Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a three-component sequential tandem reaction

Article abstract of DOI:10.1016/j.tet.2012.09.045

A novel one-pot three-component reaction of 6-amino-uracil, isatin, and acetophenone was accomplished through a programmed pH variation for the synthesis of 5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives. The reaction was c

Full text of DOI:10.1016/j.tet.2012.09.045

Tetrahedron 68 (2012) 9706e9712
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a three-component
sequential tandem reaction
*
Kurosh Rad-Moghadam , Seyyedeh Cobra Azimi
Chemistry Department, University of Guilan, PO Box, 41335-19141 Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Received in revised form 26 August 2012
Accepted 10 September 2012
Available online 16 September 2012
A novel one-pot three-component reaction of 6-amino-uracil, isatin, and acetophenone was accom-
plished through a programmed pH variation for the synthesis of 5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]
pyrimidine-2,4(3H,7H)-dione derivatives. The reaction was conducted in a sequential tandem manner to
give the oxindole substituted pyrrolo[2,3-d]pyrimidine products in good to excellent yields. Despite of
timing all the processes were carried out in one pot. Most of these novel compounds show narrow to
good spectrum of antimicrobial activities in vitro.
Keywords:
Multicomponent reaction
Amino-uracil
Ó 2012 Elsevier Ltd. All rights reserved.
Isatin
2-Oxindole
Pyrrolo[2,3-d]pyrimidine
1. Introduction
pharmacological properties.5e8 A number of indole derivatives
have shown antibacterial,9 antiviral,10 protein kinase inhibitory11 as
The invention of concise synthetic methodologies for the con-
struction of complex molecules is a pivotal focal point of researches
aiming to facilitate the preparation of compound libraries and
elaborate syntheses in the field of modern medicinal chemistry.
Natural and biologically relevant systems are diverse and often
complex molecules, which encourage organic chemists to emulate
nature’s efficiency in the development of new synthetic methods
and reactions for assembling novel compounds. A potential ap-
proach toward this goal is to combine two or more distinct re-
actions into a single transformation, thereby effecting tandem
reactions.1 Tandem reactions widely occur in living organisms and
many were discovered by chemists on mimicry to save synthetic
operations while maximizing the build-up of structural and func-
tional complexity using simple starting materials.2 As such, tandem
reactions are of increasing importance in modern organic chemis-
try. One-pot tandem reactions by virtue of their convergence, ele-
gance, and highly step-economy are particularly appealing in the
context of rapid target-oriented synthesis.3 These reactions fall
under the fold of green chemistry, as they obviate the isolation and
purification of intermediates leading to a reduction in pollution.4
3-Substituted indoles are the structural units of many natural
and biologically interesting compounds possessing various
well as potential anticancer activities; indole-3-carbinols have been
reported to exhibit anticancer activities against a number of human
cancers through acting on different cellular signaling pathways.12
1-Aroylindoles and 3-aroylindoles have shown potent cytotoxicity
against different human cancer cell lines.13 Indole alkaloids are
quite prevalent in nature and form a prominent class of bioactive
natural products.14 Two diastereoisomeric triseindole alkaloids,
occurring as enantiomeric pairs, designated as (ꢀ)-gelliusinus A
and B I represent the major components of a deep water Caledonian
sponge15 and vibrindole A II is a metabolite of the marine bacte-
rium, Vibrio parahaemalyticus, which is isolated from the toxic
mucus of the boxfish Ostracion cubicus16 (Scheme 1).
Prompted by the biological activities of indoles,17e24 and in line
with our interest in the synthesis of heterocyclic compounds,25e29
herein we report a novel and efficient method for the assembling of
5-(2-oxoindolin-3-yl)-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
derivatives. These compounds belong to the class of oxindolyl-7-
deazapurines and to the best of our knowledge this is the first re-
port on their synthesis.
2. Results and discussion
To approach the synthesis of the oxindolylpyrrolo[2,3-d]py-
rimidines 4, we based our experiments on a three-component re-
action between the model substrates 6-amino-1,3-dimethyluracil
1a, isatin 2a, and acetophenone 3a. Our initial trials centered on
* Corresponding author. Fax: þ98 131 3220066; e-mail addresses: radmm880@
gmail.com, radmm@guilan.ac.ir (K. Rad-Moghadam).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.045

K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
9707
the pH of the reaction mixture to be acidic, as we expected, led to
condensation of the in situ obtained oxindole intermediate with 6-
amino-1,3-dimethyluracil 1a to give the product 4a. Certainly, the
choice of an appropriate reaction medium is of crucial importance
for effecting a successful tandem reaction. In this regard, we
attempted to determine the optimum conditions by examining the
effect of solvent and catalyst variations on progress of the model
reaction. The results were collected in Table 1. It could be seen that
the best yield of the product is obtained by the sequential use of
piperidine (10 mol %) and p-toluenesulfonic acid (p-TSA, 40 mol %)
in refluxing ethanol at 80 ꢁC (Table 1, entry 8).
After determination of piperidine and p-toluenesulfonic acid as
suitable catalysts, a variety of isatin derivatives, acetophenones,
and amino-uracils were employed under similar conditions to
evaluate the substituent scope of this reaction. As Table 2 shows, all
the cyclocondensation reactions proceeded efficiently and afforded
the products 4aep in fairly high yields.
H3C
HN
NH
HN
N
H
NH2
NH2
Vibrindole A II
Br
NH2
HO
N
H
Gelliusines
A and B I
Scheme 1. Instances of the indole alkaloids.
effecting the reaction in the absence of any catalyst, but resulted in
low conversions even under prolonged (15 h) refluxing in ethanol
(Table 1, entry 1).
Encouraged by these results, we attempted to expand the scope
of this synthetic method by using naphthalenamines in place of
Table 1
Optimization of the reaction conditionsa
O
N
Me
N
Me
NH
O
O
O
O
Me
O
O
N
Me
1) Base
+
+
O
N
N
NH2
2) Acid, Reflux
H
N
Me
H
1a
2a
3a
4a
Entry
Solvent
Base catalyst
Acid catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
H2O
THF
CH3CN
d
d
15
7
6
8
8
5
7
2
3
7
6
4
8
23c
73c
80c
30
24
68
46
94
75
60
d
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
HCl
d
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Et2NH
Piperidine
Piperidine
Piperidine
Piperidine
H2O/EtOH
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
9
10
11
12
13
CH3COOH
65
L-Proline
74
d
93d
a
A mixture of 6-amino-1-methyluracil (1 mmol), acetophenone (1.5 mmol), isatin (1 mmol), and the catalysts (10 mol % of the base and 40 mol % of the acid).
Isolated yields of 4a.
The side product 5 is formed.
Product 6 is formed.
b
c
d
A
short course of experimentations indicated that under
amino-uracil partner. However, naphthalenamines remained en-
tirely unreactive when we tried to enter them into a similar re-
action. This failure may be ascribed to the aromatic character of 1-
and 2-naphthalenamines restricting their action as enamines, in
comparison with amino-uracils. Similar endeavors we made to
employ 1- or 2-naphthols in place of amino-uracils also remained
unsuccessful to give the corresponding compounds comprising of
naphthofuran moiety.
Attempts to bring acenaphthoquinone, ninhydrin, or phenan-
threne-9,10-dione into the sequential tandem reactions with ace-
tophenone and amino-uracils were unsatisfactory as they gained
multiple of products polluted with unreacted substrates or other-
wise completely remained unreactive.
acidic conditions the desired reaction is superseded by a three-
component condensation between two molecules of 6-amino-1,3-
dimethyluracil 1a and isatin 2a to give the 1,10,3,30-tetrame-
thyl-1H-spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimi-
dine]-2,20,4,40,60(10H,3H,30H,70H,10H)-pentaone 5a (Scheme 2).30
Moreover, under mild basic conditions the reaction no longer
proceeds beyond the addition of acetophenone 3a on isatin 2a,
leaving 6-amino-1,3-dimethyluracil 1a completely unreacted aside.
Upon these observations, we thought to bring the three compo-
nents into a sequential tandem reaction in one pot to synthesize the
oxindolylpyrrolo[2,3-d]pyrimidines simply by inverting the pH of
the reaction medium. The key-step validating this protocol is the
quick base-catalyzed addition of acetophenone on isatin, which
goes to completion in a few minutes to give the intermediate 3-
hydroxy-3-benzoylmethylindolin-2-one. Afterward, by changing
A plausible mechanism for the formation of 5-(2-oxoindolin-3-
yl)-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-diones 4aep from the
three components is depicted in Scheme 3. Compounds 4aep are

9708
K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
Me
O
N
HN
N Me
O
O
O
Me
N
O
N
N
H
Me
O
N
Me
N
p-TSA / EtOH, Reflux
5a
Me
NH
O
O
N
O
O
1) Base
2) Acid
O
Me
O
N
Me
+
+
NH2
O
EtOH, Reflux
N
N
H
H
Me
1a
2a
Piperidine
3a
4a
O
HO
O
N
H
6a
Scheme 2. The competing reactions of the three components and their relative conditions.
Table 2
Synthesis of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-diones 4aep under the optimized conditions
R2
O
N
N
R1
R3
NH
O
O
O
O
R3
R1
O
O
N
Me
1) Piperidine
+
+
O
R4
N
N
R2
NH2
2) p-TSA/ EtOH, Reflux
R4
H
N
H
R1, R2 = Me / H
R3 = H / Cl
R4 = H / Cl / F / OCH3
(82–95%)
1
2
3
4a-p
Product
R1
R2
R3
R4
Time (h)
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
Cl
H
H
H
H
H
H
Cl
Cl
H
Cl
F
H
Cl
F
OCH3
OCH3
H
Cl
F
OCH3
H
Cl
F
2
2
2
2.5
2.5
2
2
2.5
3
2.5
2
2
3
2.5
2
94
88
91
89
92
86
90
87
84
92
85
89
95
86
92
82
H
H
H
H
Me
Me
Me
Me
H
2
a
Isolated yields.
thought to be formed through a sequence of reactions initiated by
a quick nucleophilic addition of acetophenones onto isatins under
piperidine catalysis to afford 3-hydroxy-3-aroylmethylindolin-2-
ones 6. Upon addition of p-TSA to the reaction mixture, the 3-
hydroxyindolin-2-ones 6 undergo dehydration to give the in-
termediate 3-aryloylmethylideneindolin-2-ones 7. These in-
termediates are comprised of an exocyclic alkenyl bond being
polarized by the dominant electron-withdrawing impact of indo-
lin-2-one moiety, whereupon they undergo Michael addition
preferably at the olefinic methine carbon atom. The Michael adduct
8 follows an intramolecular condensation to form the product 4.
Only a trace of the side product 9, resulting from the regioiso-
meric Michael adduct of amino-uracil and the intermediate 7, was
detected by 1H NMR spectrum of the reaction mixture. This side
product was readily distinguished by the characteristic signal of its
single olefinic proton resonating around dH 5.6. Assigning of all the
1H NMR signals of this side product is very difficult since theyappear
so weak and commonly overlapping with the signals of the main

K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
9709
Ph
O
Ph
O
O
HO
O
-H2O
1) Piperidine
H3C
+
O
O
O
p-TSA
N
N
H
N
H
H
2
3
6
7
O
Me
N
2) p-TSA
EtOH, Reflux
O
N
NH2
Me
1
O
O
Me
Me
N
N
NH2
Ph
Me
N
O
Me
N
O
NH
O
-H2O
H
H
O
O
N
N
H
H
4
8
Scheme 3. A proposed mechanism for the sequential tandem reactions.
product. Reasonably, orientation of the Michael addition onto in-
termediate 7 is predominantly directed by the oxindole carbonyl
group, owing to rigid coplanar configuration of this group with the
olefinic bond. As we have previously reported,28,29 the direction of
the Michael addition is completely reversed when two rigidly co-
planarcarbonylgroups competewith the oxindole carbonylgroupat
the opposing conjugation terminal of the olefinic bond (Scheme 4).
sharp signal of the methine proton at
d 4.60. In addition, there are
two singlet signals appeared at 10.37 and 11.88 in the spectrum
d
accounting for the presence of two NeH groups in the molecule. The
13C NMR spectrum of 4a displays 20 distinct lines with appropriate
chemical shifts corresponding to the structure of this compound.
Finally, the synthesized products 4aep were screened for
antimicrobial activity. The microorganisms used in this study
Me
H2N
N
O
N
Me
Me
H2N
N
H2N
Me
O
N
O
O
O
N
N
HN
HN
HN
Me
Me
Ph
Ph
O
O
O
O
O
O
O
O
O
O
Me
N
Me
N
O
NH
O
NH
NH
Me
Me
H
N
N
N
N
H
O
O
O
O
O
O
N
H
9
N
Me
Me
N
H
4
H
10
Trace
Major product
The sole product
Scheme 4. The favored Michael additions emerging as the determinants of selectivity.
The structures of compounds 4aep were confirmed by IR,1H and
13C NMR spectroscopy, mass spectrometry, and elemental analysis.
The IR spectrum of compound 4a, for example, shows absorption
bands at 3356, 3108,1682, and 1643 cmꢂ1 indicating the presence of
NeH and C]O groups in this molecule. Aromatic protons of this
were Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC
85327 (as gram-negative bacteria), Bacillus subtilis ATCC465,
and Staphylococcus aureus ATCC 25923 (as gram-positive bac-
teria). The minimum inhibitory concentrations (MICs) of com-
pounds 4aep were determined by microdilution method31
(Table 3). As can be seen from Table 3, good antibacterial ac-
tivities were observed for most of the compounds against all
species of gram-positive and gram-negative bacteria used in
this study.
compound were seen at
nating with proper integrals and splittings. Aliphatic region of this
spectrum exhibits two singlet peaks at 3.04 and 3.49 arising from
protons of the two methyl groups along with the characteristic
d
6.83e7.61 in its 1H NMR spectrum reso-
d

9710
K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
Table 3
4.2.1. 1,3-Dimethyl-5-(2-oxoindolin-3-yl)-6-phenyl-1H-pyrrolo[2,3-
MIC (mg/mL) values of products 4aep
d]pyrimidine-2,4(3H,7H)-dione (4a). White powder (0.362 g, 94%).
Mp 350 ꢁC decomp. IR (KBr): 3356, 3108, 3035, 1682, 1643,
1551 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6): dH 3.04 (3H, s, CH3),
3.49 (3H, s, CH3), 4.60 (1H, s, CH), 6.83 (1H, t, 3J 7.2 Hz), 6.83 (1H, d,
3J 7.6 Hz), 7.14 (1H, t, 3J 7.6 Hz), 7.43 (1H, t, 3J 7.4 Hz), 7.53 (2H, t, 3J
Product
Escherichia
coli
Pseudomonas
aeruginosa
Bacillus
subtilis
Staphylococcus
aureus
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
a
a
a
a
16
8
8
8
16
8
8
8
a
128
8
64
8
32
16
8
64
8
128
128
16
a
a
32
8
128
8
2
32
4
8
7.6 Hz), 7.62 (2H, d, 3J 7.2 Hz), 10.37 (1H, s, NH), 11.88 (1H, s, NH). 13
C
64
64
128
32
32
128
32
8
NMR (100.6 MHz, DMSO-d6): dC 27.8 (CH3), 31.0 (CH3), 44.2, 97.8,
109.5, 111.3, 121.2, 123.4, 127.7, 128.2, 128.3, 128.8, 129.3, 131.0, 131.2,
140.2, 144.0, 151.1, 157.8, 178.0. MS (EI, 70 eV) m/z: 386 (Mþ, 17), 381
(17), 368 (58), 313 (50), 260 (77), 236 (56), 183 (37), 152 (41), 83
(64), 57 (100). Anal. Calcd for C22H18 N4O3 (386.14): C, 68.38; H,
4.70; N, 14.50%. Found: C, 68.32; H, 4.65; N, 14.57%.
a
128
16
a
8
a
128
a
64
16
a
128
<2
a
a
16
8
16
128
8
32
20
a
4.2.2. 6-(4-Chlorophenyl)-1,3-dimethyl-5-(2-oxoindolin-3-yl)-1H-
pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione (4b). Cream powder
(0.369 g, 88%). Mp 355 ꢁC decomp. IR (KBr): 3362, 3296, 3138, 3050,
32
64
16
16
4
1693, 1642, 1535 cmꢂ1 1H NMR (400.13 MHz, DMSO-d6): dH 3.03
.
Norfloxacin
Tetracycline
4
(3H, s, CH3), 3.49 (3H, s, CH3), 4.61 (1H, s, CH), 6.81e6.86 (2H, m),
6.89 (1H, d, 3J 7.2 Hz), 7.14 (1H, t, 3J 7.6 Hz), 7.58 (2H, d, J 8.8 Hz), 7.63
(2H, d, J 8.8 Hz), 10.39 (1H, s, NH), 11.91 (1H, s, NH). 13C NMR
(100.6 MHz, DMSO-d6): dC 27.8 (CH3), 31.0 (CH3), 44.1, 97.9, 109.5,
112.0, 121.2, 123.4, 127.9, 128.3, 129.3, 129.9, 130.4, 130.8, 132.9,
140.3, 144.0, 151.0, 157.8, 177.9. MS (EI, 70 eV) m/z: 422 (Mþ, 37Cl, 4),
421 (3), 420 (Mþ, 35Cl,13), 386 (24), 368 (36), 339 (20), 313 (52), 260
(76), 236 (72), 196 (25), 149 (44), 109 (40), 83 (82), 57 (100). Anal.
Calcd for C22H17ClN4O3 (420.10): C, 62.79; H, 4.07; N,13.31%. Found:
C, 62.68; H, 4.24; N, 13.29%.
a: not active.
3. Conclusion
In summary, we have developed a sequential tandem protocol
for facile preparation of a new class of oxindolyl-7-deazapurine
derivatives in one pot via a novel cyclocondensation reaction
between acetophenones, isatins, and 6-amino-uracils in refluxing
ethanol. The synthesis occurs selectively subject to a sequential
application of two catalysts and we anticipate being prone to
automation by using a pH-gradient reactor. These products were
evaluated in vitro for their antibacterial activities. Almost all of
the obtained oxindolylpyrrolo[2,3-d]pyrimidine products exhibi-
ted good to excellent antibacterial activities against the tested
strains.
4.2.3. 6-(4-Fluorophenyl)-1,3-dimethyl-5-(2-oxoindolin-3-yl)-1H-
pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione (4c). White powder
(0.367 g, 91%). Mp 338 ꢁC decomp. IR (KBr): 3361, 3104, 3047, 2898,
1683, 1645, 1550, 1230, 744 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6):
dH 3.03 (3H, s, CH3), 3.48 (3H, s, CH3), 4.57 (1H, s, CH), 6.82 (1H, t, 3J
7.4 Hz), 6.83 (1H, d, 3J 7.6 Hz), 6.90 (1H, d, 3J 7.6 Hz), 7.13 (1H, t, 3J
7.8 Hz), 7.38 (2H, t, 3J 8.6 Hz), 7.64 (2H, dd, 3JHH 8.6 Hz, 4JHF 5.6 Hz),
10.39 (1H, s, NH),11.90 (1H, s, NH). 13C NMR (100.6 MHz, DMSO-d6):
dC 27.8 (CH3), 31.0 (CH3), 44.1, 97.8, 109.5, 111.4, 116.3 (d, 2JCF 22 Hz),
4. Experimental
4.1. General
3
121.2, 123.4, 127.4 (d, 4J 1 Hz) 127.8, 130.2, 130.92 (d, JCF 8.3 Hz),
130.93, 140.1, 144.0, 151.1, 157.8, 161.0 (d, 1JCF 243 Hz), 178.0. MS (EI,
70 eV) m/z: 404 (Mþ, 60), 386 (21), 261 (43), 245 (100),196 (52),152
(39), 105 (14). Anal. Calcd for C22H17FN4O3 (404.13): C, 65.34; H,
4.24; N, 13.85%. Found: C, 65.41; H, 4.28; N, 13.76%.
All of the solvents and reagents were purchased from Fluka or
Merck chemical companies. Melting points were measured on an
Electrothermal apparatus and are uncorrected. IR spectra were
obtained in KBr disks on a Shimadzu IR-470 spectrometer. 1H and
13C NMR spectra were measured with a Brucker DRX-400 AVANCE
spectrometer. Chemical shifts of 1H and 13C NMR spectra were
expressed in parts per million downfield from tetramethylsilane.
Mass spectra were recorded on a Shimadzu QP1100EX mass spec-
trometer operating at an ionization potential of 70 eV. Elemental
analyses for C, H, and N were performed using a Foss Heraus
CHNeO-rapid analyzer.
4.2.4. 5-(5-Chloro-2-oxoindolin-3-yl)-1,3-dimethyl-6-phenyl-1H-
pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione (4d). Cream powder
(0.373 g, 89%). Mp 335 ꢁC decomp. IR (KBr): 3295, 3198, 1690, 1637,
1527, 1478 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6): dH 3.04 (3H, s,
CH3), 3.49 (3H, s, CH3), 4.67 (1H, s, CH), 6.82 (1H, d, 3J 8.4 Hz), 6.88
(1H, br s), 7.18 (1H, dd, 3J 8.4 Hz and 4J 1.2 Hz), 7.43 (1H, t, 3J 7.2 Hz),
7.53 (2H, t, 3J 7.6 Hz), 7.60 (2H, d, 3J 7.2 Hz), 10.52 (1H, s, NH), 11.92
(1H, s, NH). 13C NMR (100.6 MHz, DMSO-d6): dC MS (EI, 70 eV) m/z:
422 (Mþ, 37Cl, 6), 421 (Mþþ1, 9), 420 (Mþ, 35Cl, 16), 368 (25), 313
(39), 260 (43), 236 (54), 167 (20), 149 (55), 123 (24), 83 (63), 57
(100). Anal. Calcd for C22H17ClN4O3 (420.10): C, 62.79; H, 4.07; N,
13.31%. Found: C, 62.70; H, 4.11; N, 13.28%.
4.2. Typical experimental procedure for synthesis of 4a
A mixture of isatin (0.147 g, 1 mmol), acetophenone (0.09 mL,
1.5 mmol), and piperidine (two drops, 0.1 mmol) in ethanol
(95.5%, 1 mL) was heated at 80 ꢁC for about 5 min. To the solid
obtained at this stage was added 6-amino-1,3-dimethyluracil
(0.155 g, 1 mmol), p-toluenesulfonic acid monohydrate (0.076 g,
0.04 mmol), and EtOH (95.5%, 2 mL). The mixture was stirred and
heated gently at 80 ꢁC. After completion of the reaction (115 min),
as monitored by TLC using 5:1 ratio of ethyl acetate/n-hexane, the
reaction mixture was cooled to room temperature and then fil-
tered. The separated solids were washed twice with 10 mL
of water and 3 mL of hot ethanol (95.5%) to obtain the pure
product 4a.
4.2.5. 5-(5-Chloro-2-oxoindolin-3-yl)-6-(4-chlorophenyl)-1,3-
dimethyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(4e). White powder (0.417 g, 92%). Mp 370 ꢁC decomp. IR (KBr):
3301, 3178, 1697, 1682, 1636, 1558 cmꢂ1 1H NMR (400.13 MHz,
.
DMSO-d6): dH 3.04 (3H, s, CH3), 3.48 (3H, s, CH3), 4.68 (1H, s, CH),
6.84 (1H, d, 3J 8.4 Hz), 6.88 (1H, br s), 7.18 (1H, dd, 3J 8.4 Hz and 4J
1.2 Hz), 7.60 (4H, s), 10.53 (1H, s, NH), 11.95 (1H, s, NH). 13C NMR
(100.6 MHz, DMSO-d6): dC 27.8 (CH3), 31.0 (CH3), 44.2, 97.8, 110.8,
111.1, 123.4, 125.2, 127.7, 129.3, 129.9, 130.2, 130.6, 133.0, 133.2,

K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
9711
140.4, 143.0, 151.0, 157.9, 177.6. MS (EI, 70 eV) m/z: 458 (3), 457
(7), 456 (Mþ, 35Cl, 37Cl, 42), 455 (Mþþ1, 35Cl, 35Cl, 18), 454 (Mþ,
35Cl, 35Cl, 61), 420 (28), 368 (17), 313 (36), 245 (86), 196 (44), 167
(36), 149 (82), 83(61), 57 (100). Anal. Calcd for C22H16Cl2N4O3
(454.06): C, 58.04; H, 3.54; N, 12.31%. Found: C, 58.12; H, 3.52; N,
12.26%.
Anal. Calcd for C20H14N4O3 (358.11): C, 67.03; H, 3.94; N, 15.63%.
Found: C, 67.12; H, 3.97; N, 15.57%.
4.2.10. 6-(4-Chlorophenyl)-5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]
pyrimidine-2,4(3H,7H)-dione (4j). White powder (0.360 g, 92%). Mp
370 ꢁC decomp. IR (KBr): 3160, 3030, 2825, 1737, 1702, 1654, 1623,
1587, 1465 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6): dH 4.57 (1H, s,
CH), 6.78e6.82 (2H, m), 6.88 (1H, d, 3J 7.6 Hz), 7.12 (1H, t, 3J 7.6 Hz),
7.53 (2H, d, 3J 8.8 Hz), 7.57 (2H, d, 3J 8.8 Hz), 10.26 (1H, s, NH), 10.35
(1H, s, NH), 11.53 (1H, s, NH), 11.80 (1H, s, NH). 13C NMR (100.6 MHz,
DMSO-d6): dC 44.1, 98.3, 109.4, 111.3, 121.2, 128.1, 129.2, 129.4, 129.6,
130.1, 130.2, 131.0, 132.6, 140.4, 144.0, 151.5, 159.0, 178.0. MS (EI,
70 eV) m/z: 392 (Mþꢂ2, 37Cl, 5), 391 (3), 390 (Mþꢂ2, 35Cl, 16), 279
(14), 180 (15), 139 (55), 111 (47), 91 (16), 64 (33), 44 (100). Anal.
Calcd for C20H13ClN4O3 (392.07): C, 61.16; H, 3.34; N, 14.26%. Found:
C, 61.09; H, 3.42; N, 14.18%.
4.2.6. 5-(5-Chloro-2-oxoindolin-3-yl)-6-(4-fluorophenyl)-1,3-
dimethyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H) dione (4f). White
powder (0.376 g, 86%). Mp 300 ꢁC decomp. IR (KBr): 3307, 3104,
3053, 1698, 1682, 1634, 1553, 1223, 740 cmꢂ1. 1H NMR (400.13 MHz,
DMSO-d6): dH 3.04 (3H, s, CH3), 3.48 (3H, s, CH3), 4.63 (1H, s, CH),
3
6.83 (1H, d, J 8.4 Hz), 6.89 (1H, br s), 7.18 (1H, dd, 3J 8.4 Hz and 4
J
1.2 Hz), 7.38 (2H, t, 3J 8.8 Hz), 7.63 (2H, dd, JHH 8.8 Hz and JHF
5.6 Hz), 10.53 (1H, s, NH), 11.93 (1H, s, NH). 13C NMR (100.6 MHz,
DMSO-d6): dC 27.8 (CH3), 31.0 (CH3), 44.2, 97.6, 110.5, 110.8, 116.2 (d,
3
4
2JCF 21.5 Hz), 123.4, 125.2, 127.5 (d, JCF 1 Hz), 127.7, 130.5, 131.1 (d,
4
3JCF 8.3 Hz), 133.2, 140.2, 143.0, 151.0, 157.9, 162.3 (d, 1JCF 244 Hz),
177.7. MS (EI, 70 eV) m/z: 440 (Mþ, 37Cl, 5), 439 (Mþþ1, 35Cl, 6), 438
(Mþ, 35Cl, 14), 368 (40), 329 (35), 285 (18), 264 (21), 245 (49), 167
(22), 149 (56), 83 (62), 57 (100). Anal. Calcd for C22H16ClFN4O3
(438.09): C, 60.21; H, 3.67; N, 12.77%. Found: C, 60.14; H, 3.62; N,
12.82%.
4.2.11. 6-(4-Fluorophenyl)-5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]
pyrimidine-2,4(3H,7H)-dione (4k). White powder (0.319 g, 85%).
Mp 360 ꢁC decomp. IR (KBr): 3188, 3103, 3048, 2821, 1721, 1698,
1665, 1576, 1459, 1218, 832 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6):
dH 4.52 (1H, s, CH), 6.79e6.83 (2H, m), 6.88 (1H, d, 3J 7.2 Hz), 7.12
(1H, t, 3J 7.6 Hz), 7.32 (2H, t, J 8.8 Hz), 7.58 (2H, dd, 3JHH 8.8 Hz, 3JHF
5.4 Hz), 10.24 (1H, s, NH), 10.35 (1H, s, NH), 11.51 (1H, s, NH), 11.75
(1H, s, NH). 13C NMR (100.6 MHz, DMSO-d6): dC 44.1, 97.8, 109.4,
110.7, 116.1 (d, JCF 21.5 Hz), 121.2, 123.4, 127.7, 128.5 (d, JCF 1 Hz),
129.7, 130.7, (d, 3JCF 8.2 Hz), 131.1, 140.2, 144.0, 151.5, 159.0, 162.6 (d,
1JCF 236 Hz), 178.1. MS (EI, 70 eV) m/z: 376 (Mþ, 14), 374 (Mþꢂ2, 22),
345 (9), 279 (10), 180 (21), 153 (13), 123 (100), 95 (74), 75 (23), 44
(27). Anal. Calcd for C20H13FN4O3 (376.10): C, 63.83; H, 3.48; N,
14.89%. Found: C, 63.79; H, 3.39; N, 15.01%.
4.2.7. 6-(4-Methoxyphenyl)-1,3-dimethyl-5-(2-oxoindolin-3-yl)-1H-
pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione (4g). White powder
(0.374, 90%). Mp 360 ꢁC decomp. IR (KBr): 3348, 3122, 3047, 1684,
1643, 1547, 1316, 1249 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6): dH
3.03 (3H, s, CH3), 3.48 (3H, s, CH3), 3.80 (3H, s, OCH3), 4.55 (1H, s,
CH), 6.81e6.85 (2H, m), 6.90 (1H, d, 3J 7.2 Hz), 7.09 (2H, d, 3J 8.6 Hz),
7.15 (1H, d, 3J 7.2 Hz), 7.53 (2H, d, 3J 8.6 Hz), 10.36 (1H, s, NH), 11.80
(1H, s, NH). 13C NMR (100.6 MHz, DMSO-d6): dC 27.7 (CH3), 31.0
(CH3), 44.2, 55.7 (CH3), 97.7, 109.5, 110.4, 114.8, 121.2, 123.4, 123.6,
127.8,130.2,131.0,131.1, 139.8, 143.9, 151.1,157.8, 159.5, 178.1. MS (EI,
70 eV) m/z: 417 (Mþþ1, 4), 385 (7), 278 (38), 255 (19), 221 (44), 193
(23), 149 (43), 129 (41), 111 (37), 97 (36), 71 (46), 43 (100). Anal.
Calcd for C23H20N4O4 (416.15): C, 66.34; H, 4.84; N, 13.45%. Found:
C, 66.26; H, 4.86; N, 13.42%.
2
4
4.2.12. 6-(4-Methoxyphenyl)-5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-
d]pyrimidine-2,4(3H,7H)-dione (4l). White powder (0.345 g, 89%).
Mp 360 ꢁC decomp. IR (KBr): 3365, 3178, 3033, 2837, 1697, 1658,
1255, 742 cmꢂ1 1H NMR (400.13 MHz, DMSO-d6): dH 3.78 (3H, s,
.
CH3), 4.52 (1H, s, CH), 6.79e6.85 (2H, m), 6.88 (1H, d, 3J 7.2 Hz), 7.05
(2H, d, 3J 8.8 Hz), 7.11 (1H, t, 3J 7.6 Hz), 7.48 (2H, d, 3J 8.8 Hz), 10.20
(1H, s, NH), 10.33 (1H, s, NH), 11.42 (1H, s, NH), 11.62 (1H, s, NH). 13C
NMR (100.6 MHz, DMSO-d6): dC 44.2, 55.7, 98.0, 109.8, 113.6, 114.6,
121.2, 123.8, 127.7, 129.3, 129.9, 130.6, 131.3, 139.9, 144.0, 151.5,
159.0, 159.3, 178.3. MS (EI, 70 eV) m/z: 388 (Mþ, 6), 386 (Mþꢂ2, 16),
357 (3), 257 (61), 186 (32), 171 (28), 155 (26), 135 (100), 92 (29),
77(48), 44 (39). Anal. Calcd for C21H16N4O4 (388.12): C, 64.94; H,
4.15; N, 14.43%. Found: C, 64.87; H, 4.23; N, 14.39%.
4.2.8. 5-(5-Chloro-2-oxoindolin-3-yl)-6-(4-methoxyphenyl)-1,3-
dimethyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(4h). Cream powder (0.391 g, 87%). Mp 350 ꢁC decomp. IR (KBr):
3335, 3292, 1699, 1681, 1647, 1558, 1246, 1029, 741 cmꢂ1. 1H NMR
(400.13 MHz, DMSO-d6): dH 3.04 (3H, s, CH3), 3.48 (3H, s, CH3), 3.80
(3H, s, OCH3), 4.61 (1H, s, CH), 6.83 (1H, d, 3J 8.4 Hz), 6.86 (1H, br s),
7.10 (2H, d, 3J 8.6 Hz), 7.17 (1H, dd, 3J 8.4 Hz, 4J 1.2 Hz), 7.52 (2H, d, 3J
8.6 Hz), 10.50 (1H, s, NH), 11.84 (1H, s, NH). 13C NMR (100.6 MHz,
DMSO-d6): dC 27.8 (CH3), 31.0 (CH3), 44.3, 55.7 (OCH3), 97.5, 109.6,
110.8,114.8,123.3, 123.4, 125.1,127.7,130.3, 131.5, 133.4, 139.9, 143.0,
151.1, 157.9, 159.6, 177.8. MS (EI, 70 eV) m/z: 452 (Mþ, 37Cl, 27), 451
(Mþþ1, 35Cl, 23) 450 (Mþ, 35Cl,100), 421 (24), 337 (15), 315 (13), 259
(12), 190 (21), 134 (43), 91 (45), 57 (62), 41 (53). Anal. Calcd for
C23H19ClN4O4 (450.11): C, 61.27; H, 4.25; N, 12.43%. Found: C, 61.33;
H, 4.19; N, 12.39%.
4.2.13. 1-Methyl-5-(2-oxoindolin-3-yl)-6-phenyl-1H-pyrrolo[2,3-d]
pyrimidine-2,4(3H,7H)-dione (4m). White powder (0.353 g, 95%).
Mp 360 ꢁC decomp. IR (KBr): 3332, 3140, 3048, 1698, 1684, 1667,
1618,1542,1317, 741 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6): dH 3.39
(3H, s, CH3), 4.59 (1H, s, CH), 6.82 (1H, d, 3J 8.0 Hz), 6.83 (1H, t, 3J
8.0 Hz), 6.90 (1H, d, 3J 7.2 Hz), 7.13 (1H, t, 3J 7.6 Hz), 7.43 (1H, t, 3J
7.6 Hz), 7.53 (2H, t, 3J 7.6 Hz), 7.62 (2H, d, 3J 7.6 Hz), 10.36 (1H, s, NH),
10.53 (1H, s, NH),11.85 (1H, s, NH). 13C NMR (100.6 MHz, DMSO-d6):
dc 29.9 (CH3), 44.2, 98.7, 110.4, 110.7, 123.4, 125.3, 127.7, 128.3, 128.4,
128.9, 129.4, 131.0, 133.3, 141.5, 142.9, 150.9, 158.3, 176.7. MS (EI,
70 eV) m/z: 372 (Mþ, 9), 368 (37), 304 (29), 236 (39), 213 (24), 185
(16), 158 (70), 149 (55), 105 (91), 57 (100). Anal. Calcd for
C21H16N4O3 (372.12): C, 67.73; H, 4.33; N,15.05%. Found: C, 67.68; H,
4.30; N, 15.11%.
4.2.9. 5-(2-Oxoindolin-3-yl)-6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-
2,4(3H,7H)-dione (4i). White powder (0.300 g, 84%). Mp 360 ꢁC
decomp. IR (KBr): 3284, 3189, 1702, 1681, 1646, 1618, 1560, 1314,
1177 cmꢂ1 1H NMR (400.13 MHz, DMSO-d6): dH 4.58 (1H, s, CH),
.
6.80e6.84 (2H, m), 6.89 (1H, d, 3J 7.6 Hz), 7.12 (1H, t, 3J 7.6 Hz), 7.38
(1H, t, 3J 7.2 Hz), 7.48 (2H, t, 3J 7.6 Hz), 7.57 (2H, d, 3J 7.8 Hz), 10.23
(1H, s, NH), 10.34 (1H, s, NH), 11.49 (1H, s, NH), 11.72 (1H, s, NH). 13C
NMR (100.6 MHz, DMSO-d6): dC 44.2,109.4,110.7,121.2,123.4,127.8,
128.0, 128.2, 128.5, 129.2, 130.6, 131.1, 131.4, 140.2, 144.0, 151.5,
159.0, 178.1. MS (EI, 70 eV) m/z: 358 (Mþ, 15), 327 (6), 259 (4), 180
(10), 135 (13), 127 (40), 105 (45), 97 (24), 84 (37), 55 (86), 43 (100).
4.2.14. 5-(5-Chloro-2-oxoindolin-3-yl)-1-methyl-6-phenyl-1H-pyr-
rolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(4n). White
powder
(0.349 g, 86%). Mp 370 ꢁC decomp. IR (KBr): 3173, 3035, 1716, 1697,
1663, 1557, 1472 cmꢂ1.1H NMR (400.13 MHz, DMSO-d6): dH 3.41 (3H,
s, CH3), 4.66 (1H, s, CH), 6.82 (1H, d, 3J 8.0 Hz), 6.87 (1H, s, CH), 7.18

9712
K. Rad-Moghadam, S.C. Azimi / Tetrahedron 68 (2012) 9706e9712
(1H, d, 3J 8.0 Hz), 7.43 (1H, t, 3J 7.4 Hz), 7.54 (2H, t, 3J 7.6 Hz), 7.61 (2H,
d, 3J 7.6 Hz), 10.51 (1H, s, NH), 10.57 (1H, s, NH), 11.89 (1H, s, NH). 13
University Press: Cambridge, 2001; pp 168e198; (c) Tietze, L. F.; Hautner, F. In
Stimulating Concepts in Chemistry; Vogtle, F., Stoddart, J., Shibasaki, F. M., Eds.;
€
C
Wiley-VCH: Weinheim, 2000; pp 38e64; (d) Tietze, L. F.; Beifuss, U. Angew.
Chem. 1993, 105, 137e170 Angew. Chem., Int. Ed. Engl. 1993, 32, 131e163; (e)
Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (f) Thompson, L. A. Curr. Opin. Chem.
Biol. 2000, 4, 324e337; (g) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev.
1997, 97, 449e472.
2. (a) Yanovskaya, L. A.; Dombrovsky, V. A.; Khusid, A. Kh Tsiklopropani s funkt-
sionalnimi gruppami. Sintez I primenenie; Nauka: Moscow, 1980; (b) Tsuji, T.;
Nishida, S. The Chemistry of the Cyclopropyl Group; Wiley and Sons: New York,
NY, 1987; (c) Boche, G.; Walbirsky, H. M. Cyclopropane Derived Intermediates;
John Wiley and Sons: New York, NY, 1990; (d) Rappoport, Z. The Chemistry of the
Cyclopropyl Group; Wiley and Sons: New York, NY, 1996.
3. (a) Posner, G. H. Chem. Rev. 1986, 86, 831e834; (b) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 131e163; (c) Bunce, R. A. Tetrahedron 1995, 48,
13103e13159.
4. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford Uni-
versity Press: New York, NY, 2000.
5. Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715e720.
6. Mancini, I.; Guella, G.; Pietra, F.; Debitus, C.; Waikedre, J. Helv. Chim. Acta 1996,
79, 2075e2082.
7. Bokesch, H. R.; Pannell, L. K.; McKee, T. C.; Boyd, M. R. Tetrahedron Lett. 2000, 41,
6305e6308.
8. Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000, 63, 447e451.
9. Ford, J.; Capon, R. J. J. Nat. Prod. 2000, 63, 1527e1528.
10. Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-Paloma, L.; Riccio, R.
Tetrahedron 2000, 56, 3743e3748.
NMR (100.6 MHz, DMSO-d6): dc 29.9 (CH3), 44.2, 98.5, 110.5, 110.7,
123.4,125.2,127.6,128.2,128.4,128.9,129.3,131.0,133.3,141.5,142.9,
150.9, 158.2, 177.7. MS (EI, 70 eV) m/z: 406 (Mþ, 35Cl, 3), 395 (6), 379
(10), 368 (80), 353 (16), 313 (32), 236 (42),149 (39),111 (40), 97 (67),
57 (100). Anal. Calcd for C21H15ClN4O3 (406.08): C, 62.00; H, 3.72; N,
13.77%. Found: C, 61.96; H, 3.78; N, 13.74%.
4.2.15. 5-(5-Chloro-2-oxoindolin-3-yl)-6-(4-fluorophenyl)-1-methyl-
1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione (4o). White powder
(0.390 g, 92%). Mp 380 ꢁC decomp. IR (KBr): 3179, 3038, 1716, 1685,
1662, 1619, 1553, 1472, 1218, 840 cmꢂ1 1H NMR (400.13 MHz,
.
DMSO-d6): dH 3.40 (3H, s, CH3), 4.62 (1H, s, CH), 6.82 (1H, d, 3J
8.4 Hz), 6.88 (1H, br s, CH), 7.17 (1H, dd, 3J 8.4 and 4J 1.0 Hz), 7.38
(2H, t, 3J 8.6 Hz), 7.64 (2H, dd, 3JHH 8.6 Hz, 4JHF 5.2 Hz), 10.52 (1H, s,
NH), 10.54 (1H, s, NH), 11.90 (1H, s, NH). 13C NMR (100.6 MHz,
2
DMSO-d6): dc 29.9 (CH3), 44.2, 98.4, 110.6, 110.7, 116.2 (d, JCF
21.0 Hz), 123.4, 125.2, 127.5 (d, 4JCF 1 Hz), 127.6, 131.1 (d, 3JCF 8.0 Hz),
133.3, 141.4, 142.9, 150.9, 158.2, 161.1, 161.8 (d, 1JCF 245 Hz) 177.7. MS
(EI, 70 eV) m/z: 426 (Mþ, 37Cl, 2), 424 (Mþ, 35Cl, 7), 394 (18), 368
(80), 351 (36), 313 (51), 264 (25), 236 (60), 111 (45), 83 (83), 57
(100). Anal. Calcd for C21H14ClFN4O3 (424.07): C, 59.37; H, 3.32; N,
13.19%. Found: C, 59.41; H, 3.35; N, 13.11%.
11. Olgen, S.; Akaho, E.; Nebioglu, D. J. Enzyme Inhib. Med. Chem. 2003, 18, 485e490.
12. Ahmad, A.; Sakr, W. A.; Rahman, K. M. Curr. Drug Targets 2010, 11, 652e666.
13. Liou, J. P.; Chang, Y. L.; Kuo, F. M.; Chang, C. W.; Tseng, H. Y.; Wang, C. C.; Yang,
Y. N.; Chang, J. Y.; Lee, S. J.; Hsieh, H. P. J. Med. Chem. 2004, 47, 4247e4257.
14. Aygun, A.; Pindur, U. Curr. Med. Chem. 2003, 10, 1113e1127.
15. (a) Wang, L.; Han, J.; Tian, H.; Sheng, J.; Fan, Z.; Tang, X. Synlett 2005, 337e339;
(b) Bifulco, G.; Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod. 1995, 58,
1254e1260.
4.2.16. 6-(4-Chlorophenyl)-1-methyl-5-(2-oxoindolin-3-yl)-1H-pyr-
rolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(4p). White
powder
16. (a) Zhang, Z. H.; Yin, L.; Wang, Y. M. Synthesis 2005, 1949e1954; (b) Bell, R.;
Carmeli, S.; Sar, N. J. Nat. Prod. 1994, 57, 1587e1590.
(0.332 g, 82%). Mp 380 ꢁC decomp. IR (KBr): 3165, 3054, 1710, 1691,
1684, 1618, 1559, 1463, 744 cmꢂ1. 1H NMR (400.13 MHz, DMSO-d6):
dH 3.40 (3H, s, CH3), 4.59 (1H, s, CH), 6.81e6.86 (3H, m), 7.13 (1H, t, 3J
7.4 Hz), 7.59 (2H, d, 3J 8.8 Hz), 7.63 (2H, d, 3J 8.8 Hz), 10.38 (1H, s,
NH), 10.55 (1H, s, NH), 11.88 (1H, s, NH). 13C NMR (100.6 MHz,
DMSO-d6): dc 29.9 (CH3), 44.1, 98.8, 109.4, 112.0, 121.2, 123.4, 127.8,
128.3, 129.3, 129.9, 130.4, 130.9, 132.9, 141.6, 143.9, 150.9, 158.1,
177.8. MS (EI, 70 eV) m/z: 408 (Mþ, 37Cl, 4), 407 (Mþ, 5), 406 (Mþ,
16), 374 (6), 360 (100), 313 (20), 239 (8), 180 (24), 89 (17), 69 (20),
55 (25). Anal. Calcd for C21H15ClN4O3 (406.08): C, 62.00; H, 3.72; N,
13.77%. Found: C, 62.08; H, 3.74; N, 13.69%.
17. Kılıc, Z.; Isgor, Y. G.; Olgen, S. Chem. Biol. Drug Des. 2009, 74, 397e404.
18. Showalter, H. D. H.; Sercel, A. D.; Leja, B. M.; Wolfangel, C. D.; Ambroso, L. A.;
Elliott, W. L.; Fry, D. W.; Kraker, A. J.; Howard, C. T.; Lu, G. H.; Moore, C. W.;
Nelson, J. M.; Roberts, B. J.; Vincent, P. W.; Denny, W. A.; Thompson, A. M. J. Med.
Chem. 1997, 40, 413e426.
19. Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J. Med. Chem.
1998, 41, 2588e2603.
20. Mohammadi, M.; McMahon, G.; Sun, L.; Tang, C.; Hirth, P.; Yeh, B. K.; Hubbard,
S. R.; Schlessinger, J. Science 1997, 276, 955e960.
21. Zeligs, M. A. J. Med. Food 1998, 1, 67e82.
22. Rehn, S.; Bergman, J. Tetrahedron 2005, 61, 3115e3123.
23. Muthusamy, S.; Gunanathan, C. Synlett 2002, 1783e1786.
24. Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2009, 50, 3959e3962.
25. Rad-Moghadam, K.; Sharifi-Kiasaraie, M. Tetrahedron 2009, 65, 8816e8820.
26. Rad-Moghadam, K.; Sharifi-Kiasaraie, M.; Taheri-Amlashi, H. Tetrahedron 2010,
66, 2316e2321.
Acknowledgements
27. Rad-Moghadam, K.; Sharifi-Kiasaraie, M.; Azimi, S. C. Tetrahedron 2012, 68,
6472e6476.
We gratefully acknowledge the financial support from the Re-
28. Rad-Moghadam, K.; Youseftabar-Miri, L. Synlett 2010, 1969e1973.
29. Rad-Moghadam, K.; Youseftabar-Miri, L. J. Fluorine Chem. 2012, 135, 213e219.
30. Dabiri, M.; Azimi, S. C.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64,
7307e7311.
search Council of University of Guilan.
References and notes
31. NCCLS. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria,
Which Grows Aerobically Approved Standard M7-A5, 5th ed.; NCCLS: Villanova,
PA, 2000.
1. (a) Ho, T. L. Tandem Organic Reactions; Wiley: New York, NY, 1992; (b) Nicolaou,
K. C.; Yue, E. W.; Oshima, T. In The New Chemistry; Hall, N., Ed.; Cambridge