Synthesis of α-alkylated β-ketoesters by alkoxycarbonylation/ Michael addition domino reaction

Article abstract of DOI:10.1021/jo3026143

The palladium-catalyzed alkoxycarbonylation of an α-chloro ketone can be efficiently combined to a Michael addition reaction in a new two-step domino reaction, allowing the synthesis of original highly functionalized α-alkylated β-ketoesters. The scope of the reaction was extended to several α-chloro ketones and Michael acceptors with moderate to very good yields.

Full text of DOI:10.1021/jo3026143

Article
pubs.acs.org/joc
Synthesis of α‑Alkylated β‑Ketoesters by Alkoxycarbonylation/
Michael Addition Domino Reaction
Benoit Wahl, Yann Philipson, Helene Bonin, Andre Mortreux, and Mathieu Sauthier*
́
̀
́
Unite
d’Ascq, France
́
de Catalyse et Chimie du Solide, UMR CNRS 8181, Universite
́
Lille Nord de France, ENSCL BP 90108, 59652 Villeneuve
S
* Supporting Information
ABSTRACT: The palladium-catalyzed alkoxycarbonylation of an α-
chloro ketone can be efficiently combined to a Michael addition
reaction in a new two-step domino reaction, allowing the synthesis of
original highly functionalized α-alkylated β-ketoesters. The scope of
the reaction was extended to several α-chloro ketones and Michael
acceptors with moderate to very good yields.
Scheme 1. Alkoxycarbonylation/Michael Addition Domino
Reaction
INTRODUCTION
■
Domino-type transformations have recently emerged as a green
and powerful synthetic tool since they allow the reduction of
the environmental impact of multistep synthesis by reducing
the number of purification procedures.1,2 One-pot trans-
formations involving a carbonylation step are of particular
interest since carbon monoxide is a cheap carbonyl source
which is moreover totally incorporated in the final product.3−5
Several examples of domino-type transformations including
carbonylative steps, such as multicomponent carbonylative
coupling reactions,6 hydroformylation/acetal formation and
related sequences,7 or allylic alkylation/Pauson−Khand reac-
tions,8,9 have already been reported in the literature. In this
field, we recently studied palladium-catalyzed domino processes
under carbonylative conditions by developing a new palladium-
catalyzed pseudo-domino type I sequence combining the
alkoxycarbonylation of an α-chloro ketone and the subsequent
allylic alkylation of the β-ketoester intermediate.10 We also
developed the palladium-catalyzed pseudodomino carbon-
ylative/decarboxylative allylation of α-chloro ketones that
represents a new selective method for the monoallylation of
carbonyl compounds.11 In both cases, the domino sequences
involved the methoxycarbonylation of a chloro ketone12
yielding a β-ketoester, followed by a second palladium-catalyzed
step to build additional carbon−carbon bonds. Such sequences
are possible only if the two metal-catalyzed reactions are fully
compatible with each other. In particular, the second step has
to be compatible with the presence of carbon monoxide, which
can act as a ligand to palladium and can thus readily block the
catalytic reaction by coordinating the metal center. However,
this difficulty is obviously overcome in the case of a
noncatalyzed second step. Aiming at developing original
carbonylative domino sequences, we now wish to report a
new domino reaction involving, in a first step, the palladium-
catalyzed alkoxycarbonylation of an α-chloro ketone, followed,
in a second step, by the addition of the enolate intermediate
species to a Michael acceptor to yield new highly functionalized
α-alkylated-β-ketoester (Schemes 1 and 2). Several examples of
Scheme 2. Mechanism of the Palladium-Catalyzed
Alkoxycarbonylation/Michael Addition Domino Reaction
domino reactions including a Michael addition step have been
reported in the literature,13−19 but to the best of our
knowledge, this work represents the first example in which
the Michael donor is in situ generated via an alkoxycarbony-
lation reaction.
Received: November 30, 2012
Published: January 27, 2013
© 2013 American Chemical Society
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Article
entry 5). Increasing the amount of Michael acceptor 2a to 4
equiv allowed us to reach an optimized yield of 73% in 15 h
(entry 9). The addition of 1 mol % of hydroquinone to prevent
the potential competitive radical polymerization of methyl
acrylate proved to be ineffective (entry 7 vs 8). It is noteworthy
that a minimum of 10 bar CO pressure is required to reach
good yields (entries 10−12) as well as a temperature of 90 °C
(entries 13 and 14).
RESULTS/DISCUSSION
■
Our preliminary task consisted of verifying the feasibility and
the compatibility of both reactions involved in the domino
sequence as the presence of a reactive acrylate could potentially
interfere with the palladium-catalyzed reaction. We had already
showed that the best catalytic system for the alkoxycarbony-
lation reaction consisted of 2 equiv of Xantphos as an ancillary
ligand for 1 equiv of palladium (usually [Pd(acac)2], 0.5 mol
%).12 To our great pleasure, early experiments showed that the
tri-n-butylamine was suitable for both alkoxycarbonylation and
Michael addition steps. The tri-n-butylamine/tri-n-butylammo-
nium chloride buffer, obtained after the alkoxycarbonylation
step, was thus basic enough to deprotonate the intermediate β-
ketoester. We consequently investigated the optimization of the
reaction conditions with tri-n-butylamine using 2-chloroaceto-
phenone and methyl acrylate as model substrates in the
presence of [Pd(acac)2] as palladium source in methanol
(Table 1).
A kinetic study was done under the optimized conditions by
analyzing the composition of the reaction mixture by gas
chromatography (Figure 1). This experiment evidenced the
Table 1. Methoxycarbonylation/Michael Addition of 2-
Chloroacetophenone 1a and Methyl Acrylate 2a:
a
Optimization of the Reaction Conditions
Figure 1. Evolution of the formation of the intermediate β-ketoester
4a and the expected product 3aa (reaction performed at 90 °C, under
10 bar CO, with 6 mmol of 2-chloroacetophenone, 24 mmol of methyl
acrylate, 18 mmol of NBu3, 1 mol % of [Pd(acac)2], 2 mol % of
Xantphos, and 20 mL of distilled MeOH).
b
b
NBu3
(equiv)
2a
(equiv)
T
(°C)
CO
(bars)
3aa
4a
entry
(%)
(%)
1
2
1.2
1.2
1.5
2
90
90
90
90
90
90
90
90
90
90
90
90
70
110
10
10
10
10
10
10
10
10
10
5
68
47
31
18
14
14
41
39
5
expected fast formation of the ketoester 4a under these
conditions. The presence of the activated olefin does not
prevent the palladium-catalyzed transformation. However, the
Michael addition proved to be much slower than the
alkoxycarbonylation step in these conditions. Whereas the
first step is over in less than 1 h, the second step requires
almost 22 h to lead to completion, in agreement with the fact
that Michael additions promoted by weak bases are usually
quite slow and require long reaction times.20
With these optimized conditions in hands, the scope of
reaction was then extended using several α-chloro ketones with
methyl acrylate in MeOH (Table 2). Since the rate of the
Michael addition step is quite slow and dependent on the
nature of the nucleophile, the reaction time had thus to be
optimized for each substrate. The reaction mixture was
analyzed by GC in order to check the remaining amount of
intermediate β-ketoester after 15 h, and the reaction was run
until no more ketoester could be detected.
2.5
2.5
2.5
2.5
2.5
1.2
26
31
57
67
63
27
35
73
62
75
73
52
72
3
4
5
3
6
4.5
3
7
c
8
3
1.2
9
3
4
4
4
4
4
4
10
11
12
13
14
3
14
5
3
20
40
10
10
3
5
3
27
1
3
a
Reaction conditions: 2-chloroacetophenone (1 equiv, 3 mmol),
methyl acrylate (1.2−4 equiv), NBu3 (1.2−4.5 equiv), [Pd(acac)2] (1
mol %), Xantphos (2 mol %), CO (5−40 bar), MeOH (10 mL), 70−
b
c
110 °C, 15 h. Determined by gas chromatography. 1 mol % of
hydroquinone was added.
Chloro ketones bearing an electron-withdrawing group in the
para-position of the phenyl group (1b−d) were converted with
moderate to good yields (entries 2−4, 49−70%) with, however,
slower reaction rates in the presence of strong electron-
withdrawing groups on the aryl moiety. The low yield observed
with the p-carbomethoxyphenyl derivative (1d, entry 4) could
be explained by the formation of the double Michael adduct. 2-
chloro-1-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)-1-ethanone 1e
could not be converted to the desired product 3ea, although
the formation of the intermediate β-ketoester (49% after 33h of
reaction) could be detected (entry 5). The use of chloroacetone
1f led to a low yield of 3fa (27%, entry 6), but the formation of
the double Michael adduct was observed as well. Finally, when
the chloropinacolone 1g was used, a GC yield of 30% of 3ga
In the absence of methyl acrylate 2a, the reaction yielded
68% of the expected methyl 3-oxo-3-phenylpropanoate 4a
(entry1). In the presence of 2.5 equiv of methyl acrylate, the
desired domino product 3aa could be observed, together with
the intermediate β-ketoester 4a after 15 h of reaction (entry 2).
Although the major product was the β-ketoester, a significant
and encouraging amount of the desired product could be
obtained (26%), proving the feasibility of the domino sequence.
Stronger bases cannot be used as they are known to be
detrimental to the carbonylation reaction; the yield could,
however, be raised by increasing the quantity of NBu3 (entries
3−6) with an optimum reached for 3 equiv of NBu3 (67%,
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2f as Michael acceptors, disappointing yields were obtained
(Table 3, entries 8 and 9). Indeed, after 15 h of reaction, 50%
and 30%, respectively, of the intermediate ketoesters were still
remaining in the reaction mixture. However, the yields of
Michael addition products could not be improved even after
prolonged reaction times. Finally, we were pleased to find that
acrolein was an interesting reactant. Indeed, the unexpected
and original enal spiro derivative 3ah was isolated as the major
product albeit in modest yield (20% isolated yield). The
formation of this compound can be explained by the addition of
the ketoester to two molecules of acrolein, followed by an
intramolecular aldolization/crotonization step leading to the
cyclized conjugated compound (Scheme 3). Compound 3ah is
thus obtained from an original multistep reaction that combines
inter- and intramolecular transformations, thus showing the
high complexity that can be attained through this type of
domino transformation.
Table 2. Scope of the Reaction with Various Chloro Ketones
and Methyl Acrylate in MeOH
a
Finally, we also extended the scope of the reaction to
secondary and tertiary alcohols. The reaction turned out to be
efficient with 2-propanol (Table 4, entry 1), whereas the yield
with the bulkier 2-methyl-2-propanol was not satisfactory even
after prolonged reaction times (Table 4, entry 2).
In conclusion, we have developed a new simple and efficient
two-step domino reaction starting from α-chloro ketones and
carbon monoxide and involving an alkoxycarbonylation
reaction followed by a Michael addition. Using optimized
conditions, we could prepare highly functionalized α-alkylated-
β-ketoesters, including 12 original products, with good yields
using the same base in a one-pot reaction. The scope of the
domino reaction could be extended to primary and secondary
chloro ketones with various Michael acceptors, including
methyl acrylate, methyl vinyl ketone, and cyclic enones.
EXPERIMENTAL SECTION
General remarks concerning the reactants, solvents, or equipment
used, as well as NMR and HRMS spectra, are given in the Supporting
Information.
■
General Procedure for the Alkoxycarbonylation/Michael
Addition Domino Reaction. Reactions were performed in a
stainless steel autoclave equipped with a magnetic stirrer. [Pd(acac)2]
(9.1 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)-
xanthene (34.7 mg, 0.06 mmol), and α-chloro ketone (3 mmol)
were weighted and placed in the autoclave under N2. Then, by using
syringes, 10 mL of alcohol, n-tributylamine (9 mmol), and the Michael
acceptor were successively added into the reactor. The reactor was
charged with 10 bar of carbon monoxide, and the mixture was stirred
at 90 °C for 15 h. After being cooled at room temperature, the reactor
was carefully degassed. The mixture was diluted with diethyl ether,
washed with a HCl solution (1 N) and water, dried over MgSO4, and
concentrated under vacuum. After flash chromatography column on
silica gel (petroleum ether/ethyl acetate 90:10 to 80:20), the domino
reaction product was isolated.
Dimethyl 2-benzoylpentanedioate (3aa): yellowish oil; Rf1 =
0.30 (petroleum ether/ethyl acetate 80:20); yield 76%, 528 mg; H
NMR (300 MHz, CDCl3) δ 8.04−8.00 (m, 2H), 7.62−7.56 (m, 1H),
7.52−7.45 (m, 2H), 4.52 (t, J = 7.1 Hz, 1H), 3.68 (s, 3H), 3.67 (s,
3H), 2.48−2.42 (m, 2H), 2.34−2.26 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 195.0, 173.3, 170.1, 136.0, 133.8, 128.9, 128.9, 52.7, 52.6,
51.8, 31.4, 24.1; HRMS (ESI-) calcd for C14H15O5 [M − H]−
263.0925, found 263.09122.
a
Reaction conditions: chloro ketone (3 mmol), [Pd(acac)2] (1 mol
%), Xantphos (2 mol %), NBu3 (3 equiv), methyl acrylate (4 equiv),
CO (10 bar), MeOH (10 mL), 90 °C. Isolated yield (GC yield).
b
was obtained despite a prolonged reaction time of 141 h, the
major compound being the intermediate β-ketoester (66%,
entry 7). The use of a stronger base, such as the proton sponge,
did not improve the Michael addition product yield (85%
intermediate ketoester remaining after 85 h, entry 8).
The domino reaction was then performed using other
Michael acceptors such as methyl vinyl ketone (MVK) 2b or
cyclic enones 2c and 2d (Table 3) to yield original highly
functionalized products.
Interestingly, the intermediate ketoesters that had showed
low reactivities with methyl acrylate were fully converted when
MVK was used (Table 3, entries 2−3 vs Table 2, entries 5 and
7), even though long reaction times were required. Cyclo-
hexanone 2c and cyclopentenone 2d could also be successfully
used to afford the expected products with good to excellent
yields (Table 3, entries 4−7, 71−86%). The reaction was also
efficient with 3-chloro-2-butanone 1h, a secondary chloro
ketone, however requiring a long reaction time (58 h instead of
15 h, 71% GC yield, entry 6). The product was isolated with an
unsatisfactory purity. With acrylonitrile 2e or dimethyl fumarate
Dimethyl 2-(4-chlorobenzoyl)pentanedioate (3ba): yellowish
oil; Rf = 0.15 (petroleum ether/ethyl acetate 90:10); yield 70%, 302
mg; 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 8.6 Hz, 2H), 7.44 (d, J
= 8.6 Hz, 2H), 4.47 (t, J = 7.0 Hz, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 2.43
(t, J = 7.0 Hz, 2H), 2.27 (q, J = 7.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 193.4, 172.7, 169.4, 139.7, 133.9, 129.9, 128.8, 52.1, 52.0,
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a
Table 3. Scope of the Reaction with Various Chloro Ketones and Other Michael Acceptors in MeOH
a
Reaction conditions: chloro ketone (3 mmol), [Pd(acac)2] (1 mol %), Xantphos (2 mol %), NBu3 (3 equiv), Michael acceptor (4 equiv), CO (10
b
c
d
bar), MeOH (10 mL), 90 °C. Isolated yield. MeOH: 2 mL Gas chromatography yield
51.2, 30.7, 23.6; HRMS (ESI-) calcd for C14H14ClO5 [M − H]−
297.05352, found 297.05237.
Dimethyl 2-(4-fluorobenzoyl)pentanedioate (3ca): yellowish
(s, 3H), 2.44−2.39 (m, 2H), 2.28−2.21 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 194.6, 173.3, 169.8, 166.2, 139.1, 134.5, 130.1, 128.8, 52.9,
52.8, 52.7, 51.9, 31.2, 23.9; HRMS (ESI-) calcd for C16H17O7 [M −
H]− 321.09798, found 321.09671.
oil; Rf = 0.20 (petroleum ether/ethyl acetate 90:10); yield 70%, 258
1
mg; H NMR (300 MHz, CDCl3) δ 8.10−8.02 (m, 2H), 7.18−7.10
Dimethyl 2-acetylpentanedioate (3fa): yellowish oil; Rf = 0.25
(m, 2H), 4.49 (t, J = 7.0 Hz, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 2.44 (m,
2H), 2.28 (q, J = 7.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 193.4,
173.3, 170.0, 167.9, 164.5, 132.5, 132.4, 131.7, 131.6, 116.3, 116.0,
52.7, 52.6, 51.8, 31.2, 24.1; HRMS (ESI-) calcd for C14H14FO5 [M −
H]− 281.08308, found 281.08170.
1
(petroleum ether/ethyl acetate 90:10); yield 27%, 165 mg; H NMR
(300 MHz, CDCl3) δ 3.73 (s, 3H), 3.66 (s, 3H), 3.56 (t, J = 7.2 Hz,
1H), 2.38−2.32 (m, 2H), 2.24 (s, 3H), 2.18−2.10 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 202.4, 173.1, 169.8, 58.2, 52.6, 51.8, 31.4, 29.2,
23.1; HRMS (ESI-) calcd for C9H13O5 [M − H]− 201.07685, found
201.07555.
Dimethyl 2-(4-(methoxycarbonyl)benzoyl)pentanedioate
(3da): yellowish oil; Rf = 0.10 (petroleum ether/ethyl acetate
Methyl 2-benzoyl-5-oxohexanoate (3ab):21 yellowish oil; Rf =
1
90:10); yield 49%, 142 mg; H NMR (300 MHz, CDCl3) δ 8.10−
1
8.01 (m, 4H), 4.51 (t, J = 6.9 Hz, 1H), 3.90 (s, 3H), 3.64 (s, 3H), 3.62
0.20 (petroleum ether/ethyl acetate 80:20); yield 74%, 549 mg; H
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7.41 (m, 4H), 4.30 (dd, J = 9.0 Hz, J = 6.6 Hz, 2H), 3.63 (d, J = 5.1
Hz, 3H), 2.83−2.72 (m, 1H), 2.42−1.33 (m, 8H); 13C NMR (75
MHz, CDCl3) δ 209.8, 209.7, 193.5, 193.4, 168.9, 168.6, 136.5, 134.1,
134.0, 129.1, 129.1, 128.7, 128.7, 59.4, 59.0, 52.8, 52.8, 45.8, 45.4, 41.3,
38.4, 38.4, 29.6, 28.9, 24.7, 24.7; HRMS (ESI-) calcd for C16H17O4 [M
− H]− 273.11214, found 273.11188.
Scheme 3. Methoxycarbonylation Followed by Double
Michael Addition of Acrolein and Subsequent Cyclization
Methyl 3-oxo-2-(3-oxocyclohexyl)butanoate (3fc):22 yellow-
ish oil; Rf = 0.15 (petroleum ether/ethyl acetate 80:20); yield 75%, 398
mg; obtained as a 1:1 mixture of diastereomers with a single
1
stereogenic center at the cyclohexanone ring: H NMR (300 MHz,
CDCl3) δ 3.73 (s, 3H), 3.71 (s, 3H), 3.40 (d, J = 6.0 Hz, 1H), 3.38 (d,
J = 5.7 Hz, 1H), 2.63−2.47 (m, 2H), 2.43−2.23 (m, 6H), 2.21 (s, 3H),
2.19 (s, 3H), 2.16−1.97 (m, 4H), 1.91−1.78 (m, 2H), 1.75−1.59 (m,
2H), 1.50−1.31 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 209.6, 209.5,
201.6, 201.5, 168.8, 168.6, 65.0, 64.6, 52.66, 52.6, 45.4, 45.1, 41.2, 41.1,
37.9, 29.7, 29.1, 28.7, 24.6, 24.6; HRMS (ESI-) calcd for C11H15O4 [M
− H]− 211.09649, found 211.09595.
Table 4. Scope of the Reaction with 2-Chloroacetophenone
1a and Cyclohexenone 2c with Secondary and Tertiary
Alcohols
Methyl 3-oxo-2-(3-oxocyclopentyl)-3-phenylpropanoate
(3ad):23 yellowish oil; Rf = 0.20 (petroleum ether/ethyl acetate
80:20); yield 75%, 279 mg; obtained as a 1:1 mixture of diastereomers
a
1
with a single stereogenic center at the cyclopentanone ring: H NMR
(300 MHz, CDCl3) δ 7.91−7.86 (m, 4H), 7.49−7.43 (m, 2H), 7.37−
7.31 (m, 4H), 4.30 (dd, J = 9.6 Hz, J = 6.9 Hz, 2H), 3.52 (s, 3H), 3.49
(s, 3H), 2.99−2.88 (m, 2H), 2.34 (td, J = 19.2 Hz, J = 7.8 Hz, 2H),
2.16−1.94 (m, 7H), 1.75−1.69 (m, 1H), 1.65−1.56 (m, 1H), 1.46−
1.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 217.3, 217.3, 193.7,
193.5, 169.2, 169.1, 136.4, 136.2, 134.1, 129.1, 128.8, 59.2, 58.9, 52.8,
43.4, 43.0, 38.4, 38.3, 36.9, 36.7, 28.1, 27.6; HRMS (ESI-) calcd for
C15H15O4 [M − H]− 259.09758, found 259.09653.
Methyl 2-benzoyl-4-cyanobutanoate (3ae): yellowish oil; Rf =
1
0.10 (petroleum ether/ethyl acetate 80:20); yield 16%, 112 mg; H
NMR (300 MHz, CDCl3) δ 8.05−7.97 (m, 2H), 7.67−7.59 (m, 1H),
7.57−7.46 (m, 2H), 4.57 (t, J = 7.0 Hz, 1H), 3.71 (s, 3H), 2.63−2.41
(m, 2H), 2.40−2.29 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 193.8,
169.3, 135.7, 134.3, 129.1, 128.9, 118.8, 53.0, 51.8, 24.7, 15.4; HRMS
(ESI-) calcd for C13H12NO3 [M − H]− 230.08172, found 230.08088.
Methyl 1-benzoyl-3-formylcyclohex-3-enecarboxylate (3ah):
yellowish oil; Rf = 0.15 (petroleum ether/ethyl acetate 90:10); yield
20%, 125 mg; 1H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 7.87−7.82
(m, 2H), 7.65−7.53 (m, 1H), 7.50−7.41 (m, 2H), 6.84−6.78 (m, 1H),
3.69 (s, 3H), 2.86 (d, J = 1.5 Hz, 2H), 2.47−2.25 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 195.6, 193.1, 173.4, 148.9, 138.6, 133.1, 130.0,
128.7, 128.4, 55.6, 52.8, 28.2, 28.1, 23.5; HRMS (ESI+) calcd for
C17H19O4 [M + H]+ 287.12779, found 287.12698.
a
Reaction conditions: 2-chloroacetophenone (3 mmol), [Pd(acac)2]
(1 mol %), Xantphos (2 mol %), NBu3 (3 equiv), cyclohexenone (4
equiv), CO (10 bar), alcohol (10 mL), 90 °C. Isolated yield.
b
NMR (300 MHz, CDCl3) δ 8.04−8.00 (m, 2H), 7.61−7.55 (m, 1H),
7.51−7.45 (m, 2H), 4.47 (dd, J = 7.7, 6.5 Hz, 1H), 3.67 (s, 3H), 2.69−
2.48 (m, 2H), 2.30−2.16 (m, 2H), 2.12 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 208.0, 195.3, 170.4, 135.9, 133.9, 128.9, 128.8, 52.6, 52.4,
40.6, 30.1, 22.9; HRMS (ESI-) calcd for C14H15O4 [M − H]−
247.09758, found 247.09639.
Methyl 2-(2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbonyl)-5-
oxohexanoate (3eb): yellowish oil; Rf = 0.20 (petroleum ether/
ethyl acetate 80:20); yield 73%, 218 mg; 1H NMR (300 MHz, CDCl3)
δ 7.53−7.42 (m, 3H), 7.16 (dd, J = 7.7, 1.7 Hz, 2H), 4.13 (t, J = 7.2
Hz, 1H), 3.71 (s, 3H), 2.68−2.47 (m, 2H), 2.30 (s, 3H), 2.28−2.16
(m, 2H), 2.13 (s, 3H), 1.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
208.3, 191.2, 171.2, 138.1, 137.2, 129.6, 129.3, 128.9, 128.1, 119.2,
107.7, 54.5, 52.4, 41.0, 30.1, 23.2, 13.3, 12.8; HRMS (ESI+) calcd for
C20H24NO4 [M + H]+ 342.16998, found 342.16831.
Methyl 5-oxo-2-pivaloylhexanoate (3gb): yellowish oil; Rf1 =
0.20 (petroleum ether/ethyl acetate 80:20); yield 85%, 581 mg; H
NMR (300 MHz, CDCl3) δ 6.08 (s, 0.25H), 4.00 (dd, J = 8.0, 5.9 Hz,
1H), 3.67 (s, 3H), 3.62 (t, J = 6.2 Hz, 0.5H), 3.32 (s, 0.75H), 2.66 (t, J
= 6.2 Hz, 0.5H), 2.51 (t, J = 6.9 Hz, 2H), 2.17 (s, 0.75H), 2.11 (s, 3H),
2.09−1.93 (m, 2H), 1.16 (s, 9H), 1.10 (s, 2.25H); 13C NMR (75
MHz, CDCl3) δ 210.2, 207.8, 170.2, 52.4, 50.7, 45.5, 40.7, 30.0, 28.3,
26.1, 23.6; HRMS (ESI+) calcd for C12H21O4 [M + H]+ 229.14344,
found 229.14250.
Isopropyl 3-oxo-2-(3-oxocyclohexyl)-3-phenylpropanoate
(3ac-iPr): yellowish oil; Rf = 0.15 (petroleum ether/ethyl acetate
80:20); yield 66%, 202 mg; obtained as a 1:1 mixture of diastereomers
1
with a single stereogenic center at the cyclohexanone ring: H NMR
(300 MHz, CDCl3) δ 8.00−7.95 (m, 4H), 7.62−7.56 (m, 2H), 7.50−
7.44 (m, 4H), 5.04−4.94 (m, 2H), 4.21 (t, J = 9.3 Hz, 2H), 2.86−2.76
(m, 2H), 2.51−2.39 (m, 2H), 2.29−2.16 (m, 4H), 2.12−1.91 (m, 4H),
1.77−1.67 (m, 2H), 1.61−1.50 (m, 1H), 1.45−1.33 (m, 1H), 1.16−
1.10 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 210.0, 193.6, 193.5,
168.0, 167.8, 136.8, 133.9, 129.0, 128.9, 128.7, 128.6, 69.6, 69.5, 60.0,
59.5, 46.0, 45.3, 41.4, 38.2, 38.1, 29.7, 28.8, 24.7, 21.7, 21.6; HRMS
(ESI-) calcd for C18H21O4 [M − H]− 301.14898, found 301.14815.
tert-Butyl 3-oxo-2-(3-oxocyclohexyl)-3-phenylpropanoate
(3ac-tBu): yellowish oil; Rf = 0.15 (petroleum ether/ethyl acetate
80:20); yield 13%, 76 mg; obtained as a 1:1 mixture of diastereomers
1
with a single stereogenic center at the cyclohexanone ring: H NMR
(300 MHz, CDCl3) δ 7.97−7.86 (m, 4H), 7.56−7.48 (m, 2H), 7.47−
7.36 (m, 4H), 4.07 (t, J = 8.6 Hz, 2H), 2.82−2.62 (m, 2H), 2.51−2.29
(m, 4H), 2.27−2.08 (m, 4H), 2.08−1.80 (m, 4H), 1.73−1.46 (m, 5H),
1.27 (s, 9H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 210.0,
193.7, 193.6, 167.5, 167.2, 136.8, 136.7, 133.6, 133.5, 128.8, 128.7,
128.5, 128.4, 82.6, 82.5, 60.8, 60.2, 45.8, 45.2, 41.2, 37.9, 37.9, 29.6,
28.6, 27.8, 27.7, 24.6, 24.6; HRMS (ESI-) calcd for C19H23O4 [M −
H]− 315.16018, found 315.15933.
Methyl 3-oxo-2-(3-oxocyclohexyl)-3-phenylpropanoate
(3ac): yellowish oil; Rf = 0.20 (petroleum ether/ethyl acetate
80:20); yield 86%, 263 mg; obtained as a 1:1 mixture of diastereomers
with a single stereogenic center at the cyclohexanone ring: H NMR
(300 MHz, CDCl3) δ 7.98−7.93 (m, 4H), 7.60−7.53 (m, 2H), 7.48−
1
1551
dx.doi.org/10.1021/jo3026143 | J. Org. Chem. 2013, 78, 1547−1552

The Journal of Organic Chemistry
Article
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General synthetic procedures; H and 13C NMR. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+33) 3-20-33-63-01. E-mail: mathieu.sauthier@univ-
lille1.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from ANR CP2D 2008 and Cost Action D40
“Innovative Catalysis: New Processes and Selectivities” are
gratefully acknowledged.
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