A new synthesis of the linearly fused [1,2,4]triazolo[1,5-b]isoquinoline ring. Observation of an unexpected Dimroth rearrangement

Article abstract of DOI:10.1016/j.tet.2007.10.103

A new and general synthesis of the linearly fused [1,2,4]triazolo[1,5-b]isoquinoline ring system starting from 2,3-diaminoisoquinolinium salts has been elaborated. Starting compounds bearing an alkyl group in position 4 easily reacted with aldehydes to yield the cyclized products. In the case of a lack of electron donating group in position 4 (e.g., unsubstituted or 4-cyano substituted diamino derivatives) a Dimroth rearrangement took place under the same reaction conditions to yield 3-isoquinolylhydrazones. The mechanism of this unexpected transformation has been verified by isotope labelling experiments. Clarification of the reaction mechanism allowed finding proper reaction conditions to eliminate the rearrangement route, and thus, to perfect successful ring closure to the fused triazoles.

Full text of DOI:10.1016/j.tet.2007.10.103

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1101e1113
www.elsevier.com/locate/tet
A new synthesis of the linearly fused [1,2,4]triazolo[1,5-b]isoquinoline
ring. Observation of an unexpected Dimroth rearrangement
a
a
a
a
Laszlo Filak , Zsuzsanna Riedl , Orsolya Egyed , Matyas Czugler , Cuong N. Hoang ,
c
´
´
´
´ ´
Joachim G. Schantl , Gyorgy Hajos
b
a,
*
´
¨
a Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri u´t 59, H-1025 Budapest, Hungary
b Faculty of Chemistry and Pharmacy, University of Innsbruck, A-6020 Innrain 52a, Austria
c Chemistry Faculty, University of Natural Sciences, National University of HCM, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam
Received 2 August 2007; received in revised form 15 October 2007; accepted 26 October 2007
Available online 1 November 2007
´
Dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract
A new and general synthesis of the linearly fused [1,2,4]triazolo[1,5-b]isoquinoline ring system starting from 2,3-diaminoisoquinolinium
salts has been elaborated. Starting compounds bearing an alkyl group in position 4 easily reacted with aldehydes to yield the cyclized products.
In the case of a lack of electron donating group in position 4 (e.g., unsubstituted or 4-cyano substituted diamino derivatives) a Dimroth rearrange-
ment took place under the same reaction conditions to yield 3-isoquinolylhydrazones. The mechanism of this unexpected transformation has
been verified by isotope labelling experiments. Clarification of the reaction mechanism allowed finding proper reaction conditions to eliminate
the rearrangement route, and thus, to perfect successful ring closure to the fused triazoles.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Triazole; Hydrazone; Dimroth rearrangement; 15N labelling
1. Introduction
of this synthetic activity seemed of interest and extension of
the established procedure to the hitherto scarcely studied line-
arly fused benzologue of triazolopyridine: triazolo[1,5-b]iso-
quinoline has been decided. Literature survey revealed that
only two derivatives of this tricyclic ring system obtained by
a different approach have been reported earlier.3
In our earlier publications we have described a relatively
facile access to fused [1,2,4]triazoles.1 These compounds
were obtained by treatment of 1,2-diaminopyridinium salts
with various aldehydes in the presence of a base. During
this transformation, a ring closure occurred followed by spon-
taneous oxidation of the primarily formed intermediate to give
the heteroaromatic end product. This procedure allowed the
synthesis of a set of [1,2,4]triazolo[1,5-a]pyridines and its an-
gularly fused benzologues: [1,2,4]triazolo[1,5-a]quinolines
and [1,2,4]triazolo[5,1-a]isoquinolines.
2. Results and discussion
For the synthesis of the desired linearly fused triazoles,
application of our earlier established protocol seemed the
most straightforward procedure. Thus, 2,3-diaminoisoquinoli-
nium salts (2) have been synthesized by direct N-amination of
somesubstituted3-aminoisoquinolines(1)4 byO-tosyl-hydroxyl-
amine (TSH)5,6 (Scheme 1) and these compounds were reacted
with aldehydes.
Based on some recent records on the valuable biological
activity of some related fused [1,2,4]triazoles,2 continuation
Thus, experiments for ring closure starting from the 4-
substituted diaminium salts 2bed yielded the expected
* Corresponding author. Tel.: þ36 14381110; fax: þ36 14381145.
´
E-mail address: ghajos@chemres.hu (G. Hajos).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.103

1102
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
R1
H
2
Yield (%)
R1
R1
a
b
c
d
e
85
48
66
72
21
NH2
NH2
NH2
TSH or MSH
CH2Cl2, rt.
CH3
C2H5
N
N
1
2
A
CH2Ph
CN
A= TsO or MesO
Scheme 1.
[1,2,4]triazoles 3aej in good yields. When, however, the 4-un-
substituted 2a was treated under the same reaction conditions
with various aldehydes, an unexpected product: the hydr-
azones 4aed were formed (Scheme 2).
Figure 1. Molecular structure representation7 of compound 4c with the
H-bridge attachments indicated by broken lines.
The firm proof of the constitution of this hydrazone was
provided by X-ray crystal structure determination (Fig. 1).
A two-fold rotation axis at {0,y,1/4} arranges two 4c mole-
cules into a dimeric assembly. Thus, the crystal structure dis-
plays only one symmetric pair of stronger intermolecular
contacts, namely a H-bridge with donor—H/acceptor atoms
of N(10)—H(1N)/N(2) [ꢀx,y,1/2ꢀz]. The H-bridge donore
yield (Scheme 3). Physical data (mp, NMR, IR) of this product
and those of the compound obtained as a result of the above
mentioned route starting from 2 proved to be entirely identical.
H
H
N
N
NH2
CH3C6H4CHO
CH3CN
N
N
˚
N
acceptor geometry is characterized by DeH¼0.90 A, H/A¼
O
O
CH3
ꢁ
˚
˚
5
2.18 A, D/A¼3.0735(14) A and DeH/A¼171 . No other
productive contacts are visible within van der Waals radii
sum, and the N20 atom apparently does not play role in main-
taining the crystal structure. Apart from two approaches that
might perhaps be taken as indicative for weak CeH/p
most other contacts appear to be weakly repulsive.
6
Indium/MeOH
4a
Scheme 3.
Although, upon the crystallographic analysis there was no
doubt about the structure of 4c,8 preparative evidence has also
been found in the case of one of the derivatives. Thus, 3-hydr-
azinoisoquinoline-N-oxide9 (5) was reacted with 4-methylbenz-
aldehyde to yield the hydrazone-N-oxide 6, which could be
successfully reduced by elemental indium10 to 4a in acceptable
Formation of the hydrazone 4 could be rationalized in two
ways (Fig. 2):
(i) Although many results were in agreement with our
earlier structural assignment for 2,4 we now had to
Yield
(%)
Yield
(%)
R1
R2
R1
R2
3
g
3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
a
CH3
CH3
CH3
4-CH3-C6H4
Ph
61
60
56
37
4-CH3-C6H4
Ph
55
58
47
42
43
39
R1
h
i
b
c
d
e
R2-CHO
N
N
R2
C3H7
C3H7
N
DBU, EtOH
CH3
j
3
C2H5 4-CH3-C6H4
R1
C2H5
C2H5
Ph
NH2
CH3
f
N
NH2
A
2
R1 = H
R2-CHO
DBU, EtOH
Yield
(%)
R2
H
4
N
N
R2
a
N
4-CH3-C6H4
Ph
35
b
c
d
51
36
49
4
C3H7
CH3
Scheme 2.

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1103
NHNH2
i)
N
H
b
H
N
R2
TsO
N
NH2
TSH
N
N
R2CHO
d
a
NH2
NH2
ii)
N
TsO
c
TSH = O-tosylhydroxylamine
Figure 2. Alternative mechanisms for the formation of hydrazones (d) from amines (a).
question the exact structure of this compound, and had
to consider that in the course of the N-amination of 1 it
might be the exo-amino group that participates in the
conversion to yield a hydrazine (i.e., in Fig. 2, amina-
tion of a would give b rather than c). In this case forma-
tion of a hydrazone (d) would be trivial.
isotope excess). In the directly detected 15N spectrum of 2a*
and 2b* only signals of the N10 amine nitrogen atoms
(ꢀ306.0 and ꢀ304.8 ppm, respectively) appeared. Accord-
ingly, structure b in Figure 2 can be ruled out.
Both 2a* and 2b* were then subjected to the above de-
scribed reactions with aldehydes. The observed nitrogen
chemical shifts of compound 4d are indicative of the hydr-
azone structure. Selective labelling in compounds 3c* and
4d* was assessed by comparing the crosspeak intensities of
(ii) An alternative mechanism would be formation of an N-
amino salt (c) as originally assumed. This compound
can undergo a ring transformation reaction during
which the ring-nitrogen atom of the isoquinoline ring
and the nitrogen atom of the amino group attached to
position 3 would be exchanged to give the product
(d). Such a conversion could be a Dimroth-type rear-
rangement11 taking place via temporary ring opening
of the pyridine moiety followed by a repeated ring
closure.
1
the He15N HMQC spectra with those of the corresponding
unlabelled derivatives. Accordingly, labelled nitrogen atoms
were found at ꢀ134.1 ppm in 3c* and at ꢀ81.0 ppm in 4d*.
Contrary to the triazole product 3c*, where the labelled nitro-
gen retains its original position, the hydrazone 4d* contains
15
the N label in the side chain (N20) (Scheme 4).
The proposed reaction mechanism is shown in Figure 3.
Thus, the first step is the condensation reaction of c and an
aldehyde to form an azomethinimine side chain (e), and this
species would be attacked by a nucleophile to give the second
intermediate (f). The role of the nucleophile can be fulfilled
either by the solvent (alcohol, water) or another molecule of
c bearing a basic nitrogen atom. In this stage of the events,
an electrocyclic ring openingdwith participation of three
electron pairs as shown by the arrowsdcan occur to afford
a ring-opened species (g), which can undergo a 180ꢁ turn along
the bond between the two non-cyclic carbon atoms. The result
of this motion is shown by the tautomeric form h. Finally,
a subsequent electrocyclization to i and elimination of the
protonated form of the nucleophile yields the hydrazone d.
This mechanism seemed to be in entire accordance with the
result of the above mentioned isotope labelling since the N-
amino nitrogen atom will move to the hydrazone-nitrogen
position in the course of the reaction sequence. There is, how-
ever, another possibility for the change of these nitrogen
atoms: if in intermediate e an NeN cleavage would happen
and the resulting azomethine fragment would participate in
By the help of detailed NMR investigations, the structure of
2 could be verified unambiguously. For two selected deriva-
tives (2a and 2b), three nitrogen atoms have been observed
at natural abundance by running 1He15N correlation measure-
ments. The amine nitrogen atoms in 2a were identified by the
H4e(C3)N20 and H1e(N2)N10 crosspeaks of the 1He15N
gHMQC spectrum (ꢀ324.5 and ꢀ306.0 ppm), while N2 ap-
peared at ꢀ211.2 ppm, showing correlation to H4 and N20H2
protons (Scheme 4). Similar nitrogen shifts have been found
for 2b (ꢀ325.3, ꢀ304.8 and ꢀ212.0 ppm). Simultaneously,
the amine nitrogen atoms were verified from the 1He15N
gHSQC experiment according to their direct NH couplings.
In order to prove the fact of selective amination of the iso-
quinoline ring nitrogen atom followed by a subsequent trans-
formation to hydrazone 4 (i.e., a/c/d pathway, Fig 2)
15N stable-isotope labelling was introduced. The 15N labelled
derivatives 2a* and 2b* have been prepared by reaction of 1a
and 1b with 15N labelled O-tosylhydroxylamine4 (prepared
from commercially available 15N-hydroxylamine of 20%
R
1 = CH3
R1
R1 = H
CH3
4
1
C3H7CHO
DBU, reflux
H
3
4
NH2 CH3CHO,
N
3
N
2
DBU, rt, 16 h
N
*
CH3
2
C3H7
3
N
*
2
1
N
1
N
4
N
NH2
*
Tos
2a*, 2b*
4d*
3c*
Scheme 4.

1104
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
NH2
NH2
NH2
NH2
N
R2CHO
Nu
N
N
-TsOH
N
R2
R2
N
Nu
H
TsO
TsO
e
c
f
H
N
CHR2
NHN=CHR2
NHN=CHR2
NH2
N
NH
NH
N
N
- NuH
N
R2
Nu
H
h
Nu
H
Nu
H
g
d
i
Figure 3. Proposed mechanism of the Dimroth rearrangement to isoquinolylhydrazones.
R1
a [1,3] sigmatropic rearrangement, this would also result in
the same product (d) and the N-amino nitrogen atom would
get to the same position as it did in the Dimroth-type
rearrangement.
NH2
N
CH3C6H4CHO
CH3CN
DBU
4a
2a
N
EtOH, rt.
A
In order to check this, another 15N-labelled derivative con-
taining the isotope N-atom in the 3-amino group (1a#) have
been synthesized. The synthesis is outlined in Scheme 5. The
location of the applied 15N isotope label throughout this reac-
tion pathway was followed by 1He15N HMQC measurements.
First 3-isoquinolyl triflate 712 was subjected to a palladium cata-
lyzed amination13 by using 15N-labelled formamide to yield
3-formamidoisoquinoline (8). The formyl group was removed
by aqueous acidic hydrolysis to give 3-aminoisoquinoline
(1a#; the labelled nitrogen at ꢀ334.5 ppm), which gave, upon
N-amination, the labelled diamino salt 2a# (ꢀ322.0 ppm). Reac-
tion of 2a# with 4-methylbenzaldehyde yielded the hydrazone
4a# (ꢀ116.8 ppm) in which the 15N atom was found in the
ring-nitrogen position. This finding, i.e., change of the position
of the isotopic label, is in clear accordance with the proposed
Dimroth-route, because in a sigmatropic transformation the
position of the 15N atom would not have changed.
9
CH3
A= BF4 or MesO
R2CHO
2b
3a-c
CH3CN
Scheme 6.
The successful isolation of the intermediate 9 raised the
question if similar intermediates are also formed along the
pathway to 3 starting from 2bed. Interestingly, reactions of
2bed with some selected aldehydes did not lead to isolation
of the intermediates related to 9. Instead, 2b yielded the tri-
azoles 3aec, whereas reaction of two other diaminoisoquinoli-
nium salts (2c,d) allowed the isolation of another intermediate
dihydrotriazolium salt 10e in the form of a solid of very low
solubility (Scheme 7). Intermediate 10e when treated with
a base easily underwent oxidation to the triazole (3h). The
fact that intermediate 9, which was obviously also formed along
the reaction pathway, could not be isolated suggests that in these
cases the cyclization to the dihydrotriazole is very fast. Further-
more, the interesting difference observed between 2b and 2c,d
might be due to the bad solubility of the isolated 10aef.
All these findings suggested that the triazole synthesis
might also be carried out with 2a if any nucleophilic attack
leading to ring transformation can be excluded. This supposi-
tion proved to be true: treatment of 2a with some aldehydes in
acetonitrile in the presence of molecular sieves21 (in order to
remove traces of the nucleophilic water) gave rise to the tri-
azoles 3k,l,m (Scheme 8) being unsubstituted in position 10
(i.e., in position 4 of the isoquinoline moiety).
It is important to note that, in principle, the above discussed
ring opening can also occur in an earlier stage of the reaction
pathway and, thus, the diaminoisoquinolinium salt (Fig. 3, c)
could also be subjected to this transformation. In this case,
the condensation with the aldehyde would be the last step.
In order to check this possibility 2a was reacted with the alde-
hyde in the absence of base (i.e., in acetonitrile) in order to
make difficulties for the rearrangement route. After a 5 h re-
flux the supposed intermediate 9 was obtained in considerable
yield. Furthermore, treatment of this compound with DBU in
ethanol afforded 4a (Scheme 6). This finding reveals that the
azomethine salt 9 is most probably an intermediate along the
rearrangement of 2a to 4a.
*
H
HCONH2, Cs2CO3,
OTf
*
NH2
N
*
xantphos, Pd2(DBA)3
HCl
CHO
N
dioxane
N
N
7
1a#
8
H
N
*
NH2
TSH
CH2Cl2
4-CH3-C6H4-CHO
DBU, EtOH
N
N
*
N
NH2
CH3
TsO
2a#
4a#
Scheme 5.

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1105
R1
Table 1
15N chemical shifts (ppm) of compound 2a, 4d, 9, 3m and 10d
H
N
R2CHO
CH3CN
NaOH
R2
2'
2c,d
3i
H
N
2'
N
NH2
2
N
H
NH2
2
N
CH3
N
TsO
N
N
NH2
N
10
1'
1'
TsO
2a
BF4
CH3
Y
R1
R2
10
(%)
4d
a
b
c
d
e
f
C2H5
C2H5
C2H5
4-CH3-C6H4
90
89
89
78
88
53
9
N-2 ꢀ211.2
N-10 ꢀ306.0
N-20 ꢀ324.5
ꢀ125.0
ꢀ253.0
ꢀ81.0
ꢀ186.5
ꢀ91.2
Ph
C3H7
ꢀ323.5
CH2Ph 4-CH3-C6H4
1
N
CH2Ph
CH2Ph
C3H7
Ph
N
N
4
H
1
N
3
C3H7
CH3
4
N
N
H
3
Scheme 7.
TsO
3m
10d
N-1
N-3
N-4
ꢀ179.3
ꢀ134.1
ꢀ154.6
ꢀ310.6
ꢀ276.0
ꢀ191.3
Yield
(%)
R2
3
R2CHO
CH3CN,
molecular sieve
N
R2
2a
N
N
k
l
4-CH3C6H4
Ph
54
47
35
3k,l,m
m
C3H7
CN
H
CH3C6H4CHO
DBU
N
Scheme 8.
N
2e
83%
N
CH3
Nitrogen shifts, indicative of the different structures, are
summerized in Table 1. The resonances of the amines (N-10,
N-20 in 2a, N-20 in 9, N-1, N-3 in 10d) occur at relatively
low frequencies. The amine type sp3 N-atom in the hydrazone
(N-10 in 4d) is shifted downfield about 50 ppm owing to the
partial delocalization of the electron lone pair into the double
bond system. The chemical shifts of the isoquinoline ring-
nitrogen atoms lie between ꢀ120 and ꢀ220 ppm. The most
deshielded nitrogen atoms appear in the C]N bond of the
hydrazones (N-20 in 4d and N-10 in 9).
These results indicate that the outstanding behaviour of 2a
in comparison to 2bed, i.e., the fact that this compound un-
dergoes Dimroth rearrangement rather than yielding triazoles,
may well be due to the relatively enhanced positive charge and
sensitivity towards nucleophilic attack in position 1 of the
isoquinoline ring. This suggestion was satisfactorily supported
by transformation of 2,3-diamino-4-cyanoisoquinolinium
mesitylate (2e) where, because of the strongly electron with-
drawing cyano group, an even higher preference for the rear-
rangement was experienced. Thus, while formation 4a from
2a took place in 24 h in 35% yield only, the corresponding
cyano derivative 4e was obtained from 2e in 5 h in high
(83%) yield (Scheme 9).
4e
Scheme 9.
with aldehydes can follow two different pathways. In the
case of isoquinolinium derivatives containing electron donat-
ing groups in position 4, ring closure to new linearly fused
triazoloisoquinolines take place, whereas in other cases,
due to the sensitivity of position 1 against nucleophiles,
a Dimroth rearrangement occurs to yield new isoquinolylhy-
drazones. Clarification of the reaction mechanism of this un-
expected rearrangement by the help of N-labelling also
allowed finding proper reaction conditions to direct the reac-
tion pathway to the originally intended triazole-formation
route.
4. Experimental part
4.1. General methods
Melting points were determined by a Buchi apparatus and
¨
are uncorrected. The IR spectra were recorded on a Thermo
Nicolet Avatar 320 FTIR spectrometer. Experiments were per-
formed on Varian INOVA-200 or Varian INOVA-400 spec-
trometers equipped with a 5 mm inverse detection z-gradient
probe. H and C NMR spectra were measured at rt (25 ꢁC)
in an appropriate solvent. 1H and 13C chemical shifts are
3. Conclusion
1
13
From the investigations described in this paper one can
conclude that reaction of 2,3-diaminoisoquinolinium salts

1106
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
expressed in parts per million (d) referenced to residual sol-
vent signals, 15N chemical shifts to the neat nitromethane. J
values are given in hertz. The complete signal assignment
was performed by running 2D heteronuclear (1He13C and
1He15N) gHSQC and gHMQC measurements. The pulse pro-
grams were taken from the Varian software library. The ele-
mental analysis has been carried out with an Elementar
Vario EL III apparatus. Chromatographic separations were
carried out on Merck Kieselgel 60 (230e400 mesh). Reactions
were monitored with Merck Kieselgel 60 F254-precoated TLC
plates (0.25 mm thickness). All the chemicals and solvents
were used as supplied.
C, 82.02; H, 6.02; N, 11.96. Found: C, 82.00; H, 6.31; N,
12.02.
4.3. General procedure for N-amination of substituted
3-amino-isoquinolines
A solution of isoquinoline-3-amines (10 mmol) in CH2Cl2
was added to a solution of TSH reagent (15 mmol) in
CH2Cl2 (40 mL) at 0 ꢁC. The reaction mixture was stirred at
rt for 1 h. The deposited yellow crystals were filtered off,
and washed with ether. The product was recrystallized from
2-propanol.
Syntheses of isoquinolin-3-amine (1a),18 4-methylisoqui-
nolin-3-amine (1b),19 3-aminoisoquinoline-4-carbonitrile,20
2,3-diamino-isoquinolinium 4-methylbenzenesulfonate (2a)4
and 2,3-diamino-4-methylisoquinolinium 4-methylbenzene-
sulfonate (2b)4 have been published earlier. Novel derivatives
(i.e., 1c, 1d, 2c, 2d) have been prepared according to these lit-
erature procedures.
4.3.1. 2,3-Diamino-4-ethylisoquinolinium 4-methyl-
benzenesulfonate (2c)
This compound was obtained from 4-ethylisoquinolin-3-
amine (1c, 1.72 g, 10 mmol) to give the title compound 2c
(2.37 g, 66%) as yellow crystals, mp 133e137 ꢁC. IR (KBr)
nmax: 3230, 3129, 2972, 1649, 1195, 1121, 1034, 1011, 814,
1
681, 597 cmꢀ1. H NMR (CDCl3þDMSO-d6) d (ppm): 9.18
4.2. General procedure for substituted
3-amino-isoquinolines
(1H, s, H1), 7.9 (1H, d, J¼8.4 Hz, H8), 7.82 (1H, d, J¼
8.9 Hz, H5), 7.7 (1H, t, J¼8.9 Hz, H6), 7.48 (2H, br s,
C3eNH2), 7.42 (2H, m, H3þH5(anion)), 7.32 (3H, m, H2þ
H6(anion)þH7), 2.9 (2H, q, J¼7.0 Hz, CH2), 2.2 (3H, s,
CH3(anion)), 1.05 (3H, t, J¼7.0 Hz, CH3). 13C NMR
(CDCl3þDMSO-d6) d (ppm): 15.1, 20.8, 30.4, 114.3, 120.0,
122.2, 125.3, 125.5 (2C), 128.1 (2C), 128.5, 129.0, 134.7,
137.6, 138.2, 142.9, 148.3. Anal. Calcd for C18H21N3O3S
(359.44): C, 60.15; H, 5.89; N, 11.69; S, 8.92. Found: C,
60.03; H, 6.10; N, 11.44; S, 8.92.
Amixtureof1-bromo-4-ethylisoquinolin-3-amine(0.27 mol),
DMF (450 mL), TEA (40 mL) and palladium-charcoal catalyst
(10%, 2 g) was subjected to catalytic hydrogenation under nor-
mal pressure for 4 h. The reaction mixture was filtered, the
filtrate was evaporated to one fifth of the original volume,
and the residue was poured onto ice-water (500 mL). The pre-
cipitated crystals were filtered off and recrystallized from
toluene.
4.3.2. 2,3-Diamino-4-benzylisoquinolinium 4-methyl-
benzenesulfonate (2d)
4.2.1. 4-Ethylisoquinolin-3-amine (1c)
This compound was obtained from 1-bromo-4-ethylisoqui-
nolin-3-amine (67.8 g, 0.27 mol) to give the title compound 1c
(23.7 g, 51%) as orange crystals, mp 108e110 ꢁC. IR (KBr)
nmax: 3477, 3304, 3168, 2963, 1633, 1580, 1377, 759 cmꢀ1. 1H
NMR (CDCl3) d (ppm): 8.8 (1H, s, H1), 7.8 (2H, m, H5þH8),
7.57 (1H, t, J¼8 Hz, H6), 7.21 (1H, t, J¼8 Hz, H7), 4.5 (2H,
br s, NH2), 2.9 (2H, m, CH2), 1.2 (3H, m, CH3). 13C NMR
(CDCl3) d (ppm): 12.8 (CH3), 19.5 (CH2), 111.2 (C4), 121.4
(C5), 122.6 (C6), 124.6 (C8a), 128.7 (C7), 130.4 (C8), 136.7
(C4a), 149.8 (C1), 151.9 (C3). Anal. Calcd for C11H12N2
(172.23): C, 76.71; H, 7.02; N, 16.27. Found: C, 76.37; H,
6.87; N, 16.31.
This compound was obtained from 4-benzylisoquinolin-3-
amine (1d, 2.13 g, 10 mmol) to give the title compound 2d
(3.04 g, 72%) as yellow crystals, mp 200e206 ꢁC. IR (KBr)
nmax: 3415, 3210, 3113, 1644, 1507, 1202, 1121, 1035, 1011,
1
684, 569 cmꢀ1. H NMR (DMSO-d6) d (ppm): 9.3 (1H, s,
H1), 8.0 (1H, d, J¼8.4 Hz, H8), 7.82 (1H, d, J¼8 Hz, H5), 7.7
(1H, t, H6), 7.6 (2H, br s, C3eNH2), 7.46 (2H, m,
H3þH5(anion)), 7.4 (2H, br s, NeNH2), 7.38 (1H, t, H7), 7.2
(2H, m, H20þH60), 7.15 (3H, m, H30þH40þH50), 7.05 (2H,
m, H2þH6(anion)), 4.4 (2H, s, CH02), 2.22 (3H, s, CH3(anion)).
13C NMR (DMSO-d6) d (ppm): 21.4 (CH3 (anion)), 31.1
0
(CH2 ), 115.0 (C4), 120.7 (C1 (anion)), 122.9 (C5), 126.0
(C6), 126.1 (C3þC5 (anion)), 127.1(C7), 128.7 (C2þC6 (an-
ion)), 128.8 (C20þC60), 129.2 (C30þC50), 129.7 (C40), 135.4
(C8), 138.2 (C8a), 138.3 (C4a), 138.8 (C10), 143.6 (C1),
146.3 (C4 (anion)), 149.0 (C3). Anal. Calcd for C23H23N3O3S
(421.51): C, 65.54; H, 5.50; N, 9.97. Found: C, 65.41; H,
5.39; N, 9.93.
4.2.2. 4-Benzylisoquinolin-3-amine (1d)
This compound was obtained from 4-benzyl-1-bromoiso-
quinolin-3-amine (84.5 g, 0.27 mol) to give the title compound
1d (41.4 g, 72%) as orange crystals, 112e120 ꢁC. IR (KBr)
nmax: 3373, 3330, 3187, 2677, 1623, 1584, 1460, 1452, 750,
1
733 cmꢀ1. H NMR (CDCl3þDMSO-d6) d (ppm): 8.8 (1H, s,
H1), 7.82 (1H, m, H8), 7.73 (2H, m, H5þH6), 7.40 (1H, t, H7),
7.10 (5H, m, Ph), 5.8 (2H, br s, NH2), 4.2 (2H, s, CH2). 13C
NMR (CDCl3þDMSO-d6) d (ppm): 31.1, 106.2, 122.0, 122.0,
123.7, 126.4, 128.8 (2C), 128.9 (2C), 129.0, 130.9, 137.6,
141.0, 150.8, 155.0. Anal. Calcd for C16H14N2 (243.3):
4.3.3. 2,3-Diamino-4-cyanoisoquinolinium 2,4,6-trimethyl-
benzenesulfonate (2e)
The solution of 3-aminoisoquinoline-4-carbonitrile (1e,
0.563 g, 3.3 mmol) in CH2Cl2 was added to the solution of
MSH reagent (1.419 g, 6.6 mmol) in CH2Cl2 (40 mL) at

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1107
0 ꢁC. The reaction mixture was stirred at rt for 4.5 h. The de-
4.4.2. 10-Methyl-2-phenyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3b)
posited yellow crystals were filtered off, and washed with
ether. The product was recrystallized from MeOH four times
to give the title compound 2e (0.267 g, 21%) as yellow crys-
tals, mp 231e234 ꢁC. IR (KBr) nmax: 3308, 3141, 2219,
This compound was prepared by Method A from 2b
(0.690 g, 2 mmol) and benzaldehyde (2.12 g, 20 mmol) to
give the title compound 3b (0.303 g, 58%) as light yellow crys-
tals, mp 196e199 ꢁC. IR (KBr) nmax: 3063, 1630, 1610, 1460,
1662, 1161, 1086, 1012, 682 cmꢀ1 1H NMR (CD3OD)
.
d (ppm): 2.18 (3H, s, CH3(anion)); 2.56 (6H, s, 2ꢂCH3-
(anion)), 6.78 (2H, s, H30þH50(anion)), 7.57 (1H, dd,
J¼7.9þ7.3 Hz, H7), 7.87 (1H, d, J¼8.7 Hz, H5), 8.01 (1H,
dd, J¼8.7þ7.3 Hz, H6), 8.05 (1H, d, J¼7.9 Hz, H8), 9.42
(1H, s, H1). 13C NMR (CD3OD) d (ppm): 23.6, 26.0 (2C),
91.3, 116.6, 124.0, 125.9, 130.9, 131.6, 134.2, 134.4 (2C),
142.8, 142.9 (2C), 143.4, 144.4, 155.4, 155.6. For elemental
analysis this compound was converted to perchlorate salt.
Anal. Calcd for C10H9ClN4O4 (284.66): C, 42.19; H, 3.19;
N, 19.68. Found: C, 41.88; H, 3.50; N, 19.56.
1439, 1393, 1286, 1250, 714 cmꢀ1 1H NMR (DMSO-d6)
.
d (ppm): 9.8 (1H, s, H5), 8.38 (2H, m, H20þH60), 8.06 (2H,
m, H6þH9), 7.40e7.65 (5H, m, H30þH40þH50þH7þH8),
2.98 (3H, s, CH3). 13C NMR (DMSO-d6) d (ppm): 13.4,
119.1, 122.9, 124.0, 125.9, 126.1, 127.7, 127.9 (2C), 129.0,
129.6 (2C), 131.1, 131.3, 131.6, 150.6, 165.0. Anal. Calcd
for C17H13N3 (259.31): C, 78.74; H, 5.05; N, 16.20. Found:
C, 78.45; H, 5.01; N, 16.18.
4.4.3. 10-Methyl-2-propyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3c)
This compound was prepared by Method A from 2b
(0.690 g, 2 mmol) and butyraldehyde (1.44 g, 20 mmol) to
give the title compound 3c (0.210 g, 47%) as light yellow crys-
tals, mp 108e110 ꢁC. IR (KBr) nmax: 3063, 2962, 2929, 2872,
4.4. General procedure for preparation of
[1,2,4]triazolo[1,5-b]isoquinolines (3aem)
1
Method A: To the solution of 2bed (2 mmol) and aldehyde
(20 mmol) in EtOH (30 mL) DBU (1.4 mL) was added, and
the mixture was stirred at rt. The progress of the reaction
was monitored by TLC. After disappearance of the starting
material the reaction mixture was evaporated, water (50 mL)
was added and the mixture was extracted with chloroform.
The organic layer was dried over Na2SO4, and evaporated.
The residue was flash chromatographed over silica, by using
hexaneeEtOAc 4:1 as eluent. The product was recrystallized
from EtOAc.
1609, 1480, 1468, 1392, 1258, 743 cmꢀ1. H NMR (CDCl3)
d (ppm): 9.62 (1H, s, H5), 7.98 (1H, dd, J¼8þ2.5 Hz, H6),
7.96 (1H, dd, J¼8.2þ3 Hz, H9), 7.51 (1H, ddd, J¼
8.2þ8þ2.5 Hz, H8), 7.38 (1H, ddd, J¼8þ8þ3 Hz, H7), 2.85
(3H, s, CH3), 2.84 (2H, m, C10H2), 1.82 (2H, m, C20H2),
0.95 (3H, m, C30H3). 13C NMR (CDCl3) d (ppm): 14.2
(CH3), 14.8 (C30), 22.3 (C20), 31.0 (C10), 118.2 (C10), 122.3
(C5a), 124.0 (C6), 125.4 (C7), 125.6 (C5), 127.6 (C9), 128.7
(C8), 130.8 (C9a), 150.0 (C10a), 169.0 (C2). 15N NMR
(CDCl3) d (ppm): ꢀ132.0 (N3), ꢀ176.0 (N1). Anal. Calcd
for C14H15N3 (225.29): C, 74.64; H, 6.71; N, 18.65. Found:
C, 74.27; H, 6.76; N, 18.50.
Method B: To the solution of 2a (0.993 g, 3 mmol) and
aldehyde (30 mmol) in abs acetonitrile (40 mL) was added
˚
molecular sieves (3.0 g, FLUKA, UOP type, 4 A) and the mix-
ture was stirred at rt overnight. The progress of the reaction
was monitored by TLC. The reaction mixture was filtered
and evaporated, the residue was flash chromatographed over
silica by using hexaneeEtOAc 4:1 as eluent. The product
was recrystallized from EtOAc.
4.4.4. 10-Ethyl-2-p-tolyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3d)
This compound was prepared by Method A from 2c
(0.718 g, 2 mmol) and 4-methylbenzaldehyde (2.4 g,
20 mmol) to give the title compound 3d (0.360 g, 42%) as light
yellow crystals, mp 202e204 ꢁC. IR (KBr) nmax: 3059, 2969,
1611, 1453, 1392, 1323, 1286, 1177, 739 cmꢀ1 1H NMR
.
4.4.1. 10-Methyl-2-p-tolyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3a)
(200 MHz, CDCl3) d (ppm): 9.2 (1H, s, H5), 8.32 (2H, m,
H20þH60), 8.0 (1H, d, J¼8 Hz, H6), 7.8 (1H, d, J¼8.5 Hz,
H9), 7.2e7.5 (4H, m, H30þH50þH7þH8), 3.6 (2H, q,
CH3). 13C NMR (CDCl3) d (ppm): 14.5, 20.7, 21.5, 122.7,
123.1, 123.9, 125.1, 125.5, 126.8, 127.6, 127.7 (2C), 128.5,
129.4 (2C), 130.2, 140.2, 150.1, 165.7. Anal. Calcd for
C19H17N3 (287.36): C, 79.41; H, 5.96; N, 14.62. Found: C,
79.17; H, 5.98; N, 14.52.
This compound was prepared by Method A from 2b
(0.690 g, 2 mmol) and 4-methylbenzaldehyde (2.4 g,
20 mmol) to give the title compound 3a (0.300 g, 55%) as light
yellow crystals, mp 218e220 ꢁC. IR (KBr) nmax: 3065, 3021,
0
J¼7.5 Hz, CH2), 2.42 (3H, s, CH3 ), 1.44 (3H, t, J¼7.5 Hz,
2920, 1611, 1444, 1394, 1290, 1249, 1178, 768 cmꢀ1 1H
.
NMR (DMSO-d6þCDCl3) d (ppm): 9.74 (1H, s, H5), 8.22
(2H, m, H20þH60), 8.02 (2H, m, H6þH9), 7.60 (1H, t,
J¼8.0 Hz, H8), 7.42 (1H, t, J¼7.5 Hz, H7), 7.38 (2H, m,
H30þH50), 3.0 (3H, s, CH3), 2.40 (3H, s, CH03). 13C NMR
(DMSO-d6þCDCl3) d (ppm): 13.3, 21.8, 118.8, 122.8,
123.8, 125.5, 125.8, 127.6 (2C), 127.8, 128.7, 128.9, 130.0
(2C), 131.2, 140.6, 150.6, 165.1. Anal. Calcd for C18H15N3
(273.33): C, 79.10; H, 5.33; N, 15.37. Found: C, 78.70; H,
5.51; N, 15.32.
4.4.5. 10-Ethyl-2-phenyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3e)
This compound was prepared by Method A from 2c
(0.718 g, 2 mmol) and benzaldehyde (2.12 g, 20 mmol) to
give the title compound 3a (0.350 g, 43%) as light yellow crys-
tals, mp 198e200 ꢁC. IR (KBr) nmax: 3063, 2966, 2931, 1609,

1108
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1460, 1393, 1326, 1287, 712 cmꢀ1
.
1H NMR (200 MHz,
(335.40): C, 82.36; H, 5.11; N, 12.53. Found: C, 82.10; H,
5.13; N, 12.45.
CDCl3) d (ppm): 9.22 (1H, s, H5), 8.40 (2H, m, H20þH60),
8.03 (1H, d, J¼8 Hz, H6), 7.8 (1H, d, J¼8 Hz, H9), 7.20e
7.60 (5H, m, H30þH40þH50þH7þH8), 3.55 (2H, q,
J¼7.5 Hz, CH2), 1.47 (3H, t, J¼7.5 Hz, CH3). 13C NMR
(CDCl3) d (ppm): 14.5, 21.2, 122.7, 123.1, 124.0, 125.2,
125.7, 126.8, 127.7, 127.8 (2C), 128.6 (2C), 130.1, 130.3,
131.4, 150.1, 165.6. Anal. Calcd for C18H15N3 (273.33): C,
79.10; H, 5.53; N, 15.37. Found: C, 79.10; H, 5.65; N, 15.32.
4.4.9. 10-Benzyl-2-propyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3i)
This compound was prepared by Method A from 2d
(0.870 g, 2 mmol) and butyraldehyde (1.44 g, 20 mmol) to
give title compound 3i (0.504 g, 56%) as white crystals, mp
134e137 ꢁC. IR (KBr) nmax: 3049, 2960, 2870, 1608, 1495,
1
1424, 1328, 742 cmꢀ1. H NMR (200 MHz, CDCl3) d (ppm):
9.2 (1H, s, H5), 8.0 (1H, d, J¼9 Hz, H6), 7.8 (1H, d,
4.4.6. 10-Ethyl-2-methyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3f)
J¼8.4 Hz, H9), 7.0e7.5 (7H, m, H7þH8þPh), 4.90 (2H, s,
0
0
CH2), 3.0 (2H, t, J¼7.3 Hz, C1eH2 ), 2.0 (2H, m, C2eH2 ),
This compound was prepared by Method A from 2c
(0.718 g, 2 mmol) and acetaldehyde (0.88 g, 20 mmol) to
give the title compound 3f (0.250 g, 39%) as light yellow crys-
tals, mp 80e88 ꢁC. IR (KBr) nmax: 3212, 2972, 1770, 1738,
1552, 1331, 1285, 1057, 951 cmꢀ1. 1H NMR (CDCl3) d (ppm):
9.18 (1H, s, H5), 8.0 (1H, d, J¼8.5 Hz, H6), 7.80 (1H, d,
J¼8.5 Hz, H9), 7.44 (1H, dd, J¼8.5þ7.6 Hz, H8), 7.35 (1H,
dd, J¼8.5þ7.6 Hz, H7), 3.50 (2H, q, J¼7.8 Hz, CH2), 2.71
1.05 (3H, t, J¼7.3 Hz, CH3 ). 13C NMR (CDCl3) d (ppm):
0
14.1, 22.0, 31.3, 33.0, 121.1, 122.3, 123.6, 124.7, 125.1, 126.3,
126.8, 128.2, 128.4 (2C), 128.5 (2C), 130.9, 139.6, 150.6,
169.9. Anal. Calcd for C20H19N3 (301.38): C, 79.70; H,
6.35; N, 13.94. Found: C, 79.63; H, 6.41; N, 13.93.
4.4.10. 10-Benzyl-2-methyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3j)
(3H, s, CH3 ), 1.40 (3H, t, J¼7.8 Hz, CH3). 13C NMR
0
This compound was prepared by Method A from 2d
(0.870 g, 2 mmol) and acetaldehyde (0.88 g, 20 mmol) to
give the title compound 3j (0.311 g, 38%) as white crystals,
mp 142e150 ꢁC. IR (KBr) nmax: 3523, 3062, 2928, 1736,
(CDCl3) d (ppm): 14.6, 15.1, 20.9, 122.6, 123.3, 124.0,
125.0, 125.4, 127.0, 128.1, 130.4, 149.8, 165.9. Anal. Calcd for
C13H13N3 (211.26): C, 73.91; H, 6.20; N, 19.89. Found: C,
73.53; H, 6.17; N, 19.58.
1
1497, 1453, 1306, 701 cmꢀ1. H NMR (200 MHz, CDCl3)
d (ppm): 9.2 (1H, s, H5), 8.0 (1H, d, J¼8.2 Hz, H6), 7.8
(1H, d, J¼7.8 Hz, H9), 7.0e7.5 (7H, m, H7þH8þPh), 4.85
(2H, s, CH2), 2.7 (3H, s, CH3). 13C NMR (CDCl3) d (ppm):
14.9, 32.9, 120.8, 122.3, 123.6, 124.6, 125.2, 126.2, 126.8,
128.2, 128.3 (2C), 128.5 (2C), 131.0, 139.4, 150.6, 166.1.
Anal. Calcd for C18H15N3 (273.33): C, 79.10; H, 5.53; N,
15.37. Found: C, 79.15; H, 5.75; N, 15.24.
4.4.7. 10-Benzyl-2-p-tolyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3g)
This compound was prepared by Method A from 2d
(0.870 g, 2 mmol) and 4-methylbenzaldehyde (2.4 g, 20 mmol)
to give the title compound 3g (0.640 g, 61%) as light yellow
crystals, mp 238e239 ꢁC. IR (KBr) nmax: 3074, 3058, 3032,
2919, 1609, 1455, 1436, 1392, 741, 696 cmꢀ1 1H NMR
.
(200 MHz, CDCl3þTFA) d (ppm): 9.6 (1H, s, H5), 8.22 (2H,
m, H20þH60), 8.08 (2H, m, H6þH9), 7.74e7.96 (2H, m,
H7þH8), 7.4 (2H, m, H30þH50), 7.03e7.22 (5H, m, Ph), 4.95
4.4.11. 2-p-Tolyl-[1,2,4]triazolo[1,5-b]isoquinoline (3k)
This compound was prepared by Method B from 2a
(0.993 g, 3 mmol) and 4-methylbenzaldehyde (3.6 g, 30 mmol)
to give the title compound 3k (0.420 g, 54%) as yellow crystals,
mp 286e289 ꢁC. IR (KBr) nmax: 3050, 3020, 1642, 1613, 1437,
(2H, s, CH2), 2.4 (3H, s, CH3 ). 13C NMR (CDCl3þTFA)
0
d (ppm): 21.6, 32.3, 119.0, 119.8, 123.9, 124.8, 127.4, 127.7
(2C), 128.0, 128.2 (2C), 129.1 (2C), 129.2, 130.4 (2C), 133.8,
135.8, 136.0, 145.4, 158.3, 159.6. Anal. Calcd for C24H19N3
(349.43): C, 82.49; H, 5.48; N, 12.03. Found: C, 82.10; H,
5.34; N, 11.90.
1
1328, 1282, 827, 739 cmꢀ1. H NMR (CDCl3) d (ppm): 9.38
(1H, s, H5), 8.30 (2H, m, H20þH60), 8.18 (1H, s, H10), 7.80
(2H, m, H6þH9), 7.47 (1H, t, J¼8.0 Hz, H8), 7.38 (1H, t,
0
J¼8.0 Hz, H7), 7.30 (2H, m, H30þH50), 2.41 (3H, s, CH3 ).
13C NMR (CDCl3) d (ppm): 21.7, 110.6, 122.5, 125.9, 126.1,
126.5, 127.1, 127.9 (2C), 128.4, 128.6, 129.6 (2C), 133.9, 140.8,
150.9, 166.7. HRMS (EI): Mþ, found: 259.1117. C17H13N3 re-
quires: 259.1110. Anal. Calcd for C17H13N3 (259.31): C, 78.74;
H, 5.05; N, 16.20. Found: C, 78.37; H, 4.95; N, 16.01.
4.4.8. 10-Benzyl-2-phenyl-[1,2,4]triazolo[1,5-b]-
isoquinoline (3h)
This compound was prepared by Method A from 2d
(0.870 g, 2 mmol) and benzaldehyde (2.12 g, 20 mmol) to
give the title compound 3h (0.600 g, 60%) as light yellow crys-
tals, mp 193e195 ꢁC. IR (KBr) nmax: 3071, 3026, 1630, 1608,
1459, 1452, 1433, 1395, 1286, 707 cmꢀ1. 1H NMR (200 MHz,
CDCl3þTFA) d (ppm): 9.6 (1H, s, H5), 8.2 (4H, m, H20þ
H60þH6þH9), 7.51e7.95 (5H, m, H30þH40þH50þH7þH8),
7.20e7.0 (5H, m, Ph), 5.0 (2H, s, CH2). 13C NMR (CDCl3þ
TFA) d (ppm): 32.3, 119.3, 122.8, 123.9, 124.8, 127.3, 127.8
(2C), 128.3 (2C), 129.0 (2C), 129.2, 129.6 (2C), 133.8, 134.0,
135.9, 136.0, 139.8, 158.3, 160.4. Anal. Calcd for C23H17N3
4.4.12. 2-Phenyl-[1,2,4]triazolo[1,5-b]isoquinoline (3l)
This compound was prepared by Method B from 2a
(0.993 g, 3 mmol) and benzaldehyde (3.18 g, 30 mmol) to
give the title compound 3l (0.350 g, 57%) as yellow crystals,
mp 288e290 ꢁC. IR (KBr) nmax: 3051, 1639, 1457, 1400,
1331, 1283, 1256, 712 cmꢀ1. 1H NMR (CDCl3) d (ppm): 9.36
(1H, s, H5), 8.40 (2H, m, H20þH60), 8.18 (1H, s, H10), 7.82
(2H, m, H6þH9), 7.42e7.55 (4H, m, H30þH40þH50þH8),

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1109
7.36 (1H, t, J¼7.5 Hz, H7). 13C NMR (CDCl3) d (ppm): 110.8,
122.6, 126.0, 126.1, 126.5, 127.1, 128.0 (2C), 128.6, 128.9
(2C), 129.2, 130.0, 130.6, 131.2, 134.0. HRMS (EI): Mþ,
found: 245.0950. C16H11N3 requires: 245.0953. Anal. Calcd
for C16H11N3 (245.28): C, 78.35; H, 4.52; N, 17.13. Found:
C, 78.05; H, 4.62; N, 16.94.
compound 4b (0.250 g, 51%) as orange crystals, mp 179e
183 ꢁC. IR (KBr) nmax: 3187, 2981, 1629, 1593, 1566, 1438,
1
1229, 1136, 865, 749 cmꢀ1. H NMR (CDCl3) d (ppm): 8.9
(1H, s, H1), 8.53 (1H, s, N1H0), 7.82 (2H, m, H8þH5), 7.72e
7.48 (5H, m, Ph), 7.42 (2H, m, H4þH6), 7.30 (2H, m,
N]CHþH7). 13C NMR (CDCl3) d (ppm): 99.2, 123.8,
125.3, 125.9, 126.7 (2C), 128.0, 128.9 (2C), 129.1, 130.9,
135.3, 139.1, 139.4, 151.5, 152.8. HRMS (EI): Mþ, found:
247.1105. C16H13N3 requires: 247.1110. Anal. Calcd for
C16H13N3 (247.29): C, 77.71; H, 5.30; N, 16.99. Found: C,
77.53; H, 5.17; N, 16.67.
4.4.13. 2-Propyl-[1,2,4]triazolo[1,5-b]isoquinoline (3m)
This compound was prepared by Method B from 2a
(0.993 g, 3 mmol) and butyraldehyde (2.16 g, 30 mmol) to
give the title compound 3m (0.220 g, 35%) as yellow crystals,
mp 118e121 ꢁC. IR (KBr) nmax: 3047, 2959, 2870, 1641,
1612, 1470, 1324, 1255, 746 cmꢀ1
.
1H NMR (CDCl3)
4.5.3. (E )-3-(2-Butylidenehydrazinyl)isoquinoline (4c)
d (ppm): 9.30 (1H, s, H5), 8.10 (1H, s, H10), 7.81 (1H, dd,
J¼8.2þ2.2 Hz, H6), 7.78 (1H, dd, J¼8þ2 Hz, H9), 7.47
(1H, ddd, J¼8þ7.8þ2.2 Hz, H8), 7.37 (1H, ddd, J¼8.2þ
7.8þ2 Hz, H7), 3.0 (2H, m, CH2), 1.92 (2H, m, CH2), 1.05
This compound was prepared from 2a (0.663 g, 2 mmol)
and butyraldehyde (1.44 g, 20 mmol) to give the title com-
pound 4c (0.310 g, 36%) as orange crystals, mp 94e96 ꢁC.
IR (KBr) nmax: 3192, 2954, 1627, 1591, 1434, 1219,
13
(3H, m, CH3). C NMR (CDCl3) d (ppm): 14.2 (C30), 22.0
863 cmꢀ1 1H NMR (CDCl3) d (ppm): 8.84 (1H, s, H1),
.
(C20), 31.4 (C10), 110.2 (C10), 122.1 (C5a), 125.8 (C6), 126.2
(C7), 126.3 (C5), 127.1 (C9), 128.5 (C8), 133.7 (C9a), 150.3
(C10a), 170.4 (C2). 15N NMR (CDCl3), d (ppm): ꢀ134.1 (N3),
ꢀ154.6 (N4), ꢀ179.3 (N1). Anal. Calcd for C13H13N3
(211.26): C, 73.91; H, 6.20; N, 19.89. Found: C, 73.68; H,
6.16; N, 19.70.
8.04 (1H, s, N1H0), 7.78 (1H, d, J¼8.5 Hz, H8), 7.64 (1H, d, J¼
8.3 Hz, H5), 7.51 (1H, dd, J¼8.5þ8.0 Hz, H6), 7.34 (1H, s,
H4), 7.26 (1H, dd, J¼8.5þ8.0 Hz, H7), 7.20 (1H, t, J¼
7.5 Hz, N]CH ),0 2.4 (2H, m, C4eH02), 1.6 (2H, m, C5eH20 ),
1.0 (3H, m, CH3 ). 13C NMR (CDCl3) d (ppm): 14.0, 20.6,
34.5, 98.6, 123.4, 125.0, 125.7, 127.9, 130.7, 139.2, 143.6,
151.5, 153.4. HRMS (EI): Mþ, found: 213.1257. C13H15N3 re-
quires: 213.1266. Anal. Calcd for C13H15N3 (213.28): C, 73.21;
H, 7.09; N, 19.70. Found: C, 73.03; H, 6.88; N, 19.31.
4.5. General procedure for substituted 3-methylidene-
hydrazinyl-isoquinolines (4aed)
To the solution of 2a,e (2 mmol) and aldehyde (20 mmol)
in EtOH (30 mL) was added DBU (1.4 mL), and the mixture
was stirred at rt. The progress of the reaction was monitored
by TLC. After disappearance of the starting material the reac-
tion mixture was evaporated, water (50 mL) was added, and
the mixture was extracted with chloroform. The organic layer
was dried over Na2SO4, and evaporated. The residue was flash
chromatographed over silica by using hexaneeEtOAc 4:1 as
eluent.
4.5.4. (E )-3-(2-Ethylidenehydrazinyl)isoquinoline (4d)
This compound was prepared from 2a (0.663 g, 2 mmol)
and acetaldehyde (0.88 g, 20 mmol) to give the title compound
4d (0.180 g, 49%) as orange crystals, mp 128e133 ꢁC. IR
(KBr) nmax: 3189, 3032, 2975, 1629, 1591, 1358, 1130,
1
747 cmꢀ1. H NMR (CDCl3) d (ppm): 8.84 (1H, s, H1), 8.2
(1H, N10H ), 7.78 (1H, dd, J¼8þ3 Hz, H8), 7.64 (1H, dd,
J¼8.1þ3 Hz, H5), 7.50 (1H, ddd, J¼8.1þ7.5þ3 Hz, H6),
7.34 (1H, s, H4), 7.20e7.28 (2H, m, H7þN20]CH ), 2.1
(3H, s, CH3). 13C NMR (CDCl3) d (ppm): 18.4 (CH3), 98.5
(C4), 123.5 (C7), 125.0 (C4a), 125.7 (C5), 128.0 (C8), 130.7
(C6), 139.2 (C8a), 139.6 (N20]CH), 151.5 (C1), 153.4
4.5.1. (E )-3-(2-(4-Methylbenzylidene)hydrazinyl)-
isoquinoline (4a)
15
This compound was prepared from 2a (0.663 g, 2 mmol)
and 4-methylbenzaldehyde (2.4 g, 20 mmol) to give the title
compound 4a (0.180 g, 35%) as orange crystals, mp 213e
215 ꢁC. IR (KBr) nmax: 3188, 3031, 2981, 1626, 1593, 1454,
1134, 741, 465 cmꢀ1. 1H NMR (DMSO-d6) d (ppm): 10.8 (1H,
s, N1H0), 8.95 (1H, s, H1), 8.04 (1H, s, N]CH ), 7.88 (1H,
d, J¼8.2 Hz, H8), 7.75 (1H, d, J¼8.7 Hz, H5), 7.54e7.58
(3H, m, H6þH20þH60), 7.38 (1H, s, H4), 7.27 (1H, m, H7),
(C3). N NMR (CDCl3) d (ppm): ꢀ81.0 (N20), ꢀ125.0
(N2), ꢀ253.0 (N10). Anal. Calcd for C11H11N3 (213.28): C,
71.33; H, 5.99; N, 22.69. Found: C, 71.27; H, 6.00; N, 22.32.
4.5.5. (E )-3-(2-(4-Methylbenzylidene)hydrazinyl)-
isoquinoline-4-carbonitrile (4e)
This compound was prepared from 2e (0.768 g, 2 mmol)
and 4-methylbenzaldehyde (2.4 g, 20 mmol) to give the title
compound 4e (0.477 g, 83%) as brown crystals, mp 128e
133 ꢁC. IR (KBr) nmax: 3232, 3048, 2965, 2202, 1620, 1587,
7.21 (2H, m, H30þH50), 2.30 (3H, s, CH3 ). 13C NMR
0
(DMSO-d6) d (ppm): 21.6, 97.6, 123.7, 124.8, 125.9, 126.6
(2C), 128.4, 130.0 (2C), 131.2, 133.5, 138.7, 139.0, 139.9,
152.1, 154.1. Anal. Calcd for C17H15N3 (261.32): C, 78.13;
H, 5.79; N, 16.08. Found: C, 77.76; H, 5.74; N, 16.07.
1
1578, 1556, 1510, 1417 cmꢀ1. H NMR (CDCl3) d (ppm):
8.97 (1H, s, H1), 8.74 (1H, s, N10H ), 8.12 (1H, dd, J¼
8.5þ1.1 Hz, H5), 7.86 (1H, dd, J¼8.5þ1.2 Hz, H8), 7.82
(1H, s, N20]CH ), 7.77 (1H, ddd, J¼8.5þ7þ1.2 Hz, H6),
7.75 (2H, m, H20þH60), 7.44 (1H, ddd, J¼8.5þ7þ1.1 Hz,
H7), 7.24 (2H, m, H30þH50), 2.38 (3H, s, CH3). 13C NMR
(CDCl3) d (ppm): 21.7 (CH3), 82.3 (C4), 116.9 (CN), 123.4
4.5.2. (E )-3-(2-Benzylidenehydrazinyl)isoquinoline (4b)
This compound was prepared from 2a (0.663 g, 2 mmol)
and benzaldehyde (2.12 g, 20 mmol) to give the title

1110
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
(C5), 123.9 (C8a), 125.3 (C7), 127.6 (C20þC60), 128.8 (C8),
129.8 (C30þC50), 131.7 (C10), 133.5 (C6), 138.7 (C4a),
140.3 (C40), 142.8 (N20]CH), 153.9 (C3), 156.2 (C1). Anal.
Calcd for C18H14N4 (286.33): C, 75.50; H, 4.93; N, 19.57.
Found: C, 75.60; H, 4.85; N, 19.60.
138 ꢁC). In the NMR spectrum two signal sets of the amide
rotamers are present. 1H NMR (CDCl3) d (ppm): 9.4þ9.8 (1H,
CONH ), 8.6þ9.45 (1H, s, CHO), 9.1 (1H, s, H1), 8.4þ7.26
(1H, s, H4), 7.91 (1H, d, H8), 7.85þ7.75 (1H, d, H5), 7.68
(1H, t, H7), 7.50 (1H, t, H6). 13C NMR (CDCl3) d (ppm):
109.1þ103.9 (C4), 125.8þ126.0 (C8), 126.2 (C8a), 126.6þ
126.8 (C5), 127.5þ127.8 (C6), 131.0þ131.3 (C7), 137.9
(C4a), 145.4þ146.3 (C3), 150.9þ152.1 (C1), 159.2þ162.9
(CHO). m/z (ES ionization) 174 (MHþ 15N), 173 (MHþ), 146
(MHþ 15Nꢀ28), 145 (MHþꢀ28).
4.6. (E )-3-(2-(4-Methylbenzylidene)hydrazinyl)-
isoquinoline 2-oxide (6)
To the solution of 3-hydrazinylisoquinoline-2-oxide9 (5)
(0.350 g, 2 mmol) in acetonitrile (30 mL), 4-methylbenzalde-
hyde (3 mL) was added, and the mixture was refluxed for
4 h. Upon cooling, the product was precipitated, filtered off,
and recrystallized from acetonitrile to yield title compound 6
(0.420 g, 76%) as orange crystals, mp 195e200 ꢁC. IR
(KBr) nmax: 3163, 3019, 2920, 1644, 1531, 1510, 1218, 856,
4.8. 15N-Labelled isoquinolin-3-amine (1a#)
N-(Isoquinolin-3-yl)formamide (8, 1.8 g, 10.5 mmol) was
heated in 10% HCl (120 mL) at boiling point. The solution
was cooled at rt, and it was neutralized with 10% NaOH.
The mixture was extracted with chloroform (3ꢂ30 mL), the
organic layer was dried over Na2SO4, evaporated and the res-
idue was recrystallized from toluene to yield 0.910 g (61%) of
product as yellow crystals. Physical and spectroscopic data of
this product (mp, IR, NMR) were identical with those of the
earlier isolated compound.
1
739 cmꢀ1. H NMR (CDCl3) d (ppm): 9.9 (1H, br s, N10H ),
8.76 (1H, s, H1), 8.0 (1H, s, N20]CH ), 7.70 (1H, d, J¼
8 Hz, H5), 7.65 (1H, s, H4), 7.64 (2H, m, H20þH60), 7.62 (1H,
d, J¼7.9 Hz, H8), 7.50 (1H, dd, J¼7.9þ7.7 Hz, H7), 7.34 (1H,
dd, J¼8þ7.7 Hz, H6), 7.23 (2H, m, H30þH50), 2.42 (3H, s,
CH3). 13C NMR (CDCl3) d (ppm): 21.7 (CH3), 101.4 (C4),
122.8 (C4a), 125.3 (C6), 125.4 (C5), 125.5 (C8), 127.1
(C20þC60), 129.6 (C7), 129.7 (C30þC50), 131.8 (C8a), 132.0
(C10), 135.5 (C1), 140.2 (C40), 144.2 (N20]CH), 145.6 (C3).
Anal. Calcd for C17H15N3O (277.32): C, 73.63; H, 5.45; N,
15.15. Found: C, 73.37; H, 5.07; N, 15.06.
4.9. (E )-3-Amino-2-(4-methylbenzylideneamino)-
isoquinolinium tetrafluoroborate (9)
A solution of 2a (0.662 g, 2 mmol) and 4-methylbenzalde-
hyde (2.4 g, 20 mmol) in abs acetonitrile (30 mL) was refluxed
for 5 h. The progress of the reaction was monitored by TLC.
After disappearance of the starting material the reaction mix-
ture was evaporated and then acetonitrile (5 mL) and tetra-
fluoroboric acid (50%, 1 mL) was added. Upon addition of
ether the product separated as an orange solid, it was filtered
off and recrystallized from acetonitrile to give the title com-
pound 9 (0.405 g, 58%) as orange crystal, mp 214e217 ꢁC.
IR (KBr) nmax: 3466, 3359, 1659, 1599, 1035, 877, 817,
4.6.1. Reduction of 6 to 4a
To a solution of 6 (0.277 g, 1 mmol) in saturated NH4Cl
(3 mL) and MeOH (5 mL), indium (0.137 g) was added and
refluxed for 1 h. The reaction mixture was diluted with
MeOH (15 mL) and refluxed for an additional 7 h. After neu-
tralization with saturated NaHCO3 and extraction with chloro-
form, the organic layer was dried over Na2SO4 and
evaporated. The residue was subjected to flash chromatogra-
phy over silica by using hexaneeEtOAc 2:1 as eluent. Yield:
0.063 g (24%). Physical and spectroscopic data (mp, IR,
NMR) of this product were identical with 4a, which was ear-
lier isolated from 2a and 4-methylbenzaldehyde.
1
749 cmꢀ1. H NMR (DMSO-d6) d (ppm): 9.70 (1H, s, H1),
9.16 (1H, s, N10]CH ), 8.04 (2H, m, H20þH60), 7.92 (1H,
dd, J¼8þ2.3 Hz, H8), 7.87 (2H, s, N20H2), 7.82 (1H, dd,
J¼8þ2.5 Hz, H5), 7.73 (1H, ddd, J¼8þ7.7þ2.3 Hz, H6),
7.46 (2H, m, H30þH50), 7.42 (1H, ddd, J¼8þ7.7þ2.5 Hz,
H7), 7.36 (1H, s, H4), 2.43 (3H, s, CH3). 13C NMR
(DMSO-d6) d (ppm): 22.1 (CH3), 105.7 (C4), 121.2 (C8a),
125.5 (C5), 126.5 (C7), 129.1 (C8), 129.3 (C10), 130.5
(C30þC50), 131.3 (C20þC60), 135.5 (C6), 138.2 (C1), 140.9
(C4a), 145.6 (C40), 148.3 (C3), 169.3 (N10]CH). 15N NMR
(DMSO-d6) d (ppm): ꢀ91.2 (N10), ꢀ186.5 (N20), ꢀ323.5
(NH2). Anal. Calcd for C17H16BF4N3 (349.13): C, 58.48; H,
4.62; N, 12.04. Found: C, 58.25; H, 4.30; N, 11.97.
4.7. N-(Isoquinolin-3-yl)formamide (8)
Pd2(DBA)3CHCl3 (0.206 g, 0.2 mmol), Cs2CO3 (2.608 g,
8 mmol) and xantphos (0.347 g) were placed in a two necked
round bottom flask. Dioxane (20 mL) was added to the mix-
ture, and heated at 100 ꢁC under Ar atmosphere. Isoquino-
lin-3-yl trifluoromethanesulfonate12 (7) (1.108 g, 4 mmol)
and formamide (0.360 mg, 8 mmol, containing 20% excess
of 15N-labelled formamide) was dissolved in dioxane
(5 mL), and the solution was added to the reaction mixture.
It was stirred for 4 h. The progress of the reaction was moni-
tored by TLC. After disappearance of the starting material the
reaction mixture was filtered on Celite and evaporated. The
residue was subjected to flash chromatography over silica by
using hexaneeEtOAc 4:1 as eluent to give the title compound
8 (0.406 g, 59%) as white crystals, mp 134e136 ꢁC (lit.2
4.10. General procedure for 2,3-dihydro-1H-
[1,2,4]triazolo[1,5-b]isoquinolin-4-ium 4-
methylbenzenesulfonates (10aef)
A solution of 2c,d (3 mmol) and the appropriate aldehyde
(30 mmol) in abs acetonitrile (45 mL) was refluxed for 6 h.
The progress of the reaction was monitored by TLC. After

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1111
disappearance of the starting material the reaction mixture was
cooled down to rt, the deposited yellow crystals were filtered
off, and washed with ether. The product was boiled in hot
EtOAc, filtered off and washed with EtOAc.
d (ppm): 9.4 (1H, s, H5), 9.0 (1H, d, J¼8.7 Hz, H3), 8.8
(1H, s, H1), 8.03 (1H, dd, J¼9þ2 Hz, H6), 7.97 (1H, dd,
J¼8.7þ2 Hz, H9), 7.8 (1H, ddd, J¼8.7þ8þ2 Hz, H8), 7.5
(1H, ddd, J¼9þ8þ2 Hz, H7), 7.4 (2H, m, H3þH5(anion)),
7.02 (2H, m, H2þH6(anion)), 5.4 (1H, m, H2), 2.95 (2H, m,
00
0
4.10.1. 10-Ethyl-2-p-tolyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10a)
CH2 ), 2.22 0(3H, s, CH3(anion)), 1.8 (2H, m, CH2 ), 1.4
(2H, m, CH2 ), 1.2 (3H, m, CH3 ), 0.92 (3H, m, CH3 ). 13C
NMR (DMSO-d6) d (ppm): 13.6 (C30), 14.3 (C200), 17.5
(C20), 19.7 (CH3(anion)), 21.4 (C100), 37.6 (C10), 74.5 (C2),
114.4 (C10), 122.5 (C5a), 122.6 (C9), 126.1 (C3þC5(anion)),
126.5 (C8), 128.7 (C2þC6(anion)), 130.2 (C7), 135.0 (C6),
135.5 (C5), 137.5 (C9a), 138.3 (C1(anion)), 144.9 (C4(an-
ion)), 146.3 (C10a). Anal. Calcd for C22H27N3O3S (413.53):
C, 63.90; H, 6.58; N, 10.16; S, 7.75. Found: C, 63.78; H,
6.57; N, 10.16; S, 8.02.
00
0
This compound was prepared from 2c (1.077 g, 3 mmol)
and 4-methylbenzaldehyde (3.6 g 30 mmol) to give the title
compound 10a (1.25 g, 90%) as yellow crystals, mp 170e
172 ꢁC. IR (KBr) nmax: 3095, 1648, 1473, 1444, 1216, 1176,
1
1034, 1011, 814 cmꢀ1. H NMR (DMSO-d6) d (ppm): 9.42
(1H, s, H5), 9.3 (1H, s, H1), 9.25 (1H, d, J¼9.2 Hz, H3),
8.1 (1H, d, J¼8.0 Hz, H6), 8.0 (1H, d, J¼8.0 Hz, H9), 7.82
(1H, t, J¼8.0 Hz, H8), 7.5 (1H, t, J¼8.0 Hz, H7), 7.4 (4H,
m, H3þH5(anion)þH20þH60), 7.22 (2H, m, H30þH50), 7.04
(2H, m, H2þH6(anion)), 6.4 (1H, d, J¼9.2 Hz, H2), 3.0
4.10.4. 10-Benzyl-2-p-tolyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10d)
00
0
(2H, m, CH2 ), 2.3 (3H, s, CH3 ), 2.22 (3H, s, CH3(anion)),
1.2 (3H,m, CH3 ). 13C NMR (DMSO-d6) d (ppm): 13.7,
This compound was prepared from 2d (1.305 g, 3 mmol)
and 4-methylbenzaldehyde (3.6 g, 30 mmol) to give the title
compound 10d (1.23 g, 78%) as yellow crystals, mp 202e
204 ꢁC. IR (KBr) nmax: 3170, 3056, 1651, 1510, 1232, 1181,
00
19.8, 21.4, 21.5, 75.8, 114.4, 122.7, 126.2 (2C), 126.6, 127.8
(2C), 128.7 (2C), 130.0 (2C), 130.4, 135.0 (2C), 135.1,
135.4, 137.6, 138.3, 139.9, 144.5, 146.4. HRMS (EI): Mþ,
found: 290.1642. C19H20N3 requires: 290.1652. Anal. Calcd
for C26H27N3O3S (461.58): C, 67.65; H, 5.90; N, 9.10; S,
6.95. Found: C, 67.43; H, 6.10; N, 9.09; S, 7.22.
1170, 1121, 1033, 1010, 679 cmꢀ1 1H NMR (DMSO-d6)
.
d (ppm): 9.6 (2H, s, H1þH5), 9.38 (1H, d, J¼9.0 Hz, H3),
8.10 (1H, d, J¼8.3 Hz, H6), 7.90 (1H, d, J¼8.0 Hz, H9),
7.80 (1H, t, J¼8.0 Hz, H8), 7.50 (1H, t, J¼8.0 Hz, H7), 7.45
(4H, m, H3þH5(anion)þH20þH60), 7.25 (6H, H30þH50þ
H200þH300þH500þH600), 7.18 (1H, m, H400), 7.05 (2H, m,
H2þH6 (anion), 6.46 (1H, d, J¼9.0 Hz, H2), 4.40 (2H, m,
4.10.2. 10-Ethyl-2-phenyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10b)
CH2 ), 2.30 (3H, s, CH3 ), 2.22 (3H, s, CH3(anion)). 13C NMR
(DMSO-d6) d (ppm): 21.4, 21.5, 31.6, 75.8, 110.9, 122.7,
123.2, 126.2 (2C), 126.6, 127.2, 127.8 (2C), 128.7 (2C),
128.8 (2C), 129.3 (2C), 130.0 (2C), 130.5, 135.3, 135.5, 136.2,
138.2, 138.4, 138.8, 139.9, 145.5, 146.3. 15N NMR (DMSO-
d6) d (ppm): ꢀ191.3 (N4), ꢀ276.0 (N3), ꢀ310.6 (N1). HRMS
(EI): Mþ, found: 352.1807. C24H22N3 requires: 352.1808.
Anal. Calcd for C31H29N3O3S (523.19): C, 71.10; H, 5.58;
N, 8.02; S, 6.12. Found: C, 70.88; H, 5.32; N, 8.11; S, 6.32.
00
0
This compound was prepared from 2c (1.077 g, 3 mmol)
and benzaldehyde (3.18 g, 30 mmol) to give the title com-
pound 10b (1.21 g, 89%) as yellow crystals, mp 168e
175 ꢁC. IR (KBr) nmax: 3095, 1650, 1446, 1203, 1159, 1121,
1
1031, 1008, 682 cmꢀ1. H NMR (DMSO-d6) d (ppm): 9.5
(1H, s, H5), 9.4 (1H, d, J¼9.0 Hz, H3), 9.35 (1H, s, H1),
8.1 (1H, d, J¼8.5 Hz, H6), 8.0 (1H, d, J¼8.5 Hz, H9), 7.85
(1H, t, J¼8.5 Hz, H8), 7.4 (2H, m, H3þH5(anion)), 7.35 (1H,
t, J¼8.5 Hz, H7), 7.4e7.45 (5H, m, Ph), 7.02 (2H, m,
H2þH6(anion), 6.45 (1H, d, J¼9.0 Hz, H2), 3.0 (2H, m,
CH2 ), 2.2 (3H, s, CH3(anion)), 1.2 (3H, m, CH3 ). 13C
NMR (DMSO-d6) d (ppm): 13.7, 19.8, 21.4, 75.9, 114.5,
122.7, 122.8, 126.1 (2C), 126.6, 127.8 (2C), 128.7 (2C),
129.5 (2C), 130.3, 130.4, 135.0, 135.1, 137.6, 138.3, 138.5,
144.4, 146.3. HRMS (EI): Mþ, found: 276.1490. C18H18N3 re-
quires: 276.1495. Anal. Calcd for C25H25N3O3S (447.55): C,
67.09; H, 5.63; N, 9.39; S, 7.16. Found: C, 66.81; H, 5.42;
N, 9.36; S, 7.36.
4.10.5. 10-Benzyl-2-phenyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10e)
00
00
This compound was prepared from 2d (1.305 g, 3 mmol)
and benzaldehyde (3.18 g, 30 mmol) to give the title com-
pound 10e (1.35 g, 88%) as yellow crystals, mp 198e
200 ꢁC. IR (KBr) nmax: 3094, 3051, 1701, 1650, 1220, 1171,
1
1122, 1034, 1011, 681 cmꢀ1. H NMR (DMSO-d6) d (ppm):
9.56 (2H, s, H1þH5), 9.40, (1H, d, J¼9.0 Hz, H3), 8.11
(1H, d, J¼8.0 Hz, H6), 7.90 (1H, d, J¼8.0 Hz, H9), 7.80 (1H,
t, J¼8.0 Hz, H8), 7.57 (2H, m, H20þH60), 7.50 (1H, t,
J¼8.0 Hz, H7), 7.46 (5H, m, H3þH5(anion)þH30þH40þH50),
7.14e7.30 (5H, m, Ph00), 7.08 (2H, m, H2þH6(anion)), 6.50
CH3(anion)). 13C NMR (DMSO-d6) d (ppm): 21.4, 31.6, 75.8,
110.9, 122.7, 123.2, 126.2 (2C), 126.7, 127.2, 127.8 (2C),
128.7 (2C), 128.8 (2C), 19.3 (2C), 129.5 (2C), 129.8, 130.2,
4.10.3. 10-Ethyl-2-propyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10c)
This compound was prepared from 2c (1.077 g, 3 mmol)
and butyraldehyde (2.16 g 30 mmol) to give the title com-
pound 10c (1.12 g, 89%) as yellow crystals, mp 151e
156 ꢁC. IR (KBr) nmax: 3116, 2953, 1651, 1495, 1217, 1171,
00
(1H, d, J¼9.0 Hz, H2), 4.40 (2H, m, CH2 ), 2.24 (3H, s,
1124, 1033, 1010, 684, 595 cmꢀ1 1H NMR (DMSO-d6)
.

1112
L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
130.3, 130.5, 135.3, 136.2, 138.2, 138.8, 145.4, 146.3. HRMS
(EI): Mþ, found: 338.1649. C23H20N3 requires: 338.1652.
Anal. Calcd for C30H27N3O3S (509.62): C, 70.70; H, 5.34;
N, 8.25; S, 6.29. Found: 70.42; H, 5.52; N, 8.28; S, 6.24.
4.13. Transformation of (E )-3-amino-2-(4-methyl-
benzylideneamino)isoquinolinium tetrafluoroborate (9)
into (E )-3-(2-(4-methylbenzylidene)hydrazinyl)-
isoquinoline (4a) under basic conditions
4.10.6. 10-Benzyl-2-propyl-2,3-dihydro-1H-[1,2,4]-
triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10f)
To the solution of 9 (0.200 g, 0.57 mmol) in EtOH (20 mL)
was added DBU (1.4 mL), and the mixture was stirred at rt.
The progress of the reaction was monitored by TLC. After dis-
appearance of the starting material the reaction mixture was
evaporated. The residue was subjected to flash chromatogra-
phy over silica by using hexaneeEtOAc 2:1 as eluent, to
give 4a (0.101 g, 67%) as yellow crystals. All physical and
spectroscopic data of this product (4a) were identical with
those of the earlier isolated compound obtained from 2a and
4-methylbenzaldehyde.
This compound was prepared from 2d (1.305 g, 3 mmol)
and butyraldehyde (2.16 g, 30 mmol) to give the title com-
pound 10f (0.76 g, 53%) as yellow crystals, mp 161e
164 ꢁC. IR (KBr) nmax: 3062, 2962, 1783, 1650, 1455, 1170,
1
1122, 1033, 1010, 682 cmꢀ1. H NMR (DMSO-d6) d (ppm):
9.52 (1H, s, H5), 9.05 (1H, s, H1), 8.97 (1H, d, J¼7 Hz,
H3), 8.07 (1H, dd, J¼8.2þ3 Hz, H6), 7.84 (1H, dd, J¼8þ
2 Hz, H9), 7.75 (1H, ddd, J¼8þ7.8þ3 Hz, H8), 7.47 (1H,
ddd, J¼8.2þ7.8þ2 Hz, H7), 7.43 (2H, m, H3þH5(anion),
7.30e7.10 (5H, m, Ph00), 7.05 (2H, m, H2þH6(anion), 5.40
Acknowledgements
00
(1H, m, q, J¼7 Hz, H2), 4.34 (2H, s, CH2 ), 2.2 (3H, s,
Financial supports OTKA T047317, T042642, NKFP 1A/
005/2004 and projects GVOP-3.2.1-2004-04-0311/3.0, GVOP-
3.2.1-2004-04-0210/3.0 and GVOP-3.2.2.-2004-07-0003/3 are
gratefully acknowledged.
0
0
CH3(anion)), 1.72 (2H, m, C1eH2 ), 1.40 (2H, m, C2eH2 ),
0.91 (3H, t, J¼7 Hz, CH3 ). 13C NMR (DMSO-d6) d (ppm):
0
14.3, 17.5, 21.4, 31.6, 37.5, 74.5, 110.8, 122.5, 123.0, 126.1
(2C), 126.5, 127.2, 128.7 (2C), 128.8 (2C), 129.3 (2C),
130.4, 135.3, 136.5, 138.2, 138.3, 138.9, 146.0, 146.2. Anal.
Calcd for C27H29N3O3S (475.60): C, 68.18; H, 6.15; N,
8.84; S, 6.74. Found: C, 68.02; H, 6.16; N, 8.84; S, 7.07.
Supplementary data
1He15N gHMQC spectra of compounds 2a and 4d. Supple-
mentary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2007.10.103.
4.11. General procedure for reaction of 4-methyl-
2,3-diamino-isoquinolinium 4-methylbenzenesulfonate
(2b) with aldehydes without the presence of DBU
References and notes
A solution of 2b (690 mg, 2 mmol) and the appropriate al-
dehyde (20 mmol) in abs acetonitrile (30 mL) was refluxed for
the period specified below. The progress of the reaction was
monitored by TLC. After disappearance of the starting mate-
rial the reaction mixture was evaporated, 50 mL of 10%
Na2CO3 was added, and the mixture was extracted with chlo-
roform. The organic layer was dried over Na2SO4 and then it
was evaporated. Ether was added to the residue, whereupon
a crystalline solid separated. The product was filtered off
and recrystallized from EtOAc to yield 3a (0.202 g, 37%) or
3c (0.200 g, 47%). All physical and spectroscopic data of these
products were identical with those of the products obtained
from 2b and aldehyde under basic conditions.
1. (a) Timari, G.; Messmer, A.; Zagyva, A.; Miskolczi, I.; Schantl, J. G.
´
Monatsh. Chem. 1995, 126, 1213; (b) Hoang, C. N.; Riedl, Zs.; Timari,
´
G.; Hajos, G.; Schantl, J. G. Arkivoc 2001, 2, 1060.
2. (a) Frederick, K. S.; Kalgutkar, A.; Hatch, H. L.; Nguyen, H. T.; Choo,
E. F.; Henne, K. R. Drug Metab. Rev. 2006, 38, 214; (b) Chadlaoui, M.;
´
Abarca, B.; Ballesteros, R.; Ramırez de Arellano, C.; Aguilar, J.; Aucejo,
´
~
R.; Garcıa-Espana, E. J. Org. Chem. 2006, 24, 9030; (c) McClure, K. F.;
Letavic, M. A.; Kalgutkar, A. S.; Gabel, C. A.; Audoly, L.; Barberia, J. T.;
Braganza, J. F.; Carter, D.; Carty, T. J.; Cortina, S. R.; Dombroski, M. A.;
Donahue, K. M.; Elliott, N. C.; Gibbons, C. P.; Jordan, C. A.; Kuperman,
A. V.; Labasi, J. M.; LaLiberte, R. E.; McCoy, J. M.; Naiman, B. L.;
Nelson, K. L.; Nguyen, H. T.; Peese, K. M.; Sweeney, F. J.; Taylor,
T. J.; Trebino, C. E.; Abramov, Y. A.; Laird, E. R.; Volberg, W. A.;
Zhou, J.; Bach, J.; Lombardo, F. Bioorg. Med. Chem. Lett. 2006, 16, 4339.
3. Tamura, Y.; Iwaisaki, M.; Miki, Y.; Ikeda, M. Heterocycles 1977, 6, 949.
4.12. Oxidation of 10-benzyl-2-phenyl-2,3-dihydro-1H-
[1,2,4]triazolo[1,5-b]isoquinolin-4-ium 4-methyl-
benzenesulfonate (10e) under basic conditions
´
4. Messmer, A.; Hajos, G. J. Org. Chem. 1981, 46, 843.
5. Glover, E. E.; Rowbottom, K. T. J. Chem. Soc., Perkin Trans. 1 1976, 368.
6. In the case of 1e the N-aminating reagent O-mesityl-hydroxylamine
(MSH) was used. Tamura, Y.; Minemakawa, J.; Sumoto, K.; Fujii, S.;
Ikeda, M. J. Org. Chem. 1973, 38, 1241.
The suspension of 10e (0.255 g, 0.5 mmol) in 10% NaOH
(20 mL) was heated until boiling. After cooling the mixture
was extracted with chloroform. The organic layer was dried
over Na2SO4, evaporated and the residue was recrystallized
from EtOAc to yield 0.153 g (91%) of product. All physical
and spectroscopic data of this product 3h were identical
with those of the earlier isolated compound obtained from
2d and benzaldehyde.
7. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.
8. A crystal of 4c (C13H15N3, Mr¼213.28, pale yellow block, size:
0.60ꢂ0.45ꢂ0.25 mm) was mounted on a glass fibre. Cell parameters
were determined by least-squares fitting of the setting angles of 25
(36.97ꢃqꢃ39.86ꢁ) reflections. Monoclinic, space group C2/c,
ꢁ
ꢁ
˚
˚
˚
a¼16.258(1) A, b¼7.444(1) A, c¼19.484(1) A, a¼90.00 , b¼93.76(1) ,
3
g¼90.00ꢁ, V¼2353.0(4) A , T¼296(2) K, Z¼8, F(000)¼912, Dx¼
˚
1.204 Mg/m3, m¼0.577 mmꢀ1
. Intensity data were collected on an
Enraf-Nonius CAD4 four-circle diffractometer (graphite monochromator;

L. Fila´k et al. / Tetrahedron 64 (2008) 1101e1113
1113
˚
Cu Ka radiation, l¼1.54180 A) at 296(2) K in the range 4.55ꢃq
Synthesis 2005, 1340; (c) Sako, M.; Kawada, H. J. Org. Chem. 2004,
69, 8148.
ꢃ74.83ꢁ using u/2q scans. Backgrounds were measured 1/2 the total
time of the peak scans. The intensities of three standard reflections
were monitored regularly (every 60 min). The intensities of the standard
reflections indicated a crystal decay of 1% (the data were corrected for
decay). A total of 5132 reflections were collected of which 2401 were
unique [R(int)¼0.0112, R(s)¼0.0113]; intensities of 2049 reflections
were greater than 2s(I ).14 Completeness to q¼0.988. An empirical
absorption correction15 was applied to the data (the minimum and maxi-
mum transmission factors were 0.723 and 0.869). The initial structure
model was provided by direct methods16 (and subsequent difference syn-
theses). Anisotropic full-matrix least-squares refinement on F2 for all non-
hydrogen atoms17 yielded the final model (R1¼0.0389 and wR2¼0.1245
for 2049 [I>2s(I )] and R1¼0.0433 and wR2¼0.1288 for all (2401) inten-
sity data, GOF¼1.064). The maximum and minimum residual electron
12. Timari, G.; Soos, T.; Hajos, Gy.; Messmer, A.; Nacsa, J.; Molnar, J.
Bioorg. Med. Chem. Lett. 1996, 23, 2831.
13. Wallace, J. D.; Klauber, J. D.; Chen, C.; Volante, P. R. Org. Lett. 2003, 24,
4749.
14. Harms, K. XCAD4 Data Reduction Program for CAD4 Diffractometers;
Philipps-Universitat Marburg: Germany, 1996.
¨
15. Reibenspies, J. DATCOR Program for Empirical Absorption Correction;
Texas A & M University: College Station, TX, 1989.
16. Sheldrick, G. M. SHELXS-97 Program for Crystal Structure Solution;
University of Gottingen: Gottingen, Germany, 1997.
17. Sheldrick, G. M. SHELXL-97 Program for Crystal Structure Refinement;
¨
¨
University of Gottingen: Gottingen, Germany, 1997.
¨
¨
18. Johnson, F.; Nasatavicus, W. A. J. Org. Chem. 1962, 27, 3953.
19. Win, H.; Tickelmann, H. J. Org. Chem. 1967, 32, 359.
density in the final difference map was 0.17 and ꢀ0.15 e Aꢀ3. Hydrogen
˚
atomic positions, calculated from assumed geometries, were included in
structure factor calculations but they were not refined. The isotropic dis-
placement parameters of the hydrogen atoms were approximated from
the U(eq) value of the atom to which they were bonded.22
20. (a) Suzuki, H.; Abe, H. Synthesis 1995, 763; (b) Hiroya, K.; Jouka, R.;
Kameda, M.; Yasuhara, A.; Sakamoto, T. Tetrahedron 2001, 57, 9697.
21. Onaka, M.; Seki, T.; Masui, Y. J. Synth. Org. Chem. Jpn. 2005, 63, 492.
22. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographyc Data
Centre as supplementary publication number CCDC 656158. Copies of
the data can be obtained, free of charge, on application to CCCD, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44(0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
9. Hajos, G.; Messmer, A. J. Heterocycl. Chem. 1976, 13, 881.
10. Yadav, J. S.; Subba Reddy, B. V.; Muralidhar Reddy, M. Tetrahedron Lett.
2000, 41, 2663.
11. (a) Subbotina, O. J.; Fabian, W.; Tarasov, V. E.; Volkova, N. N.; Bakulev,
A. V. Eur. J. Org. Chem. 2005, 2914; (b) Widyan, K.; Kurz, T.