A straightforward metal-free synthesis of 2-substituted thiazolines in air

Article abstract of DOI:10.1039/c5gc00286a

A base-catalysed procedure for the synthesis of 2-substituted thiazolines from nitriles and cysteamine hydrochloride under solvent-free conditions is presented. This straightforward approach allows high conversion for a broad range of nitriles and an easy

Full text of DOI:10.1039/c5gc00286a

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A straightforward metal-free synthesis of
2-substituted thiazolines in air†
Cite this: DOI: 10.1039/c5gc00286a
Michael Trose, Faïma Lazreg, Mathieu Lesieur and Catherine S. J. Cazin*
Received 6th February 2015,
Accepted 30th March 2015
A base-catalysed procedure for the synthesis of 2-substituted thiazolines from nitriles and cysteamine
hydrochloride under solvent-free conditions is presented. This straightforward approach allows high con-
version for a broad range of nitriles and an easy isolation of the desired products.
DOI: 10.1039/c5gc00286a
www.rsc.org/greenchem
2-Substituted thiazolines are important heterocyclic com-
pounds present in a great number of natural products used in
the food and pharmaceutical industries.1 Currently, thiazoline-
based compounds are used as antibiotics,2 anticarcinogens,3
anti-inflammatories4 and antithrombotics.5 Similarly to oxazo-
lines, thiazolines are well-known ligands in metal-catalysed
transformations, such as hydrosilylation,6 allylic substitution,7
Diels–Alder reaction,8 cyclopropanation,9 Henry reaction10 and
C–P bond11 formation. Considering their broad applicability,
finding a straightforward and inexpensive methodology to syn-
thesise these compounds could be of great interest to the
general synthetic community. During the last decades, several
procedures leading to this end have been reported. These can
be divided into two different approaches: cyclodehydration of
thioamides12 and condensation of carbonyl compounds13
namely, N-acylbenzotriazoles14 and nitriles with aminothiols.
Among these possibilities, nitriles are inexpensive and readily
available reagents, which explain their wider use as starting
materials for this reaction. Different methodologies for the
preparation of thiazolines have been reported to date and
these are summarised in Scheme 1. The common approach
requires an electrophile to activate the nitrile 1 towards the
nucleophilic attack of cysteamine 2. Procedures involving
proton donor polyoxometallates, such as tungstophosphoric
acid (TPA),15 have also been developed, but rather harsh con-
ditions were required in such protocols, i.e. high temperature
(110 °C). Heterogeneous catalysts (for example, Dowex-50
W-hydrogen ion exchange resins)16 are also able to promote
the reaction. Unfortunately, under these conditions, the scope
remains narrow and only para-substituted benzonitriles can be
used. Other types of electrophiles are used to activate nitriles
such as tribromomelamine (TBM) which is able to generate
Br+ in situ.17 However, a prior preparation of TBM is required
Scheme 1 Synthesis of 2-substituted thiazolines.
using this approach. This involves bromination of the corres-
ponding melamine in the presence of excess NaOH.
Metal catalysis has also been considered for this transform-
ation. In 2012, Li and co-workers developed a methodology
using a catalytic amount of a CuI2IL4 (L = methacrylate)
complex and cysteamine hydrochloride 3 instead of its neutral
analogue 2.18 Unfortunately, a fairly high catalyst loading
(8 mol%) and an excess of base (2 equiv. of NaOAc) were
required, as well as the need for independent preparation of
the CuI2IL4 catalyst.
In addition, an important drawback to all the aforemen-
tioned procedures exists in the purification step. Indeed, puri-
fication by column chromatography is necessary in order to
obtain pure product. Despite the existence of these procedures
(and maybe because of their existence), a more general and
straightforward approach towards the synthesis of thiazolines
4 is highly desirable. Well-defined copper N-heterocyclic
carbene (NHC) complexes are well-known to be active catalysts
in a plethora of reactions such as click-chemistry,19 the boryl-
ation of alkynes,20 the synthesis of phenols21 and many
others.22 While testing two of our well-defined copper
N-heterocyclic carbene complexes23,24 in this transformation,
using benzonitrile 1a and cysteamine hydrochloride 3 as
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST,
UK. E-mail: cc111@st-andrews.ac.uk; Fax: +44 (0)1334463808
†Electronic supplementary information (ESI) available: Optimisation details and
full characterisation data. See DOI: 10.1039/c5gc00286a
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Table 1 Optimisation of the reaction conditions for the synthesis of
2-phenyl-4,5-dihydrothiazolea
Entry
Base
Loading (mol%)
Time (h)
Conversionb (%)
1
2
3
CsOH
KOH
NaOH
NaOH
NaOH
NaOH
10
10
10
5
20
20
16
16
16
16
2
>99
>99
>99
4
91
5c
6c
>99 (98)d
94
1
a Reaction conditions: 1a (0.5 mmol), 3 (1 mmol), base (5–20 mol%),
80 °C, 16 h. b Determined by GC, based on benzonitrile. c 0.75 mmol of
3. d Isolated yield.
model substrates, we found that the base alone is capable of
promoting this reaction (Table 1).25 All bases tested gave excel-
lent results (Table 1). Amongst these, NaOH was selected for
further investigation as it is inexpensive. When the amount of
NaOH is decrease to 5 mol% (Table 1, entry 4), a slight decrease
in conversion is observed (91%). Finally, the time parameter
and the amount of 3 were investigated. After 2 hours and using
only 0.75 mmol of 3, quantitative conversion was observed
using 20 mol% of NaOH (Table 1, entry 5). When the time is
further decreased to 1 hour (Table 1, entry 6), a modest decrease
in conversion is detected (94%). In order to eliminate the possi-
bility of metal contaminants in the NaOH actually catalysing
the reaction, a test using semiconductor grade NaOH was per-
formed. Gratifyingly, full conversion was obtained reinforcing
the role of NaOH as the sole promoter of the reaction (see ESI†).
With the optimised conditions in hand, the scope of the reac-
tion was investigated on a range of nitrile derivatives (Fig. 1).
For all substrates, the reaction proceeds with quantitative conver-
sion and excellent isolated yield. Both electron withdrawing
(EWG) and electron donating (EDG) groups are tolerated.
However, an effect of the nature of the substitution was
observed on the reaction time. In the case of para-substituted
benzonitriles bearing EWG (4b–4d), the reaction proceeds with a
shorter reaction time compared to substrates bearing EDG
(4e–4g). Regarding the position on the aryl ring, as expected,
ortho-substituted benzonitriles (4l–4n) reacts more slowly than
the corresponding meta- (4h–4j) and para-substituted (4b–4d)
derivatives. When the steric hindrance is higher, as for 2,6-di-
methylbenzonitrile, no conversion was observed. The synthesis
of benzyl thiazolines has been achieved in excellent yields (4o–
4q). As previously noted, the substitution does not affect the con-
version but only the reaction time, with ortho-substituted benzyl
nitriles reacting more slowly than 2-phenylacetonitrile and the
para-substituted analogue. Heteroaromatic nitriles show great
reactivity, reaching full conversion to the desired product after
15 minutes! The outcome of the reaction is independent of the
size of the ring, the position and the nature of the heteroatom,
making this a general procedure leading to polyheterocyclic
compounds (4r–4v). Interestingly, a simple extraction using
Fig. 1 Formation of 2-substituted thiazolines from nitriles and cyste-
amine hydrochloride. Reaction conditions: 1 (1 mmol), 3 (1.5 mmol),
NaOH (0.2 mmol), 80 °C, solvent-free. a Isolated yield. b 3 (3 mmol).
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water and ethyl acetate was sufficient to purify and remove
excess of 3, eliminating any need for column chromatography.
When aliphatic nitriles are used, moderate to good yields are
obtained (4w–4y).
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In order to control the progress of the reaction and to ident-
ify intermediates, in situ IR measurements were performed,
using a ReactIR system (see ESI†). However, no signals of a
possible stable intermediate were identified. It is possible that
the base initiates the HCl scavenging process, liberating the
cysteamine that acts as a nucleophile towards the nitrile. As
the reaction goes on, the generated ammonia becomes the
HCl scavenger forming NH4Cl and closing the catalytic cycle.
Unfortunately, the synthesis of oxazolines was not possible
under these conditions. However, efforts to investigate the
mechanism and possibly expand the scope to these interesting
structures are the subject of future studies.
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Conclusions
In conclusion, a straightforward procedure for the conversion
of nitriles and cysteamine hydrochloride to 2-substituted thi-
azolines is reported. The reaction is promoted by a catalytic
amount of NaOH under solvent-free conditions. A broad
variety of aromatic, benzyl, heteroaryl and aliphatic nitriles
can be converted into the desired product. This simple syn-
thetic protocol is rendered even more attractive as product iso-
lation can be performed using a simple extraction technique.
14 A. R. Katritzky, C. Cai, K. Suzuki and S. K. Singh, J. Org.
Chem., 2004, 69, 811.
Experimental
General procedure for the preparation of 2-substituted
15 (a)
I.
Mohammadpoor-Baltork,
M.
Moghadam,
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thiazolines
In air, a vial was charged with the nitrile (1 mmol), cysteamine
hydrochloride (1.5 mmol) and NaOH (0.2 mmol). The reaction
was stirred at 80 °C for the appropriate time. The crude product
was dissolved in ethyl acetate (2 mL) and water (10 mL) was
added. The aqueous layer was then extracted with ethyl acetate
(3 × 10 mL). The combined organic layers were dried over MgSO4,
filtered and dried under vacuum to yield the desired product.
16 A. Bazgir, M. M. Amini and Y. Fazaeli, Open Catal. J., 2009,
2, 163.
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Acknowledgements
The authors are grateful to the Royal Society (University
Research Fellowship to CSJC) for financial support. We also
thank the EPSRC National Mass Spectrometry Service Centre
in Swansea for High Resolution Mass Spectrometry.
23 O. Santoro, A. Collado, A. M. Z. Slawin, S. P. Nolan and
C. S. J. Cazin, Chem. Commun., 2013, 49, 10483.
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Notes and references
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109, 1371.
25 A precedent using a weak base (e.g., NaOAc) has been
reported, although a very low yield was obtained (15%); for
more details, see ref. 18.
2 R. J. Boyce, G. C. Mulqueen and G. Pattenden, Tetrahedron,
1995, 51, 7321.
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