A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives through Regioselective Bromination of Tetronic Acid Derived γ-Lactones and Metal-Catalyzed Postfunctionalization

Article abstract of DOI:10.1002/ejoc.201500663

The synthesis of a series of diverse methyl and benzyl γ-ylidenetetronate derivatives was accomplished through the condensation of methyl and benzyl tetronates with (hetero)aryl aldehydes in a new two- or three-step aldolisation/dehydration sequence. The bromination of methyl and benzyl γ-ylidenetetronates occurred under mild conditions to provide the corresponding C-3-brominated γ-unsaturated lactones. Di- and tribrominated γ-lactones were prepared under slightly different conditions. Some brominated materials were employed in representative Stille, Suzuki-Miyaura, and Sonogashira cross-coupling reactions to yield functionalized methyl and benzyl γ-ylidenetetronate derivatives. Compounds that resulted from the Sonogashira cross-coupling reactions were desilylated and converted into 1,2,3-triazole derivatives through a copper(I)-catalyzed 1,3-dipolar cycloaddition reaction with benzyl azide.

Full text of DOI:10.1002/ejoc.201500663

FULL PAPER
DOI: 10.1002/ejoc.201500663
A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives through Regioselective
Bromination of Tetronic Acid Derived γ-Lactones and Metal-Catalyzed
Postfunctionalization
Nicolas Chopin,[a] Hikaru Yanai,[b] Shinya Iikawa,[a] Guillaume Pilet,[c]
Jean-Philippe Bouillon,*[d] and Maurice Médebielle*[a]
Keywords: Synthetic methods / Halogenation / Cross-coupling / Cycloaddition / Lactones / Oxygen heterocycles
The synthesis of a series of diverse methyl and benzyl γ-yl-
idenetetronate derivatives was accomplished through the
condensation of methyl and benzyl tetronates with (hetero)-
aryl aldehydes in a new two- or three-step aldolisation/de-
hydration sequence. The bromination of methyl and benzyl
γ-ylidenetetronates occurred under mild conditions to pro-
vide the corresponding C-3-brominated γ-unsaturated lact-
ones. Di- and tribrominated γ-lactones were prepared under
slightly different conditions. Some brominated materials
were employed in representative Stille, Suzuki–Miyaura, and
Sonogashira cross-coupling reactions to yield functionalized
methyl and benzyl γ-ylidenetetronate derivatives. Com-
pounds that resulted from the Sonogashira cross-coupling
reactions were desilylated and converted into 1,2,3-triazole
derivatives through a copper(I)-catalyzed 1,3-dipolar cyclo-
addition reaction with benzyl azide.
been developed as potent antibacterials and inhibitors of
bacterial peptidoglycan biosynthesis.[3]
Introduction
γ-Lactones derived from tetronic acids, γ-ylidenetetron-
ates, and tetronic acid derivatives, which are isolated from
natural sources or synthesized as potential chemotherapeu-
tic agents, have been known to display interesting biological
activity (Figure 1).[1] In connection to our work, some note-
worthy examples of γ-lactones from natural sources include
a group of 5-arylidenetetronates that can be extracted from
fungal sources.[1a–1f] Pulvinic acid derivatives and pulvinone
analogues are representative examples of this family of
compounds, with some having radioprotective and anti-
oxidant properties[2a–2c] as well as anti-influenza A virus
(H1N1) activity.[2d] Non-natural 5-arylidenetetronates have
[a] Université Claude Bernard Lyon 1 (UCBL), Institut de Chimie
et Biochimie Moléculaires et Supramoléculaires (ICBMS),
UMR CNRS-UCBL-INSA Lyon 5246,
43 bd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
E-mail: maurice.medebielle@univ-lyon1.fr
http://www.icbms.fr/smith
[b] Tokyo University of Pharmacy and Life Sciences, School of
Pharmacy,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: yanai@toyaku.ac.jp
[c] Université Claude Bernard Lyon 1 (UCBL), Laboratoire des
Multimatériaux et Interfaces (LMI), UMR CNRS-UCBL 5615,
43 bd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
E-mail: guillaume.pilet@univ-lyon1.fr
Figure 1. γ-Ylidenetetronate and tetronic acid derivatives from nat-
ural sources or designed as chemotherapeutic agents.
[d] Université de Rouen, Chimie Organique Bioorganique:
Réactivité et Analyses (COBRA), IRCOF, UMR CNRS-
Université de Rouen – INSA Rouen 6014,
In our current research program directed towards the
synthesis and biological evaluation of new therapeutic
agents as possible anti-infective agents, halogenated γ-lact-
ones derived from tetronic acids were identified as useful
synthetic platforms for the preparation of diverse γ-ylidene-
76821 Mont Saint-Aignan, France
E-mail: jean-philippe.bouillon@univ-rouen.fr
http://www.lab-cobra.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500663.
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6259

J.-P. Bouillon, M. Médebielle et al.
FULL PAPER
tetronates (R1, R2, R3, and R4, Scheme 1) prepared by a
metal-catalyzed cross-coupling postfunctionalization step.[4]
These halogenation sequences, which are relatively rare in
the literature,[5] start from γ-benzylidene tetronates, and the
resulting products are used in the development of new valu-
able organic entities and chemotherapeutic agents.
Figure 2. Structures of the aldehydes 2–20 used in the aldolisation
processes.
Scheme 1. General access to the targets.
Herein, we disclose our results for the synthesis of γ-lact-
ones that are derived from methyl and benzyl tetronates,
the regioselective bromination of these γ-lactones, and their
use in specific Stille,[6] Suzuki–Miyaura,[7] and Sonoga-
shira[8] cross-coupling reactions. To demonstrate the syn-
thetic utility of our strategy, examples of CuI-catalyzed 1,3-
dipolar cycloadditions of acetylenic-derived γ-benzylidene
tetronates with benzyl azide[9] are also presented. These cy-
cloaddition reactions provide access to pharmaceutically
relevant 1,2,3-triazoles,[10] which contain the tetronic acid
derived motif.
Results and Discussion
The starting methyl and benzyl tetronates 1a and 1b were
either commercially available (i.e., 1a, R1 = Me) or known
(i.e., 1b, R1 = Bn).[5b,5c] New lactones 1c and 1d were pre-
Scheme 2. Synthesis of 5-arylidenetetronates (method A) from
methyl and benzyl tetronate (DMAP = 4-(dimethylamino)pyridine.
pared in a similar manner to 1b in unoptimized yields of 50 through an esterification with trifluoroacetic anhydride and
and 37%, respectively, by treating p-fluoro- and p-meth- an elimination reaction with 1,8-diazabicyclo[5.4.0]undec-7-
oxybenzyl chlorides (1.1 equiv.) with potassium carbonate ene (DBU) as the base[5b,5c] in dichloromethane. Com-
(2.0 equiv.) in N,N-dimethylformamide (DMF) at room pounds 42,[1i,1j] 43,[3a] and 51[1i] are known compounds or
temperature. Aldehydes 2–20 (see Figure 2), which were to have been previously reported in the literature. Compounds
be used in the aldolisation/dehydration sequence (Scheme 1, 42, 44, 47–54, 56, 58, 60, 61, 63, and 64 were obtained as
general structure I) were either commercially available (i.e., the (Z) stereoisomer (in our preliminary communication,[4]
2–6 and 8–20) or prepared by using a known procedure the (Z) stereochemistry of ferrocenyl derivative 50 was con-
(i.e., 7).[11]
firmed by single-crystal X-ray diffraction analysis). Com-
The first approach (method A) to prepare γ-ylidene- pounds 43, 45, 46, 55, 57, 59, and 62 were obtained as two
tetronates I follows literature procedures that were devel- stereoisomers after column chromatography (in favor of the
oped for analogues of I.[1j,5b,5c] Tetronates 1a–1d were thermodynamically more stable (Z) stereoisomer; Scheme 2
treated with nBuLi (1.1 equiv.) and aldehydes 2–15 and Table 1). By using aldehyde 9, we directly obtained the
(1.5 equiv.) in tetrahydrofuran (THF) at –78 °C to room ferrocenyl dehydrated compounds 50 and 61 (Table 1,
temperature (overnight) to yield the corresponding aldol Entries 9 and 20) without isolation of the aldol products.
adducts 21–41 as diastereoisomeric mixtures in good yields, Pyridinyl derivatives 59 and 60 (Table 1, Entries 18 and 19)
after workup and filtration through silica gel (Scheme 2).
were found to be unstable during the aldolisation/de-
The aldol adducts were converted directly into γ-lactones hydration sequence. In addition, the dehydration reactions
42–64 by a two-step/one-pot sequence that proceeded of products that were formed from substituted benzyl te-
6260
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6259–6269

A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives
tronates 1c and 1d (Table 1, Entries 21–23) were less ef- 1b in acetonitrile (65 °C, overnight) was discovered and ap-
ficient than the dehydration reactions of substrates pre- plied to the synthesis of γ-lactones 47, 53, 55, 56, 58, and
pared from 1a and 1b. However, the aldolisation reactions 65–70 (Table 2). All the final products were obtained in
worked equally well in all cases. Because some of the yields moderate to good yields as (Z) isomers as confirmed by
(overall yields for the aldolisation/dehydration sequence) single-crystal X-ray diffraction analysis of compound 66
presented in Table 1 were only moderate, we studied a (Figure 3).[12] In the reaction with aldehyde 17 (Table 2, En-
model reaction and determined that slight changes in the try 9), the trimethylsilyl group was removed during the
reaction conditions for the aldolisation and dehydration aldolisation/dehydration sequence, and the final product 69
steps (performing the reaction at room temperature for was isolated in only 22% yield. Replacing DBU with other
2.5 h for the esterification and using of 2.0 equiv. of DBU bases (i.e., K2CO3, NaH) or changing the solvents (THF,
for 45 min for the dehydration) could provide 44 in a more MeOH, CH2Cl2) gave only the aldol products along with
satisfactorily 53% isolated yield (compared with 28% yield; incomplete conversion of the starting materials. In addition,
Table 1, Entry 3) with a Z/E ratio of 19:1. Although this performing the reaction in neat DBU at room temperature
optimization study was only carried out with tetronate 1a or 65 °C provided only the aldol product. Therefore
and aldehyde 3, there is hope that some of the yields pro- CH3CN was critical for the successful outcome of the ald-
vided in Table 1 can indeed be improved.
olisation/dehydration reaction sequence. It possible that the
cyanomethyl anion (pKa of CH3CN = 31.3) generated in
the course of the reaction induces the dehydration of the
resulting aldol, with both steps occurring at 65 °C
Table 1. Synthesis of 5-arylidenetetronates (method A) from methyl
and benzyl tetronates.
Table 2. Synthesis of 5-arylidenetetronates from methyl and benzyl
tetronates (method B).
Entry R1
R2
Compound
[% yield][a]
Z/E[b]
[c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4-F-Bn
4-F-Bn
4-MeO-Bn
C6H5
42 (39)
43 (44)
44 (28)
45 (32)
46 (60)
47 (43)
48 (65)
49 (46)
50 (95)[e]
51 (39)
52 (47)
53 (54)
54 (40)
55 (85)
56 (57)
57 (36)
58 (18)
59 (43)
60 (13)
61 (54)[e]
62 (27)
63 (14)
64 (21)
4-BrC6H4
4-FC6H4
3,4-F2C6H3
2,4-F2C6H3
4-CF3C6H4
89:11
[c]
96:4
88:12
[c]
[c,d]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
4-FcC6H4
2-furanyl
9
Fc[d]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3,4-(MeO)2C6H3
C6H5
2-BrC6H4
4-BrC6H4
4-FC6H4
4-CF3C6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-pyridinyl
3-pyridinyl
Fc[d]
4-MeOC6H4
4-CF3C6H4
4-CF3C6H4
95:5
[c]
85:15
[c]
81:19
[c]
[c]
93:7
[c]
[c]
[a] Overall isolated yield (aldolisation/dehydration sequence) after
silica gel chromatography. [b] Ratio of stereoisomers. [c] Only (Z)
isomer was identified. [d] Fc = ferrocenyl. [e] Obtained directly
without isolation of the aldol.
This first approach gave the desired molecules of general
structure I, but a more practical approach that avoids cryo-
genic temperatures and the use of nBuLi, especially for pos-
sible scaleup, was envisaged.
(method B) that uses DBU (2 equiv.) as the base, aldehydes
3, 6, 10, 13, and 16–20 (1.2 equiv.), and tetronates 1a and used.
A one-pot procedure
[a] Isolated yield after silica gel chromatography. Only (Z) isomer
was isolated. [b] 2-[(Trimethylsilyl)ethynyl]benzaldehyde (17) was
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6261

J.-P. Bouillon, M. Médebielle et al.
FULL PAPER
(Scheme 3). The fact that the dehydrated products were Table 3. C-3 Bromination of 5-arylidenetetronate derivatives.
never formed in the reaction in neat DBU indicates that it
probably is not involved in the dehydration step. This new
procedure, which warrants further optimization, is more
convenient that the previous approach (method A), as this
one-pot procedure can be easily adapted to the preparation
of milligram to gram quantities of 5-arylidenetetronates of
general structure I after evaporation of the volatiles and
purification by chromatography.
Entry R1
R2
Compound [% yield][a][b]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Bn
C6H5
4-BrC6H4
71 (91)[c],[8]
72 (73)[c]
4-CF3C6H4
3,4-(MeO)2C6H3
3,4-F2C6H3
C6H5
4-CF3C6H4
3,4-(MeO)2C6H3
73 (62)[d]
74 (60)[c]
75 (81)[c]
76 (79)[c]
Bn
Bn
77 (65)[c]
78 (40)[c], 78 (64)[d]
[a] Isolated yield after silica gel chromatography. [b] Only (Z) iso-
mer was identified. [c] Br2 (1.5 equiv.) and pyridine (1.2 equiv.) were
employed. [d] Br2 (1.2 equiv.) and pyridine (2.0 equiv.) were em-
ployed.
Figure 3. Single crystal X-ray diffraction analysis of (Z)-γ-lactone
66.
Figure 4. Single-crystal X-ray diffraction analysis of C-3-bromin-
ated (Z)-γ-lactone 78.
Under slightly different conditions, the reaction was car-
ried out by using bromine (1.0 equiv.) in the absence of pyr-
idine in dichloromethane at 0 °C for 1 h. Under more dilute
conditions (c = 0.02 m), the exocyclic dibromination of the
two model γ-lactones 42[4] and 52 was achieved diastereo-
selectively to provide dibrominated compounds 79 and 80
in moderate to good yields (Scheme 4). The stereochemistry
Scheme 3. Proposed mechanism for the formation of the γ-lactones
in CH3CN in the presence of DBU (method B).
With a series of γ-unsaturated lactones obtained through of compound 79 was previously established[4] by single-crys-
two different procedures (methods A and B), we then pur- tal X-ray diffraction analysis. However, if lactones 42, 47,
sued the preparation of the key brominated materials. We and 52 were treated with an excess amount of bromine
previously reported[4] feasibility studies of the reactions of (2.0 equiv.) without pyridine in the same solvent but at 0 °C
γ-lactone 42 as a model compound with N-bromo- to room temperature for 1 h (c = 0.1 m), tribrominated lact-
succinimide (NBS) and bromine. The introduction of a bro- ones 81[4]–83 were obtained in good yields (Scheme 4).
mine atom at the C-3 position of γ-unsaturated lactones 42,
The results of the regioselective reactions with bromine
43, 45, 47, 51, 52, 56, 58 was best achieved by using in the presence or absence of pyridine deserve some com-
bromine (1.2–1.5 equiv.) in the presence of pyridine (1.2– ments. The combination of pyridine and bromine is the sys-
2.0 equiv.) in anhydrous dichloromethane at room tempera- tem of choice for the selective introduction of the bromine
ture for 20 min to 2 h (concentration of substrate c = 0.1 m). atom at the C-3 position of the methyl and benzyl tetron-
The resulting brominated materials 71–78 were obtained as ates (Table 3), without brominating the exocylic double
the (Z) isomer in moderate to excellent yields after purifica- bond. Although the reasons of such selectively in the pres-
tion by column chromatography (Table 3). The ence of pyridine remain unclear, a complex between pyr-
stereochemistry and proof of structure 78 was established idine and bromine (pyridinium tribromide or pyridinium
by using single-crystal X-ray diffraction analysis (Fig- hydrobromide perbromide)[14] might be the active species
ure 4).[13]
and, therefore, activate the C-3 position of the tetronate
6262
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6259–6269

A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives
The brominated γ-benzylidene methyl and benzyl tetron-
ates were then used in several typical Suzuki–Miyaura,
Stille, and Sonogashira cross-coupling reactions (Tables 5
and 6).
Table 5. Suzuki–Miyaura[a] and Stille[b] cross-coupling reactions.
Scheme 4. Dibromination and tribromination reactions of γ-lact-
ones 42, 47, and 52.
Entry R1
R2
X, Y
Suzuki–Miyaura
Stille product
[% yield][c]
product [% yield][c]
1
2
5
6
Me
Bn
Me
Bn
C6H5 Br, H
C6H5 Br, H
C6H5 H, Br
C6H5 H, Br
89 (99)
90 (47)
91 (96)
–
89 (74)
90 (67)
91 (74)
92 (61)
through its enol ether moiety. Exocyclic bromination does
not require such activation, as the critical factor to favor
the dibromination over the tribromination reaction was the
concentration of bromine (Scheme 4). The marked differ-
ences in reactivity underline the distinctions between
bromine and the tribromide ion in an electrophilic attack.
From dibrominated lactones 79 and 80, the correspond-
ing exocyclic bromo-olefinic lactones 84 and 85 were pre-
pared in excellent 88 and 85% yields by a base-induced
[DBU (2.0 equiv.)] anti elimination of HBr (Table 4, En-
tries 1 and 2). The (Z) stereochemistry of 84 had already
been established by single-crystal X-ray diffraction analysis,
according to our preliminary communication.[4] The di-
bromination/base-promoted debromination sequence (i.e.,
42Ǟ79Ǟ84) can also be conducted in a one-pot procedure
in 50% overall yield. However, the treatment of tribromin-
ated 81–83 derivatives with DBU (2.0 equiv.) in dichloro-
methane (0 °C to room temperature) for 0.5 h gave mixtures
of the corresponding (Z)- and (E)-bromo-olefinic lactones
86–88 in moderate to good yields after purification by silica
gel chromatography (Table 4, Entries 3–5). The (Z) and (E)
isomers of compound 85 were separated after two success-
ive column chromatography procedures.
[a] Reagents and conditions: PhB(OH)2 (2 equiv.), Pd(PPh3)4
(0.1 equiv.), and K2CO3 (2 equiv.) in PhMe at 75 °C overnight.
[b] Reagents and conditions: PhSnBu3 (2 equiv.) and Pd(PPh3)4
(0.1 equiv.) in PhMe at 75 °C overnight. [c] Isolated yield.
Table 6. Sonogashira cross-coupling reactions.[a]
Entry R1
R2
X, Y
Compound [% yield][b]
1
2
3
4
5
6
7
Me C6H5
Me 4-CF3C6H4
Me 3,4-(MeO)2C6H3 Br, H
Bn
Bn
Me C6H5
Bn C6H5
Br, H
Br, H
93 (78)
94 (73)
95 (93)
96 (93)
97 (82)
98 (82)[c]
99 (83)[c]
C6H5
4-CF3C6H4
Br, H
Br, H
H, Br
H, Br
[a] Reagents and conditions: Trimethylsilylacetylene (1.5 equiv.),
Pd(PPh3)2Cl2 (0.1 equiv.), CuI (0.1 equiv.), and Et3N (2 equiv.) in
PhMe at 75 °C overnight. [b] Isolated yield. [c] Only one isomer (Z)
was obtained.
Table 4. Elimination reactions of di- and tribrominated γ-lactones
79–83.
For the Suzuki–Miyaura cross-coupling reactions, phenyl
boronic acid [PhB(OH)2, 2.0 equiv.] was used as the cou-
pling partner with C-3-brominated derivatives 71 and 76
and exocyclic brominated γ-benzylidene methyl and benzyl
tetronates 84 and 85 in the presence of Pd(PPh3)4
(0.1 equiv.) and anhydrous K2CO3 (2.0 equiv.) in toluene at
75 °C overnight (Table 5). Moderate to excellent yields were
achieved for coupling products 89–92.
Alternatively, these C-3 arylated γ-benzylidene methyl
and benzyl tetronates could be prepared by a Stille coupling
reaction using PhSnBu3 (2.0 equiv) and Pd(PPh3)4
(0.1 equiv.) in toluene at 75 °C overnight (Table 5). Gen-
Entry R1
R2
R3
Compound
[% yield][a]
Z/E[b]
[c]
1
2
3
4
5
Me
Bn
Me
Me
Bn
C6H5
C6H5
C6H5
4-CF3C6H4 Br
C6H5 Br
H
H
Br
84 (88)
85 (85)
86 (62)
87 (60)
88 (81)
1/0.3
≈1:1
≈1:0.6
≈1:0.3
[a] Isolated yield after silica gel chromatography. [b] Ratio of
stereoisomers. [c] Only (Z) isomer present.
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6263

J.-P. Bouillon, M. Médebielle et al.
FULL PAPER
erally, both the Suzuki–Miyaura and Stille reactions gave formation was attempted in a solvent mixture (tBuOH/
good yields, but they were substrate dependent. CH2Cl2/H2O, 1:0.5:1.0 v/v/v) with sodium l-ascorbate
A Sonogashira cross-coupling reaction was attempted by (0.1 equiv.) as the reductant and CuSO4·5H2O (0.05 equiv.)
using trimethylsilylacetylene (1.5 equiv.) as the coupling as the copper source at room temperature overnight. The
partner with C-3-brominated derivatives 71, 73, 74, 76, and use of dichloromethane as a cosolvent was critical to
77 and exocyclic brominated derivatives 84 and 85 as the achieve the best yields of unknown 1,2,3-triazole derivatives
starting materials. The C-3 and exocyclic coupled products 106–110 (Table 8). Because 1,2,3-triazole skeletons have
93–99 were prepared in good to excellent yields by using been recognized as privileged scaffolds in many medicinal-
Pd(PPh3)2Cl2 (0.1 equiv.) in the presence of CuI (0.1 equiv.) oriented research programs,[10] the combination of such het-
and Et3N (2 equiv.) in toluene at 75 °C overnight (Table 6). erocyclic units with a tetronic acid unit and their derivatives
Compounds 93 and 98 were previously prepared under may offer great potential in the development of new chemo-
slightly different conditions (Et3N was used as the solvent therapeutic agents.
at 50 °C), as described in our preliminary communication.[4]
Here, compounds 98 (Table 6, Entry 6) and 99 (Table 6, En-
Table 8. Copper(I)-catalyzed 1,3-dipolar cycloaddition reactions.[a]
try 7) were obtained as a single isomer with the proposed
(Z) configuration. There was noticeably no erosion of ste-
reochemistry in the cross-coupling reaction of enantiopure
84 to give 98, and the reaction that gave 99 was also re-
markably stereospecific despite that the starting material 85
was present as a Z/E (1:0.3) mixture.
Notably, the cross-coupling reactions of exocyclic halo-
genated γ-benzylidene tetronates are not common, al-
though a Suzuki–Miyaura reaction of an iodoalkene deriva-
tive of tetronic acid was recently used in the preparation of
vulpinic acid.[15]
The Sonogashira coupling products 93, 94, and 96–99
were desilylated to provide acetylenic compounds 100–105
in moderate to good yields. The desilylation proceeded ex-
tremely fast (5 min) by using tetrabutylammonium fluoride
(1.1 equiv.) in THF at 0 °C (Table 7). When the reaction
was performed at room temperature, lower product yields
resulted, whereas performing the reaction longer than 5 min
(either at 0 °C or room temperature) produced several side
products. The desilylation did occur by using K2CO3 as a
base in MeOH, but the addition of the methoxide anion to
the exocyclic bond also occurred.
Entry R1
R2
X, Y
Compound [% yield][b]
1
2
3
4
5
Me
Me
Bn
Me
Bn
C6H5
HCϵC–, H
106 (41)[4]
107 (66)
108 (62)
109 (66)
110 (68)
4-CF3C6H4 HCϵC–, H
C6H5
C6H5
C6H5
HCϵC–, H
H, HCϵC–
H, HCϵC–
[a] Reagents and conditions: BN3 (1.5 equiv.), sodium l-ascorbate
(0.1 equiv.), and CuSO4·5H2O (0.05 equiv.) in tBuOH/CH2Cl2/H2O
(1:0.5:1.0 v/v/v) at room temp., overnight. [b] Isolated yield.
Conclusions
A new one-pot synthesis that is readily amenable for
Compound 100–102, 104, and 105 were then employed in scaleup has been presented for γ-benzylidene methyl and
a copper(I)-catalyzed 1,3-dipolar cycloaddition with benzyl benzyl tetronates. The bromination of several γ-benzylidene
azide (1.5 equiv.) as a model 1,3-dipole reaction. This trans- tetronate derivatives have also been performed selectively
under mild conditions to provide access to useful molecular
entities for postfunctionalization. The Suzuki–Miyaura,
Stille, and Sonogashira cross-coupling reactions of the
brominated derivatives were employed as model coupling
Table 7. Desilylation reactions of Sonogashira coupling products.[a]
partners to readily provide additional diversity. The re-
sulting Sonogashira products were useful for the syntheses
of biologically relevant 1,2,3-triazole-derived γ-benzylidene
methyl and benzyl tetronates. Most of the materials de-
scribed herein are new compounds, and the methods can
be employed for the preparation of new chemotherapeutic
agents as well as for the design of new scaffolds and organic
substances for materials science. Many of the yields are not
yet optimized, and there is certainly room for improvement.
We are currently studying the scope and limitations of these
cross-coupling reactions by using various boronic acids and
alkyne coupling partners. Preliminary biological evalu-
ations of some of these materials as well as new derivatives
are currently under way, and complete biological data will
be presented in future papers.
Entry R1 R2
X, Y
Compound [% yield][b]
1
2
3
4
5
6
Me C6H5
Me 4-CF3C6H4 Me3Si–CϵC–, H
Bn C6H5
Bn 4-CF3C6H4 Me3Si–CϵC–, H
Me C6H5
Bn C6H5
Me3Si–CϵC–, H
100 (83)[8]
101 (89)
102 (80)
Me3Si–CϵC–, H
103 (56)
H, Me3Si–CϵC–
H, Me3Si–CϵC–
104 (81)[c]
105 (50)[c]
[a] Reagents and conditions: Bu4NF (1.1 equiv.), THF, 0 °C, 5 min.
[b] Isolated yield. [c] Only the (Z) isomer was obtained.
6264
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6259–6269

A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives
product was passed through a short column of silica gel (mixture
of PE and AcOEt), and the crude aldol adducts were determined
to be sufficiently pure for use in the dehydration step by the 1H
and 19F NMR spectroscopic data. The crude aldol product
(5.30 mmol) was dissolved in dry DCM (40 mL, 0.13 m), and a
catalytic amount of DMAP (0.53 mmol, 0.1 equiv.) was added.
Freshly distilled triethylamine (10.6 mmol, 2.0 equiv.) was then
added, and the resulting mixture was cooled to 0 °C. Trifluoro-
acetic anhydride (TFAA, 5.83 mmol, 1.1 equiv.) was added drop-
wise, and the solution was warmed to room temperature over 2 h.
DBU (10.6 mmol, 2.0 equiv.) was added, and the mixture was
stirred at room temperature for 0.5 h. Water (20 mL) was added,
and the aqueous layer was extracted with AcOEt (3ϫ 30 mL). The
combined organic layers were washed with brine (40 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under re-
duced pressure to give the crude product, which was purified by
silica gel column chromatography.
Experimental Section
General Methods: Solvents were distilled before use. Reagents were
obtained commercially and used without further purification. The
1H, 19F, and 13C NMR spectroscopic data were recorded with a
Bruker Avance 300 spectrometer (in CDCl3 unless otherwise cited)
at 300, 282, and 75 MHz, respectively. Chemical shifts are reported
in ppm [s (singlet), d (doublet), dd (doublet of doublet), t (triplet),
m (multiplet), br. (broad)] relative to the solvent peak (δH
7.26 ppm for CHCl3, δC = 77.0 ppm for CDCl3) or CFCl3 (δF
=
=
0.00 ppm for 19F NMR spectra). Coupling constants (J) are re-
ported in Hertz. TLC was performed on Merck silica Gel 60 F254
plates with detection by UV light. Silica gel column chromatog-
raphy was performed on Macherey–Nagel silica gel 60M (0.04–
0.063 mm). The solvents that were employed for chromatography,
workup, and recrystallization are dichloromethane (DCM), ethyl
acetate (AcOEt), hexane (HX), and petroleum ether (PE). Mass
spectra were recorded with a Finnigan MAT 95 [EI or ESI+]. Melt-
ing points were measured in capillary tubes on a Büchi apparatus.
Compounds 1a, 1b, 2–6, 8–15, and 16–20 were commercially avail-
able. Compound 7 was prepared as described in ref.[15] Compounds
42[1i,1j] and 51[1i,1j] are known compounds with spectroscopic data,
whereas compound 43 is mentioned in the literature[3a] with no data
available. Compounds 71, 79, 84, 86, 93, 98, 100, and 106 have
already been described in our preliminary communication.[4]
(Z)-5-(4-Fluorobenzylidene)-4-methoxyfuran-2(5H)-one (44): Purifi-
cation by silica gel column chromatography (PE/AcOEt, 2:1) af-
1
forded 44 (28% yield) as a white solid; m.p. 155–156 °C. H NMR
(300 MHz, CDCl3): δ = 7.76–7.69 (m, 2 H), 7.09–7.01 (m, 2 H),
6.16 (s, 1 H), 5.26 (s, 1 H), 3.96 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.0, 168.5, 162.8 (d, J = 249.4 Hz), 141.8 (d, J =
2.7 Hz), 132.3 (d, J = 8.3 Hz), 128.6 (d, J = 3.5 Hz), 115.8 (d, J =
21.6 Hz), 106.5, 88.1, 59.2 ppm. 19F NMR (282 MHz, CDCl3): δ =
–113.68 (m) ppm. HRMS (ESI+): calcd. for C12H9FNaO3 [M +
Na]+ 243.0428; found 243.0427.
Typical Procedure for the Synthesis of the Starting Benzyl Lactone
Derivatives 1b–1d: To a suspension of tetronic acid (5.0 g, 50 mmol)
and anhydrous K2CO3 (13.8 g, 100 mmol) in dry DMF (100 mL)
was added 4-methoxybenzyl chloride (7.46 mL, 55 mmol) at room
temperature under argon, and the resulting suspension was stirred
overnight. The DMF was then removed under reduced pressure,
and water (50 mL) was added. The aqueous phase was then ex-
tracted with AcOEt (3ϫ 50 mL), and the combined organic layers
were washed with brine (1ϫ 50 mL), dried with Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure.
Recrystallization from AcOEt afforded the desired compound as a
colorless solid.
(Z)-4-(Benzyloxy)-5-(3,4-dimethoxybenzylidene)furan-2(5H)-one
(58): Purification by silica gel column chromatography (PE/AcOEt,
from 3:1 to 1:1) afforded 58 (18% yield) as a yellow solid; m.p.
149–150 °C. 1H NMR (300 MHz, CDCl3): δ = 7.45 (m, 5 H), 7.39–
7.38 (m, 1 H), 7.30–7.27 (m, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.23
(s, 1 H), 5.30 (s, 1 H), 5.13 (s, 2 H), 3.92 (s, 3 H), 3.91 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.6, 168.6, 149.8, 148.8, 140.7,
133.9, 128.9, 128.7, 127.9, 125.3, 124.3, 112.6, 110.8, 107.9, 88.4,
74.0, 55.71, 55.68 ppm. HRMS (ESI+): calcd. for C20H18NaO5 [M
+ Na]+ 361.1046; found 361.1034.
4-(4-Fluorobenzyloxy)furan-2(5H)-one (1c): Colorless solid (50%
yield); m.p. 118–119 °C. 1H NMR (300 MHz, CDCl3): δ = 7.40–
7.33 (m, 2 H), 7.15–7.07 (m, 2 H), 5.19 (s, 1 H), 5.03 (s, 2 H), 4.67
(s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 178.9, 173.3, 163.1
(d, J = 248.7 Hz), 130.2 (d, J = 8.8 Hz), 129.8 (d, J = 3.3 Hz), 115.9
(d, J = 22.2 Hz), 89.8, 73.8, 67.9 ppm. HRMS (ESI+): calcd. for
C11H9FNaO3 [M + Na]+ 231.0428; found 231.0418.
General Procedure for the One-Pot Aldolisation/Dehydration Reac-
tion Sequence: (see Table 2, method B). Under argon, the lactone
(4.38 mmol) and the aldehyde (5.26 mmol, 1.2 equiv.) were dis-
solved in CH3CN (15 mL). DBU (8.76 mmol, 2 equiv.) was then
added, and the mixture was stirred at 65 °C overnight. The solvent
was removed under reduced pressure, and the crude product was
purified by silica gel column chromatography.
4-(4-Methoxybenzyloxy)furan-2(5H)-one (1d): Colorless solid (37%
yield); m.p. 88–89 °C. H NMR (300 MHz, CDCl3): δ = 7.30 (d, J
(Z)-4-Methoxy-5-[2-(phenylethynyl)benzylidene]furan-2(5H)-one
(65): Purification by silica gel column chromatography (PE/AcOEt,
5:1) afforded 65 (73% yield) as a white solid; m.p. 121–122 °C. H
NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 8.1 Hz, 1 H), 7.46–7.43
(m, 3 H), 7.28–7.14 (m, 5 H), 6.84 (s, 1 H), 5.18 (s, 1 H), 3.88 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.2, 168.5, 142.9,
133.6, 132.3, 131.5, 130.4, 128.7, 128.6, 128.4, 123.8, 123.0, 105.3,
94.9, 88.4, 87.4, 59.4 ppm. HRMS (ESI+): calcd. for C20H14NaO3
[M + Na]+ 325.0835; found 325.0835.
1
1
= 8.7 Hz, 2 H), 6.92 (d, J = 8.7 Hz, 2 H), 5.18 (s, 1 H), 4.99 (s, 2
H), 4.64 (s, 2 H), 3.82 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 178.9, 173.4, 160.3, 130.0, 125.7, 114.2, 89.5, 74.4, 67.9,
55.3 ppm. HRMS (ESI+): calcd. for C12H12NaO4 [M + Na]+
243.0628; found 243.0630.
General Procedure for the Aldol Reactions: (see Scheme 2,
method A). To a solution of the lactone (7.0 mmol) in dry THF
(70 mL) was slowly added nBuLi (1.0 m solution in hexane,
7.7 mmol, 1.1 equiv.) at –78 °C under argon. The mixture was
stirred at –78 °C for 15 min, and then the aldehyde (10.5 mmol,
1.5 equiv.) was added at –78 °C. The resulting mixture was then
warmed to room temperature and then stirred at this temperature
overnight. Water (20 mL) was added, and the aqueous phase was
extracted with AcOEt (3ϫ 40 mL). The combined organic layers
were washed with brine (50 mL), dried with Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure. The crude
(Z)-4-(Benzyloxy)-5-[4,4-(dimethylamino)benzylidene]furan-2(5H)-
one (67): Purification by silica gel column chromatography (PE/
AcOEt, 3:1) afforded 67 (30% yield) as a yellow wax. 1H NMR
(300 MHz, CDCl3): δ = 7.66 (d, J = 9.0 Hz, 2 H), 7.43 (m, 5 H),
6.67 (d, J = 9.0 Hz, 2 H), 6.22 (s, 1 H), 5.24 (s, 1 H), 5.11 (s, 2 H),
3.01 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8, 169.3,
150.6, 139.1, 134.2, 132.2, 128.9, 128.8, 127.9, 120.2, 111.8, 109.1,
87.7, 73.9, 40.0 ppm. HRMS (ESI+): calcd. for C20H20NO3 [M +
H]+ 322.1438; found 322.1427.
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6265

J.-P. Bouillon, M. Médebielle et al.
FULL PAPER
General Procedure for the C-3-Bromination Reactions: (see Table 3).
white solid; m.p. 109–112 °C. 1H NMR (300 MHz, CDCl3): δ =
To a solution of the lactone (0.145 mmol) and pyridine 7.72 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 5.36 (s, 1 H),
(0.290 mmol, 2 equiv.) in DCM (1.45 mL, 0.1 m) was slowly added
bromine (0.174 mmol, 1.2 equiv.) at room temperature under ar-
gon. The resulting solution was stirred at room temperature for 1 h.
The reaction was quenched with a saturated solution of Na2S2O3
(20 mL), and the resulting mixture was extracted with DCM (3ϫ
20 mL). The combined organic phases were dried with Na2SO4 and
filtered. The filtrate was concentrated under reduced pressure to
give the crude product, which was purified by silica gel column
chromatography.
4.52 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.5, 164.4,
139.3, 131.6 (q, J = 32.6 Hz), 130.5, 128.8 (q, J = 280.1 Hz), 125.5
(q, J = 3.7 Hz), 89.2, 81.6, 61.0, 51.3 ppm. 19F NMR (282 MHz,
CDCl3 ): δ = –62.88 (s) ppm. HRMS (ESI+): calcd. for
C13H8Br3F3NaO3 [M + Na]+ 528.7868; found 528.7880.
(؎)-4-(Benzyloxy)-3,5-dibromo-5-[bromo(phenyl)methyl]furan-
2(5H)-one (83): Purification by silica gel column chromatography
(DCM) afforded 83 (65% yield) as a white solid; m.p. 139–140 °C.
1H NMR (300 MHz, CDCl3): δ = 7.59–7.57 (m, 2 H), 7.51–7.48
(m, 5 H), 7.39–7.37 (m, 3 H), 5.91–5.78 (m, 2 H), 5.32 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.4, 164.8, 135.4, 133.7, 130.1,
129.7, 129.5, 129.0, 128.54, 128.48, 90.3, 81.9, 75.3, 52.7 ppm.
HRMS (ESI+): calcd. for C18H13Br3NaO3 [M + Na]+ 536.8307;
found 536.8281.
(Z)-3-Bromo-5-(4-bromobenzylidene)-4-methoxyfuran-2(5H)-one
(72): Purification by silica gel column chromatography (PE/AcOEt,
1
4:1) afforded 72 (73% yield) as a white solid; m.p. 134–136 °C. H
NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 8.4 Hz, 2 H), 7.48 (d,
J = 8.4 Hz, 2 H), 6.19 (s, 1 H), 4.40 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.0, 163.3, 142.4, 132.0, 131.9, 130.8,
123.6, 107.4, 80.8, 59.8 ppm. HRMS (ESI+): calcd. for
C12H8Br2NaO3 [M + Na]+ 380.8732; found 380.8733.
General Procedure for the Elimination Reactions of Di- and Tribrom-
inated Lactones: (see Table 4). To a solution of the brominated de-
rivative (0.245 mmol) in DCM (5 mL, 0.05 m) was added DBU
(0.588 mmol, 2 equiv.) at 0 °C under argon, and the resulting solu-
tion was warmed to room temperature and stirred for 0.5–2 h. The
reaction was quenched with water (20 mL), and the mixture was
extracted with DCM (3ϫ 20 mL). The combined organic layers
were washed with brine (20 mL), dried with Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure to give the
crude product, which was purified by silica gel column chromatog-
raphy.
(Z)-5-Benzylidene-4-(benzyloxy)-3-bromofuran-2(5H)-one (76): Pu-
rification by silica gel column chromatography (PE/AcOEt, 5:1) af-
1
forded 76 (79% yield) as a white solid; m.p. 124–125 °C. H NMR
(300 MHz, CDCl3): δ = 7.72 (d, J = 6.3 Hz, 2 H), 7.46 (m, 5 H),
7.39–7.33 (m, 3 H), 6.30 (s, 1 H), 5.75 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.2, 162.8, 142.2, 134.5, 131.8, 130.6,
129.3, 129.1, 128.8, 128.7, 128.0, 108.9, 81.6, 73.7 ppm. HRMS
(ESI+): calcd. for C18H13BrNaO3 [M + Na]+ 378.9940; found
378.9926.
4-(Benzyloxy)-5-[bromo(phenyl)methylene]furan-2(5H)-one (85): Pu-
rification by silica gel column chromatography (PE/AcOEt, 1:1) af-
forded 85 (85% yield) as a mixture of Z/E (1:0.3) isomers. The (Z)
and (E) isomers could be separated after a second column
chromatography procedure (PE/AcOEt, 4:1). Data for (Z) isomer:
White solid; m.p. 94–95 °C. 1H NMR (300 MHz, CDCl3): δ = 7.43–
7.40 (m, 2 H), 7.35–7.23 (m, 6 H), 6.84–6.81 (m, 2 H), 5.42 (s, 1
H), 4.89 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.2,
166.6, 142.1, 135.7, 133.3, 129.8, 129.5, 128.5, 128.4, 128.0, 126.7,
109.0, 91.9, 73.9 ppm. HRMS (ESI+): calcd. for C18H13BrNaO3
[M + Na]+ 378.9940; found 378.9925. Data for (E) isomer: White
solid; m.p. 135 °C. 1H NMR (300 MHz, CDCl3): δ = 7.68–7.65 (m,
2 H), 7.50–7.35 (m, 8 H), 5.50 (s, 1 H), 5.21 (s, 2 H) ppm. Selected
13C NMR (75 MHz, CDCl3): δ = 169.1, 166.5, 140.4, 136.1, 133.8,
129.9, 129.7, 128.8, 128.1, 127.4, 108.5, 92.0, 74.6 ppm. HRMS
(ESI+): calcd. for C18H13BrNaO3 [M + Na]+ 378.9940; found
378.9929.
General Procedure for the Exocyclic Dibromination Reactions: (see
Scheme 4). To a solution of the lactone (0.495 mmol) in DCM
(25 mL, 0.02 m) was slowly added bromine (1 drop 3 min–1
,
0.495 mmol, 1 equiv.) at 0 °C under argon, and the resulting solu-
tion was stirred for 1 h at this temperature. The reaction was
quenched at 0 °C with a saturated aqueous Na2S2O3 solution
(30 mL), and the resulting mixture was extracted with DCM (3ϫ
30 mL). The combined organic layers were washed with brine
(30 mL), dried with Na2SO4, and filtered. The filtrate was concen-
trated under reduced pressure to give the crude product, which was
purified by silica gel column chromatography.
(؎)-4-(Benzyloxy)-5-bromo-5-[bromo(phenyl)methyl]furan-2(5H)-
one (80): Purification by silica gel column chromatography (DCM/
PE, 2:1) afforded 80 (65% yield) as a white solid; m.p. 155–157 °C.
1H NMR (300 MHz, CDCl3): δ = 7.65–7.62 (m, 2 H), 7.50–7.45
(m, 5 H), 7.40–7.38 (m, 3 H), 5.39 (s, 1 H), 5.38 (s, 1 H), 5.27–5.26
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 178.8, 167.6,
135.9, 133.1, 130.0, 129.5, 129.4, 129.0, 128.4, 128.2, 90.2, 89.5,
75.6, 52.4 ppm. HRMS (ESI+): calcd. for C18H14Br2NaO3 [M +
Na]+ 458.9202; found 458.9221.
3-Bromo-5-{bromo[4-(trifluoromethyl)phenyl]methylene}-4-methoxy-
furan-2(5H)-one (87): Purification by silica gel column chromatog-
raphy (DCM) afforded 87 (60% yield) as a mixture of Z/E (approx-
imately 1:0.6) isomers (not separated); white solid. Data for Z/E
isomers: 1H NMR (300 MHz, CDCl3): δ = 7.72–7.62 (m, 6 H), 7.50
(d, J = 8.1 Hz, 2 H), 4.48 (s, 3 H), 4.02 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 163.2, 163.0, 162.9, 161.4, 142.1, 141.0,
139.4, 139.1, 131.5 (q, J = 32.5 Hz), 131.4 (q, J = 32.7 Hz), 130.2,
130.1, 125.1 (q, J = 3.8 Hz), 124.8 (q, J = 3.7 Hz), 123.5 (q, J =
271.0 Hz), 123.6 (q, J = 270.7 Hz), 107.7, 106.7, 84.65, 84.58, 60.1,
59.8 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.85 (s, minor),
–62.98 (s, major) ppm.
General Procedure for the Tribromination Reactions: (see Scheme 4).
To a solution of the lactone (0.108 mmol) in DCM (1.1 mL, 0.10 m)
was slowly added bromine (0.216 mmol, 2.0 equiv.) at 0 °C under
argon. The resulting solution was then slowly warmed to room
temperature over 1 h. The reaction was quenched with a saturated
aqueous solution of Na2S2O3 (20 mL), and the mixture was ex-
tracted with DCM (3ϫ 20 mL). The combined organic phases were
dried with Na2SO4 and filtered. The filtrate was concentrated under
reduced pressure to give the crude product, which was purified by
silica gel column chromatography.
General Procedure for Suzuki Coupling Reactions: (see Table 5).
Brominated γ-benzylidene methyl or benzyl tetronate
(0.196 mmol), K2CO3 (0.392 mmol, 2 equiv.), phenylboronic acid
(؎)-3,5-Dibromo-5-{bromo[4-(trifluoromethyl)phenyl]methyl}-4- (0.392 mmol, 2 equiv.), and Pd(PPh3)4 (0.0196 mmol, 0.1 equiv.)
methoxyfuran-2(5H)-one (82): Purification by silica gel column were dissolved in toluene (2.0 mL, 0.1 m) under argon. The mixture
chromatography (PE/AcOEt, 2:1) afforded 82 (60 % yield) as a
was stirred overnight at 75 °C. The reaction was quenched with
6266
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6259–6269

A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives
water (20 mL), and the aqueous phase was extracted with ethyl
acetate (3 ϫ 20 mL). The combined organic layers were washed
with brine (20 mL), dried with Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure to give the crude product,
which was purified by silica gel column chromatography to afford
the coupling product.
raphy (PE/AcOEt, 4:1) afforded 99 (83% yield) as a beige solid;
m.p. 141 °C. 1H NMR (300 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H),
7.31–7.25 (m, 6 H), 6.90–6.87 (m, 2 H), 5.39 (s, 1 H), 4.90 (s, 2 H),
0.23 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.1, 167.0,
147.4, 133.6, 133.4, 129.7, 128.48, 128.39, 128.3, 127.8, 126.8,
109.6, 108.7, 100.6, 92.2, 73.8, –0.31 ppm. HRMS (ESI+): calcd.
for C23H22NaO3Si [M + Na]+ 397.1230; found 397.1225.
General Procedure for Stille Coupling Reactions: (see Table 5).
Brominated γ-benzylidene methyl or benzyl tetronate
(0.188 mmol), phenyltributylstannane (0.376 mmol, 2 equiv.), and
Pd(PPh3)4 (0.0188 mmol, 0.1 equiv.) were dissolved in toluene
(3 mL, 0.06 m) under argon. The mixture was stirred overnight at
75 °C. The reaction was quenched with water (20 mL), and the
aqueous phase was extracted with ethyl acetate (3ϫ 20 mL). The
combined organic layers were washed with brine (20 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under re-
duced pressure to give the crude product, which was purified by
silica gel column chromatography to afford the coupling product.
General Procedure for the Desilylation Reactions: (see Table 7). To
a solution of the silylated derivative (0.29 mmol) at 0 °C in THF
(6 mL, 0.05 m) was slowly added tetra-n-butylammonium fluoride
(TBAF, 0.1 m solution in THF, 0.31 mmol, 1.1 equiv.). The mixture
was stirred at 0 °C for 5 min, and water (20 mL) was added. The
aqueous layer was extracted with AcOEt (3ϫ 20 mL), and the com-
bined organic phases were washed with water (20 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure to give the crude product, which was purified by silica gel
column chromatography.
(Z)-5-Benzylidene-4-(benzyloxy)-3-phenylfuran-2(5H)-one (90): Pu-
rification by silica gel column chromatography (PE/DCM, 1:1) af-
forded 90 (47% yield for Suzuki coupling; 67% yield for Stille cou-
(Z)-3-Ethynyl-4-methoxy-5-[4-(trifluoromethyl)benzylidene]furan-
2(5H)-one (101): Purification by silica gel column chromatography
(from DCM/PE, 2:1 to DCM) afforded 101 (89% yield) as a yellow
1
1
pling) as a white solid; m.p. 129 °C. H NMR (300 MHz, CDCl3):
solid; m.p. 181 °C. H NMR (300 MHz, CDCl3): δ = 7.81 (d, J =
δ = 7.79 (d, J = 8.1 Hz, 2 H), 7.56–7.53 (m, 2 H), 7.45–7.35 (m, 9
H), 7.21–7.20 (m, 2 H), 6.33 (s, 1 H), 5.07 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.8, 162.6, 142.8, 134.9, 132.6, 130.5,
130.0, 129.2, 128.9, 128.8, 128.73, 128.65, 128.6, 128.4, 127.8,
108.2, 106.6, 74.6 ppm. HRMS (ESI+): calcd. for C24H18NaO3 [M
+ Na]+ 377.1148; found 377.1140.
8.1 Hz, 2 H), 7.60 (d, J = 8.1 Hz, 2 H), 6.29 (s, 1 H), 4.44 (s, 3 H),
3.40 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.5, 166.7,
142.9, 135.4, 130.7, 130.6 (q, J = 32.4 Hz), 125.6 (q, J = 3.8 Hz),
123.8 (q, J = 277.0 Hz), 107.5, 87.3, 86.0, 72.2, 60.2 ppm. 19F NMR
(282 MHz, CDCl3): δ = –62.85 (s) ppm. HRMS (ESI+): calcd. for
C15H9F3NaO3 [M + Na]+ 317.0396; found 317.0385.
5-(Diphenylmethylene)-4-methoxyfuran-2(5H)-one (91): Purification
by silica gel column chromatography (DCM) afforded 91 (96 %
yield for Suzuki coupling; 74% yield for Stille coupling) as a yellow
solid; m.p. 169 °C. 1H NMR (300 MHz, CDCl3): δ = 7.43–7.29 (m,
8 H), 7.23–7.20 (m, 2 H), 5.31 (s, 1 H), 3.61 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.2, 168.3, 139.3, 137.4, 136.6,
130.7, 130.5, 128.5, 128.1, 128.0, 127.6, 126.9, 90.1, 59.0 ppm.
HRMS (ESI+): calcd. for C18H14NaO3 [M + Na]+ 301.0835; found
301.0833.
(Z)-5-Benzylidene-4-(benzyloxy)-3-ethynylfuran-2(5H)-one (102):
Purification by silica gel column chromatography (PE/AcOEt, 5:1)
1
afforded 102 (80% yield) as a brown solid; m.p. 140 °C. H NMR
(300 MHz, CDCl3): δ = 7.75–7.72 (m, 2 H), 7.49–7.44 (m, 5 H),
7.40–7.32 (m, 3 H), 6.33 (s, 1 H), 5.80 (s, 2 H), 3.47 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.2, 166.9, 141.5, 134.3, 131.9,
130.8, 129.4, 129.2, 128.8, 128.7, 128.3, 109.7, 87.0, 86.3, 74.3,
72.8 ppm. HRMS (ESI+): calcd. for C20H14NaO3 [M + Na]+
325.0835; found 325.0827.
General Procedure for Sonogashira Coupling Reactions: (see
Table 6). Brominated γ-benzylidene methyl or benzyl tetronate
(0.355 mmol), CuI (0.036 mmol, 0.1 equiv.), and Pd(PPh3)2Cl2
(0.036 mmol, 0.1 equiv.) were dissolved in toluene (3 mL, 0.1 m).
Trimethylsilylacetylene (0.530 mmol, 1.5 equiv.) and freshly dis-
tilled Et3N (0.710 mmol, 2 equiv.) were added, and the resulting
mixture was stirred at 75 °C overnight. The reaction was quenched
with water (20 mL), and the aqueous phase was extracted with
AcOEt (3ϫ 20 mL). The combined organic phases were washed
with brine (20 mL), dried with Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure to give the crude product,
which was purified by silica gel column chromatography.
General Procedure for the Copper(I)-Catalyzed 1,3-Dipolar Cyclo-
addition: (see Table 8). To the solution of the alkyne (0.149 mmol)
and benzyl azide (0.223 mmol, 1.5 equiv.) in tBuOH (1.0 mL) and
DCM (0.5 mL) were successively added a solution of sodium l-
ascorbate (0.0149 mmol, 0.1 equiv.) in water (0.5 mL) and a solu-
tion of CuSO4·5H2O (0.0074 mmol, 0.05 equiv.) in water (0.5 mL).
The solution was stirred overnight at room temperature. The sol-
vents were removed under reduced pressure, and water (10 mL) was
added. The aqueous layer was extracted with DCM (3ϫ 10 mL).
The combined organic phases were washed with water (10 mL),
dried with Na2SO4, and filtered. The filtrate was concentrated un-
der reduced pressure to give the crude product, which was purified
by silica gel column chromatography.
(Z)-4-Methoxy-5-[4-(trifluoromethyl)benzylidene]-3-[(trimethylsil-
yl)ethynyl]furan-2(5H)-one (94): Purification by silica gel column
chromatography (PE/AcOEt, 4:1) afforded 94 (73% yield) as a yel-
(Z)-3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-4-methoxy-5-[4-(trifluoro-
methyl)benzylidene]furan-2(5H)-one (107): Purification by silica gel
column chromatography (PE/AcOEt, 2:1) afforded 107 (66% yield)
as a yellow solid; m.p. 159 °C. 1H NMR (300 MHz, CDCl3): δ =
8.07 (s, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H),
7.41–7.31 (m, 5 H), 6.41 (s, 1 H), 5.57 (s, 2 H), 4.41 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.2, 163.0, 144.3, 137.0, 135.9,
134.2, 130.5, 130.2 (q, J = 32.6 Hz), 129.2, 128.9, 128.2, 125.6 (q,
J = 3.8 Hz), 124.0, 123.9 (q, J = 270.1 Hz), 106.9, 95.8, 62.2,
54.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.76 (s) ppm.
HRMS (ESI+): calcd. for C22H16F3N3NaO3 [M + Na]+ 450.1036;
found 450.1025.
1
low solid; m.p. 156 °C. H NMR (300 MHz, CDCl3): δ = 7.80 (d,
J = 8.1 Hz, 2 H), 7.59 (d, J = 8.1 Hz, 2 H), 6.25 (s, 1 H), 4.44 (s,
3 H), 0.23 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.9,
166.4, 143.2, 135.5, 130.6, 130.4 (q, J = 28.3 Hz), 125.6 (q, J =
3.7 Hz), 123.8 (q, J = 271.0 Hz), 107.0, 104.6, 92.7, 88.7, 60.0,
–0.53 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.83 (s) ppm.
HRMS (ESI+): calcd. for C18H17F3NaO3Si [M + Na]+ 389.0791;
found 389.0776.
(Z)-4-(Benzyloxy)-5-[1-phenyl-3-(trimethylsilyl)prop-2-ynylidene]-
furan-2(5H)-one (99): Purification by silica gel column chromatog-
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6267

J.-P. Bouillon, M. Médebielle et al.
FULL PAPER
J. Org. Chem. 2011, 76, 5924–5935; q) C. Ghobril, J. Kister, R.
Baati, Eur. J. Org. Chem. 2011, 3416–3419; r) S. Dubois, F.
Rodier, R. Blanc, R. Rahmani, V. Héran, J. Thibonnet, L.
Commeiras, J.-L. Parrain, Org. Biomol. Chem. 2012, 10, 4712–
4719; s) A. Bidon-Chanal, A. Fuertes, D. Alonso, D. I. Pérez,
A. Martínez, F. J. Luque, M. Medina, Eur. J. Med. Chem. 2013,
60, 479–489; t) J. Rouleau, A. Korovitch, C. Lion, M. Hémadi,
N.-T. Ha-Duong, J.-M. El Hage Chahine, T. Le Gall, Tetrahe-
dron 2013, 69, 10842–10848; u) K. Katakawa, D. Yonenaga, T.
Terada, N. Aida, A. Sakamoto, K. Hoshino, T. Kumamoto,
Heterocycles 2014, 88, 817–825; v) R. Weixler, T. Bach, Synthe-
sis 2014, 46, 2663–2671.
a) S. Meunier, M. Hanédanian, M. Desage-El Murr, S. Nowac-
zyk, T. Le Gall, S. Pin, J.-P. Renault, D. Boquet, C. Crémignon,
C. Mioskowski, F. Taran, ChemBioChem 2005, 6, 1234–1241;
b) D. Habrant, S. Poigny, M. Ségur-Derai, Y. Brunel, B. Heur-
taux, T. Le Gall, A. Strehle, R. Saladin, S. Meunier, C. Mios-
kowski, A. Wagner, J. Med. Chem. 2009, 52, 2454–2464; c) B.
Nadal, S. A.-L. Thetiot-Laurent, S. Pin, J.-P. Renault, D.
Cressier, G. Rima, A. Le Roux, S. Meunier, A. Wagner, C.
Lion, T. Le Gall, Bioorg. Med. Chem. 2010, 18, 7931–7939; d)
H. Gao, W. Guo, Q. Wang, L. Zhang, M. Zhu, T. Zhu, Q. Gu,
W. Wang, D. Li, Bioorg. Med. Chem. Lett. 2013, 23, 1776–1778.
a) S. Antane, C. E. Caufield, W. Hu, D. Keenye, P. Labthavikul,
K. Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen,
G. Singh, Y. Yang, Bioorg. Med. Chem. Lett. 2006, 16, 176–
180; b) T. S. Mansour, C. E. Caufield, B. Rasmussen, R. Copar,
G. Krishanmurthy, K. M. Morris, K. Svenson, J. Bard, C.
Smeltzer, S. Naughton, S. Antane, Y. Tang, A. Severin, D. Qua-
gliato, P. J. Petersen, G. Singh, ChemMedChem 2007, 2, 1414–
1417.
(Z)-5-[(1-Benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methylene]-4-meth-
oxyfuran-2(5H)-one (109): Purification by silica gel column
chromatography (PE/AcOEt, 1:1) afforded 109 (66% yield) as a
1
yellow solid; m.p. 199 °C. H NMR (300 MHz, CDCl3): δ = 8.28
(s, 1 H), 7.40–7.30 (m, 10 H), 5.55 (s, 2 H), 5.26 (s, 1 H), 3.58 (s, 3
H) ppm. Selected 13C NMR (75 MHz, CDCl3): δ = 171.3, 167.5,
139.0, 134.5, 132.8, 130.3, 129.0, 128.6, 128.3, 127.9, 127.5, 126.0,
117.5, 90.0, 59.1, 54.1 ppm. HRMS (ESI+): calcd. for C21H18N3O3
[M + H]+ 360.1343; found 360.1346.
Single-Crystal X-ray Diffraction Analyses: Single-crystal X-ray
studies were carried out by using a Gemini diffractometer and the
related analysis software.[16] Absorption corrections based on the
crystal faces were applied to the data sets (analytical).[17] The struc-
tures were solved by direct methods using the SIR97 program[18]
combined with Fourier difference syntheses and refined against F
using reflections with [I/σ(I) Ͼ 3] by using the CRYSTALS pro-
gram.[19] All atomic displacement parameters for non-hydrogen
atoms were refined with anisotropic terms. The hydrogen atoms
were theoretically located on the basis of the conformation of the
supporting atom and refined by using the riding model.
[2]
[3]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, preparation of compounds, and 1H,
19F, and 13C NMR spectra.
Acknowledgments
This work was supported by the Agence Nationale de la Recherche
(ANR) (ANR-11-EMMA-04-QUINOLAC) and the Ministère de
l’Enseignement Supérieur et de la Recherche (Ph. D. fellowship to
S. I.). Additional support was provided by the Centre National de
la Recherche Scientifique (CNRS) and the Université Claude Ber-
nard Lyon 1 (UCBL). H. Y. and M. M. are grateful to the PICS
exchange program of CNRS (grant number 05871) for fostering
our international collaboration. The authors also thank Julien Bos-
son and Clément de Saint Jores for some materials syntheses and
Florian Albrieux, Christian Duchet, Nathalie Enriques, and Reyn-
ald Hélye from the Centre Commun de Spectrométrie de Masse
(CCSM) of Université Claude Bernard Lyon 1 for assistance and
access to the mass spectrometry facility.
[4]
[5]
For our preliminary communication, see: S. Iikawa, N. Chopin,
G. Pilet, J.-P. Bouillon, M. Médebielle, Tetrahedron Lett. 2013,
54, 4577–4581.
a) H.-D. Stachel, M. Jungkenn, C. Koser-Gnoss, H. Poschen-
rieder, J. Redlin, Liebigs Ann. Chem. 1994, 9, 961–964; b) Y.
Bourdreux, E. Bodio, C. Willis, C. Billaud, T. Le Gall, C. Mios-
kowski, Tetrahedron 2008, 64, 8930–8937; c) B. Nadal, J. Rou-
leau, H. Besnard, P. Thuéry, T. Le Gall, Tetrahedron 2011, 67,
2605–2611.
R. Selig, D. Schollmeyer, W. Albrecht, S. Laufer, Tetrahedron
2011, 67, 9204–9213.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483; b)
S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–
9695.
[6]
[7]
[8]
[9]
a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470; b) R. Chinchilla, C. Nájera, Chem. Rev.
2007, 107, 874–922; c) R. Chinchilla, C. Nájera, Chem. Soc.
Rev. 2011, 40, 5084–5121.
a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596–2599; Angew. Chem.
2002, 114, 2708; b) M. Meldal, C. W. Tornøe, Chem. Rev. 2008,
108, 2952–3015.
[1] For reviews, see: a) B. L. Royles, Chem. Rev. 1995, 95, 1981–
2001; b) A. L. Zografos, D. Georgiadis, Synthesis 2006, 3157–
3188; c) R. Schobert, A. Schlenk, Bioorg. Med. Chem. 2008,
16, 4203–4221; d) D. Georgiadis, Tetronic Acids, in: Natural
Lactones and Lactams: Synthesis Occurrence and Biological Ac-
tivity (Ed: T. Janecki), Wiley-VCH, Weinheim, Germany, 2013,
p. 1–49; e) L. Vieweg, S. Reichau, R. Schobert, P. F. Leadlay,
R. D. Süssmuth, Nat. Prod. Rep. 2014, 31, 1554–1584; f) M. H.
Lacoske, E. A. Theodorakis, J. Nat. Prod. 2015, 78, 562–575;
g) H. Yanai, Green and Catalytic Methods for γ-Lactone Syn-
thesis in: Green Synthetic Approaches for Biologically Relevant
Heterocycles (Ed: G. Brahmachari), Elsevier, Amsterdam,
2015, p. 257–289; for selected papers, see: h) K. Rehse, J.
Lehmke, Arch. Pharm. 1985, 318, 11–14; i) A. C. Campbell,
M. S. Maidment, J. H. Pick, D. F. M. Stevenson, J. Chem. Soc.
Perkin Trans. 1 1985, 1567–1576; j) A. Pelter, R. I. H. Al-Bay-
ati, M. T. Ayoub, W. Lewis, P. Pardasini, R. Hansel, J. Chem.
Soc. Perkin Trans. 1 1987, 717–742; k) A. J. Poss, M. H. Bro-
dowski, Tetrahedron Lett. 1989, 30, 2505–2508; l) J. Uenishi,
R. Kawahama, O. Yonemitsu, J. Org. Chem. 1997, 62, 1691–
1701; m) A. S. Kende, J. I. M. Hernando, J. B. J. Milbank, Tet-
rahedron 2002, 58, 61–74; n) D. Albrecht, B. Basler, T. Bach, J.
Org. Chem. 2008, 73, 2345–2356; o) M. Fleck, T. Bach, Chem.
Eur. J. 2010, 167, 6015–6032; p) R. Weixler, J. P. Hehn, T. Bach,
[10]
[11]
[12]
J. Hou, X. Liu, J. Shen, G. Zhao, P. G. Wang, Expert Opin.
Drug Discov. 2012, 7, 489–501.
Compound 7: CAS 1272–43–1; X. Yin, Y. Li, Y. Zhu, X. Jing,
Y. Li, D. Zhu, Dalton Trans. 2010, 41, 9929–9935.
Compound 66: orthorhombic, Pbca, a = 15.375(1) Å, b =
12.338(1) Å,
c = 15.512(1) Å, V =
2942.6(2) Å3, refined
formula: C18H17NO3, molecular weight: 295.3 gmol–1, Z = 8,
d = 1.333 gcm–3, μ = 0.091 mm–1, R[I/σ(I) Ͼ 3] = 0.0413,
Rw[I/σ(I) Ͼ 3] = 0.0456, S = 1.13, Δρmax = 0.19 e-Å–3, Δρmin
= –0.18 e-Å–3, number refined parameters: 199, number reflec-
tions used: 2407. CCDC-1059356 (for 66) contains the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Compound 78: monoclinic, P21/n, a = 12.2321(9) Å, b =
[13]
7.9932(5) Å,
c = 18.823(1) Å, β = 101.404(6)°, V =
1804.1(2) Å3, refined formula: C20H17Br1O5, molecular weight:
6268
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6259–6269

A Rapid Entry to Diverse γ-Ylidenetetronate Derivatives
417.26 gmol–1, Z = 4, d = 1.536 gcm–3, μ = 2.307 mm–1,
R[I/σ(I) Ͼ 3] = 0.0363, Rw[I/σ(I) Ͼ 3] = 0.0456, S = 1.10,
Δρmax = 0.25 e– Å–3, Δρmin = –0.39 e– Å–3, number refined pa-
rameters: 235, number reflections used: 2099. CCDC-1061804
(for 78) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[15] B. Nadal, P. Thuéry, T. Le Gall, Tetrahedron Lett. 2009, 50,
2430–2433.
[16] CrysAlisPro, v. 1.171.33.46 (release 27–08–2009, CrysAlis171.-
NET), Oxford Diffraction Ltd. 2009.
[17] J. de Meulenaar, H. Tompa, Acta Crystallogr. 1965, 19, 1014–
1018.
[18] G. Cascarano, A. Altomare, C. Giacovazzo, A. Guagliardi,
A. G. G. Moliterni, D. Siliqi, M. C. Burla, G. Polidori, M. Ca-
malli, Acta Crystallogr. Sect. A 1996, 52, C-79.
[19] D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge,
CRYSTALS Issue 11, Chemical Crystallography Laboratory,
Oxford, UK, 1999.
[14] a) S.-H. Yang, Synlett 2009, 8, 1351–1352; b) M.-F. Ruasse,
Adv. Phys. Org. Chem. 1993, 28, 2072–91; c) A. Boschi, C. Chi-
appe, A. De Rubertis, M.-F. Ruasse, J. Org. Chem. 2000, 65,
8470–8477; d) C. Giordano, L. Coppi, J. Org. Chem. 1992, 57,
2766–2768.
Received: May 22, 2015
Published Online: August 14, 2015
Eur. J. Org. Chem. 2015, 6259–6269
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6269