Electronic Effects on the cis/trans Selectivity in Formation of Isoxazolidine-Fused Eight-Membered Ring via an Intramolecular Nitrone-Alkene Cycloaddition

Article abstract of DOI:10.1007/s10593-016-1938-z

[Figure not available: see fulltext.] An intramolecular nitrone-alkene cycloaddition involving in situ generated nitrones demonstrated reaction profiles different from those previously reported for pyrimidine system. Tuning the electron density of the ben

Full text of DOI:10.1007/s10593-016-1938-z

DOI 10.1007/s10593-016-1938-z
Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
Electronic effects on the cis/trans selectivity in formation
of isoxazolidine-fused eight-membered ring via
an intramolecular nitrone-alkene cycloaddition
1
1
1
1
Jinbao Xiang , Tong Zhu , Qun Dang , Xu Bai *
1
The Center for Combinatorial Chemistry and Drug Discovery of Jilin University,
The School of Pharmaceutical Sciences and The College of Chemistry, Jilin University,
1
266 Fujin Road, Changchun, Jilin 130021, P. R. China; е-mail: xbai@jlu.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
016, 52(8), 601–608
Submitted July 8, 2016
Accepted August 15, 2016
2
An intramolecular nitrone-alkene cycloaddition involving in situ generated nitrones demonstrated reaction profiles different from those
previously reported for pyrimidine system. Tuning the electron density of the benzene ring had a significant effect on cis/trans selectivi-
ty. These reactions were useful for the synthesis of novel tricyclic hexahydrobenzo[b]isoxazolo[3,4-f][1,4]diazocin-4(1H)-ones and hexa-
hydroisoxazolo[3,4-f]pyrido[3,2-b][1,4]diazocin-4(1H)-one under mild reaction conditions in good yields.
Keywords: isoxazolidines, tricyclic compounds, cis/trans selectivity, eight-membered rings, electronic effects, fused-ring systems,
nitrone-alkene cycloaddition.
Eight-membered heterocycles, which often occur in
various natural products and pharmacologically active
substances, have attracted considerable attention because of
their unusual structural features and interesting biological
1
effects. For example, balasubramide (1) was isolated from
Clausena indica that grows in the central mountain rain-
2
forests of Sri Lanka. (–)-Heliannuol A (2) was isolated
from aqueous extracts of fresh sunflower leaves (Helianthus
annuus L. var. SH-222) and exhibits strong allelopathic
activity.3 Benzolactam-V8 (3) is a potent activator of
4
protein kinase C. Nefopam (4) is a centrally-acting non-
5
opioid analgesic drug. Buflavine (5) possesses interesting
6
adrenolytic and antiserotonin activities. Pyrimido[4,5-b]-
[
1,5]oxazocine derivative 6 has been observed to be
7
a neurokinin-1 (NK ) receptor antagonist (Fig. 1).
1
1
,3-Dipolar cycloadditions of nitrones are powerful
synthetic methodologies and have often been utilized in the
synthesis of natural products and biologically active
molecules. The intramolecular 1,3-dipolar cycloaddition
8
between nitrones and alkenes can form two new rings
simultaneously, providing direct access to fused or bridged
polycyclic isoxazolidines of considerable complexity with
high levels of regio- and stereocontrol.8 Thus far, the
intramolecular nitrone-alkene cycloaddition reaction have
been successfully used for the construction of isoxazoli-
,9
Figure 1. Natural and synthetic examples of 8-membered heterocycles.
0
009-3122/16/52(8)-0601©2016 Springer Science+Business Media New York
601

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
Scheme 1
Scheme 2
dines fused with 4- to 7-membered rings.10 However, few
examples have been reported where the synthesis of
isoxazolidines fused with 8-membered rings has been achieved
by intramolecular nitrone-alkene cycloaddition reactions.11
Recently, we communicated an intramolecular nitrone-
alkene cycloaddition in pyrimidine derivatives leading to
a novel cis-fused tricyclic compound containing an
Several key precursors 12a–c were prepared in 37–66%
overall yields from compounds 9a–c as depicted in
Scheme 3. Treatment of derivatives 9a–c,e with 2-(benzyl-
amino)ethan-1-ol followed by reduction yielded com-
pounds 10a–c,e. Compound 10d was obtained by reacting
nitroaniline 9d with 2-(benzylamino)ethan-1-ol. Reductive
amination of compounds 10a–c resulted in substituted
amines 11a–c. Direct acylation of compounds 11a–c
afforded products 12a–c. However, a direct acylation of
compound 11d proved to be problematic. The selective
protection of the hydroxyl group in compounds 11d,e with
TMSCl, subsequent acylation of the amino group with
acryloyl chloride and TFA removal of TMS gave com-
pounds 12d,e.
Oxidation of compounds 12a–c under the Parikh–Doering
conditions cleanly generated the respective aldehydes 7a–c,
which were used immediately without further purification
(Table 1). Initially, the cyclization reaction of crude
aldehyde 7a with N-methylhydroxylamine hydrochloride
was investigated under our previously reported reaction
8
-membered ring and isoxazolidine system (Scheme 1).12 It
is worth noting that the desired tricyclic product was not
obtained when N-allylamine analog was used. The results
revealed that the electronic effects seem to be important for
enhanced reactivity. Although the preliminary scope of the
intramolecular nitrone-alkene cycloaddition was studied in
the pyrimidine system, the electronic effects of other
aromatic rings remained to be investigated. During our
studies, we noticed that benzene derivatives demonstrated
reaction profiles different from those of the pyrimidine
system, and the tuning of electron density in the benzene ring
had a significant effect on the cis/trans selectivity (Scheme 2).
Herein, the details of these studies are presented.
12
Scheme 3
Table 1. Synthesis of benzo[b]isoxazolo[3,4-f][1,4]diazocin-4(1H)-ones 8*
Entry
X
R
Time, h
cis-8 isomer (Yield, %)
trans-8 isomer (Yield, %)
cis-8 : trans-8 ratio
1
2
3
4
5
CH
CH
CH
CH
N
CO
2
Me
10
24
28
8
a (62)
b (39)
c (20)
d (71)
e (65)
a (5)
b (28)
c (35)
d (0)
93:7
58:42
36:64
100:0
100:0
H
OMe
NO
H
2
3
e (0)
*
Overall yield (three steps) from compound 12 and isolated using flash chromatography.
6
02

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
Figure 2. X-ray crystallography data for compounds cis-8a and trans-8a with atoms represented by thermal vibration ellipsoids of 30%
probability.
conditions using NaOAc in CH
2
Cl
2
, giving 62% isolated
profiles different from those previously reported for
pyrimidine substrates, and the tuning of electron density in
the benzene ring had a significant effect on the cis/trans
selectivity of these cycloaddition reactions.
yield of ester cis-8a (J3a,11a = 8.4 Hz) and 5% isolated yield
of ester trans-8a (J3a,11a = 6.9 Hz) (entry 1). This result was
quite different from the previously reported case when only
cis-isomer was obtained from analogous pyrimidine
derivative. To unambiguously determine the configuration
of both cycloadducts, X-ray crystallographic analyses of
compounds cis-8a and trans-8a were performed (Fig. 2).
The electronic effects on the cis/trans selectivity were
further explored by using benzene derivatives with
substituents of different electronic profiles or a pyridine
derivative, and the results are summarized in Table 1.
Experimental
1H and 13C NMR data were obtained on a Varian
Mercury 300 NMR spectrometer (300 and 75 MHz,
respectively) with TMS as internal standard and CDCl as
3
solvent unless otherwise stated. HRMS analysis was
performed on an Agilent 1290-micrOTOF-Q II mass
spectrometer. Melting points were determined with a
Beijing Keyi Electro-Optical Factory XT5 melting point
apparatus and are uncorrected. Dichloromethane was dried
As shown in Table 1, good overall yields (55–71%) of
the desired products 8 were obtained for the three reaction
steps (oxidation of alcohols to aldehydes, formation of
nitrones, and cycloaddition). The reaction was sensitive to
electronic factors of the benzene ring substituents. The
reaction proceeded faster when electron-withdrawing group
was attached to benzene ring (entries 1 and 4 vs entries 2
and 3). It is noteworthy that tuning the electron density of
the benzene ring had a significant effect on the cis/trans
selectivity. The presence of an electron-withdrawing group
favored the exo adducts cis-8 (entries 4 and 1), while an
electron-donating group favored the endo adducts trans-8
over CaH and distilled prior to use. DMSO was dried over
2
4 Å molecular sieves. All other commercial reagents were
used as received without additional purification.
Methyl 3-amino-4-[benzyl(2-hydroxyethyl)amino]-
benzoate (10a). Anhydrous K
2
CO (8.292 g, 60 mmol)
3
was added to a stirred solution of methyl 4-fluoro-3-nitro-
OH
benzoate (9a) (3.983 g, 20 mmol) and BnNH(CH
)
2 2
(4.536 g, 30 mmol) in THF (20 ml). The resulting solution
was stirred for 5 h at 60°C. The precipitate was collected
by filtration. The resulting clear solution was concentrated
(
entry 3), which indicated that decreasing the electron
in vacuo and CH
layer was washed with water, dried over MgSO
Cl
2 2
(300 ml) was added. The organic
density of the aromatic ring leads to a higher amount of the
exo diastereomer being formed. As expected, only the
product cis-8e was obtained in 65% yield when precursor
4
, and
concentrated in vacuo. Purification by flash chromato-
graphy (petroleum ether–EtOAc, 4:1 to 1:1 v/v) afforded
methyl 4-(benzyl(2-hydroxyethyl)amino)-3-nitrobenzoate
(6.440 g), which was dissolved in EtOH (150 ml). The
resulting solution was hydrogenated over Pd/C catalyst
(1.288 g, 10% w/w) by stirring for 2 h under a hydrogen
atmosphere (balloon). The Pd/C catalyst was then filtered
off. The resulting clear solution was concentrated in vacuo.
Purification by flash chromatography (petroleum ether–
EtOAc, 1:1 to 1:5 v/v) afforded the desired product 10a.
1
2e was used (entry 5). These results are in line with those
previously reported for the intermolecular nitrone-alkene
cycloaddition.13 Minor variations in the electronic
properties of dipolarophiles led to important changes in the
ratio of the cis/trans isomers formed, possibly through
secondary orbital interactions that may occur in the
transition state.8
g,13c
In conclusion, novel tricyclic isoxazolidine-fused eight-
membered rings were successfully constructed via an
intramolecular nitrone-alkene cycloaddition. The benzene
derivatives used as substrates demonstrated reaction
1
Yield 4.866 g (81%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 3.16 (2H, t, J = 5.4, CH
2
OH); 3.57 (2H, t,
); 4.18 (2H, s,
J = 5.4, NCH
2
CH
2
OH); 3.87 (3H, s, CH
3
6
03

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
PhCH
2
); 7.01–7.07 (1H, m, H Ar); 7.19–7.31 (5H, m,
(7.805 g, 50 mmol) in pyridine (5 ml, 62 mmol) was treated
by the addition of BnNH(CH OH (9.374 g, 62 mmol). The
resulting solution was stirred for 6 days at reflux. The
solvent was removed in vacuo and CH Cl (400 ml) was
added. The organic layer was washed with water, dried
1
3
H Ar); 7.38–7.42 (2H, m, H Ar). C NMR spectrum,
2 2
)
δ, ppm: 52.0; 55.3; 58.1; 59.9; 116.7; 120.3; 123.0; 126.9;
1
27.4; 128.4; 128.9; 137.8; 141.2; 142.8; 167.3. Found, m/z:
2
2
+
3
01.1554 [M+H] . C17
H
21
N
2
O . Calculated, m/z: 301.1547.
3
2-[(2-Aminophenyl)(benzyl)amino]ethan-1-ol (10b).
over MgSO , and concentrated in vacuo. Purification by
4
A stirred solution of 1-fluoro-2-nitrobenzene (9b) (7.055 g,
0 mmol) in pyridine (5 ml, 62 mmol) was treated by the
addition of BnNH(CH OH (9.374 g, 62 mmol). The
resulting solution was stirred for 2 h at reflux. The solvent
was removed in vacuo and CH Cl (500 ml) was added.
The organic layer was washed with water, dried over
MgSO , and concentrated in vacuo. Purification by flash
flash chromatography (petroleum ether–EtOAc, 4:1 to 1:1
5
v/v) afforded the desired product 10d. Yield 7.155 g (50%),
1
2
)
2
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 3.21 (2H, t,
J = 5.4, CH
(2H, s, PhCH ); 7.01 (1H, d, J = 9.0, H Ar); 7.19–7.31 (5H,
13
2
OH); 3.67 (2H, t, J = 5.4, NCH
2
CH OH); 4.26
2
2
2
2
m, H Ar); 7.52–7.56 (2H, m, H Ar). C NMR spectrum,
4
δ, ppm: 54.5; 56.7; 59.8; 109.8; 113.5; 122.4; 127.5; 128.5;
chromatography (4:1 to 1:1 petroleum ether–EtOAc, v/v)
afforded 2-[benzyl(2-nitrophenyl)amino]ethan-1-ol (12.030 g),
which was dissolved in EtOH (250 ml). The resulting
solution was hydrogenated over Pd/C catalyst (2.406 g,
128.6; 137.4; 142.9; 143.0; 144.5. Found, m/z: 288.1351
+
[M+H] . C15
H
18
N
3
O . Calculated, m/z: 288.1343.
3
2-[(3-Aminopyridin-2-yl)(benzyl)amino]ethan-1-ol (10e).
A stirred solution of 2-chloro-3-nitropyridine (9e) (7.925 g,
1
0% w/w) by stirring for 2.5 h under a hydrogen
50 mmol) and BnNH(CH
2
)
2
OH (8.316 g, 55 mmol) in
N (8.36 ml,
60 mmol). The resulting solution was stirred for 4 h at
reflux. The solvent was removed in vacuo and CH Cl
(500 ml) was added. The organic layers were washed with
saturated NaHCO , dried over anhydrous MgSO , and
atmosphere (balloon). The Pd/C catalyst was filtered off.
The resulting clear solution was concentrated in vacuo.
Purification by flash chromatography (petroleum ether–
EtOAc, 1:1 to 1:5 v/v) afforded the desired product 10b.
n-BuOH (100 ml) was treated by the addition of Et
3
2
2
1
Yield 8.723 g (72%), pale-yellow oil. H NMR spectrum,
3
4
δ, ppm (J, Hz): 3.12 (2H, t, J = 5.4, CH
2
OH); 3.49 (2H, t,
); 6.71–6.79
concentrated in vacuo. Purification by flash chromato-
graphy (petroleum ether–EtOAc, 4:1 to 1:1 v/v) afforded
2-[benzyl(3-nitropyridin-2-yl)amino]ethan-1-ol (11.9 g),
which was dissolved in EtOH (300 ml). The resulting
solution was hydrogenated over 10% Pd/C catalyst (2.38 g)
and stirred for 3 h under a hydrogen atmosphere (balloon).
The Pd/C catalyst was filtered off. The resulting clear
solution was concentrated in vacuo. Purification by flash
chromatography (petroleum ether–EtOAc, 1:1 to 1:5 v/v)
afforded the desired product 10e. Yield 9.611 g (79%),
J = 5.4, NCH
2
CH
2
OH); 4.10 (2H, s, PhCH
2
(
2H, m, H Ar); 6.98 (1H, td, J = 7.5, J = 1.5, H Ar); 7.09
1H, dd, J = 7.8, J = 1.5, H Ar); 7.23–7.29 (5H, m, H Ar).
(
1
3
C NMR spectrum, δ, ppm: 56.6; 60.0; 60.2; 115.9; 119.2;
1
24.0; 126.0; 127.2; 128.4; 129.0; 136.8; 138.5; 143.6. Found,
+
m/z: 243.1498 [M+H] . C15
H
19
2
N O. Calculated, m/z:
2
43.1492.
2
-[(2-Amino-4-methoxyphenyl)(benzyl)amino]ethan-
1
2
6
-ol (10c). A stirred solution of 1-fluoro-4-methoxy-
1
-nitrobenzene (9c) (8.555 g, 50 mmol) in pyridine (5 ml,
2 mmol) was treated by the addition of BnNH(CH
white solid, mp 61–63°C. H NMR spectrum, δ, ppm (J, Hz):
2
)
2
OH
3.40 (2H, t, J = 4.8, CH OH); 3.74 (2H, t, J = 4.8,
2
(
9.374 g, 62 mmol). The resulting solution was stirred for
h at reflux. The solvent was removed in vacuo and
CH Cl (500 ml) was added. The organic layer was washed
with water, dried over MgSO , and concentrated in vacuo.
NCH
2
CH
2
OH); 4.37 (2H, s, PhCH ); 6.86 (1H, dd, J = 7.8,
2
4
J = 4.8, H Ar); 6.97 (1H, dd, J = 7.8, J = 1.5, H Ar); 7.24–
7.41 (5H, m, H Ar); 7.74 (1H, dd, J = 4.8, J = 1.5, H Ar).
2
2
1
3
4
C NMR spectrum, δ, ppm: 51.8; 52.8; 59.1; 119.8; 122.6;
Purification by flash chromatography (4:1 to 1:1 petroleum
ether–EtOAc, v/v) afforded 2-[benzyl(4-methoxy-2-nitro-
phenyl)amino]ethan-1-ol (12.990 g), which was dissolved
in EtOH (250 ml). The resulting solution was hydrogenated
over 10% Pd/C catalyst (2.598 g) by stirring for 3 h under a
hydrogen atmosphere (balloon). The Pd/C catalyst was
filtered off. The resulting clear solution was concentrated
in vacuo. Purification by flash chromatography (1:1 to 1:5
127.2; 127.6; 128.7; 136.4; 136.6; 138.6; 150.0. Found, m/z:
+
244.1452 [M+H] . C14
H
18
3
N O. Calculated, m/z: 244.1444.
Synthesis of compounds 11a–e (General method).
Sodium methoxide (6.482 g, 120 mmol) was added to a stirred
solution of the appropriate compound 10a–e (20 mmol) and
paraformaldehyde (3.6 g, 120 mmol) in MeOH (320 ml). The
resulting solution was stirred for 2 h at reflux. When the
solution was cooled to 0°C, NaBH (4.536 g, 120 mmol)
4
petroleum ether–EtOAc, v/v) afforded the desired product
was added portionwise to the mixture within 10 min. The
resulting solution was then stirred for 1 h at reflux. When
the solution was cooled to 0°C, the reaction mixture was
treated with saturated aqueous citric acid to adjust pH to 7.
The solvent was removed in vacuo and water (100 ml) was
1
1
0c. Yield 8.850 g (65%), pale-yellow oil. H NMR
spectrum, δ, ppm (J, Hz): 3.06 (2H, t, J = 5.4, CH
.45 (2H, t, J = 5.4, NCH CH OH); 3.74 (3H, s, CH ); 4.03
2H, s, PhCH ); 6.25 (1H, d, J = 2.7, H Ar); 6.33 (1H, dd,
2
OH);
3
2
2
3
(
2
J = 8.7, J = 2.7, H Ar); 7.01 (1H, d, J = 8.7, H Ar); 7.20–
added. Then the aqueous phase was extracted with CH
(3×100 ml). The combined CH Cl layer was dried over
anhydrous MgSO and concentrated in vacuo. Purification
Cl
2 2
1
3
7
5
1
.30 (5H, m, H Ar). C NMR spectrum, δ, ppm: 55.2;
2
2
7.1; 60.2; 60.6; 101.2; 104.3; 124.8; 127.1; 128.2; 129.0;
4
+
29.9; 138.7; 144.9; 157.8. Found, m/z: 273.1607 [M+H] .
by flash chromatography (petroleum ether–EtOAc, 1:1 to
1:5 v/v) afforded the desired product 11a–e.
Methyl 4-[benzyl(2-hydroxyethyl)amino]-3-(methyl-
amino)benzoate (11a). Yield 5.407 g (86%), pale-yellow
C
16
2
H
21
N
2
O . Calculated, m/z: 273.1598.
2
-[(2-Amino-4-nitrophenyl)(benzyl)amino]ethan-1-ol
(
10d). A stirred solution of 2-fluoro-5-nitroaniline (9d)
6
04

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
1
oil. H NMR spectrum, δ, ppm (J, Hz): 2.82 (3H, s, NCH
.11 (2H, t, J = 5.4, CH OH); 3.51–3.54 (2H, m,
NCH CH OH); 3.88 (3H, s, CO CH ); 4.11 (2H, s,
PhCH ); 7.01 (1H, d, J = 8.1, H Ar); 7.15–7.18 (2H, m,
H Ar); 7.20–7.29 (4H, m, H Ar); 7.36 (1H, dd, J = 8.1,
3
);
CH
2
Cl
2
(4×20 ml). The combined organic layers were dried
and concentrated in vacuo.
3
2
over anhydrous MgSO
4
2
2
2
3
Purification by flash chromatography (petroleum ether–
EtOAc, 3:1 to 1:4 v/v) afforded the desired product 12a–c .
Methyl 4-[benzyl(2-hydroxyethyl)amino]-3-(N-methyl-
acrylamido)benzoate (12a). Yield 884 mg (80%), pale-
2
13
J = 1.8, H Ar). C NMR spectrum, δ, ppm: 30.5; 51.9;
1
5
1
[
5.1; 58.2; 59.8; 110.9; 118.4; 122.2; 127.1; 127.3; 128.3;
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 3.23–3.30
28.8; 137.6; 140.8; 145.4; 167.7. Found, m/z: 315.1709
(2H, m, CH
NCH CH
PhCH
J = 16.8, J = 1.8, COCH=CH
2
OH); 3.35 (3H, s, NCH
3
); 3.67 (2H, t, J = 5.7,
3
+
M+H] . C18
H
23
N
2
O
3
. Calculated, m/z: 315.1703.
2
2
OH); 3.89 (3H, s, CO
2
CH ); 4.33–4.44 (2H, m,
2
-{Benzyl[2-(methylamino)phenyl]amino}ethan-1-ol
2
); 5.58 (1H, dd, J = 10.2, J = 2.1) and 6.46 (1H, dd,
1
(
11b). Yield 4.613 g (90%), pale-yellow oil. H NMR
); 3.09 (2H, t,
CH OH); 4.05
); 6.63 (1H, dd, J = 8.4, J = 1.5, H Ar); 6.73
2
); 6.12 (1H, dd, J = 16.8,
spectrum, δ, ppm (J, Hz): 2.73 (3H, s, NCH
3
J = 10.2, COCH=CH ); 7.09 (1H, d, J = 8.7, H Ar); 7.12–
2
J = 5.1, CH
2
OH); 3.45 (2H, t, J = 5.1, NCH
2
2
2
7.20 (2H, m, H Ar); 7.24–7.32 (3H, m, H Ar); 7.75 (1H, d,
(
2H, s, PhCH
J = 2.1, H Ar); 7.91 (1H, dd, J = 8.7, J = 2.1, H Ar).
1
3
(
1H, td, J = 7.8, J = 1.5, H Ar); 7.06–7.12 (2H, m, H Ar);
C NMR spectrum, δ, ppm: 35.8; 52.1; 52.8; 56.3; 59.8;
13
7
3
1
.19–7.31 (5H, m, H Ar). C NMR spectrum, δ, ppm:
121.1; 123.4; 127.5; 127.9; 128.0; 128.3; 128.5; 130.0;
0.7; 56.5; 60.2; 60.3; 110.6; 117.3; 123.4; 126.4; 127.3;
131.9; 134.4; 137.1; 151.1; 166.1; 166.2. Found, m/z:
+
28.3; 129.1; 136.3; 138.4; 146.5. Found, m/z: 257.1650
369.1821 [M+H] . C21
H
25
N
2
O . Calculated, m/z: 369.1809.
4
+
[
M+H] . C16
H
21
N
2
O. Calculated, m/z: 257.1648.
N-{2-[Benzyl(2-hydroxyethyl)amino]phenyl}-N-methyl-
acrylamide (12b). Yield 838 mg (90%), pale-yellow oil.
2
-{Benzyl[4-methoxy-2-(methylamino)phenyl]amino}-
ethan-1-ol (11c). Yield 5.269 g (92%), pale-yellow oil.
1
H NMR spectrum, δ, ppm (J, Hz): 3.08–3.20 (2H, m,
1
H NMR spectrum, δ, ppm (J, Hz): 2.68 (3H, s, NCH
.05 (2H, t, J = 4.5, CH OH); 3.43 (2H, t, J = 5.1,
NCH CH OH); 3.78 (3H, s, OCH ); 3.99 (2H, s, PhCH );
.15 (1H, d, J = 2.7, H Ar); 6.25 (1H, dd, J = 8.4, J = 2.7,
H Ar); 6.99 (1H, d, J = 8.4, H Ar); 7.20–7.31 (5H, m,
3
);
CH
NCH
J = 2.1) and 6.45 (1H, dd, J = 16.8, J = 2.1, COCH=CH
6.13 (1H, dd, J = 16.8, J = 10.2, COCH=CH ); 7.08–7.17
2
OH); 3.38 (3H, s, NCH
2
3
); 3.61 (2H, t, J = 5.4,
2
3
2
CH
2
OH); 4.19 (2H, s, PhCH
); 5.55 (1H, dd, J = 10.2,
);
2
2
3
2
2
6
2
13
(4H, m, H Ar); 7.22–7.32 (5H, m, H Ar). C NMR
spectrum, δ, ppm: 36.4; 53.0; 57.7; 59.8; 123.0; 123.8;
127.6; 128.2; 128.4; 128.6; 128.8; 129.0; 130.2; 137.2;
13
H Ar). C NMR spectrum, δ, ppm: 30.5; 55.3; 57.1; 60.3;
6
1
1.0; 97.3; 101.2; 124.2; 127.2; 128.3; 129.1; 129.6; 138.6;
+
+
47.9; 158.6. Found, m/z: 287.1759 [M+H] . C17
H
23
N
2
O
2
.
137.4; 147.6; 166.1. Found, m/z: 311.1762 [M+H] .
Calculated, m/z: 287.1754.
C
19
H
23
N
2
O . Calculated, m/z: 311.1754.
2
2-{Benzyl[2-(methylamino)-4-nitrophenyl]amino}ethan-
N-{2-[Benzyl(2-hydroxyethyl)amino]-5-methoxyphenyl}-
1
1
-ol (11d). Yield 5.664 g (94%), yellow oil. H NMR
spectrum, δ, ppm (J, Hz): 2.89 (3H, s, NCH ); 3.17 (2H, t,
J = 5.4, CH OH); 3.64 (2H, t, J = 5.4, NCH CH OH); 4.21
2H, s, PhCH ); 6.98 (1H, d, J = 8.7, H Ar); 7.16–7.19 (2H,
N-methylacrylamide (12c). Yield 960 mg (94%), pale-
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 3.02–3.08
1
3
2
2
2
(2H, m, CH
NCH CH
5.53 (1H, dd, J = 10.2, J = 2.1) and 6.44 (1H, dd, J = 16.8,
J = 2.1, COCH=CH ); 6.12 (1H, dd, J = 16.8, J = 10.2,
COCH=CH
2
OH); 3.36 (3H, s, NCH
3
); 3.56 (2H, t, J = 5.4,
(
2
2
2
OH); 3.79 (3H, s, OCH
3
); 4.05 (2H, s, PhCH );
2
m, H Ar); 7.24–7.29 (3H, m, H Ar); 7.40 (1H, d, J = 2.7,
1
3
H Ar); 7.51 (1H, dd, J = 8.7, J = 2.7, H Ar). C NMR
spectrum, δ, ppm: 30.3; 54.6; 56.8; 59.7; 104.0; 111.8; 121.6;
2
2
); 6.68 (1H, d, J = 3.0, H Ar); 6.85 (1H, dd,
1
3
27.5; 128.4; 128.6; 137.2; 142.5; 145.2; 145.4. Found, m/z:
J = 9.0, J = 3.0, H Ar); 7.07 (1H, d, J = 9.0, H Ar); 7.13–
+
13
02.1502 [M+H] . C16
-{Benzyl[3-(methylamino)pyridin-2-yl]amino}ethan-
-ol (11e). Yield 4.682 g (91%), white solid, mp 105–107°C.
H
20
N
3
O
3
. Calculated, m/z: 302.1499.
7.16 (2H, m, H Ar); 7.22–7.31 (3H, m, H Ar). C NMR
2
spectrum, δ, ppm: 36.6; 54.0; 55.7; 58.9; 59.7; 114.1;
1
115.2; 124.6; 127.5; 128.0; 128.4 (2C); 129.1; 137.4;
1
+
H NMR spectrum, δ, ppm (J, Hz): 2.80 (3H, s, NCH
.35 (2H, t, J = 4.8, CH OH); 3.72 (2H, t, J = 4.8,
NCH CH OH); 4.29 (2H, s, PhCH ); 6.84 (1H, dd, J = 7.8,
3
);
139.0; 140.9; 156.3; 166.0. Found, m/z: 341.1868 [M+H] .
3
2
C
20
H
25
N
2
O . Calculated, m/z: 341.1860.
3
2
2
2
Synthesis of compounds 12d,e. A solution of trimethyl-
J = 1.5, H Ar); 6.97 (1H, dd, J = 7.8, J = 4.8, H Ar); 7.26–
silyl chloride (0.573 ml, 4.5 mmol) in anhydrous CH
Cl
2 2
7
.37 (5H, m, H Ar); 7.68 (1H, dd, J = 4.8, J = 1.5, H Ar).
C NMR spectrum, δ, ppm: 30.4; 52.0; 53.3; 59.0; 116.4;
(4.5 ml) was added dropwise to a stirred solution of com-
1
3
pound 11d,e (3.0 mmol) and DIPEA (0.784 ml, 4.5 mmol)
1
20.4; 127.2; 127.8; 128.7; 134.2; 138.6; 139.5; 149.9.
in anhydrous CH
2
2
Cl (9 ml) at 0°C. The resulting solution
+
Found, m/z: 258.1606 [M+H] . C15
20 3
H N O. Calculated, m/z:
was allowed to warm to 25°C. After 2 h, DIPEA (0.836 ml,
4.8 mmol) and DMAP (73 mg, 0.6 mmol) were added, the
resulting solution was cooled to 0°C, and a solution of
2
58.1601.
Synthesis of compounds 12a–c (General method).
DIPEA (0.784 ml, 4.5 mmol) was added to a stirred
acryloyl chloride (0.39 ml, 4.8 mmol) in anhydrous CH
Cl
2 2
solution of the appropriate compound 11a–c (3.0 mmol) in
(9 ml) was added dropwise. The reaction mixture was then
allowed to warm to 25°C. After 2 h, a solution of TFA
CH
2
Cl (30 ml). The resulting solution was cooled to 0°C,
2
and a solution of acryloyl chloride (0.292 ml, 3.6 mmol) in
anhydrous CH Cl (30 ml) was added dropwise over 2 h.
The reaction mixture was washed with saturated aqueous
Na CO (50 ml). The water layer was extracted with
(2.23 ml, 30 mmol) in CH
2
2
Cl (4.5 ml) was added dropwise
2
2
at 0°C. The resulting solution was stirred for 30 min at 0°C.
The reaction mixture was then diluted with CH Cl (30 ml),
washed with saturated aqueous Na CO (50 ml). The water
2
2
2
3
2
3
6
05

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
layer was extracted with CH
2
Cl
2
(4×20 ml). The combined
and
δ, ppm (J, Hz): 2.44 (3H, s, ONCH
CH NCH); 3.07 (1H, d, J = 14.4) and 3.58 (1H, dd,
J = 14.7, J = 9.9, BnNCH CH); 3.17 (3H, s, CONCH );
3.51 (1H, dd, J = 17.1, J = 8.4, COCH); 3.89 (3H, s,
CO CH ); 3.95 (1H, t, J = 8.4) and 4.39 (1H, t, J = 8.1,
NOCH ); 4.51–4.69 (2H, m, PhCH ); 7.14 (1H, d, J = 8.7,
3
); 2.51 (1H, br. s,
organic layers were dried over anhydrous MgSO
4
3
concentrated in vacuo. Purification by flash chromato-
graphy (3:1 to 1:4 petroleum ether–EtOAc, v/v) afforded
the desired product 12 d,e.
2
3
2
3
N-{2-[Benzyl(2-hydroxyethyl)amino]-5-nitrophenyl}-
N-methylacrylamide (12d). Yield 842 mg (79%), yellow
2
2
H Ar); 7.23–7.26 (2H, m, H Ar); 7.30–7.39 (3H, m, H Ar);
7.76 (1H, d, J = 2.1, H Ar); 7.89 (1H, dd, J = 8.7, J = 2.1,
H Ar). 13C NMR spectrum, δ, ppm: 37.0; 43.5; 49.8; 52.1;
52.8; 59.4; 66.7; 70.2; 119.8; 122.7; 127.5; 128.0; 129.0;
1
solid, mp 89–90°C. H NMR (6.10 ppm/6.66 ppm)
indicated the ratio of two rotamers of compound 12d to be
1
4
:1. H NMR spectrum, δ, ppm (J, Hz): 3.33 (2.61H, s,
NCH
NCH
0.36H, m, PhCH
3
); 3.35–3.44 (1.95H, m, CH
); 3.66–3.80 (1.94H, m, NCH
); 4.45–4.58 (1.64H, m, PhCH
2
OH); 3.47 (0.67H, s,
CH OH); 4.21–4.43
); 5.62
130.6; 131.5; 132.2; 137.3; 150.8; 166.1; 170.3. Found, m/z:
+
3
2
2
396.1924 [M+H] . C22
H
26
N
3
O . Calculated, m/z: 396.1918.
4
(
(
2
2
Methyl (3aR*,11aS*)-10-benzyl-1,5-dimethyl-4-oxo-
1,3,3a,4,5,10,11,11a-octahydrobenzo[b]isoxazolo[3,4-f]-
[1,4]diazocine-7-carboxylate (trans-8a). Yield 9 mg
0.81H, dd, J = 10.2, J = 1.8) and 6.48 (0.82H, dd, J = 16.8,
); 5.89 (0.20H, dd, J = 9.9, J = 1.8)
); 6.10 (0.80H, dd,
); 6.66 (0.20H, dd, J = 16.5,
); 7.07–7.18 (3.38H, m, H Ar); 7.28–
.34 (2.75H, m, H Ar); 7.94 (0.56H, d, J = 2.7, H Ar); 8.07
0.17H, d, J = 2.4, H Ar); 8.10 (0.82H, dd, J = 9.0, J = 2.7,
J = 1.8, COCH=CH
2
o
1
and 6.55 (0.18H, d, J = 2.1, COCH=CH
J = 16.8, J = 10.2, COCH=CH
J = 10.2, COCH=CH
2
(5%), pale-yellow solid, mp 125–126 C.
H
NMR
); 2.81 (2H,
CH); 3.13 (1H, ddd, J = 15.0,
NCH); 3.25 (3H, s, CONCH ); 3.23
(1H, dd, J = 10.2, J = 6.9, COCH); 3.78 (1H, t, J = 8.4) and
4.42 (1H, t, J = 7.2, NOCH ); 3.93 (3H, s, CO CH ); 4.20
2
spectrum, δ, ppm (J, Hz): 2.57 (3H, s, ONCH
3
2
dd, J = 18.6, J = 6.9, BnNCH
J = 8.4, J = 6.3, CH
2
7
(
3
3
13
H Ar). C NMR spectrum (major rotamer), δ, ppm: 35.7;
3.0; 56.0; 60.0; 120.4; 124.3; 126.7; 127.7; 127.8; 128.1;
2
2
3
5
(2H, s, PhCH ); 7.18–7.26 (4H, m, H Ar); 7.27–7.31 (1H,
2
1
28.8; 129.4; 133.3; 136.7; 140.6; 152.7; 166.1. Found, m/z:
m, H Ar); 7.61 (1H, d, J = 8.4, H Ar); 7.88 (1H, d, J = 2.1,
+
13
3
56.1620 [M+H] . C19
H
22
N
3
O
4
. Calculated, m/z: 356.1605.
H Ar); 8.01 (1H, dd, J = 8.4, J = 2.1, H Ar). C NMR
N-{2-[Benzyl(2-hydroxyethyl)amino]pyridin-3-yl}-
spectrum, δ, ppm: 37.3; 44.2; 51.2; 52.5; 56.9; 61.1; 68.3;
N-methylacrylamide (12e). Yield 859 mg (92%), pale-
72.7; 127.8; 128.1; 128.6; 128.7; 128.8; 129.2; 130.1; 138.0;
1
+
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 3.16 (3H, s,
142.0; 153.1; 165.9; 170.6. Found, m/z: 396.1924 [M+H] .
NCH
m, PhCH
dd, J = 16.8, J = 2.1, COCH=CH
J = 10.2, COCH=CH ); 6.85 (1H, dd, J = 7.5, J = 4.8,
H Ar); 7.14–7.17 (2H, m, H Ar); 7.19–7.29 (4H, m, H Ar);
3
); 3.58–3.79 (4H, m, NCH
2
CH
2
OH); 4.49–4.64 (2H,
C
22
H
26
N
3
O . Calculated, m/z: 396.1918.
4
2
); 5.43 (1H, dd, J = 10.2, J = 2.1) and 6.30 (1H,
); 5.71 (1H, dd, J = 16.8,
(3aR*,11aR*)-10-Benzyl-1,5-dimethyl-3,3a,5,10,11,11a-
hexahydrobenzo[ ]isoxazolo[3,4- ][1,4]diazocin-4(1 )-
one (cis-8b). Yield 66 mg (39%), pale-yellow solid, mp 97–
2
b
f
H
2
o
1
98 C. H NMR spectrum, δ, ppm (J, Hz): 2.47 (1H, br. s,
CH NCH); 2.52 (3H, s, ONCH ); 3.00 (1H, d, J = 13.2)
and 3.42–3.47 (1H, m, BnNCH CH); 3.09 (3H, s,
CONCH ); 3.36–3.39 (1H, m, COCH); 3.95 (1H, t, J = 8.4)
and 4.38 (1H, t, J = 8.1, NOCH ); 4.36 (1H, d, J = 15.3)
and 4.55 (1H, d, J = 15.0, PhCH ); 6.97–7.08 (2H, m,
H Ar); 7.19–7.25 (4H, m, H Ar); 7.28–7.36 (3H, m, H Ar).
1
3
8
.20 (1H, dd, J = 4.8, J = 1.8, H Ar). C NMR spectrum,
δ, ppm: 35.6; 53.2; 53.8; 60.7; 116.1; 127.0; 127.2; 127.7;
27.9 (2C); 128.4; 138.3; 138.9; 146.5; 156.1; 166.0.
3
3
2
1
3
+
Found, m/z: 312.1715 [M+H] . C18
12.1707.
Synthesis of compounds 8a–e (General method). Com-
pound 12a–e (0.50 mmol) in CH Cl (20 ml) was treated
with DIPEA (0.697 ml, 4.0 mmol) and DMSO (0.709 ml,
0 mmol). The reaction mixture was cooled to 0–2°C and
SO -pyridine (320 mg, 2.0 mmol) was added in two
portions. The resulting solution was stirred for 2 h at 0–2°C.
The reaction mixture was then diluted with CH Cl (20 ml),
washed with 0.2 M aqueous KHSO (20 ml), water (20 ml),
and brine (20 ml), dried over MgSO , filtered, and diluted
with CH Cl to give a solution of crude aldehyde 7a–e in
CH Cl (50 ml). NaOAc (49 mg, 0.60 mmol) and N-methyl-
H
22
N
3
O
2
. Calculated, m/z:
2
3
2
1
3
2
2
C NMR spectrum, δ, ppm: 36.9; 43.7; 50.0; 53.4; 60.3;
67.0; 70.0; 122.9; 123.1; 127.6; 127.9; 128.8 (2C); 129.2;
+
1
135.5; 138.2; 147.0; 170.7. Found, m/z: 338.1871 [M+H] .
3
C
20
H
24
N
3
O . Calculated, m/z: 338.1863.
2
(3aR*,11aS*)-10-Benzyl-1,5-dimethyl-3,3a,5,10,11,11a-
2
2
hexahydrobenzo[b]isoxazolo[3,4-f][1,4]diazocin-4(1H)-
one (trans-8b). Yield 47 mg (28%), pale-yellow solid, mp
109–110 C. H NMR spectrum, δ, ppm (J, Hz): 2.55 (3H, s,
4
o
1
4
2
2
ONCH
m, CH
COCH); 3.78 (1H, t, J = 8.1) and 4.42 (1H, t, J = 8.4,
NOCH ); 4.18 (2H, s, PhCH ); 7.17–7.25 (4H, m, H Ar);
3
); 2.72–2.83 (2H, m, BnNCH
2
CH); 3.13–3.21 (1H,
2
2
3
NCH); 3.22 (3H, s, CONCH
3
); 3.24–3.31 (1H, m,
hydroxylamine hydrochloride (50 mg, 0.60 mmol) were added
to the above solution. The mixture was stirred for the
corresponding time at 25°C, then washed with saturated
2
2
7.26–7.31 (3H, m, H Ar); 7.33–7.39 (1H, m, H Ar); 7.55
13
aqueous Na
2
CO
3
(25 ml), dried over MgSO
4
, and concen-
(1H, dd, J = 8.1, J = 1.5, H Ar). C NMR spectrum,
δ, ppm: 37.2; 44.2; 51.0; 56.8; 61.4; 68.3; 73.0; 126.4;
trated in vacuo. Purification by flash chromatography
(
petroleum ether–EtOAc, 5:1 to 1:2 v/v) afforded the
127.2; 127.5; 127.7; 128.5; 128.7; 129.2; 138.6; 141.8;
+
desired product 8a–e.
148.8; 170.8. Found, m/z: 338.1873 [M+H] . C20
Calculated, m/z: 338.1863.
H
24
N
3
2
O .
Methyl (3aR*,11aR*)-10-benzyl-1,5-dimethyl-4-oxo-
1
[
,3,3a,4,5,10,11,11a-octahydrobenzo[b]isoxazolo[3,4-f]-
(3aR*,11aR*)-10-Benzyl-7-methoxy-1,5-dimethyl-
1,4]diazocine-7-carboxylate (cis-8a). Yield 122 mg
3,3a,5,10,11,11a-hexahydrobenzo[b]isoxazolo[3,4-f][1,4]-
diazocin-4(1H)-one (cis-8c). Yield 37 mg (20%), pale-
1
(
62%), white solid, mp 133–134°C. H NMR spectrum,
6
06

Chemistry of Heterocyclic Compounds 2016, 52(8), 601–608
1
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 2.48 (1H, br. s,
structural analysis were obtained by slow evaporation from
CH Cl /petroleum ether. Crystals of compound trans-8a
CH
3
NCH); 2.55 (3H, s, ONCH
.30–3.37 (1H, m, BnNCH CH); 2.99 (3H, s, CONCH
.26–3.29 (1H, m, COCH); 3.79 (3H, s, OCH ); 3.97 (1H,
); 4.19 (1H, d,
); 6.60 (1H, d,
3
); 2.92–2.99 (1H, m) and
2
2
3
3
2
3
);
suitable for X-ray structural analysis were obtained by slow
evaporation from EtOAc/petroleum ether. The X-ray struc-
tural study was performed on an automated Rigaku
R-AXIS RAPID IP diffractometer (graphite monochromator,
λ(MoKα), ω-scanning). Empirical accounting for absorp-
tion and the correction of systematic errors were performed
with the SADABS software. The structure was solved by a
direct method and refined by full matrix method of least
3
t, J = 8.7) and 4.42 (1H, t, J = 8.1, NOCH
2
J = 14.4, ) and 4.35 (1H, d, J = 14.1, PhCH
2
J = 3.0, H Ar); 6.85 (1H, dd, J = 9.0, J = 3.0, H Ar); 7.19–
1
3
7
4
1
1
.33 (6H, m, H Ar). C NMR spectrum, δ, ppm: 37.0;
4.0; 50.0; 54.2; 55.7; 61.3; 67.2; 69.7; 112.6; 115.0;
26.4; 127.5; 128.4; 128.6; 138.0; 138.7; 139.9; 156.4;
+
2
70.7. Found, m/z: 368.1977 [M+H] . C21
26
H N
3
O
3
. Calcu-
squares by F hkl with anisotropic thermal parameters for all
14
lated, m/z: 368.1969.
3aR*,11aS*)-10-Benzyl-7-methoxy-1,5-dimethyl-
non-hydrogen atoms, using the SHELXTL package. The
hydrogen positions at the carbon atoms were calculated.
The complete crystallographic dataset was deposited at the
Cambridge Crystallographic Data Center (the deposit
numbers are CCDC 1010955 (compound cis-8a) and
CCDC 1010956 (compound trans-8a)).
(
3
,3a,5,10,11,11a-hexahydrobenzo[b]isoxazolo[3,4-f][1,4]-
diazocin-4(1H)-one (trans-8c). Yield 64 mg (35%), white
1
solid, mp 124–125°C. H NMR spectrum, δ, ppm (J, Hz):
2
3
–
.56 (3H, s, ONCH
.13–3.18 (1H, m, CH
3.27 (1H, m, COCH); 3.74–3.79 (1H, m) and 4.41 (1H, t,
); 3.80 (3H, s, OCH ); 4.15 (2H, s, PhCH );
.66 (1H, d, J = 3.0, H Ar); 6.90 (1H, dd, J = 9.0, J = 3.0,
3
); 2.70–2.81 (2H, m, BnNCH
2
CH);
3
NCH); 3.19 (3H, s, CONCH
3
); 3.23
The Supplementary information file containing NMR
spectra of the synthesized compounds is available at http://
link.springer.com/journal/10593.
J = 6.9, NOCH
2
3
2
6
H Ar); 7.17–7.25 (4H, m, H Ar); 7.27–7.30 (1H, m, H Ar);
1
3
This work was supported by a grant from the Sci-Tech
Development Project of Jilin Province in China
7
3
1
1
.45 (1H, d, J = 9.0, H Ar). C NMR spectrum, δ, ppm:
7.0; 44.2; 51.1; 55.6; 57.1; 61.6; 68.3; 73.2; 111.0; 114.9;
(
No. 20160520039JH) and a grant from the Norman Bethune
27.4; 128.3; 128.4; 128.7; 138.8; 141.5; 142.6; 158.1;
+
Program of Jilin University (No. 2015330). Additional support
was provided by Changchun Discovery Sciences, Ltd.
70.8. Found, m/z: 368.1977 [M+H] . C21
26
H N
3
O . Calcu-
3
lated, m/z: 368.1969.
(
3aR*,11aR*)-10-Benzyl-1,5-dimethyl-7-nitro-3,3a,5,10,11,11a-
References
hexahydrobenzo[b]isoxazolo[3,4-f][1,4]diazocin-4(1H)-
1
. (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757.
one (cis-8d). Yield 136 mg (71%), yellow solid, mp 169–
1
(b) Sieburth, S. M.; Cunard, N. T. Tetrahedron 1996, 52,
1
70°C. H NMR spectrum, δ, ppm (J, Hz): 2.41 (3H, s,
6
251. (c) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881.
ONCH
and 3.67 (1H, dd, J = 15.0, J = 9.6, BnNCH
s, CONCH ); 3.51–3.60 (1H, m, COCH); 3.98 (1H, t,
J = 8.4) and 4.41 (1H, t, J = 8.1, NOCH ); 4.63 (1H, d,
); 7.15 (1H, d,
3
); 2.52 (1H, br. s, CH
3
NCH); 3.14 (1H, d, J = 15.3)
(
d) Yet, L. Chem. Rev. 2000, 100, 2963. (e) Kleinke, A. S.;
2
CH); 3.21 (3H,
Webb, D.; Jamison, T. F. Tetrahedron 2012, 68, 6999.
. Riemer, B.; Hofer, O.; Greger, H. Phytochemistry 1997, 45, 337.
. (a) Macías, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.;
Fronczek, F. R. J. Org. Chem. 1994, 59, 8261. (b) Harrison, B.;
Crews, P. J. Org. Chem. 1997, 62, 2646. (c) Kishuku, H.;
Shindo, M.; Shishido, K. Chem. Commun. 2003, 350.
. (a) Endo, Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. J. Am.
Chem. Soc. 1996, 118, 1841. (b) Kozikowski, A. P.; Wang, S.;
Ma, D.; Yao, J.; Ahmad, S.; Glazer, R. I.; Bogi, K.; Acs, P.;
Modarres, S.; Lewin, N. E.; Blumberg, P. M. J. Med. Chem.
3
2
3
2
J = 15.9) and 4.70 (1H, d, J = 16.2, PhCH
2
J = 9.3, H Ar); 7.24–7.26 (2H, m, H Ar); 7.31–7.42 (3H,
m, H Ar); 8.01 (1H, d, J = 2.7, H Ar); 8.11 (1H, dd, J = 9.3,
13
4
J = 2.7, H Ar). C NMR spectrum, δ, ppm: 37.3; 43.4;
4
9.7; 52.8; 59.5; 66.6; 70.2; 118.9; 125.1; 126.4; 127.4;
1
3
28.3; 129.2; 131.0; 136.3; 140.1; 152.4; 170.1. Found, m/z:
+
83.1715 [M+H] . C20
H
23
N
4
O . Calculated, m/z: 383.1714.
4
1
997, 40, 1316.
(
3aR*,11aR*)-10-Benzyl-1,5-dimethyl-3,3a,5,10,11,11a-
5
. (a) Jasinski, D. R.; Preston, K. L. Psychopharmacology 1987,
hexahydroisoxazolo[3,4-f]pyrido[3,2-b][1,4]diazocin-4(1H)-
9
1, 273. (b) Novelli, A.; Groppetti, A.; Rossoni, G.; Manfredi, B.;
one (cis-8e). Yield 110 mg (65%), white solid, mp 202–
Ferrero-Gutiérrez, A.; Pérez-Gómez, A.; Desogus, C. M.;
Fernández-Sánchez, M. T. Amino Acids 2007, 32, 323.
1
2
03°C. H NMR spectrum, δ, ppm (J, Hz): 2.22 (3H, s,
6
. (a) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.;
Mathee, S. Phytochemistry 1995, 40, 307. (b) Hoarau, C.;
Couture, A.; Deniau, E.; Grandclaudon, P. J. Org. Chem.
ONCH
and 3.52 (1H, dd, J = 15.3, J = 9.6, BnNCH
s, CONCH ); 3.43–3.49 (1H, m, COCH); 3.89 (1H, t,
J = 8.4) and 4.37 (1H, t, J = 7.2, NOCH ); 4.67 (1H, d,
J = 14.7) and 5.18 (1H, d, J = 14.7, PhCH ); 6.80 (1H, dd,
3
); 2.26 (1H, br. s, CH
3
NCH); 3.13 (1H, d, J = 15.3)
2
CH); 3.19 (3H,
3
2
002, 67, 5846.
2
7
8
. Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med.
Chem. 2005, 13, 5717.
2
J = 7.5, J = 4.8, H Ar); 7.27–7.36 (4H, m, H Ar); 7.37–7.43
. For reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 863. (b) Rück-Braun, K.; Freysoldt, T. H. E.;
Wierschem, F. Chem. Soc. Rev. 2005, 34, 507. (c) Pellissier, H.
Tetrahedron 2007, 63, 3235. (d) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247. (e) Brandi, A.; Cardona, F.;
Cicchi, S.; Cordero, F. M.; Goti, A. Chem.–Eur. J. 2009, 15,
(
2H, m, H Ar); 8.25 (1H, dd, J = 4.8, J = 1.8, H Ar).
1
3
C NMR spectrum, δ, ppm: 37.2; 43.2; 49.8; 50.0; 55.2;
6
6.5; 70.3; 115.2; 125.2; 127.6; 128.7 (2C); 137.8; 138.7;
+
1
47.7; 155.8; 170.5. Found, m/z: 339.1823 [M+H] .
C
19
H
23
N
4
O . Calculated, m/z: 339.1816.
2
7
2
808. (f) Nájera, C.; Sansano, J. M. Org. Biomol. Chem.
009, 7, 4567. (g) Kissane, M.; Maguire, A. R. Chem. Soc.
X-ray structural study of compounds cis-8a and
trans-8a. Crystals of compound cis-8a suitable for X-ray
6
07

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59, 4375. (b) Jiang, S.; Mekki, B.; Singh, G.; Wightman, R. H.
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van der Gen, A. Eur. J. Org. Chem. 1998, 2513. (d) Marco-
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11. Tanino, T.; Yamaguchi, M.; Matsuda, A.; Ichikawa, S. Eur.
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9
. (a) Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G.
Chem.–Eur. J. 2010, 16, 3842. (b) Bakthadoss, M.; Murugan, G.
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Guerrand, H. D. S.; Oram, N. Org. Lett. 2011, 13, 1267.
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d) Shing, T. K. M.; So, K. H. Org. Lett. 2011, 13, 2916.
(
e) Krenske, E. H.; Agopcan, S.; Aviyente, V.; Houk, K. N.;
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1
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h) Bakthadoss, M.; Sivakumar, G.; Sharada, D. S. Synthesis
2
(
6
08