A convenient synthesis of trifluoroacetamide derivatives of diaza[3 2]cyclophanes and triaza[33]cyclophanes

Article abstract of DOI:10.1055/s-2007-1000825

The diaza[3₂]cyclophane skeleton has been constructed by the bis-N-alkylation of 1,4-bis[(4-nitrophenylsulfonylamino)methyl]benzene with 1,4-bis(halomethyl)benzene in the presence of sodium hydride. The 4-nitrophenylsulfonyl (Ns) amides in the bridge chains of the cyclophane were effectively deprotected by sodium ethanethiolate and the resulting free amine moieties were reprotected as the trifluoroacetamide under mild conditions to afford 3,7-bis(trifluoroacetyl)-3,7-diaza-1,5(1,4)-dibenzenacyclooctaphane in 26% overall yield. This Ns-amide method has also been applied for the preparation of a higher homologue, the trifluoroacetamide derivative of triaza[3₃]cyclophane, 3,5,7-tris(trifluoroacetyl)-3,7,10-triaza-1, 5(1,3,5)-dibenzenabicyclo[3.3.3]undecaphane, in 18% overall yield. Thus, the present procedure provides a convenient synthetic route to azacyclophane derivatives possessing trifluoroacetamide groups in the bridge chains. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000825

PAPER
39
A Convenient Synthesis of Trifluoroacetamide Derivatives of
Diaza[32]cyclophanes and Triaza[33]cyclophanes
A
Convenient
S
yn
i
thesis
o
d
f
Azacyclop
e
hanes ki Okamoto,*a Hiroyuki Takemura,b Kyosuke Satakea
a
Division of Chemistry and Biochemistry, The Graduate School of Natural Science and Technology, Okayama University,
Tsushima-Naka 3-1-1, Okayama 700-7530, Japan
E-mail: hokamoto@cc.okayama-u.ac.jp
Department of Chemistry and Biological Science, Japan Women’s University, Tokyo 112-8681, Japan
b
Received 22 August 2007; revised 10 October 2007
R = COCF3, PO(OEt)2; path b, R = CN) resulted in the
formation of higher oligomers 4 rather than the desired di-
aza[32]cyclophane 3.5,7–11 The Ts-amide methods are thus
effective for preparing the Ts-amide derivative of di-
Abstract: The diaza[32]cyclophane skeleton has been constructed
by the bis-N-alkylation of 1,4-bis[(4-nitrophenylsulfonylami-
no)methyl]benzene with 1,4-bis(halomethyl)benzene in the pres-
ence of sodium hydride. The 4-nitrophenylsulfonyl (Ns) amides in
the bridge chains of the cyclophane were effectively deprotected by aza[32]cyclophane. However, absorption of the aromatic
sodium ethanethiolate and the resulting free amine moieties were
Ts-amide chromophores overlaps with that of the di-
reprotected as the trifluoroacetamide under mild conditions to af-
aza[32]cyclophane chromophore thus preventing evalua-
ford 3,7-bis(trifluoroacetyl)-3,7-diaza-1,5(1,4)-dibenzenacyclooc-
tion of the photoproperties of the aza[32]cyclophane
taphane in 26% overall yield. This Ns-amide method has also been
system. Additionally, deprotection of the Ts-amide moi-
applied for the preparation of a higher homologue, the trifluoro-
eties required severe conditions, such as Birch reduction
conditions or a highly acidic medium.7,10 Thus, a simple
synthetic route is needed for the construction of an azacy-
clophane possessing bridge nitrogen substituents that dis-
play no absorption band in the absorption region of the
azacyclophane chromophore (>250 nm).
acetamide derivative of triaza[33]cyclophane, 3,5,7-tris(trifluoro-
acetyl)-3,7,10-triaza-1,5(1,3,5)-dibenzenabicyclo[3.3.3]undeca-
phane, in 18% overall yield. Thus, the present procedure provides a
convenient synthetic route to azacyclophane derivatives possessing
trifluoroacetamide groups in the bridge chains.
Key words: cyclophanes, sulfonamides, amides, chromophores,
amines
We now describe the convenient synthesis of the title ni-
trogen-bridged cyclophanes 11 and 15. In the present pro-
cedure, 4-nitrobenzenesulfonamide (Ns-amide) was used
as the activating group (cf., Scheme 1, path a). The Ns-
amide method was developed by Fukuyama and was used
for the synthesis of a variety of functionalized amines,12
Cyclophanes possessing nitrogen atoms in their bridge
chains have been of photochemical interest because they
sometimes display different reactions than those of the
corresponding carbon-bridged analogues or nonbridged
chromophores.1–4 We have recently disclosed that di-
aza[32]cyclophane 11 afforded an interesting octahedrane
cage upon photoirradiation, while the corresponding car-
bon-bridged analogue, [32]cyclophane, was almost inert
under the same conditions.2 Thus, it would be interesting
to reveal the details of the unique photoproperties of the
diazacyclophane system. Although the diaza[32]cyclo-
phane 11 has been prepared by Shinmyozu et al.,5 the
yield was quite low.6 Thus, it is highly desirable to estab-
lish an efficient synthetic route to the azacyclophane sys-
tem.
Ar
Ar
RN
H
NR
H
Br
Br
+
+
+
2
1
Ar =
(a)
R = Ts, COCF3, PO(OEt)2
Ar
RN
Ar
RN
NR
NR
Ar
RN
NR
Ar
Conventionally, there are two methodologies for the con-
struction of diaza[32]cyclophane as shown in Scheme 1;
(i) cyclization of amide-activated diamine 1 and xylylene
dihalide 2 (path a)5,7,8 and (ii) coupling of 4-toluene-
sulfonamide (Ts-amide) or cyanamide 5 with xylylene di-
halide 2 (path b).9–11 Among these procedures, the Ts-
amide methods (Scheme 1, path a, R = Ts; path b, R = Ts)
have been used as practical routes to the diaza[32]cyclo-
phane skeleton 3,7,10 while the others (Scheme 1, path a,
Ar
3
Ar
n
4 (n = 1, 3)
Ar =
R = Ts, CN
(b)
Ar
RNH2
Br
Br
5
2
SYNTHESIS 2008, No. 1, pp 0039–0044
x
x
.
x
x
.2
0
0
7
Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-1000825; Art ID: F15307SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

40
H. Okamoto et al.
PAPER
however, it has rarely been used for the construction of (Scheme 2). These new Ns-amides were characterized by
azacyclophanes. The Ns-amide method would be promis- their 1H NMR and IR spectra as well as elemental analy-
ing for the synthesis of the azacyclophane skeletons be- ses.
cause (i) the electronic structure of the Ns-amide is similar
The synthetic route to the diaza[32]cyclophane skeleton
using the bis-Ns-amide 6 is shown in Scheme 3. Ns-
amide 6 was treated with sodium hydride in N,N-dimeth-
ylformamide to generate the corresponding bis-amidate
to that of the Ts-amide, thus, effective formation of the di-
aza[32]cyclophane skeleton is expected,7 and (ii) func-
tional group conversion is easy since the Ns group can be
removed by a thiolate reagent.12
anion. The bis-amidate anion and 1,4-bis(chlorometh-
The doubly and triply armed Ns-amides 6 and 7, as pre- yl)benzene (8) were coupled under high-dilution condi-
cursors for the azacyclophanes 11 and 15, were readily tions at 70 °C to afford the desired dimeric adduct 9 as
prepared by the reaction of 1,4-bis- and 1,3,5-tris(ami- well as tetramer 10. As the solubility of these Ns-amides
nomethyl)benzenes, respectively, with 4-nitrobenzene- 9 and 10 in common organic solvents was quite poor, they
sulfonyl chloride (NsCl) under the usual conditions12 were characterized by 1H NMR spectroscopy and used in
the following reaction without separation: Ns-amides 9
and 10 displayed 1H NMR spectral patterns that were sim-
NsCl
ilar to those of the corresponding Ts-amide deriva-
NsN
NNs
H2N
NH2
Et3N
tives.7b,10
H
H
CH2Cl2
6
Removal of the Ns groups and reprotection by trifluoro-
acetylation were accomplished through the following suc-
cessive reaction sequence. The mixture of Ns-amides 9
and 10 was treated with sodium ethanethiolate at 50 °C,13
then the resulting bridge amine moieties were acetylated
with trifluoroacetic anhydride to afford the corresponding
trifluoroacetamides, 11 and 12. These azacyclophanes
were successfully isolated by silica gel chromatography
and the overall yields were 26% for 11 and 5% for 12.
Their physical data were identical to those already report-
ed.5 In the present reaction, no higher oligomer, such as a
hexamer (cf., Scheme 1, 4, n = 3)5,7–10 was obtained. As
previously discussed, direct coupling of 1,4-bis[(trifluoro-
acetylamino)methyl]benzene with 1,4-bis(bromometh-
(45%)
H2N
H NNs
NsCl
Et3N
H
NNs
H2N
NsN
CH2Cl2
NH2
H
7
(72%)
O
S
Ns =
NO2
O
Scheme 2
Ns
Ns
NaH
N
N
NsN
NNs
H
6
8
H
Ns
N
N
Ns
+
DMF
70 °C
N
N
9
Ns
Ns
Cl
Cl
10
1) EtSNa
DMSO
50 °C
2) TFAA, Et3N
dioxane
r.t.
F3COC
COCF3
N
N
N
F3COC
N
N
COCF3
+
N
11
(26% overall)
F3COC
COCF3
12
(5% overall)
Scheme 3
Synthesis 2008, No. 1, 39–44 © Thieme Stuttgart · New York

PAPER
A Convenient Synthesis of Azacyclophanes
41
yl)benzene afforded the tetramer 12 as the main product Concerning triaza[33]cyclophane synthesis, Vögtle re-
and the dimeric cyclophane 11 was only a minor product ported that coupling of 1,3,5-tris[(tosylamino)meth-
(Scheme 1, path a).5,6 Thus, the present procedure pro- yl]benzene with tribromide 13 produced a Ts-amide
vides a practical route to the diaza[32]cyclophane 11.
derivative of triaza[33]cyclophane,14 and one of the
present authors has reported that reaction of cyanamide 5
(R = CN) and tribromide 13 afforded an N-cyano deriva-
tive of triaza[33]cyclophane.11
The trifluoroacetamide possesses advantages over the
conventional Ts-amides; (i) facile functional group con-
version on the bridge nitrogen atoms is possible as previ-
ously shown,3,5 (ii) the absorption band of the The bridge functional group transformation was investi-
trifluoroacetamide does not overlap with that of the aza- gated as in the case of diaza[32]cyclophane 9. The bridge
cyclophane system, thus the unique photochemical prop- Ns-amide was converted into its trifluoroacetamide by
erties of the azacyclophane chromophore2 can be successive treatment of the Ns-amide 14 with sodium
investigated.
ethanethiolate and trifluoroacetic anhydride to afford tri-
fluoroacetamide 15.13 The resulting triaza[33]cyclophane
15 was characterized by spectroscopic and elemental
analyses.
The present Ns-amide method was applied for preparation
of a higher-bridged cyclophane system, triaza[33]cyclo-
phane 15 (Scheme 4). Tris-Ns-amide 7 and tribromide 13
were coupled under similar conditions as in the case of di- The structural features of the azacyclophanes, 11 and 15,
azacyclophane 9. A triply bridged cyclophane skeleton 14 were investigated by 1H and 19F NMR spectroscopy. The
was obtained in an unexpectedly high yield (65%). The aromatic protons of diazacyclophane 11 appeared as a pair
tris-Ns-amide 14 was isolated from the reaction mixture of singlets at d = 6.74 and 6.82, and a pair of doublet sig-
as a 3:2 complex of 14 and N,N-dimethylformamide (the nals at d = 6.73 and 6.84 (at 21.8 °C, DMSO-d6). Since the
ratio was determined by 1H NMR spectroscopy). An N,N- activation energy for a ring flipping motion is much lower
dimethylformamide-free analytical sample of 14 was ob- than that for the amide rotation,1,15–17 two rotamers are
tained by recrystallization from a mixed solvent of di- considered at ambient temperature due to the restricted ro-
methyl sulfoxide–ethanol.
tation of the amide moieties (Figure 1). Thus, the syn, C2v
isomer of 11 displayed the two singlet signals while the
H
NNs
NaH
H
NsN
F3COC
Ns
Ns
NNs
1) EtSNa
DMSO
30 °C
H
N
N
7
N
Ns
N
COCF3
DMF
70 °C
2) TFAA, Et3N
dioxane
r.t.
Br
N
N
F3COC
14
(65%)
15
(28%)
Br
Br
13
Scheme 4
F3C
CF3
O
O
CF3
N
N
N
N
O
F3C
O
11-C2v
11-C2h
F3C
F3C
N
N
O
CF3
O
O
O
N
N
CF3
N
N
F3C
F3C
O
O
15-C3v
15-Cs
Figure 1
Synthesis 2008, No. 1, 39–44 © Thieme Stuttgart · New York

42
H. Okamoto et al.
PAPER
anti, C2h symmetrical one showed two doublets in the ar- ties of the azacyclophanes 11 and 15 are underway.
omatic region. These 1H NMR spectral features are con- Furthermore, the present azacyclophanes 11 and 15 would
sistent with those already reported.5 At 85 °C, the be promising platforms for construction of a highly func-
aromatic signals coalesced to show a single peak at d = tionalized azacyclophane system since the bridge substit-
6.80.
uents can be easily modified using various kinds of
functional groups.3,5
In the 19F NMR spectrum of the diazacyclophane 11, two
signals assigned to the trifluoroacetyl groups were ob-
served at d = –67.59 and –67.47 (Figure 2a). These obser-
vations are consistent with the coexistence of the two
rotamers.
All melting points were uncorrected. 1H NMR spectra were collect-
ed with Varian Mercury 300 (300 MHz), XVR-500 (500 MHz) or
Inova AS600 (600 MHz) spectrometers. 19F NMR spectra (564
MHz) were measured using C6F6 (d = –162.9) as an internal stan-
dard. IR spectra were measured with Jasco FT-IR 5000 spectropho-
tometer. Silica gel chromatography was performed using silica gel
60 (63–230 mm). The preparative liquid chromatography was car-
ried out using silica gel 60 (40–60 mm, Wakogel LP-60).
1,4-Bis[(4-nitrophenylsulfonylamino)methyl]benzene (6)
To a mixture of 1,4-bis(aminomethyl)benzene (0.75 g, 5.5 mmol)
and Et3N (0.56 g, 5.5 mmol) in CH2Cl2 (20 mL) was dropwise added
a soln of NsCl (2.22 g, 10 mmol) in CH2Cl2 (10 mL) at 0 °C. The
mixture was stirred at 0 °C for 30 min. The precipitate formed was
collected, washed with CHCl3, then recrystallized (MeCN) to afford
6 (1.28 g, 45%) as off-white plates; mp 235–236 °C.
IR (KBr): 1154, 1309, 1352, 1539, 3270 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.99 (d, J = 6.2 Hz, 4 H,
CH2Ar), 7.11 (s, 4 H, ArH), 7.99 (m, 4 H, Ns), 8.37 (m, 4 H, Ns),
8.51 (t, J = 6.2 Hz, 2 H, NH).
Figure 2 19F NMR spectra of (a) diazacyclophane 11 and (b) triaza-
cyclophane 15 (564 MHz, CDCl3).
Anal. Calcd for C20H18N4O8S2: C, 47.43; H, 3.58; N, 11.06. Found:
C, 47.52; H, 3.53; N, 10.71.
For the structure of triazacyclophane 15, two C3v- and Cs-
symmetrical rotamers are also possible as depicted in
Figure 1. Actually, in the 1H NMR spectrum, triazacyclo-
1,3,5-Tris[(4-nitrophenylsulfonylamino)methyl]benzene (7)
To a soln of 1,3,5-tris(aminomethyl)benzene18 (6.68 g, 40.4 mmol)
and Et3N (11.65g, 115.2 mmol) in CH2Cl2 (200 mL) was dropwise
phane 15 displayed complex signals of aromatic protons added a soln of NsCl (25.5 g, 115.2 mmol) in CH2Cl2 (100 mL) at 0
°C. The mixture was stirred at 0 °C for 30 min. The precipitated salt
was filtered off and the filtrate was concentrated under reduced
at ambient temperature, d = 6.67–6.88 (DMSO-d6), due to
the restricted rotation of the three amide moieties. At ele-
pressure. The residue was washed with H2O and dried. The crude
vated temperature (95 °C), these signals coalesced into a
product was recrystallized (THF–EtOH) to afford 7 (20.18 g, 72%)
single peak at d = 6.81 as expected for [33]cyclophane
as pale yellow crystals; mp 225–226 °C.
IR (KBr): 1164, 1311, 1350, 1528, 3308 cm–1.
skeleton.14,17 For the two rotamers, three non-equivalent
trifluoroacetyl groups are expected (Figure 1). In the 19F
1H NMR (300 MHz, DMSO-d6): d = 3.88 (d, J = 6.3 Hz, 6 H,
NMR spectrum, triazacyclophane 15 displayed three sig-
CH2Ar), 6.91 (s, 3 H, ArH), 7.97 (m, 6 H, Ns), 8.35 (m, 6 H, Ns),
nals at d = –67.31, –67.30, and –67.28 as shown in
8.50 (t, J = 6.3 Hz, 3 H, NH).
Figure 2b that supported the coexistence of these rota-
Anal. Calcd for C27H24N6O12S3: C, 45.00; H, 3.36; N, 11.44. Found:
mers.
C, 45.19; H, 3.40; N: 11.44.
In summary, the present Ns-amide coupling method pro-
vides a convenient route to nitrogen-bridged [32]- and 3,7-Bis(trifluoroacetyl)-3,7-diaza-1,5(1,4)-dibenzenacyclo-
octaphane (11)
[33]cyclophane skeletons (Schemes 3 and 4). The Ns-pro-
tecting groups on the bridge nitrogen atoms can be re-
moved by the reaction of the Ns-amides, 9 and 14, with
sodium ethanethiolate under the mild conditions, and the
resulting free-amine bridges are reprotected by a common
procedure, e.g., trifluoroacetylation by trifluoroacetic an-
hydride, thus the azacyclophanes 11 and 15 are obtained
in reasonable overall yields (11: 26%, 15: 18%).
To a soln of bis-Ns-amide 6 (2.53 g, 5.0 mmol) in DMF (100 mL)
was added NaH (60% in mineral oil, 440 mg, 11 mmol), and the
mixture was stirred at r.t. for 2 h. The resulting dark red soln and a
soln of 1,4-bis(chloromethyl)benzene (8, 876 mg, 5 mmol) in DMF
(100 mL) were added dropwise to DMF (240 mL) at 70 °C over a
period of 4 h. The soln was then stirred overnight at 70 °C. The mix-
ture was cooled to r.t. and the precipitate formed was collected by
suction filtration (fraction A, 1.39 g). The filtrate was concentrated
to ca. 100 mL under reduced pressure and the precipitated products
were collected (fraction B, 1.03 g). Fraction A mainly contained 9
and fraction B was a mixture of 9, 10, and unidentified materials.
The trifluoroacetamide bridge chains satisfy the demands
for our investigations; (i) no absorption of the trifluoroac-
etamide function in the wavelength region >250 nm and
(ii) facile functional group conversion on the bridge nitro-
gen atoms. Currently, investigations on the photoproper-
9
1H NMR (300 MHz, DMSO-d6): d = 4.39 (br, 8 H, CH2Ar), 6.89 (s,
8 H, Ar), 8.23 (m, 4 H, Ns), 8.46 (m, 4 H, Ns).
Synthesis 2008, No. 1, 39–44 © Thieme Stuttgart · New York

PAPER
A Convenient Synthesis of Azacyclophanes
43
10
preparative liquid chromatography (silica gel, hexane–EtOAc, 1:1)
to afford 15 (352 mg, 28%); mp 247–247.5 °C.
IR (KBr): 1135, 1680 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.05 (br, 16 H, CH2), 6.82 (s,
16 H), 8.07 (m, 8 H, Ns), 8.37 (m, 8H, Ns).
Fraction A was suspended in DMSO (20 mL) and a soln of EtSNa
(1.16 g, 13.8 mmol) in DMSO (15 mL) was slowly added at 50 °C.
The resulting dark-red soln was stirred for a further 30 min at 50 °C.
The mixture was poured into brine (200 mL) and extracted with
CHCl3 (4 × 40 mL). The combined extracts were washed with H2O,
dried (anhyd Na2SO4), and concentrated under reduced pressure.
The residue was dissolved in dioxane (15 mL) and Et3N (892 mg,
9.16 mmol) was added. To the soln was added a soln of TFAA (1.91
g, 9.16 mmol) in dioxane (5 mL). The mixture was stirred at r.t. for
30 min. The solvent was evaporated under reduced pressure and the
residue was chromatographed (silica gel, CHCl3). The crude prod-
uct was separated by preparative liquid chromatography (silica gel,
hexane–EtOAc, 1:1) to afford the trifluoroacetamide derivative 11
(523 mg).
1H NMR (600 MHz, CDCl3): d = 4.74 (br, 6 H, CH2Ar), 4.85 (br, 6
H, CH2Ar), 6.64–6.78 (6 H, ArH).
19F NMR (564 MHz, CDCl3): d = –67.31, –67.30, –67.28.
MS (FAB): m/z = 568 [M + H]+.
Anal. Calcd for C24H18F9N3O3: C, 50.80; H, 3.20; N, 7.41. Found:
C, 50.52; H, 3.13; N: 7.29.
Acknowledgment
The authors are grateful to the SC-NMR Laboratory of Okayama
University for the NMR spectral measurements. H. Okamoto thanks
Professor Teruo Shinmyozu (IMCE, Kyushu University) for his ac-
tive discussions and the gift of 1,3,5-tris(bromomethyl)benzene.
Fraction B was successively treated with EtSNa (850 mg, 10.1
mmol) in DMSO and TFAA (1.41 g, 6.74 mmol) in dioxane as de-
scribed for fraction A. By the repeated chromatographic separation
as stated above, diazacyclophane 11 (20 mg) and tetramer 12 (108
mg) were isolated. The total yields of the azacyclophanes, 11 and
12, were thus 543 mg (26%) and 108 mg (5%), respectively.
References
(1) (a) Okamoto, H.; Yamaji, M.; Satake, K.; Tobita, S.;
Kimura, M. J. Org. Chem. 2004, 69, 7860. (b) Okamoto,
H.; Kimura, M. In New Trends in Structural Organic
Chemistry; Takemura, H., Ed.; Research Signpost: Kerala
India, 2005, 105.
11
Mp 212–213 °C (Lit.5 211–213 °C).
(2) Okamoto, H.; Satake, K.; Ishida, H.; Kimura, M. J. Am.
Chem. Soc. 2006, 128, 16508.
12
Mp 237–238 °C (Lit.5 238–239 °C).
(3) (a) Usui, M.; Nishiwaki, T.; Anda, K.; Hida, M. Nippon
Kagaku Kaishi 1988, 1052. (b) Usui, M.; Nishiwaki, T.;
Anda, K.; Hida, M. Nippon Kagaku Kaishi 1989, 237.
(4) Okamoto, H.; Satake, K.; Kimura, M. Chem. Lett. 1997, 873.
(5) Shinmyozu, T.; Shibakawa, N.; Sugimoto, K.; Sakane, H.;
Takemura, H.; Sako, K.; Inazu, T. Synthesis 1993, 1257.
(6) Shinmyozu et al. has reported that, according to the method
shown in Scheme 1, path a, (R = COCF3), the
The 1H NMR data were identical to those already reported.5
3,5,7-Tris(4-nitrophenylsulfonyl)-3,7,10-triaza-1,5(1,3,5)-
dibenzenabicyclo[3.3.3]undecaphane (14)
A mixture of tris-Ns-amide 7 (3.60 g, 5 mmol) and NaH (60% in
mineral oil, 660 mg, 16.5 mmol) in DMF (200 mL) was stirred at
r.t. for 2 h. The resulting dark-red soln and a soln of 1,3,5-tris(bro-
momethyl)benzene (13, 3.57 g, 10 mmol) in DMF (200 mL) were
added dropwise to DMF (200 mL) at 70 °C over a period of 4 h. The
resulting soln was stirred overnight at 70 °C. The soln was concen-
trated to ca. 40 mL, and the precipitate formed was collected and
successively washed with DMF, H2O, and EtOH, then dried under
reduced pressure to afford Ns-amide 14 (2.90 g, 65% as 3:2 com-
plex of 14–DMF). A DMF-free analytical sample was obtained by
recrystallization (DMSO–EtOH) as off-white fine crystals; mp
>300 °C.
diaza[32]cyclophane 11 was prepared and isolated as its
N-methyl derivative in 0.5% overall yield after removal of
the trifluoroacetyl groups followed by methylation on the
bridge nitrogen atoms.5 Our own examination according to
their method [Scheme 1, path a (R = COCF3)] resulted in a
3% yield of diazacyclophane 11.
(7) (a) Usui, M.; Nishiwaki, T.; Anda, K.; Hida, M. Chem. Lett.
1984, 1561. (b) Bottino, F.; Grazia, M. D.; Finocchiaro, P.;
Fronczek, F. R.; Mamo, A.; Pappalardo, S. J. Org. Chem.
1988, 53, 3521.
IR (KBr): 1170, 1350, 1524, 3308 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 4.44 (br, 12 H, CH2Ar), 6.90
(s, 6 H, ArH), 8.22 (m, 6 H, Ns), 8.46 (m, 6 H, Ns).
(8) Takemura, H.; Wen, G.; Shinmyozu, T. Synthesis 2005,
2845.
(9) (a) Takemura, H.; Shinmyozu, T.; Inazu, T. Coord. Chem.
Rev. 1996, 156, 183. (b) Takemura, H.; Wen, G.;
Shinmyozu, T. In New Trends in Structural Organic
Chemistry; Takemura, H., Ed.; Research Signpost: Kerala
India, 2005, 125.
(10) Takemura, H.; Suenaga, M.; Sakai, K.; Kawachi, H.;
Shinmyozu, T.; Miyahara, Y.; Inazu, T. J. Inclusion
Phenom. 1984, 2, 207.
Anal. Calcd for C36H30N6O12S3: C, 51.79; H, 3.62; N, 10.07. Found:
C, 51.49; H, 3.57; N, 9.84.
3,5,7-Tris(trifluoroacetyl)-3,7,10-triaza-1,5(1,3,5)-dibenzenabi-
cyclo[3.3.3]undecaphane (15)
To a suspension of the Ns-amide 14 (3:2 complex of 14-DMF, 1.77
g, 2.0 mmol) in DMSO (20 mL) was dropwise added a soln of EtS-
Na (1.52 g, 18 mmol) in DMSO (20 mL). The mixture was stirred
at 30 °C for 14 h. The resulting dark-red soln was poured into brine
(200 mL) and extracted with CHCl3 (4 × 50 mL). The combined ex-
tracts were washed with H2O, dried (anhyd Na2SO4), and concen-
trated under reduced pressure. The residue was dissolved in dioxane
(20 mL), and Et3N (0.95 g, 12 mmol) was added. To the soln was
dropwise added a soln of TFAA (2.52 g, 12 mmol) in dioxane (5
mL) at 0 °C. The mixture was then stirred at r.t. for 30 min. The sol-
vent was removed under reduced pressure, and the residue was sep-
arated by chromatography (silica gel, CHCl3) followed by
(11) Wen, G.; Matsunaga, M.; Matsunaga, T.; Takemura, H.;
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(13) In the originally reported Ns-amide strategy, PhSH–K2CO3
or HSCH2CO2H–LiOH mixtures were used as the typical
deprotection reagents of Ns group, and aprotic solvents, e.g.
Synthesis 2008, No. 1, 39–44 © Thieme Stuttgart · New York

44
H. Okamoto et al.
PAPER
(14) (a) Vögtle, F.; Neumann, P. J. Chem. Soc. D 1970, 1464.
(b) Schwierz, H.; Vögtle, F. Synthesis 1999, 295.
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MeCN or DMF, were used.12 In the present study, EtSNa
was used for the deprotection of the cyclophanes 9 and 14
because this reagent is commercially available as a
convenient thiolate source. Additionally, the bridge Ns
amide parts are sterically hindered, we considered that
primary alkyl thiolate would serve as an effective
deprotection agent in the present case. As for the solvent
employed in this work, the solubility of the Ns-protected
cyclophanes 9 and 14 in the originally reported solvents was
poor, thus, we selected DMSO in which Ns amides 9 and 14
were slightly soluble and the deprotection proceeded
successfully.
Synthesis 2008, No. 1, 39–44 © Thieme Stuttgart · New York