Reactivity-controlled regioselectivity: A regiospecific synthesis of 1,2-disubstituted benzimidazoles

Article abstract of DOI:10.1002/ejoc.200901056

We demonstrate exceptional levels of regioselectivity in the tandem, animation reactions between 1,2-differentiated dihaloarenes and N-substituted amidines, The regiochemical outcome of this Cul-catalyzed reaction is achieved through a combination of N¹/N² chemoselectivity on the amidine and reactivity-controlled X¹/X² chemoselectivity on the 1,2-dihaloarene. This reaction proves to be fairly general for the regiospecific synthesis of 1,2-substituted benzimidazoles.

Full text of DOI:10.1002/ejoc.200901056

FULL PAPER
DOI: 10.1002/ejoc.200901056
Reactivity-Controlled Regioselectivity: A Regiospecific Synthesis of
1,2-Disubstituted Benzimidazoles
Xiaohu Deng*[a] and Neelakandha S. Mani[a]
Keywords: Regioselectivity / Copper catalysis / Amination / Heterocycles
We demonstrate exceptional levels of regioselectivity in the
tandem amination reactions between 1,2-differentiated di-
haloarenes and N-substituted amidines. The regiochemical
outcome of this CuI-catalyzed reaction is achieved through a
combination of N1/N2 chemoselectivity on the amidine and
reactivity-controlled X1/X2 chemoselectivity on the 1,2-di-
haloarene. This reaction proves to be fairly general for the
regiospecific synthesis of 1,2-substituted benzimidazoles.
less hindered nitrogen.[6] This makes the sterically more hin-
dered products extremely difficult to obtain.[7] Therefore, a
Introduction
The benzimidazole scaffold is a “privileged” structural regiospecific benzimidazole synthesis remains a significant
motif[1] for the development of bioactive compounds in the challenge for synthetic chemists.[8]
pharmaceutical industry. Benzimidazole derivatives are
The recent development of the metal-catalyzed Buch-
widely found in commercial drugs such as Prilosec, Nex- wald–Hartwig amination reaction[9] makes the alternative
ium, Protonix, (proton pump inhibitors) Atacand (hyper- C–N bond disconnection a viable strategy to construct the
tension), Famvir (antiviral), and Vermox (broad spectrum benzimidazole ring regiospecifically via an intramolecular
anthelmintic) as well as numerous experimental drug candi- amination cyclization (path c).[10] However, it usually takes
dates.[2] Therefore, it is not surprising that the efficient syn- a multi-step synthesis to prepare the requisite o-halo-phen-
thesis of benzimidazoles has always been a topic of interest ylamidine precursor. Very recently, Ma[11] and Buchwald[12]
for organic and medicinal chemists.[3] The classic synthesis and co-workers independently developed an elegant re-
of benzimidazoles involves the condensation of carboxylic gioselective benzimidazole synthesis based on a cascade ar-
acids (or their variants) with 1,2-diaminoarenes (Scheme 1, ylamination/condensation process (path d). Despite these
path a).[4] However, this method is usually not suitable for progresses, a facile, regiospecific benzimidazole synthesis is
the regioselective synthesis of N-substituted benzimidazoles. still in high demand. Herein, we report a modular, regios-
Because of the difficulty of differentiating the two nitrogen pecific synthesis of 1,2-substituted benzimidazoles with a
atoms, a mixture of two regioisomers is often obtained.[5] distinctive bond disconnection, starting from 1,2-dihalo-
N-Substitution reactions of 1H-benzimidazoles are usually arenes and 1,2-disubstituted amidines. Taking advantage of
not regiospecific either (path b). Furthermore, N-substitu- the reactivity difference of the two differentiated halides
tion reactions typically favor substitution onto the sterically (I–Br, I–Cl, or Br–Cl), exclusive regioselectivity is achieved,
Scheme 1. Literature syntheses of N-substituted benzimidazoles.
[a] Johnson & Johnson Pharmaceutical Research & Development,
regardless of the steric and electronic characters of the sub-
LLC,
strates. Both starting materials are readily available and the
reaction scope is quite broad. We believe that this method-
ology is a valuable contribution to the benzimidazole syn-
thesis toolkit.
3210 Merryfield Row, San Diego, California 92121, USA
Fax: +1-858-320-3354
E-mail: xdeng@its.jnj.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901056.
680
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 680–686

Regiospecific Synthesis of 1,2-Disubstituted Benzimidazoles
regioisomer 1 was isolated in 29% yield (Scheme 3). The
low yield of 1 was probably partially due to the instability
of the compound during the purification process at room
temperature.[16] Careful nOe studies revealed that the amin-
ation reaction took place exclusively at the N1 position. No
N2 amination product 3 was observed whatsoever. This ex-
clusive N1 chemoselectivity is particularly interesting be-
cause this is the first time that the high level of chemoselec-
tivity in the metal-catalyzed C–N bond formation reactions
was achieved on substrates with two closely associated ni-
trogen atoms such as amidines. In the literature, sporadic
examples were found for the chemoselective C–N bond for-
mation on substrates with two reactive nitrogen atoms.
However, the process appears to be extremely complex, with
the outcome highly dependent on the substrates,[17] met-
als,[18] ligands,[19] and bases.[20] Recent mechanistic studies
showed that two interdependent events, i.e., coordination of
the NH to the metal atom and the subsequent deproton-
ation of the metal–NH complex,[21] played crucial roles in
the chemoselectivity. However, the exact origin of this ex-
clusive N1 chemoselectivity requires further exploration.
Another important observation was that the C–N double
bond of compound 1 took exclusively the E conformation
presumably because of the thermodynamical stability. Ap-
parently, in the case of the benzimidazole synthesis through
the tandem double aminations of 1,2-dihaloarenes, the Z/E
isomerization would have to take place first to align the
N2 atom to the requisite Z conformation for the second
amination to occur.
Results and Discussion
In recent years, Cu-mediated amination reaction has
been extensively studied because of the cheaper metal price
and the complementary reactivity in many cases, compared
to the Pd-catalyzed reactions.[13] We recently reported a
CuI-catalyzed tandem amination reaction of 1,2-dihalo-
arenes with guanidines and amidines, which provided a fac-
ile, one-step synthesis of 1-H-2-substituted benzimid-
azoles.[14] In that study, one particularly important aspect
of this reaction, i.e. regioselectivity, was left out because
of the equivalence of the two nitrogen atoms of the 1-H-
benzimidazole product (Scheme 2). In contrast, with N-sub-
stituted amidine starting material (R2 ϶ H), the two nitro-
gen atoms are differentiated, which potentially would afford
two distinct regioisomeric 1,2-disubstituted benzimidazole
products. Although it has been shown that regioselectivity
could be achieved through the sequential C–N and C–O
bond formation in the analogous benzoxazole synthesis,[15]
to the best of our knowledge, the regioselectivity on sub-
strates with two closely associated nitrogen atoms such as
amidines has not been reported. To control the regiochem-
ical outcome of this tandem amination reaction, we recog-
nized that three factors would play critical roles (Scheme 2):
a) the N1:N2 chemoselectivity on the first amination step;
b) the steric and electronic effect of the R3 substituent on
the arene ring; and c) the reactivity difference of the two
differentiated halides. Which of these three controlling fac-
tors is the determining factor and if/how they interfere with
each other were the main questions we tried to answer.
The second controlling factor we examined was the steric
effect of the substituents on the aromatic ring (Table 1, En-
tries 1–3). The same standard reaction conditions were pur-
posely used without individual optimization for the direct
comparison reason. Because of the low reactivity of 1,2-
dibromides, low conversions and yields were observed on
Entries 1 and 2. Nevertheless, useful amount of materials
were obtained for the studies of the regioselectivity of the
reaction. Assuming that electronically the reactivity of the
two halides is similar, any observed regioselectivity should
be dictated by the steric effect of the substituents. With 3,4-
dibromotoluene, the steric effect was rather small, affording
two stable, chromatographically inseparable regioisomers in
Scheme 2. Tandem amination of 1,2-dihaloarenes with amidines.
To determine the N1:N2 chemoselectivity of the first a 1:1.1 ratio (Entry 1). Compound 4b was slightly favored
amination step, we chose to study the mono-amination presumably to avoid the interaction between the methyl
reaction of 3,4-dichloro-1-iodobenzene with N-phenylacet- group and the N-phenyl group. Increasing the size of the
amidine. Under the same amination conditions used in our substituent to a bulkier tert-butyl group only slightly in-
previous paper with N-unsubstituted amidines,[14a] single creased the regioselectivity to a 1:1.4 ratio (Entry 2). In con-
Scheme 3. The N1:N2 chemoselectivity.
Eur. J. Org. Chem. 2010, 680–686
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
681

X. Deng, N. S. Mani
FULL PAPER
trast, 1,2-diiodo-3,5-dimethylbenzene, with a methyl sub- on the more reactive iodide (also N1-selective) and the tan-
stituent close to the halides, gave rise to exclusive re- dem intramolecular amination (at the N2 position) on the
gioisomer
6
(Entry 3).[22] This regiospecificity likely bromide afforded the benzimidazole product regiospecif-
stemmed from the steric hindrance of the methyl substitu- ically. Not surprisingly, when the steric control and the reac-
ent adjacent to the I2 atom forcing the first amination reac- tivity control were matched, a single product 7 was isolated
tion take place at the I1 atom, far away from the methyl (Entry 6). Interestingly, in the case that steric control and
group.
reactivity control were mismatched, the reactivity difference
of the two halides was the dominant factor to afford a sin-
gle regioisomer 8 exclusively (Entry 7). In addition to the
I–Br and I–Cl 1,2-dihalide combinations, the Br–Cl combi-
nation also provided the same degree of regioselectivity al-
though the reaction was usually sluggish (Entry 8).
Table 1. Steric and reactivity control of regioselectivity.
With the knowledge that the N1 chemoselectivity and the
reactivity control were the dominant factors, we further ex-
plored a number of 1,2-differentiated dihaloarenes bearing
various functional groups (Table 2). In all cases, single re-
gioisomers were isolated, suggesting that reactivity control
overruled the electronic and steric effects of the substituents
on the arene ring. A heteroaromatic pyridine ring was com-
patible with the reaction conditions (Entry 5). It is worth
noting that in the presence of electron-withdrawing cyano
Table 2. Reaction scope: 1,2-dihaloarenes.
[a] Isolated yield. [b] Two regioisomers combined. The ratio was
determined on the basis of 1H NMR integration of the purified
product.
The reactivity control of differentiated halides on the re-
gioselectivity was next studied (Table 1, Entries 4–8). In our
previous paper,[14a] we found that the first amination step
was the rate-determining step, with the reaction rate of
IϾBrϾϾCl (unreactive). The second intramolecular amin-
ation step appeared to be rather fast for I, Br and Cl and
did not affect the overall reaction rate. Thus, when the two
halides are differentiated, there are two possible scenarios,
match and mismatch of the steric control and the reactivity
control. When the steric effect was minimum, single re-
gioisomers were obtained exclusively (Entries 4 and 5). Ap-
[a] Isolated yield. [b] 3-Bromo-4-chlorotoluene (≈ 40%) remained
unreacted. [c] The solvent was DMA. [d] The reaction temperature
was at 130 °C. [e] Decomposition of the dihalide was observed even
parently, the first amination reaction occurred preferentially at 100 °C with DMA as the solvent.
682 Eur. J. Org. Chem. 2010, 680–686
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Regiospecific Synthesis of 1,2-Disubstituted Benzimidazoles
group, the reaction took place at lower temperature (Entry various alkyl groups (Table 3, Entries 1–3) did not affect
6). Unfortunately, the nitro group appeared to be incompat- the regioselectivity of this reaction. Amidines with various
ible with the reaction conditions (Entry 7). Even at 100 °C, aromatic groups at the R2 position (Entries 4–7) also af-
complete decomposition of the 3-chloro-4-iodo-1-nitroben- forded the desired benzimidazole products regiospecifically.
zene was observed within 3 h.
Electron-donating substituents on the phenyl ring such as
We next investigated the scope of the reaction with re- methyl (Entry 5) and methoxy (Entry 6) were also well tol-
spect to different amidines that were readily prepared from erated in the reaction. In contrast, substrates with electron-
corresponding amines and nitriles. All the reactions were withdrawing substitutents on the R2 arene ring proved
performed under the standard conditions without individ- problematic. With N-(4-cyanophenyl)acetamidine, decom-
ual optimization. At the R2 position, the steric bulkiness of position of the amidine to 4-cyanoaniline was the major
side reaction (Entry 7). Nevertheless, by lowering the reac-
tion temperature to 100 °C, the desired benzimidazole 22
was isolated in a moderate yield. Unfortunately, the dissoci-
Table 3. Reaction scope: amidines.
ation of N-(4-nitrophenyl)benzamidine to 4-nitroaniline
and benzonitrile was facile even at 100 °C and no amination
product was observed (Entry 8). At the R1 position, either
alkyl (Entry 5–7, 11) or aromatic (including heteroarom-
atic) groups (Entries 1–4, 9–10) were tolerated, again af-
fording the benzimidazole products regioselectively. The
only exception was with 2-iminopiperidine where the minor
regioisomer 25b was observed in a 1:4 (25b/25a) ratio (En-
try 11). We believe that the regioselectivity drop was the
result of the poor N1:N2 selectivity at the first amination
step.
Conclusions
In summary, the regioselectivity of the reaction of 1,2-
dihaloarenes with N-substituted amidines was carefully
studied. The first amination step is exclusively N1-selective
on the amidines, and the chemoselectivity on the 1,2-di-
haloarenes is predominantly controlled by the halide reac-
tivity differences. On the basis on these findings, a highly
regiospecific benzimidazole synthesis was developed. Both
starting materials are readily available, and the reaction
scope is quite broad. One drawback of this methodology is
the low yield on some substrates, which might result from
the instability of the substrates and products under the
high-temperature conditions. The search for more active
catalyst systems is ongoing and will be reported in due
course.
Experimental Section
General Experimental Methods: 1H and 13C NMR spectra were re-
corded at a 600-MHz or a 500-MHz NMR spectrometers. The nOe
and NOSEY experiments were performed using the literature
method[25] with a mixing time of 0.8 s. Flash column chromatog-
raphy was performed using Merck silica gel 60. HRMS (ESI) was
performed on a µTof apparatus.
The reaction flasks were flame-dried prior to use. DMA and NMP
was purchased from commercial sources and used as it was. CuI
was purchased from Aldrich with at least 99.99% purity. All the
[a] Isolated yield. [b] 100 °C in DMA for 16 h. 3-Bromo-4-iodotol-
halides were purchased from commercial sources and used without
uene (≈ 25%) remained unreacted. 4-Cyanoaniline was the major
further purification. Amidines were either purchased from com-
side product. [c] Complete decomposition of the amidine to benzo-
mercial sources or prepared from the corresponding nitriles and
nitrile and 4-nitroaniline took place at 100 °C for 1 h in DMA.
amines by the literature procedures.[26] The detailed 1H NMR
[d] DMA was the solvent. [e] Two isomers combined. Ratio was
determined on the basis of 1H NMR integration of the purified
product.
chemical shift assignments could be found in the Supporting Infor-
mation section.
Eur. J. Org. Chem. 2010, 680–686
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
683

X. Deng, N. S. Mani
FULL PAPER
Typical Procedure for the Regioselective Benzimidazole Synthesis
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 152.1, 143.2, 137.9,
133.0, 131.6, 129.3, 129.2, 128.7, 126.3, 120.6, 116.7, 21.3, 17.6,
14.3 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C16H16N2
237.1386; found 237.1386.
2,6-Dimethyl-1-phenyl-1H-benzimidazole (4a):
A Schlenk tube
equipped with a strong magnetic stirring bar was charged with CuI
(43 mg, 0.22 mmol, 0.15 equiv.), N-phenylacetamidine (282 mg,
2.1 mmol, 1.4 equiv.), and Cs2CO3 (1.5 g, 4.5 mmol, 3 equiv.). The
Schlenk tube was evacuated and backfilled with N2 three times.
Under N2, DMA or NMP (4 mL), 2-bromo-1-iodo-4-methylben-
zene (445 mg, 1.5 mmol, 1.0 equiv.) and N,NЈ-dimethylethylenedi-
amine (39 mg, 0.45 mmol, 0.3 equiv.) were added sequentially via
syringe. The reaction mixture was stirred under N2 at the indicated
temperature (150 °C) for 24 h and then cooled to room tempera-
ture. The inorganic salt was filtered off and washed with EtOAc.
The filtered EtOAc solution was washed with brine, dried with
MgSO4, and concentrated. The crude product was purified on silica
gel with EtOAc/hexanes as the eluents to afford the pure title com-
pound (176 mg, 0.79 mmol, 53%).
2,6-Dimethyl-1-phenyl-1H-benzimidazole (4a): Following the gene-
ral procedure, the title compound was obtained in 53% yield
(176 mg). Rf = 0.13 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.61 (d, J = 8.2 Hz, 1 H), 7.56–7.52 (m, 2 H), 7.50–
7.47 (m, 1 H), 7.33 (dd, J = 8.3, 1.2 Hz, 2 H), 7.06 (dd, J = 8.2,
1.0 Hz, 1 H), 6.90 (s, 1 H), 2.47 (s, 3 H), 2.39 (s, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 150.9, 140.7, 136.7, 136.2, 132.5,
129.8, 128.6, 127.0, 123.8, 118.5, 109.8, 21.6, 14.4 ppm. HRMS-
ESI (m/z): [M + H]+ calcd. for C15H14N2 223.1230; found 223.1224.
2,5-Dimethyl-1-phenyl-1H-benzimidazole (4b): Following the gene-
ral procedure, the title compound was obtained in 57% yield
(190 mg). Rf = 0.13 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.57–7.52 (m, 3 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.36–
7.31 (m, 2 H), 7.00 (s, 2 H), 2.48 (s, 3 H), 2.47 (s, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 151.4, 143.0, 136.3, 134.6, 132.0,
129.8, 128.6, 127.0, 123.9, 118.8, 109.4, 21.5, 14.4 ppm. HRMS-
ESI (m/z): [M + H]+ calcd. for C15H14N2 223.1230; found 223.1223.
N-(3,4-Dichlorophenyl)-NЈ-phenylacetamidine (1): Following the ge-
neral procedure, the title compound was obtained in 29% yield
(121 mg). Rf = 0.1 (1:4 EtOAc/hexanes). 1H NMR (500 MHz,
CDCl3): δ = 13.78 (br. s, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.48–7.43
(m, 2 H), 7.41 (d, J = 2.4 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.25 (d, J
= 7.5 Hz, 2 H), 7.15 (dd, J = 8.5, 2.4 Hz, 1 H), 2.16 (s, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 165.9, 135.1, 134.9, 133.9, 132.9,
131.5, 130.0, 128.8, 127.7, 125.7, 125.2, 16.0 ppm. HRMS-ESI
(m/z): [M + H]+ calcd. for C14H12Cl2N2 279.0450; found 279.0445.
7-Chloro-2-methyl-1-phenyl-1H-benzimidazole (7): Following the
general procedure, the title compound was obtained in 24% yield
(87 mg). Rf = 0.23 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.65 (d, J = 7.7 Hz, 1 H), 7.56–7.47 (m, 3 H), 7.37–
7.30 (m, 2 H), 7.19–7.10 (m, 2 H), 2.37 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 153.4, 144.5, 136.4, 132.2, 129.3, 129.1,
128.8, 123.9, 122.7, 117.9, 116.1, 14.3 ppm. HRMS-ESI (m/z): [M
+ H]+ calcd. for C14H11ClN2 243.0684; found 243.0673.
Mixture of 2,6-Dimethyl-1-phenyl-1H-benzimidazole (4a) and 2,5-
Dimethyl-1-phenyl-1H-benzimidazole (4b): (Table 1, Entry 1) Fol-
lowing the general procedure, the title compounds (an inseparable
mixture of 4a and 4b in a 1:1.1 ratio according to 1H NMR integra-
tion of the purified product) were obtained in 11% combined yield
(36 mg).[23] Rf = 0.12 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3, 4a): δ = 7.61 (d, J = 8.2 Hz, 1 H), 7.56–7.52 (m, 2 H), 7.50–
7.47 (m, 1 H), 7.38–7.33 (m, 2 H), 7.08 (dd, J = 8.2, 1.0 Hz, 1 H),
6.91 (s, 1 H), 2.48 (s, 3 H), 2.41 (s, 3 H) ppm. 4: 1H NMR
(600 MHz, CDCl3): δ = 7.56–7.52 (m, 3 H), 7.50–7.48 (m, 1 H),
7.38–7.33 (m, 2 H), 7.01 (s, 2 H), 2.49 (s, 3 H), 2.48 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3, 4a+4b, 1:1.1): δ = 151.4, 151.0, 143.0,
140.7, 136.7, 136.3, 136.3, 134.6, 132.5, 132.0, 129.9, 129.8, 128.7,
128.6, 127.1, 127.0, 123.9, 123.8, 118.8, 118.5, 109.9, 109.4, 21.7,
21.5, 14.4, 14.4 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for
C15H14N2 223.1230; found 223.1227.
2,4-Dimethyl-1-phenyl-1H-benzimidazole (8): Following the general
procedure, the title compound was obtained in 38% yield (127 mg).
1
Rf = 0.21 (1:1 EtOAc/hexanes). H NMR (600 MHz, CDCl3): δ =
7.53 (ddd, J = 7.9, 4.6, 1.2 Hz, 2 H), 7.50–7.45 (m, 1 H), 7.35–7.30
(m, 2 H), 7.11–7.02 (m, 2 H), 6.97–6.91 (m, 1 H), 2.71 (s, 3 H),
2.51 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 150.6, 141.8,
136.3, 136.1, 129.8, 128.8, 128.6, 127.0, 122.8, 122.4, 107.5, 16.7,
14.4 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C15H14N2
223.1230; found 223.1225.
2,7-Dimethyl-1-phenyl-1H-benzimidazole (9): Following the general
procedure, the title compound was obtained in 10% yield (33 mg).
About 65% starting material 3-bromo-2-chlorotoluene remained
unreacted. Rf = 0.18 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.78 (d, J = 8.3 Hz, 1 H), 7.75–7.71 (m, 1 H), 7.70–
7.65 (m, 2 H), 7.47–7.43 (m, 2 H), 7.42–7.36 (m, 1 H), 7.18 (d, J
= 7.4 Hz, 1 H), 2.66 (s, 3 H), 1.93 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 150.9, 134.1, 131.5, 131.4, 130.4, 129.5,
128.5, 128.0, 126.3, 123.5, 113.5, 17.4, 11.9 ppm. HRMS-ESI (m/z):
[M + H]+ calcd. for C15H14N2 223.1230; found 223.1225.
Mixture of 6-tert-Butyl-2-methyl-1-phenyl-1H-benzimidazole (5a)
and Methyl-1-phenyl-1H-benzimidazole (5b): (Table 1, Entry 2) Fol-
lowing the general procedure, the title compounds (an inseparable
mixture of 5a 5b in a 1:1.4 ratio according to 1H NMR integration
of the purified product) were obtained in 14% combined yield
(55 mg).[24] Rf = 0.3 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3) 5a δ = 7.86 (d, J = 8.7 Hz, 1 H), 7.77–7.69 (m, 3 H), 7.62
(dd, J = 8.6, 1.4 Hz, 1 H), 7.49–7.40 (m, 2 H), 7.16 (d, J = 1.5 Hz,
1 H), 2.78 (s, 3 H), 1.32 (s, 9 H) ppm. 1H NMR (600 MHz, CDCl3,
5b): δ = 7.90 (s, 1 H), 7.77–7.69 (m, 3 H), 7.54 (dd, J = 8.8, 0.9 Hz,
1 H), 7.49–7.41 (m, 2 H), 7.19 (d, J = 8.8 Hz, 1 H), 2.81 (s, 3 H),
1.39 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3, 5a + 5b): δ =
151.0, 150.8, 150.3, 150.3, 133.3, 132.4, 132.3, 131.3, 131.2, 131.2,
130.95, 130.87, 129.0, 126.8, 126.7, 125.0, 124.6, 115.0, 111.7,
111.2, 107.6, 35.3, 31.5, 31.4, 12.0, 12.0 ppm. HRMS-ESI (m/z):
[M + H]+ calcd. for C18H20N2 265.1699; found 265.1693.
6-Chloro-2-methyl-1-phenyl-1H-benzimidazole (10): Following the
general procedure, the title compound was obtained in 41% yield
(149 mg). Rf = 0.25 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.64 (d, J = 8.5 Hz, 1 H), 7.62–7.58 (m, 2 H), 7.56–
7.52 (m, 1 H), 7.38–7.33 (m, 2 H), 7.23 (dd, J = 8.5, 2.0 Hz, 1 H),
7.11–7.09 (m, 1 H), 2.50 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 152.5, 141.2, 137.0, 135.5, 130.1, 129.2, 128.4, 127.0,
123.0, 119.8, 110.1, 14.4 ppm. HRMS-ESI (m/z): [M + H]+ calcd.
for C14H11ClN2 243.0684; found 243.0674.
2,5,7-Trimethyl-1-phenyl-1H-benzimidazole (6): Following the gene-
ral procedure, the title compound was obtained in 51% yield
(181 mg). Rf = 0.16 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.54–7.47 (m, 3 H), 7.38 (s, 1 H), 7.32 (dd, J = 6.7, Rf = 0.14 (1:4 EtOAc/hexanes). H NMR (600 MHz, CDCl3): δ =
2.9 Hz, 2 H), 6.75 (s, 1 H), 2.42 (s, 3 H), 2.33 (s, 3 H), 1.86 (s, 3 7.80 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53–7.49 (m, 2 H), 7.48–7.44 (m,
7-Chloro-1,2-diphenyl-1H-benzimidazole (11): Following the general
procedure, the title compound was obtained in 29% yield (132 mg).
1
684
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 680–686

Regiospecific Synthesis of 1,2-Disubstituted Benzimidazoles
1 H), 7.42–7.38 (m, 2 H), 7.38–7.33 (m, 2 H), 7.33–7.28 (m, 1 H),
22.0, 21.4 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C17H18N2
7.28–7.18 (m, 4 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 154.0, 251.1543; found 251.1535.
144.8, 137.0, 132.8, 129.7, 129.7, 129.6 (2 C), 129.3, 128.8, 128.2,
1-Benzyl-6-methyl-2-phenyl-1H-benzimidazole (18): Following the
124.9, 123.2, 118.7, 116.7 ppm. HRMS-ESI (m/z): [M + H]+ calcd.
general procedure, the title compound was obtained in 11% yield
(49 mg). Rf = 0.07 (1:4 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.74 (d, J = 8.2 Hz, 1 H), 7.70–7.62 (m, 2 H), 7.48–
7.38 (m, 3 H), 7.38–7.27 (m, 3 H), 7.15–7.12 (m, 1 H), 7.12–7.08
(m, 2 H), 7.00 (s, 1 H), 5.41 (s, 2 H), 2.43 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 153.7, 141.3, 136.6, 136.4, 133.1, 130.2,
for C19H13ClN2 305.0840; found 305.0834.
5-Methyl-1,2-diphenyl-1H-benzimidazole (12): Following the gene-
ral procedure, the title compound was obtained in 20% yield
(85 mg). About 40% starting material 3-bromo-4-chlorotoluene re-
mained unreacted. Rf = 0.14 (1:4 EtOAc/hexanes). 1H NMR
(600 MHz, CDCl3): δ = 7.67 (s, 1 H), 7.58–7.51 (m, 2 H), 7.47– 129.7, 129.2, 129.0, 128.7, 127.7, 125.9, 124.3, 119.5, 110.3, 48.2,
7.38 (m, 3 H), 7.33–7.23 (m, 5 H), 7.10 (d, J = 8.2 Hz, 1 H), 7.06 21.8 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C21H18N2
(d, J = 1.0 Hz, 1 H), 2.49 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 152.3, 143.4, 137.2, 135.4, 132.7, 130.1, 129.8, 129.4,
129.3, 128.4, 128.3, 127.3, 124.8, 119.6, 110.0, 21.6 ppm. HRMS-
ESI (m/z): [M + H]+ calcd. for C20H16N2 285.1386; found 285.1377.
299.1543; found 299.1530.
6-Methyl-1,2-diphenyl-1H-benzimidazole (19): Following the gene-
ral procedure, the title compound was obtained in 56% yield
(239 mg). Rf = 0.55 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.76 (d, J = 8.2 Hz, 1 H), 7.57–7.52 (m, 2 H), 7.49–
7.39 (m, 3 H), 7.33–7.22 (m, 5 H), 7.17–7.12 (m, 1 H), 7.03–6.99
(m, 1 H), 2.42 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
151.9, 141.1, 137.4, 137.1, 133.4, 130.1, 129.8, 129.3, 129.2, 128.4,
128.2, 127.4, 124.5, 119.3, 110.2, 21.8 ppm. HRMS-ESI (m/z): [M
2-Methyl-1-phenyl-5-trifluoromethyl-1H-benzimidazole (13): Fol-
lowing the general procedure, the title compound was obtained in
24% yield (99 mg). Rf = 0.42 (1:1 EtOAc/hexanes). 1H NMR
(600 MHz, CDCl3): δ = 8.01 (d, J = 0.7 Hz, 1 H), 7.64–7.58 (m, 2
H), 7.57–7.55 (m, 1 H), 7.44 (dd, J = 8.5, 1.2 Hz, 1 H), 7.39–7.34
(m, 2 H), 7.19 (d, J = 8.4 Hz, 1 H), 2.53 (s, 3 H) ppm. 13C NMR + H]+ calcd. for C20H16N2 285.1386; found 285.1376.
(151 MHz, CDCl3): δ = 153.8, 142.2, 138.4, 135.4, 130.2, 129.4,
2,6-Dimethyl-1-o-tolyl-1H-benzimidazole (20): Following the gene-
127.0, 124.9 (q, J = 272 Hz, 1 C), 124.9 (q, J = 32 Hz, 1 C), 119.6
ral procedure, the title compound was obtained in 49% yield
(q, J = 3.7 Hz, 1 C), 116.7 (q, J = 3.7 Hz, 1 C), 110.3, 77.3, 77.1,
(174 mg). Rf = 0.20 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
76.9, 14.5 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C15H11F3N2
CDCl3): δ = 7.63 (d, J = 8.2 Hz, 1 H), 7.47–7.39 (m, 2 H), 7.38–
277.0947; found 277.0941.
7.33 (m, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.07 (dd, J = 8.2, 1.1 Hz,
2-Methyl-3-phenyl-3H-imidazo[4,5-b]pyridine (14): Following the
general procedure, the title compound was obtained in 39% yield
(122 mg). Rf = 0.11 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
MeOD): δ = 8.47 (dd, J = 4.8, 1.3 Hz, 1 H), 8.25 (dd, J = 8.2,
1.3 Hz, 1 H), 7.74–7.64 (m, 3 H), 7.63–7.59 (m, 2 H), 7.57 (dd, J
= 8.2, 4.8 Hz, 1 H), 2.73 (s, 3 H) ppm. 13C NMR (151 MHz,
MeOD): δ = 155.3, 147.5, 133.7, 131.7, 131.2, 129.8, 128.8, 128.4,
125.6, 122.5, 13.5 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for
C13H11N3 210.1026; found 210.1021.
1 H), 6.69 (s, 1 H), 2.38 (s, 3 H), 2.36 (s, 3 H), 1.97 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 151.1, 140.8, 136.5, 136.4, 134.9,
132.4, 131.4, 129.5 128.4, 127.3, 123.6, 118.5, 109.8, 21.6, 17.3, 13.9
ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C16H16N2 237.1386;
found 237.1382.
1-(4-Methoxyphenyl)-2,6-dimethyl-1H-benzimidazole (21): Follow-
ing the general procedure, the title compound was obtained in 48%
yield (182 mg). Rf
(600 MHz, CDCl3): δ = 7.61 (d, J = 6.3 Hz, 1 H), 7.27–7.21 (m, 2
=
0.14 (1:1 EtOAc/hexanes). 1H NMR
2-Methyl-3-phenyl-3H-benzimidazole-5-carbonitrile (15): Following H), 7.10–7.03 (m, 3 H), 6.89 (s, 1 H), 3.88 (s, 3 H), 2.44 (s, 3 H),
the general procedure, the title compound was obtained in 31%
2.39 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 159.7, 151.4,
yield (108 mg). Rf
0.28 (1:1 EtOAc/hexanes). 1H NMR 140.7, 137.1, 132.3, 128.8, 128.3, 123.6, 118.4, 115.0, 109.9, 55.6,
(600 MHz, CDCl3): δ = 7.79 (d, J = 8.3 Hz, 1 H), 7.68–7.62 (m, 2
21.6, 14.3 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C16H16N2O
=
H), 7.62–7.57 (m, 1 H), 7.53 (dd, J = 8.3, 1.5 Hz, 1 H), 7.45 (d, J 253.1335; found 253.1330.
= 0.9 Hz, 1 H), 7.39–7.35 (m, 2 H), 2.56 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 155.3, 145.6, 136.2, 134.9, 130.3, 129.7,
126.9, 126.1, 119.9, 119.8, 114.8, 105.5, 14.5 ppm. HRMS-ESI
(m/z): [M + H]+ calcd. for C15H11N3 234.1026; found 234.1016.
4-(2,6-Dimethylbenzimidazol-1-yl)benzonitrile (22): Following the
general procedure, the title compound was obtained in 41% yield
(152 mg). In addition to ca. 25% unreacted starting material 3-
bromo-4-iodotoluene, decomposition product of the amidine, 4-
aminobenzonitrile was also isolated. Rf = 0.19 (1:1 EtOAc/hex-
1,6-Dimethyl-2-phenyl-1H-benzimidazole (16): Following the gene-
ral procedure, the title compound was obtained in 48% yield
(160 mg). Rf = 0.39 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.75–7.71 (m, 2 H), 7.69 (d, J = 8.2 Hz, 1 H), 7.52–
1
anes). H NMR (600 MHz, CDCl3): δ = 7.97–7.84 (m, 2 H), 7.62
(d, J = 8.2 Hz, 1 H), 7.58–7.50 (m, 2 H), 7.17–7.06 (m, 1 H), 6.93
(s, 1 H), 2.52 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR (151 MHz,
7.43 (m, 3 H), 7.15 (d, J = 0.7 Hz, 1 H), 7.14–7.09 (m, 1 H), 3.78 CDCl3): δ = 150.2, 140.8, 140.2, 135.8, 133.9, 133.3, 127.7, 124.5,
(d, J = 3.9 Hz, 3 H), 2.51 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 153.3, 141.0, 136.8, 132.7, 130.3, 129.5, 129.3, 128.6,
124.0, 119.3, 109.6, 31.5, 21.9 ppm. HRMS-ESI (m/z): [M + H]+
calcd. for C15H14N2 223.1230; found 223.1228.
118.9, 117.8, 112.5, 109.5, 21.7, 14.6 ppm. HRMS-ESI (m/z): [M +
H]+ calcd. for C16H13N3 248.1182; found 248.1174.
1-Benzyl-2-(4-methoxyphenyl)-6-methyl-1H-benzimidazole
(23):
Following the general procedure, the title compound was obtained
in 16% yield (78 mg). Rf = 0.33 (1:1 EtOAc/hexanes). 1H NMR
(600 MHz, CDCl3): δ = 7.71 (d, J = 8.2 Hz, 1 H), 7.61–7.55 (m, 2
H), 7.37–7.26 (m, 3 H), 7.13–7.08 (m, 3 H), 6.97 (s, 1 H), 6.95–6.90
(m, 2 H), 5.38 (s, 2 H), 3.81 (s, 4 H), 2.42 (s, 3 H) ppm. 13C NMR
1-Isopropyl-6-methyl-2-phenyl-1H-benzimidazole (17): Following
the general procedure, the title compound was obtained in 24%
yield (90 mg). Rf = 0.41 (1:1 EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3): δ = 7.70 (d, J = 8.2 Hz, 1 H), 7.65–7.59 (m, 2 H), 7.51–
7.45 (m, 3 H), 7.41 (d, J = 0.7 Hz, 1 H), 7.10 (dd, J = 8.2, 0.7 Hz, (151 MHz, CDCl3): δ = 160.8, 153.7, 141.3, 136.7, 136.4, 132.8,
1 H), 4.78 (hepta, J = 7.0 Hz, 1 H), 2.52 (s, 3 H), 1.62 (d, J = 130.6, 129.0, 127.6, 125.9, 124.1, 122.5, 119.2, 114.1, 110.2, 55.3,
7.0 Hz, 6 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 153.1, 141.9,
48.2, 21.8 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for C22H20N2O
133.8, 132.0, 131.2, 129.5, 129.4, 128.6, 123.6, 119.7, 112.2, 48.6,
329.1648; found 329.1645.
Eur. J. Org. Chem. 2010, 680–686
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
685

X. Deng, N. S. Mani
FULL PAPER
[9]
a) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
6338–6361; b) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534–
1544.
6-Methyl-1-phenyl-2-(pyridin-4-yl)-1H-benzimidazole (24): Follow-
ing the general procedure, the title compound was obtained in 56%
yield (240 mg). Rf
=
0.12 (1:1 EtOAc/hexanes). 1H NMR
[10]
a) C. T. Brain, S. A. Brunton, Tetrahedron Lett. 2002, 43, 1893–
1895; b) G. Evindar, R. A. Batey, Org. Lett. 2003, 5, 133–136;
c) C. T. Brain, J. T. Steer, J. Org. Chem. 2003, 68, 6814–6816;
d) B. G. Szczepankiewicz, J. J. Rohde, R. Kurukulasuriyz, Org.
Lett. 2005, 7, 1833–1835; e) J. Alen, K. Robeyns, W. M.
De Borggraeve, L. Van Meervelt, F. Compernolle, Tetrahedron
2008, 64, 8128–8133; f) Z. Li, H. Sun, H. Jiang, H. Liu, Org.
Lett. 2008, 10, 3263–3266; g) S. Murru, B. K. Patel, J. Le Bras,
J. Muzart, J. Org. Chem. 2009, 74, 2217–2220; h) X. Lv, W.
Bao, J. Org. Chem. 2009, 74, 5618–5621.
(600 MHz, CDCl3): δ = 8.54 (dd, J = 4.6, 1.6 Hz, 2 H), 7.78 (d, J
= 8.3 Hz, 1 H), 7.60–7.51 (m, 3 H), 7.43 (dd, J = 4.5, 1.7 Hz, 2 H),
7.35–7.30 (m, 2 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.02 (s, 1 H), 2.45
(s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.9, 148.8,
140.9, 137.7, 137.6, 136.5, 134.6, 130.2, 129.1, 127.4, 125.2, 123.0,
119.8, 110.4, 21.9 ppm. HRMS-ESI (m/z): [M + H]+ calcd. for
C19H15N3 286.1339; found 286.1328.
Mixture of 8-Methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole
(25a) and 7-Methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole
(25b): (Table 3, Entry 11) Following the general procedure, the title
compounds (an inseparable mixture of 25a/25b in a 4:1 ratio deter-
mined by 1H NMR integration of the purified product) were ob-
tained in 29% combined yield (81 mg). Rf = 0.20 (5% MeOH in
EtOAc). Two sets of peaks (4:1, 25a/25b): 1H NMR (600 MHz,
CDCl3): δ = 7.69 (d, J = 8.4 Hz, 1 H), 7.62 (s, 0.25 H), 7.41 (d, J
= 8.4 Hz, 0.25 H), 7.32 (s, 1 H), 7.28 (d, J = 8.4 Hz, 1.25 H), 4.24
(t, J = 6.1 Hz, 2.5 H), 3.34 (t, J = 6.2 Hz, 2.5 H), 2.52 (s, 3 H),
2.48 (s, 0.75 H), 2.27–2.23 (m, 2.5 H), 2.12–2.08 (m, 2.5 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 149.9, 149.9, 136.9, 136.1, 131.6,
131.5, 129.5, 129.3, 127.8, 127.0, 114.9, 114.7, 110.6, 110.4, 43.0,
42.9, 22.3, 22.3, 21.6, 21.5, 21.3, 21.3, 18.3, 18.3 ppm. HRMS-ESI
(m/z): [M + H]+ calcd. for C12H14N2 187.1230; found 187.1237.
[11]
[12]
[13]
B. Zou, Q. Yuan, D. Ma, Angew. Chem. Int. Ed. 2007, 46,
2598–2601.
N. Zheng, K. W. Anderson, X. Huang, H. N. Nguyen, S. L.
Buchwald, Angew. Chem. Int. Ed. 2007, 46, 7509–7512.
For the general reviews of Cu-mediated amination reaction: a)
S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42,
5400–5449; b) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem.
Rev. 2004, 248, 2337–2364; c) M. Kienle, S. R. Dubbaka, K.
Brade, P. Knochel, Eur. J. Org. Chem. 2007, 4166–4176; d) G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–
3131; e) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450–1460;
f) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed. 2008, 47,
3096–3099; g) Q. Cai, H. Zhang, B. Zou, X. Xie, W. Zhu, G.
He, J. Wang, X. Pan, Y. Chen, Q. Yuan, F. Liu, B. Lu, D. Ma,
Pure Appl. Chem. 2009, 81, 227–234; h) F. Monnier, M.
Taillefer, Angew. Chem. Int. Ed. 2009, 48, 6954–6971.
a) X. Deng, H. McAllister, N. S. Mani, J. Org. Chem. 2009,
74, 5742–5745. One single example was also reported: b) R. D.
Viirre, G. Evindar, R. A. Batey, J. Org. Chem. 2008, 73, 3452–
3459.
Supporting Information (see also the footnote on the first page of
this article): NMR spectra (1H, 13C, COSY, nOe, NOSEY) of com-
pounds 1, 4–25.
[14]
[15]
[16]
Similar regiochemistry control has been observed in the synthe-
sis of benzoxazoles: G. Altenhoff, F. Glorius, Adv. Synth. Catal.
2004, 346, 1661–1664.
The reaction was rather clean as revealed by HPLC and TLC
analysis and presumably higher-yielding. It was noticed that
the purified compound completely decomposed within 1–2 d
at room temperature.
M. Wolter, A. Klapars, S. L. Buchwald, Org. Lett. 2001, 3,
3803–3805.
X. Huang, K. W. Anderson, D. Zim, L. Liang, A. Klapars,
S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653–6655.
A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am.
Chem. Soc. 2001, 123, 7727–7729.
Acknowledgments
We wish to thank Ms. Heather McAllister for analytical support
and Dr. Daniel J. Pippel for proof-reading this manuscript.
[1] D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
103, 893–930.
[2] M. Alamgir, D. St. C. Black, N. Kumar, Synthesis reactivity and
biological activity of benzimidazoles, in: Topics in Heterocyclic
Chemistry, Springer, Berlin, Heidelberg, 2007, vol. 9, pp. 87–
118, and references cited therein.
[3] M. R. Grimmett, in: Imidazole and Benzimidazole Synthesis
Best Synthetic Methods (Eds.: O. Meth-Cohn, A. R. Katritzky),
Academic Press, London, 1997.
[4] a) D. Villemin, M. Hammadi, B. Martin, Synth. Commun.
1996, 26, 2895–2899; b) A. Beu-Alloum, S. Bakkas, M. Soufia-
oui, Tetrahedron Lett. 1998, 39, 4481–4484; c) D. Yang, D.
Fokas, J. Li, L. Yu, C. M. Balkino, Synthesis 2005, 47–56; d)
M. Shen, T. G. Driver, Org. Lett. 2008, 10, 3367–3370.
[5] T. Ishida, T. Suzuki, S. Hirashima, K. Mizutani, A. Yoshida,
I. Ando, S. Ikeda, T. Adachi, H. Hashimoto, Bioorg. Med.
Chem. Lett. 2006, 16, 1859–1863.
[6] L. J. Goossen, T. Knauber, J. Org. Chem. 2008, 73, 8631–8634.
[7] a) Y. Taniguchi, E. T. Kool, J. Am. Chem. Soc. 2007, 129, 8836–
8844; b) J.-F. Bonfanti, C. Meyer, F. Doublet, J. Fortin, P.
Muller, L. Queguiner, T. Gevers, P. Janssens, H. Szel, R. Wille-
brords, P. Timmerman, K. Wuyts, P. van Remoortere, F.
Janssens, P. Wigerinck, K. Andries, J. Med. Chem. 2008, 51,
875–896; c) C. Chassaing, M. Berger, A. Heckeroth, T. Ilg, M.
Jaeger, C. Kern, K. Schmid, M. Uphoff, J. Med. Chem. 2008,
51, 1111–1114.
[17]
[18]
[19]
[20]
[21]
B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald, J. Am.
Chem. Soc. 2008, 130, 13552–13554.
a) A. Shafir, P. A. Lichtor, S. L. Buchwald, J. Am. Chem. Soc.
2007, 129, 3490–3491; b) M. R. Biscoe, T. E. Barder, S. L.
Buchwald, Angew. Chem. Int. Ed. 2007, 46, 7232–7235.
Extensive nOe or NOSEY NMR experiments were used to as-
sign the regiochemistry of the benzimidazole products; for de-
tails see Supporting Information.
Incomplete reaction, ca. 50% 3,4-dibromotoluene remained.
Incomplete reaction, ca. 60% 3,4-dibromo-1-tert-butylbenzene
remained.
[22]
[23]
[24]
[25]
[26]
K. Stott, J. Keeler, Q. N. Van, A. J. Shaka, J. Magn. Reson.
1997, 125, 302–324.
a) P. Oxley, M. W. Partridge, W. F. Short, J. Chem. Soc. 1947,
1112–1116; b) A. Marsura, L.-D. Cuong, G. Gellon, Synthesis
1985, 5, 537–541; c) S. B. Ferreira, M. S. Costa, N. Boechat,
R. J. S. Beserra, M. S. Genestra, M. M. Canto-Cavalheiro,
W. B. Kover, V. F. Ferreira, Eur. J. Med. Chem. 2007, 42, 1388–
1395.
[8] K. R. Hornberger, J. G. Badiang, J. M. Salovich, K. W. Kuntz,
K. A. Emmitte, M. Cheung, Tetrahedron Lett. 2008, 49, 6348–
6351.
Received: September 17, 2009
Published Online: December 14, 2009
686
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 680–686