Synthesis and insecticidal activity of novel N-oxydihydropyrroles: 4-hydroxy-3-mesityl-1-methoxymethoxy derivatives with various substituents at the 5-position

Article abstract of DOI:10.1016/S0968-0896(02)00474-1

This paper reports the synthesis and insecticidal activity of a series of novel 4-hydroxy-3-mesityl-1-methoxymethoxy-1,5-dihydro-2H-pyrrol-2-one derivatives, in which the substituents at the 5-position were varied with a number of alkyl and spirocycloalky

Full text of DOI:10.1016/S0968-0896(02)00474-1

Bioorganic & Medicinal Chemistry 11 (2003) 761–768
Synthesis and Insecticidal Activity of Novel
N-Oxydihydropyrroles: 4-Hydroxy-3-mesityl-1-methoxymethoxy
Derivatives with Various Substituents at the 5-Position
Mitsuru Ito,a,* Hideshi Okui,a Harumi Nakagawa,a Shigeru Mio,a Ayako Kinoshita,a
Takashi Obayashi,a Takako Miura,a Junko Nagai,a Shinji Yokoi,a Reiji Ichinose,b
Keiji Tanaka,a Seiichiro Kodama,c Toshiaki Iwasaki,d Takaaki Miyake,d Miho Takashiod
and Jun Iwabuchid
aAgroscience Research Laboratories, Sankyo Co., Ltd., 1041 Yasu, Yasu-cho, Yasu-gun, Shiga 520-2342, Japan
bCrop Protection Department, Sankyo Co., Ltd., 7-12, Ginza 2-chome, Chuo-ku, Tokyo 104-8113, Japan
cMarketing Department, Agrochemicals Division, Agro & Specialty Chemicals Group, Nippon Kayaku Co., Ltd., 11-2,
Fujimi 1-chome, Chiyoda-ku, Tokyo 102-8172, Japan
dResearch & Development Laboratories, Agro & Specialty Chemicals Group, Nippon Kayaku Co., Ltd., 225-1, Koshikiya,
Ageo-city, Saitama 362-0064, Japan
Received 9 August 2002; accepted 24 September 2002
Abstract—This paper reports the synthesis and insecticidal activity of a series of novel 4-hydroxy-3-mesityl-1-methoxymethoxy-1,5-
dihydro-2H-pyrrol-2-one derivatives, in which the substituents at the 5-position were varied with a number of alkyl and spiro-
cycloalkyl groups. Investigation of the structure–activity relationships revealed that small alkyl and spirocyclohexyl groups had a
favorable effect on the insecticidal activity of these agents against Myzus persicae.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
the very least its market value is reduced. For a com-
pound to be effective against these pests, it needs to
have a novel mode of action because they multiple so
rapidly that the chemical-resistant strains frequently
emerge.7,8 And it is also desirable for an agent to pos-
sess a systemic property, a character to be absorbed
from a plant’s roots or leaves and transferred to other
parts of the plant, when combating these sucking pests.
A systemic insecticide can spread all through a plant
and kill any targeted insects that feed on it.3
Crop damage by insects remains a serious problem in
modern agriculture. The organophosphates, carba-
mates, pyrethroids, and several other classes of insecti-
cides have been used so intensively worldwide that
significant insect resistance to them has emerged.1ꢀ4 In
addition, a growing social awareness of the residual
agrochemicals in the environment underlines the need
for the development of novel, highly potent, target-
selective, and environmentally innocuous insecticides
with low mammalian toxicity.1ꢀ6
In our previous study, we reported the synthesis and
insecticidal activity of a new series of N-oxydihydro-
pyrrole derivatives (1),9,10 which were designed based on
the insecticidal and acaricidal agents reported by
Bayer’s groups (Fig. 1).11ꢀ14 Our interest focused on
how the modification of the 1-position (–ORgroup in
structure 1) influenced the insecticidal activity against
the above pests. The derived compounds demonstrated
significant systemic insecticidal activity against hemi-
ptera pests such as the brown planthopper (Nilaparvata
lugens) and M. persicae. In addition, the early structure–
In an upland field, hemiptera pests such as the green
peach aphid (Myzus persicae) and cotton aphid (Aphis
gossypii) cause serious damage to many crops, for
example cucumber and cabbage. Once they pierce a
plant and suck its sap, often the plant is blighted, or at
*Corresponding author. Tel.: +81-77-586-1223; fax: +81-77-586-
2538; e-mail: mtitou@shina.sankyo.co.jp
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00474-1

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Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
activity study revealed that substituents such as small
alkoxy and alkoxyalkoxyl groups exert more potent
insecticidal activity than others. The affected insects
died before or during ecdysis without completing molt-
ing. This symptom is unique for hemiptera pests, and
the derivatives appear to provide a new mode of action.
On the other hand, these derivatives also showed some
phytotoxicity against rice and cucumber. While this phy-
totoxic damage could be alleviated by modifying the 1-
position,9 the extent of improvement was not satisfactory.
amino acid esters (4a–4k in Scheme 2), a task that could
be accomplished by several available synthetic meth-
ods.16ꢀ21 Ultimately, we chose the processes20,21 starting
from amino acid esters via schiff base intermediates (10
and 11), as various alkyl groups could be easily intro-
duced to the a-carbon of the intermediates. In practice,
the alkyl groups can be introduced in combination with
methyl or ethyl groups using a slightly modified version
of the procedure in ref 20 (Route 1 in Scheme 2).
Appropriate amino acid esters (8 and 9) were converted
to schiff bases (10 and 11) by the condensation with 4-
methoxybenzaldehyde in absolute methanol in the pre-
sence of sodium bicarbonate.22 The a-carbons of the
resultant schiff bases were variously alkylated in the
presence of t-BuOK to give 12a–12g, which were then
oxidized with m-chloroperbenzoic acid (mCPBA) to
give the corresponding oxaziridines. Treatment of these
oxaziridines with hydroxylamine hydrochloride in
methanol gave the N-hydroxyamino acid esters, which
were taken up as salt free forms (4a–4g) by treatment
with sodium bicarbonate.
Among the derivatives studied in the previous work,9
compound
2 controlled M. persicae perfectly at
0.01 ppm in systemic application, but it also exerted
severe phytotoxicity against cucumber at 50 ppm in
foliage application. Based on the structure (2) as a lead,
we attempted to vary the substituents at the 5-position
of the dihydropyrrole ring (R1 and R2 groups in 3),
substituents we had fixed to the dimethyl group in the
previous study,9 and tried to gain further insight into
both the structure–activity relationships and potential
for alleviating the phytotoxicity.
To obtain N-hydroxyamino acid esters with cycloalkyl
groups (4h–4k), we opted for a direct hydroxyamination
method10,23 (Route 2 in Scheme 2) over the above
alkylation procedure since the starting materials for the
former method seemed more readily accessible. This
direct method was originally used for preparing
2-monosubstituted-2-hydroxyamino acid esters from
corresponding esters,23 but we conjectured that it would
also be applicable to 2,2-disubstituted counterparts.
Appropriate esters (13h–13k) were successfully con-
verted to the desired N-hydroxyamino acid esters (4h–
4k) through the following four subsequent treatments:
with lithium diisopropylamide, with 1-chloro-1-nitroso-
cyclohexane 14, with diluted hydrochloric acid, and
with sodium bicarbonate.
In this article, we report the synthesis of a series of 5,5-
disubstituted-4-hydroxy- 3-mesityl-1-methoxymethoxy-1,5-
dihydro-2H-pyrrol-2-one derivatives (3) and an assess-
ment of their insecticidal activity against M. persicae. We
also briefly refer to the phytotoxicity of the derivatives
(Fig. 1).
Results and Discussion
Chemistry
Scheme 1 outlines the synthetic route to prepare 5,5-dis-
ubstituted N-oxydihydropyrrole derivatives (3). Hydro-
xyamino acid esters with various substituents on a-
carbon (4a–k) were acylated into 6a–k with mesitylacetyl
chloride 515 under the two-phase reaction condition
developed by our group.9,10 The desired compounds (3a–
3k) were yielded in one pot by methoxymethylation of
the hydroxy group with chloromethyl methyl ether in
the presence of sodium hydride in DMF, followed by
cyclization via an intramolecular Claisen condensation
by treatment with potassium tert-butoxide (t-BuOK).
These N-hydroxyamino acid esters (4a–4k) were trans-
formed to the desired 5,5-disubstituted-N-oxydihydro-
pyrroles (3a–3k) by the method mentioned above
(Scheme 1).
Biological evaluation
All the derivatives prepared in this work (3a–3k) exhib-
ited high insecticidal activity against hemiptera pests
such as M. persicae and A. gossypii at 200 ppm in contact
tests. To highlight the structure–activity relationships of
In our approaches, modification at C-5 in 3 depended
on the preparation of the 2,2-disubstituted-2-hydroxy-
Scheme 1. Synthetic route to 3a–3k.

Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
763
Scheme 2. Preparation of N-hydroxyamino acid esters (4a–4k).
these derivatives, Table 1 shows their insecticidal activity
against M. persicae at lower concentrations.
systemic activity. Oxygen-introduced derivative (3j) and
methoxy-substituted derivative (3k) at the 40-position of
the spirocyclohexyl ring conspicuously improved the
activity.
Compounds with short linear alkyl (3a and 3b) or
alkoxy (3d) groups showed relatively high systemic and
contact insecticidal activity, while other longer or bran-
ched alkyl substitutions tended to decrease the efficacy.
It was interesting to note that the diethyl group (3g)
decreased the efficacy, while its cyclic counterpart (3h)
exhibited both systemic and contact activities. Spiro-
cyclohexane derivative (3i) also showed moderate
On the other hand, almost all of these derivatives exer-
ted severe phytotoxicity against cucumber at 500 ppm.
The only exception was 3e, a derivative that had lost
insecticidal activity. The derivatization presented in the
study was not demonstrably effective in alleviating the
phytotoxicity. Further modification of other parts of the
Figure 1. Structures of the lead compounds (1, 2) and derivatives explored in the present work (3).

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Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
Table 1. Insecticidal activity and phytotoxicity of 5,5-disubstituted N-oxydihydropyrrole derivativesa
Compd
R1
R2
M. persicae
CSb
Systemic test
0.01 ppm
Contact test
10 ppm
Spray test
500 ppm
0.1 ppm
1 ppm
2
Me
Me
Me
Me
Me
Me
Me
Et
Me
4
4
1
0
4
0
0
0
4
0
0
0
0
0
0
0
4
3
3
0
4
0
0
0
0
1
0
0
0
0
0
0
4
3
3
3
3
0
3
3
3a
3b
3c
3d
3e
3f
3g
Et
Allyl
i-Pr
MeOCH2CH2
c-Hex-CH2
Bn
Et
3h
3i
2
3
4
4
0
0
4
0
2
0
0
0
2
3
3
3
c
3j
—
4
—
0
3k
aThe insecticidal activity and phytotoxicity were each graded into five classes from 0 to 4. See text.
bCS, Cucumis sativus (cucumber).
cNot determined.
dihydropyrrole ring will clearly be necessary for separat-
ing the insecticidal potency from phytotoxicity.
spectrometer. 1H NMRspectra were recorded at
200 MHz on a Varian Gemini 200 spectrometer with
tetramethylsilane as an internal standard. Mass spectra
(MS) and high-resolution mass spectra (HRMS) were
obtained with a JEOL JMS-D300 mass spectrometer
and a VG Auto Spec M mass spectrometer. Regular
silica gel (Daisogel 1001W, 63–210 mesh) was used for
all column chromatography procedure except the pur-
ification of schiff bases and hydroxylamines, which was
performed using a neutral silica gel (Silica gel 60, spherical,
neutrality, 150 mesh, Nacalai Tesque).
Conclusion
We designed a series of novel 4-hydroxy-3-mesityl-1-
methoxymethoxy-1,5-dihydro-2H-pyrrol-2-one deriva-
tives (3) and developed general methods to synthesize
them via the preparation of variously substituted
N-hydroxyamino acid esters. Structure–activity rela-
tionships revealed that small alkyl and spirocyclohexyl
groups were favorable for the insecticidal activity against
M. persicae, while other dialkyl groups tended to
decrease the activity. The derivatization did not appear
to attenuate their phytotoxicity against cucumber.
Methyl 2-[(E)-(4-methoxyphenyl)methylidene]aminopro-
panoate (10).22 p-Anisaldehyde (41.7 mL, 0.34 mol) was
added to a stirred suspension of l-alanine methyl ester
hydrochloride (8, 50.10 g, 0.36 mmol) and Na2CO3
(57.20 g, 0.54 mol) in methanol (300 mL) at 0 ꢁC, and the
reaction mixture was stirred at 20 ꢁC for 2 h and then at
ambient temperature for 12 h. After adding ethyl ether
to the reaction mixture, the organic layer was washed
with brine, dried over anhydrous magnesium sulfate
(MgSO4), and concentrated under reduced pressure to
an oil. Treatment of this oil by neutral silica gel column
chromatography (EtOAc/hexane, 1/4) yielded the com-
Experimental
Synthetic procedure
General. All melting points (mp) are uncorrected. IR
spectra were measured on
a Perkin-Elmer 1600

Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
765
1
pound 10 (63.62 g, 80.2%) as a colorless oil. H NMR
(CDCl3) d: 8.24 (1H, s), 7.72 (2H, d, J=8.8 Hz), 6.93
(2H, d, J=8.8 Hz), 4.12 (1H, q, J=6.6 Hz), 3.85 (3H, s),
3.75 (3H, s), 1.52 (3H, d, J=6.6 Hz).
Compounds 4b–4f were synthesized by the same
procedure.
Methyl 2-hydroxyamino-2-methyl-4-pentenoate (4b).20
1
Yield: 38.6%; colorless oil; H NMR(CDCl ) d: 5.85–
3
Methyl 2-[(E)-(4-methoxyphenyl)methylidene]aminobu-
tanoate (11). This was prepared from methyl 2-amino-
butanoate hydrochloride (9) using the same procedure.
Yield: 86.2%; colorless oil; 1H NMR(CDCl 3): 8.20
(1H, s), 7.73 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz),
3.85 (3H, s), 3.75 (3H, s), 2.08–1.81 (3H, m), 0.91 (3H, t,
J=7.3 Hz).
5.64 (2H, m), 5.16 (2H, s), 5.11–5.09 (1H, m), 3.76 (3H,
s), 2.53–2.30 (2H, m), 1.34 (3H, s).
Methyl 2-hydroxyamino-2,3-dimethylbutanoate (4c).20
1
Yield: 58.9%; colorless oil; H NMR(CDCl ) d: 3.75
3
(3H, s), 1.88 (1H, quint, J=7.0 Hz), 1.31 (3H, s), 0.88
(6H, dd, J=7.0, 7.7 Hz).
Methyl 2-hydroxyamino-2-methylbutanoate.20 Potassium
tert-butoxide (t-BuOK; 8.76 g, 77.8 mmol) was added to
a stirred solution of 10 (17.11 g, 77.8 mmol) and
Methyl 2-hydroxyamino-4-methoxy-2-methylbutanoate
1
(4d). Yield: 69.3%; colorless oil; H NMR(CDCl ) d:
3
3.76 (3H, s), 3.49 (2H, t, J=5.9 Hz), 3.33 (3H, s), 2.15–
1.84 (2H, m), 1.33 (3H, s); IR(neat) cm ꢀ1: 3275, 2951,
1732, 1452, 1374, 1306, 1243, 1197, 1118, 1056;
HRMS(FAB) calcd for C7H15NO4 178.1079, found
178.1077.
1,4,7,10,13,16-hexaoxacyclooctadecane
(18-crown-6;
1.87 g, 7.8 mmol) in toluene (170 mL) at 0 ꢁC, and then
the mixture was stirred for 10 min at the same tempera-
ture. After adding ethyliodide (8 mL, 0.10 mol) and
stirring for 1 h at 0 ꢁC, the solution was mixed with a
saturated aqueous solution of sodium bicarbonate, the
water layer was extracted with ethyl acetate (EtOAc),
and the combined organic layer was washed with brine,
and dried (MgSO4). Concentration of the product under
reduced pressure yielded 12a as an oil that was ready for
use without further purification (crude product,
14.00 g).
Methyl 3-cyclohexyl-2-hydroxyamino-2-methylpropano-
ate (4e). Yield: 9.0%; brownish prisms; mp 64–66 ꢁC;
1H NMR(CDCl ) d: 3.74 (3H, s), 1.68–0.89 (13H, m),
3
1.39 (3H, s); IR(KBr) cm ꢀ1: 3282, 2933, 1735, 1458,
1438, 1374, 1256, 1231, 1210, 1156, 1108, 1027;
HRMS(EI) calcd for C11H21NO3 215.1521, found
215.1523.
Na2CO3 (8.33 g, 78.6 mmol) and 3-chloroperoxybenzoic
acid (mCPBA; content ca. 75%, 12.60 g, ca. 62.0 mol)
were added to a stirred solution of crude 12a in 1,2-
dichloroethane at 0 ꢁC, and then the reaction mixture
was stirred at the same temperature for 1 h and at
ambient temperature for 2 h. After adding water and
extracting the mixture with dichloromethane (CH2Cl2),
the combined organic layer was washed with brine,
dried (MgSO4), and concentrated under reduced pres-
sure to give the corresponding oxaziridine as an oil that
was used without further purification (crude product,
13.50 g).
Methyl
2-hydroxyamino-2-methyl-3-phenylpropanoate
(4f).20 Yield: 14.2%; colorless prisms; mp 78–80 ꢁC; H
NMR(CDCl 3) d: 7.35–7.22 (3H, m), 7.20–7.13 (2H, m),
5.10 (2H, br s), 3.73 (3H, s), 2.99 (2H, ABq, J=14.7 Hz,
Án=27.2 Hz), 1.33 (3H, s).
1
Methyl 2-ethyl-2-(hydroxyamino)butanoate (4g). This
was prepared using the same procedure from (11) and
iodoethane. Yield: 47.0%; colorless oil; 1H NMR
(CDCl3) d: 3.76 (3H, s), 1.82–1.58 (4H, m), 0.87 (6H, t,
J=7.5 Hz); IR(neat) cm ꢀ1: 3275, 2970, 1733, 1457,
1383, 1340, 1293, 1239, 1136; HRMS(EI) calcd for
C7H15NO3 161.1052, found 161.1052.
The hydroxylamine hydrochloride (3.50 g, 50.4 mmol)
was added to a stirred solution of the crude oxaziridine
in methanol (130 mL) at ambient temperature, and
then the mixture was stirred at the same temperature
for 12 h. After condensing the reaction mixture under
reduced pressure, ethyl ether and 1 N HCl were added,
the mixture was separated, and the organic layer was
then extracted with 1 N HCl. The combined water
layer was washed with ethyl ether and adjusted to ca.
pH 8 with NaHCO3. The mixture was extracted with
EtOAc and the combined organic layer was washed
with brine, dried with MgSO4, and concentrated under
reduced pressure to give a syrup. Treatment of this
syrup by neutral silica gel column chromatography
(EtOAc/hexane, 1/4) yielded the title compound (4a,
4.71 g, 41.1% in three steps) as a brownish oil. 1H
NMR(CDCl 3) d: 4.92 (2H, br s), 3.76 (3H, s), 1.64
(2H, q, J=7.7 Hz), 1.35 (3H, s), 0.88 (3H, t,
J=7.7 Hz); IR(neat) cm ꢀ1: 3273, 2974, 1732, 1460,
1253, 1150, 1068, 1007; HRMS calcd for C6H13NO3
147.0894, found 147.0894.
Methyl 1-(hydroxyamino)cyclohexanecarboxylate (4i). A
hexane solution of n-BuLi (1.58 mol/L, 7 mL,
10.8 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU; 1.33 mL, 11.0 mmol) were added
to a stirred solution of diisopropylamine (1.54 mL,
11.1 mmol) in THF (10 mL) at ꢀ78 ꢁC, and then the
reaction mixture was stirred at the same temperature for
1 h. The reaction was continued by adding methyl
cyclohexanecarboxylate (13i, 1.42 g, 10.0 mmol) at
ꢀ78 ꢁC, stirring at the same temperature for 1 h, adding
1-chloro-1-nitrosocyclohexane (14, 1.62 g, 11.0 mmol) at
ꢀ78 ꢁC, stirring at the same temperature for another
1 h, and finally adding 1 N HCl (20 mL) and stirring at
ambient temperature for 3 h. After the water layer was
separated, the organic layer was extracted with 1 N HCl,
and then the combined water layer was washed with
ethyl ether, adjusted to ca. pH 9 with NaHCO3, and
extracted with EtOAc. The combined organic layer was
washed with brine, dried (MgSO4), and concentrated
under reduced pressure to a syrup. Treatment of this

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Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
syrup by neutral silica gel column chromatography
(EtOAc/hexane, 1/4) yielded the title compound (14i,
1.02 g, 59%) as colorless prisms. Mp 39–41 ꢁC; 1H
Methyl 2-[hydroxy(mesitylacetyl)amino]-2,3-dimethylbu-
tanoate (6c). Yield: 41.9%; mp 154–156 ꢁC; 1H
NMR(DMSO- d6) d: 9.92 (1H, s), 6.78 (2H, s), 3.69
(2H, d, J=4.8 Hz), 3.49 (3H, s), 2.58–2.34 (1H, m),
2.19 (3H, s), 2.10 (6H, s), 1.31 (3H, s), 0.92 (6H,
dd, J=7.0, 16.1 Hz); IR(KBr) cm ꢀ1: 3137, 2948,
1742, 1597, 1432, 1377, 1257, 1203, 1191, 1114;
HRMS(EI) calcd for C18H27NO4 321.1940, found
321.1941.
NMR(CDCl ) d: 3.76 (3H, s), 1.94–1.80 (2H, m), 1.73–
3
1.47 (8H, m); IR(KBr) cm ꢀ1: 3261, 2933, 1724, 1448,
1431, 1281, 1240, 1148, 1108, 1084, 1070, 1032; HRMS(EI)
calcd for C8H15NO3 173.1052, found 173.1053.
Compounds 4h, 4j and 4k were synthesized using the
same procedure.
Methyl
2-[hydroxy(mesitylacetyl)amino]-4-methoxy-2-
Methyl
1-(hydroxyamino)cyclopentanecarboxylate
methylbutanoate (6d). Yield: 27.8%; mp 126–128 ꢁC; H
NMR(CDCl 3) d: 8.04 (1H, s), 6.83 (2H, s), 3.77 (2H, s),
3.67 (3H, s), 3.72–3.06 (2H, m), 3.37 (3H, s), 2.23 (9ꢀH1,
1
(4h).20 Yield: 23.4%; brownish prisms; 1H NMR
(CDCl3) d: 3.77 (3H, s), 20.5–1.75 (8H, m).
s), 2.16 (2H, t, J=3.9 Hz), 1.51 (3H, s); IR(KBr) cm
:
Ethyl 4-(hydroxyamino)tetrahydro-2H-pyran-4-carboxy-
1
3153, 2878, 1735, 1608, 1429, 1403, 1262, 1194, 1122;
HRMS(EI) calcd for C18H27NO5 337.1889, found
337.1890.
late (4j). Yield: 90.2%; colorless oil; H NMR(CDCl )
3
d: 4.25 (2H, q, J=7.2 Hz), 3.89–3.63 (4H, m), 2.15–2.02
(2H, m), 1.76–1.65 (2H, m), 1.31 (3H, t, J=7.2 Hz); IR
(KBr) cmꢀ1: 3391, 2964, 1730, 1470, 1445, 1391, 1304,
1256, 1205, 1148, 1106, 1016; HRMS(EI) calcd for
C8H15NO4 189.1001, found 189.1002.
Methyl 3-cyclohexyl-2-[hydroxy(mesitylacetyl)amino]-2-
methylpropanoate (6e). Yield: 34.7%; mp 190–191 ꢁC;
1H NMR(CDCl 3) d: 6.84 (2H, s), 6.23 (1H, s), 3.80 (2H,
s), 3.69 (3H, s), 2.24 (3H, s), 2.22 (6H, s), 2.05–1.60 (5ꢀH1,
:
Methyl 1-(hydroxyamino)-4-methoxycyclohexanecarbox-
ylate (4k). Yield: 63.5%; mp 42–45 ꢁC; 1H NMR
(DMSO-d6) d: 4.22 (2H, q, J=7.1 Hz), 3.38–3.31 (1H,
m), 3.33 (3H, s), 2.17–2.06 (2H, m), 1.92–0.46 (6H, m),
1.29 (3H, t, J=7.1 Hz); IR(KBr) cm ꢀ1: 3260, 2944,
1731, 1452, 1371, 1257, 1224, 1189, 1090, 1030;
HRMS(FAB) calcd for C10H19NO4 218.1392, found
218.1392.
m), 1.56 (3H, s), 1.50–0.90 (8H, m); IR(KBr) cm
3117, 2922, 2853, 1738, 1604, 1448, 1255, 1229, 1134;
HRMS(EI) calcd for C22H33NO4 375.2410, found
375.2411.
Methyl 2-[hydroxy(mesitylacetyl)amino]-2-methyl-3-phe-
nylpropanoate (6f). Yield: 45.0%; mp 154–156 ꢁC; 1H
NMR(DMSO- d6) d: 10.00 (1H, s), 7.29–7.25 (3H, m),
7.13–7.09 (2H, m), 6.80 (2H, s), 3.69 (2H, s), 3.50 (3H,
s), 3.16 (2H, ABq, J=13.2 Hz, Án=49.9 Hz), 2.20 (3H,
s), 2.14 (6H, s), 1.23 (3H, s); IR(KBr) cm ꢀ1: 3152, 2947,
1747, 1608, 1455, 1426, 1286, 1215, 1196, 1106;
HRMS(EI) calcd for C22H27NO4 369.1940, found
369.1941.
Methyl 2-[hydroxy(mesitylacetyl)amino]-2-methylbutano-
ate (6a). A solution of mesitylacetyl chloride15 (5,
0.98 g, 4.98 mmol) in EtOAc (10 mL) was added drop-
wise to a stirred two-phase solution of 4a (0.77 g,
5.23 mmol) and NaHCO3 (0.63 g, 7.5 mmol) in EtOAc
(8 mL) and water (7 mL) at ca. 0 ꢁC, and then the mix-
ture was stirred at 0 ꢁC for 1 h and at ambient tempera-
ture for 2 h. The organic layer was separated, washed
with brine, dried (MgSO4), and concentrated under
reduced pressure to a brownish oil. Treatment of this oil
by silica gel column chromatography (EtOAc/hexane,
1/4) yielded the desired title compound (6a, 0.60 g, 39%)
Methyl 2-ethyl-2-[hydroxy(mesitylacetyl)amino]butano-
ate (6g). Yield: 9.4%; mp 192–193 ꢁC; 1H NMR
(CHCl3) d: 6.85 (2H, s), 6.42 (1H, s), 3.83 (2H, s), 3.71
(3H, s), 2.24 (3H, s), 2.23 (6H, s), 2.19–1.96 (4H, m),
0.88 (6H, t, J=7.5 Hz); IR(KBr) cm ꢀ1: 3140, 2975,
1740, 1602, 1464, 1445, 1299, 1240, 1204, 1134;
HRMS(EI) calcd for C18H27NO4 321.1940, found
321.1939.
as a white powder. Mp 175–176 ꢁC; H NMR(DMSO-
1
d6) d: 9.94 (1H, s), 6.76 (2H, s), 3.66 (2H, s), 3.48 (3H,
s), 2.17 (3H, s), 2.08 (6H, s), 2.01–1.65 (2H, m), 1.30
(3H, s), 0.78 (3H, t, J=7.3 Hz); IR(KBr) cm ꢀ1: 3151,
2946, 1740, 1609, 1425, 1294, 1244, 1202, 1152;
HRMS(EI) calcd for C17H25NO4 307.1784, found
307.1783.
Methyl 1-[hydroxy(mesitylacetyl)amino]cyclopentanecar-
ꢁ
1
boxylate (6h). Yield: 53.6%; mp 161–163 C; H NMR
(DMSO-d6) d: 10.06 (1H, s), 6.76 (2H, s), 3.67 (2H, s),
3.50 (3H, s), 2.17 (3H, s), 3.08 (6H, s), 2.18–2.00 (4H,
m), 1.80–1.52 (4H, m); IR(KBr) cm ꢀ1: 3138, 2954,
1746, 1590, 1518, 1441, 1274, 1194, 1144, 1011;
HRMS(EI) calcd for C18H25NO4 319.1784, found
319.1782.
Compounds 6b–6k were synthesized by the same
procedure.
Methyl 2-[hydroxy(mesitylacetyl)amino]-2-methyl-4-pen-
tenoate (6b). Yield: 45.1%; mp 164–165 ꢁC; H NMR
1
Methyl 1-[hydroxy(mesitylacetyl)amino]cyclohexanecar-
boxylate (6i). Yield: 29.1%; mp 196–197 ꢁC; H NMR
1
(CDCl3) d: 6.85 (2H, s), 6.13 (1H, s), 6.0–5.75 (1H, m),
5.20–5.15 (1H, m), 5.11 (1H, br.s), 3.80 (2H, s), 3.69
(3H, s), 2.95–2.82 (1H, m), 2.66–2.55 (1H, m), 2.24 (3H,
s), 2.22 (6H, s), 1.54 (3H, s); IR(KBr) cm ꢀ1: 3150, 2938,
1737, 1609, 1433, 1256, 1130; HRMS(EI) calcd for
C18H25NO4 319.1784, found 319.1783.
(DMSO-d6) d: 9.94 (1H, s), 6.78 (2H, s), 3.70 (2H, s),
3.52 (3H, s), 2.19 (3H, s), 2.10 (6H, s), 2.10–1.36 (10H,
m); IR(KBr) cm ꢀ1: 3136, 2936, 1744, 1602, 1488, 1430,
1210, 1161, 1133; HRMS(EI) calcd for C19H27NO4
333.1940, found 333.1939.

Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
767
Ethyl
4-[hydroxy(mesitylacetyl)amino]tetrahydro-2H-
1688, 1636, 1608, 1457, 1371, 1315, 1157, 1074;
HRMS(EI) calcd for C19H27NO4 333.1940, found
333.1940.
pyran-4-carboxylate (6j). Yield: 12.3%; mp 143–145 ꢁC;
1H NMR(CDCl 3) d: 6.85 (2H, s), 6.46 (1H, s), 4.21 (2H,
q, J=7.1 Hz), 3.89 (2H, s), 3.90–3.65 (4H, m), 2.50–2.05
(4H, m), 2.23 (9H, s), 1.27 (3H, t, J=7.1 Hz); IR(KBr)
cmꢀ1: 3152, 2882, 1736, 1600, 1444, 1420, 1289, 1250,
1118, 1101; HRMS(EI) calcd for C19H27NO5 349.1889,
found 349.1889.
4-Hydroxy-3-mesityl-5-(2-methoxyethyl)-1-methoxyme-
thoxy-5-methyl-1,5-dihydro-2H-pyrrol-2-one (3d). Yield:
62.4%; colorless oil; 1H NMR(DMSO- d6) d: 11.44 (1H,
s), 6.86 (2H, s), 4.88 (2H, ABq, J=7.3 Hz, Án=8.2 Hz),
3.50 (3H, s), 3.18 (3H, s), 2.26–1.91 (13H, m), 1.41 (3H,
s); IR(KBr) cm ꢀ1: 2934, 1660, 1453, 1386, 1367, 1328,
1158, 1116, 1091, 1067; HRMS(EI) calcd for
C19H27NO5 349.1889, found 349.1889.
Methyl 1-[hydroxy(mesitylacetyl)amino]-4-methoxycy-
clohexanecarboxylate (6k). Yield: 20.4%; amorphous;
1H NMR(CDCl 3) d: 6.85 (2H, s), 6.44 (1H, s), 4.19 (2H,
q, J=5.2 Hz), 3.89 (2H, s), 3.48–3.40 (1H, m), 3.33 (3H,
s), 2.24 (3H, s), 2.23 (6H, s), 2.46–2.10 (4H, s), 1.88–1.66
(4H, m), 1.27 (3H, t, J=5.2 Hz); IR(KBr) cm ꢀ1: 3151,
2941, 1740, 1602, 1431, 1217, 1196, 1177, 1101, 1032;
HRMS(EI) calcd for C21H31NO5 377.2202, found
377.2202.
5-Cyclohexylmethyl-4-hydroxy-3-mesityl-1-methoxyme-
thoxy-5-methyl-1,5-dihydro-2H-pyrrol-2-one (3e). Yield:
1
38.5%; amorphous; H NMR(DMSO- d6) d: 11.34 (1H,
s), 6.86 (2H, s), 4.87 (2H, ABq, J=7.3 Hz, Án=7.0 Hz),
3.46 (3H, s), 2.24 (3H, s), 2.20–2.18 (2H, m), 2.09 (3ꢀH1,
s), 2.02 (3H, s), 1.81–0.80 (14H, m); IR(KBr) cm
:
5-Ethyl-4-hydroxy-3-mesityl-1-methoxymethoxy-5-methyl-
1,5-dihydro-2H-pyrrol-2-one (3a). NaH (60% dispersion
in mineral oil, 82.0 mg, 2.1 mmol) was added to a stirred
solution of 6a (0.60 g, 1.95 mmol) and chloromethyl
methyl ether (0.16 mL, 2.1 mmol) in DMF (6 mL) at
0 ꢁC, and then the reaction mixture was stirred at the
same temperature for 1 h and at the ambient tempera-
ture for 12 h. Next, the reaction solution was mixed with
DMF (10 mL) and t-BuOK (0.25 g, 2.23 mmol) at
ambient temperature and stirred at the same tempera-
ture for 3 h. After pouring the mixture into water, the
water layer was washed with ethyl ether, acidified to ca.
pH 3 with 1 N HCl, and extracted with EtOAc. The
combined organic layer was washed with brine, dried
(MgSO4), and concentrated under reduced pressure to a
syrup. Treatment of this syrup by silica gel column
chromatography (EtOAc/hexane, 1/2) yielded the title
compound (3a, 0.33 g, 53%) as colorless prisms; mp
157–159 ꢁC; 1H NMR(CDCl 3) d: 6.91 (2H, s), 5.01 (2H,
d, J=2.9 Hz), 3.58 (3H, s), 2.28 (3H, s), 2.18 (3H, s),
2.14 (3H, s), 1.95–1.77 (2H, m), 1.51 (3H, s), 0.89 (3H, t,
J=7.3 Hz); IR(KBr) cm ꢀ1: 2936, 2632, 1646, 1611,
1454, 1386, 1366, 1314, 1157, 1075; HRMS(EI) calcd for
C18H25NO4 319.1784, found 319.1784.
2922, 1654, 1591, 1450, 1390, 1368, 1332, 1314, 1294,
1157; HRMS(EI) calcd for C23H33NO4 387.2410, found
387.2411.
5-Benzyl-4-hydroxy-3-mesityl-1-methoxymethoxy-5-methyl-
1,5-dihydro-2H-pyrrol-2-one (3f). Yield: 49.0%; amor-
phous; 1H NMR(DMSO- d6) d: 11.39 (1H, s), 7.32–7.15
(5H, m), 6.77 (1H, s), 6.65 (1H, s), 5.04 (2H, ABq,
J=7.3 Hz, Án=23.3 Hz), 3.56 (3H, s), 3.08 (2H, Abq,
J=13.6 Hz, Án=39.9 Hz), 2.16 (3H, s), 1.98 (3H, s),
1.54 (3H, s), 1.15 (3H, s); IR(KBr) cm ꢀ1: 2929, 1654,
1592, 1484, 1449, 1341, 1307, 1276, 1216, 1186, 1158,
1088; HRMS(EI) calcd for C23H27NO4 381.1940, found
381.1941.
5,5-Diethyl-4-hydroxy-3-mesityl-1-methoxymethoxy-1,5-
dihydro-2H-pyrrol-2-one (3g). Yield: 33.7%; mp 147–
149 ꢁC; H NMR(CDCl ) d: 6.92 (2H, s), 5.01 (2H, s),
1
3
3.56 (3H, s), 2.28 (3H, s), 2.19 (6H, s), 1.95–1.77 (4H,
m), 0.91 (6H, t, J=7.4 Hz); IR(KBr) cm ꢀ1: 2967, 1663,
1623, 1611, 1460, 1384, 1291, 1183, 1158, 1072;
HRMS(EI) calcd for C19H27NO4 333.1940, found
333.1940.
4-Hydroxy-3-mesityl-1-methoxymethoxy-1-azaspiro[4.4]-
non-3-en-2-one (3h). Yield: 55.0%; mp 149–151 ꢁC; H
1
Compounds 3b–3k were synthesized by the same proce-
dure.
NMR(CDCl 3) d: 6.91 (2H, s), 5.04 (2H, s), 3.58 (3H, s),
2.28 (3H, s), 2.14 (6H, s), 2.28–1.85 (8H, m); IR(KBr)
cmꢀ1: 2951, 1678, 1605, 1482, 1438, 1307, 1292, 1201,
1171, 1159, 1095, 1074; HRMS(EI) calcd for
C19H25NO4 331.1784, found 331.1784.
5-Allyl-4-hydroxy-3-mesityl-1-methoxymethoxy-5-methyl-
1,5-dihydro-2H-pyrrol-2-one (3b). Yield: 46.0%; mp
128–130 ꢁC; 1H NMR(DMSO- d6) d: 11.34 (1H, s), 6.84
(2H, s), 5.75–5.55 (1H, m), 5.16–5.04 (2H, m), 4.90 (2H,
ABq, J=7.3 Hz, Án=7.1 Hz), 3.47 (3H, s), 2.27 (3H, s),
2.03 (6H, s), 1.41 (3H, s); IR(KBr) cm ꢀ1: 2936, 1737,
1651, 1610, 1451, 1435, 1385, 1367, 1294, 1157, 1084;
HRMS(EI) calcd for C19H25NO4 331.1784, found
331.1784.
4-Hydroxy-3-mesityl-1-methoxymethoxy-1-azaspiro[4.5]-
dec-3-en-2-one (3i). Yield: 57.6%; mp 159–161 ꢁC; H
1
NMR(CDCl 3) d: 6.90 (2H, s), 6.06 (1H, br s), 5.02 (2H,
s), 3.60 (3H, s), 2.27 (3H, s), 2.13 (6H, s), 2.30–1.50
(10H, m); IR(KBr) cm ꢀ1: 2934, 1676, 1597, 1483, 1448,
1291, 1260, 1152, 1092, 1074; HRMS(EI) calcd for
C20H27NO4 345.1940, found 345.1940.
4-Hydroxy-5-isopropyl-3-mesityl-1-methoxymethoxy-5-
methyl-1,5-dihydro-2H-pyrrol-2-one (3c). Yield: 24.7%;
amorphous; 1H NMR(CDCl 3) d: 6.90 (2H, s), 5.02 (2H,
s), 3.57 (3H, s), 2.27 (3H, s), 2.18 (3H, s), 2.12 (3H, s),
2.35–2.15 (1H, m), 1.56 (3H, s), 1.13 (3H, d, J=7.0 Hz),
1.00 (3H, d, J=7.0 Hz); IR(KBr) cm ꢀ1: 2971, 1747,
4-Hydroxy-3-mesityl-1-methoxymethoxy-8-oxa-1-aza-
spiro[4.5]dec-3-en-2-one (3j). Yield: 50.3%; mp 182–
183 ꢁC; 1H NMR(DMSO- d6) d: 11.65 (1H, s), 6.87 (2H,
s), 4.93 (2H, s), 3.95–3.85 (4H, m), 3.49 (3H, s), 2.24

768
Mitsuru Ito et al. / Bioorg. Med. Chem. 11 (2003) 761–768
(3H, s), 2.04 (6H, s), 2.21–2.05 (2H, m), 1.80–1.67 (2H,
m); IR(KBr) cm ꢀ1: 2958, 1683, 1625, 1608, 1440, 1352,
1336, 1247, 1153, 1090, 1070; HRMS(EI) calcd for
C19H25NO5 347.1733, found 347.1734.
References and Notes
1. Dent, D. Insect Pest Management; CABI: London, 2000;
p 81.
2. Holan, G.; Winkler, D. A. In Rational Approaches to
Structure, Activity, and Ecotoxicology of Agrochemicals; Dra-
ber, W., Fujita, T., Eds.; CRC: FL, 1992; p 123.
3. Conway, G. In The Doubly Green Revolution—Food for All
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4. Baker, D.R.; Fenyes, J. G.; Lahm, G. P.; Selby, T. P.; Ste-
venson, T. M. In Synthesis and Chemistry of Agrochemicals VI
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Chemical Society (Oxford University Press): Washington, DC,
2002; p 1.
4-Hydroxy-3-mesityl-8-methoxy-1-methoxymethoxy-1-
azaspiro[4.5]dec-3-en-2-one (3k). Yield: 70.4%; mp 164–
165 ꢁC; 1H NMR(DMSO- d6) d: 11.43 (1H, s), 6.87 (2H,
s), 4.98 (2H, s), 3.47 (3H, s), 3.35–3.18 (1H, m), 3.25
(3H, s), 2.24 (3H, s), 2.13–1.70 (14H, m); IR(KBr)
cmꢀ1: 2941, 1715, 1643, 1611, 1485, 1453, 1375, 1310,
1290, 1156, 1089, 1069; HRMS(EI) calcd for
C21H29NO5 375.2046, found 375.2046.
5. Halweil, B. In State of the World; Flavin, C., French, H.,
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Duplicate experiments were performed for each solution
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