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Article

2-Amino-1,3-benzothiazole: Endo N-Alkylation with α-Iodo Methyl Ketones Followed by Cyclization

by
Ivan A. Dorofeev
,
Larisa V. Zhilitskaya
,
Nina O. Yarosh
and
Bagrat A. Shainyan
*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of the Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(5), 2093; https://doi.org/10.3390/molecules28052093
Submission received: 24 January 2023 / Revised: 20 February 2023 / Accepted: 20 February 2023 / Published: 23 February 2023
(This article belongs to the Special Issue Feature Papers in Organic Chemistry)
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Versions Notes

Abstract

:
Reactions of 2-amino-1,3-benzothiazole with aliphatic, aromatic and heteroaromatic α-iodoketones in the absence of bases or catalysts have been studied. The reaction proceeds by N-alkylation of the endocyclic nitrogen atom followed by intramolecular dehydrative cyclization. The regioselectivity is explained and the mechanism of the reaction is proposed. A number of new linear and cyclic iodide and triiodide benzothiazolium salts have been obtained and their structure proved by NMR and UV spectroscopy.

Graphical Abstract

1. Introduction

The synthesis of molecular hybrids containing structural fragments showing useful properties is one of the main goals in modern organic chemistry. Such hybrids are successfully applied in the syntheses of drugs, for the creation of new materials for advanced technologies, and for the development of organic syntheses. An important example is the derivatives of 2-aminothiazole. They are used as precursors of biologically active compounds in medicine and agriculture [1,2,3,4,5], are valuable components of matrices of inert coatings in industry [6], are used to disperse dyes [7], are adsorbents of heavy metals [8], and are used as fluorescent sensors for the detection of metals [9].
α-Chlorinated and brominated ketones are known to react with S,N-heterocycles via aminothiazolium salts as key intermediates, whose subsequent intramolecular cyclization by heating in ethanol results in condensed heterocyclic compounds with bridged nitrogen atoms [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. The interest in such structures is due to their pharmacological potential. Thus, the imidazo[2,1-b]thiazole motif is proposed as a universal synthon for the design of molecules with antiviral [2], antidiabetic [12], antitumor [13,14], antifungal [15], antioxidant [15], and anti-inflammatory activity [16]. Some derivatives based on the imidazo[2,1-b]thiazole system have become commercial pharmaceuticals. Among them is an anthelmintic and immunomodulator Levamisol (trademark Ergamisol).
Prior to our studies, there were no data in the literature on the alkylation of aminothiazoles with α-iodoketones in the absence of bases or catalysts [25]. The synthesis of the salts of heterocyclic compounds is topical because of the growing interest in these compounds possessing a wide range of applications, both in science and in technique [26,27,28]. With this in mind, the goal of this work was to investigate the reactions of 2-amino-1,3-benzothiazole with aliphatic, aromatic, and heteroaromatic α-iodoketones, assuming that the high reactivity of the C–I bond in α-iodoketones might allow us to use them successfully for the synthesis of 2-amino-1,3-benzothiazole derivatives, and condensed structures on their basis, under mild conditions. Another goal of the present work was to compare the regioselectivity of N-alkylation—on the endo or exocyclic nitrogen atom of the substrate.

2. Results and Discussion

The reactions of 2-amino-1,3-benzothiazole 1 with α-iodoketones 2a–f were carried out at room temperature in acetone in the absence of bases or catalysts. The reaction proceeds by N-alkylation of the endocyclic nitrogen atom with the formation of 2-amino-1,3-benzothiazolium iodides 3a–f, which precipitated from the reaction mixture and could be isolated in pure form in a 51−74% yield (Scheme 1).
Similar reactions with α-chloro or bromoketones proceed more slowly and require heating [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. An exception is microwave activation, as was recently exemplified by a highly efficient microwave-assisted procedure (mw, 100 °C, 12–15 min) for the synthesis of benzo[d]imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazoles in aqueous media in up to 95% yields [29].
Under the conditions of Scheme 1, salts 3a–f react with elemental iodine to give 2-amino-1,3-benzothiazolium triiodides 4d,e isolated in a 90% yield (Scheme 2). The latter compounds combine the biological activity of elemental iodine with the organic component and show a wider spectrum of pharmacological properties. Drugs based on 1,3-diethylbenzimidazolium triiodides are known in the literature [27]. Unfortunately, we failed to isolate other linear triiodides in pure form. When reacting with elemental iodine, iodides 3a–c,f undergo intramolecular cyclization to give an inseparable mixture of linear 4a–c,f and cyclic triiodides 5a–c,f. This was witnessed by the presence of the 1H and 13C NMR (Supplementary Materials) signals in the spectra of these compounds at 5.7–6.4 and 52.9–54.7 ppm, corresponding to the methylene groups in the acyclic products, as well as by the signals at 8.4–9.7 and 114.2–116.4 ppm of the =CH group of the imidazole moiety in the annulated products. The thienyl derivatives were the most resistant to cyclization, which was proved by calculations (vide infra).
As follows from Scheme 2, the ratio of products 4:5 decreases in the order R = Me > 4-tolyl ≥ 4-diphenyl > 2-carbazolyl, implicitly indicating the same order of the rate of cyclization.
Iodides 3a–f, when stored in DMSO solution or with slight heating in MeOH, undergo cyclization with the formation of iodides 6a–f. The formation of the benzo[d]imidazo[2,1-b]thiazolium structure is proved by the disappearance of the methylene CH2C(O) proton signal in the 1H NMR spectrum at 5.4–6.4 ppm, typical for linear 2-aminobenzothiazolium iodides 3a–f, and the appearance of the vinyl proton signal of 5a–f at 8.4–9.0 ppm. Similar to salts 3 in Scheme 1, salts 6a–f are converted to benzo[d]imidazo[2,1-b]thiazolium triiodides 5a–f (Scheme 3).
The cyclization is fast for R = Me, whereas for R = Ph and heteroaryl, it needs to stay in DMSO solution for several weeks. To get a deeper insight, we have calculated the reaction of cyclization 3 → 5 by the B3LYP/DGDZVP method with full geometry optimization in polar medium using a PCM model with DMSO as the solvent for R = Me, Ph, 2-thienyl, and 2-carbazolyl. The results (in kcal/mol) are shown in the table.
RΔE° = E°(5 + H2O) − E°(3)ΔG° = G°(5 + H2O) − G°(3)
Me+4.0−9.2
Ph+5.2−10.8
2-thienyl+6.3−3.8
2-carbazolyl+5.9−7.5
As evident from the table, for all R the reaction is endothermic but exergonic, that is, thermodynamically allowed. The cyclization of salt 3a (R = Me) is the least endothermic and, according to Hammond’s postulate, has the lowest activation barrier. The calculation of salts 3 showed that the planes of the benzoyl or hetaroyl groups are nearly perpendicular to the benzothiazole ring. Since cyclization proceeds via the enol intermediate A followed by intramolecular dehydration (Scheme 2), the observed retardation of cyclization for R = Ph, hetaryl, is, apparently, due to the energy loss from the rotation of bulky R groups to form planar enol structure.
The calculations also allowed for explanation of the predominant endo N-alkylation of compound 1. The HOMO of molecule 1 is nearly equally localized on the endo and exo nitrogen atoms, which allows one to assume that the formation of highly polar products 3 should be charge-controlled. The Mulliken charges on the endo and exo nitrogen atoms are equal to −0.260 and −0.720, respectively, which at first glance indicates a preferable exo N-alkylation. However, if one considers the charges with summed hydrogens, the values are −0.260 and +0.420, respectively, clearly showing the preference of the endo N-alkylation.
The question of regioselectivity of alkylation is of particular interest. In most of the referenced works [10,11,12,13,14,15,16,17,18,19,20,21,29], N-alkylation is reported to take place at the endocyclic nitrogen atom of the thiazole ring. Only in the recent works of Egyptian authors [22,23,24] is it stated that the imidazo[2,1-b]thiazole skeleton is formed by N-alkylation of the exocyclic primary amino group. However, in neither of these citations was there any experimental evidence of the structure of the formed product. The only such evidence was given in our recent work [25] by isolation of the imidazothiazolium iodide salts, whose structure was confirmed by the {1H–15N} HMBC experiments. In particular, a large upfield shift of the endocyclic 15N signal with respect to that in the starting aminothiazole was observed (by ~90 ppm, from −138.5 to −227.7 ppm), and a much smaller downfield shift of the exocyclic NH2 signal (by ~11 ppm, from −301.3 to −290.1 ppm). In the cyclization product, the signals of Nendo and Nexo appear at −174.1 and −219.4 ppm, respectively [25]. Along with the results of theoretical calculations, this allows us to conclude that alkylation occurs at the endocyclic nitrogen atom.
The presence of two iodomethyl groups in the molecule of 1,3-diiodoacetone might expand the synthetic utility of the process by allowing the second molecule of compound 1 to be involved in the reaction. This could result in bis-derivatives of compound 1, by analogy with our recent work [30,31]. However, according to the NMR spectroscopy data of the reaction mixture, a mixture of the products of alkylation, cyclization and oligomerization was formed. The signals of the products of alkylation and cyclization coincide with those of compounds 3a and 5a obtained by alkylation of compound 1 with iodoacetone. The formation of the products of oligomerization is, probably, due to the heating of the reaction mixture to 65 °C in light, resulting in the appearance of HI [32]. Hydrogen iodide, in turn, can reduce the iodomethyl groups either in diiodoacetone 7, or in intermediate B (Scheme 4), as proved by the appearance of the methyl group signal at 2.2 ppm in the 1H NMR spectrum. The formed elemental iodine initiated the intramolecular cyclization of the product of N-alkylation 3a, converting it to 5a. It was impossible to separate salts 3a, 6a and 5a; therefore, the mixture was treated with elemental iodine to obtain the product of intramolecular condensation 5a (Scheme 3), whose characteristics were identical to those obtained by the reaction with iodoacetone in Scheme 2.
All products were obtained as light-yellow or dark-red solids, and their structure was proved by NMR and UV spectroscopy and elemental analysis. Unfortunately, we were unable to isolate single crystals suitable for X-ray analysis, probably because of its insolubility in most of the conventional organic solvents. Compounds 4d,e and 5a–f combine different pharmacophores in one molecule in conjunction with iodine anions and, therefore, are potentially biologically active compounds. The evaluation of biological activity of organic compounds is ongoing.

3. Experimental Section

3.1. General

Melting points were determined on a Micro-Hot-Stage PolyTherm A. Elemental analysis was carried out on a CHNS analyzer Thermo Scientific Flash 2000. The iodine was determined by mercurimetric titration. The reactions were monitored by 1H and 13C NMR spectroscopy, and by TLC on Silufol UV-254 plates with acetone as eluent, visualized by iodine vapors.

3.2. Spectral Measurements

NMR spectra were registered on a Bruker DPX 400 spectrometer at working frequencies 400.13 MHz (1H NMR) and 100.61 MHz (13C) in DMSO-d6 or acetone-d6. Chemical shifts are given in parts per million (ppm) relative to the residual signals of the solvent (DMSO: H 2.49, C 39.5; acetone: H 2.04, C 29.8). Coupling constants are reported in hertz (Hz). Abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; brs, broad singlet. UV spectra were taken on a Perkin UV-Vis Lambda 35 spectrometer for 10−4 M (products 3, 6) or 10−3 M (products 4, 5) acetonitrile solutions. The spectra of iodides have absorption maxima at 192–203 and 206–222 nm, whereas in the spectra of triiodides, longwave absorption bands at 289–298 and 359–361 nm were observed, typical for I3− anion [33].

3.3. Synthesis

Reaction of 2-amino-1,3-benzothiazole (1) with α-iodomethyl ketones (2a–f) and diiodoacetone (7) (general procedure).
A mixture of 2-amino-1,3-benzothiazole 1 [0.20 g (1.3 mmol)] and an equimolar amount of α-iodomethyl ketones 2a (0.24 g), 2b (0.34 g), 2c (0.43 g), 2d (0.33 g), 2e (0.38 g), 2f (0.45 g) or 1,3-diiodoacetone 7 (0.31 g, 1.0 mmol) in 2 mL of dry acetone was stirred at room temperature for 6–9 h. The precipitated products 3a–f were collected, washed with acetone and ether and dried under vacuum.

3.3.1. 2-Amino-3-(2-oxopropyl)-1,3-benzothiazol-3-ium iodide (3a)

Yield 0.32 g (73%), light yellow powder, m. p. 182–184 °C. Anal. Calcd. for C10H11N2IOS: C, 35.94; H, 3.32; N, 8.38; I, 37.97; S, 9.60; Found: C, 36.18; H, 3.25; N, 8.41; I, 38.08; S, 9.53. 1H NMR (DMSO-d6, δ, ppm): 10.15 (br.s, 2H, NH2); 8.05 (d, 1H, H7, 3JHH 7.2 Hz); 7.68 (d, 1H, H4, 3JHH 7.3 Hz); 7.49 (d.d, 1H, H5, 3JHH 7.3, 7.7 Hz); 7.39 (d.d, 1H, H6, 3JHH 7.2, 7.7 Hz); 5.43 (s, 2H, CH2); 2.34 (s, 3H, Me). 13C NMR (DMSO-d6, δ, ppm: 199.96 (C=O); 169.02 (C2); 138.97 (C9); 128.32 (C5); 125.89 (C6); 124.27 (C7); 122.36 (C8); 113.81 (C4); 55.07 (CH2); 28.03 (Me). UV spectrum (MeCN), λmax, nm: 203, 222.

3.3.2. 2-Amino-3-[2-(4-methylphenyl)-2-oxoethyl]-1,3-benzothiazol-3-ium iodide (3b)

Yield 0.32 g (60%), light yellow powder, m. p. 202–204 °C. Anal. Calcd. for C16H15N2IOS: C, 46.84; H, 3.68; N, 6.83; I, 30.93; S, 7.82; Found: C, 46.76; H, 3.55; N, 6.80; I, 31.05; S, 7.73. 1H NMR (DMSO-d6, δ, ppm): 10.21 (br.s, 2H, NH2); 8.08 (d, 1H, H7, 3JHH 6.3 Hz); 7.03–8.05 (m, 2H, Ho); 7.68 (d, 1H, H4, 3JHH 6.3 Hz); 7.31–7.59 (m, 3H, H5,6,m); 6.08 (s, 2H, CH2); 2.44 (s, 3H, Me). 13C NMR (DMSO-d6, δ, ppm: 190.09 (C=O); 169.42 (C2); 145.62 (Cp); 139.04 (Ci); 131.82 (C9); 129.81 (Cm); 129.17 (Co); 128.30 (C8); 125.83 (C6); 124.15 (C5), 122.33 (C7); 113.75 (C4); 52.48 (CH2); 21.80 (Me). UV spectrum (MeCN), λmax, nm: 203, 217.

3.3.3. 2-Amino-3-[2-(1,1′-biphenyl)-4-yl-2-oxoethyl]-1,3-benzothiazol-3-ium iodide (3c)

Yield 0.33 g (54%), light yellow powder, m. p. 230–232 °C. Anal. Calcd. for C21H17N2IOS: C, 53.40; H, 3.63; N, 5.93; I, 26.87; S, 6.79; Found: C, 53.29; H, 3.57; N, 5.82; I, 26.97; S, 6.70. 1H NMR (DMSO-d6, δ, ppm): 10.27 (br.s, 2H, NH2); 8.20 (d, 2H, Ho, 3JHH 7.5 Hz); 8.10 (d, 1H, H7, 3JHH 7.8 Hz); 7.98 (d, 2H, Hm, 3JHH 7.5 Hz); 7.81 (d, 2H, Ho′, 3JHH 7.3 Hz); 7.75 (d, 1H, H4, 3JHH 7.6 Hz); 7.38–7.62 (m, 5H, H5,6,m′,p); 6.16 (s, 2H, CH2). 13C NMR (DMSO-d6, δ, ppm: 190.21 (C=O); 169.42 (C2); 146.16 (Cp); 139.07 (Ci′); 139.02 (Ci); 133.11 (C9); 129.84 (Cm); 129.61 (Co); 129.15 (C5); 128.31 (Cp’); 127.52 (Cm′); 127.38 (Co′); 125.85 (C6); 124.17 (C8); 122.35 (C7); 113.79 (C4); 52.66 (CH2). UV spectrum (MeCN), λmax, nm: 203, 221.

3.3.4. 2-Amino-3-[2-(2-thienyl)-2-oxoethyl]-1,3-benzothiazol-3-ium iodide (3d)

Yield 0.36 g (70%), light yellow powder, m. p. 194–196 °C. Anal. Calcd. for C13H11N2IOS2: C, 38.81; H, 2.76; N, 6.96; I, 31.55; S, 15.94; Found: C, 38.73; H, 2.71; N, 6.89; I, 31.65; S, 15.89. 1H NMR (DMSO-d6, δ, ppm): 10.28 (br.s, 2H, NH2); 8.24–8.33 (m, 1H, H3′); 8.16–8.24 (m, 1H, H5′); 8.02–8.12 (m, 1H, H7); 7.64–7.75 (m, 1H, H4); 7.48–7.57 (m, 1H, H5); 7.37–7.48 (m, 2H, H6,4’); 6.04 (s, 2H, CH2). 13C NMR (DMSO-d6, δ, ppm: 183.33 (C=O); 169.15 (C2); 139.62 (C8); 138.48 (C2′); 136.45 (C4′); 135.39 (C5′); 129.15 (C3′); 127.92 (C5); 125.48 (C6); 123.74 (C7); 121.84 (C9); 113.24 (C4); 51.59 (CH2). UV spectrum (MeCN), λmax, nm: 202, 221.

3.3.5. 2-Amino-3-[2-(5-chloro-2-thienyl)-2-oxoethyl]-1,3-benzothiazol-3-ium iodide (3e)

Yield 0.34 g (59%), light yellow powder, m. p. 210–213 °C. Anal. Calcd. for C13H10N2ClIOS2: C, 35.75; H, 2.31; N, 6.41; Cl, 8.12; I, 29.06; S, 14.68; Found: C, 35.68; H, 2.28; N, 6.37; Cl, 7.98; I, 29.17; S, 14.60. 1H NMR (DMSO-d6, δ, ppm): 10.31(br.s, 2H, NH2); 8.12–8.24 (m, 1H, H3′); 7.96–8.11 (m, 1H, H7); 7.61–7.82 (m, 1H, H4); 7.32–7.60 (m, 3H, H5,6,4′); 6.01 (s, 2H, CH2). 13C NMR (DMSO-d6, δ, ppm: 183.28 (C=O); 169.53 (C2); 139.41 (C8); 138.96 (C2′); 138.77 (C5’); 136.07 (C4’); 129.74 (C3’); 128.28 (C5); 125.86 (C6); 124.14 (C7); 122.22 (C9); 113.59 (C4); 51.70 (CH2). UV spectrum (MeCN), λmax, nm: 202, 222.

3.3.6. 2-Amino-3-[2-(9H-carbazol-2-yl)-2-oxoethyl]-1,3-benzothiazol-3-ium iodide (3f)

Yield 0.32 g (50%), light yellow powder, m. p. 256–258 °C. Anal. Calcd. for C21H16IN3OS: C, 51.97; H, 3.32; N, 8.66; I, 26.15; S, 6.61; Found: C, 51.89; H, 3.28; N, 8.60; I, 26.25; S, 6.57. 1H NMR (DMSO-d6, δ, ppm): 10.36 (br.s, NH); 8.34–8.42 (m, 1H, H7); 8.23–8.33 (m, 2H, H1′,4′); 8.05–8.12 (m, 1H, H5′); 7.89–7.98 (m, 1H, H3′); 7.71–7.78 (m, 1H, H4); 7.58–7.66 (m, 1H, H6); 7.41–7.57 (m, 3H, 5,7’,8’); 7.21–7.29 (m, 11H, Ar); 6.26 (s, 2H, CH2). 13C NMR (DMSO-d6, δ, ppm): 190.38 (C=O); 169.46 (C2); 142.00; 139.15; 131.18; 128.29; 127.95; 127.54; 125.88; 125.81; 124.09; 122.38; 121.92; 121.85; 120.72; 119.79; 119.19; 113.84; 112.45; 112.00 (Ar); 52.66 (CH2). UV spectrum (MeCN), λmax, nm: 203, 222.

Reaction of Iodides (3a–f) and (6a–f) with Elemental Iodine (General Procedure)

A mixture of equimolar amounts (1.00 mmol) of iodides 3a–f or 6a–f and elemental iodine in 5 mL of acetone was stirred for 2–3 h at room temperature. After completion, the products 4a–f or 5a–f were precipitated by the addition of 35 mL of hexane, washed with cooled ether and dried under vacuum.

3.3.7. 2-Amino-3-[2-(2-thienyl)-2-oxoethyl]-1,3-benzothiazol-3-ium triiodide (4d)

Yield 0.59 g (91%), dark red powder, m. p. 124–126 °C. Anal. Calcd. for C13H11N2I3OS2: C, 23.80; H, 1.69; N, 4.27; I, 58.03; S, 9.77; Found: C, 23.69; H, 1.60; N, 4.20; I, 58.15; S, 9.68. 1H NMR (DMSO-d6), δ, ppm: 10.27 (br.s, 2H, NH2); 8.25 (d, 1H, H3′, 3JHH 3.4 Hz); 8.19 (d, 1H, H5′, 3JHH 5.0 Hz); 8.02 (d, 1H, H7, 3JHH 7.6 Hz); 7.68 (d, 1H, H4, 3JHH 8.2 Hz); 7.52 (d.d, 1H, H5, JHH 7.0, 8.2 Hz); 7.39–7.48 (m, 2H, H6,4′); 6.00 (s, 2H, CH2). 13C NMR (DMSO-d6), δ, ppm: 183.85 (C=O); 169.74 (C2); 140.19 (C8); 139.07 (C2′); 136.97 (C4′); 135.87 (C5′); 129.70 (C3′); 128.50 (C5); 126.08 (C6); 124.23 (C7); 122.36 (C9); 113.80 (C4); 52.04 (CH2). UV spectrum (MeCN), λmax, nm: 294, 361.

3.3.8. 2-Amino-3-[2-(5-chloro-2-thienyl)-2-oxoethyl]-1,3-benzothiazol-3-ium triiodide (4e)

Yield 0.62 g (90%), dark red powder, m. p. 199–201 °C. Anal. Calcd. for C13H10N2ClI3OS2: C, 22.61; H, 1.46; N, 4.07; Cl, 5.13; I, 55.13; S, 9.29; Found: C, 22.56; H, 1.40; N, 3.97; Cl, 4.97; I 55.23; S, 9.20. 1H NMR (acetone-d6), δ, ppm: 9.78 (br.s, 2H, NH2); 8.18 (d, 1H, H3′,3JHH 3.8 Hz); 8.07 (d, 1H, H7, 3JHH 8.3 Hz); 7.80 (d, 1H, H4, 3JHH 8.3 Hz); 7.62 (d.d, 1H, H5, 3JHH 7.6, 8.3 Hz); 7.54 (d.d, 1H, H6, 3JHH 7.6, 8.3 Hz); 7.36 (d, 1H, H4′, 3JHH 3.8 Hz); 6.23 (s, 2H, CH2). 13C NMR, acetone-d6, δ, ppm: 182.49 (C=O); 170.98 (C2); 141.10 (C9); 139.56 (C2′); 139.40 (C5′); 135.79 (C4′); 129.77 (C3′), 129.18 (C5); 127.02 (C6); 124.34 (C7); 122.75 (C8); 114.23 (C4); 52.24 (CH2). UV spectrum (MeCN), λmax, nm: 291, 361.

3.3.9. 2-Methyl-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5a)

Yield 0.56 g (93%), dark red powder, m. p. 154–156 °C. Anal. Calcd. for C10H9N2I3S. C, 21.07; H, 1.59; N, 4.91; I, 66.80; S, 5.62; Found: C, 20.91; H, 1.51; N, 4.87; I, 66.90; S, 5.58. 1H NMR (DMSO-d6, δ, ppm): 8.46 (s, 1H, CH=); 8.17–8.27 (m, 2H, H4,7); 7.70 (d.d, 1H, H5, 3JHH 7.7, 8.6 Hz); 7.61 (d.d, 1H, H6, 3JHH 7.5, 7.7 Hz); 2.46 (s, 3H, Me). 13C NMR (DMSO-d6, δ, ppm): 145.92 (C10); 135.77(C2); 131.67 (C11); 129.89 (C12); 128.29 (C8); 127.62 (C6); 126.04 (C7); 115.37 (C3); 112.32 (C5); 11.87 (CH3). UV spectrum (MeCN), λmax, nm: 289, 361.

3.3.10. 6-(4-Methylphenyl)-7H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5b)

Yield 0.39 g (89%), dark red powder, m. p. 198–200 °C. Anal. Calcd. for C16H13N2I3S. C, 29.74; H, 2.03; N, 4.34; I, 58.93; S, 4.96; Found: C, 29.65; H, 1.96; N, 4.28; I, 59.05; S, 4.88. 1H NMR (acetone-d6, δ, ppm): 9.09 (s, 1H, CH=); 8.32–8.41 (m, 2H, H5,8); 7.89 (d.d, 1H, H6, 3JHH 7.7, 7.9 Hz); 7.75–7.82 (m, 3H, H7,o); 7.46 (d, 1H, Hm, 3JHH 7.9 Hz); 2.44 (s, 3H, Me). 13C NMR (acetone-d6, δ, ppm): 144.10 (C10); 140.90 (Cp); 135.67 (C11); 132.19 (C2); 130.75 (Cm); 130.31 (Ci); 129.63 (C12); 128.56 (C8); 128.17 (C6); 125.61 (C7); 125.15 (Co); 115.15 (CH=); 110.38 (C5); 22.55 (CH3). UV spectrum (MeCN), λmax, nm: 295, 361.

3.3.11. 2-(1,1′-Biphenyl)-4-yl-)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5c)

Yield 0.60 g (86%), dark red powder, m. p. 170–171 °C. Anal. Calcd. for C21H15N2I3S. C, 35.62; H, 2.14; N, 3.96; I, 53.76; S, 4.53; Found: C, 35.53; H, 2.08; N, 3.90; I, 53.86; S, 4.47. 1H NMR (acetone-d6, δ, ppm): 9.00 (s, 1H, CH=); 8.20–8.27 (m, 2H, H5,8); 8.03 (d, 2H, Ho’, 3JHH 6.4 Hz); 7.86 (d, 2H, Ho, 3JHH 7.9 Hz); 7.70–7.81 (m, 3H, Hm,p′); 7.67 (d.d, 1H, H6, 3JHH 7.6, 7.9 Hz); 7.47–7.54 (m, 2H, Hm′); 7.42 (d.d, 1H, H7, 3JHH 7.6, 7.9 Hz). 13C NMR (acetone-d6, δ, ppm): 147.36 (C10); 145.16 (Cp); 139.76 (C11); 139.35 (Ci′); 132.21 (Ci); 131.82 (C2); 129.65 (C8); 129.37 (Cm); 129.22 (C6); 127.74 (Cm′); 127.23 (C7); 127.10 (Co); 126.64 (Cp′); 125.75 (Co′); 125.55 (C12); 113.76 (C3); 109.51 (C5). UV spectrum (MeCN), λmax, nm: 298, 361.

3.3.12. 2-(2-Thienyl)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5d)

Yield 0.55 g (88%), dark red powder, m. p. 196–198 °C. Anal. Calcd. for C13H9N2I3S2. C, 24.47; H, 1.42; N, 4.39; I, 59.67; S, 10.05; Found: C, 24.39; H, 1.36; N, 4.32; I, 59.78; S, 9.97. 1H NMR (acetone-d6, δ, ppm): 8.96 (s, 1H, CH=); 8.29–8.37 (m, 2H, H5,8); 7.85 (d.d, 1H, H6, 3JHH 7.4, 7.6 Hz); 7.69–7.78 (m, 3H, H7,3′,5′); 7.27 (d.d, 1H, H4′, 3JHH 4.3, 5.3 Hz). 13C NMR (acetone-d6, δ, ppm): 148.23 (C10); 134.90 (C2); 132.39 (C11); 130.36 (C2′); 129.35 (C3′); 129.16 (C5′); 129.07 (C8); 128.69 (C6); 128.21 (C7); 126.28 (C4′); 125.21 (C12); 115.92 (C3); 111.10 (C5). UV spectrum (MeCN), λmax, nm: 289, 361.

3.3.13. 2-(2-(5-Chloro-2-thienyl))-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5e)

Yield 0.55 g (84%), dark red powder, m. p. 191–193 °C. Anal. Calcd. for C13H8N2ClI3S2. C, 23.22; H, 1.20; N, 4.16; I, 56.61; S, 9.54; Found: C, 23.14; H, 1.16; N, 4.07; I, 56.72; S, 9.48. 1H NMR (DMSO-d6, δ, ppm): 8.61 (s, 1H, CH=); 7.94–8.03 (m, 2H, H5,8); 7.54 (d.d, 1H, H6, 3JHH 7.9, 8.1 Hz); 7.42 (d.d, 1H, H7, 3JHH 7.0, 7.9 Hz); 7.25 (d, 1H, H3′, 3JHH 3.5 Hz); 7.08 (d, 1H, H4′, 3JHH 3.5 Hz). 13C NMR (DMSO-d6, δ, ppm): 147.39 (C10); 140.41 (C2); 136.57 (C11); 131.73 (C2′); 129.40 (C5′); 127.99 (C12); 127.06 (C3′); 126.76 (C8); 125.71 (C6); 125.23 (C4′); 122.24 (C7); 113.72 (C3); 108.81 (C5). UV spectrum (MeCN), λmax, nm: 289, 361.

3.3.14. 2-(2-(9H-Carbazol-2-yl)-)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium triiodide (5f)

Yield 0.58 g (83%), dark red powder, m. p. 258–260 °C. Anal. Calcd. for C21H14I3N3S: C, 34.98; H, 1.96; N, 5.83; I, 52.79; S, 4.45. Found: C, 34.89; H, 1.90; N, 5.77; I, 52.91; S, 4.39. 1H NMR (DMSO-d6, δ, ppm): 11.50 (br.s, NH); 9.12 (s, 1H, H3); 8.09–8.28 (m, 4H, H5,4′,5′,8); 7.94 (s, 1H, H1′); 7.71 (d.d, 1H, H6, 3JHH 7.6, 8.4 Hz); 7.50–7.65 (m, 3H, H3′,7,8′); 7.41 (d.d, 1H, H7′, 3JHH 7.4, 7.6 Hz); 7.18 (d.d, 1H, H6′, 3JHH 7.4, 7.6 Hz). 13C NMR (DMSO-d6, δ, ppm): 155.17 (C10); 147.10; 141.18; 140.85; 140.15; 131.67; 129.53; 128.08; 127.25; 126.61; 125.91; 123.47; 122.32; 121.47; 120.83; 119.43; 116.29; 114.95; 111.48; 110.51; 107.79 (Ar). UV spectrum (MeCN), λmax, nm: 292, 359.

Cyclization of Iodides (3a–f)

(a) One mmol of iodides 3a–f [3a 0.33 g, 3b 0.42 g, 3c 0.47 g, 3d 0.40 g, 3e 0.44g, 3f 0.49 g] was placed in an ampoule with DMSO and kept for 1–24 h at room temperature, with monitoring by 1H NMR after 1, 12, and 24 h. Then, the reaction mixture was added dropwise to 50 mL of diethyl ether at vigorous stirring. The formed precipitate was filtered off, washed with ether and dried under vacuum.
(b) A suspension of 1 mmol of iodides 3a–f in MeOH was stirred for 7 h at 40 °C, with monitoring by 1H NMR in 1, 3.5, and 7 h. Then, the reaction mixture was added dropwise to 40 mL of diethyl ether at vigorous stirring. The formed precipitate was filtered off, washed with ether and dried under vacuum.

3.3.15. 2-Methyl-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6a)

Yield 0.28 g (86%), light yellow powder, m. p. 138–140 °C. Anal. Calcd. for C10H9N2IS. C, 37.99; H, 2.87; N, 8.86; I, 40.14; S, 10.14; Found: C, 37.88; H, 2.84; N, 8.79; I, 40.24; S, 10.03. 1H NMR (DMSO-d6, δ, ppm): 8.44 (s, 1H, CH=); 8.17–8.27 (m, 2H, H4,7); 7.69 (d.d, 1H, H5, 3JHH 7.1, 8.1 Hz); 7.59 (d.d, 1H, H6, 3JHH 8.1, 8.3 Hz); 2.44 (s, 3H, Me). 13C NMR (DMSO-d6, δ, ppm): 145.90 (C10); 136.41 (C11); 131.71 (C2); 129.81 (C12); 128.15 (C8); 127.38 (C6); 126.01 (C7); 115.21 (C3); 112.15 (C5); 12.05 (CH3). UV spectrum (MeCN), λmax, nm: 193, 210.

3.3.16. 2-(4-Methylphenyl)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6b)

Yield 0.25 g (63%), light yellow powder, m. p. 219–221 °C. Anal. Calcd. for C16H13N2IS. C, 48.99; H, 3.34; N, 7.14; I, 32.35; S, 8.17; Found: C, 48.93; H, 3.30; N, 7.08; I, 32.44; S, 8.10. 1H NMR (DMSO-d6, δ, ppm): 8.90 (s, 1H, CH=); 8.13 (d, 1H, H5, 3JHH 7.9 Hz); 8.08 (d, 1H, H8, 3JHH 8.2 Hz); 7.72 (d, 2H, Ho, 3JHH 7.8 Hz); 7.64 (d.d, 1H, H6, 3JHH 7.9, 7.8 Hz); 7.51 (d.d, 1H, H7, 3JHH 7.8, 8.2 Hz); 7.28 (d, 2H, Hm, 3JHH 7.8 Hz); 2.33 (s, 3H, Me). 13C NMR (DMSO-d6, δ, ppm): 147.28 (C10); 143.60 (Cp); 138.11 (C11); 132.06 (C2); 130.07 (Cm); 129.68 (Ci); 128.90 (C12); 127.68 (C8); 126.48 (C6); 125.78 (C7); 125.30 (Co); 114.39 (CH=); 109.43 (C5); 22.01 (CH3). UV spectrum (MeCN), λmax, nm: 192, 206.

3.3.17. 2-(1,1’-Biphenyl)-4-yl-)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6c)

Yield 0.30 g (67%), light yellow powder, m. p. 188–190 °C. Anal. Calcd. for C21H15N2IS. C, 55.52; H, 3.33; N, 6.16; I, 27.93; S, 7.06; Found: C, 55.46; H, 3.28; N, 6.10; I, 28.02; S, 7.01. 1H NMR (DMSO-d6, δ, ppm): 8.76 (s, 1H, CH=); 7.94–8.00 (m, 2H, H5,8); 7.87–7.91 (m, 2H, Ho); 7.67–7.71 (m, 2H, Hm); 7.63–7.66 (m, 2H, Ho’);7.53 (d.d, 1H, H6, 3JHH 7.9, 8.1 Hz); 7.38–7.45 (m, 3H, Hm′p′); 7.33 (d.d, 1H, H7, 3JHH 7.3, 8.1 Hz). 13C NMR (DMSO-d6, δ, ppm): 147.58 (C10); 145.13 (Cp); 140.01 (C11); 139.68 (Ci’); 132.26 (Ci); 132.07 (C2); 129.65 (C8); 129.47 (Cm); 128.01 (C6); 127.50 (Cm’); 127.37 (C7); 126.92 (Co); 126.04 (Cp′); 125.81 (Co′); 125.50 (C12); 114.06 (C3); 109.83 (C5). UV spectrum (MeCN), λmax, nm: 192, 206.

3.3.18. 2-(2-Thienyl)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6d)

Yield 0.24 g (64%), light yellow powder, m. p. 206–208 °C. Anal. Calcd. for C13H9N2IS2. C, 40.63; H, 2.36; N, 7.29; I, 33.02; S, 16.69; Found: C, 40.57; H, 2.30; N, 7.21; I, 33.13; S, 16.61. 1H NMR (DMSO-d6, δ, ppm): 8.61 (s, 1H, CH=); 7.95–8.01 (m, 2H, H5,8); 7.54 (d.d, 1H, H6, 3JHH 7.3, 8.4 Hz); 7.38–7.46 (m, 3H, H7,3′,5′); 7.10 (d.d, 1H, H4′, 3JHH 3.8, 4.9 Hz). 13C NMR (DMSO-d6, δ, ppm): 146.99 (C10); 141.13 (C2); 137.08 (C11); 131.71 (C2′); 129.23 (C3′); 128.08 (C5′); 126.88 (C8); 125.44 (C12); 125.08 (C6); 124.88 (C7); 122.88 (C4′); 113.56 (C5); 108.39 (C3). UV spectrum (MeCN), λmax, nm: 192, 206.

3.3.19. 2-(2-(5-Chloro-2-thienyl))-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6e)

Yield 0.25 g (62%), light yellow powder, m. p. 205–207 °C. Anal. Calcd. for C13H8N2ClIS2. C, 37.29; H, 1.92; N, 6.69; I, 30.31; S, 15.31; Found: C, 37.23; H, 1.88; N, 6.61; I, 30.71; S, 15.26. 1H NMR (acetone-d6, δ, ppm): 8.45 (s, 1H, CH=); 7.91–7.99 (m, 2H, H5,8); 7.57 (d.d, 1H, H6, 3JHH 7.5, 7.8 Hz); 7.46 (d.d, 1H, H7, 3JHH 7.5, 8.1 Hz); 7.27 (d, 1H, H3′, 3JHH 3.6 Hz); 6.99 (d, 1H, H4′, 3JHH 3.6 Hz). 13C NMR (acetone-d6, δ, ppm): 147.50 (C10); 140.51 (C2); 136.30 (C11); 131.04 (C2′); 129.76 (C5′); 127.73 (C12); 127.32 (C3′); 126.89 (C8); 125.61 (C6); 124.83 (C4′); 122.20 (C7); 113.47 (C3); 107.97 (C5). UV spectrum (MeCN), λmax, nm: 192, 206.

3.3.20. 2-(2-(9H-Carbazol-2-yl)-)-1H-imidazo[2,1-b][1,3]benzothiazol-4-ium iodide (6f)

Yield 0.26 g (58%), light yellow powder, m. p. 248–250 °C. Anal. Calcd. for C21H14IN3S: C, 59.97; H, 3.02; N, 8.99; I, 27.16; S, 6.86; Found: C, 59.84; H, 2.78; N, 8.64; I, 27.45; S, 6.80. 1H NMR (DMSO-d6, δ, ppm): 11.43 (br.s, NH); 8.99 (s, 1H, H3); 8.19 (d, 1H, H8, 3JHH 7.8 Hz); 8.07–8.16 (m, 3H, H5,4′,3′); 8.00 (s, 1H, H1′); 7.62–7.71 (m, 2H, H7,8′); 7.47–7.54 (m, 2H, H5′,6); 7.35–7.43 (m, 1H, H7′); 7.13–7.19 (m, 1H, H6′). 13C NMR (DMSO-d6, δ, ppm): 169.25 (C10); 146.82; 140.37; 140.09; 138.47; 131.68; 129.21; 129.07; 127.06; 125.76; 125.21; 122.28; 120.68; 120.21; 118.82; 115.96; 113.80; 111.01; 109.41; 107.16; 106.03 (Ar). UV spectrum (MeCN), λmax, nm: 203, 211.

3.4. Computational Details

All calculations were performed with full geometry optimization using the B3LYP/DGDZVP method as implemented in Gaussian 09 [34].

4. Conclusions

Based on the reaction of 2-amino-1,3-benzothiazole with α-iodoketones in the absence of bases and catalysts, both linear and cyclic iodide and triiodide salts with 2-amino-1,3-benzothiazol-3-ium and 6-R-7H-imidazo[2,1-b][1,3]benzothiazol-4-ium cations were synthesized. The experimentally observed preference for the endo N-alkylation is explained theoretically.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052093/s1. Copies of the 1H and 13C NMR spectra for all synthesized compounds can be found in Supplementary Materials.

Author Contributions

Conceptualization and validation, L.V.Z. and N.O.Y.; methodology, investigation and spectral analysis, I.A.D.; writing—original draft preparation, L.V.Z. and N.O.Y.; writing—review and editing, B.A.S.; calculations and supervision, B.A.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This work was performed with the use of equipment of the Baikal Analytical Center for Collective Use of the Siberian Branch of the Russian Academy of Sciences.

Conflicts of Interest

The authors declare no competing financial interests.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 28 02093 sch001 550
Scheme 1. The reactions of 2-amino-1,3-benzothiazole 1 with α-iodoketones 2a–f.
Scheme 1. The reactions of 2-amino-1,3-benzothiazole 1 with α-iodoketones 2a–f.
Molecules 28 02093 sch001
Molecules 28 02093 sch002 550
Scheme 2. The reactions of salts 3a–f with elemental iodine.
Scheme 2. The reactions of salts 3a–f with elemental iodine.
Molecules 28 02093 sch002
Molecules 28 02093 sch003 550
Scheme 3. Cyclization of iodides 3a–f to 6a–f and conversion of the latter to triiodides 5a–f.
Scheme 3. Cyclization of iodides 3a–f to 6a–f and conversion of the latter to triiodides 5a–f.
Molecules 28 02093 sch003
Molecules 28 02093 sch004 550
Scheme 4. Reaction of 2-aminobenzothiazole 1 with 1,3-diiodoacetone 7.
Scheme 4. Reaction of 2-aminobenzothiazole 1 with 1,3-diiodoacetone 7.
Molecules 28 02093 sch004
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MDPI and ACS Style

Dorofeev, I.A.; Zhilitskaya, L.V.; Yarosh, N.O.; Shainyan, B.A. 2-Amino-1,3-benzothiazole: Endo N-Alkylation with α-Iodo Methyl Ketones Followed by Cyclization. Molecules 2023, 28, 2093. https://doi.org/10.3390/molecules28052093

AMA Style

Dorofeev IA, Zhilitskaya LV, Yarosh NO, Shainyan BA. 2-Amino-1,3-benzothiazole: Endo N-Alkylation with α-Iodo Methyl Ketones Followed by Cyclization. Molecules. 2023; 28(5):2093. https://doi.org/10.3390/molecules28052093

Chicago/Turabian Style

Dorofeev, Ivan A., Larisa V. Zhilitskaya, Nina O. Yarosh, and Bagrat A. Shainyan. 2023. "2-Amino-1,3-benzothiazole: Endo N-Alkylation with α-Iodo Methyl Ketones Followed by Cyclization" Molecules 28, no. 5: 2093. https://doi.org/10.3390/molecules28052093

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