Synthesis of polysubstituted furans by palladium-catalyzed coupling of butatrienyl carbinols with aryl halides and triflates

Article abstract of DOI:10.1016/j.tet.2004.03.060

An efficient one-pot two-step synthesis of polysubstituted furans is described using readily available 4,5-epoxy-2-alkynyl esters as starting materials. In the first step, reduction of these with SmI₂ affords buta-1,2,3-trienyl carbinol intermediates which, in the second step, participate in Pd(0)-catalyzed cyclization reactions with aryl halides and triflates by a mechanism probably involving oxidative addition, intramolecular oxypalladation and reductive elimination steps. In this manner, up to four carbon substituents are incorporated onto the furan ring, with the aryl group being introduced at the furan 3- or 4-positions. These features make the method particularly suitable for regioselective synthesis of tetrasubstituted furans.

Full text of DOI:10.1016/j.tet.2004.03.060

Tetrahedron 60 (2004) 4139–4149
Synthesis of polysubstituted furans by palladium-catalyzed
coupling of butatrienyl carbinols with aryl halides and triflates
*
Jose M. Aurrecoechea and Elena Perez
´
´
´ ´ ´ ´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa, Universidad del Paıs Vasco, Apartado 644, 48080 Bilbao, Spain
Received 5 February 2004; revised 15 March 2004; accepted 19 March 2004
Abstract—An efficient one-pot two-step synthesis of polysubstituted furans is described using readily available 4,5-epoxy-2-alkynyl esters
as starting materials. In the first step, reduction of these with SmI2 affords buta-1,2,3-trienyl carbinol intermediates which, in the second step,
participate in Pd(0)-catalyzed cyclization reactions with aryl halides and triflates by a mechanism probably involving oxidative addition,
intramolecular oxypalladation and reductive elimination steps. In this manner, up to four carbon substituents are incorporated onto the furan
ring, with the aryl group being introduced at the furan 3- or 4-positions. These features make the method particularly suitable for
regioselective synthesis of tetrasubstituted furans.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Alkyne- and allene substrates with an internal C-, O- or
N-based nucleophile have been extensively used in
palladium-catalyzed coupling reactions with aryl-, vinyl-
or allyl halides and triflates (R-X) leading to the efficient
preparation of a variety of substituted carbocyclic and
heterocyclic structures incorporating the organic fragment
(R).1 When an oxygen nucleophile (carboxylic acid, alcohol
or ketone) is appended to an alkynyl or allenyl moiety,2,3 the
application of this strategy results in the regioselective
synthesis of substituted furans and related derivatives,4 a
topic of current interest due to the synthetic, biological and
industrial importance of these compounds.5 These reactions
proceed through the intermediacy of RPdX complexes (III)
formed by oxidative addition of R-X to Pd(0), that can
promote the coupling process typically in two different
ways. For alkyne substrates typified by I, the organopalla-
dium III activates the unsaturated system of I towards
intramolecular attack by the internal oxygen nucleophile.
After cyclization, reductive elimination follows to give the
product VI. Alternatively, the addition of RPdX across the
allene p-system of substrates II results in formation of a
Scheme 1.
precursors,4 we have introduced the use of epoxyalkynyl
new C–C bond at the central carbon of the diene, and a
esters VII as precursors of buta-1,2,3-trienyl carbinols VIII,
p-(allyl)palladium complex V which then suffers intra-
molecular nucleophilic attack to form the cyclic structure
that are substrates for a Pd(II)-promoted cycloisomerization
leading to furans X (Scheme 2).6 The overall transformation
(Scheme 1).
VII!X takes place in one pot and the presumed role of
Pd(II) is to activate the central triene double bond of VIII to
undergo nucleophilic attack by the internal hydroxyl group.
In the context of regioselective furan synthesis from acyclic
Keywords: Furans; Palladium-catalyzed coupling; Intramolecular
oxypalladation; [3]Cumulenes.
Conceivably, an analogous treatment of intermediates VIII
with organopalladium complexes III, generated in situ from
Pd(0) and R-X (where R¼aryl or vinyl) could be expected to
*
Corresponding author. Tel.: þ34-94-601-2578; fax: þ34-94-464-8500;
e-mail address: qopaufem@lg.ehu.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.060

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4140
to aldehydes or ketones 4, followed in both cases by
esterification and epoxidation (Scheme 3).
Initial exploratory studies were conducted starting from
epoxides 7a,b and iodobenzene (Table 1). Treatment of 7a
with SmI2 (2.1 equiv.) at 25 8C in THF afforded the
presumed samarium alkoxide 8a. Direct treatment of this
with PhI and catalytic Pd(PPh3)4 at various temperatures led
in all cases to degradation. In contrast, isolated alcohol 9a
(crude from 7a, 92% yield), when treated with PhI
(1 equiv.), Pd(PPh3)4 (5 mol%) and Et3N (5 equiv.) in
refluxing THF, afforded the expected arylated tetrasubsti-
tuted furan 10aa in 36% yield (two steps from 7a). A similar
yield of 10aa (33%) was obtained when isolation of
intermediate 9a was omitted and, instead, water (1 equiv.)
was added to the alkoxide 8a prior to treatment with
Pd(PPh3)4/PhI/Et3N (entry 1 of Table 1). An analogous
treatment of alcohol 9b, generated in situ from alkoxide
8b with 1 equiv. of water, produced the corresponding
furan 10ba in 26% yield (entry 2). An important
problem encountered in these preliminary experiments
was the competing formation of the corresponding
Scheme 2.
promote a similar cyclization with concomitant coupling
between the furyl and R fragments, thus leading to a more
highly substituted furan XI (Eq. (1)). While alcohols of type
VIII have been involved in alternative previous syntheses of
furans,7 prior to this work their use in Pd-catalyzed
couplings with organic halides was unprecedented.8 In
this paper we describe the results of a study on a new
Pd-catalyzed cyclization involving buta-1,2,3-trienyl carbi-
nols VIII and aryl halides or triflates. Overall, the
regioselective synthesis of polysubstituted arylated furans
XI (R¼Ar) from esters VII is achieved in a one-pot two-
step process.9 This work expands the scope of our
previously reported synthesis of 2,3,5-trisubstituted furans
from VII6 by extending it to include the 2,3,4-tri- and
2,3,4,5-tetrasubstituted patterns through the formation of
a new C–C bond at the furan 3- or 4-positions.
Table 1. Study of reaction conditions for the pd(0)-catalyzed reaction of
alcohols 9a,b with PhI
ð1Þ
Catalysta
Solvent
Tb
10c
11c
2. Results and discussion
7
1
2
3
4
5
6
7
8
7a Pd(PPh3)4
7b Pd(PPh3)4
7a Pd2dba3·CHCl3
THF
THF
THF
70
70
70
70
70
70
70
70
60
80
80
10aa (33) 11a (12)
10ba (26) 11b (16)
Representative substrates of type 7 were prepared either by
Sonogashira coupling10 between vinyl bromide (1) and
propargyl alcohol (2) fragments, or by addition of
alkynyllithium reagents, derived from suitable enynes 3,
—
—
11ad
11a (50)
11b (47)
11b (25)
11a (9)
7a Pd(Oac)2/4AsPh3 THF
10aad
—
7a PdCl2(MeCN)2
7b Pd2dba3/4TFP
7b Pd(OAc)2/3PPh3
7a Pd(PPh3)4
7b Pd(PPh3)4
7b Pd(PPh3)4
7b Pd(OAc)2
THF
THF
THF
—
—
10aad
MeCNe
DMFe
DMFe
DMFe
DMFe
DMFe
DMFe
DMFe
9
10ba (48) 11b (d)
10f
11
12
13g
14g
—
—
—
11b (50)
7b Pd(OAc)2/3PPh3
7b Pd(PPh3)4
7b Pd(PPh3)4
100 10ba (33) 11bd
70
70
70
10ba (53) 11bd
h
10ba (56)
10ba (28)
—
—
h
15g,i 7b Pd(PPh3)4
a
Unless otherwise indicated, 5 mol% of the palladium complex was used.
TFP¼tri(2-furyl)phosphine.
b
c
d
e
Bath temperature (8C) for the Pd-catalyzed step.
Isolated yield (%) of pure product for two steps from epoxides 7a or 7b.
Trace.
After the reduction step, THF was evaporated and the resulting residue
was dissolved in the appropriate solvent.
K2CO3 (5 equiv.) was employed in place of Et3N.
Two equivalents of PhI were used.
Reaction run with 10 mol% of Pd(PPh3)4.
Water was omitted.
f
Scheme 3. (a) Pd(PPh3)2Cl2, CuI, Et2NH, rt, to give 5. (b) (i) n-BuLi, THF,
278!0 8C; (ii) 4, THF, 278!rt; (iii) H2O, to give 5, or (iii) BzCl,
0 8C!rt, to give 6 (X¼Bz). (c) From 5; Ac2O, DMAP, Et3N, to give 6
(X¼Ac). (d) MCPBA, CH2Cl2, rt.
g
h
i

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4141
cycloisomerization products, the 2,3,5-trisubstituted furans
Table 2. Preparation of furans 10b from epoxide 7b and Ar-X
11a and 11b,6 that were isolated in comparatively important
amounts (10–16%). A survey of reaction conditions was
then conducted to improve the efficiency of the reaction,
proceeding in all cases without isolation of intermediate
alcohols 9. By using THF as solvent (entries 1–7),
Pd(PPh3)4 was determined to be superior to other catalysts
tested (entries 3–7), that either promoted the formation of
trisubstituted furans 11 (entries 5–7) or led to considerable
degradation (entries 3 and 4). Results improved con-
siderably with a change of solvent from THF to DMF,
which caused the yield of 10ba to increase to 48%, while the
amount of trisubstituted furan 11b decreased substantially
(entry 9). Further improvements were realized by doubling
the amount of arylating agent (entry 13), particularly when
the amount of catalyst was also increased (entry 14). Under
this latest conditions formation of furan 11b was not
observed, and these were adopted as standard conditions for
subsequent reactions. Further changes in base (entry 10) or
catalyst (entries 11 and 12) were not effective. In sharp
contrast with earlier results obtained in THF (vide supra),
the direct treatment of samarium alkoxide 8b with
Pd(PPh3)4, PhI and Et3N in DMF, without generation of
alcohol 9b, under otherwise standard conditions, also
afforded the desired 10ba (entry 15). However, even in
this case, the yield of 10ba was substantially lower (28%)
than that obtained in the presence of water (entry 14) while
the reaction time increased considerably (3 days in entry 15
vs 16 h in entry 14).
Ar-X
12
T (t)a
10bb
1
2
3
4
5
6
7d
PhI
PhOTf
p-MeCOC6H4I
p-BrC6H4I
p-MeC6H4I
p-MeC6H4OTf
p-MeOC6H4I
12a
12bc
12c
12d
12e
12f
70 (16)
70 (24)
80 (24)
70 (48)
80 (18)
80 (82)
60 (13)
10ba (56)
10ba (54)
10bb (64)
10bc (73)
10bd (53)
10bd (39)
10be (40)
12g
8
9
12h
12i
70 (22)
70 (72)
10bf (46)
10bf (53)
10
12j
70 (72)
80 (72)
10bg (52)e
10bh (53)
11
12k
a
Bath temperature (8C) for the Pd-catalyzed step. Within brackets, reaction
time (h).
Isolated yield (%) of pure product for two steps starting from epoxide 7b.
5 mol% Pd(PPh3)4 was used.
An aqueous work-up was performed after reduction with SmI2 to isolate
alcohol 9b prior to cyclization.
The 2,3,5-trisubstituted furan 11b was also obtained (5%).
b
c
d
Using the conditions of entry 14, the method was applied to
arylating agents other than PhI taking ester 7b as model
substrate. These results are collected in Table 2. A number
of aryl- (entries 1–7) and heteroaryl (entries 8–11) coupling
agents could be incorporated successfully into the sequence,
and the corresponding arylated furans 10b were obtained in
moderate-to-good yields, usually without interference from
formation of compounds of type 11. Both electron-deficient
and electron-rich aromatics have been employed success-
fully in this reaction. However, the use of 4-iodoanisole
(12g, entry 7), with a strong electron-donating p-MeO
group, was complicated by Ar–Ph exchange between Pd
and the PPh3 ligands at the level of a ArPd(PPh3)2X
intermediate (see III, R¼Ar in Scheme 1).2m,11–13 Thus,
using the standard procedure, 12g afforded a low yield
(22%) of the expected product 10be, the major product of
this reaction being 10ba (46%), the result of incorporation
of a phenyl rather than a 4-methoxyphenyl group. The
undesired formation of 10ba was completely suppressed by
carrying out the reaction from the isolated alcohol 9b. In this
manner the arylated furan 10be was obtained in an
improved 40% yield and no 10ba was found.14 When the
arylating agent contained both C–I and C–Br bonds
susceptible of oxidative addition, the reaction took place
chemoselectively at the C–I bond (entry 4) and this made it
possible to incorporate a bromoaryl group into the final
product. Bromides were effective partners, however, in the
heteroaromatic series as shown by entries 9–11. In a brief
examination, the corresponding triflates were found to give
mixed results. Thus, while phenyl triflate and phenyl iodide
gave comparable results (entries 1 and 2), the triflate was
substantially inferior to the iodide in the p-tolyl case (entries
5 and 6). Attempts to extend the reaction to cyclohexenyl
e
triflate, 2-bromo-trans-2-butene and ethyl cis-3-iodoacryl-
ate failed.
1
Interestingly, the H NMR spectra of the crude products
revealed that the expected furans 10b were accompanied in
most cases by variable amounts of dienes 13b. This was
deduced from the observation of a broad signal at d,5.0
assigned to the methine CH–O of 13b and a singlet at
d,2.3 corresponding to the side-chain methyl group. In
comparison, the corresponding furans of type 10b displayed
a characteristic multiplet at d,2.8–3.0 corresponding to the
side-chain methine proton, absent in 13b, as well as a
doublet at d,1.2–1.3 for the side-chain Me group. Upon
stirring EtOAc solutions of the crude product mixtures
with AcOH or SiO2, or simply proceeding directly to the
chromatographic purification in silica gel, dienes 13b were
completely converted into the corresponding furans 10b
(Eq. (2)).15
ð2Þ

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4142
The method has also been applied successfully to other
substrates 7 in combination with aryl halides 12, and these
results are collected in Table 3. Highly substituted furans
containing in most cases carbon substituents at all ring
positions were thus obtained efficiently from epoxides 7 in a
one-pot two-step process. Therefore, the intramolecular
oxypalladation/reductive elimination sequence appears to
be particularly well suited to the synthesis of tetrasubstituted
furans. This is a particularly interesting feature because
the regioselective introduction of four different carbon
substituents onto the furan ring is a difficult task and only a
limited number of methods have been described in the
literature that manage it efficiently.2m,3a,15a,16 The formation
of an arylated 2,3,5-trisubstituted furan 10e, lacking the C-5
substituent, was also tested (entry 6) and this required a
slight modification in the reduction step to avoid the
competing formation of iodohydrin 14, observed under the
standard reduction conditions. Compound 14 is the result of
iodide anion-promoted epoxide ring-opening, a process well
documented in the literature,17 which is facilitated in 7e,
relative to the other substrates, by the less hindered
approach of the anion to the terminal epoxide. After a
brief survey of reaction conditions, it was found that dropwise
additionofthesubstrate toanexcessSmI2 (3.1 equiv.)at10 8C
suppressed completely the unwanted formation of 14 and the
ensuing cyclization led to 10e in a reasonable yield.
Scheme 4.
ferent ring positions (entries 1–3, 5 and 7), and the
formation of bicyclic products is shown to be feasible
(entries 10 and 11). A further point of interest is the
additional flexibility that this strategy offers to the existing
methodology in the creation of regiochemical patterns
around the furan nucleus. Thus, the heterocyclic ring carbon
framework and three ring substituents are provided by the
simple vinyl halide, acetylene and aldehyde or ketone
fragments used in the assembly of the starting material 7,
whereas the fourth substituent is incorporated from the aryl
halide 12.
Table 3 also reveals good tolerance of the whole sequence
for both acid- and base-sensitive functional groups, as
shown by the presence of carbonyl, cyano and protected
hydroxyl groups in the final products (entries 3, 5, 7 and 8).
Branched substituents are readily accommodated at dif-
A plausible mechanistic interpretation for the transforma-
tion of trienes 9 into arylated furans 10 is shown in
Scheme 4. Thus, after activation of the central triene double
bond with an arylpalladium(II) XII, generated from Ar-X
and Pd(0), intramolecular oxypalladation would lead to a
Table 3. General preparation of furans 10 from epoxides 7 and Ar-X (12)
7
R1
R2
R3
R4
12
T (t)a
10bb
1
2
3
4
5
6
7
8
7ac
7ac
7bc
7cc
7dc
7ee
7fc
CH3
CH3
(CH2)2Ph
CH3
12a
12d
12a
12c
12d
12d
12c
12d
12c
12a
12c
80 (13)
70 (15)
70 (16)
70 (13)
60 (18)
60 (110)
40 (72)
100 (10)
100 (10)
70 (9)
10aa (56)
10ab (62)
10ba (56)
10c (74)
10d (76)
10e (59)
10f (63)
10ga (65)
10gb (60)
10ha (74)
10hb (68)
CH3
CH3
i-Pr
H
CH2OMOM
CH2OMOM
CH3
CH3
i-Bu
CH3
CH3
CH3
(CH2)3CN
(CH2)2Ph
(CH2)2Ard
(CH2)2Ph
(CH2)3CN
(CH2)2Ph
CH3
H
H
H
CH3
H
7gc
7gc
7he
7he
9
10
11
(CH2)4
(CH2)2Ph
H
70 (9)
a
Bath temperature (8C) for the Pd-catalyzed step. Within brackets, reaction time (h).
Isolated yield (%) of pure product for two steps from epoxides 7.
b
c
d
e
R5¼CH3.
Ar¼3,4-dimethoxyphenyl.
R5¼Ph.

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4143
new diorganopalladium complex XIV. Reductive elimi-
nation and aromatization, in this order, then affords furans
10, through dienes 13.18 As mentioned earlier, these dienes
have been observed in the crude products and they are seen
to isomerize to the corresponding furans 10. Therefore, it
can be safely concluded that reductive elimination does
indeed precede aromatization as described in Scheme 4.
the combined organic extracts were washed with brine
(50 mL) and dried (Na2SO4). The residue after evaporation
was purified by flash chromatography to yield enynols 5.
4.3. Procedure for the preparation of alcohols 5 from
enynes 3 and aldehydes or ketones 4
In a typical experiment, n-BuLi (1.24 M in hexanes,
11.3 mL, 14.0 mmol) was added dropwise to a solution of
an enyne 3 (13.0 mmol) in THF (50 mL) at 278 8C under
Ar. The resulting solution was allowed to reach 0 8C, kept
at this temperature for 1 h and cooled again to 278 8C.
A solution of an appropriate aldehyde or ketone (4,
11.0 mmol) in THF (10 mL) was added, and the reaction
mixture was allowed to reach rt. After stirring the mixture
3 h at the same temperature, it was quenched with water
(50 mL) and the aqueous layer was extracted with EtOAc
(3£50 mL). The combined organic extracts were washed
with brine (50 mL) and dried (Na2SO4). The crude products
5 were treated as indicated below for the individual cases.
3. Conclusions
Highly substituted furans are effectively prepared by
Pd(0)-catalyzed coupling of penta-2,3,4-trien-1-ols 9 and
aryl halides. The generation19 and use of these compounds
starting from epoxypropargyl esters 7 is convenient due to
(i) easy assembly of the starting materials from readily
available precursors, (ii) the possibility of incorporating
useful functionality, (iii) mild reaction conditions, and (iv)
the possibility of carrying out the transformations 7!9!10
in one-pot, without isolation of 9.20 This method should
find particular application in the regioselective synthesis of
tetrasubstituted furans.
4.4. Procedure for acetylation of alcohols 5
In a typical experiment, a mixture of 5 (8.43 mmol), DMAP
(0.310 g, 2.53 mmol), Et3N (3.52 mL, 30.0 mmol) and
Ac2O (1.81 mL, 20.0 mmol) was stirred for 3 h at rt. The
mixture was diluted with EtOAc (10 mL) and poured over
a mixture of H2O/ice (,10 mL). After separation of the
layers, the aqueous layer was extracted with EtOAc
(3£10 mL). The combined organic layers were washed
with brine (10 mL) and dried (Na2SO4). The crude products
6 were treated as indicated below for the individual cases.
4. Experimental
4.1. General
All reactions involving air- and moisture-sensitive materials
were performed using standard bench-top techniques.21
Acetic anhydride, 5-oxohexanenitrile, 4-phenylbutan-2-
one, diiodomethane, iodobenzene, DMF, CH2Cl2, diethyl-
amine and triethylamine were distilled from CaH2 and
purged with Ar. Tetrahydrofuran (THF) was freshly
distilled from sodium/benzophenone and, for reactions
with SmI2, it was deoxygenated prior to use. DMF and
triethylamine were similarly deoxygenated for Pd-catalyzed
reactions. Flash column chromatography22 was performed
on silica gel (230–400 mesh). HPLC purifications were
carried out with a LiChrosorb Si60 (7 mm, 25£2.5 cm)
4.5. Procedure for epoxydation of esters 6
In a typical experiment, to a solution of the appropriate ester
6 (10.0 mmol) in CH2Cl2 (10 mL) at 0 8C was added
MCPBA (77%, 4.43 g, 20.0 mmol). The solution was stirred
for 15 min, allowed to warm to rt and further stirred at the
same temperature (total reaction time: 5 h). 1 M NaOH
(10 mL) was added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3£10 mL), and
the combined organic extracts were washed with brine
(10 mL) and dried (Na2SO4). The residue after evaporation
was purified as indicated below for the individual cases to
yield epoxides 7.
1
column using a refraction index detector. Routine H and
13C NMR spectra were obtained at 250 and 62.9 MHz,
respectively, using CDCl3 as solvent and internal reference
1
(d 7.26 for H and d 77.0 for 13C). IR data include only
characteristic absorptions. Mass spectra were obtained at
70 eV. Solutions of SmI2 in THF were prepared from Sm
and diiodomethane using a literature procedure.23 Palladium
complexes and phosphines were purchased and used as
received, with the exception of Pd(PPh3)4, that was prepared
as reported.24 Epoxides 7a, 7b and 7h have been prepared as
reported.6
4.5.1. (E)-6-Methyl-1-phenyloct-6-en-4-yn-3-ol (5c). Pre-
pared from 5-phenylpent-1-yn-3-ol25 and 1. Elution with
90:10 hexanes/EtOAc afforded 5c (58%) as an oil: 1H NMR
d 1.84 and 1.87 (2s, total 6H), 2.05–2.15 (m, 2H), 2.31 (br s,
W1/2¼10 Hz, 1H), 2.86 (t, J¼7.8 Hz, 2H), 4.57–4.59 (m,
1H), 5.75–5.82 (m, 1H), 7.20–7.35 (m, 5H); 13C NMR d
16.2, 22.9, 31.4, 39.5, 62.2, 84.4, 93.6, 118.0, 125.9, 128.3,
128.4, 128.4, 132.8, 141.3; IR (neat) n 3355 (O–H, s), 3060
(vC–H, w), 2214 (CuC, w), 1050 (C–O, s) cm21; HRMS
calcd for C14H15O (M2CH3) 199.1123, found 199.1126.
4.2. Procedure for the preparation of alcohols 5 from
vinyl bromide 1 and propargylic alcohols 2
In a typical experiment, a solution of a propargylic alcohol
2 (30.0 mmol) in Et2NH (10 mL) was added to a solution
of trans-2-bromobut-2-ene (1) (2.84 mL, 30.0 mmol),
Pd(PPh3)2Cl2 (0.450 g, 0.640 mmol) and CuI (0.530 g,
2.81 mmol) in Et2NH (120 mL) under Ar. The resulting
solution was stirred for 15 h at rt. Then a solution of NH4Cl
(100 mL) was added, and the layers were separated. The
aqueous layer was extracted with EtOAc (3£100 mL), and
4.5.2. (4S p,5S p)-4,5-Epoxy-4-methyl-1-(2-phenylethyl)-
hex-2-ynyl acetate (7c). Alcohol 5c was acetylated and
the crude acetate, without further purification, was subjected
to the epoxidation conditions. The crude epoxide was
purified by flash chromatography (90:10 hexanes/EtOAc) to

´
J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4144
yield 7c (94% for two steps) as an oil: 1H NMR d 1.42 and
1.43 (2 d, J¼5.3 Hz, 3H), 1.53 (s, 3H), 2.05–2.11 (m, 5H,
that includes 2s at 2.05 and 2.06), 2.76 (t, J¼7.8 Hz, 2H),
2.94–3.00 (m, 1H), 5.39 (t, J¼6.5 Hz, 1H), 7.16–7.31 (m,
5H); 13C NMR d 15.4, 20.8, 22.9, 31.1, 36.0, 36.0, 52.3,
60.7, 60.7, 63.2, 81.2, 83.4, 83.4, 126.0, 128.2, 128.3, 140.4,
169.6; IR (neat) n 1741 (CvO, s) cm21; HRMS (FAB)
calcd for C17H20O3 272.1412, found 272.1405.
2.18–2.34 (m, 2H), 2.76 and 2.78 (2 d, J¼5.5 Hz, 1H), 2.87
(t, J¼7.7 Hz, 2H), 3.03 and 3.05 (2d, J¼5.5 Hz, 1H), 5.66 (t,
J¼6.5 Hz, 1H), 7.22–7.35 (m, 5H), 7.46 (t, J¼7.4 Hz, 2H),
7.59 (t, J¼7.3 Hz, 1H), 8.06 (d, J¼8.3 Hz, 2H); 13C NMR d
22.7, 31.2, 36.1, 46.9, 55.2, 63.6, 79.2, 85.1, 126.1, 128.3,
128.4, 129.5, 129.7, 133.1, 140.1, 165.2; IR (neat) n 1721
(CvO, s), 1600 (CvC, m), 1262 (C–O, s) cm21; HRMS
(FAB) calcd for C21H20O3 320.1412, found 320.1403.
4.5.3. (Z)-1-(3,4-Dimethoxy)phenyl-6-isobutyl-8-methyl-
non-6-en-4-yn-3-ol (5d). Prepared from (Z)-3-isobutyl-5-
methyhex-3-en-1-yne26 and 3-(3,4-dimethoxyphenyl)pro-
panal.27 The crude product was purified by flash chroma-
tography (80:20 hexanes/EtOAc) to yield 5d (90%) as an
4.5.7. (E)-5-Hydroxy-10-methoxymethoxy-5,8-dimethyl-
dec-8-en-6-ynenitrile (5f). Prepared from (E)-3-methyl-5-
methoxymethoxypent-3-en-1-yne28 and 5-oxahexanenitrile.
The crude product was purified by flash chromatography
(60:40 hexanes/EtOAc) to yield 5f (90%) as an oil: 1H NMR
d 1.45 (s, 3H), 1.72–1.85 (m, 7H), 1.80 (s, included in m at
1.72–1.85), 2.34–2.37 (m, 2H), 3.30 (s, 3H), 3.43 (s, 1H),
4.14 (d, J¼6.7 Hz, 2H), 4.55 (s, 2H), 5.74 (m, 1H); 13C
NMR d 16.9, 20.8, 22.8, 30.0, 41.7, 54.9, 64.5, 67.2, 81.6,
94.7, 96.8, 119.4, 122.1, 132.4.
1
oil: H NMR d 0.86–1.00 (m, 12H), 1.65–2.03 (m, 6H),
2.73–2.86 (m, 3H), 2.76 (t, J¼7.9 Hz, included in m at
2.73–2.86), 3.86 and 3.87 (2s, 6H), 4.51–4.54 (m, 1H), 5.47
(d, J¼9.3 Hz, 1H), 6.73–6.82 (m, 3H); 13C NMR d 21.9,
22.4, 26.7, 29.7, 31.0, 39.7, 46.2, 55.5, 55.7, 62.0, 83.6,
93.3, 111.0, 111.5, 118.9, 120.1, 133.9, 146.2, 147.0, 148.6;
IR (neat) n 3472 (O–H, s), 1602 (CvC, w) cm21; HRMS
calcd for C22H32O3 344.2351, found 344.2348.
4.5.8. (E)-1-(3-Cyanopropyl)-6-methoxymethoxy-1,4-
dimethylhex-4-en-2-ynyl acetate (6f). Prepared from 5f.
The crude product was purified by flash chromatography
4.5.4. (4S p,5R p)-1-[2-(3,4-Dimethoxyphenyl)ethyl]-4,5-
epoxy-4-isobutyl-6-methylhept-2-ynyl acetate (7d).
Alcohol 5d was acetylated and the crude acetate, without
further purification, was subjected to the epoxydation
conditions. The crude epoxide was purified by flash
chromatography (80:20 hexanes/EtOAc) to yield 7d (83%
(65:35 hexanes/EtOAc) to afford 6f (90%) as an oil: H
1
NMR d 1.71 (s, 3H), 1.86–2.10 (m, 10H), 1.86 and 2.02 (2s,
included in m at 1.86–2.10), 2.39–2.44 (m, 2H), 3.36 (s,
3H), 4.21 (d, J¼6.7 Hz, 2H), 4.62 (s, 2H), 5.82 (t, J¼6.7 Hz,
1H); 13C NMR d 16.6, 20.3, 21.4, 22.5, 26.2, 40.1, 54.8,
65.2, 74.1, 83.4, 92.7, 95.4, 119.0, 120.6, 133.4, 168.5; IR
(neat) n 2244 (CuN, m), 1735 (CvO, s), 1684 (CvC, w)
cm21; HRMS calcd for C16H23NO4 293.1627, found
293.1633.
1
for two steps) as an oil: H NMR d 0.94–1.11 (m, 12H),
1.25–1.41 (m, 1H), 1.61–1.78 (m, 2H), 1.96–2.07 (m, 6H),
2.07 (s, included in m at 1.61–2.07), 2.51 (d, J¼9.1 Hz,
1H), 2.69 (t, J¼7.8 Hz, 2H), 3.86 and 3.87 (2s, 6H),
5.35–5.40 (m, 1H), 6.68–6.81 (m, 3H); 13C NMR d
18.3, 19.7, 20.9, 22.4, 22.9, 25.9, 30.9, 36.4, 45.5, 55.4,
55.7, 55.9, 63.4, 70.0, 70.1, 82.0, 82.7, 111.2, 111.5, 120.1,
133.1, 147.3, 148.8, 169.7; IR (neat) n 1743 (CvO, s)
cm21; HRMS calcd for C24H34O5 402.2406, found
402.2401.
4.5.9. (4S p,5S p)-1-(3-Cyanopropyl)-4,5-epoxy-6-meth-
oxymethoxy-1,4-dimethylhex-2-ynyl acetate (7f). Pre-
pared from 6f. The crude product was purified by flash
chromatography (65:35 hexanes/EtOAc) to yield 7f (98%)
as an oil. The characterized sample was additionally purified
by HPLC (60:40 hexanes/EtOAc, 8 mL/min, tR¼27 min):
1H NMR d 1.47 (s, 3H), 1.59 (s, 3H), 1.64–2.27 (m, 6H),
1.93 (s, included in m at 1.64–2.27), 2.32–2.37 (m, 2H),
3.03 (t, J¼5.3 Hz, 1H), 3.03 (s, 3H), 3.57–3.74 (m, 2H),
4.60 (s, 2H); 13C NMR d 16.8, 20.3, 21.5, 22.7, 26.1, 40.1,
51.1, 55.1, 62.3, 66.9, 67.0, 73.5, 82.6, 83.3, 83.4, 96.5,
119.1, 168.6; IR (neat) n 2244 (CuN, m), 1739 (CvO, s)
cm21; HRMS calcd for C13H16NO3 (M2OAc-CH3)
234.1130, found 234.1121.
4.5.5. 4-Methyl-1-(2-phenylethyl)pent-4-en-2-ynyl benzo-
ate (6e). The procedure for preparation of alcohols 5 was
followed from 2-methylbut-1-en-3-yne and hydrocinnam-
aldehyde. After stirring the reaction mixture at rt for 1 h, it
was cooled to 0 8C and neat benzoyl chloride (1.2 equiv.)
was added in one portion. The mixture was stirred for 1 h
at rt and quenched with sat NH4Cl. The usual extractive
work-up with EtOAc afforded a crude product that was
purified by flash chromatography (95:5 hexanes/EtOAc) to
yield 6e (96%) as an oil: 1H NMR d 1.99 (s, 3H), 2.27–2.43
(m, 2H), 2.96 (t, J¼7.7 Hz, 2H), 5.35 (d, J¼1.6 Hz, 1H),
5.45 (s, 1H), 5.85 (t, J¼6.4 Hz, 1H), 7.24–7.40 (m, 5H),
7.47–7.53 (m, 2H), 7.59–7.65 (m, 1H), 8.15 (d, J¼7.7 Hz,
2H); 13C NMR d 23.2, 31.3, 36.4, 64.2, 85.2, 86.8, 122.8,
125.8, 126.0, 128.2, 128.3, 128.4, 128.4, 129.6, 129.7,
133.0, 140.6, 165.2; IR (neat) n 2226 (CuC, w), 1721
(CvO, s), 1604 (CvC, m) cm21; HRMS calcd for
C21H20O2 304.1463, found 304.1466.
4.5.10. (4S p,5S p)-4,5-Epoxy-6-methoxymethoxy-4-
methyl-1-(2-phenylethyl)hex-2-ynyl acetate (7g). The
alkynylation, acetylation and epoxidation procedures
described above were successively followed starting
from (E)-3-methyl-5-methoxymethoxypent-3-en-1-yne28
and hydrocinnamaldehyde, without purification of the
intermediates. The crude epoxide product was purified by
flash chromatography (80:20 hexanes/EtOAc) to yield 7g
(75%) as an oil: 1H NMR d 1.56 (s, 3H), 2.03 (s, included in
m at 2.03–2.12), 2.03–2.12 (m, 5H), 2.74 (t, J¼7.8 Hz,
2H), 3.08–3.13 (apparent t, 1H), 3.36 (s, 3H), 3.66–3.84
(m, 2H), 4.66 (s, 2H), 5.35 (t, J¼6.5 Hz, 1H), 7.14–7.30
(m, 5H); 13C NMR d 20.6, 22.8, 31.0, 35.8, 35.8, 51.0, 55.0,
62.1, 62.2, 62.9, 67.0, 81.6, 82.5, 96.5, 125.9, 128.1, 128.2,
128.2, 128.3, 140.2, 169.4; IR (neat) n 1751 (CvO, s), 1228
4.5.6. 4,5-Epoxy-4-methyl-1-(2-phenylethyl)pent-2-ynyl
benzoate (7e). Prepared from 6e. The crude product was
purified by flash chromatography (95:5 hexanes/EtOAc) to
yield 7e (89%) as an oil: 1H NMR d 1.58 and 1.59 (2s, 3H),

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
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(C–O, s) cm21; HRMS calcd for C19H24O5 332.1624, found
332.1612.
was purified by flash chromatography (hexanes) and HPLC
1
(hexanes, 9 mL/min, tR¼72 min): H NMR d 1.29 (d, J¼
6.7 Hz, 3H), 1.73–1.87 (m, 1H), 1.91 (s, 3H), 1.97–2.12
(m, 1H), 2.27 (s, 3H), 2.36–2.56 (m, 2H), 2.81–2.95 (m,
1H), 7.02–7.43 (m, 10H); 13C NMR d 9.0, 11.5, 20.5, 30.8,
33.8, 37.7, 113.6, 122.4, 125.5, 126.3, 128.1, 128.2, 1283,
129.5, 134.3, 142.4, 145.1, 152.4; IR (neat) n 3080–3020
4.5.11. 3,6-Dimethyl-8-phenylocta-3,4,5-trien-2-ol (9a).
To a solution of SmI2 (ca. 0.1 M in THF, 15.0 mL,
1.5 mmol) was added via cannula a solution of 7a (0.18 g,
0.63 mmol) in THF (2 mL) at 25 8C under Ar, and the
mixture was stirred at the same temperature for 2 h. Dry air
was bubbled through the solution to destroy excess SmI2,
the reaction mixture was allowed to reach rt and a saturated
K2CO3 solution (10 mL) was added. After separation, the
aqueous layer was extracted with EtOAc (3£10 mL), and
the combined organic layers were washed with brine
(10 mL) and dried (Na2SO4). Removal of the solvent in
vacuo afforded triene 9a (92% yield, diastereomeric
mixture), that was used without further purification: 1H
NMR d 1.34 (dd, J¼9.5, 7.9 Hz, 3H), 1.92 (s, 3H), 1.95 (s,
3H), 2.47 (t, J¼7.9 Hz, 2H), 2.82–2.89 (m, 2H), 4.27 (s,
1H), 7.17–7.32 (m, 5H).
(vC–H, s), 2950 (C–H, s), 1270 (C–O–C, s) cm21
;
HRMS calcd for C22H24O 304.1823, found 304.1827.
4.6.2. 3-(4-Bromophenyl)-4,5-dimethyl-2-(1-methyl-3-
phenylpropyl)furan (10ab). Prepared from 7a and 12d.
The crude product was purified by flash chromatography
(hexanes) and HPLC (hexanes, 8 mL/min, tR¼17 min):
1H NMR d 1.32 (d, J¼6.9 Hz, 3H), 1.79–1.92 (m, 4H), 1.92
(s, included in m at 1.79–1.92), 2.00–2.16 (m, 1H), 2.31 (s,
3H), 2.40–2.60 (m, 2H), 2.80–2.94 (m, 1H), 7.01–7.33 (m,
7H), 7.54 (d, J¼8.3 Hz, 2H); 13C NMR d 8.9, 11.5, 20.3,
30.7, 33.7, 37.5, 113.4, 120.3, 121.3, 125.5, 128.1, 128.2,
128.3, 131.1, 131.4, 133.3, 142.1, 145.4, 152.6; IR (neat) n
3024 (vC–H, w), 2922 (C–H, s), 1602 (ArC–C, m), 1071
(C–O–C, m) cm21; HRMS calcd for C22H2379BrO
382.0932, found 382.0918; HRMS calcd for C22H2381BrO
384.0912, found 384.0909.
4.5.12. 9-Hydroxy-5,8-dimethyldeca-5,6,7-trienenitrile
(9b). The procedure described above for the preparation
of 9a was followed starting from 7b. The crude product was
purified by flash chromatography (65:33:2 hexanes/EtOAc/
Et3N), to yield 9b (85% yield, diastereomeric mixture) as an
oil: 1H NMR d 1.34 (d, J¼6.3 Hz, 3H), 1.85–1.96 (m, 9H),
1.92 (s, included in m at 1.85–1.96), 2.27–2.34 (m, 2H),
2.35 (t, J¼7.1 Hz, 2H), 4.27 (m, 1H); 13C NMR d 16.4, 18.5,
18.7, 21.7, 21.9, 22.6, 23.1, 23.2, 35.1, 35.4, 70.1, 70.4,
112.5, 112.6, 117.0, 117.3, 119.5, 119.6, 153.1, 153.3,
155.8; IR (neat) n 3580–3250 (O–H, m), 2240 (CuN, m)
cm21; HRMS calcd for C12H17NO 191.1310, found
191.1302.
4.6.3. 5-(4,5-Dimethyl-3-phenylfuran-2-yl)hexanenitrile
(10ba). Prepared from 7b and 12a or 12b. The crude
product was purified by flash chromatography (97:3
hexanes/EtOAc) and HPLC (97:3 hexanes/EtOAc, 8 mL/
min, tR¼28 min): 1H NMR d 1.29 (d, J¼6.9 Hz, 3H), 1.40–
1.84 (m, 4H), 1.87 (s, 3H), 2.08–2.14 (m, 2H), 2.25 (s, 3H),
2.77–2.92 (m, 1H), 7.21–7.44 (m, 5H); 13C NMR d 8.8,
11.5, 16.6, 20.3, 23.4, 30.5, 34.5, 113.7, 119.6, 122.9, 126.5,
128.3, 129.3, 133.9, 145.3, 151.1; IR (neat) n 3090–3010
(vC–H, w), 2990–2880 (C–H, m), 2220 (CuN, m), 1610
(CvC, w) cm21; HRMS calcd for C18H21NO 276.1623,
found 276.1627.
4.6. General procedure for preparation of furans 10
from epoxides 7
In a typical experiment, to a solution of SmI2 (ca. 0.1 M in
THF, 13 mL, 1.3 mmol) was added via cannula a solution of
7 (0.60 mmol) in THF (2 mL) at 25 8C under Ar, and the
mixture was stirred at the same temperature for 1–5 h (TLC
control). Dry air was bubbled through the solution to destroy
excess SmI2, the mixture was purged with Ar for 10 min,
and then was allowed to reach rt. Removal of the solvent in
vacuo afforded a residue that was dissolved in DMF
(8.1 mL) containing H2O (0.60 mmol). After addition of
Et3N (0.42 mL, 3.01 mmol), an aryl halide or triflate
(1.20 mmol) and Pd(PPh3)4 (0.070 g, 0.06 mmol), the
solution was purged with Ar for 10 min and stirred at
the appropriate temperature until complete consumption of
the trienol intermediate (reaction temperatures and times are
given in Tables 2 and 3). The reaction mixture was allowed
to reach room temperature, the solvent was removed at
0.5 mm Hg, and the resulting oil was partitioned between
EtOAc (100 mL) and H2O (100 mL). After separation, the
aqueous layer was extracted with EtOAc (3£100 mL), and
the combined organic layers were washed with brine
(50 mL) and dried (Na2SO4). The crude product obtained
after solvent evaporation was purified as specified below for
the individual cases.
4.6.4. 5-[3-(4-Acetylphenyl)-4,5-dimethylfuran-2-yl]-
hexanenitrile (10bb). Prepared from 7b and 12c. The
crude product was purified by flash chromatography (80:20
hexanes/EtOAc) and HPLC (80:20 hexanes/EtOAc, 8 mL/
min, tR¼33 min): 1H NMR d 1.24 (d, J¼6.9 Hz, 3H), 1.32–
1.47 (m, 2H), 1.51–1.78 (m, 2H), 1.82 (s, 3H), 2.11 (t, J¼
7.0 Hz, 2H), 2.19 (s, 3H), 2.58 (s, 3H), 2.75–2.87 (m, 1H),
7.28 (d, J¼8.1 Hz, 2H), 7.96 (d, J¼8.3 Hz, 2H); 13C NMR
d 8.7, 11.2, 16.6, 20.0, 23.2, 26.3, 30.6, 34.4, 113.2,
119.4, 121.9, 128.3, 129.2, 135.0, 139.1, 145.8, 151.7,
197.4; IR (neat) n 2990–2860 (C–H, m), 2220 (CuN,
m), 1680 (CvO, s), 1610 (CvC, m), 1270 (C–O–C, s)
cm21; HRMS calcd for C20H23NO2 309.1729, found
309.1739.
4.6.5. 5-[3-(4-Bromophenyl)-4,5-dimethylfuran-2-yl]-
hexanenitrile (10bc). Prepared from 7b and 12d. The
crude product was purified by flash chromatography (92:8
hexanes/EtOAc): 1H NMR d 1.26 (d, J¼6.9 Hz, 3H), 1.39–
1.51 (m, 2H), 1.56–1.77 (m, 2H), 1.84 (s, 3H), 2.14 (t, J¼
7.1 Hz, 2H), 2.23 (s, 3H), 2.72–2.86 (m, 1H), 7.09 (d,
J¼8.3 Hz, 2H), 7.52 (d, J¼8.2 Hz, 2H); 13C NMR d 8.6,
11.3, 16.6, 20.1, 23.3, 30.5, 34.4, 113.3, 119.4, 120.4, 121.6,
130.9, 131.4, 132.8, 145.5, 151.2; IR (neat) n 3020 (vC–H,
w), 2980 (C–H, m), 2220 (CuN, m) cm21; HRMS calcd
4.6.1. 2,3-Dimethyl-5-(1-methyl-3-phenylpropyl)-4-phenyl-
furan (10aa). Prepared from 7a and 12a. The crude product

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4146
for C18H2079BrNO 345.0728, found 345.0725; HRMS calcd
for C18H2081BrNO 347.0708, found 347.0719.
nitrile (10bh). Prepared from 7b and 12k. The crude
product was dissolved in EtOAc (25 mL/mmol, based on
7b) and stirred with silica gel (1.25 g/mmol, based on 7b) at
rt for 15 min. After filtration and solvent evaporation, the
residue was purified by flash chromatography (50:50
hexanes/Et3N) and HPLC (58:42 hexanes/EtOAc, 8 mL/
min, tR¼44 min): 1H NMR d 1.24 (d, J¼6.9 Hz, 3H), 1.40–
1.46 (m, 2H), 1.49–1.79 (m, 2H), 1.82 (s, 3H), 2.15 (t,
J¼7.0 Hz, 2H), 2.21 (s, 3H), 2.67–2.81 (m, 1H), 7.29–7.34
(m, 1H), 7.50–7.53 (m, 1H), 8.45 (s, 1H), 8.52 (d, J¼
3.6 Hz, 1H); 13C NMR d 8.7, 11.4, 16.5, 20.3, 23.4, 30.8,
34.5, 113.5, 119.48, 119.5, 123.3, 129.9, 136.6, 146.0,
147.7, 150.0, 152.1; IR (neat) n 3015 (vC–H, w), 2985–
2885 (C–H, m), 2250 (CuN, w), 1616 and 1580 (ArC–C,
w) cm21; HRMS calcd for C17H20N2O 268.1576, found
268.1571.
4.6.6. 5-(4,5-Dimethyl-3-p-tolylfuran-2-yl)hexanenitrile
(10bd). Prepared from 7b and 12e or 12f. The crude
product was dissolved in EtOAc (25 mL/mmol, based on
7b) and stirred with silica gel (1.25 g/mmol, based on 7b) at
rt for 15 min. After filtration and solvent evaporation, the
residue was purified by flash chromatography (98:2 hexanes/
1
Et3N): H NMR d 1.28 (d, J¼6.9 Hz, 3H), 1.38–1.81 (m,
4H), 1.86 (s, 3H), 2.12 (t, J¼7.1 Hz, 2H), 2.24 (s, 3H), 2.40
(s, 3H), 2.76–2.90 (m, 1H), 7.11 (d, J¼7.8 Hz, 2H), 7.22 (d,
J¼7.8 Hz, 2H); 13C NMR d 8.8, 11.5, 16.7, 20.3, 21.1, 23.4,
30.5, 34.5, 113.8, 119.7, 122.7, 129.1, 129.2, 130.9, 136.2,
145.2, 151.0; IR (neat) n 3020 (vC–H, m), 2990–2880
(C–H, s), 2225 (CuN, w), 1610 (CvC, w) cm21; HRMS
calcd for C19H23NO 281.1780, found 281.1775.
4.6.11. 3-(4-Acetylphenyl)-4,5-dimethyl-2-(3-phenylpro-
pyl)furan (10c). Prepared from 7c and 12c. The crude
product was purified by flash chromatography (hexanes) and
4.6.7. 5-[3-(4-Methoxyphenyl)-4,5-dimethylfuran-2-yl]-
hexanenitrile (10be). Prepared from 7b and 12g with the
following modification. The reaction mixture after the SmI2
treatment was worked-up to isolate alcohol 7b, as described
above. Crude 7b was then reacted with 12g, Pd(PPh3)4 and
Et3N according to the general procedure. The crude product
was purified by flash chromatography (90:8:2 hexanes/
1
HPLC (90:10 hexanes/EtOAc, 4 mL/min, tR¼55 min): H
NMR d 1.92–2.00 (m, 5H), 1.92 (s, included in m at 1.92–
2.00), 2.26 (s, 3H), 2.58–2.72 (m, 7H), 2.64 (s, included in
m at 2.58–2.72), 7.11–7.33 (m, 7H), 7.99 (d, J¼8.1 Hz,
2H); 13C NMR d 9.1, 11.4, 25.9, 26.5, 30.2, 35.2, 113.4,
122.0, 125.7, 128.2, 128.4, 128.4, 129.2, 134.9, 139.5,
141.8, 145.8, 149.8, 197.7; IR (neat) n 3026 (vC–H, w),
2923 (C–H, m), 1683 (CvO, s), 1606 (CvC, s), 1268
(C–O–C, s) cm21; HRMS calcd for C23H24O2 332.1776,
found 332.1771.
1
EtOAc/Et3N): H NMR d 1.25 (d, J¼6.9 Hz, 3H), 1.41–
1.82 (m, 7H, that includes s at 1.82), 2.11 (t, J¼7.0 Hz, 2H),
2.22 (s, 3H), 2.72–2.83 (m, 1H), 3.84 (s, 3H), 6.93 (d,
J¼8.7 Hz, 2H), 7.12 (d, J¼8.7 Hz, 2H); 13C NMR d 8.9,
11.5, 16.7, 20.4, 23.5, 30.5, 34.6, 55.2, 113.8, 114.0, 119.7,
126.2, 130.5, 145.2, 151.0, 158.3; IR (neat) n 2940–2810
(C–H, m), 2210 (CuN, w), 1570 (ArC–C, m), 1500 (ArC–
H, s), 1270 and 1240 (C–O, m) cm21; HRMS calcd for
C19H23NO2 297.1729, found 297.1732.
4.6.12. 3-(4-Bromophenyl)-2-[3-(3,4-dimethoxyphenyl)-
propyl]-4-isobutyl-5-isopropylfuran (10d). Prepared
from 7d and 12d. The crude product was purified by flash
1
chromatography (98:2 hexanes/EtOAc): H NMR d 1.44
4.6.8. 5-(4,5-Dimethyl-3-thiophen-2-ylfuran-2-yl)hexane-
nitrile (10bf). Prepared from 7b and 12h or 12i. The crude
product was purified by flash chromatography (95:5
hexanes/EtOAc) and HPLC (95:5 hexanes/EtOAc, 8 mL/
min, tR¼30 min): 1H NMR d 1.27 (d, J¼6.9 Hz, 3H), 1.46–
1.92 (m, 7H), 1.92 (s, included in m at 1.46–1.92), 2.16–
2.22 (m, 5H), 2.99–3.08 (m, 1H), 6.89 (d, J¼2.4 Hz, 1H),
7.06–7.09 (dd, J¼5.0, 3.6 Hz, 1H), 7.29 (d, J¼5.1 Hz, 1H);
13C NMR d 9.0, 11.4, 16.8, 20.1, 23.4, 30.8, 34.4, 114.1,
115.7, 119.6, 124.7, 125.9, 127.2, 134.8, 145.6, 152.5; IR
(neat) n 3106 (vC–H, m), 2925 (C–H, s), 2246 (CuN, m),
1596 (ArC–C, m) cm21; HRMS calcd for C16H19NOS
273.1187, found 273.1186.
(d. J¼6.5 Hz, 6H), 1.26–1.42 (m, 7H), 1.28 (d, J¼6.9 Hz,
included in m at 1.26–1.42), 1.83–1.95 (m, 2H), 2.21 (d,
J¼7.3 Hz, 2H), 2.48–2.60 (m, 4H), 2.99 (q, J¼6.9 Hz, 1H),
3.86 (s, 6H), 6.61–6.77 (m, 3H), 7.09 (d, J¼8.3 Hz, 2H),
7.48 (d, J¼8.3 Hz, 2H); 13C NMR d 21.7, 22.3, 25.6, 25.9,
28.6, 30.4, 32.5, 34.7, 55.7, 55.8, 110.9, 111.5, 115.6, 120.1,
120.2, 121.1, 131.1, 131.3, 133.9, 134.7, 146.9, 148.6,
149.0, 154.2; IR (neat) n 2955 (C–H, s), 1515 (ArC–C, s),
1032 (C–O–C, m) cm21; HRMS calcd for C28H3579BrO3
498.1770, found 498.1765; HRMS calcd for C28H3581BrO3
500.1749, found 500.1764.
4.6.13. 3-(4-Bromophenyl)-4-methyl-2-(3-phenylpropyl)-
furan (10e). Prepared from 7e and 12d with the following
modification. The solution of 7e in THF was added
dropwise to SmI2 (,0.1 M in THF, 3 equiv. with respect
to 7e) at 10 8C and the mixture was stirred for 20 min at the
same temperature. It was then proceeded according to the
general procedure. The crude product was purified by flash
chromatography (hexanes) and HPLC (hexanes, 7 mL/min,
4.6.9. 5-(4,5-Dimethyl-3-thiophen-3-ylfuran-2-yl)hex-
anenitrile (10bg). Prepared from 7b and 12j. The crude
product was purified by flash chromatography (95:5
hexanes/EtOAc) and HPLC (95:5 hexanes/EtOAc, 8 mL/
min, tR¼30 min): 1H NMR d 1.26 (d, J¼6.9 Hz, 3H), 1.41–
1.83 (m, 4H), 1.88 (s, 3H), 2.14 (t, J¼7.0 Hz, 2H), 2.22 (s,
3H), 2.82–2.96 (m, 1H), 7.00–7.07 (m, 2H), 7.35–7.38 (m,
1H); 13C NMR d 9.0, 11.5, 16.7, 20.2, 23.5, 30.8, 34.5,
113.8, 117.7, 119.7, 121.9, 125.3, 128.5, 133.9, 145.4,
151.5; IR (neat) n 3105 (vC–H, m), 2925 (C–H, s), 2246
(CuN, m), 1599 (ArC–C, w) cm21; HRMS calcd for
C16H19NOS 273.1187, found 273.1198.
1
tR¼31 min): H NMR d 1.88–2.05 (m, 5H), 1.95 (s, inclu-
ded in m at 1.88–2.05), 2.48–2.65 (m, 4H), 7.06–7.49 (m,
8H), 7.51 (d, J¼7.5 Hz, 2H); 13C NMR d 9.0, 25.9, 30.0,
35.1, 119.1, 120.5, 121.3, 125.8, 128.3, 128.4, 130.9, 131.5,
132.6, 137.6, 141.8, 152.2; IR (neat) n 3027 (vC–H, w),
2931 (C–H, s), 1799 (s), 1760 (s), 1115 (C–O, m) cm21
;
HRMS calcd for C20H1979BrO 354.0619, found 354.0618;
HRMS calcd for C20H1981BrO 356.0599, found 356.0596.
4.6.10. 5-(4,5-Dimethyl-3-pyridin-3-ylfuran-2-yl)hexane-

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J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4147
4.6.14. 4-Hydroxy-5-iodo-4-methyl-1-(2-phenylethyl)-
pent-2-ynyl benzoate (14). Obtained from 7e in 35%
yield when the reduction step with SmI2 was performed
according to the unmodified general procedure: 1H NMR d
1.69 (s, 3H), 2.15–2.37 (m, 2H), 2.60 (s, 1H), 2.91 (t,
J¼7.1 Hz, 2H), 3.44 (d, J¼10.1 Hz, 1H), 3.52 and 3.53 (2 d,
J¼10.1 Hz, 1H), 5.66 (t, J¼6.5 Hz, 1H), 7.19–7.38 (m,
5H), 7.44–7.50 (m, 2H), 7.57–7.63 (m, 1H), 8.04–8.07 (m,
2H); 13C NMR d 20.3, 20.4, 27.8, 31.3, 36.2, 63.8, 66.5,
81.5, 87.1, 126.1, 128.4, 128.4, 128.5, 129.7, 129.8, 133.2,
140.6, 165.4; IR (neat) n 3438 (O–H, m), 1721 (CvO, s),
1287 (C–O, m), 712 (C–I, m) cm21; HRMS calcd for
C21H21IO3 448.0535, found 448.0533.
product was purified by flash chromatography (hexanes) and
1
HPLC (90:10 hexanes/EtOAc, 8 mL/min, tR¼35 min): H
NMR d 1.84–2.19 (m, 6H), 2.54–2.56 (m, 2H), 2.73–2.88
(m, 6H), 7.23–7.51 (m, 10H); 13C NMR d 21.8, 23.0, 23.2,
26.0, 30.4, 35.3, 116.8, 121.0, 125.6, 126.1, 128.1, 128.3,
128.4, 128.7, 134.0, 142.0, 148.7, 149.4; IR (neat) n 3026
(vC–H, m), 2932 (C–H, m), 1605 (ArC–C, s) cm21
;
HRMS calcd for C23H24O 316.1827, found 316.1821. This
product decomposes rapidly in the absence of solvent.
4.6.19. 3-(4-Acetylphenyl)-2-(3-phenylpropyl)-4,5,6,7-
tetrahydrobenzofuran (10hb). Prepared from 7h and
12c. The crude product was purified by flash chroma-
tography (95:5 hexanes/EtOAc) and HPLC (97:3 hexanes/
EtOAc, 10 mL/min, tR¼60 min): 1H NMR d 1.73–2.09 (m,
6H), 2.44–2.46 (m, 2H), 2.64–2.77 (m, 9H), 2.64 (s, inclu-
ded in m at 2.64–2.77), 7.13–7.36 (m, 7H), 7.97 (d, J¼
8.5 Hz, 2H); 13C NMR d 21.8, 22.8, 23.1, 26.1, 30.2, 35.2,
116.5, 120.3, 125.7, 128.2, 128.4, 128.5, 128.5, 134.7,
139.3, 141.7, 149.2, 150.3, 197.6; IR (neat) n 3026 (vC–H,
w), 2931 (C–H, m), 1686 (CvO, s), 1605 and 1582 (ArC–
H, s), 1266 (C–O–C, s) cm21; HRMS calcd for C25H26O2
358.1932, found 358.1922. This product decomposes
rapidly in the absence of solvent.
4.6.15. 5-[3-(4-Acetylphenyl)-5-methoxymethoxymethyl-
4-methylfuran-2-yl]hexanenitrile (10f). Prepared from 7f
and 12c. The crude product was dissolved in EtOAc
(125 mL/mmol, based on 7f) and AcOH was added until
pH¼5. The solution was washed with water and the aqueous
layer was back-extracted with EtOAc. The residue after
evaporation was purified by flash chromatography (70:30
hexanes/EtOAc): 1H NMR d 1.28 (d, J¼6.9 Hz, 3H), 1.42–
1.90 (m, 4H), 1.97 (s, 3H), 2.15 (t, J¼7.1 Hz, 2H), 2.64 (s,
3H), 2.80–2.89 (m, 1H), 3.43 (s, 3H), 4.53 (s, 2H), 4.70 (s,
2H), 7.31 (d, J¼7.9 Hz, 2H), 7.96 (d, J¼7.0 Hz, 2H); 13C
NMR d 8.8, 16.9, 20.0, 23.4, 26.6, 31.0, 34.5, 55.3, 58.9,
95.2, 119.0, 119.5, 122.4, 128.6, 129.6, 135.6, 138.6, 145.6,
154.3, 197.7; IR (neat) n 2930 (C–H, s), 2100 (CuN, m),
Acknowledgements
1681 (CvO, s), 1606 (CvC, m), 1034 (C–O, m) cm21
;
´
Financial support by the Ministerio de Ciencia y Tecnologıa
(BQU2000-01354) and by the Universidad del Paıs Vasco
HRMS calcd for C22H27NO4 369.1940, found 369.1936.
´
(170.310-EB001/99, 9/UPV00041.310-14471/2002 and
Fellowship to E.P) is gratefully acknowledged.
4.6.16. 3-(4-Bromophenyl)-5-methoxymethoxymethyl-4-
methyl-2-(3-phenylpropyl)furan (10ga). Prepared from
7g and 12d. The crude product was purified by flash
chromatography (95:5 hexanes/EtOAc) and HPLC (86:14
1
hexanes/EtOAc, 7 mL/min, tR¼23 min): H NMR d 1.59–
References and notes
2.01 (m, 5H), 1.97 (s, included in m at 1.59–2.01), 2.54–
2.65 (m, 4H), 3.43 (s, 3H), 4.53 (s, 2H), 4.71 (s, 2H), 7.05–
7.49 (m, 7H), 7.51 (d, J¼2.0 Hz, 2H); 13C NMR d 8.9, 25.8,
30.0, 35.2, 55.3, 58.9, 95.2, 119.1, 120.7, 122.0, 125.8,
128.2, 128.4, 131.0, 131.5, 132.5, 141.7, 145.1, 151.8; IR
(neat) n 3027 (vC–H, w), 2926 (C–H, s), 1602 (ArC–C,
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w), 1034 (C–O–C, m) cm21
; HRMS calcd for
C23H2579BrO3 428.0987, found 428.0986; HRMS calcd
for C23H2581BrO3 430.0967, found 430.0976.
4.6.17. 4-(4-Acetylphenyl)-2-methoxymethoxymethyl-3-
methyl-5-(3-phenylpropyl)furan (10gb). Prepared from
7g and 12c. The crude product was purified by flash
chromatography (95:5 hexanes/EtOAc) and HPLC (86:14
1
hexanes/EtOAc, 9 mL/min, tR¼60 min): H NMR d 1.91–
2.03 (m, 5H), 2.01 (s, included in m at 1.91–2.03), 2.56–
2.69 (m, 7H), 2.63 (s, included in m at 2.56–2.69), 3.43 (s,
3H), 4.54 (s, 2H), 4.71 (s, 2H), 7.08–7.32 (m, 7H), 7.97 (d,
J¼8.3 Hz, 2H); 13C NMR d 9.0, 26.0, 26.6, 29.9, 35.2, 55.3,
58.8, 95.2, 119.0, 122.2, 125.7, 128.2, 128.4, 128.5, 129.4,
135.2, 138.8, 141.6, 145.3, 152.3, 197.7; IR (neat) n 3026
(vC–H, w), 2928 (C–H, s), 1686 (CvO, s), 1607 (CvC,
s), 1033 (C–O, m) cm21; HRMS calcd for C25H28O4
392.1988, found 392.1993.
4.6.18. 3-Phenyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydro-
benzofuran (10ha). Prepared from 7h and 12a. The crude

´
J. M. Aurrecoechea, E. Perez / Tetrahedron 60 (2004) 4139–4149
4148
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3. For the use of allylic halides and carbonates, see:
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present in the medium, could facilitate the formation of
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strong electron-donating substituent is present in Ar.11h
1
15. The presence of dienes 13 was also observed in the crude H
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18. This mechanism is the logical extension of our earlier proposal
for formation of furans X,6 where an intermediate analogous to
vinylpalladium XIV is presumably trapped by a proton. At this
point we cannot rule out an alternative mechanism where
regioselective carbopalladation of the central triene double
bond8 is followed by bond rotation, oxapalladacycle forma-
tion1e,16i and reductive elimination. However, the necessary
regioselectivity of the carbopalladation step on an unsym-
metrical triene 9 would be difficult to justify in that case.
19. The synthesis of simple penta-2,3,4-trien-1-ols has been
previously reported by reaction of enynyloxiranes with
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C
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