Synthesis of functionalized macrocyclic derivatives of trioxabicyclo[3.3.0]nonadiene

C72-Macrocyclic systems functionalized with nitroaryl and arylamino groups were synthesized from the bisdioxine diacid dichloride 1,3,5,7-tetra-tert-butyl-2,6,9-trioxabicyclo[3.3.1]nona-3,7-diene-4,8-dicarbonyl dichloride (3).

It may also be possible to stabilize reactive intermediates and unusual functional groups in the concave interiors of the bisdioxine-derived macrocycles.Okazaki and co-workers designed bowl-shaped [8] and lantern-shaped [9] molecules containing a functionalized aryl group, which allowed the preparation of, among other things, stable simple enols [8] and a variety of unusual sulfur [9], selenium [10,11] and germanium [12] species.Clearly, the bisdioxine macrocycles such as 4 and 5 will not be nearly as rigid, but they may nevertheless exert some steric protection.Herein we report the realisation of the first step toward this end, the preparation of functionalized macrocyclic bisdioxine derivatives.

Results and Discussion
Functional group manipulation on aromatic rings often starts with the nitro group.Therefore, a synthesis of suitable nitroaromatic diols for combination with the diacid dichloride 3 was required.The desired 2-nitro-1,4-phenylene derivative 7 was prepared by treatment of hydroquinone with 3-bromopropanol followed by nitration of the resulting diol 6 (Scheme 2).The isomeric 1,2,3-trisubstituted aromatic 10 was obtained by etherification of nitroresorcinol (Scheme 3).The two diols 7 and 10 reacted readily with the diacid dichloride 3 in boiling toluene in the presence of triethylamine to afford the 2:2 adducts 8 and 11, respectively (Scheme 2 and Scheme 3).These compounds were characterized by elemental analysis and their 1 H-and 13 C NMR spectra.All proton and carbon resonances could be assigned by comparison with data for other, related, macrocycles [1][2][3][4][5][6][7] (see Supporting Information File 2 for spectral details).Since 3 is chiral (existing in enantiomeric R and S forms) [1,4], the nitro compounds 8 and 11 must also be chiral, i.e., they must exist as mixtures of diastereoisomeric forms (see the Supporting Information File 1 for drawings of the principal structures).This will also be the case for the derivatives described below.The splitting of several signals in the NMR spectra may be ascribed to the presence of mixtures of diastereoisomers and conformers.

Reduction
Several methods were attempted for the reduction of the nitro groups in 8 and 11.Reductions with NaBH 4 and sulfur [13] or with ammonium formate and Pd/C under microwave irradiation [14] were unsuccessful.However, compound 8 was completely reduced to the diamine 9 by using the classical reduction with Sn and HCl (Scheme 2).The reaction was complete in 1 h.Under the same conditions it took 3 h for the 2,6-disubstituted nitro compound 11 to be completely consumed.Compound 11 is more compact than 8 (see below), and the reduction of 11 was evidently more difficult.Although the product was largely the desired diamine 13, mass spectrometry indicated the presence of the singly reduced nitro derivative 12 as an impurity (Scheme 3).
A remarkable reaction is the ready conversion of macrocyclic as well as open-chain bisdioxine derivatives to 2,4,6,8-tetraoxaadamantanes on acid hydrolysis [4,7,15].This transformation was also achieved with the dinitro compound 8, which yielded the mono-tetraoxaadamantane derivative 14 (Scheme 4), but all attempts to convert the second bisdioxine unit were fruitless, presumably due to steric hindrance.Force-field calculations [16] indicate that the internal cavity is much smaller in 11 than in 8, and in fact it was not possible to prepare a tetraoxaadamantane derivative of nitro compound 11.There is a significant cavity in 8, obviously large enough to form one tetraoxaadamantane derivative, but this reduces the available space, with the consequence that the attack by a water molecule on the second bisdioxine unit from the concave inside of the macrocycle does not take place.

Conclusion
The difficulty of reduction of the nitro compounds, in particular the 1,2,3-trisubstituted compound 11, as well as the conversion of only one of the bisdioxine units in 8 to a tetraoxaadamantane suggests that these macrocycles provide steric protection of the functional groups.The cavity in 8 is obviously large enough to permit the formation of one tetraoxaadamantane unit, but this will reduce the available space, with the consequence that the attack by a water molecule on the second bisdioxine unit from the concave inside of the macrocycle does not take place.Moreover, no tetraoxaadamantane derivative of nitro compound 11 was obtainable.Here, the cavity is too small for the formation of a tetraoxaadamantane.Further investigations of reactivity and functional group manipulation in the macrocycles described herein are foreseen.

Bis(2-nitro-1,4-phenylene)macrocycle 8:
A sample of diacid dichloride 3 (500 mg, 1.05 mmol) was dissolved in 25 mL of toluene.The diol 7 (285 mg, 1.05 mmol) was separately dissolved in 8 mL of toluene, and 1 mL of Et 3 N in 17 mL of THF was added.The two solutions were placed in separate dropping funnels attached to a flask containing 80 mL of toluene, fitted with a reflux condenser and protected from moisture.The apparatus was flushed with N 2 .The two solutions were simultaneously added dropwise to the toluene under reflux over a 3 h period, and the resulting mixture was heated under reflux for 20 h.After cooling to 60 °C and filtering on a folded filter, the resulting solution was evaporated, and the material so obtained was triturated with 5 mL diethyl ether to form a yellow precipitate.DCFC afforded 163 mg (23%) of yellow crystals, mp 264-266 °C dec; 1

Bis(2-amino-1,4-phenylene)macrocycle 9:
A mixture of 100 mg (0.07 mmol) of 8 and 40 mg (2.4 mmol) of tin granules in 10 mL of THF was heated to reflux.Subsequently, 300 µL of conc.HCl was added dropwise, which resulted in strong gas evolution.The reaction was followed by TLC (CH 2 Cl 2 /MeOH 100:1), which indicated completion after 1 h.The reaction mixture was cooled, neutralized with 2 M NaOH, and filtered.The resulting solution was extracted with CH 2 Cl 2 and concentrated, and the residue was triturated with diethyl ether, which caused the formation of a white precipitate.The product was purified by DCFC, eluting with hexane/diethyl ether/MeOH 100:30:2 to yield 10 mg (10%) of a slightly yellow solid. 1

Bis(2-amino-1,3-phenylene)macrocycle 13:
The dinitro compound 11 (44 mg; 0.03 mmol) was reduced with 20 mg (1.69 mmol) of tin granules in 5 mL of THF and 150 µL of conc.HCl, as described for the reduction of 8 above.It took 3 h for the starting material to be fully consumed, yielding 10 mg of the diamine as a white precipitate. 1

Scheme 1 :
Scheme 1: Synthesis of macrocyclic bisdioxine derivatives (R,S-form of 4 and S-form of 5 shown; see Supporting Information File 1 for details).