Synthesis of Imidazo[2,1-b]thiazoles via Copper-Catalyzed A3-Coupling in Batch and Continuous Flow

Article abstract of DOI:10.1021/acs.joc.7b01762

A straightforward method for the synthesis of functionalized imidazo[2,1-b]thiazoles starting from benzaldehydes, 2-aminothiazoles, and alkynes under copper(I,II) catalysis was developed. The protocol allows the construction of a variety of aryl-substituted imidazo[2,1-b]benzothiazoles, -[2,1-b]thiazoles, and -[2,1-b][1,3,4]thiadiazoles. The reactions were easy to perform affording most of the desired products in 33-93% yields. The intensification of the process in a continuous-flow reactor increases the products' yields up to quantitative.

Full text of DOI:10.1021/acs.joc.7b01762

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Article
Synthesis of Imidazo[2,1-b]thiazoles via Copper-
Catalyzed A3-Coupling in Batch and Continuous-Flow
Irina V. Rassokhina, Tatyana A. Tikhonova, Sergey G. Kobylskoy, Igor Yu. Babkin,
Valerii Z Shirinian, Vladimir Gevorgyan, Igor V. Zavarzin, and Yulia Alexeevna Volkova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01762 • Publication Date (Web): 11 Aug 2017
Downloaded from http://pubs.acs.org on August 11, 2017
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Synthesis of Imidazo[2,1-b]thiazoles via Copper-Catalyzed A3-Coupling in Batch
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and Continuous-Flow
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Irina V. Rassokhina,† Tatyana A. Tikhonova,† Sergey G. Kobylskoy,‡ Igor Yu. Babkin,‡ Valerii
Z. Shirinian,† Vladimir Gevorgyan,§ Igor V. Zavarzin,† and Yulia A. Volkova†*
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†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., 119991 Moscow (Russia).
Tel.: +7 (499) 136 89 60, eꢀmail: yavolkova@gmail.com
‡ Laboratory of High Technologies, Ltd, 86 prosp. Vernadskogo, 119571 Moscow (Russia).
§
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Room
4500, Chicago, IL 60607 (USA).
Abstract
A straightforward method for the synthesis of functionalized imidazo[2,1ꢀb]thiazoles
starting from benzaldehydes, 2ꢀaminothiazoles and alkynes under copper(I,II) catalysis
was developed. The protocol allows the construction of a variety of arylꢀsubstituted
imidazo[2,1ꢀb]benzothiazoles, ꢀ[2,1ꢀb]thiazoles and ꢀ[2,1ꢀb][1,3,4]thiadiazoles. Reactions
are easy to perform affording most of the desired products in yields of 33 to 93%. The
intensification of the process in a continuous flow reactor increases the products yields up
to quantitative.
Keywords: imidazo[2,1ꢀb]thiazoles; imidazo[2,1ꢀb]benzothiazoles; copper catalysis; A3ꢀ
Coupling.
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INTRODUCTION
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Imidazo[2,1ꢀb]thiazole is one of the most important fused sulfurꢀcontaining heterocycle
widely found in a variety of biologically active agents (Figure 1),1 including a number of
drugs and drug candidates (e.g., anthelmintic levamisole,1d potent anticancer agent
Quizartinib,2 p53 inhibitor antiꢀneoplastic drug pifithrinꢀβ,3 antiꢀaging agent SRT2140,4
anxiolytic agent WAYꢀ181,1875). The prevalence of the imidazo[2,1ꢀb]thiazole motif in
medicinally relevant compounds,6 catalysts,7 phosphorescent emitting8 and electronic9
materials has inspired the development of many novel methods for their preparation.10
However, there are only limited protocols for the oneꢀpot assembly of polyfunctionalized
imidazothiazole derivatives.11 Traditional methods include heterocyclizations of 2ꢀ
aminothiazoles with αꢀbromoketones.12 Recently, Singh et al. reported a visible lightꢀ
triggered procedure in a green medium for condensation of arylacyl bromides with 2ꢀ
aminothiazole towards imidazo[2,1ꢀb]thiazoles.13 Hajra and coꢀworkers reported an
elegant Fe/Znꢀcocatalyzed aerobic oxidative cyclization of 2ꢀaminobenzothiazole and
chalcones.14 In another report, Zhu et al. demonstrated copper(II) acetateꢀpromoted
cycloaddition of αꢀmethylenyl isocyanides with 2ꢀmethylbenzothiazole.15 The metalꢀfree
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condensation of 2ꢀaminothiazole with
βꢀnitroacrylates to form imidazo[2,1ꢀ
b][1,3]benzothiazoles in a ionic liquid was reported by Meshram.16 Despite the
impressive progress made in this area, synthesis of functionalized imidazo[2,1ꢀb]thiazoles
from readily available and easily varied starting materials using a simple procedure still
remains a great challenge. The known methods suffer from the necessity of using
prefunctionalized, commercially unavailable reacting substances and limited substrate
scope.
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Figure 1. Representative drug or drug candidates containing imidazo[2,1ꢀb]thiazole
moieties.
Recently, transition metalꢀcatalyzed threeꢀcomponent coupling of aldehyde, alkyne and
amine, commonly called A3ꢀcoupling, has been established as a practical tool in modern
organic synthesis.17 Since the initial reports in 1998 the A3ꢀcoupling18 has emerged as the
most convenient and general approach for the in situ generation of labile propargylamine
intermediates for cascade heterocyclization.17,19 Numerous protocols using transitionꢀ
metal catalysis were developed for functionalized fiveꢀ and sixꢀmembered N,Oꢀ
heterocycles, e.g. quinolines,20 imidazopyridines,21 furans,22 benzofurans,23 1,4ꢀ
dihydropyridines,24 pyrroles25 and oxazoles.26 However, the use of A3ꢀcoupling in
constructing sulfurꢀcontaining heterocyclic compounds remains strictly limited.27 Only
two
solitary
examples
of
the
synthesis
of
2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ
phenylthiazolopyrimidine27a and 5ꢀbenzylꢀ6ꢀphenylimidazo[2,1ꢀb][1,3]thiazole27b were
reported. As part of our ongoing synthetic efforts toward imidazoheterocycles,28 herein
we report a general and efficient synthesis of the imidazo[2,1ꢀb]thiazole scaffold by the
copperꢀcatalyzed threeꢀcomponent coupling reaction of 2ꢀaminothiazoles with aryl
aldehydes and alkynes involving 5-exo-dig cyclization of an in situ generated
propargylamine intermediate (Scheme 1). We also demonstrate that the use of
continuousꢀflow technique allows for the full implementation of this transformation, thus
providing a more convenient and scalable method.
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Scheme 1. Proposed approach towards the imidazo[2,1-b]thiazole scaffold
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RESULTS AND DISCUSSION
We started our study by optimizing the reaction of 2ꢀaminobenzothiazole (1a) with pꢀ
chlorobenzaldehyde (2a) and ethyl propiolate (3a) to prepare imidazo[2,1ꢀ
b]benzothiazole 4a (Table 1). In the absence of additives in toluene at 120 oC, the desired
transformation did not occur (Table 1, entry 1). Screening of the dꢀmetal catalytic systems
(see SI), which hold promise for the heterocyclization to 4a, revealed superior activity of
copper salts (Table 1, entries 2ꢀ7). Among others, CuCl, CuOTf•C6H6 and Cu(OTf)2
showed promising results, providing the desired product 4a in 61%, 67%, and 55% yield,
respectively (Table 1, entries 2ꢀ4). However, the best results were achieved by
performing the reaction with the homogeneous catalytic system CuOTf•C6H6 (10 mol
o
%)/Cu(OTf)2 (10 mol %) in toluene under an inert atmosphere at 120 C. Compound 4a
was obtained in 75% yield in 2 h (Table 1, entry 8). A sharp decrease in the yield was
observed in other solvents tested and at a lower temperature (Table 1, entries 10ꢀ12), as
well as under aerobic conditions (Table 1, entry 9). The structure of imidazo[2,1ꢀ
b]thiazole 4a was confirmed by singleꢀcrystal Xꢀray diffraction (see Supporting
Information, Figure S1).
Table 1. Optimization of the reaction conditionsa
Entry
[Сu]
Solvent
T, oC
Yield
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4a,%b
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ꢀ
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Anisole
MeCN
120
120
120
120
120
120
120
120
120
110
82
ꢀ
61
67
55
<10
56
71
CuCl
CuOTf*C6H6
Cu(OTf)2
Cu(OAc)2*H2O
CuI/Cu(OTf)2
CuCl/Cu(OTf)2
CuOTf*C6H6/Cu(OTf)2
CuOTf*C6H6/Cu(OTf)2
CuOTf*C6H6/Cu(OTf)2
CuOTf*C6H6/Cu(OTf)2
CuOTf*C6H6/Cu(OTf)2
75
33c
49
9
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<10
50
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DMSO
120
a)Reaction conditions: amine 1a (0.20 mmol), aldehyde 2a (0.22
mmol), ethyl propiolate 2a (0.4 mmol), Cu salt (10 mol %), 4Å
molecular sieves and solvent (1 mL) in a Vꢀshaped vial under an
b)
c)
inert atmosphere.
performed in air.
Yield after chromatography.
Reaction was
With the optimized conditions in hand, the substrate scope was explored with a variety
of aldehydes (Table 2), alkynes (Table 3) and amines (Table 4). It was found that
functionally diverse benzaldehydes worked well in the reaction (Table 2, entries 1ꢀ14).
Both electronꢀwithdrawing groups (2ꢀCl, 3ꢀCl, 4ꢀCl, 2,4ꢀCl2, 3,4ꢀCl2, 4ꢀF, 4ꢀNO2, 3ꢀNO2)
and electronꢀdonating groups (3ꢀMe, 4ꢀOMe, 2ꢀOMe, 2,4ꢀ(OMe)2) were tolerated under
the reaction conditions. Products 4a-n were isolated in moderate to good yields. Nonꢀ
functionalized product 4i was obtained from benzaldehyde in 46% yield (Table 2, entry
9). In addition, a 3ꢀpyridinecarboxaldehyde, as well as 2ꢀthiophenecarboxaldehyde, were
tolerated under these reaction conditions (Table 2, entries 15 and 16). Corresponding
polyheterocyclic products 4o and 4p were obtained in 38% and 61% yields, respectively.
Aliphatic aldehydes did not produce the desired products under optimized conditions,
which was attributed to side decomposition processes.
Table 2. Scope of aldehydesa
Yield
%
4,
Entry
Compd
R
b
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
4ꢀClꢀC6H4
3ꢀClꢀC6H4
75
59
60
72
55
48
2ꢀClꢀC6H4
2,4ꢀCl2ꢀC6H3
3,4ꢀCl2ꢀC6H3
4ꢀFꢀC6H4
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4g
4h
4i
4ꢀNO2ꢀC6H4
3ꢀNO2ꢀC6H4
Ph
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48
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33
9
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13
4j
Tol
4k
4l
4ꢀMeOꢀC6H4
2ꢀMeOꢀC6H4
2,4ꢀ(MeO)2ꢀC6H3
4m
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14
4n
50
N
15
16
4o
4p
38
61
a)
Reaction conditions: amine 1a (0.2 mmol, 1 equiv),
aldehyde (1.1 equiv), alkyne 2a (2 equiv), CuOTf•C6H6 (10
mol %), Cu(OTf)2 (10 mol %), 4Å molecular sieves and
2
toluene (1 mL) in
a Vꢀshaped vial under an inert
atmosphere for 2 h at 120 oC. b) Yield after chromatography.
Furthermore, a number of propiolic acid esters and amides were successfully reacted to
yield methylenecarbonylꢀsubstituted imidazo[2,1ꢀb]benzothiazoles 4a,q-s (Table 3, entries
1ꢀ4). Ethynyl isopropyl ketone underwent the reaction giving product 4t in 65% yield
(Table 3, entry 5). 3ꢀ(Sulfonylmethyl)imidazo[2,1ꢀb]benzothiazoles 4u-w were
synthesized using alkylꢀ and arylꢀsubstituted ethynyl sulfones in moderate yields (Table
3, entries 6ꢀ8). Aliphatic and aryl alkynes were found to be inefficient for the elaborated
transformation under optimized batch conditions. The trace amounts of the products derived
from nꢀbutylꢀ and phenylacetylenes were detected (yields ≤ 5ꢀ7%).
Table 3. Scope of alkynesa
Yield
%
4,
Entry
Compd
R
b
1
2
3
4
5
6
7
4a
4q
4r
CO2Et
CO2Me
75
72
61
75
65
45
45
CONMe2
CONPr2
COPri
4s
4t
4u
4v
SO2Me
SO2C6H4But
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4w
SO2Tol
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a)
Reaction conditions: amine 1a (0.2 mmol, 1 equiv),
aldehyde 2a (1.1 equiv), alkyne (2 equiv), CuOTf•C6H6 (10
mol %), Cu(OTf)2 (10 mol %), 4Å molecular sieves and
toluene (1 mL) in a Vꢀshaped vial under an inert atmosphere
for 2 h at 120 oC. b) Yield after chromatography.
3
7
8
9
In addition, we were delighted to find that versatile thioamidines including functionalized 2ꢀ
aminobenzothiazoles, 2ꢀaminothiazole and 2ꢀaminoꢀ1,3,4ꢀthiadiazoles underwent smooth
reactions (Table 4). Parent imidazo[2,1ꢀb]benzothiazoles 4x and 4y, imidazo[2,1ꢀb]thiazoles 4z
and 4aa, as well as several imidazo[2,1ꢀb][1,3,4]thiadiazoles 4ab-ad, were obtained in 35ꢀ77%
yields. However, attempts to perform the reaction of tolyl aldehyde or 4ꢀnitrobenzaldehyde with
2ꢀaminothiazole accompanied by the condensation with ethyl propiolate failed (Table 4,
compounds 4ae and 4af), as complex mixtures of products were obtained.
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Table 4. Scope of heterocyclic thioamidinesa,b
S
S
N
N
MeO
Cl
N
N
Cl
Cl
O
O
OEt
OEt
4x, 77%
4y, 40%
Cl
S
S
N
N
N
N
Cl
Cl
O
O
OEt
OEt
4z, 46%
4aa, 60%
S
S
N
N
Et
N
N
N
N
Cl
Cl
O
O
OEt
OEt
4ab, 55%
4ac, 41%
S
S
N
N
O
N
N
N
Cl
R
O
O
OEt
OEt
4ad, 35%
4ae, R = Me, ꢀꢀ%
4af, R = NO2, ꢀꢀ%
a) Reaction conditions: amine
(1.1 equiv), alkyne 3a (2 equiv), CuOTf•C6H6 (10 mol %),
1 (0.2 mmol, 1 equiv), aldehyde
2
Cu(OTf)2 (10 mol %), 4Å molecular sieves and toluene (1 mL)
in a Vꢀshaped vial under an inert atmosphere for 2 h at 120
oC. b) Yield after chromatography.
Therefore, the reaction scope was found to be quite general, and the functional group tolerance
is quite good. Conversely, the elaborated batch procedure gives most products 4 in 45ꢀ65%
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yields. In some cases, the batch protocol proved to be fully inefficient (Table 4, compounds 4ae
and 4af). These limitations can be overcome by means of intensification of the process.
Therefore, we turned to continuousꢀflow synthesis in the presence of heterogeneous copper(I,II)
catalysts, which may overcome disadvantages of the batch synthesis.29 The improved heat
transfer under continuousꢀflow conditions reduces the effect of side reactions, whereas the backꢀ
pressure regulation technology can be used to eliminate solvent boiling, resulting in substantial
enhancement of reaction kinetics.30
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It should be noted that the continuousꢀflow synthesis of propargylamines via A3ꢀcoupling was
pioneered by Organ, Li and coꢀworkers.31 Several examples demonstrated the successful
transition from batch to continuousꢀflow conditions for the heterocyclization of propargylamines,
resulting in an increase in the of yield and functionalꢀgroup compatibility.32 Meanwhile, the
direct formation of imidazoheterocycles via A3ꢀcoupling strategy using continuousꢀflow
conditions is still unknown.
The continuousꢀflow study of the efficient and scalable production of imidazo[2,1ꢀ
b]thiazoles
4 was performed using pregenerated imines 6 and propiolate 3 (Tables 5,6).
The continuousꢀflow setup is represented in Figure 2 and is fully illustrated in the
Supporting Information. A steel column 4.6 mm in diameter and 200 mm in length with
steel frits filled with CuI granules (10ꢀ100 ꢁm particle size) or a catalyst system
consisting of commercially available finely divided CuI (1ꢀ4 ꢁm particle size) and 50 ꢁm
spherical silica gel in a 1 : 1 ratio was used (see Supporting Information, Figures S2,S3).
A mixture of substrates
6
and 3b in anisole was fed to the column heated up to 200 oC by
a piston pump at a rate of 0.55ꢀ1.0 mL minꢀ1 and at 15 atm to prevent alkyne external leak
using a backꢀpressure regulator.
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Figure 2. Continuousꢀflow experimental setup. a) SEM image (20 ꢁm) for granular CuI
(10ꢀ100 ꢁm particle size), b) SEM image (20 ꢁm) 1 : 1 CuI/SiO2 mixture (finelyꢀdivided
CuI 1ꢀ4 ꢁm particle size; silica gel particle size 50 ꢁm).
Imidazo[2,1ꢀb]benzothiazoles were synthesized under continuousꢀflow conditions in the
presence of the CuI/SiO2 catalyst in higher yields compared to the batch mode. Thus,
coupling products 4i, 4k, and 4l were isolated in 71%, 74%, and 60% yields, respectively
(
continuous-flow, Table 4) versus 46%, 45%, and 42% yields (batch, Table 2, entries 9,
11, 12). Additionally, scope of the continuousꢀflow protocol towards imidazo[2,1ꢀ
b]benzothiazoles was extended using methyl propiolate 3b and imines 6a-d derived from
benzaldehyde and its
pꢀOMeꢀ,
oꢀOMeꢀ, and o,pꢀdiꢀClꢀsubstituted derivatives.
Corresponding products 4ag
ꢀ
4aj functionalized at the aryl moiety were isolated in 63ꢀ
93% yields.
Table 5. Continuous-flow synthesis of imidazo[2,1-b]benzothiazolesa-c
a)
Reaction conditions: imine
6 (1.0 mmol, 1 equiv),
propiolate 3a,b (3.0 mmol, 3 equiv), CuI/SiO2 (1:1 ratio, 2.8
g), and anisole (20 mL) at 200 oC at a total flow rate of 0.55ꢀ
b)
c)
1.0 mL minꢀ1 under inert atmosphere.
Isolated yield.
Product 4aj was obtained using CuI catalyst.
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Moreover, the continuousꢀflow mode proved to be efficient for imidazo[2,1ꢀb]thiazoles
4ae and 4af that are not available under batch conditions (Tables 4,6). The products 4ae
and 4af were obtained under continuousꢀflow conditions using CuI granules as the
catalyst in 59% and 54% yields, respectively. Closely related imidazo[2,1ꢀb]thiazoles 4ak
and 4al derived from methyl propiolate 3b were isolated in 69% and 56% yields. To
enhance the diversity of available imidazo[2,1ꢀb]thiazoles, imines 6e-j derived from 2ꢀ
aminothiazole and aryl aldehydes containing electronꢀdonating and ꢀwithdrawing groups
were subjected to the reaction with methyl propiolate 3b (Table 6). The electronꢀ
withdrawing substituents in ortho and para positions, such as Cl and NO2, provided
good/high product yields (56ꢀ88% for 4al-ao). Electronꢀdonating methoxy groups
attached to the aryl moiety decreased the yield to 27% (4ap). All of these reactions were
carried out on a 1.0 mmol scale, but they can easily be scaledꢀup. Indeed, imidazo[1,2ꢀ
a]thiazole 4an was prepared in a yield of 1.8 g on the 9 mmol scale without remarkable
reduction in the yield.
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Table 6. Continuous-flow synthesis of imidazo[2,1-b]thiazolesa,b
a)
Reaction conditions: imine
6 (1.0 mmol, 1 equiv),
propiolate 3a,b (3.0 mmol, 3 equiv), CuI granules (4.2 g),
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and anisole (20 mL) at 200 C at a total flow rate of 0.55ꢀ
b)
1.0 mL minꢀ1 under inert atmosphere.
chromatography.
Yield after
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Finally, a direct comparison of the efficiency of the continuousꢀflow and batch protocols
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4
was performed using model condensation of imine 6a and ethyl propiolate 3a (Table 7).
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The yield of the coupling product ꢀ imidazo[2,1ꢀb]benzothiazole 4i ꢀ in 2h under batch
o
conditions using Cu(OTf)2 (10 mol%)/CuOTf
•
C6H6 (10 mol%) and MS 4Å at 120 C in
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toluene was equal to the yield of 4i in the threeꢀcomponent batch protocol (46%, Table 2,
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entry 9). Attempts to perform the reaction under the same conditions in a continuousꢀflow
experimental setup by passing a mixture of 6a
,
3a and Cu(OTf)2 (10 mol%)/CuOTf
•
C6H6
o
(10 mol%) in toluene through a steel column filled with MS 4Å and preheated to 120 C
failed because of the system obstruction caused by poor solubility of the starting
materials. The use of anisole instead of toluene provided dissolution and resulted in the
formation of product 4i in 64% yield (Table 7, entry 1). Notably, the principal result was
the same at 1 atm and 15 atm. Therefore, the pressure is not a crucial factor for the
cyclization efficiency. The highest yield of product 4i was achieved under continuousꢀ
o
flow conditions using a steel column filled with CuI/SiO2 at 200 C (71%, Tables 5,7).
The complete conversion was achieved in 3.1 h by passing a solution of 6a and 3a in
anisole through the “catalyst” column at 15 atm to avoid alkyne boiling. On the contrary,
the reaction performed under batch conditions in anisole in the presence of CuI/SiO2 (3
o
eqiuv, 1:1 mixture) in a sealed microreactor vial at 200 C gave compound 4i in ≤10%
yield, which can be attributed to the side decomposition processes.
Table 7. Continuous-flow vs batch conditions
Yield 4i, %c
Entry
1a
Reaction conditions
Batch
mode
Continuous-flow
mode
0
Cu(OTf)2 (10 mol%)
CuOTf*C6H6 (10 mol%)
toluene, MS 4Å
reactions in
anisole
46
64d (1 atm)
61d (15 atm)
120 oC, 2 h
CuI/SiO2 (1:1)
2b
≤10
71
anisole, 200 oC, 3.1 h
a)
Batch protocol: imine 6a (50 mg, 0.2 mmol, 1 equiv), ethyl
propiolate 3a (44 mg, 2 equiv), CuOTf•C6H6 (10 mg, 10 mol %),
Cu(OTf)2 (7 mg, 10 mol %), 4Å molecular sieves and toluene (1
mL) in a Vꢀshaped vial under an inert atmosphere for 2 h at
120 oC.
Continuous-flow protocol: imine 6a (240 mg, 1.0 mmol,
1 equiv), ethyl propiolate 3a (290 mg, 3.0 mmol, 3 equiv),
CuI/SiO2 (1:1 ratio, 2.8 g), and solvent (20 mL) at 120 oC at a
total flow rate of 0.55 mL minꢀ1 under inert atmosphere.
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b)
Batch protocol: imine 6a (50 mg, 0.2 mmol, 1 equiv), ethyl
propiolate 3a (44 mg, 2 equiv), CuI/SiO2 (1:1 ratio, 230 mg),
and anisole (1 mL) in Vꢀshaped vial under an inert
atmosphere for 3.1 h at 200 oC.
a
Continuous-flow protocol: imine 6a (240 mg, 1.0 mmol,
1 equiv), ethyl propiolate 3a (290 mg, 3.0 mmol, 3 equiv),
CuI/SiO2 (1:1 ratio, 2.8 g), and anisole (20 mL) at 15 atm at
200 oC at a total flow rate of 0.55 mL minꢀ1 under inert
atmosphere.
c)
d)
Yield after chromatography.
analysis.
Yields determined by HPLC
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These experiments clearly indicated that the homogeneous catalytic system
Cu(OTf)2/CuOTf C6H6 found for the batch mode and heterogeneous CuIꢀbased catalytic
•
systems proposed for the continuousꢀflow mode are not interchangeable. Moreover, the
yields of the target coupling products were increased only in the continuousꢀflow mode.
CONCLUSION
In conclusion, we investigated the copperꢀcatalyzed threeꢀcomponent coupling reaction
of 2ꢀaminothiazoles with aldehydes and alkynes yielding imidazo[2,1ꢀb]thiazoles under
batch and continuousꢀflow conditions. The coupling products were obtained in higher
yields in continuous flow. To the best of our knowledge, this is the first application of the
continuousꢀflow technology to the copperꢀcatalyzed condensation of alkynes with imines,
derived from heterocyclic thioamidines with aldehydes, allowing for synthesis of a
variety of substituted imidazoheterocycles. The reactions are easy to conduct, and the
functional group tolerance is quite good. High efficiency, excellent atom economy and a
wide availability of reagents imply that an extensive range of substituents can be
selectively incorporated into the imidazo[2,1ꢀb]thiazole ring.
EXPERIMENTAL SECTION
General information
NMR spectra were acquired on Bruker Avance 600, 300 spectrometers at room temperature; the
chemical shifts δ were measured in ppm relative to the solvent (1Н: CDCl3, δ = 7.27 ppm; 13C:
CDCl3, δ = 77.00 ppm). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; dd, double doublet; ddd, double double doublet. The coupling constants (J)
are in Hertz. The structures of compounds were established using 1D NMR (1H, 13C, JMOD) and
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2D NMR (1Hꢀ1H COSY, 13Cꢀ1H HSQC) spectroscopy. Highꢀresolution mass spectra (HRMS)
were measured using electrospray ionization (ESI) in positive ion mode (interface capillary
voltage 4500 V); the mass range was from m/z 50 to 3000 Da; external/internal calibration was
performed using an electrospray calibration solution. Syringe injection was used for solutions in
CH3CN (flow rate 3 mL/min). Nitrogen was applied as the dry gas. The interface temperature
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o
was set at 180 C. Scanning electron microscope (SEM) images were recorded on a Phenom
Prox electron microscope (Phenom, Netherlands) operating at 15 kV. The melting points (mp)
are uncorrected and were measured on a Boetius capillary melting point apparatus. Analytical
thinꢀlayer chromatography (TLC) was carried out on silica gel plates (silica gel 60 F254
aluminum supported plates); the visualization was accomplished with an UV lamp (365 nm). All
commercial reagents and solvents were used without additional purification. Reactions were
performed in 2 mL glass Vꢀshaped vials (Wheaton Scientific) and monitored by TLC with GF
254 silica gel coated plates. Column chromatography was performed on neutral aluminum oxide
(Brockmann II, pH 9ꢀ10) or silica gel 60 (230ꢀ400 mesh) treated with 1% triethylamine solution
in petroleum benzene. Flash chromatography was performed using automated flash
chromatography system equipped with an HPꢀSilica 15 ꢁm column. Parent N,Nꢀdipropylꢀ and
N,Nꢀdimethylpropiolamides were prepared according to the published procedure.33 Ethynyl
sulfones34 and ethynyl isopropyl ketone35 were prepared by known methods. Schiff bases were
prepared by the condensation of 2ꢀaminothiazoles with aldehydes.36
Typical experimental procedures
Batch procedure: A screwꢀcapped Vꢀshaped vial (2.0 mL) was charged with 2ꢀaminothiazole
(0.2 mmol, 1.0 equiv), aldehyde (0.22 mmol, 1.1 equiv), freshly activated 4Å molecular sieves
(150 mg) and dry toluene (1.5 mL). The vial was capped with a pressure cap and stored at 120 oC
1
for 14ꢀ24 h until complete consumption of 2ꢀaminothiazole (monitored by H NMR). The
resulting mixture containing imine was cooled to room temperature and the solvent was removed
under reduced pressure. Under inert atmosphere, the reside was redissolved in dry toluene (1
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mL) and then CuOTf C6H6 (10 mg, 0.02 mmol, 10 mol %), Cu(OTf)2 (7 mg, 0.02 mmol, 10 mol
•
3
4
5
6
7
%), alkyne (0.4 mmol, 2 equiv) and 4Å molecular sieves (100 mg) were added. The reaction
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mixture was additionally stirred in the vial capped with a pressure cap at 120 C for 2 h. After
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the completion of the reaction, the mixture was filtered through a plug of neutral aluminum
oxide (eluent – EtOAc). The filtrate was concentrated under reduced pressure to give a crude
material, which was purified by column chromatography on silica gel (eluent
Et3N:EtOAc/petroleum ether) or neutral aluminum oxide (eluent EtOAc/petroleum ether) to give
product.
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Continuous flow procedure: A solution of imine (1.0 mmol, 1 equiv) and methyl propiolate
(270 ꢁL, 3.0 mmol, 3 equiv) in dry anisole (20 mL) was delivered to a catalyst cartridge (200
mm length, 4.6 mm diameter) charged with CuI granules (4.2 g) or CuI/SiO2 (1:1 ratio, 2.8 g)
heated at 200 °C at a total flow rate of 0.55ꢀ1.0 mL minꢀ1, equating to a residence time of about
100ꢀ220 min. A 15 atm backꢀpressure regulator was applied to the system. The solvent was
removed under reduced pressure and the product was purified by silica gel flash column
chromatography (eluent hexane/EtOAc).
Ethyl [2-(4-chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4a). Yield 75% (56 mg,
1
batch procedure), yellow solid, mp 100ꢀ102 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 7.84 (d, J = 8.07 1H), 7.71ꢀ7.73 (m, 3H), 7.43ꢀ7.48 (m, 3H), 7.37
(dd, J = 7.33, 8.07 Hz, 1H), 4.29 (q, J = 7.33 Hz, 2H), 4.19 (s, 2H), 1.30 (t, J = 7.33 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 169.6 (CO), 147.7 (C), 144.9 (C), 133.7 (C), 133.0 (C), 132.2 (С),
130.4 (C), 129.2 (2×CH), 128.8 (2×CH), 126.1 (CH), 124.8 (CH), 124.4 (CH), 117.1 (C), 113.1
(CH), 61.9 (CH2), 31.7 (CH2), 14.2 (CH3); IR (KBr) 3433 (w), 1727 (s), 1495 (s), 1366 (s), 1254
(s), 1088 (s), 1030 (s), 828 (s), 743 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C19H16ClN2O2S+ 371.0616; Found 371.0617.
Ethyl [2-(3-chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4b). Yield 59% (43
1
mg, batch procedure), yellow solid, mp 86ꢀ88 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 5:1). H
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NMR (300 MHz, CDCl3): δ 7.84 (d, J = 8.67 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J = 7.27 Hz, 1H)
7.64 (dd, J = 1.67, 7.32 Hz, 1H), 7.31ꢀ7.45 (m, 4H), 4.28 (q, J = 7.26 Hz, 2H), 4.18 (s, 2H), 1.29
(t, J = 7.26 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.6 (CO), 147.8 (C), 144.7 (C), 135.8 (C),
134.6 (C), 133.0 (C), 130.5 (C), 129.9 (CH), 128.0 (CH), 127.7 (CH), 126.1 (CH), 126.0 (CH),
124.8 (CH), 124.4 (CH), 117.4 (C), 113.2 (CH), 62.0 (CH2), 31.8 (CH2), 14.2 (CH3); IR (KBr)
2981 (s), 1735 (s), 1599 (s), 1495 (s), 1370 (s), 1199 (s), 1094 (s), 1028 (s), 790 (s), 747 (s) сmꢀ
1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H16ClN2O2S+ 371.0616; Found 371.0609.
Ethyl [2-(2-chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4c). Yield 60% (44 mg,
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batch procedure), yellow solid, mp 124ꢀ126 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 7.72 (d, J = 7.33 Hz, 1H), 7.68 (d, J = 8.24 Hz, 1H), 7.55ꢀ7.58 (m,
1H), 7.48ꢀ7.51 (m, 1H), 7.41 (dd, J = 7.33, 8.24 Hz, 1H), 7.31ꢀ7.36 (m, 3H), 4.18 (q, J = 7.39
Hz, 2H), 4.02 (s, 2H), 1.21 (t, J = 7.39 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.6 (CO),
147.5 (C), 143.5 (C), 134.0 (C), 133.1 (C), 132.8 (CH+C), 130.5 (C), 130.0 (CH), 129.6 (CH),
126.8 (CH), 126.0 (CH), 124.7 (CH), 124.4 (CH), 118.7 (C), 113.1 (CH), 61.6 (CH2), 31.6
(CH2), 14.2 (CH3); IR (KBr) 3453 (w), 2974 (s), 1737 (s), 1581 (s), 1492 (s), 1364 (s), 1186 (s),
1027 (s), 768 (s), 746 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H16ClN2O2S+
371.0616; Found 371.0606.
Ethyl [2-(2,4-dichlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4d). Yield 72% (58
mg, batch procedure), yellow solid, mp 114ꢀ116 °C; Rf = 0.37 (petroleum ether ꢀ EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): δ 7.74 (d, J = 7.33 Hz, 1H), 7.69 (d, J = 8.24 Hz, 1H), 7.53 (s,
1H), 7.50 (d, J = 8.24 Hz, 1H), 7.35ꢀ7.47 (m, 3Н), 4.19 (q, J = 7.33 Hz, 2Н), 4.00 (s, 2Н), 1.22
(t, J = 7.33 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.3 (CО), 147.6 (C), 142.3 (C), 134.8 (C),
134.6 (C), 133.4 (CН), 132.8 (С), 131.3 (C), 130.3 (C), 129.6 (CH), 127.1 (CН), 126.0 (CH),
124.7 (CH), 124.3 (СН), 118.9 (С), 113.0 (СН), 61.6 (CН2), 31.5 (CH2), 14.1 (CH3); IR (KBr)
3426 (w), 2985 (s), 1717 (s), 1552 (s), 1492 (s), 1331 (s), 1210 (s), 1030 (s), 818 (s), 748 (s) сmꢀ
1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H15Cl2N2O2S+ 405.0226; Found 405.0215.
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Ethyl [2-(3,4-dichlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4e). Yield 55% (44
mg, batch procedure), yellow solid, mp 132ꢀ135 °C; Rf = 0.40 (petroleum ether ꢀ EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 1.65 Hz, 1H), 7.87 (d, J = 8.20 Hz, 1H), 7.71 (d, J =
7.92 Hz, 1H) 7.61 (dd, J = 1.65, 8.47 Hz, 1H), 7.50 (d, J = 8.47 Hz, 1H) 7.44 (dd, J = 8.20 Hz,
1H), 7.35 (dd, J = 7.92 Hz, 1H), 4.29 (q, J = 7.33 Hz, 2H), 4.17 (s, 2H), 1.31 (t, J = 7.33 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 169.4 (CO), 147.9 (C), 143.7 (C), 134.0 (C), 132.8 (C),
132.7 (C), 131.6 (C), 130.5 (CH), 130.4 (C), 129.6 (CH), 127.0 (CH), 126.2 (CH), 125.0 (CH),
124.5 (CH), 117.5 (C), 113.2 (CH), 62.0 (CH2), 31.7 (CH2), 14.2 (CH3); IR (KBr) 3435 (w),
2975 (s), 1726 (s), 1492 (s), 1371 (s), 1245 (s), 1199 (s), 1150 (s) 1026 (s), 737 (s) сmꢀ1; HRMS
(ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H14Cl2N2O2SNa+ 427.0045; Found 427.0035.
Ethyl [2-(4-fluorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4f). Yield 48% (33 mg,
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batch procedure), yellow solid, mp 86ꢀ87 °C; Rf = 0.22 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 7.68ꢀ7.81 (m, 4Н), 7.41 (dd, J = 7.76 Hz, 1H), 7.32 (dd, J = 7.76
Hz, 1H), 7.15 (dd, J = 8.52 Hz, 2Н), 4.28 (q, J = 7.33 Hz, 2Н), 4.16 (s, 2Н), 1.28 (t, J = 7.33 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 169.8 (CО), 162.5 (d, JCꢀF = 247.1 Hz, C), 147.5 (C), 145.2
(C), 133.0 (C), 130.3 (C), 130.1 (d, JCꢀF = 3.2 Hz, C), 129.7 (d, JCꢀF = 8.0 Hz, 2×CH), 126.1
(CH), 124.6 (CH), 124.4 (CH), 116.7 (C), 115.5 (d, JCꢀF = 21.4 Hz, 2×CH), 113.0 (СН), 61.8
(CН2), 31.7 (CH2), 14.2 (CH3); IR (KBr) 3435 (w), 2948 (w), 1726 (s), 1504 (s), 1487 (s), 1210
(s), 751 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H16FN2O2S+ 355.0911;
Found 355.0912.
Ethyl [2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4g). Yield 54% (41 mg,
1
batch procedure), yellow solid, mp 162ꢀ164 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 8.30 (d, J = 9.16 Hz, 2Н), 7.97 (d, J = 9.16 Hz, 2Н), 7.88 (d, J =
8.24 Hz, 1Н), 7.74 (d, J = 7.33 Hz, 1Н), 7.47 (dd, J = 7.33, 7.89 Hz, 1Н), 7.38 (dd, J = 7.89,
8.24 Hz, 1Н), 4.30 (q, J = 7.32 Hz, 2Н), 4.23 (s, 2Н), 1.30 (t, J = 7.32 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 169.3 (CО), 148.4 (C), 147.0 (C), 143.8 (C), 140.5 (C), 132.8 (C), 130.6 (С),
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128.3 (2×CH), 126.3 (CH), 125.2 (CH), 124.6 (CH), 124.0 (2×CН), 118.8 (C), 113.3 (CH), 62.2
(CН2), 32.0 (CH2), 14.3 (CH3); IR (KBr) 3425 (w), 1742 (s), 1515 (s), 1497 (s), 1339 (s), 1190
(w), 1158 (w), 745 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H16N3O4S+
382.0856; Found 382.0843.
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Ethyl [2-(3-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4h). Yield 48% (37 mg,
1
batch procedure), yellow solid, mp 153ꢀ156 °C; Rf = 0.32 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 8.71 (s, 1Н), 8.23 (d, J = 8.24 Hz, 1Н), 8.18 (d, J = 8.24 Hz, 1Н),
7.95 (d, J = 8.24 Hz, 1Н), 7.76 (d, J = 8.24 Hz, 1Н), 7.65 (dd, J = 8.24 Hz, 1Н), 7.49 (dd, J =
8.24 Hz, 1Н), 7.40 (dd, J = 8.24 Hz, 1Н), 4.33 (q, J = 7.27 Hz, 2Н), 4.23 (s, 2Н), 1.34 (t, J =
7.27 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.4 (CО), 148.7 (C), 148.3 (C), 143.8 (C), 135.8
(C), 134.0 (CH), 133.0 (C), 130.6 (С), 129.7 (CH), 126.4 (CH), 125.2 (CH), 124.6 (CH), 122.6
(CН), 122.4 (CH), 118.1 (C), 113.3 (CH), 62.3 (CН2), 32.0 (CH2), 14.2 (CH3); IR (KBr) 3444
(w), 2922 (s), 1732 (s), 1526 (s), 1493 (s), 1349 (s), 1206 (s), 1152 (s), 748 (w) сmꢀ1; HRMS
(ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H16N3O4S+ 382.0856; Found 382.0851.
Ethyl (2-phenylimidazo[2,1-b][1,3]benzothiazol-3-yl)acetate (4i). Yield 46% (31 mg, batch
procedure); yield 71% (238 mg, continuous flow procedure, residence time 3.5 h, flow rate 0.85
mL minꢀ1, CuI/SiO2 1:1 mixture), yellow solid, mp 80ꢀ82 °C; Rf = 0.20 (petroleum ether ꢀ
1
EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ 7.70ꢀ7.81 (m, 4Н), 7.47 (dd, J = 7.64 Hz, 3Н),
7.31ꢀ7.41 (m, 2Н), 4.27 (q, J = 7.12 Hz, 2Н), 4.21 (s, 2Н), 1.28 (t, J = 7.12 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 169.9 (CО), 147.6 (C), 146.0 (C), 134.0 (C), 133.2 (С), 130.5 (C), 129.1
(2×CH), 128.7 (2×CH), 127.8 (CH), 126.1 (CH) 124.7 (CH), 124.5 (CH), 117.0 (C), 113.1
(CН), 61.8 (CН2), 31.8 (CH2), 14.2 (CH3); IR (KBr) 3433 (w), 2980 (s), 1721 (s), 1582 (s), 1498
(s), 1198 (s), 1014 (s), 739 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C19H17N2O2S+ 337.1005; Found 337.1001.
Ethyl [2-(4-methylphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4j). Yield 52% (36 mg,
1
batch procedure), yellow solid, mp 74ꢀ77 °C; Rf = 0.23 (petroleum ether ꢀ EtOAc, 4:1). H
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NMR (300 MHz, CDCl3): δ 7.80 (d, J = 8.05 Hz, 1Н), 7.79 (d, J = 7.53 Hz, 1Н), 7.86 (d, J =
8.05 Hz, 2Н), 7.43 (dd, J = 7.53 Hz, 1Н), 7.36 (dd, J = 8.05 Hz, 1Н), 7.29 (d, J = 8.05 Hz, 2Н),
4.28 (q, J = 7.29 Hz, 2Н), 4.21 (s, 2Н), 2.42 (s, 3Н), 1.29 (s, J = 7.29 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 170.0 (CО), 147.5 (C), 146.2 (C), 137.5 (C), 133.2 (C), 131.1 (C), 130.5 (С),
129.4 (2×CH), 128.0 (2×CH), 126.0 (CH), 124.5 (CH), 124.4 (CН), 116.7 (C), 113.0 (CH), 62.0
(CН2), 31.9 (CH2), 21.3 (CH3), 14.2 (CH3); IR (KBr) 3386 (w), 2922 (s), 1734 (s), 1509 (s),
1487 (s), 1195 (s), 1195 (w), 1158 (s), 746 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd
for C20H19N2O2S+ 351.1162; Found 351.1165.
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Ethyl [2-(4-methoxyphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4k). Yield 45% (37
mg, batch procedure), yield 74% (271 mg, continuous flow procedure, residence time 4.1 h,
flow rate 0.55 mL minꢀ1, CuI/SiO2 1:1 mixture), yellow solid, mp 90ꢀ92 °C; Rf = 0.32
(petroleum ether ꢀ EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, J = 8.25 Hz, 1Н), 7.75
(d, J = 8.25 Hz, 1Н), 7.69 (d, J = 8.24 Hz, 2H), 7.46 (dd, J = 7.33, 8.24 Hz, 1Н), 7.27 (dd, J =
7.33, 8.24 Hz, 1Н), 7.02 (d, J = 8.24 Hz, 2Н), 4.28 (q, J = 7.32 Hz , 2Н), 4.19 (s, 2Н), 3.87 (s,
3Н), 1.28 (t, J = 7.32 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.9 (CО), 159.6 (C), 134.9 (C),
133.1 (C), 132.4 (C), 130.5 (C), 129.5 (2×СH), 126.3 (CH),125.6 (C), 124.9 (CH), 124.6 (CH),
116.4 (C), 114.3 (2×CH), 113.1 (CH), 61.9 (CН2), 55.4 (ОCH3), 31.9 (CH2), 14.3 (CH3); IR
(KBr) 2980 (w), 1725 (s), 1509 (s), 1487 (s), 1252 (s), 1196 (s), 1170 (s), 1018 (w), 835 (w),
740 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C20H19N2O3S+ 367.1111; Found
367.1102.
Ethyl [2-(2-methoxyphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4l). Yield 42% (31
mg, batch procedure), yield 60% (220 mg, continuous flow procedure, residence time 4.1 h,
flow rate 0.55 mL minꢀ1, CuI/SiO2 1:1 mixture), yellow solid, mp 175ꢀ177 °C; Rf = 0.34
(petroleum ether ꢀ EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ 7.70 (d, J = 8.49 Hz, 1Н), 7.62
(d, J = 8.49 Hz, 2Н), 7.28ꢀ7.42 (m, 3Н), 7.07 (dd, J = 7.36 Hz, 1Н), 7.00 (d, J = 8.49 Hz, 1H),
4.20 (q, J = 7.32 Hz, 2Н), 4.04 (s, 2Н), 3.79 (s, 3Н), 1.22 (t, J = 7.32 Hz, 3Н); 13C NMR (75
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MHz, CDCl3): δ 170.1 (CО), 156.5 (C), 147.3 (C), 142.2 (C), 133.2 (C), 132.0 (CH), 130.5 (C),
129.5 (СH), 126.0 (CH), 124.4 (CH), 124.3 (CH), 123.0 (C), 121.0 (CH), 118.8 (C), 113.0
(CH), 111.3 (CH), 61.3 (CН2), 55.6 (ОCH3), 31.9 (CH2), 14.2 (CH3); IR (KBr) 3436 (w), 1724
(s), 1500 (s), 1366 (s), 1253 (s), 1026 (s), 753 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+
Calcd for C20H19N2O3S+ 367.1111; 367.1106.
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Ethyl [2-(2,4-dimethoxyphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4m). Yield 33%
(26 mg, batch procedure), yellow solid, mp 88ꢀ90 °C; Rf = 0.31 (petroleum ether ꢀ EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 8.07 Hz, 1Н), 7.75 (d, J = 7.34 Hz, 1Н), 7.47 (dd, J
= 7.34 Hz, 1Н), 7.30ꢀ7.40 (m, 3Н), 6.98 (d, J = 8.07 Hz, 1H), 4.29 (q, J = 7.34 Hz, 2Н), 4.22 (s,
2Н), 3.99 (s, 3Н), 3.95 (s, 3Н), 1.29 (t, J = 7.34 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.8
(CО), 149.3 (C), 149.2 (C), 147.3 (C), 144.9 (C), 133.0 (C), 130.4 (C), 126.3 (СH), 125.8 (C),
125.0 (CH), 124.9 (CH), 120.4 (CH), 116.5 (C), 113.3 (CH), 111.5 (CH), 111.3 (CH), 61.9
(CН2), 56.1 (ОCH3), 56.0 (ОCH3), 31.9 (CH2), 14.2 (CH3); IR (KBr) 2978 (w), 1733 (s), 1510
(s), 1487 (s), 1253 (s), 1022 (w), 750 (w) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C21H21N2O4S+ 397.1217; Found 397.1212.
Ethyl [2-(1,3-benzodioxol-5-yl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4n). Yield 50%
(37 mg, batch procedure), yellow solid, mp 79ꢀ81 °C; Rf = 0.32 (petroleum ether ꢀ EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 8.07 Hz, 1Н), 7.70 (d, J = 7.34 Hz, 1Н), 7.42 (dd, J
= 7.34, 8.07 Hz, 1Н), 7.33 (dd, J = 7.34, 8.07 Hz, 1Н), 7.21ꢀ7.28 (m, 2Н), 6.90 (d, J = 8.07 Hz,
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1Н), 6.01 (s, 2Н), 4.28 (q, J = 7.33 Hz, 2Н), 4.18 (s, 2Н), 1.29 (t, J = 7.33 Hz, 3Н); C NMR
(75 MHz, CDCl3): δ 169.9 (CО), 147.9 (C), 147.3 (C), 146.0 (C), 133.1 (C), 130.4 (С), 128.1
(C), 126.0 (CH), 124.5 (CH), 124.4 (CH), 121.8 (CН), 116.4 (C), 112.9 (CH), 110.1 (C), 108.7
(СН), 108.5 (СН), 101.2 (CН2), 61.8 (СН2), 31.8 (CH2), 14.2 (CH3); IR (KBr) 2978 (w), 2905
(w), 1723 (s), 1496 (s), 1254 (s), 1235 (s), 1036 (s), 752 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M
+ H]+ Calcd for C20H17N2O4S+ 381.0904; Found 381.0895.
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Ethyl (2-pyridin-3-ylimidazo[2,1-b][1,3]benzothiazol-3-yl)acetate (4o). Yield 38% (29 mg,
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1
batch procedure), yellow solid, mp 84ꢀ86 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 5:1). H
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NMR (300 MHz, CDCl3): δ 9.00 (s, 1Н), 8.62 (d, J = 3.88 Hz, 1Н), 8.13 (d, J = 8.06 Hz, 1H),
7.84 (d, J = 8.06 Hz, 1H), 7.74 (d, J = 8.06 Hz, 1H), 7.35ꢀ7.49 (m, 3Н), 4.29 (q, J = 7.25 Hz,
2Н), 4.21 (s, 2Н), 1.30 (t, J = 7.25 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.4 (CО), 148.6
(2×CH), 148.2 (C), 142.9 (C), 135.6 (CH), 133.0 (С), 130.5 (C), 130.1 (C), 126.3 (CH), 125.0
(CH), 124.5 (CH), 123.7 (C), 117.8 (CH), 113.1 (CH), 62.0 (СН2), 31.7 (CH2), 14.2 (CH3); IR
(KBr) 3437 (s), 2926 (w), 1728 (s), 1492 (s), 1299 (s), 1208 (s), 1023 (s), 754 (s) сmꢀ1; HRMS
(ESI/QꢀTOF) m/z: [M + H]+ Calcd for C18H16N3O2S+ 338.0958; Found 338.0950.
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Ethyl [2-(5-bromo-2-thienyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4p). Yield 61% (52
1
mg, batch procedure), yellow solid, mp 77ꢀ79 °C; Rf = 0.30 (petroleum ether ꢀ EtOAc, 5:1). H
NMR (300 MHz, CDCl3): δ 7.85 (d, J = 8.16 Hz, 1Н), 7.70 (d, J = 7.63 Hz, 1Н), 7.44 (dd, J =
7.63, 8.16 Hz, 1Н), 7.34 (dd, J = 7.63 Hz, 1Н), 7.15 (d, J = 3.86 Hz, 1Н), 7.05 (d, J = 3.82 Hz,
1H), 4.25 (q, J = 7.63 Hz, 2Н), 4.21 (s, 2Н), 1.27 (t, J =7.63 Hz, 3Н); 13C NMR (75 MHz,
CDCl3): δ 169.1 (CО), 147.8 (C), 139.5 (C), 138.4 (C), 132.8 (C), 130.5 (СH), 130.4 (C), 126.2
(CH), 125.0 (CH), 124.5 (CH), 124.4 (CН), 116.5 (C), 113.1 (CH), 112.2 (С), 62.0 (СН2), 31.8
(CH2), 14.2 (CH3); IR (KBr) 2974 (s), 1729 (s), 1487 (s), 1189 (s), 818 (s), 747 (s) сmꢀ1; HRMS
+
(ESI/QꢀTOF) m/z: [M + H]+ Calcd for C17H14BrN2O2S2 422.9654; Found 422.9666.
Methyl [2-(4-chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4q). Yield 72% (51
o
mg, batch procedure), yellow solid, mp 122ꢀ124 °C (mplit 124ꢀ126 C37); Rf = 0.35 (petroleum
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ether ꢀ EtOAc, 4:1). H NMR (300 MHz, CDCl3): δ 7.79 (d, J = 8.10 Hz, 1H), 7.67ꢀ7.63 (m,
3H), 7.42ꢀ7.47 (m, 3H), 7.35 (dd, J = 7.32, 8.46 Hz, 1Н), 4.20 (s , 2H), 3.81 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 170.1 (CO), 147.7 (C), 144.8 (C), 133.7 (C), 133.0 (C), 132.2 (C), 130.5
(C), 129.2 (2×CH), 128.8 (2×CH), 126.3 (CH), 124.8 (CH), 124.5 (CH), 116.9 (C), 112.9 (CH),
52.9 (CH2), 31.5 (CH3); IR (KBr) 3432 (w), 1723 (s), 1496 (s), 1331 (s), 1210 (s), 1092 (s),
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1012 (s), 834 (s), 750 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C18H14ClN3OS+
357.0459; Found 357.0459.
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2-[2-(4-Chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]-N,N-dimethylacetamide
(4r).
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Yield 61% (45 mg, batch procedure), yellow solid, mp 229ꢀ231 °C; Rf = 0.32 (petroleum ether ꢀ
EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.12 Hz, 1H), 7.53ꢀ7.58 (m, 3H), 7.37ꢀ
7.42 (m, 3H), 7.31 (dd, J = 7.33, 8.12 Hz, 1Н), 4.17 (s, 2H), 3.15 (s, 3H), 3.07 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 168.4 (CO), 147.6 (C), 144.5 (C), 133.4 (C), 133.1 (C), 132.8 (C), 130.5
(C), 129.4 (2×CH), 128.8 (2×CH), 126.1 (CH), 124.6 (CH), 124.3 (CH), 118.5 (C), 113.1 (CH),
37.5 (CH2), 36.1 (CH3), 30.8 (CH2); IR (KBr) 3436 (w), 2924 (s), 1655 (s), 1497 (s), 1391 (s),
1128 (s), 1009 (s), 828 (s), 742 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C19H17ClN3OS+ 370.0775; Found 370.0770.
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2-[2-(4-Chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]-N,N-dipropylacetamide
(4s).
Yield 75% (63 mg, batch procedure), yellow solid, mp 85ꢀ87 °C; Rf = 0.32 (petroleum ether ꢀ
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EtOAc, 4:1). H NMR (300 MHz, CDCl3): δ 7.67 (d, J = 7.34 Hz, 1Н), 7.55 (d, J = 8.07 Hz,
1Н), 7.54 (d, J = 8.07 Hz, 2Н), 7.40 (d, J = 8.07 Hz, 2Н), 7.37 (dd, J = 8.07 Hz, 1Н), 7.29 (dd, J
= 7.34, 8.07 Hz, 1Н), 4.17 (s, 2Н), 3.32ꢀ3.42 (m, 4Н), 1.57ꢀ1.71 (m, 4Н), 0.90ꢀ0.98 (m, 6Н); 13C
NMR (75 MHz, CDCl3): δ 168.0 (CО), 147.5 (C), 144.5 (C), 133.4 (C), 133.2 (C), 133.0 (C),
130.4 (С), 129.3 (2×CH), 128.7 (2×CH), 125.9 (CH), 124.5 (CH), 124.3 (CН), 118.8 (C), 113.1
(CH), 49.9 (CН2), 48.1 (CH2), 30.9 (CH2), 22.3 (CH2), 21.0 (CH2), 11.4 (CH3), 11.3 (CH3); IR
(KBr) 3435 (w), 2960 (s), 1640 (s), 1497 (s), 1462 (s), 829 (s), 743 (s) сmꢀ1; HRMS (ESI/Qꢀ
TOF) m/z: [M + H]+ Calcd for C23H25ClN3OS+ 426.1401; Found 426.1394.
1-[2-(4-Chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]-3-methylbutan-2-one (4t). Yield
65% (48 mg, batch procedure), yellow solid, mp 153ꢀ154 °C; Rf = 0.32 (petroleum ether ꢀ
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EtOAc, 4:1). H NMR (300 MHz, CDCl3): δ 7.64 (d, J = 7.57 Hz, 1Н), 7.47 (d, J = 8.44 Hz,
2Н), 7.37 (d, J = 8.44 Hz, 2Н), 7.36ꢀ7.38 (m, 1H), 7.32 (dd, J = 7.57, 8.07 Hz, 1Н),7.28 (dd, J =
7.57, 8.07 Hz, 1Н), 4.28 (s, 2H), 2.76ꢀ2.81 (m, 1Н), 1.14 (s, 3Н), 1.13 (s, 3H); 13C NMR (75
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MHz, CDCl3): δ 210.1 (CO), 147.7 (C), 144.7 (C), 133.5 (C), 133.0 (C), 132.7 (C), 130.4 (С),
129.1 (2×CH), 128.8 (2×CH), 126.0 (CH), 124.6 (CH), 124.4 (CН), 117.6 (C), 112.6 (CH), 40.2
(CН), 37.8 (CH2), 18.4 (2×CH3); IR (KBr) 3408 (w), 2975 (s), 1712 (s), 1495 (s), 1364 (s), 1308
(s), 1086 (s), 1041 (s), 828 (s), 748 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C20H18ClN2OS+ 369.0823; Found 369.0818.
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2-(4-Chlorophenyl)-3-[(methylsulfonyl)methyl]imidazo[2,1-b][1,3]benzothiazole (4u). Yield
45% (33 mg, batch procedure), yellow solid, mp 243ꢀ245 °C; Rf = 0.32 (petroleum ether ꢀ
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EtOAc, 4:1). H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 8.24 Hz, 1Н), 7.72 (d, J = 7.33 Hz,
1Н), 7.70 (d, J = 9.16 Hz, 2Н), 7.46 (d, J = 9.16 Hz, 2Н), 7.45ꢀ7.51 (m, 1H), 7.38 (dd, J = 7.33,
8.24 Hz, 1Н), 4.95 (s, 2Н), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 150.4 (C), 147.6 (C),
134.6 (C), 133.0 (C), 131.8 (C), 130.3 (C), 129.4 (2×CH), 129.3 (2×CH), 126.3 (CH), 125.4
(CH), 124.4 (CH), 114.4 (CН), 111.8 (C), 51.3 (CН2), 39.9 (CH3); IR (KBr) 3426 (w), 2925 (w),
1499 (s), 1461 (s), 1306 (s), 1137 (s), 746 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd
+
for C17H14ClN2O2S2 377.0180; Found 377.0168.
3-{[(4-Tert-butylphenyl)sulfonyl]methyl}-2-(4-chlorophenyl)imidazo[2,1-b][1,3]benzothiazole
(4v). Yield 45% (44 mg, batch procedure), yellow solid, mp 175ꢀ176 °C; Rf = 0.26 (petroleum
ether ꢀ EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 8.26 Hz, 1Н), 7.73 (d, J = 8.26
Hz, 1Н), 7.49 (d, J = 8.81 Hz, 2Н), 7.47ꢀ7.53 (m, 1H), 7.40 (dd, J = 7.33, 8.26 Hz, 1Н), 7.22ꢀ
7.34 (m, 6H), 5.07 (s, 2Н), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 158.4 (C), 149.9 (C),
147.5 (C), 134.4 (C), 133.9 (C), 133.0 (C), 131.5 (C), 130.2 (C), 128.9 (2×CH), 128.7 (2×CH),
128.3 (2×CH), 126.2 (3×CH), 125.2 (CH), 124.3 (CH), 114.7 (CН), 112.4 (C), 53.0 (CН2), 35.3
(C), 31.0 (3×CH3); IR (KBr) 3424 (w), 2965 (s), 1494 (s), 1317 (s), 1154 (s), 1107 (s), 1013 (s),
+
837 (s), 747 (s) 501 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C26H24ClN2O2S2
495.0962; Found 495.0955.
2-(4-Chlorophenyl)-3-{[(4-methylphenyl)sulfonyl]methyl}imidazo[2,1-b][1,3]benzothiazole
(4w). Yield 53% (48 mg, batch procedure), yellow solid mp 122ꢀ125 °C; Rf = 0.20 (petroleum
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ether ꢀ EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 8.11 Hz, 1Н), 7.72 (d, J = 7.34
Hz, 1Н), 7.50 (dd, J = 7.34, 8.11 Hz, 1H), 7.36ꢀ7.42 (m, 3H), 7.20ꢀ7.27 (m, 4H), 7.06 (d, J =
8.07 Hz, 2H), 5.04 (s, 2Н), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 149.7 (C), 147.4 (C),
145.4 (C), 134.3 (C), 133.7 (C), 133.0 (C), 131.5 (C), 130.1 (C), 129.7 (2×CH), 128.9 (2×CH),
128.4 (2×CH), 128.2 (2×CH), 126.2 (CH), 125.2 (CH), 124.2 (CН), 114.6 (CH), 112.4 (C), 52.8
(CН2), 21.6 (CH3); IR (film) 3402 (w), 2923 (w), 1596 (s), 1493 (s), 1321 (s), 1166 (s), 1143 (s),
1085 (s), 1011 (s), 886 (s), 754 (s) 547 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
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C23H18ClN2O2S2 453.0493; Found 453.0486.
Ethyl [2-(4-chlorophenyl)-7-methoxyimidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4x). Yield
77% (62 mg, batch procedure), yellow solid, mp 159ꢀ163 °C; Rf = 0.33 (petroleum ether ꢀ
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EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 8.80 Hz, 1H), 7.70 (d, J = 8.07 Hz,
2H), 7.42 (d, J = 8.07 Hz, 2Н), 7.21 7.06 (d, J = 1.47 Hz, 1H), 6.99 (dd, J = 1.47, 8.80 Hz, 1H),
4.27 (q, J = 7.34 Hz, 2Н), 4.13 (s, 2Н), 3.86 (s, 3H), 1.28 (t, J = 7.34 Hz, 3Н); 13C NMR (75
MHz, CDCl3): δ 169.6 (CО), 157.0 (C), 147.0 (C), 144.3 (C), 133.4 (C), 132.5 (C), 131.8 (С),
129.1 (2×CH), 128.8 (2×CН), 127.2 (С), 116.9 (С), 113.6 (СH), 113.2 (СН), 108.9 (CH), 61.9
(CН2), 56.0 (CH3), 31.6 (CH2), 14.2 (CH3); IR (KBr) 3452 (w), 2914 (w), 1734 (s), 1496 (s),
1372 (s), 1203 (s), 825(s), 797 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C20H18ClN2O3S+ 401.0721; Found 401.0720.
Ethyl [7-chloro-2-(4-chlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4y). Yield
40% (32 mg, batch procedure), yellow solid, mp 188ꢀ190 °C; Rf = 0.32 (petroleum ether ꢀ
EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.24 Hz, 1Н), 7.68ꢀ7.70 (m, 3Н), 7.40ꢀ
7.45 (m, 3Н), 4.27 (q, J = 7.32 Hz, 2Н), 4.14 (s, 2Н), 1.29 (t, J = 7.32 Hz, 3Н); 13C NMR (75
MHz, CDCl3): δ 169.5 (CО), 147.5 (C), 145.4 (C), 133.9 (C), 132.2 (С), 131.9 (C), 131.6 (С),
130.4 (СН), 129.2 (2×CH), 128.8 (2×CН), 126.4 (СН), 124.2 (СН), 117.3 (С), 113.9 (СН), 62.0
(CН2), 31.6 (CH2), 14.2 (CH3); IR (KBr) 3430(w), 3430 (w), 2988 (s), 1725 (s), 1498 (s), 1317
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(s), 1213 (s), 832 (s), 803 (s); HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H15Cl2N2O2S+
405.0226; Found 405.0240.
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Ethyl [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4z). Yield 46% (29 mg, batch
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procedure), yellow solid, mp 111ꢀ112 °C; Rf = 0.22 (petroleum ether ꢀ EtOAc, 4:1). H NMR
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(300 MHz, CDCl3): δ 7.70 (d, J = 8.81 Hz, 2Н), 7.53 (d, J = 4.41 Hz, 1Н), 7.44 (d, J = 8.81 Hz,
2Н), 6.89 (d, J = 4.41 Hz, 1Н), 4.23 (q, J = 7.33 Hz, 2Н), 3.91 (s, 2Н), 1.30 (t, J = 7.33 Hz, 3Н);
13C NMR (75 MHz, CDCl3): δ 169.3 (CО), 149.2 (C), 144.4 (C), 133.3 (C), 132.9 (C), 129.0
(2×CH), 128.9 (2×CН), 117.9 (СH), 114.5 (C), 112.6 (СH), 61.7 (CН2), 31.6 (CH2), 14.3 (CH3);
IR (KBr) 2982 (w), 1734 (s), 1488 (w), 1468 (w), 1249 (w), 1188 (w), 836 (w), 756 (w) сmꢀ1;
HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C15H14ClN2O2S+ 321.0459; Found 321.0452.
Ethyl [6-(2,4-dichlorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4aa). Yield 60% (43 mg,
batch procedure), yellow solid, mp 80ꢀ82 °C; Rf = 0.22 (petroleum ether ꢀ EtOAc, 4:1). 1H
NMR (300 MHz, CDCl3): δ 7.49ꢀ7.50 (m, 3Н), 7.32 (dd, J = 2.20, 8.76 Hz, 1Н), 6.88 (d, J =
4.40 Hz, 1Н), 4.17 (q, J = 7.37 Hz, 2Н), 3.76 (s, 2Н), 1.25 (t, J = 7.37 Hz, 3Н); 13C NMR (75
MHz, CDCl3): δ 169.1 (CО), 149.2 (C), 141.7 (C), 134.6 (C), 134.3 (C), 133.4 (CH), 131.7 (C),
129.7 (CH), 127.2 (CН), 118.2 (СH), 116.7 (C), 112.7 (СH), 61.5 (CН2), 31.3 (CH2), 14.1
(CH3); IR (KBr) 2981 (w), 1734 (s), 1545 (s), 1476 (s), 1366 (s), 1189 (s), 1100 (s), 826 (s), 763
(s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C15H13Cl2N2O2S 355.0069; Found
355.0078.
Ethyl [6-(4-chlorophenyl)-2-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]acetate (4ab). Yield 55%
(38 mg, batch procedure), yellow solid, mp 125ꢀ127 °C; Rf = 0.32 (petroleum ether ꢀ EtOAc,
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4:1). H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 8.24 Hz, 2Н), 7.38 (d, J = 8.24 Hz, 2Н), 4.20
(q, J = 7.32 Hz, 2Н), 4.03 (s, 2Н), 3.02 (q, J = 7.33 Hz, 2Н), 1.41 (t, J = 7.32 Hz, 3H), 1.24 (t, J
= 7.33 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 169.3 (CО), 153.9 (C), 142.5 (C), 133.2 (C),
132.9 (C), 128.7 (2×CH), 128.4 (2×CН), 116.3 (С), 106.7 (С), 61.4 (CН2), 30.7 (CH2), 25.7
(СН2), 14.1 (CH3), 13.1 (СН3); IR (KBr) (w), 2936 (w), 1738 (s), 1493 (s), 1253 (w), 1191 (w),
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836 (w)сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C16H17ClN3O2S+ 350.0725; Found
350.0719.
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Ethyl [6-(4-chlorophenyl)-2-isopropylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]acetate (4ac). Yield
41% (30 mg, batch procedure), yellow solid, mp 137ꢀ138 °C; Rf = 0.32 (petroleum ether ꢀ
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EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ 7.65 (d, J = 8.20 Hz, 2Н), 7.40 (d, J = 8.20 Hz,
2Н), 4.22 (q, J = 7.24 Hz, 2Н), 4.06 (s, 2Н), 3.29ꢀ3.38 (m,1H), 1.46 (s, 3H), 1.44 (s, 3H), 1.25
(t, J = 7.24 Hz, 3Н); 13C NMR (75 MHz, CDCl3): δ 170.9 (CO), 169.4 (C), 144.0 (C), 142.4 (C),
133.3 (C), 133.0 (C), 128.8 (2×CH), 128.5 (2×CН), 116.3 (СH), 61.5 (CН2), 32.5 (CH), 30.8
(CH2), 22.3 (2×СН3), 14.2 (CH3); IR (film) 3436 (w), 2977 (s), 1738 (s), 1493 (s), 1192 (s),
1092 (s), `1029 (s), 836 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C17H19ClN3O2S+ 364.0881; Found 364.0871.
Ethyl
[6-(4-chlorophenyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]acetate
(4ad). Yield 35% (26 mg, batch procedure), yellow solid, mp 109ꢀ112 °C; Rf = 0.20 (petroleum
ether ꢀ EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ 7.65 (d, J = 8.75 Hz, 2Н), 7.41 (d, J = 8.75
Hz, 2Н), 4.75 (s, 2H), 4.22 (q, J = 7.28 Hz, 2Н), 4.06 (s, 2Н), 3.51 (s, 3H), 1.27 (t, J = 7.28 Hz,
3Н); 13C NMR (75 MHz, CDCl3): δ 169.1 (CO), 162.8 (C), 144.4 (C), 142.8 (C), 133.5 (C),
132.8 (C), 128.8 (2×CH), 128.6 (2×CН), 116.4 (C), 69.4 (CН2), 61.6 (CН2), 59.2 (CH3), 30.6
(CH2), 14.1 (CH3); IR (film) 2982 (s), 1731 (s), 1492 (s), 1190 (s), 1095 (s), 1032 (s), 835 (s)
723 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C16H17ClN3O3S+ 368.0645; Found
368.0644.
Ethyl [6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4ae). Yield 59% (177 mg,
continuous flow procedure, residence time 3.6 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 60ꢀ61 °C; Rf = 0.56 (hexane ꢀ EtOAc, 1:1). H NMR (600 MHz, CDCl3): δ
7.64 (d, J = 7.95 Hz, 2Н), 7.51 (d, J = 4.41 Hz, 1Н), 7.27 (d, J = 7.95 Hz, 2Н), 6.83 (d, J = 4.41
Hz, 1Н), 4.23 (q, J = 7.09 Hz, 2Н), 3.93 (s, 2Н), 2.41 (s, 3H), 1.30 (t, J = 7.09 Hz, 3Н); 13C
NMR (150 MHz, CDCl3): δ 168.9 (CО), 148.4 (C), 144.9 (C), 136.6 (C), 130.7 (C), 128.7
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(2×CH), 127.1 (2×CH), 117.3 (СH), 113.5 (C), 111.5 (СH), 60.9 (CН2), 31.0 (CH2), 20.6 (CH3),
13.5 (CH3); IR (KBr) 3445 (w), 2979 (s), 2917 (s), 1737 (s), 1548 (s), 1465 (s), 1375 (s), 1320
(s), 1179 (s), 1157 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C16H17N2O2S+
301.1005; Found 301.1007.
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Ethyl [6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4af). Yield 54% (179 mg,
continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 159ꢀ160 °C; Rf = 0.58 (hexane ꢀ EtOAc, 1:2). H NMR (600 MHz, CDCl3): δ
8.31 (d, J = 8.92 Hz, 2Н), 7.96 (d, J = 8.92 Hz, 2Н), 7.57 (d, J = 4.52 Hz, 1Н), 6.95 (d, J = 4.52
Hz, 1Н), 4.26 (q, J = 7.22 Hz, 2Н), 3.98 (s, 2Н), 1.32 (t, J = 7.22 Hz, 3Н); 13C NMR (150 MHz,
CDCl3): δ 168.8 (CО), 149.9 (C), 146.8 (C), 143.1 (C), 140.8 (C), 128.0 (2×CH), 124.0 (2×CH),
117.8 (СH), 116.3 (C), 113.6 (СH), 62.0 (CН2), 31.8 (CH2), 14.2 (CH3); IR (KBr) 3434 (w),
3118 (s), 1727 (s), 1598 (s), 1507 (s), 1468 (s), 1338 (s), 1314 (s), 1239 (s), 1086 (s), 852 (s)
сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C15H14N3O4S+ 332.0700; Found 332.0705.
Methyl (2-phenylimidazo[2,1-b][1,3]benzothiazol-3-yl)acetate (4ag). Yield 70% (222 mg,
continuous flow procedure, residence time 3.5 h, flow rate 0.85 mL minꢀ1, CuI/SiO2 1:1
o
mixture), yellow solid, mp 82ꢀ83 °C (mplit 75ꢀ76 C37 for 7b*H2O); Rf = 0.43 (hexane ꢀ EtOAc,
2:1). 1H NMR (600 MHz, CDCl3): δ 7.78 (d, J = 8.12 Hz, 1Н), 7.73ꢀ7.75 (m, 3Н), 7.44ꢀ7.50 (m,
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3Н), 7.35ꢀ7.40 (m, 2Н), 4.25 (s, 2Н), 3.82 (s, 3Н); C NMR (150 MHz, CDCl3): δ 170.4 (CО),
147.6 (C), 146.1 (C), 133.9 (C), 133.1 (С), 130.5 (C), 128.7 (2×CH), 128.0 (2×CH), 127.8 (CH),
126.2 (CH) 124.6 (CH), 124.5 (CH), 116.7 (C), 112.9 (CН), 52.8 (CН2), 31.6 (CH3); IR (KBr)
3436 (w), 2954 (s), 1728 (s), 1498 (s), 1216 (s), 1156 (s), 738 (s), 701 (s) сmꢀ1; HRMS (ESI/Qꢀ
TOF) m/z: [M + H]+ Calcd for C18H15N2O2S+ 323.0849; Found 323.0845.
Methyl [2-(4-methoxyphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4ah). Yield 77%
(271 mg, continuous flow procedure, residence time 4.1 h, flow rate 0.55 mL minꢀ1, CuI/SiO2 1:1
mixture), yellow solid, mp 134ꢀ136 °C (mplit 130ꢀ131 oC37); Rf = 0.49 (hexane ꢀ EtOAc, 1:1). 1H
NMR (600 MHz, CDCl3): δ 7.77 (d, J = 8.11 Hz, 1Н), 7.72 (d, J = 7.33 Hz, 1Н), 7.68 (d, J =
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8.70 Hz, 2H), 7.44 (dd, J = 7.33, 8.11 Hz, 1Н), 7.34 (dd, J = 7.33, 8.11 Hz, 1Н), 7.02 (d, , J =
8.70 Hz, 2H), 4.21 (s, 2Н), 3.87 (s, 3Н), 3.81 (s, 3Н); 13C NMR (150 MHz, CDCl3): δ 170.5
(CО), 159.3 (C), 147.4 (C), 146.0 (C), 133.2 (C), 130.4 (C), 129.3 (2×CH), 126.5 (C), 126.1
(CH), 124.5 (CH), 124.4 (CH), 116.0 (C), 114.1 (2×CH), 112.7 (CH), 55.3 (ОCH3), 52.8 (CH3),
31.6 (CH2); IR (KBr) 3401 (w), 2951 (s), 1732 (s), 1510 (s), 1490 (s), 1252 (s), 1176 (s), 1028
(s), 833 (s), 745 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C19H17N2O3S+
353.0954; Found 353.0938.
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Methyl [2-(2-methoxyphenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4ai). Yield 63%
(222 mg, continuous flow procedure, residence time 4.1 h, flow rate 0.55 mL minꢀ1, CuI/SiO2
1:1 mixture), yellow solid, mp 78ꢀ79 °C; Rf = 0.44 (hexane ꢀ EtOAc, 1:1). 1H NMR (600 MHz,
CDCl3): δ 7.73 (dd, J = 0.91, 8.01 Hz, 1Н), 7.64 (dd, J = 1.77, 7.56 Hz, 1Н), 7.61 (dd, J = 1.15,
8.04 Hz, 1H), 7.42 (ddd, J = 0.91, 7.81, 8.04 Hz, 1Н), 7.38 (ddd, J = 1.77, 7.44, 8.35 Hz, 1H),
7.34 (ddd, J = 1.15, 7.81, 8.01 Hz, 1H), 7.09 (ddd, J = 0.80, 7.44, 7.56 Hz, 1Н), 7.02 (dd, J =
0.80, 8.35 Hz, 1H), 4.07 (s, 2Н), 3.80 (s, 3Н), 3.77 (s, 3H); 13C NMR (150 MHz, CDCl3): δ
170.7 (CО), 156.4 (C), 147.4 (C), 142.3 (C), 133.2 (C), 131.9 (CH), 130.5 (C), 129.5 (СH),
126.0 (CH), 124.4 (CH), 124.3 (CH), 122.9 (C), 121.0 (CH), 118.6 (C), 112.8 (CH), 111.2
(CH), 55.6 (CH3), 52.4 (CH3), 31.7 (CH2); IR (KBr) 3401 (w), 2950 (s), 1735 (s), 1499 (s), 1483
(s), 1246 (s), 1164 (s), 1020 (s), 750 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C19H17N2O3S+ 353.0954; Found 353.0943.
Methyl [2-(2,4-dichlorophenyl)imidazo[2,1-b][1,3]benzothiazol-3-yl]acetate (4aj). Yield 93%
(359 mg, continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ
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100ꢁm), yellow solid, mp 154ꢀ155 °C; Rf = 0.41 (hexane ꢀ EtOAc, 2:1). H NMR (600 MHz,
CDCl3): δ 7.75 (d, J = 8.07 Hz, 1Н), 7.68 (d, J = 8.43 Hz, 1Н), 7.55 (d, J = 1.83 Hz, 1Н), 7.50
(d, J = 8.43 Hz, 1Н), 7.46 (dd, J = 7.33, 8.43 Hz, 1Н), 7.38 (dd, J = 7.33, 8.43 Hz, 1Н), 7.36
(dd, J = 1.83, 8.07 Hz, 1Н), 4.04 (s, 2Н), 3.74 (s, 3Н); 13C NMR (150 MHz, CDCl3): δ 169.9
(CО), 147.7 (C), 142.5 (C), 134.9 (C), 134.6 (C), 133.4 (CН), 133.0 (С), 131.3 (C), 130.5 (C),
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129.7 (CH), 127.2 (CН), 126.2 (CH), 124.8 (CH), 124.5 (СН), 118.7 (С), 112.9 (СН), 52.6
(CН3), 31.3 (CH2); IR (KBr) 3434 (w), 2948 (s), 1721 (s), 1493 (s), 1210 (s), 819 (s), 749 (s)
сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C18H13Cl2N2O2S+ 391.0069; Found
391.0061.
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Methyl [6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4ak). Yield 69% (198 mg,
continuous flow procedure, residence time 3.6 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
yellow solid, mp 67ꢀ69 °C; Rf = 0.52 (hexane ꢀ EtOAc, 1:1). 1H NMR (600 MHz, CDCl3): δ 7.62
(d, J = 7.44 Hz, 2Н), 7.52 (d, J = 4.32 Hz, 1Н), 7.28 (d, J = 7.44 Hz, 2Н), 6.87 (d, J = 4.32 Hz,
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1Н), 3.96 (s, 2Н), 3.78 (s, 3Н), 2.41 (s, 3H); C NMR (150 MHz, CDCl3): δ 170.0 (CО), 149.1
(C), 143.7 (C), 137.4 (C), 131.2 (C), 129.4 (2×CH), 127.7 (2×CH), 117.9 (СH), 114.0 (C), 112.4
(СH), 52.6 (CН3), 31.3 (CH2), 21.3 (CH3); IR (KBr) 3401 (w), 2952 (s), 2925 (s), 1721 (s), 1686
(s), 1636 (s), 1373 (s), 1305 (s), 1165 (s), 804 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+
Calcd for C15H15N2O2S+ 287.0849; Found 287.0848.
Methyl [6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4al). Yield 56% (178 mg,
continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 194ꢀ195 °C; Rf = 0.54 (hexane ꢀ EtOAc, 1:2). H NMR (600 MHz, CDCl3): δ
8.35 (d, J = 8.73 Hz, 2Н), 7.97 (d, J = 8.73 Hz, 2Н), 7.64 (d, J = 4.51 Hz, 1Н), 7.08 (d, J = 4.51
Hz, 1Н), 4.03 (s, 2Н), 3.83 (s, 3Н); 13C NMR (150 MHz, CDCl3): δ 168.9 (CО), 149.6 (C),
147.2 (C), 141.5 (C), 139.0 (C), 128.3 (2×CH), 124.2 (2×CH), 118.1 (СH), 116.3 (CH), 114.8
(С), 53.0 (CН2), 31.4 (CH3); IR (KBr) 3438 (w), 3114 (s), 1729 (s), 1600 (s), 1507 (s), 1467 (s),
1342 (s), 1225 (s), 1202 (s), 1088 (s), 996 (s), 860 (s), 852 (s), 725 (s), 667 (s) сmꢀ1; HRMS
(ESI/QꢀTOF) m/z: [M + H]+ Calcd for C14H12N3O4S+ 318.0543; Found 318.0539.
Methyl [6-(3-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4am). Yield 60% (190 mg,
continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 102ꢀ103 °C; Rf = 0.55 (hexane ꢀ EtOAc, 1:2). H NMR (600 MHz, CDCl3): δ
8.64 (dd, J = 1.84 Hz, 1Н), 8.19 (ddd, J = 1.84, 2.27, 8.08 Hz, 1Н), 8.11 (ddd, J = 1.84, 2.27,
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The Journal of Organic Chemistry
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8.08 Hz, 1Н), 7.63 (dd, J = 8.08 Hz, 1H), 7.57 (d, J = 4.52 Hz, 1Н), 6.96 (d, J = 4.52 Hz, 1H),
3.99 (s, 2Н), 3.82 (s, 3Н); 13C NMR (150 MHz, CDCl3): δ 169.3 (CО), 149.6 (C), 148.6 (C),
142.8 (C), 135.7 (C), 133.5 (CH), 129.7 (CH), 122.5 (CН), 122.2 (CH), 117.9 (СH), 115.4 (C),
113.6 (СH), 52.8 (CН3), 31.3 (CH2); IR (KBr) 3435 (w), 3119 (s), 1733 (s), 1526 (s), 1467 (s),
1349 (s), 1251 (s), 698 (s), 661(s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for
C14H12N3O4S+ 318.0543; Found 318.0534.
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Methyl [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4an). Yield 66% (202 mg,
continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 123ꢀ124 °C; Rf = 0.68 (hexane ꢀ EtOAc, 1:3). H NMR (600 MHz, CDCl3): δ
7.68 (d, J = 8.78 Hz, 2Н), 7.53 (d, J = 4.53 Hz, 1Н), 7.43 (d, J = 8.78 Hz, 2Н), 6.89 (d, J = 4.53
Hz, 1Н), 3.94 (s, 2Н), 3.79 (s, 3Н); 13C NMR (150 MHz, CDCl3): δ 169.7 (CО), 149.3 (C),
144.4 (C), 133.5 (C), 132.6 (C), 129.0 (2×CH), 128.7 (2×CН), 117.9 (СH), 114.4 (C), 112.8
(СH), 52.7 (CН2), 31.4 (CH3); IR (KBr) 3451 (w), 3114 (s), 2955 (s), 1735 (s), 1488 (s), 1465
(s), 1221 (s), 1201 (s), 1130 (s), 1091 (s), 716 (s), 663 (s) сmꢀ1; HRMS (ESI/QꢀTOF) m/z: [M +
H]+ Calcd for C14H12ClN2O2S+ 307.0303; Found 307.0296.
Methyl [6-(2,4-dichlorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4ao). Yield 88% (299
mg, continuous flow procedure, residence time 3.3 h, flow rate 1.0 mL minꢀ1, CuI, 10ꢀ100ꢁm),
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yellow solid, mp 142ꢀ143 °C; Rf = 0.51 (hexane ꢀ EtOAc, 1:1). H NMR (600 MHz, CDCl3): δ
7.52 (d, J = 2.20 Hz, 1H), 7.50 (d, J = 4.52 Hz, 1H) 7.48 (d, J = 8.07 Hz, 1Н), 7.34 (dd, J =
2.20, 8.07 Hz, 1H), 6.91 (d, J = 4.52 Hz, 1H), 3.79 (s, 2Н), 3.73 (s, 3Н); 13C NMR (150 MHz,
CDCl3): δ 169.6 (CО), 149.3 (C), 141.9 (C), 134.7 (C), 134.3 (C), 133.4 (CH), 131.6 (C), 129.7
(CH), 127.2 (CН), 118.1 (СH), 116.4 (C), 112.7 (СH), 52.4 (CН3), 31.0 (CH2); IR (KBr) 3449
(w), 3113 (s), 1736 (s), 1549 (s), 1477 (s), 1324 (s), 1204 (s), 824 (s), 762 (s), 654 (s) сmꢀ1;
HRMS (ESI/QꢀTOF) m/z: [M + H]+ Calcd for C14H11Cl2N2O2S+ 340.9913; Found 340.9902.
Methyl [6-(2,4-dimethoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetate (4ap). Yield 27% (90
o
mg, continuous flow procedure, residence time 4.8 h, flow rate 0.55 mL minꢀ1, 80 atm, 140 C,
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