Regioselective TEMPO oxidation of 2-alkylidene-1,3-propanediols to (E)-2-hydroxymethyl-2-alkenals and application to 4-alkylidene-2-penten-5-olide synthesis

Article abstract of DOI:10.1016/j.tet.2010.10.034

The oxidation system comprised of TEMPO and (diacetoxyiodo)benzene (stoichiometric) is enhanced during the conversion of primary alcohols to aldehydes by adding a catalytic amount of acids, p-TsOH and PPTS. 2-Alkylidene-1,3-propanediols, available from 1,3-dihydroxyacetone, are oxidized under the stated conditions to the corresponding (E)-2-hydroxymethyl-2- alkenals, which are utilized as an intermediate for the expeditious synthesis of 4-alkylidene-2-penten-5-olides.

Full text of DOI:10.1016/j.tet.2010.10.034

Tetrahedron 66 (2010) 9714e9720
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective TEMPO oxidation of 2-alkylidene-1,3-propanediols to (E)-2-
hydroxymethyl-2-alkenals and application to 4-alkylidene-2-penten-5-olide
synthesis
*
Wei Peng, Kazumi Ashida, Toshiaki Hirabaru, Li-Jian Ma, Tsutomu Inokuchi
Department of Medicinal and Bioengineering Science, Graduate School of Natural Science and Technology, Okayama University, Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation system comprised of TEMPO and (diacetoxyiodo)benzene (stoichiometric) is enhanced
during the conversion of primary alcohols to aldehydes by adding a catalytic amount of acids, p-TsOH and
PPTS. 2-Alkylidene-1,3-propanediols, available from 1,3-dihydroxyacetone, are oxidized under the stated
conditions to the corresponding (E)-2-hydroxymethyl-2-alkenals, which are utilized as an intermediate
for the expeditious synthesis of 4-alkylidene-2-penten-5-olides.
Received 11 August 2010
Received in revised form 14 October 2010
Accepted 15 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
TEMPO
(Diacetoxyiodo)benzene
2-Alkenal
2-Penten-5-olide
R1
R1
R1
1. Introduction
4-BzOTEMPO–
co-oxidant
CHO
OH
Although the MoritaeBayliseHillman reaction,1 a coupling
reaction of alkanals and
of base, has found wide use in producing
OH
OH
OH
+
CHO
a
,
b
-unsaturated carbonyl in the presence
-alkylidene- -hydrox-
a
b
yalkyl carbonyls, there are still some drawbacks including the
slow reaction rate as well as the limited scope of the substrates,
especially for the alkenal products. Indeed, the preparation of
(Z)-2
(E)-2
1
Scheme 1. Oxidation of 2-alkylidenepropane-1,3-diols 1 to either (E)- or (Z)-2.
2-hydroxyalkyl-2-alkenals from 2-alkenals as
a nucleophilic
counter part in the carbonecarbon bond making process is rare,
except for the example in which the coupling of acrolein and
alkanals has been realized under high pressure (1.5 kbar).2
Therefore, we envisioned that the selective oxidation of 2-alkyli-
dene-1,3-propanediols 1 would lead to 2-hydroxyalkyl-2-alkenals
2 that are not readily available by the MoritaeBayliseHillman
reaction (Scheme 1).3 Meanwhile, we have developed an efficient
oxidation method of alcohols, which is amenable to the demand
associated with the transformation of 1 to 2.
toxic and environmentally friendly.6a Another benefit of the TEMPO
oxidation is its high selectivity in the competitive oxidation of
primary alcohols in the presence of secondary ones due to the steric
factor of the N-oxoammonium group being formed on the bulky
2,2,6,6-tetramethylpiperidine scaffold.7 Therefore, we became
interested in the application of this capability to the oxidation of
1,3-propanediols 1, which would lead to versatile aldehydes 2 as
a result of the discrimination of two sterically unequivalent pri-
mary hydroxy groups on 1.
Regarding the reaction conditions for the TEMPO oxidation, the
method with (diacetoxyiodo)benzene8 (PhI(OAc)2, DAIB, stoichio-
metric) as a co-oxidant, developed by Margarita and Piancatelli
et al.,9 is highly useful in terms of the mild reaction conditions.10,11
However, this oxidizing system was sometimes regarded as being
incomplete12a and uses toxic methylene chloride (CH2Cl2) as the
Among the various oxidation procedures for alcohols,4,5 the
TEMPO oxidation, categorized as non-metallic and catalytic, is less
* Corresponding author. Tel.: þ81 86 251 8210; fax: þ81 86 251 8021; e-mail
address: inokuchi@cc.okayama-u.ac.jp (T. Inokuchi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.034

W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
9715
solvent. Several efforts to enhance the reaction rate of the TEM-
POehypervalent iodine systems have been made using the appro-
priate additives, such as water12a and ytterbium triflate.12b In our
continuous study of the TEMPO oxidation,13a,b we examined the
effect of the appropriate additive and the use of ether as the solvent
instead of CH2Cl2.
trisubstituted-olefinic diols 1 in 60e75% yields (Method A).20 On
the other hand, the DIBAL-H reduction of the diester 7, available by
the Knoevenagel condensation of ketones and malonate, gave the
diols 1 in about 30% yields (Method B) (Scheme 2).
[Method A]
H
R1
H
R1
O
2. Results and discussion
a
b
d
2
THPO
OTHP
2.1. Optimization of TEMPOeDAIB oxidation of primary
alcohols
OH OH
1
THPO
OTHP
5
6
The conditions were explored using undecanol (3) as a typical
substrate in a 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-BzOTEMPO)13eDAIB system (Table 1). As shown in entries 1 and
2, the reaction rate is significantly enhanced by the addition of
a small amount of p-toluenesulfonic acid (p-TsOH) in CH2Cl2 in
order to complete it within the prescribed time (30 min, entries 1
and 2). Similar enhancements of the reaction in tetrahydropyran
(THP) are also achieved by the addition of a small amount of
p-TsOH, pyridinium p-toluenesulfonate (PPTS), camphorsulfonic
acid (CSA) (entries 4e6), and even water (entry 7). The reaction in
cyclopentyl methyl ether (CPME, entry 8) compared to THP is
sluggish.14 Thus, among the examined ether solvents, THP should
be the solvent of choice in terms of not only the high yield, but also
lower toxicity15 and resistance toward peroxide formation with the
oxidant during the reaction.16
[Method B]
R2
R1
R2
R1
R2
R1
c
d
OHC
EtO2C
CO2Et
OH
HO
OH
7
1
2
R1 = alkyl, aryl: R2 = H, alkyl
Scheme 2. Synthesis of compounds 1 and 2. Reagents and conditions: (a) RCH2Pþ
Ph3Brꢀ, LDA, THF, 60e75%. (b) MeOHePPTS, 98%. (c) DIBAL-H, toluene, ca. 30%.
(d) 4-BzOTEMPOePhI(OAc)2, p-TsOH, THP.
The TEMPO oxidation of 1a was carried out using 4-BzOTEMPO
(catalytic)13 and DAIB (stoichiometric) in THP in the presence of
a small amount of acid (p-TsOH) to give 2a in 86% yield as an in-
separable E/Z mixture by typical column chromatography, and both
the structure and the E/Z ratio of 2a of more than 7e10:1 were
determined on the basis of the 1H NMR analysis (entry 1, Table 2).
The time-course experiment for the E/Z ratio of 2a by NMR analysis
indicates that the E/Z ratio is strictly maintained for 2 h.21,22 In
addition, (diacetoxyiodo)-2,4,6-trimethylbenzene, a more hindered
hypervalent iodine reagent, can be used for this purpose, but the
reaction is sluggish and hence the yield of 2a slightly decreases
compared to the run using DAIB (entry 2).
Table 1
Effect of solvent and additive on the oxidation of 3 to 4a
4-BzOTEMPO
PhI(OAc)2
OH
C9H19
CHO
C9H19
3
4
Entry
Solventb
Additivec
Yield (%)d 4
Recovery 3 (%)
Furthermore, the TEMPO oxidation is comparable to other
conventional methods, notably the DesseMartin oxidation.23 Thus,
as shown in Table 2, the oxidation of 1a with the DesseMartin
periodinane affords ca. 1:1 E/Z mixture of 2a in poor yield (40%)
(entry 3). The PCC oxidation24 of 1a affords E-2a as the major iso-
mer, but in low yield (33%, entry 4). The ParikheDoering oxida-
tion25 produces the desired 2a in 31% with an E/Z ratio of 2:1 (60%
of the starting 1a was recovered, entry 5). The Swern oxidation of
1a was not suitable in comparison to the ParikheDoering method.
Thus, the TEMPO oxidation in combination with DAIB should be
1
2
3
4
5
6
7
8
CH2CI2
CH2CI2
THP
THP
THP
THP
THP
CPME
None
p-TsOH
None
p-TsOH
PPTS
CSA
H2O
p-TsOH
57
91
60
97
89
96
88
54
20
d
32
d
7
d
d
34
a
Carried out using 3 (1.0 mmol), 4-BzOTEMPO (0.10 mmol), PhI(OAc)2 (1.2 mmol)
in solvent (4 mL) at room temperature for 30 min.
b
THP: tetrahydropyran, CPME: cyclopentyl methyl ether.
Catalytic amount (1 mol %) and one drop of water.
Yields are based on isolated products by LC (SiO2).
c
d
Table 2
Enhancement of the reaction rate with acid as an additive can be
rationalized by taking into account its participation in the dispro-
portionation of the TEMPO radical into the N-oxoammonium and
N-hydroxyamine.17 Furthermore, the regeneration process of the
TEMPO radical or the N-oxoammonium from N-hydroxyamine with
DAIB, formed after the oxidation of alcohols with the N-oxoam-
monium, would also be accelerated by the addition of an acid
catalyst.18,19 Similarly, the additive effect of water may be ascribable
to the formation of acetic acid from DAIB and water.8
Oxidation of 2-heptylidene-1,3-propanediol (1a) to 2aa
C6H13
C6H13
C6H13
Oxidants
CHO
OH
OH
OH
1a
OH
+
CHO
(E)-2a
(Z)-2a
Entry Oxidant (equiv)
Time (h) Yieldb (%) 2 E/Z ratioc
1
4-BzOTEMPOePhI(OAc)2
(1.2)ep-TsOH (cat.)
4
86
7e10:1
2.2. Oxidation of 2-alkylidene-1,3-propanediols and
comparison of TEMPOeDAIB method with conventional ones
2
4-BzOTEMPOe(2,4,6-Me3C6H2)I(OAc)2 16
(1.2)ep-TsOH (cat.)
72
8:1
3
4
5
DesseMartin periodinane (1.2)
PCC (1.5)
10
24
4
40
33
31
1:1
8:1
2:1
We examined the oxidation of 2-alkylidene-1,3-propanediols
DMSOeSO3Py(3)d
1 under the newly developed conditions. The substrates 1 were
a
b
c
Carried out using 1a (0.5 mmol).
Yields are based on isolated products by LC (SiO2).
Based on NMR experiments.
prepared either from 1,3-dihydroxyacetone bis-THP ether
5
or the diesters 7. Thus, the Wittig olefination of 5, producing 6,
followed by hydrolysis of the THP protecting groups produced the
d
Recovery of 1a (60%) and E/Z ratio after LC purification.

9716
W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
superior to other methods examined in this study for the oxidation
of 2-alkylidene-1,3-propanediols 1 in terms of its regioselectivity,
high performance, and easy operation.
present protocol (entry 7). The trisubstituted-olefinic diols
generally show high E-selectivities (entries 1e5, 7), while no E/Z
selectivity was found in the oxidation of the tetrasubstituted-ole-
finic diol 1i (entry 9).
2.3. Preparation of various 2-hydroxymethyl-2-alkenals
2.4. Syntheses of 4-alkylidene-2-penten-5-olides
We next attempted to prepare various 2-hydroxymethyl-2-
alkenals 2 from 1 (Table 3). We were inspired by the facts that this
structural motif was hardly accessible by the MoritaeBayliseHill-
man procedure, present in terpenoid natural products,26 and more
importantly, highly functionalized for further elaboration. Thus, the
2-alkylidene-1,3-propanediols 1, prepared by the above methods A
(entries 1e3) or methods B (entries 4, 5, 7e9), were treated with
the 4-BzOTEMPOeDAIB system in THP in the presence of p-TsOH,
affording the corresponding 2-hydroxymethyl-2-alkenals 2 in good
yields. Noteworthy is the fact that this method is smoothly applied
to the oxygenated 1f, prepared by the HornereEmmons reaction of
5 followed by subsequent procedures consisting of the DIBAL-H
reduction, 4-methoxybenzyloxylation, and THP-hydrolysis, afford-
ing the corresponding highly functionalized enal 2f (entry 6). The
dienal 2g is now available from the diene structure 1g based on the
We then examined the synthesis of the 4-alkylidene-2-penten-
5-olides 10 from the 2-hydroxymethyl-2-alkenals 2, since this
structural feature is one of the key elements in the bioactive
2-pentenolides, like the gelastatin analogues.27 Thus, the Hor-
nereWadswortheEmmons olefination28 of the aldehyde 8a, pre-
pared by the THP protection of 2a, by the Ando’s protocol29 with
tert-butyl (diphenylphosphono)acetate afforded ca. 3.5:1 mixture
of the corresponding 2Z- and 2E-enoates 9a. Without separation of
the geometric isomers, the dienoate 9a was treated with PPTS at
55 ꢁC to induce cyclization, giving 4-heptylidene-2-penten-5-olide
(10a, 73%) and the unchanged 2E-dienoate 9a (22%) as separable
products. The integrity of the olefin geometry in 2a (E/Z¼10:1)
changed to ca. 7:1 in the compounds 10a during these
conversions.
Table 3
Preparation of 2-hydroxymethyl-2-alkenals 2 by oxidation of 1 with a 4-BzOTEMPOePhI(OAc)2ep-TsOH systema,b
Entry
1
Diols 1
Products 2
Yield (%)c
86
E/Z ratiod
>10:1
R1
R1
1a, R1 = C6H13
2a
2b
2c
1b, R1 = C3H7
OHC
OHC
2
3
76
84
12:1
12:1
1c, R1 = CH2CH2CO2Et
OH OH
OH
Ph
Ph
4
5
6
83
58e
56
12:1
>10:1
3:1f
1d
2d
OH OH
OH
Fur
Fur
1e
2e
OHC
OHC
OH OH
OH
OPMB
OPMB
1f
2f
OH OH
Ph
OH
Ph
1g
2g
7
8
69
10:1
OHC
OH OH
OH
71
80
d
1h
2h
OHC
OHC
OH OH
C6H13
OH
C6H13
9
1i
2i
1:1
OH OH
OH
a
Carried out by oxidation of 1 (0.5 mmol) with 4-BzOTEMPO (10 mol %) and PhI (OAc)2(1.2 equiv) in THP (3 mL) in the presence of p-TsOH (1 mol %) at room temperature.
b
c
d
e
f
Ph¼phenyl, Fur¼2-furyl, PMB¼4-methoxyphenylmethyl.
Yields are based on products isolated by LC (SiO2).
Determined based on 1H NMR data.
Dialdehyde (18%) was produced.
The E/Z ratio changed to 10:1 during LC purification.

W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
9717
Similarly, 4-benzylidene-2-penten-5-olide 10d was prepared
from the THP ether 9d by the same reaction sequence as described
above, involving olefination to give 9d (2Z/2E¼7:1), and cyclization
to afford 10d in 84%, which was associated with the formation of
the uncyclized 2E-9d (7%). No change of the olefin geometry in 2d
(E-isomer) was found in compound 10d.
Alternatively, the aldol reaction of 8a with the lithium enolate of
tert-butyl acetate afforded the adduct 11a in 91% yield. Sub-
sequently,11a was treated with TMSCl in CH2Cl2, giving the cyclized
12a in 54% yield, which was followed by dehydration with Ac2O/
Et3N to afford the desired 10a in 93% yield with complete integrity
of the E/Z ratio of the starting 2a (E/Z¼10:1) (Scheme 3).
chromatography (SiO2; hexanes/AcOEt, 20:1 v/v) to give 6a
(R1¼C6H13) as a colorless oil (1.83 g, 67% yield): Rf¼0.65 (hexane/
AcOEt 3:1); 1H NMR (600 MHz)
d
0.87 (t, J¼7.2 Hz, 3H), 1.25e1.38 (m,
8H), 1.51e1.61 (m, 8H), 1.70 (m, 2H), 1.83 (m, 2H), 2.13 (q, J¼7.2 Hz,
2H), 3.51 (m, 2H), 3.88 (m, 2H), 3.97 (t, J¼11.4 Hz, 1H), 4.07 (d,d,
J¼21.6, 11.4 Hz, 1H), 4.25 (m, 2H), 4.62 (m, 2H), 5.69 (t, J¼7.2 Hz, 1H);
13C NMR (150.8 MHz)
d
14.1, 19.36þ19.41, 19.42þ19.51, 22.6, 25.48,
25.49, 27.57þ27.58, 29.0, 29.6, 30.58, 30.60, 31.7, 61.96þ62.00,
62.0þ62.1, 62.2þ62.3, 69.5þ69.6, 97.4þ97.5, 97.77þ97.83,
132.35þ132.38,133.46þ133.51. A mixture of the THP ether 6a (0.85 g,
2.5 mmol) and PPTS (20 mg), dissolved in MeOH (15 mL), was stirred
at 50e60 ꢁC for 24 h. The mixture was neutralized with aq NaHCO3
R1
t
BuO2C
R1
R1
R1
a
b
+
t
OHC
BuO2C
OTHP
OTHP
O
O
OTHP
8a (R1 = C6H13
)
9a (R1 = C6H13
)
10a (R1 = C6H13
10d (R1 = Ph)
)
2E-9a (R1 = C6H13
2E-9d (R1 = Ph)
)
8d (R1 = Ph)
9d (R1 = Ph)
c
OH
OH
O
R1
R1
e
d
10a
t
BuO2C
OTHP
O
11a (R1 = C6H13
)
12a (R1 = C6H13
)
Scheme 3. Syntheses of 4-alkylidene-2-pentenolides 10a and d. Reagents and conditions: (a) (PhO)2POCH2CO2tBu, NaH; 9a, 84%; 9d, 93%. (b) PPTS, CH2Cl2; 10a, 73%, 2E-9a, 22%;
10d, 84%, 2E-9d, 7%. (c) CH3CO2tBu, LDA, 11a, 91%. (d) TMSCl, CH2Cl2; 12a, 54%. (e) Ac2O/Et3N; 10a, 93%.
3. Conclusion
and concentrated. The crude products were purified by LC (SiO2;
hexanes/AcOEt, by increasing the gradient from 3:1 to 1:2 v/v) to give
1a as a colorless oil (0.42 g, 98% yield): Rf¼0.13 (hexane/AcOEt 1:1); IR
(neat) 3341, 2957, 2926, 2857, 1665, 1466, 1379, 1217, 1107, 1011, 895,
The TEMPO oxidation of primary alcohols to aldehydes is en-
hanced by the addition of a small amount of acids, p-TsOH and
PPTS. Based on this procedure, 2-hydroxymethyl-2-alkenals 2 are
easily obtained from the 1,3-diol precursors 1, prepared either by
the Wittig reaction of 1,3-dihydroxyacetone THP ether 5 or by the
DIBAL-H reduction of the Knoevenagel products 7. The resulting 2-
alkenals 2 are useful as precursors of the 4-alkylidene-2-penten-5-
olides 10, whose syntheses can easily be performed either by
employing Ando’s protocol in the HornereWadswortheEmmons
reaction followed by cyclization, or the aldol reaction of the lithium
acetateecyclizationedehydration sequence.
721, 662 cmꢀ1; 1H NMR (400 MHz)
d
0.88 (t, J¼6.8 Hz, 3H),1.24e1.38
(m, 8H), 1.98 (br, 2H), 2.08 (q, J¼7.6 Hz, 2H), 4.22 (s, 2H), 4.32 (s, 2H),
5.56 (t, J¼7.6 Hz, 1H); 13C NMR (100.6 MHz, CDCl3)
d 14.1, 22.6, 27.4,
28.9, 29.5, 31.7, 60.2, 67.8, 131.5, 136.8; HRMS (FAB) Calcd for
C10H20NaO2 [M þ Na]þ 195.1356. Found 195.1316. Anal. Calcd for
C10H20O2$H2O C, 63.12; H, 11.65. Found: C, 63.61; H, 11.56.
4.1.2. 2-Butylidene-1,3-propanediol (1b). Rf¼0.10 (hexane/AcOEt
1:1); 1H NMR (600 MHz)
d
0.91 (t, J¼7.2 Hz, 3H), 1.40 (sext, J¼7.8 Hz,
Further studies are continuing in our laboratory in order to
demonstrate the applicability of this synthetic protocol to antitumor
gelastatin and its analogues, which will be published in the future.
2H), 2.00 (br, 1H), 2.03 (br, 1H), 2.07 (q, J¼7.8 Hz, 2H), 4.22 (s, 2H),
4.32 (s, 2H), 5.56 (t, J¼7.8 Hz, 1H); 13C NMR (150.8 MHz)
d 13.7, 22.7,
29.4, 60.1, 67.7, 131.2, 137.0; MS (FAB) m/z 154.01 [M þ Na]þ.
4. Experimental section
4.1. General
4.1.3. Ethyl 6-hydroxyl-5-hydroxymethyl-4-hexenoate (1c). Rf¼0.14
(hexane/AcOEt 1:2); 1H NMR (400 MHz)
d
1.25 (t, J¼7.2 Hz, 3H),
2.30 (br, 2H), 2.43 (m, 4H), 4.13 (q, J¼7.2 Hz, 2H), 4.20 (s, 2H), 4.30 (s,
2H), 5.50 (t, J¼6.8 Hz, 1H); 13C NMR (100.5 MHz)
d 14.2, 22.6, 33.6,
59.4, 60.7, 67.2, 128.2, 139.1, 173.4; HRMS (FAB) Calcd for C9H17O4
IR spectra were recorded on a Shimadzu FTIR-8400S spec-
trometer. 1H and 13C NMR spectra were measured on either Varian
INOVA-600, 400-MR or Mercury-300 spectrometer with CDCl3 as
a solvent unless otherwise indicated.
[M þ H]þ 189.1121. Found 189.1088.
4.1.4. Preparation of 2-benzylidene-1,3-propanediol (1d) by DIBAL-H
reduction. Dimethyl 2-benzylidenepropanedioate (7d, 110 mg,
0.5 mmol) was dissolved in toluene (5 mL) and cooled at ꢀ78 ꢁC.
DIBAL-H (1.0 M in toluene, 2.5 mmol) was added dropwise. The
mixture was stirred at ꢀ78 ꢁC for 5 h and quenched by adding 1.0 N
HCl. The mixture was extracted with AcOEt and washed with brine.
Usual work up followed by purification of the crude product on LC
(SiO2; hexanes/AcOEt, by increasing the gradient from 1:1 to 1:3 v/
v) gave 1d as white solids (25.5 mg, 31% yield): Rf¼0.13 (hexane/
AcOEt 1:1); IR (KBr) 3235, 2909, 2855, 2670, 1599, 1574, 1489, 1472,
1447, 1366, 1331, 1316, 1233, 1155, 1082, 1053, 1022, 947, 937, 926,
4.1.1. Preparation of 2-heptylidene-1,3-propanediol (1a) by Wittig
reaction followed by hydrolysis. To a suspension of n-C6H13CH2Pþ
Ph3Brꢀ (5.73 g,13 mmol) in THF (15 mL) was added a solution of LDA
(25 mmol) in THF (30 mL) at ꢀ78 ꢁC. The mixture was allowed to
warm to room temperature over 2.5 h. To the red-colored mixture
was added dropwise the ketone 5 (2.07 g, 8 mmol) in THF (15 mL) at
ꢀ20 ꢁC and stirred overnight. The reaction was quenched with aq
NH4Cl at 0 ꢁC and extracted with AcOEt. The extracts were washed
with brine, and the crude products were purified by column

9718
W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
841, 795, 739, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
2.43 (br, 1H),
1H), 9.42 (s, 1H); 13C NMR (150.8 MHz)
d (E-isomer) 13.7, 21.9, 30.7,
2.47 (br, 1H), 4.40 (s, 2H), 4.45 (s, 2H), 6.65 (s, 1H), 7.25e7.37 (m,
55.8, 141.5, 156.8, 195.9; MS (FAB) m/z 129.19 [M þ H]þ.
5H); 13C NMR (150.8 MHz, CDCl3)
d
60.8, 67.7, 127.3, 128.3 (2C),
128.8 (2C), 129.8, 136.1, 139.2. Anal. Calcd for C10H12O2: C, 73.15; H,
7.37. Found: C, 73.16; H, 7.43.
4.1.12. Ethyl (E)-5-hydroxymethyl-6-oxo-4-hexenoate (2c). Yield 84%;
Rf¼0.58 (hexane/AcOEt 1:2); IR (neat) 3476, 2984, 2942, 2359, 1732,
1684, 1645, 1418, 1375, 1252, 1192, 1155, 1022, 858 cmꢀ1 1H NMR
;
4.1.5. 2-(2-Furylmethylene)-1,3-propanediol (1e). Rf¼0.21 (hexane/
(600 MHz)
2H), 2.75 (q, J¼7.2 Hz, 2H), 4.14 (m, 2H), 4.38 (s, 2H), 6.56 (t, J¼7.8 Hz,
1H), 9.43 (s, 1H); 13C NMR (150.8 MHz)
(E-isomer) 14.1, 23.9, 32.6,
d
(E-isomer) 1.25 (m, 3H), 1.73 (br, 1H), 2.57 (t, J¼7.2 Hz,
AcOEt 1:1); 1H NMR (600 MHz)
d 2.28 (br, 1H), 2.41 (br, 1H), 4.36 (s,
2H), 4.64 (s, 2H), 6.31 (d, J¼3.6 Hz, 1H), 6.33 (s, 1H), 6.41 (d,d, J¼3.6,
d
1.8 Hz, 1H), 7.42 (d, J¼1.2 Hz, 1H); 13C NMR (150.8 MHz)
d
61.2, 67.0,
55.3, 60.9, 142.3, 153.8, 172.3, 195.2; HRMS (FAB) Calcd for C9H15O4
110.9, 111.5, 116.1, 137.7, 142.5, 151.7.
[M þ H]þ 187.0965. Found 187.0980.
4.1.6. 2-(2-(4-Methoxybenzyloxy)ethylidene)-1,3-propanediol
(1f). Rf¼0.13 (hexane/AcOEt 1:1); IR (KBr) 3376, 2945, 2861, 1614, 1516,
1456, 1362,1304, 1246, 1177, 1103,1061, 1032,1005, 941, 816, 754, 708,
4.1.13. (E)-2-Hydroxymethyl-3-phenyl-2-propenal (2d). Yield 83%;
Rf¼0.60 (hexane/AcOEt 1:1); IR (neat) 3437, 3065, 2949, 2889, 2828,
2718, 1682, 1626, 1574, 1451, 1410, 1368, 1329, 1296, 1213, 1169, 1080,
667 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
2.04 (br, 2H), 3.80 (s, 3H), 4.07
(d, J¼6.0 Hz, 2H), 4.21 (s, 2H), 4.22 (s, 2H), 4.46(s, 2H), 5.77 (t, J¼6.6 Hz,
1H), 6.88 (m, 2H), 7.26 (m, 2H); 13C NMR (150.8 MHz, CDCl3)
55.3,
1018, 936, 897, 864, 827, 760, 700 cmꢀ1
;
1H NMR (400 MHz)
d
(E-
isomer)2.64(br,1H), 4.56(s, 2H), 7.41e7.49 (m, 4H), 7.57 (m, 2H), 9.62
d
(s, 1H); 13C NMR (100.6 MHz)
d 55.8, 128.9 (2C), 130.0 (2C), 130.4,
59.6, 65.2, 66.5, 72.4, 113.9 (2C), 125.3, 129.6 (2C), 129.8, 142.2, 159.3.
Anal. Calcd for C13H18O4: C, 65.53; H, 7.61. Found: C, 65.29; H, 7.63.
133.8, 140.1, 152.5, 195.8; MS (FAB) m/z 163 [M þ H]þ.
4.1.14. (E)-2-Hydroxymethyl-3-(2-furyl)-2-propenal (2e). Yield 58%;
Rf¼0.43 (hexane/AcOEt 1:1); IR (neat) 3431, 3127, 2947, 2888, 2835,
2727,1670,1624,1470,1389,1364,1281,1258,1161,1144,1076,1020,
4.1.7. 2-(3-Phenyl-2-propenylidene)-1,3-propanediol (1g). Rf¼0.19
(hexane/AcOEt 1:2); IR (KBr) 3271, 3174, 2903, 2849, 1487, 1447,
1398, 1364, 1236, 1213, 1165, 1130, 1063, 1003, 993, 970, 961, 870,
941, 930, 885, 853, 760, 687 cmꢀ1; 1H NMR (600 MHz)
d 2.79 (br,1H),
754, 692 cmꢀ1; 1H NMR (400 MHz)
d
2.01 (br, 2H), 4.35 (s, 2H), 4.53
4.77 (s, 2H), 6.58 (m, 1H), 6.91 (d, J¼3.6 Hz, 1H), 7.03 (s, 1H), 7.67
(s, 2H), 6.31 (d, J¼11.2 Hz, 1H), 6.63 (d, J¼15.6 Hz, 1H), 7.04 (d,d,
(d, J¼1.2 Hz, 1H), 9.51 (s, 1H); 13C NMR (150.8 MHz)
d 56.1, 113.0,
J¼15.6,11.2 Hz,1H), 7.23e7.44 (m, 5H); 13C NMR (100.5 MHz)
d
60.2,
119.2, 135.9, 136.2, 146.6, 150.4, 194.6; MS (FAB) m/z 154 [M þ H]þ.
67.2, 123.1, 126.6 (2C), 128.0, 128.7 (2C), 129.2, 135.0, 136.9, 138.7.
4.1.15. (E)-2-Hydroxymethyl-4-(4-methoxyphenylmethoxy)-2-bute-
nal (2f). Yield 56%; Rf¼0.65 (hexane/AcOEt 1:2); IR (neat) 3430,
2934, 2837,1684,1613,1586,1514,1464,1362,1302,1248,1175,1099,
4.1.8. 2-Cyclohexylidene-1,3-propanediol (1h). Rf¼0.18 (hexane/
AcOEt 1:1); IR (neat) 3366, 3298, 2930, 2851, 1734, 1657, 1649, 1447,
1397, 1165, 995, 853 cmꢀ1; 1H NMR (400 MHz)
d
1.58 (m, 6H), 1.90
1071, 1032, 820, 758 cmꢀ1; 1H NMR (300 MHz)
d (E-isomer) 3.81 (s,
(br, 2H), 2.26 (m, 4H), 4.33 (s, 4H); 13C NMR (100.5 MHz)
d
26.6, 28.3
3H), 4.35 (s, 2H), 4.41 (d, J¼5.4 Hz, 2H), 4.53 (s, 2H), 6.66 (t, J¼5.4 Hz,
(2C), 30.6 (2C), 61.8 (2C), 127.9, 142.6; MS (FAB) m/z 154.0 [M ꢀ H2].
1H), 6.90 (d, J¼8.7 Hz, 2H), 7.27 (d, J¼8.7 Hz, 2H), 9.44 (s, 1H); 13C
NMR (150.8 MHz) d (E-isomer) 55.3, 55.8, 66.3, 73.1,114.0 (2C),129.0,
4.1.9. 2-(2-Octylidene)-1,3-propanediol (1i). Rf¼0.26 (hexane/AcOEt
129.6 (2C), 141.9, 151.5, 159.6, 194.6; MS (FAB) m/z 235.10 [M ꢀ H]ꢀ.
1:1); IR (neat) 3354, 2957, 2928, 2859, 1659, 1468, 1414, 1379, 1238,
1148, 999, 897, 723 cmꢀ1
;
1H NMR (400 MHz)
d
0.88 (t, J¼6.8 Hz,
3H), 1.27e1.39 (m, 8H), 1.76 (s, 3H), 2.09 (m, 4H), 4.30 (s, 2H), 4.32
(s, 2H); 13C NMR (100.5 MHz)
14.1, 18.3, 22.6, 28.7, 29.3, 31.7, 34.4,
4.1.16. (E)-2-Hydroxymethyl-5-phenylpenta-2,4-dienal (2g). Yield 69%;
Rf¼0.29 (hexane/AcOEt 3:1); IR (KBr) 3331, 2843, 1674, 1653, 1614,
1591, 1450, 1281, 1188, 1175, 1132, 1013, 974, 874, 826, 754,
d
61.9, 62.4, 130.8, 138.0; HRMS (FAB) Calcd for C11H22NaO2
694 cmꢀ1 1H NMR (600 MHz)
; d (E-isomer) 2.62 (br, 1H), 4.56
[M þ Na]þ 209.1512. Found 209.1471.
(s, 2H), 7.08 (d, J¼6.6 Hz, 1H), 7.10 (d, J¼3.6 Hz, 1H), 7.30e7.41 (m,
4H), 7.54 (d, J¼3.6 Hz, 2H), 9.52 (s, 1H); 13C NMR (150.8 MHz)
d 56.0,
4.1.10. General procedure for the TEMPO oxidation. Preparation of (E)-
2-hydroxymethyl-2-nonenal (2a). A mixture of the diol 1a (86 mg,
0.5 mmol), 4-BzOTEMPO (14 mg, 0.05 mmol), PhI(OAc)2 (193 mg,
0.6 mmol), and p-TsOH (1 mg) dissolved in THP (3 mL) was stirred
at room temperature for 4 h. The reaction was quenched with
a small amount of aq Na2S2O3. The products were extracted with
AcOEt and the extracts were washed with aq NaHCO3. The crude
products were purified by LC (SiO2; hexanes/AcOEt, by increasing
the gradient from 15:1 to 3:1 v/v) to give 2a as a colorless oil
(73 mg, 86% yield): Rf¼0.67 (hexane/AcOEt 1:1); IR (neat) 3445,
2957, 2928, 2859, 2716, 1684, 1643, 1464, 1456, 1379, 1275, 1198,
1175, 1115, 1024, 901, 839, 723 cmꢀ1; 1H NMR (400 MHz) (E-isomer)
122.5, 127.7 (2C), 128.9 (2C), 129.9, 135.5, 138.8, 143.7, 150.4, 195.1;
HRMS (FAB) Calcd for C12H13O2 [M þ H]þ 189.0910, Found 189.0947.
4.1.17. 2-Cyclohexylidene-3-hydroxypropanal
(2h). Yield
71%;
Rf¼0.44 (hexane/AcOEt 1:1); IR (neat) 3430, 2932, 2857, 1717, 1667,
1620, 1447, 1402, 1352, 1337, 1312, 1292, 1260, 1175, 1013, 891, 856,
829, 756 cmꢀ1; 1H NMR (400 MHz)
d
1.64e1.69 (m, 2H), 1.71e1.78
(m, 4H), 2.43 (br, 1H), 2.49 (t, J¼6.0 Hz, 2H), 2.75 (t, J¼6.0 Hz, 2H),
4.36 (s, 2H), 10.15 (s, 1H); 13C NMR (100.6 MHz)
26.2, 28.5, 28.7,
d
29.5, 32.9, 56.2, 133.0, 166.8, 191.3; MS (FAB) m/z 154.0 [M].
4.1.18. (E)- and (Z)-2-Hydroxymethyl-3-methyl-2-nonenal (2i).
Yield 80%; Rf¼0.70 (hexane/AcOEt 1:1); IR (neat) 3439, 2957, 2928,
2859, 1668, 1626, 1466, 1377, 1304, 1157, 1017, 905, 787, 725 cmꢀ1; 1H
d
0.89 (m, 3H), 1.26e1.39 (m, 6H), 1.52 (m, 2H), 2.43 (q, J¼7.6 Hz,
2H), 2.54 (br, 1H), 4.36 (s, 2H), 6.62 (t, J¼7.6 Hz, 1H), 9.42 (s, 1H); 13C
NMR (100.6 MHz) (E-isomer)
d
14.0, 22.5, 28.5, 28.8, 28.9, 31.5, 55.9,
NMR (400 MHz)
d
(E/Z isomer) 0.89 (t, J¼6.8 Hz, 3H), 1.31 (m, 6H),
141.3, 157.1, 196.0; HRMS (FAB) Calcd for C10H19O2 [M þ H]þ
1.52 (m, 2H), 2.06 (br, 1H), 2.07þ2.23 (s, 3H), 2.35þ2.59 (t, J¼8.0 Hz,
171.1380. Found 171.1285.
2H), 4.34þ4.35 (s, 2H), 10.09þ10.13 (s, 1H); 13C NMR (100.6 MHz)
d
(E/Z isomer) 14.0, 17.9, 21.2þ22.5, 28.3, 29.2þ29.4, 31.5þ31.6,
4.1.11. (E)-2-Hydroxymethyl-2-hexenal (2b). Yield 76%; Rf¼0.54
33.2þ36.7, 56.9þ57.2, 135.5þ135.7, 162.6þ163.2, 191.7þ192.6; HRMS
(hexane/AcOEt 1:1); IR (neat) 3416, 2963, 2934, 2874, 2718, 1684,
(FAB) Calcd for C11H21O2 [M þ H]þ 185.1536. Found 185.1492.
1643, 1460, 1381, 1277, 1192, 1107, 1059, 1020, 966, 910, 847 cmꢀ1
;
1H NMR (600 MHz,)
2.40 (q, J¼7.2 Hz, 2H), 2.59 (br, 1H), 4.36 (s, 2H), 6.61 (t, J¼7.2 Hz,
d
(E-isomer) 0.98 (t, J¼7.2 Hz, 3H), 1.55 (m, 2H),
4.1.19. Preparation of (E)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-
2-nonenal (8a). A mixture of 2a (170 mg, 1.0 mmol), dihydropyran

W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
9719
(252 mg, 3.0 mmol), PPTS (25 mg, 0.1 mmol) dissolved in CH2Cl2
(5 mL) was stirred at room temperature for 4 h. The reaction was
quenched with aq NaHCO3 and concentrated. The crude product
was purified by LC (SiO2; hexanes/AcOEt, by increasing the gradient
from 7:1 to 3:1 v/v) to give 8a as a colorless oil (254 mg,100% yield):
Rf¼0.71 (hexane/AcOEt 3:1); IR (neat) 2930, 2857, 2710, 1692, 1643,
1468, 1454, 1368, 1354, 1261, 1202, 1182, 1134, 1119, 1078, 1055,
1028, 976, 907, 870, 816, 725 cmꢀ1; 1H NMR (600 MHz) (E-isomer)
The crude product was purified by LC (SiO2; hexanes/AcOEt, by
increasing the gradient from 10:1 to 3:1 v/v) to give 10a as a col-
orless oil (29 mg, 73% yield) and the unchanged E-enoate 9a (22%)
as a separable stuff. Compound 10a: Rf¼0.30 (hexane/AcOEt 5:1); IR
(neat) 2957, 2928, 2859, 1728, 1641, 1559, 1458, 1408, 1375, 1223,
1130, 1103, 1051, 1028, 910, 820, 723 cmꢀ1 1H NMR (600 MHz)
;
d
0.88 (t, J¼7.2 Hz, 3H), 1.25e1.33 (m, 6H), 1.43 (m, 2H), 2.11 (q,
J¼7.2 Hz, 2H), 5.07 (s, 2H), 5.81 (m, 2H), 6.94 (d, J¼9.6 Hz, 1H); 13C
d
0.89 (t, J¼7.2 Hz, 3H), 1.29e1.35 (m, 8H), 1.50e1.60 (m, 6H), 2.50
NMR (150.8 MHz) d 14.0, 22.5, 28.3, 28.8, 28.9, 31.6, 66.6, 116.3,
(q, J¼7.2 Hz, 2H), 3.53 (m, 1H), 3.88 (m, 1H), 4.17 (d, J¼11.4 Hz, 1H),
4.42 (d, J¼10.8 Hz, 1H), 4.66 (t, J¼3.6 Hz, 1H), 6.72 (t, J¼7.8 Hz, 1H),
127.2, 137.7, 145.3, 163.9; HRMS (FAB) Calcd for C12H19O2 [M þ H]þ
195.1380. Found 195.1398.
9.44 (s, 1H); 13C NMR (150.8 MHz) (E-isomer)
d 14.0, 19.3, 22.5, 25.4,
28.6, 29.0, 29.2, 30.5, 31.6, 58.3, 62.1, 98.6, 139.4, 159.3, 193.9; HRMS
4.1.24. (5Z)-5,6-Dihydro-5-(phenylmethylene)-2H-pyran-2-one
(10d). Yield 84%, along with the unchanged E-enoate 9d (7%) as
a separable stuff; Rf¼0.17 (hexane/AcOEt 5:1); IR (KBr) 3048, 1966,
1836, 1811, 1722, 1715, 1695, 1668, 1622, 1487, 1447, 1404, 1261,
1225, 1204, 1126, 1078, 1051, 1007, 934, 903, 854, 826, 799, 743,
(FAB) Calcd for C15H27O3 [M þ H]þ 255.1955. Found 255.1964.
4.1.20. (E)-3-Phenyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-2-
propenal (8d). Yield 91%; Rf¼0.68 (hexane/AcOEt 3:1); IR (neat)
2943, 2872, 2716,1684,1630,1574,1466,1454,1441,1370,1352,1323,
1285,1260,1202,1180,1155,1119,1076,1055,1026, 972, 936, 907, 870,
704 cmꢀ1
;
1H NMR (600 MHz)
d
5.40 (d, J¼2.4 Hz, 2H), 5.96 (d,
J¼9.6 Hz, 1H), 6.78 (s, 1H), 7.14 (d, J¼10.2 Hz, 1H), 7.20 (d, J¼7.8 Hz,
816, 760, 700 cmꢀ1; 1H NMR (600 MHz) (E-isomer)
d 1.53e1.64 (m,
2H), 7.36 (t, J¼7.2 Hz, 1H), 7.43 (t, J¼7.2 Hz, 2H); 13C NMR
4H), 1.72e1.84 (m, 2H), 3.56 (m, 1H), 3.93 (m, 1H), 4.32 (d, J¼10.8 Hz,
(150.8 MHz) d 67.6, 117.6, 128.0, 128.8 (2C), 128.9, 129.1 (2C), 134.5,
1H), 4.58(d, J¼10.8 Hz, 1H), 4.81 (t, J¼3.6 Hz,1H), 7.46(m, 4H), 7.70(m,
134.8, 145.7, 163.0. Anal. Calcd for C12H10O2: C, 77.40; H, 5.41.
Found: C, 77.44; H, 5.28.
2H), 9.64 (s, 1H); 13C NMR (150.8 MHz) (E-isomer)
d 19.4, 25.4, 30.6,
58.9, 62.3, 99.3,128.8 (2C),130.3 (2C),130.4,134.0,138.0,153.7,194.2;
HRMS (FAB) Calcd for C15H19O3 [M þ H]þ 247.1329. Found 247.1313.
4.1.25. Preparation of tert-butyl (E)-3-hydroxy-4-(2-tetrahydropyr-
anoxymethyl) undec-4-enoate (11a). To a solution of LDA (2.0 mmol)
in THF (4 mL) was added tert-butyl acetate (349 g, 3.0 mmol) in THF
(3 mL) at ꢀ78 ꢁC. After being stirred for 20 min, 8a (127 mg, 0.5 mmol)
in THF (1 mL) was added. The mixture was stirred at ꢀ60 ꢁC for 3 h,
quenched with aq NH4Cl, and the products were extracted with
AcOEt. The extracts were washed with brine and the crude product
was purified by LC (SiO2; hexanes/AcOEt, by increasing the gradient
from 10:1 to 3:1 v/v) to give 11a as a colorless oil (168 mg, 91% yield):
Rf¼0.64 (hexane/AcOEt 3:1); IR (neat) 3458, 2957, 2928, 2857, 1732,
1454, 1393, 1368, 1258, 1202, 1152, 1117, 1076, 1053, 1022, 978, 955,
4.1.21. Preparation of tert-butyl 4-(2-tetrahydropyranoxymethyl)un-
dec-2Z,4Z-dienoate (9a) by HornereWadswortheEmmons re-
t
action. To a solution of (PhO)2POCH2CO2 Bu (261 mg, 0.75 mmol) in
THF (4 mL) was added NaH (28 mg, 0.7 mmol) at ꢀ78 ꢁC. After being
stirred for 15 min, 8a (127 mg, 0.5 mmol) in THF (2 mL) was added,
and the resulting mixture was gradually warmed to 0 ꢁC over 1e2 h.
The reaction was quenched with aq NH4Cl at 0 ꢁC and the mixture
was extracted with AcOEt. The extracts were washed with brine, and
the crude product was purified by LC (SiO2; hexanes/AcOEt,15:1 v/v)
to give 9a as a colorless oil (148 mg, 84% yield), the 2Z/2E ratio of 3.5/1
was determined on the basis of 1H NMR (600 MHz): Rf¼0.74 (hexane/
AcOEt 5:1); IR (neat) 2955, 2928, 2857, 2359, 1713, 1630, 1456, 1391,
1368, 1314, 1285, 1256, 1223, 1202, 1152, 1119, 1078, 1053, 1024, 980,
907, 870, 845, 816, 766, 723 cmꢀ1 1H NMR (600 MHz)
; d 0.87 (t,
J¼7.2 Hz, 3H), 1.24e1.36 (m, 8H), 1.44 (s, 9H), 1.51e1.81 (m, 6H), 2.10
(m, 2H), 2.57 (m, 2H), 3.38 (d,d, J¼12.6, 5.4 Hz, 1H), 3.54 (m, 1H), 3.86
(m, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 4.52 (m, 1H), 4.63 (m, 1H), 5.70 (q,
953, 905, 870, 816, 723 cmꢀ1; 1H NMR (600 MHz) (2Z-isomer)
d
0.88
J¼7.2 Hz, 1H); 13C NMR (150.8 MHz)
d
14.1, 19.3þ19.4, 22.6, 25.3,
(t, J¼7.2 Hz, 3H),1.25e1.42 (m, 8H),1.46e1.60 (m,13H),1.62e1.83 (m,
2H), 2.17e2.30 (m, 2H), 3.50 (m,1H), 3.86 (m,1H), 4.20e4.41 (m, 2H),
4.58 (m, 1H), 5.63 (d, J¼12.6 Hz, 1H), 5.88 (t, J¼7.8 Hz, 1H), 6.35 (d,
27.51þ27.54, 28.1 (3C), 28.9, 29.51þ29.53, 30.5, 31.7, 42.1þ42.2,
62.1þ62.2, 62.5þ62.9, 71.9þ72.2, 80.8þ80.9, 97.8þ98.2, 132.1þ132.2,
135.3þ135.5, 171.6þ171.7; HRMS (FAB) Calcd for C21H39O5 [M þ H]þ
371.2792, Found 371.2838.
J¼12.6 Hz, 1H); 13C NMR (150.8 MHz) (2Z-isomer)
d 14.1, 19.4, 22.6,
25.5, 28.1 (3C), 28.3, 29.0, 29.3, 30.5, 31.7, 62.1, 63.1, 80.2, 97.0, 120.5,
132.8, 141.8, 146.2, 166.1; HRMS (FAB) Calcd for C21H36O4 [M]
352.2614. Found 352.2651.
4.1.26. (5E)-Tetrahydro-4-hydroxy-5-heptylidene-2H-pyran-2-one
(12a). To a solution of 11a (74 mg, 0.2 mmol) in CH2Cl2 (3 mL) was
added TMSCl (cat. one drop) at 0 ꢁC for 30 min. Then, the reaction
was warmed to room temperature for 3 h, quenched with aq
NaHCO3, and concentrated. The crude product was purified by LC
(SiO2; hexanes/AcOEt, by increasing the gradient from 3:1 to 1:1
v/v) to give 12a as a colorless oil (23 mg, 54% yield): Rf¼0.10
(hexane/AcOEt 3:1); IR (neat) 2955, 2926, 2857, 2357, 1736, 1466,
4.1.22. tert-Butyl 5-phenyl-4-(2-tetrahydropyranoxymethyl)penta-
2Z,4Z-dienoate (9d). The 2Z/2E ratio of 7/1 was determined on the
basis of 1H NMR (400 MHz). Yield 93%; Rf¼0.64 (hexane/AcOEt
5:1); IR (neat) 2942, 2870, 1715, 1622, 1456, 1393, 1368, 1285, 1256,
1215, 1150, 1078, 1055, 1028, 974, 907, 870, 816, 754, 700 cmꢀ1; 1H
NMR (400 MHz) (2Z-isomer)
d
1.45 (s, 9H), 1.48e1.83 (m, 6H), 3.45
1397, 1337, 1260, 1221, 1177, 1140, 1049, 895, 723 cmꢀ1
;
1H NMR
0.88 (t, J¼7.2 Hz, 3H), 1.25e1.41
(m, 1H), 3.81 (m, 1H), 4.46 (d, J¼12.0 Hz, 1H), 4.57 (d, J¼11.6 Hz,
1H), 4.63 (t, J¼3.6 Hz, 1H), 5.79 (d, J¼12.4 Hz, 1H), 6.57 (d,
J¼12.4 Hz, 1H), 6.85 (s, 1H), 7.24e7.39 (m, 5H); 13C NMR
(600 MHz, CDCl3) (anti isomer)
d
(m, 8H), 1.93 (br s, 1H), 2.05 (q, J¼7.8 Hz, 2H), 2.79 (d,d, J¼4.8,
1.8 Hz, 2H), 4.56 (t, J¼4.8 Hz, 1H), 4.86 (d, J¼14.4 Hz, 1H), 5.04 (d,
J¼14.4 Hz, 1H), 5.75 (t, J¼7.8 Hz, 1H); 13C NMR (150.8 MHz, CDCl3)
(100.6 MHz) (2Z-isomer)
d 19.3, 25.4, 28.1 (3C), 30.6, 62.1, 64.6,
80.5, 97.6, 122.3, 127.6, 128.2 (2C), 129.3 (2C), 134.9, 135.2, 136.1,
141.7, 166.1; HRMS (FAB) Calcd for C21H29O4 [M þ H]þ 345.2060.
Found 345.2055.
(anti isomer) d 14.0, 22.5, 27.4, 28.9, 29.1, 31.6, 39.4, 65.6, 68.1,
130.9, 131.4, 170.1; HRMS (FAB) Calcd for C12H21O3 [M þ H]þ
213.1485. Found 213.1449.
4.1.23. Preparation of (5Z)-5,6-dihydro-5-heptylidene-2H-pyran-2-
one (10a). A mixture of 9a (71 mg, 0.2 mmol), PPTS (5 mg,
0.02 mmol) dissolved in CH2Cl2 (4 mL) was stirred at 55 ꢁC for 12 h.
The mixture was neutralized with aq NaHCO3 and concentrated.
4.1.27. Preparation of 10a from 12a. To a solution of 12a (43 mg,
0.2 mmol) in THP (3 mL) was added Ac2O (60
(80
L, 0.6 mmol) at 0 ꢁC for 30 min. Then, the reaction was heated at
65 ꢁC for 24 h, quenched with aq NH4Cl, and concentrated. The crude
mL, 0.6 mmol) and Et3N
m

9720
W. Peng et al. / Tetrahedron 66 (2010) 9714e9720
16. Yasuda, H.; Uenoyama, Y.; Nobuta, O.; Kobayashi, S.; Ryu, I. Tetrahedron Lett.
2008, 49, 367.
17. Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110 .
product was purified by LC (SiO2; hexanes/AcOEt, by increasing the
gradient from 10:1 to 3:1 v/v) to give 10a as a colorless oil (36 mg, 93%
yield).
Acknowledgements
H+
+
2
N
O
N
OH
II
N
O
I
Supports by Okayama University and the Electric Technology
Research Foundation of Chugoku are gratefully acknowledged. We
are also grateful to the Advanced Science Research Center for the
NMR experiments and EA. We thank the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) for the scholarship
to W.P. We are grateful to the Showadenko Co., Manac Incorporated,
and Osaka Organic Chemical, Ltd., for the generous gifts of THP,
DAIB, and 4-BzOTEMPO, respectively.
III
18. Formation of the acetoxy(2,2,6,6-tetramethylpiperidine-1-oxy)iodobenzene
intermediate by the reaction of II and DAIB and the subsequent de-
composition to III would be assisted with acid catalyst.
A
2
Supplementary data
N
OH
N
O
I
2
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.034. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
+
N
–PhI
N
OAc
O
O
I
I
OAc
A
H+
References and notes
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