Valuable Versatile Reactivity of Thiaisatoic Anhydrides: Expedient Solid­Phase Synthesis of Thieno[1,4]diazepine-2,5-diones

Abstract

An expedient route for the generation of substituted thieno[3,2-e][1,4]diazepine-2,5-dione analogues is described herein. It was demonstrated in solution that thiaisatoic anhydride and its N-alkylated equivalents react in opposite ways with amino acids in basic conditions. This versatile reactivity was used to develop an efficient strategy on solid support. Wang resin-bound thiaisatoic anhydride was coupled with N-alkylated α-amino acids, cyclo-condensed and effectively cleaved from the polymer to provide a preliminary collection of thieno[3,2-e][1,4]diazepine-2,5-diones in 83-99% purity and 71-95% yield.

Key words

1H-thieno[3,2-d][1,3]oxazine-2,4-dione - thiaisatoic anhydride - 3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione - thienodiazepines - solid-phase synthesis

References and Notes

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35

Typical Experimental Procedure for the Ring Opening of Thiaisatoic Anhydrides 5 and 6
A stirring suspension of N-p-methoxybenzylthieno[3,2-d][1,3]oxazine-2,4-dione (6, 7.00 g, 24.22 mmol) and the corresponding α-amino acid (26.64 mmol) in H₂O (100 mL) was treated with Et₃N (7.43 mL, 53.29 mmol) at r.t. for 30 min. Drops of DMF can be added to favor complete solubility. The resulting solution was partitioned with EtOAc. The aqueous phase was extracted with EtOAc (3 × 40 mL) and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and evaporated to afford the corresponding product 8.
Acid 8e: white solid, mp 68-70 ˚C; [α]_D ^²0 -18.7 (c 0.3, DMSO). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.57 (m, 2 H), 7.46 (d, 1 H, J = 5.4 Hz), 7.26 (m, 5 H), 7.22 (d, 2 H, J = 7.3 Hz), 6.87 (d, 2 H, J = 7.1 Hz), 6.74 (d, 1 H, J = 5.4 Hz), 4.52 (q, 1 H, J = 8.0), 4.31 (d, 2 H, J = 5.5), 3.71 (s, 3 H), 3.10 (d, 2 H, J = 8.0 HZ). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 173.4, 164.6, 158.3, 154.5, 138.3, 131.8, 129.1, 129.0, 128.4, 128.1, 126.3, 117.6, 113.9, 100.6, 55.0, 53.6, 47.5, 36.1. HRMS: m/z calcd for [M + H⁺] C₂₂H₂₃N₂O₄S: 411.1379; found: 411.1360.

36

Typical Experimental Procedure for the Synthesis of Thieno[3,2- e ][1,4]diazepinediones 9 and 10
A solution of acid 8 in AcOH was magnetically stirred at reflux for 1-6 h. The resulting solution was concentrated under reduce pressure and triturated with Et₂O to afford the corresponding thienodiazepine 10. This procedure can be directly applied to the crude mixture of acids 7 and 8, after evaporation of volatile material, to attain a one-flask protocol directly to thienodiazepines 9 and 10. The workup remains the same.
(S)-1-(4-Methoxybenzyl)-3-benzyl-3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione (10e): orange solid, mp 66-68 ˚C; [α]_D ^²0 +27.5 (c 0.1, DMSO). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.50 (d, 1 H, J = 3.5 Hz), 7.81 (d, 1 H, J = 5.3 Hz), 7.37-7.20 (m, 6 H), 7.03 (d, 2 H, J = 8.5 Hz), 6.81 (d, 2 H, J = 8.6 Hz), 5.23 (d, 1 H, J = 15.5 Hz), 4.89 (d, 1 H, J = 15.5 Hz), 4.17 (m, 1 H), 3.68 (s, 3 H), 3.24 (dd, 1 H, J = 13.8, 5.3 Hz), 2.98 (dd, 1 H, J = 13.5, 9.0 Hz). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 168.6, 162.8, 158.4, 140.4, 137.8, 130.8, 129.5, 128.9, 128.4, 128.2, 126.5, 124.9, 122.7, 113.9, 55.0, 55.0, 48.6, 34.3. HRMS: m/z calcd for C₂₂H₂₁N₂O₃S [M + H⁺]: 393.1273; found: 393.1298; R _f = 0.4 (CHCl₃-EtOAc, 4:1).

37

General SPS Procedure
Wang bromide resin (5.0 g, 1.6 mmol/g) was swollen in 50 mL of DMF, treated with anhydride 1 (2.03 g, 12.0 mmol) and K₂CO₃ (2.21 g, 16.0 mmol) for 1 h at r.t. and sequentially washed with H₂O, DMF, and CH₂Cl₂ to afford the beige resin-bound anhydride 11. Thienodiazepine resin 13 was synthesized by treating a suspension of resin 11 (0.400 g, 0.56 mmol) in DMF-H₂O (10 mL, 4:1) with the respective amino acid (500 mol%) and Et₃N (1000 mol%) for 5 h at 50 ˚C, and then washed with DMF, H₂O, and CH₂Cl₂. Thienodiazepines 14 were obtained by treating diazepine resin 13 (0.400 g, 0.52 mmol) with TFA-CH₂Cl₂ (8 mL, 1:1) for 24 h.
(S)-3,4-Dihydro-3,4-dimethylthieno[3,2-e][1,4]diazepine-2,5-dione (14b): beige solid, mp 191-194 ˚C; [α]_D ^²0 +51.6 (c 0.1, DMSO). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 10.91 (s, 1 H), 7.78 (d, 1 H, J = 5.1 Hz), 6.80 (d, 1 H, J = 5.1 Hz), 4.20 (q, 1 H, J = 6.9 Hz), 2.93 (s, 3 H), 1.34 (d, 3 H, J = 7.0). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 169.2, 162.5, 138.1, 131.4, 128.5, 121.3, 54.7, 30.8, 12.6. HRMS: m/z calcd for C₈H₁₁N₂O₂S [M + H⁺]: 211.0541; found: 211.0575.