Aqueous NaHSO4 catalyzed regioselective and versatile synthesis of 2-thiazolamines

Article abstract of DOI:10.1007/s00706-008-0906-4

The green acidic catalyst NaHSO₄ was used for the synthesis of some novel substituted 2-thiazolamines in water under mild conditions in high regioselectivity.

Full text of DOI:10.1007/s00706-008-0906-4

Monatsh Chem 139, 1241–1245 (2008)
DOI 10.1007/s00706-008-0906-4
Printed in The Netherlands
Aqueous NaHSO4 catalyzed regioselective and versatile synthesis
of 2-thiazolamines
Shahnaz Rostamizadeh, Reza Aryan, Hamid R. Ghaieni, Ali M. Amani
Department of Chemistry, Faculty of Sciences, K.N. Toosi University of Technology, Tehran, Iran
Received 12 November 2007; Accepted 28 January 2008; Published online 21 April 2008
# Springer-Verlag 2008
Abstract The green acidic catalyst NaHSO4 was used halocarbonyl compound with a reactant bearing an
for the synthesis of some novel substituted 2-thiazol- N–C–S fragment such as thioamides, thioureas, or
amines in water under mild conditions in high regio- dithiocarbamic acid derivatives, which is known as
selectivity.
the Hantzsch process [6]. A plethora of reagents and
conditions have been used as a modification to the
general reaction outlined by Hantzsch, such as solid
supported thiazole synthesis [7], use of a heteroge-
neous silica chloride catalyst [8], aqueous phase syn-
thesis in the presence of cyclodextrin [9], use of
ammonium-12-molybdophosphate in methanol [10],
microwave promoted synthesis in ethanol [11], via
Lawesson’s reagent mediated cyclization [12], and
the use of ꢀ-halocarbonyl substitutes [13].
Green chemistry principles have gained their po-
sition in the heart of chemistry research fields be-
cause of economic and health related aspects [14].
Recently, designing new methodologies based on
greener solvents and catalysts are becoming very
popular among chemists. Water as the prototypical
green solvent has received considerable attention
because it is not only inexpensive and environmen-
tally friendly but also has unique antihydrophobic
effects as discovered by Breslow and coworkers at
the beginning of the 1980s [15]. When organic com-
pounds are dispersed and suspended in water, their
distinct insolubility in this medium causes them to
associate, diminish their interface with water mole-
cules, and increase the reaction rate [16]. So, the
application of water as the reaction medium has
been intensively expanded in the past two decades
[17].
Keywords Heterocycles; Water; NaHSO4; Regioselectivity;
Green catalysis.
Introduction
Thiazoles represent a very important class of hetero-
cycles. In Nature, the thiazolium ion is the chemi-
cally active center in the coenzyme derived from
vitamin B (thiamin). A large number of thiazoles
obtained from microbial and marine origins exhibit
important biological effects, such as antitumor, anti-
fungal, antibiotic, and antiviral activities [1]. Also,
thiazoles have found broad application in the discov-
ery and development of drugs used for the treatment
of allergies [2], hypertension [3], and inflammation
[4]. A novel field in which this building block has
been utilized is thiazolium-based ionic liquids [5]. In
view of these applications chemists are encouraged
to find new versatile and efficient methodologies to-
ward the synthesis of thiazoles.
The most widely used and classical synthesis ap-
proach to thiazoles involves the reaction of an ꢀ-
Correspondence: Shahnaz Rostamizadeh, Department of
Chemistry, Faculty of Sciences, K.N. Toosi University of
Technology, P. O. Box: 15875-4416, Tehran, Iran. E-mail:
shrostamizadeh@yahoo.com

1242
S. Rostamizadeh et al.
Scheme 1
Table 1 Aqueous NaHSO4 catalyzed synthesis of 2-thiazo-
lamines 3a–3k
Sodium hydrogen sulfate (NaHSO4) has been uti-
lized as a safe and efficient catalyst in a number of
transformations and syntheses [18]. Some of these
applications include selective removal of N-Boc pro-
tecting groups from protected amines [19a], synthe-
sis of bis- and tris(indolylmethanes) [19b], mild
nitrosation of secondary amines [19c], and 1,2-di-
hydroquinoline oxidation [19d]. This catalyst also
avoids problems such as corrosion and harmfulness
common to other protic acids, and can be handled
easily for use in synthesis purposes.
As a part of our ongoing research program towards
development of new and rapid methodologies for
the synthesis of heterocyclic compounds [20], we pres-
ent a new, convenient, efficient, and easy methodol-
ogy for the synthesis of substituted 2-thiazolamines.
Our initial aim was to overcome the limitations and
drawbacks of reported methods. Therefore, we have
come up with a rapid, efficient, and environmentally
benign route to prepare these useful heterocycles,
using aqueous NaHSO4 as a safe, inexpensive, and
efficient catalyst to promote the reaction.
ꢀ
Product 3
R1
R2
Time=min
Yield=%
a
b
c
d
e
f
g
h
i
H
H
H
H
Me
Me
Me
Me
Ph
Ph
Ph
H
OMe
Br
NO2
H
Br
OMe
NO2
H
NO2
OMe
25
30
25
10
30
45
30
20
35
5
quantitative
81
89
quantitative
82
85
93
90
90
quantitative
95
j
k
55
ꢀ
Isolated yield
Table 2 Screening of the amount of solvent and catalyst in
the synthesis of 4-phenyl-2-thiazolamine (3a)
ꢀ
Run Solvent
no.
Catalyst
Time= Yield=%
min
1
2
3
4
H2O
H2O
H2O
NaHSO4 (10%)
NaHSO4 (20%)
NaHSO4 (30%)
120
90
25
90
90
90
quantitative
80
Results and discussion
EtOH=H2O NaHSO4 (30%)
(1:1)
In this work, the Hantzsch process with new condi-
tions is presented in which sodium hydrogen sulfate
(30 mol%) is used in a small amount of water to
catalyze the reaction (Scheme 1).
5
EtOH=H2O NaHSO4 (30%)
(3:1)
50
75
80
6
EtOH
NaHSO4 (30%)
210
ꢀ
Isolated yield
To evaluate the scope and limitations of this new
methodology, various substituted phenacyl bromides
with electron donating and withdrawing substituents
were used to react with substituted thioureas (R1 ¼
H, Me, Ph; R2 ¼ H, OMe, Br, NO2) (Table 1, prod-
ucts 3a–3k). To optimize the reaction condition and
find the optimal amount of catalyst, the process was
performed under various conditions (Table 2).
The most interesting piece of information in Table 2
is that upon going from aqueous ethanol to pure
water as solvent, both the rate and the yield of reac-
tion are improving. As indicated in Scheme 1, in the
case of N-methyl- and N-phenylthiourea formation
of both products 3 and 4 is possible. A previous
study [21] has shown that in the presence of 10 M
HCl in EtOH (1=2 v=v) the regioisomer 4 was
formed, while changing the acidic condition led to
a mixture of isomers 3 and 4. It is interesting to point
out that in the present study, running the reaction in
aqueous sodium hydrogen sulfate at room tempera-
ture results in the formation of product 3 (R1 ¼ Me,
Ph, R2 ¼ H) as the only product. The fragmentation
pattern in mass spectra for compounds 3e–3k is in
agreement with the general pattern accepted for aro-

Versatile synthesis of 2-thiazolamines
1243
tic acids (H2SO4, HCl, HNO3, HBr, and Na2HPO4).
The results are presented in Table 4. In all cases the
Hantzsch reaction was run with 30 mol% of each
catalyst at room temperature, in which two products
were detected in the reaction mixture by TLC and no
remarkable regioselectivity was observed for most
acids (entries 2–5, Table 4). Furthermore, the prod-
ucts did not precipitate during the reaction in con-
trast to what was seen with NaHSO4 and therefore
we were not able to reuse the reaction mixture (the
catalyst). In these cases, we had to neutralize the
reaction mixture in order to obtain the desired prod-
ucts. The results obtained for HCl (Table 4, entry 1)
are in accordance to a previous study [21]. Aqueous
NaHSO4 is the only protic acid catalyst which is able
to promote the convenient synthesis of 2-thiazola-
mines and its solution in water can be recovered
easily and reused.
Scheme 2
matic thiazole ring substituents 3 and not for a dihy-
drothiazole 4. For example, the peak with m=z ¼ 134
(Mþ – 56) is due to the formation of 2-phenylthiir-
anium ion derived from the molecular ion by the loss
of the NCNHMe fragment (Scheme 2). This is in
accordance with the general pattern of fragmenta-
tion, which has been proposed for the 4-phenylthia-
zole ring system [22].
The reusability of the solution of 30mol% NaHSO4
in water was tested and the comparative results are
shown in Table 3. When 30mol% NaHSO4 in 2 cm3
water were used for each mmol of reactants, the prod-
ucts precipitated and could be easily isolated via
simple filtration.
In conclusion, we reported a new, eco-friendly,
and reusable catalytic system for the synthesis of
2-thiazolamines. Simple workup, easy recycling, re-
usability of the catalytic system, and the formation
of some new and regioselective derivatives of 2-thia-
zolamines are the most important aspects of this
process.
We then attempted to compare the reusability and
regioselectivity observed for NaHSO4 with other pro-
Table 3 Reusability of aqueous NaHSO4 in synthesis of 4-
phenyl-2-thiazolamine (3a)
Experimental
ꢀ
Melting points were recorded on a Bu¨chi B-540 apparatus. IR
spectra were recorded on an ABB Bomem Model FTLA200-
100 instrument. 1H and 13C NMR spectra were measured
with a Bruker DRX-300 Avance spectrometer at 300 and
75MHz using TMS as an internal standard. Chemical shifts
(ꢁ) are reported relative to TMS, and coupling constants (J) are
reported in Hz. Mass spectra were recorded on a Shimadzu QP
1100 EX mass spectrometer with 70eV ionization potential.
Elemental analyses of new compounds were performed with a
Vario EL III 0 Serial No. 11024054 instrument and their
results agreed favorably with calculated values.
Run no.
Time=min
Yield=%
1
2
3
4
5
25
35
40
60
90
quantitative
95
91
90
75
ꢀ
Isolated yield
Table 4 Comparison of regioselectivity for Hantzsch reaction
in water for formation of product 3e using some common
protic acids
General experimental procedure for the synthesis
of 2-thiazolamines in aqueous NaHSO4
Thiourea or its N-methyl and N-phenyl derivatives (1 mmol)
was dissolved in 2 cm3 water containing 36mg NaHSO4
(30 mol%) and 1 mmol substituted phenacyl bromide was
added to this solution. The mixture was stirred at room tem-
perature and monitored by TLC (ethyl acetate:petroleum ether
1:3). After completion of the reaction, the precipitated solids
which formed (2-thiazolamine hydrobromide) were collected
by filtration and were then neutralized with 20% NaHCO3
solution to afford the free base. The filtrate was reused five
times. The products were further purified by recrystallization
from a mixture of ethanol=water and washed with water to
afford pure products.
ꢀ
Entry
Catalyst
Time=
min
Product
ꢀꢀ
Product
ꢀꢀ
3e=%
4e=%
1
2
3
4
5
6
HCl
15
25
35
15
60
30
10
30
50
50
50
82
80
60
50
50
50
–
H2SO4
HNO3
HBr
NaH2PO4
NaHSO4
ꢀ
30% of catalyst relative to mol of phenacyl bromide
Isolated product
ꢀꢀ

1244
S. Rostamizadeh et al.
N-Methyl-4-phenyl-2-thiazolamine (3e, C10H10N2S)
White crystals, 0.155g (82%), mp 134–136ꢁC; IR (KBr): ꢂꢀ¼
N-Phenyl-4-nitrophenyl-2-thiazolamine (3j, C15H11N3O2S)
Light orange crystalline powder, 0.295g (quantitative), mp
1
3219, 3106, 3003, 2916, 1586, 1456, 1376cmꢂ1; H NMR
226–229ꢁC; IR (KBr): ꢂꢀ¼ 3288, 3145, 3102, 1622cmꢂ1
;
(300 MHz, DMSO-d6): ꢁ ¼ 2.88 (d, J ¼ 4.8 Hz, 3H), 7.02 (s,
1H), 7.25 (t, J ¼ 4.2 Hz, 1H), 7.36 (t, J ¼ 7.5 Hz, 2H), 7.55 (q,
J ¼ 4.8 Hz, 1H), 7.85 (d, J ¼ 4.2, 2H) ppm; 13C NMR (75 MHz,
DMSO-d6): ꢁ ¼ 31.0 (NHCH3), 100.7, 125.6, 127.2, 128.4,
134.9, 150.2, 169.3 (N–C–S fragment in thiazole ring) ppm;
MS (EI, 70eV): m=z (%) ¼ 190 (100) [Mþ], 162 (33), 134 (40),
102 (20), 45 (10).
1H NMR (300MHz, DMSO-d6): ꢁ ¼ 6.98 (t, J ¼ 6.0 Hz, 1H),
7.35 (t, J ¼ 7.5 Hz), 7.72 (d, J ¼ 7.5 Hz, 3H), 8.16 (d, J ¼
4.5 Hz, 2H), 8.27 (d, J ¼ 4.5Hz, 2H); 13C NMR (75 MHz,
DMSO-d6): ꢁ ¼ 108.0, 117.0, 121.5, 124.2, 126.5, 129.1,
140.5, 141.0, 146.2, 148.1, 163.5 ppm; MS (EI, 70eV): m=z
(%) ¼ 297 (100) [Mþ], 267 (30), 251 (80), 150 (75), 104 (30).
N-Phenyl-4-methoxyphenyl-2-thiazolamine
(3k, C16H14N2OS)
N-Methyl-4-bromophenyl-2-thiazolamine
(3f, C10H9BrN2S)
White crystalline powder, 0.268g (95%), mp 182–184ꢁC; IR
White crystals, 0.229g (85%), mp 146–148ꢁC; IR (KBr): ꢂꢀ¼
(KBr): ꢂꢀ¼ 3291, 3159, 3098, 2951, 1617cmꢂ1
;
1H NMR
1
3250, 3111, 3008, 2931, 1576, 1486, 1396cmꢂ1; H NMR
(300MHz, DMSO-d6): ꢁ ¼ 3.77 (s, 3H, OCH3), 6.97 (t, J ¼
8.4 Hz, 3H), 7.14 (s, 1H), 7.34 (t, J ¼ 8.4Hz, 2H), 7.71
(d, J ¼ 8.4 Hz, 2H), 7.83 (d, J ¼ 8.4Hz, 2H), 10.35 (s, 1H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 55.2, 100.8,
114.1, 117.1, 121.5, 127.1, 127.1, 129.2, 141.1, 149.4, 159.0,
163.4 ppm; MS (EI, 70eV): m=z (%) ¼ 282 (100) [Mþ], 150
(15), 93 (10), 64 (15).
(300 MHz, DMSO-d6): ꢁ ¼ 2.86 (d, J ¼ 4.8 Hz, 3H), 7.12 (s,
1H), 7.52 (t, J ¼ 2.1 Hz, 1H), 7.55 (t, J ¼ 1.8 Hz, 1H), 7.58 (q,
J ¼ 5.1 Hz, 1H), 7.76 (t, J ¼ 5.1, 1H), 7.79 (t, J ¼ 5.1 Hz, 1H)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 30.9 (NHCH3),
101.7, 120.1, 127.6, 131.3 (C–Br phenyl ring), 134.1, 148.9
(C–N thiazole ring), 169.4 (N–C–S fragment in thiazole ring)
ppm; MS (EI, 70 eV): m=z (%) ¼ 270 (100) [Mþ], 272 (98)
[Mþ þ 2], 240 (40), 214 (15), 182 (20), 133 (30), 89 (50),
45 (10).
Acknowledgements
We are grateful to the Research Council of K.N. Toosi
University of Technology for partial financial support and
Dr. K. Jadidi from Shahid Beheshti University for helpful
discussions.
N-Methyl-4-methoxyphenyl-2-thiazolamine
(3g, C11H12N2OS)
White crystals, 0.204 g (93%), mp 126–128ꢁC; IR (KBr):
ꢂꢀ¼ 3266, 3101, 3004, 2921, 1581, 1477, 1380 cmꢂ1
;
1H
NMR (300 MHz, DMSO-d6): ꢁ ¼ 2.85 (d, J ¼ 4.8Hz, 3H),
3.76 (s, 3H), 6.85 (s, 1H), 6.91 (d, J ¼ 8.7 Hz, 2H), 7.49 (q,
J ¼ 4.8 Hz, 1H), 7.75 (d, J ¼ 8.7 Hz, 2H) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢁ ¼ 31.0 (NHCH3), 55.0 (OMe), 98.6,
113.8, 126.9, 127.8, 150.0 (C–OMe in phenyl ring), 158.6 (C–
N thiazole ring), 169.3 (N–C–S fragment in thiazole ring)
ppm; MS (EI, 70 eV): m=z (%) ¼ 220 (100) [Mþ], 192 (25),
149 (50), 121 (30), 77 (20), 45(20).
References
1. Lewis JR (1996) Nat Prod Rep 13:435
2. Hargrave KD, Hess FK, Oliver JT (1983) J Med Chem
26:1158
3. Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor
DG Jr, Connolly CJC, Doherty AM, Klutchko SR, Sircar
I, Steinbaugh BA, Batley BL, Painchaud CA, Rapundalo
ST, Michniewicz BM, Olson SCJ (1992) J Med Chem
35:2562
4. Haviv F, Ratajczyk JD, DeNet RW, Kerdesky FA, Walters
RL, Schmidt SP, Holms JH, Young PR, Carter GW (1988)
J Med Chem 31:1719
5. Davies JH Jr, Forrester KJ (1999) Tetrahedron Lett
40:1621
6. Dondoni A, Merino P (1996) Thiazoles. In: Katritzky AR,
Rees CW, Scriven EFV (eds) Comprehensive Heterocy-
clic Chemistry, vol 3, Pergamon Press, Elsevier Science
Ltd., p 432
7. Kazzouli SE, Berteina-Raboin S, Mouaddib A, Guillaumet
G (2002) Tetrahedron Lett 43:3193
N-Methyl-4-nitrophenyl-2-thiazolamine (3h, C10H9N3O2S)
Light orange crystalline powder, 0.234 g (90), mp 214–217ꢁC;
IR (KBr): ꢂꢀ¼ 3255, 3111, 3003, 2916, 1601, 1498, 1378,
1335 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6): ꢁ ¼ 2.89 (d,
J ¼ 4.5 Hz, 3H), 7.43 (s, 1H), 7.71 (d, J ¼ 4.5 Hz, 1H), 8.06
(dt, J ¼ 8.7 Hz, J ¼ 2.1, 2H), 8.22 (dt, J ¼ 8.7 Hz, J ¼ 2.1, 2H)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 30.9 (NHCH3),
105.9, 123.9, 126.3, 140.8 (C–NO2), 146.0, 148.1, 169.5
(N–C–S fragment in thiazole ring) ppm; MS (EI, 70eV):
m=z (%) ¼ 235 (100) [Mþ], 207 (70), 174 (35), 121 (20), 89
(50), 30 (25).
N-Phenyl-4-phenyl-2-thiazolamine (3i, C15H12N2S)
White crystalline powder, 0.225 g (90%), mp 142ꢁC (Ref. [23]
134–136ꢁC); IR (KBr): ꢂꢀ¼ 3250, 3121, 3060, 2916,
8. Karade H, Sathe M, Kaushik MP (2007) Catalysis Com-
mun 8:741
9. Narender M, Saidi Reddy V, Sridhar R, Nageswar YVD,
Rama Rao K (2005) Tetrahedron Lett 46:5953
10. Das B, Saidi Reddy V, Ramu R (2006) J Mol Cat A
252:235
1607 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6): ꢁ ¼ 6.97 (t,
J ¼ 7.5 Hz, 1H), 7.28–7.44 (m, 6H), 7.72 (d, J ¼ 8.1 Hz,
2H), 7.90 (d, J ¼ 7.2Hz, 2H), 10.38 (s, 1H) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢁ ¼ 103.0, 117.2, 121.6, 125.8, 127.8,
128.8, 129.2, 134.3, 141.1, 149.6, 163.4ppm.
11. Kabalka GW, Mereddy AR (2006) Tetrahedron Lett
47:5171

Versatile synthesis of 2-thiazolamines
1245
12. Kiryanov AA, Sampson P, Seed AJ (2001) J Org Chem
66:7925
R, Das B (2003) Adv Synth Catal 345:557; c) Zolfigol
MA, Madrakian E, Ghaemi E, Kiani M (2000) Synth
Commun 30:2057; d) Damavandi JA, Zolfigol MA,
Karimi B (2001) Synth Comm 31:3183
13. a) Ochiai M, Nishi Y, Hashimoto S, Tsuchimoto Y, Chen
DW (2003) J Org Chem 68:7887; b) Miyamoto K, Nishi
Y, Ochiai M (2005) Angew Chem Int Ed 44:6896
14. Anastas PT, Kirchhoff MM (2002) Acc Chem Res 35:
686
15. a) Breslow R (1991) Acc Chem Res 24:159; b) Li C-J,
Chen L (2006) Chem Soc Rev 35:68
16. a) Li CJ, Chan TH (1997) Organic Reactions in Aqueous
Media, Wiley, New York; b) Li CJ (1993) Chem Rev
93:2023; c) Lubineau A, Auge J, Queneau Y (1994)
Synthesis:741
20. a) Rostamizadeh Sh, Tajik H, Yazdanfarahi S (2003) Synth
Commun 33:113; b) Rostamizadeh Sh, Sadeghi A (2002)
Synth Commun, 32:1899; c) Rostamizadeh Sh, Housaini
AGh (2004) Tetrahedron Lett 45:8753; d) Rostamizadeh
Sh, Housaini AGh (2005) Phosphorus Sulfur and Silicon
180:1321; (e) Rostamizadeh Sh, Mollahousaini K (2006)
Phosphorus Sulfur and Silicon 181:1839
21. Bramley SE, Dupplin V, Goberdhan DGC, Meakins D
(1987) J Chem Soc Perkin Trans I:639
17. Li CJ (2005) Chem Rev 105:3095
18. Kolvari E (2006) Synlett:1971
19. a) Ravindranath N, Ramesh C, Reddy M, Das B (2003)
Adv Synth Catal 345:1207; b) Ramesh C, Banerjee J, Pal
22. Porter QN (1985) In: Mass Spectrometry of Heterocyclic
Compounds, Wiley-Interscience, John Wiley & Sons
Inc., p 899
23. Bhattacharya AK (1967) Indian J Chem 5:62