Boron tribromide mediated debenzylation of benzylamino and benzyloxy groups

Article abstract of DOI:10.1016/j.tetlet.2004.03.139

The treatment of 2(or 4)-benzylamino substituted quinolines, 9-benzylaminoacridine, 2-benzylaminopyridine, a 4-benzyloxyquinoline, and an N-benzyloxyamidine with BBr₃ yields the corresponding amino or hydroxy substituted compounds. The scope and limitations of this novel reaction are discussed.

Full text of DOI:10.1016/j.tetlet.2004.03.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4093–4095
Boron tribromide mediated debenzylation of benzylamino and
benzyloxy groups
Ekaterina Paliakov and Lucjan Strekowski*
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Received 5 March 2004; accepted 24 March 2004
Abstract—The treatment of 2(or 4)-benzylamino substituted quinolines, 9-benzylaminoacridine, 2-benzylaminopyridine, a 4-benzyl-
oxyquinoline, and an N-benzyloxyamidine with BBr yields the corresponding amino or hydroxy substituted compounds. The scope
3
and limitations of this novel reaction are discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
The benzyl and substituted benzyl moieties are widely
used protecting groups for amines, alcohols, phenols,
esters, and heterocyclic amides. There is a plethora of
reagents for cleavage of such O- and N-benzyl deriva-
molecule. For example, it has been reported that by
using this reagent a methoxy group can be demethylated
selectively in the presence of a benzylamino function. In
fact, there have been no reports in the literature on
boron tribromide mediated cleavage of benzylamines.
To our best knowledge, no benzyloxy group has ever
been cleaved by this reagent either.
7
1;2
tives. In particular, boron tribromide has been suc-
cessfully used for deprotection of N-benzyluracils and
3;4
5
N-benzyl substituted heterocyclic amides. A related
cleavage of an N-(2-pyrrolylmethyl)-substituted lactam
6
has also been reported. Boron tribromide is best known
for its ability to cause selective cleavage of aryl methyl
ethers in the presence of other functional groups in the
Therefore, it was highly surprising to observe that the
attempted removal of a methyl group from N-
methoxybenzyl substituted quinolin-4-amine 1 (Scheme 1)
BBr3
polymer
Br
Br
HN
NH
HN
N
BBr
3
MeO
BBr3
OMe
F
OMe
F
N
N
BBr2
4
30 min
at 23 oC
1
2
F
H O
2
NH2
HN
N
.HBr
OH
F
N
5
F
2
(57%)
Scheme 1.
Keywords: Boron tribromide; Debenzylation; Benzylamino; Benzyloxy.
*
Corresponding author. Tel.: +1-404-651-0999; fax: +1-404-651-1416; e-mail: lucjan@gsu.edu
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.139

4094
E. Paliakov, L. Strekowski / Tetrahedron Letters 45 (2004) 4093–4095
by treatment with boron tribromide did not produce the
desired phenol derivative 2.
R
O
N
R
N
O
Me
Quinolin-4-amine 5 was isolated in 57% yield after
purification and compared to an authentic sample.
NH2
8;9
F
Moreover, the expected compound 2 was not found by
using careful chromatographic separations of crude
mixtures obtained under different conditions of the
reaction time, temperature, and ratio of 1/BBr3.
1
4 : R = Bn
15 : R = Bn
17 : R = H
ii
ii
30 min
15 min
16 : R = H
Chart 2. (ii) See Chart 1 for conditions. The mixture was quenched
with water and extracted with ether (3 ꢀ 4 mL). Compound 16 was
isolated as a hydrobromide salt 16ÆHBr following concentration of the
aqueous solution and crystallization of the residue from 95% EtOH:
The mechanism of debenzylation of 1 is proposed in
Scheme 1. The initial complexation of the basic quino-
10
line N1 atom in 1 (estimated pK of about 6.5 ) by BBr
1
a
3
yield 75%. The free base 17 pure by H NMR standard was obtained
is followed by elimination of bromide from the resultant
complex to generate a bromide salt 3. The boryl-quin-
olinium cation of 3 is expected to be highly reactive in a
nucleophilic displacement reaction at the benzylic posi-
tion with bromide acting as the nucleophile. This reac-
tion would produce 4-methoxybenzyl bromide and a
boryl-quinolinimine 4. The latter derivative is the sug-
gested direct precursor to the observed product 5.
However, 4-methoxybenzyl bromide could not be
found, even by using a highly sensitive GC–MS analysis.
3
by treatment of the aqueous solution with NaHCO (0.5 g), extraction
of the basic mixture with ether (3 ꢀ 4 mL), and then concentration of
the extract: yield 71%.
chloride. The N-(benzyloxy)amidine 15 was a gift from
Dr. D. W. Boykin, Georgia State University.
16
As can be seen from Charts 1 and 2, all these benzyl-
amino and benzyloxy derivatives undergo a cleavage of
the benzyl group upon treatment with 10 M excess of
4
-Hydroxybenzyl bromide was not found in the crude
mixture either. Apparently, these compounds, as highly
reactive toward electrophilic substitution, underwent
BBr
3
in CH
2
Cl
2
at 23 °C. The high excess of the reagent
was used to directly compare the reaction times for
consumption of the starting material, which ranged
from 15 min for 6 and 14 to 2 weeks for 9 under similar
conditions. In the reactions of 6 and 14 conducted with
11
cationic polymerization in the presence of BBr
3
.
In-
deed, the reaction of 1, in addition to 5, produced a
substantial amount of tar. More importantly, the out-
come of additional debenzylation reactions conducted
with benzyl substituted compounds is fully consistent
with the suggested mechanism.
3
5 equiv of BBr , which is comparable to the amount of
the reagent typically used for demethylation of methyl
ethers, a complete cleavage was observed in less that 1 h.
The yields of the corresponding products 10–13, 16, 17
after purification were in the range 54–88%. Their
structure was established by spectral comparison with
authentic samples obtained commercially (12, 13, 17)
The benzyl substituted heterocyclic amines 6–9 are
shown in Chart 1. Benzyloxy substituted quinoline 14
and amidine 15 (Chart 2) were also included in this
study. Each of these compounds contains a basic
13;14
17
and prepared using published chemistry (10,
11,
15
nitrogen atom, the complexation of which by BBr
would subsequently result in generation of a bromide
3
16 ). In full agreement with the proposed mechanism
(Scheme 1) the presence of benzyl bromide in all crude
mixtures was observed by using GC–MS analysis. For
the reaction of 15, the GC analysis was also conducted
in the presence of an internal standard (dibenzoyl-
methane) and gave a 95% yield of benzyl bromide.
salt with a structural feature similar to that of 3 (Scheme
1
). As with 1, compounds 6–8 were synthesized by
treatment of a 4(or 2)-chloroquinoline or 9-chloroacr-
idine with benzylamine or benzylmethylamine using
12–14
general procedures.
N-Benzylpyridine-2-amine (9)
was obtained commercially, and 4-benzyloxy-2-(4-fluoro-
As expected, dibenzylamine and N-benzylaniline are
phenyl)quinoline (14) was prepared by alkylation of 2-
(
3
inert in the presence of BBr . N-Benzylquinolin-5-
amine, N-benzylpyrimidine-2-amine, and 2-amino-1-
15
18
19
4-fluorophenyl)-4-hydroxyquinoline
with benzyl
Me
R
N
N
R
HN
R
R
N
N
N
N
H
N
Me
F
6
1
: R = Bn
7 : R = Bn
11 : R = H
8 : R = Bn
12 : R = H
9
1
: R = Bn
i
i
6 h
i
2 weeks
i
25 h
1
5 min
3 : R = H
0 : R = H
Chart 1. (i) Products 10–13 were isolated as hydrobromide salts using the following procedure. A solution of 6–9 (0.2 mmol) in CH
treated at ꢁ10 °C with BBr in CH Cl (1 M, 2 mL, 2 mmol), and the mixture was stirred at 23 °C for the indicated period of time. The reaction time
refers to consumption of the starting material as shown by GC [a capillary column coated with poly(dimethylsiloxane)] or TLC (silica gel, ether/
AcOEt/Et N) analysis of aliquots quenched with aqueous NaHCO . While stirring, the mixture was treated with water (0.2 mL), and the resultant
solid material was filtered and crystallized from ether/AcOEt (19:1). Yields: 10ÆHBr, 80%; 11ÆHBr, 54%; 12ÆHBr, 88%; 13ÆHBr, 64%.
2 2
Cl (4 mL) was
3
2
2
3
3

E. Paliakov, L. Strekowski / Tetrahedron Letters 45 (2004) 4093–4095
4095
benzyl-3-cyano-4,5-dimethylpyrrole (a commercial
product) also could not be cleaved by treatment with
11. Chang, J. Y.; Lee, S. W.; Park, P. J.; Han, M. J.
Macromolecules 1997, 30, 8075–8077, and references cited
therein.
20
this reagent. These heterocyclic amines are less basic
than compounds 1, 6–9, 14, and 15 that undergo BBr
mediated debenzylation reaction and, apparently, they are
1
1
1
2. Galy, J.; Vincent, E.; Galy, M.; Barbe, J.; Elguero, J. Bull.
Soc. Chim. Belg. 1981, 90, 947–954.
3. Strekowski, L.; Zegrocka, O.; Windham, C.; Czarny, A.
Org. Proc. Res. Dev. 1997, 1, 384–386.
4. Strekowski, L.; Say, M.; Henary, M.; Ruiz, P.; Manzel, L.;
Macfarlane, D. E.; Bojarski, A. J. J. Med. Chem. 2003, 46,
1242–1249.
3
only weakly complexed with BBr . As a result, bromide
3
salts similar to 3 (Scheme 1) may not be generated.
In conclusion, benzylamines and benzyloxy-substituted
compounds that are highly basic for strong complexa-
15. Janda, L.; Nguyen, J.; Patterson, S. E.; Strekowski, L.
J. Heterocycl. Chem. 1992, 29, 1753–1756.
tion with BBr
for the suggested generation of bromide salts similar to 3
3
and with structural features that allow
1
6. All new compounds gave satisfactory results of elemental
analysis or HRMS data.
are efficiently cleaved by treatment with BBr . Boron
3
1
Compound 1: mp 111–112 °C (from EtOH); H NMR
tribromide may be considered for deprotection of such
compounds. In addition, this report serves as a pre-
caution that the use of BBr for cleavage of various
(
DMSO-d
6
) d 3.74 (s, 3H), 4.88 (d, J ¼ 6 Hz, 2H), 6.94 (d,
J ¼ 9 Hz, 2H), 7.09 (s, 1H), 7.43 (d, J ¼ 9 Hz, 2H), 7.55 (t,
J ¼ 8 Hz, 2H), 7.76 (t, J ¼ 8 Hz, 1H), 8.04 (m, 3H), 8.12
3
functionalities may also cause undesired debenzylation
of benzylamino and benzyloxy moieties.
(
d, J ¼ 8 Hz, 1H), 8.40 (d, J ¼ 8 Hz, 1H), 9.83 (br s, 1H,
2
exchangeable with D
O).
O: mp 227–228 °C (from EtOH/
O); H NMR (DMSO-d ) d 2.98 (s, 3H), 4.59 (s, 2H),
.32–7.52 (m, 9H), 7.69 (t, J ¼ 7 Hz, 1H), 8.01 (d,
J ¼ 8 Hz, 1H), 8.08 (d, J ¼ 8 Hz, 1H), 8.29 (m, 2H).
Compound 7: mp 95–96 °C (from EtOH/CHCl );
NMR (DMSO-d ) d 3.40 (s, 3H), 5.08 (s, 2H), 7.31–7.48
Compound 6ÆHClÆ1/3H
2
1
Et
7
2
6
References and notes
1
3
H
1
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Synthesis; Wiley: New York, 1999.
6
(m, 7H), 7.55 (t, J ¼ 8 Hz, 1H), 7.89 (d, J ¼ 8 Hz, 1H),
2
3
. Kocienski, P. J. Protecting Groups; Verlag: Stuttgart, 1994.
. Kundu, N.; Hertzberg, P.; Hannon, S. Tetrahedron Lett.
8.10 (d, J ¼ 8 Hz, 1H), 8.36 (d, J ¼ 8 Hz, 1H).
1
Compound 10: mp >210 °C (decomp); H NMR (DMSO-
1
980, 21, 1109–1112.
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d
6
) d 3.04 (s, 3H), 6.89 (s, 1H), 6.35 (t, J ¼ 9 Hz, 2H), 6.98
4
5
6
7
8
9
(br d, 1H, exchangeable with D
7.69 (t, J ¼ 7 Hz, 1H), 7.92 (d, J ¼ 8 Hz, 1H), 8.14 (d,
2
O), 7.46 (t, J ¼ 7 Hz, 1H),
1
J ¼ 8 Hz, 1H), 8.23 (m, 2H).
Compound 14Æ1/4H O: mp 116–117 °C (from ether/hex-
2
1
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3
) d 5.38 (s, 2H), 7.19, (m, 3H), 7.46
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2
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1
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