One-pot two-step tandem reactions for selective synthesis of pyrrolo[2,1-a]isoquinolines and dihydro-, tetrahydro-derivatives

Article abstract of DOI:10.1016/j.tet.2011.01.046

A sequential one-pot two-step tandem reaction for selective and efficient synthesis of pyrrolo[2,1-a]isoquinoline and its dihydro- and tetrahydro-derivatives has been developed. The tandem reactions of isoquinoline, α-halogenated methylene compounds, aromatic aldehydes, and cyanoacetamide firstly give tetrahydropyrrolo[2,1-a]isoquinolines as main products. The corresponding pyrrolo[2,1-a]isoquinolines and dihydropyrrolo[2,1-a]isoquinolines can be obtained directly by controlling oxidation with DDQ. The mechanism of this tandem reaction involved the 1,3-dipolar cycloaddition of isoquinolinium ylide as the key step. A unique elimination of the amido group preferring to the cyano group has been observed.

Full text of DOI:10.1016/j.tet.2011.01.046

Tetrahedron 67 (2011) 2313e2322
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Tetrahedron
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One-pot two-step tandem reactions for selective synthesis of pyrrolo[2,1-a]-
isoquinolines and dihydro-, tetrahydro-derivatives
*
Ying Han, Hong Hou, Qin Fu, Chao-Guo Yan
College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequential one-pot two-step tandem reaction for selective and efficient synthesis of pyrrolo[2,1-a]-
Received 15 December 2010
Received in revised form 13 January 2011
Accepted 18 January 2011
isoquinoline and its dihydro- and tetrahydro-derivatives has been developed. The tandem reactions of
isoquinoline, a-halogenated methylene compounds, aromatic aldehydes, and cyanoacetamide firstly give
tetrahydropyrrolo[2,1-a]isoquinolines as main products. The corresponding pyrrolo[2,1-a]isoquinolines
and dihydropyrrolo[2,1-a]isoquinolines can be obtained directly by controlling oxidation with DDQ. The
mechanism of this tandem reaction involved the 1,3-dipolar cycloaddition of isoquinolinium ylide as the
key step. A unique elimination of the amido group preferring to the cyano group has been observed.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 22 January 2011
Keywords:
Heterocycles
Azaaromatic N-ylide
Isoquinoline
Pyrrolo[2,1-a]isoquinoline
One-pot reaction
Tandem reaction
1. Introduction
new four-component reactions of isoquinoline, active a-halogeno-
methylene compounds, aromatic aldehydes, and cyanoacetamide.
As one kind of reactive azomethine ylides, heteroaromatic N-
ylide has been used extensively in cycloadditions for the synthesis of
the fused heterocycles with a nitrogen at the point of fusion.1e4
Heteroaromatic N-ylides, such as pyridinium, thiazolium, quinoli-
nium, isoquinolinium methylides are readily available from the al-
kylation of azaaromatic heterocycles and sequential deprotonation
reaction.5e7 The 1,3-dipolar cycloaddition of heteroaromatic N-
methylides with electron-deficient alkynes and alkenes provided
a convenient route to novel nitrogen bridged heterocycles, such as
indolizines and benzo-fused derivatives.8e11 Recently we realized
that the versatile reactivityand easy in situ formation of azaaromatic
N-ylide can be used to design new multicomponent reactions and
found some interesting results. Previous work showed that poly-
substituted pyridines,11 cyclopropanes,12 dihydrofuranes,13 zwit-
terionic salts,14 and pyrido[1,2-a]benzimidazole derivatives15 could
be produced efficiently from multicomponent cyclization reactions
involving heteroaromatic N-ylide with electron-deficient alkenes
bearing versatile functional groups. In continuation of our efforts to
develop new multicomponent reactions we investigate the re-
activity of different kinds of active methylene compounds in the
reactions. Here we wish to report the efficient synthesis of pyrrolo
[2,1-a]isoquinoline and its dihydro- and tetrahydro-derivatives via
2. Results and discussions
In an exploratory study the ethanol solution of p-methoxybenzal-
dehyde, cyanoacetamide, and N-ethoxycarbonylmethylisoquino-
linium bromide, which was prepared in situ from the reaction of
isoquinoline with ethyl a-bromoacetate, was stirred at room tem-
perature for about 24 h in the presence of triethylamine as base
catalyst. After workup it was interesting to find that pyrrolo[2,1-a]
isoquinoline (1a), dihydropyrrolo[2,1-a]isoquinoline (2a), and tetra-
hydropyrrolo[2,1-a]isoquinoline (3a) were separated in about 10%,
25%, and 42% yields, respectively (Scheme 1). This result clearly
showed that an 1,3-dipolar addition of isoquinolinium ylide to in situ
formed active arylidene cyanoacetamide took place and compounds
1a and 2a came from the dehydrogenation and eliminationprocess of
initially formed 1,3-dipolar cycloadduct 3a in air. Pyrrolo[2,1-a]iso-
quinoline and its dihydro-, tetrahydro-analogs are one important
kinds of heterocycles and perform very interesting biological activi-
ties.16,17 In principle there are two most general methods for their
synthesis. One is1,3-cycloaddition ofisoquinoliniumylidewith active
alkynes and alkenes.6b,18,19 Another is the Huisgen 1,4-dipolar addi-
tion, in which the intermediate formed in situ by the addition of
isoquinoline to electron-deficient alkynes and then reacted with
dipolarophilic reagents.20,21 Here the preliminary result of one-pot
tandem reaction gave a new strategy to develop efficient synthetic
* Corresponding author. E-mail address: cgyan@yzu.edu.cn (C.-G. Yan).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.046

2314
Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
Br
CN
Et3N
N
+
+
+
ArCHO
CO2Et
+
N
EtOH, r. t.
CO2Et
CONH2
NC
Ar
1a (10%)
N
N
CO2Et
Ar
CO2Et
Ar
+
H2NOC
NC
CN
3a (42%)
2a (25%)
Scheme 1. 1,3-dipolar cycloaddition via the four-component reaction.
procedure for the selective preparation of pyrrolo[2,1-a]isoquinoline
and its tetrahydro- and dihydro-derivatives.
It has long been known that the 1,3-dipolar cycloadduct of het-
eroaromatic N-ylide with electron-deficient olefins is not always
thermally stable, which is mainly due tothe loss of aromaticity of the
heteroaromatic ring.22,23 One effective method to solve this problem
is the dehydrogenation of cycloadducts with sequential oxidation to
recover aromatic system. For this purpose versatile procedures and
oxidizing reagents were employed.24,25 Here we used one of the
most common reagents DDQ as the dehydrogenating reagent. Thus
after accomplishing the 1,3-dipolar cycloaddition, 2 M ratios of DDQ
wasadded tothe resulting mixtureand thewhole systemwas stirred
at room temperature for additional 8 h. We were delighted to find
that the dehydrogenated pyrrolo[2,1-a]isoquinoline (1a) was suc-
cessfully obtained in 85% yield (Table 1, entry 1). Then various aro-
matic aldehydes were employed in the reactions and the each
reaction proceeded smoothly to give the corresponding pyrrolo[2,1-
a]isoquinolines 1beg in 72e82% yields (Table 1, entries 2e7).
Benzaldehydes bearing with both stronger electron-donating and
electron-withdrawing substituents afforded the desired products in
very satisfactory yields. This result clearly showed that a one-pot
tow-step tandem reaction for the efficient synthesis of pyrrolo[2,1-
a]isoquinolineshas been successfullyestablished. Thepyrrolo[2,1-a]
isoquinolines 1aeg were fully characterized by 1H and 13C NMR, MS,
IR spectra, and elemental analysis. Their structures were further
confirmed by determination of the single crystal of compound 1b
(Fig. 1). It should be pointed out that in the formation process of
pyrrolo[2,1-a]isoquinolines the amido group was eliminated out,
while the cyano group was maintained in the target molecule.
Fig. 1. Molecular structure of pyrrolo[2,1-a]isoquinoline 1b.
To further extend the utility of this domino reaction, the re-
activity of other active
a-halogenated methylene compounds was
also explored. mixture of previously formed N-p-nitro-
A
benzylisoquinolinium bromide, aromatic aldehydes, and cyano-
acetoamide in the presence of triethylamine as base catalyst was
heated at about 50 ꢀC for several hours. Then 2 M ratios of DDQ were
added and the oxidation reaction was finished at room temperature
in 8 h. By using this one-pot two-step reaction procedure the
expected pyrrolo[2,1-a]isoquinolines 4aef were prepared in
77e94% yields (Table 2, entries 1e6). Under similar reaction condi-
tions, the reactions of a-phenacyl bromide and N,N-diethyl chloro-
acetamide also gave pyrrolo[2,1-a]isoquinolines 4ger in 60e80%
(Table 2, entries 7e18). Totally 18 functionalized pyrrolo[2,1-a]iso-
quinolines were successfully prepared and their structures were
fully characterized with spectroscopic methods. Two representative
single crystal structures of 4d (Fig. 2) and 4i were also determined.
Table 1
Synthesis of pyrrolo[2,1-a]isoquinolines 1aeg from reactions of ethyl
a
-bromoacetate
Br
CN
+
i: Et3N, ethanol, r.t.
N
+
+
ArCHO
CO2Et
N
ii: DDQ, r.t.
CO2Et
CONH2
NC
Ar
Entry
Compd
Ar
Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
p-CH3OC6H4
p-CH3C6H4
C6H4
85
75
72
82
82
78
78
p-FC6H4
m-ClC6H4
p-BrC6H4
m-NO2C6H4
1g

Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
2315
Table 2
Synthesis of pyrrolo[2,1-a]isoquinolines 4aer from tandem reactions
Table 3
Synthesis of tetrahydropyrrolo[2,1-a]isoquinolines 3aeg from tandem reactions
Br
E
CN
Br
E
CN
N
N
Et3N
Et3N
E
E
+
+
ArCHO
+
+
+
ArCHO
+
N
N
EtOH, r. t.
EtOH, r. t.
CONH2
CONH2
H2NOC
H2NOC
Ar
CN
Ar
CN
Entry
Compd
E
Ar
Yield (%)
Entry
Compd
E
Ar
Yield (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
CO2Et
CO2Et
CO2Et
CO2Et
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-CH3OC6H4
Ph
82
76
68
80
63
73
82
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
C6H4
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
m-ClC6H4
p-FC6H4
80
87
94
92
91
77
62
71
68
62
78
63
67
73
80
75
60
63
m-ClC6H4
m-NO2C6H4
p-(CH3)3CC6H4
p-BrC6H4
m-ClC6H4
3g
C6H4
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
m-ClC6H4
p-FC6H4
9
conditions the tandem reactions of p-nitrobenzyl bromide gave the
tetrahydropyrrolo[2,1-a]isoquinolines 3eeg in 63e82% yields (Table
3, entries 1e4). The structures of the prepared tetrahydropyrrolo
[2,1-a]isoquinolines 3aeg were also fully characterized by 1H and
13C NMR, MS, IR spectra, and elemental analysis. For examples in the
1H NMR spectrum of 3b, the two protons of amido group are an-
isotropic and showed two broadly singlet at 6.07, 6.02 ppm. The
ethoxyl group showed one quartet at 4.17 ppm and one triplet at
1.20 ppm. The three protons at tetrahydropyrrole ring display one
singlet at 5.66 ppm and two doublets at 4.54, 4.37 ppm with the
vicinal coupling constant J¼8.5 Hz. In the 1H NMR spectrum of 3f the
three protons at tetrahydropyrrole ring display one singlet at
5.86 ppm and two doublets at 5.16, 3.93 ppm with the vicinal cou-
pling constant J¼9.7 Hz. The similar peak pattern and coupling
constant were also observed in other 1H NMR spectra of the pre-
pared tetrahydropyrrolo[2,1-a]isoquinolines 3aeg. According to the
careful analysis of 1H NMR data and comparison with the earlier
reported results5,6 we could tentatively conclude that only one di-
astereoisomer of tetrahydropyrrolo[2,1-a]isoquinolines 3aeg was
produced in this tandem 1,3-dipolar addition. The X-ray diffraction
determination of single crystal 3g (Fig. 3) clearly showed that 2-p-
nitrophenyl group and 3-m-chlorophenyl group existed in trans-
configuration. These results also revealed that the isoquinolinium
ylide assisted tandem 1,3-dipolar addition is a highly diaster-
eoselective reaction.
10
11
12
13
14
15
16
17
18
C6H4
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
m-ClC6H4
m-NO2C6H4
We noticed that the pyrrolo[2,1-a]isoquinolines were efficiently
prepared by oxidation of the initially formed tetrahydropyrrolo[2,1-
a]isoquinolines with 2 M ratios of DDQ as oxidizing reagent. If less
Fig. 2. Molecular structure of pyrrolo[2,1-a]isoquinoline 4d.
These results indicated that this one-pot two-step tandem reaction
is quite general and has very broad substrate scopes.
Encouraged by these results, we turned our attention to attempt
to isolate directly the 1,3-dipolar cycloadducts of isoquinolinium
ylide. In order to block dehydrogenation and elimination process we
carried out the triethylamine catalyzed tandem reaction of N-
ethoxycarbonylmethylisoquinolinium bromide, aromatic alde-
hydes, and cyanoamide in a nitrogen atmosphere at room temper-
ature for 6 h. To our delight tetrahydropyrrolo[2,1-a]isoquinolines
existed as main products in the reaction mixture and nearly no
dehydrogenated products were detected by TLC analysis. After
workup the desired tetrahydropyrrolo[2,1-a]isoquinolines 3aed
were obtained in 62e80% yields (Table 3, entries 1e4). Under similar
Fig. 3. Molecular structure of tetrahydropyrrolo[2,1-a]isoquinoline 3g.

2316
Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
amount of DDQ was used the oxidation might be stopped at the
formation of dihydropyrrolo[2,1-a]isoquinoline stage. Thus we car-
ried out the oxidation reaction by addition of 1 M ratio of DDQ to the
system of the 1,3-dipolar cycloaddition of N-ethoxycarbonylme
thylisoquinolinium bromide, aromatic aldehydes, and cyanoaceta-
mide. The expected dihydropyrrolo[2,1-a]isoquinolines 2aef are
successfully prepared in 54e68% yields (Table 4). It should be
pointed that the very pure dihydropyrrolo[2,1-a]isoquinolines 2aef
were obtained by merely filtration and recrystallization steps. By
using 1 equiv of DDQ the amido group was eliminated and cyano
group was remained in the molecule of dihydropyrrolo[2,1-a]iso-
quinolines 2aef. The stereochemistry of 2aef should be the same
with that of the initial formed 1,3-dipolar cycloadducts 3aeg. Thus
the aryl group and the esteric group are in trans-configuration,
which was confirmed by the 1H NMR spectra and the single crystal
structure of 2b (Fig. 4). As an example in 1H NMR spectrum of 2d the
two protons of dihydropyrrole ring display two doublets at 4.59,
4.50 ppm with vicinal coupling constant J¼5.3 Hz.
the generation of ylide (B) and the rest for catalyzing the following
reaction. The second step is triethylamine catalyzed Knoevenagel
condensation of aromatic aldehyde with cyanoacetamide to give
arylidene cyanoacetamide (C). The third step is 1,3-dipolar cyclo-
addition of isoquinolinium ylide (B) to arylidene cyanoacetamide
(C) to afford the tetrahydropyrrolo[2,1-a]isoquinolin (3). By addi-
tion of DDQ as oxidizing reagent, an amido group was eliminated
from tetrahydropyrrolo[2,1-a]isoquinoline (3) to yield dihy-
dropyrrolo[2,1-a]isoquinoline (2). At last further oxidation with
DDQ gave the pyrrolo[2,1-a]isoquinoline (1) as the final product. In
this proposed reaction mechanism the key step is the 1,3-dipolar
cycloaddition of isoquinolinium ylide (B) to electron-deficient
olefin (C). These two reactants were both formed in situ from the
starting material precursors in reaction system.
In the converting process of tetrahydropyrrolo[2,1-a]isoquinoline
(3) to dihydropyrrolo[2,1-a]isoquinoline (2) one uniquefeature of this
tandem reaction is that the amido group was eliminated out and the
cyano group was maintained in the molecule. The cyano group is
a good leaving group in many organic reactions. In order to probe the
credibility of our proposed mechanistic scheme and shed more light
on the formation of pyrrolo[2,1-a]isoquinoline, we employed ethyl
cyanoacetate to replace cyanoacetamide in the tandem reaction. The
tandem reactions of N-ethoxycarbonylmethylisoquinolinium bro-
mide, ethylcyanoacetatewithp-methoxyandm-chlorobenzaldehyde
(Scheme 3) gave pyrrolo[2,1-a]isoquinolines 1a and 1e in moderate
yields. The formation of pyrrolo[2,1-a]isoquinolines 1a and 1e clearly
indicated that the ethyl ester group was eliminated and the cyano
group still remained in the molecule. This result strongly suggested
that the amido and esteric group could be eliminated more quickly
than that of cyano group in this reaction condition.
Table 4
Synthesis of dihydropyrrolo[2,1-a]isoquinolines 2aef from tandem reactions
Br
CO Et
CN
N
i: Et N, ethanol
ii: DDQ
CO Et
Ar
ArCHO
+
+
+
N
CONH
NC
Entry
Compd
Ar
Yield (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
p-CH3OC6H4
p-CH3C6H4
Ph
p-BrC6H4
m-ClC6H4
m-NO2C6H4
65
68
60
60
54
65
In summary, we have developed a new one-pot two-step re-
action involving isoquinoline, aromatic aldehyde, cyanoacetamide,
and reactive
a-halomethylene compounds for the synthesis of
pyrrolo[2,1-a]isoquinoline and its dihydro- and tetrahydro-de-
rivatives. This protocol not only provides an effective methodology
for the preparation of the functionalized pyrrolo[2,1-a]isoquino-
lines, but also opens a brand way for employing heteroaromatic N-
ylide intermediate to design new multicomponent reaction. The
mechanism of this tandem reaction believed involving 1,3-dipolar
cycloaddition of heteroaromatic N-ylide. A unique elimination of
the amido group preferring to the cyano group is also observed. We
are currently investigating the expansion of the scope of the re-
action to other a-halogen substituted carbonyl compounds and its
application to the synthesis of other heterocyclic systems.
3. Experimental section
3.1. General procedure for the synthesis of pyrrolo[2,1-a]
isoquinolines 1aeg
A mixture of ethyl
a-bromoacetate (2.2 mmol, 0.367 g) and
isoquinoline (3.0 mmol, 0.388 g) in 10 mL of ethanol was stirred at
room temperature for about 1.5 h. Then aromatic aldehyde
(2.0 mmol), cyanoacetamide (2.0 mmol, 0.168 g), and triethylamine
(4.0 mmol, 0.404 g) were added to it. The solution was stirred at
room temperature for additional 6e8 h . Then the DDQ (4.0 mmol,
0.908 g) was added. The resulting mixture was stirred at room
temperature for 8 h. The resulting precipitates were collected by
filtration and washed with cold alcohol. The crude product was
recrystallized in chloroform/ethanol to give the pure product for
analysis.
Fig. 4. Molecular structure of dihydropyrrolo[2,1-a]isoquinoline 2b.
To explain the mechanism of this one-pot multicomponent re-
action, we propose a plausible reaction course with the reaction of
ethyl
a
-bromoacetate, which is illustrated in Scheme 2. The first
-bromoacetate to isoquinoline to yield
Compound 1a: White solid, yield: 85%, mp 180e182 ꢀC, IR (KBr):
3136 (w), 2979 (w), 2209 (m),1697 (vs),1612 (m),1517 (m),1428 (m),
1402 (m),1370 (m),1298 (s),1246 (s),1187 (s),1088 (s),1033 (w), 801
step is the addition of ethyl
a
N-ethoxycarbonylmethylisoquinolinium bromide (A), which in
turn converts to isoquinolinium ylide (B) by deprotonation of
triethylamine. It is needed to state that 2 equiv amounts of trie-
thylamine were employed in the reaction. One equivalent was for
(m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.32 (d, J¼7.2 Hz, 1H, CH),
8.97 (d, J¼6.4 Hz, 1H, CH), 7.74 (s, 1H, ArH), 7.64 (d, J¼3.4 Hz, 2H,

Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
2317
Br
Et3N
Br-
+
N
CO2Et
N
N
CO2Et -HBr
CO2Et
A
B
CN
CONH2
CN
CONH2
Et3N
ArCHO
+
ArCH
C
DDQ
DDQ
N
N
N
CO2Et
CO2Et
Ar
CO2Et
Ar
H2NOC
Ar
NC
NC
CN
1
2
3
Scheme 2. The reaction mechanism of the tandem four-component reactions.
Br
CN
i: Et3N, ethanol, r.t.
ii: DDQ, r.t.
N
+
+
ArCHO
+
CO2Et
N
CO2Et
CO2Et
Ar
NC
1a: Ar = p-CH3OC6H4, 51%; 1e: Ar = m-ClC6H4, 59%
Scheme 3. The synthesis of pyrrolo[2,1-a]isoquinolines from the reactions of ethyl cyanoacetate.
ArH), 7.44 (d, J¼7.4 Hz, 2H, ArH), 7.18 (d, J¼7.2 Hz, 1H, ArH), 7.01 (d,
J¼7.4 Hz, 2H, ArH), 4.21 (d, J¼6.5 Hz, 2H, CH2), 3.88 (s, 3H, CH3O),1.09
(m), 1222 (m), 1184 (m), 1081 (m), 1012 (m), 810 (m). 1H NMR
(600 MHz, CDCl3)
d
(ppm): 9.35 (d, J¼7.4 Hz, 1H, ArH), 8.98 (d,
(t, J¼6.6 Hz, 3H, CH3).13C NMR (150 MHz, CDCl3)
d
161.0,159.8,139.5,
J¼5.4 Hz,1H, CH), 7.77 (s,1H, CH), 7.67 (d, J¼4.0 Hz, 2H, ArH), 7.47 (t,
J¼5.2 Hz, 2H, ArH), 7.22 (d, J¼7.3 Hz, 1H, ArH), 7.17 (t, J¼8.0 Hz, 2H,
ArH), 4.19 (q, J¼7.0 Hz, 2H, CH2), 1.06 (t, J¼6.9 Hz, 3H, CH3). 13C NMR
136.1, 131.6, 131.4, 131.2, 129.4, 129.1, 128.5, 127.1, 124.6, 123.8, 123.5,
117.4, 114.8, 114.3, 113.3, 87.7, 77.3, 77.1, 76.9, 60.6, 55.3, 13.8. MS
(m/z): 371.60 ([Mþ1]þ,100%). Anal. Calcd for C23H18N2O3: C 74.58, H
4.90, N 7.56. Found: C 74.64, H 5.23, N 7.29.
(150 MHz, CDCl3)
d 163.7, 162.1, 160.8, 138.6, 136.2, 131.9, 131.8,
129.6, 129.2, 128.7, 128.5, 127.2, 124.6, 123.8, 123.5, 117.0, 115.2,
115.0, 114.9, 114.5, 87.7, 60.7, 13.7. MS (m/z): 359.30 ([Mþ1]þ, 100%).
Anal. Calcd for C22H15FN2O2: C 73.73, H 4.22, N 7.82. Found: C 73.40,
H 4.61, N 7.63.
Compound 1b: White solid, yield: 75%, mp 166e168 ꢀC, IR (KBr):
3138 (w), 2983 (w), 2903 (w), 2208 (m), 1697 (vs), 1517 (m), 1406
(m), 1370 (m), 1346 (m), 1248 (m), 1189 (s), 1118 (w), 1088 (s), 1021
(w), 798 (m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.35 (d, J¼7.2 Hz,
Compound 1e: White solid, yield: 82%, mp 176e178 ꢀC, IR (KBr):
3147 (w), 2986 (w), 2214 (m), 1694 (s), 1595 (w), 1518 (w), 1433 (w),
1371 (m), 1342 (w), 1248 (m), 1187 (m), 1097 (m), 1077 (m), 802 (m),
1H, CH), 9.01 (d, J¼6.0 Hz, 1H, CH), 7.77 (d, J¼5.7 Hz, 1H, ArH), 7.66
(d, J¼3.5 Hz, 2H, ArH), 7.39 (d, J¼7.1 Hz, 2H, ArH), 7.27 (d, J¼7.8 Hz,
2H, ArH), 7.21 (d, J¼7.2 Hz,1H, ArH), 4.10 (q, J¼6.4 Hz, 2H, CH2), 2.44
(s, 3H, CH3), 1.06 (t, J¼6.4 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
747 (m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.40 (d, J¼7.4 Hz, 1H,
ArH), 9.02 (d, J¼6.7 Hz, 1H, CH), 7.80 (d, J¼6.5 Hz, 1H, CH), 7.17e7.69
(m, 2H, ArH), 7.48 (s, 1H, ArH), 7.43e7.40 (m, 3H, ArH), 7.27 (s, 1H,
ArH), 4.20 (q, J¼7.0 Hz, 2H, CH2),1.06 (t, J¼7.0 Hz, 3H, CH3). 13C NMR
d
161.1, 139.9, 138.2, 136.2, 129.9, 129.5, 129.2, 128.6, 128.5, 127.1,
126.9, 124.7, 124.0, 123.9, 123.6, 117.3, 114.9, 114.4, 87.8, 60.9, 60.6,
21.4, 13.7. MS (m/z): 355.63 ([Mþ1]þ, 100%). Anal. Calcd for
C23H18N2O2: C 77.95, H 5.12, N 7.90. Found: C 77.68, H 5.40, N 7.75.
Compound 1c: White solid, yield: 72%, mp 172e174 ꢀC, IR (KBr):
3146 (w), 2978 (w), 2210 (m), 1688 (vs), 1515 (m), 1403 (s), 1371 (s),
1342 (m), 1249 (m), 1187 (s), 1122 (w), 1087 (m), 1016 (w), 806 (w),
(150 MHz, CDCl3)
d 160.6, 137.8, 136.2, 134.3, 133.6, 130.4, 129.7,
129.2, 129.1, 128.7, 128.1, 127.2, 124.5, 123.7, 123.4, 116.8, 115.3, 114.5,
87.5, 60.8, 13.6. MS (m/z): 374.75 ([Mþ1]þ, 100%), 378.02 ([Mþ3]þ,
27%). Anal. Calcd for C22H15ClN2O2: C 70.50, H 4.03, N 7.47. Found: C
70.29, H 4.45, N 7.22.
743 (w). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.36 (d, J¼7.2 Hz, 1H,
Compound 1f: White solid, yield: 78%, mp 168e170 ꢀC, IR (KBr):
3140 (w), 2982 (w), 2211 (m), 1098 (s), 1517 (m), 1408 (m), 1370 (m),
1345 (m), 1250 (m), 1209 (w), 1187 (s), 1119 (w), 1089 (m), 1013 (w),
CH), 9.00 (d, J¼6.1 Hz, 1H, CH), 7.77 (d, J¼5.5 Hz, 1H, ArH), 7.66 (d,
J¼3.6 Hz, 2H, ArH), 7.48e7.45 (m, 5H, ArH), 7.22 (d, J¼7.2 Hz, 1H,
ArH), 4.17 (q, J¼6.4 Hz, 2H, CH2), 1.01 (t, J¼6.4 Hz, 3H, CH3). 13C NMR
800 (m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.35 (d, J¼7.4 Hz, 1H,
(150 MHz, CDCl3)
d
161.0, 139.7, 136.2, 132.6, 129.9, 129.5, 129.2,
ArH), 8.97 (d, J¼5.0 Hz, 1H, CH), 7.77 (d, J¼2.8 Hz, 1H, CH), 7.67 (d,
J¼4.8 Hz, 2H, ArH), 7.61 (d, J¼7.5 Hz, 2H, ArH), 7.37 (d, J¼7.5 Hz, 2H,
ArH), 7.23 (d, J¼7.4 Hz, 1H, ArH), 4.20 (q, J¼6.9 Hz, 2H, CH2), 1.10 (t,
128.6, 128.4, 127.8, 127.1, 124.6, 123.8, 123.7, 123.6, 117.1, 115.0, 114.5,
87.7, 60.0, 13.6. MS (m/z): 341.34 ([Mþ1]þ, 100%). Anal. Calcd for
C22H16N2O2: C 77.63, H 4.74, N 8.23. Found: C 77.85, H 5.17, N 7.76.
Compound 1d: White solid, yield: 82%, mp 174 ꢀC, IR (KBr): 3078
(w), 2976 (w), 2216 (m), 1693 (s), 1602 (w), 1519 (m), 1402 (m), 1292
J¼6.9 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
d 160.7, 138.3, 136.3,
131.7, 131.6, 131.5, 131.1, 129.7, 129.2, 128.7, 127.2, 124.6, 123.8, 123.5,
122.8, 116.9, 115.2, 114.4, 87.5, 60.8, 13.7. MS (m/z): 419.51 ([Mþ1]þ,

2318
Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
100%), 421 ([Mþ3]þ, 47%). Anal. Calcd for C22H15BrN2O2: C 63.02, H
3.61, N 6.68. Found: C 62.76, H 3.83, N 6.40.
CDCl3)
d
(ppm): 8.95 (d, J¼8.0 Hz,1H, CH), 8.32(d, J¼8.2 Hz, 2H, ArH),
7.84 (d, J¼7.2 Hz,1H, CH), 7,71 (d, J¼7.6 Hz,1H, ArH), 7.68 (t, J¼7.6 Hz,
1H, ArH), 7.61 (d, J¼7.2 Hz,1H, ArH), 7.53 (d, J¼8.2 Hz,1H, ArH), 7.48
(d, J¼8.0 Hz, 2H, ArH), 7.19 (d, J¼8.0 Hz, 2H, ArH), 7.05 (d, J¼7.2 Hz,
Compound 1g: White solid, yield: 78%, mp 196 ꢀC, IR (KBr): 3145
(w), 3081 (w), 2215 (m), 1695 (s), 1523 (s), 1403 (m), 1348 (s), 1252
(m), 1195 (s), 1095 (m), 805 (m), 747 (m). 1H NMR (600 MHz, CDCl3)
1H, ArH).13C NMR (150 MHz, CDCl3)
d 147.7,135.8,135.0,132.1,131.7,
d
(ppm): 9.43 (d, J¼7.4 Hz, 1H, CH), 9.00 (d, J¼4.6 Hz, 1H, ArH), 8.41
131.3,130.3,129.3,129.0,128.9,128.4,127.4,124.6,124.5,123.5,123.0,
122.6, 120.9, 117.7, 114.9, 85.4. MS (m/z): 468.23 ([Mþ1]þ, 100%),
450.50 ([Mþ3]þ, 58%). Anal. Calcd for C25H14BrN3O2: C 64.12, H 3.01,
N 8.97. Found: C 63.71, H 3.56, N 8.62.
(s, 1H, ArH), 8.43 (d, J¼8.2 Hz, 1H, CH), 7.87 (d, J¼7.3 Hz, 1H, ArH),
7.81 (s, 1H, ArH), 7.72e7.67 (m, 3H, ArH), 7.30 (d, J¼7.3 Hz, 1H, ArH),
4.20 (q, J¼7.0 Hz, 2H, CH2), 1.01 (t, J¼6.9 Hz, 3H, CH3). 13C NMR
(150 MHz, CDCl3)
d
160.4, 147.7, 136.6, 136.5, 136.0, 134.4, 130.0,
Compound 4e: Yellow solid, yield: 91%, mp 206e208 ꢀC, IR (KBr):
3068 (w), 2930 (w), 2208 (m), 1597 (m), 1522 (s), 1378 (m), 1349
(vs), 1289 (w), 860 (w), 793 (m), 743 (w). 1H NMR (600 MHz, CDCl3)
129.3, 129.0, 128.9, 127.3, 125.7, 124.6, 123.8, 123.5, 123.3, 116.5,
115.7, 114.6, 87.5, 61.0, 13.6. MS (m/z): 385.35 ([Mꢁ1]þ, 100%). Anal.
Calcd for C22H15N3O4: C 68.57, H 3.92, N 10.90. Found: C 68.58, H
4.26, N 10.65.
d
(ppm): 8.98 (d, J¼7.9 Hz, 1H, CH), 8.32 (d, J¼7.8 Hz, 2H, ArH), 7.84
(d, J¼7.0 Hz, 1H, CH), 7.73 (d, J¼7.5 Hz, 1H, ArH), 7.96 (t, J¼7.3 Hz,
1H, ArH), 7.62 (t, J¼7.3 Hz, 1H, ArH), 7.54 (d, J¼7.9 Hz, 2H, ArH), 7.31
(s, 3H, ArH), 7.21 (d, J¼7.0 Hz, 1H, ArH), 7.06 (d, J¼7.1 Hz, 1H, ArH).
3.2. General procedure for the synthesis of pyrrolo[2,1-a]
isoquinolines 4aer
13C NMR (150 MHz, CDCl3)
d 147.7, 135.7, 134.9, 134.6, 133.2, 131.7,
130.1, 129.7, 129.0, 128.9, 128.5, 128.4, 128.1, 127.4, 124.8, 124.6,
124.5, 123.5, 123.3, 120.9, 117.5, 114.9, 85.6. MS (m/z): 424.39
([Mþ1]þ, 100%), 426.8 ([Mþ3]þ, 38%). Anal. Calcd for C25H14ClN3O2:
C 70.84, H 3.33, N 9.91. Found: C 70.63, H 3.78, N 9.70.
A mixture of p-nitrobenzyl bromide (2.2 mmol, 0.475 g) and
isoquinoline (3.0 mmol, 0.388 g) in 10 mL of ethanol was heated at
50 ꢀC for about 4 h. Then aromatic aldehyde (2.0 mmol), cyanoa-
cetamide (2.0 mmol, 0.168 g), and triethylamine (4.0 mmol,
0.404 g) were added to it. The solution was stirred for additional
10e12 h . Then the DDQ (4.0 mmol, 0.908 g) was added. The
resulting mixture was stirred at room temperature for 8 h. The
resulting precipitates were collected by filtration and washed with
cold alcohol. The crude product was recrystallized in chloroform/
ethanol to give the pure product.
Compound 4f: Yellow solid, yield: 77%, mp 178e180 ꢀC, IR (KBr):
3080 (w), 2211 (m), 1597 (m), 1519 (s), 1344 (s), 1224 (m), 1157 (m),
1105 (m), 1045 (w), 855 (m), 769 (m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 8.98 (d, J¼8.0 Hz, 1H, CH), 8.32 (d, J¼8.4 Hz, 2H, ArH), 7.85
(d, J¼7.4 Hz, 1H, CH), 7.73 (d, J¼7.6 Hz, 1H, ArH), 7.69 (t, J¼7.4 Hz,
1H, ArH), 7.62 (t, J¼7.3 Hz, 1H, ArH), 7.54 (d, J¼7.0 Hz, 2H, ArH), 7.30
(t, J¼5.7 Hz, 2H, ArH), 7.06 (t, J¼7.0 Hz, 3H, ArH). 13C NMR (150 MHz,
Compound 4a: Yellow solid, yield: 80%, mp 184e186 ꢀC, IR (KBr):
3079 (w), 2857 (w), 2210 (s),1599 (m),1518 (vs),1454 (m),1376 (m),
1349 (vs), 1285 (m), 1106 (m), 738 (m), 705 (m). 1H NMR (600 MHz,
CDCl3) d 163.4, 161.8, 147.6, 135.9, 134.8, 131.7, 131.6, 131.5, 129.6,
128.9, 128.8, 128.5, 127.4, 127.3, 124.5, 124.4, 123.4, 123.0, 120.9,
117.8, 116.0, 115.9, 114.7, 85.6. MS (m/z): 407.55 ([Mꢁ1]þ, 100%).
Anal. Calcd for C25H14BrN3O2: C 73.70, H 3.46, N 10.31. Found: C
73.55, H 3.81, N 9.78.
CDCl3)
d
(ppm): 8.99 (d, J¼6.6 Hz, 1H, CH), 8.29 (d, J¼6.2 Hz, 2H,
ArH), 7.86 (d, J¼7.2 Hz, 1H, CH), 7.71 (d, J¼5.3 Hz, 1H, ArH), 7.67 (s,
1H, ArH), 7.60 (s, 1H, ArH), 7.54 (d, J¼5.9 Hz, 2H, ArH), 7.34 (s, 5H,
ArH), 7.05 (s, 1H, ArH). 13C NMR (150 MHz, CDCl3)
d
147.5, 136.2,
3.3. General procedure for the synthesis of pyrrolo[2,1-a]
isoquinolines 4gel
134.8, 131.7, 131.3, 130.7, 129.8, 128.9, 128.8, 128.7, 128.4, 128.2,
127.4, 124.6, 124.4, 123.5, 122.9, 121.0, 117.9, 114.6, 100.0, 85.7. MS
(m/z): 390.37 ([Mþ1]þ, 100%). Anal. Calcd for C25H15N3O2: C 77.11, H
3.88, N 10.79. Found: C 76.75, H 4.34, N 10.50.
In a 50 mL round bottom flask a mixture of phenacyl bromide
(2.2 mmol, 0.438 g) and isoquinoline (3.0 mmol, 0.388 g) in 10 mL of
ethanol was stirred at 50 ꢀC for 4 h. Then aromatic aldehyde
(2.0 mmol), cyanoacetamide (2.0 mmol, 0.168 g), and triethylamine
(4.0 mmol, 0.404 g) were added to it. The solution was stirred at
50 ꢀC for additional 18e30 h. Then the DDQ (4.0 mmol, 0.908 g) was
added. The resulting mixture was stirred at room temperature for
8 h. The resulting precipitates were collected by filtration and
washed with cold alcohol. The crude product was recrystallized in
chloroform/ethanol to give the pure product for analysis.
Compound 4b: Yellow solid, yield: 87%, mp 202e204 ꢀC, IR
(KBr): 3131 (w), 2919 (w), 2210 (m), 1595 (m), 1518 (s), 1374 (w),
1343 (vs), 1288 (w), 1110 (w), 859 (w), 795 (m). 1H NMR (600 MHz,
CDCl3)
d
(ppm): 8.96 (d, J¼8.1 Hz, 1H, CH), 8.28 (d, J¼8.3 Hz, 2H,
ArH), 7.85 (d, J¼7.4 Hz, 1H, CH), 7.69 (d, J¼7.7 Hz, 1H, ArH), 7.65 (t,
J¼7.7 Hz, 1H, ArH), 7.58 (t, J¼7.3 Hz, 1H, ArH), 7.52 (d, J¼8.3 Hz, 2H,
ArH), 7.20 (d, J¼7.6 Hz, 2H, ArH), 7.15 (d, J¼7.6 Hz, 2H, ArH), 7.02 (d,
J¼7.4 Hz, 1H, ArH), 2.35 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3)
d
38.1, 136.3, 134.7, 131.7, 130.8, 129.6, 129.5, 128.8, 128.7, 128.4,
Compound 4g: White solid, yield: 62%, mp 190 ꢀC, IR (KBr): 3058
(w), 2217 (m), 1623 (vs),1518 (m), 1450 (m), 1398 (s), 1372 (m), 1348
(s), 1292 (w), 804 (w), 780 (w), 749 (w). 1H NMR (600 MHz, CDCl3)
128.3, 127.3, 124.5, 124.4, 123.4, 122.8, 120.0, 118.0, 114.5, 85.7, 21.3.
MS (m/z): 403.54 ([Mþ1]þ, 100%). Anal. Calcd for C26H17N3O2: C
77.41, H 4.25, N 10.42. Found: C 77.28, H 4.57, N 9.84.
d
(ppm): 9.12 (d, J¼6.0 Hz, 1H, CH), 9.08 (d, J¼6.4 Hz, 1H, CH), 7.80
Compound 4c: Yellow solid, yield: 94%, mp 174e176 ꢀC, IR (KBr):
3128 (w), 2935 (w), 2210 (m), 1597 (m), 1518 (s), 1342 (vs), 1246 (s),
1176 (m), 1108 (m), 1025 (m), 859 (m), 799 (m), 748 (m). 1H NMR
(d, J¼5.4 Hz, 1H, ArH), 7.71 (s, 2H, ArH), 7.51 (d, J¼6.9 Hz, 2H, ArH),
7.24 (s, 4H, ArH), 7.13 (s, 3H, ArH), 7.08 (t, J¼6.5 Hz, 2H, ArH). 13C
NMR (150 MHz, CDCl3)
d 187.7, 139.6, 138.2, 136.7, 132.2, 131.5,
(600 MHz, CDCl3)
d
(ppm): 8.96 (d, J¼7.7 Hz, 1H, CH), 8.29 (d,
130.4, 129.8, 129.7,128.7,128.2, 128.1,127.8,127.3,124.4,124.1,123.7,
122.4, 117.4, 115.3, 86.8. MS (m/z): 373.95 ([Mþ1]þ, 100%). Anal.
Calcd for C26H16N2O: C 83.85, H 4.33, N 7.52. Found: C 83.57, H 4.51,
N 7.29.
J¼7.2 Hz, 2H, ArH), 7.85 (d, J¼6.2 Hz, 1H, CH), 7.69 (d, J¼7.3 Hz, 1H,
ArH), 7.65 (t, J¼6.3 Hz, 1H, ArH), 7.59 (d, J¼6.6 Hz, 1H, ArH), 7.53 (d,
J¼7.3 Hz, 2H, ArH), 7.24 (d, J¼7.1 Hz, 2H, ArH), 7.02 (d, J¼6.5 Hz, 1H,
ArH), 6.88 (d, J¼7.2 Hz, 2H, ArH), 3.81 (s, 3H, CH3). 13C NMR
Compound 4h: White solid, yield: 71%, mp 144 ꢀC, IR (KBr): 3138
(w), 2983 (w), 2903 (w), 2208 (m), 1697 (vs), 1517 (m), 1406 (m),
1370 (m), 1346 (m), 1248 (m), 1189 (s), 1118 (w), 1088 (s), 798 (m).
(150 MHz, CDCl3) d 159.5,147.4,136.4,134.7,131.7,131.0,130.5,128.8,
128.7,128.4,127.3,124.5,124.4,123.5,123.4,122.7,121.0,118.0,114.5,
114.3, 85.6, 55.3. MS (m/z): 419.12 ([Mþ1]þ, 100%). Anal. Calcd for
C26H17N3O3: C 74.45, H 4.09, N 10.02. Found: C 74.20, H 4.47, N 9.66.
Compound 4d: Yellow solid, yield: 92%, mp 192e194 ꢀC, IR (KBr):
3082 (w), 2210 (m),1594 (m),1519 (s),1372 (w),1343 (vs),1288 (m),
1109 (m), 1074 (w), 1008 (m), 859 (m), 792 (m). 1H NMR (600 MHz,
1H NMR (600 MHz, CDCl3)
d
(ppm): 9.07 (d, J¼7.5 Hz, 1H, ArH), 9.03
(d, J¼7.9 Hz,1H, CH), 7.76 (d, J¼7.2 Hz,1H, CH), 7.66 (d, J¼3.8 Hz, 2H,
ArH), 7.50 (d, J¼7.6 Hz, 2H, ArH), 7.24 (d, J¼7.2 Hz, 1H, ArH), 7.19 (d,
J¼7.5 Hz, 1H, ArH), 7.12 (d, J¼7.7 Hz, 1H, ArH), 7.19 (d, J¼7.5 Hz, 2H,
ArH), 7.08 (t, J¼7.5 Hz, 2H, ArH), 6.92 (d, J¼7.6 Hz, 1H, ArH), 2.21 (s,

Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
2319
3H, CH3). 13C NMR (150 MHz, CDCl3)
d
187.7, 139.7, 138.2, 138.1,
product was recrystallized in chloroform/ethanol to give the pure
product for analysis.
136.6, 132.0, 130.3, 129.7, 129.6, 128.8, 128.6, 128.5, 127.7, 127.2,
124.4, 124.0, 123.6, 122.3, 117.5, 115.1, 86.8, 21.2. MS (m/z): 387.04
([Mþ1]þ, 100%). Anal. Calcd for C27H18N2O: C 83.92, H 4.69, N 7.25.
Found: C 83.57, H 4.90, N 6.88.
Compound 4m: White solid, yield: 67%, mp 210 ꢀC, IR (KBr):
3079 (w), 2970 (w), 2934 (w), 2208 (s), 1614 (vs),1550 (m), 1521 (s),
1486 (m), 1458 (s), 1376 (s), 1275 (m), 1152 (w), 1082 (w), 798 (m).
Compound 4i: White solid, yield: 68%, mp 206 ꢀC, IR (KBr): 2963
(w), 2219 (m), 1629 (s), 1521 (s), 1454 (m), 1429 (m), 1394 (s), 1349
(s), 1250 (vs), 1176 (m), 967 (m), 896 (m), 800 (s). 1H NMR
1H NMR (600 MHz, CDCl3)
d (ppm): 8.95 (s, 1H, CH), 8.02 (d,
J¼6.8 Hz, 1H, CH), 7.70 (d, J¼6.4 Hz, 1H, ArH), 7.64 (d, J¼7.6 Hz, 3H,
ArH), 7.59 (d, J¼6.0 Hz, 1H, ArH), 7.47 (t, J¼7.5 Hz, 2H, ArH),
7.43e7.40 (m, 1H, ArH), 7.07 (d, J¼7.1 Hz, 1H, ArH), 3.82 (q, J¼6.3 Hz,
1H, CH2), 3.28 (q, J¼6.3 Hz,1H, CH2), 3.13 (q, J¼6.5 Hz,1H, CH2), 2.75
(q, J¼6.8 Hz, 1H, CH2), 1.17 (t, J¼6.9 Hz, 3H, CH3), 0.62 (t, J¼6.8 Hz,
(600 MHz, CDCl3)
d
(ppm): 9.12 (d, J¼7.3 Hz, 1H, CH), 9.06 (d,
J¼6.8 Hz, 1H, CH), 7.79 (d, J¼6.3 Hz, 1H, ArH), 7.69 (d, J¼3.6 Hz, 2H,
ArH), 7.51 (d, J¼7.4 Hz, 2H, ArH), 7.27 (t, J¼7.5 Hz, 1H, ArH), 7.23 (d,
J¼7.3 Hz, 1H, ArH), 7.17 (d, J¼7.4 Hz, 2H, ArH), 7.10 (t, J¼7.2 Hz, 2H,
ArH), 6.66 (d, J¼7.4 Hz, 2H, ArH), 3.72 (s, 3H, CH3O). 13C NMR
3H, CH3). 13C NMR (150 MHz, CDCl3)
d 161.9, 134.9, 131.4, 129.3,
129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 127.3, 124.3, 123.3, 122.7,
119.2, 118.0, 114.5, 83.5, 43.0, 39.3, 13.8, 12.3. MS (m/z): 368.75
([Mþ1]þ, 100%). Anal. Calcd for C24H21N3O: C 78.45, H 5.76, N 11.44.
Found: C 78.41, H 6.22, N 11.27.
(150 MHz, CDCl3)
d 187.7, 159.5, 139.5, 138.2, 136.7, 132.2, 131.7,
129.7,128.6, 127.8, 127.2,124.4,124.0,123.8, 123.6, 122.3, 117.6, 115.1,
113.7, 86.7, 55.2. MS (m/z): 403.80 ([Mþ1]þ, 100%). Anal. Calcd for
C27H18N2O2: C 80.58, H 4.51, N 6.96. Found: C 80.70, H 4.83, N 6.75.
Compound 4j: White solid, yield: 62%, mp 162 ꢀC, IR (KBr): 3055
(w), 2218 (m), 1627 (s), 1516 (m), 1450 (w), 1404 (m), 1378 (m), 1348
(vs), 1252 (w), 1172 (w), 895 (m), 798 (m). 1H NMR (600 MHz,
Compound 4n: White solid, yield: 73%, mp 270 ꢀC, IR (KBr): 2972
(w), 2210 (m), 1617 (vs), 1554 (w), 1521 (m), 1456 (m), 1375 (m),
1273 (m), 1150 (m), 1084 (w), 797 (m). 1H NMR (600 MHz, CDCl3)
d
(ppm): 8.94 (d, J¼8.1 Hz,1H, CH), 8.02 (d, J¼7.4 Hz,1H, CH), 7.70 (t,
CDCl3)
d
(ppm): 9.12 (d, J¼7.5 Hz, 1H, ArH), 9.06e9.04 (m, 1H, CH),
J¼7.8 Hz, 1H, ArH), 7.64 (t, J¼7.6 Hz, 1H, ArH), 7.58 (t, J¼7.4 Hz, 1H,
ArH), 7.52 (d, J¼7.8 Hz, 2H, ArH), 7.28 (d, J¼8.3 Hz, 2H, ArH), 7.06 (d,
J¼7.4 Hz, 1H, ArH), 3.82 (q, J¼6.7 Hz, 1H, CH2), 3.30 (q, J¼6.7 Hz, 1H,
CH2), 3.14 (q, J¼7.0 Hz, 1H, CH2), 2.76 (q, J¼7.0 Hz, 1H, CH2), 2.40 (s,
7.82e7.80 (m, 1H, CH), 7.71 (t, J¼3.7 Hz, 2H, ArH), 7.49 (d, J¼7.7 Hz,
2H, ArH), 7.33 (t, J¼7.4 Hz, 1H, ArH), 7.26e7.25 (m, 3H, ArH),
7.14e7.11 (m, 3H, ArH), 7.10 (s, 1H, ArH). 13C NMR (150 MHz, CDCl3)
d
187.4, 138.2, 138.0, 136.8, 132.4, 131.8, 131.3, 130.6, 130.0, 129.7,
3H, CH3), 1.19 (t, J¼7.1 Hz, 3H, CH3), 0.64 (t, J¼7.1 Hz, 3H, CH3). 13
C
129.6, 128.8, 127.9, 127.3, 124.4, 124.1, 123.6, 122.7, 122.4, 117.1, 115.1,
86.6. MS (m/z): 451.63 ([Mþ1]þ, 100%), 453.49 ([Mþ1]þ, 97%). Anal.
Calcd for C26H15BrN2O: C 69.19, H 3.35, N 6.21. Found: C 68.84, H
3.78, N 5.96.
NMR (150 MHz, CDCl3) d 162.0, 138.5, 134.9, 129.7, 129.4, 128.9,
128.7, 128.5, 128.4, 127.3, 124.3, 123.4, 122.7, 118.9, 118.1, 114.4, 83.5,
43.0, 39.3, 21.3, 13.9, 12.3. MS (m/z): 382.72 ([Mþ1]þ, 100%). Anal.
Calcd for C25H23N3O: C 78.71, H 6.08, N 11.02. Found: C 78.65, H
6.50, N 10.76.
Compound 4k: White solid, yield: 78%, mp 140 ꢀC, IR (KBr): 3137
(w), 3088 (w), 2220 (m), 1626 (s), 1521 (m), 1456 (m), 1398 (s), 1350
(vs), 969 (m), 903 (m), 805 (m), 755 (m). 1H NMR (600 MHz, CDCl3)
Compound 4o: White solid, yield: 80%, mp 226 ꢀC, IR (KBr): 2971
(w), 2209 (m), 1619 (vs), 1550 (m), 1520 (m), 1455 (m), 1375 (m),
1247 (m), 1175 (w), 872 (w), 795 (w). 1H NMR (600 MHz, CDCl3)
d
(ppm): 9.15 (d, J¼6.2 Hz,1H, CH), 9.06 (d, J¼6.1 Hz,1H, CH), 7.81 (s,
1H, ArH), 7.72 (d, J¼4.0 Hz, 2H, ArH), 7.50 (d, J¼7.0 Hz, 2H, ArH),
d
(ppm): 8.92 (d, J¼8.1 Hz, 1H, CH), 8.01 (d, J¼7.4 Hz, 1H, CH), 7.68
7.28e7.27 (m, 2H, ArH), 7.21 (s, 1H, ArH), 7.15e7.10 (m, 5H, ArH). 13C
(d, J¼7.8 Hz, 1H, ArH), 7.62 (t, J¼7.6 Hz, 1H, ArH), 7.57 (d, J¼7.9 Hz,
3H, ArH), 7.05 (d, J¼7.4 Hz, 1H, ArH), 7.01 (d, J¼8.4 Hz, 2H, ArH),
3.85 (s, 3H, CH3O), 3.82 (q, J¼6.7 Hz, 1H, CH2), 3.29 (q, J¼6.7 Hz, 1H,
CH2), 3.15 (q, J¼7.0 Hz, 1H, CH2), 2.77 (q, J¼7.0 Hz, 1H, CH2), 1.19 (t,
J¼7.0 Hz, 3H, CH3), 0.66 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (150 MHz,
NMR (150 MHz, CDCl3)
d 187.5, 138.2, 137.9, 136.8, 133.9, 133.3,
132.4, 130.7, 129.9, 129.8, 129.5, 129.4, 128.9, 128.3, 127.9, 127.3,
124.4, 124.1, 123.6, 122.6, 116.9, 115.6, 87.7. MS (m/z): 407.73
([Mþ1]þ,100%), 409.26 ([Mþ1]þ, 55%). Anal. Calcd for C26H15ClN2O:
C 76.75, H 3.72, N 6.89. Found: C 76.45, H 4.17, N 6.50.
CDCl3)
d 162.0, 159.9, 134.8, 130.2, 129.1, 128.6, 128.5, 128.4, 127.3,
Compound 4l: White solid, yield: 63%, mp 136e138 ꢀC, IR (KBr):
3026 (w), 2217 (w), 1620 (m), 1524 (m), 1445 (w), 1395 (w), 1349
124.2, 123.7, 123.3, 122.7, 118.8, 118.1, 114.4, 83.4, 55.4, 43.0, 39.4,
13.9, 12.4. MS (m/z): 398.72 ([Mþ1]þ, 100%). Anal. Calcd for
C25H23N3O2: C 75.54, H 5.83, N 10.57. Found: C 75.21, H 6.17, N
10.40.
(vs), 970 (w), 913 (w), 868 (w). 1H NMR (600 MHz, CDCl3)
d (ppm):
9.21 (d, J¼7.5 Hz, 1H, ArH), 9.07e9.05 (m, 1H, CH), 7.99 (d, J¼8.2 Hz,
1H, CH), 7.96 (t, J¼1.7 Hz, 1H, ArH), 7.86e7.84 (m, 1H, ArH),
7.76e7.74 (m, 2H, ArH), 7.70 (d, J¼7.7 Hz, 1H, ArH), 7.48 (d, J¼7.3 Hz,
2H, ArH), 7.40 (t, J¼7.9 Hz, 1H, ArH), 7.33 (d, J¼7.5 Hz, 1H, ArH), 7.23
(t, J¼7.5 Hz, 1H, ArH), 7.08 (t, J¼7.7 Hz, 2H, ArH). 13C NMR (150 MHz,
Compound 4p: White solid, yield: 75%, mp 247 ꢀC, IR (KBr): 2973
(w), 2207 (m), 1616 (vs), 1524 (s), 1435 (m), 1377 (m), 1345 (s), 1270
(m),1212 (w),1151 (w),1077 (w), 861 (w), 794 (w), 698 (w). 1H NMR
(600 MHz, CDCl3)
d
(ppm): 8.91 (d, J¼8.1 Hz, 1H, CH), 7.97 (d,
CDCl3)
d
187.1, 147.5, 138.1, 136.9, 136.8, 135.7, 133.4, 132.5, 130.2,
J¼7.4 Hz, 1H, CH), 7.70 (d, J¼7.8 Hz, 1H, ArH), 7.64 (t, J¼7.5 Hz, 1H,
ArH), 7.62e7.57 (m, 3H, ArH), 7.52 (d, J¼8.1 Hz, 2H, ArH), 7.08 (d,
J¼7.4 Hz, 1H, ArH), 3.81 (q, J¼6.7 Hz, 1H, CH2), 3.33 (q, J¼6.7 Hz, 1H,
CH2), 3.13 (q, J¼7.0 Hz, 1H, CH2), 2.79 (q, J¼6.9 Hz, 1H, CH2), 1.21 (t,
J¼6.9 Hz, 3H, CH3), 0.69 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (150 MHz,
129.8, 129.5, 129.3, 129.0, 128.0, 127.4, 125.8, 124.4, 124.0, 123.5,
122.9, 122.8, 116.6, 116.0, 86.8. MS (m/z): 418.56 ([Mþ1]þ, 100%).
Anal. Calcd for C26H15N3O3: C 74.81, H 3.62, N 10.07. Found: C 74.67,
H 3.99, N 9.64.
CDCl3)
d 161.6, 134.9, 132.2, 130.5, 128.9, 128.7, 128.4, 127.7, 127.4,
3.4. General procedure for the synthesis of pyrrolo[2,1-a]-
isoquinolines 4mer
124.1, 123.3, 122.9, 122.5, 119.2, 117.7, 114.8, 83.3, 43.1, 39.4, 14.0,
12.4. MS (m/z): 448.64 ([Mþ1]þ, 100%), 446.55 ([Mþ3]þ, 80%). Anal.
Calcd for C24H20BrN3O: C 64.58, H 4.52, N 9.41. Found: C 64.25, H
4.79, N 9.11.
In a 50 mL round bottom flask a mixture of N,N-diethyl chlor-
oacetamide (2.2 mmol, 0.329 g) and isoquinoline (3.0 mmol,
0.388 g) in 10 mL of ethanol was heated at 50 ꢀC for about 5 h. Then
aromatic aldehyde (2.0 mmol), cyanoacetamide (2.0 mmol,
0.168 g), and triethylamine (4.0 mmol, 0.404 g) were added to it.
The solution was stirred at 50 ꢀC for additional 6e8 h . Then the
DDQ (4.0 mmol, 0.908 g) was added. The resulting mixture was
stirred at room temperature for 8 h. The resulting precipitates were
collected by filtration and washed with cold alcohol. The crude
Compound 4q: White solid, yield: 60%, mp 196 ꢀC, IR (KBr): 2960
(w), 2224 (w), 1621 (w), 1523 (m), 1480 (w), 1459 (m), 1347 (m),
1380 (m), 1312 (w), 1278 (w), 1212 (w), 788 (m). 1H NMR (600 MHz,
CDCl3)
d
(ppm): 8.92 (d, J¼7.7 Hz, 1H, CH), 8.00 (d, J¼7.3 Hz, 1H,
ArH), 7.71 (d, J¼7.7 Hz, 1H, CH), 7.66e7.63 (m, 1H, ArH), 7.61e7.57
(m, 3H, ArH), 7.45e7.39 (m, 2H, ArH), 7.09 (d, J¼7.3 Hz, 1H, ArH),
3.93 (q, J¼6.7 Hz, 1H, CH2), 3.22 (q, J¼6.7 Hz, 1H, CH2), 3.14 (q,
J¼7.0 Hz, 1H, CH2), 2.77 (q, J¼7.0 Hz, 1H, CH2), 1.20 (t, J¼7.0 Hz, 3H,

2320
Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
CH3), 0.69 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
d
161.5,
d 170.5, 165.5, 136.2, 134.9, 134.5, 132.5, 130.3, 129.5, 129.2, 128.8,
135.0,134.8, 133.1,130.3,128.9, 128.7, 128.6, 128.5, 127.5,127.4,127.1,
124.2, 123.4, 122.6, 119.5, 117.6, 114.8, 83.4, 43.1, 39.4, 13.9, 12.3. MS
(m/z): 402.65 ([Mþ1]þ, 100%). Anal. Calcd for C24H20ClN3O: C 71.73,
H 5.02, N 10.46. Found: C 71.40, H 5.38, N 10.15.
126.6, 126.1, 126.0, 125.1, 124.8, 117.3, 100.1, 69.5, 69.2, 63.9, 62.1,
53.3, 14.1. MS (m/z): 422.60 ([Mþ1]þ, 100%), 424.81 ([Mþ3]þ, 27%).
Anal. Calcd for C23H20ClN3O3: C 65.48, H 4.78, N 9.96. Found: C
65.17, H 5.12, N 9.47.
Compound 4r: White solid, yield: 63%, mp 184e186 ꢀC, IR (KBr):
2976 (w), 2207 (m), 1616 (vs), 1524 (s), 1435 (m), 1377 (m), 1345 (s),
1270 (m), 1212 (w), 1151 (w), 861 (w), 794 (w). 1H NMR (600 MHz,
Compound 3d: White solid, yield: 80%, mp 166 ꢀC, IR (KBr): 3184
(m), 2987 (w), 1745 (s), 1691 (vs), 1625 (m), 1531 (s), 1490 (w), 1347
(s), 1305 (m), 1207 (m), 796 (m), 698 (m). 1H NMR (600 MHz, CDCl3)
CDCl3)
d
(ppm): 8.93 (d, J¼8.1 Hz, 1H, CH), 8.48 (s, 1H, ArH), 8.29 (d,
d
(ppm): 8.32 (s, 1H, ArH), 8.23 (d, J¼8.1 Hz, 1H, ArH), 7.81 (d,
J¼8.1 Hz, 1H, CH), 8.04 (d, J¼7.6 Hz, 1H, ArH), 7.98 (d, J¼7.3 Hz, 1H,
ArH), 7.74 (d, J¼7.7 Hz, 1H, ArH), 7.69 (q, J¼7.8 Hz, 2H, ArH), 7.63 (t,
J¼7.0 Hz, 1H, ArH), 7.14 (d, J¼7.3 Hz, 1H, ArH), 3.87 (q, J¼5.7 Hz, 1H,
CH2), 3.30 (q, J¼5.8 Hz, 1H, CH2), 3.17 (q, J¼6.3 Hz, 1H, CH2), 2.83 (q,
J¼6.4 Hz, 1H, CH2), 1.18 (t, J¼6.3 Hz, 3H, CH3), 0.73 (t, J¼6.3 Hz, 3H,
J¼7.7 Hz, 1H, ArH), 7.59 (t, J¼8.0 Hz, 1H, ArH), 7.23 (t, J¼7.5 Hz, 1H,
ArH), 7.06e7.01 (m, 2H, ArH), 6.97 (d, J¼7.6 Hz, 1H, ArH), 6.27 (d,
J¼7.6 Hz, 1H, CH), 6.10 (s, 2H, NH), 5.62 (s, 1H, CH), 5.41 (d, J¼7.6 Hz,
1H, CH), 4.57 (d, J¼8.5 Hz, 1H, CH), 4.54 (d, J¼8.5 Hz, 1H, CH),
4.22e4.19 (m, 2H, CH2), 1.23 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
CH3). 13C NMR (150 MHz, CDCl3)
d
161.3, 148.6, 135.2, 134.9, 133.2,
(150 MHz, CDCl3) d 170.2, 165.1, 148.1, 136.5, 134.6, 134.5, 132.4,
130.1, 129.2, 128.9, 128.5, 127.5, 126.2, 124.1, 123.7, 123.4, 123.3,
119.9, 117.3, 115.2, 83.4, 43.2, 39.5, 14.1, 12.4. MS (m/z): 413.77
([Mþ1]þ, 100%). Anal. Calcd for C24H20N4O3: C 69.89, H 4.89, N
13.58. Found: C 69.50, H 5.13, N 13.26.
130.2, 129.6, 126.2, 126.0, 125.2, 124.6, 123.9, 123.5, 117.1, 100.3, 69.7,
69.2, 63.8, 62.3, 53.0, 14.1. MS (m/z): 433.77 ([Mþ1]þ, 100%). Anal.
Calcd for C23H20N4O5: C 63.88, H 4.66, N 12.96. Found: C 63.65, H
4.83, N 12.67.
3.5. General procedure for the preparation of
3.6. General procedure for the preparation of
tetrahydropyrrolo[2,1-a]isoquinolines 3aeg
tetrahydropyrrolo[2,1-a]isoquinolines 3eeg
In an atmosphere of nitrogen a mixture of ethyl
a
-bromoacetate
In nitrogen atmosphere a mixture of p-nitrobenzyl bromide
(2.2 mmol, 0.475 g) and isoquinoline (3.0 mmol, 0.388 g) in 10 mL
of ethanol was heated at 50 ꢀC for about 4 h. Then aromatic alde-
hyde (2.0 mmol), cyanoacetamide (2.0 mmol, 0.168 g), and trie-
thylamine (4.0 mmol, 0.404 g) were added to it. The solution was
stirred at 50 ꢀC for additional 8e12 h . The resulting precipitates
were collected by filtration and washed with cold alcohol. The
crude product was recrystallized in chloroform/ethanol to give the
pure product for analysis.
(2.2 mmol, 0.367 g) and isoquinoline (3.0 mmol, 0.388 g) in 10 mL
of ethanol was stirred at room temperature for about 1.5 h . Then
aromatic aldehyde (2.0 mmol), cyanoacetamide (2.0 mmol,
0.168 g), and triethylamine (4.0 mmol, 0.404 g) were added to it.
The solution was stirred at room temperature for additional 6 h.
The resulting precipitates were collected by filtration and washed
with cold alcohol. The crude product was recrystallized in chloro-
form/ethanol to give the pure product.
Compound 3a: White solid, yield: 82%, mp 162 ꢀC, IR (KBr): 3445
(m), 3335 (m), 2980 (w), 1745 (s), 1698 (vs), 1612 (s), 1584 (m), 1515
(s), 1460 (m), 1364 (m),1257 (s),1181 (s), 1027 (m), 773 (m). 1H NMR
Compound 3e: Yellow solid, yield: 63%, mp 130 ꢀC, IR (KBr): 2962
(w), 1703 (m), 1668 (s), 1632 (m), 1599 (m), 1524 (s), 1460 (w), 1349
(vs), 937 (w), 854 (w), 770 (m). 1H NMR (600 MHz, CDCl3)
d (ppm):
(600 MHz, CDCl3)
d
(ppm): 7.38 (d, J¼7.9 Hz, 2H, ArH), 7.20 (t,
8.14 (d, J¼8.7 Hz, 1H, ArH), 7.41e7.37 (m, 6H, ArH), 7.23 (t, J¼7.6 Hz,
1H, ArH), 7.06 (t, J¼7.4 Hz, 1H, ArH), 7.03e7.00 (m, 2H, ArH), 6.10 (d,
J¼7.5 Hz, 1H, CH), 5.99 (s, 1H, NH), 5.89 (s, 1H, CH), 5.66 (s, 1H, NH),
5.38 (d, J¼7.5 Hz, 1H, CH), 5.20 (d, J¼9.7 Hz, 1H, CH), 3.92 (d,
J¼9.7 Hz, 1H, CH), 1.32 (s, 9H, (CH3)3). 13C NMR (150 MHz, CDCl3)
J¼6.8 Hz, 1H, ArH), 7.03 (t, J¼6.5 Hz, 1H, ArH), 6.99 (t, J¼9.5 Hz, 2H,
ArH), 6.91 (d, J¼8.0 Hz, 2H, CH), 6.23 (d, J¼7.2 Hz, 1H, CH), 5.98 (s,
1H, NH), 5.68 (s, 1H, CH), 5.63 (s, 1H, NH), 5.36 (d, J¼7.2 Hz, 1H, CH),
4.49 (d, J¼8.6 Hz, 1H, CH), 4.33 (d, J¼8.6 Hz, 1H, CH), 4.21e4.18 (m,
2H, CH2), 3.81 (s, 3H, CH3O), 1.23 (t, J¼6.0 Hz, 3H, CH3). 13C NMR
d
165.5, 134.2, 132.3, 129.4, 128.4, 128.2, 127.6, 127.4, 127.0, 126.8,
(150 MHz, CDCl3)
d
170.8, 165.9, 160.0, 134.6, 133.3, 132.6, 129.7,
126.7, 126.2, 126.0, 125.9, 125.1, 124.7, 124.1, 107.1, 99.7, 74.7, 70.3,
68.9, 64.3, 59.1, 57.1, 34.7, 34.6, 31.3, 31.2. MS (m/z): 493.69 ([Mþ1]þ,
100%). Anal. Calcd for C30H28N4O3: C 73.15, H 5.73, N 11.37. Found: C
72.84, H 5.85, N 11.13.
129.3, 126.0, 125.9, 125.6, 125.1, 124.9, 117.7, 114.8, 114.4, 99.8, 69.2,
69.1, 64.0, 61.9, 55.3, 53.5, 14.1. MS (m/z): 418.67 ([Mþ1]þ, 100%).
Anal. Calcd for C24H23N3O4: C 69.05, H 5.55, N 10.07. Found: C 68.72,
H 5.76, N 9.80.
Compound 3f: Yellow solid, yield: 73%, mp 158 ꢀC, IR (KBr): 3057
(w), 1696 (s), 1629 (m), 1589 (m), 1518 (m), 1493 (m), 1461 (w), 1347
Compound 3b: White solid, yield: 76%, mp 148e150 ꢀC, IR (KBr):
3176 (m), 2900 (w), 1742 (m), 1698 (s), 1615 (m), 1458 (w), 1380 (m),
1344 (w), 1263 (w), 1211 (s), 763 (w). 1H NMR (600 MHz, CDCl3)
(vs), 1109 (w), 937 (w), 764 (m). 1H NMR (600 MHz, CDCl3)
d (ppm):
8.15 (d, J¼8.7 Hz,1H, ArH), 7.55 (d, J¼8.5 Hz, 2H, ArH), 7.38e7.35 (m,
4H, ArH), 7.24 (d, J¼7.6 Hz, 1H, ArH), 7.08 (t, J¼7.4 Hz, 1H, ArH), 7.03
(d, J¼7.5 Hz, 1H, ArH), 6.98 (d, J¼7.6 Hz, 1H, ArH), 6.08 (d, J¼7.5 Hz,
1H, CH), 6.03 (s, 1H, NH), 5.86 (s, 1H, CH), 5.67 (s, 1H, NH), 5.39 (d,
J¼7.5 Hz, 1H, CH), 5.16 (d, J¼9.7 Hz, 1H, CH), 3.93 (d, J¼9.7 Hz, 1H,
d
(ppm): 7.44e7.43 (m, 2H, ArH), 7.39e7.34 (m, 3H, ArH), 7.20 (t,
J¼7.4 Hz, 1H, ArH), 7.03e6.96 (m, 3H, ArH), 6.24 (d, J¼7.6 Hz, 1H,
CH), 6.07 (s, 1H, NH), 6.02 (s, 1H, NH), 5.66 (s, 1H, CH), 5.35 (d,
J¼7.6 Hz, 1H, CH), 4.54 (d, J¼8.5 Hz, 1H, CH), 4.37 (d, J¼8.5 Hz, 1H,
CH), 4.17 (q, 2H, CH2), 1.20 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (150 MHz,
CH). 13C NMR (150 MHz, CDCl3)
d 152.4, 148.3, 146.2, 139.9, 134.7,
CDCl3)
d
170.7, 165.8, 134.6, 134.0, 132.6, 129.4, 129.0, 128.9, 128.5,
132.6, 132.5, 132.4, 130.5, 129.3, 127.9, 127.8, 127.5, 126.8, 126.7,
126.6, 124.8, 124.3, 122.5, 122.2, 107.5, 74.7, 70.1, 57.1. MS (m/z):
515.69 ([Mþ1]þ, 100%), 517.08 ([Mþ3]þ, 36%). Anal. Calcd for
C26H19BrN4O3: C 60.59, H 3.72, N 10.87. Found: C 60.34, H 4.23, N
10.30.
126.0, 125.9, 125.0, 117.6, 99.8, 69.3, 69.2, 64.0, 61.9, 53.9, 14.1. MS
(m/z): 388.88 ([Mþ1]þ, 100%). Anal. Calcd for C23H21N3O3: C 71.30,
H 5.46, N 10.85. Found: C 71.26, H 5.80, N 10.53.
Compound 3c: White solid, yield: 68%, mp 160e162 ꢀC, IR (KBr):
3186 (m), 2989 (w),1744 (s),1698 (vs),1627 (m),1491 (w),1424 (m),
1380 (m), 1199 (s), 1110 (w), 764 (w). 1H NMR (600 MHz, CDCl3)
Compound 3g: Yellow solid, yield: 82%, mp 142e144 ꢀC, IR (KBr):
3163 (w), 2853 (vw), 1703 (vs), 1620 (m), 1521 (m), 1459 (w), 1347
d
(ppm): 7.43 (s, 1H, ArH), 7.36e7.32 (m, 3H, ArH), 7.22 (t, J¼7.3 Hz,
(s), 1109 (w), 856 (w), 769 (m). 1H NMR (600 MHz, CDCl3)
d (ppm):
1H, ArH), 7.06e6.97 (m, 3H, ArH), 6.24 (d, J¼7.3 Hz, 1H, CH), 6.03 (s,
1H, NH), 5.73 (s, 1H, NH), 5.63 (s, 1H, CH), 5.39 (d, J¼7.4 Hz, 1H, CH),
4.50 (d, J¼8.5 Hz, 1H, CH), 4.38 (d, J¼8.4 Hz, 1H, CH), 4.23e4.20 (m,
2H, CH2), 1.24 (t, J¼6.2 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
8.16 (d, J¼8.5 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 7.39e7.36 (m, 5H, ArH),
7.24 (d, J¼7.5 Hz, 1H, ArH), 7.08 (t, J¼7.4 Hz, 1H, ArH), 7.03 (d,
J¼7.5 Hz, 1H, ArH), 6.99 (d, J¼7.5 Hz, 1H, ArH), 6.10 (d, J¼7.5 Hz, 1H,
CH), 6.06 (s, 1H, NH), 5.85 (s, 1H, CH), 5.77 (s, 1H, NH), 5.40 (d,

Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
2321
J¼7.5 Hz, 1H, CH), 5.18 (d, J¼9.6 Hz, 1H, CH), 3.94 (d, J¼9.6 Hz, 1H,
CH). 13C NMR (150 MHz, CDCl3)
152.5, 148.3, 146.7, 143.1, 135.2,
140.3,134.8,132.3,129.1,129.0,127.3,126.6,126.4,122.5,121.9,121.0,
106.5, 71.3, 70.1, 62.7, 50.5, 14.2. MS (m/z): 423.84 ([Mþ1]þ, 100%),
421.93 ([Mþ3]þ, 39%). Anal. Calcd for C22H17BrN2O2: C 62.72, H 4.07,
N 6.65. Found: C 62.50, H 4.39, N 6.51.
d
134.7, 132.6, 130.7, 128.5, 128.0, 127.8, 127.6, 127.5, 127.4, 126.9,
126.8, 126.7, 126.6, 125.8, 124.8, 124.3, 122.5, 121.1, 107.6, 74.6, 70.0,
57.2. MS (m/z): 471.50 ([Mþ1]þ, 100%), 473.51 ([Mþ3]þ, 20%). Anal.
Calcd for C26H19ClN4O3: C 66.31, H 4.07, N 11.90. Found: C 66.21, H
4.38, N 11.83.
Compound 2e: Yellow solid, yield: 54%, mp 138 ꢀC, IR (KBr): 2982
(w), 2165 (s), 1745 (s), 1631 (m), 1553 (vs), 1468 (w), 1392 (w), 1313
(w),1246 (m),1202 (m), 874 (w), 785 (w). 1H NMR (600 MHz, CDCl3)
d
(ppm): 8.63 (d, J¼8.1 Hz, 1H, ArH), 7.54 (t, J¼7.5 Hz, 1H, ArH),
3.7. General procedure for the preparation of dihydropyrrolo
[2,1-a]isoquinoline 2aef
7.40e7.36 (m, 2H, ArH), 7.33(s,1H, ArH), 7.32e7.24 (m, 3H, ArH), 6.71
(d, J¼7.2 Hz,1H, CH), 6.18 (d, J¼7.2 Hz,1H, CH), 4.61 (d, J¼5.0 Hz,1H,
CH), 4.51 (d, J¼5.0 Hz, 1H, CH), 4.37e4.27 (m, 2H, CH2), 1.34 (t,
A mixture of ethyl
a
-bromoacetate (2.2 mmol, 0.367 g) and
J¼7.1 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
d 169.2, 152.2, 143.4,
isoquinoline (3.0 mmol, 0.388 g) in 10 mL of ethanol was stirred at
room temperature about 4 h. Then aromatic aldehyde (2.0 mmol),
cyanoacetamide (2.0 mmol, 0.186 g), and triethylamine (4.0 mmol,
0.404 g) were added to it. The solution was stirred at room tem-
perature for additional 6 h . Then the DDQ (2.0 mmol, 0.454 g) was
added. The resulting mixture was stirred at room temperature for
2e4 h . The resulting precipitates were collected by filtration and
washed with cold alcohol. The crude product was recrystallized in
chloroform/ethanol to give the pure product.
135.0,134.8,132.3,130.5,129.1,128.3,127.4,127.3,126.6,126.5,125.5,
122.5, 121.0, 106.6, 71.3, 69.9, 62.7, 50.6, 14.2. MS (m/z): 377.66
([Mþ1]þ, 100%), 380.49 ([Mþ3]þ, 36%). Anal. Calcd for
C22H17ClN2O2: C 70.12, H 4.55, N 7.43. Found: C 69.85, H 4.68, N 7.29.
Compound 2f: Yellow solid, yield: 65%, mp 150 ꢀC, IR (KBr): 2987
(w), 2168 (s),1748 (m),1631 (m),1553 (vs),1538 (vs),1488 (w),1348
(m), 1321 (m), 1239 (m), 1210 (m), 810 (m), 783 (m). 1H NMR
(600 MHz, CDCl3)
d
(ppm): 8.63 (d, J¼8.1 Hz, 1H, ArH), 8.23 (s, 1H,
ArH), 8.18 (d, J¼8.1 Hz, 1H, ArH), 7.73 (d, J¼7.6 Hz, 1H, ArH),
7.59e7.55 (m, 2H, ArH), 7.44e7.39 (m, 2H, ArH), 6.76 (d, J¼7.2 Hz,1H,
CH), 6.24 (d, J¼7.2 Hz, 1H, CH), 4.68 (q, J¼5.5 Hz, 2H, CH), 4.40e4.30
(m, 2H, CH2), 1.37 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3)
Compound 2a: Yellow solid, yield: 65%, mp 162e164 ꢀC, IR (KBr):
2966 (w), 2170 (s), 1741 (m), 1692 (w), 1630 (m), 1552 (s), 1512 (m),
1247 (s), 1205 (m), 1177 (m), 1031 (m), 781 (m). 1H NMR (600 MHz,
CDCl3)
d
(ppm): 8.63 (d, J¼8.0 Hz, 1H, ArH), 7.52 (t, J¼7.3 Hz, 1H,
d 168.9, 152.6, 148.8, 143.4, 134.8, 133.7, 132.6, 130.3, 128.9, 127.4,
ArH), 7.38 (t, J¼7.46 Hz, 1H, ArH), 7.35 (d, J¼7.7 Hz, 1H, ArH), 7.27 (s,
2H, ArH), 6.90 (d, J¼8.1 Hz, 2H, ArH), 6.68 (d, J¼7.1 Hz,1H, ArH), 6.15
(d, J¼7.0 Hz, 1H, ArH), 4.59 (d, J¼4.7 Hz, 1H, CH), 4.48 (d, J¼4.4 Hz,
1H, CH), 4.38e4.26 (m, 2H, CH2), 3.80 (s, 3H, CH3O),1.35 (t, J¼7.0 Hz,
126.7,126.5,123.1,122.5,122.3,120.8,107.1, 71.0, 69.4, 63.0, 50.6,14.2.
MS (m/z): 388.78 ([Mþ1]þ, 100%). Anal. Calcd for C22H17N3O4: C
68.85, H 4.42, N 10.85. Found: C 68.76, H 4.77, N 10.45.
3H, CH3). 13C NMR (150 MHz, CDCl3)
d 169.7, 159.3, 151.7, 134.8,
Acknowledgements
133.5, 132.0, 131.3, 129.5, 129.2, 128.6, 128.3, 127.2, 126.5, 112.7,
121.4, 114.5, 113.3, 106.2, 71.7, 71.1, 62.5, 55.3, 50.5, 14.2. MS (m/z):
373.58 ([Mþ1]þ, 100%). Anal. Calcd for C23H20N2O3: C 74.18, H 5.41,
N 7.52. Found: C 73.89, H 5.93, N 7.28.
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 20972132).
Compound 2b: Yellow solid, yield: 68%, mp 144e146 ꢀC, IR (KBr):
3157 (s), 2784 (w), 2218 (m), 1694 (vs), 1591 (vs), 1506 (w), 1371 (s),
1213 (m), 1181 (m), 819 (m), 791 (m). 1H NMR (600 MHz, CDCl3)
Supplementary data
d
(ppm): 8.63 (d, J¼7.8 Hz,1H, ArH), 7.52 (t, J¼6.7 Hz,1H, ArH), 7.38 (t,
Experimental details and characterization data including 1H and
13C NMR spectra for new compounds are available free of charge via
the internet. Crystallographic data (1b: CCDC 785001; 2b: CCDC
785003; 3g: CCDC 785002; 4d: CCDC 785005; 4i: CCDC 785004)
have been deposited via the Cambridge Crystallographic Database
Centre and is available on request (http://www.ccdc.cam.ac.uk/).
Supplementary data associated with this article can be found
online at doi:10.1016/j.tet.2011.01.046.
J¼6.9 Hz, 1H, ArH), 7.35 (d, J¼7.4 Hz, 1H, ArH), 7.24 (d, J¼6.8 Hz, 2H,
ArH), 7.18 (d, J¼7.2 Hz, 2H, ArH), 6.68 (d, J¼6.1 Hz, 1H, CH), 6.15 (d,
J¼6.2 Hz,1H, CH), 4.61 (s,1H, CH), 4.48 (s,1H, CH), 4.36e4.27 (m, 2H,
CH2), 2.34 (s, 3H, CH3),1.34 (t, J¼6.8 Hz, 3H, CH3).13C NMR (150 MHz,
CDCl3)
d 169.6, 151.8, 138.4, 137.7, 134.8, 132.1, 129.8, 129.2, 127.2,
127.1, 126.5, 126.4, 122.7, 121.3, 106.2, 77.2, 71.6, 71.0, 62.5, 50.8, 21.1,
14.2. MS (m/z): 359.45 ([Mþ1]þ,100%). Anal. Calcd for C23H20N2O2: C
77.51, H 5.66, N 7.86. Found: C 77.29, H 5.94, N 7.66.
Compound 2c: Yellow solid, yield: 60%, mp 158e160 ꢀC, IR (KBr):
3046, 2166 (s),1741 (s), 1631 (m),1567 (vs),1489 (w),1463 (w), 1391
(m), 1329 (w), 1224 (m), 786 (w), 769 (w). 1H NMR (600 MHz,
References and notes
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d
(ppm): 8.63 (d, J¼7.9 Hz, 1H, ArH), 7.52 (t, J¼7.4 Hz, 1H,
ArH), 7.40e7.36 (m, 6H, ArH), 7.30 (d, J¼5.0 Hz, 1H, ArH), 6.7 (d,
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(w), 2219 (m), 1621 (s), 1519 (m), 1393 (m), 1372 (m), 1347 (s), 1292
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(ppm): 8.62 (d, J¼8.1 Hz, 1H, ArH), 7.53 (t, J¼7.5 Hz, 1H, ArH), 7.49
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2322
Y. Han et al. / Tetrahedron 67 (2011) 2313e2322
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