Double reformatsky reaction: Divergent synthesis of δ-hydroxy-β- ketoesters

Article abstract of DOI:10.1021/jo400408t

The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of δ-hydroxy-β-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters.

Full text of DOI:10.1021/jo400408t

Article
pubs.acs.org/joc
Double Reformatsky Reaction: Divergent Synthesis of δ‑Hydroxy-β-
ketoesters
Masahiro Mineno,* Yasuhiro Sawai, Kazuaki Kanno, Naotaka Sawada, and Hideya Mizufune
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 2-17-85, Juso-honmachi,
Yodogawa-ku, Osaka 532-8686, Japan
S
* Supporting Information
ABSTRACT: The double Reformatsky reaction, tandem
addition of two molecules of zinc alkanoate to a carbonyl
compound, and its synthetic application to a series of δ-
hydroxy-β-ketoesters has been developed. The key to
accelerate the double Reformatsky reaction is considered to
be a complex-induced proximity effect of the in situ generated
zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction
system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction
conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product
support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and
esters.
Scheme 1. Unexpected Reformatsky Reaction of 1a
1. INTRODUCTION
Metal-mediated C−C bond formation is an essential tool for
the development of synthetic routes to complex organic
molecules. In the history of organic chemistry, a large number
of metal-mediated nucleophilic additions to electrophiles have
been developed and applied to the synthesis of complex
molecules. As most of the targeted organic molecules contain
electrophilic groups, the use of highly reactive organometallic
reagents has often been limited due to poor functional group
tolerance. However, among the known organometallic
nucleophiles, organozinc reagents have recently attracted
renewed attention due to their high tolerance toward functional
groups.1 In particular, the classical Reformatsky reaction has
been considered as a practical tool to produce various β-
hydroxyalkanoates from α-haloalkanoates and aldehydes or
ketones.2,3 In recent years, the scope of the Reformatsky
reaction has been extended beyond aldehydes and ketones, and
continuous efforts have been directed to the development of
reactions with a great variety of electrophiles, such as nitriles4
and carboxylic acid anhydrides.5 In contrast, ester groups are
known to be essentially unreactive to Reformatsky reaction.
Though some reports of Reformatsky reaction proceeding with
esters have emerged, most of them are limited to cyclic and/or
activated esters.6,7
described to date. In addition, the product δ-hydroxy-β-
ketoester can be an important building block for various
biologically active compounds.8 Extensive efforts have been
devoted to the development of δ-hydroxy-β-ketoester synthetic
methodology, such as the addition of Chan’s diene,9 Wieler’s
dianion,10 or diketene11 to carbonyl compounds. While these
chemistries have contributed to the efficient syntheses of the
compounds, especially in the field of asymmetric synthesis, we
expected our finding would lead to another convenient and
efficient synthetic method for δ-hydroxy-β-ketoesters using
Reformatsky reagents, which have already been well-developed
as a reliable synthetic tool and recognized as highly functional
group tolerant reagents. Consequently, the detailed inves-
tigation of this reaction was considered to be a topic of great
importance for organic synthesis.
In the course of our recent drug research and development
program, we found an unexpected Reformatsky reaction when
2-benzoylpyridine (1a) reacting with ethyl bromozincacetate at
room temperature did not give the desired β-hydroxyalkanoates
(2a) but δ-hydroxy-β-ketoester (3a) instead, as the sole
product (Scheme 1).
Herein, we disclose the unusual addition of zinc alkanoates to
the ester group of in situ generated β-hydroxyalkanoates and
the establishment of a general synthesis of δ-hydroxy-β-
ketoesters directly from carbonyl compounds and zinc
alkanoates under a mild condition.
The result intrigued us because this kind of reaction to afford
δ-hydroxy-β-ketoesters directly from carbonyl compounds and
zinc alkanoates under such a mild condition has not been
Received: February 27, 2013
© XXXX American Chemical Society
A
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2. RESULTS AND DISCUSSION
Article
Scheme 3
2.1. Reaction Pathway. At the outset of this study, our
efforts were focused on identifying the reaction pathway. The
following two plausible reaction pathways were considered: (i)
self-condensation pathway, the attack of self-condensed
Reformatsky reagent (4) on carbonyl substrate (1) (Scheme
2, path a); (ii) stepwise addition pathway, after usual
Reformatsky reaction, the tandem attack of zinc alkanoate on
β-hydroxyalkanoates (2) (Scheme 2, path b).
Scheme 2. Plausible Reaction Pathways
Based on the identified reaction pathway, we termed this a
“double Reformatsky reaction”.
2.2. Evaluation of Reaction Promotion Factors. We
continued our studies by examining the factors that promoted
the reaction. Initially, the effect of a Lewis acid was studied.
Reformatsky reaction is known to be accelerated by Lewis acids
such as TMSCl18 and TiCl4.19 Since a catalytic amount of
TMSCl was used for the activation of zinc in the preparation of
the Reformatsky reagent, it was necessary to check if TMSCl
was promoting the double Reformatsky reaction. The reaction
of 1a with a TMSCl-free Reformatsky reagent was attempted,
and the reaction was found to proceed to full conversion in the
same manner as for the reaction with the TMSCl-contained
Reformatsky reagent, which demonstrated that the additional
Lewis acid was not the driving force for the double Reformatsky
reaction.20
An intensive survey of the prior literature revealed some
reports suggesting the self-condensation pathway.12 Newman
and co-workers investigated the self-condensation of Reformat-
sky reagents and indicated that self-condensation was promoted
at higher temperatures and with decreasing bulkiness of ester
alkyl groups.13 Following their study, Vaughan and co-workers
reported further studies on the behavior of self-condensed
Reformatsky reagents with carbonyl compounds.14 In both of
their studies, self-condensed Reformatsky reagents were
considered to be unreactive toward carbonyl compounds. In
addition, Utimoto and co-workers reported a synthetic method
to give δ-hydroxy-β-ketoesters directly from carbonyl com-
pounds and α-haloalkanoates, through the intermediacy of
SmI2, in which they disclosed that α-haloalkanoates can be self-
condensed and the self-condensed samarium species coupled
with carbonyl compounds to afford δ-hydroxy-β-ketoesters.15
As for the stepwise addition pathway, there has been one
example that demonstrated a secondary attack of a Reformatsky
reagent on the ester group of an α,β-unsaturated ester, with a
dithioacetal moiety that was derived from a first Reformatsky
reaction followed by subsequent dehydration.16
Our attention was subsequently directed to the bulkiness of
the zinc alkanoate. Table 1 shows the relationship between the
a
Table 1. Effect of Bulkiness of the Zinc Alkanoates
b
run
R3
ratio (1a/2/3)
1
2
3
4
Me
Et
0/<1/>99
0/<1/>99
0/75/25
0/98/2
i-Pr
t-Bu
a
Reaction conditions: 1a (2.5 mmol), alkyl bromozincacetate (3.5
equiv), THF (16 mL), room temperature, 3 days, under N2.
b
Determined by HPLC analysis
To identify if δ-hydroxy-β-ketoesters were formed via a self-
condensation pathway or a stepwise addition pathway, two
model experiments were conducted. First, the amount of self-
condensed Reformatsky reagent (4) generated during the
reaction was evaluated (Scheme 3 (a)). Ethyl bromozincacetate
was stirred under the same conditions as for Scheme 1 (at room
temperature for 24 h), but 4 was obtained in less than 1% yield
(evaluated by GC),17 which indicated that self-condensation of
Reformatsky reagents at room temperature only occurred at a
very low level. Next, the product ratio under a reactivity-
modulated condition (controlling the reaction temperature)
was investigated (Scheme 3 (b)). When a reaction mixture
containing 1a and 3.5 equiv of ethyl bromozincacetate was
stirred at −20 °C for 4 h, the ratio of 2a/3a was 97/3.
Subsequently, the mixture was stirred for 4 h at room
temperature and the ratio of 2a/3a switched to 2/98, which
indicated that 3a was formed via a stepwise addition pathway.
bulkiness of the zinc alkanoate alkyl groups and the degree of
double Reformatsky reaction. Reactions with the less hindered
methyl bromozincacetate and ethyl bromozincacetate were fully
completed (runs 1 and 2), whereas reaction with the more
hindered isopropyl bromozincacetate stopped at incomplete
conversion, and the much hindered tert-butyl bromozincacetate
only afforded a trace amount of double adduct 3 (runs 3 and 4).
The result indicated that the reaction can only readily proceed
when the zinc alkanoate has small unhindered alkyl groups.
Next, in order to clarify the substituent effect of the 2-pyridyl
group,7a,21 the reactivity of structurally and electrically
analogous ketones (1) and aldehydes (5), with and without
neighboring coordination groups, was investigated. As shown in
Table 2, 1a and 2-picolinaldehyde (5a), containing neighboring
coordination groups, were fully converted to the double
B
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However, it was found that the reactivity was independent of
the quantity and basicity of monodentate amines (runs 3−6).
On the other hand, we were encouraged to find that bidentate
amines significantly accelerated the reaction (runs 7−10). In
particular, TMEDA gave almost full conversion and was
selected as the base of choice for further studies (run 10).
Although more detailed data should be accumulated to
elucidate the beneficial effect of bidentate amines, we assume
that they may coordinate to zinc and dissociate the
Reformatsky reagent dimeric complexes,23 enhancing the
coordination ability of the β-zinc alkoxide to the ester carbonyl
as well as the reactivity of the Reformatsky reagent. Inorganic
bases did not promote the reaction (runs 11 and 12). Also,
thiophene24 and L-proline,25 which have been reported as
coordinating additives to zinc, did not remarkably promote the
reaction (runs 13 and 14).
Table 2. Examination of the Substituent Effect of a 2-Pyridyl
Group
a
b
run
substrate
R1
R2
conversion (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
5a
5b
5c
5d
2-pyridyl
phenyl
phenyl
phenyl
phenyl
phenyl
H
98
16
41
67
97
39
7
3-pyridyl
4-pyridyl
2-pyridyl
phenyl
H
3-pyridyl
4-pyridyl
H
H
38
a
Reaction conditions: substrate (2.5 mmol), ethyl bromozincacetate
2.3. Scope and Limitations. With an efficient procedure
for the double Reformatsky reaction in hand,26 the reactions
with ketones, aldehydes, nitriles, and carboxylic acid anhydrides
were performed under the optimal conditions (ethyl
bromozincacetate (5.0 equiv), TMEDA (2.0 equiv) in THF)
(Table 4).27 It was found that various electronically and
structurally diverse ketones and aldehydes could be used in the
reaction to give the corresponding δ-hydroxy-β-ketoesters in
good to excellent yields (runs 1−11). Interestingly, in the case
of p-formylbenzoic acid methyl ester (5h), the formyl moiety
was readily converted to the δ-hydroxy-β-ketoester whereas an
ester on an aromatic ring remained unchanged (run 6).
Moreover, p-nitrobenzaldehyde (5i) and p-bromobenzaldehyde
(5j) underwent reaction leaving the nitro and halide groups
unreacted, making the method attractive for further function-
alizations (runs 7 and 8). The reaction also proceeded well in
the presence of a hetero aryl group (run 9). Other than aryl
aldehydes, the reaction with alkenyl aldehyde (5l) and alkyl
aldehyde (5m) gave the corresponding products in satisfactory
yields, without any side reactions (runs 10 and 11).28
(3.5 equiv), THF (16 mL), room temperature, 3 days, under N2.
Determined by HPLC analysis.
b
Reformatsky products. In contrast, the reactions with other
analogues containing no neighboring coordination groups
(1b−d and 5b−d) resulted in remarkably decreased reactivity
and incomplete conversions. The result indicated that a
pyridine−nitrogen adjacent to the carbonyl group is beneficial
to obtain high conversion.
Subsequently, we attempted to extend the scope of available
substrates without neighboring coordination groups. To
enhance the reactivity of simple substrates, we introduced
bases as additives to the reaction, as Ojida and co-workers
indicated that pyridine might promote Reformatsky reaction
(Table 3).21 Benzophenone (1b) was used as a model
substrate, with 5 equiv of ethyl bromozincacetate,22 and it
was found that pyridine gave considerable increase in reactivity
(runs 1 and 2). Encouraged by this result, we further examined
various quantities and basicities of monodentate amines.
To further expand the scope of this reaction, the application
to nitriles and carboxylic acid anhydrides was examined (runs
12 and 13). The reaction of zinc alkanoate with a nitrile,
namely the Blaise reaction,4 is known to provide β-ketoesters
after acidic workup. Similarly, Reformatsky-type reaction with
carboxylic acid anhydride can also provide β-ketoesters.5 If the
double addition of zinc alkanoate proceeds for nitriles and
carboxylic acid anhydrides, β,δ-diketoesters were expected to be
obtained, which would expand the synthetic utility of the
reaction. However, when the double Reformatsky reactions of
benzonitrile (7) and benzoic (ethyl carbonic) anhydride (8)
were attempted, both of them afforded β-ketoester (9) as the
sole product, and no β,δ-diketoesters (10) were observed.
All products from ketones and aldehydes in Table 4 were
isolated in the form of ketoesters, and enol structures were not
observed. Furthermore, it should be stressed that all ketones
and aldehydes were exclusively converted to δ-hydroxy-β-
ketoesters, and neither β,δ-dihydroxydiesters29 (11) nor ζ-
hyroxy-β,δ-diketoesters30 (12) were detected (Figure 1).
2.4. Mechanistic Consideration. On the basis of the
above results, the mechanism for the double Reformatsky
reaction, taking the example of reactions with 5h, 7, and 8, can
be considered as follows (Scheme 4). In the case of 5h, after
the usual Reformatsky reaction at the formyl moiety, the newly
formed terminal ester of intermediate A is activated by the β-
zinc alkoxide−TMEDA complex as an internal Lewis acid
(complex-induced proximity effect), and it is subjected to
Table 3. Effect of Base on Double Reformatsky Reaction of
1b
a
b
run
additive
pyridine
conversion (%)
1
48
78
75
67
52
67
91
80
91
95
64
46
63
3
2
3
pyridine (4.0 equiv)
N-methylimidazole
i-Pr2NEt
4
5
6
DBU
7
2,2-bipyridine
1,10-phenanthroline
DABCO
8
9
10
11
12
13
14
TMEDA
K2CO3
NaHCO3
thiophene
L-proline
a
Reaction conditions: 1b (2.5 mmol), ethyl bromozincacetate (5.0
equiv), THF (23 mL), additive (2.0 eq), 25 °C, 3 days under N2.
b
Determined by HPLC analysis.
C
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a
Table 4. Synthesis of Various δ-Hydroxy-β-ketoesters
a
Reaction conditions: substrate (2.5 mmol), ethyl bromozincacetate (5.0 equiv), TMEDA (2.0 equiv), THF (23 mL), 50 °C, 1−5 h, under N2.
b
c
Ethyl bromozincacetate (10.0 equiv), TMEDA (4.0 equiv). Isolated as keto−enol tautomer (mainly β-ketoester conformation).
alkanoate is unlikely to occur (Scheme 4 (b)). Similarly, after
addition of zinc alkanoate to carboxylic acid anhydride 8, rapid
β-elimination provides ester-conjugated enolate F that is
stabilized by conjugation, which probably prohibits any further
addition of zinc alkanoate (Scheme 4 (c)).
Figure 1. Structure of 11 and 12 (undetected potential byproducts).
The assumption that doubly coupled intermediates such as
complex B are in the form of ester-conjugated enolates was
reinforced by analytical results. In the course of this study, we
obtained a white crystalline precipitate after double Reformat-
sky reaction of 1a. As the precipitate was converted to 3a after
simple acidic workup, it was considered to be the zinc complex
secondary addition of zinc alkanoate, whereas the aromatic
ester remains unreactive due to the absence of any chelation-
assisted activation (Scheme 4 (a)). After secondary addition of
zinc alkanoate to the β-hydroxyester of A, zinc complex B is
formed with an ester-conjugated enolate, as described below.
The conformation of B gives an appropriate explanation to the
fact that 11 and 12 were never detected because the terminal
ester of B will be stabilized by conjugation even under the
activation by the internal Lewis acid. In sharp contrast, after
addition of zinc alkanoate to nitrile 7, complex C is formed and
stabilized in imine−enamine tautomeric equibrium with
complex D, and consequently, secondary addition of zinc
1
of 3a. Judging from the results of H NMR and ICP-MS, the
structure seemed to consist of three atoms of zinc, two
molecules of 3a, and one molecule of THF.31
The 1D and 2D NMR analyses of the zinc complex of 3a
were conducted, and full assignment of the 1H and 13C
chemical shifts was achieved by evaluating the HMQC and
HMBC spectra.32 During the evaluations, we paid attention to a
characteristic singlet proton that is considered to be an olefinic
D
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Scheme 4. Plausible Reaction Mechanism
proton. According to the HMBC spectra, the olefinic proton
was found to be coupled with C16 and C19, which indicated
that the proton was H18, and the structure of the zinc complex
of 3a involved the ester-conjugated enolate form (Figure 2).
Figure 3. Potential transition state of the reaction of 2a to 3a.
observation that external Lewis acids, such as TMSCl, are not
required to promote the reaction.
Figure 2. Plausible structure of the zinc complex of 3a THF solvate.
3. CONCLUSION
Double Reformatsky reaction and the synthesis of various δ-
hydroxy-β-ketoesters have been developed. The key to
accelerate the double Reformatsky reaction is considered to
be a complex-induced proximity effect of the in situ generated
zinc alkoxide coordinated with the pyridyl group of the
substrate or bidentate amines. A noteworthy feature of the
reaction system is its high tolerance of functional groups due to
the moderate nucleophilicity of organozinc reagents and the
mild reaction conditions. Moreover, NMR and X-ray single-
crystal structure analyses of the zinc complex of the double
Reformatsky product have supported the proposed mechanism
of reaction site discrimination for ketones, aldehydes, nitriles,
carboxylic acid anhydrides and esters. The present versatile
synthesis can complement the known synthetic methods for δ-
hydroxy-β-ketoesters in terms of functional group flexibility.
Furthermore, since several asymmetric Reformatsky reactions
have been reported,21,35 this method can potentially be applied
to asymmetric reactions, which is the focus of ongoing research.
Furthermore, a single crystal was obtained from ethanol and
acetone (zinc complex of 3a ethanol solvate) and submitted for
X-ray single-crystal structure analysis, which revealed the
intermolecular coordination of the pyridyl group to zinc
alkoxide as proposed in Figure 2.33 Additionally, the bond
length of C16−C18 (1.358 Å) is found to be a typical olefinic
double bond length,34 which also endorses our assumption that
the doubly coupled intermediates are in the form of ester-
conjugated enolates.
The coordination of the pyridyl group to the zinc alkoxide
indicates the pyridyl group works in the same manner as
TMEDA. Therefore, it is considered that the double
Reformatsky reaction of 1a to 3a proceeds through the
activation of the ester carbonyl group of intermediate 2a by the
zinc alkoxide coordinated with the pyridyl group (Figure 3).
Furthermore, the consideration that the zinc alkoxide−pyridine
complex works as an internal Lewis acid is consistent with the
E
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NMR (500 MHz, DMSO-d6) δ 1.14 (t, J = 7.1 Hz, 3H), 3.48 (s, 2H),
3.55 (s, 2H), 4.02 (q, J = 7.3 Hz, 2H), 5.94 (s, 1H), 7.16−7.19 (m,
2H), 7.29 (t, J = 7.7 Hz, 4H), 7.42−7.44 (m, 4H); 13C NMR (125
MHz, DMSO-d6) δ 13.9, 50.2, 53.7, 60.3, 75.8, 125.5, 126.4, 127.9,
147.2, 167.0, 202.0; HRMS (ESI-Orbitrap) m/z [M + NH4]+ calcd for
C19H24NO4 330.1700, found 330.1703.
EXPERIMETAL SECTION
■
General Methods. All chemicals were obtained from commercial
suppliers and used without further purification. NMR was recorded on
500 MHz spectrometer with tetramethylsilane as an internal standard.
Chemical shifts are shown in ppm. High-resolution mass spectra
(HRMS) were measured by ESI-Orbitrap mass spectrometer.
BrZnCH2CO2Me, BrZnCH2CO2Et, and BrZnCH2CO2-i-Pr. Under N2
atmosphere, to a 200 mL round-bottom flask were added zinc powder
(11.5 g, 175.8 mmol, 2.0 equiv), dry THF (44 mL), and TMSCl (0.96
g, 8.8 mmol, 0.1 equiv). The suspension was warmed to 40−50 °C,
and α-bromoester (88.2 mmol, 1.0 equiv) in THF (110 mL) was
added dropwise to the suspension. After insoluble matter precipitated,
the light yellow supernatant solution was decanted and used for
subsequent experiments.
TMSCl-Free BrZnCH2CO2Et. To a 500 mL round-bottom flask were
added zinc powder (20 g) and aqueous 0.1 N aq HCl (200 mL). The
suspension was stirred vigorously for 10 min. The precipitate was
collected by filtration and dried in vacuo at 100 °C for at least 4 h.
Under N2 atmosphere, to a 200 mL round-bottom flask were added
the above activated zinc (11.5 g, 175.8 mmol, 2.0 equiv) and dry THF
(44 mL). The suspension was warmed to 40−50 °C, and ethyl
bromoacetate (14.7 g, 88.2 mmol, 1.0 equiv) in THF (110 mL) was
added dropwise. After insoluble matter precipitated, the light yellow
supernatant solution was decanted and used for subsequent experi-
ments.
BrZnCH2CO2-t-Bu. To a 500 mL round-bottom flask were added
zinc powder (20 g) and 0.1 N aq HCl (200 mL). After being stirred
for 10 min at room temperature, the precipitate was collected by
filtration and dried at 100 °C for at least 4 h. Under N2 atmosphere, to
a 200 mL round-bottom flask were added the above activated zinc
powder (11.5 g, 175.8 mmol, 2.0 equiv), THF (44 mL), and TMSCl
(0.96 g, 8.8 mmol, 0.1 equiv). The suspension was warmed to 40−50
°C, and tert-butyl bromoacetate (17.2 g, 88.2 mmol, 1.0 equiv) in THF
(110 mL) was added dropwise. After zinc powder precipitated, the
light yellow supernatant solution was decanted and used for
subsequent experiments.
Ethyl 5,5-Bis(4-fluorophenyl)-5-hydroxy-3-oxopentanoate (3e).
The title compound was prepared according to the general procedure
1
and isolated as a yellow oil (788.6 mg, 85% yield): H NMR (500
MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 3.42 (s, 2H), 3.53 (s, 2H),
4.18 (q, J = 7.3 Hz, 2H), 4.70 (s, 1H), 6.96−6.99 (m, 4H), 7.32−7.35
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.1, 50.3, 53.0, 61.8, 76.4,
115.2 (d, JC−F = 22.5 Hz), 127.4 (d, JC−F = 8.8 Hz), 141.7 (d, JC−F
=
3.8 Hz), 161.9 (d, JC−F = 245.0 Hz), 166.6, 203.8; HRMS (ESI-
Orbitrap) m/z [M + NH4]+ calcd for C19H22F2NO4 366.1511, found
366.1513.
Ethyl 5-Hydroxy-5,5-bis(4-methoxyphenyl)-3-oxopentanoate
(3f). The title compound was prepared according to the general
procedure and isolated as a yellow oil (755.9 mg, 87% yield): 1H NMR
(500 MHz, CDCl3) δ 1.26 (t, J = 7.3 Hz, 3H), 3.40 (s, 2H), 3.51 (s,
2H), 3.77 (s, 6H), 4.18 (q, J = 7.3 Hz, 2H), 4.53 (s, 1H), 6.81−6.83
(m, 4H), 7.26−7.28 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.1,
50.5, 53.2, 55.2, 61.6, 76.5, 113.6, 126.9, 138.4, 158.5, 166.7, 204.0;
HRMS (ESI-Orbitrap) m/z [M + NH4]+ calcd for C21H28NO6
390.1911, found 390.1909.
Ethyl 5-Hydroxy-3-oxo-5-phenylpentanoate (6a). The title
compound was prepared according to the general procedure and
isolated as a colorless oil (528.4 mg, 90% yield): 1H NMR (500 MHz,
CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H), 2.92 (dd, J = 17.3, 3.5 Hz, 1H),
3.00 (dd, J = 17.3, 9.1 Hz, 1H), 3.48 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H),
5.19 (dd, J = 9.1, 3.5 Hz, 1H), 7.20−7.42 (m, 5H). Analysis of the
spectroscopic data matched reported data.36
Diethyl 5,5′-(1,4-Phenylene)bis(5-hydroxy-3-oxopentanoate)
(6g). The title compound was prepared according to the general
procedure (terephthalaldehyde 14, 167.7 mg, 1.25 mmol) with
Reformatsky reagent (23.3 mL, 10 equiv), and TMEDA (0.75 mL, 4
1
equiv) and isolated as a light yellow oil (856.9 mg, 87% yield): H
Ethyl 5-Hydroxy-3-oxo-5-phenyl-5-(pyridin-2-yl)pentanoate (3a).
To a 100 mL round-bottom flask were added ca. 0.54 mol/L of ethyl
bromozincacetate/THF solution (16.1 mL, ca. 8.7 mmol, 3.5 equiv)
and 2-benzoyl pyridine (1a) (458.0 mg, 2.5 mmol). The yellow
solution was stirred at room temperature for 24 h. The mixture was
diluted with EtOAc (50 mL). The solution was successively washed
with 20% aq citric acid (25 mL), 10% aq NaCl (25 mL), 5% aq
NaHCO3 (25 mL), and water (25 mL). The organic layer was
concentrated in vacuo to give the crude oil. The crude oil was purified
by flash chromatography (EtOAc/Hexane) to give the title compound
NMR (500 MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 6H), 2.91 (dd, J =
17.5, 3.2 Hz, 2H), 2.99 (dd, J = 17.5, 9.1 Hz, 2H), 3.08 (brs, 2H), 3.49
(s, 4H), 4.20 (q, J = 7.1 Hz, 4H), 5.19 (dd, J = 9.1, 3.2 Hz, 2H), 7.35−
7.36 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.1, 49.9, 51.5, 61.6,
69.6, 125.9, 142.2, 166.9, 202.8; HRMS (ESI-Orbitrap) m/z [M +
NH4]+ calcd for C20H30NO8 412.1966, found 412.1977.
Methyl 4-(5-ethoxy-1-hydroxy-3,5-dioxopentyl)benzoate (6h).
The title compound was prepared according to the general procedure
1
and isolated as a colorless oil (614.4 mg, 84% yield): H NMR (500
MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H), 2.94 (dd, J = 17.6, 3.8 Hz,
1H), 2.99 (dd, J = 17.6, 8.5 Hz, 1H), 3.27 (brs, 1H), 3.49 (s, 2H), 3.91
(s, 3H), 4.20 (q, J = 7.0 Hz, 2H), 5.26 (dd, J = 8.5, 3.5 Hz,1H), 7.43−
7.45 (m, 2H), 8.01−8.03 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
14.1, 49.8, 51.4, 52.1, 61.6, 69.3, 125.5, 125.6, 129.5, 129.9, 147.6,
166.8, 202.6; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C15H18O6 295.1176, found 295.1181.
1
as a yellow oil (651.8 mg, 83% yield): H NMR (500 MHz, DMSO-
d6) δ 1.14 (t, J = 7.1 Hz, 3H), 3.46 (d, J = 15.8 Hz, 1H), 3.49 (s, 2H),
3.77 (d, J = 15.5 Hz, 1H), 4.03 (q, J = 7.3 Hz, 2H), 6.10 (s, 1H), 7.15−
7.16 (m, 1H), 7.17−7.23 (m, 1H), 7.27 (t, J = 7.0 Hz, 2H), 7.45−7.47
(m, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.73−7.76 (m, 1H), 8.47−8.48 (m,
1H); 13C NMR (125 MHz, DMSO-d6) δ 13.9, 50.2, 53.0, 60.3, 77.1,
120.3, 121.9, 125.3, 126.6, 127.9, 136.9, 146.2, 147.6, 164.6, 167.0,
201.9; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C18H20NO4
314.1387, found 314.1376.
General Procedure. δ-Hydroxy-β-ketoesters. To a 100 mL
round-bottom flask were added ca. 0.54 mol/L of ethyl bromozinca-
cetate/THF solution (23.3 mL, ca. 12.5 mmol, 5 equiv), TMEDA
(0.75 mL, 5 mmol, 2.0 equiv), and carbonyl compound (2.5 mmol, 1.0
equiv). The solution was warmed to 50 °C and stirred for 1−5 h. After
being cooled to room temperature, the mixture was diluted with
EtOAc (50 mL). The solution was successively washed with 20% aq
citric acid (25 mL), 10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL),
and water (25 mL). The organic layer was concentrated in vacuo to
give the crude oil. The crude oil was purified by flash chromatography
(EtOAc/hexane) to give the pure δ-hydroxy-β-ketoesters.
Ethyl 5-Hydroxy-5-(4-nitrophenyl)-3-oxopentanoate (6i). The
title compound was prepared according to the general procedure
and isolated as an off-white solid (625.2 mg, 90% yield): mp 75−76
1
°C; H NMR (500 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H), 2.97−
2.99 (m, 2H), 3.40 (d, J = 3.5 Hz, 1H), 3.51 (s, 2H), 4.21 (q, J = 7.3
Hz, 2H), 5.32 (ddd, J = 6.9, 5.2, 3.5 Hz 1H), 7.55−7.57 (m, 2H),
8.20−8.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 49.7, 51.2,
61.8, 68.9, 123.8, 126.5, 147.4, 149.7, 166.7, 202.5; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C13H15NO6 282.0972, found
282.0974.
Ethyl 5-(4-Bromophenyl)-5-hydroxy-3-oxopentanoate (6j). The
title compound was prepared according to the general procedure and
isolated as a colorless oil (577.3 mg, 73% yield): 1H NMR (500 MHz,
CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H), 2.90 (d, J = 17.6, 3.4 Hz, 1H), 2.96
(dd, J = 17.6, 8.8 Hz, 1H), 3.12 (d, J = 3.4 Hz, 1H), 3.48 (s, 2H), 4.20
(q, J = 7.1 Hz, 2H), 5.16 (dt, J = 8.8, 3.4 Hz, 1H), 7.24−7.26 (m, 2H),
7.47−7.49 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 49.9, 51.4,
Ethyl 5-Hydroxy-3-oxo-5,5-diphenylpentanoate (3b). The title
compound was prepared according to the general procedure and
1
isolated as a white solid (590.6 mg, 76% yield): mp 66−67 °C; H
F
dx.doi.org/10.1021/jo400408t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
61.7, 69.2, 121.6, 127.4, 131.7, 141.5, 166.8, 202.7; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for 315.0226 (79Br) and 317.0206
(81Br), found 315.0230 (79Br) and 317.0208 (81Br).
Hz, 2H), 8.01−8.13 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.47 (dd, J =
5.2, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.0, 25.1, 51.4,
59.7, 67.0, 78.8, 89.1, 123.5, 123.9, 126.1, 126.4, 127.5, 139.5, 146.3,
149.2, 164.8, 172.3, 182.6.
Ethyl 5-Hydroxy-3-oxo-5-(thiophene-3-yl)pentanoate (6k). The
Zinc Complex of 3a Ethanol Solvate. Zinc complex of 3a THF
solvate was dissolved in acetone and ethanol. The solvent was
evaporated under atmospheric pressure to give a colorless single
crystal: mp 206−207 °C dec; 1H NMR (500 MHz, CDCl3) δ 1.06 (t, J
= 6.9 Hz, 1.5H, 0.5EtOH), 1.17 (t, J = 7.1 Hz, 3H), 2.72 (d, J = 12.6
Hz, 1H), 3.45 (qd, J = 7.0, 5.0 Hz, 1H, 0.5EtOH), 3.80 (d, J = 12.6 Hz,
1H), 3.91−4.08 (m, 1H), 4.08−4.26 (m, 1H), 4.74 (s, 1H), 7.08−7.20
(m, 1H), 7.20−7.34 (m, 2H), 7.42−7.60 (m, 1H), 7.79 (d, J = 7.9 Hz,
2H), 8.01−8.17 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.39−8.60 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 14.1, 18.5, 51.3, 56.0, 59.8, 78.8,
89.1, 123.6, 124.0, 126.1, 126.4, 127.6, 139.6, 146.4, 149.2, 164.8,
172.4, 182.6. Crystal structure: see the Supporting Information
(CCDC-923389).
title compound was prepared according to the general procedure and
isolated as a yellow oil (496.6 mg, 82% yield): H NMR (500 MHz,
1
CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 2.91 (dd, J = 17.0, 3.6 Hz, 1H),
2.99 (dd, J = 17.0, 8.8 Hz, 1H), 3.46 (s, 2H), 3.56 (brs, 1H), 4.16 (q, J
= 7.1 Hz, 2H), 5.21 (dd, J = 8.8, 3.6 Hz, 1H), 7.03 (dd, J = 5.0, 1.3 Hz,
1H), 7.18−7.19 (m, 1H), 7.27 (dd, J = 5.0, 3.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.1, 49.8, 50.8, 61.5, 66.1, 121.0, 125.5, 126.3,
144.2, 167.1, 202.6; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C11H15O4S 243.0686, found 243.0688.
Ethyl (6E)-5-Hydroxy-3-oxo-7-phenylhept-6-enoate (6l). The title
compound was prepared according to the general procedure and
1
isolated as a pale yellow oil (617.5 mg, 95% yield): H NMR (500
MHz, CDCl3) δ 1.27 (t, J = 7.3 Hz, 3H), 2.86−2.87 (m, 2H), 2.96
(brs, 1H), 3.50 (s, 2H), 4.20 (q, J = 7.3 Hz, 2H), 4.79 (d, J = 6.0 Hz,
1H), 6.20 (dd, J = 15.9, 6.1 Hz, 1H), 6.63−6.66 (m, 1H), 7.24−7.26
(m, 1H), 7.29−7.32 (m, 2H), 7.36−7.38 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 14.1, 49.6, 50.0, 61.6, 68.4, 126.5, 127.8, 128.6, 129.9,
130.7, 136.4, 166.9, 202.7; HRMS (ESI-Orbitrap) m/z [M + NH4]+
calcd for C15H22NO4 280.1543, found 280.1543.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional studies on the reaction promotion factors; copies of
1H NMR and 13C NMR data for all new compounds and
HMBC and HMQC spectra of zinc complex of 3a THF
solvate; X-ray crystallographic data (CIF) and ORTEP plot for
the zinc complex of 3a ethanol solvate. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ethyl 5-Hydroxy-3-oxo-7-phenylheptanoate (6m). The title
compound was prepared according to the general procedure and
1
isolated as a yellow oil (486.2 mg, 74% yield): H NMR (500 MHz,
CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.71−1.72 (m, 1H), 1.81−1.83 (m,
1H), 2.65−2.71 (m, 3H), 2.77−2.83 (m, 1H), 2.99 (brs, 1H), 3.44,
3.45 (ABq, J = 15.8 Hz, 2H), 4.08−4.12 (m, 1H), 4.18 (q, J = 7.1 Hz,
2H), 7.16−7.20 (m, 3H), 7.26−7.29 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 14.1, 31.7, 38.1, 49.7, 49.9, 61.5, 66.8, 125.9, 128.43, 128.44,
141.7, 167.0, 203.6; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C15H21O4 265.1434, found 265.1435.
AUTHOR INFORMATION
Corresponding Author
*E-mail: masahiro.mineno@takeda.com.
■
Notes
Benzoic (Ethyl carbonic) Anhydride (8). To a solution of benzoic
acid (353.0 mg, 2.5 mmol) and THF (5 mL) was added triethylamine
(253.0 mg, 2.5 mmol, 1 equiv). The mixture was cooled to 0−10 °C.
Ethyl chloroformate (271.3 mg, 2.5 mmol, 1 equiv) was added to the
mixture, and the solution was stirred for 0.5 h at the same temperature.
The precipitate was filtered off and washed with THF (2 mL × 2). The
combined filtrate was concentrated in vacuo to give the crude oil. The
crude oil was used for further experiments without any purification: 1H
NMR (500 MHz, CDCl3) δ 1.42 (t, J = 7.1 Hz, 3H), 4.41 (q, J = 7.0
Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 8.08 (dd, J
= 8.4, 1.7 Hz, 2H).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Masahiro Kajino, Mr. Hideo Hashimoto, Mr.
Yoichiro Ishimaru, and Dr. David Cork for helpful discussions,
Mr. Mitsuhiro Nishitani for help with the X-ray single-crystal
structure analysis, Mr. Kenichi Oka for help with HRMS
analyses, and Ms. Mika Murabayashi for help with NMR
analyses.
Ethyl 3-Oxo-3-phenylpropanoate (9). The title compound was
prepared according to the general procedure (the reaction mixture
diluted with EtOAc and aqueous citric acid (20%) was stirred
overnight) (benzonitrile 27, 257.6 mg, 2.5 mmol) and isolated as a
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1
light brown oil (410.0 mg, 85.3% yield)). Keto tautomer: H NMR
(500 MHz, CDCl3) δ 1.25 (t, J = 7.3 Hz, 3H), 3.99 (s, 2H), 4.21 (q, J
= 7.2 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.91−
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1H), 7.38−7.45 (m, 3H), 7.74−7.81 (m, 2H), 12.60 (s, 1H); 13C
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3.50−3.66 (m, 2H, 0.5THF), 3.82 (d, J = 12.6 Hz, 1H), 3.98 (dd, J =
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1
(31) H NMR spectra of the precipitate indicated that it contained
0.5 molecule of THF per 3a. ICP-MS spectra showed that zinc metal
makes up 18% of the whole weight of the precipitate.
1
(32) H, 13C NMR, HMQC, and HMBC spectra can be seen in the
Supporting Information.
(33) Details are described in the Supporting Information, including a
CIF and an ORTEP plot. Additionally, CCDC-923389 contains all
crystallographic data of this publication and is available free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(34) Representative bond lengths for the crystal: C1−C15 = 1.560 Å,
C15−C16 = 1.503 Å, C16−C18 = 1.358 Å, C1−O14 = 1.404 Å, C16−
O17 = 1.318 Å, C19−O20 = 1.235 Å. Other bond lengths are
described in the Supporting Information.
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in the Supporting Information.
H
dx.doi.org/10.1021/jo400408t | J. Org. Chem. XXXX, XXX, XXX−XXX