Efficient solution phase synthesis of 2-(N-acyl)-aminobenzimidazoles

Article abstract of DOI:10.1016/S0040-4039(02)01754-9

An efficient solution phase protocol for the synthesis of 2-(N-acyl)-aminobenzimidazoles is reported. The 2-(N-acyl)-aminobenzimidazole ring system was assembled using S_NAr reactions, nitro group reduction, acylthiourea formation and cyclization with EDC. The acyl protected 2-aminobenzimidazole derivatives were obtained in high yield and purity without purification of intermediates or final products. This reaction sequence eliminates the use of highly toxic cyanogen bromide, a reagent commonly used to prepare the 2-aminobenzimidazole ring system.

Full text of DOI:10.1016/S0040-4039(02)01754-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7303–7306
Efficient solution phase synthesis of
2-(N-acyl)-aminobenzimidazoles
Punit P. Seth,* Dale E. Robinson, Elizabeth A. Jefferson and Eric E. Swayze
Ibis Therapeutics, A Division of Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA
Received 10 August 2002; accepted 21 August 2002
Abstract—An efficient solution phase protocol for the synthesis of 2-(N-acyl)-aminobenzimidazoles is reported. The 2-(N-acyl)-
aminobenzimidazole ring system was assembled using SNAr reactions, nitro group reduction, acylthiourea formation and
cyclization with EDC. The acyl protected 2-aminobenzimidazole derivatives were obtained in high yield and purity without
purification of intermediates or final products. This reaction sequence eliminates the use of highly toxic cyanogen bromide, a
reagent commonly used to prepare the 2-aminobenzimidazole ring system. © 2002 Elsevier Science Ltd. All rights reserved.
The 2-aminobenzimidazole ring system is an important
nucleus for drug discovery and as such represents the
core structure of a number of biologically significant
molecules.1,2 For applications in our antibacterial pro-
gram, we needed access to 2-(N-acyl)-aminobenzimida-
zole derivatives such as 5a–e (Scheme 1).3 Existing
methods for the solution phase synthesis of 2-
aminobenzimidazole derivatives typically involve
cyclization of an o-phenylenediamine using cyanogen
bromide or its equivalent to provide the 2-aminobenz-
imidazole ring system. Subsequent reaction of the 2-
amino group with an acid chloride of choice provides
the acylated 2-aminobenzimidazole.1 While these meth-
ods work fairly efficiently, the use of cyanogen bromide
on a large scale or on a repeated basis was found to be
undesirable. Recently, some effort has been expended
toward developing efficient solid phase strategies for
the preparation of 2-aminobenzimidazole derivatives.4–8
However, these methods are limiting with respect to the
nature of substituents one can introduce on the benzene
ring or on the N-1 ring nitrogen. To circumvent these
limitations, we decided to explore a solution phase
Scheme 1. Preparation of some representative 2-(N-benzoyl)-aminobenzimidazoles.
* Corresponding author. Fax: 760-603-4653; e-mail: pseth@isisph.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01754-9

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P. P. Seth et al. / Tetrahedron Letters 43 (2002) 7303–7306
strategy for the synthesis of 2-aminobenzimidazole
derivatives such as 5a–e. In this communication, we
report an efficient solution phase synthesis of 2-
aminobenzimidazole derivatives that does not require
the use of cyanogen bromide. Also, unlike reported
solid phase syntheses of 2-aminobenzimidazole deriva-
tives, our solution phase approach allows for concur-
rent introduction of substituents on the aromatic ring
as well as on the N-1 ring nitrogen atom.
amount of PS-trisamine resin9 and the reaction was
purified by filtering off the resin. The benzoylthioureas
were then cyclized using 1-[3-(dimethylamino)propyl]-3-
ethylcarbodimide hydrochloride (EDC) to provide the
2-(N-benzoyl)-aminobenzimidazoles 5a–g. The presence
of an electron withdrawing group (EWG) on the
thiourea was critical for efficient cyclization of 4a–g to
the corresponding 2-(N-benzoyl)-aminobenzimidazole
5a–g. In the absence of an EWG, the cyclization was
slow and low yielding, using EDC.10 The final products
5a–g were isolated in high yield and purity (90–95%)
following an aqueous workup and typically did not
require any further purification (Table 1). In some cases
where the final purities were not >95%, the products
were easily purified by trituration with CH2Cl2, ether or
hexanes. In case of compound 5g, the benzyl protecting
group was cleanly removed using Raney nickel and
hydrogen gas (50 psi) to provide benzimidazole 6g
(Scheme 1). The 5-amino substituted benzimidazole 7h
was also prepared as shown in Scheme 1. SNAr dis-
placement of fluorine in 1h, followed by sequential
treatment with BzNCS, PS-trisamine and EDC pro-
vided nitro benzimidazole 5h. Reduction of the nitro
group with 10% Pd/C provided amino benzimidazole
7h in quantitative yield.11
The synthesis was initiated by SNAr displacement of
fluorine in substituted fluoronitrobenzenes 1a–g using
methylamine and K2CO3 in a biphasic system (CH2Cl2/
H2O) to provide the nitroanilines 2a–g (Scheme 1). It is
interesting to note that the SNAr reaction of methyl-
amine with fluoronitro compounds 1a–g proceeded very
cleanly at rt and did not require any forcing conditions
or polar solvents such as DMF, DMSO or NMP,
which are typically used for solid phase SNAr displace-
ment reactions.4–7 As a result, the nitroanilines 2a–g
were easily isolated after an aqueous workup in essen-
tially quantitative yield with high purity (>95%),
thereby eliminating the need for any purification.
Reduction of the nitro group in 2a–g was accomplished
using 10% Pd/C or Raney nickel/H2 gas to yield the
corresponding phenylenediamines 3a–g, which were iso-
lated in almost quantitative yields by a simple filtration
through celite followed by solvent removal. While 10%
Pd/C catalyst worked efficiently for most reductions, it
led to complete hydrogenolysis of the ArꢀBr bond in 2d
to provide the corresponding dehalogenated phenylene-
diamine. This problem was not as severe in the case of
dichloro analog 2e where use of 10% Pd/C resulted in
dehalogenation to a much smaller degree (<5%). The
above problem was easily corrected by using Raney
nickel instead of 10% Pd/C. Surprisingly, reduction
using Raney nickel was mild enough that the labile
benzyl group in 2g survived the reaction. Treatment of
diamines 3a–g with a slight excess of benzoylisothio-
cyanate (1.1–1.2 equiv.) in CH2Cl2, provided the corre-
sponding benzoylthioureas 4a–g. The excess BzNCS in
the reaction was scavenged by the addition of a small
A variety of other amines may be substituted in place
of methylamine, as shown in Scheme 2. The SNAr
reaction of 1e with amines 8i–m proceeded smoothly to
provide the corresponding nitroanilines, which were
reduced using Raney nickel and H2 gas at atm. pressure
to provide the corresponding o-phenylenediamines 9i–
m. Reaction with BzNCS followed by removal of excess
BzNCS using trisamine resin provided the benzoylth-
ioureas 10i–m. As described above, cyclization to the
corresponding 2-aminobenzimidazoles 11i–m was
accomplished using EDC (Table 1, Scheme 2).
The use of another acylisothiocyanate was examined
(Scheme 3). FmocNCS (1 equiv.) was reacted with
phenylenediamine 3e (1 equiv.) to provide the Fmoc-
thiourea 12e. Cyclization with EDC provided the Fmoc
Table 1. Solution phase synthesis of 2-(N-benzoyl)-aminobenzimidazoles
Compounda
R1
R2
R3
Methodb
Yieldc (%)
5a
5b
5c
5d
5e
5f
5g
5h
11i
11j
11k
11l
11m
H
H
H
H
Cl
Me
OBn
H
Cl
Cl
Cl
Cl
Cl
CN
CO2Me
CF3
Br
Cl
H
H
NO2
Cl
Cl
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
PhCH2
(CH2)4OH
Cyclopropyl
Cyclobutyl
Isobutyl
A
A
A
B
B
B
B
C
B
B
B
B
B
90
89
86
95
95
82
91
90
91
88
94
82
80
Cl
Cl
a All new compounds showed satisfactory analytical data.14
11
b Ref.
.
c Overall yield of products obtained after four steps.

P. P. Seth et al. / Tetrahedron Letters 43 (2002) 7303–7306
7305
Acknowledgements
This work was supported by the Department of
Defense through DARPA Grant BAA 98-25-544 and a
NIST Advanced Technology Program Grant 97-01-
0135 awarded to the Ibis Division of Isis
Pharmaceuticals.
References
1. For a review on the synthesis of 2-aminobenzimidazoles
see: Rastogi, R.; Sharma, S. Synthesis 1983, 861–882.
2. Nawrocka, W. Boll. Chim. Farm. 1996, 135, 18–23.
3. Ecker, D. J.; Griffey, R. H. DDT 1999, 4, 420–429.
4. Wu, C. Y.; Sun, C. M. Tetrahedron Lett. 2002, 43,
1529–1533.
Scheme 2. Synthesis of 2-aminobenzimidazoles using different
amines.
5. Huang, K. T.; Sun, C. M. Biorg. Med. Chem. Lett. 2002,
12, 1001–1003.
6. Lee, J.; Doucette, A.; Wilson, N. S.; Lord, J. Tetrahedron
Lett. 2001, 42, 2635–2638.
7. Krchnak, V.; Smith, J.; Vagner, J. Tetrahedron Lett.
2001, 42, 1627–1630.
8. Refs. 4, 5 and 7 describe efficient cyclization of N-aryl-
thioureas to 2-(N-aryl)-aminobenzimidazoles on solid
support, using DCC or DIC. A limitation of this method-
ology is that the N-aryl group cannot be manipulated to
provide either unsubstituted 2-aminobenzimidazoles or
2-(N-acyl)-aminobenzimidazoles.
9. PS-trisamine resin was purchased from Argonaut Tech-
nologies Inc.
10. For cyclization of unactivated thioureas to 2-aminobenz-
imidazole derivatives in solution using iodomethane or
mercury salts, see Ref. 1.
Scheme 3. Preparation of 2-(N-acyl)-aminobenzimidazoles.
protected 2-aminobenzimidazole 13e in high yield (98%
over four steps). To further expand on the utility of the
method, 2-(N-Fmoc)-aminobenzimidazole 13e was
deprotected using piperidine in DMF12,13 and the free
2-amino group was acylated, using phenylacetylchloride
to provide 14e (85% over two steps). Since a variety of
acid chlorides are commercially available, this method
should allow for easy incorporation of further diversity
at the 2-amino position of the benzimidazole ring sys-
tem. The use of FmocNCS also provides additional
versatility to the synthesis for solid phase applications,
given the ease of deprotection of the Fmoc group on
solid support.
11. Method A: MeNH2 (40% solution in H2O, 1 mL) was
carefully added to a suspension of 5-cyano-2-fluoronitro
benzene 1a (1 mmol, 0.166 g) and K2CO3 (2 mmol, 0.276
g) in CH2Cl2 (1 mL) and the resulting biphasic solution
was stirred at rt for 14 h. The reaction was diluted with
H2O and extracted with CH2Cl2 (3×). The combined
organic layers were washed with brine, dried (MgSO4)
and concentrated to provide nitroaniline 2a, which was
then hydrogenated using 10% Pd/C (25 mg) in EtOH (10
mL) for 6 h at rt. The reaction was filtered through celite
and the filter bed was thoroughly washed with EtOH.
The resulting solution was concentrated to provide
diamine 3a which was dissolved in CH2Cl2 (2 mL) and
the reaction was cooled in an ice bath. Benzoylisothio-
cyanate (1.1 mmol, 0.163 mL) was added to the above
solution and the reaction was stirred at rt for 14 h.
Trisamine resin (25 mg, loading 1.4 mmol/g) was then
added and the reaction stirred for additional 3 h. The
reaction was then filtered and concentrated to provide
crude benzoylthiourea 4a which was dissolved in CH2Cl2
(2 mL). DIPEA (5 mmol, 0.78 mL) and EDC (1.5 mmol,
0.287 g) were sequentially added to the reaction which
was stirred for 14 h at rt. The reaction was diluted with
EtOAc and the organic phase was washed with 5% HCl,
satd Na2CO3, brine, dried (MgSO4) and concentrated to
provide benzimidazole 5a as a white solid (0.246 g, 90%
over four steps). Method B: This method was identical to
Method A, except that Raney nickel (catalytic) was used
In summary, an efficient procedure for the synthesis of
2-(N-acyl)-aminobenzimidazoles is reported. The proce-
dure features the use of an acylisothiocyanate and EDC
to effect ring closure of substituted o-phenylenedi-
amines to the corresponding 2-(N-acyl)-aminobenzimi-
dazoles. The procedure eliminates the use of highly
toxic cyanogen bromide, a reagent commonly used to
prepare the 2-aminobenzimidazole ring system. Barring
aqueous workups and filtrations, no purification of the
intermediates and final products is required. This proce-
dure complements existing solid and solution phase
strategies for the preparation of the medicinally impor-
tant benzimidazole ring system.

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P. P. Seth et al. / Tetrahedron Letters 43 (2002) 7303–7306
in place of 10% Pd/C for nitro group reduction. Method
183.4, 162.9, 147.1, 143.0, 140.8, 138.6, 138.4, 137.5,
136.5, 128.9, 124.5, 120.0, 113.5, 38.1. HRMS calcd for
C16H12N4O: 277.1084, observed: 277.1085. 5b: H NMR
C: This method was identical to Method A, except that
1h (1 mmol) was heated with MeNH2 (2 mL) in a sealed
tube at 100°C and sequentially treated with BzNCS (1.1
equiv.), PS-Trisamine (25 mg) followed by ring closure
with EDC (1.5 mmol) and DIPEA (5 mmol).
1
(400 MHz, DMSO-d6): l 12.9 (s, br, 1H), 8.25 (d, 2H,
J=6.8), 8.1 (s, 1H), 7.87 (d, 1H, J=6.8), 7.55–7.45 (m,
5H), 3.85 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz,
DMSO-d3): l 183.2, 175.7, 162.9, 147.3, 143.2, 140.7,
138.3, 137.5, 136.4, 133.6, 133.1, 122.2, 118.8, 61.6, 38.0.
HRMS calcd for C17H15N3O3: 310.1186, observed:
310.1190. 5c: 1H NMR (400 MHz, CDCl3): l 12.59 (s, br,
1H), 8.36 (d, 2H, J=6.8), 7.55–7.44 (m, 5H), 7.31 (d, 1H,
J=7.6), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3): l
181.2, 159.2, 141.7, 136.9, 135.9, 133.5, 132.5, 132.3,
129.8, 127.1, 124.7, 113.2, 112.7, 32.8. HRMS calcd for
C16H12F3N3O: 320.1005, observed: 320.1013. 5d: 1H
NMR (400 MHz, DMSO-d6): l 12.79 (s, br, 1H), 8.24 (d,
2H, J=6.8), 7.66 (s, 1H), 7.52–7.38 (m, 5H), 3.68 (s, 3H).
13C NMR (100 MHz, DMSO-d6): l 183.1, 162.2, 147.4,
140.7, 139.7, 138.9, 138.2, 137.4, 136.8, 134.6, 123.7,
120.8, 37.9. HRMS calcd for C15H12BrN3O: 330.0236;
12. Piperidine (33 mL, 0.34 mmol) was added to a solution of
13e (30 mg, 0.068 mmol) in DMF (0.3 mL). The reaction
was stirred at rt for 14 h after which it was loaded onto
a short plug of silica gel. The plug was eluted with 50%
EtOAc/hexanes followed by 10%MeOH/1%NH4OH/
CH2Cl2. The CH2Cl2 fractions were collected, concen-
trated and the resulting solid was redissolved in CH2Cl2
(0.5 mL) and DIPEA (50 mL). The reaction was cooled in
an ice bath and PhCH2COCl (0.08 mmol, 11 mL) was
added. The reaction was stirred for 14 h at rt after which
it was diluted with CH2Cl2 and the organic layer was
washed with dil. HCl, brine, dried (MgSO4) and concen-
trated to yield 14e (85% over two steps).
13. Other methods for deprotection of the Fmoc group in 13e
were also examined. We found that the Fmoc group
could be successfully deprotected using PS-trisamine
resin. Unfortunately we were never able to completely
scavenge the dibenzofulvene from the reaction using PS-
trisamine resin under a variety of conditions. We also
attempted to replace the FmocNCS with CbzNCS to
allow for cleaner deprotection. However, CbzNCS is not
commercially available and its synthesis was complicated
due to the formation of side products.
1
observed: 330.0236. 5e: H NMR (400 MHz, CDCl3): l
12.41 (s, br, 1H), 8.32 (d, 2H, J=6.8), 7.51–7.26 (m, 6H),
3.72 (s, 3H). 13C NMR (100 MHz, CDCl3): l 176.8,
154.6, 137.3, 131.6, 129.8, 129.2, 128.0, 127.9, 127.1,
126.9, 112.5, 110.4, 28.5. HRMS calcd for C15H11Cl2N3O:
1
320.0352, observed: 320.0343. 11m: H NMR (400 MHz,
CDCl3): l 12.42 (s. br, 1H), 8.31 (d, 2H, J=6.8), 7.55–
7.31 (m, 5H), 4.01 (d, 2H, J=7.6), 2.37 (m, 1H), 1.035 (d,
6H, J=6.8). 13C NMR (100 MHz, CDCl3): l 176.9,
154.9, 137.5, 131.6, 129.6, 129.2, 128.0, 27.7, 126.9, 126.7,
112.4, 110.9, 60.5, 49.9, 28.1, 20.3. HRMS calcd for
C18H17Cl2N3O: 362.0821, observed: 362.0827.
14. Analytical data for some 2-(N-benzoyll)-aminobenzimi-
1
dazoles. 5a: H NMR (400 MHz, DMSO-d3): l 12.93 (s,
br, 1H), 8.25 (d, 2H, J=6.8), 7.79 (s, 1H), 7.67–7.46 (m,
5H), 3.71 (s, 3H). 13C NMR (100 MHz, DMSO-d3): l