Synthesis of pyrido[1,2-a]benzimidazoles by photo-stimulated C-N bond formation via SRN1 reactions

Article abstract of DOI:10.1016/j.tet.2013.04.087

The photo-stimulated cyclization of 2-(2-halophenylamino)pyridines in liquid ammonia afforded pyrido[1,2-a]benzimidazoles via S_RN1 mediated C-N bond forming reactions in moderate to excellent yields (58-94%). This general synthetic strategy was also extended to a 2-(2-bromophenylamino)pyrazine to give pyrazino[1,2-a]benzimidazole. Attempts to employ this reaction using N-(2-chlorophenyl)-3-isoquinolinamine, however, resulted in C-C bond formation generating 7H-indolo[2,3-c]isoquinoline.

Full text of DOI:10.1016/j.tet.2013.04.087

Tetrahedron 69 (2013) 5487e5494
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pyrido[1,2-a]benzimidazoles by photo-stimulated CeN
bond formation via SRN1 reactions
,
b,c,
*
Silvia M. Barolo a, You Wang b, Roberto A. Rossi a , Gregory D. Cuny
*
a
ꢀ
ꢀ
INFIQC, Departamento de Química Organica, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba, Ciudad Universitaria,
ꢀ
5000 Cordoba, Argentina
b Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women’s Hospital and Harvard Medical School, 65 Landsdowne St., Cambridge,
MA 02139, USA
c Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 549A Science and Research Bldg 2, Houston,
TX 77204, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The photo-stimulated cyclization of 2-(2-halophenylamino)pyridines in liquid ammonia afforded pyrido
[1,2-a]benzimidazoles via SRN1 mediated CeN bond forming reactions in moderate to excellent yields
(58e94%). This general synthetic strategy was also extended to a 2-(2-bromophenylamino)pyrazine to
give pyrazino[1,2-a]benzimidazole. Attempts to employ this reaction using N-(2-chlorophenyl)-3-
isoquinolinamine, however, resulted in CeC bond formation generating 7H-indolo[2,3-c]isoquinoline.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 February 2013
Received in revised form 17 April 2013
Accepted 19 April 2013
Available online 25 April 2013
Keywords:
Photo-stimulate
SRN
1
Heterocycles
Pyrido[1,2-a]benzimidazoles
Pyrazino[1,2-a]benzimidazoles
7H-Indolo[2,3-c]isoquinolines
1. Introduction
compounds demonstrate interesting and potentially useful bi-
ological activities. For example, 1e3 (Fig. 1) have been reported to
Benzimidazole is a heterocycle present in an array of thera-
peutic agents and biologically active compounds.1 This heterocy-
cle can also be found embedded in numerous tricyclic rings
systems, such as pyrido[1,2-a]benzimidazoles. Many of these
possess antifungal activity via inhibition of b-1,6-glucan synthesis,
anticancer properties, and antimalarial activity through inhibition
of Plasmodium species, respectively.2e4 In addition to biological
properties, pyrido[1,2-a]benzimidazoles demonstrate character-
Fig. 1. Examples of biologically active pyrido[1,2-a]benzimidazoles 1e3.
istics making them useful to other fields, including material
science.
* Corresponding authors. E-mail addresses: rossi@fcq.unc.edu.ar (R.A. Rossi),
gdcuny@central.uh.edu (G.D. Cuny).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.087

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S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
Several strategies have been utilized for the synthesis of pyrido
pyrido[1,2-a]benzimidazoles via CeN bond construction and not a-
[1,2-a]benzimidazoles. A number of classical methods for synthe-
sizing this heterocycle have been recently demonstrated include
anionic5 and reductive cyclizations,6 condensations,7 and hyper-
valent iodine mediated dehydrogenative coupling.8 Photo-
mediated processes have been described.9e12 A number of metal-
mediated methods, including Pd,13 Cu,14 and Cu and/or Cu/Fe
CeH bond activation,15,16 have also been reported.
carbolines by CeC formation. In order to test this hypothesis, 2-(2-
bromophenylamino)pyridine (4a) was subjected to photo-
stimulation in liquid ammonia for 120 min in the presence of
2 equiv of potassium tert-butoxide. The reaction gave complete
substrate consumption and a 93% isolated yield of pyrido[1,2-a]
benzimidazole (5, Table 1, entry 1). The yield of bromide ions
generated was determined potentiometrically to be 96%. A similar
reaction conducted in DMSO for 60 min only generated 5 in 33%
yield, as determined by gas chromatography, despite a bromide ion
yield of 93% (entry 2). Photo-stimulation of the chloride derivative
4b14 in liquid ammonia for 60 min also generated 5 in excellent
yield (entry 3). Again utilizing DMSO as solvent with either 60 or
120 min photo-stimulation resulted in lower yields of 5 (entries 4
and 5). Next, a time course for the photo-stimulation of 4b in liquid
ammonia was conducted (entries 6e8). Excellent yields of 5 were
obtained after 30 and 15 min. However, a lower yield was observed
after only 5 min of irradiation. These results demonstrate that
photo-stimulated cyclization of 2-(2-halophenylamino)pyridines
occurs very rapidly compared to several metal-mediated processes,
The photo-stimulated unimolecular radical nucleophilic sub-
stitution (SRN1) reaction has emerged as another synthetically
17,18
useful methodology for bond constructions.
S 1 reactions have
RN
been utilized to mediate an array of CeC and CeN bond couplings
in the synthesis of various heterocyclic systems.19e29 Herein, we
report the use of the photo-stimulated intramolecular SRN1 re-
action of 2-(2-halophenylamino)pyridines as a method of synthe-
sizing pyrido[1,2-a]benzimidazoles.
2. Results and discussion
2.1. Photo-stimulated cyclization of 2-(2-halophenylamino)
pyridines via SRN1 reactions
Table 1
Nucleophiles derived from nitrogen have been shown to react
with aryl radicals to form CeC and/or CeN bonds. For example, the
reaction of 2-naphthylamine anion with iodoarenes via a photo-
stimulated SRN1 process gave the CeC bond product 1-aryl-2-
naphthylamines in 45e63% yield, with the N-arylation product
formed in only 2e6% yield (Fig. 2, Eq. 1).30 The electrochemical-
induced reaction of pyrrole anion with aryl chlorides gave two CeC
bond forming products (Eq. 2).31 Similar reactivity has been re-
ported for 4-methylimidazole.32 The photo-stimulation of N-(2-
halobenzyl)arylamine derived anions has been found to give
substituted phenanthridines through CeC bond formation in good
to excellent yields.21 However, the photo-stimulated reaction of N-
(2-iodobenzyl)pyridin-2-amine, where the aromatic radical in-
termediate can react to form a CeC or CeN bond, afforded only 6%
yield of benzo[c][1,8]naphthyridine through CeC bond formation
and 61% yield of 6H-pyrido[1,2-a]quinazoline through CeN bond
formation (Eq. 3).21 These results suggest that the intermolecular
coupling of radicals with nucleophiles derived from nitrogen favor
CeC bond formation. However, for intramolecular reactions CeN
bond construction may be preferred.
Optimization of photo-stimulated cyclization of 4a and 4b via SRN1 reactions to
afford 5
Entry Substrate Conditions
Reaction
time (min) 4a or 4b
Recovered Xꢀ (%) GC yield
of 5 (%)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
h
h
h
h
h
h
h
h
n
n
n
n
n
n
n
n
, NH3(l)
, DMSO
, NH3(l)
, DMSO
, DMSO
, NH3(l)
, NH3(l)
, NH3(l)
120
60
60
60
120
30
15
5
0
0
0
96
93
94
86
98
100
100
92
< 5
32
93a
33
93
44
27
98
97
81
0
NDb
0
0
0
0
Dark, NH3(l)
, NH3(l),
30 mol % p-DNB
60
5
100
10
h
n
NDb
44
a
Based on these observations, the photo-stimulated SRN1 re-
action of 2-(2-halophenylamino)pyridines was anticipated to form
Isolated yield.
Not determined.
b
Fig. 2. Examples of nitrogen nucleophiles reacting with aryl radicals to form CeC and/or CeN bonds.

S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
5489
which require prolong heating.15,16 The reaction did not proceed
without photo-stimulation (entry 9). Likewise, the photo-
stimulated reaction was partially inhibited by 1,4-dinitrobenzene
(entry 10).17
modest yield (29%). The regioselectivity of this reaction may be
influenced by the stability of carbon-base anion resonance struc-
ture V in the benzylic position of the isoquinolyl moiety, as opposed
to the nitrogen-based anion resonance structure IV, resulting in the
observed CeC bond formation (Scheme 2).
A proposed reaction mechanism for the photo-stimulated SRN
1
reaction of 2-(2-bromophenylamino)pyridine (4a) is presented in
Scheme 1.17,18 In the initiation step, the radical dianion of the sub-
strate (I) can be formed by an electron transfer (ET) reaction. For
some substrates this step is spontaneous, but in many cases such as
with 2-(2-halophenylamino)pyridines, induction by light is re-
quired. The radical dianion can then fragment yielding the distonic
radical anion II and bromide anion (Brꢀ). The resonance distonic
radical anion II can cyclize to give the conjugated radical anion III,
which by an ET to the anion of 4a can give pyrido[1,2-a]benz-
imidazole (5) and the intermediate I required to continue the
propagation cycle. Presumably, it is the pyridine nitrogen anionic
canonical form IIc, as opposed to the carbon anionic canonical form
IIb that dictates the regioselectivity resulting in generation of
3. Conclusion
In conclusion, pyrido[1,2-a]benzimidazoles were conveniently
synthesized in moderate to excellent yields utilizing photo-
stimulated cyclization of 2-(2-halophenylamino)pyridines in liq-
uid ammonia and in the presence of potassium tert-butoxide. The
reaction proceeded by SRN1 mediated CeN bond formation and was
quite tolerant to various substituents on both the phenyl and pyr-
idine rings. Pyrazino[1,2-a]benzimidazole was also prepared using
this methodology. However, the substrate N-(2-chlorophenyl)-3-
isoquinolinamine cyclized via CeC bond formation to give 7H-
indolo[2,3-c]isoquinoline 9. The photo-stimulated SRN1 mediated
synthesis of pyrido[1,2-a]benzimidazoles and related heterocycles
has several advantages over other methods, such as requiring short
reaction times (ꢁ3 h), proceeding at low temperature, and toler-
ating aryl chloride substrates. This methodology provides a com-
plementary method to other approaches, including recently
reported metal-mediated approaches, and will likely be useful for
the preparation of other fused heterocycles.
pyrido[1,2-a]benzimidazole 5 and not a-carboline.
4. Experimental section
4.1. General information and materials
Unless otherwise noted, all reagents and solvents were pur-
chased from commercial sources and used without purification.
ꢁ
DMSO was stored over molecular sieves (4 A). Silica gel
(0.063e0.200 mm) was used in column chromatography. 1H NMR
(500, 400 or 300 MHz), 13C NMR (126 or 100 MHz), and 19F NMR
(376 MHz) were conducted on a high-resolution spectrometer in
CDCl3 or CD3COCD3 as a solvent. Coupling constants are given in
hertz (Hz), and chemical shifts are reported in parts per million
(ppm). Data are reported as follows: chemical shift, integration,
multiplicity (s¼singlet, br s¼broad singlet, d¼doublet, t¼triplet,
dd¼double doublet, dt¼double triplet, td¼triple doublet,
ddd¼double double doublet, m¼multiplet), and coupling constants
(J). Gas chromatographic (GC) analyses were performed on an in-
strument with a flame ionization detector equipped with a VF-5ms
Scheme 1. Proposed mechanism of the SRN1 reaction of 2-(2-bromophenylamino)
pyridine (4a).
2.2. Scope of the photo-stimulated cyclization of 2-(2-
halophenylamino)pyridines
Next, the scope of the photo-stimulated cyclization of 2-(2-
halophenylamino)pyridines in liquid ammonia via SRN1 mediated
CeN bond forming reactions was investigated. Substrates con-
taining electron donating or electron withdrawing substituents at
the 4- or 5-positions of the phenyl underwent cyclization to give
pyrido[1,2-a]benzimidazoles 7ae7d in moderate to excellent yields
(Table 2, entries 1e4). Likewise, addition of a methyl at the 3-, 4- or
5-positions of the pyridine substrate was also well tolerated pro-
viding pyrido[1,2-a]benzimidazoles 7ee7g in excellent yields (en-
tries 5e7). However, a substrate containing a methyl at the 6-
position of the pyridine substrate (e.g., 6h) provided the desired
product 7h in 58% yield after 60 min of photo-stimulation with 22%
of the starting material recovered (entry 8). Finally, the photo-
stimulated cyclization of 2-(2-bromophenylamino)pyrazine (6i)
generated pyrazino[1,2-a]benzimidazole (7i), albeit in only 29%
yield with 71% recovery of substrate (entry 9).
column (30 mꢂ0.25 mmꢂ0.25
out on a GCeMS equipped with a quadrupole detector and a VF-
5ms column (30 mꢂ0.25 mmꢂ0.25 m). High-resolution mass
mm). GCeMS analyses were carried
m
spectra were performed in an MS/MS instrument in pure products.
These data were obtained by ESI or APPI mode ionization and TOF
detection. Melting points were performed with an electrical in-
strument and are uncorrected. The photochemical reactor consists
of an oval mirror-type wall of ca. 30 cm maximum radius equipped
with two Philips HPI-T 400 W lamps of metallic iodide inserted into
a water-refrigerated Pyrex flask placed ca. 20 cm from the reaction
vessel. The spectrum of the light source showed five broad emission
maxima at about 380, 410, 440, 530, and 570 nm.
4.2. General synthesis of 2-(2-halophenylamino)pyridines34
A mixture of aniline (3 mmol), 2-halopyridine (3 mmol), Cs2CO3
(9 mmol), Pd(OAc)2 (0.12 mmol), and BINAP (0.12 mmol) in toluene
(5 mL) under an argon atmosphere was stirred at 100 ꢃC for 14 h.
After cooling, the reaction mixture was diluted with ethyl acetate
and filtered. The filtrate was evaporated and the residue purified by
column chromatography on silica gel eluting with petroleum ether
(bp 60e80 ꢃC)/ethyl acetate to give the desired products.
With the successful syntheses of pyrido[1,2-a]benzimidazoles
via photo-stimulated cyclization of 2-(2-halophenylamino)pyri-
dines in liquid ammonia, the substrate scope was expanded to in-
clude N-(2-chlorophenyl)-3-isoquinolinamine (8). However, unlike
the pyridine substrates this material cyclized through CeC bond
formation generating only 7H-indolo[2,3-c]isoquinoline 933 in

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S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
Table 2
Substrate scope of the photo-stimulated SRN1 reaction
Entry
1
Substrate
Product
Time (min)
Xꢀ (%)
Isolated yield (%)
60
60
60
95
62
7a
6a
6b
6c
2
3
99
79
94
7b
7c
100
4
5
90
99
98
83
83
7d
6d
120
7e
7f
6e
6
7
120
60
96
94
81
6f
100
7g
6g
8
60
75
33
58a
7h
7i
6h
6i
9
180
29b
a
Starting material recovered: 22%.
Starting material recovered: 71%.
b
4.2.1. 2-(2-Bromo-4-methylphenylamino)pyridine (6a). Light tan
solid; mp 60e61 ꢃC; 1H NMR (400 MHz, CDCl3)
2.30 (s, 3H), 6.68
8.22e8.23 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
20.4, 109.3, 114.8,
d
115.5, 120.8, 128.7, 133.1, 133.4, 135.8, 137.6, 148.3, 155.4; 1H/13
C
(br s, 1H), 6.75e6.77 (m, 1H), 6.79 (d, J¼8.4, 1H), 7.09 (dd, J¼8.4, 1.2,
HSQC NMR (CDCl3) dH
7.09/128.7, 7.40/133.1, 7.48e7.52/137.6, 7.80/120.8, 8.22e8.23/
/dC 2.30/20.4, 6.75e6.77/115.5, 6.79/109.3,
1H), 7.40 (d, J¼1.2, 1H), 7.48e7.52 (m, 1H), 7.80 (d, J¼8.0, 1H),

S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
5491
117.6,119.7, 122.3, 123.1,127.5,129.6,137.5, 147.9, 149.0,155.1; HRMS
(ESI) m/z obsd 219.0702, calcd 219.0684 for C12H11ClN2 (MþHþ).
4.2.7. 2-(2-Chlorophenylamino)-3-methylpyridine (6g). Yield 90%;
white solid; mp 110e112 ꢃC; 1H NMR (500 MHz, CDCl3)
d 2.29 (s,
3H), 6.76 (dd, J¼5.0, 7.5, 1H), 6.90e6.95 (m, 2H), 7.30 (t, J¼8.0, 1H),
7.37e7.42 (m, 2H), 8.19 (d, J¼5.0, 1H), 8.71e8.73 (m, 1H); 13C NMR
(126 MHz, CDCl3) d 17.2, 116.0, 119.1, 119.6, 121.6, 121.9, 127.6, 129.0,
137.5, 138.0, 145.3, 153.3; HRMS (ESI) m/z obsd 219.0725, calcd
219.0684 for C12H12ClN2 (MþHþ).
4.2.8. 2-(2-Chlorophenylamino)-6-methylpyridine
92%; brown oil; 1H NMR (300 MHz, CDCl3)
2.47 (s, 3H), 6.66e6.72
(m, 2H), 6.80 (s, 1H), 6.88e6.94 (m, 1H), 7.20e7.25 (m, 1H),
7.36e7.46 (m, 2H), 8.00 (dd, J¼1.5, 8.4, 1H).
(6h).35 Yield
d
Scheme 2. Photo-stimulated SRN1 reaction of N-(2-chlorophenyl)-3-isoquinolinamine
(8) and proposed intermediate V.
4.3. Synthesis of 2-(2-bromophenylamino)pyrazine (6i)37
148.3; 1H/1H COSY NMR (CDCl3) dH
6.75e6.77/4.78e7.52, 6.75e6.77/8.22e8.23, 7.09/7.40, 7.09/7.80;
1H/13C HMBC NMR (CDCl3) dH
dC 2.30/128.7, 2.30/133.1, 6.75e6.77/
109.3, 6.75e6.77/148.3, 6.79/115.5, 7.09/133.1, 7.09/135.8, 7.40/
114.8, 7.40/128.7, 7.40/135.8, 7.48e7.52/148.3, 7.48e7.52/155.4,
7.80/114.8, 7.80/133.4, 7.80/135.8, 8.22e8.23/115.5, 8.22e8.23/
137.6, 8.22e8.23/155.4; GC/MS EI m/z 183 (MꢀBrþ), 262 (Mþ), 264
(Mþ2); HRMS (ESI) m/z obsd 263.0199, calcd 263.0178 for
C12H12BrN2 (MþHþ).
/dH 2.30/7.09, 2.30/7.40,
A mixture of pyrazin-2-amine (3 mmol), 2-bromoiodobenzene
(3 mmol), t-BuONa (4.5 mmol), Pd2(dba)3 (0.15 mmol), and DPPF
(0.15 mmol) in toluene (5 mL) under an argon atmosphere was
stirred at 100 ꢃC for 14 h.36 After cooling, the mixture was diluted
with ethyl acetate and filtered. The filtrate was evaporated, and
purified by silica gel column chromatography using c-hexane/
AcOEt (10:1) as eluent to give a pale yellow solid (91%). Mp
/
107e109 ꢃC (133e135 ꢃC);38 1H NMR (500 MHz, CDCl3)
d 6.93 (dt,
J¼1.5, 7.5, 2H), 7.31e7.35 (m, 1H), 7.58 (dd, J¼1.5, 8.0, 1H), 8.05 (d,
4.2.2. 2-(2-Chloro-4-trifluoromethylphenylamino)pyridine (6b). Yield
89%; white solid; mp 115e117 ꢃC; 1H NMR (500 MHz, CDCl3)
J¼3.0, 1H), 8.16e8.18 (m, 2H), 8.27 (d, J¼1.5, 1H).
d
6.89e6.92 (m, 2H), 7.07 (s, 1H), 7.47 (dd, J¼8.5, 1.5, 1H),
4.4. Synthesis of N-(2-chlorophenyl)-3-isoquinolinamine (8)
7.60e7.64 (m, 2H), 8.31e8.32 (m, 1H), 8.46 (d, J¼8.5, 1H); 13C NMR
(126 MHz, CDCl3)
d
111.7, 117.2, 117.9, 121.5, 122.8, 123.3 (q,
A mixture of 1-aminoisoquinoline (3 mmol), 2-chloroiodo
J¼33.4 Hz), 124.9 (q, J¼3.6 Hz), 126.5 (q, J¼3.9 Hz), 138.1, 140.5,
148.2, 154.0; HRMS (ESI) m/z obsd 273.0420, calcd 273.0401 for
C12H9ClF3N2 (MþHþ).
benzene (3 mmol), t-BuONa (4.5 mmol), Pd2(dba)3 (0.15 mmol),
and DPPF (0.15 mmol) in toluene (5 mL) under an argon atmosphere
was stirred at 100 ꢃC for 14 h. After cooling, the mixture was diluted
with ethyl acetate and filtered. The filtrate was evaporated, and pu-
rified by silica gel column chromatography using c-hexane/AcOEt
(10: 1) as eluent to give a pale yellow solid (85%). Mp 152e154 ꢃC; 1H
4.2.3. 2-(2-Chloro-5-methylphenylamino)pyridine (6c). Yield 92%;
white solid; mp 134e136 ꢃC; 1H NMR (500 MHz, CDCl3)
d 2.34 (s,
3H), 6.74e6.76 (m, 1H), 6.78e6.81 (m, 1H), 6.85e6.86 (m, 2H), 7.25
(d, J¼8.0, 1H), 7.51e7.55 (m, 1H), 7.86 (d, J¼1.5, 1H), 8.26e8.27 (m,
NMR (500 MHz, CDCl3) d 6.98e7.02 (m, 2H), 7.25 (s, 1H), 7.30e7.33
(m,1H), 7.37e7.40 (m,1H), 7.46 (dd, J¼1.5, 8.0,1H), 7.57e7.60 (m,1H),
1H); 13C NMR (126 MHz, CDCl3)
d 21.5, 110.0, 115.9, 120.3, 120.4,
7.63e7.65 (m,1H), 7.87e7.90(m, 2H), 9.05 (s,1H); 13C NMR (126MHz,
123.5, 129.2, 136.9, 137.6, 137.8, 148.3, 155.1; HRMS (ESI) m/z obsd
CDCl3) d 101.3, 118.8, 122.3, 123.5, 124.3, 125.0, 125.4, 127.6, 127.8,
219.0715, calcd 219.0684 for C12H12ClN2 (MþHþ).
129.9,130.8,138.0,138.4,150.7,152.1; HRMS (ESI) m/z obsd 255.0722,
calcd 255.0684 for C15H12ClN2 (MþHþ).
4.2.4. 2-(2-Chloro-5-fluorophenylamino)pyridine (6d). Yield 86%;
white solid; mp 110e112 ꢃC; 1H NMR (500 MHz, CDCl3)
d
6.60 (dt,
4.5. General procedure for the synthesis of pyrido[1,2-a]
J¼3.0, 8.0, 1H), 6.83e6.87 (m, 2H), 6.95 (s, 1H), 7.27 (dd, J¼6.0, 2.5,
benzimidazoles in liquid ammonia
1H), 7.56e7.59 (m, 1H), 8.20 (dd, J¼2.5, 11.0, 1H), 8.29 (d, J¼5.0, 1H);
13C NMR (126 MHz, CDCl3)
d
105.9 (d, J¼115.5), 108.3 (d, J¼95.0),
4.5.1. Pyrido[1,2-a]benzimidazole (5).36 Liquid ammonia (200 mL),
previously dried over Na metal, was distilled into a 250 mL three-
necked, round-bottomed flask equipped with a cold-finger con-
denser, a nitrogen inlet, and a magnetic stirrer. The base (t-BuOK,
45 mg, 0.40 mmol) and the 2-(2-bromophenylamino)pyridine
(4a,36 50 mg, 0.20 mmol) were added to the liquid ammonia and
the solution was irradiated for 120 min. The reaction was
quenched with an excess of solid NH4NO3, and the ammonia was
allowed to evaporate. Water (50 mL) was added to the residue,
and the mixture was extracted with dichloromethane (3ꢂ30 mL).
The organic extract was washed with water (2ꢂ20 mL), dried over
anhydrous MgSO4, filtered, and the solvent was removed under
reduced pressure to leave the crude product. The yield of bromide
ions in the aqueous solution was determined potentiometrically.
The crude product was purified by radial TLC eluting with petro-
leum ether (bp 60e80 ꢃC)/ethyl acetate (50:50) to give 536 (93%)
as light yellow crystals. It was recrystallized from dichloromethane
to give colorless crystals. Mp 184e185 ꢃC (lit. 179e182 ꢃC);36 1H
111.3, 116.7, 129.8 (d, J¼39.0), 137.9, 138.6, 148.1, 154.3, 161.0, 162.8;
HRMS (ESI) m/z obsd 223.0464, calcd 223.0433 for C11H9ClFN2
(MþHþ).
4.2.5. 2-(2-Chlorophenylamino)-5-methylpyridine (6e). Yield 96%;
white solid; mp 170e172 ꢃC; 1H NMR (500 MHz, CDCl3)
d 2.25 (s,
3H), 6.80e6.83 (m, 2H), 6.88 (dt, J¼1.5, 8.0, 1H), 7.21e7.24 (m, 1H),
7.36 (dd, J¼1.5, 8.0, 2H), 8.01 (dd, J¼1.0, 8.0, 1H), 8.09e8.10 (m, 1H);
13C NMR (126 MHz, CDCl3)
d 17.7, 110.1, 118.8, 121.8, 122.6, 125.2,
127.5, 129.6, 137.8, 138.7, 148.0, 152.8; HRMS (ESI) m/z obsd
219.0707, calcd 219.0684 for C12H12ClN2 (MþHþ).
4.2.6. 2-(2-Chlorophenylamino)-4-methylpyridine (6f). Yield 94%;
white solid; mp 144e146 ꢃC; 1H NMR (500 MHz, CDCl3)
d 2.32 (s,
3H), 6.68 (d, J¼5.0, 1H), 6.72 (s, 1H), 6.88 (s, 1H), 6.94 (dd, J¼1.0, 8.0,
1H), 7.26e7.30 (m, 1H), 7.41 (dd, J¼1.5, 8.0, 1H), 8.11 (dd, J¼1.0, 8.0,
1H), 8.16 (d, J¼5.0, 1H); 13C NMR (126 MHz, CDCl3)
d 21.2, 110.5,

5492
S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
NMR (400 MHz, CDCl3)
d
6.84 (t, J¼6.8, 1H), 7.35e7.44 (m, 2H),
HMBC NMR (CDCl3) dH/dC 2.56/119.4, 2.56/122.7, 2.56/135.6, 6.78/
7.53 (t, J¼7.4, 1H), 7.69 (d, J¼9.6, 1H), 7.89 (d, J¼8.4, 1H), 7.95 (d,
117.8, 6.78/125.0, 7.17/119.4, 7.17/126.8, 7.34e7.39/125.0, 7.34e7.39/
148.5, 7.65/109.9, 7.65/148.5, 7.70/122.7, 7.70/126.8, 7.72/135.6,
7.72/144.9, 8.37/109.9, 8.37/128.9, 8.37/148.5; GC/MS EI m/z 182
(Mþ, 100).
J¼8.0, 1H), 8.44 (d, J¼6.8, 1H); 13C NMR (100 MHz, CDCl3)
d 110.3,
110.4, 118.0, 119.9, 121.0, 125.2, 125.6, 128.6, 129.3, 144.5, 148.4;
1H/13
7.35e7.44/129.3, 7.53/125.6, 7.69/118.0, 7.89/110.4, 7.95/119.9,
8.44/125.2; 1H/1H COSY NMR (CDCl3) dH
dH 6.84/7.35e7.44, 6.84/
8.44, 7.35e7.44/7.53, 7.35e7.44/7.69, 7.35e7.44/7.89, 7.53/7.95;
1H/13C HMBC NMR (CDCl3) dH
dC 6.84/118.0, 6.84/125.2, 7.35e7.44/
C HSQC NMR (CDCl3) dH/dC 6.84/110.3, 7.35e7.44/121.0,
/
4.5.5. 7-Fluoropyrido[1,2-a]benzimidazole (7d).16 This compound
was obtained according to the general procedure as solid and
recrystallized from dichloromethane/petroleum ether (bp
60e80 ꢃC) as yellow crystals. Mp 194e196 ꢃC (lit. 172e173 ꢃC);16 1H
/
119.9, 7.35e7.44/125.2, 7.35e7.44/128.6, 7.35e7.44/148.4, 7.53/
110.4, 7.53/144.5, 7.69/110.3, 7.69/148.4, 7.89/125.6, 7.89/144.5,
7.95/121.0, 7.95/128.6, 8.44/110.3, 8.44/129.3, 8.44/148.4; GC/MS EI
m/z 168 (Mþ, 100).
NMR (400 MHz, CD3COCD3)
d
7.03 (t, J¼6.2, 1H), 7.23 (td, J¼9.4, 2.4,
1H), 7.55e7.56 (m, 2H), 7.66 (d, J¼9.2, 1H), 8.34 (dd, J¼8.8, 5.0, 1H),
9.09 (d, J¼6.8, 1H); 13C NMR (100 MHz, CD3COCD3)
d 104.0 (d,
JCeF¼25), 108.9 (d, JCeF¼25), 110.7, 113.2 (d, JCeF¼12), 116.7, 125.5,
4.5.2. 8-Methylpyrido[1,2-a]benzimidazole (7a).39 This compound
was purified by chromatography on silica gel eluting with petro-
leum ether (bp 60e80 ꢃC)/ethyl acetate gradient (100:0/0:100)
and then recrystallized from dichloromethane to give colorless
127.2, 130.5, 144.7 (d, JCeF¼12), 149.2, 160.6 (d, JCeF¼236); 1H/13
C
HSQC NMR (CD3COCD3) dH/dC 7.03/110.7, 7.23/108.9, 7.55e7.56/
104.0, 7.55e7.56/130.5, 7.66/116.7, 8.34/113.2, 9.09/127.2; 1H/1H
COSY NMR (CD3COCD3) dH dH 7.03/7.55e7.56, 7.03/9.09, 7.23/
7.55e7.56, 7.23/8.34, 7.55e7.56/7.66; 1H/13
HMBC NMR
(CD3COCD3) dH dC 7.03/116.7, 7.03/127.2, 7.23/104.0, 7.23/125.5,
/
crystals. Mp 127e128 ꢃC; 1H NMR (400 MHz, CDCl3)
d
2.59 (s, 3H),
C
6.81 (td, J¼6.8, 1.2, 1H), 7.35e7.39 (m, 2H), 7.64e7.68 (m, 2H), 7.82
/
(d, J¼8.4, 1H), 8.39 (dt, J¼6.8, 1.2, 1H); 13C NMR (100 MHz, CDCl3)
7.23/160.6, 7.55e7.56/108.9, 7.55e7.56/125.5, 7.55e7.56/127.2,
7.55e7.56/149.2, 7.55e7.56/160.6, 7.66/110.7, 7.66/149.2, 8.34/144.7,
8.34/160.6, 9.09/110.7, 9.09/130.5, 9.09/149.2; GC/MS EI m/z 186
(Mþ, 100).
d
21.8,110.1,118.1,119.5,125.0, 127.4,128.7,131.1,142.6,148.3; 1H/13
C
HSQC NMR (CDCl3) dH
7.35e7.39/128.7, 7.64e7.68/110.1, 7.64e7.68/118.1, 7.82/119.5, 8.39/
125.0; 1H/1H COSY NMR (CDCl3) dH
dH 6.81/7.35e7.39, 6.81/8.39,
7.35e7.39/7.64e7.68, 7.35e7.39/7.82; 1H/13C HMBC NMR (CDCl3)
dH dC 2.59/110.1, 2.59/127.4, 2.59/131.1, 6.81/118.1, 6.81/125.0,
/dC 2.59/21.8, 6.81/110.0, 7.35e7.39/127.4,
/
4.5.6. 2-Methylpyrido[1,2-a]benzimidazole (7e).14 The compound
was purified by chromatography on silica gel eluting with petro-
leum ether (bp 60e80 ꢃC)/ethyl acetate gradient (100:0/25:75)
and then recrystallized from dichloromethane to give white crys-
/
7.35e7.39/110.1, 7.35e7.39/125.0, 7.35e7.39/142.6, 7.35e7.39/148.3,
7.64e7.68/110.1, 7.64e7.68/127.4, 7.64e7.68/142.6, 7.64e7.68/148.3,
7.82/128.7, 7.82/131.1, 8.39/110.1, 8.39/128.7, 8.39/148.3; GC/MS EI
m/z 182 (Mþ, 100).
tals. Mp 152e154 ꢃC; 1H NMR (400 MHz, CDCl3)
d
2.39 (d, J¼1.2,
3H), 7.26 (dd, J¼9.2, 1.6, 1H), 7.33 (ddd, J¼8.4, 7.2, 1.2, 1H), 7.49 (ddd,
J¼8.4, 7.2, 1.2, 1H), 7.60 (d, J¼9.6, 1H), 7.83 (d, J¼8.4, 1H), 7.91 (d,
4.5.3. 8-(Trifluoromethyl)pyrido[1,2-a]benzimidazole
(7b).16 This
J¼8.4, 1H), 8.19 (d, J¼0.8, 1H); 13C NMR (100 MHz, CDCl3)
d 18.1,
compound was purified by chromatography on silica gel eluting
with petroleum ether (bp 60e80 ꢃC)/ethyl acetate gradient
(100:0/25:75) and then recrystallized from dichloromethane to
give light yellow crystals. Mp 166e167 ꢃC (lit. 158e160 ꢃC);16 1H
110.3, 117.3, 119.8, 120.7, 122.6, 125.3, 128.6, 132.6, 144.6, 147.7;
1H/13C HSQC NMR (CDCl3) dH
7.49/125.3, 7.60/117.3, 7.83/110.3, 7.91/119.8, 8.19/122.6; 1H/1H
COSY NMR (CDCl3) dH dH 2.39/8.19, 7.26/7.60, 7.26/8.19, 7.33/7.49,
7.33/7.83, 7.49/7.91; 1H/13C HMBC NMR (CDCl3) dH
dC 2.39/119.8,
/dC 2.39/18.1, 7.26/132.6, 7.33/120.7,
/
NMR (400 MHz, CDCl3)
d
6.95 (td, J¼6.8, 1.2, 1H), 7.53e7.55 (m, 1H),
/
7.73e7.78 (m, 2H), 8.00 (d, J¼8.4, 1H), 8.19e8.20 (m, 1H), 8.51 (dt,
2.39/122.6, 2.39/132.6, 7.26/122.6, 7.26/147.7, 7.33/119.8, 7.33/128.6,
7.49/110.3, 7.49/144.6, 7.60/119.8, 7.60/147.7, 7.83/125.3, 7.83/144.6,
7.91/120.7, 7.91/128.6, 8.19/132.6, 8.19/147.7; GC/MS EI m/z 182 (Mþ,
100).
J¼7.2, 1.2, 1H); 13C NMR (100 MHz, CDCl3)
108.5 (q, JCeF¼4), 111.2,
d
118.3, 120.3, 122.4 (q, JCeF¼3), 122.9 (q, JCeF¼32), 124.7 (q,
JCeF¼270), 125.4, 128.0, 130.7, 146.5, 150.3; 1H/13C HSQC NMR
(CDCl3) dH/dC 6.95/111.24, 7.53e7.55/130.72, 7.73e7.78/118.29,
7.73e7.78/122.44, 8.00/120.30, 8.19e8.20/108.47, 8.51/125.35;
1H/1H COSY NMR (CDCl3) dH
dH 6.95/7.53e7.55, 6.95/8.51,
7.53e7.55/7.73e7.78, 7.73e7.78/8.00, 7.73e7.78/8.19e8.20; 1H/13
HMBC NMR (CDCl3) dH dC 6.95/118.3, 6.95/125.4, 7.53e7.55/118.3,
4.5.7. 3-Methylpyrido[1,2-a]benzimidazole (7f).14 The compound
was purified by chromatography on silica gel eluting with ethyl
acetate/ethanol (98:2) to give light yellow crystals. Mp
/
C
/
164e165 ꢃC; 1H NMR (400 MHz, CDCl3)
d 2.45 (s, 3H), 6.65 (d,
7.53e7.55/125.4, 7.53e7.55/150.3, 7.73e7.78/108.5, 7.73e7.78/111.2,
7.73e7.78/120.3, 7.73e7.78/130.7, 7.73e7.78/146.5, 7.73e7.78/
150.3, 8.00/122.4, 8.00/122.9, 8.00/128.0, 8.19e8.20/122.4,
8.19e8.20/124.7, 8.19e8.20/146.5, 8.51/111.2, 8.51/130.7, 8.51/
J¼6.0, 1H), 7.31 (t, J¼7.6, 1H), 7.42 (s, 1H), 7.49 (t, J¼7.6, 1H), 7.82 (d,
J¼8.4, 1H), 7.89 (d, J¼8.0, 1H), 8.29 (d, J¼6.8, 1H); 13C NMR
(100 MHz, CDCl3)
d 21.8, 110.1, 113.0, 116.0, 120.0, 120.5, 124.2,
125.3, 128.6, 140.7, 144.7, 149.0; 1H/13C HSQC NMR (CDCl3) dH
2.45/21.8, 6.65/113.0, 7.31/120.5, 7.42/116.0, 7.49/125.3, 7.82/110.1,
7.89/119.6, 8.29/124.2; 1H/1H COSY NMR (CDCl3) dH
dH 6.65/7.42,
6.65/8.29, 7.31/7.49, 7.31/7.82, 7.49/7.89; 1H/13
HMBC NMR
(CDCl3) dH dC 2.45/113.0, 2.45/116.0, 2.45/140.7, 6.65/116.0, 6.65/
/dC
150.3; 19F NMR (376 MHz, CDCl3)
100).
d
ꢀ60.3; GC/MS EI m/z 236 (Mþ,
/
C
4.5.4. 7-Methylpyrido[1,2-a]benzimidazole (7c).40 This compound
was purified by chromatography on silica gel eluting with
dichloromethane/ethanol gradient (100:0/98:2) and then
recrystallized from dichloromethane to give light yellow crystals.
/
124.2, 7.31/119.6, 7.31/140.7, 7.42/113.0, 7.49/110.1, 7.49/144.7, 7.82/
125.3, 7.82/144.7, 7.89/120.5, 7.89/128.6, 8.29/140.7, 8.29/149.0;
GC/MS EI m/z 182 (Mþ, 100); HRMS (ESI) m/z obsd 183.0913, calcd
183.0917 for C12H10N2 (MþHþ).
Mp 152e153 ꢃC; 1H NMR (400 MHz, CDCl3)
d 2.56 (s, 3H), 6.78 (t,
J¼6.8, 1H), 7.17 (d, J¼8.4, 1H), 7.34e7.39 (m, 1H), 7.65 (dd, J¼9.2, 0.8,
1H), 7.70 (br s, 1H), 7.72 (d, J¼8.4, 1H), 8.37 (dd, J¼7.0, 1.2, 1H); 13C
4.5.8. 4-Methylpyrido[1,2-a]benzimidazole (7g).9 This compound
was obtained according to the general procedure as slightly col-
ored solid and recrystallized from dichloromethane/petroleum
ether (bp 60e80 ꢃC) as light yellow crystals. Mp 138e139 ꢃC; 1H
NMR (100 MHz, CDCl3) d 21.9, 109.8, 109.9, 117.8, 119.4, 122.7, 125.0,
126.8, 128.9, 135.6, 144.9, 148.5; 1H/13C HSQC NMR (CDCl3) dH
2.56/21.9, 6.78/109.9, 7.17/122.7, 7.34e7.39/128.9, 7.65/117.8, 7.70/
119.4, 7.72/109.8, 8.37/125.0; 1H/1H COSY NMR (CDCl3) dH
dH 2.56/
7.70, 6.78/7.34e7.39, 6.78/8.37, 7.17/7.72, 7.34e7.39/7.65; 1H/13
/dC
/
NMR (400 MHz, CDCl3)
J¼6.8, 1H), 7.32e7.36 (m, 1H), 7.49e7.53 (m, 1H), 7.84 (d, J¼8.0, 1H),
d
2.69 (s, 3H), 6.74 (t, J¼6.8, 1H), 7.20 (d,
C

S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
5493
7.98 (d, J¼8.4, 1H), 8.29 (d, J¼6.4, 1H); 13C NMR (100 MHz, CDCl3)
12.24/105.1, 12.24/121.1, 12.24/137.2, 12.24/147.8; GC/MS EI m/z 218
d
17.5, 110.3, 110.4, 119.9, 120.9, 122.8, 125.4, 127.5, 127.7, 129.1,
(Mþ, 100).
144.2, 149.1; 1H/13C HSQC NMR (CDCl3) dH
7.20/127.5, 7.32e7.36/120.9, 7.49e7.53/125.4, 7.84/110.3, 7.98/
119.9, 8.29/122.8; 1H/1H COSY NMR (CDCl3) dH
dH 6.74/7.20, 6.74/
8.29, 7.32e7.36/7.49e7.53, 7.32e7.36/7.84, 7.49e7.53/7.98; 1H/13
HMBC NMR (CDCl3) dH dC 2.69/127.5, 2.69/149.1, 6.74/122.8,
/dC 2.69/17.5, 6.74/110.4,
4.6. General procedure for the synthesis of pyrido[1,2-a]
benzimidazoles in DMSO
/
C
/
4.6.1. Pyrido[1,2-a]benzimidazole (5). The reaction was carried out
in a Schlenk tube equipped with a nitrogen inlet and magnetic
stirrer at room temperature. DMSO (5 mL) was dried and de-
oxygenated, t-BuOK (22 mg, 0.20 mmol) was added, 2-(2-bromo-
phenylamino)pyridine (4a, 25 mg, 0.10 mmol) was added, and the
reaction mixture was irradiated for 60 min. The reaction was
quenched with water and excess solid ammonium nitrate. The
residue was extracted with dichloromethane (3ꢂ30 mL), and the
organic extracted was washed with water (2ꢂ20 mL), dried over
anhydrous MgSO4, filtered, and concentrated to give the crude
products. The bromide ions in the aqueous solution were de-
termined potentiometrically.
6.74/127.7, 7.20/122.8, 7.20/149.1, 7.32e7.36/119.9, 7.32e7.36/
129.1, 7.49e7.53/110.3, 7.49e7.53/144.2, 7.84/125.4, 7.84/144.2,
7.98/120.9, 7.98/129.1, 8.29/127.5, 8.29/149.0; GC/MS EI m/z 182
(Mþ, 100).
4.5.9. 1-Methylpyrido[1,2-a]benzimidazole (7h).14 The compound
was purified by chromatography on silica gel eluting with ethyl
acetate/ethanol gradient (100:0/80:20) as colorless crystals. Mp
106e107 ꢃC; 1H NMR (400 MHz, CDCl3)
d
3.00 (s, 3H), 6.56 (d, J¼6.4,
1H), 7.28e7.34 (m, 2H), 7.51 (t, J¼7.6, 1H), 7.58 (d, J¼9.2, 1H), 7.95 (d,
J¼8.0, 1H), 8.11 (d, J¼8.4, 1H); 13C NMR (100 MHz, CDCl3)
d 21.3,
110.7, 114.6, 115.3, 119.6, 120.5, 125.1, 129.2, 129.9, 139.0, 145.0,
149.6; 1H/13C HSQC NMR (CDCl3) dH
7.28e7.34/120.5, 7.28e7.34/129.2, 7.51/125.1, 7.58/115.3, 7.95/119.6,
8.11/114.6; 1H/1H COSY NMR (CDCl3) dH
dH 6.56/7.28e7.34,
7.28e7.34/7.51, 7.28e7.34/7.58, 7.28e7.34/8.11, 7.51/7.95; 1H/13
HMBC NMR (CDCl3) dH dC 3.00/110.7, 3.00/139.0, 6.56/115.3, 6.56/
139.0, 7.28e7.34/119.6, 7.28e7.34/129.9, 7.28e7.34/139.0,
7.28e7.34/149.6, 7.51/114.6, 7.51/145.0, 7.58/110.7, 7.58/149.6, 7.95/
120.5, 7.95/129.9, 8.11/125.1, 8.11/145.0; GC/MS EI m/z 182 (Mþ,
100).
/dC 3.00/21.3, 6.56/110.7,
Acknowledgements
/
We thank Lic. Walter D. Guerra for conducting some of the
photo-stimulated reactions. This work was supported in part by the
C
/
ꢀ
Agencia Cordoba Ciencia, the Consejo Nacional de Investigaciones
ꢀ
Científicas y Tecnicas (CONICET), SECYT, Universidad Nacional de
ꢀ
Cordoba, and FONCYT, Argentina. Y.W. and G.D.C. also thank the
Harvard NeuroDiscovery Center (HNDC) for supporting this work.
4.5.10. Pyrazino[1,2-a]benzimidazole (7i).41 This compound was
purified by chromatography on silica gel eluting with petroleum
ether (bp 60e80 ꢃC)/ethyl acetate gradient (50:50/0:100) as
a light brown crystal. Mp 199e200 ꢃC (197e198 ꢃC);41 1H NMR
Supplementary data
NMR spectra (1H and 13C NMR) of the compounds are provided.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.04.087.
(400 MHz, CDCl3)
7.97e7.99 (m, 2H), 8.07 (d, J¼8.4, 1H), 8.36e8.37 (m, 1H), 9.30 (s,
1H); 13C NMR (100 MHz, CDCl3)
111.2, 117.8, 121.6, 123.3, 127.1,
127.2, 127.7, 142.2, 144.3, 145.8; 1H/13C HSQC NMR (CDCl3) dH
dC
d 7.50e7.54 (m, 1H), 7.63e7.67 (m, 1H),
d
References and notes
/
1. Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208e6236.
2. Takeshita,H.;Watanabe, J.; Kimura, Y.; Kawakami, K.; Takahashi, H.; Takemura, M.;
Kitamura, A.; Someya, K.; Nakajima, R. Bioorg. Med. Chem. Lett. 2010, 20,
3893e3896.
3. Refaat, H. M. Med. Chem. Res. 2012, 21, 1253e1260.
4. Ndakala, A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White, K. L.; Hudson, A.;
Fakorede, F.; Shackleford, D. M.; Kaiser, M.; Yeates, C.; Charman, S. A.; Chibale,
K. J. Med. Chem. 2011, 54, 4581e4589.
7.50e7.54/123.3, 7.63e7.67/127.2, 7.97e7.99/111.8, 7.97e7.99/
127.1, 8.07/121.6, 8.36e8.37/117.8, 9.30/145.8; 1H/1H COSY
NMR (CDCl3) dH
7.63e7.67/8.07, 7.97e7.99/8.36e8.37, 8.36e8.37/9.31; 1H/13
HMBC NMR (CDCl3) dH dC 7.50e7.54/121.6, 7.50e7.54/127.7,
/dH 7.50e7.54/7.63e7.67, 7.50e7.54/7.97e7.99,
C
/
7.63e7.67/111.2, 7.63e7.67/144.3, 7.97e7.99/117.8, 7.97e7.99/
127.2, 7.97e7.99/144.3, 7.97e7.99/145.8, 8.07/123.3, 8.07/127.7,
8.36e8.37/127.1, 8.36e8.37/142.2, 9.30/127.1, 9.30/142.2; GC/MS
EI m/z 169 (Mþ, 100).
5. Kiselyov, A. S. Tetrahedron Lett. 2006, 47, 2941e2944.
6. Ryzvanovich, G. A.; Begunov, R. S.; Rachinskaya, A. O.; Muravenko, O. V.; So-
kolov, A. A. Pharm. Chem. J. 2011, 45, 141e143.
7. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis
2007, 3155e3162.
4.5.11. 7H-Indolo[2,3-c]isoquinoline (9).33 This compound was pu-
rified by chromatography on silica gel eluting with petroleum ether
(bp 60e80 ꢃC)/ethyl acetate gradient (90:10/50:50) and then
recrystallized from ethyl acetate to give light yellow crystals. Mp
265e266 ꢃC (lit. 259e260 ꢃC);33 1H NMR (400 MHz, CD3COCD3)
8. Kutsumura, N.; Kunimatsu, S.; Kagawa, K.; Otani, T.; Saito, T. Synthesis 2011,
3235e3240.
9. Hubert, A. J. J. Chem. Soc. C: Organic 1969, 1334e1336.
10. Baklanov, M. V.; Frolov, A. N. Zh. Org. Khim. 1991, 27, 638e649.
11. Baklanov, M. V.; Frolov, A. N. Zh. Org. Khim. 1992, 28, 390e394.
12. Frolov, A. N. Zh. Obshch. Khim. 1999, 69, 1254e1261.
13. Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71,
1280e1283.
14. Wu, Z.; Huang, Q.; Zhou, X.; Yu, L.; Li, Z.; Wu, D. Eur. J. Org. Chem. 2011,
5242e5245.
15. Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132,
13217e13219.
16. Masters, K.-S.; Rauws, T. R. M.; Yadav, A. K.; Herrebout, W. A.; Van der Veken, B.;
Maes, B. U. W. Chem.dEur. J. 2011, 17, 6315e6320.
17. Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103, 71e167.
18. Bardagí, J. I.; Vaillard, V. A.; Rossi, R. A. In Encyclopedia of Radicals in Chemistry,
Biology & Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons:
Chichester, UK, 2012; Vol. 1, pp 333e364.
d
7.35 (t, J¼7.6, 1H), 7.48 (t, J¼7.6, 1H), 7.58 (t, J¼7.6, 1H), 7.66 (d,
J¼8.0, 1H), 7.90e7.94 (m, 1H), 8.26 (d, J¼8.4, 1H), 8.56 (d, J¼8.0, 1H),
8.72 (d, J¼8.4, 1H), 9.20 (s, 1H), 12.24 (br s, 1H); 13C NMR (100 MHz,
CD3COCD3)
d 105.1, 111.8, 120.0, 121.1, 122.1, 122.4, 123.5, 124.1,
124.8, 129.4, 131.2, 131.9, 137.2, 147.8, 150.6; 1H/13C HSQC NMR
(CD3COCD3) dH dC 7.35/120.0, 7.48/124.8, 7.58/123.5, 7.66/111.8,
7.90e7.94/131.2, 8.26/129.4, 8.56/122.1, 8.72/122.4, 9.20/150.6;
1H/1H COSY NMR (CD3COCD3) dH
dH 7.35/7.48, 7.35/8.56, 7.48/7.66,
7.58/7.90e7.94, 7.58/8.26, 7.90e7.94/8.72, 9.20/9.20, 12.24/12.24;
1H/13C HMBC NMR (CD3COCD3) dH
dC 7.35/111.8, 7.35/121.1, 7.48/
/
~ꢀ~
/
ꢀ
19. Vaillard, V. A.; Guastavino, J. F.; Buden, M. E.; Bardagi, J. I.; Barolo, S. M.; Rossi,
/
R. A. J. Org. Chem. 2012, 77, 1507e1519.
20. Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem. 2011, 76,
6421e6425.
122.1, 7.48/137.2, 7.58/122.4, 7.58/124.1, 7.66/120.0, 7.66/121.1,
7.90e7.94/129.4, 7.90e7.94/131.8, 8.26/131.2, 8.26/131.9, 8.26/
150.6, 8.56/105.1, 8.56/124.8, 8.56/137.2, 8.72/105.1, 8.72/123.5,
8.72/124.1, 8.72/131.9, 9.20/124.1, 9.20/129.4, 9.20/131.9, 9.20/147.8,
ꢀ
21. Buden, M. E.; Dorn, V. B.; Gamba, M.; Pierini, A. B.; Rossi, R. A. J. Org. Chem. 2010,
75, 2206e2218.
ꢀ
22. Buden, M. E.; Rossi, R. A. Tetrahedron Lett. 2007, 48, 8739e8742.

5494
S.M. Barolo et al. / Tetrahedron 69 (2013) 5487e5494
ꢀ
23. Buden, M. E.; Vaillard, V. A.; Martín, S. E.; Rossi, R. A. J. Org. Chem. 2009, 74,
4490e4498.
33. Van Baelen, G.; Meyers, C.; Lemiere, G. L. F.; Hostyn, S.; Dommisse, R.; Maes, L.;
Augustyns, K.; Haemers, A.; Pieters, L.; Maes, B. U. W. Tetrahedron 2008, 64,
11802e11809.
34. Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240e7241.
35. Bailey, D. M.; Johnson, R. E.; Connolly, J. D.; Ferrari, R. A. J. Med. Chem. 1971, 14,
439e443.
24. Barolo, S. M.; Teng, X.; Cuny, G. D.; Rossi, R. A. J. Org. Chem. 2006, 71,
8493e8499.
25. Guastavino, J. F.; Barolo, S. M.; Rossi, R. A. Eur. J. Org. Chem. 2006, 3898e3902.
26. Bardagi, J. I.; Vaillard, S. E.; Rossi, R. A. ARKIVOC 2007, 73e83.
27. Barolo, S. M.; Rosales, R.; Guío, J. E. A.; Rossi, R. A. J. Heterocycl. Chem. 2006, 43,
695e699.
36. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
1505e1510.
28. Guastavino, J. F.; Rossi, R. A. J. Org. Chem. 2012, 77, 460e472.
29. Vaillard, V. A.; Buden, M. E.; Martín, S. E.; Rossi, R. A. Tetrahedron Lett. 2009, 50,
37. Haider, N.; van der Plas, H. C. Tetrahedron 1990, 46, 3641e3650.
38. Kim, B. R.; Cho, S.-D.; Kim, E. J.; Lee, I.-H.; Sung, G. H.; Lee, S.-G.; Yoon, Y.-J.; Kim,
J.-J. Tetrahedron 2012, 68, 287e293.
ꢀ
3829e3832.
30. Pierini, A. B.; Baumgartner, M. T.; Rossi, R. A. Tetrahedron Lett. 1987, 28,
4653e4656.
39. Liubchak, K.; Nazarenko, K.; Tolmachev, A. Tetrahedron 2012, 68, 2993e3000.
40. Zhao, D.; Hu, J.; Wu, N.; Huang, X.; Qin, X.; Lan, J.; You, J. Org. Lett. 2011, 13,
6516e6519.
ꢀ
31. Chahma, M.; Combellas, C.; Thiebault, A. Synthesis 1994, 366e368.
ꢀ
32. Chahma, M.; Combellas, C.; Thiebault, A. J. Org. Chem. 1995, 60, 8015e8022.
41. Bergman, J.; Vallberg, H. Acta Chem. Scand. 1997, 51, 742e752.