A family of stilbene-ethers as photolabile protecting groups for primary alcohols offers controlled deprotection based on choice of wavelength

Article abstract of DOI:10.1016/j.tet.2013.06.074

A novel stilbene-ether type of photolabile protecting group (PPG) for hydroxyl group has been developed. It contains a stable aryl ether group in the protected form and can be deprotected by acid-catalyzed photorearrangement under 300-nm irradiation. The selective deprotection has also been achieved by irradiation of the mixture of 4-alkoxystilbene and 2-(4-alkoxystyryl)furan at 365 nm.

Full text of DOI:10.1016/j.tet.2013.06.074

Tetrahedron 69 (2013) 7325e7332
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A family of stilbene-ethers as photolabile protecting groups for
primary alcohols offers controlled deprotection based on choice of
wavelength
*
Jinn-Hsuan Ho , Ya-Wen Lee, Ying-Zhe Chen, Pin-Sian Chen, Wei-Qi Liu, Yi-Shun Ding
Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel stilbene-ether type of photolabile protecting group (PPG) for hydroxyl group has been developed.
It contains a stable aryl ether group in the protected form and can be deprotected by acid-catalyzed
photorearrangement under 300-nm irradiation. The selective deprotection has also been achieved by
irradiation of the mixture of 4-alkoxystilbene and 2-(4-alkoxystyryl)furan at 365 nm.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 29 January 2013
Received in revised form 13 June 2013
Accepted 21 June 2013
Available online 28 June 2013
Keywords:
Photolabile protecting group
Stilbene
Styrylfuran
Styrylthiophene
Alcohol
1. Introduction
O
OR
O
OR
O
NO2
Br
O
O
O
Ph
Photolabile protecting groups (PPGs) have several merits to the
conventional protecting groups. Their advantages include spatial
and temporal controls and orthogonal reaction conditions to most
of thermal reactions, so that PPGs are widely used in the areas of
organic synthesis, biochemically caged compounds, and solid-
phase synthesis.1 Some PPGs have been developed for the pro-
tection of hydroxyl group, including 2-nitrobenzene derivative A,2
coumarin-4-ylmethoxycarbonyl B,3 o-benzoylbenzoate ester C,4
3-hydroxy-2-naphthalenemethanol D,5 9-phenylxanthen-9-yl
ether E,6 and trityl ether F7 (Scheme 1). In order to phototrigger
deprotection reactions, these PPGs usually contain some acid- and
base-sensitive functional groups, such as nitro, carbonate, ester,
hydroxyl, and triphenyl ether groups.8 Therefore, to develop a new
type of PPG that can be stable under most of acidic and basic
conditions is an important issue.
O
OR
O
O
A
B
C
R2
R1
R3
OR
OH
Ph OR
Ph
Ph
O
O
Ph
D
E
F
Scheme 1. Selected photolabile protecting groups of alcohols.
acid-catalyzed photorearrangement of stilbenyl ethers reported by
Ho’s group12 has shown the ability to decompose aryl ethers under
a mild condition (Scheme 2). One of the reported examples12c was
the irradiation of 4-methoxystilbene 1. When 1 was irradiated with
5 mM of hydrochloric acid in acetonitrile ([water] is ca. 73.6 mM),13
4-naphthan-2-yl-but-3-en-2-one 2 could be obtained. And when 1
was irradiated with 0.5 M of hydrochloric acid in water/acetonitrile
([water] is ca. 2.2 M)13 solution, 1,4-dihydro-2H-phenanthren-3-
one 3 would be formed as the major product. The proposed
mechanism for the formation of compounds 2 and 3 shows mul-
tiple steps, including photocyclization, acid-catalyzed [1,9] and
[1,3] hydrogen shift, 6e retro-electrocyclic reaction, and hydrolysis.
The aromatization (DHP1 to DHP2 and DHP2 to N) and hydrolysis
Aryl alkyl ether is a stable functional group to most of acidic and
basic reaction conditions, but it is seldom used as a protecting
group. That is because decomposition of aryl alkyl ethers usually
needs strong reagents,9 such as oxidants for methyl phenyl ether10
and Lewis acids for isopropyl aryl ether.11 However, a unique
* Corresponding author. Tel.: þ886 2 2737 6642; fax: þ886 2 2737 6644; e-mail
address: jhho@mail.ntust.edu.tw (J.-H. Ho).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.074

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J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
Ar
provide
photorearrangement.
the
driving
force
for
this
acid-catalyzed
Ar
NaH
HO
Ph
+
O
1a - 1c
Ph
Ph
NMP
4
F
3a - 3c
Concept of stilbene-ether PPG
OCH3
OCH3
H+
NC
a: Ar =
b: Ar =
c: Ar =
H
O
H
hv
hv
O
S
(i)
OCH3
1d
DHP1
trans-1
cis-1
Scheme 3. Syntheses of 1aec and the structure of 1d.
(ii)
Methanol Deprotection
O
OCH3
OCH3
H
H
Table 1
Protection yields and absorption maxima of 1aed
+ CH3OH
max
abs
max
abs
(trans)a
l
(cis)a
Yield (%)
(iv)
(vi)
Entry
Compound
l
(iii)
1
2
3
4
1a
1b
1c
1d
311 nm
321 nm
331 nm
337 nm
290 nm
307 nm
298 nm
318 nm
87b
64b
89b
66c
2
N
DHP2
O
O
(v)
a
2.5ꢀ10ꢁ5 M in acetonitrile.
b
c
+ CH3OH
The yields are determined after gravity chromatography purification twice.
The yield includes cis- and trans-1d.
3
DHP3
2.2. Deprotection
(i)
6e electrocyclic reaction
acid-catalyzed [1,9]H shift
(ii)
(iii)
(iv)
(v)
(vi)
6e retro-electrocyclic reaction (with 5 mM HCl in acetonitrile
The deprotection was carried out by irradiation of N2-purged
solutions of 1aed at 300 nm ultraviolet light (Scheme 4), and the
reaction conditions and the results are reported in Table 2. First, the
irradiation of 1a in a pure acetonitrile did not release alcohol 4 and
only led to transecis isomerization (entry 1). When the irradiation
of 1a was took place in dichloromethane or acidic acetonitrile, the
alcohol 4 would be released in moderate to good isolated yields
(70e80%, entries 2e4). Deprotection of 1b and 1c also released
alcohol 4 in good yields (74e88%, entries 5e8) after only 2-h and
4-h irradiation. Finally, irradiation of 1d resulted in a poor result
(55%, entry 9) after a prolonged irradiation time. The poor depro-
tection of compound 1d may result from the substitution effect of
cyano group on photocyclization reaction.15
hydrolysis
containing 0.04 % v/v of water )
hydrolysis (with 0.5 M HCl in water/acetonitrile (4 % v/v) solution)
acid-catalyzed [1,3]H shift
Scheme 2. Mechanism of acid-catalyzed photorearrangement of stilbenyl ethers and
our concept of stilbene-ethers of PPG.
Our concept is to utilize stilbenyl ether as a protected form for
alcohols and this acid-catalyzed photorearrangement as the
deprotection step, which could change the aryl methyl ether group
of compound 1 into the vinyl methyl ether group of intermediate N,
and then release alcohol by hydrolysis of vinyl methyl ether
(Scheme 2). Development of this stilbene-ether PPG contains sev-
eral features: First, using aryl ether as a protecting group is very
stable to most of thermal reaction conditions. Second, the depro-
tection condition is mild enough to keep the protected molecule
from unwanted changes. Third, the necessity of catalytic acid for
deprotection provides a safety-catch function.2a Fourth, the selec-
tive deprotection may be achieved by different photoreactivities of
stilbene-type compounds under selected wavelength irradiation.
To the best of our knowledge, this is the first case using the pho-
toreaction of stilbene-type compounds in the field of PPGs.
Therefore, we would like to report this family of stilbene-ethers to
be a new type of PPG.
Ar
hv
2a - 2d
+
HO
Ph
cond.
O
Ph
1a - 1d
4
O
O
2c:
2a:
2b:
O
S
O
NC
2d:
O
Scheme 4. Deprotection of 1aed.
2. Results and discussion
Table 2
Deprotection of 1aed by irradiation at 300 nm
2.1. Protection of primary alcohol
Entry
Compound
Solventa
hv time
Recovery
Deprotection
(%)c
(h)
of SMb (%)
The preparations of 1aec are outlined in Scheme 3. The pre-
cursors 3aec were first synthesized by the Wittig reaction of
4-fluorobenzyl bromide and the appropriate aldehydes. Afterward
the nucleophilic aromatic substitution14 (SNAr) of 3aec with 3-
phenylpropanol 4 in presence of sodium hydride and N-methyl-2-
pyrrolidone (NMP) afforded compounds 1aec, respectively. But
compound 1d could not be synthesized in the same manner. In order
to prepare 1d, an alternative synthetic method was offered by the
Wittig reaction of 4-cyanobenzyl chloride and 4-(3-phenylpropoxy)
benzaldehyde, which was synthesized from 4-hydroxybenzaldehyde
and 3-phenyl-1-bromopropane. The synthetic yields of compounds
1aed are reported in Table 1. For the selection of irradiation wave-
length, the absorption maxima of trans and cis-1aed are also listed
in Table 1.
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1c
1c
1d
AN
6
6
10
6
2
2
4
4
48
88
27
8
15
2
0
9
2
18
0
70
76
80
88
81
74
82
55
5 mM HCl/AN
5 mM HCl/AN
DCM
5 mM HCl/AN
DCM
5 mM HCl/AN
DCM
5 mM HCl/AN
a
AN: CH3CN, DCM: CH2Cl2.
SM: starting material cis/trans-1aed.
Isolated yield of released alcohol 4.
b
c
It is worthy to mention that undehydrated dichloromethane
could let this acid-catalyzed photorearrangement work well

J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
7327
Table 3
without adding acid and moisture. Photolysis of dichloromethane
generating hydrochloric acid at the interface between the UV light-
exposed silica wall and the solvent has been reported.16 We also
used 2-(4-(N,N-dimethylamino)styryl)quinoline as acidebase in-
dicator to prove the formation of acid in the cases of the irradiated
dichloromethane and the irradiated dichloromethane solution of
1a in the quartz tubes.17 Besides, the residual water in common
dichloromethane (usually 0.1 wt. %) could be the source of water for
this photorearrangement because the concentration of residual
water is ca. 73.6 mM, while the concentration of 1a is just 3.2 mM in
our cases.
The irradiation times of 1a, b, and c (entries 3, 5, and 7 in Table
2) show that the photochemical reactivity is 1b>1c>1a. This order
of reactivity is consistent with that of Ho’s work.12a,b Photochemical
reactivity should be influenced by the reaction rate of the
acid-catalyzed [1,9] hydrogen shift of DHP1, and this rate would be
proportional to the electron density of C4 position (Scheme 5).
Because DHP1b has oxygen atom with lone pairs of electrons to
enhance the electron density on C4 atom, the reactivity of 1b is the
highest. The reactivity of 1c is lower than 1b, and that is because of
the bad overlap of orbitals between sulfur and carbon atoms.
Without the assistance of lone pairs of heteroatoms, 1a has the
lowest reactivity.
Deprotection of 1aed in acetonitrile solution containing 5 mM HCl by irradiation at
365 nma
Entry
Compound
hv time (h)
Recovery of SMb (%)
Deprotection (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1
2
3
24
0.5
1.5
2
3
1
2
3
100
100
100
84
86
46
28
9
91
77
53
93
0
0
0
16
14
54
72
91
9
23
47
7
9
10
11
12
24
a
Ratios were determined by 1H NMR of crude reaction mixtures.
SM: starting materials cis/trans-1aed.
b
non-detectable deprotection after 3-h irradiation (entry 3), and
only 16% deprotection after 24-h irradiation (entry 4). Irradiation of
1d, whose cis-form has the longest wavelength end extending to
380 nm, was even more inactive at 365 nm (entry 12). An attempt
on photochemical deprotection of 1d at 419 nm was also failed to
get a better result. However, a 3-h irradiation of 1b and 1c sur-
prisingly led to more effective deprotection in 90% and 46% yields,
respectively (entries 8 and 11). Finally, two quantitative experi-
ments proved the high efficiency on deprotection of 1b and 1c: first,
6-h irradiation of 1b at 365 nm leading to 91% deprotection; sec-
ond, 8-h irradiation of 1c at 365 nm leading to 84% deprotection.
Compounds 1a and 1b showed remarkably different photo-
reactivities under 365-nm irradiation and could be used for selec-
tive deprotection. Photolysis of a 1:1 mixture of 1a and 1b at
365 nm for 3 h afforded 2b, alcohol 4, and the recycling 1a in 92%,
80%, and 98% yields, respectively, after column chromatography
(Scheme 6). None of deprotection of 1a was observed. This excellent
selectivity means there was no intermolecular energy transfer be-
tween the excited state of 1b and the ground state of 1a. Therefore,
a successive control-release of two alcohols can be achieved by ir-
radiating the mixture of 4-alkoxystilbene 1a and 2-(4-alkoxystyryl)
furan 1b.
OR
OR
OR
C4
C4
C4
O
S
DHP1a
DHP1b
DHP1c
Scheme 5. Structureereactivity correlation of 1a, b, and c.
2.3. Selective deprotection
In order to investigate the possibility of selective deprotection
based on choice of wavelength, the UV profiles of cis-1ae1d, which
are the real starting materials for the photocyclization in-
termediates DHP1s (Scheme 2), are compared in Fig. 1. Compared
with cis-1a, compounds 1be1d have longer wavelength absorp-
tions and may be more reactive under 365-nm irradiation.
The deprotection of 1aed18 under 365-nm irradiation in acidic
acetonitrile was estimated by 1H NMR of crude reaction mixture
and the results are reported in Table 3. Photolysis of 1a led to
+
O
O
Ph
O
Ph
1a
1b
1. 365 nm, 3 hours
2. chromatography
O
+
1a
+
HO
Ph
O
2b
92%
4
98%
80%
Scheme 6. Selective deprotection of 1a and b.
2.4. Stability
The stability of compound 1a under a variety of acidic and basic
conditions is shown in Table 4. Treatment of 1a with several strong
bases, such as n-butyllithium, sodium hydride, potassium tert-
butoxide, potassium hydroxide, at different temperatures led to the
excellent recovery of 1a (entries 1e9). In contrast, reactions of
3-phenylpropyl benzoate under basic conditions resulted in hy-
drolysis of the ester group.19 When compound 1a was reacted in
acidic condition at the refluxing temperature of aqueous THF, no
Fig. 1. UVevis absorption spectra of cis-1aed (2.5ꢀ10ꢁ5 M in acetonitrile).

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J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
Table 4
Table 5
Stability of 1a (0.06 M) under various conditionsa
Protection of 5e12 with 3a by SNAr reaction and deprotection in acetonitrile solution
containing 5 mM HCl by irradiation at 300 nma
Entry
Reagent
Solvent
Conditionb
Recovery
of 1a (%)
Entry
Alcohols
Protected
forms
Protection yields
(%)b
Deprotections
(%)c
1
2
3
4
5
6
7
8
0.06 M nBuLi
0.06 M nBuLi
0.15 M nBuLi
0.15 M NaH
0.13 M NaH
THF
THF
THF
NMP
NMP
THF
THF
H2O/THF (1:1)
H2O/THF (1:1)
H2O/THF (1:3)
H2O/THF (1:9)
ꢁ78 ꢂC, 4 h
rt, 2 h
rt, 2 h
rt, 2 h
50 ꢂC, 2 h
rt, 2 h
Reflux, 2 h
Reflux, 21 h
Reflux, 2 h
Reflux, 2 h
Reflux, 2 h
98%
96%
95%
95%
96%
95%
98%
94%
99%
99%
95%
1
2
3
4
5
6
7
8
5
6
7
8
1e
1f
d
1g
1h
1i
45
45
0
38
82
23
0
85
90
d
80
83
75
d
d
t
0.33 M BuOK
9
t
0.35 M BuOK
10
11
12
0.9 M KOH
2.2 M KOH
3.0 M HCl
1.2 M HCl
d
9
d
0
10c
11d
a
Isolated yields.
b
The protection method is the SNAr reaction of 3a and alcohols 5e12 in presence
a
General procedures: 0.06 M of 1a in 5 mL of solvent was reacted under the above
conditions. The recovery of 1a was reported in isolated yields.
of sodium hydride and NMP.
The deprotection method is irradiation an acidic acetonitrile solution of 1eei at
300 nm for 6 h.
c
b
rt: room temperature.
c
[1a]¼0.04 M.
d
[1a]¼0.03 M.
alcohol. This PPG contains stable aryl alkyl ether as a protecting
functional group and has remarkable stability under strong acidic
and basic conditions. The protection procedure can be carried out
by SNAr reaction of a corresponding fluoro-compound in a good
yield, and the deprotection can easily complete by photolysis in
a catalytically acidic condition. This PPG also has the ability of
control-release when a mixture of 4-alkoxystilbene 1a and 2-(4-
alkoxystyryl)furan 1b was irradiated under 365 nm first and then
300 nm. In the further study, the multiple control-release function
of a mixture sample that contains this stilbene-ether type and other
types of PPGs will be estimated.
decomposition of stilbenyl ether happened (entry 10). This means
that aryl alkyl ether is stable enough to many thermal reaction
conditions, such as metalehalogen exchange, nucleophilic sub-
stitution, elimination reaction, acidic and basic hydrolysis of ester,
and triphenylmethyl ether, etc.
2.5. Other alcohols
In order to extend the application of this stilbene-ether type of
PPG, we have tried protections and deprotections of aryl alcohols
5e8, benzyl alcohol 9, allyl alcohol 10, secondary alcohol 11, and
tertiary alcohol 12 (Scheme 7). The results are reported in Table 5.
Protection of alcohols 5, 6, and 8 by the SNAr reaction afforded
protected compounds 1e, f, and g in lower yields (38%e45%), and
this may be because of the weaker nucleophilicity of phenoxide
anion. Alcohol 7 was nearly not protected by the same reaction,
because nitro group would weaken its nucleophilicity further. The
protection of benzyl alcohol 9 yielded protected compound 1h in
a good yield (82%). But the protection of allyl alcohol 10 afforded
compound 1i in a very low yield (23%). This may be due to the
instability of styrene part of alcohol 10 under high reaction tem-
perature. Alcohols 11 and 12, which were prepared by the reaction
of 4-phenyl-2-butanone and methyl 3-phenylpropanoate with
methylmagnesium bromide, also could not be protected by the
same SNAr reaction. The unsuccessful protection of 11 and 12 were
4. Experimental section
4.1. General information
The photochemical reactor, equipped a merry-go-round appa-
ratus encompassed with 16 monochromatic light tubes (300 nm
and 365 nm), was made by a local company. The average temper-
ature inside the photochemical reactor during operation is about
40 ꢂC. The quartz tubes of photolysis were 1.3 cm in diameter and
20 cm in length. NMR spectra were measured on a Bruker AVIII
500 MHz FT-NMR with chloroform-d1 as the standard (7.26 ppm for
1H NMR and 77.0 ppm for 13C NMR). Mass spectra were recorded on
a Finnigan MAT 95S Mass spectrometer. UVevis spectra were
recorded on a JASCO V-630 Spectrophotometer. Column chroma-
tography used silica gel with 60e120 mesh. Anhydrous N-methyl-
2-pyrrolidone (NMP) of AcroSeal packaging was purchase from
Acros Company. All other solvent and commercial reagents used as
obtained without further purification. The preparation of 5 mM HCl
in CH3CN was by simple dilution of concentrated aqueous hydro-
chloride with acetonitrile solution.
possibly due to the repulsion of
a
-methyl group.
HO
HO
OEt
HO
HO
Pr
HO
n
NO2
5
6
7
8
9
4.2. Synthesis of precursors trans-3aec
HO
HO
HO
12
10
11
The synthesis of trans-3a is used as an example: a mixture of
Scheme 7. Structures of alcohols 5e12.
4.0
g (2.78 mmol) of 4-fluorobenzyl chloride and 8.73 g
(3.30 mmol) triphenylphosphine in 12 mL of benzene was refluxed
for 2 days to yield white solid. Collect the solid by suction filtration
and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in
82% yield. Afterward, a mixture of 9.97 g (2.5 mmol) of the previous
salt, 2.37 g (2.2 mmol) of benzaldehyde, and 0.82 g (3.11 mmol) of
18-crown-6 in 56 mL of dichloromethane was stirred violently and
27 mL of 50% aqueous solution of K2CO3 was added slowly. After
addition, the reaction was stirred at room temperature for 3 days.
And then the reaction mixture was poured into water and extracted
with ethyl acetate for three times. The organic layers were com-
bined and dried with anhydrous MgSO4. The organic solvent was
Deprotection of compounds 1eei by the acid-catalyzed photo-
rearrangement showed good results (75%e90% yields). But due to
the lower protection yields, this stilbene-ether type of photolabile
protecting group is improper used for the protection of aryl, sec-
ondary, and tertiary alcohols.
3. Conclusion
In conclusion, we demonstrated a novel stilbene-ether type of
PPG for primary alcohols, including 3-phenylpropanol and benzyl

J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
7329
removed under reduced pressure and the residue was purified by
column chromatography on silica gel (ethyl acetate/hexane¼1:10)
to afford cis and trans-3a in a 95.1% yield. Refluxing the previous
mixture with catalytic iodine in benzene for 3 h and then purify the
resulting products by column chromatography on silica gel (ethyl
acetate/hexane¼1:10) afforded trans-3a in 92% yield.
7.38 (s, 1H), 7.30 (t, J¼7.5 Hz, 2H), 7.23e7.19 (m, 3H), 6.99 (d,
J¼16.2 Hz, 1H), 6.87 (d, J¼8.6 Hz, 2H), 6.77 (d, J¼16.2 Hz, 1H), 6.41
(dd, J¼3.3, 1.9 Hz, 1H), 6.30 (d, J¼3.3 Hz, 1H), 3.98 (t, J¼6.4 Hz, 2H),
2.82 (t, J¼7.8 Hz, 2H), 2.12 (p, J¼7.0, 2H). 13C NMR (125 MHz, CDCl3)
d
158.73, 153.57, 141.71, 141.45, 129.73, 128.51, 128.41, 127.52, 126.81,
125.93, 114.74, 114.56, 111.53, 107.61, 66.93, 32.12, 30.80. MS (EI,
70 eV) m/e 305 (Mþþ1, 5), 304 (Mþ, 100), 186 (87), 91 (43). HRMS
(C21H20O2) calcd: 304.1458, found: 304.1458.
The synthesis of trans-3b and 3c were in the same manner.
4.2.1. trans-4-Fluorostilbene (trans-3a).20 Yield 92%. 1H NMR
(500 MHz, CDCl3)
d
7.50 (d, J¼7.0 Hz, 2H), 7.48 (dd, J¼8.7, 5.5 Hz,
4.3.3. trans-2-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-thiophene
2H), 7.36 (t, J¼7.8 Hz, 2H), 7.26 (t, J¼7.4 Hz, 1H), 7.08 (d, J¼16.4 Hz,
(trans-1c). Yield 89%. 1H NMR (500 MHz, CDCl3)
d
7.39 (d, J¼8.7 Hz,
1H), 7.05 (t, J¼8.7 Hz, 2H), 7.02 (d, J¼16.4 Hz, 1H). 13C NMR
2H), 7.29 (t, J¼7.5 Hz, 2H), 7.23e7.19 (m, 3H), 7.15 (d, J¼4.9 Hz, 1H),
7.10 (d, J¼16.0 Hz, 1H), 7.02 (d, J¼3.4 Hz, 1H), 6.99 (dd, J¼4.9, 3.4 Hz,
1H), 6.88 (d, J¼16.0 Hz, 1H), 6.87 (d, J¼8.7 Hz, 2H), 3.98 (t, J¼6.3 Hz,
2H), 2.82 (t, J¼7.8 Hz, 2H), 2.12 (p, J¼6.9 Hz, 2H). 13C NMR (125 MHz,
1
(125 MHz, CDCl3)
d
162.35 (d, JFeC¼245.7 Hz), 137.19, 133.54 (d,
4JFeC¼3.2 Hz), 128.69, 128.52 (d, JFeC¼2.7 Hz), 127.97 (d,
5
3JFeC¼7.9 Hz), 127.66, 127.50, 126.44, 115.60 (d, JFeC¼21.8 Hz).
2
CDCl3) d 158.74,143.28,141.45,129.67,128.51,128.42,128.01,127.50,
4.2.2. trans-4-Fluorostyrylfuran (trans-3b).21 Yield 80%. 1H NMR
(500 MHz, CDCl3)
125.94, 125.33,123.68, 119.71, 114.76,114.48, 66.93, 32.12, 30.80. MS
(EI, 70 eV) m/e 321 (Mþþ1, 5), 320 (Mþ, 100), 202 (99), 91 (41).
HRMS (C21H20OS) calcd: 320.1229, found: 320.1230.
d
7.42 (dd, J¼5.5, 2.1 Hz, 2H), 7.40 (d, J¼1.45 Hz,
1H), 7.03 (t, J¼8.8 Hz, 2H), 6.99 (d, J¼16.2 Hz,1H), 6.80 (d, J¼16.2 Hz,
1H), 6.42 (dd, J¼3.3, 1.9 Hz, 1H), 6.34 (d, J¼3.25 Hz, 1H). 13C NMR
1
(125 MHz, CDCl3)
d
162.29 (d, JFeC¼245.6 Hz), 153.09, 142.13,
4.3.4. trans-1-Ethoxy-4-(4-styrylphenoxy)benzene (trans-1e). Yield
133.22 (d, 4JFeC¼3.2 Hz), 127.78 (d, 3JFeC¼7.9 Hz), 125.93, 116.34 (d,
45% (145 ꢂC for 21 h). 1H NMR (500 MHz, CDCl3)
d
7.49 (d, J¼7.4 Hz,
5JFeC¼2.2 Hz), 115.64 (d, 2JFeC¼21.3 Hz), 111.63, 108.53.
2H), 7.45 (d, J¼8.7 Hz, 2H), 7.36 (t, J¼7.5 Hz, 2H), 7.25 (t, J¼7.4 Hz,
1H), 7.07 (d, J¼16.3 Hz, 1H), 7.00 (d, J¼16.3 Hz, 1H), 6.99 (d,
J¼9.0 Hz, 2H), 6.94 (d, J¼8.7 Hz, 2H), 6.89 (d, J¼9.0 Hz, 2H), 4.03 (q,
J¼7.0 Hz, 2H), 1.43 (t, J¼7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)
4.2.3. trans-4-Fluorostyrylthiophene (trans-3c).22 Yield 83%. 1H
NMR (500 MHz, CDCl3)
d
7.43 (dd, J¼8.6, 5.4 Hz, 2H), 7.19 (d,
J¼5.1 Hz, 1H), 7.14 (d, J¼16.1 Hz, 1H), 7.06 (d, J¼3.4 Hz, 1H), 7.04 (t,
d 158.21, 155.37, 149.86, 137.47, 131.80, 128.65, 127.97, 127.75, 127.45,
J¼8.9 Hz, 2H), 7.00 (dd, J¼5.1, 3.6 Hz, 1H), 6.89 (d, J¼16.1 Hz, 1H). 13
C
127.38,126.33,120.83,117.73,115.52, 63.91,14.88. MS (EI, 70 eV) m/z
NMR (125 MHz, CDCl3)
d
162.31 (d, 1JFeC¼246.2 Hz), 142.67, 133.18
316 (Mþ, 100), 288 (18), 178 (20), 152 (8).
4
3
(d, JFeC¼3.6 Hz), 127.76 (d, JFeC¼7.8 Hz), 127.60, 127.13, 126.05,
124.32, 121.60 (d, 5JFeC¼2.5 Hz), 115.65 (d, JFeC¼21.8 Hz).
4.3.5. trans-1-Propyl-4-(4-styrylphenoxy)benzene (trans-1f). Yield
2
45% (180 ꢂC for 2 days).1H NMR (500 MHz, CDCl3)
d
7.50 (d, J¼7.3 Hz,
4.3. Protection: compounds trans-1aec and 1eei
2H), 7.47 (d, J¼8.7 Hz, 2H), 7.35 (t, J¼7.9 Hz, 2H), 7.25 (t, J¼7.3 Hz,1H),
7.15 (d, J¼8.5 Hz, 2H), 7.09 (d, J¼16.4 Hz, 1H), 7.01 (d, J¼16.4 Hz, 1H),
6.98 (d, J¼8.7 Hz, 2H), 6.96 (d, J¼8.5 Hz, 2H), 2.58 (t, J¼7.8 Hz, 2H),
1.69e1.61 (m, 2H), 0.96 (t, J¼7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3)
The synthesis of trans-1a is used as an example: A mixture of 3-
phenyl-1-propanol 4 (0.2 g, 1.47 mmol), sodium hydride (60% pu-
rity, 0.194 g, 8.08 mmol) was sealed quickly in a flask with a septum.
And then 2 mL of anhydrous NMP was added with a syringe. The
reaction mixture was stirred in an ice-water bath for 30 min, and
then at room temperature for another 30 min. Afterward, a solution
of trans-1-fluoro-4-styrylbenzene (trans-3a, 0.35 g, 1.76 mmol) and
anhydrous NMP (2.5 mL) was added with a syringe at room tem-
perature. And then the reaction mixture was stirred at 100 ꢂC for
overnight. After completion of the reaction, the reaction was
poured into water and extracted with ethyl acetate for three times.
The organic layers were combined and dried with anhydrous
MgSO4. The residue was obtained by removing organic solvent
under reduced pressure, and then purified by column chromatog-
raphy on silica gel (hexane, then ethyl acetate/hexane¼1:10) to
afford trans-1a in 87% yield.
d
157.42,154.76,137.94,137.45,132.20,129.65,128.66,127.97,127.78,
127.62, 127.42, 126.35, 119.02, 118.57, 37.32, 24.65, 13.78.
4.3.6. trans-2-(4-Styrylphenoxy)naphthalene (trans-1g). Yield 38%
(160 ꢂC for 21 h). 1H NMR (500 MHz, CDCl3)
d
7.85 (t, J¼8.9 Hz, 2H),
7.72 (d, J¼8.2 Hz, 1H), 7.52 (d, J¼8.7 Hz, 2H), 7.52e7.50 (m, 2H), 7.47
(ddd, J¼8.3, 7.0, 1.2 Hz, 1H), 7.41 (ddd, J¼8.3, 7.0, 1.4 Hz, 1H),
7.38e7.35 (m, 3H), 7.29e7.24 (m, 2H), 7.11 (d, J¼16.3 Hz,1H), 7.07 (d,
J¼8.7 Hz, 2H), 7.05 (d, J¼16.3 Hz, 1H). 13C NMR (125 MHz, CDCl3)
d
156.81, 154.91, 137.39, 134.32, 132.79, 130.23, 129.91, 128.68,
127.96, 127.91, 127.87, 127.74, 127.51, 127.14, 126.56, 126.39, 124.76,
119.96, 119.25, 114.24. MS (EI, 70 eV) m/z 323 (Mþþ1, 22), 322 (Mþ,
100), 178 (10), 127 (12), 115 (8).
The syntheses of trans-1b, 1c, and 1eei were in the same
manner.
4.3.7. 1-Benzyloxy-4-styryl-benzene (trans-1h). Yield 82% (160 ꢂC
for 21 h). 1H NMR (500 MHz, CDCl3)
d
7.49 (d, J¼7.2 Hz, 2H),
7.47e7.44 (m, 4H), 7.40 (t, J¼7.7 Hz, 2H), 7.37e7.33 (m, 3H), 7.24 (t,
4.3.1. trans-1-(3-Phenylpropoxy)-4-styrylbenzene (trans-1a). Yield
J¼7.4 Hz,1H), 7.07 (d, J¼16.4 Hz,1H), 6.98 (d, J¼16.4 Hz,1H), 6.98 (d,
87%. 1H NMR (500 MHz, CDCl3)
d
7.49 (d, J¼7.6 Hz, 2H), 7.44 (d,
J¼8.8 Hz, 2H), 5.01 (s, 2H). 13C NMR (125 MHz, CDCl3)
d 158.49,
J¼8.7 Hz, 2H), 7.35 (t, J¼7.8 Hz, 2H), 7.30 (t, J¼7.4 Hz, 2H), 7.25e7.18
(m, 4H), 7.07 (d, J¼16.3 Hz, 1H), 6.98 (d, J¼16.3 Hz, 1H), 6.89 (d,
J¼8.7 Hz, 2H), 3.99 (t, J¼6.3 Hz, 2H), 2.83 (t, J¼7.5 Hz, 2H), 2.12 (p,
137.61, 136.89, 130.39, 128.63, 128.60, 128.16, 127.99, 127.71, 127.46,
127.22, 126.74, 126.25, 115.08, 70.06.
J¼7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d
158.77, 141.47, 137.68,
4.3.8. 1-(Cinnamyloxy)-4-(trans-styryl)benzene
(trans-1i). Yield
7.49 (d, J¼7.5 Hz,
130.07, 128.62, 128.51, 128.41, 128.26, 127.69, 127.17, 126.54, 126.23,
125.94,114.75, 66.95, 32.13, 30.81. MS (EI, 70 eV) m/e 315 (Mþþ1, 4),
314 (Mþ, 98), 196 (100), 91 (49). HRMS (C23H22O) calcd: 314.1665,
found: 314.1667.
23% (100 ꢂC for 21 h). 1H NMR (500 MHz, CDCl3)
d
2H), 7.46 (d, J¼8.7 Hz, 2H), 7.41 (d, J¼7.5 Hz, 2H), 7.35 (d, J¼7.3 Hz,
2H), 7.33 (d, J¼7.3 Hz, 2H), 7.27e7.22 (m, 2H), 7.07 (d, J¼16.3 Hz,
1H), 6.98 (d, J¼16.3 Hz, 1H), 6.96 (d, J¼8.7 Hz, 2H), 6.75 (d,
J¼16.0 Hz, 1H), 6.43 (dt, J¼16.0, 5.8 Hz, 1H), 4.73 (dd, J¼5.8, 1.3 Hz,
4.3.2. trans-2-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-furan (trans-
2H). 13C NMR (125 MHz, CDCl3)
d 158.34, 137.63, 136.39, 133.13,
1b). Yield 64%. 1H NMR (500 MHz, CDCl3)
d
7.39 (d, J¼8.6 Hz, 2H),
130.37, 128.63, 128.59, 128.17, 127.93, 127.73, 127.22, 126.73, 126.58,

7330
J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
126.25, 124.32, 115.01, 68.71. MS (EI, 70 eV) m/z 312 (Mþ, 18), 195
(8), 165 (24), 117 (100), 191 (22).
were combined and dried with anhydrous MgSO4. And then the or-
ganic solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel (ethyl acetate/
hexane¼1:5) to afford 4-(3-phenylpropoxy)-benzaldehyde A in
96.3% yield.
4.4. Preparation of compounds cis-1aec
A 100 mL of acetonitrile solution containing 0.1 g of compound 1
was divided into five quartz tubes (1.3 cmꢀ20 cm), and then sealed
the tubes with septa. After excluding oxygen by bubbling with N2
for 30 min, the tubes were irradiated at 300 nm for 2 h. The reaction
mixtures were collected and the solvent was removed under re-
duced pressure. Then compound cis-1 was isolated by column
chromatography on silica gel (hexane).
4.5.2. The Wittig reaction to synthesize cis and trans-1d. A mixture
of 2.01 g (1.33 mmol) of 4-chloromethylbenzonitrile and 4.44 g
(1.96 mmol) PPh3 in 12 mL of benzene was refluxed for 2 days to
produce white solid. Collect the solid by suction filtration and (4-
cyanobenzyl)triphenylphosphonium salt was obtained in 89.3%
yield. Afterward, a mixture of 4.88 g (1.82 mmol) of the previous
salt, 2.6 g (1.08 mmol) of compound A, and 0.38 g (1.45 mmol) of
18-crown-6 in 25 mL of dichloromethane was stirred violently and
12 mL of 50% aqueous solution of K2CO3 were added slowly After
addition, the reaction was stirred at room temperature for 3 days.
And then the reaction mixture was poured into water and extracted
with ethyl acetate for three times. The organic layers were com-
bined and dried with anhydrous MgSO4. The organic solvent was
removed under reduced pressure. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane¼1:10)
to afford the mixture of cis and trans-1d in a 66.1% yield. Some of cis
and trans isomers were readily isolated by further purification.
4.4.1. cis-1-(3-Phenylpropoxy)-4-styrylbenzene (cis-1a). 1H NMR
(500 MHz, CDCl3)
d
7.31e7.15 (m, 12H), 6.73 (d, J¼8.7 Hz, 2H), 6.53
(d, J¼12.3 Hz,1H), 6.50 (d, J¼12.3 Hz,1H), 3.94 (t, J¼6.3 Hz, 2H), 2.80
(t, J¼7.8 Hz, 2H), 2.09 (p, J¼7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d
158.14, 141.50, 137.64, 130.11, 129.80, 129.58, 128.80, 128.67,
128.49, 128.40, 128.20, 126.86, 125.92, 114.18, 66.86, 32.15, 30.82.
MS (EI, 70 eV) m/e 315 (Mþþ1, 10), 314 (Mþ, 53), 196 (100), 91 (55).
HRMS (C23H22O) calcd: 314.1665, found: 314.1666.
4.4.2. cis-2-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-furan
(cis-
7.43 (d, J¼8.7 Hz, 2H), 7.34 (s, 1H),
1b). 1H NMR (500 MHz, CDCl3)
d
4.5.3. 4-(3-Phenylpropoxy)-benzaldehyde (A). 1H NMR (500 MHz,
7.32 (t, J¼7.5 Hz, 2H), 7.26e7.21 (m, 3H), 6.89 (d, J¼8.7 Hz, 2H), 6.43
(d, J¼12.6 Hz, 1H), 6.36 (dd, J¼3.4, 1.8 Hz, 1H), 6.31 (d, J¼12.6 Hz,
1H), 6.31 (d, J¼3.4 Hz, 1H), 4.01 (t, J¼6.3 Hz, 2H), 2.85 (t, J¼7.8 Hz,
CDCl3)
d
9.89 (s, 1H), 7.84 (d, J¼8.7 Hz, 2H), 7.31 (t, J¼7.5 Hz, 2H),
7.23e7.21 (m, 3H), 6.99 (d, J¼8.7 Hz, 2H), 4.06 (t, J¼6.3 Hz, 2H), 2.84 (t,
J¼7.6 Hz, 2H), 2.16 (p, J¼6.9, 2H). 13C NMR (125 MHz, CDCl3)
d 190.80,
2H), 2.15 (p, J¼7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d 158.37,
164.10,141.09,131.98,129.87,128.48,126.07,114.76, 67.25, 32.00, 30.55.
152.36, 141.50, 141.31, 130.04, 129.68, 128.51, 128.41, 127.75, 125.92,
116.57, 114.09, 111.14, 109.52, 66.86, 32.15, 30.83. MS (EI, 70 eV) m/e
305 (Mþþ1, 9), 304 (Mþ, 100), 186 (93), 91 (72). HRMS (C21H20O2)
calcd: 304.1458, found: 304.1462.
4.5.4. cis-4-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-benzonitrile
(cis-1d). 1H NMR (500 MHz, CDCl3)
d
7.51 (d, J¼8.2 Hz, 2H), 7.36 (d,
J¼8.2 Hz, 2H), 7.30 (t, J¼7.6 Hz, 2H), 7.24e7.2 (m, 3H), 7.13 (d,
J¼8.6 Hz, 2H), 6.78 (d, J¼8.6 Hz, 2H), 6.69 (d, J¼12.2 Hz, 1H), 6.47 (d,
J¼12.2 Hz, 1H), 3.96 (t, J¼6.3 Hz, 2H), 2.82 (t, J¼7.6 Hz, 2H), 2.12 (p,
4.4.3. cis-2-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-thiophene (cis-
1c). 1H NMR (500 MHz, CDCl3)
d 7.35e7.30 (m, 4H), 7.27e7.21 (m,
J¼7.0, 2H). 13C NMR (125 MHz, CDCl3)
d 158.68, 142.51, 141.36,
3H), 7.12 (d, J¼5.0 Hz, 1H), 7.01 (d, J¼3.5 Hz, 1H), 6.92 (dd, J¼5.0,
3.5 Hz, 1H), 6.89 (d, J¼8.6 Hz, 2H), 6.65 (d, J¼11.9 Hz, 1H), 6.54 (d,
J¼11.9 Hz, 1H), 4.01 (t, J¼6.3 Hz, 2H), 2.85 (t, J¼7.9 Hz, 2H), 2.15 (p,
132.82, 131.97, 130.11, 129.43, 128.44, 128.39, 126.70, 125.93, 118.97,
114.39,110.15, 66.88, 32.08, 30.72. MS (EI, 70 eV) m/e 340 (Mþþ1, 5),
339 (Mþ, 64), 221 (97), 91 (100). HRMS (C24H21ON) calcd: 339.1618,
found: 339.1625.
J¼7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d 158.51, 141.49, 140.02,
130.06, 129.43, 128.80, 128.49, 128.39, 127.77, 126.40, 125.91, 125.15,
122.38, 114.46, 66.85, 32.15, 30.82. MS (EI, 70 eV) m/e 321 (Mþþ1,
4), 320 (Mþ, 98), 202 (100), 91 (59). HRMS (C21H20OS) calcd:
320.1229, found: 320.1231.
4.5.5. trans-4-{2-[4-(3-Phenylpropoxy)-phenyl]-vinyl}-benzonitrile
(trans-1d). 1H NMR (500 MHz, CDCl3)
d
7.61 (d, J¼8.4 Hz, 2H), 7.55
(d, J¼8.4 Hz, 2H), 7.46 (d, J¼8.7 Hz, 2H), 7.30 (t, J¼7.4 Hz, 2H),
7.24e7.19 (m, 3H), 7.17 (d, J¼16.3 Hz, 1H), 6.95 (d, J¼16.3 Hz, 1H),
6.91 (d, J¼8.7 Hz, 2H), 4.00 (t, J¼6.3 Hz, 2H), 2.83 (t, J¼7.6 Hz, 2H),
4.5. Synthesis of compounds cis and trans-1d
O
2.13 (m, 2H). 13C NMR (125 MHz, CDCl3)
d 159.54, 142.24, 141.35,
O
H
KOH
Br
132.42,131.99,128.96,128.49,128.42,128.24,126.52,125.97,124.44,
119.13, 114.85, 109.99, 66.96, 32.08, 30.73. MS (EI, 70 eV) m/e 340
(Mþþ1, 4), 339 (Mþ, 53), 221 (85), 91 (100). HRMS (C24H21ON)
calcd: 339.1618, found: 339.1615.
H
+
DMSO
O
OH
A
NC
Compd A
K2CO3
NC
PPh3
4.6. Deprotection of compounds 1aei
C6H6
reflux
Cl
CH2Cl2
O
A 100 mL of acetonitrile solution containing 0.1 g of compound 1
and 5 mM HCl was divided into five quartz tubes (1.3 cmꢀ20 cm),
and then the tubes were sealed with septa. After excluding oxygen
by 30 min of bubbling with N2, the tubes were irradiated at 300 nm
for 6 h. The reaction mixtures were then collected, and neutralized
with aqueous sodium hydroxide. The resulting solution was
extracted with ethyl acetate, and then organic layers were com-
bined and dried with anhydrous MgSO4. The residue was obtained
by removing organic solvent under reduced pressure, and then
purified by column chromatography on silica gel (ethyl acetate/
hexane¼1:10) to afford 3-phenyl-1-propanol 4 and the side prod-
uct 2.
cis and trans-1d
4.5.1. Synthesis of A. A mixture of
5 g (4.1 mmol) of 4-
hydroxybenzaldehyde and grounded 9.44 g (0.17 mol) of KOH in
62 mL of DMSO was stirred at room temperature for 30 min, and then
12.17 g (1.5 mol) of 1-bromo-3-phenylpropanewas addedslowly into
the previous solution. After addition, the reaction was stirred for
another 90 min. Afterward, the reaction was poured into water and
extracted with dichloromethane for three times. The organic layers

J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
7331
4.6.1. trans-4-(Naphthalen-2-yl)-but-3-en-2-one (trans-2a).12a 1H
NMR (500 MHz, CDCl3) 7.94 (s, 1H), 7.87e7.82 (m, 3H), 7.69e7.65
d 166.58, 141.17, 132.85, 130.37, 129.53, 128.45, 128.42, 128.32,
126.01, 64.25, 32.29, 30.28.
d
(m, 2H), 7.53e7.51 (m, 2H), 6.83 (d, J¼16.2 Hz, 1H), 2.42 (s, 3H).
4.10. Synthesis of secondary and tertiary alcohols
4.6.2. trans-4-(Benzo[b]furan-5-yl)-but-3-en-2-one (trans-2b).12a,c 1H
NMR (500 MHz, CDCl3)
J¼16.2 Hz, 1H), 7.49 (d, J¼0.9 Hz, 2H), 6.77 (d, J¼2.2 Hz, 1H), 6.71 (d,
J¼16.2 Hz, 1H), 2.38 (s, 3H).
d
7.76 (s, 1H), 7.64 (d, J¼2.2 Hz, 1H), 7.61 (d,
4.10.1. 4-Phenylbutan-2-ol (11). To a stirred THF solution (15 mL) of
3-phenylpropanal 1.0 g (7.5 mmol), 7.5 mL of methylmagnesium
bromide (1 M in THF) was added dropwise at 0 ꢂC. After addition,
the reaction mixture was stirred for 1 h and then diluted with brine
and extracted with ethyl acetate. The organic layers were com-
bined, dried with MgSO4, and concentrated by reduced pressure.
The residue was purified by column chromatography on silica gel
(ethyl acetate/hexane¼1:5) to afford 4-phenylbutan-2-ol in a 65.6%
yield.
4.6.3. trans-4-(Benzo[b]thiophen-5-yl)-but-3-en-2-one (trans-2c).12a,c 1H
NMR (500 MHz, CDCl3)
d
7.94 (s, 1H), 7.86 (d, J¼8.4 Hz, 1H), 7.62 (d,
J¼16.3 Hz, 1H), 7.53 (d, J¼8.4 Hz, 1H), 7.48 (d, J¼5.4 Hz, 1H), 7.34 (d,
J¼5.4 Hz, 1H), 6.78 (d, J¼16.3 Hz, 1H), 2.39 (s, 3H).
4.6.4. trans-7-(3-Oxo-but-1-enyl)-naphthalene-2-carbonitrile
(trans-2d). 1H NMR (500 MHz, CDCl3)
d 8.25 (s, 1H), 8.00 (s, 1H),
4.10.1.1. 4-Phenylbutan-2-ol (11).24 1H NMR (500 MHz, CDCl3)
7.93 (d, J¼7.7 Hz, 1H), 7.91 (d, J¼7.7 Hz, 1H), 7.84 (dd, J¼8.6, 1.2 Hz,
1H), 7.67 (d, J¼16.2 Hz, 1H), 7.66 (dd, J¼8.6, 1.2 Hz, 1H), 6.87 (d,
J¼16.2 Hz, 1H), 2.44 (s, 3H). MS (EI, 70 eV) m/e 222 (Mþþ1, 5), 221
(Mþ, 38), 206 (100), 178 (44), 151 (54). HRMS (C15H11ON) calcd:
221.0835, found: 221.0837.
d
7.27 (t, J¼7.5 Hz, 2H), 7.19 (d, J¼7.0 Hz, 2H), 7.17 (t, J¼7.3 Hz, 1H),
3.82 (sextet, J¼6.2 Hz, 1H), 2.74 (ddd, J¼13.6, 9.3, 6.3 Hz, 1H), 2.65
(ddd, J¼13.6, 9.3, 7.1 Hz, 1H), 1.81e1.70 (m, 2H), 1.22 (d, J¼6.2 Hz,
3H). 13C NMR (125 MHz, CDCl3)
40.80, 32.10, 23.57.
d 142.02, 128.37, 125.78, 67.49,
4.10.2. 2-Methyl-4-phenylbutan-2-ol (12). To a stirred of THF solu-
tion (12 mL) of methyl 3-phenylpropanoate 1.0 g (6.1 mmol),
12.2 mL of methylmagnesium bromide (1 M in THF) was added
dropwise at 0 ꢂC. After addition, the reaction mixture was stirred
for 1 h and then diluted with brine and extracted with ethyl acetate.
The organic layers were combined, dried with MgSO4, and con-
centrated by reduced pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate/hexane¼1:5) to afford
2-methyl-4-phenylbutan-2-ol in a 54.0% yield.
4.7. Selective deprotection of compounds 1a and b
A 100 mL of acetonitrile solution containing 0.05 g of
compound 1a, 0.05 g of 1b, and 5 mM HCl was prepared and
divided into five quartz tubes (1.3 cmꢀ20 cm), and then the
tubes were sealed with septa. After excluding oxygen by 30 min
of bubbling with N2, the tubes were irradiated at 365 nm for
3 h. The reaction mixtures were then collected, and neutralized
with aqueous sodium hydroxide. The resulting solution was
extracted with ethyl acetate, and then organic layers were
combined and dried with anhydrous MgSO4. After removing
organic solvent under reduced pressure, the residue was puri-
fied by column chromatography on silica gel (ethyl acetate/
hexane¼1:10) to afford the recycling 1a, 3-phenyl-1-propanol
4, and the side product 2b in 98%, 80%, and 92% yields,
respectively.
4.10.2.1. 2-Methyl-4-phenylbutan-2-ol (12).25 1H NMR (500
MHz, CDCl3)
d
7.27 (t, J¼7.5 Hz, 2H), 7.19 (d, J¼7.6 Hz, 2H), 7.16 (t,
J¼7.3 Hz, 1H), 2.71e2.67 (m, 2H), 1.80e1.76 (m, 2H), 1.28 (s, 6H). 13
C
NMR (125 MHz, CDCl3)
d 140.50, 128.39, 128.29, 125.73, 70.90,
45.72, 30.73, 29.35, 29.27.
Acknowledgements
4.8. Stability test of compound trans-1a
We are grateful to the National Science Council of the Republic
of China (Taiwan) for financial support (NSC 101-2113-M-011-001).
Reacted 0.1 g of trans-1a under the reaction conditions listed in
Table 3. After reaction, the mixture was added into a large amount
of water. The resulting solution was extracted with ethyl acetate for
three times, and then the organic layers were combined and dried
with anhydrous MgSO4. After removing organic solvent under re-
duced pressure, the residue was purified by column chromatogra-
phy on silica gel (hexane) to recover trans-1a. (The isolated yields
are listed in Table 3.)
Supplementary data
1H and 13C NMR spectra of cis and trans-1aed, trans-1eei, trans-
3aec, 5, and 6, 1H NMR spectra of trans-2aed, and a test experi-
ment for examining the formation of acid are included in Supple-
mentary data. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.06.074.
4.9. Synthesis of 3-phenylpropyl benzoate23
References and notes
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Stirred the mixture of 0.82 g (6.0 mmol) of 3-phenyl-1-propanol,
1.68 g (11.95 mmol) of benzoyl chloride, and 0.92 g (9.0 mmol) of
aluminum oxide in a flask at room temperature for 4 h and then
suction filtrate the reaction mixture with ethyl acetate. Collected
the filtration, removed solvent under reduced pressure, and then
purified the residue by column chromatography on silica gel (ethyl
acetate/hexane¼1:15). The ester, 3-phenylpropyl benzoate, was
obtained in an 82% yield.
4.9.1. 3-Phenylpropyl benzoate. 1H NMR (500 MHz, CDCl3)
d 8.06 (d,
J¼8.0 Hz, 2H), 7.58 (t, J¼7.5 Hz, 1H), 7.46 (t, J¼7.8 Hz, 2H), 7.32 (t,
J¼7.6 Hz, 2H), 7.25e7.20 (m, 3H), 4.37 (t, J¼6.5 Hz, 2H), 2.81 (t,
J¼7.8 Hz, 2H), 2016e2.10 (m, 2H). 13C NMR (125 MHz, CDCl3)

7332
J.-H. Ho et al. / Tetrahedron 69 (2013) 7325e7332
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action mixtures showed that the yields of oxidative photocyclization products
were 57% for 1a and 13% for 1d, respectively.
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19. The consumptions of starting material after the reactions of 3-phenylpropyl
benzoate (0.08 M) under some basic conditions are described as follows: 100%
for THF solution containing 0.33 M tBuOK at room temperature for 2 h, 68% for
NMP solution with 0.13 M NaH at room temperature for 2 h, and 54% for
a mixture solution of water and THF (1:1) containing 0.9 M KOH at refluxing
temperature for 21 h.
13. Preparation of 0.5 M HCl water/acetonitrile solution: dilute ca. 0.4 mL of 12 M
concd HCl(aq) with 9.6 mL of acetonitrile (containing ca. 4% water (v/v), [H2O] is
ca. 2.2 M). And preparation of 5 mM HCl acetonitrile solution: make a 100 fold
dilution of previous solution with acetonitrile (containing ca. 0.04% water (v/v),
[H2O] is ca. 22 mM. But this concentration is lower than that of residual water
(73.6 mM) in common dichloromethane).
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ꢁ
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