Regioselective bromination of tetronic acid-derived γ-lactones and metal-catalyzed post-functionalization: An efficient access to new γ-ylidenetetronate derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.06.106

The synthesis of several methyl and benzyl γ-ylidenetetronates was accomplished and the bromination reactions of these derivatives, using bromine or N-bromosuccinimide (NBS), were found to occur under mild conditions. Several new brominated γ-unsaturated

Full text of DOI:10.1016/j.tetlet.2013.06.106

Tetrahedron Letters 54 (2013) 4577–4581
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective bromination of tetronic acid-derived
metal-catalyzed post-functionalization: an efficient access to new
-ylidenetetronate derivatives
c-lactones and
c
Shinya Iikawa a, Nicolas Chopin a, Guillaume Pilet b, Jean-Philippe Bouillon c, Maurice Médebielle a,
⇑
a Université de Lyon, Université Claude Bernard Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246 CNRS-UCBL-INSA Lyon,
Equipe SMITH, Bâtiment Curien, 43 bd du 11 Novembre 1918, 69622 Villeurbanne, France
b Université de Lyon, Université Claude Bernard Lyon 1, Laboratoire des Multimatériaux et Interfaces (LMI), UMR CNRS 5615, Bâtiment Chevreul, 43 bd du 11 Novembre 1918,
69622 Villeurbanne, France
c Université de Rouen, Chimie Organique Bioorganique Réactivité et Analyses (COBRA), IRCOF, UMR CNRS 6014, 76821 Mont Saint Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of several methyl and benzyl c-ylidenetetronates was accomplished and the bromination
Received 27 May 2013
Revised 17 June 2013
Accepted 21 June 2013
Available online 29 June 2013
reactions of these derivatives, using bromine or N-bromosuccinimide (NBS), were found to occur under
mild conditions. Several new brominated -unsaturated lactones derived from tetronic acid were pre-
pared in moderate to good yields, with some of them characterized by single crystal X-ray diffraction.
A preliminary reactivity study of two bromine-derived -benzylidene methyl tetronates, in Sonogashira
cross-coupling reactions, with also preparation of 1,2,3-triazole-derived -benzylidene methyl tetronate
under Cu(I)-catalyzed condition, was performed with an indication that these brominated -benzylidene
tetronates are useful platforms to produce diversified -lactones.
c
c
c
Keywords:
Tetronic acid
Aldol
Bromination
Sonogashira
1,2,3-Triazole
c
c
Ó 2013 Elsevier Ltd. All rights reserved.
c-Lactones derived from tetronic acids and derived molecules,
are structures that occur naturally with various biological activities
and are promising compounds that can be used in a number of syn-
thetic useful reactions to prepare bioactive materials (Fig. 1).1 In
our current research program directed to the synthesis and biolog-
O
O
O
Me
O
OH
ical evaluation of new therapeutic agents, halogenated c-lactones
Ircinin-1 (natural product)
derived from tetronic acids were identified as useful synthetic
intermediates, with the aim to prepare a set of molecules with
some diversity (R1, R2, R3, and R4), through for example, metal-cat-
alyzed cross-coupling post-functionalization (Scheme 1). These
(Antiproliferative agent)
O
O
Cl
Cl
O
O
halogenation sequences starting from the c-benzylidenetetronates
OH
O
and use of the resulting products in the development of new valu-
able organic entities and chemotherapeutic agents are relatively
scarce in the literature.2
OH
MeO
Inhibitor of bacterial
Vulpinic acid
(natural product)
peptidoglycan biosynthesis
(Antibacterial)
In this Letter, we disclose our preliminary results directed to the
O
O
O
synthesis of c-lactones derived from methyl and benzyl tetronates,
their regioselective bromination, and their use in Sonogashira3
cross-coupling reactions. In order to demonstrate the synthetic
utility of our strategy, an example of Cu(I)-catalyzed 1,3-dipolar
cycloaddition with benzyl azide as 1,3-dipole, using an acety-
O
O
O
OH
O
c
-benzylidene-derived tetronate,4 is also
Cl
lenic-derived methyl
Cl
Spirodiclofen
(-)-Okilactomycin D
(Acaricidal activity)
(natural product)
⇑
Corresponding author. Tel.: +33 4 7243 1989.
E-mail address: maurice.medebielle@univ-lyon1.fr (M. Médebielle).
Figure 1. Natural and bioactive tetronic acid derivatives.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.106

4578
S. Iikawa et al. / Tetrahedron Letters 54 (2013) 4577–4581
and elimination with 1,8-diazabicycloundec-7-ene (DBU) as a
base,2b,c using dichloromethane as solvent. All the compounds
17–22 were obtained as a Z stereoisomer after column chromatog-
raphy.5 A minor E isomer was observed when R1 = Me from the
crude product (1H NMR) but was not isolated during purification
Br
OR1
OH
OR1
O
3-4
steps
O
Br
R2
OR1
2
O
O
O
1
O
because of trace amount, while for
c
-lactones with R1 = Bn such
R2
Br
R2
isomer was not detected at all. The Z stereochemistry has been
confirmed by single-crystal X-ray diffraction for the ferrocenyl-de-
rived compound 22a (Fig. 2)6 which has been obtained directly
during the aldolization process, without requiring the esterifica-
tion/elimination step. Aldol products 11a and 12a can also be
transformed into their corresponding unsaturated lactones 17a
O
O
3
R3
OR1
Metal-catalyzed
cross coupling
reactions
R4
O
O
R2
and 18a respectively, using H2SO4 in dichloromethane.7 For
c-lac-
New functionalized
tone 21b the elimination step was not efficient compared with its
methyl analogue 21a, and in general the -OBn derivatives were
found to be prone to some decomposition during the esterifica-
tion/elimination step.
tetronic acid derived γ-lactones
with potential diversity
Scheme 1. General access to the targets.
Bromination reactions were first performed on c-lactone 17a as
a model compound and N-bromosuccinimide (NBS) as brominating
reagent. Lithiation of 17a using lithium diisopropylamide (LDA) in
THF and trapping the C-3 lithium derivative with NBS in excess
(2.3 equiv), gave 23a in a moderate 52% isolated yield while using
just NBS (2.5 equiv) in dichloromethane resulted in the dibromin-
ation on the exocyclic double bond with the formation of 24a in a
modest 24% yield (Scheme 3).
These results show that bromination on C-3 position can occur
selectively through a previous activation (in this case with LDA).
Otherwise, running the reaction with bromine (1.5 equiv) in the
presence of pyridine (1.1 equiv) in dichloromethane at room tem-
perature over 2 h (concentration of substrate, C = 0.1 M), gave 23a
in an excellent 91% isolated yield after column chromatography
purification (Scheme 4). This optimized and more practical condi-
tion was found to be general, with some slight modifications, for a
presented giving access to a pharmaceutical relevant 1,2,3-triazole
tetronic acid-derived -lactone derivative.
c
Starting lactones of general structure 1 (Scheme 1) were pre-
pared, following literature procedures developed with some ana-
logues,2b,c,5 using either methyl tetronate (commercially
available) or known benzyl derivative.2b,c The benzyl derivative
was easily prepared in 60% yield by the reaction of benzyl bromide
(1.1 equiv) and potassium carbonate (K2CO3) (2.0 equiv) in N,N-
dimethylformamide (DMF). Treating tetronates 4 (4a, R1 = Me,
4b, R1 = Bn) with n-BuLi (1.1 equiv) and aldehydes (1.5 equiv) 5–
10 in tetrahydrofuran (THF) from ꢀ78 °C to room temperature
(overnight) gave the aldols adducts 11–16 as diastereoisomeric
mixtures (1/1) in good to excellent yields, after column chromatog-
raphy purification (Scheme 2 and Table 1). These alcohols 11–16
were then transformed into the corresponding c-lactones 17–22,
in moderate to good yields (Table 1), following a two-steps/one-
pot sequence through esterification with trifluoroacetic anhydride
series of
-lactones 23, 25–28 in moderate to excellent yields (Table 2).8
When -lactone 17a was reacted with bromine (1.0 equiv) in
dichloromethane, without pyridine, at 0 °C (1 h) and quenching
c-lactones 17–21 giving the corresponding 3-brominated
c
c
OR1
OR1
1. n-BuLi (1.1 equiv)
2. R2-CHO 5-10 (1.5 equiv)
OH
R2
O
O
O
THF
O
1
R1 = Me
R = Bn
-78 °C → r.t/overnight
4a;
4b
11-16
OR1
1. (CF3CO)2O (1.1 equiv)
Et3N (2.0 equiv)/DMAP (cat.)
CH2Cl2
0 °C → r.t/2 h
11-16
O
O
2. DBU (1.0 equiv)
r.t/ 30 min
R2
(Z)
17-22
Scheme 2.
c-Lactone synthesis from methyl or benzyl tetronates.
Table 1
Preparation of the
c-ylidenetetronates and precursors
Figure 2. Single crystal X-ray diffraction of (Z)-c-lactone 22a.
R1
R2 in R2 CHO
Aldol (% yield)a
c
-Lactone (% yield)a
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
5: Ph
6: 4-F-Ph
11a (93%)
12a (82%)
13a (65%)
14a (99%)
15a (67%)
16ac
11b (94%)
12b
(99%) 13b (55%)
15b (96%)
17a (42%; 57%b)
18a (63%)b
19a (60%)
20a (34%)
21a (65%)
22a (99%)
17b (50%)
18b (90%)
19b (33%)
21b (32%)
OMe
Br
OMe
1. LDA (1.1 equiv)
2. NBS (2.3 equiv)
7: 3,4-OMe-Ph
8: 3,4-F-Ph
9: 4-CF3-Ph
10: Ferrocenyl
5: Ph
6: 4-F-Ph
7: 3,4-OMe-Ph
9: 4-CF3-Ph
O
O
O
17a
O
THF
Ph
Br
Ph
-78 °C to r.t/overnight
23a 52%
OMe
Br
NBS (2.5 equiv)
CH2Cl2
O
O
0 °C to r.t/overnight
a
b
c
Ph
Isolated yield.
Concd H2SO4 in dichloromethane at rt was used.
Not formed (see text).
24%
24a
Scheme 3. Bromination of
c-lactone 17a using N-bromosuccinimide.

S. Iikawa et al. / Tetrahedron Letters 54 (2013) 4577–4581
4579
the reaction at the same temperature, different compounds can be
obtained according to the concentration of starting material
(Scheme 5). Indeed, the reaction performed with C = 0.1 M pro-
vided predominantly compound 23a with 69% yield along traces
(<10%) of separable tribrominated analogue 30a, while the same
procedure, under more diluted conditions (C = 0.02 M), induced
the diastereoselective formation of the dibrominated compound
24a with moderate yield of 57%.9 Otherwise, the corresponding
monobrominated Z isomer 29a can be obtained with excellent
yield of 88% from the dibrominated compound 24a in the presence
of DBU (2.0 equiv) that induced the anti-elimination of HBr.10 Sin-
gle-crystal X-ray diffraction confirmed the anti-stereochemistry of
24a as well as the Z configuration of 29a (Fig. 3).11
The sequence dibromination/base-promoted debromination
(17a?24a?29a) can also be conducted in a one-pot procedure
with 50% overall yield. Finally 17a when treated with an excess
of bromine (2.0 equiv) at 0 °C for 1 h and quenching the reaction
at this temperature, gave the tribrominated compound 30a in
78% isolated yield.12 However treatment of 30a with DBU
(2.0 equiv) in dichloromethane for 30 min. gave in 86% yield the
two non-separable debrominated compounds 31a and 32a.13
Br2 (1.5 equiv)
Pyridine (1.1 equiv)
Br
OMe
OMe
With these conditions in hand to get diverse brominated c-ben-
zylidene methyl tetronate derivatives, we attempted, in a preli-
minary feasibility study, typical Sonogashira cross-coupling
reactions using 23a and 29a (Schemes 6 and 7).
CH2Cl2
O
O
O
O
17a
r.t/2 h
Ph
91%
Ph
23a
C = 0.1 M
Sonogashira cross-coupling of 23a with trimethysilylacetylene
gave the desired CAC coupling product 33a in 78% isolated yield14
which was desilylated using tetrabutylammonium fluoride to pro-
vide 34a in 72% yield.15 Use of 34a in copper(I)-catalyzed 1,3-dipo-
lar cycloaddition with benzyl azide (1.5 equiv) as a model 1,3-
dipole (t-BuOH/H2O as solvent mixture, sodium ascorbate as
reductant)4 was found to be useful to prepare unknown biologi-
Scheme 4. Optimized conditions for the C-3 bromination using model compound
17a.
Table 2
Regioselective C-3 bromination of
c
-ylidenetetronates
R1
R2
Br2 (equiv)/Pyr (equiv)/time
% Yielda
cally relevant 1,2,3-triazole-derived
c-lactone 35a in non-opti-
Me
Me
Me
Me
Me
Bn
17a: Ph
1.5/1.1/2 h
1.5/1.1/1 h
1.5/1.1/1 h
2.0/1.1/20 min
2.0/1.2/1 h
1.5/1.1/1 h
1.5/1.1/20 min
2.2/1.1/1 h
23a: 91
25a: 92
26a: 60
27a: 81
28a: 62
23b: 79
26b: 65
28b: 65
mized 41% isolated yield (Scheme 6).16 Sonogashira cross-
coupling of 29a with trimethysilylacetylene gave the desired CAC
coupling product 36a in 60% yield (Scheme 7).17 This is one of
the few examples of metal-catalyzed cross-coupling reaction on
18a: 4-F-Ph
19a: 3,4-OMe-Ph
20a: 3,4-F-Ph
21a: 4-CF3-Ph
17b: Ph
such brominated c-ylidenetetronate derivative, although a Suzu-
Bn
Bn
19b: 3,4-OMe-Ph
21b: 4-CF3-Ph
ki–Miyaura reaction of an iodo alkene derivative from tetronic acid
was recently used in the preparation of vulpinic acid.18
a
Isolated yield.
The results presented here demonstrate that bromination, using
bromine or N-bromosuccinimide (NBS), of c-benzylidene tetronate
derivatives can be performed selectively under mild conditions
giving access to useful platforms for post-functionalization. Sono-
OMe
Br
OMe
gashira cross-coupling reactions on two different brominated
c-
Br2 (1.0 equiv)
Br2 (1.0 equiv)
benzylidene methyl tetronate derivatives 23a and 29a were found
to occur quite readily, and one of the resulting coupling products
(34a) was engaged successfully in a 1,3-dipolar cycloaddition, to
CH2Cl2
CH2Cl2
O
O
O
17a
O
69%
0°C/1 h
0°C/1 h
Ph
Ph
C = 0.02 M
23a
C = 0.1 M
OMe
Br
Br
OMe
Br
Br2 (2.0 equiv)
CH2Cl2
Br
Br
+
-
Me3Si
O
O
O
O
SiMe3 (1.2 equiv)
0°C/1 h
Ph
24a
Ph
57%
30a
78%
Br
OMe
OMe
Pd(PPh3)2Cl2 (0.1 equiv)
CuI (0.1 eq.)
C = 0.1 M
DBU (2.0 equiv)
r.t/30 min
OMe
CH2Cl2
Br
OMe
CH2Cl2
O
DBU (2.0 equiv)
r.t/30 min
O
23a
O
Et3N
50 °C, overnight
O
Ph
Ph
33a
78% Ph
O
86%
31a/32a = 1/1
O
Ph
TBAF
THF
Br
O
31a
O
88%
(Z)
5 min, r.t. (1.5 equiv)
N
Bn
29a
Br
N
N
+
BnN3 (1.5 equiv)
CuSO4.5H2O (0.1 equiv)
Sodium ascorbate (4.0 equiv)
OMe
OMe
Br
OMe
Br
Ph
t-BuOH/H2O (1/1)
r.t., overnight
O
O
O
O
O
O
32a
Ph
Ph
34a 72%
35a 41%
Bn = PhCH2
Scheme 5. Bromination reactions of c-lactone 17a using bromine.
Scheme 6. Sequence of Sonogashira reaction with
c
-lactone 23a and following
Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction.
SiMe3 (1.4 equiv)
OMe
OMe
Ph
Pd(PPh3)2Cl2 (0.1 equiv)
CuI (0.1 equiv)
Ph
Br
O
O
36a
O
O
Et3N
50 °C, overnight
29a
(Z)
60%
(Z)
SiMe3
Figure 3. Single crystal X-ray diffraction of
c
-lactones 24a (left) and 29a (right).
Scheme 7. Sonogashira reaction with bromide 29a.

4580
S. Iikawa et al. / Tetrahedron Letters 54 (2013) 4577–4581
crude product was purified by a silica gel column chromatography (petroleum
yield an 1,2,3-triazole-derived
c-benzylidene methyl tetronate
ether/ethyl acetate = 2/1) to provide 102.1 mg (0.28 mmol, 57%) of 5-bromo-5-
(bromo(phenyl)methyl)-4-methoxyfuran-2(5H)-one 24a. Colorless solid, mp:
157–159 °C. 1H NMR (300 MHz, CDCl3) d 7.64–7.61 (m, 2H), 7.40–7.38 (m, 3H),
5.35 (s, 1H), 5.34 (s, 1H), 4.08 (s, 3H). 13C NMR (75 MHz, CDCl3) d 180.2, 167.5,
135.9, 130.0, 129.5, 128.5, 89.4, 89.2, 60.4, 52.5. HRMS (ESI) calcd for [M+Na]+
m/z C12H10Br2NaO3 382.8889, found 382.8884.
derivative (35a). Most of the derivatives prepared in this Letter
are new compounds and the methodology is of interest not only
in our medicinal chemistry program directed to the synthesis of
new chemotherapeutic agents, but also for the design of new scaf-
folds and organics for material science. Work is under progress to
delineate more precisely the mechanism of the bromination pro-
cesses, as well as to extend the approach to other substrates and
to exemplify other typical metal-mediated cross-coupling reac-
tions. Full account of our results, as well as biological evaluation
of some of the molecules will be presented in forthcoming papers.
10. To the solution of dibrominated
c-lactone 24a (47.0 mg, 0.13 mmol) in
dichloromethane (5 mL) was added DBU (0.04 mL, 0.26 mmol) at room
temperature under argon atmosphere, and the solution was stirred for a
further 30 mins. The reaction was quenched with water (20 mL) and worked-
up as for the synthesis of 23a. The crude product was purified by a silica gel
column chromatography (petroleum ether/ethyl acetate = 3/1) to provide
32.2 mg (0.15 mmol, 88%) of (Z)-5-(bromo)methylene)-4-methoxyfuran-
2(5H)-one 29a. Colorless solid, mp: 121–122 °C. 1H NMR (300 MHz, CDCl3) d
7.42–7.35 (m, 5H), 5.34 (s, 1H), 3.65 (s, 3H). 13C NMR (75 MHz, CDCl3) d 168.7,
166.5, 141.8, 135.4, 129.9, 129.7, 127.8, 109.4, 91.2, 59.2. HRMS (ESI) calcd for
Acknowledgments
[M+Na]+ m/z C12H9BrNaO3 302.9627, found 302.9617.
0
11. Compound 24a: CCDC 939007, monoclinic, P21/c, a = 7.4571(6) ÅA,
0
0
0
This work was supported by ANR Emergence 2011 (ANR-11-
EMMA-04-QUINOLAC) and by the Ministère de l’Enseignement
Supérieur et de la Recherche (Ph.D. fellowship to S.I.). We thank
Florian Albrieux, Christian Duchet and Reynald Hélye from the
Centre Commun de Spectrométrie de Masse de l’Université Claude
Bernard Lyon 1 for the mass spectra analyses.
b = 13.523(1) ÅA, c = 13.265(2) ÅA, b = 102.83(1), V = 1304.3(2) ÅA3, refined
formula:
C , Z = 4, d = 1.843,
12H10Br2O3, molecular weight = 362.0 g.molꢀ1
l
D
= 6.208 mmꢀ1
,
R(I/
r(I) >3) = 0.03600, Rw(I/r(I) >3) = 0.0376, S = 1.11,
q
0
q
max = 0.88 eꢀ ÅAꢀ3
,
D
min = ꢀ0.42 eꢀ ÅAꢀ3, no. refined parameters: 154, No.
reflections used: 179.Compound 29a: CCDC 939008, orthorhombic, Pbca,
0
0
0
0
a = 7.9981(5) ÅA, b = 8.6184(6) ÅA, c = 32.866(2) ÅA, V = 2265.5(2) ÅA3, refined
12H9Br1O3, molecular weight = 281.1 g molꢀ1
formula: Z = 8, d = 1.648,
= 3.616 mmꢀ1
r(I) >3) = 0.03601, Rw(I/r(I) >3) = 0.0419, S = 1.09,
C
,
l
,
R(I/
max = 0.55 eꢀ ÅAꢀ3
reflections used: 1730.
12. To a solution of
0
D
q
,
D
q
min = ꢀ0.42 eꢀ ÅAꢀ3, no. refined parameters: 145, no.
References and notes
c
-lactone 17a (100 mg, 0.495 mmol) in dichloromethane
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(5 mL) was slowly added bromine (0.051 mL, 0.99 mmol) dropwise at 0 °C
under argon atmosphere, and the solution was stirred for 1 h at 0 °C. The
reaction was quenched with saturated aqueous solution of Na2S2O3 (5 mL) and
worked-up as for the synthesis of 23a. The crude product was purified by a
silica gel column chromatography (petroleum ether/dichloromethane = 1/1) to
provide 170 mg (0.39 mmol, 78%) of 3,5-dibromo-5-(bromo(phenyl)methyl)-
4-methoxyfuran-2(5H)-one 30a. Colorless solid, mp: 189 °C. 1H NMR
(300 MHz, CDCl3) d 7.61–7.57 (m, 2H), 7.40–7.38 (m, 3H), 5.34 (s, 1H), 4.51
(s, 3H). 13C NMR (75 MHz, CDCl3) d 171.9, 164.7, 135.4, 130.1, 129.7, 128.5,
90.0, 81.5, 60.9, 52.7. HRMS (ESI) calcd for [M+Na]+ m/z C12H9Br3NaO3
460.7994, found 460.7973.
13. To the solution of
c-lactone 30a (108 mg, 0.245 mmol) in dichloromethane
(4 mL) was added DBU (0.073 mL, 0.490 mmol) at room temperature under
argon atmosphere, and the solution was stirred for a further 30 mins. The
reaction was quenched with water (20 mL) and worked-up as for the synthesis
of 23a. The crude product was purified by
(petroleum ether/ethyl acetate = 1/1) to provide 76 mg (0.21 mmol, 86%) of
(Z)-3-bromo-5-(bromo(phenyl)methylene)-4-methoxyfuran-2(5H)-one 31a
a silica gel chromatography
and
(E)-3-bromo-5-(bromo(phenyl)methylene)-4-methoxyfuran-2(5H)-one
32a as mixture 1/1. Colorless solid. 1H NMR (300 MHz, CDCl3) d 7.59–7.36
(m, 10H), 4.44 (s, 3H), 3.98 (s, 3H). 13C NMR (75 MHz, CDCl3) d 163.5, 163.2,
163.2, 161.8, 141.2, 140.0, 135.9, 135.4, 129.8, 129.8, 129.7, 129.6, 128.1, 127.8,
110.5, 109.4, 84.4, 84.1, 60.0, 59.6. HRMS (ESI) calcd for [M+Na]+ m/z
C12H8Br2NaO3 380.8732, found 380.8728.
4. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596–2599; (b) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108,
2952–3015.
14. To the solution of 23a (39 mg, 0.14 mmol), CuI (2.7 mg, 0.014 mmol) and
Pd(PPh3)2Cl2 (9.8 mg, 0.014 mmol) in Et3N (0.56 mL) was added
trimethylsilylacetylene (0.024 ml, 0.17 mmol) under argon atmosphere, and
the mixture was stirred overnight at 50 °C. The reaction was quenched with
water (20 mL) and extracted with ethyl acetate (3 ꢁ 20 mL). The combined
organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified by a
silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to
provide 32.6 mg (0.11 mmol, 78%) of (Z)-5-benzylidene-4-methoxy-3-
((trimethylsilyl)ethynyl)furan-2(5H)-one 33a. Colorless solid, mp: 100–
101 °C. 1H NMR (300 MHz, CDCl3) d 7.74–7.71 (m, 2H), 7.40–7.32 (m, 3H),
6.26 (s, 1H), 4.44 (s, 3H), 0.23 (s, 9H). 13C NMR (75 MHz, CDCl3) d 167.4, 167.0,
141.5, 132.1, 130.7, 129.3, 128.8, 109.2, 103.9, 93.2, 88.0, 59.9, ꢀ0.5. HRMS
(ESI) calcd for [M+Na]+m/z C17H18NaO3Si 321.0917, found 321.0909.
5. Full details of the synthesis of the
paper.
c
-lactones 17–22 will appear in our full
0
6. Compound 220a: CCDC 939006, monoclinic, P21/c, a = 11.2468(6) ÅA,
0
0
b = 13.0488(6) ÅA, c = 9.8189(5) ÅA, b = 109.481(6), V = 1358.5(1) ÅA3, refined
formula: Z = 4, d = 1.516,
16H14Fe1O3, molecular weight = 310.1 g molꢀ1
= 1.113 mmꢀ1
C
,
l
,
R(I/
max = 0.36 eꢀ ÅAꢀ3
reflections used: 2836.
r(I) >3) = 0.0322, Rw(I/r(I) >3) = 0.0375, S = 1.05,
0
0
D
q
,
D
q
min = ꢀ0.27 eꢀ ÅAꢀ3, No. refined parameters: 181, No.
7. Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. A.; Lewis, W.; Pardasani, P. J. Chem. Soc.,
Perkin Trans. 1 1987, 717–742.
8. To a solution of
c-lactone 17a (26.3 mg, 0.13 mmol) and pyridine (0.01 mL,
0.14 mmol) in dichloromethane (1.3 mL) was slowly added bromine (0.01 mL,
0.20 mmol) at room temperature under argon atmosphere. The resulting
solution was then stirred 2 h at room temperature. The reaction was quenched
with a saturated aqueous solution of Na2S2O3 (20 mL), and extracted with
dichloromethane (3 ꢁ 20 mL). The combined organic layers were washed with
brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced
15. To the solution of 33a (0.17 mmol) in THF (2.5 mL) was slowly added 1 M
solution of TBAF in THF (0.255 mL, 0.255 mmol, 5% water included) at room
temperature, and the solution was stirred 5 min at this temperature. The
reaction was quenched with water (20 mL) and extracted with ethyl acetate
(3 ꢁ 20 mL). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by a silica gel column chromatography (petroleum
ether/ethyl acetate = 8/1) to provide 27.7 mg (0.12 mmol, 72%) of (Z)-5-
benzylidene-3-ethynyl-4-methoxyfuran-2(5H)-one 34a. Brown solid, mp:
132–133 °C. 1H NMR (300 MHz, CDCl3) d 7.73–7.71 (m, 2H), 7.40–7.32 (m,
3H), 6.29 (s, 1H), 4.42 (s, 3H), 3.37 (s, 1H). 13C NMR (75 MHz, CDCl3) d 167.8,
167.3, 141.3, 132.0, 130.7, 129.4, 128.8, 109.6, 86.6, 85.4, 72.6, 60.1. HRMS (ESI)
calcd for [M+Na]+m/z C14H10NaO3 249.0522, found 249.0526.
pressure. The crude product was purified by
a silica gel column
chromatography (petroleum ether/ethyl acetate = 4/1) to provide 33.3 mg
(0.12 mmol, 91%) of (Z)-5-benzylidene-3-bromo-4-methoxyfuran-2(5H)-one
23a. Colorless solid, mp: 108–109 °C. 1H NMR (300 MHz, CDCl3) d 7.74–7.70
(m, 2H), 7.41–7.33 (m, 3H), 6.27 (s, 1H), 4.39 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 165.3, 163.4, 141.9, 131.9, 130.6, 129.3, 128.8, 108.8, 80.5, 59.8. HRMS (ESI)
calcd for [M+Na]+ m/z C12H9BrNaO3 302.9627, found 302.9627.
9. To the solution of c-lactone 17a (100.0 mg, 0.495 mmol) in dichloromethane
16. To the solution of 34a (24.9 mg, 0.11 mmol) and benzyl azide (18.1 mg,
(25 mL) was slowly added bromine (0.025 mL, 0.495 mmol, 1 drop/3min) at
0 °C under argon atmosphere, and the resulting solution stirred for 1 h at this
temperature. The reaction was quenched at 0 °C with a saturated aqueous
solution of Na2S2O3 (30 mL) and worked-up as for the synthesis of 23a. The
0.16 mmol) in t-BuOH (0.7 mL) was successively added a solution of L-ascorbic
acid sodium salt (86 mg, 0.44 mmol) in water (0.35 mL) and a solution of
CuSO4ꢂ5H2O (2.7 mg, 0.011 mmol) in water (0.35 mL), and the solution was
stirred overnight at room temperature. The reaction was quenched with water

S. Iikawa et al. / Tetrahedron Letters 54 (2013) 4577–4581
4581
(20 mL) and extracted with ethyl acetate (3 ꢁ 20 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified by a
silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to
provide 15.8 mg (0.04 mmol, 41%) of (Z)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-
benzylidene-4-methoxyfuran-2(5H)-one 35a. Yellow solid, mp: 96–98 °C. 1H
NMR (300 MHz, CDCl3) d 8.06 (s, 1H), 7.79–7.76 (m, 2H), 7.42–7.31 (m, 8H),
6.41 (s, 1H), 5.57 (s, 2H), 4.39 (s, 3H). 13C NMR (75 MHz, CDCl3) d 171.1, 163.5,
142.7, 134.3, 132.5, 130.6, 129.2, 129.0, 128.9, 128.8, 128.2, 128.0, 123.9, 109.0,
62.1, 54.3. HRMS (ESI) calcd for [M+Na]+m/z C21H17N3NaO3 382.1162, found
382.1159.
17. (Z)-4-Methoxy-5-(1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ylidene)furan-
2(5H)-one 36a. Pale yellow solid, mp: 126–127 °C. 1H NMR (300 MHz, CDCl3) d
7.43–7.40 (m, 2H), 7.35–7.33 (m, 3H), 5.33 (s, 1H), 3.67 (s, 3H), 0.22 (s, 9H). 13
C
NMR (75 MHz, CDCl3) d 169.5, 166.9, 147.1, 133.3, 129.7, 128.7, 127.7, 109.7,
108.5, 100.7, 91.4, 59.1, ꢀ0.3. HRMS (ESI) calcd for [M+Na]+ m/z C17H18NaO3Si
321.0917, found 321.0903.
18. Nadal, B.; Thuéry, P.; Le Gall, T. Tetrahedron Lett. 2009, 50, 2430–2433.