Reactivity Study of 1H-Thieno[3,2-d][1,3]oxazine-2,4-dione toward the Synthesis of Bicyclic 3,4-Dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione Analogues

Abstract

A series of 10 optically pure 3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione derivatives has been synthesized in 41-75% yields on treatment of 1H-thieno[3,2-d][1,3]oxazine-2,4-dione with different natural alpha-amino acids.

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

“…19 As expected, a slow (8-24 h) but completely selective nucleophilic attack was observed to afford the amides 7 as detected by LC-MS. Reaction time can be drastically reduced to five minutes by a preactivation of the a-aa with Et 3 N to afford at room temperature the same amides 7 with the same total selectivity (Scheme 2).…”

“…Nonetheless, this alternative solid-phase approach with a-aa (where R 3 = H) did not give higher yields and purities than our previously reported solution-phase protocol. 19 On the other hand, in accordance with our previous solution study with N-alkylated a-aa, simply heating the reaction mixtures of the solid-supported amides 12a-h (where R 3 = alkyl) at 50°C in DMF-H 2 O (4:1) for five hours directly afforded the corresponding resin-bound thienodiazepines 13a-h. These observations demonstrated that partial cis conformation induced by N-alkylation (R 3 π H) is essential for a cyclization in nonacidic conditions, in both solution-and solid-phase approaches.…”

“…18 Surprisingly, the selectivity of this nucleophilic attack can be satisfyingly reversed in favor of the carboxylic carbonyl to restore an isatoic anhydridelike reactivity in neutral protic conditions (amide 4, route A, Scheme 1). 19 This unexpected result demonstrated that the basicity of the medium and the nature of the solvent have a great importance in the course of the reaction. Supported by a kinetic study of the reactions of amines with isatoic anhydride, 20 we hypothesized the existence of an isocyanate intermediate 2 for which the formation could be subordinated to ionization of oxazine 1 in basic conditions, directing the nucleophilic attack toward the formation of the ureidodiacid (3, Scheme 1).…”

“…19 In our previous studies, we demonstrated that 1H-thieno [3,2-d] [1,3]oxazine-2,4-dione (1) reacts in an opposite way to isatoic anhydride when treated by a-amino acids (a-aa) in basic protic or aprotic conditions to afford ureidodiacid (3) by oxazine ring opening at the carbamic carbonyl (route B, Scheme 1). 18 Surprisingly, the selectivity of this nucleophilic attack can be satisfyingly reversed in favor of the carboxylic carbonyl to restore an isatoic anhydridelike reactivity in neutral protic conditions (amide 4, route A, Scheme 1).…”

Synthesis of Thieno[3,2‐e][1,4]diazepin‐2‐ones: Application of an Uncatalysed Pictet–Spengler Reaction

“…In this context, we have recently described a general synthetic protocol to generate new thieno [3,2-e] [1,4]diazepin-2,5-diones B by regioselective ring opening of 2-thiaisatoic anhydride A by α-amino acids, followed by intramolecular cyclocondensation reaction. [26] This methodology was further extended to the solid phase by using N-alkylated α-amino acids that led to C3,N4-substituted thieno [3,2-e] [1,4]diazepin-2,5-diones B (Figure 1). [27] More recently, diversity was introduced by Nsubstituted thienodiazepinedione ring opening with a series of organomagnesium bromides and subsequent cyclization to afford 5-arylthienodiazepin-2-one C analogues (Figure 1).…”