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Научни трудове на Съюза на учените в България - Пловдив. Серия В. Техника и технологии, т. XIV, ISSN 1311-9419 (Print), ISSN 2534-9384 (On- line), 2017. Scientific Works of the Union of Scientists in Bulgaria-Plovdiv, series C. Technics and Technologies, Vol. XIV., ISSN 1311-9419 (Print), ISSN 2534-9384 (On- line), 2017.
НОВ МЕТОД ЗА СИНТЕЗ НА 2-(1Н-ПИРОЛ-2-Щ[)БЕНЗО[с1]ТИАЗОЛ Йордан Стремски, СтелаСтаткова-Абегхе, Пламен Ангелов,
ИлиянИва нов
Пловдивски Университет „Паисий Хилеидарски" , Катедра Органична химня, ал. Ц2р Асен, 2Л,НД0Н Пловдив,България, e-mail: stab@uni-pl ovdiv.bg
A NEW METHOD FORTHESYNTHESIS OF 2-(lH-PYRROL-2-YL)BENZO[d]THAlZOLE Yoodan Slremski, Stela
U niversity oaPlovdie "PaisilHilinaarskI", Department ofOrganic Chemistry, 24TzarAsen Sta., 4000 Oloodlo, Buipaala, i-mail:stab@uninp0ovdivibg
Abstaact
Multicomponent amidoalkylation reaction of benzothiazole, alkyl chloroformates and pyrrole in the presence of triethylamine as HCl acceptor is described. Newly synthesized compounds are successfully oxidized to 2-(1H-pyrrol-2-yl)benzo[d]thiazole. The conditions for chromatographic separation and isolation of the products by column chromatography on neutral alumina are established. The isolated compounds are characterized spectrally. Keywords: Benzothiazole, Multicomponent reaction, 2-aryl benzothiazoles, Pyrroles
Introduction
Benzothiazoles are important class heterocyclic compounds that exhibit various biological activities. 2-aryl benzothiazoles have been investigated due to their medicinal properties such as antitumor, antiviral and antimicrobial drugs (Keri"et al"2015). The development of synthetic methodology toward benzothiazoles is therefore of considerable importance.
The classical strategies to synthesize of 2-substituted benzothiazoles are based on the condensation reaction of 2-aminothiophenol with benzaldehydes (Parikh "et al"2011), nitriles (Sun "et al"2013), carboxylic acids (Hein, "et al" 2009) and acyl chlorides Nadaf "et al" 2004). The direct arylation of benzothiazoles is an alternative method for the synthesis of 2-aryl benzothiazoles. In this connection other strategies are associated with decarboxylation of benzothiazole with benzoic acid or phenyl acetic acid (Song "et al"2013) and condensation of benzothiazoles with aromatic aldehydes obtained by oxidation of the various styrenes with phenyliodonium diacetate (Kamal "et al"2014). Also in the literature there are described several methods for synthesis of 2-aryl benzothiazoles, based on the reaction of N-acyliminium ions derived from benzothiazole with 2-silylthiazoles or 2-silyloxazoles (Dondoni "et al"1984), organotin compounds (Itoh"et al"1994), organoindium reagents (Beveridge"et al"2010), or silyl enol ethers (Itoh"et al"200).
We have previously used successfully adducts derived from nitrogen-containing heterocycles and acyl chlorides as electrophilic reagents in an intermolecular a-amidoalkylation reaction toward aromatic compounds such as pyrrole and indole (Venkov"et al"2001). 196
Multicomponent reactions are simple, efficient and effective method for the syntesis of heterocycles including pyrroles with diverse biological activity. This method for performing the reactions offers variety of advantages and facilities 9zHU"et al"2010).
In continuation of our interest in the field of heterocyclic compounds, we herein report a simple method for the direct coupling of pyrrole with benzothiazole, activated by alkyl chloroformates via a multicomponent reaction for the synthesis of new 2-substituted benzothiazoles (5 a, b) (Scheme 1) and subsequent oxidation to product (6) known in the literature.
Scheme 1. One-pot syntesis of 2-aryl benzothiazoles 5 a, b
Experimental
Instrumentation, Analysis, and Starting Materials:
Commercial solvents and reagents, such as benzothiazole, alkyl chloroformates, triethylamine, pyrrole and o-chloranil (3,4,5,6-tetrachloro-1,2-benzoquinone) were purchased from Sigma-Aldrich and were used without further purification. Melting points were determined on a Boetius PHMKO5 hot stage apparatus and are uncorrected. IR and MS spectra were measured on Perkin Elmer 1750 Furie Transform and Thermo Scientific™ Q Exactive™ Orbitrap™ mass spectrometers, respectively. 1H-NMR, 13C-NMR spectra were measured on Bruker Avance AV600 device in CDCl3 as solvent. Chemical shifts are given in part per million (ppm) relative to TMS and coupling constants are indicated in Hz. All the NMR spectra were taken at room temperature in CDCl3. TLC was done on precoated 0.2 mm Merck silica gel 60 plates. Neutral alumina were used for column chromatographic separation.
General one-pot procedure for the synthesis of 2-pyrrolyl benzothiazoles 5 a, b
To benzothiazole (1 mmol) dissolved in dichloromethane (5 mL) were added alkyl chloroformate (1 mmol) and pyrrole (1 mmol). The reaction mixture was stirred for 1.5 h at 0 oC (Table 1). To the mixture during the reaction triethylamine (1 mmol) was added as hydrochloric acceptor. After completion of the reaction (monitored by TLC), 30 mL CH2Cl2 was added and the mixture was extracted successively with 50 mL 10% HCl, 50 mL 3% Na2CO3 and 3x20 mL water. The combined organic layers were dried (Na2SO4) and concentrated. After the distillation of the solvent (CH2Cl2) the products were purified by column chromatography on neutral alumina using mixtures of petroleum and diethyl ether as eluents.
Ethyl-2-(1H-pyrrol-2-yl)benzo[d]thiazole-3(2H)-carboxylate (5 a) Yield: (55 %); Oil; Isolated with elluent petroleum:diethyl ether 8:1;
1H-NMR (600 MHz, CDQ3) (5, ppm): 1.41 (t, J = 6, 3H, CO7CH7CH3), 4.34 - 4.40 (m, 2H, CO9CH9CH3), 6.12 (d, J = 6, 1H, Ar), 6.33 (br. s, 1H, Ar), 6.74 (br. s, 1H, Ar), 6.88 (s, 1H, CH), 7.02 - 7.25 (m, 4H, Ar), 7.58 (br. s, 1H, NH);
13C-NMR (600 MHz, CDCl3) (5, ppm): 14.51, 60.58, 62.81, 107.95, 108.29, 117.77, 118.83,
122.27, 124.30, 125.47, 131.02, 132.07, 152.52;
m/z [M-H]- calcd. 273.07, found 273.07;
IR (KBr, cm-1): 3371, 2982, 1703, 1580, 1471, 1249, 747.
Methyl-2-(1H-pyrrol-2-yl)benzo[d]thiazole-3(2H)-carboxylate (5 b)
Yield: (67 %); M.p.: 111-113 0C; Isolated with elluent petroleum:diethyl ether 8:1;
1H-NMR (600 MHz, CDCl3) (5, ppm): 3.81 (s, 3H, CO2CH3), 6.02 (d, J = 6, 1H, Ar), 6.22 (br. s,
1H, Ar), 6.63 (br. s, 1H, Ar), 6.77 (s, 1H, CH), 6.92 - 7.14 (m, 4H, Ar), 7.51 (br. s, 1H, NH);
13C-NMR (600 MHz, CDCl3) (5, ppm): 53.51, 60.65, 107.91, 108.18, 108.34, 117.75, 118.87,
122.32, 124.45, 125.50, 130.92, 151.09;
m/z [M+Na]+ calcd. 283.05, found 283.05;
IR (KBr, cm-1): 3372, 2957, 1686, 1580, 1515, 1472, 1241, 745.
General procedure for the synthesis of product 6:
Purified product (5 a) or (5 b) (0.3 mmol) was dissolved in MeCN (5 mL), 2 eq o-chloranil (3,4,5,6-tetrachloro-1,2-benzoquinone) (0.6 mmol) added, and the mixture was stirred at room temperature for 2 h (monitored by TLC). The solvent was removed in vacuo, 30 mL CH2Cl2 was added and the mixture was extracted with 3x20 mL water. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified by column chromatography on neutral alumina using mixtures of petroleum and diethyl ether as eluents.
2-(1H-pyrrol-2-yl) benzo[d]thiazole (6)
Yield: (91, 86 %); M.p.: 158-159 0C [14]; Isolated with elluents petroleum:diethyl ether 8:1, 4:1; m/z [M-H]- calcd. 199.03, found 199.03; [M+H]+ calcd. 201.04, found 201.04; IR (KBr, cm-1): 3125, 2854, 1572, 1559, 1113, 742.
Results and discussion
Our primary aim was to develop an efficient multicomponent procedure for the synthesis of benzothiazole derivatives through the reaction of benzothiazole (1), alkyl chloroformates (2) and pyrrole (3) in the presence of triethylamine (4) (Shceme 1). The results are shown in Table 1. The reaction conditions were optimized by varying parameters such as solvent, temperature and time. Using the optimized conditions, the reactions were successfully carried out in dry dichloromethane for 1,5 h at 0 0C. As shown in Table 1, the reaction worked well with both alkyl chloroformates and the desired compounds (5 a, b) were obtained in good yields.
Table 1. Synthesis of 2-pyrrolyl benzothiazoles (5 a, b, 6)
R T, O c Time, h Yield, % tt, O c
5 a -OCH2CH3 0 1,5 55 Oil
5 b -OCH 3 0 1,5 67 111 - 113
6 Oxidation (5 a) r.t. 2 91 158 - 159 [14]
Oxidation (5 b) r.t. 2 86
Synthesized products (Table 1) were purified by column chromatography and characterized by IR, 1H-NMR, 13C-NMR and ESI-MS analysis.
The 1H-NMR spectra of compounds (5 a, b) exhibited a singlet at 5 (6.88) and (6.77) ppm for proton from benzothiazole CH group. This signal falls within the aromatic region but was
successfully distinguished from the aromatic protons on the basis of HSQC spectra in which the corresponding carbon signal appears well separated from the aromatic carbons.
Treatment of benzothiazole derivatives with o-chloranil allows formation of a range of 2-substituted benzothiazoles [10]. Products (5 a, b) were oxidized with o-chloranil to aromatic product 2-(1H-pyrrol-2-yl)benzo[d]thiazole (6) (Scheme 2) in very high yields, 91 % obtained after the oxidation of (5 a) and 86 % for (5 b), respectively (Table 1). The IR spectrum, ESI-MS and melting point of product (6) are consistent with those published earlier by other authors [7, 14].
o-Chloranil
5 a' b 2-(1 H-pyrrol-2-yl)benzo[d]thiazole
Scheme 2. Oxidation of compounds (5 a, b) with o-chloranil
Conclusion
An efficient method for multicomponent synthesis of 2-(1H-pyrrol-2-yl)benzo[d]thiazole is demonstrated. The presented methodology offers several advantages such as simple procedure, clean reaction conditions, good yields. The obtained products were purified by column chromatography and characterized spectrally. Acknowledgment
We acknowledge financial support from the Fund for scientific research of Plovdiv University - NI 15 FC 001
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