An efficient synthesis of isoindolo[2,1-a]quinoline derivatives via imino Diels-Alder and intramolecular Diels-Alder reactions with furan

Article abstract of DOI:10.1055/s-2007-965875

The straightforward synthesis of new isoindolo[2,1-a]quinoline derivatives from 2,4-disubstituted 1,2,3,4-tetrahydroquinolines bearing a furan fragment via the intramolecular Diels-Alder reaction is reported. The synthesis of key precursors was realized w

Full text of DOI:10.1055/s-2007-965875

PAPER
375
An Efficient Synthesis of Isoindolo[2,1-a]quinoline Derivatives via Imino
Diels–Alder and Intramolecular Diels–Alder Reactions with Furan
S
ynthesis of Isoind
l
olo[2,1
a
-
a
]quinoli
d
D
erivative
i
s
mir V. Kouznetsov,*a Uriel Mora Cruz,a Fedor I. Zubkov,*b Eugenia V. Nikitinab
a
Laboratorio de Química Orgánica y Biomolecular, CIBIMOL, Escuela de Química, Universidad Industrial de Santander, A.A. 678,
Bucaramanga, Colombia
Fax +57(7)6349069; E-mail: kouznet@uis.edu.co
Organic Chemistry Department of the Russian Peoples Friendship University, 6 Miklukho-Maklayia St, Moscow, 117198,
b
Russian Federation
Fax +7(495)9550779; E-mail: fzubkov@sci.pfu.edu.ru
Received 11 September 2006; revised 30 October 2006
have been poorly explored,11 we consider that tetrahydro-
quinolines with furan moiety show interesting features
that make them attractive for synthetic and pharmacolog-
ical use. As part of our ongoing research program, search-
Abstract: The straightforward synthesis of new isoindolo[2,1-
a]quinoline derivatives from 2,4-disubstituted 1,2,3,4-tetrahydro-
quinolines bearing a furan fragment via the intramolecular Diels–
Alder reaction is reported. The synthesis of key precursors was re-
alized with excellent levels of diastereoselectivity either by Povarov ing for bioactive polyheterocycles containing a nitrogen
atom from accessible aldimines,12 we were interested in
reaction or by a multicomponent condensation approach.
an efficient synthesis of isoindolo[2,1-a]quinoline deriva-
tives, a class of molecules that possess an array of biolog-
ical activities.13 Recently, we reported the straightforward
synthesis of 1,3-disubstituted 11-oxo-5-(2-oxopyrrolidin-
1-yl)-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoin-
dolo[2,1-a]quinoline-10-carboxylic acids, from 2,4-dis-
ubstituted 1,2,3,4-tetrahydroquinolines bearing a furan
fragment via the intramolecular Diels–Alder reaction.14
Herein, we wish to report our detailed study on this theme.
Key words: Povarov reaction, quinolines, furans, intramolecular
Diels–Alder reaction, isoindolo[2,1-a]quinolines
The chemistry of tetrahydroquinoline derivatives has long
been an area of interest for organic chemists due to the
presence of these scaffolds within the framework of nu-
merous biologically interesting natural products and phar-
maceutical agents. Many new methods for the synthesis of
tetrahydroquinoline derivatives have been developed.1,2
The most attractive strategy for these derivatives is the
acid-promoted imino Diels–Alder (Povarov) reaction be-
tween N-aryl-substituted aldimines and electron-rich alk-
enes, which is a route that has been a topic of continuing
interest for the last forty years.3,4 The synthesis of such
compounds by three-component reaction of a substituted
aniline, an benzaldehyde derivative, and an electron-rich
alkene in the presence of various Lewis acid catalysts has
become more popular.5 The synthesis of tetrahydroquino-
line derivatives has been studied extensively in solution,
as well as on solid phase, using [4+2]-cycloaddition reac-
tions.6 Moreover, the imino Diels–Alder reaction of N-
benzylidenanilines and enamides was synthetically useful
in the rapid construction of the 4-amidotetrahydroquino-
line system.7 These processes are well documented, main-
ly due to synthetic efforts towards the martinelline
alkaloid8 that acts as a nonpeptide bradykinin receptor an-
tagonist and 4-amido-2-carboxytetrahydroquinolines as a
selective glycine antagonists.9 On the other hand, the in-
tramolecular Diels–Alder reaction with furan as the diene
partner is a very powerful synthetic tool for the construc-
tion of rigid tricyclic nitrogen heterocycles.10 With these
facts in mind and taking into consideration that the 2-fur-
yl-1,2,3,4-tetrahydroquinoline synthesis and chemistry
Syntheses of oxoisoindolo[2,1-a]quinoline derivatives are
not numerous; various 11-oxo- and 5,11-dioxoisoindo-
lo[2,1-a]quinolines have been prepared from 1H-isoin-
dole derivatives,13a,15,16 2-(quinol-2-yl)benzoic acid and
its esters,17 or 2¢-amino-2-methoxyacetophenones.13b Re-
cently, an efficient two-step synthesis of these heterocy-
clic derivatives from 4-(arylamino)-4-(2-furyl)but-1-enes
has been reported.18
Initially, freshly distilled N-furfurylidenanilines 3a–k
(readily obtained from various anilines 1 and 2-furalde-
hydes 2) and N-vinylpyrrolidin-2-one were used in the in-
termolecular imino Diels–Alder reaction (Scheme 1). The
reactions proceeded smoothly in the presence of boron tri-
fluoride–diethyl ether complex (20 mol%) at room tem-
perature (23–25°C) in dichloromethane to give the
corresponding tetrahydroquinolines 4a–k in excellent
yields and with a highly level of selectivity. A simple pu-
rification process by recrystallization gave pure cis-2-(2-
furyl)tetrahydroquinolines 4a–k as stable crystalline sub-
stances (Table 1).
Cycloaddition of aldimine 3h with N-vinylpyrrolidin-2-
one gave a mixture of four isomers of 6,7-dichloro- and
5,6-dichlorotetrahydroquinoline derivatives in the crude
reaction as observed by GC-EIMS analysis. The diaste-
reomeric 6,7-dichlorotetrahydroquinoline derivative 4h
was separated using column chromatography (silica gel,
heptane–EtOAc, 2:1), from which the cis-isomer was ob-
tained by recrystallization.
SYNTHESIS 2007, No. 3, pp 0375–0384
x
x
.
x
x
.2
0
0
7
Advanced online publication: 08.01.2007
DOI: 10.1055/s-2007-965875; Art ID: Z19006SS
© Georg Thieme Verlag Stuttgart · New York

376
V. V. Kouznetsov et al.
PAPER
Table 1 Synthesis of cis-2-(2-Furyl)-4-(2-oxopyrrolidin-1-yl)quinolines 4a–k Using the Povarov Reaction
Entry
Product
4a
R1
R2
H
H
H
H
H
H
H
Cl
H
H
H
R3
R4
H
Ratioa cis/trans Yieldb (%)
1
2
H
H
98:2
96:4
98
96
90
94
96
96
92
77c
89
82
75
4b
4c
H
Me
OMe
OMe
Br
H
3
H
H
96:4
4
4d
4e
OMe
H
H
98:2
5
H
98:2
6
4f
H
Cl
H
98:2
7
4g
H
F
H
95:5
8
4h
4i
H
Cl
H
90:10
90:10
85:15
76:24
9
Me
OMe
OMe
H
H
10
11
4j
H
H
4k
OMe
Me
a Determined by GC-EIMS.
b Of the pure cis-isomer.
c All data are given for the cis-6,7-dichlorotetrahydroquinoline.
The relative configuration of the newly created stereo- N-vinylpyrrolidin-2-one to afford the tetrahydroquinoline
centers is cis-(2e,4e), indicating the endo-approach of N- 4b (Scheme 2) using various conditions. These condensa-
vinylpyrrolidin-2-one. The structural elucidation of tet- tions were carried out in various solvents (CH2Cl2,
1
rahydroquinolines 4a–k was made on basis of H NMR. MeCN, toluene, etc.) at room temperature in the presence
The relative trans orientation of H2, H3, and H4 was es- of various water-tolerant acidic catalysts. This cycloaddi-
tablished from the large vicinal coupling constants tion proceeded smoothly in the presence of Lewis
J2,3~J3,4 = 10.0–11.5 Hz (Table 3).
(BF3·OEt2, AlCl3, BiCl3) and Brönsted (TsOH, TFA, ox-
alic acid) acids (10–20 mol%) in acetonitrile, dichlo-
romethane, toluene, and diethyl ether. 4-Toluenesulfonic
acid (20 mol%) was the best catalyst in this multicompo-
nent condensation, giving the final product 4b in 80%
yield in 20 hours in acetonitrile at room temperature.
Thus, this multicomponent condensation between select-
ed anilines, 2-furaldehyde, and N-vinylpyrrolidin-2-one
under these chosen conditions afforded the key tetrahy-
droquinoline precursors 4a–c in good yields (Table 2).
However, in the case of 2,4-dimethoxyaniline, the desired
tetrahydroquinoline 4d was obtained in very poor yield.
R3
R3
R2
R1
R2
+
benzene, ∆
2–4 h
R1
1
CHO
O
N
NH2
R4
O
2
3a–k
R4
BF3·OEt2
CH2Cl2, r.t.
O
N
R3
O
H
R2
NH2
N
O
N
p-TsOH
MeCN
H
H
R3
R2
R1
R3
R2
1
+
H
r.t., 10–15 h
O
O
O
N
H
OHC
N
H
N
R4
R4
R1
R1
O
4a–k
4a−d
R4
2
Scheme 1
Scheme 2
As multicomponent condensations have emerged as a
powerful tool for delivering the molecular diversity need-
ed in combinatorial approaches for the preparation of bio-
active compounds, we examined the three-component
Povarov reaction between p-toluidine, 2-furaldehyde, and
In next step, the cis-tetrahydroquinolines 4a–i were readi-
ly converted into the corresponding 11-oxo-5-(2-oxopyr-
rolidin-1-yl)-6,6a,9,10,10a,11-hexahydro-6b,9-epoxyiso-
indolo[2,1-a]quinoline-10-carboxylic acids 5a–i and their
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

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Synthesis of Isoindolo[2,1-a]quinoline Derivatives
377
Table 2 Three-Component Synthesis of Synthesis of cis-2-(2-Furyl)-4-(2-oxopyrrolidin-1-yl)quinolines 4a–d
Entry
Product
4a
R1
H
R2
H
H
H
H
R3
R4
H
H
H
H
Yielda (%)
1
2
3
4
H
65
80
75
10
4b
H
Me
OMe
OMe
4c
H
4d
OMe
a Purified by column chromatography as the cis-isomer.
analogues, epoxyisoindolo[2,1-a]quinolines 6b,c,f,e The NOE experiments did not give a definitive answer to
(Scheme 3). The N-acylation of 2-(2-furyl)tetrahydro- this question. The attempts to obtain a monocrystal of a
quinolines 4 with maleic anhydride in toluene at 60 °C and sample of one of the carboxylic acids 5 failed because of
subsequent intramolecular Diels–Alder reaction with the their extremely low solubility in the vast majority of or-
furan moiety provided the final polycyclic products exo- ganic solvents.
adducts 5 in high yields and with an excellent level of se-
lectivity. The N-acylation of 2-furyltetrahydroquinolines
4b,c,f,e with acryloyl chloride resulted in the formation
of the corresponding 11-oxo-5-(2-oxopyrrolidin-1-yl)-
6,6a,9,10,10a,11-hexahydro-6b,9-epoxyisoindolo[2,1-
a]quinolines 6 in good yields. Carboxylic acids 5 are sta-
ble colorless crystalline substances, sparingly soluble in
most organic solvents and with high melting points. Their
To determine orientation of the H6a proton in compounds
5–7, a single crystal of the compound 6e was grown. An
X-ray crystal structure analysis was carried out, the result-
ing structure is shown on Figure 1.19,20 The molecular
structure of 6e consists of a pyrrolo[1,2-a]quinoline con-
densed with an oxabicyclo[2.2.1]heptane fragment. The
central hexahydropyrrolo[1,2-a]quinoline fragment has
exo-fusion [C(15)–C(16) exo-bond] with a oxabicy-
clo[2.2.1]heptene (crystallographic numbering used). The
central six-membered cycle N(1)–C(1)–C(6)–C(9) is
analogues 6 are also colorless crystalline substances, but
soluble in common solvents (Table 4).
Homonuclear and inverse-detected 2D NMR experiments folded and has a conformation envelope with C(8) deviat-
allowed the assignment of all the signals and correlations, ing (0.63 Å) from a least-squares plane defined by five
corroborating the obtained epoxyisoindolo[2,1-a]quino- other atoms. The 2-oxopyrrolidin-1-yl group occupies a
line core. From the 1H NMR spectra of compounds 5a–i, pseudoequatorial position and both protons H(7) and H(9)
the configuration of the proton H6a was judged to be (≡ H5 and H6a) are in the pseudoaxial position in the tet-
axial,12 but the orientation of this proton relative to the rahydroquinoline. The geometry of the 7-oxabicy-
6b,9-epoxy bridge remained unclear (Table 5).
clo[2.2.1]hept-2-ene is normal, with the dihedral angle
O
N
N
O
H
10
N
N
O
H
N
R3
R2
4
5
O
R3
H
R3
O
O
6
7
O
R2
1
R4
O
8
R2
N
H
O
toluene, ∆, 48–55 h
R1
R4
R1
11
R1
Cl
O
R4
5a–i
4
O
CO2H
O
HO2C
Et3N, toluene, CH2Cl2
r.t., 2–3 d
R
1 = R2 = R4 = H
O
O
N
O
N
N
N
N
4
1
R3
R3
R3
5
H3PO4
6
H
7
2
O
70 °C, 3 h
N
8
9
O
6b,c,f,e
7b,c,f
O
10
O
O
Scheme 3
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

378
V. V. Kouznetsov et al.
PAPER
Table 3 1H NMR Data of Compounds 4a–k
1H NMR (400 MHz, CDCl3/TMS) d, J (Hz)
4a
4b
4c
4d
4e
4f
2.02 (m, 2 H, CH2), 2.23 (m, 2 H, CH2), 2.49 (m, 2 H, CH2), 3.20 (m, 2 H, CH2), 4.10 (s, 1 H, NH), 4.67 (dd, J = 10.0, 4.0, 1 H,
CH), 5.68 (dd, J = 10.5, 8.0, 1 H, CH), 6.26 (d, J = 3.0, 1 Harom), 6.35 (dd, J = 3.0, 2.0, 1 Harom), 6.58 (dd, J = 8.0, 1.0, 1 Harom), 6.71
(td, J = 7.5, 7.5, 1.0, 1 Harom), 6.86 (dd, J = 7.5, 1.0, 1 Harom), 7.04 (tt, J = 7.5, 7.5, 2.0, 1 Harom), 7.38 (dd, J = 2.0, 1.0, 1 Harom
)
2.01 (m, 2 H, CH2), 2.19 (s, 3 H, CH3), 2.21 (m, 2 H, CH2), 2.49 (m, 2 H, CH2), 3.19 (dm, 2 H, CH2), 4.01 (s, 1 H, NH), 4.60 (dd,
J = 10.5, 3.5, 1 H, CH), 5.64 (dd, J = 11.0, 7.0, 1 H, CH), 6.24 (d, J = 3.0, 1 Harom), 6.33 (dd, J = 3.0, 2.0, 1 Harom), 6.50 (d, J = 8.0,
1 Harom), 6.65 (s, 1 Harom), 6.84 (d, J = 8.0, 1 Harom), 7.37 (dd, J = 2.0, 1.0, 1 Harom
)
1.99 (m, 2 H, CH2), 2.21 (m, 2 H, CH2), 2.48 (m, 2 H, CH2), 3.20 (dm, 2 H, CH2), 3.70 (s, 3 H, OCH3), 4.90 (s, 1 H, NH), 4.58 (dd,
J = 11.0, 3.0, 1 H, CH), 5.66 (dd, J = 11.5, 6.5, 1 H, H), 6.24 (dd, J = 3.0, 1.0, 1 Harom), 6.33 (dd, J = 3.0, 2.0, 1 Harom), 6.45 (dd,
J = 2.5, 1.0, 1 Harom), 6.55 (d, J = 8.0, 1 Harom), 6.65 (dd, J = 9.0, 2.5, 1 Harom), 7.37 (dd, J = 2.0, 1.0, 1 Harom
)
1.98 (m, 2 H, CH2), 2.24 (m, 2 H, CH2), 2.48 (m, 2 H, CH2), 3.20 (dm, 2 H, CH2), 3.70 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.25
(s, 1 H, NH), 4.55 (dd, J = 11.0, 3.0, 1 H, CH), 5.68 (dd, J = 11.0, 7.0, 1 H, CH), 6.06 (d, J = 2.0, 1 Harom), 6.27 (d, J = 3.0, 1 Harom),
6.34 (d, J = 2.0, 1 Harom), 6.34 (d, J = 1.5, 1 Harom), 7.37 (dd, J = 2.0, 1.0, 1 Harom
)
2.04 (m, 2 H, CH2), 2.20 (m, 2 H, CH2), 2.50 (m, 2 H, CH2), 3.20 (m, 2 H, CH2), 4.19 (s, 1 H, NH), 4.63 (m, 1 H, CH), 5.61 (t,
J = 9.0, 8.9, 1 H, CH), 6.25 (d, J = 3.3, 1 H, CH), 6.34 (dd, J = 3.2, 1.9, 1 H, CH), 6.45 (d, J = 8.5, 1 Harom), 6.93 (dd, J = 2.2, 1.0,
1 Harom), 7.11 (ddd, J = 8.5, 2.3, 0.7, 1 Harom), 7.37 (dd, J = 1.8, 0.8, 1 Harom
)
2.03 (m, 2 H, CH2), 2.21 (m, 2 H, CH2), 2.50 (m, 2 H, CH2), 3.21 (dm, 2 H, CH2), 4.14 (s, 1 H, NH), 4.64 (m, 1 H, CH), 5.62 (t,
J = 9.0, 1 H, CH), 6.25 (d, J = 3.0, 1 Harom), 6.35 (dd, J = 3.0, 2.0, 1 Harom), 6.51 (d, J = 8.0, 1 Harom), 6.80 (d, J = 2.0, 1 Harom), 6.99
(dq, J = 8.0, 2.5, 1.0, 1 Harom), 7.38 (dd, J = 2.0, 1.0, 1 Harom
)
4g
4h
4i
2.03 (m, 2 H, CH2), 2.21 (m, 2 H, CH2), 2.50 (m, 2 H, CH2), 3.22 (dm, 2 H, CH2), 4.04 (s, 1 H, NH), 4.62 (dd, J = 10.5, 3.5, 1 H,
CH), 5.64 (dd, J = 11.0, 7.0, 1 H, CH), 6.25 (d, J = 3.0, 1 Harom), 6.34 (dd, J = 3.0, 2.0, 1 Harom), 6.53 (dd, J = 4.0, 4.0, 1 Harom), 6.58
(dd, J = 3.0, 1.0, 1 Harom), 6.77 (dddd, J = 10.0, 7.0, 3.0, 1.0, 1 Harom), 7.38 (dd, J = 2.0, 1.0, 1 Harom
)
1.17 (dm, 2 H, CH2), 2.31 (m, 2 H, CH2), 2.45 (dm, 2 H, CH2), 2.74 (m, 2 H, CH2), 4.47 (s, 1 H, NH), 4.52 (m, 1 H, CH), 5.47 (t,
J = 6.5, 6.5, 1 H, CH), 6.20 (dt, J = 3.0, 1.0, 1 Harom), 6.33 (dd, J = 3.0, 2.0, 1 Harom), 6.53 (d, J = 9.0, 1 Harom), 7.11 (dd, J = 9.0, 1.0,
1 Harom), 7.37 (dt, J = 1.0, 1 Harom
)
2.00 (m, 2 H, CH2), 2.11 (s, 3 H, CH3), 2.24 (m, 2 H, CH2), 2.49 (m, 2 H, CH2), 3.19 (dm, 2 H, CH2), 3.91 (s, 1 H, NH), 4.68 (dd,
J = 10.0, 4.0, 1 H, CH), 5.71 (dd, J = 11.0, 7.0, 1 H, CH), 6.29 (d, J = 3.0, 1 Harom), 6.37 (dd, J = 3.0, 2.0, 1 Harom), 6.66 (dd, J = 7.0,
6.0, 1 Harom), 6.75 (d, J = 8.0, 1 Harom), 6.95 (dt, J = 6.0, 1.0, 1 Harom), 7.40 (dd, J = 2.0, 1.0, 1 Harom
)
4j
1.98 (m, 2 H, CH2), 2.25 (m, 2 H, CH2), 2.48 (m, 2 H, CH2), 3.18 (dm, 2 H, CH2), 3.80 (s, 3 H, OCH3), 4.47 (s, 1 H, NH), 4.62 (dd,
J = 7.7, 6.1, 1 H, CH), 5.70 (dd, J = 9.1, 8.8, 1 H, CH), 6.27 (d, J = 3.2, 1 Harom), 6.34 (dd, J = 3.2, 1.8, 1 Harom), 6.51 (m, 1 Harom),
6.65 (s, 1 Harom), 6.66 (d, J = 0.6, 1 Harom), 7.37 (dd, J = 1.8, 0.8, 1 Harom
)
4k
1.96 (m, 2 H, CH2), 2.21 (m, 2 H, CH2), 2.24 (s, 3 H, CH3), 2.45 (m, 2 H, CH2), 3.16 (dm, 2 H, CH2), 3.67 (s, 3 H, OCH3), 3.76 (s,
3 H, OCH3), 4.19 (s, 1 H, NH), 4.44 (m, 1 H, CH), 5.64 (t, J = 9.5, 1 H, CH), 5.87 (dd, J = 2.5, 1 Harom), 6.03 (d, J = 3.0, 1 Harom),
6.10 (d, J = 3.0, 1 Harom), 6.30 (d, J = 2.0, 1 Harom
)
between the planes C(10)–C(13) and C(10)–C(13)– respective aldimines. Some chemical transformations of
C(14)–C(15) equal 108.2°. The C(10)–O(1)–C(13) epoxy these interesting molecules for the preparation of func-
bridge and H(9) (≡ H6a) are in the trans-position.
tionalized 11-oxoisoindolo[2,1-a]quinolines are under
way in our laboratories.
Acid treatment (H3PO4, 70 °C, 3 h) of the crude epoxy-
isoindolo[2,1-a]quinolines 6 gave the corresponding 3-
substituted 11-oxo-5-(2-oxopyrrolidinyl)isoindolo[2,1-
a]quinolines 7, the final products in our investigation
Melting points were taken on a Fisher-Johns melting point appara-
tus and are uncorrected. IR spectra were obtained on a Nicolet Av-
atar 360-FTIR spectrophotometer as KBr pellets. 1H and 13C NMR
spectra were measured on a Bruker AM-400 spectrometer (400
MHz 1H NMR and 100 MHz 13C NMR), using CDCl3 or DMSO-d6
as the solvent. TMS was used as an internal standard. A Hewlett-
Packard (HP) 5890 A series II Gas Chromatograph interfaced to an
HP 5972 Mass Selective Detector with an HP MS ChemStation
Data system was used for MS identification at 70 eV using a 60-m
capillary column coated with HP-5 [5%-phenylpoly(dimethylsilox-
ane)]. Elemental analyses were performed on a Perkin Elmer 2400
Series II analyzer. The reaction progress was monitored using TLC
on a Silufol UV 254 TLC aluminum sheets. Column chromatogra-
phy was carried out using Merck Kieselgel 60 (230–400 mesh). All
reagents were purchased from Merck, Sigma, and Aldrich and used
1
(Scheme 3). Their structures were confirmed by H and
13C NMR spectra and MS data.
In summary, the synthesis described herein provides di-
verse isoindolo[2,1-a]quinoline derivatives: epoxyisoin-
dolo[2,1-a]quinoline-10-carboxylic acids, epoxyiso-
indolo[2,1-a]quinolines, and 11-oxo-5-(2-oxopyrrolidin-
1-yl)isoindolo[2,1-a]quinolines, useful in the preparation
of interesting small drug-like molecules. These polyhet-
erocycles are available in two-steps or three-steps and in
good yields from commercial and inexpensive N-vi-
nylpyrrolidin-2-one, anilines, and 2-furaldehydes or their
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

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Synthesis of Isoindolo[2,1-a]quinoline Derivatives
379
Table 4 Straightforward Synthesis of Epoxyisoindolo[2,1-a]quinoline-10-carboxylic Acids 5, Their Analogues 6, and Isoindolo[2,1-a]quin-
olines 7 from Tetrahydroquinolines 4
Entry
1
Product
5a
5b
5c
R1
H
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
R4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Yield (%)
80
Mp (°C)
264-265
>300
H
2
H
Me
OMe
OMe
Cl
83
3
H
75
268-269
243-244
267-268
265-266
266-267
nda
4
5d
5f
OMe
H
70
5
63
6
5g
5i
H
F
70
7
Me
H
H
60
8
6b
6c
Me
OMe
Br
82
9
H
60
nda
10
11
12
13
14
6e
H
72
nda
6f
H
Cl
87
nda
7b
7c
H
Me
OMe
Cl
95
205-206
231-232
233-234
H
98
7f
H
84
a Not determined, used crude in the following step.
system. Twinned crystals (with taking into account of racemic twin-
ning) of 6e were refined using the SHELXL-9720 program by a lit-
erature method.21
2-(2-Furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquino-
lines 4; General Procedure
A soln of aldimine 3 (8.3 mmol) in anhyd CH2Cl2 (15 mL) was
cooled to 0 °C. Over a period of 20 min, BF3·OEt2 (0.36 mL, 2.8
mmol) was added dropwise. The resulting mixture was allowed to
warm to 25°C and N-vinylpyrrolidin-2-one (1.02 g, 9.1 mmol) in
CH2Cl2 (10 mL) was then added with vigorous stirring. The mixture
was stirred at r.t. for 12 h and then poured into H2O. The organic
layer was separated and dried (Na2SO4). The organic solvent was
removed in vacuo. The residue, which was analyzed by GC-MS,
was purified by recrystallization (CH2Cl2–EtOAc, 2:1) to afford cis-
tetrahydroquinolines 4 (Table 1).
cis-2-(2-Furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-
quinoline (4a)
Mp 115–116 °C.
IR (KBr): 3320, 1670, 1147 cm–1.
Figure 1 X-ray crystal structures of compound 6e
13C NMR (100.6 MHz, CDCl3): d = 18.2, 31.2, 31.4, 42.3, 47.7,
49.6, 105.5, 110.2, 115.2, 118.5, 119.0, 126.9, 128.2, 142.0, 145.1,
155.1, 175.8.
GC-EIMS (70 eV): tR = 35.01 min, m/z (%) = 282 (M+, 6), 198 (M+
– C4H6NO, 12), 197 (M+– C4H7NO, 66), 196 (M+ – C4H8NO, 100),
168 (15), 130 (M+ – C8H10NO2, 13), 77 (6), 41 (5).
without further purification. Final purification of all products for el-
emental analyses was performed by recrystallization. The X-ray
data for 6e were collected on an Inraf-Nonius Cad-4 diffractometer
(graphite monochromator, 293(2)K, a-scanning technique). The
structure was solved by direct and Fourier techniques, and refined
by full-matrix least-squares on F2 with anisotropic thermal parame-
ters for all non-hydrogen atoms. The positions of the hydrogen at-
oms of the molecule were calculated geometrically and refined
using the riding model. The crystals of 6e proved to be twinned
crystals, monoclinic with b ~90°, that emulated an orthorhombic
cis-2-(2-Furyl)-6-methyl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetra-
hydroquinoline (4b)
Mp 194–195 °C.
IR (KBr): 3330, 1670, 1145 cm–1.
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

380
V. V. Kouznetsov et al.
PAPER
Table 5 1H NMR Data of Compounds 5 and 6
1H NMR (400 MHz, DMSO-d6) d, J (Hz)
5a
1.96 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 2.37 (m, 2 H, CH2), 2.59 (d, J = 9.0, 1 H, CH), 3.08 (dm, 2 H, CH2), 3.13 (d, J = 9.0, 1 H,
CH), 4.88 (dd, J = 11.0, 3.0, 1 H, CH), 5.05 (d, J = 2.0, 1 H, CH), 5.50 (m, 1 H, CH), 6.51 (dd, J = 5.5, 1.5, 1 H, CH), 6.61 (d,
J = 5.0, 1 H, CH), 6.97 (d, J = 8.0, 1 Harom), 7.08 (t, J = 7.5, 1 Harom), 7.24 (t, J = 8.0, 1 Harom), 8.54 (d, J = 7.5, 1 Harom), 12.30 (s, 1
H, CO2H)
5b
5c
1.96 (m, 2 H, CH2), 2.04 (m, 2 H, CH2), 2.24 (s, 3 H, CH3), 2.39 (m, 2 H, CH2), 2.57 (d, J = 9.0, 1 H, CH), 3.11 (dm, 2 H, CH2),
3.10 (d, J = 9.0, 1 H, CH), 4.83 (dd, J = 11.5, 2.5, 1 H, CH), 5.03 (d, J = 2.0, 1 H, CH), 5.45 (m, 1 H, CH), 6.50 (dd, J = 6.0, 1.0,
1 H, CH), 6.60 (d, J = 6.0, 1 H, CH), 6.76 (s, 1 Harom), 7.05 (d, J = 8.0, 1 Harom), 8.51 (d, J = 8.0, 1 Harom), 12.28 (s, 1 H, CO2H)
1.95 (m, 2 H, CH2), 1.98 (m, 2 H, CH2), 2.38 (m, 2 H, CH2), 2.57 (d, J = 9.0, 1 H, CH), 3.09 (dm, 2 H, CH2), 3.10 (d, J = 9.0, 1 H,
CH), 3.70 (s, 3 H, OCH3), 4.82 (dd, J = 11.5, 2.5, 1 H, CH), 5.03 (d, J = 1.0, 1 H, CH), 5.45 (m, 1 H, CH), 6.44 (d, J = 2.0, 1 Harom),
6.50 (dd, J = 6.0, 1.0, 1 H, CH), 6.59 (d, J = 6.0, 1 H, CH), 6.88 (dd, J = 8.0, 2.5, 1 Harom), 8.58 (d, J = 8.0, 1 Harom), 12.19 (s, 1 H,
CO2H)
5d
1.93 (m, 2 H, CH2), 2.19 (dm, 2 H, CH2), 2.42 (m, 2 H, CH2), 2.55 (d, J = 9.0, 1 H, CH), 2.95 (d, J = 9.0, 1 H, CH), 3.05 (dm, 2 H,
CH2), 3.67 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 4.24 (dd, J = 12.5, 2.5, 1 H, CH), 5.07 (d, J = 1.6, 1 H, CH), 5.52 (dd, J = 10.0,
8.0, 1 H, CH), 6.09 (d, J = 2.0, 1 Harom), 6.48 (dd, J = 6.0, 1.6, 1 H, CH), 6.52 (d, J = 2.0, 1 Harom), 6.70 (d, J = 6.0, 1 H, CH), 12.29
(s, 1 H, CO2H)
5f
2.01 (m, 2 H, CH2), 2.11 (m, 2 H, CH2), 2.40 (m, 2 H, CH2), 2.60 (d, J = 9.0, 1 H, CH), 3.15 (d, J = 9.0, 1 H, CH), 3.16 (dm, 2 H,
CH2), 4.89 (dd, J = 10.0, 4.0, 1 H, CH), 5.05 (d, J = 2.0, 1 H, CH), 5.47 (m, 1 H, CH), 6.52 (dd, J = 6.0, 1.0, 1 H, CH), 6.64 (d,
J = 4.0, 1 H, CH), 6.95 (d, J = 1.0, 1 Harom), 7.33 (dd, J = 9.0, 2.0, 1 Harom), 8.66 (d, J = 9.0, 1 Harom), 12.31 (s, 1 H, CO2H)
5g
5i
1.99 (m, 2 H, CH2), 2.09 (m, 2 H, CH2), 2.36 (m, 2 H, CH2), 2.59 (d, J = 9.0, 1 H, CH), 3.13 (dm, 2 H, CH2), 3.14 (d, J = 9.0, 1 H,
CH), 4.89 (dd, J = 11.0, 3.0, 1 H, CH), 5.05 (d, J = 2.0, 1 H, CH), 5.47 (m, 1 H, CH), 6.52 (dd, J = 6.0, 2.0, 1 H, CH), 6.61 (d,
J = 6.0, 1 H, CH), 6.78 (dd, J = 8.5, 2.5, 1 Harom), 7.13 (td, J = 8.5, 2.5, 1 Harom), 8.68 (dd, J = 9.0, 2.0, 1 Harom), 12.27 (s, 1 H, CO2H)
1.91 (q, 2 H, CH2), 2.15 (s, 3 H, CH3), 2.35 (m, 2 H, CH2), 2.47 (dm, 2 H, CH2), 2.62 (d, J = 9.0, 1 H, CH), 3.02 (d, J = 9.0, 1 H,
CH), 3.07 (dm, 2 H, CH2), 4.38 (dd, J = 13.0, 2.0, 1 H, CH), 5.11 (d, J = 1.5, 1 H, CH), 5.61 (dd, J = 10.0, 8.0, 1 H, CH), 6.49 (dd,
J = 6.0, 1.5, 1 H, CH), 6.76 (d, J = 6.0, 1 H, CH), 6.85 (t, J = 6.0, 1 Harom), 7.12 (m, 2 Harom), 12.28 (s, 1 H, CO2H)
6ba
1.62 (dd, J = 11.9, 8.8, 1 Hendo, CH), 1.99 (m, 2 H, CH2), 2.12 (m, 2 H, CH2), 2.23 (m, 1 Hexo, CH), 2.25 (s, 3 H, CH3), 2.48 (m, 2
H, CH2), 2.62 (dd, J = 8.7, 3.4, 1 Hendo, CH), 3.12 (dm, 2 H, CH2), 4.58 (dd, J = 10.9, 3.6, 1 H, CH), 5.07 (dd, J = 4.5, 1.5, 1 H,
CH), 5.61 (dd, J = 11.5, 6.8, 1 H, CH), 6.39 (d, J = 5.8, 1 H, CH), 6.43 (dd, J = 5.8, 1.7, 1 H, CH), 6.74 (s, 1 Harom), 7.03 (dd, J = 8.5,
1.9, 1 Harom), 8.54 (d, J = 8.5, 1 Harom
)
6ca
1.63 (dd, J = 11.8, 8.8, 1 Hendo, CH), 2.00 (m, 2 H, CH2), 2.13 (m, 2 H, CH2), 2.24 (m, 1 Hexo, CH), 2.48 (m, 2 H, CH2), 2.63 (dd,
J = 8.7, 3.3, 1 Hendo, CH), 3.14 (dm, 2 H, CH2), 3.73 (s, 3 H, CH3), 4.57 (dd, J = 10.8, 3.7, 1 H, CH), 5.07 (dd, J = 4.3, 1.0, 1 H,
CH), 5.62 (dd, J = 11.4, 6.9, 1 H, CH), 6.39 (d, J = 5.8, 1 H, CH), 6.44 (dd, J = 5.8, 1.4, 1 H,CH), 6.50 (dd, J = 2.6, 1 Harom), 6.79
(dd, J = 9.2, 2.8, 1 Harom), 8.63 (d, J = 9.1, 1 Harom
)
6e
1.55 (dd, J = 11.6, 8.8, 1 Hendo, CH), 1.97 (m, 5 H, CH, 2CH2), 2.38 (m, 2 H, CH2), 2.74 (dd, J = 8.7, 3.3, 1 Hendo, CH), 3.09 (dm,
2 H, CH2), 4.92 (dd, J = 8.0, 6.5, 1 H, CH), 5.07 (dd, J = 4.5, 1.5, 1 H, CH), 5.46 (t, J = 8.3, 1 H, CH), 6.48 (dd, J = 5.8, 1.7, 1 H,
CH), 6.54 (d, J = 5.8, 1 H, CH), 7.06 (dd, J = 2.2, 0.9, 1 Harom), 7.45 (ddd, J = 6.5, 2.4, 0.6, 1 Harom), 8.59 (d, J = 9.0, 1 Harom
)
6fa
1.64 (dd, J = 11.9, 8.8, 1 Hendo, CH), 2.03 (m, 2 H, CH2), 2.13 (m, 2 H, CH2), 2.23 (m, 1 Hexo, CH), 2.50 (m, 2 H, CH2), 2.63 (dd,
J = 8.7, 3.3, 1 Hendo, CH), 3.13 (dm, 2 H, CH2), 4.60 (dd, J = 10.6, 3.9, 1 H, CH), 5.07 (dd, J = 4.5, 1.5, 1 H, CH), 5.60 (dd, J = 11.1,
7.2, 1 H, CH), 6.39 (d, J = 5.8, 1 H), 6.44 (dd, J = 5.8, 1.6, 1 H, CH), 6.91 (dd, J = 2.4, 1.0, 1 Harom), 7.18 (ddd, J = 7.1, 2.5, 0.6, 1
Harom), 8.65 (d, J = 9.0, 1 Harom
)
a The solvent was CDCl3/TMS.
13C NMR (100.6 MHz, CDCl3): d = 18.2, 20.5, 31.1, 31.3, 42.2,
47.7, 49.7, 105.3, 110.1, 115.4, 119.0, 127.1, 127.8, 128.9, 141.9,
142.7, 155.2, 175.7.
13C NMR (100.6 MHz, CDCl3): d = 18.2, 31.3, 31.3, 42.3, 48.0,
50.0, 55.8, 105.4, 110.2, 112.2, 114.5, 116.6, 120.4, 139.2, 141.9,
152.9, 155.2, 175.7.
GC-EIMS (70 eV): tR = 36.51 min, m/z (%) = 296 (M+, 5), 212 (M+
– C4H6NO, 10), 211(M+ – C4H7NO, 50), 210 (M+ – C4H8NO, 100),
196 (5), 182 (7), 167 (7), 144 (M+ – C8H10NO2, 10), 130 (5), 115 (6),
91 (6), 81 (6), 44 (10).
GC-EIMS (70 eV): tR = 40.98 min, m/z (%) = 312 (M+, 9), 228 (M+
– C4H6NO, 8), 227 (M+ – C4H7NO, 42), 226 (M+ – C4H8NO, 100),
212 (6), 198 (5), 183 (5), 160 (M+ – C8H10NO2, 7), 117 (6), 81 (8),
41 (5).
cis-2-(2-Furyl)-6-methoxy-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tet-
rahydroquinoline (4c)
Mp 169–170 °C.
cis-2-(2-Furyl)-6,8-dimethoxy-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-
tetrahydroquinoline (4d)
Mp 178–179 °C.
IR (KBr): 3349, 1679, 1116 cm–1.
IR (KBr): 3392, 1681, 1153 cm–1.
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindolo[2,1-a]quinoline Derivatives
381
Table 6 COSY Correlations of Compounds 6
COSY correlations [dH/dH (H/H)]
6b
6c
6e
6f
1.62/2.23 (10endo/10exo), 1.62/2.62 (10endo/10aendo), 1.99/2.48 (4¢¢/3¢¢), 1.99/3.17 (4¢¢/5¢¢), 2.12/4.58 (6/6a), 2.12/5.61 (6/5), 2.23/1.62
(10exo/10endo), 2.23/2.62 (10exo/10aendo), 2.23/5.07 (10exo/9), 2.48/1.99 (3¢¢/4¢¢), 2.62/1.62 (10aendo/10endo), 2.62/2.23 (10aendo/10exo),
3.12/1.99 (5¢¢/4¢¢), 4.58/2.12 (6a/6), 5.07/2.23 (9/10exo), 5.07/6.43 (9/8), 5.61/2.12 (5/6), 6.39/6.43 (7/8), 6.43/5.07 (8/9), 6.43/6.39
(8/7), 6.74/7.03 (4/2), 7.03/6.74 (2/4), 7.03/8.54 (2/1), 8.54/7.03 (1/2)
1.63/2.24 (10endo/10exo), 1.63/2.63 (10endo/10aendo), 2.00/2.48 (4¢¢/3¢¢), 2.00/3.14 (4¢¢/5¢¢), 2.13/4.57 (6/6a), 2.13/5.62 (6/5), 2.24/1.63
(10exo/10endo), 2.24/2.63 (10exo/10aendo), 2.24/5.07 (10exo/9), 2.48/2.00 (3¢¢/4¢¢), 2.63/1.63 (10aendo/10endo), 2.63/2.24 (10aendo/10exo),
3.14/2.00 (5¢¢/4¢¢), 4.57/2.13 (6a/6), 5.07/2.24 (9/10exo), 5.07/6.44 (9/8), 5.62/2.13 (5/6), 6.39/6.44 (7/8), 6.44/5.07 (8/9), 6.44/6.39
(8/7), 6.50/6.79 (4/2), 6.79/6.50 (2/4), 6.79/8.63 (2/1), 8.63/6.79 (1/2)
[Ma = 4¢¢, 6, 10exo], 1.55/1.97 (10endo/10exo[M]), 1.55/2.74 (10endo/10aendo), 1.97/1.55 (M/10endo), 1.97/1.97 (M/M), 2.38/1.97 (3¢¢/M),
2.74/1.55 (10aendo/10endo), 2.74/1.97 (10aendo/10exo[M]), 3.09/1.97 (5¢¢/4¢¢[M]), 4.92/1.97 (6a/6[M]), 5.07/1.97 (9/10exo[M]), 5.07/
6.48 (9/8), 5.46/1.97 (5/6[M]), 6.48/5.07 (8/9), 6.48/6.54 (8/7), 6.54/6.48 (7/8), 7.06/7.45 (4/2), 7.45/7.06 (2/4), 7.45/8.59 (2/1),
8.59/7.45 (1/2)
1.64/2.23 (10endo/10exo), 1.64/2.63 (10endo/10aendo), 2.03/2.50 (4¢¢/3¢¢), 2.03/3.13 (4¢¢/5¢¢), 2.13/4.60 (6/6a), 2.13/5.60 (6/5), 2.23/1.64
(10exo/10endo), 2.23/2.63 (10exo/10aendo), 2.23/5.07 (10exo/9), 2.50/2.03 (3¢¢/4¢¢), 2.63/1.64 (10aendo/10endo), 2.63/2.23 (10aendo/10exo),
3.13/2.03 (5¢¢/4¢¢), 4.60/2.13 (6a/6), 5.07/2.23 (9/10exo), 5.07/6.44 (9/8), 5.60/2.13 (5/6), 6.39/6.44 (7/8), 6.44/5.07 (8/9), 6.44/6.39
(8/7), 6.91/7.18 (4/2), 7.18/6.91 (2/4), 7.18/8.65 (2/1), 8.65/7.18 (1/2)
a Multiplet of H4 pyrrolidine ring and H6, and H10exo of the epoxyisoindolo[2,1-a]quinoline core.
13C NMR (100.6 MHz, CDCl3): d = 18.3, 31.4, 31.5, 42.4, 48.0,
49.7, 55.5, 55.8, 98.0, 101.7, 105.4, 110.1, 119.6, 129.4, 141.9,
147.9, 152.6, 155.4, 175.7.
GC-EIMS (70 eV): tR = 34.85 min, m/z (%) = 300 (M+, 6), 216 (M+
– C4H6NO, 10), 215 (M+ – C4H7NO, 61), 214 (M+ – C4H8NO, 100),
198 (4), 186 (15), 148 (M+ – C8H10NO2, 11), 81 (5), 41 (3).
GC-EIMS (70 eV): tR = 46.66 min, m/z (%) = 342 (M+, 15), 258 (M+
– C4H6NO, 8), 257 (M+ – C4H7NO, 33), 256 (M+ – C4H8NO, 100),
242 (11), 190 (M+ – C8H10NO2, 6), 81 (6), 41 (5).
cis-6,7-Dichloro-2-(2-furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-
tetrahydroquinoline (4h)
Mp 154–155 °C.
cis-6-Bromo-2-(2-furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetra-
hydroquinoline (4e)
Mp 205–206 °C.
IR (KBr): 3327, 1667, 1145 cm–1.
IR (KBr): 3307, 1670, 1128 cm–1.
13C NMR (100.6 MHz, CDCl3): d = 18.1, 30.9, 31.2, 43.7, 46.4,
47.9, 105.6, 110.4, 114.5, 117.5, 121.8, 129.9, 133.2, 142.1, 145.6,
154.9, 175.0.
13C NMR (100.6 MHz, CDCl3): d = 18.1, 30.6, 31.1, 42.1, 47.4,
49.4, 105.7, 110.0, 110.2, 116.7, 120.9, 129.1, 131.0, 142.0, 144.0,
154.5, 175.7.
GC-EIMS (70 eV): tR = 49.03 min, m/z (%) = 362 (M+, 6), 278 (M+
– C4H6NO, 11), 277 (M+ – C4H7NO, 66), 276 (M+ – C4H8NO, 100),
210 (M+ – C8H10NO2, 9), 196 (25), 167 (24), 129 (8), 81 (10).
GC-EIMS (70 eV): tR = 68.06 min, m/z (%) = 350 (M+, 9), 315 (M+
– Cl, 100), 266 (M+ – C4H6NO, 40), 265 (M+ – C4H7NO, 46), 264
(M+ – C4H8NO, 59), 230 (M+ – C4H7ClNO, 49), 198 (M+
C8H10NO2, 26), 166 (8), 81 (43), 69 (9), 53 (10), 41 (34).
–
cis-2-(2-Furyl)-8-methyl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetra-
hydroquinoline (4i)
Mp 120–121 °C.
IR (KBr): 3344, 1681, 1149 cm–1.
cis-6-Chloro-2-(2-furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetra-
hydroquinoline (4f)
Mp 192–193 °C.
IR (KBr): 3326, 1672, 1145 cm–1.
13C NMR (100.6 MHz, CDCl3): d = 17.4, 18.2, 31.0, 31.4, 42.3,
48.0, 49.7, 105.5, 110.2, 117.8, 118.5, 122.2, 124.6, 129.3, 142.0,
143.1, 155.3, 175.7.
GC-EIMS (70 eV): tR = 44.71 min, m/z (%) = 296 (M+, 5), 212 (M+
– C4H6NO, 11), 211 (M+ – C4H7NO, 57), 210 (M+ – C4H8NO, 100),
196 (4), 182 (9), 167 (4), 144 (M+ – C8H10NO2, 11), 81 (9), 41 (7).
13C NMR (100.6 MHz, CDCl3): d = 18.2, 30.7, 31.2, 42.2, 47.5,
49.6, 105.7, 110.3, 116.4, 120.6, 123.2, 126.3, 128.3, 142.1, 143.6,
154.6, 175.8.
GC-EIMS (70 eV): tR = 41.78 min, m/z (%) = 316 (M+, 6), 232 (M+
– C4H6NO, 42), 231 (M+ – C4H7NO, 65), 230 (M+ – C4H8NO, 100),
196 (15), 167 (18), 164 (M+ – C8H10NO2, 13), 81 (10), 41 (9).
cis-2-(2-Furyl)-8-methoxy-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-
tetrahydroquinoline (4j)
Mp 151–152 °C.
IR (KBr): 3419, 1681, 1116 cm–1.
cis-6-Fluoro-2-(2-furyl)-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetra-
hydroquinoline (4g)
Mp 161–162 °C.
IR (KBr): 3367, 1670, 1149 cm–1.
13C NMR (100.6 MHz, CDCl3): d = 18.1, 30.8, 31.2, 42.2, 47.8,
49.8, 105.6, 110.2, 112.9, 115.1, 116.2, 120.5, 127.7, 141.3, 154.8,
155.2, 175.8.
13C NMR (100.6 MHz, CDCl3): d = 18.3, 31.2, 31.5, 42.4, 47.9,
49.5, 55.5, 105.6, 108.6, 110.3, 117.5, 118.8, 119.2, 135.1, 142.0,
146.8, 155.5, 175.8.
GC-EIMS (70 eV): tR = 51.24 min, m/z (%) = 312 (M+, 7), 228 (M+
– C4H6NO, 10), 227 (M+ – C4H7NO, 46), 226 (M+ – C4H8NO, 100),
212 (9), 196 (9), 184 (5), 160 (M+ – C8H10NO2, 7), 145 (5), 81 (8),
41 (8).
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

382
V. V. Kouznetsov et al.
PAPER
cis-6,8-Dimethoxy-2-(5-methyl-2-furyl)-4-(2-oxopyrrolidin-1-
yl)-1,2,3,4-tetrahydroquinoline (4k)
Mp 140–141 °C.
13C NMR (100.6 MHz, DMSO-d6): d = 17.6, 28.2, 30.6, 41.7, 45.1,
47.7, 48.8, 55.3, 56.0, 56.9, 81.3, 90.2, 99.4, 102.8, 119.8, 129.7,
134.0, 136.9, 154.3, 158.0, 168.0, 172.6, 174.5.
IR (KBr): 3401, 1704, 1122 cm–1.
3-Chloro-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carbox-
ylic Acid (5f)
13C NMR (100.6 MHz, CDCl3): d = 13.4, 18.1, 31.3, 31.4, 42.3,
48.0, 49.6, 55.3, 55.6, 97.9, 101.7, 105.8, 106.0, 119.5, 129.5,
147.8, 151.3, 152.4, 153.4, 175.5.
IR (KBr): 1733, 1706, 1654, 975 cm–1.
GC-EIMS (70 eV): tR = 75.26 min, m/z (%) = 356 (M+, 16), 272 (M+
– C4H6NO, 7), 271(M+ – C4H7NO, 32), 270 (M+ – C4H8NO, 100),
256 (11), 240 (6), 190 (M+ – C8H10NO2, 7), 95 (6), 85 (5), 43 (11).
13C NMR (100.6 MHz, DMSO-d6): d = 17.8, 25.0, 30.5, 42.3, 45.1,
48.5, 51.0, 55.4, 81.0, 89.2, 119.8, 125.6, 126.3, 127.3, 127.8,
134.1, 136.3, 137.8, 170.1, 172.9, 175.1.
2-(2-Furyl)tetrahydroquinolines 4a–d by Three-Component
Condensation; General Procedure
3-Fluoro-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carbox-
ylic Acid (5g)
A mixture of aniline 1 (3.2 mmol) and 2-furaldehyde 2 (3.8 mmol)
in anhyd MeCN (20 mL) was stirred at r.t. for 30 min. TsOH (20
mol%) was added. Over a period of 20 min, a soln N-vinylpyrroli-
din-2-one (5.6 mmol) in MeCN (10 mL) was added dropwise. The
resulting mixture was stirred for 10–14 h. On completion of the re-
action as indicated by TLC, the mixture was diluted with H2O (30
mL) and extracted with EtOAc (3 × 15 mL). The organic layer was
separated, dried (Na2SO4), and concentrated in vacuo and the result-
ing product was purified by column chromatography (silica gel,
petroleum ether–EtOAc) to afford pure cis-tetrahydroquinolines
4a–d.
IR (KBr): 1741, 1693, 1637, 975 cm–1.
13C NMR (100.6 MHz, DMSO-d6): d = 17.8, 25.2, 30.5, 42.4, 45.1,
51.0, 55.4, 81.0, 89.3, 112.5, 114.5, 124.4, 126.6, 128.2, 133.9,
134.2, 137.8, 156.8, 169.8, 173.0, 175.1.
1-Methyl-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carbox-
ylic Acid (5i)
IR (KBr): 1712, 1635, 1591, 972 cm–1.
13C NMR (100.6 MHz, DMSO-d6): d = 17.5, 18.9, 28.2, 30.6, 41.6,
45.1, 47.7, 49.2, 57.6, 81.6, 90.2, 124.3, 125.7, 128.0, 129.9, 133.4,
134.3, 135.3, 136.7, 169.1, 172.6, 174.5.
11-Oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-hexahydro-
5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carboxylic Acids 5;
General Procedure
Corresponding tetrahydroquinoline 4 (1.5 mmol) was dissolved in
toluene (10 mL). Then an equimolar amount of maleic anhydride
(1.5 mmol) was added in one portion to the soln. The mixture was
stirred at 100 °C for 1–5 d. Then the crystalline product was filtered
off, washed with toluene (3 × 5 mL) and anhyd MeOH (1 × 5 mL),
and dried at 100°C to give desired products 5 as white solids
(Table 4).
11-Oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-hexahydro-
5H-6b,9-epoxyisoindolo[2,1-a]quinolines 6; General Procedure
The corresponding tetrahydroquinoline 4 (1.5 mmol) was dissolved
in toluene–CH2Cl2 (10 mL) and stirred in presence of Et3N. Then
acryloyl chloride (3 mmol) was added in one portion to the soln.
The mixture was stirred at r.t. for 2–3 d. Then, it was treated with
CH2Cl2 and the organic layer was washed with H2O (3 × 10 mL) and
dried (Na2SO4). Finally, the organic layer was filtered through a
flash column (silica gel) and then concentrated by evaporation to af-
ford the products 6 as melt solids (Table 4).
11-Oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-hexahydro-
5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carboxylic Acid
(5a)
IR (KBr): 1733, 1693, 1639, 972 cm–1.
3-Methyl-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline (6b)
IR (KBr): 1681, 1611, 1073, 829 cm–1.
13C NMR (100.6 MHz, CDCl3): d = 18.1, 20.8, 25.9, 28.2, 31.1,
42.1, 47.8, 48.3, 56.7, 78.7, 89.8, 119.2, 122.8, 126.6, 129.0, 132.2,
133.2, 134.7, 137.8, 172.2, 175.9.
13C NMR (100.6 MHz, DMSO-d6): d = 17.8, 25.4, 30.6, 41.7, 45.2,
47.4, 51.0, 55.5, 81.0, 89.3, 118.1, 123.4, 123.6, 126.3, 127.9,
134.3, 137.4, 137.8, 169.9, 173.1, 175.0.
3-Methyl-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carbox-
ylic Acid (5b)
3-Methoxy-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline (6c)
IR (KBr): 1682, 1621, 1037, 826 cm–1.
13C NMR (100.6 MHz, CDCl3): d = 18.2, 25.9, 28.2, 31.1, 42.1,
47.9, 48.4, 55.3, 56.7, 78.8, 89.8, 111.8, 113.2, 120.7, 124.7, 130.7,
132.3, 137.8, 155.7, 171.9, 175.8.
IR (KBr): 1729, 1704, 1650, 977 cm–1.
13C NMR (100.6 MHz, DMSO-d6): d = 17.9, 20.6, 25.5, 30.7, 42.9,
45.1, 47.4, 51.0, 55.4, 81.0, 89.4, 118.1, 123.5, 126.4, 128.4, 132.4,
134.3, 135.0, 137.7, 169.6, 173.1, 175.0.
3-Methoxy-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carbox-
ylic Acid (5c)
3-Bromo-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline (6e)
IR (KBr): 1684, 1589, 1074, 825 cm–1.
IR (KBr): 1735, 1689, 1639, 918 cm–1.
13C NMR (100.6 MHz, DMSO-d6): d = 17.9, 25.5, 30.6, 41.8, 45.0,
47.6, 51.0, 55.2, 55.3, 80.9, 89.3, 111.2, 112.9, 119.5, 125.3, 130.8,
134.3, 137.7, 155.1, 169.1, 173.0, 175.0.
13C NMR (100.6 MHz, DMSO-d6): d = 14.7, 18.0, 20.1, 28.5, 37.4,
45.8, 67.7, 79.4, 104.8, 109.9, 116.2, 118.1, 120.3, 122.1, 126.1,
127.1, 132.1, 135.4, 172.7, 174.6.
1,3-Dimethoxy-11-oxo-5-(2-oxopyrrolidin-1-yl)-
6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-
a]quinoline-10-carboxylic Acid (5d)
3-Chloro-11-oxo-5-(2-oxopyrrolidin-1-yl)-6,6a,9,10,10a,11-
hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline (6f)
IR (KBr): 1686, 1593, 1072, 826 cm–1.
IR (KBr): 1741, 1675, 970 cm–1.
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindolo[2,1-a]quinoline Derivatives
383
13C NMR (100.6 MHz, CDCl3): d = 18.1, 25.5, 28.3, 30.9, 42.1,
47.7, 48.3, 56.7, 78.8, 89.7, 120.7, 125.0, 126.0, 128.4, 128.9,
132.0, 135.8, 138.0, 172.6, 176.0.
13C NMR (100.6 MHz, CDCl3): d = 14.2, 18.1, 31.0, 42.3, 47.8,
58.0, 60.3, 121.9, 124.4, 125.5, 126.5, 128.6, 129.0, 129.7, 132.0,
132.5, 135.3, 143.4, 165.8, 175.8.
GC-MS (70 eV): tR = 35.22 min, m/z (%) = 352 (M+, 5), 267 (M+ –
C4H7NO, 100), 232 (M+ – C4H7ClNO2, 15), 204 (M+ – C6H11ClNO,
7), 177 (M+ – C7H12ClN2O, 3), 115 (1), 77 (5), 51 (2).
11-Oxo-5-(2-oxopyrrolidin-1-yl)-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinolines 7; General Procedure
The corresponding epoxyisoindolo[2,1-a]quinoline 6 (1 g) was dis-
solved in CHCl3 (10 mL). Then the mixture was cooled and 85%
H3PO4 (3 mL) was added at once to the soln. The mixture was
stirred at 70 °C for 3 h. Finally, the mixture was neutralized and
treated with CHCl3 (3 × 20 mL). The organic layer was dried
(Na2SO4) and the solvent removed under vacuum to afford the crude
product, which was purified by column chromatography (silica gel,
petroleum ether–EtOAc) to give the desired products 7 as white sol-
ids (Table 4).
Acknowledgment
This work was supported by the grant of the Colombian Institute for
Science and Research (COLCIENCIAS, Project: CENIVAM).
V.K. thanks the Industrial University of Santander (UIS) for provi-
ding a sabbatical year (2005–2006).
References
3-Methyl-11-oxo-5-(2-oxopyrrolidin-1-yl)-5,6,6a,11-tetra-
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IR (KBr): 1678, 1498, 1287 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.71 (q, J = 12.3 Hz, 1 H, CH),
2.01 (m, 2 H, CH2), 2.30 (s, 3 H, CH3), 2.51 (m, 2 H, CH2), 2.63
(ddd, J = 12.6, 6.4, 2.6 Hz, 1 H, CH), 3.07 (t, J = 7.0 Hz, 2 H, CH2),
4.87 (dd, 12.4, 2.4, 1 H, CH), 5.76 (dd, J = 12.0, 6.3 Hz, 1 H, CH),
6.85 (s, 1 Harom), 7.14 (dd, J = 8.4, 12.0 Hz, 1 Harom), 7.46 (dd,
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8.4 Hz, 1 Harom).
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13C NMR (100.6 MHz, CDCl3): d = 18.2, 21.1, 31.2, 31.5, 42.3,
47.9, 58.1, 120.5, 120.8, 123.3, 124.2, 127.0, 128.8, 129.2, 132.1,
132.5, 134.0, 134.3, 143.6, 165.6, 175.8.
GC-EIMS (70 eV): tR = 33.18 min, m/z (%) = 332 (M+, 5), 247 (M+
– C4H7NO, 100), 232 (M+ – C5H10NO, 15), 218 (M+ – C6H12NO, 5),
204 (M+ – C7H14NO, 3), 191 (M+ – C7H13N2O, 1), 177 (M+
C8H15N2O, 1), 115 (5), 77 (3), 51 (2).
–
3-Methoxy-11-oxo-5-(2-oxopyrrolidin-1-yl)-5,6,6a,11-tetra-
hydroisoindolo[2,1-a]quinoline (7c)
IR (KBr): 1682, 1496, 1283 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.69 (q, J = 12.3 Hz, 1 H, CH),
1.99 (m, 2 H, CH2), 2.49 (m, 2 H, CH2), 2.62 (ddd, J = 12.4, 6.3, 2.5
Hz, 1 H, CH), 3.08 (t, J = 7.0 Hz, 2 H, CH2), 3.76 (s, 3 H, CH3), 4.85
(dd, J = 12.3, 2.4 Hz, 1 H, CH), 5.75 (dd, J = 12.0, 6.26 Hz, 1 H,
CH), 6.59 (dd, J = 2.9, 0.9 Hz, 1 Harom), 6.89 (dd, J = 9.0, 2.6 Hz, 1
Harom), 7.46 (dd, J = 7.5, 0.5 Hz, 1 Harom), 7.49 (t, J = 7.5 Hz, 1
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Harom), 8.44 (d, J = 9.0 Hz, 1 Harom).
13C NMR (100.6 MHz, CDCl3): d = 18.2, 31.1, 31.4, 42.4, 48.1,
55.5, 58.1, 112.2, 113.5, 121.8, 121.9, 124.2, 125.1, 128.8, 130.2,
132.0, 132.5, 143.5, 156.4, 165.5, 175.8.
GC-EIMS (70 eV): tR = 21.54 min, m/z (%) = 348 (M+, 9), 263 (M+
– C4H7NO, 100), 248 (M+ – C5H10NO, 18), 232 (M+ – C5H10NO2,
12), 220 (M+ – C7H14NO, 10), 204 (M+ – C7H14NO, 3), 193 (M+ –
C8H15N2O, 6), 177 (M+ – C8H15N2O, 1), 115 (2), 77 (6), 51 (2).
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3-Chloro-11-oxo-5-(2-oxopyrrolidin-1-yl)-5,6,6a,11-tetra-
hydroisoindolo[2,1-a]quinoline (7f)
IR (KBr): 1684, 1481, 1288 cm–1.
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1H NMR (400 MHz, CDCl3): d = 1.72 (q, J = 12.3 Hz, 1 H, CH),
2.03 (m, 2 H, CH2), 2.51 (m, 2 H, CH2), 2.63 (ddd, J = 12.5, 6.2, 2.5
Hz, 1 H, CH), 3.08 (m, 2 H, CH2), 4.90 (dd, J = 12.3, 2.4 Hz, 1 H,
CH), 5.79 (dd, J = 12.0, 6.2 Hz, 1 H, CH), 7.03 (dd, J = 2.4, 1.0 Hz,
1 Harom), 7.28 (ddd, J = 8.9, 2.5 Hz, 0.8, 1 Harom), 7.48 (dd, J = 7.5,
0.8 Hz, 1 Harom), 7.51 (t, J = 7.4 Hz, 1 Harom), 7.61 (td, J = 7.5, 1.1
Hz, 1 Harom), 7.90 (d, J = 7.6 Hz, 1 Harom), 8.49 (d, J = 8.9 Hz, 1
Harom).
Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York

384
V. V. Kouznetsov et al.
PAPER
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(19) Crystallographic data for 6e: C20H19BrN2O3, M = 415.28,
crystal dimensions: 0.15 × 0.30 × 0.50 mm, light brown
prisms, T = 293 K, space group Pc, monoclinic, a = 15.442
(1), b = 20.563 (4), c = 7.855 (2) Å, a = 90.00(3)°, Z = 2,
V = 879.0(3) Å3; rcalcd = 1.569 g/cm–3, m(Mo-Ka) = 2.36
cm–1. The final R1 value are 0.0805 (wR2 (F2) = 0.2061) for
1244 independent reflection with I > 2sI (collected/
independent reflections 3917/2230 (Rint = 0.0644)),
GOOF = 0.999. Full crystallographic data for structure 6
have been deposited with the Cambridge Crystallographic
Data Centre (CCDC) as supplementary publication numbers
CCDC 256968. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK; fax: +44 (1223)336033; e-mail:
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SHELXL-97; University of Göttingen: Germany, 1997.
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Synthesis 2007, No. 3, 375–384 © Thieme Stuttgart · New York