Soluble and polymer-supported 2- and 3-benzylated furans for the preparation of α,β-ethylenic carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2007.01.030

Soluble and polymer-supported 2- and 3-benzylated furans were subjected to a sequence involving a Diels-Alder reaction with α,β-acetylenic carbonyl compounds, a Michael addition, and a subsequent retro-Diels-Alder reaction to yield olefinic compounds. On solid support, this traceless strategy is advantageous since pure compounds were released in the thermal cycloreversion step. The fur-2-ylated resin allowed a highly diastereoselective synthesis.

Full text of DOI:10.1016/j.tet.2007.01.030

Tetrahedron 63 (2007) 2888–2900
Soluble and polymer-supported 2- and 3-benzylated furans for the
preparation of a,b-ethylenic carbonyl compounds
a
a
Sebastien Albert, Adrien Soret, Luis Blancob,a and Sandrine Deloisya,b,
*
ꢀ
a
´
Univ Paris-Sud, I.C.M.M.O., UMR 8182, Laboratoire de Syntheꢁse Organique et Methodologie, Bat. 420, Orsay Cedex F-91405, France
^
bCNRS, UMR 8182, Orsay Cedex F-91405, France
Received 21 November 2006; revised 12 January 2007; accepted 17 January 2007
Available online 20 January 2007
Abstract—Soluble and polymer-supported 2- and 3-benzylated furans were subjected to a sequence involving a Diels–Alder reaction with
a,b-acetylenic carbonyl compounds, a Michael addition, and a subsequent retro-Diels–Alder reaction to yield olefinic compounds. On solid
support, this traceless strategy is advantageous since pure compounds were released in the thermal cycloreversion step. The fur-2-ylated resin
allowed a highly diastereoselective synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
release an olefinic compound after chemical transformation
of the initial cycloadduct.11,12 In preliminary experiments,
Diels–Alder cycloaddition of maleic anhydride with the sol-
uble furan derivative 4 afforded the expected cycloadduct at
room temperature. Reduction of this compound with sodium
borohydride followed by heating of the resulting lactone led
to furan-2-(5H)-one and the starting compound 4 (Scheme
1). Reactions of the analogous polymer-bound furan 6
(vide infra) with maleic anhydride in tetrahydrofuran at var-
ious temperatures (from 20 ꢀC to 50 ꢀC) were unsuccessful.
The 13C NMR spectra of the resins showed mainly the sig-
nals of the starting material 6; in some cases, tiny signals
corresponding to the desired cycloadduct and to maleic an-
hydride were noticed. The presence of the dienophile was
unexpected since the resins were carefully washed with
THF before analysis by NMR. We concluded that it could
have been released by cycloreversion from the polymer-
supported cycloadduct after the washings. Thus, the retro-
Diels–Alder reaction occurred at too low a temperature,
precluding the use of such a polymer-bound cycloadduct
in further transformations.
The last step of a solid-phase synthesis is generally the re-
lease of the product in solution. Frequently, acidic/electro-
philic or basic/nucleophilic labile linkers are used and one
problem with these procedures is the compatibility of the
core and the substituents of the molecule with the generally
drastic conditions of the cleavage. Transition metal-medi-
ated cleavage and silicon-based linkers are compatible with
the presence of less robust substituents. Obviously the use
of photolabile linkers leads to improved cleavage character-
istics and allows the presence of structures and/or substitu-
ents, which are not stable in the above-cited conditions.1–5
Thermolabile linkers may also be envisaged in order to
preserve the integrity of a wide range of structures. To our
knowledge only four groups have used a thermal cleavage
step involving a retro-Diels–Alder reaction. The cyclorever-
sion has allowed the release of furans,6,7 buckminsterfuller-
ene C60,8 and benzoquinone.9
Moreover it was shown that C60 readily undergoes Diels–
Alder cycloaddition with cyclopentadiene- and furan-func-
tionalized polymers.8 These reactions are just some of the
numerous examples of Diels–Alder reactions performed on
solid support.10
O
O
O
1) NaBH4, EtOH
-5 °C to rt
R
maleic anhydride
Et2O or THF, rt
O
4 +
O
O
2) T > 55 °C (neat)
O
R
We have proposed the use of a furan-functionalized resin in
a sequence involving a Diels–Alder cycloaddition to im-
mobilize a dienophile and a retro-Diels–Alder reaction to
4
R = BnO
CH2
Scheme 1.
Keywords: Diels–Alder reaction; Retro-Diels–Alder reaction; Michael addi-
tion; Solid-phase synthesis.
* Corresponding author. Tel.: +33 1 69 15 47 12; fax: +33 1 69 15 62 78;
e-mail: sdeloisy@icmo.u-psud.fr
This paper deals with the use of 2- and 3-benzylated furans
in a strategy involving acetylenic dienophiles, where the
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.030

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2889
thermally stable Diels–Alder cycloadducts could be func-
tionalized before the retro-Diels–Alder reaction.
2.2. Diels–Alder reactions with acetylenic dienophiles
At first, 4,4-diethoxybut-2-ynal was selected as the dieno-
phile since the presence of a free and a protected aldehyde
should allow various chemical transformations.
2. Results and discussion
Treatment of 1,1,4,4-tetraethoxybut-2-yne 10 with pure for-
mic acid in chloroform gave 4,4-diethoxybut-2-ynal 1120,21
in 66% yield after distillation. As reported,20b tetraethoxy-
butyne 10 was prepared by reaction of diethyl phenyl ortho-
formate with bis(bromomagnesium)acetylide in variable
yields (between 24 and 65%). A more reproducible synthesis
(85% yield) was achieved by reaction of diethyl phenyl
orthoformate with the bromomagnesium derivative of
commercially available 3,3-diethoxypropyne (Scheme 3).
2.1. Preparation of 2- and 3-benzylated furans
The 2- and 3-benzylated furans 4 and 7 were synthesized in
a four-step sequence from commercially available ethyl
4-hydroxybenzoate, as shown in Scheme 2.
Reactions of the difuran-2-yl-13 and the difuran-3-yllithio-
cuprate14 with the benzylic bromide 315,16 afforded furans
4 and 7, respectively. For the synthesis of furan 4, the opti-
mum yield (94%) was obtained using a difuranyllithiocup-
rate prepared from CuBr$SMe2. However, the yields were
erratic (from 20 to 94%) and depended on the quality of
the cuprous complex. More reproducible results (76–87%)
were observed with the higher order difuranylcyano-
cuprate (C4H3O)2Cu(CN)Li2.17 The corresponding furan-
substituted resins 6 and 9 were prepared by treatment of
a chloromethylated Merrifield resin with the phenolic prod-
ucts 5 and 8 in the presence of cesium carbonate and sodium
iodide in DMF.18 Compounds 5 and 8 were obtained by hy-
drogenolysis of 4 and 7 with sodium in butan-1-ol.19 Resins
6 and 9 were purified by successive washings with DMF,
H2O, DMF, acetone, and CH2Cl2 and subsequently dried un-
der vacuum. Acidification of filtrates allowed recovery of
excesses of phenols 5 and 8. The resins 6 and 9 were charac-
terized by IR and 1H and 13C Magic Angle Spinning (MAS)
NMR spectroscopies.
Using conditions described for 2-alkylfurans,22 Diels–Alder
reaction of the furan derivative 4 (1.2 equiv) with ynal 11
in a sealed tube at 90 ꢀC under argon in the presence of
small amounts of sodium carbonate and 2,6-di-tert-butyl-4-
methylphenol (BHT) without solvent gave the cycloadduct
12 in 93% yield (Scheme 4, Table 1: entry 1). Since a liquid
is necessary to swell the resin in cases of solid-supported re-
actions, various solvents were tested under different condi-
tions for the preparation of the cycloaddition products 12
and 13, despite the fact that a very slow reaction had been
reported for the cycloaddition of ynal 11 with 2-alkylfurans
in dichloromethane or toluene.22
R1
O
O
R2
11
(EtO)2HC
CHO
CH(OEt)2
CHO
R2
Na2CO3, BHT, sealed tube
R1
1 = BnO-C6H4-CH2, R2 = H
1 = H, R2 = BnO-C6H4-CH2
4
7
12
13a/b
The soluble furans 4 and 7, similar to the furan spacer ap-
pendage of the polymers 6 and 9, were used for solution-
state study of the reaction sequence to be applied on the solid
support.
R
R
Scheme 4.
i
ii, iii
HO
CO2Et
O
CO2Et
O
X
1
X = OH
X = Br
2
3
v
v
iv
vi
O
HO
HO
O
O
O
O
2
3
4
5
6
vi
O
vii
O
O
3
O
O
8
9
7
Scheme 2. Reagents and conditions: (i) BnBr, K2CO3, AliquatÒ 336 (1 mol %), 100 ꢀC, 98%; (ii) LiAlH4, Et2O, rt, 100%; (iii) PBr3, CH2Cl2, rt, 91%; (iv) furan,
n-BuLi, Et2O, 0 ꢀC, then CuBr$SMe2, Et2O/THF, ꢁ40 ꢀC to rt, 94%; (v) Na, n-BuOH, 80 ꢀC, 98% for 5; 79% for 8; (vi) Merrifield resin, Cs2CO3, NaI, DMF, rt;
(vii) 3-bromofuran, n-BuLi, Et2O, ꢁ78 ꢀC, then CuBr$SMe2, Et2O/THF, ꢁ65 ꢀC to rt, 76%.
1) EtMgBr
HCO2H
CHCl3
(EtO)2HC
(EtO)2HC
CH(OEt)2
(EtO)2HC
CHO
2) PhOCH(OEt)2
10
11
Scheme 3.

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S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
Table 1. Diels–Alder reactions of furan 4 or 7 with ynal 11 in homogeneous
It is noteworthy that the ZnCl2-catalyzed reaction of ynal 11
and furan 4 in methylene chloride at ꢁ40 ꢀC gave only
Michael adduct 14 (Scheme 5). A similar Michael addition
product was observed in the cycloaddition of furan20a and
2-alkylfurans22 with ynal 11 in the absence of sodium
carbonate.
phasea
Entry Furan Solvent
Temp Time Cycloadduct Yield
(ꢀC)
(h)
(%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
4
4
7
7
Noneb
90
90
90
125
125
90
90
90
40
48
48
24
72
48
48
48
48
48
48
48
12
12
12
12
12
12
12
12
12
12
13a/13b
13a/13b
93
0d
Toluenec
Toluene
Toluene
Toluene
1,4-Dioxane
CH3CN
THF
86
47
42
77
69
72
0d
ZnCl2
+
BnO
4
11
CH2Cl2, -40 °C
O
CHO
CH(OEt)2
14
9
DMF
DMF
Toluene
Toluene
90
110
90
0d
68% 82:18
10
11
12
73e
87f
Scheme 5.
124
a
Unless otherwise noted, reactions were performed in vacuum-sealed tubes
after freeze-pump-thaw cycles.
Reaction was performed under argon.
Reaction was performed under argon in an open vessel after bubbling of
argon in the reaction mixture.
Degradation.
Regioisomeric ratio of 57:43.
Regioisomeric ratio of 55:45.
Most of the reported Diels–Alder reactions of acetylenic
dienophiles with furan derivatives involve acetylenedicarb-
oxylates.23 Moreover, with the exception of intramolecular
reactions,24 unsymmetrical acetylenic carbonyl compounds
used in such cycloadditions generally bear a second elec-
tron-withdrawing group.25 To prepare other 1-substituted 7-
oxabicycloheptadiene adducts, Diels–Alder reactions with
furan 4 were attempted using 3 equiv of commercially avail-
able dimethyl acetylenedicarboxylate (DMAD) or methyl
3-phenylpropiolate or the synthesized 3-phenylpropynal26
(Scheme 6). With DMAD, a toluene solution was heated at
110 ꢀC in a round-bottomed flask for 3 h (the reaction is
not air-sensitive) and the cycloadduct 15 was isolated quan-
titatively. After heating degassed toluene solutions of furan 4
and methyl phenylpropiolate or phenylpropynal in the pres-
ence of sodium carbonate and BHT in vacuum-sealed tubes
at 90 ꢀC during 24 h, no cycloadducts were detected.27,28
b
c
d
e
f
Degassed solutions of dienophile 11 (1.1 equiv) and
substituted furan 4 or 7 in the presence of sodium carbonate
(0.1 equiv) and BHT (0.1 equiv) were heated, then the
cycloadducts 12 and 13 were isolated by chromatography
(Table 1).
When a toluene solution of 4 and 11 was heated at 90 ꢀC for
48 h under an argon atmosphere after bubbling of argon in
the solution for 15 min, the ynal was totally transformed
and some furan remained unchanged, but no cycloadduct
12 was observed in the reaction mixture (entry 2). On the
other hand, the expected product 12 was isolated using tolu-
ene, 1,4-dioxane, acetonitrile or tetrahydrofuran as solvent
after heating in vacuum-sealed tubes previously degassed
solutions by freeze-pump-thaw cycles (entries 3–8). The
best result (86% yield) for this extremely air-sensitive reac-
tion was obtained by maintaining a toluene solution at 90 ꢀC
for 48 h (entry 3). Heating the toluene reaction mixture to
125 ꢀC for 24 or 72 h (entries 4 and 5) led to the product
12 in decreased yields, 47 and 42%, respectively. With
a well-degassed DMF solution heated at 90 ꢀC (entry 9) or
110 ꢀC (entry 10) no cycloadduct 12 was detected, despite
the fact that ynal 11 was totally transformed after 48 h at
O
R1
R1
COR2 (3 equiv)
Toluene
4
COR2
BnO
R
R
R
1 = CO2Me
1 = Ph
1 = Ph
R2 = OMe
2 = OMe
R2 = H
110 °C, 3 h
a
15
18
99%
0%
R
a
0%
Scheme 6. (a)Sealedtube,BHT(0.1 equiv), Na2CO3 (0.1 equiv), 90 ꢀC,24 h.
1
110 ꢀC. H and 13C NMR spectra of all samples of com-
pound 12 indicated the presence of only one diastereomer.
The reported structure with the aldehyde function close to
the benzylic appendage was proved by NOESYexperiments
(cross-peaks are present between the acetal proton and the
bridgehead proton of the oxabicyclo[2.2.1]heptadiene core).
In order to prepare the expected phenyl product 18, we envis-
aged a two-step synthesis via the brominated intermediate
17 obtained by Diels–Alder reaction of furan 4 with methyl
3-bromopropiolate 16 (Scheme 7). Treatment of methyl pro-
piolate with N-bromosuccinimide in acetone in the presence
of silver nitrate afforded methyl bromopropiolate 16.29 In
our hands, only impure lachrymatory samples of the ester
16 were isolated, with difficulty. To obviate purification,
the bromination was run in acetonitrile, then a solution of es-
ter 16 (about 3 equiv) in this solvent was collected by distil-
lation under low pressure and used in the cycloaddition step.
After heating at 110 ꢀC in a vacuum-sealed tube for two
days, a 97:3 mixture of the 3-brominated cycloadduct 17
and the 2-brominated isomer was isolated in 60% yield.
A similar regioselectivity was recently reported in the cyclo-
addition of 2-methylfuran with the same bromopropiolate
The 3-substituted furan 7 was less reactive with ynal 11.
When a degassed toluene solution was heated at 90 ꢀC for
48 h in a vacuum-sealed tube, a 57:43 mixture of the two re-
gioisomers 13a and 13b (entry 11) was isolated in 73% yield
and unreacted ynal 11 was still present in the reaction mix-
ture. A slightly better yield of the cycloadduct 13 (87%
yield) was obtained by increasing the reaction temperature
to 124 ꢀC (entry 12). The ratio of regioisomers was similar
to the previous case and the 1H NMR spectrum of the crude
reaction mixture showed the absence of ynal 11.

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2891
O
O
R1
CO2Me
i
ii
+
:
CO2Me
Br
CO2Me
R
R
CO2Me
Br
16
97
iii
3
R
1 = Br
1 = Ph
17
18
BnO
CH2
R =
R
Scheme 7. Reagents and conditions: (i) NBS, AgNO3, CH3CN, rt, 1 h; (ii) 4, CH3CN (sealed tube), 110 ꢀC, 48 h, 60%; (iii) PhB(OH)2, Pd2(dba)3, P(t-Bu)3, KF,
THF, rt, 3.5 h, 90%.
1
16.30 Reaction of phenylboronic acid (1.1 equiv) with the
adduct 17 in the presence of potassium fluoride, Pd2(dba)3,
and tris(tert-butyl)phosphine31 furnished the phenyl cyclo-
adduct 18 in high yield (90%). When standard Suzuki cou-
pling conditions were used (Pd(OAc)2, triphenylphosphine,
aqueous solution of sodium carbonate in a 5:1 mixture of
benzene and methanol at 50 ꢀC for 2.5 h), the product 18
was only obtained in 56% yield.32 Stille cross-coupling of
the brominated adduct 17 with tributylphenyltin was un-
successful or gave the expected product in a very low yield
under classical conditions.33
stable enough to be isolated at room temperature. The H
NMR spectrum of the crude isolated product 20 showed
the presence of two major isomers and (at least) four minor
diastereomers. An 87:13 mixture of enals (Z)-19 and (E)-19
and the furan 7 resulting from a retro-Diels–Alder reaction
were easily obtained after heating this mixture of diastereo-
mers 20 for 3 h at 45 ꢀC in THF (Scheme 8).
Treatment of esters 15 and 18 with benzenethiol in the pres-
ence of a catalytic amount of NaH at ꢁ78 ꢀC and subsequent
thermal retro-Diels–Alder reaction gave mainly the furan 4
and the unsaturated esters 22and 25, respectively (Scheme9).
The formation of the 3-phenyl compound 18 and, con-
sequently, the regioselective synthesis of the 3-brominated
cycloadduct 17 were ascertained by the presence of cross-
peaks between aromatic protons and the bridgehead proton
in the NOESY spectrum of compound 18.
The 1H NMR spectrum of the crude product obtained from
reaction of the diester 15 with sodium benzenethiolate
showed various signals, which could be attributed to three
isomers of the expected Michael adducts 21 (one set of sig-
nals at 6.72 (d), 6.48 (dd), and 5.34 ppm (d), another set at
6.52 (d), 6.31 (dd), and 4.92 ppm (d), and the last set at
6.25 (d), 6.21 (dd), and 5.02 ppm (d) attributed, respectively,
to the protons H-6, H-5, and H-4 of the bicyclic core;
a 0.7:0.3:1 mixture of these isomers was present). But
a retro-Diels–Alder reaction had occurred and furan 4, di-
methyl phenylsulfanylfumarate 22, and meso-dimethyl 2,3-
bis(phenylsulfanyl)succinate 2335,36 were also present. The
NMR spectrum also showed minor signals, which could be
attributed to dimethyl phenylsulfanylmaleate37 and dl-di-
methyl 2,3-bis(phenylsulfanyl)succinate.35,36 The adducts
21 were too unstable to be isolated by silica gel chromato-
graphy. After heating of this mixture for 16 h at 75 ꢀC in
toluene, the Michael adducts 21 were totally transformed.
Furan 4 and a 2:1 mixture of fumarate 22 and meso-bis-
(phenylsulfanyl)diester 23 were isolated in, respectively,
87 and 83% yields for this two-step sequence.38
2.3. Functionalization by Michael addition and retro-
Diels–Alder reaction
The functionalization of a,b-ethylenic aldehydes 12 and 13
was envisaged by Michael addition of benzenethiol using
a catalytic amount of sodium hydride (Scheme 8). When
the reaction with the cycloadduct 12 was run in THF at
ꢁ78 ꢀC, surprisingly a mixture of the starting furan 4 and
(Z)- and (E)-4,4-diethoxy-3-(phenylsulfanyl)butenal 19 (Z/
E¼75:25) was isolated after a basic aqueous work-up at
0 ꢀC and no Michael addition compound was detected. Per-
forming the reaction at room temperature yielded the furan
4, the aldehydes (E)-19 and (Z)-19, and a small amount of
4,4-diethoxy-3,3-bis(phenylsulfanyl)butanal resulting from
a second Michael addition reaction on the aldehyde 19.34
Treatment of a 55:45 mixture of cycloadducts 13a/13b with
sodium benzenethiolate at ꢁ78 ꢀC, as previously described,
gave a mixture of Michael addition products 20, which were
Reaction of sodium benzenethiolate with the monoester 18
yielded the adduct 24 as a 7:3 mixture of two diastereomers.
O
PhS
CH(OEt)2
CHO
CH(OEt)2
i, ii
+
4
CHO
85%
12
19
Z/E = 75:25
BnO
88%
O
O
SPh
CH(OEt)2
i, ii
THF, 45 °C
+
7
19
CH(OEt)2
CHO
CHO
Z/E = 87:13
80%
BnO
13 (a/b = 55:45)
20
77%
BnO
Scheme 8. Reagents and conditions: (i) PhSH (3 equiv), NaH (0.3 equiv), THF, ꢁ78 ꢀC to 0 ꢀC; (ii) treatment with aqueous NaOH, 0 ꢀC.

2892
S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
O
O
SPh
PhS
PhS
E
E
PhS
E
E
i
ii
+
:
+
4
+
22 + 23
4
+
E
E
R
R
O
E
E
E
1......... 0.15 ... 0.07 ... 0.06
15
21
22
23
1) 83%*
87%*
PhS
(2
O
O
PhS
Ph
E
SPh
SPh
H
Ph
Ph
i
ii
E
Ph
+
+
4
+
Ph
E
R
R
R
H
E
7 ................3
24
18
25
75%*
74%*
(92 8)
BnO
CH2
E = CO2Me
:
R =
* Overall yield from the corresponding starting material 15 or 18
Scheme 9. Reagents and conditions: (i) PhSH (3 equiv), NaH (0.3 equiv), THF, ꢁ78 ꢀC to 0 ꢀC, then treatment with aqueous NaOH, 0 ꢀC; (ii) toluene, 75 ꢀC,
16 h.
Column chromatography allowed the complete separation of
these isomers but a retro-Diels–Alder reaction occurred and
furan 4 and the olefinic esters 25 were present in each sam-
Comparison of 1H and 13C MAS NMR spectra of the Diels–
Alder adduct-functionalized resins 26 and 27 with those of
the soluble analogs 12 and 13 indicated a similar selectivity
of these solid-phase reactions to that observed with furans 4
and 7 in solution. Only one diastereomer was observed for
the resin 26 obtained from the fur-2-ylated polymer 6. Sim-
ilarly to the analogous compound 13 prepared in solution-
phase, the major isomer of the resin 27 is the one with the
lower field aldehyde proton signal and a similar regioselec-
tivity was observed (for 27, a 61:39 diastereomeric ratio was
obtained; for 13, this ratio was 55:45).
1
ple. Nevertheless, the main H and 13C NMR signals were
observed and an attempt was made to establish the stereo-
chemical relationships. With such 7-oxabicycloheptadienic
compounds addition generally occurs on the exo-face39
and the exo-position of the phenylsulfanyl group in the
two diastereomers was proposed. The exo-position of the
ester group of the major isomer was proved by NOESY
experiments (cross-peaks are present between the protons
in the positions 2 and 6 of the oxabicyclo[2.2.1]heptene
core). Furan 4 and a mixture of (E)- and (Z)-isomers of the
olefinic ester 25 were isolated in good yields after heating
each stereomer for 16 h at 75 ꢀC. The Z/E ratio obtained
for ester 25 was fairly constant, regardless of the starting dia-
stereomer 24 (from major isomer: Z/E¼93:7; from minor
isomer: Z/E¼90:10).
Additions of excess benzenethiol to the resins 26 and 27 in
the presence of a catalytic amount of sodium hydride were
run at ꢁ40 ꢀC (at a lower temperature, no swelling of the
resins was observed). Upon increasing the reaction mixture
temperature, GC analyses of the solvent showed the pres-
ence of the a,b-unsaturated aldehyde 19 resulting from
a retro-Diels–Alder reaction above ꢁ35 ꢀC in the former
case and above ꢁ20 ꢀC in the latter one. Thus, the Michael
adduct-functionalized resins 28 and 29 were washed, respec-
tively, at ꢁ35 ꢀC and ꢁ25 ꢀC with THF, THF/MeOH, and
THF in order to remove excess of benzenethiol and sodium
benzenethiolate. After addition of THF to the washed resin
28 the temperature was allowed to increase to ꢁ2 ꢀC. Filtra-
tion at ꢁ2 ꢀC after 15 h at this temperature and concentra-
tion of filtrates under vacuum at 20 ꢀC allowed isolation of
only pure (Z)-aldehyde 19 in 49% overall yield based on
2.4. Reactions on solid support
Treatment of the furan-substituted resins 6 and 9 at 90 ꢀC for
72 h with 4 equiv of butynal 11, in the same conditions as
those used in homogeneous phase, gave, respectively, the
supported Diels–Alder adducts 26 and 27 after successive
washings with CH2Cl2, acetone, H2O, acetone, and
CH2Cl2 (Scheme 10). The excess of ynal 11 was mainly
present in the first solvent washing and could be recovered.
O
O
PhS
CH(OEt)2
+
SPh
CHO
CH(OEt)2
CH(OEt)2
CHO
i
ii
iii
O
2
6
OHC
H
(Z)-19 49% (4 steps)
6
26
28
O
O
SPh
i
ii
iii
CH(OEt)2
+
19
9
3
O
CH(OEt)2
CHO
Z/E = 70:30
CHO
27 (a/b = 61:39)
9
29
39% (4 steps)
Scheme 10. Reagents and conditions: (i) ynal 11, Na2CO3, BHT, toluene, 90 ꢀC, vacuum-sealed tube; (ii) PhSH, cat. NaH, THF; for 28: ꢁ40 ꢀC, then ꢁ35 ꢀC
and filtration and washings at ꢁ35 ꢀC; for 29: ꢁ40 ꢀC, then ꢁ25 ꢀC and filtration and washings at ꢁ25 ꢀC; (iii) THF; with 28: ꢁ35 ꢀC, then ꢁ2 ꢀC; with 29:
ꢁ25 ꢀC, then rt and 40 ꢀC.

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2893
Merrifield resin for this four-step sequence. Further increase
of the temperature to 20 ꢀC of a suspension of the recovered
resin in THF did not release any more olefinic product. Par-
tial isomerization of the (Z)-aldehyde 19 to the (E)-isomer
was observed when the water bath was set to 40 ꢀC during
concentration. Stirring of the resin 29 in THF at 20 ꢀC for
24 h gave a 71:29 mixture of (Z)- and (E)-aldehydes 19 in
23% yield. After the reported time no release of olefinic
compounds was noticed at 20 ꢀC. When a suspension of
the recovered resin in THF was stirred for 24 h at 40 ꢀC
more aldehyde 19 was isolated (Z/E¼70:30; 16% yield).
No reaction was observed upon increasing the reaction
time at 40 ꢀC or at higher temperatures. Thus, it seems
that the retro-Diels–Alder reactions occur at different tem-
peratures for the various isomers linked to the resin 29.
using solvent (CDCl3) signals as internal standards (CHCl3
d¼7.27 ppm; CDCl3 d¼77.14 ppm). Assignments were
aided by DEPT-135 pulse, NOESY, and heteronuclear two-
dimensional experiments. Mass spectra (MS) were obtained
by electronic impact (EI, 70 eV) or positive chemical ioniza-
tion (CI) on a Nermag R10-10 spectrometer coupled with an
OK1 DP125 gas chromatographer. Electrospray (ES+) mass
spectra were performed on a Finnigan MAT 95S spectro-
meter. Relative percentages are shown in brackets. High res-
olution mass spectra (HRMS) were recorded with a Finnigan
MAT 95S (electronic impact or electrospray) spectrometer.
Elemental analyses were performed with a Perkin–Elmer
240C analyzer by the Service de Microanalyse of the Institut
de Chimie des Substances Naturelles of Gif-sur-Yvette
€
(France). Melting points were determined with a Buchi B-
545 apparatus and were uncorrected. As the solid support,
Merrifield resin (loading 0.8 mmol/g, styrene–1%DVB,
200–400 mesh) was purchased from Fluka. For MAS
NMR experiments, the resins were swollen with the minimal
volume of deuterated solvent (CDCl3) after introducing
them into the rotor. 1H and 13C NMR data were collected us-
ing a 4 mm MAS solid state probe on a Bruker DRX-400
(400 and 100 MHz, respectively) spectrometer with a spin-
ning rate of 3 kHz. Signals of the polymeric matrix were in-
dicated by Pm. Proofs of purity of aldehyde 19 released from
the resins were provided by their 1H NMR spectrum (>95%
pure). Infrared (IR) spectra of products and resins were
recorded using an FT-IR Perkin–Elmer spectrophotometer
(Spectrum One). Solvents were dried according to standard
procedures and all reactions requiring anhydrous conditions
were performed under argon. Degassed solutions were pre-
pared by freeze-pump-thaw cycles.
In both cases, IR spectroscopy of the recovered resins after
the retro-Diels–Alder reactions showed only the characteris-
tic bands of the furan-functionalized resins 6 and 9. It should
be noticed that the recovered resin 6 could be reused in
another Diels–Alder reaction/Michael addition/retro-Diels–
Alder reaction sequence.
3. Conclusion
We have shown that Diels–Alder reaction of soluble and
polymer-supported 2- and 3-benzylated furans with 4,4-di-
ethoxybut-2-ynal, followed by Michael addition of a nucleo-
phile, then retro-Diels–Alder reaction allows the preparation
of a b-substituted a,b-ethylenic aldehyde. On solid-phase,
this sequence is another example of a safety-catch strategy
since the Michael adduct is stable enough at low temperature
to remove unreacted reagents by filtration and the thermal
cycloreversion is induced at a higher temperature. Thus,
the released olefinic aldehyde is pure enough to avoid further
purification. The fur-2-ylated resin appears more promising
from a synthetic point of view since only one regioisomer
was obtained in the Diels–Alder reaction, a better diastereo-
selectivity was observed in the Michael addition, and the
yield of the final olefinic product was higher. a,b-Ethylenic
esters were also obtained, using a similar sequence via 7-oxa-
bicyclo[2.2.1]hepta-2,5-diene-2-carboxylates prepared from
dimethyl acetylenedicarboxylate or from methyl 3-bromo-
propiolate and a subsequent substitution of the bromine
atom. Synthetic applications of this traceless methodology
using various nucleophiles will be published in due course.
4.2. Preparation of fur-2-ylated and fur-3-ylated resins
6 and 9
4.2.1. Ethyl 4-(benzyloxy)benzoate (1). A mixture of ethyl
4-hydroxybenzoate (8.30 g, 50.0 mmol), potassium carbon-
ate (7.25 g, 52.5 mmol), AliquatÒ 33640 (250 mg,
0.50 mmol), and benzyl bromide (6.25 mL, 52.5 mmol)
was stirred at 100 ꢀC for 6 h, and then cooled to room tem-
perature. After dilution with Et2O (100 mL) and water
(100 mL), the decanted aqueous layer was extracted with
Et2O. The combined organic extracts were successively
washed with 1 M HCl and water, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified
by flash chromatography (pentane/Et2O: 90/10) to afford 1
(12.52 g, 98%) as a white solid: mp 44 ꢀC (lit.41 mp
45.5 ꢀC). Spectroscopic data were in agreement with
reported values.42
4. Experimental
4.1. General
4.2.2. [4-(Benzyloxy)phenyl]methanol (2). To a suspension
of lithium aluminum hydride (1.28 g, 33.7 mmol) in dry
Et2O (80 mL) maintained under argon in an ice bath was
added dropwise a solution of ester 1 (11.55 g, 45.1 mmol)
in dry Et2O (100 mL). The ice bath was removed, and the re-
action mixture was stirred at room temperature for 2 h. The
excess of lithium aluminum hydride was decomposed by
slow addition (violent reaction) of hydrated Na2SO4 until
a clear solution was obtained (approximately 30 g of
Na2SO4). Filtration through a pad of anhydrous sodium sul-
fate and removal of solvent under reduced pressure gave the
benzylic alcohol 2 (9.69 g, 100%) as a white solid: mp 86 ꢀC
In solution-phase, reactions were monitored by TLC on sil-
ica gel 60 F254 precoated plates (0.25 mm thickness) with
UV detection (254 nm) and by heating after dipping in etha-
nolic solutions of phosphomolybdic acid or p-anisaldehyde.
The products were isolated by column chromatography on
silica gel (SDS 70–220 mesh or SDS 220–440 mesh for flash
1
chromatography). H and 13C NMR spectra were recorded
on Bruker AC200 (200 and 50.3 MHz, respectively) or
Bruker AC250 (250 and 62.9 MHz, respectively) spectro-
meters. Chemical shifts (d) are given in parts per million

2894
S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
(lit.43 mp 85–86 ꢀC). The crude alcohol showed a very sat-
(pentane/Et2O: 90/10, then 50/50) to afford phenol 5
(0.974 g, 98%) as a gray oil. H NMR (250 MHz, CDCl3)
1
1
isfactory H NMR spectrum43 and was used in the sub-
sequent reaction without further purification. 13C NMR
(62.9 MHz, CDCl3) d 64.9, 70.0, 115.0, 127.5, 128.0,
128.6, 128.7, 133.5, 137.0, 158.4.
d 3.90 (s, 2H), 5.25 (br s, 1H, OH), 6.00 (d, J¼2.9 Hz, 1H,
H-3), 6.31 (dd, J¼2.0 Hz, J¼2.9 Hz, 1H, H-4), 6.80 (d,
J¼8.4 Hz, 2H), 7.13 (d, J¼8.4 Hz, 2H), 7.35 (d, J¼2.0 Hz,
1H, H-5). 13C NMR (62.9 MHz, CDCl3) d 33.6, 106.0 (C-
3), 110.3 (C-4), 115.5, 129.9, 130.3, 141.4 (C-5), 154.1
4.2.3. 1-(Benzyloxy)-4-(bromomethyl)benzene (3). Ben-
zylic bromide 3 (4.50 g) was prepared by reaction of alcohol
2 (3.37 g, 15.7 mmol) with phosphorus tribromide (1.9 mL,
20.2 mmol) in dry methylene chloride (70 mL) as described
by Cushman et al.15b NMR data were in agreement with
reported values. Recrystallization from n-hexane gave 3
(3.97 g, 91%) as white needles: mp 84 ꢀC (lit.15d mp 85–
86 ꢀC). However, due to its allergenic properties (by contact
and inhalation), compound 3 could be rapidly used in the
next step without purification.
ꢂ
(C-2), 155.0. MS (EI) m/z (%): 174 (100) [M+ ]. HRMS
(EI): calcd mass for C11H10O2: 174.0681. Found: 174.0676.
4.2.6. Fur-2-ylated resin (6): derivatization of Merrifield
resin with 5. In a 50 mL polypropylene Erlenmeyer flask
was swollen a suspension of Merrifield resin (0.687 g,
0.55 mmol) in DMF (4 mL) for 10 min. Cesium carbonate
(0.537 g, 1.65 mmol) and sodium iodide (83 mg,
0.55 mmol) were added, followed by a solution of phenolic
compound 5 (0.287 g, 1.65 mmol) in DMF (0.7 mL). The
mixture was stirred at room temperature for 24 h under argon
using an orbital shaker. The resin was then filtered off and
washed successively with DMF, H2O, DMF, acetone, and
CH2Cl2. After evaporation of solvents under reduced pres-
sure and standing in vacuo in the presence of P2O5, a pale
yellow furan-substituted resin 6 (0.707 g, 0.55 mmol) was
obtained. The combined filtrates from DMF and water wash-
ings were acidified with 1 M HCl aqueous solution and
extracted four times with Et2O. The combined ethereal frac-
tions were washed twice with water and dried over sodium
sulfate. After evaporation of the solvent under reduced pres-
sure, unreacted starting phenol 5 (186 mg) was recovered.
1H MAS NMR (400 MHz, CDCl3) d 1.50–2.04 (m, CH2-
Pm), 2.04–2.67 (m, CH-Pm), 4.24 (br s), 5.12–5.32 (m),
6.31 (br s, H-Fur), 6.60 (br s, H-Fur), 6.64–7.17 (m, HAr-
Pm), 7.17–7.76 (m, HAr-Pm), 7.62 (br s, H-Fur). 13C MAS
NMR (100 MHz, CDCl3) d 33.8 (s), 38.7–47.0 (m, CH-
Pm), 40.5 (br s, CH2-Pm), 70.1 (s), 106.1 (s, C-Fur), 110.3
(s, C-Fur), 114.9 (s), 125.8 (br s, CHAr-Pm), 126.3–132.5
(m, CHAr-Pm), 129.8 (s), 141.5 (s, C-Fur), 144.1–147.5
(m, CAr-Pm), 155.1 (s, C-Fur), 157.8 (br s). IR (KBr):
1943, 1871, 1799, 1724, 1600, 1584, 1509, 1492, 1450,
4.2.4. 2-[4-(Benzyloxy)phenylmethyl]furan (4). To
a stirred solution of freshly distilled furan (0.75 mL,
10.3 mmol) in anhydrous Et2O (5 mL) under argon at 0 ꢀC
was added dropwise a 1.6 M solution of n-butyllithium in
hexane (6.25 mL, 10.0 mmol). After stirring at room tem-
perature for 1 h a pale yellow precipitate of fur-2-yllithium
was formed and dry THF (2 mL) was added. The resulting
solution was transferred by a cannula to a suspension of cu-
prous bromide–dimethyl sulfide complex (1.03 g, 5.0 mmol)
in THF (7 mL) under argon at ꢁ40 ꢀC. The dark red solution
was then stirred for 30 min at ꢁ40 ꢀC. A solution of bromide
3 (0.817 g, 2.94 mmol) in Et2O (4 mL) was then added
dropwise. The reaction mixture was allowed to warm slowly
to room temperature overnight and then hydrolyzed during
3 h with a saturated aqueous solution of ammonium chlo-
ride. After three extractions with Et2O, the combined or-
ganic fractions were dried over sodium sulfate and the
solvents were evaporated under reduced pressure. The resi-
due was purified by silica gel column chromatography (pen-
tane/Et2O: 99.5/0.5) to give compound 4 (0.729 g, 94%) as
1
a pale yellow molten solid. H NMR (200 MHz, CDCl3)
d 3.93 (s, 2H), 5.06 (s, 2H, PhCH2), 6.00 (d, J¼2.8 Hz,
1H, H-3), 6.30 (dd, J¼2.0 Hz, J¼2.8 Hz, 1H, H-4), 6.94
(d, J¼8.6 Hz, 2H), 7.17 (d, J¼8.6 Hz, 2H), 7.32–7.50 (m,
6H, Ph and H-5). 13C NMR (62.9 MHz, CDCl3) d 33.5,
69.9, 105.9 (C-3), 110.1 (C-4), 114.8, 127.4, 127.8, 128.5,
129.6, 130.4, 137.1, 141.3 (C-5), 154.9 (C-2), 157.4. IR
(neat): 1615, 1580, 1513, 1453, 1255, 1246, 1049,
1238, 1173, 1009 cmꢁ1
.
4.2.7. 3-[4-(Benzyloxy)phenylmethyl]furan (7). To a solu-
tion of n-butyllithium (7.7 mL, 12.3 mmol) in anhydrous
Et2O (6 mL) at ꢁ78 ꢀC under argon was added dropwise
a solution of 3-bromofuran (1.14 mL, 12.7 mmol) in Et2O
(2 mL). After stirring for 1 h at ꢁ78 ꢀC, this solution was
transferred by a cannula to a suspension of cuprous bro-
mide–dimethyl sulfide complex (1.26 g, 6.1 mmol) in anhy-
drous THF (11 mL) under argon at ꢁ78 ꢀC and the reaction
mixture was stirred for 2 h at ꢁ65 ꢀC. Bromide 3 (1.0 g,
3.6 mmol) dissolved in anhydrous Et2O (8 mL) was then
added dropwise to the resulting dark red solution. The reac-
tion mixture was allowed to warm slowly to room tempera-
ture overnight and then poured into a saturated aqueous
solution of ammonium chloride. After stirring for 3 h, the
aqueous layer was extracted twice with Et2O. The organic
layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Purification by silica gel column
chromatography (pentane/Et2O: 95/5) afforded compound
ꢂ
1010 cmꢁ1. MS (EI) m/z (%): 264 (23) [M+ ], 91 (100).
Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C,
81.79; H, 6.13.
4.2.5. 4-(Fur-2-ylmethyl)phenol (5). Small shavings of so-
dium (6.0 g, 261 mmol) were added over 1.5 h to a solution
of furanic compound 4 (1.5 g, 5.7 mmol) in dried distilled
butan-1-ol (63 mL) maintained at 80 ꢀC. The solution was
stirred at 80 ꢀC for an additional 15 h (TLC showed com-
plete disappearance of compound 4, if necessary more buta-
nol and sodium could be added). After cooling to room
temperature, the dark red-brown reaction mixture was acid-
ified with 1 M HCl aqueous solution and Et2O was added.
The ethereal layer was separated and the aqueous phase
was extracted three times with Et2O. The combined organic
fractions were washed with water, dried over sodium sulfate,
and the solvent was removed under reduced pressure. The
residue was purified by silica gel column chromatography
1
7 (0.730 g, 76%) as a pale yellow molten solid. H NMR
(200 MHz, CDCl3) d 3.72 (s, 2H), 5.05 (s, 2H, PhCH2),
6.24 (br s, 1H, H-4), 6.93 (d, J¼8.5 Hz, 2H), 7.14 (d,
J¼8.5 Hz, 2H), 7.21 (br s, 1H, H-Fur), 7.29–7.49 (m, 6H,

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2895
Ph and H-Fur). 13C NMR (62.9 MHz, CDCl3) d 30.3, 70.0,
111.2 (C-4), 114.8, 124.7 (C-3), 127.5, 127.9, 128.6,
129.5, 132.7, 137.2, 139.5 (C-Fur), 143.0 (C-Fur), 157.3.
IR (neat): 1614, 1580, 1511, 1461, 1451, 1253, 1244,
4.3.2. 4,4-Diethoxybut-2-ynal (11). Using a modified pro-
cedure of Gorgues et al.,20b ynal 11 was prepared by mono-
hydrolysis of diacetal 10 (3.1 g, 13.5 mmol) with 99%
formic acid (12 mL, 318 mmol) in chloroform (24 mL) in
the presence of water (40 mg; without addition of water,
lower yields were obtained). Distillation of the crude prod-
uct under reduced pressure gave compound 11 (1.4 g,
66%) as a clear oil: bp 32 ꢀC/0.07 mmHg (lit.20 bp 73–
74 ꢀC/4 mmHg). NMR data were in agreement with reported
values.20a
ꢂ
1177, 1017 cmꢁ1. MS (EI) m/z (%): 264 (12) [M+ ], 91
(100). Anal. Calcd for C18H16O2: C, 81.79; H, 6.10; O,
12.11. Found: C, 81.65; H, 6.16; O, 11.87.
4.2.8. 4-(Fur-3-ylmethyl)phenol (8). Compound 8 was syn-
thesized following the procedure described in Section 4.2.5.
After reaction of compound 7 (0.846 g, 3.2 mmol) with
sodium (2.3 g, 100 mmol) in butan-1-ol (30 mL) at 80 ꢀC for
3 h, phenol 8 (0.440 g, 79%) was isolated by silica gel
column chromatography (petroleum ether/Et2O: 90/10). 1H
NMR (250 MHz, CDCl3) d 3.73 (s, 2H), 5.62 (br s, 1H,
OH), 6.26 (br s, 1H, H-4), 6.78 (d, J¼8.5 Hz, 2H), 7.09 (d,
J¼8.5 Hz, 2H), 7.21 (br s, 1H, H-Fur), 7.37 (br s, 1H,
H-Fur). 13C NMR (62.9 MHz, CDCl3) d 30.3, 111.3 (C-4),
115.4, 124.7 (C-3), 129.7, 132.7, 139.5 (C-Fur), 143.0 (C-
4.4. Diels–Alder reactions with 4,4-diethoxybut-2-ynal
in homogeneous phase
4.4.1. 1-[4-(Benzyloxy)phenylmethyl]-3-(diethoxy-
methyl)-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carbalde-
hyde (12). A solution of the 2-substituted furan 4 (1.0 g,
3.78 mmol) in toluene (5 mL) was added to a mixture
of 4,4-diethoxybut-2-ynal 11 (0.650 g, 4.16 mmol), BHT
(83 mg, 0.38 mmol), and sodium carbonate (40 mg,
0.38 mmol) placed in a high-pressure glass tube. The tube
was degassed under low pressure and sealed. The reaction
mixture was heated in the dark for 48 h at 90 ꢀC. After cool-
ing to room temperature and concentration in vacuo, the
crude product was purified by silica gel column chromato-
graphy (pentane/Et2O: 90/10, then 60/40) to afford adduct
ꢂ
Fur), 153.7. MS (EI) m/z (%): 174 (100) [M+ ]. HRMS
(EI): calcd mass for C11H10O2: 174.0681. Found: 174.0684.
4.2.9. Fur-3-ylated resin (9): derivatization of Merrifield
resin with 8. Resin 9 was prepared following the procedure
described in Section 4.2.6. From Merrifield resin (0.310 g,
0.25 mmol) swollen in DMF (2 mL), cesium carbonate
(0.242 g, 0.74 mmol), sodium iodide (37 mg, 0.25 mmol),
1
12 (1.37 g, 86%) as a caramel oil. H NMR (200 MHz,
and
a
solution of phenolic compound
8
(0.129 g,
CDCl3) d 1.23 (t, J¼7.1 Hz, 6H), 3.41–3.71 (m, 4H), 3.58
(d, J¼15.2 Hz, 1H) and 3.78 (d, J¼15.2 Hz, 1H) (AB syst.,
CH2-C-1), 5.03 (s, 2H, PhCH2), 5.42 (d, J¼0.9 Hz, 1H, H-
4), 5.50 (s, 1H, CH(OEt)2), 6.90 (d, J¼8.6 Hz, 2H), 6.97
(s, 1H, H-5), 7.24 (d, J¼8.6 Hz, 2H), 7.34–7.46 (m, 6H, Ph
and H-6), 10.17 (s, 1H, CHO). 13C NMR (62.9 MHz,
CDCl3) d 14.8, 34.4 (CH2-C-1), 61.2, 61.7, 69.5 (PhCH2),
82.3 (C-4), 95.6 (C-1), 97.4 (CH(OEt)2), 114.1, 127.1,
127.5, 128.2, 129.2, 130.9, 136.9, 142.8 and 144.9 (C-5,
C-6), 151.1 (C-2), 157.1, 171.3 (C-3), 187.5 (CHO). IR
(neat): 1664, 1612, 1512, 1454, 1379, 1243, 1177, 1120,
1051 cmꢁ1. MS (ES+) m/z (%): 491 (8) [M+MeOH+K]+,
459 (17) [M+K]+, 443 (100) [M+Na]+, 287 (17). HRMS
(EI): calcd mass for C26H28O5: 420.1936. Found: 420.1943.
0.74 mmol) in DMF (0.7 mL), a beige furan-substituted
resin 9 (0.319 g, 0.25 mmol) was obtained after shaking un-
der argon for 24 h at room temperature, washings, and evap-
1
oration of solvents under reduced pressure. H MAS NMR
(400 MHz, CDCl3) d 1.50–2.02 (m, CH2-Pm), 2.02–2.61
(m, CH-Pm), 4.05 (br s), 5.14–5.35 (m), 6.57 (br s, H-Fur),
6.61–7.11 (m, HAr-Pm), 7.11–7.62 (m, HAr-Pm), 7.67
(br s, H-Fur). 13C MAS NMR (100 MHz, CDCl3) d 30.4
(s), 38.9–46.5 (m, CH-Pm), 40.5 (br s, CH2-Pm), 70.1 (s),
111.3 (s, C-Fur), 114.9 (s), 125.8 (br s, CHAr-Pm), 126.4–
130.0 (m, CHAr-Pm), 129.6 (s), 139.4 (s, C-Fur), 143.1 (s,
C-Fur), 144.3–145.9 (m, CAr-Pm), 157.2 (br s). IR (KBr):
1944, 1873, 1802, 1720, 1600, 1584, 1507, 1490, 1449,
1218, 1172, 1019 cmꢁ1
.
4.4.2. 5- and 6-[4-(benzyloxy)phenylmethyl]-3-(diethoxy-
methyl)-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carbalde-
hyde (13). Compound 13 was prepared following the
procedure described above. From a solution of the 3-
substituted furan 7 (303 mg, 1.15 mmol) and 4,4-diethoxy-
but-2-ynal 11 (196 mg, 1.26 mmol) in toluene (3.5 mL) in
the presence of BHT (25 mg, 0.11 mmol) and few milli-
grams of sodium carbonate, crude compound 13 was ob-
tained after heating the vacuum-sealed tube in the dark for
48 h at 124 ꢀC. After concentration in vacuo, 1H NMR spec-
trum of the residue shows adduct 13 as a mixture of
regioisomers (52:48 ratio). Purification by silica gel column
chromatography (pentane/Et2O: 60/40) gave a mixture of
the unseparated isomers 13a/13b (421 mg, 87%, 13a/
13b¼55:45) as a pale brown oil. 1H NMR (200 MHz,
CDCl3) d 1.14–1.33 (m, 6H), 3.41–3.70 (m, 6H, OCH2CH3
and CH2-C-5/CH2-C-6), 4.96 (s, 0.55H, CH(OEt)2 major),
5.05 (s, 2H, PhCH2), 5.21 (d, J¼1.3 Hz, 0.55H, H-4 or
H-1 major), 5.44 (br s, 0.45H, H-4 or H-1 minor), 5.49 (s,
0.45H, CH(OEt)2 minor), 5.51 (br s, 0.45H, H-1 or H-4
minor), 5.70 (br s, 0.55H, H-1 or H-4 major), 6.36 (d,
4.3. Preparation of dienophile 11
4.3.1. 1,1,4,4-Tetraethoxybut-2-yne (10). To a 0.94 M solu-
tion of ethylmagnesium bromide (9.1 mL, 8.6 mmol) in
Et2O maintained under argon at ꢁ10 ꢀC was added dropwise
a solution of 3,3-diethoxypropyne (1.1 mL, 7.8 mmol) in
anhydrous THF (11 mL). The mixture was stirred for 2 h at
ꢁ10 ꢀC and a solution of diethyl phenyl orthoformate
(2.3 mL, 11.7 mmol) in THF (11 mL) was added. The reac-
tion mixture was stirred for 2 h at ꢁ10 ꢀC and then overnight
at room temperature. After hydrolysis with a saturated aque-
ous solution of ammonium chloride, the aqueous layer was
extracted three times with Et2O and the combined organic
phases were washed twice with a 2 M sodium hydroxide
aqueous solution, three times with water, dried over sodium
sulfate, and concentrated. Purification by silica gel column
chromatography (pentane/Et2O: 95/5) afforded compound
10 (1.53 g, 85%) as a clear oil: bp 58 ꢀC/0.07 mmHg
(lit.20 bp 91–93 ꢀC/0.6 mmHg). Spectroscopic data were in
agreement with reported values.20a

2896
S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
J¼1.8 Hz, 0.45H, H-6 or H-5 minor), 6.55 (d, J¼1.7 Hz,
0.55H, H-6 or H-5 major), 6.90 (d, J¼8.6 Hz, HAr minor)
and 6.92 (d, J¼8.6 Hz, HAr major) (2H), 7.06 (d,
J¼8.6 Hz, 2H, HAr), 7.30–7.48 (m, 5H, Ph), 10.09 (s,
0.45H, CHO minor), 10.14 (s, 0.55H, CHO major). 13C
NMR (62.9 MHz, CDCl3) d 15.1, 15.2, 34.4 (CH2-C-5/
CH2-C-6), 61.1 (OCH2CH3 major), 61.4 (OCH2CH3 minor),
61.6 (OCH2CH3 minor), 62.3 (OCH2CH3 major), 69.9
(PhCH2), 82.2 (C-1 or C-4 major), 84.0 (C-1 or C-4 minor),
84.8 (C-4 or C-1 minor), 86.5 (C-4 or C-1 major), 97.7
(CH(OEt)2 major), 97.9 (CH(OEt)2 minor), 114.9 (minor),
115.0 (major), 127.3, 127.8, 128.4, 129.4, 129.6, 129.8,
133.1 (C-5 or C-6 minor), 135.2 (C-5 or C-6 major), 136.9
(major), 137.0 (minor), 151.5 (C-2 minor), 152.2 (C-2 ma-
jor), 157.4 (minor), 157.6 (major), 157.7 (C-6 or C-5 major),
159.6 (C-6 or C-5 minor), 169.0 (C-3 major), 169.6 (C-3
minor), 186.7 (CHO minor), 186.8 (CHO major). IR (neat):
1658, 1612, 1511, 1454, 1242, 1176, 1055 cmꢁ1. MS
(ES+) m/z (%): 491 (11) [M+MeOH+K]+, 459 (15)
[M+K]+, 443 (100) [M+Na]+, 287 (15). HRMS (ES+): calcd
mass for C26H28O5Na: 443.1834. Found: 443.1835.
in dry toluene (3 mL) was heated at reflux, under argon,
for 3 h. After cooling to room temperature and concentration
in vacuo, the crude product was purified by silica gel column
chromatography (petroleum ether/Et2O: 2/1) to afford
adduct 15 (1.065 g, 99%) as a caramel oil. 1H NMR
(250 MHz, CDCl3) d 3.47 (s, 2H, CH2-C-1), 3.76 and 3.77
(2 s, 6H, 2 CO2Me), 5.04 (s, 2H, PhCH2), 5.68 (d,
J¼1.8 Hz, 1H, H-4), 6.91 (d, J¼8.6 Hz, 2H), 7.06 (d,
J¼5.2 Hz, 1H, H-6), 7.14–7.21 (m, 3H, H-5 and 2 HAr),
7.31–7.46 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3)
d 33.9 (CH2-C-1), 51.9 (2 CO2CH3), 69.6 (PhCH2), 83.1
(C-4), 97.5 (C-1), 114.3, 127.2, 127.6, 128.1, 128.3, 130.8,
136.8, 144.2 (C-5 or C-6), 144.8 (C-6 or C-5), 151.0 (C-2
or C-3), 155.5 (C-3 or C-2), 157.4, 162.3 (CO2), 165.0
(CO2). IR (neat): 3034, 2955, 1748, 1723, 1648, 1610,
1513, 1436, 1300, 1261, 1245, 1113, 1013 cmꢁ1. MS
(ES+) m/z (%): 429 (100) [M+Na]+. Anal. Calcd for
C24H22O6: C, 70.93; H, 5.46. Found: C, 70.92; H, 5.64.
4.6.2. Methyl 1-[4-(benzyloxy)phenylmethyl]-3-bromo-7-
oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (17) and
methyl 1-[4-(benzyloxy)phenylmethyl]-2-bromo-7-oxa-
bicyclo[2.2.1]hepta-2,5-diene-3-carboxylate. To a solution
of methyl propiolate (0.942 g, 11.22 mmol) in dry aceto-
nitrile (7.5 mL) were added silver nitrate (0.190 g,
1.1 mmol) and N-bromosuccinimide (2.30 g, 12.92 mmol).
After stirring under argon for 1 h at room temperature, the
flask was fitted with a glass distillation bridge connected
to a receiving flask and the liquids were evaporated under
low pressure (ca. 0.1 mbar) and collected at ꢁ78 ꢀC. The so-
lution of methyl 3-bromopropiolate 16 in acetonitrile was
warmed up to room temperature and introduced in a high-
pressure glass tube containing the 2-substituted furan 4
(0.987 g, 3.74 mmol). The tube was degassed under low
pressure, sealed, and the green reaction mixture was heated
in the dark for 48 h at 110 ꢀC. After cooling to room temper-
ature and concentration in vacuo, the crude product was
purified by silica gel column chromatography (petroleum
ether/CH2Cl2: 3/1) to afford a 97:3 mixture of adduct 17
and methyl 1-[4-(benzyloxy)phenylmethyl]-2-bromo-7-
oxabicyclo[2.2.1]hepta-2,5-diene-3-carboxylate (0.959 g,
60%) as a brown oil. A preparative silica gel TLC (three elu-
tions with pentane/Et2O: 9/1) has allowed the isolation of
pure samples of each regioisomer.
4.5. Lewis acid-catalyzed reaction with 4,4-diethoxybut-
2-ynal
4.5.1. 3-{5-[4-(Benzyloxy)phenylmethyl]fur-2-yl}-4,4-
diethoxybut-2-enal (14). To a suspension of anhydrous
zinc chloride (93 mg, 0.682 mmol) in dichloromethane
(0.5 mL) was added a solution of 4,4-diethoxybut-2-ynal
11 (106 mg, 0.684 mmol) in CH2Cl2 (0.6 mL). After stirring
for 15 min at room temperature until complete solubilization
of the Lewis acid, the resulting orange solution was cooled to
ꢁ40 ꢀC and furanic compound 4 (164 mg, 0.621 mmol) in
dichloromethane (0.8 mL) was introduced. The dark brown
solution was stirred for 2 h at ꢁ40 ꢀC and hydrolyzed with
water. The aqueous layer was extracted three times with
CH2Cl2 and the combined organic extracts were dried over
1
magnesium sulfate and concentrated in vacuo. H NMR
spectrum of the crude product shows Michael adduct 14 as
a mixture of diastereomers (82:18 ratio). Purification by
silica gel column chromatography (pentane/Et2O: 70/30) af-
forded pure major diastereomer (23 mg) as a yellow oil and
a mixture of the two diastereomers (154 mg, 68% overall
1
yield). Major diastereomer: H NMR (250 MHz, CDCl3)
d 1.23 (t, J¼7.2 Hz, 6H), 3.47–3.71 (m, 4H), 3.96 (s, 2H,
CH2-Fur), 5.07 (s, 2H, PhCH2), 5.23 (s, 1H, CH(OEt)2),
6.12 (d, J¼3.4 Hz, 1H, H-Fur), 6.20 (d, J¼8.0 Hz, 1H, H-
2), 6.87 (d, J¼3.4 Hz, 1H, H-Fur), 6.95 (d, J¼8.6 Hz, 2H),
7.17 (d, J¼8.6 Hz, 2H), 7.32–7.48 (m, 5H), 10.44 (d,
J¼8.0 Hz, 1H, CHO). 13C NMR (62.9 MHz, CDCl3)
d 15.2, 34.1 (CH2-Fur), 62.1, 70.1 (PhCH2), 100.8, 108.9,
115.1, 116.9, 124.4, 127.5, 128.0, 128.7, 129.2, 129.9,
137.0, 141.8, 149.4, 157.8, 159.2, 194.6 (CHO). MS (ES+)
m/z (%): 443 (100) [M+Na]+. HRMS (ES+): calcd mass for
C26H28O5Na: 443.1834. Found: 443.1834. Anal. Calcd for
C26H28O5: C, 74.26; H, 6.71. Found: C, 73.84; H, 6.81.
Methyl 1-[4-(benzyloxy)phenylmethyl]-3-bromo-7-oxabi-
cyclo[2.2.1]hepta-2,5-diene-2-carboxylate (17). 1H NMR
(250 MHz, CDCl3) d 3.57 (d, J¼15.2 Hz, 1H) and 3.68 (d,
J¼15.2 Hz, 1H) (AB syst., CH2-C-1), 3.80 (s, 3H,
CO2Me), 5.03 (s, 2H, PhCH2), 5.25 (d, J¼1.9 Hz, 1H,
H-4), 6.90 (d, J¼8.7 Hz, 2H), 7.05 (d, J¼5.3 Hz, 1H, H-6),
7.11 (dd, J¼5.2 Hz, J¼1.8 Hz, 1H, H-5), 7.20 (d,
J¼8.6 Hz, 2H), 7.30–7.47 (m, 5H, Ph). 13C NMR
(62.9 MHz, CDCl3) d 34.7 (CH2-C-1), 51.7 (CO2CH3),
69.9 (PhCH2), 87.9 (C-4), 97.4 (C-1), 114.5, 127.5, 127.9,
128.5, 128.7, 131.1, 137.1, 142.2 (C-5 or C-6), 143.7 (C-2
or C-3), 145.7 (C-6 or C-5), 149.2 (C-3 or C-2), 157.6,
163.8 (CO2). IR (neat): 2951, 1710, 1611, 1512, 1454,
4.6. Diels–Alder reactions with acetylenic esters
1435, 1310, 1242 cmꢁ1
.
4.6.1. Dimethyl 1-[4-(benzyloxy)phenylmethyl]-7-oxa-
bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (15). A
solution of the 2-substituted furan 4 (0.700 g, 2.65 mmol)
and dimethyl acetylenedicarboxylate (1.10 g, 7.75 mmol)
Methyl
1-[4-(benzyloxy)phenylmethyl]-2-bromo-7-oxa-
bicyclo[2.2.1]hepta-2,5-diene-3-carboxylate. 1H NMR
(250 MHz, CDCl3) d 3.33 (d, J¼15.2 Hz, 1H) and 3.46 (d,

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2897
J¼15.2 Hz, 1H) (AB syst., CH2-C-1), 3.79 (s, 3H, CO2Me),
5.03 (s, 2H, PhCH2), 5.66 (d, J¼1.7 Hz, 1H, H-4), 6.87–6.94
(m, 3H, H-6 and 2 HAr), 7.13 (dd, J¼5.2 Hz, J¼1.3 Hz, 1H,
H-5), 7.25 (d, J¼9.0 Hz, 2H), 7.30–7.47 (m, 5H, Ph).
155 mg, 0.369 mmol) dissolved in anhydrous THF (1.2 mL)
was added at ꢁ78 ꢀC to a suspension of sodium benzene-
thiolate in THF (1.0 mL) prepared from benzenethiol
(114 mL, 1.11 mmol) and a 60% dispersion of sodium hy-
dride (4.4 mg, 0.11 mmol) in mineral oil. After slow warm-
ing of the reaction mixture to 0 ꢀC over 4 h, treatment at this
temperature with a 2.5 M sodium hydroxide aqueous solu-
tion followed by extractions with Et2O and washings as
previously described, a crude mixture of Michael addition
products 20 was isolated. 1H NMR spectrum of the residue
shows traces of furan 7 and enal (Z)-19 and especially the
presence of two major diastereomers and, at least, four
minor isomers. This mixture was dissolved in anhydrous
THF (3 mL) and then stirred under argon at 45 ꢀC for 3 h.
After cooling to room temperature and concentration
in vacuo, 1H NMR spectrum of the crude residue shows fu-
ran 7 and enals 19 with a ratio (Z)-19/(E)-19¼87:13. Purifi-
cation by silica gel column chromatography (pentane/Et2O:
80/20) afforded furan 7 (78 mg, 80%), enals (Z)-19 (60 mg,
61%) and (E)-19 (16 mg, 16%).
4.7. Suzuki coupling reaction
4.7.1. Methyl 1-[4-(benzyloxy)phenylmethyl]-3-phenyl-
7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (18).
To a solution of the brominated adduct 17 (0.200 g,
0.47 mmol), phenylboronic acid (63 mg, 0.52 mmol), and
potassium fluoride (90 mg, 1.55 mmol) in dry THF (1 mL)
under argon were successively added a 0.1 M solution of
tris(tert-butyl)phosphine in THF (0.560 mL, 0.06 mmol)
and
a
solution of bis(benzylideneacetone)palladium
(13.6 mg, 0.02 mmol) in THF (0.5 mL). After stirring for
3.5 h at room temperature, the reaction mixture was diluted
with Et2O, filtrated over CeliteÒ, and the adsorbent was
washed with Et2O. After concentration of the filtrate
in vacuo, the crude product was purified by silica gel column
chromatography (pentane/Et2O: 4/1) to afford the phenyl-
1
ated product 18 (0.180 g, 90%) as a yellow oil. H NMR
(Z)-4,4-Diethoxy-3-(phenylsulfanyl)but-2-enal (Z)-19. Pale
yellow oil. 1H NMR (200 MHz, CDCl3) d 1.16 (t,
J¼7.1 Hz, 6H), 3.25–3.36 (m, 2H), 3.44–3.56 (m, 2H),
4.71 (s, 1H, H-4), 6.64 (d, J¼6.9 Hz, 1H, H-2), 7.36–7.41
(m, 3H, HAr), 7.51–7.56 (m, 2H, HAr), 10.19 (d, J¼6.9 Hz,
1H, CHO). 13C NMR (50.3 MHz, CDCl3) d 14.9, 62.2,
99.1 (C-4), 127.5 (C-2), 129.0, 129.2, 130.2, 133.8, 156.5
(C-3), 190.6 (CHO). MS (ES+) m/z (%): 321 (17)
[M+MeOH+Na]+, 289 (100) [M+Na]+. HRMS (ES+): calcd
mass for C14H18O3SNa: 289.0874. Found: 289.0874.
(250 MHz, CDCl3) d 3.58 (d, J¼15.0 Hz, 1H) and 3.68 (d,
J¼15.0 Hz, 1H) (AB syst., CH2-C-1), 3.73 (s, 3H,
CO2Me), 5.05 (s, 2H, PhCH2), 5.55 (d, J¼1.5 Hz, 1H,
H-4), 6.93 (d, J¼8.6 Hz, 2H), 7.12 (d, J¼5.0 Hz, 1H,
H-6), 7.17 (dd, J¼5.0 Hz, J¼1.6 Hz, 1H, H-5), 7.24 (d,
J¼8.7 Hz, 2H), 7.32–7.55 (m, 10H). 13C NMR (62.9 MHz,
CDCl3) d 35.1 (CH2-C-1), 51.5 (CO2CH3), 70.0 (PhCH2),
86.1 (C-4), 97.3 (C-1), 114.6, 127.2, 127.5, 127.9, 128.2,
128.6, 129.5, 131.1, 132.8 (C-2 or C-3), 137.3, 140.4 (C-3
or C-2), 142.3 (C-5), 146.1 (C-6), 157.6, 164.6 (CAr or
CO2), 165.9 (CO2 or CAr). IR (neat): 3033, 2949, 1713,
1612, 1581, 1512, 1494, 1455, 1434, 1331, 1269, 1240,
(E)-4,4-Diethoxy-3-(phenylsulfanyl)but-2-enal (E)-19. Pale
yellow oil. 1H NMR (250 MHz, CDCl3) d 1.31 (t,
J¼7.1 Hz, 6H), 3.61–3.89 (m, 4H), 5.38 (d, J¼7.7 Hz, 1H,
H-2), 5.70 (s, 1H, H-4), 7.32–7.58 (m, 5H, HAr), 9.99 (d,
J¼7.7 Hz, 1H, CHO). 13C NMR (50.3 MHz, CDCl3)
d 15.0, 62.7, 99.0 (C-4), 123.5 (C-2), 128.5, 130.1, 130.2,
135.6, 166.2 (C-3), 188.0 (CHO). MS (CI/NH3) m/z (%):
267 (23) [M+H]+, 221 (100) [M+HꢁEtOH]+. Anal. Calcd
for C14H18O3S: C, 63.13; H, 6.81; O, 18.02. Found: C,
63.07; H, 6.97; O, 17.98.
1177, 1001 cmꢁ1
.
4.8. Functionalization by Michael addition and retro-
Diels–Alder reaction in solution
4.8.1. (Z)- and (E)-4,4-diethoxy-3-(phenylsulfanyl)but-2-
enal (19). From Diels–Alder adduct 12. To a mixture of
a 60% dispersion of sodium hydride (3.3 mg, 0.082 mmol)
in mineral oil and THF (1 mL) under argon was added drop-
wise benzenethiol (85 mL, 0.828 mmol) at room tempera-
ture. A gas release was observed and the suspension was
then stirred for 15 min at room temperature. After cooling
at ꢁ78 ꢀC, a solution of adduct 12 (116 mg, 0.276 mmol)
in THF (1.5 mL) was added. The reaction mixture was
stirred for 2 h at ꢁ78 ꢀC and the temperature was allowed
to increase to 0 ꢀC over 3 h. A 2.5 M sodium hydroxide
aqueous solution was then added at 0 ꢀC and the aqueous
layer was extracted twice with Et2O. The combined organic
extracts were washed twice with a 2.5 M sodium hydroxide
aqueous solution, with water to neutrality, dried over sodium
sulfate, and concentrated under reduced pressure (water bath
at room temperature). 1H NMR spectrum of the crude resi-
due shows the Z and E enals 19 with a ratio (Z)-19/(E)-
19¼75:25. Chromatography on silica gel (pentane/Et2O:
90/10, then 60/40) gave the furanic compound 4 (62 mg,
85%), enals (Z)-19 (50 mg, 68%) and (E)-19 (15 mg, 20%).
4.8.2. Dimethyl phenylsulfanylfumarate 22 and meso-di-
methyl 2,3-bis(phenylsulfanyl)succinate 23. Following the
procedure described in Section 4.8.1 from Diels–Alder ad-
duct 12, a solution of cycloadduct 15 (108 mg, 0.27 mmol)
in anhydrous THF (1.5 mL) was added at ꢁ78 ꢀC to a sus-
pension of sodium benzenethiolate in THF (1.5 mL) pre-
pared from benzenethiol (93 mL, 0.93 mmol) and a 60%
dispersion of sodium hydride (3.2 mg, 0.08 mmol) in min-
eral oil. The reaction mixture was stirred for 2 h at ꢁ78 ꢀC
and the temperature was allowed to increase to 0 ꢀC over
3 h. After treatment with a 2.5 M sodium hydroxide aqueous
solution at 0 ꢀC, a crude mixture of Michael addition prod-
ucts 21 was isolated. 1H NMR spectrum of the residue shows
the presence of three diastereomers but also products result-
ing from a retro-Diels–Alder reaction (see Section 2.3). This
mixture was dissolved in anhydrous toluene (2 mL) and then
stirred under argon at 75 ꢀC for 16 h. After cooling to room
temperature and concentration in vacuo, purification by sil-
ica gel column chromatography (petroleum ether/Et2O: 4/1)
afforded furan 4 (62 mg, 87%) and a 2:1 mixture of dimethyl
From Diels–Alder adduct 13. Following the same procedure
as described above, cycloadduct 13 (13a/13b¼55:45,

2898
S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
phenylsulfanylfumarate 2237,44 and meso-dimethyl 2,3-
bis(phenylsulfanyl)succinate 2336 (97 mg, 83%).
anhydrous toluene (0.7 mL), silica gel column chromato-
graphy (petroleum ether/Et2O: 4/1) gave furan 4 (30 mg,
47%) and a 93:7 mixture of (Z)- and (E)-methyl 3-phenyl-
3-phenylsulfanylpropenoate 2545 (30 mg, 46%).
4.8.3. (Z)- and (E)-methyl 3-phenyl-3-phenylsulfanylpro-
penoate 25. Following the procedure described in Section
4.8.1 from Diels–Alder adduct 12, a solution of cycloadduct
18 (101 mg, 0.24 mmol) in anhydrous THF (1.5 mL) was
added at ꢁ78 ꢀC to a suspension of sodium benzenethiolate
in THF (1.0 mL) prepared from benzenethiol (85 mL,
0.83 mmol) and a 60% dispersion of sodium hydride
(2.8 mg, 0.07 mmol) in mineral oil. The reaction mixture
was stirred for 2 h at ꢁ78 ꢀC and the temperature was
allowed to increase to 0 ꢀC over 3 h. After treatment with
a 2.5 M sodium hydroxide aqueous solution at 0 ꢀC, a crude
mixture of Michael addition products 24 was isolated. Inte-
4.9. Reactions on solid support
4.9.1. Diels–Alder adduct-functionalized resin (26). In
a high-pressure glass tube were successively placed resin 6
(0.627 g, 0.49 mmol), sodium carbonate (20.6 mg,
0.19 mmol), BHT (42.9 mg, 0.19 mmol), and 4,4-diethoxy-
but-2-ynal 11 (302 mg, 1.93 mmol). The minimal quantity
of toluene (4.8 mL) was then introduced in order to form
a gel. The glass tube was degassed under low pressure and
sealed. After heating at 90 ꢀC for 72 h in the dark, the resin
was filtered off and washed successively with CH2Cl2, ace-
tone, H2O, acetone, and CH2Cl2. After evaporation of sol-
vents under reduced pressure and standing in vacuo in the
presence of P2O5, an orange-brown resin 26 (0.689 g,
0.49 mmol) was obtained. Concentration in vacuo of the first
filtrates obtained from washings with CH2Cl2 followed by
a purification by silica gel column chromatography (pen-
tane/Et2O: 80/20) provided unreacted ynal 11 (183 mg). 1H
MAS NMR (400 MHz, CDCl3) d 1.52 (br s), 1.33–2.00 (m,
CH2-Pm), 2.00–2.50 (m, CH-Pm), 3.68–4.23 (m), 5.06–
5.32 (m), 5.73 (br s), 5.80 (br s), 6.52–7.08 (m, HAr-Pm),
7.08–7.69 (m, HAr-Pm), 10.48 (br s, CHO). 13C MAS
NMR (100 MHz, CDCl3) d 15.2 (s), 34.8 (s), 38.1–46.7
(m, CH-Pm), 40.5 (br s, CH2-Pm), 61.6 (s), 62.1 (s), 70.0
(s), 82.7 (s), 96.1 (s), 97.8 (s), 114.5 (s), 125.8 (br s,
CHAr-Pm), 126.2–132.1 (m, CHAr-Pm), 131.3 (s), 143.2
(s), 144.3–146.7 (m, CAr-Pm), 151.5 (s), 157.7 (br s), 171.8
(s), 188.1 (s). IR (KBr): 1943, 1872, 1802, 1721, 1663,
1600, 1578, 1510, 1492, 1451, 1228, 1175, 1051,
1
gration of the olefinic proton signals in the H NMR spec-
trum of the residue shows the presence of a 7:3 mixture of
two diastereomers. Fast silica gel column chromatography
(pentane/Et2O: 1/3) has allowed to separate these diastereo-
mers but retro-Diels–Alder reaction occurred during the elu-
tion and impure compounds were isolated. The minor isomer
was in the first eluted fraction (42 mg) and the major one was
present in the second fraction (72 mg). The main spectro-
scopic characteristics of these adducts are reported below.
The relative integrations of the 1H NMR spectra were noted
for clearly separated signals.
Methyl 1-[4-(benzyloxy)phenylmethyl]-3-phenyl-3-phenyl-
sulfanyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (24):
minor isomer. 1H NMR (250 MHz, CDCl3) d 3.08 (d,
J¼14.6 Hz, 1H) and 3.25 (d, J¼14.6 Hz, 1H) (AB syst.,
CH2-C-1), 3.50 (s, 1H, H-2), 3.78 (s, 3H, CO2Me), 5.00 (s,
2H, PhCH2), 5.40 (d, J¼1.8 Hz, 1H, H-4), 6.68 (dd,
J¼5.1 Hz, J¼1.8 Hz, H-5) and 6.71 (d, J¼5.1 Hz, H-6)
(2H), 6.80–7.53 (m, HAr). 13C NMR (62.9 MHz, CDCl3)
d 37.6 (CH2-C-1), 52.0 (CO2CH3), 62.9 (C-2), 66.3 (C-3),
69.9 (PhCH2), 84.0 (C-4), 92.1 (C-1), 114.5 (CAr-H),
126.0–129.6 (various CAr-H), 130.9 (CAr-H), 134.0 (CAr-
H), 134.9 (CAr-H), 135.4 (C-5), 137.1 (CAr), 138.2 (C-6),
1027 cmꢁ1
.
4.9.2. Michael addition of benzenethiol on resin 26 and
retro-Diels–Alder reaction. In a three-necked round-bot-
tomed flask fitted with a bent solid addition bulb, a filtering
cannula, an argon inlet, and a small magnetic stirring bar
were placed a 60% dispersion of sodium hydride (1.3 mg,
0.032 mmol) in mineral oil and anhydrous THF (2 mL).
Benzenethiol (42 mL, 0.409 mmol) was added dropwise
and the suspension was stirred for 15 min at room tempera-
ture. The reaction mixture was cooled at ꢁ40 ꢀC and resin
26 (115 mg, 0.081 mmol) previously placed in the solid
addition bulb was added. After gentle stirring for 22 h at
ꢁ35 ꢀC, the liquid phase was removed through the filtering
cannula under argon and the resin maintained at ꢁ35 ꢀC was
extensively washed with THF, mixtures of THF/MeOH (in-
creasing and then decreasing MeOH ratios), and THF (the
solvents being removed each time through the cannula under
argon). Analysis by TLC and 1H NMR spectrum of the resi-
due obtained by concentration in vacuo of the combined fil-
trates show exclusively the presence of benzenethiol. After
addition of distilled THF (2 mL), the heterogeneous reaction
mixture was allowed to warm slowly to ꢁ2 ꢀC and then
gently stirred for 15 h at this temperature. The liquid phase
was removed through the filtering cannula under argon and
the resin was washed with distilled THF at ꢁ2 ꢀC (the
solvent being removed each time through the cannula). Con-
centration in vacuo (water bath at room temperature) of the
combined filtrates gave enal (Z)-19 (10.7 mg, 49% overall
145.1 (CAr), 157.5 (CAr), 170.6 (CO2). IR (neat): 1731 cmꢁ1
.
Methyl 1-[4-(benzyloxy)phenylmethyl]-3-phenyl-3-phenyl-
sulfanyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (24):
major isomer. H NMR (250 MHz, CDCl3) d 3.33 (s, 1H,
1
H-2), 3.34 (d, J¼14.4 Hz, 1H) and 3.59 (d, J¼14.4 Hz,
1H) (AB syst., CH2-C-1), 3.95 (s, 3H, CO2Me), 5.02 (s,
2H, PhCH2), 5.40 (d, J¼1.3 Hz, 1H, H-4), 6.07 (d,
J¼5.5 Hz, H-6) and 6.11 (dd, J¼5.5 Hz, J¼1.3 Hz, H-5)
(2H), 6.80–7.47 (m, HAr). 13C NMR (62.9 MHz, CDCl3)
d 35.3 (CH2-C-1), 52.0 (CO2CH3), 58.2 (C-2), 67.6 (C-3),
69.8 (PhCH2), 84.3 (C-4), 91.4 (C-1), 114.6 (CAr-H),
126.0–129.6 (various CAr-H), 130.9 (CAr-H), 131.3 (CAr),
136.5 (C-5), 137.0 (CAr), 137.6 (C-6), 137.7 (CAr-H),
143.1 (CAr), 157.5 (CAr), 171.0 (CO2). IR (neat): 1739 cmꢁ1
.
The first fraction was dissolved in anhydrous toluene
(0.4 mL) and was stirred under argon at 75 ꢀC for 16 h. After
cooling to room temperature and concentration in vacuo,
purification by silica gel column chromatography (petro-
leum ether/Et2O: 4/1) afforded furan 4 (18 mg, 28%) and
a 90:10 mixture of (Z)- and (E)-methyl 3-phenyl-3-phenyl-
sulfanylpropenoate 2545 (18 mg, 28%). After heating in
the same conditions a solution of the second fraction in

S. Albert et al. / Tetrahedron 63 (2007) 2888–2900
2899
yield with respect to Merrifield resin) as a single product,
which was identical, in all spectroscopic details, with the
synthesized material in solution-phase. Remaining resin
was filtered off and, after drying under reduced pressure
and standing in vacuo in the presence of P2O5, resin 6
(93 mg) was isolated (identified by IR spectroscopy).
20 h, filtering and washings of the resin with THF, filtrates
were concentrated under reduced pressure and enal 19
(4.0 mg, 16% overall yield with respect to Merrifield resin,
1
(Z)-19/(E)-19¼70:30 determined from H NMR spectrum)
was isolated. No more release of enal 19 was noticed after
stirring the remaining resin in THF (2 mL) at 40 ꢀC for an
additional 3 h and after shaking at 60 ꢀC for 20 h. The recov-
ered resin was filtered off and washed with THF. After drying
under reduced pressure and standing in vacuo in the presence
of P2O5, resin 9 (105 mg) was isolated (identified by IR
spectroscopy).
4.9.3. Diels–Alder adduct-functionalized resin (27).
Orange-brown resin 27 (0.314 g, 0.24 mmol) was prepared
from resin 9 (0.306 g, 0.24 mmol), sodium carbonate
(10.1 mg, 0.09 mmol), BHT (21.0 mg, 0.09 mmol), 4,4-di-
ethoxybut-2-ynal 11 (149 mg, 0.95 mmol), and toluene
(2.2 mL) analogously to the procedure described in Section
4.9.1. Concentration in vacuo of the first filtrates obtained
from washings with CH2Cl2 followed by a purification by
silica gel column chromatography (pentane/Et2O: 90/10)
Acknowledgements
This work was financially supported by the CNRS and
the University of Paris-Sud (XI), by a grant to S.A. and
ꢁ
A.S. from the Ministere de l’Education Nationale, de la
Recherche et de la Technologie.
1
provided unreacted ynal 11 (96 mg). H MAS NMR spec-
trum of the resulting resin shows polymer-supported
Diels–Alder adduct 27 as a mixture of regioisomers (61:39
ratio). H MAS NMR (400 MHz, CDCl3) d 1.57 (br s),
1
References and notes
1.33–2.04 (m, CH2-Pm), 2.04–2.59 (m, CH-Pm), 3.75–
4.11 (m), 5.14–5.38 (m), 5.57 (br s), 5.79 (br s), 5.83 (br
s), 5.87 (br s), 6.06 (br s), 6.52–7.12 (m, HAr-Pm), 7.12–
7.73 (m, HAr-Pm), 10.46 (br s, CHO minor), 10.50 (br s,
CHO major). 13C MAS NMR (100 MHz, CDCl3) d 15.2
(s), 34.5 (s), 38.9–46.5 (m, CH-Pm), 40.5 (br s, CH2-Pm),
61.3 (s), 61.6 (s), 61.8 (s), 62.4 (s), 70.1 (s), 82.4 (s), 84.1
(s), 85.0 (s), 86.6 (s), 97.9 (s), 98.1 (s), 114.9 (s), 115.0
(s), 125.7 (br s, CHAr-Pm), 125.9–130.8 (m, CHAr-Pm),
129.5 (s), 130.0 (s), 133.3 (s), 135.4 (s), 144.9–146.4 (m,
CAr-Pm), 152.4 (s), 157.9 (s), 186.9 (s). IR (KBr): 1943,
1873, 1801, 1721, 1657, 1600, 1585, 1508, 1491, 1451,
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used in Section 4.9.2) were placed a 60% dispersion of
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1
determined from H NMR spectrum). The resulting resin
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16. Caution! The benzylic bromide 3 is a highly allergenic
compound.

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