Pyridinium N-heteroarylaminides: synthesis of N-heteroarylpolyamines

Article abstract of DOI:10.1016/j.tet.2009.09.079

The synthesis of a set of new N-heteroarylpolyamines is reported. A multiple and regioselective alkylation on the exo nitrogen of pyridinium N-(heteroaryl)aminides with several polybromo compounds, followed by a clean N-N bond reduction of the corresponding pyridinium salts, provides an easy and general method to obtain the title compounds.

Full text of DOI:10.1016/j.tet.2009.09.079

Tetrahedron 65 (2009) 9782–9790
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Pyridinium N-heteroarylaminides: synthesis of N-heteroarylpolyamines
*
´
Rafael R. Castillo, Marta Cordoba, M. Luisa Izquierdo, Julio Alvarez-Builla
´
´
´
Departamento de Qu´ımica Organica, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a set of new N-heteroarylpolyamines is reported. A multiple and regioselective alkyl-
ation on the exo nitrogen of pyridinium N-(heteroaryl)aminides with several polybromo compounds,
followed by a clean N–N bond reduction of the corresponding pyridinium salts, provides an easy and
general method to obtain the title compounds.
Received 28 July 2009
Received in revised form
11 September 2009
Accepted 18 September 2009
Available online 22 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Alkylation of pyridinium aminides, especially those in which the
structure is stabilized with azines, is a well documented procedure
Polyamines are a family of compounds that are widely studied
as a result of their presence in many biological systems1a,b and their
use as chelating agents,1c–e to mention two of the most represen-
tative areas of interest. The polyamines reported to date, however,
are mostly aliphatic and very little attention has been paid to
polyamines bearing heterocyclic moieties. In the case of the com-
pounds now described, they mostly functionalised with 2-amino-
pyridine moieties, which combine in their structure two
supplementary effects in terms of basicity and coordination prop-
erties, because the molecule has two electronically different and
complementary unshared electron pairs, which produces an azine
nitrogen with high electronic density. In recent articles the ad-
vantages of using (poly)aminopyridines within artificial receptors
has been described.1f–h However, the synthesis and reactivity of
other aminoheterocycles have been even less studied.
Monoalkylation on the exocyclic nitrogen of 2-aminopyridines
is not an easy task due to the presence of two nucleophilic nitrogen
atoms in the structure, for which kinetic control favours alkylation
of the azine nitrogen. A review of the literature showed that this
problem is usually avoided either by the use of protecting group-
s,2a,b by directly synthesizing the alkylaminopyridine through
highly reactive sustrates,2c or by preparing the diazonium salt,
which is subsequently substituted with the corresponding amine.
The synthesis of 2-(N-alkylamino)pyridines is also possible from
halopyridines through SN reactions with amines2d or by employing
amination catalysts.2e,f As part of our research programme, we
explored the synthetic uses of N-(heteroaryl)pyridinium aminides
1, which offer a clear alternative because substituted alkylamino-
heterocycles can be easily obtained in a two-step regioselective and
mild procedure.3
for the highly regioselective alkylation of the exocyclic nitrogen
atom. A subsequent reduction of the N–N bond under mild condi-
tions yields the corresponding alkylaminoazine (Scheme 1).
X
R
H
N
N
Het
R
R-CH2X
[Red]
N
N
N
N
+
+
N
N
Het
Het
1
Scheme 1.
There are other advantages of the synthesis of alkylaminoazines
from pyridinium aminides. For example, multiple alkylations and
subsequent reductions are also possible to give, in a controlled
manner, families of polyaminopyridines with a range of possibili-
ties for structural variation.3
All of these precedentsdcombining alkylation, reduction and
the possibility of using a wide variety of differently functionalized
pyridinium aminides4,5dallowed us to tackle the synthesis of
several geometrically different families of polyaminoazines.3
The first target was the preparation of alkyl bromides with two
different functionalities: one with halomethyl groups for the alkyl-
ation of the corresponding pyridinium aminides and an additional
one to explore the possibility of growing the molecule, as typically
explored in dendrimer chemistry. The dihalogenated compounds
suitable to afford this synthetic route could be easily obtained from
dimethylisophthalate derivates 2, as shown in Scheme 2.6
Alkylation of pyridinium aminides3 1 with 1-benzyloxy-3,5-
bis(bromomethyl) benzene6d,e 3 or 3,5-bis(bromomethyl)phenol6f–i
4
gave the corresponding bis(heteroarylaminopyridinium)di-
* Corresponding author. Fax: þ34 91 885 46 86.
E-mail address: julio.alvarez@uah.es (J. Alvarez-Builla).
bromides 5 and 6 in excellent yields (Scheme 2, Table 1).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.079

R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
9783
N+
N
Het
N
CO2Me
MeO2C
Het
N
Het
N
4Ar
(i)
Br
Br
1
N
N
(ii) or (iii)
N
N
5
3
2
+
+
6
(iv)
6
5
2
3
1
O
O
Br
Br
R
R
2
O
R
4
R = CH2Ph
R = H
3
R = H
2a
R = CH2Ph
R = H
5
4
R = CH2Ph 2b
6
Scheme 2. (i) LiAlH4, THF,
D, 3 h. (ii) NBS, PPh3, CH2Cl2, rt, 12 h, for 3. (iii) HBr–H2O/toluene,
D
, 2 h, for 4. (iv) Acetone, rt, 12 h.
Table 1
acidic a-positions of the pyridinium rings, both of which would give
an intermediate with low reactivity.
Alkylation of different N-(heteroar-2-yl)pyridinium aminides with compounds 3
and 4
Due to the failure in the functionalization of the hetero-
arylaminopyridinium salts 5 and 6, which would have opened ac-
cess to more complicated structures, it was decided to prepare
branched alkylating agents that would react with functionalized
pyridinium aminides,4 such as 1,3,5-tris-bromomethylbenzene
73a,7 or the tetrakis-bromomethyl derivates 103b,8, which synthesis
is outlined in Scheme 4.
Het
R
Compound
Yield
N
6'
5'
2'
3'
–CH2Ph
5a
89%
Br
4'
N
6'
5'
2'
3'
2''
5''
The alkyl bromides 7 and 10 were reacted with pyridinium
aminides according to the described procedure.3a In this case,
however, intermediate mono- and dialkylated salts precipitated
together with the fully alkylated compound. In an effort to avoid
this problem, a more polar solvent was chosen and the use of DMF
was able to retain all compounds in solution, meaning that the
reaction could proceed to completion (Schemes 5 and 6).3b
Isolation of salts from the mixture was performed by evapo-
rating the solvent, redissolving the residue in the minimum
amount of DMF (1–2 mL) and adding this solution dropwise to well
stirred AcOEt. This led to precipitation of the hetero-
arylaminopyridinium bromides, while the uncharged pyridinium
aminide remained in solution. The salts 11, 13 and 14 were col-
lected by filtration and further purified by crystallization.
The N–N bond in the poly(heteroarylamino)aminopyridinium bro-
mides 11,13 and 14 was reduced using a metal/acid system such as Zn/
AcOH3b and in the case of 12c cleavage of the chlorine was not observed.
Polyamines 12, 15 and 16 were obtained as solids in good yields
except for 12d, which was obtained as an oil. The different yields
obtained in the polyalkylation and reduction processes are shown
in Tables 2 and 3 (Schemes 5 and 6).
3''
4''
–CH2Ph
5b
6a
6b
92%
95%
85%
1''
6''
4'
N
6'
2'
3'
–H
5'
4'
N
3a'
4'
2'
–H
S
5'
7a'
6'
7'
N
6'
5'
1''
6''
2'
3'
2''
3''
4''
–H
6c
91%
4'
OH
5''
Compounds 5a and 5b were prepared from the corresponding
aminides in order to check (by 1H NMR spectroscopy) the evolution
of the Suzuki reaction on salt 5a. The conditions described for the
coupling on aminides5a,b were not suitable in this case. When the
Pd cross-coupling on 5a was tested using MeCN/EtOH as solvent,
decomposition of the salt was observed. A blank test without bo-
ronic acid and Pd catalyst demonstrated decomposition of 5a,
giving detectable amounts of pyridin-2-one and 5-benzyloxy-1,3-
bis[N-(5-bromopyridin-2-yl)aminomethyl]benzene. A mechanism
for the process is postulated in Scheme 3.
Transformation of the –CH2OH group into a –CH2Br group in
compounds 11a and 11b can be used to grow the molecule. This
halogenation was carried out in concentrated hydrobromic acid, in
which the salt dissolved slowly. After 12 h the salt was isolated as
previously indicated and treated with a basic ionic exchange resin
to remove any excess acid. Trihalogenated salt 17, under the usual
conditions, reacted with pyridinium aminides to give hexasalts 18,
as shown in Scheme 7.
Ph
OH-
O
OH
H
Ph
N
H
O
N
N
+
+N
N
N
N
H
N
O
N
N
R
H
N
H
N
Br
N
N
Br
Br
5a
Br
Br
Scheme 3.
On the other hand, the alkylation of the free phenol group in
compounds 6 was tested, but substitution with alkyl halides was
not observed. This is possibly due to steric hindrance around the
phenol group and/or to the association of the phenoxide with the
Finally, reduction of hexasalt 18 to the corresponding hex-
amine was attempted, but the use of either Zn/AcOH3b or BEt3/
MeOH5a proved unsuccessful and produced only partial re-
duction, with pyridine detected in the reaction mixture. Tests

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R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
Br
Br
Br
R
R
R
(i)
(iii) or (iv)
O
2
O
O
O
W
W
R
Br
R = CO2Me; W = -(CH2)4- 8a
R = CO2Me; W = m-xylyl 8b
W = -(CH2)4- 10a
W = m-xylyl 10b
(ii)
R = CH2OH; W = -(CH2)4- 9a
R = CH2OH; W = m-xylyl 9b
Scheme 4. Reagents and conditions: (i) DMF, K2CO3, alkyl dibromide, 80 ꢁC, 24 h. (ii) LiAlH4, THF,
(for 10b3b).
D, 3 h. (iii) HBr/H2SO4,
D
, 1 h (for 10a7). (iv) NBS, PPh3, CH2Cl2, ultrasound, 90 min
Het
N
Br
Br
11
R =
R
N
N
N
6
+
Het
Br
5
3
N
R
1
4
N
1
Zn
AcOH, MeOH
DMF
2
Br
R N
7
R = H 12
Het
Scheme 5.
Het
N
N
N Het
N
R
5
6
R
1
4
O
O
1
10
DMF
R
W
R
N
3
2
N
N
N
Het
Het
Zn
AcOH, MeOH
W = -(CH2)4- 15
W = m-xylyl 16
W = -(CH2)4- 13
W = m-xylyl 14
R = H
R =
N+
Br
Scheme 6.
using ammonium formate and Pd/C (10% dry)9 allowed the
preparation of 19, although purification of the hexamine was not
achieved (Scheme 7).
a Perkin–Elmer FTIR 1725X spectrophotometer. 1H and 13C NMR
spectra were recorded on Varian Gemini (200 MHz), Unity or
Mercury (300 MHz) or Unity (500 MHz) spectrometers and values
In conclusion, N-(heteroaryl)pyridinium aminides 1 can be used
as intermediates to produce polyamines bearing 2-amino-
heteroaryl moieties. The process to generate the dendrimeric
compounds is simple and straightforward, with a combination of Pd
arylation on the heteroaryl ring and N-alkylation on the aminide
nitrogen. The process, however, becomes more difficult with poly-
substituted compounds, as both polypyridinium salts and the
resulting polyamines are very insoluble, making it increasingly dif-
ficult to manage all processes on increasing the size of the system.
Further studies on metal complexation of these polyamines are
currently in progress as well as a possible improvement of the re-
duction in hexasalts.
are given in parts per million (d) downfield from TMS. Melting
points were determined on a Stuart Scientific SMP3 melting point
apparatus using open capillary tubes and are uncorrected. Ele-
mental analyses were carried out on a Heraeus Rapid CHN analyser
and are within ꢀ0.4% of the theoretical values for all compounds
described. Mass data were collected, when given, on an Agilent
6210 Time-of-flight LC/MS.
In the NMR analysis, numbering was defined using primes, with
the highest priority ring in the molecule labelled without primes
and the lowest priority groups labelled with a prime (0), double
prime (00), etc. In some cases, substituted central rings are labelled
as Ar or Xyl and alkyl chains with a–g. In the case of compound 18a,
an extra NMR label appears in the assignment and this denotes
a difference between the external (e) and internal (i) pyridinium
aminide units.
Note that for reduced compounds the labelling has one fewer
prime labels than the precursor (due to the absence of the pyr-
idinium ring). In NMR analyses, 2D experiments were performed for
relevantcompounds, with the rest assigned on the basis of the values
obtained either from the related products or from the literature.
2. Experimental section
2.1. General
All chemicals and solvents were purchased from commercial
sources. Reactions involving ultrasound were carried out in
a Branson 1510 ultrasonic bath. Infrared spectra were recorded on

R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
9785
Table 2
were dissolved in acetone (10 mL) in a dried round-bottomed flask.
The reaction mixture was stirred at room temperature for 12 h.
During the reaction a precipitate appeared and, after completion,
the diaminopyridinium bromide was filtered off, washed with ac-
etone, and crystallized from EtOH or iPrOH with a few drops of
MeOH, to give pure diaminopyridinium bromides 5 and 6 as yellow
to brown solids.
Trialkylation and reduction of 3,5-disubstitutedpyridin-2-yl pyridinium aminides5a
Het
Alkylation
Reduction
Compound Yield Compound Yield
N
6'
5'
2'
3'
2''
5''
3''
4''
11a
11b
11c
85%
80%
87%
12a
12b
12c
79%
71%
79%
1''
6''
4'
OH
2.2.1. {5-Benzyloxy-1,3-bis[N-(5-bromopyridin-2-yl)-N-(pyridin-1-
ium)amino methyl]}benzene dibromide (5a). From 550 mg of the N-
(5-bromopyridin-2-yl)pyridinium aminide5c and 370 mg of 3, and
following the general procedure, 800 mg of the dibromide 5a were
obtained (mp>172 ꢁC dec, EtOH, 92%). IR (KBr), nmax (cmꢂ1): 2998,
2934, 1616, 1571, 1476, 1367, 1299, 1225, 1154, 1048, 996, 829, 748,
N
6'
5'
2'
3'
1'''
2'''
2''
5''
6'''
3''
4''
5'''
4'''
1''
6''
4'
HO
Cl
OH
3'''
673. 1H NMR (300 MHz, CD3OD),
d
(ppm): 9.15 (4H, dd, J¼6.8 and
N
6'
5'
1''
2'
3'
1'''
6'''
1.3 Hz, H2(6)), 8.74 (2H, tt, J¼7.8 and 1.3 Hz, H4), 8.28 (2H, d,
J¼2.0 Hz, H60), 8.19 (4H, dd, J¼7.8 and 6.8 Hz, H3(5)), 8.03 (2H, dd,
J¼9.0 and 2.4 Hz, H40), 7.38 (5H, m, HPh), 7.19 (1H, br s, H4Ar), 7.14
(2H, d, J¼9.0 Hz, H30), 7.05 (2H, d, J¼1.4 Hz, H2Ar (6Ar)), 5.36 (4H, s,
2'''
5'''
2''
5''
Cl
3'''
4'''
3''
4'
6''
4''
CH2N), 5.12 (2H, s, CH2O). 13C NMR (75 MHz, CD3OD),
d (ppm):
N
6'
5'
2'
3'
1'''
6'''
160.9, 157.0, 149.8, 149.5, 149.3, 143.0, 138.2, 137.5, 130.7, 129.7,
129.1, 128.5, 122.8, 117.0, 115.8, 112.5, 70.9, 58.5. MS (ESI, MeOH, m/
z): 793/791/789/787 (3/8/8/3, [MꢂBr]þ), 356/354 (74/51), 355
(100), 316 (15), 315 (18). HRMS (ESI-TOF, MeOH): calculated for
C35H2979Br3N6O [MꢂBr]þ: 785.99530, found 785.99497.
2'''
2''
Me
Me
1''
6''
3'''
4'''
4'
3''
11d
76%
12d
70%
4''
5''
5'''
Me
Me
Table 3
Tetraalkylation and reduction of different heteroarylpyridinium aminides4,5a
2.2.2. {5-Benzyloxy-1,3-bis[N-(5-phenylpyridin-2-yl)-N-(pyridin-1-
ium)amino methyl]}benzene dibromide (5b). From 544 mg of the N-
(5-phenylpyridin-2-yl)pyridinium aminide5a and 370 mg of 3, and
following the general procedure, 770 mg of the dibromide 5b were
obtained (mp>197 ꢁC dec, EtOH, 89%). 1H NMR (300 MHz, CD3OD),
Het
W
Alkylation
Reduction
Compound Yield Compound Yield
N
d
(ppm): 9.18 (4H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.73 (2H, tt, J¼7.8
6'
5'
2'
3'
13a
13b
85% 15a
84% 15b
85%
68%
and 1.3 Hz, H4), 8.47 (2H, dd, J¼2.4 and 0.7 Hz, H60), 8.21 (4H, dd,
J¼7.9 and 6.6 Hz, H3(5)), 8.14 (2H, dd, J¼8.6 and 2.4 Hz, H40), 7.62
(4H, dd, J¼8.3 and 1.4 Hz, H200(600)), 7.45 (11H, m, H300(500), HPh and
H400), 7.25 (3H, m, H30 and H4Ar), 7.10 (2H, d, J¼1.2 Hz, H2Ar(6Ar)),
5.41 (4H, s, CH2N), 5.15 (2H, s, CH2O). 13C NMR (75 MHz, CD3OD),
4'
N
3a'
4'
6'
2'
S
5'
-CH2CH2CH2CH2-
7a'
7'
d
(ppm): 161.0, 157.3, 149.6, 149.1, 147.1, 138.9, 138.3, 137.9, 134.1,
130.6, 130.4, 130.3, 129.7, 129.2, 129.1, 128.5, 127.7, 122.8, 117.0, 111.0,
70.9, 58.7. HRMS (ESI-TOF, MeOH): calculated for C47H4079BrN6O
[MꢂBr]þ: 783.2447, found 783.2533.
N
6'
5'
2'
3'
2''
5''
3''
4''
13c
90% 15c
74%
1''
6''
4'
2.2.3. {5-Hydroxy-1,3-bis[N-(pyridin-2-yl)-N-(pyridin-1-ium)ami-
nomethyl]}benzene dibromide (6a). From 376 mg of the N-(pyridin-
2-yl)pyridinium aminide10b and 280 mg of 4, and following the
general procedure, 614 mg of the dibromide 6a were obtained
(mp¼238–239 ꢁC, EtOH, 95%). IR (KBr), nmax (cmꢂ1): 3025, 1614,
1591, 1471, 1321, 1304, 1239, 1158, 797, 773, 682. 1H NMR (300 MHz,
N
6'
5'
2'
3'
14a
14b
87% 16a
84% 16b
79%
89%
4'
8'
5'
2
DMSO-d6),
d
(ppm): 9.64 (1H, s, OH), 9.30 (4H, d, J¼5.7 Hz, H2(6)),
8a'
N
7'
6'
1
6
2'
3'
3
4
8.75 (2H, t, J¼7.9 Hz, H4), 8.26 (4H, m, H3(5)), 8.17 (2H, dd, J¼5.2
and 1.5 Hz, H60), 7.89 (2H, dd, J¼7.9 and 1.5 Hz, H40), 7.14 (4H, m, H30
and H50), 6.93 (1H, s, H4Ar), 6.69 (2H, s, H2Ar(6Ar)), 5.28 (4H, s,
4a'
5
4'
CH2N). 1H NMR (300 MHz, CD3OD),
d
(ppm): 9.20 (4H, dd, J¼6.8 and
1.3 Hz, H2(6)), 8.44 (2H, tt, J¼7.8 and 1.3 Hz, H4), 8.22 (6H, m, H3(5)
and H60), 7.90 (2H, ddd, J¼8.9, 7.9 and 1.8 Hz, H40), 7.18 (4H, m, H30
and H50), 7.08 (1H, m, H4Ar), 6.81 (2H, d, J¼1.5 Hz, H2Ar(6Ar)), 5.32
N
6'
5'
1''
6''
2'
3'
2''
(4H, s, CH2N). 13C NMR (75 MHz, DMSO-d6),
d (ppm): 157.3, 156.0,
3''
4''
14c
70% 16c
73%
4'
147.6, 147.3, 147.0, 138.6, 135.5, 128.7, 118.6, 118.4, 114.9, 108.5, 56.0.
MS (ESI, MeOH, m/z): 543/541 (24/27, [MꢂBr]þ), 232 (35), 231
(100). HRMS (ESI-TOF, MeOH): calculated for C28H2679BrN6O
[MꢂBr]þ: 540.12732, found 540.12161.
OH
5''
2.2. Alkylation of pyridinium aminides with dibromo
derivatives. General procedure
2.2.4. {5-Hydroxy-1,3-bis[N-(benzothiazol-2-yl)-N-(pyridin-1-
ium)aminomethyl]}benzene dibromide (6b). From 500 mg of the
N-(benzothiazol-2-yl)pyridinium aminide4 and 280 mg of 4, and
following the general procedure, 739 mg of the dibromide 6b
The corresponding dibromoderivative (3 or 4) (1.0 mmol) and
the corresponding N-(heteroaryl)pyridinium aminide (2.2 mmol)

9786
R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
R
N
N
NH
X
N
N
+
R = H 18a
R =
18b
N
OH
N
N
N
N
+
N
N
+
NH
X
N
N
R
+
N
N
N
N
N
N
+
N
H
N
H
+
N
N
N
N
+
+
N
N
H
N
N
N
N
N
+
18
19
N
X
H
N
N
X = OH 11a
X = Br 17
N
1.- HBr (48%)
2.- Amberlite
IRA-67
N
R
H4NCO2H
10% Pd-C
1
DMF, r.t., 72h
MeOH, Ar, rt, 48h
Scheme 7.
were obtained (mp¼188–191 ꢁC, EtOH, 87%). IR (KBr), nmax
consumed (detected by TLC). Once the process was complete, pu-
rification of aminopyridinium salts was carried out as described
previously.3b The tri- and tetra-aminopyridinium bromides 11, 13
and 14 appeared as yellow to brown solids.
(cmꢂ1): 3485, 3189, 3016,1685,1601,1516,1441,1370,1277, 1165,
767, 737, 670. 1H NMR (300 MHz, DMSO-d6),
d (ppm): 9.86 (1H, s,
OH), 9.69 (4H, br d, J¼5.9 Hz, H2(6)), 8.82 (2H, br t, J¼7.6 Hz, H4),
8.38 (4H, ap t, J¼6.8 Hz, H3(5)), 8.02 (2H, br d, J¼7.9 Hz, H70), 7.58
(2H, br d, J¼7.9 Hz, H40), 7.40 (2H, ap t, J¼7.6 Hz, H50 or H60), 7.31
(2H, ap t, J¼7.6 Hz, H60 or H50), 7.25 (1H, br s, H4Ar), 6.92 (2H, br s,
H2Ar(6Ar)), 5.47 (4H, s, CH2). 13C NMR (75 MHz, DMSO-d6),
2.3.1. 1,3,5-Tris{pyridin-1-ium-[5-(4-hydroxymethylphenyl)pyridin-
2-yl]amino methyl}benzene bromide (11a). From 183.0 mg of the N-
[5-(4-hydroxymethylphenyl)pyridin-2-yl]pyridinium aminide,3b
312 mg of compound 11a were obtained as a dark yellow solid
(mp>192 ꢁC dec, EtOH/MeOH, 85%). IR (KBr), nmax (cmꢂ1): 3351,
3023, 1615, 1599, 1475, 1372, 1222, 1047, 1014, 810, 678. 1H NMR
d
(ppm): 166.0, 157.6, 149.1, 148.5, 147.3,134.3, 131.4,139.2, 126.3,
123.6, 121.6, 120.2, 119.3, 115.9, 58.9. MS (ESI, MeOH, m/z): 655/
653 (16/15, [MꢂBr]þ), 415 (25), 287 (24), 224 (39), 208 (100).
HRMS (ESI-TOF, MeOH): calculated for C32H2579BrN6OS2
[MꢂBr]þ: 652.07146, found 652.09369.
(300 MHz, CD3OD),
d
(ppm): 9.31 (6H, dd, J¼6.9 and 1.3 Hz, H2(6)),
8.73 (3H, tt, J¼7.7 and 1.3 Hz, H4), 8.46 (3H, dd, J¼2.4 and 0.9 Hz,
H60), 8.26 (6H, dd, J¼7.9 and 6.8 Hz, H3(5)), 8.08 (3H, dd, J¼8.1 and
2.4 Hz, H40), 7.73 (3H, s, HAr), 7.57 (6H, ap d, J¼8.6 Hz, H200(600)), 7.45
(6H, ap d, J¼8.6 Hz, H300(500)), 7.13 (3H, dd, J¼8.8 and 0.9 Hz, H30),
5.49 (6H, s, CH2N), 4.68 (6H, s, CH2O). 13C NMR (75 MHz, CD3OD),
2.2.5. (5-Hydroxy-1,3-bis{N-[(4-hydroxymethylphenyl)pyridin-2-yl]-
N-(pyridin-1-ium)aminomethyl})benzene
dibromide
(6c). From
609 mg of the N-[(4-hydroxymethylphenyl)pyridin-2-yl]pyridinium
aminide3b and 280 mg of 4, and following the general procedure,
815 mg of the dibromide 6c were obtained (mp¼188–190 ꢁC, EtOH,
91%). IR (KBr), nmax (cmꢂ1): 3368, 3023, 1599, 1475, 1372, 1014, 810,
d
(ppm): 157.1, 149.6, 149.1, 147.0, 142.9, 138.7, 137.9, 133.9, 136.6,
130.8, 130.3, 128.8, 127.6, 111.2, 64.7, 58.6. Elemental Analysis: Cal-
culated for C60H54Br3N9O3$3H2O: C¼57.98, H¼4.87, N¼10.14,
Found C¼57.61, H¼4.72, N¼10.14.
676. 1H NMR (300 MHz, DMSO-d6),
d (ppm): 9.69 (1H, s, OH), 9.38
(4H, d, J¼5.9 Hz, H2(6)), 8.77 (2H, t, J¼7.9 Hz, H4), 8.49 (2H, br s,
H60), 8.30 (4H, m, H3(5)), 8.20 (2H, d, J¼8.6 Hz, H40), 7.63 (4H, ap d,
J¼7.9 Hz, H200(600)), 7.40 (4H, ap d, J¼7.9 Hz, H300(500)), 7.26 (2H, d,
J¼8.6 Hz, H30), 7.00 (1H, br s, H4Ar), 6.74 (2H, br s, H2Ar(6Ar)), 5.35
(4H, s, CH2N), 4.52 (4H, br s, CH2O). 13C NMR (75 MHz, DMSO-d6),
2.3.2. 1,3,5-Tris{pyridin-1-ium-[3,5-bis(4-hydroxymethyl)phenyl-
pyridin-2-yl]amino methyl}benzene bromide (11b). From 253 mg of
the
N-[3,5-bis(4-hydroxymethylphenyl)pyridin-2-yl]pyridinium
aminide,5a 254 mg of compound 11b were obtained as a brown
solid (mp>162 ꢁC dec, EtOH/MeOH, 80%). IR (KBr), nmax (cmꢂ1):
3368, 2928, 1615, 1473, 1438, 1405, 1205, 1046, 1007, 822, 785, 680,
d
(ppm): 157.5, 155.4, 147.7, 147.5, 144.7, 141.8, 136.6, 135.7, 133.9,
130.5, 128.9, 126.6, 125.6, 118.6, 114.9, 108.7, 71.7, 56.3. MS (ESI,
MeOH m/z): 755/753 (11/11, [MꢂBr]þ), 337(23), 298 (18), 278 (67),
258 (100). HRMS (ESI-TOF, MeOH): calculated for C44H3879BrN6O3
[MꢂBr]þ: 752.21105, found 752.20476.
529. 1H NMR (300 MHz, CD3OD),
d
(ppm): 8.84 (6H, ap d, J¼5.9 Hz,
H2(6)), 8.59 (3H, d, J¼2.4 Hz, H60), 8.40 (3H, ap t, J¼7.7 Hz, H4), 7.83
(6H, ap t, J¼7.1 Hz, H3(5)), 7.80 (3H, d, J¼2.4 Hz, H40), 7.60 (3H, s,
HAr), 7.45 (18H, m, H2%(6%), H200(600) and H3%(5%) or H300(500)), 7.28
(6H, ap d, J¼8.0 Hz, H300(500) or H3%(5%)), 5.22 (6H, s, CH2N), 5.22
2.3. Alkylation of pyridinium aminides with tribromo and
tetrabromo derivatives. General procedure
(12H, m, CH2O). 13C NMR (75 MHz, DMSO-d6),
d (ppm): 152.3, 146.4,
146.0, 143.7, 142.5, 142.4, 138.5, 134.2, 134.1, 133.5, 133.3, 128.8,
128.3, 128.1, 127.8, 126.7, 126.4, 126.2, 61.9, 61.9, 56.6. Elemental
Analysis: Calculated for C81H72Br3N9O6$6H2O: C¼60.23, H¼5.24,
N¼7.80, Found C¼60.38, H¼5.06, N¼8.02.
To a dried round-bottomed flask, either tris-(bromomethyl)
benzene 7 (71.4 mg, 0.2 mmol) and the corresponding N-(hetero-
aryl)pyridinium aminide (0.66 mmol) or the corresponding tetra-
haloderivative (0.2 mmol, 10a: 128.4 mg or 10b: 132.4 mg) and the
N-(heteroaryl)pyridinium aminide (1.0 mmol) were suspended in
DMF (5 mL). The reaction mixture was stirred at room temperature
for up to 72 h, or until the halogenated derivative had been
2.3.3. 1,3,5-Tris{pyridin-1-ium-[3,5-bis(3-chlorophenyl)pyridin-2-
yl]aminomethyl}-benzene bromide (11c). From 259 mg of the
N-[3,5-bis(3-chlorophenyl)pyridin-2-yl]pyridinium
aminide,5a

R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
9787
266 mg of compound 11c were obtained as
a
brown solid
J¼6.4 Hz, CH2O), 1.78 (4H, m, CH2b), 1.53 (4H, m, CH2g). 13C NMR
(mp¼174–176 ꢁC, iPrOH/MeOH, 87%). IR (KBr), nmax (cmꢂ1): 3401,
(125 MHz, CD3OD), d
(ppm): 161.7 (C1Ar), 157.4 (C20), 149.7 (C2(6)),
3011, 1595, 1570, 1473, 1439, 1234, 1195, 1100, 1080, 787, 678. 1H
149.2 (C4),147.1 (C60),138.9 (C40),137.9 (C3Ar(5Ar)),134.2 (C50),130.6
(C100), 130.5 (C3(5)), 130.3 (C300(500)), 129.4 (C400), 127.8 (C200(600)),
122.3 (C4Ar), 116.5 (C2Ar(6Ar)), 111.1 (C30), 69.4 (CH2O), 58.8 (CH2N),
30.2 (CH2b), 26.9 (CH2g). Elemental Analysis: Calculated for
C86H78Br4N12O2$6H2O: C¼59.39, H¼5.22, N¼9.66, Found C¼59.69,
H¼4.89, N¼9.87.
NMR (300 MHz, CD3OD),
d
(ppm): 8.98 (6H, ap d, J¼5.4 Hz, H2(6)),
8.67 (3H, d, J¼2.3 Hz, H60), 8.51 (3H, ap t, J¼7.7 Hz, H4), 7.94 (6H, ap
t, J¼6.9 Hz, H3(5)), 7.82 (3H, d, J¼2.3 Hz, H40), 7.48 (24H, m, H200 or
H2%, H400, H500, H600, H4%, H5%, H6% and HAr), 7.17 (3H, t, J¼1.9 Hz,
H200 or H2%), 5.23 (6H, s, CH2N). 13C NMR (75 MHz, CD3OD),
d
(ppm): 153.7, 148.0, 147.8, 146.9, 140.4, 139.1, 138.9, 137.2, 136.3,
136.0, 135.9,132.2, 131.9, 131.5, 131.1, 130.1, 130.0, 129.9, 129.8, 128.8,
127.9, 126.4, 60.7. Elemental Analysis: Calculated for
C75H54Br3Cl6N9$8H2O: C¼53.69, H¼4.21, N¼7.51, Found C¼53.60,
H¼3.83, N¼7.62.
2.3.8. 1,3-Bis{3,5-bis[N-(pyridin-2-yl)-N-(pyridin-1-ium)aminome-
thyl]phenoxy methyl}benzene tetrabromide (14a). From 10b and
171 mg of the N-(pyridin-2-yl)pyridinium aminide,10b 234 mg of
14a were obtained as a light brown solid (mp>147 ꢁC dec, 87%). IR
(KBr), nmax (cmꢂ1): 3013, 1595, 1471, 1432, 1297, 1159, 1044, 776,
2.3.4. 1,3,5-Tris{pyridin-1-ium-[3,5-bis(3,5-dimethylphenyl)pyridin-
2-yl]amino methyl}benzene bromide (11d). From 250 mg of the N-
[3,5-bis(3,5-dimethylphenyl)pyridin-2-yl]pyridinium aminide,5a
686. 1H NMR (300 MHz, CD3OD),
d
(ppm): 9.17 (8H, dd, J¼6.7 and
1.5 Hz, H2(6)), 8.71 (4H, tt, J¼7.8 and 1.5 Hz, H4), 8.19 (12H, m, H3(5)
and H60), 7.89 (4H, ddd, J¼8.5, 7.3 and 1.8 Hz, H40), 7.54 (1H, br s,
H2xyl), 7.41 (3H, m, H4xyl(6xyl) and H5xyl), 7.18 (10H, m, H30, 50 and
4Ar), 7.11 (4H, d, J¼1.5 Hz, H2Ar(6Ar)), 5.34 (8H, s, CH2N), 5.14 (4H, s,
258 mg of compound 11d were obtained as
a brown solid
(mp¼173–174 ꢁC, iPrOH/MeOH, 76%). IR (KBr), nmax (cmꢂ1): 3401,
3013, 1604, 1440, 1221, 849, 702, 676. 1H NMR (300 MHz, CD3OD),
CH2O). 13C NMR (75 MHz, CD3OD), (ppm): 161.0 (C1Ar), 158.3 (C20),
d
d
(ppm): 8.81 (6H, dd, J¼6.7 and 1.3 Hz, H2(6)), 8.49 (3H, d,
149.6 (C2(6)), 149.2 (C60), 149.1 (C4), 140.7 (C40), 138.7 (C1xyl(3xyl)),
137.9 (C3Ar(5Ar)), 130.6 (C3(5)), 130.0 (C5xyl), 128.3 (C4xyl(6xyl)),
128.0 (C2xyl), 122.8 (C4Ar), 120.9 (C50), 116.9 (C2Ar(6Ar)), 111.0 (C30),
70.9 (CH2O), 58.6 (CH2N). Elemental Analysis: Calculated for
C64H58Br4N12O2$5H2O: C¼53.50, H¼4.77, N¼11.70, Found C¼53.63,
H¼4.62, N¼11.87.
J¼2.3 Hz, H60), 8.45 (3H, tt, J¼7.7 and 1.3 Hz, H4), 7.87 (6H, dd, J¼7.7
and 6.7 Hz, H3(5)), 7.63 (3H, s, HAr), 7.52 (3H, d, J¼2.3 Hz, H40), 7.10
(3H, br s, H4% or H400), 7.04 (3H, br s, H400 or H4%), 6.92 (6H, br s,
H2%(6%) or H200(600)), 6.73 (6H, br s, H200(600) or H2%(6%)), 5.29 (6H,
s, CH2N), 2.36 (18H, s, CH3), 2.35 (18H, s, CH3). 13C NMR (75 MHz,
CD3OD), d (ppm): 153.0, 147.5, 147.4, 146.0, 140.2, 140.1, 140.0, 137.7,
137.4, 137.2, 136.8, 132.7, 131.3, 131.0, 129.9, 127.6, 125.5, 116.2, 60.4,
21.5, 21.4. Elemental Analysis: Calculated for C87H84Br3N9$4H2O:
C¼66.67, H¼5.92, N¼8.04, Found C¼66.89, H¼5.69, N¼8.09.
2.3.9. 1,3-Bis{3,5-bis[N-(quinolin-2-yl)-N-(pyridin-1-ium)aminome-
thyl]phenoxy methyl}benzene tetrabromide (14b). See Ref. 3b.
2.3.10. 1,3-Bis(3,5-bis{N-[5(4-hydroxymethylphenyl)pyridin-2-yl]-N-
(pyridin-1-ium) aminomethyl}phenoxymethyl)benzene (14c). From
10b and 277 mg of the N-[(4-hydroxymethyl phenyl)pyridin-2-
yl]pyridinium aminide,3b 248 mg of 14c were obtained as a light
brown solid (mp>195 ꢁC dec, 70%). IR (KBr), nmax (cmꢂ1): 3020,
1598, 1475, 1371, 1297, 1157, 1047, 811, 676. 1H NMR (300 MHz,
2.3.5. 1,6-Bis{3,5-bis[N-(pyridin-2-yl)-N-(pyridin-1-ium)aminome-
thyl]phenoxy}hexane tetrabromide (13a). See Ref. 3b.
2.3.6. 1,6-Bis{3,5-bis[N-(benzothiazol-2-yl)-N-(pyridin-1-ium)ami-
nomethyl]phenoxy}-hexane tetrabromide (13b). From 10a and
227 mg of the N-(benzothiazol-2-yl)pyridinium aminide,4 264 mg
of 13b were obtained as a yellow solid (mp>186 ꢁC dec, 84%). IR
(KBr), nmax (cmꢂ1): 3009, 2931, 1614, 1596, 1520, 1471, 1440, 1297,
DMSO-d6),
d
(ppm): 9.41 (8H, br d, J¼6.0 Hz, H2(6)), 8.75 (4H, br t,
J¼7.8 Hz, H4), 8.49 (4H, d, J¼2.6 Hz, H60), 8.27 (8H, m, H3(5)), 8.17
(4H, dd, J¼8.7 and 2.6 Hz, H40), 7.62 (8H, d, J¼8.4 Hz, H200(600)), 7.48
(1H, br s, H2xyl), 7.39 (11H, m, H300(500), H4xyl(6xyl) and H5xyl), 7.22
(4H, d, J¼8.7 Hz, H30), 7.13 (2H, br s, H4Ar), 7.10 (4H, br s, H2Ar (6Ar)),
5.40 (8H, br s, CH2N), 5.25 (4H, t, J¼5.7 Hz, OH), 5.09 (4H, br s,
CH2O), 4.52 (8H, d, J¼5.7 Hz, CH2OH). 13C NMR (125 MHz, CD3OD),
1170, 1047, 760, 672. 1H NMR (300 MHz, CD3OD),
d (ppm): 9.52 (8H,
dd, J¼6.9 and 1.6 Hz, H2(6), 8.75 (4H, tt, J¼7.8 and 1.6 Hz, H4), 8.29
(8H, dd, J¼7.8 and 6.9 Hz, H3(5)), 7.88 (4H, dd, J¼8.0 and 1.3 Hz,
H40), 7.60 (4H, dd, J¼8.2 and 1.3 Hz, H70), 7.45 (4H, m, H50 or H60),
7.35 (4H, m, H60 or H50), 7.19 (4H, d, J¼1.7 Hz, H2Ar(6Ar)), 7.16 (2H, br
t, J¼1.7 Hz, H4Ar)), 5.51 (8H, s, CH2N), 4.06 (4H, br t, J¼6.2 Hz, CH2O),
1.81 (4H, m, CH2b), 1.56 (4H, m, CH2g). 13C NMR (75 MHz, CD3OD),
d
(ppm): 161.0 (C1Ar), 157.3 (C20), 149.6 (C2(6)), 149.1 (C4), 147.0
(C60), 143.0 (C400), 138.7 (C1xyl(3xyl)), 138.0 (C40), 136.7 (C3Ar(5Ar)),
133.9 (C100), 130.6 (C3(5)), 130.5 (C50), 130.0 (C5xyl), 128.8 (C300(500)),
128.3 (C4xyl(6xyl)), 127.9 (C2xyl), 127.7 (C200(600)), 122.7 (C4Ar), 117.0
(C2Ar(6Ar)), 111.1 (C30), 70.9 (CH2O), 64.7 (CH2OH), 58.7 (CH2N). El-
emental Analysis: Calculated for C92H82Br4N12O6$6H2O: C¼58.79,
H¼5.04, N¼8.94, Found C¼58.80, H¼4.99, N¼8.54.
d
(ppm): 167.4 (C20), 161.7 (C1Ar), 151.3 (C3a0), 150.0 (C4), 149.2
(C2(6)), 136.4 (C3Ar(5Ar)), 133.6 (C7a0), 131.0 (C3(5)), 128.7 (C40 or
C70), 125.8 (C70 or C40), 122.8 (C4Ar), 122.8 (C50 or C60), 122.4 (C50 or
C60), 117.5 (C2Ar(6Ar)), 69.5 (CH2O), 61.2 (CH2N), 30.2 (CH2b), 26.9
(CH2g). Elemental Analysis: Calculated for C70H62Br4N12O2S4$8H2O:
C¼49.59, H¼4.64, N¼9.91, S¼7.57, Found C¼49.72, H¼4.53,
N¼9.78, S¼7.27.
2.4. Reduction of tri- and tetra-aminopyridinium bromides.
General procedure
2.3.7. 1,6-Bis{3,5-bis[N-(5-phenylpyridin-2-yl)-N-(pyridin-1-ium)-
aminomethyl] phenoxy}hexane tetrabromide (13c). From 10a and
247 mg of the N-(5-phenylpyridin-2-yl)pyridinium aminide,5a
295 mg of 13c were obtained as a light brown solid (mp>179 ꢁC
dec, 90%). IR (KBr), nmax (cmꢂ1): 3026, 2935, 1597, 1472, 1376, 1299,
A solution of the polyaminopyridinium bromide (11, 13 or 14) in
AcOH/MeOH (2:1, 30 mL) was prepared in a 50 mL round-bottomed
flask. Zn dust (10 equiv per pyridinium group to be reduced) was
added and the mixture was stirred at room temperature for 12 h.
During this period a change in colour may be observed. Once the
reaction was complete, the excess solid was filtered off and the
solvent was removed from the filtrate. The residue was treated with
a mixture of 15 mL NaOH (10%) and 30 mL AcOEt. The organic layer
was separated and the aqueous layer extracted with AcOEt
(3ꢃ10 mL). The combined organic extracts were dried over MgSO4,
filtered and evaporated under vacuum. The residue was purified by
column chromatography with a suitable eluent, to give the
1165, 1050, 768, 698, 680. 1H NMR (500 MHz, CD3OD),
d (ppm): 9.27
(8H, dd, J¼6.4 and 1.3 Hz, H2(6)), 8.74 (4H, tt, J¼7.7 and 1.3 Hz, H4),
8.46 (4H, d, J¼2.2 Hz, H60), 8.25 (8H, dd, J¼7.7 and 6.4 Hz, H3(5)),
8.13 (4H, dd, J¼8.6 and 2.2 Hz, H40), 7.61 (8H, dd, J¼8.3 and 1.4 Hz,
H200(600)), 7.48 (8H, dd, J¼8.3 and 7.2 Hz, H300(500)), 7.41 (4H, tt, J¼7.2
and 1.4 Hz, H400), 7.26 (4H, d, J¼8.6 Hz, H30), 7.25 (2H, br s, H4Ar),
7.04 (4H, d, J¼1.4 Hz, H2Ar(6Ar)), 5.42 (8H, s, CH2N), 3.99 (4H, t,

9788
R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
polyaminopyridine as a white to yellow solid or oil. When possible,
the polyaminopyridine was crystallized from the indicated solvent.
of 15b were obtained as a white solid (mp¼249–252 ꢁC, acetone,
68%). IR (NaCl): nmax (cmꢂ1): 3353, 2926, 1655, 1614, 1547, 1446,
1154, 1020, 751, 723, 668. 1H NMR (300 MHz, DMSO-d6),
d (ppm):
2.4.1. 1,3,5-Tris{[5-(4-hydroxymethylphenyl)pyridin-2-yl]aminome-
thyl}benzene (12a). From 297 mg (0.25 mmol) of 11a and following
the general procedure, after chromatography with AcOEt/EtOH
(1:1), 143 mg of 12a were obtained as a white solid (mp¼186–
190 ꢁC, acetone/iPrOH, 79%). IR (KBr), nmax (cmꢂ1): 3317, 3217, 2920,
2851, 1737, 1606, 1547, 1496, 1384, 1000, 806. 1H NMR (300 MHz,
8.48 (4H, br t, J¼5.3 Hz, NH), 7.63 (4H, dd, J¼7.9 and 1.0 Hz, H4),
7.35 (4H, d, J¼7.9 Hz, H7), 7.19 (4H, ddd, J¼8.2, 7.2 and 1.0 Hz, H6),
6.99 (4H, ddd, J¼8.2, 7.9 and 1.3 Hz, H5), 6.95 (2H, br s, H4Ar), 6.83
(4H, br s, H2Ar(6Ar)), 4.53 (8H, d, J¼5.3 Hz, CH2N), 3.89 (4H, t,
J¼6.3 Hz, CH2O), 1.64 (4H, m, CH2b), 1.36 (4H, m, CH2g). 13C NMR
(75 MHz, DMSO-d6), d (ppm): 165.7 (C2), 158.3 (C1Ar), 151.8 (C3a),
DMSO-d6),
d
(ppm): 8.24 (3H, d, J¼2.3 Hz, H6), 7.63 (3H, dd, J¼8.8
140.0 (C3Ar(5Ar)), 129.8 (C7a), 125.0 (C4), 120.5 (C5 or C6), 120.4
(C6 or C5), 117.9 (C4Ar), 117.5 (C7), 111.5 (C2Ar(6Ar)), 66.8 (CH2O),
46.7 (CH2N), 28.1 (CH2b), 24.7 (CH2g). HRMS (ESI-TOF): Calcu-
lated for C50H47N8O2S4 [MþH]þ, 919.2705, found 919.2694.
and 2.3 Hz, H4), 7.46 (6H, ap d, J¼8.2 Hz, H20(60)), 7.30 (6H, ap d,
J¼8.2 Hz, H30(50)), 7.21 (3H, br s, HAr), 7.15 (3H, br t, J¼5.9 Hz, NH),
6.53 (3H, d, J¼8.8 Hz, H3), 5.13 (3H, t, J¼5.9 Hz, OH), 4.48 (12H, m,
CH2N and CH2O). 13C NMR (75 MHz, DMSO-d6),
d (ppm): 157.4,
144.8,140.1, 140.0, 136.0, 134.4, 126.6, 124.5, 124.0, 123.2, 107.6, 62.2,
43.8. HRMS (ESI-TOF, MeOH): calculated for C45H43N6O3 [MþH]þ
715.33912, found 715.33667.
2.4.7. 1,6-Bis{3,5-bis[N-(5-phenylpyridin-2-yl)aminomethyl]phenoxy}
hexane (15c). From 100 mg (6.13ꢃ10ꢂ5 mol) of 13c and following
the general procedure, after chromatography with AcOEt/hexane
(1:1), 45 mg of 15c were obtained as a white solid (mp¼102–105 ꢁC,
hexane, 74%). IR (NaCl): nmax (cmꢂ1) 3234, 3024, 2922, 2851, 1606,
1519, 1488, 1455, 1389, 1293, 1158, 818, 769, 696. 1H NMR (300 MHz,
2.4.2. 1,3,5-Tris{[3,5-bis(4-hydroxymethylphenyl)pyridin-2-yl]ami-
nomethyl}benzene (12b). From 377 mg (0.25 mmol) of 11b and
following the general procedure, after chromatography with AcOEt/
EtOH (1:1), 195 mg of 12b were obtained as a white solid
(mp>80 ꢁC dec, iPrOH, 71%). IR (KBr), nmax (cmꢂ1): 3350, 2924,1712,
1603, 1497, 1403, 1246, 1015, 819, 668. 1H NMR (200 MHz, CD3OD),
DMSO-d6),
d
(ppm): 8.27 (4H, br s, H6), 7.67 (4H, dd, J¼8.7 and
2.4 Hz, H4), 7.52 (8H, dd, J¼8.4, 1.1 Hz, H20(60)), 7.36 (8H, ap t,
J¼7.6 Hz, H30(50)), 7.21 (8H, m, H40 and NH), 6.90 (2H, br s, H4Ar), 6.74
(4H, br s, H2Ar(6Ar)), 6.56 (4H, d, J¼8.7 Hz, H3), 4.44 (8H, d, J¼6.0 Hz,
CH2N), 3.85 (4H, t, J¼6.3 Hz, CH2O), 1.63 (4H, m, CH2b), 1.36 (4H, m,
d
(ppm): 8.11 (3H, d, J¼1.9 Hz, H6), 7.34 (27H, m, H4, H20(60), H30(50),
H200(600) and H300(500)), 7.15 (3H, br s, HAr), 4.64 (6H, s, CH2N), 4.60
CH2g). 13C NMR (75 MHz, DMSO-d6),
d (ppm): 158.2 (C1Ar), 157.5
(12H, m, CH2O). 13C NMR (75 MHz, CD3OD),
d
(ppm): 156.1, 145.2,
(C2), 144.9 (C6), 141.5 (C3Ar(5Ar)), 137.5 (C10), 134.5 (C4), 128.3
(C20(60)), 125.7 (C40), 124.8 (C30(50)), 123.3 (C5), 117.6 (C4Ar), 110.9
(C2Ar(6Ar)), 107.6 (C3), 66.6 (CH2O), 43.7 (CH2N), 28.1 (CH2b), 24.8
(CH2g). HRMS (ESI-TOF, MeOH): Calculated for C66H63N8O2 [MþH]þ,
999.5074, found 999.5146.
142.6, 142.0, 141.2, 138.2, 137.8, 137.2, 130.9, 128.8, 128.6, 126.8,
126.7, 124.7, 123.8, 64.9, 64.8, 45.6. HRMS (ESI-TOF, MeOH): calcu-
lated for C66H61N6O6 [MþH]þ 1033.46471, found 1033.45614.
2.4.3. 1,3,5-Tris{[3,5-bis(3-chlorophenyl)pyridin-2-yl]aminome-
thyl}benzene (12c). From 383 mg (0.25 mmol) of 11c and following
the general procedure, after chromatography with hexane/CH2Cl2
(8:2), 181 mg of 12c were obtained as a white solid (mp¼94–97 ꢁC,
hexane, 79%). IR (NaCl), nmax (cmꢂ1): 3441, 3060, 2924, 1604, 1574,
1508, 1475, 1401, 1244, 1100, 1081, 907, 786, 733, 703. 1H NMR
2.4.8. 1,3-Bis{3,5-bis[N-(pyridin-2-yl)aminomethyl]phenoxy-
methyl}benzene (16a). From 100 mg (6.13ꢃ10ꢂ5 mol) of 14a and
following the general procedure, after chromatography with
CH2Cl2/MeOH (95:5), 42 mg of 16a were obtained as a white solid
(mp¼101–102 ꢁC, hexane/AcOEt, 79%). IR (NaCl), nmax (cmꢂ1): 3271,
2923, 2853, 1600, 1505, 1455, 1291, 1153, 711. 1H NMR (300 MHz,
(300 MHz, CDCl3),
d
(ppm): 8.27 (3H, d, J¼2.3 Hz, H6), 7.33 (27H, m,
H4, H20, H40, H50, H60, H200, H400, H500 and H600), 7.15 (3H, br s, HAr),
4.97 (3H, br t, J¼5.9 Hz, NH), 4.65 (6H, d, J¼5.6 Hz CH2N). 13C NMR
(CD3)2CO),
d
(ppm): 7.97 (4H, dd, J¼4.9 and 1.0 Hz, H6), 7.48 (1H, br
s, H2xyl), 7.34 (7H, m, H4, H4xyl(6xyl) and H5xyl), 6.98 (2H, br s, H4Ar),
6.91 (4H, br s, H2Ar(6Ar)), 6.48 (8H, m, H3 and H5), 6.15 (4H, m, NH),
5.03 (4H, s, CH2O), 4.50 (8H, br s, CH2N). 13C NMR (75 MHz,
(75 MHz, CDCl3),
d (ppm): 154.6, 145.7, 140.4, 139.8, 139.2, 135.7,
135.2, 134.8, 130.5, 130.1, 129.1, 128.2, 126.9, 126.7, 125.9, 124.9,
124.7, 124.0, 120.6, 45.2. HRMS (ESI-TOF, CH3OH): calculated for
C60H4335Cl6N6 [MþH]þ 1057.1680, found 1057.1580.
(CD3)2CO),
d (ppm): 160.0 (C1Ar), 159.9 (C2), 148.7 (C6), 143.3
(C3Ar(5Ar)), 138.7 (C1xyl(3xyl)), 137.5 (C4), 129.3 (C2xyl), 127.8
(C4xyl(6xyl)), 127.6 (C5xyl), 119.8 (C4Ar), 113.0 (C2Ar(6Ar) and C5),
108.7 (C3), 70.2 (CH2O), 45.7 (CH2N). HRMS (ESI-TOF, MeOH): Cal-
culated for C44H43N8O2 [MþH]þ, 715.3509, found 715.3483.
2.4.4. 1,3,5-Tris{[3,5-bis(3,5-dimethylphenyl)pyridin-2-yl]aminome-
thyl}benzene (12d). From 374 mg (0.25 mmol) of 11d and following
the general procedure, after chromatography with AcOEt/hexane
(8:2), 167 mg of 12d were obtained as a yellow oil (70%). IR (NaCl),
nmax (cmꢂ1): 3436, 3020, 2917, 2859, 1603, 1570, 1503, 1405, 1325,
2.4.9. 1,3-Bis{3,5-bis[N-(quinolin-2-yl)aminomethyl]-
phenoxymethyl}benzene (16b). See Ref. 3b.
909, 848, 733. 1H NMR (300 MHz, CDCl3),
d (ppm): 8.28 (3H, d,
J¼2.3 Hz, H6), 7.43 (3H, d, J¼2.3 Hz, H4), 7.16 (3H, br s, HAr), 7.06
(6H, br s, H200(600) or H20(60)), 7.00 (6H, br s, H20(60) or H200(600)), 6.95
(3H, br s, H400 or H40), 6.91 (3H, br s, H40 or H400), 4.97 (3H, t,
J¼5.6 Hz, NH), 4.64 (6H, d, J¼5.6 Hz, CH2N), 2.31 (18H, s, CH3), 2.28
2.4.10. 1,3-Bis(3,5-bis{N-[5(4-hydroxymethylphenyl)pyridin-2-yl]
aminomethyl}phenoxy methyl)benzene (16c). From 100 mg
(5.64$10–5 mol) of 14c and following the general procedure, af-
ter chromatography with AcOEt/MeOH (4:1), 50 mg of 16b were
obtained as a yellow solid (mp>145 ꢁC, acetone, 78%). IR (KBr),
nmax (cmꢂ1): 3414, 3021, 2926, 2861, 1607, 1530, 1504, 1455, 1385,
(18H, s, CH3). 13C NMR (75 MHz, CDCl3),
d (ppm): 154.6, 144.9, 147.7,
138.8, 138.5, 138.2, 137.7, 135.8, 129.5, 128.2, 126.6, 126.2, 125.0,
124.1, 122.2, 45.4, 21.4, 21.3. HRMS (ESI-TOF, CH3OH): calculated for
C72H73N6 [MþH]þ 1021.5897, found 1021.5916.
1293, 1154, 1044, 810. 1H NMR (200 MHz, CD3OD),
d (ppm): 8.15
(4H, br s, H6), 7.61 (4H, dd, J¼8.7 and 2.4 Hz, H4), 7.44 (8H, d,
J¼8.2 Hz, H20(60)), 7.44 (1H, br s, H2xyl), 7.40 (8H, d, J¼8.2 Hz,
H30(50)), 7.24 (3H, m, H4xyl(6xyl) and H5xyl), 6.99 (2H, br s, H4Ar),
6.87 (4H, d, J¼1.0 Hz, H2Ar(6Ar)), 6.51 (4H, d, J¼8.7 Hz, H3), 5.03
(4H, s, CH2O), 4.63 (8H, s, CH2OH), 4.48 (8H, s, CH2N). 13C NMR
2.4.5. 1,6-Bis{3,5-bis[N-(pyridin-2-yl)aminomethyl]phenoxy}hexane
(15a). See Ref. 3b.
2.4.6. 1,6-Bis{3,5-bis[N-(benzothiazol-2-yl)aminomethyl]phenoxy}
hexane (15b). From 100 mg (6.44$10–5 mol) of 13b and following
the general procedure, after chromatography with AcOEt, 40 mg
(75 MHz, DMSO-d6) d (ppm): 158.0 (C1Ar), 157.2 (C2), 144.8 (C6),
141.7 (C3Ar(5Ar)), 140.0 (C40), 136.8 (C1xyl(3xyl)), 135.9 (C10), 134.5
(C4), 128.0 (C2xyl), 126.5 (C30(50) and C4xyl(6xyl)), 126.3 (C5xyl),

R.R. Castillo et al. / Tetrahedron 65 (2009) 9782–9790
9789
124.5 (C20(60)), 123.3 (C5), 118.1 (C4Ar), 111.3 (C2Ar(6Ar)), 107.6
(C3), 68.5 (CH2O), 62.1 (CH2OH), 43.7 (CH2N). HRMS (ESI-TOF,
MeOH): Calculated for C72H67N8O6 [MþH]þ 1139.5184, found
1139.5209.
EtOH/MeOH, 111 mg, 85%,). IR (KBr), nmax (cmꢂ1): 3400, 3022, 1598,
1475, 1371, 1215, 998, 813, 678. 1H NMR (300 MHz, CD3OD),
d
(ppm): 9.36 (6H, d, J¼6.2 Hz, H2(6)), 9.27 (6H, d, J¼6.9 Hz, H2(6)),
8.76 (6H, m, H4 and H4), 8.52 (3H, d, J¼2.1 Hz, H60), 8.45 (3H, d,
J¼1.9 Hz, H60), 8.26 (12H, m, H3(5) and H3(5)), 8.17 (6H, m, H40 and
H40), 7.74 (3H, s, HAr), 7.61 (18H, m, H200(600), H200(600) and H300(500)),
7.34 (6H, m, H300(500)), 7.34 (3H, d, J¼8.7 Hz, H30), 7.24 (3H, d,
J¼8.7 Hz, H30), 5.50 (12H, m, CH2N), 4.79 (6H, s, CH2OH). 13C NMR
2.4.11. 1,3,5-Tris{pyridin-1-ium-[5-(4-bromomethylphenyl)pyridin-
2-yl]aminomethyl}-benzene
bromide
(17). The
tris-amino-
pyridinium bromide 11a (500 mg) was added portionwise to
hydrobromic acid (48%, 25 mL) in a 100 mL flask. The mixture was
stirred for 12 h at room temperature and the acid was evaporated
under vacuum. The residue was dissolved in MeOH and eluted
through a column filled with a solvated ion-exchange resin
(Amberlite IRA-67) in order to remove excess acid from the prod-
uct. Eluates from the column were evaporated, redissolved in DMF
(approx. 1 mL) and precipitated by adding the solution dropwise to
well stirred AcOEt (50 mL). The solid precipitate was collected by
filtration, washed with AcOEt and crystallized from EtOH with
a few drops of MeOH to give 620 mg of the halogenated tris-ami-
nopyridinium bromide 17 as a yellow solid (mp>169 ꢁC dec, EtOH/
MeOH, 95%). IR (KBr), nmax (cmꢂ1): 3400, 3018, 1615, 1598, 1475,
(75 MHz, CD3OD),
d (ppm): 157.5, 157.4, 149.7, 149.1, 147.6, 147.1,
147.1,138.8, 138.5, 137.8, 136.8, 134.9, 134.0, 133.0,131.2,130.8, 130.7,
130.2, 128.8, 128.5, 127.7, 127.3, 111.2, 111.1, 64.7, 58.8, 58.6. Ele-
mental Analysis: Calculated for C111H96Br6N18O3$8H2O: C¼56.50,
H¼5.04, N¼10.68, Found C¼56.78, H¼4.93, N¼11.01.
2.5.3. 1,3,5-Tris-{[3-(4-{pyridin-2-ylaminomethyl}phenyl)2-pyridin-
2-yl]amino methyl}benzene (19). Reduction of 250 mg of 18a was
accomplished by dissolving the product in MeOH (15 mL) under an
Ar atmosphere, followed by the addition of 100 mg of the catalyst
Pd/C (10%, dry) and 500 mg of the reducing agent, NH4HCO2
(60 equiv).9,10 After 24 h the same amounts of both catalyst and
reducing agent were added again and the mixture was allowed to
react for an additional 24 h period. After a total period of 48 h, re-
moval of the catalyst and excess of reducing agent was achieved by
evaporation of the solvent, addition of acetone and filtration of the
suspension through Celite. The residue obtained by evaporation of
the filtrate was purified by chromatography with acetone/methanol
(95:5), but only an impure fraction of 19 as the main product was
obtained. HRMS showed the peak for the calculated mass of 19:
C60H55N12 [MþH]þ¼943.4673, found: 943.9902.
1372, 1229, 814, 678. 1H NMR (300 MHz, CD3OD),
d (ppm): 9.31 (6H,
dd, J¼6.7 and 1.4 Hz, H2(6)), 8.73 (3H, tt, J¼7.8 and 1.4 Hz, H4), 8.45
(3H, d, J¼2.5 Hz, H60), 8.27 (6H, dd, J¼7.8 and 6.7 Hz, H3(5)), 8.08
(3H, dd, J¼8.7 and 2.5 Hz, H40), 7.73 (3H, s, HAr), 7.58 (12H, m,
H200(600) and H300(500)), 7.13 (3H, d, J¼8.7 Hz, H30), 5.50 (6H, s br,
CH2N), 4.64 (6H, s, CH2Br). 13C NMR (75 MHz, CD3OD),
d (ppm):
155.5, 147.9, 147.8, 145.2, 142.0, 137.2, 135.8, 134.2, 131.3, 129.4,
128.5, 127.3, 126.1, 109.4, 62.4, 56.6. Elemental Analysis: Calculated
for C60H51Br6N9$10H2O: C¼46.26, H¼4.59, N¼8.09, Found C¼46.13,
H¼4.45, N¼8.47.
Acknowledgements
2.5. Alkylation of bromomethyl tris-aminopyridinium
bromide 17 with pyridinium aminides. General procedure
´
The authors wish to thank the Ministerio de Ciencia y Tecnologıa
(CTQ2005-08902 and CTQ2008-05027/BQU2) for financial support
A
solution of tris-aminopyridinium bromide 17 (138 mg,
´
and the Ministerio de Educacion y Ciencia (MEC) and Universidad
,10b
0.1 mmol) and the corresponding aminide3b
(0.4 mmol) in DMF
´
de Alcala (UAH) for fellowships (R.R.C. and M.C.)
(5 mL) was prepared in a dried 10 mL round-bottomed flask. The re-
action mixture was stirred at room temperature for 72 h. Once the
reaction was completed, purification of the aminopyridinium salts
was performed as follows: the solvent was removed under vacuum,
the residue was redissolved in the minimum amount of DMF (approx.
1–2 mL) and the solution was added dropwise to well stirred AcOEt
(50 mL). The solid precipitate was collected by filtration, washed with
AcOEt and crystallized from EtOH with a few drops of MeOH to give
hexa-aminopyridinium bromides 18 as brown solids.
References and notes
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Johnson, E. F.; Lubben, T. H.; Stashko, M. A.; Olejniczak, E. T.; Sun, C.; Chaohong,
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2.5.1. 1,3,5-Tris{pyridin-1-ium-[5-(4-{pyridin-1-ium-[pyridin-2-yl]
aminomethyl} phenyl)pyridin-2-yl]aminomethyl}benzene bromide
(18a). Brown solid (mp>189 ꢁC dec, EtOH/MeOH, 155 mg, 82%). IR
(KBr), nmax (cmꢂ1): 3412, 3106, 3017, 1651, 1598, 1474, 1373, 816,
777, 680. 1H NMR (500 MHz, CD3OD),
d
(ppm): 9.24 (6H, dd, J¼6.8
and 1.3 Hz, H2i/e(6i/e)), 9.18 (6H, dd, J¼6.8 and 1.5 Hz, H2e/i (6e/i)),
8.71 (6H, m, H4eþi), 8.68 (3H, d, J¼1.2 Hz, H60i), 8.20 (15H, m,
H3eþi(5eþi) and H60e), 8.05 (3H, dd, J¼8.8 and 2.5 Hz, H40i), 7.89 (3H,
ddd, J¼8.4, 7.3 and 1.8 Hz, H40e), 7.68 (3H, s, HAr), 7.62 (6H, ap d,
J¼8.3 Hz, H200(600)), 7.52 (6H, ap d, J¼8.3 Hz, H300(500)), 7.22 (6H, m,
H30eþi), 7.16 (3H, dd, J¼7.2 and 5.0 Hz, H50e), 5.47 (6H, s, CH2N), 5.42
(6H, s, CH2N). 13C NMR (75 MHz, CD3OD),
d (ppm): 158.4, 157.6,
149.6, 149.2, 147.1, 140.7, 138.9, 138.5, 137.7, 135.0, 133.0, 131.0,
130.6,130.5,130.4,129.7,128.8,128.5,127.7,120.9,111.1,110.9, 58.6,
58.6. Elemental Analysis: Calculated for C90H78Br6N18$7H2O:
C¼53.59, H¼4.60, N¼12.50, Found C¼53.57, H¼4.77, N¼12.16.
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