A novel oxidative decarboxylation-synthesis of 2-amino-1,2- dihydroisoquinoline-3(4H)-one and its amide derivatives from tetrahydroisoquinoline-3-carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2011.08.007

A convenient method of synthesizing 2-amino-1,2-dihydroisoquinoline-3(4H)- one and its amide derivatives (4 or 5) is described through sydnone intermediate (3) derived from TIC (1) (tetrahydroisoquinoline-3-carboxylic acid) under acidic conditions in good

Full text of DOI:10.1016/j.tetlet.2011.08.007

Tetrahedron Letters 52 (2011) 5441–5443
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Tetrahedron Letters
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A novel oxidative decarboxylation—synthesis of 2-amino-1,2-
dihydroisoquinoline-3(4H)-one and its amide derivatives
from tetrahydroisoquinoline-3-carboxylic acid
B. Gopalan a, , Mani Umamaheswari a, P.S. Mohan b, Sridharan Rajagopal a
⇑
a Department of Medicinal Chemistry, Orchid Research Laboratories Limited, R&D Centre, Plot #476/14, Old Mahabalipuram Road, Sozhanganallur, Chennai 600 119, India
b Department of Chemistry, Bharathiar University, Coimbatore, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method of synthesizing 2-amino-1,2-dihydroisoquinoline-3(4H)-one and its amide deriva-
tives (4 or 5) is described through sydnone intermediate (3) derived from TIC (1) (tetrahydroisoquinoline-
3-carboxylic acid) under acidic conditions in good yield.
Received 8 July 2011
Revised 28 July 2011
Accepted 1 August 2011
Available online 7 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
We are actively engaged in discovery of anti-inflammatory drugs.
It is reported that 2-amino-1,2-dihydroisoquinoline-3(4H)-one and
its amide derivatives have good anti-inflammatory properties and
they inhibit metallo aminopeptidase.1a,b In the literature1a,b the title
compounds 4 or 5 have been synthesised from homophthalic acid in
five steps. N-phenylsydnone has been reported to give phenylhydr-
azine on treatment with HCl.2,3 A survey of literature revealed only
one isolated report wherein sydnone derived from proline when
treated with propiolic acid in refluxing xylene gave the correspond-
ing cyclic hydrazide.4 These reports combined with their mecha-
nism of formation of the hydrazine and hydrazide product
suggested that 4 or 5 could be easily accessed through the sydnone
intermediate 3. We undertook a systematic study on the intramolec-
ular redox reaction of sydnone derived from TIC, expanding the
scope of the reaction with various carboxylic acids.
The commercially available TIC (1) was treated with NaNO2 in
HCl to generate the N-nitroso compound5a–d (2), which on subse-
quent reaction with trifluoroacetic anhydride gave the correspond-
ing sydnone (3). Sydnone 3 was treated with concentrated HCl
under reflux condition for 12 h to give the corresponding N-amino
compound 4 in good yield (Scheme 1).6 The structure of the com-
pound was confirmed by mass and NMR spectral data.
The reaction of the sydnone 3 with acetic acid under reflux for
13 h gave the corresponding amide 5a in good yield.7 We then
turned our attention to a few other carboxylic acids. The reaction
of 3 with one equivalent of carboxylic acid in refluxing xylene for
12–16 h gave amide derivatives (5a–k) of hydrazide 5 in good yield
(Scheme 2, Table 1). To confirm the structure of the compound, the
reaction of 3 with (E)-2-(4-dimethylamino)phenyl-3-phenylacrylic
acid was carried out and the resulting the amide’s (5j), structure was
determined using single crystal X-ray diffraction analysis8 (Fig. 1).
Structures of the compounds 5a–k were determined using NMR
and mass spectrum.9 The pKa of the carboxylic acid did not change
the rate or the yield of the reaction.
O
O
RCOOH
O
O
N
xylene, reflux,
12-16h
N
R
N
NH
5a-5k
3
Scheme 2.
O
O
O
O
H+
OH
NO
OH
NaNO2/HCl
TFAA
O
N
N
N
NH
N
NH2
4
1
2
3
Scheme 1.
⇑
Corresponding author. Tel. +91 44 24501474; fax: +91 44 24501396.
E-mail address: gopalanb@orchidpharma.com (B. Gopalan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.007

5442
B. Gopalan et al. / Tetrahedron Letters 52 (2011) 5441–5443
Table 1
The proposed mechanism of the reaction is as shown in Scheme
Reaction of 3 with carboxylic acids and their yields
3. The first step of the reaction is protonation of 3 to give I which
on subsequent addition of water gives II. The intermediate II on
protonation gives III which undergoes spontaneous decarboxyl-
ation to give 4.
The formation of 5 can be explained by addition of carboxylate
ion to I after initial protonation as shown in Scheme 4, followed by
decarboxylation and intramolecular acyl transfer to give VII which
on tautomerism gives 5.
Carboxylic acid
5 (% Yield)
Acetic acid
Benzoic acid
4-Fluorobenzoic acid
E-2,3-Diphenylacrylic aid
3,4-Dimethoxybenzoic acid
Thiophene 2-carboxylic acid
Cinnamic acid
5a (73)
5b (88)
5c (75)
5d (87)
5e (71)
5f (89)
5g (69)
5h (78)
5i (89)
5j (91)
5k (78)
In conclusion we have developed a concise route to the synthe-
sis of the title compounds which are versatile intermediates to
diverse condensed heterocycles of biological importance.
Phenylacetic acid
4-F-Phenylacetic acid
(E)-2-(4-Dimethylamino)phenyl-3-phenylacrylic acid
4-Fluoro Cinnamic acid
Conditions: Reactions were done using 1 mmol of 3 and 1 mmol of carboxylic acid
in refluxing xylene for 14–16 h.
Acknowledgments
The authors thank RSIC, IIT Madras for the X-ray diffraction
analysis, Orchid research laboratories for their support and Profes-
sor K. K. Balasubramanian for his technical comments.
References and notes
1. (a) Odasso, G.; Winters, G.; Schiatti, P.; Selva, D. Farmaco 1983, 38, 199–204; (b)
Sebastien, A.; Albert, D.; Emmanuel, S.; Celine, T.; Anders, W.; Jasper, Z. H. Bioorg.
Med. Chem. 2006, 14, 7241–7257.
2. Duncan, L. B.; Joseph, P. A. H. Tetrahedron 2010, 66, 553–558.
3. Joanne, S.; Donald, D. C. J. Org. Chem. 1964, 29, 2483–2484.
4. Darshan, R.; Shakti, B. Tetrahedron Lett. 1985, 26, 5739–5742.
5. (a) Zolfigol, M. A.; Habibi, D.; Mirjalili, F. B.; Bamoniri, A. Tetrahedron Lett. 2003,
44, 3345–3349; (b) Niknam, K.; Zolfigol, M. A. Synth. Commun. 2006, 36, 2311–
2319; (c) Bamoniri, A.; Zolfigol, M. A.; Mirjalili, B. F.; Fallah, F. Russian J. Org.
Chem. 2007, 43, 1397–1400; (d) Nikitenko, A. A.; Winkley, M. W.; Zeldis, J.;
Kremer, K.; Chan, A. W.-Y.; Strong, H.; Jennings, M.; Jirkovsky, I.; Blum, D.;
Khafizova, G.; Grosu, G. T.; Venkatesaan, A. M. Org. Process Res. Dev. 2006, 10,
712–716.
6. Sydnone 3 (0.5 g, 1 mmol) was taken in 20 mL of conc. HCl and stirred overnight
under reflux. After completion of the reaction, conc. HCl was evaporated using
rotavapour at 50 °C. Resulting crude product was taken in ethylacetate (50 mL)
and sonicated for 10 min and filtered to give the product as its HCl salt 4.
Figure 1. X-ray structure of the compound 5j.
H2O
H
O
O
O
O
H+
H2O
O
O
O
N
N
N
-H+
N
N
H
N
H
I
II
3
H
O
O
O
H+
+
CO2
O
N
N
NH2
N
H
4
H
III
Scheme 3. Proposed mechanism for the formation of 4.
O
O
R
O
O
O
R
O
O
N
O
O
RCOOH
O
O
O
N
R
N
N
N
NH
N
N
V
H
H
I
3
IV
O
O
O
5
R
N
R
N
NH
N
H
O
VI
VII
Scheme 4. Proposed mechanism for the formation of 5.

B. Gopalan et al. / Tetrahedron Letters 52 (2011) 5441–5443
5443
Isolated as pale yellow solid. Yield 91%. Mp 94–98 °C; IR
m
max (KBr) 1682, 1639,
23.29, 37.00, 49.92, 53.55, 125.44, 126.43, 126.57, 127.17, 127.33, 128.06,
128.14, 128.32, 128.60, 128.85, 129.48, 129.56, 129.76, 131.58, 131.76, 134.67,
134.76, 134.97, 135.36, 166.68, 166.84; Mass (M+ +1) = 369.1.
3382 cmÀ1 1H NMR (400 MHz, CDCl3) dH 3.79 (s, 2H), 4.81 (s, 2H), 7.23–7.34 (m,
;
4H); 13C NMR (400 MHz, DMSO) dC 35.52, 51.08, 125.75, 126.73, 127.53, 127.73,
129.61, 130.65, 166.94; Mass (M+ +1) = 163.
3,4-dimethoxy-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)benzamide 5e: Pale
7. Sydnone
3
(0.3 g, 1 mmol) was taken in 15 mL of acetic acid and stirred
brown solid. Yield 71%. Mp 204–206 °C; IR mmax (KBr) 1654, 1682, 3436 cmÀ1
;
overnight under reflux. After completion of the reaction, acetic acid was
1H NMR (400 MHz, DMSO) dH3.76 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 4.77 (s, 2H),
7.08 (d, 1H, J = 8 Hz), 7.28–7.32 (m, 4H), 7.49 (d, 1H, J = 4 Hz), 7.55 (d, 1H,
J = 12 Hz), 10.75 (1H, s); 13C NMR (400 MHz, DMSO) dC 37.09, 53.77, 55.55,
55.64, 110.63, 111.01, 121.05, 124.15, 125.45, 126.44, 127.17,127.37, 131.66,
131.88, 148.31, 151.89, 164.62, 167.14; Mass (M+ +1) = 327.1.
evaporated using rotavapour at 50 °C to dryness to give the product 5a as yellow
solid. yield 73%. Mp 184–186 °C; IR m ;
max (KBr) 1653, 1694, 3552 cmÀ1 1H NMR
(400 MHz, CDCl3) dH 1.90 (s, 3H), 3.72 (s, 2H), 4.64 (s, 2H), 7.22–7.29 (m, 4H),
10.23 (s, 1H); 13C NMR (400 MHz, DMSO) dC 20.52, 36.93, 53.59, 125.44, 126.44,
127.17, 127.36, 131.65, 131.77, 166.87, 168.22; Mass (M+ +1) = 205.1.
N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)thiophene-2-carboxamide
5f:
Pale
8. X-ray crystal data of compound 5j have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number is CCDC –
829819. These data can be obtained free of charge via http://
brown solid. Yield 89%. Mp 202–204 °C; IR mmax (KBr) 1641, 1677, 3436 cmÀ1
;
1H NMR (400 MHz, DMSO) dH 3.76 (s, 2H), 4.77 (s, 2H), 7.21–7.33 (m, 5H), 7.86–
7.89 (m, 2H), 10.93 (1H, s); 13C NMR (400 MHz, DMSO) dC 37.04, 53.83, 125.46,
126.47, 127.19,127.41, 128.23, 129.43, 131.59, 131.75, 132.07, 136.76, 160.16,
167.19;; Mass (M+ +1) = 273.1.
www.ccdc.cam.ac.uk/conts/retrieving.html
or
from
the
Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk.
N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)cinnamamide 5g: Pale brown solid.
Crystal data for compound 5j: C26H25N3O2, M = 411.49, monoclinic, space group
Yield 69%. Mp 154–158 °C; IR mmax (KBr) 1655, 1689, 1638, 3209 cmÀ1 1H
;
P21/c, a = 14.7503(6) A0, b = 10.3737(4) A0, c = 14.1677(5) A0, b = 96.176(2)°,
NMR (400 MHz, DMSO) dH 3.74 (s, 2H), 4.74 (s, 2H), 6.70 (d, 1H, J = 16 Hz), 7.26–
7.28 (m, 4H), 7.44–7.45 (m, 3H), 7.57 (d, 1H, J = 16 Hz), 7.62–7.64 (m, 2H), 10.51
(s, 1H); 13C NMR (400 MHz, DMSO) dC 36.95, 53.65, 119.09, 125.50, 126.47,
127.21, 127.40, 127.83, 129.08, 130.03, 131.65, 131.74, 134.49, 164.01, 166.97;
Mass (M+ +1) = 293.1.
U = 2155.29(14) A3, Z = 4,
l
= 0.081 mmÀ1, 16224 reflections collected, 2641
independent reflections, Rint = 0.0364, final
R indices [I > 2r(I)] R1 = 0.0430,
wR2 = 0.1068, R indices (all data) R1 = 0.0631, wR2 = 0.1289. CCDC – 829819.
9. General procedure for the synthesis of 5b–k: Sydnone 3, (1 mmol) and xylene
(30 mL) were charged to
a
double necked 100 mL round-bottomed flask,
N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylacetamide 5h: Pale brown
equipped with a water cooled condenser. The stirred solution was purged
with nitrogen and heated to 140–145 °C and carboxylic acid (1 mmol) was
added slowly over a period of 15 minutes. The reaction was held at 140–145 °C
for 16 h. After completion of the reaction, the solvent was removed and the
product was purified by column chromatography using hexane–ethylacetate
mixture (6:4) as eluent to afford the product. Spectroscopic data for
representative 2-amino-1,2-dihydroisoquinoline-3(4H)-one and its amide
derivatives are given below.
solid. Yield 78%. Mp 144–148 °C; IR mmax (KBr) 1651, 1686, 3436 cmÀ1 1H
;
NMR (400 MHz, DMSO) dH 3.34 (s, 2H), 3.69 (s, 2H), 4.64 (s, 2H), 7.21–7.26 (m,
5H), 7.27–7.33 (m, 4H), 10.57 (s, 1H); 13C NMR (400 MHz, DMSO) dC 36.88,
53.46, 125.44, 126.39, 126.54, 127.13, 127.32, 128.28, 129.07, 131.57, 131.65,
135.43, 166.83, 169.03; Mass (M+ +1) = 281.1.
2-(4-fluorophenyl)-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)acetamide 5i: Pale
brown solid. Yield 89%. Mp 175–177 °C; IR mmax (KBr) 1651, 1686, 3436 cmÀ1
;
1H NMR (400 MHz, DMSO) dH 3.53 (s, 2H), 3.69 (s, 2H), 4.64 (s, 2H), 7.13–7.18
(m, 2H), 7.22–7.26 (m, 4H), 7.34–7.37 (m, 2H), 10.53 (s, 1H); 13C NMR (400 MHz,
DMSO) dC 36.87, 53.46, 114.91, 115.12, 125.45, 126.41, 127.14, 127.34, 130.89,
130.97, 131.56, 131.64, 159.93, 162.33, 166.87, 169.00 Mass (M+ +1) = 299.1.
(E)-2-(4-(dimethylamino)phenyl)-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-
phenylacrylamide 5j:Pale brown solid. Yield 89%. Mp 163–166 °C; IR mmax (KBr)
N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)benzamide 5b: Pale brown solid. Yield
88%. Mp 194–196 °C; IR mmax (KBr) 1654, 1694, 3267 cmÀ1 1H NMR (400 MHz,
;
DMSO) dH 3.76 (s, 2H), 4.78 (s, 2H),7.25–7.33 (m, 4H), 7.51–7.55 (m, 2H), 7.59–
7.63 (1H, m), 7.89–7.91 (2H, m), 10.88 (1H, s); 13C NMR (400 MHz, DMSO) dC
37.05, 53.67, 125.46, 126.45, 127.19, 127.38, 127.51, 128.54, 131.63, 131.79,
132.10, 165.11, 167.07; Mass (M+ +1) = 267.1.
1678, 1698, 3368 cmÀ1 1H NMR (400 MHz, DMSO) dH 2.93 (s, 6H), 3.70 (s, 2H),
;
4-fluoro-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)benzamide 5c: Pale brown
4.69 (s, 2H), 6.71 (d, 2H, J = 12 Hz), 7.05 (d, 2H, J = 8 Hz), 7.13–7.15 (m, 2H),
7.22–7.23 (m, 3H), 7.25–7.28 (m, 5H), 9.87 (1H, s); 13C NMR (400 MHz, DMSO)
dC 36.96, 53.51, 112.19, 122.02, 125.44, 126.40, 127.16, 127.30, 128.14, 128.27,
129.59, 130.33, 131.68, 131.59, 131.76, 133.12, 134.99, 135.39, 149.92, 166.75,
167.40; Mass (M+ +1) = 412.2.
solid. Yield 75%. Mp 220–224 °C; IR mmax (KBr) 1643, 1684, 3435 cmÀ1 1H
;
NMR (400 MHz, DMSO) dH 3.77 (s, 2H), 4.78 (s, 2H), 7.26–7.33 (m, 4H), 7.36–
7.40 (m, 2H), 7.96–7.99 (m, 2H), 10.93 (s, 1H); 13C NMR (400 MHz, DMSO) dC
37.04, 53.66, 115.50, 115.72, 125.46, 126.46, 127.20, 127.40, 128.55, 128.58,
130.24, 130.33, 131.63, 131.78, 163.10, 164.10, 165.58, 167.10; Mass (M+
+1) = 285.1.
(E)-3-(4-fluorophenyl)-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)acrylamide 5k:
Pale brown solid. Yield 89%. Mp 189–192 °C; IR mmax (KBr) 1654, 1682, 1738,
(E)-N-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2,3-diphenylacrylamide 5d: Pale
brown solid. Yield 87%. Mp 156–158 °C; IR mmax (KBr) 1646, 1682, 1736,
3419 cmÀ1 1H NMR (400 MHz, DMSO) dH 3.74 (s, 2H), 4.74 (s, 2H), 6.64 (d, 1H,
;
J = 16 Hz), 7.24–7.32 (m, 6H), 7.57 (d, 1H, J = 16 Hz), 7.69–7.72 (m, 2H), 10.51 (s,
1H); 13C NMR (400 MHz, DMSO) dC 36.92, 53.62, 115.93, 116.14, 118.94, 125.47,
126.44, 127.19, 127.37, 130.02, 130.10, 131.10, 131.13, 131.61, 131.70, 139.65,
161.77, 163.94, 164.23, 166.94; Mass (M+ +1) = 311.1.
3258 cmÀ1 1H NMR (400 MHz, DMSO) dH 3.77 (s, 2H), 4.85 (s, 2H), 7.03 (m, 2H),
;
7.14–7.24 (m, 3H), 7.25–7.28 (m, 1H) 7.32–7.33 (m, 2H) 7.37–7.46 (m, 2H),
7.47–7.49 (m, 4H), 7.91 (s, 1H), 10.47 (s, 1H); 13C NMR (400 MHz, DMSO) dC