Synthesis of benzofurans through coupling of dienylacetylenes with carbene complexes: Total synthesis of egonol

Article abstract of DOI:10.1016/S0040-4020(03)00823-8

The reaction of various carbene complexes with dienylacetylenes has been examined. The reaction has been used as the cornerstone for the preparation of the nor-neolignan natural product egonol in five steps from readily available components. In most examples of the carbene-alkyne coupling, the reaction proceeds to form benzofuran derivatives. In the case of one highly functionalized terminal alkyne, a competing rearrangement/cyclization process occurs in preference to the carbene coupling process. The use of silylated alkynes subverts this process.

Full text of DOI:10.1016/S0040-4020(03)00823-8

Tetrahedron 59 (2003) 5609–5616
Synthesis of benzofurans through coupling of dienylacetylenes
with carbene complexes: total synthesis of egonol
*
Jianwei Zhang, Yi Zhang, Yanshi Zhang and James W. Herndon
Department of Chemistry and Biochemistry, New Mexico State University, MSC 3C, Las Cruces, NM 88003, USA
Received 11 November 2002; revised 10 January 2003; accepted 16 January 2003
Abstract—The reaction of various carbene complexes with dienylacetylenes has been examined. The reaction has been used as the
cornerstone for the preparation of the nor-neolignan natural product egonol in five steps from readily available components. In most
examples of the carbene–alkyne coupling, the reaction proceeds to form benzofuran derivatives. In the case of one highly functionalized
terminal alkyne, a competing rearrangement/cyclization process occurs in preference to the carbene coupling process. The use of silylated
alkynes subverts this process. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
furan ring.6 Numerous benzofuran-containing natural
products have been efficiently synthesized according to
these methods. The synthesis of benzofurans using the
reactions in Scheme 1 involves the simultaneous construc-
tion of both rings in a single reaction process.
In a series of papers the formation of benzo- and
naphthofurans (e.g. 5, Scheme 1) from the coupling of
highly conjugated acetylene derivatives (e.g. 2) with
carbene complexes (e.g. 1) has been demonstrated.1
Reactions employing conjugated dienylacetylenes proceed
via formation of a vinylketene (3), cyclization to the
corresponding phenol derivative (4), and cyclization to the
benzofuran derivative (5). Reactions employing conjugated
enediynes (e.g. 6) proceed through formation of a ketene (7)
and generation of a chromium-complexed diradical (8),2
followed by various intra- or intermolecular hydrogen
abstraction reactions. In the example depicted in Scheme 1,
the same benzofuran products are produced in comparable
yield from the reaction of dienynes with carbene complexes
or reaction of the corresponding enediyne with carbene
complexes in the presence of 1,4-cyclohexadiene.1b
The benzofuran ring system is a common structural element
that appears in a large number of medicinally important
compounds.3 Benzofuran neolignans and nor-neolignans,
which are contained in most plants, have attracted much
attention in medicinal chemistry for their various biological
activities, including insecticidal, fungicidal, antimicrobial
and antioxidant properties.4 The most common synthetic
strategy employed for benzofuran synthesis is the annula-
tion of a furan ring onto a pre-existing benzene ring through
Sonogashira coupling followed by palladium-catalyzed
cyclization5 or through benzannulation onto a preexisting
Keywords: carbene complexes; benzofuran; Sonogashira coupling;
conjugated alkynes.
*
Corresponding author. Tel.: þ1-5056-462-487; fax: þ1-5056-462-649;
e-mail: jherndon@nmsu.edu
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00823-8

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J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
not a competing process; the cyclization selectivity was
attributed to preferential complexation and cyclization at
the non-oxygenated vinylketene ligand.1c At the inception
of these studies, routes using dienyne 11 and an enediyne
were both considered. Because of a report from the
Liebeskind group that attempts to prepare methoxy-
acetylene were usually accompanied by fires,14 the dienyne
route was employed. In this manuscript the successful
formal total synthesis of egonol is reported and several
interesting observations concerning the properties of highly
functionalized dienyne systems are reported.
2. Results and discussion
2.1. Synthesis of trienyne derivatives
The synthesis of trienyne 11 and related compounds is
depicted in Scheme 4. In the synthesis of known iodo-
alcohol 13, a larger excess of allylic Grignard reagent was
used relative to that previously reported8 and the yield was
slightly improved (51%). In addition to the desired
compound, a substantial amount of product assigned as
the diiodo compound 17 was also observed.15 Sonogashira
coupling of compound 13 and trimethylsilylacetylene
followed by Swern oxidation afforded trienyne-aldehyde
18 in 66% yield. Wittig reaction and desilylation yielded
Scheme 2.
In order to demonstrate the synthetic utility of this reaction,
efforts to synthesize the nor-neolignan natural product
egonol (9, Scheme 2) have been undertaken.7 The retro-
synthetic analysis for this compound is depicted in
Scheme 2. In theory, the readily-available iodo-alcohol
derivative 138 can be transformed to benzofuran derivative
10, a known egonol precursor.7a,e Compound 10 is itself a
naturally-occurring compound, isolated from the wood of
anaxagorea clavata.9 Egonol and related compounds have
been evaluated as antibacterial10 and anticancer agents.11
The proposed synthetic route poses three major challenges
(Scheme 3): (1) highly conjugated enol ether derivative 11
¨
is likely unstable, (2) the Dotz reaction (formation of
naphthol 15, Scheme 3) can compete with the desired
benzofuran-forming process,12 and (3) the enol ether can
undergo cyclization at the ketene carbon in intermediate 14
(resulting in 16) as has been observed with related enamine
intermediates.13 In a related system the Dotz reaction was
¨
Scheme 3.
Scheme 4.

J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
5611
trienyne 11. In addition to the dienyne required for the
synthesis of egonol, the ester analogs 20 and 21 were also
prepared. The successful synthetic route to the trienynes in
Scheme 4 required considerable yield optimization and
some interesting undesirable side reactions were noted
during the optimization process. If the Swern oxidation was
performed prior to the Sonogashira coupling, the opposite
alkene isomer (Z) of aldehyde 18 was obtained, presumably
due to isomerization of the intermediate b-iodo-a,b-
unsaturated aldehyde. It was also noted that the Wittig
reaction for the synthesis of the enol ether 19 was very
sensitive with respect to double bond isomerization. If the
temperature, reaction time, and amount of base (PhLi) are
not carefully controlled, the major product of this Wittig
reaction appears to be the product where the isolated alkene
moves into conjugation.
NMR spectrum showed that the a,b-unsaturated ester had
survived the reaction, while the allyl group was consumed.
The major product of this reaction was identified as
cinnamate ester 22 (Scheme 5), indicating failure of the
carbene-alkyne coupling. It was found that above 35–408C,
trienyne 21 cyclized to cinnamate ester 22. Two
mechanisms for the conversion of 21 to 22 are likely and
differ with regard to the origin of the methyl group attached
to the aromatic ring of 22. The first mechanism involves 1,5-
hydrogen shift to generate allene 24, which could undergo
electrocyclic ring closure to give intermediate 25 and 22
after a hydrogen shift. A similar mechanism was proposed
for cyclization of propargylindole derivatives.16 Alterna-
tively, conjugation of the terminal alkene (affording 26)
followed by rearrangement could also afford 22.17 Inter-
mediates similar to 27 have been suggested in the enyne-
Diels–Alder reaction.18 The compound where the alkyne
hydrogen is replaced by deuterium afforded compound
22-D1, featuring a deuterium in the methyl group, which is
consistent with the first mechanism.
2.2. Coupling of carbene complexes and trienynes
The coupling of dienyne 11 with carbene complex 12
afforded a complex reaction mixture. The proton NMR of
the crude reaction mixture showed no evidence of an intact
allyl group as expected for benzofuran derivative 10, and the
integration for methoxy groups of the proton NMR
spectrum was small compared with the aromatic signals.
In order to test the efficacy of the cyclization reaction, ester
21 was tested in its reaction with carbene complex 12;
compounds similar to 21 have been successfully converted
to benzofurans.1b Coupling of trienyne 21 and carbene
complex 12 did not lead to a benzofuran either. The crude
The ease of this apparently thermal cyclization was
unexpected. The successful example of benzofuran for-
mation involving a dienyne ester in Ref. 1b differs from 21
in that the substrate was an internal alkyne lacking the extra
alkene functionality of compound 21. Due to previous
successes using an internal alkyne, the coupling reaction of
silylated starting material 20 was examined (Scheme 6).
This reaction afforded the desilylated benzofuran derivative
29 in 40% yield. The crude reaction mixture was treated
with iodine prior to isolation of the final product to effect
benzofuran formation and destroy arene complexes. Prior to
iodine treatment, the likely product is ketal 28,1c which then
loses TMSOMe upon treatment with iodine.
2.3. Synthesis of egonol precursor 10
The success of benzofuran ring formation in the above
reaction suggests that use of silylated methoxydienyne 19 is
likely to provide egonol precursor 10 (Scheme 7). The
coupling reaction in dioxane at 60–708C in fact afforded the
desired compound 10 in 47% yield accompanied by the
carbene oxidation product 31 in 10–20% yield. Longer
reaction times and/or higher temperatures led to the isomers
where the alkene is conjugated. Hydroboration of 10 has
been reported to provide egonol.7a,e
Scheme 5.
Scheme 6.

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J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
All reactions were performed in an inert atmosphere created
by a slight positive pressure (ca. 0.1 psi) of nitrogen.
4.1.1. Synthesis of carbene complex 12. To a solution of
4-bromo-1,2-(methylenedioxy)benzene (2.00 g, 9.948 mmol)
in diethyl ether (30 mL) was added n-butyllithium (6.2 mL
of 1.6 M hexane solution, 9.948 mmol) dropwise under
nitrogen at 2788C. Then the mixture was stirred at 08C for
an additional 10 min, and was added directly to a suspension
of chromium hexacarbonyl (2.189 g, 9.948 mmol) in diethyl
ether (140 mL) at 08C under nitrogen over a period of
15 min. The reaction mixture was allowed to warm to room
temperature. Methyl trifluoromethanesulfonate (1.2 mL,
1.06 mmol) was added to the mixture at 08C, and stirring
was continued for an additional 2 h. The resulting deep red
solution was poured into saturated aqueous sodium
bicarbonate solution in a separatory funnel and then
extracted with 2:1 hexane/ethyl acetate (3£35 mL). The
organic layer was washed with water and saturated aqueous
sodium chloride solution successively. After drying over
magnesium sulfate, the solvent was removed on a rotary
evaporator. Purification by flash chromatography on silica
gel using 1:9 and then 1:4 ethyl acetate/hexane as the eluent
afforded carbene complex 12 as a red solid (1.725 g,
4.846 mmol, 49%). 1H NMR (CDCl3): d 7.36 (d, 1H,
J¼6.0 Hz), 7.03 (s, 1H), 6.96 (d, 1H, J¼6.0 Hz), 6.03 (s,
2H), 4.81 (s, 3H); 13C NMR (C6D6): d 341.6, 224.1, 217.2,
151.4, 148.0, 125.4, 107.7, 105.1, 101.9, 69.6; IR (neat):
2058 (m), 1941 (vs) cm21; MS (FAB): m/e 356 (M, 16), 328
(28), 300 (42), 272 (20), 244 (66), 216 (36), 149 (100);
HRMS calcd for C14H8O8Cr 355.96243, found 355.96350.
Scheme 7.
3. Conclusion
The nor-neolignan egonol has been formally synthesized in
five steps from readily available components. Synthesis of
benzofuran derivatives by this highly convergent route does
not require the convenient availability of an appropriate
aromatic ring for elaboration to the benzofuran, a strategy
employed in all previous syntheses of egonol (9) and
intermediate 10,7 and thus the method is amenable to the
preparation of wide variety of structurally related
benzofurans.
4.1.2. Improved synthesis of alcohol 13 (Z)-2-(iodo-
methylidene)-4-penten-1-ol.8 (1) Preparation of allyl-
magnesium bromide. In a two neck flask fitted with a
condenser and a dropping funnel was placed magnesium
turnings (10.0 g, 412 mmol), dry ether (30 mL), and two
crystals of iodine. A solution of allyl bromide (12.44 g,
102.9 mmol) in dry ether (110 mL) was added in small
portions until the reaction began, and then kept adding at
such a rate as to maintain gentle reflux of ether. The addition
required about 1.5 h, after which the reaction mixture was
refluxed on a heating metal for an additional hour. The
freshly prepared allylmagnesium bromide ether solution
was used immediately in the next step. (2) Coupling of
propargyl alcohol and allylmagnesium bromide. A suspen-
sion of dry copper (I) iodide (0.476 g, 2.50 mmol) in a
solution of propargyl alcohol (1.423 g, 25.00 mmol) in ethyl
ether (30 mL) was vigorously stirred and cooled at 2108C
as allylmagnesium bromide (140 mL of 0.64 M ether
solution, 90 mmol) was added. After completion of the
addition, the mixture was stirred for at least 2 h at room
temperature. A saturated solution of iodine (8.765 g,
34.00 mmol) in ether (50 mL) was then added at 2788C
(the first half portion was decolorized) and the mixture was
allowed to warm to room temperature. After 1 h, ice was
added to the mixture, which was then mixed with a saturated
sodium thiosulfate solution (30 mL) and extracted two times
with ether. The organic phases were washed with saturated
sodium chloride solution, dried over sodium sulfate, filtered
through Celite and concentrated. The residue was purified
by flash chromatography on a silica gel column with 4:1
hexane/ethyl acetate as eluent. Alcohol 13 (2.90 g, 51%)
4. Experimental
4.1. General
Nuclear Magnetic Resonance (1H and 13C) spectra were
recorded on a Varian 200 or 400 MHz spectrometer.
Chemical shifts are reported in parts per million (d)
downfield from the reference tetramethylsilane. Coupling
constants (J) are reported in hertz (Hz). The following
symbols have been used to indicate multiplicities: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet).
A Nicolet 5DXC FT-IR spectrometer was used to record the
infrared spectra and band positions are reported in
reciprocal centimeters (cm21). Band intensities are reported
relative to the most intense band. C–H stretching frequen-
cies in the region 2800–3100 cm21 are not reported. Mass
spectra (MS) were acquired at MS facilities at the
University of California-Riverside or the University of
Maryland; m/e values are reported, followed by the relative
intensity in parentheses. Flash column chromatography was
performed using thick walled glass columns and ‘flash
grade’ silica. Thin layer chromatography was done using
precoated 0.25 mm silica gel plates purchased from SAI
Adsorbents. The relative proportion of solvents in mixed
chromatography solvents refers to the volume/volume ratio.
All commercially available reagents were in reagent grade
and used without purification. Diethyl ether, THF and
dioxane were distilled from sodium benzophenone ketyl.

J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
5613
1
was obtained as an oil. H NMR (CDCl3): d 6.07 (s, 1H),
4.1.5. Synthesis of trienyne 19. To a suspension of
(methoxymethyl)triphenylphosphonium chloride (0.486 g,
1.417 mmol) in ether (12 mL) was added phenyllithium
(0.75 mL of 1.8 M cyclohexane/ether solution, 1.350 mmol)
at 2788C dropwise over a 10 min period. The resulting
yellow mixture was then warmed to room temperature and
stirred for an additional 20 min. A solution of enyne
aldehyde 18 (0.147 g, 0.766 mmol) in ether (8 mL) was
added slowly at 08C, and then the mixture was stirred
overnight. After the reaction was complete, saturated
ammonium chloride solution (10 mL) was added and the
precipitate dissolved. The reaction mixture was extracted
three times with diethyl ether, washed with sodium
bicarbonate solution, and dried over sodium sulfate.
Evaporation of the solvent and purification by flash column
chromatography (silica gel, 50:1 hexane/ethyl acetate) gave
trienyne 19 (0.153 g, 0.694 mmol, 91% yield) as a yellow
oil. This compound contains a cis and a trans isomer and a
single impurity identified as biphenyl (3–5 mol%), which
could not be efficiently separated; the ratio appears to be
0.8:1 cis/trans. These chromatographic conditions were
optimal; slower eluting solvent systems separated out
biphenyl but afforded significant amounts of aldehydic
5.90–5.70 (m, 1H), 5.20–5.00 (m, 2H), 4.24 (s, 2H), 3.10–
3.00 (m, 2H); 13C NMR (CDCl3): d 147.8, 134.4, 117.3,
77.1, 66.4, 39.2; IR (neat) 3600–3100 cm21. The spectral
data were in agreement with those reported previously for
this compound.8 The major byproduct (never obtained free
of alcohol 13) was tentatively identified as diiodo alcohol 17
1
based on its H NMR spectrum and its ability to undergo
Sonogashira coupling.19 1H NMR (CDCl3): d 5.90–5.70 (m,
1H), 5.20–5.05 (m, 2H), 4.30 (s, 2H), 3.06 (d, 2H,
J¼6.8 Hz), 1.62 (br s, 1H).
4.1.3. Synthesis of Z 2-(2-propen-1-yl)-5-trimethylsilyl-2-
penten-4-yn-1-ol. A mixture of palladium (II) chloride
(0.053 g, 0.30 mmol) and triphenylphosphine (0.158 g,
0.60 mmol) in diethylamine (30 mL) was stirred at room
temperature for 10 min, then (Z)-2-(iodomethylidene)-4-
penten-1-ol (13) (2.270 g, 10.05 mmol) in diethylamine
(30 mL) was added. After this mixture was stirred for
10 min, copper iodide (0.115 g, 0.60 mmol) and then
trimethylsilylacetylene (1.186 g, 12.06 mmol) were added.
After 20 h of stirring at room temperature, the solvent was
removed on a rotary evaporator. The residue was extracted
with hexane and filtered through Celite. The hexane solution
was washed with water, dried over sodium sulfate, and the
solvent was removed on a rotary evaporator. The residue
was purified by flash chromatography on silica gel using 9:1
hexane/ethyl acetate as eluent. The enyne alcohol (1.344 g,
1
impurities. H NMR (CDCl3): d 6.89 (d, 1H, J¼13.2 Hz,
trans isomer), 6.17 (d, 1H, J¼13.2 Hz, trans isomer), 5.99
(d, 1H, J¼6.0 Hz, cis isomer), 5.90–5.77 (m, 1H, common
to both isomers), 5.55 (d, 1H, J¼6.0 Hz, cis isomer), 5.22–
4.95 (m, 3H, common to both isomers); 3.68 (s, 3H, one
isomer) 3.65 (s, 3H, one isomer), 3.18 (d, 2H, J¼6.0 Hz, one
isomer) 2.94 (d, 1H, J¼6.0 Hz, one isomer), 0.18 (s, 9H,
common to both isomers); 13C NMR: (CDCl3): d 152.2,
149.5, 149.3, 148.0, 136.6, 135.6, 117.1, 115.1, 105.2,
104.5, 104.3, 104.1, 103.8, 103.6, 100.0, 99.6, 56.5, 56.4,
40.1, 36.7, 0.3, 20.2; IR (neat): 2123 (m), 1639 (s), 1629
(s) cm21. This compound was used immediately for
subsequent reactions.
1
69%) was obtained as a yellow oil. H NMR (CDCl3): d
5.77 (ddt, 1H, J¼17.6, 9.5, 6.0 Hz), 5.43 (s, 1H), 5.10 (d,
1H, J¼17.6 Hz), 5.08 (d, 1H, J¼9.5 Hz), 4.35 (d, 2H,
J¼6.0 Hz), 2.92 (d, 2H, J¼6.0 Hz), 1.88 (t, 1H, J¼6.0 Hz),
0.17 (s, 9H); 13C NMR (CDCl3): d 153.9, 134.9, 117.9,
107.5, 101.699.8, 63.1, 38.4, 0.1; IR (neat): 3300–3700 (s),
2127 (w) cm21; MS (EI): m/e 194 (M, 2), 179 (19), 161 (5),
153 (34), 125 (18), 99 (13), 75 (100); HRMS calcd for
C11H18OSi 194.11269, found 194.11348.
4.1.6. Synthesis of trienyne 11. To a solution of silylated
trienyne 19 (0.195 g, 0.89 mmol) in THF (10 mL) at room
temperature was added tetrabutylammonium fluoride
(1.77 mL of a 1 M THF solution, 1.77 mmol). The mixture
was stirred for 30 min at room temperature and poured into
1 M aqueous hydrochloric acid. The aqueous layer was
extracted three times with pentane. The combined pentane
extracts were washed with saturated aqueous sodium
bicarbonate solution, dried over sodium sulfate, and the
solvent was removed on a rotary evaporator. Final
purification was achieved by flash chromatography on silica
gel using 50:1 hexane/ethyl acetate as eluent. Trienyne 11
(0.124 g, 99%) was obtained as a yellow oil. This mixture
contains the cis and trans isomers in a 57:43 ratio, and they
could not be separated via column chromatography.
Numerous alkene-containing baseline impurities are visible
in this spectrum.
4.1.4. Synthesis of enyne aldehyde 18. To a solution of dry
oxalyl chloride (1.339 g, 10.59 mmol) in dichloromethane
(50 mL) at 2788C was added dimethyl sulfoxide (1.674 g,
21.46 mmol). After stirring for 10 min, a solution of the
enyne-alcohol from the previous experiment (1.344 g,
6.92 mmol) was added. After stirring for 1 h at 2788C,
triethylamine (3.499 g, 34.60 mmol) was added. The
reaction mixture was stirred for 15 min at 2788C and then
allowed to warm to room temperature and stirred for an
additional 1 h. The reaction mixture was poured into water
and extracted three times with diethyl ether. The combined
ether extracts were washed successively with 1% aqueous
hydrochloric acid, water, and 1% aqueous sodium
bicarbonate and then dried over sodium sulfate. The
solvent was removed on a rotary evaporator. The residue
was used in the next reaction without additional
purification. Enyne aldehyde 18 (1.283 g, 6.676 mmol,
96% yield) was obtained as an orange oil. 1H NMR
(CDCl3): d 10.23 (s, 1H), 6.49 (s, 1H), 5.73 (ddt, 1H,
J¼16.6, 10.4, 6.6 Hz), 5.09 (d, 1H, J¼10.3 Hz), 5.08 (d, 1H,
J¼16.6 Hz), 2.97 (d, 1H, J¼6.6 Hz), 0.20 (s, 9H); 13C NMR
(CDCl3): d 191.4, 148.9, 133.7, 125.8, 117.9, 107.3, 98.7,
Compound 11. 1H NMR (CDCl3): d 6.77 (d, 1H, J¼12.8 Hz,
trans isomer), 6.02 (d, 1H, J¼6.0 Hz, cis isomer),
5.90–5.70 (m, 1H, common to both isomers), 5.81 (s, 1H,
cis isomer), 5.51 (d, 1H, J¼12.8 Hz, trans isomer), 5.17–
5.03 (m, 2H, common to both isomers), 4.75 (d, 1H,
J¼6.0 Hz, cis isomer), 3.64 (s, 3H, trans isomer), 3.59 (s,
3H, cis isomer), 3.30–3.10 (m, 3H, common to both
isomers).
32.5, 20.6; IR (neat): 2138 (w), 1676 (s), 1595 (m) cm21
.
This compound should be used immediately in the next
reaction.

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J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
4.1.7. Synthesis of trienyne 20. To a solution of methyl
(triphenylphosphoranylidene)acetate (0.640 g, 1.91 mmol)
in dichloromethane (20 mL) at 08C was added a solution of
enyne aldehyde 18 (0.283 g, 1.47 mmol) in dichloro-
methane (18 mL). After an additional 20 h stirring at room
temperature, the solvent was evaporated and the residue was
extracted three times with hexane. The combined hexane
solution was filtered through Celite. Evaporation of the
solvent and column chromatography (silica gel, hexane/
ethyl acetate¼9:1) gave dienyne 20 (0.360 g, 98% yield) as
a yellow oil. 1H NMR (CDCl3): d 7.93 (d, 1H, J¼16.0 Hz),
6.04 (d, 1H, J¼16.0 Hz), 5.86 (ddt, 1H, J¼16.0, 9.8,
6.5 Hz), 5.73 (s, 1H), 5.10 (d, 1H, J¼9.8 Hz), 5.08 (d, 1H,
J¼16.0 Hz), 3.76 (s, 3H), 3.00 (d, 2H, J¼6.5 Hz); 13C NMR
(CDCl3): d 167.3, 146.4, 141.4, 134.3, 120.3, 117.7, 116.4,
80.1, 77.8, 51.6, 36.5, 0.29; MS (EI): m/e 248 (M, 47), 233
(36), 208 (20), 207 (100), 203 (22), 201 (22), 176 (19), 116
(21), 115 (25), 89 (87), 76 (27), 74 (83), 59 (69), 41 (21);
HRMS calcd for C14H20O2Si 248.1233, found 248.1249.
aqueous hydrochloric acid. The aqueous layer was extracted
three times with pentane. The combined pentane extracts
were washed with saturated aqueous sodium bicarbonate
solution, dried over sodium sulfate, and the solvent was
removed on a rotary evaporator. Final purification was
achieved by flash chromatography on silica gel using 50:1
hexane/ethyl acetate as eluent. Cinnamate esters 22 and
dienyne 22-D1 were obtained as a pale oil (0.214 g, 50%) in
a 2:1 ratio; deuterium incorporation is about 33%. 1H NMR
(CDCl3): d 7.63 (d, 1H, J¼16.0 Hz), 7.34–7.12 (m, 4H),
6.38 (d, 1H, J¼16.0 Hz), 3.76 (s, 3H), 2.33 (s, 2.6H); 13C
NMR (CDCl3): d 167.3, 144.9, 138.4, 134.3, 130.9, 128.6,
125.1, 117.4, 111.6, 51.4, 29.6, 21.1, 21.0 (2 lines of 3-line
signal); MS (EI): 177 (M with 2H, 32), 176 (M with all 1H,
67), 175 (21), 161 (21), 146 (51), 145 (100), 118 (18), 117
(36), 116 (32), 115 (51), 92 (10), 91 (26); HRMS calcd for
C11H12O2 176.0837, found 176.0838; HRMS calcd for
C11H11DO2 177.0900, found 177.0896. Incorporation of
deuterium at the methyl group is indicated by the following
facts: (1) in the mass spectrum, the fragment ion at 161
(M2CH3)21 is not accompanied by a significant fragment
ion at 162, (2) the methyl group protons at d 2.33 integrate
for less than 3H’s, and (3) there appears to be additional
lines in the base of the peak at d 21.1 of the 13C NMR which
might be attributed to the deuterium-labeled material.
4.1.8. Synthesis of trienyne 21. To a solution of silylated
trienyne 20 (0.258 g, 1.04 mmol) in THF (10 mL) at room
temperature was added tetrabutylammonium fluoride
(2.07 mL of a 1 M THF solution, 2.07 mmol). The mixture
was stirred for 30 min at room temperature and poured into
1 M aqueous hydrochloric acid. The aqueous layer was
extracted three times with pentane. The combined pentane
extracts were washed with saturated aqueous sodium
bicarbonate solution, dried over sodium sulfate, and the
solvent was removed on a rotary evaporator. Final
purification was achieved by flash chromatography on silica
gel using 9:1 hexane/ethyl acetate as eluent. Trienyne 21
(0.178 g, 99%) was obtained as a pale yellow oil. The proton
NMR reveals that this sample is contaminated by aromatic
compound 22 (see Section 4 for 22 below). The ratio of
21:22 is 92:8 as determined by integration of the peaks for
the CH2 peak at d 3.01 in 21 relative to the ArCH3 peak at d
4.1.11. Coupling of carbene complex 12 with trienyne 20.
A solution of trienyne 20 (194 mg, 0.78 mmol) and carbene
complex 12 (334 mg, 0.93 mmol) in dioxane (20 mL) was
heated at reflux for 24 h. The reaction mixture was allowed
to cool to room temperature and the solvent was removed on
a rotary evaporator. Hexane was added and the resulting
green suspension was filtered through Celite. Iodine
(381 mg, 1.50 mmol) was added and the solution was
stirred at room temperature for 24 h. The reaction mixture
was poured into aqueous sodium thiosulfate solution in a
separatory funnel and the aqueous layer was extracted two
times with hexane. The combined hexane layers were
washed with saturated aqueous sodium chloride solution
and dried over sodium sulfate. The solvent was removed on
a rotary evaporator and final purification was achieved by
flash column chromatography on silica gel using 19:1
hexane/ethyl acetate as the eluent. Benzofuran 29 (0.104 g,
40% yield) was obtained as a yellow oil. This compound
1
2.33 in 22. H NMR (CDCl3) (only peaks for 21 listed): d
7.90 (d, 1H, J¼16.0 Hz), 6.06 (d, 1H, J¼16.0 Hz), 5.89–
5.66 (m, 1H), 5.70 (s, 1H), 5.15–5.02 (m, 2H), 3.76 (s, 3H),
3.40 (s, 1H), 3.01 (d, 2H, J¼6.0 Hz). This compound was
used immediately for subsequent reactions.
4.1.9. Formation of cinnamate ester 22; cyclization of
trienyne 21. The procedure for synthesizing dienyne 21 was
followed except for increasing the temperature in the
product concentration step to 408C. After column chroma-
tography (silica gel/9:1 hexane/ethyl acetate), a colorless oil
(0.060 g, 40%) identified as compound 22 was obtained. 1H
NMR (CDCl3): d 7.63 (d, 1H, J¼16.0 Hz), 7.34–7.12 (m,
4H), 6.38 (d, 1H, J¼16.0 Hz), 3.76 (s, 3H), 2.33 (s, 3H); 13C
NMR (CDCl3): d 167.3, 144.9, 138.4, 134.3, 130.9, 128.6,
125.1, 117.4, 111.6, 51.4, 21.1. The spectral data are in
agreement with those reported previously for this
compound.20
1
appears to be homogenous by NMR and TLC analysis. H
NMR (CDCl3): d 7.73 (s, 1H), 7.52 (s, 1H), 7.43 (d, 2H,
J¼8.0 Hz), 7.34 (s, 1H), 6.88 (d, 1H, J¼8.0 Hz), 6.81 (s,
1H), 6.01 (ddt, 1H, J¼16.0, 10.0, 6.2 Hz), 6.00 (s, 2H), 5.11
(m, 2H), 4.03 (s, 3H), 3.48 (d, 2H, J¼6.2 Hz); 13C NMR
(CDCl3): d 165.4, 156.8, 151.8, 148.0, 137.2, 134.4, 131.2,
126.7, 125.1, 124.1, 119.3, 115.9, 114.2, 108.5, 105.4,
101.2, 99.3, 52.0, 44.7, 39.6; MS (EI): 336 (M, 0), 248 (21),
233 (19), 207 (55), 203 (13), 201 (16), 175 (12), 173 (11),
145 (12), 116 (14), 115 (21), 91 (19), 89 (65), 83 (14), 76
(23), 74 (100), 59 (64), 41 (24). HRMS calcd for C20H16O5
336.0998, found 336.0994.
4.1.10. Formation of benzene derivative 22-D1; cycliza-
tion of dienyne 21-D. To a solution of silylated trienyne 20
(0.150 g, 0.604 mmol) in THF (3 drops of D2O was added)
was added tetrabutylammonium fluoride (1.21 mL of a 1 M
THF solution, 1.21 mmol). After the addition was complete,
the mixture was heated at 458C for 12 h. The mixture was
stirred for 30 min at room temperature and poured into 1 M
4.1.12. Coupling of carbene complex 12 with trienyne 19.
A solution of trienyne 19 (180 mg, 0.82 mmol) and carbene
complex 12 (310 mg, 0.87 mmol) in dioxane (34 mL) was
heated to 608C for 32 h. The reaction mixture was allowed
to cool to room temperature. Iodine (207 mg, 0.82 mmol)
was added and the solution was stirred at room temperature

J. Zhang et al. / Tetrahedron 59 (2003) 5609–5616
5615
T. J. Chem. Soc., Perkin Trans. 1 2000, 4339–4346. A similar
reaction using internal alkynes proceeding through an alkyne
insertion mechanism has also been employed Larock, R. C.;
Doty, M. J.; Han, X. Tetrahedron Lett. 1998, 39, 5143–5146.
6. (a) Zhang, Y.; Herndon, J. W. J. Org. Chem. 2002, 67,
4177–4185. (b) Moser, W. H.; Sun, L.; Huffman, J. C. Org.
Lett. 2001, 3, 3389–3391. (c) Moreno, I.; Tellitu, I.; San
Martin, R.; Dominguez, E. Synlett 2001, 1161–1163.
(d) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.;
Hibino, S. Chem. Pharm. Bull. 2001, 49, 881–886. (e) Ho,
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E.; Lopez-Pelegrin, J. A.; Garcia-Granda, S.; Perez Priede, M.
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for 16 h. The reaction mixture was poured into aqueous
sodium thiosulfate solution in a separatory funnel and the
aqueous layer was extracted three times with 4:1 hexane/
ethyl acetate. The combined hexane layers were washed
with saturated aqueous sodium chloride solution and dried
over sodium sulfate. The solvent was removed on a rotary
evaporator and final purification was achieved by flash
column chromatography on silica gel (30 g) using 20:1
hexane/ethyl acetate as the eluent. Separation of benzofuran
10 from carbene oxidation product 31 proved to be
extremely difficult; but was achieved by use of excessive
amount of silica gel indicated. A colorless oil identified as
1
benzofuran 10 (0.119 g, 47% yield) was obtained. HNMR
(CDCl3): d 7.40 (dd, 1H, J¼8.1, 1.8 Hz), 7.31 (d, 1H,
J¼1.5 Hz), 6.96 (br d, 1H, J¼1.8 Hz), 6.86 (d, 1H,
J¼8.1 Hz), 6.79 (s, 1H), 6.61 (d, 1H, J¼1.5 Hz), 6.03 (s,
2H), 5.99 (ddt, 1H, J¼16.9, 11.3, 6.6 Hz), 5.10 (d, 1H,
J¼16.9, 5.09 Hz (d, 1H, J¼11.3 Hz), 4.02 (s, 3H), 3.44 (d,
2H, J¼6.6 Hz); 13CNMR (CDCl3): d 156.3, 148.3, 148.2,
145.0, 142.9, 138.1, 135.9, 131.3, 124.9, 119.4, 115.8,
112.8, 108.8, 107.9, 105.8, 101.5, 100.6, 56.4, 40.7. The
spectral data are in agreement with those previously
reported for this compound.9 The major byproduct of this
reaction was tentatively identified as the carbene oxidation
product 31: 1H NMR (CDCl3): d 7.63 (dd, 1H, J¼8.1,
1.8 Hz); 7.47 (d, 1H, J¼1.8 Hz), 6.82 (d, 1H, J¼8.1 Hz),
6.02 (s, 2H), 3.86 (s, 3H). The chemical shifts are consistent
with those previously reported for this compound.22
7. For previous syntheses: (a) Mali, R. S.; Massey, A. P. J. Chem.
Res. Synopses 1998, 230–231. (b) Aoyagi, Y.; Mizusaki, T.;
Hatori, A.; Asakura, T.; Aihara, T.; Inaba, S.; Hayatsu, K.;
Ohta, A. Heterocycles 1995, 41, 1077–1084. (c) Schreiber,
F. G.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1976,
1514–1518. (d) Schreiber, F. G.; Stevenson, R. Chem. Lett.
1975, 1257–1258. (e) Ritchie, E.; Taylor, R. Aust. J. Chem.
1969, 22, 1329–1330.
Acknowledgements
We thank the National Institutes of Health, the Petroleum
Research Fund, administered by the American Chemical
Society, and the National Science Foundation for financial
support of this research. We thank the reviewers for helpful
comments.
8. (a) Labaudiniere, L.; Hanaizi, J.; Normant, J. F. J. Org. Chem.
1992, 57, 6903–6908. (b) Duboudin, J. G.; Jousseaume, B.;
Bonakdar, A. J. Organomet. Chem. 1979, 168, 227–232.
9. Puentes de Diaz, A. M. Phytochemistry 1997, 44, 345–346.
10. (a) Mendonca, P. P.; Araujo, A. R.; Young, M. C. M.;
Giesbrecht, A. M. da Silva Bolzani. V., Phytochemistry 2000,
55, 597–601. (b) Hasegawa, H.; Sakai, S.; Aimi, N.;
Takayama, H.; Koyano, T. Jpn. Kokai Tokkyo Koho; 1996,
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