Domino Reaction for the Construction of New 2-Oxo[1,2,4]triazolo[5,1-c][1,4]thiazines

Abstract

The synthesis of highly functionalized α-thiohydrazones by Michael addition of 3-mercapto-2-ketones to 1,2-diazabuta-1,3-dienes is described. The phosphorylated α-thiohydrazones were hydrolyzed into β-ketophosphine oxides or phosphonates containing a mercapto ketone in the α position, while the α-thiohydrazones with a carboxylate group were subsequently transformed into 2-oxo-2,3,8,8a-tetrahydro-1H-[1,2,4]triazolo[5,1-c][1,4]thiazines by means of a domino reaction.

Key words

1,2-diazabuta-1,3-dienes - [1,4]thiazines - [1,2,4]triazol-2-ones - Michael addition - domino reaction.

References and Notes

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19

General Procedure for the Synthesis of α-Thiohydrazone 1,4-Adducts 3a-m: To an ice-cooled solution of 1,2-diazabuta-1,3-diene 1a,b,i as a mixture of E/Z isomers (1.0 mmol) in CH₂Cl₂ (5 mL), the 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2b (1.1 mmol) was added. The reaction was allowed to stir at r.t. for 4 h. The solvent was removed by rotary evaporation and the crude products were purified by crystallization for compound 3m or by flash column chromatography (silica gel, EtOAc) for compounds 3a,b,k,l to afford α-thiohydrazone 1,4-adducts derived from phosphine oxide and phosphonate-substituted 1,2-diazabuta-1,3-dienes. To obtain 3c-j, a stoichiometric amount of 1,2-diazabuta-1,3-dienes 1c-h (1.0 mmol) as a mixture of E/Z isomers [²6] was added to a solution of 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2b (1.1 mmol) in MeCN (20 mL) with magnetic stirring at r.t. The reactions were allowed to stand under these conditions for 2 h until the complete disappearance of the starting materials (monitored by TLC). The reaction solvent was then evaporated under reduced pressure and products 3c-j were purified by flash column chromatography (silica gel, EtOAc).
Ethyl 2-(Diphenylphosphoryl)-1-methyl-2-[(1-methyl-2-oxopropyl)sulfanyl]ethylidene-1-hydrazinecarboxylate (3a): yield: 433 mg (97%); obtained as a colorless solid as described in the general procedure; mp 143-145 ˚C. IR (KBr): 3457, 3195, 2978, 1733, 1533, 1436, 1236, 1042 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.19-1.23 (m, 6 H), 1.82 (s, 3 H), 1.90 (d, 3 H, ⁴ J _PH = 1.1 Hz, major), 1.91 (d, 3 H, ⁴ J _PH = 1.1 Hz, minor), 3.34 (q, 1 H, ^³ J _HH = 7.2 Hz, major), 3.40 (q, 1 H, ^³ J _HH = 6.8 Hz, minor), 4.19-4.22 (m, 2 H), 4.39 (d, 1 H, ^² J _PH = 10.0 Hz), 4.42 (d, 1 H, ^² J _PH = 9.6 Hz), 7.41-7.88 (m, 10 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.4, 13.6, 14.4, 14.4, 16.1, 16.2, 25.1, 26.7, 48.7 (d, ^³ J _PC = 6.5 Hz), 49.4 (d, ^³ J _PC = 6.0 Hz), 52.1 (d, ^¹ J _PC = 65.5 Hz), 52.6 (d, ^¹ J _PC = 66.1 Hz), 61.7, 128.1, 128.2, 128.2, 128.3, 128.4, 128.6, 129.4, 130.0, 130.4, 130.6, 130.7, 130.7, 130.9, 131.0, 131.1, 131.1, 131.2, 131.2, 131.3, 131.4, 131.9, 131.9, 147.6, 148.4, 153.6, 204.4, 204.7. ^³¹P NMR (120 MHz, CDCl₃): δ = 28.1 (major), 28.4 (minor). HRMS: m/z [M⁺] calcd for C₂₂H₂₇N₂O₄PS: 446.1429; found: 446.1434.

20

General Procedure for the Synthesis of Mercapto Diketones 4a-e: To a solution of the α-thiohydrazone 3a,b,k,l,m (1.0 mmol) in MeCN (5 mL), Amberlyst 15H ion-exchange resin (50 mg) was added. The reaction was stirred at r.t. for 2 h. The solid was then filtered through a sintered glass vacuum filtration funnel. The filtrate was concentrated to dryness in vacuum. The crude products were purified by flash column chromatography (silica gel, EtOAc) to afford the corresponding mercapto diketones 4a-e.
3-[1-(Diphenylphosphoryl)-2-oxopropyl]sulfanylbutan-2-one (4a): isomeric mixture of the keto and enol tautomers; yield: 306 mg (85%); obtained as a colorless oil as described in the general procedure. IR (film): 3435, 3046, 2921, 1705, 1431, 1362, 1197, 1117 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.94 (d, 3 H, ^³ J _HH = 7.2 Hz), 1.24 (d, 3 H, ^³ J _HH = 7.2 Hz), 1.82 (s, 3 H), 1.91 (s, 3 H), 1.96 (s, 3 H), 2.37 (s, 3 H), 2.39 (s, 3 H), 3.31 (q, 1 H, ^³ J _HH = 7.2 Hz), 4.12 (d, 1 H, ^² J _PH = 12.0 Hz), 4.15 (d, 1 H, ^² J _PH = 11.1 Hz), 7.55-7.92 (m, 10 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.1, 15.3, 21.1 (d, ^³ J _PC = 6.1 Hz), 24.6, 26.2, 26.7, 29.4, 48.6 (d, ^³ J _PC = 5.5 Hz), 48.7 (d, ^³ J _PC = 5.5 Hz), 52.5, 54.0 (d, ^¹ J _PC = 45.1 Hz), 54.7 (d, ^¹ J _PC = 45.5 Hz), 82.1 (d, ^¹ J _PC = 108.7 Hz), 128.2, 128.3, 128.5, 128.5, 128.6, 128.7, 131.1, 131.2, 131.2, 131.3, 131.4, 131.4, 131.5, 132.0, 132.2, 132.3, 132.3, 132.4, 132.5, 132.5, 132.6, 186.5 (d, ^² J _PC = 12.7 Hz), 200.8, 202.2, 203.6, 204.3, 205.9. ^³¹P NMR (120 MHz, CDCl₃):
δ = 26.8, 27.7, 41.4. HRMS: m/z [M⁺] calcd for C₁₉H₂₁O₃PS: 360.0949; found: 360.0952.

23

General Procedure for the Synthesis of [1,2,4]Triazolo[5,1- c ][1,4]thiazines 7a-h: To obtain [1,2,4]triazolo[5,1-c][1,4]thiazines 7b-h, the α-thiohydra-zones 3d-j (1 mmol) were refluxed in MeCN for 26-48 h. To prepare compounds 7b-h directly, a stoichiometric amount of 1,2-diazabuta-1,3-dienes 1d-h (1 mmol) was added to a solution of 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2a (1.1 mmol) in MeCN (20 mL) with magnetic stirring at r.t. until the disappearance of the reagent, as evidenced by disappearance of typical red color of the 1,2-diazabuta-1,3-dienes 1. The crude was then refluxed for 26-48 h. In the case of 7a the hydrazone 3c (1 mmol) was refluxed for 28 h in the presence of a stoichiometric amount of Amberlyst 15H ion-exchange resin (1 mmol). After disappearance of the starting materials (monitored by TLC), the reaction solvent was evaporated under reduced pressure and products 7a-h were purified by flash column chromatography (silica gel; EtOAc-cyclo-hexane, 50:50).
Methyl 5,8,8a-Trimethyl-2-oxo-2,3,8,8a-tetrahydro-1 H -[1,2,4]triazolo[5,1- c ][1,4]thiazine-6-carboxylate (7a): yield: 72 mg (31%); obtained as a blue oil as described in the general procedure. IR (nujol): 3243, 1753, 1712, 1643 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.22 (d, 3 H, ^³ J = 6.4 Hz), 1.39 (s, 3 H), 2.37 (s, 3 H), 2.58 (q, 1 H, ^³ J = 6.4 Hz), 3.56 (s, 3 H), 8.38 (s, 1 H), 9.15 (s, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.5 (q), 17.1 (q), 22.2 (q), 40.8 (d), 51.0 (q), 83.1 (s), 87.6 (s), 149.0 (s), 159.4 (s), 165.0 (s). MS: m/z (%) = 257 (96)[M⁺], 225 (100), 197 (67), 166 (57), 139 (81), 108 (16). Anal. Calcd for C₁₀H₁₅N₃O₃S: C, 46.68; H, 5.88; N, 16.33. Found: C, 46.82; H, 5.92; N, 16.19.