An Eco-friendly, Hantzsch-Based, Solvent-Free Approach to 2-Aminothiazoles and 2-Aminoselenazoles

Article abstract of DOI:10.1055/s-0035-1560534

We report a simple, fast, and eco-friendly solvent-free protocol for the synthesis of 2-aminothiazoles and 2-amino-1,3-selenazoles (16 examples) through Hantzsch condensation without the use of a catalyst. It is noteworthy that this type of procedure is unprecedented for the synthesis of 1,3-selenazoles. Reactions proceed to completion in a few seconds and products are obtained in moderate to excellent yields after easy workup. Moreover, the synthesis of 4-(2-amino-1,3-selenazol-4-yl)benzonitrile hydrobromide is reported for the first time.

Full text of DOI:10.1055/s-0035-1560534

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 437–440
paper
437
V. Facchinetti et al.
Paper
Synthesis
An Eco-friendly, Hantzsch-Based, Solvent-Free Approach to
2-Aminothiazoles and 2-Aminoselenazoles
Victor Facchinettia,b
Marcela M. Avellarb
Ana C. S. Neryb
Claudia R. B. Gomesb
Thatyana R. A. Vasconcelosa
Marcus V. N. de Souza*b
X
O
X
.
NH2 HBr
Br
D
N
H2N
NH2
up to 20 s
42–93%
R
R
X = S, Se
R = H, Me, CN, OMe, NO2, F, Cl, Br
16 examples
1 new compound
a Universidade Federal Fluminense, Instituto de Química, Departa-
mento de Química Orgânica, Programa de Pós-Graduação em
Química, Outeiro de São João Batista, s/no, Centro, Niterói,
24020-141, Rio de Janeiro, RJ, Brazil
b Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos –
Farmanguinhos, Rua Sizenando Nabuco 100, Manguinhos,
21041-250, Rio de Janeiro, RJ, Brazil
marcos_souza@far.fiocruz.br
Received: 01.09.2015
Accepted after revision: 15.10.2015
Published online: 03.12.2015
We recognize the potential of these methodologies,
however they have drawbacks, such as longer reaction
times, the use of toxic organic solvents, ionic liquids, or cat-
alysts, tedious workup, and harsh reaction conditions.5–11
Therefore, the development of improved economic and
environmentally friendly procedures that can eliminate or
reduce the use of volatile organic solvents without impos-
ing longer reaction times is not only desirable, but it has
also become crucial to organic synthesis. In this context, we
report a rapid, efficient solvent-free protocol for the syn-
thesis of 2-aminothiazoles and 2-amino-1,3-selenazoles
through Hantzsch cyclization from thiourea and seleno-
urea.
DOI: 10.1055/s-0035-1560534; Art ID: ss-2015-m0436-op
Abstract We report a simple, fast, and eco-friendly solvent-free proto-
col for the synthesis of 2-aminothiazoles and 2-amino-1,3-selenazoles
(16 examples) through Hantzsch condensation without the use of a
catalyst. It is noteworthy that this type of procedure is unprecedented
for the synthesis of 1,3-selenazoles. Reactions proceed to completion in
a few seconds and products are obtained in moderate to excellent
yields after easy workup. Moreover, the synthesis of 4-(2-amino-1,3-
selenazol-4-yl)benzonitrile hydrobromide is reported for the first time.
Key words thiazoles, 1,3-selenazoles, synthesis, solvent-free, hetero-
cycles
The multicomponent, solvent-free, one-pot synthesis of
various thiazole derivatives at room temperature was pre-
viously described by Dawane and Konda.12 Initially, we ex-
amined their protocol for the synthesis of 2-aminothiazole
building blocks. Unfortunately, in this case, the reaction
proceeded very slowly at room temperature with undesir-
able yields. However, to our surprise the reaction appeared
to occur instantly with release of hydrogen bromide when
the temperature was raised to the melting point of the 2-
bromoacetophenone 1. In order to investigate the optimal
conditions for this reaction, 2-bromoacetophenone (1g)
was added to a 5-mL round-bottom flask and heated to its
melting point (48–51 °C); powdered thiourea (2) was then
added directly to the flask. As expected, the results con-
firmed our initial observation as we witnessed the instant
release of HBr and the reaction proceeded to completion in
a few seconds (Scheme 1). TLC analysis showed that com-
plete conversion of 2-bromoacetophenone (1g) into the
corresponding 2-aminothiazole (3g) was not achieved
when an equimolar amount of thiourea (2) was used. We
then raised the quantity of thiourea to 1.2, 1.5 and 2 equiv-
The 2-aminothiazole and 2-amino-1,3-selenazole ring
systems have received much attention from medicinal
chemists worldwide because of their wide range of biologi-
cal activity, such as antimicrobial, anti-HIV, antioxidant, an-
ticancer, among others.1,2 In view of the importance of
these heterocyclic cores, many synthetic methodologies
have been reported in the literature.2,3 Despite this, the
Hantzsch condensation (1887)4 of α-halocarbonyl com-
pounds with thioureas or selenoureas remains a prominent
method for the synthesis of these compounds.1
In the last few years, many novel protocols that improve
Hantzsch’s original procedure have been reported. In 2008,
for example, Potewar and co-workers described the synthe-
sis of 2-aminothiazole derivatives in water for 1–2 hours.5
In 2006, the supramolecular synthesis of 2-amino-1,3-
selenazoles from selenourea in water using β-cyclodextrin
as a catalyst was described.6 Other noteworthy procedures
include solid-supported synthesis,7 the use of ionic liq-
uids8,9 or catalysts such as ammonium molybdophos-
phate,10 and reactions carried under microwave irradia-
tion.11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 437–440

438
V. Facchinetti et al.
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Synthesis
these cases and equivalent yields were obtained. Therefore,
two equivalents of selenourea (4) were optimal for this re-
action. All reactions proceeded to completion instantly
(Scheme 2).
Excess reagent was removed by washing the powdered
solid with water, except for compounds 5e,f,h in which to-
tal conversion of 2-bromoacetophenone 1e,f,h into the de-
sired product was not observed. In these cases, the sub-
stances were also washed with ethanol (1 mL). All products
were obtained in the form of an insoluble salt, as expected,
in moderate to excellent yields (Table 2).
1
S
O
5
S
2
NH2·HBr
Br
Δ
1'
4
N
H2N
NH2
3
73–86%
4'
2'
R
1a–h
2
3a–h
R
3'
Scheme 1 Solvent-free synthesis of 2-aminothiazoles 3a–h
alents, establishing the former as the best proportion in
this case. The optimal condition for each substituent is de-
scribed in Table 1.
Table 1 Reaction Conditions, Yields, and Melting Points Obtained for
Thiazoles 3a–h
Table 2 Yields and Melting Points Obtained for Selenazoles 5a–h
R
2-Aminoselenazole Yielda (%)
Mp (°C)
R
2-Amino-
thiazole
Proportion Time
(1/2)
Yield
(%)
Mp
(°C)
4-OMe
4-F
5a
5b
5c
5d
5e
5f
78
76
80
93
60
42
93
58
230–232
236–238
286–288
235–238
237–240
225–226
220–222
221–223
4-OMe
4-F
3a
3b
3c
3d
3e
3f
2:1
instant
83
73
80
86
79
85
77
69
229–231
1.2:1
2:1
10 s
236–238
286–287
235–238
236–239
225–227
220–222
222–224
4-Me
4-NO2
4-Cl
4-Me
4-NO2
4-Cl
20 s
2:1
instant
15 s
2:1
4-Br
H
4-Br
H
2:1
instant
10 s
5g
5h
3g
3h
1.2:1
2:1
4-CN
4-CN
instant
a Using a 1:2 ratio of 1/4 in all cases.
Purification was carried out by the addition of water to
the powdered solid. Pure products were obtained in the
form of insoluble salts in high yields after filtration (70–
98%). Furthermore, excess reagent can be easily recovered
from the water after evaporation. It is noteworthy that this
reaction also proved to be efficient on a gram scale (5–10
mmol).
To our knowledge, there are no solvent-free methods for
the synthesis of 2-amino-1,3-selenazoles available in the
literature. Due to the increasing importance of this core in
medicinal chemistry, we examined the scope of our proto-
col by reacting 2-bromoacetophenones 1a–h with sele-
nourea (4) in order to obtain the corresponding 1,3-
selenazole building blocks 5. It is noteworthy that product
5h has not been previously reported in the literature. Com-
plete reaction was observed when two equivalents of sele-
nourea (4) were used for all products, except for com-
pounds 5e,f,h. However, raising the quantity of selenourea
(4) to 2.5 equivalents did not improve the efficiency in
In summary, we have developed a fast and reproducible
protocol for the synthesis of various 2-aminothiazoles and
2-amino-1,3-selenazoles through Hantzsch cyclization
from thiourea and selenourea. It is noteworthy that in the
synthesis of 1,3-selenazoles, solvent-free procedures with-
out the use of a catalyst are unprecedented. All products
were obtained in moderate to excellent yields and no haz-
ardous waste was generated, making this procedure inter-
esting for green chemistry approaches. Product 5h has not
been previously reported in the literature.
All reagents were used as obtained from commercial suppliers with-
out further purification. Melting points were determined on a Buchi
Melting Point B-545 and are uncorrected. 1H NMR spectra were re-
corded using a Bruker DRX 400 spectrometer (1H at 400 MHz) in
MeOD or acetone-d6 with TMS as internal standard. MS analyses were
performed on MS micromass ZMD using electrospray ionization;
samples were introduced by the standard direct insertion probe
method. HRMS analysis was performed on a Bruker TOF compact us-
ing electrospray ionization.
1
5
Se
O
2
NH2·HBr
2-Aminothiazoles 3a–h; General Procedure
Br
Se
1'
4
N
Δ
3
The 2-bromoacetophenone 1a–h (199–278 mg, 1 mmol) was heated
to its melting point in a 5-mL round-bottom flask. Powdered thiourea
(2, 91.2–152 mg, 1.2–2 mmol; see Table 1) was then added to the
flask, and reaction proceeded to completion after a few seconds to
H2N
NH2
42–93%
4'
R
3'
2'
5a–h
R
4
1a–h
Scheme 2 Solvent-free synthesis of 2-amino-1,3-selenazoles 5a–h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 437–440

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V. Facchinetti et al.
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Synthesis
give the desired thiazoles. Powdered solid was washed with water (5–
10 mL) and filtered. Excess thiourea was recovered from water after
evaporation.
1H NMR (400 MHz, MeOD): δ = 7.71–7.65 (m, 2 H, Ph), 7.61–7.56 (m,
2 H, Ph), 7.13 (s, 1 H, H5).
13C NMR (75 MHz, DMSO-d6): δ = 168.27 (C2), 148.58 (C4), 134.05
(Ph), 131.27 (Ph), 127.48 (Ph), 120.01 (Ph), 102.32 (C5).
MS (ESI): m/z = 256.8 ([M]+, 100%), 254.9 ([M + 2]+, 98%).
4-(4-Methoxyphenyl)thiazol-2-amine Hydrobromide (3a)
[CAS Reg. No. 111317-60-3]
Beige solid; yield: 171 mg (83%); mp 229–231 °C.
1H NMR (400 MHz, acetone-d6): δ = 7.80–7.76 (m, 2 H, Ph), 6.93–6.89
4-Phenylthiazol-2-amine Hydrobromide (3g)
[CAS Reg. No. 34161-31-4]
(m, 2 H, Ph), 6.76 (s, 1 H, H5), 6.35 (br s, 2 H, NH2), 3.80 (s, 3 H, OCH3).
13C NMR (100 MHz, acetone-d6): δ = 169.7 (C2), 160.9 (C4′), 152.5
(C4), 130.1 (Ph), 128.8 (Ph), 115.4 (C3′), 101.2 (C5), 56.4 (OCH3)
White solid; yield: 137 mg (77%); mp 220–222 °C (Lit.14 181–183).
1H NMR (400 MHz, acetone-d6): δ = 7.86 (d, J = 7.2 Hz, 2 H, Ph), 7.35
(dd, J = 7.6, 7.6 Hz, 2 H, Ph), 7.25 (t, J = 7.3 Hz, 1 H, H4′), 6.93 (s, 1 H,
H5), 6.41 (br s, 2 H, NH2).
MS (ESI): m/z = 206.9 ([M]+, 100%).
13C NMR (100 MHz, acetone-d6): δ = 169.0 (C2), 151.7 (C4), 136.2 (Ph),
129.2 (Ph), 128.0 (Ph), 126.6 (Ph), 102.4 (C5).
MS (ESI): m/z = 177.0 ([M + H]+, 100%).
4-(4-Fluorophenyl)thiazol-2-amine Hydrobromide (3b)
[CAS Reg. No. 1147205-03-5]
White solid; yield: 142 mg (73%); mp 236–238 °C.
1H NMR (400 MHz, acetone-d6): δ = 7.92–7.86 (m, 2 H, Ph), 7.15–7.08
(m, 2 H, Ph), 6.91 (s, 1 H, H5), 6.43 (br s, 2 H, NH2).
4-(2-Aminothiazol-4-yl)benzonitrile Hydrobromide (3h)
[Amine CAS Reg. No. 436151-85-8]
13C NMR (100 MHz, acetone-d6): δ = 169.1 (C2), 163.0 (d, J = 242.8 Hz,
C4′), 150.6 (C4), 132.8 (d, J = 3.1 Hz, C1′), 128.5 (d, J = 7.9 Hz, C2′),
115.9 (d, J = 21 Hz, C3′), 102.6 (d, J = 1.1 Hz, C5).
Salmon solid; yield: 139 mg (69%); mp 222–224 °C.
1H NMR (400 MHz, acetone-d6): δ = 8.05 (d, J = 8.5 Hz, 2 H, Ph), 7.75
(d, J = 8.6 Hz, 2 H, Ph), 7.24 (s, 1 H, H5), 6.56 (br s, 2 H, NH2).
13C NMR (75 MHz, DMSO-d6): δ = 168.4 (C2), 148.1 (C4), 138.9 (C1′),
132.4 (Ph), 126.0 (Ph), 119.0 (CN), 109.2 (C4′), 105.4 (C5).
MS (ESI): m/z = 194.9 ([M]+, 100%).
4-(p-Tolyl)thiazol-2-amine Hydrobromide (3c)
[CAS Reg. No. 24966-91-4]
MS (ESI): m/z = 202.0 ([M + H]+, 100%)
Pale yellow solid; yield: 152 mg (80%); mp 286–287 °C.
2-Amino-1,3-selenazoles 5a–h; General Procedure
1H NMR (400 MHz, acetone-d6): δ = 7.77–7.71 (m, 2 H, Ph), 7.16 (d,
J = 7.9 Hz, 2 H, Ph), 6.85 (s, 1 H, H5), 6.38 (br s, 2 H, NH2), 2.32 (s, 3 H,
CH3).
13C NMR (75 MHz, DMSO-d6): δ = 170.1 (C2), 139.1 (C4), 139.0 (Ph),
129.5 (Ph), 125.9 (Ph), 125.6 (Ph), 101.8 (C5), 20.7 (CH3).
The 2-bromoacetophenone 1a–h (223–302 mg, 1 mmol) was heated
to its melting point in a 5-mL round-bottom flask. Powdered sele-
nourea (4, 246 mg, 2 mmol) was then added to the flask, and reaction
proceeded to completion instantly to give the desired selenazole. Sol-
ids were powdered, washed with water (5–10 mL) and filtered. Prod-
ucts 5e, 5f, and 5h, were also washed with EtOH (1 mL). Excess sele-
nourea was recovered from water after evaporation.
MS (ESI): m/z = 190.9 ([M]+, 100%).
4-(4-Nitrophenyl)thiazol-2-amine Hydrobromide (3d)
[CAS Reg. No. 69018-01-5]
Yellow solid; yield: 190 mg (86%); mp 235–238 °C (Lit.13 251–256).
1H NMR (400 MHz, MeOD): δ = 8.32 (d, J = 8.9 Hz, 2 H, H3′), 7.95 (d,
J = 8.9 Hz, 2 H, H2′), 7.30 (s, 1 H, H5).
13C NMR (125 MHz, DMSO-d6): δ = 168.54 (C2), 147.46 (C4), 145.92
(C4′), 140.61 (C1′), 126.19 (Ph), 123.83 (Ph), 106.46 (C5).
4-(4-Methoxyphenyl)-1,3-selenazol-2-amine Hydrobromide (5a)
[Amine CAS Reg. No. 930300-93-9]
Salmon solid; yield: 197 mg (78%); mp 230–232 °C.
1H NMR (400 MHz, MeOD): δ = 7.56 (d, J = 8.9 Hz, 2 H, Ph), 7.22 (s, 1
H, H5), 7.04 (d, J = 8.9 Hz, 2 H, Ph), 3.85 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): δ = 174.7 (C2), 160.4 (C4′), 138.5 (C4),
127.81 (Ph), 122.7 (Ph), 114.9 (C3′), 104.7 (C5), 55.8 (OCH3)
MS (ESI): m/z = 254.9 ([M + H]+, 100%).
MS (ESI): m/z = 221.9 ([M]+, 100%).
4-(4-Chlorophenyl)thiazol-2-amine Hydrobromide (3e)
[CAS Reg. No. 69018-04-8]
4-(4-Fluorophenyl)-1,3-selenazol-2-amine Hydrobromide (5b)
[Amine CAS Reg. No. 904929-70-0]
Pale yellow solid; yield: 166 mg (79%); mp 236–239 °C.
1H NMR (400 MHz, MeOD): δ = 7.66 (d, J = 8.6 Hz, 2 H, Ph), 7.53 (d,
J = 8.6 Hz, 2 H, Ph), 7.13 (s, 1 H, H5).
13C NMR (75 MHz, DMSO-d6): δ = 170.0 (C2), 133.7 (C4), 129.6 (Ph),
128.9 (Ph), 128.2 (Ph), 127.5 (Ph), 103.5 (C5).
Pale yellow solid; yield: 183 mg (76%); mp 236–238 °C.
1H NMR (400 MHz, acetone-d6): δ = 7.92–7.86 (m, 2 H, Ph), 7.42 (s, 1
H, H5), 7.09 (t, J = 8.9 Hz, 2 H, Ph), 6.71 (br s, 2 H, NH2).
13C NMR (100 MHz, acetone-d6): δ = 171.5 (C2), 162.2 (d, J = 244.0 Hz,
C4′), 150.1 (C4), 132.7 (d, J = 3.0 Hz, C1′), 127.7 (d, J = 8.0 Hz, C2′),
114.6 (d, J = 22 Hz, C3′), 105.0 (d, J = 2.0 Hz, C5).
MS (ESI): m/z = 210.9 ([M]+, 100%), 211.8 ([M + 1]+, 33%).
MS (ESI): m/z = 243.0 ([M + H]+, 100%).
4-(4-Bromophenyl)thiazol-2-amine Hydrobromide (3f)
[CAS Reg. No. 42056-64-4]
White solid; yield: 218 mg (85%); mp 225–227 °C (Lit.14 239–242).
4-(p-Tolyl)-1,3-selenazol-2-amine Hydrobromide (5c)
[Amine CAS Reg. No. 537692-29-8]
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Brown solid; yield: 190 mg (80%); mp 286–288 °C.
13C NMR (125 MHz, DMSO-d6): δ = 169.4 (C2), 149.4 (C4), 134.5 (C1′),
131.2 (Ph), 128.3 (Ph), 127.5 (Ph), 106.6 (C5).
MS (ESI): m/z = 224.0 ([M + H]+, 100%).
1H NMR (400 MHz, MeOD): δ = 7.51 (J = 8.2 Hz, 2 H, Ph), 7.32–7.30 (m,
3 H), 2.39 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): δ = 169.1 (C2), 150.7 (C4), 136.0 (Ph),
133.1 (Ph), 128.9 (Ph), 125.7 (Ph), 104.8 (C5), 20.7 (CH3).
4-(2-Amino-1,3-selenazol-4-yl)benzonitrile Hydrobromide (5h)
MS (ESI): m/z = 238.9 ([M + H]+, 100%).
Salmon solid; yield: 144 mg (58%); mp 221–223 °C.
1H NMR (400 MHz, acetone-d6): δ = 8.05 (d, J = 8.5 Hz, 2 H, Ph), 7.77
(s, 1 H, H5), 7.73 (d, J = 8.6 Hz, 2 H, Ph), 6.83 (br s, 2 H, NH2).
13C NMR (75 MHz, DMSO-d6): δ = 170.1 (C2), 149.5 (C4), 140.2 (C1′),
132.9 (Ph), 126.9 (Ph), 119.5 (CN), 110.7 (C4′), 109.3 (C5).
MS (ESI): m/z = 247.9 ([M – H]–, 100%).
HRMS: m/z [M + H]+ calcd for C10H7N3Se: 249.9878; found: 249.9880.
4-(4-Nitrophenyl)-1,3-selenazol-2-amine Hydrobromide (5d)
[Amine CAS Reg. No. 537692-30-1]
Yellow solid; yield: 250 mg (93%); mp 235–238 °C.
1H NMR (400 MHz, MeOD): δ = 8.36 (d, J = 8.9 Hz, 2 H, H3′), 7.89 (d,
J = 8.9 Hz, 2 H, H2′), 7.70 (s, 1 H, H5).
13C NMR (75 MHz, DMSO-d6): δ = 170.2 (C2), 147.6 (C4), 145.8 (C4′),
141.0 (C1′), 126.6 (Ph), 123.9 (Ph), 111.4 (C5).
MS (ESI): m/z = 269.9 ([M + H]+, 100%).
Acknowledgment
The authors thank Farmanguinhos and FAPERJ for financial support of
this research. We also thank FAPERJ (M.M.A.) and CNPq (A.C.S.N.)
4-(4-Chlorophenyl)-1,3-selenazol-2-amine Hydrobromide (5e)
[Amine CAS Reg. No. 537692-27-6]
Salmon solid; yield: 154 mg (60%); mp 237–240 °C.
1H NMR (400 MHz, acetone-d6): δ = 7.88 (s, 2 H, Ph), 7.51 (s, 1 H, H5),
7.36 (d, J = 8.6 Hz, 2 H, Ph), 6.73 (br s, 2 H, NH2).
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131.7 (Ph), 128.8 (Ph), 128.0 (Ph), 107.1 (C5).
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4-(4-Bromophenyl)-1,3-selenazol-2-amine Hydrobromide (5f)
[Amine CAS Reg. No. 537692-28-7]
Pale brown solid; yield: 97 mg (42%); mp 225–226 °C.
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1H NMR (400 MHz, MeOD): δ = 7.67 (d, J = 8.6 Hz, 2 H, Ph), 7.56 (d,
J = 8.6 Hz, 2 H, Ph), 7.44 (s, 1 H, H5).
13C NMR (75 MHz, DMSO-d6): δ = 174.1 (C2), 137.9 (C4), 131.9 (Ph),
129.2 (Ph), 127.9 (Ph), 122.2 (Ph), 107.5 (C5).
MS (ESI): m/z = 232.8 ([M + H]+, 100%).
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4-Phenyl-1,3-selenazol-2-amine Hydrobromide (5g)
[CAS Reg. No. 156137-79-0]
Salmon solid; yield: 208 mg (93%); mp 220–222 °C.
1H NMR (400 MHz, MeOD): δ = 7.63 (dd, J = 7.8, 1.8 Hz, 2 H, Ph), 7.51–
7.47 (m, 3 H, Ph), 7.39 (s, 1 H, H5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 437–440