Boron trifluoride-methanol complex. Mild and powerful reagent for deprotection of acetylated amines. Scope and selectivity

Article abstract of DOI:10.1016/j.tetlet.2015.12.087

A boron trifluoride-methanol complex demonstrated remarkable deprotection selectivity against commonly used amino-protecting groups in the deacetylation of acetanilides and high sensitivity to the steric hindrance of substrates. The scope and limitations of the reaction were explored.

Full text of DOI:10.1016/j.tetlet.2015.12.087

Accepted Manuscript
Boron trifluoride-methanol complex. Mild and powerful reagent for deprotec-
tion of acetylated amines. Scope and selectivity
Sergey Miltsov, Vladimir Karavan, Alexandr Misharev, Julian Alonso-
Chamarro, Mar Puyol
PII:
S0040-4039(15)30502-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.087
TETL 47134
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 October 2015
21 December 2015
22 December 2015
Please cite this article as: Miltsov, S., Karavan, V., Misharev, A., Alonso-Chamarro, J., Puyol, M., Boron trifluoride-
methanol complex. Mild and powerful reagent for deprotection of acetylated amines. Scope and selectivity,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.087
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Sergey Miltsov e-mail: smiltsov2004@mail.ru
Graphical Abstract:
Boron trifluoride-methanol complex - mild and powerful reagent
for deprotection of acetylated amines. Scope and selectivity.
Sergey Miltsov, Vladimir Karavan, Alexandr Misharev, Julian Alonso-Chamarro and Mar Puyol
R = Alkyl
X = COCH3
R = Aryl, Hetaryl
X = COCH3
R = Alkyl, Aryl, Hetaryl
RNHX
RNH2
+
X = COAr, COOCH2Ph, BF3/MeOH
COOEt, SO2R
Boron trifluoride-methanol complex. Mild and powerful reagent for
deprotection of acetylated amines. Scope and selectivity.
Sergey Miltsova*, Vladimir Karavana, Alexandr Mishareva, Julian Alonso-Chamarrob and Mar
Puyolb
a Department of Chemistry, St.Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504, Petrodvorets, Russian Federation.
b Grup de Sensors i Biosensors, Unitat de Quimica Analítica, Facultat de Ciències, Universitat Autònoma de Barcelona, 08193, Bellaterra,
Spain.
A boron trifluoride–methanol complex demonstrated remarkable deprotection selectivity against
commonly used amino-protecting groups in the deacetylation of acetanilides and high sensitivity
to the steric hindrance of substrates. The scope and limitations of the reaction were explored.
1. Introduction
Acetylation by the derivatives of acetic acid (acetic anhydride, acetyl chloride) can be considered
as the most inexpensive and simple way to protect the amino group in multistep organic
synthesis. The advantage of this approach is the ease of the protection step, that can be carried
out at room temperature. Unfortunately the deprotection step often requires rather harsh
conditions (highly acidic or basic media and elevated temperatures) causing side-reactions. It is
therefore interesting to study mild deacetylation reactions to make this protecting group more
attractive. For instance, Sihlbom1 proposed a procedure consisting of heating acetanilides at
reflux in methanol in the presence of boron trifluoride. During the course of our research
regarding the synthesis of long-wave absorbing dyes we successfully used this procedure for the
deprotection of highly labile acetylated aminocyanines.2,3 Later on it was also used in the
synthesis of azidofluoresceins4 and in the final step for the preparation of nonnatural amino

acids,5 where aromatic and heteroaromatic amines were simultaneously used as protecting
groups for the carboxylic functional group and as directing groups for the coupling reaction. It is
also noteworthy that the use of boron trifluoride did not cause racemization in the derivatives of
chiral α-acids in the latter synthetic application. Herein we establish the scope and limitations of
this highly promising synthetic method.
2. Results and Discussion
In order to study the relevance for the use of BF3 in the deprotection of acetylated amines, we
first examined the behavior of amides prepared from various aliphatic and aromatic amines and
common acylating agents using the previously reported conditions employed for the deprotection
of acetylated cyanine dyes.2,3 The reaction was carried out for 3h with 6 equivalents of BF3 and
the composition of the reaction mixture was examined by NMR or GC.
Suprisingly, the deprotection procedure was very selective. Acetylated aliphatic amines
(PhCH2NHCOCH3, PhCH2CH2NHCOCH3, n-BuNHCOCH3, N-acetylpyrrolidine) as well as
benzoylated amines (PhCH2NHCOPh, PhCH2CH2NHCOPh, PhNHCOPh) remained unchanged
and only acetanilides appeared to be reactive. The selectivity of the process towards the nature of
the amine was also proved by the selective removal of the acetyl protecting group when treating
a series of amides of 4-acetylaminophenylacetic and 4-acetylamino-(E)-cinnamic acids 1a-g with
the above reagent (Table 1).
O
X
O
X
BF3/MeOH
Y
Y
CH3COHN
H2N
1a-g
2a-g
Compound
X
Y
Yield, % a
-CH2-
-CH2-
-CH2-
-CH=CH-
-CH=CH-
-CH=CH-
-CH=CH-
-NHCH2Ph
-N(CH2)4
-NHCH2CH=CH2
-NHCH2Ph
-N(CH2)4
76 (94)
(92)
63
71
(93)
72
2a
2b
2c
2d
2e
2f
-NHCH2CH=CH2
-NHCH2CH2OCH3
(84)
2g
a Parenthesis refer to amine complexes with BF3
Table 1. Deacetylation of amides of 4-acetylaminophenylacetic and 4-acetylamino-(E)-cinnamic acids.
Upon NMR-monitoring of the reaction mixture, complete cleavage of the acetanilide group was
demonstrated and no traces of destruction of the phenylacetamide or cinnamide moieties were
detected after 3 hours. In the latter case, we observed insignificant amounts (< 5%) of Z-
isomerized products. Some products, such as free amines, which were low-melting point
substances, were difficult to separate in their pure form. Therefore, we isolated the amines as
their boron complexes instead, which were the primary reaction products by evaporating the
volatiles in vacuo and triturating the residue with Et2O to give fine non-hydroscopic powders.
The 1H NMR-spectra of the complexes agreed with those of protonated aniline derivatives. The
19F spectra showed two close singlets near -148 ppm, independent of the aniline structure. The
relation of integral intensities corresponded to the natural relation of 11B and 10B isotopes (4.05).
To further demonstrate the reaction selectivity, we used 4-aminoacetanilides, acylated with
different acylating agents as model compounds (3a-e). The protective groups that remained
unaltered during the course of the deacetylation reaction were benzoyl, methanesulfonyl,
ethoxycarbonyl and benzyloxycarbonyl groups. In order to examine the role of steric hindrance
in the acyl fragment we tested deprotection of N-acetyl-N'-pivaloyl-p-phenylenediamine (3e) and
observed only the removal of the acetyl group (Table 2).

BF3/MeOH
XHN
NH2
XHN
NHCOCH3
4a-e
X = a) PhCO-, b) EtOOC-, c) PhCH2OOC-, d) CH3SO2-, e) t-BuCO-
3a-e
Compound
Yield (free amine),%
Yield (BF3-complex)%
83
71
78
84
87
95
90
94
94
97
4a
4b
4c
4d
4e
Table 2. Deprotection of acylated 4-aminoacetanilides using BF3-MeOH.
Reaction products as well as their complexes with BF3 were separated, with the latter showing
considerably higher yields (Table 2). The acylation reaction of 4e·BF3 with 4-nitrobenzoyl
chloride using 2 equivalents of Et3N in CH2Cl2 yielded 5 in 93% yield, demonstrating that
complexes of aromatic amines with BF3 could be used for further manipulation in the same
manner as their hydrochlorides (Scheme 1).
O
O
O2N
NH2xBF3
Cl
NO2
t-BuCOHN
NH
t-BuCOHN
2 eq TEA
5 (93%)
4e
Scheme 1. Acylation of 4e-BF3 complex with 4-nitrobenzoyl chloride.
As previously stated, the deacetylation of acetanilides1 is rather sensitive to steric hindrance on
the benzene moiety. In this sense, we examined the influence of N-substitution in acetanilide on
the rate of reaction. It was observed that during the examined reactions, the time for the complete
deprotection of acetanilide (3 hours), the conversion of N-methylacetanilide was only achieved
in 10% yield and that N-ethylacetanilide remained unreacted. This result indicates the selective
deprotection of acetylated primary arylamines in the presence of similarily protected secondary
amino groups.
It was reasonable to expect that acetanilides posessing ester groups can be deprotected while
leaving the ester group unaltered, which is not possible when performing any hydrolytical
method. The ethyl ester of 4-acetaminobenzoic acid 6 was converted to ethyl p-aminobenzoate 7
containing about 10% of the corresponding methyl ester, even when the reaction was carried out
in ethanol. In order to avoid transesterification the complex of boron trifluoride with ethanol,
which was prepared by carefully adding boron trifluoride etherate to absolute ethanol, was used
and pure ethyl p-aminobenzoate was obtained in nearly quantitive yield.
BF3/EtOH
EtOOC
NH2
EtOOC
NHCOCH3
7
6
Scheme 2. Reaction of ethyl 4-acetylaminobenzoate with the boron trifluoride–ethanol complex.
Furthermore it was possible to combine the acetanilide deprotection and carboxyl group
esterification reactions in a one-step synthesis.
O
X
O
X
OH BF3/MeOH
OCH3
CH3COHN
H2N
9a-b
8a-b
X = a) OCH2, b) CH2.

Scheme 3. Reaction of 4-acetylaminophenyl-substituted acids with the boron trifluoride–methanol complex.
Some aromatic and heterocyclic amines can be synthesized by condensation only as acetylated
derivatives and their deacetylation by hydrolytical methods sometimes meets problems caused
by the instability of the heterocyclic moieties in highly acidic or basic media. Using our
approach we obtained amino-substituted 3,5-dihydro-2,3-diphenyl-5-(phenylmethylene)-3,5-
dihydro-4H-imidazol-4-ones 10 and 11 from their respective acetamides in good yields. Amino-
derivatives of 1H-pyrido[2,1-b]benzoxazole 12, 5H-3,4-thiadiazolo[3,2-a]pyrimidine 13 and
4H-pyridino[1,2–a]pyrimidine 14 were also successfully prepared from readily available
acetylated species, synthesized according to literature procedures7,8 (Figure 1). Compounds 13
and 14 were isolated as complexes with BF3 because of the high solubility of the free amines in
water. Earlier it was shown that 5H-3,4-thiadiazolo[3,2-a]pyrimidines, which have structures
very similar to compound 13, underwent cleavage of the thiadiazole ring both in acidic9 (5%
HCl) and basic10 (5% NaOH) media. This fact ensures that the conventional hydrolytical
deprotection of acetylated 13 is hardly possible. It is also worth noting that deprotection of
benzyloxycarbonyl-protected compound 14 was previously achieved8 by catalytic hydrogenation
but only with the simultaneous saturation of the pyridine ring.
O
O
MeOOC
H2N
N
N
N
N
NH2
Et
Cl
OMe
11 (84%)
10 (78%)
O
O
N
N
N
COOEt
NH2
Cl
N
N
N
H3C
NH2
EtO
O
S
O
NH2
12 (85%)
13 (78%)
14 (82%)
Figure 1. Heterocyclic and aromatic amines, prepared from acetamides.
Using our proposed deprotection procedure, we were also able to synthesize styryl dyes bearing
free amino groups, which are formally the products of the condensation of heterocyclic salts with
an active methyl group and 4-aminobenzaldehyde 20-24. The obtained diamino-substituted dyes
21 and 24 have been demonstrated to be suitable for incorporation in the main chain of
polyamides.11,12 The obtained yields of free amines for the deprotection step was 72 – 85% (
Figure 2).

NHCOCH3
Pyrrolidine
+
N
R
CH3
OHC
I
n-BuOH
BF3/MeOH
NH2
N
R
N
R
I
I
NHCOCH3
15 -19
20- 24
H2N
N
Et
NH2
NH2
N
Et
NH2
NH2
I
I
21
23
20
Et
N
N
I
Et
I
22
I
Et
N
NH2
H2N
24
Figure 2. Amino-substituted styryl dyes.
The final model reaction using this deprotection method was the synthesis of functionalized
cyanine dyes. In this case, it is desirable to start with amino-substituted heterocyclic salts which
can be prepared by reduction of the corresponding nitrated salts with SnCl2 and the separation of
the water-soluble products from aqueous reaction mixtures.13 We obtained amino-salts 26a,b
from acetylated precursors in high yields as complexes with BF3 (Scheme 4).
F3BxH2N
H3COCHN
Z
Z
BF3/MeOH
CH3
CH3
N
N
Et
I
I
Et
26a, b
25a, b
a) Z = S (92%); b) Z = C(CH3)2 (95%).
Scheme 4. Preparation of amino-substituted heterocyclic salts.
All our attempts to perform the elementary analysis of boron complexes failed. Assuming that
1
19
the products represent 1:1 amine-BF3 complexes we examined the H and F NMR spectra of
their mixtures with 4-bromoanisole and CF3CONEt2 as standard substances and observed
sufficient concordance of the defined molar relations of amine-BF3 complexes and standards
with those evaluated from spectral data (Table 3).
X
[X]/[St], by weight [X]/[St], 1H NMR
[X]/[St], 19F NMR
a
0.98
0.77
0.63
0.86
1.13
0.65
0.53
0.87
1.21
0.55
0.69
0.87
0.69
0.56
0.84
0.97
0.62
0.51
0.80
1.24
0.56
0.71
2e-BF3
4b-BF3
4c-BF3
4d-BF3
4e-BF3
9a-BF3
9b-BF3
13-BF3
14-BF3
a
b
0.61
0.86
b
a
b
b
0.64
0.52
a
a
a
a
26a-BF3
26b-BF3
a Standard: 4-bromoanisole, b Standard: CF3CONEt2
Table 3. Determination of the composition of selected amine-BF3 compounds.

3. Conclusions
We have reported a mild and highly selective method for the liberation of free aromatic and
heterocyclic amines from their acetylated derivatives. Other amides such as benzamides,
acylated aliphatic amines, some other commonly used amino group protections and ester groups
remained unaltered in the reaction conditions.
Acknowledgements
We acknowledge the Center for Magnetic Resonance and the Center for Chemical Analysis
and Materials Research of Saint Petersburg State University for performing the NMR and ES-
MS studies. This work has been supported by the Spanish Ministry of Science and Innovation
(MICINN) through projects CTQ2009-12128 and the Consolider Ingenio 2010 project CSD2006
-12 and Catalonia Government through SGR 2009 -0323.
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1
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1
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