Synthesis of N-oxydihydropyrrole derivatives

Article abstract of DOI:10.3987/COM-02-9467

N-Oxydihydropyrrole derivatives were synthesized through an intramolecular Claisen condensation reaction. The N-acylation of hindered hydroxylamines played a key role in providing the useful intermediates, which could be converted to a variety of N-oxydihydropyrrole derivatives.

Full text of DOI:10.3987/COM-02-9467

HETEROCYCLES, Vol. 57, No. 5, 2002, pp. 881 - 894, Received, 7th March, 2002
SYNTHESIS OF N-OXYDIHYDROPYRROLE DERIVATIVES
Mitsuru Ito,a,* Hideshi Okui,a Harumi Nakagawa,a Shigeru Mio,a Toshiaki Iwasaki,b
and Jun Iwabuchib
aAgroscience Research Laboratories, Sankyo Co., Ltd., 1041 Yasu, Yasu-cho, Yasu-
b
gun, Shiga, 520-2342, Japan; Research＆Development Laboratories, Agro＆
Specialty Chemicals Group, Nippon Kayaku Co., Ltd., 225-1 Horigome,
Koshikidani, Ageo-city, Saitama, 362-0064, Japan
Abstract – N-Oxydihydropyrrole derivatives were synthesized through an
intramolecular Claisen condensation reaction. The N-acylation of hindered
hydroxylamines played a key role in providing the useful intermediates, which
could be converted to a variety of N-oxydihydropyrrole derivatives.
INTRODUCTION
Crop damage by insects remains a serious problem in modern agriculture. Several classes of
insecticides, such as organophosphates, carbamates and pyrethroids, have been used worldwide.
Because of their intense use, however, the emergence of significant insect resistance to these chemical
agents has been observed. In addition, a growing social awareness of the residual agrochemicals in the
environment underlines the need to develop brand-new, highly potent, target-selective, and
environmentally innocuous insecticides with low mammalian toxicity. 1
Recently Bayer’s groups have reported a new series of insecticidal compounds depicted in the structure
(1).2 These compounds are characterized by enolated 1,3-diketone in a 5-membered ring system, and
demonstrated significant insecticidal activities against pests with important economic impacts, such as

brown rice planthopper (Nilaparvata lugens) and cotton aphid (Aphis gossypii), in our preliminary
experiments. These ring systems are structurally unique as an insecticide and found to have a new mode
of action affecting an insect molting system. These characteristics are suitable for controlling insect
pests that have already acquired resistance against the insecticides currently on the market.
The above considerations prompted us to explore new series of 5-membered heterocyclic compounds
containing 1,3-diketone moiety in search of highly effective insecticides. Regarding part Z in the
general structure (1), Bayer’s groups have already established systems with Z = O,2a S,2b CR1R2 (R1,R2 =
2d
alkyl, etc)2c and NR3 (R3 = H, alkyl, etc).
In our own experiments, introduction of a lipophilic
substituent, such as an ethyl group, at the nitrogen atom of the dihydropyrrole ring (2b) resulted in a clear
decrease in inseticidal activity compared to the original Z = NH derivative (2a). Then we turned our
attention to the introduction of a hydrophilic group and focused specifically on the dihydropyrrole
derivatives (3) with N-oxy substitution (-OR) at the 1-position – a series of compounds that have been
scarcely explored synthetically.
Me
B
B
R3
O R
O
Me
A
A
N
Z
N
Me
OR4
O
OH
O
Me
HO
HO
Me
N
N
O
GO
GO
O
MeO
Me
Xn
Xn
Me
4
5
1
2a (R3 = H)
2b (R3 = Et)
3
R4 = H, t-Bu
Z = O, S, CR1R2, NR3
A,B = H, alkyl, etc
G = H, alkyl, alkoxyalkyl,
acyl, sulfonyl, etc
X = H, alkyl, harogen, etc
n = 1 - 5
Among a few reported N-oxydihydropyrrole derivatives, compounds (4)3 were synthesized via a
regioselective hydride reduction of the corresponding maleic acid imides, and 54 was synthesized through
the cyclization of the appropriate enamino ester. However, these methods apparently lacked the ability
to yield a wide variety of derivatives, and not a single dihydropyrrole compound containing a substituted

phenyl group at the 3-position like 3 has been reported. Therefore, it was a synthetically challenging
task to develop versatile methods to construct the new structure (3).
We developed general synthetic methods for a series of N-oxydihydropyrrole derivatives (3) and wish to
report four representative routes (Schemes 1–4) in this paper.
RESULTS AND DISCUSSION
First we focused on the synthesis of the N-methoxy derivative (10) shown in Scheme 1. Ethyl 2-
methoxyamino-2-methylpropionate (7), which was prepared from ethyl 2-bromoisobutylate (6) and O-
methylhydroxylamine according to the reported method,5 was converted to an acylated form 9 in 41%
yield through a condensation reaction with mesitylacetyl chloride (8)6 in the presence of triethylamine
(Et3N) and catalytic amount of 4-dimethylaminopyridine. In spite of several possible side-reactions,
treatment of 9 with potassium tert-butoxide (t-BuOK) in N,N-dimethylformamide (DMF) afforded the
desired cyclized compound (10) in 32% yield through an intramolecular Claisen condensation reaction.
Me
ClOC
Me Me
Me
Me
OMe
OMe
Me
N
EtO2C
N
t-BuOK
Me Me
Me
NH2OMe HCl
8
Me Me
EtO2C Br
HO
Me
O
OMe
O
EtO2C
N
H
Me
Me
Me
NaOMe/MeOH
Toluene
Et3N
cat. DMAP
CH2Cl2
DMF
32%
6
7
30%
Me
Me
41%
10
9
Scheme 1
Although the above intramolecular Claisen condensation reaction successfully provided the N-
methoxydihydropyrrole derivative, the reaction was somewhat limited since the substituents at the 1-
position of the dihydropyrrole ring [-OR group in the structure (3)] utterly depend on the availability of 2-
alkoxyamino-2-methylpropionate derivatives like 7. While we examined the initial substitution reaction
of 6 with a variety of O-alkylhydroxylamines, we found that the reaction usually required such a long
time affording products in such poor yields that it could not be readily used for derivatization. Therefore
we decided to develop a more versatile method for modifying the substituent at the 1-position without
having to prepare individual 2-alkoxyamino-2-methylpropionate derivatives.

We surmised that the N-hydroxy derivative (13) was one of the suitable intermediates for this purpose and
could be prepared as shown in Scheme 2. The substitution reaction of 6 with sodium nitrite (NaNO2) by
a slightly modified version of the reported procedure7 gave a nitro derivative (11). Then 11 was partially
reduced8 by using zinc powder and ammonium chloride (NH4Cl) to produce the desired ethyl 2-(N-
hydroxyamino)-2-methylpropionate (12). (This two-step procedure to obtain 12 from 6 proved to be
comparable to the reported method,9 by which 12 was prepared from the corresponding amino acid
derivative, in terms of facility and yield.) The first trial of N-acylation of 12 with mesitylacetyl chloride
(8) in the presence of Et3N gave only trace amount of the desired N-acylated adduct (13) with O-acylated
hydroxylamine (14) as a major product. In another trial, the Mukaiyama condensation reaction10
employed between the hydroxylamine (12) and mesitylacetic acid11 by means of 2-chloro-1-
methylpyridinium iodide gave only the unwanted product (14). Several further attempts using other
base and solvent systems failed to improve the yield. Finally, we chose a two-phase reaction condition,12
employing ethyl acetate (EtOAc) and water as solvents with sodium hydrogencarbonate (NaHCO3) as a
base. Under this two-phase condition, fortunately the condensation reaction of 12 with 8 successfully
provided the desired adduct (13) predominantly (44%) over 14 (17%).
Me
ClOC
Me Me
H
N
EtO2C
Me
Me
OH
O
EtO2C
N
NH4Cl
Zn
Me
NaNO2
DMSO
Me Me
8
Me Me
EtO2C Br
Me Me
EtO2C NO2
Me
O
O
OH
+
EtO2C
N
Me
Me
Me
Me
H
EtOH-H2O
52%
NaHCO3
EtOAc-H2O
11
6
12
Me
14 17%
Me
13
92%
44%
OMe
Me Me
Me
OMe
O
O
Me
ClCH2OMe
NaH
N
EtO2C
N
t-BuOK
HO
Me
O
O
13
Me
Me
Me
DMF
97%
DMF
74%
Me
15
Me
16
Scheme 2
With the key intermediate (13) in hand, we next tried an introduction of a methoxymethyl substituent into

the hydroxy group of 13 and a subsequent cyclization. The reaction of 13 with chloromethyl methyl
ether (MOMCl) in the presence of sodium hydride (NaH) gave N-methoxymethoxy amide (15) in 97%
yield. Next intramolecular Claisen condensation of 15 with t-BuOK in DMF gave cyclized compound
(16) in 74% yield.
We next turned our attention to the substitution at the 5-position of the dihydropyrrole ring [A and B
groups in the structure (3)] for further diversity. However, we found that the previous nitrite substitution
method did not always successfully provide 2,2-disubstituted 2-nitroacetate, a precursor for the
corresponding N-hydroxyamino ester. For instance, when we tried to obtain a congested N-
hydroxyamino ester such as methyl 1-(N-hydoroxyamino)-1-cyclohexanecarbonate (19) through the same
approach used to obtain 12, the initial substitution reaction of 17 by NaNO2 did not take place and we
were left with only the elimination reaction yielding a methyl 1-cyclohexenecarbonate (20).
Reduction
NaNO2
DMSO
MeO2C Br
MeO2C NO2
MeO2C NHOH
18
19
17
CO2Me
20
It was reported that the N-hydroxyamino ester (19) itself could be prepared from the corresponding amino
acid derivative,9 but we intended to seek a more general and concise method to prepare a wide variety of
N-hydroxyamino esters. After some trial and error, we obtained 19 by applying a direct
hydroxyamination method13 to ester (21)using 1-chloro-1-nitrosocyclohexane (22),as shown in Scheme 3.
It was proved that our two-phase acylation method could be applied to this hindered N-hydroxyamino
ester (19), which reacted with mesitylacetyl chloride (8) to give both the desired N-acylated adduct (23) in
42% yield and O-acylated hydroxylamine (24) in 48% yield. The conversion of 23 into 26 was
performed in one pot as follows. The reaction of 23 with MOMCl in the presence of NaH gave N-
methoxymethoxy amide (25) in situ, which was subsequently cyclized to compound (26) in 72% yield by
additional treatment with t-BuOK via the intramolecular Claisen condensation reaction.

Me
ClOC
Me
1)
2)
LDA
DMPU
THF
1) 1N HCl
8
Me
MeO2C NOH
O
MeO2C HN O
Me
O
2) NaHCO3
Me
Me
Me
MeO2C NHOH
NaHCO3
CO2Me
EtOAc-H2O
59%
(in 4 steps)
21
19
ON Cl
Me
Me
22
42%
O
48%
23
24
OMe
OMe
MeOCH2Cl
N
O
MeO2C
Me
N
NaH
t-BuOK
HO
Me
O
23
O
Me
DMF
DMF
Me
Me
72%
(in 2 steps)
Me
26
25
Scheme 3
Although the ring construction methods mentioned above are apparently very potent, an intermediate (27)
did not gave any cyclized product by treatment of t-BuOK or several other bases, but only decomposed as
expected. It was partly due to the removal of the methoxycarbonyloxy group by the basic treatments.
We therefore attempted to introduce the methoxycarbonyloxy group to the 1-position after parent
dihdropyrrole ring has been constructed.
Me Me
OMe
O
EtO2C
Me
N
O
O
Me
Me
27
OMe
t-Bu
OMe
OMe
O
Me
OH
O
Me
Me
Me
O
O
O
O
O Me
O
N
Me
O Me
O Me
N
N
N
t-Bu
Cl
OMe
t-Bu
TMSBr
t-Bu
O
Cl
HO
Me
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
MS3A
Et3N
CH2Cl2
Et3N
CH2Cl2
CH2Cl2
Me
Me
Me
Me
69%
69%
91%
16
28
29
30
Scheme 4
It was obvious that a N-hydroxy derivative such as 29 was suited for this purpose. Compound (29) was

prepared from 16 through acylation of its hydroxy group (28, 69% yield) and subsequent removal14 of the
methoxymethyl group by trimethylsilyl bromide (TMSBr) (29, 69% yield), as shown in Scheme 4. The
intermediate (29) reacted with methyl chlorocarbonate in the presence of Et3N to give 30 in 91% yield.
Methoxycarbonylation is not the only serviceable method to modify the hydroxy group of the
intermediate (29): various reactions such as acylation, alkoxycarbonylation, alkylation or sulfonylation
can also be used to produce the corresponding derivatives.
CONCLUSION
We established four routes to synthesize a wide variety of new N-oxydihydropyrrole derivatives
employing an intramolecular Claisen condensation reaction. The series of products were subjected to
biological assays and exhibited high insecticidal activity, which will be discussed in detail elsewhere.
EXPERIMENTAL
General: All melting points are uncorrected. IR spectra were measured on a Perkin-Elmer 1600
1
spectrometer. H-NMR spectra were recorded at 200 MHz on a Varian Gemini 200 spectrometer with
tetramethylsilane as an internal standard. MS and HRMS spectra were obtained with a JEOL JMS-D300
mass spectrometer and a VG Auto Spec M mass spectrometer. Materials were obtained from
commercial suppliers where possible. Regular silica gel (Daisogel 1001W, 63-210 mesh) was used for
column chromatography except for the purification of hydroxylamines, which was performed by means
of neutral silica gel (Silica gel 60. spherical. neutrality. 150 mesh, Nacalai Tesque).
Ethyl 2-(N-mesitylacetyl-N-methoxyamino)-2-methylpropanoate (9). To a stirred solution of ethyl 2-
methoxyamino-2-methylpropionate5 (7, 161.2 mg, 1.0 mmol), 4-dimethylaminopyridine (5 mg, 0.04
mmol) and Et3N (0.15 mL, 10.8 mol) in CH2Cl2 (5 mL) was added mesitylacetyl chloride (8, 200.0 mg,
o
1.02 mmol) at 0 C and the mixture was stirred at the same temperature for 1 h. Then the reaction
mixture was poured into water and the water layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, dried [anhydrous magnesium sulfate (MgSO4)], and concentrated to an oil,
which was subjected to silica gel column chromatography (EtOAc/hexane, 1/10) to give the title

o
1
compound (9, 131.1 mg, 41 %) as colorless prisms; mp: 71-72 C (from EtOAc/hexane); H NMR
(CDCl3) δ: 6.84 (2H, s), 4.19 (2H, q, J=7.0 Hz), 3.93 (3H, s), 3.54 (2H, s), 2.24 (3H, s), 2.22 (6H, s), 1.54
(6H, m), 1.19 (3H, t, J=7.0 Hz); IR (KBr) cm-1: 2986, 1738, 1680, 1471, 1442, 1382, 1355, 1291, 1246,
1153, 1081, 1031; MS(EI) m/z: 321 (M+); Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36. Found:
C, 67.28; H, 8.44; N, 4.31.
4-Hydroxy-3-mesityl-1-methoxy-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one (10).
To a stirred
solution of 9 (131.1 mg, 0.41 mmol) in DMF (3 mL) was added t-BuOK (65.0 mg, 0.58 mmol) at ambient
temperature. After the resulting mixture was stirred at the same temperature for 30 min, the mixture was
poured into water. And then the water layer was washed with hexane, acidified to ca. pH 3 with 1N HCl
and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and
concentrated to give a syrup, which was subjected to silica gel column chromatography (EtOAc/Hexane,
o
1/2) to give the title compound (10, 35.4 mg, 32%) as a white powder; mp: 204-207 C (from
EtOAc/hexane); 1H NMR (CDCl3) δ: 6.92 (2H, s), 5.86 (1H, br s), 3.96 (3H, s), 2.28 (3H, s), 2.15 (6H, s),
1.52 (6H, s); IR (neat) cm-1: 2978, 1655, 1612, 1487, 1464, 1438, 1392, 1368, 1330, 1291, 1244, 1174,
1090; MS(EI) m/z: 275 (M+); Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.72; H,
7.68; N, 5.06.
Ethyl 2-nitro-2-methylpropionate (11).7 To a stirred suspension of NaNO2 (52.80 g, 0.77 mol) in
dimethyl sulfoxide (DMSO) (500 mL) was added ethyl 2-bromoisobutylate (6, 100.00 g, 0.51 mol) at
ambient temperature. The mixture was stirred at 80 oC for 3 h. Then the reaction mixture was poured
into ice/water and extracted with ethyl ether (Et2O). The combined organic layer was washed with brine,
dried (MgSO4) and concentrated to give a yellowish liquid, which was distilled in vacuo to give the title
compound (11, 75.58 g, 92 %) as a colorless oil; 1H NMR (CDCl3) δ: 4.27 (2H, q, J=7.2 Hz), 1.82 (6H, s),
1.29 (3H, t, J=7.2 Hz).
Ethyl 2-(N-hydroxyamino)-2-methyl-propionate (12).8 To a stirred suspension of 11 (100.00 g, 0.62
mol) and NH4Cl (132.50 g, 2.48 mol) in ethanol (EtOH) (200 mL) and water (400 mL) was added zinc
o
powder (122.50 g, 1.87 mol) in several portions with the maintenance of a temperature under 40 C and

the mixture was stirred at 35 oC for 5 h. Then the mixture was filtered and the filtrate was concentrated.
To the resultant residue were added Et2O and water. The water layer was separated and the organic layer
was extracted with 1N HCl. The combined water layer was washed with Et2O and its pH was adjusted
to ca. 10 with potassium carbonate (K2CO3). The water layer was then extracted with EtOAc. The
combined organic layer was washed with brine, dried (MgSO4) and concentrated to give a brownish oil,
which was subjected to neutral silica gel column chromatography (EtOAc/hexane, 1/4) to give the title
compound (12, 47.98 g, 52 %) as a colorless oil; 1H NMR (CDCl3) δ: 4.21 (2H, q, J=7.2 Hz), 1.32 (6H, s),
1.29 (3H, t, J=7.2 Hz).
Ethyl 2-(N-hydroxy-N-mesitylacetylamino)-2-methylpropanoate (13) and Ethyl 2-(N-
mesitylacetyloxyamino)-2-methylpropanoate (14). To a stirred two-phase solution of 12 (5.90 g, 40.1
mmol) and NaHCO3 (3.70 g, 44.0 mmol) in EtOAc (60 mL) and water (40 mL) was added dropwise a
o
solution of mesitylacetyl chloride (8, 8.70 g, 44.0 mmol) in EtOAc (40 mL) at ca. 0 C. The mixture
was stirred at ambient temperature for 3 h. The organic layer was separated, washed with brine, dried
(MgSO4) and concentrated to give a brownish oil, which was subjected to silica gel column
chromatography (EtOAc/hexane, 1/4) to separate the title compounds, 13 (5.46 g, 44 %) and 14 (2.09 g,
17 %). 13: white powder; mp: 151-153 oC (from EtOAc/hexane); 1H NMR (CDCl3) δ: 6.84 (2H, s), 6.15
(1H, br s), 4.15 (2H, q, J=7.4 Hz), 3.80 (2H, s), 2.24 (3H, s), 2.22 (6H, s), 1.54 (6H, s), 1.23 (3H, t, J=7.0
Hz); IR (KBr) cm-1: 3134, 2856, 1747, 1595, 1446, 1274; HRMS(EI) Calcd for C17H25NO4: 307.1784,
1
Found 307.1782. 14: colorless oil; H NMR (CDCl3) δ: 7.68 (1H, s), 6.84 (2H, s), 4.01 (2H, q, J=7.2
Hz), 3.64 (2H, s), 2.28 (6H, s), 2.24 (3H, s), 1.32 (6H, s), 1.16 (3H, t, J=7.0 Hz); IR (neat) cm-1: 2985,
1737, 1614, 1446, 1382, 1279, 1241, 1154, 1025; HRMS(EI) Calcd for C17H25NO4: 307.1784, Found
307.1782.
Ethyl 2-(N-mesitylacetyl-N-methoxymethoxyamino)-2-methylpropanoate (15). To a stirred solution
of 13 (1.01 g, 3.29 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.15 g, 3.75
mmol) at 0oC and the reaction mixture was stirred for 10 min. Then to the reaction mixture was added
o
o
MOMCl (0.3 mL, 3.95 mmol) at 0 C. The mixture was stirred at 0 C for 1 h and at ambient

temperature for 2 h. The reaction mixture was poured into brine and extracted with EtOAc. The
combined organic layer was washed with brine, dried (MgSO4) and concentrated to give a brownish oil,
which was subjected to silica gel column chromatography (EtOAc/hexane, 1/20) to give the title
compound (15, 1.12 g, 97 %) as a colorless oil; 1H NMR (CDCl3) δ: 6.84 (2H, s), 5.10 (2H ,s), 4.10 (2H,
q, J=7.1 Hz), 3.90 (2H, s), 3.63 (3H ,s), 2.24 (3H, s), 2.21 (6H, s), 1.52 (6H,s), 1.18 (3H, t, J=7.1 Hz); IR
(neat) cm-1: 2988, 1741, 1680, 1461, 1380, 1270, 1152, 1063; HRMS(EI) Calcd for C19H29NO5 351.2046,
Found 351.2045.
4-Hydroxy-3-mesityl-1-methoxymethoxy-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one (16).
To a
stirred solution of 15 (351.2 mg, 1.00 mmol) in DMF (7 mL) was added t-BuOK (123.8 mg, 1.10 mmol)
at ambient temperature and the reaction mixture was stirred at the same temperature for 2 h. The
mixture was poured into water and the water layer was washed with hexane. Then the water layer was
acidified to ca. pH 3 with 1N HCl and extracted with EtOAc. The combined organic layer was washed
with brine, dried (MgSO4) and concentrated to give a syrup, which was subjected to silica gel column
chromatography (EtOAc/hexane, 1/2) to give the title compound (16, 227.1 mg, 74 %) as colorless
o
1
prisms; mp: 151-153 C (from EtOAc/hexane); H NMR (CDCl3) δ: 6.91 (2H, s), 6.48 (1H, br s), 5.01
(2H, s), 3.59 (3H, s), 2.28 (3H, s), 2.14 (6H, s), 1.51 (6H, s); IR (KBr) cm-1: 2985, 2938, 2574, 1630,
1466, 1393, 1368, 1340, 1286, 1156, 1082, 1062; MS(EI) m/z: 305 (M+); Anal. Calcd for C17H23NO4: C,
66.86; H, 7.59; N, 4.59. Found: C, 66.89; H, 7.49; N, 4.40.
Methyl 1-(N-Hydroxyamino)-1-cyclohexanecarboxylate (19). To a stirred solution of
diisopropylamine (1.54 mL, 11.1 mmol) in THF (10 mL) was added 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,
o
11.0 mmol) at –78 C, and the reaction mixture was stirred at the same temperature for 1h. To the
reaction mixture, methyl cyclohexanecarboxylate (21, 1.42 g, 10.0 mmol) was added at –78 oC, and then
the reaction mixture was stirred at the same temperature for 1 h. To the reaction mixture, 1-chloro-1-
o
nitrosocyclohexane (22, 1.62 g, 11.0 mmol) was added at –78 C, and then the reaction mixture was
stirred at the same temperature for another 1 h. To the reaction mixture 1N HCl (20 mL) was added, and

the mixture was stirred at ambient temperature for 3 h. The water layer was separated and the organic
layer was extracted with 1N HCl. Then the combined water layer was washed with ether, adjusted to ca.
pH 9 with NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine,
dried (MgSO4) and concentrated to give a syrup, which was subjected to neutral silica gel column
chromatography (EtOAc/hexane, 1/4) to give the title compound (19, 1.02 g, 59 %) as yellowish needles;
mp 39-41 oC; 1H NMR (DMSO-d6) δ: 7.32 (1H, s), 5.65 (1H, br s), 3.61 (3H, s), 1.80-1.34 (10H, m); IR
(KBr) cm-1: 3261, 2933, 1724, 1448, 1431, 1281, 1240, 1148, 1108, 1084, 1070, 1032; HRMS Calcd for
C8H15NO3 173.1052, Found 173.1053.
Methyl 1-(N-hydroxy-N-mesitylacetylamino)-1-cyclohexanecarboxylate (23) and Methyl 1-(N-
mesitylacetyloxyamino)-1-cyclohexanecarboxylate (24). Compounds (23) and (24) were prepared
from 19 and mesitylacetyl chloride (8) by a procedure similar to that described for 13 and 14. 23: 42 %;
1
white powder; mp 196-197 oC (from EtOAc/hexane); H NMR (DMSO-d6) δ: 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. 24:
48 %; colorless oil; 1H NMR (CDCl3) δ: 7.70 (1H, s), 6.85 (2H, s), 3.62 (2H, s), 3.53 (3H, s), 2.27 (3H, s),
2.24 (6H, s), 1.95-1.45 (10H, m); IR (KBr) cm-1: 2937, 2860, 1740, 1456, 1215, 1134; HRMS(EI) Calcd
for C19H27NO4 333.1940, Found 333.1941.
4-Hydroxy-3-mesityl-1-methoxymethoxy-1-azaspiro[4.5]dec-3-en-2-one (26). To a stirred solution
of 23 (0.62 g, 1.86 mmol) and MOMCl (0.17 mL, 2.23 mmol) in DMF (6 mL) was added NaH (60 %
o
dispersion in mineral oil, 89.2 mg, 2.23 mmol) at 0 C and the reaction mixture was stirred at the same
temperature for 30 min and at ambient temperature for 2 h. Then to the stirred reaction mixture was
o
added DMF (6 mL) and t-BuOK (0.31 g, 2.79 mmol) at 0 C and the reaction mixture was stirred at
ambient temperature for 2 h. The mixture was poured into water and the water layer was washed with
Et2O. The water layer was acidified to ca. pH 3 with 1N HCl and extracted with EtOAc. The
combined organic layer was washed with brine, dried (MgSO4) and concentrated to give a syrup, which
was subjected to silica gel column chromatography (EtOAc/hexane, 1/1) to give the title compound (26,

72 % in 2 steps) as colorless prisms; mp 159-161 oC (from EtOAc/hexane); 1H NMR (CDCl3) δ: 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-Mesityl-1-methoxymethoxy-2,2-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl 3,3-dimethyl-
butanoate (28). To a stirred solution of 16 (147.0 mg, 0.48 mmol) and Et3N (0.115 mL, 0.83 mmol) in
CH2Cl2 (2 mL) was added 3,3-dimethylbutyryl chloride (0.09 ml, 0.65 mmol) at 0oC, and the mixture was
stirred at the same temperature for 2 h. The reaction mixture was poured into water and the water layer
was extracted with CH2Cl2. The combined organic layer was washed with brine, dried (MgSO4) and
concentrated to give an oil, which was subjected to silica gel column chromatography (EtOAc/hexane,
1/4) to give the title compound (28, 133.8 mg, 69 %) as a colorless oil; 1H NMR (CDCl3) δ: 6.82 (2H, s),
5.05 (2H, s), 3.61 (3H, s), 2.23 (3H, s), 2.18 (2H, s), 2.15 (6H, s), 1.49 (6H, s), 0.83 (9H, s); IR (neat)
cm-1: 2958, 1778, 1732, 1674, 1613, 1573, 1464, 1386, 1367, 1317, 1213, 1160, 1126, 1091, 1064;
HRMS(EI) Calcd for C23H33NO5 403.2359, Found 403.2360.
1-Hydroxy-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl 3,3-dimethylbutanoate (29).
To a stirred solution of 28 (3.47 g, 5.60 mol) in CH2Cl2 (20 mL) was added TMSBr (11.4 mL, 86.4 mol)
and molecular sieves 3A (ca. 1 g) at 0oC, and the resultant mixture was stirred at the same temperature for
4 h. The reaction mixture was poured into water and the water layer was extracted with CH2Cl2. The
combined organic layer was washed with brine, dried (MgSO4) and concentrated to give a solid, which
was subjected to silica gel column chromatography (EtOAc/hexane, 1/3) to give the title compound (29,
o
1
2.12 g, 69 %) as a white powder; mp: 191-193 C (from EtOAc/hexane); H NMR (DMSO-d6) δ: 9.74
(1H, s), 6.84 (2H, s), 2.24 (2H, s), 2.21 (3H, s), 2.07 (6H, s), 1.34 (6H, s), 0.75 (9H, s); IR (KBr) cm-1:
2956, 2867, 1787, 1687, 1611, 1480, 1464, 1368, 1321, 1213, 1177, 1146, 1097, 1077, 1035; MS(EI) m/z:
359 (M+); Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C, 70.02; H, 8.01; N, 3.57.
4-Mesityl-1-methoxycarbonyloxy-2,2-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl 3,3-dimethyl-
butanoate (30). To a stirred solution of 29 (161.0 mg, 0.45 mmol) in CH2Cl2 (1.5 mL) and Et3N (0.100

mL, 0.72 mmol) was added methyl chloroformate (0.050 mL, 0.65 mmol) at 0oC, and the mixture was
stirred at ambient temperature for 1 h. The reaction mixture was poured into water and the water layer
was extracted with CH2Cl2. The combined organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated to give a oil, which was subjected to preparative thin layer chromatography
(EtOAc/hexane, 1/3) to give the title compound (30, 171.0 mg, 91 %) as colorless prisms; mp: 138-141
oC (from EtOAc/hexane); 1H NMR (CDCl3) δ: 6.83 (2H, s), 3.95 (3H, s), 2.24 (3H, s), 2.19 (2H, s), 2.17
(6H, s), 1.10 (6H, s), 0.83 (9H, s); IR (KBr) cm-1: 2961, 1805, 1772, 1720, 1674, 1614, 1443, 1322, 1244,
1193, 1136, 1099, 1081, 1042; MS(EI) m/z: 417 (M+); Anal. Calcd for C23H31NO6: C, 66.17; H, 7.48;
N,3.35. Found: C, 66.27; H, 7.37; N, 3.12.
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