Selective phenol alkylation for an improved synthesis of 2-arylbenzimidazole H4 receptor ligands

Article abstract of DOI:10.1016/j.tetlet.2009.03.033

Alkylation of a phenol OH in the presence of a free benzimidazole NH was investigated and found to be highly dependent on the substitution of the benzimidazole and phenol rings. The modification of our original synthesis of 2-arylbenzimidazole H₄

Full text of DOI:10.1016/j.tetlet.2009.03.033

Tetrahedron Letters 50 (2009) 2490–2492
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Tetrahedron Letters
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Selective phenol alkylation for an improved synthesis of 2-arylbenzimidazole
H4 receptor ligands
*
Brad M. Savall , Jill R. Fontimayor , James P. Edwards
Johnson & Johnson Pharmaceutical Research & Development. L.L.C. 3210 Merryfield Row, San Deigo, CA 92121, USA.
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkylation of a phenol OH in the presence of a free benzimidazole NH was investigated and found to be
highly dependent on the substitution of the benzimidazole and phenol rings. The modification of our ori-
ginal synthesis of 2-arylbenzimidazole H4 receptor ligands has resulted in improved yields and ease of
isolation of final products.
Received 28 October 2008
Revised 5 March 2009
Accepted 6 March 2009
Available online 13 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
and minor amounts of dimeric products. We thus initiated a scan
of various solvents and bases to improve the selectivity of the phe-
During the development of our H4 receptor modulator program,
we were interested in synthesizing larger quantities of previously
reported 2-arylbenzimidazole derivatives.1 Our previous synthesis
allowed for rapid introduction of various points of diversity on the
2-aryl benzimidazole core via a late stage benzimidazole forma-
tion. However, upon scaling up the reactions, we encountered
problems both with the reproducibility of the late stage benzimid-
azole condensation and with the isolation of desired products.
Modification of the synthesis to incorporate the benzimidazole for-
mation earlier in the sequence resulted in very clean reactions
when performed on variously substituted benzaldehyde phenols
(Table 1). The condensation reactions were rapid under an atmo-
sphere of air and product isolation was readily accomplished by
pouring the reactions into water and filtering the resulting solid.
The products were generally isolated in greater than 90% yield
and in greater than 90% purity.
nol alkylation. The results in Table 2 demonstrated that on our test
substrate, 2-(4-hydroxyphenyl)-5-methyl benzimidazole, there
was a significant effect of the choice of base and solvent on the
course of these reactions. Acetonitrile or acetone as solvent com-
bined with Cs2CO3 as base proved to be the best combination for
selective alkylation of the phenol (entries 2 and 7). It is interesting
to note that with DMF as the solvent the reaction did not go to
completion after 24 h at 70 °C with Cs2CO3 as base, but the reac-
tion was complete with K2CO3 (entries 4 and 5). In addition, the
DMF reactions showed significantly more by-products than aceto-
nitrile or acetone.6 Other solvents scanned were likewise inferior
to acetonitrile and acetone either giving very slow reaction or
showing significant by-product formation. Although acetone was
more selective for the mono- over bis-alkylated product, the reac-
tion rate was too slow to be practical, and acetonitrile was used in
With ready access to benzimidazole phenol intermediates, we
approached the task of selectively alkylating the phenol OH in
the presence of the benzimidazole NH, of which there is limited
precedence.2,3 Not only do benzimidazole and phenol have similar
pKas, but the relative order of acidity switches depending on the
solvent: benzimidazole (pKa = 16.4 in DMSO,4 12–13 in H2O5)
and phenol (pKa = 18.0 in DMSO;4 10.0 in H2O4). This suggested
that a selective alkylation of the phenol could be achieved with
appropriate choice of solvent. Starting with conditions that we
had used for the alkylation of benzaldehyde phenols,1 K2CO3 in
acetonitrile, the desired mono-alkylated phenol was isolated as
the desired product (50% yield) along with bis-alkylation products
Table 1
Formation of benzimidazole phenols
R1
R1
O
3
R2
2
1
2
R2
OH
NH2
4
N
Na2S2O5
3
4
H
+
NH2
1
DMF, 90 °C
N
H
OH
Entry
R1
R2
Yield (%)
Purity (%)
1
2
3
4
5
6
7
8
9
3-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-Cl
–H
–H
93
>99
92
>99
>99
>95
>95
95
91
96
95
90
85
>98
92
90
90
>98
97
3-OMe
3-Cl
2-OMe
–H
2-Cl
3-Cl
2-OMe
–H
4-Cl
4-Cl
4-Cl
* Corresponding author. Tel.: +1 858 320 3393; fax: +1 858 450 2089.
E-mail address: bsavall@its.jnj.com (B.M. Savall).
Summer Intern, Johnson & Johnson Pharmaceutical Research & Development, USA.
98
85
85
10
11
4-OCH3
4-F, 3-Me
–H
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.033

B. M. Savall et al. / Tetrahedron Letters 50 (2009) 2490–2492
2491
Table 2
Optimization of alkylation of 2-(4-hydroxyphenyl)-5-methyl benzimidazole
Cl
Cs CO
Me
Me
N
2
3
N
O
Br
Cl
+
OH
CH CN,
3
N
H
N
H
70 °C
+
1.3 eq
1.0 eq
bis alkylated products
Entry
Solvent
Base
% Conversiona
Ratio
Yielda (%)
@ 30 min (%)
@ 24 h (%)
O-Alkyl:bis-alkyla
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
DMF
K2CO3
Cs2CO3
DBU
K2CO3
Cs2CO3
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
2
30
50
10
0
46
15
38
30
0
83 (n = 3)
97 (n = 2)
n/a
>99
30
48
71
94
78
3.3:1
6.0:1
50
70
Complex mixture
Complex mixture
Complex mixture
Complex mixture
16:1
Complex mixture
Complex mixture
Complex mixture
5.5:1
DMF
DMF
Acetonec
DMSO
NMP
10
Dioxane
CH3CN
68
>99
11b
30
81
a
Unless otherwise noted, results based on single experiment (n = 1).
1.1 equiv of bromochloropropane used.
Temperature = 56 °C boiling point of acetone.
b
c
subsequent reactions. Finally lowering the amount of bromochlo-
ropropane from 1.3 to 1.1 equiv (entry 11) resulted in a similar
selectivity, but in a higher overall yield of the mono-O-alkylated
product.
meta or para to the reacting center.7 In the case of these alkylation
studies, it appears that the OMe group behaves more like an EWG
than like an EDG on the benzimidazole nucleus.
The addition of substituents around the phenolic ring also had a
marked effect on the alkylation selectivity. The parent 5-chloro
benzimidazole with no substitution on the phenolic aryl ring (en-
try 5) showed a low 1.4:1 selectivity. Both 2-Cl and 3-Cl substitu-
tions on the central aromatic ring (entries 6 and 7) increased the
amount of the alkylation at the phenol. Interestingly, the 2-OMe
and 3-OMe substitution (entries 8 and 9) had similar effects on
the degree of phenol alkylation as the chloro substitution. The
combination of 5-Me substituent on the benzimidazole and a
3-Cl on the phenol (entry 10) gave very good selectivity for the de-
sired phenol alkylation product (16:1). And in the case of the final
entry 11 the presence of 2 methyl groups near the benzimidazole
N–H favors the alkylation of the phenol even though the elec-
tron-withdrawing 5-F substituent on the benzimidazole would
be predicted to increase N-alkylation.
With conditions favoring the mono O-alkylation of our test sub-
strate, we investigated the selectivity of this reaction as a function
of the electronic and steric environment around the phenol and the
benzimidazole. As seen in Table 3, phenol alkylation was favored
by the presence of a methyl group at the 4-position of the benz-
imidazole (compare entries 1–3), though sterics may play a role
in favoring the phenol over the benzimidazole, the bis-alkylated
product in this case was a 1:1 mixture of N-1 and N-3 regioisomers.
By comparing entry 1 with entries 3–5 it is clear that the presence
of an electron-withdrawing group (EWG) such as chlorine on the
benzimidazole diminishes the preference for O-alkylated products.
A mild electron-donating group (EDG) such as 5-methyl (entry
3) is equivalent to a 5-H when comparing the ratio of mono- versus
bis-alkylation products; however, 5-methyl substitution results in
higher isolated yield of O-alkyl product. The 5-OMe (entry 4) group
can act as either an EWG or an EDG depending on whether it is
To complete the synthesis of desired H4 ligands, the O-alkylated
product was treated with N-methyl piperazine in the presence of
Table 3
Scope and limitation of alkylation
R2
R2
Cl
R1
4
Cs CO
R1
5
2
3
N
N
O
Br
Cl
+
OH
1
4
CH CN,
3
70 °C
N
H
6
N
H
2
3
+
1.0 equiv
1.1 equiv
bis-alkylated products
Entry
R1
R2
% Conversion
Yield (O-alkyl) (%)
Ratio
O-Alkyl:bis-alkyl
1
2
3
4
5
6
7
8
9
H
H
H
H
H
85
95
90
71
83
95
57
82
84
82
95
48
66
81
62
54
67
36
52
71a
78
74
5:1
11:1
5:1
3.4:1
1.4:1
3.0:1
2.0:1
2.3:1
4:1
4-Me
5-Me
5-OCH3
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Me
4-Me, 5-F
H
2-Cl
3-Cl
3-OCH3
2-OCH3
3-Cl
10
11
16:1
9:1
3-Me
a
Yield of mixture of mono- and bis-alkylated products.

2492
B. M. Savall et al. / Tetrahedron Letters 50 (2009) 2490–2492
Me
(3 ml) was treated with 1-bromo-3-chloro propane (0.1 ml,
N
O
Cl
1.1 mmol) and the reaction mixture heated to 70 °C for 16 h. The
reaction mixture was cooled to rt and then diluted with chloroform
(15 ml) and filtered through a glass fritted funnel to remove inor-
ganic solids. The filtrate was concentrated under reduced pressure
and the crude residue was purified on 12 g SiO2 eluting with 0–50%
ethyl acetate/hexanes to provide the 2-[4-(3-chloro-propoxy)-phe-
nyl]-5-methyl-1H-benzimidazole (243 mg, 81% yield).
N
H
HN
N
Me
Me
K2CO3
Me
N
N
O
N
n-BuOH, 90°C
84%
N
H
1H NMR (500 MHz, DMSO-d6) d 8.42–8.31 (m, 2H), 7.73 (d,
J = 8.1, 1H), 7.63 (s, 1H), 7.46–7.36 (m, 2H), 7.34–7.23 (m, 1H),
4.47 (t, J = 6.0, 2H), 4.11 (t, J = 6.5, 2H), 2.80 (dt, J = 3.6, 1.8, 2H),
2.71 (s, 3H).
Figure 1. Nucleophilic displacement of chloroalkane.
NaI in n-BuOH at 90 °C to afford the desired alkylated diamine
product in 84% yield. The overall yield for this sequence starting
from the phenol aldehyde is 67% (Fig. 1).
These results indicate that in the case of alkylation, the phenol
and benzimidazole are very similar in reactivity and that phenol
alkylation is preferred when the steric environment around the
benzimidazole is increased. Additionally, it appears that an EWG
on the benzimidazole favors N-alkylation while the electronic
effects of phenol substitution are not easy to predict.
2.3. Representative chloride displacement: 5-methyl-2-{4-[3-
(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-
benzoimidazole
2-[4-(3-Chloro-propoxy)-phenyl]-5-methyl-1H-benzimidazole
(300 mg, 1.0 mmol), K2CO3 (276 mg, 2.0 mmol), NaI (150 mg,
1 mmol), and N-methyl piperazine (0.33 ml, 3.0 mmol) in n-buta-
nol (4 ml) were heated to 90 °C for 22 h. The reaction mixture
was cooled to rt and then diluted with chloroform and filtered
through a glass fritted funnel to remove inorganic solids. The fil-
trate was concentrated under reduced pressure and the crude res-
idue was purified on 12 g SiO2 eluting with 0–10% 2 M NH3OH in
MeOH/CH2Cl2 to provide the 5-methyl-2-{4-[3-(4-methyl-pipera-
zin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole (306 mg, 84%
yield).
2. Experimental
2.1. Representative benzimidazole condensation procedure:
2-(4-hydroxyphenyl)-5-methyl benzimidazole
A
solution of the 4-methyl-1,2-phenylenediamine (5.8 g,
47 mmol) and 4-hydroxybenzaldehyde (5.5 g, 45 mmol) in DMF
(90 ml) was treated with Na2S2O5 (8.9 g, 45 mmol) and the reac-
tion mixture heated to 90 °C for 2 h. The reaction mixture was
cooled to rt and then diluted up to 600 ml with ice/water. The
resulting suspension was stirred for 4 h then cooled to 0 °C and fil-
tered through a glass fritted funnel, washed with cold water and
the solid was dried under vacuum to yield 10.0 g (99% yield) of
2-(4-hydroxyphenyl)-5-methyl benzimidazole which was 97%
pure by HPLC.
1H NMR (400 MHz, CD3OD) d 7.98 (d, J = 8.8, 2H), 7.43 (s, 1H),
7.35 (s, 1H), 7.05 (d, J = 8.9, 3H), 4.13–4.05 (m, 1H), 2.56 (d,
J = 7.9, 7H), 2.45 (s, 4H), 2.29 (s, 3H), 2.08–1.91 (m, 1H).
References and notes
1. Lee-Dutra, A.; Arienti, K. L.; Buzard, D. J.; Hack, M. D.; Khatuya, H.; Desai, P. J.;
Nguyen, S.; Thurmond, R. L.; Karlsson, L.; Edwards, J. P.; Breitenbucher, J. G.
Bioorg. Med. Chem. Lett. 2006, 16, 6043–6048.
2. Rastogi, K. C.; Chang, J.-Y.; Pan, W.-Y.; Chen, C.-H.; Chou, T.-C.; Chen, L.-T.; Su, T.-
L. J. Med. Chem. 2002, 45, 4485–4493.
3. Kamal, A. S. O.; Ramulu, P.; Ramesh, G.; Kumar, P. P. Bioorg. Med. Chem. Lett.
2004, 14, 4791–4794.
4. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
1H NMR (400 MHz, DMSO-d6) d 14.82 (br s, 1H), 10.75 (s, 1H),
8.15 (d, J = 8.8, 2H), 7.69 (d, J = 8.3, 1H), 7.59 (s, 1H), 7.37 (d,
J = 8.5, 1H), 7.11 (d, J = 8.8, 2H), 2.54 (s, 3H).
5. Sari, H.; Covington, A. K. J. Chem. Eng. Data 2005, 50, 1425–1429.
6. The increase in by-product formation may be due to the increased solubility of
the parent benzimidazole phenols in DMF. Though a detailed study was not
performed, the more selective results were obtained in acetone and acetonitrile;
solvents in which the benzimidazole phenols have limited solubility.
7. Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E. J. J. Med. Chem.
1973, 16, 1207–1216.
2.2. Representative alkylation procedure: 2-[4-(3-chloro-
propoxy)-phenyl]-5-methyl-1H-benzimidazole
A suspension of 2-(4-hydroxyphenyl)-5-methyl benzimidazole
(224 mg, 1.0 mmol), and Cs2CO3 (489 mg, 1.5 mmol) in acetonitrile