Selective thioacylation of amines in water: A convenient preparation of secondary thioamides and thiazolines

Article abstract of DOI:10.1039/c4ra13097a

Primary thioamides have been utilised directly in water, without any derivatisation, to selectively thioacylate primary amines. By employing 2-hydroxyethylamines, the reaction can be extended to the preparation of 2-thiazolines via formation of β-hydroxythioamides.

Full text of DOI:10.1039/c4ra13097a

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Selective thioacylation of amines in water: a
convenient preparation of secondary thioamides
Cite this: RSC Adv., 2015, 5, 4484
and thiazolines†
Received 24th October 2014
Accepted 5th December 2014
*
Uma Pathak, Shubhankar Bhattacharyya and Sweta Mathur
DOI: 10.1039/c4ra13097a
www.rsc.org/advances
Primary thioamides have been utilised directly in water, without any
derivatisation, to selectively thioacylate primary amines. By employing variety of heterocycles.1a Advantages associated with primary
Primary thioamides are well known synthons to prepare a
2-hydroxyethylamines, the reaction can be extended to the prepara- thioamides are their stability, easy handling and relative ease of
tion of 2-thiazolines via formation of b-hydroxythioamides.
preparation. Primary thioamides contain two nucleophilic
centres i.e. sulfur and nitrogen and an electrophilic carbon
centre (thiocarbonyl). Depending upon the reactant and reac-
tion conditions different compounds have been obtained from
thioamides.1a In general, the reported reaction of primary thi-
oamides exploits either the sulfur or the nitrogen nucleophilic
centre to initiate the reaction while the electrophilic carbon
centre is less commonly exploited. Utilizing the electrophilicity
of thiocarbonyl carbon of primary thioamides, we wished to
explore a direct thioacylation of amines by primary thioamides.
Amine/primary thioamides reaction is generally utilized for
the preparation of amidine which proceeds with elimination of
hydrogen sulde.7,8 Though, this reaction has the potential to
generate secondary thioamides (Scheme 1), but, it has never
been explored extensively though preparation of N-substituted
thioacetamides from thioacetamide and corresponding
aliphatic amines under solventless condition has been
reported.1a,7
Most of the reported thioamide/amine reactions have been
conducted in organic solvents. But, no attempt has been made
so far, to investigate the thioamide/amine reaction in aqueous
medium. Water as a solvent oen modulates behavior of reac-
tants, consequently, leading to either altered reaction products
or enhanced rate or selectivity.9 Additionally, in this particular
reaction water may also assist in suppressing dehydration of
primary thioamides to nitriles, which is a commonly occurring
side product in thioamide/amine reaction. Considering all
these aspects we attempted thioamide/amine reaction in water.
To investigate the feasibility of the concept reaction of
Thioamides and thiazolines are well known organosulfur
compounds with diverse applications.1 Accordingly, various
methods have been reported in the literature for their prepa-
ration. Thiazolines can be prepared by thionation of oxazo-
lines.2 Condensation of b-amino thiols or b-amino alcohols with
nitriles, carboxylic acids and esters are the other common
methods available for preparation of thiazolines.3 Reactions
which employ an amino alcohol as reactant, also require a
sulfurating agent for introducing sulfur in the resultant mole-
cule. Thiazolines can also be accessed through cyclisation of b-
hydroxy thioamides.4 Secondary thioamides are generally
prepared by thionation of their oxy analogues.5 Thioacylation of
amines is another direct route to prepare secondary thioamides
but, this approach is limited by the unstability, corrosiveness
and non availability of the conventional thioacylating reagents
i.e. thioacyl chloride or thionoanhydrides. High reactivity of the
thioacylating agents also renders the acylation non selective in
presence of other susceptible functionalities such as secondary
amine or hydroxyl group, in a multifunctional chemical entity.
Due to huge industrial applications of secondary thioamides
and thiazolines, there continues to be a demand for their
improved methods of preparation in terms of mild reaction
conditions, cleaner reactions, and simple isolation of the
product. In continuation to our studies on thioamides,5c,6
herein, we report a simple preparation secondary thioamides
and thiazolines via a direct chemo selective thioacylation of
primary amines in water.
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 2390189
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra13097a
Scheme 1 Thioacylation of amines.
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butylamine with thiobenzamide was studied. Equimolar reactants having longer carbon chain (entry 9). When dipro-
amount of butylamine and thiobenzamide was reacted at 60– pylamine an open chain secondary amines, was investigated for
70 ꢀC in water. Formation of N-butylthiobenzamide as expected this reaction, no thioacylation was observed. Similar behaviour
was observed but, the reaction was limited by simultaneous was exhibited by aniline an aromatic amine. This fact rendered
formation of benzamide, N-butylbenzamide and benzonitrile. the reaction selective for aliphatic primary amines. To conrm
This indicated clearly that a thorough optimization of reaction the selective thioacylation of primary amine thiobenzamine was
conditions was required.
reacted with mixture of propylmine and dipropyl amine and
To optimise the reaction it was investigated under various aniline. Exclusive formation of N-propylthiobenzamide was
reaction conditions. Decreasing the reaction temperature was observed and dipropylamine and aniline remained unreacted.
not found helpful, as it only decreased the rate of the reaction Non reactivity with open chain secondary amines may be
without altering the outcome of the reaction. Volume of the attributed to the combined effect of steric impositions caused
solvent was also varied, to optimise the desired product by their alkyl chains and their reduced nucleophilicity in water
formation. It was noted that with 150–200 mL water per mmol of due to solvation. Similarly, because of resonance and solvation
thioamide, reaction occurred faster but, still formation of by water molecules aromatic amines also did not have sufficient
undesired products could not be prevented signicantly. Next, reactivity to undergo thioacylation. In case of nicotinamide a p
considering that high basicity of the amine may be responsible decient heterocycle reaction went well with free amine itself in
for the side products; reaction was attempted with hydrochlo- water. 2,6-Dichlorothiobenzamide in which both of the ortho
ride salt of butylamine. But, no reaction took place which may positions were occupied did not undergo thioacylation due to
be due to the reduced nucleophilicity of protonated amine. sterically hindered reaction centre. On further investigation it
Efforts were then made to progress the reaction by addition of a was observed that alicyclic secondary amine with reduced steric
small amount of the base to the reaction. We assumed that demand i.e. pyrrolidine could be thioacylated conveniently with
addition of a small amount of base will make a fraction of both aliphatic and aromatic thioamides (entry 3, 7, 9), but, six
amine available for the reaction, which upon thioacylation will membered cyclic amines such as morpholine and piperidine
release of an equivalent amount of ammonia. Ammonia being a reacted only with small chain aliphatic thioamide i.e. thio-
proton scavenger may assist the reaction further. Hence, acetamide (entry 11 and 12) and remained non reactive towards
20 mol% of sodium bicarbonate was added as promoter to aromatic thioamides. To demonstrate the selective thio-
initiate the reaction. Indeed, by employing this strategy reaction acylation among various amine functionalities within the same
occurred satisfactorily in the desired direction. Alternatively, we molecule 2-aminoethyl piperazine (entry 13) was reacted with
found that a small amount of free reactant amine itself can be thiobenzamide. As expected only primary amino group was
utilised for this purpose. An optimised procedure for thio- thioacylated leaving the other amino groups intact (Scheme 2).
acylation of amine by primary thioamides is as follows: 1 mmol
Aminoethanol, a substrate having two potential reaction
of butylamine in 150 mL of water was neutralised with 5 N HCl, centres: amino and hydroxyl, was also reacted with thio-
and 1 mmol of thiobenzamide was added to it followed by benzamide interestingly, thioacylation occurred at amino group
addition 0.25 mmol of butylamine again. Reaction was heated to yield N-(2-hydroxy-ethyl)-thiobenzamide exclusively, without
at 60–70 ꢀC till completion, and contents were neutralised with considerable subsequent cyclodehydrosulfurisation6b under the
HCl. N-Butylthiobenzamide separates as an oily layer.
reaction condition. Since b-hydroxythioamides could yield
To study the role of water in this reaction, it was conducted thiazolines upon dehydrocyclisation;4 we were curious to know
without water under various conditions. In toluene at reux, no whether this approach can be extended to thiazolines also. A
appreciable reaction occurred between thiobenzamide and variety of dehydrating agents that have been utilised in organic
amine hydrochloride (in the presence of base) which may be solvent are reported in the literature for dehydrocyclisation of b-
due to the insolubility of amine salt in toluene. Reaction of hydroxy thiobenzamides into thiazolines. But, we required a
thiobenzamide with free amine was also studied both in organic cyclodehydrating agent that can be utilized in aqueous medium
solvents as well as under solvent less condition. Under solvent in a one pot reaction in continuation with thioacylation. Tech-
less condition formation of benzonitrile 27%, thiobenzamide nically, formation of thiazoline from b-hydroxythioamides is
34%, N,N-dibutylbenzamidine 9% and N-butyl thiobenzamide possible through nucleophilic attack of sulfur onto the carbon
30% was observed. Reaction of free amine and thiobenzamide to which hydroxyl group is attached, followed by cyclo-
in toluene at reux aer 3 h resulted in benzonitrile 54%, dehydration. We reasoned that through protonation, nucleo-
benzamide 17%, thiobenzamide 21%, and N-butylth- philicity of the hydroxyl group could be suppressed; as well as it
iobenzamide 8%.
can be turned into a good leaving group. Hence, by exploiting
With the optimised reaction in hand scope of the reaction the aforementioned strategy formation of thiazoline may be
was investigated by employing a variety of amines and primary possible. To achieve this hydrochloric acid, a commonly avail-
thioamides. The developed protocol was found applicable to able protic acid was examined. Indeed, heating N-(2-hydroxy-
both aromatic as well as aliphatic thioamides. Aromatic thio-
amides reacted comparatively slower than aliphatic thioamides.
Steric factor inuenced the reactivity of amine as well as thio-
amides to a great extent. Primary amines or thioamides with
smaller carbon chain (entry 3) reacted faster in comparison to Scheme 2 Selective thioacylation of primary amine.
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ethyl)-thiobenzamide with HCl at 90–95 ꢀC resulted in the
To investigate the applicability of this newly developed one
formation of thiazoline but, a complete reaction could not be pot two step preparation of thiazolines from thioamides and
achieved. For complete dehydrocyclisation other protic acid aminoethanol, various substrates were studied. Thiazoline
such as HBr and phosphoric acid was studied, and HBr was formation was found feasible with both electron donating and
found to produce gratifying results. Faster cyclisation with HBr electron withdrawing substrates. Preparation of thiazoline from
indicated that N-(2-bromoethyl)-thiobenzamide may be
possible intermediate in the cyclisation process (Table 1).
a
unsubstituted aromatic thioamide (entry 14) was found to be
more facile than substituted thioamides. Substituted thio-
amides required a higher amount of amine and slightly longer
Table 1 Preparation of secondary thioamides and thiazolines
Temp (ꢀC)/time
(h)
Temp (ꢀC)/time (h)
Entry
R
Amine
Step A
Thioamide
Step B
Thiazoline
mp/bp ꢀCref
Yielda%
1
2
3
4
Ph
60–70/5.5
60–70/5
70–80/3
70–80/5
—
—
—
—
—
—
—
—
Oil10a
91
89
89
93
Ph
Oil10a
CH3
CH3
64–66 (ref. 10b)
48–50 (ref. 10c)
5
6
CH3
70–80/5
70–80/6
—
—
—
—
65–66 (ref. 10d)
91
93
96
7
Ph
70–80/8
70–80/8
70–80/6
70–80/6
—
—
—
—
—
—
—
73–75 (ref. 10e)
98 (ref. 10f)
Oil
88
87
87
92
8
Ph
9
C5H9
Ph
10
—
—
96 (ref. 10g)
11
12
CH3
CH3
70–80/4
70–80/6
—
—
89–91 (ref. 10h)
55–56
87
81
13
14
Ph
Ph
70–80/8
70–80/6
—
—
Oil
78
89
—
—
—
90–95/7
Oil11a
15b
16b
80–90/6
80–90/9
90–95/10
90–95/10
41–42 (ref. 11a)
43–44 (ref. 11b)
80
76
17b
18
80–90/7
—
—
90–95/12
90–92 (ref. 11c)
78
—
—
—
—
—
a
Isolated yield. b Thioamide: amine. HBr: free amine 1 : 1.5 : 0.25.
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(1): light yellow oil1a 1H NMR (400 MHz, CDCl3): d 7.73–7.70
(m, 2H), 7.45 (br, s, 1H), 7.39–7.36 (m, 3H), 3.85–3.79 (m, 2H),
1.78–1.70 (m, 2H), 1.49–1.44 (m, 2H), 1.01–0.97 (m, 3H) EI-MS:
m/z 193 [M+] (47%), 160 (16), 151 (17), 150 (53), 121 (100), 77
(29), 104 (48); anal. calcd for C11H15NS. C, 68.35; H, 7.82; N,
7.25; S, 16.59. Found C, 68.41; H, 7.69; N, 7.36; S, 16.47.
Acknowledgements
Scheme 3 Plausible mechanism for the formation of 2-thiazolines
from thioamides.
We thank Mr Avik Mazumder, Ajeet Kumar and Mr Ajay Pratap
for NMR analysis. We also thank Director, DRDE for his keen
interest and encouragement.
reaction time for thiazoline formation. Further, among
substituted thioamides, substrates with electron donating
group underwent a slow thioacylation in comparison to the
substrate having electron withdrawing groups but, cyclo-
dehydration of corresponding thioacylated intermediate was
found to occur fast (entry 16). While in case of substrate with
electron withdrawing functionalities thioacylation occurred
faster but cyclisation was found to be comparatively slower
(entry 17). The protocol was not found suitable for substrates
containing nitro groups as reaction of aminoethanol with 4-
nitro thiobenzamide led to the reduction of nitro group
(entry 18).
Based on the above observations a plausible mechanism
proposed for this transformation is as follows (Scheme 3): rst
the electrophilic thiocarbonyl carbon of thioamide undergoes a
nucleophilic attack by amine functionality of aminoethanol to
yield a b-hydroxy thioamide with the release of ammonia. Upon
acidication, the hydroxyl group gets protonated which renders
the carbon adjacent to it highly electrophilic. Intermediate 5 is
then undergoes cyclisation and simultaneous dehydration via
attack of sulfur onto the carbon adjacent to hydroxyl moiety
yielding thiazoline 6.
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Experimental
Typical experimental procedure for N-butylbenzothioamide:
butylamine 2 mmol (156 mL) and water 300 mL were taken in test
tube tted with condenser. Contents were carefully neutralised
with 5 N HCl. Thiobenzamide 2 mmol (274 mg) was added
followed by addition of 0.5 mmol (36 mL) of butyl amine.
Reaction was heated with constant stirring at 60–70 ꢀC with
constant reaction for 5.5 hours. Contents were then acidied
with dil. HCl. An oily layer separates which was isolated by
extraction with DCM. The DCM layer was washed with 5%
sodium bicarbonate solution and dried over sodium sulphate.
Solvent removal under vacuum yielded N-butylbenzothioamide
as yellow oil. If required the compound can be further puried
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