Synthesis and Reactivity of 3,4-Dimethyl-4H-1,3,4-thiadiazines

Abstract

3,4-Dimethyl-4H-1,3,4-thiadiazines, novel 8π hetero­cyclic systems, were prepared by cyclization of α-haloketones with 1,2,4-trialkylthiosemicarbazides. The desulfurization of the products afforded 5-imino-1,2-dimethylpyrazoles by valence isomerization into thia-σ-homopyrazoles.

cyclizations - heterocycles - sulfur - synthetic methodology - valence isomerization

References

Reviews:

1a Pfeiffer W.-D. In Methoden der organischen Chemie (Houben-Weyl)   Volume E9:  Thieme; Stuttgart: 1997.  p.489 

1b Beyer H. Z. Chem.  1969,  9:  361 

2a Schmidt RR. Huth H. Tetrahedron Lett.  1975,  33 

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2e Pfeiffer W.-D. Geisler K. Roßberg H. Bulka E. Z. Chem.  1982,  22:  137 

3 For a review of 8p heterocycles, see: Schmidt RR. Angew. Chem.  1975,  87:  603 

4a Sato T. Ohta M. J. Pharm. Soc. Jpn.  1955,  75:  1535 ; Chem. Abstr. 1956, 50, 10727

4b For true 4-aryl-4H-1,3,4-thiadiazines, see: Schildknecht H. Enzmann F. Gessner K. Penzien K. Römer F. Volkert O. Angew. Chem.  1966,  78:  841 

4c Ege G. Angew. Chem.  1967,  79:  618 

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4e See also: Mathes RA. J. Org. Chem.  1952,  17:  877 

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4h Saad HA. Phosphorus, Sulfur Silicon Relat. Elem.  2001,  175:  65 

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6a Bose R. Ray-Chaudhury G. J. Indian Chem. Soc.  1927,  4:  259 

6b See also: Entenmann G. Synthesis  1973,  225 

7a Pfeiffer W.-D. Dilk E. Bulka E. Z. Chem.  1982,  22:  173 

7b See also: Pfeiffer W.-D. Lachmann K. Epperlein U. Pharmazie  1994,  49:  401 

8 Tanabe Y. Mori K. Nishii Y. Heterocycles  1996,  43:  141 

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10

Typical Procedure for the Synthesis of 2-Alkylamino-3,4-dimethyl-5-aryl-2,3-dihydro-4 H -1,3,4-thiadiazines (3). An EtOH solution (20 mL) of 1,2-dimethyl-4-iso-propylthiosemicarbazide (1a) (1.47 g, 10.0 mmol) or of 1,2,4-trimethylthiosemicarbazide (1b) (1.19 g 10.0 mmol) and of the corresponding phenacyl bromide 2 (10.0 mmol) was refluxed for 1 h. After cooling to 20 °C, Et₂O was added to give a colourless precipitate. The latter was isolated by filtration and recrystallized from EtOH-Et₂O with addition of HBr. 3a: Yield: 2.20 g (70%); colourless lamella (EtOH-Et₂O); mp 160-161 °C. IR (KBr): 705 (m), 712 (m), 781 (m), 820 (m), 970 (m), 1030 (m), 1170 (m), 1311 (s), 1410 (m), 1460 (s), 1499 (s), 1610 (s), 2995 (m), 3110 (m), 3225 (s) cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ =3.22 (br s, 1 H, NH⁺), 3.36 (d, 3 H, NHMe⁺), 3.75 (s, 3 H, NMe) 4.18 (s, 3 H, NMe), 6.26 (s, 1 H, 6-H), 7.32-7.66 (m, 5 H, ArH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 30.14 (NMe), 32.52 (NMe), 43.99 (NMe), 121.78 (6-C), 124.38 (CH, Ar), 128.65 (CH, Ar), 129.90 (CH, Ar), 130.92 (Ar), 150.58 (5-C), 152.50 (2-C). MS (EI, 70 eV): m/z = 234 (17) [M⁺], 233 (11), 231 (9), 220 (31), 218 (43), 202 (23), 201 (29), 187 (48), 186 (16), 118 (23), 96 (92), 94 (100). Anal. Calcd for C₁₂H₁₆N₃BrS (314.25): C, 45.87; H, 5.13; N, 13.37. Found: C, 45.79; H, 4.56; N, 13.08. All products gave satisfactory spectroscopic and analytical data.

11

1,2-Dimethyl-3-phenyl-5-methyliminopyrazoline-hydrate hydrobromide (4). Method A: A solution of 3a (3.14 g, 10.0 mmol) in HBr acid (15 mL, 48%) was refluxed for 1 h. After refluxing for 4-5 min sulfur started to precipiate. The solvent was evaporated under reduced pressure. The residue was recrystallized from EtOH-Et₂O to give 4 as colourless lamella (1.20 g, 40%), mp 168 °C. The compound crystallized as a hydrate and hydrobromide. The water could not be completely removed in vacuo over P₄O₁₀ (140 °C). Method B: A solution of 3a (3.14 g, 10.0 mmol) in HCl acid (15 mL, concentrated) was refluxed for 1 h. The work up was carried out as described for method A. Yield: 0.90 g, 30%. Method C: A solution of 3a (3.14 g, 10.0 mmol) in glacial HOAc (10 mL) was refluxed 1 h. The mixture was poured into Et₂O (150 mL). A colourless precipitate was formed. The latter was filtered off and recrystallized from EtOH-Et₂O to give 4 as a colourless solid (1.60 g, 53%). IR (KBr): 780 (s), 805 (m), 812 (m), 924 (w), 989 (w), 1045 (m), 1082 (m), 1203 (w), 1295 (m) 1302 (m), 1430 (s), 1480 (s), 1496 (m), 1542 (m), 1645 (s), 2920 (m), 2951 (m), 3098 (s), 3225 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.78 (br s, 1 H, NH⁺), 2.99-3.01 (d, 3 H, NHMe⁺), 3.71-3.78 (d, 3 H, NHMe⁺), 4.24 (s, 3 H, NMe), 5.74 (s, 1 H, 4-H), 7.45-7.59 (s, 5 H, ArH), 8.40 (br s, 1 H, NH⁺). ¹³C NMR (75 MHz, CDCl₃): δ = 30.31 (NMe), 34.74 (NMe), 35.11 (NMe), 89.53 (CH, Hetar), 126.89 (CH, Ar), 128.8 (CH, Ar), 129.49 (CH, Ar), 131.34 (Ar), 152.10 (3-C), 153.72 (5-C). MS (EI, 70 eV): m/z = 234 (4) [M⁺], 219 (4), 201 (11), 188 (100), 172 (10), 145 (16), 102 (48). Anal. Calcd for C₁₂H₁₈N₃O (300.20): C, 48.01; H, 6.04; N, 13.98. Found: C, 48.20; H, 6.20; N, 13.98.

12 For a related derivative, see: Plescia S. Daidone G. J. Heterocycl. Chem.  1983,  20:  1153