A versatile synthesis of pyrazolo[3,4-c]isoquinoline derivatives by reaction of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes: The effect of the heterocycle on the reaction pathways

Article abstract of DOI:10.1039/b417002d

The reaction of 4-(3,4-dimethoxyphenyl)-5-aminopyrazoles 7A-D with aromatic and heterocyclic aldehydes in strong acidic media (trifluoroacetic or formic acid) has been studied. The initial azomethine derivatives 8 undergo cyclization similar to the Pictet

Full text of DOI:10.1039/b417002d

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A R T I C L E
A versatile synthesis of pyrazolo[3,4-c]isoquinoline derivatives by
reaction of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes:
the effect of the heterocycle on the reaction pathways
Sergei L. Bogza,*a Konstantin I. Kobrakov,b Anna A. Malienko,a Igor F. Perepichka,*a,c
Sergei Yu. Sujkov,a Martin R. Bryce,*c Svetlana B. Lyubchik,a Andrei S. Batsanovc and
Natalya M. Bogdana
a L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National
Academy of Sciences of Ukraine, Donetsk, 83114, Ukraine. E-mail: i_perepichka@yahoo.com
b A. N. Kosygin State Textile Academy, Moscow, 117918, GSP-1, Russia
c Department of Chemistry, University of Durham, Durham, DH1 3LE, U.K.
E-mail: i.f.perepichka@durham.ac.uk, m.r.bryce@durham.ac.uk; Fax: +44 191 334 2018
Received 9th November 2004, Accepted 12th January 2005
First published as an Advance Article on the web 8th February 2005
The reaction of 4-(3,4-dimethoxyphenyl)-5-aminopyrazoles 7A–D with aromatic and heterocyclic aldehydes in strong
acidic media (trifluoroacetic or formic acid) has been studied. The initial azomethine derivatives 8 undergo
cyclization similar to the Pictet–Spengler condensation to form the intermediate 4,5-dihydroisoquinolines 9 which
readily dehydrogenate giving 5-aryl(heteroaryl)-pyrazolo[3,4-c]isoquinoline derivatives 10 as the final products.
Whereas for benzaldehyde and its derivatives this one-pot synthesis presents a convenient general route to
5-aryl-pyrazolo[3,4-c]isoquinolines 10, in the case of heterocyclic aldehydes the product structure varies markedly
with the structure of the aldehyde used: (i) 3-pyridyl-, 3-quinolyl-, 3-thienyl-, and 1,2,3-thiadiazolyl-5-
carboxaldehydes give 5-heteroarylpyrazolo[3,4-c]isoquinolines; (ii) 1-methylbenzimidazolyl-2-carboxaldehyde gives
only intermediate azomethine 8Dh, which does not cyclize; (iii) 1-R-3-indolylcarboxaldehydes (R = H, CH3, CH2Ph)
eliminate the heteroaryl fragment resulting in 5-unsubstituted pyrazolo[3,4-c]isoquinolines 11. Thienyl-2-
carboxaldehyde reacts by both pathways (i) and (iii) depending on the reaction conditions. The single crystal X-ray
structures for 10Dj, 10Cd and 11D provide confirmation of the different types of products formed in these reactions.
Mechanisms which explain these transformations are presented.
Recently, we found that cyclization of 5-aminopyrazoles
Introduction
with formaldehyde under Pictet–Spengler conditions provides
Condensed polyazaaromatic ring systems are present in a variety
of biologically active compounds (both naturally-occurring and
exclusively 5-unsubstituted pyrazolo[3,4-c]isoquinolines.23 The
aromatic pyrazole ring annelated to the dihydroisoquinoline
synthetic). Although a large number of methods for their
moiety makes the molecule highly reactive towards oxygen/air
syntheses have been documented in the literature, many of them
(particularly because of the gain in aromatisation energy), and
require multistep procedures using intermediates which are not
under the reaction conditions yielded exclusively the aromatic
pyrazolo[3,4-c]isoquinoline core.
readily available.1
Pyrazolo[3,4-c]isoquinolines 1 are benzannelated analogues
of pyrazolo[3,4-b]pyridines, the chemical properties and bio-
logical activity of which have recently been extensively studied.2
Among compounds which contain the pyrazolo-pyridine core,
novel antidepressants,3 anxyolitics,4 and platelet aggregation
inhibitors5 have been found. Several routes to pyrazolo[3,4-c]-,
pyrazolo[4,3-c]-quinoline and -isoquinoline derivatives 1–46–8
and some other isomers (e.g. pyrazolo[3,4-b]quinolines9 and
pyrazolo[3,4-f ]quinolines10) have been described in the litera-
ture. This interest stems from the wide range of biologi-
cal activity of these polyazaarenes: e.g. as antiinflammatory,
antimalarial, antiallergic, and antiviral agents,11 acetylcholin-
esterase inhibitors,12 selective serotonin re-uptake inhibitors,13
benzodiazepine14 and interleukin 1 antagonists, as well as
11b
agents to displace specific flunitrazepam binding.15 There are
also applications in materials science: pyrazolo[3,4-b]quino-
ꢀ
ꢀ
16a,b
16a,c,d
lines,
dipyrazolo[3,4-b;4 ,3-e]pyridines
and pyrazolo[3,4-b]-
quinoxalines17 are efficient emitting materials for multilayer
organic light emitting diodes (OLED) with bright blue electrolu-
minescence. Additionally, some related tetrahydropyrazolo[3,4-
c]isoquinoline 518 and 4,5-dihydropyrazolo[3,4-c]isoquinolin-
5(4H)-one 619 derivatives are known in the literature.
Whereas the classical Pictet–Spengler reaction and its many
variations are convenient routes to tetrahydroisoquinolines,
sometimes with high stereoselectivity,20–22 further dehydration
into isoquinolines is not always an easy or high yielding reaction.
9 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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In the present paper we study in detail the reaction of 4-
(3,4-dimethoxyphenyl)-5-aminopyrazoles with various aromatic
(benzaldehydes) and heterocyclic aldehydes (pyridine, quinoline,
thiophene, indole, benzimidazole and 1,2,3-thiadiazole deriva-
tives) and establish that different products are formed depending
upon the structure of the aldehydes used. This is especially the
case for heterocyclic aldehydes, for which reaction mechanisms
are discussed.
as no other oxidants/dehydrogenating agents are present in the
reaction mixture. To prove this we performed the reaction under
nitrogen (starting from both aminopyrazoles 7 and azomethines
8). Whereas under nitrogen azomethines 8 can be obtained
from 7 in similar very high yields, prolonged reflux of 7 or
8 in trifluoroacetic or formic acid resulted in tars containing
only trace amounts of compounds 10 (TLC evidence), and no
intermediates 9 were isolated.
The course of the reaction of aminopyrazoles 7 with five-
membered heterocyclic aldehydes depends markedly on the
nature of the heterocycle. Thus, whereas reaction of 7B
with 1,2,3-thiadiazolyl-5-carboxaldehyde gave the pyrazolo[3,4-
c]isoquinoline derivative (10Bg) (Scheme 1), in contrast, 1-
methylbenzimidazolyl-2-carboxaldehyde resulted in azomethine
8Dh only, which was stable under the reaction conditions
(Scheme 2). A possible reason for the failure of azomethine
8Dh to cyclize could be that protonation occurs preferentially
on the imidazole ring thereby delocalizing the positive charge on
the benzimidazolium fragment [(8Dh-H+)ꢀ and (8Dh-H+)ꢀꢀ] and
hence decreasing the reactivity of 8Dh-H+.
Results and discussion
Synthesis
Starting aminopyrazoles 7A–D have been prepared by reaction
of the corresponding ethyl carboxylates R1CH2CO2Et (R1 =
Ph, Et, CH2Ph, Me) with 3,4-dimethoxyphenylacetonitrile in
the presence of sodium 2-propylate to yield a-propionyl-3,4-
dimethoxyphenylacetonitrile, and further reaction of the latter
with phenylhydrazine, similar to the procedures described in the
8a,c,d
literature.
5-Aminopyrazoles 7A,C,D reacted with aromatic aldehydes
(benzaldehyde, 3-chlorobenzaldehyde, 4-nitrobenzaldehyde or
4-diethylaminobenzaldehyde) in trifluoroacetic or formic acids
yielding 5-arylpyrazolo[3,4-c]isoquinolines 10Aa,10Cb,10Cd,
10Dc, respectively (Scheme 1),24 in 46–72% yields, i.e. the
reaction followed the same course as the reaction of 5-
aminopyrazoles with formaldehyde.23 The reaction with 3-
pyridyl- and 3-quinolyl-carboxaldehydes proceeded in a similar
manner, yielding analogues 10e,f, respectively.
Carrying out the reaction at reflux did not allow the isolation
or detection of any intermediates in the reaction. However,
1H NMR monitoring of the reaction of aminopyrazole 7D
with quinolyl-3-carboxaldehyde at 15–20 ◦C indicated that in
the first step the azomethine derivative 8 is formed, which
can be isolated in high to near-quantitative yields. Subsequent
cyclization of 8 in trifluoroacetic or formic acid and oxidation
of the derived 4,5-dihydropyrazolo[3,4-c]isoquinoline 9 results
in compound 10Df. We suggest that the limiting step in the
transformation of 8 into 10 is the cyclization of azomethine
8, because 4,5-dihydropyrazolo[3,4-c]isoquinolines 9 were not
detected among the products nor in the reaction mixture during
the reaction. Obviously, oxygen from the air is responsible for
the transformation of 9 into 10 (or at least it is the main oxidant),
The most interesting and unexpected results were obtained
from the reactions of formyl derivatives of thiophene and in-
dole. Thus, reaction of thienyl-3-carboxaldehyde with aminopy-
razole 7B resulted in pyrazolo[3,4-c]isoquinoline 10Bi (76%
yield) (Scheme 3). In contrast, heating aminopyrazoles 7A
or 7D for 0.5–1 h with equimolar amounts of thienyl-2-
carboxaldehyde resulted in a more complex transformation to
give 11A and 11D in low yields. Their analytical data (1H and
13C NMR spectra, combined with mixed melting point data)
were identical to the products obtained from aminopyrazoles
7 and paraformaldehyde,23 i.e. 5-unsubstituted pyrazolo[3,4-
c]isoquinolines 11 (Scheme 3). Incontrovertible proof of the
structure of compound 11D, synthesized according to Scheme 3,
was obtained by single-crystal X-ray analysis (see below).
The same products 11 were isolated when 1-R-indolyl-3-
carboxaldehydes (R = H, CH3, CH2Ph) were used in the
reaction. To clarify this unusual behavior we monitored, by TLC
1
and H NMR, the reaction of aminopyrazole 7D with thienyl-
2-carboxaldehyde and 1-R-indolyl-3-carboxaldehydes in trifluo-
roacetic acid at 15–20 ◦C. The reactions were complete after 60–
80 days. For thienyl-2-carboxaldehyde, two main products were
isolated (total yield 35%), viz. pyrazolo[3,4-c]isoquinoline 11D
and 5-(2-thienyl)pyrazolo[3,4-c]isoquinoline 10Dj (Scheme 3).
Scheme 1 Synthesis of pyrazolo[3,4-c]isoquinolines 10.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0
9 3 3

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Scheme 2 Synthesis of azomethine 8Dh and explanation of its stabilization toward further cyclization into pyrazolo[3,4-c]isoquinoline.
Scheme 3 Reaction pathways of aminopyrazoles 7 with thiophene-3- and thiophene-2-aldehydes.
(The X-ray crystal structure of 10Dj is given below). Heating
From these observations we conclude that the formation of
compounds 11 accompanied by cleavage of the heterocycle
moiety is different from the reaction of 5-aminopyrazoles
7 with other aromatic and heterocyclic carboxaldehydes (a–
g,i), which proceed via an “azomethine formation–cyclization–
oxidative aromatization” route. The difference between thienyl-
2- or indolyl-3-carboxaldehydes on the one hand, and carbox-
aldehydes (a–g,i) on the other hand, is that in the former two
compounds the formyl group is in the position of maximal
electron density of these electron rich heterocycles, which is
easily protonated.25 It is also known that electron withdrawing
substituents on C-2 of thiophene and C-3 of indole are
relatively easily eliminated by the action of strong acids,26 and
that 3-alkyl(aryl)-indoles are easily isomerized.27 As a result,
protonated azomethine 8-H+ could cyclize into protonated
dihydroisoquinoline derivative 9-H+, from which elimination of
indole (or thiophene) would give 11 (Scheme 4).
compound 10Dj in trifluoroacetic acid at reflux temperature
did not give 11D, which establishes that in the transformations
7→11 (and 8→11) elimination of the 2-thienyl fragment occurs
before the formation of the pyrazolo[3,4-c]isoquinoline core.
The reaction conditions and yields for all the above described
transformations are given in Table 1.
The reaction of aminopyrazole 7D with 1-methyl- or 1-benzyl-
indolyl-3-carboxaldehyde only gave product 11D whether the
reaction was carried out at reflux for 10–12 h or at room temper-
ature for 60–90 days. In the case of indolyl-3-carboxaldehyde, in-
termediate azomethine 8Dk was isolated when the reaction was
carried out at room temperature for several hours. Further heat-
ing of compound 8Dk in trifluoroacetic acid gave 11D as the only
product (Scheme 4). Moreover, the same product 11D was also
obtained in similar yields when aminopyrazole 7D or azome-
thine 8Dg were heated in trifluoroacetic acid under nitrogen.
9 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0

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Table 1 Reaction conditions, products and their yields in the reaction of aminopyrazoles 7 with aryl/heteroaryl aldehydes
R1
R2
Starting compound Product Yield
Conditions
Ph
Ph
7A
7C
7C
7D
7A
7B
7C
7D
7D
10Aa
10Cb
10Cd
10Dc
10Ae
10Be
10Ce
10Df
8Df
67%
74%
46%
72%
71%
66%
69%
70%
88%
75%
69%
76%
CF3CO2H, reflux, 3–5 h (or HCO2H, reflux, 10–12 h)
CF3CO2H, reflux, 3–5 h (or HCO2H, reflux, 10–12 h)
CF3CO2H, reflux, 3–5 h (or HCO2H, reflux, 10–12 h)
CF3CO2H, reflux, 3–5 h (or HCO2H, reflux, 10–12 h)
CF3CO2H, reflux, 3–5 h
CF3CO2H, reflux, 3–5 h
CF3CO2H, reflux, 3–5 h
CF3CO2H, reflux, 3–5 h
r.t., 1.5–2 h.
CF3CO2H, reflux, 3–5 h
CF3CO2H, reflux, 3–5 h
PhCH2 3-ClPh
PhCH2 4-Et2NPh
Me
Ph
Et
4-NO2Ph
3-Pyridyl
3-Pyridyl
PhCH2 3-Pyridyl
Me
Me
Me
Et
Et
Ph
3-Quinolyl
3-Quinolyl
1-Methyl-benzimidazolyl-2- 7D
1,2,3-Thiadiazolyl-5-
3-Thienyl
H
H
2-Thienyl
H
3-Indolyl
H
8Dh
7B
7B
7A
7D
7D
10Bg
10Bi
11A
11D
10Dj
11D
CF3CO2H, reflux, 3–5 h
15–26% CF3CO2H, reflux, 3–5 ha
15–22% CF3CO2H, reflux, 3–5 ha
Me
Me
21%
14%
17%
15%
CF3CO2H, 15–20 ◦C, 80–90 d; thienyl-2-carboxaldehyde
Me
7D
8Dk
11D
CF3CO2H, 15–20 ◦C, 60 d; indolyl-3-carboxaldehyde
a Reaction with either thienyl-2-, indolyl-3-, 1-methylindolyl-3-, or 1-benzylindolyl-3-carboxaldehyde.
Scheme 4 Abstraction of indole moiety in condensation of aminopyrazoles 7A,D with indole-3-aldehyde resulting in 5-unsubstituted pyra-
zolo[3,4-c]isoquinolines 11A,D.
X-Ray molecular structures of compounds 10Dj,11D and 10Cd†
The structures of 10Dj,11D·MeCN and 10Cd were confirmed
by X-ray crystallography (Figs 1–3). These are the first struc-
turally characterized pyrazolo[3,4-c]isoquinolines, similar in
bond distances to pyrazolo[3,4-b]pyridine derivatives.28 The
fused tricyclic system is planar within experimental error in 11D
and slightly puckered in 10Dj and 10Cd: the average atomic
˚
r.m.s. deviations average 0.005 (11D), 0.028 (10Dj) and 0.029 A
˚
(10Cd), the maximum ones being 0.014, 0.057 and 0.077 A,
respectively. In 10Dj the puckering can be described as planar
pyrazolopyridine and benzene moieties forming an angle of 3.1◦;
in 10Cd it is more irregular. In each case, both methoxy groups
adopt in-plane conformations, the twists around the C1–O1 and
† CCDC reference numbers 232595–232597. See http://www.rsc.org/
suppdata/ob/b4/b417002d/ for crystallographic data in .cif or other
electronic format.
Fig. 1 Molecular structure of compound 10Dj.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0
9 3 5

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Fig. 2 Molecular structure of 11D·CH3CN.
Fig. 3 Molecular structure of compound 10Cd.
Fig. 4 Crystal packing of 11D (a), and molecule overlap in single
crystals of 11Dj (b) and 11D (c).
C2–O2 bonds ranging from 0.5 to 5.9◦. The aryl substituents are
not coplanar with the fused system: the twist around the N2–
C11 bond equals 33.9◦ (10Dj), 19.9◦ (11D) and 20.5◦ (10Cd),
that around the C9–C20 bond 39.3◦ (10Dj) and 48.7◦ (10Cd).
The N4 atom in 10Cd has substantial sp2 character (the sum of
the bond angles = 359.0◦) and is conjugated with the phenylene
group (the twist around the C23–N4 bond is 6.2◦).
(B) the dihydropyrazolo[3,4-c]isoquinolines eliminate the het-
erocycle with no oxidation step.
The products formed in the reaction of aminopyrazole 7D
and thienyl-2-carboxaldehyde at ambient temperature exemplify
both transformations of intermediate 8Dj (Scheme 3), i.e.
pathways (A) and (B) are concurrent processes with comparable
reaction rates. On the other hand, the absence of the products
of type 10 in the reaction of aminopyrazoles with indolyl-
3-carboxaldehydes indicates that pathway (B) is dominant
(Scheme 4) as 3-indolyl is a better leaving group than 2-thienyl.
The more p-electron rich indole is more readily protonated at its
C-3 position in intermediate 9-H+ (as compared to protonation
at C-2 in the analogous thienyl derivative) and subsequent
elimination of indole affords 5-unsubstituted derivatives 11. If
protonation is favoured at a site other than the imine bond [as
in 8Dh-H+ (Scheme 2)] then cyclization is inhibited and the
azomethine derivative is the only isolated product.
We are currently extending the scope of this synthetic route
by replacing the donor dimethoxybenzene group in structure 7
with electron rich heterocycles. Initial results establish that 4-
(3-indolyl)-4-aminopyrazole derivatives undergo the cyclization
reaction, thus offering a convenient route to novel heterocyclic
systems with an annelated indole moiety, potentially interesting
for selective dopamine receptor binding.29
Applications of organic materials in molecular electronics,
for example LEDs based on structurally related pyrazolo-
quinolines, pyrazolo-pyridines and pyrazolo-quinoxalines,16,17
often require consideration of p–p interactions in the system
and their crystal arrangements. For the molecules considered,
the crystal packing of 10Dj and 11D is dominated by stacks
of dimethoxy-pyrazoloisoquinoline moieties (Fig. 4). In 11D
the adjacent moieties are related via inversion centers and
thus strictly parallel; the interplanar separations (alternating
˚
between 3.31 and 3.35 A) indicate a close packing mode,
phenyl substituents and the acetonitrile of crystallization fill
the interstack gaps. In 10Dj the adjacent moieties are related
by a c glide plane and are slightly (by 0.8◦) non-parallel; the
˚
mean interplanar separation (3.47 A) is larger than in 11D. No
continuous stacks exist in the structure of 10Cd.
Conclusions
In conclusion, we have established a general one-pot synthesis
of a wide range of pyrazolo[3,4-c]isoquinoline derivatives by
reaction of readily available 4-aryl-5-aminopyrazoles 7 with ben-
zaldehydes and heterocyclic aldehydes under acidic conditions.
The key azomethine intermediates 8 can undergo the following
transformations:
Experimental
General
(A) protonation of the azomethine C N bond and its
1H and 13C NMR spectra were recorded on Varian Mercury and
Varian Unity 300 instruments, operating at 200 and 300 MHz
=
cyclization (Pictet–Spengler type) to afford unstable dihydro-
pyrazolo[3,4-c]isoquinolines 9, which are oxidized to 5-aryl-
(heteroaryl)-pyrazolo[3,4-c]isoquinolines 10. This is the path-
way for pyridyl-, quinolyl-, thienyl-3- and 1,2,3-thiadiazolyl-5-
carboxaldehydes, as well as for benzaldehydes;
1
(for H), respectively. Chemical shifts were measured in ppm,
relative to tetramethylsilane (TMS) as internal reference. Elec-
tron impact (EI) mass spectra were recorded on a Micromass
AutoSpec spectrometer operating at 70 eV.
9 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0

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8c,d
8a
The aminopyrazoles 7A
and 7C were prepared as de-
General procedure for the 5-aryl-7,8-dimethoxypyrazolo[3,4-c]-
scribed previously.
isoquinolines 10Aa,10Cb,10Cd,10Dc
A solution of aminopyrazole 7 (5 mmol) and the correspond-
ing arylaldehyde (5.5 mmol) in trifluoroacetic or formic acid
(20 cm3) was refluxed (3–5 h for trifluoroacetic acid and 10–12 h
for formic acid). The solvent was evaporated and the product was
precipitated with 5% ammonia, filtered off, washed with water
and recrystallized from isopropanol and then from acetonitrile
affording colorless (10Aa and 10Cb) or light yellow (10Cd and
10Dc) solids.
1-Phenyl-3-ethyl-4-(3,4-dimethoxyphenyl)-5-amino-
pyrazole (7B)
To a warm solution of sodium 2-propylate [prepared from
sodium (3.9 g, 0.17 g-atom)] and 2-propanol (120 cm3), a
solution of 3,4-dimethoxyphenylacetonitrile (20.0 g, 0.113 mol)
and ethyl propionate (26 cm3, 0.24 mol) in 2-propanol (55 cm3)
was slowly added (WARNING: the mixture foams). The mixture
was heated with a steam bath for 4 h (crystallization of
a-propionyl-3,4-dimethoxyphenylacetonitrile sodium salt was
observed after 2.5 h) and left at room temperature overnight.
The precipitate was filtered off, washed with◦cool 2-propanol
(3 × 30 cm3), ether and dried in vacuo at 30 C. The resulting
a-propionyl-3,4-dimethoxyphenylacetonitrile sodium salt was
dissolved in water (250 cm3) and acidified with 10% aqueous HCl
to pH 2. After 2 h, the aqueous solution was decanted from the
oil; the oil was dissolved in toluene (150 cm3), and the aqueous
solution was extracted with toluene (2 × 50 cm3). The combined
toluene solutions were washed with water (until pH 7), dried
with Na2SO4 and the solvent was removed in vacuo resulting in
a-propionyl-3,4-dimethoxyphenylacetonitrile (21.0 g, 80%) as
an oil, which was used in the next step without purification.
A solution of a-propionyl-3,4-dimethoxyphenylacetonitrile
(21.0 g, 0.09 mol), phenylhydrazine (14.6 g, 0.135 mol) and
glacial acetic acid (1.0 cm3) in 2-propanol (200 cm3) was refluxed
for 6–8 h and the solvent was removed in vacuo. The residue
was stirred with water for 1 h, filtered off and recrystallized
from a minimal amount of 2-propanol affording compound 7B
(19.4 g, 67% based on 3,4-dimethoxyphenylacetonitrile), mp
87–88 ◦C (decomp.). The purity of the sample was suitable
for further syntheses. Additional crystallization from methanol
gave analytically pure 7B (16.5 g, 51%), mp 88.0–88.3 C. H
NMR (200 MHz, CDCl3): d 1.18 (3H, t, J = 8 Hz, CH3), 2.67
(2H, q, J = 8 Hz, CH2), 3.77 (2H, br.s., NH2), 3.89 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 6.86–6.96 (3H, m), 7.30 (1H, t, 3J =
7.24 Hz), 7.50 (2H, t, 3J = 7.24 Hz), 7.62 (2H, d, 3J = 7.24 Hz).
13C NMR (50 MHz, DMSO-d6): d 12.79 (CH3), 20.03 (CH2),
55.35 (OCH3), 55.54 (OCH3), 103.54, 112.55, 112.94, 120.80
(2C), 122.74, 125.77, 125.83, 128.80 (2C), 139.19, 142,89, 147.03,
148.86, 150.98. MS (EI): m/z 323 (M+, 100%). IR (m/cm−1):
3350, 1610, 1600, 1585, 1510, 1500, 1465, 1385, 1330, 1280,
1235, 1170. Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N,
12.99. Found: C, 70.50; H, 6.48; N, 13.10%.
10Aa: yield 67%, mp 199–200 ◦C. 1H NMR (200 MHz,
DMSO-d6): d 3.66 (3H, s, OCH3), 3.70 (3H, s, OCH3), 7.35
(1H, t, Jp = 7.4 Hz, N–Ph-p), 7.41 (1H, s, C-6), 7.53 (1H, s,
–
m
C-9), 7.70–7.55 (8H, m, m,p-Ph, N–Ph-m), 7.77 (2H, dd, Jo
=
=
–
–
m
8.1 Hz, Jo p = 1.8 Hz, o-Ph), 7.88 (2H, dd, Jo m = 8.1 Hz, Jo
–
–
p
1.8 Hz, o-Ph), 8.35 (2H, d, Jo = 7.9 Hz, N–Ph-o). 13C NMR
–m
(50 MHz, DMSO-d6): d 55.18 (OCH3), 55.22 (OCH3), 102.20,
107.13, 108.15, 118.11, 121.22 (2C), 126.02, 127.37, 128.44 (2C),
128.65 (2C), 128.94 (2C), 129.05 (2C), 129.36 (2C), 129.70 (2C),
133.67, 139.12, 139.29, 145.21, 146.57, 147.79, 152.92, 159.03.
MS (EI): m/z 457 (M+, 100%). IR (m/cm−1): 1625, 1600. Anal.
Calcd for C30H23N3O2 (M.W. 457.19): C, 78.75; H, 5.07; N, 9.18.
Found: C, 78.71; H, 5.00; N, 9.25%.
◦
1
10Cb: yield 74%, mp 193.5–195 C. H NMR (300 MHz,
DMSO-d6): d 3.70 (3H, s, CH3O), 3.77 (3H, s, CH3O), 4.72
(2H, s, CH2), 7.22 (1H, t, J = 6.7 Hz), 7.27–7.38 (7H, m),
7.52–7.66 (4H, m), 7.30 (1H, m), 7.82 (1H, s), 8.33 (2H, d,
J = 7.8 Hz). 13C NMR (75 MHz, DMSO-d6): d 34.51 (CH2),
55.17 (OCH3), 55.79 (OCH3), 103.06, 107.52, 107.94, 117.60,
120.91 (2C), 125.69, 126.44, 127.31, 128.19 (2C), 128.40, 128.65
(2C), 128.79, 129.04 (2C), 129.31, 130.19, 133.25, 138.17, 139.16,
141.38, 144.09, 146.75, 147.61, 153.23, 157.12. MS (EI): m/z
505 (M+, 81%). Anal. Calcd for C31H24ClN3O2 (M.W. 505.99):
C, 73.58; H, 4.78; N, 8.30. Found: C,◦73.67; H, 4.84; N, 8.22%.
◦
1
1
10Cd: yield 46%, mp 200–200.5 C. H NMR (300 MHz,
DMSO-d6): d 1.16 (6H, t, J = 6.9 Hz, CH3CH2), 3.44 (4H, q,
J = 6.9 Hz, CH3CH2), 3.75 (6H, s, OCH3), 4.71 (2H, s, CH2Ph),
6.84 (2H, d, J = 7.8 Hz), 7.22 (1H, t, J = 6.8 Hz), 7.28 (1H, s),
7.29–7.38 (5H, m), 7.57 (2H, t, J = 7.8 Hz), 7.62 (1H, s), 7.66
(2H, d, J = 8.4 Hz), 8.42 (2H, d, J = 8.1 Hz). 13C NMR (75 MHz,
DMSO-d6): d 12.41 (2CH3), 34.54 (CH2Ph), 43.58 (2CH2CH3),
55.19 (OCH3), 55.65 (OCH3), 103.09, 106.94, 108.55, 110.70
(2C), 117.61, 120.56 (2C), 125.32, 125.54, 126.37, 127.28, 128.17
(2C), 128.61 (2C), 128.97 (2C), 131.20 (2C), 138.30, 139.47,
144.01, 147.19, 147.34, 147.84, 152.74, 159.16. MS (EI): m/z 542
(M+, 100%), 527 (M+ − CH3, 34%). Anal. Calcd for C35H34N4O2
(M.W. 542.67): C, 77.46; H, 6.32; N, 10.32. Found: C, 77.36; H,
6.28; N, 10.40%.
1-Phenyl-3-benzyl-4-(3,4-dimethoxyphenyl)-5-
aminopyrazole (7C)
10Dc: yield 72%, mp 260–262 ◦C (decomp.). 1H NMR
(200 MHz, DMSO-d6): d 2.91 (3H, s, CH3), 3.77 (3H, s, OCH3),
4.09 (3H, s, OCH3), 7.29 (1H, t, Jp = 7.0 Hz, N–Ph-p), 7.34
–m
This compound was obtained from 3,4-dimethoxyphenylaceto-
nitrile, ethyl phenylacetate and phenylhydrazine as described for
7B. Yield 83%, mp 127–128 ◦C (decomp.) (from 2-propanol).
(1H, s, C-6), 7.52 (2H, dd, Jm p = 7.0 Hz, Jm o = 7.7 Hz, N–Ph-
–
–
m), 7.69 (1H, s, C-9), 8.05 (2H, d, J = 8.7 Hz, –PhNO2), 8.27 (2H,
d, Jo = 7.7 Hz, N–Ph-o), 8.41 (2H, d, J = 8.7 Hz, –PhNO2).
–
m
Intermediate
a-phenacetyl-3,4-dimethoxyphenylacetonitrile
MS (EI): m/z 440 (M+, 100%). IR (m/cm−1): 1630, 1605, 1555.
Anal. Calcd for C25H20N4O4 (M.W. 440.45): C, 68.17; H, 4.58;
N, 12.72. Found: C, 68.10; H, 4.47; N, 12.87%.
sodium salt and a-phenacetyl-3,4-dimethoxyphenylacetonitrile
were isolated and used in subsequent reactions with phenyl-
hydrazine without purification. 1H NMR (200 MHz, CDCl3): d
3.62 (3H, s, OCH3), 3.83 (2H, br.s., NH2), 3.87 (3H, s, OCH3),
3.98 (2H, s, CH2), 6.60 (1H, d, J = 1.8 Hz), 6.78 (1H, dd, J =
1.8 Hz, J = 8.24 Hz), 6.86 (1H, d, J = 8.24 Hz), 7.15 (1H,
t J = 4.6 Hz), 7.19–7.27 (4H, m), 7.32 (1H, t, J = 8.0 Hz),
7.48 (2H, t, J = 8.0 Hz), 7.65 (2H, d, J = 8.0 Hz). 13C NMR
(50 MHz, DMSO-d6): d 32.63 (CH2), 55.11 (OCH3), 55.49
(OCH3), 104.38, 112.39, 112.98, 120.84 (2C), 122.88, 125.51,
125.60, 125.99, 126.01, 127.88 (2C), 128.13 (2C), 128.85 (2C),
139.14, 139.80, 142.23, 148.25, 148.75. MS (EI): m/z 385 (M+,
100%). IR (m/cm−1): 3320, 1615, 1600, 1570, 1505, 1495, 1475,
1370, 1320, 1270, 1230, 1170. Anal. Calcd for C24H23N3O2: C,
74.78; H, 6.01; N, 10.90. Found: C, 74.67; H, 5.95; N, 11.00%.
1,3-Diphenyl-5-(3-pyridyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Ae)
A solution of aminopyrazole 7A (1.85 g, 5.0 mmol) and pyridyl-
3-carboxaldehyde (0.59 g, 5.5 mmol) in trifluoroacetic acid
(20 cm3) was refluxed for 3–5 h and the solvent was removed in
vacuo. The product was precipitated with 5% ammonia, filtered
off, washed with water and recrystallized from acetonitrile
affording compound 10Ae (1.62 g, 71%), mp 202.5–204 ◦C. 1H
NMR (200 MHz, DMSO-d6): d 3.66 (3H, s, OCH3), 3.73 (3H, s,
OCH3), 7.32 (1H, s), 7.36 (1H, t, J = 7 Hz), 7.5–7.7 (7H, m),
7.80–7.95 (2H, m), 8.21 (1H, dt, J = 4.6 Hz, J = 1.5 Hz), 8.30
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0
9 3 7

View Article Online
(2H, d, J = 8 Hz), 8.79 (1H, dd, J = 4.6 Hz, J = 1.5 Hz),
8.99 (1H, d, J = 1.5 Hz). 13C NMR (50 MHz, DMSO-d6): d
55.24 (OCH3), 55.27 (OCH3), 102.21, 107.38, 107.53, 118.20,
121.29 (2C), 123.45, 126.13, 127.39, 128.67 (2C), 128.99, 129.08
(2C), 129.35 (2C), 133.53, 135.04, 137.23, 138.99, 145.21, 146.46,
148.06, 149.83, 149.99, 153.11, 156.03. MS (EI): m/z 458 (M+,
37%), 443 (M+ − CH3, 10%), 427 (M+ − OCH3, 4%). IR
(m/cm−1): 1630, 1610, 1595, 1500, 1475, 1420, 1375, 1270, 1180.
Anal. Calcd for C29H22N4O2: C, 75.97; H, 4.84; N, 12.22. Found:
C, 75.90; H, 4.77; N, 12.35%.
1-Phenyl-3-methyl-4-(3,4-dimethoxyphenyl)-5-(quinolyl-3-
ylideneimino)-pyrazole (8Df)
This compound was obtained by stirring equimolar amounts
of aminopyrazole 7D and quinolyl-3-carboxaldehyde in formic
acid at room temperature for 1.5–2 h. Yield 88%, mp 134.5–
135.5 ◦C (from ethanol). 1H NMR (200 MHz, DMSO-d6): d 2.26
(3H, s, CH3), 3.65 (3H, s, OCH3), 3.80 (3H, s, OCH3), 6.95–7.10
(3H, m), 7.39 (1H, t, J = 7.2 Hz), 7.48–7.60 (3H, m), 7.68–7.85
(4H, m), 8.13 (2H, dd, J = 8.8 Hz, J = 10 Hz), 9.02 (1H, d, J =
4.4 Hz), 9.18 (1H, s). 13C NMR (50 MHz, DMSO-d6): d 12.63
(CH3), 55.46 (OCH3), 55.52 (OCH3), 101.31, 110.99, 112.37,
113.34, 120.49, 121.96, 123.30, 123.74 (2C), 124.29, 124.72,
126.77, 127.66, 128.84 (2C), 129.80, 137.52, 138.97, 145.10,
147.42, 148.03, 148.29, 149.06, 150.52, 161.09. MS (EI): m/z
448 (M+, 100%), 433 (M+ − CH3, 10%). IR (m/cm−1): 1635,
1600, 1665, 1510, 1505, 1460, 1410, 1370, 1330, 1270, 1265,
1170, 1150. Anal. Calcd for C28H24N4O2: C, 74.98; H, 5.39; N,
12.49. Found: C, 74.92; H, 5.30; N, 12.63%.
1-Ethyl-3-phenyl-5-(3-pyridyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Be)
This compound was obtained similarly to compound 10Ae from
aminopyrazole 7◦B and pyridyl-3-carboxaldehyde. Yield 66%,
1
mp 212.5–213.5 C (from acetonitrile). H NMR (200 MHz,
DMSO-d6): d 1.48 (3H, t, J = 8 Hz, CH3), 3.30 (2H, q, J =
8 Hz, CH2), 3.77 (3H, s, OCH3), 4.06 (3H, s, OCH3), 7.29 (1H,
t, J = 7.4 Hz), 7.36 (1H, s), 7.53 (2H, t, J = 7.4 Hz), 7.55–7.66
(2H, m), 8.10–8.32 (3H, m), 8.76 (1H, dd, J = 4.8 Hz, J =
1.5 Hz), 8.98 (1H, d, J = 1.5 Hz). 13C NMR (100 MHz, DMSO-
d6, 90 ◦C): d 11.68 (CH3), 21.84 (CH2), 55.28 (OCH3), 55.52
(OCH3), 102.49, 107.32, 108.04, 117.68, 120.35 (2C), 122.86,
124.96, 127.73, 128.42 (2C), 134.91, 136.57, 139.10, 146.44,
146.77, 147.72, 149.21, 149.50, 153.68, 155.23. MS (EI): m/z
410 (M+, 88%), 395 (M+ − CH3, 25%). IR (m/cm−1): 1620,
1610, 1600, 1510, 1470, 1425, 1370, 1270, 1175. Anal. Calcd
for C25H22N4O2: C, 73.15; H, 5.40; N, 13.65. Found: C, 73.04;
H, 5.33; N, 13.75%.
1-Phenyl-3-methyl-4-(3,4-dimethoxyphenyl)-5-(1-methyl-
benzimidazolyl-2-ylideneimino)-pyrazole (8Dh)
This compound was obtained similarly to compound
10Ae from aminopyrazole 7D and 1-methylbenzimidazolyl-2-
carboxaldehyde. Yield 75%, mp 187.5–189 ◦C (from acetoni-
1
trile). H NMR (200 MHz, DMSO-d6): d 2.21 (3H, s, CH3),
3.70 (3H, s, CH3), 3.81 (3H, s, OCH3), 3.99 (3H, s, OCH3),
6.90–7.10 (3H, m), 7.27 (1H, t, J = 7.3 Hz), 7.32–7.76 (8H, m),
8.57 (1H, s). 13C NMR (50 MHz, DMSO-d6): d 12.47 (CH3),
31.90 (NCH3), 55.34 (OCH3), 55.50 (OCH3), 110.76, 110.87,
112.20, 113.12, 120.17, 121.80, 122.89, 124.07, 124.38 (2C),
124.95, 127.00, 128.68 (2C), 136.94, 138.84, 142.39, 143.79,
146.70, 147.64, 148.03, 149.01, 153.64. MS (EI): m/z 451
(M+, 61%), 436 (M+ − CH3, 11%), 420 (M+ − OCH3, 9%),
319 (M+ − N-methylbenzimidazole, 100%), 304 ([M+ − N-
methylbenzimidazole] − CH3, 13%). IR (m/cm−1): 1630, 1610,
1550, 1505, 1470, 1400, 1380, 1325, 1260, 1140. Anal. Calcd for
C27H25N5O2: C, 71.82; H, 5.58; N, 15.51. Found: C, 71.80; H,
5.53; N, 15.50%.
1-Benzyl-3-phenyl-5-(3-pyridyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Ce)
This compound was obtained similarly to compound 10Ae from
aminopyrazole 7C and pyridyl-3-carboxaldehyde. Yield 69%,
mp 202.5–203 ◦C (from acetonitrile). 1H NMR (200 MHz,
DMSO-d6): d 3.73 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.76
(2H, s, CH2), 7.15–7.40 (8H, m), 7.50–7.70 (3H, m), 8.24 (1H,
dt, J = 8.0 Hz, J = 1.5 Hz), 8.35 (2H, d, J = 8.4 Hz), 8.77 (1H,
dt, J = 5.0 Hz, J = 1.5 Hz), 9.01 (1H, m.). 13C NMR (50 MHz,
DMSO-d6): d 34.49 (CH2), 55.23 (OCH3), 55.83 (OCH3), 103.16,
107.36, 107.99, 117.86, 120.92 (2C), 123.42, 125.72, 126.44,
127.33, 128.19 (2C), 128.65 (2C), 129.07 (2C), 135.14, 137.21,
138.18, 139.16, 144.18, 146.90, 147.78, 149.75, 149.99, 153.32,
155.89. MS (EI): m/z 472 (M+, 100%), 457 (M+ − CH3, 18%),
441 (M+ − OCH3, 8%). IR (m/cm−1): 1625, 1610, 1590, 1500,
1470, 1430, 1360, 1265, 1165. Anal. Calcd for C30H24N4O2: C,
76.25; H, 5.12; N, 11.86. Found: C, 76.15; H, 5.07; N, 12.00%.
1-Ethyl-3-phenyl-5-(1,2,3-thiadiazolyl-5)-7,8-
dimethoxypyrazolo[3,4-c]isoquinoline (10Bg)
This compound was obtained similarly to compound 10Ae from
aminopyrazole 7B and 1,2,3-thiadiazolyl-5-carboxaldehyde.
◦
1
Yield 69%, mp 243.5–244.5 C (from acetonitrile). H NMR
(200 MHz, DMSO-d6): d 1.52 (3H, t, CH3, J = 7.5 Hz), 3.37
(2H, q, CH2, J = 7.5 Hz), 3.87 (3H, s, OCH3), 4.10 (3H, s,
OCH3), 7.34 (1H, t, J = 7.2 Hz), 7.57 (2H, dd, J = 7.2 Hz, J =
8.4 Hz), 7.67 (1H, s), 8.32 (2H, d, J = 8.4 Hz), 8.40 (1H, s), 9.92
(1H, s). 13C NMR (50 MHz, DMSO-d6): d 12.73 (CH3), 22.04
(CH2), 55.47 (OCH3), 55.70 (OCH3), 102.47, 107.27, 108.09,
118.34, 120.35 (2C), 125.46, 128.61 (2C), 132.12, 140.53, 151.32,
151.88, 157.24, 164.33, 165.53, 166.12, 168.17. MS (EI): m/z 417
(M+, 100%). IR (m/cm−1): 1625, 1600, 1580, 1530, 1500, 1420,
1370, 1300, 1280, 1265, 1205, 1170. Anal. Calcd for C22H19N5O2S
(M.W. 417.48): C, 63.29; H, 4.59; N, 16.78; S, 7.68. Found: C,
63.21; H, 4.55; N, 16.85; S, 7.57%.
1-Methyl-3-phenyl-5-(3-quinolyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Df)
This compound was obtained similarly to compound 10Ae
from aminopyrazole 7D and quinolyl-3-carboxaldehyde. Yield
70%, mp 243–244 ◦C (from acetonitrile). 1H NMR (200 MHz,
DMSO-d6): d 3.0 (3H, s, CH3), 3.48 (3H, s, OCH3), 4.12 (3H, s,
OCH3), 6.88 (1H, s), 7.25 (1H, t, J = 7.3 Hz), 7.40–7.55 (4H,
m), 7.70–7.90 (3H, m), 8.15–8.30 (3H, m), 8.12 (1H, d, J =
4.4 Hz). 13C NMR (50 MHz, DMSO-d6): d 15.21 (CH3), 55.20
(OCH3), 55.85 (OCH3), 102.26, 107.22, 108.85, 118.57, 120.49
(2C), 122.11, 125.47, 125.62, 126.22, 127.15, 128.01, 129.00 (2C),
129.50, 129.71, 139.16, 142.32, 144.64, 146.35, 147.86, 147.99,
150.19, 153.95, 155.27. MS (EI): m/z 446 (M+, 100%), 431
(M+ − CH3, 17%), 415 (M+ − OCH3, 29%). IR (m/cm−1): 1635,
1600, 1580, 1505, 1470, 1430, 1380, 1270, 1180. Anal. Calcd for
C28H22N4O2: C, 75.32; H, 4.97; N, 12.55. Found: C, 75.24; H,
4.93; N, 12.68%.
1-Ethyl-3-phenyl-5-(3-thienyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Bi)
This compound was obtained similarly to compound 10Ae from
aminopyrazole 7B and thienyl-3-carboxaldehyde. Yield 76%, mp
267–269 ◦C (decomp.) (from acetonitrile). 1H NMR (300 MHz,
DMSO-d6): d 1.51 (3H, t, CH3, J = 7.45 Hz), 3.37 (2H, q, CH2,
J = 7.4 Hz), 3.85 (3H, s, OCH3), 4.06 (3H, s, OCH3), 7.28 (1H,
t, J = 6.7 Hz), 7.53 (2H, t, J = 6.7 Hz), 7.63 (1H, s), 7.66
(1H, s), 7.73 (1H, s), 7.77 (1H, d, J = 1.3 Hz), 8.10 (1H, d,
J = 1.3 Hz), 8.33 (2H, d, J = 6.7 Hz). 13C NMR (75 MHz,
DMSO-d6): d 12.08 (CH3), 22.12 (CH2), 55.49 (OCH3), 55.85
9 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0

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(OCH3), 102.30, 107.17, 108.00, 116.64, 119.78 (2C), 125.11,
128.05, 128.30, 129.00 (2C), 129.35, 139.27, 140.57, 142.07,
143.15, 146.17, 148.24, 150.26, 153.33. MS (EI): m/z 401 (M+,
100%). IR (m/cm−1): 1635, 1600, 1590, 1530, 1500, 1465, 1420,
1390, 1265, 1230, 1160. Anal. Calcd for C24H21N3O2S: C, 69.38;
H, 5.09; N, 10.11; S, 7.72. Found: C, 69.30; H, 5.05; N, 10.27; S,
7.60%.
(M+, 100%), 386 (M+ − CH3, 22%), 371 (MH+ − OCH3, 22%),
319 (MH+ − thiophene, 64%). IR (m/cm−1): 1630, 1600, 1560,
1500, 1420, 1280, 1255. Anal. Calcd for C23H19N3O2S: C, 68.81;
H, 4.77; N, 10.47; S, 7.99. Found: C, 68.70; H, 4.65; N, 10.66; S,
7.95%.
Compound 11D: yield 14%. 1H and 13C NMR spectra of the
sample were identical to those obtained from the reaction in
boiling trifluoroacetic acid as described above.
1,3-Diphenyl-7,8-dimethoxypyrazolo[3,4-c]isoquinoline (11A)
1-Phenyl-3-methyl-4-(3,4-dimethoxyphenyl)-5-(indolyl-3-
ylidenimino)-pyrazole (8Dk) and 1-methyl-3-phenyl-
7,8-dimethoxypyrazolo[3,4-c]isoquinoline (11D)
This compound was obtained similarly to compound 10Ae
from aminopyrazole 7A and heterocyclic aldehyde (thienyl-
2-aldehyde, indolyl-3-aldehyde, 1-methylindolyl-3-aldehyde or
1-benzylindolyl-3-aldehyde). Yields 15–26% depending on the
aldehyde, mp 155.5–156.5 ◦C (from acetonitrile). 1H NMR
(300 MHz, DMSO-d6): d 3.64 (3H, s, OCH3), 3.86 (3H, s, OCH3),
7.31 (1H, t, J = 8 Hz), 7.35 (1H, s), 7.53 (2H, dd, J = 8 Hz,
J = 8 Hz), 7.54 (1H, s), 7.4–7.6 (3H, m), 7.7–7.82 (2H, m), 8.34
(2H, d, J = 8 Hz), 8.91 (1H, s). 13C NMR (75 MHz, DMSO-d6):
d 55.11 (OCH3), 55.42 (OCH3), 102.08, 108.43, 109.20, 120.64
(2C), 121.21, 125.72, 125.89, 127.97, 128.40, 128.45 (2C), 128.84,
129.13 (2C), 129.36 (2C), 131.64, 147.35, 152.13, 160.65, 164.73.
MS (EI): m/z 381 (M+, 100%). IR (m/cm−1): 1625, 1605, 1600,
1530, 1510, 1470, 1425, 1265, 1170. Anal. Calcd for C24H19N3O2
(M.W. 381.43): C, 75.57; H, 5.02; N, 11.02. Found: C, 75.50; H,
4.91; N, 11.20%.
These compounds were obtained following the above method
from aminopyrazole 7D and indolyl-3-carboxaldehyde at room
temperature for 60 days.
Compound 11D: yield 17%.
Compound 8Dk: yield 15%, mp 233.5–235 ◦C (from ethanol).
1H NMR (200 MHz, DMSO-d6) d 2.25 (3H, s, CH3), 3.60 (3H, s,
OCH3), 3.77 (3H, s, OCH3), 6.87 (2H, s + s), 7.0–7.27 (2H, m),
7.22 (1H, t, J = 6 Hz), 7.35 (2H, dd, J = 8 Hz, J = 6 Hz), 7.41
(1H, d, J = 8 Hz), 7.63 (1H, s, N–H), 7.83 (2H, d, J = 8 Hz),
8.23 (1H, d, J = 8 Hz), 8.45 (1H, s), 11.75 (1H, s, N–H). 13C
NMR (50 MHz, DMSO-d6): d 13.11 (CH3), 55.19 (OCH3), 55.32
(OCH3), 108.84, 112.04, 112.10, 113.08, 114.42, 121.30, 121.39,
121.50, 122.90 (2C), 123.05, 124.43, 125.24, 125.82, 128.48 (2C),
135.00, 137.19, 139.54, 146.77, 147.17, 147.73, 148.59, 159.42.
MS (EI): m/z 436 (M+, 100%), 421 (M+ − CH3, 16%), 320
(M+ − C8H6N, 4%). IR (m/cm−1): 3210, 1630, 1610, 1600, 1655,
1515, 1505, 1470, 1405, 1370, 1325, 1265, 1250, 1185, 1140. Anal
Calcd for C27H24N4O2: C, 74.29; H, 5.54; N, 12.83. Found: C,
74.20; H, 5.45; N, 12.90%.
1-Methyl-3-phenyl-7,8-dimethoxypyrazolo[3,4-c]isoquinoline
(11D)
This compound was obtained similarly to compound 10Ae
from aminopyrazole 7D and the heterocyclic aldehyde (thienyl-
2-carboxaldehyde, indolyl-3-carboxaldehyde, 1-methylindolyl-
3-carboxaldehyde or 1-benzylindolyl-3-carboxaldehyde). Yields
15–22% depending on the aldehyde, mp 166–166.5 ◦C (from
X-Ray diffraction†
◦
1
acetonitrile). [Lit.23 mp 166–166.5 C]. H NMR (300 MHz,
Single crystals of compounds 10Dj and 11D were grown from
acetonitrile solution, and compound 10Cd gave single crystals
from DMSO-d6 in an NMR tube.
DMSO-d6): d 2.78 (3H, s, CH3), 3.90 (3H, s, OCH3), 3.99 (3H, s,
3
4
OCH3), 7.30 (1H, tt, J = 7.4 Hz, J = 1.2 Hz, p-Ph), 7.43
3
X-Ray diffraction experiments (see Table 2) for 10Dj and
11D were carried out on a 3-circle diffractometer equipped
with a SMART 1K CCD area detector and a sealed-tube X-
ray source, for 10Cd on a 3-circle diffractometer equipped
with an APEX CCD area detector and a 60 W microfocus
(1H, s), 7.54 (2H, t, J = 7.8 Hz, m-Ph), 7.61 (1H, s), 8.26
3
4
(2H, dd, J = 7.8 Hz, J = 1.2 Hz, o-Ph), 8.93 (1H, s, H-5).
13C NMR (75 MHz, DMSO-d6): d 15.12, 55.56, 55.68, 101.43,
108.24, 108.64, 120.04, 120.53 (2C), 125.37, 126.58, 129.01 (2C),
139.41, 142.11, 147.17, 147.93, 151.02, 153.71. MS (EI): m/z
319 (M+, 100%), 304 (M+ − CH3, 25%). IR (m/cm−1): 1630,
1600, 1595, 1530, 1500, 1450, 1415, 1270, 1170. Anal Calcd for
C19H17N3O2 (M.W. 319.36): C, 71.46; H, 5.37; N, 13.16. Found:
C, 71.44; H, 5.24; N, 13.20%.
R
Bede Microsourceꢀ with glass polycapillary optics. Graphite-
¯
˚
monochromated Mo–Ka radiation (k = 0.71073 A) was used in
both cases. The crystals were cooled using a Cryostream open-
flow N2 cryostat (Oxford Cryosystems). Full sphere of reciprocal
space was covered by five sets of 0.3◦ x scans, each set with
different u and/or 2h angles. The structures were solved by
direct methods and refined by full-matrix least squares against
1-Methyl-3-phenyl-5-(2-thienyl)-7,8-dimethoxypyrazolo[3,4-c]-
isoquinoline (10Dj) and 1-methyl-3-phenyl-7,8-
dimethoxypyrazolo[3,4-c]isoquinoline (11D)
Table 2 Crystal data for compounds 10Dj,11D and 10Cd
A solution of aminopyrazole 7D (5 mmol) and thienyl-2-
Compound
10Dj
11D
10Cd
carboxaldehyde (5 mmol) in trifluoroacetic acid (20 mL) was
◦
1
stirred at 15–20 C for 80–90 days (with TLC and H NMR
monitoring of the reaction). The mixture was treated with 5%
ammonia, filtered off, washed with water and dried. The product
was twice recrystallized from acetonitrile affording pyrazolo[3,4-
c]isoquinoline 10Dj.
Formula
Formula weight
T/K
C23H19N3O2S
401.47
123
C19H17N3O2·C2H3N C35H34N4O2
360.41
120
542.66
120
Symmetry
Orthorhombic Triclinic
Triclinic
¯
¯
Space group
Pca21 (# 29)
22.845(4)
11.858(2)
7.188(1)
90
90
90
1947.2(5)
4
13783
4490
P1 (# 2)
P1 (# 2)
˚
The combined mother liquors were evaporated, and the
residue was twice recrystallized from 2-propanol and then from
acetonitrile affording pyrazolo[3,4-c]isoquinoline 11D.
Compound 10Dj: yield 21%, mp 209.5–210 ◦C (from acetoni-
trile). 1H NMR (300 MHz, DMSO-d6): d 2.85 (3H, s, CH3), 3.91
(3H, s, OCH3), 4.05 (3H, s, OCH3), 7.20–7.40 (2H, m), 7.56 (2H,
dd, J = 7.8 Hz, J = 8.0 Hz), 7.60 (1H, s), 7.86 (1H, d, J =
5.0 Hz), 7.91 (1H, d, J = 5.0 Hz), 7.92 (1H, s), 8.35 (2H, d, J =
7.8 Hz). 13C NMR (50 MHz, DMSO-d6): d 15.17 (CH3), 55.33
(OCH3), 55.73 (OCH3), 102.35, 107.28, 108.02, 116.76, 119.95
(2C), 125.22, 128.19, 128.36, 128.99 (2C), 129.24 (2C), 139.36,
142.17, 143.00, 146.07, 148.14, 150.76, 153.53. MS (EI): m/z 401
a/A
7.086(1)
10.791(3)
12.850(2)
104.16(2)
105.87(2)
95.86(1)
901.2(3)
2
8.944(4)
12.945(5)
13.918(7)
64.13(2)
73.04(2)
81.00(2)
1386(1)
2
˚
b/A
˚
c/A
a/◦
b/◦
c /◦
V/A
Z
3
˚
Refls collected
Unique refls
10258
4128
2988
0.040
10374
5074
2568
0.051
Refls F2 > 2r(F2) 3735
R[F2 > 2 r(F2)]
wR(F2), all data
0.039
0.085
0.105
0.093
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0
9 3 9

View Article Online
F2 of all data, using SHELXTL software.30 Full crystallographic
data, excluding structure factors, are provided in the Electronic
Supplementary Information† and have been deposited at the
Cambridge Crystallographic Data Centre.
10 T. Kawakami, K. Uehata and H. Suzuki, Org. Lett., 2000, 2, 413–
415.
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13 G. M. Shutske and J. E. Roehr, J. Heterocycl. Chem., 1997, 34, 789–
795.
Acknowledgements
We thank The Royal Society (S.B.L.) and The Royal Society
of Chemistry Journals Grant for International Authors (I.F.P.)
for funding visits to Durham, and EPSRC for funding the
improvement to the X-ray instrumentation.
14 L. Cecchi, V. Colotta, F. Melani, G. Palazzino, G. Filacchioni, C.
Martini, G. Giannaccini and A. Lucacchini, J. Pharm. Sci., 1989, 78,
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9 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 3 2 – 9 4 0