Simple synthesis of a new family of 22-to 28-membered macrocycles containing two chalcone moieties

A new family of 22-to 28-membered tetrabenzo-macrocycles containing two chalcone moieties has been synthesized from 2 - hydroxybenzaldehyde and 2′-hydroxyacetophenone through phenol alkylation with α,ω-dibromoalkanes followed by Claisen-Schmidt reaction under high dilution condition. All the compounds of this family were found to possess both the double bonds in E-configuration. An attempt to synthesize another family of isomeric tetrabenzo-macrocycles having opposite alignment of the two chalcone moieties by reaction of 2,2′-dihydroxychalcone with α,ω-dibromoalkanes was not successful, a series of 12-to 14-membered dibenzo-macrocycles with only one chalcone moiety was obtained here.


Introduction
][10][11] Macrocycles incorporating more than one chalcone moiety have great potential in generating new compounds suitable for molecular recognition [12][13][14][15] and photophysical 16,17 studies.9][20] Synthesis of other structurally related compounds and their suitable transformations to useful hosts are also reported. 21,22Furthermore, very recently several types of macrocycles containing fused heterocyclic or homocyclic moieties have been synthesized [23][24][25][26][27][28][29] and a good number of them have shown some very interesting properties.It was therefore our endeavour to develop a simple synthesis of macrocycles containing more than one chalcone moiety.The study started with synthesis of target molecules containing two chalcone moieties by exploiting the well-known Claisen-Schmidt reaction which is one of the most simple and high-yielding organic reactions showing very high atom economy.The outcome of this study is presented herein.

Results and Discussion
A retrosynthetic analysis of the target macrocycles indicated a very simple approach for their synthesis through the use of commonly available starting materials.It was considered that generation of a bis-aldehyde by joining two benzaldehyde units with a spacer and that of a bisketone by joining two acetophenone units with another spacer followed by their Claisen-Schmidt condensation (first step intermolecular and the second step intramolecular) would lead to the target macrocycles.Hydroxybenzaldehydes and hydroxyacetophenones are readily available compounds, and our study began with the ortho compounds of these two categories.Reaction of α,ω-dibromoalkanes with 2-hydroxybenzaldehyde in 1:2 mole ratio was used to generate the required bis-aldehydes and analogous reaction involving 2′-hydroxyacetophenone was used to generate the required bis-ketones (Scheme 1).[32]  For synthesis of macrocyclic bis-chalcones utilizing the above bis-aldehydes and bis-ketones, reactions of sixteen possible combinations of reactants were performed in aqueous methanolic KOH (Scheme 2), and all of them proved to be successful.An initial study with four examples (1a+2a, 1b+2b, 1c+2c, 1d+2d) showed that application of high dilution technique increased the yield of the macrocycles significantly. 33So the high dilution technique was applied for all the combinations (concentration of each of the two components was in the range 1.5 to 1.9 × 10 -3 mol/L).Under this condition the yields of the macrocycles were moderate to good, though they varied widely (Table 1).The configurations of the double bonds of the chalcone moieties present in each macrocyclic system so obtained have been found to be E from characteristic coupling constant values in 1 H NMR spectra (Jα,β ~ 16 Hz).This structural feature was evident also from an X-ray crystallographic study of one of the members (3f, Figure 1).It may be mentioned here that under the applied reaction conditions intramolecular aldol condensation of 2 did not take place at all.In all the macrocycles 3a-p, the two α,β-unsaturated ketone moieties are aligned in the same way.There is a possibility of getting the corresponding isomeric macrocycles where these two moieties are aligned in the opposite way, i.e., the macrocycles being of the type 4. Such macrocycles also would be structurally interesting, and for their synthesis etherification involving 5a and 5b (through occurrence of an intermolecular process first and then an intramolecular process) was conceived as one of the plausible routes.Anticipating that reaction at the free OH of 2,2′-dihydroxychalcone (6) would be faster than that at its chelated OH, the mono ethers 5a and 5b would be expected to be the products of the first step of its reaction with α,ω-dibromoalkanes.It was our consideration that if it is possible to bring about the second step of the reaction in the same pot, any target compound of the series 4 with m=n may be reached readily (Scheme 3).With this synthetic planning, 6 was refluxed separately with each of the α,ω-dibromoalkanes, Br-(CH2)2-Br, Br-(CH2)3-Br, Br-(CH2)4-Br and Br-(CH2)5-Br in dry acetone with K2CO3 using the reactants at the concentration 0.067 mol/L.It was observed that reaction took place in last three of these cases yielding nonphenolic products.However, the spectral data of the products thus obtained showed that, instead of the desired compounds 4 (with m=n), cyclic compounds of general structure 7 were formed (Yield: 7a-50%, 7b-49%, 7c-54%) (Scheme 4).Thus, it may be concluded that even by using the reactants in relatively higher concentration as mentioned above, the intramolecular reactions are more facile than intermolecular ones in these cases.A careful examination of the chemical shifts of H-α and H-β of the enone system of 3a-p showed that the former proton appeared in the range δ 7.01 -7.55 while the latter in the range δ 7.52 -7.73 (vide Experimental), and the variation of chemical shift values of each of these two protons did not show any regular trend.In case of the compounds 7a-c, the variation of chemical shifts of H-β and the Ar-H ortho to carbonyl is very conspicuous (Table 2) and here also no regular trend of chemical shift values was observed.The large δ-value for H-β of 7b indicated that in the preferred conformation of this compound the said proton experiences remarkable anisotropic deshielding.Some initial work towards synthesis of macrocyclic bis-chalcones of the type 8-10 by including 3-hydroxybenzaldehyde and 3′-hydroxyacetophenone also as starting materials could be done so far.Thus, attempts towards synthesis of 8a (from 11 and 2b), 9a (from 1c and 12) and 10a (from 11 and 12) were found to be successful in the first two cases, though the yields were somewhat lower [8a (ring size 26) -35%; 9a (ring size 28) -38%].It is being planned to undertake a separate program for synthesis of these categories of macrocycles.

Conclusions
Thus, a simple method for synthesis of a new family of 22-to 28-membered macrocycles of general structure 3, all containing two chalcone moieties with E double bonds, has been developed.As an offshoot of this study, another group of 12-to 14-membered macrocycles (7)  containing one E chalcone unit has also been synthesized.The yields of the compounds 3 which are of major interest here, have been found to be much better than those for some related compounds reported by other groups. 18,19This category of compounds has the potential to find wide applicability as two of their spacers can be varied independently and widely and the two α,β-unsaturated ketone moieties present in each of them can be made to undergo condensation with varieties of suitable heteroatom containing condensing agents leading to interesting heterocycle fused macrocycles.Some works in this direction are being done currently.

Experimental Section
General.Melting points were recorded on a Köfler block.IR spectra were recorded on a Perkin Elmer FT-IR Spectrometer (Spectrum RX 1) in KBr pellets.General procedure for macrocyclisation using the bis-aldehydes 1 and the bis-ketones 2. A mixture of bis-aldehyde (1) (0.25 mmol) and bis-ketone (2) (0.25 mmol) was dissolved in a KOH solution (10%, 130-160 mL) in MeOH-H2O (3:1) and the mixture was stirred at room temperature.A precipitate began to be formed after ca. 5 h. of stirring.The stirring was continued for 72 h., the volume of the solvent was reduced to nearly half of the original by distillation under reduced pressure.The product obtained as precipitate was collected by careful filtration.The solid thus obtained was almost pure and it was further purified by column chromatography over silica gel followed by crystallization from CHCl3-petroleum ether.The analytical and spectral data of the macrocyclic products 3a-p were as follows:

Crystallographic data collection and refinement
A suitable single crystal of compound 3f (crystallized from acetone and n-hexane) was mounted on a thin glass fiber with commercially available super glue.X-ray single crystal data collection was performed at room temperature using "Bruker SMART" diffractometer, equipped with a normal focus, sealed tube X-ray source with graphite monochromated Mo-K radiation ( 0.71073Å).The structure was solved by SHELXS 97.Structure refinement was carried out using SHELXL 97.The relevant data are given in Table 3. "CCDC 887597" contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre.

Table 2 . Chemical shift values (δ) of some protons of 7a-c
Analytical samples were routinely dried in vacuo at room temperature.Microanalytical data were recorded on four Perkin-Elmer 2400 Series II C, H, N analyzers.Column chromatography was performed with silica gel (100-200 mesh) and TLC with silica gel G made of SRL Pvt. Ltd.Petroleum ether had the boiling range 60-80 °C.X-ray single crystal data collection for 3f was performed with a "Bruker SMART" diffractometer (details given at the end of this section).

Table 3 .
Important crystallographic data for compound 3f