Synthesis and structural chemistry of bicyclic hexaaza-dithia macrocycles containing pendant donor groups

A short and efficient synthesis of a series of macrobicyclic aza-thioethers with pendant allyl (8, 13, 14), cyanethyl (15), 3-aminopropyl (16), 2-methoxyacetyl (17, 19), 2-methoxyethyl (18, 20), and tertbutyloxycarbonyl substituents (22, 23) has been achieved. The parent macrobicycles 1 and 2 are readily alkylated without overalkylation and without affecting the masked thiolate functions. The protocol is also feasible for the synthesis of macrobicycles with different alkyl groups on the benzylic and central nitrogen atoms of the linking diethylene triamine units. The identity of the compounds was substantiated using ESI MS, FT-IR, H-NMR, and C-NMR spectroscopy. The crystal and molecular structures of six compounds (8, 15, 17 3DMSO, 19 2DMSO 2H2O, 20 and 23) were additionally solved. The macrocycles are rather flexible and can adopt folded or stepped conformations. The ability of the compounds to form inclusion complexes with DMSO is also demonstrated. The crystal structures are governed by extensive interand intramolecular CH p interactions.

Tetraallylated aza-thioether 9. The thioether 2 (641 mg, 1.00 mmol) and allyl bromide (509 mg, 4.21 mmol) were dissolved in EtOH (3 mL). A solution of triethylamine (404 mg, 4.00 mmol) in EtOH (1 mL) was added dropwise and the mixture was allowed to stand for 2 weeks at 0 1C. HNEt 3 Br crystallized, from which the reaction mixture was decanted off. The title compound precipitated from the mother liquor upon standing in air.  -4). This compound was additionally characterized by X-ray crystallography.
N-Allyl-bis(2-phthalimidoethyl)-amine (12). A mixture of bis(2phthalimidoethyl)-amine 11 (25.0 g, 68.8 mmol), K 2 CO 3 (9.51 g, 68.8 mmol), and allyl bromide (11.6 g, 9.59 mmol) in 700 mL of THF was stirred for 30 min at room temperature and for 12 h at 50 1C. The resulting mixture was filtered, and concentrated in vacuum to one fourth of its original volume. The resulting crystals were collected and dried under vacuum. Yield: 15  N-Allyl-bis(2-aminoethyl)-amin (13). A suspension of N-allylbis(2-aminoethyl)-amine-trihydrochloride (9.76 g, 38.6 mmol) and KOC(CH 3 ) 3 (13.0 g, 116 mmol) in 50 mL of THF was stirred at 55 1C for 3 d and filtered. The THF was removed in vacuum to give an oil, which was purified by distillation in vacuum. Yield: 5.25 g (89%). The compound is hygroscopic and could not be obtained in analytically pure form. The compound was found pure enough for the next step. IR Bisallylated aza-thioether 14. A solution of N-allyl-bis(2aminoethyl)-amine 13 (702 mg, 4.61 mmol) in EtOH (150 mL, 3 : 1, v : v) and a solution of 1,2-bis(4-tert-butyl-2,6-diformylphenylthio)ethane 10 (1.08 g, 2.30 mmol) in CH 2 Cl 2 (500 mL) were added simultaneously over the course of 3 h into a EtOH/ CH 2 Cl 2 (600 mL, 1 : 3 v : v) solvent mixture. After the resulting mixture was stirred for further 2 d, the CH 2 Cl 2 solvent was removed under reduced pressure. Sodium borohydride (690 mg, 18.24 mmol) was added and the mixture was stirred at r.t. for another 2 h. The excess reducing agent was destroyed by adding HCl conc (final pH = 1). The mixture was subsequently evaporated to dryness, re-dissolved in CH 2 Cl 2 /H 2 O (100 mL, 1 : 1 v : v), and the pH was adjusted to B13 with aqueous KOH (5 M). After stirring for 2 h, the layers were separated and the aqueous phase was extracted with dichloromethane (4 Â 150 mL). The organic fractions were combined and dried with anhydrous K 2 CO 3 . Evaporation of the solvent gave a foam, which was recrystallized from EtOH to give 1.41 g (88%) of the title compound. Found: C 68.90, H 9.29, N 12.29, S 9.11; C 40  Hexa-(cyanoethylated) azathioether 15. The thioether 1 (4.67 g, 7.62 mmol) was dissolved in acrylonitrile (3 mL) and the resulting mixture was stirred for 3 d at 80 1C. The excess acrylonitrile was evaporated, and the yellow solid was dissolved in 100 mL of a 2 : 1 CH 2 Cl 2 /CH 3 CN solvent mixture. Evaporation of the CH 2 Cl 2 provided a colorless solid, which was filtered and dried in air. Yield: 7.08 g (7.6 mmol, 99%), colorless solid. M.p. 170-172 1C.  -4). This compound was additionally characterized by X-ray crystallography.
The solution was stirred for 1 h, evaporated to dryness, and suspended in 40 mL of 3 M NaOH solution. The aqueous phase was extracted with CH 2 Cl 2 (4 Â 20 mL). The organic fractions were combined and dried with anhydrous K 2 CO 3 . Evaporation of the solvent gave 16 as a colorless solid (376 mg, 73%). The compound is hygroscopic and could not be obtained in analytically pure form, but the spectroscopic data (see ESI †) prove the formulation of this compound. m/z (ESI+, MeOH): C 52 H 98 N 12  Tetra(2-methoxyacetylated) aza-thioether 19. By analogy to the preparation of 17, compound 2 (1.60 g, 2.50 mmol) in dry chloroform (20 mL), 2-methoxyacetyl chloride (1.14 g, 10.5 mmol), and triethylamine (1.10 g, 10.0 mmol) were reacted to give a colorless solution, which was stirred for 12 h and evaporated to dryness. The residue was suspended in THF (10 mL), filtered, and dried. The colorless solid was purified by recrystallization from EtOH. Yield: 2.00 g (86%  Dicarbamoylated macrobicycle 22. To a solution of tert-butyl bis(2-aminoethyl)carbamate (2.89 g, 14.22 mmol) in EtOH/ CHCl 3 (800 mL, 3 : 1 v/v) at 0 1C was added a solution of 1,2bis(4-tert-butyl-2,6-diformylphenylthio)ethane (3.34 g, 7.11 mmol) in CHCl 3 (500 mL) over the course of 8 h. After the resulting mixture was stirred for further 2 d, the CHCl 3 solvent was removed under reduced pressure. Sodium borohydride (2.15 g, 56.88 mmol) was added and the mixture was stirred at r.t. for 18 h. The mixture was evaporated to dryness, then redissolved in CH 2 Cl 2 /H 2 O (100 mL, 1 : 1, v/v), and the pH was adjusted to B13 with aqueous KOH (5 M). After stirring for 2 h, the layers were separated and the aqueous phase was extracted with CH 2 Cl 2 (4 Â 50 mL). The organic fractions were combined and dried with anhydrous MgSO 4 . Evaporation of the solvent gave an oil, which crystallized from EtOH (10 ml) after standing for 4 weeks. Yield: 1. Methylated macrobicycle 23. To a suspension of 22 (1.13 g, 1.39 mmol) in MeOH (55 mL) was added acetic acid (4 mL) followed by formaldehyde (4 ml), and sodium cyanoborohydride (689 mg, 11.12 mmol). The resulting clear solution was stirred for 3 d at r.t., and its pH was brought to 13 with aqueous KOH (5 M). The MeOH was removed under reduced pressure, and 50 mL CH 2 Cl 2 /H 2 O (1 : 1 v/v) was added. After stirring for 2 h, the layers were separated and the aqueous phase was extracted with CH 2 Cl 2 (4 Â 25 mL). The organic fractions were combined and dried with anhydrous MgSO 4 . Evaporation gave the crude product, which was purified by recrystallization from CH 2  Compound 24ÁCF 3 COOH. To a suspension of 23 (250 mg, 0.29 mmol) in CH 2 Cl 2 (0.5 mL) was added trifluoroacetic acid (1 mL). The resulting clear solution was stirred for 2 h at r.t., and its pH was brought to 13 with aqueous KOH (5 M). The aqueous phase was extracted with CH 2 Cl 2 (4 Â 5 mL). The organic fractions were combined and dried with anhydrous MgSO 4 . Evaporation gave the crude product which was not purified further.

Crystallography
Suitable single crystals of compounds 8, 15, 17Á3DMSO, 19Á 2DMSOÁ2H 2 O, 20, and 23 were selected and mounted on the tip of a glass fibre using perfluoropolyether oil. The data sets for 8, 17Á3DMSO, 19Á2DMSOÁ2H 2 O, and 20 were collected at 183(2) K using a STOE IPDS-2 diffractometer, while those for 15 and 23 were collected on a STOE IPDS-1 diffractometer at 213(2) K. Graphite monochromated Mo-K a radiation (l = 0.71073 Å) was used throughout. The data were processed with the programs XAREA. 32 Selected details of the data collection and refinement are given in Table 1. The structures were solved by direct methods 33 and refined by full-matrix least-squares techniques on the basis of all data against F 2 using SHELXL-97. 34 PLATON was used to search for higher symmetry. 35 All non-hydrogen atoms were refined anisotropically, except for those of some disordered solvate molecules. Disorder was modelled using split atom models with restrained Cl-O, OÁ Á ÁO, C-C, and CÁ Á ÁC distances using appropriate SADI instructions implemented in the SHELXL software package. Graphics were produced with Ortep3 for Windows and PovRAY.
In the crystal structure of 8 two allyl (N1, C18, C19, C20; C21, C22, C23) and one ethylene group (C12, C13) were found to be disordered over two sites. The site occupancies of one allyl and one ethyl group were fixed (0.74/0.26). The site occupancies of the other allyl group were refined (0.55/0.45). In the crystal structure of 17Á3DMSO one DMSO solvate molecule (S5, O15, C57, C58) was found to be heavily disordered and was therefore removed from the structure (and the corresponding F o ) with the SQUEEZE procedure implemented in the PLATON program suite. Removing the DMSO molecule led to a solvent accessible void of 257 Å 3 , in good agreement with the space needed by one DMSO molecules. The solvate molecules in 19Á2DMSOÁ2H 2 O were also found to be heavily disordered and were therefore removed utilizing the SQUEEZE procedure. This led to solvent accessible voids of 628 Å 3 , attributed to the space needed for two DMSO and two H 2 O molecules.

Results and discussion
Synthesis Scheme 1 depicts the synthetic procedures for compounds 8, 9, and 15-20. The reaction of 1 with allylbromide in the presence of NEt 3 in ethanol furnished the bicycle 8 in good yields (481%). To prevent overalkylation the reaction was carried out at 0 1C. Under similar conditions, the dimethylated precursor 2 reacted preferentially in the benzylic position providing the corresponding tetraallylated system 9 (75%) as colorless needles after recrystallization from CHCl 3 /EtOH. The reductive amination of tetraaldehyde 10 with N 1 -(3-aminopropyl)-N 1methylpropane-1,3-diamine 13 under medium-dilution conditions provided the bis-allylated macrocycle 14 in excellent yield (Scheme 2). The second ligand system was prepared according to a protocol used for the cyanethylation of tetraazacycloalkanes. 36 Thus, Michael addition of 1 to acrylonitrile led quantitatively to the hexacyanethylated product 15, which can be easily purified by recrystallization. It was reported that the nitrile functions of tetra(2-cyanoethyl)tetraazacycloalkanes can be reduced to the corresponding primary amines by reduction with LiAlH 4 , diborane or H 2 -RANEY s -Nickel. [37][38][39] In our hands, the nitrile 15 failed to react in this fashion. Therefore, an alternative protocol involving reduction with LiBH 4 /Me 3 SiCl was employed. 40 This sequence provided the hexa(3-aminopropylated) macrocycle 16 in moderate to good yields.
The route used for the synthesis of the amino-thioethers with methoxymethyl substituent is depicted in Scheme 1. A reaction sequence similar to that developed for similar N 6 S 2 -type macrocycles bearing ''innocent'' alkyl groups was employed. Key-step of this procedure is the acylation of 1 with 2-methoxyacetyl chloride. Thus, in reaction with 2-methoxyacetyl chloride the amide 17 was generated quantitatively and then reduced to 18 with LiBH 4 /Me 3 SiCl. As an illustration of the utility of this sequence, the N,N 0 -dimethyl derivative 2 was also quantitatively derivatized giving the bicyclic macrocycles 19 and 20, respectively.  So far only the precursors 1 and 2 had been utilized for functionalization. In reactions with 1 all six NH donors are derivatized, while modifications of 2 involved only the benzylic NH donors. We decided to develop a method that allows the selective functionalization of the two central NH donors. In an orienting experiment, the reductive amination of the tetraaldehyde 1 with tert-butyl-bis(2-aminoethyl)carbamate 21 was undertaken. This provided the desired macrocycle 22, albeit in low yield. Having succeeded with the preparation of 22, alkylation of the N-benzyl functions and deprotection of the carbamoyl groups could be examined. Indeed, 22 readily underwent reductive methylation with formaldehyde and NaBH 3 CN to give the tetramethylated derivative 23 in 75% yields, which was fully characterized including X-ray crystallography. Finally, deprotection of 23 with trifluoroacetic acid gave the desired amine 24.
All new compounds were characterized by elemental analysis, IR, 1 H and 13 C NMR spectroscopy. Some compounds were further characterized by X-ray crystallography, in order to study their host-guest chemistry. Fig. 2 displays the molecular structure of the hexaallylated macrocycle 8. The molecule has crystallographically imposed C 2 symmetry, and adopts a folded conformation. Unlike in the permethylated derivative 3, 29 the two aromatic rings are essentially coplanar, but are twisted about the S1Á Á ÁS1 0 vector (torsional angle C1-S1Á Á ÁS1 0 -C1a = 37.81), attributed to steric interactions between the tert-butyl groups. The allyl residues are all oriented away from the cavity. There are no specific intermolecular interactions in 8. The C-S bonds are of length 1.783(1) Å (S1-C1, S1 0 -C1 0 ). Virtually the same distances are seen in 3. Fig. 3 displays the molecular structure of the hexanitrile 15. The macrobicycle adopts a folded conformation, which is similar but not identical to that seen in 8. Here, the two phenyl rings plane are bent into the cleft formed by the macrocycle, at an interplanar angle of 191. The structure is stabilised by two intermolecular CHÁ Á Áp interactions as indicated by relatively short distances between the methylene groups and the aromatic rings (C11Á Á Ácentroid(aromatic ring) = 3.823 Å). 41 In contrast to the hexaallylated macrocycle, molecules of 15 are connected via intermolecular CH 2 Á Á ÁNC interactions (N4Á Á ÁH17b 00 = 3.013, N5Á Á ÁH25b 00 2.517, N6Á Á ÁH19b 00 2.735 Å). These interactions lead to a three-dimensional network. The structure of the tetramethoxyethylated aza-thioether 20 is very similar to that of 15 (when neglecting the different N-substituents). However, the tilting of the two aryl rings is not so pronounced (51) and the C11Á Á Ácentroid distances are longer at 3.875 Å.

Crystal structures
Hexa(2-methoxyacetylated) macrobicycle 17 crystallizes from DMSO with three solvate molecules. Fig. 4 shows the structure of the macrobicycle, which forms an inclusion complex with a DMSO molecule. The guest molecule is held in place by a CHÁ Á Áp interaction of length 3.823 Å (C11Á Á Ácentroid(aromatic ring)). The other two DMSO molecules are enclathrated in the voids of the structure. The structure of 17Á3DMSO should be compared with that of the tetra(2-methoxyacetylated) derivative 19Á2DMSOÁ2H 2 O (Fig. 4, right). This compound crystallizes also Fig. 2 Molecular structure of 8 in the crystal with atomic numbering for key atoms. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity. Symmetry code used to generate equivalent atoms: 1 À x, y, 0.5 À z. Fig. 3 Left: Molecular structure of 15 in the crystal with atomic numbering for key atoms and centroids of aromatic rings. Thermal ellipsoids are set at 30% probability. Symmetry code used to generate equivalent atoms: 1/2 À x, y, 1 À z. Right: Molecular structure of 20 in the crystal. Hydrogen atoms have been omitted for clarity. Symmetry code: Àx, y, 1/2 À z. CHÁ Á Áp interactions indicated by dashed lines.
with solvate molecules, but does not form an inclusion complex. The two phenyl rings in 19 are coplanar as in the hexanitrile 15. However, the distance between the two best planes through the benzene rings is much larger at 5.087 Å. As a consequence, the phenyl rings are not involved in intermolecular CHÁ Á Áp interactions with the adjacent benzyl group (C11Á Á Ácentroid(aromatic ring) = 4.802 Å). Clearly, removal of two methoxyacetyl residues exerts more conformational flexibility on the macrocycle. Fig. 5 displays the structure of the protected macrobicycle 23, which has crystallographically imposed inversion symmetry. Unlike in the above structures, the thioether adopts a stepped conformation, presumably a consequence of the steric requirements of the N-carbamate groups. As a consequence, the macrocycles are engaged in intermolecular CHÁ Á Áp interactions. The corresponding CHÁ Á Áp distances at 3.428 Å (C11Á Á Ácentroid(aromatic ring)) are significantly shorter than in 15 or 20. This compound crystallizes without guest molecules.

Conclusion
Overall, a short and efficient protocol for the functionalization of bicyclic aza-thioethers has been described. All six secondary amine functions of the parent macrobicycles 1 and 2 are readily alkylated without overalkylation and without affecting the masked thiolate functions. The protocol is also feasible for the synthesis of macrobicycles with different alkyl groups on the benzylic and central nitrogen atoms of the linking diethylene triamine units, such that these derivatives are also now available. Six of the twelve new compounds were obtained in crystalline form, such that their molecular structures could be determined. In the solid state the macrobicycles can adopt a stepped or a folded conformation. The structures appear to be primarily governed by inter-and intramolecular CH 2 Á Á Áp interactions (involving the benzylic methylene groups and the aromatic rings) rather due to steric effects played by the N alkyl functions. The observation that DMSO, which is a good CH donor, can form an inclusion complex held in place by a CH 3 Á Á Áp interaction would be consistent with this in view.  Àx, 1 À y, Àz ( 0 ); Àx, 2 À y, Àz ( 00 ).