Reactivity of Lithium β-Ketocarboxylates: The Role of Lithium Salts

Article abstract of DOI:10.1021/jacs.7b08450

Lithium β-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li⁺) with carbon dioxide, readily undergo decarboxylative disproportionation in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable at room temperature in inert atmosphere. The availability of stable THF solutions of lithium β-ketocarboxylates 1(COOLi) in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give α-alkyl ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing group for the selective monoalkylation of lithium enolates 2(Li⁺). The roles of lithium salts in preventing the disproportionation of lithium β-ketocarboxylates 1(COOLi) and in determining the course of the reaction with bases and alkyl halides 3 are discussed.

Full text of DOI:10.1021/jacs.7b08450

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Article
On the Reactivity of Lithium #-ketocarboxylates: the Role of Lithium salts
Mateo Berton, Rossella Mello, Paul G. Williard, and María Elena González-Núñez
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08450 • Publication Date (Web): 08 Nov 2017
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Journal of the American Chemical Society
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On the Reactivity of Lithium β-ketocarboxylates: the Role of
Lithium salts
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Mateo Berton,♣,♠ Rossella Mello,♠ Paul G. Williard,♣ María Elena González-Núñez*♠
♠ Departamento de Química Orgánica, Universidad de Valencia, Avda. Vicente Andrés Estellés s.n., 46100 Burjas-
sot, Valencia, Spain.
♣ Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA
ABSTRACT: Lithium β-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li+) with carbon diox-
ide, readily decarboxylate in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable
at room temperature in inert atmosphere. The availability of stable THF solutions of lithium β-ketocarboxylates 1(COOLi)
in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give α-alkyl
ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing
group for the selective monoalkylation of lithium enolates 2(Li+). The roles of lithium salts in preventing the decarboxyla-
tion and disproportionation reactions of lithium β-ketocarboxylates 1(COOLi), and in determining the course of the reac-
tion with bases and alkyl halides 3, are discussed.
Introduction
electrophiles E (Scheme 1) have been debated around
three alternative pathways whose decarboxylation step
has a different timing in relation to C-C bond formation
(Scheme 2)1,3 namely, a) electrophilic substitution con-
certed with decarboxylation; b) decarboxylation and cap-
ture of enolate 2(M+) by the electrophile, and c) enoliza-
tion, capture of enol intermediate 2(COOM) by the elec-
trophile, and decarboxylation. The actual reaction course
in each case may, however, depend on the specific rea-
gents and conditions used.
Enzymes involved in polyketides and fatty acids synthe-
sis use carbon dioxide as a removable activating group for
performing C-C bond formation reactions at the α posi-
tion of a carbonyl group under mild conditions (Scheme
1).1 Organic chemists have successfully applied this strate-
gy to develop useful synthetic procedures such as classic
malonic and acetoacetic synthesis,2 enantioselective or-
ganocatalytic decarboxylative aldol, Mannich and Michael
reactions,3 and transition-metal catalyzed decarboxylative
C-H bond functionalization.4 The role of β-ketocarboxylic
acids 1(COOH) and their salts 1(COOM) (M: counterion)
as key intermediates in these reactions has prompted
research into the carboxylation of ketones 1 with CO25 and
the decarboxylation of β-ketoacids,6-9 since both steps are
involved in the synthetic sequence (Scheme 1).
The sequence shown in Scheme 1 has been scarcely ap-
plied to alkyl halides 3 (E = R-I or R-Br in Schemes 1 and
2). Notwithstanding, it provides a formal path for the α-
alkylation of starting ketone 1, which may circumvent the
tendency to polyalkylation of ketone enolates
Scheme 2. Reaction paths proposed for the reaction of β-
ketocarboxylates 1(COOM) (M = counterion) with elec-
trophiles E.3
The reactions of β-ketocarboxylates 1(COOM) with
Scheme 1. Carbon dioxide as removable activator for the
α-position of ketones 1. Electrophiles E: RCOSR’, RCOH,
R2C=CHCOR’, H+, among others.
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Methyl iodide (3p) in excess (4 equiv) was added at -78
oC, and the reaction mixture was gently purged with ar-
gon and allowed to warm up in an inert atmosphere. The
solution became clear at ca. -20 oC and subsequently
formed a white solid that remained unchanged up to
room temperature. The reaction mixture was quenched
with aqueous hydrogen chloride and analyzed by gas
chromatography (GC) and mass spectrometry (MS) to
show a ca. 1:1 mixture of cyclohexanone (1a) and 2-
methylcyclohexanone [1a(CH3)], exclusively.
1
2
3
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7
8
2(M+).10 The reaction of ketones 1 with magnesium methyl
carbonate and alkyl halides (the Stiles reaction)11 actually
follows this approach and has found applications in syn-
thesis. Yet it proceeds under harsh conditions (10-fold
excess reagent, dimethylformamide as the solvent, and
high temperatures), and thus fails to take full advantage
of the activation provided by the 1,3-dicarbonyl moiety.
Conversely, organocatalytic decarboxylative C-C bond
forming reactions3 have not been described for alkyl hal-
ides as electrophiles. The importance of β-
ketocarboxylates 1(COOM) as synthetic and biosynthetic
intermediates, and of the CO2-capture reactions and
products with potential applications in synthesis,3,5
prompted us to explore the reaction of lithium β-
ketocarboxylates 1(COOLi) with alkyl halides 3 in tetra-
hydrofuran (THF) as the solvent to disclose its reaction
paths, intermediates and scope.
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The control experiments aimed to capture the interme-
diate species involved, allowed to ascertain the reaction
course under these conditions. First, the reaction mixture
from the carboxylation reaction was quenched with ex-
o
cess chlorotrimethylsilane (TMSCl) at -78 C in CO2 at-
mosphere. The nuclear magnetic resonance (NMR) analy-
sis of a deuterochloroform solution of the residue after
the evaporation of the volatiles showed a mixture of
(Chart 1) trimethylsilyl β-ketocarboxylate 1a(COOTMS)
(keto:enol forms ca. 1:1) (83 %) and trimethylsilyl 2-
(trimethylsilyloxy)-cyclohex-1-ene-1-carboxylate
[2a(TMS,COOTMS)] (17 %).
Herein we report the preparation of stable THF solu-
tions of lithium β-ketocarboxylates 1(COOLi), and the
reactions of these intermediates with nitrogen bases and
alkyl halides 3. The results reported herein illustrate the
reactivity of lithium β-ketocarboxylates 1(COOLi) and
open up new opportunities for their synthetic application.
Chart 1. Products from the capture of the reaction inter-
mediates with TMSCl and dimethyl sulfate/HMPA.
Results and Discussion
The disproportionation. Lithium β-ketocarboxylates
1(COOLi) were prepared in situ by adding a THF solution
of the lithium enolate 2(Li+), generated by the reaction of
the corresponding silylenolether 2(TMS) with methyllith-
ium in anhydrous THF, to a saturated solution of CO2 in
THF at -78 oC (Scheme 3). Reactions were performed
using lithium 2-oxocyclohexane-1-carboxylate 1a(COOLi)
as a model substrate and adamantane as the internal
standard. The experimental procedures are included in
the experimental section and the Supporting Information.
The reaction of ketones 1 with lithium diisopropylamide
proved unsuitable to prepare starting enolate 2(Li+) as
diisopropylamine (DIPA) interfered with the ensuing
carboxylation reaction.12
Second, the reaction mixture was warmed to room
temperature and centrifuged. The solid was treated with
excess chlorotrimethylsilane in anhydrous THF in CO2
atmosphere, and the mixture was evaporated under vacu-
um. The NMR analysis of the residue showed a ca. 1:1
mixture of 2a(TMS,COOTMS) (47 %) and trimethylsilyl
β-ketocarboxylate [1a(COOTMS)] (53 %) (Chart 1). The
analysis of the sample by GC-MS showed that trimethylsi-
lyl β-ketocarboxylate [1a(COOTMS)] decomposed under
the analysis conditions to give the corresponding ketone
1a.
The reaction of enolate 2a(Li+) with CO2 in THF at -78
oC led to the immediate formation of a white solid.
Third, the heterogeneous mixture from the carboxyla-
tion reaction was treated with methyl iodide (3p) (2
equiv) for 90 min. at room temperature, and was
quenched with dimethylsulfate (2 equiv) and hexa-
methylphosphoramide (HMPA) (5 equiv). The analysis of
the supernatant by GC-MS showed the presence of a ca.
1:1 mixture of cyclohexanone (1a) and methyl 2-methyl β-
ketocarboxylate [1a(CH3,COOCH3)] (Chart 1).
Scheme 3. Reaction paths proposed for the reaction of β-
ketocarboxylates 1(COOM) (M = counterion) with elec-
trophiles E.
These
results
established
that
lithium
β-
ketocarboxylate 1a(COOLi) in THF solution dispropor-
tionates at -20 oC in the presence of CO2 to give ketone 1a
and the lithium enolate of lithium β-ketocarboxylate
2a(Li+,COOLi) [henceforth dianion 2a(Li+,COOLi)]
(Scheme 4). The reaction can proceed through the decar-
boxylation of 1a(COOLi) to give enolate 2a(Li+), which
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Table 1. Reaction of trimethylsilylenol ethers 1 with
undergoes a faster acid-base reaction with unreacted
1
lithium β-ketocarboxylate 1a(COOLi) than the competing
substitution with alkyl halide 3p in excess in solution. In
agreement with this, the carboxylation reaction per-
formed by flowing CO2 (1 bar) through a cold THF solu-
tion of enolate 2a(Li+), under which conditions lithium β-
ketocarboxylate 1a(COOLi) forms in the presence of un-
reacted enolate 2a(Li+), produced a 1:1 mixture of dianion
2a(Li+,COOLi) and ketone 1a which remained unchanged
for 4 h at room temperature in CO2 atmosphere. Dianion
2a(Li+,COOLi) would then be the actual nucleophile to
react with methyl iodide (3p) to give lithium α-methyl-β-
ketocarboxylate 1a(CH3,COOLi), which produces the
corresponding α-methyl ketone 1a(CH3) in the acidic
hydrolysis step. Remarkably, the non enolizable lithium
α-alkyl-β-ketocarboxylate 1a(CH3,COOLi) was stable in
solution under these reaction conditions.
methyllithium, CO2, and alkyl halides 3, followed by acid
2
3
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6
7
8
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hydrolysis.a
Product distribution
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Run
1
2c
2(TMS)
2a(TMS)
2a(TMS)
2a(TMS)
2b(TMS)
2b(TMS)
2c(TMS)
2c(TMS)
3
1(R)
1(R) %
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60
7
1
1 (%)
52
3p
3q
3r
1a(Me)
1a(Bz)
1a
1a
1a
1b
1b
1c
1c
1d
37
3
1a(Allyl)
1b(Me)
1b(Bz)
1c(Me)
1c(Allyl)
1d(Me)
93
4
3p
3q
3p
3r
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5c
6c
7
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Scheme 4. Disproportionation of lithium β-
ketocarboxylate 1a(COOLi) and reaction with ICH3 (3p).
66
97
8
2d(TMS) 3p
3
a
The carboxylation was performed by adding a THF solu-
tion of enolate 2(Li) and adamantane as internal standard to
a saturated solution of CO2 in THF at -78 oC. The alkyl halide
In order to verify the impact of the substrate structure
on the reaction course, we explored these reactions for
the enolates 2(Li+) that derived from cyclohexanone (1a),
cyclopentanone (1b), acetophenone (1c) and pinacolone
(1d). The carboxylation of enolates 2(Li+) was performed
o
3 (2 equiv) was added at -20 C. The enolate 2(Li) formed
quantitatively from the silyl enol ether 2(TMS) in all the
b
cases. Determined from GC analysis of the reaction mix-
ture. The values were not corrected for the respective re-
c
sponse factors. Minor amounts of dialkylation products
o
at -78 C, as described above. The reaction mixtures were
placed in an salt-ice bath at -20 C for 30 min, were treat-
were observed.
o
enolate 2b(R,Li+), which reacted with alkyl halide 3 or the
ketone 1b(CH3) present in the reaction medium. The low
reactivity observed for dianion 2d(Li+,COOLi) can be
attributed to the steric hindrance posed by the tert-butyl
group.
ed with a 2-fold excess of alkyl halide 3 under gentle ar-
gon flow, and were then allowed to warm to room tem-
perature upon standing for 15 h. The reaction mixtures
were analyzed by GC-MS after acidic hydrolysis. The re-
sults are shown in Table 1. The analysis by GC-MS of the
aliquots withdrawn from the solutions and quenched with
TMSCl prior to alkyl halide 3 addition showed the for-
mation of doubly silylated derivatives 2(TMS,COOTMS)
in all the cases.
These results revealed that lithium β-ketocarboxylates
1(COOLi) underwent facile disproportionation in THF
solution, even at low temperature and in a CO2 atmos-
phere, and that dianions 2(Li+,COOLi) are the actual
nucleophilic species to react with the alkyl halide 3 in
excess in the solution. A similar behavior has been de-
scribed13 for copper and palladium β-ketocarboxylates
1(COOM) (M = Cu, Pd) in dimethylformamide solution at
high temperatures. The disproportionation reaction se-
verely hampered the application of intermediates
1(COOLi) in synthesis as it depleted ca. half the starting
reagent to give ketone 1.
The reaction was general for a variety of lithium β-
ketocarboxylates 1(COOLi) and led to 2-alkylketone 1(R)
exclusively except for five-membered ring derivative
1b(COOLi), in which case the formation of polyalkylation
products suggested that secondary alkylated lithium β-
ketocarboxylate 1b(R,COOLi) decarboxylated to give
The role of lithium salts. The reaction exhibited a ra-
ther different course when performed in the presence of
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lithium iodide.14 For instance, the NMR analysis of THF-d8
For instance, absence of CO2 facilitates the reaction of
solution of lithium enolate 2a(Li+) and lithium iodide (2
1a(COOLi) with nitrogen bases to generate the dianion
2a(Li+,COOLi) required for the alkylation reaction. Oth-
erwise, CO2 would interfere by forming carbamic acid
derivatives12 or establishing strong Lewis acid-base inter-
actions with the nitrogen base.17 Note that the alkylation
of lithium β-ketocarboxylate 1a(COOLi) requires a quan-
titative acid-base reaction with the base, unlike the base-
catalyzed addition of 1a(COOLi) to carbonyls, imines or
α,β-unsaturated carbonyls in the aldol, Mannich or Mi-
chael reactions,3 where the base is regenerated in the last
proton transfer step which renders the addition product.
1
2
3
4
5
6
7
8
equiv) treated with a flow of CO2 (1 bar) at room temper-
o
ature for 2 h, and quenched with TMSCl at 0 C, showed
the presence of trimethylsilyl β-ketocarboxylate
1a(COOTMS) exclusively, as a ca. 1:2 keto:enol mixture.
The solution of lithium β-ketocarboxylate 1a(COOLi) and
lithium iodide (2 equiv) in THF-d8 proved to be indefi-
nitely stable at room temperature, even after a prolonged
purging of the solution with argon, and was unreactive
toward methyl iodide (3p) (4 equiv), even upon standing
at room temperature for 48 h. The control experiments
established that 1 equiv of lithium iodide sufficed to stabi-
lize lithium β-ketocarboxylate 1a(COOLi) in THF toward
its disproportionation into ketone 1a and dianion
2a(Li+,COOLi) (Eq. 1). This value may change in each case
depending on the variable amounts of lithium salts in the
methyllithium solutions from the reagent’s synthesis or
decomposition upon standing.
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Addition of diisopropylamine (DIPA), hexamethyldisi-
lazane (HMDS) and 1,8-diazabicyclo(5.4.0)undec-7-ene
(DBU), to a 0.2 M solution of lithium β-ketocarboxylates
1a(COOLi) and lithium iodide (1 equiv) in THF purged
with argon at room temperature gave a white solid in all
cases, except for HMDS. The reactions were monitored at
different times by withdrawing aliquots which were
quenched with TMSCl and analyzed by GC. The reaction
with HMDS was performed in THF-d8, and the solution
was analyzed by NMR after quenching with TMSCl under
the same conditions.
The results showed a nearly quantitative formation of
dianion 2a(Li+,COOLi) after 1-10 min in all cases, followed
by its progressive depletion to give a 1:1 mixture of ketone
1a and dianion 2a(Li+,COOLi). The counterion in the
dianion species, Li+ or BH+ [2a(Li+,COOLi) or 2a(BH+,
COOLi)] was not ascertained. Notwithstanding, we will
use the notation 2a(Li+,COOLi) for the dianion formed in
the acid-base reaction of 1a(COOLi) with the base based
on the assumption that presence of lithium iodide in the
reaction medium promotes the ion-exchange in
2a(BH+,COOLi) to give 2a(Li+,COOLi) and BH+I-.
This puzzling behavior is akin to a variety of anomalies
described15 for reactions that involve organolithium rea-
gents in the presence of lithium salts.16 The impact of
lithium salts on the stability of lithium β-ketocarboxylates
1a(COOLi) in THF solution can be attributed to the ox-
ophilic and strongly coordinating character of lithium
ions15,16 which may alter some key factors related to the
decarboxylation reaction, namely: i) the coordination of
the additional lithium cations with the carboxylate anion
stabilizes its negative charge density and renders it less
prone to decarboxylation;6 ii) lithium ions disaggregate β-
ketocarboxylate 1a(COOLi) in solution,16a,b which thus
diminishes its competitiveness as a proton donor toward
the enolate 2a(Li+) that formed in the decarboxylation
step, in relation to the recapture of CO2 (Scheme 4);7 iii)
the additional lithium ions favor either the enol form of
1a(COOLi) or the conformations with the σ-bond to the
carboxylate group placed off the perpendicular to the
carbonyl’s plane, which do not undergo decarboxylation
due to stereoelectronic factors.8,9 Note that the reactions
of dianions 2(Li+,COOLi) with alkyl halides 3 described
above (Table 1) produce lithium halides that may contrib-
ute to the stability of the lithium α-alkyl-β-
ketocarboxylate 1a(CH3,COOLi) formed as a product
observed in the experiments reported in Table 1 (Scheme
4). The impact of the halide anion on these reactions was
not ascertained in this work.14
The fastest disproportionation was observed for HMDS
(1 h). DIPA promoted a more extensive depletion of β-
ketocarboxylate 1a(COOLi) upon standing for long peri-
ods (14 h) to give ketone 1a and lithium diisopropylcar-
bamate(iPr)2NCOOLi. This result indicates that the sec-
ondary amine reacts with the CO2 that evolved from the
disproportionation to give the corresponding carbamic
acid (iPr)2NCOOH,12 which contributes to further neutral-
ize the reaction intermediates. The reaction with DBU led
to a fast and nearly quantitative (91 %) formation of dian-
ion 2a(Li+,COOLi) which remained in solution for ca. 5 h
before starting to slowly deplete to give the ketone 1a.
These results show that nitrogen bases promote the
disproportionation
of
lithium
β-ketocarboxylate
1a(COOLi) even in the presence of lithium iodide, by
probably performing the role of a proton carrier between
the intermediate species. The reaction may proceed
(Scheme 5) through an initial acid-base reaction of
1a(COOLi) and Li+/BH+ exchange to give dianion
2a(Li+,COOLi) and salt BH+I-, followed by the Li+/BH+ ion
exchange of unreacted 1a(COOLi), decarboxylation of the
resulting 1a(COOBH) promoted by H-bonding within the
ion pair,7 and the subsequent annihilation of enolate
The reaction with nitrogen bases. The stability of the
THF solutions of lithium β-ketocarboxylate 1a(COOLi)
and lithium iodide, purged with argon or nitrogen to strip
off CO2, opens up new opportunities to explore the reac-
tivity and applications of these intermediates in synthesis.
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Scheme 5.
Disproportionation
of
lithium
β-
Table 2. Reaction of lithium β-ketocarboxylates 1(COOLi)
with bases 4 and alkyl halides 3, in THF in the presence of
LiI.a
1
2
3
ketocarboxylate 1a(COOLi) catalyzed by nitrogen bases B.
4
5
6
7
O
O
O
H
R
H
R
1) Base
H2O
COO Li
COO Li
2) RHal
(3)
1(COOLi)/LiI
1(R,COOLi)
1(R)
8
9
Substrate
Product Yield
LiI
(equiv)
10
11
12
13
14
15
16
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Run
3
Base
1(COOLi)
1(R)
DBU 1a(Me)
DBU 1a(Bz)
DBU 1a(Allyl)
(%)b
1
2
3p
3q
3r
2
2
2
2
5
5
5
2
1
84
80
1a(COOLi)
3
82
4
3p
3p
3q
3r
DBU 1b(Bz)
DIPA 1b(Me)
DIPA 1b(Bz)
DIPA 1c(Allyl)
82c
93
95
87
5
2a(BH+). The Li+/BH+ ion exchange in β-ketocarboxylate
1a(COOLi) would be the key step in this process as it
promotes the loss of CO2 which triggers the internal acid-
base reaction of enolate 2a(BH+) (Scheme 5). Accordingly,
the disproportionation reaction was the fastest for HMDS
and the slowest for DBU, the weakest and strongest bases
in the series, respectively, with the most and least soluble
conjugate salts, HMDSH+I- and DBUH+I-, respectively.
6
7
1b(COOLi)
8
9
10
11
12
13
3r
DBU 1c(Allyl) 58d
3p
3q
3r
DBU 1c(Me)
DBU 1c(Bz)
DBU 1c(Allyl)
DBU 1d(Me)
DBU 1d(Bz)
DBU 1d(Allyl)
72
81
1
1c(COOLi)
1d(COOLi)
1
83
85
93
93
The reaction with alkyl halides 3. The reactions of
lithium β-ketocarboxylates 1(COOLi) with alkyl halides 3
were performed by adding the base (1.2 equiv) to a 0.2 M
THF solution of 1(COOLi) and lithium iodide purged with
argon, and by treating the reaction mixture with alkyl
halide 3 (1 equiv) for 15 h, at room temperature. The reac-
tion mixture was monitored by withdrawing aliquots
which were quenched with TMSCl and analyzed by gas
chromatography. The reaction mixture was treated with
hydrochloric acid and the organic phase was analyzed by
GC-MS. The reaction was optimized for a series of ketone
enolates 2(Li+) and the results are shown in Table 2.18 The
experimental procedures are described in the Supplemen-
tary Material.
3p
3q
3r
2
2
2
14
a
Reactions performed by adding 1.2 equiv of base, and 1
equiv of 3 (except for 3p: 4 equiv) to a 0.2 M solution of
1(COOLi) (except for 1b(COOLi): 0.16 M) and LiI in THF,
with adamantane used as the internal standard, at r.t. and in
an inert atmosphere, for 15 h. b Determined by the GC analy-
sis of the reaction mixture. Values were not corrected for the
respective response factors. Ketones 1(R) and 1 were the only
products except where noted. c 1b(R,R): 12 %. d 1c(R,R) 12 %.
of lithium cations to the base and β-ketocarboxylate
1(COOLi),16 which hampers both the proton abstraction
by the base, and the Li+/BH+ ion exchange of 1(COOLi)
required for the decarboxylation and disproportionation
steps. Third, excess lithium salts in solution prevents the
reaction of the base with alkyl halide 3 through competi-
tion of the lithium cations with 3 for the basic and nucle-
ophilic nitrogen atom.16 The role of alkali cations as inhib-
itors of the acid-base reactions of nitrogen bases has been
established for the carboxylation of ketones with CO2
promoted in the presence of alkali salts,5h,j,k and even for
the hydrolysis of lithium amides.19
The results in Table 2 illustrate the reactivity of lithium
β-ketocarboxylates 1(COOLi) to nitrogen bases and alkyl
halides 3 and the application of CO2 as a removable di-
recting group to control the reactivity of lithium enolates
2(Li+). The reactions proceeded under mild conditions
and required 1 equiv of alkyl halide 3. Some significant
trends related to the presence of lithium iodide in the
reaction medium were observed in these experiments.
First, alkyl bromides 3 react with lithium iodide to form
the corresponding iodides, which facilitates the SN2 reac-
tion of dianion 2(Li+,COOLi). Second, the acid-base reac-
tion of lithium β-ketocarboxylates 1(COOLi) with the
nitrogen base, and the disproportionation reaction be-
come slower as the lithium salt concentration increases.
These observations can be attributed to the coordination
The intrinsic reactivity of lithium β-ketocarboxylate
1(R, COOLi), formed as the primary reaction product, and
the complex interplay of the different factors and pro-
cesses involved, required the optimization of the reaction
conditions for each case. The reactions of our model lithi-
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um β-ketocarboxylate 1a(COOLi) were performed in the
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presence of 2 equiv of lithium iodide with DBU as the
base (Entries 1-3, Table 2). The reaction of five-membered
cyclic lithium β-ketocarboxylate 1b(COOLi) under the
same conditions led to the formation of doubly alkylated
cyclopentanone 2b(R,R) with a 13 % yield (Entry 4, Table
2). This result suggested that β-ketocarboxylate
1b(R,COOLi) decarboxylates faster than the correspond-
ing six-membered derivative 1a(R,COOLi), probably due
to stereoelectronic factors being more favorable to decar-
boxylation in the former.8,9 DIPA was used as the base in
this case as its ammonium salt, which is more soluble in
the reaction medium than that of DBU (Entries 5-7, Table
2), facilitated the proton transfer to the enolate 2b(Li+, R)
that formed after decarboxylation. The reaction required
a 5-fold excess lithium iodide to minimize the reaction of
DIPA with alkyl halide 3.20
Experimental Section
General. Reagents were purified following standard
procedures. All the reactions were performed by Schlenk
techniques using flame-dried glassware. The reported
yields were determined by gas chromatography (GC) with
a
(5%-phenyl)-methylpolysiloxane capillary column
(length 30 m, internal diameter 0.25 mm, film thickness
0.25 μm). Adamantane was used as the internal standard.
The conversion and yield values were not corrected for
the response factors of the different products. Detailed
experimental procedures and spectra are provided in the
Supporting Information.
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Reactions in the presence of lithium salts (Table 2).
General procedure. Lithium enolate 2a(Li+) was pre-
pared by adding dropwise 0.75 mL of a 1.6 M solution of
methyllithium in diethyl ether (1.2 mmol) to a stirred
solution of 1-(trimethylsilyloxy)cyclohexene (2a(TMS))
(0.195 mL, 1.0 mmol) and adamantane (0.068 g, 0.5 mmol)
The reaction conditions established for our model sub-
strate 1a(COOLi) (Entry 1, Table 2) were not suitable ei-
ther for acetophenone derivative 1c(COOLi) (Entry 8,
Table 2) since the enolizable secondary β-ketocarboxylate
1c(R,COOLi) underwent the same reactions as the start-
ing material to give the dialkylated product. Reactions
were then performed with DBU in the presence of 1 equiv
of lithium iodide (Entries 9-11, Table 2) which promoted a
fast acid-base reaction and rendered dianion
2c(Li+,COOLi) quantitatively thus removing the base from
the reaction medium. DIPA rendered similar results in
this case. Conversely, the lithium β-ketocarboxylate
1d(COOLi) that derived from pinacolone (1d), underwent
the alkylation reaction under the reaction conditions
established for our model substrate 1a(COOLi) (Entries
12-14, Table 2). In this instance the bulky tert-butyl sub-
stituent prevented further reactions of secondary β-
ketocarboxylate 1d(R,COOLi).
o
as the internal standard in THF (2.75 mL) cooled to 0 C.
The reaction mixture was allowed to warm to room tem-
perature and to stand for 1 h. This solution was added
dropwise through a PTFE cannula to a stirred solution of
lithium iodide (0.268 g, 2.0 mmol) in 1.5 mL of THF which
had been previously saturated with CO2 by cooling to -78
oC in a CO2 atmosphere (1 bar) for 1 h. After 5 min at -78
oC under stirring the reaction mixture was warmed to 0 oC
and argon was gently bubbled through for 30 min. After-
wards the solution was allowed to reach room tempera-
ture. The reaction mixture was treated with DBU (0.179
mL, 1.2 mmol) for 30 min, and then with benzyl bromide
(0.119 mL, 1.0 mmol) under stirring. The reaction advance
was monitored by withdrawing 0.1 mL aliquots and
quenching them with chlorotrimethylsilane (TMSCl)
(0.013 mL, 0.1 mmol) at room temperature; samples were
diluted with 1 mL of diethyl ether, filtered (PTFE filter,
pore size: 0.2 μm), and analyzed by GC. Once the reaction
was complete (15 h) the reaction mixture was treated with
0.5 mL of concentrated hydrochloric acid, diluted with 1
mL of diethyl ether, and dried over anhydrous MgSO4.
The GC and GC-MS analyses showed 2-benzylcyclohexan-
1-one 1a(Bz) (80 %) and cyclohexanone 1a (20 %) as the
only products. The reaction mixtures that contained lithi-
um iodide gave 4-iodo-1-butanol as a side product that
derived from the solvent.
Conclusions
The reaction of lithium enolates 2(Li+) with CO2 pro-
vides stable THF solutions of lithium β-ketocarboxylates
1(COOLi) when performed in the presence of lithium
iodide, otherwise lithium β-ketocarboxylates 1(COOLi)
disporportionate at low temperature in the presence of
excess CO2 to give ketone 1 and dianion 2(Li+,COOLi).
The availability of stable THF solutions of lithium β-
ketocarboxylates 1(COOLi) in the absence of CO2 allowed
us to explore the reaction of these intermediates with
nitrogen bases and alkyl halides 3. The complete trans-
formation represents the selective monoalkylation of
enolates 2(Li+) by using CO2 as a removable directing
group. The study described herein discloses the rather
complex behavior of lithium β-ketocarboxylates 1(COOLi)
in THF, and the role of lithium ions as Lewis acids in ion
pairing and the aggregation of basic species in solution,15,16
and the decarboxylation reaction. The availability of sta-
ble solutions of a variety of lithium β-ketocarboxylates
1(COOLi) in THF opens up new opportunities to apply
these intermediates in organic synthesis.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental proce-
dures, NMR spectra, and GC-MS data for the crude reaction
mixtures in Table 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* elena.gonzalez@uv.es
Notes
The authors declare no competing financial interests.
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10) a) Streitwieser, A.; Kim, Y.; Wang, D. Z. R. Org. Lett. 2001,
ACKNOWLEDGMENTS
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Financial support from the Spanish Ministerio de Economía,
Industria y Competitividad (CTQ2016-80503-P), and Fondos
FEDER is gratefully acknowledged. PGW was supported by
NSF grant #1464538. MB thanks the Spanish Ministerio de
Economía y Competitividad for a fellowship (BES-2011-
043933). We thank the SCSIE (Universidad de Valencia) for
access to its instrumental facilities.
8
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ABBREVIATIONS
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THF, tetrahydrofuran; GC, gas chromatography; MS, mass
spectrometry; NMR, nuclear magnetic resonance; HMPA,
hexamethylphosphoramide; DIPA, diisopropilamine; HMDS,
hexamethyldisilazane; DBU, 1,8-diazabicyclo(5.4.0)undec-7-
ene.
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solution and, thus, contributes to prevent the disproportionation
path (Scheme 5). For this reason we performed these reactions
with reactive alkyl halides 3p-r. The use of less reactive alkyl
halides 3 will require further adjustment of the reaction condi-
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