Mechanochemical solid-state synthesis of 2-aminothiazoles, quinoxalines and benzoylbenzofurans from ketones by one-pot sequential acid- and base-mediated reactions

Article abstract of DOI:10.1039/c6ob00351f

α-Chloroketones-obtained by the atom-economical chlorination of ketones with trichloroisocyanuric acid (TCCA) in the presence of p-TSA under ball-milling conditions-were set up for a sequential base-mediated condensation reaction with thiourea/thiosemicarbazides, o-phenylenediamine and salicylaldehyde to afford 2-aminothiazoles, 2-hydrazinylthiazoles, quinoxalines and benzoylbenzofurans, respectively, in respectable yields. The viability of one-pot sequential acid- and base-mediated reactions in the solid state under ball-milling conditions is thus demonstrated.

Full text of DOI:10.1039/c6ob00351f

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Mechanochemical Solid-State Synthesis of 2-Aminothiazoles, Quinoxalines and
Bezoylbenzofurans from Ketones by One-Pot Sequential Acid- and Base-Mediated
Reactions
Honnappa Nagarajaiah,* Abhaya K. Mishra, and Jarugu Narasimha Moorthy*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, INDIA
E-mail: nagarajh6@gmail.com; moorthy@iitk.ac.in
ABSTRACT
-Chloroketones–accessed by atom-economic chlorination of ketones with trichloroisocyanuric acid
(TCCA) in the presence of p-TSA under ball-milling condition–were set up for sequential base–mediated
condensation reaction with thiourea/thiosemicarbazides, o-phenylenediamine and salicyladehyde to afford
2-aminothiazoles, 2-hydrazinylthiazole, quinoxalines and benzoylbenzofurans, respectively, in
respectable yields. The viability of one-pot sequential acid– and base–mediated reactions in the solid state
under ball-milling condition is thus demonstrated.
GRAPHIC FOR TOC
OR
OR
Diverse 2-aminothiazoles, quinoxalines and benzofurans are accessed in respectable yields by one-pot
solid-state sequential acid- and base-mediated reactions under ball milling conditions.
1

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INTRODUCTION
Heterocyclic 2-aminothiazoles,1 quinoxalines2 and benzofurans3 have been widely used in medicinal
chemistry4 and agriculture.5 They have been found to exhibit diverse biological properties such as
antibacterial,6 antiviral,7 anticancer,8 anti-inflammatory,9 etc. In Chart 1 are shown a few select examples
of pharmaceutical drugs containing aminothiazole, quinoxaline and benzofuran moieties.4c,6d,10 Further,
they constitute the core nuclei of molecular systems that are building blocks of different functional
materials, e.g., organic light emitting diodes (OLEDs),11 organic semiconductors, solar cells, dyes, etc.12
Insofar as their synthesis is concerned, the approach based on 2-halocarbonyl compounds as starting
materials is the most attractive one.13 Direct synthetic protocols based on starting materials such as
ketones,14 ,-unsaturated ketones,14c alkenes,15 etc. via the intermediary -haloketones have been
reported for aminothiazoles. Additionally, the syntheses of quinoxaline16 and benzofuran17 derivatives
have also been reported. These synthetic procedures, however, are associated with certain disadvantages
such as heating, hazardous reaction conditions, formation of side products, tedious work-up procedures,
etc.
Chart 1. Select examples of biologically-active compounds containing aminothiazole, quinoxaline and
bezoylbenzofuran moieties: (a) riluzole10a (antiglutamate), (b) pramipexole4b (antidepressant), (c) abafungin4b
(antifungal), (d) varenicline16b (smoking abstinent), (e) brimonidine10b (intraocular antihypertensive), (f) (-)-BPAP6d
(antidepressant), and (g) cordarone6d (antiarrhythmic agent).
We recently showed that -halogenation of carbonyl compounds occurs in a facile manner under solvent-
free ball-milling conditions using trichloroisocyanuric acid (TCCA)/p-TSA. Some of the advantageous
attributes of TCCA as a chlorinating agent are: it is stable, cheap, readily available and environmentally
2

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benign.18,19 More importantly, it serves as a source of three chlorine atoms to permit atom economy that is
not rivaled by other chlorination reagents. Indeed, TCCA is popular as a high-purity chlorine source
compared to hypochlorite.20 We were, therefore, motivated to investigate further the reactions of -
chlorocarbonyl compoundsavailable by solid-state ball-milling reactionsto access 2-aminothiazoles,
quinoxalines and benzofurans. Of course, our objectives at the outset were to explore the viability of
sequential acid– and base–catalyzed reactions in the solid state and develop one-pot solvent-free synthesis
of the aforementioned heterocycles under ball-milling conditions as an alternative to the solution-state
synthesis. Mechanochemical ball-milling is a superlative greener technique that is increasingly becoming
popular in organic synthesis.21 Herein, we report the results of successful one-pot solid-state synthesis of
various derivatives of 2-aminothiazole, quinoxaline and benzofuran by sequential acid- and base-
mediated reactions under ball milling conditions in respectable isolated yields without isolation of the
intermediary -chloroketones.
RESULTS AND DISCUSSION
Synthesis of 2-Aminothiazole Derivatives. As mentioned earlier, we have shown in our previous
investigations that -chlorination of carbonyl compounds occurs conveniently under ball-milling
conditions with TCCA/p-TSA (25 mol%) as the reagent system; indeed, TCCA was found to be better
than the corresponding bromo-analog, namely, tribromoisocyanuric acid (TBCA), for -bromination. We
wondered if sequential -chlorination of ketones followed condensation reaction with thiourea could be
carried out in one pot under ball-milling conditions to afford 2-aminothiazoles. In a representative
reaction, crystalline p-bromoacetophenone, 0.4 molar equiv of TCCA and 0.5 molar equiv of p-TSA were
introduced into a 5 mL jar and subjected to milling with 6 balls to produce -chloro-p-
bromoacetophenone at a pre-fixed oscillation frequency of 20 Hz. After completion of -chlorination
over a period of 2 h, as judged by TLC analysis, thiourea (1.05 equiv) and K2CO3 (1.5 equiv) were
introduced into the same jar. The solid reaction mixture was subjected to milling for further 4 h.
Remarkably, the work-up followed by isolation led to 2-amino-4-(p-bromophenyl)thiazole in 90% yield
(2a, Scheme 1). It is noteworthy that the two sequential reactions require acidic and basic conditions,
respectively. The excellent isolated yield of the aminothiazole demonstrates the fact that sequential
reactions are amenable to solid-state ball milling protocols.22
In a similar manner, the ball-milling reactions with N-arylated thioureas were found to occur in a facile
manner, yielding the corresponding N-arylaminothiazoles in 83–86% isolated yields (2b-f, Scheme 1).
Further, the reactions with 1-phenyl-3-thiosemicarbazide, 1-(p-bromophenyl)-3-thiosemicarbazide and 1-
(p-methoxyphenyl)-3-thiosemicarbazide with -chloro-p-bromoacetophenonegenerated by TCCA/p-
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TSA reaction of p-bromoacetophenoneafforded respective 2-hydrazinylthiazoles in excellent isolated
yields of 83, 81 and 84%, respectively in 8–9 h of milling (2g-i, Scheme 1). The reactions of benzyl
phenyl ketones were, however, slow and occurred over longer durations leading to the corresponding
products 2j-m in isolated yields of 51–66%.
Scheme 1. Synthesis of 2-aminothiazole derivatives by consecutive -halogenation followed by base-
mediated condensation reactions under ball milling conditions at rt.a
a All reactions were performed without any extra precaution. Six balls were employed and the reactions were run
with an oscillation frequency (osc) of 20 Hz.
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The same protocol could be extended to the synthesis of 2-amino-8H-indeno[1,2-d]thiazole derivatives,
for which only a few methodologies requiring high temperatures, e.g., heating at 100 °C in ethanol, have
been reported.14a,b Thus, the reaction of indanone with TCCA/p-TSA under ball milling at rt followed by
treatment with urea/N-arylurea in the presence of K2CO3 led to 2-amino-8H-indeno[1,2-d]thiazole (4a)
and its N-aryl derivatives (4b-e, Scheme 2) in 74–82% isolated yields. It should be noted that the
chlorination of indanone led to a mixture of products, i.e., 2-chloroindanone and 2,2-dichloroindanone,
both of which react with thiourea/N-arylthiourea leading to the aminoindenothiazole or its N-aryl
derivative.
Scheme 2. Solid-state synthesis of 2-amino-8H-indeno[1,2-d]thiazole and its derivatives by consecutive
-halogenation and condensation reactions under ball milling conditions at rt.a
a
all reactions were performed without any extra precaution. Six balls were employed and an oscillation frequency
(osc) of 20 Hz was maintained throughout the reaction.
Synthesis of Quinoxalines. The reactions of -haloketones with o-phenylenediamines in the presence of
K2CO3 in acetonitrile are known to furnish quinoxalines.16b Thus, -chloro-p-bromoacetophenone,
generated by solid-state ball-milling with TCCA/p-TSA, was reacted with o-phenyelendiamine/K2CO3 in
a sequential manner as was done above, cf. Scheme 3. Indeed, the reaction was found to occur nicely at rt
leading to 2-(p-bromophenyl)quinoxaline (5a) in 78% isolated yield. When 3-methyl-1,2-diaminobenzene
was employed, a regioisomeric 50:50 mixture of the methyl derivatives of 2-(p-bromophenyl)quinoxaline,
i.e., 5b and 5b', was isolated in 82% yield. Likewise, chlorination of cyclic indanone followed by
5

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condensation with o-phenylenediamines yielded the corresponding 11H-indeno[2,1-b]quinoxalines (6,
Scheme 3) 75–81% isolated yields. In this case, the initial reaction of halogenation led to a gummy
reaction mixture. Therefore, neutral alumina was employed as a milling auxiliary. As in the case of p-
bromoacetophenone, a regioisomeric mixture of products, i.e., 6b and 6b', was isolated when 3-methyl-o-
1
phenylenediamine was employed, cf. Scheme 3; H NMR analysis of the mixture revealed the ratio
between 6b and 6b' to be ca. 1:1. Separation of these isomers by silica gel column chromatography was
unsuccessful despite several attempts.
Scheme 3. Synthesis of quinoxaline derivatives by sequential halogenation and condensation reactions
under ball milling conditions at rt. a
a
all reactions were performed without any extra precaution. Six balls were employed and an oscillation frequency
b
(osc) of 20 Hz was maintained throughout the reaction. In the case of indanone, the reaction mixture became
gummy. Therefore, neutral alumina was employed as a milling auxiliary, cf. text
Synthesis of 2-Benzoylbenzofurans. As shown in Scheme 4, the one-pot reaction of -chloro-p-
bromoacetophenonegenerated from p-bromoacetophenone with TCCA/p-TSAwith salicylaldehyde led
to hydroxy-ketone intermediate. Of course, under the basic conditions of the reaction, the dehydration
reaction was found to be too sluggish. When the reaction was continued with addition of excess p-
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TSAin amounts that nullifies the base and is present in excess to perform acid-catalyzed
dehydrationbezoylbenzofuran (7a) was isolated in a remarkable yield of 78%. The one-pot reaction
sequence with p-bromoacetopheone and 3,5-dibromosalicylaldehyde led to the corresponding (p-
bromobenzoyl)bromobenzofuran (7b) in 76% isolated yield. Extension of this protocol to other substrates
was limited by the necessity of ketones being crystalline and reactive for initial chlorination under ball
milling conditions. Otherwise, the limited examples illustrate the occurrence of 3 consecutive reactions
requiring acid, base and acid conditions in one pot.
Scheme 4. Synthesis of benzoylbenzofuran derivatives by sequential acid–base–acid mediated reactions
under ball milling conditions at room temperature.a
CONCLUSIONS
We have exploited facile -chlorination reaction of ketones with the atom-economic TCCA reagent under
ball-milling conditions to explore the viability of sequential reactions in the solid-state for one-pot
synthesis of medicinally important heterocycles. It is shown that -chlorination followed by
condensations with thiourea and N-arylthiourea lead to 2-aminothiazoles and 2-hydrazinylthiazoles in
very good isolated yields. In the same manner, the reactions of -chloroketones with o-
phenylenediamines in a sequential manner are shown to lead to quinoxalines in respectable isolated
yields. Limited cases of sequential acid-base-acid mediated halogenation, condensation and dehydration
reactions are demonstrated to access benzoylbenzofurans. The occurrence of three tandem reactionseach
mediated by an acid or baseis thus exemplified in the solid state under ball-milling conditions.
1
Electronic Supplementary Information Available. H and 13C NMR spectral reproductions of
all products.
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ACKNOWLEDGMENTS
H. N. is thankful to the Science and Engineering Research Board, New Delhi for funding under young
scientist scheme with the project no: SB/FT/CS-152/2014. A. K. M. is grateful to University Grants
Commission (UGC), New Delhi for a senior research fellowship.
EXPERIMENTAL SECTION
Materials and Methods
All reactions were carried out in a Retsch MM 200 ball mill. The products were isolated by column
chromatography over silica gel (100−200 μm) using distilled solvents. 1H and 13C NMR spectra were
recorded with JEOL 400 and 500 MHz spectrometers. FT-IR spectra were run on a Perkin Elmer
spectrometer. Mass spectra were recorded with Waters ESI-QTOF machine. TCCA was procured from
Avra company. p-Bromoacetophenone, 1-indanone, deoxybenzoin, salicyladehyde and thiourea were
purchased from Sigma Aldrich and used as received.
General Procedure for the Synthesis of 2-Aminothiazole, Quinoxaline and Benzofuran Derivatives.
In a representative reaction, the solid ketone (ca. 0.1 g, 0.5–0.8 mmol), 0.4 equivalent of nicely ground
TCCA and 0.5 equivalent of p-TSA were introduced into a 5 mL stainless steel milling jar containing 6
stainless steel balls of diameter 3.0 mm. The reaction mixture was subsequently milled at a frequency of
20 Hz for 2-8 h at rt. After the formation of the intermediate(s) as determined by TLC analyses,
thiourea/N-arylthiourea
or
1,2-diamine/substituted-1,2-diamine
or
salicylaldehyde/3,5-
dibromosalicylaldehyde (1.05 equiv) was introduced along with nicely powdered K2CO3 (1.5 equiv). The
milling was continued for the durations mentioned in Schemes 1–4. For benzoylbenzofurans, p-TSA was
additionally introduced and the milling was further continued. At the end of the reaction, the solid residue
was taken up into ethyl acetate, whereby the organic material was extracted. The latter was dried over
sodium sulfate, and the solvent removed under reduced pressure. The resultant solid residue was
subjected to a short pad silica-gel chromatography to isolate the product(s) in each case.
Spectral Data of Products
2-(2,5-Dimethylphenyl)amino-4-(p-bromophenyl)thiazole (2f). Pale yellow solid; Rf 0.70 (5%
1
EtOAc/petroleum ether); mp 128–130 °C; IR (KBr) cm-1 3219, 3106, 2971, 1561, 1454; H NMR (400
MHz, CDCl3) δ 2.28 (s, 3H), 2.35 (s, 3H), 6.77 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz,
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13
2H), 7.44 (brs, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H) ; C NMR (125 MHz, CDCl3) δ
17.4, 21.2, 102.2, 121.5, 121.5, 125.6, 126.4, 127.6, 130.9, 131.7, 133.5, 137.1, 138.3, 150.2, 166.7; ESI-
MS+: Exact mass calculated for C17H15BrN2S [M]+: 358.0139, found: 358.0139.
2-(p-Chlorophenyl)amino-4,5-diphenylthiazole (2k). Colorless crystalline; Rf 0.48 (10%
1
EtOAc/petroleum ether); mp 190–192 °C; IR (KBr) cm-1 3236, 3090, 3061, 1595, 1551, 1492, 1430; H
NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.25–7.30 (m, 8H), 7.49–
7.52 (m, 2H), 8.18 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 119.6, 121.6, 127.5, 127.7, 127.8, 128.3,
128.6, 129.0, 129.3, 129.4, 132.1, 134.9, 138.9, 145.7, 162.4; ESI-MS+: Exact mass calculated for
C21H16ClN2S [M+H]+: 363.0722, found: 363.0721.
4,5-Diphenyl-2-(p-tolyl)aminothiazole (2l). Colorless solid; Rf 0.50 (10% EtOAc/petroleum ether); mp
1
160–162 °C; IR (KBr) cm-1 3125, 3059, 2927, 1597, 1556, 1514, 1435, 1299; H NMR (400 MHz,
CDCl3) δ 2.33 (s, 3H), 7.14 (d, J = 8.2 Hz, 2H), 7.19–7.22 (m, 2H), 7.24–7.31 (m, 8H), 7.50–7.52 (m,
13
2H), C NMR (125 MHz, CDCl3) δ 20.8, 119.0, 127.3, 127.6, 128.2, 128.6, 128.9, 128.9, 129.4, 130.0,
132.4, 133.1, 135.1, 137.7, 145.6, 163.3; ESI-MS+ Exact mass calculated for C22H19N2S [M+H]+:
343.1268, found: 343.1268.
2-(2,5-Dimethylphenyl)amino-4,5-diphenylthiazole (2m). Colorless solid; Rf 0.55 (10%
1
EtOAc/petroleum ether); mp 186–188 °C; IR (KBr) cm-1 3153, 3051, 2921, 2890, 1561, 1493, 1432; H
NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.35 (s, 3H), 6.90 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H),
7.21–7.30 (m, 8H), 7.42 (s, 1H), 7.50–7.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 17.4, 21.2, 121.3,
125.4, 126.4, 127.2, 127.6, 128.2, 128.5, 128.9, 129.4, 130.9, 132.5, 135.1, 137.0, 138.5, 145.7, 164.41;
ESI-MS+: Exact mass calculated for C23H21N2S [M+H]+: 357.1425, found: 357.1428.
2-(p-Bromophenyl)amino-8H-indeno[1,2-d]thiazole (4c). Off-white solid; Rf 0.40 (10%
1
EtOAc/petroleum ether); mp 188–190 °C; IR (KBr) cm-1 3202, 3049, 2924, 1588, 1488; H NMR (400
MHz, CDCl3) δ 3.76 (s, 2H), 7.22 (td, J = 1.4, 7.3 Hz, 1H), 7.32–7.38 (m, 3H), 7.43–7.48 (m, 3H), 7.62
(d, J = 7.8 Hz, 1H), 7.78 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 32.6, 115.1, 118.6, 119.7, 124.6,
124.9, 126.9, 132.3, 137.3, 139.3, 145.3, 156.9, 168.0; ESI-MS+: Exact mass calculated for C16H11BrN2S
[M]+: 341.9826, found: 341.9821.
2-(p-Chlorophenyl)amino-8H-indeno[1,2-d]thiazole (4d). Off-white solid; Rf 0.40 (10%
1
EtOAc/petroleum ether); mp 186–188 °C; IR (KBr) cm-1 3205, 3053, 2930, 1594, 1491; H NMR (400
MHz, CDCl3) δ 3.76 (s, 2H), 7.22 (td, J = 1.4, 7.3 Hz, 1H), 7.30–7.36 (m, 3H), 7.39–7.43 (m, 2H), 7.48
(d, J = 7.5 Hz, 1H), 7.52 (brs, 1H), 7.63 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 32.6, 118.6,
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119.5, 124.6, 124.7, 124.9, 126.9, 127.8, 129.4, 137.3, 138.8, 145.3, 156.8, 168.3; ESI-MS+: Exact mass
calculated for C16H11ClN2S [M]+: 298.0331, found: 298.0333.
2-(p-Tolyl)amino-8H-indeno[1,2-d]thiazole (4e). Pale brown solid; Rf 0.35 (10% EtOAc/petroleum
1
ether); mp 188–190 °C; IR (KBr) cm-1 3207, 2914, 1596, 1562; H NMR (400 MHz, CDCl3) δ 2.34 (s,
3H), 3.73 (s, 2H), 7.16–7.22 (m, 3H), 7.29–7.34 (m, 3H), 7.46 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz,
13
1H), 7.68 (brs, 1H); C NMR (100 MHz, CDCl3) δ 20.8, 32.6, 118.5, 119.3, 124.1, 124.5, 124.6, 126.9,
130.0, 133.2, 137.6, 145.4, 156.7, 169.9; ESI-MS+: Exact mass calculated for C17H14N2S [M]+: 278.0877,
found: 278.0878.
2-(2,5-Dimethylphenyl)amino-8H-indeno[1,2-d]thiazole (4f). Colorless solid; Rf 0.35 (10%
1
EtOAc/petroleum ether); mp 192–194 °C; IR (KBr) cm-1 3155, 3053, 2916, 1584, 1559; H NMR (400
MHz, CDCl3) δ 2.30 (s, 3H), 2.36 (s, 3H), 3.72 (s, 2H), 6.93 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H),
7.19 (td, J = 0.9, 7.6 Hz, 1H), 7.30–7.34 (m, 2H), 7.44–7.47 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.4, 21.1, 32.6, 118.3, 122.3, 124.3, 124.5, 124.6, 125.8, 126.9, 127.1, 131.0,
137.0, 137.6, 138.2, 145.4, 156.7, 171.4; ESI-MS+: Exact mass calculated for C18H16N2S [M]+: 292.1034,
found: 292.1032.
7/8-Methyl-11H-indeno[2,1-b]quinoxaline (6b+6b'). Pale yellow solid; Rf 0.40 (10% EtOAc/petroleum
1
ether); isomers ratio (50:50); mp 146–148 °C; IR (KBr) cm-1 3045, 2915, 1625, 1507; H NMR (400
MHz, CDCl3) δ 2.61 (s, 3H), 4.13 (s, 2H), 7.53–7.60 (m, 3H), 7.65–7.68 (m, 1H), 7.86 (s, 0.5H), 7.95 (s,
13
0.5H), 7.98 (d, J = 8.7 Hz, 0.5H), 8.06 (d, J = 8.7 Hz, 0.5H), 8.22–8.26 (m, 1H); C NMR (125 MHz,
CDCl3) δ 21.7, 35.9, 36.0, 122.4, 122.6, 125.8, 128.0, 128.0, 128.3, 128.4, 128.7, 130.8, 130.9, 131.0,
131.4, 138.2, 139.3, 139.6, 139.7, 140.4, 141.3, 142.1, 143.3, 143.5, 153.9, 154.5, 158.5, 159.4; ESI-MS+:
Exact mass calculated for C16H12N2 [M]+: 232.1000, found: 232.1009. (It should be noted that the 1H and
1
13C NMR spectral data are for an inseparable mixture. In H NMR, some signals split up into two, while
others merge. In 13C NMR, several appear as closely spaced lines with some merged.)
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