New approach for the synthesis of 3H-pyrrolo[2,3-c]isoquinoline derivatives

Article abstract of DOI:10.1016/j.tet.2012.03.011

Synthesis of new 2,3-diaryl-3H-pyrrolo[2,3-c]isoquinoline derivatives has been elaborated starting from isoquinoline-3-amine. Buchwald-Hartwig arylation and subsequent iodination in position 4 afforded 3-arylamino-4- iodoisoquinolines. These compounds wer

Full text of DOI:10.1016/j.tet.2012.03.011

Tetrahedron 68 (2012) 3560e3565
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New approach for the synthesis of 3H-pyrrolo[2,3-c]isoquinoline derivatives
a
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Bharat Dixit , Jozsef Balog , Zsuzsanna Riedl , Laszlo Drahos , Gyorgy Hajos
a Chemistry Department, VP. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India
Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri ut 59, H-1025 Budapest, Hungary
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a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of new 2,3-diaryl-3H-pyrrolo[2,3-c]isoquinoline derivatives has been elaborated starting from
isoquinoline-3-amine. BuchwaldeHartwig arylation and subsequent iodination in position 4 afforded 3-
arylamino-4-iodoisoquinolines. These compounds were subjected to Sonogashira cross-coupling re-
actions with some selected acetylenes, and the resulting coupled products underwent cyclization in the
presence of tetrabutylammonium fluoride to give title derivatives.
Received 2 December 2011
Received in revised form 13 February 2012
Accepted 5 March 2012
Available online 12 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Fused pyrrole
Iodination
Cyclization
BuchwaldeHartwig cross-coupling
Sonogashira cross-coupling
1. Introduction
Furthermore, the related tetracyclic 7H-indolo[2,3-c]isoquinoline
(3)5 and other N-positional isomers6,7 have been reported (Scheme 1).
To the best of our knowledge, no cross-coupling methodology has
been applied along the pathways to these heterocycles.
Our previous extended studies1,2 in the area of isoquinoline
chemistry and availability of novel derivatives of this ring system,
Scheme 1. Earlier known pyrrolo[2,3-c]isoquinoline derivatives and related tetracyclic derivatives.
efforts to synthesize novel isoquinoline-fused ring systems seemed
reasonable. In this context, application of the recently established
cross-coupling methodologies seemed of particular interest. In the
present paper we report on a straightforward new synthetic pathway
to the 3H-pyrrolo[2,3-c]isoquinoline ring system starting from iso-
quinoline-3-amine. Only one research group: Biehl et al. investigated
formation of this particular ring system (2) from the 4-
formymethylisoquinolineamine (1) under acidic conditions.3,4
Some of the pyrrole-fused isoquinolines are of biological im-
portance, which provided a further motivation for our research;
pyrrolo[2,1-a]isoquinoline moieties8 are present in alkaloid fami-
lies, such as erythrina9 and lamellarin10 and, exhibit diverse bi-
ological activities.7,11
2. Results and discussion
On the basis of our expertise in the area of aminoisoquinoline
chemistry1,2,12 and cross-coupling methodologies13 the retro-
synthetic analysis for preparation of the title ring system shown in
ꢀ
* Corresponding author. E-mail address: ghajos@chemres.hu (G. Hajos).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.011

B. Dixit et al. / Tetrahedron 68 (2012) 3560e3565
3561
Fig. 1 was used. Inspection of this figure reveals that besides the
ring-closing step (b)/(a), another predominant structural modi-
fication, (c)/(b) has been planned, in which the amino group is
substituted by a phenyl ring, whereas the X atom (halogen) is ex-
changed for an acetylic moiety. Both of these transformations can
be carried out by cross-coupling methodologies (Buch-
waldeHartwig arylation of the amine and Sonogashira coupling at
the X group in position 4, respectively).
bromo analogs31 prompted us to investigate the planned trans-
formation with 4-iodoisoquinoline-3-amine.
Very little precedent can be found for the direct iodination of
azines. To the best of our knowledge, there is only one publication
for the iodination of an isoquinoline in the position 4, which was
carried out with N-iodosuccinimide (NIS).32 When 5a was sub-
jected to iodination according to this literature reference, i.e., with
maintaining the reaction mixture at room temperature for pro-
Fig. 1. Retrosynthetic analysis of preparation of the tricyclic pyrrolo[2,3-c]isoquinoline ring (a).
Concerning the ring-closing step (b)/(a) a literature survey of
related cyclizations seemed of interest. Molecules having adjacent
carbonecarbon multiple bond and nucleophilic amine were often
used for the intramolecular cyclization to various indoles,14e16 ben-
zofurans,17 isocoumarines,18 benzopyranes,19 etc. derivatives using
basic conditions,20 transition metal-catalyzed reactions,21 gold(III),22
copper(I),23 copper(II) salt-catalyzed reactions,24 and ammonium
fluoride-mediated reactions.25 The most frequently used reagents or
catalysts for these ring-closing reactions are the palladium com-
plexes,26,27 iodine-promoted and many applications together with
polymer-supported reactions28 have also been established.
longed time (24 h), a mixture of the expected 4-iodoisoquinoline-
3-amine (6) and an unexpected diiodo product (7) was obtained,
where the two products were found in a comparable ratio (Scheme
3). When, however, this reaction was repeated at lower tempera-
ture (ꢀ20 ꢁC), formation of 7 could be excluded, but the desired
iodo compound 6 was obtained in very low yield, which was not
increased even after long reaction time.
Since separation of these products seemed to be very difficult
because of their similar chromatographic behavior, the para posi-
tion of the phenyl ring was blocked by a methyl group and, thus, 5b
was subjected to iodination. Although even in this case the iodin-
ation of the phenyl ring (in ortho position to the methyl group) as
a side reaction was experienced (the diiodo compound 9 was
formed), proper work up (column chromatography on silica by
hexane/CH2Cl2 (2:1) as the eluent) allowed isolation of the desired
4-iodo-3-(4-toluidinyl)isoquinoline (8) in acceptable (50%) yield
(Scheme 3).
In accordance with some literature records30 we have found that
isoquinoline-3-amine (4)12 readily undergoes BuchwaldeHartwig
coupling reaction29 with bromobenzene derivatives to give N-aryl-3-
isoquinolineamines (5, Scheme 2). The best yields have been ach-
ieved by using Pd2(dba)2 catalyst with the JohnPhos ligand, sodium
t-butoxide as base in boiling toluene under an argon atmosphere.
Scheme 2. BuchwaldeHartwig arylation of isoquinoline-3-amine.
In order to gain an excess to the 4-halogen substituted iso-
quinolines that could enable the planned Sonogashira coupling to
an acetylene, introduction of halogen atom was necessary. Bromi-
nation of isoquinoline-3-amine in position 4 is well documented in
the literature and, thus, preparation of 4-bromoisoquinoline-3-
amine has been described.30 Unfortunately, however, all of our ef-
forts for Sonogashira coupling of this compound proved to be un-
successful. The general experience that iodohetaryl compounds
more readily participate in cross-coupling reactions than the
Sonogashira coupling33 of 8 with five various acetylenic com-
pounds was carried out successfully to give 4-ethynyl derivatives
10aee as stable crystalline substances (Scheme 4). Inclusion of the
acetylenic chain was shown by the appearance of the typical IR
absorption around 2200 cmꢀ1
.
When these compounds were subjected to ring closure re-
actions upon analogy to some related literature data to form a fused
pyrrole ring, our initial efforts even by the use of different reaction
temperatures, various solvents and palladium catalysts proved to

3562
B. Dixit et al. / Tetrahedron 68 (2012) 3560e3565
Scheme 3. Iodination of isoquinoline-3-arylamines.
Scheme 4. Sonogashira coupling at position 4 in isoquinoline-3-amine and TBAF initiated cyclization to fused pyrrole.
be unsuccessful. Inspection of the past literature data on similar
ring closure reactions revealed, however, that a quite unique re-
action condition, i.e., use of tetrabutylammonium fluoride (TBAF)
might be useful in the present case34 by activation of the acetylenic
triple bond and, thereby, promoting the cyclization.
4. Experimental part
4.1. General methods
€
Melting points were determined on a Buchi apparatus. The IR
spectra were recorded on a Thermo Nicolet Avatar 320 FT-IR
spectrometer. NMR measurements were performed on Varian
INOVA-300 and 400 spectrometer equipped with a 5 mm inverse
detection z-gradient probe. 1H and 13C NMR spectra were mea-
sured at room temperature (25 ꢁC) in an appropriate solvent. 1H
Thus, when 10 was treated with this reagent in a dioxane so-
lution, the cyclization took place smoothly and derivatives of the
3H-pyrrolo[2,3-c]isoquinoline ring system (11) have been obtained
in acceptable to excellent (44e85%) yield (Scheme 4). Evidence for
the ring closure of the pyrrole moiety was clearly shown by the
disappearance of the acetylene function in IR as well as the pres-
ence of the new aromatic CH moiety in the five-membered het-
erocycles was detected by NMR spectroscopy.
and 13C chemical shifts are expressed in parts per million (
d) ref-
erenced to TMS or residual solvent signals. The elemental analysis
has been carried out with an Elementar Vario EL III apparatus
(at the Analytical Laboratory for Organic Chemistry, Chemical
Research Center, Hungarian Academy of Sciences, H-1025 Buda-
As Hiroya et al.34 suggested, TBAF can strongly polarize the triple
bond by forming ion-pairs so that the nucleophilic nitrogen atom
can successfully attack one of the carbon atoms to carry out a 5-
endo-dig cyclization process which, in this case, results in formation
of a fused pyrrole ring.
ꢀ
pest, Pusztaszeri ut 59). The exact mass measurements were
performed using a Q-TOF Premier mass spectrometer (Waters
Corporation, 34 Maple St, Milford, MA, USA) in positive electro-
spray mode. Reactions were monitored with Merck silica gel 60
F254 TLC plates (0.25 mm thickness). All the chemicals and solvents
were used as supplied.
3. Conclusions
These studies reveal that a new and convenient approach to
pyrrolo[3,4-c]isoquinolines has been elaborated by application of
Sonogashira coupling of 4-iodo-3-anilinoisoquinolines followed by
TBAF assisted ring closure. Continuation of exploration of further
ring closure reactions to fused isoquinolines is in progress.
4.2. N-Phenylisoquinoline-3-amine (5a)
A round-bottomed flask was charged with Pd2(dba)3 (0.233 g,
0.26 mmol, 5 mol %), JohnPhos (0.152 g, 0.51 mmol, 10 mol %),

B. Dixit et al. / Tetrahedron 68 (2012) 3560e3565
3563
bromobenzene (0.800 g, 5.10 mmol), isoquinoline-3-amine
(0.734 g, 5.10 mmol), and sodium tert-butoxide (0.735 g,
7.65 mmol) followed by dry toluene (20 mL). The flask was flushed
with argon for 5 min. The resulting mixture was heated under reflux
with magnetic stirring for 5 h. After cooling down to room tem-
perature the reaction mixture was evaporated and the residue was
purified by flash column chromatography on silica gel using hexane/
EtOAc (4:1) as eluent yielding the product (0.940 g, 85%). Yellow
crystal; mp 101e102 ꢁC (lit. mp 102e103 ꢁC30); nmax (KBr, cmꢀ1):
3239, 3054, 1631, 1453, 741; dH (300 MHz, CDCl3): 6.91 (1H, s, NH),
7.08 (1H, dd, J¼6.6 Hz, 6.4 Hz, H-40), 7.20 (1H, s, H-4), 7.27e7.41 (5H,
m, H-7, H-20, H-30, H-50, H-60), 7.49e7.58 (2H, m, H-5, H-6), 7.81 (1H,
d, J¼8.2 Hz, H-8), 8.96 (1H, s, H-1); dC (75 MHz, CDCl3): 99.3 (C-4),
120.2 (C-20, C-60), 122.9 (C-40), 123.9 (C-7), 124.8 (C-8a), 125.5 (C-5),
128.0 (C-8), 129.7(C-30, C-50), 130.8 (C-6), 138.8 (C-4a), 141.3 (C-10),
152.3 (C-3, C-1). Anal. Calcd for C15H12N2 (220.26): C, 81.79; H, 5.49;
N, 12.72%. Found: C, 81.41; H, 5.56; N, 13.03%.
162.8 (C-3). Anal. Calcd for C15H11IN2 (346.16): C, 52.04; H, 3.20; N,
8.09%. Found: C, 51.95; H, 3.34; N, 7.89%.
4.5. 4-Iodo-N-p-tolylisoquinolin-3-amine (8)
A solution of N-p-tolylisoquinolin-3-amine (0.400 g, 1.71 mmol)
in THF (20 mL) at ꢀ20 ꢁC was treated with N-iodosuccinimide
(0.423 g, 1.88 mmol) and p-TsOH$H2O (0.120 g, 0.64 mmol). The
mixture was stirred at ꢀ20 ꢁC for 1 h and, then, maintained at 25 ꢁC
for 24 h. The mixture was diluted with EtOAc (30 mL) and treated
with aqueous saturated Na2SO3 (30 mL). The aqueous layer was
extracted with EtOAc (3ꢂ30 mL), dried (Na2SO4), and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel using hexane/CH2Cl2 (2:1) as the eluent. Evaporation of the
second fraction afforded 4-iodo-N-p-tolylisoquinolin-3-amine (8)
as the main product, yellow crystals (0.332 g, 54%; mp 97e100 ꢁC).
nmax (KBr, cmꢀ1): 3414, 3395, 2914,1617,1235; dH (300 MHz, CDCl3):
2.35 (3H, s, CH3), 7.05 (1H, s, NH), 7.16 (2H, m, H-30, H-50), 7.33 (1H,
dd, J¼7.7, 7.4 Hz, H-7), 7.40 (2H, m, H-20, H-60), 7.62 (1H, dd, J¼7.5,
7.5 Hz, H-6), 7.75 (1H, d, J¼8.1 Hz, H-5), 7.82 (1H, d, J¼8.7 Hz, H-8),
8.81 (1H, s, H-1); dC (75 MHz, CDCl3): 21.1 (CH3), 78.9 (C-4),121.3 (C-
20, C-60),124.1 (C-7),125.5 (C-8a),128.5 (C-8),129.5 (C-5),129.7 (C-30,
C-50), 132.3 (C-6), 132.8 (C-10), 138.3 (C-40), 140.1 (C-4a), 151.7 (C-1),
152.0 (C-3). Anal. Calcd for C16H13IN2 (360.19): C, 53.35; H, 3.64; N,
7.78%. Found: C, 53.61; H, 3.48; N, 7.72%.
4.3. N-p-Tolylisoquinolin-3-amine (5b)
Pd2(dba)3 (0.254 g, 0.277 mmol, 5 mol %), JohnPhos (0.166 g,
0.56 mmol, 10 mol %), 4-bromotoluene (0.951 g, 5.56 mmol), iso-
quinoline-3-amine (0.800 g, 5.56 mmol), sodium tert-butoxide
(0.800 g, 8.33 mmol), and dry toluene (20 mL). Reaction time (5 h)
using the same procedure described for the synthesis of 5a. Eluent:
hexane/EtOAc (4:1); yield: 1.106 g, 85%. Yellow crystals; mp
134e136 ꢁC; nmax (KBr, cmꢀ1): 3248, 3054, 1629, 1363, 820; dH
(300 MHz, DMSO-d6): 2.23 (3H, s, CH3), 7.06e7.09 (3H, m, H-4, H-30,
H-50), 7.24 (1H, dd, J¼7.5, 7.5 Hz, H-7), 7.38 (2H, m, H-20, H-60), 7.50
(1H, dd, J¼7.8, 7.5 Hz, H-6), 7.63 (1H, d, J¼7.8 Hz, H-5), 7.86 (1H, d,
J¼7.5 Hz, H-8), 8.83 (1H, s, NH), 8.98 (1H, s, H-1); dC (75 MHz,
DMSO-d6): 20.3 (CH3), 99.1 (C-4), 118.6 (C-20, C-60), 122.9 (C-7),
123.4 (C-8a), 124.8 (C-5), 127.5 (C-8), 129.2 (C-30, C-50), 129.4 (C-40),
130.3 (C-6), 138.0 (C-4a), 139.2 (C-10), 151.2 (C-1), 152.5 (C-3). Anal.
Calcd for C16H14N2 (234.29): C, 82.02; H, 6.02; N, 11.96%. Found: C,
82.31; H, 5.95; N, 11.74%.
4.6. 4-Iodo-N-(3-iodo-4-methylphenyl)isoquinolin-3-amine
(9)
This compound was obtained by work up of the first (more
apolar) chromatographic fraction. Yield: 0.233 g, 28%; yellow
crystals; mp 161e163 ꢁC; nmax (KBr, cmꢀ1): 3327, 2917, 1589, 1480,
747; dH (300 MHz, CDCl3): 2.31 (CH3), 7.17 (1H, d, J¼8.4 Hz, H-60),
7.34e7.39 (2H, m, NH, H-7), 7.62e7.69 (2H, m, H-6, H-20), 7.77 (1H,
d, J¼8.1 Hz, H-8), 7.89 (2H, m, H-5, H-50), 8.81 (1H, s, H-1); dC
(75 MHz, CDCl3): 20.5 (CH3) 80.1 (C-4), 92.1 (C-30), 121.6 (C-50),
124.5 (C-7), 125.8 (C-8a), 128.5 (C-8), 129.7 (C-5), 129.8 (C-60), 132.4
(C-6), 134.5 (C-10), 139.4 (C-40), 139.5 (C-20), 140.1 (C-4a), 151.5 (C-1),
151.6 (C-3). Anal. Calcd for C16H12I2N2 (486.08): C, 39.53; H, 2.49; N:
5.76%. Found: C, 39.31; H, 2.60; N, 5.59%.
4.4. Iodination of N-phenylisoquinolin-3-amine (5a)
A
solution of N-phenylisoquinoline-3-amine (5a, 0.200 g,
0.91 mmol) in THF (10 mL) at ꢀ20 ꢁC was treated with N-iodo-
succinimide (0.225 g, 1.0 mmol) and p-TsOH$H2O (0.064 g,
0.34 mmol). The mixture was stirred at ꢀ20 ꢁC for 1 h and, then
maintained at 25 ꢁC for 24 h. The mixture was diluted with EtOAc
(30 mL) and treated with aqueous saturated Na2SO3 (30 mL). The
aqueous layer was extracted with EtOAc (3ꢂ30 mL), dried (Na2SO4),
and concentrated in vacuo to give a mixture of 6 and 7. The residue
was purified by column chromatography on silica gel using hexane/
CH2Cl2 (2:1) as the eluent. Evaporation of the first fraction yielded
4-iodo-N-(4-iodophenyl)isoquinolin-3-amine (7) as yellow crystals
(0.129 g, 30%; mp 188e189 ꢁC); nmax (KBr, cmꢀ1): 3392, 2361, 1588,
1235, 749; dH (300 MHz, CDCl3): 7.10 (1H, s, NH), 7.33e7.40 (3H, m,
H-7, H-200, H-600), 7.61e7.64 (3H, m, H-6, H-300, H-500), 7.77e7.86 (2H,
m, H-8, H-5), 8.83 (1H, s, H-1); dC (75 MHz, CDCl3): 79.8 (C-4), 85.1
(C-400), 122.0 (C-20, C-60), 124.6 (C-7), 125.7 (C-8a), 128.3 (C-8), 129.6
(C-5), 132.3 (C-6), 137.8 (C-300, C-500), 139.8 (C-4a), 140.7 (C-10), 150.9
(C-3), 151.4 (C-1). Anal. Calcd for C15H10I2N2 (472.06): C, 38.16; H,
2.14; N, 5.93%. Found: C, 38.01; H, 2.29; N, 5.81%. Work up of the
second fraction (of smaller Rf value) afforded 4-iodo-N-(phenyl)
isoquinolin-3-amine (6) as yellow crystals (0.107 g, 34%, mp
113e115 ꢁC); nmax(KBr, cmꢀ1): 3376, 1572, 1414, 1231, 752; dH
(300 MHz, CDCl3): 7.04e7.13 (2H, m, NH, H-40), 7.33e7.40 (3H, H-7,
H-30, H-50), 7.53e7.66 (3H, m, H-6, H-20, H-60), 7.76e7.85 (2H, m, H-
8, H-5), 8.83 (1H, s, H-1); dC (75 MHz, CDCl3): 79.4 (C-4), 120.4 (C-20,
C-60), 122.8 (C-40), 124.3 (C-7), 125.6 (C-8a), 128.4 (C-8), 129.1 (C-30,
C-50), 129.5 (C-5), 132.2 (C-6), 140.0 (C-4a), 140.9 (C-10), 151.5 (C-1),
4.7. 4-(Phenylethynyl)-N-p-tolylisoquinolin-3-amine (10a)
A round-bottomed flask was charged with 4-iodo-N-p-tolyliso-
quinolin-3-amine (0.300 g, 0.83 mmol), PdCl2(PPh3)2 [dichlor-
obis(triphenylphosphine)palladium(II)] (0.023 g, 0.033 mmol,
4 mol %), CuI (0.013 g, 0.07 mmol, 8 mol %), and Et3N (0.167 g,
1.66 mmol, 0.230 mL) followed by dry acetonitrile (2 mL). The
mixture was flushed with argon for 5 min. Then phenylacetylene
(0.127 g, 1.25 mmol, 0.137 mL) was added and the mixture was
heated under reflux for 12 h with magnetic stirring. After cooling
down to room temperature the solvent was removed under re-
duced pressure. The residue was dissolved in EtOAc (30 mL) and the
mixture was washed with H2O (30 mL). The aqueous phase was
extracted with EtOAc (2ꢂ30 mL) and the collected organic phase
dried over anhydrous Na2SO4. The residue was purified by column
chromatography on silica gel using hexane/EtOAc (25:1) as the el-
uent yielding yellow crystals (0.181 g, 65%, mp 144e146 ꢁC). nmax
(KBr, cmꢀ1): 3402, 2190, 1607, 1240, 753; dH (300 MHz, CDCl3): 2.27
(3H, s, CH3), 7.09 (2H, m, H-300, H-500), 7.25e7.45 (7H, m, H-7, NH, H-
50, H-60, H-70, H-200, H-600), 7.52e7.60 (3H, m, H-6, H-40, H-80), 7.75
(1H, d, J¼7.8 Hz, H-8), 8.01 (1H, d, J¼8.4 Hz, H-5), 8.84 (1H, s, H-1);
dC (75 MHz, CDCl3): 20.8 (CH3), 83.1 (C-10), 94.2 (C-4), 101.5 (C-20),
120.5 (C-200, C-600),123.0 (C-8a),123.4 (C-30),123.7 (C-5),123.8 (C-7),
128.3 (C-8), 128.6 (C-50, C-70), 128.6 (C-60), 129.5 (C-300, C-500), 131.2
(C-6), 131.5 (C-40, C-80), 132.2 (C-400), 137.7 (C-100), 137.9 (C-4a), 151.2

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B. Dixit et al. / Tetrahedron 68 (2012) 3560e3565
(C-1), 153.5 (C-3); HRMS (ES) for C24H19N2 [MþH]þ: calcd 335.1548,
0.04 mmol, 5 mol %), Et3N (2.178 g, 21.56 mmol, 3 mL), but-3-yn-1-
ol (0.088 g, 1.25 mmol, 0.095 mL), and dry acetonitrile (2 mL). Re-
action time 2 h. Eluent: hexane/EtOAc (2:1); yield: 0.215 g, 85%;
brownish yellow crystals; mp 100e103 ꢁC; nmax (KBr, cmꢀ1): 3312,
2923, 2210, 1572, 1056, 754; dH (400 MHz, CDCl3): 2.0 (1H, br s, OH),
2.31 (3H, s, CH3), 2.90 (2H, t, J¼6.7 Hz, H30x, H30y), 3.91 (2H, t,
J¼6.7 Hz, H40x, H40y), 7.13 (2H, m, H300, H500), 7.26 (1H, dd, J¼8.2,
7.8 Hz, H7), 7.36 (1H, br s, NH), 7.47 (2H, m, H200, H600), 7.57 (1H, dd,
J¼8.5, 7.8 Hz, H6), 7.77 (1H, d, J¼8.2 Hz, H8), 7.95 (1H, d, J¼8.5 Hz,
H5), 8.86 (1H, s, H1); dC (100 MHz, CDCl3): 20.8 (CH3), 24.3 (C30),
61.3 (C40), 76.2 (C10), 94.8 (C4), 99.1 (C20), 120.3 (C200, C600), 123.2
(C8a), 123.5 (C5), 123.6 (C7), 128.2 (C8), 129.4 (C300, C500), 131.0 (C6),
131.9 (C400), 137.9 (C100), 138.0 (C4a), 150.5 (C1), 153.7 (C3); HRMS
(ES) for C20H19N2O [MþH]þ: calcd 303.1497, found 303.1504.
found 335.1552.
4.8. 4-((2-Nitrophenyl)ethynyl)-N-p-tolylisoquinolin-3-amine
(10b)
4-Iodo-N-p-tolylisoquinolin-3-amine (0.240 g, 0.667 mmol),
PdCl2(PPh3)2 (0.024 g, 0.03 mmol, 5 mol %), CuI (0.006 g,
0.03 mmol, 5 mol %), Et3N (2.178 g, 21.56 mmol, 3 mL), 1-ethynyl-2-
nitrobenzene (0.124 g, 0.84 mmol), and dry acetonitrile (2 mL).
Reaction time 3 h. Eluent: hexane/EtOAc (4:1); yield: 0.210 g, 83%;
deep purple solid; mp 170e173 ꢁC; nmax (KBr, cmꢀ1): 3384, 2182,
1569, 1240, 741; dH (300 MHz, CDCl3): 2.35 (3H, s, CH3), 7.20 (2H, m,
H-300, H-500), 7.32 (1H, dd, J¼7.8, 7.8 Hz, H-7), 7.48 (1H, dd, J¼8.0,
8.0 Hz, H-60), 7.63e7.73 (4H, m, H-6, H-70, H-200, H-600), 7.81e7.87
(2H, m, H-8, H-80), 8.05e8.11 (2H, m, H-5, NH), 8.24 (1H, d, J¼8.4 Hz,
H-50), 8.96 (1H, s, H-1); dC (75 MHz, CDCl3): 21.1 (CH3), 92.9 (C-10),
93.2 (C-4), 98.2 (C-20), 119.5 (C-30), 120.9 (C-200, C-600), 123.4 (C-8a),
123.7 (C-5), 123.9 (C-50), 125.6 (C-7), 128.5 (C-60), 128.8 (C-8), 129.7
(C-300, C-500), 131.9 (C-6), 132.5 (C-400), 133.6 (C-70), 134.6 (C-80), 137.9
(C-100), 138.5 (C-4a), 148.0 (C-40), 153.0 (C-1), 155.3 (C-3); HRMS (ES)
for C24H18N3O2 [MþH]þ: calcd 380.1399, found 380.1396.
4.12. 2-Phenyl-3-p-tolyl-3H-pyrrolo[2,3-c]isoquinoline (11a)
A mixture of 4-(phenylethynyl)-N-p-tolylisoquinolin-3-amine
(10a, 0.100 g, 0.30 mmol) and tetrabutylammonium fluoride hy-
drate (TBAF) (0.167 g, 0.60 mmol) in dioxane (10 mL) was degassed
with argon and refluxed for 24 h at 110 ꢁC. The solvent was then
removed under reduced pressure. The residue was dissolved in
EtOAc (25 mL) and the mixture was washed with H2O (25 mL). The
aqueous phase was extracted with EtOAc (2ꢂ25 mL) and the col-
lected organic phase dried over anhydrous Na2SO4. The residue was
purified by column chromatography on silica gel using hexane/
EtOAc (3:1) as the eluent yielding the product (0.067 g, 67%), white
crystals; mp 198e200 ꢁC; nmax (KBr, cmꢀ1): 3037, 1626, 1516, 1395,
753; dH (300 MHz, CDCl3): 2.32 (3H, s, CH3), 7.14e7.29 (10H, m, H-1,
H-200, H-300, H-500, H-600, H-20, H-30, H-40, H-50, H-60), 7.42 (1H, dd,
J¼7.2, 7.8 Hz, H-7), 7.66 (1H, dd, J¼7.5, 7.5 Hz, H-8), 7.95 (1H, d,
J¼8.1 Hz, H-6), 8.17 (1H, d, J¼8.4 Hz, H-9), 8.82 (1H, s, H-5); dC
(75 MHz, CDCl3): 21.4 (CH3), 100.6 (C-1), 114.4 (C-1a), 122.7 (C-9),
124.4 (C-7), 125.6 (C-5a), 127.6 (C-40), 128.5 (C-200, C-600), 128.5 (C-20,
C-60), 128.9 (C-6), 129.1 (C-30, C-50), 129.9 (C-300, C-500), 130.1 (C-8),
131.2 (C-9a), 132.8 (C-100), 134.8 (C-2), 137.6 (C-10), 138.8 (C-400),
145.6 (C-3a), 147.2 (C-5); HRMS (ES) for C24H19N2 [MþH]þ: calcd
335.1548, found 335.1549.
4.9. 4-((4-Nitrophenyl)ethynyl)-N-p-tolylisoquinolin-3-amine
(10c)
4-Iodo-N-p-tolylisoquinolin-3-amine (0.300 g, 0.833 mmol),
PdCl2(PPh3)2 (0.029 g, 0.04 mmol, 5 mol %), CuI (0.008 g,
0.04 mmol, 5 mol %), Et3N (2.178 g, 21.56 mmol, 3 mL), 1-ethynyl-4-
nitrobenzene (0.153 g, 1.041 mmol), and dry acetonitrile (2 mL).
Reaction time 2 h. Eluent: hexane/EtOAc (6:1); yield: 0.291 g, 92%;
deep maroon solid; mp 181e184 ꢁC; nmax (KBr, cmꢀ1): 3402, 2918,
2182, 1568, 1341; dH (300 MHz, CDCl3): 2.35 (3H, s, CH3), 7.17e7.25
(3H, m, NH, H-300, H-500), 7.35 (1H, dd, J¼7.2, 7.5 Hz, H-7), 7.49 (2H,
m, H-200, H-600), 7.64e7.73 (3H, m, H-6, H-40, H-80), 7.84 (1H, d,
J¼8.4 Hz, H-8), 8.03 (1H, d, J¼8.7 Hz, H-5), 8.26 (2H, m, H-50, H-70),
8.95 (1H, s, H-1); dC (75 MHz, CDCl3): 21.1 (CH3), 89.3 (C-10), 93.4 (C-
4), 100.0 (C-20), 121.1 (C-200, C-600), 123.6 (C-8a), 123.7 (C-7), 124.1 (C-
50, C-70), 124.3 (C-5), 128.8 (C-8), 129.8 (C-300, C-500), 130.1 (C-30),
131.9 (C-6), 132.1 (C-40, C-80), 133.1 (C-400), 137.5 (C-100), 138.2 (C-4a),
147.2 (C-60), 152.8 (C-1), 154.2 (C-3); HRMS (ES) for C24H18N3O2
[MþH]þ: calcd 380.1399, found 380.1403.
4.13. 2-(2-Nitrophenyl)-3-p-tolyl-3H-pyrrolo[2,3-c]
isoquinoline (11b)
This compound was prepareddsimilar to 11adfrom 4-((2-
nitrophenyl)ethynyl)-N-p-tolylisoquinolin-3-amine (10b, 0.130 g,
0.34 mmol) and TBAF (0.334 g, 1.28 mmol) in dioxane (10 mL).
Reaction time 6 h. Eluent: hexane/EtOAc (6:1); yield: (0.057 g,
44%); pale yellow crystals; mp 206e209 ꢁC; nmax (KBr, cmꢀ1): 3381,
2923, 1611, 1527, 755; dH (300 MHz, CDCl3): 2.35 (3H, s, CH3),
7.15e7.23 (5H, m, H-1, H-200, H-300, H-500, H-600), 7.43e7.61 (4H, m, H-
7, H-40, H-50, H-60), 7.75 (1H, dd, J¼7.7, 7.5 Hz, H-8), 7.84 (1H, d,
J¼8.1 Hz, H-6), 8.04 (1H, d, J¼8.1 Hz, H-30), 8.22 (1H, d, J¼8.1 Hz, H-
9), 8.94 (1H, s, H-5); dC (75 MHz, CDCl3): 21.4 (CH3), 101.5 (C-1),
114.2 (1a), 122.8 (C-9), 124.5 (C-30), 124.7 (C-7), 125.7 (C-5a), 128.0
(C-10),128.2 (C-200, C-600),129.0 (C-6),129.2 (C-40), 130.0 (C-300, C-500),
130.3 (C-8), 131.4 (C-9a), 132.7 (C-60), 133.5 (C-100), 133.6 (C-2), 133.7
(C-50), 137.8 (C-400), 145.1 (C-3a), 148.1 (C-5), 149.5 (C-20); HRMS (ES)
for C24H18N3O2 [MþH]þ: calcd 380.1399, found 380.1400.
4.10. 3-(3-(p-Tolylamino)isoquinolin-4-yl)prop-2-yn-1-ol
(10d)
4-Iodo-N-p-tolylisoquinolin-3-amine (0.300 g, 0.83 mmol),
PdCl2(PPh3)2 (0.023 g, 0.03 mmol, 4 mol %), CuI (0.013 g,
0.07 mmol, 8 mol %), Et3N (2.178 g, 21.56 mmol, 3 mL), propargyl
alcohol (0.083 g, 1.48 mmol, 0.085 mL), and dry acetonitrile (2 mL).
Reaction time 2 h. Eluent: hexane/EtOAc (3:1); yield: (0.176 g, 73%);
yellow solid; mp 120e122 ꢁC; nmax (KBr, cmꢀ1): 3361, 2918, 2210,
1573, 1427, 1013; dH (300 MHz, CDCl3): 2.20 (1H, s, OH), 2.34 (3H, s,
CH3), 4.68 (2H, s, H30x, H30y), 7.14e7.31 (4H, m, H-300, H-500, NH, H-
7), 7.46 (2H, m, H-200, H-600), 7.57 (1H, t, J¼8.1, 7.7 Hz, H-6), 7.77 (1H,
d, J¼8.2 Hz, H-8), 7.95 (1H, d, J¼8.5 Hz, H-5), 8.89 (1H, s, H-1); dC
(75 MHz, CDCl3): 21.1 (CH3), 52.1 (C-30), 79.8 (C-10), 93.9 (C-4), 99.7
(C-20), 121.0 (C-200, C-600), 123.5 (C-8a), 123.8 (C-5), 123.9 (C-7), 128.5
(C-8), 129.7 (C-300, C-500), 131.5 (C-6), 132.6 (C-400), 137.8 (C-100), 138.4
(C-4a), 151.6 (C-1), 154.1 (C-3); HRMS (ES) for C19H17N2O [MþH]þ:
calcd 289.1341, found 289.1342.
4.14. 2-(4-Nitrophenyl)-3-p-tolyl-3H-pyrrolo[2,3-c]
isoquinoline (11c)
This compound was prepared, similar to 11a from 4-((4-
nitrophenyl)ethynyl)-N-p-tolylisoquinolin-3-amine (10c, 0.160 g,
0.42 mmol) and TBAF (0.228 g, 0.87 mmol) in dioxane (10 mL). Re-
action time 3 h. Eluent: hexane/EtOAc (4:1); yield: (0.125 g, 78%);
yellow crystals; mp 242e245 ꢁC; nmax (KBr, cmꢀ1): 3419, 2922, 1519,
4.11. 4-(3-(p-Tolylamino)isoquinolin-4-yl)but-3-yn-1-ol (10e)
4-Iodo-N-p-tolylisoquinolin-3-amine (0.300 g, 0.83 mmol),
PdCl2(PPh3)2 (0.029 g, 0.04 mmol, 5 mol %), CuI (0.008 g,

B. Dixit et al. / Tetrahedron 68 (2012) 3560e3565
3565
1338, 755; dH (300 MHz, CDCl3): 2.43 (3H, s, CH3), 7.25e7.32 (4H, m, H-
References and notes
200, H-300, H-500, H-600), 7.38 (1H, s, H-1), 7.47e7.57 (3H, m, H-20, H-60, H-
7), 7.79 (1H, dd, J¼7.7, 7.4 Hz, H-8), 8.05 (1H, d, J¼8.1 Hz, H-6), 8.13 (2H,
m, H-30, H-50), 8.26 (1H, d, J¼8.1 Hz, H-9), 8.94 (1H, s, H-5); dC (75 MHz,
CDCl3): 21.4 (CH3), 103.0 (C-1), 114.3 (C-1a), 122.6 (C-9), 123.9 (C-30, C-
50), 125.0 (C-7), 125.8 (C-5a), 128.4 (C-200, C-600),129.0 (C-20, C-60),129.1
(C-6),130.4 (C-300, C-500),130.6 (C-8),131.2 (C-9a),134.3 (C-100),135.9 (C-
2), 138.4 (C-400), 139.1 (C-10), 146.4 (C-3a), 146.6 (C-40), 148.9 (C-5);
HRMS (ES) for C24H18N3O2 [MþH]þ: calcd 380.1399, found 380.1398.
ꢀ
ꢀ
1. Riedl, Zs.; Filak, L.; Egyed, O.; Hajos, Gy. Arkivoc 2009, vi, 158e166.
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7. Gonzalez-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69,
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This compound was prepared, similar to 11a, from 3-(3-(p-tol-
ylamino)isoquinolin-4-yl)prop-2-yn-1-ol (10d, 0.139 g, 0.48 mmol)
and TBAF (0.156 g, 0.60 mmol) in dioxane (10 mL) . Reaction time
5 h. Eluent: hexane/EtOAc (3:1); yield: (0.109 g, 78%); pale brown
crystals; mp 133e136 ꢁC; nmax (KBr, cmꢀ1): 3383, 2919, 1625, 1517,
759; dH (300 MHz, CDCl3): 1.78 (1H, s, OH), 2.45 (3H, s, CH3), 4.73
(2H, s, H10x, H10y), 7.07 (1H, s, H-1), 7.34e7.42 (4H, m, H-200, H-300,
H-500, H-600), 7.49 (1H, dd, J¼8.1, 8.1 Hz, H-7), 7.73 (1H, dd, J¼8.1,
8.1 Hz, H-8), 8.00 (1H, d, J¼8.4 Hz, H-6), 8.18 (1H, d, J¼8.1 Hz, H-9),
8.86 (1H, s, H-5); dC (75 MHz, CDCl3): 21.5 (CH3), 57.6 (C-10), 100.0
(C-1), 113.5 (C-1a),122.6 (C-9), 124.4 (C-7), 125.5 (C-5a),128.2 (C-200,
C-600), 129.0 (C-6), 130.2 (C-8), 130.3 (C-300, C-500), 131.4 (C-9a), 133.9
(C-100), 137.8 (C-2), 138.6 (C-400), 145.2 (C-3a), 147.6 (C-5); HRMS (ES)
for C19H17N2O [MþH]þ: calcd 289.1341, found 289.1342.
ꢀ
12. Commercially available. For the synthesis, see Balog, J.; Riedl, Zs.; Hajos, Gy.;
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2007, 63, 10320e10329; (b) Riedl, Zs.; Monsieurs, K.; Krajsovszky, G.; Dunkel,
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Lemiere, G. L. F.; Hajos, Gy Tetrahedron 2006, 62, 121e129.
14. Chen, Y.; Markina, N. A.; Larock, R. C. Tetrahedron 2009, 65, 8908e8918.
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4.16. 2-(3-p-Tolyl-3H-pyrrolo[2,3-c]isoquinolin-2-yl)ethanol
(11e)
19. Weingarten, M. D.; Padwa, A. Tetrahedron Lett. 1995, 36, 4717e4720.
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This compound was prepared, similar to 11a, from 4-(3-(p-tol-
ylamino)isoquinolin-4-yl)but-3-yn-1-ol (10e, 0.120 g, 0.40 mmol)
and TBAF (0.152 g, 0.58 mmol) in dioxane (10 mL). Reaction time
3 h. Eluent: hexane/EtOAc (2:1); yield: (0.102 g, 85%); brownish
white crystals; mp 122e125 ꢁC; nmax (KBr, cmꢀ1): 3318, 2961, 1531,
1403, 766; dH (400 MHz, CDCl3): 2.43 (3H, s, CH3), 3.00 (2H, t,
J¼6.6 Hz, H10x, H10y), 3.80 (2H, t, J¼6.6 Hz, H20x, H20y), 6.92 (1H, s,
H1), 7.29 (2H, m, H200, H600), 7.34 (2H, m, H300, H500), 7.45 (1H, dd,
J¼8.2, 7.5 Hz, H7), 7.70 (1H, dd, J¼8.5, 7.5Hz, H8), 7.97 (1H, d,
J¼8.2 Hz, H6), 8.17 (1H, d, J¼8.5 Hz, H9), 8.80 (1H, s, H5); dC
(100 MHz, CDCl3): 21.2 (CH3), 30.7 (C10), 61.3 (C20), 98.4 (C1), 113.6
(C1a),122.4 (C9),123.9 (C7),125.1 (C5a),128.3 (C200, C600),128.6 (C6),
129.7 (C8), 130.1 (C300, C500), 130.6 (C9a), 133.8 (C100), 135.6 (C2),
138.3 (C400), 144.8 (C3a), 146.2 (C5); HRMS (ES) for C20H19N2O
[MþH]þ: calcd 303.1497, found 33.1500.
€
1348e1350.
30. Van Baelen, G.; Meyers, C.; Lemiere, G. L. F.; Hostyn, S.; Dommisse, R.; Maes, B.
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Acknowledgements
The Hungarian Scientific Research Fund OTKA-NK 77784 is
gratefully acknowledged. B.C.D. thanks for the INSA-HAS bilateral
exchange programme-2011.
34. Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.; Sakamoto, T. Tetrahedron 2001,
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