Application of modified Pictet-Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines

Article abstract of DOI:10.1016/j.tet.2006.01.063

Two new thiazole and pyrazole-based arylamine substrate have been used for the Pictet-Spengler reaction. This is in contrast to the traditionally used indole/imidazole-based aliphatic amine substrates that has remained in use for the last ～100 years. The

Full text of DOI:10.1016/j.tet.2006.01.063

Tetrahedron 62 (2006) 3228–3241
Application of modified Pictet–Spengler reaction for
the synthesis of thiazolo- and pyrazolo-quinolines*
*
Srinivas Duggineni, Devesh Sawant, Biswajit Saha and Bijoy Kundu
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 11 November 2005; revised 27 December 2005; accepted 19 January 2006
Available online 17 February 2006
Abstract—Two new thiazole and pyrazole-based arylamine substrate have been used for the Pictet–Spengler reaction. This is in contrast to
the traditionally used indole/imidazole-based aliphatic amine substrates that has remained in use for the last w100 years. The condensation
of both the substrates with a variety of aldehydes in the presence of 2% TFA–DCM at 08 for 30 min or pTsOH in toluene at reflux led to the
synthesis of thiazoloquinolines and pyrazoloquinolines, respectively. Unlike aliphatic amine substrates, our substrates readily underwent
Pictet–Spengler cyclization even with aldehydes having electron donating group. The studies are based on a new concept proposed by us that
arylamines linked to an activated heterocyclic ring can lead to a variety of second-generation substrates for the Pictet–Spengler cyclization.
Our studies open up new avenues for the application of Pictet–Spengler reaction beyond syntheses of the tetrahydroisoquinolines and
tetrahydro-b-carbolines.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
histamine or dopamine/tyramine, thereby invariably resul-
ting in the formation of heterocycles based on
either tetrahydro-b-carbolines/tetrahydroimidazopyridines
or tetrahydroisoquinolines.4 Therefore, the challenge of
applying the Pictet–Spengler reaction beyond syntheses of
isoquinolines and b-carbolines appears to be associated with
the limited availability of amine substrates.
For the last w100 years, the Pictet–Spengler reaction1 has
remained as one of the most widely used methods for the
syntheses of isoquinolines and b-carbolines via C–C bond
formation.2 In general, it is a two-step method and involves
acid catalyzed condensation of an aliphatic amine attached
to a sufficiently reactive aromatic nucleus with aldehydes.3
In the first step an imine is formed, which may be activated
by acids and in the second step endo cyclization is affected
between a carbon nucleophile of a sufficiently reactive
aromatic moiety and the activated iminium ion resulting in a
N-heterocyclic ring via a new C–C bond. Over the years,
several groups have studied the detail mechanistic aspects of
this reaction and have developed a number of diastereo- and
enantio-selective methods for the Pictet–Spengler cycliza-
tion.4 It is interesting to note that the method continues to be
a significant focus of research as chemists continue to
improve upon the methodology by applying new reaction
conditions including asymmetric catalysis of the N-acyli-
minium Pictet–Spengler reaction.5 However, despite being
one of the most powerful method, the strategy has remained
unchanged ever since its inception and its use has been
limited to only three amine substrates: Trp/tryptamine, His/
Recently, we described6 a new strategy for the Pictet–
Spengler reaction by using arylamines linked to the N-1
of the imidazole (1 and 2; Fig. 1) as an alternative
substrates instead of traditionally used aliphatic amines
linked to the C-3 of the imidazole. We argued that the
iminium ion derived from an arylamine would facilitate
C–C bond formation better than an aliphatic amine since
enhancement of the electrophilic nature of the iminium
intermediate is known to be the driving force for the
cyclization.7
Though the use of substrates 1 and 2 led to the synthesis of
N-rich heterocycles: imidazoquinoxalines and an unusual
seven membered ring triazabenzoazulenes, both of them
were derived from the imidazole, an activated aromatic
nucleus used traditionally in the Pictet–Spengler reaction.
We envisaged that by applying our new concept of
‘arylamines linked to an activated heterocyclic ring’, a
variety of structurally diverse substrates can be designed
for the Pictet–Spengler reaction, which in turn may lead to
novel benzoannelated heterosystems devoid of any stereo-
chemical issues traditionally associated with a typical
* CDRI communication no. 6785.
Keywords: Thiazoloquinoline; Pyrazoloquinoline; Pictet–Spengler
reaction; C–C bond formation.
Corresponding author. Tel.: C91 522 2262411 18x4383; fax: C91 522
2623405; e-mail: bijoy_kundu@yahoo.com
*
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.063

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3229
R2
R2
N
N
H2N
R2
S
R1
R1
NH2
NH2
HN
N
N
NH2
R1
N
N
R1
NH2
N
N
N
R3
Ph
Ph
4
5
3
1 [Ref 6(a)]
2 [ref 6(b)]
[Present work]
Figure 1. Second generation substrates for the Pictet–Spengler reaction.
Pictet–Spengler reaction (Fig. 2). While the manuscript was
under preparation, Pictet–Spengler reaction was recently
demonstrated on heteroaryl amines linked to an activated
aromatic ring as substrates, which is also in accordance to
our modified strategy.8 In order to test the viability and
generality of our concept, we searched for an entirely new
generation of substrates having aryl amines linked to the C
of an activated heterocyclic ring other than the traditionally
used indoles and imidazoles. In the first instance, we
directed our efforts towards the activated heterocycles
analogous to imidazole. We envisaged that since imidazole
falls under the class of azoles, an arylamine originating from
the azoles other than the imidazole could be equally active
to facilitate the Pictet–Spengler cyclization. After screening
various azoles, our choice ultimately fell for thiazoles and
pyrazoles as an activated heterocyclic rings, which are
common substructures present in many natural and
medicinal compounds. We proposed to link the arylamine
through one of the C in the thiazole and pyrazole ring
instead of the nitrogen (as in substrates 1 and 2) in a manner
to facilitate the Pictet–Spengler cyclization. In order to
select the carbon in both the rings for linking the arylamine,
we analyzed the electrophilic substitution patterns in azoles.
The multiply bonded nitrogen atom present in azoles, is
generally known to have differential deactivating affects on
the carbon atoms in the ring.9 The a- and g-positions to the
multiply bonded N-atom are deactivated towards electro-
philic attack whereas the b-carbon is the least deactivated
and is therefore prone towards electrophilic substitution.
Thus, the C-4 position in the pyrazole while the C-5
position in the thiazole being b to the multiply bonded
nitrogen atom are the positions prone to electrophilic
substitution (Fig. 3).
X
Ar
Ar
NH2
NH2
Ar = Activated heterocyclic ring
(X = C or N)
Ar = Indoles/substituted phenyl/imidazole
HX
R-CHO
R-CHO
HX
X
Ar
N
H
R
X
Ar
N
H
R
X
X
Ar
NH
R
X
Ar
Ar
N
NH
R
R
Traditional strategy
Our modified strategy
Figure 2. Traditional and modified strategies for the Pictet–Spengler reaction.

3230
S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
respectively. Both of them are completely aromatized
Ε
compounds and devoid of any stereochemical centers. This
is in contrast to the traditional Pictet–Spengler reaction
involving substrates based on aliphatic amines linked to an
activated heterocyclic ring, which invariably furnishes
tetrahydro-derivatives with new stereochemical centre.
However, prolonged heating at reflux for 48 h under acidic
conditions has been reported to produce fully aromatic
compounds such as b-carboline.2c Literature survey
for thiazolo- and pyrazolo-quinolines revealed a single
reference for the synthesis of thiazolo[5,4-c]quinoline-2-yl-
amines analogous to our compounds 8 using disubstituted
thioureas and bromine.11 Indeed, a variety of structural
variants such as thiazolo[5,4-b]-,12 thiazolo[4,5-g]-, -[5,4-g]-,
-[4,5-h]-, -[5,4-h]-, -[4,5-f]- and -[5,4-f]-quinolines have been
reported in the literature with antibacterial,13 antispasmo-
dics,14 antiinflammatory15 and antitumor activities.16 Simi-
larly a single reference for pyrazolo[4,3-c]quinoline (CGS
9896), which is analogous to our compounds 12 have been
reported to exhibit nonsedating anxiolytic activity.17 Syn-
thesis of pyrazolo[4,3-c]quinolines have been generally
carried out by treating o-chloro-derivatives of cyano
quinolines with hydrazine hydrate.18 This is in contrast to
our method that involves generation of quinoline ring onto
the pyrazole using the Pictet–Spengler reaction. Structural
variant in the form of pyrazolo[3,4-c]quinoline ring systems
has been reported to exhibit significant biological activities
such as good affinity and selectivity for adenosine A3
receptors, benzodiazepine receptor activity and NMDA
receptor inhibition.19 Another variant, pyrazolo[3,4-b]quino-
lines has been identified as a potential candidate for the blue
light electroluminescent materials.20
β
4α
5
β
α
4
Ν
3
γ5
Ν
Η
S
Ν
Η
Pyrazole
Thiazole
Figure 3. Pattern of electrophilic substitution in pyrazole and thiazole.
Based on these facts, we envisaged that an aryl amine
originating from the g-carbon (C-5) in the pyrazole and
a-carbon (C-4) in the thiazole, which are adjacent to the
b-carbon in both the azoles, might act as novel substrates for
the Pictet–Spengler cyclization. Keeping these structural
requirements in mind, we next analyzed the structures and
synthetic feasibilities of a variety of thiazole and pyrazole
based compounds from the literature, which led to the
identification of [4-(2-amino-phenyl)-thiazol-2-yl]-phenyl-
amine (3) and 2-(2,5-diphenyl-2H-pyrazol-3-yl)-phenyl-
amine (4) as probable substrates for the Pictet–Spengler
reaction (Fig. 1). In the thiazole-based substrate 3, an aryl
amine has been allowed to originate from the C-4 position;
the C-2 position has been derivatized for introducing
diversity while the C-5 has been kept devoid of any
substitution so as to facilitate endo cyclization. Similarly in
the pyrazole-based substrate 4, an aryl amine has been
allowed to originate from the C-5 position, the C-3 has
been derivatized for introducing diversity while the C-4 has
been kept free to facilitate endo cyclization. Interestingly,
for pyrazoles, we had two options available for the
attachment of aryl amine since the C-4 involved in the
cyclization is flanked between the C-5 and C-3. The
arylamine can be linked to either of these two (Fig. 1)
positions resulting in substrates 4 with two-point diversity
and 5 with single diversity, respectively. However, in view
of the higher chemical diversity, we restricted ourself to the
substrate 4 since the synthesis for substrate 5 involves use of
o-nitroacetophenone for which only a limited commercial
diversity is available. In contrast, the synthesis of 4 involves
use of o-nitrobenzaldehydes for which a plenty of diversity
is available commercially. A careful survey of the literature
for substrates 3 and 4 revealed, a single reference wherein
an unsuccessful attempt10 was made to synthesize thiazo-
loquinolines from the thiazole-based substrate 3 using
Bischler–Napieralski reaction.
2. Results and discussion
The synthetic strategy dealing with the application of
substrate 3 for the Pictet–Spengler reaction is depicted in
Scheme 1. Substrate 3 can be readily obtained using
Hantzsch-thiazole synthesis21 by first treating 2-nitro-
phenacyl bromide with thioureas 6 followed by the
reduction of the resulting [4-(2-nitro-phenyl)-thiazol-2-yl]-
phenyl-amine 7 with SnCl2$2H2O. Diversity in thioureas
was introduced by derivatizing one of the NH2’ and this has
been accomplished by treating aryl isothiocyanates with
ammonia. For the Pictet–Spengler cyclization, the substrate
3a was treated with p-N,N-dimethylbenzaldehyde under a
variety of traditional Pictet–Spengler protocols involving
pTsOH in toluene at reflux, 2% TFA in DCM at 0 8C, AcOH
in ethanol at reflux, neat toluene at 80 8C and with
Yb(OTF)3. Interestingly, endo cyclization resulting in
thiazoloquinoline 8a(i) occurred under all conditions and
it took from 30 min (in 2% TFA) to 6 h (toluene) for
the completion of the reaction (Table 1). The crude product
(O85% based on HPLC) obtained after workup was purified
by silica gel column chromatography using EtOAc/hexane
as an eluent and characterized by LC–MS and NMR.
In this communication, we report application of 3 and 4 as
novel substrates for the Pictet–Spengler reaction leading to
the synthesis of heterocycles beyond isoquinolines and
b-carbolines. Though, substrates 3 and 4 with an arylamine
originating from the C-4 and C-5, respectively, differs from
our previously reported imidazole based substrates 1 and 2
with arylamines originating from the N-1, all four of them
are based on our new concept wherein arylamines are linked
to an activated heterocyclic ring via carbon or nitrogen and
therefore can be collectively grouped under second-
generation substrates for the Pictet–Spengler reaction
(Fig. 1).
It is interesting to note that the Pictet–Spengler reaction on 3
occurred under both protic and nonacidic aprotic media,
and, the C–C bond formation was found to be comparatively
faster than tryptamine and Trp-OMe (generally used as
substrate in the traditional Pictet–Spengler reaction) under
Pictet–Spengler reaction on substrates 3 and 4 in the
presence of aldehydes led to the synthesis of thiazolo[5,4-c]-
quinolines (8) and pyrazolo[4,3-c]quinolines (12),

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3231
O
Br
NO2
R1
HN
S
S
R1
HN
NO2
NH2
H
N
NH2
b
R1
N
N
S
a
7a-c
3a-c
6a-c
6a, 7a and 3a: R1 = C6H5
6b, 7b and 3b: R1= C6H5CH2
6c, 7b and 3c: R1= 4-Cl-C6H4CH2
c
R2 CHO
2% TFA-DCM
30 min, 0oC
R2= 4-(CH3)2N-C6H4 (i), 4-NO2-C6H4 (ii),
4-CH3-C6H4 (iii), 2-furyl (iv), 4-Br-C6H4 (v),
2-OH (vi)
R2
R2
R2
R1
HN
R1
HN
R1
HN
S
N
S
S
N
N
NH
N H
CF3COO
N
8
8a (i-v)
8b (i-v)
8c (i-vi)
Scheme 1. Pictet–Spengler reaction using (2-amino-phenyl)-thiazolo-phenyl-amine (3); conditions: (a) MeOH, rt, 2 h; (b) SnCl2$2H2O, MeOH, reflux, 2 h;
(c) 2% TFA in DCM, 0 8C, 15 min.
similar protocols. Indeed, the rate of cyclization was found
to be at par with the protocol involving highly reactive
cyclic N-acyliminium ion strategy.22 The elegant N-acyli-
minium strategy is known to enhance the reactivity of
iminium intermediates; the only limitation is that the acyl
group invariably becomes part of the final compound and
needs to be removed. Cook et al. attributed electrophilicity
of the imine double bond resulting from the condensation of
amines with aldehydes as the limiting factor for Pictet–
Spengler cyclization and applied pKa values of amines to
compare the electrophilicities of the ‘imines’.23 Thus,
comparing the pKa values of tryptamine 10.2 and Trp-
OMe 7.29 with the aniline (in the absence of pKa value
available for 3, aniline’s pKa value was taken into account)
4.2, clearly suggests that the carbon–nitrogen double bond
derived from substrate 3 is highly electrophilic, for the
nitrogen carries a less electron density than that found for
the imines derived from Trp-OMe and tryptamine,
respectively (Fig. 4).
These findings suggest that the aryl amine derived
substrates are likely to undergo the Pictet–Spengler
reaction relatively faster than the substrate derived from
aliphatic amines. The scope and limitation of our strategy
was established by synthesizing 15 compounds based on
thiazoloquinolines 8 by using three thiazole substrates
based on 3 and five aromatic aldehydes. For the Pictet–
Spengler cyclization 2% TFA–DCM protocol was used.
Purities of the crude products were typically in the
excess of 85% based on HPLC analysis and substitutions
on either 3 or aldehydes had no affect on the rate and
yield of the endo cyclized product. We were especially
pleased to see that aldehydes with electron-donating
group had no adverse effect on the rate of cyclization.
This is in contrast to the typical Pictet–Spengler reaction
where aldehydes with electron withdrawing group had
favorable affects on endo cyclization while aldehydes
with electron donating substituent such as salicylaldehyde
produced imine as the only product when treated with
Trp-OMe. Cook et al. circumvented this problem by
using Nb-benzyl Trp-OMe that furnished an iminium ion
intermediate with enhanced electrophilicity than the
imine obtained from the Trp-OMe and in turn facilitated
endo cyclization. Condensation of substrate 3c with
salicylaldehyde furnished thiazoloquinoline 8c(vi) in
78% isolated yield. We believe that in the substrate 3,
the imine intermediate derived from the aldehydes with
electron donating group is relatively more electrophilic
than the imine derived from the Trp-OMe using the same
aldehyde since the pKa value of aryl amine (4.2 for
aniline) is significantly less than that of Trp-OMe (7.29).
Table 1. Optimization of reaction involving conversion of 3a to 8a(i) using
p-N,N-dimethylbenzaldehyde under different Pictet–Spengler protocols
Entry
Conditions
Time
Product
(%)a
1
2
3
4
5
2% TFA, DCM, 0 8C
30 min
45 min
45 min
1 h
98
95
95
92
92
pTsOH (0.1 equiv), toluene, reflux
5% AcOH in EtOH, reflux
Yb(OTf)3, DCM, rt
Toluene, reflux
6 h
a Based on HPLC of crude products.

3232
S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
NH2
N
RCHO
R
N
H
N
H
pKa = 10.2
COOMe
NH2
COOMe
RCHO
N
R
N
H
N
H
pKa = 7.23
RCHO
N
N
S
HN
R
HN
R
N
R
NH2
S
pKa of aniline = 4.2
Figure 4. pKa of amines versus electrophilicity of imines.
Results of the analytical data of thiazoloquinoline
derivatives 8 are summarized in Table 2.
(enones) with N-phenylhydrazine as described earlier by
Powers et al.25 The authors established the regioselectivity
by X-ray analysis of the dihydropyrazoles. Chalcones
(enones) 9 derived from acetophenone and o-nitrobenzal-
dehydes were reacted with N-phenylhydrazine to give
dihydropyrazoles 10. As expected, the reaction furnished a
single pyrazolines regiomer; no product of the alternative
regiochemistry of addition was detected. The structure was
confirmed by 1H NMR, which showed the presence of three
alkyl protons with appropriate geminal and vicinal
constants. Next, dihydropyrazoles 10, which are quite
stable and do not suffer from aerial oxidation upon storage,
were oxidized to pyrazoles 11 using DDQ. The resulting
C-5 linked aryl nitro in 11 was then reduced to NH2
functionality via catalytic hydrogenation to give substrate 4.
Finally, 4 was subjected to Pictet–Spengler reaction by
treating it with 2-methoxybenzaldehyde in the presence
pTsOH in toluene at reflux for 18–20 h. As evident by both
The synthetic strategy for pyrazoloquinolines from substrate
4 is depicted in Scheme 2. Out of the variety of
regioselective methods reported for dihydropyrazoles
(pyrazolines) or pyrazoles, we decided to synthesize
dihydropyrazoles from enones in the first instance followed
by oxidation to give the desired pyrazole substrate 4.
Surprisingly, our initial attempts to prepare chalcones from
o-nitrobenzaldehyde and acetophenones using KOH/EtOH
as general procedure were not successful. Though, BF3$
AcOH has been reported for the synthesis of chalcones from
o-nitrobenzaldehyde by stirring it with acetophenone for
5 days,24 we decided to use ammonium acetate instead and
were pleased to see the formation of chalcones in 60% yield
after being refluxed in toluene for only 7 h. For the synthesis
of regioselective dihydropyrazoles, we treated chalcones
Table 2. Syntheses of thiazoloquinolines 8
Product
R1
R2
Isolated yield (%)
8a(i)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5–CH2
C6H5–CH2
C6H5–CH2
C6H5–CH2
C6H5–CH2
4-Cl–C6H4CH2
4-Cl–C6H4CH2
4-Cl–C6H4CH2
4-Cl–C6H4CH2
4-Cl–C6H4CH2
4-Cl–C6H4CH2
4-(CH3)2NC6H4
4-NO2C6H4
4-CH3C6H4
2-C4H3O
83
80
82
85
76
81
79
85
83
78
80
77
81
83
75
78
8a(ii)
8a(iii)
8a(iv)
8a(v)
8b(i)
8b(ii)
8b(iii)
8b(iv)
8b(v)
8c(i)
8c(ii)
8c(iii)
8c(iv)
8c(v)
8c(vi)
4-BrC6H4
4-(CH3)2NC6H4
4-NO2C6H4
4-CH3C6H4
2-C4H3O
4-BrC6H4
4-(CH3)2NC6H4
4-NO2C6H4
4-CH3C6H4
2-C4H3O
4-BrC6H4
2-OH

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3233
O
NO2
O
N
N
CHO
R2
N
N
(b)
(c)
NO2
(a)
R2
+
R2
R2
9a-c
R1
R1
R1
O2N
O2N
R1
11a-c
10a-c
9a, 10a, 11a, 4a (R1=4-CH3, R2=H )
9b, 10b, 11a, 4b(R1=4-Cl, R2=H)
9c, 10c, 11a, 4C (R1=H, R2=5-F)
(d)
CHO
N
N
N
N
N
N
N
3
R
R2
+
R2
R
e
R1
2
R1
N
H
R1
H2N
3
4
R = 4-N,N-dimethyl(i); 4-NO (ii);
2
4-Br (iii); 2-OCH3 (iv); 3,4-di-
R3
R3
13
12
OCH (v), 2-OH (vi).
3
12a (i-v)
12b (i-v)
12c (i-vi)
(f)
Scheme 2. Pictet–Spengler reaction using 2-(2,5-diphenyl-2H-pyrazol-3-yl)-phenylamine (4); conditions: (a) NH4OAc, toluene, reflux, 7 h; (b) phenyl
hydrazine, EtOH, reflux 7 h; (c) DDQ, DCM–THF (1/1), rt, 4 h; (d) SnCl2$2H2O, EtOH, reflux, 1.5 h; (e) p-TsOH, toluene, reflux, 4 h; (f) p-TsOH, toluene
reflux 4 h and DDQ, DCM–THF (1/1), rt, 2 h.
HPLC and TLC, the crude product was found to be a
mixture of two components with a major spot w85% and
minor !10%. The two spots were separated by column
chromatography using 10–30% EtOAc–hexane as mobile
phase and characterized by ESMS and NMR. One of the
components with lower Rf on TLC was found to be the
dihydropyrazoloquinolines 13 and the second component
with higher Rf was pyrazoloquinolines 12, an oxidized
product of the first component. The former had a moderate
stability, as even after purification it had a tendency to
undergo slow oxidation to 12. Such an oxidation for
dihydroimidazoquinoxaline to imine has been reported
earlier by us and TenBrink et al.26
to add an oxidizing agent after the Pictet–Spengler reaction
so as to convert the remaining 13 into 12. Thus, after the
Pictet–Spengler reaction of the substrate 4 with an aldehyde,
the resulting crude product was treated with DDQ to give 12
as the only product. The scope and limitation of our strategy
was examined by utilizing three 3,5 disubstituted pyrazoles
and five aldehydes. In all cases, the title compounds were
obtained in excellent yields (75–82%) and aldehydes with
electron-donating group had no adverse effect on the rate of
cyclization. Condensation of salicylaldehyde having
electron donating substituent with 4c furnished pyrazolo-
quinoline 12c(vi) (Table 5) in 75% yield. A comparative
profile of the Pictet–Spengler reaction of aliphatic and aryl
amine based substrates with salicylaldehyde has been
depicted in Table 4. It is thus clear that substrates with
aryl amine attached directly to either C or N of the
heterocyclic ring readily underwent Pictet–Spengler
cyclization with aldehydes bearing electron donating groups
whereas substrates derived either from aliphatic amine
(Trp-OMe) or even from aryl amine not directly linked to
the heterocycle (2) failed to undergo cyclization. The
structure of 16 compounds based on 12 has been
summarized in Table 5.
In order to synthesize 12 as the only product, we treated 4a
with 2-methoxybenzaldehyde by applying other tradi-
tionally used Pictet–Spengler protocols involving 2% TFA
in DCM at 0 8C, AcOH in ethanol at reflux, and toluene at
80 8C (Table 3). All protocols except toluene at 80 8C,
where schiff base was the only isolated product (Table 3),
were accompanied with the formation of the 13. This led us
Table 3. Ratio of pyrazoloquinoline 12 and its dihydro-derivative 13
formed during the Pictet–Spengler reaction of 4a with 2-methoxybenzal-
dehyde
Though both the substrates 3 and 4 successfully underwent
Pictet–Spengler cyclization, however, when compared with
the N-linked aryl amine substrates 1 and 2 described earlier,
we observed that C-linked aryl amine substrates 3 and 4
underwent Pictet–Spengler cyclization faster than 1 and 2.
This may be attributed to the relative decrease in the pKa
value of the aryl amine linked to the C-4 and C-5 in 3 and 4,
respectively, which are the already deactivated positions
due to the multiply bonded N-atom than the pKa value of
aryl amine linked to the nitrogen, which behaves as an
electron donor.
Entry
Conditions
12 (%)a
13 (%)a
Time
1
2
2% TFA, DCM, 08
pTsOH (0.1 equiv), tolu-
ene, reflux
20
80
80
8
2 h
5 h
3
4
5
5% AcOH in EtOH, reflux 40
60
—
—
8 h
20 h
4 and 2 h
Toluene, refluxb
—
89
(i) pTsOH (0.1 equiv),
toluene, reflux, (ii) DDQ
a Based on HPLC of crude reaction product.
b Schiff base was isolated as the only product.

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S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
Table 4. Comparative profile of substrates undergoing Pictet–Spengler cyclization with salicylaldehyde
Substrate
Reaction condition
Cyclized product
Yield (%)
Ref.
1
2
3
4
Toluene, 80 8C, 48 h
p-TsOH, toluene, 125 8C, 18 h
2% TFA–DCM
p-TsOH, toluene, reflux, 5 h
p-TsOH, toluene, reflux
Toluene, reflux
Imidazoquinoxalines
No producta
Thiazoloquinoline
Pyrazoloquinoline
Tetrahydro-b-carboline
No producta
73
—
78
75
5
6a
6b
—
—
22
22
Trp-OMe
Trp-OMe
—
a Imine was isolated as the only product.
(250 mm!4.6 mm). Mass spectra were recorded on a
Merck MS-8000 spectrometer. Phenylisothiocyanates, alde-
hydes, and o-nitrophenacylbromide, tin chloride dihydrate
etc were purchased from Aldrich and Lancaster. The
LC–Ms profile of selected compounds were generated
using High Throughput LC–MS (Lachrom MS- 8000) using
a 5 m, 10!50 mm C-18 Reverse Phase Column with a
Linear gradient 10–100% methanol–water v/v with 0.1%
formic acid over 12 min with a flow rate of 6 mL/min.
Melting points reported were uncorrected.
Table 5. Synthesis of pyrazoloquinolines 12
Product
R1
R2
R3
Isolated yield
(%)
12a(i)
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
H
H
H
H
4-CH3
H
H
H
H
H
H
H
H
4-(CH3)2N
4-NO2
4-Br
2-OCH3
3,4-Di-OCH3
4-(CH3)2N
4-NO2
79
75
76
82
80
82
80
76
79
82
80
75
77
79
80
75
12a(ii)
12a(iii)
12a(iv)
12a(v)
12b(i)
12b(ii)
12b(iii)
12b(iv)
12b(v)
12c(i)
12c(ii)
12c(iii)
12c(iv)
12c(v)
12c(vi)
4-Br
H
H
2-OCH3
3,4-Di-OCH3
4-(CH3)2N
4-NO2
4.1. General method for the preparation of
(2-nitro-phenyl)-thiazolo-phenyl-amine (7)
5-F
5-F
5-F
5-F
5-F
H
4-Br
2-Nitro phenacyl bromide (0.50 g, 2.05 mmol) was added to
a solution of 6a (0.31 g, 2.05 mmol) in methanol (5 mL).
The reaction mixture was stirred for 2 h. The reaction
mixture was evaporated and digested with water and then
extracted with ethyl acetate. The organic phase was washed
with a saturated solution of sodium bicarbonate (100 mL)
followed by brine (50 mL), dried over sodium sulfate and
evaporated to dryness under reduced pressure to obtained a
crude solid, which was further purified by recrystallization
in ethanol to afford 7a as a yellow solid.
2-OCH3
3,4-Di-OCH3
2-OH
3. Conclusion
In summary, we have identified new thiazole and pyrazole
derived substrates for the Pictet–Spengler reaction, which is
based on our concept of ‘arylamine attached to an activated
heterocyclic ring’. This in turn will set the stage for a wide
application of this powerful reaction and can be used for the
synthesis of novel polyheterocyclic skeletons based on
privileged structures. Currently work is in progress in our
lab with several second-generation substrates designed on
the basis of our new concept for the Pictet–Spengler
reaction and will be reported soon.
4.1.1. [4-(2-Nitro-phenyl)-thiazol-2-yl]-phenyl-amine
(7a). Yield 95%; yellow solid; mp 162–164 8C; IR (KBr)
nmax 1599, 1528, 1334, 1H NMR (300 MHz, DMSO)
dZ10.27 (s, 1H, NH), 7.86 (t, 2H, ArH), 7.76 (t, 1H,
ArH), 7.56 (t, 3H, ArH), 7.34 (s, 1H, thiazole H), 7.28 (t, 2H,
JZ8.1 Hz, ArH), 6.95 (t, 1H, JZ7.2 Hz, ArH); 13C NMR
(50 MHz, DMSO) dZ170.6, 163.4, 149.2, 146.1, 141.2,
132.3, 130.2, 129.2, 128.1, 124.7, 123.9, 122.3, 121.7,
117.1, 107.3; mass (ESC) m/z 298 (MCC1). Anal. Calcd
for C15H11N3O2S: C, 60.59; H, 3.73; N, 14.13. Found: C,
60.69; H, 3.53; N, 14.50.
4. Experimental
All solvents were commercially available and used without
purification. All products were characterized by H NMR.
1
13C NMR, ESMS, IR and HPLC. Analytical TLC was
performed using 2.5!5 cm plated coated with a 0.25 mm
thickness of silica gel. 60F-254 Merck and visualization was
accomplished with UV light and iodine. Column chromato-
graphy was performed using silica gel 60 Thomas Baker
4.1.2. Benzyl-[4-(2-nitro-phenyl)-thiazol-2-yl]-amine
(7b). Yield 98%; solid, mp 152–154 8C; IR (KBr) nmax
3382, 2832, 2719, 1589, 1366; 1H NMR (300 MHz, DMSO)
dZ8.18 (t, 1H, JZ5.7 Hz, NH), 7.76 (d, 2H, JZ8.1 Hz,
ArH), 7.64 (t, 1H, JZ7.65 Hz, ArH), 7.52 (t, 1H, JZ7.8 Hz,
ArH), 7.29 (m, 5H, ArH), 7.01 (s, 1H, thiazole H), 4.38 (d,
2H, JZ5.7 Hz, CH2); 13C NMR (75 MHz, DMSO) dZ
168.2, 148.8, 145.6, 139.1, 131.9, 129.9, 128.6, 128.3,
128.2, 127.7, 127.0, 123.5, 105.0, 47.7; mass (ESC) m/z 312
(MCC1). Anal. Calcd for C16H13N3O2S: C, 61.72; H, 4.21;
N, 13.50. Found: C, 61.68; H, 4.35; N, 13.45.
1
(100–200 mesh). H NMR spectra (300 MHz) are reported
as follows: chemical shifts in parts per million downfield
from TMS as internal standard (d scale), multiplicity [brZ
broad, sZsinglet, dZdoublet, tZtriplet, qZquartet, mZ
multiplet, oZoverlapped, integration and coupling constant
(Hz)]. All 13C NMR spectra (50/75 MHz) are determined
with complete proton decoupling and reported in ppm. All
spectra were recorded at 25 8C Elemental analyses were
performed on a Carlo Erba 1108 microanalyzer or
Elementar’s Vario EL III microanalyzer. Analytical
HPLC were performed on C-18 reverse-phase column
4.1.3. (4-Chloro-benzyl)-[4-(2-nitro-phenyl)-thiazol-2-
yl]-amine (7c). Yield 96%; oil; IR (neat) nmax 3377, 2928,
1
2853, 1590, 1363; H NMR (300 MHz, CDCl3) dZ8.21

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3235
(t, 1H, JZ5.25 Hz, NH), 7.74 (d, 2H, JZ7.8 Hz, ArH), 7.64
(t, 1H, JZ7.5 Hz, ArH), 7.51 (t, 1H, JZ7.65 Hz, ArH), 7.35
(m, 4H, ArH), 7.02 (s, 1H, thiazole H), 4.36 (d, 2H, JZ
5.4 Hz, CH2); 13C NMR (75 MHz, DMSO) dZ168.4, 149.2,
145.2, 138.6, 132.2, 131.9, 130.26, 129.8, 129.0, 128.6,
123.8, 105.5, 47.3; mass (ESC) m/z 346 (MCC1). Anal.
Calcd for C16H12ClN3O2S: C, 55.57; H, 3.50; N, 12.15.
Found: C, 55.79; H, 3.53; N, 12.20.
was treated with 2% TFA in DCM. The completion of
Pictet–Spengler cyclization was monitored by TLC. After
30 min, the reaction mixture was evaporated, and the
residue so obtained was triturated with 5% NaHCO3. It was
then extracted with EtOAc, washed with brine (10 mL), and
dried over sodium sulfate. EtOAC was evaporated to
dryness under reduced pressure and the crude obtained
was purified by column chromatography to afford 8a(i) as a
white solid.
4.2. General method for the preparation of
(2-amino-phenyl)-thiazolo-phenyl-amine (3)
4.3.1. [4-(4-Dimethylamino-phenyl)-thiazolo [5,4-c]
quinolin-2-yl]-phenyl-amine [8a(i)]. Yield 83%; white
solid, mp 218–220 8C; IR (KBr) nmax 3246 (br, NH), 2923,
Tin (II) chloride dihydrate (2.28 g, 10.13 mmol) was added
to a solution of 7a (0.60 g, 2.03 mmol) in ethanol (15 mL) at
80 8C. The reaction mixture was stirred for 2 h and then
poured in cold water and basified with 5% sodium
bicarbonate (pH 8). The mixture was extracted with ethyl
acetate, washed with brine (100 mL), dried over sodium
sulfate, and evaporated to dryness under reduced pressure to
afford a crude material, which was purified on a silica gel
column using hexane–ethyl acetate (70/30, v/v) as eluent to
afford 3a as an oil.
2830, 1478, 1400, 1355 cmK1 1H NMR (300 MHz,
;
DMSO): dZ11.05 (s, NH), 8.48 (d, JZ7.8 Hz, 1H), 8.04
(d, JZ8.4 Hz, 1H), 7.99 (d, JZ7.8 Hz, 2H), 7.91 (d, JZ
7.8 Hz, 2H), 7.73 (t, JZ7.35 Hz, 1H), 7.61 (t, JZ7.5 Hz,
1H), 7.47 (t, JZ7.2 Hz, 2H), 7.13 (t, JZ7.23 Hz, 1H), 6.90
(t, JZ8.1 Hz, 2H), 3.02 (s, 6H); 13C NMR (75 MHz,
DMSO) dZ166.0, 154.8, 150.9, 150.8, 146.2, 139.9, 129.0,
128.6, 126.4, 125.1, 123.1, 122.7, 120.1, 118.2, 112.3,
111.4, 39.8; mass (ESC) m/z 397 (MCC1). Anal. Calcd for
C24H20N4S: C, 72.70; H, 5.08; N, 14.33. Found: C, 72.68;
H, 5.10; N, 14.30.
4.2.1. (Amino-phenyl)-thiazol-2-yl]-phenyl-amine (3a).
Yield 96%; oil; IR (neat) nmax 3450 (br, NH), 1593; H
1
4.3.2. [4-(4-Nitro-phenyl)-thiazolo [5,4-c]quinolin-2-yl]-
phenyl-amine [8a(ii)]. Yield 80%; yellow solid, mp 234–
236 8C; IR (KBr) nmax 3366 (br, NH), 1602, 1454, 1402,
1344; 1H NMR (300 MHz, DMSO), dZ11.20 (s, 1H, NH),
8.53 (d, 1H, JZ7.8 Hz, ArH), 8.46 (d, 2H, JZ8.4 Hz, ArH),
8.32 (d, 2H, JZ8.4 Hz, ArH), 8.13 (d, 1H, JZ8.1 Hz, ArH),
7.89 (d, 2H, JZ7.8 Hz, ArH), 7.80 (t, 1H, JZ7.35 Hz,
ArH), 7.72 (t, 1H, JZ7.35 Hz, ArH), 7.47 (t, 2H, JZ
7.80 Hz, ArH), 7.15 (t, 1H, JZ7.35 Hz, ArH); 13C NMR
(75 MHz, DMSO d6), dZ166.3, 155.8, 148.4, 147.8, 146.2,
145.4, 139.9, 129.3, 129.0, 126.8, 123.9, 123.6, 123.3,
120.7, 119.6, 118.6; mass (ESC) m/z 399 (MCC1). Anal.
Calcd for C22H14N4O2S: C, 66.32; H, 3.54; N, 14.06.
Found: C, 66.31; H, 3.55; N, 14.10.
NMR (300 MHz, DMSO) dZ10.26 (s, 1H, NH), 7.56 (d,
2H, JZ7.8 Hz, ArH), 7.45 (d, 1H, JZ7.5 Hz, ArH), 7.32 (t,
2H, JZ7.5 Hz, ArH), 6.98 (m, 2H, ArH), 6.71 (d, 1H, JZ
8.1 Hz, ArH), 6.57 (t, 1H, JZ7.5 Hz, ArH), 5.92 (s, 2H,
CH2), 13C NMR (50 MHz, DMSO) dZ163.3, 150.7, 146.3,
141.4, 130.1, 129.4, 128.9, 128.6, 121.8, 118.3, 117.3,
116.5, 108.8, 103.1; mass (ESC) m/z 268.32 (MCC1).
Anal. Calcd for C15H13N3S: C, 67.39; H, 4.90; N, 15.72.
Found: C, 67.49; H, 4.73; N, 15.53.
4.2.2. [4-(2-Amino-phenyl)-thiazol-2-yl]-benzyl-amine
(3b). Yield 95%; oil; IR (neat) nmax 3450 (br, NH), 2836,
2700, 1592; 1H NMR (300 MHz, CDCl3) dZ7.41–7.33 (m
(o), 6H, ArH), 7.09 (t, 1H, JZ7.8 Hz, ArH), 6.69 (t, 1H, JZ
8.25 Hz, ArH), 6.58 (s, 1H, thiazole H), 5.47 (br s, 1H, NH),
4.52 (d, 2H, JZ6.0 Hz, CH2); mass (ESC) m/z 282 (MCC
1). Anal. Calcd for C16H15N3S: C, 68.30; H, 5.37; N, 14.93.
Found: C, 68.32; H, 5.51; N, 14.84.
4.3.3. Phenyl-(4-p-tolyl-thiazolo [5,4-c]quinolin-2-yl)-
amine [8a(iii)]. Yield 82%; white solid, mp 128–130 8C;
IR (KBr) nmax 3196 (br, NH), 2931, 2835, 1591, 1493, 1363;
1H NMR (300 MHz, CDCl3), dZ8.5 (d, 1H, JZ8.1 Hz,
ArH), 8.20 (d, 1H, JZ8.4 Hz, ArH), 7.95 (d, 3H, JZ7.8 Hz,
overlapped with NH, ArH), 7.72 (t, 1H, JZ7.65 Hz, ArH),
7.58 (m, 3H, ArH), 7.44 (t, 2H, JZ7.8 Hz, ArH), 7.35 (d,
2H, JZ7.8 Hz, ArH), 7.22 (t, 1H, JZ7.5 Hz, ArH), 2.44 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3), d 155.3, 152.4,
147.0, 139.6, 139.4, 137.3, 129.6, 129.6, 129.0, 128.0,
125.9, 124.7, 123.7, 121.2, 120.2, 21.4; mass (ESC) m/z 368
(MCC1). Anal. Calcd for C23H17N3S: C, 75.18; H, 4.66; N,
11.44. Found: C, 75.15; H, 4.65; N, 11.45.
4.2.3. [4-(2-Amino-phenyl)-thiazol-2-yl]-(4-chloro-
benzyl)-amine (3c). Yield 96%; white solid; mp 182–
184 8C; IR (KBr) nmax 3420 (br, NH), 2920, 2860, 1598; 1H
NMR (300 MHz, DMSO) dZ8.27 (t, 1H, JZ5.4 Hz, NH),
7.36 (m, 5H, ArH), 6.96 (t, 1H, JZ7.35 Hz, ArH), 6.75 (s,
1H, thiazole H), 6.64 (d, 1H, JZ7.8 Hz, ArH), 6.51 (t, 1H,
JZ7.35 Hz, ArH), 5.86 (br s, 2H, NH2), 4.45 (d, 2H, JZ
5.7 Hz, CH2); 13C NMR (50 MHz, DMSO) dZ168.7, 150.8,
146.3, 138.7, 131.8, 129.5, 128.67, 128.2, 118.3, 116.3,
116.1, 101.1, 101.2, 47.4; mass (ESC) m/z 316 (MCC1).
Anal. Calcd for C16H14ClN3S: C, 60.85; H, 4.47; N, 13.31.
Found: C, 60.77; H, 4.51; N, 13.50.
4.3.4. (4-Furan-2-yl-thiazolo [5,4-c]quinolin-2-yl)-
phenyl-amine [8a(iv)]. Yield 85%; white solid, O250 8C;
IR (KBr) nmax 3264 (br, NH), 1607, 1472, 1406, 1347. Anal.
1H NMR (300 MHz, DMSO), dZ11.13 (s, NH), 8.51 (d,
1H, JZ8.1 Hz, ArH), 8.04 (d, 2H, JZ8.4 Hz, ArH), 7.92
(d, 2H, JZ8.1 Hz, ArH), 7.75 (t, 1H, JZ7.5 Hz, ArH), 7.64
(t, 1H, JZ7.5 Hz, ArH), 7.48 (t, 2H, JZ7.5 Hz, ArH), 7.41
(d, 1H, JZ3 Hz, ArH); 13C NMR (75 MHz, DMSO), dZ
167.9, 155.9, 152.7, 146.3, 145.3, 147.0, 140.4, 129.6,
4.3. General procedure for the Pictet–Spengler reaction
on substrate 3
A mixture of 3a (0.10 g, 0.39 mmol) and p-N,N-dimethyl-
aminobenzaldehyde (0.058 g, 0.39 mmol) in DCM (2 mL)

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S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
128.9, 126.3, 123.8, 123.5, 121.0, 119.0, 116.8, 113.2,
111.1; mass (ESC) m/z 344 (MCC1). Anal. Calcd for
C20H13N3OS: C, 69.95; H, 3.82; N, 12.24. Found: C, 69.94;
H, 3.81; N, 12.25.
4.3.9. Benzyl-(4-furan-2-yl-thiazolo[5,4-c]quinolin-2-yl)-
amine [8b(iv)]. Yield 83%; solid, mp 180–182 8C; IR (KBr)
nmax 3202 (br, NH), 2930, 2832, 1592, 1489, 1364; 1H NMR
(300 MHz, DMSO), dZ7.67 (d, 1H, JZ8.1 Hz, ArH), 7.23
(d, 2H, JZ8.4 Hz, ArH), 7.02 (s, 1H, ArH), 6.88 (t, 1H, JZ
7.2 Hz, ArH), 6.72 (m, 3H, ArH), 6.57–6.48 [m (o), 5H,
ArH), 5.92 (s, 2H, CH2); mass (ESC) m/z 358 (MCC1).
Anal. Calcd for C21H15N3OS: C, 70.57; H, 4.23; N, 11.76.
Found: C, 70.59; H, 4.55; N, 11.45.
4.3.5. [4-(4-Bromo-phenyl)-thiazolo[5,4-c]quinolin-2-yl]-
phenyl-amine [8a(v)]. Yield 76%; yellow solid, mp
184–186 8C; IR (KBr) nmax 3288 (br, NH), 1601, 1476,
1
1406, 1361; H NMR (300 MHz, DMSO), dZ11.16 (br s,
1H, NH), 8.52 (d, 1H, JZ7.8 Hz, ArH), 8.13 (d, 1H, JZ
8.4 Hz, ArH), 8.03 (d, 2H, JZ7.2 Hz, ArH), 7.83 (m, 5H,
ArH), 7.70 (t, 1H, JZ7.2 Hz, ArH), 7.468 (t, 2H, JZ
7.05 Hz, ArH), 7.14 (t, 1H, JZ7.05 Hz, ArH); 13C NMR
(75 MHz, DMSO), d 166.3, 155.5, 149.7, 146.3, 140.0,
138.8, 131.8, 129.8, 129.0, 126.6, 123.3, 123.2, 120.6,
119.4, 118.6; mass (ESC) m/z 433 (MCC1). Anal. Calcd
for C22H14BrN3S: C, 61.12; H, 3.26; N, 9.72. Found: C,
61.10; H, 3.25; N, 9.73.
4.3.10. Benzyl-[4-(4-bromo-phenyl)-thiazolo[5,4-c]-
quinolin-2-yl]-amine [8b(v)]. Yield 78%; white solid, mp
175–178 8C; IR (KBr) nmax 3170 (br, NH), 2963, 2833,
1629, 1590, 1352; 1H NMR (300 MHz, DMSO), dZ7.67 (d,
1H, JZ7.8 Hz, ArH), 7.24 (d, 1H, JZ8.7 Hz, ArH), 7.05
(d, 2H, JZ8.4 Hz, ArH), 6.91 (t, 3H, JZ8.4 Hz, ArH), 6.77
(t, 1H, JZ7.5 Hz, ArH), 6.66 (d, 2H, JZ7.2 Hz, ArH), 6.55
(t, 2H, JZ7.2 Hz, ArH), 6.48 (d, 1H, JZ7.2 Hz, ArH), 3.97
(s, 2H,CH2); 13C NMR (50 MHz, DMSO), dZ156.4, 146.5,
138.2, 131.7, 129.8, 128.9, 128.6, 128.5, 127.7, 127.3,
125.9, 123.7, 123.2, 120.8, 119.9, 47.6; mass (ESC) m/z 447
(MCC1). Anal. Calcd for. C23H16BrN3S. C, 61.89; H, 3.61;
N, 9.41. Found: C, 61.90; H, 3.69; N, 9.42.
4.3.6. Benzyl-[4-(4-dimethylamino-phenyl)-thiazolo[5,
4-c]quinolin-2-yl]-amine [8b(i)]. Yield 81%; pink solid,
mp 160–162 8C; IR (KBr) nmax 3209 (br, NH), 2929, 2831,
1599, 1365; 1H NMR (300 MHz, DMSO), dZ10.20 (s,
NH), 8.48 (d, 1H, JZ7.8 Hz, ArH), 8.16 (d, 1H, JZ8.4 Hz,
ArH), 7.94 (t, 1H, JZ7.5 Hz, ArH), 7.85 (d, 2H, JZ8.4 Hz,
ArH), 7.76 (t, 1H, JZ7.35 Hz, ArH), 7.39 (m, 5H, ArH),
6.97 (d, 2H, JZ8.4 Hz, ArH), 4.84 (s, 2H, CH2), 3.08 (s, 6H,
2CH3); 13C NMR (50 MHz, DMSO), dZ167.0, 161.3,
153.6, 148.2, 138.4, 133.2, 130.8, 129.4, 128.6, 128.5,
127.8, 125.2, 120.4, 119.0, 117.8, 112.4, 47.8; mass (ESC)
m/z 411 (MCC1). Anal. Calcd for C25H22N4S: C, 73.14; H,
5.40; N, 13.65. Found: C, 73.16; H, 5.38; N, 13.59.
4.3.11. (4-Chloro-benzyl)-[4-(4-dimethylamino-phenyl)-
thiazolo[5,4-c]quinolin-2-yl]-amine [8c(i)]. Yield 80%;
white solid, mp 134–136 8C; IR (KBr) nmax 3383 (br,
1
NH), 2925, 2833, 1629, 1589, 1360; H NMR (300 MHz,
DMSO), dZ10.26 (br s, 1H, NH), 8.44 (d, 1H, JZ9 Hz,
ArH), 8.16 (d, 1H, JZ9 Hz, ArH), 7.92 (t, 1H, JZ7.35 Hz,
ArH), 7.84 (d, 2H, JZ8.7 Hz, ArH), 7.73 (t, 1H, JZ
7.35 Hz, ArH), 7.47 (q, 4H, ArH), 6.95 (d, 2H, JZ8.7 Hz,
ArH), 4.82 (s, 2H, CH2), 3.07 (s, 6H, 2!CH3); 13C NMR
(50 MHz, DMSO), dZ160.0, 152.9, 148.3, 139.1, 136.7,
132.5, 130.4, 130.08, 128.9, 127.3, 124.7, 121.4, 120.0,
118.7, 112.1, 47.7, 40.0; mass (ESC) m/z 445 (MCC1).
Anal. Calcd for C25H21ClN4S: C, 67.48; H, 4.76; N, 12.59.
Found: C, 67.49; H, 4.74; N, 12.58.
4.3.7.
Benzyl-[4-(4-nitro-phenyl)-thiazolo[5,4-c]-
quinolin-2-yl]-amine [8b(ii)]. Yield 79%; white solid, mp
205–207 8C; IR (KBr) nmax 3403 (br, NH), 2924, 2834,
1630, 1569, 1532, 1475, 1403, 1349; H NMR (300 MHz,
1
DMSO), 9.41 (br s, 1H, NH), 8.43 (t, 3H, JZ7.5 Hz, ArH),
8.28 (d, 1H, JZ8.7 Hz, ArH), 8.08 (d, 1H, JZ8.4 Hz, ArH),
7.75 (t, 1H, JZ7.5 Hz, ArH) 7.64 (t, 1H, JZ7.4 Hz, ArH),
7.47 (d, 2H, JZ7.2 Hz, ArH), 7.38 (t, 2H, JZ7.4 Hz, ArH),
7.28 (d, 1H, JZ7.2 Hz, ArH), 4.77 (d, 2H, JZ5.1 Hz, CH2);
13C NMR (50 MHz, DMSO), d 170.8, 156.3, 153.3, 148.5,
147.7, 146.3, 145.6, 138.1, 129.1, 129.0, 128.5, 127.7,
127.4, 126.4, 124.0, 123.6, 120.6, 119.8, 47.8; mass (ESC)
m/z 413 (MCC1). Anal. Calcd for C23H16N4O2S: C, 66.97;
H, 3.91; N, 13.58. Found: C, 66.98; H, 3.90; N, 13.59.
4.3.12. (4-Chloro-benzyl)-[4-(4-nitro-phenyl)-thia-
zolo[5,4-c]quinolin-2-yl]-amine [8c(ii)]. Yield 77%;
white solid, mp 220–222 8C; IR (KBr) nmax 3320 (br,
1
NH), 2963, 2833, 1629, 1590, 1352; H NMR (300 MHz,
DMSO), dZ9.44 (s, 1H, NH), 8.43 (t, 3H, ArH), 8.28 (d,
2H, JZ8.1 Hz, ArH), 8.08 (d, 1H, JZ8.1 Hz, ArH), 7.76 (t,
1H, JZ7.35 Hz, ArH), 7.64 (t, 1H, JZ7.05 Hz, ArH), 7.61
(t, 1H, JZ7.2 Hz, ArH), 7.49 (d, 2H, JZ8.4 Hz, ArH), 7.43
(d, 2H, JZ8.4 Hz, ArH), 4.75 (d, 2H, JZ5.1 Hz, CH2); 13
C
NMR (75 MHz, DMSO), dZ171.2, 156.6, 148.2, 148.1,
146.6, 145.9, 137.5, 131.3, 129.9, 129.4, 128.8, 126.8,
124.3, 123.9, 120.9, 120.2, 47.4; mass (ESC) m/z 447
(MCC1). Anal. Calcd for C23H15ClN4O2S: C, 61.81; H,
3.38; N, 12.54. Found: C, 61.82; H, 3.36; N, 12.56.
4.3.8. Benzyl-(4-p-tolyl-thiazolo[5,4-c]quinolin-2-yl)-
amine [8b(iii)]. Yield 85%; white solid, mp 162–164 8C;
IR (KBr) nma1x 3202, (br, NH), 2925, 2834, 1629, 1585,
1405, 1355; H NMR (300 MHz, DMSO), dZ9.30 (br s,
1H, NH), 8.38 (d, 1H, JZ7.8 Hz, ArH), 8.03 (d, 1H, JZ
8.1 Hz, ArH), 7.92 (d, 2H, JZ7.2 Hz, ArH), 7.69 (t, 1H,
ArH), 7.59 (t, 1H, ArH), 7.36 (m, 7H, ArH), 4.75 (s, 2H,
CH2), 2.41 (s, 3H, CH3; 13C NMR (50 MHz, DMSO), dZ
167.2, 160.0, 144.6, 142.6, 141.2, 134.0, 133.2, 131.9,
130.5, 129.8, 129.4, 129.0, 128.6, 127.9, 127.5, 127.4,
125.7, 122.4, 118.6, 117.7, 117.0, 114.6, 55.4, 51.6, 48.4,
34.0; mass (ESC) m/z 382 (MCC1). Anal. Calcd for
C24H19N3S: C, 75.56; H, 5.02; N, 11.01. Found: C, 75.56;
H, 5.03; N, 11.00.
4.3.13. (4-Chloro-benzyl)-(4-p-tolyl-thiazolo[5,4-c]-
quinolin-2-yl)-amine [8c(iii)]. Yield 81%; white solid,
mp 90–92 8C; IR (KBr) nmax 3313 (br, NH), 2922, 2830,
1583, 1484, 1402, 1351, 1H NMR (300 MHz, DMSO),
dZ9.31 (s, 1H, NH), 8.37 (d, 1H, JZ8.1 Hz, ArH), 8.03
(d, H, JZ8.4 Hz, ArH), 7.92 (d, 2H, JZ7.8 Hz, ArH), 7.71
(t, 1H, JZ7.65 Hz, ArH), 7.58 (t, 1H, JZ7.5 Hz, ArH), 7.44
(m, 6H, ArH), 4.74 (d, 2H, JZ4.8 Hz, CH2), 2.41 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO d6), dZ171.2, 156.1,

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3237
151.3, 146.8, 139.5, 137.7, 137.5, 132.3, 129.6, 129.0,
128.7, 128.0, 125.9, 123.9, 120.8, 120.0, 47.4, 21.3; mass
(ESC) m/z 416 (MCC1). Anal. Calcd for C24H18ClN3S: C,
69.30; H, 4.36; N, 10.10. Found: C, 69.28; H, 4.35; N, 10.13.
4.4.2. 3-(4-Chloro-phenyl)-5-(2-nitro-phenyl)-1-phenyl-
4,5-dihydro-1H-pyrazole (10b). Yield 87%; red solid;
mp 150–152 8C; IR (KBr) nmax 1516, 1598 cmK1; 1H NMR
(300 MHz, CDCl3) dZ8.13 (d, JZ8.1 Hz, 1H, ArH), 7.66
(d, JZ8.1 Hz, 2H, ArH), 7.55–7.51 (m, 1H, ArH), 7.46–
7.42 (m, 2H, ArH), 7.35 (d, JZ8.1 Hz, 2H, ArH), 7.19 (t,
JZ7.5 Hz, 2H, ArH), 6.94 (d, JZ7.8 Hz, 2H, ArH), 6.82 (t,
JZ7.2 Hz, 1H, ArH), 5.91–5.85 (m, 1H, –CHPh), 4.09 (dd,
JZ18.0, 12.3 Hz, 1H, –CH2–), 3.13 (dd, JZ18.0, 6.6 Hz,
1H, –CH2–); mass m/z 378.20 (MCC1). Anal. Calcd for
C21H16ClN3O2 C, 66.76; H, 4.27; N, 11.12. Found: C,
66.62; H, 4.22; N, 11.43.
4.3.14. (4-Chloro-benzyl)-(4-furan-2-yl-thiazolo[5,4-
c]quinolin-2-yl)-amine [8c(iv)]. Yield 83%; white solid,
mp 164–166 8C; IR (KBr) nmax 3225 (br, NH), 2928, 2833,
1585, 1488, 1401, 1360; 1H NMR (300 MHz, DMSO), dZ
9.35 (s, 1H, NH), 8.386 (d, 1H, JZ8.1 Hz, ArH), 8.04 (s,
1H, furan H), 7.97 (d, 1H, JZ8.4 Hz, ArH), 7.69 (t, 2H, JZ
7.8 Hz, ArH), 7.56 (d, 1H, JZ7.8 Hz, ArH), 7.50 (d, 2H,
JZ8.4 Hz, ArH), 7.44 (d, 2H, JZ8.4 Hz, ArH), 7.34 (d, 1H,
JZ3 Hz, furan H), 6.79 (t, 1H, JZ1.65 Hz, furan H), 4.76
(d, 2H, JZ5.4 Hz, CH2); 13C NMR (75 MHz, DMSO), dZ
172.2, 156.4, 152.8, 146.4, 145.2, 141.9, 137.7, 132.3,
129.9, 129.3, 128.8, 125.9, 123.9, 120.9, 116.9, 113.1,
110.9, 47.4; mass (ESC) m/z 392 (MCC1). Anal. Calcd for
C21H14ClN3OS: C, 64.36; H, 3.60; N, 10.72. Found: C,
64.35; H, 3.60; N, 10.75.
4.4.3. 5-(5-Fluoro-2-nitro-phenyl)-1,3-diphenyl-4,5-
dihydro-1H-pyrazole (10c). Yield 85%; red solid; mp
1
132–134 8C; IR nmax (KBr) 1524, 1597 cmK1; H NMR
(300 MHz, CDCl3) dZ8.28–8.24 (m, 1H, ArH), 7.74 (d,
JZ7.2 Hz, 2H, ArH), 7.43–7.36 (m, 3H, ArH), 7.25–7.17
(m, 3H, ArH), 7.13 (t, JZ7.5 Hz, 1H, ArH), 6.95 (d, JZ
8.1 Hz, 2H, ArH), 6.85 (t, JZ7.2 Hz, 1H, ArH), 5.94–5.87
(m, 1H, –CHPh), 4.15 (dd, JZ18.0, 12.6 Hz, 1H, –CH2–),
3.16 (dd, JZ17.5, 6.6 Hz, 1H, –CH2–); mass m/z 362.40
(MCC1). Anal. Calcd for C21H16FN3O2: C, 69.80; H, 4.46;
N, 11.63. Found: C, 69.74; H, 4.32; N, 11.74.
4.3.15. [4-(4-Bromo-phenyl)-thiazolo[5,4-c]quinolin-2-
yl]-(4-chloro-benzyl)-amine [8c(v)]. Yield 75%; white
solid, mp 156–158 8C; IR (KBr) nmax 3219 (br, NH),
2930, 2832, 1599, 1482, 1355; 1H NMR (300 MHz,
DMSO), d 9.37 (s, 1H, NH), 8.38 (d, 1H, JZ7.8 Hz,
ArH), 8.05 (d, H, JZ8.4 Hz, ArH), 7.97 (d, 2H, JZ8.4 Hz,
ArH), 7.80 (d, 2H, JZ8.4 Hz, ArH), 7.73 (t, 1H, JZ
7.05 Hz, ArH), 7.61 (t, 1H, JZ7.2 Hz, ArH), 7.49 (d, 2H,
JZ8.4 Hz, ArH), 7.43 (d, 2H, JZ8.4 Hz, ArH), 4.75 (d, 2H,
JZ5.1 Hz, CH2); 13C NMR (75 MHz, CD3COCD3), dZ
150.0, 146.9, 139.5, 137.4, 132.7, 131.7, 129.8, 129.6,
129.2, 128.7, 128.5, 125.8, 123.8, 123.1, 121.2, 47.4; mass
(ESC) m/z 481 (MCC1). Anal. Calcd for C23H15BrClN3S:
C, 57.45; H, 3.14; N, 8.74. Found: C, 57.43; H, 3.15;
N, 8.75.
4.5. General procedure for the synthesis of 5-(2-nitro-
phenyl)-1-phenyl-3-aryl-1H-pyrazole (11)
A solution of 5-(2-nitro-phenyl)-1-phenyl-3-p-tolyl-4,5-
dihydro-1H-pyrazole 10a (0.80 g, 2.25 mmol) in
DCM–THF (1/1, 7 mL) was treated with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ, 1.02 g, 4.50 mmol) at rt. The
reaction mixture was stirred for 4 h. The solvent was
removed under reduced pressure and the crude red residue
was chromatographed on silica gel (5:1 hexane/ethyl
acetate) to afford 11a as a yellow solid.
4.5.1. 5-(2-Nitro-phenyl)-1-phenyl-3-p-tolyl-1H-pyrazole
(11a). Yield 87%; yellow solid; mp 90–92 8C; IR (KBr) nmax
1521, 1595 cmK1; 1H NMR (300 MHz, CDCl3) dZ7.90 (d,
1H, JZ7.8 Hz, ArH), 7.79 (d, JZ7.8 Hz, 2H, ArH), 7.60 (t,
JZ6.9 Hz, 1H, ArH), 7.52 (t, JZ6.9 Hz, 1H, ArH), 7.45 (d,
JZ7.5 Hz, 1H, ArH), 7.28–7.22 (m, 7H, ArH), 6.75 (s, 1H,
]CH), 2.38 (s, 3H, CH3). 13C NMR (50.3 MHz, CDCl3)
dZ152.66, 149.18, 139.85, 139.58, 138.35, 133.29, 133.12,
130.29, 129.77, 129.44, 127.92, 126.18, 124.93, 106.07,
21.70; mass m/z 356.13 (MCC1). Anal. Calcd for
C22H17N3O2: C, 74.35; H, 4.82; N, 11.82. Found: C,
74.54; H, 4.72; N, 11.74.
4.4. General procedure for the synthesis of 5-(2-nitro-
phenyl)-1-phenyl-3-aryl-4,5-dihydro-1H-pyrazole (10)
A mixture of 3-(2-nitro-phenyl)-1-p-tolyl-propenone 9a
(1.00 g, 3.74 mmol), and phenyl hydrazine (0.808 mL,
7.48 mmol) was refluxed in ethanol for 7 h. Ethanol was
evaporated in vacuo and the residue so obtained was
purified on a silica gel column using hexane: ethyl acetate
(70:30, v/v) as eluent to afford 10a as a red solid.
4.4.1. 5-(2-Nitro-phenyl)-1-phenyl-3-p-tolyl-4,5-dihydro-
1H-pyrazole (10a). Yield 82%; red solid; mp 142–144 8C;
4.5.2. 3-(4-Chloro-phenyl)-5-(2-nitro-phenyl)-1-phenyl-
1H-pyrazole (11b). Yield 88%; yellow solid; mp 102–
IR (KBr) nmax 1521, 1597 cmK1
;
1H NMR
104 8C; IR (KBr) nmax 1530, 1599 cmK1 1H NMR
;
(300 MHz, CDCl3) dZ8.23 (d, JZ7.8 Hz, 1H, ArH), 7.63
(d, JZ8.1 Hz, 2H, ArH), 7.53–7.44 (m, 3H, ArH), 7.19 (t,
JZ7.8 Hz, 4H, ArH), 6.94 (d, JZ8.1 Hz, 2H, ArH), 6.80 (t,
JZ7.5 Hz, 1H, ArH), 5.88–5.82 (m, 1H, –CHPh), 4.11 (dd,
JZ17.5, 12.4 Hz, 1H, –CH2–), 3.14 (dd, JZ17.5, 6.6 Hz,
1H, –CH2–), 2.38 (s, 3H, CH3). 13C NMR (50.3 MHz,
CDCl3) dZ147.85, 144.68, 139.49, 138.12, 134.92, 130.91,
130.01, 129.75, 129.55, 128.95, 128.69, 126.25, 125.86,
124.99, 123.50, 119.73, 113.36, 61.05, 43.66, 21.86; mass
m/z 358.25 (MCC1). Anal. Calcd for C22H19N3O2. C,
73.93; H, 5.36; N, 11.76. Found: C, 73.71; H, 5.42; N, 11.64.
(300 MHz, CDCl3) dZ7.93 (d, JZ8.1 Hz, 1H, ArH), 7.84
(d, JZ8.4 Hz, 2H, ArH), 7.64–7.52 (m, 2H, ArH), 7.45 (d,
JZ7.2 Hz, 1H, ArH), 7.39 (d, JZ8.4 Hz, 2H, ArH), 7.28 (s,
5H, ArH), 6.75 (s, 1H, ]CH); mass m/z 376.20 (MCC1).
Anal. Calcd for C21H14ClN3O2: C, 67.12; H, 3.75; N, 11.18.
Found: C, 67.22; H, 3.82; N, 11.70.
4.5.3. 5-(5-Fluoro-2-nitro-phenyl)-1,3-diphenyl-1H-
pyrazo (11c). Yield 83%; yellow solid; mp 165–167 8C;
IR (KBr) nmax 1529, 1596 cmK1 1H NMR (300 MHz,
;

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S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
CDCl3) dZ8.01–7.97 (m, 1H, ArH), 7.91 (d, JZ7.5 Hz,
2H, ArH), 7.44 (t, JZ7.5 Hz, 2H, ArH), 7.36 (d, JZ7.5 Hz,
1H, ArH), 7.30 (s, 5H, ArH), 7.20 (d, JZ8.1 Hz, 2H, ArH),
6.79 (s, 1H, ]CH), mass m/z 360.43 (MCC1). Anal. Calcd
for C21H14FN3O2: C, 70.19; H, 3.93; N, 11.69. Found: C,
70.22; H, 3.80; N, 11.79.
layers were combined and dried over anhydrous Na2SO4
and evaporated to obtain a residue. The residue was
dissolved in DCM–THF (1/1) 10 mL and DDQ (18 mg,
0.08 mmol) was added. The resulting mixture was stirred at
rt for 2 h. Then solvent was evaporated in vacuo and the
residue so obtained was purified on column chromatography
on silica gel with hexane: ethyl acetate (80:20, v/v) as eluent
to afford 12a(i) as a white solid.
4.6. General procedure for the reduction of 5-(2-nitro-
phenyl)-1-phenyl-3-aryl-1H-pyrazole to get 4
4.7.1. Dimethyl-[4-(1-phenyl-3-p-tolyl-1H-pyrazolo[4,3-
c]quinolin-4-yl)-phenyl]-amine [12a(i)]. Yield 79%; off
white solid; mp 190–192 8C; IR (KBr) nmax 1594 cmK1; 1H
NMR (300 MHz, CDCl3) dZ8.27 (d, JZ8.4 Hz, 1H, ArH),
7.70–7.56 (m, 7H, ArH), 7.36 (d, JZ8.4 Hz, 2H, ArH), 7.30
(d, JZ7.5 Hz, 1H, ArH), 7.17 (d, JZ7.5 Hz, 2H, ArH), 6.96
(d, JZ7.8 Hz, 2H, ArH), 6.49 (d, JZ8.7 Hz, 2H, ArH), 2.92
[s, 6H, –N(CH3)2], 2.31 (s, 3H, CH3). 13C NMR (50.3 MHz,
CDCl3) dZ156.90, 151.31, 149.00, 146.32, 141.81, 141.23,
137.31, 130.90, 130.21, 129.90, 129.72, 129.01, 128.42,
127.60, 127.31, 125.41, 121.75, 115.34, 111.93, 40.80,
21.40; mass m/z 455.40 (MCC1). Anal. Calcd for
C31H26N4: C, 81.91; H, 5.77; N, 12.33. Found: C, 81.81;
H, 5.84; N, 12.43.
Tin (II) chloride dihydrate (2.28 g, 9.25 mmol) was added
to a solution of 5-(2-nitro-phenyl)-1-phenyl-3-p-tolyl-1H-
pyrazole 11a (0.65 g, 1.84 mmol) in ethanol (15 mL) at
80 8C. The reaction mixture was stirred for 1.5 h. After that
the reaction mixture was poured in cold water and basified
with 5% aqueous sodium bicarbonate solution (pH 8). The
mixture was extracted with ethyl acetate, washed with brine
(100 mL), dried over sodium sulfate, and evaporated to
dryness under reduced pressure to afford 4a
4.6.1. 2-(2-Phenyl-5-p-tolyl-2H-pyrazol-3-yl)-phenyl-
amine (4a). Yield 92%; yellow oil; IR (neat) nmax, 1596,
1
3473 cmK1; H NMR (300 MHz, CDCl3) dZ7.82 (d, JZ
7.8 Hz, 2H, ArH), 7.41 (d, JZ7.5 Hz, 2H, ArH), 7.33–7.23
(m, 5H, ArH), 7.17 (t, JZ7.5 Hz, 1H, ArH), 6.98 (d, JZ
7.5 Hz, 1H, ArH), 6.81 (s, 1H, ]CH), 6.72 (t, JZ6.9 Hz,
2H, ArH), 3.84 (br s, 2H, NH2), 2.40 (s, 3H, CH3). 13C NMR
(50.3 MHz, CDCl3) dZ152.57, 145.19, 141.40, 140.49,
138.30, 131.56, 130.53, 129.84, 129.25, 127.43, 126.13,
124.25, 118.62, 116.48, 115.96, 106.23, 21.78; mass m/z
326.80 (MCC1). Anal. Calcd for C22H19N3: C, 81.20; H,
5.89; N, 12.91. Found: C, 81.37; H, 5.62; N, 12.78.
4.7.2. 4-(4-Nitro-phenyl)-1-phenyl-3-p-tolyl-1H-pyraz-
olo[4,3-c]quinoline [12a(ii)]. Yield 75%; yellow solid;
mp 235–237 8C; IR (KBr) nmax 1524, 1598 cmK1; 1H NMR
(300 MHz, CDCl3) dZ8.30 (d, JZ8.4 Hz, 1H, ArH), 8.02
(d, JZ8.4 Hz, 2H, ArH), 7.71–7.63 (m, 9H, ArH), 7.42 (t,
JZ7.5 Hz, 1H, ArH), 7.09 (d, JZ7.8 Hz, 2H, ArH), 6.94 (d,
JZ7.8 Hz, 2H, ArH), 2.29 (s, 3H, CH3). 13C NMR
(50.3 MHz, CDCl3) dZ154.15, 148.56, 148.07, 146.13,
145.42, 141.92, 141.04, 138.96, 130.96, 130.27, 129.95,
129.80, 129.65, 128.93, 127.74, 127.15, 123.12, 122.06,
116.03, 114.47, 21.59; mass m/z 457.30 (MCC1). Anal.
Calcd for C29H20N4O2: C, 76.30; H, 4.42; N, 12.27. Found:
C, 76.42; H, 4.22; N, 12.43.
4.6.2. 2-[5-(4-Chloro-phenyl)-2-phenyl-2H-pyrazol-3-
yl]-phenylamine (4b). Yield 88%; yellow oil; IR (neat)
1
nmax 1600, 3464 cmK1; H NMR (300 MHz, CDCl3) dZ
7.86 (d, JZ8.4 Hz, 2H, ArH), 7.40 (d, JZ8.1 Hz, 3H, ArH),
7.34–7.23 (m, 4H, ArH), 7.18 (t, JZ7.5 Hz, 1H, ArH), 6.97
(d, JZ7.5 Hz, 1H, ArH), 6.81 (s, 1H, ]CH), 6.74–6.67 (m,
2H, ArH), 3.82 (br s, 2H, NH2); mass m/z 346.40 (MCC1).
Anal. Calcd for C21H16ClN3: C, 72.93; H, 4.66; N, 12.15.
Found: C, 72.82; H, 4.82; N, 12.31.
4.7.3. 4-(4-Bromo-phenyl)-1-phenyl-3-p-tolyl-1H-pyraz-
olo[4,3-c]quinoline [12a(iii)]. Yield 76%; off white solid;
mp 210–212 8C; IR (KBr) nmax 1594 cmK1 1H NMR
;
(300 MHz, CDCl3) dZ8.28 (d, JZ8.1 Hz, 1H, ArH), 7.73–
7.60 (m, 7H, ArH), 7.39–7.30 (m, 5H, ArH), 7.09 (d, JZ
7.8 Hz, 2H, ArH), 6.97 (d, JZ7.8 Hz, 2H, ArH), 2.35 (s, 3H,
CH3). 13C NMR (50.3 MHz, CDCl3) dZ155.58, 148.88,
146.27, 141.86, 141.21, 138.47, 138.19, 131.57, 131.14,
130.79, 130.21, 129.98, 129.84, 129.56, 128.84, 127.78,
126.56, 123.42, 122.00, 115.8, 114.57, 21.69; mass m/z
490.78 (MCC1). Anal. Calcd for C29H20BrN3: C, 71.03; H,
4.11; N, 8.57. Found: C, 71.42; H, 4.22; N, 8.43.
4.6.3. 2-(2,5-Diphenyl-2H-pyrazol-3-yl)-4-fluoro-phenyl-
amine (4c). Yield 86%; yellow oil; IR (neat) nmax 1595,
1
3430 cmK1; H NMR (300 MHz, CDCl3) dZ7.92 (d, JZ
7.2 Hz, 2H, ArH), 7.50–7.16 (m, 8H, ArH), 6.88 (t, JZ
8.1 Hz, 1H, ArH), 6.83 (s, 1H, ]CH–), 6.73 (d, JZ8.7 Hz,
1H, ArH), 6.71–6.63 (m, 1H, ArH), 3.67 (br s, 2H, NH2);
mass m/z 330.32 (MCC1). Anal. Calcd for C21H16FN3: C,
76.58; H, 4.90; N, 12.76. Found: C, 76.42; H, 4.86; N, 12.88.
4.7. General procedure for the Pictet–Spengler reaction
on substrate 4
4.7.4. 4-(2-Methoxy-phenyl)-1-phenyl-3-p-tolyl-1H-
pyrazolo[4,3-c]quinoline [12a(iv)]. Yield 82%; off white;
mp 216–218 8C; IR (KBr) nmax 1597 cmK1 1H NMR
;
A mixture of 2-(2-phenyl-5-p-tolyl-2H-pyrazol-3-yl)-
phenylamine 4a (0.10 g, 0.32 mmol), 4-N, N-dimethyl-
benzaldehyde (0.048 g, 0.32 mmol) and p-tolylsulphonic
acid (6.08 mg, 0.032 mmol) was refluxed in toluene for 4 h.
Toluene was evaporated in vacuo and residue so obtained
was dissolved in ethyl acetate (25 mL). The organic layer
was washed with 5% aqueous sodium bicarbonate, water
(2!10 mL) and brine solution (1!10 mL). The organic
(300 MHz, CDCl3) dZ8.30 (d, JZ8.4 Hz, 1H, ArH), 7.71–
7.61 (m, 8H, ArH), 7.36–7.26 (m, 2H, ArH), 7.09 (d, JZ
7.2 Hz, 3H, ArH), 6.88 (d, JZ7.5 Hz, 2H, ArH), 6.40 (d, JZ
8.1 Hz, 1H, ArH), 3.18 (s, 3H, –OCH3), 2.28 (s, 3H, CH3). 13
C
NMR (50.3 MHz, CDCl3) dZ157.35, 154.73, 149.72, 146.51,
141.40, 141.02, 137.70, 130.90, 130.83, 130.66, 130.17,
129.92, 129.44, 129.31, 129.17, 128.25, 127.85, 126.31,
122.04, 121.14, 116.29, 115.95, 110.57, 55.10, 21.67; mass

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
3239
m/z 442.20 (MCC1). Anal. Calcd for C30H23N3O: C, 81.61;
H, 5.25; N, 9.52. Found: C, 81.47; H, 5.22; N, 9.43.
4.7.9. 3-(4-Chloro-phenyl)-4-(2-methoxy-phenyl)-1-
phenyl-1H-pyrazolo[4,3-c]quinoline [12b(iv)]. Yield
79%; pale yellow solid; mp 242–244 8C; IR (KBr) nmax
1
1597 cmK1; H NMR (200 MHz, CDCl3) dZ8.31 (d, JZ
4.7.5. 4-(3,4-Dimethoxy-phenyl)-1-phenyl-3-p-tolyl-1H-
pyrazolo[4,3-c]quinoline [12a(v)]. Yield 80%; yellow
8.2 Hz, 1H, ArH), 7.72–7.59 (m, 9H, ArH), 7.39–7.29 (m,
1H, ArH), 7.17–7.03 (m, 5H, ArH), 6.46 (d, JZ8.2 Hz, 1H,
ArH), 3.22 (s, 3H, –OCH3). 13C NMR (50.3 MHz, CDCl3)
dZ157.21, 154.33, 148.40, 146.52, 141.22, 134.15, 131.99,
131.42, 130.99, 130.91, 130.85, 130.68, 130.19, 130.12,
129.36, 129.18, 128.96, 127.73, 126.50, 122.00, 121.31,
116.17, 115.81, 110.61, 55.06; mass m/z 462.15 (MCC1).
Anal. Calcd for C29H20ClN3O: C, 75.40; H, 4.36; N, 9.10.
Found: C, 75.42; H, 3.55; N, 9.31.
solid; mp 158–160 8C; IR (KBr) nmax 1595 cmK1 1H
;
NMR (300 MHz, CDCl3) dZ8.29 (d, JZ8.4 Hz, 1H, ArH),
7.71–7.65 (m, 6H, ArH), 7.58 (d, JZ8.1 Hz, 1H, ArH), 7.34
(t, JZ7.5 Hz, 1H, ArH), 7.25 (d, JZ6.9 Hz, 1H, ArH), 7.19
(d, JZ8.4 Hz, 2H, ArH), 7.00 (s, 1H, ArH), 6.96 (d, JZ
6.9 Hz, 2H, ArH), 6.77 (d, JZ8.4 Hz, 1H, ArH), 3.89 (s, 3H,
–OCH3), 3.55 (s, 3H, –OCH3), 2.31 (s, 3H, CH3). 13C NMR
(50.3 MHz, CDCl3) dZ156.34, 150.09, 148.86, 148.60,
146.27, 142.09, 141.30, 138.20, 132.25, 130.60, 130.41,
130.19, 130.10, 129.42, 128.75, 127.81, 126.77, 126.15,
122.95, 121.92, 115.68, 114.28, 113.77, 111.28, 56.51,
55.86, 21.65; mass m/z 472.33 (MCC1). Anal. Calcd for
C31H25N3O2: C, 78.96; H, 5.34; N, 8.91. Found: C, 78.49;
H, 5.62; N, 8.54.
4.7.10. 3-(4-Chloro-phenyl)-4-(3,4-dimethoxy-phenyl)-1-
phenyl-1H-pyrazolo[4,3-c]quinoline [12b(v)]. Yield 82%;
pale yellow solid; mp 212–214 8C; IR (KBr) nmax
1609 cmK1 1H NMR (300 MHz, CDCl3) dZ8.30 (d,
;
JZ8.1 Hz, 1H, ArH), 7.73–7.67 (m, 5H, ArH), 7.53 (d,
JZ7.2 Hz, 1H, ArH), 7.35 (t, JZ7.8 Hz, 1H, ArH), 7.28–
7.22 (overlapped, 2H, ArH), 7.16 (m, 2H, ArH), 7.05 (m,
2H, ArH), 6.67 (m, 2H, ArH), 3.89 (s, 3H, –OCH3), 3.68
(s, 3H, –OCH3). 13C NMR (50.3 MHz, CDCl3) dZ156.15,
150.36, 148.99, 146.34, 141.14, 134.52, 131.98, 131.88,
131.40, 130.68, 130.27, 129.78, 129.61, 129.32, 129.02,
128.22, 127.74, 126.71, 126.34, 123.29, 121.90, 115.60,
113.36, 111.21, 56.59, 56.05; mass m/z 492.20 (MCC1).
Anal. Calcd for C30H22ClN3O2: C, 73.24; H, 4.51; N,
8.54. Found: C, 73.57; H, 5.89; N, 8.59.
4.7.6. {4-[3-(4-Chloro-phenyl)-1-phenyl-1H-pyrazolo[4,3-
c]quinolin-4-yl]-phenyl}-dimethyl-amine [12b(i)]. Yield
82%; pale yellow solid; mp 244–246 8C; IR (KBr) nmax
1
1601 cmK1; H NMR (300 MHz, CDCl3) dZ8.27 (d, JZ
8.1 Hz, 1H, ArH), 7.69–7.63 (m, 5H, ArH), 7.56 (d, JZ
8.1 Hz, 1H, ArH), 7.39–7.20 (m, 6H, ArH), 7.12 (d, JZ
8.1 Hz, 2H, ArH), 6.50 (d, JZ8.4 Hz, 2H, ArH), 2.95 [s, 6H,
–N(CH3)2]. 13C NMR (50.3 MHz, CDCl3) dZ156.87,
151.60, 147.99, 146.60, 142.07, 141.25, 134.04, 132.01,
131.51, 131.07, 130.53, 130.22, 130.16, 129.45, 128.13,
127.77, 127.08, 125.79, 121.88, 115.49, 114.62, 112.06,
41.00; mass m/z 475.33 (MCC1). Anal. Calcd for
C30H23ClN4: C, 75.86; H, 4.88; N, 11.80. Found: C, 75.77;
H, 4.99; N, 11.54.
4.7.11. [4-(8-Fluoro-1,3-diphenyl-1H-pyrazolo[4,3-c]-
quinolin-4-yl)-phenyl]-dimethyl-amine [12c(i)]. Yield
80%; pale yellow solid; mp 193–195 8C; IR (KBr) nmax
1
1594 cmK1; H NMR (300 MHz, CDCl3) dZ8.26 (m, 1H,
ArH), 7.68–7.67 (overlapped, 5H, ArH), 7.56–7.26 (m, 5H,
ArH), 7.23–7.16 (m, 4H, ArH), 6.48 (d, JZ8.1 Hz, 2H,
ArH), 2.92 [s, 6H, –N(CH3)2]. 13C NMR (50.3 MHz,
CDCl3) dZ162.36, 156.28, 151.53, 149.17, 143.46,
141.73, 140.79, 133.31, 132.79, 132.62, 131.07, 130.29,
128.07, 127.77, 127.14, 118.66, 118.72, 115.90, 114.58,
112.11, 106.95, 106.44, 40.96; mass m/z 459.33 (MCC1).
Anal. Calcd for C30H23FN4: C, 78.58; H, 5.06; N, 12.22.
Found: C, 78.87; H, 5.25; N, 12.45.
4.7.7. 3-(4-Chloro-phenyl)-4-(4-nitro-phenyl)-1-phenyl-
1H-pyrazolo[4,3-c]quinoline [12b(ii)]. Yield 80%; yellow
solid; mp 231–233 8C; IR (KBr) nmax 1520, 1597 cmK1
;
1H NMR (200 MHz, CDCl3) dZ8.31 (d, JZ8.4 Hz, 1H,
ArH), 8.09 (d, JZ8.6 Hz, 2H, ArH), 7.76–7.61 (m, 9H,
ArH), 7.48–7.38 (m, 2H, ArH), 7.15 (d, JZ4.2 Hz, 3H,
ArH). 13C NMR (50.3 MHz, CDCl3) dZ155.27, 153.71,
148.24, 145.33, 140.85, 131.98, 131.33, 131.02, 130.54,
130.39, 130.25, 130.03, 129.65, 129.31, 129.06, 128.98,
128.52, 128.01, 127.68, 127.41, 123.37, 122.05, 115.89;
mass m/z 477.18 (MCC1). Anal. Calcd for
C28H17ClN4O2: C, 70.52; H, 3.59; N, 11.75. Found: C,
70.42; H, 3.75; N, 11.53.
4.7.12. 8-Fluoro-4-(4-nitro-phenyl)-1,3-diphenyl-1H-
pyrazolo[4,3-c]quinoline [12c(ii)]. Yield 75%; brown
solid; mp 196–198 8C; IR (KBr) nmax 1513, 1596 cmK1
;
1H NMR (200 MHz, CDCl3) dZ8.34–8.26 (m, 1H, ArH),
8.03 (d, JZ8.8 Hz, 2H, ArH), 7.70 (s, 5H, ArH), 7.62 (d,
JZ8.8 Hz, 2H, ArH), 7.48 (td, JZ8.4, 2.8 Hz, 1H, ArH),
7.29–7.10 (overlapped, 6H, ArH). 13C NMR (50.3 MHz,
CDCl3) dZ163.24, 158.31, 153.32, 148.44, 148.13,
143.01, 141.62, 140.36, 133.41, 133.23, 132.42, 130.92,
130.69, 130.45, 130.08, 129.01, 128.34, 127.66, 123.20,
119.38, 118.89, 116.70, 114.47, 107.21, 106.71; mass m/z
461.23 (MCC1). Anal. Calcd for C28H17FN4O2: C,
73.04; H, 3.72; N, 12.17. Found: C, 73.42; H, 3.85;
N, 12.01.
4.7.8. 4-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-1-phenyl-
1H-pyrazolo[4,3-c]quinoline [12b(iii)]. Yield 76%; white
solid; mp 242–244 8C; IR (KBr) nmax 1594 cmK1; 1H NMR
(300 MHz, CDCl3) dZ8.28 (d, JZ8.4 Hz, 1H, ArH), 7.74–
7.67 (m, 6H, ArH), 7.60 (d, JZ8.1 Hz, 1H, ArH), 7.40–7.34
(m, 5H, ArH), 7.16 (s, 4H, ArH). 13C NMR (50.3 MHz,
CDCl3) dZ155.18, 147.50, 146.25, 142.05, 141.00, 138.06,
134.83, 131.55, 131.41, 131.37, 131.36, 130.80, 130.39,
130.33, 129.80, 128.38, 127.72, 126.79, 123.79, 121.98,
115.75, 114.32; mass m/z 510.33 (MCC1). Anal. Calcd for
C28H17BrClN3: C, 65.84; H, 3.35; N, 8.23. Found: C, 65.73;
H, 3.39; N, 8.54.
4.7.13. 4-(4-Bromo-phenyl)-8-fluoro-1,3-diphenyl-1H-
pyrazolo[4,3-c]quinoline [12c(iii)]. Yield 77%; off white
solid; mp 194–196 8C; IR (KBr) nmax 1592 cmK1; 1H NMR

3240
S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
(300 MHz, CDCl3) dZ8.28 (m, 1H, ArH), 7.68 (s, 5H,
ArH), 7.46 (td, JZ8.1, 2.7 Hz, 1H, ArH), 7.34–7.26
(overlapped, 6H, ArH), 7.23–7.15 (m, 4H, ArH). 13C
NMR (50.3 MHz, CDCl3) dZ162.89, 157.98, 154.70,
148.76, 143.13, 140.52, 137.89, 133.19, 133.00, 132.61,
131.51, 131.25, 130.56, 130.39, 130.13, 128.64, 128.22,
127.70, 123.56, 119.09, 118.60, 116.42, 114.52, 107.10,
106.60; mass m/z 494.33 (MCC1). Anal. Calcd for
C28H17BrFN3: C, 68.03; H, 3.47; N, 8.50. Found: C,
68.41; H, 3.25; N, 8.67.
References and notes
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4.7.14. 8-Fluoro-4-(2-methoxy-phenyl)-1,3-diphenyl-1H-
pyrazolo[4,3-c]quinoline [12c(iv)]. Yield 79%; off white
solid; mp 212–214 8C; IR (KBr) nmax 1594 cmK1 1H
;
NMR (200 MHz, CDCl3) dZ8.33–8.26 (m, 1H, ArH),
7.72–7.58 (m, 6H, ArH), 7.42 (td, JZ8.0, 2.8 Hz, 1H,
ArH), 7.28–7.18 (overlapped, 6H, ArH), 7.09 (d, JZ
6 Hz, 2H, ArH), 6.39 (d, JZ8.2 Hz, 1H, ArH), 3.17 (s,
3H, –OCH3). 13C NMR (50.3 MHz, CDCl3) dZ162.81,
157.91, 157.27, 153.90, 149.62, 143.41, 140.74, 133.24,
133.06, 132.65, 130.86, 130.28, 129.43, 128.71, 128.11,
127.76, 127.62, 121.19, 118.62, 118.13, 116.85, 115.98,
110.58, 107.08, 106.59, 55.01; mass m/z 446.26 (MCC
1). Anal. Calcd for C29H20FN3O: C, 78.19; H, 4.53; N,
9.43. Found: C, 78.47; H, 4.25; N, 9.58.
4.7.15. 4-(3,4-Dimethoxy-phenyl)-8-fluoro-1,3-diphenyl-
1H-pyrazolo[4,3-c]quinoline [12c(v)]. Yield 80%; yellow
solid; mp 185–187 8C; IR (KBr) nmax 1598 cmK1 1H
;
4. (a) Czarnocki, Z.; MacLean, D. B.; Szarek, W. A. Can.
J. Chem. 1986, 64, 2205–2210. (b) Czarnocki, Z.; Suh, D.;
MacLean, D. B.; Hultin, P. G.; Szarek, W. A. Can. J. Chem.
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NMR (300 MHz, CDCl3) dZ8.29 (m, 1H, ArH), 7.68 (m,
5H, ArH), 7.44 (td, JZ8.1, 5.4 Hz, 1H, ArH), 7.31–7.24
(overlapped, 4H, ArH), 7.20–7.12 (m, 3H, ArH), 6.87 (s,
1H, ArH), 6.82 (d, JZ8.4 Hz, 1H, ArH), 3.88 (s, 3H,
–OCH3), 3.52 (s, 3H, –OCH3). 13C NMR (50.3 MHz,
CDCl3) dZ157.77, 155.52, 150.14, 148.80, 148.59,
143.14, 140.62, 133.08, 132.79, 131.91, 130.49, 130.37,
130.18, 128.56, 128.11, 127.73, 122.76, 118.92, 118.34,
116.31, 114.37, 113.63, 111.31, 107.00, 106.50, 56.47,
55.85; mass m/z 476.20 (MCC1). Anal. Calcd for
C30H22FN3O2: C, 75.78; H, 4.66; N, 8.84. Found: C,
75.57; H, 4.95; N, 8.67.
´
Kiegiel, J.; Arazny, Z. Tetrahyedron: Asymmetry 1995, 6,
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nolin-4-yl)-phenol [12c(vi)]. Yield 75%; off white solid;
mp 201–203 8C; IR (KBr) nmax 1597, 3425 cmK1 1H
;
NMR (200 MHz, CDCl3) dZ8.15 (d, JZ8.4 Hz, 1H,
ArH), 7.68–7.57 (overlapped, 6H, ArH), 7.55 (d, JZ
8.2 Hz, 1H, ArH), 7.38–7.27 (m, 3H, ArH), 7.20–7.03
(m, 5H, ArH), 6.26 (t, JZ7.4 Hz, 1H, ArH), 2.35 (s, 3H,
CH3). 13C NMR (50.3 MHz, CDCl3) dZ158.47, 156.13,
149.27, 143.79, 142.69, 141.13, 138.58, 133.60, 131.50,
130.65, 130.29, 130.11, 129.89, 129.12, 127.84. 127.29,
126.64, 122.04, 120.12, 118.22, 117.45, 115.69, 113.10,
21.72; mass m/z 427.18 (MCC1). Anal. Calcd for
C29H21N3O: C, 81.48; H, 4.95; N, 9.83. Found: C,
81.76; H, 4.55; N, 9.53.
´
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.
01.063.

S. Duggineni et al. / Tetrahedron 62 (2006) 3228–3241
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