Synthesis and antifungal activity evaluation of 3-hetaryl-2,5-dihydrofuran-2-ones. An unusual fragmentation of the oxazole ring via 2,3-selenoxide shift

Article abstract of DOI:10.1135/cccc20011809

In continuing the studies on the synthesis and evaluation of antifungal activity of the analogues of (-)incrustoporine, the replacement of the phenyl moiety at C3 of the furanone ring with a hetaryl substituent was considered. Thus, a series of 5-alkyl-3-hetaryl-2,5-dihydrofuran-2-ones with the thienyl, furyl and thiazolyl moieties attached to C3 was synthesized, and the compounds subjected to antifungal activity screening. In the preparation of compounds containing the oxazolyl fragment, the [2,3]-sigmatropic rearrangement led to the fragmentation of the oxazole ring, resulting in the formation of 3-(1-benzamido-2-oxoethylidene)-5-methyltetrahydrofuran-2-one. Somewhat surprisingly, the antifungal efficiency of the derivatives was lower in comparison with analogues containing a substituted phenyl at C3.

Full text of DOI:10.1135/cccc20011809

3-Hetaryl-2,5-dihydrofuran-2-ones
1809
SYNTHESIS AND ANTIFUNGAL ACTIVITY EVALUATION
OF 3-HETARYL-2,5-DIHYDROFURAN-2-ONES. AN UNUSUAL
FRAGMENTATION OF THE OXAZOLE RING
via 2,3-SELENOXIDE SHIFT
b
Jiří KUNEŠa1, Vojtěch BALŠÁNEKa2, Milan POURa3,* and VladimírB UCHTA
a
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University,
Heyrovského 1203, CZ-500 05 Hradec Králové, Czech Republic; e-mail: kunes@faf.cuni.cz,
1
2
3
balsanek@faf.cuni.cz, pour@faf.cuni.cz
b
Department of Biological and Medicinal Sciences, Faculty of Pharmacy, Charles University,
Heyrovského 1203, CZ-500 05 Hradec Králové, Czech Republic; e-mail: buchta@faf.cuni.cz
Received October 2, 2001
Accepted Novem ber 15, 2001
Dedicated to the memory of late Dr Václav Černý.
In con tin uin g th e studies on th e syn th esis an d evaluation of an tifun gal activity of th e an a-
logues of (–)in crustoporin e, th e replacem en t of th e ph en yl m oiety at C3 of th e furan on e
rin g with a h etaryl substituen t was con sidered. Th us, a series of 5-alkyl-3-h etaryl-2,5-dih ydro-
furan -2-on es with th e th ien yl, furyl an d th iazolyl m oieties attach ed to C3 was syn th esized,
an d th e com poun ds subjected to an tifun gal activity screen in g. In th e preparation of com -
poun ds con tain in g th e oxazolyl fragm en t, th e [2,3]-sigm atropic rearran gem en t led to th e
fragm en tation of th e oxazole rin g, resultin g in th e form ation of 3-(1-ben zam ido-2-oxo-
eth yliden e)-5-m eth yltetrah ydrofuran -2-on e. Som ewh at surprisin gly, th e an tifun gal efficien cy
of th e derivatives was lower in com parison with an alogues con tain in g a substituted ph en yl
at C3.
Keyw ord s: (–)In crustoporin e; 2,5-Dih ydrofuran -2-on es; Oxazoles; Th ioph en es; Th iazoles;
[2,3]-Sigm atropic rearran gem en t; Allylic selen oxide; An tifun gal activity.
In 1995, Zapf et al. isolated a secon dary m etabolite from th e Basidiom ycete
Incrustoporia carneola1, wh ich displayed certain an tifun gal activity again st
plan t path ogen ic fun gi. Th e structure of th is com poun d, n am ed
(–)in crustoporin e, was corroborated by a total syn th esis in 1996 (ref.2). In
con jun ction with our lon g-term projects, focused on explorin g sm all, bio-
logically active n atural com poun ds as prototypes of poten tial drugs, we
used th is substan ce as a lead structure in th e design an d syn th esis of n ovel
an tifun gals. So far, we h ave syn th esized3,4 structures with differen t substitu-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi:10.1135/cccc20011809

1810
Kuneš et al.:
en ts on th e ben zen e rin g attach ed to C3 of th e lacton e m oiety an d
m eth yl/h ydroxym eth yl/acyloxym eth yl groups at C5. Biological evaluation
of th e an alogues revealed th at an tifun gal activity is supported by substi-
tution of the benzene ring with halogens and by introducing an (acyloxy)methyl
moiety to C5 of the furanone. Most notably, 5-[(acyloxy)methyl]-3-(halophenyl)-
2,5-dihydrofuran-2-ones possessed in vitro an tifun gal activity com parable to
th at of am ph otericin B, on e of th e m ost poten t system ic an tifun gals cur-
ren tly on th e m arket. Sin ce m ost ch em ical drugs con tain h eterocyclic rin gs,
som e of wh ich are also isosteric to ph en yl, we were n aturally in terested in
replacin g th e ph en yl m oiety at C3 with a h eteroaryl on e (Fig. 1). Herein we
describe th e syn th eses an d biological evaluation of a series of com poun ds
with th ien yl, brom oth ien yl, furyl an d th iazolyl substituen ts, as well as at-
tem pts to prepare substan ces bearin g th e oxazole rin g at C3 of th e furan on e
system .
Chemistry
In order to prepare 2- an d 3-th ien yl derivatives (Sch em es 1 an d 2), we used
(2- or 3-th ien yl)acetic acids as th e startin g m aterials an d prepared th e target
com poun ds as described previously by us3. Th us, th e th ien ylacetic acids
were con verted in to th e correspon din g m eth yl esters, wh ich were en olized
with LDA. Th e quen ch in g of th e en olates with allyl brom ide furn ish ed
2-(2-th ien yl)- (1) an d 2-(3-th ien yl)pen t-4-en oic acid (2). As th e th ioph en e
rin g is extrem ely pron e to sulfon ation , th e acids could n ot be treated di-
rectly3 with H2SO4, an d th e desired cyclization to saturated lacton es 3 an d
4 was effected th rough th e addition of HBr across th e double bon d, fol-
lowed by n ucleoph ilic substitution of brom in e with th e carboxylate an ion .
Fin ally, th e en docyclic double bon d was in troduced in to lacton es 3 an d 4
via en olization , subsequen t treatm en t of th e en olates with Ph SeCl an d oxi-
O
O
3
3
Het
O
O
5
5
R
Het: 2-, 3-thienyl, 4-thiazolyl, 4-oxazolyl, 2- furyl
R: CH3, C2H5
FIG. 1
Structure of (–)in crustoporin e an d its h etaryl-an alogues
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1811
dative syn-elim in ation of th e ph en ylselan yl m oiety. Th is un even tful se-
quen ce of reaction s sm ooth ly afforded furan on es 5 an d 6.
1. MeOH/HCl
2. LDA, CH2=CHCH2Br
COOH
COOH
S
S
3. LiOH/H+
1
O
O
1. HBr/CH3COOH
2. Na2CO3
1. LDA
2. PhSeCl
S
S
O
O
3. MCPBA
5
3
NBS
O
O
1. LDA
S
S
2. PhSeCl
Br
Br
O
O
3. MCPBA
10
9
SCHEME 1
1. MeOH/HCl
2. LDA, CH2=CHCH2Br
S
S
3. LiOH
COOH
HOOC
2
S
S
1. HBr/CH3COOH
2. Na2CO3
1. LDA
2. PhSeCl
O
O
3. MCPBA
O
O
6
4
NBS
S
1. LDA
2. PhSeCl
S
Br
Br
Br
Br
3. MCPBA
O
O
O
O
8
7
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1812
Kuneš et al.:
Given our previous results, we also in ten ded to prepare brom oth ien yl an a-
logues of com poun ds 5 an d 6, sin ce we supposed th at th e in troduction of
th e brom in e would be likely to in crease an tifun gal activity. From th e syn -
th etic poin t of view, it appeared advan tageous to in troduce brom in e at th e
stage of th e saturated lacton e (3 an d 4). Sin ce brom in e itself is too reactive,
we used a m ilder brom in atin g agen t, NBS (refs5,6). However, th e reaction of
lacton e 4 with th is agen t in AcOH–MeOH gave an in separable m ixture of
3-(2-bromo-3-thienyl)-5-methyltetrahydrofuran-2-one, 3-(2,5-dibromo-3-thienyl)-
5-methyltetrahydrofuran-2-one (7) and the starting m aterial. The com poun ds
1
were iden tified by th e com parison of th e H NMR spectrum of th e m ixture
with th e spectra of lacton es 4 an d 7 (vide infra). In th e h ope th at th e com -
poun ds would becom e separable upon th e in troduction of th e double bon d,
th e m ixture was subjected to th e above described en olization /Ph SeCl/ syn-
elim in ation sequen ce. To our disappoin tm en t, on ly furan on e 6 could be sep-
arated from th e brom in ated an alogues, wh ich h ad iden tical RF values in a
n um ber of m obile ph ases. Given th ese results, lacton e 4 was treated with a
large excess of NBS to yield 3-(2,5-dibrom o-3-th ien yl)-5-m eth yltetrah ydro-
furan -2-on e 7 in 92% yield an d th is substan ce was con verted in to th e target
furan on e 8 as described above. On th e oth er h an d, lacton e 3 was selectively
brom in ated (86%) in position 5, wh ich en abled us to prepare 3-(5-brom o-
2-th ien yl)-5-m eth yl-2,5-dih ydrofuran -2-on e 10. With th e partially brom in -
ated an alogues 8 an d 10 in h an d, we also attem pted th e preparation of
fully brom in ated com poun ds. Wh ile NBS was too m ild to ach ieve
brom in ation of all position s in th e th ioph en e rin g, th e reaction of satu-
rated lacton es 3 an d 4 with Br2/AcOH gen erally led to in tractable m ixtures
of com poun ds. Fortun ately, th e sam e reaction carried out on th e m eth yl es-
ter of 3-th ien ylacetic acid (Sch em e 3) yielded th e m eth yl 2,4,5-tribrom o-
3-th ien ylacetate (11) in 95% yield an d th is com poun d was furth er con -
S
S
Br
Br
Br
COOH
Br2/CH3COOH
COOH
11
S
S
Br
Br
Br
Br
Br
1. LDA, CH2=CHCH2Br
2. LiOH
1. LDA
2. PhSeCl
O
O
Br
3. MCPBA
3. H2SO4
O
O
13
12
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1813
verted in to 3-(2,4,5-tribrom o-3-th ien yl)-5-m eth yl-2,5-dih ydrofuran -2-on e
(13) (Sch em e 3). It was in terestin g to observe th at th e m eth yl ester of th e
isom eric 2-th ien ylacetic acid gave a m ixture of com poun ds upon treatm en t
with brom in e in acetic acid.
An oth er group of derivatives in cluded th ose with a 2-(substituted
ph en yl)-4-th iazolyl m oiety, wh ere th e substituen ts on th e ben ezen e rin g
were selected accordin g to th e approach of Toppliss7. Th e startin g m ateri-
als, m eth yl esters of 2-(substituted ph en yl)-4-th iazolylacetic acids, were pre-
pared from substituted ben zon itriles, wh ich were con verted in to th e
correspon din g th ioam ides by th e addition of H2S. Th e th ioam ides were th en
subjected to a con den sation with th e m eth yl 4-ch loro-3-oxobutan oate8,
givin g rise to m eth yl esters 14a–14e, wh ich were furth er elaborated towards
th e target com poun ds 16a–16e (Sch em e 4) via th e sequen ce depicted in
Sch em e 4. In a sim ilar fash ion , we strove to prepare an oth er subset of an a-
logues bearin g a 2-(substituted ph en yl)-4-oxazolyl m oiety. Th e feasibility of
th e sequen ce was first evaluated on ben zam ide as th e startin g com poun d9.
SCHEME 4
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1814
Kuneš et al.:
As sh own in Sch em e 5, th e reaction s proceeded as plan n ed un til th e stage
of in troducin g th e double bon d, wh ich led to 3-(1-ben zam ido-2-oxo-
eth yliden e)-5-m eth yltetrah ydrofuran -2-on e 21 arisin g from th e fragm en ta-
tion of th e oxazole rin g as th e on ly isolable product. Th e structure of am ide
21 was corroborated by 2D NMR spectroscopy usin g gHSQC an d gHMBC
experim en ts. Sin ce we observed th e form ation of ph en ylselan yl com poun d
19, th e fragm en tation m ust h ave occurred upon oxidation in to th e corre-
spon din g selen oxide with MCPBA in CHCl3. In terestin gly, in stead of syn-
elim in ation with th e α-h ydrogen , th e selen oxide probably preferred
[2,3]-sigm atropic rearran gem en t10 to furn ish in term ediate 20, wh ich un der-
wen t h ydrolysis leadin g to th e fragm en tation of th e oxazole m oiety
(Sch em e 5). Un fortun ately, th e on ly observable NOE was between th e NH
group an d th e aldeh ydic proton , an d n um erous attem pts to crystallize alde-
h yde 21 failed. Con sequen tly, th e con figuration of com poun d 21 rem ain s
un resolved an d will be th e subject of furth er in vestigation .
Cl
O
O
O
O
CONH2
N
C2H5OH
COOCH3
17
1. LDA, CH2=CHCH2Br
2. LiOH
3. H2SO4
O
N
O
1. LDA
2. PhSeCl
O
O
N
O
O
PhSe
18
19
MCPBA
Nu
O
SePh
O
O
N
O
N
O
Ph
Se
O
O
O
H2O
O
20
H
O
O
N
H
O
21
SCHEME 5
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1815
Th e last an alogue, th e syn th esis of wh ich we executed, was th e 3-(2-furyl)
derivative 27 (Sch em e 6). In stead of th e path way depicted in Sch em e 1, we
tested a syn th esis based on a Stille reaction between 2-iodofuran 26 an d th e
stan n yl com poun d 25 as th e key step. 2-Iodofuran was prepared by th e di-
rect iodin ation of furan 11 an d com poun d 25 was syn th esized from propiolic
acid. Acid was esterified12, an d th e resultan t m eth yl ester was sequen tially
HO
1. LDA
2.
CH3OH
COOH
COOCH3
COOCH3
BF3·Et2O
O
22
23
1. Et3SiCl
2. Bu3SnH
Pd(PPh3)4
O
Dowex 50
MeOH/H2O
SnBu3
Bu3Sn
O
COOCH3
O SiEt3
25
24
+
O
O
O
O
I
O
[Pd2dba3]
O
O
O
+
CuI, AsPh3, NMP
26
28
27
SCHEME 6
treated with LDA an d acetaldeh yde to give th e m eth yl 4-h ydroxy-
2-h exyn oate13 (23). Followin g th e protection of th e h ydroxy group with
trieth ylsilyl ch loride, th e addition of Bu3Sn H (ref.14) across th e triple bon d
in com poun d 23 catalyzed by Pd(PPh 3)3 afforded (tributylstan n yl)alken e 24
as th e m ajor product. Upon deprotection of th e trieth ylsilyl group, th e lib-
erated h ydroxy fun ction im m ediately cyclized on to th e ester group to fur-
n ish th e secon d desired com pon en t for th e Pd couplin g, th e α-(tributyl-
stan n yl)lacton e 25. Th e couplin g15 step between 25 an d 26 was n ot an easy
task due to a som ewh at lim ited stability of both com poun ds. Not surpris-
ingly, the reaction failed under a num ber of different conditions, including
catalyst system s (Pd(Ph3)4, Pd(dba)2, “Pd(Ph3)2”, “Pd[P(2-furyl)3]2”16, solven ts
(THF, DMF). Fortun ately, upon usin g N-m eth ylpyrrolidon e as th e solven t
an d a catalytic system com posed of triph en ylarsin e as th e ligan d, Pd2(dba)3
as th e source of palladium an d Cu2I2 as th e cocatalyst17,18, th e required
tran sform ation was effected, albeit in a rath er low yield (38%) with th e
product of self-couplin g 28 bein g th e m ajor isolated com poun d (56%).
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1816
Biological Activity
Kuneš et al.:
Th e target com poun ds were evaluated for th eir in vitro an tifun gal activity
again st a set of h um an path ogen ic fun gi in cludin g th e represen tatives of
both yeast an d filam en tous strain s usin g th e m icrodilution form at of th e
NCCLS M27-A guidelin es19. Ketocon azole an d th e racem ic form of
(–)in crustoporin e2 were used as th e stan dards for com parison . Th e activi-
ties, expressed as m in im um in h ibitory con cen tration s (MICs), are sum m a-
rized in Table I. Surprisin gly, th e in troduction of a five-m em bered h etaryl
(furyl, th ien yl, 2-ph en ylth iazolyl) m oiety in to position 3 of th e lacton e rin g
does n ot in crease th e an tifun gal effect, as derivatives 5, 6, 10, 16c–16e, an d
27 are virtually in active. Th e un wan ted self-couplin g product, bislacton e
28, possesses h igh er activity th an un substituted an d m on osubstituted
h eterocyclic derivatives. As expected, th e an tifun gal activity of th e th ien yl
derivatives in creases with a h igh er degree of brom in ation , probably due to
a ch an ge in lipoph ilicity. As com pared to th e racem ic form of th e n atural
product, th e lacton es bearin g a brom oth ien yl m oiety at C3 display substan -
tially h igh er biological activity, because th e in creased lipoph ilicity of th e
com poun ds gives rise to a h igh er capability to pen etrate th e fun gal cell
wall.
In sum m ary, we h ave syn th esized a series of an alogues of (–)in crusto-
porin e with differen t five-m em bered h etaryl substituen ts attach ed to C3 of
th e lacton e rin g. Som e of th e com poun ds, h owever, could n ot be obtain ed
due to th e properties of th e h eterocyclic rin gs.
EXPERIMENTAL
Ch em istry
Th e oth er com m ercially available reagen ts were used directly, un less oth erwise in dicated.
THF was fresh ly distilled from sodium ben zoph en on e ketyl. DMF was dried over 3 Å m olecu-
lar sieves. Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. 1H an d
13C NMR spectra were recorded for CDCl3 solution s at am bien t tem perature on a Varian
Mercury-Vx BB 300 spectrom eter operatin g at 300 MHz for 1H. Ch em ical sh ifts were re-
corded as δ values in ppm an d were in directly referen ced to tetram eth ylsilan e (TMS) via th e
solven t sign al (7.26 for 1H, 77.0 for 13C in CDCl3). Couplin g con stan ts (J) are given in Hz.
Wh ere NMR spectra of m ixtures were recorded, on ly th ose data wh ich could be determ in ed
un equivocally were given . In frared spectra (waven um bers in cm –1) were recorded in CDCl3
on a Nicolet Im pact 400 spectroph otom eter. Low resolution m ass spectra were m easured on
a Magn um Fin n igan Mat apparatus. Elem en tal an alysis was carried out on a CHNS-OCE
FISONS EA 1110 in strum en t. An alytical th in -layer ch rom atograph y (TLC) was con ducted on
Merck TLC plates (silica gel 60 F254, alum in ium back), an d th e plates were visualized un der
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1817
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1818
Kuneš et al.:
UV ligh t an d in iodin e vapours. Silica gel 60 (230–400 m esh ) for colum n ch rom atograph y
was purch ased from Merck.
Preparation of Meth yl Esters of Th ien ylacetic Acids. Gen eral Procedure
A solution of a th ien ylacetic acid (1.70 g, 12 m m ol) in m eth an ol saturated with h ydrogen
ch loride (100 m l) was h eated un der reflux for 3 h . Th e solven t was rem oved in vacuo an d
th e residue redissolved in eth yl acetate. Th e solution was wash ed with 5% aqueous Na2CO3,
dried over an h ydrous Na2SO4, an d th e solven t evaporated to give th e correspon din g m eth yl
ester in quan titative yield. Th e com poun ds were used in th e n ext step with out purification
an d ch aracterization .
Meth yl (2,4,5-Tribrom o-3-th ien yl)acetate (11)
Brom in e (3.0 m l) in acetic acid (8.0 m l) was added dropwise to a solution of th e m eth yl
(3-th ien yl)acetate (2.13 g, 13.66 m m ol) in ch loroform (8.0 m l). After stirrin g at room
tem perature for 2 h , th e m ixture was diluted with eth yl acetate, wash ed with 5% aqueous
NaOH, brin e, saturated aqueous Na2S2O3, an d dried over an h ydrous Na2SO4. Th e solven t was
evaporated, an d th e residue purified by colum n ch rom atograph y (petroleum eth er–eth yl
acetate 95 : 5). Yield 5.108 g (95%), m .p. 31–33 °C. 1H NMR (CDCl3): 3.73 s, 3 H (CH3); 3.72 s,
2 H (CH2). 13C NMR (CDCl3): 169.10, 134.00, 115.87, 111.20, 110.01, 52.42, 35.83. MS, m/z (%):
394 (M+• + H, 100), 335 (79), 313 (42), 285 (3), 254 (9), 173 (10), 125 (6), 94 (33), 81 (4), 69 (11),
50 (12). IR (CDCl3), νmax: 2 955, 1 740, 1 534, 1 437, 1 406, 1 351, 1 328, 1 267.
Meth yl (2-Ph en yloxazol-4-yl)acetate (17)
A m ixture of ben zam ide (4.83 g, 39.87 m m ol) an d m eth yl 3-ch loroacetoacetate (5.00 g,
33.21 m m ol) was h eated at 120 °C for 2.5 h . After coolin g to room tem perature, eth yl ace-
tate (60 m l) was added, an d th e resultin g solution wash ed with brin e an d dried over
an h ydrous Na2SO4. Colum n ch rom atograph y (petroleum eth er–eth yl acetate 9 : 1) afforded
3.187 g (44%) of th e product. All ph ysical data an d spectral ch aracteristics were con sisten t
with th ose reported in th e literature20
.
Preparation of Meth yl an d Eth yl (2-Ph en ylth iazol-4-yl)acetates (14a–14e).
Gen eral Procedure
Substituted ben zon itriles were dissolved in pyridin e an d dry sulfan e was passed th rough th e
solution un til TLC in dicated th at th e reaction s were com plete. All ph ysical data were
con sisten t with th ose reported in literature21,22. A m ixture of a substituted th ioben zam ide
(19.16 m m ol), m eth yl 3-ch loroacetoacetate (2.00 m l, 17.42 m m ol) an d pyridin e (1.54 m l,
19.16 m m ol) in eth an ol (10 m l) was h eated un der reflux for 6 h . Th e solven t was rem oved
in vacuo, th e residue redissolved in eth yl acetate an d dried over an h ydrous Na2SO4. Th e
products were purified by colum n ch rom atograph y (petroleum eth er–eth yl acetate 95 : 5).
Methyl (2-phenylthiazol-4-yl)acetate (14a). Yield 3.55 g (83%). All ph ysical data an d spectral
ch aracteristics were con sisten t with th ose reported in th e literature20
Ethyl [2-(4-chlorophenyl)thiazol-4-yl]acetate (14b). Yield 3.40 g (69%). All ph ysical data an d
spectral ch aracteristics were con sisten t with th ose reported in th e literature23
.
.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1819
Ethyl [2-(4-methylphenyl)thiazol-4-yl]acetate (14c). Yield 3.98 g (87%). 1H NMR (CDCl3):
7.84–7.78 m , 2 H (AA′BB′); 7.25–7.19 m , 2 H (AA′BB′); 7.15 t, 1 H, J = 0.8 (th iazole); 4.21 q,
2 H, J = 7.1 (CH2); 3.88 d, 2 H, J = 0.8 (H2); 2.38 s, 3 H (Ar-CH3); 1.29 t, 3 H, J = 7.1 (CH3).
13C NMR (CDCl3): 170.43, 168.00, 149.60, 140.16, 130.89, 129.52, 126.43, 115.45, 61.00,
37.17, 21.38, 14.17. MS, m/z (%): 261 (M+• , 100), 247 (2), 216 (3), 188 (36), 161 (2), 147 (2),
135 (3), 118 (17), 91 (5), 71 (11), 51 (3). IR (CDCl3), νm ax: 2 984, 2 926, 1 732, 1 513, 1 456,
1 371.
Ethyl [2-(4-methoxyphenyl)thiazol-4-yl]acetate (14d ). Yield 3.45 g (72%). 1H NMR (CDCl3):
7.88–7.83 m , 2 H (AA′BB′); 7.11 t, 1 H, J = 0.8 (th iazole); 6.96–6.90 m , 2 H (AA′BB′); 4.21 q,
2 H, J = 7.1 (CH2); 3.86 d, 2 H, J = 0.8 (H2); 3.84 s, 3 H (OCH3); 1.29 t, 3 H, J = 7.1 (CH3).
13C NMR (CDCl3): 170.45, 167.70, 161.03, 149.47, 127.99, 126.51, 114.99, 114.15, 61.00,
55.35, 37.17, 14.17. MS, m/z (%): 277 (M+• , 100), 267 (2), 231 (4), 204 (32), 190 (2), 177 (2),
134 (15), 103 (4), 91 (4), 71 (21), 55 (3). IR (CDCl3), νm ax: 2 984, 2 938, 1 732, 1 610, 1 514,
1 458, 1 305.
Ethyl [2-(3-bromomethyl)thiazol-4-yl]acetate (14e). Yield 4.60 g (81%). All ph ysical data an d
spectral ch aracteristics were con sisten t with th ose reported in th e literature23
.
Preparation of Meth yl an d Eth yl 2-Hetarylpen t-4-en oates. Gen eral Procedure
A solution of 1.6 M butyllith ium in h exan es (8.27 m l, 13.2 m m ol) was added to a solution of
diisopropylam in e (1.77 m l, 12.6 m m ol) in dry THF (60 m l) at 0 °C un der argon . After 10 m in
at 0 °C, th e LDA solution was cooled to –60 °C an d a solution of m eth yl or eth yl h etaryl-
acetate (12 m m ol) was added. After m ain tain in g th e m ixture at –60 °C for 30 m in , allyl bro-
m ide (1.09 m l, 12.6 m m ol) was added dropwise. Th e reaction m ixture was slowly allowed to
warm to room tem perature (2 h ) in order to drive th e reaction to com pletion . Th e solution
was th en diluted with eth yl acetate (100 m l), wash ed with saturated aqueous NH4Cl, dried
over an h ydrous Na2SO4, an d con cen trated in vacuo to yield th e crude ester of th e corre-
spon din g 2-h etarylpen t-4-en oic acid. Th e products were purified by colum n ch rom atograph y
(petroleum eth er–eth er 95 : 5) an d directly used in furth er steps.
Methyl 2-(2-thienyl)pent-4-enoate. Yield 2.22 g (95%). 1H NMR (CDCl3): 7.23–7.19 m , 1 H
(Ar5); 6.98–6.93 m , 2 H (Ar3,4); 5.82–5.67 m , 1 H (H4) ;5.16–5.02 m , 2 H (H5); 3.96 dd, 1 H,
J1 = 8.3, J2 = 7.2 (H2); 3.70 s, 3 H (CH3); 2.89–2.75 m , 1 H (H3A); 2.66–2.54 m , 1 H (H3B).
13C NMR (CDCl3): 172.76, 140.61, 134.44, 126.54, 125.31, 124.53, 117.43, 52.24, 46.70,
38.68. MS, m/z (%): 196 (M+• + H, 6), 155 (100), 137 (64), 127 (60), 97 (12), 77 (3), 65 (9),
59 (7). IR (CDCl3), νm ax: 3 082, 2 954, 1 735, 1 642, 1 437, 1 338, 1 280.
Methyl 2-(3-thienyl)pent-4-enoate. Yield 2.05 g (87%). 1H NMR (CDCl3): 7.28 dd, 1 H, J1
=
5.0, J2 = 3.0 (Ar5); 7.15 dd, 1 H, J1 = 3.0, J2 = 1.4 (Ar2); 7.06 dd, 1 H, J1 = 5.0, J2 = 1.4 (Ar4);
5.81–5.65 m , 1 H (H4); 5.14–4.98 m , 2 H (H5); 3.80 dd, 1 H, J1 = 8.6, J2 = 6.8 (H2); 3.68 s,
3 H (CH3); 2.84–2.72 m , 1 H (H3A); 2.59–2.47 m , 1 H (H3B). 13C NMR (CDCl3): 173.52,
138.63, 135.02, 127.10, 125.74, 121.89, 117.10, 51.99, 46.76, 37.45. MS, m/z (%): 196 (M+• + H,
4), 155 (40), 137 (100), 127 (68), 97 (13), 91 (7), 77 (4), 65 (12), 51 (6). IR (CDCl3), νm ax: 3 082,
2 953, 1 733, 1 642, 1 437, 1 342, 1 280.
Methyl 2-(2,4,5-tribromo-3-thienyl)pent-4-enoate. Yield 3.81 g (73%), m .p. 53–54 °C. 1H NMR
(CDCl3): 5.77–5.61 m , 1 H (H4); 5.06–4.94 m , 2 H (H5); 4.04 dd, 1 H, J1 = 9.9, J2 = 5.8 (H2);
3.70 s, 3 H (CH3); 3.00–2.87 m , 1 H (H3A); 2.73–2.59 m , 1 H (H3B). 13C NMR (CDCl3):
171.25, 137.23, 134.37, 117.63, 114.94, 110.71, 110.62, 52.45, 46.38, 33.97. MS, m/z (%):
433 (M+• , 5), 391 (5), 353 (62), 333 (7), 312 (4), 293 (100), 273 (12), 254 (7), 212 (83), 186
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1820
Kuneš et al.:
(6), 161 (6), 148 (10), 134 (53), 107 (10), 89 (26), 59 (19). IR (CDCl3), νm ax: 3 082, 2 953, 1 736,
1 643, 1 521, 1 436, 1 263.
Methyl 2-(2-phenyloxazol-4-yl)pent-4-enoate. Yield 1.10 g (36%). 1H NMR (CDCl3): 8.05–7.98 m ,
2 H (Ar); 7.63 d, J = 0.8 (oxazole); 7.46–7.40 m , 3 H (Ar); 5.86–5.71 m , 1 H (H4); 5.15–5.02 m ,
2 H (H5); 3.84–3.78 m , 1 H (H2); 3.73 s, 3 H (CH3); 2.83–2.66 m , 2 H (H3). 13C NMR
(CDCl3): 172.68, 161.45, 139.29, 135.39, 134.50, 130.31, 128.66, 127.35, 126.39, 117.48,
52.13, 43.84, 35.91. MS, m/z (%): 257 (M+• , 71), 242 (5), 225 (97), 198 (100), 188 (32), 168
(9), 156 (50), 145 (6), 128 (23), 113 (18), 105 (80), 91 (14), 77 (63), 67 (45), 51 (31). IR (CDCl3),
ν
m ax: 3 082, 2 954, 1 736, 1 588, 1 555, 1 437, 1 340.
Methyl 2-(2-phenylthiazol-4-yl)pent-4-enoate. Yield 2.62
g
(80%). 1H NMR (CDCl3):
7.96–7.91 m , 2 H (Ar); 7.47–7.39 m , 3 H (Ar); 7.14 s, 1 H (th iazole); 5.88–5.73 m , 1 H (H4);
5.16–5.01 m , 2 H (H5); 4.06 dd, 1 H, J1 = 8.1, J2 = 7.0 (H2); 3.72 s, 3 H (CH3); 2.92–2.71 m ,
2 H (H3). 13C NMR (CDCl3): 171.36, 168.31, 149.68, 145.84, 133.09, 130.43, 129.00, 126.66,
126.48, 118.90, 77.67, 19.07. MS, m/z (%): 272 (M+• – H, 100), 259 (3), 214 (14), 204 (10),
180 (3), 149 (3), 129 (5), 121 (13), 104 (7), 91 (3), 77 (14), 69 (8), 51 (7). IR (CDCl3), νm ax: 3 067,
2 953, 1 735, 1 642, 1 512, 1 436, 1 267.
Ethyl 2-[2-(4-methylphenyl)thiazol-4-yl]pent-4-enoate. Yield 3.20 g (89%). 1H NMR (CDCl3):
7.85–7.79 m , 2 H (AA′BB′); 7.25–7.19 m , 2 H (AA′BB′); 7.11 d, 1 H, J = 0.6 (th iazole);
5.89–5.74 m , 1 H (H4); 5.17–5.01 m , 2 H (H5); 4.25–4.13 m , 2 H (CH2); 4.03 dd, 1 H, J1
=
8.2, J2 = 6.7 (H2); 2.90–2.70 m , 2 H (H3); 2.38 s, 3 H (Ar-CH3); 1.26 t, 3 H, J = 7.1 (CH3).
13C NMR (CDCl3): 172.44, 167.76, 154.24, 140.12, 135.02, 130.97, 129.49, 126.44, 117.11,
114.23, 60.89, 47.99, 36.65, 21.39, 14.20. MS, m/z (%): 301 (M+• , 100), 282 (23), 272 (67),
254 (14), 228 (63), 207 (18), 188 (12), 149 (17), 135 (55), 118 (32), 111 (24), 91 (31), 73 (54),
67 (30), 55 (23). IR (CDCl3), νm ax: 2 983, 2 925, 1 728, 1 642, 1 504, 1 457, 1 371, 1 262.
Ethyl 2-[2-(4-chlorophenyl)thiazol-4-yl]pent-4-enoate. Yield 2.97 g (77%), m .p. 41–43 °C.
1H NMR (CDCl3): 7.89–7.85 m , 2 H (AA′BB′); 7.41–7.37 m , 2 H (AA′BB′); 7.16 d, 1 H, J = 0.6
(th iazole); 5.88–5.73 m , 1 H (H4); 5.16–5.01 m , 2 H (H5); 4.25–4.13 m , 2 H (CH2); 4.02 dd,
1 H, J1 = 8.1, J2 = 6.8 (H2); 2.90–2.69 m , 2 H (H3); 1.25 t, 3 H, J = 7.1 (CH3). 13C NMR
(CDCl3): 172.30, 166.23, 154.62, 135.83, 134.87, 132.08, 129.05, 127.72, 117.25, 115.12,
60.97, 47.94, 36.59, 14.20. MS, m/z (%): 322 (M+• , 100), 306 (2), 292 (28), 276 (4), 248 (36),
224 (6), 208 (5), 155 (24), 138 (8), 111 (22), 85 (4), 77 (20), 69 (13), 51 (9). IR (CDCl3), νm ax
:
3 082, 2 983, 1 729, 1 642, 1 597, 1 495, 1 447, 1 263.
Ethyl 2-[2-(3-bromophenyl)thiazol-4-yl]pent-4-enoate. Yield 3.44 g (78%). 1H NMR (CDCl3):
8.11 t, 1 H, J = 1.8 (Ar2); 7.84 ddd, 1 H, J1 = 8.0, J2 = 1.7, J3 = 1.1 (Ar4); 7.53 ddd, 1 H, J1
=
8.0, J2 = 1.9, J3 = 1.1 (Ar6); 7.29 t, 1 H, J = 8.0 (Ar5); 7.19 d, 1 H, J = 0.6 (th iazole); 5.88–5.73 m ,
1 H (H4); 5.16–5.01 m , 2 H (H5); 4.25–4.14 m , 2 H (CH2); 4.04 dd, 1 H, J1 = 8.0, J2 = 6.9
(H2); 2.90–2.70 m , 2 H (H3); 1.26 t, 3 H, J = 7.1 (CH3). 13C NMR (CDCl3): 172.23, 165.73,
154.62, 135.29, 134.79, 132.79, 130.34, 129.30, 125.13, 122.98, 117.29, 115.52, 60.99,
47.87, 36.60, 14.18. MS, m/z (%): 366 (M+• , 100), 338 (15), 292 (24), 258 (5), 210 (4), 199
(10), 111 (8), 103 (3), 77 (5), 65 (6), 51 (4). IR (CDCl3), νm ax: 3 082, 2 983, 1 730, 1 593, 1 565,
1 508, 1 273.
Ethyl 2-[2-(4-methoxyphenyl)thiazol-4-yl]pent-4-enoate. Yield 3.13 g (82%). 1H NMR (CDCl3):
7.89–7.85 m , 2 H (AA′BB′); 7.07 d, 1 H, J = 0.6 (th iazole); 6.95–6.91 m , 2 H (AA′BB′);
5.89–5.72 m , 1 H (H4); 5.17–4.99 m , 2 H (H5); 4.25–4.14 m , 2 H (CH2); 4.02 dd, 1 H, J1
=
8.2, J2 = 6.9 (H2); 3.85 s, 3 H (OCH3); 2.89–2.68 m , 2 H (H3); 1.26 t, 3 H, J = 7.0 (CH3).
13C NMR (CDCl3): 172.43, 167.50, 161.06, 154.03, 135.02, 128.03, 126.50, 117.11, 114.15,
113.79, 60.89, 55.37, 47.92, 36.64, 14.20. MS, m/z (%): 317 (M+• , 100), 302 (6), 288 (48), 273
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1821
(5), 244 (55), 220 (15), 204 (13), 177 (4), 151 (41), 134 (23), 111 (20), 77 (30), 67 (16), 51
(10). IR (CDCl3), νm ax: 2 983, 2 840, 1 728, 1 609, 1 505, 1 459, 1 305, 1 254.
Preparation of 2-Hetarylpen t-4-en oic Acids. Gen eral Procedure
Th e m eth yl/eth yl 2-h etarylpen t-4-en oate (8 m m ol) was dissolved in
a m ixture of
MeOH–H2O 3 : 1 (40 m l) an d aqueous solution of LiOH (57 wt.%; 0.44 g, 10.4 m m ol) was
added to th e solution . After 20 h at am bien t tem perature, th e reaction m ixture was con cen -
trated in vacuo, diluted with water an d acidified with con cen trated HCl to pH 4. Th e m ix-
ture was extracted with eth yl acetate (3×), th e com bin ed extracts dried over an h ydrous
Na2SO4, an d solven t evaporated. Th e resultin g acids were directly used in furth er steps.
2-(2-Thienyl)pent-4-enoic acid (1). Yield 1.45 g (100%). 1H NMR (CDCl3): 7.23 dd, 1 H, J1
=
5.0, J2 = 1.4 (Ar5); 7.00 dd, 1 H, J1 = 5.0, J2 = 3.3 (Ar4); 6.96 dd, 1 H, J1 = 3.3, J2 = 1.4 (Ar3);
5.84–5.68 m , 1 H (H4); 5.18–5.03 m , 2 H (H5); 3.97 t, 1 H, J = 7.7 (H2); 2.90–2.77 m , 1 H
(H3A); 2.69–2.56 m , 1 H (H3B).
2-(3-Thienyl)pent-4-enoic acid (2). Yield 1.46 g (100%). 1H NMR (CDCl3): 7.30 dd, 1 H, J1
=
5.0, J2 = 3.0 (Ar5); 7.19 dd, 1 H, J1 = 3.0, J2 = 1.4 (Ar2); 7.09 dd, 1 H, J1 = 5.0, J2 = 1.4 (Ar4);
5.83–5.68 m , 1 H (H4); 5.16–5.02 m , 2 H (H5); 3.81 t, 1 H, J = 7.8 (H2); 2.87–2.74 m , 1 H
(H3A); 2.62–2.51 m , 1 H (H3B).
2-(2,4,5-Tribromo-3-thienyl)pent-4-enoic acid. Yield 3.27 g (98%), m .p. 74–77 °C. 1H NMR
(CDCl3): 5.75–5.59 m , 1 H (H4); 5.08–4.93 m , 2 H (H5); 4.12 dd, 1 H, J1 = 9.9, J2 = 5.5 (H2);
2.97–2.86 m , 1 H (H3A); 2.78–2.65 m , 1 H (H3B).
2-(2-Phenyloxazol-4-yl)pent-4-enoic acid. Yield 1.93 g (99%), m .p. 70–73 °C. 1H NMR
(CDCl3): 8.06–7.97 m , 2 H (Ar); 7.65 s, 1 H (oxazole); 7.48–7.40 m , 3 H (Ar); 5.88–5.72 m , 1 H
(H4); 5.18–5.03 m , 2 H (H5); 3.85 t, 1 H, J = 7.0 (H2); 2.88–2.68 m , 2 H (H3).
2-(2-Phenylthiazol-4-yl)pent-4-enoic acid. Yield 2.01 g (97%), m .p. 69–72 °C. 1H NMR
(CDCl3): 7.96–7.89 m , 2 H (Ar); 7.47–7.41 m , 3 H (Ar); 7.15 s, 1 H (th iazole); 5.87–5.72 m , 1 H
(H4); 5.15–5.03 m , 2 H (H5); 4.02 t, 1 H, J = 7.3 (H2); 2.95–2.71 m , 2 H (H3).
2-[2-(4-Methylphenyl)thiazol-4-yl]pent-4-enoic acid. Yield 2.19 g (100%), m .p. 54–56 °C. 1H NMR
(CDCl3): 7.83–7.77 m , 2 H (AA′BB′); 7.26–7.20 m , 2 H (AA′BB′); 7.11 s, 1 H (th iazole);
5.87–5.71 m , 1 H (H4); 5.15–5.02 m , 2 H (H5); 4.00 t, 1 H, J = 7.3 (H2); 2.92–2.70 m , 2 H (H3);
2.40 s, 3 H (Ar-CH3).
2-[2-(4-Chlorophenyl)thiazol-4-yl]pent-4-enoic acid. Yield 2.35 g (100%), m .p. 78–79 °C. 1H NMR
(CDCl3): 7.88–7.82 m , 2 H (AA′BB′); 7.42–7.37 m , 2 H (AA′BB′); 7.17 s, 1 H (th iazole);
5.86–5.71 m , 1 H (H4); 5.16–5.03 m , 2 H (H5); 4.02 t, 1 H, J = 7.3 (H2); 2.92–2.70 m , 2 H
(H3).
2-[2-(3-Bromophenyl)thiazol-4-yl]pent-4-enoic acid. Yield 2.70 g (100%). 1H NMR (CDCl3):
8.08 t, 1 H, J = 1.8 (Ar2); 7.82 ddd, 1 H, J1 = 8.0, J2 = 1.7, J3 = 1.1 (Ar4); 7.54 ddd, 1 H, J1
=
8.0, J2 = 1.9, J3 = 1.1 (Ar6); 7.30 t, 1 H, J = 8.0 (Ar5); 7.20 s, 1 H (th iazole); 5.86–5.71 m , 1 H
(H4); 5.16–5.03 m , 2 H (H5); 4.03 t, 1 H, J = 7.4 (H2); 2.93–2.71 m , 2 H (H3).
2-[2-(4-Methoxyphenyl)thiazol-4-yl]pent-4-enoic acid. Yield 2.24 g (97%). 1H NMR (CDCl3):
7.88–7.81 m , 2 H (AA′BB′); 7.06 s, 1 H (th iazole); 6.97–6.92 m , 2 H (AA′BB′); 5.87–5.70 m ,
1 H (H4); 5.15–5.02 m , 2 H (H5); 3.98 t, 1 H, J = 7.3 (H2); 3.85 s, 3 H (OCH3); 2.92–2.70 m ,
2 H (H3).
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1822
Kuneš et al.:
Preparation of 3-Hetaryl-5-m eth yltetrah ydrofuran -2-on es 12, 15a–15c, 15e an d 18.
Gen eral Procedure
A 2-h etarylpen t-4-en oic acid (8 m m ol) was treated with con cen trated H2SO4 (5 m l) at 0 °C
for 20 m in an d th e solution was subsequen tly poured in to brin e. Th e m ixture was n eutral-
ized with saturated aqueous Na2CO3 to pH 8 an d extracted with eth yl acetate. Th e organ ic
ph ase was dried over an h ydrous Na2SO4 an d th e solven t evaporated. Th e crude products
were purified by colum n ch rom atograph y (petroleum eth er–eth yl acetate 9 : 1) to afford th e
saturated diastereom eric lacton es th at were directly used in furth er steps.
5-Methyl-3-(2,4,5-tribromo-3-thienyl)tetrahydrofuran-2-one (12). Yield 2.33 g (69%), m .p.
119–122 °C. 1H NMR (CDCl3): diastereom er A: 5.01–4.98 m , 1 H (H5); 4.27 dd, 1 H, J1
=
10.8, J2 = 10.3 (H3); 2.72–2.49 m , 1 H (H4A); 2.33–2.09 m , 1 H (H4B); 1.48 d, 3 H, J = 6.6
(CH3); diastereom er B: 4.76–4.63 m , 1 H (H5); 4.25 dd, 1 H, J1 = 12.6, J2 = 9.3 (H3);
2.72–2.49 m , 1 H (H4A); 2.33–2.09 m , 1 H (H4B); 1.55 d, 3 H, J = 6.0 (CH3). 13C NMR
(CDCl3): diastereom er A: 174.01, 134.63, 116.51, 112.77, 111.30, 75.54, 41.10, 33.92, 21.52;
diastereom er B: 174.30, 135.23, 116.82, 113.07, 111.88, 75.15, 43.78, 35.55, 20.69. MS (m ix-
ture of diastereom ers), m/z (%): 418 (M+• – H, 34), 376 (21), 361 (6), 348 (11), 335 (5), 295
(62), 280 (45), 267 (12), 255 (8), 214 (100), 186 (9), 159 (5), 135 (60), 107 (11), 93 (20), 81
(10), 69 (19), 51 (9). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 984, 2 933, 1 770, 1 524,
1 456, 1 387, 1 342.
5-Methyl-3-(2-phenyloxazol-4-yl)tetrahydrofuran-2-one (18). Yield 1.79 g (92%), m .p. 77–80 °C.
1H NMR (CDCl3): diastereom er A: 8.05–7.98 m , 2 H (Ar); 7.69 d, 1 H, J = 0.8 (oxazole);
7.48–7.41 m , 3 H (Ar); 4.99–4.88 m , 1 H (H5); 3.97 dd, 1 H, J1 = 12.1, J2 = 8.8 (H3);
2.79–2.69 m , 1 H (H4A); 2.39–2.30 m , 1 H (H4B); 1.48 d, 3 H, J = 6.3 (CH3); diastereom er B:
8.05–7.98 m , 2 H (Ar); 7.78 d, 1 H, J = 1.1 (oxazole); 7.48–7.41 m , 3 H (Ar); 4.75–4.62 m , 1 H
(H5); 3.97 dd, 1 H, J1 = 12.1, J2 = 8.8 (H3); 2.91–2.80 m , 1 H (H4A); 2.28–2.14 m , 1 H (H4B);
1.52 d, 3 H, J = 6.3 (CH3). 13C NMR (CDCl3): diastereom er A: 175.81, 162.12, 137.54,
135.72, 130.54, 128.72, 127.18, 76.17, 38.59, 35.60, 20.90; diastereom er B: 175.39, 161.90,
137.12, 135.36, 130.48, 128.72, 126.41, 75.85, 40.19, 36.98, 20.76. MS (m ixture of
diastereom ers), m/z (%): 243 (M+• , 26), 228 (2), 207 (2), 199 (16), 184 (4), 171 (5), 156 (4),
143 (5), 128 (4), 115 (5), 105 (100), 89 (4), 77 (13), 67 (6), 51 (9). IR (CDCl3) (m ixture of
diastereom ers), νm ax: 2 985, 1 769, 1 555, 1 488, 1 449, 1 342.
5-Methyl-3-(2-phenylthiazol-4-yl)tetrahydrofuran-2-one (15a). Yield 1.80 g (87%), m .p. 86–88 °C.
1H NMR (CDCl3): diastereom er A: 7.96–7.89 m , 2 H (Ar); 7.46–7.39 m , 3 H (Ar); 7.22 d, 1 H,
J = 0.6 (th iazole); 5.08–4.94 m , 1 H (H5); 4.12 dd, 1 H, J1 = 11.8, J2 = 8.8 (H3); 2.95–2.79 m ,
1 H (H4A); 2.44–2.28 m , 1 H (H4B); 1.49 d, 3 H, J = 6.3 (CH3); diastereom er B: 7.96–7.89 m ,
2 H (Ar); 7.46–7.39 m , 3 H (Ar); 7.33 d, 1 H, J = 0.8 (th iazole); 4.77–4.60 m , 1 H (H5); 4.12 dd,
1 H, J1 = 11.8, J2 = 8.8 (H3); 2.95–2.79 m , 1 H (H4A); 2.44–2.28 m , 1 H (H4B); 1.53 d, 3 H, J =
6.1 (CH3). 13C NMR (CDCl3): diastereom er A: 176.14, 168.64, 152.20, 133.31, 130.15,
128.87, 126.48, 115.56, 76.35, 43.28, 36.61, 20.96; diastereom er B: 175.74, 168.24, 151.84,
133.41, 130.06, 128.87, 126.50, 115.94, 75.60, 44.20, 37.59, 20.87. MS (m ixture of
diastereom ers), m/z (%): 259 (M+• , 100), 231 (60), 215 (80), 200 (26), 188 (17), 175 (6), 153
(2), 136 (3), 121 (97), 112 (43), 104 (40), 97 (35), 84 (11), 77 (30), 69 (18), 51 (22). IR (CDCl3)
(m ixture of diastereom ers), νm ax: 3 116, 2 984, 1 767, 1 515, 1 461, 1 387.
3-[2-(4-Chlorophenyl)thiazol-4-yl]-5-methyltetrahydrofuran-2-one (15b). Yield 1.74 g (74%),
m .p. 131–132 °C. 1H NMR (CDCl3): diastereom er A: 7.89–7.82 m , 2 H (AA′BB′); 7.42–7.36 m ,
2 H (AA′BB′); 7.24 d, 1 H, J = 0.6 (th iazole); 5.06–4.94 m , 1 H (H5); 4.11 dd, 1 H, J1 = 11.8, J2
=
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1823
8.8 (H3); 2.93–2.77 m , 1 H (H4A); 2.42–2.28 m , 1 H (H4B); 1.49 d, 3 H, J = 6.3 (CH3);
diastereom er B: 7.89–7.82 m , 2 H (AA′BB′); 7.42–7.36 m , 2 H (AA′BB′); 7.34 d, 1 H, J = 0.6
(th iazole); 4.76–4.62 m , 1 H (H5); 4.11 dd, 1 H, J1 = 11.8, J2 = 8.8 (H3); 2.93–2.77 m , 1 H
(H4A); 2.42–2.28 m , 1 H (H4B); 1.53 d, 3 H, J = 6.3 (CH3). 13C NMR (CDCl3): diastereom er A:
176.00, 167.27, 152.42, 136.07, 131.80, 129.08, 127.70, 115.91, 76.31, 43.18, 36.54, 20.98;
diastereom er B: 175.63, 166.88, 152.05, 135.97, 131.91, 129.08, 127.70, 116.29, 75.61,
44.19, 37.58, 20.86. MS (m ixture of diastereom ers), m/z (%): 293 (M+• – H, 100), 278 (4), 265
(17), 248 (61), 234 (24), 222 (27), 180 (4), 155 (83), 138 (24), 112 (66), 97 (52), 79 (25), 69
(25), 58 (34). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 984, 1 767, 1 597, 1 498, 1 454,
1 388.
5-Methyl-3-[2-(4-methylphenyl)thiazol-4-yl]tetrahydrofuran-2-one (15c). Yield 1.87 g (85%),
m .p. 108–111 °C. 1H NMR (CDCl3): diastereom er A: 7.84–7.78 m , 2 H (AA′BB′); 7.25–7.20 m ,
2 H (AA′BB′); 7.18 d, 1 H, J = 0.8 (th iazole); 5.07–4.94 m , 1 H (H5); 4.11 dd, 1 H, J1 = 11.7, J2
=
8.8 (H3); 2.93–2.77 m , 1 H (H4A); 2.43–2.28 m , 1 H (H4B); 2.39 s, 3 H (Ar-CH3); 1.49 d, 3 H,
J = 6.3 (CH3); diastereom er B: 7.84–7.78 m , 2 H (AA′BB′); 7.29 d, 1 H, J = 0.6 (th iazole);
7.25–7.20 m , 2 H (AA′BB′); 4.75–4.62 m , 1 H (H5); 4.11 dd, 1 H, J1 = 11.7, J2 = 8.8 (H3);
2.93–2.77 m , 1 H (H4A); 2.43–2.28 m , 1 H (H4B); 2.39 s, 3 H (Ar-CH3); 1.53 d, 3 H, J = 6.0
(CH3). 13C NMR (CDCl3): diastereom er A: 176.19, 168.82, 152.01, 140.41, 130.82, 129.54,
126.42, 115.03, 76.34, 43.31, 36.65, 21.40, 20.96; diastereom er B: 175.79, 168.42, 151.66,
140.30, 130.72, 129.54, 126.42, 115.42, 75.59, 44.21, 37.62, 21.40, 20.87. MS (m ixture of
diastereom ers), m/z (%): 273 (M+• , 100), 258 (3), 245 (5), 229 (56), 214 (22), 202 (21), 189 (6),
147 (2), 135 (98), 118 (37), 112 (32), 97 (29), 91 (18), 79 (15), 69 (16), 58 (23). IR (CDCl3)
(m ixture of diastereom ers), νm ax: 2 984, 1 768, 1 511, 1 457, 1 388, 1 346.
3-[2-(3-Bromophenyl)thiazol-4-yl]-5-methyltetrahydrofuran-2-one (15e). Yield 2.66 g (98%),
m .p. 109–110 °C. 1H NMR (CDCl3): diastereom er A: 8.09 t, 1 H, J = 1.8 (Ar2); 7.82 ddd, J1
=
8.0, J2 = 1.7, J3 = 1.1 (Ar4); 7.53 ddd, J1 = 8.0, J2 = 1.9, J3 = 1.1 (Ar6); 7.29 t, J = 8.0 (Ar5);
7.27 d overlapped, 1 H (th iazole); 5.06–4.94 m , 1 H (H5); 4.12 dd, 1 H, J1 = 11.8, J2 = 8.8
(H3); 2.94–2.79 m , 1 H (H4A); 2.43–2.29 m , 1 H (H4B); 1.50 d, 3 H, J = 6.3 (CH3);
diastereom er B: 8.10 t, 1 H, J = 1.8 (Ar2); 7.82 ddd, J1 = 8.0, J2 = 1.7, J3 = 1.1 (Ar4); 7.53 ddd,
J1 = 8.0, J2 = 1.9, J3 = 1.1 (Ar6); 7.29 t, J = 8.0 (Ar5); 7.37 d, 1 H, J = 0.6 (th iazole); 4.76–4.63 m ,
1 H (H5); 4.12 dd, 1 H, J1 = 11.8, J2 = 8.8 (H3); 2.94–2.79 m , 1 H (H4A); 2.43–2.29 m , 1 H
(H4B); 1.54 d, 3 H, J = 6.3 (CH3). 13C NMR (CDCl3): diastereom er A: 175.96, 166.73, 152.49,
135.21, 132.97, 130.38, 129.24, 125.11, 122.99, 116.29, 76.32, 43.14, 36.48, 20.99;
diastereom er B: 175.58, 166.33, 152.11, 135.21, 132.87, 130.38, 129.20, 125.11, 122.99,
116.65, 75.63, 44.18, 37.58, 20.84. MS (m ixture of diastereom ers), m/z (%): 338 (M+• , 100),
311 (10), 295 (79), 280 (22), 266 (22), 212 (4), 199 (45), 182 (7), 154 (3), 112 (71), 97 (54),
79 (26), 69 (23), 58 (31). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 985, 1 768, 1 565,
1 457, 1 388, 1 346.
Preparation of 3-Hetaryl-5-m eth yltetrah ydrofuran -2-on es 3, 4 an d 15d .
Gen eral Procedure
A solution of HBr in AcOH (30 wt.%, 10 m l) was slowly added to a 2-h etarylpen t-4-en oic
acid (10 m m ol) un der argon . Th e solution was stirred for 6 h an d th e solven t rem oved in
vacuo. Th e residue was redissolved in m eth an ol (15 m l) an d Na2CO3 (2.12 g, 20 m m ol) was
added to th e solution . After stirrin g for 45 m in , th e solution was diluted with brin e an d th e
resultin g m ixture extracted with eth yl acetate. Th e organ ic ph ase was dried over an h ydrous
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1824
Kuneš et al.:
Na2SO4 an d th e solven t evaporated. Th e products were purified by colum n ch rom atograph y
(petroleum eth er–eth yl acetate 9 : 1).
5-Methyl-3-(2-thienyl)tetrahydrofuran-2-one (3). Yield 1.35 g (74%). 1H NMR (CDCl3):
diastereom er A: 7.28–7.23 m , 1 H (Ar5); 7.05–6.97 m , 2 H (Ar3,4); 4.89–4.77 m , 1 H (H5);
4.19–4.10 m , 1 H (H3); 2.67–2.57 m , 1 H (H4A); 2.17–2.04 m , 1 H (H4B); 1.47 d, 3 H, J = 6.3
(CH3); diastereom er B: 7.28–7.23 m , 1 H (Ar5); 7.05–6.97 m , 2 H (Ar3,4); 4.70–4.58 m , 1 H
(H5); 4.19–4.10 m , 1 H (H3); 2.93–2.83 m , 1 H (H4A); 2.45–2.34 m , 1 H (H4B); 1.50 d, 3 H, J =
6.3 (CH3). 13C NMR (CDCl3): diastereom er A: 175.44, 138.44, 126.97, 125.60, 124.90, 75.41,
42.84, 39.62, 20.94; diastereom er B: 175.14, 138.02, 126.80, 125.39, 124.90, 75.08, 41.24,
38.17, 20.84. MS (m ixture of diastereom ers), m/z (%): 183 (M+• + H, 21), 138 (71), 123 (100),
110 (13), 97 (11), 79 (7), 65 (7), 58 (5), 51 (6). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 984,
1 772, 1 453, 1 388, 1 344.
5-Methyl-3-(3-thienyl)tetrahydrofuran-2-one (4). Yield 1.50 g (82%). 1H NMR (CDCl3):
diastereom er A: 7.34 dd, 1 H, J1 = 5.0, J2 = 3.0 (Ar5); 7.21–7.19 m , 1 H (Ar2); 7.11–7.06 m
(Ar4); 4.84–4.72 m , 1 H (H5); 4.04–3.93 m , 1 H (H3); 2.85–2.75 m , 1 H (H4A); 2.09–1.97 m ,
1 H (H4B); 1.46 d, 3 H, J = 6.3 (CH3); diastereom er B: 7.34 dd, 1 H, J1 = 5.0, J2 = 3.0 (Ar5);
7.21–7.19 m , 1 H (Ar2); 7.11–7.06 m (Ar4); 4.69–4.57 m , 1 H (H5); 4.04–3.93 m , 1 H (H3);
2.61–2.51 m , 1 H (H4A); 2.38–2.28 m , 1 H (H4B); 1.49 d, 3 H, J = 6.3 (CH3). 13C NMR
(CDCl3): diastereom er A: 176.31, 136.27, 126.76, 126.39, 121.97, 75.23, 41.13, 37.04, 20.86;
diastereom er B: 175.98, 136.14, 126.62, 126.01, 121.59, 74.97, 42.67, 38.64, 20.76. MS (m ix-
ture of diastereom ers), m/z (%): 183 (M+• + H, 100), 137 (35), 123 (55), 110 (8), 97 (5), 65
(3), 53 (3). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 983, 1 768, 1 456, 1 387, 1 344.
3-[2-(4-Methoxyphenyl)thiazol-4-yl]-5-methyltetrahydrofuran-2-one (15d ). Yield 2.51 g (87%),
m .p. 94–95 °C. 1H NMR (CDCl3): diastereom er A: 7.89–7.82 m , 2 H (AA′BB′); 7.14 d, 1 H, J =
0.6 (th iazole); 6.96–6.91 m , 2 H (AA′BB′); 5.06–4.94 m , 1 H (H5); 4.10 dd, 1 H, J1 = 12.6, J2
=
8.0 (H3); 3.85 s, 3 H (OCH3); 2.92–2.76 m , 1 H (H4A); 2.42–2.26 m , 1 H (H4B); 1.48 d, 3 H,
J = 6.3 (CH3); diastereom er B: 7.89–7.82 m , 2 H (AA′BB′); 7.24 d, 1 H, J = 0.6 (th iazole);
6.96–6.91 m , 2 H (AA′BB′); 4.74–4.61 m , 1 H (H5); 4.10 dd, 1 H, J1 = 12.6, J2 = 8.0 (H3); 3.85 s,
3 H (OCH3); 2.92–2.76 m , 1 H (H4A); 2.42–2.26 m , 1 H (H4B); 1.53 d, 3 H, J = 6.3 (CH3).
13C NMR (CDCl3): diastereom er A: 176.21, 168.52, 161.17, 151.90, 127.99, 126.34, 114.55,
114.16, 76.34, 55.37, 43.31, 36.66, 20.96; diastereom er B: 175.80, 168.13, 161.11, 151.55,
127.98, 126.44, 114.95, 114.16, 75.57, 55.37, 44.21, 37.61, 20.88. MS (m ixture of
diastereom ers), m/z (%): 289 (M+• , 100), 261 (5), 244 (26), 230 (9), 218 (10), 201 (2), 186 (2),
173 (3), 151 (57), 134 (8), 112 (7), 97 (10), 90 (3), 77 (5), 69 (5), 58 (8). IR (CDCl3) (m ixture
of diastereom ers), νm ax: 2 982, 2 937, 1 767, 1 609, 1 514, 1 460, 1 254.
3-(5-Brom o-2-th ien yl)-5-m eth yltetrah ydrofuran -2-on e (9)
N-Brom osuccin im ide (0.75 g, 4.20 m m ol) was added to a solution of lacton e 3 (0.73 g,
4.00 m m ol) in a m ixture of CHCl3–AcOH 1 : 1 (20 m l). After 48 h at am bien t tem perature,
th e reaction m ixture was diluted with eth yl acetate (50 m l), wash ed with 5% aqueous
NaOH, brin e, saturated aqueous Na2S2O3, an d dried over an h ydrous Na2SO4. Th e solven t
was evaporated an d th e residue was purified by colum n ch rom atograph y (petroleum
eth er–eth yl acetate 95
: 5). Yield 0.90 g
(86%), m .p. 65–68 °C. 1H NMR (CDCl3):
diastereom er A: 6.93 d, 1 H, J = 3.6 (Ar); 6.76 d, 1 H, J = 3.6 (Ar); 4.87–4.75 m , 1 H (H5);
4.04 dd, 1 H, J1 = 12.6, J2 = 8.5 (H3); 2.64–2.52 m , 1 H (H4A); 2.43–2.33 m , 1 H (H4B); 1.46
d, 3 H, J = 6.3 (CH3); diastereom er B: 6.94 d, 1 H, J = 3.8 (Ar); 6.77 d, 1 H, J = 3.8 (Ar);
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1825
4.70–4.57 m , 1 H (H5); 4.04 dd, 1 H, J1 = 12.4, J2 = 8.5 (H3); 2.91–2.79 m , 1 H (H4A);
2.12–1.97 m , 1 H (H4B); 1.49 d, 3 H, J = 6.3 (CH3). 13C NMR (CDCl3): diastereom er A:
174.78, 139.78, 129.61, 125.74, 111.55, 75.22, 41.28, 37.45, 20.91; diastereom er B: 174.57,
139.40, 129.42, 125.89, 111.69, 75.40, 43.05, 38.99, 20.78. MS (m ixture of diastereom ers),
m/z (%): 260 (M+• – H, 46), 218 (52), 203 (37), 188 (11), 175 (5), 137 (68), 122 (100), 109
(23), 95 (11), 77 (4), 69 (15), 59 (7), 51 (7). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 989,
2 877, 1 753, 1 466, 1 387, 1 356, 1 207.
3-(2,5-Dibrom o-3-th ien yl)-5-m eth yltetrah ydrofuran -2-on e (7)
N-Brom osuccin im ide (1.78 g, 10.00 m m ol) was added to a solution of 4 (0.73 g, 4.00 m m ol)
in a m ixture of CHCl3–AcOH 1 : 1 (20 m l). After 24 h at am bien t tem perature, th e reaction
m ixture was diluted with eth yl acetate (50 m l), wash ed with 5% aqueous NaOH, brin e, satu-
rated aqueous Na2S2O3, an d dried over an h ydrous Na2SO4. Th e solven t was evaporated an d
th e residue was purified by colum n ch rom atograph y (petroleum eth er–eth yl acetate 95 : 5).
Yield 1.25 g (92%). 1H NMR (CDCl3): diastereom er A: 6.82 s, 1 H (Ar); 4.87–4.76 m , 1 H
(H5); 4.04 t, 1 H, J = 9.2 (H3); 2.41–2.32 m , 2 H (H4); 1.47 d, 3 H, J = 6.0 (CH3);
diastereom er B: 6.86 s, 1 H (Ar); 4.70–4.58 m , 1 H (H5); 4.02 dd, 1 H, J1 = 12.6, J2 = 8.5 (H3);
2.83–2.72 m , 1 H (H4A); 1.91–1.77 m , 1 H (H4B); 1.49 d, 3 H, J = 6.3 (CH3). 13C NMR
(CDCl3): diastereom er A: 175.29, 136.85, 128.97, 111.83, 110.97, 75.19, 40.48, 36.55, 20.80;
diastereom er B: 174.96, 137.20, 129.19, 111.94, 111.14, 75.39, 42.94, 38.57, 21.07. MS (m ix-
ture of diastereom ers), m/z (%): 340 (M+• , 71), 296 (19), 281 (6), 215 (20), 200 (21), 136
(100), 121 (18), 108 (9), 93 (6), 63 (5). IR (CDCl3) (m ixture of diastereom ers), νm ax: 2 983,
2 932, 1 774, 1 388, 1 343, 1 268.
Preparation of 3-Hetaryl-5-m eth yl-2,5-dih ydrofuran -2-on es. Gen eral Procedure
A solution of 1.6 M butyllith ium in h exan es (2.07 m l, 3.3 m m ol) was added to a solution of
diisopropylam in e (0.44 m l, 3.15 m m ol) in dry THF (5 m l) at 0 °C un der argon . After 10 m in
at 0 °C, th e LDA solution was cooled to –60 °C an d a solution of a saturated lacton e (3 mmol)
in THF (3 m l) was added. After m ain tain in g th e m ixture at –60 °C for 30 m in , a solution of
ph en ylselan yl ch loride (0.862 g, 4.5 m m ol) in THF (2 m l) was added. Th e resultin g m ixture
was slowly allowed to warm to room tem perature (over 2 h ), diluted with eth yl acetate
(20 m l), wash ed with saturated aqueous NH4Cl, dried over an h ydrous Na2SO4, an d con cen -
trated in vacuo. Th e crude ph en ylselan yl derivative was rapidly purified by colum n
ch rom atograph y (petroleum eth er–eth er 98 : 2), redissolved in CHCl3 (10 m l), an d MCPBA
(57 wt.%, 1.36 g, 4.5 m m ol) was added to th e solution at 0 °C. After stirrin g at am bien t tem -
perature for 45 m in , th e m ixture was diluted with eth yl acetate (50 m l), wash ed with 5%
aqueous Na2CO3, dried over an h ydrous Na2SO4, an d th e solven t evaporated. Products were
purified by colum n ch rom atograph y (petroleum eth er–eth yl acetate 9 : 1).
5-Methyl-3-(2-thienyl)-2,5-dihydrofuran-2-one (5). Yield 0.14 g (26%), m .p. 28–29 °C. 1H NMR
(CDCl3): 7.55 dd, 1 H, J1 = 3.6, J2 = 1.1 (Ar4); 7.38 d, 1 H, J = 1.9 (H4); 7.36 dd overlapped,
1 H, J2 = 1.1 (Ar2); 7.08 dd, 1 H, J1 = 4.9, J2 = 3.6 (Ar3); 5.17 qd, 1 H, J1 = 6.9, J2 = 1.9 (H5);
1.50 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 170.62, 145.03, 131.28, 127.64, 127.34, 127.06,
126.12, 77.37, 19.27. MS, m/z (%): 180 (M+• , 83), 165 (3), 152 (12), 137 (24), 123 (7), 109
(100), 91 (4), 77 (5), 65 (11), 51 (7). IR (CDCl3), νm ax: 2 987, 2 935, 1 754, 1 640, 1 328, 1 318.
For C9H8O2S calculated: 59.98% C, 4.47% H, 17.79% S; foun d: 59.98% C, 4.50% H, 17.91% S.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1826
Kuneš et al.:
5-Methyl-3-(3-thienyl)-2,5-dihydrofuran-2-one (6). Yield 0.17 g (31%). 1H NMR (CDCl3):
8.19–8.16 m , 1 H (Ar); 7.39 d, 1 H, J = 1.9 (H4); 7.37–7.35 m , 2 H (Ar); 5.15 qd, 1 H, J1
=
6.9, J2 = 1.9 (H5); 1.50 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 171.53, 146.21, 130.04,
126.77, 126.05, 125.68, 125.20, 77.07, 19.29. MS, m/z (%): 180 (M+• , 89), 152 (8), 137 (27),
123 (6), 109 (100), 82 (4), 65 (13), 51 (7). IR (CDCl3), νm ax: 2 986, 2 934, 1 757, 1 644, 1 319.
3-(2,5-Dibrom o-3-thienyl)-5-m ethyl-2,5-dihydrofura n-2-one (8 ). Yield 0.35 g (34%),
m .p. 74–76 °C. 1H NMR (CDCl3): 8.00 d, 1 H, J = 1.8 (H4); 7.66 s, 1 H (Ar); 5.19 qd, 1 H, J1
=
6.9, J2 = 1.8 (H5); 1.53 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 171.26, 151.68, 130.41,
130.15, 125.01, 111.71, 111.55, 77.37, 19.00. MS, m/z (%): 338 (M+• , 100), 295 (12), 267
(56), 228 (5), 186 (8), 134 (5), 121 (8), 106 (11), 93 (6), 63 (13), 50 (5). IR (CDCl3), νm ax
:
3 111, 2 987, 1 756, 1 532, 1 419, 1 324. For C9H6Br2O2S calculated: 31.98% C, 1.79% H,
9.49% S; foun d: 32.16% C, 1.39% H, 9.32% S.
5-Methyl-3-(5-bromo-2-thienyl)-2,5-dihydrofuran-2-one (10). Yield 0.41 g (53%), m .p. 84–85 °C.
1H NMR (CDCl3): 7.45 d, 1 H, J = 4.1 (Ar); 7.33 d, 1 H, J = 1.9 (H4); 7.03 d, 1 H, J = 4.1 (Ar);
5.16 qd, 1 H, J1 = 6.9, J2 = 1.9 (H5); 1.50 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 170.52,
145.08, 132.83, 130.49, 127.66, 125.52, 114.98, 77.67, 19.05. MS, m/z (%): 260 (M+• + H,
100), 232 (23), 217 (41), 201 (7), 189 (96), 151 (12), 134 (7), 122 (8), 108 (35), 91 (10), 82
(12), 69 (24), 63 (37), 50 (14). IR (CDCl3), νm ax: 2 988, 2 935, 1 755, 1 637, 1 423, 1 321. For
C9H7BrO2S calculated: 41.72% C, 2.72% H, 12.37% S; foun d: 41.96% C, 2.73% H, 12.12% S.
5-Methyl-3-(2,4,5-tribromo-3-thienyl)-2,5-dihydrofuran-2-one (13). Yield 0.37 g (30%), m .p.
138–140 °C. 1H NMR (CDCl3): 7.53 d, 1 H, J = 1.5 (H4); 5.28 qd, 1 H, J1 = 6.9, J2 = 1.5 (H5);
1.57 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 169.49, 157.23, 131.47, 127.51, 114.75,
112.61, 111.25, 78.01, 19.12. MS, m/z (%): 418 (M+• + H, 100), 373 (16), 347 (56), 309 (10),
265 (18), 211 (13), 184 (12), 133 (11), 121 (14), 106 (16), 89 (17), 77 (13), 61 (17). IR (CDCl3),
ν
m ax: 2 985, 2 935, 1 762, 1 509, 1 376, 1 318. For C9H5Br3O2S calculated: 25.93% C, 1.21% H,
9.49% S; foun d: 26.15% C, 1.15% H, 9.33% S.
5-Methyl-3-(2-phenylthiazol-4-yl)-2,5-dihydrofuran-2-one (16a). Yield 0.18 g (23%), m .p.
80–82 °C. 1H NMR (CDCl3): 8.24 s, 1 H (th iazole); 8.03–7.96 m , 3 H (2H Ar + H4), 7.50–7.43 m ,
3 H (Ar); 5.24 qd, 1 H, J1 = 6.9, J2 = 1.4 (H5); 1.55 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3):
171.36, 168.31, 149.68, 145.84, 133.09, 130.43, 129.00, 126.66, 126.48, 118.90, 77.67,
19.07. MS, m/z (%): 257 (M+• , 100), 240 (1), 229 (7), 214 (17), 201 (5), 186 (83), 152 (1), 134
(1), 121 (2), 104 (6), 97 (5), 83 (21), 65 (7), 51 (11). IR (CDCl3), νm ax: 3 125, 2 934, 1 755, 1 484,
1 359, 1 319. For C14H11NO2S calculated: 65.35% C, 4.31% H, 5.44% N, 12.46% S; foun d:
65.15% C, 4.37% H, 5.37% N, 12.17% S.
3-[2-(4-Chlorophenyl)thiazol-4-yl]-5-methyl-2,5-dihydrofuran-2-one (16b). Yield 0.25 g (29%),
m .p. 183–185 °C. 1H NMR (CDCl3): 8.24 s, 1 H (th iazole); 7.94–7.89 m , 3 H (2H AA′BB′ +
H4); 7.46–7.40 m , 2 H (AA′BB′); 5.24 qd, 1 H, J1 = 6.9, J2 = 1.7 (H5); 1.54 d, 3 H, J = 6.9
(CH3). 13C NMR (CDCl3): 171.25, 166.90, 149.84, 145.99, 136.38, 131.56, 129.22, 127.83,
126.36, 119.08, 77.68, 19.04. MS, m/z (%): 291 (M+• – H, 100), 263 (8), 248 (18), 235 (4),
220 (57), 185 (2), 137 (3), 111 (6), 97 (7), 83 (29), 75 (18), 65 (19), 51 (18). IR (CDCl3), νm ax
:
3 124, 2 986, 1 755, 1 483, 1 463, 1 359, 1 319. For C14H10ClNO2S calculated: 57.64% C,
3.45% H, 4.80% N, 10.99% S; foun d: 57.33% C, 3.69% H, 4.54% N, 10.70% S.
5-Methyl-3-[2-(4-methylphenyl)thiazol-4-yl]-2,5-dihydrofuran-2-one (16c). Yield 0.25 g (30%),
m .p. 128–130 °C. 1H NMR (CDCl3): 8.20 s, 1 H (th iazole); 7.93 d, 1 H, J = 1.7 (H4);
7.90–7.84 m , 2 H (AA′BB′); 7.28–7.23 m , 2 H (AA′BB′); 5.23 qd, 1 H, J1 = 6.9, J2 = 1.7 (H5);
2.40 s, 3 H (CH3-Ar); 1.54 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 171.37, 168.45, 149.55,
145.67, 140.74, 130.45, 129.65, 126.55, 126.49, 118.46, 77.64, 21.43, 19.07. MS, m/z (%):
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1827
271 (M+• , 97), 243 (6), 228 (14), 215 (6), 200 (100), 167 (1), 135 (2), 116 (6), 97 (5), 91 (10),
83 (19), 65 (10), 51 (6). IR (CDCl3), νm ax: 3 125, 2 987, 1 755, 1 485, 1 360, 1 319. For
C15H13NO2S calculated: 66.40% C, 4.83% H, 5.16% N, 11.82% S; foun d: 66.21% C, 4.92% H,
5.08% N, 11.55% S.
3-[2-(4-Methoxyphenyl)thiazol-4-yl]-5-methyl-2,5-dihydrofuran-2-one (16d ). Yield 0.22
g
(26%), m .p. 109–110 °C. 1H NMR (CDCl3): 8.16 s, 1 H (th iazole); 7.94–7.89 m , 3 H (2H
AA′BB′ + H4); 6.99–6.93 m , 2 H (AA′BB′); 5.23 qd, 1 H, J1 = 6.9, J2 = 1.7 (H5); 3.86 s, 3 H
(CH3O); 1.54 d, 3 H, J = 6.9 (CH3). 13C NMR (CDCl3): 171.38, 168.13, 161.39, 149.44,
145.56, 128.15, 126.49, 126.02, 118.07, 114.28, 77.62, 55.40, 19.07. MS, m/z (%): 287 (M+•
,
100), 259 (10), 244 (10), 231 (5), 216 (70), 201 (5), 173 (4), 134 (5), 103 (4), 90 (4), 83 (13),
63 (6), 51 (5). IR (CDCl3), νm ax: 3 125, 2 937, 1 755, 1 609, 1 523, 1 466, 1 360, 1 319. For
C
15H13NO3S calculated: 62.70% C, 4.56% H, 4.87% N, 11.16% S; foun d: 62.55% C, 4.75% H,
4.79% N, 10.92% S.
3-[2-(3-Bromophenyl)thiazol-4-yl]-5-methyl-2,5-dihydrofuran-2-one (16e). Yield 0.24 g (24%),
m .p. 121–123 °C. 1H NMR (CDCl3): 8.26 s, 1 H (th iazole); 8.17 t, 1 H, J = 1.9 (Ar2); 7.96 d,
1 H, J = 1.9 (H4); 7.86 ddd, 1 H, J1 = 8.0, J2 = 1.8, J3 = 1.1 (Ar4); 7.57 ddd, 1 H, J1 = 8.0, J2
=
1.8, J3 = 1.1 (Ar6); 7.32 t, 1 H, J = 8.0 (Ar5); 5.25 qd, 1 H, J1 = 6.9, J2 = 1.9 (H5); 1.55 d, 3 H,
J = 6.9 (CH3). 13C NMR (CDCl3): 171.21, 166.33, 150.01, 146.02, 134.84, 133.19, 130.47,
129.35, 126.27, 125.24, 123.11, 119.32, 77.70, 19.01. MS, m/z (%): 337 (M+• + H, 100), 307
(7), 294 (21), 279 (6), 266 (91), 185 (6), 102 (11), 83 (34), 65 (12), 51 (12). IR (CDCl3), νmax: 3 124,
2 987, 1 756, 1 565, 1 482, 1 359, 1 320. For C14H10BrNO2S calculated: 50.02% C, 3.00% H,
4.17% N, 9.54% S; foun d: 51.77% C, 3.49% H, 4.04% N, 9.20% S.
3-(1-Benzamido-2-oxoethylidene)-5-methyltetrahydrofuran-2-one (21). Yield 0.21 g (27%).
1H NMR (CDCl3): 10.80 s, 1 H (-COH); 8.55 s, 1 H (-NH-); 7.92–7.85 m , 2 H (Ar); 7.65–7.58 m ,
1 H (Ar); 7.56–7.47 m , 2 H (Ar); 4.85–4.73 m , 1 H (H5); 3.22 dd, 1 H, J1 = 19.5, J2 = 6.9 (H4);
2.92 dd, 1 H, J1 = 19.5, J2 = 6.0 (H4); 1.50 d, 3 H, J = 6.3 (CH3). 13C NMR (CDCl3): 186.66,
169.10, 164.11, 138.03, 133.06, 132.76, 128.99, 128.64, 127.76, 75.38, 39.00, 21.86. MS, m/z (%):
260 (M+• + H, 7), 241 (16), 230 (5), 172 (2), 126 (7), 105 (100), 77 (26), 51 (12). IR (CDCl3), νm ax
:
3 362, 3 026, 2 931, 1 744, 1 698, 1 675, 1 501, 1 479, 1 281.
Meth yl Propiolate
Th e com poun d was prepared an d purified accordin g to a literature procedure12. Yield 4.82 g
(44%), b.p. 98–102 °C.
Meth yl 4-Hydroxyh ex-2-yn oate
Th e com poun d was prepared accordin g to th e procedure for th e preparation of m eth yl
4-h ydroxypen t-2-yn oate13. Yield 3.55 g (96%). All spectra were con sisten t with th ose previ-
ously publish ed24
.
Meth yl 4-[(Trieth ylsilyl)oxy]h ex-2-yn oate
Ch loro(trieth yl)silan e (4.08 m l, 24.33 m m ol) was added to
a solution of m eth yl
4-h ydroxyh ex-2-yn oate (3.14 g, 22.12 m m ol) an d trieth ylam in e (3.39 m l, 24.33 m m ol) in
CH2Cl2 (100 m l) at 0 °C. After 20 h at 0 °C, th e solven t was rem oved in vacuo. Th e residue
was diluted with petroleum eth er an d th e crystals of trieth ylam m on ium ch loride rem oved
by filtration . Petroleum eth er was evaporated an d th e crude product was purified by colum n
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1828
Kuneš et al.:
ch rom atograph y (petroleum eth er). Yield 4.31 g (76%). 1H NMR (CDCl3): 4.40 t, 1 H, J = 6.3
(H4); 3.76 s, 3 H (OCH3); 1.80–1.68 m , 2 H (H5); 0.99 t, 3 H, J = 7.4 (H6); 0.97 t, 9 H, J = 7.7
(CH3); 0.69–0.60 m , 6 H (Si-CH2). 13C NMR (CDCl3): 153.93, 88.89, 75.56, 63.52, 52.66,
31.03, 9.37, 6.66, 4.60. MS, m/z (%): 256 (M+• , 13), 227 (90), 219 (100), 197 (86), 169 (32),
143 (7), 125 (36), 115 (52), 93 (31), 82 (5), 65 (25), 53 (15). IR (CDCl3), νm ax: 2 957, 2 938, 2 878,
1 713, 1 458, 1 436, 1 346, 1 258.
Meth yl (E)-2-(Tributylstan n yl)-4-[(trieth ylsilyl)oxy]h ex-2-en oate (24)
Th e com poun d was obtain ed by th e procedure of Rossi et al.14. Yield 6.61 g (81%). 1H NMR
(CDCl3): 6.01 d, 1 H, J = 8.0 (H3); 4.75–4.64 m , 1 H (H4); 3.68 s, 3 H (OCH3); 1.57–1.41 m ,
8 H (CH2 + H5); 1.36–1.23 m , 6 H (CH2); 0.99–0.83 m , 27 H (Sn-CH2 + CH3 + H6); 0.64–0.53 m ,
6 H (Si-CH2). 13C NMR (CDCl3): 171.11, 156.61, 133.92, 72.19, 51.21, 30.66, 28.85, 27.24,
13.67, 10.26, 9.70, 6.79, 4.71. MS, m/z (%): 547 (M+• , 2), 519 (100), 486 (30), 464 (13), 396
(9), 338 (8), 273 (2), 250 (4), 228 (1), 176 (1), 96 (1). IR (CDCl3), νm ax: 2 958, 2 932, 2 874, 2 854,
1 698, 1 458, 1 433.
5-Eth yl-3-(tributylstan n yl)-2,5-dih ydrofuran -2-on e (25)
Dowex 50 (H+ form ) (5.0 g) was added to a solution of m eth yl (E)-2-(tributylstan n yl)-
4-[(triethylsilyl)oxy]hex-2-enoate (5.07 g, 9.25 m m ol) in a m ixture of MeOH–H2O 5 : 1 (650 m l)
an d th e m ixture was stirred at 50 °C for 3 h . Dowex was th en filtered off an d th e solven t re-
m oved in vacuo. Th e residue was purified by colum n ch rom atograph y (petroleum eth er–eth er
95 : 5). Yield 3.74 g (93%). 1H NMR (CDCl3): 7.43 d, 1 H, J = 1.4 (H4); 4.99–4.92 m , 1 H (H5);
1.87–1.59 m , 2 H (CH2); 1.58–1.44 m , 6 H (CH2); 1.39–1.23 m , 6 H (CH2); 1.13–1.03 m , 6 H
(Sn -CH2); 0.97 t, 3 H (CH3); 0.88 t, 9 H (CH3). 13C NMR (CDCl3): 177.95, 165.13, 135.51,
85.99, 28.90, 27.14, 26.47, 13.64, 9.64, 8.97. MS, m/z (%): 400 (M+• + H, 100), 371 (19), 333
(25), 249 (31), 214 (14), 192 (50), 96 (78), 68 (30), 53 (30). IR (CDCl3), νm ax: 2 959, 2 926, 2 872,
2 853, 1 735, 1 580, 1 464, 1 331.
2-Iodofuran (26)
Th e com poun d was prepared accordin g to a literature procedure11. Yield 0.91 g (63%).
Couplin g of Com poun ds 25 an d 26
A solution of 26 (0.29 g, 1.5 m m ol) in NMP (1 m l) was added to
a suspen sion of
Pd2(dba)3·CHCl3 (0.02 g, 0.02 m m ol), triph en ylarsin e (0.05 g, 0.16 m m ol) an d CuI (0.02 g,
0.08 m m ol) in NMP (1 m l) un der argon . Th e reaction m ixture was warm ed to 50 °C an d a
solution of 25 (0.40 g, 1 m m ol) in NMP (1.5 m l) was added. Th e reaction tem perature was
m ain tain ed at 50 °C for 6 h an d a saturated aqueous solution of KF was th en added. After
stirrin g for 30 m in , th e m ixture was diluted with eth yl acetate (50 m l). Th e resultin g suspen -
sion was filtered off, th e filtrate wash ed with water, brin e, an d dried over an h ydrous
Na2SO4. Th e solven t was rem oved in vacuo an d th e residue subjected to colum n ch rom ato-
graph y (petroleum eth er–eth yl acetate 95 : 5).
5-Ethyl-3-(2-furyl)-2,5-dihydrofuran-2-one (27). Yield 0.07 g (38%). 1H NMR (CDCl3): 7.48 d,
1 H, J = 1.8 (Ar5); 7.42 d, 1 H, J = 1.8 (H4); 7.13 dd, 1 H, J1 = 3.3, J2 = 0.6 (Ar3); 6.48 dd, 1 H,
J1 = 3.3, J2 = 1.8 (Ar4); 5.08–5.01 m , 1 H (H5); 1.95–1.70 m , 2 H (CH2); 1.04 t, 3 H, J = 7.5
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

3-Hetaryl-2,5-dihydrofuran-2-ones
1829
(CH3). 13C NMR (CDCl3): 170.12, 145.28, 143.52, 142.80, 123.37, 111.71, 111.02, 82.59,
26.75, 9.13. MS, m/z (%): 178 (M+• , 100), 161 (5), 150 (47), 133 (4), 121 (70), 105 (4), 93
(90), 77 (8), 65 (43), 57 (33), 51 (10). IR (CDCl3), νm ax: 2 973, 2 936, 1 759, 1622, 1 462, 1 338.
5-Ethyl-3-(5-ethyl-2-oxo-2,5-dihydro-3-furyl)-2,5-dihydrofuran-2-one (28). Yield 0.06 g (56%),
m .p. 86–88 °C. 1H NMR (CDCl3): 8.25 d, 2 H, J = 1.1 (H4); 5.10–5.01 m , 2 H (H5); 1.96–1.69 m ,
4 H (CH2); 1.04 t, 6 H, J = 7.4 (CH3). 13C NMR (CDCl3): 171.38, 151.81, 121.89, 83.15,
26.37, 9.16. MS, m/z (%): 223 (M+• + H, 100), 204 (88), 193 (9), 176 (21), 161 (12), 147 (12),
133 (11), 119 (18), 107 (10), 91 (32), 77 (17), 65 (13), 57 (86), 51 (21). IR (CDCl3), νm ax: 2 974,
2 940, 1 758, 1 589, 1 462, 1 338. For C12H14O4 calculated: 64.85% C, 6.35% H; foun d:
64.75% C, 6.42% H.
Biological Activity Evaluation
In vitro an tifun gal activities of th e com poun ds, ketocon azole (Jan ssen –Cilag) an d racem ic
in crustoporin e, were evaluated on a pan el of on e ATCC (Candida albicans ATCC 44859) an d
seven clin ical isolates of yeasts (C. krusei E28, Candida tropicalis 156, Candida glabrata 20/I,
Trichosporon beigelii 1188) an d filam en tous fun gi (Aspergillus fumigatus 231, Absidia
corymbifera 272, Trichophyton mentagrophytes 445) from th e collection of fun gal strain s depos-
ited at th e Departm en t of Biological an d Medical Scien ces, Faculty of Ph arm acy, Ch arles
Un iversity, Hradec Králové, Czech Republic. All th e isolates were m ain tain ed on Sabouraud
dextrose agar prior to bein g tested.
Min im um in h ibitory con cen tration s (MICs) were determ in ed by th e m icrodilution form at
of th e NCCLS M27-A guidelin es10. Dim eth yl sulfoxide (100%) served as a diluen t for all
com poun ds; th e fin al con cen tration did n ot exceed 2%. RPMI 1640 (Sevaph arm a, Prague)
m edium supplem en ted with L-glutam in e an d buffered with 0.165 M m orph olin epropan e-
sulfon ic acid (Serva) to pH 7.0 by 10 M NaOH was used as th e test m edium . Th e wells of th e
m icrodilution tray con tain ed 100 µl of th e RPMI 1640 m edium with two-fold serial dilution s
of th e com poun ds (1 000 to 0.24 µm ol/l for th e n ew com poun ds) an d 100 µl of in oculum
suspen sion . Fun gal in oculum in RPMI 1640 was prepared to give a fin al con cen tration of
5 · 103 ± 0.2 cfu m l–1. Th e trays were in cubated at 35 °C an d MICs were read visually for fila-
m en tous fun gi an d ph otom etrically for yeasts as an optical den sity (OD) at 540 n m after 24
an d 48 h . Th e MIC values for th e derm atoph ytic strain (T. mentagrophytes) were determ in ed
after 72 an d 120 h . Th e MICs, defin ed as 80% in h ibition of th e growth of con trol, were de-
term in ed twice an d in duplicate. Th e deviation s from th e usually obtain ed values were n o
h igh er th an th e n earest con cen tration value up an d down th e dilution scale.
This work was financially supported by Charles University (project No. 27/1999/B) and by the
Ministry of Education, Youth and Sports of the Czech Republic (project No. MSM 11160001).
REFERENCES
1. Zapf S., Anke T., Sterner O.: Acta Chem. Scand. 1995, 49, 233.
2. Yajima A., Mori K.: Liebigs Ann. 1996, 1091.
3. PourM., Špulák M., Balšánek V., Kuneš J., Buchta V., WaisserK.: Bioorg. Med. Chem. Lett.
2000, 10, 1893.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1830
Kuneš et al.:
4. PourM., Špulák M., Buchta V., Kubanová P., Vopšralová M., Wsól V., Fáková H.,
Koudelka P., Pourová H., Schiller R.: J. Med. Chem. 2001, 44, 2701.
5. Jackson P. M., Moody Ch.: J. Chem. Soc., Perkin Trans. 1 1990, 11, 2909.
6. Corral C., Lissavetzky J.: Synthesis 1984, 10, 847 .
7. WaisserK., Čeladník M.: Cesk. Farm. 1982, 31, 129.
8. Brown D. J., Cook A. H., Heilbron I.: J. Chem. Soc. 1949, S106.
9. Meguro K., Tawada H., Sugiyama Y., Fujita T., Kawamatsu Y.: Chem. Pharm. Bull. 1986,
36, 2840.
10. Koprowski M., Krawczyk E., Skowronska A., et al.: Tetrahedron 2001, 57 1105.
11. Carman C. S., Koser G. F.: J. Org. Chem. 1983, 48, 2534.
12. House H. O., Roelofs W. L., Trost B. M.: J. Org. Chem. 1966, 31, 646.
13. Lautens M., Fillion E.: J. Org. Chem. 1997, 62, 4418.
14. Rossi R., Carpita A., Cossi P.: Tetrahedron 1992, 48, 8801.
15. Hollingworth G. J., Perkins G., Sweeney J.: J. Chem. Soc., Perkin Trans. 1 1996, 16, 1913.
16. PourM., Negishi E.: Tetrahedron Lett. 1997, 38, 525.
17. Liebeskind L. S., RiesingerS. W.: J. Org. Chem. 1993, 58, 408.
18. Farina V., Kapadia S., Kirshnan B., Wang C., Liebeskind L. S.: J. Org. Chem. 1994, 59,
5905.
19. National Committee for Clinical Laboratory Standards. Reference method for broth
dilution antifungal susceptibility testing of yeasts: Approved standard; NCCLS Document
M27-A. NCCLS, Villanova (PA) 1997.
20. Malamas M. S., Carlson R. P., Grimes D., Howell R., Glaser K.: J. Med. Chem. 1996, 39,
237.
21. Papadopoulos E.: J. Org. Chem. 1976, 41, 962.
22. Lee A. L., Mackay D., Manery E. L.: Can. J. Chem. 1970, 48, 3554.
23. Rooney C. S., Randall W. C., StereterK. B., ZieglerC., Cargoe E. J.:
J. Med. Chem. 1983,
26, 700 .
24. Hirao K., Yamashita A., Ando A., Hamada T., Yonemitsu O.: J. Chem. Soc., Perkin Trans. 1
1988, 2913.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)