Novel approach to isoindolo[2,1-a]quinolines: Synthesis of 1- and 3-halo-substituted 11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-a]quinoline-10- carboxylic acids

Article abstract of DOI:10.1055/s-2005-869948

A series of 1- and 3-halo-substituted isoindolo[2,1-a]quinolines were obtained by means of electrophilic cyclization of methallyl- and allyl-substituted isoindolo-7-carboxylic acids. The influence of halogen atoms on the stereochemistry of the formation o

Full text of DOI:10.1055/s-2005-869948

PAPER
1859
Novel Approach to Isoindolo[2,1-a]quinolines: Synthesis of 1- and 3-Halo-
Substituted 11-Oxo-5,6,6a,11-tetrahydroisoindolo[2,1-a]quinoline-10-car-
boxylic Acids
N
ovel Approach
k
to
H
alo-Su
a
bstituted Is
t
e
[2,1-
a
]quin
r
oline
s
ina V. Boltukhina, Fedor I. Zubkov,* Eugenia V. Nikitina, Alexey V. Varlamov
Organic Chemistry Department of Russian People’s Friendship University, 6, Miklukho-Maklayia St., Moscow 117198,
Russian Federation
Fax +7(095)9550779; E-mail: fzubkov@sci.pfu.edu.ru
Received 2 November 2004; revised 17 February 2005
O
N
O
O
Abstract: A series of 1- and 3-halo-substituted isoindolo[2,1-
a]quinolines were obtained by means of electrophilic cyclization of
methallyl- and allyl-substituted isoindolo-7-carboxylic acids. The
influence of halogen atoms on the stereochemistry of the formation
of key intermediates, 3a,6-epoxyisoindoles, was studied.
F
OH
Cl HN
N
H
N
N
O
Me
X
Me
Cl
N
H
COOH
Key words: furans, intramolecular Diels–Alder reactions, cycliza-
tions, electrophilic aromatic substitutions, isoindolo[2,1-a]quino-
lines
1
2
Me
O
R
R1
Only a few synthetic approaches to isoindolo[2,1-a]quin-
olines have been reported.1–13 As a rule they require poor-
ly available starting materials and involve a multi-step
synthesis. Polycyclic nitrogen heterocycles with isoindo-
lo[2,1-a]quinoline moiety have been shown to have im-
portant biological properties. In particular, it was found in
the last ten years that analogs of berberine alkaloids4,10
had effect against nitrogen-induced hypoxia and were in-
hibitors of human topoisomerase II.
N
H
N
N
NH
X
3
4
R = F, Cl, I, CF3
R1 = Cl, Br
X = H, Me
X = F, Cl, Br
Figure 1 1,2,3,4-Tetrahydroquinolines 1–4 of biological interest.
1,2,3,4-Tetrahydroquinolines possessing halogen substit-
uents in the aromatic ring are also known to show a wide
range of biological activities. Ofloxacin (1) possesses to-
poisomerase inhibiting activity,10 ( )-4-trans-2-carboxy-
5,7-dichloro-4-[3H]phenylaminocarbonylamino-1,2,3,4-
tetrahydroquinoline (2) is a potent NMDA antagonist,14 6-
Me
O
NH
NH2
OHC
O
R
R
7
halo-4-methyl-2-pyrido-1,2,3,4-tetrahydroquinolines
3
R = H, Alk, OR'
have antifungal activity,15 and halogen-substituted 2-(1H-
indol-3-yl)tetrahydroquinoline derivatives 4 possess in
vitro activity against methicillin-resistant Staphylococcus
aureus16 (Figure 1).
Me
5 Me
Me
O
4
6
3
7
6a
2
8
9
N
N
1
O
R
We have recently reported17 a new preparation of 11-oxo-
isoindolo[2,1-a]quinoline-10-carboxylic acids 5, possess-
ing electron-donating substituents R in the quinoline
fragment using 4-(N-aryl)amino-4-(2¢-furyl)but-1-enes
R
10
O
CO2H
CO2H
6
5
Scheme 1
7
18,19 as starting compounds. Intramolecular electrophilic
cyclization of 3-allyl-2-arylisoindole-7-carboxylic acids
6, derived from furfurylamines 7 and maleic anhydride is
a key step of this synthetic methodology17,20 (Scheme 1).
homoallylamines, we were interested in developing a syn-
thetic route to isoindolo[2,1-a]quinolines possessing
halogen substituents in the quinoline moiety.
As a part of our research program directed toward the de-
velopment of synthetic methodologies to prepare polycy-
clic nitrogen heterocycles on the basis of
SYNTHESIS 2005, No. 11, pp 1859–1875
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.06.2005
DOI: 10.1055/s-2005-869948; Art ID: Z20304SS
© Georg Thieme Verlag Stuttgart · New York

1860
E. V. Boltukhina et al.
PAPER
The required halo-substituted homoallylamine precursors bases 8a–h, which were treated with Grignard reagents to
9a–h and 10a–g were readily synthesized via a two-step give amines 9 and 10 in 46–83% yields (Tables 1–3).
process (Scheme 2).17–19 The condensation of halo-substi-
tuted anilines and furfural gave the corresponding Schiff
Table 1 4-N-Arylamino-4-(2¢-furyl)but-1-enes 9a–h, 10a–g
Producta
MS, M+, m/z
Rf
IR (cm–1)
Found
Calcd
261.5
306
(Silufol UV254
)
Bp (°C)/Torr or Mp (°C)
49.5–50.5c,d
51.5–52.5c,d
148–152/3
159–160/4
oilc
nC=C
nNH
Yield (%)
69
9a
9b
261 (35Cl)
307 (81Br)
245
0.35b
0.44b
0.54e
0.33f
0.44g
0.59b
0.31g
0.28g
0.30b
0.44b
0.52b
0.20f
0.60g
0.62b
0.26g
1640
1639
1658
1638
1647
1638
1642
1645
1640
1642
1631
1638
1642
1640
1645
3430
3385
3387
3386
3410
3410
3420
3440
3406
3400
3400
3400
3398
3405
3400
83
9c
245
60
9d
261 (35Cl)
307 (81Br)
245
261.5
306
61
9e
46
9f
245
142/3
47
9g
353
353
oilc
78
9h
367
367
oilc
68
10a
10b
10c
10d
10e
10f
10g
247 (35Cl)
293 (81Br)
231
247.5
292
163–166/4
160/3
79
73
231
129–133/1.5
144/5
68
247 (35Cl)
293 (81Br)
231
247.5
292
62
oilc
59
231
145–147/9
oilc
48
339
339
64
a Satisfactory microanalyses obtained: C,H,N: 0.3%.
b EtOAc–hexane (1:10).
c Purification by chromatography over Al2O3 (hexane).
d Recrystallization from pentane.
e EtOAc–hexane (1:1).
f EtOAc–hexane (1:2).
g EtOAc–hexane (1:100).
Table 2 1H NMR Spectra (CDCl3/TMS, 400 MHz) of 4-N-Arylamino-4-(2¢-furyl)but-1-enes 9a–h, 10a–g; Chemical Shifts
Prod- Chemical shifts, d
uct
1-cis
1-trans R
3A
3B
4
Furyl
Aryl
R1
NH
3¢
4¢
5¢
3¢¢
R2
Cl
5¢¢
6¢¢
9a
9b
4.83
br d
4.91
br t
1.70
s (CH3) br dd
2.67
2.56
ddd
4.54
m
6.17
dt
6.31
dd
7.36
dd
6.54
AA¢
7.09
BB¢
7.09
BB¢
6.54
AA¢
4.01
br s
4.83
br d
4.91
br t
1.70
s (CH3) dd
2.68
2.56
ddd
4.54
dt
6.17
dt
6.31
dd
7.36
dd
6.49
AA¢
7.23
BB¢
Br
F
7.23
BB¢
6.49
AA¢
4.02
br d
9c
4.85
br s
4.91
br s
1.72
s (CH3) dd
2.68
2.57
dd
4.53
dd
6.19
br d
6.32
dd
7.37
dd
6.56
AA¢F BB¢F
6.87
6.87
6.56
3.89
BB¢F AA¢F br s
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1861
Table 2 1H NMR Spectra (CDCl3/TMS, 400 MHz) of 4-N-Arylamino-4-(2¢-furyl)but-1-enes 9a–h, 10a–g; Chemical Shifts (continued)
Prod- Chemical shifts, d
uct
1-cis
1-trans R
3A
3B
4
Furyl
Aryl
R1
NH
3¢
4¢
5¢
3¢¢
R2
5¢¢
6¢¢
9d 4.88
4.93
m
1.71
s (CH3) br dd
2.72
2.64
ddd
4.62
dt
6.18
dd
6.30
dd
7.37
dd
Cl
Br
F
7.26
dd
6.63
dt
7.07
ddd
6.61
dd
4.73
br d
m
9e
9f
4.91
m
4.95
m
1.71
s (CH3) br dd
2.73
2.65
ddd
4.63
ddd
6.18
dd
6.31
dd
7.43
dd
7.43
ddd
6.58
m
7.11
td
6.58
m
4.76
br d
4.82
br s
4.88
br s
1.68 2.67
s (CH3) dd
2.58
dd
4.57
m
6.17
br d
6.27
dd
7.33
br d
6.94
dd
6.60
m
6.90
dd
6.62
d
4.27
br s
9g
4.81
br s
4.91
br s
1.69
s (CH3) dd
2.66
2.54
dd
4.53
m
6.16
br d
6.29
dd
7.34
br d
6.39
AA¢
7.38
BB¢
I
7.38
BB¢
6.39
AA¢
4.02
br s
9h 4.86
4.91
m
1.69
s (CH3) dd
2.71
2.60
ddd
4.56
dd
6.15
dt
6.30
dd
7.36
dd
I
7.33
br d
2.11
s (CH3)
7.30
dd
6.31
d
3.94
br s
m
10a
5.17
dd
5.21
dd
5.78
m (H)
2.68
m
4.54
t
6.17
br d
6.32
dd
7.38
dd
6.55
AA¢
7.12
BB¢
Cl
Br
F
7.12
BB¢
6.55
AA¢
4.04
br s
10b 5.12
5.16
m
5.72
ddt (H)
2.61–2.66
m
4.49
t
6.12
dt
6.27
dd
7.33
dd
6.46
AA¢
7.20
BB¢
7.20
BB¢
6.46
AA¢
4.00
br s
m
10c
5.16
m
5.20
m
5.78
ddt (H)
2.67
m
4.50
t
6.17
dd
6.31
dd
7.37
dd
6.56
AA¢F BB¢F
6.87
6.87
6.56
3.91
BB¢F AA¢F br s
10d 5.25
5.30
dq
5.85
ddt (H)
2.78
m
4.66
q
6.23
dt
6.35
dd
7.43
dd
Cl
7.32
ddd
6.67–6.71 7.13 6.67– 4.82
ddt
m
dt
6.71
m
br d
10e
10f
10g
5.17
dd
5.22
dd
5.76
ddt (H)
2.70
t
4.57
q
6.13
br d
6.27
dd
7.35
dd
Br
F
7.40
dd
6.55
dt
7.08
dt
6.56
d
4.73
br d
5.20
br d
5.24
ddd
5.82
ddt (H) ddt
2.74
4.61
t
6.22
dt
6.34
dd
7.40
dd
7.02
ddd
6.64
m
6.98
ddt
6.71
br dt
4.34
br s
5.15
dd
5.19
dd
5.76
ddt (H)
2.66
m
4.52
t
6.15
dd
6.30
dd
7.36
dd
6.40
AA¢
7.40
BB¢
I
7.40
BB¢
6.40
AA¢
4.05
br s
The homoallylamines 9a,b are colorless crystals, 9c–h ortho-fluoro-substituted anilines and furfural is complet-
and 10a–g are viscous oils, and were purified either by ed over a longer period (4 h) compared with their para-
distillation in vacuo or by column chromatography substituted analogues (1–2 h). This can be explained in
(Table 1). It is worth noting that ortho-bromo- and ortho- terms of steric hindrance of amino group with the bulky
iodo-substituted furfurylamines 9e, 10e and 9g, 9h, 10g, bromine atom and its reduced nucleophilic activity due to
respectively, are thermally unstable (explosive during the strong electron-withdrawing effect of fluorine.
vacuum distillation). Condensation of ortho-bromo- or
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1862
E. V. Boltukhina et al.
PAPER
Table 3 1H NMR Spectra (CDCl3/TMS, 400 MHz) of 4-N-Arylamino-4-(2¢-furyl)but-1-enes 9a–h, 10a–g; Coupling Constants
Prod- Coupling Constants, J (Hz)
uct
1-cis,2 1-
1-cis, 2,3A 2, 3B 3A,4 3B,4 3A,3B 3¢,4¢ 3¢,5¢ 4¢,5¢ 3¢¢,4¢¢ 3¢¢,5¢¢ 4¢¢,5¢¢ 4¢¢,6¢¢ 5¢¢,6¢¢ Other Constants
trans,21-trans
9a
9b
–
–
–
0.7
–
–
–
–
5.5
5.5
8.7
8.7
14.1
14.1
3.2 0.7
3.0 0.8
1.8
1.8
–
–
–
–
–
–
–
–
~8.9 J1-cis,3B = 0.8,
J3¢,NH = 0.7,
J
2¢¢,3¢¢ = ~8.9
–
–
~8.7 J1-cis,3B = 0.8,
J3¢,NH = 0.8,
J4,NH = 5.5,
J
2¢¢,3¢¢ = ~8.7
9c
–
–
–
–
–
–
–
–
–
–
5.7
5.5
8.6
8.4
14.0
14.0
3.1
–
1.5
1.8
–
–
–
–
–
–
9d
3.2 0.7
7.5
1.5
7.5
1.4
8.2
J1-cis,3B = 0.7,
J1-trans,3B
=
J1-trans,3A = 1.5,
J4,NH = 4.8
9e
–
–
–
–
–
5.3
8.4
13.9
3.2 0.8
1.8
7.7
1.5
7.7
1.5
7.7
J1-cis,3B = 0.8,
J4,NH = 5.6,
J
3¢¢,6¢¢ = 0.5
9f
–
–
–
–
–
–
–
–
–
–
5.6
5.5
8.5
8.5
14.0
14.1
2.9
3.2
–
–
1.7
1.8
8.2
–
–
7.4
–
–
–
7.4
J3¢¢,F = 11.3
9g
2.7
~8.5
J
J
2¢¢,3¢¢ = 1.8,
2¢¢,6¢¢ = 2.7
9h
–
–
–
–
–
5.2
8.8
13.9
3.2 0.8
1.7
–
2.1
–
–
8.4
J1-cis,3B = 0.8,
3¢¢,6¢¢ = 0.7
J
a
10a 10.4 17.1 1.8
6.1
6.1
7.1
7.1
7.1
6.1
6.2
6.4
6.0
6.1
6.2
6.4
6.0
–
3.1 0.6
3.2 0.8
3.2 0.7
3.2 0.9
1.8
1.8
1.8
1.8
–
–
–
–
–
–
–
~8.5
–
a
10b 10.1 17.2 ~1.5 7.1
–
–
–
–
~8.5 J3¢,NH = 0.8
a
10c 10.2 17.2 1.7
10d 10.1 17.0 1.5
7.1
7.1
–
–
–
–
–
–
a
–
7.7
1.6
7.5
7.5
J1-cis,3 = 1.0,
J1-trans,3 = 1.5
J3¢,NH = 0.8,
J4,NH = 6.0,
J
3¢¢,6¢¢ = 0.4
10e 10.1 17.2 1.5
10f 10.1 17.1 1.9
7.2
7.1
7.2
7.1
6.3
6.3
6.3
6.3
–
–
3.2 0.7
3.2 0.8
1.8
1.8
7.7
8.0
1.5
1.4
7.7
8.2
1.3
1.4
7.7
8.2
J4,NH = 7.2
J1-cis,3 = 1.1,
J1-trans,3 = 2.3,
J3¢¢,F = 11.8,
J5¢¢,F = 0.8
10g 10.2 17.2 0.8
7.0
7.0
5.7
5.7
–
2.9 0.8
1.6
–
–
–
–
8.7
J2¢¢,3¢¢ = ~8.7
a Coupling constants cannot be determined due to overlap of the corresponding signals.
The reaction of furfurylamines 9a–h and 10a–g with ma- and alkoxy-substituted amines 7.17 Providing that the acy-
leic anhydride17,20 was carried out at 20 °C and the corre- lation at nitrogen with maleic anhydride leading to the for-
sponding oxoepoxyisoindolocarboxylic acids 11a–h and mation of corresponding maleaimide 13 (Scheme 3) is the
12a–g were isolated in moderate to quantitative yields initial step of the described process, it was supposed that
(30–97%, Tables 4– 7). In the case of halo-substituted the slower reaction rate could be explained by the reduced
furfurylamines 9 and 10, the reaction rate was slow (5–10 nucleophilic activity of the amino group due to the steric
days) and the yields were lower compared to the alkyl- and electronic influence of aromatic halogens.
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1863
R2
R
R2
PhH, ∆
R
1–4 h
OHC
O
O
R1
N
N
O
O
O
R1
8a–h
NH2
O
Hal
O
NH
..
O
Me
Hal
MgCl
MgBr
Et2O
HO2C
13
THF/Et2O
Me
1
Scheme 3
R2
2
R2
3
The cycloaddition reaction was highly stereoselective,
and only the Diels–Alder exo-adducts 11a–h and 12a–g
were formed, as confirmed by comparing the values of
spin-spin coupling constants of oxabicycloheptene moiety
H-atoms with the literature data.21 The H-atoms in posi-
tion 6 of the tricycles 11 and 12 have the endo-orientation
and gave a doublet signal at d 2.55–3.24 with J5,6 = 9.0–
9.3 Hz in 1H NMR spectra (in the case of exo-orientation
6-H atom would give a doublet of doublet signal with
J6,7 = 1.5–2.0 and J5,6 = 8.5–10 Hz) (Tables 5 and 6).
O
O
4
5'
NH
NH
9a–h
2''
R1
R1
10a–g
3'
4'
O
O
O
PhH, 20 °C, 5–10 d
1'
Me
R2
R2
2'
3'
9
2
1
5
Exo-epoxyisoindolones 11a–c,f,g and 12a–c,f,g were iso-
lated as mixtures of two geometrical isomers based on the
orientation of the allyl (for 12) and methallyl (for 11)
groups in relation to the 1,7-epoxy bridge. The ratio of
isomers varies depending on the reaction conditions, but
in common it is ca. 1:1. Tricycles 11d,e,h and 12d,e pos-
sessing bulky substituents (Cl, Br, or I) in the ortho-posi-
tion of the aryl radical were isolated as mixtures of three
geometrical isomers. We suppose that this fact can be ex-
plained by the impossibility of the rotation of the aryl
fragment around C–N bond. Isomers of compounds 11
and 12 could not be separated due to poor solubility in the
commonly used organic solvents (chloroform, alcohol,
ethyl acetate).
8
7
N
4
3
N
2''
O
O
R1
R1
6
O
O
CO2H
12a–g
CO2H
11a–h
a
b
H
c
H
F
d
e
f
g
H
I
h
I
Me
R1
H
Cl Br F
R2 Cl Br
H
H
H
Scheme 2
Table 4 Compounds 11, 12, and 14–17 Prepared
Producta
MS, M+, m/z
Rf (Silufol, UV254
)
Mp (°C)
IR (cm–1)
Yield (%)
Found
Calcd
359.5
404
nC=O
nNC=O
1680c
1669c
1680c
1661c
1674c
1682c
1680c
1673c
1673c
1680c
1608c
1675c
11a
11b
11c
11d
11e
11f
359 (35Cl)
403 (79Br)
343
0.32b
0.34b
0.32b
0.34b
0.35b
0.28b
0.32b
0.30b
0.42d
0.32b
0.28b
0.35b
180.5–181
180–181
162–162.5
224–225
227.5–228
210–212
181.5–182
200
1730
1726
1726
1738
1740
1750
1740
1745
1729
1737
1702
1730
75
62
92
64
21
85
83
48
90
75
92
97
343
359 (35Cl)
403 (79Br)
343
359.5
404
343
11g
11h
12a
12b
12c
12d
451
451
465
465
345 (35Cl)
389 (79Br)
329
345.5
390
165–166.5
158–160
124.5–126
153–155
329
345 (35Cl)
345.5
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1864
E. V. Boltukhina et al.
PAPER
Table 4 Compounds 11, 12, and 14–17 Prepared (continued)
Producta
MS, M+, m/z
Rf (Silufol, UV254
)
Mp (°C)
IR (cm–1)
Yield (%)
Found
Calcd
390
nC=O
nNC=O
1699c
1680c
1685c
12e
12f
12g
389 (79Br)
329
0.32b
0.30b
0.27b
160–164
167–169
151–153
1745
1735
1740
45
52
85
329
437
437
14a
341 (35Cl)
385 (79Br)
325
341.5
386
0.54e
0.46e
0.52e
0.56e
0.48e
0.50e
0.47e
0.54e
0.48e
0.50e
0.56e
0.52e
0.33e
0.47e
0.56e
0.52e
0.51e
288.5–290f
292–293.5f
259–260.5f
268–270f
1712
1710
1740
1715
1725
1718
1720
1722
1719
1719
1715
1715
1719
1725
1702
1701
1712
1610
1608
1632
1660
1621
1608
1612
1618
1620
1620
1616
1615
1625
1621
1621
1603
1621
41
51
62
50
31
40
36
41
63
54
44
40
30
26
65
70
60
14b
14c
325
14d
341 (35Cl)
385 (79Br)
325
341.5
386
14e
279.5–280f
246–248f
14f
325
14g
433
433
300–301.5f
166–167f
15a, 16a
15b, 16b
15c, 16c
15d, 16d
15e, 16e
15f, 16f
15g, 16g
17a
327 (35Cl)
371 (79Br)
311
327.5
372
266–268f
311
237.5–239f
202–204f
327 (35Cl)
371 (79Br)
311
327.5
372
254.5–256f
222.5–226f
258.5–259f
169.5–171f
146–148f
311
419
419
327 (35Cl)
311
327.5
311
17c
17g
419
419
149.5–152f
a Satisfactory microanalyses obtained: C, H, N 0.3%.
b EtOAc–CHCl3 (1:2).
c Absorption band of C=C bond is overlapped by absorption band of NCO group.
d EtOAc.
e EtOAc–CHCl3 (1:10).
f Recrystallized from i-PrOH–DMF.
Table 5 1H NMR Spectra (DMSO-d6a or CDCl3 /TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Chemical Shifts
b
Product
Chemical Shifts, d
2
5
6
7
8
9
1¢-cis 1¢-trans R
3¢A
3¢B
CO2H Aryl
11aa
(2.5:1)
maj 5.04
t
2.95
d
2.57
d
5.07
d
6.36 6.52 4.75 and 4.77 1.71
2.19
d
12.21 7.28 (AA¢, 2 H),
dd br s s (CH3)
d
br s
7.47 (BB¢, 2 H)
min 4.80
dd
3.23
d
2.56
d
5.00
d
6.47 6.57 4.83 and 4.84 1.69
2.39
2.59
dd
12.21 7.42 (AA¢, 2 H),
br s 7.58 (BB¢, 2 H)
dd s (CH3) dd
d
m
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1865
b
Table 5 1H NMR Spectra (DMSO-d6a or CDCl3 /TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Chemical Shifts (continued)
Product
Chemical Shifts, d
2
5
6
7
8
9
1¢-cis 1¢-trans R
3¢A
3¢B
CO2H Aryl
11ba
(1.1:1)
maj 4.77– 3.24
4.84
2.58
d
5.06
d
6.48 6.58 4.77–4.84 1.71
2.20 and
12.23 7.55 (br s, 4 H)
br s
d
dd
d
m
s (CH3) 2.40
m
min 5.01– 2.96
2.57
d
5.01
d
6.37 6.52 5.01–5.08
dd
1.72
s (CH3)
2.20 and 2.40
m
12.23 7.24 (AA¢, 2 H),
5.08
m
d
d
m
br s
7.61 (BB¢, 2 H)
c
11cb
(1.3:1)
maj 4.73
dd
3.01
d
2.85
d
5.31
d
6.37 6.47 4.78 and 4.85 1.72
2. 26
2.39–
2.48
m
–
7.08 (AA¢F, 2 H),
7.23 (BB¢F, 2 H)
dd br s s (CH3) ddq
d
c
min 4.66
dd
3.15
d
2.84
d
5.25
d
6.45 6.59 4.83 and 4.92 1.73
2.55
2.39–
2.48
m
–
7.08 (AA¢F, 2 H),
7.40 (BB¢F, 2 H)
dd br s s (CH3) ddq
d
11da
(2.1:1.8:1)
maj 4.56
dd
3.18
d
2.59
d
5.05
d
6.39 6.58 4.63 and 4.70 1.57
dd br s s (CH3)
2.34
m
2.66
dd
12.18 7.32–7.59 (m, 4
br s H)
d
mid 4.94
dd
3.01
d
2.54
d
5.09
d
6.39 6.60 4.69 and 4.76 1.65
1.90– 2.27
dd
12.18 7.32–7.59 (m, 4
br s H)
dd br s s (CH3) 1.97
d
m
min 4.92
dd
2.94
d
2.54
d
5.09
d
6.48 6.54 4.65 and 4.69 1.62
1.90– 2.27
12.18 7.15 (m, 1 H),
dd br s s (CH3) 1.97
d
dd
br s
7.32–7.59 (m, 4
H)
m
11ea,d
(6:3.5:1)
maj 4.92
dd
2.98
d
2.57
d
5.08
d
6.39 6.60 4.61 and 4.67 1.64
dd br s
1.93
s (CH3) dd
2.27
dd
12.21 7.12 (dd, 1 H, H-
d
br s
6¢¢), 7.32 (td, 1 H,
H-4¢¢), 7.43 (td, 1
H, H-5¢¢), 7.73
(dd, 1 H, H-3¢¢)
mid 4.92
dd
2.92
d
2.51
d
5.08
d
6.39 6.53 4.61 and 4.63 1.60
1.93
2.39
dd
12.21 7.26 (t, 1 H, H-
dd br s s (CH3) dd
d
br s
5¢¢), 7.35 (d, 1 H,
H-6¢¢), 7.49 (td, 1
H, H-4¢¢), 7.66
(dd, 1 H, H-3¢¢)
11fa
(1.1:1)
maj 4.57
dd
3.21
d
2.55
d
5.04
d
6.49 6.59 4.66 and 4.75 1.55
2.35
2.62
dd
12.16 7.19–7.43 (m, 4
br s H)
dd br s s (CH3) dd
d
min 4.91
dd
2.99
d
2.57
d
5.08
d
6.37 6.56 4.66 and 4.71 1.66
2.02
dd
2.26
dd
12.16 7.19–7.43 (m, 4
br s H)
dd
d
br s
s
(CH3)
11ga
(1.1:1)
maj 4.79
dd
2.94
d
2.56
d
5.06
d
6.35 6.51 4.78 and 4.84 1.71
dd br s c (CH3)
2.18
m
12.23 7.08 (AA¢, 2H),
br s 7.76 (BB¢, 2 H)
d
min 5.03
m
3.23
d
2.54
d
5.00
d
6.46 6.56 4.75 and 4.84 1.70
dd br s s (CH3)
2.37
m
12.23 7.39 (AA¢, 2 H),
br s 7.70 (BB¢, 2 H)
d
11ha,d
(5:4:1)
maj 4.93
dd
2.90
d
2.54
d
5.07
d
6.36 6.52 4.65 and 4.70 1.63
dd br s
1.88
s (CH3) dd
2.22
dd
12.19 2.10 (s, 3 H, CH3-
d
br s
4¢¢), 7.10 (d, 1 H,
H-6¢¢), 7.60 (dd, 1
H, H-5¢¢), 7.63 (d,
1 H, H-3¢¢)
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1866
E. V. Boltukhina et al.
PAPER
b
Table 5 1H NMR Spectra (DMSO-d6a or CDCl3 /TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Chemical Shifts (continued)
Product
Chemical Shifts, d
2
5
6
7
8
9
1¢-cis 1¢-trans R
3¢A
3¢B
CO2H Aryl
min 4.93
dd
3.18
d
2.51
d
5.02
d
6.45 6.55 4.74 and 4.76 1.57
2.39
m
2.63
dd
12.19 2. 04 (s, 3 H, CH3-
dd
d
br s
s (CH3)
br s
4¢¢), 7.10 (d, 1 H,
H-6¢¢), 7.56 (dd, 1
H, H-5¢¢), 7.65 (d,
1 H, H-3¢¢)
12ab
(2.6:1)
maj 4.60
t
3.06
d
2.83
d
5.25
d
6.49 6.62 5.18
dd
5.16
m
5.75
m (H)
2.61
br t
9.40
br s
7.30–7.45 (m, 4
H)
d
m
min 4.55
dd
2.97
d
2.84
d
5.31
d
6.40 6.46 5.08
dd
5.75
m (H)
2.41
m
9.40
br s
7.20–7.35 (m, 4
H)
d
m
12ba
(1.3:1)
maj 4.86
dd
2.99
d
2.59
d
5.09
d
6.42 6.54 5.00
dd dd
5.03
dd
5.73
2.15–2.23 and
12.25 7.25 (AA¢, 2 H),
br s 7.61 (BB¢, 2 H)
d
ddt (H) 2.33–2.39
m
min 4.77
dd
3.09 d 2.58
d
5.01
d
6.52 6.75 5.10–5.13
dd
5.80
2.15–2.23 and
12.25 7.59 (s, 4 H)
br s
d
m
ddt (H) 2.33–2.39
m
c
12ca
(1.3:1)
maj 4.81
dd
2.96
d
2.60
d
5.06
d
6.42 6.55 4.95–5.20
dd
5.73
m (H)
2.20–2.35
m
–
–
7.15–7.35 (m, 4
H)
d
m
c
mid 4.68
dd
3.05
d
2.59
d
5.02
d
6.53 6.73 4.95–5.20
dd
5.73
m (H)
2.20–2.35
m
7.15–7.35 (m, 4
H)
d
m
12da
(3:1.8:1)
maj 4.41
dd
3.07
d
2.59
d
5.04
br s
6.52 6.68 4.95
dd
5.19
dd
5.79
ddt (H)
1.97–2.06
m
12.11 7.34–7.59 (m, 4
br s H)
d
m
mid 4.70
dd
3.01
d
2.55
d
5.10
br s
6.43 6.61 4.89–5.00
dd
5.62
ddt (H)
2.27–2.40
m
12.11 7.34–7.59 (m, 4
br s H)
d
m
min 4.73
dd
2.95
d
2.57
d
5.06
br s
6.43 6.55 4.89–5.00
dd
5.62
m (H)
2.45–2.64
m
12.11 7.16 (m, 1 H),
d
m
br s
7.34–7.59 (m, 3
H)
12ea
(2.1:1.5:1)
maj 4.69
dd
2.99
d
2.56
d
5.10
br s
6.43 6.61 4.99
dd dd
5.19
dd
5.61
m (H)
1.96–2.05
m
12.10 7.26–7.35 (m, 2
d
br s
H, H-4¢¢ + H-6¢¢),
7.45 (dt, 1 H, H-
5¢¢), 7.73 (dd, 1 H,
H-3¢¢)
mid 4.42
dd
3.06
d
2.59
d
5.04
d
6.51 6.68 4.89–5.08
dd
5.80
m (H)
2.42–2.61
m
12.10 7.14 (dd, 1 H, H-
d
m
br s
6¢¢), 7.26–7.35
(m, 1 H, H-4¢¢),
7.44 (dt, 1 H, H-
5¢¢), 7.70 (dd, 1 H,
H-3¢¢)
min 4.72
dd
2.95
d
2.58
d
5.06
br s
6.42 6.54 4.89–5.08
dd
5.58
m (H)
2.27–2.35
m
12.10 7.26–7.35 (m, 2
d
m
br s
H, H-4¢¢ + 6¢¢),
7.44 (m, 1 H, H-
5¢¢), 7.67 (m, 1 H,
H-3¢¢)
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1867
b
Table 5 1H NMR Spectra (DMSO-d6a or CDCl3 /TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Chemical Shifts (continued)
Product
Chemical Shifts, d
2
5
6
7
8
9
1¢-cis 1¢-trans R
3¢A
3¢B
CO2H Aryl
12fa
(1.1:1)
maj 4.70
dd
3.05
d
2.55
d
5.09
d
6.52 6.71 5.04
dd
5.15
dd
5.75
ddt (H)
2.12
m
12.19 7.22–7.41 (m, 4
d
m
br s
H)
min 4.46
dd
3.00
d
2.58
d
5.03
d
6.42 6.57 4.96
dd
4.99
m
5.66
ddt (H)
2.27
m
12.19 7.22–7.41 (m, 4
br s H)
d
m
12ga
(1.05:1)
maj 4.75
dd
3.07
d
2.57
d
5.08
d
6.41 6.74 5.07–5.13
dd
5.72
ddt (H)
2.17
m
12.25 7.43 (AA¢, 2 H),
br s 7.71 (BB¢, 2 H)
d
m
min 4.85
dd
2.97
d
2.56
d
5.00
d
6.51 6.53 4.99–5.04
dd
5.79
m (H)
2.34
m
12.25 7.10 (AA¢, 2 H),
br s 7.76 (BB¢, 2 H)
d
m
a EtOAc–CHCl3 (1:2).
b EtOAc.
c CO2H proton gets exchanged with DMSO-d6.
d The signals of minor isomer protons are of extremely low intensity.
Table 6 1H NMR Spectra (DMSO-d6 or CDCl3/TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Coupling Constants
Product
Coupling Constants, J (Hz)
1¢-cis,2¢ 1¢-trans,2¢ 2¢,3¢A 2¢,3¢B 3¢,3¢
2,3¢A
7.3
2,3¢B
7.3
5,6
9.1
9.1
9.2
9.2
9.0
9.1
9.1
9.1
9.2
7,8
1.6
1.6
1.4
1.4
1.6
1.7
1.6
1.5
1.7
8,9
5.7
5.8
5.6
5.6
5.9
5.8
5.7
5.7
5.6
Other Constants
a
11a
maj
min
maj
min
maj
min
maj
mid
min
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
15.5
4.5
9.8
–
a
a
a
11b
11c
11d
–
–
–
–
a
a
a
–
–
–
–
14.0
14.8
15.4
13.7
13.7
4.0
4.1
10.8
9.8
J3¢A,Me = J3¢B,Me = 0.6
J3¢A,Me = J3¢B,Me = 0.6
a
–
8.5
–
–
–
a
–
10.0
10.0
a
–
11e
11f
maj
mid
maj
–
–
–
–
–
–
–
–
–
–
–
–
14.0
14.0
15.3
4.5
4.5
6.6
9.9
9.9
7.8
9.0
9.0
9.1
1.3
1.3
1.6
5.7
5.7
5.7
J
J
3¢¢,4¢¢ = J4¢¢,5¢¢ = J5¢¢,6¢¢ = 7.8
3¢¢,4¢¢ = J4¢¢,5¢¢ = J5¢¢,6¢¢ = 8.0
–
–
min
–
–
–
–
13.5
4.0
10.3
9.1
1.6
5.7
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1868
E. V. Boltukhina et al.
PAPER
Table 6 1H NMR Spectra (DMSO-d6 or CDCl3/TMS, 400 MHz) of 3-Aryl-3-aza-6-carboxy-4-oxo-10-oxatricyclo[5.2.1.01,5]dec-8-enes
11a–h and 12a–g; Coupling Constants (continued)
Product
Coupling Constants, J (Hz)
1¢-cis,2¢ 1¢-trans,2¢ 2¢,3¢A 2¢,3¢B 3¢,3¢
2,3¢A
4.0
4.9
4.0
4.0
4.9
4.6
3.9
3.8
5.2
2,3¢B
9.7
5,6
9.2
9.2
9.1
9.1
9.2
9.2
9.2
9.1
9.2
7,8
1.7
1.7
1.5
1.5
1.5
1.5
1.7
1.7
1.5
8,9
5.7
5.8
5.6
5.6
5.8
5.8
5.7
5.9
5.8
Other Constants
a
11g
maj
min
maj
min
maj
min
maj
min
maj
–
–
–
–
–
–
J
J
J
J
2¢¢,3¢¢ = J5¢¢,6¢¢ = ~8.7
2¢¢,3¢¢ = J5¢¢,6¢¢ = ~8.9
3¢¢,5¢¢ = 1.7, J5¢¢,6¢¢ = 8.2
3¢¢,5¢¢ = 1.7, J5¢¢,6¢¢ = 8.2
a
–
–
–
–
4.9
11h
–
–
–
–
13.5
15.5
10.3
9.5
–
–
–
–
a
10.4
10.4
10.2
10.7
10.1
16.5
16.5
17.1
17.7
17.1
5.8
5.8
–
4.9
–
–
–
–
12a
12b
a
a
a
–
–
–
7.9
a
7.0
7.3
7.0
7.0
7.3
7.0
–
10.6
6.4
a
–
a
12c
12d
–
9.5
J
1¢,1¢ = 1.6, J2¢¢,3¢¢ = J5¢¢,6¢¢ =
~8.7
a
min
maj
mid
min
maj
10.1
10.6
10.3
17.1
17.2
17.4
7.0
7.0
7.1
7.0
7.0
7.1
–
4.6
4.9
5.4
5.0
5.1
5.8
9.2
9.2
9.1
9.3
9.1
1.5
1.5
1.8
1.8
1.6
5.8
5.8
5.7
5.8
5.7
–
a
–
6.9
J
–
–
1¢,1¢ = 1.5
a
–
10.1
10.1
10.1
a
a
a
a
a
–
–
–
–
–
a
12e
10.2
10.2
17.5
17.0
7.0
6.7
7.0
6.7
–
J
J
3¢¢,4¢¢ = 8.0, J3¢¢,5¢¢ = 1.3,
5¢¢,4¢¢ = J5¢¢,6¢¢ = 7.6
a
mid
–
4.9
7.0
9.2
1.7
5.8
J
J
3¢¢,4¢¢ = 8.4, J3¢¢,5¢¢ = 1.3,
5¢¢,4¢¢ = J5¢¢,6¢¢ = 7.7
a
min
maj
min
maj
min
10.3
10.4
10.4
10.1
10.6
16.4
17.3
17.3
17.1
17.6
5.7
7.2
7.4
7.0
7.0
5.7
7.2
7.4
7.0
7.0
–
4.9
4.9
5.0
3.7
4.0
10.0
10.1
5.3
9.3
9.2
9.2
9.2
9.2
1.7
1.7
1.7
1.7
1.7
5.6
5.8
5.7
5.8
5.8
–
a
12f
–
J
J
J
J
1¢,1¢ = 0.9
a
–
1¢,1¢ = 0.9
a
12g
–
6.3
2¢¢,3¢¢ = J5¢¢,6“ = ~8.8
1¢,1¢ = 1.6, J2¢¢,3¢¢ = J5¢¢,6¢¢ =
a
–
10.7
~8.6
a Coupling constants cannot be determined because of the overlap of the corresponding signals.
Table 7 Mass Spectral Data of Compounds 11, 12, and 14–17 (EI, 70 eV)
Product
m/z, rel. intensity (%)
11a
359 ([M+] (for 35Cl), 3), 304 (12), 260 (10), 206 (100), 204 (10), 135 (19), 127 (5), 117 (12), 111 (11), 99 (17), 91 (11),
77 (5), 55 (10), 44 (14), 39 (9), 28 (15)
11b
11c
403 ([M+] (for 79Br), 4), 350 (8), 338 (14), 304 (5), 250 (80), 41 (220), 204 (16), 182 (16), 171 (21), 155 (25), 143 (8),
135 (49), 125 (100), 117 (45), 105 (23), 99 (93), 91 (80), 77 (46), 71 (26), 65 (49), 55 (89), 39 (76)
343 ([M+], 13), 288 (30), 270 (3), 258 (2), 244 (11), 226 (2), 214 (2), 190 (100), 161 (2), 135 (3), 117 (2), 99 (10), 55 (5)
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1869
Table 7 Mass Spectral Data of Compounds 11, 12, and 14–17 (EI, 70 eV) (continued)
Product
m/z, rel. intensity (%)
11d
359 ([M+] (for 35Cl), 5), 304 (15), 260 (12), 206 (100), 135 (21), 127 (5), 117 (12), 111 (10), 99 (20), 91 (12), 79 (6), 75
(5), 65 (5), 55 (10), 44 (12), 39 (9), 28 (15)
11e
403 ([M+], 1), 350 (20), 304 (10), 250 (100), 190 (7), 170 (5), 155 (4), 135 (13), 117 (7), 99 (12), 91 (7), 81 (5), 69 (7),
44 (4)
11f
11g
11h
343 ([M+], 4), 299 (3), 288 (16), 244 (11), 190 (100), 135 (8), 122 (14), 99 (10), 91 (6), 79 (4), 55 (5), 28 (16)
451 ([M+] (12), 396 (26), 352 (11), 298 (100), 171 (13), 135 (25), 117 (12), 99 (11), 91 (9), 76 (6), 55 (5)
465 ([M+] (4), 433 (54), 418 (14), 410 (40), 389 (27), 366 (9), 312 (100), 256 (9), 217 (5), 185 (18), 135 (17), 128 (5),
117 (14), 99 (16), 91 (10), 55 (6)
12a
12b
12c
12d
12e
345 ([M+] (for 35Cl) (15), 304 (17), 260 (9), 246 (23), 153 (6), 140 (5), 138 (11), 127 (8), 121 (30), 111 (13), 103 (17),
99 (21), 91 (17), 77 (16), 65 (7), 55 (11), 44 (19), 41 (7)
389 ([M+] (for 79Br) (7), 373 (4), 348 (12), 304 (9), 290 (23), 250 (100), 223 (3), 190 (5), 184 (12), 171 (13), 157 (21),
145 (6), 121 (57), 103 (42), 91 (45), 65 (19), 55 (28), 39 (20), 27 (15)
329 ([M+], 4), 288 (12), 244 (9), 230 (15), 190 (100), 149 (9), 137 (5), 121 (27), 103 (14), 91 (24), 77 (10), 65 (7), 55
(12), 44 (18), 39 (18), 26 (6)
345 ([M+] (for 35Cl), 1), 310 (6), 304 (13), 260 (5), 246 (20), 206 (100), 190 (5), 138 (10), 121 (10), 111 (8), 103 (8),
99 915), 91 (12), 77 (11), 55 (7), 44 (11), 39 (10), 28 (14)
389 ([M+] (for 79Br), 7), 348 98), 310 (13), 292 (9), 250 (100), 190 (32), 170 (7), 155 (13), 121 (46), 91 (35), 77 (39), 55
(25), 39 (44)
12f
329 ([M+], 3), 288 (14), 244 (5), 230 (24), 190 (100), 122 (13), 103 (7), 99 (12), 95 (7), 77 (8), 55 (6), 44 (6), 39 (7), 27 (5)
12g
437 ([M+], 12), 396 (13), 352 (10), 338 (20), 298 (100), 219 (6), 203 (12), 171 (28), 142 (5), 121 (37), 91 (26), 77 (22),
55 (13), 39 (15)
14a
341 ([M+] (for 35Cl), 90), 326 (47), 308 (18), 297 (100), 282 (26), 266 (6), 252 (11), 238 (6), 217 (9), 178 (5), 141 (10),
115 (10), 108 (9), 102 (6), 44 (13), 36 (7), 28 (12)
14b
14c
385 ([M+] (for 79Br), 31), 370 (11), 354 (5), 341 (51), 326 (18), 297 (24), 276 (6), 262 (11), 247 (14), 232 (36), 217 (39)
325 ([M+], 88), 310 (42), 292 (18), 281 (100), 266 (30), 250 (11), 236 (16), 222 (13), 162 (6), 133 (13), 117 (6), 44 (7),
28 (6)
14d
341 ([M+] (for 35Cl), 13), 306 (59), 297 (100), 282 (10), 262 (45), 254 (26), 241 (10), 232 (10), 217 (23), 204 (14), 190
(12), 178 (23), 164 (16), 151 (12), 141 (26), 123 (24), 115 (57), 102 (48), 96 (25), 89 (42), 82 (6), 73 (39), 63 (29), 55
(8), 51 (27), 44 (55), 39 (34)
14e
343 ([M+ – 44] (for 81Br), 2), 306 (100), 262 (3), 217 (1), 109 (2), 95 (2), 81 (2), 69 (4), 43 (4)
14f
325 ([M+], 7), 310 (6), 281 (100), 266 (15), 238 (8), 226 (6), 197 (7), 170 (5), 128 (10), 115 (7), 77 (6)
433 ([M+], 100), 418 (27), 389 (52), 374 (9), 262 (6), 232 (7), 217 (8), 204 (5), 128 (3), 115 (6), 109 (4), 77 (2), 44 (2)
14g
15a, 16a
327 ([M+] (for 35Cl), 28), 311 (6), 294 (4), 283 (100), 268 (25), 254 (9), 232 (7), 217 (5), 204 (13), 178 (9), 164 (11), 151
(8), 140 (4), 128 (6), 115 (16), 102 (31), 89 (20), 75 (30), 63 (15), 51 (16), 39 (17)
15b, 16b
373 ([M+] (for 79Br), 66), 371 (69), 356 (7), 329 (100), 312 (13), 298 (7), 284 (15), 248 (19), 232 (23), 217 (9), 204 (33),
177 (6), 146 (5), 129 (4), 115 (9), 102 (19), 77 (9), 51 (4), 39 (3)
15c, 16c
15d, 16d
311 ([M+]; 63), 296 (5), 279 (9), 267 (100), 252 (26), 238 (11), 222 (21), 178 (5), 162 (6), 146 (6), 101 (5), 75 (5), 44 (6)
327 ([M+] (for 35Cl), 42), 312 (10), 294 (6), 283 (100), 268 (18), 232 (8), 204 (11), 194 (6), 178 (7), 164 (9), 151 (7), 134
(9), 123 (8), 109 (9), 102 (38), 96 (11), 89 (13), 82 (13), 75 (18), 63 (11), 58 (29), 51 (13), 36 (19)
15e, 16e
15f, 16f
15g, 16g
371 ([M+] (for 79Br), 19), 327 (10), 292 (100), 248 (13), 204 (8), 115 (7), 89 (7), 77 (9), 63 (6), 51 (7), 39 (8)
311 ([M+], 23), 267 (100), 238 (7), 224 (14), 222 (11), 162 (6), 133 (4), 44 (7), 28 (4)
419 ([M+], 100), 375 (60), 248 (11), 232 (6), 204 (10), 128 (7), 102 (6), 44 (6), 41 (7)
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1870
E. V. Boltukhina et al.
PAPER
Table 7 Mass Spectral Data of Compounds 11, 12, and 14–17 (EI, 70 eV) (continued)
Product
m/z, rel. intensity (%)
17a
327 ([M+] (for 35Cl), 9), 286 (100), 283 (22), 244 (5), 243 (5), 242 (15), 214 (12), 178 (5), 152 (10), 151 (5), 138 (6), 111
(11), 77 (9), 75 (8)
17c
17g
311 ([M+], 5), 270 (100), 226 (14), 198 (12), 170 (5), 95 (8), 77 (6), 28 (7)
419 ([M+], 12), 378 (100), 334 (8), 306 (7), 179 (10), 152 (4), 76 (8)
The intramolecular cyclization of isoindolones 11a–f and The intramolecular cyclization of fluoro-substituted ad-
12a–f leading to isoindolo[2,1-a]quinoline-10-carboxylic ducts 11c,f required a higher temperature (135–140 °C) as
acids 14a–f, 15a–f and 16a–f was carried out at 125– compared to their chloro- and bromo-substituted analogs
155 °C in the presence of concentrated ortho-phosphoric (125–130 °C). The cyclization reaction rate in the case of
and sulfuric acids (3:1 by volume) (Schemes 4 and 5 and ortho-substituted adducts 11d–f is lower (2 h) compared
Tables 4, 7–9). Intramolecular cyclization of allyl-substi- to their para-analogs 11a–c (1 h). Oxoisoindolo[2,1-
tuted epoxyisoindolones 12a–f required more drastic re- a]quinoline-10-carboxylic acids 14a–f were obtained in
action conditions (145–155 °C, Scheme 5) compared to moderate yields (31–62%, Table 4) as colorless crystals.
their methallyl substituted analogs 11a–f (125–140 °C,
In contrast to the 5,5-dimethylisoindolo[2,1-a]quinolines
14, their 5-monosubstituted homologues were formed as
mixtures of two geometrical isomers 15 and 16 according
to the orientation of the hydrogen atoms at the C-5 and C-
Scheme 4).17 It can be explained by the poor stability of
the intermediate secondary carbocation formed by proto-
nation of the allyl fragment in comparison with the tertia-
ry one formed from the methallyl fragment.
6a positions (Scheme 5). In all the cases isomer 15 with
pseudoequatorial orientation of 5-Me group was predom-
inating. The stereochemistry of isomers 15a–f and 16a–f
Me
Me
Me
R2
R2
was determined based on the spin-spin coupling constants
of the H-5 and H-6a atoms. Thus, for the prevailing iso-
mer 15 with pseudoaxial orientation of the 5-H atom, the
coupling constants were J5ax,6ax = 9.5–12.5 Hz and
J5ax,6eq = 5.6–6.9 Hz, while for the minor isomer 16 with
the pseudoequatorial orientation of the same H-atom the
constants were much smaller (J5eq,6ax = 5.5–6.2 Hz and
J5eq,6eq = 2.4–6.2 Hz) (Table 9).
H3PO4/H2SO4
(3:1)
N
N
125–140 °C
O
R1
R1
O
O
11a–f
14a–f
CO2H
CO2H
a
H
b
H
c
H
F
d
e
f
F
H
R1
Cl Br
H H
R2 Cl Br
Scheme 4
Using allyl-substituted epoxyisoindolones 12a,c,g as
model compounds we have shown (Scheme 5) that the ar-
omatization of the oxabicycloheptene fragment was a pre-
liminary step in the formation of isoindolo[2,1-
a]quinolines 14–16. Heating compounds 12a,c,g in phos-
phoric acid alone at 80 °C initiated the epoxide opening
and aromatization reaction sequence to give 3-allylisoin-
dolones 17a,c,g in good yields (53–70%, Table 4).
R2
H3PO4, 80 °C
R2
N
O
N
O
R1
O
CO2H
17a,c,g
12a–f
CO2H
In the presence of sulfuric acid, the iodo-substituted ad-
duct 12g underwent reduction leading to a mixture of 3-
iodo-substituted (15g, 16g) and unsubstituted (18, 19)
oxoisoindolo[2,1-a]quinoline-10-carboxylic acids in 33%
total yield (molar ratio 2:1). Molecular iodine was
evolved during the reaction. The desired cyclization of
11g, 12g into the corresponding 3-iodo-substituted oxo-
isoindolo[2,1-a]quinolines 14g, 15g and 16g was carried
out in the presence of phosphoric acid at 110–155 °C
(Scheme 6).
H3PO4/H2SO4 (3:1)
145–155 °C
a: R2 = Cl
c: R2 = F
g: R2 = I
Me
Me
O
H
H
R2
R2
H
H
N
N
R1
R1
O
CO2H
15a–f
CO2H
16a–f
Scheme 5
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1871
base, the reaction mixture was stirred for 1 h at r.t. The cooled mix-
ture was poured into sat. aq NH4Cl solution (300 mL) under ice
cooling and extracted with Et2O (3 × 100 mL). The organic layer
was dried (MgSO4) and concentrated. The residue was distilled in
vacuo or purified by Al2O3 (Tables 1– 3).
R
R
Me
O
I
I
H3PO4
N
110–155 °C
N
O
O
Compounds 11a–h, 12a–g; General Procedure
CO2H
CO2H
R = Me
14g, 15g, 16g
11g,12g
The appropriate homoallylamine 9, 10 (0.10 mol) was dissolved in
benzene (250 mL). An equimolar amount of maleic anhydride (0.10
mol, 9.8 g) was added in one portion to the solution. The reaction
mixture was stirred for 5–10 days at r.t. The crystalline product was
collected by filtration, washed with toluene (2 × 100 mL) and Et2O
(2 × 80 mL), and dried in air to give the desired products 11, 12 as
colorless solids. Their physical properties and spectral characteris-
tics are given in Tables 4– 7.
H3PO4 / H2SO4
(3:1)
11, 14:
12, 15, 16: R = H
135 °C
Me
N
Me
N
I
Compounds 14a–f, 15a–f, 16a–f; General Procedure
O
O
The appropriate adduct 11a–f, 12a–f (0.01 mol) was stirred with a
mixture of 85% H3PO4 and 96% H2SO4 (45 mL, 3:1 by volume) at
125–155 °C for 1 h (TLC monitoring). At the end of the reaction,
the mixture was diluted with H2O (200 mL). The precipitate ob-
tained was collected by filtration, washed with cold H2O (5 × 80
mL), and dried in air. The crude product was purified by recrystal-
lization to give the desired isoindoloquinolines 14a–f, 15a–f, 16a–
CO2H
15g, 16g
(22%)
CO2H
18, 19
(11%)
Scheme 6
We did not manage to find out any suitable conditions for
the cyclization of ortho-iodo-substituted oxoepoxyisoin-
dolone 11h. Thus, adduct 11h forms a resin in the pres-
ence of phosphoric acid even at low (60–80 °C)
temperatures.
1
f as colorless crystals. Their physical properties and H NMR and
mass spectral data are given in Tables 4, 7–9. Their 13C and 19F data
are given below.
3-Chloro-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14a)
In all the tetracyclic acids 14–16, 18 and 19, the 6a-H-
atom has a pseudoaxial orientation and the spin-spin cou-
pling constant values confirm its orientation
(J6a,6ax = 10.3–13.0 Hz and J6A,6eq = 1.8–4.4 Hz) (Table 9).
13C NMR (DMSO-d6, 100.6 MHz): d = 165.4 (s) and 165.0 (s)
(CO2H and NC=O), 148.3 (s), 141.8 (s), 133.0 (d), 130.9 (d), 130.1
(s), 128.9 (s), 128.2 (d), 127.8 (s), 127.6 (d), 126.9 (s), 126.5 (d),
125.3 (d), 56.6 (d, C-6a), 44.9 (t, C-6), 34.6 (d, C-5), 31.9 (q) and
29.7 (q, CH3-5).
In conclusion, this work demonstrates a new two-step
synthesis of 1- and 3-halo-substituted isoindolo[2,1-
a]quinoline-10-carboxylic acids interesting as potentially
biologically active compounds. It was demonstrated that
the insertion of an electron-withdrawing substituent did
not have any sufficient effect on the key step of this syn-
thetic approach – intramolecular electrophilic cyclization
of 2-allyl(methallyl)oxoepoxyisoindolones.
3-Bromo-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14b)
13C NMR (DMSO-d6, 100.6 MHz): d = 166.0 (s) and 165.6 (s)
(CO2H and NC=O), 146.3 (s), 139.2 (s), 133.0 (d), 132.7 (s), 131.0
(d), 130.1 (d), 129.8 (s), 129.5 (d), 128.6 (s), 126.3 (d), 122.2 (d),
117.7 (s), 56.1 (d, C-6a), 41.5 (t, C-6), 33.9 (d, C-5), 31.4 (q) and
30.3 (q, CH3-5).
3-Fluoro-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14c)
Melting points are uncorrected. IR spectra were obtained in KBr
pellets for solids or as thin film for oils. NMR spectra 1H (400 MHz)
and 13C (100.6 MHz) were recorded for solutions (2–5%) in CDCl3
or DMSO-d6 at 30 °C and traces of CHCl3 (1H NMR, d = 7.26),
DMSO-d5H (1H NMR, d = 2.49) and DMSO-d6 (13C NMR, d =
39.43) present in the solvents were used as the internal standard.
Chemical shifts are reported in ppm units, coupling constants (J) are
reported in Hz. The purity of the obtained substances and the com-
position of the reaction mixtures were controlled by TLC silufol
UV254 plates. The separation of the final products was carried out by
column chromatography on Al2O3 (activated, neutral, 50–200 mm)
or by recrystallization.
13C NMR (DMSO-d6, 100.6 MHz): d = 165.9 (s) and 165.3 (s)
1
(CO2H and NC=O), 159.25 (d, JC,F = 242.8 Hz, C-3), 146.2 (s),
3
139.41 (d, JC,F = 6.3 Hz, C-4a), 132.9 (d), 131.3 (d), 129.57 (d,
4JC,F = 2.7 Hz, C-11b), 129.52 (s), 128.7 (s), 126.4 (d), 122.15 (d,
3JC,F = 8.3 Hz, C-1), 113.8 (d, 2JC,F = 23.5 Hz), 113.5 (d, 2JC,F = 23.5
Hz), 56.3 (d, C-6a), 41.6 (t, C-6), 34.0 (d, C-5), 31.3 (q) and 30.3 (q,
CH3-5).
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO): d = –2.76.
1-Chloro-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14d)
Compounds 9a–h, 10a–g; General Procedure
13C NMR (DMSO-d6, 100.6 MHz): d = 165.9 (s) and 165.5 (s)
(CO2H and NC=O), 146.1 (s), 138.8 (s), 132.9 (d), 132.2 (s), 131.0
(d), 129.7 (s), 129.4 (s), 128.5 (s), 127.1 (d), 126.4 (d), 126.2 (d),
121.8 (d), 56.0 (d, C-6a), 41.4 (t, C-6), 33.8 (d, C-5), 31.3 (q) and
30.2 (q) (CH3-5).
The corresponding aldimine 8a–h (0.30 mol) was slowly added
dropwise at reflux to a stirred solution of allylmagnesium bromide
[prepared from allyl bromide (39 mL, 0.45 mol) and Mg turnings
(22.0 g, 0.90 mol) in Et2O (300 mL)] for amines 10, or to a solution
of methallylmagnesium chloride [prepared from methallyl chloride
(41 mL, 0.45 mol) and Mg (22.0 g, 0.90 mol) in a mixture of THF–
Et2O (1:1, 300 mL)] for amines 9. After the addition of the Schiff
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1872
E. V. Boltukhina et al.
PAPER
1-Bromo-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14e)
16c
13C NMR (DMSO-d6, 100.6 MHz): d = 166.3 (s) and 165.5 (s)
1
13C NMR (DMSO-d6, 100.6 MHz): d = 165.8 and 164.9 (C=O),
148.4 (s), 142.4 (s), 133.2 (d), 132.4 (s), 131.6 (d), 130.8 (d), 130.2
(s), 128.2 (d), 127.8 (s), 126.8 (d), 126.0 (d), 118.0 (s), 56.7 (C-6a),
44.9 (t, C-6), 40.5 (d, C-5), 32.0 and 29.7 (CH3-5).
(CO2H and NC=O), 159.5 (d, JC,F = ~242 Hz, C-3), 146.4 (s),
3
135.70 (d, JC,F = 7.2 Hz, C-4a), 133.1 (d), 131.5 (d), 130.5 (d,
4JC,F = 2.2 Hz, C-11b), 129.7 (s), 128.9 (s), 126.6 (d), 122.06 (d,
3JC,F = 8.3 Hz, C-1), 116.1 (d, 2JC,F = 22.6 Hz), 113.7 (d, 2JC,F = 22.5
Hz), 55.3 (d, C-6a), 33.3 (t, C-6), 30.7 (d, C-5), 23.9 (q, CH3-5).
1-Fluoro-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindo-
lo[2,1-a]quinoline-10-carboxylic Acid (14f)
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO): d = –3.71.
13C NMR (DMSO-d6, 100.6 MHz): d = 165.4 (s) and 165.0 (s)
1
(CO2H and NC=O), 154.32 (d, JC,F = 251.4 Hz, C-3), 147.8 (s),
1-Chloro-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15d)
140.6 (br d, C-4a), 132.8 (d), 130.9 (d), 130.0 (s), 127.8 (s), 127.08
3
4
(d, JC,F = 8.1 Hz, C-3), 126.4 (d), 122.5 (d, JC,F = 2.7 Hz, C-4),
120.85 (d, 2JC,F = 12.7 Hz, C-11b), 114.5 (d, 2JC,F = 19.9 Hz, C-2),
55.9 (d, C-6a), 44.4 (t, C-6), 33.9 (d, C-5), 32.2 (q) and 29.9 (q,
CH3-5).
13C NMR (DMSO-d6, 100.6 MHz): d = 165.7 and 165.0 (C=O),
148.3 (s), 137.9 (s), 133.2 (d), 131.7 (s), 130.9 (d), 130.2 (s), 128.5
(d), 128.3 (s), 127.72 (d), 127.65 (s), 126.6 (d), 126.4 (d), 58.8 (C-
6a), 38.5 (C-6), 31.3 (C-5), 21.1 (CH3-5).
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO): d = 0.60.
16d
13C NMR (DMSO-d6, 100.6 MHz): d = 165.7 and 165.0 (C=O),
148.5 (s), 140.1 (s), 133.7 (s), 133.3 (d), 132.1 (s), 130.9 (d), 128.6
(s), 128.2 (d), 128.03 (d), 127.96 (s), 126.9 (d), 125.9 (d), 56.4 (C-
6a), 37.3 (C-6), 29.7 (C-5), 21.0 (CH3-5).
3-Chloro-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15a)
13C NMR (DMSO-d6, 100.6 MHz): d = 166.1 and 165.6 (C=O),
145.9 (s), 134.7 (s), 133.3 (s), 133.1 (d), 131.4 (d), 129.7 (s), 129.4
(s), 128.5 (s), 127.6 (d), 126.7 (d), 126.4 (d), 121.71 (d), 59.1 (C-
6a), 35.5 (C-6), 31.0 (C-5), 20.5 (CH3-5).
1-Bromo-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15e)
13C NMR (DMSO-d6, 100.6 MHz): d = 165.7 and 165.0 (C=O),
148.49 (s), 138.6 (s), 133.2 (s), 133.2 (d), 131.7 (d), 131.0 (d), 130.2
(s), 128.2 (d), 127.6 (s), 127.0 (d), 126.6 (d), 118.1 (s), 58.8 (C-6a),
38.3 (C-6), 31.6 (C-5), 21.2 (CH3-5).
16a
13C NMR (DMSO-d6, 100.6 MHz): d = 166.1 and 165.6 (C=O),
146.3 (s), 135.2 (s), 133.1 (d), 133.0 (s), 131.2 (d), 129.8 (s), 129.0
(s), 128.6 (s), 127.6 (d), 126.7 (d), 126.4 (d), 121.66 (d), 55.0 (C-
6a), 33.1 (C-6), 30.4 (C-5), 23.8 (CH3-5).
16e
13C NMR (DMSO-d6, 100.6 MHz): d = 165.9 and 165.7 (C=O),
148.55 (s), 141.1 (s), 134.0 (s), 133.4 (d), 131.3 (d), 131.0 (d), 130.0
(s), 128.6 (d), 128.0 (s), 127.1 (d), 125.9 (d), 118.6 (s), 56.9 (C-6a),
37.4 (C-6), 29.7 (C-5), 19.9 (CH3-5).
3-Bromo-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15b)
13C NMR (DMSO-d6, 100.6 MHz): d = 166.4 and 165.2 (C=O),
146.0 (s), 135.6 (s), 135.2 (s), 133.0 (d), 131.6 (d), 130.4 (d), 130.0
(s), 129.9 (s), 129.6 (d), 126.3 (d), 122.1 (d), 117.7 (s), 59.3 (C-6a),
36.0 (C-6), 31.0 (C-5), 20.6 (CH3-5).
1-Fluoro-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15f)
13C NMR (DMSO-d6, 100.6 MHz): d = 165.7 (s) and 165.2 (s)
1
16b
(CO2H and NC=O), 154.7 (d, JC,F = 252.6 Hz, C-3), 147.8 (s),
13C NMR: Not recorded on account of the extremely low concentra-
tion of the solution.
136.5 (br d, C-4a), 133.1 (d), 131.2 (d), 130.1 (s), 127.9 (s), 127.25
3
4
(d, JC,F = 8.1 Hz, C-3), 126.7 (d), 123.27 (d, JC,F = 2.3 Hz, C-4),
121.96 (d, 2JC,F = 12.8 Hz, C-11b), 114.5 (d, 2JC,F = 20.2 Hz, C-2),
58.6 (d, C-6a), 38.4 (t, C-6), 30.7 (d, C-5), 20.9 (q, CH3-5).
3-Fluoro-5-methyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (15c)
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO-d6): d = 0.58.
13C NMR (DMSO-d6, 100.6 MHz): d = 166.1 (s) and 165.5 (s)
1
(CO2H and NC=O), 159.5 (d, JC,F = 242.6 Hz, C-3), 146.0 (s),
3
135.30 (d, JC,F = 7.2 Hz, C-4a), 133.1 (d), 131.67 (d), 130.85 (d,
16f
4JC,F = 2.2 Hz, C-11b), 129.6 (s), 128.8 (s), 126.6 (d), 122.06 (d,
3JC,F = 8.3 Hz, C-1), 114.5 (d, 2JC,F = 23.0 Hz), 113.5 (d, 2JC,F = 22.4
Hz), 59.4 (d, C-6a), 35.7 (t, C-6), 31.2 (d, C-5), 20.6 (q, CH3-5).
13C NMR: Not recorded on account of the extremely low concentra-
tion of the solution.
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO-d6): d = 0.41.
19F NMR (DMSO-d6, 376.5 MHz, external standard: 0.2 M C6H5F
in DMSO): d = –3.10.
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1873
Table 8 1H NMR Spectra (DMSO-d6/TMS, 400 MHz) of 5,6,6a,11-Tetrahydroisoindolo[2,1-a]quinolines 14a–g, 15a–g and 16a–e; Chemi-
cal Shifts
R
Me
5
4
R2
6
7
6a
2
8
9
N
R1
O
COOH
Product Chemical Shifts, d
R1
2
R2
Cl
4
R
CH3-
6ax
6e
6a
7
8
9
CO2H
14a
14b
14c
14d
14e
14f
8.30
d
7.38
dd
7.64
d
1.38
s (CH3)
1.47
s
1.59
t
2.50
dd
5.16
dd
7.99
br d
7.85
t
8.04
br d
9.95
br s
8.24
d
7.51
dd
Br
F
7.75
d
1.38
s (CH3)
1.46
s
1.59
t
2.49
dd
5.16
dd
7.99
d
7.85
t
8.03
br d
14.73
br s
a
8.29
dd
7.17
ddd
7.46
dd
1.37
s (CH3)
1.46
s
1.59
t
2.51
dd
5.16
dd
8.00
d
7.85
t
8.07
d
–
Cl
Br
F
7.55
dd
7.33
t
7.44
dd
1.39
s (CH3)
1.28
s
1.55
dd
2.45
dd
5.23
dd
7.98
br d
7.85
t
8.00
br d
14.45
br s
a
7.61
d
7.27
t
7.60
d
1.24
s
1.40
s
1.60
dd
2.46
dd
5.25
dd
8.00
d
7.87
t
8.03
d
–
7.22
m
7.33
m
7.42
d
1.37
s (CH3)
1.42
s
1.50
t
2.49
br d
5.21
br d
8.01
d
7.86
t
8.03
d
15.87
br s
14g
8.09
d
7.66
dd
I
7.88
d
1.36
s (CH3)
1.45
s
1.58
t
2.47
dd
5.15
dd
7.98
d
7.85
t
8.03
d
9.92
br s
8.37
d
7.40
dd
Cl
Br
F
7.54
d
3.29
m (H)
1.40
d
1.39
q
2.82
ddd
5.11
dd
7.99
br d
7.87
t
8.09
br d
14.74
br s
15a
15b
a
8.30
d
7.51
dd
7.67
d
3.30
m (H)
1.39
d
1.38
q
2.80
ddd
5.10
dd
8.00
d
7.86
t
8.07
d
–
a
15c
15d
15e
15fb
15gb
8.43
dd
7.06
td
7.14
dd
3.32
m (H)
1.47
d
1.51
ddd
2.75
ddd
4.88
dd
7.75
dd
7.82
t
8.51
dd
–
Cl
Br
F
7.44–7.47 7.32
m
7.44–7.47 3.27
m
1.25
d
1.39
dt
2.75
ddd
5.17
dd
7.97
d
7.86
t
8.02
br d
14.51
br s
t
m (H)
7.62
d
7.25
t
7.50
d
3.27
m (H)
1.20
d
1.45
dt
2.75
ddd
5.19
dd
7.96–8.03 7.85–7.90 7.96-8.03 10.16
m
m
m
br s
7.21–7.36
m
3.28
m (H)
1.36
d
1.28
q
2.77
dd
5.13
dd
7.98
t
7.86
dd
8.04
br d
10.11
br s
8.13
d
7.68
dd
I
7.81
d
3.29
m (H)
1.36
d
1.36
dd
2.76
ddd
5.09
dd
7.85
t
7.98
d
8.05
d
9.90
br s
c
8.37
d
7.38
dd
Cl
Br
F
7.48
d
3.30
m (H)
1.48
d
1.78
dt
–
5.14
dd
8.00
br d
7.87
t
8.06
br d
14.74
br s
16a
16b
a
8.30
d
7.49
dd
7.61
d
3.30
m (H)
1.46
d
1.76
dt
2.49
m
5.13
dd
8.00
d
7.86
t
8.05
d
–
c
a
16c
16d
16e
8.43
dd
7.06
td
7.13
dd
–
1.45
d
1.90
dt
2.42
ddd
4.96
dd
7.75
dd
7.82
t
8.50
dd
–
Cl
7.44–7.47 7.34
m
7.44–7.47 3.27
m
1.34
d
2.28
dt
2.88
q
5.21
t
7.97
d
7.87
t
8.00
br d
14.51
br s
t
m (H)
Br
7.64
d
7.29
t
7.39
d
3.27
m (H)
1.31
d
2.07–2.26
m
5.22
t
7.96–8.03 7.85–7.90 7.96–8.03 10.16
br s
m
m
m
a Proton of CO2H group are lacking owing to the exchange with DMSO-d6.
b The signals overlap with the signals of the corresponding protons of the major isomer.
c The signals of minor isomer protons are of extreme low intensity.
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

1874
E. V. Boltukhina et al.
PAPER
Table 9 1H NMR Spectra (DMSO-d6/TMS, 400 MHz) of 5,6,6a,11-Tetrahydroisoindolo[2,1-a]quinolines 14a–g, 15a–g and 16a–e; Coupling
Constants
R
Me
5
4
R2
6
7
6a
2
8
9
N
R1
O
COOH
Product Coupling constants, J (Hz)
5,6ax
–
5,6eq
–
5,Me
–
6a,6ax 6a,6eq 6ax,6eq 1,2
1,3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2,3
–
2,4
2.4
2.9
2.3
1.2
3,4
–
7,8
7.6
7.6
7.7
7.6
7.7
8.0
7.6
7.5
7.6
7.6
7.6
7.6
7.7
7.7
7.5
7.6
7.6
7.6
7.6
8,9
7.6
7.6
7.7
7.6
7.7
8.0
7.6
7.5
7.6
7.6
7.6
7.6
7.7
7.7
7.5
7.6
7.6
7.6
7.6
14a
14b
14ca
14d
14e
14f
12.5
12.6
12.6
10.9
10.2
12.0
13.0
12.6
12.1
12.8
10.3
13.0
12.0
13.0
11.8
13.0
12.8
~7.1b
6.5
2.3
2.5
2.6
3.9
3.8
1.8
2.0
2.6
2.5
3.1
4.4
4.8
2.8
2.5
2.6
2.3
3.4
~7.1b
6.5
12.7
12.8
12.8
13.3
13.1
13.0
13.0
12.8
12.6
13.4
13.2
13.0
12.8
13.0
13.1
13.0
13.0
13.2
8.8
9.1
8.8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.9
7.9
7.6
–
7.9
7.9
7.6
–
b
–
–
–
–
–
–
–
–
–
–
14g
15a
15b
15cc
15d
15e
15f
–
–
–
8.7
8.7
8.8
9.0
–
2.0
2.0
2.1
3.0
–
12.2
12.5
12.4
~10.3
9.5
12.0
12.2
5.9
5.5
5.8
5.9
5.6
6.1
6.3
6.9
5.7
5.8
7.2
6.7
7.0
7.0
7.0
6.8
6.8
7.2
7.2
7.0
7.0
6.9
–
–
–
–
–
–
7.8
8.0
7.8
8.0
–
–
b
b
b
–
–
–
–
15g
16a
16b
16c
16d
16e
8.7
8.5
8.8
9.0
–
–
2.0
2.0
2.2
–
b
–
–
–
b
–
–
–
b
1.2
–
–
–
b
b
–
–
7.6
8.2
–
–
7.6
8.2
b
b
b
–
–
–
–
a J1,F = 5.6, J2,F = 11.0 and J4,F = 10.5 Hz.
b Coupling constants cannot be determined due to overlap of the corresponding signals.
c J1,F = 5.5, J2,F = 9.0, J4,F = 9.5 and J7,9 = 1.5 Hz.
Compounds 14g, 15g, 16g; General Procedure
(d), 129.9 (s), 128.7 (s), 126.4 (d), 122.4 (d), 90.4 (s, C-3), 56.1 (C-
6a), 41.6 (C-6), 33.8 (C-5), 31.5 and 30.4 (CH3-5).
A mixture of corresponding adduct 11g, 12g (0.01 mol) and 85%
H3PO4 (40 mL) was stirred at 110–155 °C for 45 min (TLC moni-
toring). At the end of the reaction, the mixture was diluted with H2O
(200 mL). The precipitate obtained was collected by filtration,
washed with cold H2O (5 × 80 mL), and dried in air. The crude
product was recrystallized to give the desired isoindoloquinolines
14g, 15g, 16g as colorless crystals. Their physical properties and
spectral characteristics are given in Tables 4, 7–9).
Compounds 17a,c,g; General Procedure
A mixture of corresponding adduct 12a,c,g (0.01 mol) and 85%
H3PO4 (40 mL) was stirred at 80 °C for 1.5 h (TLC monitoring). At
the end of the reaction, the mixture was diluted with H2O (200 mL).
The precipitate obtained was collected by filtration, washed with
cold H2O (5 × 80 mL), and dried in air. The crude product was pu-
rified by recrystallization to give the desired products 17a,c,g as
colorless crystals. Their physical properties and spectral character-
istics are given in Tables 4, 10, 11).
3-Iodo-5,5-dimethyl-11-oxo-5,6,6a,11-tetrahydroisoindolo[2,1-
a]quinoline-10-carboxylic Acid (14g)
13C NMR (DMSO-d6, 100.6 MHz): d = 166.1 and 165.7 (C=O),
146.4 (s), 139.3 (s), 136.0 (d), 135.4 (d), 133.3 (s), 133.1 (d), 131.2
Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York

PAPER
Novel Approach to Halo-Substituted Isoindolo[2,1-a]quinolines
1875
Table 10 1H NMR Spectra (CDCl3/TMS, 400 or 200 MHz) of 7-Carboxyisoindoles 17a,c,g; Chemical Shifts
5"
2"
2'
R2
1'
6"
3'
4
3
3"
5
6
N
O
COOH
Product 3
4
5
6
1¢cis
1¢trans 2¢
3¢A
3¢B
2¢¢
3¢¢
R2
Cl
5¢¢
6¢¢
17a
17c
17g
5.40
dd
7.77
m
8.41
m
4.98
d
4.83
d
5.19
m
2.80
ddd
2.60
dd
7.47
s
7.47
5.33
dd
7.85–7.75
m
8.50
m
5.02
br d
4.87
br d
ca. 5.25 2.80
m
2.63
m
7.22
AA¢F
F
I
7.49
BB¢F
m
5.38
dd
7.79
br d
7.78
t
8.46
ddd
4.99
br d
4.84
dq
5.21
m
2.80
ddd
2.62
m
7.29
AA¢
7.84
BB¢
Table 11 1H NMR Spectra (CDCl3/TMS, 400 or 200 MHz) of 7-Carboxyisoindoles 17a,c,g; Coupling Constants
5"
2'
R2
1'
6"
3'
4
3
3"
5
6
N
2"
O
COOH
Product Coupling Constants, J (Hz)
3,3¢A
3,3¢B
4,5
5,6
1¢-cis,
1¢-trans
1¢-cis,2¢ 1¢-trans,2¢ 2¢,
3¢A
2¢,
3¢B
3¢A,
3¢B
2¢¢,3¢¢
5¢¢,6¢¢
a
a
a
a
a
17a
3.4
3.4
3.1
5.8
6.0
6.0
–
–
–
10.4
10.1
10.1
17.4
17.1
16.9
5.4
8.1
14.1
–
–
a
a
a
a
a
17cb
17gc
–
7.0
7.4
–
–
–
–
8.7
8.7
7.4
0.8
3.1
8.2
14.7
~8.8
~8.8
a Coupling constants cannot be determined due to overlap of the corresponding signals.
b J2¢¢,F = J6¢¢,F = 5.6 and J3¢¢,F = J5¢¢,F = 8.7 Hz.
c J1¢,3¢B = ca. 0.8, J1¢,3¢A = 1.4, J3,6 = 0.4 and J4,6 = 1.4 Hz.
(12) Epsztajn, J.; Jóźwiak, A.; Koluda, P.; Sadokierska, I.;
Wilkowska, I. D. Tetrahedron 2000, 56, 4837.
(13) Hameršak, Z.; Litvić, M.; Šepac, D.; Lesac, A.; Raza, Z.;
Acknowledgment
The authors are grateful for the financial support from the Russian
Foundation for Basic Research (grant no. 04-03-32 433).
Šunjić, V. Synthesis 2002, 2174.
(14) Grimwood, S.; Le Bourdellès, B.; Whiting, P. J. Neurochem.
1995, 64, 525.
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Synthesis 2005, No. 11, 1859–1875 © Thieme Stuttgart · New York