A three-component domino protocol for the facile synthesis of highly functionalized tetrahydroisoquinolines by creation of their benzene ring

Article abstract of DOI:10.1016/j.tet.2010.12.052

A simple and efficient one-pot synthesis of novel 6-amino-8-aryl-2-methyl/ benzyl-7-nitro-1,2,3,4-tetrahydroisoquinoline-5-carbonitriles from the reaction of 1-methyl/benzylpiperidin-4-one with β-nitrostyrenes and malononitrile in the presence of morpholi

Full text of DOI:10.1016/j.tet.2010.12.052

Tetrahedron 67 (2011) 1432e1437
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A three-component domino protocol for the facile synthesis of highly
functionalized tetrahydroisoquinolines by creation of their benzene ring
,
b,
Kamaraj Balamurugan a, Veerappan Jeyachandran a, Subbu Perumal a , J. Carlos Menendez
*
*
ꢀ
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b
ꢀ
ꢀ
Departamento de Química Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient one-pot synthesis of novel 6-amino-8-aryl-2-methyl/benzyl-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-5-carbonitriles from the reaction of 1-methyl/benzylpiperidin-4-one with -nitro-
styrenes and malononitrile in the presence of morpholine is described. This transformation proceeds
through the creation of three C]C bonds, leading to a new benzene ring, and presumably occurs via
a domino sequence involving Knoevenagel, Michael, ThorpeeZiegler, and dehydrogenation reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 November 2010
Received in revised form 16 December 2010
Accepted 17 December 2010
Available online 30 December 2010
b
CH3 OH
1. Introduction
NH
OH
HN
H3C
H3C
The field of isoquinoline alkaloids is truly enormous and com-
prises 22 subgroups,1 one of which is simple isoquinoline alkaloids,
i.e., derivatives of the parent bicyclic system without additional
fused rings. Among them, compounds derived from the tetrahy-
droisoquinoline skeleton 1 are particularly interesting. They in-
clude cactus alkaloids,2 several mammalian alkaloids,3 and the
spirobenzylisoquinoline alkaloids.4 Many tetrahydroisoquinoline
alkaloids show interesting biological activities. Thus, the closely
related cherylline5 and latifine6 are the active components of Cri-
num powellii and Crinum latifolium, respectively, which find use in
Vietnamese and Chinese traditional medicines.7 Michellamine B,
isolated from the tropical liana Ancistrocladus korupensis and hav-
ing a naphthyltetrahydroisoquinoline skeleton with axial chirality
between the naphthalene and tetrahydroisoquinoline rings,8 has
been found to be fully protective against both HIV-1 and HIV-2
1
OH
OH OCH3
R5
H3CO
OH
HO
CH3
CH3
H3CO
R7
N
CH3
NH
OH CH3
R5 = H, R7 = OH Cherylline
R5 = OH, R7 = H Latifine
Michellamine B
OH
Cl
Cl
infected cells and identified as
a candidate for further de-
velopment,9 although its cytotoxicity precluded its clinical use. The
tetrahydroisoquinoline structural motif is also present in a large
number of synthetic bioactive molecules,10 including the antide-
pressant drugs nomifensine and dichlofensine,11 which inhibit se-
rotonin and dopamine uptake mechanisms.
N
N
CH3
H3CO
CH3
NH2
Dichlofensine
Nomifensine
The biological importance of tetrahydroisoquinolines has stimu-
lated the development of a large number of synthetic approaches to
this ring system. Traditionally, they have been accessed by ring clo-
sure of iminium intermediates via PicteteSpengler reactions.12 Other
synthetic entries include intramolecular Horner13 or FriedeleCrafts
reactions,14 followed by reduction, reductive amination-transfer
hydrogenation,15 electrophilic aromatic substitution,16 Pd(II)- or Ag
(I)-catalyzed N-alkylation,17 and palladium-catalyzed alkylation/
alkenylation-aza-Michael addition reactions.18 However, these
methods require multistep sequences and are not focused on
achieving synthetic efficiency by application of the contemporary
methods involving the generation of several bonds in a single
* Corresponding authors. Tel./fax: þ91 452 2459845; e-mail addresses: subbu.
ꢀ
perum@gmail.com (S. Perumal), josecm@farm.ucm.es (J.C. Menendez).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.052

K. Balamurugan et al. / Tetrahedron 67 (2011) 1432e1437
1433
operation.19 Among these methods, multi-component reactions
(MCRs),20,21 which allow the simple and flexible assembly of three or
more building blocks in user-friendly one-pot operations, provide
convergent, atom-economic, expedient, and eco-friendly synthetic
protocols for the discovery of new chemical entities (NCEs) useful in
pharmaceutical and agrochemical industries, often on the basis of
combinatorial library generation.22 However, a large part of the work
carried out so far on multi-component reactions pertains to the
preparation of peptide-like structures employing isocyanides as
buildingblocks. The constructionofheterocycles through MCR-based
strategies is not so well developed, despite the fact that about 60% of
the drugs currentlyinthemarketorinthepipelineareheterocycles.23
For the specific case of tetrahydroisoquinolines, only a few examples
of multi-component syntheses are known.24,25
This model reaction was then performed in THF, 1,4-dioxane, and
methanol, which led to an enhancement of the isolated yield of the
product to 34%, 45%, and 54% of 5a, respectively (Table 1, entries
2e4). In ethanol, the reaction was completed in 5 h furnishing an
isolated yield of 78% of 5a (Table 1, entry 10), whilst the reaction
completely failed to occur in DMSO, DMF, and dichloromethane
(Table 1, entries 5e7), wherein the starting materials remained
unchanged. This result suggests that polar protic solvents are fa-
vorable for the reaction, perhaps by stabilizing a key intermediate
through hydrogen bonding, although the reason for the marked
difference in yield between methanol and ethanol is not clear.
CN
H2N
As a part of our recent research program aimed at the de-
velopment of new one-pot tandem/domino multi-component pro-
tocols for the assembly of novel heterocycles26 and/or the discovery
of newlead molecules with antimycobacterial activities,27 we report
here a one-pot, three-component protocol for the synthesis of
substituted tetrahydroisoquinolines based on a domino reaction
N
O2N
CH3
5a
CH3
between 1-alkylpiperidin-4-ones, malononitrile and b-nitrostyrene
(Fig. 1). Interestingly, this strategy involves the construction of the
benzene ring from a heterocyclic precursor, a disconnection almost
unknown in tetrahydroisoquinoline synthesis and that has never
been translated into a multi-component protocol.28
The product yield was influenced by the nature and the amount
of base (Table 1, entries 8e15). Thus, an attempt to reduce the
amount of morpholine led to diminished yields (entries 8e10).
Furthermore, the efficacy of the bases assayed changed in the order:
K2CO3<NaOEt<triethylamine<diethylamineztriethanolamine<mor-
pholine (entries 11e15). From these results, morpholine and
ethanol emerged as the ideal choice of baseesolvent combination
for these domino reactions. The higher efficacy of organic bases, viz.
morpholine, triethanolamine, and triethylamine in this reaction
suggests that their conjugate acids presumably enhance the elec-
trophilicity of (i) piperidone 2 toward Knoevenagel condensation
Knoevenagel
Thorpe-
NC
Ziegler
H2N
O2N
N
R
Ar
Michael
with malononitrile and (ii) b-nitrostyrene toward Michael addition.
The lower yield of 5a obtained in the presence of triethanolamine
and triethylamine suggests steric hindrance for the abstraction of
proton from 7, which could slow down the Michael addition rela-
tive to the reaction in the presence of morpholine. The fact that the
reaction proceeds more efficiently in the presence of 2 equiv of
morpholine is ascribable to the reversible Michael addition of the
latter to the Knoevenagel condensation product, competing with its
desired addition to b-nitrostyrene, which could diminish the ef-
fective concentration of the free base in the reaction mixture (see
Scheme 2).
Fig. 1. Disconnections used in this work for the construction of the tetrahy-
droisoquinoline system.
2. Results and discussion
We started our optimization studies by carrying out the reaction
between 1-methylpiperidin-4-one, malononitrile, and (E)-1-
methyl-4-[2-nitro-1-ethenyl]benzene, in equimolecular amounts,
using morpholine as the base and refluxing acetonitrile as the
solvent. After 10 h, the domino reaction provided a promising 25%
isolated yield of 6-amino-8-(4-methylphenyl)-2-methyl-7-nitro-
1,2,3,4-tetrahydroisoquinoline-5-carbonitrile 5a (Table 1, entry 1).
The optimal conditions thus established were then applied to
the preparation of a library of 6-amino-8-aryl-2-methyl(benzyl)-7-
nitro-1,2,3,4-tetrahydroisoquinoline-5-carbonitriles 5 from piper-
idones 2, malononitrile 3, and
b-nitrostyrenes 4. The reactions
Table 1
proceeded in 60e79% isolated yields (71% average), which are re-
markable considering the large number of individual steps involved
(Scheme 1 and Table 2).
Solvent- and base-screen for the synthesis of 5a
Entry
Solvent
Base (equiv)
Time, h
Yield of 5aa (%)
1
2
3
4
5
6
7
8
CH3CN
THF
1,4-Dioxane
MeOH
DMSO
DMF
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (1)
Morpholine (1.5)
Morpholine (2)
Triethanolamine (2)
Diethylamine (2)
Triethylamine (2)
NaOEt (2)
10
10
12
7
10
10
10
10
7
5
5
5
5
25
34
45
54
0b
O
NC
CN
CN
Morpholine, EtOH,
reflux, 4 h
3
H2N
O2N
0b
N
N
O2N
0b
R
45
60
78
72
70
55
50
35
R
2
Ar
Ar
9
5
4
10
11
12
13
14
15
Scheme 1.
The structure of 6-amino-8-aryl-2-methyl-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-5-carbonitriles 5 is in agreement with one and
two-dimensional NMR spectroscopic data as described below for
the case of 5a as a representative example. In the 1H NMR spectrum
EtOH
EtOH
5
5
K2CO3 (2)
a
Isolated yield after purification by column chromatography.
No reaction took place.
b

1434
K. Balamurugan et al. / Tetrahedron 67 (2011) 1432e1437
Table 2
Yields of 6-amino-8-aryl-2-methyl/benzyl-7-nitro-1,2,3,4-tetrahydroisoquinoline-
5-carbonitriles 5
Entry
R
Cmpd
Ar
Yield of 5a (%)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
4-MeC6H4
4-iPrC6H4
4-MeOC6H4
4-BrC6H4
4-FC6H4
2,4-Cl2C6H3
2-MeOC6H4
3-BrC6H4
4-MeC6H4
4-iPrC6H4
4-ClC6H4
78
71
68
60
69
62
68
72
74
72
76
79
68
70
9
10
11
12
13
14
4-BrC6H4
4-FC6H4
2,4-Cl2C6H3
a
Isolated yield after purification by column chromatography.
of 5a, the 3-CH2 hydrogens appearing as a triplet at 2.67 ppm
(J¼5.7 Hz) showed HMBC correlations with C-1, C-4, and C-4a,
appearing, respectively, at 55.8, 29.4, and 143.0 ppm. The triplet
from 4-CH2 hydrogens at 3.08 ppm (J¼5.7 Hz) showed (i) HeH-
COSY correlation with 3-CH2 hydrogens (ii) CeH-COSY correlation
with C-4 at 29.4 ppm, and (iii) HMBCs with C-4a at 143.0 ppm, C-5
at 98.6 ppm, C-8a at 124.6 ppm. The singlet of 1-CH2 hydrogens at
3.04 ppm showed (i) a CeH-COSY correlation with carbon signal at
55.8 ppm due to C-1 and (ii) HMBCs with C-4a at 143.0 ppm and
C-8a at 124.6 ppm. The 2H singlet at 5.37 ppm that vanished after
D2O wash, assignable to NH2 hydrogens, showed HMBCs with C-5
at 98.6 ppm and C-7 at 138.4 ppm (Fig. 2). The structure of the
tetrahydroisoquinolines 5 was further confirmed by a single crystal
X-ray crystallographic study of 5g29 (Fig. 3).
Fig. 3. ORTEP diagram of 5g.
12 and 13, respectively (Scheme 3 and Table 3). Besides being ap-
plicable to the preparation of bicyclic systems, these conditions
were clearly more advantageous than the previously mentioned
NC
CN
O
O2N
3.08, t, 2H,
Knoevenagel
+
NC
CN
J = 5.7 Hz
29.4
- H2O
CN H
98.6
3
Ar
5.37, s, 2H
N
CN
5
H
H
N
4
H
3
2.67, t, 2H,
H
2
H
H
H2N
J = 5.7 Hz
R
H2N
O2N
R
6
143.0
4
1
H
2
51.1
4a
6
138.4
O2N
N
Michael
N
CH3
2.31, s, 3H
45.7
124.6
CH3
8a
7
8
1'
3.04, s, 2H
55.8
N
O
2'
6'
5'
NC
CN
N
3'
O
HN
Thorpe-Ziegler
4'
CH3
Ar
CH3
N
2.39, s, 3H
O2N
R
N
21.2
Ar
R
7
8
Fig. 2. Selected HMBCs and chemical shifts of 5a.
As shown in Scheme 2, the three-component reactions pre-
sumably proceed through a domino mechanism initiated by the
condensation of the starting 1-alkylpiperidin-4-one 2 with malo-
CN
CN
H2N
O2N
H2N
O2N
O2 (air)
N
nonitrile 3 yielding an
dergoes a Michael addition to the
7. This intermediate affords 8 via an intramolecular ThorpeeZiegler
cyclizationetautomerization. Finally, is aromatized by de-
a,
b-unsaturated nitrile 6, which then un-
N
R
R
b-nitrostyrene 3 to furnish anion
Ar
Ar
5
8
8
Scheme 2.
hydrogenation to afford compounds 5. In support of this proposal,
we will mention that base-promoted treatment of alkylidenema-
lononitriles with nitroolefins in the presence of base has been re-
cently found to lead to carbocyclic systems with a substitution
pattern similar to the tetrahydroisoquinolines of the present
study.30,29 In order to verify the applicability of these observations
to our three-component reaction, we studied its generalization to
the synthesis of carbocycles by reaction of cyclic ketones, viz.
cyclopentanone 10 and cyclohexanone 11, with malononitrile and
CN
Ar
NC
CN
O
Morpholine, EtOH,
reflux, 4 h
H2N
O2N
3
n
O2N
n
10 (n = 1)
11 (n = 2)
4
Ar
12 (n = 1)
13 (n = 2)
b-nitrostyrene in the presence of morpholine. As expected, these
Scheme 3.
reactions afforded good yields of highly functionalized carbocycles

K. Balamurugan et al. / Tetrahedron 67 (2011) 1432e1437
1435
solid, yield: 71%, mp¼185e186 ꢀC; 1H NMR (300 MHz, CDCl3) dH
1.30 (d, 6H, J¼6.6 Hz, 2CH3), 2.34 (s, 3H, NeCH3), 2.69 (t, 2H,
J¼5.9 Hz, H-3), 2.92e3.01 (m, 1H, CH), 3.07 (s, 2H, H-1), 3.11 (t, 2H,
J¼5.9 Hz, H-4), 5.39 (s, 2H, NH2), 7.08 (d, 2H, J¼8.1 Hz, AreH), 7.29
(d, 2H, J¼8.1 Hz, AreH). 13C NMR (75 MHz, CDCl3) dC 23.8, 29.4, 33.8,
45.7, 51.2, 55.8, 98.5, 114.9, 124.7, 126.8, 127.6, 128.0, 131.4, 140.0,
141.7, 143.0, 149.2. Anal. Calcd for C20H22N4O2: C, 68.55; H, 6.33; N,
15.99%. Found C, 68.63; H, 6.29; N, 15.92%.
Table 3
Yields of indane (n¼1) and tetraline (n¼2) derivatives
Entry
n
Cmpd
Ar
Yielda (%)
1
2
3
4
1
1
2
2
12a
12b
13a
13b
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
71
72
75
70
a
Isolated yield after purification by column chromatography.
two-component literature methods requiring two steps and the
combination of two catalysts.
4.2.3. 6-Amino-8-(4-methoxyphenyl)-2-methyl-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-5-carbonitrile (5c). Isolated as a pale yellow
solid, yield: 68%, mp¼185e186 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.27 (s, 3H, NeCH3), 2.63 (t, 2H, J¼5.7 Hz, H-3), 2.95 (s, 2H, H-1),
3.03 (t, 2H, J¼5.7 Hz, H-3), 5.32 (s, 2H, NH2), 6.90 (d, 2H, J¼8.4 Hz,
AreH), 7.02 (d, 2H, J¼7.8 Hz, AreH). 13C NMR (75 MHz, CDCl3) dC
29.3, 45.7, 51.1, 55.2, 55.8, 98.5, 114.2, 114.9, 124.8, 126.2, 128.9,
135.9, 139.6, 141.7, 142.9, 159.7. Anal. Calcd for C18H18N4O3: C, 63.89;
H, 5.36; N, 16.56%. Found C, 63.95; H, 5.31; N, 16.50%.
3. Conclusion
In conclusion, the present work describes a facile and convergent
one-pot three-component protocol for the synthesis of polysubstituted
tetrahydroisoquinolines of potential pharmaceutical and biological
importance, via a domino Knoevenagel condensation/Michael addi-
tion/ThorpeeZiegler cyclization/air-promoted dehydrogenation se-
quence. Besides being able to generate three C]C bonds in a single
synthetic operation, this methodology has the advantage of requiring
simple and inexpensive starting materials and catalysts and is there-
fore suitable for library generation. Biological screening of the syn-
thesized tetrahydroisoquinolines is currently in progress.
4.2.4. 6-Amino-8-(4-bromophenyl)-2-methyl-7-nitro-1,2,3,4-tetra-
hydroisoquinoline-5-carbonitrile (5d). Isolated as a pale yellow
solid, yield: 60%, mp¼214e215 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.27 (s, 3H, NeCH3), 2.62 (t, 2H, J¼5.7 Hz, H-3), 2.94 (s, 2H, H-1),
3.04 (t, 2H, J¼5.7 Hz, H-3), 5.50 (s, 2H, NH2), 6.99 (d, 2H, J¼8.1 Hz,
AreH), 7.53 (d, 2H, J¼8.1 Hz, AreH). 13C NMR (75 MHz, CDCl3) dC
29.4, 45.7, 51.0, 55.7, 99.2, 114.7, 122.9, 124.3, 129.3, 132.0, 133.3,
134.9, 138.7, 142.1, 143.7. Anal. Calcd for C17H15BrN4O2: C, 52.73; H,
3.90; N, 14.47%. Found C, 52.79; H, 3.85; N, 14.52%.
4. Experimental section
4.1. General
Melting points were measured in open capillary tubes and are
uncorrected. The 1H NMR, 13C NMR, DEPT, HeH-COSY, CeH-COSY,
and HMBC spectra were recorded on a Bruker (Avance) 300 MHz
NMR instrument using TMS as internal standard and CDCl3 as
solvent. Standard Bruker software was used throughout. Chemical
4.2.5. 6-Amino-8-(4-flurophenyl)-2-methyl-7-nitro-1,2,3,4-tetrahy-
droisoquinoline-5-carbonitrile (5e). Isolated as a pale yellow solid,
yield: 69%, mp¼161e162 ꢀC; 1H NMR (300 MHz, CDCl3) dH 2.31 (s,
3H, NeCH3), 2.66 (t, 2H, J¼5.7 Hz, H-3), 2.99 (s, 2H, H-1), 3.08 (t, 2H,
J¼5.7 Hz, H-3), 5.47 (s, 2H, NH2), 7.12 (d, 4H, J¼6.6 Hz, AreH). 13
C
shifts are given in parts per million (
d
scale) and the coupling
NMR (75 MHz, CDCl3) dC 29.4, 45.7, 51.1, 55.8, 99.04, 115.8, 116.1,
124.5, 129.5, 129.6, 135.3, 138.9, 142.0, 143.5, 162.3. Anal. Calcd for
C17H15FN4O2: C, 62.57; H, 4.63; N, 17.17%. Found C, 62.63; H, 4.58; N,
17.22%.
constants are given in hertz. Silica gel-G plates (Merck) were used
for TLC analysis with a mixture of petroleum ether (60e80 ꢀC) and
ethyl acetate as eluent. Elemental analyses were performed on
a PerkineElmer 2400 Series II Elemental CHNS analyzer.
4.2.6. 6-Amino-8-(2,4-dichlorophenyl)-2-methyl-7-nitro-1,2,3,4-tet-
rahydroquinoline-carbonitrile (5f). Isolated as a pale yellow solid,
yield: 62%, mp¼194e195 ꢀC; 1H NMR (300 MHz, CDCl3) dH 2.31 (s,
3H, NeCH3), 2.66 (t, 2H, J¼5.4 Hz, H-3), 2.92 (s, 2H, H-1), 3.09 (t, 2H,
J¼5.7 Hz, H-3), 5.85 (s, 2H, NH2), 7.01 (d, 1H, J¼8.1 Hz, AreH), 7.32
(d, 1H, J¼8.1 Hz, AreH), 7.51 (d, 1H, J¼2.0 Hz, AreH). 13C NMR
(75 MHz, CDCl3) dC 29.5, 45.7, 50.8, 54.8, 55.0, 100.1, 114.6, 124.4,
127.6,129.5,129.8,132.6,133.5,135.2,136.5,142.9,144.8. Anal. Calcd
for C17H14Cl2N4O2: C, 54.13; H, 3.74; N, 14.85%. Found C, 54.20; H,
3.68; N, 14.91%.
4.2. Synthesis of tetrahydroisoquinolines (5), indanes (12),
and tetralines (13). General procedure
A mixture of 1-methylpiperidin-4-one or 1-benzylpiperidin-4-
one (2.65 mmol), malononitrile (2.65 mmol), the suitable d-nitro-
styrene (2.65 mmol), and morpholine (5.30 mmol) was refluxed in
ethanol (10 ml) for the time mentioned in Table 1. The reaction mix-
ture during reflux reached a maximum temperature of 80 ꢀC, which
was measured by inserting the thermometer inside the reaction
mixture. After completion of the reaction as monitored by TLC, the
reaction mixture was concentrated under vacuum and the residue
was subjected to column chromatography using a petroleum ether/
ethyl acetate mixture (1:1) as eluent to afford the pure product 5.
4.2.7. 6-Amino-8-(2-methoxyphenyl)-2-methyl-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-5-carbonitrile (5g). Isolated as a pale yellow
solid, yield: 68%, mp¼177e178 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.26 (s, 3H, NeCH3), 2.64 (t, 2H, J¼4.5 Hz, H-3), 2.90 (s, 2H, H-1),
3.05 (t, 2H, J¼4.5 Hz, H-3), 3.72 (s, 3H, OCH3), 5.52 (s, 2H, NH2), 6.93
(d, 2H, J¼7.8 Hz, AreH), 7.36 (d, 2H, J¼6.3 Hz, AreH). 13C NMR
(75 MHz, CDCl3) dC 29.4, 45.7, 51.1, 55.1, 55.3, 98.9, 111.1, 115.1, 120.9,
123.5, 125.1, 128.7, 130.2, 135.3, 137.5, 142.2, 143.3, 156.0. Anal. Calcd
for C17H15BrN4O2: C, 52.73; H, 3.90; N, 14.47%. Found C, 52.79; H,
3.85; N, 14.52%.
4.2.1. 6-Amino-8-(4-methylphenyl)-2-methyl-7-nitro-1,2,3,4-tetra-
hydroisoquinoline-carbonitrile (5a). Isolated as a pale yellow solid,
yield: 78%, mp¼193e194 ꢀC; 1H NMR (300 MHz, CDCl3) dH 2.31 (s,
3H, NeCH3), 2.39 (s, 3H, CH3), 2.67 (t, 2H, J¼5.7 Hz, H-3), 3.04 (s, 2H,
H-1), 3.08 (t, 2H, J¼5.7 Hz, H-3), 5.37 (s, 2H, NH2), 7.03 (d, 2H,
J¼7.8 Hz, AreH), 7.22 (d, 2H, J¼7.8 Hz, AreH). 13C NMR (75 MHz,
CDCl3) dC 21.2, 29.4, 45.7, 51.1, 55.8, 98.6, 114.9, 124.6, 127.5, 129.4,
131.2, 135.7, 138.4, 140.0, 141.7, 143.0. Anal. Calcd for C18H18N4O2: C,
67.07; H, 5.63; N, 17.38%. Found C, 67.12; H, 5.60; N, 17.43%.
4.2.8. 6-Amino-8-(3-bromophenyl)-2-methyl-7-nitro-1,2,3,4-tetra-
hydroisoquinoline-5-carbonitrile (5h). Isolated as a pale yellow
solid, yield: 72%, mp¼190e191 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.32 (s, 3H, NeCH3), 2.66 (t, 2H, J¼6.1 Hz, H-3), 2.98 (s, 2H, H-1),
3.09 (t, 2H, J¼6.1 Hz, H-3), 5.57 (s, 2H, NH2), 7.09 (dd, 1H, J¼8.1,
4.2.2. 6-Amino-8-(4-isopropylphenyl)-2-methyl-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-5-carbonitrile (5b). Isolated as a pale yellow

1436
K. Balamurugan et al. / Tetrahedron 67 (2011) 1432e1437
0.9 Hz, AreH), 7.29 (s, 1H, AreH), 7.31 (t, 1H, J¼8.1 Hz, AreH), 7.55
(dd,1H, J¼8.1, 0.9 Hz, AreH). 13C NMR (75 MHz, CDCl3) dC 29.5, 45.8,
51.1, 55.7, 99.5, 114.7, 122.8, 124.4, 126.4, 130.3, 130.5, 131.7, 134.7,
136.5, 138.4, 142.2, 144.0. Anal. Calcd for C17H15BrN4O2: C, 52.73; H,
3.90; N, 14.47%. Found C, 52.79; H, 3.85; N, 14.52%.
J¼8.1 Hz, AreH), 7.24e7.39 (m, 6H, AreH), 7.50 (d, 1H, J¼1.8 Hz,
AreH). 13C NMR (75 MHz, CDCl3) dC 29.4, 48.2, 53.5, 61.9, 100.4,
114.6, 125.0, 127.4, 127.6, 128.3, 128.4, 128.9, 129.6, 129.8, 132.8,
133.6, 135.2, 136.7, 137.4, 143.0, 145.5. Anal. Calcd for
C23H18Cl2N4O2: C, 60.94; H, 4.00; N, 12.36%. Found C, 60.86; H,
3.94; N, 12.45%.
4.2.9. 6-Amino-2-benzyl-8-(4-methylphenyl)-7-nitro-1,2,3,4-tetra-
hydro-5-isoquinolinecarbonitrile (5i). Isolated as a pale yellow solid,
yield: 74%, mp¼201e202 ꢀC; 1H NMR (300 MHz, CDCl3) dH 2.42 (s,
3H, CH3), 2.68 (t, 2H, J¼5.7 Hz, H-3), 3.05 (t, 2H, J¼5.7 Hz, H-4), 3.22
(s, 2H, H-1), 3.55 (s, 2H, CH2), 5.55 (s, 2H, NH2), 7.05(d, 2H, J¼8.1 Hz,
AreH), 7.24 (d, 2H, J¼8.1 Hz, AreH), 7.27e7.35 (m, 5H, AreH). 13C
NMR (75 MHz, CDCl3) dC 21.3, 29.3, 48.0, 54.5, 61.9, 98.6, 114.9,
124.9, 127.2, 127.5, 128.3, 128.9, 129.4, 131.3, 135.6, 137.4, 138.4,
140.1, 141.8, 143.7. Anal. Calcd for C24H22N4O2: C, 72.34; H, 5.57; N,
14.06%. Found C, 72.40; H, 5.51; N, 13.99%.
4.2.15. 5-Amino-7-(4-methylphenyl)-6-nitro-4-indanecarbonitrile
(12a). Isolated as a pale yellow solid, yield: 71%, mp¼178e179 ꢀC;
1H NMR (300 MHz, CDCl3) dH 2.03e2.13 (m, 2H, CH2), 2.38 (s, 3H,
CH3), 2.66 (t, 2H, J¼7.2 Hz, CH2), 3.11 (t, 2H, J¼7.2 Hz, CH2), 5.54 (s,
2H, NH2), 7.08 (d, 2H, J¼7.8 Hz, AreH), 7.22 (d, 2H, J¼7.8 Hz, AreH).
13C NMR (75 MHz, CDCl3) dC 21.3, 24.6, 32.1, 33.8, 95.2, 115.2, 127.1,
129.4, 133.2, 134.0, 138.2, 138.8, 142.9, 153.5. Anal. Calcd for
C17H15N3O2: C, 69.61; H, 5.15; N, 14.33%. Found C, 69.69; H, 5.06; N,
14.40%.
4.2.10. 6-Amino-2-benzyl-8-(4-isopropylphenyl)-7-nitro-1,2,3,4-tet-
rahydro-5-isoquinolinecarbonitrile (5j). Isolated as a pale yellow
solid, yield: 72%, mp¼195e196 ꢀC; 1H NMR (300 MHz, CDCl3) dH
1.31 (d, 6H, J¼6.9 Hz, 2CH3), 2.70 (t, 2H, J¼5.7 Hz, H-3), 2.94e3.01
(m, 1H, CH), 3.06 (t, 2H, J¼5.7 Hz, H-4), 3.18 (s, 2H, H-1), 3.55 (s, 2H,
CH2), 5.41 (s, 2H, NH2), 7.06 (d, 2H, J¼8.1 Hz, AreH), 7.25e7.28 (m,
7H, AreH). 13C NMR (75 MHz, CDCl3) dC 23.8, 29.3, 33.8, 48.3, 54.3,
62.1, 98.6, 114.9, 125.0, 126.7, 127.2, 127.5, 128.2, 128.9, 131.5, 135.6,
137.4, 140.2, 141.7, 143.6, 149.2. Anal. Calcd for C26H26N4O2: C, 73.22;
H, 6.14; N, 13.14%. Found C, 73.28; H, 6.08; N, 13.20%.
4.2.16. 5-Amino-7-(4-chlorophenyl)-6-nitro-4-indane-carbonitrile
(12b). Isolated as a pale yellow solid, yield: 72%, mp¼161e162 ꢀC;
1H NMR (300 MHz, CDCl3) dH 2.04e2.13 (m, 2H, CH2), 2.61 (t, 2H,
J¼7.2 Hz, CH2), 3.11 (t, 2H, J¼7.2 Hz, CH2), 5.70 (s, 2H, NH2), 7.12 (d,
2H, J¼8.1 Hz, AreH), 7.39 (d, 2H, J¼8.1 Hz, AreH). 13C NMR (75 MHz,
CDCl3) dC 24.5, 32.0, 33.8, 95.8, 114.9, 128.6, 129.0, 129.4, 133.8,
134.4, 134.8, 137.6, 143.3, 154.1. Anal. Calcd for C16H12ClN3O2: C,
61.25; H, 3.86; N, 13.39%. Found C, 61.32; H, 3.80; N, 13.30%.
4.2.17. 2-Amino-4-(4-methylphenyl)-3-nitro-5,6,7,8-tetrahydro-1-
naphthalenecarbonitrile (13a). Isolated as a pale yellow solid,
yield: 75%, mp¼184e185 ꢀC; 1H NMR (300 MHz, CDCl3) dH
1.64e1.65 (m, 2H, CH2), 1.78e1.79 (m, 2H, CH2), 2.25 (t, 2H,
J¼5.7 Hz, CH2), 2.38 (s, 3H, CH3), 2.95 (t, 2H, J¼5.7 Hz, CH2), 5.29 (s,
2H, NH2), 7.02 (d, 2H, J¼6.6 Hz, AreH), 7.22 (d, 2H, J¼6.6 Hz,
AreH). 13C NMR (75 MHz, CDCl3) dC 21.3, 21.7, 22.5, 27.5, 29.5, 98.9,
115.3, 126.9, 127.7, 129.3, 132.4, 135.8, 138.1, 141.2, 141.5, 145.8.
Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67%. Found C,
70.44; H, 5.62; N, 13.61%.
4.2.11. 6-Amino-2-benzyl-8-(4-chlorophenyl)-7-nitro-1,2,3,4-tetra-
hydro-5-isoquinolinecarbonitrile (5k). Isolated as a pale yellow
solid, yield: 76%, mp¼212e213 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.69 (t, 2H, J¼6.0 Hz, H-3), 3.05 (t, 2H, J¼5.7 Hz, H-3), 3.14 (s, 2H, H-
1), 3.55 (s, 2H, CH2), 5.55 (s, 2H, NH2), 7.10 (d, 2H, J¼8.4 Hz, AreH),
7.19e7.35 (m, 5H, AreH), 7.40 (d, 2H, J¼8.4 Hz, AreH). 13C NMR
(75 MHz, CDCl3) dC 29.4, 48.1, 54.3, 62.0, 66.6, 99.3, 114.7, 124.6,
127.4, 128.3, 128.9, 129.0, 132.9, 134.7, 134.9, 137.2, 138.9, 142.1,
144.4. Anal. Calcd for C23H19ClN4O2: C, 65.95; H, 4.57; N, 13.38%.
Found C, 65.88; H, 4.52; N, 13.44%.
4.2.18. 2-Amino-4-(4-chlorophenyl)-3-nitro-5,6,7,8-tetrahydro-1-
naphthalenecarbonitrile (13b). Isolated as a pale yellow solid, yield:
70%, mp¼191e192 ꢀC; 1H NMR (300 MHz, CDCl3) dH 1.74e1.78 (m,
2H, CH2), 1.85e1.93 (m, 2H, CH2), 2.29 (t, 2H, J¼6.3 Hz, CH2), 3.05 (t,
2H, J¼6.3 Hz, CH2), 5.52 (s, 2H, NH2), 7.17 (d, 2H, J¼8.4 Hz, AreH),
7.49 (d, 2H, J¼8.4 Hz, AreH). 13C NMR (75 MHz, CDCl3) dC 21.6, 22.4,
27.5, 29.5, 99.5, 115.1, 126.6, 128.9, 129.3, 134.0, 134.4, 135.3, 140.3,
141.5, 146.4. Anal. Calcd for C17H14ClN3O2: C, 62.30; H, 4.31; N,
12.82%. Found C, 62.23; H, 4.37; N, 12.75%.
4.2.12. 6-Amino-2-benzyl-8-(4-bromophenyl)-7-nitro-1,2,3,4-tetra-
hydro-5-isoquinolinecarbonitrile (5l). Isolated as a pale yellow solid,
yield: 79%, mp¼220e221 ꢀC; 1H NMR (300 MHz, CDCl3) dH 2.69 (t,
2H, J¼5.7 Hz, H-3), 3.05 (t, 2H, J¼5.7 Hz, H-4), 3.13 (s, 2H, H-1), 3.54
(s, 2H, CH2), 5.55 (s, 2H, NH2), 7.03 (d, 2H, J¼8.4 Hz, AreH),
7.23e7.34 (m, 5H, AreH), 7.56 (d, 2H, J¼8.4 Hz, AreH). 13C NMR
(75 MHz, CDCl3) dC 29.4, 48.1, 54.4, 62.0, 99.3, 114.7, 122.8, 124.6,
127.4, 128.3, 128.9, 129.3, 132.0, 133.4, 134.8, 137.2, 138.9, 142.1,
144.5. Anal. Calcd for C23H19BrN4O2: C, 59.62; H, 4.13; N, 12.09%.
Found C, 59.55; H, 4.20; N, 12.15%.
Acknowledgements
S.P. and J.C.M. thank MICINN, Spain and the Department of
Science and Technology, New Delhi, for funding an IndoeSpanish
collaborative major research projects (grants DST/INT/SPAIN/09
and ACI2009-0956). S.P. and J.C.M. also gratefully acknowledge
DST for funds under IRHPA program for the purchase of a high
resolution NMR spectrometer and MICINN for grant CTQ2009-
12320-BQU, respectively. K.B. thanks the Council of Scientific and
Industrial Research, New Delhi for the award of a Senior Research
Fellowship.
4.2.13. 6-Amino-2-benzyl-8-(4-fluorophenyl)-7-nitro-1,2,3,4-tetra-
hydro-5-isoquinolinecarbonitrile (5m). Isolated as a pale yellow
solid, yield: 68%, mp¼214e215 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.76 (t, 2H, J¼6.0 Hz, H-3), 3.13 (t, 2H, J¼6.0 Hz, H-4), 3.20 (s, 2H, H-
1), 3.62 (s, 2H, CH2), 5.56 (s, 2H, NH2), 7.19 (d, 2H, J¼7.5 Hz, AreH),
7.31 (d, 2H, J¼7.5 Hz, AreH), 7.34e7.41 (m, 5H, AreH). 13C NMR
(75 MHz, CDCl3) dC 29.4, 48.3, 54.3, 62.0, 99.3, 114.7, 115.9, 125.0,
127.4, 128.3, 128.9, 129.6, 130.2, 135.4, 137.3, 139.0, 141.9, 144.2,
162.7. Anal. Calcd for C23H19FN4O2: C, 68.65; H, 4.76; N, 13.92%.
Found C, 68.59; H, 4.85; N, 13.98%.
Supplementary data
4.2.14. 6-Amino-2-benzyl-8-(2,4-dichlorophenyl)-7-nitro-1,2,3,4-tet-
rahydro-5-isoquinolinecarbonitrile (5i). Isolated as a pale yellow
solid, yield: 70%, mp¼210e211 ꢀC; 1H NMR (300 MHz, CDCl3) dH
2.78 (t, 2H, J¼5.7 Hz, H-3), 3.04 (s, 2H, H-1), 3.08 (t, 2H,
J¼5.7 Hz, H-4), 3.66 (s, 2H, CH2), 5.90 (s, 2H, NH2), 7.01 (d, 1H,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.12.052. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.

K. Balamurugan et al. / Tetrahedron 67 (2011) 1432e1437
1437
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