Microwave-Assisted Domino Reactions of Propargylamines with Isothiocyanates: Selective Synthesis of 2-Aminothiazoles and 2-Amino-4-methylenethiazolines

Article abstract of DOI:10.1055/s-0035-1561985

A simple and versatile microwave-assisted protocol for the synthesis of 2-aminothiazoles has been developed. The domino reaction of propargylamines and isothiocyanates in the presence of catalytic PTSA leads to the selective synthesis of 2-aminothiazoles

Full text of DOI:10.1055/s-0035-1561985

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2
0
9
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
N. Scalacci et al.
Letter
Synlett
Microwave-Assisted Domino Reactions of Propargylamines with
Isothiocyanates: Selective Synthesis of 2-Aminothiazoles and 2-
Amino-4-methylenethiazolines
Nicoló Scalaccia,b
Chiara Pellojab,c
Marco Radic
R3
NH
R1
S
N
130–160 °C
R1
R2
S
C
N
R2
0.5 equiv PTSA
MW, 2 × 5 min
Daniele Castagnolo*a
+
NH2
R3
R3
NH
R1
S
N
a Institute of Pharmaceutical Science, King’s College London, 150
Stamford Street, SE1 9NH London, UK
b Northumbria University Newcastle, Department of Applied Sciences,
Ellison Building, Ellison Place, NE1 8ST Newcastle upon Tyne, UK1
c P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma,
Viale delle Scienze, 27/A, 43124 Parma, Italy
100–130 °C
R1 = H, Ph
2 = H, Ar
R3 = All, Bn, Ph
R2
R
13 examples, yields 47–85%
Received: 08.02.2016
Accepted after revision: 15.03.2016
Published online: 07.04.2016
tion of propargyl bromides with thioureas leading to a vari-
ety of 2-aminothiazoles substituted at the C4 position was
described by our group12 (Scheme 1).
DOI: 10.1055/s-0035-1561985; Art ID: st-2016-d0086-l
In continuation of our work on the development of nov-
el, atom economical methods for the synthesis of heterocy-
clic compounds, and due to our experience in propargyl-
amine chemistry and microwave synthesis,12,13 we became
interested in studying the reaction of propargylamines A
with isothiocyanates B with the aim to develop a one-pot
approach to substituted 2-aminothiazoles D (Scheme 1).
Abstract A simple and versatile microwave-assisted protocol for the
synthesis of 2-aminothiazoles has been developed. The domino reac-
tion of propargylamines and isothiocyanates in the presence of catalyt-
ic PTSA leads to the selective synthesis of 2-aminothiazoles at tempera-
tures above 130 °C and in a few minutes. The same reaction carried out
at lower temperatures leads to the formation of the tautomeric 2-ami-
no-4-methylenethiazolines.
Key words 2-aminothiazole, thiazoline, propargylamine, isothiocya-
nate, microwave chemistry, imidazol-thione
a) Previous work, Castagnolo et al. 2009. Ref.12
R1
1
S
R2
NH
S
K2CO3, MW
NHR2
DMF, 130 °C
2
The 2-aminothiazole ring is an important heterocyclic
nucleus that has found broad application in organic and
medicinal chemistry. Thiazole and aminothiazole scaffolds
have been recognised as privileged structural motifs in me-
dicinal chemistry. Several drug candidates endowed with
potent biological activity against hypertension, allergies,
inflammation, schizophrenia, cancer, bacterial, and viral in-
fections contain a 2-aminothiazole moiety.2 As a conse-
quence, a number of methodologies for the synthesis of 2-
aminothiazole derivatives has been developed,3 including
the Hantzsch4 and the Cook–Heilborn syntheses.5 The
Hantzsch synthesis still represents the most widely used
method for preparing aminothiazoles, despite the limita-
tions arising from the low availability of hazards associated
with the lachrymatory α-haloketone starting materials. Im-
provements of the Hantzsch synthesis have been recently
reported and are based on the in situ generation of the α-
halo carbonyl reagents from ketones.6 Other protocols for
the synthesis of aminothiazole derivatives include the use
of catalysts such as iodine,7 silica chloride,8 1,3-di-n-bu-
tylimidazolium tetrafluoroborate,9 and cyclodextrins.10,11
Recently, a microwave domino alkylation–cyclization reac-
R1
+
N
4
H2N
Br
R1
S
C
N
R2
+
A
B
R3
NH2
MW
heating
minutes
r.t.
hours/days
R3
R3
R1
S
N
R1
S
5
NH
NH
R2
4
N
C
D
R2
b) Dillard et al. 1964. Ref.14a
c) This work
Scheme 1 Different approaches to 2-aminothiazoles and 2-amino-4-
methylenethiazolines
Dillard and coworkers in 1964, and later Eloy and
Deryckere,14 first reported that the reaction of propargyl-
amines and isothiocyanates led to 2-amino-4-methylene-
thiazolines C under mild temperature conditions in basic
medium after extended reaction times (Scheme 1). More
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
N. Scalacci et al.
Letter
Synlett
recently, this approach has been adopted by Clausen and
coworkers as an efficient conjugation method in aqueous
medium.15 In all cases, the thiazoline C was obtained as the
only reaction product, whilst no traces of the corresponding
thiazole D were detected. We reasoned that, under micro-
wave irradiation and using an appropriate catalyst, the thi-
azoline C could tautomerise leading to the formation of the
corresponding thiazole D in a one-pot process. Herein, a
novel microwave domino amine nucleophilic addition–cy-
clization approach to 2-aminothiazole from propargyl-
amines is described (Scheme 1).
solvent (Table 1, entry 2). Heating the mixture at 160 °C in
DMF led to the cyclization of the thiourea 3 and to the for-
1
mation of two products in 1:1 ratio (Table 1, entry 3). H
NMR analysis of the reaction mixture revealed the forma-
tion of the desired 2-aminothiazole 4a, showing the charac-
teristic NH broad peak at δ = 5.79 ppm, together with the
imidazole derivative 6, showing the SH broad singlet at δ =
11.44 ppm. The structures of 4a and 6 were determined by
1H NMR, 13C NMR, and MS analyses. When DIPEA was used
as a base under the same reaction conditions, a mixture of
isomers 4a and 6 was also obtained in a 2:1 ratio. Interest-
ingly, the replacement of K2CO3 with a stoichiometric
amount of p-toluenesulfonic acid (PTSA) led to 4a as the
major isomer (Table 1, entry 5). Only a small amount of 6
Table 1 Reaction of Propargylamine 1a with Allyl Isothiocyanate 2a
1
S
was detected by H NMR analysis. In the presence of the
S
NH
or
Lewis acid ZnCl2 (1 equiv) the desired thiazole 4a was ob-
tained, again as the major reaction product (Table 1, entry
6), whilst a 4:1 and a 3:1 mixture of 4a/6 was obtained
when 1a and 2a were reacted in the presence of CuI and
FeCl3, respectively (Table 1, entries 7 and 8). The use of a
catalytic instead of stoichiometric amount of PTSA did not
affect the outcome of the reaction, leading to 4a/6 in 9:1 ra-
tio (Table 1, entries 9 and 10). In a further attempt to reduce
the amount of the imidazole 6, the compounds 1a and 2a
were reacted at lower temperature. When the reaction was
carried out in the presence of catalytic PTSA at 130 °C in
DCE (Table 1, entry 11), the thiazole 4a was obtained as the
only product. On the other hand when the temperature was
lowered to 100 °C, using both DCE or MECN as solvent, no
traces of 4a were detected whilst the 2-allylamino-4-meth-
ylenethiazoline 5a was isolated as single product (Table 1,
entries 12 and 13).
The proposed mechanism for the formation of the three
isomers 4a, 5a, and 6 is outlined in Scheme 2. The propar-
gylamine 1a reacts almost instantaneously with the isocya-
nate 2a leading to the formation of the thiourea intermedi-
ate 3. The latter can then undergo a 5-exo-dig cyclization
through two different pathways.14a In basic medium and at
high temperatures, the thiourea N1 nitrogen preferably acts
as the nucleophile, attacking the alkyne and leading to the
imidazole 6 (Scheme 2, path b). On the other hand, in acidic
medium, the N1 nitrogen of the thiourea intermediate is
likely to be protonated leaving the sulfur to act as the nucle-
ophile and leading at 100 °C to the formation of 5a. Upon
heating at 130 °C, 5a can tautomerise, leading to thiazole 4a
(Scheme 2, path a). When the reaction is carried out in the
presence of base at high temperatures (Table 1, entry 3), it
is likely that both pathways occur due to a combination of
catalytic and heating effects, thus leading to a mixture of 4a
and 6.
N
N
N
H
H
S
C
N
catalyst
+
4a
3
2 × 5 min
MW irradiation
NH2
1a
S
N
NH
or
N
Temp
2a
N
SH
5a
6
Entry Acid/base catalyst Additive
Solvent Temp
(°C)
Ratioa 3/4a/5a/6
(equiv)
(equiv)
(yield, %)b
1
2
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
DIPEA (1)
PTSA (1)
–
DMF
DCE
130
100
160
160
160
160
160
160
160
160
130
100
100
100/0/0/0 (82)
100/0/0/0 (78)
0/48/0/52
3
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
4
–
0/68/0/32
5
–
0/89/0/11
6
ZnCl2 (1)
0/89/0/11
7
–
CuI (1)
0/80/0/20
8
–
FeCl3 (1)
0/75/0/25
9
PTSA (0.5)
PTSA (0.1)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
–
–
–
–
–
0/90/0/10
10
11
12
13
0/85/0/15
0/100/0/0 (78)
0/0/100/0 (85)
0/0/100/0
DCE
MeCN
a Calculated by 1H NMR integration.
b Isolated yields are reported.
The reaction of propargylamine 1a with allylisothiocya-
nate 2a under microwave irradiation at different tempera-
tures and in the presence of different catalysts was first in-
vestigated (Table 1). According to our previous method,12 1a
and 2a were reacted at 130 °C in DMF and in the presence
of a stoichiometric amount of K2CO3. The reaction was car-
ried out under microwave irradiation for 2 × 5 min, leading
to the formation of the thiourea 3 as the only product (Table
1, entry 1). The same product was isolated when the reac-
tion was carried out at lower temperature and in a different
On the basis of these results, the reaction of propargyl-
amine 1a–e16,13a with different isothiocyanates 2a–c was
further investigated. The results are reported in Table 2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
N. Scalacci et al.
Letter
Synlett
S
S
S
path a
NH
2
NH
N
H
1 N+
N
H+
N
S
H
T (°C)
H
4a
C
+
5a
3
N
NH2
base
HN1
N
2a
1a
2
path b
SH
N
S
N
H
3
6
Scheme 2 Proposed mechanism for the formation of 2-aminothiazoles and imidazoles
Table 2 Synthesis of 2-Aminothiazoles 4 and 2-Amino-4-methylenethiazoline 5
R1
R3
S
C
S
NH
R3
R3
NH
S
N
S
R1
0.5 equiv PTSA
R1
+
N
NH
N
and/or
R3
or
2 × 5 min
MW irradiation
S
N
R2
1a–e
NH2
R2
R2
R1
N
2a R = All
2b R = Ph
2c R = Bn
R
7
4a–x
5a–x
Entry
Amine
R1
R2
RNCS
Solvent
Temp (°C)
Product
Ratioa 4/5/7 (yield, %)b
1
2
1a
H
H
Ph
Ph
Bn
Bn
All
All
Bn
All
All
All
All
Bn
All
All
Bn
Ph
All
Ph
Bn
All
DCE
130
100
130
100
130
160
160
130
160
130
160
160
130
130
130
130
160
160
160
refluxc
4b
100/0/0 (74)
20/80/0 (12/57)
100/0/0 (78)
25/75/0 (18/60)
32/68/0
H
H
MeCN
DCE
4b/5b
4c
3
H
H
4
H
H
MeCN
DCE
4c/5c
4d/5d
4d
5
1b
H
Ph
Ph
Ph
6
H
DMF
DMF
DCE
100/0/0 (47)
100/0/0 (56)
50/50/0
7
H
4e
8
1c
H
4-ClC6H4
4f/5f
4f
9
H
4-ClC6H4
DMF
DCE
100/0/0 (55)
0/100/0 (60)
100/0/0 (62)
100/0/0 (62)
0/0/100 (31)d
0/0/100 (27)d
0/0/100 (22)d
0/0/100 (24)d
0/0/100 (33)d
0/0/100 (21)d
0/0/100 (15)d
0/0/100 (28)d
10
11
12
13
14
15
16
17
18
19
20
1d
H
2,4-Cl2C6H3
5g
H
2,4-Cl2C6H3
DMF
DMF
DCE
4g
H
2,4-Cl2C6H3
4h
1e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
7i
MeCN
MeCN
MeCN
DMF
DMF
DMF
MeCN
7i
7j
7k
7i
7j
7k
7i
a Calculated by 1H NMR integration.
b Isolated yields are reported.
c The reaction was carried out in an oil bath and refluxing MeCN for 12 h and in the presence of 1 equiv of K2CO3.
d Unreacted starting material (45–50% yield) 1e was recovered from the reaction mixture.
When propargylamine 1a was reacted with phenyliso-
thiocyanate 2b and benzylisothiocyanate 2c at 130 °C in
DCE and in the presence of catalytic PTSA, the thiazoles 4b
and 4c were isolated as the only products in high yields (Ta-
ble 2, entries 1 and 3). On the other hand, when the same
reaction was carried out in MeCN at 100 °C, the thiazolines
5b and 5c were obtained as major products in good yields
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
N. Scalacci et al.
Letter
Synlett
together with a lesser amount of the corresponding thi-
azoles 4 (Table 2, entries 2 and 4).
Ph
Ph
R
S
C
N
R
S
N
Ph
HN
+
The introduction of a phenyl ring onto the propargyl-
amine backbone proved to affect the selectivity of the reac-
tion. In fact, when 1-phenylpropargylamine 1b and the allyl
isothiocyanate 2a were reacted in DCE at 130 °C a mixture
of 4d and 5d in a 1:2 ratio was unexpectedly obtained (Ta-
ble 2, entry 5). However, heating the mixture to 160 °C in
DMF led to 4d17 as a single product (Table 2, entry 6). No
traces of 5d or the corresponding imidazole derivative were
observed. Similarly, compound 4e18 was obtained as a sin-
gle product when 1b and 2c were reacted in DMF at high
temperatures (Table 2, entry 7). A similar trend was ob-
served when 1c was reacted with 2a leading to a mixture of
thiazole/thiazoline 4f/5f at 130 °C; whilst 4f was selectively
obtained at higher temperatures (Table 2, entries 8 and 9).
When 1-(2,4-dichloropheny)propargylamine (1d) was used
as substrate and reacted with 2a, the thiazoline 5g was
formed as the sole product at 130 °C (Table 2, entry 10);
whilst at 160 °C only 4g was isolated (Table 2, entry 11).
Thiazole 4h was also obtained as a single isomer when the
reaction was carried out at 160 °C in DMF (Table 2, entry
12). It is clear that the aryl substituent on the propargyl-
amine affects the outcome of the reaction, probably due to
a combination of steric and electronic effects. In general,
higher temperatures favour the tautomerisation of 5 into 4.
Intrigued by the effect of the aromatic ring on the outcome
of the reaction, we then focused on the reaction of the 3-
phenylpropargylamine 1e with different isothiocyanates.
When 1e was reacted with 2a–c at 130 °C, the imidazole-
thione derivatives 7i–k were obtained as the only reaction
products.19 No traces of the thiazole/thiazoline 4 and 5
were detected (Table 2, entries 13–16). At higher tempera-
ture the imidiazolethiones 7i–k were also recovered as the
only products (Table 2, entries 17–19). A substantial
amount of starting material 1e was also recovered from all
the reaction mixtures. Finally, amine 1e was reacted with
2a under standard heating conditions (reflux in oil bath) at
130 °C in the presence of one equivalent of K2CO3 and, in
this case, the imidazoline 7i was also recovered as the sole
product together with starting material 1e.
S
N
H
N
H
R
NH2
1e
2
8
9
R = All, Bn, Ph
S
C
N
R
N
R
Ph
S
R
N
Ph
N
S
N
H
NH
R
S
10
7
Scheme 3 Proposed mechanism for the formation of imidazolthiones
7
In conclusion, an efficient and versatile microwave
method for the synthesis of 2-aminothiazole and 2-amino-
thiazolines from propargylamines has been developed.20–22
A set of compounds 4 and 5 has been synthesised in short
reaction times and high yields. The formation of thiazoline
derivatives 5 occurs when propargylamines and isothiocya-
nates are reacted in the temperature range 100–130 °C, de-
pending on the substrate. At higher temperatures the selec-
tive formation of the 2-aminothiazoles 4 is favoured. The
effect of aromatic substituents on the propargylamine sub-
strate has been also investigated, showing that the presence
of a phenyl ring on the propargylamine backbone affects
the selectivity of the reaction.
Acknowledgment
DC thanks the Royal Society of Chemistry for financial support (Re-
search Fund 2015). CP is grateful to the European Union (Erasmus
Placement Program, Università degli Studi di Parma −Italy) for the
mobility grant.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561985.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Interestingly, Dethe and coworkers recently described
the formation of imidazolethiones from propargylamines
under basic conditions at room temperature.19 However, at
high temperature we observed the cyclization of 1e and for-
mation of imidazolethiones 7 both in acidic and basic medi-
um. The proposed mechanism for the formation of 7 is out-
lined in Scheme 3. The reaction of 1e with isothiocyanates
leads to the thiourea intermediate 8. The presence of a phe-
nyl ring on the alkyne moiety seems to favour the attack of
the nitrogen leading to the tautomeric imidazoline inter-
mediates 9 and 10 that upon reaction with an additional
isothiocyanate equivalent, lead to the final product 7.
References and Notes
(1) Most of this work has been carried out at Northumbria Univer-
sity Newcastle (UK), Department of Applied Sciences, before DC
relocated to King’s College London (UK), Institute of Pharma-
ceutical Science, 150 Stamford Street, SE1 9NH, London, UK.
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(20) General Procedure for the Synthesis of 2-Aminothiazoles 4
and 2-Amino-4-methylenethiazolines 5
Propargylamine 1a–e (1.0 mmol) and the appropriate isothio-
cyanate 2a–c (1.0 mmol) were suspended in an appropriate
solvent (DCE, MeCN, DMF, 1.0 mL) in a 10 mL glass vial
equipped with a small magnetic stirring bar. PTSA (0.5 mmol)
was then added to this solution, and the mixture was irradiated
under microwave conditions at the appropriate temperature
(see Tables 1 and 2) for 2 × 5 min, using an irradiation power of
300 W. The mixture was then poured into NaHCO3 solution (10
mL) and then extracted with EtOAc (2 × 10 mL). The combined
organic phases were washed with brine, dried over Mg2SO4, fil-
tered, and concentrated under reduced pressure. The crude
products were purified by flash column chromatography (SiO2;
hexanes–EtOAc, 4:1), to yield the desired products as tan-
coloured oils.
(21) 2-Aminothiazole 4a
1H NMR (400 MHz, CDCl3): δ = 6.67 (s, 1 H), 5.95–5.85 (m, 1 H),
5.79 (br s, 1 H), 5.30–5.25 (d, 1 H, J = 20 MHz), 5.17–5.14 (d, 1 H,
J = 12 MHz), 3.82 (d, 2 H, J = 4 MHz), 2.25 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.0, 135.5, 134.1, 121.1, 116.8, 48.2,
12.0 ppm. ESI-MS: m/z = 155 [M + H]+, 177 [M + Na]+.
(22) 2-Amino-4-methylenethiazoline 5a
(14) (a) Easton, N. R.; Cassady, D. R.; Dillard, R. D. J. Org. Chem. 1964,
29, 1851. (b) Eloy, F.; Deryckere, A. Chim. Ther. 1973, 4, 437.
(15) Viart, H. M.-F.; Larsen, T. S.; Tassone, C.; Andresen, T. L.; Clausen,
M. H. Chem. Commun. 2014, 50, 7800.
1H NMR (400 MHz, CDCl3): δ = 5.92–5.83 (m, 1 H), 5.24–5.19 (d,
1 H, J = 20 MHz), 5.14–5.08 (m, 3 H), 4.68 (m, 2 H), 3.89–3.88 (d,
2 H, J = 4 MHz) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3,
148.8, 134.3, 116.5, 102.5, 67.0, 46.6 ppm. ESI-MS: m/z = 155
[M + H]+, 177 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E