Construction of furo[3,4-c]pyran skeleton starting from the Baylis-Hillman adducts via the ring-closing metathesis (RCM) reaction of exo-methylene tetrahydrofuran

Article abstract of DOI:10.1016/j.tet.2006.02.038

Construction of furo[3,4-c]pyran ring skeleton was achieved starting from the Baylis-Hillman adducts. The synthesis was carried out by the successive introduction of propargyl alcohol, radical cyclization, reduction, allylation, and finally ring-closing m

Full text of DOI:10.1016/j.tet.2006.02.038

Tetrahedron 62 (2006) 4052–4058
Construction of furo[3,4-c]pyran skeleton starting from the
Baylis–Hillman adducts via the ring-closing metathesis (RCM)
reaction of exo-methylene tetrahydrofuran
*
Saravanan Gowrisankar, Ka Young Lee and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, South Korea
Received 26 December 2005; accepted 9 February 2006
Available online 9 March 2006
Abstract—Construction of furo[3,4-c]pyran ring skeleton was achieved starting from the Baylis–Hillman adducts. The synthesis was carried
out by the successive introduction of propargyl alcohol, radical cyclization, reduction, allylation, and finally ring-closing metathesis reaction.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
furopyran nucleus has been known to constitute an essential
part of many biologically important compounds.5,6
The reported methods for the synthesis of furo[3,4-c]pyran
nucleus were much limited and used either tungsten-
mediated [3C3] cycloaddition of epoxides with tethered
alkynes5a,b or intramolecular hetero-Diels–Alder
reaction.5c,d,f
Ring-closing metathesis (RCM) reaction is a powerful tool
in modern chemistry due to its wide applicability in
synthetic organic chemistry.1–3 By using the RCM reaction
tremendous cyclic compounds have been elegantly con-
structed including carbocyclic and heterocyclic rings.1–3
However, RCM reaction between the exo-methylene unit of
cyclic compound and double bond of the appropriate tether
has not been reported much.4 Barrett and co-workers have
reported the example, which dealt with the synthesis of
C-19-functionalized 1a-hydroxyvitamin D2 analogues by
the RCM reaction of exo-methylene compounds.4a In their
report, they examined silicon and phosphorous tether in the
reaction with methylene cyclohexane moiety. Botta and co-
workers have used RCM reaction of methylenecyclohexane
moiety in their synthesis of Taxuspine X in 20–25% yield.4b
Fu¨rstner and colleagues reported the successful RCM
reaction of methylenecycloalkane derivatives with ruthe-
nium carbene complexes with N,N-bis(mesityl)imidazole-2-
ylidene ligand.4c To the best of our knowledge the RCM
reaction of exo-methylene moiety with the double bond of
oxygen atom-containing tether has not been published.
2. Results and discussion
Recently, we have reported the synthesis of 3,4-disubsti-
tuted 2,5-dihydrofuran derivatives from the triple bond-
containing Baylis–Hillman adducts via radical cyclization
and iodolactonization strategy.7 Meantime we thought that
the intermediate, methylene tetrahydrofuran derivative 2a
could be used for the construction of furo[3,4-c]pyran
skeleton5,6 of 5a by using the RCM reaction as shown in
Scheme 1.
exo-Methylene tetrahydrofuran 2a was prepared as pre-
viously reported.7 Reduction of 2a with LiAlH4 was
conducted successfully to give 3a in 80% yield. Allylation
of 3a was carried out (t-BuOK, THF, allyl bromide) to give
the requisite starting material 4a in 81% yield. The RCM
reaction of 4a in the presence of 5 mol% of Grubbs type II
catalyst in CH2Cl2 at refluxing temperature afforded the
desired furo[3,4-c]pyran compound 5a in 92% yield.
Although much steric crowdedness could be arisen at the
transition state toward the formation of the corresponding
intermediate, metallacyclobutane stage (shown in Fig. 1 in
a simplified manner),3d the desired compound 5a was
synthesized in good yield.5 In addition, 5a could be
Although RCM reaction could provide very effective routes
for the synthesis of a variety of fused heterocyclic
compounds,1–3 the synthesis of furo[3,4-c]pyran skeleton
using RCM protocol has not been reported. Various
Keywords: Furo[3,4-c]pyran; Baylis–Hillman adducts; exo-Methylene
tetrahydrofuran; Ring-closing metathesis.
*
Corresponding author. Tel.: C82 62 530 3381; fax: C82 62 530 3389;
e-mail: kimjn@chonnam.ac.kr
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.038

S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
4053
OH
O
LiAlH4 (2 equiv)
MeOOC
OH
THF, 0 oC - rt, 2 h
ref. 7
COOMe
Ph
Ph
Ph
80%
O
1a
2a
3a
t-BuOK (1.5 equiv)
allyl bromide (1.5 equiv)
THF, reflux, 15 h
O
O
Grubbs cat II (5 mol%)
CH2Cl2, reflux, 2 h
Ph
92%
81%
Ph
O
O
5a
4a
90%
O
Mes
N
N Mes
Cl
Pd/C, H2 ballon
EtOH, rt, 3 h
H
Ru
Cl
Ph
Ph
PCy3
O
Grubbs catalyst II
6
Scheme 1.
transformed into 6 in 90% yield under catalytic hydrogen-
ation conditions (Pd/C, H2, EtOH, room temperature, 3 h).
We obtained 6 as a single isomer but we did not determine
the stereochemistry at this stage. Encouraged by the results
we examined the RCM reactions with similar starting
materials 4b–h and the results are summarized in Tables 1
and 2.
Mes
Cl
Ru
Cl
N
O
N
Ph
Mes
O
Figure 1. Metallacyclobutane intermediate for 5a.
Table 1. Successful RCM reaction of exo-methylene compounds and Grubbs catalyst
Entry
Substrate
Conditions
Product (%)
O
O
1
Ph
Ph
Cat (5 mol%), 2 h
Ph
O
O
4a
5a (92)
O
O
Ph
N
2
Cat (10 mol%), 80 min
Cat (5 mol%), 20 min
Cat (5 mol%), 20 min
N
Ts
Ts
4b
5b (91)
O
O
3
O
O
MeO
MeO
4ca
MeO
5c (97)
O
O
O
O
O
4
O
4da
MeO
5d (48)b
a Pure trans isomer.9
b Self-metathesis product 5g was also isolated in 24% yield.

4054
S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
Table 2. Unsuccessful RCM reaction of exo-methylene compounds and Grubbs catalyst
Entry
Substrate
Conditions
Product (%)
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
1
Cat (5 mol%), 12 h
O
O
O
O
O
4ea
5e (94)b
O
2
Cat (5 mol%), 6 h
O
O
O
O
4fa
5f (85)b
O
O
O
3
4d
Cat (5 mol%), 1 h
O
O
MeO
OMe
5g (24)b,c
O
4
5
Cat (10 mol%), 48 h
No reaction
Ph
Ph
O
4g
O
Cat (5 mol%), 3 days
3a (74)
O
4h
a Pure 4e and 4f were used, but the stereochemistry is arbitrary.
b Pure single isomer was obtained, but we did not assign the stereochemistry.
c RCM product 5d was also isolated in 48% yield.
As shown in Table 1, allyl-substituted starting materials 4b
and 4c gave the corresponding RCM products 5b and 5c
successfully in short time in good yields. We could obtain
the RCM product 5d, albeit in low yield, for the allyl ester
4d (48%, entry 4). In addition, we could isolate the
corresponding self-metathesis product 5g in 24% yield
(see also entry 3 in Table 2). Unfortunately, however,
we did not obtain the desired RCM products when we used
4e–h as the starting materials as shown in Table 2. The
methyl substituent at the 2-position (for 4e, entry 1)
increased the steric crowdedness at the transition state
toward RCM product and produced the self-metathesis
product 5e. The situation was same for the allyl ether 4f
(entry 2). For the methallyl-substituted starting material 4g
(entry 4), we failed completely to obtain any product
presumably due to the severe steric crowdedness during the
reaction progress. As expected, when we compare the
differences of reactivity of 4c and 4e, the substituent near
the metallacyclobutane moiety (like as the methyl group of
4e) made the RCM reaction difficult, while the substituent
far away from the reaction site (like as 4-methoxyphenyl
group of 4c) did not reduce the reactivity toward RCM
reaction. For the propargyl ether derivative 4h (entry 5) we
observed the deprotection of propargyl group. Deprotection
of propargyl ether moiety has been published recently.8
The synthesis of starting materials 4b–h is summarized in
Schemes 2–4.7,9,10 Synthesis of 2a–c was carried out as
reported from the corresponding Baylis–Hillman adduct.7
By following the usual organic laboratory experimental
techniques we prepared 4b, 4e, 4g, and 4h as in Scheme 2 in
reasonable yields. Synthesis of 4c was carried out from
methyl 4-methoxycinnamate (7) by following bromoetheri-
fication with propargyl alcohol (NBS, propargyl alcohol,
61%),9 radical cyclization (n-Bu3SnH, AIBN, 81%),9,10
reduction (LiAlH4, 95%), and allylation (allyl bromide,
NaH, 80%) as shown in Scheme 3. The compound 4d was
also synthesized from methyl 4-methoxycinnamate by
following alkaline hydrolysis (NaOH, 90%), allylation
(DBU, allyl bromide, 92%), bromoetherification (NBS,
propargyl alcohol, 62%),9 and radical cyclization (n-
Bu3SnH, AIBN, 81%) sequences9,10 (Scheme 3). Com-
pound 4f was also synthesized from the Baylis–Hillman
adduct of methyl vinyl ketone by following the sequential
introduction of propargyl alcohol at the primary position
(81%),7,10 reduction of acetyl group (NaBH4, 95%), radical

S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
4055
1. LiAlH4 (1.5 equiv)
THF, 0 oC, 1 h, 87% (3b)
MeOOC
Ph
4b
2. allyl bromide (2 equiv)
NaH (1.5 equiv), DMF
50 oC, 6 h, 72%
N
Ts
2b
1. LiAlH4 (1.5 equiv)
THF, rt, 77% (3e)
MeOOC
Ph
4e
2. allyl bromide (2 equiv)
NaH (2 equiv), DMF
DMF, 50 oC, 2 h, 64%
O
ref. 7,9,10
2c
1a
methallyl chloride (1.5 equiv)
NaH (2 equiv), DMF
50 oC, 2 h, 83%
4g
3a
2a
propargyl bromide (3 equiv)
NaH (1.5 equiv), DMF
60 oC, 16 h, 68%
4h
Scheme 2.
1. NBS (1.5 equiv), CH2Cl2
MeOOC
1. LiAlH4 (1.2 equiv), THF
propargyl alcohol (4.5 equiv)
- 10 oC to rt, 24 h, 61%
0 oC, 20 min, 95% (3c)
4c
O
2. allyl bromide (2 equiv)
NaH (1.5 equiv), DMF
50 oC, 6 h, 80%
2. n-Bu3SnH (1.2 equiv)
benzene, AIBN (cat)
reflux, 6 h, 81%
COOMe
MeO
COOallyl
1. NBS (1.5 equiv), CH2Cl2
propargyl alcohol (4.5 equiv)
- 10 oC to rt, 24 h, 62%
1. NaOH
aq MeOH, rt, 4 h, 90%
OMe
4d
7
2. n-Bu3SnH (1.2 equiv)
benzene, AIBN (cat)
reflux, 3 h, 81%
2. DBU (1.1 equiv)
allyl bromide (1.5 equiv)
PhH, rt, 14 h, 92%
OMe
Scheme 3.
1. n-Bu3SnH (1.3 equiv)
AIBN (cat), 1 h
2. c-HCl, ether, rt, 2 h, 72% (3f)
OH
O
1. propargyl alcohol
H2SO4, 81%
OH
O
Ph
4f
Ph
3. allyl bromide (3 equiv)
NaH (1.5 equiv), DMF
60 oC, 20 h, 89%
2. NaBH4 (1.1 equiv)
MeOH, 0 oC, 20 min, 95%
Scheme 4.
cyclization (n-Bu3SnH, AIBN, 72%),7,10 and allylation
(allyl bromide, NaH, 89%) as in Scheme 4.
3. Experimental
3.1. General procedure
In summary, we disclosed the first successful RCM reaction
of cyclic substrates with exo-methylene moiety with the
double bond of oxygen atom-containing tether. The steric
crowdedness at the metallacyclobutane intermediate stage
prohibited the successful RCM reaction in some cases,
which afforded the corresponding self-metathesis products.
More detailed scope and limitations on the RCM reaction
involving exo-methylene moiety are currently under study
and will be published in due course.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded in CDCl3. The signal positions are reported in parts
per million relative to TMS (d scale) used as an internal
standard. IR spectra are reported in cmK1. Mass spectra
were obtained from the Korea Basic Science Institute
(Gwangju branch). Melting points are uncorrected. The
elemental analyses were carried out at Korea Research
Institute of Chemical Technology, Taejon, Korea. All

4056
S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
reagents were purchased from commercial sources and used
without further treatment. The separations were carried out
by flash column chromatography over silica gel (230–400
mesh ASTM). Organic extracts were dried over anhydrous
MgSO4 and the solvents were evaporated on a rotary
evaporator under water aspirator pressure.
3.3.2. Compound 4b. Seventy-two percentage; a colorless
1
oil; IR (film) 2854, 1346, 1165 cmK1; H NMR (CDCl3,
300 MHz) d 2.43 (s, 3H), 2.82 (s, 2H), 3.09 (d, JZ9.6 Hz,
1H), 3.12 (d, JZ9.3 Hz, 1H), 3.18 (d, JZ9.3 Hz, 1H), 3.26
(d, JZ9.6 Hz, 1H), 3.81 (t, JZ2.4 Hz, 2H), 3.92 (dt, JZ5.4,
1.5 Hz, 2H), 4.67 (t, JZ2.1 Hz, 1H), 4.97 (t, JZ2.1 Hz,
1H), 5.12–5.28 (m, 2H), 5.81–5.94 (m, 1H), 7.04–7.27 (m,
5H), 7.30 (d, JZ8.1 Hz, 2H), 7.65 (d, JZ8.1 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 21.51, 40.16, 50.29, 52.83, 55.79,
72.08, 72.52, 108.30, 116.76, 126.36, 127.84, 127.89,
129.59, 130.51, 132.48, 134.51, 137.12, 143.56, 147.49;
ESIMS (m/z) 398.2 (MCCH). Anal. Calcd for
C23H27NO3S: C, 69.49; H, 6.85; N, 3.52. Found: C, 69.47;
H, 6.94; N, 3.43.
3.2. Synthesis of starting material 2a–c and 3a
Synthesis of the starting materials 2a–c was carried out
according to the reported procedures.7,9,10 Compound 3a
was prepared from 2a as follows: to a stirred solution of 2a
(464 mg, 2.0 mmol) in THF (2 mL) was added a solution of
LiAlH4 (4 mL, 1 M solution in THF) at 0 8C. The reaction
mixture was maintained at room temperature for 2 h. After
usual workup and column chromatographic purification
process (hexanes/EtOAc, 8:2) we obtained 3a as colorless
oil, 327 mg (80%).
3.3.3. Compound 4c. Eighty percentage; a colorless oil; IR
1
(film) 2839, 1612, 1516, 1250 cmK1; H NMR (CDCl3,
300 MHz) d 2.85–2.90 (m, 1H), 3.54 (d, JZ1.8 Hz, 1H),
3.57 (d, JZ2.4 Hz, 1H), 3.80 (s, 3H), 3.96 (dt, JZ5.7,
1.5 Hz, 2H), 4.41 (dq, JZ13.2, 2.4 Hz, 1H), 4.57 (dq, JZ
13.2, 2.1 Hz, 1H), 4.78 (d, JZ7.2 Hz, 1H), 5.02 (q, JZ
2.1 Hz, 1H), 5.08 (q, JZ2.1 Hz, 1H), 5.13–5.26 (m, 2H),
5.80–5.94 (m, 1H), 6.88 (d, JZ9.0 Hz, 2H), 7.29 (d, JZ
9.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 51.59, 55.26,
70.52, 71.24, 72.02, 83.70, 104.89, 113.75, 116.89, 127.68,
133.47, 134.62, 149.34, 159.16; ESIMS (m/z) 261.1 (MCC
H). Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C,
73.67; H, 7.78.
3.2.1. Compound 3a. Eighty percentage; a colorless oil; IR
(film) 3464, 1662, 1065 cmK1; 1H NMR (CDCl3, 300 MHz)
d 1.76 (br s, 1H), 2.78 (d, JZ13.5 Hz, 1H), 2.96 (d, JZ
13.5 Hz, 1H), 3.42–3.56 (m, 2H), 3.70 (d, JZ9.0 Hz, 1H),
3.84 (d, JZ9.0 Hz, 1H), 4.28–4.45 (m, 2H), 4.87 (t, JZ
2.4 Hz, 1H), 5.10 (d, JZ2.4 Hz, 1H), 7.15–7.31 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 39.31, 51.86, 64.89, 72.26,
75.34, 105.05, 126.46, 128.13, 130.17, 137.53, 151.94;
ESIMS (m/z) 205.1 (MCCH).
3.3.4. Compound 4d. Eighty-one percentage; a colorless
oil; IR (film) 1736, 1612, 1516, 1250 cmK1 1H NMR
;
3.3. Synthesis of starting materials 4a–h
(CDCl3, 300 MHz) d 3.49–3.55 (m, 1H), 3.80 (s, 3H), 4.49
(dq, JZ13.2, 2.4 Hz, 1H), 4.56–4.71 (m, 3H), 5.03–5.34 (m,
5H), 5.83–5.97 (m, 1H), 6.88 (d, JZ9.0 Hz, 2H), 7.31 (d,
JZ9.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 55.25, 57.01,
65.70, 71.47, 83.24, 106.47, 113.90, 118.66, 127.50, 131.73,
131.79, 146.47, 159.52, 170.42; ESIMS (m/z) 275.1 (MCC
H). Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C,
70.18; H, 6.54.
Synthesis of 4a was carried out as follows: To a stirred
mixture of 3a (204 mg, 1.0 mmol) and allyl bromide
(182 mg, 1.5 mmol) in dry THF (3 mL) was added
t-BuOK (168 mg, 1.5 mmol) and heated to reflux for 15 h.
After usual workup and column chromatographic purifi-
cation process (hexanes/EtOAc, 95:5) we obtained 4a as
colorless oil, 198 mg (81%). Other compounds 4b, 4e, 4g,
and 4h were synthesized similarly by using the typical
experimental procedures (Scheme 2).7,9,10 The compounds
4c and 4d were also prepared from commercial methyl
4-methoxycinnamate by following the typical organic
experimental procedures (Scheme 3).9 Compound 4f was
synthesized from the Baylis–Hillman adduct of methyl
vinyl ketone by following the known procedures as in
Scheme 4. The spectroscopic data of prepared compounds
4a–h are as follows. The spectroscopic data of the
intermediates (3b, 3c, 3e, and 3f) are also reported at the
end of this part.
3.3.5. Compound 4e. Sixty-four percentage; a colorless oil;
IR (film) 2927, 2858, 1099, 1034 cmK1; 1H NMR (CDCl3,
300 MHz) d 1.29 (d, JZ6.3 Hz, 3H), 2.84 (d, JZ13.2 Hz,
1H), 2.95 (d, JZ13.2 Hz, 1H), 3.21 (d, JZ9.0 Hz, 1H), 3.30
(d, JZ9.0 Hz, 1H), 3.63 (d, JZ9.0 Hz, 1H), 3.94–4.00 (m,
3H), 4.38–4.45 (m, 1H), 4.51 (d, JZ2.4 Hz, 1H), 4.87 (d,
JZ2.4 Hz, 1H), 5.16–5.21 (m, 1H), 5.26–5.34 (m, 1H),
5.87–6.00 (m, 1H), 7.12–7.28 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 20.33, 40.65, 51.25, 72.15, 73.27, 75.19, 78.28,
105.63, 116.69, 126.18, 127.68, 130.91, 134.78, 137.76,
155.73; ESIMS (m/z) 259.2 (MCCH). Anal. Calcd for
C17H22O2: C, 79.03; H, 8.58. Found: C, 78.95; H, 8.48.
3.3.1. Compound 4a. Eighty-one percentage; a colorless
;
oil; IR (film) 2850, 1072 cmK1
1H NMR (CDCl3,
3.3.6. Compound 4f. Eighty-nine percentage; a colorless
1
300 MHz) d 2.91 (s, 2H), 3.22 (d, JZ9.0 Hz, 1H), 3.28 (d,
JZ9.0 Hz, 1H), 3.75 (d, JZ9.0 Hz, 1H), 3.84 (d, JZ
9.0 Hz, 1H), 3.97–4.01 (m, 2H), 4.32–4.35 (m, 2H), 4.64 (t,
JZ2.4 Hz, 1H), 4.97 (t, JZ2.4 Hz, 1H), 5.16–5.34 (m, 2H),
5.87–6.01 (m, 1H), 7.13–7.29 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 39.71, 50.60, 72.14, 72.32, 72.82, 76.61, 105.28,
116.66, 126.22, 127.79, 130.61, 134.78, 137.83, 151.18;
ESIMS (m/z) 245.1 (MCCH). Anal. Calcd for C16H20O2:
C, 78.65; H, 8.25. Found: C, 78.84; H, 8.18.
oil; IR (film) 2985, 1115, 1065 cmK1; H NMR (CDCl3,
300 MHz) d 1.14 (d, JZ6.3 Hz, 3H), 2.92 (d, JZ13.2 Hz,
1H), 3.03 (d, JZ13.2 Hz, 1H), 3.45 (q, JZ6.3 Hz, 1H), 3.75
(d, JZ9.3 Hz, 1H), 3.86–3.93 (m, 1H), 4.06–4.26 (m, 3H),
4.10 (d, JZ9.3 Hz, 1H), 4.60 (t, JZ2.3 Hz, 1H), 5.06 (t, JZ
2.0 Hz, 1H), 5.17–5.22 (m, 1H), 5.31–5.38 (m, 1H), 5.93–
6.06 (m, 1H), 7.14–7.26 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 13.95, 40.95, 54.36, 69.93, 72.86, 73.77, 78.70,
105.71, 116.15, 126.14, 127.61, 131.07, 135.28, 137.98,

S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
4057
151.59; ESIMS (m/z) 259.2 (MCCH). Anal. Calcd for
C17H22O2: C, 79.03; H, 8.58. Found: C, 79.12; H, 8.53.
3.3.12. Compound 3f. Eighty-seven percentage; a colorless
1
oil; IR (film) 3440, 2924, 1072 cmK1; H NMR (CDCl3,
300 MHz) d 1.23 (d, JZ6.6 Hz, 3H), 1.99 (d, JZ3.0 Hz,
1H), 2.85 (d, JZ13.8 Hz, 1H), 2.98 (d, JZ13.8 Hz,
1H), 3.78 (d, JZ9.3 Hz, 1H), 3.84–3.90 (m, 1H), 4.06 (d,
JZ9.3 Hz, 1H), 4.12 (dt, JZ13.5, 2.8 Hz, 1H), 4.34 (dt, JZ
13.5, 2.1 Hz, 1H), 4.82 (t, JZ2.4 Hz, 1H), 5.14 (t,
JZ2.1 Hz, 1H), 7.17–7.29 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 18.17, 39.81, 54.14, 72.09, 72.97, 74.60, 105.95,
126.44, 128.01, 130.57, 137.72, 151.14. Anal. Calcd for
C14H18O2: C, 77.03; H, 8.31. Found: C, 77.09; H, 8.27.
3.3.7. Compound 4g. Eighty-three percentage; a colorless
1
oil; IR (film) 2850, 1103, 1072 cmK1; H NMR (CDCl3,
300 MHz) d 1.77 (s, 3H), 2.92 (s, 2H), 3.20 (d, JZ9.3 Hz,
1H), 3.25 (d, JZ9.3 Hz, 1H), 3.75 (d, JZ9.0 Hz, 1H), 3.85
(d, JZ9.0 Hz, 1H), 3.88 (s, 2H), 4.32 (d, JZ2.1 Hz, 1H),
4.34 (d, JZ2.1 Hz, 1H), 4.66 (t, JZ2.4 Hz, 1H), 4.88–4.91
(m, 1H), 4.96–4.99 (m, 2H), 7.14–7.29 (m, 5H); 13C NMR
(CDCl3, 75 MHz) d 19.54, 39.79, 50.61, 72.34, 72.78,
75.18, 76.54, 105.25, 111.90, 126.22, 127.81, 130.61,
137.87, 142.23, 151.24; ESIMS (m/z) 259.1 (MCCH).
Anal. Calcd for C17H22O2: C, 79.03; H, 8.58. Found: C,
79.20; H, 8.57.
3.4. The reactions of 4a–h and Grubbs catalyst
To a stirred solution of 4a (122 mg, 0.5 mmol) was added
Grubbs catalyst (21 mg, 5 mol%) and the reaction mixture
was heated to reflux for 2 h. After usual workup and column
chromatographic purification process (hexanes/EtOAc,
85:15) we obtained 5a as colorless oil, 98 mg (92%).
Other entries in Tables 1 and 2 were tried similarly under the
similar conditions. The spectroscopic data of prepared
compounds are as follows.
3.3.8. Compound 4h. Sixty-eight percentage; a colorless
1
oil; IR (film) 2117, 1454, 1099 cmK1; H NMR (CDCl3,
300 MHz) d 2.44 (t, JZ2.4 Hz, 1H), 2.87 (d, JZ12.0 Hz,
1H), 2.92 (d, JZ12.0 Hz, 1H), 3.33 (d, JZ8.7 Hz, 1H), 3.39
(d, JZ8.7 Hz, 1H), 3.76 (q, JZ9.0 Hz, 1H), 3.84 (q, JZ
9.0 Hz, 1H), 4.18 (d, JZ2.4 Hz, 2H), 4.33–4.35 (m, 2H),
4.62 (t, JZ2.4 Hz, 1H), 4.98 (t, JZ2.0 Hz, 1H), 7.16–7.29
(m, 5H); 13C NMR (CDCl3, 75 MHz) d 39.64, 50.38, 58.48,
72.29, 72.53, 74.54, 76.58, 79.64, 105.52, 126.29, 127.81,
130.71, 137.60, 150.87; ESIMS (m/z) 243.1 (MCCH).
Anal. Calcd for C16H18O2: C, 79.31; H, 7.49. Found: C,
79.35; H, 7.58.
3.4.1. Compound 5a. Ninety-two percentage; a colorless
oil; IR (film) 2924, 2854, 1103, 1041 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 2.76 (d, JZ13.2 Hz, 1H), 2.92 (d, JZ
13.2 Hz, 1H), 3.02 (d, JZ10.8 Hz, 1H), 3.07 (d, JZ8.4 Hz,
1H), 3.96 (d, JZ8.4 Hz, 1H), 3.99 (d, JZ10.8 Hz, 1H),
4.09–4.46 (m, 4H), 5.54–5.58 (m, 1H), 7.19–7.33 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 38.27, 45.87, 64.59, 67.87,
69.06, 72.58, 115.93, 126.32, 128.15, 130.65, 138.11,
141.94; ESIMS (m/z) 217.1 (MCCH). Anal. Calcd for
C14H16O2: C, 77.75; H, 7.46. Found: C, 77.79; H, 7.58.
3.3.9. Compound 3b. Eighty-seven percentage; a colorless
oil; IR (film) 3529, 2924, 1342, 1161 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 2.43 (s, 3H), 2.71 (d, JZ13.5 Hz, 1H),
2.87 (d, JZ13.5 Hz, 1H), 3.10 (d, JZ9.9 Hz, 1H), 3.23 (d,
JZ9.9 Hz, 1H), 3.34–3.49 (m, 2H), 3.79 (dt, JZ14.1,
2.4 Hz, 1H), 3.87 (dt, JZ14.1, 2.1 Hz, 1H), 4.85 (t, JZ
2.4 Hz, 1H), 5.09 (t, JZ2.1 Hz, 1H), 7.08–7.33 (m, 7H),
7.65 (d, JZ8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d
21.52, 39.90, 51.57, 52.76, 54.53, 64.58, 108.24, 126.61,
127.81, 128.21, 129.67, 130.21, 132.26, 136.83, 143.74,
148.05. Anal. Calcd for C20H23NO3S: C, 67.20; H, 6.49; N,
3.92. Found: C, 67.41; H, 6.53; N, 3.85.
3.4.2. Compound 5b. Ninety-one percentage; sticky solid;
IR (film) 2924, 2858, 1338, 1157 cmK1; 1H NMR (CDCl3,
300 MHz) d 2.34 (d, JZ9.6 Hz, 1H), 2.44 (s, 3H), 2.71 (d,
JZ13.5 Hz, 1H), 2.87 (d, JZ10.8 Hz, 1H), 2.89 (d, JZ
13.5 Hz, 1H), 3.53 (d, JZ9.6 Hz, 1H), 3.69–3.76 (m, 1H),
3.91 (d, JZ10.8 Hz, 1H), 4.01–4.31 (m, 3H), 5.49–5.52 (m,
1H), 7.13–7.35 (m, 7H), 7.71 (d, JZ8.4 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 21.52, 38.33, 45.16, 50.04, 52.51,
64.78, 67.87, 118.15, 126.52, 127.57, 128.27, 129.71,
130.69, 133.86, 137.21, 138.34, 143.59; ESIMS (m/z)
370.1 (MCCH). Anal. Calcd for C21H23NO3S: C, 68.27;
H, 6.27; N, 3.79. Found: C, 68.21; H, 6.38; N, 3.71.
3.3.10. Compound 3c. Ninety-five percentage; a colorless
oil; IR (film) 3529, 3313, 1612, 1512 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 1.66 (br s, 1H), 2.73–2.80 (m, 1H),
3.70–3.75 (m, 1H), 3.80 (s, 3H), 3.82–3.88 (m, 1H), 4.38–
4.44 (m, 1H), 4.57–4.63 (m, 1H), 4.79 (d, JZ7.4 Hz, 1H),
5.06 (q, JZ2.4 Hz, 1H), 5.10 (q, JZ2.1 Hz, 1H), 6.89 (d,
JZ8.7 Hz, 2H), 7.32 (d, JZ8.7 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 53.87, 55.26, 61.92, 71.30, 83.18, 104.88,
113.91, 127.70, 133.04, 148.97, 159.33. Anal. Calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 71.01; H, 7.30.
3.4.3. Compound 5c. Ninety-seven percentage; a colorless
1
oil; IR (film) 1516, 1250, 1030 cmK1; H NMR (CDCl3,
300 MHz) d 2.73–2.79 (m, 1H), 3.28 (t, JZ10.2 Hz, 1H), 3.81
(s, 3H), 4.05–4.28 (m, 4H), 4.40–4.47 (m, 1H), 4.64–4.71 (m,
1H), 5.60–5.63 (m, 1H), 6.90 (d, JZ9.0 Hz, 2H), 7.28 (d, JZ
9.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 46.31, 55.27,
64.31, 65.89, 66.52, 83.09, 113.96, 116.05, 127.39, 132.17,
138.96, 159.48; ESIMS (m/z) 233.1 (MCCH). Anal. Calcd
for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.51; H, 6.79.
3.3.11. Compound 3e. Seventy-seven percentage; a color-
less oil; IR (film) 3440, 2927, 1018 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 1.28 (d, JZ6.3 Hz, 3H), 2.80 (d, JZ
13.5 Hz, 1H), 2.89 (d, JZ13.5 Hz, 1H), 3.45–3.58 (m, 2H),
3.62 (d, JZ9.0 Hz, 1H), 3.96 (d, JZ9.0 Hz, 1H), 4.43–5.0
(m, 1H), 4.77 (d, JZ2.4 Hz, 1H), 5.01 (d, JZ2.1 Hz, 1H),
7.15–7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 20.26,
40.55, 52.61, 65.25, 73.00, 78.18, 105.41, 126.46, 128.05,
130.47, 137.47, 156.64. Anal. Calcd for C14H18O2: C,
77.03; H, 8.31. Found: C, 77.19; H, 8.19.
3.4.4. Compound 5d. Forty-eight percentage; a colorless
1
oil; IR (film) 1739, 1516, 1250 cmK1; H NMR (CDCl3,
300 MHz) d 3.23–3.29 (m, 1H), 3.81 (s, 3H), 4.48–4.56 (m,
1H), 4.76–4.93 (m, 3H), 5.06 (d, JZ8.7 Hz, 1H), 5.88–5.93
(m, 1H), 6.91 (d, JZ9.0 Hz, 2H), 7.48 (d, JZ9.0 Hz, 2H);
13C NMR (CDCl3, 75 MHz) d 52.08, 55.28, 68.18, 68.38,

4058
S. Gowrisankar et al. / Tetrahedron 62 (2006) 4052–4058
81.22, 112.66, 113.90, 127.73, 131.69, 141.25, 159.51,
169.84; ESIMS (m/z) 247.1 (MCCH). Anal. Calcd for
C14H14O4: C, 68.28; H, 5.73. Found: C, 68.41; H, 5.76.
References and notes
1. For the reviews on RCM reactions, see: (a) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3013. (b) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (c) Alkene
Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer:
Berlin, 1998.
3.4.5. Compound 5e. Ninety-four percentage; a colorless
1
oil; IR (film) 2924, 1103, 1026 cmK1; H NMR (CDCl3,
300 MHz) d 1.28 (d, JZ6.3 Hz, 6H), 2.84 (d, JZ13.2 Hz,
4H), 2.95 (d, JZ13.2 Hz, 2H), 3.22 (d, JZ9.0 Hz, 2H), 3.30
(d, JZ9.0 Hz, 2H), 3.62 (d, JZ9.0 Hz, 2H), 3.95 (d, JZ
9.0 Hz, 2H), 4.00–4.02 (m, 2H), 4.37–4.44 (m, 2H), 4.50–
4.52 (m, 2H), 4.86 (d, JZ2.1 Hz, 2H), 5.82–5.85 (m, 2H),
7.11–7.28 (m, 10H); 13C NMR (CDCl3, 75 MHz) d 20.33,
40.65, 51.25, 71.16, 73.36, 75.18, 78.28, 105.67, 126.22,
127.70, 129.10, 130.90, 137.73, 155.72; ESIMS (m/z) 489.3
(MCCH). Anal. Calcd for C32H40O4: C, 78.65; H, 8.25.
Found: C, 78.80; H, 8.37.
2. For the synthesis of heterocyclic compounds by RCM reaction,
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
3. For our recent publications on RCM reactions, see: (a)
Kim, J. M.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron Lett.
2004, 45, 2805. (b) Lee, J. Y.; Kim, J.; Lee, K. Y. J. Phys.
Chem. A 2004, 108, 5678. (c) Lee, K. Y.; Na, J. E.; Lee, J. Y.;
Kim, J. N. Bull. Korean Chem. Soc. 2004, 25, 1280. (d)
Lee, M. J.; Lee, K. Y.; Lee, J. Y.; Kim, J. N. Org. Lett. 2004, 6,
3313.
4. For the examples of RCM reaction with exo-methylene units,
see: (a) Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.;
Malagu, K.; Procopiou, P. A. Org. Lett. 2003, 5, 669. (b)
Renzulli, M. L.; Rocheblave, L.; Avramova, S.; Corelli, F.;
Botta, M. Tetrahedron Lett. 2004, 45, 5155. (c) Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.
J. Org. Chem. 2000, 65, 2204.
3.4.6. Compound 5f. Eighty-five percentage; a colorless oil;
1
IR (film) 2924, 1115 cmK1; H NMR (CDCl3, 300 MHz) d
1.15 (d, JZ6.3 Hz, 6H), 2.92 (d, JZ13.2 Hz, 2H), 3.03 (d,
JZ13.2 Hz, 2H), 3.48 (q, JZ6.3 Hz, 2H), 3.74 (d, JZ9.0 Hz,
2H), 3.92–4.26 (m, 10H), 4.59–4.64 (m, 2H), 5.06 (t, JZ
2.1 Hz, 2H), 5.93 (t, JZ2.7 Hz, 2H), 7.14–7.26 (m, 10H); 13C
NMR (CDCl3, 75 MHz) d 14.02, 40.97, 54.37, 69.06, 72.86,
73.76, 78.83, 105.73, 126.16, 127.63, 129.02, 131.07, 137.95,
151.58; ESIMS (m/z) 489.3 (MCCH). Anal. Calcd for
C32H40O4: C, 78.65; H, 8.25. Found: C, 78.49; H, 8.11.
5. For the synthesis and biological activities of furo[3,4-c]pyran
and pyrano[3,4-c]pyrrole ring-containing compounds, see:
(a) Madhushaw, R. J.; Li, C.-L.; Shen, K.-H.; Hu, C.-C.;
Liu, R.-S. J. Am. Chem. Soc. 2001, 123, 7427. (b) Shen,
K.-H.; Lush, S.-F.; Chen, T.-L.; Liu, R.-S. J. Org. Chem.
2001, 66, 8106. (c) Shin, K.; Moriya, M.; Ogasawara, K.
Tetrahedron Lett. 1998, 39, 3765. (d) Takano, S.; Satoh, S.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988, 59. (e)
Takano, S.; Satoh, S.; Ogasawara, K.; Aoe, K. Heterocycles
1990, 30, 583. (f) Fuhrer, C.; Messer, R.; Haner, R.
Tetrahedron Lett. 2004, 45, 4297 and further references
cited therein.
3.4.7. Compound 5g. Twenty-four percentage; a colorless
1
oil; IR (film) 1736, 1516, 1250 cmK1; H NMR (CDCl3,
300 MHz) d 3.49–3.53 (m, 2H), 3.79 (s, 6H), 4.44–4.51 (m,
2H), 4.56–4.70 (m, 6H), 5.08–5.11 (m, 2H), 5.14–5.19 (m,
4H), 5.79–5.82 (m, 2H), 6.87 (d, JZ8.7 Hz, 4H), 7.30 (d,
JZ8.7 Hz, 4H); 13C NMR (CDCl3, 75 MHz) d 55.25, 56.97,
64.33, 71.46, 83.25, 106.54, 113.92, 127.50, 127.99, 131.69,
146.41, 159.56, 170.34; ESIMS (m/z) 521.2 (MCCH).
Anal. Calcd for C30H32O8: C, 69.22; H, 6.20. Found: C,
69.10; H, 6.36.
6. For the synthesis and biological activities of other furopyran
nucleus-containing compounds, see: (a) Miyata, O.; Iba, R.;
Hashimoto, J.; Naito, T. Org. Biomol. Chem. 2003, 1, 772. (b)
Kang, S. H.; Lee, Y. M. Synlett 2003, 993. (c) Mereyala, H. B.;
Joe, M. Curr. Med. Chem. Anti-Canc. Agents 2001, 1, 293. (d)
Lau, S.; Margaretha, P. Helv. Chim. Acta 1988, 71, 498.
7. Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett.
2005, 46, 4859.
3.5. Synthesis of compound 6
A mixture of 5a (65 mg, 0.3 mmol) and 5% Pd/C (10 mg) in
EtOH (1 mL) was stirred under the atmosphere of H2
(ballon) at room temperature for 3 h. After filtration,
removal of solvent, and column chromatographic purifi-
cation process (hexanes/EtOAc, 85:15) we obtained 6 as
colorless oil, 59 mg (90%).
8. For deprotection of propargyl ethers with Grubbs catalyst,
Hahn, D.-W.; Byun, D.-M.; Tae, J. Eur. J. Org. Chem.
2005, 63.
9. For the synthesis of methylenetetrahydrofuran derivative from
cinnamates, see: (a) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron
Lett. 2005, 46, 1155. (b) Roy, S. C.; Guin, C.; Rana, K. K.;
Maiti, G. Tetrahedron 2002, 58, 2435. (c) Roy, S. C.; Guin, C.;
Rana, K. K.; Maiti, G. Synlett 2001, 226. (d) Mandal, P. K.;
Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63, 2829.
10. For the radical cyclization of propargyloxy-containing Baylis–
Hillman adducts, see: (a) Shanmugam, P.; Rajasingh, P.
Tetrahedron 2004, 60, 9283. (b) Shanmugam, P.; Rajasingh, P.
Chem. Lett. 2002, 1212. (c) Shanmugam, P.; Rajasingh, P.
Synlett 2005, 939. (d) Shanmugam, P.; Rajasingh, P.
Tetrahedron Lett. 2005, 46, 3369.
3.5.1. Compound 6. Ninety percentage; a colorless oil; IR
1
(film) 2924, 2854 cmK1; H NMR (CDCl3, 300 MHz) d
1.48–1.51 (m, 1H), 1.90–2.02 (m, 1H), 2.16–2.25 (m, 1H),
2.60 (d, JZ13.5 Hz, 1H), 3.00 (d, JZ13.5 Hz, 1H), 3.38 (d,
JZ12.0 Hz, 1H), 3.47 (d, JZ9.0 Hz, 1H), 3.57–3.74 (m,
4H), 3.84 (t, JZ8.4 Hz, 1H), 4.06 (t, JZ8.4 Hz, 1H), 7.11–
7.14 (m, 2H), 7.19–7.32 (m, 3H); 13C NMR (CDCl3,
75 MHz) d 23.31, 29.63, 39.62, 39.90, 64.41, 68.53, 70.63,
73.76, 126.40, 128.22, 130.00, 137.65; ESIMS (m/z) 219.1
(MCCH). Anal. Calcd for C14H18O2: C, 77.03; H, 8.31.
Found: C, 77.14; H, 8.23.