Crossed aldol reaction using polymer-bound lithium amides

Article abstract of DOI:10.1246/cl.2003.342

Polymer-bound lithium amides were used in an aldol reaction. The introduction of a spacer between the polymer backbone and the reactive site was important to enhance yields of the aldol products. The polymer-bound reagent was repeatedly used in the same r

Full text of DOI:10.1246/cl.2003.342

342
Chemistry Letters Vol.32, No.4 (2003)
Crossed Aldol Reaction Using Polymer-bound Lithium Amides
Atsushi Seki, Youichi Takizawa, Fusae Ishiwata, and Masatoshi Asamiꢀ
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501
(Received December 20, 2002;CL-021081)
Polymer-bound lithium amides were used in an aldol
Table 1. Aldol reaction of 3-pentanone with benzaldehyde using polymer-
bound lithium amides 1a–f
reaction. The introduction of a spacer between the polymer
backbone and the reactive site was important to enhance yields of
the aldol products. The polymer-bound reagent was repeatedly
used in the same reaction after the conversion to the lithium
amide.
i-Pr
N
Li
(CH2)nC6H4
O
1)
O
OH
O
OH
1a−f (1.2 equiv),
conditions
2) PhCHO (1.2 equiv),
+
Ph
syn-3
Ph
anti-3
−78 °C, 90 min 3) H3O+
Entry Li-amide
n
Conditionsa 3/%b syn : antic
Lithium dialkylamides are widely employed in organic
synthesis to form various carbanions by deprotonation of weakly
acidic protons in the presence of a variety of functional groups.
For example, the bases form regiodefined and geometrically
controlled enolates from carbonyl compounds to afford crossed
aldol adducts regio- and stereoselectively.1
1
2
3
4
5
6
7
8
9
10
1a
1a
1b
1c
1d
1d
1e
1f
1
1
2
4
5
5
6
7
—
—
A
B
B
B
A
B
B
B
A
B
65
71
78
87
82
90
89
87
88
91
68 : 32
69 : 31
71 : 29
71 : 29
69 : 31
73 : 27
72 : 28
71 : 29
62 : 38
62 : 38
On the other hand, much attention has been directed to
polymer-bound reagents, since polymeric reagents are easily
removed from the reaction mixture by filtration and can be
recycled.2 In spite of the importance of lithium dialkylamides in
organic synthesis, few attempts to prepare and use polymer-
bound lithium amide in organic synthesis were reported. To our
knowledge, Cohen et al. first reported the preparation of a
polymer-bound lithium dialkylamide in 1981,3a and Majewski et
al. reported polymer-supported chiral lithium dialkylamides in
enantioselective aldol reaction in 1999.3b Recently, we have
reported polymer-bound achiral lithium dialkylamides as an in
situ regenerator of chiral bases in a catalytic enantioselective
rearrangement of meso-epoxides.4 Here we wish to report
preparation of cross-linked polymer-bound lithium dialkyl-
amides with spacers between the base site and polymer backbone
and their successful use in crossed aldol reaction.
i-Pr2NLi
i-Pr2NLi
aConditions A: The enolate was generated at ꢁ78 ꢂC for 15 min.
Conditions B: The enolate was generated at ꢁ78 ꢂC for 15 min
and then the resulting mixture was allowed to warm to room temp
for 15 min.
bIsolated yield of aldol 3. cDetermined by 1H-NMR analysis.
with several aldehydes was examined under Conditions B using
1d. The results are summarized in Table 2. The corresponding
aldol adducts were obtained in moderate to good yields. It is noted
that a higher yield and/or syn/anti ratio were obtained in the
reactions using the spacer-modified polymer-bound lithium
amide 1d compared to those obtained with LDA in some cases
In the first place, we examined the aldol reaction between 3-
pentanone and benzaldehyde using 1.2 equiv of polymer-bound
lithium amide 1a4b prepared from polymer-bound N-isopropyl-
p-vinylbenzylamine (2a) and butyllithium. 1-Hydroxy-1-phenyl-
2-methyl-3-pentanone (3) was obtained in 65% yield when the
enolate was generated at ꢁ78 ꢂC for 15 min from 3-pentanone and
1a before the addition of benzaldehyde and stirring the reaction
mixture for 90 min at ꢁ78 ꢂC (Conditions A, Table 1, Entry 1).
The yield was increased to 71% by warming up the reaction
temperature gradually to room temp during the 15 min before the
addition of benzaldehyde at ꢁ78 ꢂC (Conditions B, Table 1,
Entry 2). Then we examined introduction of spacers between the
base site and the aromatic ring of the support to improve the yield
of the reaction, because the modification of polymer-bound
reagents with a spacer sometimes enhanced their performance.5
The yield of 3 was increased gradually as the length of the spacer-
chain became longer, and good yields comparable to that obtained
by employing LDA were attained using polymer-bound lithium
amides 1c–f4b,6{9 (Table 1, Entries 4–10).
Table 2. Aldol reaction of 3-pentanone or cyclohexanone with aldehydes
using 1d
1) 1d (1.2 equiv),
O
O
OH
R3 R1
O
OH
R3
−78 °C, 15 min, and then rt, 15 min
R1
R1
2) R3CHO (1.2 equiv), −78°C, 90 min
+
R2
R2
syn
R2
anti
3) H3O+
Entry R1, R2
R3
Yield/%a,b syn : antib,c
1
2
3
4
5
6
7
8
9
Et, Me
Ph
p-ClC6H4
o-MeOC6H4
90 (91) 73 : 27 (62 : 38)
88 (89) 74 : 26 (77 : 23)
84 (83) 65 : 35 (53 : 47)
trans-PhCH=CH 93 (83) 66 : 34 (60 : 40)
Ph(CH2)2
n-Pr
Ph
Ph(CH2)2
i-Pr
88 (90) 70 : 30 (71 : 29)
65 (70) 72 : 28 (70 : 30)
82 (73) 27 : 73 (25 : 75)
56 (64) 30 : 70 (29 : 71)
–(CH2)4–
59 (61)
3 : 97 (4 : 96)
aIsolated yield. bThe figures in parentheses are the results
obtained by using LDA in place of 1d. cDetermined by 1H-
NMR analysis.
As good results were obtained in the reaction of 3-pentanone
and benzaldehyde, the reaction of 3-pentanone or cyclohexanone
Copyright ꢀ 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.4 (2003)
343
Table 3. Aldol reaction of methyl ketones with aldehydes using 1d
In conclusion, the cross-linked polymer-bound lithium amide
1d with the appropriate spacer promotes crossed aldol reaction
between ketones and aldehydes to afford aldols in up to 93% yield
and is a reusable strong base. Furthermore, the effect of spacer to
increase the reactivity of the polymer-bound lithium amide would
be useful for the attachment of valuable lithium amides, e.g. chiral
lithium amides, onto the polymer.
O
O
OH
R2
1) 1d (1.2 equiv), conditions
2) R2CHO (1.2 equiv), −78 °C, 90 min 3) H3O+
R1
R1
Entry
R1
R2
Ph
Conditionsa Yield/%b
1c
2c
3
4
5
6
7
8
9
Me(CH2)2
B
A
A
A
A
A
A
B
A
67
76
88 (83)d
93 (86)d
82 (79)d
79 (73)d
81
The authors appreciate the financial support from the
Fujisawa Foundation and the Japan Securities Scholarship
Foundation. We thank Prof. Masao Tomoi (Yokohama National
University) for valuable discussions.
Ph(CH2)2
c-C6H11
i-Pr
Me2C=CH
Me
Ph
81 (84)d
80 (85)d
References and Notes
Ph
1
C. H. Heathcock, in ‘‘Modern Synthetic Methods,’’ ed. by R. Scheffold,
Verlag Helvetica Chimica Acta, Basel (1992), Vol. 6, p 1;C. H. Heathcock,
in ‘‘Comprehensive Organic Synthesis,’’ ed. by B. M. Trost and I. Fleming,
Pergamon Press, Oxford (1991), Vol. 2, p 181.
aConditions A, B: see Table 1. bIsolated yield.
cPolymer 1a was used in place of 1d. dThe figures in parentheses
are the results obtained by using LDA in place of 1d.
2
For recent reviews;S. J. Shuttleworth, S. M. Allin, R. D. Wilson, and D.
Nasturica, Synthesis, 2000, 1035;S. V. Ley, I. R. Baxendale, R. N. Bream,
P. S. Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I.
Storer, and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815;Y. R. de
Miguel, J. Chem. Soc., Perkin Trans. 1, 2000, 4213;B. Clapham, T. S.
Reger, and K. D. Janda, Tetrahedron, 57, 4637 (2001);A. Kirschning, H.
Monenschein, and R. Wittenberg, Angew. Chem., Int. Ed. Engl., 40, 650
(2001);C. A. McNamara, M. J. Dixon, and M. Bradley, Chem. Rev., 102,
3275 (2002).
(Table 2, Entries 1, 3, 4, and 7).10
Next, the aldol reaction of 2-pentanone with benzaldehyde
was carried out to examine the regioselectivity of the reaction
using 1a under Conditions B. The aldol adduct, 1-hydroxy-1-
phenyl-3-hexanone, was obtained regioselectively in 67% yield
(Table 3, Entry 1). In contrast to the results in the reaction of 3-
pentanone, Conditions A gave a better yield (76%, Table 3, Entry
2). When the reaction was carried out under Conditions A using
spacer-modified lithium amide 1d, the yield was further improved
to 88% (Table 3, Entry 3). A slightly higher yield compared to
LDA was obtained in every case in the reactions of 2-pentanone
with aldehydes using 1d under Conditions A (Table 3, Entries 3–
6). The enolate was generated regioselectively also from 4-
methyl-3-penten-2-one with 1d, and 1-hydroxy-5-methyl-1-
phenyl-4-hexen-3-one was obtained in 81% (Table 3, Entries 7
and 8). Aside reaction, e.g. 1,4-addition of lithiumamide 1dto the
carbon-carbon double bond of 4-methyl-3-penten-2-one, did not
take place. The reaction of the least hindered ketone, acetone, was
not problematic, and the corresponding crossed aldol product, 4-
hydroxy-4-phenyl-2-butanone was obtained in good yield by the
reaction with benzaldehyde using 1d (Table 3, Entry 9).
As the usefulness of spacer-modified polymer-bound lithium
amide 1d was realized, its recovery and repeated use were
examined. After quenching the reaction, the used polymer-bound
amine 2d was recovered by filtration. The polymer-bound amine
2d was successively washed with dichloromethane and water and
dried under vacuum at 90 ꢂC for 16 h. The polymer was then
treated with butyllithium to regenerate 1d. The regenerated 1d
was used in the same reaction between 3-pentanone and
benzaldehyde. The yield and syn/anti ratio of 3 did not change
significantly after the polymer 1d was used five times (Table 4).
3
a) B. J. Cohen, M. A. Kraus, and A. Patchornik, J. Am. Chem. Soc., 103,
7620 (1981). b) M. Majewski, A. Ulaczyk, and F. Wang, Tetrahedron Lett.,
40, 8755 (1999).
4
5
a) M. Asami and A. Seki, Chem. Lett., 2002, 160. b) A. Seki and M. Asami,
Tetrahedron, 58, 4655 (2002).
For example;M. Tomoi and W. T. Ford, in ‘‘Syntheses and Separations
Using Functional Polymers,’’ ed. by D. C. Sherrington and P. Hodge, John
Wiley & Sons, New York (1988), p 181;M. Tomoi, in ‘‘Handbook of Phase
Transfer Catalysis,’’ ed. by Y. Sasson and R. Neumann, Blackie Academic
& Professional, London (1997), p 424.
6
7
8
N-Isopropyl-2-(vinylphenyl)ethylamine, a monomer for the preparation of
1b, was prepared from divinylbenzene and isopropylamine in the presence
of lithium isopropylamide;M. Maeda, Y. Nitadori, and T. Tsuruta,
Makromol. Chem., 181, 2245 (1980).
Monomers for preparation of 1c–f were prepared by the treatment of excess
isopropylamine with !-bromoalkylstyrenes, which were obtained accord-
ing to the literature;M. Tomoi, E. Ogawa, Y. Hosokawa, and H. Kakiuchi,
J. Polym. Sci., Polym. Chem. Ed., 20, 3015 (1982).
Selected data for isopropyl[5-(4-vinylphenyl)pentyl]amine, a monomer for
polymer-bound amine 2d: IR(neat): 3291, 3085, 2964, 2930, 2856, 1630,
;
1562, 1512, 1461, 1378, 1362, 842, and 730 cmꢁ1 1H-NMR (270 MHz,
CDCl3) ꢀ 1.04 (6H, d, J ¼ 6:3 Hz), 1.26–1.41 (2H, m), 1.45–1.54 (2H, m),
1.56–1.68 (2H, m), 2.57 (2H, t, J ¼ 7:3 Hz), 2.60 (2H, t, J ¼ 7:6 Hz), 2.77
(1H, sept, J ¼ 6:3 Hz), 5.18 (1H, dd, J ¼ 10:9 Hz, 1.0 Hz), 5.70 (1H, dd,
J ¼ 17:5 Hz, 1.0 Hz), 6.69 (1H, dd, J ¼ 17:8 Hz, 10.9 Hz), and 7.12–7.34
(4H, m).
9
Selected data for polymer-bound amine 2d: ꢁ50 þ 100 mesh polymer-
bound isopropyl[5-(4-vinylphenyl)pentyl]amine: IR(KBr) 3083, 3060,
2925, 1493, 1377, 836, 758, and 699 cmꢁ1;Anal. Calcd for
(C8H8)0:78ꢃ(C16H25N)0:2ꢃ(C10H10
)0:02: C, 88.99;H, 8.86;N, 2.15%. Found:
C, 88.51;H, 9.05;N, 2.35%.
10 General experimental procedure using 1d: To a suspension of ꢁ50 þ 100
mesh polymer-bound isopropyl[5-(4-vinylphenyl)pentyl]amine (2d)
(1.68 mmol/g, 0.78 g, 1.3 mmol) in THF (6 mL) was added a hexane
solution of butyllithium (1.58 M, 0.76 mL, 1.2 mmol) at room temp and the
reaction mixture was stirred for 0.5 h. Ketone (1.0 mmol) in THF (2 mL)
was added dropwise to the reaction mixture at ꢁ78 ꢂC and stirring was
continued for 15 min. After the mixture was allowed to warm to room temp
for 15 min, aldehyde (1.2 mmol) was added to the mixture at ꢁ78 ꢂC. After
keeping the temperature at ꢁ78 ꢂC 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 ꢂC for 16 h. The organic filtrate
was washed with brine and dried over anhyd Na2SO4. After removal of the
solvents under reduced pressure, the crude product was purified by
preparative TLC or silica-gel chromatography, giving the b-hydroxy
ketone.
Table 4. Reuse of 1d
1) 1d (1.2 equiv),
O
O
OH
O
OH
Ph
−78 °C, 15 min, and then rt, 15 min
2) PhCHO (1.2 equiv), −78 °C, 90 min
3) H3O+
+
Ph
syn-3
anti-3
Batch No.
Yield/%a
1
2
3
4
5
6
90
87
89
90
89
89
syn : antib 73 : 27 70 : 30 69 : 31 70 : 30 71 : 29 69 : 31
aIsolated yield of aldol 3. bDetermined by 1H-NMR analysis.