An Efficient Route for Synthesis of Thiadiazino

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Utility and Synthetic Uses of Mannich Reaction: An Efficient Route for Synthesis of Thiadiazino-[1,3,5][3,2-a]benzimidazoles Abd El-Wareth A. O. Sarhana; Shams H. Abdel-Hafeza; Hassan El-Sheriefa; Tarek Aboel-Fadlb a Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt

To cite this Article Sarhan, Abd El-Wareth A. O. , Abdel-Hafez, Shams H. , El-Sherief, Hassan and Aboel-Fadl, Tarek(2006)

'Utility and Synthetic Uses of Mannich Reaction: An Efficient Route for Synthesis of Thiadiazino-[1,3,5][3,2a]benzimidazoles', Synthetic Communications, 36: 8, 987 — 996 To link to this Article: DOI: 10.1080/00397910500501243 URL: http://dx.doi.org/10.1080/00397910500501243

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Synthetic Communicationsw, 36: 987–996, 2006 Copyright # Taylor & Francis Group, LLC ISSN 0039-7911 print/1532-2432 online DOI: 10.1080/00397910500501243

Utility and Synthetic Uses of Mannich Reaction: An Efficient Route for Synthesis of Thiadiazino-[1,3,5][3,2-a]benzimidazoles

Downloaded At: 09:11 11 January 2011

Abd El-Wareth A. O. Sarhan, Shams H. Abdel-Hafez, and Hassan El-Sherief Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt

Tarek Aboel-Fadl Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt

Abstract: The utilities of the Mannich reaction in synthetic organic chemistry are reviewed. The behaviors of Mannich reactions on several bifunctional heterocyclic compounds have been reported. A new class of heterocyclic compounds, thiadiazino[1,3,5][3,2-a]benzimidazoles 12a– g, were obtained by reaction of 2-mercaptobenzimidazole with primary aliphatic amines in a one-step synthesis. An attempt to apply this reaction using primary aromatic amines lead to the formation of the well-known Mannich bases 11a– g rather than the N-substituted thiadiazines 13. Keywords: Double Mannich reaction, synthesis, cyclization, thiadiazines

INTRODUCTION The Mannich reaction is an important biosynthetic route to natural products, mainly alkaloids. In 1917 Robinson synthesized tropine alkaloid (1) with a Mannich reaction using succinaldehyde, methylamine, and acetone[1] (Scheme 1). Received in the U.K. June 1, 2005 Address correspondence to Abd El-Wareth A. O. Sarhan, Department of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt. E-mail: elwareth@ aun.edu.eg 987

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A. A. O. Sarhan et al.


Scheme 1.

A number of reviews and books describe the Mannich reaction and its importance in synthetic organic chemistry. The utility of the Mannich reaction relates in part to the fact that the protonated bases are normally soluble in water and also to the ease with which the amino group is converted to a variety of other groups.[1] In the Mannich reaction, formaldehyde (or some another aldehyde) is condensed with ammonia or ammonia derivatives and a compound containing active hydrogen.[2,3] This can formally be considered as an addition of ammonia or amines to give RNHCH2OH, followed by a nucleophilic substitution: RNH2 þ HCHO ! RNHCH2 OH: Many active hydrogen compounds give the Mannich reaction. Among these are the following[4,5] (Chart 1). The previous studies of the reaction kinetics have led to the following proposals for the mechanism of the Mannich reaction[6] (Scheme 2).

Chart 1.

Scheme 2.

Base-catalyzed reaction

The Mannich Reaction

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Scheme 3.


Acid-Catalyzed Reaction In the acid-catalyzed reaction, the free amine reacts in acid solution and the active hydrogen compound react as enol.[7] In the Mannich reaction, the reaction proceeds regioselectively[5,8 – 15] and diastereoselectively[16,17] (Scheme 3). In continuation to our work and interest in the Mannich reaction we have studied the behavior of this reaction using different bifunctional heterocyclic thiols such as 4,5-diphenylimidazole-2-thiol (1), 2-aryltriazole-5-thiol (2), and/or 1,3-diaryl-4-aminopyrazole (3) (Chart 2). The reaction of 4,5-diphenylimidazole-2-thiol (1) with primary aliphatic or aromatic amines/CH2O mixture in different reaction conditions afforded the corresponding thiadiazinoimidazole derivatives 5a –h in very good yields (Scheme 4).[18] Following the same procedures, we studied the reaction of 2-phenyltriazol5-thiol (2) with aliphatic or aromatic amines/CH2O in variant reaction conditions. The s-triazolo[3,4-b][1,3.5]thiadiazine derivatives 6a–h were obtained in very good yields (Scheme 5).[5]

Chart 2.

Scheme 4.

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Scheme 5.


Scheme 6.

In the same manner, the reaction of 1,3-diaryl-4-aminopyrazole (3) with primary aliphatic or aromatic amines under a variety of reaction conditions gave the pyrazolo[3,4-d]pyrimidine derivatives 7a – h in high yields (Scheme 6).[5]

RESULTS AND DISCUSSION In this work we focus on two main features of the Mannich reaction. The first is the behavior in different reaction conditions. Second is using the Mannich reaction as a one-pot synthesis of a new class of heterocyclic system not yet reported. A bifunctional compound such as 2-mercaptobenzimidazole (8) is used as a starting for the synthesis of thiadiazine fused with a benzimidazole ring system via application of the Mannich reaction in different reaction conditions. The reaction of 2-mercaptobenzimidazole (8) with secondary amines under Mannich conditions was studied several years ago by Zinner et al., and the desired products 9a –d were obtained (Scheme 7).[19]

Scheme 7. 9a: R, R0 ¼ H, Me, b: R, R0 ¼ H, Et, c: NR,R0 ¼ Piperidine, d: NR,R0 ¼ morphiline.


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Scheme 8.

Treatment of 2-mercaptobenzimidazole (8) with excess formaldehyde solution in water or alcohol at refluxing temperature afforded the 1,3-dihydroxymethylbenzimidazole-2-thione 10 in very good yield (Scheme 8).[19] Reaction of the 2-mercaptobenzimidazole (8) with aromatic amines in the presence of 2 mol or even excess formaldehyde in ethanol/water mixture under reflux temperature gave the corresponding N-arylaminomethylbenzimidazole-2-thiol 11a –g in very good yield (Scheme 9).[20] The neutral conditions (EtOH or EtOH/water mixture) applied on the Mannich reaction of the 2-mercaptobenzimidazole (8) with aromatic amines gave the Mannich bases 11a–g. The products 11a–g were also obtained at room temperature. On treatment of 8 with aromatic amines/formaldehyde in EtOH/AcOH mixture (20 : 1) or in acetic acid the corresponding 11a–g were also obtained in good yield. The same results were also obtained upon treatment of 2-mercaptobenzimidazole (8) with p-toluidene or p-anisidene in the presence of dioxane or pyridine as solvents at room temperature or under refluxing temperature. All attempts to cyclize the Mannich bases 11a–g to thiadiazines 12a–g using a reaction with formaldehyde in neutral or acid and or basic conditions were unsuccessful and the starting 11a–g were recovered. Treatment of 11b,c with CH2Cl2 in the presence of KOH or NaH or Na metal as strong basic medium were also unsuccessful (Scheme 10). However, reaction of the 2-mercaptobenzimidazole (8) with primary alkyl/aralkyl amines in neutral or in acidic medium afforded the cyclized thiadiazino[1,3,5][3,2-a]benzimidazoles 12a – f in very good yields (Scheme 11). Interaction of 8 with o-toluidine or 2-aminopyridine in an ethanol/acetic acid mixture containing formaldehyde at room temperature or under refluxing temperature gave the cyclized products 13f, although the product with o-toluidine could not be isolated in pure form.

Scheme 9. 11a: Ar ¼ Ph, b: Ar ¼ C6H4-Me-p, c: Ar ¼ C6H4-OMe-p, d: Ar ¼ C6H4COCH3-p, e: Ar ¼ C6H4-Br-p, f: Ar ¼ C6H4-NO2-p, g: Ar ¼ C6H4-Cl-o.

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Scheme 10.

On the other hand, reaction of the 1,3-dihydroxymethylbenzimidazole-2thione (10) with alkyl halides or aralkyl halides in aqueous ethanol containing equimolecular amounts of KOH gave 1,3-dialkyl/aralkylbenzimidazole-2thiones 15a – c rather than the formation of the excepeted 1,3-dialkoxymethylbenzimidazole-2-thione derivatives 14 in very good yield (Scheme 12). The cyclized compounds 12a–g were established using IR, NMR, and MS spectral analysis. The elemental analyses of all compounds were in satisfactory agreements with the calculated values. The IR spectra of 13a–f showed no NH signal as in the uncyclized 11a–g. The NMR spectra of these compounds exhibited the singlet signals due to the two sets of CH2 protons SCH2N and NCH2N in the thiadiazine ring. The alkyl groups N-R also appeared depending on the size and multiplicity of the R group. These compounds were also determined on the basis of their MS spectral data and elemental analysis. In conclusion, the Mannich reaction was investigated using a bifunctional compound such as 2-mercaptobenzimidazole using primary aromatic and aliphatic amines, and it has been found that the reaction proceeds via cyclization, consuming 2 mol of formaldehyde and giving the targeted thiadiazines 13a– f in good yields. However, when using primary aromatic amines, the reaction behaves as previously described in literature, giving the uncyclized

Scheme 11. 13a: R ¼ CH3, b: R ¼ CH3CH2, c: R ¼ CH(CH3)2, d: R ¼ C6H11, e: R ¼ benzyl, f: R ¼C5H4N.



Scheme 12.

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15a: R ¼ H, b: R ¼ CH3, c: R ¼ C6H5.

Mannich bases 11a– g in high yields. This behavior of 2-mercapto benzimidazole was found to be different from other 4,5-diphenylimidazole previously investigated.[5]

EXPERIMENTAL All melting points were determined using a Kofler hot-stage apparatus and are uncorrected. IR spectra were measured on a Perkin-Elmer FT spectrometer 1710 by KBr techniques. 1H NMR spectra were recorded on a Varian EM390 90-MHz NMR spectrometer (Spectral Unit, Assiut University, Egypt) and WP 200 SY and AM 300 from the Brucker company. TMS was used as an internal standard. MS spectra were obtained with a MAT 312 mass spectrometer from Finnegan company at an ionization energy of 70 eV. Elemental analyses were accomplished at the microanalytical laboratory of the Chemistry Department, Assiut University, Egypt. There were found to agree satisfactorily with their calculated values. 2-Mercaptobenzimidazole (8) is commercially available from Aldrich chemical company. 3-Substituted Thiadiazino[1,3,5][3,2-a]benzimidazoles (13a – f) General: A mixture of 2-mercaptobenzimidazole (8) and alkyl/aralkyamine was stirred in ethanol or in ethanol/acetic acid (20 : 1) at room temperature for 6 –8 h. The precipitate thus obtained was collected by filtration and crystallized from the proper solvent to give the corresponding thiadiazinobenzimidazole 13a– f in good yields.

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3-Methylthiadiazino[1,3,5][3,2-a]benzimidazoles (13a) Compound 13a was obtained as white crystals from ethanol, 1.0 g, 73.5% yield, mp 269– 2718C. IR (KBr) n 3050w, 2950m, 2900w, 1610s, 1480s, 1450s, 1405s, 1225s, 1045s, 740s cm21. 1H NMR (TFA) d 7.5 (m, 4H, arom-H), 5.45 (s, 2H, NCH2N), 5.05 (s, 2H, SCH2N), 2.8 (s, 3H, NCH3). Anal. calcd. for C10H11N3S (205.277); calcd: C, 58.51; H, 5.40; N, 20.46; S, 15.61%. Found: C, 58.38; H, 5.30; N, 20.09; S, 15.21%.


3-Ethylthiadiazino[1,3,5][3,2-a]benzimidazoles (13b) Compound 13b was obtained as white crystals from ethanol, 2.5 g, 85.4% yield, mp 215 – 2168C. IR (KBr) n 3050m, 2980s, 2920m, 2870s, 1600s, 1480s, 1445s, 1400s, 1250m, 1030s, 740s cm21. 1H NMR (CDCl3) d 6.9 – 7.2 (m, 4H, arom-H), 5.4 (s, 4H, 2 CH2N), 2.9 (q, J ¼ 7 Hz,, 2H, NCH2CH3), 1.1 (t, J ¼ 7 Hz, 3H, CH2CH3). MS (m/e) % ¼ 221 (Mþ2, 3), 220 (Mþ1, 9), 219 (Mþ, 4), 177 (4), 176 (5), 164 (18), 163 (26), 161 (67), 160 (16), 154 (3), 151 (14), 150 (100), 145 (7), 143 (15), 134 (19), 129 (9), 116 (12), 108 (11), 103 (10), 102 (16), 92 (10), 77 (7), 63 (13), 58 (14), 52 (7). Anal. calcd. for C11H13N3S (219.3038); calcd: C, 60.24; H, 5.97; N, 19.16; S, 14.61%. Found: C, 60.49; H, 5.58; N, 18.88; S, 14.41%.

3-Isopropylthiadiazino[1,3,5][3,2-a]benzimidazoles (13c) Compound 13c was obtained as white crystals from methanol, 1.3 g, 83.5% yield, mp 180 – 1818C. IR (KBr) n 3050w, 2950s, 2870s, 1605s, 1470s, 1400s, 1270s, 1040s, 740s cm21. 1H NMR (CDCl3) d 7.2-6.9 (m, 4H, arom-H), 5.45 (bs, 4H, 2 CH2N), 2.9– 2.6 [m, 1H, NCH(CH3)2], 1.6 (d, J ¼ 7 Hz, 6H, 2CH3). MS (M/e) % ¼ 233 (Mþ, 7), 219 (63), 209 (5), 183 (1), 165 (14), 162 (11), 161 (10), 160 (66), 150 (100), 146 (1), 136 (16), 132 (10), 128 (13), 120 (35), 117 (41), 106 (47), 102 (3), 92 (4), 78 (30), 77 (27), 63 (3), 62 (3), 51 (9), 50 (11), 43 (27). Anal. calcd. for C12H15N3S (233.3306); calcd: C, 61.77; H, 6.47; N, 18.01; S, 13.74%. Found: C, 61.68; H, 6.35; N, 18.00; S, 13.51%.

3-Cyclohexylthiadiazino[1,3,5][3,2-a]benzimidazoles (13d) Compound 13d was obtained as white crystals from methanol, 1 g, 46% yield, mp 199 – 2018C. IR (KBr) n 3050w, 2910s, 2850s, 1600s, 1480s, 1440s, 1410s, 1270s, 1030s, 735s cm21. 1H NMR (CDCl3) d 7.5 –6.7 (m, 4H, arom-H), 5.4 (s, 2H, NCH2N), 5.2 (s, 2H, SCH2N), 2.8 (m, 1H, NCH), 2.3 – 0.8 (m, 10H, cyclohexyl). MS (m/e) % ¼ 274 (Mþ1, 9), 273 (Mþ, 31), 272


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(M21, 69), 239 (1), 229 (1), 205 (1), 188 (4), 174 (6), 161 (29), 160 (83), 159 (17), 149 (19), 133 (13), 128 (7), 125 (7), 117 (38), 111 (10), 98 (7), 90 (12), 83 (50), 77 (12), 63 (9), 54 (100), 52 (17), 51 (9), 43 (6), 39 (38). Anal. calcd. for C15H19N3S (273.3952); calcd: C, 65.89; H, 7.00; N, 15.36; S, 11.72%. Found: C, 65.57; H, 7.21; N, 15.12; S, 11.62%.


3-Benzylthiadiazino[1,3,5][3,2-a]benzimidazoles (13e) Compound 13e was obtained as white crystals from methanol, 2.4 g, 72% yield, mp 210– 2138C. IR (KBr) n 3050w, 2930s, 2870w, 1600s, 1480s, 1440s, 1330s, 1030s, 800s, 735s cm21. 1H NMR (CDCl3) d 7.3 –6.7 (m, 9H, arom-H), 5.45 (bs, 4H, 2 NCH2N), 4.0 (s, 2H, NCH2Ph). 13C NMR (CDCl3) d 171.79 (C-11), 137.68, 131.89, 128.33, 128.20, 127.20, 123.40 (arom-C), 109.88 (arom-C), 62.23 (C-2, C-4), 54.74 (C-benzyl). MS (m/e) % ¼ 281 (Mþ, 20), 280 (M21, 96), 239 (2), 193 (2), 189 (1), 174 (7), 160 (100), 149 (11), 142 (4), 133 (7), 128 (10), 117 (38), 107 (3), 91 (53), 77 (4), 65 (10), 63 (4), 50 (4), 40 (12). Anal. calcd. for C16H15N3S (281.3746); calcd: C, 68.29; H, 5.37; N, 14.93; S, 11.39%. Found: C, 68.10; H, 5.38; N, 15.08; S, 11.27%.

3-(20 -Pyridyl)thiadiazino[1,3,5][3,2-a]benzimidazoles (13f) Compound 13f was obtained as white crystals from methanol, 0.4 g, 17.2% yield, mp IR (KBr) n 2900m, 2830w, 1600s, 1560m, 1475s, 1250m, 770s, 740s cm21. 1H NMR (CDCl3) d 7.0 –6.3 (m, 7H, arom-H), 5.1 (s, 2H, CH2N), 3.2 (s, 2H, CH2). MS (m/e) % ¼ 268 (Mþ, 20), 267 (M21, 96), 189 (1), 174 (7), 160 (100), 149 (11), 142 (4), 133 (7), 128 (10), 117 (38), 107 (3), 91 (53), 77 (4), 65 (10), 63 (4), 50 (4), 40 (12). Anal. calcd. for C14H12N4S (268.3356); calcd: C, 62.66; H, 4.50; N, 20.87; S, 11.94%. Found: C, 62.43; H, 4.31; N, 20.59; S, 11.46%.

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