General synthesis of 1-substituted 2-methylbenzimidazoles from ketones and 2-aminoacetanilide

Article abstract of DOI:10.1080/00397910701542996

A novel method for preparation of 1-substituted benzimidazoles via reductive amination of ketones with N-differentiated 1,2-diaminobenzenes is described. The method appears to be general in application to acyclic and cyclic ketones, as well as heteroatom-

Full text of DOI:10.1080/00397910701542996

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General Synthesis of 1‐Substituted
2‐Methylbenzimidazoles from Ketones and
2‐Aminoacetanilide
Svetlana A. Burova a , Roman Davis a , Russ N. Fitzgerald a , Byron S.
Johnson a & Richard T. Matsuoka a
a Chemical Development , GlaxoSmithKline, Research Triangle Park , North
Carolina
Published online: 10 Sep 2007.
To cite this article: Svetlana A. Burova , Roman Davis , Russ N. Fitzgerald , Byron S. Johnson & Richard
T. Matsuoka (2007) General Synthesis of 1‐Substituted 2‐Methylbenzimidazoles from Ketones and
2‐Aminoacetanilide, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:18, 3029-3039, DOI: 10.1080/00397910701542996
To link to this article: http://dx.doi.org/10.1080/00397910701542996
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Synthetic Communicationsw, 37: 3029–3039, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701542996
General Synthesis of 1-Substituted
2-Methylbenzimidazoles from Ketones and
2-Aminoacetanilide
Svetlana A. Burova, Roman Davis, Russ N. Fitzgerald,
Byron S. Johnson, and Richard T. Matsuoka
Chemical Development, GlaxoSmithKline, Research Triangle Park,
North Carolina
Abstract: A novel method for preparation of 1-substituted benzimidazoles via
reductive amination of ketones with N-differentiated 1,2-diaminobenzenes is
described. The method appears to be general in application to acyclic and cyclic
ketones, as well as heteroatom-substituted cyclic ketones.
Keywords: benzimidazoles, reductive amination, cyclization
In the course of developing a drug candidate, we required a short and efficient
route to benzimidazoles substituted at the 1-position with branched or cyclic
substituents. These pharmaceutically useful moieties[1] are typically syn-
thesized from ketones via the multistep sequence of reductive amination,[2]
reaction of the resulting amine with 2-halonitrobenzenes, nitro reduction,
and cyclization with orthoesters (Scheme 1). This multistep synthesis is
tedious and requires handling of often unstable 1,2-diaminobenzenes.
Other synthetic methods are specific for 1-n-alkylbenzimidazoles[3] or
N-unsubstituted benzimidazoles.[4]
Received in the USA January 31, 2007
Address correspondence to Roman Davis, Chemical Development, GlaxoSmith-
Kline, 5 Moore Drive,Research Triangle Park, NC 27709. E-mail: roman.d.davis@
gsk.com
3029

3030
S. A. Burova et al.
Scheme 1.
Our initial efforts proved ineffective. These included alkylation of benzi-
midazoles with cycloalkyl sulfonates, reductive amination of diaminoben-
zenes giving complex mixtures, and Ti-mediated amination designed for
anilines.[5]
We therefore turned our attention to reductive amination of ketones with
N-differentiated 1,2-diaminobenzenes. We report herein an efficient two-step
synthesis of 1-substituted 2-methylbenzimidazoles, which can be applied to
cyclic or acyclic ketones. The synthesis entails reductive amination with
2-aminoacetanilide, followed by acid-mediated cyclization (Scheme 2). We
have found no other examples of N-differentiated diaminobenzenes participat-
ing in reductive amination and therefore consider this to be a novel approach.
The reductive amination requires at least 6 equivalents of acetic acid
(HOAc) and 1.5 equivalents of sodium triacetoxyborohydride (STAB), in
dichloromethane (DCM) or dichloroethane (DCE) solvent. Additional
HOAc does not affect the reaction adversely, but less HOAc significantly
retards the reaction. Trifluoroacetic acid (TFA) replacement for all or part
of HOAc shortens the reaction time. Severe safety and exposure consider-
ations are associated with TFA. Material Safety Data information includes:
Danger! Corrosive. Causes Burns. Harmful if swallowed, inhaled, or
absorbed through Skin. Material is extremely destructive to the upper respir-
atory tract, eyes, and skin. Other strong acids, such as methanesulfonic acid,
proved inferior, leading to decomposition of the product anilide. During the
course of manuscript submission, the use of excess HOAc or replacing
HOAc with TFA was reported for reductive amination of 2-chloro-3-amino-
pyridines.[6] Other solvents were not as effective, in contrast to literature pre-
cedences[7] that indicated that other solvents produce only kinetic effects.
Many of the resulting alkylated anilides were not fully soluble in DCM.
Scheme 2.

Table 1. Reductive amination of ketones with 2-aminoanilides and conversion to benzimidazoles
Entry
1
Substrate ketone a
Anilide b
Yield (%)
77
Benzimidazole c
Yield (%)
84
2
3
4
86
79
83
68
67
67
(continued)

Table 1. Continued
Entry
5
Substrate ketone a
Anilide b
Yield (%)
Benzimidazole c
Yield (%)
62 (over 2 crops)
Not isolateda
6
7
0b
Not
processed
90
30

8
66
67c
9
63
55
57d
10
13%; not
isolated
aCyclization gave a complex mixture, and the desired benzimidazole was not isolated.
bOnly reduction to alcohol was observed.
cDe-acylated diamine, 25%, was also isolated.
dMixture of 90:10 trans–cis isomers.

3034
S. A. Burova et al.
Therefore, 2-methyltetrahydrofuran (MTHF) was used as a cosolvent for base-
extractive workup. MTHF has solubility properties similar to tetrahydrofuran
(THF) but easily separates from water. It is readily available, inexpensive, and
environmentally benign.[8] The product anilides were crystallized through
partial concentration of the DCM–MTHF mixture to remove the DCM and
addition of an alkane such as heptane or isooctane.
Although each reaction described was optimized for the substrate
required by our development program, the method is general for many sub-
strates (see Table 1).
The reductive amination reactions were especially efficient for cyclic
ketones containing heteroatoms in the ring (entries 1–4). The reaction with
b-tetrolone (entry 7) gave 90% yield, whereas a-tetrolone (entry 6) gave only
the ketone reduction product. However, its open analog, acetophenone (entry
8), gave 68% yield. From these results, we infer that conformational restrictions
in a-tetralone inhibit imine or enamine formation, thus leading only to ketone
reduction. Conversely, enamine formation in b-tetralone would be assisted by
enolization and conjugation, where reduction may also take place at the
enamine. 4-tert-Butylcyclohexanone (entry 5) gave a 4:1 mixture of two
isomers, from which the major isomer could be crystallized in 62% yield
over two crops. This substrate was not further investigated. However, the
isomer selectivity, applied to bicyclic ketones, such as tropanone derivatives,
and hydroxylated cyclic ketones, will be the subject of a subsequent manuscript
highlighting ReactIR data from the reductive amination.
The reactions were not affected by unsaturation elsewhere in the molecule
(entry 9). However, 2-cyclohexenone gave a complex mixture of isomers.
Other 2-aminoanilides (entry 10) also underwent reductive amination. Cycli-
zation to the benzimidazoles was easily achieved with 12 M aqueous hydrogen
chloride in ethanol. Low cyclization yields for some substrates reflect diffi-
culty of crystallization rather than reaction performance, so this step will
require optimization for each desired substrate. Surprisingly, the isobutyryla-
nilide (entry 10) gave predominately de-acylation and only 13% (by HPLC) of
the cyclized product.
In summary, we have developed an efficient two-step synthesis of 1-sub-
stituted 2-methylbenzimidazoles, which can be applied to cyclic or acyclic
ketones. The method operates across a range of ketones and is especially
robust in cyclic ketones containing heteroatoms in the ring.
EXPERIMENTAL
Starting materials, reagents, and solvents were purchased from bulk commer-
cial sources and were used without further purification. All temperatures are
uncorrected. HPLC reaction monitoring and analysis was conducted on a
Luna C18(2) 50 mm ꢀ 2 mm, 3-mm column, at 408C, flow rate of 1 mL/min,
and UV visualization at 220 nm; mobile phase A: H2O (0.05%), mobile

1-Substituted 2-Methylbenzimidazoles
3035
1
phase B: CH3CN (0.05%); gradient: 0–95% B over 8 min. H NMR spectra
were measured at 400 MHz, and 13C NMR spectra were measured at
100 MHz.
High-resolution mass spectral (HRMS) data were obtained using a Waters
Micromass Q-Tof 2 with electrospray ionization (ESI). HRMS data for each
compound were accurate within 5 ppm.
Reductive Amination
To a mixture of 2-aminoacetanilide (7 g, 46.6 mmol), ketone (51.3 mmol,
1.1 eq.), and NaBH(OAc)3 (14.8 g, 70 mmol. 1.5 eq.) in CH2Cl2 (56 mL)
at 0–58C, was added AcOH (10.6 mL, 6.0 eq.), maintaining the internal
temperature at ꢁ 208C. The solution was stirred at approximately 208C for
4 h or until complete by HPLC. MTHF (140 mL), was added to the
mixture and the pH was adjusted to 13 with 10 N NaOH (50 mL). Where
required, the biphasic mixture was heated to maintain a solution. The
organic layer was washed with H2O (70 mL) and reduced under vacuum
by approximately 60%. Heptane was added as an antisolvent, and the
resulting solid was isolated via filtration and dried under vacuum at approxi-
mately 508C. Where required, the compound was recrystallized or purified
chromatographically to provide an analytically pure sample. Yields:
55–90%.
Data
N-(2-f[1-(Phenylmethyl)-4-piperidinyl]aminogphenyl)acetamide (1b): 1H
NMR (DMSO-d6): d 9.09 (s, 1H), 7.28–7.33 (m, 4H), 7.22–7.25 (m, 1H),
7.12 (d, J ¼ 7.6 Hz, 1H), 6.97 (t, J ¼ 8.0 Hz, 1H), 6.65 (d, J ¼ 8.0 Hz, 1H),
6.53 (t, J ¼ 7.6 Hz, 1H), 4.59 (d, J ¼ 7.6 Hz, 1H), 3.46 (s, 2H), 3.22–3.29
(m, 1H), 2.76 (d, J ¼ 11.6 Hz, 2H), 2.08 (t, J ¼ 11.2 Hz, 2H), 2.03 (s, 3H),
1.9 (d, J ¼ 11.2 Hz, 2H), 1.41 (q, J ¼ 11.6 Hz, 2 H). 13C NMR (DMSO-
d6): d168.5, 141.2, 138.7, 128.7, 128.1, 126.8, 126.1, 126.0, 123.8, 115.5,
111.6, 62.2, 51.9, 49.1, 31.8, 23.4. Mp: 159.0–160.38C. HRMS: calc. for
C20H26N3O: 324.2076. Found 324.2076.
N-(2-f[1-(Phenylmethyl)-3-pyrrolidinyl]aminogphenyl)acetamide (2b): 1H
NMR (DMSO-d6): d 9.13 (s, 1H), 7.30–7.31 (m, 4H), 7.21–7.24 (m, 1H),
7.15 (d, J ¼ 7.6 Hz, 1H), 6.97 (t, J ¼ 7.6 Hz, 1H), 6.54–6.57 (m, 2H), 4.92
(d, 6.4 Hz, 1H), 3.82–3.93 (m, 1H), 3.53 (q, J ¼ 12.8 Hz, 2H), 2.78
(t, J ¼ 8.0 Hz, 1H), 2.63 (q, J ¼ 8.4 Hz, 1H), 2.45 (q, J ¼ 8.0 Hz, 1H), 2.37
(dd, J ¼ 9.2, 4.4 Hz, 1H), 2.21–2.27 (m, 1H), 1.55–1.63 (m, 1H). 13C
NMR (DMSO-d6): d 168.5, 141.5, 139.0, 128.5, 128.2, 126.8, 126.0, 125.6,
124.1, 115.9, 111.8, 60.2, 59.5, 52.6, 51.7, 32.0, 23.4. Mp: 127.3–128.38C.

3036
S. A. Burova et al.
Anal. calc. for C19H23N3O: C, 73.76; H, 7.49; N, 13.58. Found: C, 73.47;
H, 7.51; N, 13.58. HRMS: calc. for C19H24N3O: 310.1919. Found 310.1916.
N-[2-(Tetrahydro-2H-pyran-4-ylamino)phenyl]acetamide (3b): 1H NMR
(DMSO-d6): d 9.08 (s, 1H), 7.14 (d, J ¼ 8.0 Hz, 1H), 6.98 (t, J ¼ 8.0 Hz,
1H), 6.71 (d, J ¼ 8.0 Hz, 1H), 6.55 (t, J ¼ 8.0 Hz, 1H), 4.65 (d, J ¼ 8.8 Hz,
1H), 3.83–3.88 (m, 2H), 3.39–3.51 (m, 3H), 3.42 (t, J ¼ 11.2 Hz, 2H),
2.04 (s, 3H), 1.88 (d, J ¼ 11.2 Hz, 2H), 1.39 (m, 2H). 13C NMR (DMSO-
d6): d 168.5, 140.9, 126.1, 126.0, 123.9, 115.7, 111.7, 65.9, 48.0, 32.8, 23.4.
Mp: 183.2–185.08C. Anal. calc. for C13H18N2O2: C, 66.64; H, 7.74; N,
11.96. Found: C, 66.89; H, 7.76; N, 11.91. HRMS: calc. for C13H19N2O2:
235.1447. Found 235.1454.
1
N-[2-(Tetrahydro-2H-thiopyran-4-ylamino)phenyl]acetamide (4b): H NMR
(DMSO-d6): d 9.08 (s, 1H), 7.13 (d, J ¼ 8.0 Hz, 1H), 6.98 (t, J ¼ 8.0 Hz,
1H), 6.66 (d, J ¼ 8.0 Hz, 1H), 6.55 (t, J ¼ 8.0 Hz, 1H), 4.67 (d, J ¼ 7.6 Hz,
1H), 3.29–3.36 (m, 1H), 2.63–2.75 (m, 4H), 2.16–2.19 (m, 2H), 2.04
(s, 3H), 1.47–1.57 (m, 2H). 13C NMR (DMSO-d6): d 168.5, 140.7, 126.1,
126.1, 123.8, 115.6, 111.5, 49.6, 33.7, 26.8, 23.4. Mp: 145.0–146.08C.
Anal. calc. for C13H18N2OS: C, 62.37; H, 7.25; N, 11.19. Found; C, 62.31;
H, 7.27; N, 11.14. HRMS: calc. for C13H19N2OS: 251.1218. Found 251.1212.
N-(2-f[4-(1,1-Dimethylethyl)cyclohexyl]aminogphenyl)acetamide (5b): 1H
NMR (DMSO-d6): d 9.40 (s, 1H), 7.00 (t, J ¼ 8.0 Hz, 1H), 6.98
(d, J ¼ 7.6 Hz, 1H), 6.64 (d, J ¼ 8 Hz, 1H), 6.54 (t, J ¼ 7.6 Hz, 1H), 4.55
(d, J ¼ 8.0 Hz, 1H), 3.6–3.67 (m, 1H), 2.01 (s, 3H), 1.82 (d, J ¼ 11.6 Hz,
2H), 1.41–1.48 (m, 4H), 1.13–1.23 (m, 2H), 0.96–1.02 (m, 1H), 0.82
(s, 9H). 13C NMR (DMSO-d6): d 168.7, 142.0, 126.8, 126.5, 124.3, 115.7,
112.4, 47.3, 45.7, 32.5, 29.7, 27.5, 23.1, 21.0. Mp: 140–1418C. Anal. calc.
for C18H28N2O: C, 74.96; H, 9.78; N, 9.71. Found; C, 74.66; H, 9.88; N,
9.46. HRMS: calc. for C18H29N2O: 289.2280. Found 289.2273.
N-[2-(1,2,3,4-Tetrahydro-2-naphthalenylamino)phenyl]acetamide (7b): 1H
NMR (CD2Cl2): 7.27 (d, J ¼ 7.6 Hz, 1H), 7.13–7.06 (m, 5H), 6.86
(d, J ¼ 8.0 Hz, 1H), 6.75 (dd, J ¼ 7.6, 7.6 Hz, 1H), 3.93 (1H, brs), 3.74
(m, 1H), 3.16 (dd, J ¼ 8.0, 4.0 Hz, 1H), 2.92 (m, 2H), 2.70 (dd, J ¼ 8.8,
8.2, Hz, 1H), 2.18 (m, 1H), 2.09 (s, 3H0, 1.75 (m, 1H). 13C NMR
(CD2Cl2): 169.5, 142.0, 136.6, 135.4, 129.9, 129.8, 129.2, 127.7, 126.5,
126.4, 126.2, 49.6, 36.8, 29.8, 28.2, 24.1. HRMS: calc. for C18H21N2O:
281.1654. Found 281.1655.
N-f2-[(1-Phenylethyl)amino]phenylgacetamide (8b): 1H NMR (CD2Cl2): 7.37
(m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 6.64 (m, 1H),
6.47 (m, 1H), 4.57–4.47 (m, 3H), 2.18 (s, 3H), 1.5 (d, 3H, J ¼ 8.0 Hz). 13C
NMR (CD2Cl2): 169.85, 145.8, 142.5, 129.1, 127.7, 127.4, 126.4, 117.8,
114.4, 53.9, 25.6, 24.1. HRMS: calc. for C16H19N2O: 255.1497. Found
255.1494.

1-Substituted 2-Methylbenzimidazoles
3037
N-(2-f[(2E)-1-Methyl-3-phenyl-2-propen-1-yl]aminogphenyl)acetamide (9b):
1H NMR (CD2Cl2): 7.36 (m, 2H), 7.30 (m, 2H), 7.22 (m, 2H), 7.09 (m, 1H),
6.80 (d, 1H, J ¼ 10 Hz), 6.71 (m, 1H), 6.58 (d, 1H, J ¼ 20.0 Hz), 6.22 (dd,
1H, J ¼ 20.0, 7.5 Hz), 4.13 (m, 1H0, 2.16 (s, 3H), 1.4 (d, 3H, J ¼ 8.0 Hz).
13C NMR (CD2Cl2): 169.9, 142.5, 137.5, 133.6, 129.8, 129.0, 127.8, 127.7,
126.8, 126.5, 118.1, 51.5, 24.1, 22.4. HRMS: calc. for C18H21N2O: 281.1654.
Found 281.1649.
2-Methyl-N-[2-(tetrahydro-2H-thiopyran-4-ylamino)phenyl]propanamide (10b):
1H NMR (DMSO-d6): d 9.08 (s, 1H), 7.11 (d, J ¼ 8.0 Hz, 1H), 6.99
(t, J ¼ 8.0 Hz, 1H), 6.67 (d, J ¼ 8.0 Hz, 1H), 6.56 (t, J ¼ 8.0 Hz, 1H), 4.51
(d, J ¼ 8.0 Hz, 1H), 3.32–3.38 (m, 1H), 2.60–2.73 (m, 5H), 2.14–2.18
(m, 2H), 1.46–1.56 (m, 2H), 1.10 (d, J ¼ 6.8 Hz, 6H). 13C NMR (DMSO-d6):
d 175.5, 140.8, 126.2, 123.9, 115.9, 111.8, 49.4, 34.3, 33.7, 26.5, 19.7. Mp:
165.4-166.48C. Anal. calc. for C15H22N2OS: C, 64.71; H, 7.96; N, 10.06.
Found: C, 64.51; H, 8.04; N, 9.98. HRMS: Calc. for C15H23N2OS: 279.1531.
Found 279.1538.
Cyclization to Benzimidazoles
To a mixture of the acetamide (43 mmol) in EtOH (80 mL), 12 M HCl (11 mL,
129 mmol, 3 eq.) was added. The solution was heated to approximately 708C and
stirred for 4 h or until the reaction was complete by HPLC. The solution was
cooled to approximately 208C. Some products crystallized, and these were
isolated directly from the mixture as HCl salts. However, to eliminate
potential mixtures of mono and di HCl salts, the preferred form of the isolated
product was the freebase. The freebase product was obtained by neutralization
of the reaction with NaOH and extraction into CH2Cl2. The product was
isolated either by crystallization with heptane or concentrating to dryness.
The solid was isolated via filtration and dried under vacuum at approximately
508C. Where required, the compound was recrystallized or purified chromato-
graphically. Yields: 57–84%.
Data
2-Methyl-1-[1-(phenylmethyl)-4-piperidinyl]-1H-benzimidazole (1c): 1H
NMR (DMSO-d6): d 7.58 (d, J ¼ 7.6 Hz, 1H), 7.50 (d, J ¼ 7.6 Hz, 1H),
7.32–7.28 (m, 4H), 7.24–7.28 (m, 1H), 7.08–7.16 (m, 2H), 4.24–4.32
(m, 1H), 3.56 (s, 2H), 2.96 (d, J ¼ 12.0 Hz, 2H), 2.55 (s, 3H), 2.36 (qd,
J ¼ 12, 4 Hz, 2H), 2.17 (t, J ¼ 12 Hz, 2H), 1.80 (d, J ¼ 12 Hz, 2H). 13C
NMR (DMSO-d6): d 151.4, 142.9, 138.3, 133.6, 128.8, 128.2, 126.9, 121.2,
120.8, 118.6, 111.5, 61.9, 53.7, 52.4, 29.8, 14.5. HRMS: calc. for
C20H24N3: 306.1970. Found 306.1984.
2-Methyl-1-[1-(phenylmethyl)-3-pyrrolidinyl]-1H-benzimidazole (2c): 1H
NMR (DMSO-d6): d 7.98 (d, J ¼ 7.6 Hz, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H),

3038
S. A. Burova et al.
7.38 (d, J ¼ 7.2 Hz, 2H), 7.32 (t, J ¼ 7.6 Hz, 2H), 7.23 (t, J ¼ 7.2 Hz, 1H),
7.09–7.16 (m, 2H), 5.09–5.16 (m, 1H), 3.78 (d, J ¼ 12.0 Hz, 1H), 3.60
(d, J ¼ 12.0 Hz, 1H), 3.11 (t, J ¼ 8.4 Hz, 1H), 2.96 (dd, J ¼ 10.4, 3.6 Hz,
1H), 2.70 (t, J ¼ 10.0 Hz, 1H), 2.54 (s, 3H), 2.33–2.45 (m, 2H), 2.01–2.11
(m, 1H). 13C NMR (DMSO-d6): d 151.7, 142.9, 138.8, 132.7, 128.5, 128.2,
127.0, 121.1, 121.1, 118.4, 111.8, 59.2, 57.2, 53.6, 53.4, 30.3, 14.1. Mp:
93.8–94.58C. Anal. calc. for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found:
C, 78.02; H, 7.46; N, 14.55. HRMS: Calc. for C19H22N3: 292.1814. Found
292.1821.
2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazole (3c): 1H NMR
(DMSO-d6): d 7.71 (d, J ¼ 8.8 Hz, 1H), 7.51 (d, J ¼ 8.8 Hz, 1H), 7.09–
7.15 (m, 2H), 4.52–4.61 (m, 1H), 4.02 (dd, J ¼ 11.6, 4.4 Hz, 2H), 3.54
(t, J ¼ 11.6 Hz, 2H), 2.58 (s, 3H), 2.37 (qd, J ¼ 12.4, 4.4 Hz, 2H), 1.79
(dd, J ¼ 12.4, 2.4 Hz, 2H). 13C NMR (DMSO-d6): d 151.4, 142.8, 133.5,
121.3, 120.9, 118.6, 111.5, 66.6, 52.3, 30.7, 14.6. Mp: 167–1718C. Anal.
calc. for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.30; H,
7.43; N, 12.97. HRMS: calc. for C13H17N2O: 217.1341. Found 217.1339.
2-Methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-benzimidazole (4c): 1H
NMR (DMSO-d6): d 8.00–8.03 (m, 1H), 7.78–7.80 (m, 1H), 7.52–7.55
(m, 2H), 4.67 (m, 1H), 2.99 (t, J ¼ 12.0 Hz, 2H), 2.87 (s, 3H), 2.79
(d, J ¼ 12.0 Hz, 2H), 2.43 (qd, J ¼ 12.8, 3.2 Hz, 2H), 2.31 (dd, J ¼ 12.8,
3.2 Hz, 2H). 13C NMR (DMSO-d6): d 151.1, 130.5, 130.1, 125.5, 125.3,
114.2, 114.2, 56.2, 31.5, 27.5, 12.5. Mp: 2708C dec. Anal. calc. for
C13H17ClN2S: C, 58.09; H, 6.37; N, 10.42. Found: C, 58.09; H, 6.42; N,
10.39. HRMS: calc. for C13H17N2S: 233.1112. Found 233.1106.
2-Methyl-1-(1,2,3,4-tetrahydro-2-naphthalenyl)-1H-benzimidazole (7c): 1H
NMR (CD2Cl2): 7.64 (d, J ¼ 8.4 Hz, 1H), 7.48 (d, J ¼ 6.8 Hz, 1H), 7.21–
7.14 (m, 6H), 4.75–4.66 (m, 1H), 3.65 (dd, 1H, J ¼ 16.4, 11.6 Hz), 3.10
(m, 3H), 2.77–2.66 (m, 1H), 2.63 (s, 3H), 2.26–2.23 (m, 1H). 13C NMR
(CD2Cl2): 152.0, 144.0, 136.0, 135.0, 134.4, 129.7, 129.3, 126.9, 126.6,
122.0, 121.8, 119.7, 111.7, 53.8, 34.3, 30.2, 28.7, 15.4. HRMS: calc. for
C18H19N2: 263.1548. Found 263.1545.
2-Methyl-1-(1-phenylethyl)-1H-benzimidazole (8c): 1H NMR (CD2Cl2): 7.62
(d,1H, J ¼ 10.0 Hz),7.33(m, 3H),7.23(m, 2H),7.14(m, 1H),7.04(m, 2H),5.78
(q, 1H, J ¼ 9.0 Hz), 2.58 (s, 3H), 1.97 (d, 3H, J ¼ 9.0 Hz). 13C NMR (CD2Cl2):
152.2, 143.8, 140.4, 134.6, 129.2, 128.2, 126.9, 122.0, 121.8, 119.5, 111.6, 53.9,
18.8, 15.3. HRMS: calc. for C16H17N2: 237.1392. Found 237.1394.
2-Methyl-1-[(2E)-1-methyl-3-phenyl-2-propen-1-yl]-1H-benzimidazole (9c):
1H NMR (CD2Cl2): 7.65 (m, 1H), 7.47 (m, 1H), 7.40–7.38 (m, 2H), 7.35–
7.27 (m, 3H), 7.19 (m, 2H), 6.55 (s, 2H), 5.31 (q, 1H), 2.65 (s, 3H), 1.80
(d, J ¼ 8.5 Hz, 3H). 13C NMR (CD2Cl2): 151.8, 143.7, 136.7, 134.5, 131.8,
129.2, 129.1, 128.5, 126.9, 122.1, 121.9, 119.4, 111.8, 53.0, 19.2, 15.2.

1-Substituted 2-Methylbenzimidazoles
ACKNOWLEDGMENTS
3039
We gratefully acknowledge helpful discussions with Alan Millar, William
J. Smith, Elie A. Tabet, and Shiping Xie.
REFERENCES
1. (a) Examples of benzimidazoles in active pharmaceutical ingredients include anti-
secretory omeprazole (Prilosec), antihypertensive telmisartan (Micardis), and
anthelminthic albendazole (Zentel); (b) Nishiyama, Y.; Fujimoto, M.;
Sonoda, N. Synlett 2006, 109, and references cited therein; (c) Preston, P. N.
The Chemistry of Heterocyclic Compounds: Benzimidazoles and Congeneric
Tricyclic Compounds; John Wiley & Sons: New York, vol. 40, 1980.
2. (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis 2005, 1, 47;
(b) Rueckle, T.; Biamonte, M.; Grippi-Valloton, T.; Arkinstall, S.; Cambet, Y.;
Camps, M.; Chabert, C.; Church, D. J.; Halazy, S.; Jiang, X.; Martinous, I.;
Nichols, A.; Sauer, W.; Gotteland, J.-P. J. Med. Chem. 2004, 47, 6921;
(c) Wu, Z.; Rea, P.; Wickahm, G. Tetrahedron Lett. 2000, 41, 9871;
(d) Thomas, A. P.; Allott, C. P.; Gibson, K. H.; Major, J. S.; Masek, B. B.;
Oldham, A. A.; Ratcliffe, A. H.; Roberts, D. A.; Russell, S. T.;
Thomason, D. A. J. Med. Chem. 1992, 35, 377.
3. (a) Lin, S.-Y.; Isome, Y.; Stewart, E.; Liu, J.-F.; Yohannes, D. Tetrahedron Lett.
2006, 47, 2883, and references cited therein; (b) Wright, J. B. Chem. Rev. 1951,
48, 397; (c) Preston, P. N. Chem. Rev. 1974, 74, 279; (d) Gray, D. N. J. Heterocycl.
Chem. 1970, 7, 947; (e) Hudkins, R. L. Heterocycles 1995, 41, 1045;
(f) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893;
(g) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814; (h) Howarth, J.;
Hanlon, K. Tetrahedron Lett. 2001, 42, 751; (i) Hendrickson, J. B.;
Hussoin, S. M. J. Org. Chem. 1989, 54, 1144.
4. Salehi, P.; Dabiri, M.; Zolfigol, M.; Otokesh, S.; Baghbanzadeh, M. Tetrahedron
Lett. 2006, 47, 2557.
5. DiCesare, J. C.; White, C. E.; Rasmussen, W. E.; White, B. M.; McComas, C. B.;
Craft, L. E. Synth. Commun. 2005, 35, 663.
6. McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307.
7. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D.
J. Org. Chem. 1996, 61, 3849.
8. Paul, S. F. US Patent 5,697,987, December 16, 1997.
9. Fitzpatrick, S. W. US Patent 4,897,497, January 30, 1990. Methyl tetrahydrofuran
can be derived from cellulosic materials, including agricultural waste, coffee
grounds, leaves, and sawdust, and can be blended with ethanol and alkanes to
make homegrown transportation fuels. The MTHF–alkane mother liquors
(filtrates and wash) are presumably suitable for direct recycling as transportation
fuels.