Preparation of β-substituted γ-keto esters by the grignard reaction on N-acylpyrazoles

Article abstract of DOI:10.3987/COM-00-S(I)37

Various γ-keto esters were prepared by either the alcoholysis of N-(4-oxoalkanoyl)pyrazoles or the Grignard replacement of pyrazole moiety of 4-(N-pyrazolyl)-4-oxoalkanoic esters. By using 3-phenyl-ι-menthopyrazole as a chiral auxiliary, β-substituted γ-keto esters were enantioselectively obtained.

Full text of DOI:10.3987/COM-00-S(I)37

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 309 - 317, Received, 26th May, 2000
PREPARATION OF β-SUBSTITUTED γ-KETO ESTERS BY THE
GRIGNARD REACTION ON N-ACYLPYRAZOLES†
Choji Kashima,* Yoshie Shirahata, and Yoshihiro Tsukamoto
Department of Chemistry, University of Tsukuba
Ten-nodai Tsukuba, Ibaraki 305-8571, Japan
(E Mail: kashima@chac.tsukuba.ac.jp)
Abstract - Various γ−keto esters were prepared by either the alcoholysis of N-(4-
oxoalkanoyl)pyrazoles or the Grignard replacement of pyrazole moiety of 4-(N-
pyrazolyl)-4-oxoalkanoic esters. By using 3-phenyl-l-menthopyrazole as a chiral
auxiliary, β−substituted γ−keto esters were enantioselectively obtained.
γ-Keto esters are regarded as the important synthons of γ-lactones which are paid attention to their
biological activities. Although the various synthetic methods for these γ-keto esters were reported in the
literature including a few recent papers,1 a general, convenient and preparative method of γ-keto esters was
still desired, particularly that of optically active γ−keto esters.
Previously we reported the synthetic utilities concerning to pyrazoles, particularly 3-phenyl-l-
menthopyrazole as a new chiral auxiliary.2 The structural peculiarity of this auxiliary causes the
diastereofacial effect in the reactions on the substrate moiety. As the result, the asymmetric induction was
caused on acyl group of 2-acyl-3-phenyl-l-menthopyrazoles in the reactions with alkyl halides,3 diphenyl
disulfide,4 acyl chloride,5 aldehydes,6 and C=N compounds.7 Otherwise, N-acylpyrazoles are easily
converted into various acyl derivatives by the action of nucleophiles such as alcohols,8 amines,9 lithium
aluminum hydride,10 organozinc compounds11 and Grignard reagents.12 On the bases of these reactions,
we have previously prepared α-keto esters13 and chiral β-keto acid derivatives.6 In the course of these
preparative studies of keto acid derivatives, we report here the convenient preparative method of β-
substituted γ-keto esters using N-acylpyrazoles.
On our knowledge of chemical behaviors about N-acylpyrazoles, four preparative routes toward γ−keto
esters were designed through N-acylpyrazoles illustrated in Scheme 1. According to Routes 1 and 2,
α−substituted γ−keto esters are expected to be prepared by the alcoholysis of N-(4-oxoalkanoyl)pyrazoles,
which are obtained by either the α−alkylation of N-(4-oxoalkanoyl)pyrazoles (Route 1) or the reaction of
†
This paper is dedicated to Professor Shô Itô on the occasion of his 77th birthday for his brilliant achievement in the field of
heterocyclic chemistry.
.

R1
O
O
N
Me
N
Route 1
R1
R2
R1
R2
O
Me
O
O
Me
N
O
Me
N
OR3
Route 2
Route 3
N
Me
Me
N
O
Me
R2
R1
N
Me
N
O
Me
O
O
OR3
R2
OR3
O
N
Route 4
Me
R2
N
O
OR3
O
Scheme 1
α−bromoketones with N-acylpyrazoles (Route 2). The Routes 3 and 4 are consisted of the preparation of
the preparation of γ−keto esters was also anticipated by the Grignard reaction. By the treatment with
phenylmagnesium bromide, ethyl 4-phenyl-4-oxobutanoate (1aa) was obtained in good yield from ethyl 4-
(3,5-dimethylpyrazol-1-yl)-4-oxobutanoate (9aa) which was directly prepared from succinic acid
derivatives and 3,5-dimethylpyrazole. Also ethyl 4-phenyl-4-oxobutanoate (1aa) was obtained by the
treatment of 1-(4-phenyl-4-oxobutanoyl)-3,5-dimethylpyrazole (6) with BF3·OEt2 in ethanol. These facts
Table 1. Preparation of Alkyl 4-(N-Pyrazolyl)-4-oxoalkanoate
Entry
R1 R2 Pyrazolea Yield (%) De (%) Config.
____
____
____
____
____
____
____
____
____
____
1
2
3
4
5
6
7
8
9
9aa
H
Et
DMP
DMP
DMP
DMP
DMP
88b
58
57
77
64
69
51
74
15
9ba Me Et
9bb Me Me
9ca Ph Et
9da Bn Et
11ba Me Et 3-Ph-MP
11bb Me Me 3-Ph-MP
11ca Ph Et 3-Ph-MP
11da Bn Et 3-Ph-MP
72
78
27
72
3-(S)
3-(S)
3-(R)
3-(S)
a: 3,5-Dimethylpyrazol-1-yl and 3-phenyl-l-menthopyrazol-2-yl groups are
abbreviated to DMP and 3-Ph-MP, respectively.
b: Prepared by direct acylation of 3,5-dimethylpyrazole.

OEt
Me
O
O
Me
N
EtOH
MeI
Ph
1aa
Me
Cl
N
N
BF ·OEt
3
2
Me
N
O
H
O
O
O
Et N
3
LDA
6
Ph
Ph
Scheme 2
O
Ph
O
7
Me
Me
N
N
2
3
R3
Me
Me
N
BrCH COOR
2
N
R -MgX
O
OR2
O
LDA
O
O
O
R1
R1
R1
OR2
8
9
3
1
2
1
1; R =Ph
3
aa; R =H, R =Et
1
a; R =H
1
2
2; R =p-Tol
3
ba; R =Me, R =Et
1
b; R =Me
1
2
3; R =Me
3
bb; R =Me, R =Me
1
c; R =Ph
1
2
4; R =Et
3
ca; R =Ph, R =Et
1
d; R =Bn
Scheme 3
2
5; R =Bu
da; R =Bn, R =Et
showed the nucleophilic replacement of N-acylpyrazoles afforded unsubstituted γ−keto esters.
In Route 1 for α−substituted γ−keto esters, the alkylation of 6 was failed in the presence of LDA and 5-
phenyl-2(3H)-furanone (7) was formed through the cyclization of the enolate derived from keto group.
Thereaction of 1-propanoyl-3,5-dimethylpyrazole (8a) with α−bromoacetophenone in Route 2 gave the
complicated mixture of many products and could not be isolated the desired 1-(2-methyl-4-phenyl-4-
oxobutanoyl)-3,5-dimethylpyrazole. The alkylation of 9aa in Route 3 was also failed and the starting
material was recovered even under the force condition using HMPA. In route 4, alkylation of 1-acyl-3,5-
dimethylpyrazole (8) with bromoacetate esters afforded 3-substituted 4-(3,5-dimethylpyrazol-1-yl)-4-
oxobutanoic esters (9) in good yields. The subsequent Grignard reaction afforded various β−substituted
γ−keto esters (1-5) summarized in Tables 1 and 2.
When 3-phenyl-l-menthopyrazole was used instead of 3,5-dimethylpyrazole, the formation of ethyl 3-
substituted 4-(3-phenyl-l-menthopyrazol-2-yl)-4-oxobutanoates (11) was accomplished diastereoselectively
by the action of 2-acyl-3-phenyl-l-menthopyrazoles (10) with ethyl bromoacetate in the presence of LDA.
According to the previous works,3 the diastereoselectivity was evaluated from the peak intensity of 4methyl
2
3
R1
O
BrCH COOR
2
R -MgX
R1
O
N
LDA
N
R3
R1
OR2
N
N
OR2
O
O
O
3
10
11
1; R =Ph
1
2
ba; R =Me, R =Et
3
1
2; R =p-Tol
b; R =Me
1
2
bb; R =Me, R =Me
3
1
3; R =Me
c; R =Ph
1
2
ca; R =Ph, R =Et
1
d; R =Bn
1
2
Scheme 4
da; R =Bn, R =Et

Table 2. Grignard Reaction of Alkyl 4-(N-Pyrazolyl)-4-oxoalkanoate
Entry 4-(N-Pyrazolyl)-4-oxoalkanoate
Grignard Reagent
Product
Yield (%)
Opt.
Pyrazolea R1
R2
Et
Et
Et
Et
Et
Et
Et
Et
R3-MgX
Yield (%)
____
1
2
9aa
9aa
9aa
9aa
9aa
9ba
9ba
9ba
9bb
9bb
9bb
9ca
9ca
9da
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
H
H
Ph-MgBr
p-Tol-MgBr
Me-MgI
1aa
2aa
53
48
64
63
51
51
79
17
53
53
13
63
67
52
10
51
44
0
____
____
____
____
____
____
____
____
____
____
____
____
____
3
H
3aa
4
H
Et-MgI
4aa
5
H
Bu-MgBr
Ph-MgBr
p-Tol-MgBr
Me-MgBr
Ph-MgBr
p-Tol-MgBr
Me-MgI
5aa
6
Me
Me
Me
1ba
7
2ba
8
3ba
9
Me Me
Me Me
Me Me
1bb
10
11
12
13
14
15
16
17
18
19
2bb
3bb
Ph
Ph
Bn
Et
Et
Et
Et
Ph-MgBr
Me-MgI
1ca
3ca
Me-MgI
3da
11ba 3-Ph-MP Me
Ph-MgBr
Ph-MgBr
p-Tol-MgBr
Me-MgI
(S)-1ba
(S)-1bb
(S)-2bb
(R)-3ca
(S)-3da
100
85
11bb 3-Ph-MP Me Me
11bb 3-Ph-MP Me Me
85
____
11ca 3-Ph-MP Ph
11da 3-Ph-MP Bn
Et
Et
____
Me-MgI
0
a: 3,5-Dimethylpyrazol-1-yl and 3-phenyl-l-menthopyrazol-2-yl groups are abbreviated as DMP and 3-Ph-
MP, respectively.
group on 3-phenyl-l-menthopyrazole. The pyrazole derivatives were subsequently converted into
β−substituted γ−keto esters (1-3) by the action of Grignard reagents. During this conversion, the chiral
auxiliary was recovered in high yield without racemization. The absolute configuration of the products was
proved to be (S)-form by the comparison of optical rotation with authentic data.14 The enantiomer ratios
were deduced by HPLC using chiral column. In the cases of 11ca and 11da, the replacement reaction was
depressed by the steric hindrance of menthopyrazolyl group.
In conclusion, various γ−keto esters were prepared by either the alcoholysis of N-(4-oxoalkanoyl)pyrazoles
(6) or the Grignard replacement of pyrazole moiety of 3-substituted 4-(3,5-dimethylpyrazol-1-yl)-4-
oxoalkanoate esters (9). By using 3-phenyl-l-menthopyrazole as a chiral auxiliary, β−substituted γ−keto
esters (1-3) were enantioselectively prepared.

EXPERIMENTAL
1
13
Melting points are uncorrected. H NMR and C NMR spectra were obtained on JEOL JNM-EX270 (270
MHz) or Varian GEMINI 2000 (200 MHz) spectrometer in CDCl3 with TMS as an internal standard.
Specific rotations were measured on JASCO DIP-370 digital polarimeter. The enantiomer ratios were
evaluated from the peak intensity ratios of HPLC on JASCO PU-980 high performance liquid
chromatograph using CHIRALCEL OD-R column eluting with aqueous methanol. The yields of the
products were evaluated by GL Science GC-353 gas chromatograph using dimethylsiloxane type capillary
column (GL Science TC-1, 0.25 mm x 30 m). Ether and THF were dried over benzophenone ketyl radical.
Preparation of 1-Acyl-3,5-dimethylpyrzoles. 3,5-Dimethylpyrazole was acylated by carboxylic acid in
the presence of thionyl chloride and triethylamine according to the formerly described method.8 Also 1-
acyl-3,5-dimethylpyrazole was prepared by the action of acid chloride on 3,5-dimethylpyrazole in the
presence of triethylamine.
1-(4-Phenyl-4-oxobutanoyl)-3,5-dimethylpyrazole (6).
1
mp 69-70°C (from hexane); yield 85 %; H-NMR (CDCl3): δ 2.26 (3H, d, J=1.7 Hz), 2.52 (3H, s), 3.42
(2H, t, J=6 Hz), 3.58 (2H, t, J=6 Hz), 5.97 (1H, s), 7.27-7.59 (3H, m), 8.00-8.04 (2H, m); 13C-NMR
(CDCl3): δ 13.9 (CH3), 14.5 (CH3), 29.7 (CH2), 32.8 (CH2), 111.2 (CH), 128.3 (CH), 128.7 (CH), 129.0
(C), 133.3 (CH), 144.2 (C), 152.3 (C), 173.2 (C), 198.3 (C). Anal. Calcd for C15H16N2O2: C, 70.29; H,
6.29; N, 10.93. Found: C, 70.20; H, 6.42; N, 10.86.
Ethyl 4-(3,5-Dimethylpyrazol-1-yl)-4-oxobutanoate (9aa).
1
bp 140-150°C/ 5 mmHg; mp 36-37°C (from hexane); yield 90 %; H-NMR (CDCl3): δ 1.26 (3H, t, J=7.3
Hz), 2.23 (3H, s), 2.52 (3H, s), 2.72 (2H, t, J=6.6 Hz), 3.44 (2H, t, J=6.9 Hz), 4.17 (2H, q, J=7.3 Hz), 5.95
(1H, s). Anal. Calcd for C11H16N2O3: C, 58.91; H, 7.19; N, 12.49. Found: C, 58.94; H, 7.20; N, 12.39.
Ethanolysis of 1-(4-Phenyl-4-oxobutanoyl)-3,5-dimethylpyrazole (6). The mixture of 1-(4-phenyl-
4-oxobutanoyl)-3,5-dimethylpyrazole (6) (950 mg, 3.7 mmol) and BF3·OEt2 (738 mg, 5.4 mmol) in EtOH
(5 mL) was refluxed for 17 h. The resulting mixture was extracted with ether, and the organic layer was
washed with diluted hydrochloric acid (ca. 1 %), water, saturated NaHCO3 solution and NaCl solution.
After dried over anhydrous MgSO4, the ether was evaporated and ethyl 4-oxo-4-phenylbutanoate (1aa) was
1
purified by distillation under reduced pressure; bp 150-155°C/ 5 mmHg; yield 669 mg (88 %); H-NMR
(CDCl3): δ 1.27 (3H, t, J=7.3 Hz), 2.76 (2H, t, J=6.6 Hz), 3.32 (2H, t, J=6.6 Hz), 4.16 (2H, q, J=7.3 Hz),
7.27-7.60 (3H, m), 7.98-8.03 (2H, m).
Formation of 5-Phenyl-2(3H)-furanone (7). To the THF solution (5 mL) of LDA which was prepared
in situ from diisopropylamine (0.25 mL) and butyllithium (1.4 mmol), 6 (262 mg, 1.0 mmol) in THF (1 mL)
was added at -5°C. After standing for 30 min at -5°C, methyl iodide (322 mg, 2.3 mmol) in THF (1 mL)
was added to the mixture. The reaction was continued stirring for 2 h. The mixture was quenched with
acetic acid and water, and extracted with CH2Cl2. The organic layer was washed with diluted hydrochloric
acid (ca. 1%), water, saturated NaHCO3 solution and NaCl solution. After dried over anhydrous MgSO4,
solvent was evaporated. The major product was isolated by silica gel chromatography with hexane-ethyl
acetate mixture (v/v 4:1) as elution solvents, and was presumed to be 5-phenyl-2(3H)-furanone (7); yield 43

1
mg (27 %); H-NMR (CDCl3): δ 3.42 (2H, d, J=2.8 Hz), 5.79 (1H, t, J=2.8 Hz), 7.34-7.54 (3H, m), 7.57-
7.98 (2H, m).
Preparation of 3-Substituted 4-(N-Pyrazolyl)-4-oxoalkanoate (9 and 11). To the THF solution (2
mL) of LDA which was prepared in situ from diisopropylamine (0.3 mL) and butyllithium (1.2 mmol), the
appropriate N-acylpyrazole (1.1 mmol) in THF (1 mL) was added at -5°C. After standing at -5°C for 30
min, bromoacetate ester (1.5 mmol) in THF (1 mL) was added at -90°C to the mixture which was kept
stirring for 2 h at -5°C. The mixture was quenched with acetic acid and water, and extracted with CH2Cl2.
The organic layer was washed with diluted hydrochloric acid (ca. 1 %), water, saturated NaHCO3 solution
and NaCl solution. After dried over anhydrous MgSO4, solvent was evaporated. 3-Substituted 4-(N-
pyrazolyl)-4-oxoalkanoate (9 and 11) was purified by silica gel column chromatography with hexane-ethyl
acetate mixture (v/v 7:1) as elution solvents.
Ethyl 3-Methyl-4-(3,5-dimethylpyrazol-1-yl)-4-oxobutanoate (9ba).
Oil, yield 58 %; 1H-NMR (CDCl3): δ 1.21 (3H, t, J=7.2 Hz), 1.30 (3H, d, J=7.0 Hz), 2.24 (3H, s), 2.49 (1H,
ABX, J=5.4, 16.6 Hz), 2.53 (3H, s), 2.92 (1H, ABX, J=9.4, 16.6 Hz), 4.1 (2H, q, J=7.4 Hz), 4.21-4.29 (1H,
m), 5.96 (1H, s). Anal. Calcd for C12H18N2O3: C, 60.49; H, 7.61; N, 11.76. Found: C, 60.24; H, 7.73; N,
11.63.
Methyl 3-Methyl-4-(3,5-dimethylpyrazol-1-yl)-4-oxobutanoate (9bb).
bp 120-125°C/ 6 mmHg; yield 57 %; 1H-NMR (CDCl3): δ 1.31 (3H, d, J=7.3 Hz), 2.24 (3H, s), 2.50 (1H,
ABX, J=5.6, 16.9 Hz), 2.53 (3H, d, J=0.7 Hz), 2.93 (1H, ABX, J=8.9, 16.5 Hz), 3.66 (3H, s), 4.19-4.30 (1H,
m), 5.96 (1H, s); 13C-NMR (CDCl3): δ 14.3 (CH3), 15.0 (CH3), 18.1 (CH3), 35.5 (CH2), 37.8 (CH), 52.2
(CH3), 111.7 (CH), 145.0 (C), 152.5 (C), 173.0 (C), 176.3 (C). Anal. Calcd for C11H16N2O3: C, 58.91; H,
7.19; N, 12.49. Found: C, 58.61; H, 7.37; N, 12.28.
Ethyl 3-Phenyl-4-(3,5-dimethylpyrazol-1-yl)-4-oxobutanoate (9ca).
1
Oil, yield 77 %; H-NMR (CDCl3): δ 1.18 (3H, t, J=7.2 Hz), 2.20 (3H, s), 2.49 (3H, s), 2.75 (1H, ABX,
J=4.8, 17.0 Hz), 3.38 (1H, ABX, J=10.8, 17.0 Hz), 4.10 (2H, q, J=7.0 Hz), 5.60 (1H, ABX, J=4.8, 10.8 Hz),
5.89 (1H, s), 7.18-7.34 (3H, m), 7.42-7.47 (2H, m). Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N,
9.33. Found: C, 68.24; H, 6.77; N, 9.21.
Ethyl 3-Benzyl-4-(3,5-dimethylpyrazol-1-yl))-4-oxobutanoate (9da).
Oil, yield 64 %; 1H-NMR (CDCl3): δ 1.16 (3H, t, J=7.0 Hz), 2.26 (3H, s), 2.44 (1H, ABX, J=4.4, 16.8 Hz),
2.52 (3H, s), 2.68 (1H, ABX, J=9.2, 13.4 Hz), 2.86 (1H, ABX, J=10.4, 16.8 Hz), 3.24 (1H, ABX, J=4.8, 13.4
Hz), 4.04 (2H, q, J=7.2 Hz), 4.46-4.61 (1H, m), 5.95 (1H, s), 7.17-7.33 (5H, m). Anal. Calcd for
C18H22N2O3: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.89; H, 7.05; N, 9.11.
Ethyl 3-Methyl-4-oxo-4-(3-phenyl-l-menthopyrazol-2-yl)butanoate (11ba).
1
Oil, yield 69 %; H-NMR (CDCl3): δ 0.69 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=6.6
Hz), 1.13-1.35 (1H, m), 1.26 (3H, t, J=7.2 Hz), 1.43-1.61 (1H, m), 1.82 (2H, m), 2.33-2.49 (1H, m), 2.43
(1H, ABX, J=5.0, 16.8 Hz), 2.59-2.69 (1H, m), 2.73-2.83 (1H, m), 2.90 (1H, ABX, J=9.6, 16.8 Hz), 4.12
(2H, q, J=7.2 Hz), 4.21-4.33 (1H, m), 7.26-7.44 (5H, m). Anal. Calcd for C24H32N2O3: C, 72.7; H, 8.13; N,
7.06. Found: C, 72.63; H, 8.09; N, 6.99.
Methyl 3-Methyl-4-oxo-4-(3-phenyl-l-menthopyrazol-2-yl)butanoate (11bb).

1
Oil, yield 51 %; H-NMR (CDCl3): δ 0.69 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=7.0 Hz), 1.08 (3H, d, J=6.8
Hz), 1.21-1.34 (1H, m), 1.26 (3H, d, J=7.0 Hz), 1.42-1.63 (1H, m), 1.82-2.00 (2H, m), 2.35-2.60 (1H, m),
2.45 (1H, ABX, J=5.4, 16.8 Hz), 2.62-2.70 (1H, m), 2.73-2.81 (1H, m), 2.90 (1H, ABX, J=9.4, 16.8 Hz),
3.67 (3H, s), 4.21-4.31 (1H, m), 7.26-7.41 (5H, m). Anal. Calcd for C23H30N2O3: C, 72.22; H, 7.91; N,
7.32. Found: C, 72.15; H, 7.84; N, 7.32.
Ethyl 4-Oxo-3-phenyl-4-(3-phenyl-l-menthopyrazol-2-yl)butanoate (11ca).
mp 137-138°C (from hexane); yield 74 %; 1H-NMR (CDCl3): δ 0.66 (3H, d, J=6.8 Hz), 0.72 (3H, d, J=6.8
Hz), 0.82-0.92 (1H, m), 1.00 (3H, d, J=7.0 Hz), 1.21 (3H, t, J=7.1 Hz), 1.36-1.52 (1H, m), 1.79-1.93 (2H,
m), 2.41-2.58 (2H, m), 2.60-2.72 (1H, m), 2.67 (1H, ABX, J=4.8, 17.0 Hz), 3.15 (1H, ABX, J=11.0, 17.0
Hz), 4.12 (2H, q, J=7.0 Hz), 5.56 (1H, ABX, J=4.8, 11.0 Hz), 7.17-7.46 (10H, m). Anal. Calcd for
C29H34N2O3: C, 75.95; H, 7.47; N, 6.11. Found: C, 76.08; H, 7.61; N, 6.12.
Ethyl 3-Benzyl-4-oxo-4-(3-phenyl-l-menthopyrazol-2-yl)butanoate (11da).
1
mp 83-84°C (from hexane); yield 15 %; H-NMR (CDCl3): δ 0.70 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.8
Hz), 1.05-1.38 (1H, m), 1.12 (3H, d, J=7.0 Hz), 1.16 (3H, t, J=7.0 Hz), 1.44-1.63 (1H, m), 1.84-2.02 (2H,
m), 2.31-2.60 (1H, m), 2.33 (1H, ABX, J=4, 17.2 Hz), 2.54 (1H, ABX, J=10.4, 13.4 Hz), 2.31-2.60 (1H, m),
2.65-2.95 (2H, m), 2.82 (1H, ABX, J=11.0, 17.2 Hz), 3.27 (1H, ABX, J=4.2, 13.2 Hz), 4.04 (2H, q, J=7.2
Hz), 4.51-4.64 (1H, m), 7.16-7.40 (10H, m). Anal. Calcd for C29H36N2O3: C, 75.62; H, 7.88; N, 6.08.
Found: C, 75.81; H, 7.68; N, 5.70.
Conversion of 9 and 11 into γ-Keto Esters.
Under argon atmosphere, 4-(N-pyrazolyl-4-oxoalkanoate (9 and 11, 1.0 mmol) was stirred with a Grignard
reagent (1.2 mmol) in dry ether (1 mL) at rt for 1 h. The mixture was quenched with acetic acid, and the
ether solution was washed with diluted hydrochloric acid (ca. 1 %), water, a saturated NaHCO3 solution and
NaCl solution. After dried over anhydrous MgSO4, the ether was evaporated. From the gas
chromatography of the residue, the yields of the products were evaluated, as summarized in Table 2. The
products were purified by silica gel chromatography with hexane-ethyl acetate mixture (v/v 7:1) as an elution
solvent system, and were identified by the means of spectral comparison.
Ethyl 3-Methyl-4-oxo-4-phenylbutanoate (1ba).
Oil, yield 51 %; 1H-NMR (CDCl3): δ 1.19 (3H, t, J=7.1 Hz), 1.21 (3H, d, J=7.2 Hz), 2.44 (1H, ABX, J=5.9,
16.8 Hz), 2.95 (1H, ABX, J=8.6, 16.8 Hz), 3.91-4.01 (1H, m), 4.08 (2H, q, J=7.2 Hz), 7.40-7.56 (3H, m),
7.97-8.00 (2H, m).
Methyl 3-Methyl-4-oxo-4-phenylbutanoate (1bb).
1
Oil, yield 53 %; H-NMR (CDCl3): δ 1.23 (3H, d, J=7.2 Hz), 2.47 (1H, ABX, J=6.0, 16.6 Hz), 2.97 (1H,
ABX, J=8.2, 16.6 Hz), 3.65 (3H, s), 3.90-4.01 (1H, m), 7.43-7.16 (3H, m), 7.97-8.03 (2H, m). The optical
rotation of 1bb, which was prepared from 11bb, was measured; [α]D -4.1° (c 0.24, THF).
Ethyl 3,4-Diphenyl-4-oxobutanoate (1ca).
1
Oil, yield 63 %; H-NMR (CDCl3): δ 1.17 (3H, t, J=7.2 Hz), 2.70 (1H, ABX, J=4.8, 16.8 Hz), 3.37 (1H,
ABX, J=9.6, 16.8 Hz), 4.08 (2H, q, J=7.2 Hz), 5.09 (1H, ABX, J=4.8, 9.6 Hz), 7.17-7.46 (8H, m), 7.95-7.99
(2H, m).
Ethyl 4-Oxo-4-(4-methylphenyl)butanoate (2aa).

1
Oil, yield 47 %; H-NMR (CDCl3): δ 1.26 (3H, t, J=7.2 Hz), 2.41 (3H, s), 2.74 (2H, t, J=6.6 Hz), 3.29 (2H,
t, J=6.6 Hz), 4.16 (2H, q, J=7.2 Hz), 7.26 (2H, d, J=8.0 Hz), 7.89 (2H, d, J=8.2 Hz).
Ethyl 3-Methyl-4-oxo-4-(4-methylphenyl)butanoate (2ba).
Oil, yield 79 %; 1H-NMR (CDCl3): δ 1.20 (3H, t, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.40 (3H, s), 2.43 (1H,
ABX, J=5.9, 16.8 Hz), 2.93 (1H, ABX, J=8.2, 16.8 Hz), 3.89-3.97 (1H, m), 4.09 (2H, q, J=7.3 Hz), 7.25-
7.28 (3H, m), 7.88-7.91 (2H, m).
Methyl 3-Methyl-4-oxo-4-(4-methylphenyl)butanoate (2bb).
Oil, yield 53 %; 1H-NMR (CDCl3): δ 1.21 (3H, d, J=7.2 Hz), 2.40 (3H, s), 2.44 (1H, ABX, J=5.9, 16.5 Hz),
2.95 (1H, ABX, J=8.3,16.5 Hz), 3.64 (3H, s), 3.89-3.99 (1H, m), 7.25-7.43 (3H, m), 7.88-7.97 (2H, m).
Ethyl 4-Oxopentanoate (3aa).
1
Oil, yield 64 %; H-NMR (CDCl3): δ 1.26 (3H, t, J=7.2 Hz), 2.20 (3H, s), 2.57 (2H, t, J=6.2 Hz), 2.76 (2H,
t, J=6.3 Hz), 4.13 (2H, q, J=7.0 Hz).
Ethyl 3-Methyl-4-oxopentanoate (3ba).
Oil, yield 17 %; 1H-NMR (CDCl3): δ 1.15 (3H, d, J=7.2 Hz), 1.25 (3H, t, J=7.2 Hz), 2.23 (3H, s), 2.29 (1H,
ABX, J=5.4, 16.6 Hz), 2.76 (1H, ABX, J=8.6, 16.8 Hz), 2.97-3.07 (1H, m), 4.11 (2H, q, J=7.2 Hz).
Methyl 3-Methyl-4-oxopentanoate (3bb).
Oil, yield 13 %; 1H-NMR (CDCl3): δ 1.16 (3H, d, J=7.2 Hz), 2.28 (3H, s), 2.30 (1H, ABX, J=5.4, 16.8 Hz),
2.77 (1H, ABX, J=8.6, 16.6 Hz), 2.97-3.08 (1H, m), 3.66 (3H, s).
Ethyl 3-Phenyl-4-oxopentanoate (3ca).
Oil, yield 67 %; 1H-NMR (CDCl3): δ 1.21 (3H, t, J=7.3 Hz), 2.11 (3H, s), 2.52 (1H, ABX, J=4.9, 16.8 Hz),
3.20 (1H, ABX, J=9.6, 16.8 Hz), 4.11 (2H, q, J=7.3 Hz), 4.18 (1H, ABX, J=4.9, 9.6 Hz), 7.18-7.36 (5H, m).
Ethyl 3-Benzyl-4-oxopentanoate (3da).
Oil, yield 18 %; 1H-NMR (CDCl3): δ 1.21 (3H, t, J=7.2 Hz), 2.10 (3H, s), 2.31 (1H, ABX, J=4.3, 17.1 Hz),
2.59 (1H, ABX, J=8.2, 13.5 Hz), 2.74 (1H, ABX, J=10.2, 17.1 Hz), 2.91 (1H, ABX, J=6.9, 13.5 Hz), 3.20-
3.32 (1H, m), 4.06 (2H, q, J=7.3 Hz), 7.03-7.33 (5H, m).
Ethyl 4-Oxohexanoate (4aa).
Oil, yield 63 %; 1H-NMR (CDCl3): δ 1.08 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=7.2 Hz), 2.49 (2H, q, J=7.2 Hz),
2.58 (2H, t, J=6.4 Hz), 2.73 (2H, t, J=6.6 Hz), 4.13 (2H, q, J=7.2 Hz).
Ethyl 4-Oxooctanoate (5aa).
1
Oil, yield 51 %; H-NMR (CDCl3): δ 0.91 (3H, t, J=7.4 Hz), 1.23-1.41 (2H, m), 1.25 (3H, t, J=7.0 Hz),
1.51-1.65 (2H, m), 2.46 (2H, t, J=7.4 Hz), 2.54-2.62 (2H, m), 2.68-2.76 (2H, m), 4.13 (2H, q, J=7.0 Hz).
ACKNOWLEDGEMENT
The authors are grateful to the Chemical Analysis Center, University of Tsukuba, for obtaining NMR
spectral and elemental analysis data.
REFERENCES
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