Efficient synthesis of 2,11,20-triaza[3.3.3](2,6)pyridinophane

Full text of DOI:10.1021/jo961081d

8304
J . Org. Chem. 1996, 61, 8304-8306
is efficient and suitable for large-scale preparations
(Scheme 1).
The starting 2-(hydroxymethyl)-6-(bromomethyl)pyri-
dine (4) was prepared by treating 2,6-bis(hydroxymethyl)-
pyridine with hydrobromic acid.3
Efficien t Syn th esis of
2,11,20-Tr ia za [3.3.3](2,6)p yr id in op h a n e
Geunsu Lee, Masakazu Oka, Hiroyuki Takemura,
Yuji Miyahara,* Nobujiro Shimizu, and Takahiko Inazu
The condensation of 4 with p-TsNH2 in the presence
of K2CO3 in acetone required long reaction times. Even
after refluxing for 2 days the desired bisadduct, N,N-bis-
[[6-(hydroxymethyl)pyridin-2-yl]methyl]-p-tosylamide (5)
(71% yield), was accompanied by monoadduct N-[[6-
(hydroxymethyl)pyridin-2-yl]methyl]-p-tosylamide (6) (15%
yield). However, further improvement in the reaction
Department of Chemistry, Faculty of Science, Kyushu
University, Hakozaki, Higashi-ku, Fukuoka 812, J apan
Received J une 10, 1996
A number of 18-membered azacrowns have been syn-
thesized in order to utilize them as pendant groups to
capture alkali metal cations in place of 18-crown-6.1
However, the nitrogen atoms in such saturated chains
behave as rather poor donors compared to oxygen atoms.
In contrast, the nitrogen atoms in unsaturated systems
like pyridine have been recognized as excellent donors
for alkali metal and ammonium ions.2 Thus, the strong
affinity of trioxa[3.3.3](2,6)pyridinophane 1 for ammo-
nium ions has been shown by Cram et al.3 However, very
conditions was so far unsuccessful. To be noted is the
fact that when we tried to accelerate the reaction by
running it in N,N-dimethylformamide (DMF) at 100 °C,
an unexpected reaction occurred. After heating for 1 day,
a new compound was formed with consumption of p-
TsNH2 but without affecting the starting bromide. This
product proved to be N-p-tosyl-N′,N′-dimethylformami-
dine (8), which has been obtained from the reaction of
p-TsNCO and DMF.6
low yields for its synthesis have apparently precluded
further applications. While dinuclear pyridinophane 2a
and its derivatives have now been synthesized by several
methods and extensively4 studied,4a-e little is known
about the trinuclear pyridinophane 3a . This appears to
Bromination of 5 with PBr3 in chloroform readily
provided N,N-bis[[6-(bromomethyl)pyridin-2-yl]methyl]-
p-tosylamide (7) (mp 103-104 °C, 68%).
The other coupling partner 11 was obtained from 2,6-
bis(chloromethyl)pyridine (9) via the Gabriel reaction,
followed by tosylation of the resulting 2,6-bis(amino-
methyl)pyridine (11: mp 126-127 °C, 70% from 9).
The coupling of 7 and 11 was best achieved under
phase transfer conditions (aqueous KOH/n-Bu4NI/CH2Cl2)
under reflux for 24 h. The use of KOH as the base is
essential in this reaction. When NaOH was utilized, the
monosodium salt 12 immediately precipitated out, and
because of its remarkably low solubility in both aqueous
and organic phases, no coupling occurred.
be due mainly to low yields and difficult separation
procedures for the reported methods.5 Here we report a
new stepwise method which, though somewhat lengthy,
(1) For reviews, see, for example: Gokel, G. W.; Dishong, D. M.;
Schultz, R. A.; Gatto, V. J . Synthesis 1982, 997. Krakowlak, K. E.;
Bradshaw, J . S. Isr. J . Chem. 1992, 32, 3.
(2) Bell, T. W.; Guzzo, F. J . Am. Chem. Soc. 1984, 106, 6111.
(3) Newcomb, M.; Timko, J . M.; Walba, D. M.; Cram, D. J . J . Am.
Chem. Soc. 1977, 99, 6392.
(4) (a) Bottino, F.; Grazia, M. D.; Finocchiaro, P.; Fronczek, F. R.;
Mamo, A.; Pappalardo, S. J . Org. Chem. 1988, 53, 3521. (b) Che, C.-
M.; Li, Z.-Y.; Wong, K.-Y.; Poon, C.-K.; Mak, T. C. W.; Peng, S.-M.
Polyhedron 1994, 13, 771. (c) Kru¨ger, H.-J . Chem. Ber. 1995, 128, 531.
(d) Kim, W. D.; Hrncir, D. C.; Kiefer, G. E.; Sherry, A. D. Inorg. Chem.
1995, 34, 2225. (e) Kim, W. D.; Kiefer, G. E.; Maton, F.; McMillan, K.;
Muller, R. N.; Sherry, A. D. Inorg. Chem. 1995, 34, 2233.
(5) We have mentioned the synthesis of 2b and 3b by the coupling
of p-TsNH2 and 2,6-bis(bromomethyl)pyridine using NaH in refluxing
dioxane: Takemura, H.; Suenaga, M.; Sakai, K.; Kawachi, H.; Shin-
myozu, T.; Miyahara, Y.; Inazu, T. J . Inclusion Phenom. 1984, 2, 207.
Both of these methods and closely related reactions in DMF by
Pappalardo et al.4a have provided very low yields of 3b after tedious
chromatographic separation and recrystallization.
Even though high-dilution conditions were not em-
ployed, the reaction readily gave N,N′,N′′-tritosyl pyri-
dinophane 3b, mp 250-251 °C (lit.4a mp >230 °C) in 83%
(6) Logeman, W.; Artini, D. Chem. Ber. 1957, 90, 2527.
(7) The elemental analysis of the precipitate agrees more with the
monosodium salt than a disodium salt. Anal. calcd for C21H22N3O4-
S2Na: C, 53.95; H, 4.74; N, 8.99 (calcd for C21H21N3O4S2Na2: C, 51.52;
H, 4.32; N, 8.58). Found: C, 53.39; H, 4.63; N, 8.50. This Na salt was
transformed back to 10 by treatment with an excess of a KOH solution,
which dissolved the salt, but gradually, and then with HCl.
S0022-3263(96)01081-X CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 23, 1996 8305
Sch em e 1a
a
(i) TsNH2/K2CO3/acetone, reflux, 2 days; (ii) PBr3/chloroform; (iii) potassium phthalimide/DMF, 140 °C, 6 h; (iv) NH2NH2‚H2O/EtOH,
reflux, 5 h; (v) concd HCl, reflux, 2 h; (vi) TsCl/aq KOH, dioxane, rt, 8 h; (vii) KOH/n-Bu4NI, H2O/CH2Cl2, reflux, 24 h; (viii) H2SO4,
115-120 °C, 2 h.
N,N-Bis[[6-(br om om eth yl)p yr id in -2-yl]m eth yl]-p-tosyla -
m id e (7). To a solution of PBr3 (5.2 mL, 15 g, 55.4 mmol) in
CHCl3 (300 mL) was added dropwise a solution of 5 (10.0 g, 241.9
mmol) over a period of 1 h at -5 to 0 °C with magnetic stirring.
The reaction mixture was stirred for an additional 12 h at room
temperature. The reaction mixture was neutralized by addition
of 40% NaOH with cooling in an ice bath. The organic layer
was separated, dried over MgSO4, filtered, and evaporated to
give a colorless oil (1.27 g, 98%). This oil was crystallized from
a mixed solvent (benzene/diethyl ether ) 5:2) to give 7 as
colorless crystals (12.01 g, 93%): mp 103-103.5 °C; IR (KBr)
νSO 1341, 1151 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.44 (s, 3H),
4.34 (s, 4H), 4.56 (s, 4H), 7.23 (d, J ) 7.91, 4H), 7.26 (d, J )
8.25, 2H), 7.28 (d, J ) 7.92, 2H), 7.52-7.57 (dd, J ) 7.59, 7.91,
2H), 7.72 (d, J ) 8.58, 2). Anal. Calcd for C21H21N3Br2O2S: C,
46.77; H, 3.93; N, 7.79. Found: C, 46.97; H, 3.93; N, 7.63.
2,6-Bis(a m in om eth yl)p yr id in e Dih yd r och lor id e (10). A
mixture of 2,6-bis(chloromethyl)pyridine (9) (17.6 g, 100 mmol),
phthalimide K salt (37.5 g, 202 mmol), DMF (400 mL), and
K2CO3 (5.0 g, 27 mmol) was stirred and heated at 140 °C for 6
h. When cooled, the crystalline bis(phthalide) was collected by
suction filtration. Concentration of the filtrate in vacuo provided
an additional amount of the product, making a total yield of 36.2
g (91%).
A mixture of the bis(phthalide) (33.2 g, 83.5 mmol) and 100%
NH2NH2‚H2O (8.4 g, 168 mmol) in EtOH (500 mL) was stirred
and heated under reflux for 5 h. Concd HCl (50 mL) was then
added to the reaction mixture, and the mixture was heated
gently at reflux with stirring for 2 h. When cooled, the reaction
mixture was filtered and the filtrate was evaporated. The yellow
powder obtained was dissolved in hot H2O. After the insoluble
materials were filtered off, the filtrate was evaporated to give a
yellow powder (15.9 g, 90%; 81% from 9), which was used in the
following step without further purification.
yield. Although 3b has been reported to be isolated in
9% yield from the one-step coupling of 2,6-bis(chloro-
methyl)pyridine and p-TsNHNa in DMF, obtention of
pure 3b was very difficult in our hands, because 3b
produced as a trimer was very similar in solubility and
chromatographic behavior to the corresponding dimer 2b,
the major product of the reaction.
Finally, the detosylation of 3b was readily achieved by
heating in H2SO4 at 115-120 °C for 2 h. After alkaline
workup, the parent pyridinophane 3a was obtained in
91% yield as hygroscopic, but not deliquescent, crystals
from benzene with mp 136-137 °C (thoroughly dried
sample in a sealed tube; reported as an oil4a).
With pure 3a in gram quantities, complexation studies
of this pyridinophane and its derivatives are now in
progress and will be reported elsewhere.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined in
capillaries and are not corrected. Elemental analyses were
performed by Center of the Elementary Analysis of Organic
Compounds affiliated with Faculty of Science in Kyushu Uni-
versity. Fuji Davison BW-200 silica gel was utilized for column
chromatography.
N ,N -Bis[[6-(h yd r oxym e t h yl)p yr id in -2-yl]m e t h yl]-p -
tosyla m id e (5). To a mixture of p-TsNH2 (6.44 g, 37.62 mmol)
and K2CO3 (10.35 g, 75.24 mmol) in acetone (300 mL) was added
dropwise a solution of 4 (15.20 g, 75.24 mmol) in acetone (150
mL) over a period of 1 h. Stirring under reflux was continued
for 2 days. After cooling, the reaction mixture was filtered and
the filtrate was evaporated. The residual oil was separated by
column chromatography (SiO2, CHCl3/AcOEt ) 5:1) to give the
desired bisadduct 5 as colorless granules (7.22 g, 71%), along
with the monoadduct 2-(hydroxymethyl)-6-[(p-tosylamino)meth-
yl]pyridine (6) (2.38 g, 15%). A small portion of each was
crystallized from EtOH to give analytically pure samples.
5: colorless granules; mp 59-61 °C; FAB MS m/ z 414.0 (M
+ 1); 1H NMR (270 MHz, CDCl3) δ 2.44 (s, 3H), 3.92 (br, 2H),
4.54 (s, 4H), 4.57 (s, 4H), 7.01 (d, J ) 7.59, 2H), 7.21 (d, J )
7.92, 2H), 7.30 (d, J ) 8.25, 2H), 7.49-7.55 (dd, J ) 7.58, 7.92,
2H), 7.73 (d, J ) 8.25, 2H). Anal. Calcd for C21H23N3O4S‚H2O:
C, 58.45; H, 5.84; N, 9.74. Found: C, 58.68; H, 5.84; N, 9.65.
6: colorless granules; mp 123-124 °C; FAB MS m/ z 293.1
(M + 1); 1H NMR (270 MHz, CDCl3) δ 2.44 (s, 3H), 3.92 (br,
2H), 4.54 (s, 4H), 4.57 (s, 4H), 7.01 (d, J ) 7.59, 2H), 7.21 (d, J
) 7.92, 2H), 7.30 (d, J ) 8.25, 2H), 7.49-7.55 (dd, J ) 7.58,
7.92, 2H), 7.73 (d, J ) 8.25, 2H). Anal. Calcd for C14H16N2O3S:
C, 57.51; H, 5.52; N, 9.58. Found: C, 57.47; H, 5.54; N, 9.47.
When the reaction was conducted in DMF at 100 °C for 1 day,
instead of the desired coupling product, N-p-tosyl-N′,N′-dimeth-
ylformamidine 8 was isolated as colorless crystals: mp 133-
134 °C (lit.6 mp 133-134 °C); 1H NMR (400 MHz, CDCl3) δ 1.60
(s, 3H, Ts), 3.01 (s, 3H), 3.12 (s, 3H), 7.26 (d, J ) 7.92, 2H), 7.78
(d, J ) 8.25, 2H), 8.13 (s, 1H).
A small portion of the sample was recrystallized from acetone/
H2O for characterization to give colorless plates: mp >246 °C
1
dec; H NMR (270 MHz, D2O) δ 4.04 (s, 4H), 7.09 (d, J ) 7.92,
2H), 7.57 (t, J ) 7.92, 1H). Anal. Calcd for C7H13N3Cl2: C,
40.02; H, 6.24; N, 20.00. Found: C, 40.09; H, 6.25; N, 19.84.
2,6-Bis[(p-tosyla m in o)m eth yl]p yr id in e (11). A mixture
of 10 (10.0 g, 47.8 mmol) and p-TsCl (27.2 g, 142.7 mmol) in
dioxane (400 mL) was stirred at room temperature for 1 h. KOH
(1.46 g) in water (30 mL) was added dropwise to the mixture
over 1 h. The reaction mixture was stirred for an additional 6
h. Dioxane and H2O were distilled off, and then CHCl3 (200
mL) and H2O (200 mL) were added to this mixture. The organic
phase was separated and evaporated. To the residual oil was
added EtOH to give white crystals (16.2 g, 86%; 70% from 9):
mp 126-127 °C; IR (KBr) νNH 3228, νSO 1321, 1149 cm-1 1H
;
NMR (270 MHz, CDCl3) δ 2.38 (s, 6H), 4.16 (d, 4H, J ) 5.61),
5.85 (t, J ) 5.61, 2H), 7.03 (d, J ) 7.59, 2H), 7.22 (d, J ) 8.24,
4H), 7.50 (t, J ) 7.59, 1H), 7.71 (d, J ) 8.25, 4H). Anal. Calcd
for C21H23N3O4S2: C, 56.60; H, 5.26; N, 9.43. Found: C, 56.69;
H, 5.20; N, 9.43.
N ,N ′,N ′′-T r i -p -t o s y l-2,11,20-t r i a z a [3.3.3](2,6)p y r i -
d in op h a n e (3b). To a vigorously stirred and refluxing mixture
of n-Bu4NI (1.56 g) and 11 (3.20 g, 7.08 mmol) in CH2Cl2 (400

8306 J . Org. Chem., Vol. 61, No. 23, 1996
Notes
mL) and KOH (20 g) in H2O (80 mL) was added dropwise a
solution of 7 (3.82 g, 7.08 mmol) in CH2Cl2 (300 mL) over 5 h.
The mixture was stirred under reflux for 24 h. On cooling, the
organic layer was separated and evaporated. Acetone was added
to the residue to give colorless crystals. Recrystallization from
CHCl3 and benzene gave colorless granules (3.55 g, 83%): mp
250-251 °C; FAB MS m/ z 823 (M + 1); IR (KBr) νSO 1334, 1157
The chloroform phase was dried (MgSO4) and evaporated to give
a pale yellow oil, which was crystallized from benzene to give
120 mg of hygroscopic colorless crystals (91%); mp 136-137 °C
(evacuated sealed tube); FAB MS m/ z 361.3 (M + 1); IR (C4Cl6)
νNH 3310 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.32 (br, 3H), 3.94
(s, 8H), 7.09 (d, J ) 7.81, 6H), 7.55 (t, J ) 7.81, 3H). Anal. Calcd
for C21H24N6: C, 69.97; H, 6.71; N, 23.32. Found: C, 70.05; H,
6.69; N, 23.27.
cm-1 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 9H), 4.26 (s, 8H),
;
7.11 (d, J ) 7.81, 6H), 7.26 (d, J ) 7.81, 6H), 7.40 (t, J ) 7.81,
3H), 7.64 (d, J ) 7.81, 6H). Anal. Calcd for C42H42N6O6S3: C,
61.29; H, 5.14; N, 10.21. Found: C, 61.15; H, 5.14; N,10.06.
2,11,20-Tr ia za [3.3.3](2,6)p yr id in op h a n e (3a ). A mixture
of 3b (300 mg, 0.36 mmol) and concd sulfuric acid (3 mL) was
stirred at 115-120 °C for 2 h. After addition of ice, the reaction
mixture was made alkaline with aqueous sodium hydroxide. The
solution was extracted with chloroform (50 mL) in three portions.
Ack n ow led gm en t. This work is supported in part
by a Grant-in-Aid for COE Research “Design and
Control of Advanced Molecular Assembly Systems” from
the Ministry of Education, Science and Culture, J apan
(#08CE2005).
J O961081D