Bis-heteronucleophilic michael addition to divinyl sulfone: A new efficient access to macrocycles

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<54::AID-EJOC54>3.0.CO;2-R

The Michael addition of bis(nitrogen or sulfur) nucleophiles to divinyl sulfone provides the corresponding macrocyclic adducts in good yields. The structures of some new macrocyclic sulfones are established by X-ray crystallographic analysis and NMR spectroscopy. The subsequent cleavage of benzyl or tosyl groups yields the unprotected macrocyclic sulfones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<54::AID-EJOC54>3.0.CO;2-R

FULL PAPER
Bis-Heteronucleophilic Michael Addition to Divinyl Sulfone: A New Efficient
Access to Macrocycles
Marie-Laure Teyssot,[a] Martine Fayolle,[a] Christian Philouze,[b] and Claude Dupuy*[a]
Keywords: Michael addition / Synthetic methods / Macrocycles / Cryptands / Sulfones
The Michael addition of bis(nitrogen or sulfur) nucleophiles
to divinyl sulfone provides the corresponding macrocyclic
adducts in good yields. The structures of some new macro-
cyclic sulfones are established by X-ray crystallographic ana-
benzyl or tosyl groups yields the unprotected macrocyclic
sulfones.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lysis and NMR spectroscopy. The subsequent cleavage of Germany, 2003)
Introduction
Syntheses of macrocyclic compounds which contain nine
or more atoms in the ring, including at least three het-
eroatoms, have been known for a long time.[1Ϫ5] The con-
densation of two bifunctional fragments is the most usual
strategy for the construction of the macrocyclic system.
Nearly all the syntheses using this approach link nucleo-
philic heteroatoms (Z ϭ N, O, S) with electrophilic carbon
atoms (Scheme 1).
Scheme 2. A new strategy to obtain macrocycles from bis-
Michael acceptors
Conjugate addition is an important bond-forming strat-
egy applied in organic synthesis.[7] The heteronucleophilic
addition to bis-Michael acceptors[8] and the intramolecular
Michael reaction[9] have been used to obtain cyclic com-
pounds, usually five- or six-membered rings. Some diaza-
and oxaazacyclooctenes or -cyclononenes were also pre-
pared from 2,3-bis(phenylsulfonyl)-1,3-butadiene by addi-
tion of various nucleophiles.[10] More recently, Pietrusiewicz
et al. have presented the synthesis of macrocyclic systems
containing phosphorus and sulfur, based on a double con-
jugate addition of dithiolates to vinylphosphane oxides and
sulfides as Michael acceptors.[11]
Scheme 1. Construction of a macrocyclic compound from two frag-
ments
The electrophilic centre is a primary carbon atom bearing
a good leaving group such as iodide, sulfonate or a car-
boxylic function. In the course of our studies of new access
to macrocyclic compounds,[6] we planned the preparation
of macrocycles by bis-heteronucleophilic addition to bis-
Michael acceptors (Scheme 2; EWG ϭ electron-with-
drawing group).
Results and Discussion
In this paper we report our results on the bis-heteronucle-
ophilic Michael addition to divinyl sulfone (EWG ϭ SO2).
The two vinyl groups of this commercially available com-
pound are well known to be activated toward heteronucleo-
philic additions including reactions with amines,[12Ϫ21] alco-
hols,[20,22] thiols,[20,22Ϫ24] phosphanes[25] and sodium perox-
ide.[26] With primary amines, the usual product is the thio-
morpholine 1,1-dioxide derivative. Vinyl sulfones have
become generally accepted as useful intermediates in or-
ganic synthesis.[27Ϫ29] They serve efficiently as both Michael
acceptors and as 2π partners in cycloaddition reactions.
[a]
Laboratoire d’Etudes Dynamiques et Structurales de la
´
´
´
Selectivite (LEDSS 4), UMR CNRS 5616, Universite J. Fourier,
B. P. 53, 38041 Grenoble Cedex 9, France
Fax: (internat.) ϩ 33-4/76514927
E-mail: Claude.Dupuy@ujf-grenoble.fr
[b]
Laboratoire d’Etudes Dynamiques et Structurales de la
´
´
Selectivite (Service de crystallographie), UMR CNRS 5616,
´
Universite J. Fourier,
B. P. 53, 38041 Grenoble Cedex 9, France
54
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0054 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 54Ϫ62

A New Efficient Access to Macrocycles
FULL PAPER
First with a nitrogen atom as the nucleophile, we tried to reaction mixture (Scheme 4). The ratio of the two com-
find the optimal experimental conditions for the inter- pounds has been calculated on the basis of integration in
molecular addition of primary and secondary benzyl- the 1H NMR spectrum. After the first addition of the
amines (Scheme 3).
primary amine, the resulting secondary amine undergoes a
six-membered ring closure which is faster than a second
addition of a primary amine. This 6-endo-trig cyclization is
favored according to Baldwin’s rules.[31]
Since primary amines provide only the thiomorpholine
1,1-dioxide derivatives, it can be concluded that we need to
add secondary amines in order to favor the bis(aza-
Michael) addition to divinyl sulfone (Scheme 2). That is
why we used various bis-secondary amines 1Ϫ8 and bis-
(sulfonamides) 9Ϫ11 (Figure 1). This diversity will allow
the preparation of macrocycles with different sizes.
Scheme 3. Aza-Michael addition of various amines to divinyl sul-
fone
The best results were obtained with protic solvents such
as methanol, propan-2-ol or a water/propan-2-ol mixture
after 2 h of reflux (Table 1). This can be explained by an
easier and faster proton transfer on the enolate-type struc-
ture formed after the addition.[30] We chose propan-2-ol in-
stead of methanol because, in some cases, we observed the
formation of a methanol addition product. This side reac-
tion has been confirmed by refluxing divinyl sulfone in
methanol in the presence of triethylamine: 37% of the meth-
anol adduct are detected after 3 h.
Table 1. Intermolecular additions of benzylamine and dibenzylam-
ine to divinyl sulfone
Solvent[a]
BnNH2 (Ia)
Bn2NH (IIa)
Room temp. Reflux Room temp. Reflux
MeOH
iPrOH
iPrOH/H2O (2:1)
Toluene
CH2Cl2
100
77
98
58
100
100
100
84
88
93
61
84
85
89
93
59
85
30[b]
Figure 1. Utilized bis-secondary amines and tosylamides
48
33[b]
[a]
[b]
Reflux time: 2 h; yield of isolated compound. With monoad-
duct.
N,NЈ-Dibenzylethylenediamine (1) is a commercially
available product. The monoalkylation of a primary poly-
amine is not easy. It often requires an excess of a reactant.
In order to use a simple way to obtain compounds 2 and
6, we chose the reductive amination of benzaldehyde with
the corresponding polyamine in the presence of sodium tri-
acetoxyborohydride,[32] which appeared to give good yields
of monoalkylation.
While compound 3 was easily synthesized by a two-step
sequence from diethylenetriamine by benzoylation followed
by reduction with a global yield of 58%, this method did
not succeed for triethylenetetraamine. Thus, N,NЈ,NЈЈ,NЈЈЈ-
tetrabenzyltriethylenetetraamine (5) was obtained with an
overall yield of 20% using a three-step sequence[33]
(Scheme 5).
The primary amines give exclusively the cyclic adduct
even when they are neopentylic like in tert-butylamine (Ib;
90%; iPrOH) and in aminotris(hydroxymethyl)methane (Ic;
94%; iPrOH). In order to confirm these results with the
same conditions as for macrocyclization, we added
ethylenediamine to divinyl sulfone. This reaction afforded
only six-membered rings as shown in Scheme 7. Only com-
pound Id has been isolated but the presence of Ie was
proved by mass, IR, H and 13C NMR spectra of the crude
1
Diamine 4 was obtained in good yield according to a
previously published method.[34] The reaction of N-benzyl-
ethylenediamine with diethyl oxalate[35] and diethyl malo-
nate[36] provided the bis(amidobenzylamines) 7 and 8, re-
spectively. Standard tosylation methods gave the tosylated
compounds 9, 10 and 11 from the corresponding amines.[37]
Scheme 4. Aza-Michael addition of ethylenediamine to divinyl
sulfone
Eur. J. Org. Chem. 2003, 54Ϫ62
55

M.-L. Teyssot, M. Fayolle, C. Philouze, C. Dupuy
FULL PAPER
tetraazacyclotetradecane) and 1,4,10,13-tetraoxa-7,16-
diazacyclooctadecane, respectively (Scheme 7).
Scheme 5. Synthesis of N,NЈ,NЈЈ,NЈЈЈ-tetrabenzyltriethylenetetra-
amine (5)
Aza-Michael additions of bis-secondary benzylamines on
divinyl sulfone were carried out under the optimal experi-
mental conditions for intermolecular addition, i.e. in a re-
fluxing water/propan-2-ol (1:2) mixture. Reaction times
were determined by monitoring the disappearance of divi-
Scheme 7. Cryptands from commercially available macrocycles
1
nyl sulfone by H NMR spectroscopy. These reactions af-
Concerning the aza-addition of tosylated polyamines, we
used the same standard conditions as for the macrocyclic
formation by bis-nucleophilic substitution, potassium car-
bonate as base in refluxing acetonitrile. By this method, we
managed to obtain three new polyaza macrocyclic sulfones
9a, 10a and 11a with excellent yields (Figure 3). With mac-
rocycle 11a, removal of the tosyl groups was achieved in an
87% yield using the HBr/AcOH/PhOH system[38]
(Scheme 8).
ford new S,S-dioxothiaaza or S,S-dioxooxathiaaza macro-
cycles 1aϪ8a generally with high yields (Figure 2). They
vary in size from nine- to sixteen-membered rings and in-
clude diverse heteroatoms. Compounds 7a and 8a are of
particular interest because they could be selectively depro-
tected and therefore substituted by different groups in order
to change their properties.
Figure 3. New S,S-dioxothia macrocycles from divinyl sulfone
and bis(sulfonamides)
Figure 2. New S,S-dioxothia macrocycles from divinyl sulfone and
bis-secondary amines
Benzyl groups can be easily removed by hydrogenolysis,
for example 1,4-dioxa-10-thia-7,13-diazacyclopentadecane
10,10-dioxide (6b) was obtained in 98% yield (Scheme 6).
Scheme 8. Cleavage of tosyl groups
Scheme 6. Cleavage of benzyl groups in an S,S-dioxothia macrocycle
The two cryptands 12 and 13 were also prepared by the
Figure 4. New thia and oxathia macrocyclic sulfones from divinyl
same method from commercially available cyclam (1,4,7,10- sulfone and bis(thiols)
56
Eur. J. Org. Chem. 2003, 54Ϫ62

A New Efficient Access to Macrocycles
FULL PAPER
Figure 5. ORTEP drawings of the crystal structures of compounds 13 and 16a
Previous studies have shown that thiols, in the presence Experimental Section
of a base, react with divinyl sulfone to give the monoad-
duct[23] and/or the diadduct[20] according to experimental
conditions. As for amines, we first tried to add phenylmeth-
anethiol to divinyl sulfone in the presence of triethylam-
ine[39] in a water/propan-2-ol mixture (pH ϭ 8Ϫ9). This
reaction afforded 98% of the diadduct. We applied these
experimental conditions to the following commercially
available thiols: bis(2-mercaptoethyl) sulfide (14), bis(2-mer-
captoethyl) ether (15) and 4,7-dioxa-1,10-dithiadecane (16).
General Remarks: All chemicals were used as purchased unless
otherwise noted. Tetrahydrofuran was distilled under argon from
sodium/benzophenone ketyl. Acetonitrile and toluene were dried
˚
with 4-A molecular sieves prior to use. Analytical thin layer chro-
matography (TLC) was performed using Merck silica gel 60F254
aluminum sheets and spots were visualized using a UV lamp
(254 nm), iodide and/or a phosphomolybdic acid solution (5% in
ethanol). Liquid column chromatography and flash column chro-
matography were performed using Merck silica gel 60
As expected, the thia or oxathia macrocyclic sulfones 14a, (0.06Ϫ0.2 mm) and Merck silica gel 60 (0.04Ϫ0.06 mm), respect-
ively. Melting points were determined in open capillaries using a
Büchi 530 apparatus and are uncorrected. Infrared spectra were
recorded with a Nicolet Impact 400 FT spectrometer as films on
KBr plates for liquids and as KBr discs for solids. 1H and 13C
NMR spectra were recorded with a Bruker Avance 300 (1H:
300 MHz; 13C: 75.47 MHz) and a Varian 500 (1H: 500 MHz; 13C:
125.76 MHz). Chemical shifts δ are given in ppm relative to TMS
in CDCl3 as solvent or relative to the solvent chemical shift for
others. Coupling constants J are given in Hz. The following abbre-
viations are used: s singlet, d doublet, dd doublet of doublet, t
15a and 16a were obtained in good yields (Figure 4).
The Michael addition is reversible. The retro-Michael re-
action can occur mainly in the presence of a base. For ex-
ample, this reaction is used to cleave products prepared on
sulfonyl resins.[40] It is noteworthy that, in our case, no re-
tro-reaction was observed even in the presence of butylli-
thium when we performed α-alkylation experiments or by
refluxing the cyclic Michael adduct Ia overnight in a pro-
pan-2-ol/20% aqueous NaOH mixture. Furthermore, these
macrocyclic sulfones remain unchanged on silica gel, al- triplet, q quadruplet, quin quintuplet, m multiplet and ps pseudo.
Mass spectra were obtained with a ThermoFinnigan PolarisQ spec-
trometer with an ionic trap as detector. Elemental analyses were
determined by the Service Central d’Analyse du CNRS (Vernai-
son, France).
though this technique has been used to generate conjugate
systems,[41] or in acidic media like for the cleavage of tosyl
groups (Scheme 8).
All the new macrocycles were characterized by NMR
spectroscopy (1H, 13C, DEPT, COSY, HMQC, HMBC) and
Starting Materials: Divinyl sulfone (DVS), N,NЈ-dibenzylethylene-
for some of them (2a, 9a, 13, 16a), the isolated crystals were diamine, N-benzylethylenediamine, 1,3-diaminopropane, diethyl-
suitable for crystal structure analysis.[42] The structures ob-
enetriamine, diethyl oxalate, diethyl malonate, benzylamine, di-
benzylamine, tert-butylamine, tris(aminomethyl)aminomethane,
ethylenediamine, bis(2-mercaptoethyl) sulfide (14), bis(2-mercapto-
ethyl) ether (15) and 4,7-dioxa-1,10-dithiadecane (16) are commer-
cial. 1,7-Dibenzyl-4-oxa-1,7-diazaheptane (4), 1,4,7-tritosyl-1,4,7-
triazaheptane (9), 1,5,9,13-tetratosyl-1,5,9,13-tetraazatridecane
tained for cryptand 13 and macrocycle 16a are presented
in Figure 5.
Conclusion
(10), 1,5,10,14-tetratosyl-1,5,10,14-tetraazatetradecane (11) and N-
In summary, a facile synthesis of macrocyclic sulfones benzyl-2-bromoacetamide were prepared according to literature
procedures.
has been reported. The aza- or thia-Michael addition to
divinyl sulfone opens up an efficient approach to a great
variety of macrocycles. Their complexation ability is under
investigation. We also expand this strategy to other bis-
Michael acceptors such as divinyl ketone or aryl(vinyl)-
phosphane oxides.[43]
1,5-Dibenzyl-1,5-diazapentane (2): Benzaldehyde (2.12 g, 20 mmol)
and sodium triacetoxyborohydride (5.93 g, 28 mmol) in acetonitrile
(50 mL) were added successively to a stirred solution of 1,3-di-
aminopropane (741 mg, 10 mmol) in dry acetonitrile (50 mL),
under Ar. The reaction mixture was stirred at room temperature
Eur. J. Org. Chem. 2003, 54Ϫ62
57

M.-L. Teyssot, M. Fayolle, C. Philouze, C. Dupuy
FULL PAPER
for 20 h. Excess hydride was then neutralized by addition of 1 
aqueous NaOH solution until the white solid disappeared. The
aqueous phase was extracted with ethyl acetate (3 ϫ 50 mL), the
combined organic phases were dried with anhydrous sodium sulfate
and the solvent was evaporated. The crude product was purified by
column chromatography (CHCl3/MeOH/NH4OH, 100:0:0 to
89:10:1) to afford diamine 2 as a pale yellow oil (1.66 g, 6.5 mmol,
1,4,7,10-Tetrabenzyl-2,9-dioxo-1,4,7,10-tetraazadecane: Potassium
iodide (0.664 g, 4 mmol), triethylamine (445 mg, 4.4 mmol) and
N,NЈ-dibenzylethylenediamine (481 mg, 2 mmol) were added to a
stirred solution of N-benzyl-2-bromoacetamide (912 mg, 4 mmol)
in dry toluene (130 mL) under Ar. The reaction mixture was then
refluxed overnight. After evaporation of the solvent, the residue
was taken up in chloroform (100 mL) and washed successively with
1% aqueous hydrochloric acid solution (50 mL), water (50 mL) and
1
3
65%). H NMR (300 MHz, CDCl3): δ ϭ 1.75 (quint, J ϭ 6.6 Hz,
2 H), 2.73 (t, 3J ϭ 6.6 Hz, 4 H), 3.15 (br. s, 2 H), 3.78 (s, 4 H), saturated aqueous sodium hydrogen carbonate solution (50 mL).
7.24Ϫ7.31 (m, 10 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ
The organic phase was next dried with anhydrous Na2SO4 and re-
29.3, 48.0, 53.8, 127.0, 128.1, 128.4, 139.7 ppm. IR: ν˜ ϭ 3286 (NH), duced to dryness. Purification by column chromatography (CHCl3/
3081, 3028 (CHAr), 2928, 2807 (CH), 1455, 1121, 741, 703 (CHAr)
MeOH/NH4OH, 99.5:0.5:0.05) afforded the diamide (900 mg,
cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 108 (4) [BnNH2
ϩ
1.68 mmol, 84%) as a white solid. M.p. 123Ϫ124 °C. 1H NMR
H]ϩ, 120 (7) [BnNHCH2]ϩ, 255 (100) [M ϩ H]ϩ. C17H22N2 (254.4) (300 MHz, CDCl3): δ ϭ 2.58 (s, 4 H), 3.06 (s, 4 H), 3.47 (s, 4 H),
3
ϩ 1/2 H2O: calcd. C 77.52, H 8.80, N 10.64; found C 77.61, H
8.70, N 10.53.
4.35 (d, J ϭ 6.0 Hz, 4 H), 7.06 (br. s, 2 H), 7.16Ϫ7.28 (m, 20 H)
ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 43.0, 52.5, 58.1, 59.7,
127.5, 127.6, 128.6, 128.7, 128.9, 137.3, 138.3, 170.6 ppm. IR: ν˜ ϭ
3377 (NH), 3080, 3020 (CHAr), 2936, 2845 (CH), 1683 (CO), 1531
(NH), 1463, 1212, 756 (CHAr) cmϪ1. MS (DCI, NH3/isobutane):
m/z (%) ϭ 338 (11) [M Ϫ 2 BnO ϩ 2 H]ϩ, 535 (100) [M ϩ H]ϩ.
C34H38N4O2 (534.7): calcd. C 76.37, H 7.16, N 10.48; found C
75.79, H 7.11, N 10.47.
1,4,7-Tribenzoyl-1,4,7-triazaheptane: A mixture of triethylamine
(3.34 g, 33 mmol) and diethylenetriamine (1.03 g, 10 mmol) in tolu-
ene (20 mL) was added dropwise to a cold solution (0 °C) of
benzoyl chloride (4.22 g, 30 mmol) in dry toluene (40 mL) under
Ar. At the end of the addition, the reaction mixture was allowed
to warm to room temperature and stirred overnight. The solvent
was evaporated and the residue taken up with CHCl3 (100 mL), 1,4,7,10-Tetrabenzyl-1,4,7,10-tetraazadecane (5): LiAlH4 (114 mg,
washed successively with 3  hydrochloric acid solution (50 mL),
2  sodium hydroxide solution (40 mL), water (40 mL) and brine
(40 mL). The organic phase was dried with anhydrous Na2SO4 and
reduced to dryness. The crude product was then crystallized in ethyl
acetate to afford a white solid (3.01 g, 7.25 mmol, 73%). M.p.
126Ϫ127 °C. 1H NMR (300 MHz, CD3OD): δ ϭ 3.52 (br. t, 2 H),
3 mmol) was added in small portions to a stirred solution of
1,4,7,10-tetrabenzyl-2,9-dioxo-1,4,7,10-tetraazadecane (535 mg,
1 mmol), in anhydrous THF (70 mL) under Ar at 0 °C. After the
gas evolution had ceased, the reaction mixture was allowed to
warm to room temperature and refluxed overnight. It was then
cooled to 0 °C and water (0.1 mL), 15% aqueous NaOH (0.1 mL)
3.63 (br. t, 2 H), 3.80 (br. t, 2 H), 3.91 (br. t, 2 H), 7.24Ϫ7.88 (m, and water (3 mL) were added successively. The grey precipitate was
15 H), 7.54 (br. s, 2 H) ppm. 13C NMR (75.47 MHz, CD3OD): δ ϭ filtered off and the filtrate reduced to dryness. The residue was
39.3, 39.5, 46.3, 50.4, 128.1, 128.7, 130.0, 131.0, 133.2, 135.6, 136.0,
137.8, 170.4, 171.0, 175.5 ppm. IR: ν˜ ϭ 3323 (NH), 3065, 3012
taken up in chloroform (60 mL) and washed with brine (40 mL).
The organic phase was dried with anhydrous Na2SO4 and the sol-
(CHAr), 2951 (CH), 1630 (CO), 1538 (NH), 1417, 1296, 1242, vent evaporated. The residue was purified by column chromato-
1182, 794, 696 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z
graphy (CHCl3/MeOH/NH4OH, 98:2:0.1 to 89:10:1) yielding 5
(%) ϭ 104 (19) [PhCO]ϩ, 416 (100) [M ϩ H]ϩ. C25H25N3O3 (415.5): (140 mg, 0.28 mmol, 28%) as light brown oil. 1H NMR
a
calcd. C 72.27, H 6.06, N 10.11; found C 72.01, H 5.94, N 10.11.
(300 MHz, CDCl3): δ ϭ 2.54 (s, 4 H), 2.57Ϫ2.67 (m, 8 H), 2.90
(br. s, 2 H), 3.48 (s, 4 H), 3.65 (s, 4 H), 7.18Ϫ7.26 (m, 20 H) ppm.
13C NMR (75.47 MHz, CDCl3): δ ϭ 46.4, 51.9, 53.4, 53.6, 59.0,
126.8, 126.9, 128.16, 128.2, 128.3, 128.8, 139.2, 139.7 ppm. IR: ν˜ ϭ
3331 (NH), 3065, 3035 (CHAr), 2929, 2800 (CH), 1500, 1447, 749,
696 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ108 (11)
[BnNH2 ϩ H]ϩ, 120 (7) [BnNHCH2]ϩ, 134 (15) [BnNHCH2CH2]ϩ,
148 (18) [BnNHCH2CH2N]ϩ, 241 (11) [BnNHCH2CH2NHBn ϩ
H]ϩ, 253 (20) [BnNHCH2CH2NHBnCH2]ϩ, 267 (12)
[MeBnNCH2CH2NHBnCH2]ϩ, 507 (100) [M ϩ H]ϩ. C34H42N4
(506.7) ϩ 1/2 H2O: calcd. C 79.18, H 8.40, N 10.86; found C 79.27,
H 8.44, N 11.03.
1,4,7-Tribenzyl-1,4,7-triazaheptane (3): Lithium aluminum hydride
(3.4 g, 89 mmol) was added in small portions to a stirred, cold (0
°C) suspension of 1,4,7-tribenzoyl-1,4,7-triazaheptane (3.1 g,
7.47 mmol) in anhydrous tetrahydrofuran (100 mL) under Ar. The
temperature was maintained at 0 °C until gas emission had ceased.
The reaction mixture was then allowed to warm to room temper-
ature and refluxed overnight. The excess hydride was neutralized by
adding successively water (3.4 mL), 15% aqueous sodium hydroxide
solution (3.4 mL) and water (10.2 mL). The precipitate was filtered
off and the filtrate reduced to dryness under reduced pressure. The
residue was taken up in chloroform (100 mL) and washed with
brine (50 mL). The organic phase was dried with anhydrous
Na2SO4 and the solvent evaporated. The crude product was then
purified by column chromatography (CHCl3/MeOH/NH4OH,
1,10-Dibenzyl-4,7-dioxa-1,10-diazadecane
(6):
Benzaldehyde
(212 mg, 2 mmol) was added at room temperature to a stirred solu-
tion of 4,7-dioxa-1,10-diazadecane (148 mg, 1 mmol) in dry aceto-
100:0:0 to 88:10:2) yielding 3 (2.2 g, 5.9 mmol, 79%) as a colorless nitrile (10 mL) under Ar. Sodium triacetoxyborohydride (593 mg,
1
oil. H NMR (300 MHz, CDCl3): δ ϭ 2.06 (br. s, 2 H), 2.57Ϫ2.69 2.8 mmol), suspended in dry acetonitrile (20 mL), was then added.
(m, 8 H), 3.53 (s, 2 H), 3.67 (s, 4 H), 7.20Ϫ7.27 (m, 15 H) ppm.
After 20 h of stirring at room temperature, excess hydride was neu-
13C NMR (75.47 MHz, CDCl3): δ ϭ 46.7, 53.6, 53.9, 59.2, 126.7, tralized by adding 1  aqueous sodium hydroxide solution (10 mL).
126.8, 128.0, 128.1, 128.2, 128.7, 139.4, 140.2 ppm. IR: 3309 (NH),
3050, 3035 (CHAr), 2936, 2807 (CH), 1500, 1463, 749, 703 (CHAr)
The phases were separated and the aqueous phase was extracted
with ethyl acetate (3ϫ10 mL). The combined organic phases were
cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 91 (16) [Bn]ϩ, 193 washed with brine (30 mL), dried with anhydrous Na2SO4 and the
(14) [M Ϫ 2 Bn ϩ 2 H]ϩ, 269 (26) [M Ϫ BnNH2]ϩ, 281 (14) [M Ϫ
solvents evaporated. The residue was then purified by column chro-
PhCH3]ϩ, 374 (100) [M ϩ H]ϩ, 391 (6) [M ϩ NH4]ϩ. C25H31N3 matography (CHCl3/MeOH/NH4OH, 100:0:0 to 94.5:5:0.5) and
1
(373.5): calcd. C 80.39, H 8.37, N 11.25; found C 79.82, H 8.23,
N 11.20.
yielded diamine 6 as a colorless oil (215 mg, 0.65 mmol, 65%). H
NMR (300 MHz, CDCl3): δ ϭ 1.82 (br. s, 2 H), 2.79 (t, 3J ϭ
58
Eur. J. Org. Chem. 2003, 54Ϫ62

A New Efficient Access to Macrocycles
FULL PAPER
5.25 Hz, 4 H), 3.59 (m, 8 H), 3.79 (s, 4 H), 7.25Ϫ7.31 (m, 10 H) H), 3.65 (s, 2 H), 7.26Ϫ7.34 (m, 5 H) ppm. 13C NMR (75.47 MHz,
ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 48.7, 53.8, 70.2, 70.6,
CDCl3): δ ϭ 50.5, 51.0, 61.4, 127.6, 128.5, 128.7, 137.2 ppm. IR:
126.8, 128.1, 128.3, 140.3 ppm. IR: ν˜ ϭ 3323 (NH), 3096, 3065 ν˜ ϭ 3058, 3005 (CHAr), 2950, 2830 (CH), 1272, 1136 (SO2), 749,
(CHAr), 2868 (CH), 1455, 1121, 748, 703 (CHAr) cmϪ1. MS (DCI, 703 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 226 (100)
NH3/isobutane): m/z (%) ϭ 329 (100) [M ϩ H]ϩ. C20H28N2O2 [M ϩ H]ϩ. C11H15NO2S (225.3): calcd. C 58.64, H 6.71, N 6.22, S
(328.5): calcd. C 73.14, H 8.59, N 8.53; found C 72.86, H 8.82,
N 8.53.
14.23; found C 58.31, H 6.65, N 6.28, S 14.11.
4-tert-Butylthiomorpholine 1,1-Dioxide (Ib): A solution of DVS
(472 mg, 4 mmol) in iPrOH (6 mL) was added dropwise to a stirred
refluxing solution of tert-butylamine (292 mg, 4 mmol). Reaction
was completed within 1.5 h and a column chromatography puri-
fication (CHCl3/MeOH, 100:0 to 98:2) afforded thiomorpholine Ib
(728 mg, 3.8 mmol, 95%) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.12 (s, 9 H), 3.04 (m, 8 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 26.6, 44.5, 52.6, 54.6 ppm. IR: ν˜ ϭ 2982,
2875, 2830 (CH), 1334, 1303 (SO2), 1265, 1128 (SO2), 1045, 855,
718 cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 136 (26) [M Ϫ
tBu ϩ 2 H]ϩ, 192 (100) [M ϩ H]ϩ. C8H17NO2S (191.3): calcd. C
50.23, H 8.96, N 7.32, S 16.76; found C 50.56, H 9.06, N 7.28,
S 16.73.
1,10-Dibenzyl-5,6-dioxo-1,4,7,10-tetraazadecane (7): Diethyl oxal-
ate (1.46 g, 10 mmol) was added to a stirred solution of N-benzyle-
thylenediamine (3.0 g, 20 mmol) in ethanol (50 mL) . The reaction
mixture was stirred at room temperature overnight. The residue
was crystallized in an MeOH/EtOH mixture and the white precipi-
tate was filtered off. The filtrate was reduced to dryness and puri-
fied by column chromatography (CHCl3/MeOH/NH4OH, 98:2:0.1
to 89:10:1) affording 7 (2.61 g, 7.4 mmol, 74%) as a yellow solid.
M.p. 67Ϫ68 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 1.59 (br. s, 2
H), 2.81 (t, 3J ϭ 6.0 Hz, 4 H), 3.41 (q, 3J ϭ 6.0 Hz, 4 H, 3J ϭ
5.9 Hz), 3.79 (s, 4 H), 7.23Ϫ7.28 (m, 10 H), 7.85 (br. t, 2 H) ppm.
13C NMR (75.47 MHz, CDCl3): δ ϭ 39.4, 47.6, 53.4, 127.0, 128.0,
128.4, 139.9, 160.0 ppm. IR: ν˜ ϭ 3316 (NH), 3096, 3065, 3035
(CHAr), 2929, 2830 (CH), 1683 (CO), 1516, 1455, 1356, 1129, 1037,
741, 711 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 205
(8) [M Ϫ BnNHCH2CH2NH]ϩ, 222 (100) [M Ϫ BnNHCH2CH2 ϩ
2 H]ϩ, 355 (10) [M ϩ H]ϩ. C20H26N4O2 (354.5): calcd. C 67.77, H
7.39, N 15.81; found C 67.56, H 7.32, N 15.48.
4-[Tris(hydroxymethyl)methyl]thiomorpholine 1,1-Dioxide (Ic): DVS
(236 mg, 2 mmol) was added to a stirred solution of [tris(hydroxy-
methyl)amino]methane (242 mg, 2 mmol) in propan-2-ol. After re-
fluxing the reaction mixture for 3 h, the crude product was crystal-
lized from methanol and Ic was isolated as a white solid (450 mg,
1.88 mmol, 94%). M.p. 165 °C. 1H NMR (300 MHz, (CD3)2SO):
δ ϭ 3.05Ϫ3.07 (m, 4 H), 3.22Ϫ3.24 (m, 4 H), 3.48 (d, 3J ϭ 5.0 Hz,
6 H), 4.40 (t, 3J ϭ 5.0 Hz, 3 H) ppm. 13C NMR [75.47 MHz,
(CD3)2SO]: δ ϭ 45.9, 53.5, 61.5, 54.6 ppm. IR: ν˜ ϭ 3306 (OH),
2998, 2867 (CH), 1294, 1124 (SO2) cmϪ1. MS (DCI, NH3/
isobutane): m/z (%) ϭ 208 (10) [M Ϫ CH2OH]ϩ, 240 (100) [M ϩ
H]ϩ. C8H17NO5S (239.3): calcd. C 40.15, H 7.16, N 5.85, found C
40.79, H 7.26, N 6.14.
1,11-Dibenzyl-5,7-dioxo-1,4,8,11-tetraazaundecane (8): Diethyl ma-
lonate (1.6 g, 10 mmol) was added to a stirred solution of N-
benzylethylenediamine (3.0 g, 20 mmol) in chloroform (10 mL) and
the reaction mixture was heated at 50 °C for 48 h. The resulting
pink solution was then concentrated and the residue purified by
column chromatography (CHCl3/MeOH/NH4OH, 94.5:5:0.5) to af-
1
ford compound 8 (2.55 g, 6.9 mmol, 69%) as a light brown oil. H
NMR (300 MHz, CDCl3): δ ϭ 1.92 (br. s, 2 H), 2.75 (t, 3J ϭ
5.9 Hz, 4 H), 3.14 (s, 2 H), 3.34 (td, 4 H, 3J ϭ 5.8, 3J7Ϫ8 ϭ 5.9 Hz),
3.76 (s, 4 H), 7.26Ϫ7.32 (m, 10 H), 7.40 (br. t, 2 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 39.2, 43.2, 47.8, 53.4, 127.1, 128.1, 128.4,
139.9, 167.5 ppm. IR: ν˜ ϭ 3294 (NH), 3088, 3020 (CHAr), 2937,
1,2-Bis(1,1-dioxothiomorpholin-4-yl)ethane (Id): The reaction be-
tween DVS (118 mg, 1 mmol) and ethylenediamine (30 mg,
0.5 mmol) was completed within 1 h. Purification by flash column
chromatography (CHCl3/MeOH, 100:0 to 95:5) afforded Id
1
(140 mg, 0.47 mmol, 95%) as a white solid. M.p. 215Ϫ216 °C. H
2845 (CH), 1660 (CO), 1562 (NH), 1462, 741, 711 (CHAr) cmϪ1
.
NMR (300 MHz, CD3OD): δ ϭ 2.69 (s, 4 H), 3.04Ϫ3.10 (m, 16
H) ppm. 13C NMR (75.47 MHz, (CD3OD): δ ϭ 51.8, 51.95,
54.8 ppm. IR: ν˜ ϭ 2980, 2914, 2873 (CH), 1314, 1134 (SO2), 1291,
1191, 1044, 963, 873, 734 cmϪ1. MS (DCI, NH3/isobutane): m/z
(%) ϭ 297 (100) [M ϩ H]ϩ. C10H20N2O4S2 (296.4): calcd. C 40.52,
H 6.80, N 9.45, S 21.64; found C 40.68, H 6.89, N 9.46, S 21.59.
MS (DCI, NH3/isobutane): m/z (%) ϭ351 (20) [M Ϫ OH]ϩ, 369
(100) [M ϩ H]ϩ. C21H28N4O2 (368.5): calcd. C 68.45, H 7.66, N
15.21; found C 68.69, H 7.67, N 15.10.
General Procedure for the Conjugate Addition of Heteronucleophiles
to Divinyl Sulfone (DVS): DVS (0.02  in propan-2-ol) was added
dropwise to a stirred refluxing solution of the nucleophile (0.01 
in a propan-2-ol/water, 1:1). At the end of the addition, reflux was
maintained for at least 1 h. Reaction advancement was monitored
1,1,7,7-Tetrabenzyl-4-thia-1,7-diazaheptane 4,4-Dioxide (IIa): DVS
(59 mg, 0.5 mmol) was added to dibenzylamine (197 mg, 1 mmol)
and refluxed for 2 h. The residue was purified by flash column
chromatography (CHCl3) and IIa isolated as a white oil (237 mg,
0.46 mmol, 92%). 1H NMR (300 MHz, CDCl3): δ ϭ 2.89Ϫ2.97 (m,
8 H), 3.55 (s, 8 H), 7.23Ϫ7.31 (m, 20 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 46.6, 51.3, 58.5, 127.4, 128.4, 128.8,
138.3 ppm. IR: 3080, 3052, 3020 (CHAr), 2950, 2798 (CH), 1500,
1456, 1317, 1140 (SO2), 700 (CHAr) cmϪ1. MS (DCI, NH3/
isobutane): m/z (%) ϭ 91 (10) [Bn]ϩ, 316 (8) [M Ϫ NBn2]ϩ, 332 (8)
[M Ϫ 2 Bn ϩ 2 H]ϩ, 513 (100) [M ϩ H]ϩ. C32H36N2O2S (512.7):
calcd. C 74.96, H 7.08, N 5.46, S 6.25; found C 74.67, H 7.13, N
5.41, S 6.56.
1
by the disappearance of the vinylic proton signal in the H NMR
spectrum. When this signal disappeared or when its intensity no
longer evolved, the reaction mixture was reduced to dryness under
reduced pressure. (a) In the case of dibenzylamine, ethylenediamine
or phenylmethanethiol, the concentration of the nucleophile was
0.02 . (b) When the nucleophile was sulfur the solution was
brought to pH ϭ 8Ϫ9 by adding a few drops of triethylamine.
(c) For the conjugate addition of sulfonamides, the reaction was
carried out in acetonitrile in the presence of potassium carbonate
(1 equiv. by NH function) under Ar.
4-Benzylthiomorpholine 1,1-Dioxide (Ia): Benzylamine (107 mg,
4,7-Dibenzyl-1-thia-4,7-diazacyclononane 1,1-Dioxide (1a): DVS
1 mmol) was treated with DVS (118 mg, 1 mmol). The reaction was (59 mg, 0.5 mmol) and N,NЈ-dibenzylethylenediamine (120 mg,
completed within 1 h and Ia was obtained pure and quantitatively
0.5 mmol) were refluxed for 1 h. 1a was isolated by flash column
(225 mg, 1 mmol) as a white solid. M.p. 77Ϫ78 °C (ref.[16] 74
chromatography (CHCl3) as a white solid (179 mg, 0.5 mmol,
°C).1H NMR (300 MHz, CDCl3): δ ϭ 2.98 (ps t, 4 H), 3.05 (ps t, 4 100%). M.p. 107Ϫ108 °C. H NMR (300 MHz, CDCl3): δ ϭ 2.25
1
Eur. J. Org. Chem. 2003, 54Ϫ62
59

M.-L. Teyssot, M. Fayolle, C. Philouze, C. Dupuy
FULL PAPER
(s, 4 H), 3.02 (t, J ϭ 5.45 Hz, 4 H), 3.68 (m, 8 H), 7.23Ϫ7.31 (m, 1022, 741, 703 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z
3
10 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 52.3, 55.0, 55.3,
63.4, 127.4, 128.4, 129.4, 138.3 ppm. IR: ν˜ ϭ 3096, 3073, 3012
(%) ϭ 625 (100) [M ϩ H]ϩ. C38H48N4O2S (624.9) ϩ H2O: calcd.
C 70.99, H 7.84, N 8.71, S 4.99; found C 71.35, H 7.76, N 8.44,
(CHAr), 2921, 2822 (CH), 1272 (SO2), 1219, 1136 (SO2), 1113, 711, S 4.74.
680 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 359 (100)
7,13-Dibenzyl-1,4-dioxa-10-thia-7,13-diazacyclopentadecane 10,10-
[M ϩ H]ϩ. C20H26N2O2S (358.5): calcd. C 67.01, H 7.31, N 7.81,
Dioxide (6a): Diamine 6 (328 mg, 1 mmol) and DVS (118 mg,
1 mmol) were refluxed overnight. After purification by column
chromatography (cyclohexane/ethyl acetate, 5:5), macrocycle 6a
S 8.94; found C 66.57, H 7.36, N 7.80, S 8.68.
4,8-Dibenzyl-1-thia-4,8-diazacyclodecane 1,1-Dioxide (2a):
2
1
(510 mg, 2 mmol) and DVS (236 mg, 2 mmol) were refluxed over-
was isolated as a yellow oil (245 mg, 0.55 mmol, 55%). H NMR
3
night and the macrocycle 2a was isolated by column chromato-
(300 MHz, CDCl3): δ ϭ 2.66 (t, J ϭ 4.5 Hz, 4 H), 3.15Ϫ3.32 (m,
graphy (CHCl3/MeOH, 99.9:0.1) as translucent crystals (680 mg, 8 H), 3.51 (t, 3J ϭ 4.5 Hz, 4 H), 3.55 (s, 4 H), 3.66 (s, 4 H),
1.82 mmol, 91%). M.p. 143Ϫ144 °C. 1H NMR (300 MHz, CDCl3): 7.26Ϫ7.33 (m, 10 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ
3
δ ϭ 1.39 (quint, 2 H, J ϭ 6.0 Hz), 2.49 (br. s, 4 H), 2.88 (br. s, 4
48.2, 52.1, 53.3, 60.0, 70.3, 70.5, 127.2, 128.3, 128.8, 138.6 ppm.
IR: ν˜ ϭ 3088, 3020 (CHAr), 2929, 2853 (CH), 1455, 1371, 1288,
H), 3.24 (br. s, 4 H), 3.57 (s, 4 H), 7.22Ϫ7.32 (m, 10 H) ppm. 13C
NMR (75.47 MHz, CDCl3): δ ϭ 23.4, 48.0, 50.2, 52.7, 59.9, 127.5, 1121 (SO2), 1068, 749, 711 (CHAr) cmϪ1. MS (DCI, NH3/
128.4, 129.7, 137.2 ppm. IR: ν˜ ϭ 3063, 3028 (CHAr), 2976, 2920,
isobutane): m/z (%) ϭ 447 (100) [M ϩ H]ϩ. C24H34N2O4S (446.6):
calcd. C 64.54, H 7.67, N 6.27, S 7.18; found C 64.80, H 7.89, N
6.27, S 7.37.
2802 (CH), 1500, 1450, 1282, 1128 (SO2), 889, 748 (CHAr) cmϪ1
.
MS (DCI, NH3/isobutane): m/z (%) ϭ 109 (11) [BnNH4]ϩ, 282 (13)
[M Ϫ Bn ϩ H]ϩ, 373 (100) [M ϩ H]ϩ. C21H28N2O2S (372.5): calcd.
C 67.71, H 7.58, N 7.52, S 8.61; found C 67.71, H 7.59, N 7.60,
S 8.65.
1,4-Dioxa-10-thia-7,13-diazacyclopentadecane 10,10-Dioxide (6b):
6a (154 mg, 0.35 mmol) in ethanol (10 mL) was added to a suspen-
sion of 10% Pd/C (30 mg) in THF (10 mL) and the reaction mix-
ture was stirred for 2 d at room temperature under H2. The solution
4,7,10-Tribenzyl-1-thia-4,7,10-triazacyclododecane 1,1-Dioxide (3a):
Triamine 3 (374 mg, 1 mmol) was refluxed with DVS (118 mg, was filtered through Celite and reduced to dryness. The residue was
1 mmol) overnight. 3a was obtained after purification by column taken up in water (20 mL) and washed with diethyl ether (3 ϫ
chromatography (CHCl3/MeOH/NH4OH, 99:0.5:0.05) as a pale 10 mL). Solvent evaporation afforded pure 6b (90 mg, 0.34 mmol,
yellow oil (440 mg, 0.9 mmol, 90%). 1H NMR (300 MHz, CDCl3):
98%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ ϭ
3
3
δ ϭ 2.49Ϫ2.59 (m, 8 H), 3.08 (t, J ϭ 6.3 Hz, 4 H), 3.37 (t, J ϭ 2.76Ϫ2.80 (m, 6 H), 3.13 (t, 3J ϭ 5.5 Hz, 4 H), 3.40 (t, 3J ϭ 5.5 Hz,
6.3 Hz, 4 H), 3.44 (s, 2 H), 3.54 (s, 4 H), 7.22Ϫ7.29 (m, 15 H) ppm. 4 H), 3.62 (s, 4 H), 3.63 (m, 4 H) ppm. 13C NMR (75.47 MHz,
13C NMR (75.47 MHz, CDCl3): δ ϭ 48.7, 51.8, 52.1, 53.0, 58.8, CDCl3): δ ϭ 43.7, 49.0, 54.4, 69.7, 70.2 ppm. IR: ν˜ ϭ 3362 (NH),
60.3, 127.1, 127.3, 128.2, 128.3, 129.2, 129.6, 138.1, 138.4 ppm. IR:
2952, 2830 (CH), 1668, 1455, 1409, 1288, 1120 (SO2), 1030 cmϪ1
MS (DCI, NH3/isobutane): m/z (%) 149 (4)
.
ν˜ ϭ 3080, 3020 (CHAr), 2959, 2800 (CH), 1470, 1380, 1288, 1128
ϭ
(SO2), 741, 703 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z [(H2NCH2CH2OCH2)2 ϩ H]ϩ, 267 (100) [M ϩ H]ϩ. C25H34N4O4S
(%) ϭ 91 (100) [Bn]ϩ, 492 (53) [M ϩ H]ϩ. C29H37N3O2S (491.7) ϩ (266.4) ϩ 1/2 H2O: calcd. C 43.62, H 8.42, N 10.17; found C 43.70,
3/2 H2O: calcd. C 67.15, H 7.77, N 8.10, S 6.18; found C 66.97, H
7.21, N 7.95, S 6.23.
H 8.23, N 10.00.
4,13-Dibenzyl-8,9-dioxo-1-thia-4,7,10,13-tetraazacyclopentadecane
4,10-Dibenzyl-1-oxa-7-thia-4,10-diazacyclododecane
7,7-Dioxide
1,1-Dioxide (7a): DVS (118 mg, 1 mmol) was added to compound
(4a): DVS (118 mg, 1 mmol) was added to diamine 4 (284 mg, 7 (354 mg, 1 mmol) and the reaction mixture was stirred at reflux
1 mmol) and the reaction mixture was refluxed for 1 h. Purification overnight. Purification of the residue by column chromatography
by column chromatography (cyclohexane/ethyl acetate, 7:3; Et3N
(CH2Cl2/MeOH, 99:1) afforded macrocycle 7a (174 mg, 0.37 mmol,
1%) yielded 4a as a white solid (241 mg, 0.6 mmol, 60%). M.p.
37%) as a white solid. M.p. Ͼ 220 °C. 1H NMR (300 MHz,
3
73Ϫ74 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 2.67 (t, J ϭ 4.4 Hz, CDCl3): δ ϭ 2.66Ϫ2.69 (m, 4 H), 2.89 (s, 8 H), 3.28Ϫ3.34 (m, 4
3
3
3
4 H), 3.14 (ps t, 4 H, J ϭ 6.4, J ϭ 6.9 Hz), 3.29 (ps t, 4 H, J ϭ
6.4, 3J ϭ 6.9 Hz), 3.37 (t, 3J ϭ 4.4 Hz, 4 H), 3.69 (s, 4 H), ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 38.0, 48.1, 52.9, 53.5,
7.26Ϫ7.33 (m, 10 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ
59.8, 127.7, 128.6, 129.3, 137.7, 160.6 ppm. IR: ν˜ ϭ 3290 (NH),
H), 3.70 (s, 4 H), 7.25Ϫ7.36 (m, 10 H), 7.65 (br. t, 2 H, 3J ϭ 6.5 Hz)
50.1, 51.3, 53.9, 61.3, 70.6, 127.3, 128.3, 129.0, 138.4 ppm. IR: ν˜ ϭ 3077 (CHAr), 2979, 2922, 2832 (CH), 1649 (CO), 1543 (NH), 1453,
3096, 3058, 3027 (CHAr), 2936, 2890 (CH), 1515, 1455, 1364, 1303 1338, 1136 (SO2), 751, 710 (CHAr) cmϪ1. MS (DCI, NH3/
(SO2), 1258, 1151 (SO2), 1120 (CϪO), 1113, 1060, 817, 741, 696
isobutane): m/z (%) ϭ 473 (100) [M ϩ H]ϩ. C24H32N4O4S (472.6):
calcd. C 60.99, H 6.82, N 11.86, S 6.78; found C 60.96, H 6.76, N
(CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 313 (11) [M
Ϫ Bn ϩ 2 H]ϩ, 403 (100) [M ϩ H]ϩ. C22H30N2O3S (402.6): calcd. 11.63, S 6.98.
C 65.64, H 7.51, N 6.96, S 7.97; found C 65.34, H 7.39, N 6.89,
S 7.90.
4,14-Dibenzyl-8,10-dioxo-1-thia-4,7,11,14-tetraazacyclohexadecane
1,1-Dioxide (8a): Reaction of compound 8 (370 mg, 1 mmol) and
DVS (118 mg, 1 mmol) was completed in 2 h. Purification by col-
umn chromatography (CHCl3/MeOH/NH4OH, 98:2:0.1 to
95:5:0.4) yielded macrocycle 8a as a pale yellow oil (460 mg,
4,7,10,13-Tetrabenzyl-1-thia-4,7,10,13-tetraazacyclopentadecane
1,1-Dioxide (5a): Reaction of tetraamine 5 (250 mg, 0.5 mmol) and
DVS (59 mg, 0.5 mmol) was completed in 1.5 h. Column chromato-
1
3
graphy (cyclohexane/ethyl acetate, 7:3 to 5:5) yielded 5a as a yellow 0.94 mmol, 94%). H NMR (300 MHz, CDCl3): δ ϭ 2.59 (t, J ϭ
1
oil (230 mg, 0.37 mmol, 74%). H NMR (300 MHz, CDCl3): δ ϭ 5.3 Hz, 4 H), 2.94 (ps t, 4 H), 3.05 (ps t, 4 H), 3.14 (s, 2 H), 3.36
2.61Ϫ2.64 (m, 12 H), 3.0 (t, 3J ϭ 6.7 Hz, 4 H), 3.22 (t, 3J ϭ 6.7 Hz, (q, J ϭ 5.5 Hz, 4 H), 3.60 (s, 4 H), 7.22 (m, 10 H), 7.37Ϫ7.40 (m,
3
4 H), 3.43 (s, 4 H), 3.54 (s, 4 H), 7.21Ϫ7.29 (m, 20 H) ppm. 13C
NMR (75.47 MHz, CDCl3): δ ϭ 48.1, 52.1, 52.2, 52.25, 52.3, 59.3,
2 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 37.1, 44.4, 47.3,
52.3, 52.5, 58.7, 127.4, 128.4, 129.1, 137.5, 167.1 ppm. IR: ν˜ ϭ 3347
59.6, 126.9, 127.3, 128.1, 128.3, 129.0, 129.1, 138.1, 139.2 ppm. IR: (NH), 3096, 3073, 3035 (CHAr), 2936, 2830 (CH), 1675 (CO), 1546
ν˜ ϭ 3090, 3029 (CHAr), 2997, 2830 (CH), 1455, 1310, 1136 (SO2),
(NH), 1455, 1296, 1128 (SO2), 1068, 923, 741 (CHAr) cmϪ1. MS
60
Eur. J. Org. Chem. 2003, 54Ϫ62

A New Efficient Access to Macrocycles
(DCI, NH3/isobutane): m/z (%)
FULL PAPER
ϭ
487 (100) [M
ϩ
H]ϩ. (CHAr), 2930, 2873 (CH), 1608, 1477, 1346, 1159 (SO2), 1085, 947,
C25H34N4O4S (486.6) ϩ 1/2 H2O: calcd. C 60.58, H 7.12, N 11.30, 808, 741, 703 (CHAr) cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ
S 6.47; found C 60.47, H 7.02, N 11.17, S 6.88.
781 (20) [M Ϫ Ts]ϩ, 937 (6) [M ϩ H]ϩ, 954 (100) [M ϩ NH4]ϩ.
C42H56N4O10S5 (937.3): calcd. C 53.82, H 6.02, N 5.98, S 17.11;
found C 53.51, H 5.91, N 5.88, S 16.72.
4,7,10-Tritosyl-1-thia-4,7,10-triazacyclododecane 1,1-Dioxide (9a):
DVS (118 mg, 1 mmol) was added to a mixture of tosylated amine
9 (524 mg, 1 mmol) and potassium carbonate (415 mg, 3 mmol).
The reaction was completed in 3 h and after evaporation of the
solvent, the residue was taken up in a saturated NH4Cl solution
(20 mL) and extracted with ethyl acetate (2 ϫ 20 mL). The com-
bined organic phases were washed with brine (20 mL), dried with
anhydrous Na2SO4 and the solvents evaporated under reduced
pressure. The residue was purified by column chromatography
(CHCl3/MeOH/NH4OH, 99:1:0.1) affording 9a as a white solid
(664 mg, 0.97 mmol, 97%). M.p. 155Ϫ158 °C. 1H NMR (300 MHz,
CDCl3): δ ϭ 2.41 (s, 3 H), 2.42 (s, 6 H), 3.14 (m, 4 H), 3.43 (m, 4
H), 3.50 (m, 4 H), 3.75 (m, 4 H), 7.29Ϫ7.34 (m, 6 H), 7.47 (d,
1-Thia-4,8,13,17-tetraazacyclodecanonane 1,1-Dioxide (11b): 11a
(470 mg, 0.5 mmol) was added to a stirred solution of HBr (33% in
AcOH) in the presence of phenol (900 mg, 9 mmol). The reaction
mixture was stirred overnight at 80 °C. After evaporation of the
solvent, the residue was taken up in CH2Cl2 (100 mL) and water
(50 mL). The aqueous phase was washed with CH2Cl2 and reduced
to dryness. The resulting hydrobromide was dissolved in water
(10 mL) and passed through Dowex 1 ϫ 8 resin (basic form). The
collected fractions were concentrated affording crude amine 11b
(130 mg, 0.41 mmol, 81%) as a viscous oil. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.59 (m, 4 H), 1.75 (quint, 4 H, 3J ϭ 6.7 Hz),
2.70Ϫ2.76 (m, 12 H), 3.17 (t, 3J ϭ 6.1 Hz, 4 H), 3.50 (t, 3J ϭ
6.1 Hz, 4 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ 25.1, 26.6,
41.6, 46.1, 46.2, 47.8, 53.1 ppm. IR: ν˜ ϭ 3321 (NH), 2951, 2828
(CH), 1648, 1586, 1486, 1286, 1124 (SO2) cmϪ1. MS (DCI, NH3/
isobutane): m/z (%) ϭ 321 (100) [M ϩ H]ϩ. C14H32N4O2S (320.5)
ϩ HBr: calcd. C 41.89, H 8.29, N 13.96, S 7.99; found C 42.24, H
8.91, N 13.73, S 7.90.
3
3J ϭ 8.32 Hz, 2 H), 7.66 (d, J ϭ 8.32 Hz, 4 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 21.4, 44.6, 48.3, 50.8, 52.9, 127.4, 127.8,
129.8, 129.9, 131.4, 133.8, 144.4, 144.7 ppm. IR: ν˜ ϭ 3073 (CHAr),
2997, 2929 (CH), 1273, 1159 (SO2), 749 (CHAr) cmϪ1. MS (DCI,
NH3/isobutane): m/z (%) ϭ 91 (24) [Bn]ϩ, 156 (11) [Ts ϩ H]ϩ, 174
(25) [Ts ϩ NH4]ϩ, 374 (11) [M Ϫ 2 Ts ϩ H]ϩ, 528 (14) [M Ϫ Ts]ϩ,
684 (66) [M ϩ H]ϩ, 701 (100) [M ϩ NH4]ϩ, 741 (4) [M ϩ tBu]ϩ.
C29H37N3O8S4 (683.9): calcd. C 50.93, H 5.45, N 6.14, S 18.76;
found C 50.56, H 5.40, N 6.08, S 18.84.
17-Thia-1,4,8,11-tetraazabicyclo[6.6.5]nonadecane
17,17-Dioxide
(12): DVS (236 mg, 2 mmol) was added to a solution of cyclam
(0.4 g, 2 mmol) and refluxed for 16 h. Purification by column chro-
matography (CHCl3/MeOH/NH4OH, 4:1:0.2) afforded cryptand 12
as a white solid (450 mg, 1.4 mmol, 71%). M.p. 118Ϫ120 °C. 1H
NMR (300 MHz, CDCl3): δ ϭ 1.45 (dd, J ϭ 2.7, J ϭ 15.6 Hz, 2
H), 1.92Ϫ2.06 (m, 4 H), 2.44Ϫ2.74 (m, 12 H), 2.95Ϫ3.02 (m, 4 H),
3.12Ϫ3.22 (m, 4 H), 3.32 (br. s, 2 H) ppm. 13C NMR (75.47 MHz,
CDCl3): δ ϭ 25.2, 46.7, 48.5, 51.7, 53.2, 53.4, 58.6 ppm. IR: ν˜ ϭ
3283 (NH), 2974, 2898, 2822 (CH), 1470, 1303, 1151 (SO2), 772
cmϪ1. MS (DCI, NH3/isobutane): m/z (%) ϭ 319 (100) [M ϩ H]ϩ.
C14H30N4O2 (318.5) ϩ H2O: calcd. C 49.97, H 9.59, N 16.65, S
9.53; found C 49.90, H 9.26, N 16.65, S 9.48.
4,8,12,16-Tetratosyl-1-thia-4,8,12,16-tetraazacyclodecaoctane 1,1-
Dioxide (10a): DVS (118 mg, 1 mmol) was added to a solution of
10 (804 mg, 1 mmol) and potassium carbonate (276 mg, 2 mmol)
and the reaction mixture was refluxed for 2 h. After evaporation
of the solvent, the residue was taken up in CHCl3 (30 mL) and
water (20 mL), decanted and the aqueous phase was extracted with
CHCl3 (3 ϫ 10 mL). The combined organic phases were washed
with brine (15 mL), dried with anhydrous Na2SO4 and the solvents
evaporated to dryness. Purification by column chromatography
(CHCl3/MeOH/NH4OH, 99:1:0.1) afforded 10a as a white solid
(910 mg, 0.99 mmol, 99%). M.p. 179Ϫ180 °C. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.94Ϫ2.06 (m, 6 H), 2.43 (s, 12 H), 3.08Ϫ3.21 (m, 12
H), 3.47Ϫ3.52 (m, 8 H), 7.31Ϫ7.37 (dd, 8 H, 3J ϭ 8.3 Hz),
7.65Ϫ7.71 (dd, 8 H, 3J ϭ 8.3 Hz) ppm. 13C NMR (75.47 MHz,
CDCl3): δ ϭ 21.47, 21.52, 29.6, 30.4, 43.9, 47.7, 48.2, 48.9, 54.1,
127.1, 127.6, 129.8, 130.1, 133.5, 135.3, 143.6, 144.3 ppm. IR: ν˜ ϭ
3073, 3042 (CHAr), 2944, 2868 (CH), 1600, 1447, 1341, 1158 (SO2),
1091, 953, 817, 741, 696 (CHAr) cmϪ1. MS (DCI, NH3/isobutane):
m/z (%) ϭ 767 (27) [M Ϫ Ts]ϩ, 923 (35) [M ϩ H]ϩ, 940 (100) [M
ϩ NH4]ϩ. C41H54N4O10S6 (923.2) ϩ 2 H2O: calcd. C 51.34, H 6.09,
N 5.84, S 16.71; found C 51.44, H 5.79, N 5.90, S 16.73.
1
3
4,7,13,16-Tetraoxa-21-thia-1,10-diazabicyclo[8.8.5]nonadecane
21,21-Dioxide (13): After the addition of DVS (118 mg, 1 mmol) to
diaza-18-crown-6 (264 mg, 1 mmol), reflux was maintained for 1
h. Cryptand 13 was isolated by column chromatography (CHCl3/
MeOH/NH4OH, 94.5:5:0.5) as a white solid (370 mg, 0.97 mmol,
97%). M.p. 85Ϫ86 °C. 1H NMR (300 MHz, CDCl3): δ ϭ
2.61Ϫ2.69 (m, 8 H), 2.98 (t, 3J ϭ 6.7 Hz, 4 H), 3.43 (t, 3J ϭ 6.7 Hz,
4 H), 3.51Ϫ3.56 (m, 8 H), 3.58Ϫ3.64 (m, 8 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 48.3, 54.4, 57.0, 69.1, 70.3 ppm. IR: ν˜ ϭ
2966, 2875, 2807 (CH), 1364, 1272, 1121 (SO2), 741 cmϪ1. MS
4,8,13,17-Tetratosyl-1-thia-4,8,13,17-tetraazacyclodecanonane 1,1-
Dioxide (11a): DVS (118 mg, 1 mmol) was added to a solution of
11 (818 mg, 1 mmol) in the presence of potassium carbonate
(276 mg, 2 mmol). Reflux continued for 20 h and the solvent was
(DCI, NH3/isobutane): m/z (%)
ϭ 381 (100) [M ϩ
H]ϩ.
C16H32N2O6S (380.5): calcd. C 50.50, H 8.48, N 7.36, S 8.43; found
C 50.47, H 8.50, N 7.21, S 8.77.
evaporated. The residue was dissolved in a mixture of CHCl3 1,4,7,10-Tetrathiacyclododecane 1,1-Dioxide (14a): Bis(2-mercapto-
(30 mL) and water (20 mL) and the aqueous phase extracted with
CHCl3 (3 ϫ 10 mL). The combined organic phases were washed
ethyl) sulfide (172 mg, 1 mmol) was refluxed with DVS (118 mg,
1 mmol) overnight. Purification of the residue by flash column
with brine (20 mL), dried with anhydrous Na2SO4 and the solvents chromatography (CHCl3) afforded 14a as a white solid (200 mg,
evaporated to dryness. Column chromatography (CHCl3/MeOH,
0.73 mmol, 73%). M.p. 198Ϫ199 °C. 1H NMR (300 MHz, CDCl3):
3
3
99.5:0.5) yielded macrocycle 11a (887 mg, 0.95 mmol, 95%) as a δ ϭ 2.83 (s, 8 H), 3.01 (ps t, 4 H, J ϭ 7.0, J ϭ 7.8 Hz), 3.45 (ps
1
white solid. M.p. 183Ϫ184 °C. H NMR (300 MHz, CDCl3): δ ϭ t, 4 H, 3J ϭ 7.0, 3J ϭ 7.8 Hz) ppm. 13C NMR (75.47 MHz, CDCl3):
1.60 (m, 4 H), 1.94Ϫ1.98 (m, 4 H), 2.43 (s, 12 H), 3.10Ϫ3.20 (m, δ ϭ 24.6, 30.5, 30.6, 52.2 ppm. IR: ν˜ ϭ 3004, 2928 (CH), 1440,
3
12 H), 3.50 (s, 8 H), 7.29Ϫ7.35 (dd, 8 H, J ϭ 8.3 Hz), 7.64Ϫ7.70 1326 (SO2), 1265, 1143 (SO2), 1105, 961, 885, 843 cmϪ1. MS (DCI,
3
(dd, 8 H, J ϭ 8.3 Hz) ppm. 13C NMR (75.47 MHz, CDCl3): δ ϭ
NH3/isobutane): m/z (%) ϭ 213 (12) [M Ϫ CH2CH2S ϩ H]ϩ, 273
21.49, 21.53, 26.7, 28.9, 42.7, 47.4, 48.6, 49.3, 54.0, 127.1, 127.5, (15) [M ϩ H]ϩ, 290 (100) [M ϩ NH4]ϩ. C8H16O2S4 (272.4): calcd.
129.8, 130.1, 134.0, 135.7, 143.4, 144.2 ppm. IR: ν˜ ϭ 3044, 3012
Eur. J. Org. Chem. 2003, 54Ϫ62
C 35.26, H 5.92, S 47.07; found C 35.14, H 5.75, S 46.77.
61

M.-L. Teyssot, M. Fayolle, C. Philouze, C. Dupuy
FULL PAPER
[10]
[11]
A. Padwa, B. H. Norman, J. Org. Chem. 1990, 55, 4801Ϫ4807.
K. Zygo, W. Wieczorek, K. M. Pietrusiewicz, 14th International
Conference on Phosphorus Chemistry, Cincinnatti, 1998.
G. Gao, D. Yan, Chem. Commun. 2001, 107Ϫ108.
G. Hallas, R. Marsden, J. D. Heytworth, D. Mason, J. Chem.
Soc., Perkin Trans. 2 1986, 123Ϫ126.
B. U. Minbaev, M. F. Shostakovskii, A. D. Kagarlistskii, Chem.
Heterocycl. Compd. (Engl. Transl.) 1983, 19, 957Ϫ959.
K. Nagarajan, V. P. Arya, T. George, V. Sudarsaman, R. K.
Shah, A. N. Goud, S. J. Shenoy, V. Hakan, Y. S. Kulkarni, M.
K. Rao, Indian J. Chem. 1982, 21B, 928Ϫ940.
V. P. A r ya , Indian J. Chem. 1975, 13, 1262Ϫ1266.
B. A. Arbuzov, G. G. Batenko, A. B. Remizov, E. N. Klimovits-
kii, Chem. Heterocycl. Compd. (Engl. Transl.) 1972, 8,
375Ϫ379.
J. Maillard, M. Vincent, P. Delaunay, M. Rapin, Vo-Van-Tri,
G. Remond, Chim. Ther. 1969, 4, 80Ϫ88.
K. Yoda, T. Toda, Bull. Chem. Soc. Jpn. 1968, 41, 2519Ϫ2521.
E. N. Prilezhaeva, E. S. Shapiro, Dokl. Chem. (Engl. Transl.)
1967, 579Ϫ582.
A. C. Bellaart, Recl. Trav. Chim. Pays Bas 1967, 81, 156Ϫ159.
A. H. Ford-Moore, J. Chem. Soc. 1949, 2433Ϫ2440.
Lin Li, S. W. Tsai, A-L. Anderson, D. A. Keire, A. A. Ravbits-
chek, J. E. Shively, Bioconjugate Chem. 2002, 13, 110Ϫ115.
R. M. Black, K. Brewster, R. J. Clarke, J. M. Harrison, Phos-
phorus, Sulfur Silicon 1992, 71, 49Ϫ58.
Y. Nagao, H. Sakurai, Chem. Lett. 1976, 379Ϫ380.
H. Kropf, M. Ball, Tetrahedron 1972, 28, 1391Ϫ1401.
N. S. Simpkins, Tetrahedron 1990, 46, 6951Ϫ6984.
D. Enders, S. F. Müller, G. Raabe, J. Runsink, Eur. J. Org.
Chem. 2000, 879Ϫ892 and references cited therein.
Y. Kuroki, R. Lett, Tetrahedron Lett. 1984, 25, 197Ϫ200.
H. K. Oh, J. H. Yang, H. W. Lee, I. Lee, J. Org. Chem. 2000,
65, 5391Ϫ5395 and references cited therein.
7-Oxa-1,4,10-trithiacyclododecane 1,1-Dioxide (15a): DVS (118 mg,
1 mmol) was added to bis(2-mercaptoethyl) ether (138 mg, 1 mmol)
and the reaction mixture stirred overnight. The crude product was
purified by flash column chromatography (CHCl3) yielding 15a as
a white solid (210 mg, 0.82 mmol, 82%). M.p. 162Ϫ163 °C. 1H
[12]
[13]
3
NMR (300 MHz, CDCl3): δ ϭ 2.76 (t, J ϭ 4.7 Hz, 4 H), 3.11 (ps
[14]
[15]
t, 4 H), 3.41 (ps t, 4 H), 3.80 (t, J ϭ 4.7 Hz, 4 H) ppm. 13C NMR
3
(75.47 MHz, CDCl3): δ ϭ 25.7, 30.6, 51.2, 74.4 ppm. IR: ν˜ ϭ 2944,
2921, 2891, 2860 (CH), 1432, 1318 (SO2), 1288, 1158 (SO2), 1128
(CϪO), 1037, 946, 824, 756 cmϪ1. MS (DCI, NH3/isobutane): m/z
(%) ϭ 257 (22) [M ϩ H]ϩ, 274 (100) [M ϩ NH4]ϩ. C8H16O3S3
(256.4): calcd. C 37.47, H 6.29, S 37.52; found C 37.48, H 6.08,
S 37.06.
[16]
[17]
[18]
7,10-Dioxa-1,4,13-trithiacyclopentadecane 1,1-Dioxide (16a): After
addition of DVS (118 mg, 1 mmol) to a solution of 4,7-dioxa-1,10-
dithiadecane (182 mg, 1 mmol), reflux was maintained for 1 d. The
1ϩ1 cyclization product 16a (239 mg, 0.8 mmol, 80%, crystals) and
a small amount of the 2ϩ2 product (15 mg, 0.03 mmol, 3%, white
solid) were isolated by flash column chromatography (CHCl3/
MeOH, 98:2). M.p. 101Ϫ102 °C. 1H NMR (300 MHz, CDCl3):
[19]
[20]
[21]
[22]
[23]
3
δ ϭ 2.75 (t, J ϭ 4.9 Hz, 4 H), 3.07Ϫ3.11 (m, 4 H), 3.41Ϫ3.47 (m,
[24]
4 H), 3.64 (s, 4 H), 3.76 (t, 3J ϭ 4.9 Hz, 4 H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ ϭ 25.4, 32.2, 54.1, 70.6, 73.4 ppm. IR: ν˜ ϭ
2990, 2952, 2921, 2891 (CH), 1470, 1417, 1326 (SO2), 1288, 1151
(SO2), 1105 (CϪO), 1037, 923, 847, 725 cmϪ1. MS (DCI, NH3/
isobutane): m/z (%) ϭ 301 (14) [M ϩ H]ϩ, 318 (100) [M ϩ NH4]ϩ.
C10H20O4S3 (300.5): calcd. C 39.97, H 6.71; found C 39.96, H 6.85.
[25]
[26]
[27]
[28]
[29]
[30]
Acknowledgments
Our work has been generously supported by the Centre National
de la Recherche Scientifique (CNRS) and the University J. Fourier
(UJF). Financial assistance from the Ministere de l’Education Na-
tionale for a grant conceded to M.-L. T. is also gratefully acknow-
ledged.
[31]
[32]
[33]
[34]
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 18,
734Ϫ736.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryan-
off, R. D. Shah, J. Org. Chem. 1996, 61, 3849Ϫ3862.
M. A. Casadei, B. Di Rienzo, A. Inesi, F. M. Moracci, J. Chem.
Soc., Perkin Trans. 1 1992, 375Ϫ378.
V. J. Gatto, K. A. Arnold, A. M. Viscariello, S. R. Miller, C.
R. Morgan, G. W. Gokel, J. Org. Chem. 1986, 51, 5373Ϫ5384.
H. A. O. Hill, K. A. Raspin, J. Chem. Soc. A 1968, 3036Ϫ3039.
`
[1]
[35]
[36]
Y. A. Zolotov, Macrocyclic Compounds in Analytical Chemistry,
Wiley Interscience, New York, 1997, p. 1Ϫ62.
G. W. Gokel, Crown Ethers and Cryptands (Ed.: J. F. Stoddart),
´
G. Herve, H. Bernard, L. Toupet, H. Handel, Eur. J. Org.
Chem. 2000, 33Ϫ35.
[2]
[37]
[38]
Cambridge, 1991.
M. Hiraoka, Crown Ethers and Analogous Compounds, Elsevier,
A. Bencini, A. Bianchi, E. Garcia-Espan˜a, M. Micheloni, P.
Paoletti, Inorg. Chem. 1987, 26, 681Ϫ684.
B. Dietrich, B. Dilworth, J.-M. Lehn, J.-P. Souchez, M. Cesario,
J. Guilhem, C. Pascard, Helv. Chim. Acta 1996, 79, 569Ϫ587.
S. Stewer, J. Podlech, Eur. J. Org. Chem. 2002, 899Ϫ916.
D. A. Goff, R. N. Zuckermann, Tetrahedron Lett. 1996, 37,
6247Ϫ6250.
R. L. Snowden, M. Wüst, Tetrahedron Lett. 1986, 27, 699Ϫ702.
CCDC-187096, -187418, -187503 and -187703 contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/re-
trieving.html or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (in-
ternat.) ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
M.-L. Teyssot, Thesis, Universite´ Grenoble I, France, to be
published.
[3]
Amsterdam, 1992, p. 1Ϫ99.
L. F. Lindoy, The Chemistry of Macrocyclic Ligand Complex,
[4]
[39]
[40]
Cambridge University Press, Cambridge, 1989, p. 21Ϫ50.
D. Parker, Macrocycle Synthesis (Ed.: D. Parker), Oxford Uni-
[5]
versity Press, Oxford, 1996.
M. F. Sebban, P. Vottero, A. Alagui, C. Dupuy, Tetrahedron
[6]
[41]
[42]
Lett. 2000, 41, 1019Ϫ1022.
P. Perlmutter, Conjugate Addition Reactions in Organic Syn-
[7]
thesis, Tetrahedron Organic Series, vol. 9 (Eds.: J. E. Baldwin,
P. D. Magnus), Pergamon Press, Oxford, 1992.
Bis-Michael acceptors are listed in: Encyclopedia of Reagents
[8]
for Organic Synthesis (Ed.: L. A. Paquette), Wiley, Chichester,
1995.
R. D. Little, M. R. Masjedizadeh, O. Wallquist, J. I. Mc
[43]
[9]
Loughlin in Organic Reactions, vol. 47 (Ed.: L. A. Paquette),
Wiley, New York, 1995, p. 315Ϫ552.
Received July 10, 2002
[O02377]
62
Eur. J. Org. Chem. 2003, 54Ϫ62