Scholarly article on 2-(4-trifluoromethyl-phenyl)-pent-4-enoic acid methyl ester 619323-18-1 from Bioorganic and Medicinal Chemistry p. 2843

Bioorganic & Medicinal Chemistry 11 (2003) 2843–2866

Synthesis and Structure–Antifungal Activity Relationships of

3-Aryl-5-alkyl-2,5-dihydrofuran-2-ones and Their Carbanalogues:

Further Reﬁnement of Tentative Pharmacophore Group

Milan Pour,^a,* Marcel Spulak,^aVojtech Balsanek,^aJirı Kunes,^aPetra Kubanova^b

and Vladimır Buchta^b

^aLaboratory of Structure and Interactions of Biologically Active Molecules, Department of Inorganic and Organic Chemistry,

´

Faculty of Pharmacy, Charles University, Heyrovskeho 1203, CZ-500 05 Hradec Kralove, Czech Republic

´

Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203,

b

´ ´

CZ-500 05 Hradec Kralove, Czech Republic

Received 13 September 2002; accepted 25 March 2003

Abstract—Two series of 3-(substituted phenyl)-5-alkyl-2,5-dihydrofuran-2-ones related to a natural product, (ꢀ)incrustoporine,

were synthesized and their in vitro antifungal activity evaluated. The compounds with halogen substituents on the phenyl ring

exhibited selective antifungal activity against the ﬁlamentous strains of Absidia corymbifera and Aspergillus fumigatus. On the other

hand, the inﬂuence of the lenghth of the alkyl chain at C(5) was marginal. The antifungal eﬀect of the most active compound

against the above strains was higher than that of ketoconazole, and close to that of amphotericin B. In order to verify the hypothesis

about a possible relationship between the Michael-accepting ability of the compounds and their antifungal activity, a series of simple

carbanalogues, 2-(substituted phenyl)cyclopent-2-enones, was prepared and subjected to antifungal activity assay as well.

Introduction

found that in order for this type of compounds to dis-

play antifungal activity, the presence of a double bond

in conjugation with the carbonyl group of the g-lactone

moiety is necessary. The activity can be increased by the

substitution of the phenyl ring at C(3) by halogens,

while the replacement of this phenyl substituent with a

ﬁve-membered heteroaryl,³somewhat surprisingly,

reduces the antifungal eﬀect. We have also recently

shown⁴that there is probably no relationship between

chirality at C(5) and the fungistatic eﬀect, and that the

introduction of an acyloxymethyl group to C(5) of the

furanone ring has a positive inﬂuence.

The structures of biologically active natural products

have often provided useful hints in the design of new

pharmaceutical agents. Thus, a few years ago, we com-

menced a broad research programme aimed at identifying

natural products with antifungal and antimycobacterial

activity, and preparing their analogues with a view to

developing leads to novel antifungals and anti-

mycobacterials. Within the framework of this pro-

gramme, we have published a preliminary account¹on

the relationship between structural modiﬁcations of a

natural 3,5-disubstituted butenolide, (ꢀ)incrustoporine,

which was originally found to possess antifungal activ-

ity against plant pathogenic fungi,²and in vitro activity

of its synthetic derivatives (Fig. 1) against human

pathogens. In particular, the activity of the most pro-

mising derivative of the ﬁrst, 3-(substituted phenyl)-5-

methyl-2,5-dihydrofuran-2-one series against the strain

of Absidia corymbifera matched that of ketoconazole. We

Figure 1.

Based on the Michael-accepting ability of incrustopor-

ine analogues, it appeared that they could be just a

*Corresponding author. Tel.: +420-49-506-7277; fax +420-49-551-

4330; e-mail: pour@faf.cuni.cz

doi:10.1016/S0968-0896(03)00220-7

2844

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

nonspeciﬁc class of fungal inhibitors. Nevertheless, 3-(4-

nitrophenyl)-5-methyl-2,5-dihydrofuran-2-one, which is

undoubtedly one of the strongest Michael acceptors of

the originally reported 5-methyl series, showed virtually

no activity¹at all.

2-(substituted phenyl)cyclopent-2-enones, was prepared

by Pd-mediated a-arylation of 2-iodocyclopent-2-enone,

and the compounds were subjected to an antifungal

activity assay. Given their structure, 2-arylcyclopent-2-

enones have far greater Michael-accepting ability than

the corresponding lactones, because the electron with-

drawing inﬂuence of the carbonyl group is not counter-

balanced by the opposite eﬀect of the ether oxygen.

Hence, if the above hypothesis is valid, the

carbanalogues should exhibit higher antifungal activities.

In this paper, we wish to give a full account of our

studies on the 5-alkyl series, which was broadened by

several new 5-methyl derivatives together with selected

5-ethyl and 5-butyl analogues. In addition, we have

included some 5-alkyl compounds bearing adamantyl,

naphthyl, orthocondensed and pyridyl moieties at C(3).

In order to shed more light on the hypothesis between the

ability of the compounds to act as Michael acceptors and

their antifungal activity, a set of simple carbanalogues,

Results and Discussion

Synthesis and antifungal activity of 3-(substituted

phenyl)-5-methyl-2,5-dihydrofuran-2-ones

A few syntheses of 3,5-disubstituted butenolides^5,6and

3-arylbutenolides⁷composed of several steps had been

previously described. All^8,9of the 3-(substituted

phenyl)-5-methyl-2,5-dihydrofuran-2-ones 5 were pre-

pared via a simple route described in our previous

communication,¹using commercially available sub-

stituted phenylacetic acids 1 as the starting materials;

3,4-dibromophenylacetic acid 5r was prepared in a

straightforward fashion from 3,4-dibromotoluene

(Scheme 1), and 4-bromo-1-naphthylacetic acid was

prepared by the bromination of 1-naphthylacetic acid.¹⁰

The synthesis is depicted in Scheme 2. The acids were

ﬁrst converted into the corresponding methyl esters, and

the methyl ester of 3-indolylacetic acid was also

methylated on nitrogen using NaH/CH₃I. Following

the deprotonation with LDA, the ester enolates were

quenched with allyl bromide to aﬀord the methyl esters

Scheme 1. (i) NBS, AIBN; (ii) KCN; (iii) LiOH, MeOH/H₂O 3:1.

Scheme 2. (i) MeOH/H^ꢁ; (ii) LDA, C₃H₅Br; (iii) LiOH; (iv) H₂SO₄or HBr/CH₃COOH, then K₂CO₃/MeOH; (v) LDA, PhSeCl, MCPBA or H₂O₂

or NalO₄.

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2845

of 2-(substituted phenyl)pent-4-enoic acids (2). The

carboxylic group was then liberated by hydrolysis, and

the resultant acids 3a, b, e–t, u, w subjected to a proton-

mediated cyclization onto the terminal double bond to

aﬀord 3-(substituted phenyl)-5-methyltetrahydrofuran-

2-ones 4a, b, e–t, u, w as mixtures of diastereomers.

Following some experimentation, we found that the

reaction proceeded best in concentrated H₂SO₄at 0 ^ꢂC,

giving almost quantitative yield of a mixture of trans

and cis isomers in the ratio of 2:1, as determined by

NMR. In case of derivatives having an aryl moiety

strongly susceptible to an electrophilic attack (4c, 4d

and 4v), the ring closure was eﬀected by the reaction

with HBr/AcOH followed by treatment with K₂CO₃in

moist methanol. Finally, the double bond was intro-

duced by enolization of the lactones followed by treat-

ment with phenylselenenyl chloride, oxidation and

spontaneous selenoxide elimination to yield the target

compounds. For the oxidation of the intermediate phe-

nylselanyl derivatives, H₂O₂was suﬃcient in most cases.

However, the target compounds bearing a strongly

electron withdrawing aryl (e.g., 4-nitrophenyl) were

extremely prone to a nucleophilic attack of the double

bond by excess reagent and subsequent epoxide formation,

and MCPBA or KIO₄were therefore used.

The target compounds 5 and their saturated precursors

4 were evaluated for their in vitro antifungal activity on

a panel of human pathogenic fungi including the repre-

sentatives of both yeast and ﬁlamentous strains using

the microdilution format of the NCCLS M27-A guide-

lines.¹¹As disclosed before, saturated lactones 4 did not

display any fungistatic eﬀect; the activities of unsatu-

rated lactones 5, expressed as minimum inhibitory con-

centrations (MICs), are summarized in Table 1. In

general, the compounds showed selective activity

Table 1. MIC (mmol/L)^aof compounds 5a–5w

Compd

CA

24/48 h

CK

24/48 h

CT

24/48 h

CG

24/48 h

TB

24/48 h

AF

24/48 h

AC

24/48 h

TM

72/120 h

5a

5b

5c

5d

5e

5f

>125

62.5

>125

nt

>125

125

>125

125

>125

125

>125

125

>125

125

>125

31.25

>125

125

>125

125

>125

125

>125

125

>125

62.5

>125

125

>125

125

>125

125

>125

7.81

31.25

62.5

>125

125

>125

62.5

125

>125

15.63

>125

31.25

>125

15.63

>125

31.25

>125

31.25

>125

62.5

>125

62.5

>125

125

>125

31.25

62.5

31.25

125

62.5

125

5g

5h

5i

62.5

31.25

62.5

31.25

62.5

125

>125

62.5

125

>125

7.81

62.5

>125

125

>125

62.5

125

62.5

>125

62.5

>125

125

>125

62.5

5j

125

5k

5l

31.25

62.5

31.25

62.5

>125

125

5m

5n

5o

5p

5q

5r

5s

5t

62.5

>125

125

15.63

125

15.63

31.25

62.5

125

>125

125

62.5

31.25

62.5

125

31.25

62.5

125

62.5

125

>125

62.5

31.25

>125

31.25

62.5

>125

125

>125

125

>125

125

5u

5v

5w

125

>125

CA, Candida albicans ATCC 44859; CK, Candida krusei E28; CT, Candida tropicalis 156; CG, Candida glabrata 20/I; TB, Trichosporon beigelii 1188;

AF, Aspergillus fumigatus 231; AC, Absidia corymbifera 272; TM, Trichophyton mentagrophytes 445.

^aMinimum inhibitory concentration.

2846

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

against ﬁlamentous strains and, even though a wider

selection of substituents as compared to our initial

study¹was employed, chlorine- or bromine-substituted

phenyl moiety remained the most important substituent

as regards the contribution to the antifungal eﬀect.

However, it is diﬃcult to draw a deﬁnite conclusion

about the relationship between the type, position and

number of halogen atoms on the phenyl ring at C(3)

and the antifungal activity of the furanone derivative.

The 3,4-dichlorophenyl derivative 5k is the most eﬀec-

tive of all chlorophenyl derivatives; the activities of the

3-chlorophenyl and 4-chlorophenyl compounds 5i and

5h are similar, and that of the 2-chlorophenyl derivative

5j is practically negligible. Of the bromophenyl deriva-

tives, 4-bromophenyl compound 5p has also shown

moderate activity against Candida albicans, while the

3,4-dibromophenyl derivative 5r possessed the highest

activity against A. corymbifera. Thus, 3-(3,4-dichloro-

phenyl)-5-methyl-2,5-dihydrofuran-2-one 5k is the most

active compound of the 5-methyl series.

Biological activities of the compounds are summarized

in Table 2; the 3,4-dichlorophenyl derivatives 7k and 9k

have the highest activities. As compared to the 5-methyl

series, furanone 7k with the ethyl group at C(5) is

slightly more active against the ﬁlamentous strains of A.

corymbifera (AC) and Aspergillus fumigatus (AF) than

its 5-methyl counterpart 5k, while the activity of the

5-butyl analogue 9k seems to decrease. The introduction

of the isosteric pyridyl moiety instead of phenyl did not

bring any substantial improvement, either.

.

Scheme 4. Pd₂dba₃CHCl₃, AsPh₃, Cul, DMF.

Synthesis and antifungal activity of 3-(substituted

phenyl)-5-ethyl- and 3-(substituted phenyl) -5-butyl-2,5-

dihydrofuran-2-ones:comparison to standards

Thus, 3-(3,4-dichlorophenyl)-5-ethyl-2,5-dihydrofuran-

2-one 7k appears the most interesting derivative, the in

vitro activity of which against AF and AC is somewhat

better than that of ketoconazole, and not far from that

of amphotericin B. The comparison of 7k to the stan-

dards is presented in mg/mL in Table 3.

Since halogens were found to be the substituents of

choice in the ﬁrst round, only four 3-(substituted

phenyl) compounds were synthesized in the 5-ethyl and

5-butyl series (7 and 9), together with 3-(4-methylphe-

nyl)-5-ethyl-2,5-dihydrofuran-2-one (7b), as this com-

pound was the racemate of incrustoporine, and the

pyridyl derivative 11. The preparation (Scheme 3) was

identical to the route published¹²by Yajima and Mori

for the synthesis of (ꢀ)incrustoporine, with a minor

change. In the ﬁrst step, these authors used 2 molar

Synthesis and antifungal activity of 2-halophenylcyclo-

pent-2-enones:reﬁnement of the pharmacophore group

2-Arylcyclopent-2-enones, which can be considered as

carbanalogues of our g-lactones, are undoubtedly inter-

esting compounds, given the presence of the cyclo-

pentenone unit in a number of biologically active

natural products; the screening of a recently prepared

library of cross-conjugated cyclopentenones for various

biological activities has also aﬀorded useful results.¹³

Since this subseries with the ether oxygen replaced by a

methylene unit was structurally diﬀerent, the sub-

stituents on the phenyl ring were selected according to

the principles set by Toppliss.¹⁴Apart from 2-(3,4-

dichlorophenyl)cyclopent-2-enone 12k, all compounds

had been prepared before by various procedures;^15ꢀ17

recent syntheses include the Pauson–Khand reaction¹⁸

and [3+2] annulation of 3-ethoxycarbonyl-2-propenyli-

dene(triphenyl)phosphorane with glyoxals.¹⁹In view of

its simplicity and availability of the starting materials, a

.

equivalents of BF₃Et₂O per one equivalent of (2S)-

ethyloxirane. In our hands, the reaction mixture turned

into a gel, which made stirring and workup somewhat

complicated. However, using just one equivalent of the

Lewis acid was suﬃcient enough to eﬀect the reaction.

The intermediate methyl esters cyclized spontaneously

on silica gel, and were therefore used without further

characterization; saturated lactones 6 and 8 were

obtained with yields in the range 50–70%.

An exception was the synthesis of 3-(3-pyridyl)-5-ethyl-

2,5-dihydrofuran-2-one 11, which was prepared by the

Stille-type coupling of 3-tributylstannyl-5-ethyl-2,5-

dihydrofuran-2-one³with 3-iodopyridine (Scheme 4).

ꢁ

Scheme 3. (i) MeOH/H^ꢁ; (ii) LDA,

or

.

, BF₃Et₂O; (iii) LiOH; (iv) H ; (v) LDA, PhSeCl, MCPBA.

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2847

Pd-catalyzed Negishi cross-coupling using 2-iodocyclo-

pent-2-enone, available in a single step from cyclopent-

2-enone, and organozinc reagents generated from the

appropriate aryliodides, appeared as an eﬃcient route

to all derivatives of the series.

(Scheme 5); the yields of a-arylation using this protocol

are thus strongly dependent on the substitution of the

phenyl ring.

It is well known²⁰that a-iodoenones undergo Pd-cata-

lyzed reactions much less readily that their b-haloge-

nated conterparts and, consequently, more forcing

conditions must be employed in these processes. Thus,

DMF was used as a solvent, and highly reactive cata-

lysts prepared prior to the coupling by the reduction of

Scheme 5. BuLi, ZnBr₂, then Pd⁰catalyst,

.

PdCl₂(phosphine)₂with

2

equivalents of BuLi

employed. When in situ prepared Pd(PPh₃)₂was used,

the yield of coupling product 12a was 25% and, sur-

prisingly, even the more reactive Pd[P(2-furyl)₃]₂did not

increase the yield (30%) to a signiﬁcant extent in case of

enone 12b. When the combination of 2%

Much to our surprise, MICs for all compounds were

higher than 250 mmol/L (most of them did not display

any fungistatic eﬀect even at 1000 mmol/L!), which

means that (1) Michael-accepting ability does not prob-

ably play an important role in the mechanism of anti-

fungal action of incrustoporine derivatives and (2) the

pharmacophore group can be further reﬁned so as to

include the lactone moiety (Fig. 2).

.

Pd₂(dba)₃CHCl₃and 5% of tris(2-furyl)phosphine was

used as a more convenient way to generate the catalyst

system,²¹the yields were also moderate to low (32% of

12h, 16% of 12c), with the exception of the 3,4-dichloro-

phenylderivative 12k, the yield of which was 65%

Table 2. MIC (mmol/L)^aof compounds 7b, h, i, k, p and 9h, i, k, p

Compd

CA

24/48 h

CK

24/48 h

CT

24/48 h

CG

24/48 h

TB

24/48 h

AF

24/48 h

AC

24/48 h

TM

72/120 h

7b

7h

7i

>125

125

62.5

>125

62.5

125

62.5

125

>125

125

>125

125

>125

125

>125

125

>125

62.5

125

>125

62.5

125

62.5

>125

7.81

15.63

62.5

125

15.63

31.25

62.5

>125

125

>125

125

7.81

15.63

62.5

15.63

31.25

15.63

31.25

7.81

31.25

62.5

125

>125

31.25

125

62.5

125

7.81

31.25

62.5

125

15.63

31.25

7.81

31.25

7.81

62.5

31.25

62.5

7k

7p

9h

9i

31.25

125

>125

125

>125

62.5

9k

9p

11

125

>125

31.25

62.5

125

>125

CA, Candida albicans ATCC 44859; CK, Candida krusei E28; CT, Candida tropicalis 156; CG, Candida glabrata 20/I; TB, Trichosporon beigelii 1188;

AF, Aspergillus fumigatus 231; AC, Absidia corymbifera 272; TM, Trichophyton mentagrophytes 445.

^aMinimum inhibitory concentration.

Table 3. MIC (mg/mL)^aof compound 7k and ketoconazole (KET) and amphotericin B (AMB)

Compd

CA

24/48 h

CK

24/48 h

CT

24/48 h

CG

24/48 h

TB

24/48 h

AF

24/48 h

AC

24/48 h

TM

72/120 h

7k

16.1

31.1

0.06

1

>31.1

2.08

2

>31.1

8.31

2

>31.1

0.13

0.26

2

8.3

32.1

0.06

0.25

2

4

8.31

0.25

0.5

2

4

2

8.3

0.52

1.04

1

KET

AMB

16.61

2

1

4

2

1

CA, Candida albicans ATCC 44859; CK, Candida krusei E28; CT, Candida tropicalis 156; CG, Candida glabrata 20/I; TB, Trichosporon beigelii 1188;

AF, Aspergillus fumigatus 231; AC, Absidia corymbifera 272; TM, Trichophyton mentagrophytes 445.

^aMinimum inhibitory concentration.

2848

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

experiments. Where mixtures of diastereomers were

obtained (all disubstituted tetrahydrofurans), both iso-

mers are described separately as A and B. Infrared

spectra were recorded in CDCl₃on a Nicolet Impact

400 spectrophotometer. Low resolution mass spectra

were measured on a Magnum Finnigan Mat apparatus.

Elemental analysis was carried out on a CHNS-OCE

Fisons EA 1110 instrument.

Figure 2.

Conclusion

Preparation of 3,4-dibromophenylacetic acid (1r). 3,4-

Dibromobenzylbromide. NBS (1.852 g, 10.37 mmol) was

added to a solution of 3,4-dibromotoluene (2.592 g,

10.37 mmol) in tetrachloromethane (20 mL). The mix-

ture was heated to 80 ^ꢂC, a catalytic amount of AIBN

was added and the resultant mixture was heated for 8 h.

The mixture was then diluted with Et₂O, and washed

successively with 5% aqueous HCl and 5% aqueous

Na₂CO₃. The organic phase was dried over Na₂SO₄,

and the solvent evaporated. Puriﬁcation by column

chromatography (petroleum ether) aﬀorded 3,4-dibromo-

benzylbromide as yellow crystals in 90% yield.

In summary, our results have further conﬁrmed that the

substitution of the 2,5-dihydrofuranone core with a

halogenated phenyl moiety at C(3) leads to selective

antifungal activity against ﬁlamentous strains. The pre-

sence of chlorine in positions 3 and 4 of the phenyl ring

appears to be the substitution of choice. More sig-

niﬁcantly, modiﬁcations of the substituent at C(5) based

on prolonging the alkyl chain does not shift the anti-

fungal potency to a signiﬁcantly higher level. On the

contrary, the activities seem to decline slightly upon

replacement of ethyl with butyl. Regarding the assump-

tions about the pharmacophoric element, it is worthy to

mention that antifungal properties are certainly not

general to all butenolides; for example, protoanemonin

(5-methylene-2,5-dihydrofuran-2-one) displays an anti-

fungal eﬀect (MIC 15 mg/mL against C. albicans),²²

Mp 41–42 ^ꢂC, lit.²⁴43–44 ^ꢂC. ¹H NMR(300 MHz,

CDCl₃) d 7.65 d, 1H, J=2.2 Hz, (Ar); 7.58 d, 1H,

J=8.2 Hz, (Ar); 7.19 dd, 1H, J₁=2.2 Hz, J₂=8.2 Hz,

(Ar); 4.38 s, 2H, (–CH₂); ¹³C NMR(75 MHz,CDCl ) d

3

while plakortone

G

[(E)3,5-diethyl-5-(4-ethyloct-5-

138.44, 133.91, 133.84, 128.97, 124.89, 124.69, 31.18.

enyl)-2,5-dihydrofuran-2-one] was reported²³to possess

no antifungal activity. MIC of the most active derivative

against the ﬁlamentous strains AC and AF is more

favourable than that of ketoconazole as the representa-

tive of azole antifungals, and close to the eﬀect of

amphotericin B. Further investigation has been directed

towards the preparation of substances with more com-

plex substituents at C(5), as some of them have been

recently shown⁴to possess much more interesting in

vitro antifungal activity, even though not as selective.

3,4-Dibromophenylacetonitrile. 3,4-Dibromobenzyl-

bromide (3.0 g, 9.12 mmol) was suspended in ethanol–

water (3:1, 12 mL) and KCN (0.892 g, 13.68 mmol) was

added. After heating under reﬂux for 10 h, the mixture

was diluted with ethyl acetate, and washed with brine.

The organic phase was dried over Na₂SO₄, and the sol-

vent evaporated. Column chromatography of the crude

product (petroleum ether–ethyl acetate 9:1) aﬀorded

yellow crystals in 85% yield.

Mp 65–67 ^ꢂC, lit.²⁵68–69 ^ꢂC. ¹H NMR(300 MHz,

CDCl₃) d 7.64–7.59 m, 2H, (Ar); 7.15 dd, 1H,

J₁=2.2 Hz, J₂=8.2 Hz, (Ar); 3.70 s, 2H, (–CH₂). ¹³C

NMR(75 MHz, CDCl ₃) d 134.11, 132.93, 130.51,

127.91, 125.47, 124.63, 116.63, 22.87.

Experimental

General experimental procedures

THF was distilled from benzophenone ketyl; diisopro-

pyl amine was distilled from CaH₂. The majority of the

(substituted phenyl)acetic acids and (substituted pheny-

l)iodides were obtained from Aldrich and used as

received; 3,4-dibromotoluene was purchased from Lan-

caster. All anhydrous reactions were performed in

ﬂame-dried Schlenk tubes under argon. Analytical thin-

layer chromatography (TLC) was conducted on E.

Merck TLC plates (silica gel 60 F₂₅₄, aluminum back).

Silica gel 60 (230–400 mesh) for column chromato-

graphy was purchased from E. Merck. Melting points

were determined on a Koﬂer block and are uncorrected.

3,4-Dibromophenylacetic acid (1r). LiOH (0.954 g,

21.27 mmol) was added to a solution of 3,4-dibromo-

phenylacetonitrile (1.950 g, 7.09 mmol) in MeOH–H₂O

(3:1, 20 mL), and the reaction mixture was heated at

50 ^ꢂC for 72 h. CHCl₃(20 mL) was then added, and the

resultant mixture was washed with 20% aqueous NaOH

(40 mL). The aqueous layer was acidiﬁed with concd

HCl to pH=1, and the mixture extracted with ethyl

acetate (3ꢃ). The combined extracts were dried over

Na₂SO₄, and the solvent evaporated to give yellow

crystals of the desired acid in 70% yield.

¹H and ¹³C NMRspectra were recorded for CDCl

3

solutions at ambient temperature on a Varian Mercury-

1

Vx BB 300 spectrometer operating at 300 MHz for H.

Chemical shifts were recorded as d values in parts per

million (ppm), and were indirectly referenced to tetra-

ꢂ

1

Mp 104–106 C, lit.²⁶102–103 C. H NMR: (300 MHz,

CDCl₃) d 7.62–7.53 m, 2H, (Ar); 7.09 dd, 1H,

J₁=1.7 Hz, J₂=8.2 Hz, (Ar); 3.59 s, 2H, (–CH₂). ¹³C

NMR(75 MHz, CDCl ₃) d 176.61, 134.43, 133.77,

133.62, 129.55, 124.84, 123.77, 39.95.

1

methylsilane (TMS) via the solvent signal (7.26 for H,

77.0 for ¹³C in CDCl₃). All assignments were made on

the basis of NOESY, gCOSY, gHSQC and gHMBC

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2849

1-(4-Bromonaphthyl)acetic acid (1t). 1-Naphtylacetic

acid (5.275 g, 28.33 mmol) was dissolved in acetic acid

(25 mL), bromine (1.46 mL, 28.33 mmol) was added and

the mixture was heated at 80 ^ꢂC for 3 h. After standing

overnight, the crude product precipitated out of the

solution. Recrystallization from chloroform aﬀorded

white crystals (3.320 g, 44%) of 1-(4-bromonaphthyl)-

acetic acid.

Methyl 2-phenylpent-4-enoate (2a). Colorless oil, yield

1

70%. H NMR(300 MHz, CDCl ): 7.35–7.23 m, 5H,

3

(Ar); 5.81–5.67 m, 1H, (H4); 5.13–4.99 m, 2H, (H5);

3.67 dd, 1H, dd, J₁=6.9, J₂=8.5 (H2); 3.65 s, 3H, (–

OCH₃); 2.91–2.80 m, 1H, (H3a); 2.59–2.48 m, 1H,

(H3b). ¹³C NMR(75 MHz, CDCl ₃): 173.70; 138.42;

135.12; 128.52; 127.78; 127.22; 116.87; 51.81; 51.24;

37.48. IR(CDCl ): n_max1272, 1349, 1436, 1454, 1642,

3

1732, 2953, 3004, 3031 cm^ꢀ1. LR MS:m/z (%) 191

(M^ꢄ⁺+H, 8), 149 (28), 131 (100), 130 (50), 121 (61), 115

(12), 103 (6), 91 (33), 77 (13), 63 (8), 51 (12).

Mp 173–174 ^ꢂC, lit.¹⁰174.5–175.5 ^ꢂC. ¹H NMR

(300 MHz, DMSO): d 8.36–8.24 m, 1H, (Ar); 7.99–7.89

m, 1H, (Ar); 7.74 d, 1H, J=7.7 Hz, (Ar); 7.66–7.52 m,

2H, (Ar); 7.25 d, 1H, J=7.7 Hz, (Ar); 4.04 s, 2H, (H2).

¹³C NMR(75 MHz, DMSO): d 172.61, 133.45, 132.64,

131.40, 129.88, 128.97, 127.82, 127.43, 127.16, 125.19,

121.26, 38.39.

Methyl 2-(4-methylphenyl)pent-4-enoate (2b). Color-

1

less oil, yield 71%. H NMR(300 MHz, CDCl ): 7.23–

3

7.18 m, 2H, (AA⁰BB⁰); 7.17–7.12 m, 2H, (AA⁰BB⁰);

5.80–5.66 m, 1H, (H4); 5.13–4.98 m, 2H, (H5); 3.66 s,

3H, (–OCH₃); 3.62 dd, 1H, J₁=7.2, J₂=8.5, (H2); 2.88–

2.76 m, 1H, (H3a); 2.56–2.45 m, 1H, (H3b); 2.34 s, 3H,

Conversion of acids 1 into the corresponding methyl es-

ters. Acetic acids 1a–w (12 mmol) were dissolved in

methanol saturated with hydrogen chloride (100 mL)

and the solution was heated under reﬂux for 3 h.

Methanol was removed, and the residue redissolved

in ethyl acetate. The solution was washed with 5

aqueous Na₂CO₃, dried over Na₂SO₄, and the solvent

evaporated to give the methyl esters in quantitative

yields; the compounds were used without further

characterization.

(CH₃–Ar). ¹³C NMR(75 MHz, CDCl ): 174.01; 136.95;

3

135.48; 135.32; 129.30; 127.72; 116.85; 51.92; 50.92;

37.53; 21.02. IR(CDCl ): n_max1271, 1346, 1437, 1514,

3

1641, 1731, 2924, 2953, 3005 cm^ꢀ1. LRMS: m/z (%) 205

(M^.++H, 37), 163 (48), 146 (21), 145 (100), 135 (78),

128 (15), 115 (11), 105 (10), 103 (10), 91 (9), 77 (4), 65

(4), 51 (5).

Methyl 2-(4-methoxyphenyl)pent-4-enoate (2c). Color-

1

Methyl 3-(N-methylindolyl)acetate. NaH (60 wt.%,

0.880 g, 22 mmol) in mineral oil was washed under

argon with two portions of petroleum ether (2ꢃ4 mL),

and suspended in dry THF (10 mL). The suspension was

cooled to 0 ^ꢂC, and methyl 3-indolylacetate (3.784 g,

20 mmol) in THF (15 mL) was added. After 15 min at

0 ^ꢂC, methyl iodide (1.37 mL, 22 mmol) was added, and

the reaction mixture stirred for 16 h at ambient tem-

perature. The solution was then diluted with ethyl ace-

tate (50 mL), washed with brine, dried over Na₂SO₄,

and concentrated. Puriﬁcation by column chromato-

graphy (petroleum ether–ethyl acetate 98:2) aﬀorded

2.687 g (66%) of the title compound, the physical data

of which were in agreement with the literature.²⁷

less oil, yield 89%. H NMR(300 MHz, CDCl ): 7.26–

3

7.20 m, 2H, (AA⁰BB⁰); 6.88–6.83 m, 2H, (AA⁰BB⁰);

5.79–5.64 m, 1H, (H4); 5.11–4.97 m, 2H, (H5); 3.79 s,

3H, (–OCH₃Ar); 3.65 s, 3H, (–OCH₃); 3.60 dd, 1H,

J₁=7.1, J₂=8.5, (H2); 2.86–2.73 m, 1H, (H3a); 2.55–

2.43 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ₃): 173.93;

158.63; 135.19; 130.46; 128.79; 116.81; 113.90; 55.23;

51.96; 50.53; 37.68. IR(CDCl ): n_max1438, 1512, 1584,

3

1611, 1641, 1731, 2838, 2954, 3004 cm^ꢀ1. LRMS: m/z

(%) 221 (M^.++H, 4), 180 (9), 179 (100), 161 (17), 151

(35), 135 (4), 115 (5), 91 (6), 77 (3), 63 (3), 51 (4).

Methyl 2-(3-methoxyphenyl)pent-4-enoate (2d). Color-

less oil, yield 84%. ¹H NMR(300 MHz, CDCl ): 7.24 t,

3

Preparation of methyl esters of 2-substituted pent-4-

enoic acids (2a–w). Butyllithium in hexanes (1.6 M,

8.27 mL) was added to a solution of diisopropylamine

(1.77 mL, 12.6 mmol) in dry THF (60 mL) at 0 ^ꢂC under

Ar. After 10 min at 0 ^ꢂC, the LDA solution was cooled

to ꢀ60 ^ꢂC and a solution of the methyl ester of a sub-

stituted acetic acid (1a–w) (12 mmol) in THF (5 mL) was

added. After maintaining the mixture at ꢀ60 ^ꢂC for

30 min, allyl bromide (1.09 mL, 12.6 mmol) was added

dropwise. The reaction mixture was slowly allowed to

warm to room temperature (2 h) in order to drive the

reaction to completion. The solution was then diluted

with ethyl acetate (100 mL), washed with saturated

aqueous NH₄Cl, dried over Na₂SO₄, and concentrated

under reduced pressure to yield the crude methyl ester

of the corresponding 2-substituted pent-4-enoic acid.

Puriﬁcation by column chromatography (petroleum

ether–ether 95:5) aﬀorded products with yields in the

range 64–96%.

1H, J=7.9, (Ar); 6.93–6.78 m, 3H, (Ar); 5.80–5.65 m,

1H, (H4); 5.13–4.98 m, 2H, (H5); 3.80 s, 3H, (Ar–

OCH₃); 3.66 s, 3H, (–OCH₃); 3.62 dd, 1H, J₁=7.1,

J₂=8.8, (H2); 2.88–2.76 m, 1H, (H3a); 2.58–2.45 m, 1H,

(H3b). ¹³C NMR(75 MHz, CDCl ₃): 173.71; 159.70;

140.00; 135.19; 129.57; 120.24; 116.96; 113.58; 112.63;

55.16; 51.99; 51.34; 37.50. IR(CDCl ): n_max1261, 1345,

3

1436, 1492, 1600, 1642, 1732, 1838, 2954, 3005 cm^ꢀ1

.

LRMS: m/z (%) 220 (M^ꢄ⁺, 45), 205 (2), 191 (2), 179

(22), 161 (100), 151 (83), 145 (12), 134 (10), 121 (11), 108

(12), 91 (25), 77 (11), 65 (8), 51 (9).

Methyl 2-(4-nitrophenyl)pent-4-enoate (2e). Colorless

1

oil, yield 64%. H NMR(300 MHz, CDCl ): 8.21–8.15

3

m, 2H, (AA⁰BB⁰); 7.51–7.45 m, 2H, (AA⁰BB⁰); 5.75–5.59

m, 1H, (H4); 5.10–4.99 m, 2H, (H5); 3.77 t, 1H, J=7.7,

(H2); 3.68 s, 3H, (–OCH₃); 2.91–2.79 m, 1H, (H3a);

2.60–2.48 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ):

3

2850

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

172.62; 147.23; 145.64; 134.04; 129.00; 123.81; 117.93;

52.35; 51.11; 37.39. IR(CDCl ): n_max1275, 1349, 1437,

1523, 1607, 1735, 2954 cm^ꢀ1³. LRMS: m/z (%) 236

(M^ꢄ⁺+H, 13), 218 (18), 194 (5), 176 (68), 166 (39), 158

(11), 148 (19), 130 (100), 115 (25), 102 (12), 89 (17), 77

(19), 63 (17), 51 (22).

1265, 1345, 1436, 1478, 1574, 1596, 1642, 1734, 2954,

2983 cm^ꢀ1. LRMS: m/z (%) 225 (M^ꢄ⁺, 13), 205 (1), 192

(2), 183 (14), 177 (1), 165 (100), 155 (58), 139 (4), 129

(36), 115 (8), 102 (7), 91 (16), 77 (7), 63 (8), 51 (9).

Methyl 2-(2-chlorophenyl)pent-4-enoate (2j). Colorless

1

oil, yield 78%. H NMR(300 MHz, CDCl ): 7.40–7.34

3

Methyl 2-(4-trifluorophenyl)pent-4-enoate (2f). Color-

1

m, 2H, (Ar); 7.28–7.16 m, 2H, (Ar); 5.82–5.67 m, 1H,

(H4); 5.11–4.98 m, 2H, (H5); 4.25 dd, 1H, J₁=7.2,

J₂=8.0, (H2); 3.68 s, 3H, (–OCH₃); 2.87–2.75 m, 1H,

(H3a), 2.58–2.47 m, 1H, (H3b). ¹³C NMR(75 MHz,

CDCl₃): 173.15; 136.23; 134.73; 133.82; 129.58; 128.68;

less oil, yield 85%. H NMR(300 MHz, CDCl ): 7.61–

3

7.56 m, 2H, (AA⁰BB⁰); 7.45–7.40 m, 2H, (AA⁰BB⁰);

5.76–5.62 m, 1H, (H4); 5.12–4.99 m, 2H, (H5); 3.71 t,

1H, J=8.0, (H2); 3.67 s, 3H, (–OCH₃); 2.90–2.78 m,

1H, (H3a); 2.58–2.47 m, 1H, (H3b). ¹³C NMR

(75 MHz, CDCl₃): 172.97; 142.29, 142.28, 142.26 and

142.24 (J_CꢀF=1.4); 134.41; 130.18, 129.75, 129.32 and

128.89 (J_CꢀF=32.4); 129.37, 125.77, 122.17 and 118.56

(J_CꢀF=271.5); 128.28; 125.54, 125.49, 125.44 a 125.39

(J_CꢀF=3.7); 117.45; 52.21; 51.21; 37.50. LRMS: m/z

(%) 259 (M^ꢄ⁺+H, 58), 239 (21), 217 (8), 199 (100), 189

(42), 177 (9), 158 (7), 141 (8), 128 (11), 109 (5), 89 (3), 73

(3), 59 (4).

128.29; 126.98; 117.15; 52.16; 47.20; 36.89. IR(CDCl ):

3

n_max1267, 1348, 1436, 1476, 1642, 1733, 2953,

2982 cm^ꢀ1. LRMS: m/z (%) 225 (M^ꢄ⁺, 36), 207 (1), 189

(22), 183 (13), 165 (100), 155 (64), 139 (4), 129 (33), 115

(8), 102 (7), 89 (12), 77 (8), 63 (7), 51 (8).

Methyl 2-(3,4-dichlorophenyl)pent-4-enoate (2k). Col-

orless oil, yield 85%. ¹H NMR(300 MHz, CDCl ₃):

7.41 d overlapped, 1H, J=2.2, (Ar); 7.39 d overlapped,

1H, J=8.3, (Ar); 7.15 dd, 1H, J₁=2.2, J₂=8.3, (Ar);

5.75–5.59 m, 1H, (H4); 5.11–4.99 m, 2H, (H5); 3.67 s,

3H, (–OCH₃); 3.60 t, 1H, J=7.7, (H2); 2.85–2.72 m,

1H, (H3a); 2.54–2.43 m, 1H, (H3b). ¹³C NMR

(75 MHz, CDCl₃): 172.81; 138.39; 134.24; 132.52;

131.40; 130.42; 129.91; 127.28; 117.61; 52.29; 50.51;

Methyl 2-(3-trifluorophenyl)pent-4-enoate (2g). Color-

1

less oil, yield 90%. H NMR(300 MHz, CDCl ): 7.59–

3

7.41 m, 4H, (Ar); 5.77–5.62 m, 1H, (H4); 5.12–4.99 m,

2H, (H5); 3.71 dd, 1H, J₁=7.2, J₂=8.5, (H2); 3.68 s,

3H, (–OCH₃); 2.91–2.78 m, 1H, (H3a); 2.59–2.47 m, 1H,

(H3b). ¹³C NMR(75 MHz, CDCl ₃): 173.03; 139.25;

134.40; 131.48, 131.06, 130.63 and 130.21 (J_CꢀF=32.1);

131.26, 131.25, 131.23 and 131.21 (J_CꢀF=1.4); 129.30,

125.70, 122.10 and 118.50 (J_CꢀF=271.8); 128.99;

124.85, 124.80, 124.75–124.70 (J_CꢀF=3.8); 124.26,

124.21, 124.16–124.11 (J_CꢀF=3.8); 117.50; 52.23; 51.18;

37.43. IR(CDCl ): n_max1284, 1344, 1437, 1474, 1562,

3

1643, 1735, 2852, 2929, 2954 cm^ꢀ1. LRMS: m/z (%) 258

ꢄ

+

(M ꢀH, 2), 217 (38), 199 (100), 189 (73), 173 (4), 163

(27), 136 (7), 128 (34), 111 (5), 102 (8), 89 (6), 75 (11), 59

(9), 51 (10).

37.50. IR(CDCl ): n_max1274, 1330, 1436, 1450, 1643,

3

1734, 2846, 2954 cm^ꢀ1. LRMS: m/z (%) 258 (M^ꢄ⁺+H,

5), 239 (5), 217 (6), 199 (100), 189 (38), 179 (8), 159 (11),

141 (7), 128 (6), 115 (4), 89 (2), 75 (2), 59 (4).

Methyl 2-(2,4-dichlorophenyl)pent-4-enoate (2l). Col-

orless oil, yield 78%. ¹H NMR(300 MHz, CDCl ₃): 7.40

d, 1H, J=2.2, (Ar); 7.31 d, 1H, J=8.5, (Ar); 7.23 dd,

1H, J₁=2.2, J₂=8.5, (Ar); 5.79–5.64 m, 1H, (H4); 5.09–

4.98 m, 2H, (H5); 4.20 t, 1H, J=7.7, (H2); 3.68 s, 3H, (–

OCH₃); 2.85–2.72 m, 1H, (H3a); 2.56–2.44 m, 1H,

(H3b). ¹³C NMR(75 MHz, CDCl ₃): 172.80; 134.79;

134.54; 134.29; 133.43; 129.64; 129.34; 127.31; 117.50;

52.27; 46.70; 36.81. IR(CDCl ₃): n_max1263, 1348,

1437,1474, 1590, 1642, 1734, 2954, 3005 cm^ꢀ1. LR MS:

Methyl 2-(4-chlorophenyl)pent-4-enoate (2h). Colorless

1

oil, yield 78%. H NMR(300 MHz, CDCl ): 7.31–7.27

3

m, 2H, (AA⁰BB⁰); 7.26–7.21 m, 2H, (AA⁰BB⁰); 5.76–5.61

m, 1H, (H4); 5.10–4.98 m, 2H, (H5); 3.66 s, 3H, (–

OCH₃); 3.62 dd, 1H, J₁=7.4, J₂=8.0, (H2), 2.85–2.74

m, 1H, (H3a); 2.54–2.43 m, 1H, (H3b). ¹³C NMR

(75 MHz, CDCl₃): 173.27; 136.75; 134.62; 133.06;

ꢄ

+

m/z (%) 258 (M ꢀH, 16), 241 (1), 217 (28), 199 (100),

189 (81), 163 (24), 136 (5), 128 (30), 111 (6), 101 (7), 89

(5), 75 (8), 63 (7), 51 (7).

129.17; 128.63; 117.22; 52.10; 50.71; 37.52. IR(CHCl ):

3

n_max1269, 1344, 1437, 1493, 1642, 1732, 2953, 3011,

3028 cm^ꢀ1. LRMS: m/z (%) 244 (M^ꢄ⁺, 4), 207 (1), 192

(3), 183 (68), 165 (100), 155 (93), 139 (6), 129 (32), 115

(9), 102 (10), 91 (27), 75 (13), 63 (14), 51 (16).

Methyl 2-(4-fluorophenyl)pent-4-enoate (2m). Color-

1

less oil, yield 96%. H NMR(300 MHz, CDCl ): 7.31–

3

7.24 m, 2H, (AA⁰BB⁰); 7.05–6.97 m, 2H, (AA⁰BB⁰);

5.76–5.61 m, 1H, (H4); 5.10–4.97 m, 2H, (H5); 3.66 s,

3H, (–OCH₃); 3.63 dd, 1H, J₁=7.2, J₂=8.3, (H2); 2.86–

2.73 m, 1H, (H3a); 2.54–2.43 m, 1H, (H3b). ¹³C NMR

(75 MHz, CDCl₃): 173.56; 163.52 and 160.27

Methyl 2-(3-chlorophenyl)pent-4-enoate (2i). Colorless

1

oil, yield 79%. H NMR(300 MHz, CDCl ): 7.32–7.30

3

m, 1H, (Ar); 7.26–7.16 m, 3H, (Ar); 5.77–5.62 m, 1H,

(H4); 5.12–4.98 m, 2H, (H5); 3.67 s, 3H, (–OCH₃); 3.61

dd, 1H, J₁=7.1, J₂=8.5, (H2); 2.86–2.74 m. 1H, (H3a);

(J_CꢀF=245.1 Hz);

134.80;

134.08

and

134.04

(J_CꢀF=3.4 Hz); 129.42 and 129.31 (J_CꢀF=8.0 Hz);

2.55–2.44 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ):

117.14; 115.54 and 115.25 (J_CꢀF=21.2 Hz); 52.08; 50.60;

3

173.10; 140.25; 134.59; 134.30; 129.75; 128.04; 127.48;

126.07; 117.31; 52.19; 51.06; 37.50. IR(CDCl ): n_max

37.71. IR(CDCl ): n_max1273, 1437, 1510, 1605, 1642,

3

1733, 2926, 2954 cm^ꢀ1. LRMS: m/z (%) 209 (M^ꢄ⁺+H,

3

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2851

17), 167 (38), 149 (100), 139 (78), 133 (8), 109 (37), 101

(4), 83 (3), 75 (4), 63 (3), 57 (4), 51 (4).

LRMS: m/z (%) 269 (M^ꢄ⁺, 12), 251 (1), 239 (2), 227 (4),

208 (100), 199 (26), 169 (6), 157 (3), 148 (44), 129 (58),

115 (15), 102 (10), 89 (17), 77 (7), 63 (11), 51 (8).

Methyl 2-(3-fluorophenyl)pent-4-enoate (2n). Colorless

1

oil, yield 95%. H NMR(300 MHz, CDCl ): 7.35–7.20

3

Methyl 2-(3,4-dibromophenyl)pent-4-enoate (2r). Col-

1

m, 1H, (Ar); 7.15–6.90 m, 3H, (Ar); 5.80–5.60 m, 1H,

(H4); 5.15–4.95 m, 2H, (H5); 3.66 s, 3H, (–OCH₃); 3.64

dd, 1H, J₁=7.4, J₂=8.0, (H2); 2.90–2.70 m, 1H, (H3a);

orless oil, yield 75%. H NMR(300 MHz, CDCl ): d

3

7.57 d overlapped, 1H, J=2.2, (Ar); 7.56 d overlapped,

1H, J=8.2, (Ar); 7.12 dd, 1H, J₁=2.2, J₂=8.2, (Ar);

5.74–5.59 m, 1H, (H4); 5.11–4.99 m, 2H, (H5); 3.67 s,

3H, (–OCH₃); 3.58 t, 1H, J=7.7, (H2); 2.84–2.72 m,

1H, (H3a); 2.54–2.42 m, 1H, (H3b). ¹³C NMR

(75 MHz, CDCl₃): d 172.72; 139.18; 134.21; 133.61;

133.10; 128.09; 124.85; 123.57; 117.61; 52.29; 50.45;

2.60–2.40 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ):

3

173.14; 164.31 and 161.05 (J_CꢀF=245.6 Hz); 140.75 a

140.66 (J_CꢀF=7.5 Hz); 134.63; 129.98 and 129.87

(J_CꢀF=8.3 Hz); 123.61 and 123.57 (J_CꢀF=2.9 Hz);

117.4; 114.98 and 114.69 (J_CꢀF=21.8 Hz); 114.36 and

114.08 (J_CꢀF=21.2 Hz); 52.15; 51.10 and 51.08

(J_CꢀF=1.4 Hz); 37.52. IR(CDCl ₃): n_max1263, 1436,

37.37. IR(CDCl ): n_max1261, 1343, 1437, 1464, 1556,

3

1643, 1735, 2926, 2954 cm^ꢀ1. LR MS:m/z (%) 349

(M^ꢄ⁺+H, 5), 329 (2), 307 (25), 289 (100), 279 (37), 263

(4), 249 (6), 226 (29), 208 (27), 183 (3), 169 (10), 155 (3),

128 (90), 102 (18), 91 (13), 75 (12), 63 (11), 51 (12).

1449, 1489, 1591, 1615, 1642, 1734, 2845, 2954 cm^ꢀ1

.

LRMS: m/z (%) 209 (M^ꢄ⁺+H, 23), 167 (10), 149 (100),

148 (71), 139 (50), 133 (10), 128 (6), 109 (38), 101 (5), 83

(4), 75 (5), 59 (4), 51 (5).

Methyl 2-(1-naphthyl)-pent-4-enoate (2s). Colorless

1

Methyl 2-(3,4-difluorophenyl)pent-4-enoate (2o). Col-

orless oil, yield 90%. ¹H NMR(300 MHz, CDCl ₃):

7.19–6.98 m, 3H, (Ar); 5.75–5.60 m, 1H, (H4); 5.10–4.99

m, 2H, (H5); 3.67 s, 3H, (–OCH₃); 3.60 bt, 1H, J=7.7,

(H2); 2.84–2.71 m, 1H, (H3a); 2.54–2.42 m, 1H, (H3b).

¹³C NMR(75 MHz, CDCl ₃): 173.25; 151.98, 151.81,

148.68 and 148.51 (J_CꢀF=248.4 and 12.7 Hz); 151.37,

151.20, 148.09 and 147.92 (J_CꢀF=247.8 and 12.7 Hz);

135.34, 135.29, 135.27 and 135.21 (J_CꢀF=4.0 and

5.7 Hz); 134.46; 124.13, 124.08, 124.04 and 124.00

(J_CꢀF=3.7 and 6.3 Hz); 117.57; 117.38 and 117.15

(J_CꢀF=17.2 Hz); 117.03 and 116.79 (J_CꢀF=17.8 Hz);

52.18; 50.47; 37.53. IR(CDCl ): n_max1283, 1345, 1436,

1519, 1610, 1735, 2954 cm^ꢀ1³. LRMS: m/z (%) 227

(M^ꢄ⁺+H, 77), 185 (8), 167 (100), 157 (73), 127 (18), 115

(4), 101 (3), 81 (2), 63 (4).

oil,²⁸yield 89%. H NMR(300 MHz, CDCl ): d 8.13

3

bd, 1H, J=8.2 Hz, (Ar); 7.90–7.85 m, 1H, (Ar); 7.79 bd,

1H, J=7.7 Hz, (Ar); 7.60–7.42 m, 4H, (Ar); 5.90–5.74

m, 1H, (H4); 5.17–4.99 m, 2H, (H5); 4.52–4.45 m, 1H,

(H2); 3.65 s, 3H, (–CH₃); 3.08–2.95 m, 1H, (H3A); 2.72–

2.61 m, 1H, (H3B). ¹³C NMR(75 MHz, CDCl ₃): d

174.16, 135.50, 134.76, 133.96, 131.43, 129.00, 127.89,

126.40, 125.65, 125.51, 124.89, 123.02, 116.96, 52.10,

46.56, 37.24. IR(CDCl ): n_max2953, 1732, 1642, 1598,

3

1512, 1436, 1338 cm^ꢀ1. LRMS: 240 (M^ꢄ⁺, 62), 208 (3),

199 (100), 181 (68), 171 (63), 165 (25), 152 (12), 139 (14),

128 (17), 115 (8), 102 (2), 89 (3), 77 (4), 63 (5), 51 (5).

Methyl 2-(4-bromo-1-naphthyl)-pent-4-enoate (2t).

Colorless oil, yield 96%. ¹H NMR(300 MHz, CDCl ₃): d

8.36–8.28 m, 1H, (Ar); 8.17–8.10 m, 1H, (Ar); 7.77 d,

1H, J=7.8 Hz, (Ar); 7.66–7.57 m, 2H, (Ar); 7.36 d, 1H,

J=7.8 Hz, (Ar); 5.89–5.70 m, 1H, (H4); 5.19–4.97 m,

2H, (H5); 4.45 dd, 1H, J₁=8.5 Hz, J₂=6.3 Hz, (H2);

3.65 s, 3H, (–CH₃); 3.09–2.92 m, 1H, (H3A); 2.73–2.57

Methyl 2-(4-bromophenyl)pent-4-enoate (2p). Colorless

oil, yield 87%. ¹H NMR(300 MHz, CDCl ₃): 7.48–7.42 m,

2H, (AA⁰BB⁰); 7.22–7.16 m, 2H, (AA⁰BB⁰); 5.76–5.61 m,

1H, (H4); 5.10–4.98 m, 2H, (H5); 3.66 s, 3H, (–OCH₃);

3.61 t, 1H, J=7.7, (H2); 2.86–2.73 m, 1H, (H3a); 2.55–

2.42 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ₃): 173.21;

137.29; 134.61; 131.61; 129.57; 121.23; 117.27; 52.15;

m, 1H, (H3B). ¹³C NMR(75 MHz, CDCl ): d 173.72,

3

135.08, 134.83, 132.71, 132.20, 129.63, 128.20, 127.23,

127.10, 125.44, 123.47, 122.63, 117.27, 52.21, 46.45,

37.06. IR(CDCl ): n_max3082, 2953, 1732, 1642, 1509,

3

ꢄ

+

50.81; 37.48. IR(CDCl ): n_max1267, 1344, 1437, 1489,

1436, 1380 cm^ꢀ1. LRMS: 318 (M ꢀH, 31), 279 (100),

261 (50), 249 (13), 235 (5), 198 (70), 179 (36), 165 (27),

152 (20), 139 (33), 126 (13), 113 (4), 100 (3), 89 (7), 76

(8), 63 (10), 50 (8).

3

1642, 1732, 2954, 3004 cm^ꢀ1. LRMS: m/z (%) 269

(M^ꢄ⁺, 7), 251 (1), 227 (38), 209 (100), 199 (39), 183 (5),

169 (10), 148 (62), 129 (46), 115 (14), 102 (11), 89 (19),

77 (8), 63 (12), 51 (11).

Methyl 2-[3-(N-methylindolyl)]-pent-4-enoate (2u).

Colorless crystals, yield 91%. Mp 48–50 ^ꢂC. H NMR

1

Methyl 2-(3-bromophenyl)pent-4-enoate (2q). Colorless

1

oil, yield 75%. H NMR(300 MHz, CDCl ): 7.48–7.37

3

(300 MHz, CDCl₃): d 7.73–7.68 m, 1H, m, (Ar); 7.33–

7.22 m, 2H, (Ar); 7.18–7.12 m, 1H, (Ar); 7.04 s, 1H,

(Ar2); 5.92–5.76 m, 1H, (H4); 5.19–5.01 m, 2H, (H5);

3.99 dd, 1H, J₁=8.8 Hz, J₂=6.6 Hz, (H2); 3.77 s, 3H,

(N–CH₃); 3.68 s, 3H, (–CH₃); 2.98–2.84 m, 1H, (H3A);

2.75–2.61 m, 1H, (H3B). ¹³C NMR(75 MHz, CDCl ₃): d

174.52, 136.83, 135.75, 126.88, 126.73, 121.73, 119.18,

119.14, 116.68, 111.82, 109.28, 51.85, 42.68, 37.06,

m, 2H, (Ar); 7.27–7.16 m, 2H, (Ar); 5.76–5.61 m, 1H,

(H4); 5.11–4.99 m, 2H, (H5); 3.67 s, 3H, (–OCH₃); 3.60

dd, 1H, J₁=7.2, J₂=8.5, (H2); 2.86–2.74 m, 1H, (H3a);

2.55–2.43 m, 1H, (H3b). ¹³C NMR(75 MHz, CDCl ):

3

173.07; 140.53; 134.56; 130.92; 130.40; 130.05; 126.51;

122.54; 117.33; 52.20; 51.03; 37.52. IR(CDCl ): n_max

3

1265, 1344, 1437, 1475, 1570, 1733, 2954, 3006 cm^ꢀ1

.

2852

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

32.73. IR(CDCl ): n_max2952, 2916, 1731, 1641, 1474,

(300 MHz, CDCl₃): 7.27–7.21 m, 2H, (AA⁰BB⁰); 6.89–

6.83 m, 2H, (AA⁰BB⁰); 5.79–5.64 m, 1H, (H4); 5.12–4.98

m, 2H, (H5); 3.79 s, 2H, (–OCH₃Ar); 3.59 t, 1H, J=7.7,

(H2); 2.86–2.73 m, 1H, (H3a); 2.56–2.44 m, 1H, (H3b).

3

1437, 1332 cm^ꢀ1. LRMS: 243 (M^ꢄ⁺, 15), 202 (100), 184

(8), 174 (17), 168 (5), 158 (6), 144 (6), 130 (3), 115 (5),

102 (3), 89 (3), 77 (3), 59 (3), 51 (3).

Methyl 2-(3-benzo[b]thienyl)-pent-4-enoate (2v). Col-

1

2-(3-Methoxyphenyl)pent-4-enoic acid (3d). Colorless

1

orless oil, yield 76%. H NMR(300 MHz, CDCl ): d

oil. H NMR(300 MHz, CDCl ): 7.25 t, 1H, J=7.8,

3

7.90–7.82 m, 2H, m, (Ar5,7); 7.45–7.33 m, 3H,

(Ar2,4,6); 5.89–5.73 m, 1H, (H4), 5.20–5.02 m, 2H,

(H5); 4.12 dd, 1H, J₁=8.8 Hz, J₂=6.6 Hz, (H2); 3.68 s,

3H, (–CH₃); 3.01–2.86 m, 1H, (H3A); 2.77–2.62 m, 1H,

(Ar); 6.93–6.80 m, 3H, (Ar); 5.80–5.65 m, 1H, (H4);

5.13–4.98 m, 2H, (H5); 3.80 s, 3H, (Ar–OCH₃); 3.62 dd,

1H, J₁=7.2, J₂=8.2, (H2), 2.87–2.75 m, 1H, (H3a);

2.58–2.46 m, 1H, (H3b).

(H3B). ¹³C NMR(75 MHz, CDCl ): d 173.21, 140.27,

3

138.00, 134.99, 132.80, 124.43, 124.16, 123.32, 122.88,

121.65, 117.29, 52.11, 44.90, 36.62. IR(CDCl ): n_max

2-(4-Nitrophenyl)pent-4-enoic acid (3e). White crystals,

1

3

ꢂ

3080, 2953, 1733, 1642, 1436, 1428, 1279 cm^ꢀ1. LRMS:

246 (M^ꢄ⁺, 100), 231 (2), 205 (45), 187 (60), 177 (44), 171

(11), 161 (5), 147 (7), 115 (6), 102 (4), 89 (4), 63 (3).

mp 88–89 C. H NMR(300 MHz, CDCl ): 8.22–8.17

3

m, 2H, (AA⁰BB⁰); 7.52–7.47 m, 2H, (AA⁰BB⁰); 5.75–5.59

m, 1H, (H4); 5.12–5.01 m, 2H, (H5); 3.78 t, 1H, J=7.7,

(H2); 2.92–2.80 m, 1H, (H3a); 2.62–2.50 m, 1H, (H3b).

Methyl 2-(1-adamantyl)-pent-4-enoate (2w). Colorless

1

oil, yield 94%. H NMR(300 MHz, CDCl ): d 5.77–

2-(4-Trifluoromethylphenyl)pent-4-enoic acid (3f). Col-

1

3

5.60 m, 1H, (H4); 5.03 dq, 1H, J₁=17.0 Hz, J₂=3.0 Hz,

(H5A); 4.99–4.93 m, 1H, (H5B); 3.63 s, 3H, (–CH₃),

2.40–2.19 m, 2H, (H3), 2.10 dd, 1H, J₁=11.7 Hz,

J₂=3.4 Hz, (H2); 2.02–1.93 m, 3H, (CH); 1.79–1.39 m,

12H, (CH₂). ¹³C NMR(75 MHz, CDCl ₃): d 174.72,

136.55, 116.20, 57.20, 50.81, 40.01, 36.88, 34.62, 30.23,

orless oil. H NMR(300 MHz, CDCl ): 7.63–7.57 m,

3

2H, (AA⁰BB⁰); 7.48–7.42 m, 2H, (AA⁰BB⁰); 5.77–5.62 m,

1H, (H4); 5.14–5.01 m, 2H, (H5); 3.73 t, 1H, J=7.7,

(H2); 2.91–2.78 m, 1H, (H3a); 2.61–2.49 m, 1H, (H3b).

28.55. IR(CDCl ): n_max2908, 2850, 1725, 1641, 1447,

2-(3-Trifluoromethylphenyl)pent-4-enoic acid (3g).

1

3

1436, 1358, 1315 cm^ꢀ1. LRMS: 249 (M^ꢄ⁺+H, 32), 206

(2), 187 (9), 147 (2), 136 (17), 135 (100), 117 (3), 107 (4),

93 (5), 79 (5), 67 (3), 53 (3).

Colorless oil. H NMR(300 MHz, CDCl ): 7.60–7.42

3

m, 4H, (Ar); 5.78–5.63 m, 1H, (H4); 5.13–5.01 m, 2H,

(H5); 3.72 t, 1H, J=7.7, (H2); 2.92–2.78 m, 1H, (H3a);

2.62–2.49 m, 1H, (H3b).

Preparation of acids 3a–w. A methyl ester of a 2-sub-

stituted pent-4-enoic acid (2a–w) (8 mmol) was dissolved

in

a

mixture of MeOH–H₂O (3:1, 40 mL), and

2-(4-Chlorophenyl)pent-4-enoic acid (3h). Colorless oil,

lit.³⁰94–95 ^ꢂC. H NMR(300 MHz, CDCl ): 7.33–7.28

1

.

LiOH nH₂O (57 wt% LiOH, 0.436 g, 10.4 mmol) was

added to the solution. After 20 h at ambient tempera-

ture, the reaction mixture was concentrated, diluted

with water and acidiﬁed with concd HCl to pH4. The

resultant mixture was extracted with ethyl acetate (3ꢃ),

the combined extracts dried over Na₂SO₄, and the sol-

vent evaporated to give the crude acid 3 in a quantita-

tive yield.

3

m, 2H, (AA⁰BB⁰); 7.27–7.22 m, 2H, (AA⁰BB⁰); 5.76–5.61

m, 1H, (H4); 5.11–4.99 m, 2H, (H5); 3.62 t, 1H, J=7.7,

(H2); 2.85–2.74 m, 1H, (H3a); 2.56–2.44 m, 1H, (H3b).

2-(3-Chlorophenyl)pent-4-enoic acid (3i). White crys-

tals, mp 46–48 ^ꢂC. H NMR(300 MHz, CDCl ): 7.33–

1

3

7.31 m, 1H, (Ar); 7.28–7.18 m, 3H, (Ar); 5.77–5.62 m,

1H, (H4); 5.13–4.99 m, 2H, (H5); 3.61 t, 1H, J=7.7,

(H2); 2.86–2.74 m, 1H, (H3a); 2.57–2.45 m, 1H, (H3b).

2-Phenylpent-4-enoic acid (3a). White crystals, mp 31–

33 ^ꢂC, lit.²⁹34 ^ꢂC. H NMR(300 MHz, CDCl ): 7.20–

1

3

7.10 m, 5H, (Ar); 5.66–5.50 m, 1H, (H4); 4.98–4.83 m,

2H, (H5); 3.41 t, 1H, J=7.8, (H2); 2.70–2.58 m, 1H,

(H3a); 2.45–2.33 m, 1H, (H3b).

2-(2-Chlorophenyl)pent-4-enoic acid (3j). Colorless oil.

¹H NMR(300 MHz, CDCl ): 7.41–7.36 m, 2H, (Ar);

3

7.29–7.17 m, 2H, (Ar); 5.82–5.67 m, 1H, (H4); 5.11–4.99

m, 2H, (H5); 4.29 t, 1H, J=7.5, (H2); 2.88–2.75 m, 1H,

(H3a); 2.62–2.49 m, 1H, (H3b).

2-(4-Methylphenyl)pent-4-enoic acid (3b). White crys-

tals, mp 39–41 ^ꢂC, lit.³⁰91–92 ^ꢂC. H NMR(300 MHz,

1

CDCl₃): 7.23–7.19 m, 2H, (AA⁰BB⁰); 7.16–7.11 m, 2H,

(AA⁰BB⁰); 5.79–5.65 m, 1H, (H4); 5.12–4.98 m, 2H,

(H5); 3.61 t, 1H, J=7.8, (H2); 2.86–2.74 m, 1H, (H3a);

2.56–2.45 m, 1H, (H3b); 2.33 s, 3H, (CH₃–Ar).

2-(3,4-Dichlorophenyl)pent-4-enoic acid (3k). White

crystals, mp 53–55 ^ꢂC. ¹H NMR(300 MHz, CDCl ₃):

7.42 d overlapped, 1H, J=2.1, (Ar); 7.40 d overlapped,

1H, J=8.4, (Ar); 7.16 dd, 1H, J₁=2.1, J₂=8.4, (Ar);

5.75–5.59 m, 1H, (H4); 5.12–5.01 m, 2H, (H5); 3.60 t,

1H, J=7.7, (H2); 2.85–2.70 m, 1H, (H3a); 2.56–2.44 m,

1H, (H3b).

2-(4-Methoxyphenyl)pent-4-enoic acid (3c). White

crystals, mp 79–81 ^ꢂC, lit.³⁰81–81.5 ^ꢂC. ¹H NMR

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2853

2-(2,4-Dichlorophenyl)pent-4-enoic acid (3l). White

crystals, mp 37–39 ^ꢂC, lit.³²39–40 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): 7.41 d, 1H, J=2.2, (Ar); 7.32 d, 1H,

J=8.5, (Ar); 7.24 dd, 1H, J₁=2.2, J₂=8.5, (Ar); 5.79–5.64

m, 1H, (H4); 5.11–4.99 m, 2H, (H5); 4.24 t, 1H, J=7.7,

(H2); 2.87–2.74 m, 1H, (H3a); 2.59–2.47 m, 1H, (H3b).

8.36–8.28 (1H, m, Ar), 8.16–8.09 (1H, m, Ar), 7.77 (1H,

d, J=8.0 Hz, Ar), 7.66–7.56 (2H, m, Ar), 7.37 (1H, d,

J=8.0 Hz, Ar), 5.85–5.69 (1H, m, H4), 5.18–4.99 (2H,

m, H5), 4.46 (1H, dd, J₁=8.4 Hz, J₂=6.7 Hz, H2),

3.05–2.91 (1H, m, H3a), 2.73–2.60 (1H, m, H3b).

2-[3-(N-Methylindolyl)]-pent-4-enoic acid (3u). Color-

less crystals, mp 97–99 ^ꢂC. ¹H NMR(300 MHz, CDCl ₃):

d 7.72–7.67 (1H, m, Ar), 7.33–7.21 (2H, m, Ar), 7.17–

7.11 (1H, m, Ar), 7.04 (1H, s, Ar2), 5.91–5.75 (1H, m,

H4), 5.18–4.99 (2H, m, H5), 3.97 (1H, dd, J₁=8.3 Hz,

J₂=7.0 Hz, H2), 3.76 (3H, s, N–CH₃), 2.97–2.80 (1H,

m, H3a), 2.75–2.59 (1H, m, H3b).

2-(4-Fluorophenyl)pent-4-enoic acid (3m). White crys-

ꢂ

tals, mp 68–69 C, lit.³⁰67–69 C. H NMR(300 MHz,

CDCl₃): 7.32–7.24 m, 2H, (AA⁰BB⁰); 7.06–6.97 m, 2H,

(AA⁰BB⁰); 5.77–5.61 m, 1H, (H4); 5.12–4.99 m, 2H,

(H5); 3.63 t, 1H, J=7.8, (H2); 2.86–2.72 m, 1H, (H3a);

2.57–2.42 m, 1H, (H3b).

1

2-(3-Fluorophenyl)pent-4-enoic acid (3n). White crys-

tals, mp 34–36 ^ꢂC. H NMR(300 MHz, CDCl ): 7.35–

7.20 m, 1H, (Ar); 7.15–6.90 m, 3H, (Ar); 5.80–5.60 m,

1H, (H4); 5.15–4.95 m, 2H, (H5); 3.64 t, 1H, J=7.7,

(H2); 2.90–2.70 m, 1H, (H3a); 2.60–2.40 m, 1H, (H3b).

2-(3-Benzo[b]thienyl)-pent-4-enoic acid (3v). Colorless

crystals, mp 58–60 ^ꢂC. H NMR(300 MHz, CDCl ): d

7.90–7.82 (2H, m, Ar5,7), 7.44–7.33 (3H, m, Ar2,4,6),

5.89–5.73 (1H, m, H4), 5.19–5.02 (2H, m, H5), 4.12 (1H,

dd, J₁=8.6 Hz, J₂=6.7 Hz, H2), 2.99–2.87 (1H, m,

H3a), 2.76–2.65 (1H, m, H3b).

1

3

2-(3,4-Difluorophenyl)pent-4-enoic acid (3o). Colorless

oil. ¹H NMR(300 MHz, CDCl ₃): 7.21–7.00 m, 3H,

(Ar); 5.76–5.60 m, 1H, (H4); 5.12–5.01 m, 2H, (H5);

3.61 t, 1H, J=7.7, (H2); 2.84–2.72 m, 1H, (H3a); 2.55–

2.44 m, 1H, (H3b).

2-(1-Adamantyl)pent-4-enoic acid (3w). Methyl 2-(1-

adamantyl)pent-4-enoate (2.732 g, 11 mmol) was dis-

solved in a mixture of ethylene glycol–H₂O (3:1, 25 mL),

and KOH (1.234 g, 22 mmol) was added to the solution.

After heating the mixture at 210 ^ꢂC for 96 h, ethylene

glycol was removed by distillation, the residue was

diluted with water and acidiﬁed with concd HCl to pH4.

The resultant mixture was extracted with ethyl acetate

(3ꢃ), the combined extracts dried over Na₂SO₄, and the

solvent evaporated to aﬀord acid 3w as white crystals

(1.389 g, 54%).

2-(4-Bromophenyl)pent-4-enoic acid (3p). White crys-

tals, mp 40–42 ^ꢂC. ¹H NMR(300MHz, CDCl ₃): 7.48–7.42

m, 2H, (AA⁰BB⁰); 7.22–7.16 m, 2H, (AA⁰BB⁰); 5.76–5.61

m, 1H, (H4); 5.11–4.99 m, 2H, (H5); 3.61 t, 1H, J=7.7,

(H2); 2.86–2.73 m, 1H, (H3a); 2.56–2.44 m, 1H, (H3b).

Mp 87–90 ^ꢂC. H NMR(300 MHz, CDCl ): d 10.96 bs,

1

3

2-(3-Bromophenyl)pent-4-enoic acid (3q). Colorless oil.

¹H NMR(300 MHz, CDCl ): 7.49–7.39 m, 2H, (Ar);

7.28–7.16 m, 2H, (Ar); 5.77–5.62 m, 1H, (H4); 5.12–5.00

m, 2H, (H5); 3.60 t, 1H, J=7.7, (H2); 2.86–2.74 m, 1H,

(H3a); 2.57–2.45 m, 1H, (H3b).

1H, (OH); 5.82–5.66 m, 1H, (H4); 5.07 dq, 1H,

J₁=17.0 Hz, J₂=3.0 Hz, (H5A), 5.02–4.96 m, 1H,

(H5B); 2.39–2.23 m, 2H, (H3); 2.09 dd, 1H,

J₁=10.2 Hz, J₂=4.7 Hz, (H2); 2.03–1.93 m, 3H, (CH);

1.82–1.44 m, 12H, (CH₂).

3

2-(3,4-Dibromophenyl)pent-4-enoic acid (3r). White

crystals, mp 86–88 ^ꢂC. ¹H NMR(300 MHz, CDCl ₃):

7.58 d overlapped, 1H, J=2.2, (Ar); 7.57 d overlapped, 1H,

J=8.2, (Ar); 7.13 dd, 1H, J₁=2.2, J₂=8.2, (Ar); 5.75–5.60

m, 1H, (H4); 5.13–5.01 m, 2H, (H5); 3.59 t, 1H, J=7.7,

(H2); 2.85–2.73 m, 1H, (H3a); 2.56–2.44 m, 1H, (H3b).

Preparation of 3-substituted 5-methyltetrahydrofuran-

2-ones 4a–b, e–t, u, w. A neat 2-substituted pent-4-enoic

acid (3a–b, e–t, u, w) (8 mmol) was treated with concd

H₂SO₄(5 mL) at 0 ^ꢂC for 20 min, and the solution was

subsequently poured into brine. The mixture was neu-

tralized with saturated aqueous Na₂CO₃to pH8, and

extracted with ethyl acetate. The organic phase was

dried over Na₂SO₄, and the solvent evaporated. The

crude products were puriﬁed by column chromato-

graphy (petroleum ether–ethyl acetate 9:1) to aﬀord the

title saturated g-lactones as mixtures of stereoisomers

with yields in the range 66–100%.

2-(1-Naphthyl)-pent-4-enoic acid (3s). White crystals,

mp 88–89 ^ꢂC, lit.³¹86–87 ^ꢂC. ¹H NMR(300 MHz,

CDCl₃): d 8.13 (1H, bd, J=8.2 Hz, Ar), 7.90–7.85 (1H,

m, Ar), 7.80 (1H, bd, J=8.0 Hz, Ar), 7.59–7.42 (4H, m,

Ar), 5.88–5.73 (1H, m, H4), 5.17–4.99 (2H, m, H5),

4.53–4.46 (1H, m, H2), 3.07–2.94 (1H, m, H3a), 2.74–

2.62 (1H, m, H3b).

3-Phenyl-5-methyltetrahydrofuran-2-one (4a). Color-

1

less oil, yield 92%. H NMR(300 MHz, CDCl ): d A:

3

7.41–7.26 m, 5H, (Ar); 4.88–4.75 m, 1H, (H5); 3.94 dd,

1H, J₁=7.2, J₂=9.3, (H3); 2.60–2.50 m, 1H, (H4a);

2.41–2.31 m, 1H, (H4b); 1.48 d, 3H, J=6.3, (–CH₃). B:

2-(4-Bromo-1-naphthyl)-pent-4-enoic acid (3t). White

crystals, mp 70–72 ^ꢂC H NMR(300 MHz, CDCl ): d

1

3

2854

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

7.41–7.26 m, 5H, (Ar); 4.70–4.58 m, 1H, (H5); 3.90 dd,

1H, J₁=8.6, J₂=12.7, (H3); 2.84–2.73 m, 1H, (H4a);

(J_CꢀF=272.2 Hz); 128.50; 125.83, 125.78, 125.73 and

125.68 (J_CꢀF=3.8 Hz); 75.10; 47.39; 39.46; 20.72. IR

(KBr pellet): n_max1071, 1121, 1333, 1391, 1622,

1767 cm^ꢀ1. LRMS: m/z (%) 245 (M^ꢄ⁺+H, 42), 225

(13), 200 (91), 185 (90), 172 (27), 165 (60), 159 (14), 145

(15), 131 (100), 115 (16), 103 (19), 91 (13), 77 (10), 69

(13), 63 (8).

2.10–1.97 m, 1H, (H4b); 1.51 d, 3H, J=6.3, (–CH₃). ¹³

C

NMR(75 MHz, CDCl ): d A: 177.14; 136.99; 128.97;

3

127.61; 127.56; 75.14; 45.68; 37.97; 21.04. B: 176.84;

136.48; 128.83; 128.07; 127.56; 74.93; 47.70; 39.79;

20.83. IR(CDCl ): n_max1339, 1387, 1456, 1499, 1770,

3

2983 cm^ꢀ1. LR MS:m/z (%) 177 (M^ꢄ⁺+H, 48), 132

(49),131 (22), 117 (100), 115 (30), 104 (10), 103 (12), 91

(13), 77 (8), 63 (6), 51 (11).

3-(3-Trifluoromethylphenyl)-5-methyltetrahydrofuran-

2-one (4g). Colorless oil, yield 87%. ¹H NMR

(300 MHz, CDCl₃): d A: 7.62–7.45 m, 4H, (Ar); 4.89–

4.78 m, 1H, (H5); 4.01 dd, 1H, J₁=8.3, J₂=9.2, (H3);

2.63, 2.51 m, 1H, (H4a); 2.47–2.36 m, 1H, (H4b); 1.49 d,

3H, J=6.3, (–CH₃). B: 7.62–7.45 m, 4H, (Ar); 4.73–4.60

m, 1H, (H5); 3.96 dd, 1H, J₁=8.5, J₂=12.9, (H3); 2.88–

2.77 m, 1H, (H4a); 2.11–1.97 m, 1H, (H4b); 1.53 d, 3H,

J=6.0, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A:

176.06; 137.69; 131.08, 131.07, 131.05 and 131.04

(J_CꢀF=1.1 Hz); 129.38; 124.50, 124.45, 124.40 and

124.36 (J_CꢀF=3.8 Hz); 75.10; 45.20; 37.58; 21.07. B:

175.76; 137.17; 132.08, 131.65, 131.22 and 130.79

(J_CꢀF=32.4 Hz); 131.48, 131.47, 131.45 and 131.43

(J_CꢀF=1.3 Hz); 129.23; 129.22, 125.61, 122.01 and

118.41 (J_CꢀF=272.0 Hz); 124.85, 124.80, 124.75 and

124.69 (J_CꢀF=3.8 Hz); 124.52, 124.47, 124.42 and

124.36 (J_CꢀF=3.8 Hz); 75.07; 47.39; 39.53; 20.81. IR

(CDCl₃): n_max1268, 1327, 1389, 1449, 1494, 1770, 2936,

2984 cm^ꢀ1. LRMS: m/z (%) 245 (M^ꢄ⁺+H, 100), 225

(6), 200 (14), 185 (13), 172 (7), 165 (12), 151 (6), 131

(14), 115 (4), 103 (4), 91 (3), 77 (3), 51 (3).

3-(4-Methylphenyl)-5-methyltetrahydrofuran-2-one

(4b). Colorless oil, yield 67%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.18–7.17 m, 4H, (Ar); 4.86–4.74 m, 1H,

(H5); 3.90 dd, 1H, J₁=7.2, J₂=9.3, (H3); 2.58–2.47 m,

1H, (H4a); 2.39–2.27 m, 1H, (H4b); 2.34 s, 3H, (CH₃–

Ar); 1.46 d, 3H, J=6.3, (–CH₃). B: 7.18–7.17 m, 4H,

(Ar); 4.68–4.56 m, 1H, (H5); 3.86 dd, 1H, J₁=8.6,

J₂=12.7, (H3); 2.81–2.71 m, 1H, (H4a); 2.34 s, 3H,

(CH₃–Ar); 2.08–1.94 m, 1H, (H4b); 1.50 d, 3H, J=6.1,

(–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A: 177.36;

137.28; 133.94; 129.62; 127.46; 75.10; 45.29; 37.99;

21.05; 20.82. B: 177.08; 137.31; 133.45; 129.50; 127.91;

74.88; 47.36; 39.78; 21.05; 21.02. IR(CDCl ₃): n_max1267,

1345, 1387, 1453, 1516, 1769, 2934, 2983 cm^ꢀ1. LRMS:

m/z (%) 191 (M^ꢄ⁺+H, 100), 146 (38), 145 (21), 132

(22), 131(93), 115 (18), 103 (5), 91 (16), 77 (3), 65 (4), 51

(4).

3-(4-Nitrophenyl)-5-methyltetrahydrofuran-2-one (4e).

White crystals, yield 98%. Mp 102–105 ^ꢂC. H NMR

1

(300 MHz, CDCl₃): d A: 8.26–8.21 m, 2H, (AA⁰BB⁰);

7.53–7.47 m, 2H, (AA⁰BB⁰); 4.92–4.79 m, 1H, (H5);

4.10–4.03 m, 1H, (H3); 2.65–2.53 m, 1H, (H4a); 2.52–

2.39 m, 1H, (H4b); 1.51 d, 3H, J=6.5, (–CH₃). B: 8.26–

8.21 m, 2H, (AA⁰BB⁰); 7.53–7.47 m, 2H, (AA⁰BB⁰);

4.76–4.63 m, 1H, (H5); 4.03 dd, 1H, J₁=8.5, J₂=13.1,

(H3); 2.91–2.80 m, 1H, (H4a); 2.13–1.98 m, 1H, (H4b);

1.54 d, 3H, J=6.5, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d A: 175.44; 147.12; 143.93; 128.65; 123.93;

75.15; 45.07; 37.21; 20.99. B: 175.16; 147.12; 143.44;

128.97; 123.79; 75.20; 47.28; 39.23; 20.71. IR(KBr pel-

let): n_max860, 951, 1048, 1120, 1176, 1346, 1519, 1605,

1769, 2933, 2979 cm^ꢀ1. LRMS: m/z (%) 222 (M^ꢄ⁺+H,

39), 205 (10), 191 (2), 177 (100), 160 (68), 145 (10), 131

(58), 116 (91), 103 (16), 91 (53), 77 (23), 63 (16), 51 (21).

3-(4-Chlorophenyl)-5-methyltetrahydrofuran-2-one

(4h). White crystals, yield 84%. Mp 38–40 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.36–7.31 m, 2H, (AA⁰BB⁰);

7.26–7.20 m, 2H, (AA⁰BB⁰); 4.85–4.74 m, 1H, (H5); 3.91

dd, 1H, J₁=7.7, (H3); 2.57, 2.46 m, 1H, (H4a); 2.41–

2.30 m, 1H, (H4b); 1.47 d, 3H, J=6.3, (–CH₃). B: 7.36–

7.31 m, 2H, (AA⁰BB⁰); 7.26–7.20 m, 2H, (AA⁰BB⁰);

4.69–4.57 m, 1H, (H5); 3.87 dd, 1H, J₁=8.6, J₂=13.0,

(H3); 2.83–2.72 m, 1H, (H4a); 2.06–1.91 m, 1H, (H4b);

1.50 d, 3H, J=6.1, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d A: 176.64; 135.33; 133.50; 129.07; 129.02;

75.06; 44.84; 37.61; 20.96. B: 176.35; 134.84; 133.50;

129.41; 128.94; 74.96; 47.00; 39.54; 20.73. IR(CHCl ):

3

n_max1268, 1345, 1388, 1494, 1599, 1770, 2936, 2983,

3023 cm^ꢀ1. LRMS: m/z (%) 211 (M^ꢄ⁺, 3), 166 (48), 151

(46), 138 (22), 131 (100), 115 (45), 103 (23), 91 (21), 77

(20), 63 (14), 55 (4), 51 (18).

3-(4-Trifluoromethylphenyl)-5-methyltetrahydrofuran-

ꢂ

1

2-one (4f). White crystals, yield 78%. Mp 88–89 C. H

NMR(300 MHz, CDCl ₃): d A: 7.65–7.60 m, 2H,

(AA⁰BB⁰); 7.45–7.40 m, 2H, (AA⁰BB⁰); 4.89–4.76 m, 1H,

(H5); 4.04–3.96 m, 1H, (H3); 2.61–2.51 m, 1H, (H4a);

2.45–2.35 m, 1H, (H4b); 1.48 d, 3H, J=6.3, (–CH₃). B:

7.65–7.60 m, 2H, (AA⁰BB⁰); 7.45–7.40 m, 2H, (AA⁰BB⁰);

4.73–4.60 m, 1H, (H5); 3.97 dd, 1H, J₁=8.5, J₂=12.9,

(H3); 2.87–2.76 m, 1H, (H4a); 2.10–1.96 m, 1H, (H4b);

1.52 d, 3H, J=6.1, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d B: 175.95; 140.36, 140.34, 140.33 and 140.31

(J_CꢀF=1.4 Hz); 130.56, 130.12, 129.69 and 129.26

(J_CꢀF=32.6 Hz); 129.37, 125.76, 122.16 and 118.56

3-(3-Chlorophenyl)-5-methyltetrahydrofuran-2-one (4i).

Colorless oil, yield 94%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.31–7.26 m, 3H, (Ar); 7.22–7.15 m, 1H, (Ar); 4.87–

4.75 m, 1H, (H5); 3.95–3.87 m, 1H, (H3); 2.60–2.47 m,

1H, (H4a); 2.43–2.30 m, 1H, (H4b); 1.47 d, 3H, J=6.3,

(–CH₃). B: 7.31–7.26 m, 3H, (Ar); 7.22–7.15 m, 1H,

(Ar); 4.70–4.57 m, 1H, (H5); 3.87 dd, 1H, J₁=8.5,

J₂=12.9, (H3); 2.85–2.72 m, 1H, (H4a); 2.08–1.92 m,

1H, (H4b); 1.51 d, 3H, J=6.1, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 176.20; 138.68; 134.63; 130.09;

128.15; 127.76; 125.79; 75.13; 45.21; 37.64; 21.08. B:

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2855

175.89; 138.19; 134.47; 129.95; 128.15; 127.72; 126.23;

3-(4-Fluorophenyl)-5-methyltetrahydrofuran-2-one

(4m). White crystals, yield 67%. Mp 33–35 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.31–7.21 m, 2H, (AA⁰BB⁰);

7.09–7.01 m, 2H, (AA⁰BB⁰); 4.86–4.74 m, 1H, (H5); 3.92

dd, 1H, J₁=7.9, (H3); 2.57–2.46 m, 1H, (H4a); 2.41–

2.30 m, 1H, (H4b); 1.47 d, 3H, J=6.3, (–CH₃). B: 7.31–

7.21 m, 2H, (AA⁰BB⁰); 7.09–7.01 m, 2H, (AA⁰BB⁰);

4.69–4.57 m, 1H, (H5); 3.88 dd, 1H, J₁=8.5, (H3), 2.83–

2.73 m, 1H, (H4a); 2.05–1.92 m, 1H, (H4b); 1.49 d, 3H,

J=6.3, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A:

176.69; 163.18 and 159.92 (J_CꢀF=245.6 Hz); 132.51 and

74.99; 47.26; 39.53; 20.84. IR(CDCl ): n_max1346, 1388,

3

1480, 1575, 1599, 1774, 2983 cm^ꢀ1. LRMS: m/z (%) 211

(M^ꢄ⁺, 28), 166 (48), 151 (23), 138 (12), 131 (100), 115

(32), 103 (19), 91 (15), 77 (11), 63 (8), 51 (11).

3-(2-Chlorophenyl)-5-methyltetrahydrofuran-2-one (4j).

Colorless oil, yield 87%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.43–7.37 m, 1H, (Ar); 7.31–7.21 m, 3H, (Ar); 4.85–

4.74 m, 1H, (H5); 4.35–4.28 m, 1H, (H3); 2.45–2.39 m,

2H, (H4); 1.48 d, 3H, J=6.3, (–CH₃). B: 7.43–7.37 m,

1H, (Ar); 7.31–7.21 m, 3H, (Ar); 4.74–4.61 m, 1H, (H5);

4.31 dd, 1H, J₁=8.8, J₂=12.5, (H3); 2.90–2.79 m, 1H,

(H4a); 2.05–1.88 m, 1H, (H4b); 1.51 d, 3H, J=6.1, (–

CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A: 176.37; 135.26;

133.81; 129.85; 129.65; 129.00; 127.29; 75.07; 44.06;

37.33; 21.14. B: 175.86; 134.69; 133.93; 129.72; 129.65;

132.47

(J_CꢀF=3.2 Hz);

129.06

and

128.96

(J_CꢀF=8.0 Hz); 115.47 and 115.18 (J_CꢀF=21.5 Hz);

74.89; 44.42; 37.35; 20.64. B: 176.44; 163.18 and 159.92

(J_CꢀF=245.6 Hz); 132.08 and 132.03 (J_CꢀF=3.2 Hz);

129.45 and 129.34 (J_CꢀF=8.0 Hz); 115.32 and 115.04

(J_CꢀF=21.5 Hz); 74.78; 46.64; 39.40; 20.42. IR(CDCl ₃):

n_max1267, 1346, 1388, 1453, 1513, 1608, 1770, 2933,

2983 cm^ꢀ1. LRMS: m/z (%) 195 (M^ꢄ⁺+H, 21), 166 (4),

150 (45), 135 (100), 123 (13), 115 (23), 109 (18), 96 (8),

83 (5), 75 (9), 63 (5), 57 (6), 50 (6).

128.88; 127.33; 75.21; 45.96; 38.95; 20.93. IR(CDCl ):

3

n_max1270, 1348, 1388, 1444, 1480, 1770, 2934,

2984 cm^ꢀ1. LR MS:m/z (%) 211 (M^ꢄ⁺, 28), 195 (1), 184

(1), 175 (1), 166 (50), 151 (31), 131 (100), 115 (38), 103

(22), 91 (15), 77 (13), 63 (10), 51 (13).

3-(3-Fluorophenyl)-5-methyltetrahydrofuran-2-one

(4n). Colorless oil, yield 79%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.40–7.25 m, 1H, (Ar); 7.10–6.90 m, 3H,

(Ar); 4.90–4.70 m, 1H, (H5); 3.97–3.90 m, 1H, (H3);

2.60–2.45 m, 1H, (H4a); 2.45–2.30 m, 1H, (H4b); 1.47 d,

3H, J=6.3, (–CH₃). B: 7.40–7.25 m, 1H, (Ar); 7.10–6.90

m, 3H, (Ar); 4.70–4.55 m, 1H, (H5); 3.90 dd, 1H,

J₁=8.5, J₂=12.8, (H3); 2.85–2.70 m, 1H, (H4a); 2.10–

1.90 m, 1H, (H4b); 1.49 d, 3H, J=6.3, (–CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d A: 176.24; 164.41 and 161.14

(J_CꢀF=246.2 Hz); 139.13 and 139.03 (J_CꢀF=7.7 Hz);

130.41 and 130.30 (J_CꢀF=8.3 Hz); 123.69 and 123.65

(J_CꢀF=2.9 Hz); 115.20 and 114.91 (J_CꢀF=22.3 Hz);

114.62 and 114.34 (J_CꢀF=20.9 Hz); 75.13; 47.26 and

47.24 (J_CꢀF=1.7 Hz); 39.50; 21.06. B: 175.94; 164.33

and 161.07 (J_CꢀF=246.2 Hz); 138.66 and 138.56

(J_CꢀF=7.4 Hz); 130.25 and 130.14 (J_CꢀF=8.3 Hz);

123.25 and 123.21 (J_CꢀF=2.9 Hz); 114.85 and 114.56

(J_CꢀF=22.3 Hz); 114.62 and 114.34 (J_CꢀF=20.9 Hz);

74.96; 45.24 and 45.22 (J_CꢀF=1.7 Hz); 37.62; 20.82. IR

(CDCl₃): n_max1266, 1345, 1388, 1448, 1492, 1593, 1768,

2935, 2983 cm^ꢀ1. LRMS: m/z (%) 195 (M^ꢄ⁺+H, 22),

150 (52), 135 (100), 122 (17), 115 (22), 109 (17), 96 (10),

83 (3), 75 (7), 63 (5), 57 (4), 51 (7).

3-(3,4-Dichlorophenyl)-5-methyltetrahydrofuran-2-one

(4k). White crystals, quantitative yield. Mp 56–58 ^ꢂC.

¹H NMR(300 MHz, CDCl ₃): d A: 7.45–7.37 m, 2H,

(Ar); 7.17–7.11 m, 1H, (Ar); 4.86–4.74 m, 1H, (H5);

3.93–3.86 m, 1H, (H3); 2.57–2.46 m, 1H, (H4a); 2.42–

2.31 m, 1H, (H4b); 1.46 d, 3H, J=6.4, (–CH₃). B: 7.45–

7.37 m, 2H, (Ar); 7.17–7.11 m, 1H, (Ar); 4.69–4.57 m,

1H, (H5); 3.86 dd, 1H, J₁=8.5, J₂=12.9, (H3); 2.83–

2.73 m, 1H, (H4a); 2.04–1.91 m, 1H, (H4b); 1.50 d, 3H,

J=6.3, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A:

175.82; 136.76; 132.80; 131.66; 130.69; 129.60; 127.00;

75.08; 44.48; 37.29; 21.00. B: 175.53; 136.30; 132.64;

131.66; 130.56; 129.94; 127.37; 75.03; 46.65; 39.26;

20.74. IR(CHCl ): n_max1345, 1389, 1473, 1564, 1770,

3

ꢄ

2935, 2983, 3026 cm^ꢀ1. LR MS:m/z (%) 245 (M

,

+

27), 200 (68), 185 (37), 165 (100), 150 (37), 137 (15),

129 (24), 115 (20), 102 (18), 87 (5), 75 (15), 63 (8), 50

(11).

3-(2,4-Dichlorophenyl)-5-methyltetrahydrofuran-2-one

(4l). White crystals, yield 77%, Mp 45–47 ^ꢂC. H NMR

1

(300 MHz, CDCl₃): d A: 7.43 d, 1H, J=2.1, (Ar); 7.26

dd, 1H, J₁=2.1, J₂=8.5, (Ar); 7.18 d, 1H, J=8.5, (Ar);

4.85–4.73 m, 1H, (H5); 4.27 t, 1H, J=9.0, (H3); 2.44–

2.37 m, 2H, (H4), 1.48 d, 3H, J=6.6, (–CH₃). B: 7.42 d,

1H, J=2.2, (Ar); 7.28–7.19 m, 2H, (Ar); 4.73–4.61 m,

1H, (H5); 4.26 dd, 1H, J₁=8.8, J₂=12.6, (H3); 2.89–

2.78 m, 1H, (H4a); 1.97–1.82 m, 1H, (H4b); 1.50 d, 3H,

J=6.1, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A:

175.87; 134.57; 134.06; 133.84; 129.88; 129.67; 127.59;

75.05; 43.45; 37.12; 21.13. B: 175.41; 134.67; 134.06;

133.27; 130.44; 129.53; 127.66; 75.26; 45.49; 38.87;

3-(3,4-Difluorophenyl)-5-methyltetrahydrofuran-2-one

(4o). White crystals, yield 89%. Mp 29–30 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.20–6.99 m, 3H, (Ar); 4.86–

4.74 m, 1H, (H5); 3.94–3.87 m, 1H, (H3); 2.57–2.46 m,

1H, (H4a); 2.42–2.32 m, 1H, (H4b); 1.47 d, 3H, J=6.3,

(–CH₃). B: 7.21–6.99 m, 3H, (Ar); 4.70–4.57 m, 1H,

(H5); 3.87 dd, 1H, J₁=8.6, J₂=13.0, (H3); 2.84–2.74 m,

1H, (H4a); 2.04–1.91 m, 1H, (H4b); 1.51 d, 3H, J=6.1,

(–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A: 176.25;

133.67 and 133.61 (J_CꢀF=3.9 Hz); 123.83, 123.78,

123.75 and 123.70 (J_CꢀF=3.4 and 6.3 Hz); 117.66 and

20.88. IR(CDCl ): n_max1346, 1386, 1477,1560, 1591,

3

1773, 2934, 2982 cm^ꢀ1. LRMS: m/z (%) 245 (M^ꢄ⁺, 100),

226 (1), 215 (1), 200 (50), 185 (26), 165 (72), 150 (29),

137 (12), 129 (16), 115 (15), 102 (18), 87 (4), 75 (10), 63

(6), 50 (8).

117.43

(J_CꢀF=17.2 Hz);

117.27

and

117.03

(J_CꢀF=18.0 Hz); 74.95; 46.62; 39.36; 20.68. B: 175.96;

152.03, 151.87, 148.74 and 148.57 (J_CꢀF=248.8 a

2856

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

12.6 Hz); 151.49, 151.32, 148.19 and 148.03 (J_CꢀF=248.5

and 12.6 Hz); 133.22 and 133.17 (J_CꢀF=3.8 Hz); 124.22,

124.17, 124.14 and 124.09 (J_CꢀF=3.6 and 6.4 Hz); 117.81

and 117.58 (J_CꢀF=17.5 Hz); 116.98 and 116.74

(J_CꢀF=18.0 Hz); 75.02; 44.43; 37.36; 20.93. IR(CDCl ₃):

n_max1289, 1345, 1388, 1433, 1522, 1611, 1770, 2935,

2983 cm^ꢀ1. LRMS: m/z (%) 213 (M^ꢄ⁺+H, 82), 195 (1),

168 (72), 153 (100), 140 (21), 133 (43), 127 (28), 114 (11),

101 (10), 81 (3), 75 (5), 63 (9), 51 (5).

(CDCl₃): n_max1344, 1388, 1464, 1557, 1772, 2935,

2983 cm^ꢀ1. LRMS: m/z (%) 334 (M^ꢄ⁺, 4), 290 (40), 262

(7), 209 (22), 196 (23), 182 (7), 130 (100), 115 (48), 102

(27), 89 (6), 75 (11), 63 (9), 51 (11).

5-Methyl-3-(1-naphthyl)tetrahydrofuran-2-one

(4s).

White crystals, yield 66%. Mp 92–94 ^ꢂC, lit.³¹101–

102 ^ꢂC. H NMR(300 MHz, CDCl ): d A: 7.92–7.78 m,

1

3

3H, (Ar); 7.60–7.34 m, 4H, (Ar); 4.85–4.71 m, 1H, (H5);

4.67–4.56 m, 1H, (H3); 2.53–2.47 m, 2H, (H4); 1.51 d,

3H, J=6.3 Hz, (–CH₃); B: 7.92–7.78 m, 3H, (Ar); 7.60–

7.34 m, 4H, (Ar); 4.85–4.71 m, 1H, (H5); 4.67–4.56 m,

1H, (H3); 1.54 d, 3H, J=6.3 Hz, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 177.66, 134.13, 133.37, 131.34,

129.15, 128.38, 126.56, 125.94, 125.41, 124.58, 122.98,

75.55, 43.89, 38.63, 20.91; B: 176.98, 134.02, 133.06,

131.03, 129.15, 128.38, 126.43, 125.79, 125.58, 124.58,

122.82, 75.21, 44.84, 39.67, 21.07. IR(CDCl ₃): n_max

3-(4-Bromophenyl)-5-methyltetrahydrofuran-2-one

(4p). White crystals, yield 88%. Mp 52–53 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.52–7.46 m, 2H, (AA⁰BB⁰);

7.20–7.14 m, 2H, (AA⁰BB⁰); 4.86–4.73 m, 1H, (H5);

3.93–3.86 m, 1H, (H3); 2.57–2.46 m, 1H, (H4a), 2.41–

2.30 m, 1H, (H4b); 1.47 d, 3H, J=6.3, (–CH₃). B: 7.52–

7.46 m, 2H, (AA⁰BB⁰); 7.20–7.14 m, 2H, (AA⁰BB⁰);

4.70–4.56 m, 1H, (H5); 3.86 dd, 1H, J₁=8.5, J₂=13.0,

(H3); 2.83–2.72 m, 1H, (H4a); 2.05–1.91 m, 1H, (H4b);

1.50 d, 3H, J=6.1, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d A: 176.32; 135.74; 131.93; 129.26; 121.50;

75.06; 44.98; 37.65; 21.08. B: 176.03; 135.25; 131.80;

2983, 2935, 1770, 1599, 1513, 1455, 1387, 1343 cm^ꢀ1

.

LRMS: 226 (M^ꢄ⁺, 83), 198 (3), 182 (17), 167 (100), 153

(72), 139 (8), 127 (7), 115 (8), 102 (3), 89 (5), 77 (9), 63

(8), 51 (8).

129.65; 121.54; 74.96; 47.12; 39.57; 20.85. IR(CDCl ):

3

n_max1266, 1344, 1388, 1456, 1491, 1770, 2935,

2982 cm^ꢀ1. LRMS: m/z (%) 255 (M^ꢄ⁺, 7), 237 (1), 210

(48), 195 (10), 182 (8), 171 (3), 158 (2), 143 (1), 131

(100), 116 (66), 103 (16), 91 (20), 77 (13), 63 (10), 51

(13).

5-Methyl-3-(4-bromo-1-naphthyl)tetrahydrofuran-2-

1

one (4t). Colorless oil, yield 93%. H NMR(300 MHz,

CDCl₃): d A: 8.37–8.30 m, 1H, (Ar); 7.92–7.84 m, 1H,

(Ar); 7.75 d, 1H, J=7.7 Hz, (Ar); 7.68–7.57 m, 2H, (Ar);

7.21 d, 1H, J=7.7 Hz, (Ar); 4.84–4.72 m, 1H, (H5); 4.60

dd, 1H, J₁=8.4 Hz, J₂=6.5 Hz, (H3); 2.53–2.44 m, 2H,

(H4), 1.51 d, 3H, J=6.3 Hz, (–CH₃); B: 8.37–8.30 m,

1H, (Ar); 7.93–7.86 m, 1H, (Ar); 7.79 d, 1H, J=7.7 Hz,

(Ar); 7.67–7.56 m, 2H, (Ar); 7.32 d, 1H, J=7.7 Hz, (Ar);

4.84–4.72 m, 1H, (H5); 4.58 dd, 1H, J₁=12.1 Hz,

J₂=8.8 Hz, (H3); 3.01–2.86 m, 1H, (H4a); 2.18–1.99 m,

1H, (H4b); 1.54 d, 3H, J=6.3 Hz, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 177.11, 133.48, 132.47, 132.29,

129.46, 128.43, 127.42, 127.39, 125.02, 123.46, 123.10,

75.52, 43.64, 38.49, 20.91; B: 176.45, 133.14, 132.63,

132.32, 129.70, 128.43, 127.29, 127.27, 126.10, 123.29,

123.13, 75.24, 44.66, 39.62, 21.04. IR(CDCl ₃): n_max

2982, 2935, 1767, 1595, 1508, 1384, 1345 cm^ꢀ1. LR MS:

304 (M^ꢄ⁺-H, 74), 260 (13), 245 (13), 233 (20), 219 (4),

181 (100), 166 (84), 152 (55), 139 (15), 126 (10), 115 (4),

101 (4), 87 (5), 76 (6), 63 (11), 50 (7).

3-(3-Bromophenyl)-5-methyltetrahydrofuran-2-one

(4q). Colorless oil, yield 87%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.45–7.40 m, 2H, (Ar); 7.26–7.21 m, 2H,

(Ar); 4.86–4.75 m, 1H, (H5); 3.90 dd, 1H, J₁=7.6,

J₂=9.2, (H3); 2.58–2.47 m, 1H, (H4a); 2.41–2.30 m, 1H,

(H4b); 1.47 d, 3H, J=6.3, (–CH₃). B: 7.45–7.40 m, 2H,

(Ar); 7.26–7.21 m, 2H, (Ar); 4.69–4.56 m, 1H, (H5); 3.86

dd, 1H, J₁=8.5, J₂=12.8, (H3); 2.83–2.72 m, 1H,

(H4a); 2.07–1.92 m, 1H, (H4b); 1.51 d, 3H, J=6.0, (–

CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A: 176.16; 138.96;

131.01; 130.62; 130.35; 126.26; 122.81; 75.12; 45.15;

37.64; 21.06. B: 175.87; 138.47; 131.01; 130.62; 130.22;

126.70; 122.65; 74.99; 47.20; 39.53; 20.82. IR(CDCl ):

3

n_max1346, 1388, 1479, 1569, 1597, 1773, 2936,

2984 cm^ꢀ1. LRMS: m/z (%) 255 (M^ꢄ⁺, 4), 237 (1), 223

(1), 210 (30), 195 (4), 184 (7), 169 (3), 156 (2), 131 (100),

116 (40), 103 (15), 91 (20), 77 (12), 63 (8), 51 (11).

5-Methyl-3-[3-(N-methylindolyl)]tetrahydrofuran-2-one

(4u). White crystals, yield 95%. Mp 98–100 ^ꢂC. ¹H

3-(3,4-Dibromophenyl)-5-methyltetrahydrofuran-2-one

NMR(300 MHz, CDCl ): d A: 7.60–7.56 m, 1H, (Ar);

3

ꢂ

1

(4r). White crystals, yield 83%. Mp 40–42 C. H NMR

(300 MHz, CDCl₃): d A: 7.62–7.54 m, 2H, (Ar); 7.15–

7.08 m, 1H, (Ar); 4.87–4.74 m, 1H, (H5); 3.91–3.84 m,

1H, (H3); 2.58–2.45 m, 1H, (H4a); 2.42–2.31 m, 1H,

(H4b); 1.47 d, 3H, J=6.4, (–CH₃). B: 7.62–7.54 m, 2H,

(Ar); 7.15–7.08 m, 1H, (Ar); 4.70–4.56 m, 1H, (H5); 3.84

dd, 1H, J₁=8.5, J₂=12.9, (H3); 2.84–2.72 m, 1H,

(H4a); 2.05–1.90 m, 1H, (H4b); 1.51 d, 3H, J=6.1,

(–CH₃). ¹³C NMR(75 MHz, CDCl ₃) d A: 175.74;

137.55; 133.91; 132.78; 127.82; 125.20; 123.92; 75.09;

44.49; 37.34; 21.04. B: 175.44; 137.07; 133.79; 133.13;

128.20; 125.03; 123.92; 75.05; 46.65; 39.29; 20.78. IR

7.36–7.22 m, 2H, (Ar); 7.19–7.10 m, 2H, (Ar); 4.86–4.73

m, 1H, (H5); 4.17 dd, 1H, J₁=12.4 Hz, J₂=8.6 Hz,

(H3); 3.75 s, 3H, (N–CH₃); 2.65–2.53 m, 1H, (H4a);

2.45–2.32 m, 1H, (H4b); 1.49 d, 3H, J=6.3 Hz, (–CH₃);

B: 7.55–7.51 m, 1H, (Ar); 7.36–7.22 m, 2H, (Ar); 7.19–

7.10 m, 2H, (Ar); 4.73–4.62 m, 1H, (H5); 4.17 dd, 1H,

J₁=12.4 Hz, J₂=8.6 Hz, (H3), 3.76 s, 3H, (N–CH₃);

2.94–2.81 m, 1H, (H4a); 2.13–1.98 m, 1H, (H4b); 1.51 d,

3H, J=6.0 Hz, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d

3

A: 177.65, 137.25, 126.63, 126.52, 122.04, 119.31,

118.79, 109.54, 75.46, 39.24, 37.49, 32.70, 20.93; B:

177.36, 137.12, 126.94, 126.44, 121.89, 119.23, 118.75,

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2857

109.54, 75.18, 39.47, 37.74, 32.70, 20.93. IR(CDCl ):

3

3.80 s, 3H, (Ar–OCH₃); 2.59–2.48 m, 1H, (H4a); 2.39–

2.28 m, 1H, (H4b); 1.46 d, 3H, J=6.3, (–CH₃). B: 7.31–

7.24 m, 1H, (Ar); 6.89–6.80 m, 3H, (Ar); 4.68–4.55 m,

1H, (H5); 3.86 dd, 1H, J₁=8.7, J₂=12.7, (H3); 3.80 s,

3H, (Ar–OCH₃); 2.82–2.71 m, 1H, (H4a); 2.09–1.95 m,

1H, (H4b); 1.50 d, 3H, J=6.3, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 176.99; 159.90; 138.44; 129.93;

119.78; 113.53; 112.81; 75.18; 55.19; 45.64; 37.85; 20.96.

B: 176.68; 159.79; 137.95; 129.79; 120.28; 113.97;

n_max2982, 2936, 1766, 1476, 1388, 1342, 1255 cm^ꢀ1

.

LRMS: 229 (M^ꢄ⁺, 6), 185 (10), 170 (26), 157 (6), 144

(7), 130 (3), 115 (3), 102 (2), 89 (2), 77 (1), 63 (2), 51 (1).

5-Methyl-3-(1-adamantyl)tetrahydrofuran-2-one (4w).

White crystals, yield 68%. Mp 66–68 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 4.60–4.48 m, 1H, (H5); 2.40–

2.28 m, 2H, (H3+H4a); 2.28–2.14 m, 1H, (H4b); 2.05–

1.95 m, 3H, (CH); 1.95–1.45 m, 12H, (CH₂); 1.34 d, 3H,

J=6.2 Hz, (–CH₃); B: 4.44–4.30 m, 1H, (H5); 2.40–2.28

m, 2H, (H3+H4a); 2.28–2.14 m, 1H, (H4b); 2.05–1.95

m, 3H, (CH); 1.95–1.45 m, 12H, (CH₂); 1.39 d, 3H,

112.83; 74.89; 55.19; 47.60; 39.65; 20.76. IR(CDCl ):

3

n_max1156, 1246, 1299, 1468, 1603, 1764, 2838, 2981,

2999 cm^ꢀ1. LRMS: m/z (%) 206 (M^ꢄ⁺, 72), 205 (2),

191 (1), 178 (12), 162 (32), 147 (100), 131 (29), 121 (17),

115 (17), 103 (12), 91 (63), 77 (17), 65 (19), 55 (4), 51

(13).

J=6.2 Hz, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d A:

3

177.18, 74.69, 51.54, 39.54, 36.84, 34.66, 31.83, 28.31,

21.72; B: 176.62, 73.83, 49.90, 39.24, 36.71, 33.58, 30.46,

28.31, 20.88. IR(CDCl ): n_max2908, 2852, 1759, 1528,

5-Methyl-3-(3-benzo[b]thienyl)tetrahydrofuran-2-one

(4v). Colorless oil, yield 86%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.77–7.67 (2H, m, Ar5,7), 7.45–7.34 m,

3H, (Ar2,4,6); 4.88–4.66 m, 1H, (H5); 4.27 dd, 1H,

J₁=12.4 Hz, J₂=8.8 Hz, (H3); 2.63–2.52 m, 1H, (H4a);

2.47–2.35 m, 1H, (H4b); 1.50 d, 3H, J=6.3 Hz, (–CH₃);

B: 7.90–7.85 m, 2H, (Ar5,7); 7.45–7.34 m, 3H, (Ar2,4,6);

4.88–4.66 m, 1H, (H5); 4.27 dd, 1H, J₁=12.4 Hz,

J₂=8.8 Hz, (H3); 2.95–2.83 m, 1H, (H4a); 2.16–2.00 m,

1H, (H4b); 1.53 d, 3H, J=6.3 Hz, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 176.32, 140.56, 137.55, 130.98,

124.70, 124.31, 123.89, 123.06, 121.58, 75.57, 40.55,

36.82, 20.92; B: 175.89, 140.55, 137.67, 130.74, 124.55,

124.21, 123.89, 123.05, 121.52, 75.25, 41.90, 38.27,

3

1453, 1344, 1284 cm^ꢀ1. LRMS: 235 (M^ꢄ⁺+H, 52), 189

(4), 161 (4), 136 (10), 135 (100), 107 (5), 105 (6), 93 (5),

91 (8), 79 (5), 67 (3), 55 (5), 53 (3).

Preparation of tetrahydrofuranes 4c, 4d and 4v. A

solution of HBr in AcOH (30 wt%, 10 mL) was slowly

added to 2-substituted pent-4-enoic acid (3c, 3d, 3v)

(8.0 mmol) placed under Ar. The reaction mixture was

stirred for 6 h, and the solvent was then removed. The

residue was redissolved in methanol (15 mL), and

Na₂CO₃(16 mmol) was added to the solution. After

stirring for 45 min at ambient temperature, the solution

was diluted with brine, and the resultant mixture

extracted with ethyl acetate. The organic phase was

dried over Na₂SO₄, and the solvent evaporated. Pur-

iﬁcation by column chromatography (petroleum ether–

ether 85:15) aﬀorded lactones 4c, 4d and 4u in 71–86%

yields.

20.88. IR(CDCl ): n_max2984, 2935, 1771, 1430, 1388,

3

1343 cm^ꢀ1. LRMS: 232 (M^ꢄ⁺, 6), 188 (26), 173 (78), 160

(7), 147 (14), 129 (10), 115 (22), 102 (4), 89 (5), 77 (3), 63

(5), 50 (4).

Preparation of furanones 5a–u and 5w. Butyllithium

(5.5 mmol) was added to a solution of diisopropylamine

(5.3 mmol) in dry THF (15 mL) at 0 ^ꢂC under argon.

After 10 min at 0 ^ꢂC, the LDA solution was cooled to

ꢀ60 ^ꢂC, and a solution of a saturated lactone (4a–u, 4w)

(5.0 mmol) in THF (2 mL) was added. The reaction

temperature was maintained at ꢀ60 ^ꢂC for 30 min, and a

solution of phenylselenenyl chloride (7.5 mmol) in THF

(5 mL) was added. The resultant mixture was slowly

allowed to warm to room temperature (over 2 h), dilu-

ted with ethyl acetate (50 mL), washed with saturated

aqueous NH₄Cl, dried over Na₂SO₄, and concentrated.

The crude phenylselanyl derivative was rapidly puriﬁed

by column chromatography (petroleum ether–ether

98:2), dissolved in CHCl₃(10 mL), and MCPBA

(7.5 mmol) or H₂O₂(30%, 2–6 mL) were added to the

solution in several portions at 0 ^ꢂC. The reaction mix-

ture was then stirred for 2 h at ambient temperature or

until TLC indicated the reaction was complete. A fur-

ther portion of CHCl₃(10 mL) was added along with

5% aqueous Na₂CO₃(20 mL). The layers were sepa-

rated, the organic phase was washed with 5% aqueous

Na₂CO₃(20 mL), dried over Na₂SO₄, and the solvent

evaporated. Products 5a–w were puriﬁed by column

chromatography (petroleum ether–ether 9:1), and were

obtained with overall yields in the range 13–65% over

two steps.

3-(4-Methoxyphenyl)-5-methyltetrahydrofuran-2-one

(4c). White crystals, yield 71%. Mp 68–70 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.23–7.17 m, 2H, (AA⁰BB⁰);

6.93–6.86 m, 2H, (AA⁰BB⁰); 4.85–4.73 m, 1H, (H5); 3.88

dd, 1H, J₁=7.4, J₂=9.2, (H3); 3.80 s, 3H, (–OCH₃);

2.56–2.46 m, 1H, (H4a); 2.38–2.27 m, 1H, (H4b); 1.46 d,

3H, J=6.3, (–CH₃). B: 7.23–7.17 m, 2H, (AA⁰BB⁰);

6.93–6.86 m, 2H, (AA⁰BB⁰); 4.67–4.54 m, 1H, (H5); 3.84

dd, 1H, J₁=8.6, J₂=12.8, (H3); 3.80 s, 3H, (–OCH₃);

2.81–2.70 m, 1H, (H4a); 2.06–1.91 m, 1H, (H4b); 1.50 d,

3H, J=6.3, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d A:

3

177.23; 158.77; 128.82; 128.38; 114.26; 75.03; 55.32;

44.85; 38.03; 21.11. B: 176.97; 158.80; 128.99; 128.56;

114.15; 74.82; 55.32; 46.99; 39.89; 20.91. IR(CDCl ):

3

n_max1515, 1585, 1614, 1770, 2839, 2936, 2982 cm^ꢀ1

.

LRMS: m/z (%) 206 (M^ꢄ⁺, 27), 162 (29), 148 (28), 147

(100), 134 (11), 119 (14), 103 (8), 90 (13), 91 (50), 77

(17), 65 (15), 51 (18).

3-(3-Methoxyphenyl)-5-methyltetrahydrofuran-2-one

(4d). Colorless oil, yield 81%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.31–7.24 m, 1H, (Ar); 6.89–6.80 m, 3H,

(Ar); 4.86–4.74 m, 1H, (H5); 3.90 dd, 1H, J₁=7.1, (H3);

2858

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

3-Phenyl-5-methyl-2,5-dihydrofuran-2-one (5a). White

(–CH₃). ¹³C NMR(75 MHz, CDCl ): d 170.51; 152.14;

147.86; 135.43; 129.53; 127.82; 123.73; 77.08; 18.99. IR

3

crystals, yield 62%. Mp 45–46 ^ꢂC, lit.⁸47–48 ^ꢂC. ¹H

NMR(300 MHz, CDCl ₃): d 7.88–7.83 m, 2H, (Ar); 7.55

d, 1H, J=1.9, (H4); 7.46–7.38 m, 3H, (Ar); 5.16 qd, H,

J₁=1.9, J₂=6.9, (H5); 1.52 d, 3H, J=6.9, (–CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d 171.66; 148.92; 131.39;

129.48; 129.31; 128.64; 127.03; 76.71; 19.15. IR

(KBr pellet): n_max856, 976, 1136, 1345, 1511, 1600,

1743, 2983, 3074 cm^ꢀ1. LRMS: m/z (%) 219 (M^ꢄ⁺, 100),

203 (14), 189 (7), 160 (9), 148 (79), 132 (13), 118 (20),

102 (28), 90 (19), 75 (18), 63 (13), 51 (18). calcd for

C₁₁H₉NO₄: C, 60.28; H, 4.14; N 6.39; found: C, 60.28;

H, 4.08; N 6.39.

(CDCl₃): n_max1322, 1375, 1450, 1493, 1758, 2986 cm^ꢀ1

.

LRMS: m/z (%) 174 (M^ꢄ⁺, 65), 131 (25), 128 (6), 115

(5), 104 (25), 103 (100), 102 (12), 89 (3), 77 (14), 63 (8),

51 (15). calcd for C₁₁H₁₀O₂: C, 75.84; H, 5.79; found: C,

75.60; H, 5.75.

3-(4-Trifluoromethylphenyl)-5-methyl-2,5-dihy-

drofuran-2-one (5f). White crystals, yield 48%. Mp 91–

93 ^ꢂC. ¹H NMR(300 MHz, CDCl ): d 8.00–7.95 m, 2H,

3

(AA⁰BB⁰); 8.69–7.64 m, 2H, (AA⁰BB⁰); 7.67 d, 1H,

J=1.8, (H4); 5.20 qd, 1H, J₁=1.8, J₂=6.9, (H5); 1.54

3-(4-Methylphenyl)-5-methyl-2,5-dihydrofuran-2-one

(5b). White crystals, yield 51%. Mp 55–57 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.78–7.72 m, 2H, (AA⁰BB⁰); 7.49

d, 1H, J=1.9, (H4); 7.25–7.19 m, 2H, (AA⁰BB⁰), 5.14

qd, 1H, J₁=6.9, J₂=1.9, (H5); 2.38 s, 3H, (CH₃–Ar);

1.51 d, 3H, J=6.9, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d 171.83; 147.95; 139.39; 131.20; 129.32;

d, 3H, J=6.9, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d

3

171.09; 151.22; 132.89, 132.87, 132.85 and 132.83

(J_CꢀF=1.3 Hz); 131.42, 130.99, 130.56 and 130.13

(J_CꢀF=32.6 Hz); 129.93; 129.20, 125.59, 121.98 and

118.38 (J_CꢀF=272.2 Hz); 127.25; 125.43, 125.38, 125.33

and 125.28 (J_CꢀF=3.8 Hz); 76.94; 18.73. IR(KBr pel-

let): n_max848, 979, 1072, 1116, 1328, 1416, 1617,

1750 cm^ꢀ1. LRMS: m/z (%) 242 (M^ꢄ⁺, 80), 223 (11),

213 (2), 199 (30), 171 (100), 151 (33), 145 (5), 120 (6),

102 (7), 87 (3), 75 (8), 63 (5), 50 (7). calcd for

C₁₂H₉F₃O₂: C, 59.51; H, 3.75; found: C, 59.76; H, 3.85.

126.89; 126.64; 76.65; 21.35; 19.19. IR(CDCl ): n_max

3

1322, 1513, 1753, 2933, 3032 cm^ꢀ1. LRMS: m/z (%) 188

(M^ꢄ⁺, 73), 145 (20), 128 (8), 118 (33), 117 (100), 115

(44), 102 (3), 91 (12), 77 (5), 63 (10), 51 (11). calcd for

C₁₂H₁₂O₂: C, 76.57; H, 6.43; found: C, 76.52; H, 6.42.

3-(4-Methoxyphenyl)-5-methyl-2,5-dihydrofuran-2-one

(5c). White crystals, yield 45%. Mp 63–65 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.83–7.77 m, 2H, (AA⁰BB⁰); 7.43

d, 1H, J=1.9, (H4); 6.95–6.89 m, 2H, (AA⁰BB⁰); 5.13

qd, 1H, J₁=1.9, J₂=6.9, (H5); 3.82 s, 3H, (–OCH₃);

1.49 d, 3H, J=6.9 Hz, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): 172.25; 160.32; 146.97; 130.60; 128.36; 121.96;

113.97; 76.80; 55.27; 19.14. IR(CDCl ₃): n_max1257,

3-(3-Trifluoromethylphenyl)-5-methyl-2,5-dihy-

drofuran-2-one (5g). White crystals, yield 55%. Mp 39–

40 ^ꢂC. ¹H NMR(300 MHz, CDCl ): d 8.13–8.06 m, 2H,

(Ar); 7.66 d, 1H, J=1.9, (H4); 7.64–7.50 m, 2H, (Ar);

5.19 qd, 1H, J₁=1.9, J₂=6.9, (H5); 1.54 d, 3H, J=6.9,

3

(–CH₃). ¹³C NMR(75 MHz, CDCl ): d 170.90; 150.18;

3

131.64, 131.20, 130.78 and 130.34 (J_CꢀF=32.6 Hz);

130.21, 130.19, 130.17 and 130.15 (J_CꢀF=1.3 Hz);

130.14; 130.11; 129.14, 125.54, 121.94 and 118.34

(J_CꢀF=271.8 Hz); 129.11; 125.87, 125.82, 125.77 and

125.73 (J_CꢀF=3.7 Hz); 123.84, 123.79, 123.74 and

1306, 1442, 1512, 1608, 1751, 2840, 2935, 2986 cm^ꢀ1

.

LRMS: m/z (%) 204 (M^ꢄ⁺, 67), 176 (6), 161 (12), 145

(6), 134 (37), 133 (100), 115 (9), 102 (9), 89 (13), 77 (10),

63 (12), 51 (10). calcd for C₁₂H₁₂O₃: C, 70.57; H, 5.92;

found: C, 70.45; H, 5.96.

123.68 (J_CꢀF=3.9 Hz); 76.89; 19.12. IR(CDCl ): n_max

3

1268, 1336, 1346, 1451, 1488, 1758, 2935, 2987 cm^ꢀ1

.

LRMS: m/z (%) 243 (M^ꢄ⁺+H, 100), 223 (4), 199 (5),

171 (8), 151 (10), 128 (2), 102 (3), 75 (2), 63 (2), 51 (2).

calcd for C₁₂H₉F₃O₂: C, 59.51; H, 3.75; found: C, 59.48;

H, 3.91.

3-(3-Methoxyphenyl)-5-methyl-2,5-dihydrofuran-2-one

(5d). Colorless oil, yield 50%. ¹H NMR(300 MHz,

CDCl₃): d 7.54 d, 1H, J=1.8, (H4); 7.46–7.25 m, 3H,

(Ar); 6.95–6.90 m, 1H, (Ar); 5.14 qd, 1H, J₁=1.8,

J₂=6.8, (H5); 3.83 s, 3H, (Ar–OCH₃); 1.50 d, 3H,

3-(4-Chlorophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5h). White crystals, yield 56%. Mp 99–101 ^ꢂC. ¹H

NMR(300 MHz, CDCl ₃): d 7.85–7.78 m, 2H, (AA⁰BB⁰);

7.55 d, 1H, J=1.9, (H4); 7.41–7.36 m, 2H, (AA⁰BB⁰);

5.15 qd, 1H, J₁=6.9, J₂=1.9, (H5); 1.52 d, 3H, J=6.9,

J=6.8, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.53;

3

159.63; 149.30; 131.07; 130.70; 129.61; 119.36; 115.08;

112.30; 76.64; 55.27; 19.06. IR(CHCl ₃): n_max1318,

1432, 1466, 1489, 1580, 1601, 1755, 2838, 2936, 3012,

ꢄ

+

3027 cm^ꢀ1. LR MS:m/z (%) 205 (M +H, 100), 187

(2), 175 (1), 161 (12), 145 (2), 133 (28), 118 (10), 102 (7),

89 (8), 77 (1), 63 (5), 51 (2). calcd for C₁₂H₁₂O₃: C,

70.57; H, 5.92; found: C, 70.79; H, 6.16.

(–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.18; 148.99;

3

135.22; 130.19; 128.76; 128.22; 127.79; 76.77; 19.17. IR

(KBr pellet): n_max834, 977, 1093, 1144, 1322, 1492,

ꢄ

+

1745, 2993 cm^ꢀ1. LRMS: m/z (%) 208 (M ꢀH, 52),

165 (23), 139 (38), 137 (100), 127 (5), 115 (11), 101 (22),

87 (4), 75 (18), 63 (11), 51 (18). calcd for C₁₁H₉ClO₂: C,

63.32; H, 4.35; found: C, 63.14; H, 4.50.

3-(4-Nitrophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5e). Yellow crystals, yield 56%. Mp 133–135 ^ꢂC. ¹H

NMR(300 MHz, CDCl ₃): d 8.29–8.22 m, 2H, (AA⁰BB⁰);

8.09–8.03 m, 2H, (AA⁰BB⁰); 7.78 d, 1H, J=1.7, (H4);

5.23 qd, 1H, J₁=1.7, J₂=6.9, (H5); 1.56 d, 3H, J=6.9,

3-(3-Chlorophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5i). White crystals, yield 62%. Mp 50–51^ꢂ. H NMR

1

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2859

(300 MHz, CDCl₃): d 7.86–7.83 m, 1H, (Ar); 7.79–7.72

m, 1H, (Ar); 7.59 d, 1H, J=1.9, (H4); 7.36–7.33 m, 2H,

m, (Ar); 5.16 qd, 1H, J₁=1.9, J₂=6.9, (H5); 1.52 d, 3H,

¹³C NMR(75 MHz, CDCl ₃): d 171.37; 164.60 and

161.30 148.54 and 148.52

(J_CꢀF=249.1 Hz);

(J_CꢀF=1.7 Hz); 130.00; 128.85 and 128.74 (J_CꢀF=8.3 Hz);

125.52 and 125.47 (J_CꢀF=3.4 Hz); 115.62 and 115.33

(J_CꢀF=21.5Hz); 76.70; 19.08. IR(KBr pellet): n_max834,

974, 1117, 1224, 1300, 1323, 1457, 1508, 1602, 1746,

2879, 2988 cm^ꢀ1. LRMS: m/z (%) 192 (M^ꢄ⁺, 55), 175

(2), 164 (4), 149 (28), 133 (9), 127 (3), 121 (100), 115 (4),

107 (3), 101 (21), 87 (3), 81 (3), 75 (10), 62 (5), 57 (5), 50

(8). calcd for C₁₁H₉FO₂: C, 68.75; H, 4.72; found: C,

68.49; H, 4.78.

J=6.9, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.15;

3

150.06; 134.71; 131.23; 130.32; 130.01; 129.46; 127.19;

125.26; 77.21; 19.34. IR(CDCl ₃): n_max1321, 1476, 1568,

1595, 1755, 2935, 2987, 3075 cm^ꢀ1. LRMS: m/z (%) 209

(M^ꢄ⁺, 100), 191 (3), 165 (13), 137 (36), 115 (7), 102 (18),

87 (2), 75 (8), 63 (6), 51 (8). calcd for C₁₁H₉ClO₂: C,

63.32; H, 4.35; found: C, 63.47; H, 4.62.

3-(2-Chlorophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5j). White crystals, yield 59%. Mp 59–60 ^ꢂC. H NMR

1

3-(3-Fluorophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5n). White crystals, yield 65%. Mp 43–45 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.70–7.55 m, 2H, (Ar); 7.59 d, 1H,

J=1.9, (H4); 7.45–7.30 m, 1H, (Ar); 7.07 tdd, 1H,

J₁=8.3, J₂=2.6, J₃=1.0, (Ar); 5.16 qd, 1H, J₁=6.9,

J₂=1.9, (H5); 1.51 d, 3H, J=6.9, (–CH₃). ¹³C NMR

(300 MHz, CDCl₃): d 7.74 d, 1H, J=1.7, (H4); 7.68–

7.64 m, 1H, (Ar); 7.47–7.43 m, 1H, (Ar); 7.34–7.29 m,

2H, (Ar); 5.22 qd, 1H, J₁=1.7, J₂=6.9, (H5); 1.55 d,

3H, J=6.9, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d

171.43; 154.33; 132.97; 130.65; 129.99; 129.88; 129.83;

129.14; 126.70; 77.22; 19.09. IR(CDCl ₃): n_max1320,

1376, 1438, 1451, 1477, 1760, 2935, 2986 cm^ꢀ1. LRMS:

(75 MHz, CDCl₃):

(J_CꢀF=245.6 Hz);

d

170.99; 164.21 and 160.96

149.81; 131.38 and 131.26

ꢄ

+

m/z (%) 208 (M ꢀH, 53), 191 (2), 173 (7), 165 (46),

145 (7), 137 (100), 128 (9), 115 (11), 101 (25), 87 (3), 75

(18), 63 (8), 51 (14). calcd for C₁₁H₉ClO₂: C, 63.32; H,

4.35; found: C, 63.18; H, 4.54.

(J_CꢀF=8.3 Hz); 130.12 and 130.01 (J_CꢀF=8.0 Hz);

122.61 and 122.57 (J_CꢀF=3.2 Hz); 116.26 and 115.98

(J_CꢀF=21.2 Hz); 114.12 and 113.81 (J_CꢀF=23.2 Hz);

76.75; 19.10. IR(CDCl ): n_max1273, 1317, 1450, 1488,

3

1585, 1758, 2935, 2986 cm^ꢀ1. LR MS:m/z (%) 192

(M^ꢄ⁺, 71), 163 (3), 149 (31), 133 (9), 121 (100), 115 (5),

101 (20), 81 (3), 75 (9), 62 (5), 50 (7). calcd for

C₁₁H₉FO₂: C, 68.75; H, 4.72; found: C, 68.96; H, 4.89.

3-(3,4-Dichlorophenyl)-5-methyl-2,5-dihydrofuran-2-

one (5k). White crystals, yield 60%. Mp 110–111 ^ꢂC. ¹H

NMR(300 MHz, CDCl ): d 7.99 d, 1H, J=1.9, (Ar);

3

7.73 dd, 1H, J₁=8.4, J₂=1.9, (Ar); 7.60 d, 1H, J=1.9,

(H4); 7.48 d, 1H, J=8.4, (Ar); 5.17 qd, 1H, J₁=6.9,

J₂=1.9, (H5); 1.53 d, 3H, J=6.9, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 170.71; 150.15; 133.18; 132.65;

130.39; 129.17; 128.95; 128.61; 126.05; 76.87; 18.98. IR

(CHCl₃): n_max1323, 1383, 1472, 1552, 1758, 2935, 2988,

3-(3,4-Difluorophenyl)-5-methyl-2,5-dihydrofuran-2-

one (5o). White crystals, yield 60%. Mp 107–109 ^ꢂC. H

1

NMR(300 MHz, CDCl ₃): d 7.81–7.72 m, 1H, (Ar);

7.65–7.58 m, 1H, (Ar); 7.55 d, 1H, J=1.7, (H4); 7.25–

7.15 m, 1H, (Ar); 5.16 qd, 1H, J₁=1.7, J₂=6.9, (H5);

1.52 d, 3H, J=6.9, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d 171.12; 152.64, 152.48, 149.31 and 149.15

(J_CꢀF=251.4 and 12.0 Hz); 152.02, 151.85, 148.73 and

148.56 (J_CꢀF=248.1 and 12.5 Hz); 149.44 and 149.41

(J_CꢀF=1.7 Hz); 129.44; 126.46, 126.40, 126.37 and

126.32 (J_CꢀF=4.1 and 6.6 Hz); 123.53, 123.48, 123.44

and 123.39 (J_CꢀF=3.7 and 6.3 Hz); 117.69 and 117.46

(J_CꢀF=17.5 Hz); 116.41 and 116.16 (J_CꢀF=18.9 Hz);

ꢄ

+

3026 cm^ꢀ1. LRMS: m/z (%) 242 (M ꢀH, 100), 225 (4),

214 (3), 199 (33), 171 (94), 150 (7), 136 (31), 126 (7), 115

(9), 99 (13), 86 (6), 74 (13), 63 (9), 50 (14). calcd for

C₁₁H₈Cl₂O₂: C, 54.35; H, 3.32; found: C, 54.56; H, 3.25.

3-(2,4-Dichlorophenyl)-5-methyl-2,5-dihydrofuran-2-

one (5l). White crystals, yield 36%. Mp 47–49 ^ꢂC. H

1

NMR(300 MHz, CDCl ): d 7.77 d, 1H, J=1.7, (H4);

76.77; 19.01. IR(CDCl ): n_max1275, 1319, 1376, 1436,

3

7.65 d, 1H, J=8.5, (Ar); 7.47 d, 1H, J=2.2, (Ar); 7.31

dd, 1H, J₁=2.2, J₂=8.5, (Ar); 5.21 qd, 1H, J₁=1.7,

J₂=6.9, (H5); 1.54 d, 3H, J=6.9, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 171.17; 154.61; 135.14; 133.71;

131.41; 129.85; 128.05; 127.10; 126.68; 77.30; 19.02. IR

(KBr pellet): n_max1063, 1116, 1136, 1319, 1476, 1586,

1518, 1604, 1754, 2935, 2986 cm^ꢀ1. LRMS: m/z (%) 210

(M^ꢄ⁺, 65), 193 (2), 182 (4), 167 (30), 151 (7), 139 (100),

119 (21), 99 (8), 87 (6), 74 (5), 63 (8), 50 (5). calcd for

C₁₁H₈F₂O₂: C, 62.86; H, 3.84; found: C, 62.75; H, 4.00.

ꢄ

+

1755, 2933, 2982 cm^ꢀ1. LRMS: m/z (%) 242 (M ꢀH,

49), 199 (29), 174 (72), 171 (100), 149 (5), 136 (21), 127

(8), 115 (7), 98 (17), 86 (7), 74 (18), 62 (11), 50 (17).

calcd for C₁₁H₈Cl₂O₂: C, 54.35; H, 3.32; found: C,

54.16; H, 3.43.

3-(4-Bromophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5p). White crystals, yield 58%. Mp 105–106 ^ꢂC. ¹H

NMR(300 MHz, CDCl ₃): d 7.78–7.71 m, 2H, (AA⁰BB⁰);

7.56 d, 1H, J=1.9, (H4); 7.56–7.52 m, 2H, (AA⁰BB⁰);

5.15 qd, 1H, J₁=1.9, J₂=6.8 Hz, (H5); 1.52 d, 3H,

J=6.8, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.10;

3

149.05; 131.73; 130.29; 128.47; 128.23; 123.57; 76.79;

3-(4-Fluorophenyl)-5-methyl-2,5-dihydrofuran-2-one

(5m). White crystals, yield 56%. Mp 81–83 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.90–7.80 m, 2H, (AA⁰BB⁰); 7.51 d,

1H, J=1.9, (H4); 7.15–7.00 m, 2H, (AA⁰BB⁰), 5.13 qd,

1H, J₁=6.9, J₂=1.9, (H5); 1.48 d, 3H, J=6.9, (–CH₃).

19.16. IR(CDCl ): n_max1296, 1323, 1403, 1488, 1590,

3

1757, 2987 cm^ꢀ1. LRMS: m/z (%) 254 (M^ꢄ⁺+H, 69),

223 (4), 209 (30), 195 (9), 181 (100), 144 (4), 128 (12), 115

(18), 102 (55), 91 (7), 75 (38), 63 (17), 51 (39). calcd for

C₁₁H₉BrO₂: C, 52.20; H, 3.58; found: C, 52.39; H, 3.52.

2860

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

3-(3-Bromophenyl)-5-methyl-2,5-dihydrofuran-2-one

NMR(300 MHz, CDCl ₃): d 8.14 s, 1H, (Ar2); 7.84–7.76

m, 1H, (Ar7); 7.47 d, 1H, J=1.9 Hz, (H4); 7.41–7.21 m,

3H, (Ar4,5,6); 5.23 qd, 1H, J₁=6.6 Hz, J₂=1.9 Hz,

(H5); 3.82 s, 3H, (–NCH₃); 1.54 d, 3H, J=6.6 Hz, (–

(5q). White crystals, yield 61%. Mp 58–59 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.99 bs, 1H, (Ar); 7.81 bd, 1H,

J=7.8, (Ar); 7.58 d, 1H, J=1.7, (H4); 7.51 bd, 1H,

J=7.8, (Ar); 7.28 bt, 1H, J=7.8, (Ar); 5.16 qd, 1H,

J₁=1.7, J₂=6.9, (H5); 1.52 d, 3H, J=6.9, (–CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d 170.91; 149.85; 132.17;

131.29; 130.07; 130.03; 129.84; 125.52; 122.63; 76.79;

CH₃). ¹³C NMR(75 MHz, CDCl ): d 173.19, 141.08,

3

137.06, 130.62, 126.12, 125.70, 122.34, 120.54, 119.53,

109.90, 104.46, 77.84, 33.03, 19.60. IR(CDCl ): n_max

3

3127, 2984, 2934, 1747, 1643, 1524, 1474, 1376,

1319 cm^ꢀ1. LRMS: 227 (M^ꢄ⁺, 100), 198 (2), 184 (3), 156

(46), 127 (1), 115 (5), 89 (1), 63 (1). calcd for

C₁₄H₁₃NO₂: C, 73.99; H, 5.77; N, 6.16; found: C, 73.73;

H, 6.06; N, 5.93.

19.15. IR(CDCl ): n_max1321, 1474, 1561, 1592, 1754,

3

2935, 2988 cm^ꢀ1. LRMS: m/z (%) 253 (M^ꢄ⁺, 100), 237 (5),

223 (3), 209 (60), 195 (5), 181 (95), 156 (3), 145 (9), 128 (13),

115 (17), 102 (100), 87 (6), 75 (32), 63 (20), 50 (30). calcd for

C₁₁H₉BrO₂: C, 52.20; H, 3.58; found: C, 52.32; H, 3.71.

5-Methyl-3-(1-adamantyl)-2,5-dihydrofuran-2-one

(5w). White crystals, yield 13%. Mp 76–78 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 6.87 d, 1H, J=1.7 Hz, (H4); 4.92

qd, 1H, J₁=6.9 Hz, J₂=1.7 Hz, (H5); 2.07–1.98 m, 3H,

(CH); 1.88 d, 6H, J=3.0 Hz, (CH₂), 1.76–1.71 m, 6H,

(CH₂); 1.38 d, 3H, J=6.9 Hz, (CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 171.90, 147.39, 142.12, 76.47,

39.76, 36.57, 33.47, 28.05, 19.32. IR(CDCl ₃): n_max2982,

3-(3,4-Dibromophenyl)-5-methyl-2,5-dihydrofuran-2-

one (5r). White crystals, yield 47%. Mp 103–104 ^ꢂC. H

1

NMR(300 MHz, CDCl ): d 8.13 d, 1H, J=2.0, (Ar);

3

7.70 dd, 1H, J₁=2.0, J₂=8.5, (Ar); 7.65 d, 1H, J=8.5,

(Ar); 7.61 d, 1H, J=1.7, (H4); 5.16 qd, 1H, J₁=1.7,

J₂=6.9, (H5); 1.52 d, 3H, J=6.9, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 170.85; 150.15; 133.82; 131.94;

130.02; 129.31; 126.94; 125.89; 125.20; 76.88; 18.98. IR

(CDCl₃): n_max1321, 1377, 1463, 1546, 1755, 2854, 2932,

2987 cm^ꢀ1. LRMS: m/z (%) 332 (M^ꢄ⁺, 89), 304 (5), 289

(55), 261 (100), 223 (5), 207 (3), 193 (4), 180 (29), 128 (11),

115 (28), 101 (27), 87 (7), 74 (29), 63 (14), 50 (28). calcd for

C₁₁H₈Br₂O₂: C, 39.80; H, 2.43; found: C, 39.99; H, 2.58.

2908, 2852, 1748, 1453, 1320 cm^ꢀ1

. LRMS: 233

(M^ꢄ⁺+H, 100), 217 (5), 199 (2), 189 (20), 191 (15), 175

(3), 161 (7), 145 (5), 135 (17), 117 (5), 105 (8), 91 (10), 79

(6), 65 (4), 53 (5). calcd for C₁₅H₂₀O₂: C, 77.55; H, 8.68;

found: C, 77.17; H, 8.86.

5-Methyl-3-(3-benzo[b]thienyl)-2,5-dihydrofuran-2-one

(5v). The introduction of the phenylselanyl moiety was

identical to the above procedure for compounds 5a–u,

and 5w. 5-Methyl-3-(3-benzo[b]thienyl)-3-phenylsela-

nyltetrahydrofuran-2-one (1.162 g, 3 mmol) was dis-

solved in a mixture of MeOH–THF–H₂O 5:5:1 (50 mL),

and NaHCO₃(0.630 g, 7.5 mmol) and NaIO₄(3.208 g,

15 mmol) were added to the solution. After stirring for

2.5 h at ambient temperature, the mixture was diluted

with H₂O (50 mL), and extracted with ethyl acetate

(3ꢃ). The combined extracts were dried over Na₂SO₄,

and the solvent evaporated. The product was puriﬁed

by column chromatography (petroleum ether–ethyl

acetate 9:1), and was obtained as colourless crystals in

18% yield.

5-Methyl-3-(1-naphthyl)-2,5-dihydrofuran-2-one (5s).

White crystals, yield 39%. Mp 69–71 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.94–7.85 (3H, m, Ar), 7.60–7.47

(4H, m, Ar), 7.53 (1H, d, J=1.7 Hz, H4), 5.28 (1H, qd,

J₁=6.9 Hz, J₂=1.7 Hz, H5), 1.59 (3H, d, J=6.9 Hz, –

CH₃). ¹³C NMR(75 MHz, CDCl ): d 172.33, 153.70,

3

131.76, 131.03, 129.42, 128.58, 127.45, 127.27, 126.53,

125.99, 125.07, 124.40, 77.49, 19.18. IR(CDCl ): n_max

3

3063, 2985, 1754, 1591, 1509, 1319 cm^ꢀ1. LRMS: 224

(M^ꢄ⁺, 100), 207 (7), 181 (14), 165 (5), 153 (16), 152 (16),

126 (3), 102 (2), 76 (3), 63 (4), 50 (3). calcd for

C₁₅H₁₂O₂: C, 80.34; H, 5.39; found: C, 80.36; H, 5.26.

5-Methyl-3-(4-bromo-1-naphthyl)-2,5-dihydrofuran-2-

ꢂ

1

one (5t). White crystals, yield 19%. Mp 59–61 C. H

NMR(300 MHz, CDCl ₃): d 8.35–8.30 (1H, m, Ar),

7.91–7.86 (1H, m, Ar), 7.83 (1H, m, J=7.8 Hz, Ar),

7.68–7.54 (2H, m, Ar), 7.58 (1H, d, J=1.7 Hz, H4), 7.42

(1H, d, J=7.8 Hz, Ar), 5.33 (1H, qd, J₁=6.9 Hz,

J₂=1.7 Hz, H5), 1.63 (3H, d, J=6.9 Hz, –CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d 172.21, 154.18, 132.25,

132.12, 131.52, 129.36, 127.93, 127.72, 127.55, 127.43,

Mp 92–94 C. H NMR(300 MHz, CDCl ): d 8.39 s,

3

1H, (Ar2); 7.97–7.90 m, 2H, (Ar5,7); 7.70 d, 1H,

J=1.7 Hz, (H4); 7.49–7.37 m, 2H, (Ar4,6); 5.26 qd, 1H,

J₁=6.9 Hz, J₂=1.7 Hz, (H5); 1.57 d, 3H, J=6.9 Hz, (–

CH₃). ¹³C NMR(75 MHz, CDCl ): d 172.21, 147.06,

3

140.07, 137.00, 129.11, 126.04, 124.77, 124.66, 124.61,

123.16, 121.99, 77.35, 19.25. IR(CDCl ₃) n_max: 3116,

ꢄ

2986, 1758, 1636, 1425, 1319 cm^ꢀ1. LRMS: 230 (M

,

+

127.34, 124.99, 124.57, 77.79, 19.23. IR(CDCl ): n_max

92), 202 (9), 187 (23), 171 (6), 159 (100), 139 (3), 127 (4),

115 (54), 89 (5), 63 (8), 50 (6). calcd for C₁₃H₁₀O₂S: C,

67.80; H, 4.38; S, 13.92; found: C, 67.72; H, 4.48; S,

13.69.

3

2987, 2934, 1756, 1567, 1507, 1380, 1320 cm^ꢀ1. LRMS:

ꢄ

+

302 (M ꢀH, 100), 260 (43), 231 (43), 195 (3), 181 (17),

165 (13),152 (82), 126 (6), 100 (5), 87 (5), 75 (10), 63

(10), 50 (9). calcd for C₁₅H₁₁BrO₂: C, 59.43; H, 3.66;

found: C, 59.21; H, 3.77.

Preparation of 3-(substituted phenyl)-5-ethyltetrahydro-

furan-2-ones (6b, h, i, k, p) and 3-(substituted phenyl)-5-

butyltetrahydrofuran-2-ones (8h, i, k, p). Butyllithium

(11.0 mmol) was added to a solution of diisopropyl-

amine (10.5 mmol) in dry THF (50 mL) at 0 ^ꢂC under Ar.

5-Methyl-3-[3-(N-methylindolyl)]-2,5-dihydrofuran-2-

one (5u). Colorless crystals, yield 25%. Mp 89–92 ^ꢂC. ¹H

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2861

After 10 min at 0 ^ꢂC, the LDA solution was cooled to

ꢀ60 ^ꢂC, and a solution of a methyl (substituted phenyl)-

acetate (10 mmol) in THF (5 mL) was added. The reac-

tion temperature was maintained at ꢀ60 ^ꢂC for 30 min,

and epoxybutane or epoxyhexane (15.0 mmol) and

boron triﬂuoride etherate (15.0 mmol) were subse-

quently added dropwise. The reaction mixture was

slowly allowed to warm to room temperature (over

2.5 h) in order to drive the reaction to completion. The

solution was then diluted with ethyl acetate (80 mL),

washed with saturated aqueous NH₄Cl, dried over

Na₂SO₄, and concentrated. Puriﬁcation by column

chromatography (petroleum ether–ethyl acetate 9:1)

aﬀorded the corresponding methyl 2-(substituted

phenyl)-4-hydroxyhexanoate or octanoate (yields in the

range 44–69%), which was subjected to hydrolysis

without further characterisation.

28.26; 9.42. IR(CDCl ): n_max1353, 1463, 1494, 1768,

^ꢄ+,

3

2881, 2940, 2970 cm^ꢀ1. LRMS: m/z (%) 225 (M

43),

180 (72), 167 (11), 151 (100), 138 (75), 125 (12), 115 (65),

103 (50), 89 (12), 77 (22), 63 (12), 51 (15).

3-(3-Chlorophenyl)-5-ethyltetrahydrofuran-2-one (6i).

Colorless oil, yield 89%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.31–7.26 m, 3H, (Ar); 7.21–7.15 m, 1H, (Ar); 4.62–

4.51 m, 1H, (H5); 3.87 dd, 1H, J₁=7.5, J₂=9.3, (H3);

2.54–2.34 m, 2H, (H4); 1.92–1.61 m, 2H, (–CH₂–); 1.04

t, 3H, J=7.4, (–CH₃). B: 7.31–7.26 m, 3H, (Ar); 7.21–

7.15 m, 1H, (Ar); 4.49–4.37 m, 1H, (H5); 3.86 dd, 1H,

J₁=8.5, J₂=12.9, (H3); 2.80–2.69 m, 1H, (H4a); 2.08–

1.92 m, 1H, (H4b); 1.92–1.61 m, 2H, (–CH₂–); 1.05 t,

3H, J=7.4, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d A:

3

176.50; 139.01; 134.70; 130.17; 128.22; 127.80; 125.84;

80.15; 45.16; 35.56; 28.34; 9.59. B: 176.09; 138.41;

134.53; 130.03; 128.22; 127.76; 126.31; 79.84; 46.78;

The above methyl ester (5.0 mmol) was dissolved in a

mixture of MeOH–H₂O (3:1, 20 mL), and LiOH

(6.5 mmol) was added to the solution. After 20 h at

ambient temperature, the reaction mixture was cooled

to 0 ^ꢂC, and acidiﬁed with concd HCl to pH=1. The

mixture was heated to 40 ^ꢂC for 30 min, diluted with

ethyl acetate (20 mL), and washed with brine. The

organic phase was dried over Na₂SO₄, and the solvent

evaporated. Puriﬁcation by column chromatography

(petroleum ether–ethyl acetate 9:1) aﬀorded the title

g-lactones (yields in the range 76–92%).

37.29; 28.23; 9.40. IR(CDCl ): n_max1353, 1432, 1464,

3

1480, 1575, 1599, 1773, 2882, 2940, 2971 cm^ꢀ1. LR MS:

m/z (%) 225 (M^ꢄ^+,100), 179 (12), 145 (8), 138 (32), 115

(18), 103 (12), 89 (4), 77 (1), 63 (3).

3-(3,4-Dichlorophenyl)-5-ethyltetrahydrofuran-2-one

(6k). White crystals, yield 98%. Mp 66–67 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.45–7.38 m, 2H, (Ar); 7.18–

7.12 m, 1H, (Ar); 4.62–4.52 m, 1H, (H5); 3.89–3.82 m,

1H, (H3); 2.53–2.35 m, 2H, (H4); 1.92–1.62 m, 2H, (–

CH₂–); 1.04 t, 3H, J=7.4, (–CH₃). B: 7.45–7.38 m, 2H,

(Ar); 7.18–7.12 m, 1H, (Ar); 4.49–4.38 m, 1H, (H5); 3.85

dd, 1H, J₁=8.6, J₂=12.9, (H3); 2.81–2.70 m, 1H,

(H4a); 2.06–1.92 m, 1H, (H4b); 1.92–1.62 m, 2H, (–

CH₂–); 1.05 t, 3H, J=7.4, (–CH₃). ¹³C NMR(75 MHz,

CDCl₃): d A: 176.09; 137.09; 132.97; 131.81; 130.83;

129.69; 127.07; 80.10; 44.52; 35.33; 28.32; 9.60. B:

175.70; 136.51; 132.80; 131.81; 130.70; 130.06; 127.46;

3-(4-Methylphenyl)-5-ethyltetrahydrofuran-2-one (6b).

Colorless oil, yield 92%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.18–7.16 m, 4H, (Ar); 4.62–4.51 m, 1H, (H5); 3.86

dd, 1H, J₁=6.9, J₂=9.3, (H3); 2.56–2.29 m overlapped,

2H, (H4); 2.34 s overlapped, 3H, (Ar–CH₃); 1.93–1.60

m, 2H, (–CH₂–), 1.04 t, 3H, J=7.4, (–CH₃). B: 7.18–

7.16 m, 4H, m, (Ar); 4.48–4.37 m, 1H, (H5); 3.85 dd,

1H, J₁=8.5, J₂=12.7, (H3); 2.78–2.67 m, 1H, (H4a);

2.34 s, 3H, (Ar–CH₃); 2.14–1.93 m, 1H, (H4b); 1.93–

1.60 m, 2H, (–CH₂–); 1.05 t, 3H, J=7.4, (–CH₃). ¹³C

79.88; 46.22; 37.09; 28.21; 9.40. IR(CDCl ): n_max1353,

3

1474, 1563, 1772, 2882, 2940, 2971 cm^ꢀ1. LRMS: m/z

(%) 259 (M^ꢄ⁺, 19), 214 (78), 201 (4), 185 (38), 172 (100),

159 (9), 137 (37), 123 (7), 115 (30), 102 (40), 89 (4), 75

(11), 63 (8), 51 (9).

NMR(75 MHz, CDCl ): d A: 177.47; 137.24; 134.16;

3

129.61; 127.43; 80.15; 45.30; 35.99; 28.41; 21.01; 9.64. B:

177.09; 137.28; 133.56; 129.49; 127.91; 79.75; 46.93;

37.60; 28.31; 21.05; 9.43. IR(CDCl ): n_max1353, 1457,

3

1517, 1766, 2882, 2940, 2971 cm^ꢀ1. LRMS: m/z (%) 205

(M^ꢄ⁺+H, 100), 160 (43), 145 (7), 131 (60), 117 (17), 105

(7), 91 (13), 77 (2), 65 (5), 51 (3).

3-(4-Bromophenyl)-5-ethyltetrahydrofuran-2-one (6p).

White crystals, yield 90%. Mp 45–46 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.52–7.46 m, 2H, (AA⁰BB⁰);

7.20–7.14 m, 2H, (AA⁰BB⁰); 4.61–4.51 m, 1H, (H5); 3.86

dd, 1H, J₁=9.2, (H3); 2.52–2.34 m, 2H, (H4); 1.92–1.62

m, 2H, (–CH₂–); 1.04 t, 3H, J=7.4, (–CH₃). B: 7.52–

7.46 m, 2H, (AA⁰BB⁰); 7.20–7.14 m, 2H, (AA⁰BB⁰);

4.49–4.38 m, 1H, (H5); 3.85 dd, 1H, J₁=8.5, J₂=12.9,

(H3); 2.80–2.69 m, 1H, (H4a); 2.06–1.92 m, 1H, (H4b);

1.92–1.62 m, 2H, (–CH₂–); 1.05 t, 3H, J=7.4, (–CH₃).

¹³C NMR(75 MHz, CDCl ₃): d A: 176.65; 136.07;

132.05; 129.33; 121.57; 80.11; 44.97; 35.62; 28.36; 9.63.

B: 176.26; 135.48; 131.91; 129.76; 121.62; 79.83; 46.66;

37.34; 28.26; 9.42. IR(CDCl ): n_max1354, 1464, 1491,

1769, 2882, 2940, 2941 cm^ꢀ³¹. LR MS:m/z (%) 269

(M^ꢄ⁺, 6), 224 (39), 211 (4), 195 (24), 184 (36), 169 (3),

145 (18), 128 (4), 116 (100), 103 (29), 89 (8), 77 (18), 63

(8), 57 (4), 51 (12).

3-(4-Chlorophenyl)-5-ethyltetrahydrofuran-2-one (6h).

Colorless oil, yield 86%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.36–7.31 m, 2H, (AA⁰BB⁰); 7.25–7.20 m, 2H,

(AA⁰BB⁰); 4.61–4.51 m, 1H, (H5); 3.88 dd, 1H, J₁=7.5,

J₂=9.2, (H3); 2.53–2.34 m, 2H, (H4); 1.92–1.63 m, 2H,

(–CH₂–); 1.04 t, 3H, t, J=7.4, (–CH₃). B: 7.36–7.31 m,

2H, (AA⁰BB⁰), 7.25–7.20 m, 2H, (AA⁰BB⁰); 4.50–4.38 m,

1H, (H5); 3.86 dd, 1H, J₁=8.5, J₂=12.9, (H3); 2.80–

2.69 m, 1H, (H4a); 2.07–1.92 m, 1H, (H4b); 1.92–1.63

m, 2H, (–CH₂–); 1.05 t, 3H, J=7.4, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d A: 176.75; 135.54; 133.49; 129.08;

128.98; 80.11; 44.90; 35.67; 28.36; 9.63. B: 176.36;

134.95; 133.49; 129.41; 128.95; 79.82; 46.59; 37.40;

2862

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

3-(4-Chlorophenyl)-5-butyltetrahydrofuran-2-one (8h).

n_max1352, 1473, 1563, 1770, 2874, 2934, 2960,

3027 cm^ꢀ1. LRMS: m/z (%) 287 (M^ꢄ⁺, 27), 269 (1), 242

(23), 199 (2), 185 (4), 172 (100), 159 (5), 150 (14), 137

(9), 128 (5), 115 (13), 102 (18), 85 (3), 69 (1), 55 (4).

White crystals, yield 76%. Mp 51–52 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.36–7.30 m, 2H, (AA⁰BB⁰);

7.25–7.19 m, 2H, (AA⁰BB⁰); 4.67–4.56 m, 1H, (H5); 3.88

dd, 1H, J₁=7.5, J₂=9.2, (H3); 2.53–2.33 m, 2H, (H4);

1.91–1.75 m, 1H, ðꢀCHCH₂-aÞ; 1.75–1.56 m, 1H,

ðꢀCHCH₂-bÞ; 1.56–1.29 m, 4H, (–CH₂CH₂–); 0.93 t,

3H, J=7.1 Hz, (–CH₃). B: 7.36–7.30 m, 2H, (AA⁰BB⁰);

7.25–7.19 m, 2H, (AA⁰BB⁰); 4.54–4.43 m, 1H, (H5); 3.85

dd, 1H, J₁=8.7, J₂=12.7, (H3); 2.80–2.69 m, 1H,

(H4a); 2.07–1.91 m, 1H, (H4b); 1.91–1.75 m, 1H,

ðꢀCHCH₂-aÞ; 1.75–1.56 m, 1H, ðꢀCHCH₂-bÞ; 1.56–1.29

m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d A: 176.75 135.52; 133.48;

129.07; 128.98; 78.92; 44.87; 36.10; 35.06; 27.44; 22.38;

13.90. B: 176.37; 134.95; 133.48; 129.41; 128.94; 78.72;

46.59; 37.90; 34.98; 27.30; 22.41; 13.90. IR(KBr pellet):

n_max1193, 1352, 1466, 1494, 1761, 2862, 2934,

2954 cm^ꢀ1. LR MS:m/z (%) 253 (M^ꢄ⁺, 3), 208 (28), 191

(1), 167 (7), 151 (38), 138 (100), 125 (9), 115 (27), 103

(28), 89 (6), 77 (12), 63 (5), 51 (8).

3-(4-Bromophenyl)-5-butyltetrahydrofuran-2-one (8p).

White crystals, yield 89%. Mp 35–36 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d A: 7.52–7.46 m, 2H, (AA⁰BB⁰);

7.20–7.14 m, 2H, (AA⁰BB⁰); 4.67–4.56 m, 1H, (H5); 3.86

dd, 1H, J₁=7.5, J₂=9.3, (H3); 2.53–2.33 m, 2H, (H4);

1.92–1.76 m, 1H, ðꢀCHCH₂-aÞ; 1.76–1.59 m, 1H,

ðꢀCHCH₂-bÞ; 1.59–1.30 m, 4H, (–CH₂CH₂–); 0.93 t,

3H, J=7.1, (–CH₃). B: 7.52–7.46 m, 2H, (AA⁰BB⁰);

7.20–7.14 m, 2H, (AA⁰BB⁰); 4.54–4.43 m, 1H, (H5); 3.84

dd, 1H, J₁=8.6, J₂=12.6, (H3); 2.80–2.69 m, 1H,

(H4a); 2.07–1.92 m, 1H, (H4b); 1.92–1.76 m, 1H,

ðꢀCHCH₂-aÞ; 1.76–1.59 m, 1H, ðꢀCHCH₂-bÞ; 1.59–1.30

m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). ¹³C

NMR(75 MHz, CDCl ): d A: 176.67; 136.05; 132.04;

3

129.34; 121.57; 78.93; 44.95; 36.06; 35.06; 27.44; 22.39;

13.91. B: 176.28; 135.47; 131.91; 129.77; 121.61; 78.73;

46.66; 37.85; 34.99; 27.31; 22.42; 13.91. IR(KBr pellet):

n_max1180, 1352, 1466, 1490, 1636, 1770, 2870,

2962 cm^ꢀ1. LRMS: m/z (%) 297 (M^ꢄ⁺, 4), 252 (28), 211

(5), 195 (15), 184 (100), 171 (6), 141 (1), 129 (8), 116

(81), 103 (30), 89 (8), 77 (18), 63 (7), 51 (10).

3-(3-Chlorophenyl)-5-butyltetrahydrofuran-2-one (8i).

Colorless oil, yield 79%. ¹H NMR(300 MHz, CDCl ₃): d

A: 7.33–7.24 m, 3H, (Ar); 7.21–7.15 m, 1H, (Ar); 4.68–

4.58 m, 1H, (H5); 3.88 dd, 1H, J₁=7.4, J₂=9.3, (H3);

2.55–2.32 m, 2H, (H4); 1.95–1.72 m, 1H, ðꢀCHCH₂-aÞ;

1.72–1.55 m, 1H, ðꢀCHCH₂-bÞ; 1.55–1.26 m, 4H,

(–CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). B: 7.33–7.24

m, 3H, (Ar); 7.21–7.15 m, 1H, (Ar); 4.54–4.43 m, 1H,

(H5); 3.86 dd, 1H, J₁=8.6, J₂=12.7, (H3); 2.81–2.70 m,

1H, (H4a); 2.08–1.95 m, 1H, (H4b); 1.95–1.72 m, 1H,

ðꢀCHCH₂-aÞ; 1.72–1.55 m, 1H, ðꢀCHCH₂-bÞ; 1.55–1.26

m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). ¹³C

Preparation of furanones 7b, h, i, k, p and 9h, i, k, p.

Introduction of the double bond into the g-lactone ring

was carried out in the same manner as described above

for the synthesis of furanones 5a–w.

3-(4-Methylphenyl)-5-ethyl-2,5-dihydrofuran-2-one

(7b). White crystals, yield 56%. Mp 53–54 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.79–7.73 m, 2H, (AA⁰BB⁰); 7.50

d, 1H, J=1.9, (H4); 7.25–7.19 m, 2H, (AA⁰BB⁰); 4.99

ddd, 1H, J₁=1.9, J₂=5.8, J₃=6.8, (H5); 2.37 s, 3H,

(CH₃–Ar); 1.97–1.69 m, 2H, (–CH₂–); 1.06 t, 3H,

NMR(75 MHz, CDCl ): d A: 176.48; 138.99; 134.75;

3

130.18; 128.25; 127.84; 125.85; 78.97; 45.16; 36.05;

35.08; 27.43; 22.39; 13.90. B: 176.07; 138.41; 134.58;

130.04; 128.25; 127.78; 126.33; 78.73; 46.79; 37.82;

34.98; 27.30; 22.39; 13.90. IR(CDCl ): n_max1353, 1432,

3

1467, 1479, 1574, 1599, 1769, 2862, 2933, 2959 cm^ꢀ1

LRMS: m/z (%) 253 (M

.

37), 207 (13), 191 (1), 165

J=7.4, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.90;

3

^ꢄ+,

146.63; 139.34; 131.60; 129.29; 126.85; 126.71; 81.40;

(4), 151 (6), 138 (100), 125 (5), 115 (21), 103 (21), 89 (4),

77 (2), 63 (3), 55 (3).

26.72; 21.33; 9.18. IR(CDCl ): n_max1337, 1457, 1513,

3

1751, 2881, 2925, 2939, 2973 cm^ꢀ1. LRMS: m/z (%) 203

(M^ꢄ⁺+H, 89), 185 (4), 173 (8), 159 (4), 145 (40), 128

(5), 117 (100), 102 (3), 91 (13), 77 (2), 63 (7), 51 (6).

calcd for C₁₃H₁₄O₂: C, 77.20; H, 6.98; found: C, 77.37;

H, 7.18.

3-(3,4-Dichlorophenyl)-5-butyltetrahydrofuran-2-one

(8k). Colorless oil, yield 86%. ¹H NMR(300 MHz,

CDCl₃): d A: 7.46–7.37 m, 2H, (Ar); 7.18–7.12 m, 1H,

(Ar); 4.68–4.57 m, 1H, (H5), 3.86 dd, 1H, J₁=7.9,

J₂=9.1, (H3); 2.54–2.34 m, 2H, (H4); 1.92–1.76 m, 1H,

ðꢀCHCH₂-aÞ; 1.76–1.56 m, 1H, ðꢀCHCH₂-bÞ; 1.56–1.25

m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.0, (–CH₃). B:

7.46–7.37 m, 2H, (Ar); 7.18–7.12 m, 1H, (Ar); 4.55–4.44

m, 1H, (H5); 3.84 dd, 1H, J₁=8.6, J₂=12.6, (H3); 2.81–

2.70 m, 1H, (H4a); 2.06–1.92 m, 1H, (H4b); 1.92–1.76

m, 1H, ðꢀCHCH₂-aÞ; 1.76–1.56 m, 1H, ðꢀCHCH₂-bÞ;

1.56–1.25 m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.0,

(–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d A: 176.12;

137.06; 132.97; 131.82; 130.83; 129.70; 127.07; 78.93;

44.51; 35.79; 35.02; 27.41; 22.38; 13.89. B: 175.73;

136.49; 132.81; 131.82; 130.70; 130.07; 127.48; 78.78;

46.23; 37.61; 34.93; 27.29; 22.40; 13.89. IR(CHCl ₃):

3-(4-Chlorophenyl)-5-ethyl-2,5-dihydrofuran-2-one

(7h). White crystals, yield 64%. Mp 72–73 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.85–7.79 m, 2H, (AA⁰BB⁰); 7.56

d, 1H, J=1.9, (H4); 7.41–7.36 m, 2H, (AA⁰BB⁰); 5.01

ddd, 1H, J₁=1.9, J₂=5.7, J₃=6.8, (H5); 1.98–1.72 m,

2H, (–CH₂–); 1.07 t, 3H, J=7.4, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 171.45; 147.81; 135.32; 130.75;

128.87; 128.31; 127.96; 81.53; 26.66; 9.20. IR(CDCl ):

3

n_max1338, 1407, 1492, 1755, 2881, 2939, 2973 cm^ꢀ1

.

ꢄ

+

LRMS: m/z (%) 222 (M ꢀH, 71), 207 (7), 193 (10),

165 (55), 159 (5), 137 (100), 129 (6), 115 (6), 102 (25), 87

(2), 75 (19), 63 (7), 57 (33), 51 (11). calcd for

C₁₂H₁₁ClO₂: C, 64.73; H, 4.98; found: C, 64.80; H, 5.09.

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2863

3-(3-Chlorophenyl)-5-ethyl-2,5-dihydrofuran-2-one (7i).

White crystals, yield 63%. Mp 45–46 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.87–7.82 m, 1H, (Ar); 7.79–7.72

m, 1H, (Ar); 7.59 d, 1H, J=1.7, (H4); 7.38–7.30 m, 2H,

(Ar); 5.01 ddd, 1H, J₁=1.7, J₂=5.8, J₃=6.7, (H5);

1.97–1.70 m, 2H, (–CH₂–); 1.06 t, 3H, J=7.4, (–CH₃).

3-(3-Chlorophenyl)-5-butyl-2,5-dihydrofuran-2-one

(9i). White crystals, yield 56%. Mp 39–40 ^ꢂC. H NMR

1

(300 MHz, CDCl₃): d 7.86–7.83 m, 1H, (Ar); 7.79–7.74

m, 1H, (Ar); 7.59 d, 1H, J=1.9, (H4); 7.37–7.33 m, 2H,

(Ar); 5.06 ddd, 1H, J₁=1.9, J₂=5.5, J₃=7.4, (H5);

1.90–1.62 m, 2H, ðꢀCHCH₂ꢀÞ; 1.55–1.31 m, 4H, (–

CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 171.23; 149.03; 134.63; 131.22;

130.41; 129.92; 129.33; 127.05; 125.13; 80.60; 33.15;

27.11; 22.43; 13.85. IR(KBr pellet): n_max1124, 1338,

1476, 1566, 1595, 1636, 1754, 2871, 2932, 2957,

¹³C NMR(75 MHz, CDCl ): d 171.21; 148.72; 134.59;

3

131.18; 130.61; 129.89; 129.30; 127.03; 125.11; 81.54;

26.59; 9.15. IR(CDCl ): n_max1338, 1420, 1475, 1567,

3

1595, 1755, 2881, 2940, 2973 cm^ꢀ1. LRMS: m/z (%) 223

(M^ꢄ⁺, 100), 205 (6), 193 (8), 177 (3), 165 (46), 159 (5),

137 (53), 130 (8), 115 (6), 102 (37), 87 (2), 75 (12), 63 (6),

57 (28), 51 (8). calcd for C₁₂H₁₁ClO₂: C, 64.73; H, 4.98;

found: C, 64.79; H, 5.13.

ꢄ

+

3073 cm^ꢀ1. LRMS: m/z (%) 250 (M ꢀH, 94), 233 (8),

221 (3), 207 (31), 193 (13), 180 (14), 165 (33), 159 (11),

137 (75), 125 (7), 115 (14), 102 (58), 85 (100), 75 (21), 63

(8), 57 (81), 51 (14). calcd for C₁₄H₁₅ClO₂: C, 67.07; H,

6.03; found: C, 67.32; H, 6.20.

3-(3,4-Dichlorophenyl)-5-ethyl-2,5-dihydrofuran-2-one

(7k). White crystals, yield 71%. Mp 69–70 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.99 d, 1H, J=2.0, (Ar); 7.73 dd,

1H, J₁=2.0, J₂=8.4, (Ar), 7.60 d, 1H, J=1.9, (H4);

7.48 d, 1H, J=8.4, (Ar); 5.02 ddd, 1H, J₁=1.9, J₂=5.7,

J₃=6.8, (H5); 1.98–1.71 m, 2H, (–CH₂–); 1.07 t, 3H,

3-(3,4-Dichlorophenyl)-5-butyl-2,5-dihydrofuran-2-one

(9k). White crystals, yield 54%. Mp 48–49 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.99 d, 1H, J=2.0, (Ar); 7.73 dd,

1H, J₁=2.0, J₂=8.5, (Ar); 7.60 d, 1H, J=1.9, (H4);

7.48 d, 1H, J=8.5, (Ar); 5.06 ddd, 1H, J₁=1.9, J₂=5.5,

J₃=7.4, (H5); 1.91–1.67 m, 2H, ðꢀCHCH₂ꢀÞ; 1.54–1.32

m, 4H, (–CH₂CH₂–); 0.93 t, 3H, J=7.1, (–CH₃). ¹³C

NMR(75 MHz, CDCl ₃): d 171.03; 149.14; 133.47;

132.97; 130.63; 129.52; 129.39; 128.82; 126.20; 80.68;

33.12; 27.13; 22.42; 13.85. IR(KBr pellet): n_max1142,

1383, 1471, 1752, 2863, 2933, 2958, 3069 cm^ꢀ1. LR MS:

m/z (%) 284 (M ꢀH, 43), 267 (3), 253 (10), 242 (3),

227 (5), 207 (23), 199 (11), 171 (25), 149 (4), 136 (23),

115 (5), 99 (11), 85 (100), 75 (8), 63 (4), 57 (69), 51 (6).

calcd for C₁₄H₁₄Cl₂O₂: C, 58.97; H, 4.95; found: C,

58.76; H, 5.11.

J=7.4, (–CH₃). ¹³C NMR(75 MHz, CDCl ): d 171.00;

3

148.78; 133.48; 132.95; 130.62; 129.78; 129.36; 128.82;

126.20; 81.61; 26.61; 9.20. IR(CDCl ): n_max1337, 1472,

3

1553, 1756, 2881, 2940, 2974 cm^ꢀ1. LRMS: m/z (%) 256

ꢄ

+

(M ꢀH, 80), 227 (9), 207 (48), 199 (44), 193 (10), 171

(81), 164 (10), 149 (5), 136 (41), 115 (6), 99 (19), 85 (5),

75 (15), 63 (8), 57 (100), 50 (12). calcd for C₁₂H₁₀Cl₂O₂:

C, 56.06; H, 3.92; found: C, 55.90; H, 4.02.

ꢄ

+

3-(4-Bromophenyl)-5-ethyl-2,5-dihydrofuran-2-one

(7p). White crystals, yield 58%. Mp 64–65 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.77–7.72 m, 2H, (AA⁰BB⁰); 7.57

d, 1H, J=1.9, (H4); 7.56–7.51 m, 2H, (AA⁰BB⁰); 5.00

ddd, 1H, J₁=1.9, J₂=5.7, J₃=6.9, (H5); 1.95–1.71 m,

2H, (–CH₂–); 1.06 t, 3H, J=7.4, (–CH₃). ¹³C NMR

(75 MHz, CDCl₃): d 171.38; 147.91; 131.82; 130.80;

3-(4-Bromophenyl)-5-butyl-2,5-dihydrofuran-2-one

(9p). White crystals, yield 54%. Mp 52–53 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.77–7.72 m, 2H, (AA⁰BB⁰); 7.57

d, 1H, J=1.9, (H4); 7.56–7.51 m, 2H, (AA⁰BB⁰); 5.03

ddd, 1H, J₁=1.9, J₂=5.5, J₃=7.4, (H5); 1.90–1.64 m,

2H, ðꢀCHCH₂ꢀÞ; 1.56–1.31 m, 4H, (–CH₂CH₂–); 0.93 t,

3H, J=7.1, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d

171.40; 148.28; 131.83; 130.53; 128.54; 128.42; 123.60;

80.62; 33.16; 27.14; 22.43; 13.85. IR(KBr pellet): n_max

1122, 1338, 1403, 1465, 1489, 1589, 1749, 2855, 2929,

128.55; 128.40; 123.62; 81.55; 26.63; 9.20. IR(CDCl ):

3

n_max1288, 1337, 1403, 1462, 1488, 1589, 1755, 2881,

2939, 2973 cm^ꢀ1. LR MS:m/z (%) 223 (100), 205 (6),

193 (6), 177 (2), 165 (43), 159 (5), 137 (47), 130 (6), 115

(6), 102 (31), 87 (2), 75 (11), 63 (5), 57 (26), 51 (8). calcd

for C₁₂H₁₁BrO₂: C, 53.96; H, 4.15; found: C, 53.80; H,

4.26.

ꢄ

+

2958, 3070 cm^ꢀ1. LR MS:m/z (%) 296 (M +H, 85),

281 (2), 266 (4), 252 (11), 236 (9), 224 (6), 209 (35), 195

(3), 183 (70), 164 (5), 159 (6), 145 (7), 128 (10), 115 (13),

102 (98), 85 (97), 75 (26), 63 (9), 57 (100), 51 (18). calcd

for C₁₄H₁₅BrO₂: C, 59.97; H, 5.12; found: C, 56.90; H,

5.26.

3-(4-Chlorophenyl)-5-butyl-2,5-dihydrofuran-2-one

(9h). White crystals, yield 53%. Mp 53–54 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.85–7.78 m, 2H, (AA⁰BB⁰); 7.56

d, 1H, J=1.9, (H4); 7.41–7.35 m, 2H, (AA⁰BB⁰); 5.04

ddd, 1H, J₁=1.9, J₂=5.5, J₃=7.4, (H5); 1.89–1.66 m,

2H, ðꢀCHCH₂ꢀÞ; 1.56–1.31 m, 4H, (–CH₂CH₂–); 0.93 t,

3H, J=7.2, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d

171.47; 148.19; 135.29; 130.46; 128.86; 128.29; 127.97;

80.59; 33.19; 27.14; 22.43; 13.85. IR(KBr pellet): n_max

1143, 1336, 1466, 1493, 1632, 1749, 2855, 2929, 2960,

3069 cm^ꢀ1. LR MS:m/z (%) 250 (M^ꢄ^+-H, 100), 233 (7),

222 (4), 208 (6), 193 (12), 180 (8), 165 (48), 151 (7), 137

(83), 125 (8), 115 (13), 102 (53), 85 (82), 75 (18), 63 (7),

57 (78), 51 (13). calcd for C₁₄H₁₅ClO₂: C, 67.07; H, 6.03;

found: C, 67.36; H, 6.34.

5-Ethyl-3-(3-pyridyl)-2,5-dihydrofuran-2-one (11). A

solution of 3-iodopyridine (0.226 g, 1.1 mmol) in DMF

.

(1 mL) was added to a suspension of Pd₂dba₃CHCl₃

(0.021 g, 0.02 mmol), AsPh₃(0.049 g, 0.16 mmol) and

CuI (0.015 g, 0.08 mmol) in DMF (1 mL) under Ar. The

resultant mixture was warmed to 50^ꢂC, a solution of 5-

ethyl-3-(tributylstannyl)-2,5-dihydrofuran-2-one (0.401 g,

1 mmol) in DMF (1.5 mL) was added, and the tem-

perature was maintained at 50 ^ꢂC for 6 h. A saturated

2864

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

aqueous solution of KF was then added, the mixture

stirred for 30 min, and then diluted with ethyl acetate.

The resultant suspension was ﬁltered, and the ﬁltrate

was washed with water, brine, and dried over Na₂SO₄.

The solvent was removed, and the crude product pur-

iﬁed by column chromatography (petroleum ether–ethyl

acetate 7:3); yield 0.160 g (85%).

d 207.63, 159.02, 143.37, 131.58, 128.36, 128.28, 126.97,

35.72, 26.15. calcd for C₁₁H₁₀O: 83.51% C, 6.37% H;

found 83.05% C, 6.58% H.

2-(4-Methylphenyl)cyclopent-2-enone (12b). White

crystals, yield 33%. Mp 72–73 ^ꢂC. H NMR(300 MHz,

1

CDCl₃): d 7.78 t, 1H, J=2.9 Hz, (H3); 7.63–7.56 m, 2H,

(AA⁰BB⁰), 7.23–7.15 m, 2H, (AA⁰BB⁰); 2.73–2.66 m, 2H,

(–CH₂–); 2.62–2.55 m, 2H, (–CH₂–); 2.36 s, 3H, (–CH₃).

1

Colorless oil. H NMR(300 MHz, CDCl ): d 8.99–8.93

3

m, 1H, (Ar2); 8.63–8.56 m, 1H, (Ar4); 8.30–8.24 m, 1H,

(Ar6); 7.68 d, 1H, J=1.7 Hz, (H4); 7.35 ddd, 1H,

J₁=8.0 Hz, J₂=4.9 Hz, J₃=0.6 Hz, (Ar5); 5.09–5.02 m,

1H, (H5); 1.97–1.71 m, 2H, (–CH₂–); 1.06 t, 3H,

J=7.4 Hz, (–CH₃). ¹³C NMR(75 MHz, CDCl ₃): d

171.24, 149.95, 148.82, 147.94, 134.42, 129.20, 125.68,

¹³C NMR(75 MHz, CDCl ): d 207.80, 159.14, 143.24,

3

138.17, 129.06, 128.73, 126.84, 35.73, 26.09, 21.24. calcd

for C₁₂H₁₂O: 83.69% C, 7.02% H; found: 83.89% C,

7.48% H.

123.45, 81.97, 26.57, 9.16. IR(CDCl ): n_max2973, 2939,

Preparation of 12 c, h, k by Pd-catalyzed cross-coupling.

Solution I. A solution of iodobenzene (1.30 mmol) in dry

THF (5 mL) under Ar was cooled to ꢀ78 ^ꢂC. 1.6 M

BuLi in hexanes (0.86 mL, 1.37 mmol) was added, and

the mixture stirred for 20 min. A solution of dry ZnBr₂

(0.206 g, 0.91 mmol, ﬂame-dried under high vacuum) in

dry THF (5 mL) was added to the reaction mixture. The

resultant mixture was slowly allowed to warm to room

temperature, THF evaporated under vacuum, and the

organozinc compound was redissolved in DMF (5 mL).

3

1758, 1476, 1425, 1337 cm^ꢀ1. LRMS: 190 (M^ꢄ⁺+H,

82), 172 (2), 160 (7), 144 (5), 132 (23), 117 (14), 104

(100), 89 (3), 77 (17), 63 (7), 57 (11), 51 (21).

3,4-Dichlorophenyliodide. This compound was pre-

pared from the commercially available 3,4-dichloroani-

line by standard diazotation/iodination procedure. The

physical and spectral data of the product were in accord

with the literature.

.

Solution II. A suspension of Pd₂dba₃CHCl₃(0.026 g,

Preparation of 12a and 12b by Pd-catalyzed cross-cou-

pling. Solution I.

A

solution of iodobenzene

0.025 mmol) and tris(2-furyl)phosphine (0.023 g,

0.10 mmol) in dry DMF (3 mL) was stirred under Ar at

room temperature until it became a clear solution

(1.30 mmol) in dry THF (5 mL) under Ar was cooled to

ꢀ78 ^ꢂC. 1.6 M BuLi in hexanes (0.86 mL, 1.37 mmol)

was added, and the mixture stirred for 20 min. A solu-

tion of dry ZnBr₂(0.206 g, 0.91 mmol, ﬂame-dried

under high vacuum) in dry THF (5 mL) was added to

the reaction mixture. The resultant mixture was slowly

alloved to warm to room temperature, THF evaporated

under vacuum, and the organozinc compound was

redissolved in DMF (5 mL).

(10 min).

A

solution of 2-iodocyclopent-2-enone

(0.208 g, 1.00 mmol) in dry DMF (2 mL) was then

added.

Solution I was added to solution II, and the reaction

mixture was stirred for 5 h. The mixture was diluted

with ethyl acetate, washed with water and saturated

aqueous solution of NaCl, dried over Na₂SO₄, and

concentrated. Puriﬁcation by column chromatography

(petroleum ether–EtOAc 98:2) aﬀorded the products.

Solution II. A mixture of L₂PdCl₂(0.05 mmol,

L=PPh₃for 12a, tris(2-furyl)phosphine for 12b) in dry

THF (1 mL) was added to 1.6 M BuLi in hexanes

(0.07 mL, 0.11 mmol) at ꢀ78 ^ꢂC under Ar, and the

resultant mixture was stirred for 1 h. A solution of 2-

iodocyclopent-2-enone (0.208 g, 1.00 mmol) in dry

DMF (4 mL) was then added, and the mixture was

slowly allowed to warm to ambient temperature.

Compound 12c was obtained as a 2:1 mixture with

2-iodocyclopent-2-one; the mixture (0.065 g) was there-

fore dissolved in CH₃COOH (4 mL) and zinc powder

(0.50 g) was added to the solution. The reaction mixture

was stirred at room temperature for 48 h, and then

poured into saturated aqueous Na₂CO₃(15 mL). The

product was extracted into EtOAc, the organic phase

dried over Na₂SO₄, and the solvent removed. Pure

cyclopentenone 12c was obtained by column chromato-

graphy (petroleum ether–EtOAc 95:5).

Solution I was added to solution II, and the reaction

mixture was stirred for 5 h. The mixture was diluted

with ethyl acetate, washed with water and saturated

aqueous solution of NaCl, dried over Na₂SO₄, and

concentrated. Puriﬁcation by column chromatogr-

aphy (petroleum ether–EtOAc 98:2) aﬀorded the pure

products.

2-(4-Methoxyphenyl)cyclopent-2-enone (12c). White

crystals, yield 16%. Mp 104–106 ^ꢂC. ¹H NMR

(300 MHz, CDCl₃): d 7.74 t, 1H, J=2.9 Hz, (H3); 7.68–

7.63 m, 2H, (AA⁰BB⁰); 6.94–6.87 m, 2H, (AA⁰BB⁰); 3.81

s, 3H, (–OCH₃); 2.71–2.65 m, 2H, (–CH₂–); 2.60–2.55

m, 2H, (–CH₂–). ¹³C NMR(75 MHz, CDCl ₃): d 208.01,

159.63, 157.16, 142.72, 128.24, 124.23, 113.79, 55.24,

35.75, 26.03. calcd for C₁₂H₁₂O₂: C, 76.57; H, 6.43;

found: C, 76.25; H, 6.33.

2-Phenylcyclopent-2-enone (12a). White crystals, yield

25%. Mp 68–70 ^ꢂC, lit.³³71–72 ^ꢂC. ¹H NMR(300 MHz,

CDCl₃): d 7.82 t, 1H, J=2.9 Hz, (H3), 7.73–7.64 m, 2H,

(Ar); 7.43–7.29 m, 3H, (Ar); 2.73–2.66 m, 2H, (–CH₂–);

2.63–2.55 m, 2H, (–CH₂–). ¹³C NMR(75 MHz, CDCl ₃):

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

2865

2-(4-Chlorophenyl)cyclopent-2-enone (12h). White

crystals, yield 32%. Mp 65–66 ^ꢂC. H NMR(300 MHz,

Tables 1 and 2 were no higher than the nearest concen-

tration value up and down the dilution scale.

1

CDCl₃): d 7.83 t, 1H, J=2.9 Hz, (H3); 7.67–7.61 m, 2H,

(AA⁰BB⁰); 7.37–7.31 m, 2H, (AA⁰BB⁰); 2.74–2.68 m, 2H,

(–CH₂–); 2.62–2.57 m, 2H, (–CH₂–). ¹³C NMR

(75 MHz, CDCl₃): d 207.34, 159.15, 142.25, 134.22,

130.00, 128.59, 128.28, 35.69, 26.20. calcd for

C₁₁H₉ClO: C, 68.58; H, 4.71; found: C, 68.74H, 4.71.

Acknowledgements

This research was supported by Charles University

(project No. 259/2001) and the Ministry of Education of

the Czech Republic (projects Nos. MSM 111600001 and

111600002).

2-(3,4-Dichlorophenyl)cyclopent-2-enone (12k). White

crystals, yield 65%. Mp 91–93 ^ꢂC. H NMR(300 MHz,

1

CDCl₃): d 7.87 t, 1H, J=2.9 Hz, (H3); 7.84 d, 1H,

J=2.1, (Ar2); 7.57 dd, 1H, J₁=8.4 Hz, J₂=2.1 Hz,

(Ar6); 7.43 d, 1H, J=8.4 Hz, (Ar5); 2.76–2.69 m, 2H, (–

CH₂–); 2.64–2.57 m, 2H, (–CH₂–). ¹³C NMR(75 MHz,

CDCl₃): d 206.83, 159.94, 141.17, 132.55, 132.33,

131.47, 130.35, 128.78, 126.23, 35.65, 26.25. IR

(CDCl₃): n_max2923, 1703, 1552, 1472, 1439, 1404,

References and Notes

1. Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Buchta, V.;

Waisser, K. Bioorg. Med. Chem. Lett. 2000, 10, 1893.

2. Zapf, S.; Anke, T.; Sterner, O. Acta Chem. Scand. 1995, 49,

233.

3. Kunes, J.; Balsanek, V.; Pour, M.; Buchta, V. Collect.

Czech. Chem. Commun. 2001, 66, 1809.

4. Pour, M.; Spulak, M.; Buchta, V.; Kubanova, P.; Voprsa-

lova, M.; Wsol, V.; Fakova, H.; Koudelka, P.; Pourova, H.;

Schiller, R. J. Med. Chem. 2001, 44, 2701.

ꢄ

+

1315 cm^ꢀ1. LRMS: 226 (M ꢀH, 100), 207 (4), 191 (6),

163 (95), 149 (7), 135 (10), 127 (54), 113 (6), 99 (12), 86

(8), 74 (25), 63 (26), 50 (27). calcd for C₁₁H₈Cl₂O: C,

58.18; H, 3.55; found: C, 58.53; H, 3.82.

5. Buchwald, S. L.; Fang, Q.; King, S. M. Tetrahedron Lett.

1988, 29, 3445.

6. Black, T. H.; Brown, G. A.; Smith, D. C.; Martinie, S. M.

Syn. Commun. 1995, 25, 479.

Biology

In vitro antifungal activities of the compounds, ketoco-

nazole (Janssen-Cilag), and amphotericin B (Sigma-

Aldrich) were evaluated on a panel of one ATCC (C.

albicans ATCC 44859) and seven clinical isolates of

yeasts (C. krusei E28, Candida tropicalis 156, Candida

glabrata 20/I, Trichosporon beigelii 1188), and ﬁla-

mentous fungi (A. fumigatus 231, A. corymbifera 272,

Trichophyton mentagrophytes 445) from the collection of

fungal strains deposited at the Department of Biological

and Medical Sciences, Faculty of Pharmacy, Charles

University, Hradec Kralove, Czech Republic. Quality

control strains were involved. All the isolates were

maintained on Sabouraud dextrose agar prior to being

tested.

7. Gu, J. X.; Holland, H. L. Syn. Commun. 1998, 28, 3305.

8. (a) For other syntheses of 5a, see for example: Cowell, A.;

Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193. (b) DeShong,

P.; Sidler, D. R.; Rybczynski, P. J.; Slough, G. A.; Rheingold,

A. L. J. Am. Chem. Soc. 1988, 110, 2575. (c) Demnitz, F. W. J.

Tetrahedron Lett. 1989, 45, 6109. (d) Van den Hoven, B. G.; El

Ali, B.; Alper, H. J. Org. Chem. 2000, 65, 4131.

9. Compounds 5b, 5c, 5e and 5a were reported by DeShong

and coworkers, but neither the yields, nor the spectral data

were mentioned: DeShong, P.; Sidler, D. R.; Rybczynski, P. J.;

Ogilvie, A. A. J. Org. Chem. 1989, 54, 5432.

10. Ogata, Y.; Okano, M.; Kitamura, Y. J. Org. Chem. 1951,

16, 1588.

11. National Committee for Clinical Laboratory Standards.

Reference method for broth dilution antifungal susceptibility

testing of yeasts: Approved Standard, NCCLS document

M27-A; 771 E. Lancaster Avenue, Villanova, PA 19085, USA,

1997.

12. Yajima, A.; Mori, K. Liebigs Ann. Chem. 1996, 1091.

13. Jang, W. B.; Hu, H. P.; Lieberman, M. M.; Morgan, J. A.;

Stergiades, I. A.; Clark, D. S.; Tius, M. A. J. Comb. Chem.

2001, 3, 346.

14. Topliss, J. G. J. Med. Chem. 1972, 15, 1006.

15. Birch, A. J.; Dahler, P.; Narula, A. S.; Stephenson, G. R.

Tetrahedron Lett. 1980, 21, 3817.

16. Nakamura, E.-i.; Shimada, J-i.; Kuwajima, I. J. Chem.

Soc. Chem. Commun. 1983, 498.

17. Anand, R. C.; Ranjan, H. Ind. J. Chem. Sect. B 1984, 23,

1054.

18. Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.; Kerr,

W. J.; Lange, U. Tetrahedron 1996, 52, 7391.

19. Islam, Md.S.; Kawano, T.; Hatanaka, M.; Ueda, I. Tet-

rahedron Lett. 1996, 37, 5735.

20. For a recent review on Pd-catalyzed cross-coupling reac-

tions of a-haloenones, see: Negishi, E. J. Organomet. Chem.

1999, 576, 179.

21. Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Q. Tetrahedron

2000, 56, 10197.

Minimum inhibitory concentrations (MICs) were deter-

mined by the microdilution format of the NCCLS M27-

A guidelines.¹¹Dimethyl sulfoxide (100%) served as a

diluent for all compounds; the ﬁnal concentration did

not exceed 2%. RPMI 1640 (Sevapharma, Prague)

medium supplemented with l-glutamine and buﬀered

with 0.165 M morpholinepropanesulfonic acid (Serva)

to pH 7.0 by 10 N NaOH was used as the test medium.

The wells of the microdilution tray contained 100 mL of

the RPMI 1640 medium with 2-fold serial dilutions of

the compounds (125–0.24 mmol/l for the new com-

pounds) and 100 mL of inoculum suspension. Fungal

inoculum in RPMI 1640 was prepared to give a ﬁnal

concentration of 5 ꢃ 10³ꢅ0.2 cfu mL^ꢀ1. The trays were

incubated at 35 ^ꢂC and MICs were read visually for

ﬁlamentous fungi and photometrically for yeasts as an

optical density (OD) at 540 nm after 24 and 48 h. The

MIC values for the dermatophytic strain (T. menta-

grophytes) were determined after 72 h and 120 h. The

MICs were deﬁned as 80% inhibition of the growth of

control. MICs were determined twice and in duplicate.

The deviations from the usually obtained values given in

22. Martın, M. L.; San Roman, L.; Domınguez, A. Planta

Med. 1990, 56, 66.

2866

M. Pour et al. / Bioorg. Med. Chem. 11 (2003) 2843–2866

23. Gochfeld, D. J.; Hamann, M. T. J. Nat. Prod. 2001, 64, 1477.

24. Dieing, R.; Schmid, G. Chem. Ber. 1995, 128, 589.

25. Russel, P. B.; Hitchings, G. H. J. Am. Chem. Soc. 1951,

73, 3763.

26. Kaminski, J.; Skupny, A.; Stec, M.; Eckstein, Z. Przem.

Chem. 1977, 56, 23.

27. Katritzky, A. R. J. Chem. Soc. 1955, 2586.

28. Szarvasi, E.; Bayssat, M.; Fontaine, L.; Grand, M. Bull.

Soc. Chim. Fr. 1966, 1838.

29. Pickard, R. J. Chem. Soc. 1909, 95, 1015.

30. El Seoud, O. A.; do Amaral, A. T.; Campos, M. N. J.

Org. Chem. 1974, 39, 1915.

31. Casadio, S.; Pala, G.; Bruzzese, T.; Uberti, E. M. Farmaco

Ed. Sci. 1962, 17, 797.

32. Hirao, K.; Yamashita, A.; Ando, A.; Hamada, T.; Yone-

mitsu, O. J. Chem. Soc., Perkin Trans. 1 1988, 2913.

33. Khand, I. U.; Pauson, P. L. J. Chem. Res. Miniprint 1977,

168.

Article Doi

Synthesis and structure-antifungal activity relationships of 3-aryl-5-alkyl-2,5-dihydrofuran-2-ones and their carbanalogues: Further refinement of tentative pharmacophore group

DOI: 10.1016/S0968-0896(03)00220-7

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