Tandem Claisen condensation/transesterification between arylacetate enolates and arylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones: An improved synthesis of z-configured pulvinones

Article abstract of DOI:10.1055/s-2006-950378

Horner-Wadsworth-Emmons (HWE) alkenations of aromatic aldehydes with the novel phosphonate 24b led to E-configured arylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones 25a-f (79-88% yield). The latter condensed with the lithium enolates of methyl arylacetates lithio-20b-d to give, after acid treatment and crystallization, isomerically pure (Z)-pulvinones 8d-s in 75-91% yield. We also showed that Horner-Wadsworth-Emmons reactions between phosphonate 24b and aliphatic aldehydes lead to E-configured alkylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones 25g-i (82-96% yield). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950378

118
PAPER
Tandem Claisen Condensation/Transesterification between Arylacetate
Enolates and Arylmethylene-Substituted 2,2-Dimethyl-1,3-dioxolan-4-ones:
An Improved Synthesis of Z-Configured Pulvinones
Tandem
Claisen
C
a
ondensation
t
/Trans
a
esterificatio
s
n
betwe
e
z
n
E
nolates
a
a
nd 1,3-Dioxolan-
K
4-ones aczybura, Reinhard Brückner*
Institut für Organische Chemie and Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 12 June 2006; revised 4 September 2006
The most straightforward published access to pulvinones
Abstract: Horner–Wadsworth–Emmons (HWE) alkenations of ar-
omatic aldehydes with the novel phosphonate 24b led to E-config-
ured arylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones
25a–f (79–88% yield). The latter condensed with the lithium eno-
proceeds via the enol6 6 of a triketone; such triketones are
accessible by condensing7 1,3-diarylacetones8 with dieth-
yl oxalate (Scheme 2). The key step of this synthesis is the
lates of methyl arylacetates lithio-20b–d to give, after acid treat- thermal [1,3]-sigmatropic rearrangement of enol 6, as de-
scribed by Campbell et al.;9 it provided pulvinone 8b in
ment and crystallization, isomerically pure (Z)-pulvinones 8d–s in
75–91% yield. We also showed that Horner–Wadsworth–Emmons
77% yield. However, the symmetry of the triketone tau-
reactions between phosphonate 24b and aliphatic aldehydes lead to
tomer of enol 6 limits this approach to the synthesis of pul-
E-configured alkylmethylene-substituted 2,2-dimethyl-1,3-diox-
vinones with two identical aryl groups.
olan-4-ones 25g–i (82–96% yield).
Gill et al. synthesized pulvinones from unsymmetrical
acyloins like compound 710 (Scheme 2).11 Deprotonation
generated an oxy-substituted enolate, which was cyclized
by double acylation with 1,1¢-carbonyldiimidazole. Ad-
justment of the oxidation state including temporary pro-
tection of the hydroxy group gave pulvinones (e.g., 8a) in
a further three steps.12
Campbell’s second route to pulvinones9 is based on the
Dieckmann condensation of diesters like 913 (Scheme 2).
They provided tetronic acids that were dehydrogenated to
give pulvinone 8b by the three-step sequence already
mentioned for the conversion of 7 to 8a.
Key words: crossed Claisen condensation, Horner–Wadsworth–
Emmons alkenation, O-protected a-hydroxyacrylates, a-oxocar-
boxylates, stereoselective synthesis
a,b-Unsaturated g-lactones (D3-butenolides, 1, Scheme 1)
are encountered in many natural products.1 A subclass of
these compounds contains an alkylidene substituent at Cg
(g-alkylidene-D3-butenolides,2 2) and in another subclass,
a hydroxy group at Cb (tetronic acids,3 3). Several dyes
from fungi combine the aforementioned structural fea-
tures and are arylated at Ca, namely the pulvinones 4;4 ac-
cordingly, they constitute g-(arylmethylene)butenolides
with a-aryl and b-hydroxy groups, or tetronic acids with
a-aryl and g-(arylmethylene) substituents. Pulvinones
with an additional carboxy group at Ca¢ of the (arylmeth-
ylene) substituent are classified separately as pulvinic ac-
ids 5.5
Pattenden and Knight prepared pulvinone 8c with a meth-
yl group at Ob Z-selectively by a two-step aldol conden-
sation between the enolate of tetronic ester 10a14 and 4-
methoxybenzaldehyde (Scheme 2).15 This approach was
modified by the Campbell group who established the
Cg=Cexocyclic bond between a phosphorus ylide, derived
from tetronic ester 10b16 by functionalizing Cg, and ben-
zaldehyde during their synthesis of pulvinone 8b.9 The
latter was a Z/E mixture whose constituents were separat-
ed by recrystallization.
OH
Rx
Rx
Rx
β
β
β
R
γ
γ
γ
α
α
α
O
O
O
O
O
O
1
2
3
Very recently, a group from Wyeth Research synthesized
a large number of pulvinones as exemplified by their five-
step access to pulvinone 8t (Scheme 2).17 The known bro-
minated derivative 11b18 of commercially available
tetronic ester 11a was condensed with an aldehyde at Cg
to give 12 and then coupled at Ca with a boronic acid.
Cleavage of the b-OMe bond furnished the target struc-
ture (seemingly19 isomerically pure).
OH
CO2H OH
R2
R2
β
β
α´
γ
γ
α
α
R1
R1
O
O
O
O
4
5
Scheme 1 Structural survey of D3-butenolides 1: g-alkylidene-D3-
butenolides 2, tetronic acids 3, pulvinones 4, and pulvinic acids 5.
Considering the availability of starting materials, overall
number of steps, and convergency, the most efficient
route to pulvinones was developed by Ramage et al. in
1984.20,21 It began with a three-step preparation of phos-
phonium bromide 1620 (Scheme 3). The latter allowed the
synthesis of pulvinones (Z)-21a, (Z)-21b, and (Z)-8b after
SYNTHESIS 2007, No. 1, pp 0118–0130
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-950378; Art ID: T08706SS
© Georg Thieme Verlag Stuttgart · New York
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x
.
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Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
119
OMe
19 and cyclohexanone. Being an active methylene com-
pound, (Z)-19 is expected to quench one equivalent of
enolate lithio-20a, thereby delivering bis(enolate) lithio-
(Z)-19. Hence, two equivalents of lithio-20a are required
for such Claisen condensations to proceed to completion.
At the end22 of Ramage’s sequence, protonation is re-
quired, whether before or after lactone formation remains
indeterminate. All in all one pulvinone (Z)-21a was ob-
tained with complete retention of the (Z)-configuration of
enol ester (Z)-18.
O
O
Ph
O
MeO
MeO
OH
7
OH
R1
6
OH
R2
a
b–f
β
γ
α
O
O
8a: R1 = 3,4-(OH)2, R2 = 4-OH
8b: R1 = R2 = H
8c: R1 = 4-OMe, R2 = 4-OMe*
*β-OMe instead of β-OH
O
O
O
X
a)
b)
OH
O
O
OH
O
O
g–j
Ph
k, l
m–o
R2
13
14
15: R = Br
O
OMe
EtO
c)
16: R = Ph3P Br
γ
BnO
BnO
O
O
d)
O
O
O
10a: R2 = OMe
10b: R2 = H
9
O
17
BnO
BnO
O
Cl
O
OMe
OMe
OMe
Br
O
X
(Z)-18
Napht
p
β
Napht
γ
α
O
O
O
O
O
OBn
OBn
O
8t
12
11a: X = H
11b: X = Br
H
e1)
BnO
BnO
q–t
Li
O
MeO
O
Li
MeO
O
Scheme 2 Published syntheses of pulvinones, part 1. Reagents and
conditions: Ref.9: (a) 6, no solvent, 230 °C; 77% (Z)-8b. Ref.11: (b) 7,
LDA (2 equiv), THF, –78 °C; 1,1¢-carbonyldiimidazole, –78 °C to
15 °C; (c) Me2SO4, K2CO3, acetone, heat; (d) NBS, CCl4, heat, then
hn; DBU, benzene, r.t.; (e) BBr3, CH2Cl2, heat; (f) LiBr, CaCO3,
DMF, heat; 23% (Z)-8a over five steps. Ref.9: (g) 9, KO-t-Bu, t-
BuOH, heat; (h) Me2SO4, K2CO3, acetone, heat; (i) NBS, AIBN (cat.),
1,2-dichloroethane, heat; (j) LiBr, CaCO3, DMF, heat; >26% (Z)-8b
over four steps. Ref.15: (k) 10a, LiN(i-Pr)Cy, THF, –78 °C; 4-
MeOC6H4CHO, –50 °C; (l) benzene, TsOH (cat.), r.t.; 70% (Z)-8c.
Ref.9: (m) 10b, NBS, AIBN (cat.), 1,2-dichloroethane, heat; (n) Ph3P,
benzene, heat (includes cleavage of methyl tetronate); (o) benzalde-
hyde, NaOEt, EtOH, r.t.; 41% (Z)-8b and 16% (E)-8b over three steps
(plus recrystallization). Ref.17: (p) 11a, NBS, CCl4, heat (following
ref.18); (q) 11b, LiN(i-Pr)Cy, THF, –78 °C; 1-naphthaldehyde; (r) 12,
MsCl, Et3N, CH2Cl2, 0 °C; (s) 4-ClC6H4B(OH)2, K3PO4, Pd(PPh3)4,
dioxane, microwaves; (t) LiBr, DMF, microwaves; 11% over five
steps (step p, ref.18; steps q–t, ref.19).
(Z)-19
lithio-20a
OBn
OBn
O
Li
BnO
BnO
H
Li
O
MeO
MeO
O
O
lithio-(Z)-19
20a
e2)
OBn
OH
R
R
O
O
steps 4 and 5.21,22 In step 4, phosphonium salt 16 and 1,4-
diazabicyclo[2.2.2]octane generated an ylide,20 which
condensed21 with aldehyde 17 to provide the cyclohexy-
lidene acetal 18 of a b-arylated Z-configured pyruvic acid
enol. Being an enol ester, acetal (Z)-16 acts as an acylating
agent in step 5, namely a Claisen condensation with ester
enolate lithio-20a. Since closely related Claisen conden-
sations of 25a–f with lithio-20b–c, shown in Table 5, are
a key step of the present study, too, it is important to un-
derstand why each condensation gave the best yield if 2.5
equivalents of the ester enolate were used. The primary
products must be the enolate-containing b-oxo ester (Z)-
(Z)-21a: R = OBn
(Z)-21b (cf. ref.22): R = H
Scheme 3 Published syntheses of pulvinones, part 2: Ramage’s
synthesis of tribenzyl ether (Z)-21a of pulvinone (Z)-8a. Reagents
and conditions: Ref.20: a) cyclohexanone, TsOH (1 mol%), toluene,
heat, 5 h; 73%; b) NBS (1.06 equiv), AIBN (0.2 mol%), CCl4, hn,
heat, reaction time not disclosed; c) Ph3P (1.0 equiv), toluene, r.t.,
overnight; 79% over two steps; d) 16 (1.33 equiv), DABCO (1.0
equiv), toluene, r.t., 4 min; yield not given. – Ref.21: Addition of 17,
70 °C, 4 h; 80% over two steps; e1) lithio-20a (2.5 equiv), THF,
–78 °C to r.t., overnight; e2) evaporation of THF; addition of Et2O–
H2O (1:1); recrystallization of the resulting solid (H2O or AcOH–
H2O); 78% (Z)-21a.
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

120
N. Kaczybura, R. Brückner
PAPER
Table 1 Synthesis of dioxolanone-substituted phosphonates 24a–ca
The present study improves and extends Ramage’s ylide
methodology by introducing the dioxolanone-substituted
phosphonate 24b (Table 1). This is a superior reagent for
the preparation of arylmethylene-substituted dioxol-
anones 25a–f (Tables 2 and 3) because of the inherent ad-
vantage of Horner–Wadsworth–Emmons versus the
analogous Wittig alkenations: the byproduct of the
former, a phosphonate anion, is easily extracted into wa-
ter, while the byproduct of the latter, triphenylphosphine
oxide, must be removed by chromatography or crystalli-
zation. Also, the synthesis of phosphonate 24b is one step
shorter than the synthesis of Ramage’s phosphonium salt
16. Quite like Ramage’s congener (Z)-18 (Scheme 3), our
dioxolanones 25 can be transformed into pulvinones 8 ef-
ficiently and stereoselectively (Table 5). We consider this
a significantly improved access.
O
O
O
O
O
a)
b)
(RO)2P
(RO)2P
HO
O
OH
OH
O
OH
OH
22
23a–c
Yield (%)
23b
24a–c
23, 24
R
24
25
80
80
a
b
c
Me
Bu
92
95
i-Pr
95
a Reagents and conditions: (a) dialkyl phosphite (1.0 equiv), 50 °C, 5
h; (b) acetone (1.0 equiv), BF3·OEt2 (1.75 equiv), Et2O, r.t., 12 h.
b Products not purified.
Dioxolanone-substituted dialkyl phosphonates 24a–c
were obtained from the corresponding 2-(dialkoxyphos-
phoryl)-2-hydroxyacetic acids 23a–c (Table 1). These, in
turn, were prepared as published for the 2-(diethoxyphos-
phoryl)-2-hydroxyacetic acid23 by the addition of dimeth-
yl, dibutyl, and diisopropyl phosphite, respectively, to
glyoxylic acid (commercially available as the hydrate 22).
The crude dimethyl, dibutyl, and diisopropyl phospho-
nates 23a–c were ≥92% pure according to 1H NMR anal-
ysis (CDCl3). Therefore, they were subjected to acetonide
formation to give 24a–c by treatment with acetone and ex-
cess boron trifluoride–diethyl ether complex24 without
prior purification. Workup comprised hydrolysis of the
Lewis acid (by the addition of aqueous hydrogen carbon-
ate solution) and extraction with diethyl ether. This proce-
dure was inefficient in the case of the dioxolanone-
substituted dimethyl phosphonate 24a due to its high sol-
ubility in the aqueous phase. Accordingly, the isolated
yield of 24a (after purification by flash
chromatography25) was only 25%. On the other hand, the
dioxolanone-substituted dibutyl and diisopropyl phospho-
nates 24b and 24c, respectively, were only sparingly wa-
ter soluble. They could be readily extracted from the
aqueous phase with diethyl ether and purified by filtration
through a pad of silica gel to give 24b and 24c, both in
80% yield and on a 20 g and 3.5 g scale, respectively.
2). Potassium hexamethyldisilazanide and 18-crown-6 in
tetrahydrofuran28 furnished dioxolanone 25c in 55% yield
after 12 hours at –78 °C (Table 2, entry 3) but the E/Z ratio
sank to 77:23. Sodium hydride as a base29 gave the Hor-
ner–Wadsworth–Emmons product 25c in only 47% yield
but with very good E/Z selectivity 96:4 (Table 2, entry 4).
Lithium diisopropylamide30 in tetrahydrofuran/1,3-dime-
thyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (4:1) was the
best base for making compound 25c both efficiently (81%
yield) and E-selectively (E/Z 95:5; Table 2, entry 5).
When treated with lithium diisopropylamide/tetrahydro-
furan/1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-
one, diisopropyl phosphonate 24c condensed with 4-
methoxybenzaldehyde to give 25c in similar yield (78%)
but with a drop in stereoselectivity (E/Z 79:21; Table 2,
entry 6).31
As a result of these optimizations, dibutyl phosphonate
24b became the reagent of choice for the remaining Hor-
ner–Wadsworth–Emmons alkenations. As documented in
Table 3, we used only aromatic aldehydes in these reac-
tions. Most of them bear one or several oxygenated moi-
eties corresponding to the many naturally occurring
pulvinones, which contain several hydroxy groups.4 We
obtained the alkenation products 25a–f in consistently
good yields (79–88%). The E/Z selectivity, with which we
had made compound 25c (95:5), was not surpassed by the
other E/Z ratios, which spanned the range from 95:5 to
87:13. Fortunately, this lack of stereointegrity has no con-
sequence in the context of pulvinone synthesis, because
the double bond geometries of the final pulvinone 8 did
not reflect the double bond geometries of their dioxol-
anone precursors 25.
The Horner–Wadsworth–Emmons alkenation reactions
involving dibutyl phosphonate 24b and diisopropyl phos-
phonate 24c were studied with 4-methoxybenzaldehyde
as the prototype aldehyde (Table 2). The selected reaction
conditions were gleaned from Horner–Wadsworth–Em-
mons reactions of other phosphonates.26–30 In the presence
of both sodium iodide and 1,8-diazabicyclo[5.4.0]undec-
7-ene, an activator/base combination described by
Masamune and Roush,26 dibutyl phosphonate 24b deliv-
ered the 4-methoxybenzylidene-substituted dioxolanone
25c in 66% yield as a 76:24 E/Z mixture (Table 2, entry
1). In the presence of sodium iodide, 1,8-diazabicyc-
lo[5.4.0]undec-7-ene, and 1,3-dimethyl-3,4,5,6-tetrahy-
dropyrimidin-2(1H)-one31 the yield of 25c was higher
(75%) and the E/Z ratio increased to 96:4 (Table 2, entry
The E- vs. Z-configuration of dioxolanones 25a–f could
not be deduced from their 1H NMR spectra: The two last
columns of Table 3 reveal that the chemical shift of the
alkene-bound nucleus H1¢ is only marginally affected by
a change of the alkene geometry: Dd = 0.02–0.04. This
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

PAPER
Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
121
Table 2 Optimization of the Horner–Wadsworth–Emmons Alkenation of 4-Methoxybenzaldehyde with Deprotonated Phosphonates 24b,c
OMe
O
O
base, additive(s), THF
addition of OMe
(RO)2P
O
O
1´
O
O
O
24b,c
(E)-25c
O
[mixed with (Z)-25c]
(1.0–1.1 equiv)
Entry Phosphonatea Base, additive(s)
Deprotonation; condensation
Yield (%) Ratio E/Z
1
24b
DBU (1.0 equiv), NaI (1.2 equiv)
0 °C, 30 min; –78 °C to r.t., 12 h26
66
76:24
2
24b
24b
24b
24b
24c
DBU (1.0 equiv), NaI (1.2 equiv), DMPU (2.5 equiv) 0 °C, 1 h; –78 °C to r. t., 12 h27
75
55
47
81
78
96:4
3
KHMDS (1.0 equiv), 18-crown-6 (5.0 equiv)
NaH (1.0 equiv)
–78 °C, 30 min; –78 °C, 12 h28
0 °C, 1 h; 0 °C, 12 h29
77:23
96:4
4
5
LDA27 (1.5 equiv), DMPU30 (20% in THF)
LDA (1.5 equiv), DMPU (20% in THF)
–78 °C, 30 min; –78 °C, 12 h
–78 °C, 30 min; –78 °C, 12 h
95:5
631
79:21
a 24b R = Bu, 24c R = i-Pr.
phenomenon is reminiscent of the virtual independence of py. Such couplings are larger when the bonds between the
the chemical shift of the analogous proton in pulvinones nuclei under scrutiny have a zigzag rather than a U-shaped
from the double bond geometry.9 The C1¢=C geometry of array.32 The zigzag 13C=O/1H1¢ coupling in the major iso-
dioxolanones 25a–f was therefore established by a differ- mers 25b,c,f is 10.1 Hz, which gives proof for their E-con-
ent criterion, the magnitude of the three-bond coupling figuration, while the U-shaped 13C=O/1H1¢ coupling in the
3J(C=O,H1¢) between 13C=O and 1H1¢. For the major and minor isomers 25b,c,f is 3.7 Hz and this gives proof for
minor isomers of dioxolanes 25b,c,f this was observed by their Z-configuration. The E-configuration for the major
gated-decoupled one-dimensional 13C NMR spectrosco- isomers of dioxolanes 25a,d,e was assigned by analogy
with these results.
The E-selectivity of the Horner–Wadsworth–Emmons re-
Table 3 Horner–Wadsworth–Emmons Alkenations Rendering
Arylmethylene-Substituted Dioxolanones 25a–f
actions which allowed us to transform aromatic aldehydes
into dioxolanones 25a–f (Table 3) is in complete contrast
with the Z-selective Wittig alkenation by which Ramage
et al.20,21 obtained dioxolanone (Z)-18 and its benzyloxy-
LDA (1.5 equiv),
THF/DMPU (4:1),
–78 °C, 25 min;
O
O
R1
O
(BuO)2P
O
1´
O
O
addition of
Table 4 Horner–Wadsworth–Emmons Reactions Leading to Alkyl-
methylene-Substituted Dioxolanones 25g–i
O
R1
24b
25a–f
LDA (1.5 equiv),
R1
O (1.1 equiv),
O
O
O
THF/DMPU (4:1),
–78 °C, 25 min;
–78 °C, 12 h
(BuO)2P
1´
O
O
25
R1
H
Yield (%) Ratio E/Z 1H NMR d (H1¢)
R1
O
O
addition of
E
Z
(1.1 equiv),
O
24b
a
b
c
d
e
f
80
79
88
80
80
84
95:5
6.51
6.44
6.46
6.45
6.41
6.42
6.47
6.42
6.43
6.43
6.39
6.39
–78 °C, 1 h
25g–i
4-OH
87:13
95:5
25
R1
Yield (%) Ratio E/Z 1H NMR d (H1¢)
4-OMe
E
Z
3,4-(OMe)2
3,4-(OCH2O)
3,4,5-(OMe)3
87:13
89:11
90:10
g
h
i
i-Pr
96
82
95:5
100:0
96:4
5.36
5.38
5.52
5.51
–
Cy
n-C9H19 92
5.61
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122
N. Kaczybura, R. Brückner
PAPER
free analogue. For this reason we also examined some Table 5 Claisen Condensation/Transesterification Route from Alky-
lidenedioxolanones 25a–f to Pulvinones (Z)-8d–s
Horner–Wadsworth–Emmons reactions between phos-
phonate 24b and aliphatic aldehydes (Table 4). Under the
previously established conditions (Table 2, entry 5) and
R2
within one hour at –78 °C, this provided the alkylidene-
substituted dioxolanones 25g–i in 82–96% yield and with
MeO
20b–d (2.5–2.6 equiv)
LDA (2.5–2.6 equiv), THF,
–78 °C, 25 min
O
E/Z selectivities between 95:5 and 100:0. The E-configu-
ration of dioxolanone 25h was determined from
3J(C=O, H1¢) = 10.5 Hz. The E-configuration of the other
dioxolanones 25g and 25i was assigned by analogy.
20, lithio-20 R2
b
c
d
4-OMe
3,4-(OMe)2
3,4-(O-CH2-O)
The last step of our modified pulvinone synthesis consists
of the Claisen condensation between dioxolanones 25a–f
(acetonide esters) and ester enolates lithio-20b–d
(Table 5). The latter were produced by treatment of meth-
yl arylacetates 20b–d with equimolar amounts of lithium
diisopropylamide. For the reason previously discussed
(vide supra), enolates lithio-20b–d were combined with
the acetonide esters 25a–f in a 2.5:1 (8d–g) or 2.6:1 (8h–
s) ratio.33 Assuming a strictly analogous course as for
Ramage et al.’s reaction between (Z)-19 and lithio-20a
(cf. Scheme 3) and like compounds, we relied on the same
temperature profile (–78 °C to room temperature) and a
related workup procedure.22 In accordance with the mech-
anism given in Scheme 3 [lithio-(Z)-19 to (Z)-21a], lac-
tone formation became visible when a yellow precipitate
formed. Recrystallization from methanol (8d–m) or meth-
anol–water (10:1; 8n–s) afforded pulvinones 8d–s in uni-
formly good yields (75–91%).
R2
MeO
O Li
lithio-20b–d (2.5–2.6 equiv)
R1
OH
R2
O
1´
4
5
O
R1
O
O
O
O
25a–f
(Z)-8d–s
R1 key: Table 3
(Z)-8
R1
R2
Yield
(%)
1H NMR
d (H1¢)
d
e
H
4-OMe
90
90
90
91
79
78
80
80
79
81
75
78
80
80
79
82
6.58
6.61
6.52
6.49
6.59
6.52
6.56
6.53
6.76
6.55
6.77
6.53
6.74
6.72
6.70
6.70
Pulvinones 8d–s were obtained as single isomers, as
1
judged by their 300, 400 or 500 MHz H NMR spectra.
4-OH
4-OMe
This was confirmed by single sets of 1H and 13C NMR res-
onances in freshly prepared acetone-d6 solution. Small 1H f34
4-OMe
4-OMe
NMR signals assignable to a single new compound, the
g
3,4,5-(OMe)3
H
4-OMe
respective E-isomer, were observed when 1H NMR spec-
tra of the initial sample solutions were recorded after pro-
longed standing. It is noteworthy that the underlying
dioxolanones 25a–f, irrespective of their E/Z ratio (96:4–
77:23), gave the resulting pulvinones 8d–s as pure Z-iso-
mers (vide infra). This indicates that pulvinone formation
by way of Scheme 3 or Table 5 is stereoconvergent, not
stereospecific.
h
i
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
3,4-(OCH2O)
4-OH
j35
k
l
4-OMe
3,4-(OMe)2
3,4-(OCH2O)
3,4,5-(OMe)3
H
The Z-configuration of the exocyclic C1¢=C5 bond in pul-
vinone 8r was established by measuring the three-bond
coupling between H1¢ and C4. The magnitude of this cou-
pling constant (3.7 Hz; measured by gated-decoupled 13C
NMR spectroscopy) means that the underlying structure
H1¢–C1¢=C5–C4 is U-shaped.32 Plausibly, pulvinones
8d–q,s are also Z-configured.
m
n
o
p
q
r
4-OH
4-OMe
3,4-(OMe)2
3,4-(OCH2O)
3,4,5-(OMe)3
In summary, a reliable route has been established, which
gave pulvinones 8d–s as Z-isomers in two steps from aro-
matic aldehydes, phosphonate 24b, and aryl acetates
lithio-20b–d.36
s
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

PAPER
Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
123
1H NMR (300 MHz, acetone-d6): d = 3.31 (s, 4Ar2-OH), 3.82 (s,
Products were purified by flash chromatography25 on Macherey-
Nagel silica gel 60 (details given in parentheses). 1H NMR [TMS
(0.00 ppm) as internal standard in CDCl3 or acetone-d5 (2.05 ppm)
as internal standard in acetone-d6] and 13C NMR [CDCl3 (77.10
ppm) as internal standard in CDCl3 or acetone-d6 (29.80 ppm) as in-
ternal standard in acetone-d6]: Varian Mercury VX 300 or Bruker
AM 400 or DRX 500. Integrals in accordance with assignments.
The assignments of 1H and 13C NMR resonances refer to the IUPAC
nomenclature (see Figure 1) with primed and multiply primed num-
bers belonging to side chains. NMR: Dr. M. Keller, Institut für Or-
ganische Chemie and Biochemie, Universität Freiburg. Combustion
analyses: E. Hickl, Institut für Organische Chemie and Biochemie,
Universität Freiburg. HRMS (EI, 70 eV): Dr. J. Wörth, Institut für
Organische Chemie and Biochemie, Universität Freiburg. IR spec-
tra: FTIR Perkin-Elmer Spectrum 1000. Melting points: Dr. Tottoli
apparatus (Büchi), uncorrected.
4Ar1-OCH3), 6.61 (s, H1¢), AA¢BB¢ signal centered at 6.90 (H3Ar2
,
H5Ar2) and 7.67 (H2Ar2, H6Ar2), AA¢BB¢ signal centered at 6.97
(H3Ar1, H5Ar1) and 8.05 (H2Ar1, H2Ar1); 4-OH was not detected.
13C NMR (101 MHz, acetone-d6): d = 55.6 (4Ar1-OCH3), 107.8
(C1¢), 114.6, and 116.7 (C3Ar1, C5Ar1, C3Ar2, C5Ar2), 125.8 and 129.4
(C1Ar1, C1Ar2), 123.0 and 133.9 (C2Ar1, C6Ar1, C2Ar2, C6Ar2), 141.5
(C5), 168.7 (C2); C4Ar2, C3, C4, C4Ar1, and C4Ar2 were not detected
due to low signal/noise ratio.
Anal. Calcd for C18H14O5 (310.3): C, 69.22; H, 5.16. Found: C,
68.19; H, 4.92 (no better analysis could be obtained).
(Z)-4-Hydroxy-5-(4-methoxybenzylidene)-3-(4-methoxyphe-
nyl)furan-2(5H)-one [(Z)-8f]34
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.12 mL, 0.086 g, 0.85 mmol, 2.6 equiv), THF (1.0 mL), 1.5
M BuLi in hexane (0.54 mL, 0.81 mmol, 2.5 equiv), ester 20b (0.13
mL, 0.15 g, 0.81 mmol, 2.5 equiv) in THF (1.0 mL), and dioxol-
anone 25c (0.076 g, 0.33 mmol) in THF (2 mL). Yellow crystals
(MeOH); yield: 0.095 g (90%); mp 245–250 °C (Lit.9 250–253 °C).
4´´
R1
5´´
3´´
2´´
5Ar1
R1
6´´
O
6Ar1
4Ar1
OH
1H NMR (300 MHz, acetone-d6): d = 3.81 and 3.84 (2 s, 4Ar1-OCH3,
R2 2Ar2
1´
4Ar2-OCH3), 6.52 (s, H1¢), AA¢BB¢ signal centered at 6.96 (H3Ar2
,
1´
4
4
O
5
3Ar1
3
5
3Ar2
H5Ar2)* and 7.74 (H2Ar2, H6Ar2), AA¢BB¢ signal centered at 6.99
(H3Ar1, H5Ar1)* and 7.98 (H2Ar1, H6Ar1); *assignment interchange-
able.
2
2Ar1
O
2
O
6Ar2
4Ar2
O
5Ar2
(E)-25a–f
(Z)-8d–s
(Z)-4-Hydroxy-3-(4-methoxyphenyl)-5-(3,4,5-trimethoxyben-
zylidene)furan-2(5H)-one [(Z)-8g]
Figure 1
A soln of i-Pr2NH (0.17 mL, 0.12 g, 1.2 mmol, 2.6 equiv) in THF
(2 mL) and 1.5 M BuLi in hexane (0.73 mL, 1.1 mmol, 2.5 equiv)
were combined at –78 °C for 25 min while stirring. Ester 20b (0.18
mL, 0.20 g, 1.1 mmol, 2.5 equiv) in THF (2 mL) was added drop-
wise. After 25 min, dioxolanone 25f (0.133 g, 0.452 mmol) in THF
(2 mL) was added dropwise. The mixture was gradually (3 h)
warmed to r.t. and stirred overnight. Et2O–H2O (1:1, 20 mL) was
added and the organic phase was separated. The aqueous phase was
acidified until with 1 M HCl until pH 1 and then extracted with Et2O
(3 × 15 mL). The combined ethereal phases were dried (MgSO4).
Removal of the solvent in vacuo gave a solid which, after recrystal-
lization (MeOH) provided the title compound as yellow crystals
(MeOH); yield: 0.158 g (91%); mp 180–185 °C.
(Z)-5-(Benzylidene)-4-hydroxy-3-(4-methoxyphenyl)furan-
2(5H)-one [(Z)-8d]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.49 mL, 0.35 g, 3.5 mmol, 2.6 equiv), THF (4 mL), 1.5 M
BuLi in hexane (2.26 mL, 3.39 mmol, 2.5 equiv), ester 20b (0.55
mL, 0.61 g, 3.4 mmol, 2.5 equiv) in THF (4 mL), and dioxolanone
25a (0.277 g, 1.36 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.359 g (90%); mp 219–222 °C.
IR (KBr): 3425, 3055, 3000, 2940, 2835, 1705, 1630, 1610, 1515,
1450, 1425, 1400, 1310, 1290, 1255, 1185, 1155, 1130, 1100, 1035,
1000, 830 cm–1.
1H NMR (300 MHz, acetone-d6): d = 3.84 (s, 4Ar1-OCH3), 6.58 (s,
H1¢), AA¢BB¢ signal centered at 7.01 (H3Ar1, H5Ar1) and 7.92
(H2Ar1, H6Ar1), 7.33–7.39 (m, H4Ar2), 7.43–7.48 (m, H3Ar2, H5Ar2),
7.79–7.82 (m, H2Ar2, H6Ar2); 4-OH was not detected.
IR (CDCl3 soln): 3615, 3155, 2985, 2360, 2335, 2255, 1815, 1795,
1650, 1560, 1540, 1470, 1385, 1170, 1095, 985 cm–1.
1H NMR (300 MHz, acetone-d6): d = 3.78 and 3.84 (2 s, 4Ar1-OCH3,
4Ar2-OCH3), 3.88 (s, twofold intensity; 3Ar2-OCH3, 5Ar2-OCH3),
6.49 (s, H1¢), AA¢BB¢ signal centered at 7.00 (H3Ar1, H5Ar1) and
7.88 (H2Ar1, H6Ar1), 7.13 (s, H2Ar2, H6Ar2); 4-OH was not detected.
13C NMR (126 MHz, acetone-d6): d = 55.6 and 60.7 (4Ar1-OCH3,
4Ar2-OCH3), 56.5 (twofold intensity; 3Ar2-OCH3, 5Ar2-OCH3), 102.8
(C3), 107.7 (C1¢), 108.9 (C2Ar2, C6Ar2), 114.6 (C3Ar1, C5Ar1), 122.8
and 129.4 (C1Ar1, C1Ar2), 130.2 (C2Ar1, C6Ar1), 142.9 (C5), 154.5
(C3Ar2, C5Ar2), 160.1 (C4Ar1), 161.8 (C4), 168.5 (C2); C4Ar2 was not
detected.
13C NMR (126 MHz, acetone-d6): d = 55.6 (4Ar1-OCH3)I, 102.9
(C3)II, 107.3 (C1¢)I, 114.6 (C3Ar1, C5Ar1)I, 122.9 (C1Ar1)III, 129.5
(C4Ar2)I, 129.7 (C3Ar2, C5Ar2)I, 130.1 (C2Ar1, C6Ar1)I, 131.1 (C2Ar2
,
C6Ar2)I, 134.1 (C1Ar2)III, 143.6 (C5)II, 160.1 and 161.9 (C4Ar1, C4),
168.6 (C2)I.
Anal. Calcd for C18H14O4 (294.2): C, 72.96; H, 5.44. Found: C,
73.01; H, 5.28.
(Z)-4-Hydroxy-5-(4-hydroxybenzylidene)-3-(4-methoxyphe-
nyl)furan-2(5H)-one [(Z)-8e]
Anal. Calcd for C21H20O7 (384.4): C, 65.63; H, 5.21. Found: C,
65.43; H, 5.36.
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.62 mL, 0.44 g, 4.4 mmol, 2.6 equiv), THF (4 mL), 1.5 M
BuLi in hexane (2.8 mL, 4.2 mmol, 2.5 equiv), ester 20b (0.68 mL,
0.76 g, 4.2 mmol, 2.5 equiv) in THF (4 mL), and dioxolanone 25b
(0.369 g, 1.68 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.468 g (90%); mp 239–241 °C.
(Z)-5-(Benzylidene)-3-(3,4-dimethoxyphenyl)-4-hydroxyfuran-
2(5H)-one [(Z)-8h]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.13 mL, 0.094 g, 0.93 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.37 mL, 0.93 mmol, 2.5 equiv), ester 20d (0.19
g, 0.93 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25a
(0.075 g, 0.37 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.094 g (79%); mp 190–194 °C.
IR (CDCl3 soln): 3620, 3525, 3395, 3095, 2330, 2265, 2115, 1790,
1760, 1730, 1680, 1610, 1515, 1420, 1290, 1260, 1235, 1170, 1115,
1070, 1030, 1010, 985 cm–1.
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

124
N. Kaczybura, R. Brückner
PAPER
IR (CDCl3 soln): 3515, 3395, 2260, 2225, 1765, 1750, 1720, 1700,
1635, 1515, 1455, 1385, 1300, 1180, 1135, 1095, 1065, 1015, 970
cm–1.
150.0 (presumably C3Ar1 and C4Ar1), 161.2 and 162.0 (C4, C4Ar2),
168.6 (C2).
HRMS: m/z [M+] calcd for C20H18O6: 354.1103; found: 354.1096.
1H NMR (300 MHz, acetone-d6): d = 3.840 and 3.844 (2 s, 3Ar1
-
OCH3, 4Ar1-OCH3), 6.59 (s, H1¢), 7.01 (d, J(H5Ar1,H6Ar1) = 8.4 Hz,
H5Ar1), 7.33–7.38 (m, H4Ar2), 7.43–7.48 (m, H3Ar2, H5Ar2), 7.57 (dd,
J(H6Ar1,H5Ar1) = 8.5 Hz, 4J(H6Ar1,H2Ar1) = 2.1 Hz, H6Ar1), 7.62 (d,
4J(H2Ar1,H6Ar1) = 1.9 Hz, H2Ar1), 7.79–7.82 (m, H2Ar2, H6Ar2); 4-
OH was not detected.
(Z)-5-(3,4-Dimethoxybenzylidene)-3-(3,4-dimethoxyphenyl)-4-
hydroxyfuran-2(5H)-one [(Z)-8k]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20c (0.238
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25d
(0.120 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.138 g (80%); mp 191–193 °C.
13C NMR (75 MHz, acetone-d6): d = 56.1 (3Ar1-OCH3, 4Ar1-OCH3),
103.0 (C3), 107.4 (C1¢), 112.6 and 112.6 (C2Ar1, C5Ar1), 121.8
(C6Ar1), 123.1 (C1Ar1), 129.5 (C4Ar2), 129.6 (twice as intense as pre-
ceding peak, C3Ar2, C5Ar2), 131.0 (twice as intense as preceding
peak, C2Ar2, C6Ar2), 134.1 (C1Ar2), 143.5 (C5), 150.0 and 150.1
(C3Ar1, C4Ar1), 161.3 (C4), 168.5 (C2).
IR (KBr): 3430, 2995, 2940, 2840, 1700, 1630, 1600, 1515, 1465,
1430, 1325, 1260, 1140, 1025 cm–1.
1H NMR (300 MHz, acetone-d6): d = 3.841, 3.844, and 3.869 (3 s,
the low-field signal being twice as intense as each of the high-field
signals, 3Ar1-OCH3, 3Ar2-OCH3, 4Ar1-OCH3, 4Ar2-OCH3), 6.53 (s,
H1¢), 7.01 (d, J(H5Ar1,H6Ar1) = 8.6 Hz, H5Ar1), superimposes in part
7.03 (d, J(H5Ar2,H6Ar2) = 8.6 Hz, H5Ar2), 7.36 (dd,
J(H6Ar2,H5Ar2) = 8.4 Hz, 4J(H6Ar2,H2Ar2) = 1.9 Hz, H6Ar2), 7.46 (d,
4J(H2Ar2,H6Ar2) = 1.7 Hz, H2Ar2), 7.54 (dd, J(H6Ar1,H5Ar1) = 8.6 Hz,
4J(H6Ar1,H2Ar1) = 2.1 Hz, H6Ar1), 7.61 (d, 4J(H2Ar1,H6Ar1) = 2.1 Hz,
H2Ar1).
13C NMR (101 MHz, acetone-d6): d = 56.1 (3Ar1-OCH3, 3Ar2-OCH3,
4Ar1-OCH3, 4Ar2-OCH3), 102.4 (C3), 107.8 (C1¢), 112.7, 112.8,
112.8, and 114.5 (C2Ar1, C5Ar1, C2Ar2, C5Ar2), 121.8 (C6Ar1), 123.5
and 127.0 (C1Ar1, C1Ar2), 125.0 (C6Ar2), 142.0 (C5), 150.0, 150.1,
150.4 and 151.4 (C3Ar1, C4Ar1, C3Ar2, C4Ar2), 162.2 (C4), 168.6
(C2).
HRMS: m/z [M+] calcd for C19H16O5: 324.0998; found: 324.0991.
(Z)-3-(3,4-Dimethoxyphenyl)-4-hydroxy-5-(4-hydroxyben-
zylidene)furan-2(5H)-one [(Z)-8i]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20c (0.238
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25b
(0.100 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.120 g (78%); mp 198 °C.
IR (KBr): 3420, 2360, 2340, 1710, 1605, 1515, 1410, 1275, 1225,
1175, 1125, 1025, 995 cm–1.
1H NMR (400 MHz, acetone-d6): d = 3.83 (s, 3Ar1-OCH3, 4Ar1
OCH3), 6.52 (s, H1¢), AA¢BB¢ signal centered at 6.92 (H3Ar2, H5Ar2
-
)
and 7.68 (H2Ar2, H6Ar2), 7.00 (d, J(H5Ar1,H6Ar1) = 8.5 Hz, H5Ar1),
7.57 (dd, J(H6Ar1,H5Ar1) = 8.4 Hz, 4J(H6Ar1,H2Ar1) = 2.0 Hz, H6Ar1),
7.64 (d, 4J(H2Ar1,H6Ar1) = 1.9 Hz, H2Ar1); 4-OH was not detected.
HRMS: m/z [M+] calcd for C21H20O7: 384.1209; found: 384.1212.
(Z)-3-(3,4-Dimethoxyphenyl)-4-hydroxy-5-[3,4-(methylene-
dioxy)benzylidene]furan-2(5H)-one [(Z)-8l[
13C NMR (101 MHz, acetone-d6): d = 56.10 (3Ar1-OCH3, 4Ar1
-
,
,
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.14 mmol, 2.5 equiv), ester 20c
(0.238 g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone
25e (0.113 g, 0.455 mmol) in THF (2 mL). Yellow crystals
(MeOH); yield: 0.132 g (79%); mp 240–245 °C.
OCH3), 107.6 (C1¢), 112.6 and 112.7 (C2Ar1, C5Ar1), 116.6 (C3Ar2
C5Ar2), 121.5 (C6Ar1), 124.1 and 125.9 (C1Ar1, C1Ar2), 132.9 (C2Ar2
C6Ar2), 141.8 (C5), 149.7 and 150.0 (C3Ar1, C4Ar1), 158.9 (C4Ar2 or
C4); C2, C3, and either C4 or C4Ar2 were not observed due to the
low signal/noise ratio.
HRMS: m/z [M+] calcd for C19H16O6: 340.0947; found: 340.0942.
IR (KBr): 3435, 1700, 1615, 1600, 1515, 1505, 1270, 1245, 1165,
1145, 1095, 1040, 1000 cm–1.
(Z)-3-(3,4-Dimethoxyphenyl)-4-hydroxy-5-(4-methoxyben-
zylidene)furan-2(5H)-one [(Z)-8j]35
1H NMR (300 MHz, acetone-d6): d = 3.836 and 3.840 (2 s, 3Ar1
-
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20c (0.238
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25c
(0.106 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.128 g (80%); mp 190–195 °C.
OCH3, 4Ar1-OCH3), 6.08 (s, OCH2O), 6.76 (s, H1¢), 6.93 (d,
J(H5Ar2,H6Ar2) = 8.2 Hz, H5Ar2), 7.00 (d, J(H5Ar1,H6Ar1) = 8.5 Hz,
H5Ar1), 7.24 (dd, J(H6Ar2,H5Ar2) = 8.1 Hz, 4J(H6Ar2,H2Ar2) = 1.6 Hz,
H6Ar2), 7.42 (d, 4J(H2Ar2,H6Ar2) = 1.5 Hz, H2Ar2), 7.64 (dd,
J(H6Ar1,H5Ar1) = 8.5 Hz, 4J(H6Ar1,H2Ar1) = 2.1 Hz, H6Ar1), 7.71 (d,
4J(H2Ar1,H6Ar1) = 1.9 Hz, H2Ar1); 4-OH was not detected.
IR (CDCl3 soln): 3395, 3005, 2965, 2930, 2360, 2330, 2260, 2115,
1785, 1735, 1695, 1665, 1605, 1515, 1455, 1390, 1345, 1300, 1270,
1220, 980, 955, 890 cm–1.
13C NMR (101 MHz, acetone-d6): d = 56.1 (3Ar1-OCH3, 4Ar1
-
OCH3), 101.4 (C3), 102.5 (OCH2O), 108.1 (C1¢), 109.3, 110.1,
112.5 and 112.6 (C2Ar1, C5Ar1, C2Ar2, C5Ar2), 121.4 (C6Ar1), 124.0
and 128.5 (C1Ar1, C1Ar2), 126.3 (C6Ar2), 142.2 (C5), 149.0, 149.1,
149.6, and 149.9 (C3Ar1, C4Ar1, C3Ar2, C4Ar2), 162.9 (C4), 168.7
(C2).
1H NMR (300 MHz, acetone-d6): d = 3.84 (twice as intensive as the
following peak) and 3.86 (2 s, 3Ar1-OCH3, 4Ar1-OCH3, 4Ar2-OCH3),
6.56 (s, H1¢), 7.01 (d, J(H5Ar1,H6Ar1) = 8.5 Hz, H5Ar1), overlapped
by high-field part of AA¢BB¢ signal centered at 7.02 (H3Ar2, H5Ar2
)
HRMS: m/z [M+] calcd for C20H16O7: 368.0896; found: 368.0892.
and 7.76 (H2Ar2, H6Ar2), 7.55 (dd, J(H6Ar1,H5Ar1) = 8.4 Hz,
4J(H6Ar1,H2Ar1) = 2.1 Hz, H6Ar1), 7.61 (d, 4J(H2Ar1,H6Ar1) = 1.9 Hz,
H2Ar1); 4-OH was not detected.
(Z)-3-(3,4-Dimethoxyphenyl)-4-hydroxy-5-(3,4,5-trimethoxy-
benzylidene)furan-2(5H)-one [(Z)-8m]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20c (0.238
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25f
(0.134 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH);
yield: 0.153 g (81%); mp 210–212 °C.
13C NMR (101 MHz, acetone-d6): d = 55.71 and 56.1 (twice as in-
tense as preceding peak; 3Ar1-OCH3, 4Ar1-OCH3, 4Ar2-OCH3),
102.47 (C3), 107.53 (C1¢), 112.7 and 112.8 (C2Ar1, C5Ar1), 115.3
(twice as intense as preceding peak, C3Ar2, C5Ar2), 121.8 (C6Ar1),
123.5 and 126.7 (C1Ar1, C1Ar2), 132.8 (C2Ar2, C6Ar2), 141.9 (C5),
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

PAPER
Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
125
IR (KBr): 3425, 2940, 1755, 1635, 1580, 1520, 1510, 1465, 1425,
1325, 1260, 1235, 1125, 1030, 975 cm–1.
HRMS: m/z [M+] calcd for C18H12O6: 324.0634; found: 324.0627.
(Z)-4-Hydroxy-5-(4-methoxybenzylidene)-3-[3,4-(methylene-
dioxy)phenyl]furan-2(5H)-one [(Z)-8p]
1H NMR (500 MHz, acetone-d6): d = 3.78, 3.841, 3.844, and 3.88
(last signal twice as intense as preceding 3 signals; 4 s, 3Ar1-OCH3,
3Ar2-OCH3, 4Ar1-OCH3, 4Ar2-OCH3, 5Ar2-OCH3), 6.55 (s, H1¢), 7.01
(d, J(H5Ar1,H6Ar1) = 8.5 Hz, H5Ar1), 7.13 (s, H2Ar2, H6Ar2), 7.52 (dd,
J(H6Ar1,H5Ar1) = 8.5 Hz, 4J(H6Ar1,H2Ar1) = 2.0 Hz, H6Ar1), 7.57 (d,
4J(H2Ar1,H6Ar1) = 2.0 Hz, H2Ar1); 4-OH was not detected.
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20d (0.221
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25c
(0.106 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH–
H2O, 10:1); yield: 0.123 g (80%); mp 235–238 °C.
13C NMR (126 MHz, acetone-d6): d = 56.1 (twice as intense as
d = 60.7), 56.5 (twice as intense as d = 60.7), and 60.7 (3Ar1-OCH3,
3Ar2-OCH3, 4Ar1-OCH3, 4Ar2-OCH3, 5Ar2-OCH3), 102.8 (C3), 107.8
(C1¢), 108.9 (C2Ar2, C6Ar2), 112.6 and 112.7 (C2Ar1, C5Ar1), 121.9
IR (CDCl3 soln): ca. 3560, 3385, 3280, 2615, 2270, 2110, 1780,
1760, 1735, 1700, 1675, 1660, 1650, 1515, 1490, 1445, 1295, 1280,
1200, 1130, 980 cm–1.
(C6Ar1), 123.1 and 129.5 (C1Ar1, C1Ar2), 140.3 and 142.8 (C4Ar2
,
C5), 150.0 and 150.1 (C3Ar1, C4Ar1), 154.5 (twice as intense as pre-
1H NMR (500 MHz, acetone-d6): d = 3.85 (s, 4Ar2-OCH3), 6.02 (s,
ceding signal, C3Ar2, C5Ar2), 162.9 (C4), 168.4 (C2).
OCH2O), 6.74 (s, H1¢), 6.92 (d, J(H5Ar1,H6Ar1) = 8.2 Hz, H5Ar1),
AA¢BB¢ signal centered at 7.02 (H3Ar2, H5Ar2) and 7.75 (H2Ar2
,
HRMS: m/z [M+] calcd C22H22O8: 414.1315; found: 414.1310.
H6Ar2), 7.61 (d, 4J(H2Ar1,H6Ar1) = 1.7 Hz, H2Ar1), 7.63 (dd,
J(H6Ar1,H5Ar1) = 8.2 Hz, 4J(H6Ar1,H2Ar1) = 1.7 Hz, H6Ar1); 4-OH
was not detected.
(Z)-5-(Benzylidene)-4-hydroxy-3-[3,4-(methylenedioxy)phe-
nyl]furan-2(5H)-one [(Z)-8n]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.14 mmol, 2.5 equiv), ester 20d
(0.221 g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone
25a (0.093 g, 0.46 mmol) in THF (2 mL). Yellow crystals (MeOH–
H2O, 10:1); yield: 0.105 g (75%); mp 235–238 °C.
13C NMR (126 MHz, acetone-d6): d = 55.67 (4Ar2-OCH3), 101.0
(C3), 101.9 (OCH2O), 108.3, 108.4, and 108.8 (C1¢, C2Ar1, C5Ar1),
115.2 (C3Ar2, C5Ar2), 122.2 (C6Ar1), 125.2 and 126.8 (C1Ar1, C1Ar2),
132.7 (C2Ar2, C6Ar2), 141.7 (C5), 147.3 and 148.3 (C3Ar1, C4Ar1),
161.0 (C4Ar2), 163.2 (C4), 168.7 (C2).
HRMS: m/z [M+] calcd for C19H14O6: 338.0790; found: 338.0792.
IR (KBr): 3430, 3085, 3015, 2900, 1700, 1625, 1500, 1450, 1400,
1240, 1095, 1040, 1005 cm–1.
(Z)-5-(3,4-Dimethoxybenzylidene)-4-hydroxy-3-[3,4-(methyl-
enedioxy)phenyl]furan-2(5H)-one [(Z)-8q]
1H NMR (400 MHz, acetone-d6): d = 6.03 (s, OCH2O), 6.77 (s,
H1¢), 6.93 (d, J(H5Ar1,H6Ar1) = 8.2 Hz, H5Ar1), 7.35 (incompletely
resolved tt, Jortho = 7.7 Hz, 4Jmeta = 1.9 Hz, H4Ar2), 7.45 (mc, approx-
imately interpretable as dd, Jortho = Jortho = 7.5 Hz, H3Ar2, H5Ar2),
7.61 (d, 4J(H2Ar1,H6Ar1) = 1.3 Hz, H2Ar1), 7.63 (dd,
J(H6Ar1,H5Ar1) = 8.2 Hz, 4J(H6Ar1,H2Ar1) = 1.7 Hz, H6Ar1), 7.80 (mc,
approximately interpretable as br d, Jortho = 7.3 Hz, H2Ar2, H6Ar2); 4-
OH was not detected.
13C NMR (101 MHz, acetone-d6): d = 101.6 (C3), 101.9 (OCH2O),
108.1, 108.5, and 108.9 (C1¢, C2Ar1, C5Ar1), 122.4 (C6Ar1), 125.0
(C1Ar1), 129.3 (half as intense as the next 2 peaks, C4Ar2), 129.6
(C3Ar2, C5Ar2), 131.0 (C2Ar2, C6Ar2), 134.2 (C1Ar2), 143.5 (C5),
147.5 and 148.3 (C3Ar1, C4Ar1), 163.1 (C4), 168.7 (C2).
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.14 mmol, 2.5 equiv), ester 20d
(0.221 g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone
25d (0.120 g, 0.455 mmol) in THF (2 mL). Yellow crystals
(MeOH–H2O, 10:1); yield: 0.134 g (80%); mp 245–250 °C.
IR (KBr): 3435, 1700, 1615, 1600, 1515, 1505, 1460, 1405, 1270,
1245, 1165, 1145, 1095, 1040, 1000 cm–1.
1H NMR (400 MHz, acetone-d6): d = 3.86 and 3.87 (2 s, 3Ar2-OCH3,
4Ar2-OCH3), 6.03 (s, OCH2O), 6.72 (s, H1¢), 6.92 (d,
J(H5Ar1,H6Ar1) = 8.2 Hz, H5Ar1), 7.04 (d, J(H5Ar2,H6Ar2) = 8.3 Hz,
H5Ar2), 7.34 (dd, J(H6Ar2,H5Ar2) = 8.4 Hz, 4J(H6Ar2,H2Ar2) = 1.9 Hz,
H6Ar2), 7.43 (d, 4J(H2Ar2,H6Ar2) = 2.0 Hz, H2Ar2), 7.60 (d,
4J(H2Ar1,H6Ar1) = 1.4 Hz, H2Ar1), 7.62 (dd, J(H6Ar1,H5Ar1) = 8.2 Hz,
4J(H6Ar1,H2Ar1) = 1.7 Hz, H6Ar1); 4-OH was not detected.
HRMS: m/z [M+] calcd for C18H12O5: 308.0685; found 308.0678.
(Z)-4-Hydroxy-5-(4-hydroxybenzylidene)-3-[3,4-(methylene-
dioxy)phenyl]furan-2(5H)-one [(Z)-8o]
13C NMR (101 MHz, acetone-d6): d = 56.0 (3Ar2-OCH3, 4Ar2
-
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.1 mmol, 2.5 equiv), ester 20d (0.221
g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone 25b
(0.100 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH–
H2O, 10:1); yield: 0.120 g (78%), mp 201 °C.
OCH3), 101.1 (C3), 102.4 (OCH2O), 107.9 (C1¢), 109.3, 110.0,
112.2, and 112.5 (C2Ar1, C5Ar1, C2Ar2, C5Ar2), 121.2 (C6Ar1), 123.91
and 128.3 (C1Ar1, C1Ar2), 126.1 (C6Ar2), 142.2 (C5), 148.8, 148.9,
149.4 and 149.7 (C3Ar1, C4Ar1, C3Ar2, C4Ar2), 163.1 (C4), 168.7
(C2).
HRMS: m/z [M+] calcd for C20H16O7: 368.0896; found: 368.0889.
IR (KBr): 3410, 3305, 1710, 1605, 1500, 1440, 1400, 1265, 1240,
1170, 1095, 1040, 1020, 995 cm–1.
(Z)-4-Hydroxy-5-[3,4-(methylenedioxy)benzylidene]-3-[3,4-
(methylenedioxy)phenyl]furan-2(5H)-one [(Z)-8r]
1H NMR (300 MHz, acetone-d6): d = 6.03 (s, OCH2O), 6.53 (s,
H1¢), 6.92 (d, J(H5Ar1,H6Ar1) = 7.8 Hz, H5Ar1), overlaps with high-
field portion of AA¢BB¢ signal centered at 6.93 (H3Ar2, H5Ar2) and
7.69 (H2Ar2, H6Ar2), 7.52 (d, 4J(H2Ar1,H6Ar1) = 1.2 Hz, H2Ar1),
flanked by 7.54 (dd, J(H6Ar1,H5Ar1) = 8.1 Hz, 4J(H6Ar1,H2Ar1) = 1.6
Hz, H6Ar1); 4-OH was not detected.
13C NMR (101 MHz, acetone-d6): d = 100.9 (C3), 101.9 (OCH2O),
108.4, 108.8, and 108.9 (C1¢, C2Ar1, C5Ar1), 116.7 (C3Ar2, C5Ar2),
122.2 (C6Ar1), 125.4 (C1Ar1, C1Ar2), 132.9 (C2Ar2, C6Ar2), 141.1
(C5), 147.3 and 148.3 (C3Ar1, C4Ar1), 159.6 (C4Ar2), 163.2 (C4),
168.8 (C2).
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.14 mmol, 2.5 equiv), ester 20d
(0.221 g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone
25e (0.113 g, 0.455 mmol) in THF (2 mL). Yellow crystals
(MeOH–H2O, 10:1); yield: 0.126 g (79%); mp 250–255 °C.
IR (KBr): 3425, 3085, 3015, 2905, 1695, 1620, 1500, 1490, 1445,
1415, 1315, 1260, 1245, 1110, 1095, 1040 cm–1.
1H NMR (400 MHz, acetone-d6): d = 6.03 and 6.08 (2 s, OCH2OAr1
,
OCH2OAr2), 6.70 (s, H1¢), 6.92 (d, J(H5Ar1,H6Ar1) = 7.7 Hz, H5Ar1)*,
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

126
N. Kaczybura, R. Brückner
PAPER
in part overlapped by 6.94 (d, J(H5Ar2,H6Ar2) = 7.7 Hz, H5Ar2)*,
7.23 (dd, J(H6Ar2,H5Ar2) = 8.2 Hz, 4J(H6Ar2,H2Ar2) = 1.7 Hz, H6Ar2),
7.41 (d, 4J(H2Ar2,H6Ar2) = 1.7 Hz, H2Ar2), 7.59 (d,
4J(H2Ar1,H6Ar1) = 1.7 Hz, H2Ar1), 7.61 (dd, J(H6Ar1,H5Ar1) = 7.7 Hz,
4J(H6Ar1,H2Ar1) = 1.7 Hz, H6Ar1); 4-OH was not detected; *assign-
ments interchangeable.
the organic phase first extracted with H2O (3 × 50 mL) and then
dried (Na2SO4). Evaporation of the solvent in vacuo and purifica-
tion of the non-volatile residue by flash chromatography (silica gel,
column diameter 12 cm, cyclohexane–EtOAc, 3:1) yielded 24b
(38.6 g, 80%).
IR (CDCl3 soln): 2965, 2940, 2910, 2875, 1805, 1465, 1435, 1390,
1260, 1125, 1030, 960 cm–1.
13C NMR (101 MHz, acetone-d6): d = 100.9 (C3), 101.8 and 102.4
(OCH2OAr1, OCH2OAr2), 108.2, 108.3, 108.8, 109.3, and 110.0 (C1¢,
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J(H4¢,H3¢) = 7.4 Hz, 2 ×
3 H4¢), 1.42 (qt, J(H3¢,H2¢) = J(H3¢,H4¢) = 7.3 Hz, 2 × 2 H3¢), 1.58
and 1.72 [2 s, 2-(CH3)2], the last signal superimposes in part 1.70 (br
tt, J(H2¢,H1¢) = J(H2¢,H3¢) = 7.0 Hz, 2 × 2 H2¢), 4.19 (mc, 2 × 2
H1¢), 4.69 (d, 2J(H4,P) = 11.0 Hz, H4).
C2Ar1, C5Ar1, C2Ar2, C5Ar2), 122.1 (C6Ar1), 125.0 and 128.2 (C1Ar1
,
C1Ar1), 126.2 (C6Ar2), 142.0 (C5), 147.2, 148.2, 148.9, and 148.9
(C3Ar1, C4Ar1, C3Ar2, C4Ar2), 163.2 (C4), 168.5 (C2).
Selected signal from gated-decoupled (126 MHz, acetone-d6):
d = 163.23 (d, 3JC4,H1¢ = 3.7 Hz, C4; proof of origin of this doublet
splitting: selective irradiation of dH1¢ = 6.70 makes resonance at
13C NMR (126 MHz, CDCl3): d = 13.6 (2 × C4¢), 18.6 (2 × C3¢),
26.5 and 26.9 [2-(CH3)2], 32.5 and 32.5 (2 d, 3J(C2¢,P) = 5.4 Hz, 2
dC4 = 163.2 collapse into s).
2
× C2¢), 67.7 and 67.9 (2 d, J(C1¢,P) = 7.0 Hz, 2 × C1¢), 71.3 (d,
3
Anal. Calcd for C19H12O7 (352.1): C, 64.78; H, 3.43. Found: C,
64.51; H, 3.52.
1J(C4,P) = 169.5 Hz, C4), 113.2 (d, J(C2,P) = 5.4 Hz, C2), 167.2
(C5).
Anal. Calcd for C13H25O6P (308.3): C, 50.65; H, 8.12. Found: C,
50.75; H, 8.11.
(Z)-4-Hydroxy-3-[3,4-(methylenedioxy)phenyl]-5-(3,4,5-tri-
methoxybenzylidene)furan-2(5H)-one [(Z)-8s]
Prepared analogously as described for pulvinone (Z)-8g from i-
Pr2NH (0.16 mL, 0.12 g, 1.1 mmol, 2.5 equiv), THF (1.0 mL), 2.5
M BuLi in hexane (0.45 mL, 1.14 mmol, 2.5 equiv), ester 20d
(0.221 g, 1.14 mmol, 2.5 equiv) in THF (1.0 mL), and dioxolanone
25f (0.134 g, 0.455 mmol) in THF (2 mL). Yellow crystals (MeOH–
H2O, 10:1); yield: 0.148 g (82%); mp 210–212 °C.
2-(Diisopropoxyphosphoryl)-2-hydroxyacetic Acid (23c)
A mixture of dihydroxyacetic acid 22 (1.25 g, 13.6 mmol) and di-
isopropyl phosphite (2.26 mL, 2.26 g, 13.6 mmol, 1.0 equiv) was
stirred at 60 °C for 5 h. The resulting product (23c, 3.1 g, 95%) was
not purified but directly converted into dioxolanone 24c.
1H NMR (300 MHz, CDCl3): d = 1.37 (d, J(H2¢,H1¢) = 6.0 Hz, 4 ×
IR (KBr): 3435, 3005, 2945, 1710, 1635, 1620, 1580, 1505, 1455,
1425, 1400, 1335, 1295, 1250, 1235, 1155, 1135, 1040, 995 cm–1.
2
3 H2¢), 4.51 (d, J(H2,P) = 16.3 Hz, H2), 4.83 (sept, J(H1¢,H2¢) =
6.4 Hz, 2 × H1¢), 5.50 (br s, 1-OH, 2-OH).
1H NMR (400 MHz, acetone-d6): d = 3.78 (s, 4Ar2-OCH3), 3.88 (s,
twofold intensity, 3Ar2-OCH3, 5Ar2-OCH3), 6.03 (s, OCH2O), 6.70
4-(Diisopropoxyphosphoryl)-2,2-dimethyl-1,3-dioxolan-5-one
(24c)
A soln of crude hydroxy acid 23c (3.50 g, 14.7 mmol) and 2,2-
dimethoxypropane (2.74 mL, 2.28 g, 21.9 mmol, 1.5 equiv) in tolu-
ene (60 mL) was treated as described for the conversion 23b into
24b until the title compound was obtained (3.3 g, 80%) as a color-
less oil.
1H NMR (300 MHz, CDCl3): d = 1.37 and 1.39 (2 d,
J(H2¢,H1¢) = 6.0 Hz, 4 × 3 H2¢), 1.57 and 1.72 [2 s, 2-(CH3)2], 4.62
(d, 2J(H4,P) = 11.0 Hz, H4), 4.79–4.91 (mC, 2 × H1¢).
(s, H1¢), 6.93 (d, J(H5Ar1,H6Ar1) = 8.2 Hz, H5Ar1), 7.11 (s, H2Ar2
,
H6Ar2), 7.59 (d, 4J(H2Ar1,H6Ar1) = 1.7 Hz, H2Ar1), 7.61 (dd,
J(H6Ar1,H5Ar1) = 8.2 Hz, 4J(H6Ar1,H2Ar1) = 1.7 Hz, H6Ar1); 4-OH
was not detected.
13C NMR5 (101 MHz, acetone-d6): d = 56.48 (twofold intensity,
3Ar2-OCH3, 5Ar2-OCH3), 60.6 (4Ar2-OCH3), 101.3 (C3), 101.9
(OCH2O), 108.4, 108.5, and 108.8 (C1¢, C2Ar1, C5Ar1, C2Ar2, C6Ar2),
122.3 (C6Ar1), 124.9 and 129.5 (C1Ar1, C1Ar2), 140.1 (C4Ar2), 142.7
(C5), 147.4 and 148.3 (C3Ar1, C4Ar1), 154.3 (C3Ar2, C5Ar2), 163.1
(C4), 168.5 (C2).
13C NMR (126 MHz, CDCl3): d = 23.8 (d, 3J(C2¢,P) = 2.4 Hz, C2¢),
23.9 (d, 3J(C2¢,P) = 3.0 Hz, C2¢), 24.2 (d, 3J(C2¢,P) = 2.1 Hz, C2¢),
24.2 (d, 3J(C2¢,P) = 2.7 Hz, C2¢), 26.6 [d, 4J(2-CH3,P) = 1.5 Hz, 2-
2-(Dibutoxyphosphoryl)-2-hydroxyacetic Acid (23b)
A mixture of dihydroxyacetic acid 22 (10.6 g, 113 mmol) and dibu-
tyl phosphite (22.1 mL, 20.9 g, 113 mmol, 1.0 equiv) was stirred at
50 °C for 5 h. The resulting product (23b, 28.9 g, 95%) was not pu-
rified but directly converted into dioxolanone 24b.
1
(CH3)1], 26.9 [2-(CH3)2], 71.7 (d, J(C4,P) = 170.5 Hz, C4), 73.1
and 73.2 (2 d, 2J(C1¢,P) = 7.0 Hz, 2 × C1¢), 112.9 (d, 3J(C2,P) = 5.4
Hz, C2), 167.3 (C5).
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J(H4¢,H3¢) = 7.4 Hz, 2 ×
3 H4¢), 1.42 (qt, J(H3¢,H2¢) = J(H3¢,H4¢) = 7.6 Hz, 2 × 2 H3¢), 1.68
(br tt, J(H2¢,H1¢) = J(H2¢,H3¢) = 6.6 Hz, 2 × 2 H2¢), 4.20 (mc, 2 × 2
H1¢), 4.58 (d, 2J(H2,P) = 16.3 Hz, H2), 5.50 (br s, 1-OH, 2-OH).
(E)-5-Benzylidene-2,2-dimethyl-1,3-dioxolan-4-one [(E)-25a]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and benzaldehyde (0.19 mL, 0.20
g, 1.8 mmol, 1.1 equiv). Flash chromatography (4 cm, cyclohex-
ane–EtOAc, 5:1) provided the title compound as an oil; yield: 0.27
g (80%); ratio E/Z 95:5.
4-(Dibutoxyphosphoryl)-2,2-dimethyl-1,3-dioxolan-5-one (24b)
Method A: A soln of crude hydroxy acid 23b (3.77 g, 14.1 mmol)
and 2,2-dimethoxypropane (2.64 mL, 2.19 g, 21.1 mmol, 1.5 equiv)
in toluene (60 mL) was heated in an inverse H2O-separator at reflux
for 12 h. The solvent was removed under reduced pressure and the
residue purified by flash chromatography (silica gel, column diam-
eter 6 cm, cyclohexane–EtOAc, 3:1). This provided 24b (3.46 g,
80%) as a colorless oil.
IR (CDCl3 soln): 3000, 2940, 1780, 1650, 1495, 1455, 1390, 1365,
1225, 1180, 1045, 995, 935, 920, 905, 880 cm–1.
1H NMR (300 MHz, CDCl3):
(E)-25a: d = 1.67 [s, 2-(CH3)2], 6.51 (s, H1¢), 7.28–7.38 (m, H3¢¢,
H4¢¢, H5¢¢), 7.71–7.74 (m, H2¢¢, H6¢¢).
Method B: At r.t., BF3·OEt2 (34.6 mL, 38.9 g, 274 mmol, 1.75
equiv) was added dropwise to a soln of crude hydroxy acid 23b
(42.0 g, 157 mmol) in Et2O (70 mL) and acetone (11.8 mL, 9.11 g,
157 mmol, 1.0 equiv) and stirring continued overnight. Sat. aq
NaHCO3 (50 mL) was added. The aqueous phase was discarded and
(Z)-25a: d = 1.73 [s, 2-(CH3)2], 6.47 (s, H1¢), 7.66–7.69 (m, H2¢¢,
H6¢¢); the remaining Ar-H were not identified unequivocally.
13C NMR (126 MHz, CDCl3):
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

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Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
127
(E)-25a: d = 26.9 [2-(CH3)2], 110.4 (C2), 115.1 (C1¢), 128.3 (C3¢¢,
C5¢¢), 128.4 (C4¢¢), 129.9 (C2¢¢, C6¢¢), 132.0 (C1¢¢), 138.0 (C5),
161.5 (C4).
13C NMR (101 MHz, CDCl3):
(E)-25c: d = 26.8 [2-(CH3)2], 55.4 (4¢¢-OCH3), 110.2 (C2), 113.8
(C3¢¢, C5¢¢), 115.4 (C1¢), 124.7 (C1¢¢), 131.6 (C2¢¢, C6¢¢), 136.7 (C5),
159.8 (C4¢¢), 161.9 (C4).
(Z)-25a: d = 27.0 [2-(CH3)2], 108.4 (C1¢), 128.6 (C4¢¢), 128.7 (C3¢¢,
C5¢¢), 129.6 (C2¢¢, C6¢¢); the resonances of C2, C4, C5, and C1¢¢
were not detected.
(Z)-25c: d = 27.1 [2-(CH3)2], 114.3 (C3¢¢, C5¢¢), 131.2 (C2¢¢, C6¢¢);
the other 13C nuclei were not detected.
Anal. Calcd for C12H12O3 (204.2): C, 70.59; H, 5.88. Found: C,
70.34; H, 6.07.
Selected signals from gated-decoupled 13C NMR (126 MHz,
3
CDCl3): d = 161.9 (d, J(C4,H1¢) = 10.1 Hz, C4(E)-25c), 164.2 (d,
3J(C4,H1¢) = 3.7 Hz, C4(Z)-25c).
(E)-5-(4-Hydroxybenzylidene)-2,2-dimethyl-1,3-dioxolan-4-one
[(E)-25b]
Anal. Calcd for C13H14O4 (234.3): C, 66.67; H, 5.98. Found: C,
66.59; H, 5.75.
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and 4-hydroxybenzaldehyde
(0.223 g, 1.83 mmol, 1.1 equiv). Flash chromatography (4 cm, cy-
clohexane–EtOAc 5:1) provided the title compound as a solid;
yield: 0.288 g (79%); ratio E/Z 87:13.
(E)-5-(3,4-Dimethoxybenzylidene)-2,2-dimethyl-1,3-dioxolan-
4-one [(E)-25d]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.512 g, 1.66 mmol), and 3,4-dimethoxybenzaldehyde
(0.304 g, 1.83 mmol, 1.1 equiv). Flash chromatography (4 cm, cy-
clohexane–EtOAc, 5:1) provided the title compound as an oil;
yield: 0.35 g (80%); ratio E/Z 87:13.
IR (film): 3400, 3000, 2940, 1760, 1610, 1540, 1515, 1440, 1390,
1380, 1365, ca. 1280, 1180, 1055, 1000, 920, 880, 830, 765 cm–1.
1H NMR (300 MHz, CDCl3):
(E)-25b: d = 1.65 [s, 2-(CH3)2], 4.79 (s, OH), 6.44 (s, H1¢), AA¢BB¢
signal centered at 6.81 (H3¢¢, H5¢¢) and 7.69 (H2¢¢, H6¢¢).
IR (film): 3095, 3005, 2940, 2840, 1770, 1595, 1515, 1465, 1390,
1375, 1330, 1270, 1215, 1180, 1140, 1025, 910, 900, 800 cm–1.
1H NMR (500 MHz, CDCl3):
(Z)-25b: d = 1.72 [s, 2-(CH3)2], 4.82 (s, OH), 6.42 (s, H1¢), AA¢BB¢
signal centered at ca. 6.85 (partly superimposed by E-isomer; H3¢¢,
H5¢¢) and 7.58 (H2¢¢, H6¢¢).
13C NMR (126 MHz, CDCl3):
(E)-25d: d = 1.66 [s, 2-(CH3)2], 3.90 and 3.93 (2 s, 3¢¢-OCH3, 4¢¢-
OCH3), 6.45 (s, H1¢), 6.83 (d, J(H5¢¢,H6¢¢) = 8.4 Hz, H5¢¢), 7.13 (dd,
J(H6¢¢,H5¢¢) = 8.4 Hz, 4J(H6¢¢,H2¢¢) = 2.0 Hz, H6¢¢), 7.83 (d,
4J(H2¢¢,H6¢¢) = 2.0 Hz, H2¢¢).
(E)-25b: d = 26.8 [2-(CH3)2], 110.5 (C2), 115.4 (C3¢¢, C5¢¢), 115.7
(C1¢)*, 124.6 (C1¢¢), 131.8 (C2¢¢, C6¢¢), 136.6 (C5), 156.2 (C4¢¢),
162.3 (C4); *interchangeable with C3¢¢/C5¢¢ of (Z)-25b.
(Z)-25d: d = 1.72 [s, 2-(CH3)2], 3.908 and 3.913 (2 s, 3¢¢-OCH3, 4¢¢-
OCH3), 6.43 (s, H1¢), 6.89 (d, J(H5¢¢,H6¢¢) = 8.4 Hz, H5¢¢), 7.23 (d,
4J(H2¢¢,H6¢¢) = 2.0 Hz, H2¢¢), ca. 7.27 (dd, J(H6¢¢,H5¢¢) = 9.3 Hz,
4J(H6¢¢,H2¢¢) = 2.7 Hz, H6¢¢).
(Z)-25b: d = 27.0 [2-(CH3)2], 108.7 (C1¢), 111.9 (C2), 115.8 (C3¢¢,
C5¢¢)*, 125.8 (C1¢¢), 131.5 (C2¢¢, C6¢¢), 135.6 (C5); signals of C4
and C4¢¢ not detected; *interchangeable with C1¢ of (E)-25b.
13C NMR (126 MHz, CDCl3, slightly contaminated):
Selected signals from gated-decoupled 13C NMR (126 MHz,
(E)-25d: d = 26.8 [2-(CH3)2], 55.9 and 56.0 (3¢¢-OCH3, 4¢¢-OCH3),
110.4 (C2), 110.7 (C5¢¢), 112.6 (C2¢¢), 116.0 (C1¢), 123.8 (C6¢¢),
125.2 (C1¢¢), 136.7 (C5), 148.6 and 149.5 (C3¢¢, C4¢¢), 162.0 (C4).
3
CDCl3): d = 162.4 (d, J(C4,H1¢) = 10.1 Hz, C4(E)-25b), 164.6 (d,
3J(C4,H1¢) = 3.7 Hz, C4(Z)-25b).
Anal. Calcd for C12H12O4 (220.2): C, 65.45; H, 5.45. Found: C,
65.39; H, 6.08.
(Z)-25d: d = 27.1 [2-(CH3)2], 108.8 (C1¢), 111.3 (C5¢¢), 112.5
(C2¢¢), 123.3 (C6¢¢), 126.0 (C1¢¢), 135.8 (C5), 149.0 and 149.7 (C3¢¢,
C4¢¢); the resonances of C2 and C4 were not identified.
(E)-5-(4-Methoxybenzylidene)-2,2-dimethyl-1,3-dioxolan-4-one
[(E)-25c]
HRMS: m/z [M+] calcd for C14H16O5: 264.0998; found: 264.0991.
At –78 °C 2.5 M BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv) was
added dropwise to a soln of i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol,
1.5 equiv) in THF (1.0 mL) and DMPU (0.2 mL). Stirring at that
temperature was continued for 1 h. A soln of dioxolanone 24b
(0.512 g, 1.66 mmol) in THF (1.0 mL) and DMPU (0.2 mL) was
added, followed 25 min later by 4-methoxybenzaldehyde (0.24 mL,
0.24 g, 1.8 mmol, 1.1 equiv) in THF (1.0 mL). After stirring at –
78 °C overnight, sat. aq. NH4Cl (5 mL) was added. The phases were
separated. The aqueous phase was extracted with EtOAc (3 × 5
mL). The combined organic phases were dried (Na2SO4) and then
evaporated in vacuo. Purification of the residue by flash chromatog-
raphy (column diameter 3 cm, cyclohexane–EtOAc, 5:1) furnished
the title compound as an oil; yield: 0.341g (88%); ratio E/Z 95:5.
(E)-2,2-Dimethyl-5-[3,4-(methylenedioxy)benzylidene]-1,3-di-
oxolan-4-one [(E)-25e]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and 3,4-(methylenedioxy)benzal-
dehyde (0.274 g, 1.83 mmol, 1.1 equiv). Flash chromatography (4
cm, cyclohexane–EtOAc, 5:1) provided the title compound as a sol-
id; yield: 0.33 g (80%); ratio E/Z 89:11.
IR (film): 3000, 2945, 2900, 1770, 1690, 1605, 1495, 1450, 1385,
1340, ca. 1255, 1180, 1110, 1040, 1000, 930, 810, 760 cm–1.
1H NMR (300 MHz, CDCl3):
IR (film): 2995, 2940, 2840, 1780, 1605, 1515, 1460, 1305, 1220,
1175, 1035, 995, 920, 905, 830, 765 cm–1.
1H NMR (300 MHz, CDCl3):
(E)-25e: d = 1.65 [s, 2-(CH3)2], 5.97 (s, OCH2O), 6.41 (s, H1¢), 6.77
(d, J(H5¢¢,H6¢¢) = 8.2 Hz, H5¢¢), 7.10 (dd, J(H6¢¢,H5¢¢) = 8.2 Hz,
4J(H6¢¢,H2¢¢) = 1.3 Hz, H6¢¢), 7.55 (d, 4J(H2¢¢,H6¢¢) = 1.8 Hz, H2¢¢).
(Z)-25e: d = 1.71 [s, 2-(CH3)2], 5.99 (s, OCH2O), 6.39 (s, H1¢), 6.82
(d, J(H5¢¢,H6¢¢) = 8.1 Hz, H5¢¢), ca. 7.11 (dd, not entirely separated
from the H6¢¢ signal of (E)-25e ⇒ J(H6¢¢,H5¢¢) invisible,
4J(H2¢¢,H6¢¢) = 1.9 Hz, H6¢¢), 7.29 (d, 4J(H2¢¢,H6¢¢) = 1.6 Hz, H2¢¢).
(E)-25c: d = 1.65 [s, 2-(CH3)2], 3.82 (s, 4¢¢-OCH3), 6.46 (s, H1¢),
AA¢BB¢ signal centered at 6.88 (H3¢¢, H5¢¢) and 7.73 (H2¢¢, H6¢¢).
(Z)-25c: d = 1.71 [s, 2-(CH3)2], 3.83 (s, 4¢¢-OCH3), 6.43 (s, H1¢),
AA¢BB¢ signal centered at ca. 6.91 (H3¢¢, H5¢¢) and 7.62 (H2¢¢, H6¢¢).
13C NMR (75 MHz, CDCl3):
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

128
N. Kaczybura, R. Brückner
PAPER
(E)-25e: d = 26.8 [2-(CH3)2], 101.3 (OCH2O), 108.2 and 109.9
(C2¢¢, C5¢¢), 110.4 (C2), 115.6 (C1¢), 125.0 (C6¢¢), 126.2 (C1¢¢),
136.9 (C5), 147.7 and 147.9 (C3¢¢, C4¢¢), 161.7 (C4).
(E)-5-(Cyclohexylmethylene)-2,2-dimethyl-1,3-dioxolan-4-one
[(E)-25h]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and cyclohexanecarbaldehyde
(0.22 mL, 0.21 g, 1.8 mmol, 1.1 equiv). Flash chromatography (4
cm, petroleum ether–acetone, 4:1) provided the title compound as a
solid; yield: 0.29 g (82%); pure (E) isomer.
(Z)-25e: d = 27.0 [2-(CH3)2], 101.4 (OCH2O), 108.6, 108.7 and
109.2 (C1¢, C2¢¢, C5¢¢), 111.8 (C2), 124.8 (C6¢¢), 127.3 (C1¢¢); sig-
nals of C4, C5, C3¢¢, and C4¢¢ not detected.
HRMS: m/z [M+] calcd for C13H12O5: 248.0685; found: 248.0679.
(E)-2,2-Dimethyl-5-(3,4,5-trimethoxybenzylidene)-1,3-diox-
olan-4-one [(E)-25f]
IR (KBr): 2935, 2850, 2360, 2330, 1785, 1735, 1720, 1680, 1445,
1380, 1345, 1300, 1230, 1185, 1145, 995, 915 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03–1.45 (m, H2 × 2 H2¢¢, H2 ×
2 H3¢¢), 1.59 [s, 2-(CH3)2], 1.68–1.95 (m, 2 H4¢¢), 3.16 (tdt,
J(H1¢¢,H2¢¢ax) = 11.0 Hz, J(H1¢¢,H1¢) = 10.9 Hz, J(H1¢¢,H2¢¢eq) = 3.3
Hz, H1¢¢), 5.38 (d, J(H1¢,H1¢¢) = 10.5 Hz, H1¢).
13C NMR (101 MHz, CDCl3; contaminated with cyclohexanecarb-
aldehyde): d = 25.6 (twice as intense as the following peak, 2 ×
C3¢¢), 25.9 (C4¢¢), 26.7 [2-(CH3)2], 33.3 (C1¢¢), 33.6 (twice as in-
tense as the preceding peak, 2 × C2¢¢), 110.0 (C2), 121.1 (C1¢),
136.4 (C5), 162.5 (C4).
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.6 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and 3,4,5-trimethoxybenzalde-
hyde (0.359 g, 1.83 mmol, 1.1 equiv). Flash chromatography (4 cm,
cyclohexane–EtOAc, 3:1) provided the title compound as a solid;
yield: 0.41g (84%); ratio E/Z 90:10.
IR (film): 3060, 3000, 2965, 1775, 1585, 1460, 1330, 1265, 1225,
1200, 1135, 1000, 740, 705 cm–1.
1H NMR (300 MHz, CDCl3):
Selected signal from gated-decoupled 13C NMR (126 MHz,
(E)-25f: d = 1.67 [s, 2-(CH3)2], 3.87 (s, 4¢¢-OCH3), 3.88 (s, twofold
intensity; 3¢¢-OCH3, 5¢¢-OCH3), 6.42 (s, H1¢), 7.14 (s, H2¢¢, H6¢¢).
CDCl3): d = 162.6 (d, 3J(C4,H1¢) = 10.5 Hz, C4(E)-25h).
HRMS: m/z [M+] calcd for C12H18O3: 210.1256; found: 210.1255.
(Z)-25f: d = 1.73 [s, 2-(CH3)2], 6.39 (s, H1¢), 6.93 (s, H2¢¢, H6¢¢).
13C NMR (101 MHz, CDCl3):
(E)-2,2-Dimethyl-5-nonylidene-1,3-dioxolan-4-one [(E)-25i]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and nonanal (0.31 mL, 0.26 g, 1.8
mmol, 1.1 equiv). Flash chromatography (4 cm, petroleum ether–
acetone, 4:1) provided the title compound as a solid; yield: 0.37 g
(92%); ratio E/Z 96:4.
(E)-25f: d = 26.8 [2-(CH3)2], 56.3 (twice as intense as the following
peak, 3¢¢-OCH3, 5¢¢-OCH3), 61.0 (half as intense as the preceding
peak, 4¢¢-OCH3), 107.6 (C2¢¢, C6¢¢), 110.5 (C2), 115.8 (C1¢), 127.5
(C1¢¢), 137.7 (C4¢¢), 138.6 (C5), 152.9 (C3¢¢, C5¢¢), 161.8 (C4).
(Z)-25f: d = 27.1 [2-(CH3)2], 107.3 (C2¢¢, C6¢¢), 108.7 (C1¢), 128.5
(C1¢¢), 153.4 (C3¢¢, C5¢¢); the other 13C nuclei were not detected.
Selected signals from gated-decoupled 13C NM (126 MHz, CDCl3):
d = 161.8 (d, 3J(C4,H1¢) = 10.1 Hz, C4(E)-25f), 163.8 (d,
3J(C4,H1¢) = 3.7 Hz, C4(Z)-25f).
IR (film): 2925, 2855, 2360, 2335, 1790, 1735, 1695, 1680, 1650,
1460, 1385, 1355, 1320, 1225, 1130, 1025, 995 cm–1.
1H NMR (400 MHz, CDCl3):
Anal. Calcd for C15H18O6 (294.3): C, 61.22; H, 6.12. Found: C,
61.02; H, 6.11.
(E)-25i: d = 0.88 (t, J(H9¢,H8¢) = 7.0 Hz, 3 H9¢), 1.27–1.43 (m, 2
H3¢, 2 H4¢, 2 H5¢, 2 H6¢, 2 H7¢, 2 H8¢), 1.59 [s, 2-(CH3)2], 2.55 (dt,
J(H2¢,H1¢) = 7.8 Hz*, J(H2¢,H3¢) = 7.7 Hz*, 2 H2¢), 5.52 (t,
J(H1¢,H2¢) = 8.4 Hz, H1¢); *interchangeable.
(E)-5-(2-Methylpropylidene)-2,2-dimethyl-1,3-dioxolan-4-one
[(E)-25g]
Prepared analogously as described for benzylidenedioxolanone (Z)-
25c from i-Pr2NH (0.35 mL, 0.26 g, 2.5 mmol, 1.5 equiv), 2.5 M
BuLi in hexane (1.0 mL, 2.5 mmol, 1.5 equiv), phosphoryldioxol-
anone 24b (0.511 g, 1.66 mmol), and isobutyraldehyde (0.17 mL,
0.135 g, 1.8 mmol, 1.1 equiv). Flash chromatography (4 cm, petro-
leum ether–acetone, 4:1) provided the title compound as an oil;
yield: 0.27 g (96%); ratio E/Z 95:5.
(Z)-25i: d = 1.62 [s, 2-(CH3)2], 5.61 (t, JH1¢,H2¢ = 7.8 Hz, H1¢).
13C NMR (101 MHz, CDCl3; contaminated with nonanal):
(E)-25i: d = 14.2 (C9¢), 22.7 and 24.4 (C7¢, C8¢), 26.7 [2-(CH3)2],
29.2, 29.3, 29.5, and 29.9 (C3¢, C4¢, C5¢, C6¢), 31.9 (C2¢), 109.9
(C2), 115.6 (C1¢), 137.5 (C5), 162.6 (C4).
HRMS: m/z [M+] calcd for C14H24O3: 240.1725; found: 240.1724.
1H NMR (400 MHz, CDCl3):
(E)-25g: d = 1.03 (d, J(H3¢,H2¢) or J(2¢-CH3,H2¢) = 6.6 Hz, 2¢-CH3,
3 H3¢), 1.59 [s, 2-(CH3)2], 3.48–3.53 (mC, H2¢), 5.36 (d,
J(H1¢,H2¢) = 10.4 Hz, H1¢).
Acknowledgment
We thank the Fonds der Chemischen Industrie for continuous finan-
cial support.
(Z)-25g: d = 1.07 (d, J(H3¢,H2¢) or J(2¢-CH3,H2¢) = 6.6 Hz, 2¢-CH3,
3 H3¢), 1.62 [s, 2-(CH3)2], 5.51 (d, J(H1¢,H2¢) = 9.1 Hz, H1¢).
13C NMR (101 MHz, CDCl3):
References
(E)-25g: d = 23.4 (twice as intense as the following peak, 2¢-CH3, 3
H3¢), 24.1 (C2¢), 26.7 [2-(CH3)2], 110.0 (C2), 122.4 (C1¢), 136.2
(C5), 162.6 (C4).
(Z)-25g: d = 26.8 [2-(CH3)2]; the other 13C nuclei were not detected.
HRMS: m/z [M+] calcd for C9H14O3: 170.0943; found: 170.09441.
(1) Reviews: (a) Rao, Y. S. Chem. Rev. 1976, 76, 625.
(b) Pattenden, G. Prog. Chem. Nat. Prod. 1978, 35, 133.
(2) Reviews: (a) Knight, D. W. Contemp. Org. Synth. 1994, 1,
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Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

PAPER
Tandem Claisen Condensation/Transesterification between Enolates and 1,3-Dioxolan-4-ones
129
(3) Review: (a) Tejedor, C.; Garcia-Tellado, F. Org. Prep.
Proced. Int. 2004, 36, 33. For recent syntheses of tetronic
(ethoxycarbonyl)methyl phenylacetate followed by O-
methylation.9
(17) Antane, S.; Caufield, C. E.; Hu, W.; Keeney, D.;
acids using Dieckmann condensations, see: (b) Sodeoka,
M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.; Ueda, K.;
Osada, H. J. Med. Chem. 2001, 44, 3216. (c) Mitsos, C. A.;
Zografos, A. L.; Igglessi-Markopoulou, O. J. Org. Chem.
2000, 65, 5852. For a recent synthesis of tetronic acids by
cyclization of g-bromo-b-oxocarboxylic acids, see:
(d) Tabake, K.; Mase, N.; Nomoto, M.; Daicho, M.; Tauchi,
T.; Yoda, H. J. Chem. Soc., Perkin Trans. 1 2002, 500. For
a recent synthesis of tetronic acids by acid-treatment of the
2:1-adducts formed from aldehydes and methyl propiolate,
see: (e) Aragón, D. T.; López, G. V.; Garcia-Tellado, F.;
Marrero-Tellado, J. J.; de Armas, P.; Terrero, D. J. Org.
Chem. 2003, 68, 3363. For a recent synthesis of tetronic
acids by lactonization of g-hydroxy-b-oxo esters resulting
from the [2,3]-Wittig rearrangement of g-(allyloxy)-b-oxo
esters, see: (f) Pévet, I.; Meyer, C.; Cossy, J. Tetrahedron
Lett. 2001, 42, 5215. For a recent synthesis of tetronic acids
by the oxidation of b-hydroxy-g-butyrolactones, see:
(g) Kapferer, T.; Brückner, R.; Herzig, A.; König, W. A.
Chem. Eur. J. 2005, 11, 2154.
Labthavikul, P.; Morris, K.; Naughton, S. M.; Petersen, P. J.;
Rasmussen, B. A.; Singh, G.; Yang, Y. Bioorg. Med. Chem.
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(18) Reffstrup, J.; Boll, P. M. Phytochemistry 1979, 18, 325.
(19) Caufield, C. E.; Antane, S. A.; Morris, K. M.; Naughton, S.
M.; Quagliato, D. A.; Andrae, P. M.; Enos, A.; Chiarello, J.
F. WO 2005/019196, 2005.
(20) Ramage, R.; Griffiths, G. J.; Shutt, F. E.; Sweeney, J. N. A.
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J. Chem. Soc., Perkin Trans. 1 1984, 1539.
(22) Each of Ramage et al.’s three pulvinones emerged from a
slightly different protocol:21 (Z)-21a: Scheme 3, steps (e1)
and (e2) (there appeared to be no addition of acid other than
in one of the two recrystallization procedures); (Z)-21b was
obtained from PhCHO and lithio-20a in 71% yield
analogously as described in (e1); step (e2) was replaced by no
evaporation of THF, adding H2O, refluxing (30 min),
evaporating the solvents, adding Et2O–H2O (1:1), keeping
the aqueous phase, adding HCl (to pH 1), isolating the
resulting solid; (Z)-8b was obtained from PhCHO and the
lithium enolate of methyl phenylacetate in 94% yield
analogously as described in (e1); step (e2) was replaced by
evaporating THF, adding Et2O–H2O (1:1), keeping the
aqueous phase, adding HCl (to pH 1), isolating the resulting
solid. We followed a blend of the three procedures, replacing
Ramage’s step (e2) by no evaporation of THF (i.e., like
towards (Z)-21b), no refluxing with H2O (i.e., unlike
towards (Z)-21b), adding Et2O–H2O (1:1), etc.
(23) (a) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem.
Soc. 1998, 120, 4345. Analogous addition of dialkyl
phosphites/dialkyl H-phosphonates to butyl glyoxylate:
(b) Pudovik, A. N.; Gur’yanova, I. V. J. Gen. Chem. USSR
(Engl. Transl.) 1967, 37, 1566; Zh. Obshch. Khim., 1967, 37,
1649. Analogous addition of diethyl phosphite/diethyl H-
phosphonate to ethyl glyoxylate, liberated from its
hemi(ethyl acetal): (c) Schmidt, U.; Langner, J.;
Kirschbaum, B.; Braun, C. Synthesis 1994, 1138.
(24) Method is given in: Gerlach, U.; Hünig, S. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1283; Angew. Chem. 1987, 99, 1323.
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2923.
(4) Review: (a) Brückner, R. Curr. Org. Chem. 2001, 5, 679,
Section 7. Recent synthesis of pulvinones using
methodology from ref. 9: (b) Klostermeyer, D.; Knops, L.;
Sindlinger, T.; Polborn, K.; Steglich, W. Eur. J. Org. Chem.
2000, 4, 603.
(5) Reviews: (a) Brückner, R. Curr. Org. Chem. 2001, 5, 679,
Sections 8–9. (b) Pattenden, G. Prog. Chem. Nat. Prod.
1978, 35, 133, Sections III.1, III.3, and IV.2. (c) Gill, M.;
Steglich, W. Prog. Chem. Nat. Prod. 1987, 51, 1, Section
2.1.3. Syntheses of pulvinic acids by Suzuki couplings with
tetronic esters containing a triflate substituent at Cb:
(d) Ahmed, Z.; Langer, P. Tetrahedron 2005, 61, 2055.
(e) Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 64, 3753; and
literature cited therein. For more applications of Langer’s
methodology, see: (f) Heurtaux, B.; Lion, C.; Le Gall, T.;
Mioskowski, C. J. Org. Chem. 2005, 70, 1474. (g) Desage-
El Mur, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C.;
Amekraz, B.; Moulin, C. Angew. Chem. Int. Ed. 2003, 42,
1289; Angew. Chem., 2003, 115, 1327.
(6) Sheley, C. F.; Shechter, H. J. Org. Chem. 1970, 35, 2367.
(7) Claisen, L.; Ewan, T. Justus Liebigs Ann. Chem. 1895, 284,
245.
(8) Huang, R. L. J. Chem. Soc. 1957, 4089.
(9) Campbell, A. C.; Maidment, M. S.; Pick, J. H.; Stevenson,
D. F. M. J. Chem. Soc., Perkin Trans. 1 1985, 1567.
(10) Type 7 compounds were obtained by the addition of
substituted benzylmagnesium chlorides to the C≡N bond of
the O-trimethylsilylated cyanohydrin of arylacetaldehydes,
followed by hydrolysis.11
(11) Gill, M.; Kiefel, M. J.; Lally, D. A.; Ten, A. Aust. J. Chem.
1990, 43, 1497.
(12) Method is given in ref. 9.
(26) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R. Tetrahedron Lett. 1984, 25,
2183.
(27) Diaryl phosphonates (ArO)2P(=O)CH2CO2Et undergoing Z-
selective Horner–Wadsworth–Emmons reactions with a-
chiral aldehydes in the presence of NaI, DBU, and HMPA:
Ando, K.; Oishi, T.; Hirama, M.; Hiroali, O.; Ibuka, T. J.
Org. Chem. 2000, 65, 4745; in order to minimize health
hazards, we replaced HMPA by DMPU.
(13) Ester 9 was prepared by the alkylation of potassium
phenylacetate with ethyl 2-bromo-3-phenylpropionate.9
(14) Tetronic ester 10a was obtained by the base-mediated
condensation of (4-methoxyphenyl)acetonitrile with diethyl
oxalate followed by O-methylation of the enol and
anhydride formation: Knight, D. W.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1979, 62. Hydride reduction provided
a separable mixture of 10a and hydroxy-10a which was once
more reduced giving more 10a.
(28) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(29) Kokin, K.; Iitake, K.-I.; Takaguchi, Y.; Aoyama, H.;
Hayashi, S.; Motoyoshiya, J. Phosphorus, Sulfur Silicon
Relat. Elem. 1998, 133, 21.
(30) Methyl 2-(tert-butyldimethylsiloxy)-2-
(dimethoxyphosphoryl)acetate, upon deprotonation with
LDA in pure THF, and 4-methoxy-2-
(methoxymethoxy)benzaldehyde condense with seemingly
perfect Z/E selectivity: Boehlow, T. R.; Harburn, J. J.;
Spilling, C. D. J. Org. Chem. 2001, 66, 3111.
(15) Knight, D. W.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1979, 70.
(16) Tetronic ester 10b was obtained differently than tetronic
(31) (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(b) Related finding: Boschelli, D.; Takemasa, T.; Nishitani,
Y.; Masamune, S. Tetrahedron Lett. 1985, 26, 5239.
ester 10a, namely by the Dieckmann condensation of
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York

130
N. Kaczybura, R. Brückner
PAPER
(32) Vogeli, U.; von Philipsborn, W. Org. Magn. Reson. 1975, 7,
617.
benzylidene)-4-hydroxy-3-(4-methoxyphenyl)furan-2(5H)-
one: Edwards, R. L.; Gill, M. J. Chem. Soc., Perkin Trans. 1
1973, 1921.
(33) In a related condensation using lithium diisopropylamide/
ester 26/dioxolanone 25c, we ascertained that the yield of
pulvinone 28 decreased from 60% to 40% upon changing the
reactant ratio from 2.5:2.5:1 to 2.5:1.25:1 (Scheme 4). The
analogous condensation using lithium diisopropylamide/
carboxylic acid 27/dioxolanone 25c (2.2:1.1:1 ratio of the
reactants) did not give pulvinone 28 under the conditions
otherwise identical to those of Table 5 (Kaczybura, N.
Dissertation; Universität Freiburg: Germany, 2005).
(36) We could not extend our approach to a synthesis of pulvinic
acids 32 and 33. While dioxolanone 31 was accessible by a
Horner–Wadsworth–Emmons reaction between
phosphonate 24b and a-oxo ester 29 (79% yield), it did not
react with the ester enolate 30 by Claisen condensation/
transesterification (Scheme 5).
OMe
MeO2C
OMe
O
OMe
OMe
OMe
29
Li
O
Ot-Bu 30
MeO2C
O
O
O
b)
I
I
HO
O
a)
(BuO)2P
MeO
O
O
O
OMe
first LDA,
subsequently
27
26
O
O
24b
31
O
OMe
O
O
O
O
25c
OH
CO2H
32
OMe
and/or
OH
OMe
OMe
OH
HO2C
O
O
I
MeO
O
O
28
33
Scheme 4
Scheme 5 Reagents and conditions: a) 24b (1.0 equiv), LDA
(1.7 equiv), THF, –78 °C, 30 min; 29, 2.5 h; 79% (60:40 mixture
of unassigned isomers); (b1) 30 (2.5 equiv), THF, –78 °C, 2 h, to
r.t., 0–2 h; (b2) evaporation of THF; addition of Et2O–H2O (1:1),
60 °C, 1 h.
(34) Earlier description of pulvinone (Z)-8f: Ojima, N.;
Takenaka, S.; Seto, S. Phytochemistry 1973, 12, 2527.
(35) Pulvinone (Z)-8j was synthesized in a mixture which also
contained the isomeric pulvinone (Z)-5-(3,4-dimethoxy-
Synthesis 2007, No. 1, 118–130 © Thieme Stuttgart · New York