A straightforward synthesis of indazolo[3,2-a]isoquinolin-6-amines

Article abstract of DOI:10.1016/j.tetlet.2013.07.106

4-Substituted 1-bromoisoquinolin-3-amines were subjected to Suzuki coupling with o-nitrophenylboronic acid to yield 1-(2-nitrophenyl) isoquinolinamines, which participated in Cadogan cyclization with triethyl phosphite under microwave irradiation in a sealed vial to yield fluorescent indazolo[3,2-a] isoquinolin-6-amines. The new compounds were also functionalized by transformation of the amino group.

Full text of DOI:10.1016/j.tetlet.2013.07.106

Tetrahedron Letters 54 (2013) 5338–5340
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Tetrahedron Letters
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A straightforward synthesis of indazolo[3,2-a]isoquinolin-6-amines
⇑
József Balog, Zsuzsanna Riedl, György Hajós
Research Center for Natural Sciences, Institute of Organic Chemistry, Hungarian Academy of Sciences, Pusztaszeri út 59, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Substituted 1-bromoisoquinolin-3-amines were subjected to Suzuki coupling with o-nitrophenylbo-
ronic acid to yield 1-(2-nitrophenyl) isoquinolinamines, which participated in Cadogan cyclization with
triethyl phosphite under microwave irradiation in a sealed vial to yield fluorescent indazolo[3,2-a]iso-
quinolin-6-amines. The new compounds were also functionalized by transformation of the amino group.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 28 May 2013
Revised 5 July 2013
Accepted 19 July 2013
Available online 27 July 2013
Keywords:
Suzuki coupling
Nitrene
Indazole
Cyclization
Fluorescence
Although significant literature data are available on the reactiv-
ity of pyridinamines and its two bicyclic analogues: quinolin-2-
amines and isoquinolin-1-amines,1 far fewer results have been
described on the transformations of isoquinolin-3-amines.2 An obvi-
ous reason is the difficulty in obtaining such amines and the non-
straightforward methods for the syntheses of these compounds.
Consideration of novel ring-closure possibilities starting from
functionalized isoquinolin-3-amines revealed that 1-bromoiso-
quinolin-3-amine could serve as an excellent starting compound
for ring-closure to indazolo[3,2-a]isoquinolines bearing an amino
group at position 6. Inspection of the literature revealed that rela-
tively few derivatives of this heteroaromatic ring system have been
published.3–6 These examples did not include functional groups on
the ring other than a halogen atom.
A possible pathway to the indazolo[3,2-a]isoquinoline ring sys-
tem is shown in Scheme 1 as a retrosynthetic analysis. Thus, the
desired tetracyclic ring (1) could be available by a reductive Cado-
gan cyclization7 of o-nitrophenylisoquinoline (3) involving the at-
tack of an intermediate nitrene (2) on the nitrogen atom of the
isoquinoline ring. This ring-closure has already been described
for one single (unsubstituted) derivative of an indazolo[3,2-a]iso-
quinoline ring,8 where the starting compound for the ring-closure
was prepared from a 3,4-dihydroisoquinoline derivative in poor
yield.9 In our synthetic plan, however, the starting compound (3)
was to be synthesized by a simple Suzuki coupling of commercially
available 1-bromoisoquinolin-3-amine (4) or its easily accessible
derivatives10 with 2-nitrophenylboronic acid.
Herein we report a concise, two-step reaction to indazolo[3,2-
a]isoquinolin-6-amines starting from 4-substituted 1-bromoiso-
quinolin-3-amines as depicted in Scheme 2.
Five different substituted 1-bromoisoquinolin-3-amines (4a–e)
were subjected to Suzuki-coupling with 2-nitrophenylboronic acid.
The best results11 were achieved at 95 °C with palladium [tetra-
kis(triphenylphosphine)palladium(0)] as the catalyst and sodium
carbonate as base. The new 1-arylisoquinolines (3a–e) were ob-
tained as yellow crystals in high yields (73–92%). Treatment of
compounds (3) with triethyl phosphite under microwave irradia-
tion—in analogy to successful cyclizations to related carbazoles7—
resulted in formation of the expected tetracyclic compounds 1a–e
in a short reaction time (20 min) in excellent 79–91% yields.12 The
physical characteristics (appearance, mp) and yields of the Suzuki-
coupling products 3a–e and the ring-closed indazolo[3,2-a]iso-
quinolin-6-amines 1a–e are summarized in Table 1.
The reaction proceeds via formation of a reactive electrophilic
nitrene which readily attacks the adjacent nucleophilic ring nitro-
gen atom to give a new five-membered ring. Formation of the new
indazolo[3,2-a]isoquinoline ring system was supported by spectro-
scopic data (i.e., a downfield shift of the aryl protons in the 1H NMR
spectra in accordance with the extended aromatic delocalization
and disappearance of the NO2 absorption in the IR; fundamental
change of the UV spectra of 1 related to those of 3).
The new indazoloisoquinoline 1a, interestingly, exhibited fluo-
rescence behavior with very strong emission intensity (Fig. 1). In
acetonitrile, the absorption and fluorescence spectra show approx-
imately mirror symmetry, with a stronger vibronic structure in the
absorption spectrum a phenomenon which often occurs. The sin-
glet energy is 289 kJ molÀ1 and does not change considerably with
the nature of the solvent. Similarly, the fluorescence yield (/f),
⇑
Corresponding author. Tel./fax: +36 1 4381119.
E-mail address: hajos.gyorgy@ttk.mta.hu (G. Hajós).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.106

J. Balog et al. / Tetrahedron Letters 54 (2013) 5338–5340
5339
R
R
R
R
NH2
NH2
NO2
NH2
NH2
N
N
N
N
N
N
Br
4
3
2
1
Scheme 1. Retrosynthetic analysis of indazolo[3,2-a]isoquinolin-6-amines (1) from substituted 1-bromoisoquinolin-3-amines (4).
B(OH)2
Entry
a
R
R
R
R
H
NH2
NO2
NH2
NO2
NH2
b
c
d
e
(EtO)3P, MW
Me
Pd (PPh3)4, Na2CO3, 95°C
N
N
N
Et
N
Br
Bn
4
3
1
COOEt
Scheme 2. Two-step synthesis of indazolo[3,2-a]isoquinoline-6-amines (1).
Table 1
Physical characteristics (appearance, mp) and yields of the Suzuki-coupling products 3a–e and the ring-closed indazolo[3,2-a]isoquinolin-6-amines 1a–e
Product
Color
Mp (°C)
Yield (%)
Product
Color
Mp (°C)
Yield (%)
3a
3b
3c
3d
3e
Yellow
Red
Orange
Pale orange
Yellow
154–155
157–158
155–156
199–201
165–166
84
86
77
73
92
1a
1b
1c
1d
1e
Yellow
Yellow
Yellow
Yellow
Yellow
190–191
140–141
150–152
183–184
112–113
91
79
82
86
86
proved to be 0.45, both in MeCN and methanol. Acidification of the
solvent did not change the appearance of the spectra to any great
extent, except the vibronic structure was lost. However, while
the absorption coefficient decreased only slightly after adding 5%
trifluoroacetic acid to the acetonitrile solution (the basicity of the
compound is low, consequently a considerable amount of acid is
needed to reach full protonation), the fluorescence intensity de-
creased by two orders of magnitude (Fig. 1).13,14 This is most prob-
ably caused by a protonation-induced internal conversion channel,
which competes effectively with the fluorescence.
10000
5000
0
Φ
τ
f = 0.46
= 4.72 ns
5
10
15
20
25
30
time (ns)
3
0
-3
The transition belongs to the molecular orbitals that have not
been influenced by the amino group very much. Furthermore, the di-
pole moment of the molecule does not seem to change considerably
on excitation. The lifetime of the singlet excited state is 4.72 ns in
x100
acetonitrile, while the radiactive rate coefficient (kf = /f/s) is
300
400
500
600
9.7 Â 107 sÀ1. Using this value and the emission spectrum, the tran-
sition dipole moment of 3.95 Debye can be derived,15 which is a rea-
wavelength (nm)
sonable value, considering the
p–
p⁄ character of the transition
Figure 1. Absorption and fluorescence spectra of 1a (full lines) and of the
protonated form (dotted lines) in acetonitrile at 25 °C (the weak fluorescence
signal of the protonated derivative is multiplied by a factor of one hundred). Inset:
fluorescence decay curve of 1a in acetonitrile measured at 25 °C (excitation 375 nm,
detection 450 10 nm).
mentioned above. In methanol and n-hexane the decay parameters,
as expected, proved to be similar: 4.35 and 4.68 ns, respectively.16
To the best of our knowledge, this is the first case in which an
amino derivative with this ring system has been synthesized. The
CH3
CH3
CH3
Br
N
OEt
N
NR'R"
N
N
N
N
HNR'R"
NaNO2/HBr
HC(OEt)3
N
N
1b
6
7
5
Scheme 3. Transformations of 7-methylindazolo[3,2-a]isoquinolin-6-amine (1b).

5340
J. Balog et al. / Tetrahedron Letters 54 (2013) 5338–5340
1.34 mmol), 2-nitrophenylboronic acid (0.268 g, 1.61 mmol), Pd(PPh3)4
(0.077 g, 0.067 mmol, 5 mol %), and Na2CO3 (0.284 g, 2.68 mmol) followed by
adding toluene (8 mL), EtOH (4 mL) and H2O (0.5 mL). The mixture was flushed
with argon for 5 min and, then, was heated under reflux for 12 h with magnetic
stirring. After cooling to room temperature, the solvent was removed under
reduced pressure. The residue was purified by flash column chromatography
on silica using hexane/EtOAc (1:1) as the eluent yielding yellow crystals 3a
(0.298 g, 84%, mp 154–155 °C).
presence of the amino functionality allows further transformations
as shown in Scheme 3. Thus, reaction of 1b with triethyl orthofor-
mate afforded the imino ether 5, which was reacted in situ with
secondary amines to give various amidines 6.17 Furthermore,
diazotisation of 1b in hydrobromic acid led to the formation of
6-bromoindazolo[2,3-a]isoquinoline (7, 120–121 °C, 32%).18
These results reveal that our two-step microwave-assisted ring-
closure technique provides a convenient approach to the hitherto
sparingly studied indazolo[3,2-a]isoquinoline ring system. Further
functionalization of the ring system is in progress.
12. Typical procedure for ring-closure to indazolo[3,2-a]isoquinolin-6-amines (1). The
nitrophenyl compound (3, 1 mmol) was suspended in triethyl phosphite
(4 mL) in a tightly sealed 10 mL glass vial equipped with a small stirring
magnet. The mixture was irradiated in the cavity of an Anton Paar monowave
300 machine for 20 min at
a pre-selected temperature of 200 °C. After
completion of the reaction the vial was cooled to 55 °C by gas jet cooling.
The reaction mixture was transferred to a 10 mL flask and the excess triethyl
phosphite was removed under reduced pressure. The residue was treated with
hexane and the resulting precipitate was filtered off to give the product. In
cases when the mother liquor also contained a substantial amount of product,
it was also purified on silica gel.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.106.
13. (a) Demeter, A.; Mile, V.; Bérces, T. J. Phys. Chem. A 2007, 111, 8942; (b) Cserép,
}
G. B.; Enyedi, K.; Demeter, A.; Mezo, G.; Kele, P. Chem. Asian J. 2013, 8, 494.
14. Kubinyi, M.; Varga, O.; Baranyai, P.; Kállay, M.; Mizsei, R.; Tárkányi, G.; Vidóczy,
T. J. Mol. Struct. 2011, 1000, 77.
15. Lewis, J. E.; Maroncelli, M. Chem. Phys. Lett. 1998, 282, 197.
16. For experimental conditions of UV and fluorescence measurements, see
Supplementary data.
References and notes
1. Dennis, N. Pyridines and their Benzo Derivatives: Reactivity of Substituents. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. W., Rees, C. W., Scriven, E.
F. V., Eds.; Elsevier, 1996; pp 91–134.
2. For examples, see: (a) Dixit, B.; Balog, J.; Riedl, Zs.; Drahos, L.; Hajos, Gy.
Tetrahedron 2012, 68, 3560; (b) Manley, P. W.; Furet, P.; Bold, G.; Brueggen, J.;
Mestan, J.; Meyer, T.; Schnell, C. R.; Wood, J. J. Med. Chem. 2002, 45, 5687; (c)
Honda, T.; Mogi, H.; Ban, M.; Aono, H.; Nagahara, H. Bioorg. Med. Chem. Lett.
2011, 21, 1782; (d) Chrzastek, L.; Mianowska, B.; Sliwa, W. Aust. J. Chem. 1994,
47, 2129.
3. Zhao, J.; Wu, Ch.; Li, P.; Ai, W.; Chen, H.; Wang, C.; Shi, F.; Larock, R. C. J. Org.
Chem. 2011, 76, 6837.
4. Zhao, J.; Li, Pan; Wu, C.; Chen, H.; Ai, W.; Sun, R.; Ren, H.; Shi, F.; Larock, R. C.
Org. Biomol. Chem. 2012, 10, 1922.
5. Zhang, L.; Xiao, Q.; Ye, S.; Wu, J. Chem. Asian J. 2012, 7, 1909.
6. Yamashita, Y.; Hayashi, T.; Masumura, M. Chem. Lett. 1980, 1133.
7. Appukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett 2005, 127.
8. Stanforth, S. P. J. Heterocycl. Chem. 1987, 24, 531.
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10. Johnson, F.; Nasutavicus, W. A. J. Org. Chem. 1962, 27, 3953.
11. Typical procedure for the synthesis of 3 by Suzuki coupling of 4: A round-
bottomed flask was charged with 1-bromoisoquinolin-3-amine (4a, 0.300 g,
17. Synthesis
isoquinolin-6-amine (6):
5-methylindazolo[3,2-a]isoquinolin-6-amine
of
(E)-5-methyl-N-(morpholin-4-ylmethylidene)indazolo[3,2-a]
round-bottomed flask was charged with
(1b, 0.100 g, 0.40 mmol),
A
morpholine (0.500 g, 5.74 mmol, 0.5 mL), triethyl orthoformate (5 mL), and
toluene (5 mL). The mixture was heated at 110 °C for 16 h with stirring. After
cooling to room temperature, the excess triethyl orthoformate and toluene
were removed in vacuo. The residue was dissolved in CHCl3 (20 mL) and the
solution washed with H2O (20 mL). The aqueous phase was extracted with
CHCl3 (2 Â 20 mL) and the combined organic phase dried over anhydrous
Na2SO4. The solution was filtered and evaporated. The residue was triturated
with Et2O to give a brown powder (115 mg, 83%), mp 165–168 °C.
18. 5-Methylindazolo[3,2-a]isoquinolin-6-amine (1b, 0.300 g, 1.21 mmol) was
dissolved in 48% aqueous HBr (0.86 mL). After cooling to 0 °C, NaNO2 (0.09 g,
1.3 mmol) was added slowly to the stirred solution at 0–5 °C. This solution was
then poured into a flask containing CuBr (0.25 g, 1.7 mmol) and 48% aqueous
HBr (1 mL). The solution was heated to reflux for 3 h, cooled, and poured into
H2O. The aqueous solution was extracted with dichloromethane (3 Â 30 mL).
The organic layer was washed with 1 M NaOH (40 mL) and H2O (40 mL) and,
then, dried over Na2SO4. After removal of the solvent, yellow crystals of 7 were
obtained (75 mg, 20%, mp 193–195 °C).