Synthesis of 1,4-benzodiazepines

Reagents and conditions i) Bpoc-OPh, KH ii) a) KH. b) tBuLi, 3-butenyl-chiorodimethylsilane iii) a) nBuLi, b) tBuLi, c) MejSnCI iv) 9-BBN, then HjO  

Protection of 4-bromoaniline 166 as the 2-(4-methylphenyl)isopropyl carbamate (Mpc group) and sequential deprotonation, lithium-halogen exchange and trapping of the aryl anion with 

(Aminomethyl)polystyrene resin 29 was then directly acylated with 177 in NMP to give resin 178. 

except for the carbamate deprotection of the Mpc group. While treatment of silyl-linked 180 with 3% TFA caused no detectable 2-aminobenzophenone cleavage from the resin, 181 showed less stability under acidic conditions. Cleavage of the Bpoc carbamate (as in the silicon 

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Scheme 3.5 Synthesis of 1,4-benzodiazepin-2-ones (83) by cyclative cleavage [172].

Marcaccini S, Miliciani M, Pepino R (2005) A facile synthesis of 1, 4-benzodiazepine derivatives via Ugi four-component condensation. Tetrahedron Lett 46 711-713... 

Bunin, B. A., Ellman, J. A. (1992) A general and expedient method for the solid phase synthesis of 1,4-benzodiazepine derivatives./ Am ChemSoc 114, 10997-10998. 

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. 

Reactions between 1,5-bis nitrogen nucleophiles and 1,2-bis electrophile equivalents have been used in the synthesis of 1,4-benzodiazepines (67AHC(8)2l). Chloroacetyl chloride has been much used as the two-carbon fragment in the synthesis of 2-oxo-1,4-benzodiazepine systems, e.g. (356) and (357) (68CRV747). 

The most selective example is represented by the synthesis of 1,4-benzodiazepin-2,5-diones 37 via Ugi reaction with different a-aminoesters. The use of aromatic aldehyde 35 leads in some cases to very high stereoselectivity in the preparation of intermediate 36, and a single diastereoisomer is isolated after crystallization (Scheme 1.15) [43]. 

Scheme 2.53. Synthesis of 1,4-benzodiazepine-5-ones by Ugi-4CR/N-deprotection/SNAr.

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). 

SCHEME 9.11 Solid-phase parallel synthesis of 1,4-benzodiazepine-2,5-diones20... 

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. 

C Boojamra, K Burow, L Thompson, J. Ellman. Solid-phase synthesis of 1,4-benzodiazepine-2,5-diones. Library preparation and demonstration of synthesis generality. J Org Chem 62 1240-1256, 1997. 

The solid-phase synthesis of 1,4-benzodiazepines has been conducted using a traceless silicon anchor 8g that was prepared via a preformed handle. Cleavage from the resin was effected with HF [352] because the anchoring group was inert to concentrated aqueous TFA due to the highly electron-deficient character of the benzodiazepine ring. 

Benzodiazepine-2,5-diones represent a versatile pharmacophore with a wide range of pharmaceutical utility which can function as opiate receptor antagonist, anticonvulsant agents ° and glycoprotein mimics. Goff et alT developed a solid-phase synthesis of 1,4-benzodiazepine-... 

Considerable attention continues to be paid to the synthesis of 1,4-benzodiazepines. Medazepam and a number of related products have been synthesised from 2-benzoyl aryltriflates <94tl9189> and two syntheses of imidazo[4,5-e][l,4]diazepin-8-ones are reported <94CHEio26>, <94H(38)1oo7>. 9H-... 

Scheme 4.14 Synthesis of 1,4-benzodiazepines through domino N-alkylation/ring open-...

As early as 1985, a palladium-catalyzed carbonylative procedure for the synthesis of 1,4-benzodiazepines was reported. Starting from 2-haloanilines and amino acids, the desired seven-membered heterocycles were formed in moderate yields. More recently, an efficient, one-pot method for the synthesis of dibenzodiazepinone derivatives involving copper-catalyzed tandem C-N bond formation was reported. Using various halo amide and 2-iodoaniline derivatives as substrates, an array of dibenzcxliazepinone... 

Bunin, B.A. and Ellman, J.A. (1992) A General and Expedient Method for the Solid-Phase Synthesis of 1,4-Benzodiazepine Derivatives,/. Amer. Chem. Soc., 114, 10646-10647. 

Shirakawa, Hiyama, and coworkers demonstrated the straightforward synthesis of 1,4-benzodiazepine and 1,5-benzodiazocine derivatives by the insertion of ar5mes into five- and six-membered cyclic urea derivatives [105]. When the reaction was carried out in the presence of CsF at room temperature, the desired products were formed in 53-89% yields (Scheme 78). 

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