a simple and advantageous synthesis of the privileged 1, 4

Research ArticleA Simple and Advantageous Synthesis of the Privileged14-Benzodiazepine Nucleus

Neetu Jain and Dharma Kishore

Department of Chemistry Banasthali University Banasthali Rajasthan 304022 India

Correspondence should be addressed to Neetu Jain toneetuyahoocom

Received 30 April 2014 Revised 5 July 2014 Accepted 11 July 2014 Published 11 August 2014

Academic Editor Hideto Miyabe

Copyright copy 2014 N Jain and D Kishore This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

A novel domino approach has been described for an easy access of the privileged nucleus of 5-carbomethoxy substituted14-benzodiazepin-2-ones 4(andashi) from an in situ methanolic hydrolysis of an incipient species formed from the interactionof 1-chloroacetylisatin 2(andashi) hexamethyldisilazane and n-butyl lithium The reaction is believed to take place through aconsecutive series of intramolecular reactions in a cascade to first generate a highly reactive carbene intermediate 3(andashi) from1-chloroacetylisatin and n-butyl lithium which is simultaneously trapped by hexamethyldisilazane before undergoing its in situhydrolysis with methanol to initiate its concomitant cyclocondensation to produce 4(andashi) in high yield and purity

1 Introduction

Exploration of synthetic processes that lead to the develop-ment of small molecules of medicinal interest by telescopingthemulticomponent operations into a single step or resortingto a process such as domino reactions is a rapidly emergingsubject in medicinal chemistry Ever since Koch et al [1]carried out a quantitative analysis of physiologically activenatural product scaffolds and showed that ones with twoor three rings were most often found in bioactive naturalproducts the interest on various facets of the chemistryof small molecules has expanded exponentially thereafterBenzodiazepines and their analogues have been recognizedrecently to belong to the class of privileged heterocyclicstructures [2ndash5] by virtue of their ability to form ligands toa number of functionally and structurally discrete biologicalreceptors [6ndash13] This property stimulated chemists to utilizetheir potential in the design and development of molecularprobes for biological evaluations Ubiquitous presence of thisnucleus in the psychopharmacologically active agents and inmolecules active against HIV infection for example TIBO(1) [14ndash17] and FDA approved dipyrido diazepine analoguenevirapine (2) [18ndash24] in Figure 1 provided an impetusfor an enormous research effort to be directed towards

the development of their structural analogues of medicinalimportance [25 26]

2 Results and Discussion

This communication reports the application of a noveldomino process for an easy access of the privileged nucleusof 5-carbomethoxy substituted 14-benzodiazepin-2-ones4(andashi) from the ring expansion of 1-chloroacetylisatins2(andashi) initiated by hexamethyldisilazane under the influenceof n-butyl lithiumN-Butyl lithium formed an obvious choicesince it has been used as a catalyst in amination of activealkyl halides with hexamethyldisilazane Amination of 1-chloroacetylisatin (2) formed the key step in allowing it toundergo ring expansion to give 4 Ogata and Matsumotorsquos[27] original procedure which employed Delepine reactionin the amination of 2 with methanolic solution of hexamineproduced 4 in low yieldThis called out to revisit this reactionto augment the scope of this reaction in view of the yield ofthis product

It is believed that Delepine reaction proceeded with theformation of the hexaminium ion We surmise that it wasthe bulky nature of hexamine which hindered its formation

Hindawi Publishing CorporationAdvances in ChemistryVolume 2014 Article ID 628326 6 pageshttpdxdoiorg1011552014628326

2 Advances in Chemistry

N

N

N NN

HN

O

S(O)

HN

Cl

CH3

CH3

H3C1 2

H3C

Figure 1

from 2 We assumed that this problem could possibly becircumvented by carrying out the amination of 2 with lessbulkier agents In consideration of the potential of hex-amethyldisilazane [28] in amination reaction in our initialattempt we replaced hexamine with this reagent Howevercontrary to our expectation 2 resisted its reaction with thisreagent and caused it to be recovered unchanged from thereaction mixture A search for possible use of a catalyst inthis reaction revealed that n-butyl lithium has been used inaminations employing hexamethyldisilazane This providedoptimism for this reaction too to succeed with the use ofthis catalyst This expectation turned into a reality in all theruns using a wide variety of substituted 1-chloroacetylisatinderivatives to produce 4 in an exceptionally high yield andpurity (Table 1)

We suggest that this reaction proceedswith the base catal-ysed dehydrochlorination of 2 to generate an acyl carbeneintermediate 3 which is subsequently trapped by hexam-ethyldisilazane The relatively small size of carbene precludesthe steric factor in the reaction with hexamethyldisilazaneThe hydrolysis of bis(trimethylsilyl) group from this withmethanol sets the stage for it to undergo ring expansion togive 4

In view of the extremely weak nucleophilic character ofisatinylamide nitrogen of 3 the possibility of the rearrange-ment of the acyl carbene intermediate had to be ruled out(No rearranged product was however traceable from thereaction mixture)

As the carbene was not likely to be trapped by thetertiary amine (hexamine) its reactionwith hexaminewas notexamined

3 Experiment

All the melting points were taken in open capillaries and areuncorrected The purity of all the compounds were checkedby TLC using the solvent systems (benzene methanol9 1 vv) and silica gel G as adsorbent IR spectra wererecorded on Shimadzu FTIR-8400 infrared spectrometerusing KBr 1H NMR were recorded on Bruker AC 300Fin CDCl

3+ DMSO-d

6(2 1 vv TMS as internal reference

and chemical shifts expressed in 120575 ppm) and mass spectra

were recorded on Jeol-JMS-D-D-300 mass spectrometerReagents 5-fluoro- 5-chloro- 5-bromo- 5-iodo- 5-methyl-5-methoxy- 5-nitro- and 57-dimethylisatins were procuredfrom commercial sources and used as such in the reactionwithout further purifications (see Scheme 1)

31 General Methods for the Preparation of 2(andashi) from 1(andashi)5-Fluoroisatin (1b 0068mol) was vigorously refluxed withchloroacetyl chloride (0090mol) for 7 h and themixturewascooled overnight at 0ndash5∘C The crude product which settledwas filtered washed with 20mL of ether air-dried and thenrecrystallised from ethyl acetate to give 2b yield 88 mp165-166∘C Other compounds 2(a cndashi) were prepared from1(a cndashi) using this procedure

32 General Methods for the Preparation of 4(andashi) from 2(andashi) 5-Fluoro-1-chloroacetylisatin (2b 001mol) was dissolvedin dry THF (20mL) and to this solution n-butyl lithium(001mol) and hexamethyldisilazane (001mol) were addedThe reactionmixture was magnetically stirred for 2 h at roomtemperature The progress of reaction was checked by TLCMethanol (20mL) was added to the reaction mass and themixture was refluxed for 5 h It was then poured on crushedice filtered air-dried and recrystallised from methanol togive 4b yield 87 mp 198ndash200∘C Other compounds 4(acndashi) were prepared from 2(a cndashi) using the same procedure

4 Conclusion

In summary a high yielding n-butyl lithium catalysedone-pot domino process has been developed to the facileaccess of the privileged nucleus of methyl-13-dihydro-2H-14-benzodiazepin-2-one-5-carboxylates 4(andashi) at ambienttemperature from the ring expansion of the corresponding 1-chloroacetylisatins 2(andashi) under the influence of hexamethyl-disilazane

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Advances in Chemistry 3

Table1Ph

ysicalandspectraldataof

thec

ompo

unds

2(andashi)and4(andashi)

Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield(

)IR

(KBr)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

2aC 1

0H6C

lNO

322361

210ndash

1291

173516801675

756ndash

719(m

4HA

rH)432

(s2HC

H2)

53715

367

270265

626618

2bC 1

0H5C

lFNO

32416

0165ndash66

88175517251700

781ndash72

3(m

3HA

rH)433

(s2HC

H2)

49714

967

249240

580569

2cC 1

0H5C

l 2NO

325806

153ndash55

94178517401720

781ndash753(m

3HA

rH)432

(s2HC

H2)

465446

42

19519

0543531

2dC 1

0H5BrC

lNO

330251

178ndash79

90178017351710

796ndash

761(m3HA

rH)432

(s2HC

H2)

39703962

16715

6463459

2eC 1

0H5C

lINO

33495

1206ndash

0789

177017251690

780ndash

750(m

3HA

rH)428

(s2HC

H2)

28952889

1211

17338327

2fC 1

1H8C

lNO

32376

4185ndash86

92176517201690

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

285

(s3HC

H3)

55605551

339328

589580

2gC 1

1H8C

lNO

425364

223ndash25

90178017401705

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

373

(s3HO

CH3)

52095197

318312

552542

2hC 1

0H5C

lN2O

526861

130ndash

3291

178517451710

872ndash809(m

3HA

rH)452

(s2HC

H2)

44714

456

18817

110431037

2iC 1

2H10ClNO

32516

7168ndash70

921740

17001685

740ndash

712(m

2HA

rH)432

(s2HC

H2)

235

(s6HC

H3)

57275719

401397

557546

4aC 1

1H10N

2O3

21821

172ndash75

85319017251675

80(s1HN

H)79

8ndash76

5(m

4HA

rH)

448

(s2HC

H2)365(s3HO

CH3)

MS119898119911(

)21821(M+

100

)21020

(75

)10716(35

)

60556048

462452

12841279

4bC 1

1H9FN

2O3

23620

198ndash200

87322017351690

82(s1HN

H)808

(d1HA

rH)77

8(d

1HA

rH)

766(s1HA

rH)456

(s2HC

H2)378

(s3HO

CH3)

MS119898119911(

)23620(M

+75)20517

(100)17716(35

)

55935588

384379

11861176

4cC 1

1H9C

lN2O

325265

176ndash

7884

321517281684

81(s1H

NH)79

0(s1HA

rH)78

1(d

1HA

rH)

760(d1HA

rH)448

(s2HC

H2)370

(s3HO

CH3)MS119898119911(

)25265(M

+100

)25457

(M+2

33

)

52295223

359351

11091100

4dC 1

1H9BrN

2O3

2979

8243ndash45

86320817211675

80(s1HN

H)79

0(s1HA

rH)77

5(d

1HA

rH)

750(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)MS119898119911(

)29798(M

+100

)2999

0(M

+2100)17716(35

)

444744

41

305299

94393

6

4eC 1

1H9IN

2O3

34411

187ndash88

90320017101670

80(s1HN

H)78

5(s1HA

rH)76

6(d

1HA

rH)

740(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

MS119898119911(

)344

11(M

+75)20517

(100)14716(35

)

3839

3829

264

259

814807


Table1Con

tinued

Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield

()

IR(K

Br)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

4fC 1

2H12N

2O3

23224

205ndash06

85318817231672

80(s1HN

H)78

4(s1HA

rH)75

6(d

1HA

rH)

742(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

234

(s3HC

H3)

MS119898119911(

)23224(M

+72)1772

5(25

)1491

7(100)

62606252

521517

12061196

4gC 1

2H12N

2O4

24808

182ndash85

87320217281677

80(s1HN

H)78

8(d1HA

rH)77

5(d

1HA

rH)

743(s1HA

rH)433

(s2HC

H2)312

(s3HO

CH3)

363

(s3HO

CH3)

MS119898119911(

)24808(M

+68)24011

(100)16345

(36

)

58065798

487479

11291119

4hC 1

1H9N

3O5

26305

202ndash05

83322817351698

80(s1HN

H)812

(s1HA

rH)79

8(d

1HA

rH)

766(d1HA

rH)455

(s2HC

H2)342

(s3HO

CH3)

MS119898119911(

)26305(M

+65)20117

(100)17080

(35

)

50205013

345334

15961589

4iC 1

3H14N

2O3

24626

215ndash17

88318517201670

80(s1HN

H)74

0(s2HA

rH)430

(s

2HC

H2)

310

(s3HO

CH3)234(s3Hfor

two

CH3)

MS119898119911(

)246

26(M

+100

)14517

(86

)10416

(27

)

63406331

573569

11381133

a Allthem

eltingpo

ints(M

P)w

erefou

ndto

beidenticalto

thea

uthenticsamples

prepared

accordingto

thep

rocedu

rerepo

rted

intheliterature

[22]

MWMolecular

Weightcaldexpcalculatedexp

erim

ental


O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

CHR2

R2

R2

R2R2

R1

R1

R1

R1

R1

R1

R2

N

N

N

N

N

N

CC C

C

CH2Cl

n-BuLi THF

NH

SiMe3

SiMe3SiMe3

SiMe3HN

H

H

2

Me OH

MeOOCCOOMe

H2N

CH2

N CH

Δ2(andashi) 3(andashi)

4(andashi)

1 2 3 and 4(andashi)

R1 = R2 = H

R1 = Cl R2 = HR1 = Br R2 = HR1 = I R2 = HR1 = Me R2 = HR1 = OMe R2 = HR1 = NO2 R2 = HR1 = Me R2 = Me

(a)(b)(c)(d)(e)(f)(g)(h)(i)

R1 = F R2 = H

Scheme 1 Schematic presentation of the synthesis of the compounds

Acknowledgments

The authors are grateful to the Director of CDRI LucknowIndia for providing the spectral data of the compounds and tothe Department of Science and Technology DST New DelhiIndia for providing the financial assistance to ldquoBanasthaliCentre for Education and Research in Basic Sciencesrdquo undertheir CURIE (Consolidation of University Research for Inno-vation and Excellence in Women Universities) programme

References

[1] M A Koch A Schuffenhauer M Scheck et al ldquoChartingbiologically relevant chemical space a structural classificationof natural products (SCONP)rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 102 no48 pp 17272ndash17277 2005

[2] W Nawroca B Sztuba A Opolski J Wietrzk MW Kowalskaand T Glowiak ldquoSynthesis and antiproliferative activity in vitro

of novel 15-benzodiazepines Part IIrdquo Archive der Pharmazie-Pharmaceutical and Medicinal Chemistry vol 334 no 1 pp 3ndash10 2000

[3] B E Evans K E Rittle M G Bock et al ldquoMethods fordrug discovery development of potent selective orally effectivecholecystokinin antagonistsrdquo Journal of Medicinal Chemistryvol 31 no 12 pp 2235ndash2246 1988

[4] R Yarchoan H Mitsuya R V Thomas et al ldquoIn vivoactivity against HIV and favorable toxicity profile of 2101584031015840-dideoxyinosinerdquo Science vol 245 no 4916 pp 412ndash415 1989

[5] J R Lokensgard C C Chao G Gekker S Hu and P KPeterson ldquoBenzodiazepines glia and HIV-1 neuropathogene-sisrdquoMolecular Neurobiology vol 18 no 1 pp 23ndash33 1998

[6] J Poupaert P Carato E Colacino and S Yous ldquo2(3H)-benzoxazolone and bioisosters as ldquoprivileged scaffoldrdquo in thedesign of pharmacological probesrdquo Current Medicinal Chem-istry vol 12 no 7 pp 877ndash885 2005

[7] D J Triggle ldquo14-dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003


[8] R W DeSimone K S Currie S A Mitchell J W Darrow andDA Pippin ldquoPrivileged structures applications in drug discov-eryrdquo Combinatorial Chemistry and High Throughput Screeningvol 7 no 5 pp 473ndash493 2004

[9] A A Patchett and R P Nargund ldquoChapter 26 Privilegedstructures an updaterdquo Annual Reports in Medicinal Chemistryvol 35 pp 289ndash298 2000

[10] J Yang Q Dang J Liu Z Wei J Wu and X Bai ldquoPreparationof a fully substituted purine libraryrdquo Journal of CombinatorialChemistry vol 7 no 3 pp 474ndash482 2005

[11] J Liu Q Dang ZWei H Zhang and X Bai ldquoParallel solution-phase synthesis of a 2689-tetrasubstituted purine library via asulfur intermediaterdquo Journal of Combinatorial Chemistry vol 7no 4 pp 627ndash636 2005

[12] Q Dang and J E Gomez-Galeno ldquoAn efficient synthesisof pyrrolo[23-d]pyrimidines via inverse electron demandDiels-Alder reactions of 2-amino-4-cyanopyrroles with 135-triazinesrdquo Journal of Organic Chemistry vol 67 no 24 pp8703ndash8705 2002

[13] P Bhuyan R C Boruah and J S Sandhu ldquoStudies on uracils 10A facile one-pot synthesis of pyrido[23-d]- and pyrazolo[34-d]pyrimidinesrdquo Journal of Organic Chemistry vol 55 no 2 pp568ndash571 1990

[14] R H Smith Jr W L Jorgen J Tirado-Rives et al ldquoPredictionof binding affinities for TIBO inhibitors of HIV-1 reverse tran-scriptase using Monte Carlo simulations in a linear responsemethodrdquo Journal of Medicinal Chemistry vol 41 no 26 pp5272ndash5286 1998

[15] B A Roberte K Andries J Desayter et al ldquoPotent and selectiveinhibition ofHIV-1 replication in vitro by a novel series of TIBOderivativesrdquo Nature vol 343 no 6257 pp 470ndash474 1990

[16] H J Breslin M J Kukla T Kromis et al ldquoSynthesis and anti-HIV activity of 1345-tetrahydro-2H-14- benzodiazepin-2-one (TBO) derivatives Truncated 4567-tetrahydro-5-methyl-imidazo[451-jk][14]benzodiazepin-2(1H)-ones (TIBO) ana-loguesrdquo Bioorganic and Medicinal Chemistry vol 7 no 11 pp2427ndash2436 1999

[17] W Ho M J Kukla H J Breslin et al ldquoSynthesis and anti-HIV-1 activity of 4567-tetrahydro-5-methylimidazo-[451-jk][14]benzodiazepin-2(1H)-one (TIBO) derivatives 4rdquo Jour-nal of Medicinal Chemistry vol 38 no 5 pp 794ndash802 1995

[18] B D Puodziunaite R Janciene L Kosychova and Z Stum-breviciute ldquoOn the synthetic way to novel peri-annelatedimidazo[15]benzodiazepinones as the potent non-nucleosidereverse transcriptase inhibitorsrdquo Arkivoc vol 2000 no 4 pp512ndash522 2000

[19] M D Braccio G Grossi G Roma L Vargiu M Muraand M E Marongiu ldquo15-Benzodiazepines Part XII Synthe-sis and biological evaluation of tricyclic and tetracyclic 15-benzodiazepine derivatives as nevirapine analoguesrdquo EuropeanJournal of Medicinal Chemistry vol 36 no 11-12 pp 935ndash9492001

[20] A Kamal M V Rao N Laxman G Ramesh and GS Reddy ldquoRecent developments in the design synthe-sis and structure-activity relationship studies of pyrrolo[21-c][14]benzodiazepines as DNA-interactive antitumour antibi-oticsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol2 no 2 pp 215ndash254 2002

[21] P Sharma B Vashistha R Tygai et al ldquoApplication ofmicrowave induced Delepine reaction to the facile one pot

synthesis of 7-substituted 13-dihydro-2H-[14]-benzodiazepin-2-one-5-methyl carboxylates from the corresponding 1-chloroacetylisatinsrdquo International Journal of Chemical Sciencesvol 8 no 1 2010

[22] A Singh R Sirohi S Shastri and D Kishore ldquoA facile one-potsynthesis of 7-substituted-5-methoxycarbonyl-1H-2 3-dihydro-1 4-benzodiazepin-2-ones from 5-substituted-119873-chloroacetylisatinsrdquo Indian Journal of Chemistry B vol 42B no 12 pp 3124ndash3127 2003

[23] P D Popp ldquoThe chemistry of isatinrdquo inAdvances in HeterocyclicChemistry vol 18 pp 1ndash58 1975

[24] M Pal N K Sharma Priyanka and K K Jha ldquoSynthetic andbiological multiplicity of isatin a reviewrdquo Journal of AdvancedScientific Research vol 2 no 2 pp 35ndash44 2011

[25] N Blazevic D Kolbah B Belin V Sunjic and F Kajfez ldquoHex-amethylenetetramine ldquoA versatile reagent in organic synthesisrdquordquoSynthesis pp 167ndash176 1979

[26] B Rigoa P Caulieza D Fasseurb and D Couturierb ldquoReactionof hexamethyldisilazane with diacylhydrazines an easy 134-oxadiazole synthesisrdquo Synthetic Communications vol 16 no 13pp 1665ndash1669 1986

[27] M Ogata and H Matsumoto ldquoA convenient synthesis of5-substituted 13-dihydro-2H-14-benzodiazepine-2-onesrdquoChemistry and Industry p 1067 1976

[28] H Fujishima H Takeshita S Suzuki M Toyota and MIhara ldquoHexamethyldisilazanes mediated one-pot intramolec-ular Michael addition-olefination reactions leading to ejvo-olefinated bicyclo[640]dodecanesrdquo Journal of the ChemicalSociety Perkin Transactions 1 no 18 pp 2609ndash2616 1999

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

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International Journal of


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Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


N

N

N NN

HN

O

S(O)

HN

Cl

CH3

CH3

H3C1 2

H3C

Figure 1

from 2 We assumed that this problem could possibly becircumvented by carrying out the amination of 2 with lessbulkier agents In consideration of the potential of hex-amethyldisilazane [28] in amination reaction in our initialattempt we replaced hexamine with this reagent Howevercontrary to our expectation 2 resisted its reaction with thisreagent and caused it to be recovered unchanged from thereaction mixture A search for possible use of a catalyst inthis reaction revealed that n-butyl lithium has been used inaminations employing hexamethyldisilazane This providedoptimism for this reaction too to succeed with the use ofthis catalyst This expectation turned into a reality in all theruns using a wide variety of substituted 1-chloroacetylisatinderivatives to produce 4 in an exceptionally high yield andpurity (Table 1)

We suggest that this reaction proceedswith the base catal-ysed dehydrochlorination of 2 to generate an acyl carbeneintermediate 3 which is subsequently trapped by hexam-ethyldisilazane The relatively small size of carbene precludesthe steric factor in the reaction with hexamethyldisilazaneThe hydrolysis of bis(trimethylsilyl) group from this withmethanol sets the stage for it to undergo ring expansion togive 4

In view of the extremely weak nucleophilic character ofisatinylamide nitrogen of 3 the possibility of the rearrange-ment of the acyl carbene intermediate had to be ruled out(No rearranged product was however traceable from thereaction mixture)

As the carbene was not likely to be trapped by thetertiary amine (hexamine) its reactionwith hexaminewas notexamined

3 Experiment

All the melting points were taken in open capillaries and areuncorrected The purity of all the compounds were checkedby TLC using the solvent systems (benzene methanol9 1 vv) and silica gel G as adsorbent IR spectra wererecorded on Shimadzu FTIR-8400 infrared spectrometerusing KBr 1H NMR were recorded on Bruker AC 300Fin CDCl

3+ DMSO-d

6(2 1 vv TMS as internal reference

and chemical shifts expressed in 120575 ppm) and mass spectra

were recorded on Jeol-JMS-D-D-300 mass spectrometerReagents 5-fluoro- 5-chloro- 5-bromo- 5-iodo- 5-methyl-5-methoxy- 5-nitro- and 57-dimethylisatins were procuredfrom commercial sources and used as such in the reactionwithout further purifications (see Scheme 1)

31 General Methods for the Preparation of 2(andashi) from 1(andashi)5-Fluoroisatin (1b 0068mol) was vigorously refluxed withchloroacetyl chloride (0090mol) for 7 h and themixturewascooled overnight at 0ndash5∘C The crude product which settledwas filtered washed with 20mL of ether air-dried and thenrecrystallised from ethyl acetate to give 2b yield 88 mp165-166∘C Other compounds 2(a cndashi) were prepared from1(a cndashi) using this procedure

32 General Methods for the Preparation of 4(andashi) from 2(andashi) 5-Fluoro-1-chloroacetylisatin (2b 001mol) was dissolvedin dry THF (20mL) and to this solution n-butyl lithium(001mol) and hexamethyldisilazane (001mol) were addedThe reactionmixture was magnetically stirred for 2 h at roomtemperature The progress of reaction was checked by TLCMethanol (20mL) was added to the reaction mass and themixture was refluxed for 5 h It was then poured on crushedice filtered air-dried and recrystallised from methanol togive 4b yield 87 mp 198ndash200∘C Other compounds 4(acndashi) were prepared from 2(a cndashi) using the same procedure

4 Conclusion

In summary a high yielding n-butyl lithium catalysedone-pot domino process has been developed to the facileaccess of the privileged nucleus of methyl-13-dihydro-2H-14-benzodiazepin-2-one-5-carboxylates 4(andashi) at ambienttemperature from the ring expansion of the corresponding 1-chloroacetylisatins 2(andashi) under the influence of hexamethyl-disilazane

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper


Table1Ph


thec

ompo

unds


Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield(

)IR

(KBr)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

2aC 1

0H6C

lNO

322361

210ndash

1291

173516801675

756ndash

719(m

4HA

rH)432

(s2HC

H2)

53715

367

270265

626618

2bC 1

0H5C

lFNO

32416

0165ndash66

88175517251700

781ndash72

3(m

3HA

rH)433

(s2HC

H2)

49714

967

249240

580569

2cC 1

0H5C

l 2NO

325806

153ndash55

94178517401720

781ndash753(m

3HA

rH)432

(s2HC

H2)

465446

42

19519

0543531

2dC 1

0H5BrC

lNO

330251

178ndash79

90178017351710

796ndash

761(m3HA

rH)432

(s2HC

H2)

39703962

16715

6463459

2eC 1

0H5C

lINO

33495

1206ndash

0789

177017251690

780ndash

750(m

3HA

rH)428

(s2HC

H2)

28952889

1211

17338327

2fC 1

1H8C

lNO

32376

4185ndash86

92176517201690

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

285

(s3HC

H3)

55605551

339328

589580

2gC 1

1H8C

lNO

425364

223ndash25

90178017401705

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

373

(s3HO

CH3)

52095197

318312

552542

2hC 1

0H5C

lN2O

526861

130ndash

3291

178517451710

872ndash809(m

3HA

rH)452

(s2HC

H2)

44714

456

18817

110431037

2iC 1

2H10ClNO

32516

7168ndash70

921740

17001685

740ndash

712(m

2HA

rH)432

(s2HC

H2)

235

(s6HC

H3)

57275719

401397

557546

4aC 1

1H10N

2O3

21821

172ndash75

85319017251675

80(s1HN

H)79

8ndash76

5(m

4HA

rH)

448

(s2HC

H2)365(s3HO

CH3)

MS119898119911(

)21821(M+

100

)21020

(75

)10716(35

)

60556048

462452

12841279

4bC 1

1H9FN

2O3

23620

198ndash200

87322017351690

82(s1HN

H)808

(d1HA

rH)77

8(d

1HA

rH)

766(s1HA

rH)456

(s2HC

H2)378

(s3HO

CH3)

MS119898119911(

)23620(M

+75)20517

(100)17716(35

)

55935588

384379

11861176

4cC 1

1H9C

lN2O

325265

176ndash

7884

321517281684

81(s1H

NH)79

0(s1HA

rH)78

1(d

1HA

rH)

760(d1HA

rH)448

(s2HC

H2)370

(s3HO

CH3)MS119898119911(

)25265(M

+100

)25457

(M+2

33

)

52295223

359351

11091100

4dC 1

1H9BrN

2O3

2979

8243ndash45

86320817211675

80(s1HN

H)79

0(s1HA

rH)77

5(d

1HA

rH)

750(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)MS119898119911(

)29798(M

+100

)2999

0(M

+2100)17716(35

)

444744

41

305299

94393

6

4eC 1

1H9IN

2O3

34411

187ndash88

90320017101670

80(s1HN

H)78

5(s1HA

rH)76

6(d

1HA

rH)

740(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

MS119898119911(

)344

11(M

+75)20517

(100)14716(35

)

3839

3829

264

259

814807


Table1Con

tinued

Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield

()

IR(K

Br)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

4fC 1

2H12N

2O3

23224

205ndash06

85318817231672

80(s1HN

H)78

4(s1HA

rH)75

6(d

1HA

rH)

742(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

234

(s3HC

H3)

MS119898119911(

)23224(M

+72)1772

5(25

)1491

7(100)

62606252

521517

12061196

4gC 1

2H12N

2O4

24808

182ndash85

87320217281677

80(s1HN

H)78

8(d1HA

rH)77

5(d

1HA

rH)

743(s1HA

rH)433

(s2HC

H2)312

(s3HO

CH3)

363

(s3HO

CH3)

MS119898119911(

)24808(M

+68)24011

(100)16345

(36

)

58065798

487479

11291119

4hC 1

1H9N

3O5

26305

202ndash05

83322817351698

80(s1HN

H)812

(s1HA

rH)79

8(d

1HA

rH)

766(d1HA

rH)455

(s2HC

H2)342

(s3HO

CH3)

MS119898119911(

)26305(M

+65)20117

(100)17080

(35

)

50205013

345334

15961589

4iC 1

3H14N

2O3

24626

215ndash17

88318517201670

80(s1HN

H)74

0(s2HA

rH)430

(s

2HC

H2)

310

(s3HO

CH3)234(s3Hfor

two

CH3)

MS119898119911(

)246

26(M

+100

)14517

(86

)10416

(27

)

63406331

573569

11381133

a Allthem

eltingpo

ints(M

P)w

erefou

ndto

beidenticalto

thea

uthenticsamples

prepared

accordingto

thep

rocedu

rerepo

rted

intheliterature

[22]

MWMolecular


erim

ental


O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

CHR2

R2

R2

R2R2

R1

R1

R1

R1

R1

R1

R2

N

N

N

N

N

N

CC C

C

CH2Cl

n-BuLi THF

NH

SiMe3

SiMe3SiMe3

SiMe3HN

H

H

2

Me OH

MeOOCCOOMe

H2N

CH2

N CH


4(andashi)


R1 = R2 = H


(a)(b)(c)(d)(e)(f)(g)(h)(i)

R1 = F R2 = H


Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Ph


thec

ompo

unds


Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield(

)IR

(KBr)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

2aC 1

0H6C

lNO

322361

210ndash

1291

173516801675

756ndash

719(m

4HA

rH)432

(s2HC

H2)

53715

367

270265

626618

2bC 1

0H5C

lFNO

32416

0165ndash66

88175517251700

781ndash72

3(m

3HA

rH)433

(s2HC

H2)

49714

967

249240

580569

2cC 1

0H5C

l 2NO

325806

153ndash55

94178517401720

781ndash753(m

3HA

rH)432

(s2HC

H2)

465446

42

19519

0543531

2dC 1

0H5BrC

lNO

330251

178ndash79

90178017351710

796ndash

761(m3HA

rH)432

(s2HC

H2)

39703962

16715

6463459

2eC 1

0H5C

lINO

33495

1206ndash

0789

177017251690

780ndash

750(m

3HA

rH)428

(s2HC

H2)

28952889

1211

17338327

2fC 1

1H8C

lNO

32376

4185ndash86

92176517201690

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

285

(s3HC

H3)

55605551

339328

589580

2gC 1

1H8C

lNO

425364

223ndash25

90178017401705

772ndash70

3(m

3HA

rH)432

(s2HC

H2)

373

(s3HO

CH3)

52095197

318312

552542

2hC 1

0H5C

lN2O

526861

130ndash

3291

178517451710

872ndash809(m

3HA

rH)452

(s2HC

H2)

44714

456

18817

110431037

2iC 1

2H10ClNO

32516

7168ndash70

921740

17001685

740ndash

712(m

2HA

rH)432

(s2HC

H2)

235

(s6HC

H3)

57275719

401397

557546

4aC 1

1H10N

2O3

21821

172ndash75

85319017251675

80(s1HN

H)79

8ndash76

5(m

4HA

rH)

448

(s2HC

H2)365(s3HO

CH3)

MS119898119911(

)21821(M+

100

)21020

(75

)10716(35

)

60556048

462452

12841279

4bC 1

1H9FN

2O3

23620

198ndash200

87322017351690

82(s1HN

H)808

(d1HA

rH)77

8(d

1HA

rH)

766(s1HA

rH)456

(s2HC

H2)378

(s3HO

CH3)

MS119898119911(

)23620(M

+75)20517

(100)17716(35

)

55935588

384379

11861176

4cC 1

1H9C

lN2O

325265

176ndash

7884

321517281684

81(s1H

NH)79

0(s1HA

rH)78

1(d

1HA

rH)

760(d1HA

rH)448

(s2HC

H2)370

(s3HO

CH3)MS119898119911(

)25265(M

+100

)25457

(M+2

33

)

52295223

359351

11091100

4dC 1

1H9BrN

2O3

2979

8243ndash45

86320817211675

80(s1HN

H)79

0(s1HA

rH)77

5(d

1HA

rH)

750(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)MS119898119911(

)29798(M

+100

)2999

0(M

+2100)17716(35

)

444744

41

305299

94393

6

4eC 1

1H9IN

2O3

34411

187ndash88

90320017101670

80(s1HN

H)78

5(s1HA

rH)76

6(d

1HA

rH)

740(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

MS119898119911(

)344

11(M

+75)20517

(100)14716(35

)

3839

3829

264

259

814807


Table1Con

tinued

Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield

()

IR(K

Br)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

4fC 1

2H12N

2O3

23224

205ndash06

85318817231672

80(s1HN

H)78

4(s1HA

rH)75

6(d

1HA

rH)

742(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

234

(s3HC

H3)

MS119898119911(

)23224(M

+72)1772

5(25

)1491

7(100)

62606252

521517

12061196

4gC 1

2H12N

2O4

24808

182ndash85

87320217281677

80(s1HN

H)78

8(d1HA

rH)77

5(d

1HA

rH)

743(s1HA

rH)433

(s2HC

H2)312

(s3HO

CH3)

363

(s3HO

CH3)

MS119898119911(

)24808(M

+68)24011

(100)16345

(36

)

58065798

487479

11291119

4hC 1

1H9N

3O5

26305

202ndash05

83322817351698

80(s1HN

H)812

(s1HA

rH)79

8(d

1HA

rH)

766(d1HA

rH)455

(s2HC

H2)342

(s3HO

CH3)

MS119898119911(

)26305(M

+65)20117

(100)17080

(35

)

50205013

345334

15961589

4iC 1

3H14N

2O3

24626

215ndash17

88318517201670

80(s1HN

H)74

0(s2HA

rH)430

(s

2HC

H2)

310

(s3HO

CH3)234(s3Hfor

two

CH3)

MS119898119911(

)246

26(M

+100

)14517

(86

)10416

(27

)

63406331

573569

11381133

a Allthem

eltingpo

ints(M

P)w

erefou

ndto

beidenticalto

thea

uthenticsamples

prepared

accordingto

thep

rocedu

rerepo

rted

intheliterature

[22]

MWMolecular


erim

ental


O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

CHR2

R2

R2

R2R2

R1

R1

R1

R1

R1

R1

R2

N

N

N

N

N

N

CC C

C

CH2Cl

n-BuLi THF

NH

SiMe3

SiMe3SiMe3

SiMe3HN

H

H

2

Me OH

MeOOCCOOMe

H2N

CH2

N CH


4(andashi)


R1 = R2 = H


(a)(b)(c)(d)(e)(f)(g)(h)(i)

R1 = F R2 = H


Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

Entry

Molecular

form

ula

MW

MP

(∘ C)a

Yield

()

IR(K

Br)cmminus1

1 HNMR(C

DCl

3-DMSO

-d6)120575pp

mElem

entalanalysis

C(caldexp)

H(caldexp)

N(caldexp)

4fC 1

2H12N

2O3

23224

205ndash06

85318817231672

80(s1HN

H)78

4(s1HA

rH)75

6(d

1HA

rH)

742(d1HA

rH)432

(s2HC

H2)312

(s3HO

CH3)

234

(s3HC

H3)

MS119898119911(

)23224(M

+72)1772

5(25

)1491

7(100)

62606252

521517

12061196

4gC 1

2H12N

2O4

24808

182ndash85

87320217281677

80(s1HN

H)78

8(d1HA

rH)77

5(d

1HA

rH)

743(s1HA

rH)433

(s2HC

H2)312

(s3HO

CH3)

363

(s3HO

CH3)

MS119898119911(

)24808(M

+68)24011

(100)16345

(36

)

58065798

487479

11291119

4hC 1

1H9N

3O5

26305

202ndash05

83322817351698

80(s1HN

H)812

(s1HA

rH)79

8(d

1HA

rH)

766(d1HA

rH)455

(s2HC

H2)342

(s3HO

CH3)

MS119898119911(

)26305(M

+65)20117

(100)17080

(35

)

50205013

345334

15961589

4iC 1

3H14N

2O3

24626

215ndash17

88318517201670

80(s1HN

H)74

0(s2HA

rH)430

(s

2HC

H2)

310

(s3HO

CH3)234(s3Hfor

two

CH3)

MS119898119911(

)246

26(M

+100

)14517

(86

)10416

(27

)

63406331

573569

11381133

a Allthem

eltingpo

ints(M

P)w

erefou

ndto

beidenticalto

thea

uthenticsamples

prepared

accordingto

thep

rocedu

rerepo

rted

intheliterature

[22]

MWMolecular


erim

ental


O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

CHR2

R2

R2

R2R2

R1

R1

R1

R1

R1

R1

R2

N

N

N

N

N

N

CC C

C

CH2Cl

n-BuLi THF

NH

SiMe3

SiMe3SiMe3

SiMe3HN

H

H

2

Me OH

MeOOCCOOMe

H2N

CH2

N CH


4(andashi)


R1 = R2 = H


(a)(b)(c)(d)(e)(f)(g)(h)(i)

R1 = F R2 = H


Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

CHR2

R2

R2

R2R2

R1

R1

R1

R1

R1

R1

R2

N

N

N

N

N

N

CC C

C

CH2Cl

n-BuLi THF

NH

SiMe3

SiMe3SiMe3

SiMe3HN

H

H

2

Me OH

MeOOCCOOMe

H2N

CH2

N CH


4(andashi)


R1 = R2 = H


(a)(b)(c)(d)(e)(f)(g)(h)(i)

R1 = F R2 = H


Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

a simple and advantageous synthesis of the privileged 1, 4

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