New synthetic methodology for construction of the 3,4-dihydroisoquinolinone skeleton: A key structure for isoquinoline alkaloids

Article abstract of DOI:10.1016/j.phytol.2011.04.017

We hereby report a new method for preparation of 3,4-dihydroisoquinolin- 1(2H)-one as well as isoquinolin-1(2H)-one skeleton starting from the methyl 2-(3-methoxy-3-oxopropyl)benzoate. The ester functionality, adjacent to the methylene, was regiospecifically converted to the desired acyl azide. The isocyanate was transformed into the monoisocyanate by Curtius rearrangement followed by trapping with aniline. The formed urea derivative was cyclized with NaH to give a 3,4-dihydroisoquinolin-1(2H)-one derivative. Incorporation of a double bond into the six-membered ring followed by removal of the substituent resulted in the formation of isoquinolin-1(2H)-one skeleton.

Full text of DOI:10.1016/j.phytol.2011.04.017

Phytochemistry Letters 4 (2011) 407–410
Contents lists available at ScienceDirect
Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol
New synthetic methodology for construction of the 3,4-dihydroisoquinolinone
skeleton: A key structure for isoquinoline alkaloids
¨
*
Berk Mu¨jde, Sevil Ozcan, Metin Balci
Department of Chemistry, Middle East Technical University, Inonu Bulvari, 06800 Ankara, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history:
We hereby report a new method for preparation of 3,4-dihydroisoquinolin-1(2H)-one as well as
isoquinolin-1(2H)-one skeleton starting from the methyl 2-(3-methoxy-3-oxopropyl)benzoate. The
ester functionality, adjacent to the methylene, was regiospecifically converted to the desired acyl azide.
The isocyanate was transformed into the monoisocyanate by Curtius rearrangement followed by
Received 2 March 2011
Received in revised form 14 April 2011
Accepted 21 April 2011
Available online 14 May 2011
trapping with aniline. The formed urea derivative was cyclized with NaH to give
a 3,4-
dihydroisoquinolin-1(2H)-one derivative. Incorporation of a double bond into the six-membered ring
followed by removal of the substituent resulted in the formation of isoquinolin-1(2H)-one skeleton.
ß 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
Keywords:
Isoquinolinone
Dihydroisoquinolinone
Acyl azide
Curtius rearrangement
1. Introduction
2007) involves a palladium-catalyzed three-component coupling
reaction between aryl halides, carbon monoxide, and amines. This
Isoquinolines are the member of alkaloids found in several
bioactive natural products (Shamma, 1972; Shamma and Moniot,
1978; Glushkov and Shklyaev, 2001; Krane and Shamma, 1982).
Many naturally occurring alkaloids such as dorianine 1 (Shamma,
1972; Shamma and Moniot, 1978), N-methylcoryaldine 2 (Lee
et al., 1992), thalflavine 3 (Aly et al., 1989), ruprechstyril 4 (Awuah
and Capretta, 2010) and narciclasine 5 (Gonzalez et al., 1999)
contain isoquinoline backbone ring structure (Fig. 1)
Isoquinolinone skeletons, biogenetically derived from the
amino acid phenylalanine, exhibit antidepressant (Sulkovski and
Wille, 1969), anti-inflammatory (Kubo et al., 1979), analgesic
(Senda et al., 1981), and hypolipidemic (Hasegava et al., 1994)
characteristics. Furthermore, they also act as inhibitors of
lipoxygenase (Van Duzer and Roland, 1995) and cholesterol
biosynthesis (Ashton et al., 1990). The substituted isoquinolinone
derivatives are also used as building blocks in organic synthesis.
In view of their great therapeutic value of such motifs in various
biologically active compounds, various synthetic methods have
been developed for the synthesis of isoquinolinone derivatives.
Among the synthetic methods, Gabriel and Colman synthesized
isoquinolone derivatives via ring enlargement process starting
from phthalimide derivatives (Delcey et al., 1995). Another
synthetic method to prepare the cyclic amides (Beccalli et al.,
reaction was modified by using a slight excess amount of carbon
monoxide in the form of its molybdenum complex, Mo(CO)6 (Ren
and Yamane, 2010). For the synthesis of N-substituted isoquino-
linones, 2-methoxycarbonylstyrene oxides were reacted with
substituted amines to yield 4-hydroxy-1(2H)-isoquinolinones
(Sugimoto et al., 1995).
In this paper, we describe a novel route for the synthesis of
dihydroisoquinolinone skeleton based upon Curtius rearrange-
ment of the azide derived from 2-(2-carboxyethyl)benzoic acid 8.
2. Results and discussion
The starting material 9 was synthesized from commercially
available
b-naphtol 6, which was first oxidized to cinnamic acid
derivative 7 by reaction with peroxyacetic acid (Fig. 2). Diacid 7
was then reacted with Raney Nickel in basic aqueous solution to
give the desired saturated diacid 8 as described in the literature
(Page and Tarbell, 1963; Dengiz et al., 2010). The corresponding
diester 9 (Srinivas and Das, 2003) was synthesized by refluxing of
diacid 8 in methanol with thionyl chloride.
Our plan for the construction of the desired heterocyclic ring
system, dihydroisoquinolinone (Ozcan and Balcı, 2008; Ozcan
et al., 2007, 2011; Delio¨meroglu et al., 2010), involved an
intramolecular cyclization reaction of the isocyanate 13, generated
by Curtius rearrangement (Scriven and Turnbull, 1988) of the
corresponding acyl azide 12. For this reason the diester was
submitted to hydrolysis reaction. Recently, we reported that the
* Corresponding author. Tel.: +90 312 2105140; fax: +90 312 2103200.
E-mail address: mbalci@metu.edu.tr (M. Balci).
1874-3900/$ – see front matter ß 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.phytol.2011.04.017

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B. Mu¨jde et al. / Phytochemistry Letters 4 (2011) 407–410
2
Fig. 1. Structures of some natural products containing isoquinolinone skeleton.
Fig. 2. Synthesis of methyl 2-(3-methoxy-3-oxopropyl)benzoate 9.
reactivity of the ester groups, connected to a furan ring, is different
(Koza et al., 2009, 2010). The ester functionality adjacent to the
methylene group in 9 is more reactive than the aromatic one. For
regiospecific hydrolysis, the diester 9 was treated with K2CO3 at
60 8C for 2 h. The desired monoester 10 was formed in 86% yield
(Fig. 3).
The most general and versatile synthesis of acyl azides involves
the reaction of acyl chlorides with NaN3 in an aqueous medium.
The monoester 10 was treated with oxalyl chloride in methylene
chloride followed by addition of a solution of NaN3 in water. This
azide formation method was successful and provided acyl azide 12
in 83% yield. Finally, 12 was refluxed in benzene to give the
corresponding isocyanate derivative 13 in high yield. Isocyanate 13
was chosen as a model compound to explore further reactions.
Treatment of 13 with aniline in methylene chloride gave the
urethane derivative 14 in 65% yield.
with potassium t-butoxide to give the isoquinolinone 17 in
74% yield.
In conclusion, we have developed a new synthetic methodology
for the construction of N-substituted 3,4-dihydroisoquinolin-1-
(2H)-one derivative. The isocyanate 13 can be trapped with
different nucleophiles so that the substituents attached to N-atom
can be controlled. Furthermore, by starting from at benzene ring
substituted diesters 9, further substituted dihydroisoquinolin-1-
(2H)one derivatives can be synthesized. Application of this
methodology opens up a new area for the synthesis of various
substituted isoquinolinone derivatives. Furthermore, introduction
of a double bond into the six-membered ring opens up new routes
of synthesizing of various at benzene ring as well as at nitrogen
atom substituted isoquinolinone derivatives.
Finally, we focused our effort to the ring closure reaction of 14,
already bearing the necessary functionalities as shown in Fig. 4. The
ring-closure reaction of 14 was accomplished by treatment with
NaH in THF at 0 8C. The NMR spectral studies indicated that the
cyclization product 16 was formed as the product in 70% yield. In the
cyclization reaction of 15, two cyclization products, 15 and 18, are
expected as a result of the attack of the two different amide
functionalities to the ester carbonyl group. The formation of the six-
membered ring was preferred over the eight-membered ring 18
(Fig. 5).
3. Experimental
3.1. General
Melting points are uncorrected. Infrared spectra were obtained
from KBr pellets on an FT-IR Bruker Vertex 70 instrument. The 1
H
and 13C NMR spectra were recorded on a Bruker-Biospin (DPX-400)
instrument. Apparent splitting is given in all cases. Column
chromatography was performed on silica gel (60-mesh, Merck),
and TLC was carried out on Merck 0.2 mm silica gel 60 F254
analytical aluminum plates. Elemental analyses were carried out
on a Leco-932 model CHNS analyzer.
For conversion of 3,4-dihydroisoquinolin-1(2H)-one skeleton
15 into isoquinolinone 17, urea derivative 15 was treated with
N-bromosuccinimide (NBS) in the presence of radical initiator,
azaisobutyronitrile (AIBN) at reflux temperature of benzene.
Brominated isoquinolinone derivative 16 was isolated after
column chromatography in 70% yield. For removal of the
amide functionality and introduction of a double bond into
the molecule, the brominated compound 17 was reacted
3.2. Methyl 2-(3-methoxy-3-oxopropyl)benzoate 9
To a stirred solution of diacid 8 (2.0 g, 10.3 mmol) in methanol
(30 mL) was added thionyl chloride (1.02 mL, 12.36 mmol) and
[(Fig._3)TD$FIG]
Fig. 3. Synthesis of urea derivative 14 starting from the diester 9.

[
B. Mu¨jde et al. / Phytochemistry Letters 4 (2011) 407–410
409
added oxalyl chloride (0.5 mL, 5.76 mmol) and stirred at room
temperature for 1 h. After completion of the reaction, solvent was
evaporated to give the acyl chloride (0.97 g, 4.27 mmol, 89%) 11.
1H-NMR (400 MHz, CDCl3)
d 7.96 (br d, J3,4 = 7.8 Hz, 1H, H-3), 7.41
(dt, J4,5 = J5,6 = 7.7 Hz, J3,5 = 1.5 Hz, 1H, H-5), 7.30 (dt,
J3,4 = J4,5 = 7.8 Hz, J4,6 = 1.4 Hz, 1H, H-4), 7.28 (d, J5,6 = 7.5 Hz, 1H,
H-6), 3.88 (s, 3H, –OCH3), 3.29 (AA0BB0-system, 4H, H-7 and H-8);
13C-NMR (100 MHz, CDCl3)
d 173.2, 167.4, 140.7, 132.6, 131.4,
131.2, 129.0, 127.0, 52.1, 48.4, 30.2.
3.5. Methyl 2-(3-azido-3-oxopropyl)benzoate 12
To a solution of methyl 2-(3-chloro-3-oxopropyl)benzoate (11)
(0.97 g, 4.27 mmol) in acetone (25 mL) was added a solution of
sodium azide(1.5 g, 23 mmol) in water(25 mL) dropwise at 0 8C and
stirred for 1 h at 0 8C. The mixture was extracted with ethyl acetate
(3 ꢁ 25 mL), and the combined extracts was washed with saturated
sodium bicarbonate and water, and dried over MgSO4. After
concentration of the solvent, acyl azide 12 (0.84 g, 83%), unstable
at room temperature, was obtained as a pale yellow viscous liquid.
Fig. 4. Synthesis of isoquinolin-1(2H)-one (17).
solution was heated up to reflux temperature (70–80 8C). The
reaction was monitored by TLC. After the completion of the reaction
(4 h), methanol and excess thionyl chloride were evaporated to give
diester 9 (2.14 g, 9.6 mmol, 94%) as a pale yellow viscous liquid. 1H-
1H-NMR (400 MHz, CDCl3)
d7.96 (d, J3,4 = 7.8 Hz, 1H, H-3), 7.41 (br t,
J4,5 = J5,6 = 7.7 Hz, 1H, H-5), 7.2–7.3 (m, H-4 and H-6), 3.88 (s, 3H, –
OCH3), 3.58 (t, J7,8 = 6.8 Hz, 2H, H-7a), 2.71 (t, J7,8 = 6.8 Hz, 2H, H-8);
13C-NMR(100 MHz, CDCl3)
d179.7, 167.4, 141.9, 139.7, 131.0, 130.8,
NMR (400 MHz, CDCl3)
d
7.88 (d, J5,6 = 8.0 Hz, 1H, H-6), 7.40 (t,
129.3, 126.3, 52.1, 43.8, 38.3; IR (KBr, cmꢀ1) 2956, 2152 (N3), 1742,
1689, 1600, 1437, 1300, 1046, 850, 741.
J4,3 = J4,5 = 6.5 Hz, 1H, H-4), 7.25 (m, 2H, H-3 and H-5), 3.86 (s, 3H, –
OCH3), 3.63 (s, 3H, –OCH3), 3.25 (t, J7,8 = 7.0 Hz, 2H, H-8) 2.65 (t,
J7,8 = 7.0 Hz, 7.0 Hz, H-7); 13C-NMR (100 MHz, CDCl3)
d
173.2, 167.4,
3.6. Methyl 2-(2-isocyanatoethyl)benzoate 13
142.4, 132.9, 131.0, 130.8, 129.3, 126.3, 51.9, 51.4, 35.4, 29.8; IR (KBr,
cmꢀ1) 3726.4, 2952.1, 2256.3, 1718.9, 1601.7, 1576.8, 1489.6,
1366.3, 1257.8, 1131.3, 907.5, 648.1.
A solution of methyl 2-(3-azido-3-oxopropyl)benzoate (12)
(1.0 g, 4.29 mmol) in dry benzene (25 mL) was heated under reflux
for 1 h. The solvent was evaporated to give isocyanate 13 (0.82 g,
98% as pale yellow viscous liquid). 1H-NMR (400 MHz, CDCl3)
d
3.3. 3-(2-(Methoxycarbonyl)phenyl)propanoic acid 10
7.89 (d, J3,4 = 7.8 Hz, 1H, H-3), 7.39 (t, J4,5 = J5,6 = 7.5 Hz, 1H, H-5),
7.16–7.28 (m, H-4 and H-6), 3.82 (s, 3H, –OCH3), 3.53 (t,
J7,8 = J7a,b,8b = 6.7 Hz, 2H, H-7) 2.66 (t, J7,8 = 6. 7 Hz, H-8); 13C-
To a stirred solution of diester 9 (2.14 g, 9.6 mmol) in 50 mL of
methanol/H2O (1:1) was added excess potassium carbonate (3.0 g,
21 mmol) and the resulting solution was stirred at 60 8C for 2 h.
After the completion of the reaction, the mixture was cooled to
room temperature and the solution was acidified by dropwise
addition of HCl solution. The unreacted starting material 9 and the
monoester 10 were extracted with ethyl acetate. The organic phase
was extracted with aqueous NaOH solution (10%, 3 ꢁ 25 mL). The
aqueous phase was acidified and then extracted with ethyl acetate
(3 ꢁ 25 mL). The combined organic extracts were dried (MgSO4)
and the solvent was removed to give the monoester 10 (1660 mg,
NMR (100 MHz, CDCl3)
d 167.4, 139.4, 132.5, 131.0, 130.8, 129.8,
128.3, 122.2, 52.1, 43.8, 36.3; IR (KBr, cmꢀ1) 2953, 2271 (NCO),
1716, 1490, 1353, 1265, 1086, 966.1, 752, 582.
3.7. Methyl 2-(2-(3-phenylureido)ethyl)benzoate 14
To a stirred solution of ethyl 2-(3-isocyanato-3-oxopropyl)-
benzoate (13) (0.82 g, 4.0 mmol) in methylene chloride (25 mL)
was added aniline (600 mg, 6.45 mmol) at room temperature and
the resulting mixture was stirred for 2 h at the same temperature.
After concentration of solvent, the residue was purified over a silica
gel (20 g) column eluting with hexane/ethyl acetate (1:1) to give
the urea derivative 14 (775 mg, 65%). White solid, Mp: 131–144 8C.
86%), Mp: 70–71 8C. 1H-NMR (400 MHz, CDCl3)
d 11.12 (br s, 1H, –
COOH), 7.95 (d, J3,4 = 7.6 Hz, 1H, H-3), 7.45 (t, J4,5 = J5,6 = 7.6 Hz, 1H,
H-5), 7.31 (m, H-4 and H-6) 3.91 (s, 3H, –OCH3), 3.31 (t,
J7,8 = 7.7 Hz, 2H, H-8) 2.66 (t, J7,8 = 7.7 Hz, 2H, H-7); 13C-NMR
(100 MHz, CDCl3)
d
173.2, 167.4, 142.4, 132.9, 131.0, 130.8, 129.3,
1H-NMR (400 MHz, CDCl3)
d 7.84 (d, 7.2 Hz, H-15), 7.38 (dt, J = 7.5
and 1.4 Hz, 1H), 7.30–7.17 (m, 7H), 6.96 (t, J = 7.3 Hz, 1H), 5.4 (br. s,
NH, H-10) 3.81 (s, 3H, –OCH3), 3.42 (dt, J = 7.5 and 6.5 Hz, 2H), 3.09
(t, J = 7.5 Hz, 2H); 13C-NMR (100 MHz, CDCl3)
d 168.2, 156.3, 149.9,
126.3, 51.2, 35.4, 29.8; IR (KBr, cmꢀ1) 3300–3000, 1678, 1599,
1492, 1308, 1215, 1150, 809, 680, 536.
3.4. Methyl 2-(3-chloro-3-oxopropyl)benzoate 11
139.2, 132.4, 131.6, 130.8, 129.4, 128.9 (2C), 126.6, 123.0, 120.4
(2H), 52.2, 42.0, 34.9. IR (KBr, cmꢀ1) 3354, 3316, 3022, 2947, 1721,
1629, 1593, 1557, 1443, 1314, 1247, 1108, 1087, 1028, 968; anal.
calcd. for C17H18N2O3; C, 68.44; H, 6.08; N, 9.39. Found: C, 68.53; H,
5.82; N, 9.74.
To a stirred solution of 3-(2-(methoxycarbonyl)phenyl)propa-
[(Fig._5)TD$FIG]
noic acid (10) (1.0 g, 4.8 mmol) in 25 mL of dichloromethane was
3.8. 1-Oxo-N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide
15
To a stirred solution of methyl 2-(2-(3-phenylureido)ethyl)-
benzoate (7) (0.68 g, 2.28 mmol) in dry THF (25 mL) was added
sodium hydride (0.063 g, 2.74 mmol) at 0 8C and the resulting
mixture was stirred for 1 h at the same temperature. After
Fig. 5. Possible cyclization products of 14.

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B. Mu¨jde et al. / Phytochemistry Letters 4 (2011) 407–410
completion of the reaction, water was added dropwise and
aqueous phase was extracted with ethyl acetate (3 ꢁ 25 mL).
The combined organic extracts were dried over MgSO4.
Removal of the solvent gave the crude product, which was
chromatographed on silica gel (20 g) eluting with hexane/ethyl
acetate (3:2) to give dihydroquinolinone derivative 19
(0.41 g, 68%). Mp: 162–163 8C from ethyl acetate/hexane
Acknowledgements
The authors are indebted to TUBITAK (Scientific and Techno-
logical Research Council of Turkey) (Grant 108-M168), the
Department of Chemistry at Middle East Technical University
and TUBA (Turkish Academy of Sciences) for financial support of
this work.
(5:1). 1H-NMR (400 MHz, CDCl3)
J9,10 = 6.8 Hz, J8,10 = 1.0 Hz
d
11.78 (bs, –NH), 8.13 (dd,
H-10), 7.58 (dd,
1H,
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= J19,20 = 7.5 Hz, 2H, H-17, H-19), 7.27 (d, J7,8 = 7.5 Hz, 1H, H-
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carboxamide 16
To a solution of oxo-N-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (15) (0.41 g, 1.54 mmol) in dry benzene (10 mL) N-
bromosuccinimide (0.27 g, 1.54 mmol) and azaisobutyronitrile
(0.05 g, 0.03 mmol) were added and the resulting mixture was
refluxed for 5 h. Then the mixture was filtered and the solvent was
evaporated. The residue was chromatographed on silica gel (20 g)
eluting with hexane/ethyl acetate (3:2) to give 16 (0.37 g, 70%) as
colorless solid. The obtained product was crystallized from ethyl
acetate/hexane (5:1) to give white solid of 16. Mp: 151–152 8C
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1H, –NH), 8.21 (dd, J9,10 = 7.8 Hz, J8,10 = 1.2 Hz 1H, H-10), 7.62 (dt,
J = 7.5 and 1.2 Hz, 1H) 7.63–7.12 (m, 7H), 5.44 (t, J = 3.1 Hz, 1H, H-
3) 5.20 (dd, J = 14.9, and 3.1 Hz, 1H, H-2a), 3.93 (dd, J = 14.9, and
3.1 Hz, 1H, H-2b); 13C-NMR (100 MHz, CDCl3)
d 166.3, 151.8, 139.6,
136.8, 134.3, 132.0 (2C), 129.9, 129.8, 127.7, 126.9, 122.0 (2C),
116.9, 48.5, 43.1; IR (KBr, cmꢀ1) 3129, 3033, 1701, 1657, 1592,
1546, 1500, 1486, 1440, 1389, 1292, 1176, 1149, 1014, 958; anal.
calcd. for C16H13BrN2O2; C, 55.67; H, 3.80; N, 8.12. Found: C, 55.45;
H, 3.68; N, 8.13.
3.10. Isoquinolin-1(2H)-one 17
Page, G.A., Tarbell, D.S., 1963.
4, 136–140.
b-(o-Carboxyphenyl)propionic acid. Org. Synth. Coll.
To a solution of 4-bromo-1-oxo-N-phenyl-3,4-dihydroiso-
quinoline-2(1H)-carboxamide (16) (0.75 g, 2.17 mmol) in t-
BuOH (10 mL) was added t-BuOK (1.0 g, 8.92 mmol) and the
mixture was refluxed for 15 min. Removal of the solvent
followed by column chromatography on silica gel (15 g) eluting
with hexane/ethyl acetate (3:2) gave 17. The obtained product
was crystallized from ethyl acetate/hexane (5:1) to give white
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hexane, Lit Mp = 203–204 8C) (Takaki et al., 1978). 1H-NMR
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(400 MHz, CDCl3)
d 9.19 (bs, 1H, NH), 8.34 (d, J7,8 = 7.9 Hz, 1H, H-
8), 7.60 (dt, J7,8 = J6,7 = 7.9 Hz, J5,7 = 1.3 Hz, 1H, H-7), 7.48 (d,
J5,6 = 7.8, 1H, H-5), 7.44 (dt, J6,7 = J5,6 = 7.8 Hz, J6,8 = 1.1 Hz, 1H, H-
6), 7.00 (bt, J1,9 = J9,10 = 7.3 Hz, 1H, H-9), 6.44 (d, J9,10 = 7.3 Hz,
1H, H-10); 13C-NMR (100 MHz, CDCl3)
d 162.7, 138.1, 133.0,
127.5, 127.2, 127.1, 126.3, 107.5, 99.9; IR (KBr, cmꢀ1) 3517,
3205, 3004, 2253, 1735, 1534, 1476, 1437, 1370, 1335, 1216,
1163, 1111, 1074, 937.