Eco-friendly synthesis of 1,4-benzodiazepine-2,5-diones in the ionic liquid [<Emphasis Type="Italic">bmim</Emphasis>]Br

The green reaction of isatoic anhydrides with α-amino acids in presence of the ionic liquid 1-butyl-3-methylimidazolium bromide afforded 1,4-benzodiazepine-2,5-diones in excellent yields in absence of a catalyst. The reaction workup is simple and the ionic liquid was easily recovered from the reaction and reused. The methodology was quite general and a range of cyclic and acyclic α-amino acids were examined to produce 1,4-benzodiazepine-2,5-diones. Correspondence: Khosrow Jadidi, Department of Chemistry, Shahid Beheshti University, PO Box 1983963113, Tehran, Iran.     

Clean synthesis of azo compounds using Magtrieve? in the ionic liquid [bmim][Br]

A series of azo compounds, N-aryl-2-phenyldiazenecarboxamides, and 4-substituted-1,2,4-triazoline-3,5-diones, were synthesized using Magtrieve™, a magnetically retrievable and recyclable oxidant, in the ionic liquid [bmim][Br] under neutral condition. This procedure has several advantages, such as greenness, mild reactions, simple manipulation, and reusability of reagent and solvent.     

Solid-phase synthesis of 7-acylamino-1,4-benzodiazepine-2,5-diones

A method for the synthesis of polymer-bound 7-acylamino-benzodiazepine-2,5-diones is described. The amino group of an alpha-amino acid is linked to polystyrene or TentaGel resin via reductive amination of polymer-bound 4-alkoxy-2,6-dimethoxybenzaldehyde. Acylation with unprotected 5-nitroanthranilic acid is followed by base-catalyzed ring closure. Reduction of the nitro group yields enantiomerically pure 7-aminobenzodiazepin-2,5-dione attached via the N-4 atom to the resin. Acylation of the amino group on the aromatic ring with acid chlorides in N-methylpyrrolidone (no DMF, no base!) followed by cleavage from the resin using TFA/Me(2)S/water (90:5:5) provides the acylated benzodiazepinones in 52-69% (PS resin) and 41-48% (TG resin) yield (based on the theoretical loading) and >70% purity (HPLC, 210 nm). Using Fmoc-protected tyrosine fluoride in NMP gives the amino acid-coupled benzodiazepinones in 24% (PS resin) and 31% (TG resin) yield.     

Solid-phase synthesis of 4-methylcarboxy-1,4-benzodiazepine-2,5-diones

A solid-phase synthesis of 1,4-benzodiazepinone-2,5-diones is described. This new route can afford benzodiazepinone bearing a N-urethane-protected amine and a carboxylic acid function. This kind of building block is valuable as a dipeptide mimic or beta-turn mimetic, and it can be introduced in place of any amino acid in peptide synthesis. Using an "analytical probe" strategy, we optimized the synthesis of a model compound on SynPhase Lanterns. Therefore, the efficiency of several linkers was investigated.     

Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

Liquid-phase combinatorial synthesis of 1,4-benzodiazepine-2,5-diones as the candidates of endothelin receptor antagonism

A library of 1,4-benzodiazepine-2,5-dione dicarboxylate derivatives containing aryl substituents at N(1)- and N(4)-positions to mimic the amino acid residues of Try-13, Phe-14, and Asp-18 in endothelin-1 is established by using the starting materials of alpha-amino esters, hydroxybenzaldehydes, nitrobenzoyl chlorides, and benzyl bromides in a polyethylene resin-bound liquid-phase synthesis. All of the six synthetic steps are conducted under mild conditions to give the desired products with reasonable yields and purity. The poly(ethylene glycol) support plays as a part of ester linkage that is released at the final step.     

Highly enantioselective synthesis of rigid, quaternary 1,4-benzodiazepine-2,5-diones derived from proline

[reaction: see text] Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality.     

Synthesis of novel 4-amino-1,4-benzodiazepine-2,5-diones for anticonvulsant testing

A series of novel 4-amino-1,4-benzodiazepine-2,5-diones was synthesized via two pathways. The first method involved reductive alkylation of unsymmetrical hydrazines with glyoxylic acid, followed by Fisher esterification. The resulting N-aminoglycinate ethyl ester was subsequently o-nitrobenzoylated, reduced, and thermally cyclized to obtain 4-dialkylaminobenzodiazepinones. In the second method methylhydrazine was acetylated at N_α then benzoylated at N_β to give 1,2-diacylhydrazines. Alkylation with ethyl bromoacetate and reduction of the nitro group, followed by thermal cyclization yielded 4-acetamidobenzodiazepinones. All title compounds were evaluated in mice in MES seizure and sc Met seizure threshold tests for anticonvulsant activity, and in the rotorod test for neurotoxicity. Activity and toxicity were both minimal.     

Novel Efficient Method for Synthesis of N_(1,4)-Disubstituted-1,4-benzodiazepine-2,5-diones

A novel and efficient method was developed for the liquid-phase synthesis of N1,4-disubstituted-benzodiazepine-2,5-diones with 2-chloro-5-nitrobenzoic acid as initiating material via 4 step reactions containing esterification,Ulmn reaction,acylation,alkylation and cyclization. The reaction conditions were mild and the overall yields of the products ranged from 45% to 71%.     

Synthesis of 4-substituted pyrano[4,3-b]pyran-2,5-diones in an ionic liquid

The mildly basic ionic liquid N,N,N,N-tetramethylguanidinium triflate (TMGTf) was found to be a very effective solvent for the reaction between 4-hydroxy-6-methyl-2H-pyran-2-one, Meldrum's acid, and aldehydes to afford some novel pyrano[4,3-b]pyran-2,5-diones in high yields at room temperature. The stages, through which these reactions might proceed, depend largely on the nature of the aldehyde substrates. The reaction of aliphatic aldehydes has given access to some novel carboxylated products.     

One pot conversion of azido arenes to N-arylacetamides and N-arylformamides: synthesis of 1,4-benzodiazepine-2,5-diones and fused [2,1-b]quinazolinones

Sodium iodide in acidic media has been employed for the synthesis of N-arylformamides and N-arylacetamides. The NaI/acetic acid reagent system has also been extended for the synthesis of 1,4-benzodiazepine-2,5-diones, pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones, and fused [2,1-b]quinazolinones.     

Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones

A simple, green and catalyst free one pot synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazolidine-2, 4-dione (TZD), aromatic aldehyde and urea analogues is described. The ionic liquid has been used as a solvent as well as catalyst for this reaction. This reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, simple experimental workup procedure and no by-products.     

Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, pK_a, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.     

A new resin-bound universal isonitrile for the Ugi 4CC reaction: preparation and applications to the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones

[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.