Tetrahedron Letters Volume 55, Issue 12,2014, Pages 2022–20

Synthesis of indene derivatives via reactions

of vinylidenecyclopropanes with the N -acyliminium cations generated from

hydroxylactams

Alexander V.Stepakov a ,?,Anna 9953f6a104a1b0717ed5dd1arina a ,Vitaly M.Boitsov b ,Vladislav V.Gurzhiy a ,Alexander P.Molchanov a ,Rafael R.Kostikov a

a Chemistry Department,Saint-Petersburg State University,Universitetsky prosp.26,St-Petersburg 198504,Russian Federation

b

Saint-Petersburg Academic University—Nanotechnology Research and Education Centre RAS,Khlopin Str.8/3,St-Petersburg 194021,Russian Federation

a r t i c l e i n f o Article history:

Received 23November 2013Revised 21January 2014Accepted 12February 2014

Available online 20February 2014Keywords:

Hydroxylactams

Vinylidenecyclopropanes N -Acyliminium cation 1H -Indenes Lewis acid

a b s t r a c t

A novel route for the synthesis of 1H -indene derivatives via the reactions of vinylidenecyclopropanes (VCPs)with the N -acyliminium cations generated from hydroxylactams is described.

ó2014Elsevier Ltd.All rights reserved.

The 1H -indene subunit appears in compounds displaying a con-siderable range of biological activity:cyclooxygenase-2(COX-2)inhibitors,1oxytocin antagonists,2estrogen receptor modulators,3an 5-HT6serotonin receptor 4and in compounds with antiprolifer-ative activity.5Indene derivatives are also used as precursors of metallocene complexes for catalytic polymerization processes and as functional materials.6Consequently,a number of approaches to the synthesis of the indene ring system have been developed,including new methods such as intramolecular cyclization of tetraaryl substituted 1,3-butadienes,7cycloaddition of methylenecyclopropanes with acetals,8cycloisomerizations of alkynes,9annulation of benzylic alcohols with alkynes,10rear-rangement of ortho -(alkynyl)styrenes,11and cycloisomerization of arylvinylcyclopropenes.12Tsuji and co-workers have reported a novel synthetic method for the preparation of indenes by the reaction of aliphatic ketones with aryl-substituted alkynes in the presence of NbCl 3(DME)13

The chemistry of vinylidenecyclopropanes has been explored extensively.Novel intramolecular rearrangements and cycloaddi-tion reactions have been studied.14,15However,reactions of

vinylidenecyclopropanes with N -acyliminium cations have not been previously studied.N -Acyliminium ions are known as impor-tant reactive species in organic synthesis for the construction of carbon–carbon bonds.16Numerous examples of N -acyliminium ion based intramolecular cyclizations can be found in the synthesis of alkaloid derivatives.17Recently,Wang and Zhang reported the ?rst examples of the Lewis acid catalyzed [4+2]cycloaddition reac-tions of N -acyliminium ions with alkenes.18In continuation of our earlier work,19we have studied the reactions of non-activated vinylidenecyclopropanes (VCPs)with N -acyliminium cations.In the present work we show for the ?rst time that 1-(2-methylprop-enylidene)-2,2-diarylcyclopropanes react with the N -acyliminium cations generated from hydroxylactams to give the corresponding 5-[2-methyl-1-(3-Ar 1-1H -inden-2-yl)prop-1-enyl]-1-Ar 2-1H -pyrro l-2(5H )-ones and 3-[2-methyl-1-(3-Ar 1-1H -inden-2-yl)prop-1-enyl]-2-Ar 2-isoindolin-1-ones in moderate yields.Of the Lewis acids and solvents screened,the combination of BF 3áOEt 2and dichloromethane produced the best results in these reactions.In our initial studies,the reaction of 1a with VCP 2a was investigated.Under a nitrogen atmosphere,compound 1a was reacted with an equimolar amount of 2a in the presence of BF 3áOEt 2(1.0equiv)in CH 2Cl 2at ambient temperature for one hour,to give 3-{2-methyl-1-[6-methyl-3-(4-methylphenyl)-1H -in-den-2-yl]prop-1-en-1-yl}-2-phenylisoindolin-1-one (3a )in 41%

9953f6a104a1b0717ed5dd1a/10.1016/j.tetlet.2014.02.039

0040-4039/ó2014Elsevier Ltd.All rights reserved.

?Corresponding author.Fax:+78124286939.

E-mail address:alstepakov@yandex.ru (A.V.Stepakov).

isolated yield (Table 1,entry 1).Although several other products could be seen in the TLC analysis of the reaction mixture,no other potential products were successfully isolated.When the reaction of 1a with VCP 2a was carried out at low temperature (à20°C),the corresponding indene 3a was produced in 36%yield.Under re?uxing conditions,product 3a was isolated in only 14%yield.The reactions of hydroxylactams 1with VCPs 2were carried out in dichloromethane under similar conditions to those described previously (Table 1).The reactions proceeded smoothly to give the corresponding indene derivatives 3in moderate yields at room temperature.The presence of either electron-donating or electron-withdrawing substituents on the benzene ring of the VCPs 2had only a slight effect upon the yields of the produced indenes 3.For example,decreased yields of the indenes 3were obtained by using VCPs 2with electron-donating groups (MeO)on the benzene ring (Table 1,entries 2and 4).The presence of electron-donating or electron-withdrawing groups on the phenyl ring of the hydroxylactams 1also had a minor effect upon the yields of the produced indenes 3.2-[Bis(4-methoxyphenyl)methylene]-5,5-dimethyldihydrofuran-3(2H )-one (4)was isolated in 7–9%yields as the side product in all the cases of the reactions with bis(4-methoxyphenyl)vinylidenecyclopropane (2d ).In cases where R 1was a phenyl group,or R 2a methyl group (VCPs 2e –g ),complicated reaction mixtures were formed under the standard conditions (Table 1,entries 10–12).Dihydrofuranone 4is the oxidation prod-uct of VCP 2d ;its formation might occur either due to aerial oxy-gen or during chromatographic separation.The exact reaction mechanism for the formation of 4is still not 9953f6a104a1b0717ed5dd1aing degassed solvent resulted in only a slight decrease of the amount of 4in the reaction mixture.The reaction of 2d with BF 3áOEt 2in CH 2Cl 2re-sulted in the formation of dihydrofuranone 4in 23%yield.Forma-tion of analogous products 4was not observed from VCPs 2a –c .The compositions and structures of the products 3and 4were established by elemental and spectral analyses.The structures of compounds 3c and 4were con?rmed by X-ray diffraction analysis (Figs.1and 2).20,21The single crystal of 3c clearly showed that the aryl group on the indene segment and the aryl ring of the phthal-

Table 1

Reactions of hydroxylactams 1a –c with vinylidenecyclopropanes 2a –d

Entry Ar

R 1R 2

R 3

R 4Yield of 3a (%)1Ph (1a )Me 4-MeC 6H 44-MeC 6H 4(2b )Me 41(3a )2Ph (1a )

Me 4-MeOC 6H 44-MeOC 6H 4(2d )MeO 32(3b )b 34-MeC 6H 4(1b )Me 4-MeC 6H 44-MeC 6H 4(2b )Me 39(3c )44-MeC 6H 4(1b )Me 4-MeOC 6H 44-MeOC 6H 4(2d )MeO 29(3d )c 54-MeC 6H 4(1b )Me Ph

Ph (2a )

H 40(3e )64-ClC 6H 4(1c )Me 4-ClC 6H 44-ClC 6H 4(2c )Cl 66(3f )74-ClC 6H 4(1c )Me Ph

Ph (2a )

H 43(3g )8Ph (1a )

Me 4-ClC 6H 44-ClC 6H 4(2c )Cl 58(3h )94-MeC 6H 4(1b )Me 4-ClC 6H 44-ClC 6H 4(2c )Cl 44(3i )10Ph (1a )Me Me Ph (2e )H —d 11Ph (1a )Ph Me Ph (2f )H —d 12

Ph (1a )

Ph

Ph

Ph (2g )

H

—d

a Isolated yield.

b 7%of 4was also formed.

c 9%of 4was also formed.

d

A complicated reaction mixture was observed.

A.V.Stepakov et al./Tetrahedron Letters 55(2014)2022–20262023

imide fragment were face-to-face aligned.As could be seen from the NMR spectra,it was apparent that compounds 3a –i existed as a mixture of rotamers at ambient temperature on account of slow C3–C1and C1–C2bond rotation.In all cases,the presence of rotamers made the NMR spectra complex.At room temperature,the 1H NMR spectra of products 3a –i revealed two sets of signals for each CH 3group of the isopropylidene fragment.Similarly,the 1

H NMR spectra of compounds 3have two sets of signals belonging to the methylene group of the indene ring.Rotational isomerism was con?rmed by temperature-dependent NMR experiments on compounds 3a ,f ,g :coalescence was observed at 75–80°C (see Sup-plementary information ,Figs.43–45).

For the next step in our study,we treated VCPs 2a –d with hydroxylactams 5a –d (Table 2).The reactions proceeded smoothly at room temperature producing the corresponding indene deriva-tives 6in trace-to-moderate yields (Table 2).It should be noted that the yield did not improve upon stirring the reaction for a long-er period of time or at a higher temperature.The formation of a trace amount of indene 6was observed in the reaction of 5c with

Table 2

Reactions of hydroxylactams 5a –d with vinylidenecyclopropanes 2a –d

Entry Ar

R R Yield of 6(%)1Ph (5a )

4-MeC 6H 4(2b )Me 43(6a )24-MeC 6H 4(5b )4-MeC 6H 4(2b )Me 45(6b )34-MeOC 6H 4(5d )4-MeC 6H 4(2b )Me 42(6c )4Ph (5a )

Ph (2a )H 40(6d )54-MeC 6H 4(5b )Ph (2a )H 28(6e )64-ClC 6H 4(5c )Ph (2a )H 37(6f )74-MeOC 6H 4(5d )Ph (2a )

H 31(6g )84-MeC 6H 4(5b )4-ClC 6H 4(2c )Cl 55(6h )94-ClC 6H 4(5c )4-ClC 6H 4(2c )Cl 57(6i )104-MeC 6H 4(5b )4-MeOC 6H 4(2d )MeO (6j +4)b 11

4-ClC 6H 4(5c )

4-MeOC 6H 4(2d )

MeO

—c

a Isolated yield.

b A chromatographically inseparable mixture of 6j and 4was obtained.

c

Only a trace amount of the indene was observed;dihydrofuranone 4was isolated in 12%yield.

2024 A.V.Stepakov et al./Tetrahedron Letters 55(2014)2022–2026

VCP2d,which contains electron-donating groups(MeO)on the phenyl rings,and only the dihydrofuranone4was isolated in this case(Table2,entry11).The reaction of hydroxylactam5b with VCP2d led to an inseparable mixture of6j and4(Table2,entry 10).The reaction products were puri?ed by preparative thin-layer chromatography on silica.The structures of6b and6h were estab-lished unequivocally by X-ray diffraction analysis(Figs.3and 4).22,23In the reaction of5-hydroxy-1-phenylpyrrolidin-2-one(7) with2a,no indene product was observed,but dimer8derived from7under the reaction conditions was produced as a mixture of isomers(Scheme1)18,24

Based on the above results,a plausible mechanism for the for-mation of compounds3and6is proposed in Scheme2.Activation of the C–O by BF3áOEt2leads to the formation of N-acyliminium cations9.Next,regioselective attack of the N-acyliminium cations 9on the central carbon atom of the allene system results in the for-mation of cyclopropyl cation10,which undergoes a cyclopropyl–allyl rearrangement to give cation11.This undergoes cyclization to give substituted indenes3and6.Clearly,the steric factors are favorable to the addition of the N-acyliminium cations to the viny-lidenecyclopropanes from the less sterically hindered side.

In conclusion,we have developed novel Lewis acid(BF3áOEt2) mediated reactions of vinylidenecyclopropanes(VCPs)with the N-acyliminium cations generated from hydroxylactams,which can be utilized for the synthesis of indene derivatives. Acknowledgments

We gratefully acknowledge the?nancial support from the Rus-sian Foundation for Basic Research(Project No.12-03-01008-a). This research made use of resources from the X-ray Diffraction Centre,the Centre for Magnetic Resonance and the Centre for Chemical Analysis and Materials of Saint-Petersburg State University.

Supplementary data

Supplementary data(experimental procedures,characteriza-tion data,and copies of NMR spectra)associated with this article can be found,in the online version,at 9953f6a104a1b0717ed5dd1a/10.1016/ j.tetlet.2014.02.039.These data include MOL?les and InChiKeys of the most important compounds described in this article.References and notes

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20.Crystallographic data for the structure3c have been deposited with the

Cambridge Crystallographic Data Centre as supplementary publication number CCDC936478.Copies of these data can be obtained on application to CCDC,12 Union Road,Cambridge CB21EZ,UK(email:deposit@9953f6a104a1b0717ed5dd1a).

21.Crystallographic data for the structure4have been deposited with the

Cambridge Crystallographic Data Centre as supplementary publication number CCDC970376.Copies of these data can be obtained on application to CCDC,12 Union Road,Cambridge CB21EZ,UK(email:deposit@9953f6a104a1b0717ed5dd1a).

22.Crystallographic data for the structure6b have been deposited with the

Cambridge Crystallographic Data Centre as supplementary publication number CCDC936477.Copies of these data can be obtained on application to CCDC,12 Union Road,Cambridge CB21EZ,UK(email:deposit@9953f6a104a1b0717ed5dd1a).

23.Crystallographic data for the structure6h have been deposited with the

Cambridge Crystallographic Data Centre as supplementary publication number CCDC963391.Copies of these data can be obtained on application to CCDC,12 Union Road,Cambridge CB21EZ,UK(email:deposit@9953f6a104a1b0717ed5dd1a).

24.Spectroscopic and analytical characterizations for8have been previously

reported in Ref.18a.

2026 A.V.Stepakov et al./Tetrahedron Letters55(2014)2022–2026

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