Deprotection of N-benzylbenzimidazoles and N-benzylimidazoles with triethylsilane and Pd/C

Article abstract of DOI:10.1016/j.tetlet.2015.03.127

The benzyl group is a protecting group for benzimidazoles and imidazoles that can survive acidic, basic, oxidizing, and reducing conditions. Deprotection, however, can require vigorous and potentially non-chemoselective methods. The triethylsilane–Pd/C reduction system is an exceptionally mild, convenient, and efficient method for deprotecting N-benzylbenzimidazoles that are unsubstituted at the 2- and 4-positions as well as suitably substituted N-benzylimidazoles.

Full text of DOI:10.1016/j.tetlet.2015.03.127

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Deprotection of N-benzylbenzimidazoles and N-benzylimidazoles
with triethylsilane and Pd/C
⇑
Thomas H. Graham
Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065-0900, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzyl group is a protecting group for benzimidazoles and imidazoles that can survive acidic, basic,
oxidizing, and reducing conditions. Deprotection, however, can require vigorous and potentially non-
chemoselective methods. The triethylsilane–Pd/C reduction system is an exceptionally mild, convenient,
and efficient method for deprotecting N-benzylbenzimidazoles that are unsubstituted at the 2- and 4-
positions as well as suitably substituted N-benzylimidazoles.
Received 23 February 2015
Revised 18 March 2015
Accepted 27 March 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Imidazole
Benzyl
Deprotection
Triethylsilane
Palladium on carbon
Modern synthetic chemistry continues to rely on protecting
groups to manage chemo- and regioselectivity despite efforts to
diminish the need for protecting groups.1 For the synthesis of phar-
maceuticals, the protection of heterocyclic nitrogens is often
required and the benzyl group is valued for this application
because of its ability to survive acidic, basic, oxidizing, and reduc-
ing conditions.2 Inherent in the robustness of the benzyl group is
the potential for significant challenges when the group must be
removed.3 An especially challenging and capricious system is the
deprotection of N-benzylbenzimidazoles which is typically accom-
plished with catalytic hydrogenolysis often at elevated tempera-
tures or pressures,4 ammonium formate and Pd/C,5 potassium
tert-butylate and oxygen in DMSO,6 methyl lithium or lithium
diisopropylamide in THF,7 or sodium metal in liquid ammonia.8
Given the importance of benzimidazoles as a privileged structural
motif in biologically active molecules, reliable methods of depro-
tection with enhanced chemoselectivity would be generally
useful.9
0 °C and limiting the reaction time (Table 1, entry 1). The loss of the
benzyl group under these extraordinarily mild conditions did not
go unnoticed and therefore several additional experiments were
conducted to define the unique reactivity of the triethylsilane–
Pd/C system. Conducting the reaction with 1a at ambient tempera-
ture for a longer time resulted in complete benzyl removal to give
3 in 84% isolated yield (entry 2). N-Benzylbenzimidazole (1b) was
Table 1
Development of the triethylsilane–Pd/C reduction system
Et3SiH
Pd/C
N
N
N
N
N
R
THF
N
H
Bn
Bn
1a, R = SMe
2
3
1b, R = H
Entrya
Compd
Reductant
Time (h)
1:2:3 yieldb (%)
Triethylsilane and Pd/C form an exceptionally mild reduction
system that can accomplish a variety of transformations.10 A recent
study revealed that the triethylsilane–Pd/C system is a convenient
method for reducing heterocyclic thioethers under mild reaction
conditions.11 During these studies, the concomitant debenzylation
of benzimidazole 1a was minimized by conducting the reaction at
1c
2
3
1a
1a
1b
1a
1b
1b
Et3SiH (3 equiv)
Et3SiH (3 equiv)
Et3SiH (2 equiv)
H2 (1 atm)
H2 (1 atm)
Et3SiH (10 equiv)
8
14
14
18
18
14
0:87:11
0:0:84
0:0:99
94:2:0
90:—:6
91:—:4
4
5
6d
a
b
c
Reactions were conducted at ambient temperature unless noted otherwise.
Isolated yields after purification by chromatography on silica gel.
Reaction was conducted at 0 °C, see Ref. 11.
⇑
Tel.: +1 732 594 2918; fax: +1 732 594 2210.
E-mail address: thomas.graham@merck.com
d
Reaction solvent was methanol (McMurray conditions).
http://dx.doi.org/10.1016/j.tetlet.2015.03.127
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2
T. H. Graham / Tetrahedron Letters xxx (2015) xxx–xxx
Table 3
then subjected to similar conditions and afforded benzimidazole
(3) in nearly quantitative yield (entry 3). Control reactions using
hydrogen instead of triethylsilane as the reductant resulted in
the recovery of a majority of the unreacted starting materials
(entries 4 and 5) and only a trace of benzimidazole was isolated
from 1b.12 McMurray reported conditions for the reductive
removal of benzyl protecting groups using Pd/C and large excesses
of triethylsilane with methanol as the reaction solvent.13 These
conditions resulted in the recovery of unreacted starting material
and only a trace of benzimidazole (entry 6).14 The results indicate
that the triethylsilane and Pd/C system has exceptional reactivity
for the debenzylation of protected benzimidazole. In addition,
the use of an aprotic solvent such as tetrahydrofuran is unique
from previous reports of debenzylation methods using tri-
ethylsilane and Pd/C.
Effect of substitution at the 2-position of the benzimidazole
Et3SiH
Pd/C
N
N
N
R
R
N
H
THF, rt
Bn
6
7
Entry
R
Yield (%) in 7 (6)a
1
2
3
4
5
6
Me
Ph
t-Bu
3 (96)
1 (94)
7 (87)
67 (9)
(88)
N(Me)2
NHEt
OMe
14 (42)
a
Isolated yields after purification by chromatography on silica gel; parentheses
indicate recovered starting material.
Having identified the triethylsilane–Pd/C system as a unique
and mild method for the deprotection of N-benzylbenzimidazole,
the scope of the transformation was studies (Table 2). The trans-
formation tolerated electron donating and electron withdrawing
groups and was mostly unaffected by substituents at the 4- to 7-
ring positions. Notable exceptions were the 4-methoxycarbonyl
(entry 11) and the 4-methyl (entry 13) substituents that resulted
in a majority of the starting material being recovered and sug-
gested that sterics may influence the progress of the reaction.15
Substitution at the 2-position of the benzimidazole was also
studied (Table 3). Methyl, phenyl, and tert-butyl substitution
afforded only traces of the deprotected benzimidazole and a major-
ity of the starting material was recovered (entries 1–3). With N-
benzyl-2-dimethylaminobenzimidazole, the desired product was
obtained in 67% yield and 9% of the starting material was recovered
(entry 4). In contrast, N-benzyl-2-ethylaminobenzimidazole
afforded only recovered starting material, a result that may be
explained by the steric congestion from the in situ triethylsi-
lylation of the 2-ethylamino substituent (i.e., N–H to N–TES) (entry
5).11 N-Benzyl-2-methoxybenzimidazole was deprotected to a
minor extent with a poor recovery of the unreacted starting
material (entry 6). The results indicate that substitution at the 2-
position of the benzimidazole is detrimental to the progress of
the debenzylation.
The scope of the debenzylation was also studied with imida-
zoles to gain additional understanding of the factors that influence
the reactivity (Table 4). N-Benzylimidazole was rapidly depro-
tected in 2 h to afford imidazole in 92% yield (entry 1).16 The
deprotection of N-benzyl-2-methylimidazole required 24 h for
completion and afforded the product in 97% yield (entry 2).17 The
4- or 5-methylimidazole analogs (3:1 mixture) were efficiently
debenzylated in 12 h (entry 3). Phenyl substitutions at the 2- or
4-positions, as well as methyl substitution at both the 2- and
4-positions, were detrimental to the efficiency of the reaction
(entries 4–6). These results suggest that increasing steric con-
straint on the ring system leads to a decrease in reaction efficiency.
To demonstrate the chemoselectivity and the sensitivity of this
reaction to steric influences, the following competition
experiments were conducted (Scheme 1).
A
mixture of
Table 4
Deprotection of imidazoles
Et3SiH
R2
R3
R2
R3
N
N
N
Pd/C
R1
R1
THF, rt
N
H
9
Bn
8
Table 2
Entry
R1
R2
R3
Yield (%) in 9 (8)a
Effect of substitution at the 4- to 7-positions of the benzimidazole
1
H
Me
H
Ph
H
Me
H
H
Me/H
H
Ph
Me
H
H
H/Me
H
H
92
97
99
45 (52)
(92)
16 (78)
R1
R1
2
Et3SiH
Pd/C
3b
4
R2
R3
R2
R3
N
N
N
N
H
5
6
THF,rt
R4
R4
H
Bn
4
5
a
Isolated yields after purification by chromatography on silica gel; parentheses
indicate recovered starting material.
Entry
R1
R2
R3
R4
Yield (%) in 5 (4)a
b
Starting material was a 3:1 mixture of the 4-methyl and 5-methyl isomers.
1
H
H
H/F
H
H
H
OMe
H
H
H
Me
F
H
Cl
CF3
H
H
OMe
H
H
H
Me
F
H
Cl
H
CF3
H
H
OMe
H
H
H
H
H
F/H
H
H
H
H
H
H
OMe
H
CO2Me
H
92
97
94
92
94
94
99
99
99
96
(91)
92
6 (92)
99
2
3b
4
Et3SiH
Pd/C
N
N
N
N
N
5
6
7
8
R
Ph
N
H
THF
rt, 14 h
Bn
Bn
R = Ph or H
1:1 mixture
90%
97%
9
R1
Me
10
11
12
13
14
Et3SiH
Pd/C
N
N
N
CO2Me
H
Me
H
H
H
H
N
H
N
N
THF
rt, 14 h
H
H
Me
95%
Bn
Bn
R2
Me
R1/R2 = Me/H or H/Me
1:1 mixture
95%
a
Isolated yields after purification by chromatography on silica gel; parentheses
indicate recovered starting material.
b
Starting material was a 1:1 mixture of mono-fluoro isomers.
Scheme 1. Competition reactions to demonstrate selectivity.
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T. H. Graham / Tetrahedron Letters xxx (2015) xxx–xxx
3
MacDonald, G.; Minne, G.; Oehlrich, D.; Pieters, S.; Surkyn, M.; Trabanco, A. A.;
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N-benzyl-2-phenylbenzimidazole and N-benzylbenzimidazole
afforded recovered N-benzyl-2-phenylbenzimidazole in 90% yield
and benzimidazole in 97% yield. In a similar manner, a 1:1 mixture
of the N-benzyl-4-methylbenzimidazole and N-benzyl-7-methyl-
benzimidazole afforded the recovered 4-methyl isomer in 95%
yield and the deprotected 7-methyl isomer in 95% yield. The
results of these experiments demonstrated that excellent
chemoselectivity can be achieved with the triethylsilane–Pd/C
reduction system and offer the opportunity for selective deprotec-
tions on suitably functionalized systems.
The experimental results in the tables above suggest several
important features of the transformation. Table 1 demonstrates
that triethylsilane is the preferred hydride donor because the reac-
tion does not progress with hydrogen under otherwise identical
conditions.18 Table 2 indicates that substitution at the 4-position
can attenuate the reactivity, suggesting that sterics may influence
the outcome. The sensitivity to sterics may also explain the results
of Tables 3 and 4 where increased steric congestion results in
decreased yields. These data suggest that the nitrogen atom across
the ring from the benzyl nitrogen must be unencumbered by steric
constraints and is important to the reactivity of the system.
N-Benzylindole and N-benzylpyrrole were unreactive to the reac-
tion conditions and implicate the transannular nitrogen in the
unique reactivity of the triethylsilane–Pd/C system for the depro-
tection of N-benzylbenzimidazoles and N-benzylimidazoles.19
In conclusion, the deprotection of N-benzylbenzimidazoles and
N-benzylimidazoles with triethylsilane and Pd/C occurs under
extraordinarily mild conditions. The reaction is exceptionally effi-
cient for N-benzylbenzimidazole substrates that are unsubstituted
at the 2- and 4-positions as well as certain N-benzylimidazoles.
The unique reactivity of the triethylsilane–Pd/C system and the
straightforward procedure afford a convenient method for the
deprotection of suitably functionalized N-benzylbenzimidazoles
and N-benzylimidazoles.20
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and Pd/C (0.3 equiv Pd) in 10% acetic acid/ethanol at ambient temperature,
refer to: Meyer, E. A.; Donati, N.; Guillot, M.; Schweizer, W. B.; Diederich, F.;
Stengl, B.; Brenk, R.; Reuter, K.; Klebe, G. Helv. Chim. Acta 2006, 89, 573–581.
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hydrogen gas likely acts as the ultimate reductant. In the present case, with
THF as the solvent, less triethylsilane is required and presumably less
hydrogen gas is generated. For
a study of the effect of hydrogen
concentrations on selectivity with Pd/C reductions, refer to: Teschner, D.;
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D.; Schlögl, R. Science 2008, 320, 86–89.
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significantly improve the conversion and a majority of the starting material
was recovered. Additional studies are necessary to understand and overcome
the low conversions for the less reactive substrates.
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17. Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515–516.
18. A possible role of the triethylsilane is for the formation of a relatively stable N-
triethylsilylbenzimidazole that would prevent catalyst poisoning by the
benzimidazole product. The results (Table 2, entries 11–14) do not support
this hypothesis and efforts to isolate a triethylsilyl-benzimidazole adduct have
been unsuccessful.
Supplementary data
Supplementary data (experimental procedures, reagent tables
and spectral data) associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.03.127.
19. For a singular example of the debenzylation of an N-benzyl indole using
triethylsilane-Pd/C, refer to: Rao, D. R.; Kankan, R. N.; Chikhalikar, S. V.;
Ghagare, M.; (Cipla, Ltd). A Process for the Synthesis of Naratriptan. WO2011/
021000A2, 24 February 2011.
20. General procedure: A 16 mL vial with a PTFE/silicone septum and a nitrogen-
bubbler line was charged with N-benzylbenzimidazole (208.1 mg, 1.0 mmol),
Pd/C (10 wt %, dry powder, reduced) (20 mg) and THF (5 mL). The mixture was
References and notes
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l
L, 2.0 mmol) and then stirred under
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syringe filter and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (0–10% MeOH/dichloromethane) to afford
benzimidazole as a colorless solid (117.6 mg, 99%). The reactions generally
exhibit an induction period of 5–30 min as indicated by the initiation of gas
release (i.e., bubbling) from the reaction mixture. The use of Pd/C on a dry
matrix is imperative as wet Pd/C results in decreased yield or no reaction.
4. (a) Salikov, R. F.; Platonov, D. N.; Frumkin, A. E.; Lipilin, D. L.; Tomilov, Y. V.
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Please cite this article in press as: Graham, T. H. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.127