Regiospecific synthesis of 3-alkyl-4-hydroxybenzimidazoles as intermediates for an expedient approach to potent EP3 receptor antagonists

Article abstract of DOI:10.1016/j.tetlet.2010.01.005

Regiospecific construction of 3-alkyl-4-hydroxybenzimidazoles is detailed. The synthetic route involves a novel O- to N-acyl transfer reaction to address the observed exclusive O-acylation of 2-amino-3-nitrophenol starting material. This efficient route p

Full text of DOI:10.1016/j.tetlet.2010.01.005

Tetrahedron Letters 51 (2010) 1380–1382
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regiospecific synthesis of 3-alkyl-4-hydroxybenzimidazoles as intermediates
for an expedient approach to potent EP3 receptor antagonists
*
Wayne Zeller , Alex S. Kiselyov, Jasbir Singh
deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, IL, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Regiospecific construction of 3-alkyl-4-hydroxybenzimidazoles is detailed. The synthetic route involves a
novel O- to N-acyl transfer reaction to address the observed exclusive O-acylation of 2-amino-3-nitro-
phenol starting material. This efficient route provides the targeted 3-alkyl-4-hydroxybenzimidazoles in
good yields, in five steps, without the use of chromatographic purification. These key intermediates were
subsequently elaborated, as shown, to provide acylsulfonamide-derived potent EP3 receptor antagonists.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 November 2009
Revised 27 December 2009
Accepted 5 January 2010
Available online 11 January 2010
During the course of an investigation into the generation of EP3
receptor antagonists, we sought to construct a series of 3-alkyl-4-
alkoxybenzimidazoles as potential EP3 receptor antagonists. Tradi-
tionally, 3-alkyl-4-hydroxybenzimidazoles have been generated
through the reduction of the 3-nitro-2-alkyl-2-amido-phenol1 or
sulfamidephenol2 derivatives followed by ring closure. A related
approach involves ring closure of 3-amido-2-alkyl-2-aminophenol
derivatives to arrive at the 3-alkyl-4-hydroxybenzimidazoles,3
whereas 2-amino-3-alkyl-benzimidazoles have been produced
through cyclizations of 2-alkylamino-3-thiourea-anisoles4 or via
the intermediate cyclic ureas.5 Procedures to selectively alkylate
either N1 or N3 of 4-hydroxy/alkoxybenzimidazole derivatives
have been met with limited success1c,5 with the majority of these
protocols6 resulting in the generation of a mixture of regioisomers.
In this Letter, we describe the regiospecific generation of 3-al-
kyl-4-hydroxybenzimidazoles via a five-step synthetic sequence
that results in high yields of the targeted molecules. The current re-
port emphasizes the ease of the sequence wherein no chromato-
graphic purification is required through the isolation of the
3-alkyl-4-hydroxybenzimidazole. Subsequent to the submission
of our initial communication of this synthetic route,7 a similar ap-
proach was reported by the Johnson & Johnson group.8 The utility
of this reaction scheme is exemplified here by further elaboration
of the key intermediates 6 and 14 to give rise to potent EP3 recep-
tor antagonists 9 and 17, respectively.
amino substituent, we observed exclusive O-acylation of the phe-
nol functionality when limiting equivalent of acyl chloride
(1 equiv), and 1 were used in the presence of DMAP (1.0 equiv)
in CH2Cl2.9 Evidence for exclusive O-acylation include (a) absor-
bances in the IR spectrum of compound 10 at 1742 cmÀ1 for ester
C@O, and 3492 and 3382 cmÀ1 for the typical NH2 asymmetrical
and symmetrical N–H stretches and (b) a broad singlet at d 6.19
in the 1H NMR integrating for two protons. We reasoned out that
the O-acylated compound could be transformed into the respective
N-acylated compound via an intramolecular acyl transfer proce-
dure.10 A five-membered transition state for this reaction appeared
feasible (Scheme 1). In addition, the resulting amides, 3 and 11, are
expected to be more thermodynamically stable than the corre-
sponding esters 2 and 10. Also, the reverse amide-to-ester conver-
sion is unlikely in the presence of excess base due to the
deprotonation of amides 3 and 11. Indeed, both amides 3 and 11
were prepared in high yields and purity upon the treatment of
compounds 2 and 10 with sodium hydride in THF, cleanly and in
an essentially quantitative yield (Scheme 2). Relevant spectral data
for compound 11 include an IR absorption at 3341 and 1650 cmÀ1
for the phenol hydroxyl and amide carbonyl absorptions, respec-
tively. The 1H NMR spectrum of compound 11 included absorp-
tions at d 11.16 and 9.77 for the phenolic and amide proton
absorptions, respectively. Hydrogenation of the nitro compound
3 was accomplished to afford the amine derivative 4 in a quantita-
The initial synthetic sequence was intended to involve direct N-
acylation of 2-amino-3-nitrophenol (1) to furnish the expected
amides 3 or 11. However, due to the electron-withdrawing ability
of the C-3 nitro substituent lowering the nucleophilicity of the C-2
Ar
O
OH
O
O
Ar
NH
NH2
* Corresponding author. Tel.: +1 630 904 2218.
NO2
NO2
E-mail addresses: jsingh@decode.com, jasbir.singh3@gmail.com (J. Singh).
Present address: US Dairy Forage Research Center, 1925 Linden Drive West,
Madison, WI 53706, USA.
Scheme 1. Intramolecular O-acyl to N-acyl migration.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.005

W. Zeller et al. / Tetrahedron Letters 51 (2010) 1380–1382
1381
Ar
OH
H
OH
OH
H
(c)
O
O
(b)
N
Ar
N
Ar
(a)
NH2
NO2
NH2
O
O
NO2
NH2
NO2
1
4 Ar = 2,4-dichlorophenyl (quant)
12 Ar = Naphthyl (89%)
2 Ar = 2,4-dichlorophenyl (98.7%)
10 Ar = Naphthyl (99%)
3 Ar = 2,4-dichlorophenyl (quant)
11 Ar = Naphthyl (quant)
OMe
O
OH
OH
Ar
H
(f)
(g)
(d)
(e)
O
Ar
N
Ar
N
N
N
N
NH2
5 Ar = 2,4-dichlorophenyl (quant)
13 Ar = Naphthyl (quant)
6 Ar = 2,4-dichlorophenyl (56%)
14 Ar = Naphthyl (35%)
7 Ar = 2,4-dichlorophenyl (54%)
15 Ar = Naphthyl (55%)
Cl
O
S
N
Cl
O
S
O
OH
O
O
H
Ar
(h)
O
Ar
N
N
N
N
8 Ar = 2,4-dichlorophenyl (91%)
16 Ar = Naphthyl (55%)
9 Ar = 2,4-dichlorophenyl (71%)
17 Ar = Naphthyl (52%)
Scheme 2. Reagents and conditions: (a) for 2: 2,4-dichlorobenzoyl chloride, DMAP, CH2Cl2, 20 °C, 16 h; for 10: 2-naphthoyl chloride, DMAP, CH2Cl2, 20 °C, 16 h; (b) NaH, THF;
(c) for 4: H2, Raney nickel, EtOH, rt, 16 h; for 12: SnCl2Á2H2O (10 equiv), 6 N aq HCl, EtOH, 70 °C, 1 h; (d) BH3, THF; (e) HC(OEt)3, pTsOH, EtOH, 75 °C, 1 h; (f) methyl
bromoacetate, K2CO3, DMF, rt, 16 h; (g) 15% aqueous NaOH, EtOH, H2O, rt, 16 h; (h) 4,5-dichlorothiophene-2-sulfonamide, EDCI, DMAP, CH2Cl2, rt, 4 h.
3. (a) Katritzky, A. R.; Musgrave, R. P.; Rachwal, B.; Zaklika, C. Heterocycles 1995,
41, 345–352; (b) Patent Appl.; AstraZeneca UK Limited; WO2008/56150.
4. Merck and Co., Inc. WO2005/65680.
tive yield. Alternatively, compound 11 was reduced using tin chlo-
ride conditions to provide the amine compound 12 (89% yield).
Condensation of 5 with triethyl orthoformate in EtOH in the pres-
ence of p-toluenesulfonic acid provided the 3-alkyl-4-hydroxy-
benzimidazole 6 after purification by a simple trituration. Exposure
of compound 13 under similar conditions provided compound 14.
The respective 4-hydroxybenzimidazoles 6 and 14 were subjected
to the O-alkylation with bromoacetic acid methyl ester followed
by the NaOH-mediated hydrolysis to yield the respective acids 8
and 16. The final coupling of key pharmacophore component 4,5-
dichlorothiophene-2-sulfonamide was achieved with EDCI/DMAP
to afford the targeted molecules 9 and 17. These peri-substituted
benzimidazole analogs have previously been reported to be potent
and isoform selective EP3 receptor anatagonists.11
5. (a) Ohshima, E.; Takami, H.; Sato, H.; Mohri, S.; Obase, H.; Miki, I.; Ishii, A.;
Shirakura, S.; Karasawa, A.; Kubo, K. J. Med. Chem. 1992, 35, 3402–3413; (b)
Guerret, P.; Ancher, J.-F.; Langlois, M. J. Heterocycl. Chem. 1983, 20, 1525–1532;
(c) Iemura, R.; Hori, M.; Ohtaka, H. Chem. Pharm. Bull. 1989, 37, 962–966; (d)
Swayze, E. E.; Seth, P. P.; Griffey, R. H.; Jefferson, E. A. US2005/124638; 2005.;
(e) Aktiebolaget Hassle; US 5106,862; 1992.; (f) Kawato, H. C.; Nakayama, K.;
Inagaki, H.; Ohta, T. Org. Lett. 2001, 3, 3451–3454; (g) Kissei Pharmaceutical Co.,
Ltd; EP1849795, 2007.
6. For an example of a regiospecific alkylation, see Ref. 5a, footnote 8.
7. Singh, J.; Gurney, M. E.; Hategan, G.; Yu, P.; Zembower, D.; Zhou, N. WO2006/
44415.
8. Zhang, X.; Urbanski, M.; Patel, M.; Zeck, R. E.; Cox, G. G.; Bian, H.; Conway, B. R.;
Beavers, M. P.; Rybczynski, P. J.; Demarest, K. T. Bioorg. Med. Chem. Lett. 2005,
15, 5202–5206.
9. Acylation of compound 1 with aryl acetyl chlorides (Et3N and CH2Cl2) or with
aryl acetic acids (EDCI, HOBt, and DMF) has been reported to provide the N-
acylated compounds directly. See Ref. 8 for details.
In conclusion, the procedure described in this Letter12 allows for
the expeditious access to 3-alkyl-4-hydroxybenzimidazoles 6 and
14 in overall good yields without requiring chromatographic puri-
fication. The final products were obtained following chromato-
graphic purification yielding compounds 9 and 17 in 20% and
25% overall unoptimized yield, respectively, via the eight-step se-
quence as shown in Scheme 2. Both high yields and feasibility of
the synthetic sequence is expected to be amenable to scale up of
4-substituted benzimidazoles and respective parallel synthesis of
their derivatives.
10. A literature report by Griffiths, D. W.; Bender, M. L. Bioorg Chem. 1975, 4, 84–
92, points out that intramolecular acyl transfers of this type have been
measured and occur as much as 105 times faster than the transfer of the acyl
group to the surrounding water molecules, would support the authors notion
of the stated acyl migration being intramolecular. However, in the absence of
cross-over experiments inter-molecular acyl migration could not be ruled out.
11. Singh, J.; Zeller, W.; Zhou, N.; Hategen, G.; Mishra, R.; Polozov, A.; Yu, P.; Onua,
E.; Zhang, J.; Ramírez, J.; Sigthorsson, G.; Thorsteinnsdottir, M.; Kiselyov, A.;
Zembower, D.; Andrésson, T.; Gurney, M. J. Med. Chem. 2010, 53, 18–36.
12. Synthesis of compound 9 is provided as a representative example.
Synthesis of 2,4-dichloro-benzoic acid 2-amino-3-nitro-phenyl ester (2): To a
500 mL, round-bottomed, one-necked flask equipped with a magnetic stir bar
and
a septum was added 2-amino-3-nitrophenol (4.25 g, 27.6 mmol),
References and notes
anhydrous CH2Cl2 (140 mL), 4-(dimethylamino)pyridine (3.37 g, 27.6 mmol),
and 2,4-dichlorobenzoyl chloride (5.78 g, 3.87 mL, 27.6 mmol). The reaction
mixture was allowed to stir at room temperature overnight. The reaction
mixture was diluted with CH2Cl2 (300 mL) and the mixture was washed with
H2O (2 Â 200 mL), dried (Na2SO4), and concentrated to give 8.91 g (98.7%) of a
yellow-orange solid. 1H NMR analysis indicated the material 2 was pure
enough to carry on to the next step. 1H NMR (500 MHz, CDCl3) d 6.25 (br s, 2H),
6.77 (dd, J = 8.5, 8.0 Hz, 1H), 7.43 (m, 1H), 7.45 (m, 1H), 7.60 (d, J = 2.0 Hz, 1H),
8.04 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 8.5, 1.5 Hz, 1H) ppm.
1. (a) Kubo, K.; Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.; Furukawa, Y.;
Nishikawa, K.; Nakat, T. J. Med. Chem. 1993, 36, 1772–1784; (b) Evans, D.; Hicks,
T. A.; Williamson, W. R. N.; Dawson, W.; Meacock, S. C. R.; Kitchen, E. A. Eur. J.
Med. Chem. 1996, 31, 635–642; (c) Pfizer Inc.; WO2008/35195.; (d) Fujisawa/
Daicel; WO2004/108686.
2. Horner, L.; Schwenk, U.; Junghanns, E. Justus Liebigs Ann. Chem. 1953, 579, 204–
210.

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W. Zeller et al. / Tetrahedron Letters 51 (2010) 1380–1382
Synthesis of 2,4-dichloro-N-(2-hydroxy-6-nitro-phenyl)-benzamide (3): To
a
with 1:1 hexanes/acetone (6 mL each time) and the resulting dark brown solid
500 mL, round-bottomed, one-necked flask containing 2 (8.91 g, 27.2 mmol)
was added a magnetic stir bar and anhydrous THF (300 mL) and the reaction
vessel was placed under a N2 atmosphere. Sodium hydride (1.08 g, 44.9 mmol,
60% in oil dispersion) was added in portions cautiously to the stirring reaction
mixture over a period of 2 min. After an additional 2 min, H2 gas evolution
occurs (fairly rapidly) and a slight exotherm was observed. The mixture was
stirred at room temperature for 1 h. TLC analysis at this time shows reaction
complete. The mixture was allowed to stir at room temperature overnight. The
mixture was cautiously quenched through the slow addition of water (50 ml)
dropwise and then in small portions. The mixture was poured into EtOAc (1 L)
and water (200 mL). The aqueous layer was acidified to a pH ꢀ1 with 1 N
aqueous HCl and extracted. The layers were separated and the aqueous layer
was extracted with EtOAc (100 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated in vacuo to give 3, (9.36 g) as a tan solid.
1H NMR (500 MHz, CDCl3) d 7.34 (t, J = 8.0 Hz, 1H), 7.44 (m, 2H), 7.57 (d,
J = 2.0 Hz, 1H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 8.74 (s, 1H),
10.62 (br s, 1H) ppm.
was filtered and dried to give 6, 570 mg (56%). 1H NMR (500 MHz, DMSO-d6) d
5.70 (s, 2H), 6.55 (overlapping doublets, apparent triplet, J = 8.5, 8.0 Hz, 2H),
6.98 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 7.69
(d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 9.85 (s, 1H) ppm. MS, Calcd (M) 292.02; Found
(ESI+): 293.5, Found (ESIÀ): 291.1.
Synthesis of [3-(2,4-dichloro-benzyl)-3H-benzoimidazol-4-yloxy]-acetic acid
methyl ester (7): To a 5 mL vial containing a magnetic stir bar and compound
6
(60 mg, 0.204 mmol) were added anhydrous DMF (0.8 mL), anhydrous
potassium carbonate (34 mg, 0.246 mmol), and methyl bromoacetate (24 L,
l
0.246 mmol). The reaction mixture was stirred at room temperature overnight.
The reaction mixture was concentrated in vacuo to give a residue which was
dissolved in 1:1 hexanes/acetone (1 mL) and was purified by column
chromatography on flash silica gel (6 g) utilizing 4:1 hexanes/acetone
followed by 7:3 hexanes/acetone as eluent to give 7, 40 mg (54%) of
a
semisolid. 1H NMR (500 MHz, CDCl3) d 3.75 (s, 3H), 4.66 (s, 2H), 5.77 (s, 2H),
6.61 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 8.5, 2.0 Hz, 1H), 7.17
(t, J = 8.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H)
ppm. MS (ESI+) Calcd (M+H) 365.7; Found: 365.6.
Synthesis of N-(2-amino-6-hydroxy-phenyl)-2,4-dichloro-benzamide (4): To
250 mL hydrogenation vessel was added an aqueous slurry of Raney nickel
(700 mg) and it was cautiously diluted with EtOH (60 mL). Compound
a
Synthesis of [3-(2,4-dichloro-benzyl)-3H-benzoimidazol-4-yloxy]-acetic acid (8):
To a 50 mL round-bottomed, one-necked flask containing compound 7 (32 mg,
0.088 mmol) were added absolute ethanol (0.5 mL), water (0.5 mL), and 15%
3
(700 mg, 2.14 mmol) was added as a solid. The sides of the vessel were rinsed
with EtOH (10 mL) and the mixture was subjected to hydrogenation in a Parr
shaker at 50 psi of H2 gas at room temperature overnight. The reaction mixture
was filtered through a pad of Celite and the pad was rinsed with EtOH
(400 mL). The filtrate was concentrated in vacuo to give a quantitative yield of
a dark brown solid, 4. 1H NMR (500 MHz, DMSO-d6) d 4.74 (br s, 2H), 6.15 (dd,
J = 8.0, 2.0 Hz, 1H), 6.23 (dd, J = 8.0, 1.0 Hz, 1H), 6.81 (dd, apparent t, J = 8.0 Hz,
1H), 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H),
9.20 (v br s, 2H) ppm. MS (ESI+) Calcd (M) 296; Found: 297.4 (M+H).
aqueous sodium hydroxide (25
allowed to stir at room temperature overnight. The mixture was
concentrated in vacuo to give solid. The solid was dissolved in water
lL, 93 lmol). The reaction mixture was
a
(3 mL) and made acidic through the addition of 1 N aqueous HCl (0.25 mL). pH
of the solution was 2–3 by litmus paper. The resulting precipitate was filtered
and dried. The aqueous filtrate was extracted with EtOAc (3 Â 1 mL) and the
organic extracts were concentrated in vacuo to give a solid. This solid was
combined with the isolated precipitate to give 28 mg (91%), 8, as an off-white
solid. 1H NMR (500 MHz, DMSO-d6) d 4.69 (s, 2H), 5.80 (s, 2H), 6.70 (d,
J = 8.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz,
2H), 7.66 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 12.95 (br s, 1H) ppm. LC/MS = 95%, MS
(ESI+) Calcd (M+H) 349.2; Found: 349.2.
Synthesis of 3-amino-2-(2,4-dichloro-benzylamino)-phenol (5): To
a 250 mL
round-bottomed, one-necked flask equipped with magnetic stir bar,
a
a
reflux condenser and placed under a N2 atmosphere was added compound 4
(635 mg, 2.14 mmol). Anhydrous THF (31 mL) was added followed by dropwise
addition of 1 M BH3 in THF (8.6 mL, 8.6 mmol). The reaction mixture was
heated at reflux overnight. The reaction was cooled and cautiously quenched
by dropwise addition of methanol (50 mL). The resulting mixture was
Synthesis of 4,5-dichloro-thiophene-2-sulfonic acid {2-[3-(2,4-dichloro-benzyl)-
3H-benzoimidazol-4-yloxy]-acetyl}-amide (9): To
a 3 mL vial containing a
magnetic stir bar and compound (21 mg, 0.060 mmol) was added
8
concentrated on
methanol (50 mL) and reconcentrated. This redissolution of the residue in
methanol and reconcentration was repeated two more times to give
a
rotary evaporator. The residue was again dissolved in
anhydrous CH2Cl2 (2 mL) followed by DMAP (14.7 mg, 0.120 mmol), which
made the solution homogenous. 4,5-Dichlorothiophene-2-sulfonamide
(15.5 mg, 0.066 mmol) was added followed by EDCI (23 mg, 0.12 mmol). The
reaction was stirred at room temperature for 4 h and then diluted with CH2Cl2
and water (5 mL each). The aqueous layer was made acidic through the
addition of 1 N aqueous HCl until a pH of 2–3 was reached (litmus paper). The
layers were separated and the aqueous layer was extracted with CH2Cl2 (5 mL).
The combined organic layers were concentrated in vacuo and dried under
vacuum. The resulting solid was triturated with hot CH2Cl2 (3 mL) and the
cooled solution was filtered and dried to give 26 mg (71%) of 9 as an off-white
solid. 1H NMR (500 MHz, DMSO-d6) d 4.59 (s, 2H), 5.91 (s, 2H), 6.85 (d,
J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.5,
2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 8.98 (s,
1H). LC/MS = 97.8% purity, MS (ESI+) Calcd (M+H) 564.4; Found: 564.4
a
quantitative yield of a brown oil, 5. 1H NMR (500 MHz, DMSO-d6) d 3.38 (br
s, 2H), 4.35 (br s, 1H), 4.61 (s, 2H), 6.05 (dd, J = 8.0, 1.5 Hz, 1H), 6.15 (dd, J = 8.0,
1.5 Hz, 1H), 6.51 (t, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 7.53 (m, 2H),
8.85 (br s, 1H) ppm. MS (API+) Calcd (M) 282.02, Found: 283.2 (M+H).
Synthesis of 3-(2,4-dichloro-benzyl)-3H-benzoimidazol-4-ol (6): To a 20 mL vial
containing a magnetic stir bar was added compound 5 (980 mg, 3.46 mmol)
and absolute EtOH (8 mL). To this stirring suspension were added triethyl
orthoformate (0.634 mL, 3.81 mmol) and p-toluenesulfonic acid monohydrate
(33 mg, 0.173 mmol). The vial was capped and placed in an oil bath at 75 °C for
1 h. At this time the cap was removed from the vial and the oil bath
temperature was increased to 95–100 °C, boiling off the solvent. The last traces
of solvent were removed under high vacuum. The residue was triturated twice