An expedient preparation of amine-free lithium enolates using immobilized amide reagents

Article abstract of DOI:10.1016/j.tetlet.2012.12.067

Amine-free lithium enolates can be prepared by a simple procedure using polymer-immobilized lithium amides derived from known, easily accessible immobilized secondary amines, or from a new bidentate amine [lithium diisopropylamide (LDA) or lithium cyclohe

Full text of DOI:10.1016/j.tetlet.2012.12.067

Tetrahedron Letters 54 (2013) 1103–1106
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An expedient preparation of amine-free lithium enolates using
immobilized amide reagents
⇑
Ryszard Lazny , Karol Wolosewicz
Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Amine-free lithium enolates can be prepared by a simple procedure using polymer-immobilized lithium
amides derived from known, easily accessible immobilized secondary amines, or from a new bidentate
amine [lithium diisopropylamide (LDA) or lithium cyclohexylisopropylamide (LICA) analogues]. The pro-
cedure involves physical separation of the polymeric amine reagent and the enolate formed by simple
washing with solvents. The amine-free enolates were identified by their characteristic NMR signals in
THF solution. The enolates (and an azaenolate) obtained were used in selected reactions with electro-
philes (PhCHO, MeCHO, PhCH = CHCOCN, BnBr) giving improved results. The higher reactivity of the lith-
ium enolates toward ‘difficult electrophiles’ is demonstrated by quantitative levels of deuterium
incorporation on D2O quenching, where the standard LDA-based method, that is, in the presence of amine
gives a ca. 50% yield. Recycling of used polymers via the ‘filtration procedure’ is also easier and uncom-
plicated by possible side reactions with electrophiles and their possible effects on the polymeric regents.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 25 September 2012
Revised 26 November 2012
Accepted 13 December 2012
Available online 25 December 2012
Keywords:
Base-free enolates
Deprotonation
Lithiation
Polymeric reagents
Polymer-supported reagents
Lithium enolates of ketones, esters, and other carbonyl com-
pounds are seemingly simple and widely used nucleophilic reac-
tants in organic synthesis.1,2 Lithiated carbonyl compounds are
most conveniently prepared by deprotonation with lithium amide
bases (LDA, LiHDMS, LICA, LiTMP, etc.).3 The complex aggregation
of enolates with amine by-products,4–7 excess lithium amides
used,8,9 and donor solvents, as well the associated equilibria10 are
not appreciated widely by organic chemists. In synthetic practice
the complexation and aggregation of these reagents with secondary
amine by-products formed from the lithium amides used is usually
not considered, although it carries important consequences.5,11–13 It
has been shown that the amines present in the reaction mixtures
bind with metal enolates and influence the reactivity and selectivity
of their reactions.4 Most notable is the hindered alkylation14 and
deuteration4 of enolates prepared using, for example, LDA, which
may be rationalized by internal proton return.15 In order to improve
the alkylation yield and deuterium incorporation, special protocols
were devised.5,14,16 Amine-free enolates can be prepared by a few
procedures and are used for structural and physicochemical stud-
ies.17 Amine-free enolates result from reactions of isolated silyl enol
ethers with methyllithium18 or t-BuOLi.19,20 Some ester enolates
prepared with LDA in hexane solutions precipitate and can be iso-
lated and crystallized as amine-free solids.21 Volatile amines, such
as DIPA formed from LDA, present in the enolate–amine mixture,
can be removed by evaporation under vacuum.22 There is however,
no simple preparative, one-step procedure for making solutions of
lithiated amine-free ketones, esters, or like C–H acids susceptible
to nucleophilic additions of alkyllithiums. All the current methods
require manipulations of sensitive enolates (evaporation, crystalli-
zation, filtration, etc.) and/or additional synthetic steps (preparation
of silyl ether derivatives).
During our studies on deprotonations of covalently-immobi-
lized ketones (mostly nortropinone derivatives)23–25 with chiral
lithium amides, we observed that the complexation of the lithium
amides with ketones (or chiral amine by-products with ketone
enolates), which is believed to be involved in the enantioselective
differentiation,13 is weak enough to allow for washing of the chi-
ral reagents from the polymeric support.25 This prompted us to
see if a reversed situation, that is, immobilized lithium amide
and dissolved ketone, could be used for the preparation of
amine-free enolates. Utilization of this simple notion has not been
reported, to the best of our knowledge. Immobilized lithium
amide reagents, both chiral26–28 and achiral,29 have been used
in reactions of ketone enolates including aldol reactions,26,27 sily-
lations,28 and other reactions.27,30 However, in all the reported
procedures the reactions with electrophiles were effected in the
presence of polymeric amines, and washing of the polymeric car-
rier was performed after completion of the reaction and quench-
ing. This is likely based on the assumption of strong binding
(aggregation) of the resulting enolates with secondary amines,
and/or the necessary presence of the amine in the reaction with
the electrophile. Herein, we report that amine-free enolates can
be separated from polymers and can be used advantageously in
synthetic reactions.
⇑
Corresponding author. Tel.: +48 85 745 7834; fax: +48 85 745 7589.
E-mail address: lazny@uwb.edu.pl (R. Lazny).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.067

1104
R. Lazny, K. Wolosewicz / Tetrahedron Letters 54 (2013) 1103–1106
Table 2
X
Efficiency of ketone enolate syntheses (Scheme 2)
N
N
N
X
Lithium
amide
Ketone
Conversion of
ketone into
lithium enolate
in filtered
Washed
lithium
enolate
from
Ketone
extracted
from polymer
after
1: X = H 1a: X = Li
2: X = H 2a: X = Li
solution
polymer
(%)
quenching (%)
O
N
X
1a
2a
3a
2a
2a
a
a
a
-Tetralone
-Tetralone
-Tetralone
P96
P98
P95
P98
P98
80
74
46
70
20
25
55
20a
nd
3 :X = H 3a: X = Li
Figure 1. Immobilized amines and the corresponding lithium amides tested in this
Tropinone
N-Benzylnor-
granatanone
study.
P98
2a
Cyclohexanone P98
74
10a
iso-propylamine
a
The low overall recovery results from loss of more volatile ketones during
or
evaporation of solvents.
i-Pr
1
2
1a
2a
HN
N
H
n-BuLi
Cl
THF
or
The polymer-supported secondary amine precursors of the
amides were prepared from Merrifield gel by standard methods
(Scheme 1, Table 1).
i-Pr
3
3a
Merrifield
polymer
HO
N
H
After a typical reaction of the polymeric lithium amide and the
test ketone in THF, the liquid phase was separated from the poly-
mer and the polymer washed with a small portion of solvent
(Scheme 2).31 Direct NMR analysis (via the No-D NMR technique)32
of the THF solutions showed high conversions into enolates (Ta-
ble 2) as judged from the integration of characteristic enolate
and ketone signals. For comparison the enolates were prepared
using the literature method, that is, repetitive vacuum evapora-
tions of mixtures resulting from reaction of LDA and the ketones.22
The mass of the ketones formed from the enolates and recovered
from the polymer also indicated high, although not quantitative,
enolate extraction (Table 2). The estimated yield of enolate extrac-
tion in the case of volatile ketones such as tropinone or cyclohex-
anone was lower due to their volatility; this could also be inferred
from the yields of the products in the subsequent reactions of the
enolates with electrophiles (e.g., the aldols, Scheme 2).
Scheme 1. Preparation of polymer-supported secondary amine precursors of
polymeric lithium amides.
Table 1
Loading and yield of the prepared supported amines
Amine Loadinga
(mmol/g)
Theoretical loading
(mmol/g)
Yield of aminationa
(%)
1
2
3
1.61b
1.44b
0.850c
1.64b
1.44b
1.08c
98
100
79
a
Based on gravimetric analysis of the amount of HCl released or bound by the gel
(mass of Et3NÁHCl).
b
Prepared from high-loading Merrifield polymer (Fluka, 1.70 mmol/g).
Prepared from standard-loading Merrifield polymer (Novabiochem 1.20 mmol/g).
c
From these data in Table 2, it is clear that the simple amide 1a
and the bidentate (LICA analogue 2a) outperform the spacer-
modified analogue of LDA 3a. The much lower recovery (extraction)
of enolates from 3a is most likely a result of higher affinity of
lithium to oxygen. Binding of lithium to the tertiary nitrogen atom,
although weaker than to oxygen, could also be responsible for
slightly diminished enolate recovery from 2a compared to simple
amide 1a.
To test the hypothesis, four ketones (a-tetralone, tropinone,
cyclohexanone, and N-benzylnorgranatanone) were selected and
used as probes. Possible enolate washing from three polymer-
supported amide reagents (1a, 2a, 3a, Fig. 1) was best assessed using
the most suitable ketone for gravimetric analysis, a-tetralone. The
Li amides derived from amines 1–3 represented immobilized
LDA and lithium cyclohexylisopropylamide (LICA). The additional
nitrogen atom in 2 was expected to stabilize the amide owing to
its bidentate nature and chelation of lithium,13 making the reagent
robust and easier to prepare and to work with.
Characteristic NMR data of representative enolates (including
one ester) obtained directly from the THF solutions washed off
the polymer 2, are shown in Table 3.
1, 2 or 3
1a, 2a or 3a
O
XLi
X
electrophile
E
α
R1
H
R1
R1
β
R2
R2
electrophiles:
MeCHO
FILTRATION
R2
5
ketone, ester
or
amine-free enolate 4
or azaenolate
solution
X = O, N-N(Me)2
PhCHO
PhCH=CH(CO)CN
BnBr
dimethyl hydrazone
O
H
OH
O
OH
O
OH
O
O
H
H
N-NMe2
Ph
O
OH
Ph
Ph
Ph
N
N
N
Me
N
Ph
Bn
Me
Me
Me
5e, 91%,
5d, 92%,
exo, anti-5c, 92%,
exo, anti 98%
exo, anti-5a and exo, syn-5a
anti-5b, 87%,
anti/syn 75:25
purity > 90%
purity > 97%
yield and selectivity in Table 4
Scheme 2. Selected reactions of amine-free lithium enolates and azaenolates.

R. Lazny, K. Wolosewicz / Tetrahedron Letters 54 (2013) 1103–1106
1105
Table 3
Characteristic 1H NMR and 13C NMR data of selected lithium enolates 4 obtained via the method shown in Scheme 2
Carbonyl compound
1H NMR (400 MHz) spectra recorded
in THF using the No-D method
13C NMR (100 MHz) spectra recorded
in THF using the No-D method
1H b
Others
13C
a
13C b Others
Cyclohexanone
4.11 (br s, 1H)
1.98–1.95 (m, 2H), 1.90–1.87 (m, 2H), 1.62–1.58 (m, 2H),
1.48–1.44 (m, 2H)
159.6 89.6
33.9, 25.8, 25.2, 24.7
Cyclopentanone
3-Pentanone
(E and Z)
N-Methyl-4-
piperidone
3.82 (d, J = 1.5 Hz, 1H)
3.95–3.85 (m, 1H)
1.20–1.16 (m, 2H), 2.02–1.98 (m, 2H)a
166.9 88.1
163.9 85.6
163.6 84.3
157.9 88.4
33.5, 29.8, 23.0
27.4, 13.3, 12.9
33.3, 12.8, 11.3
56.4, 54.8, 46.4, 34.6
2.05–1.95 (m, 2H), 1.52–1.42 (m, 3H), 1.05–0.95 (m, 3H)
4.04 (br s, 1H)
2.82–2.18 (m, 2H), 2.40 (t, J = 5.8 Hz, 2H), 2.19 (s, 3H),
2.00–1.97 (m, 2H)
a-Tetralone
4.96 (t, J = 4.6 Hz, 1H)
7.87 (d, J = 7.6 Hz, 1H), 7.07–6.96 (m, 3H), 2.75 (t, J = 7.2 Hz,
2H), 2.35–2.29 (m, 2H)
157.9 94.5
139.4, 138.5, 126.4, 126.1, 125.7,
123.2, 30.8, 24.1
Acetophenone
Tropinone
4.33 (s, 1H), 4.08 (s, 1H) 7.80 (d, J = 7.3 Hz, 2H), 7.21–7.17 (m, 2H), 7.13–7.09 (m, 1H) 166.4 80.3
144.7, 127.8, 126.6, 126.3
60.2, 59.2, 40.2, 36.7, 36.4, 30.5
4.17 (d, J = 4.9 Hz, 1H)
3.02 (d, J = 4.7 Hz, 2H), 2.41–2.36 (m, 1H), 2.24 (s, 3H),
1.92–1.88 (m, 1H), 1.62–1.58 (m, 2H), 1.43–1.35 (m, 2H)
1.10 (s, 9H)
156.9 94.2
t-Butyl acetate
4.51 (br s, 2H)
165.8 87.1
35.5, 28.9
a
Some enolate signals were masked by solvent signals (THF).
Table 4
Selectivity in the aldol reaction of tropinone lithium enolate depending on the presence of an amine and the conditions used
Entry
Reaction of the ketone with the lithium amide
Time Temperature (°C)
Enolate generated with LDA—reaction in the presence of amine (DIPA)
Reaction of the enolate with PhCHO
Yield (%)
Selectivity (exo, anti to exo, syn)
Time
Temperature (°C)
1
2
30 min
30 min
À78
10 min
10 min
À78
95
98:2
25:75
a
0
0
58 (12% of by-products)
Enolate generated with immobilized lithium amide 2a—reaction without separation of the enolate from the polymeric amine
a
a
3
4
4 h
2 h
À78
2 h
10 min
À78
84 (33% of by-products)
60 (20% of by-products)
54:46
17:83
0
0
Enolate generated with immobilized lithium amide 2a—amine-free reaction with separated polymeric amine
5
6
7
8
9
4 h
30 min
2 h
À78
À78
0
0
À78
10 min
10 min
10 min
10 min
10 min
À78
À78
À78
0
69
71
61
56
60
99:1
98:2
97:3
15:85
93:7
30 min
4 ha
À78
a
Formation of bisaldol and other unidentified products was evident from NMR analysis of the reaction mixture.
The THF solutions of enolates, filtered from the polymeric car-
Recycling of polymers 1 and 2 after repetitive use with various
ketones was tested for up to five cycles with no detectable detri-
mental effect on the activity, loading, or purity of the prepared
products, contrary to the procedure without enolate separation.
Physical separation of the lithiation step from the electrophilic
reaction prevents any problems including the known alkylation
of lithium amide precursors (secondary amines).4
rier were used directly in reactions with electrophiles. The proce-
dure provided the simplest way for performing amine-free
enolate reactions. Comparison of the results of the aldol reaction
of tropinone with benzaldehyde under amine-free conditions, that
is, an enolate solution filtered from the polymeric reagent, with the
standard method, that is, the reaction in the presence of polymeric
amine, showed better control over side reactions giving less
bis-aldol and other unidentified by-products (Table 4). The diaste-
reoselectivity found was the same as with LDA in solution. Inter-
estingly, changing to amine-free conditions was helpful for a
higher reaction temperature with benzaldehyde (Table 4, 0 °C).
At higher temperatures (generally >À18 °C), the reaction in the
presence of amines, regardless of polymeric or DIPA, was severely
complicated by by-products. Moreover, the filtered enolates re-
acted with other electrophiles (Scheme 2) giving better results.33
The yields and crude product purities (typically >95% by NMR)
compared favorably with those results under regular conditions
(ca. 75% yield after purification).34,35 Attempted direct alkylation
The new method was found to be valuable for the generation of
enolates for selective deuteration. Deuteration of, LDA or other
lithium amide generated, enolates is known to be hindered4 by
the internal proton return phenomenon.15 Several methods for
improving the scarce deuterium incorporation after quenching
enolates with heavy water have been proposed including addition
of an extra equivalent of n-BuLi after deprotonation,4 removal of
the amine, or the use of silyl enol ethers.16 Use of the polymeric
lithium amide reagent combined with its separation before
quenching the enolate with D2O offers a simple (as exemplified
by
a
-tetralone reactions in Scheme 3)42 and highly effective means
-deuteration of carbonyl compounds.43 The mono-
of selective
a
of
a
-tetralone enolate was however plagued by polyalkylation.
deuteration of the amine-free enolate prepared both by tedious
repetitive evaporation of DIPA, or by polymeric amide/filtration
achieves a quantitative level, as detected by NMR analysis (Table 5).
Quenching the enolate-amine aggregate5 with D2O gave, in our
hands at best, ca. 50% deuterium incorporation.
This could be circumvented by the use of azaenolate (a dim-
ethylhydrazone derivative)36 and a suitable carbonyl regenerating
method.37,38 In light of the known lithiation of polymer-immobi-
lized hydrazones,39–41 it was not surprising that the reversed case
of polymeric amide reaction followed by filtration and benzylation
(BnBr) was also effective (91%, Scheme 2).
In conclusion, we have shown that contrary to current
common practice, lithium enolates can be separated from the

1106
R. Lazny, K. Wolosewicz / Tetrahedron Letters 54 (2013) 1103–1106
16. Eames, J.; Weerasooriya, N.; Coumbarides, G. S. Eur. J. Org. Chem. 2002, 181–
i-Pr
Li
187.
N
O
17. Kolonko, K. J.; Biddle, M. M.; Guzei, I. A.; Reich, H. J. J. Am. Chem. Soc. 2009, 131,
11525–11534.
18. Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462–4464.
19. Duhamel, P.; Cahard, D.; Poirier, J.-M. J. Chem. Soc., Perkin Trans. 1 1993, 2509–
2511.
i-Pr
H
D2O
LDA
O
O
20. Cahard, D.; Duhamel, P. Eur. J. Org. Chem. 2001, 1023–1031.
21. Rathke, M. W.; Sullivan, D. F. J. Am. Chem. Soc. 1973, 95, 3050–3051.
22. Kim, Y. J.; Bernstein, M. P.; Roth, A. S. G.; Romesberg, F. E.; Williard, P. G.; Fuller,
D. J.; Harrison, A. T.; Collum, D. B. J. Org. Chem. 1991, 56, 4435–4439.
23. Lazny, R.; Nodzewska, A. Tetrahedron Lett. 2003, 44, 2441–2444.
24. Lazny, R.; Nodzewska, A.; Sienkiewicz, M. Polish J. Chem. 2006, 80, 659–662.
25. Lazny, R.; Nodzewska, A.; Sienkiewicz, M. Lett. Org. Chem. 2010, 7, 21–26.
26. Majewski, M.; Ulaczyk, A.; Wang, F. Tetrahedron Lett. 1999, 40, 8755–8758.
27. Majewski, M.; Ulaczyk-Lesanko, A.; Wang, F. Can. J. Chem. 2006, 84, 257–268.
28. Ma, L.; Williard, P. G. Tetrahedron: Asymmetry 2006, 17, 3021–3029.
29. Seki, A.; Ishiwata, F.; Takizawa, Y.; Asami, M. Tetrahedron 2004, 60, 5001–5011.
30. Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981, 103, 7620–7629.
31. General procedure for the preparation of the amine-free enolate solution of 4: The
immobilized amine (1, 0.600 g, 1.61 mmol/g, 0.966 mmol, placed in a solid-
phase synthesis vessel fitted with a sintered glass filter disc combined with a
siphon tube and stopcock) was dried under vacuum in a desiccator for 24 h,
flushed with argon for 10 min, washed with THF (3 Â 5 mL), then suspended in
THF (4 mL), and the suspension cooled to 0 °C. After 15 min, n-BuLi (2.5 M in
hexanes, 1.2 mL, 3.0 mmol) was added. The suspension was intermittently
agitated by a flow of argon (the polymer turned brown). After 1.5 h, the THF
solution was separated by applying a positive pressure of argon and the gel
washed with THF (4 Â 5 mL)-the filtered solutions were discarded. The
polymeric gel (lithium amide) was covered with THF (<1 mL) and the
suspension was cooled to À78 °C. A solution of a ketone or other enolate
precursor (0.80 mmol) in THF (2 mL) was added dropwise and the mixture
agitated intermittently for 1.5 h. The enolate solution was siphoned from the
polymer through a sintered glass filter, and collected in a flask. For the NMR
analysis in THF, the solution was warmed to, rt and an aliquot transferred (ca.
1 mL, using a syringe) to a dry, Ar-filled and sealed with a septum NMR tube.
The spectra in THF were recorded at once by the No-D NMR method.
32. Hoye, T. R.; Eklov, B. M.; Ryba, T. D.; Voloshin, M.; Yao, L. J. Org. Lett. 2004, 6,
953–956.
evaporation
of DIPA
D
H
Li
O
5f
α-tetralone
H
1. amide 2
D2O
2. filtration
Scheme 3. Deuteration of
amine-free enolate.
a-tetralone enolate via an amine-aggregate and via an
Table 5
Efficiency of deuteration of the enolate via Scheme 3
Method of lithium enolate
generation
Deuteration of ketone (% deuterium
incorporation) by 1H NMR
LDA
48–51
LDA, evaporation of DIPA
110–112a
Lithium amide 2a, filtration 104–106a
a
A level of deuteration exceeding 100% (by NMR) is the result of a small per-
centage of a,a-dideuterated ketone being present.
polymer-supported reagents used to generate them (lithium
amides and amines), and used favorably for reactions with
electrophiles. Filtration from the polymeric reagents is the simplest
method, conceptually and technically, for making amine-free
enolates for spectroscopic and physicochemical studies. The
obtained lithiated derivatives react cleanly minimizing product
purification. Recycling of the polymeric reagents used in this way
is also unproblematic.
33. Typical procedure for the amine-free enolate aldol reaction: To an immobilized
lithium amide 2a prepared from immobilized amine (2, 0.600 g, 1.44 mmol/g,
0.865 mmol), was added
a solution of N-benzylnorgranatanone (0.154 g,
0.672 mmol) in THF (3 mL) and the mixture was agitated. After 1.5 h the
solution was separated from the polymeric reagent (siphoned from the
polymer through a sintered glass filter) and collected in a flask cooled to
À78 °C. The polymeric gel was additionally washed with THF (3 Â 5 mL) and
the washings were combined with the siphoned filtrate and cooled to À78 °C.
Benzaldehyde (0.09 mL, 0.88 mmol) was added to the combined solutions, and
the resulting mixture was stirred for 15 min. The reaction was quenched with
saturated aqueous NH4Cl solution (5 mL) and the mixture diluted with H2O
(15 mL) and extracted with CH2Cl2 (3 Â 15 mL). The combined extracts were
dried (Na2SO4) and concentrated under vacuum to give 9-benzyl-2-[1-
hydroxybenzyl]-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-5c) as a yellow oil
(0.221 g, 98%). The polymeric reagent was washed (H2O, MeOH, THF), dried
and reused in other experiments.
Acknowledgments
This work was supported by the University of Bialystok
(BST-125) and the National Science Center, Poland (Grant No.
NN204 546939). The authors are grateful to Dr. L. Siergiejczyk for
recording the NMR spectra.
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lithium
hexamethyldisilazide;
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2,2,6,6-
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42.
a-Tetralone was suitable for testing deuteration because of its low volatility
and lack of a basic amine nitrogen, in contrast to the other ketones used in this
study.
43. Typical procedure for the amine-free enolate deuteration:
A solution of a-
tetralone [3,4-dihydronaphthalen-1(2H)-one, 0.154 g, 0.672 mmol] in THF
(3 mL) was added to a suspension of lithium amide 2a (0.600 g, 1.44 mmol/g,
0.865 mmol) at À78 °C and the mixture was agitated intermittently by a flow
of argon. After 1.5 h, the solution was siphoned from the polymer through a
sintered glass filter and collected in a flask cooled to À78 °C. The polymer was
washed with THF. D2O (0.5 mL, 22.5 mmol) was added to the combined, cooled
to À78 °C, filtrate and the resulting mixture was stirred for 2–5 min, then dried
over anhydrous CaSO4, filtered, and the drying agent washed (THF 2 Â 5 mL).
The combined organic solutions were concentrated under vacuum to give 2-
deutero-3,4-dihydronaphthalen-1(2H)-one (5f).
12. Reich, H. J. J. Org. Chem. 2012, 77, 5471–5491.
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Yamamoto, Y.; Tomioka, K.; Maddaluno, J. Org. Lett. 2009, 11, 1907–1910.
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