An approach to the synthesis of 4-aryl and 5-aryl substituted thiazole-2(3: H)-thiones employing flow processing

Article abstract of DOI:10.1039/c6ra15488c

A method for the preparation of 4-aryl and 5-aryl substituted thiazole-2(3H)-thiones is described. Flow processing is employed as a tool, and supported acids and bases used to facilitate both the synthetic strategy and product isolation. The methodology is applicable to a range of substrates.

Full text of DOI:10.1039/c6ra15488c

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An Approach to the Synthesis of 4-Aryl and 5-Aryl Substituted
Thiazole-2(3H)-thiones Employing Flow Processing
Monaem Balti,a Shelli. A. Miller,b Mohamed Lotfi Efrita and Nicholas E. Leadbeaterb,*
Received 00th January 20xx,
Accepted 00th January 20xx
A method for the preparation of 4-aryl and 5-aryl substituted thiazole-2(3H)-thiones is described. Flow processing is
employed as a tool, and supported acid and bases used to facilitate both the synthetic strategy and product isolation. The
DOI: 10.1039/x0xx00000x
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methodology
is
applicable
to
a
range
of
substrates.
substituted thiazole thiones involves the reaction of ammonium
dithiocarbamate, with αꢀhaloꢀsubstituted aldehydes or
ketones at reflux in ethanol as the solvent (Scheme 1).10
Introduction
3,
Indoleamine 2,3ꢀdioxygenase (IDO) is an extrahepatic haemꢀ
containing enzyme that catalyses the oxidative catabolism of
(Lꢀtryptophan along the kynurenine pathway.1 It is
overexpressed in many human tumors and is correlated with
poor survival prognosis in several cancer types. The efficacy of
therapeutic vaccination or chemotherapy can be improved by
concomitant administration of an IDO inhibitor, making IDO a
new therapeutic target.2 Marine natural products have found
application as IDO inhibitors but, given their molecular
complexity, their synthesis can pose a challenge.3 As a result,
simpler, smallꢀmolecule compounds are attractive. Within this
category, 4ꢀphenylthiazoleꢀ2(3H)ꢀthione, 1a, has been studied
in some detail both from an in-silico4 and in-vitro perspective.5
The compound, with an inhibitory potency (IC50) of about 40
mM, exists almost exclusively as the thiazoleꢀ2(3H)ꢀthione
Although
3 is not commercially available, its synthesis from
carbon disulfide and ammonia is well described.11 Alternative
approaches to 4ꢀsubstituted thiazole thiones involve the
reaction of
3
with a variety of hypervalent iodine compounds.12
S
O
HN
S
hal
NH4
∆
EtOH
S
+
H2N
S
1
3
R
R
Scheme 1 Preparation of 4-aryl substituted thiazole thiones
When using the classical approach to 4ꢀaryl substituted
thiazoleꢀ2(3H)ꢀthione, problems arise from the formation of
sideꢀproducts as a result of the decomposition of ammonium
dithiocarbamate. In such cases, isolation of the product poses a
particular challenge. In an attempt to overcome these issues, we
decided to investigate the possibility of using flow processing
as a tool and report our results here.
tautomer rather than the2ꢀmercaptothiazole, 2a 6
Thiazoleꢀ
2(3H)ꢀthiones have also found application as ligands in
colorimetric analysis7 and coordination chemistry.8
.
S
SH
By turning to flow processing, reactions can often be
streamlined, multiple steps can be linked together, and reactions
that were challenging in batch are now available for chemists to
use.13,14 There is also better control of heating and mixing,
allowing for reactions to be performed under very precise and
reproducible conditions. Flow chemistry is not, however, a
panacea. Reactions that involve the manipulation of solids, and
reactions that are by their very nature slow pose challenges
although solutions for the former are already on the way.15
HN
S
N
S
1a
2a
The effects that substituents on the aromatic ring, as well as
the position of the ring on the thiazole thione scaffold, have on
the biological and metal complexation properties of the
resultant compounds has sparked interest in the synthesis of
analogs of 1a 9
. The classical method for preparing 4ꢀaryl
Results and discussion
We selected 1a as a representative 4ꢀaryl substituted thiazoleꢀ
2(3H)ꢀthione target. Using 2ꢀbromoacetophenone, 4a, and
starting materials we immediately encountered a challenge. The
solubility of in a variety of polar solvents was poor, making
3 as
3
pumping the reaction mixture a challenge due to clogging of the
tubing. We decided to transition to using the more soluble
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triethylammonium dithiocarbamate,
5, in place of 3
. This atoms.16 The 3ꢀbromo substituted analog (Entry 6) could serve
reagent was prepared by adding aqueous ammonia to a diethyl as a starting material for further diversification through metalꢀ
ether solution of carbon disulfide and triethylamine at 0°C with catalyzed crossꢀcoupling reactions.
stirring. Allowing the mixture to warm to room temperature,
Table 2 Preparation of 4-aryl substituted thiazole thiones in flowa
and stirring overnight resulted in an 86% of
was used promptly without any further purification. Using 0.05
M ethanol solutions of 4a and , and pumping each at a flow
5 as a solid, which
5
rate of 0.5 mL/min through a 10 mL capacity coil (1 mL/min
combined flow rate; 10 min residence time) at room
temperature gave a 38% yield of 6, the hydrated intermediate
Entry
R
Product
1a
Yield (%)
92
along the pathway to 1a (Table 1, Entry 1). Increasing the
relative stoichiometry of 5:4 from 1:1 to 1.2:1 increased the
yield of 6a considerably (Entries 2 and 3). Reducing the flow
rate of each solution to 0.2 mL/min (hence increasing the
1
2
3
4
5
6
H
2-OMe
4-OMe
4-Me
2-F
1b
91
1c
96
1d
91
1e
89
residence time to 25 min) further improved the yield of
6 to
3-Br
1f
94
90% (Entry 4). To convert 6a to 1a, we simply passed the
reaction mixture through a second coil, heated to 40 °C. We
were able to obtain a 94% isolated yield of 1a (Entry 5).
Passing the reaction mixture through just one coil heated to 40
°C led to incomplete conversion (Entry 6) so the twoꢀcoil
approach was favored. The product mixture required
purification to remove the triethylamine byproduct. To
streamline the process, we passed the crude product mixture
obtained from the second coil through a cartridge packed with
Amberlyst A15, a macro reticular polystyreneꢀbased ionꢀ
exchange resin with strongly acidic sulfonic acid groups, to
scavenge the triethylamine byproduct. Optimal results were
obtained when 4.6 eq of A15 was employed (Entry 7).
a Runs were performed on a small scale using injection loops (2 mL of each
solution) but also could be scaled up.
Having prepared a number of 4ꢀaryl substituted thiazoleꢀ
2(3H)ꢀthiones, our attention turned next to the synthesis of 5ꢀ
aryl analogs. The preparation of 5ꢀaryl substituted thiazoleꢀ
2(3H)ꢀthiones (
7) requires a somewhat different approach.
Approaches in the literature center around the treatment of
carbon
disulfide
with
either
αꢀaminoacetophenone
hydrochlorides17 or 2ꢀarylꢀ1ꢀazirines.18 The former is
operationally simpler, involving the reaction of the requisite αꢀ
aminoacetophenone hydrochloride,
CS2 followed by dehydration of the hydroxythiazolidineꢀ2ꢀ
thione, , using trifluoroacetic acid (Scheme 2). Yields are
8, with triethylamine and
Table 1 Optimization of conditions for the preparation of 4-aryl substituted thiazole
thiones in flowa
9
often good but reaction times are long (generally around 48 h)
and, as with the 4ꢀaryl congeners, purification of the product is
complicated due to contamination with triethylamine. We
investigated the synthesis of a range of 5ꢀaryl substituted
thiazoleꢀ2(3H)ꢀthiones building on our approach used for the 4ꢀ
aryl substituted analogs.
[4a]
[5] Coil 1 Coil 2 A15
Flow
6a
1a
Entry
(M)
(M)
(°C)
25
25
25
25
25
40
25
(°C)
(eq.) (mL/min) (%) (%)
1
2
3
4
5
6
7
0.050 0.05
0.055 0.05
0.060 0.05
0.060 0.05
0.060 0.05
0.060 0.05
0.060 0.05
-
-
-
1.0
1.0
1.0
0.4
0.4
0.4
0.4
38
47
82
90
-
-
-
-
-
-
-
-
-
-
40
-
-
94
33
92
-
52
-
40
4.6
Scheme 2 Preparation of 5-aryl substituted thiazole thiones
a A solution of triethylammonium dithiocarbamate (5) (1.2 mmol) in ethanol (20
mL) and a solution of 2-bromoacetophenone (4a) (1 mmol) in ethanol (20 mL)
were prepared. Runs were performed on a small scale using injection loops (2 mL
of each solution).
Our first objective was to prepare the requisite
αꢀaminoacetophenone hydrochloride (
was achieved by reaction of αꢀbromo acetophenones,
hexamethylenetetramine to give the corresponding iminium
8) starting materials. This
4
, with
With optimized conditions in hand, we prepared
a
representative range of 4ꢀaryl substituted thiazoleꢀ2(3H)ꢀ salts, which were hydrolysed by ethanolic hydrochloric acid
thiones. The results are shown in Table 2. The protocol is yielding the αꢀaminoacetophenone hydrochlorides.19 With these
applicable to a number of αꢀbromoacetophenone starting in hand, we turned to the synthesis of the heterocycles. To
materials. Both 2ꢀ and 4ꢀmethoxy substituted compounds could avoid the complications observed when using triethylamine as
be prepared in excellent yield (Table 2, Entries 2 and 3). The 2ꢀ the base in the reaction, we decided to employ Amberlyst A21,
fluoro analog (Entry 5) is of note, given the fact that the a macro reticular resin with alkyl amine functionality, as a
physiological and chemical properties of small molecules (e.g. supported base and flow a mixture of αꢀaminoacetophenone
chemical/metabolic stability, lipophilicity, and binding hydrochloride and CS2 through it. We selected 5ꢀ
selectivity) are greatly altered by incorporation of fluorine phenylthiazoleꢀ2(3H)ꢀthione, 7a, as a representative target for
2 | J. Name., 2012, 00, 1-3
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Table 4 Preparation of 5-aryl substituted thiazole thiones in flowa
optimizing reaction conditions. Using a 0.2 M solution of αꢀ
aminoacetophenone hydrochloride 8a in ethanol, and an excess
of CS2, we passed the reaction mixture through a bed of 4 eq of
A21 at room temperature at a flow rate of 0.4 mL/min,
corresponding to a residence time of approximately 40 min
(Table 3, entry 1). None of the hydroxythiazolidineꢀ2ꢀthione
intermediate 9a was obtained. Increasing the quantity of A21 to
8 eq while keeping all other factors constant still did not yield
9a (Entry 2). However, operating at 80 °C, a 19% yield of 9a
was obtained. (Entry 3). Reducing the flow rate, first to 0.1
mL/min (Entry 4) and then to 0.05 mL/min (Entry 5) resulted in
a much more respectable 81% yield. The dehydration step was
then performed by passing the mixture of 9a through a bed of
Amberlyst A15. Using 4.6 eq of A15 and operating the reactor
at room temperature, no conversion to 7a was observed (Entry
6). However, by increasing the reactor temperature to 80 °C, an
89% yield of 7a was obtained (Entry 7).
Entry
R
Product
7a
Yield (%)
89
1
2
3
4
5
6
H
2-OMe
4-OMe
4-Me
2-F
7b
84
7c
87
7d
88
7e
76
3-Br
7f
84
a Runs were performed on a small scale using injection loops (2 mL of each
solution) but also could be scaled up.
To compliment previous calculations performed on 1aꢀc, we
decided to perform calculations on the two possible tautomers
for all of the compounds prepared in this current study to probe
the difference in energy between the thiazoleꢀ2(3H)ꢀthione and
the thiazoleꢀ2ꢀthiol tautomers. We find that in each case, the
thiazoleꢀ2(3H)ꢀthione tautomer is the more stable, the degree to
which being dependent on the substituent on the aromatic ring
(Table 5).
Table 3 Optimization of conditions for the preparation of 5-aryl substituted thiazole
thiones in flowa
R 1
R 2
Flow
9a
7a
Entry
R 1 (°C)
R 2 (°C)
(eq. A21)
(eq. A15)
(mL/min) (%) (%)
1
2
3
4
5
6
7
4
8
8
8
8
8
8
25
25
80
80
80
80
80
-
-
-
-
-
-
0.4
0.4
0.4
0.2
0.1
0.1
0.1
0
0
-
-
-
19
43
81
-
-
-
-
-
-
4.6
4.6
25
80
0
89
-
Table 5 Energetics for the isomeric conversion of 1 to 2 or 7 to 10a
a A solution of 2-phenyl-2-oxoethanaminium chloride (8a) (4 mmol) in ethanol (20
mL) and a reservoir of carbon disulfide were prepared. Runs were performed on a
small scale using injection loops (2 mL of each solution).
Entry
1
Most stable tautomer ΔE (kJ / mol)
1a
1b
1c
1d
1e
1f
25.6
43.7
26.5
26.5
38.2
19.7
30.7
32.5
31.6
27.8
34.5
30.4
2
We next prepared a representative range of 5ꢀaryl substituted
thiazoleꢀ2(3H)ꢀthiones. The results are shown in Table 4. For
direct comparison, the same group of αꢀbromoacetophenone
starting materials were used as in the study of 4ꢀaryl substituted
congeners, in this case being first converted to the
corresponding αꢀaminoacetophenone hydrochlorides. Good
yields of the desired 5ꢀaryl substituted thiazoleꢀ2(3H)ꢀ
thioneproducts were obtained, albeit globally slightly lower
than those obtained in the case of the 4ꢀaryl analogs.
3
4
5
6
7
7a
7b
7c
7d
7e
7f
8
9
10
11
12
a Performed using Gaussian 09.20 Ground state optimizations were performed in
the gas phase at the DFT(PBEPBE)/6-311g(d,p) level of theory.21
Conclusions
In summary, we present a strategy for the synthesis of 4ꢀaryl
and 5ꢀaryl substituted thiazoleꢀ2(3H)ꢀthiones. We employ flow
processing as a tool, and use supported acid and bases to
facilitate both the synthetic strategy and product isolation. The
methodology is applicable to a range of substrates, including
those bearing biologically relevant (OMe and F) and
synthetically useful (Br) handles. Computations show that for
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all the compounds prepared, the thiazoleꢀ2(3H)ꢀthione is more to the inlet port of cartridge 1. The outlet port of cartridge 1 was
stable than the thiazoleꢀ2ꢀthiol tautomer.
connected to the inlet port of cartridge 2 and the exit of
cartridge 2 directly interfaced with a 100 psi back pressure
regulator after which there was a short length of tubing leading
to a collection vessel. The flow system was primed using the
equipment manufacturer’s suggested startꢀup sequence. The
entire system was flushed with ethanol for 5 min at a flow rate
of 0.5 mL / min on each pump. The flow rate of each pump was
then decreased to 0.05 mL / min (giving a combined flow rate
of 0.1 mL / min) and cartridges heated to 80 °C (cartridge 1)
and 40 °C (cartridge 2). Once at the target temperatures, the
flow was then changed from solvent to reagents by means of a
switch on the flow unit. Solution A was pumped by pump A
and solution B by pump B. The reaction mixture was then
flowed through the system and the product collected. Once the
requisite volume of reagents had been loaded into the first
reactor coil, the flow was changed back to solvent and the
system run until the remainder of the reaction mixture has
passed through the entire configuration. Once all the product
had exited the unit, the flow of ethanol solvent was stopped.
The contents of the collection vessel were decanted into a round
bottom flask, and the organic solvent removed using rotary
evaporation, leaving behind crystalline product 8a in 89%
Experimental section
Representative experimental procedure for the synthesis of 4-aryl
substituted thiazole-2(3H)-thiones:
Preparation of 4-Phenylthiazole-2(3H)-thione (1a): Two stock
solutions were prepared – Solution A: Triethylammonium
dithiocarbamate (1.2 mmol) in ethanol (20 mL); Solution B: 2ꢀ
bromoacetophenone (1 mmol) in ethanol (20 mL).
A
combination of a Vapourtec R2 Pump Module and a Vapourtec
R4 Reactor Module was employed for the reaction. The flow
system was equipped with two 10ꢀmL volume stainlessꢀsteel
coils in series (coil 1 and coil 2). Two pumps were employed
(pump A and pump B), the outlets of which were joined to a Tꢀ
piece and the outlet of the Tꢀpiece attached to the “reagent in”
port of the first reactor coil. The “reagent out” port of the
second reactor coil was attached to a cartridge containing
Amberlyst 15 and the exit of the cartridge directly interfaced
with a 100 psi back pressure regulator after which there was a
short length of tubing leading to a collection vessel. The flow
system was primed using the equipment manufacturer’s
suggested startꢀup sequence. The entire system was flushed
with ethanol for 5 min at a flow rate of 0.5 mL / min on each
pump. The flow rate of each pump was then decreased to 0.2
mL / min (giving a combined flow rate of 0.4 mL / min) and the
reactor coils heated to 25 °C (coil 1) and 40 °C (coil 2). Once at
the target temperatures, the flow was then changed from solvent
to reagents by means of a switch on the flow unit. Solution A
was pumped by pump A and solution B by pump B. The
reaction mixture was then flowed through the two coils and the
cartridge containing Amberlyst 15 and the product collected.
Once the requisite volume of reagents had been loaded in to the
first reactor coil, the flow was changed back to solvent and the
system run until the remainder of the reaction mixture has
passed through the entire configuration. Once all the product
had exited the unit, the flow of ethanol solvent was stopped.
The contents of the collection vessel were decanted into a round
bottom flask, and the organic solvent removed using rotary
evaporation, leaving behind crystalline product 1a in 92%
1
yield. H NMR (400 MHz, CD3OD): 7.48 (s, 1H, C=CHꢀNH),
7.33ꢀ7.43 (m, 3H, ArCH), 7.61 (d, J = 8.8 Hz, 2H, ArCH). 13C
NMR (100 MHz, CD3OD): 109.63 (ArCꢀS), 125.77, 129.22,
129.40, 131.25 (5CHAr, CAr), 141.57 (C=CHꢀNH), 178.53
(C=S). HRMS (ESI) m/z calculated for calculated for C9H8NS2
[M+H]+: 194.0098, found 194.0104.
Computational Studies
Quantum chemical calculations were performed using Gaussian
09. All optimized geometries were calculated using PBEPBE/6ꢀ
311g(d,p) level of theory. Stationary points were characterized
by frequency calculations at 298 K, with structures at energy
minima showing no negative frequencies. Electronic energies
are obtained by the sum of electronic and zeroꢀpoint energies.
The zeroꢀpoint energy correction factor was obtained using
frequency analysis. All energy values shown are in kJ / mol.
1
Acknowledgements
yield. H NMR (400 MHz, CD3OD): 6.98 (s, 1H, C=CHꢀS),
7.61 (d, J = 8.8 Hz, 2H, ArH), 7.43 (m, 3H, ArCH). 13C NMR
(100 MHz, CD3OD): 108.61(C=CHꢀS), 125.67, 128.87, 129.02,
129.13 (CAr), 142.39 (ArC=CHꢀS), 190.85 (C=S). MS: m/z
[M+H]+ 194.1.
We gratefully acknowledge financial support from Faculté des
Sciences, Université de Tunis and the University of
Connecticut.
Representative experimental procedure for the synthesis of 5-aryl
substituted thiazole-2(3H)-thiones:
Preparation of 5-Phenylthiazole-2(3H)-thione
(7a): Two
reagent reservoirs were readied – Solution A: 2ꢀphenylꢀ2ꢀ
oxoethanaminium chloride (8a) (4 mmol) in ethanol (20 mL);
Solution B: Carbon disulfide. The flow system was equipped
with two cartridges, one containing Amberlyst A21 (cartridge
1) and one containing Amberlyst A15 (cartridge 2). Two pumps
were employed (pump A and pump B), the outlets of which
were joined to a Tꢀpiece and the outlet of the Tꢀpiece attached
4 | J. Name., 2012, 00, 1-3
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VCH, Weinheim, 2013. (c) C. Wiles and P. Watts, Micro Reaction
Technology in Organic Synthesis. CRC Press, Boca Raton FL, 2011. (d)
S. V. Luis and E. GarciaꢀVerdugo (Eds) Chemical Reactions and
Processes under Flow Conditions Royal Society of Chemistry,
Cambridge UK, 2010.
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DOI: 10.1039/C6RA15488C
ARTICLE
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TOC TEXT:
A route to substituted thiazoleꢀ2(3H)ꢀthiones is reported, flow
processing and supported reagents being used to facilitate
synthesis and product isolation
TOC GRAPHIC:
6 | J. Name., 2012, 00, 1-3
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