Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles via Copper-Catalyzed [4 + 1] Heterocyclization of α-(N-Hydroxy/aryl)imino-β-oxodithioesters with α-Diazocarbonyls

Article abstract of DOI:10.1021/acs.joc.7b01601

An efficient chemoselective practical route to fully substituted thiazoles and 2,3-dihydrothiazoles has been devised by [4 + 1] heterocyclization of α-(N-hydroxy/aryl)imino-β-oxodithioesters with in situ generated Cu-carbenoids of diazocarbonyls. The α-(N-hydroxy/aryl)imino-β-oxodithioesters are readily accessible by the reaction of β-oxodithioesters with nitrous acid/nitrosoarenes. The overall transformation involves sequential N-O/C-N bonds cleavage followed by cascade C-N/C-S bonds formation in one-pot. This new strategy allows full control over the introduction of various sensitive functional groups at different positions of the thiazole ring, broadening the arsenal of synthetic methods to obtain such scaffolds.

Full text of DOI:10.1021/acs.joc.7b01601

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Article
Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles
via Copper-Catalyzed [4 + 1] Heterocyclization of #-(N-
hydroxy/aryl)imino-#-oxodithioesters with #-Diazocarbonyls
Abhijeet Srivastava, Gaurav Shukla, Dhananjay Yadav, and Maya Shankar Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01601 • Publication Date (Web): 25 Sep 2017
Downloaded from http://pubs.acs.org on September 26, 2017
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Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles via
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Copper-Catalyzed [4
+
1] Heterocyclization of -(N-
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hydroxy/aryl)imino--oxodithioesters with -Diazocarbonyls
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Abhijeet Srivastava, Gaurav Shukla, Dhananjay Yadav, and Maya Shankar Singh*
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005,
Uttar Pradesh, India
ABSTRACT: An efficient chemoselective practical route to fully substituted thiazoles and 2,3-
dihydrothiazoles has been devised by [4 + 1] heterocyclization of -(N-hydroxy/aryl)imino--
oxodithioesters with in situ generated Cu-carbenoids of diazocarbonyls. The -(N-
hydroxy/aryl)imino--oxodithioesters are readily accessible by the reaction of -oxodithioesters
with nitrous acid/nitrosoarenes. The overall transformation involves sequential N–O/CN bonds
cleavage followed by cascade C–N/CS bonds formation in one-pot. This new strategy allows
full control over the introduction of various sensitive functional groups at different positions of
the thiazole ring, broadening the arsenal of synthetic methods to obtain such scaffolds.
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INTRODUCTION
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Among the N, S-heterocyclic frameworks, thiazoles are versatile privileged scaffolds present in
many natural products1 and biologically active compounds.2 Some of the accepted drugs are
dasatinib (anti-cancer), ritonavir (anti-HIV), nizatidine (anti-ulcer), and fentiazac (anti-
inflammatory) among several medicines.2e Natural products containing thiazole moieties include
apratoxins, firefly luciferin, dolastatin E, mirabazole, tantazoles, piscibactin, etc. These
molecules show a wide range of biological activities such as anticancer, antimicrobial,
antimalarial, anti-tuberculosis, and neurotoxic properties.2f Further, they have been utilized as
synthetic intermediates/ligands,3 and find extensive applications in functional materials.4a-d The
less explored 2,3-dihydrothiazole core is also found to be active in various biological
evaluations.4e-g Moreover, some thiazole derivatives have found application as liquid crystals for
ferroelectric display5a,b and as cosmetic sunscreens.5c Therefore, many methods have been
developed for the synthesis of thiazole derivatives.6,7 Direct synthetic protocols based on starting
materials such as ketones,8a-d α,β-unsaturated ketones8e and alkenes8f via the intermediary α-
haloketones are reported for aminothiazoles. Recently, Jiang and co-workers9a developed a
strategy for 2-aminothiazoles via copper-catalyzed coupling of oxime acetates with
isothiocyanates. 2,4,5-Trisubstituted thiazoles are synthesized by the reaction of -nitroepoxides
with thioureas under strongly basic conditions.9b Although the reported approaches are useful
tools towards the construction of thiazole frameworks, most of them are associated with certain
disadvantages with respect to their practical execution in the laboratory. Therefore, exploring
more efficient and flexible strategies and improvement in the existing synthetic methods of
thiazoles are highly desired and could be recognized as strategic issues.
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We recently reported the -functionalization of -oxodithioesters (DTEs), which were
further transformed to 1,2,3-thiadiazoles.10a In this context, -(N-hydroxy)imino--
oxodithioester is a new underdeveloped class of precursor, which has not been much explored.
As they could represent excellent synthetic precursors for N, S-heterocycles, herein we
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synthesized
-(N-hydroxy)imino--oxodithioesters10a
(2)
and
-(N-aryl)imino--
oxodithioesters10b (4) by the reaction of -oxodithioesters (1) with nitrous acid and nitrosoarenes
(3), respectively (Scheme 1a).
Scheme 1. -Functionalization of -Oxodithioesters (1) to 2 and 4 and Further
Transformation to Fully Substituted Thiazoles (6) and 2,3-Dihydrothiazoles (7)
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In particular, the -functionalization of -oxodithioesters enables their site-specific
derivatization to provide valuable materials. Diazocarbonyls play an important role as a coupling
partner, and are versatile intermediates used as precursors of metal carbenoids for various
synthetic transformations.11 To the best of our knowledge, diazocarbonyls have not been used as
coupling partner with -imino dithioesters till yet. Consequently, we treated -imino dithioesters
2 and 4, separately with diazocarbonyls (5) in the presence of catalytic Cu(I) species, which
afforded fully substituted thiazoles (6) and 2,3-dihydrothiazoles (7) in excellent yields (Scheme
1b).
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Ila and co-workers12 reported synthesis of 1-aroyl(or acyl)-2-aryl-(or ethoxycarbonyl)-4-
thioalkyl thiazoles from ketoketene N, S-acetals via multistep processes. Our group has a long
standing interest in exploiting the reactivity of -oxodithioesters, which are potential platform
for the construction of diverse important heterocycles.13 However, none of the above protocols
involve the diazocarbonyl-based coupling reactions. In continuation of our recent interest
towards the -functionalization of -oxodithioesters, which were further transformed into
promising heterocycles,14 herein, we modified our previous procedure10a of -functionalization
of DTEs by replacing aqueous HCl with HCl in CH3OH. This process reduced the reaction time
significantly and enhanced the yield of oximes up to 98% (Scheme 1a, 2a-d, 2f, 2i, 2j, 2p). The
-(N-hydroxy/aryl)imino--oxodithioesters display not only high stability, but also intriguing
reactivity. However, to date, -N-arylimino--oxodithioesters have never been exploited as a
stable substrate for the synthesis of heterocycles. Herein, we disclose the first chemoselective
one-pot synthesis of fully substituted thiazoles and 2,3-dihydrothiazoles by Cu-catalyzed [4 + 1]
heterocyclization of -imino--oxodithioesters with diazocarbonyls in good to high yields.
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RESULTS AND DISCUSSION
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Heterocyclization using transition-metals15 and addition of carbon nucleophile to nitroso
compounds has been a topic of continued interest during recent years.16 Utilizing nucleophilic
propensity of -carbon of -oxodithioester toward -functionalization, treatment of
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nitrosoarenes with dithioesters provided -imino-dithioesters concurrently introducing aryl
group on nitrogen of imines (Scheme 1a). The chemical properties of -imino-β-oxodithioesters
(2 and 4) can be featured by the presence of three electrophilic and three nucleophilic (N, O and
S) centers. Initially, the dithioester 1b and nitrosoarene 3b were taken as model substrates to
optimize the reaction conditions for the synthesis of -arylimino--oxodithioesters 4. In this
context, we first carried out the above test reaction without any solvent and base at room
temperature. Reaction failed to provide any product even after 24 h of stirring (Table 1, entry 1).
After this failure, we performed the test reaction in methanol at room temperature, which
triggered the reaction forming the desired product in a trace amount, and most of the reactants
remained unreacted (Table 1, entry 2). Elevating the reaction temperature to 50 °C afforded the
very complex TLC pattern of several overlapping spots within 15 min, which could not be
isolated (Table 1, entry 3). It seems that at higher temperature decomposition of the substrates
occurred. Therefore, next we performed the reaction at lower temperature, which increased the
yield of desired compound 4bb to 10-15% (Table 1, entries 4 and 5). To increase the efficiency
of the reaction, next we used 5 mol % of triethylamine at -20 °C and -30 °C, separately. To our
pleasure, the yield of the desired product 4bb was increased to 55% and 65%, respectively
within 1 h (Table 1, entries 6 and 7). Further increase in the amount of triethylamine (10 mol %)
could not improve the result (Table 1, entry 8). Next, solvents like acetonitrile and
dichloromethane (DCM) were screened (Table 1, entries 9 and 10). DCM superseded over
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acetonitrile and proved itself as a best solvent for this base catalyzed -imination of -
oxodithioesters with nitrosoarenes (Table 1, entry 10). Hence the optimized reaction conditions
for the synthesis of 4bb is 1:1 stoichiometric ratio of -oxodithioester 1b and nitrosoarene 3b in
DCM at -30 °C in the presence of 5 mol % of triethylamine under inert atmosphere.
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Table 1. Optimization of Reaction Conditions for the Synthesis of 4
entry
1b
3b
solvent base (mol %) temp (°C)
time
24 h
yielda (%)
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2
1 mmol 1 mmol
-
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rt
n.r.b
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3OH
1 mmol 1 mmol CH3CN
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rt
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- 30
- 30
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Et3N (5)
Et3N (5)
Et3N (10)
Et3N (5)
Et3N (5)
1h
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1 h
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1 h
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30 min
15 min
10
1 mmol 1 mmol
DCM
aIsolated yield. bNo reaction. cComplex TLC pattern. dDecomposition of the reactants occurred.
Under the optimized reaction conditions, the scope of -(N-aryl)imino--oxodithioesters 4
was explored (Scheme 2). A variety of DTEs (1) bearing different substituents such as alkyl,
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aryl, hetaryl and 2-naphthyl at R1 moiety, and methyl, ethyl, propyl and 2-methallyl at R2 moiety
proved to be the suitable substrates for this base-catalyzed -imination of -oxodithioesters with
nitrosoarenes (3), which is functionally embedded with methyl benzoate, phenyl and 2,3,4,5,6-
pentafluorophenyl groups. No obvious steric/electronic effects were observed for this
transformation. The bulky 2-naphthyl group at R1 moiety of dithioester 1m and 2,3,4,5,6-
pentafluorophenyl group of nitrosoarene 3 did not show any steric/electronic effect, and the
reaction underwent smoothly to give the corresponding products 4ma and 4nc in 98% yield
within 5 min. It is clear that the substrates are widely substituent tolerant.
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Scheme 2. Synthesis of -(N-Aryl)imino--oxodithioesters 4
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The recent advances in cross-coupling reactions using transition-metal catalysis have led to
the development of effective methods for the construction of carbon-sulfur bonds.17 The goal of
-imination of DTEs 1 is to realize the synthesis of N, S-heterocycles via cascade CN/CS
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bond formations in one-pot. Due to the presence of many active centers, the reactions of -
imino--oxodithioesters with various reagents may lead to the formation of diverse heterocyclic
systems, where the sulfur atom could be present either in the ring system or as an external
substituent. In view of great significance of N, S-heterocycles,18 our focus herein is to utilize
diazocarbonyls as one of the reaction partner for the first time towards cyclization with -imino-
-oxodithioesters that could generate N, S-heterocyclic frameworks. Most of the cycloaddition
reaction of diazocarbonyls as carbenoid coupling partner has been achieved with extrusion of
nitrogen in the presence of metals.11a,j,19 Other dimensions of metal carbenoids include X-H
insertion,20a 1,2-hydride shift,20b,c and 1,2-C→C or 1,2-X→C bond migration (e.g., X = O, N, S,
Si).20d-f
The -imino--oxodithioesters 2b and 4bb, and diazocarbonyl 5a were chosen as model
substrates to optimize the reaction conditions (Table 2, top). To test the feasibility of our
hypothesis, first we used Rh(OAc)2, the most common metal catalyst used for metal carbenoids
reaction. Treatment of 1 mmol of 2b (or 4bb) with diazocarbonyl 5a (1.5 mmol) in the presence
of 20 mol % of Rh(OAc)2 in THF at room temperature could give the target products 6ba and
7bba in 22% and 17% yield, respectively (Table 2, entry 1). Inspired by the above result, next
we performed the above test reaction in different solvents such as dioxane, CH3CN, CH3OH,
DMSO, DMF, and DCM (Table 2, entries 2-7). Among above all screened solvents, DCM was
found to be a solvent of choice for this transformation, in which the desired products 6ba and
7bba were formed in 37% and 35% yield, respectively at room temperature (Table 2, entry 7).
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To increase the efficacy of the reaction, we increased the temperature from room temperature to
50 °C. Subsequently, the test reaction was carried out at 50 °C in DCM. Work up of the reaction
(2b with 5a) provided 6ba in 47% yield, while the reaction between 4bb and 5a at 50 °C failed
with no trace of 7bba (Table 2, entry 8). It could be due to the decomposition of -N-arylimino-
-oxodithioester at higher temperature. Therefore, we decided to perform the test reaction at
lower temperatures. Reaction at -20 °C in DCM could not provide the better result (Table 2,
entry 9). Thus, the optimized reaction temperature for the formation of 6ba was found to be 50
°C and for 7bba at room temperature in DCM. After screening the catalytic role of RhII for this
heterocyclization, we next screened [Rh(COD)Cl]2 and RhCl(PPh3)3 but no improvement in the
result was observed (Table 2, entries 10 and 11).
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Among the various employed metals, copper is one of the most favorable metal for C-S
bond forming reactions due to its low cost and low toxicity.21 Therefore, we next performed the
above model reaction in the presence of different copper catalysts like Cu(OTf)2, CuCl, CuBr,
22
CuI, Cu(CH3CN)4BF4, and Cu(CH3CN)4PF6 separately. Notably, copper catalysts facilitated
the formation of desired products in improved yields under standard conditions (Table 2, entries
12-17). To our delight, Cu(CH3CN)4PF6 furnished the desired thiazoles 6ba and 7bba in 90%
and 88% yield, respectively within 30 min (Table 2, entry 17). Further to check the generality of
the reaction, we checked some other metal-catalysts such as Pd(OAc)2, AgOTf, AgOAc and
AgSbF6 (Table 2, entries 18-21). Silver catalysts triggered the reaction well affording the desired
products in good yields, but could not provide better result than Cu(CH3CN)4PF6 catalyst (Table
2, entry 17). Finally, we performed the test reaction without any catalyst under standard
conditions. No trace of the desired product was formed even after 48 h (Table 2, entry 22). Thus,
the best yield, cleanest reaction, and most facile workup were achieved employing 1:1.5
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stoichiometric ratio of 2 (or 4) and 5 in DCM in the presence of 10 mol % of Cu(CH3CN)4PF6 at
50 °C for thiazole 6ba and at room temperature for dihydrothiazole 7bba.
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Table 2. Optimization of Reaction Conditionsa for the Synthesis of Thiazoles 6 and 7
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entry catalystb
solvent
temp (°C)
time (h)
yieldd (%)
6ba 7bba 6ba 7bba 6ba 7bba
1
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
Rh(OAc)2
THF
rt
rt
rt
12
10
15
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9
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5
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13
17
20
10
2
1,4-Dioxane rt
3
CH3CN
CH3OH
DMSO
DMF
rt
rt
rt
10
24
24
15
3
e
e
4
rt
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-
e
e
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rt
rt
-
-
6
rt
rt
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37
47
32
14
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7
DCM
rt
rt
f
8
DCM
50c
50
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2
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9
DCM
-20 -20
20
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8
16
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6
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8
e
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[Rh(COD)Cl]2 DCM
50c
50c
50c
rt
rt
rt
-
e
RhCl(PPh3)3
Cu(OTf)2
DCM
DCM
-
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CuCl
DCM
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14g CuBr
rt
rt
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rt
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rt
rt
rt
1
15 CuI
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
50c
50c
50c
50c
50c
50c
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50c
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0.7
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16g Cu(CH3CN)4BF4
17g Cu(CH3CN)4PF6
18 Pd(OAc)2
19 AgOTf
0.5
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20 AgOAc
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21 AgSbF6
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22 no catalyst
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n.r.h
n.r.h
aReaction was carried out with 0.2 mmol of 2b/4bb and 0.3 mmol of 5a (added
b
in drop wise fashion within 5 min), DCM (0.5 mL). The reactions were
c
performed with 20 mol % catalyst unless otherwise stated. For the formation of
6ba, after drop wise addition of 5a into 2b at rt, the temperature was raised to 50
d
e
f
or 60 °C. Isolated yield. Trace amount. Decomposition occurred, complex
TLC pattern. g10 mol % of catalyst. hNo reaction.
Next, the protocol generality was investigated by performing the reactions of various -(N-
hydroxy)imino--oxodithioesters 2 with -diazocarbonyls 5a-c (Scheme 3). It is noteworthy that
methyl, phenyl, 4-methoxyphenyl, 3,4-methylenedioxy phenyl, 4-trifluoromethylphenyl and 3-
bromophenyl groups at R1 moiety of -(N-hydroxy)imino DTEs 2 were well tolerated affording
the corresponding thiazoles 6 in 72-93% yields.
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Scheme 3. Synthesis of 2,4,5-Trisubstituted Thiazoles 6
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After the successful utilization of -(N-hydroxy)imino--oxodithioesters 2, we next
explored reaction scope of -(N-aryl)imino--oxodithioesters 4 with -diazocarbonyls 5a-c.
Reaction of 4 with 5 under standard conditions afforded the corresponding 2,3-dihydrothiazoles
7 in 74-96% yields within 15-30 minutes (Scheme 4). Our studies revealed that precursors 2 and
4 bearing different substituents such as methyl, ethyl, and methallyl at R2 moiety were also
tolerated well under the standard reaction conditions. Variation of the alkyl moieties to methyl,
ethyl and methallyl in -(N-hydroxy)imino DTEs 2 did not obviously alter the reaction
efficiency, leading to dihydrothiazoles 7 up to 96% yield. However, when the bulkiness of the -
imino-dithioester 4 was increased by introducing 2-naphthyl group at R1 moiety, methallyl group
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at R2 moiety and pentafluorophenyl group as N-aryl substituent, the product yields were dropped
to 75% (7nca), and 77% (7lba). In contrast to most of the known substituted thiazoles, the
present trisubstituted thiazoles 6 and tetrasubstituted dihydrothiazoles 7 bear three readily
convertible functional groups, i.e., ester/carbonyl, carbonyl, and alkythio at the 2-, 4-, and 5-
positions of the thiazole backbone. This structural feature is highly desired for thiazole
derivatives to be used as organic synthons.
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Scheme 4. Synthesis of 2,3-Dihydrothiazoles 7
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The -imino--oxodithioesters 2b and 4bb were readily synthesized in one step from the
corresponding -oxo/-enolic dithioesters and nitroso compounds by dehydrative coupling via
7
8
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intermediate B and isolated before being used in the reaction (Scheme 5a). Alternatively, the -
imino--oxodithioesters 2b and 4bb could also be generated in situ via a base promoted
coupling, enabling the entire process to be performed in one-pot. Mechanistically this [4 + 1]
heterocyclization can be explained as chemoselective nucleophilic attack by thiocarbonyl sulfur
(over carbonyl oxygen) of -imino--oxodithioester 2b/4bb to metal carbenoid A to generate an
adduct sulfur ylide intermediate C. Intermediate C further reacts with diazoacetate 5a to form
zwitterionic intermediate D, regenerating Cu-carbenoid A, thus completing the catalytic cycle.
Finally, intermediate D undergoes intramolecular N-cyclization affording 2,3-dihydrothiazole
7bba. Formation of thiazole 6ba involves moderate heating to 50 °C that facilitates dehydration
leading to aromaticity (Scheme 5b). The overall transformation involves the formation of two
new C−N bonds and one new C−S bond by both intermolecular and intramolecular reactions.
Scheme 5. Preliminary Results and Proposed Pathway
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CONCLUSION
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In summary, we have reported an efficient regioselective route to -(N-hydroxy/aryl)imino--
oxodithioesters (2 and 4) in high yields by the reaction of -oxodithioesters 1 with nitrous acid
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and nitrosoarenes 3, respectively. Further these -imino--oxodithioesters are utilized as 4 atoms
synthons toward Cu-catalyzed [4 + 1] heterocyclization with diazocarbonyl as one carbon
synthon to develop a straightforward general approach for diversity oriented synthesis of 2,4,5-
trisubstituted thiazoles 6 and 2,3,4,5-tetrasubstituted 2,3-dihydrothiazoles 7. The chemoselective
concise one-pot strategy reported herein allows a novel entry to fully substituted thiazoles and
2,3-dihydrothiazoles with full control over substitution at the various ring positions, which would
otherwise be more difficult to prepare by alternative routes.
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EXPERIMENTAL SECTION
General: All the reactions were carried out in a flame or oven dried glass wares under an argon
or nitrogen atmosphere with freshly distilled dry solvents under anhydrous conditions unless
otherwise indicated. Chromatograms were visualized by fluorescence quenching with UV light at
254 nm. NMR spectra were recorded at room temperature on 300 MHz, 500 MHz spectrometers.
1
The residual solvent signals were taken as the reference 7.26 ppm for H NMR spectra and 77.0
ppm for 13C NMR spectra in CDCl3. Sometimes the TMS signal at 0.0 ppm was used an internal
1
standard for H NMR spectra. Chemical shift () is reported in ppm, coupling constants (J) are
given in Hz. Melting points are uncorrected.
Materials: All solvents were distilled under argon and dried before use. Catalysts used in this
protocol Rh(OAc)2, [Rh(COD)Cl]2, RhCl(PPh3)3, CuCl, CuBr, CuI, Cu(OTf)2, Pd(OAc)2,
AgOTf, AgOAc and AgSbF6 were purchased from Sigma-Aldrich Chemicals Pvt. Ltd.
Cu(CH3CN)4BF4 and Cu(CH3CN)4PF6 were prepared following the literature procedure.23
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Modified Procedure for the Synthesis of -(N-hydroxy)imino--oxodithioesters10a (2a-d, 2i,
5
6
7
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2j). Step 1: In a round bottom flask, -oxodithioester 1 (1.0 mmol) was taken with 10 mL of dry
methanol. Step 2: Flask was immersed into ice-bath. Step 3: To this 1.0 mL of ‘4 M HCl in
methanol’ was added slowly. Pause: The reaction mixture become turbid when the acid was
added; wait till homogeneity of reaction mixture. Step 4: Portion wise addition of NaNO2 (3.0
mmol) for about 5 minutes. Pause: A careful slow addition of sodium nitrite resulted into
redness of reaction mixture. Reaction mixture was stirred for stipulated period of time. NaCl
started to form and settled down to bottom. Completion of reaction was monitored through TLC.
Step 5: Whole reaction mixture was filtered on Buckner funnel. Step 6: Filtrate was collected
and poured into ice cold water and filtered it again on Buckner funnel. Step 7: Filtered material
was dried and recrystallized from DCM-Methanol mixture (1:1). Note: In case of synthesis of 2i,
during step 6, poured reaction mixture in ice cold water, and was kept as such in freeze at 5 °C
for 2 h.
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General Procedure for the Synthesis of -(N-aryl)imino--Oxodithioesters 4. Step 1:
Maintain temperature of methanol bath of JULABO FT902 (JULABO Gmbh, Germany) at either
30 °C (except 4kc, 4nc) or 50 °C (for 4kc and 4nc). Step 2: In an oven dried two-neck round
bottom flask, 1.0 mmol of 1, and 1.0 mmol of 3 was taken and sealed it with double channel
balloon adopter followed by flushing with argon for 4 to 5 times with the help of vacuum pump.
Step 3: 5 mL of dry dichloromethane was added into round bottom flask of step 2, through the
help of cannula. Step 4: This set-up of step 3, was immersed into cold methanol bath of
JULABO. Step 5: 5 mol % of Et3N was added in drop-wise fashion to it through syringe. Pause:
A careful slow addition of triethylamine resulted into dark redness of reaction mixture
immediately. Reaction mixture was stirred for stipulated period of time. Completion of reaction
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was monitored through TLC. Step 6: No need of work-up for the resulted reaction mixture of
step 5. The reaction mixture was chromatographed (silica gel, hexane/ethyl acetate = 19:1) to
afford -(N-aryl)imino--oxodithioesters as sticky solids, Rf = 0.50 (hexane/ethyl acetate =
90/10).
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General Procedure for the Synthesis of Thiazoles 6 (6ba for example). Step 1: Two two-neck
round bottom flasks were coded as A and B. Step 2: In A, 10 mol % of Cu(CH3CN)4PF6 were
taken and sealed with double channel balloon adopter and flushed with argon for 4 to 5 times
with the help of vacuum pump. Step 3: In B, 0.2 mmol of 2b was taken, sealed with double
channel balloon adopter and flushed with argon for 4 to 5 times with the help of vacuum pump.
In this 0.5 mL of dry DCM was added. Step 4: The whole reaction mixture of B was transferred
into A through the help of cannula. Step 5: In A, 0.3 mmol of 5a was added in drop-wise fashion
in 5 minutes. Step 6: The whole set-up of A was put into pre-heated oil bath at 50 °C and left for
stipulated period of time. Pause: A careful addition of 5a resulted into pale yellow coloration of
reaction mixture after its completion. Step 7: Aqueous work up of reaction mixture was
performed while using ethyl acetate as organic phase. Organic phase was separated and dried
over Na2SO4. Step 8: The reaction mixture was chromatographed (silica gel, hexane/ethyl
acetate = 6:1) to afford thiazoles, Rf = 0.45 (hexane/ethyl acetate = 70/30).
General Procedure for the Synthesis of 2,3-Dihydrothiazoles 7. Similar procedure as for the
synthesis of 6, except step 6 in which whole set up was left for stipulated period of time at room
temperature. The reaction mixture was chromatographed (silica gel, hexane/ethyl acetate = 9:1)
to afford 2,3-dihydrothiazoles, Rf = 0.60 (hexane/ethyl acetate = 80/20).
For 2a-d, 2f and 2j - see reference 10 (a).
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Methyl 3-(3-bromophenyl)-2-(N-hydroxyimino)-3-oxopropanedithioate (2i): The product was
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1
obtained as red solid; (0.31 g, 98%); mp 124-126 °C; H NMR (500 MHz, CDCl3): δ 12.46 (br,
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9
1H), 7.95 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.15 Hz, 1H), 7.35-7.32 (m, 1H), 2.64 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 217.9, 191.0, 157.3, 136.8, 136.7, 131.6, 130.5, 127.8,
123.0, 17.9. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd. for C10H8BrNNaO2S2 339.9072; Found:
339.9073.
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Ethyl 3-(4-trifluoromethylphenyl)-2-(N-hydroxyimino)-3-oxopropanedithioate (2p): The product
1
was obtained as red solid; (0.29 g, 90%); mp 138-140 °C; H NMR (500 MHz, CDCl3): δ 7.84
(d, J = 7.85 Hz, 2H), 7.72 (d, J = 7.90 Hz, 2H), 3.18 (q, J = 7.46 Hz, 2H), 1.24 (t, J = 6.92 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 218.4, 191.5, 157.5, 138.0, 134.9, 134.7, 134.4, 134.1,
129.1, 125.75, 125.72. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd. for C12H10F3NNaO2S2
343.9997; Found: 343.9997.
Methyl 2-[N-{methylbenzoate-4-yl}imino]-3-oxobutanedithioate (4ab): The product was
1
obtained as red sticky solid; (0.26 g, 88%). H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.5 Hz,
2H), 6.84 (d, J = 8.5 Hz, 2H), 3.80 (s, 3H), 2.54 (s, 3H), 2.48 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 224.2, 196.6, 166.5, 163.4, 151.5, 130.8, 130.3, 127.0, 119.6, 118.9, 52.1, 26.0, 18.8.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C13H14NO3S2 296.0410; Found: 296.0417.
Methyl 2-[N-{methylbenzoate-4-yl}imino]-3-phenyl-3-oxopropanedithioate (4bb): The product
was obtained as red sticky solid; (0.34 g, 95%). 1H NMR (500 MHz, CDCl3): δ 6.60 (d, J = 8.45
Hz, 2H), 6.42 (d, J = 7.30 Hz, 2H), 6.23-6.20 (m, 1H), 6.10-6.07 (m, 2H), 5.73 (d, J = 8.50 Hz,
2H), 2.56 (s, 3H), 1.44 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 222.9, 193.5, 166.4, 163.5,
150.9, 134.5, 134.5, 130.5, 129.1, 128.9, 127.6, 125.4, 122.6, 119.9, 52.1, 18.7. HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C18H16NO3S2 358.0566; Found: 358.0573.
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Ethyl 2-[N-{phenyl}imino]-3-phenyl-3-oxopropanedithioate (4ca): The product was obtained as
red sticky solid; (0.30 g, 94%). 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J = 7.20 Hz, 2H), 7.48-
7.43 (m, 1H), 7.35-7.30 (m, 2H), 7.19-7.14 (m, 2H), 7.04-6.96 (m, 3H), 3.28 (q, J = 7.45 Hz,
2H), 1.41 (t, J = 7.42 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 223.4, 195.0, 163.2, 146.9, 135.0,
134.2, 129.2, 129.0, 128.9, 126.6, 120.8, 29.4, 11.9. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd.
for C17H15NOS2Na 336.0487; Found: 336.0493.
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Propyl 2-[N-{phenyl}imino]-3-(4-tolyl)-3-oxopropanedithioate (4ea): The product was obtained
1
as red sticky solid; (0.30 g, 85%). H NMR (300 MHz, CDCl3): δ 7.59 (d, J = 8.04 Hz, 2H),
7.19-7.11 (m, 4H), 7.04-6.97 (m, 3H), 3.25 (t, J = 7.50 Hz, 2H), 2.32 (s, 3H), 1.87-1.75 (m, 2H),
1.09 (t, J = 7.50 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 223.6, 194.6, 163.5, 147.0, 145.4,
132.6, 129.7, 129.3, 129.0, 126.5, 120.9, 37.2, 21.8, 20.6, 13.8. HRMS (ESI/Q-TOF) m/z:
[M+Na]+ Calcd. for C19H19NOS2Na 364.0800; Found: 364.0801.
Methyl 2-[N-{phenyl}imino]-3-(4-methoxyphenyl)-3-oxopropanedithioate (4fa): The product was
obtained as red sticky solid; (0.30 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 8.76 Hz,
2H), 7.21-7.16 (m, 2H), 7.06-6.99 (m, 3H), 6.80 (d, J = 8.73 Hz, 2H), 3.79 (s, 3H), 2.68 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 224.3, 193.3, 164.5, 163.3, 146.9, 131.7, 129.0, 128.1, 126.6,
120.9, 114.2, 55.5, 18.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C17H16NO2S2 330.0617;
Found: 330.0628.
Ethyl 2-[N-{phenyl}imino]-3-(4-methoxyphenyl)-3-oxopropanedithioate (4ga): The product was
obtained as red sticky solid; (0.31 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 8.79 Hz,
2H), 7.21-7.16 (m, 2H), 7.06-6.98 (m, 3H), 6.80 (d, J = 8.79 Hz, 2H), 3.79 (s, 3H), 3.27 (q, J =
7.44 Hz, 2H), 1.42 (t, J = 7.44 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 223.6, 193.3, 164.5,
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163.5, 147.0, 131.7, 129.0, 128.2, 126.5, 120.9, 114.2, 55.6, 55.5, 29.5, 11.9. HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C18H18NO2S2 344.0773; Found: 344.0773.
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Methyl 2-[N-{phenyl}imino]-3-(4-chlorophenyl)-3-oxopropanedithioate (4ha): The product was
obtained as red sticky solid; (0.31 g, 92%). 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.46 Hz,
2H), 7.31-7.25 (m, 2H), 7.22-7.17 (m, 2H), 7.08-7.03 (m, 1H), 6.97 (d, J = 7.53 Hz, 2H), 2.69 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 224.0, 194.0, 162.5, 146.6, 140.8, 133.3, 130.4, 129.4,
129.1, 126.9, 120.9, 93.5, 18.6. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C16H13ClNOS2
334.0122; Found: 334.0128.
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Methyl 2-[N-{methylbenzoate-4-yl}imino]-3-(2-bromophenyl)-3-oxopropanedithioate (4ib): The
product was obtained as red sticky solid; (0.43 g, 98%). 1H NMR (500 MHz, CDCl3): δ 7.88 (d,
J = 8.50 Hz, 2H), 7.65 (dd, J1 = 7.50 Hz, J2 = 1.80 Hz, 1H), 7.51 (d, J = 8.15 Hz, 1H), 7.27 (d, J
13
= 7.55 Hz, 1H), 7.25 (s, 1H), 3.85 (s, 3H), 2.72 (s, 3H). C NMR (125 MHz, CDCl3): δ 223.0,
191.6, 166.4, 162.4, 150.9, 135.0, 134.2, 132.6, 130.5, 130.3, 127.6, 122.4, 119.5, 118.7, 52.1,
18.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C18H15BrNO3S2 435.9671; Found: 435.9677.
E/Z Ethyl 2-[N-{2,3,4,5,6-pentafluorophenyl}imino]-3-(2-furoyl)-3-oxopropanedithioate (4kc):
The product was obtained as red sticky solid; (0.39 g, 98%). 1H NMR (500 MHz, CDCl3): δ 7.64
(s, 1H), 7.25 (d, J = 5.7 Hz, 1H), 6.58-6.57 (m, 1H), 2.92 (q, J = 7.30 Hz, 2H), 2.82 (q, J = 7.31
13
Hz, 2H), 1.37 (t, J = 7.35 Hz, 3H), 1.24 (t, J = 7.12 Hz, 3H). C NMR (125 MHz, CDCl3): δ
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177.1, 151.9, 147.8, 147.4, 147.3, 120.3, 112.8, 112.7, 112.2, 32.5, 27.9, 15.1, 14.5. F NMR
(470 MHz, CDCl3): δ -148.54 (d, J = 22 Hz, 2F), -158.88 (t, J = 22.17 Hz, 1F), -162.13 to -
162.31 (m, 2F). HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C15H9F5NO2S2 393.9989; Found:
393.9999.
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Methyl 2-[N-{phenyl}imino]-3-(2-naphthoyl)-3-oxopropanedithioate (4ma): The product was
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obtained as red sticky solid; (0.34 g, 98%). H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), 7.86-
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7.76 (m, 4H), 7.57-7.46 (m, 2H), 7.14 (d, J = 7.63 Hz, 2H), 7.04 (d, J = 7.53 Hz, 2H), 6.98 (d, J
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= 7.18 Hz, 1H), 2.70 (s, 3H). C NMR (75 MHz, CDCl3): δ 224.1, 195.1, 163.0, 146.8, 136.1,
132.5, 132.3, 132.1, 129.9, 129.3, 128.0, 127.1, 126.7, 123.6, 120.9, 18.6. HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd. for C20H16NOS2 350.0668; Found: 350.0676.
(2-Methyl)allyl
2-[N-{2,3,4,5,6-pentafluorophenyl}imino]-3-(2-naphthoyl)-3-
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oxopropanedithioate (4nc): The product was obtained as red sticky solid; (0.47 g, 98%). H
NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 7.92 (d, J = 8.30 Hz, 1H), 7.87-7.84 (m, 2H), 7.81-7.79
(m, 1H), 7.64-7.61 (m, 1H), 7.58-7.55 (m, 1H), 5.13 (s, 1H), 5.02 (s, 1H), 3.96 (s, 2H), 1.89 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 219.8, 190.8, 169.4, 137.8, 136.4, 132.3, 132.0, 130.9,
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130.4, 130.0, 129.7, 129.2, 128.9, 128.1, 127.4, 124.7, 123.3, 116.5, 42.9, 22.2, 21.5, 21.1. F
NMR (470 MHz, CDCl3): δ -148.25 (s, 2F), -158.73 (s, 1F), -161.60 (s, 2F). HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C23H15F5NOS2 480.0510; Found: 480.0476.
Ethyl 2-[N-{4-bromophenyl}imino]-3-(3,4-methylenedioxyphenyl)-3-oxopropanedithioate (4od):
The product was obtained as red sticky solid; (0.41 g, 93%). 1H NMR (500 MHz, CDCl3): δ 7.32
(d, J = 8.55 Hz, 2H), 7.21 (d, J = 9.30 Hz, 2H), 7.19 (s, 1H), 6.87 (d, J = 8.60 Hz, 2H), 6.73 (d, J
= 7.75 Hz, 1H), 6.01 (s, 2H), 3.27 (q, J = 7.35 Hz, 2H), 1.41 (t, J = 7.50 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 222.5, 192.2, 163.4, 153.0, 148.5, 145.8, 132.0, 129.6, 126.9, 122.5, 120.0,
108.3, 107.7, 102.2, 29.6, 11.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C18H14BrNNaO3S2
457.9491; Found: 457.9491.
Ethyl
2-[N-{methylbenzoate-4-yl}imino]-3-(4-trifluoromethylyphenyl)-3-oxopropanedithioate
(4pb): The product was obtained as red sticky solid; (0.39 g, 90%). 1H NMR (500 MHz, CDCl3):
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δ 7.88 (d, J = 8.50 Hz, 2H), 7.78 (d, J = 8.10 Hz, 2H), 7.62 (d, J = 8.15 Hz, 2H), 6.97 (d, J = 8.50
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Hz, 2H), 3.84 (s, 3H), 3.30 (q, J = 7.38 Hz, 2H), 1.43 (t, J = 7.30 Hz, 3H). C NMR (75 MHz,
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CDCl3): δ 221.8, 192.8, 166.2, 162.7, 150.4, 137.1, 135.7, 135.4, 135.1, 134.9, 130.6, 129.1,
127.9, 126.0, 119.8, 52.1, 29.5, 11.8. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C20H16F3NNaO3S2 462.0416; Found: 462.0416.
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tert-Butyl 4-acetyl-5-(methylthio)thiazole-2-carboxylate (6ab): The product was obtained as
yellow oil; (0.04 g, 72%). 1H NMR (500 MHz, CDCl3): δ 2.68 (s, 3H), 2.61 (s, 3H), 1.63 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 194.3, 158.1, 155.8, 152.7, 147.0, 84.4, 28.1, 22.7, 14.1. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd. for C11H16NO3S2 274.0566; Found: 274.0576.
Ethyl 4-benzoyl-5-(methylthio)thiazole-2-carboxylate (6ba): The product was obtained as yellow
solid; (0.06 g, 90%); mp 110-112 °C; 1H NMR (300 MHz, CDCl3): δ 8.32 (d, J = 7.74 Hz, 2H),
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7.58-7.45 (m, 3H), 4.46 (q, J = 7.06 Hz, 2H), 2.66 (s, 3H), 1.43 (t, J = 7.08 Hz, 3H). C NMR
(75 MHz, CDCl3): δ 187.0, 159.8, 159.5, 151.4, 146.9, 137.2, 132.8, 130.8, 128.3, 62.8, 20.7,
14.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C14H14NO3S2 308.0410; Found: 308.0410.
Ethyl 4-benzoyl-5-(ethylthio)thiazole-2-carboxylate (6ca): The product was obtained as yellow
solid; (0.06 g, 88%); mp 107-109 °C; 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J = 7.26 Hz, 2H),
7.56-7.45 (m, 3H), 4.47 (q, J = 7.00 Hz, 2H), 3.10 (q, J = 7.31 Hz, 2H), 1.51 (t, J = 7.35 Hz, 3H),
1.44 (t, J = 7.05 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 187.1, 159.6, 157.7, 151.6, 147.3,
137.3, 132.9, 130.9, 128.3, 62.8, 31.9, 14.2, 13.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C15H16NO3S2 322.0566; Found: 322.0572.
Ethyl 4-benzoyl-5-[(2-methylallyl)thio]thiazole-2-carboxylate (6da): The product was obtained
as yellow solid; (0.06 g, 82%); mp 121-123 °C; 1H NMR (300 MHz, CDCl3): δ 8.29 (d, J = 7.59
Hz, 2H), 7.59-7.45 (m, 3H), 5.18 (s, 1H), 5.07 (s, 1H), 4.47 (q, J = 7.08 Hz, 2H), 3.71 (s, 2H),
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1.90 (s, 3H), 1.43 (t, J = 7.09 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 187.2, 159.7, 152.0, 148.1,
138.3, 137.2, 133.0, 130.9, 128.4, 116.8, 62.8, 44.9, 44.8, 44.7, 21.5, 14.2. HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd. for C17H18NO3S2 348.0723; Found: 348.0723.
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Ethyl 4-(p-bromobenzoyl)-5-(methylthio)thiazole-2-carboxylate (6ia): The product was obtained
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as yellow solid; (0.07 g, 93%); mp 162-164 °C; H NMR (300 MHz, CDCl3): δ 8.48 (s, 1H),
8.30 (d, J = 7.89 Hz, 1H), 7.70-7.66 (m, 1H), 7.39-7.34 (m,1H), 4.47 (q, J = 7.11 Hz, 2H), 2.68
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(s, 3H), 1.45 (t, J = 7.12 Hz, 3H). C NMR (75 MHz, CDCl3): δ 185.3, 160.7, 159.4, 151.6,
146.2, 138.9, 135.6, 133.7, 129.9, 129.4, 122.5, 62.9, 20.8, 14.1. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd. for C14H13BrNO3S2 385.9515; Found: 385.9515.
Ethyl 4-[(3’,4’-methylendioxy)benzoyl]-5-(methylthio)thiazole-2-carboxylate (6ja): The product
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was obtained as yellow solid; (0.05 g, 77%); mp 127-129 °C; H NMR (300 MHz, CDCl3): δ
8.12 (d, J = 8.16 Hz,1H) 7.84 (s, 1H), 6.89 (d, J = 8.22 Hz, 1H), 6.04 (s, 2H), 4.47 (q, J = 7.02
Hz, 2H), 2.66 (s, 3H), 1.44 (t, J = 7.02 H, 3H). 13C NMR (75 MHz, CDCl3): δ 184.8, 159.5,
159.3, 151.8, 151.3, 147.8, 147.0, 131.5, 127.7, 110.6, 108.0, 101.8, 62.8, 20.7, 14.2. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd. for C15H14NO5S2 352.0308; Found: 352.0308.
2-Benzoyl-4-(4-methoxybenzoyl)-5-methylthio thiazole (6fc): The product was obtained as yellow
1
solid; (0.31 g, 85%); mp 122-124 °C; H NMR (500 MHz, CDCl3): δ 8.30-8.26 (m, 2H), 7.51-
7.46 (m, 3H), 7.15-7.12 (m, 1H), 7.01 (d, J = 8.60 Hz, 2H), 6.64 (d, J = 8.55 Hz, 1H), 3.68 (s,
3H), 2.65 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 188.8, 186.8, 160.1, 159.6, 143.5, 142.4,
137.5, 136.1, 134.8, 132.9, 131.9, 131.3, 131.0, 130.3, 129.3, 128.6, 127.8, 125.4, 113.8, 55.2,
19.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C19H16NO3S2 370.0566; Found: 370.0566.
2-Benzoyl-4-(4-triflluoromethylbenzoyl)-5-ethylthio thiazole (6pc): The product was obtained as
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yellow solid; (0.38 g, 90%); mp 134-136 °C; H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 7.75
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Hz, 2H), 7.53 (d, J = 7.45 Hz, 2H), 7.46-7.43 (m, 1H), 7.40 (d, J = 8.05 Hz, 1H), 7.27 (d, J =
8.35 Hz, 1H), 7.19-7.7.16 (m, 2H), 3.06 (q, J = 7.31 Hz, 2H), 1.42 (t, J = 7.22 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 188.2, 186.8, 160.2, 137.4, 134.9, 134.8, 133.5, 132.7, 132.4, 131.2, 129.9,
129.2, 128.7, 128.6, 128.5, 128.0, 126.0, 125.131.2, 14.7. HRMS (ESI/Q-TOF) m/z: [M+H]+
Calcd. for C20H15F3NO2S2 422.0491; Found: 422.0491.
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tert-Butyl
4-acetyl-3-(methylbenzoate-4-yl)-5-(methylthio)-2,3-dihydrothiazole-2-carboxylate
1
(7abb): The product was obtained as yellow sticky solid; (0.07 g, 80%). H NMR (500 MHz,
CDCl3): δ 7.98 (d, J = 8.55 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.49 (s, 1H), 3.89 (s, 3H), 2.54 (s,
3H), 2.04 (s, 3H), 1.54 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 190.0, 167.4, 166.5, 151.2,
146.7, 131.4, 131.0, 125.0, 117.5, 83.6, 73.3, 52.1, 27.9, 27.6, 19.5. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd. for C19H24NO5S2 410.1090; Found: 410.1091.
Ethyl
4-benzoyl-3-(methylbenzoate-4-yl)-5-(methylthio)-2,3-dihydrothiazole-2-carboxylate
1
(7bba): The product was obtained as yellow powder; (0.08 g, 91%); mp 117-119 °C; H NMR
(500 MHz, CDCl3): δ 8.15 (d, J = 7.85 Hz, 2H), 7.77-7.75 (m, 2H), 7.31-7.28 (m, 1H), 7.22-7.19
(m, 2H), 6.82 (d, J = 9.00 Hz, 2H), 5.67 (s, 1H), 4.44 (tt, J1 = 14.27 Hz, J2 = 3.77 Hz, J3 = 6.97
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Hz, 2H), 3.80 (s, 3H), 2.58 (s, 3H), 1.43 (t, J = 7.07 Hz, 3H). C NMR (125 MHz, CDCl3): δ
184.4, 169.2, 166.4, 151.1, 147.3, 137.3, 132.3, 131.0, 130.6, 129.0, 127.9, 124.8, 118.0, 72.4,
62.9, 51.9, 19.8, 14.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C22H22NO5S2 444.0934;
Found: 444.0937.
tert-Butyl 4-benzoyl-3-(methylbenzoate-4-yl)-5-(methylthio)-2,3-dihydrothiazole-2-carboxylate
1
(7bbb): The product was obtained as yellow powder; (0.08 g, 88%); mp 147-149 °C; H NMR
(500 MHz, CDCl3): δ 8.16-8.14 (m, 2H), 7.75 (d, J = 8.6 Hz, 2H), 7.31-7.27(m, 1H), 7.22-7.19
(m, 2H), 6.82 (d, J = 8.5 Hz, 2H), 5.57 (s, 1H), 3.80 (s, 3H), 2.58 (s, 3H), 1.62 (s, 9H). 13C NMR
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(125 MHz, CDCl3): δ 184.3, 167.9, 166.5, 151.3, 147.3, 137.3, 132.3, 131.0, 130.8, 129.1, 128.0,
124.7, 118.0, 84.0, 73.3, 52.0, 28.1, 19.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C24H26NO5S2 472.1247; Found: 472.1255.
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Ethyl 4-(4-methoxybenzoyl)-5-(methylthio)-3-phenyl-2,3-dihydrothiazole-2-carboxylate (7faa):
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The product was obtained as yellow powder; (0.06 g, 74%); mp 161-163 °C; H NMR (300
MHz, CDCl3): δ 8.27 (d, J = 8.73 Hz, 2H), 7.15-7.09 (m, 2H), 6.93-6.86 (m, 3H), 6.72 (d, J =
8.70 Hz, 2H), 5.59 (s, 1H), 4.41 (q, J = 3.60 Hz, 2H), 3.74 (s, 3H), 2.54 (s, 3H), 1.41 (t, J = 7.06
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Hz, 3H). C NMR (75 MHz, CDCl3): δ 170.0, 163.0, 147.6, 132.9, 131.8, 130.4, 129.5, 124.0,
119.9, 113.2, 73.4, 62.6, 55.2, 20.0, 14.2. HRMS (ESI/Q-TOF) m/z: [M] Calcd. for C21H21NO4S2
415.0912; Found: 415.0907.
tert-Butyl
4-(2-bromobenzoyl)-3-(methylbenzoate-4-yl)-5-(methylthio)-2,3-dihydrothiazole-2-
carboxylate (7ibb). The product was obtained as yellow powder; (0.11 g, 96%); mp 176-178 °C.
1H NMR (500 MHz, CDCl3): δ 7.99 (d, J = 7.50 Hz, 1H), 7.80 (d, J = 8.55 Hz, 2H), 7.33 (d, J =
7.55 Hz, 1H), 7.14-7.11 (m, 1H), 7.03-6.99 (m, 1H), 6.84 (d, J = 8.65 Hz, 2H), 5.47 (s, 1H), 3.83
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(s, 3H), 2.61 (s, 3H), 1.61 (s, 9H). C NMR (125 MHz, CDCl3): δ 183.5, 167.4, 166.5, 151.1,
150.8, 138.4, 133.5, 131.4, 130.8, 129.8, 126.2, 124.8, 121.2, 118.1, 83.8, 73.3, 52.0, 28.0, 19.6.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C24H25BrNO5S2 550.0352; Found: 550.0352.
Ethyl
4-(2-furoyl)-3-(2,3,4,5,6-pentafluorophenyl)-5-(ethylthio)-2,3-dihydrothiazole-2-
1
carboxylate (7kca): The product was obtained as yellow sticky solid; (0.08 g, 81%). H NMR
(500 MHz, CDCl3): δ 7.76 (d, J = 3.65 Hz, 1H), 7.54 (s, 1H), 6.45-6.44 (m, 1H), 5.38 (s, 1H),
4.34 (ABX3 pattern: qdd, J1 = 20.20 Hz, J2 = 10.65 Hz, J3 = 3.30 Hz, 2H), 3.04 (dq, J1 = 20.25
Hz, J2 = 7.28 Hz, 1H), 2.86 (dq, J1 = 20.10 Hz, J2 = 7.28 Hz, 1H), 1.34 (td, J1 = 7.22 Hz, J2 =
13
3.31 Hz, 6H). C NMR (125 MHz, CDCl3): δ 169.6, 168.1, 151.3, 147.2, 141.0, 131.9, 119.6,
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112.2, 70.9, 62.7, 31.1, 15.0, 14.1. 19F NMR (470 MHz, CDCl3): δ -148.54 (d, J = 23.15 Hz, 1F),
-148.85 (d, J = 23.05 Hz, 1F), -158.79 to -158.92 (m, 1F), -161.81 to -161.95 (m, 1F), -162.13 to
-162.26 (m, 1F). HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd. for C19H14F5NNaO4S2 502.0177;
Found: 502.0189.
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Methyl 4-(p-phenylbenzoyl)-3-phenyl-5-(methylthio)-2,3-dihydrothiazole-2-carboxylate (7lab):
The product was obtained as yellow powder; (0.07 g, 77%); mp 143-145 °C; 1H NMR (300
MHz, CDCl3): δ 8.93 (s, 1H), 8.13 (d, J = 8.61 Hz, 1H), 7.80 (d, J = 6.81 Hz, 2H), 7.65-7.58 (m,
2H), 7.42-7.33 (m, 3H), 7.01-6.96 (m, 2H), 6.82 (d, J = 7.83 Hz, 2H), 6.75 (t, J = 7.18 Hz, 1H)
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5.57 (s, 1H), 4.40 (q, J = 4.53 Hz, 2H), 2.51 (s, 3H), 1.38 (t, J = 7.08 Hz, 3H). C NMR (75
MHz, CDCl3): δ 183.6, 169.8, 147.5, 138.4, 136.0, 132.0, 130.9, 129.6, 129.1, 128.7, 128.2,
124.3, 119.9, 73.6, 62.7, 20.0, 14.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C26H24NO3S2
462.1192; Found: 462.1201.
Ethyl 4-(2-naphthoyl)-3-(2,3,4,5,6-pentafluorophenyl)-5-(2-methylallylthio)-2,3-dihydrothiazole-
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2-carboxylate (7nca): The product was obtained as yellow sticky solid; (0.08 g, 75%). H NMR
(500 MHz, CDCl3): δ 8.84 (s, 1H), 8.06 (d, J = 8.55 Hz, 1H), 7.91 (d, J = 8.00 Hz, 1H), 7.78 (dd,
J1 = 11.85, J2 = 8.35 Hz, 2H), 7.56-7.48 (m, 2H), 5.46 (s, 1H), 5.03 (s, 1H), 4.92 (s, 1H), 4.41
(ABX3 pattern: qdd, J1 = 20.31 Hz, J2 = 10.83 Hz, J3 = 3.55 Hz, 2H), 3.60 (d, J = 13.65 Hz, 1H),
3.44 (d, J = 13.50 Hz, 1H), 1.75 (s, 3H), 1.41 (t, J = 7.15 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 183.0, 168.2, 140.3, 137.0, 135.3, 134.7, 134.5, 132.4, 131.1, 129.9, 129.6, 128.4, 128.0, 127.7,
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126.6, 124.8, 115.5, 70.0, 62.6, 44.0, 29.8, 21.2, 14.2. F NMR (470 MHz, CDCl3): δ -148.31
(br, 2F), -158.10 (t, J = 22.85 Hz, 1F), -161.61 (t, J = 21.65 Hz, 2F). HRMS (ESI/Q-TOF) m/z:
[M+Na]+ Calcd. for C27H20F5NNaO3S2 588.0697; Found: 588.0712.
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dihydrothioazole (7odc): The product was obtained as yellow sticky solid; (0.45 g, 81%). H
NMR (500 MHz, CDCl3): δ 8.55 (d, J = 8.25 Hz, 1H), 7.98 (d, J = 7.35 Hz, 2H), 7.78 (d, J =
8.55 Hz, 2H), 7.72-7.69 (m, 2H), 7.60-7.57 (m, 2H), 7.53 (d, J = 8.25 H, 1H), 7.26 (s, 2H), 6.81
(d, J = 8.65 Hz, 2H), 6.51 (s, 1H), 2.98 (dq, J1 = 13.70 Hz, J2 = 6.70 Hz, 1H), 2.82 (dq, J1 =
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12.60 Hz, J2 = 7.25 Hz, 1H), 1.43 (t, J = 7.07 Hz, 3H). C NMR (125 MHz, CDCl3): δ 188.7,
183.8, 166.3, 151.1, 134.3, 132.4, 131.2, 129.7, 129.3, 128.7, 125.3, 125.07, 125.04, 118.5, 74.4,
31.2, 14.8. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd. for C26H20BrNO4S2Na 575.9909; Found:
575.9909.
2-Benzoyl-3-(N-{methyl
benzoate-4-yl}imino)-5-ethylthio-4-(4-trifluoromethylphenyl)-2,3-
1
dihydrothiazole (7pbc): The product was obtained as yellow sticky solid; (0.53 g, 95%). H
NMR (500 MHz, CDCl3): δ 8.55 (d, J = 8.25 Hz, 2H), 7.98 (d, J = 7.75 Hz, 2H), 7.78 (d, J =
9.00 Hz, 2H), 7.72-7.69 (m, 1H), 7.60-7.57 (m, 2H), 7.53 (d, J = 8.25 H, 2H), 6.81 (d, J = 8.55
Hz, 2H), 6.53 (s, 1H), 3.81 (s, 3H), 2.98 (dq, J1 = 12.50 Hz, J2 = 7.31 Hz, 1H), 2.82 (dq, J1 =
13
12.80 Hz, J2 = 7.30 Hz, 1H), 1.26 (t, J = 7.22 Hz, 3H). C NMR (125 MHz, CDCl3): δ 189.2,
184.2, 166.7, 151.5, 144.9, 140.5, 134.7, 131.6, 130.1, 129.7, 129.1, 125.6, 125.4, 125.4, 118.9,
74.8, 52.4, 31.6, 15.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C28H23F3NO4S2 558.1015;
Found: 558.1015.
ASSOCIATED CONTENT
Supporting Information
1
19
13
Synthesis of starting materials, copies of H, F and C NMR spectra of all new compounds.
The Supporting Information is available free of charge on the ACS Publications website.
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