Versatile synthesis of acylfuranones by reaction of acylketenes with α-hydroxy ketones: Application to the one-step multicomponent synthesis of cadiolide B and its analogues

Article abstract of DOI:10.1002/ejoc.201300166

Functionalized acylfuranones have been prepared in a one-step procedure by thermal fragmentation of the corresponding dioxinones in the presence of hydroxy ketones in basic conditions. Multicomponent reactions also occur on addition of an aldehyde as a third reaction partner resulting in an expeditious access to cadiolide B and its analogues. A new method for the synthesis of acylfuranones is described based on the fragmentation of dioxinones to acylketenes followed by trapping with hydroxy ketones. Addition of an aldehyde as a third reaction partner leads to a supplementary aldolization/crotonization sequence resulting in an expeditious synthesis of cadiolide B and its analogues. Copyright

Full text of DOI:10.1002/ejoc.201300166

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FULL PAPER
DOI: 10.1002/ejoc.201300166
Versatile Synthesis of Acylfuranones by Reaction of Acylketenes with
α-Hydroxy Ketones: Application to the One-Step Multicomponent Synthesis
of Cadiolide B and Its Analogues
Philippe Alexandre Peixoto,[a] Agathe Boulangé,[a] Stéphane Leleu,*[a] and Xavier Franck*[a]
Dedicated to Professor Kozo Shishido on the occasion of his retirement
Keywords: Synthetic methods / Multicomponent reactions / Oxygen heterocycles / Natural products / Ketenes
Functionalized acylfuranones have been prepared in a one-
step procedure by thermal fragmentation of the correspond-
ing dioxinones in the presence of hydroxy ketones in basic
conditions. Multicomponent reactions also occur on addition
of an aldehyde as a third reaction partner resulting in an ex-
peditious access to cadiolide B and its analogues.
cey[7] in 1954 using diketene (Scheme 1). This methodology
was later extended by other groups to the preparation of
tetronic acid derivatives.[8] Unfortunately, this method suf-
fers big limitations related to the scope of the R functional
group. The majority of other methods used for the con-
struction of the acylfuranone skeleton generally require two
or three steps. Indeed, the most often described procedure
remains the esterification reaction between an α-hydroxy
ketone and a β-keto acid (or ester or malonate) followed by
an intramolecular Knoevenagel cyclization reaction.[9]
Acylfuranones can also be obtained by the direct acylation
of furanones[10] or by an intramolecular lactonization/oxi-
dation sequence.[11] Finally, one particular and limited
method involves the photosensitive oxidation of furan de-
rivatives.[12] In this article, we describe a new, easy and ver-
satile access to acylfuranones by the reaction of α-hydroxy
ketones 2 with acylketenes 3 in the presence of a base
(Scheme 1). The interest in using acylketenes lies in their
high reactivity towards hindered alcohols and their easy
generation by thermal fragmentation of functionalized di-
oxinones 1.[13]
Introduction
Functionalized acylfuranones are present in many natu-
ral[1] and synthetic[2] products. Among them, cadiolides A–
I (Figure 1), isolated from the Indonesian marine ascidians
of the genus Botryllus,[3] present fascinating and similar an-
tibacterial activities to vancomycin and platensimycin.[4]
Moreover, they also share a common feature with refecoxib,
a selective inhibitor of the COX-2 enzyme, promoting inter-
esting anti-inflammatory activity.[5] Epicocconone is an-
other example of an acylfuranone-containing natural prod-
uct currently used as a fluorescent protein stain.[6]
Under these conditions, the fast trapping of the acylket-
ene by the hydroxy moiety of a hydroxy ketone leads to an
intermediate β-keto ester 4. This intermediate then sponta-
neously cyclizes through an intramolecular Knoevenagel
condensation to yield the desired furanone cycle. This syn-
thetic strategy has already been employed by our group for
the synthesis of epicocconone analogues[14] and we now
wish to report the scope and limitations of this methodol-
ogy in the reactions of various acylfuranones. Furthermore,
an extension of the method to the expeditious synthesis of
compounds of interest possessing the cadiolide framework
is also described based on a multicomponent approach.
Figure 1. Acylfuranone moieties in cadiolide B and epicocconone.
The direct synthesis of acylfuranones is very little re-
ported in literature. The first method was described by La-
[a] Normandie Univ., COBRA, UMR 6014 et FR 3038, CNRS,
Univ. Rouen, INSA Rouen,
1 rue Tesnières, 76821 Mont-Saint-Aignan, Cedex, France
Fax: +33-2-35522959
E-mail: stephane.leleu@univ-rouen.fr
xavier.franck@insa-rouen.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300166.
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P. A. Peixoto, A. Boulangé, S. Leleu, X. Franck
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Table 1. Optimization of the reaction conditions for the synthesis
of acylfuranone 9.
Entry
Dioxinone 1a
Base
(amount [equiv.])
Yield of 9
[equiv.]
[%]
1
2
3
4
5
6
7
1.05
1.05
1.05
1.20
1.50
2.00
1.50
DIEA (0.5)
DIEA (1.0)
DIEA (2.0)
DIEA (0.5)
DIEA (0.5)
DIEA (0.5)
Et3N (0.5)
58
64
71
74
87
83
100
appearance of side-products that were not observed with
0.5 equiv. of base (crude 1H NMR spectra). Thus, in an
attempt to prevent the formation of undesired products at
a very low level, we used a sub-stoichiometric amount of
base (0.5 equiv.) and increased the quantity of dioxinone
from 1.05 to 2 equiv. (entries 1 and 4–6). The yield of acyl-
furanone 9 improved from 58% (1.05 equiv. dioxinone) to
87% (1.5 equiv. dioxinone). Increasing the amount of dioxi-
none to 2 equiv. resulted in no further increase in the con-
version. Finally, the use of triethylamine instead of DIEA
gave even higher yields (compare entries 5 and 7).
Having determined the optimal conditions for the one-
step synthesis of furanone by using a simple model reac-
tion, we turned our attention to more functionalized diox-
inones and α-hydroxy ketones. The reactions of five α-hy-
droxy ketones (2a–e, either commercially available or syn-
thesized by using a standard procedure[15]) and nine diox-
inones (1a–f, j–l) were considered. Two different routes were
used to prepare the functionalized dioxinones 1 (Scheme 3).
The first involved a cyclization reaction between a β-keto
acid or a β-keto ester and acetone under acidic condi-
tions,[16] and the second involved the direct functionaliza-
tion of the lithium enolate derived from the commercially
available methyldioxinone.[17]
Scheme 1. Synthetic routes to acylfuranones.
Results and Discussion
The reaction conditions for the one-step synthesis of
acylfuranones were determined for a simple model reaction
between commercially available dioxinone 1a with α-hy-
droxy ketone 2a in toluene at reflux and in the presence of
a base. Molecular sieves (4 Å) were also added to trap re-
leased water and prevent destruction of the ketene
(Scheme 2, Table 1).
Scheme 3. Retrosynthetic routes to dioxinones 1.
In the first case, β-keto esters 7b–e were synthesized from
the corresponding carboxylic acids 5b–e via their Weinreb
amides[18] (Scheme 4). Dioxinones 1b–e bearing aromatic,
heteroaromatic or alkyl groups were obtained in good
yields by the reactions of 7b–e with acetone in the presence
of acetic anhydride and sulfuric acid by using a slight modi-
fication of the procedure of Gebauer and Blechert.[19]
More functionalized dioxinone derivatives like sulfone 1f,
silyl enol ethers 1j–k or silyl ether 1l were synthesized by
Scheme 2. Model reaction for the synthesis of acylfuranones.
Various parameters were considered, such as the amount the second method (Scheme 5). Indeed, the reaction of the
of base or dioxinone 1a, and the nature of the base. The lithium enolate prepared from the commercially available
results in Table 1 show that the amount of base and dioxi- methyldioxinone 1a with electrophiles such as bromine (fol-
none has a significant effect on the yield of the cyclization lowed by displacement of the bromine atom by sodium
reaction. Indeed, even though increasing the amount of benzenesulfinate), acid chlorides or benzaldehyde gave rise
base (iPr2NEt) from 0.5 to 2.0 resulted in an increase in to the corresponding dioxinone 1f, β-keto-dioxinones 1g,h
the conversion (Table 1, entries 1–3), it also resulted in the and β-hydroxy-dioxinone 1i. Note that dioxinones 1j–k
2
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Synthesis of Acylfuranones
Scheme 4. Synthetic route to dioxinones 1a–e.
(bearing a silyl enol ether) were prepared from the corre-
sponding ketones and used directly because of their insta-
bility with time.
Scheme 6. Various acylfuranones obtained from the reactions of 1
with 2a–e.
Scheme 5. Synthetic route to dioxinones 1f–l.
To study the scope and limitations of this reaction, we
Microwave irradiation (110 °C, 5 min) instead of conven-
first looked at the influence of the degree of the substitution tional heating was used with the aim of improving the yield
(R2 and R3) on the hydroxy ketones 2a–c. As can be seen of the condensation reaction with 2b. Unfortunately, the
in Scheme 6, good to excellent yields were obtained when yields dropped dramatically from 88 to 10% in the case of
tertiary hydroxy ketone 2a was used, whereas moderate acylfuranone 8 (by using hydroxy ketone 2b) but remained
yields were usually obtained when primary hydroxy ketone the same for acylfuranone 9 (by using hydroxy ketone 2a).
2b was engaged. These results can be explained by either These results suggest a thermal degradation of the less sub-
the Thorpe–Ingold effect in the case of tertiary hydroxy stituted acylfuranones arising from hydroxy ketone 2b. The
groups or a possible enolization of the lactone leading to nature of R1 and R4 showed little influence on reaction out-
degradation in the case of primary hydroxy groups. In the comes as the Me, Ph and p-MeOPh substituents gave sim-
case of secondary hydroxy groups (R2 = H, R3 = Me), the ilar yields of furanones when R4 was an aromatic group
yields remained low (24% for 24, 26% for 25). This can be (compare 12/14/15, 20/22/23). A drop in yield was noted by
explained by the fact that the starting hydroxy ketone 2c is switching R1 from an aliphatic to an aromatic group with
sold as a mixture of monomer and dimer.
R4 aliphatic (compare 16/18/19). This reduction in yield
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P. A. Peixoto, A. Boulangé, S. Leleu, X. Franck
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suggests a higher tendency of the furanone to be enolized further react in situ with an aldehyde by an aldolization/
in the case of 18 and 19 compared with 16, leading to poly- crotonization sequence (Scheme 7). This idea was evaluated
merization-type side products. Finally, for the more func- with dioxinone 1d and hydroxy ketone 2e in the presence of
tionalized dioxinones 1j,k, two equiv. of base were required p-MeOPhCHO (33). Unfortunately, by using this approach
to achieve satisfactory yields. For example, dioxinones 1j with the previous reaction conditions, only 12% of acylfur-
and 1k bearing a silyl enol ether gave rise to furanones 30 anone 23 was obtained with no trace of the desired addition
and 32 bearing a 1,3-diketo side-chain in which one ketone compound 34a (Table 2, entry 1). Increasing the amount of
is present in its enol form. Dioxinone 1l bearing a β-silyloxy base from 0.5 equiv. to 2 equiv. proved to be effective and
group provided furanone 29 bearing an hydroxylated side- allowed us to increase the yield of 23 to 49% and 34a was
chain in 91% yield with no β-elimination. Dioxinone 1f obtained in 23% yield (entry 2). The addition of more base
with the sulfonyl group yielded the furanone 31 in 59% and aldehyde did not increase the yield of either the fur-
yield.
anone or the addition product (entry 3). In an attempt to
Thus, acylfuranones 8–32 have been prepared in good to promote the formation of 34a, we performed the reaction
excellent yields from the reactions of hydroxy ketones 2a–e with microwave irradiation. This proved to be successful as
with 1, with yields ranging from 50–100% for ketones bear- we obtained 34a in a one-pot sequence in a yield of 77%
ing tertiary hydroxys, 29–88% for primary hydroxys, and (300 W, 150 °C during 5 min).
24–26% for secondary hydroxys.
Table 2. Optimization parameters.
Application to the Synthesis of Cadiolide B and Its
Analogues
Entry
1d
33
Et3N
Activation
Yield [%]
[equiv.][a] [equiv.][a] [equiv.][a] conditions
23
34a
The methodology developed above was then extended to
the synthesis of analogues of cadiolide B by a one-step
multicomponent reaction involving dioxinone derivatives
and α-hydroxy ketones in the presence of an aldehyde as
the third reaction partner. To date, only one total synthesis
of cadiolide B has been reported,[20] which gave an overall
yield of 42% in six steps from commercially available 4-
bromo-2,5-dihydro-2-oxofuran. Our strategy allowed us to
obtain in only one step the skeleton of cadiolide B 34a as
well as analogues 34b–e of the natural product.
1
2
3
4
1.2
1.5
1.5
2
1.5
1.2
2
0.5
2
4
thermal
thermal
thermal
MW[b]
12
49
43
0
0
23
21
77
1.2
2
[a] Relative to 2e. [b] In the absence of molecular sieves.
Thus, by taking advantage of the previously observed
facile enolization of unsubstituted aromatic acylfuranones
such as 14, 15, 22 and 23, we envisioned that they would
Figure 2. Analogues of cadiolide prepared by the multicomponent
approach.
Scheme 7. One-pot multicomponent sequence.
4
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Synthesis of Acylfuranones
cessively added at room temperature. After 2 h, the reaction was
quenched at room temperature with a saturated solution of
NaHCO3 and the mixture extracted twice with CH2Cl2. The com-
bined organic layers were then washed with a saturated solution of
NH4Cl and brine. The organic layer was then dried with anhydrous
MgSO4, filtered, and concentrated under vacuum. The crude resi-
due was then purified by flash chromatography on silica gel by
using an appropriate gradient of a cyclohexane/EtOAc mixture as
eluent to give the desired Weinreb amide 6b–e.
By using microwave irradiation and different aldehydes,
dioxinones and hydroxy ketones, a set of cadiolide ana-
logues were prepared in yields ranging from 25 to 61% (ex-
cept when p-(dimethylamino)benzaldehyde was used, which
gave only 4% of 34e, Figure 2).[20] This reaction worked well
for aromatic dioxinones and hydroxy ketones. When ali-
phatic substituents were used, the yields were moderate, but
still satisfactory bearing in mind the six consecutive trans-
formations involved (thermal fragmentation of dioxinone/
N-Methoxy-N-methylbenzamide (6b): Following procedure A, benz-
oic acid (2.44 g, 20 mmol) was used to afford 6b as a yellow oil in
98% yield (2.93 g, 19.6 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 80:20). Analyses
are similar to those described in the literature.[22] 1H NMR
(300 MHz, CDCl3): δ = 3.29 (s, 3 H), 3.48 (s, 3 H), 7.21–7.40 (m,
3 H), 7.53–7.64 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
33.8, 61.0, 128.05, 128.13, 130.6, 134.2, 169.9 ppm.
acylketene
dration).
trapping/cyclization/dehydration/aldol/dehy-
Finally, cadiolide B was synthesized in an overall yield of
48% from dioxinone 1d after removal of the methyl groups
with BBr3 and bromination[21] of the phenolic groups
(Scheme 8).
N-Methoxy-N-methyloctanamide (6c): Following procedure A,
octanoic acid (3.2 mL, 20 mmol) was used to afford 6c as a yellow
oil in 86% yield (3.23 g, 17.2 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 80:20). Analyses
are similar to those described in the literature.[23] 1H NMR
(300 MHz, CDCl3): δ = 0.85 (t, J = 6.8 Hz, 3 H), 1.26–1.33 (m, 8
H), 1.58–1.63 (m, 2 H), 2.38 (t, J = 7.7 Hz, 2 H), 3.16 (s, 3 H), 3.66
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 22.9, 25.0,
29.4, 29.7, 32.0, 32.5, 33.0, 61.5, 175.1 ppm. IR (neat): ν = 2929,
˜
2856, 1670, 1466, 1414, 1388, 1177, 998 cm–1. MS (ESI): m/z = 188
[M + H]+.
N,4-Dimethoxy-N-methylbenzamide (6d): Following procedure A,
p-methoxybenzoic acid (3.41 g, 20 mmol) was used to afford 6d as
a white solid in 95% yield (3.71 g, 19 mmol) after purification by
flash chromatography on silica gel (cyclohexane/EtOAc, 60:40).
Analyses are similar to those described in the literature.[22] M.p.
70 °C. 1H NMR (300 MHz, CDCl3): δ = 3.35 (s, 3 H), 3.56 (s, 3
H), 3.84 (s, 3 H), 6.89 (d, J = 8.9 Hz, 2 H), 7.71 (d, J = 8.9 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 34.2, 55.6, 61.2, 113.6,
Scheme 8. Synthesis of cadiolide B.
Conclusions
We have developed an efficient method for the one-pot
synthesis of acylfuranones from easily available starting ma-
terials such as dioxinones and hydroxy ketones. The meth-
126.3, 130.9, 161.8, 169.7 ppm. IR (neat): ν = 2935, 1637, 1608,
˜
odology was extended to the one-pot multicomponent syn- 1512, 1459, 1421, 1375, 1305, 1254, 1173, 1029, 842 cm–1. MS
(ESI): m/z = 196 [M + H]+.
thesis of densely functionalized furanone cores. This diver-
sity-oriented approach gave expeditious access to various
small-ring compounds with potentially high antimicrobial
activities and will most certainly find a broad range of ap-
plications in medicinal chemistry.
N-Methoxy-N-methylfuran-2-carboxamide (6e): Following pro-
cedure A, 2-furoic acid (2.24 g, 20 mmol) was used to afford 6e as
a yellow oil in 94% yield (2.72 g, 18.8 mmol) after purification by
flash chromatography on silica gel (cyclohexane/EtOAc, 70:30).
Analyses are similar to those described in the literature.[22] 1H
NMR (300 MHz, CDCl3): δ = 3.34 (s, 3 H), 3.76 (s, 3 H), 6.50 (dd,
J = 1.7, 3.6 Hz, 2 H), 7.02 (d, J = 3.4 Hz, 1 H), 7.47 (d, J = 1.7 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 33.1, 61.4, 111.7,
117.4, 145.3, 145.6, 159.1 ppm. MS (ESI): m/z = 156 [M + H]+. IR
Experimental Section
1
General: H (300 MHz) and 13C NMR (75 MHz) spectra were re-
corded in CDCl3 with a Bruker DPX 300 spectrometer. 1H and 13
C
(neat): ν = 2938, 1705, 1618, 1392, 1228, 1178, 977, 756 cm–1.
˜
NMR chemical shifts (δ) are quoted in ppm with CHCl3 as refer-
ence. Mass spectra were recorded with a Finnigan LCQ Advantage
MAX (ion trap) spectrometer equipped with an electropray (ESI)
source. IR spectra were recorded with a Perkin–Elmer FT-IR Spec-
trum 100 spectrometer equipped with an ATR accessory.
General Procedure for the Synthesis of tert-Butyl Esters 7b–e (Pro-
cedure B): n-Butyllithium (nBuLi, 1.2 m in hexane, 3.1 equiv.) was
added at –78 °C to a THF solution (for a solution of 0.1 molL–1)
containing diisopropylamine (DIPA; 3 equiv.) in a round-bottomed
flask flushed with argon. After 30 min at 0 °C, the medium was
recooled to –78 °C and freshly distilled tBu acetate (3 equiv.) was
added. After 30 min at –78 °C, Weinreb amide 6b–e (1 equiv.) was
added at this temperature. After 1 h, the reaction was quenched at
room temperature with a saturated solution of NaHCO3 and the
mixture extracted twice with EtOAc. The combined organic layers
were then washed with a saturated solution of NH4Cl. The organic
layer was then dried with anhydrous MgSO4, filtered, and concen-
trated under vacuum. The crude residue was then purified by flash
General Procedure for the Synthesis of Weinreb Amides 6b–e (Pro-
cedure A): Oxalyl chloride [(COCl)2; 1.25 equiv.] and DMF
(0.004 equiv.) were added at room temperature to a CH2Cl2 solu-
tion (for a solution of 0.1 molL–1) containing acid 5b–e (1 equiv.)
in a round-bottomed flask flushed with argon. After 1.5 h, the sol-
vent and the excess oxalyl chloride were removed by evaporation
under vacuum. CH2Cl2 (for a solution of 0.1 molL–1), N,O-dimeth-
ylhydroxylamine (1.4 equiv.), and Et3N (3 equiv.) were then suc-
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chromatography on silica gel by using an appropriate gradient of
a cyclohexane/EtOAc mixture as eluent to give the desired tert-
butyl ester 7b–e.
silica gel using an appropriate gradient of a cyclohexane/EtOAc
mixture as eluent to give the desired dioxinone 1b–e.
2,2-Dimethyl-6-phenyl-4H-1,3-dioxin-4-one (1b): Following pro-
cedure C, tert-butyl ester 7b (4.27 g, 19.4 mmol) was used to afford
1b as a white solid in 73% yield (2.89 g, 14.2 mmol) after purifica-
tion by flash chromatography on silica gel (cyclohexane/EtOAc,
80:20), m.p. 66 °C. 1H NMR (300 MHz, CDCl3): δ = 1.78 (s, 6 H),
5.87 (s, 1 H), 7.40–7.66 (m, 3 H), 7.67 (d, J = 7.4 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 25.2, 91.4, 106.8, 126.5, 129.0,
tert-Butyl 3-Oxo-3-phenylpropanoate and tert-Butyl (Z)-3-Hydroxy-
3-phenylacrylate (7b): Following procedure B, Weinreb amide 6b
(2.93 g, 19.6 mmol) was used to afford 7b as a colourless oil in 99%
yield (4.27 g, 19.4 mmol) after purification by flash chromatog-
raphy on silica gel (cyclohexane/EtOAc, 80:20). A mixture of the
keto ester and enol forms (78:22) were obtained. 1H NMR
(300 MHz, CDCl3): δ = 1.32 (s, 7 H), 1.42 (s, 2 H), 3.77 (s, 1.6 H),
5.48 (s, 0.2 H), 7.25–7.46 (m, 3 H), 7.63 (d, J = 7.0 Hz, 0.4 H), 7.81
(d, J = 7.5 Hz, 1.6 H), 12.67 (s, 0.2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 27.7, 28.2, 47.2, 81.0, 81.7, 88.7, 125.8, 128.3, 128.4,
128.6, 130.9, 133.4, 133.6, 136.1, 166.6, 170.7, 173.0, 192.9 ppm.
131.2, 132.3, 162.1, 165.2 ppm. IR (neat): ν = 2998, 1727, 1450,
˜
1389, 1363, 1279, 1225, 1204, 990, 770, 691 cm–1. HRMS (ESI):
calcd. for [C12H12O3 + H]+ 205.0865; found 205.0869.
6-Heptyl-2,2-dimethyl-4H-1,3-dioxin-4-one (1c): Following pro-
cedure C, tert-butyl ester 7c (3.79 g, 15.7 mmol) was used to afford
1c as a yellow oil in 71% yield (2.52 g, 11.1 mmol) after purification
by flash chromatography on silica gel (cyclohexane/EtOAc, 80:20).
1H NMR (300 MHz, CDCl3): δ = 0.80–0.84 (m, 3 H), 1.22–1.23
(m, 8 H), 1.45–1.50 (m, 2 H), 1.62 (s, 6 H), 2.14 (t, J = 7.5 Hz, 2
H), 5.16 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 22.7,
25.1, 25.8, 28.98, 29.01, 31.7, 33.7, 93.2, 106.3, 161.5, 172.3 ppm.
IR (neat): ν = 3062, 2980, 2933, 1732, 1688, 1637, 1599, 1450, 1408,
˜
1369, 1326, 1326, 1278, 1154, 690 cm–1. MS (ESI): m/z = 221 [M
+ H]+.
tert-Butyl 3-Oxodecanoate (7c): Following procedure B, Weinreb
amide 6c (3.23 g, 17.2 mmol) was used to afford 7c as a colourless
oil in 91% yield (3.79 g, 15.7 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 75:25). 1H
NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.8 Hz, 3 H), 1.21–1.22
(m, 8 H), 1.41 (s, 9 H), 1.50–1.55 (m, 2 H), 2.14 (t, J = 7.3 Hz, 2
H), 3.28 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3, 22.8,
23.7, 28.2, 29.2, 29.3, 31.9, 43.1, 50.9, 82.0, 166.7, 203.7 ppm. IR
IR (neat): ν = 2999, 2929, 2858, 1732, 1634, 1463, 1392, 1463, 1392,
˜
1271, 1205, 1013, 901, 806 cm–1. MS (ESI): m/z = 227 [M + H]+.
6-(4-Methoxyphenyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (1d): Fol-
lowing procedure C, tert-butyl ester 7d (4.66 g, 18.6 mmol) was
used to afford 1d as a yellow solid in 82% yield (3.57 g, 15.3 mmol)
after purification by flash chromatography on silica gel (cyclohex-
(neat): ν = 2930, 2857, 1716, 1457, 1410, 1369, 1318, 1252,
˜
1
1149 cm–1. MS (ESI): m/z = 243 [M + H]+.
ane/EtOAc, 80:20), m.p. 68 °C. H NMR (300 MHz, CDCl3): δ =
1.77 (s, 6 H), 3.84 (s, 3 H), 5.77 (s, 1 H), 6.92 (d, J = 9.0 Hz, 2 H),
7.71 (d, J = 9.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
25.2, 55.7, 89.5, 106.5, 114.4, 123.5, 128.4, 162.4, 163.0, 165.1 ppm.
tert-Butyl 3-(4-Methoxyphenyl)-3-oxopropanoate (7d): Following
procedure B, Weinreb amide 6d (3.71 g, 19 mmol) was used to af-
ford 7d as a yellow oil in 98% yield (4.66 g, 18.6 mmol) after purifi-
cation by flash chromatography on silica gel (cyclohexane/EtOAc,
IR (neat): ν = 2999, 2940, 2842, 1721, 1607, 1513, 1363, 1252, 1179,
˜
1027, 804 cm–1. MS (ESI): m/z = 235 [M + H]+. HRMS (ESI):
1
60:40). H NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H), 3.79 (s, 2
calcd. for [C13H14O4 + H]+ 235.0970; found 235.0976.
H), 3.80 (s, 3 H), 6.87 (d, J = 9.0 Hz, 2 H), 7.71 (d, J = 9.0 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.9, 47.1, 55.5, 81.7,
6-(Furan-2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (1e): Following
procedure C, tert-butyl ester 7e (3.72 g, 17.7 mmol) was used to
afford 1e as a red oil in 64% yield (2.20 g, 11.3 mmol) after purifi-
cation by flash chromatography on silica gel (cyclohexane/EtOAc,
113.8, 129.2, 130.8, 163.8, 167.0, 191.5 ppm. IR (neat): ν = 2978,
˜
2935, 2841, 1732, 1678, 1602, 1512, 1326, 1260, 1171, 1028,
841 cm–1. MS (ESI): m/z = 251 [M + H]+.
1
80:20). H NMR (300 MHz, CDCl3): δ = 1.71 (s, 6 H), 5.74 (s, 1
tert-Butyl 3-(Furan-2-yl)-3-oxopropanoate (7e): Following pro-
cedure B, Weinreb amide 6e (2.72 g, 18.8 mmol) was used to afford
7e as a white solid in 94% yield (3.72 g, 17.7 mmol) after purifica-
tion by flash chromatography on silica gel (cyclohexane/EtOAc,
70:30), m.p. 76 °C. 1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 9 H),
3.73 (s, 2 H), 6.53 (dd, J = 1.7, 3.6 Hz, 2 H), 7.23 (d, J = 3.6 Hz,
1 H), 7.58 (d, J = 1.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 28.2, 47.2, 82.4, 112.9, 118.3, 147.1, 152.4, 166.5, 181.9 ppm.
H), 6.49 (dd, J = 1.7, 3.6 Hz, 1 H), 6.86 (d, J = 3.6 Hz, 1 H), 7.53
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.0, 89.6, 107.0,
112.5, 114.2, 146.2, 146.3, 156.4, 161.6 ppm. IR (neat): ν = 3134,
˜
3000, 2945, 1727, 1679, 1641, 1470, 1361, 1278, 1205, 1017 cm–1.
MS (ESI): m/z = 195 [M + H]+.
2,2-Dimethyl-6-(phenylsulfonylmethyl)-4H-1,3-dioxin-4-one
(1f):
nBuLi (7.9 mL, 11 mmol, 1.4 m in hexane) was added at –78 °C to
a THF solution (100 mL) of DIPA (1.6 mL, 11 mmol) in a round-
bottomed flask flushed with argon. After 30 min at 0 °C, the solu-
tion was recooled to –78 °C and 2,2,6-trimethyl-2,4-dihydro-1,3-di-
oxin-4-one (1a; 1.4 mL, 10 mmol) was added. After 30 min at
–78 °C, bromine (0.6 mL, 11 mmol) was added at this temperature.
After 2 h at –40 °C, the reaction was quenched at 0 °C with H2O
and the mixture extracted twice with EtOAc. The combined or-
ganic layers were washed with Na2S2O3 and then with 1 n HCl.
The combined organic layers were then dried with MgSO4, filtered
and concentrated under vacuum. The crude residue was dissolved
in a DMF (50 mL) containing sodium benzenesulfinate (2.0 g,
12 mmol). After 0.5 h at room temp., the reaction was quenched at
0 °C with brine and the mixture extracted twice with EtOAc. The
organic layer was then washed three times with brine. The com-
bined organic layers were dried with MgSO4, filtered and concen-
trated under vacuum. The crude product was purified by flash
chromatography on silica gel using cyclohexane/EtOAc (60:40) as
IR (neat): ν = 1732, 1681, 1469, 1154, 762 cm–1. MS (ESI): m/z =
˜
211 [M + H]+.
General Procedure for the Synthesis of Dioxinones 1b–e (Pro-
cedure C): Acetic anhydride (15 equiv.) and sulfuric acid (1 equiv.)
were added at 0 °C to an acetone solution (10 equiv.) containing
tert-butyl ester 7b–e (1 equiv.) in a round-bottomed flask flushed
with argon. The medium was then warmed slowly to room tem-
perature over 10 min. After 45 min, the reaction was quenched at
room temperature with an aqueous solution containing sodium
carbonate (30 equiv.) and EtOAc (100 mL) was added. The bi-
phasic medium was then stirred for 40 min (hydrolysis of the re-
maining acetic anhydride) and the aqueous layer was extracted
twice with EtOAc. The combined organic layers were then washed
with a saturated solution of NH4Cl. The organic layer was dried
with anhydrous MgSO4, filtered and concentrated under vacuum.
The crude residue was finally purified by flash chromatography on
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30166
/KAP1
Date: 08-04-13 11:37:56
Pages: 13
Synthesis of Acylfuranones
eluent to give the dioxinone 1f as a brown solid in 31% yield
(885 mg, 3.1 mmol), m.p. 110 °C. H NMR (300 MHz, CDCl3): δ
omethanesulfonate (TBSOTf; 1.5 equiv.) were added at room temp.
1
to a CH2Cl2 solution (0.1 molL–1) containing dioxinone 1g,h
= 1.63 (s, 6 H), 3.98 (s, 2 H), 5.29 (s, 1 H), 7.62 (t, J = 7.0 Hz, 2 (1 equiv.) in a round-bottomed flask flushed with argon. After 2 h,
H), 7.73 (t, J = 7.0 Hz, 1 H), 7.92 (d, J = 7.0 Hz, 2 H) ppm. 13C the reaction was quenched at room temp. with a saturated solution
NMR (75 MHz, CDCl3): δ = 25.0, 60.2, 99.3, 107.8, 128.4, 129.6,
of NaHCO3 and the mixture extracted twice with of CH2Cl2. The
134.7, 138.5, 158.5, 159.9 ppm. IR (neat): ν = 1705, 1639, 1375, combined organic layers were washed with a saturated solution of
˜
1313, 1278, 1204, 1154, 1082, 1017, 911, 799, 740, 725, 687 cm–1. NH4Cl and then dried with MgSO4, filtered and concentrated un-
MS (ESI): m/z = 283 [M + H]+, 300 [M + H2O]+.
der vacuum. The crude product (100% conversion) was quickly
purified by flash chromatography on silica gel with a mixture of
cyclohexane/EtOAc (9:1) as eluent to give the silylated dioxinones
1j,k, which were directly engaged in the next step.
General Procedure for the Synthesis of Dioxinones 1g,h (Pro-
cedure D): nBuLi (1.2 m in hexane, 2.0 equiv.) was added at –78 °C
to a THF solution (0.1 molL–1) of DIPA (2 equiv.) in a round-
bottomed flask flushed with argon. After 30 min at 0 °C, the solu-
tion was recooled to –78 °C and 2,2,6-trimethyl-2,4-dihydro-1,3-di-
oxin-4-one (1a; 2 equiv.) was added. After 30 min at –78 °C, ben-
zoyl chloride (1 equiv.) was finally added at this temperature. After
2 h at –40 °C, the reaction was quenched at 0 °C with 1 n HCl and
the mixture extracted twice with EtOAc. The combined organic
layers were then dried with MgSO4, filtered and concentrated under
vacuum. The desired product was finally precipitated by using a
1:10 mixture of Et2O/pentane (first Et2O and then pentane) to give
the desired dioxinone 1g,h.
6-[(Z)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylvinyl]-2,2-dimethyl-
4H-1,3-dioxin-4-one (1j): Following procedure E, dioxinone 1g
(1.23 g, 5 mmol) was used to afford 1j as a yellow oil in 98% yield
(1.77 g, 4.9 mmol). 1H NMR (300 MHz, CDCl3): δ = –0.06 (s, 6
H), 0.97 (s, 9 H), 1.69 (s, 6 H), 5.41 (s, 1 H), 5.85 (s, 1 H), 7.30–7.36
(m, 3 H), 7.44–7.47 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= –3.5, 18.4, 25.1, 25.9, 93.7, 103.5, 105.6, 126.8, 128.4, 129.9,
138.5, 161.8, 162.4, 163.6 ppm.
(Z)-4-{1-[tert-Butyl(dimethyl)silyloxy]-2-(2,2-dimethyl-4-oxo-4H-
1,3-dioxin-6-yl)vinyl}benzonitrile (1k): Following procedure E, diox-
inone 1h (1.1 g, 4.0 mmol) was used to afford 1k as a red oil in
88% yield (1.38 g, 3.5 mmol). 1H NMR (300 MHz, CDCl3): δ =
–0.03 (s, 6 H), 1.00 (s, 9 H), 1.72 (s, 6 H), 5.52 (s, 1 H), 5.87 (s, 1
H), 7.00 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 2 H) ppm.
2,2-Dimethyl-6-(2-oxo-2-phenylethyl)-4H-1,3-dioxin-4-one (1g): Fol-
lowing procedure D, benzoyl chloride (2.3 mL, 20 mmol) was used
to afford 1g as a white solid in 46% yield (2.26 g, 9.2 mmol), m.p.
1
114 °C. H NMR (300 MHz, CDCl3): δ = 1.70 (s, 6 H), 3.90 (s, 2
H), 5.41 (s, 1 H), 7.49 (t, J = 7.7 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1
H), 7.93 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 25.1, 43.4, 97.1, 107.4, 128.4, 129.0, 134.2, 136.0, 160.9, 165.3,
2,2-Dimethyl-6-[2-(trimethylsilyloxy)-2-phenylethyl]-4H-1,3-dioxin-
4-one (1l): Imidazole (413 mg, 6 mmol) and trimethylsilyl chloride
(0.76 mL, 6 mmol) were added at 0 °C to a DMF solution (50 mL)
of dioxinone 1i (1.24 g, 5 mmol) in a round-bottomed flask flushed
with argon. After 2 h at 0 °C, the reaction was quenched with water
and the mixture extracted twice with CH2Cl2. The organic layer
was then washed three times with brine. The combined organic
layers were then dried with MgSO4, filtered and concentrated under
vacuum. The crude product was purified by flash chromatography
on silica gel using cyclohexane/EtOAc (95:5) as eluent to give the
silylated dioxinone 1l as a yellow oil in 77% yield (1.23 g,
193.2 ppm. IR (neat): ν = 3098, 2999, 2962, 2930, 1716, 1687, 1644,
˜
1392, 1377, 1222, 1019, 822 cm–1. MS (ESI): m/z = 247 [M + H]+.
4-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl]benzonitrile (1h):
Following procedure D, p-cyanobenzoyl chloride (1.82 g, 11 mmol)
was used to afford 1h as a red solid in 44% yield (1.30 g, 4.8 mmol),
m.p. 77 °C. 1H NMR (300 MHz, CDCl3): δ = 1.71 (s, 6 H), 3.91
(s, 2 H), 5.43 (s, 1 H), 7.81 (d, J = 8.5 Hz, 2 H), 8.03 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.1, 43.5, 97.5, 107.6,
117.7, 127.5, 128.8, 132.5, 132.9, 138.7, 160.6, 193.4 ppm. IR
1
3.85 mmol). H NMR (300 MHz, CDCl3): δ = 0.00 (s, 9 H), 1.64
(neat): ν = 2234, 1724, 1691, 1636, 1375, 1270, 1204, 1015,
˜
(s, 3 H), 1.67 (s, 3 H), 2.49 [A(ABX), JAB = 21.0, JAX = 6.6 Hz, 1
H], 2.64 [B(ABX), JAB = 21.0, JBX = 12.6 Hz, 1 H], 4.92 [X(ABX),
JAX = 6.6, JBX = 12.6 Hz, 1 H], 5.25 (s, 1 H), 7.29–7.34 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 0.2, 25.0, 25.5, 45.1,
72.0, 95.4, 106.5, 126.0, 128.0, 128.6, 143.4, 161.3, 168.7 ppm. IR
838 cm–1. MS (ESI): m/z = 270 [M – H]+.
6-(2-Hydroxy-2-phenylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (1i):
nBuLi (32.3 mL, 42 mmol, 1.3 m in hexane) was added at –78 °C
to a THF solution (200 mL) containing DIPA (5.9 mL, 42 mmol)
in a round-bottomed flask flushed with argon. After 30 min at
0 °C, the solution was recooled to –78 °C and 2,2,6-trimethyl-2,4-
dihydro-1,3-dioxin-4-one (1a; 5.8 mL, 42 mmol) was added. Fi-
nally, after 30 min at –78 °C, benzaldehyde (3.6 mL, 35 mmol) was
added. After 2 h at –40 °C, the reaction was quenched at 0 °C with
1 n HCl and the mixture extracted twice with EtOAc. The com-
bined organic layers were then dried with MgSO4, filtered and con-
centrated under vacuum. The crude product was purified by flash
chromatography on silica gel using cyclohexane/EtOAc (70:30) as
eluent to give the dioxinone 1i as a yellow solid in 98% yield (8.5 g,
(neat): ν = 1727, 1632, 1385, 1374, 1272, 1250, 1207, 1087, 1068,
˜
1010, 941, 836, 806, 752, 701 cm–1. MS (ESI): m/z = 321 [M +
H]+.
General Procedure for the Synthesis of α-Hydroxy Ketones 2d,e
(Procedure F):[15] Sodium formate (3 equiv.) was stirred in ethanol
(0.1 molL–1) for 15 min in a round-bottomed flask and the relevant
acetophenone (1 equiv.) was then added. The mixture was stirred
at 70 °C overnight. The solution was filtered hot and concentrated
under vacuum. The crude residue was then purified by flash
chromatography on silica gel using an appropriate gradient of cy-
clohexane/EtOAc as eluent to give the desired α-hydroxy ketone
2d,e.
1
34 mmol), m.p. 75 °C. H NMR (300 MHz, CDCl3): δ = 1.63 (s, 3
H), 1.64 (s, 3 H), 2.57 [A(ABX), JAB = 21.9, JAX = 7.5 Hz, 1 H],
2.62 (br. s, 1 H), 2.68 [B(ABX), JAB = 21.9, JBX = 12.3 Hz, 1 H],
4.95 [X(ABX), JAX = 7.5, JBX = 12.3 Hz, 1 H], 5.27 (s, 1 H), 7.28–
7.36 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.7, 25.4,
43.2, 71.2, 95.3, 106.8, 125.8, 128.3, 128.8, 142.9, 161.4, 168.6 ppm.
2-Hydroxy-1-phenylethanone (2d): Following procedure F, 2-
bromoacetophenone (4.02 g, 20 mmol) was used to afford 2d as a
white solid in 44% yield (1.20 g, 8.8 mmol) after purification by
flash chromatography on silica gel (cyclohexane/EtOAc, 80:20),
m.p. 82 °C. 1H NMR (300 MHz, CDCl3): δ = 3.58 (br. s, 1 H), 4.86
(s, 2 H), 7.46 (t, J = 7.4 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 7.88
(d, J = 7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 65.7,
IR (neat): ν = 3424, 1691, 1641, 1375, 1281, 1204, 1015, 805, 750,
˜
700 cm–1. MS (ESI): m/z = 249 [M + H]+.
General Procedure for the Synthesis of Silylated Dioxinones 1j,k
(Procedure E): DIEA (3 equiv.) and tert-butyldimethylsilyl trifluor-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30166
/KAP1
Date: 08-04-13 11:37:56
Pages: 13
P. A. Peixoto, A. Boulangé, S. Leleu, X. Franck
FULL PAPER
127.9, 129.2, 133.6, 134.5, 198.7 ppm. IR (neat): ν = 3420, 3389,
(d, J = 9.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.9,
55.7, 70.6, 114.6, 121.8, 123.6, 130.6, 163.1, 164.5, 171.7,
˜
1682, 1598, 1583, 1447, 1407, 1292, 1231, 1104, 971, 752 cm–1.
196.8 ppm. IR (neat): ν = 1745, 1686, 1602, 1512, 1254, 1176, 1023,
˜
2-Hydroxy-1-(4-methoxyphenyl)ethanone (2e): Following pro-
cedure F, 2-bromo-4-methoxyacetophenone (4.68 g, 20 mmol) was
used to afford 2e as a white solid in 90% yield (2.99 g, 18 mmol)
after purification by flash chromatography on silica gel (cyclohex-
ane/EtOAc, 80:20), m.p. 112 °C. 1H NMR (300 MHz, CDCl3): δ =
3.58 (br. s, 1 H), 3.89 (s, 3 H), 4.83 (s, 2 H), 6.97 (d, J = 8.9 Hz, 2
H), 7.91 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
830 cm–1. MS (ESI): m/z = 231 [M – H]+.
3-Benzoyl-4-methylfuran-2(5H)-one (12): Following procedure G,
hydroxyacetone 2b (0.07 mL, 1 mmol) and dioxinone 1b (306 mg,
1.5 mmol) were used to afford 12 as a yellow oil in 60% yield
(121 mg, 0.6 mmol) after purification by flash chromatography on
silica gel (cyclohexane/EtOAc, 80:20). 1H NMR (300 MHz,
CDCl3): δ = 2.21 (s, 3 H), 4.88 (s, 2 H), 7.48 (t, J = 10.5 Hz, 2 H),
7.63 (t, J = 10.5 Hz, 1 H), 7.87 (d, J = 10.5 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.0, 73.0, 127.7, 128.8, 129.7, 134.3,
= 55.7, 65.1, 114.3, 126.4, 130.2, 164.5, 196.8 ppm. IR (neat): ν =
˜
3419, 3376, 1683, 1670, 1605, 1577, 1512, 1226, 1185, 1104, 1030,
977, 834, 821 cm–1.
136.2, 169.2, 170.6, 189.8 ppm. IR (neat): ν = 1752, 1658, 1598,
˜
General Procedure for the Synthesis of Acyfuranones 8–28 (Pro-
cedure G): Et3N (0.5 equiv.), dioxinone 1a–e (1.5 equiv.) and molec-
ular sieves (4 Å, 200 mgmol–1) were added at room temp. to a tolu-
ene solution (0.1 molL–1) of α-hydroxy ketone 2a–e (1 equiv.) in a
round-bottomed flask flushed with argon. The mixture was then
heated to 110 °C. After 3 h, the reaction was quenched at room
temp. with 1 n HCl and the mixture extracted with EtOAc. The
aqueous layer was then extracted twice with ethyl acetate. The com-
bined organic layers were then dried with MgSO4, filtered and con-
centrated under vacuum. The crude residue was purified by flash
chromatography on silica gel using an appropriate gradient of cy-
clohexane/EtOAc as eluent to give the desired acylfuranone 8–28.
1447, 1320, 1242, 888 cm–1. MS (ESI): m/z = 203 [M + H]+.
3-Benzoyl-4,5,5-trimethylfuran-2(5H)-one (13): Following pro-
cedure G, 3-hydroxy-3-methylbutan-2-one (2a; 0.11 mL, 1 mmol)
and dioxinone 1b (306 mg, 1.5 mmol) were used to afford 13 as a
white solid in 90% yield (207 mg, 0.9 mmol) after purification by
flash chromatography on silica gel (cyclohexane/EtOAc, 70:30),
1
m.p. 126 °C. H NMR (300 MHz, CDCl3): δ = 1.57 (s, 6 H), 2.11
(s, 3 H), 7.47 (t, J = 7.4 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 7.84
(d, J = 7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.6,
24.8, 86.6, 126.4, 128.8, 129.6, 134.2, 136.4, 168.8, 175.8,
190.2 ppm. IR (neat): ν = 1742, 1655, 1345, 1289, 925, 894, 767,
˜
693, 670 cm–1. MS (ESI): m/z = 229 [M – H]+.
3-Acetyl-4-methylfuran-2(5H)-one (8): Following procedure G, hy-
droxyacetone 2b (0.07 mL, 1 mmol) and 2,2,6-trimethyl-2,4-dihy-
dro-1,3-dioxin-4-one (1a; 0.20 mL, 1.5 mmol) were used to afford
8 as a yellow oil in 88% yield (123 mg, 0.88 mmol) after purifica-
tion by flash chromatography on silica gel (cyclohexane/EtOAc,
3-Benzoyl-4-phenylfuran-2(5H)-one (14): Following procedure G, α-
hydroxy ketone 2d (136 mg, 1 mmol) and dioxinone 1b (306 mg,
1.5 mmol) were used to afford 14 as a colourless oil in 53% yield
(140 mg, 0.53 mmol) after purification by flash chromatography on
silica gel (cyclohexane/EtOAc, 70:30). 1H NMR (300 MHz,
CDCl3): δ = 5.35 (s, 2 H), 7.32–7.44 (m, 7 H), 7.57–7.62 (m, 1 H),
7.91–7.94 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 70.7,
125.8, 127.9, 129.0, 129.1, 129.4, 129.7, 132.2, 134.7, 135.5, 161.2,
1
70:30). H NMR (300 MHz, CDCl3): δ = 2.40 (s, 3 H), 2.52 (s, 3
H), 4.74 (s 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.9, 30.3,
72.7, 125.3, 171.4, 174.6, 194.9 ppm. IR (neat): ν = 1754, 1714,
˜
1362, 1210, 1163, 1020 cm–1. MS (ESI): m/z = 139 [M – H]+.
3-Acetyl-4,5,5-trimethylfuran-2(5H)-one (9): Following pro-
cedure G, 3-hydroxy-3-methylbutan-2-one (2a; 0.11 mL, 1 mmol)
and 2,2,6-trimethyl-2,4-dihydro-1,3-dioxin-4-one (1a; 0.20 mL,
1.5 mmol) were used to afford 9 as a white solid in 100% yield
(168 mg, 1 mmol) after purification by flash chromatography on
silica gel (cyclohexane/EtOAc, 50:50), m.p. 47 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.34 (s, 3 H), 2.56 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.3, 24.4, 30.2, 85.7,
170.8, 191.5 ppm. IR (neat): ν = 1730, 1664, 1636, 1596, 1453,
˜
1331, 1241, 1039, 921, 877, 759, 678 cm–1. MS (ESI): m/z = 263
[M – H]+.
3-Benzoyl-4-(4-methoxyphenyl)furan-2(5H)-one (15): Following
procedure G, α-hydroxy ketone 2e (166 mg, 1 mmol) and dioxinone
1b (306 mg, 1.5 mmol) were used to afford 15 as a yellow solid in
52% yield (153 mg, 0.52 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30), m.p.
123.6, 169.4, 180.9, 195.4 ppm. IR (neat): ν = 1760, 1691, 1288,
˜
1030 cm–1. MS (ESI): m/z = 167 [M – H]+. C9H12O3 (168.19): calcd.
1
120 °C. H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H), 5.32 (s, 2
C 64.27, H 7.19; found C 64.23, H 7.21.
H), 6.85 (d, J = 9.0 Hz, 2 H), 7.36 (d, J = 9.0 Hz, 2 H), 7.46 (t, J
= 7.5 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.94 (d, J = 7.5 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.4, 70.5, 114.7, 121.3,
123.0, 128.9, 129.6, 129.8, 134.5, 135.6, 160.8, 162.6, 171.2,
3-Acetyl-4-phenylfuran-2(5H)-one (10): Following procedure G, α-
hydroxy ketone 2d (136 mg, 1 mmol) and 2,2,6-trimethyl-2,4-dihy-
dro-1,3-dioxin-4-one (1a; 0.20 mL, 1.5 mmol) were used to afford
10 as a colourless oil in 30% yield (61 mg, 0.30 mmol) after purifi-
cation by flash chromatography on silica gel (cyclohexane/EtOAc,
192.0 ppm. IR (neat): ν = 2926, 2855, 1734, 1662, 1597, 1514, 1333,
˜
1261, 1240, 1179, 1024, 830, 674 cm–1. MS (ESI): m/z = 293 [M –
1
H]+.
80:20). H NMR (300 MHz, CDCl3): δ = 2.55 (s, 3 H), 5.15 (s, 2
H), 7.43–7.56 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 31.0,
4-Methyl-3-octanoylfuran-2(5H)-one (16): Following procedure G,
hydroxyacetone 2b (0.07 mL,1 mmol) and dioxinone 1c (339 mg,
1.5 mmol) were used to afford 16 as a colourless oil in 50% yield
(112 mg, 0.5 mmol) after purification by flash chromatography on
silica gel (cyclohexane/EtOAc, 80:20). 1H NMR (300 MHz,
CDCl3): δ = 0.79–0.84 (m, 3 H), 1.22–1.24 (m, 8 H), 1.53–1.58 (m,
2 H), 2.36 (s, 3 H), 2.88 (t, J = 7.4 Hz, 2 H), 4.71 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1, 14.6, 22.6, 23.3, 29.1, 29.2,
71.1, 126.3, 128.4, 129.4, 129.7, 132.5, 165.2, 171.2, 196.4 ppm. IR
(neat): ν = 1744, 1693, 1623, 1447, 1332, 1220, 1175, 1047, 999,
˜
762, 692 cm–1. MS (ESI): m/z = 203 [M + H]+.
3-Acetyl-4-(4-methoxyphenyl)furan-2(5H)-one (11): Following pro-
cedure G, α-hydroxy ketone 2e (166 mg, 1 mmol) and 2,2,6-tri-
methyl-2,4-dihydro-1,3-dioxin-4-one (1a; 0.20 mL, 1.5 mmol) were
used to afford 11 as a yellow oil in 30% yield (70 mg, 0.30 mmol,
30%) after purification by flash chromatography on silica gel (cy-
clohexane/EtOAc, 70:30). 1H NMR (300 MHz, CDCl3): δ = 2.59
(s, 3 H), 3.87 (s, 3 H), 5.16 (s, 2 H), 6.95 (d, J = 9.0 Hz, 2 H), 7.62
31.7, 42.2, 72.4, 125.1, 171.0, 173.4, 197.4 ppm. IR (neat): ν = 2921,
˜
2859, 1758, 1692, 1627, 1375, 1020, 933 cm–1. MS (ESI): m/z = 223
[M – H]+.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30166
/KAP1
Date: 08-04-13 11:37:56
Pages: 13
Synthesis of Acylfuranones
4,5,5-Trimethyl-3-octanoylfuran-2(5H)-one (17): Following pro-
cedure G, 3-hydroxy-3-methylbutan-2-one (2a; 0.11 mL, 1 mmol)
and dioxinone 1c (339 mg, 1.5 mmol) were used to afford 17 as a
colourless oil in 57% yield (144 mg, 0.57 mmol) after purification
by flash chromatography on silica gel (cyclohexane/EtOAc, 70:30).
3-(4-Methoxybenzoyl)-4-phenylfuran-2(5H)-one (22): Following
procedure G, α-hydroxy ketone 2d (136 mg, 1 mmol) and dioxinone
1d (351 mg, 1.5 mmol) were used to afford 22 as a white solid in
54% yield (158 mg, 0.54 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30), m.p.
1H NMR (300 MHz, CDCl3): δ = 0.77–0.81 (m, 3 H), 1.19–1.23 98 °C. 1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H), 5.33 (s, 2
(m, 8 H), 1.41 (s, 6 H), 1.48–1.55 (m, 2 H), 2.25 (s, 3 H), 2.87 (t, J H), 6.92 (d, J = 9.0 Hz, 2 H), 7.35–7.44 (m, 5 H), 7.91 (d, J =
= 16.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.2, 14.2,
9.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.7, 70.7,
22.7, 23.4, 24.4, 29.1, 29.2, 31.8, 42.3, 85.7, 123.8, 169.3, 180.4,
114.4, 126.1, 127.8, 128.7, 129.2, 129.4, 132.0, 132.2, 160.4, 164.9,
198.2 ppm. IR (neat): ν = 2934, 2853, 1751, 1689, 1624, 1282, 1039,
171.1, 189.8 ppm. IR (neat): ν = 1748, 1596, 1571, 1254, 1173,
˜
˜
967, 921 cm–1. MS (ESI): m/z = 251 [M – H]+.
1026, 846, 768, 690 cm–1. MS (ESI): m/z = 293 [M – H]+.
3-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)furan-2(5H)-one
(23):
3-Octanoyl-4-phenylfuran-2(5H)-one (18): Following procedure G,
α-hydroxy ketone 2d (136 mg, 1 mmol) and dioxinone 1c (339 mg,
1.5 mmol) were used to afford 18 as a colourless oil in 29% yield
(83 mg, 0.29 mmol) after purification by flash chromatography on
silica gel (cyclohexane/EtOAc, 70:30). 1H NMR (300 MHz,
CDCl3): δ = 0.84–0.88 (m, 3 H), 1.24–1.27 (m, 8 H), 1.58–1.67 (m,
2 H), 2.88 (t, J = 7.5 Hz, 2 H), 5.16 (s, 2 H), 7.44–7.54 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 29.0,
29.1, 31.7, 43.0, 70.8, 126.3, 128.0, 129.2, 129.4, 132.1, 164.0, 171.1,
Following procedure G, α-hydroxy ketone 2e (166 mg, 1 mmol) and
dioxinone 1d (351 mg, 1.5 mmol) were used to afford 23 as a yellow
solid in 61% yield (198 mg, 0.61 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30), m.p.
1
170 °C. H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.86 (s, 3
H), 5.30 (s, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 6.93 (d, J = 8.7 Hz, 2
H), 7.36 (d, J = 8.7 Hz, 2 H), 7.91 (d, J = 8.7 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 55.5, 55.6, 70.5, 114.3, 114.8, 121.5,
123.3, 128.8, 129.8, 132.2, 160.0, 162.5, 164.8, 171.5, 190.4 ppm.
199.6 ppm. IR (neat): ν = 2928, 2853, 1764, 1705, 1618, 1450, 1241,
˜
IR (neat): ν = 1735, 1597, 1508, 1248, 1159, 1021, 833 cm–1. MS
1157, 977, 765, 690 cm–1. MS (ESI): m/z = 285 [M – H]+.
˜
(ESI): m/z = 325 [M + H]+.
4-(4-Methoxyphenyl)-3-octanoylfuran-2(5H)-one and (Z)-3-(1-Hy-
droxyoctylidene)-4-(4-methoxyphenyl)furan-2(3H)-one (19): Follow-
ing procedure G, α-hydroxy ketone 2e (166 mg, 1 mmol) and dioxi-
none 1c (339 mg, 1.5 mmol) were used to afford 19 as a colourless
oil in 25% yield (79 mg, 0.25 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30). A mix-
3-Acetyl-4,5-dimethylfuran-2(5H)-one and (Z)-3-(1-Hydroxyethyl-
idene)-4,5-dimethylfuran-2(3H)-one (24): Following procedure G, 3-
hydroxybutan-2-one (2c; 0.09 mL, 1 mmol) and 2,2,6-trimethyl-2,4-
dihydro-1,3-dioxin-4-one (1a; 0.20 mL, 1.5 mmol) were used to af-
ford 24 as a colourless oil in 24% yield (37 mg, 0.24 mmol) after
purification by flash chromatography on silica gel (cyclohexane/
EtOAc, 70:30). A mixture of the ketone and its enol form (25:75)
was formed. 1H NMR (300 MHz, CDCl3): δ = 1.49 (d, J = 7.0 Hz,
0.75 H), 1.69 (s, 2.25 H), 2.37 (s, 0.75 H), 2.38 (s, 2.25 H), 2.55 (s,
2.25 H), 2.56 (s, 0.75 H), 3.65 (br. s, 0.75 H), 4.91 (q, J = 6.8,
14.0 Hz, 0.25 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.9, 14.3,
17.7, 23.3, 30.3, 30.5, 79.7, 105.0, 124.7, 125.0, 168.3, 170.6, 174.8,
1
ture of the ketone and its enol form (60:40) was formed. H NMR
(300 MHz, CDCl3): δ = 0.84–0.88 (m, 3 H), 1.25–1.28 (m, 8 H),
1.62–1.67 (m, 2 H), 2.64 (t, J = 7.4 Hz, 0.8 H), 2.92 (t, J = 7.4 Hz,
1.2 H), 3.62 (s, 0.4 H), 3.87 (s, 1.8 H), 3.88 (s, 1.2 H), 5.15 (s, 1.2
H), 5.36 (s, 0.4 H), 6.93–6.97 (m, 2 H), 7.56 (d, J = 9.0 Hz, 1.2 H),
7.89 (d, J = 9.0 Hz, 0.8 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.2, 22.7, 23.6, 29.0, 29.1, 29.2, 31.7, 43.1, 49.0, 55.6, 55.7, 66.5,
70.6, 114.2, 114.6, 121.9, 123.9, 127.0, 130.2, 130.3, 162.9, 163.4,
178.3, 195.5, 195.6 ppm. IR (neat): ν = 1754, 1677, 1630, 1362,
˜
1325, 1232, 1185, 1011, 908 cm–1. MS (ESI): m/z = 153 [M – H]+.
164.2, 166.9, 171.6, 190.1, 200.2, 202.9 ppm. IR (neat): ν = 2921,
˜
3-Benzoyl-4,5-dimethylfuran-2(5H)-one and (Z)-3-[Hydroxy(phen-
yl)methylene]-4,5-dimethylfuran-2(3H)-one (25): Following pro-
cedure G, 3-hydroxybutan-2-one (2c; 0.09 mL, 1 mmol) and dioxi-
none 1b (306 mg, 1.5 mmol) were used to afford 25 as a white solid
in 26% yield (56 mg, 0.26 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30), m.p.
98 °C. A mixture of the ketone and its enol form (75:25) was
formed. 1H NMR (300 MHz, CDCl3): δ = 1.56 (d, J = 7.0 Hz, 2.25
H), 1.75 (s, 0.75 H), 2.10 (s, 0.75 H), 2.14 (s, 2.25 H), 4.47 (br. s,
0.25 H), 5.04 (q, J = 6.8, 13.6 Hz, 0.75 H), 7.44–7.50 (m, 2 H),
7.58–7.63 (m, 1 H), 7.82–7.86 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.4, 13.5, 18.1, 23.6, 80.2, 105.9, 127.2, 127.5, 128.8,
128.9, 129.6, 129.7, 134.3, 134.5, 136.1, 136.2, 167.6, 169.2, 169.9,
2853, 1745, 1692, 1602, 1515, 1260, 1182, 1064, 1030, 973,
830 cm–1. MS (ESI): m/z = 287 [M – H]+.
3-(4-Methoxybenzoyl)-4-methylfuran-2(5H)-one (20): Following
procedure G, hydroxyacetone 2b (0.07 mL, 1 mmol) and dioxinone
1d (351 mg, 1.5 mmol) were used to afford 20 as a white solid in
61% yield (142 mg, 0.61 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 60:40), m.p.
1
102 °C. H NMR (300 MHz, CDCl3): δ = 2.19 (s, 3 H), 3.88 (s, 3
H), 4.86 (s, 2 H), 6.95 (d, J = 8.1 Hz, 2 H), 7.85 (d, J = 8.1 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 55.7, 72.9, 114.1,
127.9, 129.3, 132.2, 164.6, 168.0, 170.8, 188.1 ppm. IR (neat): ν =
˜
1746, 1602, 1575, 1259, 1181, 1015, 838, 788 cm–1. MS (ESI): m/z
= 231 [M – H]+.
172.9, 190.1 ppm. IR (neat): ν = 3427, 3062, 1754, 1652, 1595,
˜
1351, 1246, 1061, 901, 769, 693, 672 cm–1. MS (ESI): m/z = 217
3-(4-Methoxybenzoyl)-4,5,5-trimethylfuran-2(5H)-one (21): Follow-
ing procedure G, 3-hydroxy-3-methylbutan-2-one (2a; 0.11 mL,
1 mmol) and dioxinone 1d (351 mg, 1.5 mmol) were used to afford
21 as a yellow solid in 71% yield (185 mg, 0.71 mmol) after purifi-
cation by flash chromatography on silica gel (cyclohexane/EtOAc,
[M – H]+.
3-(Furan-2-ylcarbonyl)-4,5,5-trimethylfuran-2(5H)-one (26): Follow-
ing procedure G, 3-hydroxy-3-methylbutan-2-one (2a; 0.11 mL,
1 mmol) and dioxinone 1e (291 mg, 1.5 mmol) were used to afford
70:30), m.p. 67 °C. 1H NMR (300 MHz, CDCl3): δ = 1.56 (s, 6 H), 26 as a yellow solid in 65% yield (143 mg, 0.65 mmol) after purifi-
2.08 (s, 3 H), 3.86 (s, 3 H), 6.93 (d, J = 8.5 Hz, 2 H), 7.82 (d, J = cation by flash chromatography on silica gel (cyclohexane/EtOAc,
8.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.5, 24.8,
70:30), m.p. 103 °C. 1H NMR (300 MHz, CDCl3): δ = 1.55 (s, 6
55.7, 86.5, 114.0, 126.6, 129.4, 132.1, 164.5, 169.0, 174.8, H), 2.19 (s, 3 H), 6.59 (br. s, 1 H), 7.36 (d, J = 3.6 Hz, 1 H), 7.68
188.5 ppm. IR (neat): ν = 1746, 1597, 1569, 1253, 1176, 1071, 1021,
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.6, 24.6, 86.5,
112.8, 121.6, 125.4, 148.0, 151.9, 168.4, 176.3, 177.4 ppm. IR
˜
921, 905 cm–1. MS (ESI): m/z = 259 [M – H]+.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30166
/KAP1
Date: 08-04-13 11:37:56
Pages: 13
P. A. Peixoto, A. Boulangé, S. Leleu, X. Franck
FULL PAPER
(neat): ν = 3133, 2986, 1728, 1639, 1464, 1395, 1338, 1273, 1079, CDCl3): δ = 13.7, 24.4, 85.6, 97.2, 120.1, 127.6, 128.7, 133.0, 135.5,
˜
1028, 944, 772 cm–1. MS (ESI): m/z = 219 [M – H]+.
168.9, 176.4, 178.3, 189.2 ppm. IR (neat): ν = 2909, 1742, 1633,
˜
1596, 1524, 1462, 1369, 1254, 1036, 827, 793, 781, 694 cm–1. MS
3-(Furan-2-ylcarbonyl)-4-(4-methoxyphenyl)furan-2(5H)-one (27):
Following procedure G, α-hydroxy ketone 2e (166 mg, 1 mmol) and
dioxinone 1e (291 mg, 1.5 mmol) were used to afford 27 as a yellow
oil in 43% yield (122 mg, 0.43 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 70:30). 1H
(ESI): m/z = 273 [M + H]+.
4,5,5-Trimethyl-3-[2-(phenylsulfonyl)acetyl]furan-2(5H)-one
(31):
Following procedure H, 3-hydroxy-3-methylbutan-2-one (2a;
0.11 mL, 1.0 mmol), dioxinone 1f (423 mg, 1.5 mmol) and DIEA
NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 5.28 (s, 2 H), 6.54– (0.35 mL, 2 mmol) were used to afford 32 as a white solid in 59%
6.56 (m, 1 H), 6.89 (d, J = 9.0 Hz, 2 H), 7.24–7.26 (m, 2 H), 7.43 (d,
J = 9.0 Hz, 1 H), 7.62 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 55.5, 70.6, 113.0, 114.7, 121.4, 121.6, 122.0, 129.9, 148.4, 151.9,
yield (183 mg, 0.59 mmol) after purification by flash chromatog-
raphy on silica gel (cyclohexane/EtOAc, 70:30), m.p. 100 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.44 (s, 6 H), 2.31 (s, 3 H), 4.90 (s,
162.1, 162.7, 171.0, 178.2 ppm. IR (neat): ν = 1747, 1647, 1604, 2 H), 7.54 (t, J = 7.7 Hz, 2 H), 7.65 (t, J = 7.7 Hz, 1 H), 7.90 (d,
˜
1516, 1461, 1261, 1184, 1061, 1023 cm–1. MS (ESI): m/z = 283 [M –
J = 7.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6, 24.2,
64.7, 86.3, 123.0, 128.4, 129.3, 134.3, 139.6, 168.9, 183.8,
H]+.
184.7 ppm. IR (neat): ν = 2915, 1748, 1695, 1624, 1446, 1334, 1306,
˜
3-(Furan-2-ylcarbonyl)-4-phenylfuran-2(5H)-one (28): Following
procedure G, α-hydroxy ketone 2d (136 mg, 1 mmol) and dioxinone
1e (291 mg, 1.5 mmol) were used to afford 28 as a yellow solid in
39% yield (99 mg, 0.39 mmol) after purification by flash
1297, 1269, 1157, 1123, 1058, 980, 886, 759, 687 cm–1. MS (ESI):
m/z = 307 [M – H]+.
(Z)-4-[1-Hydroxy-3-(4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-
yl)-3-oxoprop-1-enyl]benzonitrile (32): Following procedure H, 3-hy-
chromatography on silica gel (cyclohexane/EtOAc, 70:30), m.p.
1
128 °C. H NMR (300 MHz, CDCl3): δ = 5.31 (s, 2 H), 6.54–6.56 droxy-3-methylbutan-2-one (2a; 0.11 mL, 1.0 mmol), dioxinone 1k
(m, 1 H), 7.40–7.48 (m, 6 H), 7.61 (s, 1 H) ppm. 13C NMR (278 mg, 1.5 mmol) and Et3N (0.28 mL, 2 mmol) were used to af-
(75 MHz, CDCl3): δ = 70.8, 113.1, 121.5, 124.9, 127.9, 129.2, 129.4,
ford 32 as a yellow solid in 50% yield (149 mg, 0.5 mmol) after
precipitation in EtOAc. Decomp. 200 °C. 1H NMR (300 MHz,
CDCl3): δ = 1 53 (s, 6 H), 2.49 (s, 3 H), 7.47 (s, 1 H), 7.77 (d, J =
8.7 Hz, 2 H), 8.08 (d, J = 8.7 Hz, 2 H), 16.1 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.0, 24.6, 86.0, 97.8, 116.0, 118.2,
120.1, 128.1, 132.6, 139.2, 168.9, 178.8, 180.0, 185.8 ppm. IR
132.3, 148.4, 151.9, 162.6, 170.6, 177.7 ppm. IR (neat): ν = 1733,
˜
1633, 1459, 1332, 1201, 1082, 1059, 1024, 939, 843, 762, 689,
589 cm–1. MS (ESI): m/z = 253 [M – H]+.
General Procedure for the Synthesis of Acylfuranones 29–32 (Pro-
cedure H): Et3N or DIEA (2 equiv.) as base and the appropriate
dioxinone (1.5 equiv.) were added at room temp. to a toluene solu-
tion (0.1 molL–1) of 3-hydroxy-3-methylbutan-2-one (2a; 1 equiv.)
and molecular sieves (4 Å, 200 mg per mmol) in a round-bottomed
flask flushed with argon. The mixture was then heated to 110 °C.
After 3 h, the reaction was quenched at room temp. with 1 n HCl
and the mixture extracted with EtOAc. The combined organic lay-
ers were then dried with MgSO4, filtered and concentrated under
vacuum. The crude residue was dissolved in a mixture of THF/1 n
HCl (10:1). After 2 h, the aqueous layer was extracted with EtOAc.
The combined organic layers were then dried with MgSO4, filtered
and concentrated under vacuum (except for the sulfone derivative
31). The crude was then purified by flash chromatography on silica
gel using an appropriate gradient of cyclohexane/EtOAc as eluent
to give the desired acylfuranones 29–32.
(neat): ν = 2224, 1758, 1636, 1515, 1487, 1328, 1291, 1257, 1210,
˜
1061, 1036, 967, 843, 818, 687 cm–1. MS (ESI): m/z = 296 [M –
H]+.
General Procedure for the Synthesis of Acylfuranones 34a–h (Pro-
cedure I): Toluene (for a solution of 1.0 molL–1), Et3N (2.0 equiv.)
and the appropriate α-hydroxy ketone (1 equiv.), dioxinone
(2 equiv.) and aldehyde (1 equiv.) were added to a 15 mL tube
flushed with argon. The tube was sealed and then heated in a mi-
crowave reactor. Over 1.5 min, the temperature was raised to
150 °C, held for 5 min, and then cooled for 10 min. The reaction
was quenched at room temperature with 1 n HCl and the mixture
extracted with EtOAc. The combined organic layers were then
dried with MgSO4, filtered and concentrated under vacuum. The
crude was then purified by flash chromatography on silica gel using
an appropriate gradient of cyclohexane/EtOAc as eluent to give the
desired acylfuranones 34a–h.
3-(3-Hydroxy-3-phenylpropanoyl)-4,5,5-trimethylfuran-2(5H)-one
(29): Following procedure H, 3-hydroxy-3-methylbutan-2-one (2a;
0.08 mL, 0.7 mmol), dioxinone 1l (332 mg, 1.0 mmol) and DIEA
(0.24 mL, 1.4 mmol) were used to afford 29 as a yellow solid in
91 % yield (175 mg, 0.64 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 50:50), m.p.
90 °C. 1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.36 (s, 3
(5Z)-3-(4-Methoxybenzoyl)-5-(4-methoxybenzylidene)-4-(4-meth-
oxyphenyl)furan-2(5H)-one (34a): Following procedure I, α-hydroxy
ketone 2e (83 mg, 0.5 mmol), dioxinone 1d (234 mg, 1.0 mmol) and
p-methoxybenzaldehyde (33; 0.06 mL, 0.5 mmol) were used to af-
ford 34a as a yellow solid in 77% yield (170 mg, 0.77 mmol) after
H), 3.20 (d, J = 4.0 Hz, 1 H), 3.41 (d, J = 6.0 Hz, 2 H), 5.21–5.26 purification by flash chromatography on silica gel (cyclohexane/
(m, 1 H), 7.25–7.42 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ EtOAc, 60:40). Analyses are similar to those described in the litera-
1
= 13.6, 24.4, 24.5, 50.7, 70.3, 86.1, 123.5, 125.9, 127.8, 128.6, 142.9,
ture.[21] M.p. 188 °C. H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3
H), 3.82 (s, 3 H), 3.85 (s, 3 H), 6.23 (s, 1 H), 6.84 (d, J = 8.9 Hz,
2 H), 6.90 (d, J = 7.9 Hz, 2 H), 6.93 (d, J = 7.9 Hz, 2 H), 7.36 (d, J
= 8.9 Hz, 2 H), 7.80 (d, J = 7.9 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 55.8, 55.8, 55.9, 114.2, 114.7, 114.9, 117.4, 121.8,
123.1, 126.1, 129.6, 131.2, 132.5, 133.4, 146.1, 157.4, 161.4, 161.7,
169.4, 182.1, 197.5 ppm. IR (neat): ν = 3441, 1724, 1696, 1630,
˜
1370, 1287, 1198, 1065, 1015, 921, 744, 700 cm–1. MS (ESI): m/z =
273 [M – H]+.
(Z)-3-(3-Hydroxy-3-phenylacryloyl)-4,5,5-trimethylfuran-2(5H)-one
(30): Following procedure H, 3-hydroxy-3-methylbutan-2-one (2a;
0.11 mL, 1.0 mmol), dioxinone 1j (541 mg, 1.5 mmol) and Et3N
(0.28 mL, 2 mmol) were used to afford 30 as a white solid in 91%
yield (248 mg, 0.9 mmol) after purification by flash chromatog-
raphy on silica gel (cyclohexane/EtOAc, 80:20), m.p. 127 °C. 1H
164.6, 167.2, 188.7 ppm. IR (neat): ν = 2934, 2840, 1755, 1655,
˜
1639, 1600, 1511, 1460, 1425, 1377, 1305, 1259, 1175, 1028, 973,
919, 838, 732 cm–1. MS (ESI): m/z = 443 [M + H]+.
(Z)-5-Benzylidene-3-(4-methoxybenzoyl)-4-(4-methoxyphenyl)furan-
NMR (300 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.44 (s, 3 H), 7.41– 2(5H)-one (34b): Following procedure I, α-hydroxy ketone 2e
7.52 (m, 4 H), 7.97 (d, J = 7.7 Hz, 2 H) ppm. 13C NMR (75 MHz,
(50 mg, 0.3 mmol), dioxinone 1d (141 mg, 0.6 mmol) and benzalde-
10
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Synthesis of Acylfuranones
hyde (0.03 mL, 0.3 mmol) were used to afford 34b as a yellow oil
in 61 % yield (76 mg, 0.18 mmol) after purification by flash
chromatography on silica gel (cyclohexane/EtOAc, 80:20). 1H
5.4 Hz, 1 H), 7.39 (d, J = 13.2 Hz, 2 H), 7.50 (d, J = 2.4 Hz, 1 H),
7.78 (d, J = 13.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
55.5, 112.7, 114.4, 114.6, 118.1, 121.0, 121.2, 121.3, 125.7, 131.0,
NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H), 3.84 (s, 3 H), 6.27 (s, 133.3, 145.7, 147.7, 152.0, 158.4, 161.3, 161.5, 166.4, 176.1 ppm.
1 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 8.7 Hz, 2 H), 7.37–7.44 IR (neat): ν = 1744, 1639, 1600, 1562, 1507, 1456, 1392, 1303, 1252,
˜
(m, 5 H), 7.80–7.85 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ 1175, 1021, 823 cm–1. MS (ESI): m/z = 403 [M + H]+.
= 55.5, 55.7, 114.1, 114.6, 116.8, 121.3, 124.1, 129.1, 129.3, 130.0,
(Z)-3-(4-Methoxybenzoyl)-5-(4-methoxybenzylidene)-4-methylfuran-
131.0, 131.2, 132.3, 133.0, 147.5, 156.9, 161.6, 164.5, 166.6,
2(5H)-one (34g): Following procedure I, hydroxyacetone 2b
188.2 ppm. IR (neat): ν = 1754, 1730, 1655, 1593, 1571, 1506, 1372,
˜
(0.07 mL, 1.0 mmol), dioxinone 1d (468 mg, 2.0 mmol) and p-
methoxybenzaldehyde (33; 0.11 mL, 1.0 mmol) were used to afford
1250, 1166, 1026, 970, 837 cm–1. MS (ESI): m/z = 413 [M + H]+.
(Z)-3-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)-5-(4-nitrobenzyl- 34g as a yellow solid in 25% yield (87 mg, 0.25 mmol) after purifi-
idene)furan-2(5H)-one (34c): Following procedure I, α-hydroxy
ketone 2e (50 mg, 0.3 mmol), dioxinone 1d (141 mg, 0.6 mmol) and
p-nitrobenzaldehyde (46 mg, 0.3 mmol) were used to afford 34c as
a yellow oil in 55% yield (75 mg, 0.16 mmol) after purification by
flash chromatography on silica gel (cyclohexane/EtOAc, 70:30). 1H
cation by flash chromatography on silica gel (cyclohexane/EtOAc,
80:20), m.p. 176 °C. 1H NMR (300 MHz, CDCl3): δ = 2.34 (s, 3
H), 3.86 (s, 3 H), 3.88 (s, 3 H), 6.28 (s, 1 H), 6.95 (d, J = 9.0 Hz,
2 H), 6.96 (d, J = 9.0 Hz, 2 H), 7.83 (d, J = 9.0 Hz, 2 H), 7.87 (d,
J = 9.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.5, 55.6,
NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H), 3.83 (s, 3 H), 6.30 (s, 55.7, 113.8, 114.0, 114.7, 124.2, 125.5, 129.9, 132.3, 133.2, 146.7,
1 H), 6.86 (d, J = 13.2 Hz, 2 H), 6.93 (d, J = 12.9 Hz, 2 H), 7.38
(d, J = 12.9 Hz, 2 H), 7.80 (d, J = 13.2 Hz, 2 H), 7.96 (d, J =
13.2 Hz, 2 H), 8.23 (d, J = 13.2 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 55.5, 55.7, 113.0, 114.2, 114.7, 120.6, 124.1, 125.5,
128.9, 130.9, 131.5, 132.2, 139.1, 147.6, 149.9, 156.1, 161.9, 164.7,
158.3, 161.2, 164.4, 167.2, 188.2 ppm. IR (neat): ν = 1751, 1639,
˜
1600, 1568, 1514, 1357, 1306, 1258, 1172, 1024, 948, 826, 784 cm–1.
MS (ESI): m/z = 351 [M + H]+.
(Z)-5-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-3-octanoylfur-
an-2(5H)-one (34h): Following procedure I, α-hydroxy ketone 2e
(166 mg, 1.0 mmol), dioxinone 1c (453 mg, 2.0 mmol) and p-meth-
oxybenzaldehyde (33; 0.11 mL, 1.0 mmol) were used to afford 34h
165.8, 187.6 ppm. IR (neat): ν = 1770, 1590, 1512, 1341, 1257,
˜
1166, 1017, 827, 793 cm–1. MS (ESI): m/z = 458 [M + H]+.
(Z)-3-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)-5-(2-methylbenzyl- as a yellow oil in 36% yield (156 mg, 0.36 mmol) after purification
idene)furan-2(5H)-one (34d): Following procedure I, α-hydroxy
ketone 2e (166 mg, 1.0 mmol), dioxinone 1d (469 mg, 2.0 mmol)
and o-tolualdehyde (0.12 mL, 1.0 mmol) were used to afford 34d as
a yellow solid in 45% yield (192 mg, 0.45 mmol) after purification
by flash chromatography on silica gel (cyclohexane/EtOAc, 80:20),
by flash chromatography on silica gel (cyclohexane/EtOAc, 80:20).
1H NMR (300 MHz, CDCl3): δ = 0.83–0.88 (m, 3 H), 1.25–1.30
(m, 8 H), 1.53–1.58 (m, 2 H), 2.89 (t, J = 7.5 Hz, 2 H), 3.85 (s, 3
H), 3.88 (s, 3 H), 6.11 (s, 1 H), 6.92 (d, J = 6.9 Hz, 2 H), 7.01 (d,
J = 6.9 Hz, 2 H), 7.39 (d, J = 6.9 Hz, 2 H), 7.78 (d, J = 6.9 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 22.9, 23.9, 29.4,
29.4, 32.0, 42.9, 55.7, 55.7, 114.1, 114.9, 119.6, 120.7, 121.7, 126.1,
1
m.p. 174 °C. H NMR (300 MHz, CDCl3): δ = 2.92 (s, 3 H), 3.82
(s, 3 H), 3.84 (s, 3 H), 6.52 (s, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.93
(d, J = 8.7 Hz, 2 H), 7.19–7.31 (m, 3 H), 7.41 (d, J = 8.7 Hz, 2 H),
131.5, 133.7, 146.6, 160.4, 161.8, 167.6, 196.9 ppm. IR (neat): ν =
˜
7.83 (d, J = 8.7 Hz, 2 H), 8.22 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR 1751, 1683, 1600, 1549, 1507, 1376, 1303, 1252, 1175, 1028, 983,
(75 MHz, CDCl3): δ = 20.5, 55.7, 55.9, 114.0, 114.3, 114.7, 121.7,
829 cm–1. MS (ESI): m/z = 435 [M + H]+.
124.3, 127.0, 129.5, 130.1, 130.8, 131.2, 131.4, 131.7, 132.5, 138.3,
(Z)-3-(4-Hydroxybenzoyl)-5-(4-hydroxybenzylidene)-4-(4-hydroxy-
phenyl)furan-2(5H)-one (35): BBr3 (0.37 mL, 2.15 mmol) was added
at –78 °C to a CH2Cl2 solution (2 mL) of acylfuranone 34a (95 mg,
0.21 mmol) in a round-bottomed flask flushed with argon. The me-
dium was then warmed slowly to room temp. over 20 h. The reac-
tion was quenched at –78 °C with MeOH then at room temp. with
H2O and the mixture extracted twice with EtOAc. The combined
147.7, 157.1, 161.8, 164.7, 167.0, 188.5 ppm. IR (neat): ν = 1754,
˜
1594, 1565, 1511, 1376, 1255, 1168, 1024, 973, 839, 756 cm–1. MS
(ESI): m/z = 427 [M + H]+.
(Z)-5-[4-(Dimethylamino)benzylidene]-3-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)furan-2(5H)-one (34e): Following procedure I, α-hy-
droxy ketone 2e (50 mg, 0.3 mmol), dioxinone 1d (141 mg,
0.6 mmol) and p-dimethylaminobenzaldehyde (46 mg, 0.3 mmol) organic layers were then dried with MgSO4, filtered and concen-
were used to afford 34e as a red oil in 4% yield (5 mg, 0.01 mmol)
after purification by flash chromatography on silica gel (cyclohex-
ane/EtOAc, 80:20). 1H NMR (300 MHz, CDCl3): δ = 3.06 (s, 6 H),
3.81 (s, 3 H), 3.83 (s, 3 H), 6.21 (s, 1 H), 6.69 (d, J = 8.9 Hz, 2 H),
trated under vacuum. The crude product was purified by
chromatography on silica gel by using cyclohexane/EtOAc (40:60)
as eluent to give the acylfuranone 35 as a yellow solid in 94% yield
(79 mg, 0.20 mmol). Analyses are similar to those described in the
6.85 (d, J = 8.6 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = literature.[21] M.p. 262 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
8.9 Hz, 2 H), 7.77 (d, J = 8.9 Hz, 2 H), 7.83 (d, J = 8.6 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.2, 55.5, 55.6, 112.0,
113.9, 114.3, 119.0, 121.0, 121.2, 122.2, 129.9, 131.0, 132.3, 133.5,
144.5, 151.5, 157.4, 161.2, 164.2, 167.4, 188.7 ppm. MS (ESI): m/z
= 456 [M + H]+.
6.33 (s, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H),
6.89 (d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 7.68 (d, J =
8.7 Hz, 2 H), 7.74 (d, J = 8.7 Hz, 2 H), 10.15 (br. s, 1 H), 10.28 (br.
s, 1 H), 10.69 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 115.5, 115.8, 116.1, 116.4, 119.3, 121.4, 124.0, 127.4, 130.8, 132.1,
133.0, 144.6, 155.9, 159.5, 159.6, 163.2, 166.1, 188.0 ppm. MS
(ESI): m/z = 399 [M – H]+.
(Z)-3-(Furan-2-ylcarbonyl)-5-(4-methoxybenzylidene)-4-(4-methoxy-
phenyl)furan-2(5H)-one (34f): Following procedure I, α-hydroxy
ketone 2e (166 mg, 1.0 mmol), dioxinone 1e (388 mg, 2.0 mmol) Cadiolide B: A brominating agent (0.69 mL) prepared from Br2
and p-methoxybenzaldehyde (33; 0.11 mL, 1.0 mmol) were used to
afford 34f as a red solid in 53% yield (212 mg, 0.53 mmol) after
(0.03 mL) and KBr (150 mg) in H2O (1 mL) was added dropwise
to a solution of acylfuranone 35 (26 mg, 0.065 mmol) in dioxane/
H2O (2 mL, 1:1). The mixture was stirred for 24 h, treated with
purification by flash chromatography on silica gel (cyclohexane/
1
DCM, 20:80), m.p. 54 °C. H NMR (300 MHz, CDCl3): δ = 3.82 brine and the mixture extracted with Et2O. The organic layer was
(s, 3 H), 3.83 (s, 3 H), 6.24 (s, 1 H), 6.46 (dd, J = 2.4, 5.4 Hz, 1 H),
washed with brine and then with Na2S2O3. The combined organic
6.90 (d, J = 13.2 Hz, 2 H), 6.94 (d, J = 13.2 Hz, 2 H), 7.15 (d, J = layers were then dried with Na2SO4, filtered and concentrated un-
Eur. J. Org. Chem. 0000, 0–0
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P. A. Peixoto, A. Boulangé, S. Leleu, X. Franck
FULL PAPER
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on silica gel using a gradient of EtOAc/MeOH (100:0 to 90:10) to
give Cadiolide B as a black solid in 67% yield (38 mg, 0.044 mmol).
Analyses are similar to those described in the literature.[3,4a] 1H
NMR (300 MHz, [D6]DMSO): δ = 6.40 (s, 1 H), 7.55 (s, 2 H), 7.91
(s, 2 H), 8.12 (s, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
109.7, 111.8, 112.0, 112.2, 114.0, 122.3, 122.8, 127.1, 130.2, 133.0,
133.7, 134.8, 146.2, 152.6, 154.8, 156.2, 165.3, 184.3 ppm. MS
(ESI): m/z (%) = 879 (8), 878 (14), 877 (30), 874 (78), 873 (100),
871 (84), 868 (30), 867 (6).
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for 1b–1k, and 8–35.
Acknowledgments
We gratefully acknowledge the Région Haute Normandie for finan-
cial support to A. B. and P. A. P. and the Agence Nationale de la
Recherche for a grant (Programme Blanc 2010, ANR-2010-BLAN-
732-01).
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Received: January 30, 2013
Published Online: ᭿
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30166
/KAP1
Date: 08-04-13 11:37:56
Pages: 13
Synthesis of Acylfuranones
Multicomponent Reaction
A new method for the synthesis of acylfur-
anones is described based on the fragmen-
tation of dioxinones to acylketenes fol-
lowed by trapping with hydroxy ketones.
Addition of an aldehyde as a third reaction
partner leads to a supplementary aldoli-
zation/crotonization sequence resulting in
an expeditious synthesis of cadiolide B and
its analogues.
P. A. Peixoto, A. Boulangé, S. Leleu,*
X. Franck* ...................................... 1–13
Versatile Synthesis of Acylfuranones by
Reaction of Acylketenes with α-Hydroxy
Ketones: Application to the One-Step Mul-
ticomponent Synthesis of Cadiolide B and
Its Analogues
Keywords: Synthetic methods / Multicom-
ponent reactions / Oxygen heterocycles /
Natural products / Ketenes
Eur. J. Org. Chem. 0000, 0–0
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