Total synthesis of saturated and unsaturated di-trans-N-substituted cyclam-based macrocycles through a versatile intermediate

Article abstract of DOI:10.1016/S0040-4020(00)00382-3

A total synthesis of di-trans-N-substituted cyclam-type macrocycles through a versatile intermediate is described for the first time. This synthesis uses readily available low-cost commercial reagents. This synthesis was designed in such a way that the pr

Full text of DOI:10.1016/S0040-4020(00)00382-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4759±4764
Total Synthesis of Saturated and Unsaturated
di-trans-N-substituted Cyclam-based Macrocycles Through a
Versatile Intermediate
*
M. Teresa Barros and Fernando Sineriz
Ä
à Â
Faculdade de Ciencias e Tecnologia da Universidade Nova de Lisboa, Departamento de Quõmica, 2825-114 Monte de Caparica, Portugal
Received 22 February 2000; accepted 8 May 2000
AbstractÐA total synthesis of di-trans-N-substituted cyclam-type macrocycles through a versatile intermediate is described for the ®rst
time. This synthesis uses readily available low-cost commercial reagents. This synthesis was designed in such a way that the products and
some intermediates could be selectively deprotected providing versatility both during the synthesis and for the utility of the ®nal product.
Thus, it should be possible to form cryptand molecules with trans bridges with good selectivity. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
necessary. Indeed, most of the reported syntheses of such
compounds consist of the direct derivatisation of the non-
protected macrocyclic molecule.6,7 This approach has
normally led to mixtures of isomers with low yields. For
the above reasons we were stimulated to develop a
protocol for the preparation of di-trans-N-substituted
Polyazamacrocycles are well known1 to form stable
complexes with transition elements and heavy metal ions.
The applications of these chelating ligands have been
developed rapidly in areas such as chemistry and bio-
chemistry:2±5 analogous of enzymes, catalysis, puri®cation
of waste waters, radiochemical agents, selective coordina-
tion of dioxygen from air or potent inhibitors of HIV. The
number and nature of the N-substituents can increase the
selectivity for metal sequestration as well as the stability
of the formed complexes. Numerous methods for the
synthesis of poly-N-functionalized macrocycles have been
described in literature6±12 and normally for their inter-
esting applications in the coordinating properties as
cryptands or cyclophanes.2,13±17 trans-Disubstituted
macrocycles have been studied far less due to dif®culties
encountered in their preparation. This stems from their
lack of symmetry which means that a stepwise strategy is
macrocycles, via a total synthesis, using relatively
inexpensive reagents.
Our strategy for the synthesis of these cyclam-based
compounds consisted in the systematic addition of arms to
built a convenient open chain and a ®nal cyclisation step to
obtain the macrocycle. The advantages of this method are an
easy functionalization of the trans-N atoms by using two
different kinds of protecting groups and the possibility of
synthesizing saturated or unsaturated macrocycles. These
further ring systems give a rigidity to the overall cycle
which in¯uences the properties when interacting with
anions.16,17
Scheme 1.
Keywords: aza compounds; macrocycles; asymmetry; cyclisation.
* Corresponding author. Fax: 1351-212-948-550; e-mail: mtbarros@dq.fct.unl.pt
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00382-3

4760
M. T. Barros, F. SinÄeriz / Tetrahedron 56 (2000) 4759±4764
Scheme 2. (a) TsCl, benzene, 74%; (b) acrylonitrile, 93%; (c) (Boc)2O, Net3, 95%; (d) NaH, DMF, 87%.
Scheme 3. (a) CoCl2, NaBH4, methanol, 87%; (b) TsCl, pyridine, 80%; (c) CF3COOH, 99%.
We report here the complete synthesis of two different
trans-N-substituted azamacrocycles 1 and 2 (Scheme 1),
obtained in 2 steps from the same precursor, namely 1,8-
N,N0-bistosyl-1,5,8,12-tetraazadodecane 12. The synthesis
of this versatile intermediary 12 was accomplished in
seven steps.
between 6a±c and 8a±c respectively have compelled us
to choose the double protected Boc-compound 9 for carry-
1
ing on our synthetic route. The H NMR spectrum of 9
displays the presence of the protective groups, namely
tert-butoxycarbonyl (two singlets at 1.44 and 1.47 ppm)
and tosyl (four aromatic protons). A broad signal at
4.90 ppm, which disappeared after addition of D2O, proved
the presence of one acidic proton that we have attributed to
the amino group N-8. The characteristic band at 3387 cm21
in its IR spectrum con®rms this function. As further con-
®rmation of the proposed structure we have attributed the
signal at 118 ppm in the 13C NMR spectrum to the carbon
atom of the nitrile group and the band at 2245 cm21 in the IR
spectrum to the CN stretching vibration.
Results and Discussion
From the readily available diamine 3 (Scheme 2) we have
prepared the monotosylated compound 4 as described by
Kirsanov,18 increasing the yield to 74% by a modi®cation
of the puri®cation method. A conjugated addition of 4 to
acrylonitrile in acetonitrile led to the derivative 5, with a
very good yield (93%).
Attempted LiAlH4 reduction of 9 led to complete degrada-
tion and the formation of an intractable mixture. We have
achieved (Scheme 3) the desired reduction of the nitrile
function to a primary amine by using NaBH4 and CoCl2.19
A selective tosylation then furnished the tetra-N-substituted
compound 11, from which the N-Boc protective groups have
been easily removed under acidic conditions affording 12
(nearly quantitative yield). The fact that the amine functions
N-5 and N-12 of the so formed compound 12 could be
protected with different groups, leading to various di-
trans-N-substituted macrocycles after cyclisation, make it
a very important and versatile intermediate.
Our synthetic strategy required the condensation of a third
arm with the tosylated amine function just obtained 5. This
made necessary a selective protection of the secondary
amine function. For this purpose we have tried three protect-
ing groups, namely tert-butoxycarbonyl, o-nitrobenzene-
sulfonyl and benzoyl, leading to the compounds 6a±c in
²
95, 50 and 83% yields, respectively. Unfortunately, the
direct condensation with the commercial hydrochloride
amine 7 did not work and we recovered, in each case, the
starting material. Therefore, we protected 7 with the same
groups and obtained the three derivatives 8a±c in 95, 72 and
93% yields, respectively. The results (yield, ease of puri®-
cation and stability of the products) of the condensation
Synthetic applications of 12 may be realized in many ways.
For example, an activation of the amino groups (Scheme 4)
with the tri¯uoromethanesulfonyl or o-nitrobenzenesulfonyl
derivatives, leading to 13 and 14 in 70 and 74% yields,
respectively, followed by a cyclisation with dibromoethane
or a,a0-dibromo-m-xylene in presence of K2CO3, according
²
We noticed, in the NMR spectra (1H and 13C NMR) of some of these
compounds, the presence of rotational conformers.

M. T. Barros, F. SinÄeriz / Tetrahedron 56 (2000) 4759±4764
4761
under ef®cient stirring, tosyl chloride (38.13 g, 0.20 mol)
dissolved in benzene (150 mL). The mixture was stirred
for an additional 3 h. The white precipitated that appeared
was ®ltered and treated with 1 M aqueous hydrochloric acid
(100 mL). The remaining solid was ®ltered off and the
®ltrate was treated with NaOH until the appearance of
white needles of the desired product 4 which was ®ltrated
and dried (31.71 g, 74%). mp: 127±1288C (lit: 121±
1238C)18. 1H NMR d 2.42 (s, 3H, CH3 (Ts)), 2.79 (t,
Jˆ5.5 Hz, 2H, CH2±NH2), 2.80 (bs, 2H, NH2), 2.95 (t,
Jˆ5.5 Hz, 2H, CH2±NHTs), 7.30 (d, Jˆ7.7 Hz, 2H, C6H4
(Ts)), 7.75 (d, Jˆ7.7 Hz, 2H, C6H4 (Ts)). 13C NMR d 21.30
(CH3 (Ts)), 40.64 (CH2±NH2), 45.21 (CH2±NHTs), 126.90,
129.60, 136.80, 143.28 (C6H4 (Ts)). FT-IR (KBr): 3359
(NH2), 3297 (NH), 1147 (SO2). Anal. Calcd for
C9H14N2O2S (214.28): C 50.45, H 6.58, N 13.07, S 14.96.
Found: C 50.64, H 6.60, N 13.04, S 14.96.
Scheme 4. (a) (CF3SO2)2, 2708C/rt, 70%; (b) 1,2-dibromoethane, K2CO3,
DMF, 35%; (c) ClSO2(o-NO2Ph), 74%; (d) a,a0-dibromoxylene, K2CO3,
DMF, 64%.
1-N-Cyanoethyl-4-N0-tosyl-ethylenediamine (5). A solu-
tion of 4 (30.00 g, 0.14 mol) in acetonitrile (100 mL) was
heated at 408C. After 30 min, acrylonitrile (11.27 mL,
0.17 mol) in acetonitrile (150 mL) was added. The reaction
mixture was re¯uxed over three additional hours and then
brought down to room temperature. Concentration of the
solvents in vacuum afforded a pale yellow solid which
was recrystallized (CH2Cl2/hexane) to give 5 as a white
to Panetta's procedure20 gave the two expected azamacro-
cycles 1 and 2.
Conclusion
1
solid (34.81 g, 93%). mp: 56±588C. H NMR d 2.42 (s,
3H, CH3 (Ts)), 2.44 (t, Jˆ6.6 Hz, 2H, CH2±CN), 2.70 (t,
Jˆ5.5 Hz, 2H, CH2±CH2±NHTs), 2.78 (t, Jˆ6.6 Hz, 2H,
CH2±CH2±CN), 2.79 (bs, 1H, NH), 2.98 (t, Jˆ5.5 Hz, 2H,
CH2±NHTs), 7.31 (d, Jˆ8.0 Hz, 2H, C6H4 (Ts)), 7.74 (d,
Jˆ8.0 Hz, 2H, C6H4 (Ts)). 13C NMR d 18.73 (CH2±CN),
21.49 (CH3 (Ts)), 42.31, 44.31, 47.39 (3£CH2±NH), 118.54
(CN), 127.10, 129.77, 136.63, 143.57 (C6H4 (Ts)). FT-IR
(KBr): 3315, 3224 (NH), 2250 (CN), 1147(SO2). Anal.
Calcd for C12H17N3O2S (267.34): C 53.91, H 6.41, N
15.72, S 11.99. Found: C 54.05, H 6.47, N 15.72, S
11.89.
In this report we have demonstrated that our strategy for the
synthesis of large-ring compounds can be applied to the
preparation of various di-trans-N-substituted macrocycles.
Our examples show that compound 12 can be used as a very
versatile synthon, prepared in seven steps in a overall 39%
yield, in order to synthesize derivatives of cyclam family
including cyclophanes. Two novel macrocycles 1 and 2
were synthesized using this process. These compounds
offer the opportunity for selective deprotection21,22 of the
nitrogen atoms in the ring allowing the possibility of the
preparation of a range of trans-substituted macrocycles.
1-N-(tert-Butoxycarbonyl)-1-N-cyanoethyl-4-N0-tosyl-
ethylenediamine (6a). The diamine 5 (29.00 g, 0.11 mol)
and triethylamine (23.0 mL, 0.17 mol) were mixed with
50 mL of chloroform. A solution of di-tert-butyldicarbonate
(23.70 g, 0.11 mol) in chloroform was added slowly at room
temperature. After the addition was completed, the tempera-
ture was raised to re¯ux for 2 h. The solution was then
allowed to cool to room temperature and washed with 1 N
aqueous hydrochloric acid (50 mL), water (2£25 mL), satu-
rated aqueous sodium bicarbonate (50 mL) and brine
(50 mL). The organic layer was dried over magnesium
sulphate, and the solvent was evaporated to afford a pale
yellow solid. Recrystallization (CH2Cl2/hexane) afforded 6a
as a white solid (37.70 g, 0.10 mol, 95%). mp: 120±1228C.
1H NMR d 1.45 (s, 9H, (CH3)3C), 2.42 (s, 3H, CH3 (Ts)),
2.57 (bs, 2H, CH2±CN), 3.07 (bs, 2H, CH2±CH2±NHTs),
3.38 (t, Jˆ5.6 Hz, 2H, CH2±CH2±CN), 3.44 (bs, 2H, CH2±
NHTs), 5.40 (bs, 1H, NH), 7.30 (d, Jˆ7.7 Hz, 2H, C6H4
(Ts)), 7.73 (d, Jˆ7.7 Hz, 2H, C6H4 (Ts)). 13C NMR d
17.52 (CH2±CN), 21.53 (CH3 (Ts)), 28.30 ((CH3)3C),
42.07, 44.60, 48.10 (3£CH2±N), 81.35 ((CH3)3C), 118.07
(CN), 127.04, 129.84, 136.83, 143.60 (C6H4 (Ts)), 155.50
(CO (Boc)). FT-IR (KBr): 3270 (NH), 2249 (CN), 1693
(CO). Anal. Calcd for C17H25N5O4S (367.46): C 55.57, H
Experimental
General
Reagents and solvents were puri®ed before use.23 All reac-
tions were run under a positive pressure of dry argon. Flash
chromatography was performed on silica gel from
Macherey±Nagel (Kieselgel 60 M). Preparative TLC was
performed on glass plates coated with 1 mm of silica gel
(Macherey±Nagel, Kieselgel DGF254). Analytical TLC:
Aluminium-backed silica gel Merck 60 F254. Melting points
were determined with a capillary apparatus and were uncor-
rected. NMR spectra were recorded on a Bruker AMX-400
apparatus (1H at 400 MHz and 13C at 100 MHz) in CDCl3
with chemical shift values (d) in ppm down®eld from tetra-
methylsilane. FT-IR (n, cm21) spectra were obtained using
Ä
thin ®lms on NaCl windows or in KBr pellets. Micro-
analyses were performed by the IST analytical services in
Lisbon using a combustion apparatus.
N-Tosyl-ethylenediamine (4). To a solution of ethylenedia-
mine (40.11 mL, 0.60 mol) in benzene (80 mL)Ð
CAUTION: very toxicÐat 408C was added slowly (1 h),

4762
M. T. Barros, F. SinÄeriz / Tetrahedron 56 (2000) 4759±4764
6.86, N 11.44, S 8.72. Found: C 55.60, H 6.89, N 11.35, S
8.67.
was taken up in concentrated ammonia solution (300 mL)
and CH2Cl2 (200 mL). The oil was then washed with satu-
rated aqueous sodium bicarbonate (100 mL) and brine
(100 mL). The organic layer was dried over magnesium
sulphate. Solvent removal afforded 23.9 g (45.24 mmol,
87%) of the title compound as a very viscous brown oil
that foamed under vacuum. The residue obtained was used
in the next reaction without further puri®cation. 1H NMR d
1.44 (s, 18H, 2£(CH3)3C), 1.65 (m, 2H, CH2±CH2±CH2),
1.72 (m, 2H, CH2±CH2±CH2), 2.43 (s, 3H, CH3 (Ts)), 2.70
(bs, 2H, CH2±NH2), 3.16 (m, 6H, 3£CH2±N), 3.30 (bm, 2H,
CH2±N), 3.35 (bs, 2H, CH2±N), 5.00 (bs, 1H, NHBoc), 7.31
(d, Jˆ7.7 Hz, 2H, C6H4 (Ts)), 7.68 (d, Jˆ7.7 Hz, 2H, C6H4
(Ts)). 13C NMR d 22.00 (CH3 (Ts)), 28.90 (2£(CH3)3C),
29.35, 31.12 (2£CH2±CH2±CH2), 37.61, 39.84, 45.12,
47.40, 47.59, 47.81 (6£CH2±N), 79.84, 80.10 (2£
(CH3)3C), 127.60, 130.30, 136.10, 143.80 (C6H4 (Ts)),
155.90, 156.50 (2£CO (Boc)). FT-IR (®lm): 3370 (NH),
absence of nitrile band, 1693 (CO).
N-(tert-Butoxycarbonyl)-3-chloropropylamine (8a). 3-
Chloropropylamine hydrochloride (7) (11.0 g, 0.11 mol)
and triethylamine (18.42 mL, 0.13 mol) were mixed in
chloroform (50 mL). A solution of di-tert-butyldicarbonate
(23.79 g, 0.11 mol) in 50 mL of chloroform was added
slowly. Using the same work-up than the one for 6a, a
brown oil was obtained as a crude product. Kugelrohr
distillation gave 20.05 g (95%) of 8a as a colourless solid
below 48C. 1H NMR d 1.44 (s, 9H, (CH3)3C), 1.96 (m, 2H,
CH2±CH2±CH2), 3.28 (m, 2H, CH2±NHBoc), 3.59 (t,
Jˆ6.4 Hz, 2H, CH2±Cl), 4.80 (bs, 1H, NH). 13C NMR d
28.53 ((CH3)3C), 32.78 (CH2±CH2±CH2), 38.10 (CH2±
NHBoc), 42.51 (CH2±Cl), 79.00 ((CH3)3C), 156.00 (CO
(Boc)). FT-IR (®lm): 3349 (NH), 1693 (CO). Anal. Calcd
for C8H16ClNO2 (193.67): C 49.61, H 8.33, N 7.23. Found:
C 49.88, H 8.56, N 7.29.
1,8-N,N0-Bis(tert-butoxycarbonyl)-1-N-cyanoethyl-4-N00-
tosyl-1,4,8-triazaoctane (9). To a solution of 6a (35.00 g,
99.50 mmol) in DMF (100 mL) under argon at 08C, was
added sodium hydride (5.60 g, 60% paraf®n, 0.11 mol) in
small portions. After the addition was ®nished and no more
hydrogen was evolved, the reaction was heated to 608C. A
solution of 8a (18.40 g, 0.10 mol) in DMF (100 mL) was
then added dropwise and the reaction mixture was main-
tained at 1108C during another 4 h. The solvent was then
evaporated to leave a brown oil. This sticky oil was
dissolved in dichloromethane (100 mL) and washed with
saturated aqueous sodium bicarbonate (100 mL) and brine
(100 mL). The organic layer was dried over magnesium
sulphate and the solvent was evaporated to afford a pale
brown oil. That was puri®ed by ¯ash column chromato-
graphy (acetone/ether/hexane 1:1:4) to yield 43.36 g
(87%) of 9 as a colourless oil. Unchanged starting materials
6a (3.50 g, 10%) and 8a (1.80 g, 10%) were also recovered.
1H NMR d 1.44 (s, 9H, (CH3)3C), 1.47 (s, 9H, (CH3)3C),
1.70 (m, 2H, CH2±CH2±CH2), 2.42 (s, 3H, CH3 (Ts)), 2.60
(m, 2H, CH2±CN), 3.16 (m, 6H, 3£CH2±N), 3.47 (m, 4H,
2£CH2±N), 4.95 (bs, 1H, NHBoc), 7.32 (d, Jˆ7.7 Hz, 2H,
C6H4 (Ts)), 7.68 (d, Jˆ7.7 Hz, 2H, C6H4 (Ts)). 13C NMR d
17.45 (CH2±CN), 21.33 (CH3 (Ts)), 28.15, 28.25
(2£(CH3)3C), 28.86 (CH2±CH2±CH2), 37.13, 44.59,
47.35, 47.90, 48.34 (5£CH2±N), 78.95, 80.88 (2£
(CH3)3C), 118.10 (CN), 127.02, 129.73, 135.4, 143.56
(C6H4 (Ts)), 154.70, 155.86 (2£CO (Boc)). FT-IR (®lm):
3387 (NH), 2249 (CN), 1697 (CO). Anal. Calcd for
C25H40N4O6S (524.68): C 57.23, H 7.68, N 10.68, S 6.11.
Found: C 56.98, H 7.76, N 10.44, S 5.91.
1,8-N,N0-Bis(tert-butoxycarbonyl)-5,12-N00,N000-bistosyl-
1,5,8,12-tetraazadodecane (11). Compound 10 (20.0 g,
38.0 mmol) was dissolved in a mixture of chloroform
(150 mL) and pyridine (7.48 mL, 76.00 mmol). Tosyl
chloride (7.97 g, 41.80 mmol) was added in portions under
stirring. After the addition was ®nished the reaction mixture
was re¯uxed over 16 h and then cooled to rt. The solution
was diluted with more chloroform (100 mL) and washed
with 1 M hydrochloric acid (50 mL), water (2£50 mL),
saturated aqueous sodium bicarbonate (50 mL) and brine
(50 mL). The organic layer was dried over magnesium
sulphate and the solvent was evaporated to afford a brown
foam of crude product. The residue was placed on ¯ash
silica gel column and eluted with hexane/ether (1:5).
Solvent evaporation afforded 20.8 g (30.4 mmol, 80%) of
the title compound as a ®ne yellow powder. 1H NMR d 1.39
(s, 9H, (CH3)3C), 1.43 (s, 9H, (CH3)3C), 1.69 (m, 4H,
2£CH2±CH2±CH2), 2.40 (s, 3H, CH3 (Ts)), 2.41 (s, 3H,
CH3 (Ts)), 2.85 (bs, 2H, CH2±N), 3.13 (m, 6H, 3£CH2±
N), 3.24 (m, 4H, 2£CH2±N), 4.88 (bs, 1H, NHBoc), 5.90
(bs, 1H, NHTs), 7.30 (m, 4H, C6H4 (Ts)), 7.66 (d, Jˆ7.6 Hz,
2H, C6H4 (Ts)), 7.73 (d, Jˆ7.6 Hz, 2H, C6H4 (Ts)). 13C
NMR d 22.00, 22.03 (2£CH3 (Ts)), 28.54 (CH2±CH2±
CH2), 28.87, 28.96 (2£(CH3)3C), 29.61 (CH2±CH2±CH2),
37.84, 40.30, 44.57 (3£CH2±N), 47.49 (2£CH2±N), 47.89
(CH2±N), 79.71, 81.09 (2£(CH3)3C), 127.50, 127.60,
130.20, 130.40, 136.25, 138.04, 143.57, 144.29 (2£C6H4
(Ts)), 156.60 (2£CO (Boc)). FT-IR (®lm): 3394 (NH),
1686 (CO). Anal. Calcd for C32H50N4O8S2 (682.89): C
56.28, H 7.38, N 8.20, S 9.39. Found: C 56.03, H 7.57, N
8.12, S 9.43.
1,8-N,N0-Bis(tert-butoxycarbonyl)-5-N00-tosyl-1,5,8,12-
tetraazadodecane (10). To a solution of 9 (27.28 g,
52.00 mmol) in methanol was added 24.73 g (0.10 mol) of
CoCl2´6H2O. After stirring at rt for about 30 min, the dark-
blue solution was cooled to 08C and 7.87 g (0.21 mol) of
sodium borohydride was added in small portions. A black
precipitated [Co(II)B] appeared and hydrogen was involved.
Once the addition was ®nished, tlc showed no remaining
starting material. The solution was treated with 5 M aqueous
hydrochloric acid (20 mL) in order to destroy the boride.
The solvents were evaporated and the obtained brown oil
1,8-N,N0-Bistosyl-1,5,8,12-tetraazadodecane (12). To a
cooled solution (08C) of 11 (9.59 g, 14.00 mmol) in chloro-
form (30 mL) was added dropwise tri¯uoroacetic acid
(10.78 mL, 0.14 mol). After the addition was ®nished the
temperature was allowed to warm at rt and the reaction
mixture stirred for about 1 h more. Solvents were evapo-
rated and the residue dissolved in dichloromethane
(100 mL) and washed with aqueous sodium bicarbonate
(50 mL) and brine (50 mL). After drying and evaporating
the solvent the resulting brown foam (6.76 g, 99%) was used
in the next reaction without further puri®cation. 1H NMR d

M. T. Barros, F. SinÄeriz / Tetrahedron 56 (2000) 4759±4764
4763
1.59 (m, 2H, CH2±CH2±CH2), 1.68 (m, 2H, CH2±CH2±
CH2), 2.42 (s, 6H, 2£CH3 (Ts)), 2.58 (t, Jˆ6.0 Hz, 2H,
CH2±N), 2.68 (t, Jˆ5.8 Hz, 2H, CH2±N), 2.76 (t,
Jˆ6.4 Hz, 2H, CH2±N), 2.98 (t, Jˆ5.6 Hz, 2H, CH2±N),
3.03 (t, Jˆ6.0 Hz, 2H, CH2±N), 3.15 (m, 2H, CH2±N),
7.31 (m, 4H, C6H4 (Ts)), 7.70 (d, Jˆ8.0 Hz, 2H, C6H4
(Ts)), 7.74 (d, Jˆ8.0 Hz, 2H, C6H4 (Ts)). 13C NMR d
21.29 (2£CH3 (Ts)), 27.83, 31.32 (2£CH2±CH2±CH2),
38.66, 42.68, 47.58, 47.84, 48.32, 48.80 (6£CH2±N),
127.11, 127.33, 129.70, 129.87, 135.56, 137.20, 143.10,
143.65 (2£C6H4 (Ts)). FT-IR (®lm): 3583 (NH2), 3290
(NH), absence of carbonyl band.
CH2±CH2), 48.74, 48.91, 50.32, 50.95 (4£2£CH2±N),
120.20 (q, Jˆ323 Hz, 2£CF3), 128.37, 130.89, 134.64,
145.23 (2£C6H4 (Ts)). FT-IR (®lm): Absence of amino
band. Anal. Calcd for C26H34´F6N4O8S4 (772.81): C 40.41,
H 4.43, N 7.25, S 16.59. Found: C 40.63, H 4.31, N 7.16, S
16.26.
1,8-N,N0-Bis(2-nitrobenzenesulfonyl)-5,12-N00,N000-bis-
tosyl-1,5,8,12-tetraazadodecane (14). To a stirred solution
of 12 (6.51 g, 13.50 mmol) in 50 mL of chloroform was
added triethylamine (10 mL, 72,0 mmol) followed by 2-
nitrobenzenesulfonyl chloride (6.60 g, 29.70 mmol) in
portions. The reaction mixture was stirred at rt for 16 h.
The solution was then diluted with more chloroform
(100 mL) and washed with 1 N hydrochloric acid
(50 mL), water (2£50 mL), saturated aqueous sodium bicar-
bonate (50 mL) and brine (50 mL). The organic layer was
dried over magnesium sulphate and the solvent was evapo-
rated to afford a pale green powder. The residue was puri®ed
by ¯ash column chromatography. Elution with AcOEt/hex-
ane (3:2) afforded 14 (8.52 g, 74%) as a pale green powder.
1H NMR d 1.84 (m, 4H, 2£CH2±CH2±CH2), 2.41 (s, 3H,
CH3 (Ts)), 2.43 (s, 3H, CH3 (Ts)), 2.96 (m, 3H, CH2±N and
CHH±N), 3.20 (m, 5H, 2£CH2±N and CHH±N), 3.40 (t,
Jˆ6.8 Hz, 2H, CH2±N), 3.50 (t, Jˆ7.8 Hz, 2H, CH2±N),
4.99 (t, Jˆ6.4, 1H, NHTs), 5.82 (t, Jˆ6.2, 1H, NHR),
7.30 (m, 4H), 7.71 (m, 3H), 7.74 (m, 6H), 7.83 (m, 1H),
8.02 (m, 1H), 8.12 (m, 1H), (2£C6H4 (Ts), 2£C6H4 (SO2-o-
(NO2)Ph)). 13C NMR d 22.10 (2£CH3 (Ts)), 29.22, 29.69
(2£CH2±CH2±CH2), 40.74, 41.27, 47.31, 47.82, 48.59,
49.00 (6£CH2±N), 124.80, 125.00 125.70, 125.90, 130.40,
130.60, 131.20, 131.40, 132.70, 132.90, 133.50, 134.20,
134.30, 134.60, 135.60, 137.20, 144.10, 144.60, 148.50,
148.60 (2£C6H4 (Ts), 2£C6H4 (SO2-o-(NO2)Ph)). FT-IR
(®lm): 3305 (NH), 1542 (NO2), 1336 (C±NO2). Anal.
Calcd for C36H42N6O12S4 (852.97): C 47.88, H 4.73, N
9.85, S 15.03. Found: C 47.73, H 4.80, N 9.34, S 14.88.
1,8-N,N0-Bistosyl-5,12-N00,N000-bis(tri¯uoromethanesul-
fonyl)-1,5,8,12-tetraazadodecane (13). To compound 12
(1.00 g, 2.00 mmol) in CH2Cl2 (40 mL) was added triethyl-
amine (1.10 mL, 8.00 mmol) under stirring. The mixture
was cooled to 2708C and tri¯uoromethanesulfonic
anhydride (1.35 mL, 8.00 mmol) added. The temperature
was allowed to rise and the mixture was stirred for an addi-
tional 2 h at rt. The solution was then treated with 3 M
NaOH (20 mL) and extracted with more CH2Cl2. The
organic layer was washed with water (2£20 mL), 1 M
hydrochloric acid (20 mL), water (20 mL), saturated
aqueous sodium bicarbonate (20 mL) and brine (20 mL).
The organic layer was dried over magnesium sulphate and
the solvent was evaporated to afford a pale yellow oil. Flash
chromatography (AcOEt/hexane 3:2) yielded 13 (1.04 g,
70%) as a colourless oil. 1H NMR d 1.88 (m, 4H,
2£CH2±CH2±CH2), 2.42 (s, 3H, CH3 (Ts)), 2.44 (s, 3H,
CH3 (Ts)), 2.94 (m, 2H, CH2±N), 3.21 (t, Jˆ5.9 Hz, 2H,
CH2±N), 3.28 (t, Jˆ7.5 Hz, 2H, CH2±N), 3.38 (t, Jˆ5.8 Hz,
2H, CH2±N), 3.49 (bs, 2H, CH2±N), 3.55 (bs, 2H, CH2±N),
5.14 (t, Jˆ6.2 Hz, 1H, NHTs), 6.26 (bs, 1H, NHTf), 7.31 (d,
Jˆ8.0 Hz, 2H, C6H4 (Ts)), 7.35 (d, Jˆ8.2 Hz, 2H, C6H4
(Ts)), 7.69 (d, Jˆ8.2 Hz, 2H, C6H4 (Ts)), 7.70 (d,
Jˆ8.0 Hz, 2H, C6H4 (Ts)). 13C NMR d 21.25 (2£CH3
(Ts)), 28.39, 29.10 (2£CH2±CH2±CH2), 39.85, 40.96,
46.81, 47.12, 47.84, 48.30 (6£CH2±N), 119.72 (q,
Jˆ320 Hz, CF3), 119.80 (q, Jˆ322 Hz, CF3), 127.05,
127.23, 129.96, 130.26, 134.72, 136.06, 144.04, 144.59
(2£C6H4 (Ts)). FT-IR (®lm): 3274 (NH), 721 (CF3). Anal.
Calcd for C24H32 F6N4O8S4 (746.77): C 38.60, H 4.32, N
7.50, S 17.17. Found: C 38.87, H 4.27, N 7.31, S 16.93.
2,9-N,N0-Bis(2-nitrobenzenesulfonyl)-6,13-N00,N000-bis-
tosyl-2,6,9,13-tetraaza [14] (1,5)benzenecyclophane (2).
To a solution of 14 (6.40 g, 0.40 mmol) in dry DMF
(20 mL) was added potassium carbonate (0.55 g,
4.00 mmol). After stirring 30 min at rt a,a0-dibromo-m-xy-
lene (0.11 g, 0.40 mmol) was added. The reaction mixture
was kept under re¯ux for 2 h; after this time the solvent was
removed and the residue was dissolved in dichloromethane
(50 mL), washed with saturated aqueous sodium bicarbo-
nate (50 mL) and brine (50 mL). The organic layer was
dried over magnesium sulphate and the solvent was evapo-
rated to afford a pale yellow powder. Puri®cation by ¯ash
chromatography (AcOEt/hexane 3:2) yielded 2 (0.38 g,
1,8-N,N0-Bistosyl-4,11-N00,N000-bis(tri¯uoromethanesul-
fonyl)-1,4,8,11-tetraazacyclotetradecane (1). Dry DMF
(10 mL) was added to a ¯ask containing 13 (0.20 g,
0.20 mmol) and potassium carbonate (0.28 g, 10.20 mmol)
under an argon atmosphere. The mixture was heated for 1 h
at 808C and then a solution of 1,2-dibromoethane (17.23 ml,
10.20 mmol)ÐCAUTION: very toxicÐin 10 mL of DMF
was added dropwise. The reaction mixture was maintained
at 1108C for 24 h, then was cooled to rt. After solvent
removal the residue was dissolved in dichloromethane
(25 mL) and washed with saturated aqueous sodium
bicarbonate (25 mL) and brine (25 mL). The residue was
puri®ed by preparative TLC (AcOEt/hexane 2:3) to yield
1
64%). H NMR d 1.59 (m, 4H, 2£CH2±CH2±CH2), 2.42
(s, 3H, CH3 (Ts)), 2.45 (s, 3H, CH3 (Ts)), 2.72 (t, Jˆ7.4 Hz,
2H, CH2±CH2±N), 2.92 (t, Jˆ7.4 Hz, 2H, CH2±CH2±N),
3.00 (m, 4H, 2£CH2±CH2±N), 3.18 (t, Jˆ7.0 Hz, 2H, CH2±
CH2±N), 3.31 (t, Jˆ7.4 Hz, 2H, CH2±CH2±N), 4.15 (s, 2H,
N±CH2±Ar), 4.48 (s, 2H, N±CH2-Ar), 7.30 (m, 8H), 7.54
(d, Jˆ8.0 Hz, 2H), 7.61 (m, 1H), 7.72 (m, 7H), 8.03 (m, 2H)
(2£C6H4 (Ts), 2£C6H4 (SO2-o-(NO2)Ph), C6H4 (m-xyleno)).
13C NMR d 22.20 (2£CH3 (Ts)), 29.25, 29.52 (2£CH2±
CH2±CH2), 47.57, 48.23, 48.43, 48.78, 53.89, 54.99
(8£CH2±N), 124.70, 125.10, 128.00, 128.40, 128.70,
129.10, 130.00, 130.50, 130.70, 131.50, 132.30, 132.60,
1
1 (54 mg, 35%). H NMR d 2.02 (m, 4H, 2£CH2±CH2±
CH2), 2.42 (s, 6H, 2£CH3 (Ts)), 3.13 (bs, 4H, 2£CH2±N),
3.26 (bm, 4H, 2£CH2±N), 3.64 (bm, 8H, 4£CH2±N), 7.34
(d, Jˆ8.0 Hz, 4H, C6H4 (Ts)), 7.67 (d, Jˆ8.0 Hz, 4H, C6H4
(Ts)). 13C NMR d 22.09 (2£CH3 (Ts)), 28.17 (2£CH2±

4764
M. T. Barros, F. SinÄeriz / Tetrahedron 56 (2000) 4759±4764
 Â
9. Lazar, I. Tetrahedron Lett. 1999, 40, 381±382.
132.70, 134.40, 134.60, 137.70, 138.20, 144.60 (2£C6H4
(Ts), 2£C6H4 (SO2-o-(NO2)Ph), C6H4 (m-xyleno)). FT-IR
(®lm): absence of amino band, 1544 (NO2), 1344
(C±NO2), 1160 (SO2). Anal. Calcd for C42H46N6O12S4
(955.11): C 52.82, H 4.85, N 8.80, S 13.43. Found: C
52.81, H 4.85, N 8.76, S 13.33.
10. Alcock, N. W.; Balakrishnan, K. P.; Moore, P.; Pike, G. A.
J. Chem. Soc., Dalton Trans. 1987, 889±894.
11. Alcock, N. W.; Moore, P.; Omar, H. A. A. J. Chem. Soc.,
Dalton Trans. 1986, 985±989.
12. Dickins, R. S.; Howard, J. A. K.; Lehmann, C. W.; Moloney,
J.; Parker, D.; Peacock, R. D. Angew. Chem., Int. Ed. Engl. 1997,
36, 521±523.
Acknowledgements
13. Royal, G.; Dahaoui-Gindrey, V.; Dahaoui, S.; Tabard, A.;
Guilard, R.; Pullumbi, P. Eur. J. Org. Chem. 1998, 1971±1975.
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Ã
We thank FundacËaÄo para a Ciencia e a Tecnologia for a
grant conceded to F.S. (Praxis XXI/BD/17007/98). M. T. B.
thanks Paula Correia da Silva for useful and encouraging
discussions.
15. Weisman, G. R.; Rogers, M. E.; Wong, E. H.; Jasinski, J. P.;
Paight, E. S. J. Am. Chem. Soc. 1990, 112, 8604±8605.
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Â
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