A new synthetic method for (Aza)n[3n]cyclophanes by diethyl phosphoramidates

Article abstract of DOI:10.1055/s-2005-872171

(Aza)_n[3ⁿ]cyclophanes are synthesized by the N-alkylation of diethyl phosphoramidates with bis(bromomethyl)arenes under phase-transfer conditions or anhydrous conditions in the presence of an appropriate base. The method affords N-(d

Full text of DOI:10.1055/s-2005-872171

PAPER
2845
A New Synthetic Method for (Aza)n[3n]cyclophanes by Diethyl
Phosphoramidates
Synthesis of
A
zacy
i
clopha
r
nes by
P
o
hosphoramid
y
ates uki Takemura,*a Gang Wen,b Teruo Shinmyozub
a
Department of Chemistry, Faculty of Science, Kyushu University, Ropponmatsu 4-2-1, Chuo-ku, Fukuoka, 810-8560 Japan
Fax +81(92)7264755; E-mail: takemura@chem.rc.kyushu-u.ac.jp
b
Institute for Materials Chemistry and Engineering, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
Fax 81(92)6422735; E-mail: shinmyo@ms.ifoc.kyushu-u.ac.jp
Received 14 March 2005; revised 18 May 2005
or benzene and gave corresponding amine hydrochlo-
rides. A related application for the synthesis of macrocy-
clic compounds was reported.4 We thus applied this
method for the synthesis of (aza)n[3n]cyclophanes.
Abstract: (Aza)n[3n]cyclophanes are synthesized by the N-alkyla-
tion of diethyl phosphoramidates with bis(bromomethyl)arenes un-
der phase-transfer conditions or anhydrous conditions in the
presence of an appropriate base. The method affords N-(diethoxy-
phosphoryl)(aza)n[3n]cyclophanes in moderate yields and can be
applied to the synthesis of various types of azacyclophanes. The N-
phosphorylated cyclophanes are highly soluble in organic solvents
and the diethoxyphosphoryl groups are readily cleaved under acidic
conditions to give the corresponding secondary amines.
The N,N¢-bis[(diethoxyphosphoryl)aminomethyl]arenes
3–7 (general structure ≡ 1) were prepared by treatment of
corresponding amines with phosphonic acid diethyl ester
and CCl4 (Scheme 1) in CH2Cl2 under phase-transfer con-
ditions (triethylbenzylammonium chloride, 20% aq
NaOH) at low temperatures (0–5 °C). The resultant phos-
phoramidate derivatives were purified by silica gel chro-
matography with CH2Cl2 as an eluent and gave essentially
pure phosphoramidates in modest to good yields
(Table 1). The phosphoramidates are highly soluble in
common organic solvents and they are generally colorless
oils or low-melting crystals.
Key words: cyclophanes, phosphorylations, amines, host–guest
systems, macrocycles
In host–guest chemistry, hydrophobic interaction plays an
important role for the inclusion of guest molecules into
the cavity of host molecules. Hydrophobic interaction be-
comes much more important in polar solvents than in non-
polar solvent, especially it is most effective in aqueous
media. Therefore many water-soluble host molecules are
designed and used for the study of host–guest interactions
and construction of artificial enzyme system.1 In this re-
spect, azacyclophanes are convenient molecules for intro-
ducing functional groups on N atoms and making them
soluble in water. During the course of our azacyclophane
studies, convenient and widely applicable synthetic meth-
ods have been explored and developed.2 There are several
established synthetic methods, but each has own availabil-
ities and drawbacks. Thus, development of new and vari-
ous types of synthetic methods is favorable because the
best method should be chosen for the synthesis of target
molecule.
20% aq NaOH
Ar(CH2NH2)2
(EtO) P(O)H CCl
Ar[CH2NHP(O)(OEt)2]2
+
+
2
4
CH2Cl2, 0–5 °C
1
O
EtO P OEt
N
A or B
Ar(CH2Br)2
Ar
Ar
1
+
N
EtO P OEt
O
A: NaH, benzene, dioxane, or DMF
B: 50% aq NaOH/toluene, n-Bu4NHSO4
2
Scheme 1 Preparation of N,N¢-bis[(diethoxyphosphoryl)amino-
methyl]arenes and coupling with bis(bromomethyl)arenes
We wish to describe here a new synthetic method of
(aza)n[3n]cyclophanes by N-alkylation reaction of N,N¢-
dialkylphosphoramidates 1 with bis(bromomethyl) com-
pounds in the presence of base such as aqueous NaOH un-
der phase-transfer conditions or NaH under anhydrous
conditions.
The resultant diethyl phosphoramidates were coupled
with corresponding bis(bromomethyl) compounds under
phase-transfer conditions (50% aq NaOH/toluene,
Bu4NX) or anhydrous conditions such as NaH/benzene,
NaH/dioxane, or NaH/DMF. Besides the diaza[3.3]cyclo-
phanes, its tetramers and hexamers were obtained except
in the paracyclophane case, in which diaza[3.3]paracyclo-
phane was not formed (Scheme 2). The use of Cs2CO3 as
a base did not give cyclic products. For example, a reac-
tion between 1,4-bis(bromomethyl)benzene and the ami-
date 3 in DMF in the presence of Cs2CO3 at 60 °C for 16
hours did not give macrocyclic compounds 8 or 9 but a
mixture of acyclic compounds was obtained.
Zwierzak et al. reported that diethyl N-alkyl- or N-
arylphosphoramidates can be readily alkylated with pri-
mary alkyl halides3 and afford respective secondary
amines. Removal of diethoxyphosphoryl group proceeded
smoothly at room temperature with gaseous HCl in THF
SYNTHESIS 2005, No. 17, pp 2845–2850
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872171; Art ID: F05405SS
© Georg Thieme Verlag Stuttgart · New York

2846
H. Takemura et al.
PAPER
R
N
R
R
R
R
R
N
N
N
N
N
N
N
N
Br
A
+
3
+
benzene
R
R
Br
R
N
R
9
8 11%
14%
R
R
R
N
R
R
N
N
N
N
B
4
4
5
R N
N R
+
+
R
N
+
N
R
Br
Br
N
N
N
R
R
R
10 12%
11 9%
12 8%
R
R
N
N
R
R
R
R
N
N
N
N
N
N
N
B
N
R
+
N
N R
+
N
R
N
+
N
R
Br
Br
N
N
N
N
R
R
13 16%
14 12%
15 8%
R
N
R
N
N
R
R
N
N
N
N
N
N
N
A
N
N
N
N
+
R
N
N R
N
+
N
+
R
N
R
N
Br
Br
N
N
N
N
dioxane
R
R
N
R
R
16 42%
17 5%
18 3%
A: NaH, benzene or dioxane, reflux
B: 50% aq NaOH/toluene, Bu4NHSO4
O
P
R =
EtO
OEt
Scheme 2 Synthesis of [(EtO)2PO]n(aza)n[3n]cyclophanes
As shown in Scheme 3, alkylation of the amidate 3 by but- bis(chloromethyl)anthracene under NaH/DMF or NaH-
2-yne-1,4-diol ditosylate (NaH, DMF) provided [8]para- dioxane conditions, in which the latter gave better yield
cyclophane-4-yne 19 in 9% yield. Furthermore, di- (41%) than the former (5%). Related diaza[3.3]paracy-
aza[3.3]paracyclo(9,10)anthracenophane derivative 20 clo(9,10)anthracenophane derivative was reported by
was prepared by the reaction of the amidate 3 and 9,10- Okamoto et al.5
Synthesis 2005, No. 17, 2845–2850 © Thieme Stuttgart · New York

PAPER
Synthesis of Azacyclophanes by Phosphoramidates
2847
ble materials, and therefore, further treatments are
convenient. Actually, N-Ts-(aza)n[3n]paracyclophanes are
difficult to separate each other because of their low solu-
bility.2a Furthermore, cleavage of Ts group of N-Ts-aza-
cyclophanes or macrocyclic compounds are sometimes a
problem. Several cleavage conditions were developed in
order to overcome this problem and it is necessary to
choose better method of deprotection.6 In this respect, re-
cently developed azacyclophane synthetic methods which
employ CF3CONH2,2b NH2CN,2c Ns (o,p-nitrobenzene-
sulfonamide),7 and SES (b-trimethylsilylethanesulfon-
amides)8 should be considered, as well as this
phosphoramidate method according to the properties of
target cyclophanes and their starting materials.
Table 1 N,N¢-Bis[(diethoxyphosphoryl)aminomethyl]arenes Pre-
pared
Product
Yield (%) Product
Yield (%)
31
72
NHR
N
NHR
NHR
5
RHN
3
89
52
54
NHR
RHN
NHR
NHR
4
NHR
6
The N-protected diethoxyphosphoryl group was readily
removed by treatment with 15% HBr in AcOH (commer-
cially available) at room temperature. After the usual
work-up, secondary amine 22 was obtained in 99% yield
(Scheme 4).
O
NHR
R =
P
OEt
OEt
RHN
7
O
O
15% HBr/AcOH, r.t.
99%
EtO
EtO
P
N
N
P
OEt
OEt
HN
NH
NaH, DMF
9%
TsO
R
N
10
22
N
R
3
+
+
OTs
Scheme 4 Cleavage of phosphoryl group
19
R
N
Cl
In summary, the advantages of this method are as follows:
NaH, DMF
5%
(1) Starting material, phosphonic acid diethyl ester is in-
expensive, and N-phosphorylation of the corresponding
amine proceeds smoothly.
3
NaH, dioxane
41%
Cl
N
R
(2) The resultant N-phosphorylated cyclophanes are high-
ly soluble in common organic solvents and easy to handle
and separate.
20
R
N
Br
NaH, benzene, reflux
(3) Although the yields of N-phosphorylated cyclophanes
are modest, this method can be applied for the synthesis of
various azacyclophanes including pyridinophanes, a cy-
clophane containing an acetylenic unit, and anthra-
cenophane. Especially, higher oligomers, which are not
obtained by toluenesulfonamide method, are obtained.
+
6
Br
N
N
Br
R
R
21
O
EtO
P OEt
R =
Scheme 3 Synthesis of [(EtO)2PO]n(aza)n[3n]cyclophanes
(4) The protecting groups are readily removed.
However, triply-bridged cyclophane, triaza[33](1,3,5)cy-
clophane 21 was not obtained, but the reason is not clear
so far. Similarly, the reaction between the amidate 7 and
9,10-bis(chloromethyl)anthracene did not afford the ex-
pected (aza)n[3n](9,10)anthracenophane.
All melting points were measured on Yanaco MP-S3 apparatus, and
are uncorrected. The 1H NMR spectra were recorded on JEOL
JNM-GX 270 (270MHz) spectrometer. Chemical shifts are reported
as d values (ppm) relative to the internal tetramethylsilane. Mass
spectra were measured on JEOL JMS-HX110A spectrometer. Ele-
mental analyses were performed by the Service Centre of the Ele-
mentary Analysis of Organic Compounds affiliated to the Faculty of
Science, Kyushu University.
A special feature of this method is that one can obtain
higher cyclic oligomers which are difficult to prepare by
other cyclization methods. For example, hexaaza deriva- Silica gel chromatography was performed on Merck silica gel 60
(43–60 mm), Fuji Silysia BW-300 and BW-350 (NH type), Merck
silica gel PF254 for preparative TLC, and Merck silica gel F254 (0.2
mm on glass) for analytical purpose. Sephadex LH-20 and EtOH
were used for gel filtration chromatography. For the separation of
oligomers which are difficult to separate by the silica gel or Sepha-
dex chromatography, recycle preparative HPLC on GPC (JAIGEL-
tives, 9,12,15, and 18, which are the potential ligands of
polynuclear metal complexes, were obtained.
Different from commonly used N-tosyl-protected cyclo-
phanes, cyclic phosphoramidate derivatives are very solu-
Synthesis 2005, No. 17, 2845–2850 © Thieme Stuttgart · New York

2848
H. Takemura et al.
PAPER
N,N¢,N¢¢,N¢¢¢-Tetrakis(diethoxyphosphoryl)-2,11,20,29-tetra-
1H and 2H) with CHCl3 as eluent was used (LC-908, Japan Analyt-
ical Industry Co., Ltd.).
aza[3.3.3.3]paracyclophane (8) and N,N¢,N¢¢,N¢¢¢,N¢¢¢¢,N¢¢¢¢¢-
Hexakis(diethoxyphosphoryl)-2,11,20,29,38,47-hexa-
aza[3.3.3.3.3.3]paracyclophane (9); Typical Procedure
Phosphonic acid diethyl ester, and 1,3- and 1,4-bis(aminometh-
yl)benzenes and were purchased from Tokyo Kasei Co. Ltd. Ben-
zene, dioxane, and DMF were dried over molecular sieves 4Å. 9,10-
Bis(aminomethyl)anthracene was prepared according to the litera-
ture method.9
Method A (in benzene): To a stirred mixture of benzene (150 mL)
and NaH (60%, 1.10 g), was added dropwise a solution of the ami-
date 3 (4.90 g, 10.2 mmol) in benzene (200 mL) and a solution of
1,4-bis(bromomethyl)benzene (3.30 g, 12.5 mmol) in benzene (200
mL) simultaneously over a period of 1 h at r.t. After the addition,
the mixture was refluxed overnight. After cooling, H2O (100 mL)
was added and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 and the combined organic layers were
washed with brine, dried (MgSO4), filtered, and concentrated to
dryness. The residue was separated by Sephadex (LH-20) chroma-
tography with EtOH to give the crude product (3.50 g). A sample
(100 mg) was subjected to preparative recycle HPLC (GPC, CHCl3)
to afford pure tetraaza[34]paracyclophane derivative 8 (17 mg,
11%) and hexaaza[36]paracyclophane derivative 9 (21mg, 14%).
N,N¢-1,4-Bis[(diethoxyphosphoryl)aminomethyl]benzene (3);
Typical Procedure
To a stirred mixture of NaOH (12.0 g, 25 mmol) in H2O (60 mL),
BnEt3NCl (1.50 g, 8.1 mmol), CCl4 (40 mL, 414 mmol) and CH2Cl2
(100 mL), was added dropwise a CH2Cl2 solution (100 mL) of 1,4-
bis(aminomethyl)benzene (6.81 g, 50.0 mmol) and a CH2Cl2 solu-
tion (100 mL) of phosphonic acid diethyl ester (18.0 g, 130 mmol)
simultaneously over a period of 1 h at 0–5 °C. After addition, the
mixture was stirred at 0–5 °C for 10 h and then at r.t. for 3 h. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic phases were washed with
brine, dried (MgSO4), filtered, and the filtrate was concentrated to
dryness. The residue was purified by silica gel chromatography
with CH2Cl2 to give 3 (14.7 g, 72%); colorless crystals (CH2Cl2–
hexane); mp 93.0–94.3 °C.
8
Colorless oil.
1H NMR: d = 1.36 (t, J = 7 Hz, 24 H, OCH2CH3), 3.99–4.17 (m, 32
H, CH2N and OCH2CH3), 6.94 (s, 16 H, ArH).
1H NMR: d = 1.30 (t, J = 7 Hz, 12 H, OCH2CH3), 3.11–3.14 (m, 2
H, NH), 3.97–4.13 (m, 12 H, CH2N and OCH2CH3), 7.30 (s, 4 H,
ArH).
HRMS (FAB, M + H+): m/z calcd for C48H73N4O12P4: 1021.4175;
found: 1021.4164 (100).
9
HRMS (FAB, M + H+): m/z calcd for C16H31N2O6P2: 409.1657;
Colorless oil.
found: 409.1636 (100).
1H NMR: d = 1.35 (t, J = 7 Hz, 36 H, OCH2CH3), 4.03–4.15 (m, 48
H, CH2N and OCH2CH3), 7.27 (s, 24 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C72H109N6O18P6: 1531.6224;
N,N¢-1,3-Bis[(diethoxyphosphoryl)aminomethyl]benzene (4)
Colorless oil (89%).
1H NMR: d = 1.29 (t, J = 7 Hz, 12 H, OCH2CH3), 3.52–3.54 (m, 2
H, NH), 3.95–4.11 (m, 12 H, CH2N and OCH2CH3), 7.24–7.29 (m,
3 H, ArH), 7.33 (s, 1 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C16H31N2O6P2: 409.1657;
found: 409.1667 (100).
found: 1531.6233 (100).
N,N¢-Bis(diethoxyphosphoryl)-2,11-diaza[3.3]metacyclophane
(10), N,N¢,N¢¢,N¢¢¢-Tetrakis(diethoxyphosphoryl)-2,11,20,29-tet-
raaza[3.3.3.3]metacyclophane (11), and N,N¢,N¢¢,N¢¢¢,N¢¢¢¢,N¢¢¢¢¢-
Hexakis(diethoxyphosphoryl)-2,11,20,29,38,47-hexa-
aza[3.3.3.3.3.3]metacyclophane (12); Typical Procedure
Method B: To a stirred mixture of aq NaOH (15 g in 15 mL of H2O),
Bu4NHSO4 (300 mg), and toluene (100 mL), was added dropwise a
toluene solution (50 mL) of the amidate 4 (4.08 g, 10.0 mmol) and
a toluene solution (50 mL) of 1,3-bis(bromomethyl)benzene (3.43
g, 13.0 mmol) simultaneously over a period of 1 h at reflux temper-
ature. After addition, the mixture was refluxed for 11 h. After cool-
ing, H2O (50 mL) was added and the organic layer was separated,
washed with brine, dried (MgSO4), and filtered. The filtrate was
concentrated to dryness in vacuo to give dark yellow oil. The oil
was subjected to Sephadex (LH-20) chromatography with EtOH as
an eluent. The first fraction (1.76 g) contained [34]metacyclophane
and its higher oligomers, whereas the second fraction (0.93 g) con-
tained mainly [32]metacyclophane. Further separation of a sample
(100 mg) of the first fraction by recycle HPLC (GPC, CHCl3) af-
forded tetraaza[34]- and hexaaza[36]metacyclophanes 11 (18 mg,
6%) and 12 (18 mg, 6%). Separation of the second fraction (100 mg)
provided diaza[32]- 10 (60 mg, 11%) and tetraaza[34]azacyclophane
11 (9 mg, 2%, total 8%).
N,N¢-2,6-Bis[(diethoxyphosphoryl)aminomethyl]pyridine (5)
Colorless oil (31%).
1H NMR: d = 1.21 (t, J = 7 Hz, 12 H, OCH2CH3), 3.89–4.04 (m, 8
H, OCH2CH3), 4.13 (d, J = 14 Hz, 4 H, CH2N), 7.16 (d, J = 7 Hz, 2
H, ArH), 7.57 (t, J = 7 Hz, 1 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C15H30N3O6P2: 410.1610;
found: 410.1623 (100).
N,N¢,N¢¢-1,3,5-Tris[(diethoxyphosphoryl)aminomethyl]ben-
zene (6)
Colorless oil (52%).
1H NMR: d = 1.29 (t, J = 7 Hz, 18 H, OCH2CH3), 3.46–3.50 (m, 3
H, NH), 3.97–4.17 (m, 18 H, CH2N and OCH2CH3), 7.33 (s, 3 H,
ArH).
HRMS (FAB, M + H+): m/z calcd for C21H43N3O9P3: 574.2212;
found: 574.2186 (100).
N,N¢-9,10-Bis[(diethoxyphosphoryl)aminomethyl]anthracene
(7)
10
Colorless crystals (54%); mp 214.5–216 °C (CH2Cl2–hexane).
Colorless oil.
1H NMR: d = 1.32 (t, J = 7 Hz, 12 H, OCH2CH3), 2.82–2.95 (m, 2
H, NH), 3.99–4.16 (m, 8 H, OCH2CH3), 5.09 (t, J = 6 Hz, 4 H,
CH2N), 7.57–7.60 (m, 4 H, ArH), 8.39–8.45 (m, 4 H, ArH).
1H NMR: d = 1.41 (t, J = 7 Hz, 12 H, OCH2CH3), 4.15–4.23 (m, 16
H, CH2N and OCH2CH3), 6.91–6.93 (m, 8 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C24H37N2O6P2: 511.2127;
HRMS (FAB, M + H+): m/z calcd for C24H35N2O6P2: 509.1970;
found: 511.2151 (100).
found: 509.1993 (100).
Synthesis 2005, No. 17, 2845–2850 © Thieme Stuttgart · New York

PAPER
Synthesis of Azacyclophanes by Phosphoramidates
2849
11
16
Colorless oil.
Colorless oil.
1H NMR: d = 1.32 (t, J = 7 Hz, 24 H, OCH2CH3), 3.97–4.18 (m, 32
H, CH2N and OCH2CH3), 7.27–7.33 (m, 16 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C48H73N4O12P4: 1021.4175;
1H NMR: d = 1.43 (t, J = 7 Hz, 12 H, OCH2CH3), 4.16–4.24 (m, 8
H, OCH2CH3), 4.47 (d, J = 16 Hz, 8 H, CH2N), 6.98 (d, J = 7 Hz, 4
H, ArH), 7.25(t, J = 7 Hz, 2 H, ArH).
found: 1021.4129 (100).
HRMS (FAB, M+H+): m/z calcd for C22H35N4O6P2: 513.2032;
found: 513.2039 (100).
12
Colorless oil.
17
Colorless oil.
1H NMR: d = 1.29 (t, J = 7 Hz, 36 H, OCH2CH3), 3.98–4.15 (m, 48
H, CH2N and OCH2CH3), 7.16–7.23 (m, 24 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C72H109N6O18P6: 1531.6224;
1H NMR: d = 1.26 (t, J = 7 Hz, 24 H, OCH2CH3), 3.99–4.14 (m, 16
H, OCH2CH3), 4.27 (d, J = 14 Hz, 16 H, CH2N), 7.29 (d, J = 10 Hz,
8 H, ArH), 7.58 (t, J = 10 Hz, 4 H, ArH).
found: 1531.6202 (100).
HRMS (FAB, M + H+): m/z calcd for C44H69N8O12P4: 1025.3985;
N,N¢-Bis(diethoxyphosphoryl)-2,11-diaza[3.3]metacyc-
lo(2,6)pyridinophane (13), N,N¢,N¢¢,N¢¢¢-Tetrakis(diethoxyphos-
phoryl)-2,11,20,29-tetraaza[3.3.3.3]metacyclo(2,6)pyridino
phane (14), and N,N¢,N¢¢,N¢¢¢,N¢¢¢¢,N¢¢¢¢¢-Hexakis(diethoxyphos-
phoryl)-2,11,20,29,38,47-hexaaza[3.3.3.3.3.3]metacyclo(2,6)py-
ridinophane (15)
Method B: A crude product obtained from the amidate 4 (4.08 g,
10.0 mmol) and 2,6-bis(bromomethyl)pyridine (3.45 g, 13.0 mmol)
was subjected to Sephadex (LH-20) chromatography (EtOH). The
first fraction (0.88 g) contained [36]cyclophane and its higher oligo-
mers, and the second fraction (1.69 g) contained lower oligomers.
Each sample (150 mg) of the fraction was further separated by re-
cycle HPLC (GPC, CHCl3) to afford 13, 14, and 15.
found: 1025.4000 (100).
18
Colorless oil.
1H NMR: d = 1.22 (t, J = 7 Hz, 36 H, OCH2CH3), 4.01–4.08 (m, 24
H, OCH2CH3), 4.23 (d, J = 14 Hz, 24 H, CH2N), 7.22 (d, J = 10 Hz,
12 H, ArH), 7.55(t, J = 10 Hz, 6 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C66H103N12O18P6: 1537.5939;
found: 1537.5991 (100).
N,N¢-Bis(diethoxyphosphoryl)-2,7-diaza[8]paracyclophane-4-
yne (19)
Method A (in DMF): A reaction mixture obtained from the amidate
3 (2.04 g, 5.00 mmol) and 2-butyne-1,4-diol ditosylate (2.56 g, 6.49
mmol) was treated as described above to give the crude product
(1.35 g). The crude product was subjected to silica gel column chro-
matography with EtOAc to afford 19 as a colorless oil (206 mg,
9%).
1H NMR: d = 1.28–1.35 (m, 12 H, OCH2CH3), 4.01–4.16 (m, 12 H,
CH2N and OCH2CH3), 4.52 (d, J = 16 Hz, 4 H, CH2N), 7.25–7.30
(m, 4 H, ArH).
13
Colorless oil (72 mg, 16%).
1H NMR: d = 1.41 (t, J = 7 Hz, 12 H, OCH2CH3), 4.14–4.45 (m, 16
H, CH2N and OCH2CH3), 6.89–7.51 (m, 6 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C23H36N3O6P2: 512.2079;
found: 512.2016 (100).
14
HRMS (FAB, M + H+): m/z calcd for C20H32N2O6P2: 459.1814;
found: 459.1782 (100).
Colorless oil (53 mg, 12%).
1H NMR: d = 1.24 (t, J = 7 Hz, 24 H, OCH2CH3), 4.02–4.15 (m, 32
H, CH2N and OCH2CH3), 7.15–7.28 (m, 12 H, ArH).
N,N¢-Bis(diethoxyphosphoryl)-2,11-diaza[3.3]paracy-
clo(9,10)anthracenophane (20)
HRMS (FAB, M + H+): m/z calcd for C46H71N6O12P4: 1023.4081;
found: 1023.4128 (100).
Method A (in dioxane): A reaction mixture obtained from the ami-
date 3 (960 mg, 2.00 mmol) and 9,10-bis(chloromethyl)anthracene
(720 mg, 2.60 mmol) was treated as described above to give the
crude product, which was subjected to silica gel column chromatog-
raphy with CHCl3–EtOAc (1:1) as eluent to afford 21 (506 mg,
41%) as colorless crystals; mp 185.5–187 °C (CH2Cl2–hexane).
1H NMR: d = 1.45 (q, J = 7 Hz, 12 H, OCH2CH3), 4.00 (d, J = 6 Hz,
4 H, CH2N), 4.21–4.37 (m, 8 H, OCH2CH3), 5.41 (d, J = 4 Hz, 4 H,
CH2N), 5.98 (s, 4 H, ArH), 7.55 (m, 4 H, ArH), 8.57 (m, 4 H, ArH).
15
Colorless oil (57 mg, 8%).
1H NMR: d = 1.29 (t, J = 7 Hz, 36 H, OCH2CH3), 3.98–4.15 (m, 48
H, CH2N and OCH2CH3), 7.16–7.23 (m, 18 H, ArH).
HRMS (FAB, M + H+): m/z calcd for C69H106N9O18P6: 1534.6082;
found: 1534.6206 (100).
N,N¢-Bis(diethoxyphosphoryl)-2,11-diaza[3.3](2,6)pyridi-
nophane (16), N,N¢,N¢¢,N¢¢¢-Tetrakis(diethoxyphosphoryl)-
2,11,20,29-tetraaza[3.3.3.3](2,6)pyridinophane (17), and
N,N¢,N¢¢,N¢¢¢,N¢¢¢¢,N¢¢¢¢¢-Hexakis(diethoxyphosphoryl)-
2,11,20,29,38,47-hexaaza[3.3.3.3.3.3](2,6)pyridinophane (18)
Method A (in dioxane): A reaction mixture obtained from the ami-
date 5 (2.05 g, 5.00 mmol) and 2,6-bis(bromomethyl)pyridine (1.35
g, 5.10 mmol) was treated as described above and the resultant mix-
ture was separated by silica gel column chromatography with
CH2Cl2–EtOAc (1:1), followed by preparative silica gel TLC
(CH2Cl2–EtOAc, 1:1) to afford 16 (1.08 g, 42%), 17 (128 mg, 5%),
and 18 (77 mg, 3%).
HRMS (FAB, M + H+): m/z calcd for C32H41N2O6P2: 611.2440;
found: 611.2345 (100).
2,11-Diaza[3.3]metacyclophane (22)
Compound 10 (102 mg, 0.200 mmol) was added to 15% HBr/AcOH
(10 mL) and the mixture was stirred for 2 h at r.t. The resultant so-
lution was poured into H2O (100 mL) and made alkaline with aq
NaOH. The solution was extracted with CH2Cl2 (3 × 30 mL). The
extracts were combined and dried (MgSO4). Removal of the solvent
yielded a colorless powder which was almost pure 22 (47 mg, 99%).
All the spectral data were identical with an authentic sample of the
2,11-diaza[3.3]metacyclophane.
Synthesis 2005, No. 17, 2845–2850 © Thieme Stuttgart · New York

2850
H. Takemura et al.
PAPER
(3) (a) Zwierzak, A. Synthesis 1975, 507. (b) Zwierzak, A.
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Synthesis 2005, No. 17, 2845–2850 © Thieme Stuttgart · New York