We considered the use of the proton as polyamine
protecting group, testing the notion that the monoamine
resulting from single deprotonation of a polyammonium
compound could allow for selective acylation. We deproto-
nated 1‚4HCl in methanol with 1 equiv of triethylamine
(TEA), and the resulting amine was trapped with 1 equiv of
ethyl trifluoroacetate. Subsequent addition of excess TEA
and 3.5 equiv of BOP-activated 2,3-dimethoxybenzoic acid
resulted in 69% yield of mono(trifluoroacetamide) 4, 12%
of di(trifluoroacetamide) 5, 2% of tris(trifluoroacetamide) 6,
and 5% of tetrakis(2,3-dimethoxybenzamide) 8. These results
show a marked improvement in selectivity and yield of 4.
In deprotonations with TEA, each equivalent produced an
equivalent of the conjugate acid, TEA‚H+(pKa in water )
11.1).11 To avoid the possible back-protonation of aminom-
ethyl groups on the adamantane core by TEA‚H+, we
switched the base to an alkoxide, whose (alcohol) conjugate
acids have considerably higher pKa. One equivalent of
potassium t-butoxide (t-BuOK) was used to deprotonate 1‚
4HCl, followed sequentially by addition of 1 equiv of ethyl
trifluoroacetate, excess TEA, and 3.5 equiv of BOP-activated
2,3-dimethoxybenzoic acid to produce unsymmetric mono-
trifluoroacetamide 4 in 92% yield. We also isolated 2% of
symmetric tetrakis(2,3-dimethoxybenzamide) 8. Under these
reaction conditions, we did not observe di(trifluoroacetamide)
5 or tris(trifluoroacetamide) 6. Data in Table 2 summarize
yield of the unsymmetric mono(trifluoroacetamide)-mono-
(2,3-dimethoxybenzamide) 12 and 62% of symmetric bis-
(2,3-dimethoxybenzamide) 13. However, monodeprotonation
of the ethylene diamine dihydrochloride (11‚2HCl) with 1
equiv of sodium methoxide followed sequentially by reaction
with 1 equiv of ethyl trifluoroacetate, excess base, and 1
equiv of BOP-activated 2,3-dimethoxybenzoic acid gave
markedly better results. Chromatographic separation of the
crude mixture provided unsymmetric 12 in 86% yield and
10% of symmetric diamide 13 (Table 3).
Table 3. Isolated Yields for Selective Acylation of Ethylene
Diamine Starting from the Neutral Amine and from the
Bis(ammonium) Salt
substrate
base
none
NaOCH3
solvent
% 12
% 13
11
11‚2HCl
CH2Cl2
CH3OH
30
86
62
10
Additional examples suggest the generality of the proce-
dure (Table 4). The two primary amine functions in 1,2-
diaminopentane (14) are unsymmetrically acylated by this
procedure to produce 15 in 83% yield (entry 1).
Tris(2-aminoethyl)amine (TREN) (17) has long been used
as a backbone for the synthesis of polydentate ligands,
including some where the three amines have been selectively
acylated to bear different amide units.3 The present pro-
cedure allows for differentiation of the equivalent primary
amine groups in TREN to produce 18 in good yield (entry
2).
Table 2. Isolated Yields (Based on Amine) for Selective
Acylation by Deprotonation of 1‚4HCl (Data for Acylation of
Neutral Tetraamine 1 Are Given for Comparison; the
Compounds Refer to Structures in Scheme 1)
Discrimination between primary and secondary amines in
polyamines such as spermine (20) has been readily ac-
complished by earlier workers; however, differentiation
between the two primary amines has been more difficult.12
The proton here is a useful protecting group. The pKa
difference between the two primary ammonium ions in 20‚
4HCl is sufficient (8.1 and 8.9) to allow for the production
of unsymmetrically acylated 21 in 87% yield as the only
product with a spermine backbone (entry 3). The location
of the trifluoroacetamide on a primary amine was established
substrate
base
% 4
% 5
% 6
% 7
% 8
1
none
TEA
t-BuOK
32
69
92
8
12
0
16
2
0
0
0
0
0
5
2
1‚4HCl
1‚4HCl
the degree of selectivity in acylation obtained under our
various conditions.
We applied this procedure to ethylenediamine (11) (Scheme
3). As reference, we reacted free diamine 11 with 1 equiv
1
by H NMR: the spectrum of 21 exhibited a one-proton
signal at 8.42 ppm for the primary benzamide and a one-
proton triplet for the primary trifluoroacetamide proton at
6.82 ppm.
Scheme 3
We have extended the use of the proton as a protecting
group to selectively alkylate a diamine (Scheme 4). Pipera-
zine (22) has been used to link disparate molecular fragments.
The preparation of 23 where one of the two equivalent
amines has been selectively attached to an NBD unit has
been reported in quantitative yield based on NBD chloride
and a 3-fold excess of piperazine.13 We produced this
molecule in 96% yield by the reaction of NBD chloride with
an equimolar amount of the monoamine resulting from single
deprotonation of bisammonium salt 22‚2HCl.
of ethyl trifluoroacetate, followed by an equivalent of BOP-
activated 2,3-dimethoxybenzoic acid, which produced a 30%
(13) Nudelman, R.; Ardon, O.; Hader, Y.; Chen, Y. l.; Libman, J.;
Shanzer, A. J. Med. Chem. 1998, 41, 1671-1678.
Org. Lett., Vol. 9, No. 24, 2007
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