15 and 30-Membered polyolefinic macrocycles. Periphery modification by aromatic nucleophilic substitution of fluorine

Article abstract of DOI:10.1016/S0040-4020(02)00934-1

Tris[(4-fluorophenyl)sulfonyl]-1,6,11-triazacyclopentadeca-3,8,13-triene is a pivotal 15-membered triolefinic macrocycle from which a vast array of different derivatives are prepared by substitution of fluorine atoms.

Full text of DOI:10.1016/S0040-4020(02)00934-1

Tetrahedron 58 (2002) 7769–7774
15 and 30-Membered polyolefinic macrocycles. Periphery
modification by aromatic nucleophilic substitution of fluorine
*
Marcial Moreno-Man˜as and Jan Spengler
`
Department of Chemistry, Universitat Autonoma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Received 15 April 2002; revised 10 July 2002; accepted 5 August 2002
Abstract—Tris[(4-fluorophenyl)sulfonyl]-1,6,11-triazacyclopentadeca-3,8,13-triene is a pivotal 15-membered triolefinic macrocycle from
which a vast array of different derivatives are prepared by substitution of fluorine atoms. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
membered macrocycles containing olefinic double bonds
are still more scarce.6,7
Nitrogen-containing 15-membered macrocycles are com-
mon.1 – 3 However, nitrogen-containing, 15-membered
macrocycles featuring internal olefinic double bonds are
uncommon. Apart from the contribution of our group, the
few examples described contain only one double bond, and
the key step for their preparation is metathesis.4,5 Thirty-
Tris(arenesulfonyl)-1,6,11-triazacyclopentadeca-3,8,13-tri-
enes such as 8 (Scheme 1) are 15-membered triolefinic
macrocycles containing three units (–CH2–CHvCH–
CH2–N(SO2–Ar)–). Members of this family of macro-
cycles are easily accessible with configurations E,E,E8 and
Scheme 1. Preparation of 8; reagents and conditions: (i) (E)-BrCH2CHvCHCH2Br (2) (sixfold molar), K2CO3, CH3CN; (ii) (Boc)2O, Et3N, DMAP,
dichloromethane; (iii) 2 (0.5 fold molar), K2CO3, CH3CN; (iv) TFAA, dichloromethane; vs K2CO3, CH3CN.
Keywords: macrocycles; aromatic nucleophilic substitution; alkene; phosphane; palladium complex; nitrogen heterocycle; cyclization.
*
Corresponding author. Tel.: þ34-935811254; fax: þ34-935811265; e-mail: marcial.moreno@uab.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00934-1

7770
M. Moreno-Man˜as, J. Spengler / Tetrahedron 58 (2002) 7769–7774
Figure 1. Products formed in the reactions between 4 and 7.
E,E,Z.9 These macrocycles are excellent ligands for
palladium(0), platinum(0), and silver(I) by coordination
through the olefins.9,10 The palladium(0)-macrocycle com-
plexes are recoverable catalysts in Suzuki cross-couplings11
and in the telomerization of butadiene.12 In particular the
polystyrene-anchored version can be recovered by simple
filtration.11 Recent developments include the preparation of
15-membered macrocycles featuring ferrocene units at the
sulfonamide groups. These ferrocene-containing macro-
cycles coordinate palladium(0), and the corresponding
complexes exhibit catalytic activity in Suzuki cross-
couplings and in the Heck reaction.13 Twenty-membered
macrocycles featuring four (–CH2 –CHvCH–CH2 –
N(SO2–Ar)–) units have also been prepared.14
30-membered macrocycles containing six repeated units can
be isolated. On the other hand, we required a versatile
pivotal 15-membered macrocycle which by simple trans-
formations, could be converted into more complicated
architectures. In this paper, we present the studies of
4-fluorophenyl series, the analysis of the influence of
concentration on the formation of macrocycles, and
the aromatic nucleophilic substitution of fluorine with
phosphorus, nitrogen, and sulfur nucleophiles.
2. Results
Preparation of tris[(4-fluorophenyl)sulfonyl]-1,6,11-triaza-
cyclopentadeca-3,8,13-triene, 8 (Scheme 1) was performed
either by reaction of 1,14-dibromo-5,10-diaza-5,10-bis[(4-
fluorophenyl)sulfonyl]tetradeca-2,12-diene, 3, with 4-fluoro-
phenylsulfonamide, 1, or by reaction of 1,9-dibromo-5-aza-
5-[(4-fluorophenyl)sulfonyl]nona-2,7-diene, 4, with N,N0-bis-
[(4-fluorophenyl)sulfonyl]-2-butene-1,4-diamine, 7. Thus,
reaction of 1 with an excess 2 in the presence of potassium
carbonate affords a mixture of 3 (17% yield) and 4
(49% yield), easily separable by column chromatography.
Reaction of 3 with sulfonamide 1 afforded 8 in 50% yield.
Alternatively, reaction of dibromide 4 with bissulfonamide
7 afforded 8 in yields around 40% in several different
batches. The route 4þ7 is preferred albeit longer due to the
higher yield of 4 with respect to 3 in the condensation of
arenesulfonamides with dibromobutene 2. Both synthetic
routes are ultimately based on simple or commercially
available starting materials: p-fluorobenzenesulfonamide, 1,
and (E)-1,4-dibromo-2-butene, 2.
All 15 and 20-membered macrocycles can be synthesized
stepwise from easily available arenesulfonamides and
1,4-dibromobutenes. Moreover, high dilution is a non-
crucial factor in their preparation. However, a more
profound study has revealed that under certain conditions
Table 1. Effect of concentration in the formation of 8–10
[4] and [7]/temperature
(8C)a
8, %
(crudeb–purec)
9, %
(crudeb–pure)
10, %d
0.0065/70
0.0127/70
0.0248/70
0.0248/rt
0.0496/70
0.0992/70
72
20
15
20
30
32–6e
20
–
–
16
12
29
7.11 gf
82–43
63–41
50–34
32–23
20
a
Conditions: anhydrous K2CO3 (10 equiv.) was added to a stirred solution
of 7 in acetonitrile (80 mL). Then, 4 in acetonitrile (20 mL) was added
and the mixture stirred for 12 h.
b
c
d
No special precautions concerning high dilution have been
adopted. However, we felt that higher concentration ought
to favor the formation of higher rings and, eventually, of
polymeric materials. Indeed, this is the case. Thus, increased
concentrations afforded insoluble material 10, probably
polymeric in nature. Indeed, at intermediate concentrations
(Fig. 1 and entry 5 in Table 1) the formation of the
Monitored by NMR.
Recrystallization from ethyl acetate–hexane.
The residue insoluble in acetonitrile was washed with water, filtered, and
dried.
Column chromatography through silica gel with CHCl3–trifluoroacetic
acid (95:5 (v/v)).
e
f
With higher concentration of starting materials larger amounts of
completely insoluble material were obtained.

M. Moreno-Man˜as, J. Spengler / Tetrahedron 58 (2002) 7769–7774
7771
Scheme 2. Nucleophilic aromatic substitutions in 8; reagents and conditions: (i) Ph2PH, NaOH, DMSO; (ii) 1-propanethiol or p-methylthiophenol, K2CO3,
DMSO, rt; (iii) morpholine, 1008C; (iv) ethanolamine, 1008C; (v) PdCl2, hydrazine hydrate, DMSO, 1208C.
30-membered macrocycle, hexakis[(4-fluorophenyl)sulfonyl]-
1,6,11,16,21,26-hexaazacyclotriaconta-3,8,13,18,23,28-
hexaene, 9, gained importance. Mixtures were monitored by
1H and 19F NMR, compound 8 featuring in CDCl3 a broad
singlet and a singlet at d 5.65 (1H) and 2105.37 (19F),
whereas 9 presents the signals at d 5.56 and 2105.33,
respectively. A pure sample of 9 was isolated and
characterized by MALDI-TOF mass spectrometry
(m/z¼1385.1 (MþNa) and 1401.0 (MþK)). Moreover, a
third component showed broad peaks at 5.51 and 2105.31.
Table 1 contains the distribution of 8, 9, and higher products
10 depending on concentration. Material 10 was made of
polymer 10a and macrocycles 10b. MALDI-TOF mass
spectra of 10 showed two series of peaks corresponding to n
values from 5 to 24, with n¼6 predominating. The
difference between consecutive peaks within one series
corresponds to m/z¼227 Da (fragment F–Ph–SO2–N–
CH2–CHvCH–CH2–), whereas the difference of corre-
sponding peaks of different series is m/z¼52 Da (CH2–
CHvCH–CH2–2H).
presents two singlets at 29.07 (2P) and 29.43 (1P) ppm,
showing the typical behavior of palladium(0) complexes of
15-membered macrocycles 8.10 Further evidence of the
existence of a palladium atom coordinated with the three
olefins derives from the chemical shift of olefinic protons
which give signals at high field d,5. Moreover, the 31P
NMR chemical shifts indicate coordination of phosphorus
atoms with palladium atom (see above). Elemental analysis
is compatible with structure 16 where external palladium is
coordinated by two phosphanes, defining a sort of PdL2
complex. This requires 2.5 overall palladium atoms per
macrocycle. MALDI-TOF mass spectrum of 16 exhibits a
cluster of peaks at m/z 1288–1291 (C66H60N3O6P3PdS3þH)
corresponding to the monomeric complex with a centrally
coordinated palladium atom but decoordinated phosphorus
atoms. Since this rather insoluble material showed little
catalytic activity in Suzuki and Tsuji–Trost reactions,
further studies on its structure were not performed.
3. Conclusion
Nucleophilic aromatic substitution with phosphorus,15,16
nitrogen,17–20 and sulfur21,22 have been performed in
p-fluorobenzenesulfonyl derivatives. Examples with sulfur
nucleophiles are more scarce. This synthetic tool has proved
very valuable for replacement of the three fluorine atoms of
8 (Scheme 2). Thus, treatment of 8 with the conjugate base
of diphenylphosphane afforded 11 in 66% yield. Triple
substitution was achieved with sulfur nucleophiles under
potassium carbonate in DMSO. In this manner trisulfides
12 and 13 were isolated in 77 and 68% yields. Macrocycle
8 was simply heated in amines such as morpholine or
monoethanolamine to afford compounds 14 and 15 in 85
and 77% yield, respectively.
In summary, we have prepared a 15-membered macrocycle
featuring three olefins and three p-fluorophenylsulfonyl
moieties. The fluorine atoms can be replaced by nucleo-
philic aromatic substitution affording more complicated
architectures. Under certain concentration conditions
30-membered macrocycles featuring six olefinic double
bonds are accessible.
4. Experimental
4.1. General
1
19F (223 MHz), 31P (101 MHz), H (250 MHz), and 13C
The macrocyclic triphosphane 11 (Scheme 2) was loaded
with palladium(0) to afford oligomeric material 16, featur-
ing two different types of palladium(0) in two different
environments. We thought that 16 could be an insoluble and
easily recoverable catalyst. The 31P NMR spectrum of 16
(62.5 MHz) NMR chemical shifts are expressed relative to
trifluoroacetic acid, to phosphoric acid, to chloroform (d
7.26 (1H) and 77.00 (13C)), and tetramethylsilane, respec-
tively. MALDI-TOF spectra were recorded on a system

7772
M. Moreno-Man˜as, J. Spengler / Tetrahedron 58 (2002) 7769–7774
1
equipped with a pulsed nitrogen laser (337 nm), operating in
positive-ion reflector mode, and using 19 kV acceleration
voltage. Matrices (a-cyanocinnamic acid) were prepared at
5 mg/mL in THF. Analytes were dissolved at concentration
between 0.1 and 5 mg/mL in THF or chloroform.
1093 cm21; H NMR (CDCl3) d 3.83 (d, J¼6.4 Hz, 4H),
3.92 (dd, J¼6.7, 0.7 Hz, 4H), 5.60 (m, 2H), 5.84 (m, 2H),
7.23 (m, 2H), 7.85 (m, 2H); 13C NMR (CDCl3) d 31.1, 48.2,
116.4 (d, J¼23.0 Hz), 129.2, 129.8 (d, J¼8.6 Hz), 130.9,
136.0 (br), 165.0 (d, J¼252.7 Hz); 19F NMR (CDCl3) d
2105.35. Anal. calcd for C14H16Br2FNO2S: C, 38.12; H,
3.56; N, 3.17; S, 7.27; found: C, 38.35; H, 3.55; N, 3.15; S,
7.19.
4.1.1. N-(tert-Butyloxycarbonyl)-4-fluorobenzenesulfon-
amide, 5. It was prepared in 96% yield by treating 1 with
(Boc)2O, triethylamine, and dimethylaminopyridine in
dichloromethane according to a general method.23 It
presented mp 112–1148C; IR (KBr) 3270, 1743, 1591,
Product 3 (0.9 g, 15%) presented mp 93–958C; IR (KBr)
1
1593, 1492, 1338, 1152 cm21; H NMR (CDCl3) d 3.75–
1
1346, 1153, 546 cm21; H NMR (CDCl3) d 1.43 (s, 9H),
3.82 (m, 8H), 3.90 (m, 4H), 5.51–5.76 (m, 4H), 5.82 (m,
2H), 7.19–7.28 (m, 4H), 7.80–7.90 (m, 4H); 13C NMR
(CDCl3) d 31.2, 48.2, 48.4, 116.4 (d, J¼22.1 Hz), 129.1,
129.7 (d, J¼9.6 Hz), 130.7, 135.9 (d, J¼3.8 Hz), 165.0 (d,
J¼255.3 Hz); 19F NMR (CDCl3) d 2105.30. Anal. calcd for
C24H26Br2F2N2O4S2: C, 43.13; H, 3.92; N, 4.19; S, 9.59;
found: C, 43.33; H, 3.85; N, 4.13; S, 9.45.
7.22–7.29 (m, 2H), 8.05–8.11 (m, 2H); 13C NMR (CDCl3)
d 27.8, 84.3, 116.1 (d, J¼22.9 Hz), 131.1 (d, J¼9.5 Hz),
134.8 (br), 149.2, 165.6 (d, J¼254.6 Hz); 19F NMR (CDCl3)
d 2103.72. Anal. calcd for C11H14FNO4S: C, 47.98; H,
5.12; N, 5.08; S, 11.64; found: C, 47.82; H, 5.11; N, 5.09; S,
11.56.
4.1.2. (E)-N,N0-Bis(tert-butyloxycarbonyl)-N,N0-bis[(4-
fluorophenyl)sulfonyl]-2-butene-1,4-diamine, 6. Anhydrous
K2CO3 (7.60 g, 55.0 mmol) was added under stirring at
658C to a solution of 5 (3.70 g, 13.4 mmol) in CH3CN
(70 mL). After 30 min, 2 (1.43 g, 6.7 mmol) in CH3CN
(10 mL) was added and the suspension was stirred for 15 h
at 658C. The mixture was filtered and evaporated to afford 6
(3.67 g, 91%), mp 138–1408C; IR (KBr) 1732, 1591, 1494,
4.1.5. Tris[(4-fluorophenyl)sulfonyl]-1,6,11-triazacyclo-
pentadeca-3,8,13-triene, 8. From 1 and 3. A mixture of 1
(0.27 g, 1.54 mmol) in CH3CN (40 mL) and anhydrous
K2CO3 (0.85 g, 6.2 mmol) was stirred at 658C for 30 min.
Then, 3 (1.03 g, 1.54 mmol) in CH3CN (10 mL) was added
and the suspension was stirred overnight at 658C. After
filtration and evaporation the residue was recrystallized
from ethyl acetate/hexane to afford 8 (0.52 g, 50%).
1
1350, 1155 cm21; H NMR (CDCl3) d 1.37 (s, 18H), 4.51
(m, 4H), 5.95 (m, 2H), 7.17–7.23 (m, 4H), 7.94–8.00 (m,
4H); 13C NMR (CDCl3) d 27.8, 47.5, 84.7, 115.9 (d, J¼
23.0 Hz), 129.0, 131.0 (d, J¼9.6 Hz), 135.9, 150.4, 165.3
(d, J¼256.2 Hz); 19F NMR (CDCl3) d 2104.45. Anal. calcd
for C26H32F2N2O8S2: C, 51.82; H, 5.35; N, 4.65; S, 10.64;
found: C, 51.67; H, 5.39; N, 4.71; S, 10.47.
From 4 and 7. To a solution of 7 (see Table 1 for
concentration) in CH3CN (80 mL) anhydrous K2CO3
(10 equiv.) was added at the temperature indicated in the
table and stirred for 30 min. Then, 4 in acetonitrile (20 mL)
was added. The mixture was stirred at rt for 12 h. The
reaction mixture was filtered and the filtrate was evaporated.
Column chromatography through silica gel (ethyl acetate/
hexane) failed to separate of 8 and 9. Therefore, the residue
from acetonitrile evaporation was digested in ethyl acetate.
The portion soluble in ethyl acetate was 80% pure 8
(monitored by NMR), and recrystallization from ethyl
acetate/hexane gave pure 8. The ethyl acetate insoluble part
was ca. 70% pure 9 (monitored by NMR), from which a pure
sample of 9 was obtained by column chromatography using
silica gel with CHCl3/TFA (95:5). The initial acetonitrile
insoluble solid residue directly from the reaction mixture,
also containing inorganic salts, was washed with water,
filtered and dried. It was 10 in ca. 80% purity (monitored by
NMR). Higher concentrations of starting materials produced
larger amounts of completely insoluble 10.
4.1.3. (E)-N,N0-Bis[(4-fluorophenyl)sulfonyl]-2-butene-
1,4-diamine, 7. A solution of 6 (3.25 g, 5.4 mmol) in
TFA/CH2Cl2 (20 mL, 1:1) was stirred at rt for 4 h. Then, the
solution was evaporated and the residue recrystallized from
EtOH to afford 7 (1.90 g, 88%), mp 174–1778C; IR (KBr)
1
3278, 1596, 1497, 1430, 1328, 1165 cm21; H NMR ([D6]
DMSO) d 3.31 (br, 4H), 5.53 (br, 2H), 7.42 (m, 4H), 7.83
(m, 6H); 13C NMR ([D6] DMSO) d 43.9, 116.4 (d, J¼
23.0 Hz), 128.0, 129.7 (d, J¼9.6 Hz), 137.2, 164.3 (d, J¼
250.5 Hz); 19F NMR ([D6] DMSO) d 2106.71 (br). Anal.
calcd for C16H16F2N2O4S2: C, 47.75; H, 4.01; N, 6.96; S,
15.94; found: C, 47.79; H, 3.87; N, 6.92; S, 15.82.
4.1.4. N,N-Bis[(E)-4-bromo-2-butenyl]-(4-fluorophenyl)-
sulfonamide, 4, and (E,E,E)-1,14-dibromo-N,N0-bis[(4-
fluorophenyl)sulfonyl]-5,10-diazatetradeca-2,7,12-tri-
ene, 3. Anhydrous K2CO3 (15.00 g, 110 mmol) was added
to a solution of 1 (3.00 g, 17.1 mmol) in CH3CN (100 mL).
The mixture was stirred at 658C for 30 min. Then, 2
(21.00 g, 102.0 mmol) in CH3CN (50 mL) was added and
the suspension was stirred overnight at 658C. After filtration
and evaporation, the resulting residue was chromatographed
with mixtures of hexane/ethyl acetate of increasing polarity.
First, 2 (12.20 g) was recovered, then 4 followed by 3 were
eluted.
Macrocycle 8 had mp 146–1488C; IR (KBr) 1591, 1493,
1340, 1155 cm21; 1H NMR (CDCl3) d 3.72 (br, 12H), 5.62
(br, 6H), 7.23 (m, 6H), 7.82 (m, 6H); 13C NMR (CDCl3) d
50.6, 116.4 (d, J¼23.0 Hz), 129.7 (d, J¼9.6 Hz), 129.4,
135.2 (d, J¼3.8 Hz), 165.1 (d, J¼255.3 Hz); 19F NMR
(CDCl3) d 2105.37; MALDI-TOF MS m/z: 705.2 [Mþ
Na]þ, 721.2 [MþK]þ. Anal. calcd for C30H30F3N3O6S3: C,
52.85; H, 4.44; N, 6.16; S, 14.11; found: C, 52.74; H, 4.70;
N, 6.07; S, 14.02.
4.1.6. (E,E,E,E,E,E)-1,6,11,16,21,26-Hexakis[(4-fluoro-
phenyl)sulfonyl]-1,6,11,16,21,26-hexaazacyclotriaconta-
3,8,13,18,23,28-hexaene, 9. Presented mp 198–2088C;
;
IR (KBr) 1593, 1494, 1341, 1157 cm21 1H NMR
Product 4 (3.8 g, 49%) presented mp 48–558C (normally
obtained as oil); IR (film) 1592, 1493, 1339, 1154,

M. Moreno-Man˜as, J. Spengler / Tetrahedron 58 (2002) 7769–7774
7773
(CDCl3/TFA) d 3.74 (br, 24H), 5.59 (br, 12H), 7.26 (m,
12H), 7.83 (m, 12H); 13C NMR (CDCl3/TFA) d 49.3, 117.0
(d, J¼22.9 Hz), 129.4, 130.1 (d, J¼9.5 Hz), 133.9 (br),
164.0 (d, J¼255.6 Hz); 19F NMR (CDCl3) d 2105.33;
MALDI-TOF MS m/z: 1385.1 [MþNa]þ, 1401.0 [MþK]þ.
Anal. calcd for C60H60F6N6O12S6: C, 52.85; H, 4.44; N,
6.16; S, 14.11; found: C, 52.82; H, 4.26; N, 5.91; S, 14.17.
C39H51N3O6S6: C, 55.09; H, 6.05; N, 4.94; S, 22.63;
found: C, 54.79; H, 6.09; N, 4.78; S, 22.41.
4.1.9. (E,E,E)-1,6,11-Tris{[4-(p-tolylthio)phenyl]sulfo-
nyl}-1,6,11-triazacyclopentadeca-3,8,13-triene, 13.
A
solution of 8 (0.10 g, 0.15 mmol) in DMSO (1 mL) was
stirred under argon with anhydrous K2CO3 (0.20 g). Then
p-methylthiophenol (0.07 g, 0.59 mmol) was added and the
mixture was stirred for 12 h at rt. The excess of thiol was
extracted with hexane (5 mL) from the DMSO phase. Upon
addition of 5% H2SO4 (20 mL) product 13 precipitated.
It was recrystallized from CHCl3/hexane to afford pure 13
(0.10 g, 68%), mp 76–808C; IR (KBr) 1580, 1338,
Material 10 presented mp 155–1658C; IR (KBr) 1593,
1494, 1341, 1155 cm21; 1H NMR (CDCl3/TFA) d 3.71 (br,
4H), 5.48 (br, 2H), 7.23 (m, 2H), 7.81 (m, 2H); 13C NMR
(CDCl3/TFA) d 48.6, 116.7 (d, J¼21.9 Hz), 128.9, 129.8 (d,
J¼8.6 Hz), 134.6, 165.4 (d, J¼255.6 Hz); 19F NMR
(CDCl3) d 2105.31; MALDI-TOF MS m/z for 10bþK:
1174.2, 1401.2, 1628.2, 1855.3, 2082.3, 2309.4, 2536.5,
2763.6, 2992.7, 3218.7; for 10aþK and 10bþK at lower
resolution: 3400.8 and 3453.2, 3626.9 and 3679.7, 3854.0
and 3906.3, 4076.6 and 4133.6, 4360.7, 4536.9 and 4588.6,
4761.1 and 4815.1, 4988.7 and 5041.0, 5271.5, 5496.8.
1
1161 cm21; H NMR ([D6] DMSO) d 2.36 (s, 9H), 3.61
(s, 12H), 5.40 (s, 6H), 7.21 (d, J¼8.4 Hz, 6H), 7.31 (d, J¼
7.9 Hz, 6H), 7.43 (d, J¼7.9 Hz, 6H), 7.64 (d, J¼8.4 Hz,
6H); 13C NMR (CDCl3) d 21.2, 50.6, 126.8, 127.0, 127.5,
129.4, 130.6, 134.8, 135.6, 139.8, 146.1; MALDI-TOF MS
m/z: 994.0 [MþH]þ, 1016.0 [MþNa]þ, 1032.0 [MþK]þ.
Anal. calcd for C51H51N3O6S6þ1 CHCl3): C, 56.10; H,
4.70; N, 3.77; found: C, 55.12; H, 4.59; N, 3.69.
4.1.7. (E,E,E)-1,6,11-Tris{[4-(diphenylphosphino)-
phenyl]sulfonyl}-1,6,11-triazacyclopentadeca-3,8,13-tri-
ene, 11. Diphenylphosphane (0.12 mL, 0.66 mmol) was
added to a solution of 8 (0.10 g, 0.15 mmol) in DMSO
(1 mL) maintained under argon atmosphere. Then, a
suspension of NaOH in DMSO was added dropwise at rt
until the reaction mixture showed a stable yellow-orange
color for 10 min. 5% Sulphuric acid was added dropwise
until the color disappeared. The solution was stirred
vigorously with hexane (2£20 mL) to extract the excess of
diphenylphosphine. The DMSO phase was diluted with 5%
H2SO4 (20 mL) and stirred again vigorously. The precipi-
tate was filtered, washed with water (2£5 mL) and pressed
on porous plate. The powder obtained was recrystallized
from EtOH/THF (ca. 15 mL/7 mL), the crystals were
filtered off and dried under high vacuo to afford 11
(0.12 g, 66%), mp 152–1558C; IR (KBr) 1581, 1435,
4.1.10. (E,E,E)-1,6,11-Tris[(4-morpholinophenyl)sulfonyl]-
1,6,11-triazacyclopentadeca-3,8,13-triene, 14. Macro-
cycle 8 (0.10 g, 0.15 mmol) was stirred in morpholine
(2.0 mL) for 12 h at 1008C. The formed precipitate was
filtered off and recrystallized from CHCl3/THF to afford
14 (0.11 g, 85%), mp 239–2428C; IR (KBr) 1593, 1332,
1
1157 cm21; H NMR (CDCl3) d 3.32 (t, J¼4.9 Hz, 12H),
3.67 (s, 12H), 3.89 (t, J¼4.9 Hz, 12H), 5.59 (s, 6H), 6.93 (d,
J¼9.1 Hz, 6H), 7.66 (d, J¼8.9 Hz, 6H); MALDI-TOF MS
m/z: 883.5 [MþH]þ, 905.5 [MþNa]þ, 920.4 [MþK]þ.
Anal. calcd for C42H54N6O9S3þ1 CHCl3: C, 51.52; H, 5.43;
N, 8.38; found: C, 51.17; H, 5.58; N, 8.23.
4.1.11. (E,E,E)-1,6,11-Tris{[4-(2-hydroxyethylamino)-
phenyl]sulfonyl}-1,6,11-triazacyclopentadeca-3,8,13-tri-
ene, 15. Macrocycle 8 (0.10 g, 0.15 mmol) was stirred in
monoethanolamine (3.0 mL) for 18 h at 1008C. 1 M HCl
(75 mL) was added to the solution cooled at rt and the
formed precipitate was pressed on a porous plate to afford
15 (0.93 g, 77%), mp 91–938C (THF/pyridine); IR (KBr)
1
1342, 1162, 697, 604 cm21; H NMR (CDCl3) d 3.72 (br,
12H), 5.60 (br, 6H), 7.37–7.87 (m, 42H); 13C NMR
(CDCl3) d 50.5, 126.6 (d, J¼5.8 Hz), 128.7 (d, J¼6.7 Hz),
129.3, 133.5 (d, J¼16.3 Hz), 133.9 (d, J¼19.2 Hz), 135.4
(d, J¼10.6 Hz), 138.9, 144.5 (d, J¼16.3 Hz); 31P NMR
(CDCl3) d 23.78; ESIMS MS m/z: 1178.5 [M2H]þ, 1179.5
[M]þ, 1180.3 [MþH]þ, 1196.2 [MþNH4]þ, 1213.3
[MþNa]þ. Anal. calcd for C66H60N3P3S3þ1H2O: C,
66.15; H, 5.21; N, 3.51; S, 8.03; found: C, 65.91; H, 5.10;
N, 3.51; S, 7.92.
3382, 1599, 1340, 1319, 1159 cm21 1H NMR ([D6]
;
DMSO) d 3.13 (m, 6H), 3.54 (m, 18H), 4.76 (br, 3H),
5.45 (br, 6H), 6.57 (t, J¼5.5 Hz, 3H), 6.65 (d, J¼8.9 Hz,
6H), 7.42 (d, J¼8.9 Hz, 6H); MALDI-TOF MS m/z: 827.3
[MþNa]þ, 843.3 [MþK]þ. Anal. calcd for C36H48N6O9-
S3þ1H2O: C, 52.54; H, 6.12; N, 10.21; S, 11.69; found: C,
52.35; H, 6.05; N, 10.25; S, 11.30.
4.1.8. (E,E,E)-1,6,11-Tris{[4-(propylthio)phenyl]sulfonyl}-
1,6,11-triazacyclopentadeca-3,8,13-triene, 12. Macrocycle
8 (0.10 g, 0.15 mmol) in DMSO (1 mL) was stirred under
argon with anhydrous K2CO3 (0.20 g). Then propanethiol
(0.07 mL, 1.1 mmol) was added and the mixture was stirred
for 12 h at rt. The excess of thiol was extracted with hexane
(5 mL) from the DMSO phase. Upon addition of 5% H2SO4
(20 mL) product 12 precipitated; it was recrystallized from
MeOH to afford pure 12 (0.10 g, 77%), mp 125–1288C; IR
(KBr) 1580, 1342, 1162 cm21; 1H NMR (CDCl3) d 1.09 (t,
J¼7.3 Hz, 9H), 1.76 (m, 6H), 3.00 (t, J¼7.2 Hz, 6H), 3.69
(s, 12H), 5.61 (s, 6H), 7.36 (d, 6H, J¼8.8 Hz), 7.66 (d, 6H,
J¼8.8 Hz); 13C NMR (CDCl3) d 13.4, 22.0, 34.0, 50.6,
126.8, 127.4, 129.4, 135.1, 144.8; MALDI-TOF MS m/z:
872.2 [MþNa]þ, 888.1 [MþK]þ. Anal. calcd for
4.1.12. Palladium(0) complex of (E,E,E)-1,6,11-tris{((4-
diphenylphosphino)phenyl(sulfonyl}-1,6,11-triazacyclo-
pentadeca-3,8,13-trienepalladium(0), 16. PdCl2 (0.03 g,
0.17 mmol) was added under argon in a solution of 11
(0.10 g, 0.085 mmol) in DMSO (2 mL) maintained at
1208C. Hydrazine hydrate (0.1 mL) was added in one
portion to the red solution. The dark reaction mixture was
quickly cooled down to rt and stirred for 12 h. The
precipitate was filtered off, washed with EtOH (2£10 mL)
and dried to afford material 16 (0.10 g, 41%), mp 198–
1
2048C; IR (KBr) 1437, 1341, 1162, 1118 cm21; H NMR
(CDCl3) d 1.80 (m, 4H), 2.84 (m, 2H), 3.10 (m, 2H), 3.72 (m,
2H), 3.95 (m, 2H), 4.64 (m, 4H), 4.78 (m, 2H), 7.30–8.00

7774
M. Moreno-Man˜as, J. Spengler / Tetrahedron 58 (2002) 7769–7774
(m, 60H); 31P NMR (CDCl3) d 29.07 (s, 2P), 29.43 (s, 1P);
MALDI-TOF MS m/z: 1288.3 [C66H60N3O6P3PdS3þH]þ.
Anal. calcd for C66H60N3O6P3Pd2.5S3: C, 50.45; H, 4.18; N,
2.91; found: C, 49.33 and 49.18; H, 4.02 and 3.90; N, 2.63
and 2.63.
`
8. Cerezo, S.; Cortes, J.; Galvan, D.; Lago, E.; Marchi, C.;
´
Molins, E.; Moreno-Man˜as, M.; Pleixats, R.; Torrejon, J.;
Vallribera, A. Eur. J. Org. Chem. 2001, 329–337.
`
9. Cortes, J.; Moreno-Man˜as, M.; Pleixats, R. Tetrahedron Lett.
2001, 42, 4337–4339.
`
10. Cerezo, S.; Cortes, J.; Lago, E.; Molins, E.; Moreno-Man˜as,
´
M.; Parella, T.; Pleixats, R.; Torrejon, J.; Vallribera, A. Eur.
Acknowledgements
J. Inorg. Chem. 2001, 1999–2006.
`
11. Cortes, J.; Moreno-Man˜as, M.; Pleixats, R. Eur. J. Org. Chem.
We are indebted for a Marie Curie Individual Fellowship
of the European Community Programme ‘Improving
Human Research Potential and the Socio-economic
Knowledge Base’ (Contract HPMF-CT-2000-00471, to
J. S.). Financial support from DGESIC (Project PB98-
0902) and CIRIT-Generalitat de Catalunya (Project
SGR2000-0062) is gratefully acknowledged.
2000, 239–243.
12. Estrine, B.; Blanco, B.; Bouquillon, S.; Henin, F.; Moreno-
Man˜as, M.; Muzart, J.; Pena, C.; Pleixats, R. Tetrahedron Lett.
2001, 42, 7055–7057.
13. Llobet, A.; Masllorens, E.; Moreno-Man˜as, M.; Pla-Quintana,
´
A.; Rodrıguez, M.; Roglans, A. Tetrahedron Lett. 2002, 43,
1425–1428.
14. Blanco, B.; Cerezo, S.; Moreno-Man˜as, M.; Pleixats, R.;
Spengler, J. Tetrahedron Lett. 2001, 42, 9001–9003.
15. Herd, O.; Langhans, K. P.; Stelzer, O.; Weferling, N.;
Sheldrick, W. S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1058–1059.
References
1. For a general monograph on macrocyclic compounds see:
Dietrich, B.; Viout, P.; Lehn, J.-M. Aspects de la Chimie des
16. Bitterer, F.; Herd, O.; Hessler, A.; Ku¨hnel, M.; Rettig, K.;
´
Composes Macrocycliques. InterEditions/CNRS: Paris, 1991.
2. Macrocycle Synthesis. A Practical Approach. Parker, D., Ed.;
Oxford University: Oxford, 1996.
¨
Stelzer, O.; Sheldrick, W. S.; Nagel, S.; Rosch, N. Inorg.
Chem. 1996, 35, 4103–4113.
17. Morgan, Jr. T. K.; Lis, R.; Lumma, Jr. W. C.; Nickisch, K.;
Wohl, R. A.; Phillips, G. B.; Gomez, R. P.; Lampe, J. W.;
DiMeo, S. V.; Marisca, A. J.; Forst, J. J. Med. Chem. 1990, 33,
1091–1097.
3. (a) Kaden, T. A. Comprehensive Heterocyclic Chemistry, II,
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier:
Oxford, 1996; Vol. 9, pp 789–807 Chapter 9.28. (b) Gokel,
G. W.; Fedders, M. F. Comprehensive Heterocyclic
Chemistry, II, Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Elsevier: Oxford, 1996; Vol. 9, pp 863–892 Chapter
9.31.
18. Smith, III., W. J.; Sawyer, J. S. Tetrahedron Lett. 1996, 37,
299–302.
19. You, F.; Twieg, R. J. Tetrahedron Lett. 1999, 40, 8759–8762.
20. Wang, C.-C.; Li, J. J.; Huang, H.-C.; Lee, L. F.; Reitz, D. B.
J. Org. Chem. 2000, 65, 2711–2715.
4. Ripka, A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chim.
Lett. 1998, 8, 357–360.
21. Sartori, P.; Bauer, G. J. Fluorine Chem. 1979, 14, 201–221.
22. Baxter, I.; Ben-Haida, A.; Colquhoun, H. M.; Hodge, P.;
Kohnke, F. H.; Williams, D. J. Chem. Eur. J. 2000, 6,
4285–4296.
5. Goldring, W. P. D.; Weiler, L. Org. Lett. 1999, 1, 1471–1473.
6. Hay, R. W.; Richens, D. T.; Wyllie, G.; Danby, A.; Clifford, T.
Transition Met. Chem. 1995, 20, 220–223.
7. Drew, M. G. B.; Rodgers, A.; McCann, M.; Nelson, S. M.
J. Chem. Soc., Chem. Commun. 1978, 415–416.
23. Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379–380.