Single-Pot Preparation of 4-Amino-2-(het)aryl-5-Substituted Thiazoles Employing Functionalized Dithioesters as Thiocarbonyl Precursors

Article abstract of DOI:10.1021/acs.joc.1c00616

An effective, diversity oriented, one-pot reaction of 4-amino-2-(het)aryl/alkyl-5-functionalized thiazoles has been disclosed, utilizing aryl/heteroaryl/alkyl dithioesters as thiocarbonyl coupling partners in a modified Thorpe-Ziegler type cyclization. The reaction proceeds at room temperature, under mild conditions, in excellent yields, displaying broad functional group compatibility at 2 and 5 positions of thiazoles. This synthetic strategy has been further expanded for the one-pot construction of two highly potent tubulin polymerization inhibitors, i.e., 2-(het)aryl-4-amino-5-(3,4,5-trimethoxyaroyl) thiazoles, in high yields.

Full text of DOI:10.1021/acs.joc.1c00616

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Single-Pot Preparation of 4‑Amino-2-(het)aryl-5-Substituted
Thiazoles Employing Functionalized Dithioesters as Thiocarbonyl
Precursors
Anusha Avadhani,† Pethaperumal Iniyavan,† Yogendra Kumar, and Hiriyakkanavar Ila*
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ABSTRACT: An effective, diversity oriented, one-pot reaction of 4-amino-
2-(het)aryl/alkyl-5-functionalized thiazoles has been disclosed, utilizing
aryl/heteroaryl/alkyl dithioesters as thiocarbonyl coupling partners in a
modified Thorpe−Ziegler type cyclization. The reaction proceeds at room
temperature, under mild conditions, in excellent yields, displaying broad
functional group compatibility at 2 and 5 positions of thiazoles. This
synthetic strategy has been further expanded for the one-pot construction of
two highly potent tubulin polymerization inhibitors, i.e., 2-(het)aryl-4-
amino-5-(3,4,5-trimethoxyaroyl) thiazoles, in high yields.
he thiazole heterocyclic core is present in several
biologically active microbial and marine natural products,
acyclic precursors.1,2 The latter route is found to be more
versatile in terms of efficiency and for diversity generation in
functionalized thiazoles. Among this group, one of the most
prominent methods for the construction of 2,4,5-trisubstituted
thiazoles is classical Hantzsch synthesis, involving condensa-
tion of an α-haloketone or its variants with thioamide.1,9,10 The
other promising method for thiazole synthesis is based on
thionation followed by ring-closure of α-acyl aminoketones
and precursors with numerous thionating agents such as P2S5,
Lawesson’s, or Belleau’s reagent (Gabriel synthesis).11,12
Another attractive method of synthesizing substituted
thiazoles includes base mediated intramolecular Thorpe−
Ziegler type cyclization of N-cyanodi/thioimidate intermedi-
ates, such as A−C, which provides a useful synthesis of 4-
amino-2,5-substituted thiazoles (Scheme 1).13−16 The inter-
mediates A and B are generated in situ via reaction of
cyanamide with either CS2 or aryl isothiocyanate,13a,16b
respectively, in the presence of base, followed by successive
alkylation with one equivalent of MeI (for A) and activated
methylene halides, furnishing directly the 2-(methylthio)/
arylamino-4-amino-5-substituted thiazoles (Scheme 1, eq
1).13−16 Kirsch and co-workers have developed an alternate,
one-pot three component sequential procedure for 2-(N-
secondary amino)-4-amino-5-substituted thiazoles via stable
dimethyl N-cyanodithioimidocarbonate precursor D,14a,b via
displacement of one of the (methylthio) groups by secondary
T
and also in synthetic compounds’1,2 displaying broad range of
biological activity.3 Thus, several substituted thiazoles exhibit
biological activities such as anti-inflammatory, antibacterial,
antiviral, antifungal, anticancer, tubulin polymerization inhib-
itor, CDK inhibitor, and Src/AB1 inhibitor such as Dasatinib
(Figure 1),3 besides acting as peptidomimetics and enzyme
Figure 1. Biologically important multifunctionalized thiazoles.
inhibitors.4 Due to the presence of synthetic thiazoles in
various marketed drugs, this core occupies an important place
in the drug discovery process.3,5 Thiazole derivatives have also
found applications in material science,6a as liquid crystals for
ferroelectric displays,6b and as cosmetic sunscreens.6c As a
consequence, considering the structural heterogeneity of
complex naturally occurring thiazoles, as well as the biological
activity of synthetic analogues, new versatile protocols
continue to appear in the literature for the synthesis of
multifunctionalized thiazoles.1,2,7,8
Received: March 15, 2021
Published: June 10, 2021
Synthetic approaches for substituted thiazoles can be
classified in two groups, i.e., derivatization of preconstructed
heterocyclic core1,2,8 and construction of thiazole ring from
https://doi.org/10.1021/acs.joc.1c00616
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continuation of these research works, we additionally thought
of employing these (het)aryl/alkyldithioesters 1 as thiocar-
bonyl coupling partners in a modified Thorpe−Ziegler
synthesis for developing an effective one-pot construction of
4-amino-2-(het)aryl/alkyl-5-functionalized thiazoles, which
could be subsequently elaborated into thiazolo-fused nitrogen
heterocycles.23 We have successfully realized this target and
presented in this manuscript a concise one-pot, three step,
diversity oriented construction of a series of 2-substituted-4-
amino-5-functionalized thiazoles 3 (Scheme 3).
Scheme 1. Synthesis of 4-Amino-2,5-Substituted Thiazoles
via Intramolecular Thorpe−Ziegler Reaction
Scheme 3. One-Pot Three Step Construction of 2-
Substituted-4-Amino-5-Functionalized Thiazoles
amine, followed by sequential in situ treatment with sodium
sulfide and excess of activated methylene halides (Scheme 1,
eq 2). These methods appear to be useful for the synthesis of
4-amino-2,5-substituted thiazoles with various functionalities at
5-position such as ester, nitrile, and carbonyl substituents;
however, substituent diversity at 2-position is limited only to 2-
(methylthio)- or arylamino functionalities.17
Since the past few years, we have been exploring newly
designed organosulfur intermediates18−21 which are readily
obtained by the condensation of the appropriate active
methylene derivatives with functionalized dithioesters in the
presence of base, followed by alkylation of the generated
enethiolate intermediates. By utilizing these precursors, we
have developed new synthetic routes for a variety of (het)aryl/
alkylsubstituted, sulfur containing, as well as sulfur-free five
membered heterocycles,20,20a such as pyrazoles, isoxazoles,
oxazoles, imidazoles, thiophenes,20a thiazoles,2 and the
corresponding benzo/heterofused analogues, i.e., indoles,19c,d
benzothiophenes,19b,e,21 and benzofurans.19f These methods
provide alternate way for regiospecific introduction of (het)aryl
groups in various heterocycles from built-in precursors by
utilizing (het)aryl/alkyldithioesters, instead of transition metal
catalyzed coupling reactions.8 Although the synthesis of
various (het)aryl/alkyldithioesters has been previously de-
scribed in the literature,22 their potential synthetic applications
as thiocarbonyl coupling partners for the synthesis of various
(het)aryl/alkyl substituted heterocycles had not been explored
until we undertook their systemic investigation.
During the course of above studies, we have recently
reported an efficient one-pot Thorpe−Ziegler type construc-
tion of 2-(het)aryl-3-substituted-4-amino/hydroxythiophenes
with several reactive functionalities at 5 positions, by
condensation of various arylacetonitriles (or arylacetates)
with broad range of (het)aryldithioesters as thiocarbonyl
precursors and activated methylene halides in the presence of a
base. These 4-amino(hydroxy)-5-functionalized thiophenes
were subsequently transformed into thieno-fused 5- or 6-
membered nitrogen/oxygen heterocycles either in a one-pot
protocol or in a two-step procedure (Scheme 2).21 As a
The dithioester 1a and bromoacetonitrile 2a were selected
as representative substrates, to study their reaction with
cyanamide, in the presence of several bases/solvents, with a
goal to optimize reaction conditions, to develop one-pot
strategy for the construction of thiazole 3a, without isolation of
N-cyanothioimidate salt 4a (Table 1). Thus, the reaction of
cyanamide with dithioester 1a using excess of NaH (4 equiv),
followed by addition of bromoacetonitrile 2a afforded the
thiazole 3a in only 53% yield along with other side products
(entry 1). However, a dramatic increase in the yield of 3a was
noticed when NaH was added sequentially; i.e., cyanamide was
Table 1. Reaction Condition Optimization for the One-Pot
a
Synthesis of Thiazole 3a
a
entry
base
solvent temperature (°C) time (h) yield (%), 3a
b
1
NaH
NaH
NaH
NaH
K2CO3
K2CO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
EtOH
EtOH
MeOH
MeOH
DMF
DMF
rt
rt
rt
90
rt
70
rt
60
80
rt
65
rt
3
3
6
53
76
55
62
0
68
0
52
20
0
c
2
d
3
4
5
6
7
8
9
e
2
f
24
12
12
12
12
12
12
24
12
f
f
f
Et3N
f
KOH
Me0Na
Me0Na
tBuOK
tBuOK
f
10
11
12
f
30
45
70
f
f
13
90
Scheme 2. Synthesis of 2,3,5-Substituted-4-Amino/Hydroxy
Thiophenes and Thieno-Fused Heterocycles
a
Reaction conditions: 1a (1 mmol), cyanamide (1 mmol), and 2a
b
(1.2 mmol). Reaction was performed with 4 equiv of NaH in the first
step. NaH (2 equiv) and cyanamide (1 equiv) were stirred in DMF
c
for 10 min, followed by addition of 1a (1 mmol) and further stirring
for 3 h, and subsequent addition of 2a (1.2 mmol); after additional 1
d
h stirring, NaH (2 equiv) was added. 2 equiv of NaH was used.
e
Reaction was conducted by sequentially adding 2 equiv of NaH and
f
heating at 90 °C (oil bath). All reactions were conducted by
sequentially adding 2 equiv of base.
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initially reacted with dithioester 1a in the presence of 2 equiv
of NaH, later addition of bromoacetonitrile 2a, and subsequent
addition of 2 equiv of NaH (entry 2). Reducing the amount of
NaH resulted in a decreased yield of thiazole 3a (entry 3).
Similarly, at higher temperature, a lower yield of 3a was
obtained (entry 4). On the other hand, no reaction was
observed when weaker bases like K2CO3 or Et3N were
employed at rt (entries 5, 7), whereas at higher temperature,
moderate yields of 3a were obtained (entries 6, 8). Similar
behavior was also observed with bases like KOH or NaOMe in
solvents like EtOH or MeOH, respectively, yielding thiazole 3a
in low yields at higher temperature (Table 1 entries 9−11).
However, a good yield of 3a was obtained with tBuOK as base,
although at higher temperature after prolonged heating (oil
bath) (entries 12−13). We therefore employed NaH as base
for optimal reaction conditions, by its sequential addition in
two lots at rt in DMF as solvent for our further studies (Table
1, entry 2).
Scheme 4. Construction of 2-Arylated/4-Amino-5-
Substituted Thiazoles 3
a
After establishing the favorable reaction parameters for one-
pot construction of thiazole 3a, we next examined the scope
and generality of this protocol, and the results are displayed in
Scheme 4. Various (het)aryl/alkyldithioesters 1 and activated
methylene halides 2 selected for this study are shown in Chart
1. Thus, both aryl- (1a) and (het)aryldithioesters with 2-
thienyl- (1h), 2-(N-methylpyrrolyl)- (1k), and 3-(1-N-
methyl)indolyl- (1m) moieties reacted smoothly with
cyanamide and bromoacetonitrile 2a in sequential manner, to
afford the corresponding 2-(het)aryl-4-amino-5-cyanothiazoles
3a−d in excellent yields (Scheme 4). The reaction was next
extended to phenacyl bromide 2b and its dimethoxy-variant 2c
for the construction of 2-(het)aryl-4-amino-5-aroylthiazoles
3e−j (Scheme 4). Thus, the thioimidate salts obtained from
cyanamide and aryldithioesters 1a, 1f and (het)aryldithioesters
1l,m reacted smoothly with phenacyl bromides 2b,c affording
the related thiazole 3e−i in high yields. Interestingly, when the
4-fluorophenyl dithioester 1c was employed in the reaction
with phenacyl bromide 2c, product thiazole was characterized
as 2-[(4-methylthio)phenyl]-4-amino-3-arylthiazoles 3j, in
which the 4-fluoro group was replaced by methylthio group
(eliminated during the reaction) via SNAr process (Scheme 4)
and no trace of the corresponding 2-(4-fluoro)phenylthiazole
3j′ could be isolated from the reaction mixture.
a
Reaction conditions: H2N-CN (1 mmol), NaH (2 mmol), 1 (1
mmol) in DMF (2−3 mL) stirring for 3 h at rt, followed by addition
of DMF (1 mL) solution of 2 (1.2 mmol), and addition of NaH (2
b
mmol) and further stirring for 4 h Stirred for 12 h. Yield of isolated
products.
Chart 1. (Het)aryl/Alkyldithioesters 1 and Activated
Methylene Halides 2 Employed for the Synthesis of
Functionalized Thiazoles 3, 5
Further diversity in terms of various functionalities at 2- and
5-position of thiazoles 3 was achieved by using activated
methylene halides like chloroacetone 2e and ethyl bromoace-
tate 2f, which on reaction with cyanamide and the
corresponding dithioesters furnished the respective 4-amino-
5-acetyl- (3k−m) and 4-amino thiazole-5-carboxylates 3n−p
in high yields. The scope of the reaction was further widened
by the synthesis of 2-(n-butyl)-thiazole-4-carboxylates 3q with
a 2-alkyl side chain in a moderate yield. Similarly, by utilizing
bromonitromethane 2g as active methylene halide coupling
partners and (het)aryldithioesters 1a, 1e, 1h,i, as thiocarbonyl
components, it was possible to synthesize novel 2-(het)aryl-5-
nitro 4-aminothiazoles 3r−u in excellent yields, thus adding
further diversity at the 5-position of thiazoles 3 (Scheme 4).
The thiazole 3t was found to be highly fluorescent. We further
extended the reaction for the preparation of 2-(het)aryl-4-
aminothiazole-5-carboxamides 3v−w by reacting the corre-
sponding thioimidate salts 4 with bromoacetamide 2h;
however, the reaction requires longer time (24 h) for
completion yielding the products 3v−w in good yields.
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Finally, we could also synthesize 2-substituted 4-amino-
thiazole-5-acrylates 3x−z, with extended conjugation, in good
yields, by reaction of few dithioesters 1a, 1g, 1k with ethyl
bromocrotonate 2i under identical conditions (Scheme 4).
To further demonstrate the versatility of this newly
developed methodology, we also synthesized 4-amino-2-
phenyl- and 2-(thiophen-3-yl)-5-(2,3,4-trimethoxybenzoyl)
thiazoles 5a−b in high yields, which are shown to display
very strong antiproliferative (tubulin polymerization inhib-
itory) activity, comparable to combretastatin,24 through this
one pot protocol, by employing (trimethoxy)phenacyl bromide
2d and phenyl-, 3-thienyl- dithioesters 1b and 1j, respectively,
under optimized conditions (Scheme 5). On the other hand,
EXPERIMENTAL SECTION
■
General Information. All chemicals and solvents were purchased
from commercial sources and used as received unless indicated.
Standard procedures were followed for the drying of solvents. Thin
layer chromatography (TLC) technique was used to monitor all the
reactions employing standard TLC silica gel plates, and visualization
was accomplished using UV light. 100−200 mesh silica gel was used
for the column chromatography purification of compounds. Bruker
(400 MHz) Ultrashield FT-NMR spectrometer was used for
recording the NMR spectra using CDCl3 and DMSO-d6 as solvents.
Chemical shifts (δ) are given in ppm (δ for CDCl3 is 7.26, δ for
1
DMSO-d6 is 2.50 for in H NMR, δ for CDCl3 is 77.16 and δ for
DMSO-d6 39.52 in 13C NMR) with TMS as internal standard. The J
values in Hertz (Hz) refer to the coupling constants. The designation
for the splitting patterns are s for singlet, d for doublet, t for triplet, q
for quartet, quint for quintet, sextet for sextet, dd for doublet of a
doublet, dt for doublet of a triplet, ddd for doublet of doublet of a
doublet, m for multiplet, and br for broad signal. Fourier transform
infrared instrument (Agilent technologies) was utilized for recording
the infrared spectra and HRMS spectra were recorded on a 6538
UHD accurate mass Q-TOF LC/MS spectrometer through ESI
mode. An electrothermal capillary melting point apparatus was used
for recording the melting points and were uncorrected. The
precursors 2a, 2b, 2e−i were purchased from commercial suppliers,
whereas 2c,25 2d26 were synthesized according to the reported
literature procedures. The methyl (het)/aryl/alkyldithioester com-
pounds 1a−o were synthesized according to the reported literature
protocols.20a,22
Scheme 5. Synthesis of Antiproliferative Tubulin
Polymerization Inhibitors 5a,b
General Procedure for the Synthesis of Thiazoles 3a−z,
5a,b. To an ice-cooled stirred suspension of NaH (60% suspension in
mineral oil) (67 mg, 2.0 mmol, 2.0 equiv) and appropriate dithioester
1 (1.0 mmol, 1.0 equiv) in DMF (2 mL), a solution of cyanamide (42
mg, 1.0 mmol, 1.0 equiv) in DMF (1 mL) was added, under N2
atmosphere. After further stirring at room temperature for 3 h, a
solution of activated methylene halides 2 (1.2 mmol, 1.2 equiv) in
DMF (1 mL) was added to the reaction mixture at 0 °C, along with
addition of another lot of NaH (60% suspension in mineral oil) (67
mg, 2.0 mmol, 2.0 equiv) after 1 h. The stirring was continued for 4 h
at room temperature (monitored by TLC), and the quenching of the
reaction mixture was subsequently carried out with saturated NH4Cl
solution (25 mL). The reaction mixture was extracted with EtOAc (2
× 25 mL) and the collected organic layer was further water (3 × 25
mL) washed and brine (25 mL) washed, and then dried over
anhydrous Na2SO4 and concentrated under a vacuum, and the crude
residue was purified by silica gel chromatography.
previously, these compounds have been obtained in moderate
yields in three steps from cyanamide by first converting it to N-
cyanoimidodithiocarbonate D,15a,b and then successively
reacting it with sodium sulfide, trimethoxyphenacyl bromide
in the presence of K2CO3, furnishing the corresponding 2-
(methylthio)-4-amino-5-(trimethoxybenzoyl)thiazole 6 in 52%
yield (Scheme 5). Subsequent palladium catalyzed, Cu(I)Tc
mediated Liebeskind−Srogl coupling of 2-methylthio- group in
6 with respective arylboronic acids in the presence of TFP
provided 2-phenyl- and 2-(thiophen-3-yl)-4-amino-5-
(trimethoxy)benzoyl thiazoles 5a,b in moderate yields of
52% and 58%, respectively (Scheme 5).24
In summary, an efficient, straightforward, one-pot protocol
for the synthesis of 4-amino-2-(het)aryl-5-substituted thiazoles,
by employing a broad range of (het)aryl/alkyldithioesters as
thiocarbonyl partners and a variety of activated methylene
halides, has been developed. Since some of these thiazoles
display significant biological activity, the present methodology
enables preparation of thiazoles having two points of diversity
and is highly flexible and amenable for the high throughput
chemical synthesis of thiazole based libraries. Further, these 4-
aminothiazoles 3 bearing a range of functionalities at 5-
position serve as potentially valuable precursors for the
construction of thiazolo-fused nitrogen heteroaromatic com-
pounds,23 through subsequent derivatization of these function-
alities, which is presently under progress in our laboratory and
will be published later.
4-Amino-2-(4-methoxyphenyl)thiazole-5-carbonitrile (3a).
Yield 176 mg (76%) from 200 mg (1 mmol) of 1a, 144 mg (1.2
mmol) of 2a; yellow solid; mp 202−204 °C; Rf 0.2 (2:8
1
EtOAc:hexane); IR (neat, cm−1) 3340, 3213, 2195, 1023; H NMR
(400 MHz, DMSO-d6) δ 7.84 (d, J = 8.8 Hz, 2H), 7.25 (brs, 2H),
7.07 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 169.6, 166.2, 162.1, 128.1, 124.4, 114.8, 114.7, 67.7,
55.5; HRMS (ESI) m/z [M + H]+ calcd for C11H10N3OS 232.0545,
found 232.0537.
4-Amino-2-(thiophen-2-yl)thiazole-5-carbonitrile (3b). Yield
155 mg (75%) from 175 mg (1 mmol) of 1h, 144 mg (1.2 mmol) of
2a; yellow solid; mp 200−202 °C; Rf 0.2 (6:4 EtOAc:hexane); IR
1
(neat, cm−1) 3213, 3172, 2925, 2194, 704; H NMR (400 MHz,
DMSO-d6) δ 7.84 (d, J = 4.8 Hz, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.30
(brs, 2H), 7.19 (t, J = 4.4 Hz, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 165.8, 163.4, 135.2, 131.3, 129.2, 128.9, 114.6, 67.9;
HRMS (ESI) m/z [M + H]+ calcd for C8H6N3S2 208.0003, found
207.9983.
4-Amino-2-(1-methyl-1H-pyrrol-2-yl)thiazole-5-carbonitrile
(3c). Yield 140 mg (69%) from 170 mg (1 mmol) of 1k, 144 mg (1.2
mmol) of 2a; yellow solid; mp 210−212 °C; Rf 0.21 (7:3
1
EtOAc:hexane); IR (neat, cm−1) 3390, 3351, 2194; H NMR (400
MHz, CDCl3) δ 6.78 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 4.0, 1.6 Hz,
1H), 6.15 (dd, J = 4.0, 2.4 Hz, 1H), 5.01 (brs, 2H), 3.95 (s, 3H);
13C{1H} NMR (100 MHz,CDCl3) δ 164.6, 163.8, 128.9, 125.5, 115.0,
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114.7, 109.3, 70.7, 37.2; HRMS (ESI) m/z [M + H]+ calcd for
C9H9N4S 205.0548, found 205.0556.
102.2, 56.2, 56.0, 15.0; HRMS (ESI) m/z [M + H]+ calcd for
C19H19N2O3S2387.0837, found 387.0843.
4-Amino-2-(1-methyl-1H-indol-3-yl)thiazole-5-carbonitrile
(3d). Yield 182 mg (72%) from 220 mg (1 mmol) of 1m, 144 mg (1.2
mmol) of 2a; yellow solid; mp 208−210 °C; Rf 0.2 (3:7
1-(4-Amino-2-(3,4-dimethoxyphenyl)thiazol-5-yl)ethanone
(3k). Yield 180 mg (65%) from 230 mg (1 mmol) of 1d,139 mg (1.5
mmol) of 2e; yellow solid; mp 202−204 °C; Rf 0.3 (3:7
1
EtOAc:hexane); IR (neat, cm−1) 3247, 3309, 1634; H NMR (400
1
EtOAc:hexane); IR (neat, cm−1) 3412, 3356, 2197, 1251; H NMR
MHz, DMSO-d6) δ 7.63 (brs, 2H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H),
7.46 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.84 (s, 6H), 2.31
(s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 188.4, 169.3, 163.4,
151.9, 148.9, 124.9, 120.0, 111.9, 108.9, 101.9, 55.7, 55.6, 29.4;
HRMS (ESI) m/z [M + H]+ calcd for C13H15N2O3S 279.0803, found
279.0796.
(400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.33−7.25 (m, 2H), 7.13 (brs, 2H), 3.87 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 165.9, 165.3, 137.1, 132.4,
124.4, 122.9, 121.6, 120.3, 115.5, 110.9, 108.6, 64.5, 33.1; HRMS
(ESI) m/z [M + H]+ calcd for C13H11N4S 255.0704, found 255.0681.
4-Amino-2-(4-methoxyphenyl)thiazol-5-yl)(phenyl)-
methanone (3e). Yield 255 mg (82%) from 200 mg (1 mmol) of 1a,
239 mg (1.2 mmol) of 2b; yellow solid; mp 208−210 °C; Rf 0.25 (4:6
1-(4-Amino-2-(thiophen-2-yl)thiazol-5-yl)ethanone (3l).
Yield 165 mg (74%) from 175 mg (1 mmol) of 1h, 139 mg (1.5
mmol) of 2e; yellow solid; mp 203−205 °C; Rf 0.31 (4:6
1
EtOAc:hexane); IR (neat, cm−1) 3412, 3375, 1594; H NMR (400
1
EtOAc:hexane); IR (neat, cm−1) 3411, 3300, 2924, 1742; H NMR
MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 6.8 Hz, 2H),
7.55−7.47 (m, 3H), 6.95 (d, J = 8.8 Hz, 4H), 3.88 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 187.3, 172.5, 165.5, 162.7, 141.2, 131.4,
128.7, 128.6, 127.7, 125.6, 114.5, 102.4, 55.6; HRMS (ESI) m/z [M +
H]+ calcd for C17H15N2O2S 311.0854, found 311.0851.
(4-Amino-2-(4-(dimethylamino)phenyl)thiazol-5-yl)-
(phenyl)methanone (3f). Yield 277 mg (86%) from 210 mg (1
mmol) of 1f, 239 mg (1.2 mmol) of 2b; yellow solid; mp 215−217
°C; Rf 0.26 (4:6 EtOAc:hexane); IR (neat, cm−1) 3362, 2920, 1604;
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.2 Hz, 2H), 7.83 (d, J =
8.8 Hz, 2H), 7.52−7.46 (m, 3H), 6.97 (brs, 2H), 6.68 (d, J = 8.8 Hz,
2H), 3.06 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.9, 173.7,
165.8, 152.9, 141.5, 131.2, 128.6, 128.5, 127.7, 120.5, 111.6, 101.6,
40.2; HRMS (ESI) m/z [M + H]+ calcd for C18H18N3OS 324.1171,
found 324.1150.
(4-Amino-2-(1-methyl-1H-imidazol-2-yl)thiazol-5-yl)-
(phenyl)methanone (3g). Yield 221 mg (78%) from 172 mg (1
mmol) of 1l, 239 mg (1.2 mmol) of 2b; yellow solid; mp 205−207
°C; Rf 0.23 (4:6 EtOAc:hexane); IR (neat, cm−1) 3241, 3193, 1611,
1324; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.52
(t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.14 (s, 1H), 7.04 (s,
1H), 6.87 (brs, 2H), 4.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 187.8, 165.1, 163.3, 140.8, 139.9, 131.7, 130.2, 128.6, 127.9, 125.6,
102.7, 35.9; HRMS (ESI) m/z [M + H]+ calcd for C14H13N4OS
285.0810, found 285.0782.
(400 MHz, CDCl3) δ 7.59 (s, 1H), 7.49 (s, 1H), 7.10 (s, 1H), 6.67
(brs, 2H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.7,
163.9, 162.9, 136.8, 130.1, 128.5, 128.4, 103.5, 29.5; HRMS (ESI) m/
z [M + H]+ calcd for C9H9N2OS2225.0156, found 225.0147.
1-(4-Amino-2-(1-methyl-1H-pyrrol-2-yl)thiazol-5-yl)-
ethanone (3m). Yield 137 mg (62%) from 170 mg (1 mmol) of 1k,
139 mg (1.5 mmol) of 2e; yellow solid; mp 220−222 °C; Rf 0.2 (3:7
1
EtOAc:hexane); IR (neat, cm−1) 3121, 3072, 1609, 1357; H NMR
(400 MHz, CDCl3) δ 6.83 (dd, J = 4.0, 1.6 Hz, 1H), 6.79 (t, J = 2.2
Hz, 1H), 6.56 (brs, 2H), 6.17 (dd, J = 4.0, 2.8 Hz, 1H), 3.99 (s, 3H),
2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.5, 163.2,
163.1, 128.9, 126.2, 115.1, 109.2, 101.9, 37.3, 29.7; HRMS (ESI) m/z
[M + H]+ calcd for C10H12N3OS 222.0701, found 222.0688.
Ethyl 4-amino-2-(4-methoxyphenyl)thiazole-5-carboxylate
(3n). Yield 181 mg (65%) from 200 mg (1 mmol) of 1a, 334 mg
(2.0 mmol) of 2f; yellow solid; mp 225−227 °C; Rf 0.3 (3:7
1
EtOAc:hexane); IR (neat, cm−1) 3437, 3307, 1669; H NMR (400
MHz, CDCl3) δ 7.87 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H),
5.87 (brs, 2H), 4.32 (q, J = 14.4, 7.2 Hz, 2H), 3.87 (s, 3H), 1.37 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 170.6,
164.5, 162.3, 128.4, 125.9, 123.6, 114.5, 60.6, 55.6, 14.7; HRMS (ESI)
m/z [M + H]+ calcd for C13H15N2O3S 279.0803, found 279.0794.
Ethyl 4-amino-2-(1-methyl-1H-indol-2-yl)thiazole-5-carbox-
ylate (3o). Yield 217 mg (72%) from 220 mg (1 mmol) of 1m, 334
mg (2.0 mmol) of 2f; brown solid; mp 223−225 °C; Rf10.2 (3:7
EtOAc:hexane); IR (neat, cm−1) 3413, 3323, 1652, 1225; H NMR
(400 MHz, CDCl3) δ 8.18 (d, J = 6.8 Hz, 1H), 7.81 (s, 1H), 7.37 (t, J
= 6.0 Hz, 1H), 7.34−7.30 (m, 2H), 5.96 (s, 2H), 4.33 (q, J = 14.2, 7.0
Hz, 2H), 3.85 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.0, 164.7, 163.1, 137.6, 130.8, 125.3, 123.2, 121.9,
120.9, 110.7, 110.2, 60.3, 33.5, 14.8; HRMS (ESI) m/z [M + H]+
calcd for C15H16N3O2S 302.0963, found 302.0959.
(4-Amino-2-(1-methyl-1H-indol-3yl)thiazol-5-yl)(phenyl)-
methanone (3h). Yield 239 mg (72%) from 220 mg (1 mmol) of
1m, 239 mg (1.2 mmol) of 2b; yellow solid; mp 220−222 °C; Rf 0.22
1
(4:6 EtOAc:hexane); IR (neat, cm−1) 3387, 3160, 1718; H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 9.6 Hz,
3H), 7.51−7.45 (m, 3H), 7.33−7.29 (m, 3H), 7.06 (brs, 2H), 3.80 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.7, 168.1,165.5, 141.6,
137.7, 131.6, 131.1, 128.5, 127.7, 125.2, 123.3, 122.1, 121.1, 110.6,
110.3, 100.7, 33.6; HRMS (ESI) m/z [M + H]+ calcd for
C19H16N3OS 334.1014, found 334.1012.
(4-Amino-2-(4-methoxyphenyl)thiazol-5-yl)(3,4-
dimethoxyphenyl)methanone (3i). Yield 303 mg (82%) from 200
mg (1 mmol) of 1a, 311 mg (1.2 mmol) of 2c; yellow solid; mp 251−
253 °C; Rf 0.21 (4:6 EtOAc:hexane); IR (neat, cm−1) 3340, 3213,
2195, 1023; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 9.0, 3.8 Hz,
2H), 7.55 (ddd, J = 8.0, 3.8, 2.0 Hz, 1H), 7.44 (dd, J = 3.6, 2.0 Hz,
1H), 6.99 (brs, 2H), 6.96−6.91 (m, 3H), 3.96 (s, 3H), 3.95 (s, 3H),
3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0, 171.9,
165.4, 162.5, 151.8, 148.9, 133.7, 128.5, 125.5, 121.4, 114.4, 110.9,
110.2, 101.9, 56.0, 55.5; HRMS (ESI) m/z [M + H]+ calcd for
C19H19N2O4S 371.1066, found 371.1062.
(4-Amino-2-(4-methylthio)phenyl))thiazol-5-yl)(3,4-
dimethoxyphenyl)methanone (3j). Yield 289 mg (75%) from 185
mg (1 mmol) of 1c, 311 mg (1.2 mmol) of 2c; yellow solid; mp 212−
214 °C; Rf 0.2 (5:5 EtOAc:hexane); IR (neat, cm−1) 3377, 3262,
1618, 1174; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H),
7.55 (dd, J = 7.8, 1.8 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.27 (d, J =
2.0 Hz, 1H), 7.25 (s, 1H), 6.93 (d, J = 8.4 Hz, 3H), 3.96 (s, 6H), 2.52
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.2, 171.5, 165.3,
151.9, 149.0, 143.9, 133.6, 129.1, 127.0, 125.8, 121.4, 110.9, 110.1,
Ethyl 4-amino-2-(pyridine-3-yl)thiazole-5-carboxylate (3p).
Yield 139 mg (56%) from 170 mg (1 mmol) of 1n, 334 mg (2.0
mmol) of 2f; yellow solid; mp 219−221 °C; Rf 0.2 (3:7
1
EtOAc:hexane); IR (neat, cm−1) 2955, 2924, 1726, 1604; H NMR
(400 MHz, CDCl3) δ 9.16 (d, J = 2.4 Hz, 1H), 8.68 (dd, J = 4.8, 1.6
Hz, 1H), 8.18 (dt, J = 8.0, 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H),
6.01 (s, 2H), 4.32 (q, J = 14.2, 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 164.2, 163.3, 151.8,
147.9, 133.8, 129.1, 123.8, 94.8, 60.8, 14.6; HRMS (ESI) m/z [M +
H]+ calcd for C11H12N3O2S 250.0650, found 250.0647.
Ethyl 4-amino-2-butylthiazole-5-carboxylate (3q). Yield 102
mg (45%) from 150 mg (1 mmol) of 1o, 334 mg (2.0 mmol) of 2f;
white solid; mp 207−209 °C; Rf 0.2 (1:9 EtOAc:hexane); IR (neat,
1
cm−1) 3498, 3212, 1662, 1296; H NMR (400 MHz, CDCl3) δ 5.88
(brs, 2H), 4.26 (q, J = 14.2, 7.0 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H),
1.72 (quint, J = 7.6 Hz, 2H), 1.41 (sextet, J = 7.4 Hz, 2H), 1.32 (t, J =
7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 175.9, 164.3, 162.6, 128.9, 60.4, 33.7, 31.6, 22.2, 14.6, 13.8;
HRMS (ESI) m/z [M + H]+ calcd for C10H17N2O2S 229.1011, found
229.1008.
2-(4-Methoxyphenyl)-5-nitrothiazol-4-amine (3r). Yield 183
mg (73%) from 200 mg (1 mmol) of 1a, 154 mg (1.1 mmol) of 2g;
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Note
orange solid; mp 202−204 °C; Rf10.32 (2:8 EtOAc:hexane); IR (neat,
cm−1) 3356, 3212, 1610, 1018; H NMR (400 MHz, DMSO-d6) δ
9.13 (brs, 1H), 8.29 (brs, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.12 (d, J =
8.8 Hz, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
171.2, 163.4, 158.8, 129.1, 123.9, 116.1, 114.9, 55.7; HRMS (ESI) m/
z [M + Na]+ calcd for C10H9N3NaO3S 274.0262, found 274.0262.
5-Nitro-2-(thiophen-2-yl)thiazol-4-amine (3s). Yield 177 mg
(78%) from 175 mg (1 mmol) of 1h, 154 mg (1.1 mmol) of 2g;
orange solid; mp 243−245 °C; Rf 0.2 (1:9 EtOAc:hexane); IR (neat,
NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 14.8 Hz, 1H), 7.69 (d, J =
8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.84 (brs, 2H), 5.49 (d, J =
14.8 Hz, 1H), 3.65 (s, 3H), 2.50 (s, 4H), 1.58 (s, 6H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 167.6, 167.1, 161.4, 152.8, 135.4, 127.6,
121.3, 114.2, 107.4, 99.4, 50.8, 48.0, 24.9, 23.9; HRMS (ESI) m/z [M
+ H]+ calcd for C18H22N3O2S 344.1433, found 344.1413.
(4-Amino-2-phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)-
methanone (5a). Yield 285 mg (77%) from 168 mg (1 mmol) of 1b,
347 mg (1.2 mmol) of 2d; yellow solid; mp 157−159 °C (reported
156−158 °C);24a Rf 0.2 (6:4 EtOAc:hexane); IR (neat, cm−1) 3482,
1
cm−1) 2916, 2721, 1530; H NMR (400 MHz, DMSO-d6) δ 9.19
1
3401, 2922, 1616; H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.2,
(brs, 1H), 8.26 (brs, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 3.6
Hz, 1H), 7.27 (t, J = 4.2 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 164.9, 158.4, 135.1, 134.1, 131.9, 129.4, 115.8; HRMS (ESI) m/
z [M + H]+ calcd for C7H6N3O2S2 227.9901, found 227.9889.
2-(5-(Dimethylamino)thiophen-2-yl)-5-nitrothiazol-4-amine
(3t). Yield 210 mg (78%) from 215 mg (1 mmol) of 1i, 154 mg (1.1
mmol) of 2g; dark brown solid; mp 202−204 °C; Rf 0.3 (4:6
1.0 Hz, 2H), 7.53−7.44 (m, 3H), 7.13 (s, 2H), 6.99 (brs, 2H), 3.94
(s, 6H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.7,
172.5, 165.5, 153.2, 141.1, 136.2, 132.7, 131.9, 129.2, 126.9, 105.4,
102.7, 61.1, 56.5; HRMS (ESI) m/z [M + H]+ calcd for C19H19N2O4S
371.1066, found 371.1064.
(4-Amino-2-(thiophen-3-yl)thiazol-5-yl)(3,4,5-
trimethoxyphenyl)methanone (5b). Yield 304 mg (81%) from
175 mg (1 mmol) of 1j, 347 mg (1.2 mmol) of 2d; yellow solid; mp
200−202 °C (reported 198−200 °C);24a Rf 0.27 (4:6 EtOAc:hexane);
IR (neat, cm−1) 3313.1, 3270.8, 1620.9, 1132.0; 1H NMR (400 MHz,
CDCl3) δ 7.99 (dd, J = 3.2, 1.2 Hz, 1H), 7.52 (dd, J = 5.2, 1.2 Hz,
1H), 7.40 (dd, J = 5.0, 3.0 Hz, 1H), 7.10 (d, J = 4.0 Hz, 2H), 6.97
(brs, 2H), 3.93 (s, 6H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 186.4, 167.0, 165.3, 153.1, 140.9, 136.1, 134.9, 127.2, 126.6,
126.0, 105.3, 105.2, 101.8, 60.9, 56.3; HRMS (ESI) m/z [M + H]+
calcd for C17H17N2O4S2 377.0630, found 377.0622.
1
EtOAc:hexane); IR (neat, cm−1) 2922.2, 2853.3, 1576.1; H NMR
(400 MHz, DMSO-d6) δ 8.98 (brs, 1H), 8.13 (brs, 1H), 7.78 (d, J =
4.8 Hz, 1H), 6.21 (d, J = 4.4 Hz, 1H), 3.10 (s, 6H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 167.0, 164.3, 159.6, 136.5, 115.6, 105.4,
41.9; HRMS (ESI) m/z [M + Na]+ calcd for C9H10N4NaO2S2
293.0143, found 293.0143.
2-(2-Methoxyphenyl)-5-nitrothiazol-4-amine (3u). Yield 210
mg (70%) from 200 mg (1 mmol) of 1e, 154 mg (1.1 mmol) of 2g;
yellow solid; mp 230−232 °C; Rf 0.32 (4:6 EtOAc:hexane); IR (neat,
1
cm−1) 2922.2, 2853.3, 1576.1; H NMR (400 MHz, DMSO-d6) δ
8.64 (brs, 2H), 8.24 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.6 Hz, 1H), 7.32
(d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 4.08 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 165.1, 158.1, 157.3, 134.3, 128.1,
121.1, 119.5, 118.0, 112.6, 56.3; HRMS (ESI) m/z [M + H]+ calcd
for C10H10N3O3S 252.0443, found 252.0427.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00616.
■
sı
4-Amino-2-phenylthiazole-5-carboxamide (3v). Yield 147 mg
(67%) from 170 mg (1 mmol) of 1b, 166 mg (1.2 mmol) of 2h;
yellow solid; mp 255−257 °C; Rf 0.32 (8:2 EtOAc:hexane); IR (Neat,
Copies of 1H NMR and 13C NMR spectra of compounds
3a−v, 3x−z, and 5a,b (PDF)
1
cm−1) 2922.2, 2853.3, 1576.1; H NMR (400 MHz, DMSO-d6) δ
8.03 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.0 Hz, 1H), 7.57 (t, J = 7.4 Hz,
2H), 7.50 (brs, 4H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 180.9,
155.7, 136.6, 134.0, 131.8, 129.4, 128.3, 127.4; HRMS (ESI) m/z [M
+ H]+ calcd for C10H10N3OS 220.0545, found 220.0540.
AUTHOR INFORMATION
Corresponding Author
■
Hiriyakkanavar Ila − Jawaharlal Nehru Centre for Advanced
Scientific Research, Bangalore 560064, India; orcid.org/
0000-0002-6971-8374; Email: hila@jncasr.ac.in
4-Amino-2-(3,4-dimethoxy phenyl)thiazole-5-carboxamide
(3w). Yield 175 mg (77%) from 228 mg (1 mmol) of 1d, 166 mg (1.2
mmol) of 2h; yellow solid; mp 265−267 °C; Rf 0.32 (9:2
1
Authors
EtOAc:hexane); because of insolubility in most of the solvents H
and 13C{1H} could not be recorded; HRMS (ESI) m/z [M + H]+
calcd for C12H14N3O3S280.0756, found 280.0737.
Anusha Avadhani − Jawaharlal Nehru Centre for Advanced
Scientific Research, Bangalore 560064, India
Pethaperumal Iniyavan − Jawaharlal Nehru Centre for
Advanced Scientific Research, Bangalore 560064, India
Yogendra Kumar − Jawaharlal Nehru Centre for Advanced
Scientific Research, Bangalore 560064, India
(E)-Ethyl 3-(4-amino-2-(4-methoxyphenyl)thiazol-5-yl)-
acrylate (3x). Yield 234 mg (77%) from 200 mg (1 mmol) of 1a,
215 mg (1.2 mmol) of 2i; red solid; mp 234−236 °C; Rf 0.25 (3:7
EtOAc:hexane); IR (neat, cm−1) 2999.5, 2951, 1718.9; 1H NMR
(400 MHz, DMSO-d6) δ 7.99 (d, J = 15.2 Hz, 1H), 7.82 (d, J = 9.2
Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.89 (brs, 2H), 5.57 (d, J = 15.2
Hz, 1H), 3.82 (s, 3H), 3.66 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 167.3, 167.2, 161.9, 161.4, 135.5, 128.2, 125.4, 114.9,
108.9, 100.7, 55.7, 51.2; HRMS (ESI) m/z [M + H]+ calcd for
C14H15N2O3S 291.0803, found 291.0785.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00616
Author Contributions
†A.A. and P.I. contributed equally in this work.
(E)-Ethyl 3-(4-amino-2-(1-methyl-1H-pyrrol-2-yl)thiazol-5-
yl)acrylate (3y). Yield 210 mg (76%) from 170 mg (1 mmol) of
1k, 215 mg (1.2 mmol) of 2i; yellow solid; mp 230−232 °C; Rf 0.31
Notes
The authors declare no competing financial interest.
1
(4:6 EtOAc:hexane); IR (neat, cm−1) 3445, 3146, 1365, 1121; H
ACKNOWLEDGMENTS
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 14.8 Hz, 1H), 6.76−6.74 (m,
2H), 6.16 (dd, J = 3.8, 2.6 Hz, 1H), 5.73 (d, J = 15.2 Hz, 1H), 4.66
(brs, 2H), 3.98 (s, 3H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 168.1, 160.8, 158.2, 133.4, 128.4, 126.4, 114.5, 111.4, 109.1,
102.5, 51.6, 37.2; HRMS (ESI) m/z [M + H]+ calcd for C12H14N3O2S
264.0807, found 264.0805.
■
We acknowledge Professor C. N. R. Rao, FRS, for encourage-
ment and support of our research. We thank JNCASR,
Bangalore for financial assistance (to A.A.), Council of
Scientific and Industrial Research (CSIR, New Delhi) for
CSIR-SRF (Senior research fellowship), CSIR award no 09/
733(0228)/2017/-EMR-I (to Y.K.), Science and Engineering
Research Board (SERB, New Delhi) for National Postdoctoral
fellowship (NPDF) (to P.I.), JNCASR, Bangalore for financial
(E)-Ethyl 3-(4-amino-2-(4-(piperidin-1-yl)phenyl)thiazol-5-
yl)acrylate (3z). Yield 253 mg (71%) from 250 mg (1 mmol) of
1g, 215 mg (1.2 mmol) of 2i; yellow solid; mp 234−236 °C; Rf 0.2
1
(6:4 EtOAc:hexane); IR (neat, cm−1) 3412, 3392, 1705, 1589; H
8513
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J. Org. Chem. 2021, 86, 8508−8515

The Journal of Organic Chemistry
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Note
Heuser, S. Synthesis of 2-(o-hydroxyaryl)-4-arylthiazoles by regiose-
lective Pd(0)-catalyzed cross-coupling. Tetrahedron Lett. 2000, 41,
1707−1710.
assistance, and Hindustan Lever Research Professorship (to
H.I.).
(7) (a) Kikelj, D.; Urleb, U. Product Class 17: Thiazoles. In Science
of Synthesis, Schaumann, E., Ed.; Thieme: Stuttgart, 2002; Vol. 11, p
627−833. (b) Wang, Y.; Liu, X.; Zhu, B.; Guo, P.; Pei, Y.; He, Q.;
Cao, H. Cu(I)-Catalyzed Three-Component Cyclization for the
Construction of Functionalized Thiazoles. J. Org. Chem. 2020, 85,
10118−10124 and references cited therein. (c) Narasimhamurthy, K.
H.; Sajith, A. M.; Joy, M. N.; Rangappa, K. S. An Overview of Recent
Developments in the Synthesis of Substituted Thiazoles. Chemis-
trySelect 2020, 5, 5629−5656 and references cited therein.
(8) (a) Hodgetts, K. J.; Kershaw, M. T. Synthesis of 2-Aryl-
oxazolo[4,5-c]quinoline-4(5H)-ones and 2-Aryl-thiazolo[4,5-c]-
quinoline-4(5H)-ones. Org. Lett. 2003, 5, 2911−2914 and references
therein. (b) Hodgetts, K. J.; Kershaw, M. T. Regiocontrolled
Synthesis of Substituted Thiazoles. Org. Lett. 2002, 4, 1363−1365.
(c) Hammerle, J.; Spina, M.; Schnurch, M.; Mihovilovic, M. D.;
Stanetty, P. A Comparative Study on Stille Cross-Coupling Reactions
of 2-Phenylthiazoles and 2-Phenyloxazoles. Synthesis 2008, 2008,
3099−3107.
DEDICATION
■
This paper is dedicated to Prof. Domenico Spinelli on the
occasion of his 89th birthday.
REFERENCES
■
(1) (a) Metzger, J. V. In Comprehensive Heterocyclic Chemistry;
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