Base-promoted regioselective synthesis of 1,2,3,4-terahydroquinolines and quinolines from N-boc-3-piperidone

Article abstract of DOI:10.1016/j.tet.2019.130695

An efficient synthesis of 1,2,3,4-tetrahydroquinolines with donor and acceptor group has been delineated by base mediated ring transformation of 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles by N-boc-3-piperidone followed by consecutive deprotection

Full text of DOI:10.1016/j.tet.2019.130695

Journal Pre-proof
Base-promoted regioselective synthesis of 1,2,3,4-terahydroquinolines and quinolines
from N-boc-3-piperidone
Shally, Ismail Althagafi, Divya Singhal, Rahul Panwar, Ranjay Shaw, Amr Elagamy,
Ramendra Pratap
PII:
S0040-4020(19)31070-1
https://doi.org/10.1016/j.tet.2019.130695
TET 130695
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 August 2019
Revised Date: 5 October 2019
Accepted Date: 14 October 2019
Please cite this article as: Shally , Althagafi I, Singhal D, Panwar R, Shaw R, Elagamy A, Pratap R,
Base-promoted regioselective synthesis of 1,2,3,4-terahydroquinolines and quinolines from N-boc-3-
piperidone, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130695.
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Base-promoted regioselective synthesis of
,2,3,4-terahydroquinolines and quinolines
from N-Boc-3-piperidone
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1
a
b
a
a
a
a
a
Shally, Ismail Althagafi, Divya Singhal, Rahul Panwar, Ranjay Shaw, Amr Elagamy and Ramendra Pratap
a
Department of Chemistry, University of Delhi, North campus, Delhi, India-110007
b
Department of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
R
O
R
R
CN
CN
CN
N
O
O
Boc
Ar
Ar
Ar
R= SCH
3
, NR
2
HN
N
Ar= Aryl, hetroaryl
86-95%
54-95%
Moderate to high Yield
Wide functinalization scope
Mild reaction condition
Easily accessible precursor

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Base-promoted regioselective synthesis of
,2,3,4-terahydroquinolines and quinolines
from N-Boc-3-piperidone
Leave this area blank for abstract info.
1
a
b
a
a
a
a
a
Shally, Ismail Althagafi, Divya Singhal, Rahul Panwar, Ranjay Shaw, Amr Elagamy and Ramendra Pratap
a
Department of Chemistry, University of Delhi, North campus, Delhi, India-110007
b
Department of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
R
O
R
R
CN
CN
CN
N
O
O
Boc
Ar
Ar
Ar
R= SCH
3
, NR
2
HN
N
Ar= Aryl, hetroaryl
86-95%
54-95%
Moderate to high Yield
Wide functinalization scope
Mild reaction condition
Easily accessible precursor

1
Tetrahedron
journal homepage: www.elsevier.com
Base-promoted regioselective synthesis of 1,2,3,4-terahydroquinolines and
quinolines from N-Boc-3-piperidone
a
b
a
a
a
a
Shally, Ismail Althagafi, Divya Singhal, Rahul Panwar, Ranjay Shaw, Amr Elagamy and Ramendra
Pratap
a,
∗
a
Department of Chemistry, University of Delhi, North campus, Delhi, India-110007
Department of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of 1,2,3,4-tetrahydroquinolines with donor and acceptor group has been
delineated by base mediated ring transformation of 6-aryl-4-substituted-2H-pyran-2-one-3-
carbonitriles by N-boc-3-piperidone followed by consecutive deprotection of Boc group under
acidic conditions. This reaction involves 2 new bond formations namely C4a-C5 and C8a-C8 in
order to create the nucleus. Various donor and acceptor functional groups like aryl, heteroaryl,
nitrile, methylsulfanyl and secondary amine were installed in 1,2,3,4-tetrahydroquinolines. We
extended our approach to synthesize the fused 1,2,3,4-tetrahydroquinolines by using 2-
oxobenzo[h]chromenes as precursor. Further, we synthesized fused and isolated quinolines
through aromatization of 1,2,3,4-tetrahydroquinolines by DDQ in excellent yields. Single-crystal
X-ray analysis of the Boc protected tetrahydroisoquinoline 6t showed the steric hinderance
between N-Boc and aryl group.
Available online
Keywords:
1
,2,3,4-tetrahydroquinolines
Quinolines
Base
deprotection
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
,2,3,4-Tetrahydroquinolines are extremely important motif
In general, tetrahydroquinolines can be achieved by Povarov
13 14
reaction and reductions of quinolines by using various
reducing agents. These methods have limited substrate scope and
required very harsh reaction condition. To overcome this
problem, various research groups have reported the synthesis of
1
and present as main skelton or substructure of various natural
products and pharmaceutical agents. Tetrahydroquinoline based
molecules exhibit diverse biological activities, such as antiHIV,
antifungal,
antialzheimer, antipsychotic, antidepressants, antitumor, and
vasodillator activities. They are also reported for control gene
expression in ecdysone responsive system. The compounds with
these skeleton are also used in preparation of molecular glasses,
pesticides, antioxidants, fluorescent dyes and dye-sensitized solar
1
2
1
,2,3,4-tetrahydroquinolines by inter- and intramolecular
3
4
5
5
antimalarial,
antibacterial,
antidiabetic,
cyclizations reaction in presence of palladium, iridium, gold,
6
6
6
6
15
rhodium and cobalt based catalytic system. Apart from
6
transition metal catalyzed synthesis, acid catalyzed cyclization
7
16
approach is also used.
1,2,3,4-Tetrahydroquinolines are
achieved by BF .OEt mediated reaction of N-arylimines and
3
2
17
arylvinylidenecyclopropanes. In another method, reaction of 2-
aminoarylaldehydes and alkenyltrifluoroborates provides
8
cells. Additionally, tetrahydroquinoline based scaffolds are also
used as chiral ligands in asymmetric synthesis. Due to
9
tetrahydroquinolines in the presence of TMSCl and Et N
3
remarkable significance of tetrahydroquinolines, various research
groups are interested in the development of new synthetic
approach. The development of such fluorescence molecules with
large stokes shift and photo-stability is much important in
biological applications. The organic dyes with high photo-
stability are beneficial for long term cellular imaging, which is of
great importance for biological processes, pathological pathways,
18
followed by hydrogenation. Since, presence of functional
groups limits the scope of synthesis of tetrahydroquinoline
nucleus, further modification could be required and multiple
steps needed. Konishi et.al. reported a site-selective C-H
borylation of tetrahydroquinoline at C-8 position through iridium
10
19a
catalyzed reaction, which may be use as precursor for the
synthesis
of
8-aryl-1,2,3,4-tetrahydroquinolines.
The
11
and therapeutic effects
.
The molecules with large stokes shift
functionalized quinolines were also afforded by benzanulaion
(typically, ꢀλ > 80) can minimize the signal to noise ratio
19b,c
reactions.
12
between excitation source and emission for cellular imaging.
—
——
∗
Corresponding author. Tel/Fax: +91 27666646; Email address: ramendrapratap@gmail.com (Ramendra Pratap)

2
Tetrahedron
a
The earlier reported approach for the synthesis of 1,2,3,4-
Table 1: Optimization of reaction conditions
tetrahydroquinoline ring includes one or more bond formation as
shown in retrosynthetic approach and possible bonds are N-C2,
C2-C3, C3-C4, C4-C4a, and C8a-N. Herein, we have developed
a new approach, which involved 2 bond formation namely C4a-
C5 and C8a-C8 in the same pot to create the tetrahydroqinolines
13
N
O
O
N
N
CN
O
CN
CN
base, solvent
temp.
DCM , TFA
r.t
N
Boc
N
(
Figure 1).
Boc
HN
4
5
6
7g
4
5
o
4
a
4a
Entry
Base
Et
Solvent
T ( C)
t (h)
Yield
%) 3
3
(
Our strategy
1
N
H
2
b
d
1
2
3
4
5
6
7
8
9
3
N
DMSO
DMF
DMSO
DMSO
DMF
r.t.
r.t.
60
r.t.
r.t.
90
r.t.
r.t.
r.t.
90
r.t.
90
r.t.
r.t.
r.t.
90
12
12
12
12
12
12
8
6
6
5
4
4
12
3
6
8
-
8
a
N
8a
N
8
b
d
H
H
Et N
Et N
-
3
II
d
I
-
3
C4a-C5 and C8a-C8
bond formation
b
any of one or two
bond formation
Cs
Cs
2
CO
CO
3
45
45
42
45
60
60
58
55
57
61
95
90
70
70
b
2
3
Figure 1. Synthesis of 1,2,3,4-tetrahydroquinolines through disconnection
Cs CO3 DMSO
2
b
approach (Earlier versus our approach)
LiOH
KOH
KOH
KOH
NaH
DMSO
DMSO
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
b
b
2
. Result and discussion
1
0
b
1
1
To perform our synthetic approach 6-aryl-2-oxo-4-(sec.amino)-
20
12
NaH
KO Bu
2
2
H-pyran-3-carbonitriles and 2-oxo-4-(sec.amino)-5,6-dihydro-
H-benzo[h]chromene-3-carbonitriles 4 were used as precursor
t
b
1
1
1
3
4
5
b
NaNH
2
and synthesized in two steps from 2-cyano-3,3-
bis(methylthio)acrylate 1. The first step provides 3 by reaction of
b
NaNH
NaNH
NaNH
2
16
17
2
2
DMSO
THF
1
and aryl methyl ketones and 2-tetralones 2 respectively. The
Reflux
12
a) All reactions were performed by stirring 2-oxo-6-phenyl-4-piperidin-1-yl-
H-pyran-3-carbonitrile 4 (0.5 mmol), 5 (0.6 mmol) and base (1.0 mmol) in
solvent (5.0 mL) at different temperature and crude obtained was treated
with TFA in dichloromethane at room temperature; (b) Room temperature
aminated pyrans 4 can be achieved by amination of synthesized
2
compounds with various secondary amine under reflux
21
conditions (Scheme 1).
o
Once, we had precursor in our hand, we started the optimization
of reaction conditions for the synthesis of tetrahydroquinolines.
During the optimization of reaction conditions, we performed the
ring transformation reaction followed by deprotection of Boc
group of crude under acidic condition. To study, we have
selected 2-oxo-6-phenyl-4-piperidin-1-yl-2H-pyran-3-carbonitrile
was ranging between 25-35 C, (c) Isolated yield was reported, (d) 2-
pyranone left unconsumed
yield of desired product was isolated (Table 1, entries 8-10).
However, used of sodium hydride in DMSO at room temperature
and 90 C provides 55 and 57% yield respectively (Table 1,
entries 11-12). Then potassium tertiary butoxide was used as base
in DMSO and 61 % of tetrahydroquinoline was obtained (Table
, entry 13), while sodamide in DMSO at room temperature
provides 95 % of desired product in a shorter reaction time
Table 1, entry 14). Then, we tested sodamide in DMF at room
temperature and afforded 90% of desired product (Table 1,
entries 15). On the other hand conducting the reaction at higher
temperature in DMSO provided 70 % of the compound (Table 1,
entry 16). Then, we switched the solvent DMSO to THF at reflux
temperature to afford 7g in a good yield (Table 1 entry 17). The
optimization of reaction condition shows that reaction of 2-
pyranone 4 and 5 in DMSO in presence of sodamide at room
temperature act as best reaction condition. The crude thus
obtained was treated with TFA in DCM to afford 7 in excellent
yield.
o
4
and 3-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 as
1
model substrates. Deprotection of Boc group was performed by
literature procedure using TFA in dichloromethane at room
22
(
temperature. We started the assessment by using triethyl amine
o
as a base in DMSO and DMF at r.t. and 60 C, but no reaction
was observed (Table 1, entries 1, 2 and 3). Then, we used cesium
carbonate in DMSO and DMF at room temperature as well as at
o
9
0 C and yield of desired product up to 45% was obtained
(
Table 1, entries 4-6). Use of lithium hydroxide in DMSO
followed by deprotection of Boc group provides 45%
tetrahydroquinolines (Table 1, entry 7). Then, we moved to
potassium hydroxide in DMF and DMSO and 58-60 %
SMe
O
CN
MeOOC
MeS
CN
We tried to isolate the Boc protected tetrahydroisoquinolines but
proton NMR shows presence of some aliphatic impurity which
was difficult to remove, so we crystallized one compound and the
structure of the Boc protected product was confirmed by X-ray
crystallographic analysis (Figure 2; Table 1 in SI). Using the
optimized reaction conditions, the scope and general applicability
of this methodology was investigated and a series of highly
functionalized tetrahydroquinolines was synthesized in 65-95 %
yield. Further, we observed that various electron donating and
withdrawing aryl group in pyran ring didn’t affect the yield
significantly. The bulky aryl group like naphthyl and 2-
substituted aryl group in pyran ring significantly reduce the yield
due to steric hindrance. Interestingly, 8-heteroatyl-1,2,3,4-
tetrahydroquinolines was achieved in good yield.
KOH/DMSO
r.t
+
R
O
O
R
SMe
2
1
3
NHR /EtOH Reflux
2
NR2
CN
O
O
R
4
Scheme 1: Synthesis of 6-aryl-2-oxo-4-(sec.amino)-2H-pyran-3-carbonitriles
and 2-oxo-4-(sec.amino)-5,6-tetrahydro-2H-benzo[h]chromene-3-
carbonitriles

3
X
X
isoquinoline skeleton. Mechanistically, if reaction follows path
A, carbanion generated at position 2 of N-Boc-3-piperidone
attacks at C-6 of pyran via Michael addition followed by ring
opening and provides intermediate A. The intermediate A
undergoes decarboxylation and protonation and provides
intermediate B. In the presence of excess of base intermediate B
N
O
N
CN
O
CN
1
. NaNH , DMSO, r.t.
2
N
2. DCM , TFA, r.t
Ar
O
Boc
Ar
HN
5
4
X
X
7
CH Ph
2
N
N
O
N
CN
O
CN
N
1. NaNH
, DMSO, r.t
2
CN
N
N
2. DCM , TFA, r.t
O
Boc
CN
HN
5
4
Ar
R
R
8
HN
Ar
HN
7
a-d
7
e-f
7
7
7
7
a) Ar = 4-Br.C H ; 89%
b) Ar = 2.4.(Cl) C H ; 70%
c) Ar = 2-napthyl; 65%
d) Ar = Thienyl; 91%
6
4
7
7
e) Ar = 4-OMe.C H ; 80%
f) Ar = 4-Br.C H ; 81%
6
4
2
6 3
6
4
O
N
N
CN
CN
Ar
Ar
HN
HN
7
o-t
7g-n
Scheme 3. Scope of 2-oxobenzo[h]chromenes for the synthesis of fused
a,b
7
7
7
7
7
7
7
7
g) Ar = C H ; 95%
7o) Ar = C H ; 95%
quinolines [All reactions were performed by stirring 4 (0.5 mmol), 5 (0.6
6
5
6 5
h) Ar = 4-CH .C H ; 95%
7p) Ar = 4-CH .C H ; 95%
mmol) and sodamide (1.0 mmol) in DMSO (5.0 mL) at room temperature and
crude obtained was treated with TFA in dichloromethane at room temperature
25-35 C), (b) Isolated yield is reported.]
3
6
4
3
6 4
i) Ar = 4-OMe.C H ; 80%
7q) Ar = 4-F.C H ; 84%
6
4
6 4
o
(
j) Ar = 3.4.(OMe) C H ; 80% 7r) Ar = 4-Cl.C H ; 85%
2
6
3
6 4
k) Ar = 4-F.C H ; 89%
7s) Ar = 4-Br.C H ; 81%
6 4
7t) Ar = 4-OMe.C H ; 88%
6 4
6
4
l) Ar = 4-Cl.C H ; 84%
6
4
m) Ar = 2-Thienyl; 90%
n) Ar = 2-Furyl; 88%
Scheme 2. Synthesis of various functionalized 1,2,3,4-tetrahydro-
a,b
quinolines [a) All reactions were performed by stirring 4 (0.5 mmol), 5 (0.6
mmol) and sodamide (1.0 mmol) in DMSO (5.0 mL) at room temperature and
crude obtained was treated with TFA in dichloromethane at room temperature
o
(
25-35 C), (b) Isolated yield was reported.]
We further investigated the scope of reaction for the synthesis of
naphtho-fused quinolines; hexahydro-1-aza-
benzo[c]phenanthrenes 8. The ring transformation of 2-
oxobenzo[h]chromenes with under similar reaction
Figure 2. ORTEP diagram of tert-butyl 5-cyano-8-(4-methoxyphenyl)-6-
morpholino-3,4-dihydroquinoline-1(2H)-carboxylate 6t
4
5
conditions afforded fused tetrahydroquinolines and interestingly,
good yield of product was observed (Scheme 3).
To further investigate the scope of reaction, we have used
compound 3 as a precursor to check the tolerance of reaction on
functional group. Previously, we have observed that presence of
methylthio group provides some side reaction and afford
23
complex mixture or low yield of product. Interestingly, reaction
of 3 with 5 in presence of NaNH in DMSO afforded the desired
2
product 9 in the moderate yield 52-64% (Scheme 4).
A plausible mechanism for the formation of 7 is shown in
scheme 5. The structural investigation of 2-pyranone shows that
C2, C4 and C6 position is highly reactive towards nucleophilic
attack and position C6 is more reactive due to extended
conjugation with electron withdrawing groups. The compound 5
can generate two different nucleophiles at position 2 and 4 and
their involvement in the reaction can provides quinoline or
Scheme 4:
Synthesis of methylthio group containing 1,2,3,4-
tetrhydroquinolines 9a,b.[ a)All reactions were performed by stirring 3 (0.5
mmol), 5 (0.6 mmol) and sodamide (1.0 mmol) in DMSO (5.0 mL) at room
temperature and crude obtained was treated with TFA in dichloromethane at
o
room temperature (25-35 C), (b) Isolated yield was reported.

4
Tetrahedron
Further, we have aromatized the tetrahydroquinolines by using
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in toluene to
24
afford the quinoline in excellent yield (Scheme 6). This reaction
works smoothly and provides the functionalized quinolines in
excellent yield.
O
S
NH3
O
S
+
NaNH2
CH3
H3C
H C
2
CH Na
3
base
R
N
C
O
Alternatively, compound 7 can also aromatized to produce 8-
aryl-6-(sec.amino)-quinoline-5-carbonitriles in moderate yield in
presence PIDA using toluene as solvent. We tried the different
ratio of 1,2,3,4-tetrahydroquinoline and DDQ and 1:2 ratio works
perfectly for aromatization reaction. We have selected both
isolated and fused quinolines as substrate for aromatization and
isolated the product in excellent yield. Interestingly, in case of
fused tetrahydroquinolines the bridge ethylene group was not
oxidized even in presence excess of DDQ.
6
sodamide
sodamide
or
R
O
R
O
Ar
O
N
O
N
H
H
N Boc
C
C
O
1
or
O
NaDMSO
NaDMSO
x
Ar
O
O
Ar
Boc
Path A
N Boc
Path B
O
N
5
N
ring-opening
O
Boc
O
R
R
R
R
-CO
+
CN
2
CN
NC
Ar
CN
OH
H+
Ar
Boc
Ar
N
Ar
Enolization
O
HN
3
. Conclusions
Boc N
N Boc
C
7
A
6 pi -cyclization
In summary, we have developed an efficient transition metal
TFA / DCM r.t
R
CO2 +H+
-
TFA / DCM r.t
R
free approach for the synthesis of highly functionalized 1,2,3,4-
tetrahydroquinoline, which can easily provides quinoline simply
by oxidation in presence of DDQ. The amusing qualities of the
synthetic chemistry include high regioselectivity, easily available
starting material and wide functional group tolerance. This
method provides new class of functionalized fused and isolated
base
R
R
CN
H
CN
NH
CN
-
H2O
CN
OH
+
H+
Ar
Boc
Ar
Ar
Boc
O
Ar
N
N
N
Boc
H
D
10
B
base
1
,2,3,4-tetrahydroquinolines and quinolines. This method open a
Scheme 5. Plausible mechanism for the synthesis of 8-aryl-6-substituted-
new avenue for the construction of highly functionalized 1,2,3,4-
tetrahydroquinolines and quinolines from easily accessible
precursor under basic condition through C4a-C5 and C8a-C8
bond formation reactions.
1
,2,3,4-tetrahydroquinoline-5-carbonitriles
NR2/SCH3
O
NR /SCH3
2
CN
CN
Cl
CN
CN
Toulene
Reflux
4
. Experimental
Ar
Ar
12
Cl
HN
N
O
4
.1. General
7
11
Ph
All the required reagents and solvents were purchased from
N
N
Sigma Aldrich, Spectrochem and Alfa Aesar. These compounds
were directly used without further purification. The required
precursors; 2H-pyran-2-one has been synthesized earlier by
N
N
N
N
CN
CN
CN
CN
20,22,23
various research groups
and extensively used for ring
N
S
N
N
Cl
transformation reactions. Herein, we have synthesized some
newly functionalized 2-pyranones along with reported
compounds and characterization data for new compounds has
been provided in experimental section. IR spectrophotometer was
used to study the stretching frequencies and data were reported in
MeO
12c; 93%
12d; 87%
1
2a;, 92%
12b; 85%
O
O
O
SCH3
CN
N
N
N
CN
CN
CN
-
1
N
wave number (cm ). The proton NMR (400 MHz) and carbon
NMR (100 MHz) spectra were recorded in CDCl solution
residual peaks of chloroform at 7.26 ppm for H and 77.0 ppm
N
H3C
N
N
F
Br
3
1
2e; 90%
12g; 81%
12h; 96%
1
1
2f; 90%
(
a
Scheme 6. Synthesis of functionalized quinolines [Reaction was carried out
by refluxing tetrahydroquinolines (0.2 mmol), DDQ (0.4 mmol) in toulene
3.0 mL) at 120 C and isolated yield is reported.]
13
for C were used as reference) or in DMSO-d solution (residual
6
1
13
o
peaks of DMSO at 2.50 ppm for H and 39.5 ppm for C were
used as reference). The coupling constant J are reported in Hz
and signal patterns for proton NMR is reported as s, singlet; d,
doublet; br, broad signal; t, triplet; q, quartet; m, multiplet; dd,
double doublet etc. High-resolution mass spectra were recorded
on a quadrupole-time-of-flight mass spectrometer.
(
provides carbanion, which undergoes intramolecular
cyclization by involving carbonyl carbon to afford intermediate
D. In addition, intermediate A can also provides intermediate C
by decarboxylation, protonation and enolization. Intermediat C
can undergo 6π-electrocyclization to afford intermediate D,
which undergoes aromatization by loss of water to give the N-
Boc-1,2,3,4-tetrahydroquinolines. At last, we performed the
deprotection of Boc group under acidic condition to afford the
functionalized 1,2,3,4-tetrahydroquinolines. If the reaction
follows another path B, reaction involves the carbanion generated
4
.2. General Procedure for the synthesis of 8-
aryl/heteroaryl-1,2,3,4-tetrahydroquinolines 7: To a vacuum
dried RB flask a mixture of the appropriate 6-aryl-2-oxo-4-
(sec.amino)-2H-pyran-3-carbonitrile 4 (0.5 mmol), N-boc-3-
piperidone 5 (0.6 mmol), NaNH (1.0 mmol) in DMSO (5.0 ml)
2
from
position
4
of
N-Boc-3-piperidone
and
was stirred at r.t. for 3 h. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture
was poured slowly onto ice–water with constant stirring. The
mixture was quenched with 10% aqueous HCl. The resulting
tetrahydroisoquinoline can be achieved following the same
mechanistic pathways as reported for path A. The reaction
provides exclusively 1,2,3,4-tetrahydroquinolines, which support
the formation of carbanion at position 2 of 3-piperidone. Most
likely, presence of Boc group supports the formation of
carbanion at C2 due to additional negative Inductive effect.
precipitate was collected by filtration, washed with H O, and
2
dried. Crude product was treated with TFA (10 mmol) in DCM

5
(
3.0 mL) at room temperature for 30-35 minutes and then poured
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
3.0 mL) at room temperature for 30-35 minutes. Then reaction
the reaction mixture onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
(
3
mixture was poured onto crushed ice. Reaction mixture was
The combined organic layer was dried over anhydrous Na SO4
2
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
and than evaporated in vacuo. Crude products 7 were purified by
silica gel column chromatography using 10% ethyl acetate in
hexane.
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7a yellow
solid; yield: 170 mg (89%); mp = 145–147 °C; IR (KBr): 3401,
Tert-butyl
5-cyano-8-(4-methoxyphenyl)-6-(piperidin-1-
yl)-3,4-dihydroquinoline-1(2H)-carboxylate 6i
–
1
1
2
1
2
926, 2206, 1441-1670 cm ; H NMR (400 MHz, CDCl ): δ
3
A mixture of 6-(4-methoxyphenyl)-2-oxo-4-(piperidin-1-yl)-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.155 g), N-boc-3-piperidone 5
.94-2.00 (m, 6H), 2.95 (t, J = 6.8 Hz, 2H), 3.15 (t, J = 5.6 Hz,
H), 3.46 (t, J = 6.8 Hz, 4H), 6.39 (s, 1H, ArH), 7.28 (d, J = 8
Hz, 2H, ArH), 7.56 (d, J = 8.8 Hz, 2H, ArH); C NMR (100
(0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
13
mL) was stirred at r.t. for 3 hours. After completion, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The crude
products thus obtained was purified by column chromatography on
neutral alumina using 5% ethyl acetate in hexane as an eluent to
afford 6i as yellow solid; yield: 192 mg (86%); mp = 85–87 °C;
MHz, CDCl ): δ 21.8, 25.5, 26.4, 41.7, 50.5, 98.0, 114.5, 114.5
3
119.1, 122.0, 126.0, 130.6, 131.2, 131.8, 132.0, 137.4; HRMS
+
(ESI): m/z [M + H] calcd for C20
H21BrN
: 382.0913; found:
3
382.0907.
8
-(2,4-Dichlorophenyl)-6-(pyrrolidin-1-yl)-1,2,3,4-
–1
1
tetrahydroquinoline-5-carbonitrile7b
IR (KBr): 3055, 2931, 2212, 1448-1665 cm ; H NMR (400
MHz, CDCl ): δ 0.974 (s, 9H), 1.78-1.88 (m, 6H), 3.00-3.14 (m,
A mixture of 6-(2,4-dichlorophenyl)-2-oxo-4-(pyrrolidin-1-yl)-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.167 g), N-boc-3-piperidone 5
(0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 3.5 hours. When the compound 4 was
completely consumed in the reaction as indicated by TLC, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
3
8
7
2
1
H), 3.82-3.85 (m, 5H), 6.81 (s, 1H, ArH), 6.95 (brm, 2H, ArH),
13
.26-7.34 (brm, 2H, ArH); C NMR (100 MHz, CDCl ): δ 23.8,
3
4.0, 26.0, 27.3, 28.2, 42.7, 53.3, 55.2, 80.2, 103.7, 114.0, 117.0,
18.0, 128.8, 129.7, 130.7, 131.8, 140.1, 142.1, 154.8, 159.2;
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 448.2595;
27
34
3
3
found: 448.2609.
Tert-butyl
5-cyano-8-(4-methoxyphenyl)-6-morpholino-
3
,4-dihydroquinoline-1(2H)-carboxylate 6t
mixture of 6-(4-methoxyphenyl)-4-morpholino-2-oxo-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.156 g), N-boc-3-piperidone 5
0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
A
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
(
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7b yellow
solid; yield: 130 mg (70%); mp = 83–85 °C; IR (KBr): 3396,
mL) was stirred at r.t. for 3 hours. After completion, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The crude
products thus obtained was purified by column chromatography on
neutral alumina using 5% ethyl acetate in hexane as an eluent to
afford 6t as Yellow solid; yield: 200 mg (89%); mp = 76–78 °C;
–
1
1
2
1
3
924, 2216, 1439-1606 cm ; H NMR (400 MHz, CDCl ): δ
3
.85-1.91 (m, 6H), 2.88 (t, J = 6.4 Hz, 2H), 3.08-3.12 (m, 2H),
.37-3.40 (m, 4H), 6.24 (s, 1H, ArH), 7.15 (d, J = 8.2 Hz, 1H,
–1
1
ArH), 7.26 (dd, J = 2.0 Hz, 8.0 Hz, 1H, ArH), 7.43 (d, J = 1.6
IR (KBr): 3053, 2959, 2217, 1450-1696 cm ; H NMR (400
13
Hz, 1H, ArH); C NMR (100 MHz, CDCl ): δ 21.8, 25.5, 26.4,
MHz, CDCl ): δ 0.979 (s, 9H), 1.87 (s, 1H), 2.26 (s, 1H), 3.09-
3
3
4
1
1.7, 50.5, 114.5, 119.1, 126.0, 127.5, 127.7, 129.5, 129.8, 132.2,
32.3, 134.0, 134.2, 134.6, 135.7; HRMS (ESI): m/z [M + H]
3
.21 (m, 6H), 3.82 (s, 3H, -OMe), 3.86-3.91 (m, 6H), 6.82 (s, 1H,
+
13
ArH), 6.94-6.96 (m, 2H, ArH), 7.31-7.35 (m, 2H, ArH);
C
calcd for C H Cl N : 372.1029; found: 372.1014.
NMR (100 MHz, DMSO-d ): δ 23.4, 25.7, 28.1, 42.6, 51.8, 55.4,
20 20
2
3
6
6
1
6.4, 79.7, 103.0, 114.0, 116.6, 118.0, 118.5, 129.1, 130.3, 131.3,
46.7, 153.0, 154.0, 159.2; HRMS (ESI): m/z [M + H] calcd for
8
-(Naphthalen-2-yl)-6-(pyrrolidin-1-yl)-1,2,3,4-
+
tetrahydroquinoline-5-carbonitrile 7c
C H N O : 450.2387; found: 450.2374.
26
32
3
4
A
mixture of 6-(naphthalen-2-yl)-2-oxo-4-(pyrrolidin-1-yl)-2H-
8
-(4-Bromophenyl)-6-(pyrrolidin-1-yl)-1,2,3,4-
pyran-3-carbonitrile 4 (0.5 mmol, 0.158 g), N-boc-3-piperidone 5
(0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 3.5 hours. When the compound 4 was
completely consumed in the reaction as indicated by TLC, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained 0
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
tetrahydroquinoline-5-carbonitrile 7a
A mixture of 6-(4-bromophenyl)-2-oxo-4-(sec.amino)-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.172 g), N-boc-3-piperidone 5 (0.6 mmol,
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
0
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was

6
Tetrahedron
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
using 10% ethyl acetate in hexae as an eluent to afford 7e yellow
3
The combined organic layer was dried over anhydrous Na SO and
solid; yield: 176 mg (80%); mp = 136–138 °C; IR (KBr): 3407,
2
4
–1
1
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7c yellow
solid; yield: 115 mg (65%); mp = 86–88 °C; IR (KBr): 3410,
2
1
2
924, 2215, 1447-1605 cm ; H NMR (400 MHz, CDCl ): δ
.91 (quint, J = 8 Hz, 2H), 2.59-2.64 (m, 4H), 2.89 (t, J = 6 Hz,
H), 3.00-3.01 (brm, 4H), 3.12-3.15 (brm, 2H), 3.53 (s, 2H, -
3
CH ), 3.77 (s, 3H, -OMe), 3.90 (br, 1H, NH), 6.59 (s, 1H, ArH),
2
–
1
1
2
1
2
931, 2215, 1445-1601 cm ; H NMR (400 MHz, CDCl ): δ
3
6.91 (d, J = 14.4 Hz, 2H, ArH), 7.18-7.21 (m, 2H, ArH), 7.23-
1
3
.95-2.05 (m, 6H), 2.99 (t, J = 6.6 Hz, 2H), 3.15 (t, J = 5.2 Hz,
H), 3.47-3.51 (m, 4H), 6.53 (s, 1H, ArH), 7.50-7.54 (m, 3H,
ArH), 7.85-7.92 (m, 4H, ArH); C NMR (100 MHz, CDCl ): δ
7
5
.27 (m, 5H); C NMR (100 MHz, CDCl ): δ 21.3, 26.3, 41.4,
3
2.1, 53.2, 55.3, 62.7, 107.3, 114.4, 117.2, 119.2, 125.3, 127.3,
13
3
128.3, 129.2, 129.5, 130.0, 130.2 131.1, 138.2, 146.4, 159.3;
+
2
1
1
2.0, 25.5, 26.4, 41.5, 50.5, 97.7, 115.4, 119.4, 125.2, 125.6,
25.7, 126.1, 126.5, 127.1, 128.3, 131.1, 131.6, 133.6, 134.8,
HRMS (ESI): m/z [M + H] calcd for C H N O: 439.2492;
28
31
4
found: 439.2479.
+
36.0; HRMS (ESI): m/z [M + H] calcd for C H N : 354.1965;
24
24
3
6
-(4-Benzylpiperazin-1-yl)-8-(4-bromophenyl)-1,2,3,4-
found: 354.1974.
tetrahydroquinoline-5-carbonitrile 7f
6
-(Pyrrolidin-1-yl)-8-(thiophen-2-yl)-1,2,3,4-
A mixture of 4-(4-benzylpiperazin-1-yl)-6-(4-bromophenyl)-2-oxo-
tetrahydroquinoline-5-carbonitrile 7d
2
H-pyran-3-carbonitrile 4 (0.5 mmol, 0.224 g), N-boc-3-piperidone
A mixture 2-oxo-4-(pyrrolidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.136 g), N-boc-3-piperidone 5 (0.6 mmol,
5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 3 hours. When the compound 4 was
completely consumed in the reaction as indicated by TLC, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
mixture was poured onto crushed ice. Reaction mixture was
The combined organic layer was dried over anhydrous Na SO and
2
4
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7f yellow
solid; yield: 198 mg (81%); mp = 143–145 °C; IR (KBr): 34113,
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7d yellow
solid; yield: 141 mg (91%); mp = 130–132 °C; IR (KBr): 3397,
–1
1
3
1
028, 2217, 1446-1597 cm ; H NMR (400 MHz, CDCl ): δ
.86 (quint, J = 7.6 Hz, 2H), 2.59 (brm, 4H), 2.90 (t, J = 6.92 Hz,
3
–
1
1
2
1
923, 2201, 1439-1646 cm ; H NMR (400 MHz, CDCl ): δ
3
2H), 2.99 (brm, 2H), 3.12-3.16 (m, 2H), 3.49-3.54 (m, 2H), 3.79
.96-2.03 (m, 6H), 2.96 (t, J = 6.4 Hz, 2H), 3.22 (brm, 2H), 3.48
(
7
s, 2H, -CH ), 6.55 (s, 1H, ArH), 7.17-7.20 (m, 4H, ArH), 7.23-
.28 (m, 3H, ArH), 7.50 (d, J = 7.6 Hz, 2H); C NMR (100
2
13
(brm, 4H), 6.59 (s, 1H, ArH), 7.12 (dd, J = 4.0 Hz, 5.2 Hz, 1H,
ArH), 7.23 (d, J = 3.2 Hz, 1H, ArH) 7.38 (d, J = 4.8 Hz, 1H,
MHz, CDCl ): δ 21.1, 26.3, 41.3, 51.8, 53.1, 62.6, 108.0, 117.0,
3
13
ArH); C NMR (100 MHz, DMSO-d ): δ 20.4, 25.0, 26.0, 41.4,
6
119.0, 122.1, 125.8, 127.6, 128.3, 129.6, 129.8, 130.5, 132.1,
+
5
1
0.2, 115.0, 118.5, 120.6, 121.3, 123.6, 130.6, 131.0, 131.1,
31.6, 132.6, 146.2; HRMS (ESI): m/z [M + H] calcd for
1
36.8, 138.0, 146.2; HRMS (ESI): m/z [M + 2H] calcd for
+
C H BrN : 489.1472; found: 489.1475.
27
29
4
C H N S: 310.1372; found: 310.1375.
18
20
3
8
-Phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline-5-
6
-(4-Benzylpiperazin-1-yl)-8-(4-methoxyphenyl)-1,2,3,4-
carbonitrile 7g
tetrahydroquinoline-5-carbonitrile 7e
A
mixture of 2-oxo-6-phenyl-4-(piperidin-1-yl)-2H-pyran-3-
A mixture of 4-(4-benzylpiperazin-1-yl)-6-(4-methoxyphenyl)-2-
oxo-2H-pyran-3-carbonitrile 4 (0.5 mmol, 0.200 g), N-boc-3-
piperidone 5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in
DMSO (5.0 mL) was stirred at r.t. for 3 hours. When the compound
carbonitrile 4 (0.5 mmol, 0.140 g), N-boc-3-piperidone 5 (0.6 mmol,
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
4
was completely consumed in the reaction as indicated by TLC, the
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (3.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography

7
using 10% ethyl acetate in hexae as an eluent to afford 7g yellow
2.94-2.97 (m, 6H), 3.17 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H, -OMe),
solid; yield: 150 mg (95%); mp = 113-115 °C; IR (KBr): 3421,
6.63 (s, 1H, ArH), 6.93-6.98 (m, 2H, ArH), 7.27-7.31 (m, 2H,
–1
1
13
2
1
2
926, 2216, 1419-1489 cm ; H NMR (400 MHz, DMSO-d ): δ
ArH); C NMR (100 MHz, CDCl ): δ 21.4, 24.0, 24.0, 26.3,
6
3
.43-1.44 (m, 2H), 1.58-1.59 (m, 4H), 1.77-1.79 (m, 2H), 2.78-
.84 (m, 6H), 3.06 (brm, 2H), 4.80 (br, 1H, NH), 6.59 (s, 1H,
41.4, 54.2, 55.3, 107.4, 114.3, 117.2, 119.1, 125.3, 125.4, 130.0,
+
130.4, 131.0, 148.3, 159.2; HRMS (ESI): m/z [M + H] calcd for
13
ArH), 7.34-7.44 (m, 5H, ArH); C NMR (100 MHz, CDCl ): δ
C H N O: 348.2070; found: 348.2081.
3
22 26
3
2
1
1.4, 24.0, 26.3, 29.6, 41.4, 54.2, 107.7, 117.2, 119.0, 125.4,
8
-(3,4-Dimethoxyphenyl)-6-(piperidin-1-yl)-1,2,3,4-
27.8, 128.8, 129.0, 131.2, 137.5, 138.3, 148.1; HRMS (ESI):
tetrahydroquinoline-5-carbonitrile 7j
+
m/z [M + H] calcd for C H N : 318.1965; found: 318.1961.
21
24
3
A mixture of 6-(3,4-dimethoxyphenyl)-2-oxo-4-(piperidin-1-yl)-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.170 g), N-boc-3-piperidone 5
6
-(Piperidin-1-yl)-8-(p-tolyl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile 7h
(0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 3 hours. When the compound 4 was
completely consumed in the reaction as indicated by TLC, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
A
mixture of 2-oxo-4-(piperidin-1-yl)-6-(p-tolyl)-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.147 g), N-boc-3-piperidone 5 (0.6 mmol,
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(
3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7j yellow
solid; yield: 152 mg (80%); mp = 103–105 °C; IR (KBr): 3403,
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7h yellow
solid; yield: 157 mg (95%); mp = 140–142 °C; IR (KBr): 3417,
–1
1
2926, 2214, 1459-1644 cm ; H NMR (400 MHz, CDCl ): δ
3
1.44-1.48 (m, 2H), 1.65-1.73 (m, 4H), 1.93 (quint, J = 7.2 Hz,
2H), 2.90 (t, J = 6.4 Hz, 6H), 3.13 (t, J = 5.4 Hz, 2H), 3.82 (s,
3H, -OMe), 3.85 (s, 3H, -OMe), 6.59 (s, 1H, ArH), 6.81-6.82 (m,
–
1
1
2
1
924, 2218, 1490-1650 cm ; H NMR (400 MHz, CDCl ): δ
3
13
.50 (quint, J = 6 Hz, 2H), 1.72-1.77 (m, 4H), 1.98 (quint, J = 8
1H, ArH), 6.85-6.86 (m, 2H, ArH); C NMR (100 MHz,
Hz, 2H), 2.39 (s, 3H), 2.96-2.99 (m, 6H), 3.18 (t, J = 5.3 Hz, 2H),
CDCl ): δ 21.4, 24.0, 26.3, 29.6, 41.4, 54.1, 55.9, 55.9, 107.4,
3
13
6
.66 (s, 1H, ArH), 7.24-7.28 (m, 4H, ArH); C NMR (100 MHz,
111.4, 112.0, 117.2, 119.0, 121.1, 125.3, 130.7, 131.1, 137.6,
+
CDCl ): δ 21.1, 21.4, 24.0, 26.3, 29.6, 41.4, 54.1, 107.4, 117.2,
148.1, 148.6, 149.1; HRMS (ESI): m/z [M + H] calcd for
3
1
19.0, 119.1, 125.2, 128.6, 129.6, 131.2, 135.2, 137.6, 148.1;
C H N O : 378.2176; found: 378.2163.
23
28
3
2
+
HRMS (ESI): m/z [M + H] calcd for C H N : 332.2121; found:
3
22
26
3
8
-(4-Fluorophenyl)-6-(piperidin-1-yl)-1,2,3,4-
32.2123.
tetrahydroquinoline-5-carbonitrile 7k
8
-(4-Methoxyphenyl)-6-(piperidin-1-yl)-1,2,3,4-
A mixture of 6-(4-fluorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-
tetrahydroquinoline-5-carbonitrile 7i
3
-carbonitrile 4 (0.5 mmol, 0.149 g), N-boc-3-piperidone 5 (0.6
A mixture of 6-(4-methoxyphenyl)-2-oxo-4-(piperidin-1-yl)-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.155 g), N-boc-3-piperidone 5
mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL)
was stirred at r.t. for 4 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
(0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 3 hours. When the compound 4 was
completely consumed in the reaction as indicated by TLC, the crude
mixture was poured drop-wise onto ice–water with constant stirring
and neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(
3.0 mL) at room temperature for 30-35 minutes. Then reaction
neutralized with NaHCO
The combined organic layer was dried over anhydrous Na
3
and extracted with DCM (25.0 mL×3).
SO and
mixture was poured onto crushed ice. Reaction mixture was
2
4
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7k yellow
solid; yield: 149 mg (89%); mp = 125–127 °C; IR (KBr): 3417,
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexae as an eluent to afford 7i yellow
solid; yield: 139 mg (80%); mp = 80–82 °C; IR (KBr): 3412,
–1 1
2933, 2217, 1491-1653 cm ; H NMR (400 MHz, CDCl ): 1.42-
3
1.48 (m, 2H), 1.66-1.69 (m, 4H), 1.91 (quint, J = 6.4 Hz, 2H),
2.88-2.91 (m, 6H), 3.12 (t, J = 5.6 Hz, 2H), 3.75 (br, 1H, NH),
6.55 (s, 1H, ArH), 7.03-7.08 (m, 2H, ArH), 7.25-7.29 (m, 2H,
–
1
1
2
1
926, 2216, 1444-1606 cm ; H NMR (400 MHz, CDCl ): δ
3
.49-1.53 (m, 2H), 1.70-1.75 (m, 4H), 1.92 (quint, J = 6 Hz, 2H),

8
Tetrahedron
13
ArH); C NMR (100 MHz, CDCl ): δ 21.4, 24.0, 26.3, 29.6,
21.3, 24.1, 26.4, 26.5, 41.6, 54.3, 108.4, 117.2, 119.7, 123.4,
126.0, 126.2, 126.7, 127.8, 138.1, 139.7, 148.0; HRMS (ESI):
3
4
1
1.5, 54.3, 108.0, 116.0 (d, JC-F = 20 Hz), 117.1, 119.1, 125.6,
30.2, 130.6 (d, JC-F = 10 Hz), 134.2, 137.6, 148.2, 162.3 (d, J
+
m/z [M + H] calcd for C H N S: 324.1529; found: 324.1520.
C-F
19 22
3
+
=
240 Hz); HRMS (ESI): m/z [M + H] calcd for C H FN :
21
23
3
8
5
-(Furan-2-yl)-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline-
-carbonitrile 7n
3
36.1871; found: 336.1870.
8
-(4-Chlorophenyl)-6-(piperidin-1-yl)-1,2,3,4-
A mixture of 6-(furan-2-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.135 g), N-boc-3-piperidone 5 (0.6 mmol,
0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
tetrahydroquinoline-5-carbonitrile 7l
A mixture of 6-(4-chlorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-
3
-carbonitrile 4 (0.5 mmol, 0.157 g), N-boc-3-piperidone 5 (0.6
mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL)
was stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(
3.0 mL) at room temperature for 30-35 minutes. Then reaction
neutralized with NaHCO
The combined organic layer was dried over anhydrous Na
3
and extracted with DCM (25.0 mL×3).
mixture was poured onto crushed ice. Reaction mixture was
2
SO and
4
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7n yellow
solid; yield: 136 mg (88%); mp = 103–105 °C; IR (KBr): 3451,
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7l yellow
solid; yield: 148 mg (84%); mp = 105-107 °C; IR (KBr): 3413,
–1
1
2928, 2215, 1450-1676 cm ; H NMR (400 MHz, CDCl ): δ
3
1.53-1.60 (m, 2H), 1.70-1.84 (m, 4H), 2.01 (quint, J = 6 Hz, 2H),
2.98 (t, J = 7.8 Hz, 6H), 3.34 (t, J = 6.6 Hz, 2H), 6.52-6.53 (m,
1H, ArH), 6.63-6.68 (m, 1H, ArH), 7.03 (s, 1H, ArH), 7.50-7.52
–
1
1
2
1
2
6
930, 2216, 1488-1653 cm ; H NMR (400 MHz, CDCl ): δ
3
.49-1.55 (m, 2H), 1.74 (brm, 4H), 1.93 (quint, J = 6.4 Hz, 2H),
.95-2.98 (m, 6H), 3.19 (t, J = 5.4 Hz, 2H), 3.79 (br, 1H, NH),
.61 (s, 1H, ArH), 7.30-7.33 (m, 2H, ArH), 7.39-7.42 (m, 2H,
13
(m, 1H, ArH); C NMR (100 MHz, CDCl ): δ = 21.1, 24.0, 26.4,
3
29.0, 41.4, 54.0, 108.3, 111.0, 113.0, 116.8, 119.6, 126.1, 126.3,
13
+
ArH); C NMR (100 MHz, CDCl ): δ 21.4, 24.1, 26.3, 29.6,
127.7, 138.7, 139.3, 149.0; HRMS (ESI): m/z [M + H] calcd for
3
4
1
1.5, 54.2, 115.8, 116.0, 119.0, 119.1, 129.1, 130.2, 130.3, 130.6,
30.7, 136.7, 148.2; HRMS (ESI): m/z [M + H] calcd for
C H N O: 308.1757; found: 308.1744.
19
22
3
+
6
-Morpholino-8-phenyl-1,2,3,4-tetrahydroquinoline-5-
C H ClN : 352.1575; found: 352.1579.
21
23
3
carbonitrile 7o
6
-(Piperidin-1-yl)-8-(thiophen-2-yl)-1,2,3,4-
A mixture of 4-morpholino-2-oxo-6-phenyl-2H-pyran-3-carbonitrile
tetrahydroquinoline-5-carbonitrile 7m
4
(0.5 mmol, 0.141 g), N-boc-3-piperidone 5 (0.6 mmol, 0.119 g),
A mixture of 2-oxo-4-(piperidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.143 g), N-boc-3-piperidone 5 (0.6 mmol,
sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was stirred at r.t.
for 3 hours. When the compound 4 was completely consumed in the
reaction as indicated by TLC, the crude mixture was poured drop-
wise onto ice–water with constant stirring and neutralized with 10%
aq. HCl. The resulting precipitate was collected by filtration, washed
with water and dried. The obtained crude product was treated with
TFA (10.0 mmol, 0.76 ml) in DCM (3.0 mL) at room temperature
for 30-35 minutes. Then reaction mixture was poured onto crushed
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 4 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
ice. Reaction mixture was neutralized with NaHCO
with DCM (25.0 mL×3). The combined organic layer was dried over
anhydrous Na SO and excess of solvent was removed under
and extracted
3
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
2
4
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
vacuum. The crude products thus obtained was purified by silica gel
column chromatography using 10% ethyl acetate in hexane as an
eluent to afford 7o yellow solid; yield: 152 mg (95%); mp = 130–
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7m yellow
solid; yield: 145 mg (90%); mp = 130–132 °C; IR (KBr): 3408,
–1 1
132 °C; IR (KBr): 3417, 2922, 2217, 1420- 1576 cm ; H NMR
(400 MHz, CDCl ): δ 1.98 (quint, J = 6.8 Hz, 2H), 2.97 (t, J = 6.6
3
Hz, 2H), 3.02 (t, J = 4.2 Hz, 4H), 3.19 (t, J = 5.6 Hz, 2H), 3.86 (t,
J = 4.6 Hz, 4H), 6.67 (s, 1H, ArH), 7.35-7.39 (m, 3H, ArH),
–
1
1
2
1
2
925, 2215, 1435-1568 cm ; H NMR (400 MHz, CDCl ): δ
3
13
.49-1.55 (m, 2H), 1.73–1.75 (m, 4H), 1.99 (quint, J = 6.8 Hz,
H), 2.95-2.98 (m, 6H), 3.24 (t, J = 5.4 Hz, 2H), 4.37 (br, 1H,
7.43-7.46 (m, 2H, ArH); C NMR (100 MHz, DMSO-d ): δ =
6
20.4, 26.1, 41.0, 52.3, 66.4, 106.6, 116.7, 119.2, 125.3, 127.7,
NH), 6.79 (s, 1H, ArH), 7.11 (dd, J = 3.6 Hz, J = 5.2 Hz, 1H,
ArH), 7.19 (dd, J = 1.2 Hz, J = 3.6 Hz, 1H, ArH), 7.37 (dd, J =
128.7, 128.8, 130.6, 131.0, 138.0, 145.5; HRMS (ESI): m/z [M +
+
H] calcd for C H N O: 320.1757; found: 320.1745.
20
22
3
13
1
.2 Hz, J = 5.2 Hz, 1H, ArH); C NMR (100 MHz, CDCl ): δ
3

9
6
-Morpholino-8-(p-tolyl)-1,2,3,4-tetrahydroquinoline-5-
A mixture of 6-(4-chlorophenyl)-4-morpholino-2-oxo-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.158 g), N-boc-3-piperidone 5 (0.6 mmol,
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
carbonitrile 7p
0
A
mixture
carbonitrile 4 (0.5 mmol, 0.148 g), N-boc-3-piperidone 5 (0.6 mmol,
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7o yellow
solid; yield: 159 mg (95%); mp = 130–132 °C; IR (KBr): 3415,
926, 2217, 1445-1665 cm ; H NMR (400 MHz, CDCl ): δ
.91 (quint, J = 8 Hz, 2H), 2.38 (s, 3H, -CH ), 2.96 (t, J = 8 Hz,
H), 3.01-3.03 (m, 4H), 3.18 (t, J = 12 Hz, 2H), 3.85-3.87 (m,
H), 6.67 (s, 1H, ArH), 7.21-7.25 (m, 4H, ArH); C NMR (100
MHz, CDCl ): 21.0, 21.2, 26.2, 41.5, 52.7, 67.0, 107.2, 117.0,
19.1, 126.3, 128.7, 129.0, 129.7, 130.2, 132.0, 134.7, 138.0;
of
4-morpholino-2-oxo-6-(p-tolyl)-2H-pyran-3-
stirred at r.t. for 4 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7r yellow
solid; yield: 151 mg (85%); mp = 130–132 °C; IR (KBr): 3395,
926, 2217, 1452-1570 cm ; H NMR (400 MHz, CDCl ): δ
.98 (quint, J = 6.8 Hz, 2H), 2.96 (t, J = 6 Hz, 2H), 3.01-3.03 (m,
4H), 3.19 (t, J = 4.8 Hz, 2H), 3.86 (t, J = 4.2 Hz, 4H), 6.63 (s,
H, ArH), 7.29-7.32 (m, 2H, ArH), 7.40-7.42 (m, 2H, ArH); C
NMR (100 MHz, CDCl ): δ 21.0, 26.3, 41.5, 52.7, 67.0, 108.0,
116.7, 116.8, 119.0, 126.4, 128.4, 129.2, 130.3, 131.6, 134.1,
0
(
3
(
2
4
3
2
4
–1
1
2
1
3
–1
1
2
1
2
4
3
13
1
3
3
13
+
1
3
36.2; HRMS (ESI): m/z [M + H] calcd for C H ClN O:
20
21
3
3
54.1368; found: 354.1344.
1
+
HRMS (ESI): m/z [M + H] calcd for C H N O: 334.1914;
8-(4-Bromophenyl)-6-morpholino-1,2,3,4-tetrahydroquinolin
e -5-carbonitrile 7s
21
24
3
found: 334.1918.
-(4-Fluorophenyl)-6-morpholino-1,2,3,4-
tetrahydroquinoline-5-carbonitrile7q
8
A mixture of 6-(4-bromophenyl)-4-morpholino-2-oxo-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.249 g), N-boc-3-piperidone 5 (0.6 mmol,
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
A mixture of 6-(4-fluorophenyl)-4-morpholino-2-oxo-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.150 g), N-boc-3-piperidone 5 (0.6 mmol,
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
stirred at r.t. for 3 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
(4.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7s yellow
solid; yield: 162 mg (81%); mp = 145–147 °C; IR (KBr): 3395,
2
1
3
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
2
4
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7q yellow
solid; yield: 142 mg (84%); mp = 130–132 °C; IR (KBr): 3400,
–1
1
953, 2217, 1443-1677 cm ; H NMR (400 MHz, CDCl ): δ
3
.99 (quint, J = 6.4 Hz, 2H), 2.96-2.98 (m, 2H), 3.00-3.03 (m,
–
1
1
4H), 3.22 (t, J = 5.6 Hz, 2H), 3.86 (t, J = 4.4 Hz, 4H), 6.63 (s,
H, ArH), 7.25-7.28 (m, 2H, ArH), 7.52 (d, J = 8.4 Hz, 2H,
2
2
4
7
922, 2216, 1441-1652 cm ; H NMR (400 MHz, CDCl ): δ
3
1
.01-2.05 (m, 2H), 3.01 (quint, J = 6.4 Hz, 2H), 3.12-3.14 (m,
H), 3.19-3.23 (m, 2H), 3.91-3.93 (m, 4H), 6.79 (s, 1H, ArH),
.13-7.18 (m, 2H, ArH), 7.37-7.40 (m, 2H, ArH); C NMR (100
13
ArH); C NMR (100 MHz, CDCl ): δ 21.1, 26.3, 41.4, 52.8,
67.1, 108.1, 116.8, 118.7, 122.1, 126.0, 130.0, 130.6, 132.2,
1
3
13
+
37.0, 138.0, 146.2; HRMS (ESI): m/z [M + H] calcd for
MHz, CDCl ): δ 21.0, 26.3, 41.6, 52.7, 67.0, 107.7, 116.0 (d, J
3
C-F
C H BrN O: 398.0863; found: 398.0864.
20
21
3
=
20 Hz), 116.7, 119.2, 126.4, 130.7 (d, JC-F = 10 Hz), 131.0,
1
33.6, 137.3, 146.4, 162.4 (d, J = 250 Hz); HRMS (ESI): m/z
8-(4-Methoxyphenyl)-6-morpholino-1,2,3,4-
tetrahydroquinoline-5-carbonitrile 7t
C-F
+
[
M + H] calcd for C H FN O: 338.1663; found: 338.1656.
20
21
3
A
mixture of 6-(4-methoxyphenyl)-4-morpholino-2-oxo-2H-
pyran-3-carbonitrile 4 (0.5 mmol, 0.156 g), N-boc-3-piperidone 5
0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0
mL) was stirred at r.t. for 4 hours. When the compound 4 was
8
-(4-Chlorophenyl)-6-morpholino-1,2,3,4-tetrahydroquinline
-5-carbonitrile 7r
(

10
Tetrahedron
completely consumed in the reaction as indicated by TLC, the
1.94 (quint, J = 6 Hz, 6H), 2.59 (brm, 4H), 2.91 (t, J = 6.4 Hz,
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (3.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
2H), 3.16-3.22 (m, 6H), 4.68 (br, 1H, NH), 7.13-7.24 (m, 3H,
ArH), 7.97 (d, J = 7.6 Hz, 1H); C NMR (100 MHz, DMSO-d6):
δ 20.6, 24.3, 25.7, 26.0, 28.7, 41.1, 51.3, 110.1, 117.2, 123.7,
13
1
1
25.4, 125.6, 126.1, 126.4, 127.1, 127.4, 127.8, 132.3, 137.5,
+
39.3; HRMS (ESI): m/z [M + H] calcd for C H N : 330.1965;
22
24
3
found: 330.1955.
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
6
-(4-Methylpiperidin-1-yl)-1,2,3,4,7,8-hexahydronaphtho[2,1-
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 7t Yellow
solid; yield: 154 mg (88%); mp = 123–125 °C; IR (KBr): 3408,
h]quinoline-5-carbonitrile 8b
A
mixture of 4-(4-methylpiperazin-1-yl)-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile 4 (0.5 mmol, 0.160 g), N-boc-3-
piperidone 5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in
DMSO (5.0 mL) was stirred at r.t. for 5 hours. When the compound
–
1
1
2
1
924, 2215, 1444-1606 cm ; H NMR (400 MHz, CDCl ): δ
3
.97 (quint, J = 6.8 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.99-3.01
(
(
(
m, 4H), 3.19 (t, J = 5.2 Hz, 2H), 3.83 (s, 3H, -OMe,), 3.84-3.86
4
was completely consumed in the reaction as indicated by TLC, the
m, 4H), 6.63 (s, 1H, ArH), 6.96 (d, J = 8.8 Hz, 2H, ArH), 7.29
13
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (4.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
d, J = 8.4 Hz, 2H, ArH); C NMR (100 MHz, CDCl ): δ 21.2,
3
2
1
6.3, 41.4, 52.8, 55.3, 67.1, 107.3, 114.4, 117.0, 119.0, 125.6,
30.0, 130.1, 131.2, 138.2, 146.2, 159.3; HRMS (ESI): m/z [M +
+
H] calcd for C H N O : 350.1863; found: 350.1857.
21
24
3
2
4
.3. General Procedure for 6-sec.amino-1,2,3,4,7,8-
hexahydro-1-aza-benzo[c]phenanthrene-5-carbonitriles 8: 2-
Oxobenzo[h]chromenes 4 (0.5 mmol), N-boc-3-piperidone 5 (0.6
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
3
2
4
mmol), NaNH (1.0 mmol) and DMSO (5.0 ml) was added to RB
2
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 13% ethyl acetate in hexane as an eluent to afford 8b yellow
solid; yield: 143 mg (80%); mp = 98–100 °C; IR (KBr): 3395,
2
2
2
2
flask. The resulting solution was stirred at r.t. for 3 h until the 2-
oxobenzo[h]chromenes 4 was completely consumed (monitored
by TLC). After completion of the reaction, the reaction mixture
was poured onto crushed ice. The mixture was neutralized with
–1
1
951, 2214, 11422-1579 cm ; H NMR (400 MHz, CDCl ): δ
3
1
0% aq. HCl and resulting precipitate was collected by filtration
and dried. Crude product treated with TFA (10 mmol) in DCM
3mL) at room temperature for 30-35 min. After completion, the
.07 (quint, J = 7.6 Hz, 2H), 2.63-2.66 (m, 2H), 2.73-2.76 (m,
H), 2.97 (t, J = 5.6 Hz, 4H), 3.25 (t, J = 5.2 Hz, 2H), 3.38 (brm,
(
H), 3.79-3.89 (m, 7H), 6.81 (dd, J = 1.2 Hz, J = 8.4 Hz, 2H,
reaction mixture was poured onto crushed ice with vigorous
13
ArH), 6.86 (s, 1H, ArH), 7.99 ( d, J = 9.9 Hz, 1H); C NMR
stirring followed by neutralization with NaHCO and extracted
3
(100 MHz, CDCl ): δ 21.6, 23.8, 26.0, 30.5, 41.5, 46.4, 51.3,
3
with dichlromethane (25.0 mL×3). The combined organic layer
was dried over anhydrous Na SO and than solvent was removed
5
1
7.5, 107.8, 118.2, 123.8, 125.4, 126.1, 127.4, 128.0, 132.5,
+
2
4
32.7, 136.8, 139.1, 140.4, 143.3; HRMS (ESI): m/z [M + H]
under vacuum. The crude was purified by silica gel column
chromatography using mixture of hexane/ethyl acetate (85:15) to
calcd for C H N : 359.2230; found: 359.2234.
23
27
4
6
-(Piperidin-1-yl)-1,2,3,4,7,8-hexahydronaphtho[2,1-
obtain
a
pure
6-sec.amino-1,2,3,4,7,8-hexahydro-1-aza-
h]quinoline-5-carbonitrile 8c
benzo[c]phenanthrene-5-carbonitriles 8.
A
mixture 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-
6
-(Pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydronaphtho[2,1-
benzo[h]chromene-3-carbonitrile 4 (0.5 mmol, 0.153s g), N-boc-3-
piperidone 5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in
DMSO (5.0 mL) was stirred at r.t. for 5 hours. When the compound
h]quinoline-5-carbonitrile 8a
A mixture of 6-(4-bromophenyl)-4-morpholino-2-oxo-2H-pyran-3-
carbonitrile 4 (0.5 mmol, 0.146 g), N-boc-3-piperidone 5 (0.6 mmol,
4
was completely consumed in the reaction as indicated by TLC, the
0
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (4.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
stirred at r.t. for 5 hours. When the compound 4 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
(
4.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 15% ethyl acetate in hexane as an eluent to afford 8c yellow
solid; yield: 138 mg (80%); mp = 143-145 °C; IR (KBr): 2924,
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 15% ethyl acetate in hexane as an eluent to afford 8a yellow
solid; yield: 124 mg (75%); mp = 130–132 °C; IR (KBr): 3398,
–1
1
2
6
225, 1606 cm ; H NMR (400 MHz, CDCl ): δ 1.41-1.62 (m,
3
H), 1.96 (quint, J = 6 Hz, 2H), 2.55-2.58 (m, 2H), 2.65-2.69
(m, 2H), 2.89 (t, J = 6.8 Hz, 4H), 3.14-3.21 (m, 4H), 4.63 (br,
–1
1
2
933, 2216, 1431-1698 cm ; H NMR (400 MHz, CDCl ): δ
3

1
1
1
H, NH), 7.14-7.23 (m, 3H, ArH), 7.96 (d, J = 7.6 Hz, 1H, ArH);
67.8, 110.2, 117.7, 124.1, 125.0, 125.3, 126.2, 127.5, 128.0,
1
3
+
C NMR (100 MHz, CDCl ): δ 21.4, 24.1, 24.6, 26.1, 26.8, 29.4,
132.5, 137.0, 139.9, 140.0, 141.2; HRMS (ESI): m/z [M + H]
3
4
1
1.6, 52.2, 118.0, 121.2, 124.3, 125.5, 126.0, 126.2, 127.2, 127.5,
28.0, 131.3, 132.6, 136.7, 140.2; HRMS (ESI): m/z [M + H]
calcd for C H N O: 346.1914; found: 346.1915.
22
24
3
+
4
.4. General Procedure for 6-(methylthio)-8-aryl-1,2,3,4-
tetrahydroquinoline-5-carbonitrile 9: mixture of 4-
(methylthio)-2-oxo-6-aryl-2H-pyran-3-carbonitriles (0.5
mmol), N-boc-3-piperidone 5 (0.6 mmol), NaNH (1.0 mmol) in
calcd for C H N : 344.2121; found: 344.2141.
23
26
3
A
1
0-Methoxy-6-(piperidin-1-yl)-1,2,3,4,7,8-
3
hexahydronaphtho[2,1-h]quinoline-5-carbonitrile 8d
2
DMSO was stirred at room temp for 1 h. Then reaction mixture
was poured in to crushed ice with vigorous stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration and dried. Crude product treated with TFA
A mixture 8-methoxy-2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile 4 (0.5 mmol, 0.168 g), N-boc-3-
piperidone 5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in
DMSO (5.0 mL) was stirred at r.t. for 5 hours. When the compound
(10 mmol) in DCM (3.0 mL) at room temperature for 20-25
4
was completely consumed in the reaction as indicated by TLC, the
minutes. Then mixture was poured onto crushed ice and
neutralized with saturated NaHCO3 solution followed by
extraction with DCM (25.0 mL×3). The combined organic layer
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (4.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
was dried over anhydrous Na SO and then evaporated the
2 4
solvent under reduced pressure. The crude was purified by silica
gel column chromatography using hexane/ethyl acetate mixture
(90:10) as an eluent to obtain 6-(methylthio)-8-aryl-1,2,3,4-
tetrahydroquinoline-5-carbonitriles 9.
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 12% ethyl acetate in hexane as an eluent to afford 8d yellow
solid; yield: 146 mg (78%); mp = 130–132 °C; IR (KBr): 3391,
6
-(Methylthio)-8-phenyl-1,2,3,4-tetrahydroquinoline-5-
carbonitrile 9a
A mixture of 4-(methylthio)-2-oxo-6-phenyl-2H-pyran-3-carbonitrile
3 (0.5 mmol, 0.121 g), N-boc-3-piperidone 5 (0.6 mmol, 0.119 g),
sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was stirred at r.t.
for 3 hours. When the compound 3 was completely consumed in the
reaction as indicated by TLC, the crude mixture was poured drop-
wise onto ice–water with constant stirring and neutralized with 10%
aq. HCl. The resulting precipitate was collected by filtration, washed
with water and dried. The obtained crude product was treated with
TFA (10.0 mmol, 0.76 ml) in DCM (4.0 mL) at room temperature
for 30-35 minutes. Then reaction mixture was poured onto crushed
–1
1
2
1
2
930, 2215, 1450-1650 cm ; H NMR (400 MHz, CDCl ): δ
.54-1.64 (m, 6H), 1.99 (quint, J = 5.2 Hz, 2H), 2.54-2.57 (m,
H), 2.66-2.69 (m, 2H), 2.88 (t, J = 6.4 Hz, 4H), 3.16 (t, J = 5.2
3
Hz, 4H), 3.77 (s, 3H, -OMe), 6.71-6.74 (m, 1H, ArH), 6.77-6.78
13
(
m, 1H, ArH), 7.92 (d, J = 8.4 Hz, 1H, ArH); C NMR (100
MHz, CDCl ): δ 21.2, 22.6, 24.0, 24.7, 26.0, 29.6, 42.0, 52.4,
3
5
1
5.3, 111.3, 113.6, 113.7, 114.0, 118.0, 124.9, 124.9, 127.2,
35.8, 138.1, 139.2, 142.2, 159.0; HRMS (ESI): m/z [M + H]
+
calcd for C H N O: 374.2227; found: 374.2228.
24
28
3
ice. Reaction mixture was neutralized with NaHCO and extracted
3
6
-Morpholino-1,2,3,4,7,8-hexahydronaphtho[2,1-
with DCM (25.0 mL×3). The combined organic layer was dried over
h]quinoline-5-carbonitrile 8e
anhydrous Na SO4 and excess of solvent was removed under
2
vacuum. The crude products thus obtained was purified by silica gel
column chromatography using 10% ethyl acetate in hexane as an
eluent to afford 9a yellow solid; yield: 88 mg (62%); mp = 78–80
A
mixture of 4-morpholino-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile 4 (0.5 mmol, 0.154 g), N-boc-3-
piperidone 5 (0.6 mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in
DMSO (5.0 mL) was stirred at r.t. for 3 hours. When the compound
–1 1
°
C; IR (KBr): 3425, 2923, 2219, 1487-1559 cm ; H NMR (400
MHz, CDCl ): δ 1.98 (quint, J = 7.2 Hz, 2H), 2.45 (s, 3H, -SMe),
4
was completely consumed in the reaction as indicated by TLC, the
3
2
.98 (t, J = 6.6 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), 7.05 (s, 1H,
crude mixture was poured drop-wise onto ice–water with constant
stirring and neutralized with 10% aq. HCl. The resulting precipitate
was collected by filtration, washed with water and dried. The
obtained crude product was treated with TFA (10.0 mmol, 0.76 ml)
in DCM (4.0 mL) at room temperature for 30-35 minutes. Then
reaction mixture was poured onto crushed ice. Reaction mixture was
1
3
ArH), 7.34-7.39 (m, 3H, ArH), 7.43-7.46 (m, 2H, ArH);
NMR (100 MHz, CDCl ): δ = 19.1, 20.8, 26.4, 41.2, 115.1,
3
116.5, 125.5, 126.5, 128.1, 128.8, 129.1, 130.5, 131.2, 137.4,
141.3; HRMS (ESI): m/z [M + H] calcd for C H N S:
C
+
1
7
17
2
281.1107; found: 281.1092.
-(Methylthio)-8-(p-tolyl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile 9b
mixture 4-(methylthio)-2-oxo-6-(p-tolyl)-2H-pyran-3-
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
3
6
The combined organic layer was dried over anhydrous Na SO and
2
4
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 15% ethyl acetate in hexane as an eluent to afford 8e yellow
solid; yield: 140 mg (81%); mp = 150–152 °C; IR (KBr): 3397,
A
of
carbonitrile 3 (0.5 mmol, 0.128 g), N-boc-3-piperidone 5 (0.6 mmol,
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
0
–
1
1
2
1
2
4
951, 2215, 1422-1558 cm ; H NMR (400 MHz, CDCl ): δ
stirred at r.t. for 3 hours. When the compound 3 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
3
.97 (quint, J = 6.4 Hz, 2H), 2.56-2.59 (m, 2H), 2.65-2.68 (m,
H), 2.89 (t, J = 6.8 Hz, 4H), 3.16-3.29 (m, 4H), 3.73-3.84 (m,
H), 7.13-7.24 (m, 3H, ArH), 7.95 (d, J = 7.6 Hz, 1H, ArH);
13
C
NMR (100 MHz, CDCl ): δ 21.4, 24.7, 26.2, 29.3, 41.5, 51.0,
3

1
2
Tetrahedron
(
3.0 mL) at room temperature for 30-35 minutes. Then reaction
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 9d yellow
solid; yield: 71 mg (52%); mp = 90–92°C; IR (KBr): 3418, 2926,
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 9b yellow
solid; yield: 95 mg (64%); mp = 80–82 °C; IR (KBr): 3414,
3
2
4
–1
1
2
216, 1450-1607 cm ; H NMR (400 MHz, CDCl ): δ 2.02
3
(quint, J = 6.8 Hz, 2H), 2.48 (s, 3H, -SMe), 3.01 (t, J = 6.4 Hz,
2
1
H), 3.39 (t, J = 5.4 Hz, 2H), 6.54 (dd, J = 1.6 Hz, J = 3.2 Hz,
H, ArH), 6.67 (d, J = 2.8 Hz, 1H, ArH), 7.44 (s, 1H, ArH), 7.53
–1
1
13
2
1
924, 2218, 1438- 1608 cm ; H NMR (400 MHz, CDCl ): δ
.91 (quint, J = 6.8 Hz, 2H), 2.32 (s, 3H, -SMe), 2.38 (s, 3H, -
3
(d, J = 1.6 Hz, 1H, ArH); C NMR (100 MHz, CDCl ): δ 19.3,
3
2
0.5, 26.6, 41.2, 108.6, 111.6, 115.3, 116.5, 118.3, 126.0, 126.8,
+
CH ), 2.92 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 5.6 Hz, 2H), 4.19 (br,
3
129.0, 140.8, 142.2, 151.6; HRMS (ESI): m/z [M + H] calcd for
13
1
H, NH), 6.98 (s, 1H, ArH), 7.16-7.18 (m, 4H, ArH); C NMR
C H N OS: 271.0900; found: 271.0903.
15
15
2
(100 MHz, CDCl ): δ 19.1, 20.8, 21.1, 26.4, 41.1, 115.0, 116.6,
3
4
.5. General Procedure for the synthesis of fused and
1
25.3, 126.4, 128.6, 129.8, 130.6, 131.2, 134.3, 138.0, 141.4;
+
isolated quinolines 12: Compound 12 were synthesized by
reaction of tetrahydroquinolines (7, 8 and 9) and (2,3-dichloro-
HRMS (ESI): m/z [M + H] calcd for C H N S: 295.1263;
18
19
2
found: 295.1269.
-(4-Methoxyphenyl)-6-(methylthio)-1,2,3,4-
tetrahydroquinoline-5-carbonitrile 9c
A mixture of 6-(4-methoxyphenyl)-4-(methylthio)-2-oxo-2H-pyran-
5
,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol), in toluene
o
8
(3.0 mL) at 120 C. The mixture was reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines. The excess
of solvent was removed under reduced pressure and crude
product was purified by column chromatography using 8%
ethylacetate in hexane.
3
-carbonitrile 3 (0.5 mmol, 0.136 g), N-boc-3-piperidone 5 (0.6
mmol, 0.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL)
was stirred at r.t. for 3 hours. When the compound 3 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
6
-(4-Benzylpiperazin-1-yl)-8-(4-methoxyphenyl)quinoline-
5
-carbonitrile 12a
A
mixture of 6-(4-benzylpiperazin-1-yl)-8-(4-methoxyphenyl)-
1,2,3,4-tetrahydroquinoline-5-carbonitrile 7e (0.2 mmol, 0.087 g),
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol,
0.090 g), in toluene (3.0 mL) was stirred at reflux for 1 hours until
TLC show complete consumption of tetrahydroquinolines 7e. The
excess of solvent was removed under reduced pressure and crude
product was purified bsilica gel column chromatography using 10%
ethylacetate in hexane as an eluent to afford 12a yellow solid; yield:
72 mg (92%); mp = 138–140 °C; IR (KBr): 2925, 2217, 1450-
(4.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
The combined organic layer was dried over anhydrous Na SO and
excess of solvent was removed under vacuum. The crude products
thus obtained was purified by silica gel column chromatography
using 10% ethyl acetate in hexane as an eluent to afford 9c yellow
solid; yield: 88 mg (56%); mp = 83–85°C; IR (KBr): 3416, 2925,
3
2
4
–
1
1
1606 cm ; H NMR (400 MHz, CDCl ): δ 2.71 (t, J = 4.6 Hz,
4H), 3.56 (t, J = 4.6 Hz, 4H), 3.61 (s, 2H, -CH ), 3.88 (s, 3H, -
OMe), 7.04 (d, J = 8.4 Hz, 2H, ArH), 7.27-7.38 (m, 6H, ArH),
7.47 (dd, J = 3.6 Hz, J = 8.4 Hz, 1H, ArH), 7.61 (d, J = 9.2 Hz,
2H, ArH), 8.42 (d, J = 8.4 Hz, 1H, ArH), 8.81 (d, J = 3.6 Hz,
1H, ArH); C NMR (100 MHz, CDCl ): δ 51.1, 53.0, 55.3, 62.8,
95.4, 113.6, 117.2, 122.1 123.0, 127.2, 128.3, 129.2, 130.5,
131.5, 131.6, 132.2, 137.4, 141.4, 146.5, 148.5, 155.0, 159.8;
3
2
–1
1
2
218, 1434-1607 cm ; H NMR (400 MHz, CDCl ): δ 1.92
3
(quint, J = 8 Hz, 2H), 2.38 (s, 3H, -SMe), 2.91 (t, J = 6.6 Hz, 2
H), 3.16 (t, J = 5.6 Hz, 2H), 3.77 (s, 3H, -OMe), 6.91 (d, J = 7.6
Hz, 2H, ArH), 6.97 (s, 1H, ArH), 7.22 (d, J = 8.8 Hz, 2H, ArH);
1
3
3
13
C NMR (100 MHz, CDCl ): δ 19.1, 20.8, 26.3, 41.2, 55.3,
3
1
1
3
14.5, 114.8, 116.6, 125.3, 126.4, 129.4, 130.0, 130.4, 131.3,
41.5, 159.4; HRMS (ESI): m/z [M + H] calcd for C H N OS:
+
+
18
19
2
HRMS (ESI): m/z [M + H] calcd for C H N O: 435.2179;
28 27
4
11.1213; found: 311.1219.
-(Furan-2-yl)-6-(methylthio)-1,2,3,4-tetrahydroquinoline-
-carbonitrile 9d
mixture of 6-(furan-2-yl)-4-(methylthio)-2-oxo-2H-pyran-3-
found: 435.2175.
8-Phenyl-6-(piperidin-1-yl)quinoline-5-carbonitrile 12b
mixture of 8-phenyl-6-(piperidin-1-yl)-1,2,3,4-
8
5
A
A
tetrahydroquinoline-5-carbonitrile 7g (0.2 mmol, 0.063 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 7g. The excess
of solvent was removed under reduced pressure and crude product
was purified bsilica gel column chromatography using 6%
ethylacetate in hexane as an eluent to afford 12b yellow solid; yield:
carbonitril 3 (0.5 mmol, 0.136 g), N-boc-3-piperidone 5 (0.6 mmol,
.119 g), sodamide (1.0 mmol, 0.039 g) in DMSO (5.0 mL) was
0
stirred at r.t. for 2 hours. When the compound 3 was completely
consumed in the reaction as indicated by TLC, the crude mixture was
poured drop-wise onto ice–water with constant stirring and
neutralized with 10% aq. HCl. The resulting precipitate was
collected by filtration, washed with water and dried. The obtained
crude product was treated with TFA (10.0 mmol, 0.76 ml) in DCM
5
1
1
7
3 mg (85%); mp = 128-130 °C; IR (KBr): 2922, 2225, 1445-
638 cm ; H NMR (400 MHz, CDCl ): δ 1.67-171 (m, 2H),
.80-1.85 (m, 4H), 3.49-3.53 (m, 4H), 7.39-7.40 (m, 1H, ArH),
.43-7.55 (m, 4H, ArH), 7.64 (d, J = 12 Hz, 2H, ArH), 8.42-8.44
–
1
1
3
(3.0 mL) at room temperature for 30-35 minutes. Then reaction
mixture was poured onto crushed ice. Reaction mixture was
neutralized with NaHCO and extracted with DCM (25.0 mL×3).
13
3
(m, 1H, ArH), 8.78-8.79 (m, 1H, ArH); C NMR (100 MHz,
The combined organic layer was dried over anhydrous Na SO and
2
4

1
3
CDCl ): δ 24.0, 26.2, 52.6, 94.7, 117.4, 123.0, 128.0, 128.2,
(m, 2H, ArH), 8.37-8.39 (m, 1H, ArH), 8.76 (dd, J = 0.8 Hz, J
3
13
1
28.8, 130.2, 130.3, 130.5, 132.1, 138.4, 141.1, 148.2, 155.6;
= 3.6 Hz, 1H, ArH); C NMR (100 MHz, CDCl ): δ 51.4, 66.8,
96.6, 115.1 (d, JC-F = 30 Hz), 116.8, 122.0, 123.2, 130.3, 132.0
3
+
HRMS (ESI): m/z [M + H] calcd for C H N : 314.1652; found:
21
20
3
3
14.1670.
(d, JC-F = 10 Hz), 132.3, 134.0, 141.4, 146.0, 149.0, 154.7, 162.8
+
(d, JC-F = 280 Hz); HRMS (ESI): m/z [M + H] calcd for
8
1
-(4-Chlorophenyl)-6-(piperidin-1-yl)quinoline-5-carbonitrile
2c
C H FN O: 334.1350; found: 334.1352.
20
17
3
8
2f
-(4-Bromophenyl)-6-morpholinoquinoline-5-carbonitrile
A
mixture of 8-(4-chlorophenyl)-6-(piperidin-1-yl)-1,2,3,4-
1
tetrahydroquinoline-5-carbonitrile 7l (0.2 mmol, 0.070 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 7l. The excess
of solvent was removed under reduced pressure and crude product
was purified by silica gel column chromatography using 10%
ethylacetate in hexane as an eluent to afford 12c yellow solid; yield:
5 mg (93%); mp = 143–145 °C; IR (KBr): 2927, 2225, 1441-
606 cm . H NMR (400 MHz, CDCl ): δ = 1.58-1.64 (m, 2H),
.71-1.77 (m, 4H), 3.43 (t, J = 5.4 Hz, 4H), 7.28 (s, 1H, ArH),
.36-7.40 (m, 3H, ArH), 7.48-7.51 (m, 2H, ArH), 8.33 (dd, J =
.2 Hz, J = 4 Hz, 1H), 8.68 (dd, J = 1.2 Hz, J = 8 Hz, 1H);
A
mixture
of
8-(4-bromophenyl)-6-morpholino-1,2,3,4-
tetrahydroquinoline-5-carbonitrile 7s (0.2 mmol, 0.079 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 7s. The excess
of solvent was removed under reduced pressure and crude product
was purified by silica gel column chromatography using 8%
ethylacetate in hexane as an eluent to afford 12f yellow solid; yield:
71 mg (90%); mp = 145–147 °C; IR (KBr): 2923, 2208, 1450-
1584 cm ; H NMR (400 MHz, CDCl ): δ 3.52 (t, J = 4.6 Hz,
4H), 3.95 (t, J = 4.6 Hz, 4H), 7.38 (s, 1H, ArH), 7.51-7.54 (m,
3H, ArH), 7.64 (d, J = 7.6 Hz, 2H, ArH), 8.46 (d, J = 7.6 Hz,
1H), 8.83-8.85 (m, 1H); C NMR (100 MHz, CDCl ): δ 51.4,
67.0, 96.8, 116.7, 122.0, 123.0, 123.3, 130.4, 131.3, 132.0, 132.4,
6
1
1
7
1
–1 1
3
–1
1
3
13
C
NMR (100 MHz, CDCl ): δ 24.0, 26.1, 52.6, 95.0, 117.2, 122.8,
23.0 128.3, 130.6, 131.6, 132.1, 134.4, 136.7, 141.0, 145.2,
48.2, 155.5; HRMS (ESI): m/z [M + H] calcd for C H ClN :
48.1262; found: 348.1280.
3
13
1
1
3
3
+
21
19
3
+
137.0, 141.2, 145.8, 149.1, 154.7; HRMS (ESI): m/z [M + H]
calcd for C H BrN O: 394.0550; found: 394.0542.
20
17
3
6
1
-(Piperidin-1-yl)-8-(thiophen-2-yl)quinoline-5-carbonitrile
2d
6-Morpholino-7,8-dihydronaphtho[2,1-h]quinoline-5-
carbonitrile 12g
A
mixture of 6-(piperidin-1-yl)-8-(thiophen-2-yl)-1,2,3,4-
tetrahydroquinoline-5-carbonitrile 7m (0.2 mmol, 0.064 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 7m. The excess
of solvent was removed under reduced pressure and crude product
was purified by silica gel column chromatography using 8%
ethylacetate in hexane as an eluent to afford 12d yellow solid; yield:
A
mixture of 6-morpholino-1,2,3,4,7,8-hexahydronaphtho[2,1-
h]quinoline-5-carbonitrile 8e (0.2 mmol, 0.069 g), (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090 g), in toluene
(3.0 mL) was stirred at reflux for 1 hours until TLC show complete
consumption of tetrahydroquinolines 8e. The excess of solvent was
removed under reduced pressure and crude product was purified by
silica gel column chromatography using 12% ethylacetate in hexane
as an eluent to afford 12f yellow solid; yield: 55 mg (81%); mp =
163–165 °C; IR (KBr): 2924, 2211, 1443-1601 cm ; H NMR
(400 MHz, CDCl ): δ 2.81-2.84 (m, 2H), 2.97-3.01 (m, 2H),
3.47-3.52 (m, 4H), 3.92-3.96 (m, 4H), 7.33-7.35 (m, 2H, ArH),
7.37-7.42 (m, 1H, ArH), 7.53 (dd, J = 4 Hz, J = 8 Hz, 1H, ArH),
8.50-8.54 (m, 2H, ArH), 8.95 (dd, J = 1.6 Hz, J = 4.4 Hz, 1H,
5
1
1
7
5 mg (87%); mp = 146–148 °C; IR (KBr): 2924, 2215, 1445-
–1
1
–1
1
608 cm ; H NMR (400 MHz, CDCl ): δ 1.65-170 (m, 2H),
3
.79-1.82 (m, 4H), 3.44-3.51 (m, 4H), 7.37-7.38 (m, 1H, ArH),
3
.42-7.50 (m, 3H, ArH), 7.62 (d, J = 6.8 Hz, 1H, ArH), 8.40-8.42
13
(m, 1H, ArH), 8.76-8.77 (m, 1H, ArH); C NMR (100 MHz,
CDCl ): δ 24.0, 26.2, 52.6, 94.7, 122.8, 128.0, 128.2, 128.8,
3
13
1
30.2, 130.3, 130.5, 132.0, 135.5, 138.1, 138.4, 146.6, 155.6;
ArH); C NMR (100 MHz, CDCl ): δ 25.2, 29.5, 51.5, 67.3,
100.5, 117.0, 122.2, 126.0, 126.8, 128.6, 128.7, 131.7, 132.1,
132.8, 138.9, 139.0, 139.2, 142.0, 149.2, 153.1; HRMS (ESI):
3
+
HRMS (ESI): m/z [M + H] calcd for C H N S: 320.1216;
19
18
3
found: 320.1223.
+
m/z [M + H] calcd for C H N O: 342.1601; found: 342.1605 .
22
20
3
8
-(4-Fluorophenyl)-6-morpholinoquinoline-5-carbonitrile
1
2e
6-(Methylthio)-8-(p-tolyl)quinoline-5-carbonitrile 12h
mixture of 6-(methylthio)-8-(p-tolyl)-1,2,3,4-
A
mixture
of
8-(4-fluorophenyl)-6-morpholino-1,2,3,4-
A
tetrahydroquinoline-5-carbonitrile 7q (0.2 mmol, 0.067 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 7q. The excess
of solvent was removed under reduced pressure and crude product
was purified by silica gel column chromatography using 8%
ethylacetate in hexane as an eluent to afford 12e yellow solid; yield:
tetrahydroquinoline-5-carbonitrile 9b (0.2 mmol, 0.059 g), (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) DDQ 11 (0.4 mmol, 0.090
g), in toluene (3.0 mL) was stirred at reflux for 1 hours until TLC
show complete consumption of tetrahydroquinolines 9b. The excess
of solvent was removed under reduced pressure and crude product
was purified by silica gel column chromatography using 10%
ethylacetate in hexane as an eluent to afford 12h white solid; yield:
56 mg (96%); mp = 138–140 °C; IR (KBr): 2921, 2213, 1436-
6
1
4
1
0 mg (90%); mp = 140–142 °C; IR (KBr): 2928, 2218, 1434-
–1
1
–1 1
606 cm ; H NMR (400 MHz, CDCl ): δ 3.44 (t, J = 5.4 Hz,
1652 cm ; H NMR (400 MHz, CDCl ): δ 2.44 (s, 3H, -SMe), 2.
3
3
H), 3.87 (t, J = 4.6 Hz, 4H), 7.09-7.14 (m, 2H, ArH), 7.30 (s,
H, ArH), 7.43 (dd, J = 4 Hz, J = 8.8 Hz, 1H, ArH), 7.53-7.58
69 (m, 3H, -CH ), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.53-7.55 (m,
3
2H, ArH), 7.56 (d, J = 4.0 Hz, 1H, ArH), 7.62 (s, 1H, ArH), 8.46

1
4
Tetrahedron
(
dd, J = 1.6 Hz, J = 8.4 Hz, 1H, ArH), 8.93 (dd, J = 1.6 Hz, J
Parker, E. M.Tetrahydroquinoline sulfonamides as vasopressin 1b
receptor antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 6018–
13
=
4.0 Hz, 1H, ArH); C NMR (100 MHz, CDCl ): δ 16.0, 21.4,
3
6
022. (c) Smirnova, T. A.; Gavrilov, M. Y.; Nazmetdinov, F. Y.;
1
1
05.8, 115.4, 123.4, 127.0, 129.1, 129.6, 130.5, 132.7, 135.0,
38.8, 143.6, 145.2, 146.2, 150.2; HRMS (ESI): m/z [M + H]
Kolla, V. E.; Kon’shin, M. E. Synthesis and antidepressant
activity of acylhydrazides of 2-chloroand 2-anilino-5,6,7,8-
tetrahydroquino line-4-carboxylic acids. Pharm. Chem. J. 1999,
+
calcd for C H N S: 295.1263; found: 295.1261.
18
19
2
3
3, 370. (d) Alqasoumi, S. I.; Al-Taweel, A. M.; Alafeefy, A. M.;
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Acknowledgements
RP thanks CSIR (Project No. 02(0286)/16/EMR-II) for
providing financial assistance. DS also thanks CSIR (Project No.
0
2(0286)/16/EMR-II) for providing RA fellowship. S, RP, thank
UGC and RS thank CSIR for providing research fellowship. AE
thank Department of Biotechnology (DBT) and The World
Academy of Sciences (TWAS) for research fellowship. We thank
USIC, Delhi University for providing instrumentation facility.
7
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Electronic Supporting Information: H and C spectra of the
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Supporting Information
Base-promoted regioselective synthesis of 1,2,3,4-
terahydroquinolines and quinolines from N-Boc-3-piperidone
Shally, Ismail Althagafi, Divya Singhal, Rahul Panwar, Ranjay Shaw, Amr Elagamy and
Ramendra Pratap*
Department of Chemistry, University of Delhi, North Campus, Delhi, India, Pin-110007
Table of Contents:
SN
1
2
Content
Page no
2-4
5-43
X-ray crystallography data of 6t
1
13
H NMR and C NMR Spectra
1

X-ray Crystallographic Data for compound 6t
Crystal data for C H N O (CCDC No 1918629): A yellow crystal (0.220 x 0.200 x 0.180 mm )
3
2
6
31
3
4
was mounted on a capillary tube for indexing and intensity data collection at 298K on an Oxford
1
Xcalibur Sapphire3 CCD single-crystal diffractometer (MoKα radiation, λ = 0.71073 Å).
Routine Lorentz and polarization corrections were applied, and an absorption correction was
performed using the ABSCALE 3 program [CrysAlis Pro software system, Version 171.34;
Oxford Diffraction Ltd., Oxford, U.K., 2011]. Data reduction was performed with the
1
2
CrysAllis-PRO. The structure was solved by direct methods using SIR-92 program and refined
on F2 using all data by full matrix least-squares procedures with SHELXL-2016/6 incorporated
3
in WINGX 1.8.05 crystallographic collective package. The hydrogen atoms were placed at the
calculated positions and included in the last cycles of the refinement. All calculations were done
4
-5
using the WinGX software package. Crystallographic data collection and structure solution
parameters are summarized in Table S1. This data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.uk/data_request/cif.
Figure 1. ORTEP diagram of 6t; thermal ellipsoids are drown at the 50% probability level
2

Table 1. Crystal data and structure refinement for 6t
CCDC No.
1918629
Empirical formula
C H N O
4
2
6
31
3
Formula weight
449.54
293
Temperature/k
Crystal system
triclinic
P -1
Space group
a/Å
b/Å
c/Å
α/°
β/°
9.4402(4)
12.1551(7)
12.3895(7)
98.825(5)
111.143(5)
γ/°
104.139(4)
3
Volume/Å
1239.09(13)
Z
2
3
ρcalcg/cm
1.205
-
1
ꢀ
/mm
F(000)
Θ range for data collection/°
Index ranges
Reflections collected
0.082
480.0
2.854 to 25.000
2
-11<=h<=11, -14<=k<=14, -20<=l<=20
14950
Independent reflections
4350 [R = 0.0281, R
= 0.0323]
sigma
int
Data/restraints/parameters
4350/304/354
3

2
Goodness-of-fit on F
1.064
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å
R = 0.0539, wR = 0.1298
1
2
R = 0.0753, wR = 0.1409
1
2
-3
0.21/-0.23
References
(1) CrysAlisPro, v. 1.171.33.49b, Oxford Diffraction Ltd., 2009.
(2) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Cryst. 1993, 26,
3
43.
(
3) Sheldrick, G. M. SHELXL-2014/7: Program for the solution of crystal structures,
University of Gottingen, Gottingen, Germany, 2014.
(
4) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr., 2008, 64, 112.
5) Farrugia, L. J. WinGX, v. 1.70, An Integrated System of Windows Programs for the
Solution, Refinement and Analysis of Single-Crystal X-ray Diffraction Data, Department
of Chemistry, University of Glasgow, 2003.
(
4

1
13
HNMR and C NMR spectrum of tert-butyl 5-cyano-8-(4-methoxyphenyl)-6-(piperidin-1-yl)-3,4-
dihydroquinoline-1(2H)-carboxylate
5

1
13
HNMR and C NMR spectrum of tert-butyl 5-cyano-8-(4-methoxyphenyl)-6-morpholino-3,4-
dihydroquinoline-1(2H)-carboxylate
6

1
13
HNMR and C NMR spectrum of 8-(4-bromophenyl)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile
7

1
13
HNMR and C NMR spectrum of 8-(2,4-dichlorophenyl)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile
8

1
13
HNMR and C NMR spectrum of 8-(naphthalen-2-yl)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile
9

1
13
HNMR and C NMR spectrum of 6-(pyrrolidin-1-yl)-8-(thiophen-2-yl)-1,2,3,4-tetrahydroquinoline-5-
carbonitrile
1
0

1
13
HNMR
and
C
NMR
spectrum
of
6-(4-benzylpiperazin-1-yl)-8-(4-methoxyphenyl)-1,2,3,4-
tetrahydroquinoline-5-carbonitrile
1
1

1
13
HNMR
and
C
NMR
spectrum
of
6-(4-benzylpiperazin-1-yl)-8-(4-bromophenyl)-1,2,3,4-
tetrahydroquinoline-5-carbonitrile
1
2