Palladium-catalyzed N-heteroannulation of N-allyl- or N-benzyl-2-nitrobenzenamines: synthesis of 2-substituted benzimidazoles

Article abstract of DOI:10.1016/j.tet.2007.05.010

A palladium-catalyzed reductive N-heteroannulation of N-allyl- or N-benzyl-2-nitrobenzenamines, using carbon monoxide as the ultimate reducing agent, affording 2-substituted benzimidazoles has been developed.

Full text of DOI:10.1016/j.tet.2007.05.010

Tetrahedron 63 (2007) 7077–7085
Palladium-catalyzed N-heteroannulation of N-allyl- or N-benzyl-
2-nitrobenzenamines: synthesis of 2-substituted benzimidazoles
*
€
Jeremiah W. Hubbard, Adam M. Piegols and Bjorn C. G. Soderberg
€
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, United States
Received 2 April 2007; revised 26 April 2007; accepted 1 May 2007
Available online 6 May 2007
Abstract—A palladium-catalyzed reductive N-heteroannulation of N-allyl- or N-benzyl-2-nitrobenzenamines, using carbon monoxide as the
ultimate reducing agent, affording 2-substituted benzimidazoles has been developed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cases.9 For example, reaction of N-allyl-2-nitrobenzenamine
with sodium ethoxide gave the corresponding 2-ethenyl-1-
hydroxybenzimidazole (Scheme 1).10 1-Hydroxybenzimid-
azoles are readily reduced to benzimidazoles using, for
example, Fe–HCl10 or zinc dust in ethanol.11
Transition metal-catalyzed reductive N-heteroannulations of
2-substituted nitroarenes are emerging as a powerful tool in
the synthesis of a variety of nitrogen containing fused het-
erocyclic compounds.1 Particularly useful and diverse are
the palladium-catalyzed reactions using carbon monoxide
as the ultimate reducing agent. Palladium-catalyzed reduc-
tive N-heteroannulation has been utilized in the synthesis
of indoles,2 2H-indazoles,2j quinolines,2j 4(1H)-quino-
lones,3 dihydroquinoxalines,4 quinazolines,5 4(3H)-quin-
azolinones,6 pyrrolines,7 and 2,1-benzoisoxazole.2j
2-Substituted benzimidazoles have also been prepared in
low yields (6–40%) from N-alkyl and N-benzyl substituted
2-nitrobenzenamines using an excess of iron oxalate and
lead shots at 220–240 ꢀC.12 It is not clear if the metal addi-
tives are actually involved in the reaction since pyrolysis of
N-benzyl-2-nitrobenzenamine at 200–220 ꢀC for 1 h in the
absence of any catalyst or solvent gave benzaldehyde
(26%), 2-nitrobenzenamine (50%), and 2-phenylbenzimid-
azole (48%).13 In addition, heating N-benzyl-2-nitrobenzen-
amine in a mixture of benzylamine and benzyl alcohol gave
2-phenylbenzimidazole in 60% yield.14
In contrast, annulation to form a benzimidazole has only
been reported in a single case using a ruthenium-catalyst
and N-allyl 2-nitrobenzenamine (1) as the substrate.8 Reac-
tion of 1 using triruthenium dodecacarbonyl (7 mol %) at
elevated temperature and carbon monoxide pressure gave
2-ethenylbenzimidazole 2 (Scheme 1). It is interesting to
note that both a higher yield of 2 and the formation of 2-
methylquinoxaline (3) were observed using cyclooctene as
the solvent.
The benzimidazole-forming reactions discussed above all
require relatively harsh reaction conditions. Based on the
relatively mild palladium-catalyzed N-heteroannulations to
give indoles recently developed in our laboratories, we at-
tempted to use similar reaction conditions for the formation
of benzimidazoles. In our initial experiment, N-2-(propen-
1-yl)benzenamine 5 was prepared by nucleophilic aromatic
substitution of methyl 2-bromo-3-nitrobenzoate with
Base mediated reactions of N-alkyl-, N-allyl- or N-benzyl-2-
nitroaromatic compounds to give2-substituted 1-hydroxy- or
1-alkoxybenzimidazoles have been reported in a number of
H
N
N
N
N
N
N
NaOEt
Ru3(CO)12, 170 °C
CO (60 atm)
45%
N
OH
NO2
H
4
1
In acetonitrile:
In cyclooctene:
2 (28%)
2 (42%)
3 (0%)
3 (14%)
Scheme 1.
* Corresponding author. Tel.: +1 304 293 3435x6434; fax: +1 304 293 4904; e-mail: bjorn.soderberg@mail.wvu.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.010

7078
J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
CO2Me
N
CO2Me
Br
MeO2C
H
N
H2N
87%
Pd(dba)2, dppp, CO (6 atm)
1,10-phenanthroline, 70 °C, 34%
N
H
NO2
NO2
5
6
Scheme 2.
Table 1. Optimization of the reactiona
O
O
N
Ru3(CO)12, dioxane
CO (40 atm), 200 °C, 9%
Entry
Catalyst
Ligands
Solvent
Pressure
(atm)
Yield of
26 (%)
N
N
NO2
1
2
3
4
5
6
7
8
Pd(dba)2
Pd(dba)2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
—
dppp/phen
phen
phen
phen
phen
phen
phen
dppp/phen
phen
phen
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
NMP
PhMe
6
6
6
1
3
10
14
14
20
6
20
59
28
19b
33
52
40
28
23
0d
Scheme 3.
1-amino-2-propene. Reductive N-heteroannulation of 5
gave the 2-ethenyl substituted benzimidazole 6 in 34% yield
(Scheme 2). To our knowledge, this represents only the third
case of a transition metal-catalyzed reductive annulation of
a nitrobenzene via the activation of the carbon–hydrogen
bond of an sp3-hybridized carbon. In addition to the single
case shown in Scheme 1, Watanabe et al. reported the
formation of 7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-
12(6H)-one albeit, in low isolated yield (Scheme 3).6
9
10
11
12
13
14
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
phen
phen
phen
phen
2c
6
6
6
0
26
30
34
a
The temperature was 120 ꢀC for all reactions.
2-Nitrobenzenamine of 22% was also isolated.
Argon was used in place of CO.
b
c
d
There are numerous methods for the preparation of 2-
substituted benzimidazoles. The two most utilized are
Philips synthesis involving a condensation of 1,2-diamino-
benzenes with carboxylic acids or acid derivatives in the
presence of an acid15 and oxidative condensations of 1,2-
diamines with aromatic aldehydes.16 Encouraged by the
result seen in Scheme 2, we decided to examine the scope
and limitation of the palladium-catalyzed formation of
2-substituted benzimidazoles from N-allyl- or N-benzyl-2-
nitrobenzenamines described in Scheme 2.
Compound 10 in 96% yield was recovered. dba¼bis(dibenzylidene)-
acetone; dppp¼bis(1,3-diphenylphosphino)propane; phen¼1,10-phenan-
throline.
that varying amounts of starting material (10) were obtained
in most cases. Unfortunately, we were unable to quantify the
amount of 10 since it co-elutes with bis(dibenzylidene)ace-
tone. In our initial reaction both bis(1,3-diphenylphosphi-
no)propane and 1,10-phenanthroline were used as ligands.
This combination has previously been successfully em-
ployed in the synthesis of 1,2-dihydro-4(3H)-carbazolones2h
and b-carbolines.3 However, for the transformation of 10 to
26 a much higher yield was realized using only 1,10-phenan-
throline as the ligand. Dimethyl formamide was shown to be
a better solvent compared to, for example, acetonitrile, N-
methylpyrrolidinone, and toluene (entries 2 and 12–14).
DMF has previously been found by Davies et al. to be opti-
mal for the cyclization of 2-nitro-1-alkenylarenes to give in-
doles.2e Palladium diacetate was examined as a catalyst but
did not perform as well (entry 3). It should be noted that re-
action of 10 in the absence of palladium bis(dibenzylidene-
acetone) resulted in a 96% recovery of the starting material
(entry 10). No reaction was observed replacing carbon mon-
oxide with an argon atmosphere (entry 11). A carbon mon-
oxide pressure of 6 atm was found to be optimal for this
catalyst system; lowering or raising the pressure only re-
sulted in diminishing yields (entries 4–9). In contrast to
the Ru3(CO)12 catalyst previously reported, we did not ob-
serve the formation of a quinoxaline under any reaction
conditions, including using cyclooctene as the solvent em-
ploying compound 1 or any of the substrates examined (cf.
Scheme 1). Reaction of 1 in cyclooctene resulted in quanti-
tative recovery of the starting material.
2. Results and discussion
In order to examine the palladium-catalyzed N-heteroannu-
lation to give benzimidazoles, a variety of N-allyl- or N-ben-
zyl-2-nitrobenzenamines were synthesized and the results of
these reactions are summarized in Table 2. The annulation
precursors were prepared by Buchwald–Hartwig type palla-
dium-catalyzed amination of 2-halo-1-nitroarenes (entries 1,
7, 9–12, and 17–19),17 reductive amination of 2-nitrobenz-
enamines with aldehydes (entries 6, 8, and 14),18 nucleo-
philic aromatic substitution using 2-halo-1-nitroarenes and
amines (entries 2, 3, and 15),19,20 or according to literature
procedures. Reactions forming either new compounds or
alternative methods for the preparation of previously pub-
lished compounds have yields reported in parenthesis in
Table 2.
N-Benzyl-2-nitrobenzenamine (10) was used as a model
substrate for the initial screening of the reaction conditions
(Table 1). This compound was selected since the product
2-phenyl-benzimidazole (26) is substantially more stable
compared to 2-ethenyl-benzimidazoles (such as 6). The lat-
ter compounds are very prone to polymerization.21 The
screening reactions were performed at 120 ꢀC for 20–24 h
in all cases, and the amount of product was determined after
purification by column chromatography. It should be noted
Using the conditions described above and with an array of
substrates in hand, the scope and limitation of the annulation

J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
Table 2. Synthesis and N-heterocyclization of N-benzyl-/N-allyl-2-nitroarenes
7079
Entry
Nitrobenzene
N-Substituted-2-nitroarenea,b
Benzimidazolea,b
Yield
H
N
N
I
1
1 (81%)
2 (46%)
N
H
NO2
NO2
MeO2C
N
MeO2C
Br
MeO2C
H
N
2
3
5 (87%)
7 (48%)
6 (74%)
N
H
NO2
NO2
H
H
N
N
O
O
H
N
24 (22%)
25 (54%)
N
N
H
NO2
MeO2C
Br
H
Ph
N
N
Ph
4
5
6
8c
N
H
NO2
NO2
H
N
d
9c
Ph
NO2
N
Br
H
N
10 (83%)
26 (83%)
27 (56%)
N
H
NO2
NO2
OMe
NO2
N
Br
H
N
OMe
7
11 (92%)
N
H
NO2
NO2
Br
H
N
d
8
9
12 (25%)
13 (74%)
NO2
NO2
MeO
Br
N
H
N
28 (76%)
29 (52%)
30 (60%)e
N
H
MeO
NO2
MeO
NO2
Me
N
Me
N
Br
10
14 (58%)
MeO
MeO
NO2
N
MeO
MeO
MeO
MeO
NO2
Me
N
Me
N
I
11
12
13
14
15 (54%)
16 (83%)
17c
NO2
N
NO2
H
N
d
Br
O2N
NO2
O2N
Cl
NO2
Cl
Cl
N
H
N
31 (64%)
31 (58%)
N
H
Cl
Cl
NO2
NH2
NO2
H
N
N
18 (35%)
N
H
NO2
(continued)

7080
J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
Table 2. (continued)
Entry
Nitrobenzene
N-Substituted-2-nitroarenea,b
Benzimidazolea,b
MeO2C
Yield
MeO2C
H
N
N
15
19 (79%)
32 (45%)
MeO2C
N
H
NO2
Br
H
N
NO2
N
d
16
17
20c
NO2
Br
N
N
33f
N
21 (85%)
22 (68%)
MeO
NO2
MeO
MeO
NO2
Br
N
N
N
34 (44%)
35 (83%)
18
NO2
NO2
N
N
I
19
23 (84%)
36 (61%)
N
N
N
NO2
NO2
a
See Section 3 for experimental details.
Isolated yields of pure compound in parenthesis.
Prepared according to a literature procedure.
No benzimidazole, starting material, or any other identified products were observed.
In addition, 28% of 15 was also isolated.
Approximately 90% pure; the yield was not calculated.
b
c
d
e
f
reaction was examined next. Relatively long reaction
times (2–8 d) were required for the reaction to go to
completion as monitored by TLC. All four N-allylated 2-
nitrobenzenamines examined underwent annulation to give
2-alkenyl-substituted benzimidazoles (Table 2, entries
1–4). N-Benzyl-2-nitroaminobenzene (10) and substrates
having a functionalized N-benzyl substituent all but one re-
acted to form benzimidazole derivatives (entries 6, 7, and
17–19). No identifiable products or starting materials were
obtained from the N-(4-nitrobenzyl) derivative (12, entry
8). It should be noted that N-4-nitrobenzyl-2-nitrobenzen-
amine (16) undergoes cyclization to give the corresponding
1-oxygenated benzimidazole under basic conditions de-
scribed in Scheme 1.22 Functional groups on the 2-nitro-
benzenamine ring were also tolerated including methoxy-,
chloro-, and carbomethoxy-groups. Although all starting
materials were consumed, no product was identified using
16 having an electron-withdrawing nitro group (entry 12),
or from reaction of the pyridine derivative 2023 (entry 16).
was observed (entries 10 and 11). When two different meth-
ylenes were present in the same molecule (22, entry 18),
only the benzylic methylene reacted to form the benzimid-
azole nucleus.
The mechanism of the N-heteroannulation to form benz-
imidazoles is presently unclear. A metal-bound nitrene fol-
lowed by carbon–hydrogen bond insertion was suggested
for the two ruthenium-catalyzed reactions seen in Schemes
1 and 2. Ruthenium,7,25 palladium,2k and selenium,26 in
the presence of carbon monoxide, have been shown to cata-
lyze the formation of 2-arylbenzimidazoles from the 2-nitro-
N-(phenylmethylene)benzenamine, the imine derived from
reaction of 2-nitrobenzenamine and benzaldehyde. Thus,
an oxidation of the amine to an imine (NH–CH2 to
N]CH) followed by cyclization was initially considered
as a possible reaction path. However, reaction of preformed
2-nitro-N-(phenylmethylene)benzenamine under our reac-
tion conditions did not produce the corresponding 2-phenyl-
benzimidazole (26) but only resulted in hydrolysis of the
imine back to the original starting materials. Another mech-
anistic possibility is a base mediated cyclization to form an
N-hydroxybenzimidazole followed by a palladium-cata-
lyzed deoxygenation. This does not appear to be the case
since no reaction is observed in the absence of palladium
and the starting material is recovered unchanged even after
prolonged reaction times. We were unable to identify any
It is evident from the examples in Table 2 that in order for
a methylene group to participate in the cyclization it must
be activated by an adjacent aryl or alkenyl group. For exam-
ple, N-(2-phenyl-1-ethyl)-2-nitrobenzenamine (9) did not
produce the expected 2-benzylbenzimidazole24 but pro-
duced minute quantities of a number of unidentified products
(entry 5). No reaction on the methyl group of either 14 or 15

J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
7081
intermediates by quenching the reaction prior to complete
consumption of the starting material. Only starting material
and product were observed.
mixture was stirred at ambient temperature (23 h). Concen-
trated sulfuric acid (5 drops) was added and three portions of
2-propen-1-ylamine (330 mL, 4.40 mmol) were added (im-
mediately, after 21.5 h, and after 24 h). The solution was
heated at 50 ꢀC for this entire period and for an additional
23 h after the last addition. The solvents were removed on
a rotary evaporator at water aspirator pressure and the resi-
due was purified by chromatography (hexanes/EtOAc, 9:1)
to give 5 (890 mg, 3.77, 87%) as a pale brown solid. Mp
In summary, we have developed a relatively mild and expe-
dient palladium-catalyzed synthesis of 2-alkenyl- or 2-aryl-
substituted benzimidazoles starting from readily available
N-allyl- or N-benzyl-2-nitrobenzenamines. The reaction in-
volves, at least formally, an unusual insertion into an sp3-
hybridized carbon–hydrogen bond. The reaction sequence
is flexible and a variety of functional groups are tolerated.
Although numerous methods for the preparation of benz-
imidazoles exist, the presented reaction may offer an advan-
tage when acid sensitive or oxidation prone functional
groups are present in the target molecule. Present studies
are focused on the synthesis of more complex polycyclic
benzimidazoles.
1
60–61 ꢀC; H NMR: d 8.56 (br s, 1H), 8.08 (dd, J¼7.2,
1.2 Hz, 1H), 7.97 (dd, J¼7.8, 1.8 Hz, 1H), 6.69 (t,
J¼7.8 Hz, 1H), 5.85–5.91 (m, 1H), 5.32 (d, J¼16.8 Hz,
1H), 5.22 (d, J¼10.2 Hz, 1H), 3.91 (s, 3H), 3.61 (s, 2H);
13C NMR: d 167.7, 145.3, 137.4, 136.9, 133.6, 131.5,
118.0, 116.8, 114.6, 52.4, 49.1; IR (neat): 1687, 1523,
1344, 1121 cmꢁ1; Anal. Calcd for C11H12N2O4: C, 55.93;
H, 5.12. Found: C, 56.05; H, 5.58; HRMS calcd for
C11H13N2O4 (M+H+): 237.0875, found: 237.0870.
3. Experimental section
3.1. General procedures
3.1.3. N-(2-Propen-1-yl) 2-(N-(2-propen-1-yl))amino-3-
nitrobenzamide (7). To a solution of 2-bromo-3-nitroben-
zoic acid (2.06 g, 8.37 mmol) in benzene (20 mL) at 0 ꢀC
was added oxalyl chloride (4.0 mL, 45.9 mmol) via syringe.
The resulting solution was stirred (0 ꢀC, 10 min, ambient
temperature, 1 h, and at reflux, 1 h), and the solvent and
excess reagents were removed. The crude product was
dissolved in benzene (20 mL), N-(2-propen-1-yl)amine
(2.0 mL, 26.7 mmol) in benzene (10 mL) was added via
pipette, and the resulting solution was stirred at ambient
temperature (68 h). The solvent was removed on a rotary
evaporator at water aspirator pressure and the crude product
was purified by chromatography (hexanes/EtOAc, 6:4) to
give 7 (1.05 g, 4.02 mmol, 48%) as a yellow solid followed
by N-(2-propen-1-yl) 2-bromo-3-nitrobenzamide (740 mg,
2.60, 31%) as a yellow solid. Data for 7: mp 59–60 ꢀC;
1H NMR: d 8.16 (dd, J¼9.0, 1.2 Hz, 1H), 7.76 (dd, J¼7.8,
1.2 Hz, 1H), 7.64 (br s, 1H), 6.85 (t, J¼7.8 Hz, 1H),
6.72 (br s, 1H), 5.96–5.84 (m, 2H), 5.29–5.25 (m, 2H),
5.23–5.18 (m, 2H), 4.07 (t, J¼6.0 Hz, 2H), 3.80 (t,
J¼6.0 Hz, 2H); 13C NMR: d 167.2, 143.7, 137.8, 136.4,
133.8, 133.4, 128.7, 126.6, 117.6, 117.5, 117.5, 50.6, 42.5;
IR (neat): 3311, 1637, 1488, 1270, 925 cmꢁ1; Anal. Calcd
for C13H15N3O3: C, 59.76; H, 5.79. Found: C, 59.43; H,
6.06.
All NMR spectra were determined in CDCl3 at 600 MHz (1H
NMR) and 150 MHz (13C NMR). The chemical shifts are
expressed in d values relative to Me4Si (0.00, H and 13C)
1
or CDCl3 (77.00, 13C) internal standards. Tetrahydrofuran
(THF) and diethyl ether were distilled from sodium benzo-
phenone ketyl prior to use. Toluene, hexanes, and EtOAc
were distilled from calcium hydride. Chemicals prepared ac-
cording to literature procedures have been footnoted the first
time used; all other reagents were obtained from commercial
sources and used as received. All reactions were performed
in oven-dried glassware under an argon atmosphere unless
otherwise stated. Solvents were removed from crude reac-
tion mixtures and products on a rotary evaporator at water
aspirator pressure. Melting points were determined on a
MelTemp and are uncorrected. Elemental analyses were
performed in the Department of Chemical Engineering,
College of Engineering and Mineral Resources, West
Virginia University.
3.1.1. N-(2-Propen-1-yl)-2-nitrophenylamine (1).
A
solution of 1-iodo-2-nitrobenzene (124 mg, 0.498 mmol),
N-(2-propen-1-yl)amine (50 mL, 0.666 mmol), palladium
diacetate (Pd(OAc)2, 11.7 mg, 0.052 mmol), 2,20-bis(di-
phenylphosphino)-1,10-binaphthyl (binap, 47.1 mg, 0.076
mmol), and cesium carbonate (228 mg, 0.700 mmol) in tol-
uene (6 mL) was stirred (30 min) under argon atmosphere
followed by heating at 80 ꢀC (44.75 h). The mixture was
cooled to ambient temperature, diluted with EtOAc
(6 mL), filtered (Celite), and the Celite was washed with
a few milliliter of EtOAc. The solvents were removed on
a rotary evaporator at water aspirator pressure and the crude
product was purified by column chromatography on silica
(hexanes/EtOAc, 9:1) to give 1 (72.2 mg, 0.405 mmol,
81%) as an orange oil. Analytical data are in complete agree-
ment with published values.20
3.1.4. N-Benzyl-2-nitrobenzenamine (10). To a solution of
2-nitrobenzenamine (300 mg, 2.17 mmol), benzaldehyde
(420 mL, 4.13), glacial acetic acid (750 mL, 13.1 mmol),
and dichloromethane (10 mL) was added sodium triacet-
oxyborohydride (1.29 g, 6.09 mmol) and the reaction mix-
ture was stirred at ambient temperature (90.5 h). Additional
benzaldehyde (210 mL, 2.06 mmol) was added and the solu-
tion was stirred at ambient temperature (28.75 h). Additional
sodium triacetoxyborohydride (648 mg, 3.06 mmol) was
added and the solution was stirred at ambient temperature
(23.5 h). The mixture was diluted with sodium bicarbonate
(aqueous 10 mL) and washed with EtOAc (4ꢂ10 mL). The
combined organic phases were dried (MgSO4), filtered,
and the solvents were removed on a rotary evaporator at
water aspirator pressure. The crude product was purified by
chromatography (hexanes then hexanes/EtOAc, 95:5) to
give 10 (409 mg, 1.80 mmol, 83%) as an orange solid. Mp
73–74 ꢀC (lit.27 72 ꢀC)
3.1.2. Methyl 3-nitro-2-(N-(2-propen-1-yl))aminobenzo-
ate (5). To a solution of methyl 2-bromo-3-nitrobenzoate
(1.12 g, 4.31 mmol) in dichloromethane (50 mL) was added
2-propen-1-ylamine (350 mL, 4.66 mmol) and the reaction

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J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
3.1.5. N-(4-Methoxybenzyl)-2-nitrobenzenamine (11). A
solution of 2-bromo-1-nitrobenzene (230 mg, 1.14 mmol),
4-methoxybenzylamine (170 mL, 1.31 mmol), Pd(OAc)2
(23.6 mg, 0.105 mmol), binap (94.0 mg, 0.151 mmol), and
cesium carbonate (460 mg, 1.41 mmol) in toluene (6 mL)
was reacted, as described for 1 (rt, 30 min; 80 ꢀC, 28.5 h),
to give after purification by chromatography (hexanes/
EtOAc, 9:1) 11 (270 mg, 1.05 mmol, 92%) as a yellow solid.
Mp 94–95 ꢀC (lit.28 81–82 ꢀC).
and chromatography (hexanes/EtOAc, 98:2) 15 (262 mg,
1
0.962 mmol, 54%) as a yellow solid. Mp 97–99 ꢀC; H
NMR: d 7.85 (d, J¼9.6 Hz, 1H), 7.32–7.22 (m, 5H), 6.45
(d, J¼1.8 Hz, 1H), 6.38 (dd, J¼9.6, 2.4 Hz, 1H), 4.33 (s,
2H), 3.74 (s, 3H), 2.74 (s, 3H); 13C NMR: d 163.4, 148.3,
136.8, 133.8, 128.9, 128.4, 127.4, 127.2, 105.0, 104.0,
58.5, 55.5, 40.3; IR (neat): 1613, 1567, 1501, 1450, 1415,
1216 cmꢁ1; Anal. Calcd for C15H16N2O3: C, 66.16; H,
5.92. Found: C, 65.94; H, 6.22.
3.1.6. N-4-Nitrobenzyl-2-nitrobenzenamine (12). A solu-
tion of 2-nitrobenzenamine (552 mg, 4.00 mmol), 4-nitro-
benzaldehyde (605 mg, 4.01 mmol), and benzene (50 mL)
was heated at reflux (110 ꢀC, 47 h followed by 130 ꢀC for
67 h) while removing water via a Dean–Stark trap. After
cooling to ambient temperature, dichloromethane (20 mL)
and sodium triacetoxyborohydride (2.37 g, 11.2 mmol)
were added and the reaction mixture was stirred at ambient
temperature (23.25 h). Workup as described for 10 gave
after chromatography (hexanes/EtOAc, 9:1) 12 (270 mg,
0.988 mmol, 25%) as a yellow solid. Mp 127–129 ꢀC
(lit.22 133–135 ꢀC).
3.1.10. N-Benzyl-2,4-dinitrobenzenamine (16). Reaction
of 1-bromo-2,4-dinitrobenzene (494 mg, 2.00 mmol), ben-
zylamine (290 mL, 2.66 mmol), Pd(OAc)2 (45.5 mg,
0.203 mmol), binap (197 mg, 0.316 mmol), and cesium car-
bonate (914 mg, 2.81 mmol) in toluene (6 mL), as described
for 1 (30 min at rt, 19.5 h at 80 ꢀC), gave after dilution,
filtration, and chromatography (hexanes/EtOAc, 9:1 then
8:2) 16 (454 mg, 1.66 mmol, 83%) as a yellow solid. Mp
115–117 ꢀC (lit.30 115–116 ꢀC).
3.1.11. N-Benzyl-5-chloro-2-nitrobenzenamine (18). 5-
Chloro-2-nitrobenzenamine (599 mg, 3.47 mmol), benzal-
dehyde (68 mL, 6.68 mmol), and acetic acid (1.2 mL, 21.0
mmol), in dichloromethane (20 mL) with sodium triacetoxy-
borohydride (2.07 g, 9.77 mmol), were reacted as described
for 7. Additional benzaldehyde (340 mL, 3.34 mmol, after
19.75 h), sodium triacetoxyborohydride (1.03 g, 4.86
mmol, after 20 h), benzaldehyde (340 mL, 3.34 mmol, after
26.5 h), and triacetoxyborohydride (1.03 g, 4.86 mmol, after
27 h) were added, and the reaction mixture was stirred for an
additional 20.25 h. Workup as described for 10 gave after
chromatography (hexanes then hexanes/EtOAc, 98:2) 18
(322 mg, 1.23 mmol, 35%) as an orange solid. Mp 96–
98 ꢀC (lit.31 100–101 ꢀC).
3.1.7. N-Benzyl-4-methoxy-2-nitrobenzenamine (13). Re-
action of 4-bromo-3-nitro-1-methoxybenzene (461 mg,
2.00 mmol), benzylamine (290 mL, 2.66 mmol), Pd(OAc)2
(45.1 mg, 0.201 mmol), binap (188 mg, 0.302 mmol), and
cesium carbonate (914 mg, 2.81 mmol) in toluene (6 mL),
as described for 1 (30 min at rt, 16.5 h at 80 ꢀC), gave after
dilution, filtration, and chromatography (hexanes then hex-
anes/EtOAc, 98:2) 13 (380 mg, 1.48 mmol, 74%) as a red
solid. Mp 104–105 ꢀC (lit.29 105–106 ꢀC); 1H NMR:
d 8.35 (br s, 1H), 7.65 (d, J¼2.4 Hz, 1H), 7.37–7.33 (m,
4H), 7.29 (t, J¼6.6 Hz, 1H), 7.08 (dd, J¼9.6, 3.0 Hz, 1H),
6.78 (d, J¼9.6 Hz, 1H), 4.54 (d, J¼5.4 Hz, 2H), 3.78 (s,
3H); 13C NMR: d 149.9, 141.1, 137.6, 131.4, 128.9, 127.6,
127.1, 127.0, 115.6, 107.3, 55.9, 47.3; IR (neat): 1569,
1515, 1281, 1031 cmꢁ1; Anal. Calcd for C14H14N2O3: C,
65.11; H, 5.46. Found: C, 65.01; H, 5.73.
3.1.12. Methyl 2-(N-benzylamino)-3-nitrobenzoate
(19).32 A solution of methyl 2-bromo-3-nitrobenzoate
(261 mg, 1.00 mmol) and benzylamine (230 mL, 2.11
mmol) in dichloromethane (10 mL) was stirred at ambient
temperature (23 h). Additional benzylamine (12 mL,
1.10 mmol) was added and the solution was stirred at ambi-
ent temperature (24 h). The solution was washed with so-
dium carbonate (4ꢂ10 mL) and then the organic phase
was dried (MgSO4), filtered, and the solvents were removed
on a rotary evaporator at water aspirator pressure. Purifica-
tion by chromatography (hexanes/EtOAc, 9:1) gave 19
(225 mg, 0.791 mmol, 79%) as a yellow solid. Mp 96–
97 ꢀC; 1H NMR: d 8.77 (br s, 1H), 8.09 (dd, J¼7.8,
1.8 Hz, 1H), 7.99 (dd, J¼8.4, 1.8 Hz, 1H), 7.34 (t,
J¼7.8 Hz, 2H), 7.30–7.28 (m, 3H), 6.71 (t, J¼7.8 Hz, 1H),
4.16 (d, J¼4.2 Hz, 2H), 3.88 (s, 3H); 13C NMR: d 167.7,
145.3, 137.6, 137.3, 136.9, 131.6, 128.9, 127.9, 127.9,
116.9, 114.7, 52.4, 51.0; IR (neat): 1699, 1577, 1490,
1259, 1105 cmꢁ1; Anal. Calcd for C15H14N2O4: C, 62.93;
H, 4.93. Found: C, 63.28; H, 5.30.
3.1.8. N-Benzyl-N-methyl-4-methoxy-2-nitrobenzen-
amine (14). A solution of 2-bromo-5-methoxy-1-nitro-
benzene (500 mg, 2.16 mmol), N-benzyl-N-methyl amine
(370 mL, 2.87 mmol), Pd(OAc)2 (49.3 mg, 0.220 mmol), bi-
nap (202 mg, 0.325 mmol), and cesium carbonate (984 mg,
3.02 mmol) in toluene (6 mL), as described for 1 (30 min at
rt, 19.75 h at 80 ꢀC), gave after dilution, filtration, and chro-
matography (hexanes/EtOAc, 95:5) 14 (340 mg, 1.25 mmol,
58%) as a dark red oil. 1H NMR: d 7.29–7.27 (m, 4H), 7.22–
7.20 (m, 2H), 7.11 (d, J¼9.6 Hz, 1H), 6.98 (dd, J¼9.0,
3.0 Hz, 1H), 4.14 (s, 2H), 3.73 (s, 3H), 2.64 (s, 3H); 13C
NMR: d 154.0, 143.9, 139.7, 137.5, 128.2, 128.0, 127.1,
123.4, 119.8, 109.0, 60.2, 55.6, 41.1; IR (neat): 1519,
1496, 1452, 1292, 1033, 863, 696 cmꢁ1; Anal. Calcd for
C15H16N2O3: C, 66.16; H, 5.92. Found: C, 66.31; H, 6.21.
3.1.9. N-Benzyl-(5-methoxy-2-nitrophenyl)-N-methyl-
amine (15). Reaction of 2-iodo-4-methoxy-1-nitrobenzene
(500 mg, 1.79 mmol), N-benzyl-N-methyl amine (300 mL,
2.33 mmol), Pd(OAc)2 (40.7 mg, 0.181 mmol), binap
(168 mg, 0.269 mmol), and cesium carbonate (819 mg,
2.51 mmol) in toluene (6 mL), as described for 1 (45.5 h at
80 ꢀC, 23.25 h at 120 ꢀC), gave after dilution, filtration,
3.1.13. 2-(4-Methoxy-2-nitrophenyl)-2,3-dihydro-1H-iso-
indole (21). Reaction of 2-bromo-5-methoxy-1-nitro-
benzene (375 mg, 1.62 mmol), isoindoline (255 mg, 2.14
mmol), Pd(OAc)2 (36.2 mg, 0.161 mmol), binap (151 mg,
0.242 mmol), and cesium carbonate (738 mg, 2.27 mmol)
in toluene (6 mL), as described for 1 (30 min at rt, 19.5 h
at 80 ꢀC) gave after dilution, filtration, and chromatography

J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
7083
(hexanes/EtOAc, 9:1) 21 (374 mg, 1.38 mmol, 85%) as a red
solid. Mp 103–104 ꢀC (lit.33 112 ꢀC).
Pd(dba)2 (34.8 mg, 0.061 mmol), and 1,10-phenanthroline
monohydrate (21.7 mg, 0.120 mmol) in DMF, (6 mL) as
described for 2 (CO, 120 ꢀC, 47 h), gave after extraction
and chromatography (hexanes/EtOAc, 6:4) 24 (50.1 mg,
0.221 mmol, 22%) as a 7:1 mixture of rotamers as a pale
3.1.14. 2-(2-Nitro-1-phenyl)-1,2,3,4-tetrahydroisoquino-
line (22). Reaction of 2-bromo-1-nitrobenzene (404 mg,
2.00 mmol), 1,2,3,4-tetrahydroisoquinoline (330 mL, 2.64
mmol), Pd(OAc)2 (45.5 mg, 0.203 mmol), binap (187 mg,
0.301 mmol), and cesium carbonate (915 mg, 2.81 mmol)
in toluene (6 mL), as described for 1 (6 h at rt, 40.75 h at
80 ꢀC), gave after dilution, filtration, and chromatography
(hexanes/EtOAc, 95:5) 22 (344 mg, 1.35 mmol, 68%) as
an orange solid. Mp 98–100 ꢀC (lit.34 100–102 ꢀC).
1
yellow solid. Mp 192–195 ꢀC; major rotamer: H NMR
(DMSO-d6): d 13.11 (br s, 1H), 9.91 (br s, 1H), 7.86 (d,
J¼7.8 Hz, 1H), 7.68 (d, J¼7.8 Hz, 1H), 7.33 (t, J¼7.8 Hz,
1H), 6.85 (dd, J¼18.0, 11.4 Hz, 1H), 6.38 (d, J¼14.4 Hz,
1H), 6.01 (10-line ddt, J¼17.4, 10.8, 5.4 Hz, 1H), 5.80 (d,
J¼11.4 Hz, 1H), 5.30 (dd, J¼17.4, 1.2 Hz, 1H), 5.15 (dd,
J¼10.2, 1.2 Hz, 1H), 4.09 (t, J¼5.4 Hz, 2H); 13C NMR:
d 164.3, 151.2, 140.8, 135.3, 134.5, 126.1, 122.8, 122.6,
122.5, 122.0, 115.0, 114.8, 41.1; IR (neat): 1637, 1610,
1554, 1429, 1251 cmꢁ1; Anal. Calcd for C13H13N2O: C,
68.70; H, 5.77. Found: C, 68.81; H, 6.01. Minor rotamer:
1H NMR (DMSO-d6): d 12.42 (br s, 1H), 8.81 (br s, 1H),
7.73 (t, J¼8.4 Hz, 2H), 7.22 (t, J¼7.8 Hz, 1H), 6.96 (dd,
J¼18.0, 11.4 Hz, 1H), 6.43 (d, J¼17.4 Hz, 1H), 5.60–5.92
(m, 1H), 5.62 (d, J¼11.4 Hz, 1H), 5.21 (d, J¼17.4 Hz,
1H), 5.11 (d, J¼10.2 Hz, 1H), 3.98 (br s, 2H).
3.1.15. 2-(2-Nitrophenyl)-2,3-dihydro-1H-benzo[de]-
isoquinoline (23). Reaction of 2-iodonitrobenzene
(124 mg, 0.498 mmol), 2,3-dihydro-1H-benzo[de]isoquino-
line (109 mg, 0.644 mmol), Pd(OAc)2 (11.8 mg, 0.053
mmol), binap (46.7 mg, 0.075 mmol), and cesium carbonate
(229 mg, 0.703 mmol) in toluene (6 mL), as described for 1
(30 min at rt, 91.25 h at 80 ꢀC), gave after dilution, filtration,
and chromatography (hexanes/EtOAc, 6:4) 23 (121 mg,
1
0.417 mmol, 84%) as a yellow solid. Mp 104–108 ꢀC; H
NMR: d 7.77 (d, J¼7.8 Hz, 1H), 7.71 (d, J¼8.4 Hz, 2 h),
7.41 (t, J¼7.8 Hz, 2H), 7.31 (t, J¼8.4 Hz, 1H), 7.21 (d,
J¼6.6 Hz, 2H), 7.14 (d, J¼9.0 Hz, 1H), 6.96 (t, J¼7.8 Hz,
1H), 4.63 (s, 4H); 13C NMR: d 145.3, 143.3, 133.4, 132.1,
128.0, 126.6, 126.0, 125.8, 121.8, 121.7, 121.7, 55.2; IR
(neat): 1602, 1520, 1355, 1214, 802, 752 cmꢁ1; Anal. Calcd
for C18H14N2O2: C, 74.47; H, 4.86. Found: C, 74.23; H, 5.23.
3.1.19. 2-(2-Phenyl-1-ethenyl)-1H-benzimidazole (25).
Reaction of 8 (267 mg, 1.05 mmol),35 Pd(dba)2 (37.0 mg,
0.064 mmol), and 1,10-phenanthroline monohydrate
(22.8 mg, 0.127 mmol) in DMF (6 mL), as described for 2
(CO, 120 ꢀC, 92.75 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 6:4) 25 (126 mg, 0.570 mmol,
54%) as a yellow-brown solid. Mp 202–204 ꢀC (lit.36 201–
202 ꢀC).
3.1.16. 2-Ethenyl-1H-benzimidazole (2). To a threaded
ACE Glass pressure tube were added 1 (72.2 mg, 0.405
mmol), bis(dibenzylideneacetone)palladium (Pd(dba)2,
14.1 mg, 0.025 mmol), and 1,10-phenanthroline monohy-
drate (8.40 mg, 0.047 mmol) in DMF (6 mL). The tube was
fitted with apressure head and after thesolution was saturated
with CO (four cycles to 6 atm of CO) the reaction mixture
was heated at 120 ꢀC under CO (6 atm, 47 h). The mixture
was diluted with EtOAc (10 mL) and washed with water
(4ꢂ10 mL). The combined organic phases were dried
(MgSO4), filtered, and the solvents were removed on a rotary
evaporator at water aspirator pressure. Purification by
chromatography (hexanes/EtOAc, 2:8) gave 2 (27.1 mg,
0.188 mmol, 46%) as a pale brown solid. Mp 149–153 ꢀC
(lit.21b 184 ꢀC).
3.1.20. 2-Phenyl-1H-benzimidazole (26). Reaction of 10
(114 mg, 0.502 mmol), Pd(dba)2 (17.7 mg, 0.031 mmol),
and
1,10-phenanthroline
monohydrate
(10.4 mg,
0.058 mmol) and DMF (6 mL), as described for 2 (CO,
120 ꢀC, 139.75 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 9:1) 26 (80.7 mg, 0.416 mmol,
83%) as a white solid. Mp 302–303 ꢀC (lit.37,38 285–
286 ꢀC).
3.1.21. 2-(4-Methoxyphenyl)-1H-benzimidazole (27). Re-
action of 11 (250 mg, 0.968 mmol), Pd(dba)2 (33.7 mg,
0.059 mmol), and 1,10-phenanthroline monohydrate
(21.3 mg, 0.118 mmol) in DMF (6 mL), as described for 2
(CO, 120 ꢀC, 65.5 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, in order 8:2, 1:1) 27 (121 mg,
0.540 mmol, 56%) as a pale brown solid. Mp 222–225 ꢀC
(lit.37 222–225 ꢀC).
3.1.17. Methyl 2-ethenyl-1H-benzimidazole-4-carboxyl-
ate (6). Reaction of 5 (37.8 mg, 0.160 mmol), Pd(dba)2
(7.30 mg, 0.013 mmol), and 1,10-phenanthroline monohy-
drate (4.0 mg, 0.022 mmol) in DMF (6 mL), as described
for 2 (CO, 120 ꢀC, 70.5 h), gave after extraction and chroma-
tography (hexanes/EtOAc, 7:3) 6 (24.1 mg, 0.119 mmol,
3.1.22. 5-Methoxy-2-phenyl-1H-benzimidazole (28). Re-
action of 13 (128 mg, 0.498 mmol), (Pd)dba)2 (17.7 mg,
0.031 mmol), 1,10-phenanthroline monohydrate (10.7 mg,
0.060 mmol) in DMF (6 mL), as described for 2 (CO,
120 ꢀC, 193.75 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 7:3) 28 (85.5 mg, 0.378 mmol,
76%) as a faint yellow solid. Mp 142–143 ꢀC (lit.39 143–
144 ꢀC).
1
74%) as a red solid. Mp 64–71 ꢀC; H NMR: d 7.94 (dd,
J¼7.8, 0.6 Hz, 1H), 7.88 (dd, J¼7.8, 1.2 Hz, 1H), 7.29 (t,
J¼7.8 Hz, 1H), 6.85 (dd, J¼18.0, 11.4 Hz, 1H), 6.26 (d, J¼
18.0 Hz, 1H), 5.73 (d, J¼11.4 Hz, 1H), 3.98 (s, 3H); 13C
NMR: d 167.0, 151.3, 144.5, 134.4, 126.1, 125.0, 125.0,
121.9, 121.7, 113.2, 52.1; IR (neat): 1702, 1431, 1291,
1137, 931 cmꢁ1; HRMS calcd for C11H11N2O2 (M+H+):
203.0821, found: 203.0815.
3.1.23. 5-Methoxy-1-methyl-2-phenyl-1H-benzimidazole
(29). Reaction of 14 (136 mg, 0.499 mmol), Pd(dba)2
(17.8 mg, 0.031 mmol), and 1,10-phenanthroline monohy-
drate (10.9 mg, 0.061 mmol) in DMF (6 mL), as described
for 2 (CO, 120 ꢀC, 67.75 h), gave after extraction and
3.1.18. N-(2-Propen-1-yl) 2-ethenyl-1H-benzimidazole-4-
carboxamide (24). Reaction of 7 (261 mg, 1.00 mmol),

7084
J. W. Hubbard et al. / Tetrahedron 63 (2007) 7077–7085
chromatography (hexanes/EtOAc, 9:1 then 1:1) 29
(61.4 mg, 0.258 mmol, 52%) as a white solid.40 Mp 123–
126 ꢀC; 1H NMR: d 7.75 (d, J¼7.8 Hz, 2H), 7.53–7.48 (m,
3H), 7.30 (s, 1H), 7.27 (d, J¼9.0 Hz, 1H), 6.98 (d,
J¼8.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR:
d 156.4, 153.9, 143.6, 131.3, 130.2, 129.6, 129.3, 128.6,
112.8, 110.0, 101.9, 55.8, 31.7; IR (neat): 1467, 1158,
1025, 833, 803, 770 cmꢁ1; Anal. Calcd for C15H14N2O: C,
75.61; H, 5.92. Found: C, 75.49; H, 6.42; HRMS calcd for
C15H15N2O (M+H+): 239.1184, found: 239.1179.
(15.1 mg, 0.026 mmol), and 1,10-phenanthroline monohy-
drate (8.9 mg, 0.050 mmol) in DMF (6 mL), as described
for 2 (CO, 120 ꢀC, 76 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 7:3) 33 (34.3 mg, approximately
90% pure by 1H NMR).43 Spectral data from impure 33: 1H
NMR: d 7.96 (d, J¼7.2 Hz, 1H), 7.49 (d, J¼7.2 Hz, 1H),
7.46 (t, J¼7.2 Hz, 1H), 7.41 (dt, J¼7.2, 1.2 Hz, 1H), 7.26
(d, J¼2.4 Hz, 1H), 7.24 (dd, J¼7.2, 1.8 Hz, 1H), 6.87 (dd,
J¼6.6, 1.8 Hz, 1H), 4.91 (s, 2H), 3.84 (s, 3H); 13C NMR:
d 158.7, 156.1, 149.1, 143.3, 129.4, 129.2, 128.6, 127.3,
123.9, 121.7, 112.6, 109.8, 103.2, 55.8, 47.3; HRMS calcd
for C15H13N2O (M+H+): 237.1028, found: 237.1023.
3.1.24. 6-Methoxy-1-methyl-2-phenyl-1H-benzimidazole
(30). Reaction of 15 (134 mg, 0.492 mmol), Pd(dba)2
(17.4 mg, 0.030 mmol), and 1,10-phenanthroline monohy-
drate (10.6 mg, 0.059 mmol) in DMF (6 mL), as described
for 2 (CO, 120 ꢀC, 115.5 h), gave after extraction and chro-
matography (hexanes/EtOAc, in order 9:1, 7:3, 3:7) 15
(38.1 mg, 0.140 mmol, 28%) followed by 30 (70.6 mg,
3.1.28. 5,6-Dihydrobenz[4,5]imidazo[2,1-a]isoquinoline
(34) and benz[4,5]imidazo[2,1-a]isoquinoline (35). Reac-
tion of 22 (127 mg, 0.499 mmol), Pd(dba)2 (17.3 mg,
0.030 mmol), and 1,10-phenanthroline monohydrate
(11.1 mg, 0.062 mmol) in DMF (6 mL), as described for 2
(CO, 120 ꢀC, 67.5 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 9:1) 35 (6.6 mg, 0.030 mmol,
6%) as a pale yellow solid followed by 34 (48.9 mg,
0.222 mmol, 44%) as a pale brown solid.40 Data for 35:
mp 107–108 ꢀC (lit.44,45 129–130 ꢀC). Data for 34: mp
148–149 ꢀC; 1H NMR: d 8.30 (dd, J¼7.8, 1.8 Hz, 1H),
7.84–7.81 (m, 1H), 7.42–7.34 (m, 3H), 7.31–7.25 (m, 3H),
4.32 (t, J¼7.2 Hz, 2H), 3.27 (t, J¼7.2 Hz, 2H); 13C NMR:
d 149.1, 144.0, 134.7, 134.2, 130.1, 128.0, 127.7, 126.7,
125.6, 122.6, 122.4, 119.8, 109.0, 40.4, 28.2; IR (neat):
1482, 1448, 1326, 775, 734 cmꢁ1; Anal. Calcd for
C15H12N2: C, 81.79; H, 5.49. Found: C, 81.49; H, 5.92.
1
0.296 mmol, 60%) as a white solid. Mp 145–147 ꢀC; H
NMR: d 7.70 (t, J¼7.2 Hz, 3H), 7.48–7.43 (m, 3H), 6.93
(dd, J¼9.0, 2.4 Hz, 1H), 6.78 (s, 1H), 3.85 (s, 3H), 3.74 (s,
3H); 13C NMR: d 156.6, 152.8, 137.3, 130.2, 129.3, 129.1,
128.5, 120.1, 111.5, 93.1, 55.7, 31.5; IR (neat): 1462,
1216, 1084, 1023, 809 cmꢁ1; Anal. Calcd for C15H14N2O:
C, 75.61; H, 5.92. Found: C, 75.38; H, 6.43. HRMS calcd
for C15H15N2O (M+H+): 239.1184, found: 239.1179.
3.1.25. 5-Chloro-2-phenyl-1H-benzimidazole (31). Reac-
tion of N-benzyl-4-chloro-2-nitrobenzenamine (17)41
(131 mg, 0.499 mmol), Pd(dba)2 (17.2 mg, 0.030 mmol),
and 1,10-phenanthroline monohydrate (11.0 mg, 0.061
mmol) in DMF (6 mL), as described for 2 (CO, 120 ꢀC,
46.5 h), gave after extraction and chromatography (hex-
anes/EtOAc, 9:1 then 1:1) 31 (72.9 mg, 0.319 mmol,
64%) as a pale brown solid. Mp 210–212 ꢀC (lit.37 206–
210 ꢀC).
3.1.29. 7H-Benzimidazo[2,1-a]benz[de]isoquinoline (36).
Reaction of 23 (102 mg, 0.351 mmol), Pd(dba)2 (11.3 mg,
0.020 mmol), and 1,10-phenanthroline monohydrate
(8.0 mg, 0.044 mmol) in DMF (6 mL), as described above
for 2 (CO, 120 ꢀC, 112 h), gave after extraction and chroma-
tography (hexanes/EtOAc, 7:3 then 1:1) 36 (54.9 mg,
0.214 mmol, 61%) as a yellow solid. Mp 210–212 ꢀC
(lit.46 212–213 ꢀC).
Alternative procedure: reaction of 18 (131 mg,
0.499 mmol), Pd(dba)2 (18.0 mg, 0.031 mmol), and 1,10-
phenanthroline monohydrate (11.6 mg, 0.064 mmol) in
DMF (6 mL), as described for 2 (CO, 120 ꢀC, 74 h), gave
after extraction and chromatography (hexanes/EtOAc, 1:1)
31 (67.4 mg, 0.295 mmol, 59%) as a pale brown solid.
Acknowledgements
This work was supported by a research grant from the
National Institute of General Medical Sciences, National
Institutes of Health (R01 GM57416) and the Donors of the
American Chemical Society Petroleum Research Fund
(40665-AC1). NSF-EPSCoR (Grant #1002165R) is grate-
fully acknowledged for the funding of a 600 MHz Varian In-
ova NMR and an LTQ-FT Mass Spectrometer and the NMR
and MS facilities in the C. Eugene Bennett Department of
Chemistry at West Virginia University.
3.1.26. Methyl 2-phenyl-1H-benzimidazole-4-carboxyl-
ate (32). Reaction of 19 (143 mg, 0.503 mmol), Pd(dba)2
(17.6 mg, 0.031 mmol), and 1,10-phenanthroline monohy-
drate (11.0 mg, 0.061 mmol) in DMF (6 mL), as described
for 2 (CO, 120 ꢀC, 139.5 h), gave after extraction and chro-
matography (hexanes/EtOAc, 9:1 then 7:3) 32 (56.7 mg,
0.225 mmol, 45%) as a pale brown solid. Mp 123–126 ꢀC
(lit.42 125–127 ꢀC).
Alternative method: reaction of 19 (99.3 mg, 0.349 mmol),
Pd(dba)2 (12.6 mg, 0.022 mmol), 1,10-phenanthroline
monohydrate (7.8 mg, 0.043 mmol), and 1,3-bis(diphenyl-
phosphino)propane (8.9 mg, 0.022 mmol) in DMF (5 mL),
as described for 2 (CO, 120 ꢀC, 138.5 h), gave after extrac-
tion and chromatography (hexanes/EtOAc, 9:1 then 7:3) 32
(47.4 mg, 0.188 mmol, 54%) as a pale brown solid.
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