Synthesis of pulvinones via tandem Dieckmann condensation-alkoxide β-elimination

Article abstract of DOI:10.1016/j.tet.2011.02.011

A series of pulvinones were prepared in three steps from a common precursor, methyl 3-phenylglycidate. This compound was readily converted to several diesters containing an ether function. Then, treatment of these compounds with lithium hexamethyldisilazide afforded the corresponding pulvinones, via tandem Dieckmann condensation-alkoxide β-elimination. The use of a 2,2,2-trifluoroethyl ether instead of a methyl ether facilitated the ?-elimination and led to better yields of product.

Full text of DOI:10.1016/j.tet.2011.02.011

Tetrahedron 67 (2011) 2605e2611
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pulvinones via tandem Dieckmann condensationealkoxide
b-elimination
a
a
a
b
a,
*
ꢀ ꢁ
ꢀ
Brice Nadal , Julien Rouleau , Helene Besnard , Pierre Thuery , Thierry Le Gall
ˇ
a CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Bat. 547, 91191 Gif-sur-Yvette, France
ˇ
b CEA, IRAMIS, UMR 3299 CEA/CNRS, SIS2M, LCCEf, Bat. 125, 91191 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pulvinones were prepared in three steps from a common precursor, methyl 3-phenylglycidate.
This compound was readily converted to several diesters containing an ether function. Then, treatment of
these compounds with lithium hexamethyldisilazide afforded the corresponding pulvinones, via tandem
Received 25 November 2010
Received in revised form 2 February 2011
Accepted 3 February 2011
Available online 4 March 2011
Dieckmann condensationealkoxide
a methyl ether facilitated the -elimination and led to better yields of product.
Ó 2011 Elsevier Ltd. All rights reserved.
b-elimination. The use of a 2,2,2-trifluoroethyl ether instead of
b
Keywords:
Epoxide
Dieckmann condensation
b
-Elimination
Tetronic acid
Pulvinone
1. Introduction
from the diol derived from an alkyl cinnamate, or more conve-
niently, from the corresponding epoxide.
Pulvinones are benzylidene-4-hydroxy-3-phenyl-5-furan-2
(5H)-one pigments isolated from several fungi, including boletus
Suillus grevillei1 and mold Aspergillus terreus.2 Natural or synthetic
compounds of this class display interesting biological activities,
such as anticoagulant3 or anti-inflammatory4 properties. Inhibitors
of bacterial cell wall biosynthesis have been recently reported.5
In connection with previous studies concerning the antioxidant
activity of the related pigments pulvinic acids,6,7 we became in-
terested in an efficient synthetic access to pulvinones.8 Pulvinone
was first obtained as a by-product in the synthesis of pulvinic acid
by Volhard9 and its structure was ascertained by a synthesis by
Claisen and Ewan.10 Several syntheses were then reported.11e15 The
The retrosynthetic analysis is summarized in the Scheme 1.
Herein we wish to present the implementation of this scheme,
which led to the synthesis of several pulvinones having various Ar2
groups.
various synthetic strategies toward pulvinones have been discussed
15b
€
in a recent report by Bruckner’s group.
As for us, we focused on an adaptation of our previously de-
scribed synthesis of pulvinic acids derivatives from dimethyl tar-
trate,7 which relied on the use of a LaceyeDieckmann condensation
for the formation of the tetronic acid moiety,16 the exocyclic double
bond being created by dehydration of an alcohol precursor.
According to this strategy, a pulvinone would then be accessible
Scheme 1. Planned synthesis of pulvinones.
2. Results and discussion
The starting material, methyl 3-phenylglycidate (3), was easily
prepared as previously reported by Darzens reaction of methyl
chloroacetate and benzaldehyde.17
The opening of methyl 3-phenylglycidate was realized using two
alcohols, methyl alcohol and 2,2,2-trifluoroethyl alcohol, under
boron trifluoride diethyl etherate catalysis.18
* Corresponding author. Tel.: þ33 16908 7105; fax: þ33 16908 7991; e-mail
address: thierry.legall@cea.fr (T. Le Gall).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.011

2606
B. Nadal et al. / Tetrahedron 67 (2011) 2605e2611
The corresponding alcohols 4a,b were obtained as mixture of dia-
stereoisomers, due to the intermediacy of a carbocation (Scheme 2).
a good yield in pulvinone 1a starting from methyl ether 8 (entries
1e3). It is noteworthy that tetronic acids intermediates, which had
not undergone the b-elimination step, were present in the crude
product, aside from the pulvinone and other unidentified by-prod-
ucts. Using moreequivalents of base did notimprove theyield either.
The reaction was then carried out using as starting material the
2,2,2-trifluoroethyl ether 9a (a mixture of syn- and anti-isomers),
prepared from alcohol 4b and 4-methoxyphenylacetic acid 7a
(Scheme 3). Much better results were obtained from this precursor
(Table 1, entries 4 and 5). The conditions leading to the best yield in
pulvinone 1a (78%) involved a treatment with the base at ꢀ78 ꢁC
for 1 h, followed by stirring at room temperature overnight.
The leaving ability of 2,2,2-trifluoroethoxide was expected to be
higher than that of methoxide on the basis of the pKa values of the
conjugate alcohols (15.07 for methanol, 12.32 for 2,2,2-tri-
fluoroethanol).19 It is also noteworthy that Bruckner et al. showed
€
that a 2,2,2-trifluoroethyl ester was an electrophile superior to
Scheme 2. Synthesis of alcohols 4a,b.
a methyl or an ethyl ester in a Dieckmann reaction.15b
In every case, pulvinone 1a was isolated as a mixture of isomers,
the Z-isomer being always predominant. Their spectral character-
istics were in agreement with those reported in the literature.15c
The ethylenic protons of the E-isomer and the Z-isomer appear at
At first, the mixture of syn- and anti-alcohols 4a was converted
to diester 8 by treatment with 4-methoxyphenylacetic acid (7a), in
the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethyl-
amino)pyridine (DMAP) in dichloromethane, at room temperature
(Scheme 3).
d
¼6.59 ppm and
d
¼6.82 ppm, respectively, in acetone-d6.
Following these first results, we embarked in the preparation of
several pulvinones starting from esters 9. The two isomeric 2,2,2-
trifluoroethyl ethers syn-4b or anti-4b were first separated by
chromatography. Esters 9 were then prepared, in yields varying
from 50 to 100%, from diverse arylacetic acids 7 and either syn-4b
or anti-4b (Table 2).
The attribution of the syn/anti configurations was based on the
X-ray structure of anti-9i, the 4-fluorophenylacetate obtained from
anti-4b (Fig. 1).20
Table 2
Synthesis of diesters 8
Scheme 3.
Entry
4b
7
Ar
9
Yield (%)
The direct conversion of diester 8 to the corresponding pulvi-
none necessitated that both the Dieckmann condensation and the
-elimination of the alkoxide would occur successively. Several
conditions were tested, that led to pulvinone 1a, having a 4-
methoxyphenyl group at the 3-position of the tetronic acid ring
(Scheme 3, Table 1).
1
2
3
4
5
6
7
8
syn-4b
anti-4b
anti-4b
syn-4b
syn-4b
anti-4b
syn-4b
anti-4b
anti-4b
syn-4b
syn-4b
anti-4b
7b
7b
7c
7d
7e
7e
7f
C6H5
C6H5
syn-9b
anti-9b
anti-9c
syn-9d
syn-9e
anti-9e
syn-9f
anti-9f
anti-9g
syn-9h
syn-9i
85
64
67
81
80
88
84
100
60
50
61
61
b
4-MeC6H4
2-(MeO)C6H4
3-(MeO)C6H4
3-(MeO)C6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
4-ClC6H4
4-BrC6H4
4-FC6H4
4-FC6H4
7f
Table 1
9
7g
7h
7i
Optimization for the preparation of 1a
10
11
12
Entry
R
Ether Conditions
Z/E ratioa Yieldb (%)
7i
anti-9i
1
2
3
4
5
Me
Me
Me
CF3CH2 9a
CF3CH2 9a
8
8
8
ꢀ78 ꢁC, 1 h, then rt, 1 h
10/3
ꢀ78 ꢁC, 4 h, then rt, overnight 10/2
ꢀ78 ꢁC, 1 h, then rt, overnight 10/3
16
14
19
61
78
Conditions similar to those described for the preparation of 1a
were then applied to the synthesis of several pulvinones 1bei de-
rived from diesters 9. Both syn- and anti-isomers have been used
and in some cases the reaction was performed from a mixture of
isomers. The results are summarized in Table 3.
ꢀ78 ꢁC, 1 h, then rt,1 h
10/1
ꢀ78 ꢁC, 1 h, then rt, overnight 10/3
Ratio according to 1H NMR integrations.
a
b
Yield in Z/E isomers mixture.
The corresponding pulvinones were purified either by pre-
cipitation of the crude product in diethyl ether or tert-butyl methyl
ether or by silica gel chromatography, and then isolated in 54e77%
yield. Usually, a given pulvinone was obtained in similar yields from
both anti- and syn-isomers of the corresponding diester 9, as well
as from a mixture of isomers (see entries 7e9, for the synthesis of
pulvinone 1f).
Ether 8 was thus treated at ꢀ78 ꢁC with 3.5 equiv lithium hexa-
methyldisilazide (LiHMDS), according to the conditions previously
reported to perform the Dieckmann condensation from a dimethyl
tartrate-derived ester.7
Despite several attempts in which the reaction time and the re-
action temperature were modified, it was not possible to obtain

B. Nadal et al. / Tetrahedron 67 (2011) 2605e2611
2607
3. Conclusion
In summary, a novel, straightforward three-step synthetic ac-
cess to a series of pulvinones, obtained from methyl 3-phenyl-
glycidate and various arylacetic acids was developed. The approach
relied on a tandem Dieckmann condensationeb-elimination.
4. Experimental section
4.1. General
Fig. 1. Molecular structure of diester anti-9i.
THF was freshly distilled from sodium benzophenone ketyl.
Dichloromethane was freshly distilled over P2O5. Reactions were
performed under an argon atmosphere. TLC: Silica Gel 60 F254 plates
with detection by UV light and by an ethanol solution of phospho-
Table 3
Synthesis of pulvinones 1
molybdicacid.Columnchromatography:40e63
points were uncorrected. NMR: 400.133 and 100.624 MHz for 1H and
13C, respectively. Chemical shifts (
mmsilicagel. Melting
d) are inparts per million (s¼singlet,
d¼doublet, t¼triplet, m¼multiplet, br¼broad), coupling constants (J)
are in hertz. In the descriptions of 1H NMR spectra, the term Ar cor-
responds to the aryl groupthatoriginates from the arylacetic acid; the
notations o-AreH, m-AreH, p-AreH indicate the proton positions on
the aryl group, which are ortho, meta, para to the tetronic acid ring.
Entry
9
Ar
1
Z/E ratioa
Yield (%)
1
2
3
4
5
6
7
8
syn-9b
C6H5
C6H5
1b
1b
1c
1d
1e
1e
1f
1f
1f
1g
1h
1i
92/8
74
71
74
54
55
70
68
63
76
65
71
77
syn/anti-9b
anti-9c
syn-9d
syn-9e
anti-9e
syn-9f
>98/2b
97/3
4-MeC6H4
2-(MeO)C6H4
3-(MeO)C6H4
3-(MeO)C6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
4-ClC6H4
4.2. General procedure for the reaction of methyl
phenylglycidate with an alcohol
96/4
96/4
97/3
97/3
Boron trifluoride diethyl etherate (350 mL, 2.8 mmol, 0.2 equiv)
anti-9f
97/3
9
syn/anti-9f
anti-9g
syn-9h
anti-9i
>98/2b
97/3
was added dropwise to a solution of methyl 3-phenylglycidate
(2.5 g, 14.0 mmol, 1 equiv) in 2,2,2-trifluoroethanol (15 mL) at 0 ꢁC
under argon. The mixture was stirred at 0 ꢁC for 30 min and at room
temperature for 2 h. The mixture was then diluted with Et2O,
washed with a saturated NaHCO3 solution. The aqueous layers were
extracted with Et2O, the organic layers were combined and dried
over MgSO4. The solvent was removed under reduced pressure and
the crude oil was purified by flash chromatography (5e30% AcOEt/
cyclohexane) to afford the alcohols syn-4b (1.99 g, 51%) as a color-
less oil and anti-4b (1.0 g, 25%) as a white solid.
10
11
12
4-BrC6H4
4-FC6H4
>98/2b
>98/2b
a
Ratio according to 1H NMR integrations.
b
Only one isomer was observed in the 1H NMR spectrum.
All the reactions led to the predominant formation of the pul-
vinone as the Z-isomer. Since anti-elimination is likely to occur
under the reaction conditions, one could have expected that anti-9
would have produce a E-pulvinone and that syn-9 would have led
to a Z-pulvinone. The outcome might be explained either by an
epimerization of the stereogenic center on the tetronic acid prior to
the elimination of the alkoxide, or by a conversion of the E-pulvi-
none to the more thermodynamically stable Z-isomer under the
basic conditions. It has been reported by Campbell et al.4 that
the alkaline hydrolysis of the acetate of a E-pulvinone usually led to
the Z-pulvinone, which implies that an isomerization had occurred
under these conditions.
4.2.1. syn-Methyl 2-hydroxy-3-phenyl-3-(2,2,2-trifluoroethoxy)prop-
anoate (syn-4b). IR (NaCl film) nmax¼3507, 3033, 2957, 2901, 2850,
1747, 1453, 1440, 1280, 1164, 1112, 1021, 966 cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d
¼7.38e7.32 (5H, m, PheH), 4.88 (1H, d,
J¼2.8 Hz, CHPh), 4.26 (1H, d, J¼2.8 Hz, CHCO2Me), 3.85e3.75 (1H,
m, CHCF3), 3.77 (3H, s, CO2CH3), 3.64e3.54 (m, 1H, CHCF3); 13C NMR
(100 MHz, CDCl3):
d
¼172.2,135.6,128.9,128.7 (2C),127.6 (2C),123.9
(q, J¼279.6 Hz), 83.5, 74.6, 66.1 (q, 33.7 Hz), 52.7; MS, [MþNa]þ:
(ESIþ) m/z 301.1 [MþNa]þ; HRMS (ESIþ) m/z calcd for C12H13O4F3Na,
[MþNa]þ: 301.0664, found: 301.0671.
The X-ray structure of the Z-configurated fluorinated pulvinone
1i, was determined, revealing the planarity of this compound
(Fig. 2)20
4.2.2. anti-Methyl
2-hydroxy-3-phenyl-3-(2,2,2-trifluoroethoxy)
propanoate (anti-4b). Mp 61e62 ꢁC; IR (NaCl film) nmax¼3479,
3035, 2956, 2901, 1744, 1453, 1440, 1280, 1165, 1131, 1003,
967 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d¼7.38e7.27 (5H, m, PheH),
4.75 (1H, d, J¼4.5 Hz, CHPh), 4.49 (1H, d, J¼4.5 Hz, CHCO2Me),
3.88e3.74 (1H, m, CHCF3), 3.70 (3H, s, CO2CH3), 3.72e3.62 (m, 1H,
CHCF3); 13C NMR (100 MHz, CDCl3):
d¼172.1, 135.0, 129.1, 128.7
(2C), 127.7 (2C), 123.9 (q, J¼279.1 Hz), 84.1, 74.3, 66.5 (q, 34.5 Hz),
52.6; MS (ESIþ) m/z 301.1 [MþNa]þ; HRMS (ESIþ) m/z calcd for
C12H13F3NaO4, [MþNa]þ: 301.0664, found: 301.0652.
4.3. General procedure for the esterification of alcohols syn-
4b and anti-4b
Alcohol syn-4b (500 mg, 1.797 mmol, 1 equiv), DCC (445 mg,
Fig. 2. Molecular structure of pulvinone 1i (co-crystallized with DMSO).
2.16 mmol, 1.2 equiv), and DMAP (110 mg, 0.898 mmol, 0.5 equiv)

2608
B. Nadal et al. / Tetrahedron 67 (2011) 2605e2611
were added to phenylacetic acid (294 mg, 2.16 mmol, 1.2 equiv) in
CH2Cl2 (5 mL) at room temperature, under nitrogen. The mixture
was stirred at room temperature for 12 h and the solvent was re-
moved under reduced pressure. Et2O was added and the mixture
was filtered. The filtrate was washed with sodium acetate buffer
(pH¼5) and the aqueous layer was extracted with Et2O. The organic
layers were combined, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (0e5% AcOEt/cyclohexane) to afford compound syn-9b
(605 mg, 85%) as a colorless oil.
Rf¼0.40 (25% AcOEt/cyclohexane); mp 68e69 ꢁC; IR (NaCl film)
nmax¼3032, 2955, 1748, 1517, 1492, 1454, 1437, 1415, 1363, 1280,
1209, 1160, 1133, 1010, 967; 1H NMR (400 MHz, CDCl3):
d
¼7.38e7.29 (3H, m, mePheHþpePheH), 7.24e7.22 (2H, m,
oePheH), 7.08 (2H, d, J¼8.1 Hz, oeAreH), 7.02 (2H, d, J¼8.1 Hz,
meAreH), 5.29 (1H, d, J¼6.3 Hz, CHCO2Me), 4.81 (1H, d, J¼6.3 Hz,
CHPh), 3.78e3.61 (2H, m, CHCF3), 3.71 (3H, s, OCH3), 3.57 (2H, s,
CH2CO), 2.32 (3H, s, CH3); 13C NMR (100 MHz, CDCl3):
d
¼170.1,
168.0, 137.0, 135.1, 130.3, 129.4 (2C), 129.3 (2C), 129.2, 128.7 (2C),
127.8 (2C),123.8 (q, J¼279.1 Hz), 74.8, 66.6 (q, J¼34.5 Hz), 52.6, 40.5,
21.2; MS (ESIþ) m/z 433.1 [MþNa]þ; HRMS (ESIþ) m/z calcd for
C21H21F3NaO5 [MþNa]þ: 433.1239, found: 433.1255.
4.3.1. (2S,3R)-Methyl
3-phenyl-2-(2-phenylacetoxy)-3-(2,2,2-tri-
fluoroethoxy)propanoate (syn-9b). IR (NaCl film) nmax¼3066, 3033,
2955, 2850, 1748, 1496, 1454, 1437, 1280, 1243, 1216, 1158, 1133,
4.3.5. (2S,3R)-Methyl 2-(2-(2-methoxyphenyl)acetoxy)-3-phenyl-3-
(2,2,2-trifluoroethoxy)propanoate (syn-9d). Alcohol syn-4b (500 mg,
1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), DMAP
(110 mg, 0.898 mmol, 0.5 equiv), and 2-methoxyphenylacetic acid
(358 mg, 2.16 mmol, 1.2 equiv) were used following the general
procedure to afford compound syn-9d as a colorless oil (618 mg,
81%). IR (NaCl film) nmax¼3066, 3033, 3008, 2941, 2842, 1749, 1603,
1069,1030, 968 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.39e7.27 (8H,
m, 5PheHþ3 AreH), 6.20 (2H, m, AreH), 5.35 (1H, d, J¼3.9 Hz,
CHCO2Me), 5.14 (1H, d, J¼3.9 Hz, CHPh), 3.94e3.82 (1H, m, CHCF3),
3.77 (3H, s, OCH3), 3.76 (1H, d, J¼15.3 Hz, CH2CO), 3.71 (1H, d,
J¼15.3 Hz, CH2CO), 3.71e3.61 (1H, m, CHCF3); 13C NMR (100 MHz,
CDCl3):
d
¼170.6, 167.6, 134.5, 133.3, 129.4 (2C), 129.2, 128.8 (2C),
128.6 (2C), 127.5, 127.2, 123.8 (q, J¼279.9 Hz), 81.9, 75.3, 66.4 (q,
J¼34.5 Hz), 52.6, 40.7; MS (ESIþ) m/z 419.1 [MþNa]þ; HRMS (ESIþ)
m/z calcd for C20H19O5F3Na, [MþNa]þ: 419.1082, found: 419.1095.
1497, 1457, 1439, 1281, 1250, 1153, 1099, 1030, 968 cmꢀ1 1H NMR
;
(400 MHz, CDCl3):
d
¼7.34 (3H, m, PheH), 7.28 (2H, m, PheH), 7.25
(1H, ddd, J¼1.8, 7.5, 8.1 Hz, p-AreH), 7.11 (1H, dd, J¼1.8, 7.5 Hz,
o-AreH), 6.89 (1H, dt, J¼1.0, 7.5 Hz, meAreH), 6.82 (1H, dd, J¼1.0,
8.1 Hz, meAreH), 5.29 (1H, d, J¼3.8 Hz, CHCO2Me), 5.08 (1H, d,
J¼3.8 Hz, CHPh), 3.84e3.75 (1H, m, CHCF3), 3.72 (3H, s, CO2CH3),
3.71 (2H, m, CH2CO), 3.67e3.57 (1H, m, CHCF3), 3.64 (3H, s, OCH3);
4.3.2. Methyl 2-(2-(4-methoxyphenyl)acetoxy)-3-phenyl-3-(2,2,2-tri-
fluoroethoxy)propanoate (9a). A mixture of alcohols anti- and syn-4b
(781 mg, 2.8 mmol, 1 equiv), DCC (695 mg, 3.37 mmol, 1.2 equiv),
DMAP (171 mg, 1.40 mmol, 0.5 equiv), and 4emethoxyphenylacetic
acid (562 mg, 3.37 mmol, 1.2 equiv) were used following the general
procedure to afford compound 9a as a yellow oil (3/2 mixture of syn/
anti isomers, 882 mg, 61%). TLC Rf¼0.60 (30% AcOEt/cyclohexane); IR
(NaCl film) nmax¼3325, 3035, 2934, 2848, 1748, 1615, 1584, 1514,
13C NMR (100 MHz, CDCl3):
d¼171.1, 167.9, 157.7, 134.8, 131.1, 129.1,
128.9 (2C), 128.8, 127.7 (2C), 123.8 (q, J¼280.6 Hz), 122.5, 120.6,
110.6, 82.1, 75.3, 66.4 (q, J¼34.5 Hz), 55.4, 52.6, 35.6; MS (ESIþ) m/z
449.1 [MþNa]þ; HRMS (ESIþ) m/z calcd for C21H21F3NaO6,
[MþNa]þ: 449.1188, found: 449.1188.
1455, 1279, 1249, 1161, 1133, 1033, 967 cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d
¼7.38e7.26 (5H, m, PheH), 7.09e7.02 (2H, m, o-AreH),
4.3.6. (2S,3R)-Methyl 2-(2-(3-methoxyphenyl)acetoxy)-3-phenyl-3-
(2,2,2-trifluoroethoxy)propanoate (syn-9e). Alcohol syn-4b (500 mg,
1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), DMAP
(110 mg, 0.898 mmol, 0.5 equiv), and 3-methoxyphenylacetic acid
(358 mg, 2.16 mmol, 1.2 equiv) were used following the general
procedure to afford compound syn-9e as a colorless oil (530 mg,
69%). TLC Rf¼0.60 (30% AcOEt/cyclohexane); IR (NaCl film)
nmax¼3065, 3033, 3008, 2956, 2840, 1747, 1602, 1587, 1493, 1455,
6.87e6.78 (2H, m, p-AreH), 5.29 (1H, d, J¼6.5 Hz, CHCO2Me minor
diast.), 5.28 (1H, d, J¼3.8 Hz, CHCO2Me major diast.), 5.08 (1H, d,
J¼3.8 Hz, CHPh major diast.), 4.82 (1H, d, J¼6.5 Hz, CHPh minor
diast.), 3.90e3.66 (2H, m, CH2CF3), 3.79 (3H, s, OCH3), 3.75e3.60 (2H,
m, CH2CO), 3.71 (3H, s, ArOCH3); 13C NMR (100 MHz, CDCl3):
d
¼171.0,170.6,168.0,167.7,158.8,135.0,134.5,130.1 (2C),129.3,129.2,
128.8 (2C), 128.7 (2C), 127.8 (2C), 127.5 (2C), 125.4, 125.3, 123.7(q,
J¼280.7 Hz), 123.6 (q, J¼280.7 Hz), 114.1 (2C), 82.0, 81.7, 75.3, 74.7,
66.4 (q, J¼34.6 Hz), 66.3 (q, J¼34.6 Hz), 55.4, 52.7, 52.5; MS (ESIþ)
m/z 449 [MþNa]þ; HRMS (ESIþ) m/z calcd for C21H21F3NaO6
[MþNa]þ: 449.1188, found: 449.1183.
1438, 1414, 1360, 1279, 1216, 1163, 1099, 1042, 1001, 967 cmꢀ1
;
1H
NMR (400 MHz, CDCl3):
d
¼7.32e7.25 (5H, m, PheH), 7.22e7.16 (1H,
m, meAreH), 6.81e6.78 (1H, m, peAreH), 6.75e6.72 (2H, m,
oeAreH), 5.28 (1H, d, J¼3.8 Hz, CHCO2Me), 5.07 (1H, d, J¼3.8 Hz,
CHPh), 3.86e3.75 (1H, m, CHCF3), 3.77 (3H, s, CO2CH3), 3.71 (3H, s,
OCH3), 3.70 (1H, d, J¼15.4 Hz, CH2CO), 3.64 (1H, d, J¼15.4 Hz,
CH2CO), 3.65e3.58 (1H, s, CHCF3); 13C NMR (100 MHz, CDCl3):
4.3.3. (2R,3R)-Methyl 3-phenyl-2-(2-phenylacetoxy)-3-(2,2,2-trifluoro-
ethoxy)propanoate (anti-9b). Alcohol anti-4b (301 mg, 1.08 mmol,
1 equiv), DCC (268 mg, 1.3 mmol, 1.2 equiv), DMAP (66 mg,
0.541 mmol, 0.5 equiv), and phenylacetic acid (177 mg, 1.3 mmol,
1.2 equiv) were used following the general procedure to afford
compound anti-9b as a yellow oil (406 mg, 95%). TLC Rf¼0.60 (30%
d
¼170.5, 167.6, 159.8, 134.6, 134.5, 129.6, 129.2, 128.8 (2C), 127.5 (2C),
123.8 (q, J¼279.4 Hz), 121.8, 114.9, 81.9, 75.3, 66.6 (q, J¼35.4 Hz),
55.2, 52.8, 40.7; MS (ESIþ) m/z 449 [MþNa]þ; HRMS (ESIþ) m/z calcd
for C21H21F3NaO6, [MþNa]þ: 449.1188, found: 449.1197.
AcOEt/cyclohexane); 1H NMR (400 MHz, CDCl3):
d¼7.39e7.10 (10H,
m, AreH), 5.33 (1H, d, J¼6.2 Hz, CHCO2Me), 4.83 (1H, d, J¼6.2 Hz,
4.3.7. (2R,3R)-Methyl 2-(2-(3-methoxyphenyl)acetoxy)-3-phenyl-3-
CHPh), 3.90e3.60 (2H, m, CHCF3), 3.70 (3H, s, OCH3), 3.62 (2H, s,
(2,2,2-trifluoroethoxy)propanoate
(anti-9e). Alcohol
anti-4b
CH2CO); 13C NMR (100 MHz, CDCl3):
d¼170.3, 168.2, 135.0, 133.2,
(500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv),
DMAP (110 mg, 0.898 mmol, 0.5 equiv), and 3-methoxyphenyl-
acetic acid (358 mg, 2.16 mmol, 1.2 equiv) were used following the
general procedure to afford compound anti-9e as a white solid
(677 mg, 88%). Mp 48e50 ꢁC; IR (NaCl film) nmax¼3034, 3007, 2955,
2839, 1748, 1602, 1586, 1493, 1456, 1438, 1278, 1209, 1164, 1049,
129.4 (2C), 129.2, 128.7 (2C), 128.6 (2C), 127.7 (2C), 127.2, 123.8 (q,
J¼278.3 Hz), 81.7, 74.8, 66.2 (q, J¼34.6 Hz), 52.4, 40.8; HRMS (ESIþ)
m/z calcd for C20H19F3NaO5 [MþNa]þ: 419.1082, found: 419.1081.
4.3.4. (2R,3R)-Methyl 3-phenyl-2-(2-(p-tolyl)acetoxy)-3-(2,2,2-tri-
fluoroethoxy)propanoate (anti-9c). Alcohol anti-4b (538 mg,
1.93 mmol, 1 equiv), DCC (479 mg, 2.32 mmol, 1.2 equiv), DMAP
(118 mg, 0.965 mmol, 0.5 equiv), and p-tolylacetic acid (348 mg,
2.32 mmol, 1.2 equiv) were used following the general procedure to
afford compound anti-9c as a colorless solid (528 mg, 67%). TLC
1009, 967 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.33 (3H, m, PheH),
7.25 (2H, m, PheH), 7.19 (1H, dd, J¼6.8, 8.3 Hz, m-AreH), 6.81 (1H,
m, AreH), 6.74 (2H, m, AreH), 5.35 (1H, d, J¼6.1 Hz, CHCO2Me), 4.86
(1H, d, J¼6.1 Hz, CHPh), 3.74 (4H, m, CHCF3þOCH3), 3.70 (3H, s,
OCH3), 3.69e3.62 (1H, m, CHCF3), 3.62 (1H, d, J¼15.3 Hz, CH2CO),

B. Nadal et al. / Tetrahedron 67 (2011) 2605e2611
2609
3.58 (1H, d, J¼15.3 Hz, CH2CO); 13C NMR (100 MHz, CDCl3):
d
¼170.1,
(110 mg, 0.894 mmol, 0.5 equiv), and 4-bromophenylacetic acid
(464 mg, 2.16 mmol, 1.2 equiv) were used following the general
procedure to afford compound syn-9h as a colorless oil (348 mg,
41%). TLC Rf¼0.60 (30% AcOEt/cyclohexane); IR (NaCl film)
nmax¼3033, 2955, 2850,1748,1490,1453,1437,1360,1280,1216,1157,
168.1, 159.7, 134.9, 134.5, 129.5, 129.1, 128.6 (2C), 127.9 (2C), 123.6 (q,
J¼279.1 Hz), 121.6, 114.8, 112.9, 81.6, 74.7, 66.2 (q, J¼34.5 Hz), 55.0,
52.4,
40.8;
MS
(ESIþ)
m/z
449.4
[MþNa]þ,
327.1
[MꢀCF3CH2OHþH]þ; HRMS (ESIþ) m/z calcd for C21H21F3NaO6,
[MþNa]þ: 449.1188, found: 449.1190.
1097, 1013, 968 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d¼7.39 (2H, d,
J¼8.3 Hz, m-AreH), 7.35e7.24 (5H, m, PheH), 7.02 (2H, d, J¼8.3 Hz,
o-AreH), 5.28 (1H, d, J¼3.8 Hz, CHCO2Me), 5.09 (1H, d, J¼3.8 Hz,
CHPh), 3.91e3.79 (1H, m, CHCF3), 3.72 (3H, s, OCH3), 3.67e3.57 (1H,
m, CHCF3), 3.63 (1H, s, CH2CO), 3.62 (1H, s, CH2CO); 13C NMR
4.3.8. (2S,3R)-Methyl 2-(2-(3,4-dimethoxyphenyl)acetoxy)-3-phenyl-
3-(2,2,2-trifluoroethoxy)propanoate
(syn-9f). Alcohol
syn-4b
(500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv),
DMAP (110 mg, 0.898 mmol, 0.5 equiv), and 3,4-dimethoxyphenyl-
acetic acid (423 mg, 2.16 mmol, 1.2 equiv) were used following the
general procedure to afford compound syn-9f as a colorless oil
(691 mg, 84%). IR (NaCl film) nmax¼3006, 2956, 2838, 1747, 1593,
(100 MHz, CDCl3):
d
¼170.1, 167.5, 134.4, 132.3, 131.7 (2C), 131.2 (2C),
129.2, 128.8 (2C), 127.4 (2C), 123.7 (q, J¼279.3 Hz), 121.3, 81.9, 75.3,
66.4 (q, J¼34.5 Hz), 52.6, 40.1; MS (ESIþ) m/z 499.0, 497.0 [MþNa]þ;
HRMS (ESIþ) m/z calcd for C20H2279BrF3NO5, [MþNH4]þ: 492.0633,
found: 4492.0618.
1516, 1454, 1440, 1266, 1238, 1158, 1097, 1029, 969 cmꢀ1 1H NMR
;
(400 MHz, CDCl3):
d
¼7.26 (5H, m, PheH), 6.74 (1H, m, AreH), 6.68
(1H, br s, oeAreH), 6.67 (1H, m, AreH), 5.27 (1H, d, J¼3.7 Hz,
CHCO2Me), 5.05 (1H, d, J¼3.7 Hz, CHPh), 3.82 (3H, s, OCH3),
3.83e3.74 (1H, m, CHCF3), 3.78 (3H, s, OCH3), 3.68 (3H, s, OCH3),
3.64e3.54 (1H, m, CHCF3), 3.62 (1H, d, J¼15.5 Hz, CH2CO), 3.56 (1H,
4.3.12. (2R,3R)-Methyl
2-(2-(4-fluorophenyl)acetoxy)-3-phenyl-3-
(2,2,2-trifluoroethoxy)propanoate (anti-9i). Alcohol anti-4b (500 mg,
1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), DMAP
(110 mg, 0.898 mmol, 0.5 equiv), and 4-fluorophenylacetic acid
(464 mg, 3.01 mmol, 1.7 equiv) were used following the general
procedure to afford compound anti-9i as a white solid (576 mg, 77%).
TLC Rf¼0.60 (30% AcOEt/cyclohexane); mp: 53e54 C; IR (NaCl film)
nmax¼3067, 3033, 2957, 2850,1748,1606,1512,1455,1363,1280,1224,
d, J¼15.5 Hz, CH2CO); 13C NMR (100 MHz, CDCl3):
¼170.7, 167.5,
d
148.8, 148.1, 134.4, 129.0, 128.6 (2C), 127.4 (2C), 125.7, 123.7 (q,
J¼279.9 Hz), 121.5, 112.4, 111.1, 81.8, 75.0, 66.2 (q, J¼34.5 Hz), 55.5,
55.7, 52.5, 40.1; MS (ESIþ) m/z 479.2 [MþNa]þ; HRMS (ESIþ) m/z
calcd for C22H23O7F3Na, [MþNa]þ: 479.1294, found: 479.1292.
1163, 1136, 1013, 967 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d¼7.38e7.30
(3H, m, m-PheHþp-PheH), 7.23e7.21 (2H, m, oePheH), 7.11e7.07
(2H, m, oeAreH), 6.97e6.93 (2H, m, m-AreH), 5.36 (1H, d, J¼3.9 Hz,
CHCO2Me), 4.82 (1H, d, J¼3.9 Hz, CHPh), 3.75e3.62 (2H, m, CH2CF3),
3.72 (3H, s, OCH3), 3.59 (2H, s, CH2CO); 13C NMR (100 MHz, CDCl3):
4.3.9. (2R,3R)-Methyl 2-(2-(3,4-dimethoxyphenyl)acetoxy)-3-phenyl-
3-(2,2,2-trifluoroethoxy)propanoate
(anti-9f). Alcohol
anti-4b
(500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv),
DMAP (110 mg, 0.898 mmol, 0.5 equiv), and 3,4-dimethoxyphenyl-
acetic acid (423 mg, 2.16 mmol, 1.2 equiv) were used following the
general procedure to afford compound anti-9f as an amorphous
colorless solid (820 mg, 99%). IR (NaCl film) nmax¼3005, 2955, 2838,
d
¼169.9, 168.0, 161.9 (d, J¼245.5 Hz), 134.7, 130.8 (2C, d, J¼8.2 Hz),
129.2, 128.7 (d, J¼3.4 Hz), 128.5 (2C), 127.6 (2C), 123.5 (q, J¼278.8 Hz),
115.3 (2C, d, J¼21.5 Hz), 81.5, 74.6, 66.1 (q, J¼34.7 Hz), 52.4, 39.8; MS
(ESIþ) m/z 437.2 [MþNa]þ; HRMS (ESIþ) m/z calcd for C20H18F4NaO5,
[MþNa]þ: 437.0988, found: 437.0981.
1748, 1593, 1516, 1455, 1440, 1267, 1238, 1159, 1028, 967 cmꢀ1 1H
;
NMR (400 MHz, CDCl3):
d
¼7.27 (3H, m, PheH), 7.19 (2H, m, PheH),
6.73 (1H, d, J¼7.7 Hz, AreH), 6.66 (1H, m, AreH), 6.65 (1H, br s,
oeAreH), 5.29 (1H, d, J¼6.1 Hz, CHCO2Me), 4.80 (1H, d, J¼6.1 Hz,
CHPh), 3.80 (3H, s, OCH3), 3.72e3.66 (1H, m, CHCF3), 3.65 (3H, s,
OCH3), 3.64e3.57 (1H, m, CHCF3), 3.55 (1H, d, J¼14.7 Hz, CH2CO),
4.4. General procedure for the synthesis of pulvinones
A 1 M solution of LiHMDS in THF (0.832 mL, 0.832 mmol,
3.5 equiv) was added dropwise at ꢀ78 ꢁC to a solution of diester
syn-9h (113 mg, 0.238 mmol,1 equiv) in THF (5 mL) under nitrogen.
The mixture was stirred at ꢀ78 ꢁC for 15 min and for 24 h at room
temperature. The reaction was quenched with 2 mL of saturated
NH4Cl solution and acidified with 5 mL of 2 N HCl solution. The
mixture was extracted with 2ꢂ10 mL of CH2Cl2 and the solvent was
removed under reduced pressure. The crude product was purified
by precipitation in tert-butyl methyl ether to afford pulvinone 1h as
a yellow solid (58 mg, Z/E ꢃ98/2, 71%).
3.50 (1H, d, J¼14.7 Hz, CH2CO); 13C NMR (100 MHz, CDCl3):
¼170.4,
d
168.0, 148.8, 148.1, 134.8, 129.0, 128.5 (2C), 127.6 (2C), 125.6, 123.5 (q,
J¼278.3 Hz), 121.4, 112.3, 111.0, 81.5, 74.5, 66.1 (q, J¼34.5 Hz), 55.7,
55.6, 52.3, 40.2; MS (ESIþ) m/z 479.1 [MþNa]þ; HRMS (ESIþ) m/z
calcd for C22H23F3NaO7, [MþNa]þ: 479.1294, found: 479.1284.
4.3.10. (2R,3R)-Methyl 2-(2-(4-chlorophenyl)acetoxy)-3-phenyl-3-
(2,2,2-trifluoroethoxy)propanoate
(anti-9g). Alcohol
anti-4b
(500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv),
DMAP (110 mg, 0.898 mmol, 0.5 equiv), and 4-chlorophenylacetic
acid (368 mg, 2.16 mmol, 1.2 equiv) were used following the gen-
eral procedure to afford compound anti-9g as a white powder
(462 mg, 60%). Mp 48e50 ꢁC; IR (NaCl film) nmax¼3035, 2955, 2907,
4.4.1. (Z)-5-Benzylidene-3-(4-bromophenyl)-4-hydroxyfuran-2(5H)-
one (1h). Mp 248e249 ꢁC; IR (KBr pellet) nmax¼3073, 3029, 1691,
1656, 1605, 1584, 1490, 1420, 1391, 1251, 1009 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
d
¼7.93 (2H, dm, J¼8.6 Hz, m-AreH), 7.74 (2H,
2850, 1749, 1493, 1454, 1279, 1212, 1161, 1133, 1095, 1016, 967 cmꢀ1
;
d, J¼7.4 Hz, o-PheH), 7.62 (2H, d, J¼8.6 Hz, o-AreH), 7.46 (2H, t,
1H NMR (400 MHz, CDCl3):
d
¼7.35e7.28 (3H, m, PheH), 7.22e7.18
J¼7.4 Hz, m-PheH), 7.37 (1H, t, J¼7.4 Hz, p-PheH), 6.76 (1H, s, CH);
(4H, m, PheHþo-AreH), 7.03 (2H, d, J¼8.5 Hz, m-AreH), 5.30 (1H, d,
J¼8.5 Hz, CHCO2Me), 4.82 (1H, d, J¼8.5 Hz, CHPh), 3.77e3.69 (1H,
m, CHCF3), 3.68 (3H, s, OCH3), 3.67e3.61 (1H, m, CHCF3), 3.56 (2H, s,
13C NMR (100 MHz, DMSO-d6):
d¼167.7, 164.6, 142.3, 132.6, 131.2
(2C), 130.2 (2C), 129.3, 129.0 (2C), 128.9, 128.8 (2C), 119.9, 108.0,
98.7; MS (ESIþ) m/z 345.0, 343.0 [MþH]þ; MS (ESIꢀ) m/z 340.8,
342.8 [MꢀH]ꢀ; HRMS (ESIþ) m/z calcd for C17H12O379Br, [MþH]þ:
342.9970, found: 342.9973.
CH2CO); 13C NMR (100 MHz, CDCl3):
d¼169.8, 168.1, 134.8, 133.1,
131.7, 130.7 (2C), 129.2, 128.6 (4C), 127.6 (2C), 123.6 (q, J¼278.3 Hz),
81.5, 74.7, 66.1 (q, J¼34.5 Hz), 52.4, 40.0; MS (ESIþ) m/z 453.1
[MþNa]þ, 331.1 [MꢀCF3CH2OHþH]þ; HRMS (ESIþ) m/z calcd for
C20H18O5ClF3Na, [MþNa]þ: 453.0693, found: 453.0699.
4.4.2. (Z)-5-Benzylidene-3-(4-methoxyphenyl)-4-hydroxyfuran-2
(5H)-one (1a). LiHMDS (1 M in THF, 1.7 mL, 1.7 mmol, 3.5 equiv)
and diester 9a (mixture of syn- and anti-isomers, 200 mg,
0.48 mmol) were used following the general procedure to afford
pulvinone 1a as a yellow solid (86 mg, Z/E¼10/1, 61%). Mp
221e222 ꢁC (lit.15a mp 219e222 ꢁC; lit.15c mp 223e226 ꢁC); IR (KBr
4.3.11. (2S,3R)-Methyl
2-(2-(4-bromophenyl)acetoxy)-3-phenyl-3-
(2,2,2-trifluoroethoxy)propanoate (syn-9h). Alcohol syn-4b (500 mg,
1.8 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), DMAP

2610
B. Nadal et al. / Tetrahedron 67 (2011) 2605e2611
pellet) nmax¼3002, 2937, 2833, 2619, 1893, 1704, 1631, 1607, 1573,
1515,1494,1449,1424,1402,1346,1332,1310,1291,1253,1182,1157,
1130, 1101, 1037, 998, 920, 872, 831, 747, 690, 655, 613, 571,
J¼8.8 Hz, AreH), 6.75 (1H, s, CH), 3.78 (3H, s, OMe); 13C NMR
(100 MHz, DMSO-d6):
d
¼167.8, 164.1, 159.0, 142.4, 132.7, 131.1, 130.1
(2C), 129.3, 129.0 (2C), 128.9, 119.6, 112.8, 112.6, 107.7, 99.9, 55.0; MS
(ESIþ) m/z 295.1 [MþH]þ; MS (ESIꢀ) m/z 292.9 [MꢀH]ꢀ; HRMS
(ESIþ) m/z calcd for C18H15O4, [MþH]þ: 295.0970, found: 295.0981.
532 cmꢀ1; 1H NMR (400 MHz, acetone-d6):
d
¼10.97 (1H, br s, OH);
7.94 (2H, d, J¼8.8 Hz, o-AreH), 7.82 (2H, d, J¼7.4 Hz, o-PheH),
7.48e7.32 (3H, m, m-PheH, p-PheH), 7.01 (2H, d, J¼8.8 Hz, m-
AreH), 6.59 (1H, s, CH), 3.83 (1H, s, OCH3); 13C NMR (100 MHz,
4.4.7. (Z)-5-Benzylidene-3-(3,4-dimethoxyphenyl)-4-hydroxyfuran-
2(5H)-one (1f). LiHMDS (1 M in THF, 1.533 mL, 1.533 mmol,
3.5 equiv) and diester syn-9f (200 mg, 0.438 mmol) were used
following the general procedure to afford pulvinone 1f as a brown
solid (97 mg, Z/E¼97/3, 68%). Mp 190e192 ꢁC (lit.15a mp
190e194 ꢁC); IR (KBr pellet) nmax¼3061, 3002, 2940, 2835, 1696,
DMSO-d6):
d
¼168.0, 162.2, 158.3, 142.5, 132.8, 130.0 (2C), 129.0 (2C),
128.7, 128.6 (2C), 122.1, 113.8, 107.2, 100.4, 55.1; MS (ESIþ) m/z 295
[MþH]þ.
4.4.3. (Z)-5-Benzylidene-4-hydroxy-3-phenylfuran-2(5H)-one
(1b). LiHMDS (1 M in THF, 1.766 mL, 1.766 mmol, 3.5 equiv) and
diester 9b (200 mg, 0.504 mmol, syn/anti mixture) were used fol-
lowing the general procedure to afford pulvinone 1b as a yellow
solid (94 mg, Z/E ꢃ98/2, 71%). Mp 245e246 ꢁC (lit.4 mp
250e251 ꢁC); IR (KBr pellet) nmax¼3084, 3052, 3004, 1702, 1659,
1630, 1602, 1518, 1453, 1392, 1257, 1139, 1027 cmꢀ1 1H NMR
;
(400 MHz, acetone-d6):
d
¼7.81 (2H, d, J¼7.2 Hz, o-PheH), 7.61 (1H,
d, J¼2.0 Hz, o-AreH), 7.56 (1H, dd, J¼8.4, 2.0 Hz, o-AreH), 7.45 (2H,
m, m-PheH), 7.36 (1H, m, p-PheH), 7.01 (1H, d, J¼8.4 Hz, m-AreH),
6.59 (1H, s, CH), 3.84 (6H, s, 2OMe); 13C NMR (100 MHz, acetone-
1624, 1492, 1450, 1410, 1253, 1153, 1123, 1006 cmꢀ1
;
1H NMR
d6):
d
¼168.6, 162.0, 150.1, 150.0, 143.6, 134.1, 131.1 (2C), 129.8 (2C),
(400 MHz, DMSO-d6):
d
¼7.95 (2H, d, J¼7.6 Hz, m-AreH), 7.75 (2H,
129.6, 123.2, 121.9, 112.6, 112.5, 107.5, 103.0, 56.1 (2C); MS (ESIþ) m/z
325.1 [MþH]þ; MS (ESIꢀ) m/z 322.9 [MꢀH]ꢀ.
d, J¼7.4 Hz, o-PheH), 7.45 (4H, m, o-AreHþm-PheH), 7.36 (1H, m,
p-PheH), 7.30 (1H, m, p-AreH), 6.75 (1H, s, CH); 13C NMR (100 MHz,
DMSO-d6):
d
¼167.9, 163.8, 142.4, 132.7, 130.1, 129.8, 129.0, 128.8,
4.4.8. (Z)-5-Benzylidene-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-
one (1g). LiHMDS (1 M in THF, 1.625 mL, 1.625 mmol, 3.5 equiv)
and diester anti-9g (200 mg, 0.464 mmol) were used following the
general procedure to afford pulvinone 1g as a yellow solid (90 mg,
Z/E¼97/3, 65%). Mp 247e248 ꢁC; IR (KBr pellet) nmax¼3063, 3004,
1698, 1658, 1625, 1591, 1493, 1450, 1420, 1395, 1249, 1155, 1129,
128.3, 127.3, 127.2, 107.7, 100.2; MS (ESIþ) m/z 265.1 [MþH]þ; MS
(ESIꢀ) m/z 262.9 [MꢀH]ꢀ.
4.4.4. (Z)-5-Benzylidene-4-hydroxy-3-(p-tolyl)furan-2(5H)-one
(1c). LiHMDS (1 M in THF, 0.290 mL, 0.29 mmol, 3.5 equiv) and
diester anti-9c (34 mg, 0.083 mmol) were used following the gen-
eral procedure to afford pulvinone 1c as a yellow solid (17 mg, Z/
E¼97/3, 74%). Mp 234e235 ꢁC; IR (KBr pellet) nmax¼3011, 2913,
1095, 1002 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼8.01 (2H, d,
J¼8.6 Hz, m-AreH), 7.74 (2H, d, J¼8.0 Hz, o-PheH), 7.46 (4H, m, o-
AreHþm-PheH), 7.36 (1H, m, p-PheH), 6.74 (1H, s, CH); 13C NMR
1699, 1657, 1625, 1451, 1422, 1399, 1252, 1150, 1003, 916 cmꢀ1
;
1H
(100 MHz, DMSO-d6):
d
¼167.9, 165.0, 142.6, 132.8, 131.2, 130.1 (2C),
NMR (400 MHz, DMSO-d6):
d¼7.84 (2H, d, J¼8.1 Hz, m-AreH), 7.74
129.2, 129.0 (2C), 128.8, 128.4 (2C), 128.3 (2C), 107.7, 98.3; MS (ESIþ)
m/z 299.1 [MþH]þ; MS (ESIꢀ) m/z 296.8 [MꢀH]ꢀ; HRMS (ESIþ) m/z
calcd for C17H12O3Cl, [MþH]þ: 299.0475, found: 299.0489.
(2H, d, J¼7.6 Hz, o-PheH), 7.47 (2H, m, m-PheH), 7.37 (1H, m, p-
PheH), 7.25 (2H, d, J¼8.1 Hz, o-AreH), 6.72 (1H, s, CH), 2.32 (3H, s,
CH3); 13C NMR (100 MHz, DMSO-d6):
d¼167.9, 163.1, 142.4, 136.6,
132.7, 130.1, 129.0, 128.9, 128.8, 127.1, 126.8, 107.4, 100.3, 20.9; MS
(ESIþ) m/z 279.1 [MþH]þ; HRMS (ESIþ) m/z calcd for C18H15O3,
[MþH]þ: 279.1021, found: 279.1031.
4.4.9. (Z)-5-Benzylidene-3-(4-fluorophenyl)-4-hydroxyfuran-2(5H)-
one (1i). Diester anti-9i (200 mg, 0.48 mmol) was used following
the general procedure to afford pulvinone 1i as a yellow solid
(90 mg, Z/E >98/2, 77%). Mp 260e262 ꢁC (lit.3 mp 256e260 ꢁC); 1H
4.4.5. (Z)-5-Benzylidene-4-hydroxy-3-(2-methoxyphenyl)furan-2
(5H)-one (1d). LiHMDS (1 M in THF, 1.642 mL, 1.642 mmol,
3.5 equiv) and diester syn-9d (200 mg, 0.469 mmol) were used
following the general procedure to afford pulvinone 1d as a yellow
solid (74 mg, Z/E¼96/4, 54%) after a purification by flash chroma-
tography (10e20% AcOEt/cyclohexane containing 0.5% HCO2H). Mp
120e123 ꢁC; IR (NaCl film) nmax¼3061, 2940, 2844,1752,1619,1600,
NMR (400 MHz, acetone-d6):
d
¼8.03 (2H, dd, J¼8.8, 5.6 Hz, o-
AreH), 7.81 (2H, d, J¼7.5 Hz, o-PheH), 7.48e7.44 (2H, m, m-PheH),
7.39e7.31 (1H, m, p-PheH), 7.23e7.17 (2H, m, m-AreH), 6.64 (1H, s,
CH); 13C NMR (100 MHz, DMSO-d6):
d
¼137.9, 163.7, 160.9 (d,
J¼244.6 Hz), 142.3, 132.7, 130.1 (2C), 129.2 (2C, d, J¼7.7 Hz), 129.0
(2C), 128.9, 126.3, 115.2 (2C, d, J¼20.7 Hz), 107.7, 99.2; MS (ESIþ) m/z
283 [MþH]þ; HRMS (ESIþ) m/z calcd for C17H12O3F, [MþH]þ:
283.0770, found: 283.0780.
1494, 1461, 1333, 1246, 1232, 1011, 970 cmꢀ1 1H NMR (400 MHz,
;
acetone-d6):
d
¼10.0 (1H, s, OH), 7.85 (2H, dm, J¼7.2 Hz, o-PheH),
7.63 (1H, dd, J¼1.7, 7.6 Hz, o-AreH), 7.46 (2H, m, m-PheH), 7.38 (2H,
p-AreHþp-PheH), 7.11 (1H, dd, J¼1.1, 8.4 Hz, m-AreH), 7.06 (1H, dt,
J¼1.1, 7.6 Hz, m-AreH), 6.45 (CH), 3.95 (3H, s, OMe); 13C NMR
Acknowledgements
ꢀ ꢀ
ꢀ ꢀ
Financial supports by the Delegation Generale pour l’Armement
(DGA) and by the Agence Nationale de la Recherche (ANR) are
gratefully acknowledged.
(100 MHz, acetone-d6):
d
¼168.5, 163.5, 157.5, 143.6, 134.1, 131.6
(2C), 131.1, 130.6, 129.7 (2C), 129.5, 121.7, 118.6, 112.2, 107.2, 100.1,
56.5; MS (ESIþ) m/z 295.1 [MþH]þ; MS (ESIꢀ) m/z 292.9 [MꢀH]ꢀ;
HRMS (ESIþ) m/z calcd for C18H15O4, [MþH]þ: 295.0970, found:
295.0970.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.011.
4.4.6. (Z)-5-Benzylidene-4-hydroxy-3-(3-methoxyphenyl)furan-2
(5H)-one (1e). LiHMDS (1 M in THF, 1.642 mL, 1.642 mmol,
3.5 equiv) and diester anti-9e (200 mg, 0.469 mmol) were used
following the general procedure to afford pulvinone 1e as a yellow
solid (96 mg, Z/E¼97/3, 70%). Mp 202e204 ꢁC; IR (KBr pellet)
nmax¼3067, 3005, 2918, 2833, 1700, 1658, 1626, 1575, 1486, 1415,
1402, 1253, 1232, 1124, 1017, 991 cmꢀ1; 1H NMR (400 MHz, DMSO-
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