Synthesis of 2-alkyl-substituted benzimidazoles by thermal decomposition of 2-azidobenzenamines in the presence of an aldehyde

Article abstract of DOI:10.1080/00397910600941497

2-Substituted benzimidazoles were prepared by reaction of 2-azidoaminobenzenes with aldehydes under thermal conditions. The reaction probably proceeds via a sequential imine formation, azide decomposition forming a nitrene, and electrocyclization. Copyright Taylor & Francis Group, LLC.

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Synthesis of 2‐Alkyl‐Substituted
Benzimidazoles by Thermal Decomposition of
2‐Azidobenzenamines in thePresence of an
Aldehyde
Jeffery M. Wallace a , Björn C. G. Söderberg a & Jeremiah W. Hubbard a
a C. Eugene Bennett Department of Chemistry, West Virginia University,
Morgantown, West Virigina, USA
Published online: 23 Nov 2006.
To cite this article: Jeffery M. Wallace , Bjrn C. G. Sderberg & Jeremiah W. Hubbard (2006) Synthesis of
2‐Alkyl‐Substituted Benzimidazoles by Thermal Decomposition of 2‐Azidobenzenamines in thePresence of an
Aldehyde, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 36:22, 3425-3439, DOI: 10.1080/00397910600941497
To link to this article: http://dx.doi.org/10.1080/00397910600941497
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Synthetic Communicationsw, 36: 3425–3439, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941497
Synthesis of 2-Alkyl-Substituted
Benzimidazoles by Thermal Decomposition
of 2-Azidobenzenamines in the
Presence of an Aldehyde
¨
¨
Jeffery M. Wallace, Bjorn C. G. Soderberg,
and Jeremiah W. Hubbard
C. Eugene Bennett Department of Chemistry, West Virginia University,
Morgantown, West Virigina, USA
Abstract: 2-Substituted benzimidazoles were prepared by reaction of 2-azidoamino-
benzenes with aldehydes under thermal conditions. The reaction probably proceeds
via a sequential imine formation, azide decomposition forming a nitrene, and
electrocyclization.
Keywords: Alkaloids, azide, benzimidazole, nitrene
INTRODUCTION
Thermal decomposition of organic azides is known to produce highly reactive
nitrene intermediates. The nitrenes subsequently undergo a variety of
reactions including carbon-hydrogen bond insertions and electrocyclic
reactions forming nitrogen-containing heterocycles.[1] Thermolysis of
imines formed from 2-azidobenzenamines and aromatic aldehydes has been
shown to produce 2-aryl-substituted benzimidazoles.[2,3] In a related
fashion, indazoles, indoles, and triazoles are formed from 2-azidobenzalde-
hyde imines,[4,5] 2-azidostyrenes, and 2-azidophenylazo compounds, respect-
ively.[6] An example of a thermal decomposition of a 2-azidobenzeneamine
Received in USA March 15, 2006
¨
¨
Address correspondence to Bjorn C. G. Soderberg, C. Eugene Bennett Department
of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA. E-mail:
bjorn.soderberg@mail.wvu.edu
3425

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3426
Scheme 1.
imine is shown in Scheme 1. Thus, reaction of 1 in a refluxing mixture
of HOAc–ethanol furnished benzimidazole 2 in excellent yield. No
examples of substituted 2-azidobenzenamines or the use of aliphatic
aldehydes were reported by the authors.[2] To the best of our knowledge,
only the imine formed from reaction of 2-azidobenzenamine with 2,2-diphe-
nylethanal has been isolated.[3] However, thermal decomposition of this imine
failed to furnish the expected benzimidazole. The absence of additional
examples of aliphatic aldehydes is probably a reflection of the instability of
the corresponding imines.
We have previously reported a synthesis of enamines via reaction of
2-nitrobenzenamines with aliphatic aldehydes in the presence of molecular
sieves. The isolated enamines were cyclized using a palladium-catalyzed
reductive N-heteroannulation to give quinoxaline derivatives.[7] In an effort
to probe the mechanism of the latter reaction, attempts were made to
prepare the corresponding enamines derived from 2-azidobenzenamines.
However, a complex mixture of products, in addition to starting material,
was isolated using molecular sieves. Employing the conditions used to
prepare the imines discussed in the preceding paragraph, we isolated benzimi-
dazole 4, in 61% yield, from reaction of 2-azido-4-chlorobenzenamine (3)
with 2-methylpropanal (Scheme 2). The benzimidazole is probably derived
from a sequential imine formation–thermal nitrene formation–electrocycliza-
tion. This result is surprising in light of previously reported difficulties with
the imine formation from aliphatic aldehydes, and that formation of benzimi-
dazoles from 2-azidobenzenamine imines was observed at substantially higher
reaction temperatures, 130–1408C.
Scheme 2.

2-Alkyl-Substituted Benzimidazoles
3427
2-Substituted benzimidazoles are usually prepared from reaction of
1,2-diaminobenzenes with aldehydes,[8] carboxylic acids, esters, or amides
under a variety of conditions.[9–11] Some more recently developed method-
ologies include a titanium dioxide–mediated photochemically promoted
reaction of 1,2-dinitroaryls with alcohol solvents,[12] zinc[13]—or
indium[14]—2-bromo-2-nitropropane mediated reductive cyclizations of
2-nitrobenzenamine-derived aromatic imines, palladium-catalyzed intramole-
cular amination of amidines derived from 2-halobenzenamines,[15] palladium-
catalyzed reaction of 1,2-diaminobenzenes with aromatic iodides in the
presence of carbon monoxide,[16] and cobalt-catalyzed direct 2-arylation of
benzimidazole,[17] to name only a few.
Based on our initial result, described here is a relatively mild route to
2-substituted benzimidazoles via a sequential in situ imine formation–
thermal nitrene formation–electrocyclization.
RESULTS AND DISCUSSION
The 2-azidobenzenamines (8–13) required for the cyclizations were
prepared according to the procedure of Hall and Patterson or by slight modi-
fications thereof.[18] The general synthetic sequence is outlined in Scheme 3
for the preparation of the novel 3-azido-2-aminopyridine (8). Thus, reaction
of 2-amino-3-nitropyridine with phthaloyl chloride gave 5 in excellent
yield. The nitro group was reduced to an amine (6), and the amine was
further transformed to an azide (7) via the corresponding diazonium salt.
The phthalimido group was removed using hydrazine to give the expected
2-azidobenzenamine 8.
Scheme 3.

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3428
The isolated 2-azidobenzenamines were reacted with a selection of
aliphatic and aromatic aldehydes, and the results are summarized in
Table 1. In a typical experiment, an ethanol solution containing the azide
and a slight excess (20%) of the aldehyde was heated at reflux for 24 h. The
crude product mixtures were purified by chromatography on silica gel using
gradient elution. A number of colored streaking bands were observed, but
no other products were identified apart from those discussed in the subsequent
paragraphs. Initially, HOAc was added to the reaction mixture but it was later
shown to afford slightly lower yield of products from aliphatic aldehydes. For
example, reaction of 2-azido-5-chlorobenzenamine (9) with 2-methylpropanal
gave the expected benzimidazole 15 in 76% in the absence and in 67% in the
presence of HOAc (entry 1).
Thermal decomposition of the 2-azidobenzenamines, occurring at ca.
658C for the parent compound[3] prior to condensation, and the relatively
slow condensation to form the imines are two factors negatively affecting
the yield of benzimidazole. Benzimidazoles derived from formal loss of the
2-substituent were observed in some cases (entries 1, 4, 10, 11). This was
particularly pronounced using 2-phenylethanal where the major product
obtained was 5-methylbenzimidazole (26) and not the expected 2-benzyl-5-
methylbenzimidazole (25). The ratio of 25 to 26 was increased slightly
from 1 : 4 to 2 : 3 in the presence of added HOAc, but the overall yield
remained the same. It is presently unclear how the alkyl group is lost during
the reaction. Attempts to trap radical intermediate using 1,4-cyclohexadiene
failed to provide any additional information regarding the mechanism (entry 11).
For the methoxy-substituted aminoazide 13, the starting material decom-
posed rapidly as evidenced by a color change from yellow to dark brown. This
does not appear to be a light-driven process because the same color change
was observed after carefully wrapping the reaction vessel with aluminum
foil prior to addition of solvent and the aldehyde. An almost identical yield
of benzimidazole was realized in the absence of light.
For the successful examples in the two previously published studies,[2,3]
the overall yield of benzimidazole starting from 2-azidoaminobenzene
ranged from 24 to 84%. The present one-pot methodology affords 2-substi-
tuted benzimidazoles in similar yields and compares favorably in some
cases. The yield of 2-phenyl-substituted benzimidazole 22 was the highest,
substantially higher compared to related literature examples. Furfural has pre-
viously been reported to fail to form an imine with 2-azidobenzeneamines.[3]
In contrast, a 37% yield of 2-(2-furyl)-5-methylbenzimidazole (30) was
realized using our one-pot procedure presumably via the corresponding
imine (entry 16). Aza-benzimidazoles (imidazopyridines) are also of
synthetic interest. However, reaction of 2-amino-3-azidopyridine (8) with
2-methylpropanal gave a very disappointing yield of the expected 3-azabenzi-
midazole (entry 17). The major product was 2,3-diaminopyridine (32),
obtained from reduction of the starting material. Related reductions of
aromatic azides under acidic conditions have been reported.[19–21]

Table 1. Formation of 2-alkyl-substituted benzimidazoles
Entrya
Azideb
Aldehyde
Benzimidazole (s)c
1
2
3
4
5
9, R ¼ 5-Cl
10, R ¼ 4-Cl
11, R ¼ 4-Me
12, R ¼ 6-Me
13, R ¼ 4-OMe
15, R ¼ 5-Cl (76%, 67%)
16 (6%)d
19 (8%)
15, R ¼ 5-Cl (66%, 61%)
17, R ¼ 5-Me (71%, 50%)
18, R ¼ 4-Me (69%)
20, R ¼ 5-OMe (44%)
R0CHO
6
7
10
10
R0 ¼ C6H13
21 (63%, 64%)
22 (82%)d
R0 ¼ Ph
R0CHO
8
9
11
R0 ¼ n-C6H13
R0 ¼ n-C16H33
23 (75%, 46%)
24 (67%)
(continued)

Table 1. Continued
Entrya
Azideb
Aldehyde
Benzimidazole (s)c
10
11
12
13
14
15
16
R0 ¼ PhCH2
R0 ¼ PhCH2
R0 ¼ Me
25 (10%, 19%)
25 (27%)e
27 (33%)
26 (40%, 30%)
26 (27%)
R0 ¼ t-Bu
28 (25%)
26 (18%)
R0 ¼ H
R0 ¼ MeCH ¼ CH
R0 ¼ 2-furyl
29 (14%)
30 (37%, 54%f)
17
8
31 (7%)
32 (33%)
aFor reaction conditions and details see the experimental section.
bThe compounds are numbered from the amino group having the azido group in the 2-position.
cIsolated yields of pure products. The second yield in the parentheses corresponds to reactions with added HOAc.
dIn the presence of HOAc.
eWith HOAc and 2 equiv. of 1,4-cyclohexadiene.
fWith HOAc and 3 equiv. of aldehyde.

2-Alkyl-Substituted Benzimidazoles
3431
Scheme 4.
As a final example, reaction of cyclopropylethanal, prepared in situ by
pyridinium chlorochromate (PCC) oxidation of cyclopropylethanol, with 11
furnished the cyclopropylmethyl-substituted benzimidazole 33 in low yield
(Scheme 4).
In conclusion, a simple methodology for the preparation of 2-alkylbenzi-
midazoles via reaction of 2-azidobenzenamines with aldehydes has been
developed.
EXPERIMENTAL
All NMR spectra were determined in CDCl3 at 270 or 600 MHz (1H NMR)
and at 67.5 or 150 MHz (13C NMR) unless otherwise indicated. The
1
chemical shifts are expressed in d values relative to Me4Si (0.0 ppm, H
and 13C) or CDCl3 (77.0 ppm, 13C) internal standards. 1H-1H coupling
constants are reported as calculated from spectra; thus a slight difference
between Ja,b and Jb,a is usually obtained. Results of APT (attached proton
test) and 13C NMR experiments are shown in parentheses where, relative to
CDCl3, (2) denotes CH3 or CH and (þ) denotes CH2 or C.
Tetrahydrofuran (THF) and diethyl ether were distilled from sodium
benzophenone ketyl prior to use. Toluene, pyridine, hexanes, and ethyl
acetate were distilled from calcium hydride. Chemicals prepared according
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 under an argon atmosphere in oven-dried
glassware unless otherwise stated. Solvents were removed from reaction
mixtures and products on a rotary evaporator at water aspirator pressure.
Chromatography was performed on silica gel 60 (35–75 mm, VWR). High
resolution mass spectra (HRMS) were performed at University of California
Riverside Mass Spectrometry Center. Elemental analyses were performed in
the Department of Chemical Engineering, College of Engineering and
Mineral Resources, West Virginia University.
3-Nitro-2-phthalimidopyridine (5). To a refluxing solution of phthaloyl
chloride (4.0 mL, 27.7 mmol) in toluene (50 mL), a solution of 2-amino-3-
nitropyridine (3.00 g, 21.6 mmol) and pyridine (6.0 mL, 74.2 mmol) in

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3432
toluene (50 mL) was added dropwise. The reaction was stirred at reflux
for 42 h. The resulting mixture was filtered while hot through an oven-
heated fritted funnel, and the solvent was removed under reduced pressure.
Recrystallization of the crude product from acetic acid gave 5 (5.56 g,
1
20.7 mmol, 96%) as a yellow solid. Mp 171–1738C; H NMR (270 MHz) d
8.94 (dd, J ¼ 4.9 and 1.7 Hz, 1H), 8.56 (dd, J ¼ 8.2 and 1.5 Hz, 1H), 8.03–
7.98 (m, 2H), 7.90–7.80 (m, 2H), 7.65 (dd, J ¼ 8.2 and 4.7 Hz, 1H); 13C
NMR (67.5 MHz) d 165.5 (þ), 153.3 (2), 142.5 (þ), 139.1 (þ), 134.9
(2), 134.5 (2), 131.7 (þ), 124.6 (2), 124.3 (2); IR (neat) 1786, 1735,
1592, 1541, 1355 cm21; HRMS (DCI, NH3) calcd. for C13H8N3O4 (MHþ)
270.0515, found 270.0524; anal. cald. for C13H7N3O4: C, 58.00; H, 2.62.
Found: C, 57.60; H, 2.56.
3-Amino-2-phthalimidopyridine (6). Compound 5 (3.50 g, 12.9 mmol),
Pd/C (700 mg, 10% Pd), and ethanol (50 mL) were combined in a threaded
pressure tube fitted with a Teflonw cap attached to a hydrogenation
apparatus. The tube was flushed three times with hydrogen gas. The reaction
flask was pressurized with hydrogen gas (4 atm) and stirred at 608C for
15 h. After releasing the pressure, the open flask was heated gently to
dissolve the solid product. The hot solution was filtered through an oven-
heated fritted funnel packed with Celitew and washed with hot ethyl acetate.
The solvent was removed at reduced pressure, and the crude residue was recrys-
tallized from ethanol to give 6 (1.50 g, 6.4 mmol, 50%) as a yellow solid. Mp
204–2068C; 1H NMR (270 MHz) d 8.10 (t, J ¼ 3.0 Hz, 1H), 8.00–7.93
(m, 2H), 7.83–7.77 (m, 2 H), 7.23 (d, J ¼ 3.2 Hz, 2H), 3.85 (br s, 2H); 13C
NMR (67.5 MHz) d 166.9 (þ), 140.0 (þ), 139.8 (2), 134.5 (2), 132.8 (þ),
132.1 (þ), 125.5 (2), 125.3 (2), 124.0 (2); IR (neat) 3434, 1716, 1469,
1377 cm21; HRMS (EI) calc. for C13H9N3O2 239.0695; found 239.0703.
3-Azido-2-phthalamidopyridine (7). To a solution of 6 (1.50 g, 6.06 mmol)
in H2O (60 mL) at 08C, HCl (conc., 15 mL) was added. Small amounts of ice
were added periodically to keep the solution at 08C. The solution of the
formed amine hydrochloride was stirred for 5 min. Sodium nitrite (500 mg,
7.25 mmol) dissolved in 10 mL of H2O was added to the cold solution, and
the reaction was stirred for 3.5 h. The remaining insoluble solid was
removed by rapid filtration. The filtrate was added to a beaker and cooled to
08C in an ice bath. Sodium azide (485 mg, 7.46 mmol) dissolved in water
(10 mL) was added together with small amounts of diethyl ether to stop the
resulting foaming. The solution was stirred (2 h), and the resulting solid
was removed by filtration and washed with cold diethyl ether to give
7 (970 mg, 3.66 mmol, 60%) as an off-white solid. Mp 167–1698C; 1H
NMR (270 MHz) d 8.47 (dd, J ¼ 1.5 and 4.7 Hz, 1H), 8.00–7.94 (m, 2H),
7.85–7.78 (m, 2H), 7.68 (dd, J ¼ 8.2 and 1.5 Hz, 1H), 7.50 (dd, J ¼ 8.2
and 4.7 Hz, 1H); 13C NMR (67.5 MHz) d 166.3, 145.6 (2), 137.2, 135.3,
134.5 (2), 132.0 (þ), 127.9 (2), 125.6 (2), 124.0 (2); IR (neat) 2126,

2-Alkyl-Substituted Benzimidazoles
3433
1723, 1455, 1374 cm21; HRMS (DCI, NH3) calcd. for C13H8N5O2 (MHþ)
266.0678; found 266.0683. Anal. cald. for C13H7N5O2: C, 58.87; H, 2.66.
Found: C, 58.77; H, 2.77.
2-Amino-3-azidopyridine (8). To a solution of 7 (840 mg, 3.2 mmol)
dissolved in THF (20 mL) and ethanol (5 mL), hydrazine hydrate (85%
aqueous, 1.5 mL) was added. The reaction was stirred at ambient temperature
(26 h). The insoluble solid was removed by filtration, and the filtrate was evap-
orated to dryness under reduced pressure. To the resulting solid, HCl (10%
aqueous, 100 mL), was added and the formed precipitate was removed by
filtration. The filtrate was washed with diethyl ether (3 ꢀ 50 mL). The
aqueous layer was made basic with NaOH (aqueous, 3 M) and was
extracted with diethyl ether (4 ꢀ 50 mL). The combined organic phases
were dried (MgSO4) and filtered, and the solvent was removed at reduced
pressure, affording 8 (412 mg, 3.1 mmol, 96%) as a brown solid. Mp 71–
1
738C; H NMR (270 MHz) d 7.86 (dd, J ¼ 4.9 and 1.5 Hz, 1H), 7.23 (dd,
J ¼ 7.7 and 1.5 Hz, 1H), 6.70 (dd, J ¼ 7.7 and 4.9 Hz, 1H), 4.74 (br s, 2H);
13C NMR (67.5 MHz) d 150.9 (þ), 143.4 (2), 124.5 (2), 120.3 (þ), 113.4
(2); IR (neat) 3453, 2120, 1629, 1487, 1257 cm21; HRMS (EI) calc. for
C5H5N5 135.0545; found 135.0542. Anal. cald. for C5H5N5: C, 44.44; H,
3.73. Found: C, 44.11; H, 4.07.
5-Chloro-2-(1-methylethyl)benzimidazole (15).[22] To a refluxing solution
of 2-azido-5-chlorobenzenamine (9)[23] (300 mg, 1.78 mmol) in ethanol
(50 mL), a solution of 2-methylpropanal (195 mL, 2.15 mmol) in ethanol
(20 mL) was added dropwise. The reaction was stirred at reflux for 24 h,
followed by evaporation of the solvent at reduced pressure. The crude solid
was purified by column chromatography (hexanes–EtOAc, in order 8 : 2,
7 : 3, 1 : 1, and 3 : 7) affording 15 (262 mg, 1.35 mmol, 76%) as a brown
solid. Mp 189–1908C (lit.[24] 192–1948C); 1H NMR (600 MHz) d 7.51
(s, 1H), 7.43 (d, J ¼ 8.4 Hz, 1H), 7.18 (dd, J ¼ 8.4 and 1.8 Hz, 1H), 3.28
(septet, J ¼ 6.6 Hz, 1H), 1.47 (d, J ¼ 7.2 Hz, 6H); 13C NMR (150 MHz) d
161.2, 127.8, 122.7, 114.5 (br), 29.1, 21.5. Three carbons were not observed
due to the slow exchange of the N-H proton, causing signal broadening.
Reaction of 2-azido-4-chlorobenzenamine (10)[18,25] (174 mg, 1.03 mmol)
with 2-methylpropanal (115 mL, 1.27 mmol) in ethanol (70 mL), as described
previously (reflux, 24 h), after chromatography (hexanes–EtOAc, in order
9 : 1, 8 : 2, 7 : 3, 1 : 1, and 3 : 7) gave 15 (132 mg, 0.68 mmol, 66%) as a
brown solid.
5-Chloro-2-(1-methylethyl)benzimidazole (15) and 5-chlorobenzimida-
zole (16). Commercially available. Reaction of 9 (250 mg, 1.48 mmol) with
2-methylpropanal (400 mL, 4.40 mmol) and AcOH (500 mL) in ethanol
(20 mL), as described for 15 (reflux, 21 h), after chromatography (hexanes–
EtOAc, in order 8 : 2, 7 : 3, 1 : 1, 4 : 6, and 3 : 7) gave 15 (194 mg,

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3434
0.97 mmol, 67%) followed by 16 (13 mg, 0.085 mmol, 6%). Mp for 16 118–
1218C (lit.[24] 120–1258C).
5-Methyl-2-(1-methylethyl)benzimidazole (17).[26] Reaction of 2-azido-4-
methylbenzenamine 11[18] (300 mg, 2.02 mmol) with 2-methylpropanal
(220 mL, 2.42 mmol) in ethanol (70 mL), as described for 15 (reflux, 24 h),
after chromatography (hexanes–EtOAc, in order 9 : 1, 8 : 2, 7 : 3, 1 : 1, 3 : 7,
and EtOAc) gave 17 (249 mg, 1.43 mmol, 71%) as a brown solid. Mp
1
158–1598C (lit.[24] 154–1578C). H NMR (600 MHz) d 7.44 (d, J ¼ 8.4 Hz,
1H), 7.35 (s, 1H), 7.02 (dd, J ¼ 8.4 and 1.8 Hz, 1H), 3.30 (septet, J ¼ 7.2 Hz,
1H), 2.44 (s, 3H), 1.47 (d, J ¼ 7.2 Hz, 6H); 13C NMR (150 MHz) d 160.0,
138.5 (broad signal), 137.0 (broad signal), 131.8, 123.4, 114.5 (broad signal),
114.0 (broad signal), 29.1, 21.7, 21.6.
4-Methyl-2-(1-methylethyl)benzimidazole (18)[27] and 4-methylbenzimi-
dazole (19).[28] Reaction of 2-azido-6-methylbenzenamine 12[18] (280 mg,
1.89 mmol) with 2-methylpropanal (210 mL, 2.31 mmol) in ethanol (70 mL),
as described for 15 (reflux, 24 h), gave after chromatography (hexanes–
EtOAc, in order 9 : 1, 8 : 2, 7 : 3, 1 : 1, 3 : 7, and EtOAc) 18 (226 mg,
1.30 mmol, 69%) as a brown solid and 19 (21 mg, 0.16 mmol, 8%) as an off-
1
white solid. Data for 18: mp 206–2088C; H NMR (270 MHz, DMSO-d6) d
7.28 (d, J ¼ 7.7 Hz, 1H), 7.01 (t, J ¼ 7.3 Hz, 1H), 6.91 (d, J ¼ 6.9 Hz, 1H),
3.16 (septet, J ¼ 6.9 Hz, 1H), 2.49 (s, 3H), 1.35 (s, J ¼ 6.9 Hz, 6H). [Lit. for
18:[27] 1H NMR (200 MHz, DMSO-d6) d 12.02 (br s, 1H), 7.26 (br s, 1H),
6.99 (dd, J ¼ 7.7 and 7.4 Hz, 1H), 6.87 (ddt, J ¼ 7.4, 1.1, and 0.8 Hz, 1H),
3.14 (septet, J ¼ 7.0 Hz, 1H), 2.48 (s, 3H), 1.34 (d, J ¼ 7.0 Hz, 6H).] Data
1
for 19: mp 118–1218C (lit.[24] 142–1498C). H NMR (270 MHz) d 8.60 (br
s, 1H), 8.12 (s, 1H), 7.49 (d, J ¼ 7.9 Hz, 1H), 7.20 (t, J ¼ 7.4 Hz, 1H), 7.10
1
(d, J ¼ 7.4 Hz, 1H), 2.62 (s, 3H). [Lit. H NMR data for 19:[29] d 10.10
(s, 1H), 8.17 (s, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H), 7.21 (t, J ¼ 7.6 Hz, 1H), 7.11
(d, J ¼ 7.7 Hz, 1H), 2.63 (s, 3H).]
5-Methoxy-2-(1-methylethyl)benzimidazole (20).[30] Reaction of 2-azido-4-
methoxybenzenamine 13[18] (136 mg, 0.82 mmol) with 2-methylpropanal
(130 mL, 1.42 mmol) in ethanol (70 mL), as described for 15 (reflux,
24.5 h), after chromatography (hexanes–EtOAc, in order of elution 1 : 1,
and 2 : 8) gave 20 (69 mg, 0.36 mmol, 44%) as a faint brown solid. Mp
1
130–1318C, H NMR (600 MHz) d 7.43 (br d, J ¼ 8.4 Hz, 1H), 7.04 (br s,
1H), 6.85 (dd, J ¼ 7.8 and 1.8 Hz, 1H), 3.82 (s, 3H), 3.22 (septet,
J ¼ 7.2 Hz, 1H), 1.44 (d, J ¼ 7.2 Hz, 6H); 13C NMR (150 MHz) d 159.5,
156.1, 115 (br), 111.3, 108 (br), 55.9, 29.0, 21.5.
5-Chloro-2-hexylbenzimidazole (21). Reaction of 10 (302 mg, 1.79 mmol)
with heptanal (290 mL, 2.08 mmol) in ethanol (70 mL), as described for 15
(reflux, 24 h), after chromatography (hexanes–EtOAc, in order 9 : 1, 8 : 2,

2-Alkyl-Substituted Benzimidazoles
3435
and 7 : 3) gave 21 (266 mg, 1.12 mmol, 63%) as a brown solid. Mp
1
120–1228C; H NMR (270 MHz) d 12.01 (br s, 1H), 7.53 (d, J ¼ 2.0 Hz,
1H), 7.45 (d, J ¼ 8.4 Hz, 1H), 7.19 (dd, J ¼ 8.6 and 2.0 Hz, 1H), 2.97
(t, J ¼ 7.6 Hz, 2H), 1.85 (pentet, J ¼ 7.4 Hz, 2H), 1.40–1.10 (m, 6H), 0.79
(t, J ¼ 6.9 Hz, 3H); 13C NMR (67.5 MHz) d 157.3 (þ), 139.3 (þ), 137.0
(þ), 127.7 (þ), 122.6 (2), 115.1 (2), 114.4 (2), 31.3 (þ), 29.3 (þ), 28.9
(þ), 28.4 (þ), 22.3 (þ), 13.8 (2); IR (neat) 2921, 2360, 1450, 1024 cm21
;
HRMS (EI) calc. for C13H17C1 N2 236.1080; found 236.1071. Anal. calcd.
for C13H17ClN2: C, 65.95; H, 7.24. Found: C, 66.27, H, 7.52.
5-Chloro-2-phenylbenzimidazole (22).[16] Reaction of 10 (250 mg,
1.48 mmol) with benzaldehyde (450 mL, 4.43 mmol), and AcOH (500 mL) in
ethanol (20 mL), as described for 15 (reflux, 21 h), after chromatography
(hexanes–EtOAc, in order 9 : 1, 8 : 2, 7 : 3, and 1 : 1) gave 22 (268 mg,
1.21 mmol, 82%) as a faint brown solid. Mp 213–2148C (lit.[16] 209–2108C);
1H NMR (270 MHz, DMSO-d6) d 8.17 (dd, J ¼ 8.2 and 2.0 Hz, 2H), 7.68–
7.49 (m, 5H), 7.23 (dd, J ¼ 8.7 and 2.0 Hz, 1H). [Lit.[16] 1H NMR (300 MHz,
DMSO-d6) d 12.8 (br s, 1H), 8.18 (d, J ¼ 7.2 Hz, 2H), 7.5 (m, 5H), 7.19
(dd, J ¼ 8.2 and 1.0 Hz, 1H).]
2-Hexyl-5-methylbenzimidazole (23).[31] Reaction of 11 (305 mg,
2.06 mmol) with heptanal (330 mL, 2.36 mmol) in ethanol (70 mL), as
described for 15 (reflux, 24 h), after chromatography (hexanes–EtOAc, in
order 8 : 2, 7:3, 1 : 1, 3 : 7, and EtOAc) gave 23 (334 mg, 1.54 mmol, 75%)
1
as a brown solid. Mp 79–838C (lit.[31] 79–808C); H NMR (600 MHz) d
7.43 (d, J ¼ 8.4 Hz, 1H), 7.32 (s, 1H), 7.03 (dd, J ¼ 8.4 and 1.8 Hz, 1H),
2.89 (t, J ¼ 7.8 Hz, 2H), 2.44 (s, 3H), 1.82 (pentet, J ¼ 7.8 Hz, 2H), 1.36
(pent, J ¼ 7.2 Hz, 2H), 1.28–1.22 (m, 4H), 0.83 (t, J ¼ 6.6 Hz, 3H); 13C
NMR (150 MHz) d 155.0, 131.8, 123.5, 114.8 (broad signal), 31.4, 29.3,
29.0, 28.3, 22.5, 21.6, 14.0.[30]
2-Hexadecyl-5-methylbenzimidazole (24).[32] Reaction of 11 (114 mg,
0.77 mmol) with heptadecanal (297 mg, 1.16 mmol) in ethanol (70 mL), as
described for 15 (reflux, 38.5 h), after chromatography (hexanes–EtOAc, in
order 8 : 2, and 7 : 3) gave 24 (185 mg, 0.52 mmol, 67%) as a beige solid. Mp
1
72–738C; H NMR (270 MHz) d 8.33 (br s, 1H), 7.43 (d, J ¼ 8.3 Hz, 1H),
7.31 (br s, 1H), 7.04 (dd, J ¼ 8.1 and 1.0 Hz, 1H), 2.86 (t, J ¼ 5.8 Hz, 2H),
2.45 (s, 3H), 2.37 (t, J ¼ 7.5 Hz, 1H), 1.80 (pent, J ¼ 6.7 Hz, 2H), 1.67 (pent,
J ¼ 7.3 Hz, 1H), 1.25 (brs, 24H) 0.88 (t, J ¼ 6.9 Hz, 3H); 13C NMR
(150 MHz) d 155.0, 137.3, 135.7, 132.2, 123.9, 114.2, 114.0, 36.0, 31.9, 29.70,
29.69, 29.66, 29.65, 29.63, 29.61, 29.51, 29.49, 29.35, 29.32, 29.30, 28.7, 28.3,
25.7, 22.7, 21.5, 14.1; IR (neat) 2916, 2849, 1706, 1467, 798, 721 cm21
.
2-Benzyl-5-methylbenzimidazole (25)[33] and 5-methylbenzimidazole
(26).[25] Reaction of 11 (300 mg, 2.02 mmol) with phenylethanal (280 mL,

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3436
2.39 mmol) in ethanol (70 mL), as described for 15 (reflux, 24 h), after
chromatography (hexanes–EtOAc, in order 8 : 2, 7 : 3, 1 : 1, 3 : 7, and
EtOAc) gave 25 (47 mg, 0.21 mmol, 10%) as a brown solid and 26 (107 mg,
0.81 mmol, 40%) as an off-white solid. Compound 25: 139–1408C (lit.[34]
mp 146–1478C). Compound 26: mp 107–1108C (lit.[34] 114–1178C).
Alternative procedure: Reaction of 11 (300 mg, 2.00 mmol), ethanol (70 mL
total), phenylacetaldehyde (0.300 mL, 2.60 mmol), and glacial HOAc
(25 mL, 0.44 mmol) as described for 15 (reflux, 24 h), after chromatography
(hexanes–EtOAc, in order 8 : 2, 7 : 3, 1 : 1, 3 : 7, and EtOAc) gave 25
(87 mg, 0.39 mmol, 19%) as a brown solid and 26 (79 mg, 0.60 mmol,
30%). Alternative procedure for 26: Reaction of 11 (306 mg, 2.07 mmol)
with paraformaldehyde (78 mg, 2.60 mmol) in ethanol (70 mL), as described
for 15 (reflux, 24 h), after chromatography (hexanes–EtOAc, in order 6 : 4,
1 : 1, 3 : 7, and EtOAc) gave 26 (49 mg, 0.37 mmol, 18%) as an off-white solid.
2,5-Dimethylbenzimidazole (27).[25] Reaction of 11 (302 mg, 2.04 mmol)
with ethanal (140 mL, 2.33 mmol) in ethanol (70 mL), as described for 15
(reflux, 24 h), after chromatography (hexanes–EtOAc, in order 9 : 1, 8 : 2,
7 : 3, 1 : 1, 3 : 7, and EtOAc) gave 27 (99 mg, 0.67 mmol, 33%) as a brown
solid. Mp 200–2028C (lit.[24] 202–204.58C).
5-Methyl-2-(1,1-dimethylethyl)benzimidazole (28).[35] Reaction of 11
(300 mg, 2.02 mmol) with 2,2-dimethylpropanal (270 mL, 2.97 mmol) in
ethanol (70 mL), as described for 15 (reflux, 24 h), after chromatography
(hexanes–EtOAc, in order 9 : 1, 8 : 2, 7 : 3, 1 : 1, 3 : 7, and EtOAc) gave 28
(94 mg, 0.50 mmol, 25%) as a brown solid. Mp 239–2428C (lit.[35]
1
205–2088C); H NMR (DMSO-d6, 270 MHz) d 11.90 (br s, 1H), 7.40–7.12
(m, 2H), 6.91 (d, J ¼ 7.6 Hz, 1H), 2.37 (s, 3H), 1.36 (s, 9H) [lit.[35] 1
H
NMR (DMSO-d6, 300 MHz) d 7.40–7.10 (m, 2H), 6.95–6.85 (m, 1H), 2.38
(s, 3H), 1.39 (s, 9H).]
(E)-5-Methyl-2-(1-propenyl)benzimidazole (29).[36,37] Reaction of 11
(308 mg, 2.08 mmol) with trans-2-butenal (200 mL, 2.41 mmol) in ethanol
(70 mL), as described for 15 (reflux, 24 h), after chromatography (hexanes–
EtOAc, in order 95 : 5, 9 : 1, 8 : 2, 7 : 3, 1 : 1, 3 : 7, and EtOAc) gave 29
(50 mg, 0.29 mmol, 14%). Mp 185–1968C (lit.[37] 186.58C).
2-(2-Furyl)-5-methyl-benzimidazole (30).[38] Reaction of 11 (147 mg,
1.00 mmol) with furfural (100 mL, 1.20 mmol) in ethanol (70 mL), as
described for 15 (reflux, 24 h), after chromatography (hexanes–EtOAc, in
order 7 : 3, 1 : 1, and 2 : 8) gave 30 (73 mg, 0.37 mmol, 37%) as a yellow-
1
orange solid. Mp 188–1928C (lit.[38] 196–1978C); H NMR (600 MHz) d
7.50 (dd, J ¼ 8.4 and 3.6 Hz, 1H), 7.37 (br s, 2H), 7.12 (t, J ¼ 3.6 Hz, 1H),
7.05 (d, J ¼ 8.4 Hz, 1H), 6.42 (dd, J ¼ 4.2 and 1.8 Hz, 1H), 2.42 (s, 3H);
13C NMR (150 MHz) d 145.5, 144.1, 143.6, 138.4, 137.3, 132.8, 124.4,

2-Alkyl-Substituted Benzimidazoles
3437
115.1, 114.5, 112.1, 110.5, 21.6; IR 2923, 1522, 1422, 907, 731 cm21
.
Alternative procedure: Reaction of 11 (148 mg, 1.00 mmol) with furfural
(250 mL, 3.02 mmol) and HOAc (0.4 mL) in ethanol (20 mL), as described
for 15 (reflux, 48 h), after chromatography (hexanes–EtOAc, in order 7 : 3
and 1 : 1) gave 30 (106 mg, 0.54 mmol, 54%) as a yellow-orange solid.
2-(1-Methylethyl)imidazo[4,5-b]pyridine (31)[39] and 2,3-diaminopyridine
(32).[25] Reaction of 8 (302 mg, 2.23 mmol) with 2-methylpropanal (250 mL,
2.75 mmol) in ethanol (70 mL), as described for 15 (reflux, 24 h), after chrom-
atography (hexanes–EtOAc, in order 9 : 1, 8 : 2, 7 : 3, 1 : 1, 3 : 7 and EtOAc)
gave 31 (27 mg, 0.17 mmol, 8%) and 32 (81 mg, 0.74 mmol, 33%) as
brown solids. Analytical data for 31: mp 146–1498C (lit.[39] 157–1598C);
1H NMR (270 MHz) d 8.36 (dd, J ¼ 4.9 and 1.5 Hz, 1H), 8.07
(d, J ¼ 7.9 Hz, 1H), 7.25 (dd, J ¼ 7.9 and 4.9 Hz, 1H), 3.40 (septet,
J ¼ 7.2 Hz, 1H), 1.58 (d, J ¼ 7.2 Hz, 6H); 13C NMR (67.5 MHz) d 162.4
(þ), 149.2 (þ), 141.6 (2), 136.0 (þ), 127.1 (2), 117.7 (2), 29.7 (2), 21.3
(2); IR (neat) 2971, 2750, 1609, 1410, 1271 cm21. Data for 32: mp
107–1108C (lit.[40] mp 110–1158C).
2-Cyclopropylmethyl-5-methylbenzimidazole (33). A mixture of 2-cyclo-
propylethanol (300 mg, 3.48 mmol) and pyridinium chlorochromate
(980 mg, 4.55 mmol) dissolved in CH2Cl2 (50 mL) was stirred at ambient
temperature (7 h). The resulting mixture was filtered through a fritted funnel
packed with a thin layer of silica gel. The filtrate containing crude cyclopro-
pylethanal[41] was added to a threaded ACE-glass pressure tube. To the
solution was added 11 (310 mg, 2.09 mmol), and the tube was capped with
a Teflonw screw cap. The reaction was stirred at 1008C (24 h), followed by
evaporation of the solvents under reduced pressure. The crude product was
purified by chromatography (hexanes–EtOAc, in order 9 : 1, 8 : 2, 7 : 3, 1 : 1,
1
and 3 : 7) to give 33 (73 mg, 0.39 mmol, 11%). Mp 155–1578C; H NMR
(270 MHz) d 7.45 (d, J ¼ 8.2 Hz, 1H), 7.34 (s, 1 H), 7.03 (d, J ¼ 8.2 Hz,
1H), 2.87 (d, J ¼ 7.2 Hz, 2H), 2.44 (s, 3H), 1.29–1.13 (m, 1H), 0.58–0.50
(m, 2H), 0.28–0.22 (m, 2H); 13C NMR (67.5 MHz) d 154.8 (þ), 138.5 (þ),
137.0 (þ), 131.6 (þ), 123.3 (2), 114.4 (2), 114.1 (2), 34.0 (þ), 21.5 (2),
9.5 (2), 4.8 (þ); IR (neat) 3005, 2919, 2865, 1449, 1282 cm21; HRMS
(EI) calc. for C12H14N2 (M-Hþ) 185.1079; found 185.1078.
ACKNOWLEDGMENT
Support has been provided by a grant from the National Institutes of Health
(R01 GM57416). National Science Foundation’s Experimental Program to
Stimulate Competitive Research (NSF-EPSCoR) (grant no. 1002165R) is
gratefully acknowledged for the funding of a 600-MHz Varian Inova NMR

¨
J. M. Wallace, B. C. G. Soderberg, and J. W. Hubbard
3438
and the NMR facility in the C. Eugene Bennett Department of Chemistry at
West Virginia University.
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