Nucleophilic substitution accompanying carbon-carbon bond cleavage assisted by a nitro group

Article abstract of DOI:10.1246/bcsj.80.2413

A 2-nitrated 3-oxoester reacted with amines or alcohols to afford unsymmetrical malonic acid derivatives as a result of nucleophilic substitution accompanying C-C bond cleavage. The 2-nitrated 3-oxoester easily formed ammonium salts with amines. When the amine is liberated from the salt under equilibrium, nucleophilic amine and electrophilic keto ester locate close to each other. This intimate pair effect causes a pseudo intramolecular reaction to occur, giving rise to effective substitution under mild conditions.

Full text of DOI:10.1246/bcsj.80.2413

ꢀ 2007 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 80, No. 12, 2413–2417 (2007) 2413
Nucleophilic Substitution Accompanying Carbon–Carbon
Bond Cleavage Assisted by a Nitro Group
Yumi Nakaike,1 Noriko Taba,2 Shinobu Itoh,3 Yoshito Tobe,1
ꢀ2
ꢀ2
Nagatoshi Nishiwaki, and Masahiro Ariga
1Divisions of Frontier Materials Science, Graduate School of Engineering Science, Osaka University,
Toyonaka, Osaka 560-8531
2Department of Chemistry, Osaka Kyoiku University, Kashiwara, Osaka 582-8582
3Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585
Received June 26, 2007; E-mail: nishi@cc.osaka-kyoiku.ac.jp
A 2-nitrated 3-oxoester reacted with amines or alcohols to afford unsymmetrical malonic acid derivatives as a re-
sult of nucleophilic substitution accompanying C–C bond cleavage. The 2-nitrated 3-oxoester easily formed ammonium
salts with amines. When the amine is liberated from the salt under equilibrium, nucleophilic amine and electrophilic keto
ester locate close to each other. This intimate pair effect causes a pseudo intramolecular reaction to occur, giving rise to
effective substitution under mild conditions.
Introduction of three halogen atoms at the ꢀ-position acti-
vates a carbonyl group to cause nucleophilic substitution by
hydroxide ion, which is well-known as the haloform reaction.1
Similar activation of a carbonyl group can be achieved by in-
troducing only one nitro group. Although some other deacyla-
tions are known,2–5 the nucleophile has been limited to water,
except for a few cases.6,7 There are some reports on deacyla-
tion of 2-nitroketones giving carboxylic acids, though harsh
conditions are necessary.8,9 Deacylation is considered to pro-
ceed more easily if an additional electron-withdrawing group
is introduced to the nitroketones. Indeed, during the course
of our study on nitration of 1,3-dicarbonyl compounds, we
have observed that 2-nitro-1,3-diketones are easily hydrolyzed
by ambient moisture at room temperature.10 We planned to
exploit the present deacylation to organic synthesis, in which
a 2-nitro-3-oxoester was used as a novel acylating agent of
nucleophiles, such as amines and alcohols. In this work, our
attention focused on unsymmetrical malonic acid derivatives,
which are important synthetic intermediates for elaborate syn-
theses of polyfunctionalized systems.11,12 In spite of their syn-
thetic utility, they are not always readily available, because
one of the two equivalent carbonyl groups of diethyl malonate
must be selectively transformed.
Table 1. Nitration of 3-Oxoester 1
O
O
O
O
O
O
Reagent, H2SO4
EtO
OEt
CH2Cl2
EtO
OEt
NO2
Temp. 1 h
1
2
Run
Reagent
Temp/ꢁC
Yield/%b)
1a)
2a)
3a)
4
fuming HNO3
fuming HNO3
fuming HNO3
HNO3
ꢂ10
ꢂ5
0
48
86
38c),d)
59
ꢂ5
5
NH4NO3
ꢂ5
57
a) Fuming HNO3 (d ¼ 1:52). b) Isolated yield. c) Mixture
containing unidentified by-products. d) Yield was determined
by 1H NMR using 1,1,2,2-tetrachloroethane as the internal
standard.
from the reaction mixture after nitration, because only 2
dissolved in the organic layer.
When a solution of 2-nitro-3-oxoester 2 and propylamine 3a
in dichloromethane was stirred at room temperature for 1 day,
nucleophilic substitution proceeded quantitatively at the cen-
tral carbonyl group to give amide ester 4a together with ethyl
nitroacetate 5. Product 4a was easily isolated by column chro-
matography on silica gel (Table 2, Run 1). Nitrated compound
2 could be employed for the subsequent reaction in a dichloro-
methane solution without concentration or further purification.
Bulkier primary amines 3b and 3c and secondary amines 3d
and 3e could be employed for the present acylation, and the
corresponding amide esters 4b–4e formed in moderate yields
(Runs 2–5). In the case of morpholine 3e, acylation proceeded
even at room temperature. Functionalized amide ester 4f was
also prepared by using allylamine 3f (Run 6). These results
showed the present reaction was considerably affected by the
bulkiness of amines, which prompted us to study the selective
Result and Discussion
Synthesis of the 2-nitro-3-oxoester, diethyl 2-nitro-3-oxo-
pentanedioate (2), was performed by nitration of 3-oxoester 1
according to Laikhter’s method using two phase reaction (di-
chloromethane–sulfuric acid).9 In this nitration, controlling
the reaction temperature was found to be crucial, and the yield
of 2 was improved up to 86% after optimizing the reaction
conditions (Table 1). The electron-withdrawing property of
the nitro group of 2 prevents the formation of polynitrated
keto esters during the nitration of 1. Furthermore, nitrated
compound 2 was easily isolated by separating the organic layer
Published on the web December 13, 2007; doi:10.1246/bcsj.80.2413

2414 Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007)
Table 2. Synthesis of Unsymmetrical Amide Esters 4
Synthesis of Unsymmetrical Malonate Derivatives
O
O
O
O
O
O
R1R2NH 3
Solv. 1 day
R1
+
O2N
EtO
OEt
EtO
N
R2
OEt
NO2
2
4
5
Run
R1
Pr
i-Pr
t-Bu
Et
(CH2)2O(CH2)2
CH2=CHCH2
Ph
p-NO2C6H4
p-MeOC6H4
R2
Solv.
Temp/ꢁC
Yield of 4a)/%
1
2
3
4b)
5
6
7
H
H
H
Et
a CH2Cl2
b CH2Cl2
c CH2Cl2
d CHCl3
e CHCl3
f CHCl3
g CH2Cl2
h CHCl3
i CH2Cl2
rt
40
40
60
rt
quant.
62
41
50
68
80
45
55
quant.
H
H
H
H
rt
40
60
rt
8
9
a) All of products 4 except for 4h have been reported in Refs. 6, 13,
and 14. b) Reaction time: 2 days.
O
O
O
O
CHCl3
rt 1 d
2
2
NH2
+
+
+
NH2
NH2
NH2
H2N
H2N
EtO
N
EtO
N
H
H
3j
4j 70%
4j' 0%
O
O
O
O
H
N
CH2Cl2
rt 1 d
H
N
+
Et
EtO
N
EtO
N
Et
H
Et
3k
4k 72%
4k' 0%
Scheme 1. Chemoselective modification of 1,2-diamines 3j and 3k.
Table 3. Acylation of Alcohols
O
O
O
O
O
O
ROH 6
O2N
+
EtO
OEt
OEt
1 day
EtO
OR
NO2
2
7
5
Run
ROH
(molar amount)
Temp/ꢁC
Yield of 7d)/%
1
MeOH
MeOH
MeOH
i-PrOH
t-BuOH
(solv.)
(20)
(5)
(solv.)
(solv.)
a rt
92
99
89
59
38c)
2a)
3a)
4
a 60
a 60
b 65
c 80
5b)
a) Chloroform was used as the solvent. b) 1 molar amount of KOBut was
1
added. c) Yield based on H NMR. d) Ref. 16.
acylation of diamines 3j and 3k. When diamine 3j was acylat-
ed by using commercially available ethyl chloroformylace-
tate15 in the presence of triethylamine, the difference in bulki-
ness between the two amino groups was not recognized, and
both 4j and 4j0 were afforded in 50% yield.6 In the acylation
of diamine 3k by ethyl chloroformylacetate, a mixture of 4k
and the double-acylated product was produced. On the other
hand, nitrated keto ester 2 acylated exclusively less hindered
primary amino groups of 3j and 3k without any modification
of the bulky amino group leading to 4j and 4k, respectively
(Scheme 1).
tion of the reaction mixture (Table 2, Run 7). Quite different
reactivities were observed between substituted anilines 3h
and 3i. Whereas aniline 3h with an electron-withdrawing
group afforded anilide ester 4h in a moderate yield under heat-
ed conditions (Run 8), aniline 3i, which was substituted with
an electron-donating group, underwent acylation to give 4i in
quantitative yield even at room temperature (Run 9). These re-
sults show that electronic property of amines is an important
factor for the present reaction.
Alcohols were also usable as nucleophiles for this reaction.
When a solution of nitrated compound 2 in methanol 6a was
stirred at room temperature, unsymmetrical diester 7a was ob-
tained in a high yield (Table 3, Run 1). The amount of meth-
anol 6a could be decreased to 5 molar amounts by conducting
Less nucleophilic aromatic amines 3g–3i similarly reacted
with 2 to afford anilide esters 4g–4i, respectively. In the case
of aniline 3g, the yield of 4g was low owing to the complica-

Y. Nakaike et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007) 2415
Intimate Pair
O
O
3
O
1
O
O
O
O
O
O
2
4
+
4
5
EtO
OEt
EtO
OEt
EtO
OEt
+
RNH2
H H
+
O
NO2
_
H
_
RNH3
_ N
N
+
O
O
8
O
2
RNH2
3
Scheme 2. A plausible mechanism for the reaction of 2 with an amine.
the reaction in a chloroform solution under reflux conditions
(Runs 2 and 3). Furthermore, sterically hindered isopropanol
6b and tert-butyl alcohol 6c could be employed giving diesters
7b and 7c in moderate yields, though the addition of potassium
tert-butoxide was necessary in the latter case (Runs 4 and 5).
To clarify the reaction mechanism, we monitored the reac-
tions of 2 and propylamine 3a or methanol 6a by 1H NMR us-
ing chloroform-d as a solvent at room temperature. The signals
for the diastereotopic protons at the 4-position of 2 were ob-
served separately. In the reaction with propylamine 3a, these
signals became equivalent immediately after the addition of
3a to a solution of 2, and the signals of N-methylene protons
of 3a shifted to 3.0 from 2.6 ppm. These changes indicate that
amine 3a removes a hydrogen at the 2-position of 2 to form 8.
Then, signals of 4a and 5 gradually increased as those of 8
decreased, and 8 was completely consumed within 3 h. It is
noteworthy that the reaction quantitatively proceeded without
formation of any detectable by-products. In the reaction of 2
with methanol 6a, however, the diastereotopic methylene sig-
nals did not change, indicating that a nitroalkanide correspond-
ing to 8 does not form. Furthermore, 30 h were required for
consumption of 2.
On the basis of above the results, a plausible mechanism is
proposed in Scheme 2. The key step of the present reaction is
the formation of ammonium nitroalkanide 8, which involves
the removal of the hydrogen at the ꢀ-position of the nitro
group. Because the 2-position is connected with a nitro and
two carbonyl groups, the hydrogen at this position is acidic
enough for the formation of nitroalkanide 8. When the amine
is liberated from 8 under equilibrium, the nucleophile and
the electrophile, namely, the amine and 2, are located close
to each other, which is called an intimate pair. Nucleophilic
substitution by the amine easily occurs at the 3-position to af-
ford amide ester 4a accompanied by elimination of nitroace-
tate 5 as a result of C2–C3 bond cleavage assisted by the elec-
tron-withdrawing property of the nitro group. Because of this
intimate pair effect, the reaction process is thought to be a
pseudo intramolecular one, thus, acylation of the amine occurs
without by-products under mild conditions. On the other hand,
the reaction of 2 with methanol 6a is considerably slower,
since less basic methanol does not form the corresponding in-
timate pair. However, the lower nucleophilicity of methanol is
another reason for the slow reaction.
O
O
O
O
O
O
ROH 6
CDCl3 rt
+
OEt
EtO
OEt
EtO
OH
OR
NO2
NO2
2
7
5
N
ROH :
EtOH
,
6d
6e
O
O
O
O
O
O
EtO
NH OH
8'
OEt
EtO
OEt
_
_
O
NO2
N
O
N
OH
Intimate Pair
Scheme 3. Comparison of the reactivity between alcohols
6d and 6e.
salt 80 formed just after addition of aminoethanol 6d. Signifi-
cant difference in the reactivity between alcohols 6d and 6e
was observed. Although the reaction of 6d with 2 afforded
7d in 90% yield after 2 h, 7e was obtained in only 6% yield
after the same reaction period. The reactivity of 6e did not in-
crease even when triethylamine was added to a reaction mix-
ture. These results support that the reaction of 6d proceeds
by a pseudo intramolecular process in which an intimate pair
is formed after the deprotonation of 2 with the dimethylamino
group (Scheme 3). Furthermore, whether the reaction proceed-
ed in the pseudo intramolecular process or the intermolecular
process was determined by the experimental results under
dilute conditions. When the concentration of both 2 and 6e
(62.5 mmol dmꢂ3) was decreased to the half of original, the
conversion giving 7e substantially decreased from 17% to 3%
after 6 h, which suggests the reaction is an intermolecular pro-
cess. On the other hand, aminoalcohol 6d (62.5 mmol dmꢂ3
)
was similarly converted to 7d (90% after 2 h) in spite of
the dilute conditions, supporting the pseudo intramolecular
process.
We have previously observed an intimate pair effect in the
reaction of 2-aryl-3-oxoesters with amines, in which the acid-
ity of the hydrogen at the 2-position is promoted by bulkiness
of an aryl group, forming the intimate pair after forming am-
monium enolate.6 However, the acidity of the hydrogen at 2-
position is promoted by a nitro group in 2-nitro-3-oxoester 2
in the present reaction. The strong electron-withdrawing effect
of a nitro group prevents multiple nitration of 1, whereas a
complex mixture is sometimes observed due to polyarylation
in the case of 2-aryl-3-oxoester. Moreover, the electrophilicity
To confirm the acceleration effect by forming the intimate
pair, we monitored the reaction of 2-dimethylaminoethanol
6d (124 mmol dmꢂ3) and ethanol 6e (124 mmol dmꢂ3) by
1H NMR using chloroform-d as the solvent at 24 ꢁC. Both
nucleophiles underwent O-acylation with 2 to give the corre-
sponding diesters 7d and 7e, respectively. In the case of 6d,

2416 Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007)
Synthesis of Unsymmetrical Malonate Derivatives
chloromethane (1.5 mL), propylamine 3a (119 mL, 1.45 mmol)
was added, and the resultant mixture was stirred for 1 day at
room temperature. After concentration under reduced pressure,
the residue was subjected to chromatography on silica gel afford-
ing 4a as a dark yellow oil (eluted with AcOEt, 246 mg, quant.).
1H NMR (400 MHz, CDCl3, TMS) ꢁ 0.94 (t, J ¼ 7:3 Hz, 3H,
NHCH2CH2CH3), 1.29 (t, J ¼ 7:1 Hz, 3H, OCH2CH3), 1.56 (tq,
J ¼ 7:1, 7.3 Hz, 2H, NHCH2CH2CH3), 3.25 (dt, J ¼ 6:5, 7.1 Hz,
2H, NHCH2CH2CH3), 3.31 (s, 2H, COCH2CO), 4.20 (q, J ¼ 7:1
Hz, 2H, OCH2CH3), 7.10–7.20 (br t, 1H, NH); 13C NMR (100
MHz, CDCl3, TMS) ꢁ 11.4 (p), 14.2 (p), 22.6 (s), 41.4 (s), 41.7
(s), 61.8 (s), 165.3 (q), 169.5 (q). Other amide esters 4 and diesters
7 were prepared in the same way.
of the carbonyl group is considerably increased by an adjacent
nitro group, which enables substitution with an alcohol under
milder conditions than those employed in the case of 2-aryl-
3-oxoester.
Conclusion
We demonstrated 2-nitro-3-oxoester could be used as ac-
ylating reagents by introducing a nitro group at the ꢀ-position.
Unsymmetrical malonic acid derivatives, amide esters 4 and
diesters 7 were easily prepared upon treatment of diethyl 2-
nitro-3-oxopentanedioate 2 with various amines and alcohols
in moderate to high yields under mild conditions without
any special reagents. In the present reaction, the nitro group
plays the following roles: it (a) increases the acidity of the hy-
drogen at 2-position, which enables the formation of ammoni-
um nitroalkanides 8 to cause the pseudo intramolecular pro-
cess, (b) improves the electophilicity of the adjacent carbonyl
group, and (c) assists C–C bond cleavage to release the ester
function as nitroacetate 5. Consequently, this work provided
new aspects in the chemistry of 3-oxoesters, which have been
studied for a long time.
Ethyl 3-Allylamino-3-oxopropanoate (4f).14 Yellow oil, IR
(neat) 3083sh (NH), 1741 (CO), 1664 (CO) 1645 (C=C), 1553
1
and 1332 cmꢂ1 (NO2); H NMR (400 MHz, CDCl3, TMS) ꢁ 1.30
(t, J ¼ 7:2 Hz, 3H, OCH2CH3), 3.34 (s, 2H, COCH2CO), 3.91–
3.94 (m, 2H, NHCH2), 4.21 (q, J ¼ 7:2 Hz, 2H, OCH2CH3), 5.15
(dd, J ¼ 1:4, 10.2 Hz, 1H, CH2CH=CHH), 5.22 (dd, J ¼ 1:4,
17.1 Hz, 1H, CH2CH=CHH), 5.87 (ddt, J ¼ 5:5, 10.2, 17.1 Hz,
1H, CH2CH=CHH), 7.2–7.3 (br, 1H, NH): 13C NMR (100 MHz,
CDCl3, TMS) ꢁ 14.1 (p), 41.0 (s), 41.9 (s), 61.7 (s), 116.4 (s),
133.7 (t), 164.8 (q), 169.9 (q); MS (EI) (m=z) 171 (Mþ, 15%),
126 (15), 56 (100).
Experimental
Melting points were determined on a Yanaco micro-melting-
point apparatus and are uncorrected. All reagents and solvents
were commercially available and used as received. 1H and
13C NMR spectra were measured on a Bruker DPX-400 at 400
MHz and at 100 MHz, respectively, with TMS as an internal
standard. Assignments of 13C NMR spectra were performed by
DEPT experiments and are indicated as p (primary), s (secondary),
t (tertiary), and q (quaternary). IR spectra were recorded on a
Horiba FT-200 IR spectrometer. Mass spectra were recorded on a
JEOL JMS-AX505HA. Elemental microanalyses were performed
using a Yanaco CHN corder.
Ethyl 3-(p-Nitroanilino)-3-oxopropanoate (4h).
Yellow
powder, mp 104–105 ꢁC; IR (neat) 3313 (NH), 1725 (CO), 1695
(CO), 1556 and 1305 cmꢂ1 (NO2); 1H NMR (400 MHz, CDCl3,
TMS) ꢁ 1.35 (t, J ¼ 7:1 Hz, 3H, OCH2CH3), 3.52 (s, 2H,
COCH2CO), 4.29 (q, J ¼ 7:1 Hz, 2H, OCH2CH3), 7.75 (d, J ¼
9:2 Hz, 2H, aromatic), 8.23 (d, J ¼ 9:2 Hz, 2H, aromatic), 9.85
(s, 1H, NH); 13C NMR (100 MHz, CDCl3, TMS) ꢁ 14.4 (p), 41.7
(s), 62.7 (s), 119.9 (t), 125.4 (t), 143.6 (q), 144.1 (q), 163.9 (q),
170.3 (q). MS (FAB) (m=z) 253 (Mþ þ 1, 100%); Found: C,
52.18; H, 4.48; N, 10.94%. Calc. for C11H12N2O5: C, 52.38; H,
4.80; N, 11.11%.
Preparation of Diethyl 2-Nitro-3-oxopentanedioate (2). Ni-
tration was conducted according to modified Laikhter’s method.9
Mixed acid was prepared by slowly adding fuming nitric acid
(0.45 mL, 10 mmol, d ¼ 1:52) to 18 M sulfuric acid (1.9 mL,
34 mmol) at ꢂ10 ꢁC in an ice-salt bath. To a solution of diethyl
3-oxopentanedioate (1) (1.3 mL, 10 mmol) in dichloromethane
(7 mL), the mixed acid was slowly dropped with vigorously stir-
ring over 30 min at ꢂ5 ꢁC, and the mixture was stirred at the
same temperature for further 1 h. After addition of cold dichloro-
methane (10 mL), the organic layer was immediately separated,
dried over MgSO4, and concentrated to give nitrated 3-oxoester
2 as a yellow oil (2.12 g, 86%). IR (neat) 3200–3400 br (OH),
1747 (CO), 1668 (C=C), 1569 and 1373 cmꢂ1 (NO2); 1H NMR
(400 MHz, CDCl3, TMS) ꢁ 1.29 (t, J ¼ 6:9 Hz, 3H, OCH2CH3),
1.34 (dd, J ¼ 7:1, 7.1 Hz, 3H, OCH2CH3), 3.74 (d, J ¼ 17:2 Hz,
1H, COCHHCO), 3.84 (d, J ¼ 17:2 Hz, 1H, COCHHCO), 4.22
(q, J ¼ 6:9 Hz, 2H, OCH2CH3), 4.35–4.41 (m, 2H, OCH2CH3),
5.39 (s, 1H, CHNO2); 13C NMR (100 MHz, CDCl3, TMS) ꢁ 13.6
(p), 13.7 (p), 46.6 (s), 62.0 (s), 63.7 (s), 92.8 (t), 159.7 (q), 165.9
(q), 186.5 (q). In the NMR spectrum of 2, signals due to two kinds
of enol forms were also observed, which were too small to be as-
signed. Satisfactory elemental analysis and mass spectroscopy
could not be performed because of its instability. Nitrated 3-
oxoester 2 was used for the subsequent acylation immediately
after work up.
Hydrochloride of Ethyl 3-(2-Dimethylaminoethoxy)-3-oxo-
propanoate (7d). When oxoester 2 (672 mg, 2.73 mmol) was
allowed to react with dimethylaminoethanol 6d (275 mL, 2.73
mmol) in dichloromethane (3 mL) according to the general proce-
dure, O-acylation proceeded to afford 7d. However, it was diffi-
cult to isolate 7d, since this product gradually formed a salt with
ethyl nitroacetate 5, a by-product of the reaction. Hence, diester
7d was isolated as its hydrochloride. After addition of 1 M
(=mol dmꢂ3) hydrochloric acid (2.73 mL, 2.73 mmol) to the reac-
tion mixture, the aqueous solution was washed once with benzene
(20 mL) to remove liberated ethyl nitroacetate. Then, the aqueous
layer was evaporated to afford 7d as the hydrochloride (385 mg,
60%).
The salt consists of two isomers A and B, of which the struc-
tures were not assigned. The ratio A/B was variable depending
on the solvent (A/B = 1/2 in CDCl3, 4/1 in CD3CN, and 1/1
1
in DMSO-d6). In the H NMR spectrum, the integrals of isomers
A and B are indicated as HA and HB, respectively. The presence
of chloride in 7d was confirmed by using both a Beilstein test
and qualitative analysis using silver nitrate. Satisfactory elemental
analysis was not obtained because it was hygroscopic.
1
Colorless oil, IR (neat) 1747 (CO), 1728 cmꢂ1 (CO); H NMR
(400 MHz, CDCl3, TMS) ꢁ 1.29 (t, J ¼ 7:1 Hz, 3HA, OCH2CH3),
1.33 (t, J ¼ 6:9 Hz, 3HB, OCH2CH3), 2.87–2.98 (br s, 6HA
+
6HB, NCH3), 3.31–3.39 (br, 2HA + 2HB, NCH2CH2), 3.42 (s,
2HB, COCH2CO), 3.51 (s, 2HA, COCH2CO), 4.20 (q, J ¼ 7:1 Hz,
2HA, OCH2CH3), 4.25 (q, J ¼ 6:9 Hz, 2HB, OCH2CH3), 4.6–4.75
Preparation of Ethyl 3-Propylamino-3-oxopropanoate (4a).6
To a solution of 2-nitrated 3-oxoester 2 (358 mg, 1.45 mmol) in di-

Y. Nakaike et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007) 2417
(br, 2HA + 2HB, OCH2CH2), 12.4–12.8 (br, 1HA + 1HB, NH);
13C NMR (100 MHz, CDCl3, TMS) ꢁ 15.9 (p, CA), 16.0 (p, CB),
42.8 (s, CA), 43.1 (s, CB), 45.5 (p, CA), 45.7 (p, CB), 57.9 (s,
CA), 58.0 (s, CB), 61.2 (s, CA), 63.4 (s, CA), 63.6 (s, CB), 66.7
(s, CB), 167.8 (q, CA), 168.2 (q, CA), 169.3 (q, CB), 170.1 (q, CB);
MS (EI) (m=z) 203 (Mþ ꢂ 1, 65%), 158 (100).
1409. b) T. L. Gilchrist, A. Rahman, J. Chem. Soc., Perkin Trans.
´
1 1998, 1203. c) A. Ahibo-Coffy, J.-C. Prome, Tetrahedron Lett.
1976, 17, 1503.
4
The acetyl group was activated by an adjacent acyl group,
which in turn served as a leaving group: a) A. R. Katritzky, Z.
Wang, M. Wang, C. R. Wilkerson, C. D. Hall, N. G. Akhmedov,
J. Org. Chem. 2004, 69, 6617. b) S. Nakatsu, A. T. Gubaidullin,
V. A. Mamedov, S. Tsuboi, Tetrahedron 2004, 60, 2337.
The Comparison of the Reaction Rates Using Propylamine
and Methanol. To a solution of 2-nitro-3-oxoester 2 (24.7 mg,
0.100 mmol) and 1,1,2,2-tetrachloroethane (internal standard, 9.0
mL) in CDCl3 (300 mL), propylamine 3a (8.2 mL, 0.10 mmol), or
methanol 6a (4.1 mL, 0.10 mmol) was added. The reaction mix-
tures were stood at room temperature, and the 1H NMR spectra
were measured at appropriate intervals. The amounts of amide
ester 4a and diester 7a were determined by comparing their peak
integrals with that of the internal standard.
5
Deacylation was reported in which acyl group was activat-
ed by electron-withdrawing effect of a bromo group and a steric
effect of bulky group: Y. Hu, D. Bai, Tetrahedron Lett. 1998,
39, 2375.
6
The acyl group of 3-oxoesters is activated by bulky aryl
group. N. Nishiwaki, D. Nishida, T. Ohnishi, F. Hidaka, S.
Shimizu, M. Tamura, K. Hori, Y. Tohda, M. Ariga, J. Org. Chem.
2003, 68, 8650.
The Comparison of the Reaction Rates Using 2-Dimethyl-
aminoethanol 6d and Ethanol 6e. To a solution of 2-nitro-3-
oxoester 2 (12.4 mg, 0.050 mmol) and 1,1,2,2-tetrachloroethane
(internal standard, 9.0 mL) in CDCl3 (300 mL), aminoethanol 6d
(5.0 mL, 0.05 mmol) or ethanol 6e (3.0 mL, 0.05 mmol) was added.
The reaction mixtures were stood at room temperature, and the
1H NMR spectra were measured at appropriate intervals. The
amounts of malonates 7d and 7e were determined by comparing
their peak integrals with that of the internal standard.
7
1143.
8
836.
9
R. Ballini, G. Bosica, D. Fiorini, Tetrahedron 2003, 59,
T. Simmons, K. L. Kreus, J. Org. Chem. 1968, 33,
A. L. Laikhter, V. P. Kislyi, V. V. Semenov, Mendeleev
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10 When 3-nitro-2,4-pentanedione was left in the air at room
temperature for about a day, acetic acid and unidentified products
were obtained. This result indicates that the diketone reacts with
ambient moisture. Hence, a less reactive 2-nitro-3-oxoester was
employed, because of its relative stability in the air.
11 a) A. J. Clark, C. P. Dell, J. M. McDonagh, J. Geden, P.
Mawdsley, Org. Lett. 2003, 5, 2063. b) R. V. Hoffman, S. Madan,
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12 V. F. Kucherov, L. A. Yanovskaya, in The Chemistry of
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London, 1969, pp. 175–209.
Y. N. acknowledges to the supports by the Sasakawa Scien-
tific Research Grant from The Japan Science Society and
by The Global COE (center of excellence) Program ‘‘Global
Education and Research Center for Bio-Environmental
Chemistry’’ of Osaka University.
Supporting Information
Spectral data of 4b–4e, 4g, 4i–4k, and 7a–7c. This material is
available free of charge on the Web at: http://www.csj.jp/journals/
bcsj/.
13 A. Goeta, M. M. Salter, H. Shah, Tetrahedron 2006, 62,
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