Crossed aldol reaction using cross-linked polymer-bound lithium dialkylamide

Article abstract of DOI:10.1016/j.tet.2004.04.026

Cross-linked polymer-bound lithium dialkylamides were employed in crossed aldol reaction of various carbonyl compounds with aldehydes to afford the corresponding β-hydroxycarbonyl compounds. The introduction of spacer chains to the polymer-bound lithium d

Full text of DOI:10.1016/j.tet.2004.04.026

Tetrahedron 60 (2004) 5001–5011
Crossed aldol reaction using cross-linked polymer-bound
lithium dialkylamide
*
Atsushi Seki, Fusae Ishiwata, Youichi Takizawa and Masatoshi Asami
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University, 79-5 Tokiwadai,
Hodogaya-ku, Yokohama 240-8501, Japan
Received 12 February 2004; revised 10 April 2004; accepted 12 April 2004
Abstract—Cross-linked polymer-bound lithium dialkylamides were employed in crossed aldol reaction of various carbonyl compounds with
aldehydes to afford the corresponding b-hydroxycarbonyl compounds. The introduction of spacer chains to the polymer-bound lithium
dialkylamide between the base moiety and the polystyrene backbone effectively enhanced yields of the desired aldol adducts. Sometimes
better yields were obtained by using the polymer-bound reagent having an appropriate spacer-chain with those obtained using lithium
diisopropylamide under homogeneous conditions. Repeated use of these polymeric reagents was demonstrated with no loss of efficiency.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
stronger base than polymer-bound trityllithium for the
deprotonation of 1,1-diphenyl-2-chloroethylene was
reported in 1981.25
Sterically hindered non-nucleophilic strong bases are useful
reagents in preparing carbanions, which undergo various
reactions with a variety of electrophiles to afford the
corresponding products. Although diisopropylamino-
magnesium bromide was first introduced as a sterically
hindered non-nucleophilic metal amide in organic syn-
thesis,1 lithium dialkylamides represented by lithium
diisopropylamide (LDA) are widely employed as a hindered
non-nucleophilic strong base for the generation of various
carbanions by deprotonation of weakly acidic protons in the
presence of a variety of functional groups.2 For example, the
lithium dialkylamides form regio- and geometrically
controlled enolates from carbonyl compounds,3,4 which
facilitate regio- and stereoselective crossed aldol reactions.4
Recently, asymmetric synthesis using chiral lithium dialkyl-
amides has been studied extensively.5–15
Immobilization of chiral metal dialkylamide and its use in
enantioselective deprotonation reactions of ketones have
emerged.26,27 In 1999 Majewski et al. prepared soluble and
insoluble polymer-supported chiral lithium dialkylamides,
then examined the asymmetric crossed aldol reaction of
some cyclic ketones to benzaldehyde and enantioselective
deprotonation reactions of tropinone, followed by an
acylation with trichloroethyl chloroformate.26 They showed
that good enantioselectivity was obtained using the soluble
polymer in the presence of lithium chloride. Polymer-
supported chiral magnesium dialkylamides were also
prepared and were shown to be effective in the deprotona-
tion of 4-substituted and 2,6-disubstituted cyclohexanones,
affording the corresponding optically active enol silyl
ethers.27 A stoichiometric amount of polymer-supported
chiral lithium dialkylamide has also been employed in the
reaction of cyclohexene oxide.28 During the course of our
investigation on the enantioselective isomerization of meso-
epoxides into highly optically active allylalcohol deriva-
tives, we have already reported the preparation and the use
of polymer-bound achiral lithium N-alkyl-4-vinylbenzyl-
amide in a catalytic system as an effective regenerator of
chiral bases.29,30
Much attention has been directed to polymer-bound
reagents in recent years, because they are easily removed
from the reaction medium and can be reused many times
easily in comparison with their non-immobilized
reagents.16–24 However, only a few have been reported on
the preparation and utilization of polymer-bound metal
dialkylamide in organic synthesis in spite of the importance
of metal dialkylamides.25–31 The first attempt to use cross-
linked polystyrene-supported lithium dialkylamide as a
Although polymer-supported metal dialkylamides were
employed in the generation of chiral enolates from cyclic
ketones as mentioned above,26,27 generation of metal
enolates by polymer-supported simple achiral metal amides
and utilization of the enolate in aldol reaction have not been
Keywords: Supported reagents; Lithium dialkylamides; Aldol reaction;
b-Hydroxycarbonyl compounds; Deprotonation; Lithium enolates.
*
Corresponding author. Tel./fax: þ81-45-339-3968;
e-mail address: m-asami@ynu.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.026

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A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
investigated systematically. In this article we report in detail
on the preparation of polymer-bound lithium dialkylamides
1a–f and their use in crossed aldol reactions between
various carbonyl compounds such as ketones, esters, and
amides, and aldehydes since aldol reaction is one of the
most fundamental and important reactions (Scheme 1).31
presence of lithium tetrachlorocuprate (0.009 equiv.) at rt
overnight.
Each of the resulting monomer 4a–f (20 mol%) was
copolymerized with styrene (78 mol0%) and divinylbenzene
(2 mol%) in the presence of 2,2 -azobisisobutyronitrile
(AIBN) according to the method similar to that described
previously,30 and the corresponding polymer-bound dialkyl-
amines 3a–f were obtained. The procedures are
summarized in Scheme 2.
2.2. Crossed aldol reaction between 3-pentanone and
benzaldehyde using polymer-bound lithium N-isopropyl-
4-vinylbenzylamide
In the first place, the aldol reaction of 3-pentanone with
benzaldehyde was examined by using 1.2 equiv. of
polymer-bound lithium N-isopropyl-4-vinylbenzylamide
1a as a base. Namely, to a suspension of polymer-bound
N-isopropyl-4-vinylbenzylamine 3a (amine content:
1.68 mmol/g; particle size: 50–100 mesh; cross-linked
with 2 mol% of divinylbenzene, 750 mg, 1.3 mmol) in
THF (6 mL) was added a hexane solution of butyllithium
(1.54 M, 0.78 mL, 1.2 mmol) dropwise at rt and the reaction
mixture was stirred for 0.5 h. A THF (2 mL) solution of
3-pentanone (86.1 mg, 1.0 mmol) was added to the reaction
mixture at 278 8C and stirring was continued at the
temperature for 15 min. After an addition of THF (2 mL)
solution of benzaldehyde (127 mg, 1.2 mmol), the reaction
mixture was stirred at 278 8C for 90 min. 1-Hydroxy-2-
methyl-1-phenyl-3-pentanone (2a) was obtained in 65%
yield after the work up of the reaction (Conditions A,
Table 1, entry 1). As insufficient formation of the lithium
enolate of 3-pentanone was assumed to be the reason for the
rather low yield, the reaction temperature was gradually
increased to rt during the 15 min in order to complete the
generation of the enolate after stirring the mixture at 278 8C
for 15 min. The yield of aldol 2a was increased to 71%
(Conditions B, Table 1, entry 2). Although still lower than
Scheme 1.
2. Results and discussion
2.1. Synthesis of precursors of lithium dialkylamides
N-Isopropyl-4-vinylbenzylamine (4a) (n¼1) was easily
obtained by the alkylation of isopropylamine (4.0 equiv.)
by 4-vinylbenzyl chloride (1.0 equiv.) at rt for 24 h in 80%
yield. N-Isopropyl-2-(vinylphenyl)ethylamine (4b) (n¼2)
was prepared from isopropylamine (0.96 equiv.) and
divinylbenzene (1.0 equiv.) in the presence of a catalytic
amount of lithium isopropylamide (0.04 equiv.) according
to a procedure similar to that reported by Tsuruta et al.32
N-Isopropyl-v-(4-vinylphenyl)alkylamines (4c–f) (n$4)
were obtained in good yields (73–86%) by the reaction of
isopropylamine (4.0 equiv.) and bromoalkylstyrenes 5c–f
(1.0 equiv.) at rt for 48 h. The v-bromoalkylstyrenes 5c–f
were obtained in reasonable yields (36–54%) by the cross-
coupling reaction33 of a,v-dibromoalkanes (1.0 equiv.)
with 4-vinylbenzylmagnesium chloride (1.0 equiv.) in the
Scheme 2.

A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
5003
Table 1. Aldol reaction of 3-pentanone with benzaldehyde using polymer-bound lithium dialkylamides 1a–f
Entry
Li-amide
n
Conditionsa
Yield (%)b
syn:antic
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1
1
2
2
4
4
5
5
6
6
7
7
—
—
A
B
A
B
A
B
A
B
A
B
A
B
A
B
65
71
65
78
80
87
82
90
80
89
77
87
88
91
68:32
69:31
69:31
71:29
68:32
71:29
69:31
69:31
69:31
72:28
68:32
71:29
62:38
62:38
1c
1d
1d
1e
1e
1f
1f
LDA
LDA
9
10
11
12
13
14
a
Conditions A: the enolate was generated at 278 8C for 15 min. Conditions B: the enolate was generated at 278 8C for 15 min and then the resulting mixture
was allowed to warm to rt for 15 min.
Isolated yield of aldol 2a.
b
c
Determined by 1H NMR analysis.
those obtained using LDA (Table 1, entries 13 and 14),
slightly higher syn/anti ratios were obtained in the reaction
using polymer 1a (Table 1, entries 1 and 2).
none and cyclohexanone with several aldehydes using 1d
was examined under Conditions B employing a procedure
similar to that described in Section 2.2. The results are
summarized in Table 2 along with the results obtained using
LDA in place of 1d. In most cases the yields were
comparable to those obtained using LDA and slightly
higher selectivities were observed in some cases (Table 2,
entries 1, 3, 4, 7, and 9) when the spacer-modified polymer-
bound reagent 1d was used.
2.3. Effect of spacer-modified polymer-bound lithium
dialkylamides on the aldol reaction between 3-pentanone
and benzaldehyde
Next, we examined polymer-bound lithium dialkylamide
with several spacers between the base site and the polymer
support so as to improve the yield of the aldol reaction, since
the modification of polymer-bound reagents with spacers
sometimes enhance their performance.34,35 The aldol
reaction between 3-pentanone and benzaldehyde was
examined using polymer-bound lithium dialkylamide
1b–f under Conditions A and B as described in Section
2.2. Although the same yield (65%) was observed using
polymer 1a or 1b under Conditions A (Table 1, entries 1 and
3), the yield was improved to 78% using polymer 1b under
Conditions B (Table 1, entry 4). Then spacer-modified
polymer-bound lithium dialkylamide 1c–f was employed in
the reaction under Conditions A as well as Conditions B. As
the chain length was elongated up to a pentylene group, the
yield of aldol 2a was gradually improved to 90% under
Conditions B (Table 1, entry 8), although longer spacers
(n.5) had very little influence on the yield (Table 1, entries
10 and 12). Thus, almost the same yield as LDA (Table 1,
entries 13 and 14) was realized using 1d under Conditions
B. The syn/anti ratio of the product 2a was higher in every
case than that observed when LDA was used.
2.5. Aldol reaction of methyl ketones with several
aldehydes using spacer-modified polymer-bound lithium
dialkylamide
Next, the aldol reaction of several methyl ketones with
aldehydes was investigated in order to examine the
regioselectivity of the reaction. The results are summarized
in Table 3. At first, the aldol reaction between 2-pentanone
and benzaldehyde was carried out using polymer-bound
lithium dialkylamide 1a under Conditions B. The aldol
adduct, 1-hydroxy-1-phenyl-3-hexanone (2k), was obtained
regioselectively in 67% yield (Table 3, entry 1). In contrast
to the cases of the reaction of 3-pentanone shown in Table 1,
Conditions A gave a better yield (76% yield, Table 3, entry
2). By using spacer-modified polymer-bound lithium
dialkylamide 1d under Conditions A, the yield of aldol 2k
was further increased to 88% (Table 3, entry 3). Then, under
Conditions A, the aldol reaction of 2-pentanone with
3-phenylpropanal, cyclohexanecarbaldehyde, or 2-methyl-
propanal was examined using 1a as well as 1d. Correspond-
ing aldol adducts 2l–n were obtained in good to high yields
using 1d. Better yields as compared to those by using LDA
were obtained for all aldehydes examined using 1d (Table 3,
entries 3, 5, 7, and 9).
2.4. Aldol reaction of 3-pentanone and cyclohexanone
with aldehydes using spacer-modified polymer-bound
lithium dialkylamide
As good results were obtained in the reaction of 3-penta-
none and benzaldehyde using 1d, the reaction of 3-penta-
Enolate was also regioselectively generated from 4-methyl-
3-penten-2-one with polymer 1a and 1d, and 1-hydroxy-5-

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A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
Table 2. Aldol reaction of 3-pentanone and cyclohexanone with aldehydes using spacer-modified polymer 1d
Entry
Aldol adduct
R1
R2
R3
Yield (%)a,b
syn:antib,c
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Ph
90 (91)
88 (89)
84 (83)
93 (83)
82 (78)
88 (90)
65 (70)
82 (73)
59 (61)
56 (64)
73:27 (62:38)
74:26 (77:23)
65:35 (53:47)
66:34 (60:40)
40:60 (29:71)
70:30 (71:29)
72:28 (70:30)
27:73 (25:75)
3:97 (4:96)
p-ClC6H4
o-MeOC6H4
trans-PhCHvCH
c-C6H11
Ph(CH2)2
n-Pr
Ph
i-Pr
Ph(CH2)2
–(CH2)4–
–(CH2)4–
–(CH2)4–
2j
30:70 (29:71)
a
Isolated yield of aldol 2a–j.
The figures in parentheses are the results obtained by using LDA in place of polymer-bound lithium dialkylamide 1d.
b
c
Determined by 1H NMR analysis.
methyl-1-phenyl-4-hexen-3-one (2o) was obtained in 81%
yield in both cases (Table 3, entries 10–12). A side reaction,
e.g. 1,4-addition of polymer 1a and 1d to the carbon–
carbon bond of 4-methyl-3-penten-2-one, was not
problematic (Table 3, entry 11).
methyl ketones, and the corresponding aldol products
were obtained in good yields by the subsequent reaction
with aldehydes.
2.6. Aldol reaction of propionic acid esters with
aldehydes using polymer-bound lithium dialkylamides
Then the reaction of acetone, the least hindered ketone, with
benzaldehyde was examined using polymer-bound lithium
dialkylamide 1a and 1d. The aldol, 4-hydroxy-4-phenyl-2-
butanone (2p), was obtained only in a moderate yield (60%)
when 1a was used. The yield was improved to 80% using
1d.
As polymer-bound lithium dialkylamides 1a and 1d were
successfully employed to generate enolates from ketones
and to afford the corresponding aldols in the reaction with
aldehydes, we next examined the generation of enolates
from propionic acid esters and their reaction with aldehydes.
As described above, polymer-bound lithium dialkylamide
effectively generates the enolate regioselectively from
Enolate of 2,6-dimethylphenyl propionate (DMP
propionate) was generated using 1a at 278 8C for 15 min
Table 3. Aldol reaction of methyl ketones with several aldehydes using polymer-bound lithium dialkylamides
Entry
Aldol adduct
R1
R2
Li-amide
Conditionsa
Yield (%)b
1
2
3
4
5
6
7
8
2k
2k
2k
2l
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me2CvCH
Me2CvCH
Me2CvCH
Me
Ph
Ph
Ph
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
i-Pr
i-Pr
Ph
Ph
Ph
1a
1a
1d
1a
1d
1a
1d
1a
1d
1a
1d
1d
1a
1d
B
A
A
A
A
A
A
A
A
B
B
A
A
A
67
76
88 (83)c
57
2l
93 (86)c
63
2m
2m
2n
2n
2o
2o
2o
2p
2p
82 (79)c
60
9
79 (73)c
81
10
11
12
13
14
81 (84)c
81
60
Ph
Ph
Me
80 (85)c
a
Conditions A: the enolate was generated at 278 8C for 15 min. Conditions B: the enolate was generated at 278 8C for 15 min and then the resulting mixture
was allowed to warm to rt for 15 min.
Isolated yield of aldol 2k–p.
b
c
The figures in parentheses are the results obtained by using LDA in place of polymer-bound lithium amide 1a and 1d.

A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
5005
Table 4. Aldol reaction of propionic acid aryl esters with aldehydes using polymer-bound lithium dialkylamides
Entry
Ara
R
Adduct
Base
Yield (%)b
syn:antic
1
2
3
4
5
6
7
DMP
DMP
BHT
BHT
BHT
BHT
BHT
Ph
Ph
Ph
Ph
c-C6H11
i-Pr
n-Pr
2q
2q
2r
2r
2s
2t
1a
1d
1a
1d
1d
1d
1d
32d
17:83
23:77 (11:89)e
7:93
72 (85)e
25f
92 (97)e
64
79
3:97 (,2:98)e
,2:98
,2:98
2u
82
3:97
a
DMP¼2,6-dimethylphenyl. BHT¼2,6-di-tert-butyl-4-methylphenyl.
Isolated yield of aldol 2q–u.
b
c
d
e
f
Determined by 1H NMR analysis.
The 2,6-dimethylphenyl propionate was recovered in 68%.
The figures in parentheses are the results obtained by using LDA in place of polymer-bound lithium amides 1a and 1d.
The 2,6-di-tert-butyl-4-methylphenyl propionate was recovered in 70%.
(Conditions A) and the reaction of the enolate with
benzaldehyde was carried out at 278 8C for 90 min
(Table 4, entry 1). 3-Hydroxy-2-methyl-3-phenylpropionic
acid 2,6-dimethylphenyl ester (2q) was obtained in only
32% yield (syn/anti¼17:83) with the recovery of the starting
material (68%). Then, the reaction temperature was
gradually increased to rt during the 15 min after stirring
the mixture at 278 8C for 15 min (Conditions B). However,
the yield was not improved using 1a. The yield of 2q was
considerably improved to 72% using spacer-modified
polymer 1d (Table 4, entry 2).
stereoselectivity (syn/anti¼7:93) but in low yield (25%)
(Table 4, entry 3). The yield was enhanced to 92% using
spacer-modified polymer 1d with high anti-selectivity
(Table 4, entry 4). Then, the aldol reaction of BHT
propionate with cyclohexanecarbaldehyde, 2-methyl-
propanal, and butanal was examined using polymer 1d
and the corresponding anti-aldols 2s–u were obtained in
good to high yields with very high stereoselectivities
(Table 4, entries 5–7).
2.7. Aldol reaction of N,N-dimethylpropionamide with
aldehydes using polymer-bound lithium dialkylamides
Then, the aldol reaction of more hindered aryl ester, 2,6-di-
tert-butyl-4-methylphenyl propionate (BHT propionate)
with aldehydes was examined to improve syn/anti ratio of
the product. The reaction of BHT propionate and benzal-
dehyde using polymer 1a afforded aldol 2r with higher
The generation of enolate and its reaction was also
examined for N,N-dimethylpropionamide. 3-Hydroxy-
2,N,N-trimethyl-3-phenylpropionamide (2v) was obtained
in 77% yield (syn/anti¼64:36) by the reaction with
Table 5. Aldol reaction of N,N-dimethylpropionamide with aldehydes using polymer-bound lithium dialkylamides
Entry
R
Adduct
Base
Conditionsa
Yield
(%)b
syn:antic
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
i-Pr
2v
2v
2v
2w
2w
2x
2x
2y
2y
1a
1a
1d
1a
1d
1a
1d
1a
1d
A
B
B
B
B
B
B
B
B
77
96
64:36
64:36
99 (97)d
88
83
62:38 (59:41)d
74:26
74:26
93
93
94
98
86:14
82:18
85:15
84:16
i-Pr
a
Conditions A: the enolate was generated at 278 8C for 15 min. Conditions B: the enolate was generated at 278 8C for 15 min and then the resulting mixture
was allowed to warm to rt for 15 min.
Isolated yield of aldol 2v–y.
b
c
d
Determined by 1H NMR analysis.
The figures in parentheses are the results obtained by using LDA in place of polymer-bound lithium amides 1a and 1d.

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A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
benzaldehyde after the generation of the enolate under
Conditions A using 1a (Table 5, entry 1). The yield was
improved to 96% by employing Conditions B (Table 5,
entry 2). Almost quantitative yield was achieved when 1d
was used in place of 1a (Table 5, entry 3).
between N,N-dimethylpropionamide and aldehydes in good
yields. In particular, 1d modified with a pentamethylene
spacer effectively promoted crossed aldol reaction between
various carbonyl compounds and aldehydes to afford the
corresponding adducts in up to 99% yield. The reagent
showed higher syn/anti selectivities compared to those
obtained using LDA under homogeneous conditions in most
cases. The method for the recovery and reuse of the base 1d
was also demonstrated. The effect of the alkylene spacers on
the reactivity of the polymer-bound lithium dialkylamide
revealed by this work would be useful for the attachment of
valuable lithium dialkylamides, e.g. chiral lithium dialkyl-
amides, onto the polymer.
The reaction was applied to 3-phenylpropanal, cyclo-
hexanecarbaldehyde, and 2-methylpropanal using 1a and
1d under Conditions B. Corresponding adducts 2w–y were
obtained in high yields with good syn/anti selectivities
(Table 5, entries 4–9).
2.8. Reusability of polymer-bound lithium dialkylamide
for the aldol reaction
As the usefulness of spacer-modified polymer-bound
lithium dialkylamide 1d was realized in the aldol reaction
of ketones and carboxylic acid derivatives with aldehydes to
afford various b-hydroxycarbonyl compounds, its recovery
and repeated use were examined in the reaction between
3-pentanone and benzaldehyde under Conditions B. After
quenching the aldol reaction using phosphate buffer (pH 7),
the mixture was filtered through a glass filter. The recovered
spacer-modified polymer-bound amine 3d was successively
rinsed with dichloromethane and water, and then dried
under vacuum at 90 8C for 16 h. The dried polymer 3d
swollen in THF was then treated with a hexane solution of
butyllithium to regenerate polymer-bound lithium dialkyl-
amide 1d by the same procedure for the conversion of a new
precursor 3d to polymer 1d. The regenerated polymer 1d
was used in the aldol reaction between 3-pentanone and
benzaldehyde again. The results are shown in Table 6. The
yield and syn/anti selectivity of aldol adduct 2a scarcely
changed after the polymer-bound lithium dialkylamide 1d
was used five times.
4. Experimental
4.1. General
All air-sensitive reactions were carried out under an
atmosphere of argon. Tetrahydrofuran (THF) and diethyl
ether were distilled under argon over sodium benzophenone
ketyl before use. 4-Vinylbenzyl chloride was distilled over
calcium hydride under reduced pressure. Lithium tetra-
chlorocuprate in tetrahydrofuran was purchased from
Aldrich. Commercially available solution of butyllithium
in hexane (Kanto Chemical Co., Inc.) was used to generate
lithium dialkylamides. Proton NMR spectra were measured
with a JEOL MY60 spectrometer at 60 MHz, a JEOL
EX270 spectrometer at 270 MHz, or with a JEOL AL400
spectrometer at 400 MHz, using CDCl3 as solvent. Carbon
NMR spectra were recorded at 68 MHz with a JEOL EX270
spectrometer or at 100 MHz with a JEOL AL400 spec-
trometer using CDCl3 as solvent. The chemical shifts are
given in ppm relative to tetramethylsilane (d scale) used as
an internal standard. Infrared spectra were taken on a
Perkin–Elmer Paragon 1000 spectrometer. Mass spectra
were measured on a JEOL JMS-600 mass spectrometer
using electron impact (EI). Melting points were measured
on a Bu¨chi 535 apparatus and are uncorrected. Elemental
analyses were carried out on a Perkin–Elmer 2400 CHN
analyzer or a Perkin–Elmer 2400 II CHNS/O analyzer. TLC
analyses were done on silica-gel 60 F254-coated plates
(E. Merck). Column chromatography was carried out with
Wakogel C-200 gel unless otherwise specified. Preparative
TLC was performed on silica-gel-coated plates (Wakogel
B-5F, 20 cm£20 cm).
Table 6. Reuse of polymer-bound lithium dialkylamide
Batch no.
Yield of 2a (%)a
syn:antib
1
2
3
4
5
6
90
87
89
90
89
89
73:37
70:30
69:31
70:30
71:29
69:31
4.2. Preparation of 4-vinylbenzylmagnesium chloride
A solution of 4-vinylbenzyl chloride (25.0 g, 0.165 mol) in
diethyl ether (25 mL) was added dropwise to a mixture of
magnesium (4.5 g, 0.19 mol) for 2 h after activation of
magnesium with a small piece of iodine in diethyl ether
(75 mL) at 0 8C. After stirring for 1 h at 0 8C, the reaction
temperature was allowed to increased to rt for 30 min and
the mixture was stirred for 1 h. The resulting solution was
directly used for the next cross-coupling reaction.
a
Isolated yield of aldol 2a.
Determined by 1H NMR analysis.
b
3. Conclusions
Various polymer-bound lithium dialkylamides 1a–f cross-
linked with divinylbenzene were derived from the corre-
sponding N-isopropyl-v-(vinylphenyl)alkylamines (4a–f).
The spacer served for an increase of the reactivity of the
reagent, and 1b–f was more effective than 1a in crossed
aldol reaction, although polymer 1a promoted the reaction
4.3. Synthesis of v-bromoalkylstyrenes
4.3.1. 1-(4-Bromobutyl)-4-vinylbenzene (5c). A solution
of 4-vinylbenzylmagnesium chloride prepared from

A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
5007
0.165 mol of 4-vinylbenzyl chloride in diethyl ether
(100 mL) was added dropwise for 3 h to a solution of 1,3-
dibromopropane (33.3 g, 0.165 mol) in THF (150 mL) in
the presence of lithium tetrachlorocuprate (0.1 M, 15 mL,
1.5 mmol) at 0 8C.33 After the addition was completed the
mixture was stirred overnight at rt. Methanol (5 mL) was
then added to cease the reaction. The reaction mixture was
filtered and the filtrate was concentrated under reduced
pressure in the presence of 2,2-diphenyl-1-picrylhydrazil
(DPPH). The resulting mixture was poured into water and
extracted with toluene (3£50 mL). The combined organic
layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. Then the residue was distilled in vacuo in
the presence of DPPH to give 1-(4-bromobutyl)-4-vinyl-
(5c), the cross-coupling reaction with 1,6-dibromohexane
(40.3 g, 0.165 mol) and 4-vinylbenzylmagnesium chloride
was conducted to yield 1-(7-bromoheptyl)-4-vinylbenzene
as a colorless oil (18.0 g, 39%). Bp 114 8C/0.060 mmHg. IR
(neat): 3085, 3005, 2934, 2858, 1907, 1817, 1629, 1512,
1458, 1437, 1251, 991, 907, 844; 1H NMR (CDCl3): 1.31–
1.46 (m, 6H), 1.55–1.66 (m, 2H), 1.84 (quint, J¼7.1 Hz,
2H), 2.59 (t, J¼7.6 Hz, 2H), 3.39 (t, J¼6.9 Hz, 2H), 5.18 (d,
J¼11.9 Hz, 1H), 5.69 (d, J¼16.5 Hz, 1H), 6.68 (dd, J¼10.9,
17.5 Hz, 1H), 7.12 (d, J¼7.9 Hz, 2H), 7.32 (d, J¼8.6 Hz,
2H); 13C NMR (CDCl3): 28.1, 28.7, 29.1, 31.3, 32.8, 34.0,
35.6, 112.7, 126.0, 128.4, 134.9, 136.5, 142.3; MS: (m/z) %:
282 (Mþþ2, 26), 280 (Mþ, 26), 118 (15), 117 (100), 115
(10), 91 (8). Exact mass for C15H21Br: 280.0827. Found
280.0829.
benzene (20.9 g, 53%) as
a
colorless oil (bp
77 8C/0.028 mmHg). IR (neat): 3085, 3005, 2938, 2858,
1629, 1512, 1458, 1437, 1407, 1251, 991, 907, 844, 827; 1H
NMR (CDCl3): 1.70–1.94 (m, 4H), 2.62 (t, J¼7.3 Hz, 2H),
3.40 (t, J¼6.6 Hz, 2H), 5.19 (dd, J¼1.0, 10.9 Hz, 1H), 5.71
(dd, J¼1.0, 17.8 Hz, 1H), 6.69 (dd, J¼10.7, 17.7 Hz, 1H),
7.13 (d, J¼7.9 Hz, 2H), 7.33 (d, J¼8.3 Hz, 2H); 13C NMR
(CDCl3): 29.7, 32.1, 33.6, 34.6, 113.0, 126.2, 128.5, 135.3,
136.5, 141.5; MS: m/z (%): 240 (Mþþ2, 23), 238 (Mþ, 23),
117 (100), 115 (13), 91 (8). Exact mass for C12H15Br:
238.0357. Found 238.0357.
4.4. Synthesis of v-(isopropylamino)alkylstyrenes (4a–f)
4.4.1. N-Isopropyl-4-vinylbenzylamine (4a). To iso-
propylamine (47.3 g, 0.40 mol) was added 4-vinylbenzyl
chloride (30.5 g, 0.20 mol) at 0 8C and the mixture was
stirred at rt for 24 h. Then dichloromethane and 4 M
aqueous solution of sodium hydroxide were added to the
reaction mixture. The aqueous solution was extracted with
dichloromethane. The combined organic layer was washed
with saturated aqueous sodium chloride solution and was
dried with anhydrous sodium carbonate. The solvent and
isopropylamine were evaporated and the residual oil was
purified by column chromatography (silica gel, hexane/
ethyl acetate¼10:1) and distillation under reduced pressure
in the presence of 2,2-diphenyl-1-picrylhydrazil (DPPH) to
yield N-isopropyl-4-vinylbenzylamine36,37 as a colorless oil
(28.0 g, 80%), bp 66 8C/0.6 mmHg (lit.36 bp
68 8C/1 mmHg). IR (neat): 3307, 2966, 1630, 1511, 1470,
1380, 1338, 1175, 990, 906, 830, 757, 721; 1H NMR
(CDCl3): 1.08 (d, J¼6.3 Hz, 6H), 1.36 (br s, 1H), 2.83 (sept,
J¼6.2 Hz, 1H), 3.75 (s, 2H), 5.20 (dd, J¼0.66, 10.9 Hz,
1H), 5.71 (dd, J¼1.0, 17.5 Hz, 1H), 6.69 (dd, J¼10.9,
17.5 Hz, 1H), 7.27 (d, J¼8.2 Hz, 2H), 7.37 (d, J¼8.3 Hz,
2H); 13C NMR (CDCl3): 22.8, 47.9, 51.2, 113.2, 126.1,
128.2, 136.1, 136.5, 140.3.
4.3.2. 1-(5-Bromopentyl)-4-vinylbenzene (5d). By a
procedure similar to that for 1-(4-bromobutyl)-4-vinyl-
benzene (5c), the cross-coupling reaction with 1,4-dibromo-
butane (35.6 g, 0.165 mol) and 4-vinylbenzylmagnesium
chloride was conducted to give 1-(5-bromopentyl)-4-
vinylbenzene as a colorless oil (22.4 g, 54%). Bp 98 8C/
0.045 mmHg; IR (neat): 3085, 2934, 2857, 1630, 1512,
1
1459, 1246, 991, 906, 832; H NMR (CDCl3): 1.41–1.54
(m, 2H), 1.58–1.69 (m, 2H), 1.83–1.93 (m, 2H), 2.61 (t,
J¼7.6 Hz, 2H), 3.40 (t, J¼6.8 Hz, 2H), 5.20 (dd, J¼0.99,
10.9 Hz, 1H), 5.70 (d, J¼0.99, 17.5 Hz, 1H), 6.69 (dd,
J¼10.9, 12.8 Hz, 1H), 7.13 (d, J¼7.9 Hz, 2H), 7.33 (d,
J¼7.9 Hz, 2H); 13C NMR (CDCl3): 27.8, 30.5, 32.6, 33.8,
35.4, 112.9, 126.1, 128.5, 135.2, 136.6, 142.0; MS: (m/z)
%: 254 (Mþþ2, 23), 252 (Mþ, 11), 117 (100), 115 (12),
91 (8). Exact mass for C13H17Br: 252.0514. Found
252.0512.
4.4.2. N-Isopropyl-2-(vinylphenyl)ethylamine (4b). To
15.4 g of distilled technical 55 wt% divinylbenzene
(65 mmol) in THF (48 mL) was added dropwise the mixture
of isopropylamine (3.84 g, 65 mmol) in THF (17 mL) and a
hexane solution of butyllithium (1.57 M solution, 1.7 mL,
2.6 mmol) for 2 h at 0 8C.32 After stirring for 36 h at 0 8C,
2-propanol was added to the reaction mixture. The resulting
mixture was concentrated under reduced pressure, diluted
with ethyl acetate, and washed with water. The organic layer
was dried over sodium sulfate and concentrated. The residue
was distilled in vacuo in the presence of 2,2-diphenyl-1-
picrylhydrazil (DPPH) to give N-isopropyl-2-(vinylphenyl)-
4.3.3. 1-(6-Bromohexyl)-4-vinylbenzene (5e). By a pro-
cedure similar to that for 1-(4-bromobutyl)-4-vinylbenzene
(5c), the cross-coupling reaction with 1,5-dibromopentane
(37.9 g, 0.165 mol) and 4-vinylbenzylmagnesium chloride
was conducted to give 1-(6-bromohexyl)-4-vinylbenzene as
a colorless oil (15.8 g, 36%). Bp 104 8C/0.045 mmHg. IR
(neat): 3085, 3006, 2933, 2857, 2361, 1630, 1512, 1458,
1438, 1259, 1225, 991, 907, 839; 1H NMR (CDCl3): 1.26–
1.68 (m, 6H), 1.80–1.95 (m, 2H), 2.60 (t, J¼7.6 Hz, 2H),
3.40 (t, J¼6.9 Hz, 2H), 5.19 (dd, J¼0.99, 10.9 Hz, 1H), 5.70
(dd, J¼0.99, 17.8 Hz, 1H), 6.69 (dd, J¼10.9, 17.8 Hz, 1H),
7.13 (d, J¼7.9 Hz, 2H), 7.33 (d, J¼8.3 Hz, 2H); 13C NMR
(CDCl3): 28.0, 28.3, 31.2, 32.7, 34.0, 35.5, 112.7, 126.0,
128.4, 134.9, 136.5, 142.1; MS: (m/z) %: 268 (Mþþ2, 25),
266 (Mþ, 28), 118 (15), 117 (100), 115 (11), 91 (8). Exact
mass for C14H19Br: 266.0670. Found: 266.0670.
ethylamine as
a
colorless oil (6.38 g, 52%), bp
49 8C/0.030 mmHg. IR (neat): 3306, 3087, 3007, 2965,
2867, 2827, 1630, 1512, 1474, 1442, 1379, 1338, 1174, 990,
906, 714; 1H NMR (CDCl3): 1.02 (d, J¼6.1 Hz, 6H), 2.38–
3.00 (m, 5H), 5.12 (d, J¼10.8 Hz, 1H), 5.72 (d, J¼17.4 Hz,
1H), 6.64 (dd, J¼10.1, 17.5 Hz, 1H), 6.94–7.38 (m, 4H);
MS: (m/z) %: 189 (Mþ, 2), 131 (15), 117 (10), 115 (12), 91
(13), 72 (100). Exact mass for C13H19N: 189.1518. Found
189.1517.
4.3.4. 1-(7-Bromoheptyl)-4-vinylbenzene (5f). By a simi-
lar to that procedure for 1-(4-bromobutyl)-4-vinylbenzene

5008
A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
4.4.3. N-Isopropyl-4-(4-vinylphenyl)butylamine (4c). To
1-(4-bromobutyl)-4-vinylbenzene (4.78 g, 20 mmol) was
added isopropylamine (4.73 g, 80 mmol) at 0 8C. After
stirring at room temperature for 48 h, 4 M aqueous solution
of sodium hydroxide was added to the reaction mixture until
most precipitate dissolved. The aqueous solution was
extracted with dichloromethane. The combined organic
layer was washed with saturated aqueous sodium chloride
solution and was dried with anhydrous sodium carbonate.
The solvent and isopropylamine were evaporated, and the
residual oil was purified by silica gel chromatography with
Chromatorex DM1020 (2100þ200 mesh, Fuji Silysia
Chemical Ltd) using hexane/ether (1:0–0:1) as eluent,
giving N-isopropyl-4-(4-vinylphenyl)butylamine as a color-
less oil (3.72 g, 86%). IR (neat): 3086, 2932, 2864, 1630,
1512, 1472, 1379, 1174, 990, 904, 842; 1H NMR (CDCl3):
1.04 (d, J¼6.3 Hz, 6H), 1.48–1.68 (m, 4H), 2.57–2.64 (m,
4H), 2.76 (sept, J¼6.3 Hz, 1H), 5.18 (dd, J¼0.66, 10.9 Hz,
1H), 5.70 (dd, J¼0.50, 17.3 Hz, 1H), 6.20 (dd, J¼10.9,
17.8 Hz, 1H), 7.13 (d, J¼8.6 Hz, 2H), 7.31 (d, J¼7.9 Hz,
2H); 13C NMR (CDCl3): 23.0, 29.3, 30.1, 35.6, 47.4, 48.7,
112.8, 126.1, 128.6, 135.1, 136.7, 142.3; MS: (m/z) %: 217
(Mþ, 40), 202 (57), 117 (34), 72 (100). Exact mass for
C15H23N: 217.1831. Found 217.1830.
a procedure similar to that for N-isopropyl-4-(4-vinyl-
phenyl)butylamine, alkylation of isopropylamine (4.73 g,
80 mmol) with 1-(7-bromoheptyl)-4-vinylbenzene (5.62 g,
20 mmol) was conducted to yield N-isopropyl-7-(4-vinyl-
phenyl)heptylamine as a colorless oil (4.03 g, 78%). IR
(neat): 3086, 2932, 2864, 1630, 1512, 1472, 1379, 1174; 1H
NMR (CDCl3): 1.04 (d, J¼6.3 Hz, 6H), 1.25–1.41 (m, 6H),
1.32 (br s, 1H), 1.43–1.51 (m, 2H), 1.54–1.65 (m, 2H),
2.50–2.61 (m, 4H), 2.77 (sept, J¼6.3 Hz, 1H), 5.18 (dd,
J¼1.0, 10.9 Hz, 1H,), 5.69 (dd, J¼1.0, 17.5 Hz, 1H), 6.69
(dd, J¼10.9, 17.5 Hz, 1H), 7.13 (d, J¼7.9 Hz, 2H), 7.32 (d,
J¼7.9 Hz, 2H); 13C NMR (CDCl3): 23.1, 27.4, 29.2, 29.4,
30.5, 31.4, 35.7, 47.6, 48.7, 112.6, 125.9, 128.4, 134.9,
136.6, 142.4; MS: (m/z) %: 259 (Mþ, 46), 245 (25), 244
(100), 117 (27), 115 (10). Exact mass for C18H29N:
259.2300. Found 259.2302.
4.5. Preparation of polymer-bound N-isopropyl-v-
(vinylphenyl)alkylamine (3a–f)
Preparation of 2 mol% cross-linked, 20 mol% ring-substi-
tuted v-isopropylaminoalkylated polystyrene in micro-
porous form was carried out by the suspension
copolymerization of N-isopropyl-v-(vinylphenyl)alkyl-
amine (20 mol%), styrene (78 mol%), and divinylbenzene
(2 mol%) by the procedure described.30,38 Polymer-bound
N-isopropyl-4-vinylbenzylamine (3a) was prepared accord-
ing to the literature procedure.30
4.4.4. N-Isopropyl-5-(4-vinylphenyl)pentylamine (4d).
By a procedure similar to that for N-isopropyl-4-(4-
vinylphenyl)butylamine, alkylation of isopropylamine
(4.73 g, 80 mmol) with 1-(5-bromopentyl)-4-vinylbenzene
(5.06 g, 20 mmol) was conducted to yield N-isopropyl-5-(4-
vinylphenyl)pentylamine as a colorless oil (4.07 g, 83%). IR
(neat): 3291, 3085, 2964, 2930, 2856, 1630, 1562, 1512,
1461, 1378, 1362, 1174, 990, 905, 842; 1H NMR (CDCl3):
1.04 (d, J¼6.3 Hz, 6H), 1.26–1.41 (m, 2H), 1.45–1.54 (m,
2H), 1.56–1.68 (m, 2H), 2.57 (t, J¼7.3 Hz, 2H), 2.60 (t,
J¼7.6 Hz, 2H), 2.77 (sept, J¼6.3 Hz, 1H), 5.18 (dd,
J¼0.99, 10.9 Hz, 1H,), 5.70 (dd, J¼0.99, 17.5 Hz, 1H),
6.69 (dd, J¼10.9, 17.8 Hz, 1H), 7.13 (d, J¼7.9 Hz, 2H),
7.33 (d, J¼8.3 Hz, 2H); 13C NMR (CDCl3): 22.9, 27.0, 30.2,
31.2, 35.5, 47.4, 48.6, 112.7, 126.0, 128.4, 135.0, 136.6,
142.3; MS: (m/z) %: 231 (Mþ, 32), 217 (10), 216 (60), 117
(29), 72 (100). Exact mass for C16H25N: 231.1987. Found
231.1986.
4.5.1. Polymer-bound N-isopropyl-5-(4-vinylphenyl)-
pentylamine (3d). A solution of gelatin (0.106 g), poly-
(diallyldimethylammonium chloride-co-sulfur dioxide)
(1.1 g, from Nittobo, Japan), boric acid (0.41 g,
5.9 mmol), and sodium nitrate (23 mg, 0.33 mmol) in
water (33 mL) was adjusted to pH 9.5 with 25 wt% aqueous
sodium hydroxide and was placed in a 50 mL round-bottom
flask fitted with a reflux condenser and a mechanical stirrer.
To the solution was added a mixture of N-isopropyl-5-(4-
vinylphenyl)pentylamine (1.39 g, 6.0 mmol), styrene
(2.44 g, 23.4 mmol), 142 mg of technical 55% divinyl-
benzene (0.60 mmol), and 2,20-azobisisobutyronitrile
(32 mg, 0.19 mmol). The flask was purged with nitrogen
for 40 min at rt, and a nitrogen atmosphere was maintained
throughout the polymerization. The mixture was stirred at
70 8C for 1 day. Stirring speed in this preparation was
430 rpm. The insoluble polymer was obtained by filtration
with a glass funnel, and it was washed thoroughly with hot
water, methanol, THF, and CH2Cl2, successively. Cross-
linked polymer-bound reagent 3d was obtained as beads
after removal of the solvent under reduced pressure
(,1 mmHg) at 90 8C for 16 h. Sieving the polymer beads
through a sieve (50–100 mesh) gave the fraction (2.97 g,
76%) of uniform particle size. The amine content deter-
mined by elemental analysis (C, 88.51; H, 9.05; N, 2.35)
was 1.68 mmol/g. IR (KBr): 3083, 3060, 2925, 1493, 1377,
836, 758, 699.
4.4.5. N-Isopropyl-6-(4-vinylphenyl)hexylamine (4e). By
a procedure similar to that for N-isopropyl-4-(4-vinyl-
phenyl)butylamine, alkylation of isopropylamine (4.73 g,
80 mmol) with 1-(6-bromohexyl)-4-vinylbenzene (5.34 g,
20 mmol) was conducted to yield N-isopropyl-6-(4-vinyl-
phenyl)hexylamine as a colorless oil (3.58 g, 73%). IR
(neat): 3350, 3085, 2963, 2855, 1630, 1512, 1465, 1406,
1
1378, 1337, 1262, 1174, 1120, 991, 904, 831; H NMR
(CDCl3): 1.04 (d, J¼5.9 Hz, 6H), 1.32–1.64 (m, 8H), 2.54–
2.74 (m, 4H), 2.77 (sept, J¼6.3 Hz, 1H), 5.18 (d, J¼9.9 Hz,
1H), 5.69 (d, J¼17.8 Hz, 1H), 6.69 (dd, J¼10.9, 17.5 Hz,
1H), 7.12 (d, J¼7.9 Hz, 2H), 7.32 (d, J¼7.9 Hz, 2H); 13C
NMR (CDCl3): 21.6, 27.1, 28.8, 29.0, 31.2, 35.5, 46.5,
49.2, 112.8, 126.1, 128.5, 135.0, 136.6, 142.4; MS: (m/z) %:
245 (Mþ, 28), 231 (11), 230 (58), 128 (16), 117 (28),
72 (100). Exact mass for C17H27N: 245.2144. Found
245.2144.
4.5.2. Polymer-bound N-isopropyl-2-(vinylphenyl)ethyl-
amine (3b). The title compound was obtained by a
procedure similar to that for polymer-bound N-isopropyl-
5-(4-vinylphenyl)pentylamine (83% yield). The amine
content determined by elemental analysis (C, 88.41; H,
9.06; N, 2.30) was 1.64 mmol/g. IR (KBr): 3433, 3026,
4.4.6. N-Isopropyl-7-(4-vinylphenyl)heptylamine (4f). By

A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
5009
2962, 2924, 2850, 1602, 1493, 1451, 1377, 1174, 1028, 758,
699, 540.
278 8C for 90 min, the reaction was quenched with
phosphate buffer (pH 7). The resin was filtered off, washed
with CH2Cl2 and H2O, and dried in vacuo at 90 8C for 16 h.
The organic filtrate was washed with brine and dried over
anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the crude product was purified by
preparative TLC or silica-gel chromatography, giving the
b-hydroxycarbonyl compound.
4.5.3. Polymer-bound N-isopropyl-4-(4-vinylphenyl)-
butylamine (3c). The title compound was obtained by a
procedure similar to that for polymer-bound N-isopropyl-5-
(4-vinylphenyl)pentylamine (82% yield). The amine con-
tent determined by elemental analysis (C, 88.97; H, 10.54;
N, 2.38) was 1.70 mmol/g. IR (KBr): 3433, 3026, 2962,
2924, 2850, 1602, 1493, 1451, 1377, 1174, 1028.
4.6.1. 1-Hydroxy-2-methyl-1-phenyl-3-pentanone (2a).
Yield 90% as a colorless oil (Table 1, entry 8); data
consistent with that reported in literatures.39,40
4.5.4. Polymer-bound N-isopropyl-6-(4-vinylphenyl)-
hexylamine (3e). The title compound was obtained by a
procedure similar to that for polymer-bound N-isopropyl-5-
(4-vinylphenyl)pentylamine (73% yield). The amine con-
tent determined by elemental analysis (C, 86.99; H, 10.41;
N, 2.23) was 1.59 mmol/g. IR (KBr): 3313, 3083, 3060,
3027, 2922, 2853, 1666, 1602, 1511, 1492, 1452, 1378,
1362, 1336, 1173, 1029.
4.6.2. 1-(4-Chlorophenyl)-1-hydroxy-2-methyl-3-penta-
none (2b). Yield 88% as a colorless oil (Table 2, entry 2);
data consistent with that reported in a literature.39
4.6.3. 1-Hydroxy-1-(2-methoxyphenyl)-2-methyl-3-
pentanone (2c). Yield 84% as a colorless oil (Table 2,
entry 3). Aldol 2c was further purified by preparative thin-
layer chromatography (silica-gel, hexane/diethyl ether 3:1)
to separate syn-2c and anti-2c as colorless oils; data
consistent with that reported in a literature.39
4.5.5. Polymer-bound N-isopropyl-7-(4-vinylphenyl)-
heptylamine (3f). The title compound was obtained by a
procedure similar to that for polymer-bound N-isopropyl-5-
(4-vinylphenyl)pentylamine (67% yield). The amine con-
tent determined by elemental analysis (C, 87.99; H, 9.88; N,
2.05) was 1.46 mmol/g. IR (KBr): 3315, 3083, 3061, 3027,
2925, 2853, 1660, 1602, 1511, 1494, 1453, 1378, 1337,
1179, 1029.
4.6.4. 5-Hydroxy-4-methyl-7-phenyl-6-hepten-3-one
(2d). Yield 93% as a pale yellow oil (Table 2, entry 4);
data consistent with that reported in a literature.39
4.6.5. 1-Cyclohexyl-1-hydroxy-2-methyl-3-pentanone
(2e). Yield 82% as a colorless oil (Table 2, entry 5); data
consistent with that reported in literatures.41,42
4.6. Aldol reactions using polymer-bound lithium
dialkylamides (1a–f), general procedure
Conditions A. To a suspension of polymer-bound N-iso-
propyl-4-vinylbenzylamine 3a (amine content: 1.68 mmol/
g; particle size: 50–100 mesh; cross-linked with 2 mol% of
divinylbenzene, 750 mg, 1.3 mmol) in THF (6 mL) was
added a hexane solution of butyllithium (1.54 M, 0.78 mL,
1.2 mmol) at rt and the reaction mixture was stirred for
0.5 h. Carbonyl compound (1.0 mmol) in THF (2 mL) was
added dropwise to the reaction mixture at 278 8C and
stirring was continued for 15 min. A THF (2 mL) solution of
aldehyde (1.2 mmol) was added to the mixture at 278 8C.
After keeping the temperature at 278 8C for 90 min, the
reaction was quenched with phosphate buffer (pH 7). The
resin was filtered off, washed with CH2Cl2 and H2O, and
dried in vacuo at 90 8C for 16 h. The organic filtrate was
washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the crude
product was purified by preparative TLC or silica-gel
chromatography, giving the b-hydroxycarbonyl compound.
4.6.6. 5-Hydroxy-4-methyl-7-phenyl-3-heptanone (2f).
Yield 88% as a colorless oil (Table 2, entry 6); data
consistent with that reported in literatures.39,40
4.6.7. 5-Hydroxy-4-methyl-3-octanone (2g). Yield 65% as
a colorless oil (Table 2, entry 7); data consistent with that
reported in literatures.41,42
4.6.8. 2-(Hydroxyphenylmethyl)cyclohexanone (2h).
Yield 82% as a white solid (Table 2, entry 8). Aldol 2h
was further purified by preparative thin-layer chromato-
graphy (silica-gel, hexane/diethyl ether 3:1) to separate syn-
2h and anti-2h as white crystals; data consistent with that
reported in literatures.43,44
4.6.9. 2-(1-Hydroxy-2-methylpropyl)cyclohexanone (2i).
Yield 59% as a colorless oil (Table 2, entry 9); data
consistent with that reported in literatures.44–46
Conditions B. To a suspension of polymer-bound N-iso-
propyl-4-vinylbenzylamine 3a (amine content: 1.68 mmol/
g; particle size: 50–100 mesh; cross-linked with 2 mol% of
divinylbenzene, 750 mg, 1.3 mmol) in THF (6 mL) was
added a hexane solution of butyllithium (1.54 M, 0.78 mL,
1.2 mmol) at rt and the reaction mixture was stirred for
0.5 h. Carbonyl compound (1.0 mmol) in THF (2 mL) was
added dropwise to the reaction mixture at 278 8C and
stirring was continued for 15 min. The mixture was allowed
to warm at rt for 15 min and was cooled to 278 8C again.
Then a THF (2 mL) solution of aldehyde (1.2 mmol) was
added to the mixture. After keeping the temperature at
4.6.10. 2-(1-Hydroxy-3-phenylpropyl)cyclohexanone
(2j). Yield 56% as a viscous oil (Table 2, entry 10); data
consistent with that reported in literatures.47,48
4.6.11. 1-Hydroxy-1-phenyl-3-hexanone (2k). Yield 88%
as a colorless oil (Table 3, entry 3); data consistent with that
reported in a literature.49
4.6.12. 6-Hydroxy-8-phenyl-4-octanone (2l). Yield 93%
as a colorless oil (Table 3, entry 5); IR (neat): 3464, 3027,
2934, 2875, 1708, 1496, 1455, 1408, 1378, 1128, 1098,
1032, 749, 701; 1H NMR (CDCl3): 0.91 (t, J¼7.4 Hz, 3H),

5010
A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
1.53–1.89 (m, 4H), 2.39 (t, J¼7.4 Hz, 2H), 2.47–2.87 (m,
2H), 2.57 (t, J¼6.1 Hz, 2H), 3.49 (s, 1H), 4.00–4.10 (m,
1H), 7.18–7.31 (m, 5H); 13C NMR (CDCl3): 13.5, 16.8,
31.6, 38.0, 45.3, 48.9, 66.7, 125.6, 128.2, 128.3, 141.7,
212.0; MS: (m/z) %: 220 (Mþ, 8), 203 (13), 202 (72), 159
(15), 149 (22), 131 (24), 117 (23), 115 (15), 105 (11), 104
(11), 92 (23), 91 (86), 72 (14), 71 (100), 57 (16), 55 (11).
Exact mass for C14H20O2: 220.1463. Found 220.1465.
134.7, 141.6, 141.9, 145.7, 176.9; Exact mass for C25H41O3
(MþH)þ: 389.3058. Found 389.3056.
4.6.20. (2R p,3R p)-3-Hydroxy-2,4-dimethylpentanoic
acid 2,6-di-tert-butyl-4-methylphenyl ester (2t). Yield
79% as a white solid (Table 4, entry 6); data consistent with
that reported in a literature.53
4.6.21. 3-Hydroxy-2-methylhexanoic acid 2,6-di-tert-
butyl-4-methylphenyl ester (2u). Yield 82% as a white
solid (Table 4, entry 7); mp 93.5–94.4 8C; IR (CHCl3):
3537, 2965, 2874, 1730, 1482, 1421, 1180, 1103; 1H NMR
(CDCl3): 0.95 (t, J¼7.0 Hz, 3H), 1.19–1.62 (m, 25H), 2.31
(s, 3H), 2.78 (quint, J¼7.4 Hz, 1H), 3.49 (d, J¼4.4 Hz, 1H),
3.81–3.89 (m, 0.97H), 4.15–4.19 (m, 0.03H), 7.12 (d,
J¼2.9 Hz, 2H); 13C NMR (CDCl3): 13.5, 14.2, 18.6, 21.6,
31.45, 31.52, 35.2, 35.3, 36.1, 46.3, 72.4, 126.9, 127.1,
134.7, 141.6, 141.9, 145.7, 176.3; Exact mass for C22H37O3
(MþH)þ: 349.2743. Found 349.2744.
4.6.13. 1-Cyclohexyl-1-hydroxy-3-hexanone (2m). Yield
82% as a white solid (Table 3, entry 7); mp 39.2–40.4 8C;
IR (neat): 3364, 3289, 2956, 2934, 2894, 2854, 1705, 1447,
1405, 1377, 1353, 1310, 1270, 1127, 1033, 993, 892, 883;
1H NMR (CDCl3): 0.90–1.41 (m, 9H), 1.55–1.87 (m, 7H),
2.42 (t, J¼7.3 Hz, 2H), 2.48–2.64 (m, 2H), 2.97 (d,
J¼3.6 Hz, 1H), 3.55–3.77 (1H, m); 13C NMR (CDCl3):
13.4, 16.8, 25.9, 26.0, 26.2, 28.0, 28.6, 42.9, 45.4, 46.0,
71.5, 212.4. Exact mass for C12H22O2: 198.1620. Found
198.1593.
4.6.14. 6-Hydroxy-7-methyl-4-octanone (2n). Yield 79%
as a colorless oil (Table 3, entry 9); data consistent with that
reported in a literature.50
4.6.22. 3-Hydroxy-2,N,N-trimethyl-3-phenylpropiona-
mide (2v). Yield 99% as a white solid (Table 5, entry 3);
data consistent with that reported in a literature.54
4.6.15. 1-Hydroxy-5-methyl-1-phenyl-4-hexen-3-one
(2o). Yield 81% as a colorless oil (Table 3, entry 11); IR
(neat): 3448, 3086, 3062, 3030, 2975, 2910, 1681, 1618,
1494, 1449, 1383, 1359, 1204, 1115, 1063, 1043, 1013, 824,
4.6.23. 3-Hydroxy-2,N,N-trimethyl-5-phenylpentana-
mide (2w). Yield 83% as a colorless oil (Table 5, entry
5); IR (neat): 3416, 2936, 1622, 1496, 1456, 1401, 1147,
1
1041, 930; H NMR (CDCl3): 1.10–1.26 (m, 3H), 1.49–
1
800, 701; H NMR (CDCl3): 1.91 (d, J¼1.3 Hz, 3H), 2.18
1.99 (m, 2H), 2.55–2.72 (m, 2H), 2.85–3.02 (m, 7H), 3.59–
3.65 (m, 0.26H), 3.91 (br d, J¼9.2 Hz, 0.74H), 4.20–4.41
(m, 0.26H), 4.73 (br s, 0.74H), 7.15–7.30 (m, 5H); 13C
NMR (CDCl3): 9.7, 15.2, 32.3, 32.4, 35.3, 35.7, 37.3, 37.7,
40.0, 40.2, 70.3, 73.6, 125.6, 128.1, 128.4, 141.9, 142.1,
176.4, 177.5; MS: (m/z) %: 235 (Mþ, 46), 217 (38), 149
(30), 144 (21), 130 (57), 111 (21), 101 (73), 91 (100), 83
(28), 72 (86), 69 (27), 57 (47), 55 (40). Exact mass for
C14H21NO2: 235.1572. Found 235.1570.
(d, J¼1.3 Hz, 3H), 2.82 (s, 1H), 2.84 (d, J¼0.66 Hz, 1H),
3.71 (d, J¼2.4 Hz, 1H), 5.15–5.20 (m, 1H), 6.05 (s, 1H),
7.25–7.40 (m, 5H); 13C NMR (CDCl3): 21.0, 27.8, 52.1,
70.1, 123.6, 125.6, 127.4, 128.4, 143.0, 157.6, 200.6; MS:
(m/z) %: 204 (Mþ, 16), 186 (14), 162 (18), 120 (35), 107
(15), 106 (13), 105 (38), 83 (100), 79 (16), 77 (28), 55 (22).
Exact mass for C13H16O2: 204.1150. Found 204.1153.
4.6.16. 4-Hydroxy-4-phenyl-2-butanone (2p). Yield 80%
as a colorless oil (Table 3, entry 14); data consistent with
that reported in a literature.51
4.6.24. 3-Cyclohexyl-3-hydroxy-2,N,N-trimethyl-
propionamide (2x). Yield 93% as a colorless oil (Table 5,
entry 7); IR (neat): 3418, 2925, 2852, 1623, 1451, 1418,
1401, 1318, 1259, 1160, 1136, 983, 628; 1H NMR (CDCl3):
0.84–1.26 (m, 7H), 1.35–1.44 (m, 1H), 1.60–1.78 (m, 5H),
1.96–2.04 (m, 0.2H), 2.10–2.21 (m, 0.8H), 2.81–3.11 (m,
7H), 3.15–3.34 (m, 0.18H), 3.42–3.52 (m, 0.82H), 4.28 (d,
J¼8.6 Hz, 0.18H), 4.78 (s, 0.82H); 13C NMR (CDCl3): 9.5,
15.6, 26.1, 26.4, 26.5, 28.5, 28.7, 28.8, 29.9, 30.1, 35.3,
36.1, 37.4, 37.8, 39.5, 42.0, 75.4, 79.1, 177.0, 177.8; MS:
(m/z) %: 214 (Mþþ1, 8), 213 (Mþ, 4), 198 (46), 195 (40),
131 (10), 130 (100), 101 (96), 95 (14), 83 (10), 72 (57), 55
(11). Exact mass for C12H23NO2: 213.1729. Found
213.1726.
4.6.17. 3-Hydroxy-2-methyl-3-phenylpropionic acid 2,6-
dimetylphenyl ester (2q). Yield 72% as a highly viscous
colorless oil (Table 4, entry 2); data consistent with that
reported in literatures.52,53
4.6.18. 3-Hydroxy-2-methyl-3-phenylpropionic acid 2,6-
di-tert-butyl-4-methylphenyl ester (2r). The syn/anti ratio
was determined by 1H NMR analysis of the crude product in
1
comparison with the H NMR data of the 3-hydroxy-2-
methyl-3-phenylpropionic acid 2,6-dimethylphenyl ester.52
Yield 92% as a highly viscous oil (Table 4, entry 4); data
consistent with that reported in a literature.53
4.6.25. 3-Hydroxy-2,4,N,N-tetramethylpentanamide
(2y). Yield 98% as a colorless oil (Table 5, entry 9); IR
(neat): 3423, 2961, 2875, 1625, 1508, 1467, 1419, 1401,
4.6.19. (2R p,3R p)-3-Cyclohexyl-3-hydroxy-2-methyl-
propionic acid 2,6-di-tert-butyl-4-methylphenyl ester
(2s). Yield 64% as a highly viscous oil (Table 4, entry 5);
IR (CHCl3): 3547, 2930, 2856, 1728, 1599, 1421, 1366,
1128, 1106; 1H NMR (CDCl3): 1.19–1.82 (m, 32H), 2.31 (s,
3H), 2.91 (quint, J¼7.6 Hz, 1H), 3.53 (d, J¼4.6 Hz, 1H),
3.59 (dt, J¼3.7, 7.5 Hz, 1H), 7.12 (d, J¼3.9 Hz, 2H); 13C
NMR (CDCl3): 13.6, 21.6, 25.3, 26.3, 26.5, 26.7, 30.6,
31.48, 31.52, 35.2, 35.3, 39.6, 43.2, 77.8, 126.9, 127.1,
1
1260, 1163, 1103, 1002, 986; H NMR (CDCl3): 0.85 (d,
J¼7.3 Hz, 2.5H), 0.90 (d, J¼6.6 Hz, 0.48H), 0.98 (d,
J¼6.6 Hz, 0.48H), 1.04 (d, J¼6.6 Hz, 2.5H), 1.13 (d,
J¼7.3 Hz, 2.5H), 1.25 (d, J¼7.3 Hz, 0.48H), 1.63–1.81 (m,
1H), 2.82–3.10 (m, 7H), 3.20–3.33 (m, 0.16H), 3.41 (d,
J¼9.2 Hz, 0.84H), 4.28 (d, J¼7.9 Hz, 0.16H), 4.78 (s,
0.84H); 13C NMR (CDCl3): 9.5, 15.6, 18.2, 18.9, 19.8, 19.9,

A. Seki et al. / Tetrahedron 60 (2004) 5001–5011
5011
22. Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57,
4637–4662.
30.2, 32.2, 35.5, 35.8, 36.7, 37.4, 76.7, 177.7; MS: (m/z) %:
174 (Mþþ1), 173 (Mþ), 158 (52), 155 (20), 140 (17), 130
(100), 101 (83), 100 (20), 73 (19), 72 (96), 57 (15). Exact
mass for C9H19NO2: 173.1416. Found 173.1418.
23. Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew.
Chem. Int. Ed. Engl. 2001, 40, 650–679.
24. McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002,
102, 3275–3300.
25. Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc.
1981, 103, 7620–7629.
Acknowledgements
26. Majewski, M.; Ulaczyk, A.; Wang, F. Tetrahedron Lett. 1999,
40, 8755–8758.
The present work was supported in part by the Fujisawa
Foundation and the Japan Securities Scholarship Foun-
dation. We would like to express our sincere appreciation to
Professor Masao Tomoi (Yokohama National University)
for his valuable comments and discussions.
27. Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem. Commun.
2001, 1722–1723.
¨
28. Johansson, A.; Abrahamsson, P.; Davidsson, O. Tetrahedron:
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29. Asami, M.; Seki, A. Chem. Lett. 2002, 160–161.
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