Synthesis and characterization of S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline acetamide analogues

Article abstract of DOI:10.14233/ajchem.2017.20398

S(-)1-Phenyl-1,2,3,4-tetrahydro isoquinoline acetamide analogues are prepared by sequence of reactions which involve a metal hydride reduction of 3,4-dihydroisoquinoline followed by separation of S-form with mandelic acid (chiral reagent) by resolution. The product S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline is treated with halosubstituted acetyl chlorides to obtain tetrahydro isoquinoline acetyl chloride which is further employed to synthesize acetamide derivatives of tetrahydro isoquinoline using various substituted aryl amines. The products were characterized by advanced spectroscopic techniques.

Full text of DOI:10.14233/ajchem.2017.20398

Asian Journal of Chemistry; Vol. 29, No. 5 (2017), 1035-1038
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20398
Synthesis and Characterization of S(-)1-Phenyl-1,2,3,4-Tetrahydro IsoquinolineAcetamideAnalogues
1
2,*
1
3
N. KRISHNA RAO , M. SURENDRA BABU , M.V. BASAVESWARA RAO , R. KESHAVI ,
3
3
3,*
N. SUNDARA RAO , N.H. ESWARA PRASAD and Y.L.N. MURTHY
1
2
3
Department of Chemistry, Krishna University, Machilipatnam-521 328, India
Department of Chemistry, GITAM University, Hyderabad-502 329, India
Department of Organic Chemistry, School of Chemistry, Andhra University, Visakhapatnam-530 003, India
*
Corresponding author: Fax: +91 8912525611; Tel: + 91 9849229804; E-mail: murthyyln@gmail.com; surendra@gitam.edu
Received: 8 November 2016; Accepted: 13 January 2017; Published online: 10 March 2017;
AJC-18294
S(-)1-Phenyl-1,2,3,4-tetrahydro isoquinoline acetamide analogues are prepared by sequence of reactions which involve a metal hydride
reduction of 3,4-dihydroisoquinoline followed by separation of S-form with mandelic acid (chiral reagent) by resolution. The product
S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline is treated with halosubstituted acetyl chlorides to obtain tetrahydro isoquinoline acetyl
chloride which is further employed to synthesize acetamide derivatives of tetrahydro isoquinoline using various substituted aryl amines.
The products were characterized by advanced spectroscopic techniques.
Keywords: 1-Phenyl-3,4-dihydro isoquinoline, Resolution, Aryl amines, Acetamide analogues of tetrahydro isoquinoline.
which depends on the optical resolution of the racemic mixture
using a chiral molecule such as mandelic acid.
INTRODUCTION
Tetrahydro isoquinolines are heterocyclic fused ring
The pictet-spengler reaction was the most suitable method
for the synthesis of substituted 1,2,3,4-tetrahydro isoquinoline.
The highly substituted, optically pure tetrahydro isoquinoline
having a quaternary carbon as stereo center was synthesized
by Kaluza and co-workers [11]. A catalytic enantioselective
quaternary carbon prepared a similar to Reissert reaction with
quinolines by Funabashi et al. [12]. 1-Substituted isoquinolines
systems, which contain hetero atom ‘N’, positioned at 2 in the
fused ring molecule. These isoquinolines are the most impor-
tant intermediates in the drug development molecules. These
are also an important class in alkaloid compounds and they
exhibit wide biological properties. The various natural products
possess tetrahydro isoquinolines and its derivatives such as
cactus alkaloids (peyoruvic acid) [1], mammalian alkaloids
(
or) 3,4-dihydro isoquinolines were used as starting materials
for the synthesis of Reissert compounds [13-17]. Kubota et al.
18] also synthesized various N-acetyl-1,2,3,4-tetrahydro
(
(
[
salsoline caroboxilic acid) [2-4], the esteinascidine family
ET743) [5-8] and spiro-benzo quinoline alkaloids (parfumine)
9,10].
[
isoquinoline derivatives and also studied the pharmacological
activity which are potent molecules.
Many pharmaceutical drug molecules are made up of
tetrahydro isoquinoline and its derivatives such as solofenacin
I), (+) cryptostyline (II) and (+) cryptostyline (III).
(
EXPERIMENTAL
MeO
MeO
MeO
Melting points of the products were measured using MR-
VIS visual melting range apparatus and are uncorrected. IR
N
N
Me MeO
Me
1
spectra were recorded on a Shimadzu-IR Affinity. H NMR
N
O
13
and C NMR spectra were recorded on a Bruker DRX 400
MHz spectrometer and 100 MHz respectively. NMR spectra
were obtained in the solution using CDCl as solvent using
O
N
MeO
MeO
OMe
OMe
OMe
3
TMS as an internal standard. Elemental (C, H, N) analysis
were done using FLASH EA analyzer.
Solifenacin
I
(+)Cryptostyline II
(+)Cryptostyline III
1-Phenyl-3,4-dihydro isoquinoline is widely used in the
industrial production of this particular tetrahydro isoquinoline
Thin layer chromatography was carried out to check the
progress of the reaction. Spots were visualized using iodine

1
036 Rao et al.
Asian J. Chem.
and exposing to UV light. Characterization of the products
primarily conformed by NMR technique.
was taken in round bottom flask and then cooled to 0 °C.
Sodium borohydride (1.5 equiv.) was added in portions at 0 °C
and then slowly warmed to room temperature.After 3 h stirring,
methanol was evaporated and the residue was taken in
dichloromethane. Water was added in fractions and washed
twice with dichloromethane.All the dichloromethane fractions
General procedure for synthesis of S(-)1-phenyl-1,2,3,4-
tetrahydro isoquinoline acetyl amide derivatives (8a-8h):
S(-)1-Phenyl-1,2,3,4-tetrahydro isoquinoline acetyl chloride
(
1.0 equiv) and substituted aryl amine (a-h) (1.2 equiv) were
dissolved in dichloromethane. To this triethylamine (2.0 equiv)
was added at room temperature. Then reaction mixture was
heated to reflux temperature with constant stirring. Reaction
was monitored by TLC and after completion of the reaction,
the mixture was diluted with dichloromethane and water was
added. Both the layers were separated and dichloromethane
fraction was washed with brine solution, dried over anhydrous
2 4
were combined, dried over anhydrous Na SO , solvent was
removed, purified by column chromatography using silica gel
as stationary phase and mixture of ethyl acetate and hexanes
as elutent to obtain pure racemic 1-phenyl-1,2,3,4-tetrahydro-
isoquinoline 5 in 88 % yield as white solid.
1
rac-1-Phenyl-1,2,3,4-tetrahydroisoquinoline: H NMR
3
(400 MHz, CD OD) δ: 7.30-7.18 (m, 5H), 7.12-7.07 (m, 2H),
2 4
Na SO , The concentrated crude was loaded on silica gel column
6.99-6.95 (m, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.02 (s, 1H),
13
for purification. By eluting the column with hexane and ethyl
acetate mixture, pure S(-)1-phenyl-1,2,3,4-tetrahydro isoquino-
line acetyl amide derivatives (8a-8h) were obtained in good
to excellent yields.
3.08-2.92 (m, 3H), 2.75-2.84 (m, 1H). C NMR (100 MHz,
CD OD) δ: 142.4, 136.0, 133.4, 127.3, 127.1, 126.5, 126.2,
125.6, 124.6, 123.83, 59.9, 39.6, 27.0, LCMS (m/z): 210.16,
15N. Elemental analysis (%): Calculated: C-86.08,
3
m.f.: C15
H
Synthesis of N-(2-phenyl ethyl)-benzamide (3): To the
suspension of benzoic acid (1, 1.2 equiv) in dichloromethane,
phenylethylamine (2, 1.0 equiv) followed by carbonyldiimi-
dazole (CDI) (1.2 equiv). Then the reaction mixture was heated
to reflux. The reaction mixture was washed with saturated brine
H-7.22, N-6.69, Obtained: C-86.10, H-7.21, N-6.68.
Resolution of rac-1-phenyl-1, 2,3,4-tetrahydroiso-
quinoline for S-isomer (6): Optically active (S)-mandelic acid
(0.5 equiv) was added to the solution of racemic compound 5
(1.0 equiv) in mixture of toluene and methanol solvents at
room temperature. The resulting suspension was stirred at 80
°C to make homogeneous reaction mixture. The stirring was
continued with heating at 80 °C until completion of reaction.
It was found that after 30 min the reaction was completed. The
solution was allowed to cool to room temperature. Mandelic
acid resolves diastereomeric mixture to S-form of 5, which
was filtered from the solution. The filter cake was washed once
with toluene and air-dried to yield compound 6 (S-form) as a
white solid in 47 % yield. Compound 6 was treated with 2 M
Sodium hydroxide solution and the toluene was added. Two
layers were separated. Toluene fraction was dried over anhydrous
2 4
solution, dried over anhydrous Na SO and concentrated to get
crude product. Pure product 3 was obtained in 95 % yield after
column chromatography (silica gel; hexanes and ethyl acetate).
1
N-Phenylethylbenzamide: H NMR (400 MHz, CDCl
3
)
δ: 7.70 (d, J = 8.4 Hz, 2H), 7.49-7.30 (m, 5H), 7.25-7.22 (m,
3
2
1
H), 6.32 (br s, 1H), 3.68-3.73 (m, 2H), 2.93 (t, J = 7.2 Hz,
13
H). C NMR (100 MHz, CDCl
31.4, 128.8, 128.7, 128.6, 126.9, 126.6, 41.2, 35.7. LCMS
15NO, Elemental analysis (%):
Calculated: C-79.97, H-6.71, N-6.22. Obtained: C-79.98, H-
.69, N-6.20.
Synthesis of 1-phenyl-3,4-dihydroisoquinoline (4):
Compound 3 was dissolved in xylene and P (1.2 equiv)
followed by POCl (3.0 equiv) were added at room tempe-
3
) δ: 167.6, 139.0, 134.7,
(
m/z): 226.21. m.f.: C15H
6
2 4
Na SO , concentrated and purified on silica gel column (eluted
O
2 5
using mixture of hexane and ethyl acetate) to obtain pure S-isomer.
1
S-1-Phenyl-1,2,3,4-tetrahydroisoquinoline: H NMR
3
rature. The reaction mixture was then refluxed. Reaction was
monitored by thin layer chromatobraphy and after completion
of the reaction, hot reaction solution was poured into ice and
carefully the pH of solution was adjusted to 12 using 20 %
NaOH. Later, water was added to dissolve precipitated phos-
phates. Then toluene was added to extract using 1 N HCl. The
aqueous fraction was made alkaline using 20 % NaOH under
ice-cooling condition. Again the product was extracted using
6
(400 MHz, Acetone-D ) δ: 7.31-7.20 (m, 5H), 7.10-7.08 (m,
2H), 7.00-6.96 (m, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.03 (s, 1H),
3.23-3.19 (m, 1H), 3.03-2.96 (m, 2H), 2.78-2.68 (m, 1H), 2.36
1
3
(Br s, 1H). C NMR (100 MHz, Acetone-D
135.7, 129.0, 128.9, 128.0, 127.8, 127.0, 125.9, 125.3, 62.1,
42.3, 30.0. LCMS (m/z): 210.16, m.f.: C15 15N. Elemental
6
) δ: 145.7, 139.1,
H
analysis (%): Calculated; C-86.08, H-7.22, N-6.69, Obtained;
C-86.10, H-7.21, N-6.68.
toluene, dried over anhydrous Na
2
SO
4
, solvent was evaporated
under vacuum, which yielded the desired product 4 in 92 % as
Synthesis of S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline
acetyl chloride (7): Potassium carbonate was added to the
solution of S-1-phenyl-1,2,3,4-tetrahydro isoquinoline
(compound 6) in acetone at room temperature. After stirring
for 30 min, chloroacetyl chloride was added and then reaction
mixture was allowed to stir at reflux temperature. Reaction
was monitored by TLC and found completed in 4 h. Reaction
mixture was filtered acetone was evaporated and was purified
by column chromatography using silica gel as stationary phase
and mixture of hexanes and ethyl acetate as eluent to get pure
yellow colored viscous liquid.
1
1
-Phenyl-3,4-dihydroisoquinoline: H NMR (400 MHz,
3
CDCl ) δ: 7.62-7.52 (m, 2H), 7.39-7.30 (m, 4H), 7.22-7.18
13
(
m, 3H), 3.80 (t, J = 6.8 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H). C
NMR (100 MHz, CD OD) δ165.11, 141.18, 139.00, 138.69,
31.02, 130.50, 129.16, 129.04, 128.06, 127.19, 126.03, 45.84,
7.33. LCMS (m/z): 206.18. m.f.: C15 13N. Elemental analysis
3
1
2
H
Calculated: C-86.92, H-6.32, N-6.76, Obtained: C-86.93, H-
6
.30, N-6.75.
Reduction of 1-phenyl-3,4-dihydroisoquinoline (5):
-Phenyl-3,4-dihydroisoquinoline in methanol (4, 1.0 equiv)
acetyl chloride derivative 7 as white solid in 95 % yield.
1
3
H NMR (400 MHz, CDCl ) δ: 7. 35-7.98 (m, 7H), 6.86
1
(br s, 1H), 6.64-6.58 (m, 2H), 4.73 (s, 2H), 4.50 (s, 1H), 3.31-

Vol. 29, No. 5 (2017)
Synthesis and Characterization of S(-)1-Phenyl-1,2,3,4-Tetrahydro Isoquinoline Acetamide Analogues 1037
1
3
2
1
7
.56 (m, 4H). C NMR (100 MHz, CDCl
42.7, 133.4, 129.2, 128.2, 128.2, 126.4, 126.2, 126.1, 126.0,
0.0, 62.7, 50.9, 27.0. LCMS (m/z): 285.6, m.f.: C17
3
) δ:172.5, 143.5,
6.97 (m, 7H), 6.86 (s, 1H), 6.65-6.57 (m, 3H), 6.50 (d, J = 8.4
Hz, 1H), 4.61 (s, 2H), 4.51 (s, 1H), 3.1-2.86 (m, 3H), 2.84-
13
H16NOCl,
3
2.52 (m, 1H). C NMR (100 MHz, CDCl ) δ: 169.0, 143.4,
Elemental analysis (%): Calculated C-71.45, H-5.64, N-4.90,
Obtained; C-71.58, H-5.63, N-4.88.
143.0, 142.6, 138.1, 136.1, 130.0, 128.9, 128.5, 128.2, 126.9,
126.2, 126.0, 125.7, 113.2, 58.4, 54.4, 48.8, 29.2. LCMS (m/z):
(
S)-2-(1-Phenyl-1,2,3,4-tetrahydroisoquinolin -2(1H)-
21 3
343.07, m.f.: C22H N O, Elemental analysis (%): Calculated:
1
yl)-N-(p-tolyl)acetamide (8a): H NMR (400 MHz, CDCl
3
)
C-76.94, H-6.16, N-12.24, Obtained: C-76.96, H-6.14, N-12.23.
δ: 7.39-7.01 (m, 10H), 6.91 (s, 1H), 6.91-6.62 (m, 2H), 5.31
(
(S)-2-(1-Phenyl-1,2,3,4-tetrahydroisoquinolin-2(1H)-
1
yl)-N-(pyrimidin-2-yl)-acetamide (8g): H NMR (400 MHz,
s, 1H), 4.66 (s, 2H), 4.50 (s, 1H), 3.90-3.46 (m, 4H), 3.16 (s,
13
3
1
1
H). C NMR (100 MHz, CDCl ) δ: 169.0, 142.0, 136.0,
3
CDCl
9H), 6.56 (t, J = 8.0 Hz, 1H), 4.61 (s, 2H), 4.48 (s, 1H), 3.08-
3
) δ: 8.24 (d, J = 8 Hz, 1H), 8.23 (s, 1H), 7.35-6.92 (m,
39.1, 134.5, 129.9, 128.8, 128.3, 128.3, 128.0, 126.5, 126.4,
13
26.0, 121.2, 58.4, 54.4, 48.7, 28.8, 24.8. LCMS (m/z): 355.67,
3
2.51 (m, 4H), C NMR (100 MHz, CDCl ) δ: 169.1, 163.2,
m.f.: C24
H
24
N
2
O, Elemental analysis (%): Calculated: C-80.87,
H-6.79, N-7.86, Obtained: C-80.89, H-6.76, N-7.85.
S)-N-(4-Bromophenyl)-2-(1-phenyl-1,2,3,4-tetra-
158.2, 138.1, 136.1, 130.0, 128.84, 128.78, 128.5, 128.3,
128.2, 126.2, 126.0, 125.7, 58.4, 55.2, 48.8, 27.8, LCMS (m/z):
(
20 4
343.41, m.f.: C21H N O, Elemental analysis (%): Calculated:
1
hydroisoquinolin-2(1H)-yl)acetamide (8d): H NMR (400
MHz, CDCl ) δ: 7.37-7.08 (m, 9H), 6.88-6.57 (m, 4H), 4.64
s, 2H), 4.48 (s, 1H), 3.14-2.89 (m, 3H), 2.69-2.58 (m, 1H).
C-73.23, H-5.85, N-16.27, Obtained: C-73.24, H-5.84, N-16.25.
(S)-N-(1H-Imidazol-2-yl)-2-(1-phenyl-1,2,3,4-tetra-
1
hydroisoquinolin-2(1H)-yl)acetamide (8h): H NMR (400
3
(
13
C NMR (100 MHz, CDCl
3
) δ: 151.4, 149.4, 145.4, 132.0,
3
MHz, CDCl ) δ: 7.33-04 (m, 3H), 6.97 (d, J = 8.0 Hz, 2H),
1
1
31.6, 128.9, 128.8, 128.6, 126.5, 122.9, 120.2, 116.8, 110.5,
10.2, 108.5, 56.1, 55.9, 53.0, 8.1. LCMS (m/z): 420.37, m.f.:
6.87 (br s, 1H), 6.61 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 4.48 (s,
13
3
1H), 3.10-2.55 (m, 4H). C NMR (100 MHz, CDCl ) δ: 169.1,
C
23
H
21
N
2
OBr, Elemental analysis (%): Calculated: C-65.57,
H-5.02, N-6.65, Obtained: C-65.59, H-5.00, N-6.63.
S)-2-(1-Phenyl-1,2,3,4-tetrahydroisoquinolin -2(1H)-
143.0, 138.1, 134.7, 130.0, 129.9, 128.22, 128.20, 128.1,
127.8, 127.3, 125.73, 125.69, 122.4, 58.4, 55.2, 48.8, 28.7.
LCMS (m/z): 331.40, m.f.: C20H20O, Elemental analysis (%):
(
1
yl)-N-(pyridin-2-yl)acetamide (8f): H NMR (400 MHz,
CDCl ) δ: 8.04 (d, J = 4.4 Hz, 1H), 7.44-7.40 (m, 1H), 7.34-
Calculated: C-72.27, H-6.06, N-16.86, Obtained: C-72.29, H-
6.05, N-16.83.
3
O
H
N
NH2
N
CDI
P O / POCl
2
5
3
OH +
CH Cl
2
O
xylene
2
2
1
3
4
NaBH4
OH
MeOH, rt
HO
O
O
Cl
NH
O
N
Cl
Cl
NH
toluene
Recimization
K CO , acetone
2
3
NH2
6
( S - form)
5
7
Et N
3
R
CH Cl
2
2
NH2
NH2
NH2
NH2
NH2
R
O
NH2
=
R
N
N
H
Me
a
OH
b
Br
d
NO2
e
c
8
a-8h
NH2
NH
N
(
S)-N-aryl-2-(1-phenyl-3,4-
dihydroisoquinolin-2(1H)-yl)acetamide
N
H N
2
N
N
NH2
g
f
h
Scheme-I: Synthetic route for 1-phenyl-I,2,3,4-tetrahydroisoquinoline derivatives

1
038 Rao et al.
RESULTS AND DISCUSSION
The biological activity reported for S(-)1-phenyl-1,2,3,4-
Asian J. Chem.
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3
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1
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ACKNOWLEDGEMENTS
1
1
1
The authors are very much grateful to Andhra University
for providing NMR spectra data (NMR Research center). One
of the authors (MSB) is highly grateful to Head, Department
of Organic Chemistry, Andhra University, Visakhapatnam,
India for sanction permission to carry out these investigations
for his Ph.D. thesis research work.
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