New fluorescent isoquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.07.143

Various structural modifications of 3-amino and 3-hydroxyisoquinolines have been carried out to provide new fluorescent derivatives. The transformations involved nucleophilic substitution of a bromine atom or a triflate moiety at positions 1 and 3, respectively, as well as the condensation reaction of a 3-amino group with triethyl orthoformate and subsequent transformation with amines to give amidines. The new compounds have been studied by fluorescence spectroscopy.

Full text of DOI:10.1016/j.tetlet.2011.07.143

Tetrahedron Letters 52 (2011) 5264–5266
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Tetrahedron Letters
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New fluorescent isoquinoline derivatives
⇑
József Balog, Zsuzsanna Riedl, György Hajós , Zsombor Miskolczy, László Biczók
Chemical Research Center of the Hungarian Academy of Sciences, Pusztaszeri út 59-67, 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:
Various structural modifications of 3-amino and 3-hydroxyisoquinolines have been carried out to provide
new fluorescent derivatives. The transformations involved nucleophilic substitution of a bromine atom or
a triflate moiety at positions 1 and 3, respectively, as well as the condensation reaction of a 3-amino
group with triethyl orthoformate and subsequent transformation with amines to give amidines. The
new compounds have been studied by fluorescence spectroscopy.
Received 16 June 2011
Revised 15 July 2011
Accepted 29 July 2011
Available online 6 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoquinoline-amine
Formimidate
Fluorescence spectrum
Amidine
Quantum yield
During the course of our recent research in the area of substi-
tuted isoquinoline-3-amine derivatives1,2 we observed visible fluo-
rescence in some cases. These findings prompted us to explore
fluorescence of this kind in isoquinoline derivatives in detail by
carrying out structural changes and studying the fluorescence
properties of the resulting compounds. As the preliminary visual
observations occurred mostly with amino compounds, we decided
to synthesize various isoquinoline derivatives containing free and
substituted amino groups at different positions. For this purpose,
transformations of isoquinoline-3-triflate as well as 1-bromoiso-
quinoline-3-amine and its 4-alkyl derivatives—both compound
types have been described previously in the literature2,3—seemed
of interest.
For comparison of the behavior of primary and tertiary amines,
3-morpholinoisoquinoline (2) was synthesized first. Although 2
has already been described,4 we found that this compound could
be prepared more conveniently from 1 with morpholine. Thus,
heating triflate3 1 in morpholine under reflux conditions (at
130 °C) afforded the desired compound in acceptable yield (75%)5
(Scheme 1).
(b) Primary amines (3a–f and 6a–c) were, then transformed
into amidines 5 and 8. Thus, the primary amines were treated with
triethyl orthoformate to give the water-sensitive formimidates 4
and 7.7 These compounds when reacted with morpholine in boiling
toluene gave rise to the new amidines 5a–f and 8a–c.8
Of the possible 28 structures involved in Schemes 1 and 2, nine
derivatives (2, 3d, 5b, 5c, 5f, 6a, 6b, 6c and 8b) were selected for
detailed photophysical studies. The structures of these selected
compounds are separately shown in Figure 1.
Table 1 summarizes the photophysical properties of the selected
compounds. The location of the maximum of the first absorption
[kmax(abs)] and the fluorescence [kmax(fl)] bands shifts moderately
to higher wavelength upon modification of the molecular structure.
The largest displacement was observed for compounds 6c and 6b.
The fluorescence quantum yield (Uf) and fluorescence lifetime (sf
)
decreased substantially upon introduction of the bromine atom at
position 1 mainly due to acceleration of the triplet formation by
the presence of the heavy atom.9 Comparison of the properties of
5c and 5f confirmed that the bromine atom brings about consider-
ablefluorescencequenching. Therate constantof fluorescenceemis-
sion (kf) and radiationless deactivation (knr) from the singlet excited
A further set of differently substituted isoquinoline-amines and
the applied reaction pathways are shown in Scheme 2.
state were calculated using kf = Uf
ships, respectively. As shown in Table 1, kf is insensitive to variation
/
sf and knr = (1 ꢀ Uf)/sf relation-
(a) The bromine atom at position 1 of isoquinolines 3a–c was
substituted by hydrogen (catalytic hydrogenation over Pd/C accord-
ing to literature procedures5) to give derivatives 3d–f. Furthermore,
the same bromine atom was also substituted by a morpholine
moiety to yield 1-morpholino compounds 6a–c.6
of the molecular structure. Changing the 3-amino substituent to a
N
OTf
O
morpholine
130 °C
N
N
2
1
⇑
Corresponding author.
E-mail address: ghajos@chemres.hu (G. Hajós).
Scheme 1. Synthesis of 3-morpholinoisoquinoline (2).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.143

J. Balog et al. / Tetrahedron Letters 52 (2011) 5264–5266
5265
X
Br
Br
R
R
a
b
c
R
X
H
R
O
N
OEt
NH2
N
N
HC(OEt)3
Me
N
N
130 °C
p-TsOH
N
morpholine
100 °C
toluene
Br Bn
X
X
3
4
5
d
e
H
H
H
H
Me
Bn
morpholine
130 °C
f
R
N
R
O
R
N
OEt
N
N
NH2
R
HC(OEt)3
N
N
N
a
b
c
130 °C
p-TsOH
H
morpholine
100 °C
toluene
N
O
N
Me
Bn
O
O
6
8
7
Scheme 2. Various transformations of 4-substituted 1-bromoisoquinoline-3-amines (3a–c).
NH2
Me
NH2
O
N
NH2
N
NH2
N
N
O
N
N
N
N
O
N
O
2
3d
6a
6c
6b
Me
O
Me
O
O
N
N
N
N
O
N
N
N
N
N
N
N
N
O
Br
N
Br
5b
5c
8b
5f
Figure 1. Structures of the isoquinoline-amines selected for photophysical studies.
Table 1
Photophysical properties of the isoquinoline-amines in acetonitrile
0.6
0.6
0.4
0.2
0.0
3d
2
6a
6b
6c
5b
5c
5f
8b
kmax(abs)a (nm) 363 366 371 377 377 372
370
451
363
434
370
456
0.4
0.2
0.0
kmax(fl) (nm)
Uf
431 457 457 468 461 451
0.28 0.22 0.25 0.16 0.19 0.0064 0.0082 0.068 0.11
sf (ns)
12.4 14.4 7.7 4.9 4.6 ꢁ0.1
ꢁ0.1
2.2
3.1
42
3.1
3.5
29
b
b
kf (107 sꢀ1
)
2.3 1.5 3.2 3.3 4.1
knr/(107 sꢀ1
)
5.8 5.4 9.7 17
18
>400
>400
a
The locations of all absorption maxima are given in Ref. 13.
Fluorescence lifetime is too small to determine precisely.
b
3-morpholino moiety barely affected knr, but the introduction of the
morpholine moiety at C-1 accelerated energy dissipation from the
singlet excited state. Replacement of the H4 atom in 6a with methyl
or benzyl groups (i.e. 6b and 6c) led to further increase in knr. The fas-
ter nonradiative deactivation in the case of 8b compared to 6b prob-
ably implies that the amidine moiety also promotes the transition
from the singlet excited to the ground state.
Very little information is available on the fluorescence charac-
teristics of isoquinoline-3-amines. Utilization of the 4-phenyl
derivative as a colorimetric Hg2+ sensor has been reported.12 As
representative examples, Figure 2 presents the absorption and
200
300
400
Wavelength / nm
500
600
Figure 2. Absorption and fluorescence spectra of isoquinoline-3-amine (3d) (thin
line) and 1-morpholinoisoquinoline-3-amine (6a) (thick line).
fluorescence spectra of compounds 3d and 6a. These spectra reveal
that introduction of the morpholine moiety at position 1 of the iso-
quinoline causes a significant bathochromic shift (26 nm) in the
fluorescence spectrum, whereas a somewhat smaller displacement
occurs for the absorption bands.

5266
J. Balog et al. / Tetrahedron Letters 52 (2011) 5264–5266
(1H,dd, J = 7.5, 6.9 Hz, H-7), 7.48–7.38 (2H, m, H-8, H-6), 7.89 (1H, d, J = 8.5 Hz,
These results indicate that the prepared compounds represent a
H-5); dC (75 MHz, CDCl3): 52.0 (C-20,C-60), 67.3 (C-30, C-50), 94.5 (C-4), 116.4 (C-
8a), 122.1 (C-5), 125.6 (C-7), 125.7 (C-8), 129.9 (C-6), 141.5 (C-4a), 152.8 (C-3),
161.2 (C-1). m/z (EI): 230.3 (M+H); Anal. calcd for C13H15N3O (229.27): C,
68.10; H, 6.59; N, 18.33. Found: C, 68.01; H, 6.70; N, 18.25. 4-methyl-1-
morpholinoisoquinoline-3-amine (6b): Yield: 55%; yellow crystals; mp: 143–
145 °C; mmax (KBr, cmꢀ1) 3365, 2957, 1633, 1564, 1114, 755; dH (300 MHz,
CDCl3): 2.30 (3H, s, H-4-CH3), 3.33 (4H, t, J = 9.1 Hz, H-20,H-60), 3.95 (4H, t,
J = 9.2 Hz, H-30, H-50), 4.26 (2H, s, NH2), 7.19 (1H, dd, J = 7.5, 7.8 Hz, H-7), 7.51
(1H, dd, J = 7.8, 7.5 Hz, H-6), 7.72 (1H, d, J = 8.5 Hz, H-8), 7.99 (1H, d, J = 8.4 Hz,
new valuable group of fluorescent isoquinoline derivatives. Com-
parison of the fluorescence spectra of the variously substituted
derivatives shows some significant changes as a consequence of
structural variations.
Acknowledgments
H-5); dC (75 MHz, CDCl3): 11.5 (Ca
), 52.2 (C-20,C-60), 67.4 (C-30,C-50), 99.5 (C-4),
The support of OTKA 77784, K75015, Nanotransport (CRC-HAS-
2009) and Hungarian GVOP-3.2.1.-2004-04-0210/3.0 projects are
gratefully acknowledged.
117.0 (C-8a), 121.6 (C-5), 122.3 (C-7), 126.1 (C-8), 129.8 (C-6), 139.8 (C-4a),
150.2 (C-3), 159.3 (C-1). m/z (EI): 244.3 (M+H); Anal. calcd for C14H17N3O
(243.30): C, 69.11; H, 7.04; N, 17.27. Found: C, 69.01; H, 7.15; N, 17.32. 4-
benzyl-1-morpholinoisoquinoline-3-amine (6c): Yield: 60%; pale brown
crystals; mp 82–84 °C; mmax (KBr, cmꢀ1): 3353, 2844, 1614, 1561, 1112, 762;
dH (300 MHz, CDCl3): 3.39 (4H, s, H-20,H-60), 3.97 (4H, s, H-30,H-50), 4.18 (4H, s,
H-4-CH2, NH2), 7.16-7.26 (6H, m, H-2,H-300,H-400,H-500,H-600, H-7), 7.48 (1H, dd,
J = 7.5, 7.2 Hz, H-6), 7.72 (1H, d, J = 8.5 Hz, H-8), 8.02 (1H, d, J = 8.3 Hz, H-5); dC
Supplementary data
Supplementary data (analytical data including 1H and 13C NMR
spectral assignments, UV and fluorescence spectra for the most
important compounds as well as absorption and fluorescence spec-
tra of selected compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.07.143.
(75 MHz, CDCl3+DMSO-d6): 31.7 (Ca
), 52.1 (C-20,C-60), 67.3 (C-30,C-50), 102.2
(C-4), 116.9 (C-8a), 121.7 (C-5), 122.3 (C-7), 126.2 (C-400), 126.5 (C-8), 128.3 (C-
300,C-500), 128.9 (C-200,C-600), 130.2 (C-6), 139.5 (C-100), 140.1 (C-4a), 150.9 (C-3),
160.0 (C-1). m/z (EI): 320.4 (M+H); Anal. calcd for C20H21N3O (319.40): C,
75.21; H, 6.63; N, 13.16. Found: C, 75.15; H, 6.42; N, 12.85.
7. A mixture of the appropriate isoquinoline-amine derivative (3 or 6, 1 mmol), p-
TsOH (0.1 mol) and triethyl orthoformate (5 ml) was heated under reflux for
16 h with stirring. Excess triethyl orthoformate was removed by vacuum
distillation, 8% aqueous NaHCO3 solution (20 ml) was added and the product
was extracted with CH2Cl2 (2 ꢂ 20 ml). The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated to yield the crude product as a
yellow solid (75–90%) which was recrystallized from i-PrOH.
8. To a solution of formimidate derivative (4 or 7, 1 mmol) in dry toluene (5 ml)
was added morpholine (2 mmol). The solution was heated at 100 °C for 1 h
with stirring. After evaporation of the solvent the residue was dissolved in
CH2Cl2 (20 ml) and the solution washed with H2O (20 ml). The aqueous phase
was extracted with CH2Cl2 (2 ꢂ 20 ml) and the collected organic phase dried
over anhydrous Na2SO4. The solution was filtered, evaporated, and the crude
product (80–90%) recrystallized from i-PrOH.
References and notes
1. Riedl, Zs.; Filák, L.; Egyed, O.; Hajós, G. Arkivoc 2009, vi, 158.
2. Filák, L.; Riedl, Z.; Egyed, O.; Czugler, M.; Hoang, C. N.; Schantl, J. G.; Hajós, G.
Tetrahedron 2008, 64, 1101.
3. Tímári, G.; Soós, T.; Hajós, G.; Messmer, A.; Nacsa, J.; Molnár, J. Bioorg. Med.
Chem. Lett. 1996, 23, 2831.
4. Zdrojewski, T.; Jonczyk, A. Tetrahedron 1995, 51, 12439.
5. (a) Isoquinoline 3-triflate (1) (150 mg, 0.54 mmol) was dissolved in morpholine
(1 ml) and the solution was heated at 130 °C for 6 h with stirring. After cooling,
CH2Cl2 (10 ml) was added and the mixture was washed with H2O (2 ꢂ 10 ml).
The organic layer was dried over anhydrous Na2SO4 and concentrated. The
residue was purified by flash column chromatography on silica gel to give
bright yellow crystals of 2, 86 mg (75%), mp 124–126 °C (Lit mp 126–
127.5 °C4); (b) A similar procedure was applied for the transformation of 3a–
9. The fluorescence quantum yield was determined relative to that of quinine
sulfate in 1 N H2SO4, for which a reference yield of Uf = 0.546 was taken.10
Fluorescence lifetimes were measured using time-correlated single-photon
counting as described previously.11
c
into 6a–c. Thus, a solution of 1-bromoisoquinoline-3-amine 3a (0.22 g,
10. Melhuish, W. H. J. Phys. Chem. 1961, 65, 229.
1 mmol) in morpholine (2 ml) was refluxed for 24 h. The reaction mixture was
evaporated, H2O (10 ml) was added and the precipitated solid was filtered.
Recrystallization from EtOH yielded 0.1 g (45%) of product 6a, mp 151–154 °C.
6. Analytical and spectral data of 6a–c: 1-morpholinoisoquinoline-3-amine (6a):
11. Megyesi, M.; Biczók, L.; Jablonkai, I. J. Phys. Chem. C. 2008, 112, 3410.
12. Wan, Y.; Niu, W.; Behof, W. J.; Wang, Y.; Boyle, P.; Gorman, C. B. Tetrahedron
2009, 65, 4293.
13. Locations of all absorption maxima in nm for the compounds listed in Table 1:
3d: 207, 234, 281, 291, 363; 2: 209, 243, 290, 366; 6a: 205, 239, 301, 371; 6c:
204, 240, 305, 377; 6b: 207, 239, 305, 377; 5b: 217, 264, 273, 318, 372; 5c: 214,
264, 273, 320, 370; 5f: 213, 262, 270, 314, 363; 8b: 212, 264, 272, 327, 370.
Yield: 45%; brownish yellow crystals; mp 151–154 °C; m
max (KBr, cmꢀ1): 3348,
2847, 1638, 1557, 1109, 858; dH (300 MHz, CDCl3): 3.38 (4H, tt, J = 9.2 Hz, H-20,
H-60), 3.94 (4H, tt, J = 9.2 Hz, H-30, H-50), 4.26 (2H, NH2), 6.36 (1H, s, H-4), 7.15