Mechanistic considerations on the oxime-nitrone isomerization and intramolecular cycloaddition reaction of 3-(Alk-2-enylamino)propionaldehyde oximes

Article abstract of DOI:10.1246/bcsj.74.917

To elucidate the scope and features of the intramolecular oxime olefin cycloaddition in the 3-(alk-2-enylamino)propionaldehyde oximes, four 3-(N-substituted allylamino)propionaldehyde oximes were prepared and their thermal behaviors in protic and aprotic solvents (n-butanol and toluene) were studied. To better understand the isomerization process of oxime to NH-nitrone, the thermal reaction of 3-(N-substituted cinnamylamino)propionaldehyde oximes in ethanol or toluene was examined, in which the formation of cyclic nitrone could be interrupted due to steric and/or electronic grounds. Under mild conditions, 3-(alk-2-enylamino)- and 3-(acryloylamino)-2,2-dimethylpropionaldehyde oximes underwent thermally induced 1,3-dipolar cycloaddition, resulting in perhydroisoxazolo[4,3-c]pyridine derivatives. The activation enthalpy in the conversion of N-benzyl oxime indicated that the geminal methyl groups at the 2-position in this oxime should be insufficient to control its conformation necessary for the oxime-nitrone isomerization and/or the intramolecular cycloaddition step of the resulting NH-oxime.

Full text of DOI:10.1246/bcsj.74.917

c. Jpn.
© 2001 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 74, 917—925 (2001)
917
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
Mechanistic Considerations on the Oxime–Nitrone Isomerization and
Intramolecular Cycloaddition Reaction of 3-(Alk-2-enylamino)propi-
onaldehyde Oximes
Mechanistic Considerations on the Oxime
M. Noguchi et al.
01
7
Michihiko Noguchi,* Hirofumi Okada, Masayuki Tanaka, Satoshi Matsumoto, Akikazu Kakehi,† and
Hidetoshi Yamamoto
5
SJA8
09-2673
344
tober
Department of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwadai, Ube 755-8611
†Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University,
Wakasato, Nagano 380-8553
00
01
(Received October 2, 2000)
3-(Alk-2-enylamino)- and 3-(acryloylamino)-2,2-dimethylpropionaldehyde oximes underwent thermally induced
1,3-dipolar cycloaddition under mild conditions, leading to perhydroisoxazolo[4,3-c]pyridine derivatives. The features
of the intramolecular oxime–olefin cycloaddition in this system and the roles of the geminal methyl groups at the 2-posi-
tion and the alkenylamino nitrogen in the oxime–nitrone isomerization process are discussed based on kinetic studies.
Since a new concept concerning the isomerization of oxime
to nitrone through the thermal 1,2-hydrogen shift was pro-
posed by Grigg and co-workers,1 and the existence of the re-
sultant NH-nitrone was elucidated by forming intramolecular
cycloaddition products (named the intramolecular oxime olefin
cycloaddition; IOOC), extensive investigations on the synthe-
sis of highly functionalized isoxazolidine derivatives have
been developed by many groups.2 Nevertheless, only a few re-
ports on a further mechanistic elucidation of the oxime–nitrone
isomerization have been found;3 we have demonstrated that a
facile oxime–nitrone isomerization takes place in the oximes
of heterocyclic aldehydes bearing the N-alk-2-enylbenzylami-
no moiety at the adjacent position.3a,b The alkenylbenzylamino
nitrogen in the oximes, therein, could play the role as an in-
tramolecular catalyst in the isomerization of oxime to NH-ni-
trone.
In a previous paper,4 we showed that the thermal reaction of
3-(N,N-diallylamino)-propionaldehyde oxime with more con-
formational flexibility in protic solvents, such as ethanol
(EtOH) and butan-1-ol (n-BuOH), gave the cycloadduct (C)
through an NH-nitrone (A) via a 1,2-H shift of the oxime (path
a). On the other hand, a similar reaction in toluene afforded a
tricyclic product (D) through cyclic nitrone (B) via an ene-type
reaction (ATP reaction)5 (path b) of the oxime together with
the above-mentioned NH-nitrone cycloadduct (Scheme 1).
The existence of equilibrium among the oxime and NH-nitrone
(A) and cyclic nitrone (B) was suggested based on the effects
of the utilized solvents.
In order to obtain further information on the oxime–nitrone
isomerization process of this system, we examined the thermal
behaviors of further 3-(alk-2-enylamino)propionaldehyde
oximes.
Scheme 1.

918 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Mechanistic Considerations on the Oxime
cloaddition reaction of cyclic nitrone 6a with oxime 3a pro-
ceeds easily under ordinary reaction conditions. A similar
propensity with respect to the solvents utilized was observed in
the reaction of N-tosyl 3b and N-mesyl oxime 3c; the thermal
reactions of 3b and 3c in toluene afforded dimers 7b,c as major
products, while NH-nitrone cycloadducts 4b,c were obtained
as major products in a similar reaction in n-BuOH (Scheme 2
and Table 1). The reactions of N-benzoyl 3d and N-Boc oxime
3e were also examined in toluene and/or n-BuOH. However,
Results and Discussion
Oxime–Nitrone Isomerization and Cycloaddition Reac-
tion. In order to elucidate the scope and features of the
IOOC in the 3-(alk-2-enylamino)propionaldehyde oximes,
four 3-(N-substituted allylamino)propionaldehyde oximes 3a–
d were prepared and their thermal behaviors in both protic and
aprotic solvents examined (Scheme 2). The reaction of N-ben-
zyl oxime 3a in n-BuOH under reflux for 24 h gave cis-fused
NH-nitrone cycloadduct 4a in 78% yield.4 A similar reaction
in toluene (in 0.2 M solution) (1 M ꢀ 1 mol/dmꢁ3) under re-
flux for 24 h gave 4a (42%), isoxazoline 5a (2%), cyclic nitro-
ne 6a (3%), and dimeric product 7a (44%). Isoxazoline 5a
was a secondary product from 4a and product 7a was formed
by the dimeric cycloaddition reaction of cyclic nitrone 6a and
oxime 3a, respectively. Product 7a was obtained as a single
isomer and the structure was deduced as being a perhydroisox-
azolo[2,3-d][1,4]diazepine derivative from the 13C NMR spec-
trum; the carbon signal at the lowest field (δ 74.2) among the
sp3-carbon signals was assigned to methine one (2-C) by a dis-
tortionless enhancement by a polarization transfer (DEPT)
measurement. However, the stereochemistry of product 7a
could not be deduced. A similar reaction of 3a at 0.1 M con-
centration afforded almost the same results, and at 0.02 M con-
centration an increase in the yield of cyclic nitrone 6a and a
slightly depressed formation of dimeric product 7a were ob-
served (Table 1, runs 3 and 4). This means that the dimeric cy-
1
the H and 13C NMR spectra of these products provided only
very broad signals at a range of ꢁ50 to 60 ˚C and, unfortunate-
ly, no information on the product structures could be obtained,
except for 4e.6
To obtain a more precise understanding of the isomerization
process of oxime to NH-nitrone, the thermal reaction of 3-(N-
substituted cinnamylamino)propionaldehyde oximes 10a–d
was examined, in which the formation of cyclic nitrone could
be interrupted owing to steric and/or electronic grounds.
Oximes 13a–c, having dipolarophile moieties activated by a
single carbonyl component, were also prepared (Scheme 3).
The reaction of oxime 10a–c in EtOH or toluene under reflux
for 30–36 h gave NH-nitrone cycloadducts 14a–c in good
yields (Scheme 3 and Table 2). A similar reaction of N-ben-
zoyl oxime 10d proceeded smoothly to give a single product
by TLC and HPLC; however, its structural confirmation was
1
not attained owing to signal broadening in the H and 13C
NMR spectra. The reaction of oximes 13 having activated di-
Scheme 2.
Table 1.
Thermal Reaction of Oximes 3a–c
Run Oxime
Solvent
Time/h
Product yield/%a)
Recovered oxime/%
1
2
3
4
4
5
6
7
3a
3a
3a
3a
3b
3b
3c
3c
n-BuOHb)
Toluenec)
Toluened)
Toluenee)
Toluene
24
24
50
50
12
108
18
10
4a/78
4a/42
4a/36
4a/40
4b/20
4b/60
4c/18
4c/50
—
5a/2
5a/2
5a/6
—
—
6a/3
6a/7
6a/12
6b/8
—
—
3a/6
3a/6
3a/3
3a/3
3b/2
3b/27
3c/2
7a/44
7a/44
7a/28
7b/62
7b/10
7c/66
7c/12
n-BuOH
Toluene
n-BuOH
—
—
—
6c/8
8c/6
3c/12
a) Based on isolated products. b) Ref. 4. c) At 0.2 M. d) At 0.1 M. e) At 0.02 M.

M. Noguchi et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 919
Scheme 3.
Table 2.
Thermal Reaction of Oximes 10 and 13
hyde 12e at 0 ˚C for 5 h afforded almost the same results. As
expected, the reaction of oximes 13, having activated dipolaro-
phile moieties, proceeded smoothly to give NH-nitrone cy-
cloadducts 15.
Run Oxime
Solvent
Time/h
Product yield/%a)
1
2
3
4
5
6
7
8
10a
10b
10c
13a
13a
13b
13c
13c
EtOHb)
Toluene
Toluene
EtOH
Benzene
EtOH
36
36
30
24
30
30
48
48
14a/quant
14b/92
Oxime–Nitrone Isomerization Process. Our next con-
cern was focused on mechanistic considerations of the IOOC
in this system. Based on a previous discussion,3 it is reason-
able to assume that the oxime–nitrone isomerization process of
IOOC is the rate-determining step. The rates of the conversion
of oxime 10a in several solvents were examined using an
HPLC method (see Experimental section). In these cases the
rates of the disappearance of oxime 10a were first-order with
respect to the oxime concentrations. Replacing dioxane with
propiononitrile (EtCN) as a solvent resulted in a small increase
in the reaction rates of oxime 10a, though a similar conversion
in n-BuOH was accelerated (11.0 times faster than in dioxane).
Also, the relative rates of the conversion of oximes 10a–d and
13c in n-BuOH at 80 ˚C are summarized in Table 3. Therein,
lowering the basicity of the alkenylamino nitrogen of the
oximes by replacing the benzyl group with tosyl or acetyl re-
sulted in a small decrease of the reaction rate, in contrast with
the cases of 2-(N-substituted allylamino)-4-oxo-4H-pyri-
do[1,2-a]pyrimidine-3-carbaldehyde oximes 17; the reaction
of N-benzyl oxime 17a in dioxane was 45-times faster than N-
phenylsulfonyl oxime 17b.3b Finally, the activation energy for
the conversion of oxime 10a into perhydroisoxazolopyridine
14a in n-BuOH was estimated to be 115 kJ molꢁ1 from the Ar-
rhenius plot. The activation enthalpy and entropy for the con-
version at 339 K were estimated to be 71 kJ molꢁ1 and ꢁ129 J
14c/88
15a/81
15a/72
15b/82c)
15c/quant
15c/quant
EtOH
Benzene
a) Based on isolated products. b) Ref. 4. c) Oxime 13b
was recovered in 9% yield.
polarophile moieties was also examined; N-acryloyl-13a, N-
crotonoyl-13b, and N-cinnamoyl-benzylamino oxime 13c
were easily converted to the corresponding cis-fused perhy-
droisoxazolopyridines 15a–c in a reaction in EtOH or benzene
under reflux. On the other hand, ethyl 4-[N-(3-hydroxyimino-
2,2-dimethylpropyl)benzylamino]crotonate (13d) was not sta-
ble even at room temperature, and gave cis- and trans-fused
′
NH-nitrone cycloadduct 15d and 15d together with an intrac-
table mixture of products, including a cyclic nitrone. Oxime
13e, having a dipolarophile moiety activated by two carbonyl
components, could not be isolated under the usual oximation
conditions, and spontaneously cyclized to give cis- and trans-
fused NH-nitrone cycloadducts, 15e and 15e , and cyclic nitro-
ne 16e together with an intractable mixture of products, in-
′
cluding the dimer (Scheme 3). A similar oximation of alde-

920 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Mechanistic Considerations on the Oxime
Table 3.
13c
Rates for the Conversion of Oxime 10a–d and
solvents utilized; therefore, the results of the reaction of
oximes 3 demonstrated in Table 1 were explainable (Scheme
4).
Oxime
Solvent
Temp/˚C
105 k/sꢁ1 Relative rate
The activation enthalpy in the conversion of oxime 10a im-
plied that the geminal methyl groups at the 2-position in 10a
should be insufficient to control its conformation necessary for
the oxime–nitrone isomerization and/or the intramolecular cy-
cloaddition step of the resulting NH-oxime. The role of the
alkenylamino nitrogen in the isomerization of oxime to NH-ni-
trone seems to be delicate; the relative rates of the conversion
of N-benzyl 10a, N-tosyl 10b, and N-acetyl oxime 10c were
1.0, 0.68, and 0.16, respectively. The role of the alkenylamino
nitrogen of oxime 10a as an intramolecular catalyst was not
very effective, as expected. We have suggested that this can be
ascribed to the high conformational mobility of oxime 10a
compared with the corresponding heteocyclic aldehyde
oximes, 17a and 18a.
10a
10a
10a
10a
Dioxanea)
Dioxaneb)
EtCNa)
97.2
97.2
97.2
97.2
1.61
1.64
4.26
1.00
1.02
2.64
n-BuOHa)
17.7
11.0
10a
10b
10c
10d
13c
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
80.1
80.1
80.1
80.1
80.1
4.00
2.78
0.648
0.637
4.38
1.00
0.675
0.162
0.159
1.10
a) Performed at 2.2ꢂ10ꢁ3 M. b) At 2.2ꢂ10ꢁ2 M.
molꢁ1 Kꢁ1. The value of the activation entropy in the IOOC of
10a was negatively larger (more than 45 J molꢁ1 Kꢁ1) than
those of oxime 17a (ꢁ84 J molꢁ1 Kꢁ1)3b and 4-(N-allylbenzyl-
amino)coumarin-3-carbaldehyde oxime (18a) (ꢁ68 J molꢁ1
Kꢁ1)3a (Fig. 1).
Further investigations on the oxime–nitrone isomerization
assisted by intramolecular interactions are in progress, and the
details will be reported elsewhere.
Experimental
In conclusion, the reaction features of the oxime–nitrone
isomerization and intramolecular cycloaddition reaction of 3-
(N-substituted allylamino)propionaldehyde oximes 3 are sum-
marized below; a thermal reaction of the oximes gave NH-ni-
trone (E) via a 1,2-H shift (path c), leading to NH-nitrone cy-
cloadducts 4, and cyclic nitrone (F) via an ene-type reaction
(ATP reaction)5 (path d) followed by dimerization with oxime
3 gave 7. The existence of an equilibrium among oxime and
NH-nitrone (E) and cyclic nitrone (F) is plausible. The 1,2-H
shift process is known to involve an ionic species,1 while the
ATP reaction appears to be nearly concerted.5 The former pro-
cess should be accelerated by protic solvents, such as n-BuOH,
while the latter would not be so affected by the polarity of the
General. Mps were measured on a Yanagimoto micro-melt-
ing-point apparatus and are uncorrected. IR spectra were mea-
sured on a JASCO IR-Report-100 spectrophotometer from sam-
1
ples as KBr pellets or NaCl discs. H NMR and 13C NMR spectra
1
were measured on a JEOL EX-270 (270 MHz for H and 67.8
MHz for 13C) spectrometer in deuteriochloroform (CDCl3) solu-
tions, unless otherwise stated. Tetramethylsilane was used as an
internal standard and the J-values are given in Hz. The splitting
patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad signal; and ov, overlapping with each other.
The mass spectra were determined on a JEOL JMS-SX102A spec-
trometer. Elemental analyses were performed on a Yanagimoto
MT-5 CHN analyser. All non-aqueous reactions were run under a
Fig. 1.
Activation parameters for conversion of oxime–nitrone isomerization of 10a, 17a, and 18a.
Scheme 4.

M. Noguchi et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 921
positive pressure of argon or nitrogen. All of solvents were dried
by standard methods before use. The progress of the reactions
was monitored by TLC (Silica Gel 60F-254, Merck). Chromato-
graphic purification was performed with Wakogel C-200 (100–
200 mesh, Wako Pure Chemical Industries) and/or Silica Gel 60
(230–400 mesh, Merck). The starting oximes, 3a and 10a, are
known.4
(COPh). Found: C, 69.10; H, 7.93; N, 10.63%. Calcd for
C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%.
3-(N-t-Butoxycarbonylallylamino)-2,2-dimethylpropional-
dehyde Oxime (3e). Yield 86%; colorless oil; IR (NaCl) 3350,
1690 cmꢁ1. This compound was a (1:1) mixture of two atropiso-
mers in CDCl3 and gave broad signals in 1H and 13C NMR spectra.
1H NMR (270 MHz) δ 1.11 (s, 6 H, 2-Me2), 1.47 (s, 9 H, –CMe2),
3.19 (br s, 2 H, 3-H2), 3.87 (br, 2 H, >NCH2CHꢀ), 5.03–5.09 (ov,
2 H, –CHꢀCH2), 5.73 (ov, 1H, –CHꢀCH2), 7.34 (br, 1 H, 1-H),
8.39 (br, 1 H, OH); another isomer δ 1.11 (s, 6 H, 2-Me2), 1.44 (s,
9 H, –CMe2), 3.22 (br s, 2 H, 3-H2), 3.79 (br, 2 H, >NCH2CHꢀ),
5.09 (ov, 2 H, –CHꢀCH2), 5.73 (ov, 1H, –CHꢀCH2), 7.38 (br, 1
H, 1-H), 8.35 (br, 1 H, OH); 13C NMR (67.8 MHz) δ 23.5, 23.7 (2-
Me2), 28.0 (CMe3), 39.4, 39.5 (2-C), 51.1, 51.7 (>NCH2CHꢀ),
55.2 (3-C), 79.7 (CMe3), 116.0, 116.3 (–CHꢀCH2), 133.5, 133.7
(–CHꢀCH2), 157.3 (CO2), 157.5 (1-C); Found: C, 60.63; H, 9.79;
N, 10.85%. Calcd for C13H24N2O3: C, 60.91; H, 9.44; N, 10.93%.
HRMS (EI) m/z 256.1783. Calcd for C13H24N2O3: 256.1787.
Preparation of Oximes 10. General Procedures: 3-Cin-
namylamino-2,2-dimethylpropionaldehyde (8) was prepared using
cinnamylamine oxalate in 88% yield, similarly to the method for
Preparation of Oximes. Preparation of Oximes 3. Gen-
eral Procedures: A Mannich reaction of isobutyraldehyde (1.83
mL, 20 mmol), allylamine oxalate (2.67 g, 20 mmol), and 37%
aqueous formaldehyde (1.58 mL, 21 mmol) in EtOH (30 mL)
gave 3-allylamino-2,2-dimethylpropionaldehyde (1) in 56% yield,
similarly to the reported method.7 Aldehyde 1 (0.30 g, 2.1 mmol)
was allowed to react with tosyl chloride (0.60 g, 3.0 mmol) in the
presence of Et3N (0.58 mL, 4.2 mmol) and DMAP (0.13 g, 1.0
mmol) in THF (10 mL) to give N-tosyl aldehyde 2b (0.35 g, 64%).
A mixture of N-tosyl aldehyde 2b (0.74 g, 5.0 mmol) with hydrox-
ylamine hydrochloride (0.21 g, 6.0 mmol) and sodium acetate
(0.245 g, 6.0 mmol) in aqueous acetonitrile (1/3) (10 mL) was
stirred at room temperature for 4 h. After evaporating the solvent,
the residue was extracted between 3%-aqueous sodium hydrogen-
carbonate and dichloromethane. The organic layer was washed
with brine, dried over anhydrous magnessium sulfate, and the pre-
cipitates were filtered off. The filtrate was evaporated to dryness
and the residue was subjected to column chromatography on silica
gel to give oxime 3b (0.67 g, 86%) by elution with hexane/ethyl
acetate (5/1).
3-allylamino-2,2-dimethylpropionaldehyde (1).
Tosylation,
acetylation, and benzoylation of the aldehyde gave the corre-
sponding N-protected aldehydes 9b–d in 75–91% yields, which
were oximized by the usual method.
3-[(E)-N-Tosylcinnamylamino]-2,2-dimethylpropionalde-
hyde Oxime (10b). Yield 91%; colorless prisms from hexane–
1
2,2-Dimethyl-3-(N-tosylallylamino)propionaldehyde Oxime
(3b). Colorless oil; IR (NaCl) 3450, 1340, 1180 cmꢁ1; 1H NMR
(270 MHz) δ 1.17 (s, 6 H, 2-Me2), 2.43 (s, 3 H, Me), 3.22 (s, 2 H,
3-H2), 3.84 (d, J ꢀ 6.3 Hz, >NCH2CHꢀ), 5.08–5.15 (ov, 2 H,
ꢀCH2), 5.32 (m, 1 H, –CHꢀCH2), 7.30, 7.70 (each br d, J ꢀ 8.3
benzene; mp 120–121 ˚C; IR (KBr) 3300, 1320, 1160 cmꢁ1; H
NMR (270 MHz) δ 1.17 (s, 6 H, 2-Me2), 2.42 (s, 3 H, Me), 3.26
(s, 2 H, 3-H2), 3.98 (d, J ꢀ 5.9 Hz, 2 H, >NCH2CHꢀ), 5.62 (td, J
ꢀ 6.9 and 15.8 Hz, 1 H, –CHꢀCHPh), 6.37 (d, J ꢀ 15.8 Hz, 1 H,
–CHꢀCHPh), 7.15–7.34 (ov, 7 H, Ar-H), 7.40 (s, 1 H, 1-H), 7.73
(br d, J ꢀ 8.3 Hz, 2 H, Ar-H), 8.34 (br s, 1 H, OH); 13C NMR
(67.8 MHz) δ 21.3 (Me), 23.7 (2-Me2), 38.6 (2-C), 51.2
(>NCH2CHꢀ), 55.1 (3-C), 122.9 (–CHꢀCHPh), 126.3, 127.3,
128.2, 128.4, 129.6, 135.9, 137.1, 143.4 (Ph-C), 134.6
(–CHꢀCHPh), 157.3 (1-C). Found: C, 65.19; H, 7.07; N, 7.29%.
Calcd for C21H26N2O3S: C, 65.26; H, 6.78; N, 7.25%.
Hz, each 2 H, ArH), 7.36 (s, 1 H, 1-H), 7.76 (br s, 1 H, OH); 13
C
NMR (67.8 MHz) δ 21.5 (Me), 23.9 (2-Me2), 38.7 (2-C), 51.8 (3-
C), 55.0 (>NCH2CHꢀ), 120.1 (ꢀCH2), 127.3, 129.7, 137.2, 143.4
(Ar–C), 132.2 (–CHꢀCH2), 157.6 (1-C). Found: C, 57.86; H,
7.33; N, 8.70%. Calcd. for C15H22N2O3S: C, 58.04; H, 7.15; N,
9.02%.
Similarly, mesylation with mesyl chloride/Et3N–DMAP, ben-
zoylation with benzoyl chloride/Et3N-DMAP, and a reaction with
t-butyl chloroformate/Et3N–DMAP of the aldehyde gave the cor-
responding N-protected aldehydes 2c–e in 67–88% yields, which
were oximized by the usual method.
3-[(E)-N-Acetylcinnamylamino]-2,2-dimethylpropionalde-
hyde Oxime (10c). Yield 78%; colorless prisms from EtOH; mp
140–141 ˚C; IR (KBr) 3250, 1620 cmꢁ1. This compound was a
1
(4:1) mixture of two atropisomers in CDCl3. H NMR (270 MHz)
major isomer: δ 1.15 (s, 6 H, 2-Me2), 2.15 (s, 3 H, COMe), 3.45
(s, 2 H, 3-H2), 4.09 (br d, J ꢀ 5.0 Hz, 2 H, >NCH2CHꢀ), 6.08 (td,
J ꢀ 5.0 and 15.8 Hz, 1 H, –CHꢀCHPh), 6.40 (d, J ꢀ 15.8 Hz, 1
H, –CHꢀCHPh), 7.26–7.52 (ov, 7 H, Ph and 1-H, and OH); minor
isomer (assigned signals) δ 1.18 (s, 2-Me2), 2.15 (s, COMe), 3.35
(s, 3-H2), 4.18 (d, J ꢀ 6.3 Hz, >NCH2CHꢀ); 13C NMR (67.8
MHz) δ 21.8, 22.2 (COMe), 23.8, 24.2 (2-Me2), 39.2, 39.6 (2-C),
48.8, 52.2 (>NCH2CHꢀ), 53.9, 56.3 (3-C), 123.9, 124.4
(–CHꢀCHPh), 126.4, 127.7, 128.0, 128.5, 128.7, 128.8, 136.0
(Ph-C), 131.7, 133.0 (–CHꢀCHPh), 157.0, 157.1 (1-C), 172.0
(COMe). Found: C, 69.89; H, 8.11; N, 10.09%. Calcd for
C16H22N2O2: C, 70.04; 8.08; 10.21%.
3-[(E)-N-Benzoylcinnamylamino]-2,2-dimethylpropionalde-
hyde Oxime (10d). Yield 68%; colorless oil; IR (NaCl) 3320,
1620 cmꢁ1; 1H NMR (270 MHz) δ 1.24 (s, 6 H, 2-Me2), 3.63 (s, 2
H, 3-H2), 4.07 (d, J ꢀ 5.0 Hz, 2 H, >NCH2CHꢀ), 5.93 (dt, J ꢀ
15.8 and 5.6 Hz, 1 H, –CHꢀCH–Ph), 6.34 (d, J ꢀ 15.8 Hz, 1 H,
–CHꢀCH–Ph), 7.22–7.39 (ov, 10 H, Ph), 7.49 (s, 1 H, 1-H); 13C
NMR (67.8 MHz) δ 23.9 (2-Me2), 39.9 (2-C), 52.0 (3-C), 52.9
(>NCH2CHꢀ), 124.4 (>NCH2CHꢀ), 126.4, 126.5, 128.0, 128.4,
3-(N-Mesylallylamino)-2,2-dimethylpropionaldehyde Ox-
ime (3c). Yield 93%; colorless needles from hexane–benzene;
mp 87 ˚C; IR (KBr) 3325, 1320, 1170 cmꢁ1; 1H NMR (270 MHz)
δ 1.16 (s, 6 H, 2-Me2), 2.88 (s, 3 H, SO2Me), 3.25 (s, 2 H, 3-H2),
3.89 (d, J ꢀ 6.6 Hz, 2 H, >NCH2CHꢀ), 5.26–5.33 (ov, 2 H,
CHꢀCH2), 5.82 (m, 1 H, –CHꢀCH2), 7.38 (s, 1 H, 1-H), 7.57 (s,
1 H, OH); 13C NMR (67.8 MHz) δ 23.8 (2-Me2), 38.9 (2-C), 39.7
(SO2Me), 51.9 (3-C), 54.7 (>NCH2CHꢀ), 120.5 (–CHꢀCH2),
132.1 (–CHꢀCH2), 157.6 (1-C). Found: C, 45.97; H, 7.90; N,
11.84%. Calcd for C9H18N2O3S: C, 46.13; H, 7.74; N, 11.96%.
3-(N-Benzoylallylamino)-2,2-dimethylpropionaldehyde Ox-
ime (3d). Yield 81%; colorless needles from hexane–benzene;
1
mp 103.5–105.5 ˚C; IR (KBr) 3300, 1600 cmꢁ1; H NMR (270
MHz) δ 1.22 (s, 6 H, 2-Me2), 3.56 (s, 2 H, 3-H2), 3.90 (d, J ꢀ 4.3
Hz, 2 H, >NCH2CHꢀ), 5.08–5.17 (ov, 2 H, –CHꢀCH2), 5.53 (m,
1 H, –CHꢀCH2), 7.36 (ov, 5 H, Ph), 7.46 (s, 1 H, 1-H), 7.72 (br s,
1 H, OH); 13C NMR (67.8 MHz) δ 23.9 (2-Me2), 39.9 (2-C), 52.1
(3-C), 53.3 (>NCH2CHꢀ), 117.6 (–CHꢀCH2), 126.4, 128.4,
129.4, 136.5 (Ph-C), 133.2 (–CHꢀCH2), 157.7 (1-C), 173.2

922 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Mechanistic Considerations on the Oxime
128.6, 129.5, 136,6 (Ph-C), 132.8 (ꢀCHPh), 157.9 (1-C), 173.2
(COPh). Found: C, 75.21; H, 7.40; N, 8.22%. Calcd for
C21H24N2O2: C, 74.97; H, 7.19; N, 8.33%.
MHz) δ 1.05 (s, 6 H, 2-Me2), 1.27 (t, J ꢀ 7.2 Hz, CH2CH3), 2.69
(s, 2 H, 3-H2), 3.18 (dd, J ꢀ 1.3 and 5.9 Hz, 2 H, >NCH2CHꢀ),
3.59 (s, 2 H, CH2Ph), 4.19 (q, J ꢀ 7.2 Hz, 2 H, CH2CH3), 5.96 (td,
J ꢀ 1.3 and 15.8 Hz, 1 H, ꢀCHCO2Et), 6.92 (td, J ꢀ 5.9 and 15.8
Hz, 1 H, >NCH2CHꢀ), 7.23–7.31 (ov, 5 H, Ph), 9.42 (s, 1 H,
1-H); 13C NMR (67.8 Hz) δ 14.2 (CH2CH3), 20.4 (2-Me2), 47.9
(2-C), 55.8 (CH2Ph), 60.0 (5-C), 60.3 (CH2CH3), 60.8 (3-C),
123.3 (>NCH2CHꢀ), 127.1, 128.1, 128.7, 138.6 (Ph-C), 145.2
(ꢀCHCO2Et), 166.0 (CO2), 206 (1-C). Found: C, 70.99; H, 8.23;
N, 4.39%. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62%.
Ethyl N-Benzyl-N-(2-formyl-2-methylpropyl)fumaramate
(12e). Colorless oil; IR (NaCl) 1710 cmꢁ1; 1H NMR (270 MHz)
δ 1.11 (s, 6 H, 2-Me2), 1.27 (t, J ꢀ 7.3 Hz, 3 H, CH2CH3), 3.54 (s,
3 H, 3-H2), 4.20 (q, J ꢀ 7.3 Hz, 2 H, CH2CH3), 4.65 (s, 2 H,
CH2Ph), 6.81 (d, J ꢀ 15.2 Hz, 1 H, –COCHꢀ), 7.10–7.40 (ov, 6
H, Ph-H and ꢀCHCO2Et), 9.57 (s, 1 H, 1-H); 13C NMR (67.8
MHz) δ 14.0 (CH2CH3), 20.2 (2-Me2), 47.9 (2-C), 52.6 (3-C),
53.2 (>NCH2Ph), 61.0 (CH2CH3), 126.3, 128.0, 129.0, 135.9 (Ph-
C), 132.3 (–COCHꢀ), 133.1 (ꢀCHCO2Et), 165.3, 166.1 (>NCO–
and CO2), 203.2 (1-C). Found: C, 67.77; H, 7.27; N, 4.54%. Cal-
cd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41%. HRMS (EI) m/z
317.1617. Calcd for C18H23NO4: 317.1628.
Thermal Behaviors of Oximes. Thermal Reaction of Ox-
imes 3. General Procedures: A solution of oxime 3a (0.478
g, 2.0 mmol) in toluene (10 mL) was heated under reflux for 24 h,
and the solvent was evaporated. The residue was subjected to col-
umn chromatography on silica gel to give the recovered oxime 3a
[0.029 g, 6%; hexane/ethyl acetate (5/1)], 7a [0.210 g, 44%; hex-
ane/ethyl acetate (4/1)], 4a4 [0.201 g, 42%; hexane/ethyl acetate
(3/1)], 5a4 [0.010 g, 2%; hexane/ethyl acetate (1/1)], and 6a
(0.014 g, 3%; ethyl acetate), respectively.
Preparation of Oximes 13. General Procedures: 3-Ben-
zylamino-2,2-dimethylpropionaldehyde (11) was similarly pre-
pared using benzylamine oxalate in 75% yield. The reaction of
the aldehyde with acryloyl chloride, crotonoyl chloride, cin-
namoyl chloride, ethyl (E)-3-chloroformylacrylate gave the corre-
sponding 3-[N-(3-substituted propenoyl)benzylamino]-2,2-dime-
thylpropionaldehydes 12a-c and 12e in 70–89% yields, which
were oximized by the usual method. Ethyl 4-[N-(2-formyl-2-me-
thylpropyl)benzylamino]crotonate (12d) was obtained by an ordi-
nary Mannich reaction of isobutyraldehyde using ethyl 4-benzy-
laminocrotonate hydrochloride.
3-(N-Acryloylbenzylamino)-2,2-dimethylpropionaldehyde
Oxime (13a). Yield 72%; colorless oil; IR (NaCl) 3250, 1640
cmꢁ1. This compound was a (4:1) mixture of two atropisomers in
1
CDCl3. H NMR (270 MHz) major isomer δ 1.09 (s, 6 H, 2-Me2),
3.43 (s, 2 H, 3-H2), 4.58 (s, 2 H, CH2Ph), 5.56 (dd, J ꢀ 2.3 and 7.9
Hz, 1 H, –CHꢀCH2), 6.25–6.32 (ov, 2 H, ꢀCH2), 7.02–7.35 (ov,
6 H, Ph and 1-H), 8.21 (br, 1 H, OH); minor isomer (assigned sig-
nals) δ 1.09 (s, 2-Me2), 3.28 (s, 3-H2), 4.67 (s, CH2Ph), 5.69 (br,
–CHꢀCH2), 6.46 (ov, ꢀCH2), 8.49 (br, OH); 13C NMR (67.8
MHz) δ 24.2, 24.4 (2-Me2), 39.5, 40.0 (2-C), 53.0, 54.1 (CH2Ph),
54.7, 55.0 (3-C), 126.4, 127.6, 127.9, 128.2, 128.4, 128.6, 136.6,
137.0, 137.2 (Ph-C), 128.8, 129.0 (–CHꢀCH2), 156.8, 157.7
(1-C), 167.8, 168.4 (CO). Found: C, 60.44; H, 7.70; N, 10.91%.
Calcd for C15H20N2O2: C, 60.10; H, 7.94; N, 10.56%. HRMS (EI)
m/z 260.1514. Calcd for C15H20N2O2: 260.1525.
3-(N-Crotonoylbenzylamino)-2,2-dimethylpropionaldehyde
Oxime (13b). Yield 68%; colorless oil; IR (NaCl) 3230, 1650
cmꢁ1. This compound was a (4:1) mixture of two atropisomers in
1-Benzyl-3,6,6-trimethyl-2,3,6,7-tetrahydro-1H-1,4-diaze-
pine 4-Oxide (6a). Colorless oil. This compound was not very
stable and the structure was determined based on the spectroscop-
1
CDCl3. H NMR (270 MHz) major isomer δ 1.15 (s, 6 H, 2-Me2),
1.79 (dd, J ꢀ 1.3 and 6.9 Hz, ꢀCHMe), 3.48 (s, 2 H, 3-H2), 4.64
(s, 2 H, CH2Ph), 6.23 (qd, J ꢀ 1.3 and 4.9 Hz, 1 H, –CHꢀCHMe),
6.96 (m, 1 H, ꢀCHMe), 7.10–7.42 (ov, 6 H, Ph and OH), 8.74 (s,
1 H, 1-H); minor isomer (assigned signals) δ 1.90 (dd, J ꢀ 1.3 and
7.1 Hz, ꢀCHMe), 3.34 (s, 3-H2), 4.74 (s, CH2Ph), 6.30 (m,
–CHꢀCH-Me); 13C NMR (67.8 MHz) δ 18.1, 18.2 (ꢀCHMe),
23.8, 24.0 (2-Me2), 39.2, 39.6 (2-C), 49.7, 52.5 (CH2Ph), 54.2,
54.8 (3-C), 121.5, 121.7 (–CHꢀCHMe), 126.2, 127.5, 127.9,
128.5, 128.8, 136.7, 136.9 (Ph-C), 137.2, 142.8 (–CHꢀCHMe),
156.4, 157.3 (1-C), 167.8, 168.3 (CO). Found: C, 70.55; H, 8.19;
N, 10.00%. Calcd for C16H22N2O2: C, 70.96; H, 8.46; N, 9.88%.
HRMS (EI) m/z 274.1672. Calcd for C16H22N2O2: 274.1682.
3-[(E)-N-Cinnamoylbenzylamino]-2,2-dimethylpropional-
dehyde Oxime (13c). Yield 74%; colorless prisms from hex-
ane–benzene; mp 112–114 ˚C; IR (NaCl) 3230, 1640 cmꢁ1. This
1
ic data given below: H NMR (270 MHz) δ 1.09, 1.15 (each s,
each 3 H, 6-Me2), 1.44 (d, J ꢀ 7.3 Hz, 3 H, 3-Me), 2.36, 2.43
(each d, J ꢀ 12.5 Hz, each 1 H, 7-H2), 2.60 (dd, J ꢀ 5.9 and 13.9
Hz, 1 H, 2-H), 2.70 (1 H, dd, J ꢀ 2.3 and 13.9 Hz, 1 H, 2-H), 3.49,
3.57 (each d, J ꢀ 13.2 Hz, each 1 H, CH2Ph), 4.16 (m, 1 H, 3-H),
6.94 (s, 1 H, 5-H) and 7.18–7.27 (ov, 5 H, Ph); 13C NMR (67.8
MHz) δ 17.1 (3-Me), 26.3, 27.7 (6-Me2), 36.7 (6-C), 59.3 (2-C),
63.9 (7-C), 66.3 (CH2Ph), 70.1 (3-C), 127.4, 128.4, 128.9, 138.4
(Ph-C), 147.1 (5-C).
2-[N-Benzyl-N-(3-hydroxyimino-2,2-dimethylpropyl)ami-
nomethyl]-4,4,8-trimethyl-6-benzyl-perhydroisoxazolo[2,3-
1
d][1,4]diazepine (7a). Colorless oil; IR (NaCl) 3300 cmꢁ1; H
NMR (270 MHz) δ 0.69, 0.82 (each s, each 3 H, 4-Me2), 0.99 (d, J
ꢀ 6.3 Hz, 3 H, 8-Me), 1.06 (s, 6 H, 4′-Me2), 1.59 (ddd, J ꢀ 2.7,
5.5, and 12.2 Hz, 1 H, 3-H), 2.00 (ddd, 3-H, J ꢀ 4.0, 5.9, and 12.2
Hz, 1 H, 3-H), 2.37 (s, 2 H, 3′-H2), 2.49 (dd, J ꢀ 4.3 and 12.5 Hz,
1 H, 7-H), 3.25 (m, 1 H, 8-H), 3.54 (s, 2 H, CH2Ph), 3.65, 3.74
(each d, J ꢀ 13.9 Hz, each 1 H, CH2Ph), 4.02 (m, 1 H, 2-H), 7.18–
1
compound was a (3:1) mixture of two atropisomers in CDCl3. H
NMR (270 MHz) major isomer δ 1.18 (6 H, s, 2-Me2), 3.56 (s, 2
H, 3-H2), 4.72 (s, 2 H, CH2Ph), 6.80 (d, J ꢀ 15.5 Hz, 1 H,
–CHꢀCHPh), 7.14–7.59 (ov, 11 H, Ph and 1-H), 7.73 (d, J ꢀ 15.5
Hz, 1 H, ꢀCHPh), 8.35 (br, 1 H, OH); minor isomer (assigned
signals) δ 3.44 (s, 3-H2), 4.79 (s, CH2Ph), 6.92 (d, J ꢀ 15.5 Hz,
7.35 (ov, 10 H, Ph), 7.38 (s, 1 H, 5′-H), 8.23 (br s, 1 H, OH); 13
C
NMR (67.8 MHz) δ 10.7 (8-Me), 20.6, 27.3 (4-Me2), 23.8, 24.0
(4′-Me2), 35.8 (4-C), 36.6 (3-C), 39.0 (4′-C), 57.1 (8-C), 57.5 (1′-
C), 60.8, 64.9 (CH2Ph), 61.7 (3a-C), 64.8 (6-C), 70.1 (3-C), 74.6
(2-C), 126.8, 126.9, 128.0ꢂ2, 129.0, 129.2, 139.7, 140.1 (Ph-C),
158.7 (5′-C). Found: C, 73.14; H, 9.46; N, 10.99%. Calcd for
C30H44N4O2: C, 73.13; H, 9.00; N, 11.37%. HRMS (EI) m/z
492.3465. Calcd for C30H44N4O2: 492.3465.Similarly, thermal
reaction of oximes 3b,c gave NH-nitrone adducts 4b,c, cyclic
nitrones 6b,c, and dimers 7b,c. 7,7-Dimethyl-5-tosylperhydroiso-
–CHꢀCHPh), 7.79 (d, J ꢀ 15.5 Hz, ꢀCHPh), 8.43 (br, OH); 13
C
NMR (67.8 MHz) δ 24.2, 24.5 (2-Me2), 39.6, 40.1 (2-C), 50.5,
53.1 (CH2Ph), 55.0, 55.4 (3-C), 117.6, 117.7 (6-C), 126.6–130.0
(Ph-C), 137.2, 137.4 (Ph-C), 143.7, 143.8 (ꢀCHPh), 156.8, 156.9
(1-C), 167.9, 168.4 (CO). Found: C, 75.07; H, 7.29; N, 8.22%.
Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33%.
Ethyl 4-[N-(2-Formyl-2-methylpropyl)benzylamino]croto-
1
nate (12d). Colorless oil; IR (NaCl) 1720 cmꢁ1; H NMR (270

M. Noguchi et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 923
xazolo[4,3-c]pyridine (4b) was known.4
(8-C), 61.7, 61.8 (3a-C and 5-C), 74.4 (2-C), 158.0 (5′-C); FAB
MS m/z (rel intensity) 469 (Mꢃ ꢃ H; base peak), 468 (44), 389
(26). Found: C, 45.90; H, 7.70; N, 11.83%. Calcd for
C18H36N4O6S2: C, 46.13; H, 7.74; N, 11.96%.
Thermal Reaction of Oximes 10 and 13. A similar reaction
and work-up for oximes 10 and 13 gave NH-nitrone cycloadducts
14 and 15, respectively; the results are summarized in Table 2. 5-
Benzyl-7,7-dimethyl-3-phenylperhydroisoxazolo[4,3-c]pyridine
(14a) is known.4
3,6,6-Trimethyl-1-tosyl-2,3,6,7-tetrahydro-1H-1,4-diazepine
4-Oxide (6b). Pale yellow oil. This compound was not very sta-
ble, and the structure was determined based on the spectroscopic
data given below: 1H NMR (270 MHz) δ 1.23, 1.43 (each s, each 3
H, 6-Me2), 1.63 (d, J ꢀ 6.9 Hz, 3 H, 3-Me), 2.82 (s, 3 H, Me),
2.92 (d, J ꢀ 13.2 Hz, 1 H, 7-H), 3.26–3.33 (ov, 2 H, 2-H and 7-H),
3.50 (dd, J ꢀ 5.6 and 14.5 Hz, 1 H, 2-H), 4.50 (m, 1 H, 3-H), 7.00
(s, 1 H, 5-H) , 7.34, 7.64 (each br d, J ꢀ 8.3 Hz, each 2 H, Ar-H).
2-[N-(3-Hydroxyimino-2,2-dimethylpropyl)-N-tosylamino-
methyl]-4,4,8-trimethyl-6-tosyl-perhydroisoxazolo[2,3-d]-
[1,4]diazepine (7b). Colorless needles from hexane–benzene;
mp 174–175 ˚C; IR (KBr) 3300, 1320, 1140 cmꢁ1; 1H NMR (270
MHz) δ 0.67, 0.97 (each s, each 3 H, 4-Me2), 1.11, 1.13 (each s,
each 3 H, 4′-Me2), 1.17 (d, J ꢀ 6.3 Hz, 3 H, 8-Me), 1.65 (br q, J ꢀ
11.5 Hz, 1 H, 3-H), 1.86 (m, 1 H, 3-H), 2.35 (d, J ꢀ 13.9 Hz, 1 H,
5-H), 2.38, 2.41 (each s, each 3 H, Meꢂ2), 2.74 (dd, J ꢀ 4.0 and
13.2 Hz, 1 H, 7-H), 3.12–3.21 (ov, 2 H, 1′-H and 3a-H), 3.28 (d, J
ꢀ 13.9 Hz, 1 H, 5-H), 3.40–3.62 (ov, 5 H, 7-H2, 8-H, and 3′-H2),
3.65 (d, J ꢀ 14.5 Hz, 1 H, 1′-H), 7.26–7.31 (ov, 4 H, Ar-H), 7.40
(s, 1 H, 5′-H), 7.61, 7.67 (each br d, J ꢀ 8.3 Hz, each 2 H, Ar-H),
8.11 (s, 1 H, OH); 13C NMR (67.8 MHz) δ 9.65 (8-Me), 19.8, 26.2
(4-Me2), 21.4, 21.5 (Meꢂ2), 23.2, 24.4 (4′-Me2), 36.2 (3-C), 36.3
(4-C), 38.6 (4′-C), 50.1 (2-C), 55.5 (7-C), 55.6 (3-C), 56.7 (8-C),
61.1 (3a-C), 61.8 (6-C), 74.9 (2-C), 127.0, 127.2, 129.7, 135.7,
137.4, 143.4 (Ph-C), 157.8 (5′-C); FAB MS m/z (rel intensity) 621
(Mꢃ ꢃ H; base peak), 620 (48), 532 (8), 465 (26). Found: C,
57.82; H, 7.28; N, 9.02%. Calcd for C30H44N4O6S2: C, 58.04; H,
7.14; N, 9.03%.
7,7-Dimethyl-5-tosyl-3-phenylperhydroisoxazolo[4,3-c]pyri-
dine (14b). Colorless needles from EtOH; mp 187–188 ˚C; IR
1
(KBr) 3220, 1330, 1155 cmꢁ1; H NMR (270 MHz) δ 0.97, 1.12
(each s, each 3 H, 7-Me2), 2.45 (s, 3 H, SO2Me), 2.45–2.57 (ov, 2
H, 4-H and 6-H), 2.83 (m, 1 H, 3a-H), 3.13–3.17 (ov, 2 H, 6-H and
7a-H), 3.80 (br s, 1 H, 3a-H), 5.94 (br, 1 H, NH), 7.26–7.39 (ov, 7
H, Ar-H), 7.66 (br d, J ꢀ 8.3 Hz, 2 H, Ar-H); 13C NMR (67.8
MHz) δ 21.5 (Me), 24.6, 26.7 (7-Me2), 32.6 (7-C), 45.6 (4-C),
47.5 (3a-C), 52.4 (6-C), 63.1 (7a-C), 83.6 (3-C), 125.0, 127.5,
127.7, 128.6, 129.8, 133.3, 140.8, 143.8 (Ph-C). Found: C, 65.08;
H, 7.00; N, 7.30%. Calcd for C21H26N2O3S: C, 65.26; H, 6.78; N,
7.25%.
5-Acetyl-7,7-dimethyl-3-phenylperhydroisoxazolo[4,3-c]pyr-
idine (14c). Colorless oil; IR (NaCl) 3200, 1630 cmꢁ1
. This
1
compound was a (4:1) mixture of two atropisomers in CDCl3. H
NMR (270 MHz) major isomer δ 1.00, 1.04 (each s, each 3 H, 7-
Me2), 2.11 (s, 3 H, COMe), 2.68 (m, 1 H, 3a-H), 3.03 (br t, J ꢀ
13.0 Hz, 1 H, 4-H), 3.18–3.32 (ov, 4 H, 6-H2, 7a-H, and NH), 4.61
(dd, J ꢀ 6.3 and 13.2 Hz, 1 H, 4-H), 4.85 (d, J ꢀ 2.0 Hz, 1 H, 3-
H), 7.28–7.41 (ov, 5 H, Ph); minor isomer (assigned signals) δ
0.97, 1.02 (each s, 7-Me2), 2.18 (s, COMe), 2.82 (d, J ꢀ 13.2 Hz,
6-H), 3.35 (dd, J ꢀ 11.2 and 13.9 Hz, 4-H), 3.88 (ddd, J ꢀ 1.6,
6.6, and 13.9 Hz, 4-H), 4.03 (d, J ꢀ 13.2 Hz, 6-H), 4.81 (d, J ꢀ
1.7 Hz, 3-H); 13C NMR (67.8 MHz) δ 21.3, 21.4 (COMe), 24.2,
24.3, 26.3 (7-Me2), 32.6, 33.3 (7-C), 40.7, 45.8 (4-C), 47.1, 47.7
(3a-C), 47.9, 52.9 (6-C), 64.0, 64.7 (7a-C), 83.9, 84.1 (3-C),
125.3, 127.9, 128.7, 140.7 (Ph-C), 168.9 (COMe). Found: C,
70.00; H, 8.31; N, 10.01%. Calcd for C16H22N2O2: C, 70.04; H,
8.08; N, 10.21%.
5-Mesyl-7,7-dimethylperhydroisoxazolo[4,3-c]pyridine (4c).
Colorless prisms from hexane–benzene; mp 168–169 ˚C; IR
1
(KBr) 3200, 1320, 1160 cmꢁ1; H NMR (270 MHz) δ 1.00, 1.19
(each s, each 3 H, 7-Me2), 2.73–2.78 (ov, 2 H, 4-H and 6-H), 2.78
(s, 3 H, SO2Me), 2.88 (m, 1 H, 3a-H), 3.19 (d, J ꢀ 12.2 Hz, 1 H,
6-H), 3.26 (br s, 1 H, 7a-H), 3.71 (d, J ꢀ 7.9 Hz, 1 H, 3-H), 3.74
(m, 1 H, 4-H), 3.94 (dd, J ꢀ 4.6 and 7.9 Hz, 1 H, 3-H), 5.89 (br s,
1 H, NH); 13C NMR (67.8 MHz) δ 24.6, 26.2 (7-Me2), 32.6 (7-C),
34.5 (SO2Me), 40.0 (3a-C), 44.6 (4-C), 51.3 (6-C), 64.8 (7a-C),
71.8 (3-C). Found: C, 45.96; H, 7.74; N, 11.91%. Calcd for
C9H18N2O3S: C, 46.13; H, 7.74; N, 11.96%.
5-Benzyl-7,7-dimethylperhydroisoxazolo[4,3-c]pyridin-4-
one (15a). Colorless prisms from hexane–benzene; mp 90–91
1
1-Mesyl-3,6,6-trimethyl-2,3,6,7-tetrahydro-1H-1,4-diaze-
pine 4-Oxide (6c). Pale-yellow oil. This compound was not
very stable, and the structure was determined based on the spec-
˚C; IR (KBr) 3200, 1630 cmꢁ1; H NMR (270 MHz) δ 0.85 (s, 6
H, 7-Me2), 2.66 (dd, J ꢀ 1.3 and 12.5 Hz, 1 H, 6-H), 3.23 (d, J ꢀ
12.5 Hz, 1 H, 6-H), 3.27–3.37 (ov, 4 H, 3a-H, 6-H, 7a-H, and NH),
3.94 (br t, J ꢀ 7.8 Hz, 1 H, 3-H), 4.48 (br d, J ꢀ 7.8 Hz, 1 H, 3-
H), 4.41, 4.61 (each d, J ꢀ 14.5 Hz, each 1 H, CH2Ph), 7.17–7.28
(ov, 5 H, Ph); 13C NMR (67.8 MHz) δ 23.3, 25.2 (7-Me2), 33.0 (7-
C), 48.9 (3a-C), 50.8 (CH2Ph), 53.9 (6-C), 66.5 (7a-C), 77.6 (3-
C), 127.6, 128.4, 128.6, 136.5 (Ph-C), 169.9 (4-CO). Found: C,
69.29; H, 8.00; N, 10.61%. Calcd for C15H20N2O2: C, 69.20; H,
7.74; N, 10.76%.
5-Benzyl-3,7,7-trimethylperhydroisoxazolo[4,3-c]pyridin-4-
one (15b). Colorless prisms from hexane–benzene; mp 79–80
˚C; IR (KBr) 3170, 1620 cmꢁ1; 1H NMR (270 MHz) δ 0.91 (br s,
6 H, 7-Me2), 1.44 (d, J ꢀ 6.3 Hz, 3 H, 3-Me), 2.73 (d, J ꢀ 12.9
Hz, 1 H, 6-H), 2.90 (dd, J ꢀ 5.3 and 8.6 Hz, 1 H, 3a-H), 3.30 (d, J
ꢀ 12.9 Hz, 1 H, 6-H), 3.37 (d, J ꢀ 8.6 Hz, 1 H, 7a-H), 4.17 (br, 1
H, 3a-H), 4.49, 4.65 (each d, J ꢀ 14.5 Hz, each 1 H, CH2Ph), 5.4–
5.8 (br, 1 H, NH), 7.24–7.36 (ov, 5 H, Ph); 13C NMR (67.8 MHz)
δ 19.3 (3-Me), 23.0, 25.3 (7-Me2), 32.2 (7-C), 50.5 (CH2Ph), 53.6
(6-C), 54.4 (3a-C), 66.5 (7a-C), 82.6 (3-C), 127.5, 128.3, 128.5,
136.5 (Ph-C), 169.3 (4-CO). Found: C, 69.89; H, 8.41; N,
10.11%. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21%.
1
troscopic data given below: H NMR (270 MHz) δ 1.27, 1.33
(each s, each 3 H, 6-Me2), 1.63 (d, J ꢀ 7.3 Hz, 3 H, 3-Me), 2.85
(s, 3 H, SO2Me), 3.17, 3.39 (each d, J ꢀ 13.2 Hz, each 1 H, 7-H2),
3.35–3.55 (ov, 2 H, 2-H2), 4.40 (m, 1 H, 3-H), 7.03 (s, 1 H, 5-H).
2-[N-(3-Hydroxyimino-2,2-dimethylpropyl)-N-mesylami-
nomethyl]-4,4,8-trimethyl-6-mesylperhydroisoxazolo[2,3-d]-
[1,4]diazepine (7c). Colorless prisms from ethyl acetate; mp
188 ˚C; IR (KBr) 3400, 1330, 1170 cmꢁ1; 1H NMR (270 MHz) δ
0.95, 0.99 (each s, each 3 H, 4-Me2), 1.14, 1.16 (each s, each 3 H,
4′-Me2), 1.23 (d, J ꢀ 3.0 Hz, 3 H, 8-Me), 1.75 (ddd, J ꢀ 10.9,
11.2, and 12.5 Hz, 1 H, 3-H), 2.10 (ddd, J ꢀ 2.0, 5.6, and 12.5 Hz,
1 H, 3-H), 2.69 (d, J ꢀ 13.9 Hz, 1 H, 5-H), 2.78, 2.92 (each s,
each 3 H, SO2Meꢂ2), 3.10 (dd, J ꢀ 4.0 and 12.9 Hz, 1 H, 7-H),
3.29 (dd, J ꢀ 3.3 and 11.2 Hz, 1 H, 3a-H), 3.32–3.43 (ov, 2 H, 1′-
H and 5-H), 3.42 (s, 2 H, 3′-H2), 3.52–3.58 (ov, 2 H, 7-H and 1′-
H), 3.69 (m, 1 H, 8-H), 4.13 (m, 1 H, 2-H), 7.20 (s, 1 H, 5′-H),
7.41 (s, 1 H, OH); 13C NMR (67.8 MHz) δ 9.76 (8-Me), 20.2, 26.2
(4-Me2), 23.0, 24.3 (4′-Me2), 35.7, 39.7 (SO2Meꢂ2), 36.0 (3-C),
36.6 (4-C), 38.6 (4′-C), 50.2 (1′-C), 54.9 (3′-C), 55.3 (7-C), 55.9

924 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Mechanistic Considerations on the Oxime
(EI) m/z 318.1934. Calcd for C18H26N2O3: 318.1924.
Aldehyde 12e was oximized by similar procedures as in the
preparation of oxime 13d. Column chromatographic separation
on silica gel afforded perhydroisoxazolopyridines 15e (53%; hex-
5-Benzyl-7,7-dimethyl-3-phenylperhydroisoxazolo[4,3-c]pyr-
idin-4-one (15c). Colorless prisms from hexane–benzene; mp
1
98–100 ˚C; IR (KBr) 3160, 1620 cmꢁ1; H NMR (270 MHz) δ
0.93, 0.95 (each s, each 3 H, 7-Me2), 2.80 (d, J ꢀ 12.5 Hz, 1 H, 6-
H), 3.36 (br, 1 H, 7a-H), 3.41 (d, J ꢀ 12.5 Hz, 6-H), 3.52 (br, 1 H,
3a-H), 4.52, 4.76 (each d, J ꢀ 14.5 Hz, each 1 H, CH2Ph), 5.43 (br
s, 1 H, 3-H), 5.84 (br, 1 H, NH), 7.21–7.53 (ov, 10 H, Ph); 13C
NMR (67.8 MHz) δ 23.2, 25.2 (7-Me2), 32.6 (7-C), 50.9 (CH2Ph),
54.0 (6-C), 55.1 (3a-C), 66.5 (7a-C), 86.7 (3-C), 125.6, 127.6,
127.9, 128.4, 128.6, 128.7, 136.6, 139.8 (Ph-C), 169.3 (4-CO).
Found: C, 74.96; H, 7.38; N, 8.31%. Calcd for C21H24N2O2: C,
74.97; H, 7.19; N, 8.33%.
Oximization of Aldehydes 12d,e and IOOC Reaction of
Oximes 13d,e. A solution of aldehyde 12d (0.303 g, 1.0 mmol),
hydroxylamine hydrochloride (0.035 g, 1.2 mmol), sodium acetate
(0.050 g, 1.2 mmol) in MeOH (12 mL) was stirred at room tem-
perature for 12 h. The solvent was evaporated and the residue was
treated with a 3% aqueous solution of sodium hydrogencarbonate
and extracted with dichloromethane (3ꢂ20 mL). The organic lay-
er was dried and evaporated to dryness. The residue was subject-
ed to column chromatography on silica gel to give oxime 13d
[0.010 g, 3%; hexane/ethyl acetate (4/1)] and perhydroisoxazol-
opyridines 15d [0.124 g, 39%; hexane/ethyl acetate (3/1)] and
′
ane/ethyl acetate ꢀ 3/1) and 15e (9%; hexane/ethyl acetate ꢀ
3/1), and cyclic nitrone 16e (11%; ethyl acetate), respectively.
Ethyl (3RS,3aRS,7aRS)-5-Benzyl-7,7-dimethyl-4-oxoperhy-
droisoxazolo[4,3-c]pyridine-3-carboxylate (15e). Colorless
1
oil; IR (NaCl) 3220, 1730, 1660 cmꢁ1; H NMR (270 MHz) δ
0.87, 0.92 (each s, each 3 H, 7-Me2), 1.32 (m, 3 H, CH2CH3), 2.83
(d, J ꢀ 12.5 Hz, 1 H, 6-H), 3.23 (d, J ꢀ 8.3 Hz, 1 H, 7a-H), 3.56
(dd, J ꢀ 2.0 and 8.2 Hz, 1 H, 3a-H), 4.23 (m, 2 H, CH2CH3), 4.48,
4.70 (each d, J ꢀ 14.5 Hz, each 1 H, CH2Ph), 4.95 (d, J ꢀ 2.0 Hz,
1 H, 3-H), 6.63 (br, 1 H, NH), 7.26–7.36 (ov, 5 H, Ph); 13C NMR
(67.8 Hz) δ 14.0 (CH2CH3), 22.1, 25.0 (7-Me2), 33.1 (7-C), 51.0
(CH2Ph), 52.7 (3a-C), 54.2 (6-C), 61.5 (CH2CH3), 65.6 (7a-C),
82.4 (3-C), 127.5, 128.3, 128.5, 136.2 (Ph-C), 168.0 (CO2), 171.5
(4-CO). Found: C, 64.52; H, 7.43; N, 8.31%. Calcd for
C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. HRMS (EI) m/z
332.1752. Calcd for C18H24N2O4: 332.1737.
Ethyl (3RS,3aRS,7aSR)-5-Benzyl-7,7-dimethyl-4-oxoperhy-
′
droisoxazolo[4,3-c]pyridine-3-carboxylate (15e ). Colorless
1
oil; IR (NaCl) 3220, 1730, 1660 cmꢁ1; H NMR (270 MHz) δ
′
15d [0.067 g, 21%; hexane/ethyl acetate (3/1)], respectively.
1.00, 1.03 (each s, each 3 H, 7-Me2), 1.34 (t, J ꢀ 7.3 Hz, 3 H,
CH2CH3), 2.99 (d, J ꢀ 13.2 Hz, 1 H, 6-H), 3.07–3.17 (ov, 2 H, 3a-
H and 7a-H), 3.14 (d, J ꢀ 13.2 Hz, 1 H, 6-H), 4.27 (m, 2 H,
CH2CH3), 4.49, 4.61 (each d, J ꢀ 14.5 Hz, each 1 H, CH2Ph), 4.74
(d, J3–3a ꢀ 7.6 Hz: ax–ax trans, 1 H, 3-H), 5.67 (br d, J ꢀ 11.8 Hz,
1 H, NH), 7.22–7.38 (ov, 5 H, Ph); 13C NMR (67.8 MHz) δ 14.1
(CH2CH3), 19.6, 28.2 (7-Me2), 31.9 (7-C), 49.5 (CH2Ph), 54.1
(3a-C), 60.3 (6-C), 61.9 (CH2CH3), 70.4, 70.6 (3-C and 7a-C),
127.8, 128.3, 128.8, 136.8 (Ph-C), 168.1 (4-CO), 171.9 (CO2).
HRMS (EI) m/z 332.1732. Calcd for C18H24N2O4: 332.1737.
1-Benzyl-3-ethoxycarbonylmethyl-6,6-trimethyl-2-oxo-
2,3,6,7-tetrahydro-1H-1,4-diazepine 4-Oxide (16e). Colorless
oil; IR (NaCl) 1740, 1650 cmꢁ1; 1H NMR (270 MHz) δ 1.09–1.28
(ov, 9 H, 6-Me2 and CH2CH3), 2.48 (dd, J ꢀ 5.3 and 16.8 Hz, 1 H,
3-CHHCO2Et), 2.59 (dd, J ꢀ 8.6 and 16.8 Hz, 1 H, 3-
CHHCO2Et), 3.31, 3.60 (each d, J ꢀ 13.5 Hz, each 1 H, 7-H2),
4.10 (q, J ꢀ 7.3 Hz, 2 H, CH2CH3), 4.35 (dd, J ꢀ 5.3 and 8.3 Hz,
1 H, 3-H), 4.65, 4.84 (each d, J ꢀ 17.5 Hz, each 1 H, CH2Ph),
7.19–7.39 (ov, 6 H, 5-H and Ph); 13C NMR (67.8 MHz) δ 14.1
(CH2CH3), 23.8, 24.0 (6-Me2), 34.1 (6-C), 39.9 (3-CH2CO2Et),
52.6 (CH2Ph), 54.4 (7-C), 58.4 (3-C), 61.0 (CH2CH3), 126.5,
127.8, 130.0, 136.6 (Ph-C), 157.4 (5-C), 171.0, 173.2 (2-C and
CO2). HRMS (EI) m/z 332.1742. Calcd for C18H24N2O4:
332.1737.
Kinetic Studies. General Procedures: A stirred solution
of oxime 10a (7.0 mg), naphthalene (5.5 mg) and n-BuOH (10
mL) in a test tube under nitrogen was inserted into one neck of a
two-neck flask. A condenser was fitted to the other neck, and the
flask was filled with an appropriate solvent, such as THF (bp 66.0
˚C), benzene (bp 80.1 ˚C), propiononitrile (bp 97.2 ˚C), and n-
BuOH (bp 117 ˚C) until the solvent was up to the solution of the
test tube. The outer flask was sunk in a thermostated oil bath and
heated to keep the solvent in the flask boiling. At an appropriate
interval with a total of nine to fourteen data points, 0.05 mL each
of the n-BuOH solution was withdrawn with a micro syringe
through a septum rubber cap. The collected sample was immedi-
ately cooled in an ice-salt bath to stop the reaction, and was ana-
lyzed by HPLC. HPLC measurements were performed with a Hi-
tachi L-6200 instrument using UV detector (Hitachi L-4000; 254
Ethyl 4-[N-(3-Hydroxyimino-2,2-dimethylpropyl)benzyl-
amino]crotonate (13d). Colorless oil. This compound was not
very stable, and the structure was determined based on the spec-
troscopic data given below: 1H NMR (270 MHz) δ 1.07 (s, 6 H, 2-
Me2), 1.30 (t, J ꢀ 7.2 Hz, 3 H, CH2CH3), 2.50 (s, 2 H, 3-H2), 3.20
(dd, J ꢀ 1.3 and 6.3 Hz, 2 H, >NCH2CHꢀ), 3.64 (s, 2 H, CH2Ph),
4.20 (q, J ꢀ 7.2 Hz, 2 H, CH2CH3), 5.93 (td, J ꢀ 1.3 and 15.7 Hz,
1 H, ꢀCHCO2Et), 6.94 (td, J ꢀ 6.3 and 15.7 Hz, 1 H, >NCH2–
CHꢀ), 7.23–7.34 (ov, 5 H, Ph), 7.96 (s, 1 H, 1-H); 13C NMR (67.8
MHz) δ 14.2 (CH2CH3), 23.9 (2-Me2), 38.9 (2-C), 56.0 (CH2Ph),
60.3 (5-C), 60.4 (CH2CH3), 63.9 (3-C), 123.2 (ꢀCHCO2Et),
127.1, 128.3, 128.8, 138.0 (Ph-C), 145.8 (>NCH2CHꢀ), 158.4 (1-
C), 166.3 (CO2). HRMS (EI) m/z 318.1942. Calcd for
C18H26N2O3: 318.1924.
Ethyl (3RS,3aRS,7aRS)-5-Benzyl-7,7-dimethylperhydroiso-
xazolo[4,3-c]pyridine-3-carboxylate (15d). Colorless oil; IR
(NaCl) 3200, 1740 cmꢁ1; 1H NMR (270 MHz) δ 0.93, 1.14 (each
s, each 3 H, 7-Me2), 1.26 (t, J ꢀ 6.9 Hz, 3 H, CH2CH3), 2.05–2.25
(ov, 3 H, 3a-H, 4-H, and 6-H), 2.78–2.90 (ov, 2 H, 4-H and 6-H),
3.19 (s, 2 H, CH2Ph), 4.14–4.26 (m, 2 H, CH2CH3), 6.13 (br, 1 H,
NH), 7.42–7.33 (ov, 5 H, Ph); 13C NMR (67.8 MHz) δ 14.1
(CH2CH3), 25.2, 27.9 (7-Me2), 32.6 (7-C), 45.8 (3a-C), 53.2 (4-
C), 60.6 (6-C), 61.3 (CH2Ph), 62.6 (CH2CH3), 64.4 (7a-C), 80.9
(3-C), 127.0, 128.2, 128.6, 138.5 (Ph-C), 171.8 (CO2). HRMS
(EI) m/z 318.1924. Calcd for C18H26N2O3: 318.1924.
Ethyl (3RS,3aRS,7aSR)-5-Benzyl-7,7-dimethylperhydroiso-
′
xazolo[4,3-c]pyridine-3-carboxylate (15d ). Colorless oil; IR
1
(NaCl) 3200, 1740 cmꢁ1; H NMR (270 MHz) δ 1.02 (s, 6 H, 7-
Me2), 1.25 (t, J ꢀ 7.3 Hz, 3 H, CH2CH3), 1.82 (br d, J ꢀ 11.6 Hz,
1 H, 6-H), 2.11 (t, J ꢀ 10.6 Hz, 1 H, 4-H), 2.30 (m, 1 H, 3a-H),
2.51 (d, J ꢀ 11.6 Hz, 1 H, 6-H), 2.55 (d, J3a–7a ꢀ 10.9 Hz: ax–ax
trans, 1 H, 7a-H), 3.23 (dd, J ꢀ 3.3 and 10.6 Hz, 1 H, 4-H), 3.51,
3.57 (each d, J ꢀ 13.2 Hz, each 1 H, CH2Ph), 4.07 (d, J3–3a ꢀ 10.2
Hz: ax–ax trans, 1 H, 3-H), 4.12 (m, 2 H, CH2CH3), 5.6 (br, 1 H,
NH), 7.25–7.32 (ov, 5 H, Ph); 13C NMR (67.8 MHz) δ 14.1
(CH2CH3), 18.2, 27.3 (7-Me2), 33.3 (7-C), 49.7 (3a-C), 54.9 (4-
C), 61.3 (CH2CH3), 61.9 (CH2Ph), 65.0 (6-C), 73.0 (7a-C), 79.0
(3-C), 127.1, 128.3, 128.5, 138.4 (Ph-C), 171.8 (CO2). HRMS

M. Noguchi et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 925
nm). To measure the rates of the disappearance of the oximes
10b–d and 13c, naphthalene was utilized as an internal standard.
A Wakosil-II5C18HG (id 4.6 mmꢂ250 mm) column was used;
the flow rate of the elution was 0.8 mL minꢁ1 (47 kg cmꢁ2) and
the elution solvent was acetonitrile–H2O (7:3). All rates of con-
version of oximes 10 under several conditions (solvent, concentra-
tion, and temperature) were first-order with respect to the oxime
concentration. The obtained rate constants [k (sꢁ1)ꢂ105] were as
below: for 10a in n-BuOH, 1.63 (66 ˚C), 4.00 (80 ˚C), 17.7 (97
˚C), and 44.6 (117 ˚C). The relative rates for the conversion of
oximes 10a–d and 13c are summarized in Table 3.
7875 (1996) and references cited therein.
a) M. Gotoh, T. Mizui, B. Sun, K. Hirayama, and M.
3
Noguchi, J. Chem. Soc., Perkin Trans. 1, 1995, 1857. b) M.
Gotoh, B. Sun, K. Hirayama, and M. Noguchi, Tetrahedron, 52,
887 (1996). c) C. O’Mahony and F. Heaney, Chem. Commun.,
1996, 167; F. Heaney and C. O’Mahony, J. Chem Soc., Perkin
Trans. 1, 1998, 341; F. Heaney, and S. Bourke, J. Chem Soc.,
Perkin Trans. 1, 1998, 955; F. Heaney, S. Bourke, D. Cunning-
ham, and P. McArdle, J. Chem. Soc., Perkin Trans. 2, 1998, 547.
Also see Ref. 1a and 1c.
4
M. Noguchi, H. Okada, S. Nishimura, Y. Yamagata, S.
Takamura, M. Tanaka, A. Kakehi, and H. Yamamoto, J. Chem.
Soc., Perkin Trans. 1, 1999, 185.
References
5
R. Grigg, J. Markandu, T. Perrior, S. Surendrakumar, and
W. J. Warnock, Tetrahedron, 48, 6929 (1992); R. Bishop, P. R.
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1
a) R. Grigg, H. Q. N. Gunaratne, and J. Kemp, J. Chem.
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2
a) M. H. Norman and C. H. Heathcock, J. Org. Chem., 52,
6
Reaction of oxime 3e in n-BuOH under reflux for 30 h
226 (1987). b) R. Grigg, F. Heaney, J. Markandu, S.
gave 4e (40%) together with two other products. 5-t-Butoxycar-
bonyl-7,7-dimethylperhydroisoxazolo[4,3-c]pyridine (4e): Color-
less prisms from hexane; mp 122–123 ˚C; IR (KBr) 3170, 1690
Surendrakumar, M. Thornton-Pett, and W. J. Warnock, Tetrahe-
dron, 47, 4007 (1991). c) R. Grigg, M. J. Dorrity, F. Heaney, J. F.
Malone, S. Rajviroongit, V. Sridharan and S. Surendrakumar, Tet-
rahedron, 47, 8297 (1991). d) A. Hassner and R. Maurya, Tetra-
hedron Lett., 30, 5803 (1989). e) A. Hassner, K. M. Lokanatha
Rai, and W. Dehaen, J. Org. Chem., 56, 2775 (1991). f) A.
Hassner, R. Maurga, O. Friedman, and H. E. Gottlieb, J. Org.
Chem., 58, 4539 (1993). g) A. Hassner, S. Singh, R. Sharma, and
R. Maurya, Tetrahedron, 49, 2317 (1993). h) A. Hassner, K. M.
Lokanatha Rai, and W. Dehaen, Synth. Commun., 24, 1669 (1994).
i) A. Hassner, E. Falb, A. Nudelman, A. Albeck, and H. E.
Gottlieb, Tetrahedron Lett., 35, 2397 (1994). j) U. Chiacchio, G.
Buemi, F. Casuscelli, A. Procopio, A. Rescifina, and R. Romeo,
Tetrahedron, 50, 5503 (1994). k) U. Chiacchio, A. Corsaro, V.
Pistarà, A. Rescifina, G. Romeo, and R. Romeo, Tetrahedron, 52,
1
cmꢁ1. This compound gave broad signals in H and 13C NMR
spectra. 1H NMR (270 MHz) δ 0.97, 1.06 (each s, each 3 H, 7-
Me2), 1.47 (s, 9 H, –CMe3), 2.60–2.94 (ov, 3 H, 3a-H, 4-H, and 6-
H), 3.15 (br d, J ꢀ 3.6 Hz, 1 H, 7a-H), 3.5 (br, 1 H, 4-H), 3.66 (d,
J ꢀ 7.6 Hz, 1 H, 3-H), 3.89 (dd, J ꢀ 5.3 and 7.6 Hz, 1 H, 3-H), 4.1
(br, 1 H, 4-H), 5.7 (br, 1 H, NH); 13C NMR (67.8 MHz) δ 24.4,
24.6 (7-Me3), 28.4 (CMe3), 32.5 (7-C), 39.4 (3a-C), 41.9, 42.8 (4-
C), 49.0, 50.1 (6-C), 66.1 (7a-C), 72.1 (3-C), 79.7 (CMe3), 154.8
(CO2). Found: C, 60.78; H, 9.76; N, 10.97%. Calcd for
C13H24N2O3: C, 60.91; H, 9.44; N, 10.93%.
7
H. G. O. Becker, W. Ecknig, E. Fanghänel, and S. Rommel,
Wiss. Z. Techn., 11, 38 (1968); Chem. Abstr., 71, 60938 (1970).