Synthesis of 6-amino-3,4-dihydroisoquinolinium derivatives by ring-opening reactions of acridizinium ions

Article abstract of DOI:10.1021/ol702792r

The reaction of the 9-fluoroacridizinium (9-fluorobenzo[b]quinolizinium) or the 9-aminoacridizinium (9-aminobenzo[b]quinolizinium) ion with primary alkyl amines gives with high diastereoselectivity 6-amino-3,4-dihydroisoquinolinium derivatives as main products, which exhibit pronounced absorption and fluorescence properties. It is proposed that the reaction proceeds via a nucleophilic ring-opening followed by an aza Diels-Alder reaction.

Full text of DOI:10.1021/ol702792r

ORGANIC
LETTERS
2008
Vol. 10, No. 5
757-760
Synthesis of
6-Amino-3,4-dihydroisoquinolinium
Derivatives by Ring-Opening Reactions
of Acridizinium Ions
Hans-Jo1
rg Deiseroth,† Anton Granzhan,‡ Heiko Ihmels,*,‡ Marc Schlosser,† and
Maoqun Tian‡
UniVersita¨t Siegen, Organische Chemie II and Anorganische Chemie I,
Adolf-Reichwein-Strasse 2, D-57068 Siegen, Germany
ihmels@chemie.uni-siegen.de
Received November 19, 2007
ABSTRACT
The reaction of the 9-fluoroacridizinium (9-fluorobenzo[b]quinolizinium) or the 9-aminoacridizinium (9-aminobenzo[b]quinolizinium) ion with
primary alkyl amines gives with high diastereoselectivity 6-amino-3,4-dihydroisoquinolinium derivatives as main products, which exhibit
pronounced absorption and fluorescence properties. It is proposed that the reaction proceeds via a nucleophilic ring-opening followed by an
aza Diels−Alder reaction.
Isoquinoline derivatives are naturally occurring alkaloids and
promising lead structures in drug discovery.1 Therefore,
several methods to synthesize derivatives of isoquinoline,
or 1,2-dihydro- and 1,2,3,4-tetrahydroisoquinoline derivatives
have been reported.2 In addition, N-alkylated isoquinolinium
compounds with biological activity have been identified
recently.3 Although several synthetic routes to isoquinolinium
derivatives are known,2 relatively few studies have been
reported on the synthesis and investigation of 3,4-dihydroiso-
quinolinium ions. In most cases, rather simple structures are
obtained by N-alkylation of the corresponding isoquinoline
precursor. The resulting products are usally applied as
substrates for subsequent reactions, such as 1,3-dipolar
cycloadditions,4 addition reactions,5 or oxidation reactions.6
Herein, we report the unexpected synthesis of 4-pyridyl-3,4-
dihydroisoquinolinium derivatives by the reaction of acrid-
izinium (benzo[b]quinolizinium) ions with primary alky-
lamines.
(3) (a) Ponte-Sucre, A.; Faber, J. H.; Gulder, T.; Kajahn, I.; Pedersen,
S. E. H.; Schultheis, M.; Bringmann, G.; Moll, H. Antimicrob. Agents
Chemother. 2007, 51, 188. (b) Nishiyama, Y.; Moriyasu, M.; Ichimaru,
M.; Iwasa, K.; Kato, A.; Mathenge, S. G.; Mutiso, P. B. C.; Juma, F. D.
Phytochemistry 2004, 65, 939. (c) Kim, H.-J.; Park, J. E.; Jin, S.; Kim,
J.-H.; Song, K. Chem. Biol. 2006, 13, 881. (d) Kim, J.; Lee, S.; Choi, J.;
Paik, Y.; Lee, Y.; Joo, H. PCT Int. Appl. WO 2006129978, 2006.
(4) For recent examples: (a) Fejes, I.; To˜ke, L.; Nyerges, M.; Pak, C. S.
Tetrahedron 2000, 56, 639. (b) Fejes, I.; Nyerges, M.; Szo¨llo˜sy, AÄ .; Blasko´,
G.; To˜ke, L. Tetrahedron 2001, 57, 1129. (c) Nyerges, M.; Somfai, B.;
To´th, J.; To˜ke, L.; Dansco´, A.; Blasko´, G. Synthesis 2005, 2039.
(5) (a) Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1681. (b) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8,
143.
† Anorganische Chemie I.
‡ Organische Chemie II.
(1) (a) Bringmann G. In Drugs against parasitic diseases: R&D
methodologies and issues; Fairlamb, A. H., Ridley, R. G., Vial, H. J., Eds.;
World Health Organisation: Geneva, 2003; p 145. (b) Bentley, K. W. The
Isoquinoline Alkaloids; Hardwood Academic: Amsterdam, 1998; Vol. 1.
(2) Alvarez, M.; Joule, J. A. In Six-Membered Hetarenes with One
Nitrogen or Phosphorus Atom; Black, D., Ed.; Science of Synthesis, Vol.
15; Georg Thieme Verlag: Stuttgart, 2004; p 661.
10.1021/ol702792r CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

During our studies on the synthesis of N-substituted
9-aminoacridizinium derivatives by nuclecophilic substitution
reactions of the corresponding 9-fluoroacridizinium ion (1a),
we discovered that the substituted 9-aminoacridizinium
derivative was the main reaction product when a secondary
aliphatic amine or a substituted aniline was used as reactant
(Scheme 1, path A).7 However, when primary alkyl amines
Scheme 1. Synthesis of 3,4-Dihydroisoquinolinium
Derivatives
Figure 1. Structure of 3,4-dihydroisoquinolinium derivative 2a
ClO4 in the solid state as derived from X-ray diffraction analysis.
The thermal ellipsoids for non-H atoms are shown with 50%
probability (gray: C; white: H; green: N; red: O; blue: F;
yellow: Cl).
solid state (Figure 1) and by only one set of NMR signals,
even in the crude product.
To assess whether the 3,4-dihydroisoquinolinium structure
is generally formed in the reaction of aliphatic amines with
the fluoroacridizinium ion 2a, we extended the study to
several selected amines (Scheme 1, path B). The reaction of
compound 1a with cyclohexylamine, isopropylamine, n-
dodecylamine, and 3-aminomethylpyridine gave the corre-
sponding dihydroisoquinolinium derivatives 2c-f in mod-
erate to low yields. With benzylamine as reagent, the
formation of the dihydroisoquinolinium 2g was indicated by
1H NMR spectroscopic analysis of the crude reaction mixture
(40-50% yield), but the product could not be isolated by
chromatography and/or crystallization in analytically pure
form. When tert-butylamine was employed as nucleophile,
the corresponding dihydroisoquinolinium could not be
detected from the reaction mixture, indicating that the
reaction is sensitive toward steric interactions between the
substrate and the nucelophile. Finally, with a donor-
substituted acridizinium ion such as the 9-aminoacridizinium
(1b), the same reaction may be performed, i.e., the reaction
with n-butylamine gave the corresponding isoquinolinium
derivative 2b in 15% yield.
The formation of the 3,4-dihydroisoquinolinium ions 2
may be explained by an initial nucleophilic ring-opening,
followed by an aza (imino) Diels-Alder reaction9 of the
intermediates, and subsequent nucleophilic aromatic substitu-
tion of the fluorine atom (Scheme 2). Considering the
reactivity of position 6 of the acridizinium ion toward
nucleophiles,10 the formation of derivatives 2a-g is likely
to be induced by the addition of the amine to the acridizinium
ion 1a and a subsequent electrocyclic ring-opening reaction
were made to react with the salt 1a at similar conditions,
the N-substituted 9-aminoacridizinium derivative was formed
in very low yields, i.e., less than 5%,7b whereas another
product was formed in significant amounts. Thus, the reaction
of 9-fluoroacridizinium (1a) with 2 molar equiv of n-
butylamine gave a major product, which was readily
1
separated by chromatography and whose H NMR and 13C
NMR data revealed a partially saturated bicyclic heterocycle
instead of the expected tricyclic acridizinium unit. Eventually,
X-ray diffraction analysis of a well-crystallized perchlorate
salt, prepared by ion methathesis of the crude product,
showed unambiguously that the 3,4-dihydroisoquinolinium
derivative 2a was formed as the main product (Figure 1).
This structural assignment is consistent with the one- and
1
two-dimensional H NMR spectroscopic analysis, mass-
spectrometric data, and combustion analysis (cf. Supporting
Information). Especially characteristic of the 3,4-dihydroiso-
quinolinium structure are the singlet of the iminium proton
H-1 (δ ) 8.99 in acetone-d6) and the signals of the protons
H-3 (δ ) 6.48) and H-4 (δ ) 4.84), which appear as slightly
broadened singlets due to a very small spin-spin coupling
constant, in agreeement with a dihedral angle between these
protons of 79°, as observed from the X-ray diffraction data,
and the 1H NMR data of related 3,4-dihydroisoquinolinium
ions.8 Notably, the product 2a is formed with high diaste-
reoselectivity, i.e., the substituents at C3 and C4 have an
anti configuration, as clearly indicated by the stucture in the
(6) (a) Page, C. B. B.; Buckley, B. R.; Appleby, L. F.; Alsters, P. A.
Synthesis 2005, 3405. (b) Bohe´, L.; Kammoun, M. Tetrahedron Lett. 2004,
45, 747. (c) Bohe´, L.; Kammoun, M. Tetrahedron Lett. 2002, 43, 803. (d)
Page, P. C. B.; Rassias, G. A.; Barros, D.; Bethell, D.; Schilling, M. B. J.
Chem. Soc, Perkin Trans. 1 2000, 3325. (d) Page, P. C. B.; Rassias, G. A.;
Barros, D.; Ardakani, A.; Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin,
A. M. Z. J. Org. Chem. 2001, 6926. (e) Lusinchi, X.; Hanquet, G.
Tetrahedron 1997, 53, 13727.
(9) (a) Rowland, G. B.; Rowland, E. B.; Zhang, Q.; Antilla, J. C. Curr.
Org. Chem. 2006, 10, 981. (b) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron
2001, 57, 6099. (c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1.
(7) (a) Granzhan, A.; Ihmels, H. Org. Lett. 2005, 7, 5119. (b) Granzhan,
A.; Ihmels, H. ArkiVoc 2007, Viii, 136.
(8) Verin, S. V.; Tosunyan, D. E.; Zakharov, P. I.; Shevtsov, V. K.;
Kuznetsov, E. V. Chem. Heterocycl. Compd. 1990, 26, 980.
(10) (a) Bradsher C. K. In ComprehensiVe Heterocyclic Chemistry;
Boultier A. J., McKillop, A., Eds.; Oxford: Pergamon Press, 1985; Vol. 2,
p 525. (b) Bradsher, C. K.; Sherer, J. P. J. Org. Chem. 1967, 32, 733. (c)
Krapcho, A. P.; Cadamuro, S. A.; Macnee, L. ArkiVoc 2007, ix, 28.
758
Org. Lett., Vol. 10, No. 5, 2008

Scheme 2. Proposed Mechanism for the Formation of
Dihydroisoquinolinium Derivatives 2 by the Reaction of Primary
Amines with 9-Fluoroacridizinium (1a)
Scheme 3. Synthesis of 3-Aryl-4-pyridyl-substituted
Dihydroisoquinolinium Derivatives
substituent of the diene as well as additional attractive
secondary orbital interactions are likely to result in an endo-
type addition (Scheme 2) to give the anti configuration of
the C3 and C4 substituents. Such a diastereoselectivity was
also observed in the synthesis of dihydroisoquinolinium
derivatives by a cycloaddition reaction of benzo[c]pyrylium
salts with substituted benzaldimines,8 which represents
another example of a direct access to the dihydroisoquion-
linium system by the aza Diels-Alder reaction.
Finally, the proposed mechanism also explains the pref-
erential formation of N-substituted 9-aminoacridizinium ions
upon reaction of 9-fluoroacridizinium (1a) with secondary
aliphatic amines.7b In the latter case, the corresponding
intermediate 4, even if it is formed at the reaction conditions
(as indicated by the dark coloration of the reaction medium),
cannot form a tautomer 4′, thus preventing the sequential
steps which lead to the formation of the dihydroisoquino-
linium product.
Considering the π-conjugation between the amino sub-
stituent and the endocyclic iminium functionality, the
6-amino-3,4-dihydroisoquinolinium ions 2 resemble the
structure of polymethine dyes, which are among the most
versatile functional dyes.12 Interestingly, only a few 6-amino-
3,4-dihydroisoquinolinium derivatives are reported13 and little
is known about their electronic absorption and emission
properties. Nevertheless, it may be proposed that, in the same
way as the aminoquinolinium derivatives,14 the 6-amino-3,4-
dihydroisoquinolinium derivatives exhibit a high potential
to be used as fluorescent probes. Therefore, we investigated
the photophysical properties of the cyclohexyl-substituted
derivative 2e as a representative example (Table 1). The
to give the intermediate 4, which exists in a tautomeric
equilibrium with the pyridylmethylbenzaldimine 4′. The
imine 4′ (R ) alkyl) may then react in a Diels-Alder-type
reaction with the tautomeric enamine 4, which adopts the
cis-trans configuration preferentially due to steric repulsion
between the amino and the pyridyl substituent. The resulting
tetrahydroisoquinoline 5 is transformed to the dihydroiso-
quinolinium 6 by the elimination of amine. A subsequent
nucleophilic aromatic substitution of the fluorine atom in
the isoquinolinium system with excess amine eventually
yields the final product 2. It should be noted that the ring-
closure to give the isoquinolinium 5 may also take place in
a stepwise process rather than in a concerted reaction.
Although it is difficult to obtain unambiguous experimental
support to distinguish between the two mechanisms, the pro-
posed aza Diels-Alder pathway is in agreement with several
known synthetic routes to nitrogen-containing heterocycles.8,9
The corresponding imine 4′ could not be isolated under
the reaction conditions, probably due to a rapid subsequent
reaction. Nevertheless, it has been shown for the parent
acridizinium and methyl-substituted derivatives that the
reaction with nitrogen nucleophiles yields the corresponding
(2-pyridylmethyl)benzcarbaldimine derivatives; however, the
formation of dihydroisoquinolinium ions was not observed.10c
Additional supporting evidence for the proposed formation
of the intermediate imine was provided by the isolation of
the aldoxime 4′ (R ) OH) that is formed in the reaction of
1a with hydroxylamine (cf. Supporting Information).
Table 1. Absorption and Emission Properties of 2e in
Moreover, the reaction of n-butylamine and 1a in the
presence of an excess of benzaldehyde gives the dihydroiso-
quinolinium 2h (Scheme 3).11 This observation is consistent
with the proposed imine intermediate, because under these
conditions the formation of the corresponding benzaldimine
is most likely. Moreover, this result demonstrates that in the
presence of excess aldehyde, the reaction provides a general
access to 3-aryl-4-pyridyl-dihydroisoquinolinium derivatives.
The proposed aza Diels-Alder cycloaddition between the
imine 4′ and the diene 4 would explain the high diastereo-
selectivity of the product formation, because the steric
repulsion of the aryl substituent of the imine and the pyridyl
Different Solvents
solventa
λabs/nmb
ꢀ/104 M-1 cm-1
λem/nmc
φfd
H2O
CH3OH
EtOH
2-PrOH
CH3CN
DMSO
CH2Cl2
CHCl3
THF
411
412
414
415
400
412
413
405
407
3.96
4.57
4.55
4.61
4.49
4.43
4.31
4.18
3.82
449
448
447
447
445
450
440
451
449
0.13
0.18
0.25
0.33
0.21
0.23
0.60
0.33
0.29
a In order of decreasing ET(30) values. b Long-wavelength absorption
maximum, c(2e) ) 5.0 × 10-5 M. c Emission maximum, c(2e) ) 1.0 ×
10-5 M; excitation wavelength, λex ) 410 nm. d Fluorescence quantum yield,
measured relative to Coumarin 153 (φf ) 0.38, c ) 1.0 × 10-5 M in EtOH).
(11) With ethanal as aldehyde, the reaction did not take place, presumably
because the intermediate enolate interferes with the reaction.
Org. Lett., Vol. 10, No. 5, 2008
759

aminoisoquinolinium derivative 2e has a relatively strong
long-wavelength absorption band with maxima ranging from
400 nm (in CH3CN) to 415 nm (in 2-PrOH) and emission
maxima between 440 (in CH2Cl2) and 451 nm (in CHCl3),
with emission quantum yields from approximately 0.10 to
0.60.16 The Stokes shift of derivative 2e varies from 1725
cm-1 (2-PrOH) to 2518 cm-1 (CHCl3).
In summary, we have discovered an unexpected access to
6-amino-3,4-dihydroisoquinolinium derivatives starting from
easily available acridizinium ions. These compounds exhibit
promising absorption and emission properties and may be
further investigated as potential fluorescent probes.
Acknowledgment. Generous support by the Deutsche
Forschungsgemeinschaft is gratefully acknowledged. We
thank Bayer Industry Services GmbH, Germany, for the
donation of chemicals, and Mrs. Sandra Uebach, University
of Siegen, for technical assistance.
Figure 2. Absorption and emission spectrum of the 6-amino-3,4-
dihydroisoquinolinium derivative 2e in methanol (absorption spec-
trum: c ) 5 × 10-5 M; emission spectrum: c ) 10-5 M).
Supporting Information Available: Synthetic proce-
dures; full characterization and 1H and 13C NMR spectra of
all new compounds; crystallographic data of 2a. This material
is available free of charge via the Internet at http://pubs.acs.org.
absorption and emission spectra of 2e in methanol are shown
in Figure 2. Such as in the case of aminoquinolinium14 and
aminoacridizinium derivatives,15 the 3,4-dihydroisoquino-
linium ions exhibit only a marginal solvatochromism. The
OL702792R
(14) Van den Berg, O.; Jager, W. F.; Picken, S. J. J. Org. Chem. 2006,
71, 2666.
(12) (a) Kim, S.-H., Ed. Functional Dyes; Elsevier, Amsterdam, 2006.
(b) Zollinger, H. Color Chemistry, 3rd ed.; VCH: Weinheim, Germany,
2003. (b) Mishra, A.; Behera, R. K.; Behera, P. K.; Mishra, B. K.; Behera,
G. B. Chem. ReV. 2000, 100, 1973.
(13) (a) Bogza, S. L.; Suikov, S. Y.; Bogdan, N. M.; Nikolyukin, Y. A.;
Dulenko, V. I. Chem. Heterocycl. Compd. 2004, 40, 1421. (b) Bogza, S.
L.; Nikolyukin, Y. A.; Zubritsky, M. Y.; Dulenko, V. I. Chem. Heterocycl.
Compd. 1995, 31, 272.
(15) Granzhan, A.; Ihmels, H.; Viola, G. J. Am. Chem. Soc. 2007, 129,
1254.
(16) The exceptionally high fluorescence quantum yield observed in
CH2Cl2, as compared to yields in the other solvents, is also observed in the
case of related cationic fluorophores and is presumably due to a high
polarizability of this solvent; cf. refs 14 and 15.
(17) Jones, G.; Jackson, W. R.; Choi, C. Y.; Bergmark, W. R. J. Phys.
Chem. 1985, 89, 294.
760
Org. Lett., Vol. 10, No. 5, 2008