Stereoselective synthesis of azepines through the conjugate addition of formamides to nitroalkenes and subsequent intramolecular nitrile oxide cycloaddition reaction

Article abstract of DOI:10.1016/j.tet.2008.09.070

A concise and stereoselective formation of azepines is achieved through the conjugate addition of formamides to nitroalkenes and the subsequent intramolecular nitrile oxide cycloaddition (INOC) reaction. High cis-selectivity was observed. The one-pot modification of the two reactions provides direct preparation of azepines from nitroalkenes and formamides in moderate yields. The formyl group was readily removed by an acidic treatment without significant epimerization.

Full text of DOI:10.1016/j.tet.2008.09.070

Tetrahedron 64 (2008) 11081–11085
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Stereoselective synthesis of azepines through the conjugate addition of
formamides to nitroalkenes and subsequent intramolecular nitrile
oxide cycloaddition reaction
,
a
b
Akio Kamimura a , Takayuki Yoshida , Hidemitsu Uno
*
a Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
b Integrated Center for Sciences, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and stereoselective formation of azepines is achieved through the conjugate addition of
formamides to nitroalkenes and the subsequent intramolecular nitrile oxide cycloaddition (INOC) re-
action. High cis-selectivity was observed. The one-pot modification of the two reactions provides direct
preparation of azepines from nitroalkenes and formamides in moderate yields. The formyl group was
readily removed by an acidic treatment without significant epimerization.
Received 8 September 2008
Received in revised form 24 September
2008
Accepted 24 September 2008
Available online 1 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
only to cyclic lactams.13 This is probably due to the instability of
b
-nitroamines that tends to cause the retro-Michael reaction dur-
The intramolecular nitrile oxide cycloaddition (INOC) reaction is
a useful method to prepare heterocyclic compounds.1,2 4,5-Dihy-
droisoxazole, the cycloadduct of nitrile oxide, is regarded as a useful
ing the INOC reaction under Mukaiyama conditions.11 Recently, we
found that formamides, the smallest amide of all the amide de-
rivatives, underwent smooth conjugate addition to nitroalkenes to
synthetic precursor for
g
-amino alcohols and
b-hydroxy ketones.
give b
-nitroamides,14 which worked as a useful precursor for the
There have been many examples applying the present methodol-
ogy to the preparation of five- or six-membered carbo- and het-
erocyclic compounds3 as well as the preparation of medium- or
large-sized cyclic compounds.4,5 On the other hand, the preparation
of the precursor for the INOC reaction from commercially available
starting material generally was not easy and required long steps.
Primary aliphatic nitro compounds are readily prepared from the
conjugate addition of a variety of nucleophiles to nitroalkenes.6 The
nitro group is converted into nitrile oxide by treatment with phenyl
isocyanate,7 the conjugate addition to the nitroalkenes and the
following generation of nitrile oxide should be expected to be
a facile and convenient strategy for INOC reaction. There have been
several reports of such a methodology by Hassner,8 Kurth,9 and
Yao.10 They successfully prepared five- and six-membered carbo-,
oxa-, and thio-cyclic compounds, and one-pot conversion to bi-
cyclic isoxazoles from nitroalkenes was utilized in some of these
protocols. If such nitro compounds include a nitrogen atom in
a tether unit, these compounds are expected to be a good precursor
for the aza-heterocyclic compounds through the INOC reaction.11
However, nitrogen-nucleophiles have rarely been used through the
conversion,12 and the addition of amides to nitroalkene was limited
INOC reaction to prepare five- and six-membered aza-heterocyclic
compounds in a stereoselective manner.15 In this paper, we report
that the present method is effective for the preparation of azepine
derivatives. These medium-sized rings have been recognized rela-
tively hard to be prepared through the INOC reaction thus far.16 We
have also succeeded in modifying these reactions in a one-pot
manner that achieved direct preparation of azepines from nitro-
alkenes. The formyl group was readily removed under an acidic
treatment to give N–H azepines without significant epimerization.
2. Results and discussion
The preparation of the INOC precursors 3 was smoothly carried
out by the conjugate addition of secondary formamide 1 to nitro-
alkene 2 (Scheme 1). The results are summarized in Table 1.
NO2
R
t
BuOK
H
N
N
OHC
THF, -50 °C, 2-4 h
OHC
R
NO2
2
3
1
* Corresponding author. Tel.: þ81 836 85 9231; fax: þ81 836 85 9201.
E-mail address: ak10@yamaguchi-u.ac.jp (A. Kamimura).
Scheme 1. Conjugate addition of alkenyl amides to nitroalkene.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.070

11082
A. Kamimura et al. / Tetrahedron 64 (2008) 11081–11085
Table 1
The N-formyl group was readily removed by the treatment of 4
Preparation of INOC precursor 3
under acidic conditions (Scheme 2). For example, treatment of 4a
with ethanolic diluted HCl solution at a gently refluxing tempera-
ture resulted in the smooth removal of the formyl group, giving
N–H azepine 5a in 74% yield (entry 1). The diastereomeric ratio of
5a was found to be 87:13, which was close to the original di-
astereomeric ratio of 4a (89:11). No significant epimerization was
observed during the removal of the formyl group except for the
deprotection of 4b (entries 1 and 3–5). The reaction conditions for
the removal were somewhat critical; the treatment of 4a at room
temperature resulted in no removal of the formyl group, while
vigorous reflux of 4a under the present conditions resulted in the
complete removal of the formyl group but induced undesirable
epimerization giving a 1:1 mixture of the two diastereomers of 5a.
It should be mentioned that the treatment of compound 5c (cis/
trans¼96:4) underwent the conversion to 4c in 87% yield by
treatment with ethyl formate. This re-formylated 4c showed an
identical NMR spectrum to the original one and the diastereomeric
ratio was found to be 96:4. Thus, the present deprotection of the
formyl group occurred successfully with retaining the stereo-
chemistry of 4 in the azepine ring.
Entry
R
iPr
3
Yield (%)a
1
2
3
4
5
3a
3b
3c
3d
3e
85
80
53
81
48
cC6H11
Pr
C5H11
C6H13
a
Isolated yield.
The addition reaction completed within 2–4 h and corre-
sponding adducts 3 were isolated after the usual workup. For ex-
ample, the treatment of N-(4-pentenyl)formamide 2 with tBuOK in
THF with subsequent addition of 3-methyl-1-nitro-1-butene
resulted in the smooth formation of adduct 3a in 85% yield (entry 1).
Compound 3 contained rotational isomers due to the tertiary amide
unit. A variety of nitroalkenes were used in the reaction to give
a series of precursors for the INOC reaction.
Exposure of the precursors 3 to phenyl isocyanate under basic
conditions resulted in the smooth generation of nitrile oxide that
immediately attacked the internal alkene unit to give bicyclic iso-
xazoles 4 in a moderate yield (Scheme 2). The results are summa-
rized in Table 2.
The stereochemistry was determined by X-ray crystallographic
analysis. Compound 5a was converted to N-tosyl derivatives 6 by
the treatment with tosyl chloride in 64% yield (Scheme 3). Com-
pound 6 gave good crystals after recrystallization from CH2Cl2.
Crystallographic data for 6 unambiguously revealed cis-configura-
tion between the isopropyl group and the isoxazole ring.17
O
NO2
N
N
R
H
PhNCO, Et3N
THF, rt
R
N
O
OHC
O
N
OHC
N
TsCl, Et3N,
H
H
cis-4
3
CH2Cl2
O
N
HN
N
Ts
H
conc. HCl, EtOH
reflux, 30-36 h.
5a
R
6; 64%
HN
Scheme 3. Preparation of N-tosyl azepine 6.
cis-5
The present INOC reaction was performed in a one-pot manner
in combination with conjugate addition of formamides to nitro-
alkenes (Scheme 4). For example, nitroalkene 1a was added to
Scheme 2. INOC reaction to prepare azepines 4 and 5.
The yields of bicycloazepines 4 were in the range of 50–71%
(entries 1–5), although the reaction was performed under the usual
concentration (0.2 M); no high-dilution technique was required.
For example, precursor 3a underwent the INOC reaction to give
azepine 4a in 71% yield (entry 1). The NMR of 4a looked somewhat
complicated because of the existence of rotational isomers due to
the tertiary formamide unit. Since VT NMR for compounds 4 never
showed simple spectra, we checked GC analysis for their purities
and diastereomeric ratios. To our surprise, one of the diastereomers
of 4 was formed selectively through the reaction, because the GC
analysis for the reaction mixture of 4 revealed that the di-
astereomeric ratio was generally high. In particular, the selectivity
reached as high as 95:5 when the R group was a primary alkyl
group (entries 3, 4, and 5). Thus, the present method provides
a useful preparation of azepines from nitroalkenes in a stereo-
selective manner.
t
a mixture of formamide 2 and BuOK in THF. The addition was
completed in 10 min and the reaction was quenched by the addi-
tion of AcOH. Then phenyl isocyanate and Et3N were added to the
reaction mixture, which was allowed to heat to the refluxing
temperature. After the usual workup and purification through flash
column chromatography, 4a was isolated in 41% yield. Thus, the
azepine ring was prepared in one step from nitroalkene and
formamides. It should be noted that the addition of AcOH was
essential to progress the INOC reaction. Without AcOH addition, no
desired INOC adducts were observed in the reaction mixture.
NO2
O
t
N
1) BuOK
CHO
HN
H
THF, rt, 10 min
2) AcOH (1 eq)
then PhNCO,
N
Table 2
OHC
4a; 41%
Scheme 4. One-pot preparation of azepine 4a.
cat. Et3N, reflux
INOC reaction of b-nitroamides 3
Entry
R
iPr
4
Yield (%)a
cis/transb
5
Yield (%)a
cis/transb
1
2
3
4
5
4a
4b
4c
4d
4e
71
65
50
52
59
89/11
90/10
95/5
95/5
96/4
5a
5b
5c
5d
5e
74
88
79
89
94
87/13
69/31
96/4
90/10
93/7
cC6H11
Pr
C5H11
C6H13
We assume that the present azepine synthesis proceeded
through a mechanism similar to the five- and six-membered ring
formation.15 Scheme 5 depicts a plausible mechanism in which two
transition states A and B generate trans-4 and cis-4, respectively.
a
Isolated yields.
Determined by GC analysis.
b

A. Kamimura et al. / Tetrahedron 64 (2008) 11081–11085
11083
Transition state B should be favorable because of less steric hin-
drance from the interaction between R and the formyl group.
115.5, 116.0, 137.0, 137.5, 163.7, 163.9. Anal. Calcd for C11H20N2O3: C,
57.87; H, 8.83; N, 12.27. Found: C, 57.50; H, 8.75; N, 11.94.
3.2.1. 1-Cyclohexyl-2-nitro-1-[(N-formyl-N-4-
H
O
pentenyl)amino]ethane [3b]
O
R
N
N
R
Yellow oil. 1H NMR (CDCl3)
d 0.88–1.80 (m, 11H), 1.45–1.89 (m,
N
C
O
C
H
N
OHC
OHC
4H), 2.02–2.13 (m, 2H), 2.92–3.32 (m, 2H), 3.69 (dt, 0.5H, J¼3.7,
10.0 Hz), 3.89 (dt, 0.5H, J¼4.3, 10.6 Hz), 4.49–4.70 (m, 2H), 4.99–
5.16 (m, 2H), 5.68–5.88 (m, 1H), 8.01 (s, 0.5H), 8.10 (s, 0.5H). 13C
H
B
A
NMR (CDCl3) d 25.5, 25.7, 25.8, 25.9, 27.5, 28.7, 30.1, 30.5, 30.6, 31.4,
O
37.7, 41.3, 49.4, 61.8, 62.4, 75.6, 75.7, 115.6, 116.1, 137.1, 137.6, 163.7,
163.9. Anal. Calcd for C14H24N2O3: C, 62.66; H, 9.01; N,10.44. Found:
C, 62.32; H, 9.02; N, 10.23.
N
N
H
H
R
R
N
N
OHC
cis-4
OHC
trans-4
3.2.2. 2-(N-Formyl-N-4-pentenyl)amino-1-nitropentane [3c]
Yellowoil.1HNMR(CDCl3)
d
0.96 (t, 3H, J¼7.1 Hz),1.26–1.94 (m, 4H),
2.04–2.10 (m, 2H), 3.00–3.31 (m, 2H), 4.01–4.29 (m,1H), 4.39–4.59 (m,
Scheme 5. Plausible origin of stereoselectivity.
2H), 4.98–5.15 (m, 2H), 5.69–5.88 (m,1H), 8.07 (s,1H).13C NMR (CDCl3)
Thus, we have succeeded in forming stereoselective aza-
heterocyclic compounds from the conjugate adducts of nitroalkene
and formamides. High stereoselectivity was observed in the for-
mation of bicyclic azepines. These two-step reactions were per-
formed in one-pot to achieve facile stereoselective formation of
azepine rings. The treatment of the adducts under acidic conditions
resulted in the smooth removal of the formyl group with minimum
loss of the diastereomeric ratio. As nitroalkenes and formamides
are readily available, the present method can be a useful in the
formation of aza-heterocyclic compounds in a stereoselective
manner. Further studies on this issue are now under way in our
laboratory.
d
13.6, 13.9, 19.3, 19.9, 28.0, 29.1, 30.7, 31.6, 32.3, 32.5, 40.7, 48.9, 56.2,
56.9, 76.5, 76.9, 116.0, 116.6, 137.1, 137.7, 163.6, 164.1. Anal. Calcd for
C11H20N2O3: C, 57.87; H, 8.83; N,12.27. Found: C, 57.47; H, 8.74; N,11.87.
3.2.3. 2-(N-Formyl-N-4-pentenyl)amino-1-nitroheptane [3d]
Yellow oil. 1H NMR (CDCl3)
d 0.90 (m, 3H), 1.20–1.40 (m, 6H),
1.52–1.74 (m, 2H), 2.05–2.13 (m, 2H), 3.00–3.31 (m, 2H), 4.00–4.27
(m, 1H), 4.40–4.60 (m, 2H), 5.00–5.18 (m, 2H), 5.70–5.88 (m, 1H),
8.08 (s, 1H). 13C NMR (CDCl3)
d 13.9, 22.4, 25.5, 26.1, 27.8, 28.9, 30.0,
30.1, 30.5, 31.1, 31.4, 40.4, 48.4, 55.9, 57.0, 76.3, 77.2, 115.6, 116.2,
137.0, 137.5, 163.5, 163.9. Anal. Calcd for C13H24N2O3: C, 60.91; H,
9.44; N, 10.93. Found: C, 61.01; H, 9.45; N, 10.69.
3. Experimental section
3.1. General
3.2.4. 2-(N-Formyl-N-4-pentenyl)amino-1-nitrooctane [3e]
Yellow oil. 1H NMR (CDCl3)
d 0.81–0.96 (m, 5H), 1.16–1.42 (m,
8H), 1.64–1.98 (m, 2H), 2.07–2.13 (m, 2H), 2.99–3.31 (m, 2H), 4.01–
4.27 (m, 1H), 4.39–4.59 (m, 1H), 5.00–5.15 (m, 2H), 5.69–5.88 (m,
All 1H and 13C NMR spectra were recorded on JEOL GSX-270
(270 MHz for 1H and 67.5 MHz for 13C) spectrometer. All the re-
actions in this paper were performed under nitrogen atmosphere
unless otherwise mentioned. CH2Cl2 was dried over CaH2, and
distilled under nitrogen before use. High resolution mass spectra
(HRMS) were measured at Integrated Center for Sciences, Ehime
University, Matsuyama, Japan.
1H), 8.07 (m, 1H). 13C NMR (CDCl3)
d 14.1, 22.6, 25.9, 26.6, 27.9, 28.8,
29.0, 29.1, 30.2, 30.4, 30.6, 31.5, 31.6, 31.7, 40.6, 48.8, 56.3, 57.1, 76.5,
77.4, 115.9, 116.5, 137.1, 137.6, 163.6, 164.0. HRMS (EIþ M) m/z
270.1942. Calcd for C14H26N2O3 270.1943.
3.3. INOC reaction of 3, preparation of cis-7-formyl-8-
isopropyl-3a,4,5,6-tetrahydro-3H,8H-isoxazolo[3,4-c]
azepine 4a. General procedure
3.2. Conjugate addition of N-4-pentenylformamide to
3-methyl-1-nitro-1-butene 3a. General procedure
Under a nitrogen atmosphere, phenyl isocyanate (0.609 mL,
5.62 mmol) was added to a solution of 3a (0.5129 g, 2.25 mmol) and
Et3N (0.946 mL, 6.74 mmol) in dry THF (15 mL) and the resulting
solution was heated at the refluxing temperature for 1.5 h. Diphenyl
urea precipitated gradually. After disappearance of 3a in TLC de-
tection, the reaction mixture was cooled and filtered. The filtrate
was then concentrated in vacuo and the residue was subjected to
flash chromatography (silica gel, hexane/EtOAc¼5:1, 3:1, 1:1 then
1:2 in v/v) to give 4a in 71% yield (0.3342 g, 1.59 mmol). The
compound consisted of about 1:1 mixture of rotational isomers.
t
Under a nitrogen atmosphere, BuOK (1.35 g, 12.0 mmol) was
added to a solution of formamide (1.132 g, 10.0 mmol) in dry THF
(30 mL) at 0 ꢀC. The solution was stirred for an additional 1 h. After
cooling to ꢁ50 ꢀC, nitroalkene (1.38 g, 12.0 mmol) was added to the
solution and the reaction mixture was stirred for 3 h at the same
temperature. Saturated NH4Cl(aq) (25 mL) was added to the re-
action mixture and THF was removed using a rotary evaporator.
Water (5 mL) was added to the mixture and the resulting aqueous
solution was extracted with EtOAc (3ꢂ50 mL). The organic phase
was combined and dried over Na2SO4. After filtration, EtOAc was
removed from the filtrate to give crude adduct 3a, which was pu-
rified through flash chromatography (silica gel, hexane/EtOAc¼7:1
then 3:1 in v/v) to give pure 3a in oil in 85% yield (1.937 g,
8.49 mmol). The compound consisted of about 1:1 mixture of ro-
Colorless oil. 1H NMR (CDCl3)
d
0.95 (d, 3H, J¼7.0 Hz), 1.18 (d, 3H,
J¼6.7 Hz), 1.44–1.79 (m, 4H), 2.37–2.63 (m, 2H), 2.91–3.08 (m, 1H),
4.05 (d, 1H, J¼6.3 Hz), 4.07–4.15 (m, 1H), 4.19–4.37 (m, 2H), 8.12 (s,
0.5H), 8.28 (s, 0.5H). 13C NMR (CDCl3)
d 18.7, 18.8, 19.0, 19.3, 20.7,
24.1, 26.2, 26.6, 27.1, 29.4, 30.1, 31.5, 38.5, 42.2, 44.7, 45.9, 49.8, 50.0,
54.3, 54.9, 62.1, 62.4, 74.5, 75.0, 75.6, 75.8, 160.2, 162.2, 162.3, 163.1.
HRMS (EIþ Mþ) m/z 210.1369. Calcd for C11H18N2O2 210.1368.
tational isomers. Yellow oil. 1H NMR (CDCl3)
d 0.94–0.99 (m, 3H),
1.00–1.07 (m, 3H), 1.81–1.98 (m, 0.5H), 2.09 (m, 2H), 2.41–2.51 (m,
0.5H), 2.94–3.35 (m, 2H), 3.65 (dt, J¼3.8, 9.7 Hz, 0.5H), 3.81 (dt,
J¼4.3, 10.1 Hz, 0.5H), 4.51–4.68 (m, 2H), 4.99–5.11 (m, 2H), 5.69–
3.3.1. cis-7-Formyl-8-cyclohexyl-3b,4,5,6-tetrahydro-3H,
8H-isoxazolo[3,4-c]azepine [4b]
5.75 (m, 1H), 8.04 (s, 0.5H), 8.11 (s, 0.5H). 13C NMR (CDCl3)
d
19.6,
Yellow oil. 1H NMR (CDCl3)
d
0.84–1.95 (m, 10H), 2.00–2.27 (m,
19.8, 19.9, 27.4, 28.6, 28.7, 28.8, 30.5, 31.3, 41.2, 49.0, 62.6, 63.5, 75.7,
1H), 2.54 (t, 1H, J¼8.2 Hz), 2.87–3.11 (m, 1H), 3.99–4.17 (m, 2H),

11084
A. Kamimura et al. / Tetrahedron 64 (2008) 11081–11085
4.17–4.59 (m, 2H), 8.09 (s, 0.5H), 8.27 (s, 0.5H). 13C NMR (CDCl3)
23.9, 25.1, 25.2, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.6, 27.2, 28.0,
30.9, 40.1, 48.4, 51.0, 60.6, 74.0, 164.3. HRMS (EIþ M) m/z 222.1731.
Calcd for C13H22N2O 222.1732.
d
28.4, 28.7, 29.1, 29.3, 29.7, 30.4, 31.3, 32.3, 35.1, 35.6, 38.3, 39.4, 42.2,
46.0, 46.8, 49.7, 50.0, 52.7, 54.2, 60.8, 61.3, 74.4, 74.8, 75.4, 75.5,
159.7, 162.0, 162.1, 162.9, 163.5. HRMS (EIþ M) m/z 250.1682. Calcd
for C14H22N2O2 250.1681.
3.4.2. cis-8-Propyl-3c,4,5,6,7,8-hexahydro-3H-isoxazolo-
[3,4-c]azepine [5c]
Yellow oil. 1H NMR (CDCl3)
d
0.95 (t, 3H, J¼6.3 Hz), 1.46–2.00 (m,
9H), 2.79–2.92 (m, 2H), 3.41 (dt, 1H, J¼6.6, 17.8 Hz), 3.49 (dd, 1H,
3.3.2. cis-7-Formyl-8-propyl-3c,4,5,6-tetrahydro-3H,
8H-isoxazolo[3,4-c]azepine [4c]
J¼5.4, 8.7 Hz), 3.92 (t, 1H, J¼8.2 Hz), 4.41 (dd, 1H, J¼8.1, 9.9 Hz). 13C
NMR (CDCl3) d 13.9, 19.5, 29.7, 30.1, 34.5, 45.7, 50.6, 55.0, 74.8, 166.2.
Yellow oil. 1H NMR (CDCl3)
d
0.95 (t, 3H, J¼6.7 Hz), 1.16–1.97 (m,
HRMS (FABþ Mþ1) m/z 183.1499. Calcd for C10H19N2O 183.1497.
6H), 2.10–2.27 (m, 2H), 2.53 (t, 1H, J¼11. 4 Hz), 2.89–3.15 (m, 2H),
4.00–4.12 (m, 2H), 4.20–4.42 (m, 2H), 8.12 (s, 0.5H), 8.26 (s, 0.5H).
3.4.3. cis-8-Pentyl-3d,4,5,6,7,8-hexahydro-3H-isoxazolo-
[3,4-c]azepine [5d]
13C NMR (CDCl3)
d
13.1, 13.3, 18.4, 18.5, 24.1, 26.3, 27.9, 29.2, 30.2,
31.8, 32.2, 32.3, 32.4, 32.8, 38.6, 39.9, 43.9, 46.9, 47.0, 48.8, 49.3,
49.5, 55.5, 56.9, 56.0, 74.5, 74.8, 75.6, 75.8, 161.0, 162.4, 163.3, 163.4,
163.6. HRMS (EIþ M) m/z 210.1369. Calcd for C11H18N2O2 210.1368.
Yellow oil. 1H NMR (CDCl3)
d
0.89 (t, 3H, J¼6.8 Hz), 1.25–1.99 (m,
13H), 2.81–2.91 (m, 2H), 3.38–3.44 (m, 1H), 3.47 (dd, 1H, J¼5.4,
8.7 Hz), 3.91 (t, 1H, J¼8.2 Hz), 4.41 (dd, 1H, J¼8.0, 9.9 Hz). 13C NMR
(CDCl3) d 13.9, 22.5, 26.0, 29.5, 30.0, 31.3, 32.3, 45.6, 50.5, 55.3, 74.8,
3.3.3. cis-7-Formyl-8-pentyl-3d,4,5,6-tetrahydro-3H,
166.0. HRMS (EIþ M) m/z 210.1733. Calcd for C12H22N2O 210.1732.
8H-isoxazolo[3,4-c]azepine [4d]
Yellow oil. 1H NMR (CDCl3)
d
0.81–0.95 (m, 3H), 1.14–1.97 (m,
3.4.4. cis-8-Hexyl-3e,4,5,6,7,8-hexahydro-3H-isoxazolo-
10H), 2.12–2.28 (m, 2H), 2.52 (t, 1H, J¼11. 4 Hz), 2.89–3.15 (m, 2H),
[3,4-c]azepine [5e]
4.04–4.20 (m, 2H), 4.20–4.40 (m, 2H), 8.12 (s, 0.5H), 8.26 (s, 0.5H).
Yellow oil. 1H NMR (CDCl3)
d
0.87 (t, 3H, J¼6.0 Hz), 1.25–2.00 (m,
13C NMR (CDCl3)
d
13.6, 13.7, 22.1, 24.1, 24.9, 25.0, 26.4, 28.0, 29.3,
15H), 2.81–2.92 (m, 2H), 3.38–3.43 (m, 1H), 3.47 (dd, 1H, J¼5.4,
30.2, 30.3, 30.4, 30.9, 31.1, 31.9, 32.9, 38.6, 40.0, 43.9, 47.1, 49.2, 49.4,
49.5, 55.8, 56.4, 74.6, 74.8, 75.7, 75.9, 161.0, 162.5, 163.3, 163.4, 163.6.
HRMS (EIþ M) m/z 238.1682. Calcd for C13H22N2O2 238.1681.
8.7 Hz), 3.91 (t, 1H, J¼8.2 Hz), 4.41 (dd, 1H, J¼8.1, 9.9 Hz). 13C NMR
(CDCl3) d 14.0, 22.6, 26.3, 29.2, 29.6, 30.1, 32.4, 32.8, 45.7, 50.6, 55.4,
74.8, 166.1. HRMS (EIþ M) m/z 224.1890. Calcd for C13H24N2O
224.1889.
3.3.4. cis-7-Formyl-8-hexyl-3e,4,5,6-tetrahydro-3H,
8H-isoxazolo[3,4-c]azepine [4e]
3.5. One-pot procedure for the preparation of 4a
Yellow oil. 1H NMR (CDCl3)
d 0.76–0.97 (m, 3H), 1.15–2.01 (m,
t
12H), 2.16–2.25 (m, 2H), 2.52 (t, 1H, J¼11. 3 Hz), 2.91–3.13 (m, 2H),
Under a nitrogen atmosphere, BuOK (0.155 g, 1.38 mmol) was
4.05–4.20 (m, 2H), 4.20–4.39 (m, 2H), 8.12 (s, 0.5H), 8.26 (s, 0.5H).
added to a solution of formamide (0.1409 g, 0.1.25 mmol) in dry THF
(7 mL) at 0 ꢀC. The solution was stirred for an additional 1 h. After
cooling to ꢁ50 ꢀC, nitroalkene (0.173 g, 1.50 mmol) was added to
the solution and the reaction mixture was stirred for 2 h at the
same temperature. AcOH (0.079 mL, 1.38 mmol) was added to the
reaction mixture, which was then allowed to warm to room tem-
perature. Et3N (0.53 mL, 3.75 mmol) and phenyl isocyanate
(0.339 mL, 3.13 mmol) were added to the mixture and the reaction
mixture was heated at the refluxing temperature for 15 h. After
cooling to room temperature, the precipitate was removed by fil-
tration. The filtrate was concentrated and the residue was subjected
to flash chromatography (silica gel/hexane/EtOAc, 3:1 then 1:2 v/v)
to give 4a in 41% yield (0.1062 g). GC and NMR data were identical
to the authentic sample of 4a.
13C NMR (CDCl3)
d 13.6, 13.7, 22.2, 22.3, 24.2, 25.2, 25.3, 26.4, 28.0,
28.3, 28.4, 28.6, 29.4, 30.3, 30.4, 31.2, 31.3, 31.4, 31.9, 32.9, 38.7, 40.0,
44.0, 47.1, 49.2, 49.4, 49.6, 55.9, 56.4, 74.8, 75.7, 75.9, 161.1, 162.5,
163.3, 163.4, 163.7. HRMS (EIþ M) m/z 252.1837. Calcd for
C14H24N2O2 252.1838.
3.4. Removal of the formyl group. Preparation of cis-8-
isopropyl-3a,4,5,6,7,8-hexahydro-3H-isoxazolo[3,4-c]
azepine 5a. General procedure
A solution of 4a (0.1435 g, 0.637 mmol) in ethanol (6 mL) and
concd. HCl (1 mL) was heated gently at the refluxing temperature
(bath temperature was 90 ꢀC) for 30 h. The reaction was monitored
by GC analysis. After completion of the reaction, NaHCO3(aq) (5 mL)
was added to neutralized the solution, and the mixture was
extracted with EtOAc (3ꢂ50 mL). The organic phase was combined
and dried over Na2SO4. After filtration, the solvent was removed
using a rotary evaporator to give crude product, which was purified
through flash column chromatography (silica gel/hexane/EtOAc,
3:1 then 1:2 v/v) to give 5a in 74% yield (0.0859 g, 0.472 mmol).
3.6. Reformylation of 5c
A solution of 5c (ds ratio was 94:6, 0.0206 mg, 0.113 mmol) in
ethyl formate (6 mL) was heated to refluxing temperature for 6 h.
The reaction mixture was concentrated by rotary evaporator and
the residue was purified by flash chromatography (silica gel/hex-
ane/EtOAc, 3:1 then 1:2 v/v) to give 4c in 87% yield (0.0207 g). The
NMR data were identical to the authentic sample of 4c and GC
analysis showed the diastereomeric ratio was 94:6.
Yellow oil. 1H NMR (CDCl3)
d
1.19 (d, 3H, J¼7.1 Hz), 1.23 (d, 3H,
J¼7.0 Hz), 1.44–1.73 (m, 5H), 2.15–2.30 (m, 1H), 2.73–2.86 (m, 1H),
2.99 (d, 1H, J¼7.2 Hz), 3.09 (ddd, 1H, J¼9.7, 10.7, 13.1 Hz), 3.36–3.49
(m, 1H), 3.83 (dd, 1H, J¼8.0, 10.3 Hz), 4.46 (dd, 1H, J¼8.0, 10.2 Hz).
3.7. Preparation of cis-8-isopropyl-7-(p-toluenesulfonyl)-
3a,4,5,6,7,8-hexahydro-3H-isoxazolo[3,4-c]azepine 6
13C NMR (CDCl3)
d 18.6, 19.0, 28.4, 28.8, 30.7, 48.8, 51.2, 61.8, 74.2,
164.6. HRMS (EIþ M) m/z 182.1417. Calcd for C10H18N2O 182.1419.
To a solution of 5a (0.1071 g, 0.588 mmol) in CH2Cl2 (10 mL)
Et3N (0.164 mL, 1.175 mmol) and DMAP (0.05 g) were added. Then
TsCl (0.168 g, 0.880 mmol) was added to the solution and the re-
action mixture was stirred for 10 h at 0 ꢀC. Water (20 mL) was
added to the reaction mixture, which was extracted with CH2Cl2
(3ꢂ30 mL). The organic phase was combined and dried over
Na2SO4. After filtration, the filtrate was concentrated in vacuo and
3.4.1. cis-8-Cyclohexyl-3b,4,5,6,7,8-hexahydro-3H-isoxazolo-
[3,4-c]azepine [5b]
Yellow oil. 1H NMR (CDCl3)
d 1.07–1.39 (m, 4H), 1.50–1.80 (m,
11H), 2.05 (m, 1H), 2.71–2.80 (m, 1H), 3.05 (d, 1H, J¼7.0 Hz), 3.04–
3.10 (m, 1H), 3.37–3.47 (m, 1H), 3.83 (dd, 1H, J¼8.0, 10.2 Hz), 4.45
(dd, 1H, J¼8.0, 10.2 Hz). 13C NMR (CDCl3)
d 26.2, 26.5, 28.7, 28.9,

A. Kamimura et al. / Tetrahedron 64 (2008) 11081–11085
11085
Chicchio, U.; Corsaro, A.; Librando, V.; Rescifina, A.; Romeo, R.; Romeo, G.
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the residue was subjected to flash chromatography (silica gel/
hexane–EtOAc 10:1 then 5:1 v/v) to give 6 in 64% yield (0.126 g).
White solid. Mp 133 ꢀC. 1H NMR (CDCl3)
d
0.73 (d, 3H, J¼6.7 Hz),1.10
(d, 3H, J¼6.6 Hz), 1.39–1.58 (m, 1H), 1.66–1.91 (m, 3H), 1.99–2.18 (m,
1H), 2.43 (s, 3H), 2.90–3.12 (m, 2H), 3.75 (dd, 1H, J¼8.1, 9.9 Hz), 4.05
(d,1H, J¼15.6 Hz), 4.34 (dd,1H, J¼8.0, 9.6 Hz), 4.44 (d,1H, J¼9.2 Hz),
7.30 (d, 2H, J¼7.9 Hz), 7.72 (d, 2H, J¼8.3 Hz). 13C NMR (CDCl3)
d 19.9,
20.6, 21.8, 28.9, 30.0, 31.0, 45.5, 51.5, 61.0, 75.1, 127.7, 130.1, 138.6,
144.0, 163.6. Anal. Calcd for C17H24N2O3S: C, 60.69; H, 7.19; N, 8.32.
Found: C, 60.30; H, 7.06; N, 8.21.
References and notes
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17. Crystallographic data (excluding structure factors) for the structures cis-6 have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 687340. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].