Syntheses of diazadithiacrown ethers containing two 8-hydroxyquinoline side arms

Ten new diazadithiacrown ethers containing two 8-hydroxyquinoline (HQ) sidearms attached through the HQ 7-positions and four new diazadithiacrown ethers containing two HQ sidearms attached through the HQ 2-positions have been prepared. Some of these new ligands also contain a hydroxymethyl substituent. The starting macrocyclic diazadithiacrown ethers were obtained by treatment of a bis( α -chloroamide) with the appropriate dimercaptan using K 2 CO 3 as the base followed by reduction of the resulting macrocyclic dithiadiamide by BH 3 -THF or by NaBH 4 in the presence of BF 3 -ether as a catalyst. HQ-containing ligands 23-32 were synthesized by a Mannich reaction of the secondary macrocyclic diamines with the substituted-8-hydroxyquinoline. HQ-containing ligands 33-36 were prepared by reductive amination of the secondary macrocyclic diamines with 8-hydroxyquinoline-2-carbaldehyde. The HQ-containing diazadithiacrown ethers which also contain a hydroxymethyl group on the macroring 23-29 , 33 , and 35 are more soluble in polar solvents than those without the hydroxymethyl group.


Introduction
In general, the complexing ability and selectivity of lariat ethers for metal ions can be varied by changing certain parameters such as the acidity of the phenolic OH group; the size of the crown ether ring; type, number, and position of the complexing crown ether heteroatoms; the stereochemistry imposed by the arms which connect the phenolic group to the macro ring; and the pH of media. 1 For example, diaza-18-crown-6 containing two 5-chloro-8-hydroxyquinoline (CHQ) groups attached through the CHQ 7-position (1, Figure 1) exhibits a stronger affinity for Mg 2+ than for Ba 2+ (log K value in MeOH for Mg 2+ is 6.82, for Ba 2+ 3.60) and its isomer, diaza-18-crown-6 bearing two CHQ groups attached through the CHQ 2-position 4, has a stronger affinity for Ba 2+ than for Mg 2+ (log K value in MeOH for Ba 2+ is 12.2). 2 Ligands 3 and 5, the HQ analogs of 1 and 4, respectively (1 and 4 with the chlorine atoms removed), do not exhibit the same complexing properties as do 1 and 4. 3 Increasing the number of macroring nitrogen atoms and changing the size of macroring could change the affinity of the ligand toward the heavy metal ions.For example, for ligand 5, the log K value in MeOH for Cu 2+ is 4.39 while its tetraaza-15-crown-5 analog 6 has a log K value for Cu 2+ of 15.5. 4 Ligand 2, which has a 5-nitro substituent on each 8-hydroxyquinoline, has a high affinity and selectivity for Hg 2+ and has proven to be a chemosensor for Hg 2+ . 5Diaza-18-crown-6 with two 4-methyl(or nitro)-6-aminophenol groups attached through the phenol 2-positions, 7 and 8 form dinuclear complexes with one Cu 2+ complexed to the two 6-aminophenols and one Na + in the macroring cavity. 6Diazadithia (ortrithia) crown ethers 9 containing two HQ side arms have also been synthesized. 7,8These new azathia ligands have poor solubilities in MeOH and, therefore, their complexing properties with metal ions cannot be conveniently studied.A few of ligands 9 have a hydroxymethyl substituent attached to the macro ring and are therby more soluble in methanol.Herein, we report the synthesis of a series of new diazadithiacrown ethers bearing 5-substituent (or 2-methyl)-HQ side-arms.Some of these new ligands contain a hydroxymethyl group on the macroring.A report on the affinities of some of these new ligands for metal ions and their possible use as sensors for metal ions will be reported in due course.

Results and Discussion
The CHQ and HQ side arms are best attached to the diazadithiacrown ethers through macroring NH groups.][11] The NH functions of the secondary bis(α-chloroamide)s are unreactive toward alkylating agents including thiols. 7,12In the present case, bis(α-chloroamide)s 10-12 were treated with the appropriate dimercaptans using K2CO3 as the base to form macrocyclic diamides 13-15 in yields of 46%-61% as shown in Scheme 1.The macrocyclic diamides were in turn reduced to the desired diazadithiacrown ethers 16, 17, and 22 by either B 2 H 6 -THF or the NaBH 4 -BF 3 -THF complex (Scheme 1).Ligands 1821 shown in Scheme 1 were prepared as reported. 7Satisfactory elemental analyses were obtained for the new macrocyclic diamides or for new HQ and CHQ armed ligands 23-36 prepared from them.

Scheme 1
The products of the Mannich reaction of the diazadithiacrown ethers with HQ (23 and 27) and 8hydroxyquinaldine (26) were mixtures.Each of these two starting materials has no substituent on the quinoline 5-position.Thus, both the 5 and 7 positions could be aminomethylated under these reaction conditions.Although we did not look for the side products in these reactions, we recently showed by a careful 1 H NMR analysis that when diazatrithiacrown ether 18 was treated with 8hydroxyquinaldine, the product mixture proved to be about 90% of the desired product where both quinoline substituents were attached through the 8-hydroxyquinaldine 7-position, about 9% of the product with one 8-hydroxyquinaldine attached through its 7-position and the other through its 5position and the remaining product had both 8hydroxyquinaldine groups attached through their 5positions.Thus, we suspect that products 23, 26 and 27 are mixtures where the HQ groups are attached through their 7-and 5-positions.

Scheme 2
HQ has been attached to diaza-18-crown-6 3 and a series of tetraaza-15(and 16)-crown-5 ligands 4 through the HQ 2-position by a reductive amination process using NaBH(OAc) 3 . 18In the present case, 8-hydroxyquinoline-2-carbaldehyde and the appropriate ligand (16-18 or 20) were treated with NaBH(OAc) 3 to form the bis(8-hydroxyquinolin-2-ylmethyl)-substituted ligands 33-36 in yields of 46% -66% (Scheme 3).It is important to note that the hydroxy group of HQ did not have to be protected for this reaction as previously reported. 4s, 4H), 3.49-3.66(m, 16H); 13  General procedure B to synthesize crown ethers ( 16) and ( 17) 4,7 (Scheme 1) To a solution of 10.0 mmol of macrocyclic diamide in 30 mL of dry THF was added 80 mL of a solution of borane in THF (1 mol per liter of THF).The mixture was stirred for 72 h at room temperature and the solvent was evaporated under reduced pressure.To this residue was added a dilute solution of NaOMe in MeOH, and the mixture was refluxed overnight.After the MeOH was evaporated, some water was added and the mixture was extracted several times by portions of CHCl 3 until all the product was extracted from the water.The combined CHCl 3 extracts were dried (Na 2 SO 4 ), filtered, and evaporated to give the crude product which was purified by chromatography on silica gel (eluent: CH 2 Cl 2 : MeOH: NH 4 OH = 50 : 5 : 1).11-Hydroxymethyl-1,7-diaza-4-oxa-10,13-dithiacyclopentadecane (16).Ligand 16 (2.33g, 46%) was obtained as a low melting solid by the reduction of 2.96 g (9.6 mmol) of 13 with 38 mL of borane-THF complex in 30 mL of THF according to general procedure B; in 100 mL of THF was stirred at 0-5 °C and 13.2 g (93 mmol) of BF 3 -Et 2 O was added over a 3-hour period.The mixture was allowed to warm to room temperature and water was slowly added until H 2 stopped evolving.The mixture was neutralized with aqueous 20% NaOH to pH of 8 or 9.The THF was evaporated and the aqueous solution was extracted 3 times with 20 mL portions of CH 2 Cl 2 .The combined extracts were dried (Na 2 SO 4 ) and the solvent was evaporated.The crude product was purified by chromatography on silica gel (CH 2 Cl 2 : MeOH: NH 4 OH = 50 : 5 : 1) to give 0.76 g (32%) of 22; 1 H NMR: δ 2.76-2.82(m, 16H), 3.60-3.70(m, 12H); 13

Figure 1 .
Figure 1.Compounds mentioned in the introduction.