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Article

Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids

by
Itzia I. Padilla-Martínez
1,
José Miguel González-Encarnación
1,
Efrén V. García-Báez
1,
Alejandro Cruz
1,* and
Ángel Andrés Ramos-Organillo
2
1
Instituto Politécnico Nacional-UPIBI, Laboratorio de Química Supramolecular y Nanociencias, Av. Acueducto s/n, Barrio la Laguna Ticomán 07340, México City, Mexico
2
Facultad de Ciencias Químicas, Universidad de Colima, Km 9 Carr. Colima-Coquimatlán, Coquimatlán 28400, Colima, Mexico
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(18), 3391; https://doi.org/10.3390/molecules24183391
Submission received: 15 August 2019 / Revised: 6 September 2019 / Accepted: 10 September 2019 / Published: 18 September 2019
(This article belongs to the Section Organic Chemistry)
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Abstract

:
In this investigation, the reaction of 2-dithiomethylcarboimidatebenzothiazole with a series of six chiral amino-acids was studied. The reaction proceeds through the isolable sodium salt of SMe-isothiourea carboxylates as intermediates, whose reaction with methyl iodide in stirring DMF as solvent affords SMe-isothiourea methyl esters. The presence of water in the reaction leads to the corresponding urea carboxylates as isolable intermediates, whose methyl esters were obtained. Finally, the urea N-methyl amide derivatives were isolated when SMe-isothiourea or urea methyl esters were reacted with methylamine in the presence of water. The structures of synthesized compounds were established by 1H and 13C nuclear magnetic resonance and the structures of SMe-isothiourea methyl esters derived from (l)-glycine, (l)-alanine, (l)-phenylglycine, and (l)-leucine, by X-ray diffraction analysis. This methodology allows to functionalize 2-aminobenzothiazole with SMe-isothiourea, urea, and methylamide groups derived from chiral amino acids to get benzothiazole derivatives containing coordination sites and hydrogen bonding groups. Further research on the biological activities of some of these derivatives is ongoing.

1. Introduction

Benzothiazole is an aromatic bicyclic ring system that consists of a thiazole ring fused with a benzene ring. The benzothiazole moiety is small but a very interesting compound with wide biological activities. At the beginning of the 1970s, it was found that benzothiazole derivatives possessed pharmacological antiviral [1,2,3], antibacterial [3,4,5,6], antimicrobial [7,8,9], fungicidal [10,11], antiallergic [12,13,14], antidiabetic [15,16,17], antitumoral [18,19,20,21], anti-inflammatory [22,23] and anthelmintic [24,25,26] activities.
A continuous interest in this class of compounds follows nowadays and numerous efforts to synthesize new biologically active heterocyclic compounds derived from the benzothiazole moiety have been made in the last 50 years. Several of these derivatives were found to possess anticonvulsant [27,28,29] and antioxidant [30,31,32] activities. In this context, some results related to molecules containing benzothiazole nuclei in medicinal chemistry have been summarized elsewhere [33,34].
On the other hand, guanidines are an important class of compounds that are found widely throughout nature and as biologically active synthetic compounds, and several uses in organic chemistry are known [35,36,37,38]. For example, the natural amino acid arginine has a guanidine group as side chain, whilst cimetidine, a synthetic guanidine-derived compound, was the first drug used to treat peptic ulcers.
Typically, the reaction of amines with thioureas [39] or isothioureas [40,41,42] is the most commonly used method to obtain guanidines. Particularly, the isothiourea group has been bonded to a solid phase as precursor of guanidines [43]. In the last decade, it has been recognized that isothioureas can also serve as remarkably potent inhibitors for a range of enzymatic systems [44,45,46]. On the other hand, inhibition of nitric oxide synthase (NOS) has led to their use in the treatment of a range of life-threatening conditions, including septic shock, acute kidney failure, and rejection after transplantation surgery [47].
In this sense, we report a synthetic way to prepare symmetrical and nonsymmetrical guanidines 4 derived from 2-aminobenzothiazole 1 by the reaction of 2-dithiomethylcarboimidatebenzothiazole 2 with primary amines in refluxing ethanol [48]. The reaction proceeds through the formation of SMe-isothioureas 3, as intermediates, and the displacement of two MeSH molecules [49], Scheme 1.
In this contribution, we applied this methodology in the reaction of 2 with a series of chiral amino acids to form the corresponding SMe-isothiourea carboxylates 5, which were further transformed into the corresponding isourea carboxylates 6, methyl ester derivatives 8–10 and 12, and isourea amides 11, and 13. This methodology allows the functionalization of 2-aminobenzothiazole to introduce groups such as isothioureas, isoureas ureas, amides, and guanidines derived from chiral amino acids. These functional groups give properties such as coordinating sites, hydrogen bonding interactions, and water solubility, among others, required for the interaction with biomolecules. The reactions were carried out without modification of the chiral center configuration and all compounds were optically pure isolated as shown in the analyzed X-ray structures of compounds 8b,c and 9f.

2. Results and Discussion

2.1. Reactions and Characterization

Six amino acids Aa–f were tested: glycine (R = H, a), (l)-alanine (R = Me, b), (l)-phenylglycine (R = Ph, c), (l)-phenylalanine (R = Bn, d), (l)-valine (R = iPr, e), and (l)-leucine (R = iBu, f), represented as the zwitterions Ba–f. Each amino acid was transformed in situ into the corresponding sodium carboxylate Ca–f by reaction with one molar equivalent of sodium hydroxide in stirring ethanol for 2 h at room temperature, Scheme 2.
The reaction of one molar equivalent of 2-dithiomethylcarboimidatebenzothiazole 2 with the corresponding amino-acid carboxylates Ca–f at refluxing ethanol for eight hours was carried out. In these conditions, the reaction proceeds by nucleophilic attack of the amino group of the amino-carboxylates C to the carbonimidothioate group of compound 2, with elimination of thiomethanol gas to afford the corresponding SMe-isothiourea-carboxylates 5a–f in 40–86% yields. The 1H NMR spectroscopic data of compounds 5a–f are listed in Table S3. A singlet for the SMe group is found in the 2.35–2.44 ppm range, whose integration area are in a 3:4 proportion in relation to the aromatic hydrogen atoms. The chemical shift of the NH group to high frequency (10.6–11.4 ppm) is explained due to a hydrogen bonding interaction with the nitrogen atom of the benzothiazole moiety, as depicted in Scheme 3. On the other hand, the 13C NMR data, listed in Table S4, show characteristic signals from 13.9 to 14.1 and 169.7 to 171.6 ppm ranges for the SMe and OC=O groups, respectively.
In the case of the reaction of compound 2 with valine- (Ce, R = iPr) or leucine- (Cf, R = iBu) carboxylates, an insoluble yellowish solid appeared in the reaction mixture, which was identified as compound 7. The 1H NMR spectrum shows two singlets at 2.6 ppm (SMe) and 3.9 (NMe) each in a 3:4 proportion with respect to the aromatic hydrogen atoms. In the 13C NMR spectrum, the signals for SMe, NMe, and the thiocarbonyl group at 18.6, 33.7, and 208.7 ppm, respectively, appeared. To explain these results, a sigmatropic rearrangement of compound 2 to form compound 7 in 15% yield is proposed, as depicted in Scheme 4, in agreement with 1H and 13C NMR data.
Isorea carboxylate compound 6c was isolated as byproduct in 20% yield, from the remaining mother liquors of 5c. No signal for the SMe group was present in the NMR spectra of compound 6c, but two interchangeable protons with deuterium were observed at 11.8 ppm, corresponding to the isourea OH, and at 8.3 ppm, attributed to the urea NH. 1H and 13C NMR spectroscopic data of compound 6c are listed in Tables S5 and S6, respectively. The substitution of the remaining SMe group in compound 5c by one molecule of water afforded compound 6c as one of the two possible tautomers, Table S5.
To improve the yields of the sodium salt of SMe-isotiourea carboxylates 5b–f, the reactions were carried out using anhydrous ethanol and stirring for 4 days at room temperature to avoid hydrolysis. In these conditions, the reaction proceeds more slowly to afford the corresponding SMe-isothiourea-carboxylates 5b–f in 62–95% yields. On the other hand, the complete hydrolysis of SMe-isotiourea carboxylates 5b–f in a refluxing mixture of ethanol:water 1:1 was carried out. In these conditions, the second thiomethanol gas molecule was eliminated to afford the corresponding isourea carboxylates 6b–e as the only products in 65–75% yields. The hydrolysis of compound 5a required more drastic conditions such as refluxing in DMF/H2O mixtures to obtain 6a in 40% yield.
The corresponding SMe-isothiourea carboxylate methyl esters 8a–d were obtained in 56–83% yields after the methylation of carboxylates 5a–d with one molar equivalent of methyl iodide in DMF as solvent, whose 1H and 13C NMR chemical shifts are listed in Tables S7 and S8, respectively. In general, their spectra are very similar compared to the corresponding carboxylates 5a–d, except for the OMe group signals which are in the 3.75–3.83 and 45–53 ppm ranges in 1H and 13C NMR spectra, respectively. The 13C NMR data of esters 8c,d in CDCl3 show broad signals for C2, C9, and C11, suggesting that the usually fast proton exchange between N3 and N12 through tautomeric equilibria becomes slower because of the steric effects of the phenyl and benzyl moieties from the amino-acid residue.
The use of one equivalent of iodomethane in the reaction of SMe-isothiourea-carboxylates 5e or 5f, afforded the respective methyl esters 8e (49% yield) or 8f (51% yield) in mixture with the corresponding N3-Me methyl esters 9e (8% yield) or 9f (25% yield) and their hydroiodides 9e∙HI or 9f∙HI. Compound 5f was reacted with two molar equivalents of CH3I; however, compounds 8f and 9f∙HI remained. This last compound precipitated from the reaction mixture and was separated for further analysis. A 1H and 13C chemical shifts comparison between compounds 9e, 9f∙HI, and 9f is depicted in Figure 1. The characteristic 1H (13C) NMR signals of 9f∙HI, are the SMe group at δ 3.1 (18.3), N–Me at 3.8 (56.5), and N–H at 9.1 ppm. The high frequency shift of the NH suggests a hydrogen bonding interaction with the sulfur atom and/or with the carbonyl oxygen atom, Figure 1. The nitrogen atom of the N–Me group on the benzothiazole produces an electronic effect on C4 of the aromatic ring, shifting it to low frequencies: 114.1 ppm for 9f∙HI and ≈ 110 ppm for 9e and 9f.
The isourea-carboxylates 6a–d can also be methylated to afford the isourea methyl esters 10a–d in 30–90% yields, Scheme 3. However, the methylation reaction of the sodium salts of isourea-carboxylates 6e or 6f afforded the corresponding methyl esters 10e (66%) or 10f (54%) in mixture with their N–Me esters 12e (24%) or 12f (21%). 1H and 13C NMR data of compounds 10a–f are listed in Tables S9 and S10, respectively, and those of urea-methyl esters 12e and 12f are depicted in Figure 2.
Isourea carboxylate methyl esters 10a–f or 12e,f were reacted with methylamine to afford their corresponding isourea amides 11a–f or urea-amides 13e,f in 60–97% yield or 20% and 46% yields, respectively. The 1H and 13C NMR spectra of compounds 11a–f are listed in Tables S11 and S12 and those of compounds 13e,f are depicted in Figure 2. The 1H NMR spectrum of isourea-amides 11a–f show three deuterium labile hydrogen atoms in the 8.4–10.9, 7.0–10.6, and 7.1–8.1 ppm ranges, as well as the characteristic doublet in 2.5–3.0 ppm range for the NHMe group. The C4 NMR frequencies were found at approximately 110 ppm in both NMe esters 12e,f and their amides 13e,f. The 10 ppm shift to low frequencies compared with their NH analogues 10a–f and 11a–f was due to the electronic effect of the NMe group on C4. In compounds 13e and 13f, the urea NH appears as a doublet at 5.9 (3J = 9.3 Hz) and 5.7 ppm (3J = 8.2 Hz); and the amide NH appears at lower frequency as a quartet at 6.6 (3J = 4.4 Hz) and 6.4 ppm (3J = 4.7 Hz), respectively.
Isothiourea carboxylate methyl esters 8a–f contain both SMe and OMe groups, which are susceptible to substitution with nucleophiles such as methylamine. The reaction of compounds 8a with one molar equivalent of methylamine produces a complex mixture of several methylated compounds. However, in the presence of an excess of methylamine, the isourea-amide compound 11a precipitated as a white solid. In these conditions, the SMe group was substituted because of the formation of MeNH3OH in aqueous medium. The last procedure was also used with the urea methyl esters 8b–f and 9e,f to obtain compounds 11b–f and 13e,f in 45–60% yields.

2.2. Molecular Structure of Compounds 8a–c and 9f

The SMe-isothiourea methyl esters (S)-8a–c and (S)-9f were purified by crystallization from ethanol and suitable crystals for X-ray diffraction analysis were isolated. The molecular structures of compounds 8a and 8c, displayed in Figure 3 and Figure 4, show that the N12H is engaged in intramolecular three-centered hydrogen bonding interaction with the benzothiazole nitrogen and carbonyl oxygen atoms. The distances and angles associated with this N3···H12···O14 interaction are N12H···N3 = 2.01 Å, 132° (8a) and 2.03 Å, 132° (8c); N12H···O14 = 2.31 Å, 107° (8a) and 2.21 Å, 111° (8c), forming the corresponding adjacent six (S6) and five (S5)-membered rings. This hydrogen bonding interaction fixes the stereochemistry of the imine N10–C11 bond and only the (E) isomer of 8a and 8c was produced. In addition, the lateral side chain is almost in the same plane of the benzothiazole, including the carbon atoms of both OMe and SMe groups. In general, the SMe group is the most deviated from the mean plane [N(10)-C(11)-S(23)-C(24) −6.18(1)°] compared with the OMe group [O(14)-C(14)-O(15)-C(16) 0.25(1)°]. In the structure of compound (S)-8b, displayed in Figure 5, only the intramolecular hydrogen bonding interaction with benzothiazole nitrogen atom was observed, N12H···N3 (2.06 Å, 133°), forming the corresponding six membered ring (S6). Therefore, the isothiourea group is in the same plane of the benzothiazole, including the chiral carbon atom, N(10)-C(11)-N(12)-C(13) −178.71(1)° and S(23)-C(11)-N(12)-C(13) 0.16(1)°. In this case, the carbon atom of the SMe group is deviated from the benzothiazole ring planes, N(10)-C(11)-S(23)-C(24) = 5.19(1)° and the carboxylate group is almost perpendicular to the plane of the molecule C(14)-C(13)-N(12)-C(11) = −85.82(1).
The structure of compound 9f is displayed in Figure 6. Two intramolecular noncovalent bonding interactions were observed, one of them is that of N14 with benzothiazole sulfur atom, S···N14 (2.687 Å), the other of S12 with carbonyl carbon atom S12···C16 (3.123 Å), forming in both cases a five (S5)-membered ring. The first interaction causes both exocyclic nitrogen atoms to be almost in the same plane of the benzothiazole rings, including the chiral carbon and methylene carbon atoms of the isobutyl group. The SMe group is approximately 10° deviated from the mean plane, S12-C11-N10-C2 −169.8(4) compared with a small deviation of N10 [N10-C2-N3-C23 −3.6(7)°] and C11 [S1-C2-N10-C11 2.1(7)°].The second interaction maintain the C=O and the isopropyl groups to be opposite each other deviated from the mean plane C16-C15-N14-C11 −70.1(5) and N14-C15-C19-C20 −66.1(6), respectively. Intermediate bond lengths values between single and double character for C2-N3 [1.330(5) Å], C2-N10 [1.309(6) Å], N10-C11 [1.369(5) Å], whereas double bond for C11-N14 [1.283(6) Å] and single bond for N14-C15 [1.461(6) Å] were observed.

3. Materials and Methods

Melting points were measured on an IA 9100 apparatus (Electrothermal, Staffordshire, UK) and are uncorrected. IR spectra were recorded using a 3100 FT-IR Excalibur Series spectrophotometer (Varian, Randolph, MA, USA) equipped with an ATR system. Mass spectra were obtained in a 3900-GC/MS system (Varian, Palo Alto, CA, USA) with an electron ionization mode. Elemental analyses (EA) were performed on a 2400 elemental analyzer (Perkin-Elmer, Waltham, MA, USA). 1H- and 13C-NMR spectra were recorded on a Varian Mercury 300 (1H, 300.08; 13C, 75.46 MHz) instrument in DMSO-d6 solutions for compounds 5a–f and 6a–f, and CDCl3 in solutions for compounds 8a–f, 9a–f, 10a–f, 11a–f, 12e,f, and 13e,f; SiMe4 was used as the internal reference. Chemical shifts are in ppm and nJ(H-H) in hertz.
Crystals suitable for X-ray analysis of 8a, 8b, 8c, and 9f were obtained after solvent evaporation from saturated ethanol solutions. Single-crystal X-ray diffraction data were recorded on a D8 Quest CMOS (Bruker, Karlsruhe, Germany) or Nonius Kappa (Rotterdam, the Netherlands) area detector diffractometers with Mo K α radiation, λ = 0.71073 Å. A table listing the crystallographic data is provided as Supplementary Material in Table S2. The structures were solved by direct methods using SHELXS97 [50] program of WinGX package [51]. The final refinement was performed by full-matrix least-squares methods on F2 with SHELXL97 [50] program. H atoms on C were geometrically positioned and treated as riding atoms, with C–H = 0.93–0.98 Å, and with Uiso(H) = 1.2Ueq(C). The program Mercury was used for visualization, molecular graphics, and analysis of crystal structures [52]. The software used to prepare material for publication was PLATON [53]. Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC numbers 1949131 (8a), 1949129 (8b), 1413575 (8c) and 1949130 (9f). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-01-223-336-033 or E-Mail: [email protected]).

3.1. Experimental Section

2-Aminobenzothiazole 1, CS2, iodomethane, glycine, (l)-alanine, (l)-phenyl-glycine, (l)-phenylalanine, (l)-valine, (l)-leucine, DMF, ethyl alcohol and NaOH were commercial products, which were used as received. Yields, physical appearances, melting points, IR frequencies, and elemental analysis of compound 5a–f and 8a–f are listed in Table S1.

3.2. General Method for Isothiourea Carboxylates 5a–f

Amino acid (3.94 mmol), NaOH (3.94 mmol), and 15 mL of ethanol were added into a 100 mL round flask and the mixture was stirred for 2 h at room temperature. Then, compound 2 (1.0 g, 3.94 mmol) was added and the mixture was stirred for additional 96 h at room temperature.

3.2.1. Sodium (E)-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Acetate 5a

As a general method, starting from 0.295 g of glycine, compound 5a precipitated from the reaction mixture, ethanol was eliminated, the resulting mixture was cooled to room temperature and 10 mL of acetone were added, the resulting suspension was filtered and washed with cold acetone, obtaining 5a.3H2O as a cream color powder (1.14 g, 82%); mp = 220 °C (dc).

3.2.2. Sodium (S,E)-(+)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Propionate 5b

As a general method, starting from 0.35 g of l-alanine, ethanol was evaporated from the homogeneous reaction mixture, the resulting gummy product was dissolved in 10 mL of acetone and filtered, acetone was eliminated and a transparent yellowish ionic liquid compound 5b.2H2O was obtained (1.08 g, 78%), which resulted to be soluble in chloroform.

3.2.3. Sodium (R,E)-(+)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Phenyl-Acetate 5c

As a general method, starting from 0.594 g of l-phenylglycine, ethanol was eliminated from the reaction mixture and then suspended in acetone (10 mL). The suspension was filtered and the remaining solid washed with cold acetone and dried to obtain a white powder (1.29 g, 86%).

3.2.4. Sodium (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-3-Phenyl-Propionate 5d

As a general method, starting from 0.650 g of l-phenylalanine, from the same procedure as 5b, compound 5d was obtained as brownish liquid (1.26 g, 81%).

3.2.5. Sodium (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-3-Methyl-Butanonate 5e

As a general method, starting from 0.673 g of l-valine, from the same procedure as 5b, compound 5e was obtained as clear liquid (1.09 g, 80%).

3.2.6. Sodium (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-4-Methyl-Pentanonate 5f

As a general method, starting from 0.516 g of l-leucine, from the same procedure as 5b compound 5f was obtained as yellowish liquid (1.17 g, 81%)

3.3. General Method for Isourea Carboxylates 6a–f

Starting from isothiourea carboxylates 5a–f (3.0 mmol), 10 mL of ethanol and 10 mL of water were added into a 100 mL round flask and the mixture was refluxed for 72 h. For isothiourea 5a, DMF was used instead of ethanol. The solvent was evaporated from the reaction mixture and the residue suspended in acetone, the suspension was cooled and filtered, the precipitate was washed with acetone and dried. In the hydrolysis of isothioureas 5e,f, the reaction mixture was filtered and the solvents were evaporated. 5 mL of acetone were added and 50 mL of CHCl3 were slowly added, the mixture was stirred until a beige solid precipitates, which was filtered and washed with CHCl3 to get 6e,f.

3.3.1. Sodium (3-Benzothiazol-2-Yl-Isoureido)-Acetate 6a

0.32 g, 40% yield; white powder; mp = 210 °C (dc).

3.3.2. Sodium 2-(3-Benzothiazol-2-Yl-Isoureido)-Propionate 6b

White powder; 0.6 g, 70% yield; mp = 205 °C (dc).

3.3.3. Sodium (3-Benzothiazol-2-Yl-Isoureido)-Phenyl-Acetate 6c

White powder; 0.75 g, 72% yield; mp = 250 °C (dc).

3.3.4. Sodium 2-(3-Benzothiazol-2-Yl-Isoureido)-3-Phenyl-Propionate 6d

White powder; 0.81 g, 75% yield; mp = 149–150 °C.

3.3.5. Sodium 2-(3-Benzothiazol-2-Yl-Isoureido)-3-Methyl-Butirate 6e

White powder; 0.61 g, 65% yield; mp = 199–201 °C.

3.3.6. Sodium 2-(3-Benzothiazol-2-Yl-Isoureido)-4-Methyl-Pentanonate 6f

White powder; 0.69 g, 70% yield; mp = 201–203 °C.

3.4. General Method for SMe-Isothiourea Carboxylate Methyl Esters 8a–f and 9e,f or Isourea Carboxylate Methyl Esters 10a–f and Urea Methyl Ester 12e,f

In a 100 mL round flask, 3.0 mmol of the corresponding isothiourea carboxylate 5a–f or urea carboxylate 6a–f were dissolved in DMF (10 mL), methyl iodide (3.5 mmol) were added and the mixture was stirred for 12 h on an ice bath and then 12 h at room temperature. At the end of the reaction, 50 mL of water were added and the corresponding ester was extracted with CHCl3. Chloroform was eliminated and the O-methyl compounds were purified by crystallization in ethanol. Compounds 9e or 9f were separated from 8e or 8f by crystallization from their ethanol mixture. Compounds 12e or 12f were separated from 10e or 10f using a chloroform/acetone 10:1 mixture in a silica gel chromatography column. 12e and 12f were precipitated from hexane.

3.4.1. (E)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Acetic Acid Methyl Ester 8a

White crystals; 0.73 g, 83% yield; mp = 145–146 °C.

3.4.2. (S,E)-(+)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Propionic Acid Methyl Ester 8b

White crystals; 0.74 g, 80% yield; mp = 100–101 °C.

3.4.3. (S,E)-(+)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-Phenyl-Acetic Acid Methyl Ester 8c

White crystals; 0.83 g, 75% yield; mp = 133–134 °C.

3.4.4. (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-3-Phenyl-Propionic Acid Methyl Ester 8d

White crystals; 0.64 g, 56% yield; mp = 84–85 °C.

3.4.5. (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-3-Methyl-Butanoic Acid Methyl Ester 8e

Viscous liquid; 0.49 g, 49% yield.

3.4.6. (S,E)-(−)-2-(3-Benzothiazol-2-Yl-2-Methyl-Isothioureido)-4-Methyl-Pentanonic Acid Methyl Ester 8f

Viscous liquid; 0.53 g, 51% yield.

3.4.7. 3-Methyl-2-[2-Methyl-3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Isothioureido]-Butyric Acid Methyl Ester 9e

White crystals; 0.084 g, 8% yield; mp = 163–164 °C; MS: M + H = 352.1 (79.1%).

3.4.8. 4-Methyl-2-[2-Methyl-3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Isothioureido]-Pentanoic Acid Methyl Ester 9f

White crystals; 0.27 g, 25% yield; mp = 177–178 °C; MS: M + H = 366.0 (80.1%).

3.4.9. (3-Benzothiazol-2-Yl-Isoureido)-Acetic Acid Methyl Ester 10a

White powder; 0.65 g, 82% yield; mp = 170–180 °C; MS: M + H = 266.06 (85%).

3.4.10. 2-(3-Benzothiazol-2-Yl-Isoureido)-Propionic Acid Methyl Ester 10b

White powder; 0.68 g, 86% yield; mp = 149–150 °C; MS: M + H = 280.07 (85.6%).

3.4.11. (3-Benzothiazol-2-Yl-Isoureido)-Phenyl-Acetic Acid Methyl Ester 10c

White powder; 0.73 g, 72% yield; mp = 112–114 °C; MS: M + H = 342.1 (83.1%).

3.4.12. 2-(3-Benzothiazol-2-Yl-Isoureido)-3-Phenyl-Propionic Acid Methyl Ester 10d

White powder; 0.32 g, 30% yield, 70–71 °C (mp), MS: M + H = 356.1 (80.6%).

3.4.13. 2-(3-Benzothiazol-2-Yl-Isoureido)-3-Methyl-Butyric Acid Methyl Ester 10e

Viscous liquid; 0.6 g, 66% yield; MS: M + H = 308.1 (82.7%).

3.4.14. 2-(3-Benzothiazol-2-Yl-Isoureido)-4-Methyl-Pentanoic Acid Methyl Ester 10f

Viscous liquid; 0.52 g, 54% yield; MS: M + H = 321.0 (84.1%).

3.4.15. 3-Methyl-2-[3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Ureido]-Butyric Acid Methyl Ester 12e

White powder; 0.23 g, 24% yield; mp = 100–101 °C; MS: M + H = 322.1 (83%).

3.4.16. 4-Methyl-2-[3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Ureido]-Pentanoic Acid Methyl Ester 12f

White powder; 0.21 g, 21% yield; mp = 87–89 °C; MS: M + H = 336.1 (82%).

3.5. General Method for Isourea Amides 11a–f or Urea-Amides 13e,f

In a 100 mL round flask, 3.00 mmol of the corresponding isourea carboxylate methyl esters 10a-f or urea methyl esters 12e,f were dissolved in ethanol (10 mL), methyl amine 40% in water (3.5 mmol) were added and the mixture was refluxed for 24 h. At the end of the reaction, the precipitate was filtered and washed with plenty of acetone.

3.5.1. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-Acetamide 11a

White powder; 0.63g, 80% yield; mp = 260–270 °C (dc); MS: M + H = 265.1 (82.1%).

3.5.2. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-Propionamide 11b

White powder; 0.81g, 97% yield; mp = 250–260 °C (dc), MS: M + H = 279.09 (84.8%).

3.5.3. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-2-Phenyl-Acetamide 11c

White powder; 0.98 g, 96% yield; mp = 270–290 °C (dc); MS: M + H = 341.1 (77.9%).

3.5.4. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-3-Phenyl-Propionamide 11d

White powder; 1.06 g, 93% yield, mp = 270–280 °C (dc); MS: M + H = 355.1 (77.5%).

3.5.5. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-3-Methyl-Butiramide 11e

White powder; 0.55g, 60% yield; mp = 205–207 °C (dc), MS: M + H = 307.12 (80.1%).

3.5.6. 2-[3-(3H-Benzothiazol-2-Ylidene)-Ureido]-N-Methyl-4-Methyl-Pentylamide 11f

White powder; 0.6 g, 63% yield; mp = 138–140 °C; MS: M + H= 321.1 (76.1%).

3.5.7. 3,N-Dimethyl-2-[3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Ureido]-Butiramide 13e

White powder; 0.2 g, 20% yield; mp = 205–206 °C; MS: M + H = 321.1 (79.1%).

3.5.8. 4-Methyl-2-[3-(3-Methyl-3H-Benzothiazol-2-Ylidene)-Ureido]-Pentanoic Acid Methylamide 13f

White powder; 0.46 g, 46% yield; mp = 210–212 °C, MS: M + H = 335.1 (79.9%).

4. Conclusions

A six sodium salt series of isothiourea-carboxylate benzothiazoles 5a–f, as well as their methyl ester derivatives 8a–f, were obtained in moderate to good yields by the reaction of dimethylcarbonimidate benzothiazole 2 with sodium salts of glycine, (l)-alanine, (l)-phenylglycine, (l)-phenylalanine, (l)-valine, and (l)-leucine in stirring ethanol at room temperature and further methylation under mild conditions. The reaction is stereo selective, only the E-isomer was isolated, the X-ray structure of (R,E)-methyl-2-((benzothiazol-2-ylimino)(methyl-thio)methylamino)-2-phenylacetate 8c confirmed the stereochemistry of the reaction. The structures of 8a and 8c are stabilized by three center hydrogen bonding interactions N3···H12···O14 between the amino N12H12 with the nitrogen atom of benzothiazole ring and the oxygen atom of the carbonyl group, forming two intramolecular adjacent S(6) and S(5) rings, respectively. This finding suggests the stereochemical assistance of the reaction by hydrogen bonding. When the same reactions were carried out in the presence of water, the urea-carboxylate benzotiazoles 6a–f were obtained. Their further methylation produced the corresponding methyl esters 10a–f. In the methylation reaction of sodium isothiourea-carboxylates 5e,f and urea-carboxylates 6e,f, the corresponding N3Me methyl esters 9e,f and 12e,f were produced as byproducts, which were isolated. Methyl esters 8a–f or 10a–f and 9e,f or 12e,f were used as starting materials to produce the corresponding urea carboximides 11a–f and 13e,f by the reaction with methyl amine. Further studies on the synthesis of chiral guanidines from SMe-isothioureas 8 are in progress.

Supplementary Materials

The following are available online. Table S1. Complementary data of SMe-isothiourea carboxylates 5a–f and their methyl esters 8a–f. Table S2. X-ray crystal data of compounds 8a, 8b, 8c and 9f. Table S3. 1H NMR data of compounds 5a–f (DMSO-d6). Table S4. 13CNMR data of compounds 5a–f (DMSO-d6). Table S5. 1H NMR data of compounds 6a–f (DMSO-d6). Table S6. 13CNMR data of compounds 6a–f (DMSO-d6). Table S7. 1HNMR data of compounds 8a–d (CDCl3). Table S8. 13C NMR data of compounds 8a–d (CDCl3). Table S9. 1H NMR data of compounds 10a–f (CDCl3). Table S10. 13CNMR data of compounds 10a–f (CDCl3). Table S11. 1H NMR data of compounds 11a–f (CDCl3). Table S12. 13C NMR data of compounds 11a–f (CDCl3).

Author Contributions

Reseach, A.C. and J.M.G.-E.; original draft preparation, writing-review and editing, A.C. and I.I.P.-M.; X-ray diffraction data curation, E.V.G.-B. and Á.A.R.-O.

Funding

This research received no external funding.

Acknowledgments

A. Cruz thanks Secretaría de Investigación y Posgrado del IPN (SIP-IPN) for financial support, Grants 20180754 and 20196686 and COTEBAL-IPN as well as CONACYT, México for the sabbatical study financial support (2018–2019).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Molecules 24 03391 sch001 550
Scheme 1. Dithiomethylcarboimidatebenzothiazole 2, SMe-isothioureas 3 and guanidines 4 starting from 2-aminobenzothiazole 1.
Scheme 1. Dithiomethylcarboimidatebenzothiazole 2, SMe-isothioureas 3 and guanidines 4 starting from 2-aminobenzothiazole 1.
Molecules 24 03391 sch001
Molecules 24 03391 sch002 550
Scheme 2. Generation of sodium carboxylates C from neutral amino acids A.
Scheme 2. Generation of sodium carboxylates C from neutral amino acids A.
Molecules 24 03391 sch002
Molecules 24 03391 sch003 550
Scheme 3. Synthesis of SMe-isothiourea carboxylates 5a–f, isourea-carboxylates 6a–f, their corresponding methyl esters 8a–f, 9e,f, 10a–f, and 12e,f, isourea-amides 11a–f and urea-amides 13e,f derived from benzothiazole and amino acids.
Scheme 3. Synthesis of SMe-isothiourea carboxylates 5a–f, isourea-carboxylates 6a–f, their corresponding methyl esters 8a–f, 9e,f, 10a–f, and 12e,f, isourea-amides 11a–f and urea-amides 13e,f derived from benzothiazole and amino acids.
Molecules 24 03391 sch003
Molecules 24 03391 sch004 550
Scheme 4. Sygmatropic rearrangement of compound 2. The numbers on the atoms are the 1H and 13C chemical shifts in CDCl3.
Scheme 4. Sygmatropic rearrangement of compound 2. The numbers on the atoms are the 1H and 13C chemical shifts in CDCl3.
Molecules 24 03391 sch004
Molecules 24 03391 g001 550
Figure 1. 1H and 13C NMR data in CDCl3 of compounds 9e, 9f, and 9f HI.
Figure 1. 1H and 13C NMR data in CDCl3 of compounds 9e, 9f, and 9f HI.
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Molecules 24 03391 g002 550
Figure 2. 1H and 13C NMR data in CDCl3 of urea carboxylate methyl esters 12e, 12f, and their corresponding urea NMe amides 13e, 13f.
Figure 2. 1H and 13C NMR data in CDCl3 of urea carboxylate methyl esters 12e, 12f, and their corresponding urea NMe amides 13e, 13f.
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Molecules 24 03391 g003 550
Figure 3. X-ray diffraction structure of compound 8a. Bond lengths (Å): S(1)–C(2) 1.7624(1), S(1)–C(8) 1.7342(1), S(23)–C(11) 1.7599(1), S(23)–C(24) 1.7927(1), N(3)–C(2) 1.3115(1), N(3)–C(9) 1.3855(1), N(10)–C(2) 1.3621(1), N(10)–C(11) 1.3104(1), N(12)–C(11) 1.3308(1), N(12)–C(13) 1.4402(1), O(14)–C(14) 1.1936(1), O(15)–C(14) 1.3291(1), O(15)–C(16) 1.4530(1). Bond angles (Deg.): C(2)–S(1)–C(8) 89.25(1), C(11)–S(23)–C(24) 1102.17(1).Torsion angles (Deg.): S(23)–C(11)–N(10)–C(2) 179.34(1), N(10)–C(11)–S(23)–C(24) −6.18(1), N(10)–C(11)–N(12)–C(13) 178.17(1), N(12)–C(13)–C(14)–O(14) 2.25(1), N(12)–C(13)–C(14)–O(15) −177.67(1), O(14)–C(14)–O(15)–C(16) 0.25(1).
Figure 3. X-ray diffraction structure of compound 8a. Bond lengths (Å): S(1)–C(2) 1.7624(1), S(1)–C(8) 1.7342(1), S(23)–C(11) 1.7599(1), S(23)–C(24) 1.7927(1), N(3)–C(2) 1.3115(1), N(3)–C(9) 1.3855(1), N(10)–C(2) 1.3621(1), N(10)–C(11) 1.3104(1), N(12)–C(11) 1.3308(1), N(12)–C(13) 1.4402(1), O(14)–C(14) 1.1936(1), O(15)–C(14) 1.3291(1), O(15)–C(16) 1.4530(1). Bond angles (Deg.): C(2)–S(1)–C(8) 89.25(1), C(11)–S(23)–C(24) 1102.17(1).Torsion angles (Deg.): S(23)–C(11)–N(10)–C(2) 179.34(1), N(10)–C(11)–S(23)–C(24) −6.18(1), N(10)–C(11)–N(12)–C(13) 178.17(1), N(12)–C(13)–C(14)–O(14) 2.25(1), N(12)–C(13)–C(14)–O(15) −177.67(1), O(14)–C(14)–O(15)–C(16) 0.25(1).
Molecules 24 03391 g003
Molecules 24 03391 g004 550
Figure 4. X-ray diffraction structure of compound 8c. Bond length (Å): S(1)–C(2) 1.753(2), N(3)–C(2) 1.301(3), N(10)–C(2) 1.372(3), N(10)–C(11) 1.306(3), N(12)–C(11) 1.338(3), N(12)–C(13) 1.452(3), S(23)–C(11) 1.770(2). Bond angles (Deg.): S(1)–C(2)–N(10) 115.55(16), N(3)–C(2)–N(10) 129.2 (2), C(2)–N(10)–C(11) 120.36(17), N(10)–C(11)–N(12) 126.08(18). Torsion angles (Deg.): N(3)–C(2)–N(10)–C(11) −1.25, C(24)–S(23)–C(11)–N(10) 1.41(19), C(24)–S(23)–C(11)–N(12) −179.90(17), N(12)–C(13)–C(14)–O(14) 6.2(3), C(16)–O(15)–C(14)–O(14) −0.1(4).
Figure 4. X-ray diffraction structure of compound 8c. Bond length (Å): S(1)–C(2) 1.753(2), N(3)–C(2) 1.301(3), N(10)–C(2) 1.372(3), N(10)–C(11) 1.306(3), N(12)–C(11) 1.338(3), N(12)–C(13) 1.452(3), S(23)–C(11) 1.770(2). Bond angles (Deg.): S(1)–C(2)–N(10) 115.55(16), N(3)–C(2)–N(10) 129.2 (2), C(2)–N(10)–C(11) 120.36(17), N(10)–C(11)–N(12) 126.08(18). Torsion angles (Deg.): N(3)–C(2)–N(10)–C(11) −1.25, C(24)–S(23)–C(11)–N(10) 1.41(19), C(24)–S(23)–C(11)–N(12) −179.90(17), N(12)–C(13)–C(14)–O(14) 6.2(3), C(16)–O(15)–C(14)–O(14) −0.1(4).
Molecules 24 03391 g004
Molecules 24 03391 g005 550
Figure 5. X-ray diffraction structure of compound 8b. Bond Lengths (Å): S(1)–C(2) 1.7618(1), S(1)–C(8) 1.7300(1), S(23)–C(11) 1.7667(1), S(23)–C(24) 1.7919(1), O(14)–C(14) 1.1870(1), O(15)–C(14) 1.3134(1), O(15)–C(16) 1.4522(1), N(3)–C(2) 1.2954(1), N(3)–C(9) 1.3912(1), N(10)–C(2) 1.3592(1), N(10)–C(11) 1.3043(1), N(12)–C(11) 1.3295(1), N(12)–C(13) 1.4527(1). Bond Angles (Deg.): C(2)–S(1)–C(8) 89.62(1), C(11)–S(23)–C(24) 101.25(1). Torsion angles (Deg.): N(3)–C(2)–S(1)–C(8) –0.35(1), N(10)–C(2)–S(1)–C(8) 179.59(1), S(1)–C(2)–N(3)–C(9) 0.18(1), N(10)–C(2)–N(3)–C(9) −179.74(1), S(1)–C(2)–N(10)–C(11) −177.17(1), N(3)–C(2)–N(10)–C(11) 2.75(1), N(10)–C(11)–S(23)–C(24) 5.19(1), N(12)–C(11)–S(23)–C(24) −173.79(1), S(23)–C(11)–N(10)–C(2) 179.27(1), N(12)–C(11)–N(10)–C(2) −1.88(1), S(23)–C(11)–N(12)–C(13) 0.16(1), N(10)–C(11)–N(12)–C(13) −178.71(1), C(14)–C(13)–N(12)–C(11) −85.82(1), C(17)–C(13)–N(12)–C(11) 147.32(1), C(17)–C(13)–C(14)–O(14) 140.21(1).
Figure 5. X-ray diffraction structure of compound 8b. Bond Lengths (Å): S(1)–C(2) 1.7618(1), S(1)–C(8) 1.7300(1), S(23)–C(11) 1.7667(1), S(23)–C(24) 1.7919(1), O(14)–C(14) 1.1870(1), O(15)–C(14) 1.3134(1), O(15)–C(16) 1.4522(1), N(3)–C(2) 1.2954(1), N(3)–C(9) 1.3912(1), N(10)–C(2) 1.3592(1), N(10)–C(11) 1.3043(1), N(12)–C(11) 1.3295(1), N(12)–C(13) 1.4527(1). Bond Angles (Deg.): C(2)–S(1)–C(8) 89.62(1), C(11)–S(23)–C(24) 101.25(1). Torsion angles (Deg.): N(3)–C(2)–S(1)–C(8) –0.35(1), N(10)–C(2)–S(1)–C(8) 179.59(1), S(1)–C(2)–N(3)–C(9) 0.18(1), N(10)–C(2)–N(3)–C(9) −179.74(1), S(1)–C(2)–N(10)–C(11) −177.17(1), N(3)–C(2)–N(10)–C(11) 2.75(1), N(10)–C(11)–S(23)–C(24) 5.19(1), N(12)–C(11)–S(23)–C(24) −173.79(1), S(23)–C(11)–N(10)–C(2) 179.27(1), N(12)–C(11)–N(10)–C(2) −1.88(1), S(23)–C(11)–N(12)–C(13) 0.16(1), N(10)–C(11)–N(12)–C(13) −178.71(1), C(14)–C(13)–N(12)–C(11) −85.82(1), C(17)–C(13)–N(12)–C(11) 147.32(1), C(17)–C(13)–C(14)–O(14) 140.21(1).
Molecules 24 03391 g005
Molecules 24 03391 g006 550
Figure 6. X-ray diffraction structure of compound 9f. Bond Lengths (Å). S1–C2 1.757(5), S1–C8 1.748(5), S12–C11 1.766(5), S12–C13 1.790(5), O16–C16 1.200(7), O17–C16 1.336(6), O17–C18 1.457(8), N3–C2 1.360(5), N3–C9 1.388(6), N3–C23 1.463(6), N10–C2 1.309(6), N10–C11 1.369(5), N14–C11 1.283(6), N14–C15 1.461(6), C4–C5 1.374(8). Torsion angles (Deg.): N3–C2–S1–C8 −2.4(4), N10–C2–S1–C8 175.6(5), S1–C2–N3–C9 2.3(5), S1–C2–N3–C23 −178.2(4), N10–C2–N3–C9 −175.8(4), N10–C2–N3–C23 3.6(7), S1–C2–N10–C11 2.1(7), N3–C2–N10–C11 179.9(4), N10–C11–S12–C13 −5.6(4), N14–C11–S12–C13 175.1(4), S12–C11–N10–C2 −169.8(4), N14–C11–N10–C2 9.6(7), S12–C11–N14–C15 −2.3(6), N10–C11–N14–C15 178.5(4), C16–C15–N14–C11 −70.1(5), C19–C15–N14–C11 169.6(4), N14–C15–C19–C20 −66.1(6).
Figure 6. X-ray diffraction structure of compound 9f. Bond Lengths (Å). S1–C2 1.757(5), S1–C8 1.748(5), S12–C11 1.766(5), S12–C13 1.790(5), O16–C16 1.200(7), O17–C16 1.336(6), O17–C18 1.457(8), N3–C2 1.360(5), N3–C9 1.388(6), N3–C23 1.463(6), N10–C2 1.309(6), N10–C11 1.369(5), N14–C11 1.283(6), N14–C15 1.461(6), C4–C5 1.374(8). Torsion angles (Deg.): N3–C2–S1–C8 −2.4(4), N10–C2–S1–C8 175.6(5), S1–C2–N3–C9 2.3(5), S1–C2–N3–C23 −178.2(4), N10–C2–N3–C9 −175.8(4), N10–C2–N3–C23 3.6(7), S1–C2–N10–C11 2.1(7), N3–C2–N10–C11 179.9(4), N10–C11–S12–C13 −5.6(4), N14–C11–S12–C13 175.1(4), S12–C11–N10–C2 −169.8(4), N14–C11–N10–C2 9.6(7), S12–C11–N14–C15 −2.3(6), N10–C11–N14–C15 178.5(4), C16–C15–N14–C11 −70.1(5), C19–C15–N14–C11 169.6(4), N14–C15–C19–C20 −66.1(6).
Molecules 24 03391 g006

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Padilla-Martínez, I.I.; González-Encarnación, J.M.; García-Báez, E.V.; Cruz, A.; Ramos-Organillo, Á.A. Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids. Molecules 2019, 24, 3391. https://doi.org/10.3390/molecules24183391

AMA Style

Padilla-Martínez II, González-Encarnación JM, García-Báez EV, Cruz A, Ramos-Organillo ÁA. Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids. Molecules. 2019; 24(18):3391. https://doi.org/10.3390/molecules24183391

Chicago/Turabian Style

Padilla-Martínez, Itzia I., José Miguel González-Encarnación, Efrén V. García-Báez, Alejandro Cruz, and Ángel Andrés Ramos-Organillo. 2019. "Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids" Molecules 24, no. 18: 3391. https://doi.org/10.3390/molecules24183391

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