One pot, three-component synthesis of novel 3,4-dihydrophthalazin-2(1H)-yl- 4-phenyl-4H-pyrans

Article abstract of DOI:10.1016/j.tetlet.2014.02.020

Green and efficient one pot, three-component synthesis of novel 2-amino-6-(1,4-dioxo-3,4-dihydrophthalazin)-2(1H)-yl-4-phenyl-4H-pyran-3, 5-dicarbonitriles 6 has been developed by condensing 3-(1,4-dioxo-3,4- dihydrophthalazin-(1H)-yl)-3-oxopropanenitrile 3, benzaldehydes 4 and active methylene compounds 5 using l-proline as catalyst in EtOH at RT.

Full text of DOI:10.1016/j.tetlet.2014.02.020

Tetrahedron Letters 55 (2014) 2177–2182
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One pot, three-component synthesis of novel 3,
4-dihydrophthalazin-2(1H)-yl-4-phenyl-4H-pyrans
⇑
P. Praveen Kumar , Y. Dathu Reddy, Ch. Venkata Ramana Reddy, B. Rama Devi, P. K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad (AP) 500 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Green and efficient one pot, three-component synthesis of novel 2-amino-6-(1,4-dioxo-3,4-dihydroph-
thalazin)-2(1H)-yl-4-phenyl-4H-pyran-3,5-dicarbonitriles 6 has been developed by condensing 3-(1,4-
dioxo-3,4-dihydrophthalazin-(1H)-yl)-3-oxopropanenitrile 3, benzaldehydes 4 and active methylene
Received 25 December 2013
Revised 4 February 2014
Accepted 10 February 2014
Available online 20 February 2014
compounds 5 using L-proline as catalyst in EtOH at RT.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
Phthalic anhydride
Benzaldehydes
Active methylene compounds
Multi-component reactions have been proved as an important
tool for the syntheses of many multi-substituted heterocyclic
ring-containing compounds.1 Synthesis of different substituted
4H-pyrans has been studied in the literature.2–5 To the best of
our knowledge, phthalazine moieties containing different substi-
tuted 4H-pyrans have not been studied.
Keeping these results in mind and in continuation of our earlier
work on phthalic anhydride,19,20 we now wish to report green and
efficient, one-pot, three component synthesis of novel 2-amino-6-
(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl-4-phenyl-4H-pyran-3,
5-dicarbonitriles by condensing 3-(1,4-dioxo-3, 4-dihydrophthala-
zin-(1H)-yl)-3-oxopropanenitrile, benzaldehydes and active meth-
ylene compounds.
Phthalazines are important heterocycles that are known to pos-
sess multiple biological activities such as antimicrobial, anticon-
vulsant, antifungal, anticancer and anti-inflammatory.6 Carling
et al. reported7 the synthesis of 3-phenyl-6-(2-pyridyl)methyl-
oxy-1,2,4-triazolo[3,4-a]phthalazines and analogues which were
found to be a key structural element of certain CNS—active drugs.
Jain et al. reported8 the synthesis of keto-glutamine tetra peptide
analogues containing a 2-oxo-pyrrolidine ring as a glutamine side
chain mimic which showed improved inhibition against hepatitis A
virus 3C proteinase. Grasso et al. reported9 the synthesis of 6,7-
methylenedioxyphthalazin-1(2H)-ones which were found to be
potent anticonvulsant. Nomoto et al. reported10 the synthesis of
6,7-dimethoxyphthalazine derivatives which showed relatively
potent cardiotonic activity comparable to that of amrinone.
Watanabe et al. reported11 the synthesis of 4-benzylamino-1-
chloro-6-substituted phthalazines which were found to be vasore-
laxant activatives and a number of methods have been reported for
the synthesis of phthalazine derivatives.12–18 Therefore, it was con-
sidered worthwhile to synthesize phthalazine moiety containing
4H-pyrans.
As illustrated in Scheme 1, treatment of phthalic anhydride (1)
with ethyl cyanohydrazide21 (2) in acetic acid at RT for 1 h resulted
in the formation of 3-(1,4-dioxo-3, 4-dihydrophthalazin-(1H)-yl)-
3-oxopropanenitrile (3). The structure of this product was assigned
on the basis of its spectral data. (For details, please see Experimen-
tal section).
An interesting observation made here was that in the 1H NMR
spectrum of 3 the –NH– proton appeared at d 11.1 as a weak but
slightly broadened peak integrating for one proton and the
–CH2–proton signal appeared at d 4.1 as a sharp singlet integrating
for two protons. Both these signals disappeared from the spectrum
on addition of D2O to the solution. The exchange of –NH– proton
with deuterium is well known but the –CH2– proton exchange
with deuterium in the absence of any added base is unusual. In
O
O
O
H2
C
O
C
H2
C
Acetic acid/RT
N
C
CN
O
H2NHN
CN
NH
O
O
2
1
3
⇑
Corresponding author. Tel.: +91 9989789732; fax: +91 040 23057787.
E-mail address: padampraveenku@gmail.com (P.P. Kumar).
Scheme 1. Synthesis of 3 from 1 & 2.
http://dx.doi.org/10.1016/j.tetlet.2014.02.020
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2178
P. P. Kumar et al. / Tetrahedron Letters 55 (2014) 2177–2182
NH2
CN
the present case, this may be due to the fact that the –CH2– protons
form an enol with adjoining –CO– leading to the formation of a six-
membered chelate 3A as shown below:-
O
O
O
O
X
O
C
NH
H2
C
O
O
C
CN
X
N
CN
EtOH/RT/L-proline
N
H2C
Ar
Ar
H
NH
4
3
5
H
6
O
O
C
O
O
C
N
CH3
,
N
,
,
C
,
,
X = -CN, -COOC2H5
Ar =
C
N
C
H
OCH3
CH3
NO2
N
C
Cl
f
a
b
a
b
c
d
e
H
H
NH
NH
Scheme 2. Synthesis of 6a–6l by one-pot syntheses.
O
O
3A
3
Table 2
The effect of amount of L-proline in the preparation of 6a by 3, 4a & 5a in EtOH
Entry
Solvent
Mol % of
L
-proline
Time (h)
6a (%)–
Then, for the one pot, three-component reaction of 3, benzaldehyde
4a and malononitrile 5a were stirred together for 1 h at RT in the
green solvent ethanol in the presence of the green catalyst L-proline.
The corresponding novel 2-amino-6-(1,4-dioxo-3,4-dihydrophthal-
azin-2(1H)-yl-4-phenyl-4H-pyran-3,5-dicarbonitrile 6a was ob-
tained in excellent yields on simple work-up of reaction mixtures.
(For details, please see Experimental section). These results are
shown in Table 1, entry 1.
1
2
3
4
6
7
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
—
12
3
2
1
1
—
10
20
30
50
100
70
75
85
85
85
1
–
Refers to yields of crude products only.
Both the catalyst and the solvent play a vital role in determining
the success of the reaction in terms of rate and yields. In the ab-
sence of catalyst in any solvent, there was hardly any progress in
the reaction even after stirring the reactants for 10 h. Various cat-
alysts were also screened for this reaction in the present work,
which include L-proline, piperidine, triethylamine and pyridine
(Table 1). The solvents used in the present work are EtOH, MeOH
and DMSO. Among all the catalysts and solvents used in the pres-
Table 3
Characterization data, reaction time and yields of 6 obtained from 3, 4 & 5 via one-pot
synthesis
Entry
Starting material used
Product obtained
Time (h)
Yield–
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
3
3
4a
4b
4c
4d
4e
4f
4a
4b
4c
4d
4e
4f
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
6a
6b
6c
6d
6e
6f
6g
6h
6i
1
1
1
1.5
1.5
1.5
2
2
2
85
83
80
85
82
80
85
83
80
80
83
82
ent work, L-proline and ethanol proved to be the best (Table 1, en-
try 1) (Scheme 2).
To find out the optimum concentration of the catalyst, the one-
pot reaction was carried out by varying the amount of
(Table 2). However, reaction with 30 mol % -proline as a catalyst
at RT for 1 h in EtOH gave good yield (85%) (Table 2, entry 4). Fur-
ther increase in amount of -proline in mentioned reaction did not
L-proline
10
11
12
6j
6k
6l
2
2
2
L
L
–
have any significant effect on the product yield.
Refers to yields of crude products only.
After having optimized the reaction conditions, the generality of
the reaction was confirmed by carrying out the condensation of
several others 4a–4f and 5a–5b using L-proline as a catalyst at
C–H acidity of the active methylene compounds. The cyano func-
tional group has a stronger electron- withdrawing ability than
the ester group, so it is easier for malononitrile bearing two cyano
groups to generate an anion than with ethyl cyanoacetate in the
presence of base and hence react much faster in one-pot synthesis.
The structures of these products have been established on the basis
of their spectral data. (Scheme 1) (Table 3).
The synthesis of 6 could also be achieved in two variable but
identical end-product giving step-wise syntheses. Thus, a mixture
of 3 and 4 was stirred at RT for 20 min in the presence of
RT for 1–2 h in EtOH 6a–6l giving very good yields and no side
product formation was detected. In all cases, the three component
reaction proceeded smoothly to give the corresponding products
6a–6l in high yields. As shown in Table 3, it was found that this
method works with a wide variety of substrates. It is worthy to
mention that the reaction of 3, 4 & 5a (malononitrile) could get
higher yield and require shorter reaction time than the reaction
of 3, 4 and 5b (ethyl cyanoacetate). This can be ascribed to the
30 mol % L-proline in EtOH to form 7. The reaction was monitored
Table 1
by TLC. The structures of these products have been established ear-
lier on the basis of their spectral data. (Scheme 3) (Table 4).
Furthermore, the compound 7 was assigned E-configuration on
the presumption that bulky groups in a trans position would confer
thermal stability on the molecule. This has been found to be the
case by a careful examination of the Frame-work molecular models
of both E and Z-configurations of 7 wherein it was observed
that there were minimum number of steric interactions in the
E-configuration.
Effect of solvent, catalyst & temperature on reaction of 3, 4a & 5a at RT yielding 6a
Entry
Solvent
Catalyst
-Proline
Time (h)
6a (%)
1
Ethanol
1
85
L
2
3
4
5
6
7
8
Ethanol
Ethanol
Ethanol
methanol
Methanol
Methanol
Methanol
Pyridine
2.5
2.5
1.5
2
2.5
3
65
55
70
70
65
60
75
Triethyl amine
Piperidine
Piperidine
Pyridine
Triethyl amine
1.5
L-Proline
Then, 7 was reacted with 5 in the presence of 30 mol % L-proline
9
10
11
12
DMSO
DMSO
DMSO
DMSO
Piperidine
Pyridine
Triethyl amine
3.5
4
4.5
3
50
45
40
40
in EtOH to form the final product 6 (Scheme 3) (Table 5). Similarly,
a mixture of 4 and 5 was stirred at RT for 20–30 min in the
presence of 30 mol %
was monitored on TLC. Then, 8 was reacted with 3 in the presence
L
-proline in EtOH to form 8.22 The reaction
L-Proline

P. P. Kumar et al. / Tetrahedron Letters 55 (2014) 2177–2182
2179
O
O
O
O
O
C
NH
H2
C
N
C
C
CN
Ar
N
CN
EtOH/RT
EtOH/R
CN
T/L-proli
ne
NH HC
Ar-CHO/L-proline
H2C
4
NH2
CN
O
3
7
X
5
O
O
X
O
N
Ar
NH
6
EtOH/RT/L-proline
O
CN
O
CN
EtOH/RT/L-proline
H2C
Ar
C
H
8
C
Ar CH
4
X
X
O
H2
5
N C C CN
NH
O
3
Scheme 3. Step-wise synthesis of 6.
2-amino-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl-4-phenyl-
4H-pyran-3,5dicarbonitrile with simple work up procedures in
green methods.
Table 4
Characterization data, reaction time and yields of 7 obtained from 3 & 4
Entry
Starting material
Product
Time (min)
Yield–
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
7a
7b
7c
7d
7e
7f
20
20
20
30
25
25
85
85
80
75
85
80
Experimental section
Melting points are uncorrected and were determined in open
capillary tubes in sulfuric acid bath. TLC was run on silica gel—G
and visualization was done using iodine or UV light. IR spectra
were recorded using Perkin–Elmer 1000 instrument in KBr pellets.
1H NMR spectra were recorded in DMSO-d6 and CD3OD using TMS
as internal standard using 400 MHz spectrometer. Mass spectra
were recorded on Agilent-LCMS instrument. Starting materials 1,
4a–4f and 5a–5b were obtained from commercial sources and used
as such.
–
Refers to yields of crude products only.
Table 5
Characterization data, reaction time and yields of 6a–6l
Entry
Starting material used
Product obtained
Time (h)
Yield–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7a
7b
7c
7d
7e
7f
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
8g
8h
8i
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
3
3
3
3
3
3
3
3
3
6a
6b
6c
6d
6e
6f
6g
6h
6i
1
1
1
1.5
1.5
1.5
2
2
2
2
2
2
1
1
1
1.5
1.5
1.5
2
75
73
75
75
73
72
70
70
75
75
75
75
75
70
75
74
74
72
70
70
75
73
73
73
Preparation of 3
A mixture of 1 (10 mM), 2 (10 mM) and acetic acid (20 ml) was
stirred at RT for 1 h. At the end of this period, a colourless solid sep-
arated out from reaction mixture which was collected by filtration
of the mixture, washed with hexane (10 ml) and dried. The crude
product was recrystallized from ethanol to obtain pure 3.
Compound 3: Mp: 150–152 °C; IR (KBr): 3293–3518 cmꢀ1
(broad, medium, –NH–), 1748 cmꢀ1 (sharp, strong, –CO–),
1682 cmꢀ1 (sharp, strong, –CO– of amide group), 1614 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 4.2 (s, 2H, CH2), 7.9–8.0 (m, 4H, Ar-H), 11.1 (s, 1H,
–NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz): d 36.9,
114.8, 124.8, 131.1, 136.2, 164.1, 164.8, 166.1; HRMS calcd for
6j
6k
6l
6a
6b
6c
6d
6e
6f
6g
6h
6i
C
11H7N3O3 [M+H]+: 230.0314. Found: 230.0311.
2
2
2
2
Preparation of 6a–6l from 3, 4a–4f & 5a–5b by one-pot synthesis
8j
8k
8l
3
3
3
6j
6k
6l
A mixture of 3 (10 mM), 4a–4f (10 mM), 5a–5b (10 mM),
2
30 mol % L-proline and EtOH (20 ml) was stirred at RT for 1–2 h.
–
Refers to yields of crude products only.
At the end of this period, a colourless solid separated out from
reaction mixture which was collected by filtration of the mixture,
washed with hexane (10 ml) and dried. The crude product was
recrystallized from ethanol to obtain pure 6a–6l.
of 30 mol %
(Scheme 3) (Table 5).
Encouraged by the above results, synthesis of 6 has been
achieved successfully through tandem synthesis by using step-
wise sequences ð3 þ 4 ! 7 ! 6Þ&ð4 þ 5 ! 8 ! 6Þ (Scheme 4)
L-proline in EtOH to form the final product 6.
Compound 6a: Mp: 138–140 °C; IR (KBr): 3306–3401 cmꢀ1
(broad, medium, –NH–), 2218 cmꢀ1 (sharp, strong, –CN–),
1706 cmꢀ1 (sharp, strong, –CO– of amide group), 1659 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 6.1 (s, 1H, –CH), 7.5–8.1 (m, 9H, Ar-H), 9.6 (s, 2H,
–NH2), 11.6 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-
d6, 100 MHz): d 48.5, 75.5, 86.3, 114.6, 115.1, 124.5, 127.9, 128.6,
129.7, 130.7, 134.1, 136.0, 155.8, 157.4, 163.0, 163.6; HRMS calcd
for C21H13N5O3 [M+H]+: 384.0427. Found: 384.0424.
5
3
Conclusion
In summary, we have successfully adapted a simple one pot as
well as step-wise and tandem process for the synthesis of novel

2180
P. P. Kumar et al. / Tetrahedron Letters 55 (2014) 2177–2182
O
O
O
O
O
C
NH
H2
C
E
tOH/RT/L
CN
N
C
C
CN
Ar
-proline/
N
CN
EtOH/RT
NH HC
Ar-CHO/L-proline
H2C
4
NH2
CN
O
3
7
X
5
X
O
O
O
N
Ar
NH
6
EtOH/RT/L-proline
O
O
CN
CN
EtOH/RT/
L-proline
H2C
Ar
C
H
8
C
Ar CH
4
X
X
O
H2
5
N C C CN
NH
O
3
Scheme 4. Tandem synthesis of 6.
Compound 6b: Mp: 180–182 °C; IR (KBr): 3309–3405 cmꢀ1
(broad, medium, –NH–), 2210 cmꢀ1 (sharp, strong, –CN–),
1716 cmꢀ1 (sharp, strong, –CO– of amide group), 1656 cmꢀ1
(sharp, strong, –CO– of amide group) 1H NMR (DMSO-d6,
100 MHz): d 2.3 (s, 1H, –CH3), 6.1 (s, 1H, –CH), 7.5–8.1 (m, 8H,
Ar-H), 9.6 (s, 2H, –NH2), 11.6 (s, 1H, –NH, D2O exchangeable);
13C NMR (DMSO-d6, 400 MHz): d 37.3, 48.1, 75.6, 86.5, 114.3,
115.1, 124.5, 127.9, 128.6, 129.6, 130.7, 134.0, 136.1, 155.6,
157.2, 163.4, 163.5; M++1 = 398.
7.5–7.9 (m, 9H, Ar-H), 9.1 (s, 2H, –NH2), 11.3 (s, 1H, –NH, D2O
exchangeable); 13C NMR (DMSO-d6, 100 MHz): d 19.8, 49.3, 57.7,
76.3, 110.9, 113.4, 115.9, 116.4, 119.9, 120.8, 125.3, 125.9, 126.9,
127.6, 128.6, 130.9, 137.0, 139.0, 140.5, 158.6, 164.1, 164.9;
M++1 = 431.
Compound 6h: Mp: 175–178 °C; IR (KBr): 3315–3418 cmꢀ1
(broad, medium, –NH–group), 2214 cmꢀ1 (sharp, strong, –CN–),
1716 cmꢀ1 (sharp, strong, –CO– of amide group), 1655 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 1.2 (s, 3H, –CH3), 1.3 (t, 3H, –CH3), 3.8 (m, 2H,
–CH2), 5.4 (s, 1H, –CH), 7.5–7.8 (m, 8H, Ar-H), 9.1 (s, 2H, –NH2),
11.2 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-d6,
100 MHz): d 19.8, 36.3, 49.3, 57.7, 77.5, 110.8, 113.4, 115.9,
116.3, 119.9, 120.8, 125.6, 126.9, 127.6, 128.3, 130.9, 137.5,
139.0, 140.6, 158.9, 164.1, 164.6; M++1 = 445.
Compound 6c: Mp: 140–142 °C; IR (KBr): 3303–3405 cmꢀ1
(broad, medium, –NH–), 2217 cmꢀ1 (sharp, strong, –CN–),
1704 cmꢀ1 (sharp, strong, –CO– of amide group), 1658 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 3.8 (s, 1H, –OCH3), 6.3 (s, 1H, –CH), 7.6–8.4 (m, 8H,
Ar-H), 9.4 (s, 2H, –NH2), 11.5 (s, 1H, –NH, D2O exchangeable);
13C NMR (DMSO-d6, 100 MHz): d 48.3, 53.9, 75.3, 85.6, 114.1,
115.3, 124.7, 127.9, 128.6, 129.7, 130.6, 134.1, 136.0, 155.8,
157.0, 163.3, 163.6; M++1 = 414.
Compound 6i: Mp: 170–172 °C; IR (KBr): 3313–3415 cmꢀ1
(broad, medium, –NH–), 2218 cmꢀ1 (sharp, strong, –CN–),
1715 cmꢀ1 (sharp, strong, –CO– of amide group), 1656 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 1.5 (t, 3H, –CH3), 3.6 (s, 2H, –OCH3), 4.1 (m, 2H,
–CH2), 5.8 (s, 1H, –CH), 7.5–8.0 (m, 8H, Ar-H), 9.3 (s, 2H, –NH2),
11.1 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-d6,
100 MHz): d 19.8, 47.3, 49.4, 57.5, 78.7, 110.8, 113.0, 115.6,
116.7, 118.5, 120.9, 125.6, 126.4, 127.3, 127.4, 130.5, 137.3,
139.9, 141.5, 158.9, 164.0, 164.1; M++1 = 461.
Compound 6d: Mp: 160–162 °C; IR (KBr): 3304–3402 cmꢀ1
(broad, medium, –NH–), 2211 cmꢀ1 (sharp, strong, –CN–),
1704 cmꢀ1 (sharp, strong, –CO– of amide group), 1655 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
100 MHz): d 6.0 (s, 1H, –CH), 7.1–8.3 (m, 8H, Ar-H), 9.7 (s, 2H,
–NH2) 11.0 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-d6,
100 MHz): d 48.1, 75.5, 85.5, 114.5, 115.0, 124.9, 127.6, 128.7,
129.7, 130.6, 134.2, 136.6, 155.4, 157.8, 163.2, 163.6; M++1 = 429.
Compound 6e: Mp: 180–182 °C; IR (KBr): 3306–3404 cmꢀ1
(broad, medium, –NH–), 2214 cmꢀ1 (sharp, strong, –CN–),
1702 cmꢀ1 (sharp, strong, –CO– of amide group), 1655 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
100 MHz): d 2.2 (s, 1H, –CH3), 6.2 (s, 1H, –CH), 7.5–8.2 (m, 8H,
Ar-H), 9.7 (s, 2H, –NH2), 11.6 (s, 1H, –NH, D2O exchangeable);
13C NMR (DMSO-d6, 400 MHz): d 37.3, 48.1, 75.3, 86.4, 114.5,
115.3, 124.5, 127.6, 128.7, 129.7, 130.6, 134.1, 136.0, 155.8,
157.0, 163.2, 163.7; M++1 = 398.
Compound 6j: Mp: 88–90 °C; IR (KBr): 3312–3418 cmꢀ1 (broad,
medium, –NH–), 2218 cmꢀ1 (sharp, strong, –CN–), 1718 cmꢀ1
(sharp, strong, –CO– of amide group), 1657 cmꢀ1 (sharp, strong,
–CO– of amide group); 1H NMR (DMSO-d6, 400 MHz): d 1.3 (t,
3H, –CH3), 4.0 (m, 2H, –CH2), 6.1 (s, 1H, –CH), 7.3–8.1 (m, 8H,
Ar-H), 8.8 (s, 2H, –NH2), 11.2 (s, 1H, –NH, D2O exchangeable);
13C NMR (DMSO-d6, 100 MHz): d 19.3, 49.4, 56.7, 75.3, 110.8,
113.4, 116.9, 117.4, 119.9, 120.8, 125.3, 126.9, 127.6, 128.7,
130.3, 137.0, 139.4, 141.5, 158.1, 164.6, 164.9; M++1 = 476.
Compound 6k: Mp: 120–122 °C; IR (KBr): 3319–3419 cmꢀ1
(broad, medium, –NH–), 2218 cmꢀ1 (sharp, strong, –CN–),
1717 cmꢀ1 (sharp, strong, –CO– of amide group), 1653 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 1.2 (s, 3H, –CH3), 1.3 (t, 3H, –CH3), 3.9 (m, 2H,
–CH2), 5.4 (s, 1H, –CH), 7.3–7.8 (m, 8H, Ar-H), 9.0 (s, 2H, –NH2),
11.2 (s, 1H, –NH, D2O exchangeable); 13CNMR (DMSO-d6,
100 MHz): d 19.8, 37.6, 49.4, 57.4, 78.7, 110.9, 113.3, 115.8,
116.9, 118.6, 120.6, 125.6, 126.9, 127.0, 127.3, 130.5, 137.0,
141.0, 159.1, 164.6, 164.9; M++1 = 445.
Compound 6f: Mp: 178–180 °C; IR (KBr): 3302–3401 cmꢀ1
(broad, medium, –NH–), 2217 cmꢀ1 (sharp, strong, –CN–),
1707 cmꢀ1 (sharp, strong, –CO– of amide group), 1653 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 5.8 (s, 1H, –CH), 7.0–7.7 (m, 8H, Ar-H), 9.1 (s, 2H,
–NH2), 10.9 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-
d6, 100 MHz): d 48.5, 75.3, 86.2, 114.6, 115.3, 124.5, 127.6, 128.7,
129.7, 130.6, 134.1, 136.0, 155.8, 157.0, 163.2, 163.7; M++1 = 418.
Compound 6g: Mp: 206–208 °C; IR (KBr): 3310–3416 cmꢀ1
(broad, medium, –NH–), 2216 cmꢀ1 (sharp, strong, –CN–),
1713 cmꢀ1 (sharp, strong, –CO– of amide group), 1654 cmꢀ1
(sharp, strong, –CO– of amide group); 1H NMR (DMSO-d6,
400 MHz): d 1.2 (t, 3H, –CH3), 3.9 (m, 2H, –CH2), 5.4 (s, 1H, –CH),
Compound 6l: Mp: 85–87 °C; IR (KBr): 3313–3416 cmꢀ1 (broad,
medium, –NH–), 2215 cmꢀ1 (sharp, strong, –CN–), 1713 cmꢀ1
(sharp, strong, –CO– of amide group), 1654 cmꢀ1 (sharp, strong,
–CO– of amide group); 1H NMR (DMSO-d6, 400 MHz): d 1.2 (t,

P. P. Kumar et al. / Tetrahedron Letters 55 (2014) 2177–2182
2181
3H, –CH3), 4.1 (m, 2H, –CH2), 6.0 (s, 1H, –CH), 7.4–8.2 (m, 8H, Ar-
H), 9.0 (s, 2H, –NH2), 10.8 (s, 1H, –NH, D2O exchangeable); 13C
NMR (DMSO-d6, 100 MHz): d 18.4, 44.9, 57.7, 73.5, 113.0, 114.4,
116.9, 117.3, 119.9, 120.9, 125.6, 126.9, 127.3, 128.7, 130.5,
137.0, 138.4, 141.8, 157.4, 164.6, 164.6; M++1 = 465.
(DMSO-d6, 100 MHz): d 82.9, 82.9, 120.1, 124.9, 126.0, 129.1,
131.4, 131.5, 132.0, 132.2, 132.3, 135.1, 138.4,145.8, 166.4, 166.4,
166.4; M++1 = 352.
Preparation of 6a–6l from 7a–7f & 5a–5b via step-wise reaction
Preparation of 7a–7f from 3 & 4a–4f
A mixture of 7a–7f (10 mM), 5a–5b (10 mM), 30 mol % L-proline
and EtOH (20 ml was stirred at RT for 1–2 h. At the end of this per-
iod, a colourless solid separated out from reaction mixture which
was collected by filtration of the mixture, washed with hexane
(10 ml) and dried. The crude product was recrystallized from eth-
anol to obtain pure 6a–6l.
A mixture of 3 (10 mM), 4a–4f (10 mM), 30 mol % L-proline and
EtOH (20 ml) was stirred at RT for 20 min. At the end of this period,
a colourless solid separated out from the mixture which was col-
lected by filtration of the mixture, washed with hexane (10 ml)
and dried. The crude product was recrystallized from ethanol to
obtain pure 7a–7f.
Preparation of 8a–8l from 4a–4f & 5a–5b
Compound 7a: Mp: 200–202 °C; IR (KBr): 3267–3518 cmꢀ1
(broad, medium, –NH–), 2258 cmꢀ1 (sharp, strong, –CN–),
1749 cmꢀ1 (sharp, strong, –CO– group), 1683 cmꢀ1 (sharp, strong,
–CO– of amide group), 1613 cmꢀ1 (sharp, strong, –CO– of amide
group); 1H NMR (DMSO-d6, 400 MHz): d 7.6–8.4 (m, 10H, Ar-H
and NC-C@CH), 11.4 (s, 1H, –OH, D2O exchangeable); 13C NMR
(CD3OD, 100 MHz): d 81.3, 81.4, 117.2, 122.9, 124.0, 127.2, 128.4,
128.5, 129.0, 129.1, 129.6, 133.0, 136.1, 143.4, 164.4, 164.5,
164.8; HRMS calcd for C18H11N3O3 [M+H]+: 318.0423. Found:
318.0426.
A mixture of 4a–4l (10 mM), 5a–5b (10 mM), L-proline and
EtOH (20 ml) was stirred at RT for 20 min. At the end of this period,
a colourless solid separated out from the mixture which was col-
lected by filtration of the mixture, washed with hexane (10 ml)
and dried. The crude product was recrystallized from ethanol to
obtain pure 8a–8l.
Preparation of 6a–6l from 3 & 8a–8l via step-wise reaction
Compound 7b: Mp: 195–197 °C; IR (KBr): 3266–3513 cmꢀ1
(broad, medium, –NH–), 2253 cmꢀ1 (sharp, strong, –CN–),
1742 cmꢀ1 (sharp, strong, –CO– group), 1684 cmꢀ1 (sharp, strong,
–CO– of amide group), 1617 cmꢀ1 (sharp, strong, –CO– of amide
group); 1H NMR (DMSO-d6, 400 MHz): d 2.3 (s, 3H, CH3), 7.1–8.3
(m, 9H, Ar-H and NC-C@CH), 11.3 (s, 1H, –OH, D2O exchangeable);
13C NMR (DMSO-d6, 100 MHz): d 35.6, 81.3, 81.4, 117.2, 122.9,
124.0, 127.2, 128.4, 128.5, 129.0, 129. 1, 129.6, 133.0, 136.1,
143.4, 164.4, 164.5, 164.8; M++1 = 332.
A mixture of 3 (10 mM), 8a–8l (10 mM), L-proline and EtOH
(20 ml) was stirred at RT for 1–2 h. At the end of this period, a col-
ourless solid separated out from reaction mixture which was col-
lected by filtration of the mixture, washed with hexane (10 ml)
and dried. The crude product was recrystallized from ethanol to
obtain pure 6a–6l.
Acknowledgments
Compound 7c: Mp: 228–230 °C; IR (KBr): 3263–3515 cmꢀ1
(broad, medium, –NH–), 2252 cmꢀ1 (sharp, strong, –CN–),
1743 cmꢀ1 (sharp, strong, –CO– group), 1682 cmꢀ1 (sharp, strong,
–CO– of amide group), 1616 cmꢀ1 (sharp, strong, –CO– of amide
group); 1H NMR (DMSO-d6, 400 MHz): d 3.8 (s, 3H, OCH3), 7.1–
8.4 (m, 9H, Ar-H and NC-C@CH), 11.6 (s, 1H, –OH, D2O exchange-
able); 13C NMR (DMSO-d6, 100 MHz): d 53.1, 82.0, 82.0, 117.1,
122.9, 124.5, 127.2, 128.3, 128.6,129.1, 129.7, 133.0, 136.0, 144.4,
164.3, 164.5, 164.8; M++1 = 348.
Authors are thankful to the authorities of Jawaharlal Nehru
Technological University Hyderabad, for providing laboratory facil-
ities and for financial support to two of them (PPK & YDR).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
020.
Compound 7d: Mp: 220–222 °C; IR (KBr): 3263–3512 cmꢀ1
(broad, medium, –NH–), 2251 cmꢀ1 (sharp, strong, –CN–),
1740 cmꢀ1 (sharp, strong, –CO– group), 1681 cmꢀ1 (sharp, strong,
–CO– of amide group), 1616 cmꢀ1 (sharp, strong, –CO– of amide
group); 1H NMR (DMSO-d6, 100 MHz): d 7.1–8.3 (m, 9H, Ar-H
and NC-C@CH), 11.0 (s, 1H, –OH, D2O exchangeable); 13C NMR
(DMSO-d6, 400 MHz): d 81.3, 81.5, 117.9, 122.0, 124.4, 127.2,
128.2, 128.5, 129.0, 129.1, 129.5,133.0, 136.0, 143.3, 164.4, 164.5,
164.6; M++1 = 363.
References and notes
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Compound 7e: Mp: 230–232 °C; IR (KBr): 3263–3512 cmꢀ1
(broad, medium, –NH–), 2250 cmꢀ1 (sharp, strong, –CN–),
1741 cmꢀ1 (sharp, strong, –CO– group), 1681 cmꢀ1 (sharp, strong,
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group); 1H NMR (DMSO-d6, 100 MHz): d 2.2 (s, 3H, CH3), 7.2–8.3
(m, 9H, Ar-H and NC-C@CH), 11.2 (s, 1H, –OH, D2O exchangeable);
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124.0, 127.2, 128.4, 128.5, 129.1, 129.1,129.6, 133.1, 136.2, 142.3,
164.4, 164.5, 164.7; M++1 = 332.
Compound 7f: Mp: 170–172 °C; IR (KBr): 3267–3518 cmꢀ1
(broad, medium, –NH–), 2258 cmꢀ1 (sharp, strong, –CN–),
1749 cmꢀ1 (sharp, strong, –CO– group), 1683 cmꢀ1 (sharp, strong,
–CO– of amide group), 1613 cmꢀ1 (sharp, strong, –CO– of amide
group); 1H NMR (DMSO-d6, 400 MHz): d 5.7–7.7 (m, 9H, Ar-H
and NC-C@CH), 10.9 (s, 1H, –OH, D2O exchangeable); 13C NMR

2182
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