Easy access to thiazolines and thiazines via tandem S-alkylation- cyclodeamination of thioamides/haloamines

Article abstract of DOI:10.1039/c1gc15285h

This is the first report of a facile synthesis of thiazolines and thiazines from a self-catalyzed, water assisted tandem S-alkylation-cyclodeamination reaction of thioamides/haloamines. The reaction is clean and efficient with simple product work-up, and is applicable to a variety of substrates.

Full text of DOI:10.1039/c1gc15285h

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COMMUNICATION
Easy access to thiazolines and thiazines via tandem
S-alkylation-cyclodeamination of thioamides/haloamines†
Uma Pathak,* Shubhankar Bhattacharyya, Vishwanath Dhruwansh, Lokesh Kumar Pandey, Rekha Tank and
Malladi V. S. Suryanarayana
Received 16th March 2011, Accepted 4th May 2011
DOI: 10.1039/c1gc15285h
This is the first report of a facile synthesis of thia-
zolines and thiazines from a self-catalyzed, water as-
sisted tandem S-alkylation-cyclodeamination reaction of
thioamides/haloamines. The reaction is clean and efficient
with simple product work-up, and is applicable to a variety
of substrates.
accessible in a great variety. To explore the possibility of thiazo-
line formation from thioamides and haloamines, we attempted
the reaction in various solvents by reacting equimolar amounts
of 2-bromoethylamine hydrobromide salt, thiobenzamide and
triethylamine. Triethylamine was added to make the amine
free. As expected, 2-Phenyl-4, 5-dihydro-[1, 3]-thiazole, was
formed along with benzonitrile, benzamide, polymeric amine
and unreacted thiobenzamide. The reaction profile (Scheme 1)
suggested that, since in the first step (i.e. S-alkylation) the amine
moiety is not involved, formation of 1 was also feasible with
protonated 2-bromoethylamine. Hence, to further improve the
reaction, we attempted it without triethylamine. In solvents like
chloroform, ethyl acetate, toluene, benzene, and tetrahydrofuran
no reaction occurred, mainly due to the insolubility of the salt
in these solvents. In polar solvents like acetonitrile, ethanol and
methanol though, the reactants were soluble but, even after
allowing the reaction for long time at reflux, significant product
formation was not achieved. In methanol, a somewhat better
conversion into the desired product (10%) was obtained. A more
polar solvent than methanol that we could envisage was water.
Thiazolines and thiazines are of considerable interest because of
their biological and industrial importance.1 They exhibit a wide
range of pharmacological activities such as antidiabetic, an-
ticancer, anti-HIV, antitumor, antidepressive, bioluminescence
etc.1–6 Several methods exist for the preparation of thiazolines
and thiazines.7 Current methods of their synthesis rely on con-
densation of b-amino thiols8 or b-amino alcohols9 with nitriles,
carboxylic acids and esters.10–11 In the case of amino alcohols, for
introducing sulfur a sulfurating agent has to be used. The other
exploitable synthetic procedures are the cyclisation of N-(w-
hydroxy) thioamides12,13 and acylamino thiols,14 and thionation
of oxazolines.15 Despite these procedures, there continues to be a
demand for improved methods for their preparation in terms of
mild reaction conditions, cleaner reactions, and simple isolation
of the product.
Thioamides are well known to react with alkyl halides to yield
imidothiolic ester via S-alkylation. Considering this reaction we
reasoned that the reaction of 2-halo-ethylamine with primary
thioamides may result in the formation of thiazolines via S-
alkylation, and subsequent cyclodeamination of S-alkylated
product. Nevertheless, due to the potential side reactions
such as transamidation, and self-condensation of susceptible
haloamines; this is not generally considered a very favorable
route for the preparation of thiazoline, hence it has never been
extensively explored.
Scheme 1
The use of water as a medium for organic synthesis is one of
the latest challenges in organic synthesis. Water is non-toxic,
safe and cost effective. In view of the potential advantages
of replacing organic solvents with water, many reactions are
being discovered that can be accomplished in water and the
progress here has been dramatic.16 Additionally, water facilitates
ion separation through solvation which often results in altered
behavior of reactants in an aqueous environment. There is no
report available for the preparation of thiazolines in water hence,
considering all these points we were curious to know whether
this reaction would occur in water.
Haloamines are commercially available or alternatively can
also be prepared conveniently from amino alcohols which are
Synthetic Chemistry Division, Defence R & D Establishment, Jhansi
Road, Gwalior-474002 (M. P.), India. E-mail: sc_drde@rediffmail.com;
Fax: +91 751 2341148; Tel: +91 751 2231921
† Electronic supplementary information (ESI) available: General de-
tails, experimental procedures, characterisation data, and copies of
1H, 13C NMR and mass spectra for selected compounds. See DOI:
10.1039/c1gc15285h
To investigate a water compatible thioamide-haloamine reac-
tion we conducted the reaction in water. Howver, when water
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Table 1 Formation of thiazolines and thiazines from thioamides and haloamines
Entry no.
1.
Thioamide
Amine·HBr/HCl
Producta
Yield (%)b
91
Time
3 h
mp (◦C)
Oil17a
2.
3.
4.
5.
6.
7.
8.
90
79
83
89
87
90
96
2.5 h
5 h
44–4517a
Oil17a
3 h
41–4217a
43–4417b
90–9217c
198–19917c
135–13717b
2 h
2.5 h
2.5 h
4 h
9.
87
86
25 min
30 min
150–15217b
71–7217d
10.
11.
12.
13.
14.
15.
81
86
92
91
88
2 h
Oil
2 h
oil
15 min
2 h
111–11317b
Oil
2.5 h
80–8217e
a All the products gave satisfactory spectral data. b Yield refers to isolated products.
was used as the solvent thiobenzamide remained insoluble, and
after a prolonged reaction it converted to benzamide with a
modest formation of thiazoline. Previously, while working with
haloamines we had noticed that hydrated salts of these amines
behave very similar to ionic liquids in terms of their solubilizing
capability. Hence, the reaction was investigated once again by
taking a very limited amount of water.
For this, 2-bromoethylamine hydrobromide was dissolved in
a small quantity of water (40–50 ml per mmol) at 60–70 ◦C
and thiobenzamide was added to it. After few minutes the
reaction mixture become homogeneous which was then allowed
to progress at the same temperature and monitored by TLC
and GC-MS. We expected that initially we may get 3, and with
the help of a base, 3 could be cyclised to 5 (Scheme 2). But,
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Conclusions
In conclusion, the first water assisted green synthesis of thiazo-
lines and thiazines from thioamides and w-haloamines has been
reported. A clean and efficient reaction, simple isolation of the
product and wide application to a variety of substrates renders
this method practical.
Experimental
Typical experimental procedure for 2-phenyl-4,5-dihydro-[1,3]-
thiazole: 250 ml of water was added to 2-bromoethyamine
hydrobromide salt (5.5 mmol) and mixed thoroughly. To this
thiobenzamide (5 mmol) was added and the reaction mixture
Scheme 2
◦
was heated at 60–70 C for three hours. Contents were cooled
and neutralized with cold 5% sodium carbonate solution. Yellow
oil gets separated which was extracted with ethyl acetate.18 Sol-
vent removal under vacuum yielded 2-phenyl-4,5-dihydro-[1,3]-
thiazole as a yellow oil. If required the compound can be further
purified by column chromatography. Data for 1; 2-Phenyl-4,5-
dihydro-[1,3]-thiazole: Yellow oil, 1H NMR (400 MHz, CDCl3):
d 7.9-7.8 (m, 2H), 7.4-7.3 (m, 3H), 4.45 (t, 2H, J = 8.4 Hz), 3.40
(t, 2H, J = 8.0 Hz); 13C NMR (100.6 MHz, CDCl3) d 167.69,
132.87, 130.68, 128.06, 127.97, 64.85, 33.82; EIMS: m/z 163
[M+], 117, 104, 77, 60.
analysis of the reaction after two hours revealed unexpectedly,
to our delight, a direct formation of 2-phenyl-[1,3]-thiazoline
5. When the same reaction was carried out with free amino
halide only a 40% conversion into the desired product was
observed.
The formation of 5 from thioamides and protonated amino-
halide in the presence of water was rationalized as follows: first
an imidothiolinium species 3 is formed via S-alkylation. Imine
nitrogen of imidothiolic ester being mildly basic is not able to
hold the proton strongly in the presence of water and undergoes
reversible protonation. The free iminium nitrogen is attacking
the electrophilic carbon attached to the ammonium ion, leading
to clean formation of thiazoline 5. Additionally, the presence
of water is also suppressing the dehydration of thioamide.
Further, employment of protonated aminohalide is inhibiting
the undesired side reactions such as transamidation and self-
condensation leaving S-alkylation and subsequent cyclisation
the only available reaction path way.
Acknowledgements
We thank Mr Avik Mazumder, Ajeet Kumar and Mr Ajay
Pratap for NMR analysis. We also thank Dr R. Vijayaraghavan
Director, DRDE for his keen interest and encouragement. Dr
Rekha Tank gives thanks to CSIR, New Delhi for providing a
Research Associate Fellowship.
With a suitable reaction system in hand, we then set to examine
the scope of this transformation. Our results are compiled in
Table 1. Diverse thioamides bearing different functional groups
were reacted with bromoethylamine and bromopropylamine.
The reaction of bromopropylamine with thioamides yielded
2-substituted thiazines in a similar fashion. To study the S-
alkylation with halides in water; simple alkyl halides such as
butyl iodide, butyl bromide and butyl chloride were treated
with thiobenzamide. The order of reaction was found to be
I = Br > Cl. When 2-chloroethylamine was reacted with
thiobenzamide, as per our anticipation a slow reaction occurred
and formation of corresponding nitrile and amide was also
noticed.
Thionicotinamide reacted◦with bromoethyl amine at a slightly
higher temperature 95–100 C under almost solventless condi-
tions (experimental procedure 2, ESI†). Although the desired re-
action occurred at higher temperature, it took a shorter reaction
time (15 min) to reach completion (entry 12). Thioamides having
electron withdrawing groups and sterically hindered thioamides
exhibited a similar tendency (entry 9, 10). With aliphatic and
unsubstituted or electronically rich thioamides, application of
higher temperature led to significant dehydration of thioamides
producing nitrile as a side product. Reaction of thiourea with
2-bromoethylamine hydrobromide resulted in the formation of
2-amino thiazoline (entry 15).
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