Synthesis of functionalized cyclotriveratrylene analogues with C 1-symmetry and the application for 1,4-Michael addition of alcohols to unsaturated aryl ketone

Article abstract of DOI:10.1016/j.tet.2013.06.077

C₁-symmetric cyclotriveratrylene analogues 2-8 with various functional groups at one benzene moiety were prepared starting from the selectively demethylated compound 1. Through the chemical resolution, a pair of enantiomers of C₁-sym

Full text of DOI:10.1016/j.tet.2013.06.077

Tetrahedron 69 (2013) 7308e7313
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Synthesis of functionalized cyclotriveratrylene analogues with
C1-symmetry and the application for 1,4-Michael addition of
alcohols to unsaturated aryl ketone
*
Jing-Ru Song, Zhi-Tang Huang, Qi-Yu Zheng
Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy
of Sciences, Beijing 100190, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 April 2013
Received in revised form 27 May 2013
Accepted 21 June 2013
Available online 28 June 2013
C1-symmetric cyclotriveratrylene analogues 2e8 with various functional groups at one benzene moiety
were prepared starting from the selectively demethylated compound 1. Through the chemical resolution,
a pair of enantiomers of C1-symmeric compound 1 could be separated with gram scale. Compound 8,
which possessed an N-linked imidazolium unit at the upper rim of the macrocyclic skeleton through
a methylene linker, was successfully applied to 1,4-Michael addition reaction of alcohol to unsaturated
aryl ketone. Its supramolecular catalytic activity as an NHC precursor was demonstrated by the chem-
selectivity to aromatic alcohol than alkyl alcohol.
Keywords:
Cyclotriveratrylene
C1-symmetry
Ó 2013 Elsevier Ltd. All rights reserved.
Chemical resolution
N-Heterocyclic carbene
Michael addition
1. Introduction
difficult upon condensation due to the different electron-giving
capability of the substituents at the benzene.1b Another way is
Cyclotriveratrylene (CTV) is a kind of macrocyclic host with
a bowl-shaped cavity.1 Since of the discovery, a great deal of its
analogues with different functional groups and extended arms
have been synthesized.2 The excellent binding modes and deeper
cavity make CTV and its analogues get broad usages in selective
recognition,2h,3 liquid crystal,4 supramolecular assemblies,5 porous
materials,6 xenon biosensing,7 and fullerene separations.3b,8 If the
substituents of the upper rim are different, CTV analogues may be
chiral.9 Though much attention has been focused on this macro-
cycle and numerous achievements have been made, C1-symmetric
analogues, such as mono-functionalized or the derivatives bearing
two different functional groups at only one of the three benzene
units have rarely been reported. To the best of our knowledge, there
are only two relative reports involving the synthesis, which bear
hydroxyl or methyl group instead of one methoxy of the cyclo-
originating from the cyclotriveratrylene through selective deme-
thylation and then incorporation of the new functional group(s).
On the other side, oxa-Michael reaction is one of the most ef-
fective routes to form the CeO bond, which is a key component of
many biologically active compounds. Many research groups have
reported relative investigations with great progress.11 However,
there still remains challenge due to the undesired oligomerization
of the Michael acceptor. Recently, N-heterocyclic carbenes (NHCs)
have emerged as a powerful and effective organic catalyst to vari-
ous reactions.12 In 2010, Scheidt group reported the conjugated
addition of alcohol using a free carbene without oligomerization of
the substrate.13
In this paper, we demonstrated the second synthetic route for
C1-symmetric CTV analogues and firstly prepared three useful
macrocycles bearing one formyl group (4), double functionalities
(5) like salicylaldehyde and N-linked imidazolium group (8), re-
spectively. We also attempted the resolution of C1-symmetric CTV
analogue to explore the feasibility of the chemical resolution
method. Simultaneously, with compound 8 in hand, we further
investigated its supramolecular catalytic activity as an NHC pre-
cursor to the 1,4-Michael addition reaction of alcohol to un-
saturated aryl ketone.
,
10
triveratrylene molecule.1b C1-symmetric CTV analogues can be
generated by two different methods. The first way is to directly
introduce a benzene unit with two different groups. This is much
* Corresponding author. Tel.: þ86 10 6265 2811; fax: þ86 10 6255 4449; e-mail
address: zhengqy@iccas.ac.cn (Q.-Y. Zheng).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.077

J.-R. Song et al. / Tetrahedron 69 (2013) 7308e7313
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ꢀ
2. Result and discussion
2.1. Synthesis
distance 2.667 A). In a crystal cell, the molecules with same chi-
rality stack staggered in column along b axis, and one methyl group
of upper CTV is included by the cavity of lower molecule with
CeH/p interactions. The adjacent column is stacked by the op-
The synthetic route to the corresponding molecules is described
in Scheme 1. Treating compound 110 with trifluoromethanesulfonic
anhydride in a mixed solvent of dichloromethane and pyridine,
compound 2 was obtained in virtually quantitative yield.
posite chiral substrate with opposite orientation. Thus, the whole
crystal is racemic. Weak CeH/O interactions (CeH/O distance
ꢀ
ꢀ
2.475 A and C/O distance 3.409 A) between the formyl groups and
methoxy groups connect these two columns.
Scheme 1. The synthetic route to compounds 2e8.
After removing the ester group, compound 3 was obtained. Then
introduction of a formyl group into compound 3 by using 1,1-
dichloromethyl methyl ether in the presence of titanium tetra-
chloride was achieved in moderate yield to give the monoformyl
group compound 4. Compound 5 was prepared by selective
demethylation of compound 4. Reduction of the formyl group of
2.3. Chemical resolution of compound 1
C3-symmetric CTV analogues can be resolved to obtain optically
active isomers.5f,14 However there is no trial to resolve the C1-
symmertric molecule. Here we make the first attempt to prepare
the optically pure C1-symmetric CTV analogues by chemical
resolution (Scheme 2). Firstly, the diastereoisomer mixture 9 was
prepared starting from the racemic compound 1 with (ꢀ)-cam-
phanic acid chloride. Upon column chromatography, this mixture
compound
4 using sodium borohydride followed by chlor-
omethylation with thionyl chloride, and finally alkylation of the 1-
methylimidazole afforded N-linked imidazolium unit compound 8.
All of the products were confirmed by NMR, IR, MS spectra, and
elemental analysis.
could be separated easily with [
a
]
20 (CHCl3, c 0.0102) values þ22.5ꢁ
D
and ꢀ21.6ꢁ, respectively. Then reductive cleavage of the chiral
auxiliary group, optically pure (þ)-1 and (ꢀ)-1 were obtained with
20
[a
]
(CHCl3, c 0.002) values þ80ꢁ and ꢀ84ꢁ, respectively. The CD
D
2.2. Crystal structure of compound 5
spectra of (þ)-1 and (ꢀ)-1 were measured and they showed mirror
images of each other, indicating the success of the separation
By slow evaporation the solution of compound 5 in dichloro-
methane and acetone, colorless crystal suitable for X-ray diffraction
was obtained. Compound 5 crystallizes in the monoclinic P21/n
with the asymmetric unit having one molecule 5 (Fig. 1). There is
a typical intramolecular hydrogen bond between the hydroxyl
ꢀ
group and formyl group (OeH/O distance 2.060 A and O/O
Fig. 1. Crystal structure of compound 5. (a) Ball and stick view of the asymmetric unit.
C: gray, H: white, O: red. (b) Ball and stick view of the molecules in one cell. C: gray, O:
red, H: white. Specially, one enantiomer molecule was shown light blue, and the op-
posite enantiomer molecule was shown brown.
Scheme 2. Chemical resolution of compound 1.

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J.-R. Song et al. / Tetrahedron 69 (2013) 7308e7313
method (Fig. 2). The excited result proves the feasible chemical
resolution of C1-symmetric CTV analogues, which is important for
optical resolution on a larger scale, laying foundation for the further
application research of chiral C1-symmetric analogues.
interaction (p/p interaction) of the CTV cavity and aromatic al-
cohol, which does not exist when using the alkyl alcohols. That was
typical molecular recognition in supramolecular catalysis.15
Fig. 3. 1H NMR spectra: compound 10 (top); compound 15 (middle); the mixture by
one-pot reaction (bottom).
Fig. 2. CD spectra of (þ)/(ꢀ)-1 (c¼2.3ꢂ10ꢀ4 M in DCM).
2.4. 1,4-Michael addition of alcohol
ꢁ
Semeril and Matt synthesized calix[4]arene-based mono-
phosphanes showing a fast SuzukieMiyaura cross-coupling.16
Yasuda and Baba had designed a tripodal cage-shaped catalyst,
which can accelerate the hetero-DielseAlder addition of benzal-
dehyde more effectively than that of butanal.17 Both of the two
manifested a cavity inclusion action that assisted the reaction.
Similarly, our carbene catalyst gave the same influence to the al-
cohol substrates and presented the chem-selectivity to aromatic
substrate with a high ratio in the competitive reaction.
To test the catalytic activity of compound 8, 1,4-Michael addition
of alcohol to a,b-unsaturated ketone was applied. We began our
study using the reaction condition reported by Scheidt with a little
modification. The results are summarized in Table 1.
Table 1
For aromatic alcohols, regardless of the electron-donating or the
electron-withdrawing groups, high yields were obtained (Table 1,
entries 2 and 3) though a little lower toward electron-withdrawing
alcohol. Addition of the primary alcohols gave higher yields than
the secondary alcohols for aromatic nucleophiles (Table 1, entries 1
and 5), while the alkyl nucleophiles did not show obvious differ-
ence (Table 1, entries 6 and 8). Unexpectedly, 3-hydroxymethyl
pyridine only gave the oligomerized product of the unsaturated
ketone. The intermolecular hydrogen bond between the nitrogen
atom and hydroxyl group of substrates may hinder the activation of
the alcohol by the NHC.
1,4-Michael addition of alcohol
24 h
Entry
1
Substrate
Product
Yielda (%)
73
10
2
3
11
12
76
68
The proposed mechanism is illustrated in Scheme 3. Macrocyclic
carbene catalyst is generated from compound 8 under the base, and
then NHCealcohol complex A and activated ketone by lithium salt
accelerate the 1,4-addition of the alcohol. For the aromatic alcohol,
4
13
74
inclusion between the catalyst and substrate by
p/p interaction
facilitates the reaction, thus inducing the chem-selectivity. Hy-
drogen bonds between the 3-hydroxymethyl pyridine block the
formation of complex A, and result in the unsuccessful addition.
5
14
65
6
7
H3CeOH
15
16
46
50
3. Conclusion
8
17
45
Starting from the selectively demethylated compound 1, we
synthesized several C1-symmetric cyclotriveratrylene analogues
with various functional groups at one benzene moiety. Through the
chemical resolution, a pair of enantiomers of C1-symmeric CTV
analogues has been successfully separated with gram scale firstly.
Especially, the 1,4-Michael addition reaction catalyzed by one de-
rivative contained a flexible N-linked imidazolium unit has been
investigated. The CTV-based catalyst presents an outstanding ac-
tivity to the conjugate addition that demonstrates the macrocyclic
NHC precursor as an efficient catalyst compared to traditional
carbenes. Interestingly, the catalyst showed an uncommon higher
a
Isolation yield based on substrate.
Compound 8 showed good activity in the addition reaction with
the alcohol, with the reactivity toward the benzyl alcohol and an-
alogues, unexpected, higher than that toward the alkyl alcohols,
which did not manifest in other simple NHC catalytic reactions.13
Reacting the ketone with benzyl alcohol and methanol in one pot,
we got a mixed product with a 10/15¼5:1 molar proportion from 1H
NMR (Fig. 3), another proof to the higher activity toward aromatic
alcohols. The chem-selectivity may result from the hosteguest

J.-R. Song et al. / Tetrahedron 69 (2013) 7308e7313
7311
Water was then added, and the mixture was extracted three times
with dichloromethane. The combined organic layer was washed
with water, brine, and then dried with sodium sulfate. Filtration
and evaporation of the solvent afforded a residue, which was pu-
rified by column chromatography (PE/EA¼2:1) to obtain a pale
yellow solid (2.43 g, 98%). Mp 116e118 ꢁC; 1H NMR (CDCl3)
d 7.18 (s,
1H), 6.97 (s, 1H), 6.85 (s, 1H), 6.82 (s, 2H), 6.74 (s, 1H), 4.82e4.71 (m,
3H), 3.86e3.84 (m, 15H), 3.62e3.55 (m, 3H); 13C NMR (CDCl3)
d
149.60,148.18,148.01,140.73,137.27,133.02,132.45,131.51,130.82,
130.27, 123.71, 114.63, 113.33, 113.26, 113.04, 112.90, 56.32, 56.23,
56.11, 56.04, 36.89, 36.67, 36.16; FT-IR 3439, 2936, 2847, 1612,
n
1510, 1446, 1418, 1236, 1252, 1221, 1141, 1089, 999, 942, 882 cmꢀ1
;
MS (ESI): m/z 568.5 ([M]þ). Anal. Calcd for C27H27F3O8S$2/3H2O: C,
55.85; H, 4.92. Found: C, 55.86; H, 4.72.
4.2.2. Compound 3. Compound 2 (1.987 g, 3.5 mmol), dppp (22 mg,
0.053 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol), tributylamine
(3 ml), formic acid (2 ml), DMF (20 ml) were mixed in a 100 ml flask.
The mixture was heated to 100 ꢁC for 18 h under nitrogen. Then,
water was added, and the mixture was extracted with dichloro-
methane for three times. The organic phase was washed with water,
brine, and then dried with sodium sulfate. Filtration and evapora-
tion of the solvent afforded a residue, which was purified by column
chromatography (PE/EA¼1:1) to obtain a white solid (1.32 g, 89%).
Mp 186e187 ꢁC; 1H NMR (CDCl3)
d
7.28 (s, 1H), 6.90 (s, 1H), 6.85 (s,
1H), 6.82 (s, 3H), 6.67 (d, 1H, J¼8 Hz), 4.81e4.73 (m, 3H), 3.84 (m,
12H), 3.75 (s, 3H), 3.62e3.54 (m, 3H); 13C NMR (CDCl3)
158.33,
147.90, 140.91, 132.28, 132.08, 131.32, 131.02, 115.88, 113.34, 113.06,
112.04, 56.15, 55.34, 37.11, 36.71, 36.19; FT-IR 3441, 2990, 2927,
d
n
2829,1609, 1577, 1517, 1478,1463, 1393, 1263, 1225, 1203, 1147, 1089,
1037, 991, 846 cmꢀ1; MS (ESI): m/z 421.4 ([MþH]þ). Anal. Calcd for
C27H28O5$0.3H2O: C, 73.32; H, 6.77. Found: C, 73.58; H, 6.71.
Scheme 3. The proposed mechanism for the 1,4-addition reaction.
4.2.3. Compound 4. Titanium tetrachloride (0.8 ml) was added to
a solution of 3 (1.318 g, 3.13 mmol) in dichloromethane (30 ml)
under nitrogen at ꢀ78 ꢁC. Then, 1,1-dichloromethyl methyl ether
(0.55 ml) was slowly added with syringe. The mixture was stirred at
ꢀ78 ꢁC for 5 h. Then the solution was poured into a beaker with ice-
water and stirred for 10 min. The aqueous phase was extracted with
dichloromethane for three times. The organic phase was washed
with water, 10% NaHCO3 aqueous solution, brine, and then dried
with sodium sulfate. Filtration and evaporation of the solvent
afforded a residue, which was purified by column chromatography
activity to aromatic substrates than the alkyl substrates, which may
result from the molecular recognition between the substrate and
catalyst, and this is also the first example of CTV-based catalyst
performing the chem-selectivity.
4. Experimental section
4.1. General information
(EA/DCM¼1:25) to obtain
a
white solid (1.09 g, 77%). Mp
10.33 (s, 1H), 7.82 (s, 1H), 6.94 (s,
Melting points were taken on an electrothermal melting point
apparatus and without correction. FT-IR spectra were recorded on
a Thermo-Nicolet 6700 spectrometer using KBr discs for solid
products and neat for oil products. Elemental analysis for C, H, and
N were performed by a Flash EA 1112 elemental analyzer. H NMR
and C NMR spectra were recorded at ambient temperature on
a Bruker (400 MHz) NMR spectrometer. X-ray diffraction data on
single crystals were collected on a Rigaku RAXISRAPID diffrac-
tometer with graphite monochromated Mo Ka radiation (lMo
224e227 ꢁC; 1H NMR (CDCl3)
d
1H), 6.84 (t, 3H), 6.80 (s, 1H), 4.86e4.71 (m, 3H), 3.89 (s, 3H), 3.84
(m, 12H), 3.68e3.55 (m, 3H); 13C NMR (CDCl3)
d
189.16, 160.34,
148.18, 148.05, 147.86, 147.79, 132.56, 132.48, 131.36, 131.17, 129.88,
129.75, 123.70, 113.20, 113.12, 112.94, 112.86, 112.79, 56.13, 56.03,
56.00, 55.65, 37.41, 36.60, 35.79; FT-IR
n 3440, 2930, 2843, 1677,
1608, 1517, 1462, 1394, 1265, 1227, 1144, 1089, 999, 740, 612 cmꢀ1
;
MS (ESI): m/z 449.5 ([MþH]þ). Anal. Calcd for C27H28O6$0.4H2O: C,
71.16; H, 6.37. Found: C, 71.14; H, 6.29.
ꢀ
¼0.71073 A) at 173 K. CD spectra were conducted on JASCO J-810
K
a
spectropolarimeter. Compound 1 was synthesized according to the
literature method.10 Methanol, ethanol, isopropyl alcohol,
dichloromethane, chloroform, and toluene were dried by standard
procedures. Unless otherwise noted, all reagents were purchased
from commercial suppliers and used without purification.
4.2.4. Compound 5. AlCl3 (599 mg, 4.54 mmol) was added to a so-
lution of 4 (503 mg,1.12 mmol) in dichloromethane. The mixture was
stirred for 20 h at room temperature. Then the solution was poured
into a breaker with ice-water. The aqueous phase was extracted with
dichloromethane for three times. The organic phase was washed
with water, brine, and then dried with sodium sulfate. Filtration and
evaporation of the solvent afforded a residue, which was purified by
column chromatography (EA/DCM¼1:25) to obtain a white solid
4.2. Synthesis of cyclotriveratrylene analogues 2e9
4.2.1. Compound 2. A solution of triflic anhydride was slowly added
under nitrogen to an ice-cooled solution of 1 (1.9 g, 4.35 mmol) in
a mixture of pyridine (16 ml) and dichloromethane (50 ml). The
solution was warmed to room temperature and stirred for 18 h.
(220 mg, 45%). Mp 257e259 ꢁC; 1H NMR (CDCl3)
d
10.72 (s, 1H), 9.81
(s, 1H), 7.48 (s, 1H), 6.99 (s, 1H), 6.82 (br, 4H), 4.80e4.68 (m, 3H),
3.86e3.84 (m, 12H), 3.66e3.56 (m, 3H); 13C NMR (CDCl3)
195.64,
159.91, 150.01, 148.14, 147.99, 134.97, 132.05, 132.01, 131.98, 130.96,
d

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J.-R. Song et al. / Tetrahedron 69 (2013) 7308e7313
129.33, 119.76, 118.36, 113.15, 113.06, 112.89, 56.28, 56.14, 56.04,
55.99, 37.09, 36.648, 35.76; FT-IR 3440, 2931, 2843, 1653, 1608, 1519,
(CDCl3) d 7.04 (s, 1H), 6.94 (s, 1H), 6.85e6.82 (m, 3H), 6.77 (s, 1H),
n
4.82e4.72 (m, 3H), 3.85e3.78 (m, 12H), 3.78 (s, 3H), 3.61e3.54 (m,
3H), 2.59e2.53 (m, 1H), 2.22e2.15 (m, 1H), 2.01e1.94 (m, 1H),
1.77e1.72 (m, 1H), 1.15 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H); 13C NMR
1478,1448,1393,1351,1262,1225,1144,1088,1031, 997, 848, 811, 740,
613 cmꢀ1; MS (MALDI-TOF): m/z 434.0 ([M]þ). Anal. Calcd for
C26H26O6$0.8H2O: C, 69.57; H, 6.20. Found: C, 69.64; H, 5.99.
(CDCl3) d 178.21, 165.34, 148.99, 147.95, 147.90, 147.82, 138.76,
137.51, 132.49, 132.11, 131.81, 131.36, 131.02, 123.78, 113.96, 113.31,
113.08, 91.25, 56.37, 56.12, 55.88, 55.03, 54.75, 36.86, 36.65, 36.18,
30.88, 29.10, 16.67, 16.60, 9.88; FT-IR n 2932, 2850, 1787, 1609, 1510,
4.2.5. Compound 6. NaBH4 (880 mg, 23 mmol) was added to an ice-
cooled solution of 4 (1.30 g, 2.9 mmol) in methanol (10 ml) under
nitrogen. Upon 10 min, the solution was warmed to room tem-
perature and stirred overnight. After evaporation of the solvent,
water was added, and the aqueous phase was extracted with
dichloromethane for three times. The organic phase was washed
with water, brine, and then dried with sodium sulfate. Filtration
and evaporation of the solvent afforded a white solid, which was
used next step without further purification (1.228 g, 94%). Mp
1464, 1395, 1342, 1315, 1261, 1224, 1195, 1088, 1047, 996 cmꢀ1
;
HRMS (ESI) calcd for [MþNa]þ: m/z 639.2564, found: 639.2561.
(þ)-9: mp 168e174 ꢁC; 1H NMR (CDCl3)
d 7.05 (s,1H), 6.94 (s,1H),
6.83e6.81(m,3H), 6.76(s,1H),4.81e4.73(m,3H), 3.85e3.83(m,12H),
3.78 (s, 3H), 3.61e3.54 (m, 3H), 2.60e2.53 (m,1H), 2.21e2.14 (m, 1H),
2.00e1.94 (m, 1H), 1.79e1.70 (m, 1H), 1.15e1.11 (m, 9H); 13C NMR
(CDCl3) d 178.32, 165.53, 149.07, 147.99, 147.88, 147.84, 138.68, 137.62,
132.58, 132.22, 131.65, 131.27, 130.92, 123.75, 114.07, 113.17, 113.09,
113.01, 91.26, 56.29, 56.14, 55.96, 55.06, 54.76, 36.90, 36.67, 36.23,
215e216 ꢁC; 1H NMR (CDCl3)
5H), 4.83e4.71 (m, 3H), 4.66e4.53 (m, 2H), 3.84 (s, 15H), 3.62e3.54
(m, 3H), 2.16 (br, 1H); 13C NMR (CDCl3)
156.00, 147.86, 147.75,
140.14, 132.12, 131.93, 131.83, 131.70, 131.29, 130.45, 127.80, 113.29,
113.11, 111.61, 61.70, 56.20, 56.10, 55.40, 37.04, 36.58, 36.03; FT-IR
d
7.25 (d, 1H, J¼4.8 Hz), 6.85e6.82 (m,
d
30.87, 29.02, 16.75, 16.72, 9.93; FT-IR n 2932, 2848, 1768, 1609, 1510,
1464, 1446, 1395, 1315, 1261, 1224, 1195, 1144, 1088, 1045, 996 cmꢀ1
;
n
HRMS (ESI) calcd for [MþNa]þ: m/z 639.2564; found: 639.2559.
3415, 2932, 2844, 2247, 1611, 1578, 1514, 1478, 1464, 1394, 1262,
1222, 1194, 1143, 1087, 996, 922, 847, 725, 617 cmꢀ1; MS (MALDI-
TOF): m/z 450.0 ([M]þ). Anal. Calcd for C27H30O6$0.85H2O: C, 69.61;
H, 6.86. Found: C, 69.31; H, 6.37.
4.3. General procedure for the 1,4-Michael addition
To an oven-dried vial equipped with magnetic stirring bar were
added compound 8 (19 mg, 0.0345 mmol) and LiCl (29 mg,
0.69 mmol) under nitrogen atmosphere. The vial was then sealed.
Under nitrogen atmosphere, toluene (1 ml) was added. The reaction
4.2.6. Compound 7. A solution of SOCl2 (1 ml) in 2 ml CHCl3 was
added slowly to an ice-cooled solution of 6 (258 mg, 0.57 mmol) in
CHCl3 (5 ml). After addition, the mixture was warmed to 70 ꢁC
under nitrogen for 2 h. Evaporation of the solvent afforded a viscous
liquid. Diethyl ether was added to the residue, stirred for 5 h, and
then filtrated, dried in vacuum afford a white solid for the next step
without further purification (155 mg, 58%). Mp 227e229 ꢁC; 1H
was cooled to ꢀ78 ꢁC and nBuLi (14
mL, 0.0336 mmol, 2.4 M in
hexanes) was added through a syringe. The reaction was allowed to
warm to room temperature. After 10 min, a mixture of ketone
(100 mg, 0.685 mmol), alcohol (2.055 mmol), and toluene (1 ml)
was added to the vial through a syringe. The mixture was stirred
under N2 atmosphere at room temperature for 24 h. Upon com-
pletion of the reaction, the mixture was concentrated and the
residue was purified by column chromatography with EtOAc/
petroleum¼1:30 to afford the corresponding products.
NMR (CDCl3)
4.65e4.50 (m, 2H), 3.84 (s, 15H), 3.62e3.54 (m, 3H); 13C NMR
(CDCl3) 155.94, 148.00, 147.84, 141.39, 132.25, 132.18, 131.80,
131.65, 131.05, 124.50, 113.31, 113.23, 113.11, 112.22, 56.20, 56.16,
55.79, 41.38, 37.15, 36.66, 36.05; FT-IR 3441, 2931, 2905, 2842,
d 7.34 (s, 1H), 6.85e6.81 (m, 5H), 4.83e4.73 (m, 3H),
d
n
1610, 1520, 1460, 1394, 1350, 1262, 1226, 1194, 1143, 1090, 999, 848,
4.3.1. 3-Benzyloxy-1-phenylbutane-1-one
(10). Yellow
oil
741 cmꢀ1; MS (MALDI-TOF): m/z 467.0 ([MꢀH]þ). Anal. Calcd for
(126.4 mg, 73%). 1H NMR (CDCl3)
d
7.97 (d, 2H, J¼7.2 Hz), 7.57 (t, 1H,
C
27H29ClO5$0.25H2O: C, 68.49; H, 6.28. Found: C, 68.79; H, 6.11.
J¼7.2 Hz), 7.46 (t, 2H, J¼7.6 Hz), 7.32e7.25 (m, 5H), 4.55 (dd, 2H,
J¼11.6, 25.6 Hz), 4.26e4.22 (m, 1H), 3.43 (dd, 1H, J¼7.2, 9.6 Hz), 2.99
(dd, 1H, J¼6.0, 10.0 Hz), 1.33 (d, 3H, J¼6.0 Hz); 13C NMR (CDCl3)
4.2.7. Compound 8. Compound
7 (155 mg, 0.33 mmol), 1-
methylimidazole (33 mg, 0.4 mmol), and 5 ml CHCl3 were mixed.
The mixture was heated to 70 ꢁC under nitrogen for 48 h. After
evaporation of the solvent, diethyl ether was added to the residue,
stirred overnight, then filtrated, dried in vacuum afford a white solid
without further purification (170 mg, 93%). Mp 196e198 ꢁC; 1H NMR
d 198.82, 138.64, 137.40, 133.20, 128.68, 128.42, 128.33, 127.79,
127.61, 72.12, 71.12, 46.03, 20.35.
4.3.2. 3-(4-Methoxybenzyloxy)-1-phenylbutane-1-one (11). Color-
less oil (146 mg, 76%). 1H NMR (CDCl3)
d 7.96e7.94 (m, 2H),
(CDCl3)
d
10.97 (s,1H), 7.98 (s,1H), 7.24 (s,1H), 7.12 (s,1H), 6.98 (s,1H),
7.58e7.54 (m, 1H), 7.47e7.44 (m, 2H), 7.20 (d, 2H, J¼8.8 Hz), 6.83 (d,
2H, J¼8.8 Hz), 4.52 (d, 1H, J¼10.8 Hz), 4.43 (d, 1H, J¼8.8 Hz),
4.23e4.19 (m, 1H), 3.78 (s, 3H), 3.40 (dd, 1H, J¼6.4, 10 Hz), 2.97 (dd,
6.84e6.78 (m, 4H), 5.56e5.39 (m, 2H), 4.84e4.67 (m, 3H), 4.00 (s,
3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.82 (s, 9H), 3.75e3.53 (m, 3H);13C NMR
(CDCl3)
d
155.65, 148.21, 147.96, 147.63, 142,73,138.37, 133.91, 133.15,
1H, J¼6.4, 10 Hz), 1.31 (d, 3H, J¼6 Hz); 13C NMR (CDCl3)
d 198.84,
132.39, 131.82, 131.09, 130.70, 122.28, 122.04, 120.44, 113.67, 113.18,
113.06, 112.77, 11.92, 57.10, 56.15, 56.03, 55.94, 55.68, 47.95, 37.07,
159.17, 137.39, 133.16, 130.73, 129.37, 128.65, 128.31, 113.82, 71.76,
70.77, 55.35, 46.05, 20.37.
36.56, 36.39, 35.63; FT-IR n 3420, 3102, 2957, 2842, 1612, 1571, 1518,
1461,1446,1395,1268,1223,1197,1148,1086, 993, 739, 617 cmꢀ1; MS
(ESI): m/z 515.2 ([M]þ). Anal. Calcd for C31H35ClN2O5$3H2O: C, 61.53;
H, 6.83; N, 4.63. Found: C, 61.16; H, 6.43; N, 4.93.
4.3.3. 3-(4-Chlorobenzyloxy)-1-phenylbutane-1-one (12). Colorless
oil (138 mg, 68%). 1H NMR (CDCl3)
d 7.98e7.91 (m, 2H), 7.60e7.56
(m, 2H), 7.49e7.46 (m, 2H), 7.28e7.20 (m, 3H), 4.56 (d, 1H, J¼12 Hz),
4.46 (d, 1H, J¼12 Hz), 4.25 (t,1H, J¼6 Hz), 3.42 (dd,1H, J¼6.8,16 Hz),
2.98 (dd, 1H, J¼6.8, 16 Hz), 1.34 (d, 3H, J¼6 Hz); 13C NMR (CDCl3)
4.2.8. Compound 9. (ꢀ)-Camphanic acid chloride (330 mg,
1.52 mmol) was added to the solution of compound 1 (430 mg,
0.98 mmol) in 10 ml dry pyridine. The mixture was stirred at room
temperature overnight. Then, water was added and pale yellow
precipitate was obtained. After filtration and wash with water, the
residue was dried in vacuum and then purified by column chro-
matography (CHCl3/EA¼50:1) to afford white solid of (þ)-9
(174 mg) and (ꢀ)-9 (229 mg). (ꢀ)-9: mp 171e174 ꢁC; 1H NMR
d
198.64,137.28, 137.15,133.22, 129.02, 128.66,128.48,128.27, 72.22,
70.26, 45.92, 20.26; FT-IR n 3060, 2971, 2930, 1684, 1597, 1580, 1491,
1448, 1373, 1339, 1296, 1133, 1087, 1015, 808, 753, 690 cmꢀ1; HRMS
(ESI) calcd for [MþNaþ]: m/z 311.0809; found: 311.0803.
4.3.4. 3-(1-Naphthalenemethoxy)-1-phenylbutane-1-one
(13).
Yellow oil (154 mg, 74%). 1H NMR (CDCl3)
d
7.93e7.78 (m, 5H),

J.-R. Song et al. / Tetrahedron 69 (2013) 7308e7313
7313
7.57e7.39 (m, 7H), 5.05 (d, 1H, J¼11.2 Hz), 4.964 (d, 1H, J¼11.2 Hz),
4.40e4.35 (m, 1H), 3.46 (dd, 1H, J¼6.8, 9.6 Hz), 3.01 (dd, 1H, J¼6,
Nature Science Foundation of China (20932004), and the Chinese
Academy of Science.
10 Hz), 1.38 (t, 3H, J¼5.6 Hz); 13C NMR (CDCl3)
d 198.83, 137.30,
134.02, 133.82, 133.16, 131.82, 128.67, 128.63, 128.53, 128.30, 128.16,
126.59, 126.19, 125.78, 125.31, 124.24, 72.14, 69.66, 46.07, 20.29; FT-
Supplementary data
IR n 3058, 2966, 2924, 1676, 1596, 1510, 1447, 1370, 1333, 1196, 1132,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.077.
1077, 999, 791, 772, 750 cmꢀ1; HRMS (ESI) calcd for [MþH]þ: m/z
305.1536; found: 305.1533.
References and notes
4.3.5. 3-(1-Phenylethoxy)-1-phenylbutane-1-one (14). Yellow oil
(120 mg, 65%). 1H NMR (CDCl3)
d
7.96 (d, 1H), 7.84 (d, 1H), 7.57e7.22
(m, 8H), 4.58e4.51 (m, 1H), 4.12e3.95 (m, 1H), 3.42e3.22 (m, 1H),
2.96e2.88 (m, 1H), 1.41e1.12 (m, 6H); 13C NMR (CDCl3)
199.18,
1. (a) Robinson, G. M. J. Chem. Soc. 1915, 107, 267; (b) Lindsey, A. S. J. Chem. Soc.
1965, 1685.
d
2. (a) Umezawa, B.; Hoshio, O.; Hara, H.; Ohyama, K.; Mitsubay, S.; Sakakiba, J.
Chem. Pharm. Bull. 1969, 17, 2240; (b) Umezawa, B.; Hoshio, O.; Sakakiba, J.
Chem. Pharm. Bull. 1968, 16, 177; (c) Sato, T.; Akima, T.; Uno, K. J. Chem. Soc.,
Perkin Trans. 1 1973, 891; (d) Poupko, R.; Luz, Z.; Spielberg, N.; Zimmermann, H.
J. Am. Chem. Soc. 1989, 111, 6094; (e) Garcia, C.; Malthete, J.; Collet, A. Bull. Soc.
Chim. Fr. 1993, 130, 93; (f) Ahmad, R.; Hardie, M. J. Supramol. Chem. 2006, 18, 29;
(g) Sanseverino, J.; Aubert, E.; Espinosa, E.; Chambron, J. C. J. Org. Chem. 2011, 76,
1914; (h) Arduini, A.; Calavacca, F.; Demuru, D.; Pochini, A.; Secchi, A. J. Org.
Chem. 2004, 69, 1386; (i) Yu, J.-T.; Huang, Z.-T.; Sun, J.; Zheng, Q.-Y. Org. Biomol.
Chem. 2012, 10, 1359; (j) Peyrard, L.; Dumartin, M. L.; Chierici, S.; Pinet, S.; Jo-
nusauskas, G.; Meyrand, P.; Gosse, I. J. Org. Chem. 2012, 77, 7023; (k) Han, X.-N.;
Chen, J.-M.; Huang, Z.-T.; Zheng, Q.-Y. Eur. J. Org. Chem. 2012, 6895.
3. (a) Eckert, J. F.; Byrne, D.; Nicoud, J. F.; Oswald, L.; Nierengarten, J. F.; Numata,
M.; Ikeda, A.; Shikai, S.; Armaroli, N. New J. Chem. 2000, 24, 749; (b) Huetra, E.;
Isla, H.; Perez, E. M.; Bo, C.; Martin, N.; de Mendoza, J. J. Am. Chem. Soc. 2010,
132, 5351; (c) Konarev, D. V.; Khasanov, S. S.; Vorontsov, I. I.; Saito, G.; Antipin,
M. Y.; Otsuka, A.; Lyubovskaya, R. N. Chem. Commun. 2002, 2548; (d) Konarev,
D. V.; Khasanov, S. S.; Saito, G.; Otsuka, A.; Yoshida, Y.; Lyubovskaya, R. N. J. Am.
Chem. Soc. 2003, 125, 10074.
198.62, 144.52. 143.83, 137.43, 137.20, 133.14, 132.98, 128.63, 128.51,
128.40, 128.32, 128.29, 127.50, 127.43, 126.38, 126.32, 75.15, 70.56,
69.44, 46.76, 45.92, 24.57, 24.11, 21.68, 19.96; FT-IR
n 3060, 2971,
2927, 1682, 1596, 1447, 1367, 1281, 1210, 1196, 1132, 1078, 999, 751,
690 cmꢀ1; HRMS (ESI) calcd for [MþNaþ]: m/z 291.1355; found:
291.1351.
4.3.6. 3-Methoxy-1-phenylbutane-1-one (15). Yellow oil (56 mg,
46%). 1H NMR (CDCl3)
d
7.96 (d, 2H, J¼7.6 Hz), 7.56 (t, 1H, J¼7.2 Hz),
7.46 (t, 2H, J¼7.6 Hz), 4.02e3.97 (m, 1H), 3.36e3.31 (m, 4H),
2.94e2.88 (m, 1H), 1.25 (d, 3H, J¼6.0 Hz); 13C NMR (CDCl3)
d 198.77,
133.21, 128.68, 128.27, 73.61, 56.56, 45.56, 19.69.
4.3.7. 3-Ethoxy-1-phenylbutane-1-one (16). Colorless oil (66 mg,
50%). 1H NMR (CDCl3)
ꢁ
4. (a) Malthete, J.; Collet, A. J. Am. Chem. Soc. 1987, 109, 7544; (b) Zimmermann, H.;
d
7.96 (d, 2H, J¼7.6 Hz), 7.55 (t, 1H, J¼7.2 Hz),
Bader, V.; Poupko, R.; Wachtel, E. J.; Luz, Z. J. Am. Chem. Soc. 2002, 124, 15286.
5. (a) Sumby, C. J.; Hardie, M. J. Angew. Chem., Int. Ed. 2005, 44, 6395; (b) Ronson,
T. K.; Fisher, J.; Harding, P.; Hardie, M. J. Angew. Chem., Int. Ed. 2007, 46, 9086; (c)
Westcott, A.; Fisher, J.; Harding, L. P.; Rizkallah, P.; Hardie, M. J. J. Am. Chem. Soc.
2008, 130, 2950; (d) Ronson, T. K.; Fisher, J.; Harding, L. P.; Rizkallan, P. J.;
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N. J.; Robson, R. Angew. Chem., Int. Ed. 2010, 49, 2896; (f) Xu, D.; Warmuth, R. J.
Am. Chem. Soc. 2008, 130, 7520.
6. (a) McKeown, N. B.; Gahnem, B.; Msayib, K. J.; Budd, P. M.; Tattershall, C. E.;
Mahmood, K.; Tan, S.; Book, D.; Langmi, H. W.; Walton, A. Angew. Chem., Int. Ed.
2006, 45, 1804; (b) Yu, J.-Y.; Sun, J.; Huang, Z.-T.; Zheng, Q.-Y. CrystEngCommun
2012, 14, 112; (c) Yu, J.-Y.; Chen, Z.; Sun, J.; Huang, Z.-T.; Zheng, Q.-Y. J. Mater.
Chem. 2012, 22, 5369.
7.45 (t, 2H, J¼7.6 Hz), 4.10e4.07 (m, 1H), 3.60e3.55 (m, 1H),
3.48e3.42 (m, 1H), 3.36e3.32 (m, 1H), 2.94e2.89 (m, 1H), 1.25 (d,
3H, J¼6.4 Hz), 1.14 (t, 3H, J¼6.8 Hz); 13C NMR (CDCl3)
d 198.94,
137.45, 133.13, 128.64,128.28, 71.95, 64.23, 45.97, 20.46, 15.61; FT-IR
n
3060, 2972, 2928, 1685, 1597, 1448, 1372, 1293, 1211, 1132, 1096,
1001, 752, 690 cmꢀ1; HRMS (ESI) calcd for [MþH]þ: m/z 193.1223;
found: 193.1221.
4.3.8. 3-Isopropoxy-1-phenylbutane-1-one
(64 mg, 45%). 1H NMR (CDCl3)
(17). Colorless
7.96 (d, 2H, J¼7.6 Hz), 7.54 (t, 1H,
oil
d
7. (a) Zhang, S.; Echegoyen, L. J. Am. Chem. Soc. 2005, 127, 1315; (b) Abrahams, B. F.;
FitzGerald, N. J.; Hudson, T. H.; Robson, R.; Waters, T. Angew. Chem., Int. Ed.
J¼7.2 Hz), 7.45 (t, 2H, J¼7.6 Hz), 4.15 (m, 1H), 3.66 (m, 1H), 3.30 (dd,
€
2009, 48, 3129; (c) Schroder, L.; Lowery, T. J.; Hilty, C.; Wemmer, D. E.; Pines, A.
1H, J¼6.8, 9.2 Hz), 2.60 (dd, 1H, J¼6, 10 Hz), 1.24 (d, 3H, J¼6 Hz), 1.13
Science 2006, 314, 446; (d) Aaron, J. A.; Chambers, J. M.; Jude, K. M.; Costanzo, L.
D.; Dmochowski, I. J.; Christianson, D. W. J. Am. Chem. Soc. 2008, 130, 6942; (e)
Ruiz, E. J.; Sears, D. N.; Pines, A.; Jameson, C. J. J. Am. Chem. Soc. 2006, 128, 16980.
8. (a) Steed, J. W.; Junk, P. C.; Atwood, J. L. J. Am. Chem. Soc. 1994, 116, 10346; (b)
Wang, L.; Wang, G.-T.; Zhao, X.; Jiang, X.-K.; Li, Z.-T. J. Org. Chem. 2011, 76, 3531.
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Soc., Perkin Trans. 11981, 1630; (b) Colletand, A.; Gabard, J. J. Org. Chem. 1980, 45,
5400.
(d, 3H, J¼6 Hz), 1.05 (d, 3H, J¼6 Hz); 13C NMR (CDCl3)
d 199.24,
133.11, 128.76, 128.62, 128.51, 128.34, 128.15, 69.77, 69.72, 46.52,
23.15, 22.49, 21.51; FT-IR n 3060, 2970, 2930, 1683, 1597, 1580, 1448,
1376, 1330, 1213, 1001, 752, 690 cmꢀ1; HRMS (ESI) calcd for
[MþH]þ: 207.1379; found: 207.1377.
10. Chakrabarti, A.; Chawla, H. M.; Hundal, G.; Pant, N. Tetrahedron 2005, 61, 12323.
11. (a) Kisanga, P. B.; Ilankumaran, P.; Fetterly, B. M.; Verkade, J. G. J. Org. Chem.
2002, 67, 3555; (b) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc.
2003, 125, 8696.
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2007, 46, 3107; (b) Sarkar, D. S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266;
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Q.; You, S.-L. Org. Lett. 2011, 13, 4080; (e) Chen, X.-Y.; Wen, M.-W.; Ye, S.; Wang,
Z.-X. Org. Lett. 2011, 13, 1138; (f) Shen, L.-T.; Sun, L.-H.; Ye, S. J. Am. Chem. Soc.
2011, 133, 15894.
4.4. Crystal structure of 5
ꢀ
ꢀ
C
26H26O6, M¼434.47, monoclinic, a¼16.340(3) A, b¼7.6251(15) A,
ꢀ
c¼16.917(3) A,
a
¼90.00ꢁ,
b
¼91.81(3)ꢁ,
g
¼90.00ꢁ, V¼2106.7(7),
T¼173(2) K, space group P2(1)/n, Z¼4,
m
(MoK
a
)¼0.097 mmꢀ1,10,723
reflections measured, 4799 independent reflections (Rint¼0.0317).
The final R1 values were 0.0748 (I>2s
(I)). The final wR (F2) values
were 0.1509 (I>2s (I)). The final R1 values were 0.0853 (all data). The
13. Phillips, E. M.; Riedrich, M.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 13179.
14. Canceill, J.; Collet, A.; Gabard, J.; Gottarelli, G.; Spada, G. P. J. Am. Chem. Soc.
1985, 107, 1299.
final wR (F2) values were 0.1569 (all data). The goodness of fit on F2
was 1.172. CCDC number: 932872.
15. (a) Wezenberg, S. J.; Kleij, A. W. Angew. Chem., Int. Ed. 2008, 47, 2354; (b)
Richeter, S.; Julius Rebek, J. J. Am. Chem. Soc. 2004, 126, 16280; (c) Shirakawa, S.;
Moriyama, A.; Shimizu, S. Org. Lett. 2007, 9, 3117; (d) Hu, S.; Li, J.; Xiang, J.; Pan,
J.; Luo, S.; Cheng, J.-P. J. Am. Chem. Soc. 2010, 132, 7216.
Acknowledgements
ꢁ
16. Monnereau, L.; Semeril, D.; Matt, D.; Toupet, L. Chem.dEur. J. 2010, 16, 9237.
This work was supported by the Major State Basic Research
Development Program of China (2011CB932501), the National
17. Nakajima, H.; Yasuda, M.; Takeda, R.; Baba, A. Angew. Chem., Int. Ed. 2012, 51,
3867.