Fused isoquinolines: 3-aryl-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]- isoquinoline-1,5-dione-2-spiro-4′-(1′-alkyl-1′, 4′-dihydropyridine)s

Article abstract of DOI:10.1016/j.tet.2003.10.009

Previously unknown 3-arylamino-1,2-dihydro-1-isoquinolones were obtained by condensation of 2-cyanomethylbenzoic acid with arylamines. Isonicotinoylation of the compounds was shown to proceed at the carbon atom in the 4-position to give 3-arylamino-4-isonicotinoyl-1,2-dihydro-1-isoquinolones which were quaternized with alkylating agents and formed the corresponding pyridinium salts. Deprotonation of the latter induced intramolecular conjugated addition with the pyrrole ring closure and formation of spiro compounds. The structure of the products was confirmed by NMR, IR and UV spectroscopy and by synthesis of the model compound, 3-(4-tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3- c]isoquinoline-1,5-dione.

Full text of DOI:10.1016/j.tet.2003.10.009

Tetrahedron 60 (2004) 211–217
Fused isoquinolines: 3-aryl-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]-
isoquinoline-1,5-dione-2-spiro-40-(10-alkyl-10,40-dihydropyridine)s
*
Tat’yana T. Kucherenko, Roman Gutsul, Vladimir M. Kisel and Vladimir A. Kovtunenko
Department of Organic Chemistry, Taras Shevchenko National University, Vladimirskaya Str. 60, 01017 Kyiv, Ukraine
Received 21 May 2003; revised 9 September 2003; accepted 2 October 2003
Abstract—Previously unknown 3-arylamino-1,2-dihydro-1-isoquinolones were obtained by condensation of 2-cyanomethylbenzoic acid
with arylamines. Isonicotinoylation of the compounds was shown to proceed at the carbon atom in the 4-position to give 3-arylamino-4-
isonicotinoyl-1,2-dihydro-1-isoquinolones which were quaternized with alkylating agents and formed the corresponding pyridinium salts.
Deprotonation of the latter induced intramolecular conjugated addition with the pyrrole ring closure and formation of spiro compounds. The
structure of the products was confirmed by NMR, IR and UV spectroscopy and by synthesis of the model compound, 3-(4-tolyl)-2,3,4,5-
tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione.
q 2003 Elsevier Ltd. All rights reserved.
The preparative access to 1,4-dihydropyridines via the
addition of nucleophilic agents to pyridinium salts was first
isoquinolones (4) may be appropriate substrates for this
purpose.
1
¨
developed by Krohnke in 1967. This idea, in its
intramolecular version, was used later in the synthesis of
the alkaloid nauclefine2 involving cyclization of quaternized
nicotinamides and isonicotinamides induced by coupled
addition. Such a cyclization process is of the exo-trig type3
and can be considered as an intramolecular modification of
the Michael reaction. Additional examples of the cycliza-
tion of similar substrates have been reported.4,5 This
heterocyclization method was extended further, using
4-aryl-substituted pyridinium salts.6,7 We have shown that
quaternary salts of hetaryl 4-pyridyl ketones can also
undergo the heterocyclization.8
Using the method proposed earlier for preparation of
3-anilino-1,2-dihydro-1-isoquinolone (2, R¼H),9 we intro-
duced p-toluidine, ethyl 4-aminobenzoate, 4-bromoaniline
or 4-nitroaniline into reaction with 2-cyanomethylbenzoic
acid and obtained the previously unknown 3-arylamino-1,2-
dihydro-1-isoquinolones (2a–d) in good yields.
1
In their H NMR spectra, compounds 2a–d exhibit signals
of two exchangeable NH protons, at 10.66–11.35 and 7.78–
9.20 ppm, referring to N(2)H and N(3p)H, respectively. This
assignment is based on the correlation of 1H NMR spectra of
2a–d and their transformation products. Among other
spectroscopic peculiarities of compounds 2a–d, there
should be intimated the paramagnetic shift (ca. 0.5 ppm)
Continuing the study into the exo-trig ring closure, we
surmised that 3-arylamino-4-isonicotinoyl-1,2-dihydro-1-
Keywords: Acylation; Quaternization; 1,4-Dihydropyridines; Spiro compounds.
*
Corresponding author. Tel.: þ380-044-329-34-93; e-mail address: vkovtunenko@univ.kiev.ua
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.009

212
T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
0
0
0
p
of the doublet signal from the C(8)H proton and the
diamagnetic shift (by more than 1 ppm) of the singlet
from the C(4)H proton relative to the corresponding signals
in isoquinoline. In the first case, this is due to magnetic
anisotropy of the neighboring CvO group and in the
second—to quasi-aromaticity of the pyridone ring.
N
(2 )H, N(3 ) and C(5 )H protons in 5a–d appear already at
lower field, in the region of 11.5–12.2, 9.4–9.8 and 7.9–
8.3 ppm (as against 11.8–12.0, 8.6–9.3 and 6.8–7.8 ppm in
4a,b), respectively. At the same time, the stretching
vibration frequency of the ketone carbonyl in salts 5a–d
(near 1670 cm21) remains unchanged. The color of the solid
quaternary salts 5a–d is deeper as compared to the starting
compounds 4a,b and 2a,b.
The acylation of 3-anilino-1,2-dihydro-1-isoquinolone was
not studied earlier. Since isoquinolones 2a–d have several
nucleophilic centers, the acylation, in principle, may
proceed at different sites. To determine the main direction
of the reaction, we studied first isonicotinoylation of the
substrates with isonicotinoyl chloride. The products are
Solutions of 5a–d are instantly decolorized when treated
with bases (e.g. triethylamine, piperidine, morpholine or
pyridine) and, after dilution with water, easily-crystallizable
from DMF precipitates can be isolated. The 1H NMR and IR
spectra of the properly purified products give grounds to
suggest that they have the structure of spiro-annelated
1,4-dihydropyridines 7. The signal of the isoquinoline NH
proton remains in structures 7 at 11.51–11.96 ppm, but the
proton N(3p)H disappears and a new characteristic pattern
corresponding to four a- and b-protons of the 1,4-di-
hydropyridine moiety arises as two doublets at 6.38–6.59
and 4.33–4.51 ppm. In all cases the coupling constants
for these protons are equal to 8 Hz that is typical of olefin
cis-protons. In the 13C NMR spectra of 7a and 7c taken in
DMSO-d6, the signals of the spiro carbon atoms are
observed at 88.8 and 88.7 ppm, respectively. The enamine
character of the dihydr0opyridine moiety is reflected in
chemical shifts of its C-2 ,60 and C-30,50 atoms, i.e. 96.5 and
79.1 ppm for 7a and 96.8 and 76.0 ppm for 7c.
1
formed generally in good yields (60–85%). Based on H
NMR spectra, they were identified as 3-arylamino-4-
isonicotinoyl-1,2-dihydro-1-isoquinolones (4a–d), that is,
1
the acylation takes place at the C-4 atom. In the H NMR
spectra of compounds 4a–d, the signal of the C(4)H proton,
observed in the starting substrates 2a–d at 5.91–6.42 ppm,
is absent, but both exchangeable NH protons remain in the
molecules and resonate as singlets in the region of 11.52–
12.00 and 8.60–9.66 ppm. It should be noted that the effect
of the acyl residue at the C-4 atom in 4a–d on chemical
shifts is much stronger for the NH than for C(5)H protons. IR
spectra of compounds 4a–d show an additional band
between 1660 and 1725 cm21 which is absent in starting
2a–d and can be assigned to stretching vibrations of the
ketone carbonyl group. Its position in the spectra points to a
considerable conjugation of this function with both N-2 and
N-3p atoms as is also evidenced in the 1H NMR spectra. The
introduction of the acyl group into molecules 2 causes only
a small bathochromic shift (D 13 nm) of their long-wave
absorption bands in UV spectra. Such a shift as well as a
small hyperchromic effect observed are quite predictable for
a benzoyl (isonicotinoyl in our case) substituent in the
conjugated system.10 3-Arylamino-4-isonicotinoyl-1,2-
dihydro-1-isoquinolones (4a–d) are smoothly quaternized
in acetonitrile solutions. Although the compounds have
several nucleophilic centers, the electrophilic agents attack
exclusively the pyridine nitrogen atom to form quaternary
The transformation of quaternary salts 5 into spiro
compounds 7 evidently proceeds via intermediates of type
6 which are formed upon deprotonation of the starting salts
and then undergo cyclization through intramolecular
addition to the electrophilic site in the 4-position of the
pyridinium group. It is significant that the sequential
transformations 5![6]!7 run easily. For example, the
contour of the electronic absorption spectrum taken for salt
5a in methanol reproduces in detail that of spiro compound
7a but differs in band shape from the spectrum of ketone 4a.
This suggests that the spiro structure is thermodynamically
more favorable as compared to the structure of the
quaternary salt because even such a weak base as
the methanol solvent is able to deprotonate the latter
(Scheme 1).
1
salts 5a–d as evidenced by H NMR spectra.
The influence of the acyl residue on the heterocyclic system
is more distinct in the salts than in the free bases. Primarily
proton-containing groups closest to the substituent suffer
considerable paramagnetic shifts: the NMR signals of the
There is no need for preliminary preparation of salts 5 in

T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
213
Scheme 1.
order to obtain spiro compounds 7. It is possible first to treat
the isonicotinoylated derivatives 4a–d with alkylating
agents and then, without isolation of the salts 5a–d, to
treat the reaction mixture with a base. In this way
compounds 7c and 7f–i were obtained in sufficiently high
yields. Of particular interest is the one-pot preparation of
7d, were benzoyl chloride was used in place of the
alkylating agent. The benzoyl substituent in the resulting
structure 7d has the strongest effect just on the dihydro-
pyridine ring whose enamine protons exhibit considerable
KBr or CsI disks. Electronic spectra of 5£1025 M solutions
of 2a, 3, 4a, 5a and 7a in methanol were obtained on a
1
Specord M40 spectrophotometer. H NMR spectra were
taken on a Mercury 400 (Varian) spectrometer (400 MHz)
in DMSO-d6. 13C NMR spectra were measured in DMSO-d6
on the same instrument at 100 MHz. Chemical shifts are
reported in ppm (d) vs. TMS used as the internal standard.
The assignment of signals from aromatic protons was
confinned by the COSY HH correlation performed for 7e
and 7h. In all cases the vicinal coupling constants of
aromatic protons are in the range of 7.4–8.4 Hz. TLC on
Silufol UV-254 plates was used to monitor the progress of
the reactions and to check the purity of the compounds
prepared. 2-Cyanomethylbenzoic acid was obtained by the
reported procedure.14
1
paramagnetic shift in the H NMR spectrum.
The basis for the spiro structure 7 is the heterocyclic 3H-
pyrrolo[2,3-c]isoquinoline system (1) which is poorly
studied. It is known that its derivatives are formed in the
reactions of 3-amino-2-methyl-1,2-dihydro-l-isoquinolone
with oxalyl chloride11 and 3-aminoisocarbostyril with
p-bromophenacyl bromide.12 In the last case the product
is 2-(4-bromophenyl)-4,5-dihydro-3H-pyrrolo[2,3-c]iso-
quinolin-5-one which was studied as a selective inhibitor
of cAMP-dependent proteinkinase.13 In order to verify the
spiro structure of 7, we synthesized 3-(4-tolyl)-2,3,4,5-
tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione (3) as a
model compound by the classical method, that is, by
reacting 3-(4-toluidino)-1,2-dihydro-l-isoquinolone (2a)
1.1. General procedure for preparation of 3-arylamino-
l,2-dihydro-1-isoquinolones (2a–d)
A suspension of 2-cyanomethylbenzoic acid (10.0 mmol)
and the equimolar amount of p-toluidine (for 2a), ethyl
4-aminobenzoate (for 2b), 4-bromoaniline (for 2c), or
4-nitroaniline (for 2d) in chlorobenzene (5 mL) was heated
at reflux for 5 h, after which time the solvent was evaporated
and the residue was triturated with 2-propanol, filtered,
washed with a small amount of 2-propanol, dried, and
purified by crystallization from appropriate solvents.
1
with chloroacetyl chloride. The comparison of H NMR
spectra shows a close similarity between chemical shifts of
protons in the fused heterocyclic systems of compounds 3
and 7a. The methylene group C(2)H2 in 3 gives a singlet
signal at 4.24 ppm which is absent in 7a. Also IR spectra of
3 and 7a are very similar in shapes of absorption bands and
1.1.1. 3-(4-Toluidino)-1,2-dihydro-1-isoquinolone (2a). A
colorless solid; (1.5 g, yield 60%); mp 181 8C (from glacial
AcOH); [Found: C, 76.68; H, 5.59; N, 11.31. C16H14N2O:
requires C, 76.78; H, 5.64; N, 11.19%]; lmax (log 1): 210
(4.37), 370 (3.79) nm; nmax (KBr): 3270 (N–H), 3080, 2959
(C–H), 1650 (CvO), 1600 cm21 (CvC); dH: 10.71 (1H, s,
NH-2), 7.98 (1H, d, J¼8.0 Hz, H-8), 7.78 (1H, s, NH-3p),
7.48 (1H, t, J¼8.0 Hz, H-6), 7.35 (1H, d, J¼8.0 Hz, H-5),
7.15 (2H, d, J¼8.2 Hz, H-30, H-50), 7.14 (1H, t, J¼8.0 Hz,
H-7); 7.10 (2H, d, J¼8.2 Hz, H-20, H-60), 5.91 (1H, s, H-4),
2.32 (3H, s, CH3).
vibrational frequencies in the region of 1700–1400 cm21
.
The structure similarity of 3 and 7a having the same
chromophore also follows from likeness of their electronic
spectra between 250 and 400 nm.
1. Experimental
Melting points of compounds were determined on a
¨
Boetius-type apparatus and are uncorrected. IR spectra
were measured with a Pye Unicam SP3-300 instrument in
1.1.2. 3-(4-Ethoxycarbonylanilino)-1,2-dihydro-1-iso-
quinolone (2b). A colorless solid; yield (2.22 g, 72%); mp

214
T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
243 8C (from 2-propanol); [Found: C, 69.98; H, 5.11; N,
8.98. C18H16N2O3 requires C, 70.12; H, 5.23; N, 9.09%];
1.2.1. 4-Isonicotinoyl-3-(4-toluidino)-1,2-dihydro-l-iso-
quinolone (4a). Obtained from 2a as a light yellow solid;
(1.08 g, yield 61%); mp 278 8C; [Found: C, 72.70; H, 4.78;
N, 10.89. C22H17N3O2 requires C, 74.35; H, 4.82; N,
11.82%]; nmax (log 1): 293 (4.34), 383 (4.06) nm; nmax
(KBr): 3180, 3050 (N–H), 1675, 1620 (CvO), 1575,
1530 cm21; dH: 11.96 (1H, s, NH-2), 8.69 (2H, d, J¼4.4 Hz,
H-200, H-600), 8.60 (1H, s, NH-3p), 8.15 (1H, d, J¼7.4 Hz,
H-8), 7.42 (2H, d, J¼4.4 Hz, H-300, H-500), 7.32 (2H, d,
J¼7.4 Hz, H-30, H-50)0, 7.22 (1H, t, J¼7.4 Hz, H-6), 7.21
(2H, d, J¼7.4 Hz, H-2 , H-60), 7.17 (1H, t, J¼7.4 Hz, H-7),
6.83 (1H, d, J¼7.4 Hz, H-5), 3.00 (3H, s, CH3).
n
max (KBr): 3050 (N–H), 2970 (C–H), 1630 cm21 (CvO);
dH: 11.10 (1H, s, NH-2), 8.65 (1H, s, NH-3p), 8.07 (1H, d,
J¼8.2 Hz, H-8), 7.87 (2H, d, J¼8.4 Hz, H-30, H-50), 7.58
(1H, t, J¼8.2 Hz, H-6), 7.51 (1H, d, J¼8.2 Hz, H-5), 7.29
(1H, t, J¼8.2 Hz, H-7), 7.16 (2H, d, J¼8.4 Hz, H-20, H-60),
6.31 (IH, s, H-4), 4.26 (2H, q, J¼7.6 Hz, OCH2), 1.30 (3H, t,
J¼7.6 Hz, CH3).
1.1.3. 3-(4-Bromoanilino)-1,2-dihydro-1-isoquinolone
(2c). A colorless solid; (2.55 g, yield 81%); mp 233 8C
(from glacial AcOH); [Found: C, 55.13, Br 25.17; N, 8.72.
C15H11BrN2O requires C, 57.16, Br 25.35; N, 8.89%]; nmax
(KBr): 3140 (N–H), 2950 (C–H), 1660 (CvO), 1600,
1560, 1540 cm21; dH: 10.66 (1H, s, NH-2), 8.01 (1H, d,
J¼8.0 Hz, H-8), 7.93 (1H, s, NH-3p0 ), 7.46 (1H, t, J¼8.0 Hz,
H-6), 7.40 (2H, d, J¼8.4 Hz, H-3 , H-50), 7.30 (1H, d, J¼
8.0 Hz, H-5), 7.14 (1H, t, J¼8.0 Hz, H-7), 7.12 (2H, d,
J¼8.4 Hz, H-20, H-60), 5.99 (1H, s, H-4).
1.2.2. 3-(4-Ethoxycarbonylanilino)-4-isonicotinoyl-l,2-
dibydro-1-isoquinolone (4b). Obtained from 2b as a
colorless solid; (1.45 g, yield 70%); mp 261 8C; [Found:
C, 69.68; H, 4.61; N, 10.11. C24H19N3O4 requires C, 69.72;
H, 4.63; N, 10.16%]; nmax (CsI): 3000 (N–H), 1725, 1670,
1610 (CvO), 1570 cm21; dH: 11.82 (1H, s, NH-2), 9.28
(1H, s, NH-3p), 8.40 (2H, d, J¼3.6 Hz, H-200, H-600), 8.22
(1H, d, J¼7.4 Hz, H-8), 7.79 (1H, d, J¼7.4 Hz, H-5), 7.68
(2H, d, J¼7.6 Hz, H-30, H-50), 7.57 (1H, t, J¼7.4 Hz, H-6),
7.38 (1H, t, J¼7.4 Hz, H-7), 7.38 (2H, d, J¼3.6 Hz, H-300,
H-500), 6.79 (2H, d, J¼7.6 Hz, H-20, H-60), 4.24 (2H, q, J¼
7.8 Hz, OCH2); 1.34 (3H, t, J¼7.8 Hz, CH3).
1.1.4. 3-(4-Nitroanilino)-1,2-dihydro-1-isoquinolone
(2d). A colorless solid; (2.39 g, yield 85%); mp 286 8C
(from glacial AcOH); [Found: C, 63.9; H, 4.23; N, 14.08.
C15H11N3O3 requires C, 64.05; H, 3.94; N, 14.94%]; nmax
(KBr): 3380 (N–H), 1655 (CvO), 1600, 1560, 1505 cm21
(CvC); dH: 11.35 (1H, s, NH-2), 9.20 (1H, s, NH-3p), 8.11
(IH, d, J¼8.0 Hz, H-8), 7.64 (IH, t, J¼8.0 Hz, H-6), 7.58
(1H, d, J¼8.0 Hz, H-5), 7.40 (2H, d, J¼8.4 Hz, H-30, H-50),
7.14 (1H, t, J¼8.0 Hz, H-7), 7.12 (2H, d, J¼8.4 Hz, H-20,
H-60), 6.42 (1H, s, H-4).
1.2.3. 3-(4-Bromoanilino)-4-isonicotinoyl-1,2-dihydro-1-
isoquinolone (4c). Obtained from 2c as a colorless solid;
(1.34 g, yield 64%); mp 305 8C; [Found: C, 59.97; H,
3.32, Br 18.96; N, 9.96. C21H14BrN3O2 requires C, 60.02;
H, 3.36, Br 19.1; N, 10.00%]; nmax (CsI): 3180, 3100
(N–H),1670, 1610 (CvO), 1570, 1505 cm21; dH: 11.52
(1H, s, NH-2), 9.66 (1H, s, NH-3p), 8.47 (2H, d, J¼4.0 Hz,
H-200, H-600), 8.14 (1H, d, J¼8.4 Hz, H-8), 7.53 (1H, d,
J¼8.4 Hz, H-5), 7.42 (1H, t, J¼8.4 Hz, H-6), 7.38 (2H,
d, J¼4.0 Hz, H-300, H-500), 7.28 (2H, d, J¼8.4 Hz, H-30,
H-500), 7.207 (1H, t, J¼8.4 Hz, H-7), 6.90 (2H, d, J¼8.4 Hz,
H-2 , H-6 ).
1.1.5. Preparation of 3-(4-tolyl)-2,3,4,5-tetrahydro-1H-
pyrrolo[2,3-c]isoquinoline-1,5-dione (3). A suspension of
isoquinolone 2a (0.5 g, 2.0 mmol) in anhydrous dioxane
(50 mL) was heated under reflux until it became homo-
geneous. Chloroacetyl chloride (0.2 mL, 2.5 mmol) was
then added to the resultant solution and the mixture was
refluxed for 4H, and concentrated. The residue was treated
with a concentrated soda solution and the solid was filtered
off, washed with water, and crystallized from 2-propanol to
give 3 as a light yellow solid. Yield (0.33 g, 58%); mp
285 8C; [Found: C, 73.90; H, 4.83; N, 9.58. C18H14N2O2
requires C, 74.47; H, 4.86; N, 9.65%]; nmax (log 1): 238
(4.46), 247 (4.45), 284 (4.25), 316 (4.15), 370 (3.91) nm;
nmax (KBr): 3140, 3060 (N–H), 1670 infl., 1645 (CvO),
1625, 1580, 1525, 1505, 1445, 1400 cm21; dH: 11.91
(1H, s, NH-4), 8.31 (1H, d, J¼7.6 Hz, H-9), 8.02 (1H, d,
J¼7.6 Hz, H-6)0 , 7.61 (1H, t, J¼7.6 Hz, H-8), 7.270(2H, 0d,
J¼8.0 Hz, H-3 , H-50), 7.23 (2H, d, J¼8.0 Hz, H-2 , H-6 ),
7.22 (1H, 1, J¼7.6 Hz, H-7), 4.24 (2H, s, CH2), 2.37 (3H, s,
CH3).
1.2.4. 4-Isonicotinoyl-3-(4-nitroanilino)-1,2-dihydro-1-
isoquinolone (4d). Obtained from 2d as a sandy-colored
solid; (1.64 g, yield 85%); mp 282 8C; [Found: C, 65.26; H,
3.60; N, 14.47. C21H14N4O4 requires C, 65.28; H, 3.65; N,
14.50%]; nmax (KBr): 3090 (N–H), 1660, 1640 (CvO),
1595, 1515 cm21; dH: 12.00 (1H, s0,0 NH-2), 9.37 (1H, s
NH-3p), 8.42 (2H, d, J¼4.8 Hz, H-2 , H-600),0 8.26 (1H, d,
J¼8.4 Hz, H-8), 7.93 (2H, d, J¼8.4 Hz, H-3 , H-50), 7.84
(1H, d, J¼8.4 Hz, H-5), 7.64 (1H, t, J¼8.4 Hz, H-6), 7.46
(1H, t, H 8.4 Hz, H-7), 7.440(2H, 0d, J¼4.8 Hz, H-300, H-500),
6.79 (2H, d, J¼8.4 Hz, H-2 , H-6 ).
1.3. General procedure for preparation of 1-alkyl-4-(3-
arylamino-1-oxo-1,2-dihydro-4-isoquinolinoyl)-
pyridinium salts (5a–d)
1.2. General procedure for preparation of 3-arylamino-
4-isonicotinoyl-l,2-dihydro-1-isoquinolones (4a–d)
A mixture of isoquinolone 4a or 4b and an excess of the
appropriate alkylating agent in anhydrous acetonitrille
(15–20 mL) was refluxed for 10 h. The volatiles were
removed in vacuum and the residue was triturated with
2-propanol and washed on a filter with the same solvent.
A mixture of the appropriate isoqiunolone 2a–d (5.0 mmol)
and isonicotinoyl chloride (5.1 mmol) in anhydrous
dioxane (20 mL) was heated at reflux for 3 h. After
evaporation of the solvent in vacuum, the residue was
treated with a saturated soda solution, filtered off, washed
with water and 2-propanol, and recrystallized from
dimethylformamide.
1.3.1. 1-Methyl-4-[1-oxo-3-(4-toluidino)-1,2-dihydro-4-
isoquinolinoyl]pyridinium tosylate (5a). Obtained from

T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
215
isoquinolone 4a (0.7 g, 2.0 mmol) and methyl tosylate
(0.42 g, 2.2 mmol) as a bright red solid; yield (0.81 g, 75%);
mp 230 8C (from AcOH); [Found: C, 66.48; H, 4.98; N,
7.73. C30H27N3O5S requires C, 66.53; H, 5.02; N, 7.76%];
1.4. General and typical procedures for preparation of
3-aryl-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-
1,5-dione-2-spiro-4-[1-alkyl(acyl)-1,4-dihydropyridine]s
(7a–i)
lmax (log 1) 238 (4.66); 247 (4.55); 284 (4.40); 316 (4.25);
370 (3.93) nm; nmax (KBr): 3480, 3080 (N–H), 16705,
1630 (CvO), 1555, 1525 cm21; dH: 11.50 (1H, s, NH-2 ),
9.78 (1H, s, NH-30p), 8.890 (2H, d J¼6.4 Hz, H-2, H-6),
8.16 (1H, d, J¼8.4 Hz, H-8 ), 8.04 (2H, d, J¼6.4 Hz, H-3,
H-5), 7.88 (1H, d, J¼8.4 Hz, H-50), 7.53 (1H, t, J¼8.4 Hz,
H-60), 7.46 (2H, d, J¼8.0 Hz, H-300, H-500), 7.33 (1H, t, J¼
8.4 Hz, H-70), 7.06 (4H, m, C6H4SO3), 6.85 (2H, d, J¼
8.0 Hz, H-200, H-600), 4.25 (3H, s, NCH3), 2.31 (6H, s,
400-CH3þCH3C6H4SO3.
1.3.2. 1-Ethyl-4-[10-oxo-30-(400-toluidino)-10,20-dihydro-40-
isoquinolinoyl] pyridinium iodide (5b). Obtained from
isoquinolone 4a (1.06 g, 3.0 mmol) and ethyl iodide
(0.62 g, 4.0 mmol); yield (1.22 g, 80%); mp 246 8C (from
DMF); [Found: C, 56.30; H, 4.29; N, 8.19. C24H22IN3O2
requires C, 56.37; H, 4.34; N, 8.22%]; nmax (KBr):
3500, 3050 (N–H), 1675, 1615 (CvO), 1560, 1525 cm2l;
dH 11.69 (1H, s, NH-20), 9.44 (1H, s, NH-30p), 8.94 (2H,
d, J¼6.4 Hz, H-2, H-6), 8.18 (1H, d, J¼8.4 Hz, H-80),
8.10 (1H, d, J¼8.4 Hz, H-50), 8.05 (2H, d, J¼6.4 Hz,
H-3, H-5), 7.60 (1H, t, J¼ 8.0 Hz, H-60), 007.37 (1H, t,
J¼8.0 Hz, H-70), 7.00 (2H, d, J¼8.4 Hz, H-3 , H-500), 6.75
(2H, d, J¼8.4 Hz, H-200, H-600), 4.50 2H, (q, J¼7.8 Hz,
NCH2), 2.27 (3H, s, 400-CH3), 1.31 (3H, t, J¼7.8 Hz,
CH2CH3).
Method A (for 7a, 7b, 7e). The appropriate pyridinium salt
5a, 5b or 5c (5 mmol) was dissolved on heating in
anhydrous pyridine (about 2 mL) and, after cooling, the
resultant solution was diluted with water (30 mL). The
precipitate formed was separated by filtration, washed with
water, dried, and crystallized from dimethylformamide.
Method B (for 7c, 7f–i). A mixture of the appropriate
isoquinolone 4a–d (5 mmol) and alkylating agent (6 mmol)
was refluxed in anhydrous acetonitrile (30 mL) for 6H, and
concentrated under a reduced pressure. The residue was
dissolved in pyridine (10 mL) on heating and after cooling
the resulting solution was diluted with water (30 mL). The
precipitate formed was filtered off, washed with water,
dried, and crystallized from dimethylformamide.
Method C (for 7d). To isoquinolone 4a (1.78 g, 5 mmol)
dissolved on heating in anhydrous pyridine (30 mL) was
added dropwise benzoyl chloride (1.4 g, 10 mmol). The
mixture was heated at reflux for 1H, and concentrated under
a reduced pressure. The solid residue was triturated with
a saturated solution of soda, washed with water and
2-propanol on a filter, dried, and crystallized from
dimethylformamide.
1.4.1. 3-(4-Tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]-
isoquinoline-1,5-dione-2-spiro-40-(10-methyl-10,40-dihydro-
pyridine) (7a). Obtained by Method A from salt 5a as light
yellow crystals; (1.48 g, yield 80%); mp 270 8C; [Found: C,
74.70; H, 5.12; N, 11.32. C23H19N3O2: requires C, 74.78; H,
5.18; N, 11.37%]; lmax (log 1): 238 (4.72), 247 (4.63), 284
(4.44), 316 (4.20), 370 (4.01) nm; nmax (KBr): 3500, 3140,
1.3.3. 4-[3-(4-Ethoxycarbonylanilino)-1-oxo-l,2-dihydro-
4-isoquinolinoyl]-1-ethylpyridinium
iodide
(5c).
Obtained from isoquinolone 4b and ethyl iodide taken in
the same mole ratio as in Section 1.3.2; (1.02 g, yield
60%); mp 295 8C (from DMF); [Found: C, 54.82; H, 4.22;
N, 7.33. C26H24IN3O4 requires C, 54.85; H, 4.25; N,
7.38%]; nmax (KBr): 3510, 3000 (N–H), 1720, 1675, 1610
(CvO), 15600, 1530 cm21; dH: 12.18 (1H, s, NH-20), 9.37
(1H, s, NH-3 p), 8.92 (2H, d, J¼6.4 Hz, H-2, H-6), 8.34
(1H, d, J¼8.4 Hz, H-80), 8.27 (1H, d, J¼8.4 Hz, H-50),
8.09 (2H, d, J¼6.4 Hz, H-3, H-5), 7.7200(1H, t, J¼8.4 Hz,
H-60), 7.71 0(2H, d, J¼8.8 Hz, H-300, H-5 ), 7.49 (1H, t, J¼
8.4 Hz, H-7 ); 6.75 (2H, d, J¼8.8 Hz, H-200, H-600), 4.43 (2H,
q, J¼7.8 Hz, NCH2), 4.27 (2H, q, J¼7.8 Hz, OCH2), 1.34
(3H, t, J¼7.8 Hz, OCH2CH3), 1.19 (3H, t, J¼7.8 Hz,
NCH2CH3).
3050 (N–H), 1650, 1620 (CvO), 1575, 1518, 1400 cm21
;
dH: 11.65 (1H, s, NH-4), 8.30 (1H, d, J¼8.0 Hz, H-9), 8.05
(1H, d, J¼8.0 Hz, H-6); 7.65 (1H, t, J¼8.0 Hz, H-8), 7.22
(1H, t, J¼8.0 Hz, H-7), 7.20 (2H,0d0 , J¼8.0 Hz, H-300, H-500),
7.09 (2H,0d, J¼8.0 Hz, H-200, H-6 ), 6.44 (2H, d, J¼7.2 Hz,
H-20, H-6 ), 4.33 (2H, d, J¼7.2 Hz, H-30, H-50), 2.90 (3H, s,
NCH3), 2.39 (3H, s, 400-CH3); dC,: 96.5 (C-20.60), 88.8
(spiro-C), 79.1 (C-30.50).
1.4.2. 3-(4-Tolyl)-2,3,4,5-tetrabydro-1H-pyrrolo[2,3-c]-
isoquinoline-1,5-dione-2-spiro-40-(10-ethyl-10,40-dibydro-
pyridine) (7b). Obtained by Method A from salt 5b;
(1.57 g, yield 82%); mp 331 8C; [Found: C, 75.11; H, 5.48;
N, 10.91. C24H21N3O2 requires C, 75.18; H, 5.52; N,
10.96%]; nmax (KBr): 3510, 3150, 3060 (N–H), 1655, 1625
(CvO), 1585, 1525 cm21; dH: 11.51 (1H, s, NH-4), 8.30
(1H, d, J¼7.8 Hz, H-9), 7.99 (1H, d, J¼7.8 Hz, H-6), 7.58
(1H, t, J¼7.8 Hz, H-8), 7.1700 (1H, t, J¼7.8 Hz, H-7), 7.14
(2H, d, J¼8.0 Hz, H-300, H-5 ), 7.03 (2H, 0d, J¼8.0 Hz, H-200,
H-600), 6.38 (2H, d, J¼7.6 Hz, H-20, H-6 ), 4.34 (2H, d, J¼
7.6 Hz, H-30, H-50), 3.20 (2H, q, J¼7.8 Hz, NCH2), 2.36
(3H, s, 400-CH3), 0.95 (3H, 1, J¼7.8 Hz, CH2CH3).
1.3.4. 4-[3-(4-Ethoxycarbonylanilino)-1-oxo-l,2-dihydro-
4-isoquinolinoyl]-1-methylpyridinium
iodide
(5d).
Obtained from isoquinolone 4b (0.5 g, 1.2 mmol) and
methyl iodide (0.3 g, 2.1 mmol) added in two equal portions
5H, apart; yield (0.48 g, 72%); mp 228 8C (from AcOH);
[Found: C, 54.02; H, 3.93; N, 7.52. C25H22IN3O4 requires C,
54.07; H, 3.99; N, 7.57%]; nmax (KBr): 3500, 3030 (N–H),
1725, 1670, 1610 (CvO), 1575, 1525 cm21; dH: 12.06 (1H,
s, NH-20), 9.41 (1H, s, NH-30p), 8.86 (2H, d, J¼6.0 Hz, H-2,
H-6), 8.26 (1H, d, J¼7.8 Hz, H-80), 8.23 (1H, d, J¼7.8 Hz,
H-50), 8.09 0(0 2H, d, J¼6.0 Hz, H-3, H-5), 7.750 (2H, d, J¼
8.0 Hz, H-3 , H-500), 7.68 (1H, t, J¼7.8 Hz, H-060 ), 7.47 (1H,
t, J¼7.8 Hz, H-70), 6.82 (2H, d, J¼8.0 Hz, H-2 , H-600), 4.29
(2H, q, J¼8.0 Hz, OCH2), 4.18 (3H, s, NCH3), 1.36 (3H, t,
J¼8.0 Hz, CH2CH3).
1.4.3. 3-(4-Tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]-
isoquinoline-1,5-dione-2-spiro-40-(10-benzyl-10,40-di-
hydropyridine) (7c). Obtained by Method B from

216
T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
isoquinolone 4a and benzyl chloride; (1.74 g, yield 78%);
mp 340 8C; [Found: C, 78.14; H, 5.11; N, 9.39. C29H23N3O2
requires C, 78.18; H, 5.20;N, 9.43%]; nmax (KBr): 3490,
3140, 3060, 2950 (N–H), 1645, 1620 (CvO), 1580, 1525,
1495, 1435, 1405 cm21; dH: 11.65 (1H, s, NH-4), 8.30 (1H,
d, J¼7.6 Hz, H-9), 7.99 (1H, d, J¼7.6 Hz, H-6), 7.64 (1H, t,
J¼7.6 Hz, H-8), 7.22 (1H, t, J¼7.6 Hz, H-7), 7.19 (2H,00d,
J¼8.0 Hz, H-300, H-500), 7.09 (2H, d, J¼8.0 Hz, H-200, H-6 ),
6.83–7.21 (5H, m, Ph), 6.50 (2H, d, J¼7.8 Hz, H-20, H-60),
4.43 (2H, d, J¼7.8 Hz, H-30, H-50), 4.41 (2H, s, NCH2), 2.38
(3H, s, 400-CH3); dC,: 96.8 (C-20.60), 88.7 (spiro-C), 79.0
(C-30.50).
291 8C; [Found: C, 61.59; H, 4.01, Br 17.73; N, 9.32.
C23H18BrN3O2: requires C, 61.62; H, 4.05; Br 17.82; N,
9.37%]; nmax (KBr): 3505, 3150, 3060, 3000 (N–H), 1670
infl., 1650, 1620 (CvO), 1580, 1505, 1435, 1405 cm21; dH:
11.73 (1H, s, NH-4), 8.29 (1H, d, J¼8.0 Hz, H-9), 7.99 (1H,
d, J¼8.0 Hz, H-6), 7.59 (1H, t, J¼8.0 Hz, H-8), 7.49 (2H, d,
J¼8.2 Hz, H-300, H-500), 7.20 (1H, t, J¼8.0 Hz, H-7), 7.11
(2H, d, J¼8.2 Hz, H-200, H-600), 6.43 (2H,0d, J¼7.2 Hz, H-20,
H-60), 4.35 (2H, d, J¼7.2 Hz, H-30, H-5 ), 3.23 (2H, q, J¼
7.8 Hz, NCH2), 0.97 (3H, t, J¼7.8 Hz, CH3).
1.4.8. 3-(4-Nitrophenyl)-2,3,4,5-tetrahydro-1H-pyrrolo-
[2,3-c]isoquinoline-1,5-dione-2-spiro-40-(10-methyl-10,40-
dihydropyridine) (7h). Obtained by Method B from
isoquinolone 4d and dimethyl sulfate as an ocher-colored
solid; (1.38 g, yield 69%); mp 319 8C; [Found: C, 65.97; H,
3.99; N, 13.92. C22H16N4O4 requires C, 66.00; H, 4.03; N,
13.99%]; nmax (KBr): 3500, 3420, 3120 (N–H), 1670 infl.,
1645, 1620 (CvO), 1575, 1485, 1415 cm21; dH: 11.96
(1H, s, NH-4),008.30 (1H, d, J¼8.2 Hz, H-9), 8.18 (2H, d,
J¼8.2 Hz, H-3 , H-500), 8.04 (1H, d, J¼8.2 Hz, H-6), 7.61
(1H, t, J¼8.2 Hz, H-8), 7.46 (2H, d, J¼8.2 Hz, 0H-200,0H-600),
7.25 (1H, t, J¼0 8.2 Hz, H-7), 6.55 (2H, br.s, H-2 , H-6 ), 4.52
(2H, br.s, H-3 , H-50), 3.06 (3H, s, NCH3).
1.4.4. 3-(4-Tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]-
isoquinoline-l,5-dione-2-spiro-40-(10-benzoyl-10,40-di-
hydropyridine) (7d). Obtained by Method C; (1.68 g, yield
73%); mp 250 8C; [Found: C, 75.75; H, 4.58; N, 9.10.
C29H21N3O3 requires C, 75.80; H, 4.61; N, 9.14%]; nmax
(KBr): 3130, 3060, 2950 (N–H), 1670 infl., 1660, 1625
(CvO), 1585, 1525, 1455 cm21; dH: 11.88 (1H, s, NH-4),
8.28 (1H, d, J¼8.2 Hz, H-9), 8.02 (1H, d, J¼8.0 Hz, H-6),
7.63 (1H, t, J¼8.0 Hz0, H-8), 7.37–7.56 (5H, m, Ph), 7.24
(2H, d, J¼7.2 Hz, H-2 , H-60), 7.23 (2H, d, J¼8.0 Hz, H-300,
00
H-5 ), 7.19 (1H, t, J¼8.0 Hz, H-7), 7.16 (2H, d, J¼8.0 Hz,
00
H-2 , H-600), 5.03 (2H, d, J¼7.2 Hz, H-30, H-50), 2.38 (3H, s,
400-CH3).
1.4.9. 3-(4-Nitrophenyl)-2,3,4,5-tetrahydro-1H-pyrrolo-
[2,3-c]isoquinoline-l,5-dione-2-spiro-40-(10-ethyl-10,40-
dihydropyridine) (7i). Obtained by Method B from
isoquinolone 4d and ethyl iodide; (1.76 g, yield 85%); mp
291 8C; [Found: C, 66.58; H, 4.31; N, 13.47. C23H18N4O4
requires C, 66.66; H, 4.38; N, 13.52%]; nmax (KBr): 3500,
3140, 3040 (N–H), 1670 infl., 1655, 1625 (CvO), 1585,
1535, 1510, 1440, 1405 cm21; dH: 11.96 (1H, s, NH-4), 8.31
(1H, d, J¼8.2 Hz, H-9), 8.15 (2H, d, J¼8.2 Hz, H-300, H-500),
8.04 (1H, d, J¼8.2 Hz, H-6), 7.62 (1H, t, J¼8.2 Hz, H-8),
7.46 (2H, d, J¼8.2 Hz, H-200, H-600), 7.26 (1H, t, J¼08.2 Hz,
H-7), 6.59 (2H, br.s, H-2, H-6(0), 4.51 (2H, br.s, H-3 , H-50),
3.35 (2H, q, J¼7.8 Hz, NCH2), 1.08 (3H, t, J¼7.8 Hz, CH3).
1.4.5. 3-(4-Ethoxycarbonylphenyl)-2,3,4,5-tetrahydro-
1H-pyrrolo[2,3-c]isoquinoline-1,5-dione-2-spiro-40-(10-
ethyl-10,40-dihydropyridine) (7e). Obtained by Method A
from salt 5c; (1.74 g, yield 79%); mp 238 8C; [Found: C,
70.70; H, 5.21; N, 9.47. C26H23N3O4 requires C, 70.74; H,
5.25; N, 9.52%]; nmax (KBr): 3510, 3130, 3010 (N–H),
1730, 1670 infl., 1650, 1620 (CvO), 1588, 1550, 1520,
1500, 1405 cm21; dH: 11.94 (1H, s, NH-4), 8.32 (1H, d,
J¼8.0 Hz, H-9), 8.0200(1H, d, J¼8.0 Hz, H-6), 7.91 (2H, d,
J¼8.0 Hz, H-300, H-5 ), 7.60 (1H, t, J¼8.0 Hz, H-8), 7.28
(2H, d, J¼8.0 Hz, H-200, H-600), 7.22 (1H, t, J¼8.0 Hz, H-7),
6.44 (2H, 0d, J¼7.2 Hz, H-20, H-60), 4.39 (2H, d, J¼7.2 Hz,
H-30, H-5 ), 4.34 (2H, q, J¼7.8 Hz, OCH2), 3.24 (2H, q,
J¼7.8 Hz, NCH2), 1.37 (3H, t, J¼7.8 Hz, OCH2CH3), 1.03
(3H, t, J¼7.8 Hz, NCH2CH3).
References and notes
1.4.6. 3-(4-Ethoxycarbonylphenyl)-2,3,4,5-tetrahydro-
1H-pyrrolo[2,3-c]isoquinoline-1,5-dione-2-spiro-40-(10-
benzyl-10,40-dihydropyridine) (7f). Obtained by Method B
from isoquinolone 4b and benzyl chloride; (1.79 g, yield
71%); mp 301 8C; [Found: C, 73.91; H, 4.96; N, 8.29.
C31H25N3O4: requires C, 73.94; H, 5.00; N, 8.34%]; nmax
(KBr): 3500, 3140, 3020 (N–H), 1728, 1670 infl., 1650,
1620 (CvO), 1580, 1540, 1520, 1405 cm21; dH 11.85 (1H,
s, NH-4), 8.33 (1H, d, J¼8.2 Hz, H-9), 8.0200(1H, d, J¼
8.2 Hz, H-6), 7.90 (2H, d, J¼8.2 Hz, H-300, H-5 ), 7.63 (1H,
t, J¼8.2 Hz, H-8), 7.28 (2H, d, J¼8.2 Hz, H-200, H-600), 7.23
(1H, 1, J¼8.2 Hz, H-07), 6.907.21 (5H, m, Ph), 6.53 (2H, d,
J¼7.2 Hz, H-20, H-6 ), 4.43 (2H, s, NCH2), 4.39 (2H, d,
J¼7.2 Hz, H-30, H-50), 4.37 (2H, q, J¼7.8 Hz, OCH2), 1.42
(3H, t, J¼7.8 Hz, CH3).
¨
1. Ahlbrecht, H.; Krohnke, F. Liebigs Ann. Chem. 1967, 704,
133.
2. Sainsbury, M.; Uttley, N. L. J. Chem. Soc., Perkin Trans. 1
1977, 2109.
3. Gilchrist, T. L. Heterocyclic Chemistry; Mir: Moscow, 1996;
p 91.
4. Naito, T.; Miyata, O.; Ninomiya, I. J. Chem. Soc., Chem.
Commun. 1979, 517.
5. Naito, T.; Ninomiya, I. Heterocycles 1980, 14, 959.
6. Weller, D. D.; Luellen, G. R. Tetrahedron Lett. 1981, 22,
4381.
7. Weller, D. D.; Weller, D. L. Tetrahedron Lett. 1982, 23, 5239.
8. Kysil, V. M.; Kovtunenko, V. O.; Potikha, L. M.; Turov, O. V.;
Babichev, F. S. Ukr. Khim. Zh. 1993, 59, 1070.
9. Goya, S.; Takade, A.; Tanaka, T.; Nagayama, H.; Teisuke, O.
Yakugaku Zasshi 1975, 95(3), 333. Chem. Abstr. 1975, 83,
43153h.
1.4.7. 3-(4-Bromopbenyl)-2,3,4,5-tetrahydro-1H-pyrrolo-
[2,3-c]isoquinoline-1,5-dione-2-spiro-40-(10-ethyl-10,40-
dihydropyridine) (7g). Obtained by Method B from
isoquinolone 4c and ethyl iodide; (1.91 g, yield 85%); mp
10. Tolmachev, V. N. Electronic Absorption Spectra of Organic
Compounds and Running the Spectra; Vyshcha Shkola:
Khar’koy, 1974; p 85.

T. T. Kucherenko et al. / Tetrahedron 60 (2004) 211–217
217
11. Kimoto, S.; Okamoto, M.; Ohta, S. Yakugaku Zasshi 1971, 91,
1279. Chem. Abstr. 1972, 76, 85662j.
Chem. Hoppe-Seyler 1996, 377(6), 373. Chem. Abstr. 1997,
125, 161858a.
12. Deady, L. W.; Quazi, N. H. J. Heterocycl. Chem. 1994, 31,
793.
13. Lu, Z. X.; Quazi, N. H.; Deady, L. W.; Polya, G. M. Biol.
14. Price, C. C.; Rogers, R. G.; Bachman, W. E.; Morin, R. D. In
Synthese of Organic Reagents; Izd. Inostr. Lit.: Moscow,
1952; p 267.