Efficient atom economic approaches towards macrocyclic crown diamides via ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01379-5

RCM of suitable diamides containing 1,ω-dienes led to efficient atom economic synthetic approaches towards macrocylic polyoxadiamides with 15-25-membered ring sizes.

Full text of DOI:10.1016/S0040-4039(02)01379-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6421–6426
Efficient atom economic approaches towards macrocyclic crown
diamides via ring-closing metathesis
Haider Behbehani, Maher R. Ibrahim and Yehia A. Ibrahim*
Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait
Received 7 May 2002; revised 26 June 2002; accepted 4 July 2002
Abstract—RCM of suitable diamides containing 1,v-dienes led to efficient atom economic synthetic approaches towards
macrocylic polyoxadiamides with 15–25-membered ring sizes. © 2002 Elsevier Science Ltd. All rights reserved.
The development of neutral ionophores useful in mea-
surements of intracellular as well as extracelluar cation
concentrations is a subject of considerable current inter-
est.1 In general, crown compounds and azacrown com-
pounds constitute important macrocyclic groups in
supramolecular chemistry. They have been shown to
exhibit important applications including selective ion
separation and detection, molecular recognition, cataly-
sis, biological applications as well as many other inter-
esting applications in diverse fields of supramolecular
chemistry.2,3 Of particular interest are crown ethers
incorporating amide groups, since such groups modify
the binding properties of the crown compounds with
respect to alkali metal ions.1,3 Moreover, the number of
ether oxygen, amide carbonyl groups, ring size,
lipophilic groups as well as other structural features
control the selectivity towards different ions.1,3 Syn-
thetic approaches towards such macrocycles usually
suffer from low yields, the loss of considerable amounts
of the starting precursors during the macrocyclization
step due to polymer formation, in addition to the need
for high dilution conditions and template effects.2 We
and others reported several moderate-to-good yielding
synthetic approaches towards macrocyclic crown-
amides some of which showed useful applications in ion
selective electrodes.3 However, previous synthetic
approaches suffer from a considerable decrease in yields
as the ring size increases, in favor of polymer forma-
tion.3f In the present investigation we report an efficient
synthetic approach towards crown diamides with ring
sizes extending from 15–25, using ring-closing metathe-
sis as the key macrocyclization step.
Recently, ring-closing metathesis (RCM) has been
widely used as a versatile technique for the formation
of cyclic olefins. It has been mainly applied for the
formation of five- to seven-membered carbocycles and
heterocycles.4–8 Some examples of macrocycle synthesis
via RCM have been reported.8–17 Several reviews deal-
ing with RCM and illustrating its wide range of appli-
cations have recently been published.18 Molybdenum
alkylidene (Schrock catalysts)19 and ruthenium alkyli-
Keywords: ring-closing metathesis; 1,v-dienes; bis-o-allyloxybenzamides; bis-o-allyloxyanilides; dibenzodioxadiazacycloalkenediones; tribenzodi-
oxadiazacycloalkenediones; tetrabenzodiazatetraoxacycloalkenediones; pentabenzodiazatetraoxacycloalkenediones.
* Corresponding author. Fax: (++965) 4816482; e-mail: yehiaai@kuc01.kuniv.edu.kw
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01379-5

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H. Behbehani et al. / Tetrahedron Letters 43 (2002) 6421–6426
dene (Grubbs’ catalysts)17,20 have shown the best catalytic
activity in the area of RCM. The commercial availability
and ease of handling of some of the Grubbs’ catalysts (e.g.
I) in addition to their good tolerance of normal reaction
conditions and to a wide range of functional groups
attracted our attention for possible utility in the synthesis
of crown and azacrown macrocycles. In a recent publi-
cation we demonstrated the versatile application of this
technique for the efficient atom economic synthesis of a
number of azacrown cyclic olefinic compounds with 8–24
ring sizes.21 Recently, isophthaloyl benzylic amide macro-
cycles possessing an internal olefin were prepared and
shown to spontaneously self-assemble via interlocking to
give [2]catenanes in >95% yield.22
Table 1.

H. Behbehani et al. / Tetrahedron Letters 43 (2002) 6421–6426
6423
In the present work we report our investigations on the
application of RCM with catalyst I as the key macrocy-
clization step in the synthesis of macrocyclic polyethers
containing amide groups in the macrocyclic ring.
Results obtained in this work (Table 1) provide an
efficient atom economic synthetic approach towards
macrocylic polyoxadiamides with 15–25-membered ring
sizes.
(entries 1, 3) led to 100% macrocyclization by this
technique. Moreover, only 1.25% molar ratio of the
catalyst was needed for the full RCM macrocyclization
of 6; however, using 1% molar ratio of I led to only
75% macrocyclization where 25% of the starting com-
pound 6 was recovered unreacted (entry 3). On increas-
ing the ring size to 17, (entries 2, 4, 5) the RCM
reaction could only be accomplished in reasonably
good yields by increasing the catalyst to 5% molar
ratio. However, by increasing the ring size even more to
24 and 25 (entries 6, 7, 8) macrocyclization yields of
80–100% were achieved with only 2.5% molar ratio of
the catalyst I.
Scheme 1 illustrates our synthetic routes starting from
the appropriate readily available bis-(o-hydroxy-
phenyl)amides 1–3, 20 and 21 which were, converted
via their potassium salts into the corresponding 1,v-
dienes 4–11, 22–25. Some 1,v-diene derivatives were
also readily obtained by reacting the appropriate
diamine with o-allyloxybenzoyl chloride. RCM of these
dienes (Tables 1 and 2) proceeded under mild condi-
tions using 1–5 mol% of I in refluxing CH2Cl2 to give
excellent yields of the corresponding macrocyclic
products.
The E:Z isomers of the olefinic crown diamides were
readily assigned and their ratios were determined from
1
the H and 13C NMR spectra. Full proton and carbon
1
signal assignment of E and Z 14 was made using H
NMR, NOE-difference spectra, H,H-COSY, HMQC
and HMBC NMR techniques. By irradiation of the
OCH2 the ortho aromatic protons were enhanced, thus
identified and used in the COSY experiment to assign
all the other aromatic protons. The latter were then
used to assign the different carbon signals from the 2D
HMQC and HMBC experiments.
Table 1 shows that the RCM reactions proceeded in
high yield in most cases by heating the substrate in
dichloromethane with 2.5–5 mol% of I. It is also
remarkable that the formation of the 16-membered ring
Scheme 1.

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H. Behbehani et al. / Tetrahedron Letters 43 (2002) 6421–6426
Table 2.

H. Behbehani et al. / Tetrahedron Letters 43 (2002) 6421–6426
6425
The major products in all other RCM reactions 12, 13,
16–19 were shown to be the E isomers [(15 is 1:1 (E:Z)]
with the characteristic 13C signal of the OCH2 (of the
OCH2CHꢀCHCH2O) in the range of l=66.6–70.9. On
the other hand the 13C signal of the OCH2 of the Z
isomers appeared upfield at around l=63–64. As
Rees, C. W., Eds.; Pergamon Press, 1984; Vol. 7, pp.
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1
another representative example, the H and 13C NMR
of compound 12 E and Z are given.23
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Application of RCM techniques using catalyst I to the
oxalic diamides 22 and 23 and bis-malonamides 24 and
25 was also, investigated. All attempts to metathesize
compound 22 led only to precipitation of the dimeric
ring open structure 26. Most probably this is due to the
presence of 22 in the trans conformation around the
oxamide group. Furthermore, attempts to cyclize com-
pound 26 in different solvents using Grubbs’ catalyst I
failed and gave unchanged 26. On the other hand the
application of RCM techniques to the malonic diamide
23 led to 100% formation of the macrocyle 27. Likewise
compounds 24 and 25 underwent RCM reactions with
I to give the corresponding macrocycles 28 and 29,
respectively.
The present work demonstrates the efficient application
of RCM techniques for the atom economic synthesis of
macrocyclic crown diamide derivatives with potential
diverse applications in supramolecular chemistry and as
starting compounds for further synthetic transforma-
tions. The examples of RCM presented here represent
one of the best macrocyclization reaction techniques for
the synthesis of crown compounds. It also, expands the
utility of RCM methodology and its application to the
synthesis of cyclic olefins of large ring sizes with differ-
ent functional groups. Applications of this method to
the synthesis of other functional derivatives of crown
compounds are currently under active investigation in
our laboratory.
4. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114,
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Acknowledgements
The support of the University of Kuwait received
through research grant no. SC01/00 and the facilities of
ANALAB and SAF (grants no. GS01/01, GS03/01) are
gratefully acknowledged.
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(CH2N), 63.2 (OCH2), 112.9 (CH), 122.1 (CH), 122.5 (C),
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J=3.2 Hz, OCH2), 5.98 (t, 2H, J=3.2 Hz, CHꢀ), 7.04 (d,
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7.50 (dt, 2H, J=1.6, 8.2 Hz), 7.85 (m, 2H), 8.04 (dd, 2H,
J=1.6, 7.5 Hz), 9.35 (s, 2H, NH); 13C NMR (CDCl3) l
70.9 (OCH2), 116.8 (C), 123.1 (CH), 125.4 (CH), 126.1
(CH), 126.4 (C), 128.3 (CH), 130.8 (C), 131.6 (CH), 133.0
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J=4.1 Hz, CHꢀ), 6.95 (d, 2H, J=8.2 Hz), 7.18 (t, 2H,
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1
23. Compound 12 (trans): H NMR (CDCl3) l 3.79 (m, 4H,
CH2N), 4.70 (m, 4H, OCH2), 6.33 (m, 2H, CHꢀ), 7.01 (d,
2H, J=8.2 Hz), 7.14 (t, 2H, J=8.0 Hz), 7.40 (dt, 2H,
J=1.6, 8.0 Hz), 8.24, (dd, 2H, J=1.6, 8.2 Hz), 8.17 (brs,
2H, NH); 13C NMR (CDCl3) l 40.6 (CH2N), 68.4
(OCH2), 113.3 (CH), 122.1 (CH), 122.4 (C), 130.3 (CH),
132.4 (CH), 132.9 (CH), 156.4 (C), 165.6 (CꢀO). Com-
pound 12 (cis): 1H NMR (CDCl3) l 3.72 (m, 4H, CH2N),
4.80 (d, 4H, J=6 Hz, OCH2), 6.20 (t, 2H, J=6 Hz,
CHꢀ), 7.05 (d, 2H, J=8.2 Hz), 7.14 (t, 2H, J=8.0 Hz),
7.40 (dt, 2H, J=1.6, 8.0 Hz), 8.24 (dd, 2H, J=1.6, 8.2
Hz), 8.17 (brs, 2H, NH); 13C NMR (CDCl3) l 39.5
24. The yield was determined after the reaction by first
removal of the reaction solvent, dissolving in CDCl3
1
taking the H NMR, then adding an accurately weighed
amount of CH2Cl2 and comparing the integration of the
OCH2 group of the starting, products with that of
CH2Cl2 at l 5.3 and hence getting the molar ratio which
can then be converted into percent based on the original
molar amount of the starting materials.