Development of new Wittig reagent, silylfuranmethylid, and its reactivity

Article abstract of DOI:10.1016/S0040-4020(03)00763-4

New Wittig reagents, furanmethylids b-e were successfully developed. Their preparation, reactivity, and application toward the natural products synthesis are described in detail.

Full text of DOI:10.1016/S0040-4020(03)00763-4

Tetrahedron 59 (2003) 4945–4952
Development of new Wittig reagent, silylfuranmethylid,
and its reactivity
*
Katsunori Tanaka, Toshiyuki Hata, Hirokazu Hara and Shigeo Katsumura
School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
Received 19 April 2003; revised 12 May 2003; accepted 12 May 2003
Abstract—New Wittig reagents, furanmethylids b-e were successfully developed. Their preparation, reactivity, and application toward the
natural products synthesis are described in detail. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
During our program on the synthesis of new phospholipase
A2 (PLA2) inhibitors and the elucidation of their inhibitory
mechanism,5 it was required to synthesize the g-hydroxy-
butenolide derivative 3, and hence, the corresponding
a-silylfuran derivative 2 conjugated at the 3-position
(Fig. 2(a)). However, 2 could not be easily prepared from
the sterically hindered aldehyde 1 and unstable 3-furyl-
methyl anion equivalents under the conventional Julia
coupling or aldol-dehydration conditions. Also, in our
synthetic study of a cytotoxic sesterterpenoid, (2)-spongia-
nolide A, it was necessary to develop an efficient method for
introduction of the a-silylfuran moiety conjugated at the
4-position toward the sterically hindered aldehyde of the
tricyclic terpene skeleton such as 4 (Fig. 2(b)).6 We
successfully overcame these problems by applying the
Wittig olefination reaction of 3-(2- or 5-trimethylsilyl-
furyl)triphenylphosphonium methylids b and d with the
aldehydes 1 and 4, respectively. Thus, silylfuranmethylids
b-e, and hence the corresponding Wittig salts B-E seemed to
be very useful for the synthesis of these conjugated furan
derivatives. In this paper, we disclose the novel furan-
methylids b-e and their preparation in detail, and discuss
their reactivity toward aldehydes correlated with the silyl
substituents on the furan ring, in comparison with that of a
simple non-silyl substituted furanmethylid a.7
A g-hydroxybutenolide moiety is found in various biologi-
cally active natural products, such as manoalide,1
dysidiolide,2 and spongianolide A,3 and it is also regarded
as a useful intermediate for the synthesis of (Z)-1,2-
dicarbonylethylene derivatives.
The a-silylfuran derivatives substituted at the 3- or
4-positions are recognized as the appropriate precursors of
the corresponding regioisomeric g-hydroxybutenolide
synthesis, because they can be regiospecifically oxidized
with singlet oxygen (Fig. 1).4 Thus, the silyl group directs
the formation of the carbonyl group.
2. Results and discussion
The Wittig salts B-E were prepared by the standard
procedure as shown in Scheme 1. The 2-trimethylsilyl
(TMS) derivative B was prepared in 47% yield on a 500 mg
scale from the corresponding 3-(2-TMS)furylmethanol,
which was obtained from 3-furanmethanol 6.4,8 Thus,
3-(2-TMS)furylmethanol was reacted with phosphorus
tribromide in the presence of a catalytic amount of pyridine
to give the allylbromide intermediate, which was not
Figure 1. Regiospecific synthesis of g-hydroxybutenolides.
Keywords: silylfuranmethylide; new Wittig reagent; g-hydroxybutenolide;
conjugated silylfuran.
*
Corresponding author. Tel.: þ81-79-565-8314; fax: þ81-795-65-9077;
e-mail: katsumura@ksc.kwansei.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00763-4

4946
K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
Figure 2.
purified, and then treated with triphenylphosphine in
benzene at 808C to provide the desired B as a white solid.
However, the 5 g scale preparation of B by this method
resulted in only a 21% yield at most. On the other hand, the
corresponding 2-tert-butyldimethylsilyl (TBDMS) deriva-
tive C was successfully synthesized from 3-(2-TBDMS)-
furylmethanol in a substantially improved yield even on a
5 g scale. Thus, 3-(2-TBDMS)furylmethanol, which was
obtained from 6 by an O-silylation followed by the retro-
Brook rearrangement,9 was treated with carbon tetra-
bromide and triphenylphosphine to give the allylbromide
intermediate, which was then immediately reacted with
triphenylphosphine at 808C to afford the desired C in 78%
yield. Presumably, a bulkier alkyl group of the silyl
substituent at the 2-position of the furan ring would
contribute to the stabilization of the 3-furylmethyl bromide
intermediate.
The corresponding 5-TMS and 5-TBDMS derivatives D and
E were also prepared from 3-furaldehyde as shown in
Scheme 1. According to the literature procedure,8,10 3-(5-
TMS)furaldehyde was obtained in one-pot by the treatment
of 3-furaldehyde with lithium morpholinium, followed by
lithiation and trimethylsilylation at the 5-position of the
furan ring, and then by an acidic workup. After reduction of
the aldehyde group with sodium borohydride, the corre-
sponding 3-(5-TMS)furylmethanol 7 was obtained in 82%
overall yield from 3-furaldehyde. Disappointedly, the
preparation of the corresponding TBDMS-substituted
furanmethanol 8 by the same procedure resulted in only
an 18% yield due to the low reactivity of the lithium anion
intermediate of the furan toward tert-butyldimethylsilyl
chloride. Further trials to improve the yield under the
various reaction conditions, such as increasing the reaction
temperature or using more reactive TBDMSOTf were
unsuccessful. Despite the problem regarding the preparation
of 8, both of the obtained 3-furanmethanols 7 and 8 were
successfully converted to the corresponding Wittig salts
D and E in 70–80% yields by bromination with
phosphorus tribromide followed by the reaction with
Scheme 1.

K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
Table 1. Reactivity of furanmethylids a-e toward aldehydes 9 and 10
4947
reactivity of the ylids a-e were clearly observed toward the
aldehyde 10 as shown in entries 6–10. We previously
experienced that the reaction between the epoxyaldehyde 10
and alkyl lithium or Grignard reagents did not provide the
expected alcohols, but resulted in the decomposition of 10.
Apparently, the steric hindrance around the aldehyde group
by the neighboring gem-dimethyl substituent and the base
sensitive epoxide moiety retarded the addition reaction of
anion species toward this aldehyde. However, the ylids a-e
successfully produced the desired conjugated furan deriva-
tives, and showed their individual reactivity of one another.
Thus, the silyl-free furanmethylid a provided the corre-
sponding coupling product 10a as a single (E)- stereoisomer
in only 46% yield (entry 6). Similarly, 2-TMS-furan-
methylid b gave 10b in only 53% yield, accompanied by
unidentified products due to the decomposition of the
starting material (entry 7). However, the utilization of the
2-TBDMS derivative c substantially improved the product
formation, and 10c was obtained in 73% yield (entry 8). A
similar phenomenon was observed for the reactions of the
5-silyl substituted furanmethylids d and e with aldehyde 10.
Thus, the reaction of the 5-TMS derivative d gave a
complex mixture of products from which only a small
amount of 10d was detected by observation of the
characteristic signals in its 1H NMR (yield of 10d was
less than 20%, entry 9). On the contrary, 5-TBDMS
furanmethylid e successfully provided 10e in 95% yield
(entry 10).11 Based on these results, it was suggested that the
bulky TBDMS group on the furan ring stabilized the
benzylic anion of furanmethylid,12 and it would also
protected the coupling products from their decomposition.
Thus, the bulky TBDMS group effected the production of
the conjugated furan derivatives even toward the notorious
aldehyde 10.
Entry
Aldehyde
Ylid
Product
Yield (%)
E/Za
4:5
10:7
10:7
1
2
3
4
5
6
7
8
9
10
9
9
9
9
a
b
c
d
e
a
b
c
d
e
9a
9b
9c
9d
82
99
93
88
quant.
46
53
73
20
1:1
1:1
9
9e
10
10
10
10
10
10a
10b
10c
10d
10eb
E only
E only
E only
E only
E only
95
The Wittig salts A-E were treated with n-butyllithium in ether at 08C for
15 min, and prepared furanmethylids a-e were reacted with aldehydes 9 and
10 at the same temperature.
a
Determined by 1H NMR (400 MHz).
b
Produced 10e was gradually transformed into unidentified products in
CDCl3.
triphenylphosphine, respectively. In contrast to the syn-
thesis of the 2-TMS derivative B, the 5-TMS derivative D
was successfully prepared in 67% yield even on a 5 g scale.
In order to test the reactivity of the newly developed
furanmethylids b-e and to compare their reactivity with that
of non-silyl substituted furanmethylid a, they were reacted
with the selected aldehydes 9 and 10, respectively. These
results are shown in Table 1. The Wittig salts A-E were
treated with n-butyllithium in ether at 08C for 15 min, and
the resulting red solutions of the corresponding furan-
methylids a-e were reacted with each aldehyde at the same
temperature. All of the reactions between the furan-
methylids a-e and benzaldehyde 9 smoothly provided the
corresponding conjugated furan derivatives 9a-9e in 82–
100% yields as almost equal mixtures of (E)- and (Z)-
stereoisomers (entries 1–5). Meanwhile, the differences in
The application of these developed furanmethylids is shown
in Figures 2 and 3. In addition to the examples in Figure 2,
the tricyclic furan derivative 12 was obtained in 84%
yield as a single (E)-stereoisomer by the reaction of d
with the epoxyaldehyde 11 (Fig. 3(a)).6 Furthermore, in
our synthesis of the peridinin, nor-carotenoid, the
Figure 3.

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K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
epoxyaldehyde 13 was reacted with the ylid c to produce the
corresponding furan derivative 14 in excellent yield
(Fig. 3(b)).13 The obtained silylfuran derivatives 2, 5, 12,
and 14 were then regiospecifically oxidized with singlet
oxygen to provide the corresponding g-hydroxybutenolide
derivatives as a 1:1 mixture of stereoisomers at the hydroxy
group in the butenolide ring. Thus, the efficient method for
the regiospecific synthesis of the conjugated g-hydroxy-
butenolide derivatives was realized.
To a benzene (30 mL) solution of the crude bromide
obtained above was added triphenylphosphine (1.16 g,
4.41 mmol) at room temperature. After stirring for 4 h
under the reflux condition, the reaction mixture was filtered
to give the corresponding phosphonium salt B (691 mg,
47%) as a white solid: mp 159–1608C; IR (KBr disk, cm21
)
1
3063, 2855, 2787, 1441, 1250, 1167, 1113, 839; H NMR
(400 MHz, CD3OD) d 0.01 (s, 9H), 4.66 (d, 2H,
J¼13.6 Hz), 5.81 (brs, 1H), 7.60–7.66 (m, 6H), 7.69 (d,
1H, J¼1.6 Hz), 7.74–7.79 (m, 6H), 7.91–7.96 (m, 3H); 13C
NMR (100 MHz, CD3OD) d-2.9, 21.7 (d, J¼51.0 Hz),
110.6, 117.4 (d, J¼85.6 Hz), 120.2 (d, J¼8.3 Hz), 130.1 (d,
J¼12.3 Hz), 133.8 (d, J¼9.0 Hz), 135.3 (d, J¼3.3 Hz),
148.0; FAB HRMS m/z calcd for C26H28OSiP (M2Br)þ
415.1647, found 415.1638.
In summary, we developed new Wittig reagents, the
3-furylmethyltriphenylphosphonium methylids b-e, which
are very useful for the synthesis of the conjugated furan
derivatives, and hence, the regiospecific synthesis of the
corresponding g-hydroxybutenolide derivatives. The
2-TBDMS-furanmethylid c is recommended for the syn-
thesis of the corresponding a-silylfuran derivatives con-
jugated at the 3-position, because c is easily prepared from
3-furanmethanol and provided the coupling products in high
yields with any of the aldehydes examined herein. On the
other hand, the synthesis of the a-silylfuran derivatives
conjugated at the 4-position such as 5, 9d, and 12 can be
efficiently achieved by utilizing 5-TMS-furanmethylid d.
Notably, 5-TBDMS-furanmethylid e exhibited excellent
reactivity even toward the notorious aldehyde 10, though its
preparation from 3-furaldehyde is somewhat troublesome.
3.1.2. 3-(2-tert-Butyldimethylsilylfuryl)methyltriphenyl-
phosphonium bromide (C). To a dichloromethane (35 mL)
solution of 3-(2-tert-butyldimethylsilyl)furylmethanol
(2.51 g, 11.8 mmol) was added carbon tetrabromide
(5.26 g, 20.1 mmol) at 08C. The reaction mixture was
stirred at 08C for 10 min, and triphenylphosphine (6.65 g,
20.1 mmol) was added at the same temperature. After the
mixture was stirred for 15 min, the bulk of dichloromethane
was removed in vacuo, and ether was added. The precipitate
formed was removed by decantation for several times, and
the resulting solution was concentrated in vacuo to provide
the corresponding crude bromide, which was immediately
used for the next reaction.
3. Experimental
3.1. General
To a benzene (50 mL) solution of the crude bromide
obtained above was added triphenylphosphine (6.65 g,
20.1 mmol) at room temperature. After stirring for 8 h at
508C, the reaction mixture was filtered to give the
corresponding triphenylphosphonium salt C (4.93 g, 78%)
as a white solid: mp 232–2338C; IR (KBr disk, cm21) 2953,
All commercially available reagents were used without
further purification. All solvents were used after distillation.
Tetrahydrofuran and diethylether were refluxed over and
distilled from sodium. Dichloromethane was refluxed over
and distilled from P2O5. Preparative separation was usually
performed by column chromatography on silica gel (FUJI
silysia LTD, BW-200 and BW-300) and on aluminum oxide
(Merck, Aluminum oxide 90, standardized, activity II-III)
deactivated with 5 w/% of H2O, and by thin layer
chromatography on silica gel (Merck, 20£20 cm, Silica
1
2849, 1562, 1476, 1437, 1248, 1169, 1113, 843; H NMR
(400 MHz, CD3OD) d 20.08 (s, 6H), 0.83 (s, 9H), 4.63 (d,
2H, J¼13.6 Hz), 5.81 (dd, 1H, J¼1.7, 1.0 Hz), 7.58–7.64
(m, 6H), 7.72 (d, 1H, J¼1.6 Hz), 7.74–7.79 (m, 6H), 7.91–
7.96 (m, 3H); 13C NMR (100 MHz, CD3OD) d 27.3, 16.8,
21.9 (J¼51.0 Hz), 25.2, 110.5, 117.3 (J¼85.6 Hz), 121.4
(J¼8.2 Hz), 127.8, 130.1 (J¼12.3 Hz), 133.8 (J¼9.1 Hz),
135.3 (J¼3.3 Hz), 148.1; FAB HRMS m/z calcd for
C29H34OSiP (M2Br)þ 457.2117, found 457.2116.
1
gel 60 F254, 1 mm). H NMR and 13C NMR spectra were
recorded on a JEOL a-400 spectrometer and chemical shifts
were represented as d-values relative to the internal standard
TMS. IR spectra were recorded on a JAS.CO FT/IR-8000
Fourier Transform Infrared Spectrometer. High resolution
mass spectra (HRMS) were measured on a Hitachi M-4100
Tandem Mass Spectrometer. Melting points were
uncorrected.
3.1.3. 3-(5-Trimethylsilylfuryl)methyltriphenylphospho-
nium bromide (D). To an ether (50 mL) solution of 3-(5-
trimethylsilyl)furylmethanol (2.23 g, 13.4 mmol) and
pyridine (0.87 mL, 10.7 mmol) was added phosphorus
tribromide (1.52 mL, 16.1 mmol) at 08C and stirred for
15 min at this temperature. After the reaction mixture was
stirred at room temperature for an additional 1 h, H2O was
added, and the resulting mixture was extracted with ether.
The organic layers were combined, washed with brine, dried
over MgSO4, filtered and concentrated in vacuo to give the
corresponding crude bromide, which was used without
further purification.
3.1.1. 3-(2-Trimethylsilylfuryl)methyltriphenylphospho-
nium bromide (B). To an ether (30 mL) solution of 3-(2-
trimethylsilyl)furylmethanol4,8 (500 mg, 2.94 mmol) and
pyridine (0.04 mL, 0.49 mmol) was added phosphorus
tribromide (0.34 mL, 3.53 mmol) at 08C. After the reaction
mixture was stirred at room temperature for 80 min, H2O
was added, and the resulting mixture was extracted with
ether. The organic layers were combined, washed with
brine, dried over MgSO4, filtered and concentrated in vacuo
to give the corresponding crude bromide, which was used
without further purification.
To a benzene (130 mL) solution of the crude bromide
obtained above was added triphenylphosphine (5.26 g,
20.1 mmol) at room temperature. After stirring for 2 h at
608C, the reaction mixture was filtered to give the

K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
4949
corresponding triphenylphosphonium salt D (4.45 g, 67%)
as a white solid: mp 166–1678C (recrystallization from
MeOH–hexane); IR (KBr disk, cm21) 3070, 2880, 1595,
1442, 1242, 1114, 848; 1H NMR (400 MHz, CD3OD) d 0.15
(s, 9H), 4.77 (d, 2H, J¼14.0 Hz), 6.05 (s, 1H), 7.47 (d, 1H,
J¼4.4 Hz), 7.70–7.76 (m, 12H), 7.88–7.92 (m, 3H); 13C
NMR (100 MHz, CD3OD) d-1.9, 21.2 (d, J¼51.0 Hz),
112.6, 119.5 (d, J¼85.0 Hz), 122.6, 131.4 (d, J¼12.0 Hz),
135.2 (d, J¼9.0 Hz), 136.5, 148.5 (d, J¼9.0 Hz); FAB
HRMS m/z calcd for C26H28OSiP (M2Br)þ 415.1647,
found 415.1641.
concentrated in vacuo to give the corresponding crude
bromide, which was used without further purification.
To a benzene (20 mL) solution of the crude bromide
obtained above was added triphenylphosphine (1.45 g,
5.54 mmol) at room temperature. After stirring for 3 h
under the reflux condition, the reaction mixture was
concentrated in vacuo. Recrystallization of the obtained
crude solids from ether provided the corresponding
triphenylphosphonium salt E (1.44 g, 72%) as a white
solid: mp 232–2338C; IR (KBr disk, cm21) 1437, 1252,
1
1080, 839; H NMR (400 MHz, CD3OD) d 0.12 (s, 6H),
3.1.4. 3-(5-tert-Butyldimethylsilyl)furylmethanol. To a
solution of morpholine (2.6 mL, 30.0 mmol) in THF
(240 mL) was added dropwise n-butyllithium (1.6 M
solution in hexane, 18.8 mL, 30.0 mmol) at 2788C. The
reaction mixture was stirred at 2788C for 20 min and
3-furaldehyde (2.0 mL, 23.1 mmol) was added dropwise at
the same temperature. After the mixture was stirred at
2788C for an additional 20 min, sec-butyllithium (1.0 M
solution in cyclohexane, 27.7 mL, 27.7 mmol) was added at
this temperature. The resulting mixture was stirred for 7.5 h
at 2788C, and tert-butyldimethylsilylchloride (7.00 g,
46.4 mmol) was added at the same temperature. After the
mixture was gradually warmed to room temperature and
stirred for an additional 12 h, 1N HCl solution was rapidly
added, and the resulting mixture was extracted with ether.
The organic layers were combined, washed with 1N HCl
solution, saturated aqueous NaHCO3 solution, brine, dried
over MgSO4, filtered and concentrated in vacuo to give the
crude products. Rough column chromatography on silica gel
(5% ethyl acetate in hexane) gave the corresponding 3-(5-
tert-butyldimethylsilyl)furaldehyde, which was reduced
without further purification.
0.84 (s, 9H), 4.82 (d, 2H, J¼14.2 Hz), 6.12 (d, 1H,
J¼1.2 Hz), 7.51–7.53 (m, 1H), 7.70–7.78 (m, 12H),
7.88–7.93 (m, 3H); 13C NMR (100 MHz, CD3OD) d
27.9, 16.0, 19.8 (d, J¼51.8 Hz), 25.1, 111.0 (d,
J¼9.0 Hz), 117.9 (d, J¼85.6 Hz), 122.3, 129.9 (d,
J¼12.3 Hz), 133.7 (d, J¼9.9 Hz), 135.0 (d, J¼2.4 Hz),
147.2 (d, J¼9.1 Hz), 160.2; FAB HRMS m/z calcd for
C29H34OSiP (M2Br)þ 457.2117, found 457.2116.
3.1.6. (E)- and (Z)-3-(b-Styryl)furan (9a). To a solution of
3-furylmethyltriphenylphosphonium bromide A (598 mg,
1.41 mmol) in ether (7 mL) was added dropwise n-butyl-
lithium (1.6 M solution in hexane, 0.88 mL, 1.41 mmol) at
08C. The reaction mixture was stirred at 08C for 15 min, and
an ether (1 mL) solution of benzaldehyde (100 mg,
0.942 mmol) was added at this temperature. After the
mixture was gradually warmed to room temperature and
stirred for an additional 20 min, H2O was added, and the
resulting mixture was extracted with ether. The organic
layers were combined, washed with H2O, brine, dried over
MgSO4, filtered and concentrated in vacuo to give the crude
products. Column chromatography on silica gel (1% ethyl
acetate in hexane) gave a 4:5 mixture of (E)- and (Z)-
stereoisomers (131 mg, 82%). These stereoisomers were
successfully separated by preparative TLC on silica gel (9%
ethyl acetate in hexane): Data for (E)-stereoisomer (white
solid): IR (KBr disk, cm21); 1155, 1073, 1020, 963, 870,
To a solution of the crude aldehyde obtained above in
methanol (100 mL) was added sodium borohydride
(437 mg, 11.6 mmol) at 08C. After the reaction mixture
was stirred at this temperature for 10 min, 1N HCl solution
was slowly added, and the resulting mixture was extracted
with ether. The organic layers were combined, washed with
1N HCl solution, saturated aqueous NaHCO3 solution,
brine, dried over MgSO4, filtered and concentrated in vacuo
to give the crude products. Column chromatography on
silica gel (gradually from 2 to 17% ethyl acetate in hexane)
gave the corresponding alcohol (894 mg, 18%) as a yellow
oil: IR (neat, cm21) 3337, 1470, 1252, 1076, 1020; 1H NMR
(400 MHz, CDCl3) d 0.22 (s, 6H), 0.92 (s, 9H), 4.57 (d, 2H,
J¼0.5 Hz), 6.68 (s, 1H), 7.62 (d, 1H, J¼0.7 Hz); 13C NMR
(100 MHz, CDCl3) d 26.4, 16.7, 26.3 56.6, 120.9, 124.9,
144.2, 160.2; EI HRMS m/e calcd for C11H20O2Si (Mþ)
212.1231, found 212.1250.
1
783; H NMR (400 MHz, CDCl3) d 6.66–6.67 (m, 1H),
6.82 (d, 1H, J¼16.0 Hz), 6.97 (d, 1H, J¼16.4 Hz), 7.32–
7.36 (m, 3H), 7.41–7.46 (m, 3H), 7.532–7.534 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 107.4 118.4 124.5, 126.1, 127.3,
128.4, 128.6, 137.3, 140.9, 143.7; EI HRMS m/e calcd for
C12H10O (Mþ) 170.0731, found 170.0732. Data for (Z)-
stereoisomer (colorless liquid): IR (neat, cm21); 1505,
1
1491, 1159, 1074, 1022; H NMR (400 MHz, CDCl3) d
6.115–6.119 (m, 1H), 6.38 (d, 1H, J¼12.0 Hz), 6.55 (d, 1H,
J¼12.0 Hz), 7.22–7.36 (m, 7H); 13C NMR (100 MHz,
CDCl3) d 110.2, 120.1, 122.3 127.1, 128.2, 128.7, 129.4,
137.9, 142.0, 142.5; EI HRMS m/e calcd for C12H10O (Mþ)
170.0731, found 170.0735.
3.1.5. 3-(5-tert-Butyldimethylsilylfuryl)methyltriphenyl-
phosphonium bromide (E). To an ether (30 mL) solution
of 3-(5-tert-butyldimethylsilyl)furylmethanol (784 mg,
3.69 mmol) and pyridine (0.24 mL, 2.96 mmol) was added
phosphorus tribromide (0.84 mL, 8.86 mmol) at 08C, and
the mixture was stirred for 10 min at this temperature. After
the reaction mixture was stirred at room temperature for
105 min, H2O was added, and the resulting mixture was
extracted with ether. The organic layers were combined,
washed with brine, dried over MgSO4, filtered and
3.1.7. (E)- and (Z)-3-(b-Styryl)-2-trimethylsilylfuran
(9b). To a solution of 3-(2-trimethylsilylfuryl)methyl-
triphenylphosphonium bromide B (518 mg, 1.05 mmol) in
ether (7 mL) was added dropwise n-butyllithium (1.6 M
solution in hexane, 0.65 mL, 1.05 mmol) at 08C. The
reaction mixture was stirred at 08C for 20 min, and an
ether (1 mL) solution of benzaldehyde (74 mg, 0.697 mmol)
was added at this temperature. After the mixture was
gradually warmed to room temperature and stirred for an
additional 30 min, H2O was added, and the resulting

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K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
mixture was extracted with ether. The organic layers were
combined, washed with H2O, brine, dried over MgSO4,
filtered and concentrated in vacuo to give the crude
products. Column chromatography on silica gel (2% ethyl
acetate in hexane) gave a 10:7 mixture of (E)- and (Z)-
stereoisomers (168 mg, 99%). These compounds were
separated by column chromatography on silica gel (hexane):
data for (E)-stereoisomer (white solid): IR (KBr disk,
ether (7 mL) was added dropwise n-butyllithium (1.6 M
solution in hexane, 0.66 mL, 1.06 mmol) at 08C. The
reaction mixture was stirred at 08C for 20 min, and an
ether (1 mL) solution of benzaldehyde (75 mg, 0.707 mmol)
was added at this temperature. After the mixture was
gradually warmed to room temperature and stirred for an
additional 20 min, H2O was added, and the resulting
mixture was extracted with ether. The organic layers were
combined, washed with H2O, brine, dried over MgSO4,
filtered and concentrated in vacuo to give the crude
products. Column chromatography on silica gel (3% ethyl
acetate in hexane) gave a 1:1 mixture of (E)- and (Z)-
stereoisomers (151 mg, 88%). These stereoisomers were
separated by preparative TLC on silica gel (2% ethyl acetate
in hexane): Data for (E)-stereoisomer (white solid): IR (KBr
1
cm21); 1250, 1144, 1092, 1053, 957; H NMR (400 MHz,
CDCl3) d 0.02 (s, 9H), 6.33 (d, 1H, J¼1.7 Hz), 6.46 (d, 1H,
J¼16.1 Hz), 6.78 (d, 1H, J¼16.1 Hz), 6.86–6.90 (m, 1H),
6.99 (dd, 2H, J¼7.3, 7.3 Hz), 7.09 (d, 2H, J¼7.6 Hz), 7.22
(d, 1H, J¼1.7 Hz); 13C NMR (100 MHz, CDCl3) d 0.0,
108.1, 120.7, 127.0, 128.1, 129.2, 129.6, 134.9, 138.5,
147.6, 159.1; EI HRMS m/e calcd for C15H18OSi (Mþ)
242.1126, found 242.1140. Data for (Z)-stereoisomer
1
disk, cm21); 1248, 1119, 1076, 961; H NMR (400 MHz,
1
(colorless liquid): IR (neat, cm21); 1252, 1101, 1051; H
CDCl3) d 0.29 (s, 9H), 6.82 (d, 1H, J¼16.4 Hz), 6.88 (d, 1H,
J¼0.5 Hz), 6.99 (d, 1H, J¼16.1 Hz), 7.20–7.24 (m, 1H),
7.33 (dd, 2H, J¼7.6, 7.6 Hz), 7.44 (d, 2H, J¼7.8 Hz), 7.71
(s, 1H); 13C NMR (100 MHz, CDCl3) d 21.7, 117.0, 118.4,
124.5, 126.1, 127.2, 128.0, 128.6, 137.6, 145.1, 161.9; EI
HRMS m/e calcd for C15H18OSi (Mþ) 242.1126, found
242.1141. Data for (Z)-stereoisomer (colorless liquid): IR
NMR (400 MHz, CDCl3) d 0.31 (s, 9H), 6.06 (d, 1H,
J¼1.7 Hz), 6.52–6.53 (m, 2H), 7.19–7.33 (m, 5H), 7.40 (d
1H, J¼1.7 Hz); 13C NMR (100 MHz, CDCl3) d 21.2,
110.3, 121.5, 127.0, 128.1, 129.0, 129.7, 132.1, 137.7,
145.7, 158.4; EI HRMS m/e calcd for C15H18OSi (Mþ)
242.1126, found 242.1129.
1
(neat, cm21); 1252, 1125, 1074, 910; H NMR (400 MHz,
3.1.8. (E)- and (Z)-3-(b-Styryl)-2-tert-butyldimethylsilyl-
furan (9c). To a solution of 3-(2-tert-butyldimethylsilyl-
CDCl3) d 0.18 (s, 9H), 6.35 (s, 1H), 6.37 (d, 1H,
J¼13.1 Hz), 6.51 (d, 1H, J¼12.0 Hz), 7.23–7.36 (m, 5H),
7.52 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.8, 120.1,
120.3, 122.2, 127.1, 128.2, 128.6, 129.0, 138.1, 146.1,
160.3; EI HRMS m/e calcd for C15H18OSi (Mþ) 242.1126,
found 242.1135.
furyl)methyltriphenylphosphonium bromide
C (2.21 g,
4.24 mmol) in ether (30 mL) was added dropwise n-butyl-
lithium (1.6 M solution in hexane, 2.65 mL, 4.24 mmol) at
08C. The reaction mixture was stirred at 08C for 20 min, and
an ether (2 mL) solution of benzaldehyde (300 mg,
2.83 mmol) was added at this temperature. After the mixture
was gradually warmed to room temperature and stirred for
an additional 30 min, H2O was added, and the resulting
mixture was extracted with ethyl acetate. The organic layers
were combined, washed with H2O, brine, dried over
MgSO4, filtered and concentrated in vacuo to give the
crude products. Column chromatography on silica gel
(hexane) gave a 10:7 mixture of (E)- and (Z)-stereoisomers
(746 mg, 93%). These stereoisomers were separated by
column chromatography on silica gel (hexane): Data for
(E)-stereoisomer (white solid): IR (KBr disk, cm21); 1250,
3.1.10. (E)- and (Z)-4-(b-Styryl)-2-tert-butyldimethyl-
silylfuran (9e). To a solution of 3-(5-tert-butyldimethyl-
silylfuryl)-methyltriphenylphosphonium
bromide
E
(570 mg, 1.06 mmol) in ether (7 mL) was added dropwise
n-butyllithium (1.6 M solution in hexane, 0.66 mL,
1.06 mmol) at 08C. The reaction mixture was stirred at
08C for 20 min, and an ether (1 mL) solution of benzal-
dehyde (75 mg, 0.707 mmol) was added at this temperature.
After the mixture was gradually warmed to room tempera-
ture and stirred for an additional 10 min, H2O was added,
and the resulting mixture was extracted with ether. The
organic layers were combined, washed with H2O, brine,
dried over MgSO4, filtered and concentrated in vacuo to
give the crude products. Column chromatography on silica
gel (2% ethyl acetate in hexane) gave a 1:1 mixture of (E)-
and (Z)-stereoisomers (200 mg, 100%). These compounds
were separated by column chromatography on silica gel
(gradually 0–2% ethyl acetate in hexane): Data for (E)-
stereoisomer (white solid): IR (KBr disk, cm21); 1470,
1252, 1113, 1076, 953; 1H NMR (400 MHz, CDCl3) d 0.26
(s, 6H), 0.95 (s, 9H), 6.83 (d, 1H, J¼16.4 Hz), 6.896–6.899
(m, 1H), 6.99 (d, 1H, J¼16.1 Hz), 7.21–7.26 (m, 1H), 7.34
(dd, 2H, J¼7.3, 7.3 Hz), 7.45 (dm, 2H, J¼7.8 Hz), 7.73 (d,
1H, J¼0.5 Hz); 13C NMR (100 MHz, CDCl3) d 26.3, 16.8,
26.3, 118.2, 118.5, 124.4, 126.0, 127.2, 127.9, 128.6, 137.6,
145.3, 160.4; EI HRMS m/e calcd for C18H24OSi (Mþ)
284.1595, found 284.1602. Data for (Z)-stereoisomer
(colorless oil): IR (neat, cm21); 1470, 1252, 1125, 1074;
1H NMR (400 MHz, CDCl3) d 0.15 (s, 6H), 0.89 (s, 9H),
6.380–6.383 (m, 1H), 6.40 (d, 1H, J¼12.0 Hz), 6.53 (d, 1H,
J¼12.0 Hz), 7.25–7.37 (m, 5H), 7.55 (d, 1H, J¼0.5 Hz);
13C NMR (100 MHz, CDCl3) d 26.5, 16.7, 26.2, 120.3,
1
1142, 1092, 957; H NMR (400 MHz, CDCl3) d 0.37 (s,
6H), 0.94 (s, 9H), 6.70 (dd, 1H, J¼1.7, 0.5 Hz), 6.81 (d, 1H,
J¼16.1 Hz), 7.14 (d, 1H, J¼16.1 Hz), 7.23 (dddd, 1H,
J¼7.3, 7.3, 2.0, 2.0 Hz), 7.34 (dd, 2H, J¼8.1, 8.1 Hz),
7.42–7.44 (m, 2H), 7.59 (dd, 1H, J¼2.0, 1.0 Hz); 13C NMR
(100 MHz, CDCl3) d 25.5, 17.6, 26.4, 107.1, 120.3, 126.1,
127.2, 128.2, 128.7, 135.0, 137.7, 146.9, 157.0; EI HRMS
m/e calcd for C18H24OSi (Mþ) 284.1595, found 284.1586.
Data for (Z)-stereoisomer (colorless liquid): IR (neat,
cm21); 1470, 1395, 1252, 1096; 1H NMR (400 MHz,
CDCl3) d 0.31 (s, 6H), 0.94 (s, 9H), 6.05 (dd, 1H, J¼1.7,
0.5 Hz), 6.51 (d, 1H, J¼12.2 Hz), 6.55 (d, 1H, J¼12.2 Hz),
7.19–7.31 (m, 5H), 7.40–7.41 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 25.7, 17.8, 26.4, 110.3, 121.9,
127.0, 128.0, 129.0, 129.5, 133.2, 137.7, 145.8, 157.3; EI
HRMS m/e calcd for C18H24OSi (Mþ) 284.1595, found
284.1592.
3.1.9. (E)- and (Z)-4-(b-Styryl)-2-trimethylsilylfuran
(9d). To a solution of 3-(5-trimethylsilylfuryl)methyl-
triphenylphosphonium bromide D (525 mg, 1.06 mmol) in

K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
4951
121.4, 122.1, 127.1, 128.1, 128.7, 129.0, 138.0, 146.1,
158.7; EI HRMS m/e calcd for C18H24OSi (Mþ) 284.1595,
found 284.1593.
of the epoxyaldehyde 10 (203 mg, 1.21 mmol) was added at
this temperature. After the mixture was gradually warmed to
room temperature and stirred for an additional 30 min, H2O
was added, and the resulting mixture was extracted with
ether. The organic layers were combined, washed with H2O,
brine, dried over MgSO4, filtered and concentrated in vacuo
to give the crude products. Column chromatography on
aluminum oxide (2% ethyl acetate in hexane) gave the
corresponding conjugated furan derivative 10c (305 mg,
73%) as a colorless oil: IR (neat, cm21); 1464, 1389, 1362,
3.1.11. (E)-3-[2-(1,2-Epoxy-2,6,6-trimethylcyclohexyl)-
vinyl] furan (10a). To a solution of 3-furylmethyltri-
phenylphosphonium bromide A (566 mg, 1.34 mmol) in
ether (9 mL) was added dropwise n-butyllithium (1.6 M
solution in hexane, 0.84 mL, 1.34 mmol) at 08C. The
reaction mixture was stirred at 08C for 20 min, and an
ether (1 mL) solution of the epoxyaldehyde 10 (150 mg,
0.892 mmol) was added at this temperature. After the
mixture was gradually warmed to room temperature and
stirred for an additional 2.5 h, H2O was added, and the
resulting mixture was extracted with ether. The organic
layers were combined, washed with H2O, brine, dried over
MgSO4, filtered and concentrated in vacuo to give the crude
products. Column chromatography on aluminum oxide (2%
ethyl acetate in hexane) gave the conjugated furan
derivative 10a (96 mg, 46%) as a colorless oil: IR (neat,
cm21); 1460, 1379, 1260, 1161, 1073, 1024; 1H NMR
(400 MHz, CDCl3) d 0.97 (s, 3H), 1.04–1.10 (m, 1H), 1.12
(s, 3H), 1.18 (s, 3H), 1.39–1.52 (m, 3H), 1.72–1.79 (m,
1H), 1.87–1.95 (m, 1H), 6.12 (d, 1H, J¼15.6 Hz), 6.40 (d,
1H, J¼15.9 Hz), 6.53 (d, 1H, J¼2.0 Hz), 7.36–7.37 (m,
1H), 7.41 (s, 1H); 13C NMR (100 MHz, CDCl3) d 17.1,
21.0, 25.9, 30.1, 33.7, 35.7, 65.5, 71.0, 107.5, 122.3, 123.8,
124.8, 140.4, 143.4; EI HRMS m/e calcd for C15H20O2 (Mþ)
232.1462, found 232.1450.
1
1252, 1094; H NMR (400 MHz, CDCl3) d 0.30 (s, 6H),
0.89 (s, 9H), 0.96 (s, 3H), 1.12 (s, 3H), 1.18 (s, 3H), 1.41–
1.49 (m, 4H), 1.73–1.78 (m, 1H), 1.89–1.93 (m, 1H), 6.11
(d, 1H, J¼15.6 Hz), 6.55 (d, 1H, J¼1.7 Hz), 6.58 (d, 1H,
J¼15.6 Hz), 7.50 (d, 1H, J¼1.7 Hz); 13C NMR (100 MHz,
CDCl3) d 25.6, 17.1, 17.5, 21.0, 25.8, 25.9, 26.4, 30.1, 33.7,
35.8, 65.6, 71.2, 107.3, 124.2, 124.7, 134.3, 146.6, 156.1; EI
HRMS m/e calcd for C21H34O2Si (Mþ) 346.2326, found
346.2319.
3.1.14. (E)-4-[2-(1,2-Epoxy-2,6,6-trimethylcyclohexyl)-
vinyl]-2-trimethylsilylfuran (10d). To a solution of 3-(5-
trimethylsilylfuryl)methyltriphenylphosphonium bromide
D (442 mg, 0.892 mmol) in ether (6 mL) was added
dropwise n-butyllithium (1.6 M solution in hexane,
0.56 mL, 0.892 mmol) at 08C. The reaction mixture was
stirred at 08C for 20 min, and an ether (1 mL) solution of the
epoxyaldehyde 10 (100 mg, 0.594 mmol) was added at this
temperature. After the mixture was gradually warmed to
room temperature and stirred for an additional 1 h, H2O was
added, and the resulting mixture was extracted with ether.
The organic layers were combined, washed with H2O, brine,
dried over MgSO4, filtered and concentrated in vacuo to
give the crude products. Unfortunately, the conjugated furan
derivative 10d could not be completely purified by column
chromatography, and its presence in the crude mixture was
only detected by the observation of the characteristic signals
of its 1H NMR and MS (yield was less than 20%): 1H NMR
(400 MHz, CDCl3) (characteristic signals of 10d) d 6.12 (d,
1H, J¼15.9 Hz), 6.42 (d, 1H, J¼15.6 Hz), 6.75 (s, 1H), 7.60
(s, 1H); EI HRMS m/e calcd for C18H28O2Si (Mþ)
304.1857, found 304.1855.
3.1.12. (E)-3-[2-(1,2-Epoxy-2,6,6-trimethylcyclohexyl)-
vinyl]-2-trimethylsilylfuran (10b). To a solution of 3-(2-
trimethylsilylfuryl)methyltriphenylphosphonium bromide
B (230 mg, 0.464 mmol) in ether (3.6 mL) was added
dropwise n-butyllithium (1.6 M solution in hexane,
0.29 mL, 0.464 mmol) at 08C. The reaction mixture was
stirred at 08C for 10 min, and an ether (1 mL) solution of the
epoxyaldehyde 10 (52 mg, 0.309 mmol) was added at this
temperature. After the mixture was gradually warmed to
room temperature and stirred for an additional 30 min, H2O
was added, and the resulting mixture was extracted with
ether. The organic layers were combined, washed with H2O,
brine, dried over MgSO4, filtered and concentrated in vacuo
to give the crude products. Column chromatography on
aluminum oxide (2% ethyl acetate in hexane) gave the
corresponding conjugated furan derivative 10b (57 mg,
53%) as a colorless oil: IR (neat, cm21); 1460, 1381, 1252,
3.1.15. (E)-4-[2-(1,2-Epoxy-2,6,6-trimethylcyclohexyl)-
vinyl]-2-tert-butyldimethylsilylfuran (10e). To a solution
of 3-(5-tert-butyldimethylsilylfuryl)methyltriphenylphos-
phonium bromide E (479 mg, 0.892 mmol) in ether
(5 mL) was added dropwise n-butyllithium (1.6 M solution
in hexane, 0.56 mL, 0.892 mmol) at 08C. The reaction
mixture was stirred at 08C for 40 min, and an ether (1 mL)
solution of the epoxyaldehyde 10 (100 mg, 0.594 mmol)
was added at this temperature. After the mixture was
gradually warmed to room temperature and stirred for an
additional 10 min, H2O was added, and the resulting
mixture was extracted with ether. The organic layers were
combined, washed with H2O, brine, dried over MgSO4,
filtered and concentrated in vacuo to give the crude
products. Rapid column chromatography on aluminum
oxide (2% ethyl acetate in hexane) gave the corresponding
conjugated furan derivative 10e (196 mg, 95%) which was
analyzed by the observation of the characteristic signals of
its 1H NMR and MS: 1H NMR (400 MHz, CDCl3)
(characteristic signals of 10e) d 6.11 (d, 1H, J¼15.9 Hz),
1
1098; H NMR (400 MHz, CDCl3) d 0.30 (s, 9H), 0.97 (s,
3H), 1.12 (s, 3H), 1.19 (s, 3H), 1.40–1.56 (m, 4H), 1.73–
1.80 (m, 1H), 1.88–1.95 (m, 1H), 6.10 (d, 1H, J¼15.9 Hz),
6.53 (d, 1H, J¼1.7 Hz), 6.57 (d, 1H, J¼15.9 Hz), 7.53 (d,
1H, J¼1.7 Hz); 13C NMR (100 MHz, CDCl3) d 21.0, 17.1,
21.0, 25.9, 30.1, 33.7, 35.8, 65.6, 71.2, 107.5, 123.7, 124.9,
133.8, 146.4, 158.4; EI HRMS m/e calcd for C18H28O2Si
(Mþ) 304.1857, found 304.1867.
3.1.13. (E)-3-[2-(1,2-Epoxy-2,6,6-trimethylcyclohexyl)-
vinyl]-2-tert-butyldimethylsilylfuran (10c). To a solution
of 3-(2-tert-butyldimethylsilylfuryl)methyltriphenylphos-
phonium bromide C (1.26 g, 2.41 mmol) in ether (12 mL)
was added dropwise n-butyllithium (1.6 M solution in
hexane, 1.70 mL, 2.66 mmol) at 08C. The reaction mixture
was stirred at 08C for 10 min, and an ether (2 mL) solution

4952
K. Tanaka et al. / Tetrahedron 59 (2003) 4945–4952
39, 1185. (b) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.;
Ikeda, K.; Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron
1999, 55, 1657. (c) Tanaka, K.; Katsumura, S. J. Synth. Org.
Chem. Jpn 1999, 57, 876.
6.41 (d, 1H, J¼15.6 Hz), 6.74 (s, 1H), 7.60 (s, 1H); EI
HRMS m/e calcd for C21H34O2Si (Mþ) 346.2326, found
346.2330.
6. (a) Hata, T.; Tanaka, K.; Katsumura, S. Tetrahedron. Lett.
1999, 40, 1731. (b) Furuichi, N.; Hata, T.; Soetjipto, H.; Kato,
M.; Katsumura, S. Tetrahedron 2001, 57, 8425.
Acknowledgements
We thank Dr Kayoko Saiki at Kobe Pharmaceutical
University for her high-resolution mass spectra measure-
ments. This work was supported by a Grant-in-Aid for
Scientific Research 09480145 from the Ministry of
Education, Science, Sports and Culture of Japan. K. T. is
grateful to the JSPS for a Research Fellowship for Young
Scientists.
7. (a) Okabe, M.; Tamagawa, H.; Tada, M. Synth. Commun.
1983, 13, 373. (b) van Altena, I. A.; Miller, D. A. Aust.
J. Chem. 1989, 42, 2181.
8. (a) Goldsmith, D.; Liotta, D.; Saindane, M.; Waykole, L.;
Bowen, P. Tetrahedron Lett. 1983, 24, 5835. (b) Tanis, S. P.;
Head, D. B. Tetrahedron Lett. 1984, 25, 4451.
9. (a) Bures, E. J.; Keay, B. A. Tetrahedron Lett. 1987, 28, 5965.
(b) Bures, E. J.; Keay, B. A. Tetrahedron Lett. 1988, 29, 1247.
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