An efficient synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via diastereoselective N-acyliminium ion cyclization

Article abstract of DOI:10.1016/j.tet.2015.08.007

A simple and efficient strategy is reported for the synthesis of spiro-fused pyrrolo[2,1-a]isoquinoline ring systems. The spiro[isoxazolopyrroloisoquinolines] are readily prepared via diastereoselective N-acyliminium ion cyclization of 6-hydroxy-7-(2-aryl

Full text of DOI:10.1016/j.tet.2015.08.007

Accepted Manuscript
An efficient synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via
diastereoselective N-acyliminium ion cyclization
Maria S. Ledovskaya, Alexander V. Stepakov, Alexander P. Molchanov, Rafael R.
Kostikov
PII:
S0040-4020(15)01184-9
10.1016/j.tet.2015.08.007
TET 27029
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 June 2015
Revised Date: 19 July 2015
Accepted Date: 3 August 2015
Please cite this article as: Ledovskaya MS, Stepakov AV, Molchanov AP, Kostikov RR, An efficient
synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via diastereoselective N-acyliminium ion
cyclization, Tetrahedron (2015), doi: 10.1016/j.tet.2015.08.007.
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An efficient synthesis of substituted
spiro[isoxazolopyrroloisoquinolines] via
diastereoselective N-acyliminium ion cyclization
Maria S. Ledovskaya, Alexander V. Stepakov, Alexander P. Molchanov and Rafael R. Kostikov
Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St-Petersburg 198504,
Russian Federation.
R
N
OH
N
N
C1A
O
O3
R
.
O
O1
C5
BF Et O
3
2
C4
C8
C1D
CH Cl2
C15
C17
C2
2
H
C11
C6
C10
N5
N
C16
C9
O2 C14
C13
O
C7
C18
C12
O
C1B
C1
N6
C3
single diastereomer
90-98% yields)
C1C
(
O4

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
An efficient synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via dia-
stereoselective N-acyliminium ion cyclization
∗
Maria S. Ledovskaya, Alexander V. Stepakov, Alexander P. Molchanov and Rafael R. Kostikov
Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St-Petersburg 198504, Russian Federation.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient strategy is reported for the synthesis of spiro-fused pyrrolo[2,1-
a
]isoquinoline ring systems. The spiro[isoxazolopyrroloisoquinolines] are readily
preparated via diastereoselective -acyliminium ion cyclization of 6-hydroxy-7-(2-
N
arylethyl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-ones derived from the corresponding
spirocyclic dihydroisoxazoles.
Available online
Keywords:
spiro[dihydroisoxazoles]
hydroxylactams
N-acyliminium ion
intramolecular cyclization
spiro[isoxazolopyrroloisoquinolines]
1
. Introduction
The pyrrolo[2,1-a]isoquinoline ring system is a major
1
MeO
MeO
HO
HO
RO
RO
structural fragment of Erythrina and lamellarin alkaloids
.
Cl
N
N
N
Natural products that contains pyrroloisoquinoline frame-
work (Scheme 1) display a variety of pharmacological ef-
H
H
crispine B (1)
trolline (salsoline A) (2)
crispine A (3a: R = Me)
oleracein E (3b: R = H)
fects including cytotoxic [crispine B (
1
) and lamellarin D
4a)], antitumor [crispine B (1), crispine A (3a), lamellarin
2,3
2
(
OR1
I (5a) and lamellarin K (5b)], antibacterial and antiviral
1
R O
MeO
4
activities [trolline (salsoline A) (
2)], DPPH free radical
O
O
N
N
H
scavenging activity and inhibitory activity [oleracein E (3b
and lamellarin α-20-sulfate (4b)]. Various biological activi-
)
MeO
MeO
N
5
O
O
O
O
N
ties have been found for synthetic pyrroloisoquinolines, e.g.,
6
7
8
antineoplastic, antitumor activity, antidepressant, antileu-
2
2
R O
3
R O
6
a
9
OR
R
OMe
OMe
1
OH
kemic, antiviral and activity as α2-adrenoreceptor antago-
MeO
1
MeO
1
0
11
2
3
2
(
rac)-6
nists and calcium channel blockers. In addition, com-
pounds with a pyrroloisoquinoline fragment have been de-
scribed as having hypotensive, sympatholytic and psycho-
lamellarin D (4a: R = R = R = H)
lamellarin α-20-sulfate
4b: R = Me; R = H; R = SO Na)
3
lamellarin I (5a: R = R = Me)
lamellarin K (5b: R = R = H)
1
2
1
2
3
(
1
2a
tropic activity, as well as being useful in the treatment of
Scheme 1. Representative natural active pyrrolo[2,1-
and the spiro[isoxazolopyrroloisoquinolines] from this work.
a]isoquinolines 1–
1
2b
diseases such as psoriasis.
5
6
Thereby development of simple, effective and efficient
synthetic methods for compounds containing such a struc-
tural fragment is still an important and actual challenge of
organic chemistry and many approaches have been reported
1
3
in the last years. In particular, the intramolecular trapping
of cyclic -acyliminium ions has been successfully used for
the preparation of pyrrolo[2,1-
N
1
4
a
]isoquinoline ring systems.
—
——
∗
Corresponding author. Tel: +7 812-428-4021; fax: +7-812-428-6939; e-mail: alstepakov@yandex.ru

2
Tetrahedron
R
Previously, we described the first synthesis of isoxa-
ACCEPTED MANUSCRIPT
N
N
zolopyrroloisoquinolines
intramolecular cyclization of 5-(2-arylethyl)-6-hydroxytetra-
hydro-4 -pyrrolo[3,4- ]isoxazol-4-ones in the presence of
boron trifluoride diethyl etherate. In the present work we
report a simple and efficient approach for the synthesis of
the spiro[isoxazolopyrroloisoquinolines]
8
(Scheme 2) via diastereoselective
O
O
O
Cl
OH
R
Ar
Ar
1
0a-c
H
d
7
N
N
1
5
Et3N
benzene, RT
O
a-c
O
9
11a-g
6 (Scheme 1) via
the intramolecular trapping of an -acyliminium ion as the
N
1
6
Yield
key synthetic step.
Entry
Ar
R
Product
b
(
%)
R1
H
N
1
2
3
4
5
6
Ph (9a
Ph (9a
Ph (9a
3,4-(MeO)
3,4-(MeO)
)
)
)
4-MeC
6
H
4
(
10a
10b
Et (10c
4-MeC
4-ClC
4-MeC
4-ClC H (10b
)
11a
11b
11c
11d
11e
11f
86
42
25
63
24
85
68
O
OH
H
4-ClC
CO
6
H
4
(
)
H
O
Ph
.
2
)
BF3 Et2O
N
N
O
2
2
C
C
6
6
H
H
)
)
9
3
3
(
(
9b
9b
)
)
6
H
4
(
10a
10b
10a
)
)
CH2Cl2, RT
N
R2
H
6
H
4
(
4
)
1-naphthyl (9c
1-naphthyl (9c
6
H
4
(
R1
H
O
R2
7
6
)
11g
a
(rac)-7
(rac)-8
Reaction conditions:
(1 equiv), 10 (1.5 equiv), Et
3
N (1.5 equiv), benzene,
b
RT. Isolated yield.
Scheme 2. Previous work: synthesis of pyrroloisoquinolines
clization of hydroxylactams
8 by cy-
7.
Table 2
Reduction of compounds 11a
a
4
−g
with NaBH
2
. Results and discussion
Our approach to spiro[isoxazolopyrroloisoquinolines]
N
O
N
OH
N
O
O
R
R
Ar
Ar
NaBH4
N
began with the synthesis of dihydroisoxazoles 11a pre-
pared by 1,3-dipolar cycloaddition of -(2-
arylethyl)itaconimides 9a to nitrile oxides, generated from
the corresponding hydroximoyl chlorides 10a in the pres-
−
g
CH Cl /EtOH
2 2
o
N
80 to 20 C
O
O
−
c
1
1a-g
12a-g
−
c
ence of triethylamine (Table 1). Benzonitrile oxide (generat-
ed in situ from the hydroximoyl chloride 10a in the presence
Yield of
dr of
12
Entry
Substrate Ar
R
4-MeC
b
c
1
2
(%)
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
Ph
Ph
Ph
6
H
4
12a (96)
12b (92)
12c (95)
12d (95)
12e (95)
12f (96)
2:1
5:1
11:1
5:1
9:1
1:0
of Et N) was treated with 9a in benzene at 20 °C to give а
3
4-ClC
CO Et
4-MeC
4-ClC
4-MeC
4-ClC
6 4
H
isoxazole 11a in 86% yield (Table 1, entry 1). A similar re-
actions occurred between itaconimide 9a and nitrile oxides
generated from 10b,c, giving spiro-isoxazoles 11b and 11c
in yields of 42% and 25% respectively (Table 1, entries 2
and 3). The reactions of itaconimides 9b,c with nitrile oxides
generated from hydroximoyl chlorides 10a,b lead to spiro-
2
3,4-(MeO)
3,4-(MeO)
1-naphthyl
2
C
C
6
6
H
H
3
3
6
H
4
4
2
6
H
4
6
H
7
11g
1-naphthyl
6
H
4
12g (98)
1:0
a
Reaction conditions: 11 (1 equiv), NaBH
4
(1.5 equiv), CH
2
Cl
2
/EtOH,
−
80 to
b
c
1
−
20 °C. Isolated yield. Determined by H NMR of the crude mixture.
isoxazoles 11d
, entries 4-7). The structural assignment of the isolated spi-
ro-isoxazoles 11a was made on the basis of their spectro-
−g in yields ranging from 24% to 85% (Table
Next, the intramolecular Friedel-Crafts–type reactions of
hydroxylactams 12a were investigated (Table 3). Treat-
ment of -acyliminium precursors 12a and 12b with an ex-
OEt (5 equiv) in CH Cl at room temperature
1
−
g
−
g
13
1
N
scopic data: H and C NMR spectra indicate the regio-
chemistry of the [3+2] cycloadducts 11a which are
formed by the attack of the nitrile oxide’s carbon at the CH2
cess of BF3
⋅
2
2
2
−
g
gave the spiro-cyclic racemic products 13a and 13b as a
single diastereomers in 98 and 90% yield, respectively (Ta-
ble 3, entries 1 and 2). Similarly, cyclization of hydroxylac-
tam 12c afforded exclusively to 13c in 96% yield (Table 3,
entry 3). The signals of the other possible diastereomers
terminus of the
data).
α,β-unsaturated moiety (see Supplementary
For the next step in our study, we examined the reduction
of the imide function of substrates 11a with NaBH . The
reduction was carried out in methylene chloride–ethanol at –
−
g
4
1
were not found in H NMR spectra of crude reaction mix-
tures. The
substituted aromatic ring containing hydroxylactams 12d,e
with BF3 OEt in CH Cl at room temperature proceeded
cleanly to provide spiro[isoxazolopyrroloisoquinolines]
3d,e in 98 and 92 % yields, respectively (Table 3, entries 4
and 5). Furthermore, in the case of the 1-naphthyl substitut-
ed -acyliminium ion precursors 12f,g formed the pentacy-
N-acyliminium ion cyclization of methoxy-
8
1
0 to –20 °C to provide the corresponding hydroxylactams
2a in yields ranging from 92% to 98% (Table 2). In all
-position with respect
−g
⋅
2
2
2
cases, only the carbonyl group at the
β
to the oxygen atom in the dihydroisoxazole ring was re-
duced. Presumably, this is related to the inductive effect of
1
1
7
the oxygen atom of the isoxazole ring. The signals of the
1
N
other possible regioisomers were not found in H NMR
1
clic spiro-systems 13f,g in 91 and 98% yields (Table 3, en-
spectra of crude reaction mixtures. А H NMR analysis of
1
tries 6 and 7). From the analysis of H NMR spectrum of the
crude reaction mixtures showed that the spiro-
hydroxylactams 12a−e are formed as the inseparable mix-
ture of diastereomers, while products 12f,g formed as a sin-
gle diasteremers; and the stereochemistry of these products
crude reaction mixtures it was concluded that the cyclization
of hydroxylactams 12f,g produced only a single diastere-
omers. The relative stereochemistry of the formed stereocen-
ters of spiro[isoxazolopyrroloisoquinolines] 13 was deter-
mined by single-crystal X-ray diffraction (for compound
12f,g is not yet determined (Table 2). It should be noted that
hydroxylactam 12g in CDCl for two weeks at room temper-
3
1
3d) (Fig. 1) and supported the relative configuration de-
ature is completely converted into other diastereomer.
1
duced from NMR spectroscopy. The H NMR spectrum of
compound 13f displayed a singlet at 5.19 ppm for H-C(10a),
which showed a H,H-NOESY correlation with a doublet at
Table 1
a
1,3-Dipolar cycloaddition of benzonitrile oxides to itaconimides (9a−c)
3
.97 ppm (CH group of the isoxazole ring), this fact indi-
2

3
cated that H-C(10a) and methylene group of isoxazole ring
are cis-located relative to each other.
ACCEPTED MANUSCRIPT
R
N
O
N
C1A
N
R
N
O
O
O3
O
O1
C5
1
4-A
14-B
C4
C8
C1D
C17
C15
C11
C6
C10
N5
C16
C2
C9
O2 C14
C13
C7
C18
C1B
C12
R
C1
N
O
N6
C3
O4
R
H
H
N
N
C1C
N
O
Fig. 1. ORTEP representation of compound 13d
.
O
O
1
3
15 (not found)
Table 3.
BF OEt
type cyclization of hydroxylactams 12a
3
⋅
2
-catalyzed intramoleculardiastereoselective Friedel-Crafts–
Scheme 3. Stereoselective outcome of the intramolecular N-acyliminium
cyclization into the spiro-cyclic systems 13.
a
−g
N
OH
N
N
Ar
O
O
R
R
Ar
.
BF Et O
3
2
3
. Conclusion
In summary, we have developed a simple and efficient
N
CH Cl RT
2
2,
O
O
route to spiro[isoxazolopyrroloisoquinolines] via diastere-
oselective -acyliminium ion cyclization of 6-hydroxy-7-
2-arylethyl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-ones
1
2a-g
14
N
(
derived from the corresponding spirocyclic dihydroisoxa-
zoles.
R'
R'
2
4
1
3
1
2a
9
'
8'
12
4a
1
0'
7'
11
1
0b 4b
1
0a'
N
N
2' 1'O H
1O H
6
a'
2
R
3
'
10a
5
R
3
1
'
0b'
6'
4
4'
10,5'
9
7
6
4. Experimental section
4.1. General remarks
1
',5
5'
4
N
N
8
2
'
3
'
O
O
1
3a-e
13f,g
IR spectra were obtained on an Bruker Tensor 27 spectrome-
ter. Melting points were determined on a Boetius instrument and
are uncorrected. NMR spectra were recorded on a Bruker Avance
Yield of
13 (%)
Entry
Substrate
Ar
R
R′
b
1
2
3
4
5
6
7
12a
12b
12c
12d
12e
12f
Ph
Ph
Ph
4-MeC
4-ClC
CO Et
4-MeC
4-ClC
4-MeC
4-ClC
(5 equiv.), CH
6
H
4
H
H
H
MeO
MeO
−
13a (98)
13b (90)
13c (96)
13d (98)
13e (92)
13f (91)
13g (98)
1
13
6
H
4
III spectrometer ( H, 400 MHz; C, 100 MHz). Chemical shifts δ
1
2
are reported in ppm relative to residual CHCl ( H, δ = 7.26) and
3
3,4-(MeO)
3,4-(MeO)
1-naphthyl
1-naphthyl
2
C
C
6
6
H
H
3
3
6
H
4
4
13
CDCl ( C, δ = 77.16) as internal standard. High-resolution mass
2
6
H
4
3
6
H
spectra (HRMS) were recorded on a Bruker micrOTOF 10223
spectrometer using electrospray ionization (ESI). The X-ray dif-
fraction data were performed by means of an Bruker APEX-II
CCD diffractometer with Mo-K X-ray radiation. Reactions were
monitored by TLC analysis using Silufol UV-254 plates. Thin
layer chromatography was performed on silica gel 5−40 mesh
eluted with dichloromethane/methanol. Preparation and charac-
terization of compounds 13a−g are disclosed below, while com-
pounds 9a−c, 11a−g and 12a−g described in the Supplementary
data.
12g
6
H
4
−
a
b
Reaction conditions: 12 (1 equiv.), BF
Isolated yield.
3
⋅
OEt
2
2 2
Cl , RT.
From the obtained results we can conclude that the reac-
tion occurs by direct attack on the -acyliminium ion inter-
mediate 14 by the -aromatic system linked to the nitrogen
atom of the pyrrolidinone ring to produce the spi-
ro[isoxazolopyrroloisoquinolines] 13. Formation of dia-
N
π
stereomers 13 occurs by
π-nucleophile attack on the N-
acyliminium ion from the less hindered isoxazole side, that
is, in our case, the oxygen one (transition state 14-A,
Scheme 2). The transition state 14-A should be lower in en-
ergy than the 14-B due to repulsion between the CH2-C(R)-
fragment of dihydroisoxazole ring and aromatic ring in tran-
sition state 14-B (Scheme 3).
4.2. General procedure for the synthesis of spi-
ro[isoxazolopyrroloisoquinolines] 13a-g
Boron trifluoride diethyl etherate (5 equiv) was added to vig-
orously stirred solution of corresponding hydroxylactams (12) in
anhyd. dichloromethane (3 mL) under argon. The reaction mix-
ture was stirred in a capped vial at room temperature (TLC-
control). After completion of the reaction, water was added care-
fully to the reaction mixture (6 mL). The aqueous layer was ex-

4
Tetrahedron
tracted with CH Cl (3 x 5 mL), the organic layers were com-
CH + CH from CH ), 2.92 (dd, J =12.2 Hz, J =2.6 Hz, 1H from
2 2 1 2
2
2
ACCEPTED MAN
USCRIPT
bined, dried over MgSO4 and evaporated to dryness. The product
was recrystallized with Et O (for 13a,b,d-g).
CH ), 2.66 (d, J=15.1 Hz, 1H from CH ), 2.40 (s, 3H, CH from
2 2 3
13
Tol). C NMR (100.6 MHz, CDCl ) δ 170.2 (CO), 155.3 (C=N),
3
2
1
48.3 (C ), 147.4 (C ), 140.9 (C ), 129.7 (2CH ), 128.2 (C ),
Ar Ar Ar Ar Ar
4
.2.1. (5SR,10b'SR)-3-(4-methylphenyl)-6',10b'-dihydro-4H,5'H-
spiro[isoxazole-5,1'-pyrrolo[2,1-a]isoquinolin]-3'(2'H)-one
13a), (98%) was obtained using general procedure from hydrox-
126.4 (2CH ), 126.2 (C ), 122.2 (C ), 112.1 (CH ), 107.9
Ar Ar Ar Ar
(CH ), 89.2 (Cspiro), 67.0 (CH), 55.7 (OMe), 55.3 (OMe), 44.4
Ar
(
(CH ), 42.6 (CH ), 37.4 (CH ), 29.1 (CH ), 21.5 (CH from Tol).
2
2
2
2
3
1
ylactam 12a and BF ⋅OEt . Colorless solid, m.p. 219−222 ºС. H
IR (KBr) νmax 3591, 3431, 2922, 2846, 2249, 1686, 1609, 1519,
3
2
NMR (400.1 MHz, CDCl ) δ 7.50 (d, J=8.0 Hz, 2H), 7.24 (d,
1441, 1422, 1358, 1267, 1229, 1117, 1025, 911. HRMS (ESI):
3
+
J=8.0 Hz, 2H), 7.20-7.17 (m, 2H), 7.07-7.03 (m, 1H), 6.97 (d,
J=7.8 Hz, 1H), 5.04 (s, 1H, CH), 4.49-4.45 (m, 1H, CH from
CH ), 3.87 (d, J=17.5 Hz, 1H from CH ,), 3.64 (d, J=17.5 Hz,
calcd for C H N O [M+H] 393.1814, found 393.1812; calcd
2
3
25
2
4
+
for C H N NaO [M+Na] 415.1634, found 415.1631.
23
24
2
4
2
2
1
H from CH ), 3.08-2.91 (m, 4H, isoxazoline CH + 2CH from
4.2.5. (5SR,10b'SR)-3-(4-chlorophenyl)-8',9'-dimethoxy-6',10b'-
dihydro-4H,5'H-spiro[isoxazole-5,1'-pyrrolo[2,1-a]isoquinolin]-
3'(2'H)-one (13e) (92%) was obtained using general procedure
from hydroxylactam 12e and BF ⋅OEt . Light yellow solid, de-
2
2
CH ), 2.75 (d, J=15.1 Hz, 1H from CH ), 2.41 (s, 3H, CH from
Tol). C NMR (100.6 MHz, CDCl ) δ 170.4 (CO), 155.5 (C=N),
1
2
2
3
13
3
40.7 (C ), 135.8 (C ), 130.8 (C ), 129.7 (CH ), 129.6
Ar Ar Ar Ar
3
2
1
(2CH ), 127.5 (CH ), 126.6 (2CH ), 126.3 (CH ), 126.2 (C ),
composition at 180 ºС. H NMR (400.1 MHz, CDCl ) δ 7.55 (d,
Ar
Ar
Ar
Ar
Ar
3
1
3
25.0 (CH ), 89.2 (C ), 66.3 (CH), 45.1 (CH ), 42.6 (CH ),
J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H),
Ar
spiro
2
2
7.4 (CH ), 29.7 (CH ), 21.5 (CH from Tol). HRMS (ESI): calcd
4.92 (s, 1H, CH), 4.49-4.45 (m, 1H, CH from CH ), 3.85 (s, 3H,
2
2
3
2
+
for C H N O [M+H] 333.1598, found 333.1603; calcd for
C H N NaO [M+Na] 355.1422, found 355.1417.
OMe), 3.81 (d, J=17.4 Hz, 1H from CH ,), 3.67 (d, J=17.4 Hz,
21
21
2
3
2
+
21
20
2
3
1H from CH ), 3.29 (s, 3H, OMe), 3.05-2.94 (m, 3H, isoxazoline
2
CH + CH from CH ), 2.89 (dd, J =12.2 Hz, J =2.2 Hz, 1H from
2
2
1
2
4
.2.2. (5SR,10b'SR)-3-(4-chlorophenyl)-6',10b'-dihydro-4H,5'H-
spiro[isoxazole-5,1'-pyrrolo[2,1-a]isoquinolin]-3'(2'H)-one
13b), (90%) was obtained using general procedure from hydrox-
ylactam 12b and BF ⋅OEt . White solid, m.p. 188−190 ºС (de-
CH ), 2.65 (d, J=14.5 Hz, 1H from CH ,). IR (KBr) ν
3367,
2
2
max
3079, 2921, 2851, 2254, 1695, 1603, 1516, 1463, 1432, 1360,
1272, 1234, 1164, 1092, 1038, 913. HRMS (ESI): calcd for
(
3
5
+
3
2
C H ClN O [M+H] 413.1268, found 413.1263; calcd for
22 22
2
4
1
35
+
composition). H NMR (400.1 MHz, CDCl ) δ 7.54 (d, J=8.5 Hz,
C H ClN NaO [M+Na] 435.1088, found 435.1086.
3
22 21 2 4
2
1
H), 7.41 (d, J=8.5 Hz, 2H), 7.21-7.19 (m, 2H), 7.07-7.03 (m,
H), 6.94 (d, 1H, 7.8 Hz), 5.05 (s, 1H, CH), 4.51-4.46 (m, 1H,
4.2.6. (10SR,10aSR)-3'-(4-methylphenyl)-5,10a-dihydro-4'H,6H-
spiro[benzo[f]pyrrolo[2,1-a]isoquinoline-10,5'-isoxazol]-8(9H)-
one (13f) (91%) was obtained using general procedure from hy-
droxylactam 12f and BF ⋅OEt . Light yellow solid, m.p. 185−189
CH from CH ), 3.85 (d, 1H from CH , 17.5 Hz), 3.64 (d, 1H from
CH , 17.5 Hz), 3.09-3.01 (m, 1H, CH from CH ), 2.98 (s, 2H,
isoxazoline CH ), 2.93 (dd, 1H from CH , 2.9 Hz, 12.1 Hz), 2.76
2
2
2
2
2
2
3
2
13
1
(d, 1H from CH , 15.4 Hz). C NMR (100.6 MHz, CDCl ) δ
ºС. H NMR (400.1 MHz, CDCl ) δ 7.98 (d, J=8.5 Hz, 1H), 7.78
2
3
3
1
1
70.2 (CO), 154.6 (C=N), 136.4 (C ), 135.9 (C ), 130.6 (C ),
(d, J=7.9 Hz, 1H), 7.58-7.47 (m, 5H), 7.25 (d, J=8.0 Hz, 2H),
Ar
Ar
Ar
29.8 (CH ), 129.2 (2CH ), 127.8 (2CH ), 127.6 (CH ), 127.5
7.05 (d, J=8.5 Hz, 1H), 5.19 (s, 1H, CH), 4.68 (dd, J =12.7 Hz,
Ar
Ar
Ar
Ar
1
(C ), 126.3 (CH ), 124.8 (CH ), 89.9 (Cspiro), 66.3 (CH), 44.9
J =5.2 Hz, 1H, CH from CH ), 3.97 (d, J=17.5 Hz, 1H from
Ar
Ar
Ar
2
2
(CH ), 42.2 (CH ), 37.4 (CH ), 29.7 (CH ). HRMS (ESI): calcd
CH ), 3.68 (d, J=17.5 Hz, 1H from CH ,), 3.38 (dd, 1H from
2
2
2
2
2
2
+
for C H N O [M+H] 353.1057, found 353.1062; calcd for
C H N NaO [M+Na] 375.0876, found 375.0879.
CH , J =15.5 Hz, J =2.0 Hz), 3.23-3.15 (m, 1H from CH ), 3.05-
2 1 2 2
2
0
18
2
2
+
20
17
2
2
3.00 (m, 3H, isoxazoline CH + CH from CH ), 2.43 (s, 3H, CH
2
2
3
13
from Tol). C NMR (100.6 MHz, CDCl ) δ 169.9 (CO), 155.4
3
4
.2.3. ethyl (5SR,10b'SR)-3'-oxo-2',3',6',10b'-tetrahydro-4H,5'H-
spiro[isoxazole-5,1'-pyrrolo[2,1-a]isoquinoline]-3-carboxylate
13c), (96%) was obtained using general procedure from hydrox-
(C=N), 140.7 (C ), 132.6 (C ), 132.2 (C ), 131.4 (C ), 129.6
Ar
Ar
Ar
Ar
(2CH ), 128.5 (CH ), 128.0 (C ), 126.7 (CH ), 126.6 (3CH ),
Ar
Ar
Ar
Ar
Ar
(
126.2 (C ), 125.9 (CH ), 123.3 (CH ), 122.5 (CH ), 89.0 (C
Ar Ar Ar Ar spi-
1
ylactam 12c and BF ⋅OEt . Yellow oil. H NMR (400.1 MHz,
), 66.7 (CH), 45.4 (CH ), 43.4 (CH ), 36.8 (CH ), 25.2 (CH ),
2 2 2 2
3
2
ro
CDCl ) δ 7.26-7.16 (m, 3H), 7.02 (d, J=7.6 Hz, 1H), 5.03 (s, 1H,
21.5 (CH from Tol). IR (KBr) ν
1612, 1513, 1439, 1389, 1360, 1313, 1231, 1146, 1032, 914.
3055, 2921, 2851, 1696,
3
3
max
CH), 4.48-4.44 (m, 1H, CH from CH ), 4.40-4.33 (m, 2H, CH ),
2
2
+
3
.80 (d, J=18.6 Hz, 1H from CH ), 3.46 (d, J=18.6 Hz, 1H from
HRMS (ESI): calcd for C H N O [M+H] 383.1760, found
2
25 23
2
2
+
CH ), 3.05-2.88 (m, 4H, CH +CH ), 2.74 (d, J=14.8 Hz, 1H from
383.1762; calcd for C H N NaO [M+Na] 405.1579, found
2
2
2
25 22 2 2
13
CH ,), 1.40 (t, J=7.1 Hz, 3H, CH from CO Et,). C NMR
405.1582.
2
3
2
(
100.6 MHz, CDCl ) δ 169.6 (CO), 160.2 (CO Et), 150.4 (C=N),
3
2
1
36.0 (C ), 130.1 (C ), 129.9 (CH ), 127.8 (CH ), 126.6
4.2.7. (10SR,10aSR)-3'-(4-chlorophenyl)-5,10a-dihydro-4'H,6H-
spiro[benzo[f]pyrrolo[2,1-a]isoquinoline-10,5'-isoxazol]-8(9H)-
one (13g) (98%) was obtained using general procedure from hy-
droxylactam 12g and BF ⋅OEt . Light yellow solid, m.p. 207−211
Ar
Ar
Ar
Ar
(CH ), 124.6 (CH ), 92.3 (C ), 65.7 (CH), 62.3 (CH ), 45.1
Ar Ar spiro 2
(CH ), 40.6 (CH ), 37.4 (CH ), 29.7 (CH ), 14.1 (CH from
2
2
2
2
3
+
CO Et). HRMS (ESI): calcd for C H N O [M+H] 315.1339,
found 315.1344; calcd for C H N NaO [M+Na] 337.1164,
found 337.1169.
2
17 20
2
4
3
2
+
1
17
18
2
4
ºС (decomposition). H NMR (400.1 MHz, CDCl ) δ 7.97 (d,
3
J=8.4 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.57-7.49 (m, 5H), 7.41
(
(
d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 5.16 (s, 1H, CH), 4.66
dd, J =12.8 Hz, J =5.4 Hz, 1H, CH from CH ), 3.93 (d, J=17.5
4
.2.4. (5SR,10b'SR)-8',9'-dimethoxy-3-(4-methylphenyl)-6',10b'-
dihydro-4H,5'H-spiro[isoxazole-5,1'-pyrrolo[2,1-a]isoquinolin]-
'(2'H)-one (13d) (98%) was obtained using general procedure
from hydroxylactam 12d and BF ⋅OEt . White solid, decomposi-
1
2
2
Hz, 1H from CH ), 3.64 (d, J=17.5 Hz, 1H from CH ), 3.36 (dd,
J =16.0 Hz, J =2.1 Hz, 1H from CH ), 3.20-3.12 (m, 1H from
CH ), 3.03-2.96 (m, 3H, isoxazoline CH + CH from CH ).
NMR (100.6 MHz, CDCl ) δ 169.8 (CO), 154.7 (C=N), 136.4
(C ), 132.6 (C ), 132.1 (C ), 131.5 (C ), 129.2 (2CH ), 128.5
(CH ), 127.9 (2CH ), 127.8 (C ), 127.5 (C ), 126.7 (CH ),
126.7 (CH ), 126.0 (CH ), 123.3 (CH ), 122.4 (CH ), 89.6
Ar Ar Ar Ar
(Cspiro), 66.6 (CH), 45.3 (CH ), 42.9 (CH ), 36.8 (CH ), 25.3
2
2
3
1
2
2
1
3
3
2
C
2
2
2
1
tion at 220 ºС. H NMR (400.1 MHz, CDCl ) δ 7.51 (d, J=8.0
Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 4.92
3
3
Ar
Ar
Ar
Ar
Ar
(s, 1H, CH), 4.50-4.46 (m, 1H, CH from CH ), 3.86 (s, 3H,
2
Ar Ar Ar Ar Ar
OMe), 3.83 (d, J=17.5 Hz, 1H from CH ), 3.69 (d, J=17.5 Hz,
1
2
H from CH ,), 3.26 (s, 3H, OMe), 3.05-2.94 (m, 3H, isoxazoline
2
2 2 2

5
García-Grávalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Ji-
(
1
CH ). IR (KBr) ν 3056, 2920, 2851, 1689,
A
15
C
97
C
, 1
E
44
P
0
TED
8, MANUSCRIPT
, 1
35
2
max
ménez, J. A.; Manzanares, I.; Cuevas, C.; Bailly, C. Bioorg. Med.
Chem. 2004, 12, 1697.
313, 1271, 1093, 1013, 922. HRMS (ESI): calcd for
+
C H ClN O [M+H] 403.1213, found 403.1219; calcd for
C H ClN NaO [M+Na] 425.1033, found 425.1039.
24
20
2
2
8
.
(a) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank, R.
P.; Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J.
Med. Chem. 1987, 30, 1433; (b) Maryanoff, B. E.; McComsey, D.
F.; Dukor, R. K.; Nafie, L. A.; Freedman, T. B.; Cao, X.; Day. V.
W. Bioorg. Med. Chem. 2003, 11, 2463.
+
24
19
2
2
Acknowledgments
9
.
(a) An, T.-Y.; Huang, R.-Q.; Yang, Z.; Zhang, D.-K.; Li, G.-R.;
Yao, Y.-C.; Gao, J. Phytochemistry 2001, 58, 1267; (b) Gunder-
sen, L. L.; Charnock, C.; Negussie, A. H.; Rise, F.; Teklu, S. Eur.
J. Pharm. Sci. 2007, 30, 26.
We gratefully acknowledge the financial support from the
Russian Science Foundation (Project No 14-13-00126) and Rus-
sian Foundation for Basic Research (Project No 15-03-05319).
This research made use of resources from the X-ray Diffraction
Centre, Centre for Magnetic Resonance, Educational Resourse
Center of Chemistry and the Centre for Chemical Analysis and
Materials of Saint-Petersburg State University.
1
1
0. Chung, S.-H.; Yook, J.; Min, B. J.; Lee, J. Y.; Lee, Y. S.; Jin, C.
Arch. Pharmacol. Res. 2000, 23, 353.
1. (a) Gupta, S. P.; Mathur, A. N.; Nagappa, A. N.; Kumar, D.; Ku-
maran, S. Eur. J. Med. Chem. 2003, 38, 867; (b) Poty, C.; Gibon,
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Chatelain, P.; Durant, F. Eur. J. Med. Chem. 1994, 29, 911.
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1
1
Supplementary Material
8
5
1215q); (b) C. Rossi, WO 98/55118 (Chem. Abstr., 1999, 130,
7206d).
Crystallographic data for compound 13d (CCDC-1402706)
have been deposited at the Cambridge Crystallographic Data
Centre and can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data (ex-
perimental procedures, characterization data, and copies of NMR
spectra) associated with this article can be found in the online
version, at doi:
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ACCEPTED MANUSCRIPT
An efficient synthesis of substituted spiro[isoxazolopyrroloisoquinolines] via
diastereoselective N-acyliminium ion cyclization
*
Maria S. Ledovskaya, Alexander V. Stepakov, Alexander P. Molchanov, Rafael R. Kostikov
Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St-Petersburg
1
98504, Russian Federation
Supporting information
Preparative details, physical properties and spectroscopic data for compounds 9a−c, 11a−g,
1
2a−g and 13a−g.
General. IR spectra were obtained on an Bruker Tensor 27 spectrometer. Melting points were
determined on a Boetius instrument and are uncorrected. NMR spectra were recorded on a
1
13
Bruker Avance III spectrometer ( H, 400 MHz; C, 100 MHz). Chemical shifts δ are reported in
1
13
ppm relative to residual CHCl
3
( H, δ = 7.26) and CDCl
3
( C, δ = 77.16) as internal standard.
High-resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF 10223
spectrometer using electrospray ionization (ESI). The X-ray diffraction data were performed by
means of an Bruker APEX-II CCD diffractometer with Mo-K X-ray radiation. Reactions were
monitored by TLC analysis using Silufol UV-254 plates. Thin layer chromatography was
performed on silica gel 5−40 mesh eluted with dichloromethane/methanol.
*
Corresponding author. Fax: 7-812-4286939; e-mail: alstepakov@yandex.ru

ACCEPTED MANUSCRIPT
General procedure for the synthesis of itaconic acid imides
O
O
O
Ac O, AcONa,
2
o
Et O, 30 min, rt
2
75 C, 20 min
O
H
2
N
Ar
HN
CO H
Ar
N
Ar
2
O
O
Ar = Ph, 3,4-(MeO) C H , 1-naphthyl
2
6 3
To the round bottom flask were placed 4.48 g of itaconic acid anhydride and 35 ml of
diethyl ether, then 0.04 mol of corresponding amine in 15 ml of Et O was added dropwise under
2
water bath cooling (approx. 5-10 ºC). After this the resulting mixture was stirred at room
temperature for 30 minutes and quenched with 50 ml of hexane. Formed precipitate was filtered
and twice washed with hexane. Imidoacid yield 80-95 %.
Previously synthesized imidoacid and acetic acid anhydride were placed into the round
bottom flask, then sodium acetate was added and the resulting mixture was heated at 75 ºC for 20
minutes. Attention please, the temperature must not be overheated! After this reaction mixture
was poured into ice water and leaved until oil was formed. The latter was carefully decanted
from water and imides (itaconic and citraconic imides are formed in the mixture) were extracted
by heating of organics in isooctane and chromatographically separated. Yield of desired imide
1
5-30 %.
3
-Methylene-1-(phenethyl)pyrrolidine-2,5-dione (9a)
O
N
O
Isolated by column chromatography with hexane/ethyl acetate, yield 6 %;
M.p. 53-60 ºС; light yellow solid;
1
H (400.1 MHz, CDCl
3
) δ
(double bond), 2.0 Hz), 3.85 (t, 2H, CH
.94 (t, 2H, CH , 7.8 Hz);
C (100.6 MHz, CDCl ) δ
2CHAr), 128.57 (2CHAr), 126.71 (CHAr), 120.44 (CH
CH ), 33.62 (CH );
H
: 7.34-7.24 (m, 5H), 6.36 (t, 1H, CH
2
(double bond), 2.4 Hz), 5.63 (t,
in the ring, 2.2 Hz),
1
H, CH
2
2
, 7.8 Hz), 3.29 (t, 2H, CH
2
2
1
2
3
3
C
: 173.55 (CO), 169.26 (CO), 137.80 (CAr), 133.25 (Cquat), 128.82
at double bond), 39.98 (CH ), 33.67
(
(
2
2
2
2

ACCEPTED MANUSCRIPT
-1
IR (KBr, cm ): 3457, 3430, 3075, 3029, 2960, 2940, 2867, 1888, 1771, 1704, 1666, 1433, 1406,
1
341, 1270, 1130, 1021, 956;
+
2 2
HRMS (ESI): calcd for C13H14NO [M+H] 216.1025, found 216.1025; calcd for C13H13NNaO
+
[
M+Na] 238.0844, found 238.0850.
3
-Methylene-1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidine-2,5-dione (9b)
O
N
OMe
O
OMe
Isolated by column chromatography with hexane/ethyl acetate, yield 10 %;
M.p. 123-126 ºС; yellow solid;
1
H (400.1 MHz, CDCl
H, CH (double bond), 1.9 Hz), 3.89 (s, 3H, OCH
Hz, 8.7 Hz), 3.29 (t, 2H, CH in the ring, 2.1 Hz), 2.89 (t, 2H, CH
: 173.61 (CO), 169.34 (CO), 148.92 (CAr), 147.78 (CAr), 133.17
Ar), 130.21 (Cquat), 120.85 (CHAr), 120.54 (CH at double bond), 111.94 (CHAr), 111.27 (CHAr),
5.88 (2*OMe), 40.07 (CH ), 33.71 (CH ), 33.15 (CH );
3
) δ
H
: 6.80-6.76 (m, 3H), 6.35 (t, 1H, CH
), 3.87 (s, 3H, OCH
, 7.6 Hz);
2
(double bond), 2.4 Hz), 5.63 (t,
1
2
3
3
), 3.83 (dd, 2H, CH , 7.6
2
2
2
1
3
3 C
C (100.6 MHz, CDCl ) δ
(
5
C
2
2
2
2
-1
IR (KBr, cm ): 3459, 3130, 3085, 2995, 2940, 2923, 2836, 1773, 1708, 1662, 1590, 1516, 1434,
402, 1343, 1274, 1232, 1145, 1026, 973;
1
+
4 4
HRMS (ESI): calcd for C15H18NO [M+H] 276.1236, found 276.1239; calcd for C15H17NNaO
+
[
M+Na] 298.1055, found 298.1061.
3
-Methylene-1-(2-(naphth-1-yl)ethyl)pyrrolidine-2,5-dione (9c)
O
N
O
Isolated by column chromatography with hexane/ethyl acetate, yield 10 %;
M.p. 75-81 ºС; light yellow solid;
1
3 H
H (400.1 MHz, CDCl ) δ : 8.28 (d, 1HAr, 8.4 Hz), 7.87 (d, 1HAr, 8.2 Hz), 7.79 (dd, 1HAr, 6.3
Hz, 3.0 Hz), 7.63-7.59 (m, 1HAr), 7.52 (t, 1HAr, 7.2 Hz), 7.44-7.41 (m, 2HAr), 6.39 (t, 1H,

ACCEPTED MANUSCRIPT
CH
2
(double bond), 2.4 Hz), 5.65 (t, 1H, CH
2
(double bond), 1.9 Hz), 3.98-3.94 (m, 2H, CH
2
),
3
.41-3.37 (m, 2H, CH
2
), 3.32 (t, 2H, CH
C (100.6 MHz, CDCl ) δ
Ar), 131.99 (Cquat), 128.81 (CHAr), 127.65 (CHAr), 127.06 (CHAr), 126.43 (CHAr), 125.75
CHAr), 125.52 (CHAr), 123.64 (CHAr), 120.60 (CH at double bond), 39.60 (CH ), 33.80 (CH ),
1.20 (CH );
2
, 2.1 Hz);
1
3
3
C
: 173.62 (CO), 169.41 (CO), 134.00 (CAr), 133.88 (CAr), 133.27
(
(
C
2
2
2
3
2
+
2
HRMS (ESI): calcd for C17H15NNaO [M+Na] 288.1000, found 288.0996.
General procedure for the synthesis of
-(2-arylethyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-6,8-diones
7
To vigorously stirring solution of 1.5 equiv of corresponding chloroxime and 1 equiv of
3
-methylene-1-(2-arylethyl)pyrrolidine-2,5-dione (9) in dry benzene was slowly added 1.5 equiv
of triethylamine in benzene. Formed mixture then stirred at room temperature until the reaction
was completed (TLC-control). After the reaction was completed, the water was added and the
product was extracted with ethyl acetate. The organic phase was dried over MgSO . After this,
4
the solvent was evaporated and the residue was recrystallized with ethanol.
7-Phenethyl-3-p-tolyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-6,8-dione (11a)
H C
3
N
O
O
N
O
M.p. 193-196 ºС; white solid, yield 86 %;
1
H (400.1 MHz, CDCl
.80 (m, 3H, CH + CH from CH
Hz), 2.98 (t, 2H, CH , 7.5 Hz), 2.85 (d, 1H from CH
C (100.6 MHz, CDCl ) δ : 174.91 (CO), 172.78 (CO), 155.64 (C=N), 141.19 (CAr), 137.37
Ar), 129.60 (2CHAr), 128.95 (2CHAr), 128.63 (2CHAr), 126.89 (2CHAr), 126.87 (CHAr), 125.35
Ar), 83.75 (Cquat), 43.72 (CH ), 42.58 (CH ), 40.37 (CH ), 33.31 (CH ), 21.51 (CH from Tol);
3
) δ
H
: 7.55 (d, 2H, 8.1 Hz), 7.33 (d, 2H, 7.5 Hz), 7.27-7. 24 (m, 5H), 3.91-
), 3.32 (d, 1H from CH , 16.8 Hz), 3.16 (d, 1H from CH , 18.5
, 18.5 Hz), 2.42 (s, 3H, CH );
3
2
2
2
2
2
2
3
1
3
3
C
(
(
C
C
2
2
2
2
3
-1
IR (KBr, cm ): 3483, 3063, 3026, 2995, 2949, 2868, 1787, 1708, 1610, 1455, 1406, 1356, 1253,
139, 995;
1

ACCEPTED MANUSCRIPT
+
21 2 3 20 2 3
HRMS (ESI): calcd for C21H N O [M+H] 349.1552, found 349.1548, calcd for C21H N NaO
+
[
M+Na] 371.1372, found 371.1366.
3
-(4-Chlorophenyl)-7-phenethyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-6,8-dione (11b)
Cl
N
O
O
N
O
M.p. 189-192 ºС; white solid, yield 42 %;
1
H (400.1 MHz, CDCl
.74 (m, 3H, CH + CH from CH
Hz), 2.98 (t, 2H, CH , 7.5 Hz), 2.86 (d, 1H from CH
C (100.6 MHz, CDCl ) δ : 174.65 (CO), 172.55 (CO), 154.78 (C=N), 137.31 (CAr), 136.88
Ar), 129.23 (2CHAr), 128.94 (2CHAr), 128.64 (2CHAr), 128.15 (2CHAr), 126.89 (CHAr), 126.71
Ar), 84.15 (Cquat), 43.29 (CH ), 42.40 (CH ), 40.41 (CH ), 33.28 (CH );
3
) δ
H
: 7.60 (d, 2H, 8.6 Hz), 7.43 (d, 2H, 8.6 Hz), 7.42-7.23 (m, 5H), 3.93-
), 3.31 (d, 1H from CH , 17.0 Hz), 3.17 (d, 1H from CH , 18.5
, 18.5 Hz);
3
2
2
2
2
2
2
1
3
3
C
(
(
C
C
2
2
2
2
-1
IR (KBr, cm ): 3474, 3084, 3054, 3026, 2988, 2947, 1782, 1712, 1598, 1492, 1406, 1364, 1251,
142, 1094, 994;
HRMS (ESI): calcd for C20
1
+
H
2 3
17ClN NaO [M+Na] 391.0825, found 391.0831.
6
,8-Dioxo-7-phenethyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid ethyl ester
(
11c)
O
N
O
O
EtO
N
O
M.p. 83-85 ºС; colorless solid, yield 25 %;
1
H (400.1 MHz, CDCl
3
) δ
H
: 7.34-7.20 (m, 5H), 4.40 (q, 2H, CH
, 18.0 Hz), 3.22 (d, 1H from CH
, 7.5 Hz), 2.82 (d, 1H from CH , 18.6 Hz), 1.40 (t, 3H, CH
3
2
from CO
2
Et, 7.2 Hz), 3.87-3.82
(
m, 2H, CH ), 3.68 (d, 1H from CH
2
2
2
, 18.0 Hz), 3.12 (d, 1H
from CH
2
, 18.6 Hz), 2.96 (t, 2H, CH
Et, 7.2 Hz);
2
2
from CO
2

ACCEPTED MANUSCRIPT
1
3
C (100.6 MHz, CDCl
3
) δ
C
: 173.60 (CO), 172.04 (CO), 159.46 (CO
2
Et), 150.62 (C=N), 137.13
), 42.09 (CH ),
(
C
Ar), 128.89 (2CHAr), 128.65 (2CHAr), 126.96 (CHAr), 85.90 (Cquat), 62.62 (CH
2
2
4
2.02 (CH
2
), 40.51 (CH
2
), 33.20 (CH
2
3 2
), 14.09 (CH from CO Et);
+
HRMS (ESI): calcd for C17
H
18
N
2
NaO
5
[M+Na] 353.1113, found 353.1107.
7
-[2-(3,4-Dimethoxyphenyl)ethyl]-3-p-tolyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-6,8-dione
(
11d)
H C
3
N
O
O
N
OMe
O
OMe
M.p. 168-169 ºС; white solid, yield 63 %;
1
H (400.1 MHz, CDCl
s, 3H, OMe), 3.89 (s, 3H, OMe), 3.86-3.82 (m, 3H, CH
CH , 16.8 Hz), 3.16 (d, 1H from CH , 18.5 Hz), 2.93 (t, 2H, CH
8.5 Hz), 2.42 (s, 3H, CH from Tol);
) δ : 174.98 (CO), 172.79 (CO), 155.67 (C=N), 149.02 (CAr), 147.96
Ar), 141.20 (CAr), 129.84 (CAr), 129.60 (2CHAr), 126.89 (2CHAr), 125.34 (CAr), 120.98 (CHAr),
12.12 (CHAr), 111.34 (CHAr), 83.75 (Cquat), 55.96 (OMe), 55.91 (OMe), 43.67 (CH ), 42.57
CH ), 40.45 (CH ), 32.87 (CH ), 21.50 (CH from Tol);
IR (KBr, cm ): 3482, 3064, 3033, 3001, 2962, 2941, 2923, 2843, 1789, 1715, 1590, 1519, 1408,
339, 1272, 1236, 1141, 1029, 921;
HRMS (ESI): calcd for C H N NaO [M+Na] 431.1583, found 431.1587.
3
) δ
H
: 7.55 (d, 2H, 7.9 Hz), 7.25 (d, 2H, 7.9 Hz), 6.85-6.76 (m, 3H), 3.92
+ CH from CH ), 3.32 (d, 1H from
, 7.4 Hz), 2.86 (d, 1H from CH
(
2
2
2
2
2
2
,
1
1
3
3
C (100.6 MHz, CDCl
3
C
(
C
1
2
(
2
2
2
3
-1
1
+
2
3
24
2
5
3
6
-(4-Chlorophenyl)-7-[2-(3,4-dimethoxyphenyl)ethyl]-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-
,8-dione (11e)
Cl
N
O
O
N
OMe
O
OMe

ACCEPTED MANUSCRIPT
M.p. 155-158 ºС; white solid, yield 24 %;
1
H (400.1 MHz, CDCl
s, 3H, OMe), 3.89 (s, 3H, OMe), 3.90-3.79 (m, 3H, CH
, 16.8 Hz), 3.17 (d, 1H from CH , 18.5 Hz), 2.93 (t, 2H, CH
3
) δ
H
: 7.60 (d, 2H, 8.6 Hz), 7.43 (d, 2H, 8.6 Hz), 6.84-6.75 (m, 3H), 3.91
+ CH from CH ), 3.31 (d, 1H from
, 7.6 Hz), 2.86 (d, 1H from CH
(
2
2
CH
2
2
2
2
,
1
8.5 Hz);
1
3
3 C
C (100.6 MHz, CDCl ) δ : 174.73 (CO), 172.55 (CO), 154.80 (C=N), 149.02 (CAr), 147.98
(
C
Ar), 136.90 (CAr), 129.76 (CAr), 129.24 (2CHAr), 128.15 (2CHAr), 126.68 (CAr), 121.00 (CHAr),
12.14 (CHAr), 111.35 (CHAr), 84.15 (Cquat), 55.97 (OMe), 55.92 (OMe), 43.26 (CH ), 42.40
CH ), 40.48 (CH ), 32.84 (CH );
IR (KBr, cm ): 3482, 3062, 2994, 2958, 2922, 2850, 1789, 1715, 1596, 1519, 1406, 1339, 1272,
237, 1141, 1029, 923.
HRMS (ESI): calcd for C22
1
2
(
2
2
2
-1
1
+
H
2 5
21ClN NaO [M+Na] 451.1037, found 451.1042.
7
-(2-Naphthalen-1-yl-ethyl)-3-p-tolyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-6,8-dione (11f)
H C
3
N
O
O
N
O
M.p. 183-185 ºС (CH
2
Cl
2
/MeOH); white solid, yield 85 %;
: 8.20 (d, 1H, 8.0 Hz), 7.90 (d, 1H, 8.0 Hz), 7.80 (d, 1H, 8.0 Hz),
1
H (400.1 MHz, CDCl
3
) δ
H
7
.62-7.42 (m, 6H), 7.26 (d, 2H, 6.0 Hz), 3.98 (t, 2H, CH , 8.0 Hz), 3.70 (d, 1H from CH , 17.0
2
2
Hz), 3.46-3.40 (m, 2H, CH
2
), 3.22 (d, 1H from CH
);
: 175.00 (CO), 172.91 (CO), 155.63 (C=N), 141.19 (CAr), 133.86
C ), 133.66 (C ), 132.03 (C ), 129.60 (2CH ), 128.90 (CH ), 127.76 (CH ), 127.35 (CH ),
2
, 17.0 Hz), 3.17 (dd, 1H from CH
2
, 18.5 Hz),
2
.83 (d, 1H from CH
2
, 18.5 Hz), 2.42 (s, 3H, CH
3
1
3
C (100.6 MHz, CDCl ) δ
3
C
(
Ar
Ar
Ar
Ar
Ar
Ar
Ar
1
26.88 (2CHAr), 126.45 (CHAr), 125.76 (CHAr), 125.61 (CHAr), 125.32 (CAr), 123.49 (CHAr),
3.72 (Cquat), 43.72 (CH ), 42.67 (CH ), 40.12 (CH ), 30.69 (CH ), 21.51 (CH from Tol);
8
2
2
2
2
3
-1
IR (KBr, cm ): 3473, 3056, 2985, 2948, 2922, 2851, 1783, 1707, 1597, 1509, 1437, 1398, 1354,
247, 1166, 1137, 1051, 990;
HRMS (ESI): calcd for C25
1
+
23 2 3
H N O [M+H] 399.1709, found 399.1710.
3-(4-Chlorophenyl)-7-(2-naphthalen-1-yl-ethyl)-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-6,8-
dione (11g)

ClACCEPTED MANUSCRIPT
N
O
O
N
O
M.p. 173-176 ºС (EtOH); white solid, yield 68 %;
1
H (400.1 MHz, CDCl
.62-7.41 (m, 8H), 3.98 (t, 2H, CH
CH ), 3.19 (d, 1H from CH , 16.9 Hz), 3.17 (dd, 1H from CH
3
) δ
H
: 8.19 (d, 1H, 8.4 Hz), 7.90 (d, 1H, 7.9 Hz), 7.80 (d, 1H, 7.8 Hz),
, 7.7 Hz), 3.65 (d, 1H from CH , 16.9 Hz), 3.46-3.38 (m, 2H,
, 18.5 Hz), 2.84 (d, 1H from CH
7
2
2
2
2
2
2
,
1
8.5 Hz);
1
3
3 C
C (100.6 MHz, CDCl ) δ : 174.75 (CO), 172.71 (CO), 154.78 (C=N), 136.88 (CAr), 133.86
(
(
(
CAr), 133.61 (CAr), 132.03 (CAr), 129.23 (2CHAr), 128.92 (CHAr), 128.14 (2CHAr), 127.78
CHAr), 127.38 (CHAr), 126.67 (CAr), 126.45 (CHAr), 125.77 (CHAr), 125.63 (CHAr), 123.45
CH ), 84.12 (C ), 43.29 (CH ), 42.48 (CH ), 40.17 (CH ), 30.64 (CH );
Ar
quat
2
2
2
2
-1
IR (KBr, cm ): 3479, 3057, 2987, 2950, 2922, 2851, 1786, 1709, 1596, 1493, 1402, 1351, 1247,
138, 1095, 991;
HRMS (ESI): calcd for C24
1
+
H
2 3
19ClN NaO [M+Na] 441.0982, found 441.0987.
General procedure for the reduction of
-(2-arylethyl)-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-6,8-diones
7
To vigorously stirred solution of dihydroisoxazoles 11 in CH
added 1.5 equiv of sodium borohydride in ethanol (final ratio CH Cl
the reaction flask was left in refrigerator at −20 ºC until the end of reaction (monitored by TLC).
After completion of the reduction, the reaction mixture was treated with saturated NH Cl
, solvent was removed by
2
Cl
2
/EtOH 3:1 at -78 ºC was
2
2
/EtOH must be 1:1). Then
4
solution, extracted with CH
2
Cl
2
, dried over anhyd. Na
2
SO4
concentration.
6
-Hydroxy-7-phenethyl-3-p-tolyl-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-one (12a)
H C
3
N
O
OH
N
O

ACCEPTED MANUSCRIPT
Was obtained as 5:3 mixture of two diastereomers (unseparable by chromatography), 1H and
3C NMR signals are given for major one.
1
M.p. 177-182 ºС; white solid, yield 96 %;
1
H (400.1 MHz, CDCl
3
) δ
), 3.30 (d, 1H from CH
+CH from CH ), 2.80 (s, 1H, OH), 2.56 (d, 1H from CH
2
H
: 7.49 (d, 2H, 8.1 Hz), 7.35-7. 21 (m, 7H), 4.68 (s, 1H, CH at OH),
, 17.1 Hz), 3.19 (d, 1H from CH , 17.1 Hz), 3.02-
, 18.5 Hz), 2.41 (s,
3
2
3
.87-3.50 (m, 2H, CH
.91 (m, 3H, CH
H, CH );
C (100.6 MHz, CDCl
2CHAr), 129.45 (2CHAr), 128.54 (2CHAr), 126.70 (2CHAr), 126.65 (CHAr), 125.61 (CAr), 87.80
2
2
2
2
2
3
1
3
3
C
) δ : 170.27 (CO), 157.46 (C=N), 141.22 (CAr), 138.78 (CAr), 129.52
(
(
CH at OH), 85.21 (Cquat), 43.46 (CH
2
), 41.43 (CH
2
), 41.34 (CH
2
), 33.78 (CH
2
), 21.35 (CH
3
from Tol);
-1
IR (KBr, cm ): 3136, 3051, 2923, 2852, 1710, 1653, 1468, 1403, 1339, 1158, 1090, 990;
+
HRMS (ESI): calcd for C21
H
23
N
2
O
3
[M+H] 351.1709, found 351.1712, calcd for C21
H
22
N
2
NaO
3
+
[M+Na] 373.1528, found 373.1531.
3
-(4-Chlorophenyl)-6-hydroxy-7-phenethyl-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-one (12b)
Cl
N
O
OH
N
O
M.p. 155-160 ºС (darkens after 144 ºС); light yellow solid, yield 92 %;
1
H (400.1 MHz, CDCl
3
H
) δ : 7.53 (d, 2H, 8.6 Hz), 7.41 (d, 2H, 8.6 Hz), 7.33-7. 25 (m, 5H), 4.67
(
s, 1H, CH at OH), 3.84-3.77 (m, 1H, from CH
2
), 3.57-3.50 (m, 1H, from CH ), 3.28 (d, 1H from
2
CH , 17.1 Hz), 3.16 (d, 1H from CH , 17.2 Hz), 3.11-2.89 (m, 3H, CH +CH from CH ), 2.81 (s,
2
2
2
2
1
H, OH), 2.57 (d, 1H from CH
2
, 17.2 Hz);
1
3
C (100.6 MHz, CDCl
2CHAr), 128.87 (2CHAr), 128.56 (2CHAr), 127.95 (2CHAr), 126.95 (CAr), 126.56 (CHAr), 87.82
CH at OH), 85.79 (Cquat), 43.09 (CH ), 41.40 (CH ), 41.30 (CH ), 33.74 (CH );
3 C
) δ : 170.13 (CO), 156.53 (C=N), 138.75 (CAr), 136.98 (CAr), 129.16
(
(
2
2
2
2
-1
IR (KBr, cm ): 3207, 3063, 3026, 2926, 2853, 1680, 1596, 1454, 1405, 1363, 1281, 1136, 1092,
014, 926;
HRMS (ESI): calcd for C H ClN O [M+H] 371.1162, found 371.1166, calcd for
1
+
2
0
20
2
3
+
20 2 3
C H19ClN NaO [M+Na] 393.0982, found 393.0987.

ACCEPTED MANUSCRIPT
6
-Hydroxy-8-oxo-7-phenethyl-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-3-carboxylic acid ethyl
ester (12c)
O
N
O
OH
EtO
N
O
M.p. 100-104 ºС; white solid, yield 100 %;
1
H (400.1 MHz, CDCl
.2 Hz), 3.53-3.45 (m, 2H, CH
Hz), 2.97-2.89 (m, 3H, 1H from CH
OH), 1.37 (t, 3H, CH from CO Et, 7.2 Hz);
C (100.6 MHz, CDCl ) δ : 169.64 (CO), 159.60 (CO
2CHAr), 128.65 (2CHAr), 126.71 (CHAr), 88.33 (Cquat), 87.85 (CH at OH), 62.54 (CH
2*CH ), 41.58 (CH ), 33.73 (CH ), 14.06 (CH from CO Et);
NaO [M+Na] 355.1270, found 355.1265.
3
) δ
H
: 7.33-7.22 (m, 5H), 4.63 (s, 1H, CH), 4.35 (q, 2H, CH
), 3.20 (d, 1H from CH , 18.5 Hz), 3.13 (d, 1H from CH
+ CH ), 2.54 (d, 1H from CH , 17.5 Hz), 1.87 (br s, 1H,
2
from CO
2
Et,
7
2
2
2
, 18.5
2
2
2
3
2
1
3
3
C
2
Et), 152.33 (C=N), 138.60 (CAr), 128.88
), 41.51
(
(
2
2
2
2
3
2
+
HRMS (ESI): calcd for C17
H
20
N
2
5
7
8
-[2-(3,4-Dimethoxy-phenyl)ethyl]-6-hydroxy-3-p-tolyl-1-oxa-2,7-diaza-spiro[4.4]non-2-en-
-one (12d)
H C
3
N
O
OH
N
OMe
O
OMe
M.p. 205-208 ºС; white solid, yield 95 %;
1
H (400.1 MHz, acetone-d
6
) δ
H
: 7.42 (d, 2H, 7.7 Hz), 7.16 (d, 2H, 7.7 Hz), 6.77-6.71 (m, 3H),
),
, 17.2 Hz),
, 16.9 Hz), 2.46 (br s, 1H, OH),
4
3
2
2
.70 (s, 1H, CH at OH), 3.81 (s, 3H, OMe), 3.78 (s, 3H, OMe), 3.83-3.72 (m, 1H from CH
2
.43-3.38 (m, 1H from CH
.94-2.76 (m, 3H, CH +CH from CH
.32 (s, 3H, CH );
C (100.6 MHz, acetone-d
Ar), 131.28 (CAr), 129.42 (2CHAr), 126.57 (2CHAr), 125.79 (CAr), 120.74 (CHAr), 112.04
2
), 3.26 (d, 1H from CH
2
, 17.2 Hz), 3.13 (d, 1H from CH
2
2
2
), 2.52 (d, 1H from CH
2
3
1
3
6
C
) δ : 170.56 (CO), 157.18 (C=N), 148.95 (CAr), 147.64 (CAr), 140.86
(
C

ACCEPTED MANUSCRIPT
(
CHAr), 111.28 (CHAr), 87.62 (CH at OH), 85.38 (Cquat), 55.78 (OMe), 55.75 (OMe), 43.36
CH ), 41.19 (CH ), 41.13 (CH ), 33.21 (CH ), 21.28 (CH from Tol);
(
2
2
2
2
3
-1
IR (KBr, cm ): 3413, 3370, 3141, 3036, 3001, 2959, 2922, 2840, 1687, 1590, 1518, 1454, 1411,
1
336, 1267, 1235, 1157, 1138, 1028, 924;
+
HRMS (ESI): calcd for C23
H
27
N
2
O
5
[M+H] 411.1920, found 411.1923, calcd for C23
26 2 5
H N NaO
+
[M+Na] 433.1739, found 433.1745.
3
-(4-Chlorophenyl)-7-[2-(3,4-dimethoxy-phenyl)ethyl]-6-hydroxy-1-oxa-2,7-diaza-
spiro[4.4]non-2-en-8-one (12e)
Cl
N
O
OH
N
OMe
O
OMe
Na
M.p. 181-184 ºС; light beige solid, yield 100 %;
1
H (400.1 MHz, CDCl
s, 1H, CH at OH), 3.90 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.82-3.75 (m, 1H from CH
.48 (m, 1H from CH ), 3.31 (d, 1H from CH , 17.2 Hz), 3.19 (d, 1H from CH , 17.2 Hz), 3.02
d, 1H from CH , 17.3 Hz), 2.99-2.82 (m, 2H, CH ), 2.59 (d, 1H from CH , 17.3 Hz), 1.80 (br s,
3
) δ
H
: 7.54 (d, 2H, 8.5 Hz), 7.42 (d, 2H, 8.5 Hz), 6.84-6.78 (m, 3H), 4.69
(
2
), 3.55-
3
2
2
2
(
2
2
2
1
H, OH);
1
3
C (100.6 MHz, CDCl
3 C
) δ : 170.10 (CO), 156.62 (C=N), 149.05 (CAr), 147.78 (CAr), 136.98
(
(
(
CAr), 131.18 (CAr), 129.23 (2CHAr), 127.98 (2CHAr), 126.82 (CAr), 120.78 (CHAr), 112.13
CHAr), 111.36 (CHAr), 87.73 (CH at OH), 85.84 (Cquat), 55.97 (OMe), 55.93 (OMe), 42.87
CH ), 41.39 (CH ), 41.36 (CH ), 33.28 (CH );
2
2
2
2
-1
IR (KBr, cm ): 3416, 3065, 3006, 2922, 2850, 1690, 1672, 1592, 1519, 1454, 1410, 1335, 1269,
239, 1158, 1138, 1029, 923;
HRMS (ESI): calcd for C22
1
+
H
24ClN
2
O
5
[M+H] 431.1374, found 431.1376, calcd for
+
C H23ClN NaO [M+Na] 453.1193, found 453.1199.
22 2 5

ACCEPTED MANUSCRIPT
6
-Hydroxy-7-[2-(naphthalen-1-yl)ethyl]-3-p-tolyl-1-oxa-2,7-diaza-spiro[4.4]non-2-en-8-one
(
12f)
H C
3
N
O
OH
N
O
M.p. 215-218 ºС; white solid, yield 96 %;
1
3 H
H (400.1 MHz, CDCl ) δ : 8.20 (d, 1H, 8.4 Hz), 7.89 (d, 1H, 7.6 Hz), 7.78 (dd, 1H, 7.4 Hz, 1.7
Hz), 7.59-7.42 (m, 6H), 7.24 (d, 2H, 7.9 Hz), 4.52 (d, 1H, CH at OH, 9.0 Hz), 3.92-3.85 (m, 1H
from CH ), 3.69-3.53 (m, 2H, CH ), 3.37-3.31 (m, 1H from CH ), 3.26 (d, 1H, OH, 9.0 Hz), 3.21
d, 1H from CH , 17.4 Hz), 3.01 (“t”, 2H, CH , 17.1 Hz), 2.59 (d, 1H from CH , 17.4 Hz), 2.41
2
2
2
(
2
2
2
3
(s, 3H, CH );
1
3
C (100.6 MHz, CDCl
Ar), 132.17 (CAr), 129.55 (2CHAr), 128.81 (CHAr), 127.38 (CHAr), 127.02 (CHAr), 126.71
2CHAr), 126.35 (CHAr), 125.79 (CHAr), 125.59 (CHAr), 125.44 (CAr), 123.78 (CHAr), 88.22 (CH
3 C
) δ : 170.48 (CO), 157.50 (C=N), 141.28 (CAr), 135.10 (CAr), 133.84
(
(
C
2 2 2 2 3
at OH), 85.09 (Cquat), 43.42 (CH ), 41.64 (CH ), 41.51 (CH ), 31.07 (CH ), 21.50 (CH from
Tol);
-1
IR (KBr, cm ): 3219, 3060, 3008, 2937, 2872, 2738, 1705, 1653, 1510, 1460, 1433, 1332, 1283,
166, 1122, 981;
1
+
HRMS (ESI): calcd for C25
H
25
N
2
O
3
[M+H] 401.1865, found 401.1871, calcd for C25
25 2 3
H N O
+
C H N NaO [M+Na] 423.1685, found 423.1691.
25 24 2 3
3
2
-(4-Chlorophenyl)-6-hydroxy-7-[2-(naphthalen-1-yl)ethyl]-1-oxa-2,7-diaza-spiro[4.4]non-
-en-8-one (12g)
Cl
N
O
OH
N
O
3
After staying for two weeks in CDCl at room temperature hydroxylactam was turned to other
stereoisomer (by carbon at OH). All data that not referred specially must be assigned to firstly
formed product.
M.p. 181-183 ºС; white solid, yield 98 %;

ACCEPTED MANUSCRIPT
1
1
st diastereomer: H (400.1 MHz, CDCl
dd, 1H, 7.5 Hz, 1.5 Hz), 7.57-7.40 (m, 8H), 4.49 (br s, 1H, CH at OH), 3.93-3.86 (m, 1H from
CH ), 3.70-3.53 (m, 2H, CH ), 3.36-3.30 (m, 1H from CH ), 3.18 (d, 1H from CH , 17.4 Hz),
.16-3.13 (m, 1H, OH), 3.03 (d, 1H from CH , 17.2 Hz), 2.93 (d, 1H from CH , 17.4 Hz), 2.59
3 H
) δ : 8.19 (d, 1H, 8.5 Hz), 7.88 (d, 1H, 7.5 Hz), 7.77
(
2
2
2
2
3
2
2
(
d, 1H from CH
2
, 17.2 Hz);
1
2
nd diastereomer: H (500.0 MHz, CDCl
3
+acetone-d
6
H
) δ : 8.11 (d, 1H, 8.4 Hz), 7.78 (d, 1H, 7.9
Hz), 7.66 (dd, 1H, 7.1 Hz, 2.0 Hz), 7.48-7.29 (m, 8H), 4.49 (s, 1H, CH at OH), 3.83-3.75 (m, 1H
from CH +OH), 3.57-3.51 (m, 1H from CH ), 3.47-3.41 (m, 1H from CH ), 3.26-3.19 (m, 1H
2
2
2
from CH ), 3.10 (d, 1H from CH , 17.2 Hz), 2.91 (d, 1H from CH , 17.1 Hz), 2.86 (d, 1H from
2
2
2
CH
2
, 17.2 Hz), 2.51 (d, 1H from CH
2
, 17.1 Hz);
+acetone-d
1
3
2nd diastereomer: C (125.7 MHz, CDCl
3
6
) δ
C
: 170.46 (CO), 156.29 (C=N), 136.52
(
C
Ar), 135.06 (CAr), 133.74 (CAr), 132.09 (CAr), 128.96 (2CHAr), 128.68 (CHAr), 127.88 (2CHAr),
27.23 (CHAr), 127.03 (CAr), 126.89 (CHAr), 126.21 (CHAr), 125.67 (CHAr), 125.50 (CHAr),
23.73 (CH ), 88.23 (CH at OH), 85.75 (C ), 43.04 (CH ), 41.45 (CH ), 41.31 (CH ), 30.92
1
1
Ar
quat
2
2
2
(
CH
IR (KBr, cm ): 3316, 3268, 3060, 2980, 2921, 2850, 1681, 1596, 1494, 1422, 1361, 1328, 1278,
136, 1092, 1013, 925;
2
);
-1
1
+
2 3
HRMS (ESI): calcd for C24H22ClN O [M+H] 421.1319, found 421.1324, calcd for
+
C
24
H21ClN
2
NaO
3
[M+Na] 443.1138, found 443.1144.
General procedure for the cyclization reactions
5
Equiv of boron trifluoride diethyl etherate was added to vigorously stirred solution of
corresponding hydroxylactams (12) in anhyd. dichloromethane (3 ml) under argon. The reaction
mixture was stirred in a capped vial at room temperature (TLC-control). After completion of the
reaction, water was added carefully to the reaction mixture (6 mL). The aqueous layer was
extracted with CH
2
Cl
2
(3x5 mL), the organic layers were combined, dried over MgSO4 and
O (for 13a,b,d-g).
evaporated to dryness. The product was recrystallized with Et
2

ACCEPTED MANUSCRIPT
(
5SR,10b'SR)-3-(4-methylphenyl)-6',10b'-dihydro-4H,5'H-spiro[isoxazole-5,1'-pyrrolo[2,1-
a]isoquinolin]-3'(2'H)-one (13a)
H C
3
N
O
H
N
O
1
Colorless solid, m.p. 219−222 ºС. H NMR (400.1 MHz, CDCl
3
) δ 7.50 (d, J=8.0 Hz, 2H), 7.24
(
d, J=8.0 Hz, 2H), 7.20-7.17 (m, 2H), 7.07-7.03 (m, 1H), 6.97 (d, J=7.8 Hz, 1H), 5.04 (s, 1H,
CH), 4.49-4.45 (m, 1H, CH from CH
2
), 3.87 (d, J=17.5 Hz, 1H from CH
+ 2CH from CH ), 2.75 (d, J=15.1 Hz, 1H
from CH ), 2.41 (s, 3H, CH from Tol). C NMR (100.6 MHz, CDCl ) δ 170.37 (CO), 155.46
2
,), 3.64 (d, J=17.5 Hz,
1
H from CH
2
), 3.08-2.91 (m, 4H, isoxazoline CH
2
2
13
2
3
3
(
C=N), 140.71 (CAr), 135.76 (CAr), 130.77 (CAr), 129.67 (CHAr), 129.56 (2CHAr), 127.49 (CHAr),
26.55 (2CHAr), 126.28 (CHAr), 126.22 (CAr), 124.96 (CHAr), 89.24 (Cspiro), 66.25 (CH), 45.07
1
(
CH
2
), 42.63 (CH
2
), 37.40 (CH
2
), 29.66 (CH
2
), 21.49 (CH
3
from Tol). HRMS (ESI): calcd for
+
+
C
21
H
21
N
2
O
3
[M+H] 333.1598, found 333.1603; calcd for C21
H
20
N
2
NaO
3
[M+Na] 355.1422,
found 355.1417.
(
5SR,10b'SR)-3-(4-chlorophenyl)-6',10b'-dihydro-4H,5'H-spiro[isoxazole-5,1'-pyrrolo[2,1-
a]isoquinolin]-3'(2'H)-one (13b)
Cl
N
O
H
N
O
1
White solid, m.p. 188−190 ºС (decomposition). H NMR (400.1 MHz, CDCl ) δ 7.54 (d, J=8.5
3
Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.21-7.19 (m, 2H), 7.07-7.03 (m, 1H), 6.94 (d, 1H, 7.8 Hz),
5
.05 (s, 1H, CH), 4.51-4.46 (m, 1H, CH from CH
from CH , 17.5 Hz), 3.09-3.01 (m, 1H, CH from CH
H from CH , 2.9 Hz, 12.1 Hz), 2.76 (d, 1H from CH
δ 170.16 (CO), 154.57 (C=N), 136.43 (C ), 135.89 (C ), 130.56 (C ), 129.78 (CH ), 129.18
2
), 3.85 (d, 1H from CH
2
, 17.5 Hz), 3.64 (d, 1H
), 2.93 (dd,
3
, 15.4 Hz). C NMR (100.6 MHz, CDCl )
2
2
), 2.98 (s, 2H, isoxazoline CH
2
1
3
1
2
2
Ar
Ar
Ar
Ar
(2CHAr), 127.79 (2CHAr), 127.62 (CHAr), 127.53 (CAr), 126.28 (CHAr), 124.79 (CHAr), 89.85
(
C
spiro), 66.27 (CH), 44.94 (CH
2
), 42.20 (CH
2
), 37.42 (CH
2
), 29.67 (CH
2
). HRMS (ESI): calcd
+
+
for C20
H
18
N
2
O
2
[M+H] 353.1057, found 353.1062; calcd for C20
H
17
N
2
NaO
2
[M+Na] 375.0876,
found 375.0879.

ACCEPTED MANUSCRIPT
ethyl (5SR,10b'SR)-3'-oxo-2',3',6',10b'-tetrahydro-4H,5'H-spiro[isoxazole-5,1'-pyrrolo[2,1-
a]isoquinoline]-3-carboxylate (13c)
O
N
O
EtO
H
N
O
1
Yellow oil. H NMR (400.1 MHz, CDCl
3
) δ 7.26-7.16 (m, 3H), 7.02 (d, J=7.6 Hz, 1H), 5.03 (s,
), 4.40-4.33 (m, 2H, CH ), 3.80 (d, J=18.6 Hz, 1H
), 3.46 (d, J=18.6 Hz, 1H from CH ), 3.05-2.88 (m, 4H, CH +CH ), 2.74 (d, J=14.8
1
H, CH), 4.48-4.44 (m, 1H, CH from CH
2
2
from CH
2
2
2
2
13
Hz, 1H from CH ,), 1.40 (t, J=7.1 Hz, 3H, CH from CO Et,). C NMR (100.6 MHz, CDCl ) δ
2
3
2
3
1
69.63 (CO), 160.16 (CO
2
Et), 150.38 (C=N), 135.97 (CAr), 130.05 (CAr), 129.85 (CHAr), 127.77
), 45.05 (CH ),
(CHAr), 126.60 (CHAr), 124.58 (CHAr), 92.33 (Cspiro), 65.72 (CH), 62.29 (CH
2
2
4
0.60 (CH
2
), 37.41 (CH
2
), 29.69 (CH
2
), 14.06 (CH
3
from CO
2
Et). HRMS (ESI): calcd for
+
+
C
17
H
20
N
2
O
4
[M+H] 315.1339, found 315.1344; calcd for C17
H
18
N
2
NaO
4
[M+Na] 337.1164,
found 337.1169.
(
5SR,10b'SR)-8',9'-dimethoxy-3-(4-methylphenyl)-6',10b'-dihydro-4H,5'H-spiro[isoxazole-
5
,1'-pyrrolo[2,1-a]isoquinolin]-3'(2'H)-one (13d)
MeO
OMe
H C
3
N
O
H
N
O
1
White solid, decomposition at 220 ºС. H NMR (400.1 MHz, CDCl
3
) δ 7.51 (d, J=8.0 Hz, 2H),
7
.23 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 4.92 (s, 1H, CH), 4.50-4.46 (m, 1H, CH from
CH ), 3.86 (s, 3H, OMe), 3.83 (d, J=17.5 Hz, 1H from CH ), 3.69 (d, J=17.5 Hz, 1H from
2
2
CH
2
,), 3.26 (s, 3H, OMe), 3.05-2.94 (m, 3H, isoxazoline CH
2
+ CH from CH
), 2.40 (s, 3H, CH
) δ 170.15 (CO), 155.33 (C=N), 148.33 (CAr), 147.39
C ), 140.86 (C ), 129.65 (2CH ), 128.23 (C ), 126.41 (2CH ), 126.18 (C ), 122.16 (C ),
2
), 2.92 (dd,
J
1
=12.2 Hz, J
2
=2.6 Hz, 1H from CH
2
), 2.66 (d, J=15.1 Hz, 1H from CH
2
3
1
3
from Tol). C NMR (100.6 MHz, CDCl
3
(
Ar
Ar
Ar
Ar
Ar
Ar
Ar
1
12.13 (CHAr), 107.88 (CHAr), 89.18 (Cspiro), 67.00 (CH), 55.74 (OMe), 55.31 (OMe), 44.37
), 42.63 (CH ), 37.44 (CH ), 29.10 (CH ), 21.46 (CH from Tol). IR (KBr) νmax 3591, 3431,
(CH
2
2
2
2
3

ACCEPTED MANUSCRIPT
2
922, 2846, 2249, 1686, 1609, 1519, 1441, 1422, 1358, 1267, 1229, 1117, 1025, 911. HRMS
+
(
[
ESI): calcd for C23
H
25
N
2
O
4
[M+H] 393.1814, found 393.1812; calcd for C23
H
24
N
2
NaO
4
+
M+Na] 415.1634, found 415.1631.
(
5SR,10b'SR)-3-(4-chlorophenyl)-8',9'-dimethoxy-6',10b'-dihydro-4H,5'H-spiro[isoxazole-
5
,1'-pyrrolo[2,1-a]isoquinolin]-3'(2'H)-one (13e)
MeO
OMe
Cl
N
O
H
N
O
1
Light yellow solid, decomposition at 180 ºС. H NMR (400.1 MHz, CDCl
3
) δ 7.55 (d, J=8.5 Hz,
2
H), 7.40 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H), 4.92 (s, 1H, CH), 4.49-4.45 (m, 1H, CH
from CH ), 3.85 (s, 3H, OMe), 3.81 (d, J=17.4 Hz, 1H from CH ,), 3.67 (d, J=17.4 Hz, 1H from
CH ), 3.29 (s, 3H, OMe), 3.05-2.94 (m, 3H, isoxazoline CH + CH from CH ), 2.89 (dd, J =12.2
Hz, J =2.2 Hz, 1H from CH ), 2.65 (d, J=14.5 Hz, 1H from CH ,). IR (KBr) νmax 3367, 3079,
2
2
2
2
2
1
2
2
2
2921, 2851, 2254, 1695, 1603, 1516, 1463, 1432, 1360, 1272, 1234, 1164, 1092, 1038, 913.
+
HRMS (ESI): calcd for C22
H22ClN
2
O
4
[M+H] 413.1268, found 413.1263; calcd for
+
C
22
H21ClN
2
NaO
4
[M+Na] 435.1088, found 435.1086.
(
10SR,10aSR)-3'-(4-methylphenyl)-5,10a-dihydro-4'H,6H-spiro[benzo[f]pyrrolo[2,1-
a]isoquinoline-10,5'-isoxazol]-8(9H)-one (13f)
H C
3
N
O
H
N
O
1
Light yellow solid, m.p. 185−189 ºС. H NMR (400.1 MHz, CDCl
.78 (d, J=7.9 Hz, 1H), 7.58-7.47 (m, 5H), 7.25 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.5 Hz, 1H), 5.19
s, 1H, CH), 4.68 (dd, J =12.7 Hz, J =5.2 Hz, 1H, CH from CH ), 3.97 (d, J=17.5 Hz, 1H from
3
) δ 7.98 (d, J=8.5 Hz, 1H),
7
(
1
2
2
CH ), 3.68 (d, J=17.5 Hz, 1H from CH ,), 3.38 (dd, 1H from CH , J =15.5 Hz, J =2.0 Hz),
2
2
2
1
2
3
.23-3.15 (m, 1H from CH
2
), 3.05-3.00 (m, 3H, isoxazoline CH
2
+ CH from CH
2
), 2.43 (s, 3H,
13
3 3
CH from Tol). C NMR (100.6 MHz, CDCl ) δ 169.91 (CO), 155.42 (C=N), 140.73 (CAr),

ACCEPTED MANUSCRIPT
1
32.59 (CAr), 132.15 (CAr), 131.41 (CAr), 129.57 (2CHAr), 128.48 (CHAr), 128.00 (CAr), 126.65
CHAr), 126.57 (3CHAr), 126.24 (CAr), 125.92 (CHAr), 123.34 (CHAr), 122.51 (CHAr), 88.95
spiro), 66.67 (CH), 45.42 (CH ), 43.43 (CH ), 36.82 (CH ), 25.23 (CH ), 21.50 (CH from Tol).
(
(
C
2
2
2
2
3
IR (KBr) νmax 3055, 2921, 2851, 1696, 1612, 1513, 1439, 1389, 1360, 1313, 1231, 1146, 1032,
+
914. HRMS (ESI): calcd for C25
H
23
N
2
O
2
[M+H] 383.1760, found 383.1762; calcd for
+
C
25
H
22
N
2
NaO
2
[M+Na] 405.1579, found 405.1582.
(
10SR,10aSR)-3'-(4-chlorophenyl)-5,10a-dihydro-4'H,6H-spiro[benzo[f]pyrrolo[2,1-
a]isoquinoline-10,5'-isoxazol]-8(9H)-one (13g)
Cl
N
O
H
N
O
1
Light yellow solid, m.p. 207−211 ºС (decomposition). H NMR (400.1 MHz, CDCl
J=8.4 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.57-7.49 (m, 5H), 7.41 (d, J=8.5 Hz, 2H), 7.00 (d,
J=8.5 Hz, 1H), 5.16 (s, 1H, CH), 4.66 (dd, J =12.8 Hz, J =5.4 Hz, 1H, CH from CH ), 3.93 (d,
J=17.5 Hz, 1H from CH ), 3.64 (d, J=17.5 Hz, 1H from CH ), 3.36 (dd, J =16.0 Hz, J =2.1 Hz,
), 3.20-3.12 (m, 1H from CH ), 3.03-2.96 (m, 3H, isoxazoline CH + CH from
). C NMR (100.6 MHz, CDCl ) δ 169.77 (CO), 154.65 (C=N), 136.43 (CAr), 132.57 (CAr),
3
) δ 7.97 (d,
1
2
2
2
2
1
2
1
H from CH
2
2
2
1
3
CH
2
3
1
1
8
3
32.14 (CAr), 131.52 (CAr), 129.18 (2CHAr), 128.49 (CHAr), 127.85 (2CHAr), 127.81 (CAr),
27.53 (CAr), 126.68 (CHAr), 126.66 (CHAr), 126.04 (CHAr), 123.34 (CHAr), 122.37 (CHAr),
2 2 2 2
9.56 (Cspiro), 66.57 (CH), 45.26 (CH ), 42.89 (CH ), 36.80 (CH ), 25.25 (CH ). IR (KBr) νmax
056, 2920, 2851, 1689, 1597, 1440, 1358, 1313, 1271, 1093, 1013, 922. HRMS (ESI): calcd for
+
+
C H ClN O [M+H] 403.1213, found 403.1219; calcd for C H ClN NaO [M+Na]
2
4
20
2
2
24 19
2
2
4
25.1033, found 425.1039.

ACCEPTED MANUSCRIPT
1
3
Figure 1. H NMR spectrum of 9a (CDCl , 400MHz)
1
3
Figure 2. C NMR spectrum of 9a (CDCl , 100MHz)
3

ACCEPTED MANUSCRIPT
1
3
Figure 3. H NMR spectrum of 9b (CDCl , 400MHz)
1
3
Figure 4. C NMR spectrum of 9b (CDCl , 100MHz)
3

ACCEPTED MANUSCRIPT
1
3
Figure 5. H NMR spectrum of 9c (CDCl , 400MHz)
1
3
Figure 6. C NMR spectrum of 9c (CDCl , 100MHz)
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Figure 7. H NMR spectrum of 11a (CDCl , 400MHz)
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Figure 8. C NMR spectrum of 11a (CDCl , 100MHz)

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Figure 9. H NMR spectrum of 11b (CDCl , 400MHz)
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Figure 10. C NMR spectrum of 11b (CDCl , 100MHz)
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Figure 11. H NMR spectrum of 11c (CDCl , 400MHz)
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Figure 12. C NMR spectrum of 11c (CDCl , 100MHz)