One-Pot Reaction of Carboxylic Acids and Ynol Ethers for the Synthesis of β-Keto Esters

Article abstract of DOI:10.1021/acs.joc.8b02715

An one-pot reaction of carboxylic acids and ynol ethers for the synthesis of β-keto esters has been developed. Under promotion of Ag₂O, various carboxylic acids and ynol ethers could transform to α-acyloxy enol esters, which undergo a following DMAP-catalyzed rearrangement to deliver β-keto esters rapidly. This method provides a direct approach to β-keto esters from carboxylic acids without any preactivation. The protocol features mild reaction conditions, broad substrate scope, and the products could be transformed to an array of compounds.

Full text of DOI:10.1021/acs.joc.8b02715

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Note
One-Pot Reaction of Carboxylic Acids and
Ynol Ethers for The Synthesis of #-Keto Esters
Linwei Zeng, Zhencheng Lai, and Sunliang Cui
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02715 • Publication Date (Web): 19 Nov 2018
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The Journal of Organic Chemistry
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One-Pot Reaction of Carboxylic Acids and Ynol Ethers for The Synthesis
of β-Keto Esters
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Linwei Zeng, Zhencheng Lai, and Sunliang Cui*
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
China
ABSTRACT: A one-pot reaction of carboxylic acids and ynol ethers for the synthesis of β-keto esters has been developed.
Under promotion of Ag2O, various carboxylic acids and ynol ethers could transform to α-acyloxy enol esters, which under-
goes a following DMAP-catalyzed rearrangement to deliver β-keto esters rapidly. This method provides a direct approach to
β-keto esters from carboxylic acids without any pre-activation. The protocol features mild reaction condition, broad sub-
strate scope and the products could be transformed to an array of compounds.
β-Keto esters are type of fundamental and versatile build-
ing blocks in organic synthesis, and have been widely used
in the synthesis of various heterocycles, pharmaceuticals
and natural products.1,2 Therefore, the syntheses of β-keto
esters have received considerable attention.3 The Claisen
condensation is recognized as a fundamental C-C bond
forming reaction in organic syntheses, and it is the most
popular method for the synthesis of β-keto esters.4 How-
ever, this reaction suffers from the need of a stoichiometric
Scheme 1. Synthesis of β-Keto Esters
amount of
a strong base and uncontrollable cross-
condensation between two esters.5 Other traditional
method, Blaise reaction, which synthesize β-keto esters
from nitriles and α-halo esters in the presence of Zn, re-
mains limitation because of its expensive stating materials
and narrow substrate scope.6 A direct approach to β-keto
esters involves the acylation of diethyl malonate and the
sequential hydrolysis/decarboxylation,7 and this method
has the disadvantage of diacylation and retro-
condensations. Meanwhile, a modified method has been
developed by Wemple and co-workers.8 They used mo-
noethyl potassium malonate and acyl chloride as reagents
under promotion of MgCl2 and Et3N, and the acyla-
tion/decarboxylation domino process would furnish the β-
keto esters in good yields (Scheme 1A). In 2006, Tanabe
and co-workers disclosed a nice synthesis of β-keto esters
from silyl enol ethers and activated carboxylic acid deriva-
tives under the promotion of TiCl4 (Scheme 1B).9 Recently,
Taaning and Skrydstrup reported a palladium-catalyzed
carboxylative coupling of aryl halides with monoester po-
tassium malonates (Scheme 1C).10 In addition, Maruoka
and Feng have independently established the chiral syn-
thesis of β-keto esters either using chiral auxiliary or chiral
Lewis catalyst (Scheme 1D).11 In spite of these advances,
the general and direct transformation of carboxylic acids
to β-keto esters without any pre-activation remains chal-
lenge and interesting.
Ynol ethers are type of unique alkynes with carbon–
carbon triple bonds attached to the oxygen atom and ex-
hibit dual nucleophilic and electrophilic properties.12,13
Over the past two decades, ynol ethers haven been widely
used as useful tools in organic chemistry because of their
potential to form transient ketenium ions, thus, an array of
reactions involving ynol ethers have been reported.14 Re-
cently, Zhu and coworkers reported that the carboxylic
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acids could undergo addition to ynol ethers in the presence
Page 2 of 9
DMAP was found effective to yield a rearrangement prod-
uct 3a in 87% yield (entry 6). The standard analysis identi-
fied the product to be β-keto ester, which is inconsistent
with 1HNMR, 13CNMR and MS. Moreover, the X-ray analysis
confirmed the structure.20 At this stage, we tried to use
some other catalysts to replace Ag2O to trigger this reac-
tion. The use of different silver salts such as AgOTf, AgBF4
and Ag2CO3 was found to be inferior, and the product was
formed in decreased yields (entry 7-9), while other metal
salts such as Cu(OTf)2 and PPh3AuCl were not optimal due
to the suppression of α-acyloxy enol ester intermediate
formation in the first step (entry 10-11). When the reac-
tion temperature was decreased to 80 oC, the reaction gave
a comparable 85% yield (entry 12). When the reaction was
conducted at room temperature, the yield of 3a was low-
ered to 72% (entry 13). The survey of solvents showed
that DCE, DMF, toluene and THF were not optimal and
gave the product in slightly lower yields (entries 14-17),
while the utilization of CH3CN would completely suppress
this rearrangement (entry 18). Besides, the addition of
equivalent amount of DMAP did not show significant im-
provement of the yield, which suggested that the rear-
rangement is a catalytic process (entry 19). Furthermore, a
5 mmol scale reaction was also conducted to prove the
scalability (entry 20).
of Ag2O catalyst,15,16 and our group applied this in the mul-
ticomponent synthesis of tetrahydroisoquinolines.17 Dur-
ing our research interests of ynamides and ynol ethers,18
we assumed that the structure of in situ generated α-
acyloxy enol esters intermediates are very similar to in-
dolyl acetate,19 which might undergo rearrangement to
deliver β-keto esters and constitute a direct approach to-
ward β-keto esters. Herein we would like to report a one-
pot reaction of carboxylic acids and ynol ethers for the
synthesis of β-keto esters (Scheme 1E).
We commenced our study by investigating benzoic ac-
id 1a and ynol ether 2a. Initially, we carried out the reac-
tion by mixing 1a, 2a and 5 mol % Ag2O in dioxane at 100
oC to deliver α-acyloxy enol ester intermediate, and then
added the Lewis base catalyst to test the rearrangement.
When PPh3 was added as catalyst (20 mol % amount), the
rearrangement did not occur and the α-acyloxy enol ester
intermediate was recovered (Table 1, entry 1). The utiliza-
tion of PBu3 gave the same result and there was not any
new product formation (entry 2). Meanwhile, the employ-
ment of amine type catalysts such as DBU, DABCO and
quinoline, was also found ineffective to initiate the desired
rearrangement process. To our delight, the addition of
Table 1. Reaction Optimizationa
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With the optimized reaction condition in hand, we
next tested the substrate scope. As shown in Table 2, a
variety of carboxylic acids were subjected to this one-pot
Table 2. Scope of Carboxylic Acidsa
temp.
(oC)
yield
(%)
entry cat. 1
cat. 2
solvent
1
Ag2O
PPh3
100
100
100
100
dioxane
dioxane
dioxane
dioxane
dioxane
0
0
0
0
0
2
Ag2O
PBu3
DBU
3
Ag2O
4
Ag2O
DABCO
5
Ag2O
quinoline 100
6
Ag2O
DMAP
DMAP
DMAP
DMAP
DMAP
100
100
100
100
100
100
80
dioxane 87
dioxane 64
dioxane 76
dioxane 78
dioxane trace
dioxane trace
dioxane 85
dioxane 72
7
AgOTf
AgBF4
Ag2CO3
Cu(OTf)2
8
9
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12
13
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15
16
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18
19b
20c
a
PPh3AuCl DMAP
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
rt
100
100
100
100
100
100
100
DCE
64
47
72
62
0
DMF
toluene
THF
CH3CN
dioxane 86
dioxane 83
Reaction conditions: 1a (0.28 mmol), 2a (0.25 mmol) and
a
Reaction conditions: 1 (0.28 mmol), 2a (0.25 mmol) and
Ag2O (5 mol %) were added to dioxane (2 mL) and heated at
Ag2O (5 mol %) were added to dioxane (2 mL) and heated
o
100 C for 3 h, then the catalyst (20 mol %) were added and
at 100 oC for 3 h, then DMAP (20 mol %) in dioxane (0.5 mL)
was added and the solution was kept at 100 oC for another
3 h.
b
kept at the corresponding temperature. DMAP (0.25 mmol)
was used. c 5 mmol scale.
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reaction. The substituted benzoic acids, including the or-
substituted ynol ethers were all amenable in this process
to undergo addition/rearrangement with carboxylic acids
to deliver the β-keto esters in good yields (3w-3d’). And
the moiety of pyran, cyclopropyl, para-fluorophenyl, cy-
clobutyl and alkene were amenable in the process. Re-
specting to the alkyl substituted internal ynol ethers, the
phenylethyl and ethyl substituted substrates could under-
go the one-pot addition/rearrangement with 4-
nitrobenzoic acid and 4-chlorophenylacetic acid respec-
tively to furnish the products in moderate yields (3e’ and
3f’). In addition, the terminal ynol ether was also applica-
ble in this process to deliver the β-keto ester products in
moderate yields (3g’ and 3h’).
To demonstrate the synthetic utility, a diversification
was carried out (Scheme 2). For example, the cyclization of
compound 3a with phenyl hydrazine and hydroxylamine
would deliver the heterocyclic 1,2-dihydro-3H-pyrazol-3-
one 4 and isoxazol-5(2H)-one 5 in good yields. Further-
more, the N-Cbz protected L-proline would engage in this
one-pot reaction with ynol ether 2a to deliver 3i’ with
55:45 dr value, and the following Pd(OH)2-catalyzed hy-
drogenation would remove Cbz group to constitute cycliza-
tion and isomerization for accessing 6.
1
tho-, meta-, and para- substitution, could undergo this pro-
cess smoothly to deliver the β-keto esters in moderate to
good yields (3b-3g). And the functional groups like chloro,
nitro, trifluoromethyl, N, N-dimethylamino, methoxy, could
be well tolerable. In addition, the heterocyclic carboxylic
acids with the moiety of naphthyl, furan, thiophene, pyr-
role and indole, could be applicable for direct transfor-
mation to the β-keto ester products (3h-3l). The cinnamic
acid could also participate in reaction smoothly to provide
the product 3m in 69% yield. Meanwhile, when the ali-
phatic carboxylic acids were used, including phenylacetic
acid, thiophene-3-acetic acid, isobutyric acid, cyclohex-
anecarboxylic acid, the process could deliver the corre-
sponding products in good to excellent yields (3n-3q).
Moreover, the saturated heterocyclic carboxylic acids in-
cluding the moiety of tetrahydropyran and piperidine,
were also found applicable. Interestingly, the amino acids
such as the protected glycine, L-phenylalanine and L- pro-
line could engage in this process to deliver the products
smoothly (3t-3v), and the dr values of the newly formed
stereocenter ranged from 52:48 to 58:42. Considering the
readily availability of carboxylic acid, this method provid-
ed a direct approach to β-keto esters in simple operation. It
should be noted that this protocol excludes any pre-
activation, thus broadening the substrate scope and im-
proving functional groups compatibility.
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Scheme 2. Diversifications of β-Keto Esters
On the other hand, the scope of ynol ethers was also
tested. As shown in Table 3, the para-methoxyphenyl, pa-
ra-methylphenyl, para-chlorophenyl, para-fluorophenyl
Table 3. Scope of Ynol Ethersa
Meanwhile, control reaction was conducted to probe
the reaction mechanism. As shown in Scheme 3, 1a and 2a
were coupled in the presence of Ag2O to deliver α-acyloxy
enol ester intermediate 7. 7 was isolated and then treated
with 20 mol % DMAP. Indeed, the β-keto ester 3a could be
afforded in 96% yield. This reaction showed that the one-
pot
reaction
includes
the
successive
addi-
tion/rearrangement process.
Scheme 3. Control Reaction
Based on these results and the literatures11-15, a plau-
sible reaction mechanism for this one-pot reaction was
proposed in Scheme 4. Initially, the carboxylic acids 1
would undergo addition with the ynol ethers 2 to give the
α-acyloxy enol ester A under promotion of Ag2O. The α-
acyloxy enol ester is reactive and could be attacked by
DMAP to form zwitterionic complex B, and the following
isomerization of enol ether anion to ester species C. The
next addition of carbon anion to acyl pyridium would de-
liver β-keto esters 3 and regenerate DMAP. Thus the Ag2O-
catalyzed addition of carboxylic acids to ynol ethers and
a
Reaction conditions: 1 (0.28 mmol), 2 (0.25 mmol) and
Ag2O (5 mol %) were added to dioxane (2 mL) and heated
o
at 100 C for 3 h, then DMAP (20 mol %) in dioxane (0.5
mL) was added and the solution was kept at 100 oC for
another 3 h.
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the following DMAP-catalyzed rearrangement constitute
the one-pot reaction for the synthesis of β-keto esters.
Scheme 4. Proposed Reaction Mechanism
Page 4 of 9
temperature under stirring until it was completed. Solvent
was removed under vacuum and the residue was purified
by silica gel column chromatography using ethyl ace-
tate/petroleum ether (v/v, 1:20) as eluent to give ethyl 3-
oxo-2,3-diphenylpropanoate 3a (59 mg, 87% yield) as a
white solid.
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Ethyl 3-oxo-2,3-diphenylpropanoate (3a). White solid,
o
1
(58 mg, 87% yield), m. p. 69.8-71.6 C. H NMR (400 MHz,
CDCl3, isomers seen, ratio = 95/5) δ 13.64 (s, 0.05H), 7.96
(d, J = 7.4 Hz, 1.9H), 7.57 – 7.50 (m, 0.95H), 7.47 – 7.27 (m,
6.65H), 7.24 – 7.07 (m, 0.50H), 5.61 (s, 0.95H), 4.32 – 4.13
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(m, 2H), 1.24 (t, J = 7.2 Hz, 3H); H NMR (600 MHz, DMSO-
d6) δ 8.09 – 7.99 (m, 2H), 7.66 – 7.60 (m, 1H), 7.54 – 7.47
(m, 2H), 7.44 – 7.39 (m, 2H), 7.36 – 7.32 (m, 2H), 7.30 –
7.23 (m, 1H), 6.20 (s, 1H), 4.31 – 3.96 (m, 2H), 1.15 (t, J =
7.2 Hz, 3H); 13C{1H}NMR (150 MHz, DMSO-d6) δ 194.1,
169.0, 135.1, 133.9, 133.4, 129.7, 129.0, 128.9, 128.6, 127.8,
61.1, 58.9, 14.0; HRMS (EI) m/z calcd for C17H16O3 [M]+:
268.1099; Found: 268.1091.
In summary, a one-pot reaction of carboxylic acids
and ynol ethers for accessing β-keto esters has been devel-
oped. This method provides a direct transformation of car-
boxylic acids to β-keto esters without any pre-activation.
This protocol is featured with broad substrate scope and
sufficient structural diversity. Furthermore, the products
could be diversified to an array of compounds.
Ethyl
3-(4-chlorophenyl)-3-oxo-2-phenylpropanoate
(3b). White solid, (51 mg, 68% yield), m. p. 77.8-79.5 oC. 1H
NMR (600 MHz, DMSO-d6) δ 8.07 – 8.00 (m, 2H), 7.64 –
7.54 (m, 2H), 7.41 – 7.37 (m, 2H), 7.37 – 7.33 (m, 2H), 7.31
– 7.27 (m, 1H), 6.19 (s, 1H), 4.21 – 4.06 (m, 2H), 1.15 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 193.2,
168.8, 139.0, 133.8, 133.2, 130.8, 129.7, 129.2, 128.7, 128.0,
61.2, 59.0, 14.0; HRMS (EI) Calcd for C17H15ClO3
[M]+:302.0710; Found: 302.0713.
EXPERIMENTAL SECTION
General Information. Column chromatography was
performed over silica gel (200–300mesh). Melting points
were measured with X–4 micro melting point apparatus.
HRMS were performed on Waters GCT premier time of
flight mass spectrometer (EI). 1H NMR spectra and 13C
NMR spectra were recorded on a Bruker AV-600 spectrom-
eter or a WNMR-I-400 spectrometer in DMSO-d6 or chloro-
form-d (contain internal TMS). For DMSO-d6, chemical
shifts of 1H NMR spectra were reported in ppm with the
DMSO signal at 2.500 ppm as a standard and chemical
shifts of 13C NMR spectra were reported in ppm with the
DMSO signal at 39.52 ppm as a standard. For CDCl3, chemi-
cal shifts of 1H NMR spectra were reported in ppm with the
internal TMS signal at 0 ppm as a standard and chemical
shifts of 13C NMR spectra were reported in ppm with the
chloroform signal at 77.16 ppm as a standard. 21 The data is
being reported as (s = singlet, d = doublet, t = triplet, q =
quartet, dd = double doublet, dt = double of triplet, m =
multiplet or unresolved, br = broad singlet, coupling con-
stant(s) in Hz, integration). High temperature NMR exper-
iment was conducted on a WNMR-I-400 spectrometer at
Ethyl 3-(4-nitrophenyl)-3-oxo-2-phenylpropanoate (3c).
Yellow oil, (57 mg, 73% yield). 1H NMR (600 MHz, DMSO-d6)
δ 8.35 – 8.30 (m, 2H), 8.26 – 8.22 (m, 2H), 7.42 – 7.25 (m,
5H), 6.29 (s, 1H), 4.20 – 4.07 (m, 2H), 1.15 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 193.4, 168.6,
150.2, 139.8, 132.8, 130.2, 129.7, 128.8, 128.1, 124.1, 61.4,
59.4, 14.0; HRMS (EI) m/z calcd for C17H15NO5 [M]+:
313.0950; Found: 313.0957.
Ethyl
3-oxo-2-phenyl-3-(4-
(trifluoromethyl)phenyl)propanoate (3d). Colourless oil, (63
mg, 75% yield). 1H NMR (600 MHz, DMSO) δ 8.21 (d, J = 8.4
Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.42 – 7.38 (m, 2H), 7.38 –
7.34 (m, 2H), 7.32 – 7.27 (m, 1H), 6.27 (s, 1H), 4.18 – 4.09
(m, 2H), 1.14 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz,
DMSO) δ 193.7, 168.7, 138.4, 133.1 (q, J = 32.2 Hz), 132.9,
129.7, 129.6, 128.7, 128.0, 126.0(q, J = 3.5 Hz), 123.6(q, J =
272.8 Hz), 61.3, 59.3, 13.9; HRMS (EI) m/z calcd for
C18H15F3O3 [M]+: 336.0973; Found: 336.0969.
Ethyl 3-oxo-2-phenyl-3-(o-tolyl)propanoate (3e). Col-
ourless oil, (35 mg, 50% yield). 1H NMR (600 MHz, DMSO-d6,
isomers seen, ratio = 87/13) δ 13.28 (s, 0.13H), 7.93 (d, J =
7.8 Hz, 0.87H), 7.43 – 6.96 (m, 8.13H), 6.03 (s, 0.87H), 4.22
(q, J = 7.2 Hz, 0.26H), 4.16 – 4.05 (m, 1.74H), 2.36 (s,
2.61H), 2.22 (s, 0.39H), 1.15 (t, J = 7.2 Hz, 0.39H), 1.12 (t, J
= 7.2 Hz, 2.61H);13C{1H}NMR (150 MHz, DMSO-d6, isomers
seen) δ 197.4, 172.5, 168.9, 138.2, 136.3, 135.2, 134.6,
134.1, 133.3, 132.0, 131.8, 131.3, 129.9, 129.7, 129.1, 129.0,
128.9, 128.6, 127.8, 127.5, 126.6, 126.0, 125.2, 105.8, 61.4,
61.1, 20.7, 19.2, 14.1, 14.0; HRMS (EI) m/z calcd for
C18H18O3 [M]+: 282.1256; Found: 282.1263.
o
60 C in DMSO-d6. Solvents and reagents were commercial
available and used without further purification unless oth-
erwise noted. Anhydrous solvents were purified according
to standard methods.
Typical procedure for one-pot synthesis of β-keto
esters. To an oven-dried schlenk tube was added benzoic
acid 1a (34.5 mg, 0.28 mmol) and Ag2O (2.9 mg, 0.0125
mmol), then evacuated and purged with Argon three times.
(Ethoxyethynyl)benzene 2a (36.5 mg, 0.25 mmol) was dis-
solved in anhydrous dioxane (2 mL) and added by a syringe.
o
Ethyl
3-(3-(dimethylamino)phenyl)-3-oxo-2-
The mixture was stirred at 100 C in an oil bath until the
phenylpropanoate (3f). Yellow oil, (67 mg, 87% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.43 – 7.38 (m, 2H), 7.36 –
7.25 (m, 5H), 7.25 – 7.22 (m, 1H), 6.95 (dd, J1 = 8.4 Hz, J2 =
1.8 Hz, 1H), 6.16 (s, 1H), 4.30 – 3.87 (m, 2H), 2.90 (s, 6H),
1.16 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150 MHz, DMSO-d6) δ
starting material was fully converted to α-acyloxy enol es-
ter intermediate, then 4-dimethylaminopyridine (DMAP) (6
mg, 0.05 mmol) was dissolved in anhydrous dioxane (0.5
mL) and added. The reaction was allowed to proceed at this
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194.6, 169.2, 150.5, 135.7, 133.8, 129.7, 129.4, 128.6, 127.8,
(600 MHz, DMSO-d6, isomers seen, ratio = 56/44) δ 13.09
(s, 0.44H), 7.74 (d, J = 16.2 Hz, 0.56H), 7.69 – 7.65 (m, 1H),
7.50 – 7.16 (m, 10.44H), 6.93 (d, J = 16.2 Hz, 0.56H), 6.38 (d,
J = 15.6 Hz, 0.44H), 5.57 (s, 0.56H), 4.22 – 4.10 (m, 2H),
1.18 (t, J = 7.2 Hz, 1.68H), 1.13 (t, J = 7.2Hz, 1.32H); 13C{1H}
NMR (150 MHz, DMSO-d6, isomers seen) δ 193.3, 172.5,
168.8, 166.0, 144.4, 136.9, 135.0, 134.0, 133.6, 133.2, 131.7,
131.1, 129.8, 129.7, 129.14, 129.11, 128.8, 128.6, 128.2,
127.9, 127.54, 127.51, 124.9, 119.8, 105.8, 61.3, 61.08,
61.05, 14.09, 14.08; HRMS (EI) m/z calcd for C19H18O3 [M]+:
294.1256; Found: 294.1267.
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4
5
6
7
8
117.5, 116.7, 111.8, 61.1, 59.1, 40.0, 14.1; HRMS (EI) m/z
calcd for C19H21NO3 [M]+: 311.1521; Found: 311.1524.
Ethyl
3-oxo-2-phenyl-3-(3,4,5-
trimethoxyphenyl)propanoate (3g). Colourless oil, (73 mg,
1
82% yield). H NMR (600 MHz, DMSO-d6) δ 7.44 (d, J = 7.2
Hz, 2H), 7.38 – 7.32 (m, 4H), 7.30 – 7.26 (m, 1H), 6.29 (s,
1H), 4.15 (q, J = 7.2 Hz, 2H), 3.81 (s, 6H), 3.71 (s, 3H), 1.18
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ
192.9, 169.1, 152.8, 142.3, 133.8, 130.1, 129.7, 128.6, 127.8,
106.6, 61.1, 60.2, 58.7, 56.1, 14.1; HRMS (EI) m/z calcd for
C20H22O6 [M]+: 358.1416; Found: 358.1419.
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Ethyl 3-oxo-2,4-diphenylbutanoate (3n). Colourless oil,
(56 mg, 79% yield). H NMR (600 MHz, DMSO-d6) δ 7.40 –
1
Ethyl
3-(naphthalen-2-yl)-3-oxo-2-phenylpropanoate
(3h). Colourless oil, (46 mg, 58% yield). 1H NMR (600 MHz,
DMSO-d6) δ 8.83 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 – 7.98
(m, 2H), 7.96 (d, J = 8.4 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.64 –
7.60 (m, 1H), 7.53 – 7.48 (m, 2H), 7.38 – 7.32 (m, 2H), 7.29
– 7.24 (m, 1H), 6.38 (s, 1H), 4.31 – 3.98 (m, 2H), 1.15 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 194.1,
169.0, 135.2, 133.5, 132.5, 132.1, 131.3, 129.8, 129.7, 129.3,
128.7, 128.6, 127.9, 127.8, 127.3, 124.0, 61.2, 58.9, 14.0;
HRMS (EI) m/z calcd for C21H18O3 [M]+: 318.1256; Found:
318.1239.
Ethyl 3-(furan-2-yl)-3-oxo-2-phenylpropanoate (3i).
Colourless oil, (44 mg, 69% yield). 1H NMR (600 MHz,
DMSO-d6) δ 8.05 (d, J = 0.6 Hz, 1H), 7.69 (d, J = 3.6 Hz, 1H),
7.45 – 7.41 (m, 2H), 7.38 – 7.34 (m, 2H), 7.33 – 7.29 (m,
1H), 6.75 (dd, J1 = 3.6 Hz, J2 = 1.8 Hz, 1H), 5.81 (s, 1H), 4.48
– 3.96 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150
MHz, DMSO-d6) δ 181.7, 168.4, 150.6, 149.2, 133.2, 129.6,
128.5, 128.0, 121.0, 113.1, 61.3, 58.8, 14.0; HRMS (EI) m/z
calcd for C15H14O4 [M]+: 258.0892; Found: 258.0877.
Ethyl 3-oxo-2-phenyl-3-(thiophen-2-yl)propanoate (3j).
White solid, (50 mg, 73% yield), m. p. 63.8-65.4 oC. 1H NMR
(600 MHz, DMSO-d6) δ 8.14 (dd, J1 = 3.6 Hz, J2 = 0.6 Hz, 1H),
8.07 (dd, J1 = 4.8 Hz, J2 = 0.6 Hz, 1H), 7.50 – 7.44 (m, 2H),
7.40 – 7.33 (m, 2H), 7.32 – 7.28 (m, 1H), 7.25 (dd, J1 = 4.8
Hz, J2 = 4.2 Hz, 1H), 6.06 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H),
1.16 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150 MHz, DMSO-d6) δ
186.9, 168.5, 142.3, 136.8, 135.3, 133.5, 129.6, 129.1, 128.6,
128.0, 61.3, 59.3, 14.0; HRMS (EI) m/z calcd for C15H14O3S
[M]+: 274.0664; Found: 274.0671.
7.37 (m, 2H), 7.36 – 7.31 (m, 3H), 7.30 – 7.26 (m, 2H), 7.25
– 7.21 (m, 1H), 7.10 – 7.05 (m, 2H), 5.25 (s, 1H), 4.16 – 4.07
(m, 2H), 3.90 (d, J = 16.8 Hz, 1H), 3.79 (d, J = 16.8 Hz, 1H),
1.16 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150 MHz, DMSO-d6) δ
201.6, 168.4, 133.9, 132.9, 129.8, 129.7, 128.6, 128.3, 128.0,
126.8, 63.2, 61.2, 47.9, 14.0; HRMS (EI) m/z calcd for
C18H18O3 [M]+: 282.1256; Found: 282.1259.
Ethyl 3-oxo-2-phenyl-4-(thiophen-3-yl)butanoate (3o).
Colourless oil, (57 mg, 79% yield). 1H NMR (600 MHz,
DMSO-d6, isomers seen, ratio = 92/8) δ 13.11 (s, 0.08H),
7.47 (dd, J1 = 4.8 Hz, J2 = 3.0 Hz, 0.08H), 7.45 (dd, J1 = 4.8 Hz,
J2 = 3.0 Hz, 0.92H), 7.41 – 6.82 (m, 7H), 5.23 (s, 0.92H), 4.20
– 4.05 (m, 2H), 3.92 (d, J = 17.4 Hz, 0.92H), 3.86 (s, 0.16H),
3.81 (d, J = 17.4 Hz, 0.92H), 1.16 (t, J = 7.2 Hz, 1.76H), 1.09
(t, J = 7.2 Hz, 0.24H); 13C{1H} NMR (150 MHz, DMSO-d6,
major isomer seen) δ 201.2, 168.4, 133.5, 132.9, 129.6,
129.0, 128.6, 128.0, 126.0, 123.7, 63.0, 61.2, 42.5, 14.0;
HRMS (EI) m/z calcd for C16H16O3S [M]+: 288.0820;
Found:288.0813.
Ethyl 4-methyl-3-oxo-2-phenylpentanoate (3p). Colour-
1
less oil, (47 mg, 81% yield). H NMR (600 MHz, DMSO-d6,
isomers seen, ratio = 94/6) δ 13.22 (s, 0.06H), 7.46 – 7.11
(m, 5H), 5.34 (s, 0.94H), 4.25 – 4.02 (m, 2H), 2.71 (hept, J =
6.6 Hz, 0.94H), 2.55 – 2.51 (m, 0.06H), 1.16 (t, J = 7.2 Hz,
2.82H), 1.08 (t, 0.18H), 1.05 (d, J = 6.6 Hz, 2.82H), 1.00 (d, J
= 7.2 Hz, 0.36H), 0.90 (d, J = 6.6 Hz, 2.82H); 13C{1H} NMR
(150 MHz, DMSO-d6, major isomer seen) δ 207.7, 168.6,
133.1, 129.6, 128.5, 127.9, 61.5, 61.1, 39.8, 18.4, 18.0, 14.0;
HRMS (EI) m/z calcd for C14H18O3 [M]+: 234.1256;
Found:234.1261.
Ethyl 3-cyclohexyl-3-oxo-2-phenylpropanoate (3q). Col-
ourless oil, (62 mg, 91% yield). 1H NMR (600 MHz, DMSO-d6)
δ 7.41 – 7.26 (m, 5H), 5.32 (s, 1H), 4.19 – 4.02 (m, 2H), 2.49
– 2.45 (m, 1H), 1.92 – 1.83 (m, 1H), 1.73 – 1.64 (m, 1H),
1.63 – 1.52 (m, 3H), 1.27 – 1.17 (m, 3H), 1.15 (t, J = 7.2 Hz,
3H), 1.13 – 1.05 (m, 2H); 13C{1H}NMR (150 MHz, DMSO-d6)
δ 206.7, 168.6, 133.1, 129.7, 128.5, 127.9, 61.5, 61.0, 49.5,
28.2, 27.9, 25.3, 25.1, 24.8, 14.0; HRMS (EI) m/z calcd for
C17H22O3 [M]+: 274.1569; Found:274.1573.
Ethyl
3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-2-
phenylpropanoate (3k). White solid, (51 mg, 75% yield), m.
o
p. 61.2-63.0 C. 1H NMR (600 MHz, DMSO-d6) δ 7.55 – 7.43
(m, 2H), 7.36 – 7.30 (m, 3H), 7.29 – 7.24 (m, 1H), 7.21 –
7.14 (m, 1H), 6.13 (dd, J1 = 4.2 Hz, J2 = 2.4 Hz, 1H), 5.79 (s,
1H), 4.16 – 4.03 (m, 2H), 3.81 (s, 3H), 1.16 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 183.6, 169.1,
134.7, 133.3, 129.5, 129.0, 128.3, 127.6, 121.6, 108.5, 61.0.,
59.3, 37.2, 14.1; HRMS (EI) m/z calcd for C16H17NO3 [M]+:
271.1208; Found: 271.1212.
Ethyl
3-(1-methyl-1H-indol-3-yl)-3-oxo-2-
Ethyl
3-oxo-2-phenyl-3-(tetrahydro-2H-pyran-4-
phenylpropanoate (3l). Colourless oil, (61 mg, 76% yield). 1H
NMR (600 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.16 (d, J = 7.8 Hz,
1H), 7.58 – 7.50 (m, 3H), 7.35 – 7.31 (m, 2H), 7.30 – 7.22
(m, 3H), 5.78 (s, 1H), 4.19 – 4.06 (m, 2H), 3.86 (s, 3H), 1.16
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ
187.7, 169.1, 139.0, 137.5, 134.8, 129.5, 128.3, 127.5, 126.0,
123.4, 122.7, 121.4, 114.0, 111.0, 60.9, 59.8, 33.5, 14.1;
HRMS (EI) m/z calcd for C20H19NO3 [M]+: 321.1365; Found:
321.1371.
yl)propanoate (3r). Colourless oil, (56 mg, 82% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.45 – 7.26 (m, 5H), 5.38 (s,
1H), 4.18 – 4.03 (m, 2H), 3.87 – 3.81 (m, 1H), 3.79 – 3.75
(m, 1H), 3.28 (td, J1 = 11.4 Hz, J2 = 2.4 Hz, 1H), 3.22 (td, J1 =
11.4 Hz, J2 = 2.4 Hz, 1H), 2.76 (tt, J1 = 11.4 Hz, J2 = 3.6 Hz,
1H), 1.83 – 1.76 (m, 1H), 1.54 – 1.35 (m, 3H), 1.16 (t, J = 7.2
Hz, 3H); 13C{1H}NMR (150 MHz, DMSO-d6) δ 205.5, 168.5,
132.9, 129.7, 128.6, 127.9, 66.2, 66.0, 61.2, 61.1, 46.5, 28.1,
27.8, 14.0; HRMS (EI) m/z calcd for C16H20O4 [M]+:
276.1362; Found:276.1367.
Ethyl (E)-3-oxo-2,5-diphenylpent-4-enoate (3m). Light-
yellow solid, (50 mg, 69% yield), m. p. 84.8-86.2 oC. 1H NMR
Ethyl
3-oxo-2-phenyl-3-(1-tosylpiperidin-4-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
yl)propanoate (3s). Colourless oil, (83 mg, 78% yield). 1H
Page 6 of 9
6.90 (d, J = 7.8 Hz, 2H), 6.11 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H),
3.70 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150 MHz,
DMSO-d6) δ 194.4, 169.3, 158.9, 135.1, 133.9, 130.9, 129.0,
129.0, 125.3, 114.1, 61.1, 58.1, 55.1, 14.1; HRMS (EI) m/z
calcd for C18H18O4 [M]+: 298.1205; Found:298.1211.
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2
3
4
5
6
7
8
NMR (600 MHz, DMSO-d6) δ 7.59 (d, J = 8.4 Hz, 2H), 7.43 (d,
J = 8.4 Hz, 2H), 7.35 – 7.28 (m, 3H), 7.28 – 7.25 (m, 2H),
5.29 (s, 1H), 4.16 – 3.95 (m, 2H), 3.56 – 3.51 (m, 1H), 3.49 –
3.44 (m, 1H), 2.55 – 2.51 (m, 1H), 2.39 (s, 3H), 2.26 (td, J1 =
11.4 Hz, J2 = 2.4 Hz, 1H), 2.19 (td, J1 = 11.4 Hz, J2 = 2.4 Hz,
1H), 1.96 – 1.89 (m, 1H), 1.68 – 1.62 (m, 1H), 1.51 – 1.35
(m, 2H), 1.12 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 205.5, 168.4, 143.7, 132.7, 132.4, 129.9, 129.6,
128.6, 128.0, 127.6, 61.4, 61.2, 46.1, 45.2, 45.1, 26.9, 26.6,
21.1, 14.0; HRMS (EI) m/z calcd for C23H27NO5S [M]+:
429.1610; Found:429.1615.
Ethyl
2-(4-methoxyphenyl)-3-oxo-3-(tetrahydro-2H-
pyran-4-yl)propanoate (3x). Colourless oil, (64 mg, 84%
1
yield). H NMR (600 MHz, DMSO-d6) δ 7.24 (d, J = 9.0 Hz,
2H), 6.91 (d, J = 9.0 Hz, 2H), 5.27 (s, 1H), 4.11 – 4.05 (m,
2H), 3.84 – 3.80 (m, 1H), 3.77 – 3.74 (m, 1H), 3.72 (s, 3H),
3.26 (td, J1 = 11.4 Hz, J2 = 2.4 Hz, 1H), 3.20 (td, J1 = 11.4 Hz,
J2 = 2.4 Hz, 1H), 2.71 (tt, J1 = 11.4 Hz, J2 = 3.6 Hz, 1H), 1.81 –
1.74 (m, 1H), 1.49 – 1.34 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (150 MHz, DMSO-d6) δ 205.8, 168.8, 159.0,
130.8, 124.8, 114.0, 66.3, 66.0, 61.0, 60.4, 55.1, 46.3, 28.2,
27.8, 14.0; HRMS (EI) m/z calcd for C17H22O5 [M]+:
306.1467; Found:306.1474.
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Ethyl
4-(((benzyloxy)carbonyl)amino)-3-oxo-2-
1
phenylbutanoate (3t). Colourless oil, (47 mg, 53% yield). H
NMR (600 MHz, DMSO-d6) δ 7.60 (t, J = 6.0 Hz, 1H), 7.39 –
7.29 (m, 10H), 5.23 (s, 1H), 5.01 (s, 2H), 4.15 – 4.08 (m, 2H),
4.05 (dd, J1 = 18.6 Hz, J2 = 6.0 Hz, 1H), 3.91 (dd, J1 = 18.6 Hz,
J2 = 6.0 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150
MHz, DMSO-d6) δ 200.5, 168.2, 156.4, 137.0, 132.8, 129.6,
128.6, 128.5, 128.0, 127.9, 127.8, 65.6, 61.3, 60.4, 49.5,
14.0; HRMS (EI) m/z calcd for C20H21NO5 [M]+: 355.1420;
Found:355.1435.
Ethyl 3-oxo-3-(m-tolyl)-2-(p-tolyl)propanoate (3y).
White solid, (61 mg, 83% yield), m. p. 73.8-75.8 oC. 1H NMR
(600 MHz, DMSO-d6) δ 7.88 – 7.77 (m, 2H), 7.43 (d, J = 7.2
Hz, 1H), 7.40 – 7.33 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.14 (d,
J = 7.8 Hz, 2H), 6.10 (s, 1H), 4.18 – 4.07 (m, 2H), 2.33 (s,
3H), 2.24 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (150
MHz, DMSO-d6) δ 194.3, 169.1, 138.5, 137.1, 135.2, 134.5,
130.4, 129.5, 129.2, 128.8, 126.3, 61.0, 58.5, 20.9, 20.7,
14.0; HRMS (EI) m/z calcd for C19H20O3 [M]+: 296.1412;
Found:296.1422.
Ethyl 3-cyclopropyl-3-oxo-2-(p-tolyl)propanoate (3z).
Colourless oil, (45 mg, 74% yield). 1H NMR (600 MHz,
DMSO-d6) δ 7.22 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H),
5.21 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.03 –
1.95 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H), 0.94 – 0.87 (m, 2H),
0.85 – 0.79 (m, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ
204.3, 168.7, 137.2, 130.2, 129.6, 129.2, 63.7, 60.9, 20.8,
20.2, 14.0, 11.7, 11.6; HRMS (EI) m/z calcd for C15H18O3
[M]+: 246.1256; Found:246.1257.
Ethyl
(4S)-4-(1,3-dioxoisoindolin-2-yl)-3-oxo-2,5-
diphenylpentanoate (3u). Colourless oil, (95 mg, 86% yield).
1H NMR (600 MHz, DMSO-d6) δ 7.86 – 7.75 (m, 4H), 7.35 –
7.22 (m, 5H), 7.15 – 6.99 (m, 5H), 5.37 (s, 1H), 5.26 (dd, J1 =
11.4 Hz, J2 = 4.8 Hz, 0.48H), 5.15 (dd, J1 = 11.4 Hz, J2 = 4.8 Hz,
0.52H), 4.05 (q, J = 7.2 Hz, 1.04H), 4.02 – 3.97 (m, 0.96H),
3.53 (dd, J1 = 14.4 Hz, J2 = 4.8 Hz, 0.48H), 3.44 (dd, J1 = 14.4
Hz, J2 = 4.8 Hz, 0.52H), 3.28 – 3.22 (m, 0.48H), 3.12 – 3.06
(m, 0.52H), 1.14 – 1.02 (m, 3H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 198.8, 198.5, 167.9, 167.8, 167.1, 166.9, 136.8,
136.7, 134.98, 134.97, 132.5, 132.2, 130.784, 130.777,
129.6, 129.5, 128.80, 128.78, 128.6, 128.4, 128.3, 128.2,
128.0, 126.8, 126.7, 123.50, 123.47, 61.6, 61.3, 60.1, 59.9,
59.3, 58.9, 32.72, 32.66, 13.9, 13.8; HRMS (EI) m/z calcd for
C27H23NO5 [M]+: 441.1576; Found:441.1569.
Ethyl
2-(4-chlorophenyl)-3-(4-fluorophenyl)-3-
1
Tert-butyl
(2S)-2-(3-ethoxy-3-oxo-2-
oxopropanoate (3a’). Colourless oil, (66 mg, 83% yield). H
NMR (600 MHz, DMSO-d6) δ 8.17 – 8.07 (m, 2H), 7.45 –
7.40 (m, 4H), 7.39 – 7.32 (m, 2H), 6.25 (s, 1H), 4.24 – 4.05
(m, 2H), 1.14 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 192.6, 168.6, 165.5 (d, J = 253.6 Hz), 132.9,
132.3, 132.1 (d, J = 9.7 Hz), 131.7 (d, J = 2.7 Hz), 131.5,
128.7, 116.2 (d, J = 22.1 Hz), 61.4, 58.1, 14.0; HRMS (EI)
m/z calcd for C17H14ClFO3 [M]+: 320.0616; Found:320.0619.
Ethyl 2-(4-chlorophenyl)-3-cyclobutyl-3-oxopropanoate
(3b’). Colourless oil, (49 mg, 70% yield). 1H NMR (600 MHz,
DMSO-d6, isomers seen, ratio = 92/8) δ 13.34 (s, 0.08H),
7.43 (d, J = 8.4 Hz, 1.84H), 7.39 (d, J = 8.4 Hz, 0.16H), 7.35 (d,
J = 8.4 Hz, 1.84H), 7.14 (d, J = 8.4 Hz, 0.16H), 5.17 (s, 0.92H),
4.32 – 3.96 (m, 2H), 3.56 – 3.29 (m, 1H), 2.19 – 1.78 (m,
5H), 1.72 – 1.61 (m, 1H), 1.17 (t, J = 7.2 Hz, 2.76H), 1.09 (t, J
= 7.2 Hz, 0.24H); 13C{1H}NMR (150 MHz, DMSO-d6, major
isomer seen) δ 204.4, 168.3, 132.8, 132.0, 131.5, 128.5,
61.3, 60.6, 44.6, 24.5, 24.2, 17.1, 14.0; HRMS (EI) m/z calcd
for C15H17ClO3 [M]+: 280.0866; Found:280.0874.
phenylpropanoyl)pyrrolidine-1-carboxylate (3v). Colourless
oil, (80 mg, 88% yield). 1H NMR (600 MHz, DMSO-d6, 2 dia-
stereoisomers and their rotamers seen, ratio = 41/17:
26/16 ) δ 7.48 – 7.28 (m, 5H), 5.30 (s, 0.41H), 5.26 (s,
0.17H), 5.21 (s, 0.16H), 5.17 (s, 0.26H), 4.45 (dd, J1 = 9.6 Hz,
J2 = 3.0 Hz, 0.42H), 4.42 – 4.35 (m, 0.58H), 4.17 – 4.05 (m,
2H), 3.37 – 3.21 (m, 2H), 2.27 – 2.02 (m, 1H), 1.96 – 1.41
(m, 3H), 1.39 (s, 1.53H), 1.38 (s, 1.44H), 1.30 (s, 2.34H),
1.20 – 1.13 (m, 3H), 1.04 (s, 3.69H); 1H NMR (400 MHz,
DMSO-d6, 60 ℃, 2 diastereoisomers seen, ratio = 58/42) δ
7.50 – 7.26 (m, 5H), 5.22 (s, 0.58H), 5.15 (s, 0.42H), 4.52 –
4.33 (m, 1H), 4.19 – 4.08 (m, 2H), 3.44 – 3.22 (m, 2H), 2.35
– 1.47 (m, 4H), 1.41 – 1.02 (m, 12H); 13C{1H} NMR (150
MHz, DMSO-d6, 2 diastereoisomers and their rotamers seen)
δ 203.3, 203.2, 202.9, 202.4, 168.22, 168.18, 167.9, 167.8,
154.1, 153.7, 153.0, 132.7, 132.6, 132.5, 132.1, 129.9, 129.7,
129.6, 128.54, 128.46, 128.4, 128.12, 128.05, 127.9, 79.3,
79.2, 79.0, 78.7, 65.2, 65.1, 65.0, 64.6, 61.25, 61.23, 61.16,
60.55, 60.53, 60.3, 59.2, 46.8, 46.6, 46.5, 46.4, 30.1, 28.8,
28.7, 28.5, 28.12, 28.08, 27.8, 27.5, 24.0, 23.6, 23.1, 22.2,
13.99, 13.96, 13.95; HRMS (EI) m/z calcd for C20H27NO5
[M]+: 361.1889; Found:361.1877.
Ethyl
2-(4-fluorophenyl)-3-(4-methoxyphenyl)-3-
1
oxopropanoate (3c’). Colourless oil, (60 mg, 76% yield). H
NMR (600 MHz, DMSO-d6) δ 8.01 (d, J = 8.4 Hz, 2H), 7.52 –
7.39 (m, 2H), 7.21 – 7.14 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H),
6.16 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.15 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 192.5,
169.1, 163.8, 161.8 (d, J = 244.3 Hz), 131.7 (d, J = 8.2 Hz),
Ethyl 2-(4-methoxyphenyl)-3-oxo-3-phenylpropanoate
(3w). White solid, m. p. 68.8-70.9 oC, (65 mg, 87% yield). 1H
NMR (600 MHz, DMSO-d6) δ 8.02 (d, J = 7.8 Hz, 2H), 7.66 –
7.58 (m, 1H), 7.56 – 7.45 (m, 2H), 7.32 (d, J = 9.0 Hz, 2H),
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131.5, 130.0 (d, J = 2.9 Hz), 127.8, 115.5 (d, J = 21.4 Hz),
seen) δ 202.8, 202.6, 202.5, 202.4, 168.1, 168.0, 167.74,
167.71, 154.3, 154.0, 153.5, 153.4, 136.83, 136.77, 136.7,
136.6, 132.5, 132.3, 132.1, 129.7, 129.61, 129.58, 129.5,
128.40, 128.35, 128.28, 128.2, 128.1, 128.0, 127.90, 127.86,
127.72, 127.66, 127.5, 127.4, 127.3, 66.3, 66.1, 66.0, 65.7,
65.4, 65.1, 64.9, 64.2, 61.21, 61.18, 61.11, 61.07, 60.6, 60.4,
60.0, 59.9, 47.1, 47.0, 46.5, 46.4, 29.6, 29.0, 28.6, 28.3, 23.9,
23.5, 23.0, 22.5, 14.0, 13.9, 13.8; HRMS (EI) m/z calcd for
C23H25NO5 [M]+: 395.1733; Found: 395.1716.
1
2
3
4
5
6
7
8
114.3, 61.2, 57.7, 55.8, 14.1; HRMS (EI) m/z calcd for
C18H17FO4 [M]+: 316.1111; Found: 316.1123.
Ethyl 2-(4-fluorophenyl)-3-oxohept-6-enoate (3d’). Col-
ourless oil, (53 mg, 81% yield). 1H NMR (600 MHz, DMSO-d6,
isomers seen, ratio = 93/7) δ 13.17 (s, 0.07H), 7.41 – 7.16
(m, 4H), 5.81 – 5.62 (m, 1H), 5.22 (s, 0.93H), 5.00 – 4.86 (m,
2H), 4.20 – 4.06 (m, 2H), 2.71 – 2.61 (m, 1H), 2.58 – 2.50
(m, 1H), 2.23 – 2.13 (m, 2H), 1.16 (t, J = 7.2 Hz, 2.79H), 1.08
(t, J = 7.2 Hz, 0.21H); 13C{1H} NMR (150 MHz, DMSO-d6,
major isomer seen) δ 203.2, 168.5, 161.9 (d, J = 244.2 Hz),
137.0, 131.7 (d, J = 8.3 Hz), 129.3 (d, J = 3.0 Hz), 115.5 (d, J =
21.5 Hz), 115.4, 62.3, 61.2, 40.4, 27.1, 14.0; HRMS (EI) m/z
calcd for C15H17FO3 [M]+: 264.1162; Found:264.1147.
3-Tolyl 2-(4-nitrobenzoyl)-4-phenylbutanoate (3e’). Col-
ourless oil, (63 mg, 63% yield). 1H NMR (600 MHz, DMSO-d6)
δ 8.45 – 8.36 (m, 2H), 8.32 – 8.25 (m, 2H), 7.33 – 7.17 (m,
6H), 7.07 (d, J = 7.8 Hz, 1H), 6.85 – 6.77 (m, 2H), 5.02 (t, J =
7.2 Hz, 1H), 2.80 – 2.71 (m, 2H), 2.33 – 2.29 (m, 2H), 2.28 (s,
3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 194.7, 168.2,
150.3, 150.0, 140.8, 140.2, 139.5, 130.0, 129.3, 128.5, 128.4,
126.9, 126.2, 124.2, 121.7, 118.3, 53.1, 32.7, 30.1, 20.7;
HRMS (EI) m/z calcd for C24H21NO5 [M]+: 403.1420;
Found:403.1428.
General procedure for synthesis of 4. To a round
bottom flask was added 3a (40 mg, 0.15 mmol) and
PhNHNH2 (25 mg, 0.23 mmol), then ethanol (0.5 mL) was
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
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58
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60
o
added as solvent. The mixture was stirred at 80 C in an oil
bath and reflux for 12h. Solvent was removed under vacu-
um and extracted with EtOAc (3×5 mL), the combined or-
ganic layer was washed by brine, dried over anhydrous
Na2SO4, filtered and evaporated to obtain the residue which
was purified by silica gel column chromatography using
DCM/MeOH (v/v, 20:1) as eluent to give 1,3,4-triphenyl-
1H-pyrazol-5-ol 4 (43 mg, 92% yield) as a white solid.
1,3,4-Triphenyl-1H-pyrazol-5-ol (4). White solid, (43 mg,
92% yield), m. p. 192.8-194.1 oC. 1H NMR (400 MHz, DMSO-
d6) δ 10.92 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.63 – 7.13 (m,
13H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 149.6, 148.0,
138.4, 132.1, 129.7, 129.0, 128.3, 127.7, 126.4, 126.1, 122.0;
HRMS (EI) m/z calcd for C21H16N2O [M]+: 312.1263;
Found:312.1255.
3-Tolyl 4-(4-chlorophenyl)-3-oxo-2-phenethylbutanoate
1
(3f’). Colourless oil, (62 mg, 61% yield). H NMR (600 MHz,
DMSO-d6) δ 7.38 (d, J = 8.4 Hz, 2H), 7.33 – 7.28 (m, 3H),
7.26 – 7.19 (m, 5H), 7.09 (d, J = 7.2 Hz, 1H), 6.97 – 6.84 (m,
2H), 4.10 – 4.00 (m, 3H), 2.71 – 2.61 (m, 2H), 2.31 (s, 3H),
2.28 – 2.13 (m, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ
202.6, 168.1, 150.1, 140.7, 139.4, 132.9, 131.8, 129.3, 128.5,
128.4, 128.30, 128.29, 126.9, 126.2, 121.9, 118.5, 57.0, 47.3,
32.8, 29.4, 20.8; HRMS (EI) m/z calcd for C25H23ClO3 [M]+:
406.1336; Found:406.1342.
General procedure for synthesis of 5. To a round
bottom flask was added 3a (40 mg, 0.15 mmol) and hydrox-
ylamine hydrochloride (32 mg, 0.45 mmol), then ethanol (1
o
mL) was added as solvent. The mixture was stirred at 80 C
in an oil bath and reflux for 12h. Solvent was removed un-
der vacuum and extracted with EtOAc (3×5 mL), the com-
bined organic layer was washed by brine, dried over anhy-
drous Na2SO4, filtered and evaporated to obtain the crude
product which was purified by recrystallization to give 5
(mixture of 3,4-diphenylisoxazol-5(2H)-one and 3,4-
diphenylisoxazol-5(4H)-one) (26 mg, 73% yield) as a white
solid.
Phenyl 3-oxo-3-phenylpropanoate (3g’). Colourless oil,
(26 mg, 43% yield). 1H NMR (400 MHz, CDCl3, isomers seen,
ratio = 73/27) δ 12.33 (s, 0.27H), 8.01 (d, J = 7.6 Hz, 1.46H),
7.84 (d, J = 7.6 Hz, 0.54H), 7.68 – 7.05 (m, 8H), 5.92 (s,
1
0.27H), 4.24 (s, 1.46H); H NMR (600 MHz, DMSO-d6, iso-
3,4-Diphenylisoxazol-5(2H)-one (5). White solid, (26
mers seen, ratio = 91/9) δ 12.21 (s, 0.09H), 8.04 (d, J = 7.2
Hz, 1.82H), 7.95 (d, J = 7.2 Hz, 0.18H), 7.74 – 7.51 (m, 3H),
7.48 – 7.42 (m, 2H), 7.32 – 7.26 (m, 1H), 7.24 (d, J = 7.2 Hz,
0.18H), 7.13 (d, J = 7.2 Hz, 1.82H), 6.26 (s, 0.09H), 4.52 (s,
1.82H); 13C{1H} NMR (150 MHz, DMSO-d6, major isomer
seen) δ 193.6, 166.9, 150.4, 135.7, 134.1, 129.7, 129.0,
128.6, 126.2, 121.7, 45.7; HRMS (EI) m/z calcd for C15H12O3
[M]+: 240.0786; Found:240.0777.
o
1
mg, 73% yield), m. p. 159.8-161.2 C. H NMR (400 MHz,
CDCl3, isomers seen, ratio = 77/23) δ 7.89 – 6.89 (m, 10H),
4.91 (s, 0.23H); 13C{1H} NMR (150 MHz, CDCl3, isomers
seen) δ 176.1, 172.3, 161.30, 161.27, 132.0, 131.6, 129.9,
129.3, 129.2, 129.1, 128.8, 128.7, 128.3, 128.1, 127.7, 127.4,
127.2, 102.4, 51.4; HRMS (EI) m/z calcd for C15H11NO2 [M]+:
237.0790; Found:237.0784.
General procedure for synthesis of 6. To a round
bottom flask was added 3i’ (50 mg, 0.13 mmol) and 10%
Pd(OH)2/C (5 mg), then methanol (2 mL) was added as
solvent. The mixture was stirred under H2 atmosphere (bal-
loon) at rt for 2h. The Pd/C was filtered and washed with
little methanol, the filtrate was concentrated under vacuum
to afford the residue which was then purified by silica gel
column chromatography using DCM/MeOH (v/v, 20:1) as
eluent to give (S)-1-hydroxy-2-phenyl-5,6,7,7a-tetrahydro-
3H-pyrrolizin-3-one 6 (26 mg, 94% yield) as a light-yellow
solid.
Phenyl 3-oxo-4-phenylbutanoate (3h’). Colourless oil,
(26 mg, 41% yield). H NMR (600 MHz, DMSO-d6) δ 7.45 –
1
7.41 (m, 2H), 7.36 – 7.32 (m, 2H), 7.29 – 7.26 (m, 2H), 7.25
– 7.22 (m, 2H), 7.13 – 7.08 (m, 2H), 3.97 (s, 4H); 13C{1H}
NMR (150 MHz, DMSO-d6) δ 201.4, 166.2, 150.3, 134.1,
129.9, 129.7, 128.5, 126.9, 126.1, 121.7, 48.9, 48.5; HRMS
(EI) m/z calcd for C16H14O3 [M]+: 254.0943;
Found:254.0961.
Benzyl
(2S)-2-(3-ethoxy-3-oxo-2-
phenylpropanoyl)pyrrolidine-1-carboxylate (3i’). Colourless
oil, (87 mg, 88% yield). 1H NMR (600 MHz, DMSO-d6, 2 dia-
stereoisomers and their rotamers seen, ratio = 32/23:
26/19 ) δ 7.60 – 7.01 (m, 11H), 5.31 (s, 0.32H), 5.30 (s,
0.26H), 5.25 (s, 0.19H), 5.22 (s, 0.23H), 5.10 – 4.44 (m, 3H),
4.17 – 3.94 (m, 2H), 3.50 – 3.40 (m, 1H), 3.36 – 3.18 (m,
2H), 2.33 – 1.50 (m, 4H), 1.21 – 1.03 (m, 3H); 13C{1H}NMR
(150 MHz, DMSO-d6, 2 diastereoisomers and their rotamers
(S)-1-Hydroxy-2-phenyl-5,6,7,7a-tetrahydro-3H-
pyrrolizin-3-one (6). Light yellow solid, (25 mg, 94% yield),
o
1
m. p. 191.8-193.4 C. H NMR (600 MHz, DMSO-d6) δ 7.93
(d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 7.2 Hz,
1H), 4.14 (dd, J1 = 9.0 Hz, J2 = 6.8 Hz, 1H), 3.42 – 3.37 (m,
1H), 3.09 – 2.99 (m, 1H), 2.23 – 2.15 (m, 1H), 2.12 – 1.98
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(m, 2H), 1.40 – 1.29 (m, 1H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 176.8, 172.9, 132.2, 127.7, 126.7, 125.7, 103.0,
62.8, 43.1, 28.5, 27.7; HRMS (EI) m/z calcd for C13H13NO2
[M]+: 215.0946; Found:215.0949.
thesis. J. Chem. Educ. 1983, 60, 244-246; (c) Benetti, S.; Romagnoli,
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(4) For examples, see: (a) Smith, M. B.; March, J. AdVanced Organ-
ic Chemistry, 5th ed.; John Wiley: New York, 2001; p 569. (b) Kürti,
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Synthesis; Elsevier: Burlington, 2005; p 86 and p 138.
(5) Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K., An
efficient synthesis of gamma-amino beta-ketoester by cross-
Claisen condensation with alpha-amino acid derivatives.
Tetrahedron Lett. 2003, 3163-3166.
Gram-scale experiment. To an oven-dried schlenk
tube was added benzoic acid 1a (671 mg, 5.5 mmol) and
Ag2O (58 mg, 0.25 mmol), then evacuated and purged with
Argon three times. (Ethoxyethynyl)benzene 2a (730 mg, 5
mmol) was dissolved in anhydrous dioxane (40 mL) and
o
added by a syringe. The mixture was stirred at 100 C in an
9
(6) For examples, see: (a) Wu, D.; Fu, X.; Xiao, F.; Li, J.; Zhao, N.;
Wei, W.; Sun, Y., Methoxycarbonylation of ketones with dimethyl
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Rao, H. S. P.; Rafi, S.; Padmavathy, K., The Blaise reaction.
Tetrahedron 2008, 64, 8037-8043; (c) Blaise, E. E., New reactions
of orhano-metallic derivatives (II) - alpha-alcoyl-beta-ketonic
ethers. C. R. Hebd. Séances Acad. Sci. 1901, 132, 478-480; (d)
Blaise, E. E., New reactions of organic metallic derivatives (III) -
Non-substituted beta-cetonic ethers. C. R. Hebd. Séances Acad. Sci.
1901, 132, 978-980.
(7) Breslow, D. S.; Baumgarten, E.; Hauser, C. R., A new synthesis
of beta-keto esters of the type RCOCH2COOC2H5. J. Am. Chem. Soc.
1944, 66, 1286-1288.
(8) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J., A Safe,
Economical Method for the Preparation of Beta-Oxo Esters.
Synthesis 1993, 290-292.
(9) Iida, A.; Nakazawa, S.; Okabayashi, T.; Horii, A.; Misaki, T.;
Tanabe, Y., Powerful Ti-crossed Claisen condensation between
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(10) Korsager, S.; Nielsen, D. U.; Taaning, R. H.; Skrydstrup, T.,
Access to beta-Keto Esters by Palladium-Catalyzed Carbonylative
Coupling of Aryl Halides with Monoester Potassium Malonates.
Angew. Chem., Int. Edit. 2013, 52, 9763-9766.
(11) (a) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K.,
Stereoselective Synthesis of alpha-Alkyl-beta-keto Imides via
Asymmetric Redox C-C Bond Formation between alpha-Alkyl-
alpha-diazocarbonyl Compounds and Aldehydes. J. Am. Chem. Soc.
2009, 131, 11280-11281; (b) Li, W.; Wang, J.; Hu, X. L.; Shen, K.;
Wang, W. T.; Chu, Y. Y.; Lin, L. L.; Liu, X. H.; Feng, X. M., Catalytic
Asymmetric Roskamp Reaction of alpha-Alkyl-alpha-diazoesters
with Aromatic Aldehydes: Highly Enantioselective Synthesis of
alpha-Alkyl-beta-keto Esters. J. Am. Chem. Soc. 2010, 132, 8532-
8533.
(12) For selected reviews and examples about ynol ethers, see: (a)
Zhang, L. M.; Kozmin, S. A., Bronsted acid-promoted cyclizations of
slioxyalkynes with arenes and alkenes. J. Am. Chem. Soc. 2004, 126,
10204-10205; (b) Wang, S. H.; Li, P. H.; Yu, L.; Wang, L., Sequential
and One-Pot Reactions of Phenols with Bromoalkynes for the
Synthesis of (Z)-2-Bromovinyl Phenyl Ethers and Benzo[b]furans.
Org. Lett. 2011, 13, 5968-5971; (c) Sun, J. W.; Kozmin, S. A., Silver-
catalyzed hydroamination of siloxy alkynes. Angew. Chem., Int. Edit.
2006, 45, 4991-4993; (d) Mejuch, T.; Botoshansky, M.; Marek, I.,
oil bath for 8h, DMAP (122 mg, 1 mmol) was added and the
reaction was stirred for another 5h. Solvent was removed
under vacuum and the residue was purified by silica gel
column chromatography using ethyl acetate/petroleum
ether (v/v, 1:20) as eluent to give ethyl 3-oxo-2,3-
diphenylpropanoate 3a (1.11 g, 83% yield) as a white solid.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Crystallographic data for 3a. (CIF).
Crystallographic analysis of 3a, Copies of NMR spectra of
compounds 3a – 3i’, 4 – 6 (PDF).
AUTHOR INFORMATION
Corresponding Author
slcui@zju.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the financial support from National Natu-
ral Science Foundation of China (21472163).
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