Application of the Pictet-Spengler reaction to aryl amine-based substrates having pyrimidine as a π-nucleophile: synthesis of pyrimidoquinolines with structural analogy to benzonaphthyridines present in alkaloids

Article abstract of DOI:10.1016/j.tet.2008.11.067

Synthesis of pyrimidine annulated quinolines, structurally analogous to biologically active benzonaphthyridines present in alkaloids, has been described. Our synthetic strategy is based on the modified Pictet-Spengler reaction involving substrates comprising deactivated pyrimidine ring as the nucleophilic partner whereas aryl amine originating from the C-4 of the pyrimidine ring served as the source for electrophilic partner. The resulting substrates 5-7 with diversity at 2- and 6-position after condensation with a variety of aldehydes underwent 6-endo cyclization to furnish pyrimido[5,4-c]quinolines 14 in good yields. However, attempts to further extend this strategy on new structurally analogous substrate involving the pyridine ring as nucleophilic partner failed, thus limiting the scope of the reaction.

Full text of DOI:10.1016/j.tet.2008.11.067

Tetrahedron 65 (2009) 1153–1161
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of the Pictet–Spengler reaction to aryl amine-based substrates having
pyrimidine as a
p-nucleophile: synthesis of pyrimidoquinolines with structural
analogy to benzonaphthyridines present in alkaloidsq
*
Piyush K. Agarwal, Sudhir K. Sharma, Devesh Sawant, Bijoy Kundu
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 August 2008
Received in revised form 15 October 2008
Accepted 21 November 2008
Available online 27 November 2008
Synthesis of pyrimidine annulated quinolines, structurally analogous to biologically active benzonaph-
thyridines present in alkaloids, has been described. Our synthetic strategy is based on the modified
Pictet–Spengler reaction involving substrates comprising deactivated pyrimidine ring as the nucleophilic
partner whereas aryl amine originating from the C-4 of the pyrimidine ring served as the source for
electrophilic partner. The resulting substrates 5–7 with diversity at 2- and 6-position after condensation
with a variety of aldehydes underwent 6-endo cyclization to furnish pyrimido[5,4-c]quinolines 14 in
good yields. However, attempts to further extend this strategy on new structurally analogous substrate
involving the pyridine ring as nucleophilic partner failed, thus limiting the scope of the reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
both electron-donating and electron-withdrawing groups. Thus, in
order to expand the repertoire of ‘third-generation’ substrates with
The Pictet–Spengler reaction1 discovered approximately 100
years ago remains one of the most elegant strategies for C–C bond
formation via endo cyclization. Traditionally, the substrates (first-
generation substrates) used for the Pictet–Spengler reaction such
as tryptamine/tryptophan, histidine/histamine, and dimethoxy-
phenethylamines are based on aliphatic amines that act as a source
for iminium/electrophilic partner until the year 2005, when we
disclosed a modified strategy2 for the Pictet–Spengler reaction by
demonstrating endo cyclization in substrates with aryl amines at-
tached to the activated heterocyclic rings (second-generation sub-
strates). The modified strategy has also been used successfully by
others.3
abilities to facilitate endo cyclization with all classes of aromatic
aldehydes, pyrimidine was identified as yet another class of het-
erocycle known to be associated with diminished nucleophilicity.
Pyrimidine is one of the nature’s most versatile building blocks
with established medicinal pedigree and its presence in thymine,
cytosine, and uracil, which are the essential building blocks of
nucleic acids, DNA and RNA, is one possible reason for their activity.
The motif has been given the privileged label5 as it is found to be
present in a variety of therapeutic molecules6 exhibiting activity
ranging from antiinflammatory, antibacterial, anticancer, antiviral,
antiHIV, antimalarial, antihypertensive, sedatives, and hypnotics,
anticonvulsant to antihistaminic.
During the course of further investigations with modified sub-
strates, recently we reported yet another interesting finding that
the Pictet–Spengler reaction could be affected even when aryl
amine is linked to a deactivated (poorly nucleophilic) heterocyclic
ring.4 Initially this was demonstrated on a series of deactivated
nucleophilic systems categorized under ‘third-generation’ sub-
strates: quinoxalines, triazoles, and tetrazoles, the substrates had
limitation for aldehydes with strong electron-donating group as
substituents. In contrast the second-generation substrates2c
A careful survey of the literature for the application of Pictet–
Spengler reaction on pyrimidine-based substrates revealed papers
by Duncton et al.3a and Bai et al.3b who by applying the modified
Pictet–Spengler concept (substrate 1; Fig. 1), demonstrated the 6-
endo cyclization on substrates 2 and 3 (Fig. 1) having 5-amino-
pyrimidine, as a source for the electrophilic partner, linked either to
a phenyl ring via sulfur, nitrogen or oxygen atom or to the N-1 of
the indole, respectively. In all the three substrates, the phenyl
tethered to NH, imidazole, and the indole served as p-nucleophiles.
reported earlier underwent
p
-cyclizations with aldehydes having
As opposed to the precedence of 5-aminopyrimidine being used
as a source for electrophile, the present endeavor (proposed sub-
strate 4; Fig. 1) involves use of the pyrimidine ring (a deactivated
ring) as a
for electrophile) through one of its carbons in a manner to facilitate
the -cyclization. To the best of our knowledge, this is the first
p-nucleophile after being linked to an aryl amine (source
q
CDRI communication no. 7667.
* Corresponding author. Tel.: þ91 522 2612411–18; fax: þ91 522 2623405.
E-mail address: bijoy_kundu@yahoo.com (B. Kundu).
p
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.067

1154
P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
NH2
N
NH2
NH
Cl
R
NH2
R2
N
N
N
N
(2)
(Substrate reported
by Duncton et al4a
(1)
R'
R1
(First aryl amine substrate
N
reported by us)
)
Substrates 5-7
5= R1=NH2; R2=H
NH2
Cl
6= R1=NHCH2C6H5; R2=H
7= R1=NH2; R2=C6H5
N
NH2
N
N
N
N
(4)
(3)
Figure 3. Substrates based on pyrimidine ring as nucleophilic partner for the modified
Pictet–Spengler reaction.
(Substrate reported
(Our proposed substrate)
by Bai et al4b
)
3-dimethylamino-1-(2-nitrophenyl)-propenone 9 as a common
intermediate, which was obtained by heating 1-(2-nitro-
phenyl)ethanone 8 with N,N-dimethylformamide dimethyl acetal.
For the synthesis of 5, chalcone 9 was treated with guanidine hy-
drochloride to give intermediate 10 followed by reduction of the
nitro group with Fe and HCl. For the synthesis of substrate 6,
chalcone 9 was initially treated with 1-benzylguanidine hydro-
chloride in the presence of potassium carbonate in ethanol under
reflux followed by reduction of the nitro group using Fe and HCl.
Finally, synthesis of substrate 7 was carried out by treating
2-nitroacetophenone 8 with benzaldehyde in the presence of KOH
to give chalcone 12 followed by treatment with guanidine hydro-
chloride to give pyrimidine intermediate 13. The nitro group in the
resulting intermediate 13 was reduced in the presence of Fe and
HCl to give 7. With the substrates 5–7 in hand, their abilities to
undergo a Pictet–Spengler cyclization with structurally diverse
aldehydes were investigated.
Figure 1. Substrates 2 and 3: 5-aminopyrimidine acts as a source for electrophile
after formation of imine. Substrate 4: proposed substrate with pyrimidine as
-nucleophile.
a
a
p
report involving the use of pyrimidine ring as a
the Pictet–Spengler reactions.
p-nucleophile in
2. Results and discussion
The studies commenced with the identification of a carbon in
the pyrimidine ring for linking an aryl amine by analyzing the
electrophilic substitution pattern in pyrimidines. Replacing
a CH]CH group in benzene with a heteroatom NH as in pyrrole
increases the susceptibility of the ring carbon atoms to electrophilic
attack very markedly. However, replacement of one CH group in the
benzene with nitrogen atom as in pyridine decreases the ease
of electrophilic attack at the remaining carbon atoms and
replacement of two CH groups with two nitrogen atoms as in py-
rimidine decreases it even further (Fig. 2).7
NO2
O
NO2
O
NO2
O
(i)
(vi)
N
Increasing order of activation
Decreasing order of activation
N
12
9
8
(vii)
N
(ii)
(iv)
N
H
N
N
Figure 2. Increasing/decreasing order of activation in five- and six-membered rings
with reference to benzene.8
NO2
NO2
NO2
N
Indeed, the influence of heteroatom in the six-membered
N
HN
(v)
p
-deficient pyrimidine can be predicted based on a general rule
that the effect of the heteroatom on the - and -carbons is more
pronounced than -carbon. Thus, the C-4 and C-6 in the pyrimidine
N
11
H2N
N
13
H2N
N
10
a
g
b
(viii)
(iii)
are the most deactivated toward electrophilic attack whereas C-5 is
the least deactivated and is therefore prone to electrophilic
substitutions.8
NH2
NH2
Based on these facts, it was envisaged that an aryl amine orig-
inating from the either side of the C-5 in the pyrimidine ring, might
act as a novel substrate for the Pictet–Spengler cyclization. Keeping
these structural requirements in mind, the synthetic feasibilities for
these substrates were analyzed by examining the strategies
reported in the literature for the pyrimidine-based compounds.8
The analysis ultimately led us to the identification of 2-(2,6-di-
substituted-pyrimidin-4-yl)phenylamines 5–7 as the probable
substrates for the application of the Pictet–Spengler reaction
(Fig. 3). In the three pyrimidine substrates 5–7, an aryl amine has
been allowed to originate from C-4, while the C-2 and C-6 positions
have been used for introducing diversity, and C-5, the nucleophilic
NH2
N
N
N
N
H
H2N
N
N
H2N
N
7
5
6
Scheme 1. Synthetic strategy for substrates 5, 6, and 7. Reagents and conditions: (i)
N,N-dimethylformamide dimethyl acetal, 100 ꢀC, 3 h; (ii) guanidine hydrochloride,
potassium carbonate, EtOH, refluxed, 16 h; (iii) Fe, concd HCl, reflux, 1 h; (iv) 1-ben-
zylguanidine hydrochloride, potassium carbonate, EtOH, reflux, 16 h; (v) Fe, concd HCl,
reflux, 1 h; (vi) C6H5CHO, EtOH, KOH, H2O, 3 h 0 ꢀC to rt; (vii) guanidine hydrochloride,
sodium ethoxide, N,N-dimethyl acetamide, 100 ꢀC, 2 h; (viii) Fe, concd HCl, reflux, 1 h.
carbon, has been kept free for
p
-cyclizations.
For the Pictet–Spengler cyclization (Scheme 2), the substrate 5
was treated with 4-nitrobenzaldehyde using a variety of traditional
Pictet–Spengler protocols involving pTsOH in toluene at reflux, 2%
TFA in DCM at 0 ꢀC, AcOH in ethanol at reflux, and neat toluene at
Syntheses of substrates 5–7 were carried out by the modified
procedure reported in the literature9 and has been depicted in
Scheme 1. Substrates 5 and 6 were obtained from the chalcone

P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
1155
The crude product obtained after workup was purified using
a series of column chromatography packing materials: silica gel,
neutral alumina, and basic alumina but the best recovery of the
desired compound occurred only on neutral alumina column
chromatography using EtOAc/hexane as an eluent in 63% isolated
yield. The low recovery of the compound from column chroma-
tography can be attributed to the basic nature of the compound,
which was evident from the fact that after eluting the column with
neat EtOAc, the remaining material was recovered in >90% purity.
The scope and limitation of the modified strategy with substrate 5
was established by synthesizing nine compounds based on pyr-
imido[5,4-c]quinolines 14b–j (Table 2), using nine aromatic alde-
hydes. For the Pictet–Spengler cyclization, 1% triflic acid in DMF at
120 ꢀC protocol was used and in all cases cyclization was found to
be complete within 8 h with isolated yields in the range of 56–68%.
Pleasingly, aldehydes with either electron-donating or electron-
withdrawing group had no adverse effect on the rate of cyclization.
After successfully establishing the strategy on 5, substrate 6 was
then subjected to the Pictet–Spengler reaction with a variety of
aldehydes. The crude products obtained after workup was purified
on neutral alumina column chromatography furnishing pyr-
imido[5,4-c]quinolines 14k–r (Table 2) in 50–67% isolated yields.
The NH-benzyl substitution present at position 2 in substrate 6 had
no affect on the yield and purity of the final endo cyclized products
(14k–r).
NH2
R2
N
NH
R3
(i)
R3
N
N
N
R2
R1
R1
R2
R1
N
N
N
15
5-7
14a-x
Scheme 2. General strategy for the Pictet–Spengler reaction involving substrates 5, 6,
and 7. Reagents and conditions: (i) R3CHO 1% triflic acid in DMF, 120 ꢀC, 8 h.
80 ꢀC. The protocols failed to yield the desired cyclized product 14a
and produced imine as the major product.
Dwelling on the factors affecting p-cyclization, it is well known
that the Bronsted acid plays a pivotal role in enhancement of the
electrophilicity of the imine, which in turn acts as the driving force
for the p
-cyclization.1d Thus, the use of stronger Bronsted acid may
activate the imine leading to the desired cyclized product 14. Ac-
cordingly, the amine 5 was treated with 4-nitrobenzaldehyde using
methanesulfonic acid (MSA) and triflic acid as source for proton
with the view to obtain maximum yield of 14a, and the results of
the optimization studies are listed in Table 1. During the course
of cyclization, no conversion was observed for 5 in the presence of
MSA, while presence of 1% triflic acid in DMF cleanly effected
complete conversion of 5 and afforded 14a in >85% purity based on
HPLC.
Substrate 7, however, was found to be adamant toward endo
cyclization when treated with 2-substituted aromatic aldehydes
while 4-substituted aldehydes indeed furnished endo cyclized
products albeit in low yields. This can be attributed to the steric
hindrance being conferred by the substitution at position 6 in the
substrate 7, which is next to the position 5, the site involved in the
endo cyclization. The isolated yields for pyrimido[5,4-c]quinolines
14u–x (Table 2) using 4-substituted aromatic aldehydes remained
in the range of 45–53% yields.
Table 1
Optimization of the reaction conditions for conversion of substrate 5 to 14a
Entry
Reaction conditions
Temp (ꢀC)
Time (h)
Yield of 14aa (%)
1
2
3
4
5
6
2% MSA/CH3CN
2% MSA/DMF
2% Triflic acid in ACN
2% Triflic acid in DMF
1% Triflic acid in DMF
0.5% Triflic acid in DMF
80
120
80
120
120
120
48
48
24
8
8
16
0
0
20
80
85
30
A careful survey of the literature revealed that synthesis for such
a prototype has not been reported except for the two reports
a
Based on HPLC.
Table 2
Pyrimido[5,4-c]quinolines based on 14
Entry
Substrates
Aldehyde R3-CHO
Pictet–Spengler products
Isolated yield (%)
Retention timea (tR, min)
No.
R1
R2
R3
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
7
7
7
7
7
7
4-NO2-C6H4-CHO
4-OEt-C6H4-CHO
2-OH-C6H4-CHO
4-Cl-C6H4-CHO
4-(CH3)2N-C6H4-CHO
C6H5-CHO
4-Br-C6H4-CHO
4-F-C6H4-CHO
3,4-DiCl-C6H4-CHO
3,4-DiOMe-C6H4-CHO
4-F-C6H4-CHO
14a
14b
14c
14d
14e
14f
14g
14h
14i
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-NO2-C6H4
4-OEt-C6H4
2-OH-C6H4
4-Cl-C6H4
4-(CH3)2N-C6H4
C6H5
4-Br-C6H4
4-F-C6H4
3,4-DiCl-C6H4
3,4-DiOMe-C6H4
4-F-C6H4
63
68
56
59
60
63
62
64
60
65
60
64
62
52
59
67
50
65
NRb
NRb
49
46
53
45
14.07
13.04
7.99
13.84
13.22
14.87
17.91
15.32
19.63
14.81
22.23
23.06
24.91
20.73
22.42
21.85
23.30
21.83
d
9
NH2
NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
14j
14k
14l
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NHCH2C6H5
NH2
NH2
NH2
NH2
NH2
4-Br-C6H4-CHO
4-Br-C6H4
3,4-DiCl-C6H4-CHO
2-NO2-C6H4-CHO
4-Cl-C6H4-CHO
14m
14n
14o
14p
14q
14r
14s
14t
14u
14v
14w
14x
3,4-DiCl-C6H4
2-NO2-C6H4
4-Cl-C6H4
4-NO2-C6H4-CHO
4-(CH3)2N-C6H4-CHO
4-OEt-C6H4-CHO
2-NO2-C6H4-CHO
2-OH-C6H4-CHO
4-OEt-C6H4-CHO
4-(CH3)2N-C6H4-CHO
4-NO2-C6H4-CHO
4-CN-C6H4-CHO
4-NO2-C6H4
4-(CH3)2N-C6H4
4-OEt-C6H4
2-NO2-C6H4
2-OH-C6H4
4-OEt-C6H4
4-(CH3)2N-C6H4
4-NO2-C6H4
4-CN-C6H4
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
d
19.45
19.84
18.71
17.61
NH2
a
Retention time on HPLC (C18 reverse-phase column; 150ꢁ4.8 mm; 5
mm) with a linear gradient of 0–100% CH3CN in water over 30 min, flow rate of 1.0 mL/min, and UV
detection at 220/254 nm.
b
NR¼no reaction due to steric hindrance arising from the substitution at position 6.

1156
P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
B(OH)2
N
Br
NH2
PdCl2(PPh3)2
NH2
Na2CO3, DMF ,
100 °C
NH
O
N
N
20
21
19
N
N
N
Reaction Conditions
N
AcOH, EtOH, 80 °C; toluene, reflux, 5%
TFA. DCM, reflux; neat TFA, reflux; 10%
pTsOH, toluene, reflux; 2 % TFA, CH3CN,
80 °C; Yb(OTf)3, DCM, MSA/CH3CN, reflux
Cl
17 [Ref 11]
16 [Ref 10]
Figure 4. Structural variants of pyrimido[5,4-c]quinolines 14 reported in the literature.
N
N
R1
dealing with the synthesis of its structural variants: 4-phenyl-
R1
pyrimido[5,4-c]quinoline10 16 and 1-(3-chloro phenyl)-3-ethyl-9-
N
22
methoxy-5-styryltetrahydro-pyrimido[5,4-c]quinoline11 17
in
N
18
N-Acyliminium
Pictet-Spengler
reaction
X-Cl
which quinoline is fused at positions 5 and 6 of the pyrimidine ring
(Fig. 4). On the contrary, in the pyrimido[5,4-c]quinolines 14, the
quinoline ring is fused to the positions 4 and 5 of the pyrimidine
ring. In addition, the synthetic strategies described for the com-
pounds 16 and 17 were completely different from the synthesis
reported for pyrimido[5,4-c]quinolines using modified Pictet–
Spengler strategy.
18a, R1 = 4-NO2C6H4
18b, R1 = 4-OMeC6H4
X
N
R1
N
Further it is interesting to note that the pyrimidine-based Pic-
tet–Spengler product bored a strong structural analogy to benzo-
[c][2,7]naphthyridine 18 (Fig. 5), which is a common structural
motif present in a wide range of polycyclic alkaloids isolated from
marine organisms with diverse biological activity (calcium-re-
leasing, antiviral, antimicrobial, cytotoxic to L1210 murine leuke-
mia cells).12 The only difference between the two compounds is the
presence of extra nitrogen at position 3 in 14.
23
X = CO2Et or Ac
R1 = 4-NO2C6H4 or
4-OMeC6H4
Scheme 3. Failure of synthetic attempts for benzo[c][2,7]naphthyridines 18 and 23.
This was followed by application of N-acyliminium Pictet–
Spengler strategy,14 a method widely used for facilitating 6-endo
cyclization. Accordingly, the imine 22 was treated with ethyl
chloroformate in pyridine using the methodology reported in the
literature to facilitate the 6-endo cyclization. However, this failed to
N
N
N
furnish the
p-cyclized product 23, even after carrying out the re-
N
N
action either for the prolonged period or by using different N-acyl
species reported in the literature.
A close structural examination of the pyrimidine-based sub-
strates 5–7 and pyridine based substrate 19 revealed that the
presence of an additional amino group as electron-releasing sub-
Pyrimido[5,4-c]quinoline 14
Benzo[c][2,7]naphthyridine 18
[Ref 12]
Figure 5. Structural analogy between 14 and benzo[c][2,7]-naphthyridine 18 present
in natural products.
stituent at C-2 of the pyrimidine may be facilitating the
zation. Thus, it appears that the failure of pyridine substrate 19 to
undergo -cyclization could be attributed to the lack of electron-
releasing substituents in the pyridine ring. Further, no attempts
were made to work with 2-substituted pyridines as it would lead to
a regioisomeric mixture of cyclized products.
p-cycli-
This prompted us to synthesize benzo[c][2,7]naphthyridine 18
using the modified Pictet–Spengler reaction. It was envisaged that
18 could be obtained by subjecting 2-pyridin-4-yl-phenylamine 19
to 6-endo cyclization by treating with aromatic aldehydes (Scheme
3). Accordingly, in the first instance synthesis of substrate 19 was
carried out by treating pyridine-4-boronic acid 20 with 2-bro-
moaniline 21 using Suzuki coupling reaction.13 Finally substrate 19
was subjected to Pictet–Spengler reaction by treating with 4-
nitrobenzaldehyde in the presence of 1% triflic acid in DMF in
sealed tube at 120 ꢀC. Surprisingly the initial attempts failed to
furnish the cyclized product 18a, instead the corresponding imine
22 remained as the only isolated product. The application of other
widely used Pictet–Spengler protocols, acetic acid in ethanol, tol-
uene at reflux, 5% TFA in DCM at reflux, neat TFA at reflux, 10%
pTsOH in toluene at reflux, 2% TFA in acetonitrile, Yb(OTf)3 in DCM,
MSA in CH3CN at reflux, using both p-nitrobenzaldehyde and
p-methoxybenzaldehyde, also failed to yield the 6-endo cyclized
product. Most of these conditions either produced the imine 22 as
the only product or resulted in the reactants probably due to the
degradation of 22.
p
3. Conclusion
In conclusion we have successfully identified 2-amino-
pyrimidine, under deactivated class of heterocyclic ring as a nucleo-
philic partner, which when attached to an aryl amine successfully
underwent the Pictet–Spengler reaction with aldehydes having
both electron-donating and electron-withdrawing groups. The ef-
ficacy of the strategy has been exemplified in a series of pyrimidine
rings by introducing diversity at positions 2 and 6. However, ex-
plorations of new substrates, involving the pyridine ring as nucleo-
philic partner, were futile. This example, thus presents a limitation
to the aryl amine based third generation substrates, which was
otherwise successful when applied in the past to a host of deacti-
vated heterocyclic rings such as triazole, tetrazole, and quinoxaline.

P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
1157
4. Experimental
4.4. Procedure for the synthesis of 4-(2-aminophenyl)-
pyrimidin-2-ylamine (5)
4.1. General consideration
4-(2-Nitrophenyl)pyrimidin-2-ylamine 10 (2.5 g, 11.6 mmol)
was dissolved in a mixture of ethanol (40 mL) and water (10 mL)
followed by the addition of iron powder (1.9 g, 34.71 mmol) and
concd HCl (10 mL). The reaction mixture was stirred under reflux
for 1 h, cooled, and then filtered through a pad of Celite. The filtrate
was concentrated in vacuo and compound was extracted in ethyl
acetate (15 mLꢁ3). The organic layer washed sequentially with satd
NaHCO3 and brine, and after drying over Na2SO4 was concentrated
in vacuo. The crude product so obtained was purified by re-
crystallization in EtOH to give 4-(2-aminophenyl)pyrimidin-2-yl-
amine as a yellow solid.
All solvents were commercially available and used without
purification. All products were characterized by 1H NMR, 13C NMR,
ESMS, IR, and HPLC. Analytical TLC was performed using 2.5ꢁ5 cm
plated coated with a 0.25 mm thickness of silica gel 60F254 Merck
and visualization was accomplished with UV light and iodine.
Column chromatography was performed using silica gel 60
Thomas Baker (100–200 mesh). 1H NMR spectra (200/300 MHz)
are reported as follows: chemical shifts in parts per million
downfield from TMS as internal standard (
[br¼broad, s¼singlet, d¼doublet, t¼triplet,
d
scale), multiplicity
q¼quartet,
m¼multiplet, o¼overlapped], integration, and coupling constant
(Hz). All 13C NMR spectra (50/75 MHz) were recorded at 25 ꢀC with
complete proton decoupling and reported in parts per million.
Elemental analyses were performed on a Carlo Erba 1108 micro-
analyzer or Elementar’s Vario EL III microanalyzer in the SAIF di-
vision of our institute. Analytical HPLC were performed on C18
reverse-phase column (150 mmꢁ4.8 mm). Mass spectra were
recorded on a Merck MS-8000 spectrometer and HR/EI mass
spectra were done on JEOL-600H at 70 eV. Melting points reported
were uncorrected.
Yield¼1.90 g (90%), yellow solid, mp 171–172 ꢀC, Rf¼0.50 (1:1
EtOAc/hexane); IR (KBr) nmax 3428, 3020, 1612, 1216 cmꢂ1; 1H NMR
(300 MHz, DMSO-d6)
d
¼8.20 (1H, d, J¼5.5 Hz, ArH), 7.60 (1H, d,
J¼7.2 Hz, ArH), 7.13–7.08 (1H, m, ArH), 7.01 (2H, br s, NH2), 6.96 (1H,
d, J¼5.5 Hz, ArH), 6.75 (1H, d, J¼8.1 Hz, ArH), 6.65 (2H, br s, NH2),
6.55 (1H, t, J¼7.5 Hz, ArH); 13C NMR (75 MHz, DMSO-d6)
¼166.4,
d
162.6, 158.1, 149.3, 131.1, 128.9, 116.9, 116.6, 115.2, 105.9; mass (ESþ)
m/z 187.2 (Mþþ1). Anal. Calcd for C10H10N4: C, 64.50; H, 5.41; N,
30.09. Found: C, 64.35; H, 5.37; N, 30.13.
4.5. Procedure for the synthesis of N-benzyl-N-[4-(2-nitro-
phenyl)pyrimidin-2-yl]amine (11)
4.2. Procedure for the synthesis of (E)-3-(dimethylamino)-1-
(2-nitrophenyl)prop-2-en-1-one (9)
To a stirred solution of 1-benzylguanidine hydrochloride (2.52 g,
13.62 mmol) and potassium carbonate (2.20 g, 15.89 mmol) in
ethanol (20 mL) was added (E)-3-(dimethylamino)-1-(2-nitro-
phenyl)prop-2-en-1-one 9 (1.0 g, 4.54 mmol) and reaction mixture
was refluxed for 16 h. After completion of the reaction as evident by
TLC analysis, ethanol was distilled off, water (20 mL) was added,
and the compound was extracted with ethyl acetate (15 mLꢁ3). The
organic layer washed with brine, dried over Na2SO4, and concen-
trated. The residue so obtained was triturated with diethyl ether to
furnish pure compound as a light yellow solid.
A mixture of 1-(2-nitrophenyl)ethan-1-one 8 (1.0 g, 6.05 mmol)
and N,N-dimethylformamide dimethyl acetal (0.72 g, 6.05 mmol)
was heated at 100 ꢀC for 3 h. The reaction mixture was then sub-
jected to column chromatography (100–200 silica gel) using ethyl
acetate/hexane (80:20, v/v) as eluent.
Yield¼1.10 g (85%), red solid, mp 128–129 ꢀC, Rf¼0.25 (4:1
EtOAc/hexane); IR (KBr) nmax 3029, 2884, 1640, 1521, 1362 cmꢂ1; 1H
NMR (300 MHz, DMSO-d6)
d
¼7.92 (1H, d, J¼7.7 Hz, ArH), 7.74–7.69
(1H, m, ArH), 7.64–7.48 (3H, m, ]CH, ArH), 5.34 (1H, d, J¼12.5 Hz,
Yield¼1.21 g (87%), yellow solid, mp 156 ꢀC, Rf¼0.45 (1:1 EtOAc/
]CH), 3.10 (3H, s, CH3), 2.86 (3H, s, CH3); 13C NMR (75 MHz, DMSO-
hexane); IR (KBr) nmax 3230, 2947, 1569, 1525, 1367 cmꢂ1; 1H NMR
d6)
d
¼155.3, 147.9, 137.6, 132.9, 130.1, 128.8, 123.9, 44.6, 37.1; mass
(300 MHz, CDCl3)
d
¼8.39 (1H, s, ArH), 7.85 (1H, d, J¼7.7 Hz, ArH),
(ESþ) m/z 221.1 (Mþþ1). Anal. Calcd for C11H12N2O3: C, 59.99; H,
7.68–7.54 (3H, m, ArH), 7.35–7.29 (5H, m, ArH), 6.77–6.74 (1H, m,
5.49; N, 12.72. Found: C, 59.89; H, 5.42; N, 12.62.
ArH), 5.58 (1H, br s, NH), 4.62 (2H, d, J¼1.7 Hz, CH2); 13C NMR
(75 MHz, CDCl3)
d
¼163.6, 162.1, 158.9, 149.3, 138.9, 133.5, 132.2,
4.3. Procedure for the synthesis of 4-(2-nitrophenyl)-
pyrimidin-2-ylamine (10)
130.6, 130.0, 128.6, 127.6, 127.2, 124.3, 108.8, 45.4; mass (ESþ) m/z
307.1 (Mþþ1). Anal. Calcd for C17H14N4O2: C, 66.66; H, 4.61; N,
18.29. Found: C, 66.54; H, 4.56; N, 18.36.
To
a stirred solution of guanidine hydrochloride (1.30 g,
13.62 mmol) and potassium carbonate (2.20 g, 15.89 mmol) in
ethanol (20 mL) was added (E)-3-(dimethylamino)-1-(2-nitro-
phenyl)prop-2-en-1-one 9 (1.0 g, 4.54 mmol) and the reaction
mixture was refluxed for 16 h. After completion of the reaction as
evident by TLC analysis, ethanol was distilled off, water (20 mL)
was added, and compound was extracted with ethyl acetate
(15 mLꢁ3). The organic layer washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue so obtained was
triturated with diethyl ether to furnish pure compound as a light
yellow solid.
4.6. Procedure for the synthesis of N-[4-(2-aminophenyl)-
pyrimidin-2-yl]-N-benzylamine (6)
N-Benzyl-N-[4-(2-nitrophenyl)pyrimidin-2-yl]amine 11 (1.0 g,
3.27 mmol) was dissolved in a mixture of ethanol (20 mL) and
water (5 mL) followed by the addition of iron powder (0.5 g,
9.80 mmol) and concd HCl (10 mL). The reaction mixture was stir-
red under reflux for 1 h, cooled, and then filtered through a pad of
Celite. The filtrate was concentrated in vacuo and the compound
was extracted in ethyl acetate (15 mLꢁ3). The organic layer washed
sequentially with satd NaHCO3 and brine, and after drying over
Na2SO4 was concentrated in vacuo. The crude product so obtained
was purified by recrystallization in EtOH to give N-[4-(2-amino-
phenyl)pyrimidin-2-yl]-N-benzylamine as a yellow solid.
Yield¼0.80 g (82%), yellow solid, mp 209–210 ꢀC, Rf¼0.75 (4:1
EtOAc/hexane); IR (KBr) nmax 3329, 3171, 1654, 1524, 1364 cmꢂ1; 1H
NMR (300 MHz, DMSO-d6)
d
¼8.35 (1H, d, J¼5.0 Hz, ArH), 7.98 (1H,
d, J¼7.7 Hz, ArH), 7.82–7.77 (1H, m, ArH), 7.73–7.67 (2H, m, ArH),
6.80 (1H, d, J¼5.0 Hz, ArH), 6.69 (2H, br s, NH2); 13C NMR (75 MHz,
Yield¼0.70 g (80%), yellow solid, mp 159–160 ꢀC, Rf¼0.50 (1:1
DMSO-d6)
d
¼163.4, 163.3, 159.3, 148.7, 133.2, 133.1, 130.8, 130.5,
EtOAc/hexane); IR (KBr) nmax 3232, 3032, 1613, 1587, 1552 cmꢂ1; 1H
124.4, 108.3; mass (ESþ) m/z 217.1 (Mþþ1). Anal. Calcd for
C10H8N4O2: C, 55.55; H, 3.73; N, 25.91. Found: C, 55.51; H, 3.63; N,
25.82.
NMR (300 MHz, DMSO-d6)
d
¼8.26 (1H, d, J¼5.4 Hz, ArH), 7.83 (1H, t,
J¼6.1 Hz, NH), 7.60 (1H, d, J¼7.3 Hz, ArH), 7.36–7.28 (4H, m, ArH),
7.24–7.19 (1H, m, ArH), 7.10 (1H, t, J¼7.1 Hz, ArH), 6.98 (1H, d,

1158
P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
J¼5.4 Hz, ArH), 6.73 (1H, d, J¼8.0 Hz, ArH), 6.57–6.52 (1H, m, ArH),
Yield¼0.35 g (78%), yellow solid, mp 151–152 ꢀC, Rf¼0.50 (1:3
EtOAc/hexane); IR (KBr) nmax 3507, 3395, 1601, 1530 cmꢂ1; 1H NMR
4.52 (2H, d, J¼6.0 Hz, CH2); 13C NMR (75 MHz, CDCl3)
¼161.9,159.5,
d
148.9,140.2,132.7,130.7,130.6,128.6,128.2,127.2,126.6,124.2,108.0,
43.9; mass (ESþ) m/z 277.2 (Mþþ1). Anal. Calcd for C17H16N4: C,
73.89; H, 5.84; N, 20.27. Found: C, 73.72; H, 5.96; N, 20.34.
(300 MHz, CDCl3)
d
¼8.07–8.03 (2H, m, ArH), 7.67–7.64 (1H, dd,
J¼1.2, 7.9 Hz, ArH), 7.50 (3H, t, J¼3.3 Hz, ArH), 7.41 (1H, s, ArH),
7.26–7.21 (1H, m, ArH), 6.83–6.75 (2H, m, ArH), 5.78 (2H, br s, NH2),
5.16 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3)
d
¼168.1, 166.0, 162.5,
4.7. Procedure for the synthesis of (E)-1-(2-nitrophenyl)-3-
phenylprop-2-en-1-one (12)
147.3, 137.8, 131.3, 130.4, 129.5, 128.8, 127.1, 120.0, 117.5, 117.4, 105.6;
mass (ESþ) m/z 263.3 (Mþþ1). Anal. Calcd for C16H14N4: C, 73.26; H,
5.38; N, 21.36. Found: C, 73.18; H, 5.26; N, 21.17.
To
a solution of 1-(2-nitrophenyl)ethan-1-one 8 (2.0 g,
12.1 mmol) in 50 mL of ethanol was added potassium hydroxide
(1.01 g, 18.1 mmol) in 10 mL of water over a period of 30 min at 0 ꢀC
to room temperature. Thereafter, benzaldehyde (1.35 mL,
13.3 mmol) was added slowly to the reaction mixture. The reaction
mixture was stirred at room temperature for 3 h. The solvent was
removed from the reaction mixture under reduced pressure. Water
was added and the aqueous phase was extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The crude product was purified by column chro-
matography on silica gel using hexane/ethyl acetate (90:10) as
eluent to furnish the title compound as yellow solid.
4.10. General procedure for the synthesis of pyrimido-
[5,4-c]quinolines via the Pictet–Spengler reaction from
substrates 5, 6, and 7
A mixture of 5 or 6 or 7 (1.34 mmol) and aldehyde (1.47 mmol)
in DMF (2 mL) was treated with 1% triflic acid (1 mL) at 120 ꢀC for
8 h. The completion of Pictet–Spengler cyclization was monitored
by TLC. After that the solvent was evaporated and the residue so
obtained was triturated with aq NaHCO3 (10 mL). It was then
extracted with EtOAc (20 mL), washed with brine (10 mL), and
dried over Na2SO4. EtOAC was evaporated to dryness under reduced
pressure and the crude product was purified on a neutral alumina
column using hexane/ethyl acetate (1:4, v/v) as eluent.
Yield¼2.5 g (83%), white solid, mp 126–127 ꢀC, Rf¼0.40 (1:9,
EtOAc/hexane); IR (KBr) nmax 3044, 1657, 1526, 1341 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
7.75 (1H, m, ArH), 7.70–7.64 (1H, m, ArH), 7.54–7.50 (3H, m, ArH),
d
¼8.21–8.18 (1H, dd, J¼0.1, 8.2 Hz, ArH), 7.81–
4.10.1. 5-(4-Nitrophenyl)pyrimido[5,4-c]quinolin-2-ylamine (14a)
Yield¼0.29 g (68%), yellow solid, mp >250 ꢀC, Rf¼0.58 (1:1
EtOAc/hexane); IR (KBr) nmax 3315, 3205, 1646, 1513, 1347 cmꢂ1; 1H
7.41–7.36 (3H, m, ArH), 7.26 (1H, d, J¼16.3 Hz, ]CH), 7.02 (1H, d,
J¼16.3 Hz, ]CH); 13C NMR (75 MHz, CDCl3)
¼192.9, 146.7, 146.3,
d
136.3, 134.1,133.9,131.1,130.6,129.0,128.8,128.6,126.3, 124.6; mass
(ESþ) m/z 254.2 (Mþþ1). Anal. Calcd for C15H11NO3: C, 71.14; H,
4.38; N, 5.53. Found: C, 71.26; H, 4.45; N, 5.65.
NMR (300 MHz, DMSO-d6)
J¼1.0, 8.1 Hz, ArH), 8.43 (2H, d, J¼8.8 Hz, ArH), 8.07 (3H, d, J¼8.9 Hz,
d
¼8.99 (1H, s, ArH), 8.82–8.79 (1H, dd,
ArH), 7.94–7.89 (1H, m, ArH), 7.76–7.71 (3H, m, NH and ArH); 13C
NMR (75 MHz, DMSO-d6)
d
¼162.9, 161.2, 157.3, 155.5, 147.9, 147.2,
4.8. Procedure for the synthesis of 4-(2-nitrophenyl)-6-
phenylpyrimidin-2-ylamine (13)
143.9, 132.2, 131.3, 129.32, 127.1, 123.6, 123.5, 122.9, 110.2; mass
(ESþ) m/z 318.3 (Mþþ1). Anal. Calcd for C17H11N5O2: C, 64.35; H,
3.49; N, 22.07. Found: C, 64.25; H, 3.54; N, 22.16.
To a solution of guanidine hydrochloride (2.26 g, 23.71 mmol) in
N,N-dimethyl acetamide (20 mL), sodium ethoxide (1.88 g,
27.65 mmol) was added. The reaction mixture was heated at 100 ꢀC
for 30 min and 1-(2-nitrophenyl)-3-phenylprop-2-en-1-one 12
(2 g, 7.90 mmol) was added and refluxed for 2 h. The solvent was
removed from the reaction mixture under reduced pressure. Water
was added and the aqueous phase was extracted with ethyl acetate
(15 mLꢁ3). The organic layer was dried over anhydrous Na2SO4 and
concentrated. The crude product was purified by column chroma-
tography on silica gel (hexane/ethyl acetate 60:40).
4.10.2. 5-(4-Ethoxyphenyl)pyrimido[5,4-c]quinolin-
2-ylamine (14b)
Yield¼0.27 g (63%), white solid, mp 236 ꢀC, Rf¼0.43 (1:1 EtOAc/
hexane); IR (KBr) nmax 3294, 3162, 2976, 1639, 1346, 1251 cmꢂ1; 1H
NMR (300 MHz, CDCl3)
d
¼9.19 (1H, s, ArH), 8.89 (1H, d, J¼8.1 Hz,
ArH), 8.15 (1H, d, J¼8.2 Hz, ArH), 7.88–7.83 (1H, m, ArH), 7.72 (2H, d,
J¼8.6 Hz, ArH), 7.64 (1H, t, J¼7.5 Hz, ArH), 7.09 (2H, d, J¼8.6 Hz,
ArH), 5.63 (2H, br s, NH2), 4.16 (2H, q, J¼6.9 Hz, CH2), 1.49 (3H, t,
J¼6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3þTFA)
d
¼164.9, 159.4,
Yield¼1.65 g (72%), yellow solid, mp 191–192 ꢀC, Rf¼0.45 (1:3
157.3, 138.1, 137.8, 132.5, 131.1, 126.3, 121.2, 120.9, 118.3, 116.6, 109.1,
64.7, 13.9; mass (ESþ) m/z 317.3 (Mþþ1). Anal. Calcd for C19H16N4O:
C, 72.13; H, 5.10; N, 17.71. Found: C, 72.23; H, 5.18; N, 17.64.
EtOAc/hexane); IR (KBr) nmax 3021, 1634, 1573, 1362 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
ArH), 7.73–7.58 (3H, m, ArH), 7.51–7.49 (3H, m, ArH), 7.20 (1H, s,
ArH), 5.21 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3)
d
¼8.06–8.02 (2H, m, ArH), 7.95 (1H, d, J¼7.9 Hz,
d¼166.5, 164.9,
4.10.3. 2-(2-Aminopyrimido[5,4-c]quinolin-5-yl)phenol (14c)
Yield¼0.22 g (56%), white solid, mp 228–229 ꢀC, Rf¼0.45 (1:1
EtOAc/hexane); IR (KBr) nmax 3303, 3138, 1642, 1597, 1344 cmꢂ1; 1H
163.1, 148.9, 137.1, 134.0, 132.7, 130.8, 130.7, 130.1, 128.8, 127.2, 124.5,
106.2; mass (ESþ) m/z 293.2 (Mþþ1). Anal. Calcd for C16H12N4O2: C,
65.75; H, 4.14; N, 19.17. Found: C, 65.64; H, 4.08; N, 19.24.
NMR (300 MHz, CDCl3)
d
¼12.53 (1H, s, OH), 9.43 (1H, s, ArH), 8.89
(1H, d, J¼8.0 Hz, ArH), 8.03 (1H, d, J¼8.3 Hz, ArH), 7.89–7.84 (1H, m,
4.9. Procedure for the synthesis of 4-(2-aminophenyl)-6-
phenylpyrimidin-2-ylamine (7)
ArH), 7.70–7.63 (2H, m, ArH), 7.47–7.42 (1H, m, ArH), 7.22 (1H, d,
J¼8.2 Hz, ArH), 7.06 (1H, t, J¼7.5 Hz, ArH), 5.68 (2H, br s, NH2); 13
C
NMR (75 MHz, DMSO-d6)
d
¼162.9, 162.2, 158.1, 155.0, 154.7, 147.6,
4-(2-Nitrophenyl)-6-phenylpyrimidin-2-amine
13
(0.5 g,
131.8, 131.2, 130.6, 128.9, 126.4, 124.7, 123.3, 122.9, 119.4, 115.9,
110.8; mass (ESþ) m/z 289.4; (Mþþ1); MS (HREI) m/z calcd for [Mþ]
288.1011, found 288.1013. Anal. Calcd for C17H12N4O: C, 70.82; H,
4.20; N, 19.43. Found: C, 70.62; H, 4.35; N, 19.28.
1.71 mmol) was dissolved in a mixture of ethanol (10 mL) and
water (2 mL). Iron powder (0.29 g, 5.13 mmol) and concd HCl
(2 mL) were added, the mixture was stirred under reflux for 1 h,
cooled, and filtered through a pad of Celite. The filtrate was con-
centrated in vacuo. The residue was extracted with EtOAc
(15 mLꢁ3). The organic layer washed sequentially with satd
NaHCO3 and brine, and after drying over Na2SO4 was concentrated
in vacuo. The crude product so obtained was purified by re-
crystallization in EtOH to give a yellow solid.
4.10.4. 5-(4-Chlorophenyl)pyrimido[5,4-c]quinolin-
2-ylamine (14d)
Yield¼0.24 g (59%), white solid, mp >250 ꢀC, Rf¼0.45 (1:1
EtOAc/hexane); IR (KBr) nmax 3315, 3308, 1646, 1593 cmꢂ1; 1H NMR
(300 MHz, DMSO-d6)
d
¼8.99 (1H, s, ArH), 8.80–8.77 (1H, dd, J¼1.0,

P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
1159
8.0 Hz, ArH), 8.02 (1H, d, J¼8.0 Hz, ArH), 7.91–7.86 (1H, m, ArH),
7.80 (2H, d, J¼8.4 Hz, ArH), 7.70–7.64 (5H, m, NH2, ArH); 13C NMR
(ESþ) m/z 341.4 (Mþþ1). Anal. Calcd for C17H10Cl2N4: C, 59.84; H,
2.95; N, 16.42. Found: C, 59.75; H, 2.90; N, 16.37.
(75 MHz, DMSO-d6)
d
¼162.8, 161.2, 157.9, 155.5, 147.3, 136.5, 134.1,
132.00, 131.7, 129.1, 128.5, 126.6, 123.4, 122.7, 110.2; mass (ESþ) m/z
307.4 (Mþþ1). Anal. Calcd for C17H11ClN4: C, 66.56; H, 3.61; N,18.26.
Found: C, 66.45; H, 3.49; N, 18.14.
4.10.10. 5-(3,4-Dimethoxyphenyl)pyrimido[5,4-c]quinolin-2-
ylamine (14j)
Yield¼0.29 g (65%), yellow solid, mp 212–213 ꢀC, Rf¼0.40 (1:1
EtOAc/hexane); IR (KBr) nmax 3321, 3182, 1649, 1591 cmꢂ1; 1H NMR
4.10.5. 5-[4-(Dimethylamino)phenyl]pyrimido[5,4-c]quinolin-2-
amine (14e)
(300 MHz, CDCl3)
d
¼9.20 (1H, s, ArH), 8.88 (1H, dd, J¼1.1, 8.1 Hz,
ArH), 8.15 (1H, d, J¼7.8 Hz, ArH), 7.88–7.82 (1H, m, ArH), 7.67–7.62
(1H, m, ArH), 7.36 (1H, d, J¼1.9 Hz, ArH), 7.28 (1H, d, J¼1.9 Hz, ArH),
7.05 (1H, d, J¼8.2 Hz, ArH), 5.63 (2H, s, NH2), 3.98 (6H, s, 2ꢁOCH3);
Yield¼0.24 g (60%), yellow solid, mp >250 ꢀC, Rf¼0.45 (1:1
EtOAc/hexane); IR (KBr) nmax 3295, 3130, 2922,1639,1346 cmꢂ1; 1H
NMR (300 MHz, DMSO-d6)
d
¼9.09 (1H, s, ArH), 8.74 (1H, d,
13C NMR (150 MHz, DMSO-d6)
d¼163.2, 161.9, 159.3, 156.0, 150.2,
J¼8.0 Hz, ArH), 7.96 (1H, d, J¼8.2 Hz, ArH), 7.86–7.81 (1H, m, ArH),
7.64 (3H, t, J¼8.4 Hz, ArH), 7.57 (2H, br s, NH2), 6.88 (2H, d, J¼8.7 Hz,
149.0, 147.8, 132.3, 130.6, 129.4, 126.6, 123.8, 123.3, 122.9, 113.7,
111.8, 110.9; mass (ESþ) m/z 333.3 (Mþþ1). Anal. Calcd for
C19H16N4O2: C, 68.66; H, 4.85; N, 16.86. Found: C, 68.55; H, 4.92; N,
16.78.
ArH), 3.01 (6H, s, 2ꢁCH3); 13C NMR (75 MHz, DMSO-d6)
¼162.6,
d
161.5, 159.1, 155.7, 150.9, 147.7, 131.7, 131.0, 128.8, 125.7, 124.9, 123.3,
122.2, 111.6, 110.3; DEPT 135 (75 MHz, DMSO-d6)
d
¼161.9, 132.2,
131.5, 129.3, 126.2, 123.8, 112.1, 40.3; mass (ESþ) m/z 316.4 (Mþþ1).
Anal. Calcd for C19H17N5: C, 72.36; H, 5.43; N, 22.21. Found: C, 72.25;
H, 5.33; N, 22.15.
4.10.11. N-Benzyl-N-[5-(4-fluorophenyl)pyrimido[5,4-c]quinolin-
2-yl]amine (14k)
Yield¼0.30 g (60%), white solid, mp 198–199 ꢀC, Rf¼0.40 (2:3
EtOAc/hexane); IR (KBr) nmax 3250, 3091, 1601 cmꢂ1 1H NMR
;
4.10.6. 5-Phenylpyrimido[5,4-c]quinolin-2-ylamine (14f)
(300 MHz, CDCl3)
d
¼8.96 (2H, d, J¼8.2 Hz, ArH), 8.12 (1H, d,
Yield¼0.29 g (63%), yellow solid, mp 229–230 ꢀC, Rf¼0.43 (1:1
J¼8.2 Hz, ArH), 7.87–7.81 (1H, m, ArH), 7.75–7.70 (2H, m, ArH), 7.64
(1H, t, J¼7.60 Hz, ArH), 7.44 (2H, s, ArH), 7.34 (2H, t, J¼7.2 Hz, ArH),
7.29–7.22 (3H, m, ArH), 6.18 (1H, s, NH), 4.91 (2H, s, CH2); 13C NMR
EtOAc/hexane); IR (KBr) nmax 3301, 3132, 1643, 1591 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
d
¼9.13 (1H, s, ArH), 8.89 (1H, dd, J¼1.2, 8.1 Hz,
ArH), 8.15 (1H, d, J¼8.2 Hz, ArH), 7.88–7.83 (1H, m, ArH), 7.76–7.72
(75 MHz, CDCl3)
d
¼165.6, 158.3, 157.3, 144.3, 137.8, 133.6, 132.4,
(2H, m, ArH), 7.68–7.63 (1H, m, ArH), 7.58–7.55 (3H, m, ArH), 5.64
132.3, 130.2, 128.9, 127.9, 127.2, 126.3, 124.5, 123.4, 110.7, 46.1; mass
(ESþ) m/z 381.4 (Mþþ1). Anal. Calcd for C24H17FN4: C, 75.77; H,
4.50; N, 14.73. Found: C, 75.65; H, 4.43; N, 14.67.
(2H, br s, NH2); 13C NMR (150 MHz, DMSO-d6)
d
¼163.2, 161.8, 159.6,
155.9, 147.8, 138.1, 132.4, 130.3, 129.6, 129.5, 128.9, 126.9, 123.8,
123.1,110.7; mass (ESþ) m/z 273.4 (Mþþ1). Anal. Calcd for C17H12N4:
C, 74.98; H, 4.44; N, 20.58. Found: C, 74.93; H, 4.34; N, 20.65.
4.10.12. N-Benzyl-N-[5-(4-bromophenyl)pyrimido[5,4-c]-
quinolin-2-yl]amine (14l)
4.10.7. 5-(4-Bromophenyl)pyrimido[5,4-c]quinolin-
2-ylamine (14g)
Yield¼0.37 g (64%), white solid, mp 192–193 ꢀC, Rf¼0.42 (2:3
EtOAc/hexane); IR (KBr) nmax 3248, 2924, 1596, 1549 cmꢂ1; 1H NMR
Yield¼0.29 g (62%), yellow solid, mp >250 ꢀC, Rf¼0.44 (1:1
(300 MHz, CDCl3)
d
¼8.96 (2H, s, ArH), 8.12 (1H, d, J¼8.13 Hz, ArH),
EtOAc/hexane); IR (KBr) nmax 3306, 3189, 1636, 1593 cmꢂ1; 1H NMR
7.87–7.81 (1H, m, ArH), 7.72–7.67 (2H, m, ArH), 7.64–7.60 (3H, m,
ArH), 7.74 (2H, s, ArH), 7.37–7.28 (3H, m, ArH), 6.17 (1H, s, NH), 4.91
(300 MHz, DMSO-d6)
d
¼8.99 (1H, s, ArH), 8.78 (1H, dd, J¼0.9,
7.9 Hz, ArH), 8.02 (1H, d, J¼7.9 Hz, ArH), 7.92–7.87 (1H, m, ArH),
(2H, s, CH2); 13C NMR (75 MHz, CDCl3)
d¼161.26, 158.6, 156.3, 148.0,
7.81–7.70 (5H, m, ArH), 7.68 (2H, br s, NH2); 13C NMR (150 MHz,
138.6, 136.9,132.3,131.9,131.8,131.5,129.5, 128.7,127.9,127.6,126.8,
124.1, 123.9, 123.5, 111.3; mass (ESþ) m/z 441.2 (Mþþ1). Anal. Calcd
for C24H17BrN4: C, 65.32; H, 3.88; N, 12.70. Found: C, 65.25; H, 3.75;
N, 12.76.
DMSO-d6)
d
¼163.3, 161.7, 158.4, 155.9, 147.7, 137.3, 132.4, 132.3,
131.8, 129.5, 127.0, 123.8, 123.3, 123.1, 100.6; mass (ESþ) m/z 351.3
(Mþþ1). Anal. Calcd for C17H11BrN4: C, 58.14; H, 3.16; N, 15.95.
Found: C, 58.07; H, 3.25; N, 15.89.
4.10.13. N-Benzyl-N-[5-(3,4-dichlorophenyl)pyrimido[5,4-c]-
quinolin-2-yl]amine (14m)
4.10.8. 5-(4-Fluorophenyl)pyrimido[5,4-c]quinolin-
2-ylamine (14h)
Yield¼0.35 g (62%), white solid, mp 199–200 ꢀC, Rf¼0.42 (2:3
Yield¼0.25 g (64%), yellow solid, mp 243–244 ꢀC, Rf¼0.40 (1:1
EtOAc/hexane); IR (KBr) nmax 3083, 2925, 1599, 1560 cmꢂ1; 1H NMR
EtOAc/hexane); IR (KBr) nmax 3306, 3186, 1636, 1594 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
d
¼8.96 (2H, s, ArH), 8.11 (1H, d, J¼6.1 Hz, ArH),
(300 MHz, CDCl3)
d
¼9.09 (1H, s, ArH), 8.89 (1H, dd, J¼1.0, 8.1 Hz,
7.87–7.83 (2H, m, ArH), 7.68–7.61 (2H, m, ArH), 7.56 (1H, dd, J¼1.0,
6.1 Hz, ArH), 7.45 (2H, s, ArH), 7.36–7.33 (2H, m, ArH), 7.30 (1H, d,
J¼6.2 Hz, ArH), 6.25 (1H, br s, NH), 4.92 (2H, s, CH2); 13C NMR
ArH), 8.14 (1H, d, J¼8.2 Hz, ArH), 7.89–7.83 (1H, m, ArH), 7.76–7.71
(2H, m, ArH), 7.69–7.63 (1H, m, ArH), 7.29–7.24 (2H, m, ArH), 5.64
(2H, br s, NH2); 13C NMR (75 MHz, CDCl3þTFA)
d¼167.3, 164.7,
(150 MHz, CDCl3þTFA) ¼164.7, 158.4, 155.9, 139.3, 137.6, 136.5,
d
164.2, 158.9, 158.6, 137.8, 136.2, 132.9, 132.8, 130.4, 125.5, 123.9,
123.1, 121.6, 117.4, 113.7, 110.8; mass (ESþ) m/z 291.4 (Mþþ1). Anal.
Calcd for C17H11FN4: C, 70.34; H, 3.82; N, 19.30. Found: C, 70.29; H,
3.85; N, 19.35.
135.3, 134.2, 131.8, 131.4, 129.6, 129.3, 128.9, 128.2, 127.8, 127.7,
124.9, 109.5, 109.5, 46.2; mass (ESþ) m/z 431.3 (Mþþ1). Anal. Calcd
for C24H16Cl2N4: C, 66.83; H, 3.74; N,12.99. Found: C, 66.75; H, 3.82;
N, 12.93.
4.10.9. 5-(3,4-Dichlorophenyl)pyrimido[5,4-c]quinolin-
2-ylamine (14i)
4.10.14. N-Benzyl-N-[5-(2-nitrophenyl)pyrimido[5,4-c]quinolin-2-
yl]-amine (14n)
Yield¼0.27 g (60%), yellow solid, mp >250 ꢀC, Rf¼0.43 (1:1
Yield¼0.28 g (52%), yellow solid, mp 238–239 ꢀC, Rf¼0.45 (2:3
EtOAc/hexane); IR (KBr) nmax 3306, 3180, 1641, 1594 cmꢂ1; 1H NMR
EtOAc/hexane); IR (KBr) nmax 3022, 1643, 1347, 1216 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
d
¼9.09 (1H, s, ArH), 8.90 (1H, d, J¼7.9 Hz, ArH),
(300 MHz, CDCl3)
d
¼8.97 (1H, s, ArH), 8.63 (1H, s, ArH), 8.24 (1H,
8.13 (1H, d, J¼8.2 Hz, ArH), 7.90–7.86 (2H, m, ArH), 7.71–7.64 (2H,
dd, J¼1.1, 8.1 Hz, ArH), 8.06 (1H, d, J¼8.2 Hz, ArH), 7.89–7.82 (2H, m,
ArH), 7.75–7.61 (3H, m, ArH), 7.47 (2H, s, ArH), 7.40–7.28 (3H, m,
ArH), 6.18 (1H, s, NH), 4.93 (2H, s, CH2); 13C NMR (75 MHz,
m, ArH), 7.59–7.57 (1H, m, ArH), 5.62 (2H, br s, NH2); 13C NMR
(150 MHz, DMSO-d6)
132.5, 131.9, 131.8, 131.1, 130.5, 129.6, 127.3, 123.8, 123.2, 110.6; mass
d
¼163.3, 161.7, 157.1, 155.9, 147.6, 138.7, 132.5,
CDCl3þTFA) ¼158.1, 156.3, 147.5, 139.8, 136.7, 135.3, 134.7, 133.1,
d

1160
P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
132.1, 129.7, 128.0, 128.3, 127.8, 125.9, 125.2, 125.1, 123.8, 123.3, 46.3;
mass (ESþ) m/z 408.2 (Mþþ1). Anal. Calcd for C24H17N5O2: C, 70.75;
H, 4.21; N, 17.19. Found: C, 70.75; H, 4.35; N, 17.24.
J¼8.0 Hz, ArH), 7.89–7.83 (1H, m, ArH), 7.68–7.63 (1H, m, ArH), 7.59
(2H, s, NH2), 7.26 (4H, t, J¼7.2 Hz, ArH), 7.17–7.05 (3H, m, ArH), 6.56
(2H, d, J¼8.7 Hz, ArH), 3.90 (2H, q, J¼6.9 Hz, CH2), 1.25 (3H, t,
J¼6.9 Hz, CH3); 13C NMR (75 MHz, DMSO-d6)
¼169.8, 161.2, 158.9,
d
4.10.15. N-Benzyl-N-[5-(4-chlorophenyl)pyrimido[5,4-c]quinolin-
2-yl]amine (14o)
158.1, 157.7, 146.8, 139.2, 133.4, 131.7, 131.1, 129.8, 128.7, 128.6, 127.2,
125.9, 123.7, 122.3, 113.3, 108.8, 62.9, 14.5; mass (ESþ) m/z 393.3
(Mþþ1). Anal. Calcd for C25H20N4O: C, 76.51; H, 5.14; N, 14.28.
Found: C, 76.46; H, 5.07; N, 14.15.
Yield¼0.31 g (59%), white solid, mp 208 ꢀC, Rf¼0.45 (1:1 EtOAc/
hexane); IR (KBr) nmax 3248, 3085, 1597 cmꢂ1 1H NMR (300 MHz,
;
DMSO-d6)
d
¼9.00 (1H, s, ArH), 8.83 (2H, d, J¼7.9 Hz, ArH), 8.01 (1H,
d, J¼8.1 Hz, ArH), 7.88 (1H, t, J¼7.6 Hz, ArH), 7.80 (2H, d, J¼8.4 Hz,
ArH), 7.71 (1H, d, J¼7.9 Hz, ArH), 7.65 (2H, d, J¼8.4 Hz, ArH), 7.49 (1H,
d, J¼7.3 Hz, ArH), 7.33 (2H, t, J¼7.4 Hz, ArH), 7.23 (1H, d, J¼7.2 Hz,
ArH), 4.78 (2H, d, J¼6.2 Hz, CH2); 13C NMR (75 MHz, DMSO-d6þTFA)
4.10.20. 5-(4-(Dimethylamino)phenyl)-4-phenylpyrimido[5,4-c]-
quinolin-2-amine (14v)
Yield¼0.24 g (46%), yellow solid, mp >250 ꢀC, Rf¼0.40 (1:3
EtOAc/hexane); IR (KBr) nmax 3297, 3165, 1630, 1538 cmꢂ1; 1H NMR
d
¼164.5, 162.8, 157.9, 157.5, 139.1, 138.9, 137.9, 135.2, 133.1, 129.8,
(300 MHz, DMSO-d6)
d
¼8.80 (1H, d, J¼8.2 Hz, ArH), 7.95 (1H, d,
129.6, 129.0, 128.4, 127.9, 127.8, 125.0, 123.8, 122.2, 110.0, 45.4; mass
(ESþ) m/z 397.3 (Mþþ1). Anal. Calcd for C24H17ClN4: C, 72.63; H, 4.32;
N, 14.12. Found: C, 72.56; H, 4.27; N, 14.08.
J¼7.9 Hz, ArH), 7.86–7.81 (1H, m, ArH), 7.64–7.58 (1H, m, ArH), 7.54
(2H, s, NH2), 7.30 (2H, d, J¼6.5 Hz, ArH), 7.20 (2H, d, J¼8.7 Hz, ArH),
7.13–7.05 (3H, m, ArH), 6.36 (2H, d, J¼8.8 Hz, ArH), 2.79 (6H, s,
2ꢁCH3); 13C NMR (75 MHz, DMSO-d6)
¼169.8, 161.1, 159.2, 157.8,
d
4.10.16. N-Benzyl-N-[5-(4-nitrophenyl)pyrimido[5,4-c]quinolin-2-
yl]amine (14p)
150.1, 146.9, 139.3, 131.6, 130.8, 129.8, 128.7, 128.6, 128.3, 127.2,
126.7, 125.4, 123.7, 122.0, 110.9, 108.6; mass (ESþ) m/z 392.4
(Mþþ1). Anal. Calcd for C25H21N5: C, 76.70; H, 5.41; N, 17.89. Found:
C, 76.59; H, 5.34; N, 17.72.
Yield¼0.36 g (67%), yellow solid, mp 204 ꢀC, Rf¼0.40 (2:3 EtOAc/
hexane); IR (KBr) nmax 3020, 1593, 1528, 1349 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼8.96 (2H, s, ArH), 8.45 (2H, d, J¼8.7 Hz, ArH),
8.15 (1H, d, J¼8.2 Hz, ArH), 7.95 (2H, d, J¼8.6 Hz, ArH), 7.89 (1H, d,
J¼7.0 Hz, ArH), 7.71 (1H, t, J¼7.4 Hz, ArH), 7.40 (2H, br s, NH2), 7.40–
7.29 (3H, m, ArH), 6.24 (1H, br s, NH), 4.95 (2H, s, CH2); 13C NMR
4.10.21. 5-(4-Nitrophenyl)-4-phenylpyrimido[5,4-c]quinolin-2-
amine (14w)
Yield¼0.28 g (53%), yellow solid, mp 210 ꢀC, Rf¼0.45 (1:3 EtOAc/
(75 MHz, DMSO-d6)
d
¼161.2, 160.8, 157.0, 155.0, 147.7, 147.2, 143.9,
hexane); IR (KBr) nmax 3021, 1631, 1541, 1345 cmꢂ1 1H NMR
;
139.6, 132.2, 131.2, 129.1, 128.3, 127.6,127.1, 126.8, 123.5, 122.9, 110.2,
44.4; mass (ESþ) m/z 408.3 (Mþþ1). Anal. Calcd for C24H17N5O2: C,
70.75; H, 4.21; N, 17.19. Found: C, 70.67; H, 4.34; N, 17.25.
(300 MHz, DMSO-d6)
d
¼8.89 (1H, d, J¼7.2 Hz, ArH), 8.05 (1H, d,
J¼7.9 Hz, ArH), 7.95–7.89 (1H, m, ArH), 7.85 (2H, d, J¼8.7 Hz, ArH),
7.85 (2H, d, J¼8.7 Hz, ArH), 7.77–7.72 (3H, m, ArH, NH2), 7.27 (2H, d,
J¼8.1 Hz, ArH), 7.15–7.03 (3H, m, ArH); 13C NMR (75 MHz, DMSO-
4.10.17. N-Benzyl-N-[5-(4-dimethylamino)pyrimido[5,4-c]-
quinolin-2-yl]amine (14q)
d6)
d¼169.6, 161.5, 157.6, 157.3, 147.5, 146.4, 146.2, 138.9, 132.0,
130.9, 129.9, 128.9, 127.4, 127.0, 123.8, 122.8, 122.6, 122.1, 109.0;
mass (ESþ) m/z 394.3 (Mþþ1). Anal. Calcd for C23H15N5O2: C, 70.22;
H, 3.84; N, 17.80. Found: C, 70.10; H, 3.65; N, 17.76.
Yield¼0.27 g (50%), yellow solid, mp 228 ꢀC, Rf¼0.50 (2:3 EtOAc/
hexane); IR (KBr) nmax 3241, 3081, 1590, 1349 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼9.21 (1H, s, ArH), 8.91 (1H, s, ArH), 8.12 (1H, d,
J¼8.1 Hz, ArH), 7.85–7.79 (1H, m, ArH), 7.68 (2H, d, J¼8.8 Hz, ArH),
7.60 (1H, t, J¼7.8 Hz, ArH), 7.47 (2H, s, ArH), 7.39–7.28 (3H, m, ArH),
6.89 (2H, d, J¼8.8 Hz, ArH), 6.07 (1H, t, J¼5.5 Hz, NH), 4.92 (2H, s,
CH2), 3.08 (6H, s, 2ꢁCH3); 13C NMR (75 MHz, DMSO-d6þTFA)
4.10.22. 4-(2-Amino-4-phenylpyrimido[5,4-c]quinolin-5-yl)benzo-
nitrile (14x)
Yield¼0.22 g (45%), yellow solid, mp 216–217 ꢀC, Rf¼0.50 (1:3
EtOAc/hexane); IR (KBr) nmax 3387, 3294, 2339, 1632, 1540 cmꢂ1; 1H
d
¼164.1, 162.1, 153.1, 138.6, 137.9, 134.5, 132.8, 128.5, 128.2, 127.8,
NMR (300 MHz, DMSO-d6)
d
¼8.89 (1H, d, J¼7.4 Hz, ArH), 8.03 (1H, d,
127.4, 127.2, 124.4, 122.4, 114.9, 111.8, 44.7; mass (ESþ) m/z 406.4
(Mþþ1). Anal. Calcd for C26H23N5: C, 77.01; H, 5.72; N, 17.27. Found:
C, 77.15; H, 5.62; N, 17.35.
J¼8.0 Hz, ArH), 7.94–7.88 (1H, m, ArH), 7.75–7.71 (3H, m, ArH, NH2),
7.51–7.44 (4H, m, ArH), 7.26 (2H, d, J¼7.0 Hz, ArH), 7.18 (1H, t,
J¼7.3 Hz, ArH), 7.08 (2H, t, J¼7.6 Hz, ArH); 13C NMR (75 MHz, DMSO-
d6)
d
¼169.6, 161.4,157.7,157.6,146.4, 145.5, 138.9, 131.9, 130.9, 130.4,
4.10.18. N-Benzyl-[5-(4-ethoxyphenyl)-pyrimido[5,4-c]quinolin-
2-yl]amine (14r)
129.9,128.9,128.8,127.4,126.8,123.8,122.7,118.7,109.9,108.9; mass
(ESþ) m/z 374.4 (Mþþ1). Anal. Calcd for C24H15N5: C, 77.20; H, 4.05;
N, 18.76. Found: C, 77.12; H, 4.15; N, 18.61.
Yield¼0.35 g (65%), white solid, mp 203 ꢀC, Rf¼0.46 (2:3 EtOAc/
hexane); IR (KBr) nmax 3020, 1643, 1535, 1216 cmꢂ1 1H NMR
;
(300 MHz, DMSO-d6)
d
¼9.04 (1H, s, ArH), 8.81 (1H, d, J¼7.9 Hz,
4.11. Procedure for the synthesis of 2-pyridin-4-yl-phenyl-
amine 19
ArH), 8.72 (1H, t, J¼6.2 Hz, NH), 8.0 (1H, d, J¼8.2 Hz, ArH), 7.86 (1H,
t, J¼7.5 Hz, ArH), 7.72 (2H, d, J¼8.6 Hz, ArH), 7.66 (1H, t, J¼7.7 Hz,
ArH), 7.49 (1H, d, J¼7.3 Hz, ArH), 7.33 (2H, t, J¼7.4 Hz, ArH), 7.22
(1H, t, J¼7.2 Hz, ArH), 7.12 (2H, d, J¼8.5 Hz, ArH), 4.78 (2H, d,
J¼5.91 Hz, ArH), 4.14 (2H, q, J¼6.9 Hz, CH2), 1.39 (3H, t, J¼6.9 Hz,
The solution of 2-bromoaniline 21 (1 g, 5.8 mmol) in DMF
(15 mL) was degassed with nitrogen for 15 min followed by addi-
tion of satd Na2CO3 solution (10 mL, 2 M) under continuous flow of
nitrogen. After 10 min, pyridine-4-boronic acid 20 (0.85 g,
6.97 mmol) and PdCl2(PPh3)2 (0.29 g, 0.4 mmol) were added to the
reaction mixture under a nitrogen atmosphere. The reaction mix-
ture was stirred at 100 ꢀC for 3 h. The solution was diluted with H2O
(5 mL), and then the product was extracted three times with EtOAc
(20 mL). The combined organic layer was dried over MgSO4 and the
solvent was removed in vacuo. The crude product was purified on
a silica gel column using hexane/ethyl acetate (7:3, v/v) as eluent to
afford 2-pyridin-4-yl-phenylamine 19.
CH3); 13C NMR (75 MHz, DMSO-d6)
d
¼161.4, 161.2, 159.6, 158.6,
155.8,155.3,147.2,139.8,132.1,131.5,129.5, 128.6,128.3,127.6,127.2,
126.9,126.4,123.6,122.6,114.4,110.4, 63.3, 44.5,14.4; mass (ESþ) m/z
407.3 (Mþþ1). Anal. Calcd for C26H22N4O: C, 76.83; H, 5.46; N,13.78.
Found: C, 76.65; H, 5.34; N, 13.67.
4.10.19. 5-(4-Ethoxyphenyl)-4-phenylpyrimido[5,4-c]quinolin-2-
amine (14u)
Yield¼0.26 g (49%), white solid, mp 208 ꢀC, Rf¼0.55 (1:3 EtOAc/
hexane); IR (KBr) nmax 3275, 3116, 1631, 1543 cmꢂ1
;
1H NMR
Yield¼0.84 g (85%), brown solid, mp 85–86 ꢀC, Rf¼0.40 (1:1
(300 MHz, DMSO-d6)
d
¼8.84 (1H, d, J¼7.3 Hz, ArH), 7.98 (1H, d,
EtOAc/hexane); IR (KBr) nmax 3398, 3020, 1602 cmꢂ1 1H NMR
;

P.K. Agarwal et al. / Tetrahedron 65 (2009) 1153–1161
1161
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(300 MHz, CDCl3)
d
¼8.65 (2H, d, J¼5.0 Hz, ArH), 7.41 (2H, d, J¼5.2 Hz,
ArH), 7.22–7.17 (1H, m, ArH), 7.12 (1H, d, J¼7.6 Hz, ArH), 6.84 (1H, t,
J¼7.4 Hz, ArH), 6.76 (1H, d, J¼8.0 Hz, ArH), 3.82 (2H, br s, NH2); 13
C
NMR(150 MHz,CDCl3)
d¼150.0,147.8,143.3,130.0,129.8,128.5,128.4,
124.3,123.9,118.9,116.1; mass (ESþ) m/z 171.4 (Mþþ1). Anal. Calcd for
C11H10N2: C, 77.62; H, 5.92; N,16.46. Found: C, 77.58; H, 5.93; N,16.49.
4.12. Protocols for the attempted Pictet–Spengler
reaction on 19
Substrate 19 was subjected to the various Pictet–Spengler re-
action conditions as described in the Table 1. The reaction mixture
was then quenched with satd NaHCO3 solution and then extracted
with EtOAc. The organic layer was washed with brine, dried, and
concentrated in vacuo. The crude product so obtained was purified
using neutral alumina column chromatography with hexane/ethyl
acetate (7:3, v/v) as eluent to afford 4-nitro-N-[(E)-(2-pyridin-4-
ylphenyl)methylidene]aniline 22 as the only product.
Yield¼0.36 g (90%), yellow solid, mp 185–186 ꢀC, Rf¼0.35 (1:1
EtOAc/hexane); IR (KBr) nmax 3021, 1597, 1216 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼8.62 (2H, dd, J¼1.6, 4.5 Hz, ArH), 8.50 (1H, s,
ArH), 8.30 (2H, d, J¼8.8 Hz, ArH), 7.96 (2H, d, J¼8.8 Hz, ArH), 7.52–
7.46 (2H, m, ArH), 7.43–7.38 (3H, m, ArH), 7.18–7.15 (1H, m, ArH);
13C NMR (150 MHz, CDCl3)
d¼157.9, 149.4, 149.2, 148.5, 147.1, 141.3,
133.4, 130.2, 129.9, 129.5, 127.4, 124.9, 124.1, 118.5; mass (ESþ) m/z
304.3 (Mþþ1). Anal. Calcd for C18H13N3O2: C, 71.28; H, 4.32; N,
13.85. Found: C, 71.23; H, 4.29; N, 13.89.
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Acknowledgements
P.K.A., S.K.S., and D.S. are thankful to CSIR, New Delhi, India for
fellowships.
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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.2008.11.067.
References and notes
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