TETRAHEDRON
LETTERS
Tetrahedron Letters42(2001)5121–5122
Pergamon
Reactions of7-polyfluoroalkylnorkhellins with alkyl mercaptoacetates:a simple synthesis of dihydrothienopsoralens and benzofuran derivatives of2-oxa-7-thiabicyclo[3.2.1]octane
Vyacheslav Ya.Sosnovskikh*and Boris I.Usachev
reactive carbonyl speciesDepartment of Chemistry,Ural State University,620083Ekaterinburg,Russia
Received26April2001;revised25May2001;accepted1June2001
Abstract—Newfluoro-containing derivatives of khellin were synthesized from7-polyfluoroalkylnorkhellins and alkyl mercapto-acetates.©2001Elsevier Science Ltd.All rights reserved.
The natural furochromone khellin(4,9-dimethoxy-7-
methyl-5H-furo[3,2-g][1]benzopyran-5-one),obtained
from the fruits and seeds of Ammi visnaga L.possesses
a high antiatherosclerotic and lipid-altering activity1
and is the active constituent of many modern
medicines.2In view of the unique biological properties
displayed by khellin on the one hand and by many
fluorinated heterocyclic compounds3on the other hand,
we have described recently4the synthesis of7-tri-
halomethylnorkhellins,which are highly reactive build-
ing blocks for the preparation of new khellin
derivatives with potential biological activity.
The present work is devoted to the study of the interac-
tion of these compounds with alkyl mercaptoacetates.
It is known5that the reaction of3,3-dialkyl-6-trifluoro-
methyl-2,3-dihydro-4-pyrones with alkyl mercapto-
acetates in the presence of Et3N involves both elec-
trophilic centers of the dihydropyrones and occurs
without ring cleavage to give derivatives of2-oxa-7-thia-
bicyclo[3.2.1]octane1.At the same time,the interaction
of2-trifluoromethylchromones with a threefold excess
of ethyl mercaptoacetate is a redox process that affords
dihydrothienocoumarins2and diethyl3,4-dithiadipate
in a high yield6(Scheme1).
Taking into account the results of previous work,5,6we
would expect that7-polyfluoroalkylnorkhellins3a–c,
being chromones,would react with alkyl mercapto-
acetates to form dihydrothienocoumarins2.However,
we found that,despite the structural similarly with
chromones,they behave in this reaction as dihydro-
pyrones and give compounds4a–d in53–85%yields7
(Scheme2).It should be noted that khellin,7-
perfluorobutyl-and7-trichloromethylnorkhellins do
not react with alkyl mercaptoacetates under these con-
ditions and we failed to isolate the individual reaction
products from7-perfluoroethyl-and7-perfluoro-
propylnorkhellins.
According to the1H NMR data of4a–d,which exhibit
only one set of signals,the reaction is highly stereo-
selective and results in the formation of only one
diastereomer with the cis-arrangement of the sub-
stituents in the tetrahydrothiophene ring.This is most
likely related to the formation of an intramolecular
hydrogen bond between the hydroxyl and carbonyl
groups(the IR spectra of4a–d in CHCl3solution had a
bonded peak at3470–3495cm−1,which were unchanged
upon dilution).It seems probable that little,if any,
OH···O C intramolecular hydrogen bonding interac-
tions can occur in trans-isomer.
Whenfluorokhellins3a–c were heated in a sealed
ampoule at140–150°C for  1.5h with an excess of Scheme1.
Keywords:7-polyfluoroalkylnorkhellins;alkyl mercaptoacetates;di-
hydrothienopsoralens;benzofuran derivatives of2-oxa-7-thia-bicyclo-
[3.2.1]octane.
*Corresponding author.Fax:+73432615978;e-mail:vyacheslav.
sosnovskikh@usu.ru
0040-4039/01/$-see front matter©2001Elsevier Science Ltd.All rights reserved.
PII:S0040-4039(01)00948-0
V .Ya .Sosno 6skikh ,B .I .Usache 6/Tetrahedron Letters 42(2001)5121–5122
5122Scheme    2.Reaction conditions :(i)HSCH 2CO 2R,Et 3N, 20°C,3–10days;(ii)HSCH 2CO 2R,Et 3N,140–150°C,1.5h.
References
1.Gammill,R.B.;Day,C.E.;Schurr,P.E.J .Med .Chem .1983,26,1672–1674.
2.Mashkovskii,M.  D.Lekarstvennye sredstva ;Vilnyus,1993;Vol.1,p.396.
3.Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications ;Filler,R.;Kobayashi,Y.;Yagu-polskii,L.M.,Eds.;Elsevier:Amsterdam,1993.
4.Sosnovskikh,V.Ya.;Kutsenko,V.A.Mendeleev Com -mun .2000,238–239.
5.Sosnovskikh,V.Ya.;Mel ’nikov,M.Yu.Mendeleev Com -mun .1998,198–199.
6.Sosnovskikh,V.Ya.;Usachev,  B.I.;Sevenard,  D.V.;Lork,E.;Ro ¨schenthaler,G.-V.Tetrahedron Lett .2001,42,5117–5119.
7.Preparation of 4a :a mixture of fluorokhellin 3a (0.25g,0.8mmol)and ethyl mercaptoacetate (0.5g,4.2mmol)in the presence of one drop of Et 3N without solvent was kept for 3days at room temperature.Then the reaction mixture was diluted with 5ml of ethanol and the crystalline material was isolated by filtration and washed with ethanol to give 0.25g (72%yield)of compound 4a ,mp 148–149°C.After recrystallization from butanol,the melting point did not change.1H NMR (250MHz,CDCl 3,l ,ppm,J /Hz):1.35(t,3H,MeCH 2,J =7.1),2.52(d,1H,CH H,J AX =11.7),3.50(d,1H,CHH ,J AX =11.7),4.01(s,3H,MeO),4.23(s,3H,MeO),4.28(q,2H,CH 2Me,J =7.1),4.29(s,1H,CH),5.91(s 1H,OH),6.87(d,1H,H 3,J =2.3),7.56(d,1H,H 2,J =2.3).IR (Vaseline oil,cm −1):3480(OH),3170,3140( CH),1740(C  O),1630,1610,1540(arom.).Found (%):C,49.80;H,3.75.Calcd for C 18H 17F 3O 7S (%):C,
49.77;H,3.94.
8.Preparation of 5a :a mixture of fluorokhellin 3a (0.25g,0.8mmol)and ethyl mercaptoacetate (0.5g,4.2mmol)in the presence of one drop of Et 3N without solvent was heated in a sealed ampoule at 140–150°C for 1.5h.After cooling,the reaction mixture was diluted with 5ml of ethanol –water (3:1)and the crystalline material was iso-lated by filtration and washed with aqueous ethanol to give 0.1g (34%yield)of compound 5a ,mp 187–188°C.1H NMR (400MHz,CDCl 3,l ,ppm,J /Hz):3.96–4.17(AB-part of ABX-system,2H,CH 2,2J AB =19.3;l A =4.14,l B =4.00,3J AX =4.1,3J BX =10.8),4.33–4.43(m,1H,CH),6.98(d,1H,H 3,J =2.3),7.64(d,1H,H 2,J =2.3).IR (Vaseline oil,cm −1):1720(C  O),1610,1580,1550w (arom.).Found (%):C,51.63;H,2.89.Calcd for C 16H 11F 3O 5S (%):C,51.62;H,2.98.
9.Zoubir,  B.;Refouvelet,  B.;Aubin,  F.;Humbert,P.;Xicluna,A.J .Heterocyclic Chem .1999,36,509–513.
HSCH 2CO 2Et in the presence of Et 3N,we succeeded in obtaining dihydrothienopsoralens 5a ,b in 34and 17%yields,respectively.8Fluorokhellin 3c does not react under these conditions.A similar heterocyclic system with an aryl group instead of the poly fluoroalkyl sub-stituent has recently 9been synthesized from the corre-sponding o -hydroxychalcones and ethyl mercapto-acetate.
Treatment of compound 4a with ethyl mercapto-acetate under similar conditions gave dihydrothieno-psoralen 5a in 64%yield,which indicates the intermedi-acy of compounds 4in the transformation of khellins 3into psoralens 5.
Thus,as expected,4the replacement of the methyl group in khellin by the poly fluoroalkyl group substan-tially increases the reactivity of the pyrone ring of the khellin system toward nucleophiles and makes it possi-ble to design from it new fluoro-containing hetero-cycles,which are of interest as biologically active com-pounds.
Acknowledgements
This work was supported by the RFBR (grant No.99-03-32960)and CRDF (grant No.REC-005).
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