3
78
11
2.5 83
Conclusion
In summary, we have successfully described the
iodine-controlled dimerization of KTAs for the synthe-
sis of thiazolylidenes and 1,4-dithiines. The striking
feature of the reaction is its switchable selectivity to
synthesize thiazolylidenes and 1,4-dithiines from KTAs
by controlling the amount of I2. The present synthesis
shows fascinating properties such as high regioselec-
tivity, short reaction times, mild reaction conditions,
and easy purification. Undoubtedly, this synthetic
strategy opens a convenient, effective way to con-
struct thiazolylidenes and 1,4-dithiines. We hope this
approach might be of value for others who are seek-
ing novel synthetic fragments with unique properties
for medicinal and materials chemistry. Further investi-
gations to expand the scope of KTAs as versatile
building blocks are in progress and will be reported
elsewhere in due course.
12
2.5 85
13
1m
2m
3
79
14
1n
2n
2.5 85
Experimental Section
General procedure for the preparation of thiazolyli-
denes 2
[a] Reaction conditions: A mixture of KTAs 1 (1.0 mmol), DABCO (1.0 mmol), and I2
(0.5 mmol) was stirred in EtOH (2 mL) for the appropriate reaction time at room tem-
perature. [b] Yield of isolated product.
A mixture of b-ketothioamides 1 (1.0 mmol), DABCO
(1.0 mmol), and I2 (0.5 mmol) was stirred in EtOH (2 mL)
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Table 3. Variation of KTA substrates for the synthesis of 1,4-dithiines 3.[a]
Entry
Substrate 1
Product 3
t
Yield
[h] [%][b]
1
1o
1p
1q
1r
3a 2.5 82
2
3
4
3b
3c
3d
3
3
3
77
83
79
Scheme 4. Proposed mechanism for the formation of 2 and 3.
General procedure for the preparation of 1,4-di-
thiines 3
A mixture of b-ketothioamides 1 (1.0 mmol), DABCO
(1.0 mmol), and I2 (1 mmol) was stirred in EtOH (2 mL)
for the appropriate reaction time at room temperature.
After completion of the reaction, as indicated by TLC,
the solid product was filtered, washed with EtOH, and
subsequently dried and recrystallized from CH3CN to
give the pure 1,4-dithiines 3.
5
6
7
1s
3e
3 f
3g
3
3
3
81
82
88
Acknowledgements
1t
This work was financially supported by the National
Natural Science Foundation of China (21072110 and
21372137) and the Natural Science Foundation of
Shandong Province (ZR2012M003).
Keywords: amides
·
iodine
·
regioselectivity
·
1u
synthetic methods · thiazolylidenes
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Received: November 17, 2013
Published online on March 18, 2014
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