A new and facile access to the 2-(indol-3-yl)-3-nitriloquinolines based on Friedl?nder annulations

Article abstract of DOI:10.1016/j.tet.2012.05.006

Preparation of 2-(indol-3-yl)-3-nitriloquinolines via Friedl?nder quinoline synthesis using 3-cyanoacetylindoles possessing an α-methylene group and ortho-amino arylketones have been described. This reaction took place in PEG-400 as a green solvent and it is catalyzed with polyphosphoric acid (PPA) to give novel types of quinolines containing both indoles and cyano functions in one step under thermal and microwave conditions.

Full text of DOI:10.1016/j.tet.2012.05.006

Tetrahedron 68 (2012) 6059e6064
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new and facile access to the 2-(indol-3-yl)-3-nitriloquinolines based on
€
Friedlander annulations
,
c
,
b
,
b
b
Morteza Shiri a , Mohammad Ali Zolfigol , Mahtab Pirveysian , Roya Ayazi-Nasrabadi ,
*
*
Hendrik G. Kruger c, Tricia Naicker c, Iraj Mohammadpoor-Baltork d
a Department of Chemistry, Faculty of Science, Alzahra University, Vanak, Tehran 1993893973, Iran
b Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
c School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa
d Department of Chemistry, Catalysis Division, University of Isfahan, Isfahan 81746-73441, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
€
Preparation of 2-(indol-3-yl)-3-nitriloquinolines via Friedlander quinoline synthesis using
3-cyanoacetylindoles possessing an -methylene group and ortho-amino arylketones have been de-
Received 18 February 2012
Received in revised form 11 April 2012
Accepted 1 May 2012
a
scribed. This reaction took place in PEG-400 as a green solvent and it is catalyzed with polyphosphoric
acid (PPA) to give novel types of quinolines containing both indoles and cyano functions in one step
under thermal and microwave conditions.
Available online 15 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Quinolines
Indoles
€
Friedlander quinoline synthesis
Ethylene glycol
1. Introduction
methods are known for the synthesis of molecules that have both
indole and quinoline functionalities.
Quinolines and indoles are two major classes of aza heterocyclic
compounds, which have attracted considerable attention from
chemists not only for their large broad biological activities but also
for their amazing physical properties.1e3
Usually functionalization of indoles and quinolines are performed
under carefully controlled conditions, and the diverse choice of
starting materials allows for the introduction of important functional
groups on synthones that are used in the construction of indoles and
Indolyl-quinolines show many different biological activities, for
example, as antibiotics with activity against a methicillin resistant
Staphylococcus aureus (MRSA) strain,4b dual inhibition of DNA
topoisomerases of Leishmania donovani,5 antimicrobial agents,6 and
also antifungal activity.7
2-(Indol-3-yl)quinolines are usually prepared by the addition of
indoles to quinolinium salts.8 An alternative procedure is via the
selective transition metal coupling of indoles to quinolines.6a
Cyclopentadiene and imines, which are derived from anilines and
3-formylindole were found to cyclize in the presence of In(OTf)3 to
yield the corresponding indolyl-quinolines.9 Very recently Brasse
et al. have established a new method in which indole and quinoline
react in the presence of a stoichiometric amount of HCl by means of
an auto oxidative coupling to form 2-indolyl-quinoline derivatives.10
€
quinolines. For example, in the Friedlander quinoline synthesis the
starting materials are o-aminoaryl aldehydes or ketones and a ke-
tone possessing an
a
-methylene group. Innovative utilization of
€
starting materials in Friedlander annulations led to a large variety of
aza heterocyclic compounds.1c Very recently Ryabukhin et al. have
established easy access to the synthesis of 3-fluoro-, 3-chloro-, and
€
€
3-bromoquinolines by choosing a Friedlander method with
oketones as one of the reagents.4a
a-hal-
As part of a continued project on Friedlander quinoline syn-
thesis,11 we wish to report a practical and convenient method for
Even though the importance of quinoline and indole core com-
the preparation of polysubstituted indolyl-quinolines. Our first goal
pounds is undisputed and of scientific importance, few synthetic
was to find a convenient route for the preparation of 3-
cyanoacetylindoles (CAIs) from indoles and cyanoacetic acid. The
method by Bergman et al. appeared suitable.12 It is noteworthy that
€
Friedlander annulation reactions with cyanoacetylindoles as
promising CH-active components will give quinolines containing
not only the indolyl function, but also a nitrile group, which can be
* Corresponding authors. Fax: þ98 21 88041344; e-mail addresses: mshiri@al-
zahra.ac.ir (M. Shiri), zolfi@basu.ac.ir (M.A. Zolfigol).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.006

6060
M. Shiri et al. / Tetrahedron 68 (2012) 6059e6064
easily converted to amines, tetrazoles, acids, ketones, guanidines,
amidines, and other structural units with useful pharmacophores.
3-Cyanoacetylindoles were recently used in the construction of
a large variety of aza heterocyclic compounds.13
evaluated. Under microwave conditions at 120 ꢀC it took 30 min for
the reaction to reach completion. All quinolines have been obtained
in higher yields when microwave irradiation was employed (Table 1).
3-Cyano-4-methyl-2-(N-methylindol-3-yl)-quinoline 3o and 2-
(5-bromoindol-3-yl)-3-cyano-4-methyl-quinoline 3p were isolated
in 83% and 62% (89% and 70% microwave conditions) from 2-ami-
noacetophenone 1c and their corresponding indoles 2b and 2d
(entries 14 and 15, Table 1). All of the materials are new and their
spectra and physical data were given.
To established if this reaction under MW conditions has wider
application, 2,5-dibenzoyl-1,4-phenylenediamine 1d14 was reacted
with 2a (Scheme 2). To our delight the novel anthrazoline15 4 was
isolated in 80% yield after 6 min (6ꢁ1) at 150 ꢀC.
Optimization of the conditions and finding the best catalyst and
solvent for the reactions was attempted. The best results for the
reaction of 2-aminobenzophenone 1a and 3-cyanoacetylindole 2a
was obtained in the presence of polyphosphoric acid (PPA) as cat-
alyst and polyethylene glycol 400 (PEG-400), as green solvent at
120 ꢀC to give 3a in 70% isolated yield (Scheme 1). Although the
yield is not excellent, one should recognize that a fairly complex
product is isolated in one step. Classical synthetic methods involves
a multi-step procedure, which will most likely result in much lower
overall yield.
Scheme 1.
Next the generality of the method was examined by testing al-
ternative reagents, such as o-aminoarylketones and cyanoketones.
Amine 1a reacts with CAIs bearing electron deficient groups, such as
2b, 2c, 2f and 2g under the optimized conditions and to give 3b, 3c,
3f, and 3g, respectively, in good yields (entries 1, 2, 5, and 6, Table 1).
5-Bromo and 5-chloro derivatives 3d and 3e were obtained in only
55% and 75% yields (entries 3 and 4, Table 1). However the reaction
with 3-cyano-7-nitroacetylindole did not yield product. The chloro
containing amine 1b was reacted with both electron deficient and
electron withdrawing indole derivatives 2aeg to successfully form
the corresponding quinolines 3hen (entries 7e13, Table 1).
Scheme 2.
The structure of compound (4) was established on the basis of
spectroscopic data. In the IR spectrum, stretching frequencies at
2225 and 3319 cmꢂ1 confirmed the presence of C^N and NeH
functional groups, respectively. The 1H NMR spectrum showed
To overcome the relatively long reaction times required with
conventional heating, microwave (MW) irradiation was also
Table 1
€
Friedlander method for the preparation of 2-(indol-3-yl)-3-nitriloquinolines
Run
Aminoketone 1
Cyanoketone 2
Product 3
Isolated yield (%)
Isolated yield (%)
for thermal conditionsa
for MW conditionsb
1
1a
78
67
89
80
2b
2c
3b
3c
2
3
1a
1a
55c
70
2d
3d

M. Shiri et al. / Tetrahedron 68 (2012) 6059e6064
Product 3
6061
Table 1 (continued )
Run Aminoketone 1
Cyanoketone 2
Isolated yield (%)
Isolated yield (%)
for MW conditionsb
for thermal conditionsa
4
1a
75c
86
2e
2f
3e
3f
5
1a
70
80
6
1a
74
84
3g
2g
7
8
2a
2b
75
80
86
90
1b
3h
3i
1b
9
1b
2c
56
70
3j
3k
3l
10
11
12
1b
1b
1b
2d
2e
2f
60c
50c
75
71
62
80
3m
(continued on next page)

6062
M. Shiri et al. / Tetrahedron 68 (2012) 6059e6064
Product 3
Table 1 (continued )
Run
Aminoketone 1
Cyanoketone 2
Isolated yield (%)
Isolated yield (%)
for thermal conditionsa
for MW conditionsb
13
1b
2g
2b
57
66
89
3n
14
83c
1c
3o
3p
15
1c
2d
62c
70
a
Reaction conditions: amine (1 mmol), cyanoketone (1.5 mmol), PPA (0.2 g), PEG-400 (5 mL), 120 ꢀC, 24 h unless otherwise stated.
Amine (1 mmol), cyanoketone (1.5 mmol), PPA (0.2 g), PEG-400 (5 mL), 120 ꢀC, 350 W, 30 min.
48 h.
b
c
a broad distinct singlet in the region of
NH proton (D2O exchangeable). The aromatic proton resonated in
the region of
7.23e8.48. In the 13C NMR spectrum, the apparent 12
signals indicated a symmetrical structure for the molecule. The
aromatic carbons were demonstrated in region of 106.4e157.1. In
d
11.92 corresponding to the
temperature was elevated to 120 ꢀC (conventional or 350 W, MW)
and the reaction was monitored by TLC. After 24e48 h for con-
ventional or 30 min for MW, the reaction was cooled to room
temperature and 10 mL H2O added. The organic products were
extracted with ethyl acetate (2ꢁ10 mL) and the ethyl acetate was
then evaporated and the residue was purified by column chroma-
tography using petroleum benzene/ethyl acetate as eluent.
The copies of 1H NMR and 13C NMR spectra for the all materials
are presented as Supplementary data.
d
d
the HR-mass spectrum, a sharp distinguishable peak at m/z
613.2112 corresponds to the [MþH]þ peak.
In summary, we have developed a new protocol for the syn-
thesis of 3-cyano-2-(indol-3-yl)quinolines via condensation and
cyclization of 3-cyanoacetylindoles and ortho-aminoaryl ketones in
the presence of PPA under thermal and MW conditions. The
products are prepared in a multi-step one pot procedure are
obtained in good to high yields with relative short reaction times.
The effective synthesis of quinolines with indole and also cyano
functionalities are reported. The cyano substituent can be con-
verted to other functional groups, such as amines, amides, acids,
ketones, and tetrazoles etc.
2.3. Spectral and physical data
Compound 3a: yellow powder. Mp: 259e261 ꢀC. FT-IR (KBr):
3334, 2216, 1608, 1544, 1430, 1129, 741 cmꢂ1 1H NMR (500 MHz,
.
CDCl3),
d
(ppm): 7.23e7.24 (2H, m), 7.40 (1H, t, J¼7.56 Hz),
7.46e7.47e7.48 (3H, m), 7.53e7.56 (4H, m), 7.76 (1H, t, J¼7.53 Hz),
8.18 (1H, d, J¼8.39 Hz), 8.35 (1H, d, J¼2.57 Hz), 8.67 (1H, m), 10.44
(1H, s, br). 13C NMR (125 MHz, CDCl3),
d (ppm): 112.1, 118.9, 121.6,
2. Experimental section
2.1. General
122.7, 123.2, 123.9, 127.0, 127.1, 128.6, 129.1, 129.7,129.8, 131.3, 132.6,
135.4, 137.1, 154.0, 156.8. HRMS (EI) calculated for C24H15N3 [MþH]
346.1339, found 346.1330.
Compound 3b: yellow powder. Mp: 207e209 ꢀC. FT-IR (KBr):
2928, 2220, 1561, 1544, 1477, 1376, 751 cmꢂ1 1H NMR (500 MHz,
.
CDCl3), d (ppm): 3.95 (3H, s), 7.38e7.39 (2H, m), 7.40e7.43 (2H, m),
Chemicals were purchased from Fluka, Merck and Aldrich chem-
ical companies. IR spectra were recorded on a Shimadzu Infra Red
Spectroscopy IR-435. Nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker Avance 500 and 400 MHz Spectrometer in
CDCl3 and DMSO-d6 as solvent. High resolution mass spectrometric
data was obtained using a Bruker micro TOF-Q II instrument oper-
ating at ambient temperatures. The microwave system used in these
experiments includes the following items: Micro-SYNTH labstation,
complete with glass door, dual magnetron system with pyramid-
shaped diffuser, 1000 W delivered power, exhaust system, magnetic
stirrer, ‘quality pressure’ sensor for flammable organic solvents,
ATCFO fiber optic system for automatic temperature control.
7.54e7.56 (2H, m), 7.63e7.64 (4H, m), 7.84 (1H, t, J¼8.07 Hz), 8.27
(1H, d, J¼8.42 Hz), 8.32 (1H, s), 8.81e8.82 (1H, m). 13C NMR
(100 MHz, CDCl3),
d (ppm): 33.5, 104.0, 109.5, 113.1, 118.6, 121.5,
122.9, 123.0, 123.6, 126.6, 126.8, 127.4, 128.8, 129.4, 129.54, 129.55,
131.9, 132.2, 135.0, 137.4, 149.0, 153.3, 156.4. HRMS (EI) calculated
for C25H17N3 [MþNa] 382.1320, found 382.1293.
Compound 3c: yellow powder. Mp: 230e232 ꢀC. FT-IR (KBr):
cmꢂ1. 3395, 2921, 2218, 1545, 1465, 741. 1H NMR (500 MHz, CDCl3),
d
(ppm): 2.61 (3H, s), 7.20e7.22 (2H, m), 7.34e7.36 (1H, m),
7.58e7.60 (3H, m), 7.65e7.66 (3H, m), 7.76e7.78 (2H, m), 7.88e7.90
(1H, m), 8.28 (1H, d, J¼8.41 Hz), 8.42 (1H, s, br). 13C NMR (125 MHz,
€
2.2. General procedure for the Friedlander method
CDCl3), d (ppm): 14.0, 108.2, 110.9, 117.7, 119.7, 121.1, 122.6, 124.6,
127.3, 127.7, 128.3, 130.0, 130.10, 130.17, 132.7, 135.1, 135.7, 136.3,
155.5. HRMS (EI) calculated for C25H17N3 [MþH] 360.1495, found
360.1541.
To a stirring solution of cyanoacetylindole (1.5 mmol) and amine
(1 mmol) in ethylene glycol (5 mL), were added PPA (0.2 g). The

M. Shiri et al. / Tetrahedron 68 (2012) 6059e6064
6063
Compound 3d: yellow powder. Mp: 195e197 ꢀC. FT-IR (KBr):
(1H, d, J¼8.97 Hz), 8.37 (1H, d, J¼2.86 Hz), 8.79 (1H, s, br). 13C NMR
cmꢂ1. 3355, 2216, 1543, 1423, 1139, 883. 1H NMR (500 MHz, CDCl3),
(125 MHz, CDCl3), d (ppm): 106.1, 113.7, 125.4, 125.7, 126.1, 129.3,
d
(ppm): 7.36e7.38 (1H, m), 7.43e7.45 (1H, m), 7.53e7.56 (3H, m),
129.6, 129.9, 130.2, 131.3, 133.3, 153.4. HRMS (EI) calculated for
C24H13BrClN3 [MþH] 458.0054, found 458.0043.
7.63e7.65 (4H, m), 7.88e7.90 (1H, m), 8.32 (1H, d, J¼7.29 Hz), 8.42
(1H, s), 8.70 (1H, s, br), 8.94 (1H, s). 13C NMR (125 MHz, CDCl3),
Compound 3l: yellow powder. Mp: 224e226 ꢀC. FT-IR (KBr):
3334, 2219, 1561, 1450, 1077, 706 cmꢂ1. 1H NMR (400 MHz, CDCl3),
d
(ppm): 112.6, 114.2, 116.5, 120.2, 125.3, 126.4, 126.8, 127.1, 128.3,
128.8, 129.4, 129.6, 129.7, 132.7, 149.1, 156.4. HRMS (EI) calculated
for C24H14BrN3 [MþH] 424.0444, found 424.0399.
d (ppm): 7.32e7.34 (1H, m), 7.44e7.52 (1H, m), 7.52e7.59 (3H, m),
7.65e7.67 (3H, m), 7.80e7.83 (1H, m), 8.25 (1H, d, J¼8.8 Hz), 8.49
Compound 3e: yellow powder. Mp: 247e249 ꢀC. FT-IR (KBr):
(1H, d, J¼2.8 Hz), 8.65 (1H, s, br), 8.78 (1H, d, J¼1.6 Hz). 13C NMR
3361, 2220, 1563, 1545, 1427, 1143, 700 cmꢂ1
.
1H NMR (400 MHz,
(100 MHz, CDCl3), d (ppm): 112.3, 122.3, 123.9, 124.5, 125.5, 127.6,
CDCl3),
d
(ppm): 7.32e7.34 (1H, m), 7.41e7.43 (1H, m), 7.50e7.56
128.7, 129.0, 129.3, 129.9, 131.2, 133.0, 133.3, 134.2, 134.6. HRMS (EI)
calculated for C24H13Cl2N3 [MþH] 414.0559, found 394.0540.
Compound 3m: yellow powder. Mp: 217e219 ꢀC. FT-IR (KBr):
3357, 3063, 2217, 1537, 1470, 704 cmꢂ1. 1H NMR (400 MHz, CDCl3),
(3H, m), 7.67e7.68 (4H, m), 7.87e7.89 (1H, m), 8.31 (1H, d,
J¼8.4 Hz), 8.46 (1H, d, J¼2.8 Hz), 8.64 (1H, s, br), 8.79 (1H, d,
J¼1.6 Hz). 13C NMR (100 MHz, CDCl3),
d (ppm): 112.27, 114.4, 118.4,
122.3, 123.8, 126.8, 127.1, 127.5, 127.7, 128.5, 128.8, 129.4, 129.6,
132.5, 134.6, 134.8, 148.8, 152.8, 156.6. HRMS (EI) calculated for
C24H14ClN3 [MþH] 380.0949, found 380.0992.
d
(ppm): 2.58 (3H, s), 7.20 (1H, d, J¼8.4 Hz), 7.37e7.40 (1H, m),
7.51e7.54 (2H, m), 7.56e7.59 (1H, m), 7.65e7.69 (3H, m), 7.79e7.82
(1H, m), 8.23 (1H, d, J¼8.8 Hz), 8.38 (1H, d, J¼2.8 Hz), 8.51 (1H, s),
Compound 3f: yellow powder. Mp: 217e219 ꢀC. FT-IR (KBr):
3327, 2228, 1546, 1427, 1139, 762 cmꢂ1. 1H NMR (400 MHz, CDCl3),
8.54 (1H, s, br). 13C NMR (100 MHz, CDCl3),
d (ppm): 21.8, 105.1,
111.0, 113.9, 118.2, 122.0, 124.4,125.1, 125.4, 126.7, 127.8, 129.0, 129.3,
129.8, 131.1, 131.2, 132.6, 133.0, 134.3, 134.6, 147.3, 153.8, 155.6.
HRMS (EI) calculated for C25H16ClN3 [MþH] 394.1106, found
394.1112.
d
(ppm): 2.58 (3H, s), 7.17e7.20 (2H, m), 7.35e7.38 (1H, m),
7.48e7.58 (3H, m), 7.66e7.68 (4H, m), 8.30 (1H, d, J¼8.40 Hz), 8.34
(1H, d, J¼2.8 Hz), 8.52 (1H, s), 8.55 (1H, s, br). 13C NMR (100 MHz,
CDCl3),
d
(ppm): 21.8, 104.4, 110.9, 114.1, 118.5, 121.9, 123.7, 124.9,
Compound 3n: yellow powder. Mp: 300 ꢀC (dec). FT-IR (KBr):
126.7, 126.8, 127.5, 128.8, 129.4, 129.5, 129.6, 131.1, 132.2, 134.6,
135.0, 148.9, 153.6, 156.4. HRMS (EI) calculated for C25H17N3 [MþH]
360.1495, found 360.1531.
3379, 2936, 2219, 1578, 1540, 1280, 705 cmꢂ1. 1H NMR (400 MHz,
CDCl3),
d (ppm): 3.99 (3H, s), 7.01e7.04 (1H, m), 7.40 (1H, d,
J¼8.8 Hz), 7.52 (1H, m), 7.58 (2H, m), 7.64e7.67 (3H, m), 7.76e7.80
Compound 3g: yellow powder. Mp: 251e253 ꢀC. FT-IR (KBr):
(1H, m), 8.18 (1H, d, J¼9.2 Hz), 8.33 (1H, d, J¼2.4 Hz), 8.45 (1H, d,
3375, 2948, 2215, 1544, 1479, 1146, 765 cmꢂ1. 1H NMR (400 MHz,
J¼3.2 Hz), 8.53 (1H, s, br). 13C NMR (100 MHz, CDCl3),
d (ppm): 55.8,
CDCl3),
d
(ppm): 4.00 (3H, s), 7.02 (1H, m), 7.39 (1H, d, J¼8.8 Hz),
104.5, 112.0, 113.6, 118.2, 124.3, 125.5, 128.3, 129.0, 129.3, 129.8,
131.0, 132.6, 133.1, 134.3, 147.3, 155.7. HRMS (EI) calculated for
C25H16ClN3O [MþH] 410.1055, found 410.1054.
7.47e7.49 (1H, m), 7.52e7.55 (2H, m), 7.63e7.64 (4H, m), 7.86e7.88
(1H, m), 8.25 (1H, d, J¼8.4 Hz), 8.35 (1H, d, J¼2.0 Hz), 8.43 (1H, d,
J¼2.8 Hz), 8.53 (1H, s, br). 13C NMR (100 MHz, CDCl3),
d
(ppm): 55.8,
Compound 3o: yellow powder. Mp: 200e202 ꢀC. FT-IR (KBr):
2940, 2217, 1552, 1476, 1244, 752 cmꢂ1. 1H NMR (400 MHz, CDCl3),
104.3, 111.9, 113.6, 114.3, 118.6, 123.7, 126.7, 126.9, 127.2, 128.0, 128.8,
129.4, 129.5, 131.3, 132.3, 134.9, 148.8, 153.5, 155.6, 156.5. HRMS (EI)
calculated for C25H17N3O [MþH] 376.1444, found 376.1484.
Compound 3h: yellow powder. Mp: 266e268 ꢀC. FT-IR (KBr):
d
(ppm): 3.01 (3H, s), 3.93 (3H, s), 7.29e7.35 (3H, m), 7.56e7.59 (1H,
m), 7.82e7.85 (1H, m), 8.03 (1H, d, J¼8.4 Hz), 8.19 (1H, d, J¼8.0 Hz),
8.26 (1H, s), 8.62e8.88 (1H, m). 13C NMR (100 MHz, CDCl3),
(ppm):
d
3427, 2252, 1658, 1538, 1052 cmꢂ1
.
1H NMR (500 MHz, CDCl3),
17.7, 33.4, 104.7, 109.4, 113.1, 118.8, 121.4, 122.8, 122.9, 124.0, 124.2,
126.5, 127.3, 130.0, 131.6, 132.1, 137.3, 148.2, 152.6, 153.2. HRMS (EI)
calculated for C20H15N3 [MþH] 298.1339, found 298.1424.
d
(ppm): 7.37e7.41 (2H, m), 7.50e7.52 (3H, m), 7.53e7.55 (3H, m),
7.59 (1H, d, J¼2.21 Hz), 7.65e7.68 (3H, m), 7.78 (1H, dd, J¼2.28,
8.98 Hz), 8.22 (1H, d, J¼8.98 Hz), 8.45 (1H, d, J¼2.83 Hz), 8.64 (1H, s,
Compound 3p: yellow powder. Mp: 199e201 ꢀC. FT-IR (KBr):
3450, 2976, 2937, 2222, 1563, 1432, 1375, 1239, 605 cmꢂ1. 1H NMR
br), 8.76 (1H, m). 13C NMR (125 MHz, CDCl3),
d (ppm): 105.1, 112.2,
113.6, 118.5, 121.6, 122.7, 123.2, 124.5, 125.6, 126.8, 129.0, 129.2,
129.6, 130.1, 132.6, 133.3, 134.7, 137.1, 147.5, 154.2. HRMS (EI) cal-
culated for C24H14ClN3 [MþH] 380.0949, found 380.0978.
(400 MHz, CDCl3), d (ppm): 3.05 (3H, s), 7.02e7.29 (1H, m), 7.37e7.45
(2H, m), 7.63e7.67 (1H, m), 8.09 (1H, d, J¼8.4 Hz), 8.25 (1H, d,
J¼8.4 Hz), 8.41 (1H, d, J¼2.8 Hz), 8.62 (1H, s, br), 8.88 (1H, d,
Compound 3i: yellow powder. Mp: 260e262 ꢀC. FT-IR (KBr):
J¼1.6 Hz). 13C NMR (100 MHz, CDCl3),
d (ppm): 33.6, 104.7, 109.6,
2908, 2212, 1580, 1554, 1467, 1241, 747 cmꢂ1
.
1H NMR (400 MHz,
112.7,118.3,121.6,122.9,123.1,124.2,125.4,127.2,129.0,129.3,129.8,
131.0, 132.1, 132.4, 133.0, 134.4, 137.4, 147.4, 153.5, 155.6. HRMS (EI)
calculated for C19H12BrN3 [MþH] 362.0287, found 362.0285.
Compound 4: red powder. Mp: 237e239 ꢀC. FT-IR (KBr): 3319,
2225, 1527, 1436, 1231, 1145, 742 cmꢂ1. 1H NMR (400 MHz, DMSO-
CDCl3), d (ppm): 3.94 (3H, s), 7.37e7.39 (2H, m), 7.43e7.45 (1H, m),
7.53e7.55 (3H, m), 7.65e7.67 (3H, m), 7.75 (1H, dd, J¼0.24, 9.2 Hz),
8.33 (1H, s), 8.19 (1H, d, J¼9.2 Hz), 8.78e8.81 (1H, m). 13C NMR
(100 MHz, CDCl3),
d (ppm): 33.6, 104.7, 109.6, 112.7, 118.3, 121.6,
122.9, 123.1, 124.2, 125.4, 127.2, 129.0, 129.3, 129.8, 131.0, 132.1,
132.4, 133.0, 134.4, 137.4, 147.4, 153.5, 155.6. HRMS (EI) calculated
for C25H16ClN3 [MþH] 394.1106, found 394.1232.
d6),
(10H, m), 8.22 (2H, s), 8.43 (2H, d, J¼8.0 Hz), 8.48 (2H, s), 11.92 (2H,
s, br). 13C NMR (100 MHz, DMSO-d6),
(ppm): 106.4, 118.5, 121.5,
123.2, 126.8, 127.0, 129.5, 130.1, 130.5, 134.9, 153.4, 157.1. HRMS (EI)
calculated for C42H24N6 [MþH] 613.2141, found 613.2112.
d
(ppm): 7.21e7.26 (4H, m), 7.55 (2H, d, J¼8.0 Hz), 7.74e7.80
d
Compound 3j: yellow powder. Mp: 197e199 ꢀC. FT-IR (KBr):
3394, 2925, 2212, 1613, 1572, 1424, 1233, 749 cmꢂ1
.
1H NMR
(500 MHz, CDCl3),
d (ppm): 3.05 (3H, s), 7.28e7.30 (3H, m),
7.34e7.35 (2H, m), 7.48e7.50 (1H, m), 7.61e7.63 (1H, m), 7.85e7.88
(1H, m), 8.08 (1H, d, J¼8.40 Hz), 8.24 (1H, d, J¼8.38 Hz), 8.38 (1H, d,
J¼2.08 Hz), 8.61 (1H, s, br), 8.70 (1H, m). 13C NMR (125 MHz, CDCl3),
Acknowledgements
We thank Alzahra University and Bu-Ali Sina University and also
Elites National Foundation (Iran) for financial support to our re-
search group.
d
(ppm): 18.1, 111.6, 122.0, 122.9, 123.7, 124.6, 127.1, 127.6, 130.5,
132.5, 148.02, 152.3, 155.6. HRMS (EI) calculated for C25H16ClN3
[MþH] 394.1106, found 394.1217.
Compound 3k: yellow powder. Mp: 240e242 ꢀC. FT-IR (KBr):
3328, 2221, 1542, 1444, 1143, 706 cmꢂ1. 1H NMR (500 MHz, CDCl3),
Supplementary data
d
(ppm): 7.29e7.30 (3H, m), 7.41e7.42 (2H, m), 7.43e7.44 (1H, d,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.05.006.
J¼2.21 Hz), 7.55e7.56 (3H, m), 7.68 (1H, dd, J¼2.21, 8.97 Hz), 8.12

6064
M. Shiri et al. / Tetrahedron 68 (2012) 6059e6064
7. Dekker, W. H.; Selling, H. A.; Overeem, J. E. J. Agric. Food Chem. 1975, 23, 785.
References and notes
8. (a) Hamana, M.; Kumadaki, I. Chem. Pharm. Bull. 1971, 19, 1669; (b) Yadav, J. S.;
Reddy, B. V. S.; Sathaiah, K.; Vishnumurthy, P. Synlett 2005, 2811; (c) Heralagi,
R. V.; Kalyane, N. V.; Srikanth, G.; Zambare, Y. B. J. Pharm. Res. 2009, 2, 1144.
9. Nagarajan, R.; Perumal, P. T. Tetrahedron 2002, 58, 1229.
10. Brasse, M.; Ellman, J. A.; Bergman, R. G. Chem. Commun. 2011, 5019.
11. (a) Zolfigol, M. A.; Salehi, P.; Ghaderi, A.; Shiri, M.; Tanbakouchian, Z. J. Mol.
Catal. A: Gen. 2006, 259, 253; (b) Zolfigol, M. A.; Salehi, P.; Ghaderi, A.; Shiri, M. J.
Chin. Chem. Soc. 2007, 54, 267; (c) Zolfigol, M. A.; Salehi, P.; Shiri, M.; Ghaderi, A.
Catal. Commun. 2007, 8, 1214; (d) Zolfigol, M. A.; Salehi, P.; Shiri, M.; Rastegar, T.;
Ghaderi, A. J. Iran. Chem. Soc. 2008, 5, 490.
€
1. (a) Marco-Contelles, J.; Carreiras, M. D. The Friedlander Reaction; Lambert Aca-
demic: Saarbrucken, Germany, 2010; (b) Marco-Contelles, J.; Perez-Mayoral, E.;
Samadi, A.; Carreiras, M. D.; Soriano, E. Chem. Rev. 2009, 109, 2652; (c) Shiri, M.;
Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Friedlander Annulation in the
Synthesis of Azaheterocyclic Compounds In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic: Oxford, 2011; Vol. 185, p 139.
2. (a) McCormick, J. L.; McKee, T. C.; Cardellina, J. H., II; Boyd, M. R. J. Nat. Prod.
1996, 59, 469; (b) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in Natural
Product Synthesis; Wiley-VCH GmbH &. KGaA: Weinheim, 2011; (c) Chan-Bacab,
€
€
12. Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760.
~
M. J.; Pena-Rodríguez, L. M. Nat. Prod. Rep. 2001, 18, 674.
13. (a) Zhao, K.; Xu, X. P.; Zhu, S. L.; Shi, D. Q.; Zhang, Y.; Ji, S. J. Synthesis 2009, 2697;
(b) Thirumurugan, P.; Nandakumar, A.; Lakshmi, N. V.; Kumar, P. V. N. P.; Pe-
rumal, P. T. Magn. Reson. Chem. 2010, 48, 554; (c) Geng, L.-J.; Yu, J.-G.; Feng, G.-L.
J. Chem. Res., Synop. 2010, 333; (d) Geng, L.-J.; Feng, G.-L.; Yu, J.-G. J. Chem. Res.
Synop. 2010, 565; (e) Chen, T.; Xu, X.-P.; Liu, H.-F.; Ji, S.-J. Tetrahedron 2011, 67,
5469; (f) Thirumurugan, P.; Nandakumar, A.; Muralidharan, D.; Perumal, P. T. J.
Comb. Chem. 2010, 12, 161; (g) Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett.
2009, 50, 4145; (h) Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620;
(i) Thirumurugan, P.; Mahalaxmi, S.; Perumal, P. T. J. Chem. Sci. 2010, 122, 819; (j)
Sun, C.; Ji, S. J.; Liu, Y. Tetrahedron Lett. 2007, 48, 8987; (k) Zhu, S. L.; Ji, S. J.; Su,
X. M.; Sun, C.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777; (l) Zhu, S. L.; Ji, S. J.; Zhao,
K.; Liu, Y. Tetrahedron Lett. 2008, 49, 2578; (m) Quiroga, J.; Trilleras, J.; Sanchez,
A. I.; Insuasty, B.; Abonia, R.; Nogueras, M.; Cobo, J. Lett. Org. Chem. 2009, 6, 381;
(n) Chen, T.; Xu, X. P.; Ji, S. J. J. Comb. Chem. 2010, 12, 659; (o) Lakshmi, N. V.;
Thirumurugan, P.; Noorulla, K. M.; Perumal, P. T. Bioorg. Med. Chem. Lett. 2010,
20, 5054; (p) Nandakumar, A.; Thirumurugan, P.; Perumal, P. T.; Vembu, P.;
Ponnuswamy, M. N.; Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252.
14. Liu, S.; Jiang, P.; Song, G.; Liu, R.; Zhu, H. Dyes Pigm. 2009, 81, 218.
15. For more information about anthrazolines see Ref. 1c.
3. (a) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010,
110, 2250; (b) Joule, J. A. In Science of Synthesis; Thomas, E. J., Ed.; Georg
Thieme: Stuttgart, New York, NY, 2000; Vol. 10, p 361; (c) Sundberg, R. J. In-
doles; Academic: London, 1996; (d) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875; (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (f) Top.
Heterocycl. Chem.; Gribble, G. W., Ed.; Heterocyclic Scaffolds II: Reactions and
Applications of Indoles; Springer: Berlin, Heidelberg, 2010; Vol. 26; (g) Shiri, M.
Chem. Rev. doi.org/10.1021/cr2003954.
4. (a) Ryabukhin, S. V.; Naumchik, V. S.; Plaskon, A. S.; Grygorenko, O. O.; Tol-
machev, A. A. J. Org. Chem. 2011, 76, 5774; (b) Kumaravel, G.; Hoemann, M. Z.;
Melikian-Badalian, A.; Cuny, D. G.; Hauske, J. R.; Heefner, D. L.; Roosi, R. F. 1998,
WO9857952.
5. Ray, S.; Sadhukhan, P. K.; Mandal, N. B.; Mahato, S. B.; Majumder, H. K. Biochem.
Biophys. Res. Commun. 1997, 230, 171.
6. (a) Cuny, D. G.; Hauske, J. R.; Hoemann, M. Z.; Chopra, I. 2002, US6376670B1. (b)
Cuny, D. G.; Hauske, J. R.; Heefner, D. L.; Hoemann, M. Z.; Kumaravel, G.;
Melikian-Badalian, A.; Roosi, R. F. 2001 US6207679B1. (c) Cuny, D. G.; Hauske, J.
R.; Heefner, D. L.; Hoemann, M. Z.; Kumaravel, G.; Melikian-Badalian, A.; Roosi,
R. F.; Xie, R. L. 2000, US6103905A1.