Intramolecular diels-alder furan-mediated synthesis of 8-Aryl-3,4-di- hydroisoquinolin-1(2 H)-ones, convenient precursors of indeno[1,2,3- ij ]isoquinolines

Article abstract of DOI:10.1055/s-0033-1339693

We describe herein preliminary studies on the intramolecular Diels-Alder furan-mediated synthesis of 8-aryl-3,4-dihydroisoquinolin-1(2H)-ones that constitutes a new, formal synthesis of indeno[1,2,3-ij]isoquinolines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339693

LETTER
▌2221
lIenttetr ramolecular Diels–Alder Furan-Mediated Synthesis of 8-Aryl-3,4-di-
hydroisoquinolin-1(2H)-ones, Convenient Precursors of Indeno[1,2,3-ij]iso-
quinolines
8-Aryl-3,4-dihydroisoquinolin-1(2H)-ones
Mónica Treus,a,b Laurence M. Harwood,*b Juan C. Estévez,a Cristian Salas,c Michael G. B. Drew,b Ramón J. Estévez*a
a
Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS),
Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax +34(981)591014; E-mail: ramon.estevez@usc.es
b
Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
Fax +44(118)3786121; E-mail: l.m.harwood@reading.ac.uk
c
Departamento de Química Orgánica, Pontificia Universidad Católica de Chile, 702843 Santiago de Chile, Chile
Received: 06.08.2013; Accepted after revision: 12.08.2013
to be dopamine antagonists, probably due to the fact that
Abstract: We describe herein preliminary studies on the intramo-
the phenyl group is not restricted to the coplanar disposi-
lecular Diels–Alder furan-mediated synthesis of 8-aryl-3,4-dihy-
tion of this group in both the aporphines and indeno[1,2,3-
droisoquinolin-1(2H)-ones that constitutes a new, formal synthesis
ij]isoquinolines. In addition, 8-aryltetrahydroisoquino-
lines have been used for the preparation of indeno[1,2,3-
ij]isoquinolines 3.5c
of indeno[1,2,3-ij]isoquinolines.
Key words: alkaloids, 8-arylisoquinolines, indeno[1,2,3-ij]iso-
quinolines, Bischler–Napieralski cyclization, intramolecular Diels–
Alder furan reaction
Isoquinoline alkaloids have been the subject of intensive
research directed towards finding effective syntheses of
these compounds.3c,6 Classical methods for the generation
of the isoquinoline framework (Bischler–Napieralski,
Pictet–Spengler, and Pomeranz–Fritsch reactions) are of
limited scope, because they consist of a ring closure to
generate the nitrogen heterocycle. It involves an intramo-
lecular electrophilic attack on an activated (substituted)
benzene ring, but, in the absence of electron-releasing
substituents, this cyclization step either fails or proceeds
in low yield.
The isoquinoline ring system is widely distributed in na-
ture and many of the isoquinoline alkaloids isolated have
important pharmacological properties.1 For example,
aporphines (1, Figure 1) exhibit a range of pharmacologi-
cal activities, including antibiotical, antifungal, antimi-
crobial, and dopaminergic effects.2 Of particular interest
is the potent dopamine agonist apomorphine.3 A second
class of isoquinoline alkaloids is that of the indeno[1,2,3-
ij]isoquinolines (3),4 which differ from aporphines in the
size of the C ring. These are attractive, because their phar-
macological properties have not yet been studied, but
some in vitro bioassays have shown that some of them in-
hibit the synthesis of RNA and DNA in mouse thymus
cells.
Searching for synthetic approaches not subject to the
above limitations, we realized that the intramolecular
Diels–Alder reaction of furan (IMDAF)7 is a promising
alternative for the synthesis of isoquinolines,8 including 2-
methyl-3,4-dihydroisoquinolin-1(2H)-one.8e In connec-
tion with our continuous interest on isoquinolines,9 we
considered that the IMDAF reaction appeared to be a suit-
able, not yet explored strategy for the preparation of 8-ar-
ylisoquinolines 8. Our synthetic plan relied on the
generation of the key starting building blocks 6 (Scheme
1). Further construction of the ABC ring system of these
targets 8 was envisaged via an IMDAF reaction leading to
adducts 7, followed by aromatization of the B ring.
3
4
5
4
4
3
3
2
5
6
2
5
6
7
A
A
R
R
B
R
B
NMe
NMe
NMe
1
1
6a
7
8
C
D
1
C
11
10
10
7
D
8
9
8
1
2
3
9
R'
R'
R'
This strategy for the preparation of 8-arylisoquinolines 8
requires a substituent on the nitrogen atom of the Diels–
Alder precursors 6 that facilitates the cycloaddition reac-
tion.8c We chose a benzyl group as a protecting group for
the nitrogen atom of these substrates 6, which could be
easily prepared by coupling different trans-cinnamoyl
chorides 4 with 2-(2-furyl)ethylamine (5), itself readily
obtained from furfuraldehyde.10
Figure 1
8-Aryltetrahydroisoquinolines 2 are mimetics of apor-
phines 1 and indeno[1,2,3-ij]isoquinolines 3 that maintain
the integrity of the 8-phenyl-1,2,3,4-tetrahydroisoquino-
line subunit, but the C ring of both tetracyclic isoquino-
lines derivatives 1 and 3 is absent.5 They have been shown
Reaction of this furylethylamine 5 with trans-cinnamoyl
chloride 4a in dichloromethane and pyridine at room tem-
perature gave 98% yield of the desired amide 6a as a col-
orless oil. After several unsuccessful attempts to promote
SYNLETT 2013, 24, 2221–2224
Advanced online publication: 04.10.2013
DOI: 10.1055/s-0033-1339693; Art ID: ST-2013-B0021-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2222
M. Treus et al.
LETTER
O
R1
R1
O
Cl
14–19 kbar
Et3N
NBn
+
CH2Cl2
r.t., 3–17 h
70–98%
CH2Cl2
25–30 °C, 7–8 d
48–55%
O
NHBn
5
O
R2
R2
4
5
6
5
4
4
3
3
6
7
6
7
O
8a
NBn
NBn
1
HCl (aq)
1
8
8
H
MeOH
reflux, 4–6 h
60–85%
O
O
R1
R2
R1
R2
( )-7
8
Scheme 1 a : R1 = R2 = H; b: R1 = R2 = OMe; c: R1 = H, R2 = OMe.
the IMDAF cyclization of 6a,11 which resulted in the re- quinolin-1-one 8b resulted in 70% yield, as easily estab-
covery of the starting material, satisfactory results were lished from its spectroscopic and analytical data.13
achieved when a solution of this compound in dichloro-
Finally, once 6c was obtained from 4c and 5, a solution of
methane was subjected to high pressure (19·103 bar) for
6c in dichloromethane was subjected to a pressure of
eight days. Under these conditions, a 49% yield of cyclo-
19·103 bar for seven days to give a 55% yield of cycload-
adduct 7a was obtained,12 and a 25% of the starting mate-
duct 7c after column chromatography, together with 30%
rial was recovered. The exo configuration expected for 7a
of the recovered starting material.
1
was confirmed by H NMR, COSY, and NOE experi-
The exo configuration expected for compound 7c was un-
ambiguously confirmed by single-crystal X-ray15 analysis
(Figure 2).
ments.13
Finally, refluxing a solution of compound 7a in methanol
and aqueous hydrochloric acid for five hours produced a
85% yield of the desired N-benzylisoquinolin-1-one
(8a),14 as a result of the opening of the oxabicycle system
and aromatization of the resulting material.
Aromatization of 7c as before provided a 60% yield of the
desired 8-arylisoquinoline 8c.
To sum up, we report here preliminary results on the intra-
molecular Diels–Alder furan-mediated synthesis of 8-
aryl-3,4-dihydroisoquinolin-1(2H)-ones, synthetic pre-
cursors of indeno[1,2,3-ij]isoquinolines. Accordingly,
this constitutes a new, formal synthesis of these targets.
In order to explore the scope of this new approach to 8-aryl-
isoquinolines 8, we decided to attempt the preparation of
substituted 8-arylisoquinolines 8b and 8c.
Thus, 2-(2-furyl)ethylamine (5) was reacted with trans-
3,5-dimethoxycinnamoyl chloride (4b), in order to obtain
cinnamoylamide 6b. When a solution of 6b in dichloro-
methane was subjected to high pressure (14·103 bar) at 30
°C for eight days, a 48% yield of the expected racemic cy-
cloadduct 7b resulted, with 47% of starting material re-
covered. Finally, when oxabicyclo[2.2.1]heptene 7b was
subjected to the aromatization conditions applied for the
transformation of 7a into 8a, the expected 8-arylliso-
Work is now in progress aimed at the optimization of this
promising IMDAF reaction, as a preliminary stage for its
application to the preparation of a wide range of 8-substi-
tuted isoquinolines and related substrates, including
8-styrylisoquinolines and naphtho[1,2-h]isoquinolines.
Acknowledgment
We thank the Xunta de Galicia (CN2011/037) for financial support
and for providing pre- and postdoctoral funding to M.T.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
References and Notes
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(2) (a) Ríos, J. L.; Máñez, S.; Giner, R. M.; Recio, M. C. The
Alkaloids; Vol. 53; Cordell, G. A., Ed.; Academic: New
Figure 2 ORTEP diagram of 7c
Synlett 2013, 24, 2221–2224
© Georg Thieme Verlag Stuttgart · New York

LETTER
York, 2000, 57. (b) Guinaudeau, H.; Leboeuf, M.; Cavé, A.
8-Aryl-3,4-dihydroisoquinolin-1(2H)-ones
2223
Selected Physical and Spectroscopic Data
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Compound 7a: 1H NMR (CDCl3, 250 MHz): δ = 2.23–2.29
(m, 2 H, CH2CN), 2.60 (d, 1 H, J = 4.9 Hz, H8a), 3.19–3.27
(m, 1 H, CH2-N), 3.44–3.56 (m, 1 H, CH2N), 3.72 (t, 1 H,
J = 4.7 Hz, H8), 4.34 (d, 1 H, J = 14.7 Hz, CH2Ph), 4.84 (d,
1 H, J = 14.7 Hz, CH2Ph), 5.13 (d, 1 H, J = 4.6 Hz, H7), 6.27
(s, 2 H, HC=CH), 7.12–7.41 (m, 10 H, 10 × ArH) ppm. 13
C
NMR (CDCl3, 62.5 MHz): δ = 26.0 (CH2), 43.2 (CH2), 50.3
(CH2), 50.6 (CH), 50.7 (CH), 81.4 (CH), 87.5 (C), 126.5
(CH), 127.4 (CH), 128.0 (2 × CH), 128.1 (2 × CH), 128.3 (2
× CH), 128.6 (2 × CH), 136.5 (CH), 137.1 (CH + C), 139.8
(C), 171.2 (C=O) ppm. MS (CI): m/z (%) = 332 (53) [M +
1]+, 131 (100). HRMS: m/z calcd for C22H22NO2: 331.1572;
found: 331.1580.
Compound 7b: 1H NMR (CDCl3, 250 MHz): δ = 2.21–2.27
(m, 2 H, CH2CN), 2.56 (d, 1 H, J = 4.8 Hz, H8a), 3.18–3.24
(m, 1 H, CH2N), 3.40–3.48 (m, 1 H, CH2N), 3.65 (t, 1 H,
J = 4.7 Hz, H8), 3.70 (s, 6 H, 2 × OCH3), 4.39 (d, 1 H,
J = 14.7 Hz, CH2Ph), 4.77 (d, 1 H, J = 14.7 Hz, CH2Ph),
5.07 (dd, 1 H, J = 4.6, 1.4 Hz, H7), 6.23–6.30 (m, 3 H, 3 ×
ArH), 6.44–6.46 (m, 2 H, HC=CH), 7.20–7.26 (m, 5 H, 5 ×
ArH) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 26.0 (CH2),
43.2 (CH2), 50.2 (CH2), 50.6 (CH), 51.8 (CH), 55.2 (2 ×
OMe), 81.3 (CH), 87.4 (C), 98.3 (CH), 106.4 (2 × CH),
127.3 (CH), 127.9 (2 × CH), 128.6 (2 × CH), 136.5 (CH),
137.0 (CH + C), 142.2 (2 × C), 160.5 (2 × COMe), 171.1
(C=O). MS (CI): m/z (%) = 392 (100) [M + 1]+. HRMS: m/z
calcd for C24H25NO4: 391.1783; found: 391.1778.
Compound 7c: mp 101–102 °C (MeOH). 1H NMR (CDCl3,
250 MHz): δ = 2.19–2.25 (m, 2 H, CH2CN), 2.56 (d, 1 H,
J = 4.9 Hz, H8a), 3.14–3.23 (m, 1 H, CH2N), 3.40–3.46 (m, 1
H, CH2N), 3.67 (t, 1 H, J = 4.7 Hz, H8), 3.69 (s, 3 H, OMe),
4.36 (d, 1 H, J = 14.7 Hz, CH2Ph), 4.77 (d, 1 H, J = 14.7 Hz,
CH2Ph), 5.08 (1 H, dd, J = 4.8, 0.9 Hz, H7), 6.22 (d, 1 H, d,
J = 5.9 Hz, CH=CH), 6.25 (d, 1 H, J = 5.9 Hz, CH=CH),
6.64–6.67 (m, 1 H, m, ArH), 6.82–6.86 (m, 2 H, m, 2 × ArH),
7.07–7.24 (m, 6 H, 6 × ArH) ppm. 13C NMR (CDCl3, 62.5
MHz): δ = 26.4 (CH2), 43.7 (CH2), 50.7 (CH2), 51.1 (CH),
52.1 (CH), 55.6 (OMe), 81.8 (CH), 87.9 (C), 112.2 (CH),
114.6 (CH), 120.9 (CH), 127.9 (CH), 128.6 (2 × CH), 128.9
(2 × CH), 129.6 (CH), 137.0 (CH), 137.6 (CH + C), 142.0
(C), 159.9 (COMe), 171.6 (C=O) ppm. MS (CI): m/z (%) =
362 (100) [M + 1]+. Anal. Calcd for C23H23NO3: C, 76.43; H,
6.41; N, 3.87. Found: C, 76.30; H, 6.37; N, 3.83.
Compound 8a: mp 138–140 °C (MeOH). 1H NMR (CDCl3,
250 MHz): δ = 2.82 (t, 2 H, J = 6.3 Hz, CH2CN), 3.45 (t, 2
H, J = 6.3 Hz, CH2N), 4.63 (s, 2 H, CH2Ph), 7.05–7.30 (m,
13 H, 13 × ArH) ppm. 13C NMR (CDCl3, 62.5 MHz): δ =
29.6 (CH2), 44.9 (CH2), 50.1 (CH2), 126.1 (CH), 126.6 (CH),
127.3 (CH), 127.6 (2xCH), 127.8 (C), 128.0 (2 × CH), 128.2
(2 × CH), 128.5 (2 × CH), 130.4 (CH), 130.6 (CH), 137.8
(C), 139.8 (C), 142.9 (C), 144.1 (C), 163.8 (C=O) ppm. MS
(CI): m/z (%) = 314 (100) [M + 1]+. HRMS: m/z calcd for
C22H19NO: 313.1467; found: 313.1466.
(10) Dornow, A.; Gellrich, M. Justus Liebigs Ann. Chem. 1955,
594, 177.
(11) Unsuccessful conditions to promote the IMDAF cyclization
of 6a that resulted in the recovering of the starting material:
(a) toluene, reflux, 5 d; (b) 145 °C, 21 h (no solvent);
(c) MgBr2, THF, MS, reflux, 21 h; (d) AlCl3, THF, MS,
reflux, 3 d; (e) 11·103 bar, CH2Cl2, 20 °C, 1 d.
(12) Synthesis of (4aR,7S,8aS)-2-Benzyl-8-phenyl-
2,3,4,7,8,8a-hexahydro-1H-4a,7-epoxyisoquinolin-1-one
(7a)
A solution of amide 6a (60 mg, 0.181 mmol) in anhydrous
CH2Cl2 (2 mL) was subjected to high pressure (19·103 bar)
at 27 ° C for 7 d. On depressurization, the solution was
filtered through a plug of cotton wool to remove the solid
matter, and the solvent was removed off under reduced
pressure to afford 50 mg of crude material. Purification by
column chromatography on silica (eluant: 1:1 light PE–
Et2O) furnished the cycloadduct 7a as a colorless oil (29 mg,
49% yield) and 15 mg (25% yield) of recovered starting 6a
(64% yield of 7a on the basis of recovered starting material).
(13) All new compounds gave satisfactory analytical and
spectroscopic data.
Compound 8b: 1H NMR (CDCl3, 250 MHz): δ = 2.90 (t, 2
H, J = 6.2 Hz, CH2CN), 3,52 (t, 2 H, J = 6.2 Hz, CH2N), 3.80
(s, 6 H, 2 × OCH3), 4.71 (s, 2 H, CH2Ph), 6.45–6.48 (m, 3 H,
3 × ArH), 7.13–7.40 (m, 8 H, 8 × ArH) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 29.6 (CH2), 45.2 (CH2), 50.3 (CH2),
55.2 (2 × OMe), 98.9 (CH), 106.7 (2 × CH), 126.2 (CH),
127.3 (CH), 128.0 (2 × CH + C), 128.5 (2 × CH), 130.3
(CH), 130.4 (CH), 137.9 (C), 139.8 (C), 143.9 (C), 145.0
(C), 159.9 (2 × COMe), 163.6 (C=O) ppm. MS (CI): m/z
(%): 374 (100) [M + 1]+. HRMS: m/z calcd for C24H23NO3:
373.1678; found: 373.1677.
Compound 8c: 1H NMR (CDCl3, 250 MHz): δ = 2.82 (t, 2
H, J = 6.4 Hz, CH2CN), 3.45 (t, 2 H, J = 6.4 Hz, CH2N), 3.75
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2221–2224

2224
M. Treus et al.
LETTER
the mixture was refluxed for 4 h. The solution was
neutralized with 2 M aq NaOH and extracted with CH2Cl2
(3 × 8 mL). The pooled organic extracts were washed with
H2O (15 mL) and dried (anhydrous sodium sulfate).
Removal of the solvent under reduced pressure afforded a
residue, which was purified by preparative TLC on silica
(eluant: 1:1 light PE–Et2O) to give 40 mg (85% yield) of
isoquinoline 8a as a white solid.
(s, 3 H, OMe), 4.70 (s, 2 H, CH2Ph), 6.70–6.82 (m, 3 H, 3 ×
ArH), 7.16–7.31 (m, 9 H, 9 × ArH) ppm. 13C NMR (CDCl3,
62.5 MHz): δ = 30.1 (CH2), 45.5 (CH2), 50.6 (CH2), 55.6
(OMe), 112.5 (CH), 114.5 (CH), 121.4 (CH), 126.7 (CH),
127.8 (CH), 128.4 (2 × CH), 128.5 (3 × CH), 130.9 (CH),
131.0 (CH), 138.4 (C), 140.3 (C), 144.4 (C), 144.8 (C),
159.4 (COMe), 164.1 (C=O) ppm. MS (CI): m/z (%) = 344
(100) [M + 1]+. HRMS: m/z calcd for C22H21NO2: 343.1572;
found: 343.1580.
(15) The crystallographic data of compound 7c have been
included in the Supporting Information.
(14) Synthesis of 2-Benzyl-8-phenyl-3,4-dihydroisoquinolin-
1(2H)-one (8a)
Concentrated HCl (0.1 mL) was added to a solution of
cycloadduct 7a (50 mg, 0.151 mmol) in MeOH (5 mL), and
Synlett 2013, 24, 2221–2224
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