Synthesis of multilayered [3.3](3,5)pyridinophanes

Article abstract of DOI:10.1055/s-0028-1083633

Two- to four-layered [3.3](3,5)pyridinophanes (PyPs) have been synthesized by the (4-tolylsulfonyl)methyl isocyanide (TosMIC) method. The coupling reaction between 3,5-bis[2-iso-cyano-2-(4-tolylsulfonyl)ethyl]pyridine (TosMIC adduct) and bis(chloromethyl) or tetrakis(bromomethyl) compounds in the presence of sodium hydride in N,N-dimethylformamide or sodium hydroxide and tetrabutylammonium iodide under high-dilution conditions gave the two-layered dione or three- and four-layered tetraones. Wolff-Kishner reduction of the ketones afforded the desired two- to four-layered [3.3](3,5)PyPs. The structure of the dione units take an anti geometry whereas the cyclophane units take a syn geometry in solution. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083633

PAPER
3749
Synthesis of Multilayered [3.3](3,5)Pyridinophanes1
S
ynthesisof Multilaye
a
s
5)Pyridino
a
phanes hiko Shibahara,*a Motonori Watanabe,b Kazuhiro Aso,a Teruo Shinmyozu*b
a
b
Received 2 July 2008; revised 21 August 2008
N
Abstract: Two- to four-layered [3.3](3,5)pyridinophanes (PyPs)
have been synthesized by the (4-tolylsulfonyl)methyl isocyanide
(TosMIC) method. The coupling reaction between 3,5-bis[2-iso-
cyano-2-(4-tolylsulfonyl)ethyl]pyridine (TosMIC adduct) and
bis(chloromethyl) or tetrakis(bromomethyl) compounds in the pres-
ence of sodium hydride in N,N-dimethylformamide or sodium
hydroxide and tetrabutylammonium iodide under high-dilution con-
ditions gave the two-layered dione or three- and four-layered tetra-
ones. Wolff–Kishner reduction of the ketones afforded the desired
two- to four-layered [3.3](3,5)PyPs. The structure of the dione units
take an anti geometry whereas the cyclophane units take a syn
geometry in solution.
N
Y
Y
X
X
N
N
[3.3](2,6)PyPs
X = CH2, NH, O, S, Se
[3.3](3,5)PyPs
Y = NH, S
Figure 1 [3.3](2,6)- and [3.3](3,5)Pyridinophanes
ered MCPs incorporating pyridine rings at both ends may
form larger supramolecules upon complexation with the
transition metals and new types of supramolecules may
serve as catalysts, inclusion hosts, and nanometer-scale
materials. We now report the synthesis of two- to four-
layered [3.3](3,5)PyPs 1–3 and their structures in solution
by 1H NMR studies.
Key words: cyclophanes, pyridines, coupling reaction, ketones,
Wolff–Kishner reduction
[3.3]Metapyridinophanes (MPyPs) are composed of two
pyridine rings and two three-atom bridges connected to
them. Among the various types of [3.3]MPyPs, the
[3.3](2,6)PyPs have been studied in detail and the 2,11-di-
aza,2 dithia,3 dioxa,4 and diselena derivatives5 have been
synthesized along with all the carbon parent cyclophanes6
(Figure 1). These PyPs have served as ligands for transi-
tion-metal complexes, and various kinds of metal com-
plexes have been prepared.5,7 Their conformational
isomerism has also attracted much attention.8 In contrast,
a limited number of [3.3](3,5)PyP are known to date,
mainly due to the instability of the coupling precursor,
3,5-bis(halomethyl)pyridine. In our recent preparation of
2,11-diaza[3.3](3,5)PyP, freshly prepared 3,5-bis(chlo-
romethyl)pyridine was used for the coupling reaction.9
One of the major advantages of the [3.3](3,5)PyPs over
the [3.3](2,6)PyPs is the potential ability to form self-
assembled supramolecules upon coordination, because
the cyclophanes take syn geometry and the nitrogen lone
pair electrons can readily coordinate to metals without
steric hindrance by the bridges. For example, the forma-
tion of the double-decker type 2:2 complexes has been re-
ported in 2,11-diaza-10 and dithia[3.3](3,5)PyPs.11
Multilayered [3.3](3,5) PyPs 1–3 were synthesized by the
TosMIC method in the critical coupling reaction
(Scheme 1). The synthetic key intermediates for the syn-
thesis of multilayered PyPs are bis(chloromethyl)pyridine
49 and its TosMIC adduct 6. 3,5-Bis(chloromethyl)pyri-
dine (4) was synthesized by chlorination of 3,5-lutidine
with N-chlorosuccinimide in carbon tetrachloride fol-
lowed by column chromatography on silica gel (n-hex-
ane–EtOAc, 3:1; Rf = 0.20) to give 4 in 32% yield. The
chloride 4 was immediately reacted with (4-tolylsulfo-
nyl)methyl isocyanide (TosMIC, 5) under phase-transfer
conditions, and the crude product was purified by column
chromatography on silica gel (EtOAc–n-hexane, 3:2;
Rf = 0.34) to give the TosMIC adduct 6 in 14% yield. The
reason for the relatively low yield of the TosMIC adduct
6 may be ascribed to the instability of the chloride 4. 3,5-
Bis(chloromethyl)pyridine (4) was coupled with the
TosMIC adduct 6 in the presence of sodium hydride in
N,N-dimethylformamide at room temperature for 24
hours under nitrogen, followed by hydrolysis of the cyclic
adduct with concentrated hydrochloric acid to give the
two-layered dione 7 in 35% yield. Wolff–Kishner reduc-
tion of 7 and purification by column chromatography on
silica gel (CH2Cl2–EtOH, 9:1; Rf = 0.46) afforded the
two-layered PyP 1 in 93% yield. Thus, the parent
[3.3](3,5)PyP has been synthesized for the first time, and
successful isolation of the TosMIC adduct 6 was a key
step in the synthesis of the multilayered [3.3](3,5)PyPs.
In previous papers, we reported the synthesis of multilay-
ered [3.3]cyclophanes by the (4-tolylsulfonyl)methyl iso-
cyanide (TosMIC) method (metacyclophanes; MCPs)12
and (4-ethylphenylsulfonyl)methyl isocyanide (EbsMIC)
method (paracyclophanes; PCPs).13 Therefore, multilay-
Tetrakis(bromomethyl) compounds 8 and 10 are versatile
synthetic intermediates for the one-pot synthesis of three-
and four-layered [3.3]MCPs, respectively.12 1,2,4,5-Tet-
rakis(bromomethyl)benzene (8) was coupled with the
SYNTHESIS 2008, No. 23, pp 3749–3754
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1083633; Art ID: F15008SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

3750
M. Shibahara et al.
PAPER
NC
Ts
Ts
NC
Cl
Cl
n-Bu4NI, NaOH, CH2Cl2/H2O
14%
H3C
SO2CH2NC
2
+
+
N
N
4
5
6
NC
Ts
Ts
NC
1) NaH, DMF
2) concd HCl
3) KOH soln
N
N
Cl
Cl
O
NH2NH2·H2O, KOH,
HOCH2CH2OCH2CH2OH
Hi1
93%
35%
Hi1
O
N
N
N
N
6
4
Ha
Ha
7
1
N
N
O
Br
Br
Br
Br
1) n-Bu4NI, NaOH, CH2Cl2/H2O
2) concd HCl
NC
Ts
2
Ts
NC
NH2NH2·H2O, KOH,
O
O
Hi2
3) KOH soln
HOCH2CH2OCH2CH2OH
+
Hi2
75%
4.5%
Hi1
N
O
Hi1
8
N
N
6
Ha
2
9
Ha
N
N
O
Br
1) n-Bu4NI, NaOH, CH2Cl2/H2O
2) concd HCl
3) KOH soln
NC
Ts
Ts
NC
O
NH2NH2·H2O, KOH,
HOCH2CH2OCH2CH2OH
Br
2
+
15%
81%
Hi3
Br
Br
Hi3
O
N
Hi2
Hi1
3
Hi2
6
Hi1
O
10
N
N
11
Ha
Ha
Scheme 1 Synthetic route to two- to four-layered [3.3](3,5)pyridinophanes 1–3
TosMIC adduct 6 in the presence of sodium hydroxide havior of the [3.3]MCPs and related systems in detail.13b,14
and tetrabutylammonium iodide in a mixture of dichlo- Moreover, we have recently reported the structural prop-
romethane and water under phase-transfer conditions at erties of the multilayered [3.3]MCPs in solution and in the
reflux, followed by hydrolysis with concentrated hydro- solid state,12 in which the [3.3]MCP moiety takes the syn
chloric acid to provide the desired three-layered tetraone geometry whereas the [3.3]MCP-dione moiety takes the
9 in 4.5% yield. The Wolff–Kishner reduction of the tetr- anti geometry. This indicated that the original stable con-
aone 9 gave the three-layered [3.3](3,5)PyP 2 in 75% formations are maintained even in the multilayered
yield after purification by column chromatography (silica [3.3]MCPs. Similarly, the [3.3]MCP units assume syn
gel, CH2Cl2–EtOH, 9:1; Rf = 0.46). A similar coupling re- geometry in multilayered [3.3](3,5)PyPs 1–3 (Figure 2).
action of 5,7,14,16-tetrakis(bromomethyl)[3.3]MCP 10 The Hi1 protons of the two-layered 1 appear at the normal
prepared by the one-step bromomethylation of position, which is comparable to that of [3.3]MCP, while
[3.3]MCP12 with the TosMIC adduct 6 afforded the four- the inner aromatic protons, Hi2 in the three-layered 2 and
layered tetraone 11, which was converted into the four- Hi2 and Hi3 in the four-layered 3, are moderately shielded
layered [3.3](3,5)PyP 3 by Wolff–Kishner reduction in due to the diamagnetic ring current effect of the stacked
81% yield after purification by column chromatography aromatic rings. This indicates the syn-syn and syn-syn-syn
(silica gel, CH2Cl2–EtOH, 9:1; Rf = 0.53).
geometries for 2 and 3, respectively. All the aromatic pro-
tons of 2 and 3 are assigned on the basis of their NOESY
spectra, in which the correlations are observed between
Hi1–Hi2, Ha–Hb, and Ha–Hc in the three-layered 2
(Figure 3). As for the four-layered 3, the correlations are
It is known that [3.3]MCP and its dione adopt different
syn and anti geometry as stable conformers in solution, re-
spectively, and we have studied the conformational be-
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PAPER
Synthesis of Multilayered [3.3](3,5)Pyridinophanes
3751
multilayered [3.3](3,5)PyPs 1–3 take the all-syn confor-
mation, while the [3.3](3,5)PyP-dione moieties in 7, 9,
and 11 assume anti geometry. Currently, we are investi-
gating their structures in the solid state, complexation be-
havior, and conformational analysis, and these results will
be reported elsewhere.
N
N
Hi3
All melting points were measured on a Stuart Scientific Melting
Point Apparatus SMP3, and are uncorrected. The 1H and 13C NMR
spectra were measured using Jeol JNM-AL300, Jeol JNM-ECA600,
and Bruker ARX-300 spectrometers; internal reference was TMS
and the solvent was CDCl3 or CD2Cl2 unless otherwise noted. The
MS (FAB-MS, m-nitrobenzyl alcohol) were obtained using a Jeol
JMS-SX/SX 102A mass spectrometer. The IR spectra were mea-
sured with a Nicolet Impact 400D spectrophotometer. The elemen-
tal analyses were performed by the Service Centre of the
Elementary Analysis of Organic Compounds affiliated with the
Faculty of Science, Kyushu University.
Hi2
Hi2
Hi1
N
N
Hi1
N
N
Ha
Hi1
Ha
3
Ha
2
Ha: 7.84
Hi1: 6.89
Hi2: 6.22
Hi3: 5.96
1
Ha: 7.77
Hi1: 7.07
Hi2: 6.16
Ha: 7.90
Hi1: 7.13
The analytical TLC was performed on Silica gel 60 F254 Merck. Col-
umn chromatography was performed on Kanto silica gel 60N (63–
210 mm).
N
O
All solvents and reagents were of reagent quality, commercially
purchased, and used without further purification, except as noted.
3,5-Bis(chloromethyl)pyridine9 and TosMIC (except for the use of
dioxane in place of DME)15 were prepared according to the litera-
ture procedures.
O
N
O
Hi3
O
O
O
Hi2
Hi2
3,5-Bis[2-isocyano-2-(4-tolylsulfonyl)ethyl]pyridine (6)
A mixture of n-Bu4NI (0.73 g), CH2Cl2 (50 mL), and NaOH (8 g)
dissolved in H2O (32 mL) was stirred in an ice bath. To the mixture
was added in one portion to a soln of TosMIC (5, 7.33 g, 37.5 mmol)
in CH2Cl2 (40 mL). After 30 min, to the mixture in an ice bath was
added freshly prepared chloride 4 (1.80 g, 10.2 mmol) in CH2Cl2
(50 mL) in one portion and the mixture was stirred for ca. 10 h in
the ice bath. The mixture was then allowed to warm up to r.t. over-
night. The mixture was washed with H2O, dried (MgSO4), filtered,
and concentrated to a volume of ca. 30 mL at 25 °C. The concentrate
was purified by column chromatography (silica gel, CH2Cl2 then
EtOAc–hexane, 3:2; Rf = 0.34). The eluate was concentrated to a
volume of ca. 30 mL, then CCl4 was added (100 mL). The soln was
concentrated to a volume of ca. 30 mL at 35 °C. The precipitate was
collected by filtration and suspended in a small amount of cold ac-
etone. The insoluble solid was collected by filtration to give the
TosMIC adduct 6 (721 mg, 14%) as a white powder; mp 105 °C
(dec).
N
O
Hi1
O
Hi1
O
N
Hi1
O
N
Ha
N
Ha
11
9
Ha
Ha: 8.29
Hi1: 5.72
Hi2: 5.32
Hi3: 7.01
7
Ha: 8.50
Hi1: 6.69
Hi2: 5.58
Ha: 8.51
Hi1: 6.07
Figure 2 Selected 1H NMR data of the aromatic protons of multi-
layered [3.3](3,5)PyPs and diones (d, 300 MHz, CDCl3)
observed between Hi1–Hi2, Ha–Hb, and Ha–Hc, while the
correlation between Hi1–Hi3 is not observed (Figure 4).
These results suggest the all-syn geometries for 2 and 3. In
contrast, multilayered [3.3](3,5)PyPs with dione units
take an anti geometry as shown in Hi1 in the two-layered
7, Hi1 and Hi2 in the three-layered 9, and Hi1 and Hi2 in the
four-layered 11 due to the ring current effect of the faced
IR (KBr): 2136, 1333, 1151 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.50 (s, 6 H, CH3), 3.07 (dd,
J = 14.0, 11.2 Hz, 2 H, CH2CH), 3.61 (dd, J = 14.1, 3.2 Hz, 2 H,
CH2CH), 4.58 (dd, J = 11.1, 3.3 Hz, 2 H, CH2CH), 7.46 (d, J = 8.0
aromatic rings, and this suggests anti, anti-anti, and anti- Hz, 4 H, TsH), 7.56 (t, J = 2.1 Hz, 1 H, PyH), 7.90 (dd, J = 6.7, 1.6
Hz, 4 H, TsH), 8.53 (d, J = 2.1 Hz, 2 H, PyH).
13C NMR (150 MHz, CD2Cl2): d = 22.0, 32.3, 73.6, 129.9, 130.4,
130.8, 131.3, 138.2, 147.8, 150.6, 167.1.
HRMS (FAB): m/z [M + H]+ calcd for C25H24N3O4S2: 494.1208;
found: 494.1206.
syn-anti geometries for 7, 9, and 11, respectively. Thus
multilayered [3.3]PyPs take structures similar to the cor-
responding multilayered [3.3]MCPs in solution.
In conclusion, we have synthesized the TosMIC adduct of
3,5-bis(chloromethyl)pyridine 6, and the coupling of 6
with the bis- or tetrakis(halomethyl) compounds 4, 8, and
10 in the presence of sodium hydride in N,N-dimethyl-
formamide or sodium hydroxide and tetrabutylammoni-
um iodide in a mixture of dichloromethane and water
under phase-transfer conditions gave the two- to four-
layered [3.3](3,5)PyPs 1–3, respectively. Similar to the
structure of the multilayered [3.3]MCPs in solution,
Two-Layered [3.3](3,5)Pyridinophane (1)
To a mixture of NaH (60%, 0.25 g, 10.4 mmol) and DMF (80 mL)
was dropwise added a mixture of chloride 4 (317 mg, 1.80 mmol)
and TosMIC adduct 6 (887 mg, 1.80 mmol) dissolved in DMF (200
mL) at r.t. over a period of 7 h and the mixture was stirred at r.t. for
an additional 16 h. The solvent was removed under reduced pres-
sure and MeOH was added to the residue and the insoluble solid was
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3752
M. Shibahara et al.
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Figure 3 NOESY spectrum of three-layered [3.3](3,5)pyridinophane 2
collected by filtration to give the cyclic TosMIC adduct as a pale
brown powder.
1H NMR (300 MHz, CDCl3): d = 2.0–2.2 (m, 4 H, CH2CH2CH2),
2.76 (t, J = 5.8 Hz, 8 H, CH2CH2CH2), 7.13 (t, J = 1.9 Hz, 2 H,
ArH), 7.90 (d, J = 1.9 Hz, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 29.3, 33.4, 134.7, 134.0, 147.5.
HRMS (FAB): m/z [M + H]+ calcd for C16H19N2: 239.1548; found:
239.1549.
To a mixture of the cyclic TosMIC adduct and CH2Cl2 (150 mL)
was added concd HCl (5 mL) and it was stirred at r.t. After 3 h,
KOH (10 g) dissolved in H2O (30 mL) was added and the mixture
was stirred at r.t. for 1 h. The mixture was extracted with CH2Cl2.
The CH2Cl2 soln was washed with H2O, dried (MgSO4), and con-
centrated to dryness. The resulting residue was washed with acetone
to give the dione 7 (169 mg, 35% for two steps) as colorless needles
(CHCl3); mp 212 °C (dec).
IR (KBr): 1698 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.62 (s, 8 H, CH2COCH2), 6.07 (t,
J = 2.1 Hz, 2 H, ArH), 8.51 (d, J = 2.1 Hz, 4 H, ArH).
Anal. Calcd for C16H18N2: C, 80.63; H, 7.61; N, 11.75. Found: C,
80.38; H, 7.57; N, 11.77.
Three-Layered [3.3](3,5)Pyridinophane (2)
A mixture of n-Bu4NI (1.50 g), NaOH (25 g) dissolved in H2O (75
mL) and CH2Cl2 (800 mL) was heated to reflux with stirring. To the
mixture was dropwise added a mixture of tetrabromide 8 (758 mg,
1.69 mmol) and TosMIC adduct 6 (1.67 g, 3.38 mmol) in CH2Cl2
over a period of 11 h, and the mixture was refluxed for an additional
11 h. The cooled mixture was washed with H2O and concentrated to
a volume of ca. 200 mL.
13C NMR (75 MHz, CDCl3): d = 47.5, 129.0, 142.6, 149.8, 203.4.
HRMS (FAB): m/z [M + H]+ calcd for C16H15N2O2: 267.1134;
found: 267.1131.
Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C,
72.09; H, 5.32; N, 10.48.
To the concentrate was added concd HCl (50 mL) and the mixture
was stirred at r.t. After 3.5 h, 3 M HCl (200 mL) was added in one
portion and the mixture was stirred at r.t. for 1.5 h. The aqueous soln
was basified by the addition of NaOH and the precipitate was fil-
tered. The crude product was suspended in CHCl3 (200 mL) at
reflux and filtered. The filtrate was concentrated to dryness, sus-
pended in a small amount of acetone and pyridine and sonicated.
The insoluble solid was recrystallized (CHCl3) to give the tetraone
9 (34.3 mg, 4.5%) as an ivory powder (CHCl3); mp 250 °C (dec).
A mixture of the dione 7 (85 mg, 0.319 mmol), 98% NH2NH2·H2O
(5 mL), KOH (820 mg), and diethylene glycol (20 mL) was heated
at 130 °C for 3.5 h and then at 200 °C for 2 h with stirring. After
cooling, the mixture was poured into ice water and extracted with
CH2Cl2. The CH2Cl2 soln was washed with H2O, dried (MgSO4),
and concentrated to dryness. Purification of the residue by column
chromatography (silica gel, CH2Cl2–EtOH, 9:1; Rf = 0.46) pro-
duced the two-layered pyridinophane 1 (71 mg, 93%) as colorless
prisms (acetone–THF); mp 241 °C (dec).
IR (KBr): 1701 cm–1.
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Synthesis of Multilayered [3.3](3,5)Pyridinophanes
3753
Figure 4 NOESY spectrum of four-layered [3.3](3,5)pyridinophane 3
1H NMR (300 MHz, CDCl3): d = 3.66 (s, 8 H, CH2COCH2), 3.69 (s,
8 H, CH2COCH2), 5.58 (s, 2 H, Hi2), 6.69 (d J = 2.1 Hz, 2 H, Hi1),
8.50 (d, J = 2.1 Hz, 4 H, Ha).
HRMS (FAB): m/z [M + H]+ calcd for C28H25N2O4: 453.1814;
found: 453.1812.
mixture was dropwise added a mixture of tetrabromide 10 (489 mg,
0.804 mmol) and TosMIC adduct 6 (800 mg, 1.62 mmol) in CH2Cl2
over a period of 7 h, and the mixture was refluxed for an additional
12 h. The cooled mixture was washed with H2O and concentrated to
a volume of ca. 200 mL.
To the concentrate was added concd HCl (15 mL) and the mixture
was stirred at r.t. After 4 h, KOH (20 g) dissolved in H2O (80 mL)
was added in one portion and the mixture was stirred for 4.5 h at r.t.
The mixture was then extracted with CH2Cl2. The CH2Cl2 soln was
washed with H2O, dried (MgSO4), and concentrated to dryness. The
residue was suspended in acetone and collected by filtration to give
the crude ketone, which was suspended in pyridine and the insolu-
ble solid was recrystallized (CHCl3) to give the pure tetraone 11 (68
mg, 15%) as colorless needles (CHCl3); mp 250 °C (dec).
A mixture of the tetraone 9 (65.8 mg, 0.145 mmol), KOH (2 g), 98%
NH2NH2·H2O (5 mL), and diethylene glycol (25 mL) was heated at
130 °C for 12 h and then at 200 °C for 4 h with stirring. After cool-
ing, the mixture was poured into ice water and extracted with
CH2Cl2. The CH2Cl2 soln was washed with brine, dried (MgSO4),
and concentrated to dryness. Purification of the residue by column
chromatography (silica gel, CH2Cl2–EtOH, 9:1; Rf = 0.46) pro-
duced the three-layered pyridinophane 2 (43.3 mg, 75%) as a white
powder (CH2Cl2–acetone); mp 285 °C (dec).
1H NMR (600 MHz, CDCl3): d = 1.9–2.1 (m, 8 H, CH2CH2CH2),
2.5–2.7 (m, 16 H, CH2CH2CH2), 6.17 (s, 2 H, Hi2), 7.08 (s, 2 H,
Hi1), 7.78 (s, 4 H, Ha).
13C NMR (150 MHz, CDCl3): d = 27.8, 32.7, 33.5, 134.0, 134.9,
135.4, 140.1, 146.7.
IR (KBr): 1702 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.9–2.1 (m, 4 H, CH2CH2CH2),
2.81 (t, J = 5.5 Hz, 8 H, CH2CH2CH2), 3.36 (s, 16 H, CH2COCH2),
5.32 (s, 2 H, Hi2), 5.72 (t, J = 2.0 Hz, 2 H, Hi1), 7.01 (s, 2 H, Hi3),
8.29 (d, J = 2.0 Hz, 4 H, Ha).
HRMS (FAB): m/z [M + H]+ calcd for C40H39N2O4: 611.2910;
found: 611.2924.
HRMS (FAB): m/z [M + H]+ calcd for C28H33N2: 397.2644; found:
397.2640.
A mixture of the tetraone 11 (142 mg, 0.233 mmol), 98%
NH2NH2·H2O (8 mL), and diethylene glycol (25 mL) was heated at
130 °C with stirring. After 20 h, KOH (2 g) was added and heated
at 200 °C for 6 h with stirring. After cooling, the mixture was
poured into ice water and extracted with CH2Cl2. The CH2Cl2 soln
was washed with brine, dried (MgSO4), and concentrated to dry-
ness. Purification of the residue by column chromatography (silica
Anal. Calcd for C28H32N2: C, 84.80; H, 8.13; N, 7.06. Found: C,
84.77; H, 8.03; N, 7.07.
Four-Layered [3.3](3,5)Pyridinophane (3)
A mixture of n-Bu4NI (0.75 g), NaOH (10 g) dissolved in H2O (50
mL ) and CH2Cl2 (450 mL) was heated to reflux with stirring. To the
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M. Shibahara et al.
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gel, CH2Cl2–EtOH, 9:1; Rf = 0.53) produced the four-layered pyri-
dinophane 3 (105 mg, 81%) as colorless prisms (CH2Cl2–acetone);
mp 245 °C (dec).
1H NMR (600 MHz, CDCl3): d = 1.8–2.0 (m, 12 H, CH2CH2CH2),
2.4–2.7 (m, 24 H, CH2CH2CH2), 5.97 (s, 2 H, Hi2), 6.21 (s, 2 H,
Hi3), 6.91 (s, 2 H, Hi1), 7.84 (d, J = 1.5 Hz, 4 H, Ha).
13C NMR (150 MHz, CDCl3): d = 26.2, 27.7, 32.4, 32.7, 33.2,
134.0, 134.4, 134.8, 134.8, 135.8, 140.4, 146.8.
HRMS (FAB): m/z [M + H]+ calcd for C40H47N2: 555.3739; found:
555.3739.
(7) (a) Fronczek, F. R.; Mamo, A.; Pappalardo, S. Inorg. Chem.
1989, 28, 1419. (b) Sakaba, H.; Kabuta, C.; Horino, H.;
Arai, M. Bull. Chem. Soc. Jpn. 1990, 63, 1822. (c) Krüger,
H.-J. Chem. Ber. 1995, 128, 531. (d) Koch, W. O.; Barbieri,
A.; Grodzicki, M.; Schünemann, V.; Trautwein, A. X.;
Krüger, H.-J. Angew. Chem., Int. Ed. Engl. 1996, 35, 422.
(e) Kelm, H.; Krüger, H.-J. Eur. J. Inorg. Chem. 1998,
1381. (f) Sciarone, T.; Hoogboom, J.; Schlebos, P. P. J.;
Budzelaar, P. H. M.; Gelder, R.; Smits, J. M. M.; Gal, A. W.
Eur. J. Inorg. Chem. 2002, 457. (g) Albelta, B.; Carina, R.;
Policar, C.; Poussereau, S.; Cano, J.; Guilhem, J.;
Tchertanov, L.; Blondin, G.; Delroisse, M.; Girerd, J.-J.
Inorg. Chem. 2005, 44, 6959. (h) Moriguchi, T.; Kitamura,
S.; Sakata, K.; Tsuge, A. Polyhedron 2001, 20, 2315.
(8) Sako, K.; Tatemitsu, H.; Onaka, S.; Takemura, H.; Osada,
S.; Wen, G.; Rudzinski, J. M.; Shinmyozu, T. Liebigs Ann.
1996, 1645.
Anal. Calcd for C40H46N2: C, 86.59; H, 8.36; N, 5.05. Found: C,
86.35; H, 8.34; N, 5.01.
Acknowledgment
We are indebted to Professor Takahiko Inazu for his helpful sug-
gestions. We gratefully acknowledge the financial support by a
Theme Project of Molecular Architecture of Organic Compounds
for Functional Design (Professor Tahsin J. Chow), Institute of Che-
mistry, Academia Sinica, Taiwan R.O.C. and for the financial sup-
port from a Grant-in-Aid for Scientific Research (B) (No.
18350025) from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. We are also grateful to Miss Keiko Ideta
(Institute for Materials Chemistry and Engineering, Kyushu Uni-
versity) for the NMR measurements.
(9) Satou, T.; Shinmyozu, T. J. Chem. Soc., Perkin Trans. 2
2002, 393.
(10) Satou, T.; Sabae, M.; Iizuka, S.; Akita, M.; Shinmyozu, T.
unpublished results.
(11) Tsuge, A.; Matsubara, A.; Moriguchi, T.; Sei, Y.;
Yamaguchi, K. Tetrahedron Lett. 2006, 47, 6607.
(12) Shibahara, M.; Watanabe, M.; Iwanaga, T.; Ideta, K.;
Shinmyozu, T. J. Org. Chem. 2007, 72, 2865.
(13) (a) Shibahara, M.; Watanabe, M.; Iwanaga, T.; Matsumoto,
T.; Ideta, K.; Shinmyozu, T. J. Org. Chem. 2008, 73, 4433.
(b) Muranaka, A.; Shibahara, M.; Watanabe, M.;
Matsumoto, T.; Shinmyozu, T.; Kobayashi, N. J. Org.
Chem. in press.
References
(14) (a) Sako, K.; Hirakawa, T.; Fujimoto, N.; Shinmyozu, T.;
Inazu, T.; Horimoto, H. Tetrahedron Lett. 1988, 29, 6275.
(b) Sako, K.; Shinmyozu, T.; Takemura, H.; Suenaga, M.;
Inazu, T. J. Org. Chem. 1992, 57, 6536. (c) Shinmyozu, T.;
Hirakawa, T.; Wen, G.; Osada, S.; Takemura, H.; Sako, K.;
Rudzinski, J. M. Liebigs Ann. 1996, 205. (d) Takemura, H.;
Kariyazono, H.; Yasutake, M.; Kon, N.; Tani, K.; Sako, K.;
Shinmyozu, T.; Inazu, T. J. Org. Chem. 1999, 64, 9077.
(e) Satou, T.; Shinmyozu, T. J. Chem. Soc., Perkin Trans. 2
2002, 393. (f) Sako, K.; Meno, T.; Takemura, H.;
Shinmyozu, T.; Inazu, T. Chem. Ber. 1990, 123, 639.
(g) Isaji, H.; Yasutake, M.; Takemura, H.; Sako, K.;
Tatemitsu, H.; Inazu, T.; Shinmyozu, T. Eur. J. Org. Chem.
2001, 2487.
(1) Multilayered [3.3]Cyclophanes, Part 4. For parts 1, 2, and 3,
see refs. 12, 13a and 13b.
(2) (a) Bottino, F.; Grazia, M. D.; Finocchiaro, P.; Fronczek, F.
R.; Mamo, A.; Pappalardo, S. J. Org. Chem. 1988, 53, 3521.
(b) Takemura, H.; Wen, G.; Shinmyozu, T. Synthesis 2005,
2845.
(3) Vögtle, F.; Schunder, L. Chem. Ber. 1969, 102, 2677.
(4) Newcomb, M.; Timko, J. M.; Walba, D. M.; Cram, D. J.
J. Am. Chem. Soc. 1977, 99, 6392.
(5) Muralidharan, S.; Hojjatie, M.; Firestone, M.; Freiser, H.
J. Org. Chem. 1989, 54, 393.
(6) Shinmyozu, T.; Hirai, Y.; Inazu, T. J. Org. Chem. 1986, 51,
1551.
(15) Hoogenboom, B. E.; Oldenziel, O. H.; van Leusen, A. M.
Org. Synth. Coll. Vol. VI; John Wiley & Sons: London,
1988, 987.
Synthesis 2008, No. 23, 3749–3754 © Thieme Stuttgart · New York