Modular synthesis of thiazoline and thiazole derivatives by using a cascade protocol

Article abstract of DOI:10.1039/c7ra05993k

Thiazolines and thiazoles are an integral part of numerous natural products, a number of drugs, and many useful molecules such as ligands for metal catalysis. We report the first common synthetic protocol for the synthesis of thiazoles and thiazolines. Novel molecules are efficiently synthesized by using readily available and inexpensive substrates. The reaction conditions are mild and pure products are obtained without work-up and column purification.

Full text of DOI:10.1039/c7ra05993k

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Modular synthesis of thiazoline and thiazole
derivatives by using a cascade protocol†
Cite this: RSC Adv., 2017, 7, 32647
*
Zakeyah A. Alsharif and Mohammad A. Alam
Thiazolines and thiazoles are an integral part of numerous natural products, a number of drugs, and many
useful molecules such as ligands for metal catalysis. We report the first common synthetic protocol for the
synthesis of thiazoles and thiazolines. Novel molecules are efficiently synthesized by using readily available
and inexpensive substrates. The reaction conditions are mild and pure products are obtained without work-
up and column purification.
Received 29th May 2017
Accepted 21st June 2017
DOI: 10.1039/c7ra05993k
rsc.li/rsc-advances
(2,3-dichloro-5,6-dicyanobenzoquinone) to form thiazoles (entry
C).9 In a continuation of our efforts to get novel small molecule
heterocycles10,11 by using domino protocol,12 we report the
synthesis of thiazoline and thiazole derivatives using a domino
protocol, mild reaction conditions, and readily available
substrates (Scheme 1).
HFIP is one of the uorinated solvents with unique proper-
ties such as high hydrogen bonding donor ability, low nucleo-
philicity, high ionizing power, and the ability to solvate water.
HFIP is used to promote a wide range of reactions and this
promoter and solvent helps to avoid metal catalyst and added
reagents. HFIP mediated products are easily isolated in high
yield. HFIP is an environmentally benign solvent as it can be
recovered and recycled and also most of the reactions do not
need work-up and tidy purication.13 Due to unique properties
and environmentally benign nature, HFIP has been used as
solvent and promoter for a wide range of reactions.14–16 We have
found HFIP as the best solvent and promoter for the synthesis
of pyridopyrimidinones.12 Keeping in mind the benign nature of
Introduction
Dihydro-1,3-thiazole (thiazoline) and thiazole derivatives are
known as drugs, natural products, and pharmacologically active
synthetic molecules.1 Some of the approved drugs are dasatinib
(anticancer), ritonavir (anti-HIV), nizatidine (anti-ulcer), and
fentiazac (anti-inammatory), among several medicines.2
Natural products containing both or one of the thiazoline and
thiazole moieties include apratoxins, rey luciferin, dolastatin
E, mirabazole, tantazoles, piscibactin, etc. These molecules
show a wide range of biological activities such as anticancer,
antimicrobial, antimalarial, anti-tuberculosis, neurotoxic, and
many other useful properties.3 A large number of synthetic
derivatives have been reported for their wide pharmacological
applications.3,4 Thiazoline derivatives also received recent
attention in organic synthesis and asymmetric catalysis as
ligands.5 Thiazole based efficient solar cells, organic semi-
conductors and electronics have also been receiving attention
in recent years.6,7
Results and discussion
Because of the great value of thiazoline and thiazole derivatives,
several groups have reported the synthesis of thiazolines over the
past few decades, but the methods are limited to the condensa-
tion reaction of cysteamine and cysteine with carboxylic acids
and its derivatives (entry A).8 Thiazoles are mostly synthesized by
the condensation of a-haloketones with thioamides, the
Hantzsch thiazole synthesis (entry B).2 Recently, Li et al. have
reported the synthesis of thiazolines by reacting alkenes with
bromine followed by the reaction of thioamides in a one pot
reaction. Thiazoline derivative has also been oxidized with DDQ
Department of Chemistry and Physics, College of Science and Mathematics, Arkansas
State University, Jonesboro, AR 72467, USA. E-mail: malam@astate.edu; Tel:
+1-870-973-3319
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra05993k
Scheme 1 Synthesis of thiazoline and thiazole derivatives.
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Table
1 Reaction of N-phenylthiourea with methyl 4-
bromocrotonatea
S. no.
Solvent
Yield (%)
1
2
3
4
5
6
7
8
HFIP
90
74
50
55
60
50
65
55
60
48
40
NR
NR
NR
NR
NR
64
2,2,2-Triuroethanol
CH2Cl2
CHCl3
CH3OH
CH3CH2OH
Isopropanol
1-Propanol
2-Butanol
CH3CN
THF
Acetone
DMF
DMSO
9
10
11
12
13
14
15
16
17
Scheme 2 Synthesis of thiourea-derived thiazolines.
H2O
Neat
The encouraging outcome of the reaction prompted us to use
other thiourea derivatives to synthesize a library of novel
molecules (Scheme 2). The nature of the N-substituent of thio-
urea did not alter the outcome of the reactions. Electron
donating, such as methyl and methoxy groups on the phenyl
ring gave clean products (2, 3, & 4) in an average of 92% yield.
Moderately electron withdrawing groups such as halogens gave
the products (5, 6, & 7) without affecting the yield. Other elec-
tron withdrawing substances like triuoromethyl and carbox-
ylic acid gave the products (8, 9, & 10) in excellent yield (ꢁ90%).
The reaction of benzyl thiourea with the electrophile formed the
product (11) in quantitative yield. Allyl thiourea and thiourea
produced corresponding thiazolines (12 & 13 (ref. 17)) in 78%
and 69% yields respectively.
HFIP : MeOH (1 : 1)
a
Reaction conditions: substrate (1.0 mmol), Michael acceptor (1.1
mmol), sodium acetate (1.1 mmol), and HFIP solvent (5 mL).
HFIP, this solvent has been used as a promoter and the reaction
medium for this domino reaction. In this methodology, work-
up and column purication are not required. Pure products
are obtained by ltration followed by recrystallization with ethyl
acetate or ether. HFIP (bp ¼ 58.2 ꢀC) is easily recovered by
distillation and recycled.
Based on our experience with HFIP,12 we tried the reaction of
phenyl thiourea with ethyl 4-bromocrotonate (E1) to synthesize
thiazoline. The product formation was promising and we ob-
tained a clean product in 90% yield (entry 1, Table 1). The same
reaction in 2,2,2-triuroethanol (TFE) gave the product in 74%
yield (entry 2). We tried the reaction with other common labo-
ratory solvents. Halogenated solvents; dichloromethane and
chloroform (entries 3 and 4), produced thiazoline derivative (1)
in almost 50% yield. The reaction in polar protic solvents;
methanol, ethanol, isopropanol, 1-propanol, and 2-butanol
(entries 5–9) also gave the product in modest yield. The polar
aprotic solvents such as acetonitrile and tetrahydrofuran
(entries 10 and 11) afforded the compound (1) in less than 50%
yield but the reaction in acetone (entry 12) gave unidentiable
products. The reaction in DMSO, DMF, or water failed to give
any product. A solvent mixture of HFIP and methanol (1 : 1) is
also effective to get the product in 64% yield. One equivalent
CH3CO2Na and 8 hours reuxing are required for the complete
product formation. Progress of the reaction was monitored by
thin layer chromatography (TLC). The pure product (1) is iso-
lated by ltration to get rid of the salt followed by recrystalli-
zation with methyl tert-butyl ether. The reaction in multigram
scale also afforded the product (1) formation without affecting
the purity and yield.
Encouraged by the reaction of thiourea derivatives, we tried
the reaction with thiobenzamides, and found the product
Scheme 3 Synthesis of thiazole derivatives.
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Scheme 5 Synthesis of thiazole derivative.
Fig. 1 Representative example of 2,4-disubstituted thiazoline and
thiazole derivatives.
products (18, 19, & 20) in good yield. The reaction of the elec-
trophile with triuoromethyl thiobenzamide afforded the
product (21) in quantitative yield. 2-Pyridinethioamide reacted
with the electrophile under the standard reaction condition to
give the product (22) in quantitative yield. Methyl substituted
thiazoline (23) was also obtained in very good yield by reacting
thioacetamide with the electrophile (E1). Thus, this method-
ology is equally applicable to heterocyclic and alkyl based thi-
oamide substrates (Scheme 3).
To extend the scope of the protocol, we tried the reaction
with thiosemicarbazones (Scheme 4). Molecules of this class are
known to show useful pharmacological properties.20,21 Benzal-
dehyde derived thiosemicarbazone reacted smoothly to give the
product (24) in 90% yield. Irrespective of the nature of the
substituents on the phenyl ring, products were formed in good
to excellent yield. Hydroxy derivative afforded the product (25)
formation in excellent yields (Scheme 3). Electron donating
such as methoxy and hydroxy groups gave the products (14, 15,
& 16) in ꢁ80% yield. In this series of molecules, formation of 2-
hydroxyphenyl thiazoline derivative (15) is very signicant. This
moiety is found in a large number of naturally occurring side-
rophores such as piscibactin (Fig. 1). Siderophores are very
important molecules because of their antibacterial activities.18
This compound19 could be a potential antibacterial agent and
this methodology could be used to synthesize a number new
thiazoline based siderophores. p-Tolyl derivative were formed
the product (17) in quantitative yield and the product was ob-
tained by ltration followed by evaporation of the solvent.
Halogenated substrates like uoro, and chloro gave the
Scheme 4 Synthesis of thiosemicarbazone derived thiazolines.
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Scheme 6 Plausible mechanism for the formation of thiazoline and thiazole derivatives.
in 80% yield. Pyrazole and amine substituted products (26 & 27) bonding hexauoroisopropanol as a solvent. Ease of synthesis
were formed in 79% and 60% yield respectively. Fluoro and and scalability to multigram scale have been the strength of the
chloro derivatives gave thiazolines (28, 29, & 30) in ꢁ78% yield. developed methodology. It gives immense scope to generate
Disubstituted halogen substrates formed expected products (31 a library of new molecules required for drug discovery and
& 32). Nitro substituted thiazolines (33 & 34) were formed in an biological study. Synthesis and biological studies of more
average of 83% yield. Indole derived thiosemicarbazide reacted thiazoline and thiazole derivatives, particularly thiazoline-
smoothly to give the product (35). Ketone derived thio- androstane will be reported in due course.
semicarbazones reacted to afford expected thiazolines (36 & 37)
in good yield. Naphthalene substituted thiazolines were formed
(38 & 39) in an average of 69% yield (Scheme 4).
Conflict of interest
Reaction of thiourea derivatives with a slightly modied
electrophile, 4-bromo-3-ethoxycrotonate electrophile (E2)
afforded thiazole derivatives (40 & 41) in excellent yield. Reac-
tion of thiobenzamide derivatives gave the products (42 & 43) in
quantitative yield. Thus, application of this methodology is
equally applicable to synthesize thiazole derivatives (Scheme 5).
Based on the product outcome, solvent effect, and the role of
base, we propose following mechanism for this methodology
(Scheme 6). The reaction starts with SN2 substitution of
bromine of crotonate derivative (E1 or E2) by the thioamide
derivative. The resultant iminium bromide (A) reacts with the
base (CH3CO2Na) to form imine derivative (B), which undergoes
intramolecular Michael addition to form the thiazoline skeleton
(C). Strong hydrogen bonding of HFIP with the carbonyl carbon
of the Michael acceptor (B) facilitates the intramolecular
Michael addition to form the thiazoline derived enol (C). The
fate of this thiazole derivative (C) depends on the substituent
(R0). For R ¼ H, it undergoes keto–enol tautomerism to form
thiazoline and for R ¼ OEt, it undergoes elimination to form exo
ylideneacetate derivative (D). [1,3]-Hydrogen shi12 of ylide-
neacetate (D) leads to the formation of thiazole derivative
(Scheme 6).
The authors declare no conict of interest.
Acknowledgements
This work was supported by the College of Science and Math-
ematics, Arkansas State University, Jonesboro, Arkansas State-
wide MS facility, Grant Number P30 GM103450 from the
National Institute of General Medical Sciences of the National
Institutes of Health (NIH) for recording mass spectra, the
Arkansas INBRE program, supported by grant funding from the
National Institutes of Health (NIH) National Institute of General
Medical Sciences (NIGMS) (P20 GM103429) and Arkansas
Biosciences Institute-Arkansas State University (ABI-A-state,
Grant no. 200127). Zakeyah Ali Alsharif is thankful to the
Saudi Arabian Cultural Mission (SACM) for giving scholarship
for her master's program.
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