Synthesis of l,4-benzodiazepine-2,5-diones

Featuring a cyclisation-assisted cleavage strategy (cf. Chapter 1.7), first described by Camps et al., Mayer et developed a solid-phase synthesis of 1,4-benzodiazepinediones. 

---

Faggi C, Marcaccini S, Pepino R, Pozo MC (2002) Studies on isocyanides and related compounds synthesis of l,4-benzodiazepine-2,5-diones via Ugi four-component condensation. Synthesis 18 2756-2760... 

Mayer, J. P. Zhang, J. Bjergarde, K. Lenz, D. M. Gaudino,J. J. Solid-Phase Synthesis of l,4-Benzodiazepine-2,5-diones, Tetrahedron Lett. 1996, 37, 8081. 

An elegant two-step synthesis of l,4-benzodiazepine-2,5-diones was reported by Keating and Armstrong [84], Products 148 arising from the Ugi-4CR reaction between anthranilic acids, 1-isocyano-l-cyclohexene 1, aldehydes, and amines were converted into l,4-benzodiazepine-2,5-diones 149 on treatment with methanolic HC1 (Scheme 2.54). 

A solid-phase extension of the UDC strategy for the preparation of highly pure and diverse arrays of l,4-benzodiazepine-2,5-diones has been reported. The method employed Wang resin-bound a-amino adds [75]. Another interesting solid-phase synthesis of l,4-benzodiazepine-2,5-diones was reported by Chen et al. [18b] that employed the Rink-isocyanide resin as the convertible isocyanide. 

Boojamara GC, Burow KM, Thompson LA, Ellman JA, Solid phase synthesis of l,4-benzodiazepine-2,5-diones. Library preparation and demonstration of synthesis generality, J. Org. Chem., 62 1240-1256, 1997. 

The solid phase synthesis of many organic molecules utilizes carbodiimide mediated reactions. An example is the synthesis of l,4-benzodiazepine-2,5-dione using EDCCl in NMP in a key synthesis step. Often carbodiimides are used in the synthesis of complex proteins. A recent example is the synthesis of the tripeptide backbone of the novel immunosuppressent sanglifehrin A. In the synthesis of the marine alkaloid, variolin B, the formation of an annelated pyrimidine ring is achieved using a carbodiimide mediated cyclization process. 

C. G. Burow, K. M. Thompson, L. A. Ellman, J. A. Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-diones. Library Preparation and Demonstration of Synthesis Generality, Boojamra, J. Org. Chem. 1997,62, 1240. 

An alternative procedure for the solution-phase preparation of 1,4-benzodiaze-pine-2,5-diones was reported by Hulme et al. [85]. This method combines the UDC strategy and the use of the convertible 1-isocyano-l-cyclohexene 1. The Ugi-4CR between 1, N-Boc-protected anthranilic acids, amines, and aldehydes afforded the N-Boc-protected Ugi adducts 150 which, on treatment with HCl/MeOH or 10% TFA in DCE underwent N-deprotection, cyclohexenamide cleavage, and cydi-zation to the desired l,4-benzodiazepine-2,5-diones 151 (Scheme 2.55). Hulme and Cherrier [74a] reported another high-yield one-pot solution-phase synthesis of 1,4-benzodiazepine-2,5-diones that used ethyl glyoxylate in a Ugi-4CR to give 152 and then 153 (Scheme 2.55). 

Moroder L, Lutz J, Grams F, Rudolph-Bohner S, Osapay G, Goodman M, Kolbeck W, A new efficient method for the synthesis of 1,4-benzodiazepine-2, 5-dione diversomers, Biopolymers, 38 295-300, 1996. 

Semiautomated Parallel Synthesis A Library of l,4-Benzodiazepine-2,5-Diones... 

A recent paper by Boojamra et al. (145) rejxMted the synthesis of a 2508-membered SP discrete library L4 of l,4-benzodiazepine-2,5-diones, further exploiting the first... 

Hui X, Desrivot J, Bories C, Loiseau PM, Franck X, Hocquemiller R, Figadtae B (2006) Synthesis and antiprotozoal activity of some new synthetic substituted quinoxalines. Bioorg Med Chem Lett 16(4) 815-820. doi 10.1016/j.bmcl.2005.11.025 Hulme C, Tang S-Y, Bums CJ, Morize 1, Labaudiniere R (1998) Iminoved procedure for the solution phase preparation of l,4-benzodiazepine-2,5-dione libraries via Armstrong s convertible isonitrile and the Ugi reaction. J Org Chem 63(22) 8021—8023. doi 10.1021/jo980622r Humplett WJ, Lamon RW (1964a) 4-Thiazoline-2-thiones. 1. The Stmcture of intermediate... 

Boojmara CG, Burow K, Ellman JA. An expedient and high-yielding method for the solid-phase synthesis of diverse l,4-benzodiazepine-2,5-diones. J Org Chem 1995 60 5742-5743. 

Another early solid-phase synthesis focused on preparing l,4-benzodiazepine-2, 5-diones, a structure common to many different classes of drugs.20 The route started with preparation of a custom resin-linker (9.61) (Scheme 9.10). The resulting resin was divided into 10 equal portions. Each portion was mixed with a different a-amino acid in the presence of NaBH(OAc)3 to form amine 9.62 (Scheme 9.11). Each of the 10 different batches of amine 9.62 was in turn evenly divided into 12 portions for a new total of 120 individual batches of resin. Each batch was loaded into a tube with a fritted bottom. The... 

The synthesis of these heterocycles was approached using two similar strategies. Fmoc-amino acid-derivatized Wang resins were N-deprotected (87) and coupled with either o-nitrobenzoic acid or N-Fmoc-anthranilic acid (88 and 89). Reduction of the nitro group with 2 m Sn( l, /DMF or Fmoc cleavage with piperidine/DMF, respectively, produced 90, which was cyclized with NaOtBu/THF at 60 °C. Extraction of the crude materials yielded 11 different l,4-benzodiazepine-2,5-diones 91 in yields of 45-80% with an average purity of 90% (Scheme 24) [39]. 

An efficient conversion of 5-chloro-)V-methylisatoic anhydride and glycine into 7-chloro-l-methyl-3,4-dihydro-lJT-l,4-benzodiazepine-2,5-dione has been described. Further reaction of its (V-acetyl derivative with phenylmagnesium chloride followed by treatment with hydroxylamine and then sodium bisulphite provides another new synthesis of Diazepam in ca. 50% overall yield. The 1,4,5-benzotriazocinium salts (103), prepared by the cyclization of (2-chloro-acetamido)benzophenone ATV-dimethylhydrazones (102), reacted with sodium methoxide in a Stevens-type reaction to give 3-amino-l,4-benzodiazepin-2-ones (104) in good yield. The same products were also obtained by direct treatment of (102) with base. 

Zhu and co-workers developed a palladium- and copper-catalyzed procedure for the synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and l,4-benzodiazepine-2,5-diones. A distinctly different catal3ffic property of palladium and copper catalysts was uncovered that leads to the development of a divergent synthesis of two... 

In 2008, Cipolla and Nicotra, focused on the synthesis of conformationally constrained l,4-benzodiazepine-2,5-diones (97-101), containing both a monosaccharide, fructose and a proline moiety (Fig. 28). ° The D-proline moiely is connected to fructose through a spiro junction that provides a high conformational rigidity. 

Boojl995 Boojamra, C.G., Burow, K.M. and Ellman, J.A., An Expedient and High-Yielding Method for the Solid-Phase Synthesis of Diverse l,4-Benzodiazepine-2,5-diones, J. Org. Chem., 60(1995) 5742-5743. 

---