Synthesis of cyclic ethers from 3- and 4-hydroxyalkylphosphonium salts

Article abstract of DOI:10.1246/bcsj.78.2209

The reaction of 6-methylene-1,3-dioxepanes derived from 3-hydroxyalkyltriphenylphosphonium salts and paraformaldehyde with trimethylsilyl trifluoromethanesulfonate in the presence of N,N- diisopropylethylamine yielded novel 4-formyltetrahydropyrans. 3-Met

Full text of DOI:10.1246/bcsj.78.2209

Ó 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 2209–2213 (2005) 2209
Synthesis of Cyclic Ethers from 3- and 4-Hydroxyalkylphosphonium Salts
ꢀ
Kentaro Okuma, Osami Sakai, Tetsuji Hayano, Kosei Shioji, and Haruo Matsuyama1
Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku, Fukuoka 814-0180
1Department of Applied Chemistry, Faculty of Engineering, Muroran Institute of Technology,
27-1 Mizumoto-cho, Muroran 050-8585
Received June 15, 2005; E-mail: kokuma@fukuoka-u.ac.jp
The reaction of 6-methylene-1,3-dioxepanes derived from 3-hydroxyalkyltriphenylphosphonium salts and para-
formaldehyde with trimethylsilyl trifluoromethanesulfonate in the presence of N,N-diisopropylethylamine yielded novel
4-formyltetrahydropyrans. 3-Methylenetetrahydropyrans were synthesized by the reaction of 4-hydroxyalkyltriphenyl-
phosphonium iodides with DBU and paraformaldehyde. 2,3-Dihydro-3-methylenebenzofuran was also obtained by
the reaction of 2-hydroxybenzyltriphenylphosphonium bromide with butyllithium, followed by the addition of paraform-
aldehyde.
Cyclic ethers are important compounds for the synthesis of
natural products. Since their synthetic utility in the formation
of tetrahydropyrans 1 appears to be promising, many reports
on the synthesis of substituted tetrahydropyrans have appeared.
Typical methods include the acid-catalyzed cyclization of
epoxy alcohols and terminal alkenols,1,2 the Pd-catalyzed in-
tramolecular 1,4-dialkoxyalkylation of terminal dienals,3 the
reaction of hydroxyallylsilane with aldehydes in the presence
of TMSOTf,4 the palladium-catalyzed trimethylenemethane
reaction,5 and the reaction of acetals with 2-(trimethylsilyloxy-
ethyl)allyltrimethylsilane.6 Previously, we communicated the
synthesis of tetrahydropyrans 1 by the ring contraction of
1,3-dioxepanes 2 produced from sequential Wittig reactions.7
We report herein on the full details of this reaction and a dif-
ferent type of the formation of six-membered cyclic ethers
from phosphonium ylides.
O
Ph3P CH2
Ph3P
O
(CH2O)n
toluene
O
+
O
R
R
R
3
2a: R = Ph
2b: R = Me
2c: R = Et
2d: R = Bu
2e: R = m-ClC6H4
Scheme 1.
Table 1. One-Pot Synthesis of 6-Methylene-1,3-dioxepanes 2
Conditions
Products
Yield/%
Epoxide
R
Time/h
Temp
2
Ph
Ph
Me
Et
Bu
1
1
3
3
2
1
80 ꢁC
reflux
reflux
reflux
reflux
reflux
2a
2a
2b
2c
2d
2e
26
56
33
52
56
58
Results and Discussion
One-Pot Synthesis of 6-Methylene-1,3-dioxepanes. Sub-
stituted 6-methylene-1,3-dioxepanes 2 were previously synthe-
sized by the reaction of 1,2ꢀ5-oxaphospholanes 3 with para-
formaldehydes.8 Since 1,2ꢀ5-oxaphospholane 3 was easily
hydrolyzed to give the corresponding diphenylphosphine ox-
ide, we first tried a one-pot synthesis of 2. The treatment of
methylenetriphenylphosphorane with styrene oxide, followed
by the addition of paraformaldehyde, resulted in the formation
of 6-methylene-4-phenyl-1,3-dioxepane (2a) in 56% yield
(Scheme 1). Other reactions were carried out in a similar
manner (Table 1).
Since a new Wittig olefination by using 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) as a base was developed,9 we ap-
plied this method to the synthesis of 2. When 3-hydroxy-3-
arylpropylphosphonium salts 4 were treated with DBU and
paraformaldehyde, corresponding dioxepanes 2 were obtained
in almost quantitative yields (Scheme 2, Table 2).
m-ClC6H4
O
OH
R
Ph3P
O
(CH2O)n
Ph3P
Br
DBU
O
R
R
3
4a: R = Ph
2a: R = Ph
4b: R = p-ClC6H4
4c: R = m-ClC6H4
4d: R = Me
2f : R = p-ClC6H4
2e: R = m-ClC6H4
2b: R = Me
Scheme 2.
Ring Contraction of Dioxepanes 2. Since dioxepanes 2
are novel 7-membered cyclic acetals, their reactivity is our
next interest. If these acetals react with a Lewis acid, a new
type of aldehydes or alcohols will be formed. However, a
normal Lewis acid, such as diethyl ether–borontrifluoride
By using this improved method, dioxepanes 2 were synthe-
sized on a large scale and could be used for their further inves-
tigation.
Published on the web December 9, 2005; DOI 10.1246/bcsj.78.2209

2210 Bull. Chem. Soc. Jpn., 78, No. 12 (2005)
Cyclic Ethers from Hydroxyalkylphosphonium Salts
Table 2. Reaction of Salts 4 with DBU Followed by the
Addition of Paraformaldehyde
O
OTMS
O
H
O
H+
(i-Pr)2NEt
4
Conditions
Products
Yield/%
R
Time/h
Temp
2
R
2
4a
4a
4b
4c
4d
Ph
Ph
p-ClC6H4
m-ClC6H4
Me
5
5
5
6
5
rt
2a
2a
2f
2e
2b
0
96
90
92
52
O
R
O
1
R
+
TMSOTf
reflux
reflux
reflux
reflux
5
2a: R = Ph
2d: R = Bu
2e: R = m-ClC6H4
1a: R = Ph
1b: R = Bu
1c: R = m-ClC6H4
5a: R = Ph
Scheme 3.
Table 3. Reaction of 6-Methylene-1,3-dioxepanes 2 with TMSOTf
2
Conditions
Products
R
Time/h
Temp
Base (equiv)
1
cis:trans
Yield/%
2a
2a
2a
2a
2d
2e
Ph
Ph
Ph
Ph
Bu
5
1
3
3
6
3
rt
0.5
0.5
1
2
2
1a
1a
1a
1a
1b
1c
—
—
—
1:1
1:1
1:1
0
0
10
77
40
29a)
reflux
reflux
reflux
reflux
reflux
m-ClC6H4
2
a) 2e was recovered in 40% yield.
TMS
O
Ph3P
+
NaI
O
C
Ph3P
O
2
+
O
R
Cl
R
O
R
I
TMS OTf
9a: R = Ph
9b: R = Me
TMSO
R
6
OH
NaBH4
MeOH
Ph3P
O
R
5
I
O
TMS
R
8a: R = Ph
8b: R = Me
7
H
(i-Pr)2EtN
Scheme 5.
Scheme 4.
Gonzalez et al. have reported on the synthesis of 3-deoxy-3-
nitroheptoseptanosides by the reaction of 1,4-dioxepanes with
nitromethane in the presence of potassium fluoride as a cata-
lyst.14 Fukuzawa et al. reported on the effective transformation
of aldoximes of 1,3-dioxepanes to nitriles by dehydration in
the presence of scandium(III) triflate.15 However, there is no
report on ring contraction from methylene-1,3-dioxepanes.
Synthesis of Tetrahydropyrans from 4-Hydroxyalkyl-
phosphonium Salts. It has been reported that reaction of
ꢁ-oxido ylides with paraformaldehyde afforded 3-methylene-
tetrahydrofurans.16 We have extended this method to the syn-
thesis of tetrahydropyrans by using ꢂ-oxido ylides, prepared
from 4-hydroxyalkyltriphenylphosphonium salts 8 and bases.
4-Hydroxy-4-phenylbutyltriphenylphosphonium iodide (8a)
was synthesized by the following two-step reaction. 4-Chloro-
butyrophenone reacted with triphenylphosphine in the pres-
ence of sodium iodide to give 4-oxo-4-phenylbutyltriphenyl-
phosphonium iodide (9a), which was reduced by NaBH4 to
afford 8a (Scheme 5).
or SnCl2, gave polymeric mixtures. We then chose trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) as a Lewis acid.
TMSOTf is a good reagent for a Michaelis–Arbuzov rear-
rangement,10 the formation of thioacylsilanes,11 and the ring
expansion of 1,2,3-methanochromanes.12 Dioxepane 2a was
treated with TMSOTf in the presence of N,N-diisopropyl-
ethylamine, followed by the addition of 1 M HCl to give the
corresponding cis- and trans-4-formyl-2-phenyltetrahydropy-
rans (1a) (Scheme 3, Table 3). A mixture of cis- and trans-enol
ethers 5 was also obtained as an intermediate.
Gassman et al. reported that the reaction of acetals with
TMSOTf, followed by the addition of N,N-diisopropylethyl-
amine, afforded the corresponding vinyl ethers in good
yields.13 In view of this result, we proposed the following
mechanism. An initial attack of 2 with TMSOTf resulted in
the formation of an oxonium ion intermediate 6, which was
further attacked by a double bond to give six-membered cyclic
carbocation 7, which finally produced the tetrahydropyran 1,
by the abstraction of a proton with diisopropylethylamine
(Scheme 4).
The treatment of salt 8a with butyllithium, followed by the
addition of paraformaldehyde resulted in the formation of

K. Okuma et al.
Bull. Chem. Soc. Jpn., 78, No. 12 (2005) 2211
OH
I
O
O
Ph3P
O
C
O
R
O
H
H
OH
(CH2O)n
reflux
R
H
Ph3P
C
C
O
CH
Ph3P
+
Ph3P C
8a: R = Ph
8b: R = Me
H
H
R
10
O
O
R
10a: R = Ph
10b: R = Me
11a: R = Ph
11b: R = Me
O
H
+ Base
R
H
R
H
12
13
14
Scheme 6.
Scheme 7.
Table 4. Reaction of 4-Hydroxylphosphonium Salts 7 with Base and Paraformaldehyde
8
Conditions
Solvent
Products
R
Base
Time/h
10
Yield/%
11
Yield/%
8a
8a
8a
8a
8b
Ph
Ph
Ph
Ph
Me
BuLi
NaH
DBU
DBU
DBU
Toluene
Benzene
Benzene
CH3CN
CH3CN
6
10a
10a
10a
10a
10b
26
19
30
65
35
11a
11a
11a
11a
11b
12
28
41
15
20
16
16
16
16
5-methylene-2-phenyltetrahydropyran (10a) in 26% yield
along with 1-phenyl-4-pentenol (11a) (12%). When the reac-
tion was carried out by using DBU as a base, tetrahydropyran
10a was obtained in 65% yield (Scheme 6, Table 4).
The reaction might proceed as follows. ꢂ-Oxido ylide 12
reacted with paraformaldehyde to give the corresponding be-
taine 13, which further reacted with another paraformaldehyde
to afford another type of betaine 14, which finally cyclized to
afford 10 (Scheme 7).
PPh3
PPh
3 (CH2O)n
BuLi
O
O
OH
15
18
16 51%
+
OH
17 24%
DBU
+ Ph3P=O 86%
Synthesis of 3-Methylenetetrahydrofuran.
Since 3-
CH2
O
CH3
methylenetetrahydrofuran was synthesized by ꢁ-oxide ylide
with paraformaldehyde,16 we then applied the present method
to the synthesis of benzofuran derivative. Commercially avail-
able 2-hydroxybenzyltriphenyphosphonium bromide (15) was
treated with butyllithium, followed by the addition of para-
formaldehyde to give 2,3-dihydro-3-methylenebenzofuran (16)
in 51% yield along with o-vinylphenol (17), the normal Wittig
reaction product, and triphenylphosphine oxide. When DBU
was used as a base, the rearranged products (o-cresol and tri-
phenylphosphine oxide) were obtained. Since the acidity of
ꢃ-proton of salt 15 was lower than that of benzyltriphenyl-
phosphonium bromide, DBU could not synthesize the ꢁ-oxide
phosphonium ylide 18. Thus, a strong base plays an important
role for the synthesis of benzofuran (Scheme 8).
PPh3
OH
O
PPh3
85%
+ Ph3P=O
81%
Scheme 8.
phenylphosphonium bromide (7.75 g, 22 mmol) in one portion.
After refluxing for 2 h, styrene oxide (2.40 g, 20 mmol) was added
to this red solution. After refluxing for 14 h, paraformaldehyde
(2.40 g, 60 mmol equivalent) was added to this suspension. After
refluxing for 3 h, the reaction mixture was poured into water
and the toluene layer was separated. The water layer was extracted
with dichloromethane (25 mL) three times. The combined extract
was dried over MgSO4, filtered, and evaporated to give a pale-
yellow oil, which was chromatographed over silica gel by elution
with hexane to give 6-methylene-4-phenyl-1,3-dioxepane (2a)
(2.13 g, 11.2 mmol), colorless oil (100–110 ꢁC/1.9 mmHg). The
spectral data were identical with that of an authentic sample.8 An-
other reaction was carried out in a similar manner. 2b: bp 40–
55 ꢁC/20 mmHg (lit.8 bp 45–55 ꢁC/17 mmHg). 2c: bp 75–85 ꢁC/
20 mmHg (lit.8 bp 80–90 ꢁC/20 mmHg). 2d: Colorless oil; bp
100–110 ꢁC/25 mmHg. 1H NMR (CDCl3) ꢂ 0.91 (t, 3H, J ¼ 7 Hz,
CH3), 1.22–1.62 (m, 6H, CH2), 2.40 (m, 2H, allyl CH2), 3.50 (m,
1H, CHBu), 4.24 (d, 1H, J ¼ 14 Hz, OCHH), 4.38 (d, 1H,
J ¼ 14 Hz, OCHH), 4.64 (d, 1H, J ¼ 7 Hz, OCHHO), 4.92 (brs,
2H, =CH2), 4.99 (d, 1H, J ¼ 7 Hz, OCHHO). 13C NMR (CDCl3)
ꢂ 14.07 (CH3), 22.65 (CH2), 28.01 (CH2), 35.75 (CH2), 43.31
(CH2), 73.13 (CH2O), 79.09 (OCH), 94.56 (OCH2O), 113.84
In summary, we have succeeded in the synthesis of exo-
methylene cyclic ethers starting from hydroxyalkylphospho-
nium salts.
Experimental
General. All chemicals were obtained from commercial sup-
pliers and were used without further purification. Analytical TLC
was carried out on precoated plates (Merck silica gel 60, F254)
and flash column chromatography was performed with silica
(Merck, 70–230 mesh). All reactions were carried out in a nitro-
gen atmosphere. NMR spectra were measured on a JEOL GSX-
400 (400 MHz for 1H, 100 MHz for 13C). The melting points were
uncorrected.
One-Pot Synthesis of 6-Methylene-4-phenyl-1,3-dioxepane
(2a). To a suspension of sodium hydride (60% mineral oil disper-
sion, 1.12 g, 28 mmol) in toluene (200 mL) was added methyltri-

2212 Bull. Chem. Soc. Jpn., 78, No. 12 (2005)
Cyclic Ethers from Hydroxyalkylphosphonium Salts
(CH2=), 145.59 (=C). Anal. Calcd for C10H18O2: C, 70.55; H,
1
C10H18O2: C, 70.55; H, 10.66%. Found: C, 70.29; H, 10.56%.
Both isomers could not be separated. cis-1b: 1H NMR (CDCl3)
ꢂ 0.89 (t, 3H, J ¼ 8 Hz, CH3), 1.20–2.00 (m, 10H, CH2), 2.50
(m, 1H, CH), 3.29 (m, 1H, CH), 3.48 (t, 1H, J ¼ 12 Hz, OCHH),
4.12 (brd, 1H, J ¼ 12 Hz, OCHH), 9.61 (d, 1H, J ¼ 1 Hz, CHO).
13C NMR (CDCl3) ꢂ 14.16 (CH3), 22.82 (CH2), 25.83 (CH2),
27.64 (CH2), 31.21 (CH2), 36.11 (CH2), 48.01 (CH), 66.93 (CH2),
76.82 (CH), 202.48 (CHO). trans-1b: Colorless oil; 1H NMR
(CDCl3) ꢂ 0.89 (t, 3H, J ¼ 8 Hz, CH3), 1.20–1.65 (m, 7H, CH2),
1.89 (m, 1H, CHH), 2.03 (d, 1H, J ¼ 14 Hz, CHH), 2.10 (d, 1H,
J ¼ 16 Hz, CHH), 2.67 (brs, 1H, CH), 3.26 (brs, 1H, CH), 3.41
(dt, 1H, J ¼ 12 Hz and 3 Hz, OCHH), 3.86 (brd, 1H, J ¼ 12 Hz,
OCHH), 9.80 (s, 1H, CHO). 13C NMR (CDCl3) ꢂ 13.98 (CH3),
22.63 (CH2), 24.58 (CH2), 27.48 (CH2), 30.11 (CH2), 35.74
(CH2), 44.39 (CH), 64.63 (CH2), 74.18 (CH), 202.68 (CHO).
1c: Colorless oil: Anal. Calcd for C12H13ClO2: C, 64.15; H,
5.83%. Found: C, 63.87; H, 5.87%. Both isomers could not be
separated. cis-1c: 1H NMR (CDCl3) ꢂ 1.54 (m, 1H, CHH), 1.73
(m, 1H, CHH), 1.92 (brd, 1H, J ¼ 14 Hz, CHH), 2.13 (brd, 1H,
J ¼ 14 Hz, CHH), 2.68 (br, 1H, CH), 3.62 (dt, 1H, J ¼ 12 Hz and
3 Hz, OCHH), 4.28 (brd, 1H, J ¼ 12 Hz, OCHH), 4.36 (brd, 1H,
J ¼ 12 Hz, OCH), 7.18–7.38 (m, 4H, Ar), 9.64 (CHO). 13C NMR
(CDCl3) ꢂ 25.62 (CH2), 33.41 (CH2), 48.24 (CH2), 67.63 (CH),
78.31 (OCH), 124.11, 126.16, 129.91, 134.59, 144.30 (Ar),
202.25 (CHO). trans-1c: 1H NMR (CDCl3) ꢂ 1.85 (m, 1H, CHH),
2.05 (m, 1H, CHH), 2.12 (brd, 1H, J ¼ 14 Hz, CHH), 2.33 (brd,
1H, J ¼ 14 Hz, CHH), 2.77 (brs, 1H, CH), 3.57 (dt, 1H, J ¼ 12
Hz and 3 Hz, OCHH), 4.01 (brd, 1H, J ¼ 12 Hz, OCHH), 4.36
(brd, 1H, J ¼ 12 Hz, OCH), 7.20–7.38 (m, 4H, Ar), 9.89 (CHO).
13C NMR (CDCl3) ꢂ 24.40 (CH2), 31.79 (CH2), 44.63 (CH2),
64.98 (CH), 75.89 (OCH), 125.33, 127.23, 128.06, 141.92 (Ph),
203.32 (CHO).
10.66%. Found: C, 70.29; H, 10.56%. 2e: Colorless oil, H NMR
(CDCl3) ꢂ 2.60–2.76 (m, 2H, allyl CH2), 4.33 (d, 1H, J ¼ 14 Hz,
OCHH), 4.47 (d, 1H, J ¼ 14 Hz, OCHH), 4.56 (dd, 1H, J ¼ 2 Hz,
J ¼ 10 Hz, OCHAr), 4.79 (d, 1H, J ¼ 7 Hz, OCHHO), 5.03 (brs,
2H, =CH2), 5.11 (d, 1H, J ¼ 7 Hz, OCHHO), 7.20–7.42 (m, 4H,
Ar). 13C NMR (CDCl3) ꢂ 46.03 (CH2), 73.48 (OCH2), 80.62
(ArCH), 94.69 (OCH2O), 115.48 (=CH2), 124.28, 126.40, 129.94,
144.51 (Ar), 145.01 (=C). HRMS Calcd for C12H22ClO2: Mþ,
224.0604. Found: 224.0608 (Mþ). Anal. Calcd for C12H13ClO2:
C, 63.93; H, 5.90%. Found: C, 64.15; H, 5.83%.
Reaction of 3-Hydroxy-3-p-chlorophenyltriphenylphospho-
nium Bromide (4b) with DBU Followed by the Addition of
Paraformaldehyde. To a solution of 4b (2.55 g, 5.0 mmol) in
dichloromethane (35 mL) was added DBU (2.28 g, 15.0 mmol)
in one portion. After refluxing for 30 min, paraformaldehyde
(0.45 g, 15 mmol) was added in one portion and refluxed for 5 h.
The reaction mixture was washed with water (15 mL ꢂ 3), dried
over sodium sulfate, filtered, and evaporated to give pale-yellow
orange oily crystals, which were chromatographed over silica
gel by elution with hexane–dichloromethane (1:1) to afford 3-p-
chlorophenyl-5-methylene-1,3-dioxepane (1.08 g, 4.5 mmol). 2f:
1
Colorless oil: H NMR (CDCl3) ꢂ 2.62 (dd, 1H, J ¼ 13 Hz, J ¼
1 Hz, allyl CHH), 2.70 (dd, 1H, J ¼ 13 Hz, J ¼ 10 Hz, allyl
CHH), 4.33 (d, 1H, J ¼ 14 Hz, OCHH), 4.50 (d, 1H, J ¼ 14 Hz,
OCHH), 4.56 (dd, 1H, J ¼ 2 Hz, J ¼ 10 Hz, OCHAr), 4.79 (d,
1H, J ¼ 7 Hz, OCHHO), 5.03 (brs, 2H, =CH2), 5.11 (d, 1H, J ¼
7 Hz, OCHHO), 7.32 (s, 4H, Ar). 13C NMR (CDCl3) ꢂ 46.07
(CH2), 73.52 (OCH2), 80.71 (ArCH), 94.69 (OCH2O), 115.42
(=CH2), 127.53, 128.79, 133.50, 141.01 (Ar), 145.10 (=C). Anal.
Calcd for C12H13ClO2: C, 64.15; H, 5.83%. Found: C, 63.86; H,
5.87%.
Reaction of Dioxepane 2a with TMSOTf in the Presence of
N,N-Diisopropylethylamine.
A mixture of cis- and trans-trimethylsiloxymethylene-2-phen-
yltetrahydropyrans (5a) (0.40 g, 1.54 mmol) was obtained when
the mixture was extracted with water. cis- and trans-5a: Colorless
oil; 1H NMR (CDCl3) ꢂ 0.19 (s, 18H, TMS), 1.98 (d, 1H, J ¼ 12:0
Hz, CHH), 2.00 (d, 1H, J ¼ 12 Hz, CHH), 2.07 (m, 1H, CHH),
2.20 (m, 2H, CH2), 2.33 (m, 1H, CHH), 2.73 (d, 1H, J ¼ 12:0
Hz, CHH), 2.97 (d, 1H, J ¼ 12:0 Hz, CHH), 3.51 (m, 2H, OCHH),
4.17 (m, 2H, OCHH), 4.25 (m, 2H, OCH), 6.18 (s, 2H, =CH),
7.22–7.43 (m, 10H, Ph). 13C NMR (CDCl3) ꢂ ꢃ0:32 (TMS), 25.99
(CH2), 30.21 (CH2), 33.74 (CH2), 38.26 (CH2), 68.51 (OCH2),
68.53 (OCH2), 79.91 (OCH), 81.16 (OCH), 116.87 (=C), 116.98
(=C), 125.71, 125.85, 127.29, 128.16, 132.01 (=CHOTMS),
132.11 (=CHOTMS), 142.43, 142.51 (Ph). HRMS Calcd for
C15H22O2Si: Mþ, 262.1389. Found: 262.1371 (Mþ).
To a solution of 2a (0.19 g,
1.0 mmol) and N,N-diisopropylethylamine (0.26 g, 2.0 mmol) in
dichloromethane (10 mL) was added a solution of TMSOTf
(0.22 g, 1.0 mmol) in dichloromethane (4 mL). After refluxing
for 2 h, the reaction mixture was poured into aqueous 1 M HCl
and the dichloromethane layer was separated. The aqueous layer
was extracted with dichloromethane (5 mL) three times. The com-
bined extract was washed with water, dried over MgSO4, filtered,
and evaporated to give a pale-yellow oil, which was distilled by
bulb to bulb to give a mixture of cis- and trans-4-formyl-2-phenyl-
tetrahydropyrans (1a) (0.21 g, 1.1 mmol, 77%). bp 110–140 ꢁC/
2 mmHg. HRMS Calcd for C11H14O2: 199.0994. Found:
1
199.0981 (Mþ). cis-1a: H NMR (CDCl3) ꢂ 1.58 (q, 1H, J ¼ 12
Hz, CHH), 1.68 (dq, 1H, J ¼ 12 Hz and 4 Hz, CHH), 1.88 (d,
1H, J ¼ 10 Hz, CHH), 2.10 (d, 1H, J ¼ 13 Hz, CHH), 2.66 (tt,
1H, J ¼ 12 Hz and 4 Hz, CHH), 3.64 (t, 1H, J ¼ 11 Hz, OCHH),
4.27 (dd, 1H, J ¼ 11 Hz and 4 Hz, OCHH), 4.38 (d, 1H, J ¼
12 Hz, OCH), 7.23–7.37 (m, 5H, Ph), 9.62 (CHO). 13C NMR
(CDCl3) ꢂ 25.50 (CH2), 33.23 (CH2), 48.17 (CH2), 67.34 (CH),
78.77 (OCH), 125.59, 127.53, 128.21, 141.80 (Ph), 201.85
(CHO). trans-1a: 1H NMR (CDCl3) ꢂ 1.91 (m, 1H, CHH), 2.05
(m, 1H, CHH), 2.12 (brd, 1H, J ¼ 11 Hz, CHH), 2.32 (brd, 1H,
J ¼ 14 Hz, CHH), 2.77 (brs, 1H, CH), 3.64 (dt, 1H, J ¼ 12 Hz
and 3 Hz, OCHH), 4.01 (dd, 1H, J ¼ 12 Hz and 4 Hz, OCHH),
4.30 (dd, 1H, J ¼ 12 Hz and 3 Hz, OCH), 7.23–7.37 (m, 5H,
Ph), 9.88 (CHO). 13C NMR (CDCl3) ꢂ 24.23 (CH2), 31.79 (CH2),
44.63 (CH2), 64.98 (CH), 75.89 (OCH), 125.33, 127.23, 128.06,
141.92 (Ph), 203.32 (CHO).
Synthesis of 4-Hydroxy-4-phenylbutyltriphenylphospho-
nium Iodide (8a). To a solution of triphenylphosphine (2.62 g,
10 mmol) in toluene (100 mL) was added a solution of 4-chloro-
butyrophenone (2.00 g, 11 mmol) and sodium iodide (1.80 g, 12
mmol) in toluene (25 mL). After stirring for 8 h, colorless crystals
were precipitated, which were filtered to give colorless crystals of
3-benzoylpropyltriphenylphosphonium iodide (9a) (4.28 g, 8.0
mmol). To a solution of salts 9a in methanol (50 mL) was added
sodium tetrahydroborate (0.30 g, 8.0 mmol) in one portion. After
refluxing for 6 h, the reaction mixture was poured into water
(50 mL) and extracted from dichloromethane (20 mL) three times.
The combined extract was dried over MgSO4, filtered, and evapo-
rated to give a colorless solid, which was recrystallized from
methanol to give colorless crystals of 4-hydroxy-4-phenylbutyltri-
phenyphosphonium iodide (8a) (3.75 g, 7.0 mmol). 1H NMR
(CDCl3) ꢂ 1.60–1.70 (m, 1H, CH2), 1.77–1.90 (m, 1H, CH2),
1b:
Colorless oil: 70–75 ꢁC/0.3 mmHg. Anal. Calcd for

K. Okuma et al.
Bull. Chem. Soc. Jpn., 78, No. 12 (2005) 2213
2.05 (m, 2H, CH2), 3.50–3.65 (m, 1H, PCHH), 3.85–3.95 (m, 1H,
PCHH), 4.98 (m, 1H, PhCH), 7.05–7.32 (m, 5H, Ph), 7.60–7.80
(m, PPh3). 13C NMR (CDCl3) ꢂ 19.10 (CH2), 22.36 (d, CH2),
38.80 (d, CH2), 71.74 (CH), 109.99, 118.30, 126.10, 126.75,
128.15, 130.60, 133.67, 135.04, 145.15 (Ph). Elemental analysis
was carried out by changing to its tetraphenylborate. mp 160–
161 ꢁC, Anal. Calcd for C52H48BOP: C, 85.47; H, 6.62%. Found:
C, 85.72; H, 6.85%.
crystals, which were chromatographed over silica gel by elution
with hexane–dichloromethane and dichloromethane to afford 2,3-
dihydro-3-methylenebenzofuran (16) (0.14 g, 1.05 mmol), o-vinyl-
phenol (17) (0.058 g, 0.48 mmol), and triphenylphosphine oxide
(0.48 g, 1.72 mmol). 16: Colorless oil: bp 85–105 ꢁC/20 mmHg
(lit.20 75–80 ꢁC/12 mmHg).
When 15 (0.90 g, 2.0 mmol) was treated with DBU (0.61 g,
4.0 mmol), followed by the addition of paraformaldehyde
(0.30 g, 10 mmol) in refluxing dichloromethane, o-cresol (0.18 g,
1.70 mmol) was obtained in 85% yield along with triphenylphos-
phine oxide (0.45 g, 1.62 mmol).
8b: mp 186–188 ꢁC. 1H NMR (CDCl3) ꢂ 1.16 (d, 3H, J ¼ 6:4
Hz, Me), 1.68–1.91 (m, 4H, CH2CH2), 3.52 (m, 1H, PCHH), 3.82
(m, 1H, PCHH), 4.05 (m, 1H, CH), 7.65–7.85 (m, 15H, Ph).
13C NMR (CDCl3) ꢂ 19.61 (Me), 23.20 (CH2), 24.38 (d, JP{C
50 Hz, CH2), 38.58 (d, JP{C ¼ 16 Hz), 66.20, 118.43 (d, JP{C
¼
¼
References
86 Hz), 130.71 (d, JP{C ¼ 12 Hz), 133.93, 135.24 (Ph). Anal. Calcd
for C23H26OPI: C, 57.99; H, 5.50%. Found: C, 58.09; H, 5.53%.
Reaction of Salt 8a with Butyllithium Followed by the
Addition of Paraformaldehyde. To a suspension of salt 8a
(0.538 g, 1.0 mmol) in benzene (30 mL) was added a solution of
butyllithium (2.5 M in hexane, 1.0 mL) in hexane at room temper-
ature. After stirring for 2 h, paraformaldehyde (0.30 g, 10 mmol)
was added to this solution in one portion. After refluxing for
8 h, the reaction mixture was poured into water (30 mL) and ex-
tracted with dichloromethane (20 mL ꢂ 3). The combined extract
was dried over MgSO4, filtered, and evaporated to give pale-
yellow crystals, which were chromatographed over silica gel by
elution with hexane: dichloromethane (1:1) to afford 5-methyl-
ene-2-phenyltetrahydropyran (10a). Colorless oil; 0.045 g, 0.26
mmol. 135–150 ꢁC/2 mmHg (lit.17 100–150 ꢁC/16 mmHg). 1-
Phenyl-4-pentenol (11a) was eluted second (0.020 g, 0.12 mmol).
The spectral data were identical with the reported one.18 By
elution with dichloromethane, triphenylphosphine oxide (0.21 g,
0.76 mmol) was obtained.
1
H. Matsukura, M. Morimoto, H. Koshino, and T. Nakata,
Tetrahedron Lett., 38, 5545 (1997); M. Tokumasa, A. Sasaoka,
R. Takagi, Y. Hiraga, and K. Ohtaka, J. Chem. Soc., Chem.
Commun., 1997, 875.
2
(1997).
3
N. Greeves and W. M. Lee, Tetrahedron Lett., 38, 6449
R. C. Larock, H. Yang, P. Pace, S. Cacchi, and G. Fabrizi,
Tetrahedron Lett., 39, 237 (1998).
D. Yang, M.-K. Wong, X.-C. Wang, and Y.-C. Tang,
J. Am. Chem. Soc., 120, 6611 (1998).
B. M. Trost, S. A. King, and T. Schmidt, J. Am. Chem.
Soc., 111, 5902 (1989).
4
5
6
Jpn., 74, 569 (2001).
7
Tetrahedron Lett., 41, 2171 (2000).
8
cycles, 50, 125 (1999).
T. Oriyama, A. Ishiwata, and T. Suzuki, Bull. Chem. Soc.
K. Okuma, T. Hayano, K. Shioji, and H. Matsuyama,
K. Okuma, Y. Tanaka, I. Shuzui, and K. Shioji, Hetero-
Reaction of Salts 8a with DBU Followed by the Addition of
Paraformaldehyde. To a solution of salt 8a (0.538 g, 1.0 mmol)
in acetonitrile (20 mL) was added DBU (0.38 g, 2.5 mmol) in
acetonitrile (5 mL) at room temperature. After refluxing for 2 h,
paraformaldehyde (0.30 g, 10 mmol) was added in one portion.
After being stirred for 10 h, the reaction mixture was poured into
water and extracted with dichloromethane (15 mL) three times.
The combined extract was washed with water, dried over MgSO4,
and evaporated to give a pale-yellow oil, which was chromato-
graphed over silica gel by elution with hexane–dichloromethane
to give a colorless oil of tetrahydropyrans 10a (0.113 g, 0.65
mmol). 1-Phenyl-4-pentenol (11a) was eluted next (0.025 g, 0.15
mmol).19 Similarly, 2-methyl-5-methylenetetrahydropyran (10b)
was obtained in 35% yield. 10b: Colorless oil: bp 70–95 ꢁC/
25 mmHg). 1H spectral data of 10b was identical with the reported
data.17
Reaction of 2-Hydroxybenzyltriphenylphosphonium Bro-
mide (15) with BuLi Followed by the Addition of Para-
formaldehyde. To a solution of 2-hydroxybenzyltriphenylphos-
phonium bromide (15) (0.90 g, 2.0 mmol) in THF (30 mL) was
added BuLi (2 M in hexane, 3.0 mL) at room temperature. After
stirring for 1 h, paraformaldehyde (0.30 g, 10 mmol) was added
in one portion and the suspension was refluxed for 5 h. The reac-
tion mixture was poured into water and extracted with dichloro-
methane (15 mL ꢂ 3). The combined extract was dried over
sodium sulfate, filtered, and evaporated to give pale-orange oily
9
76, 1675 (2003).
10 P.-Y. Renard, P. Varian, E. Leclerc, A. Vallex, and C.
Mioskowski, Angew. Chem., Int. Ed. Engl., 42, 2389 (2003).
11 A. Degl’Innocenti, A. Capperucci, D. C. Oniciu, and A. R.
Katritzky, J. Org. Chem., 65, 9206 (2000).
12 Y. Sugita, K. Kawai, H. Hosoya, and I. Yokoe, Hetero-
cycles, 51, 2029 (1999).
13 P. G. Gassman, S. J. Burns, and K. B. Pfister, J. Org.
Chem., 58, 1449 (1993).
K. Okuma, O. Sakai, and K. Shioji, Bull. Chem. Soc. Jpn.,
14 F. S. Gonzalez, A. V. Berenguel, and J. M. Molina, Carbo-
hydr. Res., 209, 155 (1991).
15 S. Fukuzawa, Y. Yamaishi, H. Furuya, K. Terao, and
F. Iwasaki, Tetrahedron Lett., 38, 7203 (1997).
16 K. Okuma, Y. Kamahori, K. Tsubakihara, K. Yoshihara,
Y. Tanaka, and K. Shioji, J. Org. Chem., 67, 7355 (2002).
17 J. van der Louw, J. van der Baan, G. J. J. Out,
F. J. J. De Kanter, F. Bichkelhaupt, and G. W. Klumpp,
Tetrahedron, 48, 9901 (1992).
18 A. C. Dupont, V. H. Audia, P. P. Waid, and J. P. Carter,
Synth. Commun., 20, 1011 (1990).
19 M. Tokuda, Y. Yamada, T. Takagi, H. Suginome, and
A. Furusaki, Tetrahedron, 43, 281 (1987).
20 H. Bhandal, V. F. Patel, G. Pattenden, and J. J. Russel,
J. Chem. Soc., Perkin Trans. 1, 1990, 2691.