MoO₂Cl₂(dmf)₂-Catalyzed Domino Reactions of ω-Nitro Alkenes to 3,4-Dihydro-2H-1,4-benzothiazines and Other Heterocycles

Abstract

Using the transformation of allyl 2-nitrophenyl thio­ethers to 3,4-dihydro-2H-1,4-benzothiazines as an example the reductive cyclization of ω-nitroalkenes to saturated N-heterocycles can be performed highly selective and with high yields if a combination of MoO₂Cl₂(dmf)₂ as a catalyst and Ph₃P as reducing agent are employed.

catalysis - domino reaction - heterocycles - nitroso ene reaction - reductive cyclization

References and Notes

1a Merisor E. Conrad J. Klaiber I. Mika S. Beifuss U. Angew. Chem. Int. Ed.  2007,  46:  3353 

1b Merisor E. Conrad J. Mika S. Beifuss U. Synlett  2007,  2033 

2 Merisor E. Beifuss U. Tetrahedron Lett.  2007,  48:  8383 

3a Napolitano A. Memoli S. Prota G. J. Org. Chem.  1999,  64:  3009 

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3d Matsuoka H. Kuroki T. Yano K. Takeda Y. J. Labelled Compd. Radiopharm.  1997,  39:  363 

4 Courtin A. von Tobel H.-R. Auerbach G. Helv. Chim. Acta  1980,  63:  1412 

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6 Sanz R. Escribano J. Pedrosa MR. Aguado R. Arnáiz FJ. Adv. Synth. Catal.  2007,  349:  713 

7 Sanz R. Escribano J. Aguado R. Pedrosa MR. Arnáiz FJ. Synthesis  2004,  1629 

8 Sanz R. Escribano J. Fernández Y. Aguado R. Pedrosa MR. Arnáiz FJ. Synlett  2005,  1389 

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10

General Procedure for the Synthesis of Thioethers 7a-d In an oven dried 250 mL three-necked round-bottom flask
2-nitro thiophenol 9 (16.11 mmol) was dissolved in freshly distilled dry THF (50 mL) under Ar. Sodium hydride (80%) (24.16 mmol) was added in several portions at 0 ˚C during 10 min, and after complete addition the reaction mixture was stirred for 30 min at 0 ˚C. Freshly distilled allyl bromide (64.44 mmol) was added dropwise at 0 ˚C; after complete addition the reaction mixture was allowed to stir at r.t. for 12.5 h. Then the reaction mixture was poured into sat. NH₄Cl (100 mL) and extracted with TBME (3 × 100 mL). The combined organic phases were washed with brine (100 mL) and dried over anhyd MgSO₄. The solvents were removed under reduced pressure, and the crude product was purified by Kugelrohr distillation or by flash column chromatog-raphy on silica gel (cyclohexane-EtOAc, 20:1).

11

General Procedure for the (EtO) ₃ P-Mediated Domino Reaction under Microwave Conditions A 10 mL process vial was charged with a mixture of 7 (1 mmol), (EtO)₃P (1.07 mL, 6 mmol) and toluene (3 mL). The vial was sealed, placed into the cavity of the microwave reactor, and irradiated with microwaves at 200 ˚C for 30-35 min, after removing (EtO)₃P and (EtO)₃PO by Kugelrohr distillation under reduced pressure, the remaining residue was diluted with hot EtOAc (50 mL). The organic phase was washed with brine (3 × 20 mL) and dried over MgSO₄. Solvent was removed under reduced pressure, and the remaining residue was purified by flash chromatography on silica gel (cyclohexane-EtOAc, 20:1).

12

General Procedure for the Mo(VI)-Catalyzed Domino Reaction under Microwave Conditions with Ph ₃ P as a Reagent A 10 mL process vial was charged with a mixture of 7 (1 mmol), Ph₃P, MoO₂Cl₂(dmf)₂, and toluene (3 mL). The vial was sealed, placed into the cavity of the microwave reactor, and irradiated with microwaves at 200 ˚C for 30-240 min, after filtration and removal of the solvent the reaction mixture was poured into H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over MgSO₄, and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography on silica gel (cyclohexane-EtOAc, 20:1). Alternatively, the reaction mixture can also be purified by flash column chroma-tography without any workup procedure.

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Selected Data for 1-(3-Methylbut-2-enylsulfanyl)-2-nitrobenzene (7a, Figure 2) R _f = 0.52 (cyclohexane-EtOAc, 20:1). UV/vis (MeCN):
λ_max (log ε) = 245 (4.20), 380 (3.43) nm. IR (ATR): 2914, 1593, 1565, 1508, 1452, 1376, 1333, 1303, 1252, 1170, 1103, 1061, 1044, 981, 852, 780, 730 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.74 (br s, 3 H, 4′-H), 1.76 (br s, 3 H, 5′-H), 3.60 (d, ^³ J = 7.8 Hz, 2 H, 1′-H), 5.31 (sept, ^³ J = 7.6 Hz, ⁴ J = 1.4 Hz, 1 H, 2′-H), 7.24 (ddd, ^³ J = 7.2 Hz, ^³ J = 8.2 Hz, ⁴ J = 1.4 Hz, 1 H, 4-H), 7.41 (dd, ^³ J = 8.2 Hz, ⁴ J = 1.2 Hz,
1 H, 6-H), 7.54 (ddd, ^³ J = 7.2 Hz, ^³ J = 8.2 Hz, ⁴ J = 1.5 Hz,
1 H, 5-H), 8.19 (dd, ^³ J = 8.2 Hz, ⁴ J = 1.5 Hz, 1 H, 3-H). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 18.25 (C-5′), 26.00 (C-4′), 31.27 (C-1′), 117.18 (C-2′), 124.65 (C-4), 126.33 (C-3), 127.29 (C-6), 133.61 (C-5), 138.80 (C-1), 139.03 (C-3’), 146.25 (C-2). MS (EI, 70 eV): m/z (%) = 223 (20) [M⁺], 206 (5), 155 (36), 139 (100), 138 (23), 125 (8), 117 (3), 69 (1). HRMS (EI): m/z [M⁺] calcd for C₁₁H₁₃NO₂S: 223.0667; found: 223.0664. Anal. Calcd for C₁₁H₁₃NO₂S: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.18; H, 5.92; N, 6.62.

Figure 2

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Selected Data for 3-Isopropenyl-3,4-dihydro-2 H -benzo[1,4]thiazine (8a, Figure 3)
R _f = 0. 54 (cyclohexane-EtOAc, 20:1). UV/vis (C₂H₅OH): λ_max (log ε) = 230 (4.36), 313 (3.67) nm. IR (ATR): 3397, 2927, 1647, 1589, 1477, 1417, 1306, 1263, 1237, 1156, 1107, 1075, 1033, 957, 899, 838, 738 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.83 (s, 3 H, 3′-H), 2.98 (overlapped, 1 H, 3-H), 2.98 (dd, ^³ J = 3.9 Hz, ^² J = 12.5 Hz, 1 H, 2b-H), 3.04 (dd, ^³ J = 7.3 Hz, ^² J = 12.5 Hz, 1 H, 2a-H), 4.08 (br dd, ^³ J = 3.9 Hz, ^³ J = 7.2 Hz, 1 H, 3-H), 5.03 (br s, 1 H, 2′-H), 5.11 (br s, 1 H, 2′-H), 6.54 (dd, ^³ J = 8.0 Hz, ^² J = 1.3 Hz, 1 H, 5-H), 6.64 (ddd, ^³ J = 7.5 Hz, ^³ J = 7.5 Hz, ^² J = 1.3 Hz, 1 H, 7-H), 6.93 (ddt, ^³ J = 7.3 Hz, ^³ J = 8.0 Hz, ^² J = 1.6 Hz, 1 H, 6-H), 7.02 (dd, ^³ J = 7.8 Hz, ^² J = 1.5 Hz, 1 H, 8-H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.22 (C-3′), 30.19 (C-2), 57.16 (C-3), 112.95 (C-2′), 115.66 (C-5), 115.88 (C-9), 118.5 (C-7), 125.93 (C-6), 127.74 (C-8), 142.01 (C-10), 145.81 (C-1′). MS (EI, 70 eV): m/z (%) = 191 (100) [M⁺], 163 (18), 150 (46), 117 (21), 109 (11), 65 (5). HRMS (EI): m/z [M⁺] calcd for C₁₁H₁₃NS: 191.0769; found: 191.0783. Anal. Calcd for C₁₁H₁₃NS: C, 69.07; H, 6.85; N, 7.32. Found: C, 69.15; H, 6.90; N, 7.27.

Figure 3