Synthesis of bis-(3,5)pyrazolophanes via double cycloadditive macrocyclisation

Article abstract of DOI:10.1016/j.tet.2003.09.088

Double cycloadditive macrocyclisation of bis-hydrazonoyl chlorides 5 were performed with bis-allyl ethers 9 and 10, bis-vinyl ether 14 and bis-propargyl ether 18. The title compounds having a 18-, 19-, 22- or 24- membered ring annulated to the pyrazole units were obtained with good overall yield.

Full text of DOI:10.1016/j.tet.2003.09.088

Tetrahedron 59 (2003) 9315–9322
Synthesis of bis-(3,5)pyrazolophanes via double
cycloadditive macrocyclisationq
b
b
Giorgio Molteni,a Tullio Pilati and Alessandro Ponti
,
*
a
`
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Golgi 19, 20133 Milano, Italy
bConsiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy
Received 30 June 2003; revised 3 September 2003; accepted 26 September 2003
Abstract—Double cycloadditive macrocyclisation of bis-hydrazonoyl chlorides 5 were performed with bis-allyl ethers 9 and 10, bis-vinyl
ether 14 and bis-propargyl ether 18. The title compounds having a 18-, 19-, 22- or 24- membered ring annulated to the pyrazole units were
obtained with good overall yield.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results
Macrocyclic compounds encompasses an astonishing
variety of structural types ranging from macrolide anti-
biotics to crown ethers, cryptands, calixarenes, spherands
and so on.1 Due to their unique complexating ability
towards metal cations,2,3 both natural and synthetic
macrocycles have acquired wide interest in the field of
host–guest supramolecular chemistry.3 As a consequence, a
number of strategies have been devoted to the synthesis of
macrocyclic systems,4 including that based upon a multiple
1,3-dipolar cycloaddition sequence.5 This latter approach
have been pioniered by Garanti and co-workers in a 1975
paper which describes the formation of macrocyclic
compounds using intermolecular followed by intra-
molecular cycloadditions of nitrile oxides bearing an
alkenyl dipolarophile.6 Our recent contributions in this
field is concerned with the use of suitably functionalised
nitrilimines as precursors of a variety of (1,5) pyrazolo-
phanes7 and bis-(3,5) pyrazolophanes.8 Following the
multiple cycloadditive macrocyclisation between bis-nitrile
oxides and bifunctional dipolarophiles introduced by Kim
and co-workers,9 we now wish to report a version of the
same methodology based upon the double cycloaddition
between the bis-hydrazonoyl chlorides 5 and bis-dipolaro-
philes 9, 10, 14 and 18 in the presence of silver carbonate as
the basic agent.
Bis-hydrazonoyl chlorides 5 were synthesised as depicted in
the Scheme 1, following a procedure previously elaborated
by us.10 The corresponding nitrilimines 6 were generated in
situ upon treatment of 5 with silver carbonate in dry dioxane
at room temperature. Schemes 2 and 3 illustrate the reaction
outcomes of intermediates 6 with bis-allyl ethers 9 and 10
and bis-vinyl ether 14, respectively, while detailed data are
collected in Tables 1 and 2. Macrocyclic structures 12, 13,
15 and 16 were established through analytical and spectral
data. In particular, as far as 1H NMR spectra are concerned,
the protons in the 4- and 5- positions of the 4,5-
dihydropyrazole rings show resonances which are in perfect
agreement with literature data.11 It must be added that the
remaining aliphatic protons give rise to complex over-
lapping multiplets, as is common for macrocycles.9 Since all
the above macrocyclic products contains two stereocentres,
we assigned the chiral structure rac-13 rather than the meso-
12 one in the light of the 1H NMR signal of the 4-pyrazolinic
protons of 13, which was splitted in the presence of
Eu(hfc)3 [tris(heptafluoropropyl hydroxymethylene-(þ)-
camphorato(europium-(III)]. This behaviour finds
precedents in the literature7 and just matches that observed
in our previous paper for similar bis-(3,5)pyrazolophanes.8
Furthermore, compound 12d gave crystals suitable for
X-ray diffractometric analysis (Fig. 1),12 thus demonstrating
unambiguously the above assignments.13 When using the
bis-propargyl ether 18 as the dipolarophile (Scheme 4) the
intermediate hydrazonoyl chloride 19 was actually isolated
when stopping the reaction after 24 h, the latter was further
converted to 20. For the sake of comparison, bis-4,5-dihydro
pyrazole macrocycles 12a and 13a also gave 20 by
oxidation with DDQ.
q Supplementary data associated with this article can be found at doi:
10.1016/j.tet.2003.09.088
Keywords: 1,3-dipolar cycloadditions; macrocycles; pyrazoles; bis-
nitrilimines.
*
Corresponding author. Tel.: þ39-02-50314141; fax: þ39-02-50314139;
e-mail: giorgio.molteni@unimi.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.088

9316
G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
Scheme 1.
Scheme 2.

G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
9317
Scheme 3.
Table 1. Dipolar cycloaddition between bis-hydrazonoyl chlorides 5 and
bis-allylethers 9 and 10
Entry
Time (h)
Products and yields
(%)a
Yield ratio
12
13
11
12:13
a
b
c
d
72
110
56
24
26
31
40
12
17
16
19
–
–
–
7
67:33
60:40
66:34
68:32
96
a
Isolated yields.
Table 2. Dipolar cycloaddition between bis-hydrazonoyl chlorides 5a,b
and bis-vinylether 14
Entry
Time (h)
Products and yields
(%)a
Yield ratio
15
16
17
15:16
Figure 1. ORTEPIII plot of 12d at 90 K. Except those linked to the two
stereogenic carbon atoms, hydrogen atoms were omitted for clarity.
Ellipsoids at 50% probability level. H atoms not to scale.
a
b
60
96
22
24
22
17
11
16
50:50
58:42
a
Isolated yields.
3. Discussion
As a further stage of our work, we undertook the
conformational analysis of cycloadducts meso-12a and
rac-13a by full optimisation of about 2500 input structures
obtained from a MM3 simulated annealing run. The main
conformational features are shared by almost all of the
optimised conformers, while the most stable conformations
are pictured in Figure 2. In both cases the macrocyclic ring
is almost planar even if lower part of the cycle (i.e. that
containing carbonyl groups) is more rigid than the upper
part, which then shows a larger variation among the
optimised structures. A summary of the distances between
the methylenic hydrogens in the 4-position of the faced 4,5-
dihydropyrazole rings is reported in Table 3, where the
Boltzmann average approximates the real thermal average
as closely as our structure sampling is representative of an
equilibrium ensemble.
It have been recognised that nitrilimine cycloadditions to
monosubstituted ethylenes are controlled from the HOMO
of the 1,3-dipole,14 thus leading to 5-substituted-4,5-
dihydropyrazoles.11 This regioselectivity is just obeyed in
both the inter- and the intramolecular cycloaddition
sequence leading to the 4,5-dihydropyrazole macrocycles
meso-12 and rac-13. This behaviour can be accounted for by
considering that the tether joining the reactive groups in the
nitrilimine intermediate 8 is long and flexible enough to
allow the formation of the above bridged-ring structures. As
far as the diastereoselection is concerned, it can be inferred
from Table 1 that the diastereoisomeric ratio meso-12:rac-
13 ranges between 60:40 and 68:32. These low diastereo
preferences may be due to the large distance between the
first- and the newly- formed stereocentre. The role of silver

9318
G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
Scheme 4.
carbonate as the choice basic agent for the efficient synthesis
of pyrazole macrocycles is of interest. Its low solubility in
dioxane determines the slow generation of the nitrilimine 6
which leads to the cycloadducts meso-12 and rac-13 via the
labile hydrazonoyl chloride 7. Conversely, in a control
experiment (see Section 5), the reaction between bis-
hydrazonyl chloride 5a and bis-allyl ether 9 in the presence
of triethylamine gave no characterisable product, but only
tarry material.
The above considerations can also be applied to the
formation of macrocycles meso-15 and rac-16. The latter,
however, showed a marked lability towards acidic species
giving the bis-pyrazole derivatives 17 by extrusion of
ethylene glycol(s), in close analogy with the behaviour of
5-alkoxy-4,5-dihydropyrazoles.15
Due to the presence of bulky aryl groups and of planar units,
the macrocycle adopts conformations in which the hydro-
gens in the 4- position of the two 4,5-dihydropyrazole rings
face each other. These interannular hydrogen–hydrogen
distance are rather short, particularly in meso-12a because
the coplanar arrangement of the pyrazole rings. Moreover,
in meso-12a the Boltzmann-average distances are about one
standard deviation shorter than the mean distances,
indicating that more stable conformers have shorter
hydrogen–hydrogen distances. Conversely, in rac-13a the
Boltzmann-average distances are close to the mean
distances, thus showing that more stable conformer have
longer hydrogen–hydrogen distances.
Figure 2. The two most stable confomers of meso-12a (a) and rac-13a
(b) among those obtained by full geometry optimisation of ,2500 input
structures at the AM1 level. Dashed lines denote the interannular distances
summarised in Table 3 and discussed in the text; for the sake of clarity they
have been drawn only for meso-12a.
Table 3. Computed interannular distances between the hydrogens in the
4-positions of the facing 4,5-dihydropyrazole rings of cycloadducts
meso-12a and rac-13a
4. Conclusions
meso-12a
rac-13a
The described double cycloadditive macrocyclisation
involving the bis-hydrazonoyl chlorides 5 deserves some
interesting features: (i) the overall yield of the resulting 4,5-
dihydropyrazole macrocycles is worthy of note, and (ii) due
to the availability and the low cost of the starting materials,
the present approach constitutes a valuable entry for the
Minimum
Maximum
Mean
2.61 1.77 1.97 1.70 4.52 2.80 2.80 2.12
5.15 4.91 5.25 3.45 6.72 5.08 5.45 3.79
4.27 3.75 3.56 2.48 5.13 3.82 4.01 2.78
0.57 0.49 0.78 0.31 0.29 0.32 0.59 0.36
Std. Dev.a
Boltzmann averageb 3.72 3.38 2.69 2.14 5.22 3.82 3.85 2.58
a
multi-gram synthesis of
pyrazolophanes.
a
variety of bis-(3,5)
Standard deviation from the mean.
Thermal Boltzmann average.
b

G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
9319
1
5. Experimental
1720 cm21; H NMR (CDCl3) d 4.06 (4H, t, J¼5.0 Hz),
4.55 (4H, t, J¼5.0 Hz), 6.86–7.65 (8H, m), 8.35 (2H, br s);
MS m/z 536 (Mþþ2). Anal. calcd for C20H18Cl4N4O5:
C, 44.80; H, 3.38; N, 10.45. Found: C, 44.85; H, 3.42; N,
10.50.
Melting points were determined with a Bu¨chi apparatus in
open tubes and are uncorrected. IR spectra were recorded
with a Perkin–Elmer 1725 X spectrophotometer. Mass
1
spectra were determined with a VG-70EQ apparatus. H
NMR (300 MHz) spectra were taken with a Bruker AC 300
or a Bruker AMX 300 instrument (in CDCl3 solutions at
room temperature). Chemical shifts are given as ppm from
tetramethylsilane and J values are given in Hz.
5.2.3. Compound 5c. 2.96 g, 83%. White powder; mp 116–
1188C (from hexane–benzene); IR (nujol) 3280,
1
1715 cm21; H NMR (CDCl3) d 2.27 (6H, s), 4.62 (4H,
s), 7.00–7.26 (8H, m), 8.35 (2H, br s); MS m/z 450 (Mþ).
Anal. calcd for C20H20Cl2N4O4: C, 53.23; H, 4.47; N, 12.41.
Found: C, 53.28; H, 4.51; N, 12.49.
Compounds 1,16 2,16 9,17 1017 and 1818 are known in the
literature. Compound 14 was used as supplied from Aldrich.
5.2.4. Compound 5d. 2.96 g, 75%. White powder; mp 96–
5.1. General procedure for the proparation of bis-2-
chloroacetoacetates 3 and 4
988C (from hexane–benzene); IR (nujol) 3270, 1720 cm21
;
1H NMR (CDCl3) d 2.39 (6H, s), 3.90 (4H, t, J¼5.0 Hz),
4.47 (4H, t, J¼5.0 Hz), 7.10–7.30 (8H, m), 8.26 (2H, br s);
MS m/z 494 (Mþ). Anal. calcd for C22H24Cl2N4O5:
C, 53.34; H, 4.88; N, 11.31. Found: C, 53.38; H, 4.92; N,
11.37.
A solution of sulfuryl chloride (2.84 g, 28.5 mmol) in dry
chloroform (25 mL) was slowly added (30 min) to a
solution of 1 or 2 (12.0 mmol) in dry chloroform (50 mL),
and keeping the temperature in the range 0–58C. After 4 h at
room temperature, the organic solution was washed with 5%
aqueous sodium hydrogen carbonate (2£25 mL). The
organic layer was washed with water (2£25 mL) and dried
over sodium sulfate. The solvent was removed affording bis-
2-chloroacetoacetates 3 and 4 as undistillable thick oils
which were used without further purification.
5.3. General procedure for the dipolar cycloaddition
between bis-hydrazonoyl chlorides 5 and bis-allyl ethers
9 and 10
A solution of the bis-hydrazonyl chlorides 5 (5.0 mmol) and
bis-allylethers 9 or 10 (5.0 mmol) in dry dioxane (250 mL)
was treated with silver carbonate (2.76 g, 10.0 mmol) and
stirred in the dark at room temperature for the time indicated
in Table 1. The undissolved material was then filtered off,
the solvent evaporated, and the residue chromatographed on
a silica gel column with ethyl acetate–hexane 1:2. Major
cycloadducts meso-12 were eluted first, followed by minor
rac-13 and 11.
5.1.1. Compound 3. 3.41 g, 95%. Pale yellow oil; IR (nujol)
1740 cm21; 1H NMR (CDCl3) d 2.40 (6H, s), 4.48 (4H, s),
4.80 (2H, s); MS m/z 298 (Mþ). Anal. calcd for
C10H12Cl2O6: C, 40.16; H, 4.04. Found: C, 40.22; H, 4.09.
5.1.2. Compound 4. 2.80 g, 68%. Pale yellow oil; IR (nujol)
1
1740 cm21; H NMR (CDCl3) d 2.40 (6H, s), 4.25–4.57
(8H, m), 4.86 (2H, s); MS m/z 342 (Mþ). Anal. calcd for
C12H16Cl2O7: C, 42.00; H, 4.70. Found: C, 41.94; H, 4.64.
5.3.1. Compound meso-12a. 0.67 g, 24%. Pale yellow
needles; mp 97–1008C (from diisopropyl ether); IR (nujol)
1
1725 cm21; H NMR (CDCl3) d 3.18 (2H, dd, J¼18.2,
5.2. General procedure for the preparation of bis-
hydrazonoyl chlorides 5
6.5 Hz), 3.23 (2H, dd, J¼18.2, 11.6 Hz), 3.37–3.54 (8H,
m), 4.40–4.70 (6H, m), 7.10–7.30 (8H, m); MS m/z 560
(Mþ). Anal. calcd for C26H26Cl2N4O6: C, 55.62; H, 4.67; N,
9.98. Found: C, 55.66; H, 4.65; N, 10.07.
A solution of 3 or 4 (8.0 mmol) in methanol (8 mL) was
added to a cold aqueous solution of the appropriate
aryldiazonium chloride (16.0 mmol) with vigorous stirring
and ice-cooling. During the addition, the pH was adjusted to
5 by adding sodium acetate. The mixture was allowed to
stand overnight with stirring at room temperature and was
then extracted with diethyl ether (2£75 mL). The organic
layer was washed firstly with 5% sodium hydrogen-
carbonate (2£25 mL), then with water (2£75 mL), and
dried over sodium sulfate. Evaporation of the solvent gave a
solid and subsequent recrystallisation gave the bis-
hydrazonoyl chlorides 5 in the pure state.
5.3.2. Compound meso-12b. 0.84 g, 26%. Yellow prisms;
mp 154–1568C (from diisopropyl ether–dichloromethane);
1
IR (nujol) 1725 cm21; H NMR (CDCl3) d 3.21 (2H, dd,
J¼17.9, 7.6 Hz), 3.30 (2H, dd, J¼17.9, 11.5 Hz), 3.40–3.80
(16H, m), 4.49 (2H, dd, J¼13.7, 6.3 Hz), 4.58 (2H, dd,
J¼13.7, 5.3 Hz), 4.66 (2H, dddd, J¼11.5, 7.6, 6.3, 5.3 Hz),
7.00–7.30 (8H, m); MS m/z 648 (Mþ). Anal. calcd for
C30H34Cl2N4O8: C, 55.48; H, 5.28; N, 8.63. Found: C,
55.52; H, 5.31; N, 8.69.
5.3.3. Compound meso-12c. 0.81 g, 31%. Yellow needles;
mp 95–978C (from ethanol); IR (nujol) 1725 cm21 1H
;
5.2.1. Compound 5a. 2.40 g, 61%. Pale yellow powder; mp
148–1508C (from diisopropyl ether); IR (nujol) 3280,
NMR (CDCl3) d 2.29 (6H, s), 3.20 (2H, dd, J¼17.6, 6.7 Hz),
3.31 (2H, dd, J¼17.6, 11.4 Hz), 3.40–3.80 (8H, m), 4.30–
4.50 (6H, m), 6.95–7.10 (8H, m); MS m/z 520 (Mþ). Anal.
calcd for C28H32N4O6: C, 64.60; H, 6.20; N, 10.76. Found:
C, 64.66; H, 6.16; N, 10.81.
1
1720 cm21; H NMR (CDCl3) d 4.57 (4H, s), 6.88–7.60
(8H, m), 8.36 (2H, br s); MS m/z 492 (Mþþ2). Anal. calcd
for C18H14Cl4N4O4: C, 43.93; H, 2.87; N, 11.38. Found: C,
43.98; H, 2.92; N, 11.44.
5.2.2. Compound 5b. 1.99 g, 51%. Pale yellow powder; mp
115–1208C (from diisopropyl ether); IR (nujol) 3270,
5.3.4. Compound meso-12d. 1.22 g, 40%. Yellow prisms;
mp 152–1558C (from diisopropylether–dichloromethane);

9320
G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
1
IR (nujol) 1725 cm21; H NMR (CDCl3) d 2.25 (6H, s),
3.19 (2H, dd, J¼18.0, 7.8 Hz), 3.31 (2H, dd, J¼18.0,
11.8 Hz), 3.40–3.80 (16H, m), 4.32 (2H, dd, J¼13.1,
6.7 Hz), 4.52 (2H, dd, J¼13.1, 5.3 Hz), 4.68 (2H, dddd,
J¼11.8, 7.8, 6.7, 5.3 Hz), 6.90–7.00 (8H, m); MS m/z 608
(Mþ). Anal. calcd for C32H40N4O8: C, 63.14; H, 6.62; N,
9.20. Found: C, 63.18; H, 6.65; N, 9.25.
5.4. General procedure for the dipolar cycloaddition
between bis-hydrazonoyl chlorides 5a,b and bis-vinyl
ethers 14
A solution of the bis-hydrazonoyl chloride 5a or 5b
(5.0 mmol) and bis-vinylether 14 (0.57 g, 5.0 mmol) in
dry dioxane (250 mL) was treated with silver carbonate
(4.14 g, 15.0 mmol) and stirred in the dark at room
temperature for the time indicated in Table 2. The
undissolved material was filtered off, the solvent was
evaporated, and then the residue was chromatographed on
a silica gel column with ethyl acetate–hexane–triethyl-
amine 49:49:2. Bis-pyrazoles 17 were eluted first, followed
by major cycloadducts meso-15 and minor rac-16.
5.3.5. Compound rac-13a. 0.37 g, 12%. Pale yellow
powder; mp 250–2518C (from diisopropyl ether); IR
;
(nujol) 1730 cm21 1H NMR (CDCl3) d 3.22 (2H, dd,
J¼18.0, 6.9 Hz), 3.30 (2H, dd, J¼18.0, 11.5 Hz), 3.35–3.58
(8H, m), 4.40 (2H, dd, J¼13.0, 7.8 Hz), 4.67 (2H, dddd,
J¼11.5, 7.8, 6.9, 6.4 Hz), 4.78 (2H, dd, J¼13.0, 6.4 Hz),
7.05–7.20 (8H, m); MS m/z 560 (Mþ). Anal. calcd for
C26H26Cl2N4O6: C, 55.62; H, 4.67; N, 9.98. Found: C,
55.60; H, 4.70; N, 10.05.
5.4.1. Compound 17a. 0.26 g, 11%. White needles; mp
150–1518C (from diisopropyl ether–dichloromethane); IR
1
(nujol) 1730 cm21; H NMR (CDCl3) d 4.70 (4H, s), 6.95
5.3.6. Compound rac-13b. 0.55 g, 17%. Yellow powder;
mp 167–1708C (from diisopropyl ether–dichloromethane);
(2H, d, J¼2.5 Hz), 7.40–7.70 (8H, m), 7.95 (2H, d,
J¼2.5 Hz); MS m/z 470 (Mþ). Anal. calcd for
C22H16Cl2N4O4: C, 56.07; H, 3.42; N, 11.89. Found: C,
56.11; H, 3.44; N, 11.95.
1
IR (nujol) 1715 cm21; H NMR (CDCl3) d 3.12 (2H, dd,
J¼18.5, 8.1 Hz), 3.30 (2H, dd, J¼18.5, 11.6 Hz), 3.33–3.67
(16H, m), 4.25 (2H, dd, J¼12.8, 7.7 Hz), 4.40 (2H, dddd,
J¼11.6, 8.1, 7.7, 6.0 Hz), 4.66 (2H, dd, J¼12.8, 6.0 Hz),
7.00–7.20 (8H, m); MS m/z 648 (Mþ). Anal. calcd for
C30H34Cl2N4O8: C, 55.48; H, 5.28; N, 8.63. Found: C,
55.44; H, 5.25; N, 8.66.
5.4.2. Compound 17b. 0.41 g, 16%. White needles; mp
109–1118C (from diisopropyl ether–dichloromethane); IR
;
(nujol) 1730 cm21 1H NMR (CDCl3) d 3.90 (4H, t,
J¼5.3 Hz), 4.50 (4H, t, J¼5.3 Hz), 6.95 (2H, d,
J¼2.5 Hz), 7.40–7.70 (8H, m), 7.90 (2H, d, J¼2.5 Hz);
MS m/z 514 (Mþ). Anal. calcd for C24H20Cl2N4O5: C,
55.93; H, 3.91; N, 10.87. Found: C, 55.98; H, 3.87; N, 10.93.
5.3.7. Compound rac-13c. 0.42 g, 16%. Pale yellow
powder; mp 160–1628C (from diisopropylether); IR
1
(nujol) 1720 cm21; H NMR (CDCl3) d 2.27 (6H, s), 3.16
(2H, dd, J¼17.8, 6.4 Hz), 3.25 (2H, dd, J¼17.8, 12.0 Hz),
3.32–3.87 (12H, m), 4.60–4.70 (2H, m), 6.99–7.12 (8H,
m); MS m/z 520 (Mþ). Anal. calcd for C28H32N4O6: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.64; H, 6.22; N, 10.83.
5.4.3. Compound meso-15a. 0.63 g, 22%. Pale yellow
needles; mp 90–918C (from diisopropyl ether–dichloro-
1
methane); IR (nujol) 1730 cm21; H NMR (CDCl3) d 3.21
(2H, dd, J¼19.4, 2.7 Hz), 3.33 (2H, dd, J¼19.4, 8.7 Hz),
3.40–3.50 (8H, m), 4.42–4.70 (2H, ddd, J¼11.4, 7.4,
2.8 Hz), 4.63 (2H, ddd, J¼11.4, 7.4, 2.8 Hz), 5.82 (2H, dd,
J¼8.7, 2.7 Hz), 7.20–7.30 (8H, m); MS m/z 576 (Mþ).
Anal. calcd for C26H26Cl2N4O7: C, 54.08; H, 4.54; N, 9.70.
Found: C, 54.12; H, 4.57; N, 9.76.
5.3.8. Compound rac-13d. 0.58 g, 19%. Yellow powder;
mp 165–1678C (from diisopropylether–dichloromethane);
1
IR (nujol) 1730 cm21; H NMR (CDCl3) d 2.27 (6H, s),
3.14 (2H, dd, J¼17.9, 7.1 Hz), 3.26 (2H, dd, J¼17.9,
11.9 Hz), 3.50–3.90 (16H, m), 4.35–4.45 (4H, m), 4.60–
4.70 (2H, m), 7.00–7.20 (8H, m); MS m/z 608 (Mþ). Anal.
calcd for C32H40N4O8: C, 63.14; H, 6.62; N, 9.20. Found: C,
63.20; H, 6.66; N, 9.27.
5.4.4. Compound meso-15b. 0.75 g, 24%. Yellow needles;
mp 156–1588C (from diisopropylether); IR (nujol)
1
1730 cm21; H NMR (CDCl3) d 3.13 (2H, dd, J¼19.4,
3.2 Hz), 3.18 (2H, dd, J¼19.4, 8.2 Hz), 3.40–3.60 (12H,
m), 4.30–4.60 (4H, m), 5.45 (2H, dd, J¼8.2, 3.2 Hz), 7.15–
7.30 (8H, m); MS m/z 620 (Mþ). Anal. calcd for
C28H30Cl2N4O8: C, 54.11; H, 4.87; N, 9.02. Found: C,
54.15; H, 4.91; N, 9.08.
5.3.9. Compound 11. 0.28 g, 7%. Pale yellow powder; mp
61–638C (from diisopropylether); IR (nujol) 1725 cm21; 1H
NMR (CDCl3) d 2.21 (6H, s), 3.12 (2H, dd, J¼17.6, 7.3 Hz),
3.21 (2H, dd, J¼17.6, 11.6 Hz), 3.30–3.90 (24H, m), 4.30–
4.40 (10H, m), 5.11 (2H, dd, J¼10.5, 1.8 Hz), 5.20 (2H, dd,
J¼17.6, 1.8 Hz), 5.75–5.90 (2H, m), 6.9–7.00 (8H, m); MS
m/z 794 (Mþ). Anal. calcd for C42H58N4O11: C, 63.46; H,
7.35; N, 7.05. Found: C, 63.50; H, 7.38; N, 7.12.
5.4.5. Compound rac-16a. 0.63 g, 22%. Pale yellow
powder; mp 164–1668C (from diisopropyl ether–dichloro-
1
methane); IR (nujol) 1730 cm21; H NMR (CDCl3) d 3.15
(2H, dd, J¼19.4, 3.1 Hz), 3.27 (2H, dd, J¼19.4, 8.7 Hz),
3.40–3.50 (8H, m), 4.55 (2H, t, J¼10.0 Hz), 4.61 (2H, t,
J¼10.0 Hz), 5.82 (2H, dd, J¼8.7, 3.1 Hz), 7.20–7.30 (8H,
m); MS m/z 576 (Mþ). Anal. calcd for C26H26Cl2N4O7: C,
54.08; H, 4.54; N, 9.70. Found: C, 54.14; H, 4.56; N, 9.78.
5.3.10. Reaction between bis-hydrazonoyl chloride 5a
and bis-allyl ether 10 in the presence of triethylamine. A
solution of the bis-hydrazonoyl chloride 5a (1.22 g,
2.5 mmol) and bis-vinylether 12 (0.36 g, 2.5 mmol) in dry
dioxane (125 mL) was treated with triethylamine (1.52 g,
15.0 mmol) and refluxed for 3 h. The solvent was
evaporated, and then the residue was chromatographed on
a silica gel column with ethyl acetate–hexane–triethyl-
amine 1:1. No characterisable products were isolated.
5.4.6. Compound rac-16b. 0.53 g, 17%. Yellow powder;
mp 150–1528C (from diisopropylether); IR (nujol)
1
1720 cm21; H NMR (CDCl3) d 3.22 (2H, dd, J¼19.5,
3.7 Hz), 3.32 (2H, dd, J¼19.5, 8.8 Hz), 3.40–3.60 (12H,

G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
9321
m), 4.40–4.55 (4H, m), 5.94 (2H, dd, J¼8.8, 3.7 Hz), 7.20–
7.30 (8H, m); MS m/z 620 (Mþ). Anal. calcd for
C28H30Cl2N4O8: C, 54.11; H, 4.87; N, 9.02. Found: C,
54.07; H, 4.90; N, 9.10.
Therefore, 2500 input structures were collected for each
macrocycle. Each of these was fully optimised at the AM1
level by means of the Gaussian9819 package. Thermally-
averaged intramolecular distances were obtained from the
AM1-computed distances and energies and the Boltzmann
distribution.
5.4.7. Dipolar cycloaddition between bis-hydrazonoyl
chloride 5a and bis-propargyl ether 18. A solution of the
bis-hydrazonoyl chloride 5a (2.46 g, 5.0 mmol) and bis-
propargylether 18 (0.69 g, 5.0 mmol) in dry dioxane
(250 mL) was treated with silver carbonate (2.76 g,
10.0 mmol) and stirred in the dark at room temperature.
After 48 h silver carbonate (2.76 g, 10.0 mmol) was added
again and the mixture was stirred for 72 h. The undissolved
material was filtered off, the solvent was evaporated, and
then the residue was chromatographed on a silica gel
column with diethyl ether–hexane 5:1. First fractions
contained the hydrazonoyl chloride 19 (0.24 g, 8%).
6. Supplementary Material
Two colour figures in which the 14 most stable conformers
of meso-12a and rac-13a are superimposed are available as
Supplementary Material.
Acknowledgements
1
Undistillable orange oil; IR (nujol) 3280, 1735 cm21; H
Thanks are due to MURST and CNR for financial support.
One of us (G. M.) is grateful to Professor Luisa Garanti for
helpful suggestions.
NMR (CDCl3) d 2.35 (1H, t, J¼2.4 Hz), 3.50–3.60 (4H, m),
4.17 (2H, d, J¼2.4 Hz), 4.54–4.78 (6H, m), 6.96 (1H, s),
7.10–7.40 (8H, m), 8.35 (1H, br s); MS m/z 592 (Mþ). Anal.
calcd for C26H23Cl3N4O6: C, 52.59; H, 3.90; N, 9.43.
Found: C, 52.63; H, 3.88; N, 9.48.
References
Further elution gave 20 (0.39 g, 14%). Pale yellow solid; mp
110–1128C (from diisopropyl ether); IR (nujol) 1740 cm21
;
1. Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry.
VCH: Weinheim, 1993.
1H NMR (CDCl3) d 3.40–3.60 (4H, m), 4.50–4.80 (8H, m),
6.95 (2H, s), 7.15–7.30 (8H, m); MS m/z 556 (Mþ). Anal.
calcd for C26H22Cl2N4O6: C, 56.03; H, 3.98; N, 10.05.
Found: C, 56.08; H, 4.02; N, 10.11.
2. Inone, I.; Gokel, G. W. Cation Binding by Macrocycles:
Complexation of Cationic Species by Crown Ethers; Marcel
Dekker: New York, 1990.
3. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; New
York: New York, 2000.
5.4.8. Intramolecular cycloaddition of hydrazonoyl
chloride 19. A solution of the hydrazonoyl chloride 19
(0.24 g, 0.4 mmol) in dry acetonitrile (24 mL) was treated
with silver carbonate (0.28 g, 1.0 mmol) and stirred in the
dark at room temperature for 96 h. The undissolved material
was filtered off and washed with acetonitrile (2£15 mL).
The solvent was evaporated, and then the residue was
chromatographed on a silica gel column with diethyl ether
giving 20 (0.12 g, 54%).
4. Macrocyclic Synthesis: A Practical Approach; Parker, D., Ed.;
Oxford University Press: Oxford, 1996.
5. (a) Molteni, G.; Zecchi, G. Trends Heterocycl. Chem. 1997, 5,
127. (b) Kim, B. H.; Jeong, E. J.; Hwang, G. T.; Venkatesan,
N. Synthesis 2001, 2191. (c) Maas, G.; Gettwert, V.; Krebs, F.;
Schmidtberg, G. Chem. Eur. J. 2000, 6, 1646.
6. Garanti, L.; Sala, A.; Zecchi, G. J. Org. Chem. 1975, 40, 2403.
´
7. (a) Broggini, G.; Bruche, L.; Garanti, L.; Zecchi, G. J. Chem.
Soc., Perkin Trans. 1 1994, 433. (b) Broggini, G.; Garanti, L.;
Molteni, G.; Zecchi, G. J. Chem. Res. (S) 1995, 385. J. Chem.
Res. (M) 2389. (c) Broggini, G.; Garanti, L.; Molteni, G.;
Zecchi, G. Tetrahedron 1997, 53, 3005. (d) Broggini, G.;
Molteni, G.; Pilati, T. Tetrahedron: Asymmetry 2000, 11,
1975.
5.4.9. DDQ oxidation of cycloadducts 12a and 13a. A
solution of 12a or 13a (0.28 g, 0.5 mmol) and DDQ (0.57 g,
2.5 mmol) in dry benzene (50 mL) was refluxed for 16 h.
The crude was taken up with dichloromethane (100 mL), the
undissolved tarry material was filtered off and the solvent
was evaporated at reduced pressure. The residue was
chromatographed on a silica gel column with diethyl ether
giving 20 (0.23 g, 84% from 12a; 0.22 g, 79% from 13a).
8. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron
1998, 54, 2843.
9. Kim, B. H.; Jeong, E. J.; Jung, W. H. J. Am. Chem. Soc. 1995,
117, 6390.
5.5. Computational details
10. Garanti, L.; Sala, A.; Zecchi, G. Synthesis 1975, 666.
11. (a) Shimizu, T.; Hayashi, Y.; Nishio, T.; Teramura, K. Bull.
Chem. Soc. Jpn 1984, 57, 787. (b) Shawali, A. S.; Ezmirly,
S. T. J. Heterocycl. Chem. 1988, 25, 257.
In order to generate a large non-biased number of input
structures for the subsequent optimisation of macrocycles
meso-12a and rac-13a we proceeded as follows. A guess
structure was optimised with the MM3 force field as
implemented in the Hyperchem Release 2 package. This
structure was used as input for a molecular dynamic run
carried out with the same force-field and software as before.
The details of the dynamic run are as follows: starting
temperature¼1 K raised to 300 K in 10 ps; constant
temperature run for 250 ps with time step for dynamics¼1
fs; macrocycle structures were collected every 100 fs.
12. Burnett, M. N.; Johnson, C. K. ORTEPIII: Report ORNL-
6895; Oak Ridge National Laboratory: Tennessee, USA.
13. Crystallographic data (excluding structure factors) for
structure 12d have been deposited with the Cambridge
Crystallographic data Centre as supplementary publication
number CCDC 211378.
14. (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am.
Chem. Soc. 1973, 95, 7301. (b) Houk, K. N.; Caramella, P.
J. Am. Chem. Soc. 1976, 98, 6397.

9322
G. Molteni et al. / Tetrahedron 59 (2003) 9315–9322
15. Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1967, 4179.
16. Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431.
17. Kuznetsov, N. V.; Makarenko, V. E. Ukr. Khim. Zh. 1981, 47,
876. Chem. Abstr. 95, 186578.
S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Rega, N.; Salvador, P.; Dannenberg, J. J.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R.L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.
Gaussian98, Revision A.11.3; Gaussian, Inc.: Pittsburgh,
2002.
18. Karaev, S. F.; Guseinov, Sh. O.; Garaeva, Sh. V. Zh. Org.
Khim. 1993, 29, 1492. Chem. Abstr. 121, 133511.
19. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,