Synthesis of a heterocyclic receptor for carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(00)01934-1

The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting from readily available 1-tetralone derivatives. This host possesses a six-membered lactam moiety and a carboxamide at the en

Full text of DOI:10.1016/S0040-4039(00)01934-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 261–263
Synthesis of a heterocyclic receptor for carboxylic acids
Gregory Moore, Vincent Levacher, Jean Bourguignon and Georges Dupas*
Laboratoire de Chimie Organique Fine et He´te´rocyclique UPRESA 6014, IRCOF-INSA, B.P. 08,
76131 Mont Saint Aignan Cedex, France
Received 13 September 2000; accepted 30 October 2000
Abstract—The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been
achieved starting from readily available 1-tetralone derivatives. This host possesses a six-membered lactam moiety and a
carboxamide at the end of a flexible arm. The association constant with benzoic acid and the stoichiometry of the complex have
1
been determined using H NMR dilution experiments. © 2000 Elsevier Science Ltd. All rights reserved.
substrate.4 Our goal was to design a cleft receptor for
For several years, we have been interested in the design
carboxylic acids. The concave nature of the cleft also
and synthesis of new receptors for acids and amines. In
three previous papers, we described the synthesis of
flexible receptors for amines,1 acids2 or both acids and
amines.3 These hosts possessed a heterocyclic structure
with a flexible arm containing a carboxamide moiety
allowing supplementary hydrogen bonding with the
guest. The binding interaction between substrate and
receptor will be significantly enhanced if the receptor
topography is inherently complementary to that of the
reduces the probability of self complexation.4
We selected the design described in Fig. 1. The three bind-
ing points are ensured by a five- or a six-membered lac-
tam and a remote carboxamide incorporated on the ben-
zene ring of a heterocyclic structure having a bowl shape.
In order to obtain this bowl shape, ring B must be satura-
ted and a cis-fusion between rings B and C is required.
Figure 1. Cleft receptor design (left) and proposed receptor design (right).
Scheme 1. (i) 1) PTSA, pyrrolidine, toluene, reflux, 4 h. 2) Acrylamide, 90–100°C, 38 h; (ii) H2/Pd-C, EtOH, 3 bar, rt.
Keywords: molecular recognition; carboxylic acids; molecular modelling; coupling reactions.
* Corresponding author. Fax: 00 33 2 35 52 29 62; e-mail: georges.dupas@insa-rouen.fr
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01934-1

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G. Moore et al. / Tetrahedron Letters 42 (2001) 261–263
Synthesis of the host
exchange reaction was carried out on 4b and subse-
quent quenching with methanol-d or iodine afforded
compounds 4e,f. While no coupling reaction could be
achieved with the free iodolactam 4f, the N-methylated
lactam 6c afforded the diester 7a via reaction with
diethyl malonate under cuprous iodide catalysis
(Scheme 3). This sequence of reactions clearly showed
that the NꢀH lactam must be protected in order to
achieve the cross coupling. We had no success with the
Z group (COOCH2Ph) so we selected the p-methoxy-
benzyl moiety (PMB) as a protecting group, since it is
stable under the reductive conditions leading to a cis-
ring junction and could be conveniently removed under
mild oxidative conditions. After conversion of the iodo-
lactam 4f into its PMB derivative 6d, this latter com-
pound afforded the diester 7b. Reduction of the
carbonꢀcarbon double bond yielded 8 as a single
diastereoisomer (J=4.0 Hz as in 5). Alkaline hydroly-
sis of 8 and subsequent decarboxylation10 led to the
acid 9, which was converted into the carboxamide
under classical pepditic coupling conditions (EDCI,
HOBT, n-PrNH2).11 Oxidative cleavage of the PMB
group with CAN12 yielded the targeted host 10.13
The main problem was to design a synthetic route
affording both the tricyclic structures depicted in Fig. 1
with n=1 or 2 and the possibility of functionalising the
benzene ring. References concerning the syntheses of
these tricyclic lactams are rather scarce.5 A retrosyn-
thetic analysis showed that 7-substituted a-tetralones
would be valuable precursors of the required tricyclic
structure. The 7-methoxy- or the 7-nitrotetralones are
commercially available and the 7-bromo derivative
could be conveniently synthesised.6 As the synthesis of
the five-membered lactam (Fig. 1, n=1) is tedious we
decided to add an extra carbon atom. Molecular mod-
elling (MM2 force field implemented in PCMODEL®)
showed that the six-membered lactam could also ensure
three binding points with a carboxylic acid.
We first tried the Stork enamine reaction on the tetra-
lones 1a,b (Scheme 1). Reaction of acrylamide with the
intermediate pyrrolidine enamine led to the
benz[h]quinolines 2a,b in low yields due to side poly-
merisation reaction. The replacement of acrylamide by
methacrylamide did not improve these yields.
Alternatively (Scheme 2), the tetralones 1a–d were re-
acted with methacrylamide under conditions published
by the Corriu’s group.7 While no reaction occurred
with 7-nitrotetralone (1c), this method afforded the
benzo[h]quinolines 4a,b,d in medium yields (Scheme 2).
The unsubstituted compound 4a was reduced with hy-
drogen under palladium catalysis. The 4a–10b ring
junction of the resulting product 5 was shown to be cis
since a small coupling constant was observed between
the corresponding hydrogen atoms (J=4.0 Hz). In
order to introduce the side chain we tried various
cross-coupling reactions between the 7-bromo deriva-
tive 4b and diethyl malonate, acetylacetone, or ethyl
cyanoacetate.8 Whatever the conditions,9 no conversion
was achieved with either the lactam 4b or with its
N-methyl derivative 6a obtained via methylation with
KOH/DMSO/MeI. It is well known that iodine is more
reactive in this kind of reaction. The bromine lithium
Complexation studies
Having at hand the two hosts 5 and 10, we carried out
the complexation studies of carboxylic acids using
NMR experiments. We studied first the self association
of 5 and 10. On dilution of a host solution, an upfield
chemical shift of the amide protons was observed. The
chemical shift values were noted as a function of the
concentration and Horman–Dreux14 analysis of these
data gave no dimerisation constant (Kd) for 5 and
Kd=20 M−1 for 10. On addition of the guest to the
host solutions, a downfield chemical shift of the amide
protons of the host was observed. The stoichiometry of
the complexes was 1/1 as shown by the continuous
variation method of Job.15 With benzoic acid, the asso-
ciation constant (Ka) was 80 M−1 for 5 and 200 M−1 for
10. This binding study clearly shows that the presence
of the supplementary carboxamide moiety in com-
Scheme 2. (i) Methacrylamide, Si(OMe)4, CsF, 80°C, neat; (ii) 1) 2.2 equiv. n-BuLi. 2) 3.3 equiv. tert-BuLi. 3) 5 equiv. MeOD
or I2; (iii) H2/Pd-C, EtOH, 1 bar, rt; (iv) 1) KOH, DMSO. 2) MeI or PMBCl.

G. Moore et al. / Tetrahedron Letters 42 (2001) 261–263
263
Scheme 3. (i) NaH, EtOOC-CH2-COOEt, CuI, dioxane; (ii) H2/Pd-C, EtOH, 1 bar, rt; (iii) 1) 3% NaOH. 2) CuI, MeCN; (iv) 1)
n-propylamine, HOBT, EDCI, DMSO. 2) CAN, H2O, MeCN, rt.
pound 10 led to a significant increasing of the associa-
tion constant.
1311–1314. (b) Corriu, R. J. P.; Perz, R. Tetrahedron
1986, 42, 2293–2301.
8. Sugai, S; Ikawa, H.; Okasaki, T.; Akaboshi, S.; Ikegami,
S. Chem. Lett. 1982, 597–600.
9. We did not try the following recently published condi-
tions: Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2000, 122, 1360–1370. Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157.
10. Toussaint, O.; Capdevielle, P.; Maumy, M. Synthesis
1986, 1029–1031.
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