2.3- Disubstituted benzodiazepines

Several 2- and 2,3-disubstituted benzodiazepines have been prepared by reactions involving o-phenylenediamine and 3-ketoaldehydes/2-hy-droxymethyleneketones (67JPR166 70JOU450 70ZOR450 79MI1), and a... 

Disubstituted benzodiazepines appear to be more readily hydrolyzed than 2,4-disubstituted analogs (67CB584). Hydrolysis involves attack at the 2- or 4-positions, and this is easier in the absence of a blocking substitutent. 

An alternative approach to the synthesis of benzodiazepines involves the reaction of /3-chlorovinyl carbonyl compounds with o-phenylenedi-amine. In the first example methyl /3-chlorovinyl ketone was used to obtain 5-methylbenzodiazepinium chloride.31 An extensive investigation has been made of the use of /3-chlorovinylaldehydes for the preparation of 2,3-substituted benzodiazepines.3233 The preferred conditions for reaction were in alcoholic hydrogen chloride. By this means a variety of 2-aryl-, 2,3-cycloalkeno-, and 2,3-diarylbenzodiazepines was prepared. If no acid is present an uncyclized anil results, formed by condensation of one amino group with the aldehyde. Since the /3-chlorovinylaldehydes are themselves readily obtained by reaction of a-methylene ketones with phosphoryl chloride and N, JV-dimethylformamide or jV-methylformani-lide,34 this provides an attractive route to 2,3-disubstituted benzodiazepines. 

The deprotonation of C-3 substituted l,4-benzodiazepin-2-ones with JCHMDS afforded an enantiopure, conformationally chiral enolate with a relatively bulky N — I substituent, which provided a sufficient barrier to enolate racemization. In contrast, LHMDS proved to be ineffective in this transformation, and KHMDS served as an operationally simpler alternative to a mixed base consisting of LDA/n-BuLi. At —100 °C a simultaneous addition of KHMDS and an excess of benzyl bromide to the substrate provided the alkylated product in 75% ee (78% yield). However, the simultaneous addition could not be carried out with a more reactive benzyl iodide. Ultimately, the best result was achieved in a stepwise addition mode, when the deprotonation with KHMDS (20 min) at — 109°C (THF-HMPA) was followed by the addition of an excess of benzyl iodide affording the 3,3-disubstituted benzodiazepine in 97% ee (93% yield) (eq 68). ... 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

Although the Sonogashira-coupling of heterocycles is usually limited to their bromo and iodo derivatives, in certain cases the cross-coupling might also be achieved on activated chloro compounds. The chloro derivative shown in 8.23. was coupled with trimethylsilylacetylene.32 In another example the imidoyl chloride subunit of the 5-chloro-1,4-benzodiazepine derivative shown in 8.27. coupled efficiently with phenylacetylene to give the expected disubstituted acetylene derivative.15... 

For the final step involving functionalization at N( ) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the N( 1 )-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinox-alinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid. 

The parent ion is observable in most of the spectra that have been recorded, and in some instances it is the base peak. An M+ - 28 ion also appears in most examples,11,16,30,43,103,104,135 accurate mass measurements having shown this to arise from loss of N2.103 Breakdown patterns for three substituted aryl derivatives (62, Scheme 21) are essentially the same as for their benzodiazepine isomers.103 Some examples have been reported in which extrusion of a disubstituted alkyne by a reverse 1,3-dipolar cycloaddition reaction is an important process.135... 

Benzodiazepine synthesis has been reviewed (B-91MI906-01). The method generally applied the appropriately o-disubstituted benzene with a 1,3-bis carbon electrophile, e.g. o-phenylenedia-mine + RCOCHR COR — (389) — (390) for 1,5-benzodiazepines. 

LY300164, an orally administered benzodiazepine developed by Eli Lilly (India-napolis/IN, USA), is efficaceous against amylotropic lateral sclerosis (ALS, Lou Gehrig s disease). In an early key step, a 3,4-disubstituted phenylacetone is reduced to the (S)-alcohol by yeast whole cells from Zygosacchamyces rouxii (ATCC 14462) in > 99.9% e.e. and 96% yield. The subsequent steps encompass a series of chemical steps (Figure 13.30). Volumetric productivity is optimized in remarkable fashion the ketone substrate is introduced adsorbed on an XAD-7 resin to keep the concentration in solution (2 g L-1) below the toxicity limit (6 g L-1). Product alcohol likewise is adsorbed so that a loading of 80 g L-1 of substrate or product is achieved. 

X-ray crystal structures have also been reported on two 1,5-benzodiazepine bases, the 2,4-disubstituted base (26) (88JHC305) and the N-substituted base (27) (79CSC981), wherein a diimine structure is not possible. 

No diazo coupling took place between less-reactive benzenediazo-nium chloride and 2,4-disubstituted (methyl or phenyl) benzodiazepines (81JHC1341). 

Benzodiazepines 392 are generally prepared from the appropriately o-disubstituted benzene (e.g., 0-phenylenedia-mine) and a 1,3-bis carbon electrophile (Scheme 210) . For example, acetylated derivatives of BaylisHillman adducts 393 derived from ethyl acrylate and aromatic or heteroaromatic aldehydes readily react with 0-phenylenediamine under the influence of base to provide l,4-benzodiazepin-2-ones 394 in good overall yields (Scheme 211) <2006S4205>. 

A trifluoroacetic acid-catalyzed PictetSpengler reaction between the N,N-disubstituted aniline 93 and aromatic or aliphatic aldehydes afforded fused 1,4-benzodiazepines 94 in high yields after stirring at reflux in acetonitrile for 1648 h (Scheme 49). Electron-deficient aromatic aldehydes provided the best yields of 94, attributed to facile imine formation, while ketones were uniformly unreactive <2006T2563, CHEC-III(13.06.9.1.8)212>. 

Disubstituted-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine derivatives, (VI), prepared by Kronenthal (4) were effective as farnesyl protein transferase inhibitors and used in the treatment of colon cancer and other proliferative diseases. 

Willy B, Dallos T, RomingerE, Schonhaher J, Muller TJJ (2008) Three-component synthesis of cryofluorescent 2,4-disubstituted 3H-l,5-2 benzodiazepines - conformational control of emission properties. Eur J Org Chem 4796-4805... 

Irradiation of 2,4-disubstituted 1,5-benzodiazepines with a high-pressure mercury arc under an oxygen atmosphere yields 2-acylquinoxalines as oxidative ring-contraction products. A solvent effect is observed in these reactions. ... 

A methodology for the synthesis of analogs of asmarine, marine alkaloids with a unique tetrahydro[l,4]diazepino[l,2,3-g,h]purine 120 (THDAP) strueture has been developed. Three cyclization methods were applied for the preparation of the 9,9-disubstituted 10-hydroxy-THDAP system aminomereurization, iodocyclization and acid-catalyzed cychzation <05JOC199>. A series of 2-phenyl[l,2,3]triazolo[l,2-a][l,2,4]benzotriazin-l,5-diones 121 have been synthesized and identified as affinity central benzodiazepine-receptor ligands <05JMC2936>. 

Oxazepam (116) can be converted into a range of 3-(disubstituted-amino) derivatives, in moderate yield, by its reaction with the appropriate 2-amino-4,5-dihydro-l,3,2-dioxaphosphole. A direct route to the 3-amino-derivatives has also been reported.l,3-Dihydro-2//-l,4-benzodiazepin-2-ones react with most isocyanates to give the 1-carbamoyl derivative however, (114), on reaction with trichloroacetyl isocyanate and subsequent hydrolysis, gave the 3-amido-derivative. The latter has been converted into a range of 3-esters.Continuing work on the electrolytic reduction of 2,3-dihydro-l,4-diazepinium salts has shown that the AW-dibenzyl-6-phenyl-compound gives a diazepine dimer and an unexpected rearrangement product, which is 1,4-di-imidazolidinyl-butadiene. ... 

R= -Bu) afforded l,3-benzodiazepin-4-one (22). With 15 (R=cyclohexyl), amixture of indole-3-carboxamide (25%) and l,3-benzodiazepin-4-one (58%) was obtained. The latter cyclized product probably arises from a nitrogen-copper species. In a full account of their indole syntheses methodology, Saegusa presented more examples of the chemistfy already given in this chapter, plus a new application was the synthesis of 2,3-disubstituted indoles 24. Thus, as shown in equation 4 (Scheme 3) base-induced alkylation of ortto-(acylmethyl)phenyl isocyamides 10 prior to cyclization led to 2,3-disubstituted indoles 24 [5]. 

As an efficient bifunctional catalyst, proline has been used as a Br0nsted acid in combination with a nucleophilic Lewis base catalyst in the asymmetric BH reaction. Miller and co-workers [119] disclosed that in the L-proline-catalyzed BH reaction of MVK and electron-deficient aldehydes the imidazole-tailed peptide 67 was an efficient co-catalyst. A matched/mismatched phenomenon of two chiral catalysts was observed in this reaction. Furthermore, Zhou and co-workers [120] synthesized various chiral amines and screened them as co-catalysts of L-proline in the BH reaction of MVK and aldehydes, revealing that chiral benzodiazepine 68 and aminoalcohol 69 were efficient catalysts. Interestingly, the intramolecular reaction shown in Scheme 9.34 could be directly catalyzed by L-proline in DMF solvent, while the addition of imidazole resulted in enhancement of the enantioselectivity with opposite configurational product [121]. A similar process was realized in the intramolecular reaction shown in Scheme 9.35 with 70 as co-catalyst of iV-methylimidazole. Moreover, Cordova and co-workers [122] reported in 2007 the first example of asymmetric aza-BH reaction between (3-mono- or disubstituted acroleins and aldimines. By utilizing L-proline as catalyst in combination with... 

Jiang et al. [108] introduced a gallimn(lll) triflate-catalyzed [4+2 + 1] cycloaddition reaction for the synthesis of a new class, 3,4-disubstituted-l,5-benzodiazepines (144), containing only a C=C bond without C=N bond in the heterocyclic moiety (Scheme 37). The reaction of o-phenylenediamines (142) and alkynoates (ethyl propiolate) (143) xmder solvent-free and ultrasonic irradiation conditions was accomplished in 10 min at 25 °C, whereas the traditional method at 25 °C took Ih. Products were obtained in 82-90% yield. 

SCHEME 3 7 Synthesis of 3,4 disubstituted-l,5-benzodiazepines using gallivun(lll) as catalyst. 

SCHEME 40.17. Synthesis of disubstituted 1,4-benzodiazepine via carboamination reaction of aniline derivative. 

A new series of 2,4-disubstituted-2,3-dihydro substituted-1,5-benzodiazepine derivatives was synthesized by the condensation of o-phenylenediamine and various 1-(4 -substituted phenyl)-3-(3-mono-, or 4-mono-, or 3,4-di-, or 3,4,5-tri-sub-stituted phenyl)-2-propene-l-one under microwave irradiation. The modification of coupling microwaves with the solvent-free technique is an easy, rapid, efficient and convenient protocol for the synthesis of 1,5-benzodiazepines. The microwave irradiation is better over the classical reflux heating because the solid-supported reactions gave better yield (58-86%) and these reactions were completed within 4-6 min in comparison to hours under conventional heating. However, it was observed that long exposure time to the microwave irradiation resulted in decomposition of compounds to dark tarry mixtures (Sharma and Joshi, 2012). 

---