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Article

New Route to 3-Alkylthiazolo[3,2-a]benzimidazole Derivatives

UMR “Chirotechnologies: Catalyse et Biocatalyse”, Université Paul Cézanne Aix-Marseille III, 13397 Marseille CEDEX 20 France
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Author to whom correspondence should be addressed.
Molecules 2005, 10(2), 327-333; https://doi.org/10.3390/10020327
Submission received: 29 October 2004 / Accepted: 16 December 2004 / Published: 28 February 2005
(This article belongs to the Special Issue Sulfur-Nitrogen Heterocycles)

Abstract

:
3-Alkyl-thiazolo[3,2-a]benzimidazole derivatives are obtained in high yields via the corresponding 4-alkyl-N-3-(2-aminophenyl)-thiazoline-2-thiones which are easily prepared from 1,2-diaminobenzene, CS2 and halogenoketones. This new route compares advantageously with the classical mercaptobenzimidazole routes in term of simplicity, isolated yields and availability of the starting materials.

Introduction

3-Methyl-thiazolo[3,2-a]benzimidazole (1a) is available for screening purposes in three libraries according to Chem. Abstracts. So far the reported synthetic routes leading to thiazolo[3,2-a]benzimidazole skeleton begin from the preformed 2-mercaptobenzimidazole which is condensed at the mercapto-group with various electrophiles such as alpha-haloketones [1], propargyl halides [2] or 1,2,3-tribromopropane [3] followed by cyclization to form the thiazole ring in the last step (Scheme 1).
Scheme 1.
Scheme 1.
Molecules 10 00327 g001
A variation involved the reaction of enol ester which acts as nucleophile on the S-S dimer of mercaptobenzimidazole which acts as an electrophile [4]. The enol ester and the dimer were prepared in situ and this “umpolung” reactivity resulted in the same sequence of bond formation as before. We report herein a new synthesis starting from a preformed thiazolium salts.

Results and Discussion

Curiously enough, the reaction sequence in which the C=N bond is formed in the last step from preformed activated thiazole ring has never been attempted to the best of our knowledge. The leaving group in position 2 of thiazolium salt will be expelled during cyclization. This approach is depicted in Scheme 2.
Scheme 2.
Scheme 2.
Molecules 10 00327 g002
Among the possible leaving groups in position 2 of the thiazolium salts, the methylthio group was particularly attractive since it could be easily generated by methylation at sulphur of the parent thiazoline-2-thione derivative. (Scheme 3)
Scheme 3.
Scheme 3.
Molecules 10 00327 g003
N-(2-Aminophenyl)-4-methyl-thiazoline-2-thione (4a) has been first described in 1998 [5]. This compound attracted our attention due to our long standing interest in the atropisomers of N-arylthiazoline-2-thione derivatives in terms of barriers to racemization and chiral recognition mechanisms on chiral stationary phases [6,7,8,9,10]. Compound 4a is readily available in high yield by reacting chloroacetone in CH3CN with the dithiocarbamate obtained quantitatively from 1,2-diamino-benzene and CS2 in the presence of triethylamine [5]. In our hands, the isolated yield in recrystallized thiazoline-2-thione derivative was 64%. The thiazolinethione reaction with iodomethane in anhydrous acetone at rt afforded the thiazolium salt 3a (X-=I- in Scheme 2 and Scheme 3) in quantitative yield. The reaction was monitored by TLC until the total disappearance of the starting thiazoline-thione was confirmed. As expected, due to the very high nucleophilicity of the sulphur atom, no methylation occurred on the amino group. After evaporation of acetone and methyl iodide in excess, NMR data were recorded on the crude reaction medium without any attempts to isolate the thiazolium salts. In the same reactor, the crude thiazolium salt when refluxed in methanol eliminated MeSH to yield 3-methyl-thiazolo[3,2-a]benzimidazolium iodide (2a) as a single compound after evaporation of the solvent. NMR data of this crude reaction mixture were recorded again to check the disappearance of the S-Me signal and the appearance of the protonated thiazolobenzimidazole 2a. It may prove of interest to obtain directly the iodide salt. More generally, in the reaction sequence we are reporting, the counter anion is coming from the methylating agent and thus a wide variety of 3-methyl-thiazolo[3,2-a]benzimidazolium salts differing by the associated anion could be directly obtained. It must be stressed that obtaining pure isolated and recrystallized iodide salts was not our goal and thus no further analysis were performed on the crude iodide salts. The free 3-methyl-thiazolo[3,2-a]benzimidazole (1a) is easily obtained in pure state by treatment with aqueous NaHCO3 followed by careful extraction in CH2Cl2. In the starting thiazoline-2-thione derivative 4a the aryl group and the heterocycle are situated in two perpendicular planes giving rise to stable atropisomers [11], it results from this spatial arrangement that in the 1H-NMR spectrum the 4-methyl group is highly shielded (δ = 1.93 ppm), whereas in the final product 1a the methyl group is highly deshielded due to the planarity of the structure (δ = 2.70 ppm). In the two non-isolated thiazolium and thiazolo[3,2-a]benzimidazolium iodide intermediates, the chemical shifts of the proton of that particular methyl group appeared at 2.25 ppm and 2.92 ppm respectively. The reaction sequence was also exemplified with success to yield 1b starting from the already described N-(2-aminophenyl)-4,5-dimethyl-thiazoline-2-thione (4b) [12].
It was of interest to check the robustness of the reaction sequence in case of strong steric repulsion between the substituent in position 4 of the thiazolium salts and the aryl group, which shall adopt a coplanar arrangement in the final product. We prepared the corresponding analogues starting from chloropinacolone to obtain the 3-tert-butyl-thiazolo[3,2-a]benzimidazole (1c). The cyclization rate is slower than in the case of the 3-methyl analogues leading to 1a or 1b. After 12 hours reflux in methanol the mixture is composed of 16% of the unchanged thiazolium salt (3c) and 84% of 3-tert-butyl-thiazolo[3,2-a]benzimidazolium iodide 2c. However, the transformation is quantitatively achieved after 41 hrs without the formation of any by-product.

Conclusions

The thiazolium route we have exemplified for the first time, compares advantageously to the mercaptobenzimidazole routes in term of simplicity, isolated yield and availability of the starting materials.

Experimental

General

1H-NMR spectra were recorded at 300 or 200 MHz and 13C-NMR spectra at 75 or 50 MHz on Bruker Avance DPX-300 or 200 instruments. Chemical shifts are reported in ppm with the signal for residual solvent as internal standard. J values are reported in Hz. Melting points were measured using a Kofler hot stage apparatus and are not corrected. Flash column chromatography was performed with silica gel 60 (230-400 mesh). TLC were carried out on Merck 60F254 silica plates.

N-(2-Aminophenyl)-4-methyl-thiazoline-2-thione (4a).

The already reported synthesis of 4a [5], has been used with very slight modifications. Triethylamine (68.6 mL, 492 mmol) was added to a suspension of 1,2-phenylenediamine (28 g, 259 mmol) in CS2 (600 mL). After stirring for 2 h, the dithiocarbamate salt was filtered off, washed with Et2O and used without further purification. 1-Chloro-propan-2-one (20 mL, 251 mmol) was added to a suspension of 70 g (245 mmol) of dithiocarbamate salt in 600 mL of acetonitrile. After stirring for 12-48 h at r.t., the solvent was removed in vacuo and 66 mL of 36% HCl was added and the mixture was left under stirring for 20 min. Water (400 mL) was added and the mixture was extracted with CH2Cl2 (3 x 400 mL). The organic phase was washed with water (3 x 200 mL), dried over MgSO4 and evaporated. Recrystallisation in absolute ethanol afforded (4a, 35 g, 64 %) as a white powder with m.p. 180°C (lit.[5]: 184°C); Rf 0.22 (CH2Cl2). The 1H-NMR (CDCl3, 300 MHz) and 13C-NMR (CDCl3, 75 MHz) were in agreement with literature data for this compound [5].

N-(2-Aminophenyl)-4, 5-dimethyl-thiazoline-2-thione (4b).

The same procedure as for 4a was used with 3-chloro-butan-2-one (2.45 mL, 24.2 mmol) to afford 4b (5.2 g, 73 %) as a white powder upon recrystallisation in ethanol 96%. In this case, HCl was replaced by H2SO4 [5,12]. White powder with m.p. 149°C (lit.[5,12]: 139-140°C); Rf 0.20 (CH2Cl2). The 1H-NMR (CDCl3, 300 MHz) and 13C-NMR (CDCl3, 75 MHz) were in agreement with literature data for this compound [5,12].

N-(2-aminophenyl)-4-tert-butyl-thiazoline-2-thione (4c).

The same procedure as for 4a was used with 1,2-phenylenediamine (1 g, 9.2 mmol) and 1-chloro-pinacolone (1.21 mL, 9.2 mmol) to afford, after column chromatography on silica gel with CH2Cl2 elution, 4c (0.8 g, 44%) as a crystalline white powder with m.p. 190°C; Rf 0.42 (CH2Cl2); 1H-NMR (CDCl3, 200 MHz): δ = 1.17 (s, 9H, CH3), 3.62 (s, 2H, NH2), 6.41 (s, 1H, =CH), 6.80-7.40 (m, 4H, Ar); 13C-NMR (CDCl3, 50 MHz): δ = 29.48 (CH3), 34.74 (C-(CH3)3), 106.08 (=CH), 117.37, 118.83, 125.68, 130.55, 131.00, 144.04, 153.45, 190.91 (C=S); Anal. For C13H16N2S2: calcd. C 59.05, H 6.10, N 10.59, S, 24.25; found C 59.04, H 6.23, N 10.58, S 24.50.

General Procedure for the synthesis of the thiazolo[3,2-a]benzimidazole (1a, 1b, 1c).

N-(2-Aminophenyl)-thiazoline-2-thione (2.25 mmol) and CH3I (1.4 mL, 10 eq) were stirred in 10 mL of acetone at r.t. for 3 h. Evaporation of the excess of CH3I and acetone afforded quantitatively the thiazolium iodide. NMR and TLC were taken on the crude reaction medium to check the completeness of the methylation. (NMR data shown). In the same vessel, crude 2-methylthio-N-(2-aminophenyl)-thiazolium iodides (2.25 mmol) were refluxed in 20 mL of methanol for 12 h (41 h for the tert-Bu-derivative). Evaporation of the methanol afforded quantitatively the thiazolo[3,2-a]benzimidazolium iodides (NMR data shown). To these crude solids, 20 mL of a saturated NaHCO3 solution was added and the solution was extracted with CH2Cl2 (3 x 10 mL). The organic phase was dried over MgSO4 and evaporated to afford quantitatively the thiazolo[3,2-a]benzimidazole derivatives.

3-Methyl-thiazolo[3,2-a]benzimidazole (1a).

Pale yellow powder m.p. 162°C (lit.[1]160-165°C); Rf 0.45 (CH2Cl2/AcOEt 9/1). NMR data are consistent with literature data [1]. 1H-NMR (CDCl3, 200 MHz): δ = 2.70 (d, 3H, CH3, J = 1.2), 6.31 (q, 1H, =CH, J = 1.2), 7.10-7.40 (m, 2H, Ar), 7.70-7.85 (m, 2H, Ar); 13C-NMR (CDCl3, 50 MHz): δ = 14.33 (CH3), 104.46 (=CH), 110.31, 119.04, 120.47, 123.06, 129.75, 130.23, 157.15(C=N).

2,3-Dimethyl-thiazolo[3,2-a]benzimidazole (1b).

White powder m.p. 151°C (lit. [1c] 154-156°C); Rf 0.45 (CH2Cl2/AcOEt 9/1). NMR data are consistent with literature data [1c]. 1H-NMR (CDCl3, 200 MHz): δ = 2.19 (q, 3H, CH3, J = 6.0), 2.43 (q, 3H, CH3, J = 6.0), 7.00-7.30 (m, 2H, Ar), 7.50-7.70 (m, 2H, Ar); 13C-NMR (CDCl3, 50 MHz): δ = 11.52, 12.36, 110.15, 116.03, 118.88, 120.27, 122.67, 124.47, 130.31, 147.82, 155.00.

3-tert-Butyl-thiazolo[3,2-a]benzimidazole (1c).

Colorless oil; Rf 0.70 (CH2Cl2/AcOEt 9/1); 1H-NMR (CDCl3, 200 MHz): δ = 1.61 (s, 9H, CH3), 6.41 (s, 1H, =CH), 7.20-7.50 (m, 2H, Ar), 7.80-7.90 (m, 1H, Ar), 7.95-8.05 (m, 1H, Ar); 13C-NMR (CDCl3, 50 MHz): δ = 28.40, 33.44, 102.79, 113.90, 119.24, 120.28, 122.95, 130.06, 143.74, 148.92, 158.65; Anal. For C13H14N2S: Calcd. C 67.79, H 6.13, N 12.16, S 13.92; found C 67.76, H 6.31, N 11.85, S 14.17.

NMR reference data for the non- isolated thiazolium and thiazolo-benzimadazolium iodide intermediates.

2-Methylthio-N-(2-aminophenyl)-4-methyl-thiazolium iodide (3a),

1H-NMR (CD3OD, 200 MHz): δ = 2.25 (d, 3H, CH3, J = 1.1), 2.93 (s, 3H, S-CH3), 6.75-7.45 (m, 4H, Ar) , 7.84 (q, 1H, =CH, J = 1.1); 13C-NMR (CD3OD, 50 MHz): δ = 13.87 (CH3), 18.13 (S-CH3), 118.03, 118.78, 118.94, 119.68, 128.41, 134.15, 145.26, 148.17, 181.66 (C-S).

2-Methylthio-N-(2-aminophenyl)-4,5-dimethyl- thiazolium iodide (3b).

1H-NMR (CD3OD, 300 MHz): δ = 2.14 (q, 3H, CH3, J = 0.6), 2.56 (q, 3H, CH3, J = 0.6), 2.90 (s, 3H, S-CH3), 6.80-7.40 (m, 4H, Ar); 13C-NMR (CD3OD, 50 MHz): δ = 12.12 (=C-CH3), 12.81(=C-CH3), 18.37(S-CH3), 118.61, 118.80, 120.36, 128.48, 130.26, 134.00, 143.64, 145.10, 177.73 (C-S).

2-Methylthio-N-(2-aminophenyl)-4-tert-butyl- thiazolium iodide (3c).

1H-NMR (CD3OD, 200 MHz): δ = 1.32 (s, 9H, CH3), 2.88 (s, 3H, S-CH3), 6.70-7.50 (m, 4H, Ar) , 7.85 (s, 1H, =CH); 13C-NMR (CD3OD, 50 MHz): δ = 18.13 (S-CH3), 29.84 (3C, CH3), 36.49 (C-(CH3)3), 117.84, 118.03, 118.61, 120.92, 130.24, 134.28, 145.89, 159.80, 184.37 (C-S).

3-Methyl-thiazolo[3,2-a]benzimidazolium iodide (2a)

1H-NMR (CD3OD, 300 MHz): δ = 2.92 (d, 3H, CH3, J = 1.2), 7.26 (q, 1H, =CH, J = 1.2), 7.55-7.75 (m, 2H, Ar) , 7.80-7.90 (m, 1H, Ar) , 8.15-8.25 (m, 1H, Ar); 13C-NMR (CD3OD, 75 MHz): δ = 14.21, 112.02, 114.37, 115.50, 125.58, 128.03, 129.20, 134.32, 138.14, 155.85.

2,3-Dimethyl-thiazolo[3,2-a]benzimidazolium iodide (2b)

1H-NMR (CD3OD, 200 MHz): δ = 2.56 (q, 3H, CH3, J = 1.0), 2.84 (q, 3H, CH3, J = 1.0), 7.50-7.95 (m, 3H, Ar), 8.20-8.30 (m, 1H, Ar); 13C-NMR (CD3OD, 50 MHz): δ = 12.18 (CH3), 12.38 (CH3), 114.06, 115.61, 123.30, 125.21, 127.54, 129.26, 138.23, 153.25 (C=N).

3-tert-Butyl-thiazolo[3,2-a]benzimidazolium iodide (2c)

1H-NMR (CD3OD, 200 MHz): δ = 1.67 (s, 9H, CH3), 7.25 (s, H, =CH), 7.50-7.70 (m, 2H, Ar), 7.80-7.95 (m, 1H, Ar), 8.25-8.35 (m, 1H, Ar); 13C-NMR (CD3OD, 50 MHz): δ = 28.98, 34.75, 110.16, 116.26, 117.19, 124.93, 127.45, 129.43, 139.99, 146.94, 157.96.

Acknowledgements

We thank European Union “Training and Mobility in Research” program for grants to F.A and M.R. Socrates-Erasmus program is thanked for grant to M.H.

References and Notes

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  2. Balasubramanian, K. K.; Nagarajan, R. Synthesis 1976, 3, 189.
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  10. Roussel, C.; Vanthuyne, N.; Serradeil-Albalat, M.; Vallejos, J. C. J. Chromatogr. A 2003, 995, 79–85.
  11. These atropisomers are nicely separated by chiral HPLC on CHIRALCEL OD-H, mobile phase hexane / ethanol (50/50), 1 mL/min, 25°C, detection UV 254 nm and on-line polarimeter Jasco OR-1590, retention times Rt in minutes, retention factor k = (Rt - Rt0) / Rt0, selectivity factor α and resolution Rs are reported below : (4a) Rt(+) = 4.72 , Rt(-) = 5.82, k(+) = 0.52, k(-) = 0.88, α = 1.68 and Rs = 3.05.; (4b) Rt(+) = 4.59 , Rt(-) = 6.52, k(+) = 0.48, k(-) = 1.10, α = 2.29 and Rs = 4.87.; (4c) Rt(+) = 4.51 , Rt(-) = 6.17, k(+) = 0.45, k(-) = 0.99, α = 2.18 and Rs = 4.25.
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  • Samples Availability: Available from the authors.

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MDPI and ACS Style

Roussel, C.; Andreoli, F.; Roman, M.; Hristova, M.; Vanthuyne, N. New Route to 3-Alkylthiazolo[3,2-a]benzimidazole Derivatives. Molecules 2005, 10, 327-333. https://doi.org/10.3390/10020327

AMA Style

Roussel C, Andreoli F, Roman M, Hristova M, Vanthuyne N. New Route to 3-Alkylthiazolo[3,2-a]benzimidazole Derivatives. Molecules. 2005; 10(2):327-333. https://doi.org/10.3390/10020327

Chicago/Turabian Style

Roussel, Christian, Federico Andreoli, Mihaela Roman, Maria Hristova, and Nicolas Vanthuyne. 2005. "New Route to 3-Alkylthiazolo[3,2-a]benzimidazole Derivatives" Molecules 10, no. 2: 327-333. https://doi.org/10.3390/10020327

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