Extension of the library of biologically active γ-alkylidene butenolides

Article abstract of DOI:10.1055/s-0028-1083181

γ-Alkylidene butenolides bearing a deoxyriboside, a steroid, and a metallocene moiety were synthesized by stereoselective sequential cross-coupling lactonization procedure from the corresponding functionalized terminal alkynes with 3-iodopropenoic acids.

Full text of DOI:10.1055/s-0028-1083181

PAPER
3465
Extension of the Library of Biologically Active g-Alkylidene Butenolides
B
iological Ac
t
e
ive
g
-Alky
t
B
r
utenolides Novák,a Milan Pour,b Marcel Špulák,b Ivan Votruba,c Martin Kotora*a,c
a
Department of Organic and Nuclear Chemistry and Centre for New Antivirals and Antineoplastics, Faculty of Science,
Charles University, Hlavova 8, 128 43 Praha 2, Czech Republic
Fax +420(2)21951326; E-mail: kotora@natur.cuni.cz
Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy,
Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Praha 6,
Czech Republic
b
c
Received 23 June 2008; revised 4 July 2008
(Chamaemelum nobile),22 and bovolide (isolated from
butter).23 Among the synthesized g-alkylidene buteno-
lides, cardenolide24 and digoxin25 derivatives are worth
mentioning.
Abstract: g-Alkylidene butenolides bearing a deoxyriboside, a ste-
roid, and a metallocene moiety were synthesized by stereoselective
sequential cross-coupling lactonization procedure from the corre-
sponding functionalized terminal alkynes with 3-iodopropenoic
acids. The high selectivity of the butenolide ring formation was se-
cured by the Pd/Cu salt ratio. The resulting compounds were tested
for antifungal and cytostatic properties. Most notably, g-alkylidene
butenolides bearing deoxyriboside moiety showed promising cyto-
static activity in the micromolar range.
Although the mechanism of the biological effect of these
agents is still unclear, we can speculate that their activity
could be attributed to an interaction with the cystein resi-
dues of functional proteins resulting in covalent bond for-
mation via a Michael type addition.26 Indeed, thiols such
as N-acetylcysteamine were shown to add smoothly
across the exo-methylene moiety of tetrodecamycine fur-
nishing the corresponding S-alkylation products.27 How-
ever, these derivatives continued to possess a marked
antibacterial activity in vitro. This may be due to a retro-
Michael reaction regenerating tetrodecamycin as the bio-
logically active component.
Key words: cross-coupling, lactones, catalysis, antitumor agents,
palladium
g-Alkylidene butenolide moiety is a structural feature of
many compounds produced by nature or synthesized in
the laboratory. A number of them are of pharmacological
interest as they have a broad array of potentially useful
medicinal and biological properties such as antibacterial,
cytotoxic, antitumor, and enzyme inhibitory activity. The
most simple compound in this series is protoanemonin
(Anemone pulsatilla),1 which is well known for its strong
antibacterial and antifungal properties. All other g-alky-
lidene butenolides can be considered as its substituted
congeners. Examples of these substances are
melodorinol2a and its oxidized derivatives (Melodorum
fruticosum),2b rubrolides (colonial tunicate Ritterella ru-
bra),3 dihydroxerulin, xeruline and xerulinic acid (Xerula
melanotricha),4 goniobutenolide A (Goniothalamus gi-
ganteus),5 freelingyne (Eremophila freelingii),6 macula-
lactones (Kyrtuthrix maculans),7 cochinolide (Homalium
cochinchinensis),8 lissoclinolide (Amphidinium car-
terae),9 peridinin (Amphidinium carterae),10 didehydros-
temofoline (Stemona collinsae),11 nostoclide I (Peltigera
canina),12 neopatulin (Aspergillus clavatus),13 ellipsoi-
done A and B (Hemsleya ellipsoidea),14 aporpinone A
(Aporpium caryae),15 acetoxyfimbrolide B (Delicea fim-
brilata),16 uncinine (Artabotrys uncinatus),17 pyrrhoxan-
thine (Gyrodinium resplendens),10c,18 ligustilide and
related compounds (genera within the family Apiaceae),19
eremolactone (Eremophila freelingii),20 tetrenoline
(Micropolyspora venezuelensis),21 thiophenebutenolide
The synthesis of the g-alkylidene butenolide framework
can be accomplished by various methodologies. General-
ly, existing methods can be divided into two categories: i)
transition metal catalyzed procedures and ii) condensation
reactions.28 The aforementioned transition metal based
procedures are based on three strategies: i) reaction of ter-
minal alkynes with halopropenoic acids,29 ii) cyclization
of enynoic acids,30 and iii) cyclocarbonylation of halovi-
nyl ketones.31 Among these methods, the former is of spe-
cial interest, because it uses easily accessible reactants
(terminal alkynes and halopropenoic acids) and is usually
carried out under mild reaction conditions with a high de-
gree of selectivity with respect to the stereochemistry on
the g-alkylidene moiety. However, it should be noted that
the formation of a-pyrones as side products can be ob-
served (Scheme 1). Herein we would like to report the
synthesis of new g-alkylidene butenolides and their anti-
fungal and cytostatic activity.
The choice of moieties in new g-alkylidene butenolide
was based on the following presumptions. The deoxyribo-
X
COOH
Pd cat.
+
+
O
O
R
O
O
SYNTHESIS 2008, No. 21, pp 3465–3472
x
x.
x
x
.
2
0
0
8
R
R
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083181; Art ID: Z14608SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

3466
P. Novák et al.
PAPER
side moiety was chosen because of its structural resem-
blance to ester groups in melodorinol.2 The estrone
moiety was chosen because isoprenoids (cardenolides,
etc.) with similar structure were prepared and new type of
g-alkylidene butenolide would represent its positional iso-
mer.24,25 Finally, the ferrocene moiety was selected be-
cause of its beneficial influence on many biological
properties.32
R
O
TolO
O
TolO
O
3α or 3β
R
I
+
1a–d
R
COOH
Pd cat.
conditions
+
O
TolO
As a standard method for the construction of the g-alky-
lidene butenolide moiety, we decided to use a simple, yet
stereoselective sequential cross-coupling lactonization
procedure based on the Sonogashira reaction of terminal
alkynes with (Z)-3-halopropenoic acids followed by Pd-
catalyzed addition of the carboxylic moiety onto the triple
bond.29,33 Considering the attached functional groups, our
effort was aimed at varying the substitution at both g-alky-
lidene and position 4 of the butenolide moiety. At the out-
set, we decided to study the preparation of g-alkylidene
butenolides prepared from the reaction of a- and b-ano-
mers of 1-ethynyl-1,2-dideoxy-3,5-di-O-(4-toluoyl)-D-ri-
bofuranose (2a and 2b) and representatives of propenoic
acids such as (Z)-3-iodopropenoic acid (1a), (Z)-3-iodo-3-
methylpropenoic acid (1b), (Z)-3-iodo-3-phenylpropeno-
ic acid (1c), and (Z)-3-iodo-3-(biphenyl-1-yl)propenoic
acid (1d) (Scheme 2). As expected, initial experiments of
the reaction of 2 with 1a indicated that it would be neces-
sary to tune the reaction conditions to achieve high selec-
tivity of g-alkylidene butenolide formation while
minimizing the amount of a-pyranones (Table 1). When
the reaction of 2a with 1a was catalyzed by Pd(PPh3)4 or
Pd(PhCN)2Cl2 (5 mol%) in combination with CuI (5
mol%), mixtures of butenolide 3aa and pyrone 4aa were
obtained in 2:1 and 3:2 ratios, respectively (entries 1 and
2). In addition, considerable amounts (22 and 20%) of 1,3-
diyne 5, the product of the starting alkyne 2a dimeriza-
tion, were isolated. The substitution of CuI by silver salts,
AgCl (entries 3 and 4) or Ag2CO3 (entry 5) which are
known to promote the formation of the butenolide
moiety34 as well as the coupling reaction,35 did not have
the expected effect: in all cases only mixtures of 3aa and
4aa were obtained. Moreover, the presence of AgCl also
had a detrimental effect on the overall yields of the desired
products (10 and 12%). The use of Pd(PPh3)4 catalyzed
only the oxidative dimerization of the starting alkyne to
form dimer 5a (entry 6). Gratifyingly, using a combina-
tion of 10 mol% of Pd(PPh3)4 and 20 mol% of CuI led se-
lectively to g-alkylidene butenolide 3aa (entry 7). A
similar phenomenon was also observed in the reaction of
2b with 1a. Catalysis of the reaction by Pd(PPh3)4 or
Pd(PhCN)2Cl2 (5 mol%) in combination with CuI (5
mol%) yielded mixtures of butenolide 3ab and pyranone
4ab in 4:1 and 3:1 ratios, respectively (entries 8 and 9).
However, in these cases the formation of the dimer 5b was
not observed. This result is in accordance with previous
observations pertaining to the different behavior of both
anomeric alkynes.36 On the other hand, the combination of
10 mol% of Pd(PPh3)4 and 20 mol% of CuI led again se-
lectively to g-alkylidene butenolide 3ab (entry 10).
O
O
O
TolO
4α or 4β
TolO
TolO
2α or 2β
+
O
TolO
O
TolO
OTol
OTol
5
Scheme 2 Formation of g-alkylidene butenolides 3 and pyranones 4
Table 1 Reaction Conditions for the Coupling of 1a with 2a and 2b
Entry
2
Pd cat.a
2a Pd(PPh3)4
2a Pd(PhCN)2Cl2 CuI
Additivea 3 + 4 (%)b 3/4
5 (%)b
1
2
CuI
41
28
12
10
2:1
3.2
1:1
1:1
1:1
–
22
20
–
3
2a Pd(PPh3)4
AgCl
4
2a Pd(PhCN)2Cl2 AgCl
–
5
2a Pd(PPh3)4
2a Pd(PPh3)4
2a Pd(PPh3)4
2b Pd(PPh3)4
Ag2CO3 44
–
6
–
–
60
–
CuId
CuI
47e
37
67
63f
–
c
7
8
4:1
3:1
–
–
9
2b Pd(PhCN)2Cl2 CuI
–
CuId
–
c
10
2b Pd(PPh3)4
a Amount used: 5 mol%, unless otherwise noted.
b Isolated yields.
c Amount used: 10 mol%.
d Amount used: 20 mol%.
e g-Alkylidene butenolide 3aa was formed selectively.
f g-Alkylidene butenolide 3ab was formed selectively.
With optimized reaction conditions in hand, we decided to
extend the reaction of 2a and 2b to other 3-iodopropenoic
acid derivatives 1b–d as well (Table 2). The reaction of
2a with 1b–d afforded selectively the corresponding
products 3ba–3da in 87, 90, and 48% isolated yields (en-
tries 1–3). Similar results were also obtained for the reac-
tions of 2b giving rise to 3bb, 3cb, and 3db in 85, 88 and
50% isolated yields, respectively (entries 4–6).
Next we turned our attention to the synthesis of g-alky-
lidene butenolides bearing a steroid moiety. As a starting
compound, we decided to use the commercially available
Synthesis 2008, No. 21, 3465–3472 © Thieme Stuttgart · New York

PAPER
Biologically Active g-Alkylidene Butenolides
3467
R
HO
conditions
A or B
R
I
R
H
+
O
1a–d
6
+
Fe
Fe
COOH
1a–d
I
COOH
O
H
H
HO
8
9a–d
conditions A or B
Scheme 4 Formation of g-alkylidene butenolides 9
HO
Table 4 Butenolides 9 Prepared from 1 and 8
O
A, Yield (%)a
B, Yield (%)a
H
H
Entry
1
9
7a–d
O
H
1
2
3
4
1a, R = H
1b, R = Me
1c, R = Ph
1d, R = C6H4Ph
9a 62
9b 79
9c 76
9d –
56
85
99
99
HO
Scheme 3 Formation of g-alkylidene butenolides 7
Table 2 Butenolides 3 Prepared from 1 and 2
a Isolated yields.
Entry
1
2
Product 3
3ba
Yield (%)a
1
2
3
4
5
6
1b, R = Me
1c, R = Ph
1d, R = C6H4Ph
1b, R = Me
1c, R = Ph
1d, R = C6H4Ph
2a
2a
2a
2b
2b
2b
87
90
48
85
88
50
(Scheme 4). In this instance, the above mentioned catalyt-
ic systems A and B were also used. Under both reaction
conditions (A and B) only the formation of the corre-
sponding g-alkylidene butenolides 9a–d was observed
again in good yields (Table 4). As in the case of com-
pounds 7, the yields of 9 were generally higher or even
quantitative when conditions B were employed (entries
2–4).
3ca
3da
3bb
3cb
3db
a Isolated yields.
Given the numerous biological activities of the g-alky-
lidene butenolides and the antifungal activity of the parent
protoanemonin,37 we decided to investigate the activity of
the prepared compounds against potentially pathogenic
yeasts and molds by using the microdilution broth meth-
od. The strains included Candida albicans, Candida trop-
icallis, Candida krusei, Candida glabrata, Trichosporon
beigelii, Trichosporon mentagrophytes, Aspergillus fumi-
gatus, and Absidia corymbifera. Disappointingly, none of
the tested compounds exhibited potentially useful levels
of inhibition (IC80 >125 mmol/L). The only exception was
the ferrocene-containing g-alkylidene butenolide 9a, the
IC80 of which was 31.25 mmol/L against Candida albi-
cans.
Table 3 Butenolides 7 Prepared from 1 and 6
Entry
1
7
A, Yield (%)a
B, Yield (%)a
1
2
3
4
1a, R = H
1b, R = Me
1c, R = Ph
1d, R = C6H4Ph
7a 26
7b 78
7c 12
7d 47
69
74
60
a Isolated yields.
Preliminary in vitro cytostatic activity tests of the repre-
sentatives of the prepared g-alkylidene butenolides were
performed using the following cell cultures: mouse leuke-
mia L1210 cells; human promyelocytic leukemia HL60
cells; human cervix carcinoma HeLa S3 cells; and human
T lymphoblastoid CCRF-CEM cell line. Out of the set of
compounds, only those bearing the deoxyriboside moiety
3ca, 3da, 3cb, and 3db, showed promising activity
(Table 5). Interestingly, while the phenyl derivatives 3ca
and 3cb showed activity against HeLa S3 and CCRF-
CEM cell lines, the biphenyl 3da and 3db derivatives
were active against L1210 and leukemia HL60 cells. With
the activities being in lower level of the micromolar range,
this novel type of compounds represents a new potential
structural lead in the search for antiproliferative drugs. In
this regard it is worth of mentioning that butenolide 3db
17a-ethynylestradiol (6). The reactions of 6 with various
3-iodopropenoic acids 1a–d were carried out under two
different catalytic conditions A [10 mol% Pd(PPh3)4, 10
mol% CuI] and B [10 mol% Pd(PPh3)4, 20 mol% CuI]
(Scheme 3). These two catalytic systems were used to
evaluate the effect of CuI amount on the course of the re-
action. Surprisingly, both systems resulted in the selective
formation of g-alkylidene butenolides 7a–d, unlike the re-
actions with 2. On the other hand, the yields of the prod-
ucts were generally higher under conditions B (Table 3).
Most markedly it was shown in the reactions with 1a (A,
12%; B, 69%, entry 1) and 1c (A, 10%; B, 60%, entry 3).
Finally, we studied the formation of g-alkylidene buteno-
lides bearing the ferrocenyl moiety by the reaction of
ethynylferrocene (8) with 3-iodopropenoic acids 1a–d
Synthesis 2008, No. 21, 3465–3472 © Thieme Stuttgart · New York

3468
P. Novák et al.
PAPER
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 42 mg (47%) of the title compound as a colorless
oil; Rf = 0.23 (2:1 hexane–EtOAc); [a]D 0 (c 0.00145 g/mL,
CHCl3).
Table 5 Cytostatic Activity Test of g-Alkylidene Butenolides 3
Buten- IC50, mmol/La
olide
L1210
HL60
NA
HeLa S3
CCRF-CEM
IR (ATR Ge): 1780, 1717, 1613, 1274, 1179, 1106, 758 cm–1.
1H NMR (400 MHz, C6D6): d =1.81–1.87 (m, 1 H), 1.96 (s, 3 H),
1.99 (s, 3 H), 2.33–2.40 (m, 1 H), 4.33 (dd, J = 11.6, 4.8 Hz, 1 H),
4.43 (dd, J = 11.6, 4.8 Hz, 1 H), 4.47 (td, J = 4.8, 2.4 Hz, 1 H), 5.01
(d, J = 8 Hz, 1 H), 5.15–5.20 (m, 1 H), 5.32–5.35 (m, 1 H), 5.41 (d,
J = 4.8 Hz, 1 H), 6.14 (d, J = 4.8 Hz, 1 H), 6.89–6.93 (m, 4 H),
8.01–8.05 (m, 2 H), 8.14–8.18 (m, 2 H).
13C NMR (100 MHz, C6D6): d = 22.03, 22.06, 39.40, 65.27, 74.47,
77.66, 83.00, 116.17, 120.90, 128.24, 128.58, 130.10 (4 ×), 130.70
(2 ×), 130.82 (2 ×), 143.47, 144.36, 144.64, 149.72, 166.49, 166.84,
169.08.
3aa
3da
3ca
3db
NA
NA
NA
24.64 0.22 NA
NA
23.86 0.34 12.99 0.14
NA NA
34.32 0.58 NA
NA
22.50 1.02 8.68 1.18
a NA: not available.
had cytostatic activity in the similar range as natural melo-
dorinol.2
HRMS (FAB+): m/z calcd for C26H24O7 + Na+: 471.141973; found:
471.143262.
In conclusion, we have shown that stereoselective sequen-
tial cross coupling-lactonization of 3-halopropenoic acid
with terminal alkynes bearing deoxyriboside, steroid and
metallocene moiety is a synthetically useful and efficient
method that allows the preparation of variously substitut-
ed g-alkylidene butenolides. Moreover, the screening of
different reaction conditions revealed that the competition
(5Z)-5-{[1a-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-methylfuran-2(5H)-one (3ba)
From 1b (0.4 mmol, 85 mg), 2a (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 80 mg (87%) of the title compound as a colorless
oil; Rf = 0.29 (2:1 hexane–EtOAc); [a]D –13.3 (c 0.003 g/mL,
between the formation of g-alkylidene butenolide and CHCl3).
IR (ATR Ge): 1780, 1717, 1610, 1271, 1176, 1103, 751 cm–1.
pyranone rings can be easily controlled by using excess
CuI, the use of which is more economical than that of Ag
salts. In addition, biological evaluation of the prepared
compounds revealed that the deoxyribose functionalized
g-alkylidene butenolides could be promising leads in the
research of new potential antineoplastic agents.
1H NMR (400 MHz, C6D6): d = 1.23 (s, 3 H), 1.84–1.90 (m, 1 H),
1.96 (s, 3 H), 1.99 (s, 3 H), 2.36–2.42 (m, 1 H), 4.33 (dd, J = 11.6,
5.2 Hz, 1 H), 4.45 (dd, J = 11.6, 5.2 Hz, 1 H), 4.50 (td, J = 5.2, 2.8
Hz, 1 H), 5.20 (d, J = 7.6 Hz, 1 H), 5.23–5.28 (m, 1 H), 5.27 (s, 1
H), 5.36–5.39 (m, 1 H), 6.89–6.92 (m, 4 H), 8.01–8.05 (m, 2 H),
8.15–8.19 (m, 2 H).
13C NMR (100 MHz, C6D6): d = 11.52, 22.12, 22.14, 39.51, 65.39,
74.81, 77.80, 83.15, 112.32, 118.17, 128.33, 128.64, 130.15 (2 ×),
130.21 (2 ×), 130.76 (2 ×), 130.92 (2 ×), 144.44, 144.71, 150.97,
154.65, 166.47, 166.94, 168.54.
HRMS (FAB+): m/z calcd for C27H26O7 + Na+: 485.157623; found:
485.157022.
Starting 3-iodopropenoic acids 1 were prepared by standard proce-
dures by the reaction of corresponding propynoic acids with NaI un-
2
der acidic conditions.1 Pd(PPh3)4 and ethynylferrocene (8)3 were
prepared according to the previously reported procedures. 17a-
Ethynylestradiol (6) and MeCN were purchased from Sigma-
Aldrich. NMR spectra were recorded on a Varian Unity 400
INOVA instrument at 400 MHz (1H) and 100.6 MHz (13C) or Varian
300 MHz (1H) and 75.5 MHz (13C) as solutions in C6D6, CD3OD, or
CDCl3, and are referenced to the residual solvent signal. IR spectra
were recorded on a Bruker IFS 88 instrument. Mass spectra were re-
corded on a Finnigan MAT Incos 50 spectrometer. HR mass spectra
were recorded on a ZAB-SEQ VG Analytical spectrometer. Optical
rotations were measured using an Autopoll III polarimeter (Rudolph
Research) at 20 °C.
(5Z)-5-{[1a-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-phenylfuran-2(5H)-one (3ca)
From 1c (0.4 mmol, 110 mg), 2a (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 94 mg (90%) of the title compound as a colorless
oil; Rf = 0.26 (2:1 hexane–EtOAc); [a]D –37.7 (c 0.0061 g/mL,
CHCl3).
Reaction of Ethynyldeoxyribosides 2 with 3-Iodopropenoic
Acids 1; General Procedure
IR (ATR Ge): 1766, 1715, 1610, 1270, 1177, 1102, 752 cm–1.
1H NMR (400 MHz, C6D6): d = 1.79–1.85 (m, 1 H), 1.96 (s, 3 H),
2.00 (3 H), 2.32–2.39 (m, 1 H), 4.30–4.42 (m, 3 H), 5.33–5.38 (m,
2 H), 5.62 (d, J = 8 Hz, 1 H), 5.64 (s, 1 H), 6.84 (d, J = 7.6 Hz, 2 H),
6.90–6.95 (m, 5 H), 7.00–7.05 (m, 2 H), 7.90–7.95 (m, 2 H), 8.16–
8.20 (m, 2 H).
13C NMR (100 MHz, C6D6): d = 22.03, 22.08, 39.34, 65.29, 75.00,
77.65, 83.19, 116.42, 117.40, 128.21, 128.94, 129.19 (2 ×), 129.59
(2 ×), 130.04 (2 ×), 130.12 (2 ×), 130.64 (2 ×), 130.77, 130.84 (2 ×),
131.11, 144.34, 144.39, 149.19, 156.94, 166.34, 166.83, 167.80.
Into degassed MeCN (4 mL) were added 1a- or 1b-ethynyl-1,2-
dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranose (2a or 2b; 0.2 mmol,
75.6 mg), Pd(PPh3)4 (0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg),
and the appropriate 3-iodopropenoic acid 1 (79 mg, 0.4 mmol).
Et3N (0.8 mmol, 110 mL) was then added and the mixture was
stirred at 50 °C for 48 h. The volatiles were evaporated under re-
duced pressure and the residue was subjected to column chromatog-
raphy.
(5Z)-5-{[1a-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}furan-2(5H)-one (3aa)
From 1a (0.4 mmol, 79 mg), 2a (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
HRMS (FAB+): m/z calcd for C32H28O7 + Na+: 547.173273; found:
547.173843.
Synthesis 2008, No. 21, 3465–3472 © Thieme Stuttgart · New York

PAPER
Biologically Active g-Alkylidene Butenolides
3469
(5Z)-5-{[1a-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-(1¢¢,1¢¢¢-biphenyl-4¢¢-yl)furan-2(5H)-one (3da)
From 1d (0.4 mmol, 140 mg), 2a (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 57 mg (48%) of the title compound as a colorless
oil; [a]D 0 (c 0.00755 g/mL, CHCl3); Rf = 0.30 (2:1 hexane–
EtOAc) .
130.15 (2 ×), 130.80 (2 ×), 130.84 (2 ×), 144.31, 144.67, 151.88,
154.70, 166.69, 166.76, 168.42.
HRMS (FAB+): m/z calcd for C27H26O7 + Na+: 485.157623; found:
485.155809.
(5Z)-5-{[1b-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-phenylfuran-2(5H)-one (3cb)
From 1c (0.4 mmol, 110 mg), 2b (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 92 mg (88%) of the title compound as a colorless
oil; Rf = 0.26 (2:1 hexane–EtOAc); [a]D –65.5 (c 0.00275 g/mL,
CHCl3).
IR (ATR Ge): 1765, 1714, 1610, 1268, 1179, 1103, 751 cm–1.
1H NMR (400 MHz, C6D6): d = 1.86–2.08 (m, 1 H), 1.87 (s, 3 H),
1.96 (s, 3 H), 2.30–2.36 (m, 1 H), 4.30 (dd, J = 11.6, 5.2 Hz, 1 H),
4.40 (dd, J = 11.6, 5.2 Hz, 1 H), 4.45 (td, J = 5.2, 1.6 Hz, 1 H), 5.37–
5.40 (m, 1 H), 5.41–5.47 (m, 1 H), 5.74–5.76 (m, 2 H), 6.76–6.78
(m, 2 H), 6.90–6.92 (m, 2 H), 7.01–7.03 (m, 2 H), 7.16–7.22 (m, 2
H), 7.24–7.27 (m, 3 H), 7.40–7.42 (m, 2 H), 7.87–7.89 (m, 2 H),
8.17–8.19 (m, 2 H).
13C NMR (100 MHz, C6D6): d = 21.93, 22.04, 39.08, 65.30, 75.03,
77.84, 83.50, 116.50, 117.21, 127.95, 128.30, 128.82 (2 ×), 1 signal
was overlapped by C6D6 signals, 129.23, 129.77 (2 ×), 129.94 (2 ×),
130.07 (2 ×), 130.13 (2 ×), 130.62 (2 ×), 130.85 (2 ×), 140.95,
143.82, 144.35, 144.46, 149.15, 156.69, 166.29, 166.83, 167.90.
IR (ATR Ge): 1730, 1704, 1610, 1283, 1264, 1182, 1100, 1065, 751
cm–1.
1H NMR (400 MHz, C6D6): d = 1.72–1.80 (m, 1 H), 1.95 (s, 3 H),
2.01 (s, 3 H), 2.22–2.27 (m, 1 H), 4.28 (td, J = 4.8, 2.4 Hz, 1 H),
4.37 (dd, J = 11.6, 5.2 Hz, 1 H), 4.48 (dd, J = 11.6, 5.2 Hz, 1 H),
5.37–5.43 (m, 1 H), 5.44–5.48 (m, 2 H), 5.63 (s, 3 H), 6.83 (d,
J = 8.8 Hz, 2 H), 6.90–6.96 (m, 5 H), 6.99–7.01 (m, 2 H), 8.07–8.10
(m, 4 H).
HRMS (FAB+): m/z calcd for C38H32O7 + Na+: 623.204573; found:
623.203877.
13C NMR (100 MHz, C6D6): d = 22.02, 22.10, 39.84, 65.60, 75.26,
77.86, 84.00, 114.91, 117.49, 128.20, 129.18 (2 ×), 129.60 (2 ×), 2
signals were overlapped by C6D6 signals, 130.02 (2 ×), 130.14,
130.74 (2 ×), 130.85 (2 ×), 130.92, 144.17, 144.64, 150.26, 157.01,
166.64, 166.73, 167.77.
(5Z)-5-{[1b-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}furan-2(5H)-one (3ab)
From 1a (0.4 mmol, 79 mg), 2b (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 56 mg (63%) of the title compound as a colorless
oil; Rf = 0.23 (2:1 hexane–EtOAc); [a]D –16.8 (c 0.0199 g/mL,
CHCl3).
MS (FAB+): m/z (%) = no molecular peak, 279 (9), 149 (8), 119
(100).
(5Z)-5-{[1b-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-(1¢¢,1¢¢¢-biphenyl-4¢¢-yl)furan-2(5H)-one (3db)
From 1d (0.4 mmol, 140 mg), 2b (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 60 mg (50%) of the title compound as a colorless
oil; Rf = 0.30 (2:1 hexane–EtOAc); [a]D –39.5 (c 0.01075 g/mL,
CHCl3).
IR (ATR Ge): 1781, 1718, 1610, 1273, 1180, 1108, 755 cm–1.
1H NMR (400 MHz, C6D6): d = 1.72–4.80 (m, 1 H), 1.966 (s, 3 H),
1.998 (s, 3 H), 2.14–2.19 (m, 1 H), 4.24 (td, J = 4.4, 2 Hz, 1 H), 4.38
(dd, J = 11.6, 4.8 Hz, 1 H), 4.54 (dd, J = 11.6, 4.8 Hz, 1 H), 4.78 (d,
J = 7.6 Hz, 1 H), 5.24–5.29 (m, 1 H), 5.38 (d, J = 5.6 Hz, 1 H),
5.43–5.45 (m, 1 H), 6.09 (d, J = 5.6 Hz, 1 H), 6.89–6.93 (m, 4 H),
8.03–8.07 (m, 2 H), 8.14–8.18 (m, 2 H).
IR (CCl4): 1777, 1725, 1611, 1266, 1178, 1102, 1021, 962, 839
cm–1.
13C NMR (100 MHz, C6D6): d = 22.03, 22.09, 39.86, 65.48, 74.70,
77.74, 83.92, 114.80, 120.97, 128.26, 128.58, 130.11 (2 ×), 130.14
(2 ×), 130.83 (4 ×), 143.49, 144.35, 144.67, 150.57, 166.65, 166.77,
169.05.
HRMS (FAB+): m/z calcd for C26H24O7 + Na+: 471.141973; found:
471.142390.
1H NMR (400 MHz, C6D6): d = 1.80–1.85 (m, 1 H), 1.87 (s, 3 H),
2.01 (s, 3 H), 2.28–2.32 (m, 1 H), 4.27–4.31 (m, 1 H), 4.39 (dd,
J = 12, 4 Hz, 1 H), 4.53 (dd, J = 12, 4 Hz, 1 H), 5.43 (m, 1 H), 5.47–
5.55 (m, 1 H), 5.53 (s, 1 H), 5.72 (s, 1 H), 6.81 (d, J = 8 Hz, 2 H),
6.94 (d, J = 8 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 7.16–7.20 (m, 3
H), 7.22–7.29 (m, 4 H), 7.39–7.43 (m, 2 H), 8.08–8.11 (m, 4 H).
13C NMR (100 MHz, C6D6): d = 21.99, 22.13, 39.92, 65.61, 75.30,
77.97, 84.05, 115.04, 117.21, 128.01 (2 ×), 128.32 (2 ×), 128.37,
128.59, 129.24, 129.62, 129.76 (2 ×), 129.91 (2 ×), 130.03 (2 ×),
130.17 (2 ×), 130.71 (2 ×), 130.86 (2 ×), 140.87, 144.05, 144.24,
144.69, 150.25, 156.67, 166.67, 166.74, 167.94.
(5Z)-5-{[1b-1,2-Dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranosyl]-
1¢-methylene}-4-methylfuran-2(5H)-one (3bb)
From 1b (0.4 mmol, 85 mg), 2b (0.2 mmol, 75.6 mg), Pd(PPh3)4
(0.02 mmol, 23 mg), CuI (0.04 mmol, 7.6 mg), and Et3N (0.8 mmol,
110 mL). Column chromatography on silica gel (2:1 hexane–
EtOAc) afforded 78.5 mg (85%) of the title compound as a colorless
oil; Rf = 0.29 (2:1 hexane–EtOAc); [a]D 0 (c 0.001 g/mL, CHCl3).
MS (EI): m/z (%) = no molecular peak, 509 (0.3), 368 (2), 310 (4),
256 (5), 136 (10), 119 (22).
IR (ATR Ge): 1780, 1708, 1613, 1271, 1179, 1103, 755 cm–1.
Reaction of 17a-Ethynylestradiol (6) with 3-Iodopropenoic
Acids 1; General Procedures
1H NMR (400 MHz, C6D6): d = 1.24 (s, 3 H), 1.79–1.87 (m, 1 H),
1.96 (s, 3 H), 2.00 (s, 3 H), 2.22–2.27 (m, 1 H), 4.27 (td, J = 4.8, 2.4
Hz, 1 H), 4.40 (dd, J = 11.6, 4.8 Hz, 1 H), 4.59 (dd, J = 11.6, 4.8 Hz,
1 H), 4.98 (d, J = 8 Hz, 1 H), 5.22 (s, 1 H), 5.32–5.38 (m, 1 H),
5.45–5.47 (m, 1 H), 6.87–6.93 (m, 4 H), 8.05–8.09 (m, 2 H), 8.13–
8.17 (m, 2 H).
Method A: Into degassed MeCN (7 mL) were added 17a-ethynyl-
estradiol (6; 0.5 mmol, 148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg),
CuI (0.05 mmol, 9.5 mg), and the appropriate 3-iodopropenoic acid
1 (1 mmol). Et3N (2 mmol, 278 mL) was then added and the mixture
was stirred at 50 °C for 20 h. The solvent was evaporated under
reduced pressure and the residue was subjected to column chroma-
tography on silica gel.
13C NMR (100 MHz, C6D6): d = 11.39, 22.02, 22.10, 39.95, 65.56,
74.98, 77.81, 83.94, 110.78, 118.14, 128.26, 128.58, 130.08 (2 ×),
Method B: As above, but with 0.1 mmol of CuI (19 mg).
Synthesis 2008, No. 21, 3465–3472 © Thieme Stuttgart · New York

3470
P. Novák et al.
PAPER
(5Z)-5-[(Estradiol-17¢a-yl)methylene]furan-2(5H)-one (7a)
Method A: 1a (1 mmol, 198 mg), 17a-ethynylestradiol (6; 0.5
mmol, 148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol,
9.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (1:1 hexane–EtOAc) afforded 47 mg (26%) of the title
compound as a white solid.
Method B: 1c (1 mmol, 274 mg), 17a-ethynylestradiol (6; 0.5 mmol,
148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol, 19 mg),
and Et3N (2 mmol, 278 mL). Column chromatography on silica gel
(1:1 hexane–EtOAc) afforded 132 mg (60%) of the title compound
as a white solid; mp 244 °C; Rf = 0.20 (2:1 hexane–EtOAc); [a]D
–11.1 (c 0.0009 g/mL, DMSO).
Method B: 1a (1 mmol, 198 mg), 17a-ethynylestradiol (6; 0.5
mmol, 148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol,
19 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (1:1 hexane–EtOAc) afforded 126 mg (69%) of the title
compound as a white solid. mp 269 °C; Rf = 0.17 (2:1 hexane–
EtOAc); [a]D +142.3 (c 0.0123 g/mL, CHCl3).
IR (ATR Ge): 3319, 2924, 1699, 1247, 768 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.86 (m, 1 H), 0.94 (s, 3 H),
1.23–1.52 (m, 4 H), 1.65–1.73 (m, 2 H), 1.83–1.97 (m, 4 H), 2.15–
2.21 (m, 1 H), 2.31–2.34 (m, 1 H), 2.66–2.78 (m, 2 H), 5.62 (s, 1 H),
6.42 (d, J = 2.4 Hz, 1 H), 6.47 (dd, J = 8.6, 2.8 Hz, 1 H), 6.53 (d,
J = 1.2 Hz, 1 H), 6.83 (d, J = 1.2 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 1 H),
7.53–7.56 (m, 3 H), 7.79–7.82 (m, 2 H), 8.96 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.59, 23.75, 26.08, 27.31,
29.15, 33.28, 35.68, 1 signal was overlapped by DMSO-d6 signals,
43.18, 48.48, 48.87, 84.00, 102.02, 106.92, 112.66, 114.86, 125.95,
126.95 (2 ×), 129.20 (2 ×), 130.13, 130.78, 135.24, 137.05, 154.12,
154.89, 161.87, 170.19.
IR (ATR Ge): 3402, 2981, 2927, 2863, 1779, 1753, 1498, 1243,
1114, 935 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.96 (s, 3 H), 1.22–1.32 (m, 1 H),
1.36–1.49 (m, 5 H), 1.72–1.78 (m, 1 H), 1.86–2.02 (m, 4 H), 2.26–
2.27 (m, 1 H), 2.38–2.44 (m, 1 H), 2.71–2.78 (m, 2 H), 5.59 (s, 1 H),
6.21 (d, J = 5.6 Hz, 1 H), 6.46 (d, J = 2.8 Hz, 1 H), 6.52 (dd, J = 8.4,
2.8 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 5.6 Hz, 1 H).
13C NMR (100 MHz, CD3OD): d = 14.47, 24.43, 27.75, 28.85,
30.83, 33.88, 37.56, 41.34, 45.14, 50.25, 50.88, 84.92, 113.86,
116.20, 119.12, 123.62, 127.32, 132.57, 138.94, 147.74, 149.85,
156.07, 172.31.
MS (EI): m/z (%) = 442 (1), 404 (1), 213 (10), 149 (14), 41 (100).
HRMS (EI): m/z calcd for C29H30O4: 442.214410; found:
442.213063.
(5Z)-5-[(Estradiol-17¢a-yl)methylene]-4-(1¢¢,1¢¢¢-biphenyl-4¢¢-
yl)furan-2(5H)-one (7d)
MS (EI): m/z (%) = 366 (12), 256 (7), 226 (8), 213 (20), 185 (6), 159
(13), 41 (100).
Method A: 1d (0.78 mmol, 270 mg), 17a-ethynylestradiol (6; 0.39
mmol, 115 mg), Pd(PPh3)4 (0.039 mmol, 45 mg), CuI (0.078 mmol,
7.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (1:1 hexane–EtOAc) afforded 95 mg (47%) of the title
compound as a white solid; mp 253 °C; Rf = 0.11 (2:1 hexane–
EtOAc); [a]D +46.3 (c 0.00475, DMSO).
HRMS (EI): m/z calcd for C23H26O4: 366.183110; found:
366.183936.
(5Z)-5-[(Estradiol-17¢a-yl)methylene]-4-methylfuran-2(5H)-
one (7b)
Method A: 1b (1 mmol, 212 mg), 17a-ethynylestradiol (6; 0.5
mmol, 148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol,
9.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (1:1 hexane–EtOAc) afforded 149 mg (78%) of the title
compound as a white solid.
IR (ATR Ge): 3360, 2929, 1694, 1622, 1027, 1006, 767 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.75–0.87 (m,1 H), 0.95 (s, 1
H), 1.23–1.53 (m, 4 H), 1.66–1.95 (m, 6 H), 2.18–2.21 (m, 1 H),
2.32–2.36 (m, 1 H), 2.66–2.75 (m, 2 H), 5.66 (s, 1 H), 6.42 (s, 1 H),
6.47 (d, J = 8.8 Hz, 1 H), 6.59 (s, 1 H), 6.89 (s, 1 H), 6.97 (d, J = 8.8
Hz, 1 H), 7.41–7.53 (m, 4 H), 7.75–7.93 (m, 5 H), 8.98 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.61, 23.78, 26.10, 27.32,
29.16, 33.31, 35.69, 39.97, 1 signal was overlapped by DMSO-d6
signals, 43.19, 48.50, 48.89, 84.04, 101.84, 106.66, 112.67, 114.87,
125.97, 126.78 (2 ×), 127.36 (2 ×), 127.63 (2 ×), 128.13, 129.07
(2 ×), 130.15, 134.06, 137.08, 138.94, 142.37, 153.50, 154.90,
161.91, 170.20.
Method B: 1b (1 mmol, 212 mg), 17a-ethynylestradiol (6; 0.5
mmol, 148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol,
19 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (1:1 hexane–EtOAc) afforded 140 mg (74%) of the title
compound as a white solid; mp 264 °C; Rf = 0.20 (2:1 hexane–
EtOAc); [a]D +137.7 (c 0.0069 g/mL, CHCl3).
IR (ATR Ge): 3387, 2924, 1741, 1228, 954 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.96 (s, 3 H), 1.23–1.32 (m, 1 H),
1.36–1.49 (m, 5 H), 1.76 (m, 1 H), 1.86–2.02 (m, 4 H), 2.21 (s, 3 H),
2.24 (m, 1 H), 2.41 (m, 1 H), 2.73 (m, 2 H), 5.56 (s, 1 H), 6.08 (s, 1
H), 6.45 (d, J = 2.8 Hz, 1 H), 6.51 (dd, J = 8.4, 2.8 Hz, 2 H), 7.01
(d, J = 8.4 Hz, 1 H).
HRMS (FAB+): m/z calcd for C35H34O4 + H+ : 519.253535; found:
519.255786.
Reaction of Ethynylferrocene (8) with 3-Iodopropenoic Acids 1;
General Procedure
Conditions A: Into degassed MeCN (4 mL) were added ethynylfer-
rocene (8; 0.5 mmol, 105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI
(0.05 mmol, 9.5 mg), and the appropriate 3-iodopropenoic acid 1
(0.75 mmol). Et3N (2 mmol, 278 mL) was then and the mixture was
stirred at 50 °C for 20 h. The solvent was evaporated under reduced
pressure and the residue was subjected to column chromatography.
13C NMR (100 MHz, CD3OD): d = 12.15, 14.50, 24.48, 27.75,
28.83, 30.84, 33.96, 37.16, 41.34, 45.10, 50.35, 50.80, 84.88,
113.84, 116.19, 116.44, 119.16, 127.31, 132.59, 138.95, 150.58,
156.06, 158.62, 171.45.
MS (EI): m/z (%) = 380 (54), 362 (8), 239 (22), 226 (37), 213 (76),
159 (68), 41 (100).
Conditions B: As above, but with 0.1 mmol of CuI (19 mg).
HRMS (EI): m/z calcd for C24H28O4: 380.198760; found:
380.199325.
(5Z)-5-(Ferrocenyl-1¢-methylene)furan-2(5H)-one (9a)
Conditions A: 1a (0.75 mmol, 149 mg), ethynylferrocene (8; 0.5
mmol, 105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol,
9.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (2:1 CHCl3–hexane) afforded 87 mg (62%) of the title
compound as a dark red solid.
(5Z)-5-[(Estradiol-17¢a-yl)methylene]-4-phenylfuran-2(5H)-
one (7c)
Method A: 1c (1 mmol, 274 mg), 17a-ethynylestradiol (6; 0.5 mmol,
148 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol, 9.5
mg), and Et3N (2 mmol, 278 mL). Column chromatography on silica
gel (1:1 hexane–EtOAc) afforded 26 mg (12%) of the title com-
pound as a white solid.
Conditions B: 1a (1 mmol, 198 mg), ethynylferrocene (8; 0.5 mmol,
105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol, 19 mg),
Synthesis 2008, No. 21, 3465–3472 © Thieme Stuttgart · New York

PAPER
Biologically Active g-Alkylidene Butenolides
3471
and Et3N (2.9 mmol, 400 mL). Column chromatography on silica gel
(2:1 CHCl3–hexane) afforded 78 mg (56%) of the title compound as
a dark red solid; mp 112 °C; Rf = 0.14 (1:2 hexane–CHCl3).
IR (CHCl3): 2968, 2914, 2866, 1774, 1748, 1649, 1105, 818 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.16 (s, 5 H), 4.44–4.48 (m, 2 H),
4.76–4.80 (m, 2 H), 5.95 (s, 1 H), 6.13 (d, J = 4.8 Hz, 1 H), 7.35 (d,
J = 4.8 Hz, 1 H).
(5Z)-5-(Ferrocenyl-1¢-methylene)-4-(1¢¢,1¢¢¢-biphenyl-4¢¢-yl)fu-
ran-2(5H)-one (9d)
Conditions A: Prepared from 1d (0.75 mmol, 263 mg), ethynylfer-
rocene (8; 0.5 mmol, 105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI
(0.05 mmol, 9.5 mg), and Et3N (2 mmol, 278 mL). Column chroma-
tography on silica gel (2:1 CHCl3–hexane) afforded 213 mg (99%)
of the title compound as a dark red solid; mp 224 °C; Rf = 0.23 (1:2
hexane–CHCl3).
13C NMR (100 MHz, CDCl3): d = 69.74 (5 ×), 70.76 (2 ×), 71.18
(2 ×), 76.00, 115.94 (2 ×), 143.44, 146.73, 170.68.
IR (CHCl3): 3098, 3079, 3025, 1753, 1747, 1643, 1579, 1483, 1345,
921, 830, 771 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.19 (s, 5 H), 4.48–4.52 (m, 2 H),
4.83–4.87 (m, 2 H), 6.16 (s, 1 H), 6.18 (s, 1 H), 7.39–7.43 (m, 1 H),
7.48–7.52 (m, 2 H), 7.54–7.58 (m, 2 H), 7.63–7.67 (m, 2 H), 7.73–
7.77 (m, 2 H).
MS (EI): m/z (%) = 280 (100), (4), 224 (12), 158 (8).
HRMS (EI): m/z calcd for C15H12FeO2: 280.018669; found:
280.019412.
13C NMR (100 MHz, CDCl3): d = 69.91 (5 ×), 71.04 (2 ×), 71.39
(2 ×), 1 signal was overlapped by CDCl3 signals, 112.40, 115.77,
127.10, 127.67, 128.03, 128.92, 128.99, 129.59, 139.87, 143.15,
146.00, 156.51, 169.25.
(5Z)-5-(Ferrocenyl-1¢-methylene)-4-methylfuran-2(5H)-one
(9b)
Conditions A: 1b (0.75 mmol, 159 mg), ethynylferrocene (8; 0.5
mmol, 105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol,
9.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (2:1 CHCl3–hexane) afforded 117 mg (79%) of the title
compound as a dark red solid.
MS (EI): m/z (%) = 432 (100), 367 (4), 256 (7), 216 (7), 149 (22).
HRMS (EI): m/z calcd for C27H20FeO2: 432.081269; found:
432.081759.
Conditions B: 1b (1 mmol, 212 mg), ethynylferrocene (8; 0.5 mmol,
105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol, 19 mg),
and Et3N (2.9 mmol, 400 mL). Column chromatography on silica gel
(2:1 CHCl3–hexane) afforded 126 mg (85%) of the title compound
as a dark red solid; mp 83 °C; Rf = 0.21 (1:2 hexane–CHCl3).
Acknowledgment
This project was supported by Project No. 1M0508 (Centre for
New Antivirals and Antineoplastics) and by Projects Nos.
MSM0021620857 and 0021620822 from the Ministry of Education
of the Czech Republic.
IR (CHCl3): 3099, 2924, 2198, 1770, 1739, 1649, 1595, 1345, 923,
842, 814 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.19 (s, 3 H), 4.15 (s, 5 H), 4.41–
4.45 (m, 2 H), 4.75–4.79 (m, 2 H), 5.90 (s, 1 H), 5.95 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.76, 69.58 (5 ×), 70.55 (2 ×),
70.81 (2 ×), 76.14, 111.28, 113.81, 147.71, 154.31, 169.89.
References
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MS (EI): m/z (%) = 294 (100), 279 (1), 229 (4), 149 (8).
HRMS (EI): m/z calcd for C16H14FeO2: 294.034319; found:
294.033806.
(5Z)-5-(Ferrocenyl-1¢-methylene)-4-phenylfuran-2(5H)-one
(9c)
Conditions A: 1c (0.75 mmol, 205 mg), ethynylferrocene (8; 0.5
mmol, 105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.05 mmol,
9.5 mg), and Et3N (2 mmol, 278 mL). Column chromatography on
silica gel (2:1 CHCl3–hexane) afforded 136 mg (76%) of the title
compound as a dark red solid.
Conditions B: 1c (1 mmol, 274 mg), ethynylferrocene (8; 0.5 mmol,
105 mg), Pd(PPh3)4 (0.05 mmol, 57.8 mg), CuI (0.1 mmol, 19 mg)
and Et3N (2.9 mmol, 400 mL). Column chromatography on silica gel
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as a dark red solid; mp 205–210 °C; Rf = 0.29 (1:2 hexane–CHCl3).
IR (CHCl3): 2962, 2920, 2866, 1760, 1754, 1745, 1739, 1643, 1353,
1090, 929, 818, 773, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.17 (s, 5 H), 4.46–4.50 (m, 2 H),
4.79–4.83 (m, 2 H), 6.10 (s, 1 H), 6.15 (s, 1 H), 7.46–7.54 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 69.72 (5 ×), 70.88 (2 ×), 71.22
(2 ×), 76.32, 112.56, 115.73, 128.42 (2 ×), 129.00 (2 ×), 130.18,
130.77, 145.97, 156.92, 169.26.
MS (EI): m/z (%) = 356 (100), 291 (4), 262 (16), 178 (10).
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356.049144.
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