Selective nitrogen protection of hydroxyalkylbenzimidazoles using 2,2,2-trichloroethylchloroformate

Article abstract of DOI:10.1016/j.tetlet.2005.07.037

A method for selective N-protection of hydroxyalkylbenzimidazoles using 2,2,2-trichloroethylchloroformate (Troc-Cl) applicable to various alkyl chain lengths has been developed. In the specific case of 5-(1-[2,2,2-trichloroethyl formyl]-benzimidazol-2-yl)-propan-1-ol, migration of Troc from the benzimidazole to the primary alcohol occurs in the presence of triethylamine, allowing the choice of selective N-Troc or O-Troc protection.

Full text of DOI:10.1016/j.tetlet.2005.07.037

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6311–6313
Selective nitrogen protection of hydroxyalkylbenzimidazoles
using 2,2,2-trichloroethylchloroformate
Richard C. Woudenberg and E. Bryan Coughlin*
Department of Polymer Science and Engineering, Conte Research Center, University of Massachusetts,
120 Governors Drive, Amherst, MA 01003, USA
Received 18 June 2005; revised 8 July 2005; accepted 8 July 2005
Available online 28 July 2005
Abstract—A method for selective N-protection of hydroxyalkylbenzimidazoles using 2,2,2-trichloroethylchloroformate (Troc-Cl)
applicable to various alkyl chain lengths has been developed. In the specific case of 5-(1-[2,2,2-trichloroethyl formyl]-benz-
imidazol-2-yl)-propan-1-ol, migration of Troc from the benzimidazole to the primary alcohol occurs in the presence of triethyl-
amine, allowing the choice of selective N-Troc or O-Troc protection.
Ó 2005 Elsevier Ltd. All rights reserved.
The commercialization of polymer electrolyte mem-
brane fuel cells (PEMFCs) is becoming an increasingly
important goal as the demand for clean, efficient, and
portable energy rises. The polymer membrane in the cell
acts as an electronic barrier and as the proton conduc-
tion medium between the anode and cathode. Presently,
membranes require the addition of small molecules such
as water, phosphoric acid, and heterocycles to facilitate
proton conduction. Polymers containing covalently
bound imidazole and benzimidazole as protogenic moi-
eties have been investigated by several research
groups,1–3 and both show proton conduction at operat-
ing temperatures from 120 to 200 °C, however, a full
range of polymeric materials has not been investigated.
We are interested in preparing polymer electrolyte mem-
branes from well-defined homo and block copolymers
that contain immobilized heterocyclic side chains. In
preparing benzimidazole functional acrylate monomers
1 and 2 (Fig. 1), a novel selective protection/deprotec-
tion scheme of the benzimidazole amine was identified.
N
OH
n
3 n=3
4 n=5
N
H
Figure 2. Hydroxyalkylbenzimidazole precursors.
The acrylate synthesis proceeds from the corresponding
hydroxyalkylbenzimidazoles 3 and 4 (Fig. 2), prepared
by reaction of 1,2-phenylene diamine with c-butyrol-
actone or e-caprolactone, respectively, in the presence
of a catalytic amount of p-toluenesulfonic acid at
200 °C for two hours. The resulting materials contain
two nucleophiles, a primary alcohol, and the 2° amine
in the benzimidazole ring. Selective synthesis of 1 and 2
requires protection of the amine, however, the di-nucleo-
philic nature of hydroxyalkylbenzimidazoles complicates
protection schemes. Competing reactions can result in a
mixture of N-, O-, and doubly protected materials; there-
fore, a selective protection scheme must be identified.
Selective N-protection of 3 with benzyl bromide was
reported by Indusegaram et al.,4 subsequently, we
prepared N-benzyl 4 according to the reported method.
However, N-debenzylation by common hydrogenolysis
methods failed,5 consistent with the literature reports
for N-benzyl aromatic heterocycles. Several alternate
N-debenzylation methods have been reported, however,
these reaction conditions are either incompatible or
experimentally inconvenient. Haddach et al. report
the use of potassium tert-butoxide/DMSO and oxy-
gen to afford clean N-debenzylation of aromatic
N
O
n
1 n=3
2 n=5
O
N
H
Figure 1. Benzimidazole functional acrylate monomers.
Keywords: 2,2,2-Trichloroethylchloroformate; Troc; Benzimidazole;
Selective N-protection.
*
Corresponding author. Tel.: +1 4135771616; fax: +1 4135450082;
e-mail: coughlin@mail.pse.umass.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.037

6312
R. C. Woudenberg, E. B. Coughlin / Tetrahedron Letters 46 (2005) 6311–6313
heterocycles.6 The method is tolerant to many func-
tional groups, but not esters, making this method
impractical in our case. Rao and Pandey reported a mild
N-debenzylation procedure using sodium in liquid
ammonia with t-BuOH at À78 °C that is tolerant to
ester functionality,7 however, use of liquid ammonia
for synthesis on a 5–10 g scale is not attractive. Finally,
there are reports of substituting a more labile protecting
group for the N-benzyl.8,9 Rawal et al. report displacing
the N-benzyl with 2,2,2-trichloroethoxycarbonyl (Troc)
and deprotecting with Zn/acetic acid, and Campbell
et al. report substituting with b-trimethylsilylethyl chlo-
roformate (Teoc) then deprotecting with tetra-n-butyl-
ammonium fluoride in THF.
this vein, we were able to prepare N-Troc protected
hydroxyalkylbenzimidazoles 5 and 6 in good yield by
reacting 3 and 4 directly with 2,2,2-trichloroethylchloro-
formate (Troc-Cl) at 0 °C in the presence of potassium
carbonate as an acid scavenger (Scheme 1). The more
nucleophilic benzimidazole amine reacts preferentially,
resulting in the N-troc protected material when the stoi-
chiometric ratio of Troc-Cl to amine is close to 1:1 and
the Troc-Cl concentration is kept at a minimum during
the reaction. An excess of Troc-Cl greater than
2–3 mol % can result in formation of some doubly pro-
tected material, and addition of Troc-Cl too quickly
results in a mixture of N-, O-, and doubly protected
materials.
Rather than performing a two-step debenzylation, we
decided to investigate a direct route to N-Troc hydroxy-
alkylbenzimidazoles. The Troc group can be removed
under relatively mild conditions and is stable to acidic
environments.10 Additionally, it has been reported that
Troc can be used to selectively protect primary alcohols
in the presence of secondary alcohols,11 exploiting the
nucleophilicity difference of the two alcohols. Following
The benzimidazole acrylate 1 was prepared by reaction
of 5 with acryloyl chloride in dichloromethane, followed
by neutralization with triethylamine. After removal of
the reaction solvent under reduced pressure, the N-troc
was rapidly removed in the presence of basic methanol
(Scheme 2). Whereas, benzimidazole acrylate 2 was pre-
pared by reacting 6 with acryloyl chloride in the pres-
ence of triethylamine in dichloromethane, followed by
troc removal. Under basic conditions, 5 undergoes an
internal rearrangement from N-troc to O-troc 7 presum-
ably through a seven-membered cyclic intermediate.
Subsequent addition of acryloyl chloride forms the
benzimidazole acrylamide 8. Upon addition of basic
methanol, the acrylamide is cleaved and the O-troc is
transformed into the methyl carbonate 9 (Scheme 3).
This type of rearrangement is not observed for 6, most
likely due to the five methylene spacer between the benz-
imidazole and the alcohol resulting in a nine-membered
cyclic intermediate which is not as favorable as the
seven-membered intermediate. This rearrangement
O
N
N
OH
n
N
OH
n
Cl
O
CCl3
N
H
K2CO3, 0 °C
O
O
3 n=3
4 n=5
CCl3
5 n=3(82%)
6 n=5(90%)
Scheme 1. Selective nitrogen protection of hydroxyalkyl-
benzimidazoles.
O
1.
Cl
N
N
OH
n
N
O
n
2. Triethylamine
O
N
H
3. 0.01 M NaOH/MeOH
1 min, RT
O
O
1 n=3 (68%)
2 n=5 (73%)
CCl3
5 n=3
6 n=5
Scheme 2. Preparation of benzimidazole functional acrylate monomers.
N
N
N
N
O
N
OH
CCl3
NEt3
O
O
CCl3
N
H
O
O
H
O
O
7
O
5
CCl3
O
O
O
N
Cl
N
0.01 M NaOH/MeOH
CCl3
O
O
O
O
N
N
H
O
9
8
Scheme 3. Transformation of N-Troc hydroxypropylbenzimidazole to 5-(1H-benzimidazol-2-yl)-propylmethyl carbonate.

R. C. Woudenberg, E. B. Coughlin / Tetrahedron Letters 46 (2005) 6311–6313
6313
expands the utility of the protection scheme by allowing
Supplementary data
selective protection of either the benzimidazole amine or
the alcohol in hydroxypropylbenzimidazoles through an
intramolecular rearrangement. O-Troc is not cleaved to
the parent alcohol by basic methanol, but there are sev-
eral methods reported that demonstrate clean removal
of troc-protected alcohols.10 Additionally, the N-Troc
to O-Troc rearrangement was found to occur catalytically
with triethylamine and dimethylaminopyridine, and with
an equimolar amount of potassium carbonate, however,
only minimal conversion was observed in the presence
of pyridine.
An experimental section with procedural details and
characterization information is included in a supplemen-
tary data file. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.07.037.
References and notes
1. Schuster, M.; Meyer, W. H.; Wegner, G.; Herz, H. G.; Ise,
M.; Kreuer, K. D.; Maier, J. Solid State Ionics 2001, 145,
85–92.
In summary, we have identified a selective N-protection
method for hydroxyalkylbenzimidazoles using 2,2,2-tri-
chloroethylchloroformate. The scheme allows for the
one-step protection of the benzimidazole nitrogen in
the presence of a primary alcohol, exploiting the differ-
ence in nucleophilicity of the two groups. Once pro-
tected, a variety of functional groups can be selectively
attached at the hydroxyl site, followed by rapid N-troc
removal under mild basic conditions. Further, Troc-Cl
can also be used to selectively protect the alcohol in
hydroxypropylbenzimidazoles by performing a base
catalyzed internal rearrangement of 5 in the presence
of triethylamine.
2. Persson, J. C.; Jannasch, P. Macromolecules 2005, 38,
3283–3289.
3. Densmore, C. G.; Rasmussen, P. G.; Goward, G. R.
Macromolecules 2005, 38, 416–421.
4. Indusegaram, S.; Katsifis, A. G.; Ridley, D. D.; Vonwiller,
S. C. Aust. J. Chem. 2003, 56, 819–827.
5. Hydrogenation using H2/Pd-carbon and catalytic transfer
hydrogenation (CTH) using 1,4-cyclohexadiene/Pd-car-
bon or ammonium formate/magnesium.
6. Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V.
Tetrahedron Lett. 2002, 43, 399–402.
7. Rao, T. S.; Pandey, P. S. Synth. Commun. 2004, 34, 3121–
3127.
8. Rawal, V. H.; Jones, J. J.; Cava, M. P. J. Org. Chem. 1987,
52, 19–28.
9. Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.;
Rhodes, R. A. Tetrahedron Lett. 1987, 28, 2331–2334.
10. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley and Sons: New York, 1999,
pp 617.
Acknowledgements
Mass spectral data were obtained from the University of
Massachusetts Mass Spectrometry Facility which is sup-
ported, in part, by the National Science Foundation.
11. Imoto, M.; Kusunose, N.; Kusumoto, S.; Shiba, T.
Tetrahedron Lett. 1988, 29, 2227–2230.