A rapid, mild, and efficient method for C-5 iodination/thiocyanation of 2-aminothiazoles

Article abstract of DOI:10.1080/10426507.2016.1149851

An efficient, green, rapid multitasking protocol for the selective C-5 substitution of 2-aminothiazole using iodic acid and aqueous PEG-400 was developed. The method found suitable for C-5 substitution i.e. iodination and thiocyanation of 2-amino thiazole

Full text of DOI:10.1080/10426507.2016.1149851

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A Rapid, Mild and Efficient Method for C-5
Iodination/Thiocyanation of 2-Aminothiazoles
Madhav J. Hebade, Rahul D. Kamble, Shrikant V. Hese, Pratima P. Mogle, Ajay
N. Ambhore, Shuddhodan N. Kadam & Bhaskar S. Dawane
To cite this article: Madhav J. Hebade, Rahul D. Kamble, Shrikant V. Hese, Pratima P. Mogle,
Ajay N. Ambhore, Shuddhodan N. Kadam & Bhaskar S. Dawane (2016): A Rapid, Mild and
Efficient Method for C-5 Iodination/Thiocyanation of 2-Aminothiazoles, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2016.1149851
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1149851
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Feb 2016.
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A Rapid, Mild and Efficient Method for C-5 Iodination/Thiocyanation of 2-Aminothiazoles
Madhav J. Hebade, Rahul D. Kamble1, Shrikant V. Hese, Pratima P. Mogle, Ajay N. Ambhore,
Shuddhodan N. Kadam, Bhaskar S. Dawane1,*
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University Nanded (MS)
India-431606
*Correspondence author Email: bhaskardawane@rediffmail.com
1Author Contributed Equally with First Author
Abstract
An efficient, green, rapid multitasking protocol for the selective C-5 substitution of 2-
aminothiazole using iodic acid and aqueous PEG-400 was developed. The method found suitable
for C-5 substitution i.e. iodination and thiocyanation of 2-amino thiazole using iodine and
ammonium thiocyanate respectively. Iodic acid was found to be a good oxidant and aqueous
PEG-400 as green reaction solvent.
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Keywords
Aq. PEG-400, Iodination, Thiocyanation, Iodic Acid, 2-Aminothiazole
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Introduction
Aromatic and hetero-aromatic molecules are important compounds in synthetic organic
chemistry, and widely used in the pharmaceutical and chemical industries. Substituted arenes and
substituted heterocycles are valuable intermediates in the synthesis of a wide variety of organic
compounds through C-C bond formation by transition metal [1]. They can be easily
functionalized through metal catalyzed cross coupling reaction [2, 3]. These derivatives have
been used in the synthesis of many interesting natural products and also bioactive material.
Thiazoles are emerging as an important class of heterocycles due to their broad spectrum of
biological activities [4, 5]. Natural and synthetic molecules containing thiazole scaffold play a
significant role in pharmaceutical due to their anti-inflammatory [6] anti HIV, antibacterial [7]
properties. The literature survey revealed that C-5 substituted amino thiazole exhibits versatile
biological activity such as; (5-F) substitution of an aminothiazole moiety possees thromboprotein
receptor agonist’s activity with an improved hepatic safety profile in rodent toxicology studies
[8]. C-5 (5-Br) substituted aminothiazole found as fructose-01,6-bisphosphatase inhibitors for the
treatment of Type-2 diabetes [9].
Among those methods reported to achieve substitution (iodination and thiocyanation) of
heteroaromatic and aromatic compounds, such as ICl/Ag2SO4/H2SO4 [10], HNO3/H2SO4 [11],
KMnO4/H2SO4 [12], Pb(OAC)4/HOAc [13], NIS/CF3COOH [14], I2-tetra butyl ammonium
peroxydisulfate [15], I2-thallium acetate [16], I2--F-TEDA-BF4 [17], tetrafluoroborate-CF3 SO3H
[18], BuLi-F3CCH2 I [19], NaOCl-NaI [20] PhI(OAc)2 i.e. DIB [21] for iodination and
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oxone/NH4SCN [22], I2/NH4SCN [23], FeCl3/NH4SCN [24], CAN/NH4SCN [25], acidic K-10
clay/NH4SCN [26], HIO3/ NH4SCN [27], Mn(OAc)/NH4SCN [28], trichoroisocyanuric acid/
NH4SCN [29] have been employed for thiocyanation.
However, most of the method suffers from major drawback such as use of harsh conditions [11,
29], heavy metal catalyst [10, 13, 16, 24, 28], use of halogenated solvents [27, 29] and longer
reaction time [21]. Moreover, there was no report found in the literature for the utility of a single
reagent for both processes, i.e. iodination as well as for thiocyanation efficiently. Hence, there
has been much interest in the development of alternative methods here mild, green and possibly
multitasking and more selective reagents are employed.
In order to overcome these major shortcomings of existing methodology, here in we reported an
exceedingly simple, mild and efficient multitasking reagent for iodination/thiocyanation of aryl
substituted 2-aminothiazoles. An iodine/ammonium thiocyanate combined with iodic acid in
aqueous PEG-400 has found to be an excellent reagent for efficient iodination/thiocyanation of
aryl substituted 2-aminothiazoles. A variety of substituted thiazoles were investigated for the
iodination/thiocyanation reaction with iodine/ammonium thiocyanate by using iodic acid as a
mild and efficient oxidant. Iodic acid, iodine/ammonium thiocyante was proven as a selective
reagent for iodination/thiocyanation of thiazole at C-5 carbon.
Result and Discussion
As part of our systematic studies on the development of green, sustainable methodologies [30],
here we explored synthetic method having multitasking and multi-operational application using
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iodic acid and aqueous PEG-400 as a green catalytic system for C-5 iodination of 2-amino
thiazole derivatives (Scheme 1).
Accordingly, we envisioned that the thiocyanation of 2-aminothiazole with iodic acid and
ammonium thiocyanate could be carried out, affording the corresponding C-5 thiocyanated
derivatives (Scheme 2). A review of the literature revealed that, there were no reports concerning
C-5 substitution of 2-aminothiazole using HIO3 in aqueous PEG-400. Our method holds a tag of
a novel route which first time utilizes the HIO3/PEG-400-H2O as a green catalytic system for
multitasking operations.
Initially, studies were focused on examining the feasibility of the iodination, thiocyanation and
optimizing reaction conditions that could be applied to a variety of 2-aminothiazole derivatives.
C-5 iodination of 4-(4-bromophenyl)thiazol-2-amine was chosen as a model reaction. The
optimal reaction conditions used previously for the iodination of activated arenes were initially
employed in the present case [31]. The effects of varying the catalyst, solvent and reaction
temperature on the model reaction were then examined. Table 1 shows the results of the reaction
using several iodinating and oxidizing agents.
These results show that both I2/HIO3 in CHCl3 and I2/HIO3 in PEG-400 were demonstrate an
excellent catalytic system for the iodination of 2-aminothiazole, although in CHCl3 yield of
reaction at lower side. The use of PEG-400 as a solvent in the reaction played an important role,
with iodic acid being an excellent catalytic system. In particular, the use of I2/NH4SCN with 1
equiv of iodic acid was the most efficient for C-5 iodination/thiocyanation. Although I2/HIO3 in
CHCl3 (Table 1, entry 5) were also efficient as the present catalytic system, the results were
inferior to those of I2/HIO3 in PEG-400 (Table 1, entry 8, 9). To our delight similar conditions
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worked for thiocyanation with a desired quantitative yield [31]. These results show that solvent
and oxidant is interdependent. For example, when ethanol employed as the solvent, KI/KIO3,
KI/HIO3 and I2/HIO3 were observed to be good catalyst for the reaction. However, it was worth
noting that in the solvent PEG-400, catalyst KI/KIO3, KI/HIO3 and I2/HIO3 were found as better
oxidizing agents (Table 1, entry 2, entry 4 and entry 8). From an environmental point of view,
water is an attractive option, and its ability to enhance the rate of reaction and affect the
selectivity of various organic transformation reactions due to high hydrogen bonding [32]. We
also observed water as solvent for the model reaction. The result shows an overall decrease in the
yield of product (entry 6) Table 1. Furthermore, the use of PEG-400 and water in combination
leads to the highest yield of the product, this might be due to the phase transfer nature of PEG-
400.
We further studied the scope of this method for 2-aminothiazoles as summarized in Table 2. All
the thiazoles having a hydroxyl, methoxyl or methyl group at the para, meta, or ortho positions,
respectively, could not give the desired C-5 substituted 2-aminothiazole, even after higher
catalyst loading. Electron-donating groups gave a deleterious effect on the C-5 substitution of 2-
aminothiazole. A possible reason for this is due positive mesomeric effect of electron donating
substituents such as oxygen, methoxyl and methyl which activate the arene ring and substitution
mainly occurs at ortho to electron donating substituent of arene ring instead of C-5 position of 2-
aminothiazole (Scheme 3). More importantly, this protocol could be applied to 2-aminothiazole
having electron withdrawing group, efficiently affording the C-5 substitution.
The structure of compounds 2a-k and 3a-k were established by their IR, 1H NMR, 13C NMR and
Mass spectral analysis. The disappearance of singlet of thiazole C-5 proton from δ 7.02 ppm and
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appearance of peak at 111 ppm in 13C NMR confirms the C-5 substitution along with mass
spectral analysis indicate M+ ion corresponding to the molecular weight, the appearance M+ and
M+2 pattern confirms the presence of chlorine. Furthermore thiocyantion was confirmed by IR
spectrum. The appearance of C≡N stretching vibration band at 2150 cm1 in the IR spectra of
compound 3a-k confirms the thiocyanation at C-5 position.
Experimental
All reagents were obtained from commercial suppliers and used without further purification.
Reaction progress was monitored through thin layer chromatography (TLC) on pre-coated Merck
alu-foil plate (silica gel 60F-254, 0.25 mm thickness) visualized by iodine vapors. Melting points
were determined by open capillary method and are uncorrected. IR spectra were recorded (in
KBr pallets) on Perkin Elmer spectrophotometer.1H NMR spectra were recorded on a
Avance/Bruker 300/400 MHz using TMS as an internal standard. All NMR spectra were
obtained in DMSO d6/deuterated chloroform (CDCl3); chemical shifts are reported in parts per
million, and coupling constant in hertz (Hz). Multiplicities are reported as follows: s (singlet), d
(doublet), t (triplet), m (multiplet). The mass spectra were recorded on Maldi spectrometer and
1
mass values are reported in m/z. The Supplemental Materials contains sample IR, mass, H and
13C NMR spectra for products 2 and 3 (Figures S 1 -- S 23)
General procedure for synthesis of 2a-k
To a mixture of 2-aminothiazole 1a-k (1 mmol), iodine (1 mmol) dissolved in (10 mL) of PEG
400 and water mixture, iodic acid (1 mmol) dissolved in water (1 mL) was added with stirring
and then the reaction mixture was stirred for 10-15 min at room temparature. After completion of
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reaction (As indicated by TLC) the reaction mixture was diluted with ice cold water. The solid
product was filtered, washed with saturated solution of sodium thiosulfate to remove excess of
iodine and later with cold water. The crude products were further purified by column
chromatography. All the compounds were characterized by spectral analysis technique. All the
remaining derivatives 2a-k were prepared according to the typical procedure given above with
more than 90% yield.
General procedure for synthesis of 3a-k
To a mixture of 2-aminothiazole 1a-k (1 mmol), ammonium thiocyanate (1 mmol) dissolved in
(10 mL) of PEG 400 and water mixture, iodic acid (1 mmol) dissolved in water (1 mL) was
added with stirring and then the reaction mixture was stirred for 10-15 min at room temparature.
After completion of reaction (As indicated by TLC) the reaction mixture was diluted with ice
cold water and neutralised with sodium bicarbonate. The solid product was filtered, washed with
cold water. The crude products were further purified by column chromatography (Petrolium
ehter/Ethyl acetate) 20%. All the remaining derivatives 2a-k were prepared according to the
typical procedure given above with more than 90% yield.
Spectral data of selected compounds
4-(4-Chloro-phenyl)-5-iodo-thiazol-2-ylamine (2a); Isolated as a brown solid; mp 173-175°C;
IR (KBr, υ, cm1): 3466, 3268, 3080, 1631; 1HNMR (300MHz, DMSO-d6) δH: 7.37 (s, 2H, NH2),
7.47 (d, 2H, J = 7.2 Hz, Ar-H), 7.79 (d, 2H, J = 7.4 Hz, Ar-H); 13C NMR (DMSO-d6) δC: 112.1,
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128.2, 129.7, 132.5, 133.9, 150.9, 171.7; HRMS calculated for C9H6ClIN2S [M]+: 336.5798;
Found 336.8744 [M]+.
4-(4-Nitro-phenyl)-5-iodo-thiazol-2-ylamine (2b); Isolated as a orange solid; mp 162-164°C;
IR (KBr, υ, cm1): 3466, 3278, 3064, 1617; 1HNMR (300MHz, DMSO-d6) δH: 7.47 (s, 2H, NH2),
8.01 (d, 2H, J = 6.8 Hz, Ar-H), 7.26 (d, 2H, J = 7.2 Hz, Ar-H); 13C NMR (DMSO-d6) δC: 123.4,
129.0, 141.2, 146.3, 149.8, 171.7; HRMS calculated for C9H6IN3O2S [M]+: 347.1323; Found
346.8764 [M]+.
4-(4-Bromo-phenyl)-5-iodo-thiazol-2-ylamine (2c); Isolated as a brown solid; mp 158-160°C;
1
IR (KBr, υ, cm1): 3466, 3283, 3080, 1631; HNMR (300MHz, DMSO-d6) δH: 7.36 (s, 2H,
NH2), 7.62 (d, 2H, J = 7.3 Hz, Ar-H), 7.74 (d, 2H, J = 8.1 Hz, Ar-H); 13C NMR (DMSO-d6) δC:
111.2, 120.9, 127.5, 130.1, 130.9, 134.0, 150.8, 171.5; HRMS calculated for C9H6BrIN2S [M]+:
381.0308; Found 381.0269 [M]+.
4-(4-Floro-phenyl)-5-iodo-thiazol-2-ylamine (2d); Isolated as a yellow solid; mp 143-145°C;
IR (KBr, υ, cm1): 3441, 3280, 3067, 1613; 1HNMR (300 MHz, DMSO-d6) δH: 7.34 (d, 2H, J =
7.0 Hz, Ar-H), 7.67 (d, 2H, J = 7.2 Hz, Ar-H), 7.82 (s, 2H, NH2); 13C NMR (DMSO-d6) δC:
111.1, 121.1, 127.3, 130.6, 131.0, 134.0, 151.0, 171.5; HRMS calculated for C9H6FIN2S [M]+:
320.1252; Found 319.8243 [M]+.
4-(3-Nitro-phenyl)-5-iodo-thiazol-2-ylamine (2e); Isolated as a orange solid; mp 177-179°C;
1
IR (KBr, υ, cm1): 3468, 3264, 3057, 1627; HNMR (300 MHz, DMSO-d6) δH: 7.48 (s, 2H,
NH2), 7.71-8.33 (m, 3H, J = 7.6 Hz, Ar-H), 8.68 (s, 1H, J = 7.3 Hz, Ar-H),; 13C NMR (DMSO-
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d6) δC: 122.3, 122.4, 129.7, 133.9, 136.3, 147.5, 149.2, 171.7; HRMS calculated for C9H6IN3O2S
[M]+: 347.1323; Found 346.8498 [M]+.
4-(3,4-Dichloro-phenyl)-5-iodo-thiazol-2-ylamine (2f); Isolated as a brown solid; mp 153-
155°C; IR (KBr, υ, cm1): 3434, 3254, 3039, 1607; 1HNMR (300 MHz, DMSO-d6) δH: 7.31 (s,
13
2H, NH2), 7.59 (d, 2H, J = 6.9 Hz, Ar-H), 7.78 (s, 1H, Ar-H); C NMR (DMSO-d6) δC: 111.7,
128.1, 129.7, 132.5, 133.9, 151.1, 171.7; HRMS calculated for C9H5Cl2IN2S [M]+: 371.0249;
Found 369.8595 [M]+.
4-(2-Floro-phenyl)-5-iodo-thiazol-2-ylamine (2g); Isolated as a pale yellow solid; mp 150-
1
152°C; IR (KBr, υ, cm1): 3447, 3273, 3062, 1603; HNMR (300 MHz, DMSO-d6) δH: 7.15 (s,
13
2H, NH2), 7.41-7.67 (m, 4H, J = 7.9 Hz, Ar-H); C NMR (DMSO-d6) δC: 111.2, 121.3, 127.3,
130.5, 131.1, 133.8, 151.1, 171.5; HRMS calculated for C9H6FIN2S [M]+: 320.1252; Found
319.3265 [M]+.
4-(2-Bromo-phenyl)-5-iodo-thiazol-2-ylamine (2h); Isolated as a brown solid; mp 168-170°C;
1
IR (KBr, υ, cm1): 3460, 3273, 3077, 1635; HNMR (300 MHz, DMSO-d6) δH: 7.32 (s, 2H,
NH2), 7.60 (d, 2H, J = 7.1 Hz, Ar-H), 7.68 (d, 2H, J = 8.1 Hz, Ar-H); 13C NMR (DMSO-d6) δC:
110.9, 121.0, 127.6, 130.1, 131.0, 133.9, 150.8, 171.5; HRMS calculated for C9H6BrIN2S [M]+:
381.0308; Found 382.8264 [M]+.
4-(3-Bromo-phenyl)-5-iodo-thiazol-2-ylamine (2i); Isolated as a brown solid; mp 147-149°C;
1
IR (KBr, υ, cm1): 3461, 3243, 3083, 1616; HNMR (300 MHz, DMSO-d6) δH: 7.33-7.42 (m,
13
3H, J = 7.4 Hz, Ar-H), 7.72 (s, 1H, Ar-H), 7.81 (s, 2H, NH2); C NMR (DMSO-d6) δC: 111.1,
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121.2, 126.9, 130.1, 130.9, 134.1, 151.2, 171.5; HRMS calculated for C9H6BrIN2S [M]+:
381.0308; Found 380.9564 [M]+.
4-(3-Chloro-phenyl)-5-iodo-thiazol-2-ylamine (2j); Isolated as a brown solid; mp 171-173°C;
1
IR (KBr, υ, cm1): 3454, 3278, 3069, 1627; HNMR (300 MHz, DMSO-d6) δH: 7.35 (s, 2H,
NH2), 7.59-7.64 (m, 3H, J = 7.8 Hz, Ar-H), 7.70 (s, 1H, Ar-H); 13C NMR (DMSO-d6) δC: 111.5,
128.0, 129.7, 132.6, 134.2, 151.3, 171.7; HRMS calculated for C9H6ClIN2S [M]+: 336.5798;
Found 335.9709 [M]+.
4-([1,1'-biphenyl]-4-yl)-5-iodothiazol-2-amine (2k); Isolated as a yellow solid; mp 153-155°C;
1
IR (KBr, υ, cm1): 3441, 3221, 3090, 1623; HNMR (300 MHz, DMSO-d6) δH: 7.23-7.30 (m,
5H, Ar-H), 7.46 (d, 2H, J = 7.8, Ar-H), 7.72 (d, 2H, J = 6.8, Ar-H), 7.81 (s, 2H, NH2); 13C NMR
(DMSO-d6) δC: 111.1, 124.2, 127.2, 127.6, 127.9, 128.1, 129.2, 131.1, 140.9, 141.1, 154.2,
170.4; HRMS calculated for C15H11IN2S [M]+: 378.2307; Found 378.8234 [M]+.
4-(4-Chloro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3a); Isolated as a yellow solid; mp 138-
1
140°C; (KBr, υ, cm1): 3381, 3286, 3095, 2150, 1640; HNMR (300 MHz, DMSO-d6) δH: 7.55
(s, 2H, NH2), 7.79 (d, 2H, J = 7.2 Hz, Ar-H), 7.81 (d, 2H, J = 7.7 Hz, Ar-H); 13C NMR (DMSO-
d6) δC: 92.3, 111.9, 128.4, 130..5, 131.7, 133.7, 157.1, 170.8; HRMS calculated for C10H6BrN3S2
267.7577 [M]+: found 266.9692 [M]+.
4-(4-Nitro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3b); Isolated as a brown solid; mp 160-
1
162°C; (KBr, υ, cm1): 3383, 3276, 3091, 2148, 1642; HNMR (300 MHz, DMSO-d6) δH: 7.92-
8.37 (m, 6H, 4H, Ar-H + 2H, NH2); 13C NMR (DMSO-d6) δC: 95.2, 111.7, 123.1, 123.6, 129.5,
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129.9, 138.9, 147.2, 155.7, 170.9; HRMS calculated for C10H6BN4O2S2 [M]+: 278.3102; found
277.9532 [M]+.
4-(4-Bromo-phenyl)-5-thiocyanato-thiazol-2-ylamine (3c); Isolated as a pale yellow solid; mp
148-150°C; (KBr, υ, cm1): 3381, 3286, 3095, 2150, 1640; 1HNMR (300 MHz, DMSO-d6) δH: δ
13
7.48 (d, 2H, J = 6.7 Hz, Ar-H), 7.62 (d, 2H, J = 7.2 Hz, Ar-H), 7.73 (s, 2H, NH2); C NMR
(DMSO-d6) δC: 92.9, 111.5, 122.9, 131.0, 131.6, 132.4, 157.9, 171.5; HRMS calculated for
C10H6BrN3S2 [M]+: 312.2087: found 310.9187 [M]+.
4-(4-Floro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3d); Isolated as a yellow solid; mp 163-
1
165°C; (KBr, υ, cm1): 3373, 3268, 3059, 2160, 1622; HNMR (300 MHz, DMSO-d6) δH: δ
7.22-7.32 (m, 4H, Ar-H), 7.78 (s, 2H, NH2); 13C NMR (DMSO-d6) δC: 98.9, 114.6, 114.9, 130.1,
130.3, 131.4, 159.8, 163.1, 164.5, 171.5; HRMS calculated for C10H6FN3S2 [M]+: 251.3031:
found 250.9984 [M]+
4-(3-Nitro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3e); Isolated as a yellow solid; mp 159-
1
161°C; (KBr, υ, cm1): 3378, 3267, 3083, 2156, 1622; HNMR (300 MHz, DMSO-d6) δH: 7.79-
8.02 (m, 3H, J = 7.4 Hz, Ar-H), 8.30 (s, 1H, Ar-H), 8.63 (s, 2H, NH2); 13C NMR (DMSO-d6) δC:
111.8, 123.3, 123.6, 130.1, 134.2, 134.7, 147.7, 171.0; HRMS calculated for C10H6BN4O2S2
[M]+: 278.3102; found 277.9935 [M]+.
4-(3,4-Dichloro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3f); Isolated as a yellow solid; mp
1
169-172°C; (KBr, υ, cm1): 3380, 3283, 3091, 2152, 1638; HNMR (300 MHz, DMSO-d6) δH:
7.53 (d, 2H, J = 7.4 Hz, Ar-H), 7.73 (s, 1H, Ar-H), 7.78 (s, 2H, NH2); 13C NMR (DMSO-d6) δC:
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91.9, 111.8, 123.0, 130.9, 131.3, 132.7, 158.0, 171.7; HRMS calculated for C10H5Cl2N3S2 [M]+:
302.2028; found 300.9503 [M]+.
4-(2-Floro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3g); Isolated as a yellow solid; mp 187-
1
190°C; IR (KBr, υ, cm1): 3440, 3234, 3062, 2212, 1608; HNMR (300 MHz, DMSO-d6) δH:
13
7.10 (s, 2H, NH2), 7.40-7.68 (m, 4H, J = 7.9 Hz, Ar-H); C NMR (DMSO-d6) δC: 91.9, 111.2,
121.3, 127.3, 130.1, 131.1, 132.9, 151.0, 171.5; HRMS calculated for C10H6FIN3S2 [M]+:
251.3031; Found 250.9987 [M]+.
4-(2-Bromo-phenyl)-5-thiocyanato-thiazol-2-ylamine (3h); Isolated as a yellow solid; mp 166-
168°C; (KBr, υ, cm1): 3369, 3269, 3059, 2154, 1614; 1HNMR (300 MHz, DMSO-d6) δH: δ 7.61
(m, 3H, J = 7.9 Hz, Ar-H), 7.69 (s, 1H, Ar-H), 7.73 (s, 2H, NH2); 13C NMR (DMSO-d6) δC: 99.1,
111.3, 122.0, 131.9, 132.8, 134.2, 158.0, 171.6; HRMS calculated for C10H6BrN3S2 [M]+:
312.2087: 310.9187 [M]+
4-(3-Bromo-phenyl)-5-thiocyanato-thiazol-2-ylamine (3i); Isolated as a yellow solid; mp 142-
1
144°C; (KBr, υ, cm1): 3387, 3263, 3035, 2157, 1632; HNMR (300 MHz (DMSO-d6) δH: 7.53
(m, 3H, J = 8.2 Hz, Ar-H), 7.60 (s, 1H, Ar-H), 7.73 (s, 2H, NH2); 13C NMR (DMSO-d6) δC: 92.0,
112.1, 123.2, 131.2, 131.6, 132.2, 158.3, 171.5; HRMS calculated for C10H6BrN3S2 [M]+:
312.2087; found 310.9184 [M]+.
4-(3-Chloro-phenyl)-5-thiocyanato-thiazol-2-ylamine (3j); Isolated as a brown solid; mp 171-
173°C; IR (KBr, υ, cm1): 3454, 3278, 3069, 2189, 1622; 1HNMR (300 MHz, DMSO-d6) δH:
13
7.30 (s, 2H, NH2), 7.51-7.68 (m, 3H, J = 7.8 Hz, Ar-H), 7.71 (s, 1H, Ar-H); C NMR (DMSO-
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d6) δC: 92.0, 112.2, 123.0, 129.9, 132.6, 134.2, 158.3, 171.7; HRMS calculated for C10H6ClIN3S2
[M]+: 267.7577; Found 266.9692 [M]+.
4-([1,1'-biphenyl]-4-yl)-5-thiocyanato-thiazol-2-amine (3k); Isolated as a brown yellow solid;
1
mp 183-185°C; IR (KBr, υ, cm1): 3451, 3231, 3059, 2209, 1613; HNMR (300 MHz, DMSO-
d6) δH: 7.13-7.24 (m, 5H, Ar-H), 7.36 (d, 2H, J = 7.3, Ar-H), 7.52 (d, 2H, J = 6.9, Ar-H), 7.73 (s,
2H, NH2); 13C NMR (DMSO-d6) δC: 91.8, 111.1, 124.2, 129.2, 132.6, 134.7, 128.1, 129.2, 131.1,
140.9, 142.1, 154.2, 170.5; HRMS calculated for C16H11IN3S2 [M]+: 309.4086; Found 309.0234
[M]+.
Conclusion
In conclusion, we have developed a simple, convenient, green and multitasking protocols for the
iodination of aryl thiazoles in excellent yield. The protocol is highly efficient and facile in PEG-
400 and water for 2-aminothiazole bearing electron withdrawing substituents. The noteworthy
advantages of the reaction conditions include multi-operational utility, no harsh chemicals, metal
free reagents, avoidance of corrosive, volatile and toxic organic solvents and the relative ease of
safe experimental procedure. This method is an attractive strategy for iodination/thiocyanation of
aryl substituted thiazole under eco-friendly conditions.
Acknowledgments
The authors PPM and RDK are sincerely thankful to the UGC-CSIR, New Delhi for JRF Award
no. F. 17-3/2007 (SA-I). Authors ANA and SNK acknowledges UGC, New Delhi for FIP Under
FDP Programm award F. No. 36-33/14 (WRO) and F. No. 38-07/14 (WRO).
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Table 1. Optimization condition for the synthesis of 4-(4-bromophenyl)-5-iodothiazol-2-amine
Ent Reagent
Time
(Min)
Yield (%)b
ry
1
2
3
4
5
6
7
8
9
KI/KIO3 EtOH
120
70
80
KI/KIO3 PEG-400
KI/HIO3 EtOH
82
50
84
KI/HIO3 PEG-400
40
80
I2/HIO3
I2/HIO3
I2/HIO3
I2/HIO3
I2/HIO3
CHCl3
60
89 [28]
78
Water
60
EtOH
70
90
PEG-400
40
91
a
PEG-400-H2O
10-15
95
aReaction conditions: 1a + Molar equivalent of oxidant: iodine source = 1:1, 10 ml of PEG-
400:H2O (8:2) at rt 10min.
bIsolated yield by column chromatography.
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Table 2.C-5 substitution of 2-aminothiazoles derivatives
Product
Code
R
Reaction
Time (Min)
m.p. (°C)
2a
2b
2c
2d
2e
2f
4-Cl
4-NO2
4-Br
4-F
12
10
10
13
12
11
15
10
10
12
14
12
10
10
12
10
15
12
14
10
12
12
173-175
162-164
158-160
143-145
177-179
153-155
150-152
168-170
147-149
171-173
153-155
138-140
160-162
148-150
163-165
159-161
169-172
187-190
166-168
142-144
171-173
183-185
3-NO2
3,4-Cl
2-F
2g
2h
2i
2-Br
3-Br
3-Cl
2j
2k
3a
3b
3c
3d
3e
3f
4-Ph
4-Cl
4-NO2
4-Br
4-F
3-NO2
3,4-Cl
2-F
3g
3h
3i
2-Br
3-Br
3-Cl
3j
3k
4-Ph
Reaction conditions: Molar equivalent of oxidant: iodine source = 1:1, 10 mL of PEG400:H2O
(8:2) at rt; .aIsolated yield by column chromatography.
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R
R
HIO3 /
PEG-400-H2O
N
N
NH2
I2 Stirred at RT
10-15 Min
NH2
S
S
I
1 a-k
2 a-k
Scheme 1: C-5 Iodination of 2-aminothiazole.
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Scheme 2: C-5 thiocyanation of 2-aminothiazole.
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Scheme 3: Effect of electron donating groups on substitution of 2-aminothiazole.
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