synthetic strategies applicable in the synthesis of privileged scaffold: 1,4-benzodiazepine

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Synthetic Strategies Applicable in the Synthesis ofPrivileged Scaffold: 1,4-benzodiazepineNavjeet Kaur a & Dharma Kishore aa Department of Chemistry , Banasthali University , Banasthali , Rajasthan , IndiaAccepted author version posted online: 15 Aug 2013.

To cite this article: Synthetic Communications (2013): Synthetic Strategies Applicable in the Synthesis of Privileged Scaffold:1,4-benzodiazepine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic OrganicChemistry, DOI: 10.1080/00397911.2013.772202

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT 1

Synthetic strategies applicable in the synthesis of privileged scaffold: 1,4-benzodiazepine

Navjeet Kaur1, Dharma Kishore1 1Department of Chemistry, Banasthali University, Banasthali, Rajasthan, India

E-mail: [email protected]

Abstract

The development of new synthetic approaches to the 1,4-benzodiazepine ring system and

their further elaboration have provided access to a broad range of functionalized

derivatives. In this review an attempt has been made to summarize those synthetic

strategies involved for the synthesis of ‘privileged scaffold’ 1,4-benzodiazepine in with

progress of time.

KEYWORDS: 1,4-benzodiazepine, Catalytic, Combinatorial, Microwave,

Photochemical, Ionic liquid and Synphase Lanterns synthesis.

INTRODUCTION

The search for efficient and mild methodologies for the preparation of heterocycles is a

challenge of increasing impact for chemists involved in the construction of organic

molecules with enhanced complexity and chemical diversity.[1]

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Compounds containing diazepine moieties are of significant interest in medicinal and

pharmaceutical research due to their important biological activities. Among them 7-

membered ring 1,4-benzodiazepine heterocycles have captured the imagination of

medicinal and organic chemists for the past 50 years. Besides being core unit of

commercial drugs such as diazepam, oxazepam, laurazepam, anthramycin, and

mazhethramycin; there are numerous diazepines that are described with anti-

inflammatory, anticancer, anti-HIV, antibacterial, herbicidal, PAF receptor antagonist

anxiolytic, anticonvulsant, anti-ischemic, sedative, hypnotic, and muscle relaxant

activities. Benzodiazepines fused with other heterocyclic systems are reported to possess

tranquilizing, antispasmodic, and prenasrcotic properties. They are well-known CNS

depressant, and are also used as antitumor and antibiotics.[2–5]

The synthesis of these analogues and homologues filed a patent application in May 1958

claiming 2-amino-1,4-benzodiazepine-4-oxides bearing various substituents in the benzo

and phenyl rings. Because of the novelty of these products, the patent was granted within

a year (July 1959) and without difficulty. Bunin et al. synthesized a small library of 192

molecules and screened these compounds against the cholecystokinin A receptor yielded

active compounds. Subsequently, a larger library of 1680 1,4-benzodiazepines was

synthesized and screened against a number of receptor and enzyme targets. Inhibitors of

pp60s-src tyrosine kinase and ligands that block an autoimmune DNA-antibody

interaction implicated in systemic lupus erythematosus were identified.[6,7]

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Owing to their versatile applications various methods for the synthesis of

benzodiazepines have been reported for their preparation. Conversely, the commonly

employed methods involve the reactions of o-phenylenediamines with α,β-unsaturated

carbonyl compounds, with ketones in the presence of NaBH4, polyphosphoric acid or

SiO2, Al2O3/P2O5 or AcOH under microwave conditions, amberlyst-15 in the ionic liquid

1-butyl-3-methylimidazoliumbromide ([bmim]Br), CeCl3·7H2O/NaI supported on silica

gel, InBr3, Sc(OTf)3, sulfated zirconia, InCl3, CAN, ZnCl2 under thermal conditions,

AgNO3, cyclocondensation of 1,2-diamines with ketones, enones, β-haloketones, using

ytterbium triflate, BF3-etherate, polyphosphoric acid, MgO and POCl3, ionic liquids,

under microwave irradiation, SbCl3-Al2O3 and zinc montmorillonite heterogeneous

catalyst, Ag3PW12O40, CH3COOH, MCM-41 zeolite, piperidine-AcOH, intramolecular N-

arylation, anti-aminopalladation/β-hydride elimination, ring-expansion of anhydrides

with amines, Mitsunobu reactions, 1,3-dipolar cycloaddition, electrophilic aromatic

substitution, and multicomponent reactions especially those using amino acids etc.

Survey of literature shows various method of benzodiazepine synthesis suffers from one

or other limitations such as harsh reaction conditions, expensive reagents, low yields,

relatively long reaction time, and formation of side products. The main disadvantage of

the existing methods is that the catalysts are destroyed in work-up procedure and cannot

be recovered or re-used.[8–10]

The interest in understanding conformational aspects of monocyclic 1,4-benzodiazepines

in the context of peptidomimetics has stimulated the development of new preparative

methodologies and procedures designed to improve limitations associated with

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previously established routes to these compounds. Synthetic approaches to 1,4-

benzodiazepines are generally well described, but the development and application of

new methodology, particularly using transition metal catalysis, has resulted in innovative

bond-construction strategies that broaden the range and nature of functionality both

within the ring and incorporated into substituents. Moreover, the well-established utility

of 1,4-benzodiazepines as drug scaffolds in medicinal chemistry has provided a

significant impetus to develop combinatorial, microwave, photochemical, ionic liquid,

and synphase lanterns assisted synthesis that allow access to large numbers of structurally

diverse compounds suitable for high-throughput screening campaigns. The search is still

being continued for a better methodology for the synthesis of benzodiazepines in terms of

simplicity, reusability, environmentally friendly, and economic viability could be

achieved. This review article will highlight these synthetic strategies for the synthesis of

novel 1,4-benzodiazepine derivatives.

Synthetic Strategies Applicable For Synthesis Of 1,4-Benzodiazepines

Conventional Synthesis

The first compounds of this type were prepared in 1891 by Auwers and von

Meyenburg[11] by treatment of amino-or acetaminoacetophenone oximes with a

Beckmann mixture (Scheme 1).

Treatment of anthranilic acid with chloral gave the imine, which could in turn be reacted

with phenyhdrazine to give the intermediate, whose further ring closure and acetylation

with acetic anhydride provided 1,4-benzodiazepine (Scheme 2).[12]

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It has been shown that treatment of the amide with PhMgBr yields the benzodiazepine

(Scheme 3).[13]

1,4-benzodiazepine-2,5-diones prepared precursors from anthranilic acids using the Ugi

reaction, a four-component process that allowed considerable structural diversity to be

introduced in a combinatorial fashion (Scheme 4).[14]

In their synthesis of 1,4-benzodiazepin-2,5-diones, Ellman and co-workers[15] employ the

lithium salt of acetanilide as a base in their N-alkylation procedure of their compounds

(Scheme 5).

The most extensively used methods for preparing 1,4-benzodiazepines begins with an

ortho-aminobenzophenone (Scheme 6). The first step involves treatment of the

appropriate aminobenzophenone with haloacetyl halide to afford the amide, followed by

the addition of ammonia to first displace the chlorine giving the glycinamide. Then

cyclization by imine formation will give the benzodiazepine.[16]

Structurally related nitrile imines, generated in situ, add to the pendant alkene to afford

fused 1,4-benzodiazepin-3-one and 1,4-benzodiazepin-5-one derivatives depending upon

the oxidation state at C-3 and C-5 of the starting material (Scheme 7).[17]

The first example of 1,4-benzodiazepine-5-one that incorporates an unsubstituted 2,3-

carbon-bond was obtained by hydrolyzing the acetal in THF in the presence of

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Amberlyst-15 resin. Subsequent heating of the product in toluene with azeotropic

removal of water gave the 1H-benzo[e][1,4]diazepin-5(4H)-one (Scheme 8).[18]

In the optimized cyclization conditions developed by Dr. Polo Lam of the Carlier

research group (Virginia Tech, 2003) de-blocking of the carbamate occurs with

trifluoroacetic acid (TFA) in dichloromethane (DCM) to give the free amine. This is

followed by cyclization under conditions of a 1:1 mixture of NaHCO3:NH4Cl at pH 7 in

methanol (Scheme 9).[19]

Early attempts at synthesizing 1,4-benzodiazepin-2-one enantiomerically enriched

benzodiazepines by reacting enantiomerically pure (S)-phenyl alanine hydrochloride (S)

with 2-amino-5-chlorobenzophenone by refluxing in pyridine (Scheme 10).[19]

Condensation of an amino acid-derived anilide and a ketoamide afforded 1,4-

benzodiazepin-2-ones in which the initially formed imine tautomerizes to an exocyclic

enamide (Scheme 11).[20]

Reaction of diamine with benzotriazole and formaldehyde produced N,N-bis(1H-1,2,3-

benzotriazol-1-ylmethyl)-N-[2-(N-methylanilino)ethyl]amine[21] which on treatment with

AlCl3 removed only one benzotriazolyl moiety to form 4-benzotriazolylmethyl-1-methyl-

2,3,4,5-tetrahydro-1H-1,4-benzodiazepine via the intramolecular Friedel-Crafts reaction

(Scheme 12).

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The intramolecular alkylation of an aryl amide by an activated bromide, readily available

by bromination of a malonamide methylene with pyridinium tribromide provided an

example of a ring closure to furnish 3-carboxymethyl-1,4-benzodiazepin-2,5-diones

(Scheme 13).[22]

The ring-closure reaction afford 1,4-benzodiazepines in a 7-endo-trig-process in which a

substituted iminium derivative, typically generated in situ, is captured by the aryl ring

(Scheme 14).[23]

The reaction of 2-aminobenzylamine with the reactive diketonitrile, derived from aspartic

acid, in CH2Cl2 proceeded smoothly to furnish the 1,4-benzodiazepin-3-one (Scheme

15).[24]

Reaction of the dilithio anion of 1-vinylbenzotriazole with an aryl isocyanate led to a

fused 1,4-diazepine ring formation via an intramolecular Michael addition of the

intermediate aryl amide to the vinyl moiety (Scheme 16).[25]

Racemic 3-amino-2,3-dihydrobenzo-1,4-diazepine-2-ones were obtained when

amidobenzotriazoles were exposed to a saturated solution of NH3 in MeOH (Scheme

17).[26]

Heating ethylenediamine with methyl 2-chloro-3-nitrobenzoate and Na2CO3 in butanol at

80oC effected a dual SN2Ar/acylation reaction to afford 9-nitro-3,4-dihydro-1H-

benzo[e][1,4]diazepin-5(2H)-one (Scheme 18).[27]

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The oxidation of N-alkoxyamides with phenyliodine(III)bis(trifluoroacetate) (PIFA)

afforded an acyl nitrenium ion (Scheme 19) that under acid catalysis was trapped by a

pendant phenyl ring, a process that has been used to prepare synthetic precursors to the

antitumor antibiotic.[28]

Aryl fluorides are suitable substrates for ring closures in the absence of transition metal

catalysis when activated by the presence of a powerful electron-withdrawing substituent

(Scheme 20).[29]

Acylation of α-amino esters with 2-azidobenzoylchloride gives the corresponding 2-

azidobenzoyl derivatives which, on treatment with phosphines, form iminophosphoranes

and cyclization products via the tandem Staudinger/intramolecular aza-Wittig reaction,

providing a simple route to 1,4-benzodiazepin-5-ones (Scheme 21).[30]

A number of procedures based on intramolecular cycloaddition protocol have been

developed, including the intramolecular cycloaddition of an aryl azide to an alkene which

provides triazolino-fused diazepine derivatives that extrude upon heating (Scheme 22).[31]

The key step in most syntheses of tetrahydro-1,4-benzodiazepin-3-ones is closure of the

heterocyclic ring by intramolecular nucleophilic aromatic substitution (Scheme 23). To

accelerate substitution, a carboxyl ester or a nitro group is usually placed para to the

leaving group.[32]

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Substituted 1,4-benzodiazepine-3,5-diones can be prepared by capturing an amide with a

carboxylic acid that has been activated as the mixed anhydride (Scheme 24).[33]

Heating N-[2-(arylamino)phenyl]amides under strongly acidic conditions or with

powerful chlorinating agents like phosphoryl chloride effects a Bischler–Napieralski-type

cyclization to afford 1,4-benzodiazepine derivatives (Scheme 25).[34]

Pipecolic acid derived N-1,4-benzodiazepin-2,5-dione was prepared from reacting R/S

pipecolic acid with isatoic anhydride in DMSO and heating at 160°C for 3 hours,

followed by stirring at room temperature overnight (Scheme 26).[35]

Initially, isatoic anhydride was allowed to react with benzylamine and chloroacetyl

chloride. The generated dipeptide derivative was then cylized to 1,4-benzodiazepine-2,5-

dione (Scheme 27).[36]

The intramolecular alkylation of a BOC-protected aniline by bromoamide using NaH in

DMF provided an example of a ring closure to 1,4-benzodiazepin-3-ones, a

straightforward and effective procedure that, surprisingly, has not been more broadly

exploited (Scheme 28).[37]

Pyrimidine fused 5,6-dihydrobenzodiazepines were prepared via a Pictet-Spengler

cyclization, (Scheme 29) based on the intramolecular electrophillic substitution of phenyl

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ring of 5-amino-6-chloro-4-(N-methylanilino)oyrimidine by iminium intermediate

formed with an aldehyde in one pot.[38]

The reaction of isatoic anhydride with p-methoxyaniline gave amide, which was

subsequently alkylated with 3-methoxybenzyl chloride to afford compound which was

subjected to amidation with methyl malonyl chloride. The product was treated with two

equivalents of sodium tert-butoxide to effect an intramolecular alkylation reaction,

forming 1,4-benzodiazepine-2,5-dione (Scheme 30).[39]

5-Chloroisatoic anhydride was heated with the hydrochloride salt of L-aspartic acid

dimethyl ester in pyridine to afford the desired 1,4-benzodiazepine-2,5-dione (Scheme

31).[40]

The parent 1,2,3-triazolo-1,4-benzodiazepine scaffold was prepared from known

aldehyde employing a reductive amination, followed by a thermally induced,

intramolecular Huisgen cycloaddition (Scheme 32).[40]

1,4-benzodiazepine is prepared from Boc protected 3-chloro-aniline via the formation of

dianion species with tert-BuLi followed by deprotection of Boc group. Chloroacetylation

of compounds with chloroacetyl chloride in the presence of N,N-diisopropylethylamine

(DIEA) in dichloromethane (DCM) gave the corresponding N-(chloroacetyl)-2-

aminobenzophenone derivatives whose reaction with hexamethylenetetramine (HMTA)

in EtOH in the presence of NH4OAc provided 1,4-benzodiazepine ring (Scheme 33).[41]

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The aromatic azido acid was prepared from anthranilic acid by diazotization reaction

using NaNO2 and dil. HCl in Et2O at 0oC followed by treatment with NaN3, which on

further reaction yielded 1,4-benzodiazepine derivative (Scheme 34).[42]

Jin-Yuan Wang et al.[43] have developed a new strategy for the synthesis of 1,4-

benzodiazepine (Scheme 35). The reaction proceeds through the N-benzylation and

highly regioselective ring-opening reaction of aziridine by bromide anion followed by

Et3N mediated intramolecular nucleophilic displacement of the bromide by the amide

nitrogen.

Benzodiazepines were readily prepared in excellent yields through the condensation of

isatoic anhydride with the appropriate L-amino acids in aqueous solution in the presence

of triethylamine followed by cyclization in refluxing glacial acetic acid (Scheme 36).[44]

Aniline derivatives on reaction with benzoyl chloride in presence of aluminium chloride

and CCl4 provided intermediate whose further reaction with hexamine/NH4Cl in the

presences of absolute ethanol produced 7-chloro-5-phenyl-1,3-dihydro-1H,3H-1,4-

benzodiazepine-2-one (Scheme 37).[45]

The treatment of diketones with glacial acetic acid for 2 h leads to pyrrolobenzodiazepine

(Scheme 38).[46]

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Peptidic coupling of substituted 2-aminobenzophenones with protected glycine in the

presence of dicyclohexylcarbodiimide (DCC) gives amides. The Boc-protecting group

was removed by treatment with hydrochloric acid in isopropanol. Finally,

benzodiazepines were obtained by cyclization using 5% acetic acid in CH2Cl2 (Scheme

39).[47]

It is interesting to note that 3H-1,4-benzodiazepines were obtained when o-

azidobenzaldimines were allowed to react with triphenylphosphane in toluene at 80°C for

8 h by Domino-Staudinger/Aza-Wittig/Isomerization reaction (Scheme 40).[48]

Base catalyzed condensation reaction of 1,2-diamines with carbonyl compounds, is an

efficient method for the synthesis of fused 1,4-benzodiazepines (Scheme 41). The

principle of reaction is similar to Friedlaender Synthesis.[49]

Condensation reaction of the o-phenylenediamine and unsaturated carbonyl compounds

in presence of 10 mol% of molecular iodine at room temperature resulted in the

formation of benzo-[b]-1,4-diazepines (Scheme 42).[50]

Reaction of N-methyl anthranilamide with the acid chloride of R-benzotriazolyl-CBZ-

glycine gave intermediate, which underwent thermal cyclization (180°C, DMSO) with

the elimination of benzotriazole. Bis(lactam) was selectively converted to the imidoyl

chloride in high yield by treatment with POCl3 and N,N-dimethylaniline at reflux for 5 h,

followed by an aqueous workup and chromatography. Alternatively the reaction can be

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performed in only a few minutes by refluxing in neat POCl3, although on a practical scale

the workup is more difficult (Scheme 43).[51]

The reaction of carboxylic acids and L-proline methyl ester, followed by hydrolysis of

the amidoesters with LiOH, and final treatment of the resulting carboxylic acids, with

methoxylamine in satisfactory yields. Nevertheless, the decisive cyclization step had to

be optimized with respect to the solvent, temperature of the reaction, and the presence of

additives. Chemistry with hypervalent iodine reagents often requires low nucleophilic

polar solvents, such as dichloromethane or trifluoroethanol (TFEA), and, in some cases,

the aid of additives, such as boron trifluoride or trifluoroacetic acid, to enhance their

activity. Cyclization of methoxyamides was best carried out in CH2Cl2 as solvent in the

absence of any additive and working at room temperature, optimal conditions to afford

pyrrolodiazepine additionally, the use of 3 equiv of TFA. Finally, the appended N-

methoxy groups were easily removed with molybdenum hexacarbonyl in refluxing

aqueous acetonitrile to afford the target pyrrolodiazepines (Scheme 44).[52]

Ugi reaction between aldehyde, amine, isonitrile, and carboxylic acid synthesized

pyrrolo[1,2-a][1,4]benzodiazepine. The Ugi condensation can be readily applied in

combinatorial chemistry approaches and is an effective synthetic method to the assembly

of differently substituted derivatives of benzodiazepine. The reaction of aldehyde acids

with the corresponding isonitriles and amines in methanol at 40°C led to novel

pyrrolo[1,2-a][1,4]diazepine heterocyclic structures. The reaction presumably follows the

same initial course as the classical Ugi condensation with an intermediate imine being

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attacked by the isonitrile to give a nitrilium intermediate, which then undergoes

intramolecular cyclization. With respect to amine component, various aliphatic and

aromatic primary amines, such as substituted anilines, linear and branched aliphatic

amines, and nitrogen-containing compounds, were tolerated without any limitations

(Scheme 45).[53]

The facile azide Ugi five-center four-component reaction yielded substituted

tetrazolo[1,5-a][1,4]benzodiazepiness. The desired tetrazolodiazepines were synthesized

by simply mixing 1 mmol of a ketone with 1.2 mmol of sodium azide, 1.2 mmol of

ammonium chloride, and 1 mmol of the corresponding isocyanide in aqueous methanol.

After 24-48 h of vigorous stirring at room temperature, the target products precipitated

from the reaction mixture (Scheme 46).[54]

N-Boc-R-amino-aldehydes have been demonstrated to be suitable bifunctional starting

materials. Thus, novel applications of Boc-glycinal were used in the Ugi-4CR for the

synthesis of BDZs utilizing the Ugi-deprotection-cyclization (UDC) strategy. Anthranilic

acid derivatives have been shown to react in the Ugi-4CR for the synthesis of 1,4-

benzodiazepine scaffolds. In the first step (Ugi), methyl anthranilate serves as an amine

component for the Ugi-4CR together with an isocyanide, Boc-glycinal, and a carboxylic

acid. The Boc protection group is cleaved in the second step (deprotection), and then the

free amine group is condensed with the orthogonal ester group to form the 1,4-diazepine

ring in the third step (cyclization). The UDC strategy allows the access of 1,4-

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benzodiazepine-6-ones with different substitutions derived from the isocyanide and

carboxylic acid inputs (Scheme 47).[55]

Microwave Assisted Synthesis

Microwave assisted synthesis approach has been applied in the synthesis of Circumdatin

E analogues (substituted quinazolinobenzodiazepine alkaloids) (Scheme 48).[56]

Use of microwaves to facilitate a 7-exo aza-Michael cyclization event sets substitution

patterns on BDZ arising from the bifunctional substrates o-nitrobenzaldehyde or o-

nitrobenzylamine (Scheme 49).[57]

Fujii, Ohno and co-workers elaborated a microwave assisted novel concise route to

indole fused 1,4-benzodiazepines (Scheme 50). They utilized N-mesyl-2-ethynylanilines

and secondary amines as precursors for a copper-catalyzed one-pot three component

coupling reaction.[58]

Application of the readily available and expendable n-butylisonitrile including N-Boc-α-

amino acids with amines and aldehydes in Ugi-deprotection-cyclization has also been

exploited to generate diketopiperazines (Scheme 51). The deployment of N-Boc-

anthranilic acids in the UDC-MMS methodology furnished 1,4-benzodiazepine-2,5-

diones.[59]

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2-(1Hbenzimidazol-2-yl)aniline derivatives resulted into the synthesis of 5H-

benzimidazo[1,2-d][1,4]benzodiazepin-6-(7H)-ones as given follows (Scheme 52):[60]

Reaction mixtures requiring only anthranilic acid/derivatives, various NH-Boc protected

amino acids, triphenyl phosphine and pyridine generated a range of natural products

(Scheme 53). This clearly demonstrates the powerful combination of MW and

multicomponent synthesis.[61]

Microwave-assisted irradiation with Ni2B for the synthesis of diazepines involving azido

reduction and cyclization afforded pyrrolo[2,1-c][1,4]-benzodiazepine-2,5-dione (Scheme

54).[62]

Yan and co-workers reported Ugi products possessing a protected amino group and an

amide underwent sequential deprotection/cyclization microwave-assisted protocol for a

solution phase fluorous parallel synthesis of a library of biaryl-substituted 1,4-

benzodiazepine-2,5-dione (Scheme 55).[63]

Application of microwave induced Delepine reaction to the facile one pot synthesis of 7-

and 5,7- dimethyl substituted, 1, 3- dihydro-2H-[1, 4] -benzodiazepin-2-one-5-methyl

carboxylate derivatives from the corresponding 1-chloroacetyl isatin has been described

(Scheme 56).[64]

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Veena Yadav et al. has developed an efficient microwave assisted protocol for the

exclusive one pot synthesis of N-amino-methyl substituted 1,4-benzodiazepine

derivatives by the reaction of N-amino-methylsubstituted isatoic anhydride with glycine

and L-proline respectively has been described (Scheme 57).[65]

An efficient synthesis of 1,4-benzodiazepin-2-ones is described by condensation between

2-aminobenzophenone and Boc-protected amino acids via microwave-assisted irradiation

(Scheme 58).[66]

The 2-methyl-1,4-benzodiazepin-5-ones were synthesized by Santagada and co-workers

through microwave-assisted intramolecular azide cycloaddition reaction in DMF at a

ceiling temperature of 80oC (Scheme 59).[67]

Photochemical Synthesis

Irradiation of the potassium salts of N-phthaloylanthranilamide at 300 nM in aqueous

acetone afforded 1,4-benzodiazepin-5-ones after a photoinduced decarboxylation that

generated a radical, which was trapped by the carbonyl moiety (Scheme 60).[68]

Reaction of 4-fluoro-3-methyl-benzoic acid with (Boc)2O and oxalyl chloride/MeOH

afforded methyl derivative; subsequent treatment with NBS in CCl4 under photochemical

irradiation afforded methylenebromo derivative. Reactions of methylenebromo derivative

with allyamine and subsequent couplings with (S)-Boc-Ala-OH provided product whose

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cyclization followed by loss of the Boc group at 125°C in DMSO, yielded the desired

product (Scheme 61).[69]

Catalytic Synthesis

Benzophenone derivative on treatment with tert-butyl alcohol resulted in displacement of

the activated chlorine with tert-butylamine, which were further chloroacetylated with

chloroacetyl chloride and provided 1,4-benzodiazepin-2-one with catalyst SnCl2 (Scheme

62).[70]

This is a method to synthesize a set of oxaproline derived 1,4-benzodiazepin-2,5-diones

that did not involve NH-free oxaproline (Scheme 63).[71]

The benzodiazepine-3-one an intermediate in the synthesis of a glycoprotein antagonist,

was isolated in 56% yield after oxidation of the substituted hydroquinone using Fremy’s

salt under acidic conditions (Scheme 64).[72]

Heating a solution of (S)-2-amino-N-butyl-N-(2-iodobenzyl)propanamide in toluene at

85oC in the presence of 10 mol% Pd2(dba)3/CHCl3, the bidentate phosphine ligand 2,2-

bis(diphenyl-phosphanyl)-1,1-binaphthyl (BINAP) and Cs2CO3 or t-BuOK, as base,

promoted ring closure to the 1,4-benzodiazepine-3-one (Scheme 65).[73]

The nitro groups was reduced to corresponding amines (S)- by use of Fe powder and

NH4Cl and the methyl ester of (S)- was hydrolyzed to corresponding sodium carboxylate

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(S)- in the presence of 2 N NaOH in CH3CN in quantitative yield. Subsequent

intramolecular amide coupling of (S)- in the presence of DCC/HOBT in CH2Cl2 at room

temperature for 18 hours afforded the desired product (Scheme 66).[74]

Tetrahydro-1,4-benzodiazepin-2-one scaffold with a protected hydroxyl group at carbon

7, was synthesized in solution phase with two different R1 groups by employing amino

acid building blocks (Scheme 67).[75]

The possibility of exploring a new Ti-/Cu-catalyzed sequential one-pot process for the

generation of 1,4-benzodiazepine-2,5-diones and 1,4-benzodiazepine-2-ones had been

envisaged (Scheme 68).[76]

The Pd-catalyzed cyclization of the allyl anthranilamide to a benzo-1,4-diazepin-5-one

was optimized to provide good selectivity for the formation of the seven-membered ring

(Scheme 69).[77]

The carbonylation of N1-(2-iodophenyl)-N1-methylbenzene-1,2-diamine, catalyzed by

Pd complexed to a silica-based dendrimer ligand, provided 5-methyl-5H-

dibenzo[b,e][1,4]diazepin-11(10H)-one (Scheme 70).[78]

Thus, the (substituted)benzaldehydes were coupled with α-amino acid derivatives, e.g.,

the esters of L-valine and L-aspartic acid, via reductive amination reactions using

NaBH(OAc)3 as the reducing agent. The resulting amines were then reacted with 2-

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nitrobenzoyl chloride (or its analogs) to afford amides. The nitro groups in were smoothly

reduced by zinc powder, and the resulting anilines, without isolation, cyclized on

treatment with p-toluenesulfonic acid to give 1,4-benzodiazepine-2,5-diones (Scheme

71).[39]

The commercially available and inexpensive isatoic anhydride was converted in a one-

pot reaction to the nitro derivative, which on further reduction with freshly prepared

SnCl2 in methanol under reflux, followed by reaction with MgCl2/DMF afforded

quinazolino[3,2-d][1,4]benzodiazepine (Scheme 72).[79]

Acid catalyzed recyclization of N-(furfuryl)anthranilamides resulted into pyrrolo[1,2-

a][1,4]benzodiazepine-5-one under heating at 60-70oC in AcOH in the presence of conc.

HCl (Scheme 73).[80]

Peptidic coupling of 2-aminobenzophenone with suitably protected alanine or lysine

could be achieved by the in situ formation of acyl-fluoride compounds with the use of

tetramethylfluoroformamidinium hexafluorophosphate (TFFH). Boc and Cbz protecting

groups were completely removed respectively by treatment with 20% trifluoroacetic acid

(TFA) in methylene chloride and by Pd-catalyzed hydrogenolytic cleavage. Cyclization

to obtain the diazepine core was achieved using 5% of acetic acid in methylene chloride

(Scheme 74).[81]

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N-1,4-disubstituted-benzodiazepine-2,5-diones is obtained from 2-chloro-5-nitrobenzoic

acid as initiating material via 6 step reactions containing esterification, Ulmn reaction,

acylation, alkylation and cyclization (Scheme 75).[82]

The Pd-catalyzed coupling with 4-bromobiphenyl afforded 1,4-benzodiazepine (Scheme

76).[83]

When a solution of N-(5-methylfurfuryl)-2-nitrobenzamide in AcOH was heated with Fe

to reflux and then the reaction mixture kept for 1 h at room temperature, the target

pyrrolobenzodiazepines were formed via reduction and their one pot cyclization (Scheme

77).[84]

Condensation of α-aminonitriles with 2-nitrobenzoyl chloride gives the corresponding

Schiff bases, which furnish, upon reduction with Zn, the corresponding 2-amino-3,4-

dihydro-5H-1,4-benzodiazepin-5-ones (Scheme 78).[85]

In an attempt to develop an analogous synthetic route for the 2-amino-3H-1,4-

benzodiazepine through the condensation of α-aminonitrile with 2-nitrobenzaldehyde was

investigated (Scheme 79).[85]

Compound on etherification with quinazolinone precursors using K2CO3 in acetone

provided the corresponding nitro thioacetals. Further, reduction of nitro compounds by

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using SnCl2.2H2O in methanol followed by deprotection employing HgCl2/CaCO3

afforded the desired PBD conjugates (Scheme 80).[86]

The nitro group was reduced to the amine with SnCl2.2H2O in methanol to afford amine

derivative, followed by protection of the amine with Fmoc-Cl in dioxane. Cleavage of the

diethyl thioacetal group with HgCl2/CaCO3 resulted in immediate ring closure to the

Fmoc-protected carbinolamine (Scheme 81).[86]

Recently, Joshua et al. has reported the synthesis of saturated 1,4-benzodiazepines via

Pd-catalyzed carboamination reactions using sodium tert-butoxide base and xylene as a

solvent at refluxing condition (Scheme 82).[87]

Fries rearrangement was carried on anilide derived from Cbz-Val-OH. The presence of

the benzylic carbamate in the substrate prevented the photochemical reaction from taking

place with formation of several byproducts. Thus, reaction was carried out on anilide

derived from N-Boc-Ala-OH (R1) Me, (R2) H, that gave intermediate in acceptable

yields under standard conditions. This compound was then coupled with Cbz-Gly-OH

with DCC/DMAP. Benzodiazepines were then obtained in 70% yield after treatment with

ammonium formate in the presence of Pd-(OH)2/C (20%) in i-PrOH in a microwave

monomode cavity (Scheme 83).[88]

N-4-Hydroxy-1,4-benzodiazepines were synthesized in a single step from synthetically

versatile acylnitroso-derived hetero-Diels-Alder cycloadducts. Treatment of anthranilic

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acid based cycloadduct with palladium(0) was anticipated to induce a cycloadduct ring

opening, followed by an intramolecular nucleophilic attack on the palladium allyl

complex to form the 1,4-benzodiazepine core. N-tosyl cycloadduct was chosen in the

pursuit of benzodiazepine formation. Cycloadduct was synthesized, from anthranilic acid.

The tosyl group was introduced by reacting with p-toluenesulfonyl chloride and sodium

carbonate, to give N-tosyl anthranilic acid. An EDC coupling of acid and the acylnitroso

hetero-Diels-Alder reaction give the desired N-tosyl cycloadduct. Treatment of

cycloadduct with palladium(0) provided the targeted benzodiazepine. To increase the

yield of benzodiazepine formation, the pKa was lowered further by incorporating a nitro

group onto the sulfonamide. Coupling of acid with O-tert-butyldimethylsilyl

hydroxylamine followed by removal of the silyl protecting group provided hydroxamic

acid. Oxidation of the hydroxamic acid in the presence of cyclopentadiene gave the

desired cycloadduct in 81% yield from acid. Treatment of cycloadduct with palladium(0)

provided benzodiazepine (Scheme 84).[89]

By employing an intramolecular Pd(0)-mediated ring opening of an acylnitroso-derived

cycloadduct, new hydroxamic acid containing benzodiazepines have been synthesized.

Subsequent N-O bond reduction of the hydroxamate has provided access to amide

analogues. Treatment of cycloadduct with Pd(OAc)2 and PPh3 at 40°C for 10 min

generated nitrone. Oxazoline N-oxides are versatile synthons and have been used in[3+2]

cycloadditions. After isolation and purification, re-subjection of nitrone to Pd(OAc)2 and

PPh3 in refluxing THF gave benzodiazepine. Several palladium reagents were explored

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and the polymer-bound triphenylphosphine-Pd(0) emerged as the most practical due to

the ease of product isolation and increased yield (Scheme 85).[90]

The N-allylisatoic anhydrides were reacted with 3-bromopropylamine hydrobromide in

the presence of triethylamine as base. The purified allylamino benzamides slowly self-

condensed and were directly protected as the stable trifluoro-acetamides. The allylic

double bond was subjected to ozonolysis followed by quenching with dimethyl sulfide.

The resulting crude hemiaminal intermediates were dehydrated in refluxing toluene with

camphorsulfonic acid (CSA) as catalyst to afford the bicyclic enamides. The pivotal step,

the tributyltin hydride mediated radical cyclization afforded the ring-closure tricyclic

compounds in excellent yields. The trifluoroacetyl groups were removed in methanolic

aqueous potassium carbonate solution to yield the amino compounds. The benzyl

protecting group was removed by palladium-carbon-catalyzed hydrogenation using

ammonium formate as the hydrogen source (Scheme 86).[91]

The triazolobenzodiazepine which bears an R-amino nitrile function would be a useful

point of embarkation for the preparation of a number of tricyclic and tetracyclic analogs.

The benzodiazepine scaffold was thus prepared in 69% overall yield from aldehyde via a

facile two-step sequence that involved a Strecker reaction as the MCAP, followed by a

dipolar cycloaddition. Careful control of temperature in this conversion is essential

because elimination of hydrogen cyanide to produce the known imine is observed at

temperatures above 60oC. N-Acetylation of the R-aminonitrile gives an amide that

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undergoes dipolar cycloaddition at room temperature to afford benzodiazepine in 96%

yield (Scheme 87).[92]

A new synthesis of 1,4-benzodiazepines and 1,4-benzodiazepin-5-ones is reported. The

Pd-catalyzed coupling ofN-allyl-2-aminobenzylamine derivatives with aryl bromides

afforded the heterocyclic products in good yield. Although much effort has been directed

towards the construction of unsaturated 1,4-benzodiazepines, fewer methods for the

synthesis of saturated derivatives have been developed (Scheme 88). [93]

Synphase Lanterns Based Synthesis

1,4-Benzodiazepine is prepared in four steps on SynPhase Lanterns (Scheme 89). The

synthesis involves the attachment of a pre-formed 2-aminobenzophenone

hydroxymethylphenoxy compound to aminomethylated Lanterns. The solid supported

primary aniline is then acylated with an Fmoc protected amino acid fluoride. Subsequent

Fmoc deprotection followed by acid-catalysed intramolecular cyclisation generates a 1,4-

benzodiazepine.[94]

Ionic Liquid Based Synthesis

The green reaction of isatoic anhydrides with amino acids in presence of the ionic liquid

1-butyl-3-methylimidazolium bromide afforded 1,4-benzodiazepine-2,5-dione in

excellent yields in absence of a catalyst (Scheme 90).[95]

Combinatorial Synthesis

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The synthesis of 1,4-benzodiazepine-2,5-diones is initiated by loading an R-amino ester

onto the aldehyde-derivatized support by reductive amination employing NaBH(OAc)3 in

DMF with 1% AcOH (Scheme 91).[96]

In one of the early reports of small molecule library synthesis, DeWitt and co-workers

described an alternative strategy (Scheme 92) by treating each of five amino acid resins

with each of eight 2-amino benzophenone imines for the synthesis of 1,4-benzodiazepin-

2-ones.[97]

A[[2-(4-biphenyl)isopropyl]oxy]carbonyl (Bpoc)-protected (aminoaryl)stannane, which is

prepared in four steps in solution, is coupled to the solid support through the HMP linker.

Stille coupling can then be carried out with a range of different acid chlorides and the

catalyst Pd2(dba)/CHCl3 (Scheme 93).[98]

Plunkett and Ellman[99] have also demonstrated a silyl linkage strategy for the synthesis

of benzodiazepine derivatives (Scheme 94).

A synthetic route to the 1,4-benzodiazepine-2,5-dione class was also reported by

Zuckermann and co-workers[100] at Chiron (Scheme 95). In this study the 1,4-

benzodiazepine-2,5-dione was synthesized from the N-terminus of a support-bound

peptoid intermediate.

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Fmoc protected 2-aminobenzophenone by treatment with piperidine in DMF and

coupling on R-N-Fmoc amino acid fluoride, followed by removal of the Fmoc protecting

group by treatment with piperidine in NMP in presence of 5% AcOH, resulted in

synthesis of benzodiazepine derivative on solid support (Scheme 96).[101]

Bhalay et al.[102] synthesized tetrahydro-1,4-benzodiazepin-2-ones on the solid phase

Wang resin in a single cyclization/cleavage step via a 7-exo-trig cyclization (Scheme 97).

The reductive alkylation of resin-bound primary amine with different substituted o-

nitrobenzaldehydes generated a secondary amine, which was treated further with methyl

chlorooxoacetate. The nitro group was reduced with tin(II) chloride. During the overnight

reduction, an in situ intramolecular cyclization occurred to provide, following HF

cleavage, the desired 4,5-dihydro-1H-1,4-benzodiazepine-2,3-dione (Scheme 98).[103]

Polymer bound 4-N-naphthylethyl-1,4-benzodiazepine-2,5-dione was synthesized on

Merrifield resin. The alkoxide from diol was condensed with the Merrifield resin and

were chlorinated using triphenylphosphine and triphosgene. N-(R)-(+)-1-(1-

Naphthyl)ethane-2-aminobenzamide was prepared from R-(+)-1,1-ethylnaphthylamine

and K2CO3. The amidation step of the o-aminobenzamide supported on solid phase was

performed with bromoacetyl bromide in the presence of TEA and DMAP to give the

resins o-amidonaphthylbenzamide. The use of sodium methoxide in refluxing methanol

yielded naphthylamide. The last reaction involved the detachment of benzodiazepine

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from the polymeric support by treatment with THF/TFA (1:1) for 30 min to obtain N-

naphthylethylamine-1,4-benzodiazepine-2,5-dione (Scheme 99).[104]

The resulting 1,4-benzodiazepine-2-one scaffold was loaded onto the 4-formyl-3,5-

dimethoxyphenoxy (PL-FDMP) resin by reductive amination in high yield (>95%), even

when only 1.5 equiv of the scaffold was used (Scheme 100).[105]

Heating the Wang resin-bound anthranilic ester at 150oC with a primary amine in a

microwave apparatus effected a tandem N-alkylation-intramolecular cyclization that

proceeded with concomitant cleavage of the 1,4-disubstituted-1,4-benzodiazepine-2,5-

dione product from the resin (Scheme 101).[106]

PEG5000 monomethyl ether is used as the support to construct a library of 1,4-

benzodiazepine-2,5-diones. As the target 1,4-benzodiazepine-2,5-dione requires an N4-

aryl substituent, we deliberately used the PEG-bound benzaldehydes to couple with the

esters of α-amino acids (Scheme 102).[39]

A novel and efficient strategy has been developed to synthesize privileged tetrahydro-1,4-

benzodiazepines with excellent yields and purities; this synthetic pathway was

established by the revitalization of the Leuckart-Wallach (LW) reaction via solid phase

synthesis (Scheme 103).[107]

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The simple amination of the bromoacetal resin with primary amines in dimethyl sulfoxide

(DMSO), the resulting secondary amine was coupled with anthranilic acid or chloro-

anthranilic acid. The reductive amination of an aldehyde or ketone in dimethylformamide

(DMF) resulted in compound (Scheme 104).[108]

The N-benzylation of the resin under the reported conditions gave the N-Benzylated

anthranilate resin, which on further reaction with N-Fmoc-protected phenylalanine in the

presence of POCl3 and pyridine in CH2Cl2 at room temperature afforded the amino acid

coupled anthranilic resin. Deprotection of the resin in 20% piperidine-DMF at room

temperature directly furnished the 1,4-benzodiazepine-2,5-dione derivative (Scheme

105).[109]

Line S. Laustsen et al.[109] has developed an efficient solid-phase method for the parallel

synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives (Scheme 106). A key step

in this procedure involves catching crude 2-aminobenzoimine products on an amino acid

Wang resin.

The novel protocol was established for the resin-bound anthranilic acid derivatives for the

preparation of the 1,4-benzodiazepine-2,5-dione derivatives with amino-related

benzamido functionality at the 7-position from the resin intermediate (Scheme 107).[110]

CONCLUSION

In conclusion, we reported on a various methods for the generation of 1,4-

benzodiazepines, which are relevant heterocycles for medicinal chemistry. Efforts

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towards the exploration of new synthetic methods are of great interest with aim to access

more sustainable processes, taking advantage of the concepts of green chemistry and

step-economy in multistep syntheses. The aim of this review was to demonstrate the wide

synthetic strategies of 1,4-benzodiazepines.

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ACCEPTED MANUSCRIPT


86. Ahmed, K.; Rajesh, V. C. R. N. C. S.; Janaki, R.; Swapna, P.; Reddy, K. S.;

Mallareddy, A.; Narasimha M. P.; Mukesh, C.; Sastry, G. N.; Aarti, J.; Surekha, Z.;

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ACCEPTED MANUSCRIPT


103. Adel, N.; Nhi, A. O.; Richard, A. H. Tetrahedron Lett 2001, 42, 5141.

104. Ignacio, A. R.; Margarita, P.; Socorro, H.; Domingo, M.; Georgina, P. L.; Daniel,

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2004, 6, 207.

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Herbertz, T. Angew Chem Int Ed Engl 2005, 44, 5830.

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Dow

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3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 1.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 2.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 3.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 4.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 5.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 6.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 7.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 8.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 9.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 10.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 11.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 12.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 13.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 14.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 15.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 16.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 17.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 18.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 19.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 20.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 21.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 22.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 23.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 24.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 25.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 26.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 27.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 28.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 29.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 30.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 31.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 32.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 33.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 34.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 35.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 36.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 37.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 38.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 39.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 40.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 41.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 42.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 43.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 44.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 45.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 46.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 47.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 48.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 49.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 50.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 51.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 52.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 53.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 54.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 55.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 56.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 57.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 58.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 59.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 60.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 61.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 62.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 63.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 64.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 65.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 66.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 67.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 68.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 69.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 70.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 71.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 72.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 73.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 74.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 75.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 76.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 77.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 78.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 79.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 80.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 81.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 82.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 83.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 84.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 85.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 86.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 87.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 88.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 89.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 90.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 91.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 92.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 93.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 94.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 95.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 96.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 97.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 98.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 99.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 100.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 101.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 102.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 103.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 104.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 105.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 106.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

ACCEPTED MANUSCRIPT


Scheme 107.

Dow

nloa

ded

by [

Uni

vers

ity L

ibra

ry U

trec

ht]

at 0

3:21

31

Aug

ust 2

013

synthetic strategies applicable in the synthesis of privileged scaffold: 1,4-benzodiazepine

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