Why are benzimidazoles efficiently acylated with esters? Identification of a tetrahedral hemiacetal alkoxide intermediate

Article abstract of DOI:10.1016/j.tetlet.2005.05.068

2-Lithio benzimidazoles were acylated with esters, lactones, and lactams. The tetrahedral hemiacetal intermediates responsible for the efficient conversion were characterized by low temperature NMR.

Full text of DOI:10.1016/j.tetlet.2005.05.068

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5081–5084
Why are benzimidazoles efficiently acylated with esters?
Identification of a tetrahedral hemiacetal alkoxide intermediate
Ken-ichi Asakawa,b J. J. Dannenberg,c Kenneth J. Fitch,a Stan S. Hall,d Chie Kadowaki,b
Sandor Karady,a,* Satoshi Kii,b Kenji Maeda,b Benjamin F. Marcune,a Toshiaki Mase,b
a,
a
Ross A. Miller,a,* Robert A. Reamer and David M. Tschaen
*
aProcess Research Department, Merck and Co., PO Box 2000, Rahway, NJ 07065, USA
bProcess Research Department, Banyu Pharmaceutical Co., Ltd, 9-1 Kamimutsuna 3-chome, Okazaki, Aichi 444-0858, Japan
cDepartment of Chemistry, City University of New York-Hunter College and Graduate School, 695Park Avenue, New York,
NY 100021, USA
dDepartment of Chemistry, Rutgers University, Newark, NJ 08876, USA
Received 15 November 2004; revised 11 May 2005; accepted 16 May 2005
Available online 14 June 2005
Abstract—2-Lithio benzimidazoles were acylated with esters, lactones, and lactams. The tetrahedral hemiacetal intermediates
responsible for the efficient conversion were characterized by low temperature NMR.
Ó 2005 Published by Elsevier Ltd.
Substituted benzimidazoles are important intermediates
for the synthesis of various drugs and natural products.
Substituents at the 2-position are generally introduced
by reaction of the 2-lithio derivative of N-protected
benzimidazoles with electrophiles.1 The dimethoxy-
methyl N-protecting group has been used because of
its easy removal and ketones were obtained by acylation
of the corresponding carbanion.2 In some cases when
esters were used as acylating agents the yields were
low and bis addition products dominated.3 It was re-
ported that at low temperature, the reaction was more
reproducible and higher yielding.4 We discovered that
the stability of a tetrahedral intermediate hemiacetal
alkoxide plays a critical role in these reactions.
Furthermore, in a recent letter, a hydrogen bond stabi-
lized hemiacetal intermediate derived from an ester was
identified by NMR.12 Hemiacetals produced by the addi-
tion of heterocyclic carbanions, including indoles and
benzimidazoles to some lactones, are stable.13
In connection with the synthesis of an important drug
candidate, we explored various routes for the efficient
synthesis of benzimidazole 2-ketones. After testing vari-
ous alternatives, we found that N-dimethoxymethyl
benzimidazole can be efficiently acylated with esters
when deprotonated by LDA. In this letter, we present
evidence that a tetrahedral intermediate of limited sta-
bility is responsible for the selective reaction and present
a general method for the preparation of 2-acyl
benzimidazoles.
Tetrahedral intermediates have been postulated to govern
the reactivity of Weinreb type N-methoxyamides,5 N-
methylamino pyridyl amides,6 phenyl 2-pyridyl ketone
O-acyl oximes,7 lactones,8 and 2-mercapto pyridine
esters.9 In the last case, experimental evidence rejected
the attractive postulate.10 Ester derived hemiacetal inter-
mediates were trapped by silylation and characterized.11
When the lithiated orthoamide 2a was reacted with an
equivalent amount of methyl benzoate at À78 °C, the
desired ketone 4a was produced and after acid deprotec-
tion, ketone 5a was obtained. Only a trace of the bis
addition product 7a was detected. When the lithiate 2a
was used in excess and the reaction mixture was allowed
to warm to room temperature, bis adduct 7a became the
dominant product (Scheme 1).
Keywords: Acylation; Ketones; Benzimidazole; Tetrahedral intermedi-
ate; Hemiacetal alkoxide.
*
This prompted us to examine the temperature profile
of the reaction. Two equivalents of 2a were allowed
Corresponding authors. Tel.: +1 732 594 4085; fax: +1 732 594
6703; e-mail: sandor_karady@merck.com
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.068

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K. Asakawa et al. / Tetrahedron Letters 46 (2005) 5081–5084
X
OLi
R
OMe
X
X
O
X
R1
LDA
Li
N
+
N
N
N
R
N
OH
X
R1
R1
R1
R1
X
4
3
1
2
R
N
R1
NH
O
X
+
OH
R
6
a) R=Ph, R1=(MeO)2CH-, X=N
X
R
N
H
b) R=t-Bu, R1=(MeO)2CH-, X=N
c) R=Ph, R1=CH3, X=N
d) R=Ph, R1=(MeO)2CH-, X=C
X
5
NH
7
Scheme 1.
to react with methyl benzoate at À78 °C, aliquots were
quenched at increasing temperatures and the product ra-
tios were evaluated by liquid chromatography. It is clear
from the results, shown in Chart 1, that at temperatures
below À40 °C, addition to the ketone was minimal and
only at higher temperatures did alcohol formation
become dominant.
100
90
80
70
60
50
40
30
20
10
0
Benzimidazole
5a
7a
Surprisingly, N-methyl benzimidazole 1c showed similar
temperature profile (Chart 2). The possibility that slow
reactivity of ketone 4a at low temperature is responsible
for the selectivity observed, was tested next. Ketone 4a
reacted rapidly with 2a at À78 °C to produce the tertiary
alcohol 6a. This suggested that below À40 °C, a limited
stability intermediate is protecting the ketone from fur-
ther reactions.
-70 -60 -50 -40 -30 -20 -10
0
10 rt
Chart 1.
100
90
80
70
60
50
40
30
20
10
0
Because of the chelating ability of the dimethoxymethyl
protecting group and the imidazole nitrogen, we sus-
pected formation of a stabilized tetrahedral hemiacetal
lithium alkoxide intermediate. We first detected the
intermediate by a simple NMR experiment. When the
lithiated benzimidazole 2a was reacted with methyl ben-
zoate in deuterated THF, NMR at room temperature
showed only broad signals and no ketone carbonyl. This
mixture was remarkably stable as it was stored in the
refrigerator for several days without decomposition.
Addition of water instantly generated the signals of
the protected ketone 4a. Cooling the mixture to
1c
4c
6c
-70 -60 -50 -40 -30 -20 -10
0
10 rt
Chart 2.
1
À30 °C, sharpened the NMR signals and H, 13C, and
2D-HMBC were used to characterize the intermediate.
Selected NMR data is presented with the two possible
structures 3a-T1 and 3a-T2 (Scheme 2).
one methoxy group is complexed to lithium as in 3-T2.
However, a similar experiment with N-methyl benzimid-
azole showed an analogous intermediate presumably
3c-T1. The similarity between the NMR characteristics
The significant 1H chemical shift differences between the
two orthoamide methoxy groups of 3a suggested that
R
Li
N
N
δC=101.9
O
δC=101.7
R
O
N
N
Li
O
O
N
O
O
Li
δH=3.21, δC=50.6
δH=6.35, δC=105.9
R
O
O
N
O
O
δH=3.18, δC=49.9
δH=2.31, δC=53.7
δH=3.43, δC=30.4
δH=3.38, δC=55.5
3a-T1
3a-T2
3c-T1
Scheme 2.

K. Asakawa et al. / Tetrahedron Letters 46 (2005) 5081–5084
Table 1. Acylation of 1-dimethoxymethyl benzimidazole 1a
5083
of the intermediates derived from 3a and 3c, specifically
the chemical shifts of the tetrahedral centers and the
attached OMe groups advocated a T1 type structure.
A sharp, major 6Li NMR signal was also observed,
but this is not diagnostic since the chemical shifts of
LDA, 2a, and 3a are very similar.
Acylating agent
Product 5, R group
Isolated yield (%)
O
78
EtO
O
93
70
A similar experiment with ethyl pivalate also produced
an analogous chelated tetrahedral intermediate but in
this case, it converted to the ketone 4b on warming to
À40 °C. It is reasonable to assume that these observed
dominant intermediates are responsible for the major
product formation.
Me
EtO
Me
O
EtO
O
60
90
60
76
70
76
EtO
In order to clearly distinguish between the two forms of
complexation, the reactivity of dimethoxymethyl indole
1d was examined. Deprotonation with t-BuLi at 0 °C,
and reaction with an equivalent of methyl benzoate at
À78 °C only generated the bis addition product 7d, indi-
cating that in this case when only T2 type chelation is
possible, no stable intermediate formed and the ketone
4d was converted rapidly to the alcohol 7d by a rapid
second addition.
O
N
EtO
N
O
S
S
EtO
O
Theoretical DFT calculation at the B3LYP/6-31G(d,p)
level were performed on structures 3a-T1 and 3a-T2
using the GAUSSIAN 0316 suite of programs. The
geometries of each structure were completely optimized,
vibrational frequencies (all real) and enthalpies at 298 K
were obtained. This indicated that five member ring T-1
structure is calculated to be 4.8 kcal lower in enthalpy
than the seven member T-2.
N
EtO
N
N
O
N
N
O
N
Based on the combined evidence, we propose that both
N-methyl and dimethoxymethyl benzimidazoles form
analogous chelated intermediates of the type of T1,
which protects the ketone from further reaction at low
temperature. Understanding the stability of the inter-
mediate enabled us to develop a general method for
the acylation of benzimidazoles with esters.14 It was
critical to generate the lithiate 2 in the presence of the
ester or add the ester in slight excess, at low tempera-
ture and allow the reaction to proceed at that tempera-
ture. Short exposure to 2 N HCl solution removed the
protecting group and generated the desired ketone.
The data summarized in Table 1, illustrates the versatil-
ity of the method. Aliphatic, aromatic, heterocyclic and
amino esters, urethanes, lactones, and lactams can be
used to acylate 2a, producing the corresponding car-
bonyl derivatives of benzimidazole in respectable yields.
No attempt was made to optimize the yield of these
reactions.
O
O
OH
81
60
81
60
O
O
HO
O
O
O
N
N
EtO
O
EtO
O
EtO
83
OEt
OEt
OEt
OEt
There are obvious cost and environmental advantages of
using esters rather than acid chlorides for acylation.
Also significant are the examples where the correspond-
ing acid chlorides are not available or would require the
use of protecting groups. A very practical one-pot pro-
cedure was also demonstrated for the preparation of
benzimidazole ketones starting from o-phenylenedi-
amine.15 Here the protected benzimidazole was gener-
ated in one step with triethyl orthoformate and after
the volatile byproducts were removed by distillation,
lithiation, and acylation followed by deprotection pro-
duced the desired ketone in 76% overall isolated yield.
H
N
O
NH2
NH2
1. HC(OEt)3
N
2. LDA, methyl benzoate

5084
K. Asakawa et al. / Tetrahedron Letters 46 (2005) 5081–5084
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We propose that the methodology presented here can be
applied to the acylation of imidazoles with a variety of
esters type reagents. It is critical to conduct the reaction
at the correct low temperature to prevent the collapse of
the tetrahedral intermediate to ketone and thereby avoid
a second addition.
References and notes
14. Dimethoxymethyl benzimidazole 1a was prepared as fol-
lows: A solution of benzimidazole (10 g), and benzenesulf-
onic acid (0.3 g) in trimethyl orthoformate (50 ml) was
heated to reflux for 10 h followed by slow distillation for
2 h. The product was isolated by fractional distillation bp:
120–125 °C and 3 mm. N-Methyl benzimidazole was the
major byproduct contaminating all fractions. Alternatively,
1a can be generated in situ and acylated without isolation as
follows: the solution of benzimidazole (6.6 g), trimethyl
orthoformate (23 ml) and benzenesulfonic acid (0.3 g) in
toluene (60 ml) was heated to reflux then slowly distilled to
remove half of the solvent. Toluene (60 ml) was added again
and 40 ml was removed by slow distillation. The cooled
solution was neutralized with 0.8 ml of diisopropylamine,
THF (60 ml), and methyl benzoate (8.4 g) were added. The
mixture was cooled to À78 °C and LDA solution (34 ml,
2 M, in THF/heptane) was added dropwise. After aging for
2 h at that temperature, and warming to room temperature,
2 N HCl (57 ml) was added and the mixture was agitated for
an hour. The pH was adjusted to 9 with 50% NaOH, 15 g
NaCl was added and the layers were separated. The organic
layer was washed with 10% sodium bicarbonate solution
and concentrated to produce the ketone 5a in 76% yield.
15. Same procedure as described above starting with
o-phenylenediamine and triethyl orthoformate.
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