NEW AZA-CROWN-ETHERS AND THEIR USE

Abstract: New aza-crown-ethers having the general formula <IMAGE> in which a) X is oxygen and R is hydrogen, alkyl, aralkyl, aryl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylalkyl, carbamoylalkyl, nitrophenyldiazophenyl or <IMAGE>in which n is 2 or 3, or b) X is N-R', and R and R' together form the group <IMAGE>in which n is 2 or 3. The new aza-crown-ethers have complexing ability, particularly towards sodium and potassium.

Description: NEW AZA-CROWN-ETHERS AND THEIR USE This invention relates to novel aza-crown-ethers. Crown-ethers is ' originally a designation given to cyclic oligo ers of ethylene oxide, but which is also used for analogs thereof in which one cr more of the oxygen atoms 5 have been replaced by other hetero atoms. Thus, aza- crown-ethers contain one or more nitrogen atoms . There are known several different crown ethers and a discussion of thes'e is found inter alia in Tetrahedron 6_, 461 (1980) . The crown ether ' s are particularly useful in view of 10 their superior complexing ability which may be utilized in several ways, i. a. for the extraction of metal ions into organic solvents and for separation. From the above article it is known that bicyclic aza-crown-ethers, also called cryptands , in which the rings are linked together 15 through two or more nitrogen atoms in each ring, possess particularly superior complexing ability and-yield - complexes called cryptates. e• have now found a new group of aza-crown-ethers having generally superior complexing ability, depending 20 on the ion to be complexed. Their complexing ability with respect to stability and selectivity towards ions such as V. . and Ca has been further' improved by linking together two crown ether moieties by means of one or more πethylene chains containing two or more methylene groups 25 between the nitrogen atoms in the crown ether moieties in question. Model considerations show that complexes of "sandwich"- structure have the most favourable conformation and will accordingly give the most stable complexes when the 30 distance between the two crown ether moieties .corresponds to a bridge having two -ethylene groups. The described compounds in which two crown ether moieties have been linked together with methylene chains are compounds which give very strong complexes and also 0MPI BAD ORIGINAL A + ++ exhibit a great selectivity for Na and Ca For certain applications such as ion transport in lipophilie membranes, it may be suitable to anchor the molecules to larger hydrophobic groups or. polymeric compounds. This anchoring should take place by attachment to one of the methylene groups in the chain between the two crown ether moieties. The new aza-crown-ethers according to the invention have the following general formula: in. which a) X is oxygen ' and R is hydrogen, alkyl, aralkyl, aryl, alkoxyalkyl, " hydroxyalkyl, alkoxycarbonylalkyl, carbamoyl- alkyl, nitrophenyldiazophenyl or in which n is 2 or 3, or b) X is -R 1 , and R and R' together form the group CH -, in which n is 2 or 3- Among these compounds the compound of formula 22 below ' has been previously described by means of -formula in DE "Offer.legungsschrift" 2250321, example 9. The - compound has been referred to only as a suggested synthesis route, without physical data. This cannot be considered as a description, but enly as a speculative suggestion. N-mεthyl-1—aza-4,7 ,10-tric:-:acyclododecane (formula 11 below) has been previously implied by Kuo et al. , Tetrahedron Letters no. 44, pages 4273-4276 (1978) . The yield therein is r.inimal, and physical data for the co - ound have not been iveπ- Thus, the ccn-oound BA O OH Q MM cannot be considered to have been described in the article. Further, the 2-hydroxy-deriv-ative of the compound r of formula 6 below has been described (Lochard et al. ,' 5 J. Chem. Soc., Perkin Trans. 1, " 1973 (6) 577-81, see compound no. 4 on page 579) . The hydroxyphenyl group therein has an important function in the * complexing process of the .cation, and must in this connection be considered as essentially different from the phenyl 10 group. - Compounds in which X and R have the meanings given under a) , are generally prepared by reacting a compound . of the formula 15 with am a ine of the formula H 2 N - .R. In certain cases it is suitable to modify R after ring closure to obtain an R having a desired meaning". This may -for instance take place "by introducing ' a further 20 group into R, for instance rhe introduction of a nitro- phenyldiazo group in a phenyl group, by removal of R, for instance the removal " of a benzyl group to form a compound in which R is hydrogen, or by replacement of o.ne group by another and modifying the group, for instance 25 by reduction. For the preparation of a compound in which two rings are linked together with an alkylene bridge, two corpounds in which R is hydrogen are suitably linked together by means of a suitable coupling agent, such as oxalyl chloride 30 and subsequent reduction, cr e hylene or propylene tosylate or iodide. The compounds in which X and R have the meanings given- under b) , are suitably prepared by . reacting a compound of the formula in which B represents a protective group, with a suitable .bridging agent, such as ethylene or propylene ditosylate, so that two such compounds are linked together by means of a bridge between the two unprotected nitrogen atoms. Then, the protective group is removed and a further bridge between the two rings is formed. In order t avoid the formation of polymeric material it is here particularly advantageous to use template cation. When . the bridge is an ethylene bridge, lithium is " a suitable cation. The following examples illustrate the preparation of the. new compounds. In the examples reference is ' made to formulae which have been compiled after the examples. Melting points (mp) were measured on a Kofler hot- stage apparatus and are uncorrεcteά. Gas liquid chromatographic analyses were performed on a Hewlett- Packard 5700A Gas Chromatograph equipped with a flame ionisation detector. Dilute solutions in dichloromethane or the reaction solvent were Injected into a 2 m x 2 mm 10% SP 2100 on Chromosorb W A* DMCS 80/100 column using nitrogen as carrier gas (flow rate 20 ml/min) . The tempera ture of the column was initially 100 C, increasing at 16°/m immediately after injection up to a maximum cf 280 C. Approx. retention times ft:..,) are quoted in minutes. Analytical thin layer chrornategr-aphy (tic) was carried out on Merck plates pre-co=te -with Kieseigel 60F-254. The eluant systems used were iT.) a 10% solution of methanol in chloroform and (E) a 20* solution of ethyl acetate in OMPI 4 1P0 chloroform. Elemental analyses were carried out at Mikroanalytisches Laboratorium Use Beetz, 8640 Kronach, West Germany. Infra-red spectra were recorded " on a Jasco IRA-1 spectrophotometer and, unless stated other- wise, run as thin films between sodium chloride discs. Absorptions are given in cm . Proton nuclear magnetic resonance spectra ' were recorded on a Varian ' HA 100 spectrometer and were run as solutions in deuterochloroform except where otherwise stated, chemical shifts (6(H) " ) being quoted in ppm relative to tetramethyl-silane (TMS) as lock and internal standard. Coupling constants (J) are given in Hz. Carbon-13 nuclear magnetic resonance spectra were recorded at 15 MHz on a JE0L * JNM-FX60 Fourier Transform spectrometer, with protons noise decoupled, and run in acetonitrile solution (unless otherwise stated) . Chemical shifts (6(C)) are quoted in ppm relative to internal TMS or the solvent (CH-CN, 5 1.75; CH.-.0H, δ 49.90, relative -to internal TMS ' ) . Assignments of particular signals to particular carbon atoms in the molecule is based upon (a) the height of the signal, which was .in direct proportion to the number of equivalent atoms assigned a particular chemical shift, except in the case of quaternary carbons {which were readily identified by their propor- - tionally lower signal heights), (b) re-running the spectrum under conditions of proton off-resonance (only in useful cases) , and (c) self-consistent analogy between the spectra of the crowns .studied. Mass spectra were recorded with a Micromass 7070F spectrometer. Electron impact mass spectra (70 eV) were run after direct insertion of the sample into the source maintained at ca 230 C. Only readily assigned m/e_ (rel. intensity%) values and the base peak are quoted. Chemical ionisation mass spectra gave a quasi-molecular ion (M+l) as the only significant signal and were obtained using isobutane as ionisation gas. Analytical grade reagents and solvents were used where available throughout the following preparations. Aceto- nitrile and N,N-dimethylformamide were dried over molecular sieves. Dichloromethane .was purified by passing through a column of alumina and then distilled from calcium hydride. Pyridine and- tetrahydrofuran were dried by distillation from calcium hydride and lithium aluminium hydride, respectively, immediately before use. Example 1 a) Bis--2- (2-chloroethoxy)-ethyl ether (1) Thi nyl chloride (195 g, 1.64 mol) was added to a mechanically stirred and ice—cooled solution of tetra- ethylene glycol .(150 g, C.77 mol) in dry pyridine (135 g, 1.71 mol) at a rate such that the temperature of the reaction mixture remained below 50 C. Stirring was then continued at room temperature overnight (during which time the initially-formed precipitate had largely redissolved) before adding water -(20 ml) and extracting with ether .(100 ml, x 5) , adding a further 20 ml of water before each subsequent extraction. The ether layers were combined, washed with water (100 ml) , brine (100 ml), dried (MgSO.) and concentrated in vacuo. Distillation of the residue through a short Vigreux column gave the dichloride (1) (148 g, 83%) as a colourless liquid, bp 106-108°C/0.1 mm Hg t ? 8.5, 5(H) 3.43-3.77 (complex symmet. m, OCH 2 CH 2 Cl) and 3.56 (sharp s, 0CH_CK 2 0) , m/e (rel. intensity) 153 (0.6) , 151 (1.3), 139 (3.3), 137 (10), 109 (13) , 107 (40), 65 (32) and 63 (100) . ' b) 3is-2-{2-iodoethoxy)-ethyl ether (2) Powdered sodium iodide (lOO g, 0.67 mol) was added to a solution of the dichloride (1) (65.0 g, 0.28 mol) in acetone (150 ml) , and .the stirred mixture heated under reflux for 70 h. After cooling, the reaction mixture was filtered (washing with acetone) and the filtrate concen¬ trated in vacuo, diluted with ethyl acetate (2C0 ml) an " extracted with 20% sodium thiosulphate solution (50 πl) . GINAL} . WiFU The organic layer was washed with water (100 ml) , brine (100 ml) and dried (MgSO .) . Removal of the solvent in vacuo gave the diiodide (2) as a very pale yellow oil, t " 10.5. Glc showed the presence of about 2% * 5 of the chloro-iodide (2b) as the only significant impurity _(t R 9.3). δ (H) 3.19 (4H, t, J 7 , OCH 2 CH 2 I) , 3.58 (8H, s, OCH 2 CH 2 0) and 3.70 (4H, t, J 7, OCH 2 CH 2 I) , m/e 229 (1.5) , 199 (7) and 155 (100). Crystallisation from ether solution gave the diiodide 10 (2) as needles, mp 92-93 , initially colourless but soon becoming yellow.on storage. c) N-benzyl-l-aza-4 ,7 ,10-trioxacyclododecane (3) A stirred solution of the diiodide (2) (30.0 g oil, equivalent to 0.073 mol .dichloride (1)) and benzylamine 15 (8.2 g, 0.77 mol) in dry acetonitrile (1 litre) containing suspended powdered anhydrous sodium carbonate (30 g) was heated under reflux under an atmosphere of nitrogen for 18 hours. The cooled, solution was decanted from most ' of the solid and concentrated in vacuo. The residues from 20 decantation and concentration were combined and partitioned between water (600 ml) and ether (300 ml) . The aqueous layer was re-extractec with ether (200 ml x 2) , and the combined* organic layers washed with water (200 ml) , brine (200 ml) and dried (Na-SO.). After removing the ether in. 25 vacuo, the residue was distilled through a short path, collecting material volatile at 0.05 mm Hg w τ ith a bath temperature up to 200 C. The distillate was redistilled through a .short Vigreux column to give the pure aza-crown (3 (10.5 g, 54%) as a colourless oil, bp 140-143°/0.05 mm Hg, 30 t R 11.5 C 15 H 23 N0 3 (265 - 3 -* requires: C 57.89, H 8.74, N 5.28% Found: • C 57.75, H 8.68, N 5.20%. 5 (H) 2.69 (4H, t, J 5, CCH„CH.,::) , 3.55 (4H, t, J 5, OCH 2 CH 2 N) , 3.60 (1CH, s, OCH 2 CH 2 0 and FhCH,Nj and 7.02-7.30 35 (5H, m, ArH) ' , BAD δ (C) 55 . 65 (N-C (ring) ) , 61. 42 (H-C-Ph) , 70. 64 , 70. 97 and 71. 75 (0-C) , 127 .59 {C — θ) * ) , 128 . 95 and 129 - 79 (remaining tert . arom. c_) and 141.09- quatern. arom. C) , m/e_ 265 . {M + , 2 ) and 91 ( 100) . Example 2 N- (2-Methoxyethyl)-l-aza-4,7 ,10-trioxacyclododecane (4) ' A stirred solution of the diiodide (2) (oil, 15.4 g, equivalent to 0.038 mol dichloride (1)) and 2-methoxy- ethy ' lamine (2.9 g, 0.039 mol) in dry acetonitrile (0.5 " 1) containing suspended powdered anhydrous sodium carbonate . (15 g) was heated under reflux under an atmosphere of nitrogen for 18 h. The cooled suspension 'was filtered and the filtrate concentrated j Ln vacuo to give a semi-solid This was extracted with chloroform (50 ml x 3) , each time decanting the clear solution from the crystalline residue. After filtration, the combined extracts were concentrated in vacuo and the residue-was distilled through a short path collecting material volatile at 0.01 mm with a bath temperature up to 250 C. (No distillation was observed before the bath temperature reached about 180 , although the main fraction subsequently distilled steadily at 110- 115 C)-. The distillate was redistilled through a short Vigreux column to give the pure aza-crown (4) (4.5 g, 51%) , as a colourless oil, bp " 10G-102 C/0.005 mm Hg, t 7.8 (C 1]L H 23 N0 4 (233,3) -requires: C 56.63, H 9.94, * 5.01% Found: C 56.52, H 9.87, N 6.14%) • c (H) 2.69 (2H, t, J 6, CH 3 0CK 2 CH 2 K) , 2.73 (4H, t, J 4.5, CH 2 OCH 2 CH 2 ) , 3.27 (3H, s, CH,0) , 3.43 .(2H, t, J 6,- CK 3 OCH 2 CH 2 N) , 3.58 (t*, J 4.5, CH 2 0CH 2 CH 2 N) and 3.50 (s*, OCH 2 CH 2 0 (* these signals together integrate for 12 H) c (C) 56.*59 (N-C (ring)) , 56.55 (N-C (side chain)) , 58-36 (0-CH 3 ) , 71.01, 71.01 and 71. ? (0-C (ring)) (obscuring CE 3 0C) ) , [c(C) (+ excess KaCNS) 65.55, 66.40 and 66.86 (0-C (ring)) and 69.20 (CH OC) ] , π/β 233 (M ÷ , 0.5) and 188 flOC) . 6AD Example 3 ■ N- (2-Hydroxyethyl)-l-aza-4 ,7 ,10-trioxacyclododecane (5) Ethanolamine . (2.4 g, 0.039 mol) was used instead of •2-methoxy-ethylamine as substrate in the process described in Example 2. The first distillation commenced when ' the bath temperature was over 200 , the main fraction distilli at about 130°C/0.1 mm Hg. Redistillation gave the aza- crown (5) (3.9 g, 4 . 8%) as a very pale yellow oil,* bp 106-108°C/0.01 mm Hg, t_ 9.3) (C 10 K 21 N0 4 (219 - 3 ) requires: C 54.77, H 9.65; N 6.39% Found: C 54.45, H 9.53, N 6.10%) v_ 3,300 (broad, OH) , δ (H) (CD 3 CN) 2.53 (2H, t, J 5.5 ' , HOCH 2 CH_ 2 ) , 2. " 60 (4H, t, 'J 4.5, CH 2 OCH 2 CH 2 ) , 3.36 (t*, J 5.5, H0CH 2 CH 2 N) , 3.45 (t*, J 4.5, CH 2 OCH 2 ) and 3.52 (s*. OCH 2 CH 2 0) (* these signals together integrate for 15 H, and obscure ' HOCH 2 CH 2 N) , 5 (C) 55. 78 (N-C .(ring) ) , 57 .53 (N-C (side chain) ) , 59. 93 * ' (0-C (side chain) ) , 69. 87 , * 71 , 10 and 71.23 (0-C (ring) ) , ' m/e 219 (M + , 1. 6) and 188 (100) , (M+l) + (isobutane ) 220. Example 4 N-?henyl-l-aza-4,7 , 10-trioxacyclododecane (6) Aniline (1.9 g, 0.020 mol) was used instead of benzyl- a ine as substrate in the procedure of Example lc for the preparation of N-benzyl-l-aza-4,7,10-trioxacyclododecane (3 but using 8.0 g (≡ 0.O19 mol) diiodide (2), 8 g sodium carbonate and 300 ml acetonitrile, and heating under reflux for 5 days. The extractions were performed using 1/4 of the described quantities. After removing the ether in vacuo the residue was distilled through a short path, collecting the aza-crown ( 6 ) .2 . 5 a , 51?) at 150-152 C/ 0.0C5 mm Hg as a pale y -ellow viscous oil * , —tI* * 11.7. Considerable darkening of the residue occurred during this distillation. δ (H) 3.47 (4H, t, J 5, OCH CH K) , 3.54 (8H, s, OCH 2 CH_ 2 0) , 3.76 (4H, t, J 5, OCH 2 CH 2 N) , 6.42-6.66 (3H, unsymmet. , N-Ar-O, p-H) and 6.91-7.14 (2H, , N-Ar-m-H) , δ (C) 52.72 (N-C (ring)), 70.06, 70.58 and 72.01 (0-C), .113.24 and 129.86 ( - §> 4 ' ) , 116.68 {remaining ter ' t. arom. C and 149.66 (quatern. arom C) , m/e 251 (M + , 19) 105 (100.) and -78 (36). Example 5 . N- [4- (4-nitrophenyldiazo)-phenyl]-l-aza-4 ,7 ,10-trioxa- ' cyclododecane (7) 4-nitroaniline (6.50 g, 0.047 mol) was dissolved with ' warming in a mixture of water (15 ml) and hydroohloric acid (36%, 10.5 ml, 0.104 mol). The stirred solution was cooled in ice while a solution of potassium nitrite (4.1 g, 0.048 mol) ' in water (7 ml) was added slowly enough to keep the temperature -below 5 . The resulting solution of 4-ni rophenyldiazonium chloride'was diluted to 250 ml with iced water. An aliquot (17 ml) of the diluted solution was withdra and the aza-crown (6) from example 4 (0.80 g, 3.2 mmol) was added to ' it with stirring at 0 C. A solution of potassium acetate (0.38 g, 3.9 mmol) in water (3 ml) was added and stirring continued 'for 30 minutes at 5°C. " The precipitated dLye was filtered off, washed consecutively with water, 10% acetic acid, water and ethanol, and dried in air. Recrystallisation from toluene (50 ml) gave the azo-dye -(7) (0.65 g, 51%) as orange-red needles, ir.p 165.6-166°C C 20 K 2i 4 0 5 (400.4) requires: C 5 ' 9.99, H 6.04, N 13.99% Found: C 60.75, H 6.00, N 13.67%, ζ (H) 3.54 (8H, s, OCH 2 CH 2 0) , 3.61 (4H, t, J 5. OCK 2 CH 2 ΪT) , 3. S3 (4H, t, J 5, 0CH 2 CH_,N), 6.67 (2H, d, -7 9, CH 2 tT-Ar- -H) , 7.63 (2H, d, J 9, CH.N-Ar-r-H) , 7.71 (2H, d, J 9, • 0 2 N-Ar-m-H) and 8.11 (2H, d, J 9, 0-,N-Ar-o-H) , m/e 4 0 (M + , 100) , ''■_ma_„x (MeCN) 479 mm (unchan ed on the addition of either Li-, 2ϊa- cr K-CNS) "BUREA O PI Example 6 N- [Ethoxycarbon lmethyl3-l-aza-4,7,10-trioxacyclododecane ( Glycine ethyl ester hydrochloride (6.5 g, 0.047 mol) was used instead of 2-methoxyethylamine as substrate in the 5 procedure for the preparation of the aza-crown * (4) , but using 18.5 g (≡ O.045mol) diiodide (2) and 18 g sodium carbonate, and heating under reflux for 48 h. The first distilllation commenced when the bath temperature was over.200°, the main fraction then distilling at 138-140 C/ 1 0 0.05 mm Hg. Considerable darkening of the residue occurred during this distillation. Redistillation, gave the aza- crown (8) *(3.5 g, 30%) as a colourless oil, bp 118-122 C/ .0.01 mm Hg, ' '—t_.. 10/3, 15 .6 (H) 1.24 (3H, t, J 7, OCH 2 CH 3 ) , 2.88 (4H,- J 5, OCH 2 CH_ 2 N) , 3.43 (2H, s, NCH 2 C0 2 ), 3.56 (t*, J 5, OC 2 CH 2 ) , 3.60 (s*, 0G I 2 C — 2°' and *07 (2H ' g ' J 7 ' 0C 2 CH 3 )' ( * theΞe s i gnals * ■ together integrate for 12 H) , δ(C) 14.61 (C0 2 -C-C) , 55.52 (N-C (ring)), 57.27 - (C0 2 -C-C) , 0 60.71 (N-C (side chain)) , 70.77, 70.77 and 71.45 (0-C (ring) and 172.38. (0=C) , m/e 261 (M "1" , 1.0). and 188 (100) . Example 7 N- (Carbamoylmethyl)-l-aza- ,7 ,10-trioxacyclododecane (9) 5 The use of glycinamide hydrochloride (1.25 g, 0.011 mol) instead of glycine ester hydrochloride as substrate in the - process of Example 6, except using 4.5 g (=0.011 mol) diiodide (2) , 5 g sodium carbonate and 200 ml acetonitrile, gave a residue, after concentration of the chloroform Q solution, from which the aza-crown (9) (0.6 g, 24-H was sublimed at 250°C/0.0i mm as needles, mo 106-108 σ C, t-_, 11.5, — F- max (nu o1 mull) 3330, 3130 ( K 2 ) and 16S0 (C=0) , δ(H) (CD 3 CN) 2.60 (4H, t, J. .5-,, OC^CH^N) ' , 3.00 (2H, s, NCH 2 CONH 2 ) , -3.40 (4H, t, J 4.5, OCH^CP^N) , 3.53 (8H, s, / ( 0-MPI BAD ORIGINAL f V y, WIPO ,^ OCH 2 CH 2 0) and 5.77 (br, NH,), 6(C) 56.36 (N-C (ring))., 59.80 (N-C (side chain)) , 69.15, 70.71 and 71.49 (0-C (r ng)), m/e 232 (M +~ , 0.3) and 188 (100). Example 8 l-Aza-4 ,7,10-trioxacyclododecane (10) 10% Palladium on activated carbon catalyst (0.5 g) was added to a solution of the K-benzyl-aza-12-crown-4 (3) of Example Ic in acetic acid- (10 ml) and the suspension stirred at 60 C under 3 atmospheres of hydrogen for 15 hour The cooled mixture was filtered through, a bed of celite, using ethanol for washing. The solution was. concentrated in- vacuo and the residue dissolved in water (10 ml) . After basification with 30% potassium " carbonate solution (20 ml) - the solution was extracted with chloroform (25 ml x 4) .and the combined organic layers washed with 10% potassium carbonate solution (10 ml) , brine (20 ml) and dried (Na_S0^) The solvent was removed in vacuo and the residue distilled (air condenser) to give the aza-crown (10) (2.3 g, 85%) , bp 72-74°C/0.01 mm Hg, mp 59-60°C, t 7.1. Sublimation 60 C/0.01 mm Hg gave needles of unchanged mp C g H 17 K0 3 (175.2) requires: C 54.83, H 9.78, N 7.99% Found: " C 54.72, ' H 9.58, N 8.03%. max (nuj J ol mull) 3300 (NH) , - 5(H) 2.70 (5H, symm. with t structure, J 5, 0CH 2 CH NH*) and 3.44-3.72 (12H, unsymm. m. 0CH 2 ) (*exchanges with O^O , after which the m integrates for 4H) , δ(C). 48.73 (N-C) , 69.16, 69.81 and 71.11 (0-C), m/e 175 (M + , 0,9) .and 57 (200; • (M+l) ÷ (iεobutane) 176. Example 9 N-Methvl-l-aza- ,7 ,10-trio: -cyclododecane (11) Redistilled phenyl chl rofor ate (3.0 g, 0.019 mcl) was added to a stirred solution of -benzyl-aza-12-crown-4 (3) prepared in Example lc (4.0 g, 0.015 πol) in dry tetrahydrofuran (50 ml) containing suspended anhydrous potassium carbonate (2 g) and stirring continued overnight. The reaction mixture was shaken well with 10% potassium hydroxide solution (50 ml) and extracted with ethyl acetate 5 (50 ml x 3) . The -combined organic layers were washed with water (30 ml), brine (30 ml) and dried (MgSO.) . Removal of the solvents in vacuo gave an equimolar mixture of N-phenoxycarbonyl-aza-12-crown-4) (lib) and benzyl chloride as an oil, v 1720 (urethane C=0) , max 10 δ.H) 3.40-3.98 (16H, m, crown ring protons) , 4.45 (2H, s, ' PhCH 2 Cl) and 6.88-7.20 (10H, m, ArH) , m/e (crown) 202 (M + -OPh, 27) and 114 (100). This mixture was dissolved in dry tetrahydrofuran (200 ml) and the stirred solution cooled to 0 C. Lithium 1.5 aluminium hydride (2.5 g, 0.066 mol) was added in one portion, and stirring was continued for 18 hours. Excess metal hydride was destroyed by the carefu •addition of a mixture of water (5 ml) a-nd tetrahydrofuran (20_ml) to- the ice-cooled suspension, which was then 0 stirred for an additional 30 minutes before filtering on a. sintered glass funnel, the residue being well washed with tetrahydrofuran. The filtrate was concentrated in vacuo , dissolved in water (50 ml) and extracted with ether * (20 ml x 3) . The ether extracts (containing phenol) were 5 discarded,- and the aqueous layer " concentrated in vacuo. After removal of the last traces of water by concentration of an absolute ethanolic solution, the residue was distilled through a short Vigreux column to give the aza-crown (11) (2.1 g, 74%) as a colourless oil, 0 . bp 65-67°C/0.1 mm, t R 6.7 C Q H 19 0 3 (189.3) requires: C 57.11, H 10.12, N 7.40% Found: C 57.37, H 10.08, N 7.19%. δ.H) 2.29 (3H, s, CH 3 ) , 2.58 (4H, t, J 4.5, OCK^H^N) , -3.58 (4H, t, J 4.5, -0CK.,CH_,") and 3.60 (8H, s, CCH-,CH_0) , 5 δ (C ) 44 . 83 (N-CH 3 ) , 53. 2 8 (IT-C (ring ) ) , 70. 2 3 , 71. 01 and 71. 53 (0-C ) , + m/e 18 9 - (M , 4 ) and 71 ( 100 ; (M + l ) ' . (sobutane ) 130. fDKtATr O.MPI offlβi «. ^ D :° Example 10 1,2-Bis- (l-aza-4,7 ,lO-triexacyclododecan-l-yl)-ethane (12) Method ja) : . * A solution o_f redistilled oxalyl chloride (0.26 g, 2.04 mmol) in dry, ethanol-free dichloromethane (about 8 ml aliquot from standard solution) was added dropwise via a syringe to a stirred solution of aza-12-crown-4 (10) prepar in Example 8 (0.71 g, 4.06 mmol) -and triet-hylamine (1.5 g) in pure dichloromethane (30 ml) . The clear solution was concentrated in vacuo to give a crystalline residue which was dissolved in dry tetrahydrofuran (100 ml) . The . 'stirred solution was cooled to 0 C and lithium aluminium hydride (1.0 g) added. After s.tirring at room temperature fσ'r 18 hours, -excess metal hydride was destroyed by the careful addition of a mixture of water (10 ml) and tetrahydrofuran (50 ml) with ice-cooling. Stirring was continμed for 30 minutes before filtering (washing the residue with tetrahydrofuran) and concentrating the filtrate in va ' cuo. Distillation of the residue (the ,H NMR spectrum of which w identical to that quoted below) at 0.05 mm-Hg through a sho path, with an air bath temperature rising to 200°C, gave the pure "headphones" (12) (0.65 g, 85%) as a colourless viscous oil, slowly solidifying on storage at 0°C, 5(H) 2.59 (4H, s, NCH 2 CH 2 N) , 2.66 (8H, t, J 5, OCH 2 CH 2 N) , 3.56 (8K, t, J 5, OCH 2 CH 2 N) and 3.59 (16H, s, OCH 2 CH 2 0) , δ(C) 55.98 (N-C (bridge)), 56.50 (N-C (ring)) , 71.09, 71.09 and 71.87 (0-C) , . m/e 376 (M + , 2) and 188 (lOO) Method (b) : Ethylene ditosylate was prepared using the general procedure for ditosylating oligoethylene glycols of ristiansen and Dale. Recrystallisation from absolute ethanol (15 ml/g) gave needles, mp 127-128 C C, 5(H) 2.38 (6H, s, CH 3 ) , 4.08 (4H, s, CCK 7 ) , 7.17 a d 7.56 (two 4H, d, J 8, " arom. X system) . BURE TT 0MPI BAD ORIGINAL A stirred solution of aza-12-crown-4 (10) prepared accordin to Example 8 (1.95 g, ' ll.l mmol) and ethylene ditosylate (2.16 g, 5.8 mmol) in dry acetonitrile (60 ml) containing s pended powdered anhydrous sodium carbonate (2.5 g) was heat under reflux under an atmosphere of nitrogen for.48 hours. The suspension was cooled 'and filtered, and .the filtrate concentrated in vacuo to give the crystalline 1:1 complex of the '-headphones" (12) with sodium p-toluenesulphonate containing a trace of unreacted ethylene ditosylate 10 (Complex: δ 2.26 (3H, s, CH-Ar) , 2.30-2.84 (complex *, OCH 2 CH 2 N) , 2.40 - ' (s*, NC^C^N) , 3.25* ^ 3.90 (24H, m, 0CH 2 CH 2 0) , 6.94 and 7.64 (two 2K, d, J 8, arom. A 2 2 system (* these signals together integrate for 12 H) . The free. ligand was distilled from the crude complex 15 at 0.01 mm -through a short path with an air bath temperatur rising slowly to 2 ' 50 C. Redistillation using the same technique gave the pure "headphones" (12) (1.75 g, 84%) , haying physical properties identical to those described in Method (a) 20 . Example 11 ' ' 1,3-Bis— (l-aza-4 ,7 ,10-trioxacyciododecan-l-yl) -propane (13) A stirred solution of aza-12-crown-4 (10) prepared according to Example 8 (0.30 g, 1.7 mmol) and 1,3-diiodo- propane (0.29.g, 0.98 mmol) in dry acetonitrile (10 ml) 25 -containing suspended anhydrous sodium carbonate (0.5 g). was heated under reflux for 20 hours, cooled and filtered. . The filtrate was concentrated in- vacuo and the residue partitioned between water (40 ml) and ether (25 ml) . The ether layer (containing excess diiodopropane) was discarded 30 and the aqueous layer extracted with chloroform (20 ml x 4) . The chloroform extracts were cor.bined, washed with brine (20 ml), dried (Na-SO,,) and concentrated in vacuo. The residue was purified by distillation at 0.01 mm through a short path, with an air bath temperature rising to. 200 Z ■35 to. give the "headphones" (13) (0.28 g, 84%) as a colourless, viscous oil C- n H., Q N n O c (390.5) requires: C 58.43, Η 9.81% ±y Jo -i o Found: C 57.87, H 10,19%, δ(H) 1.61 (2H, br. quint., J 7, NCH 2 CH 2 CH 2 ' N) , 2.48 (4H, br. t, J 7, NCH 2 CH 2 CH N) , 2.64 (8H, t, J 5, OCH 2 CH 2 N) , 3.57 (t * *, J 5,-OCH 2 CH 2 ) and 3.59 (s*, OCH 2 CH 2 0) (* together integrate for 24 H), . ' ■ δ(C) 26.36 (NCCCN) , 55.45 (NCCCN) , 56.10 (N-C (ring)), 70.97, 70.97 and 71.75 (0-C), m/e 390 (M + , 5) and 188 (100). Example 12 Synthesis of a cation complexing doubly N,N'-bridged .bis (1,7-dioxa-4,10-diazacyclododecane " ) • (1,4,10,13-tetraaza-7,16,21,26-tetraoxa-tricyclo- [11,5,5,5 ' ]-octacosane The tetr.ahydrcpyranyl ether of 2- (2-chloroethoxy) - ethanol (14) was reacted with tosylamide in DMF in the presence of suspended NaH to give the bis-tetrahydro- pyranyl ether (15 . ) . Treatment with p-toluensulfoni ' c acid in methanol yielded the free diol " (16) , which was converted to the di esylate (17) with methaneεulfonyl chloride in pyridine. Compounds 15-17 were oils whose purity was checked by n.n.r, n s. and t.l.c. Adapting the above procedure for preparing ono-az -12-crown-4 compound by double alkylation of primary amines with - l,ll-diiodo-3,6,9-trioxaundecane, the dimesylate (17) was heated with benzylamine in refluxing acetonitrile containing Nal and suspended Na^CO-. for 48 hours to give the disubstituted diaza-crown (18) , .p. 95 C (60%). LiAlH. * reduction in THF yielded the monosubstituted diaza-crown (19), m.p. 48-50°C (91%). The first bridge was established by refluxing an -acetonitrile solution containing the diaza-crown (19) and ethylene ditosylate, in the presence of suspended a C0_ for 48 hours. The crude product was an oil which solidified on standing and had the correct spectral data for the bis-crown (20) _(m/e 554] . It was directly B URE A OMPI debenzylated by hydrogenolysis over Pd/C to yield the bis- crown (21) (b.p. 24 . θ :/0.05 mm Hg, m.p. 98-100°C, m/£ 374) in a yield of 85% based on (19) . The closing of the ' second bridge with ethylene * di,tosyla presented difficulties. In the absence of a template cation only polymeric material' was ' formed, while the presence of sodium salts (carbonate or tosylate) led only to complexatio of the ligand (21) and no reaction. In view of the lower co ordination number of lithium, it was expected that this cati might leave the two weakest donor atoms (^NH) free to underg reaction, but still be sufficiently strongly -sandv.-iched intr molecularly to exert a template effect. -In fact, reaction took place when a solution of the bis-crown (21) , dried Li- ' tosylate, ethylene ditosylate and ethyldiisopropyla ine in acetonitrile was heated in a sealed tube at 105 C for 4 days Contact with a brine solution during work-up led to isolatio of a Na-tosylate complex ("cryptate") of the cage ligarid (22 (cryptand") as .pale yellow needles (81%). The chemical ioni zation mass spectrum (isobutane) corresponded to the dissoci ated protonated ligand (m/e_ 401, . (M+l) ), while the field de sorption mass spectrum corresponded to the cation complex (m/e 423, (M+23) +). The 13C n.m.r. spectrum in acetonitrile showed three lines for the ligand in the expected intensity ratio 8:4:8 with shifts very close to those observed for chemically comparable carbon atoms of the c mplexεd singly bridged* bis-crown ligand (Example lO) and the related simple aza crown (Example 2)" carrying a 2-methoxyethyl side arm (se the table) . These shifts did not change after passage throu a cation exchange resin or a mixed-bed iόn exchange res n (elution -with water, then with aqueous dimethyla ine) . Pyrolys ' is in vacuo (150-220°C/0.05 Kg) liberated the ligand, m.p. 160 C, which had all three C lines moved by about 4 ppm downfield, similar to what is observed for the related ligands (see the table) . This means that the most likely conformation of the compiexed ligand, which undoubt¬ edly has all nitrogen lone pairs pointing into the cavity, is not retained by the free ligand. Space-filling molecular models do not allow much conformational choice for this tricyclic molecule and suggest that two of the nitrogen lone pairs are turned out and that both. 12,-πιembered rings adopt a conformation with a reduced number of upfield y-interactions- When the free lignad is contacted with a salt solution containing Li, Na and K cations and Br and BF .t anions, a .complex with KaBF. crystallizes (m.p. >310 C) . The X-ray structure determination confirms the expected cubic arrangement of the eight done: atoms. Table 13 C n.m.r. chemical shifts for free and Na+-complexed aza-crown 11gands. ring ring bridge 0CH 2 . CH 2 ' NCH 2 4,4 ' ' ,10,10*-bis-ethylene- free 65.8 52.2. 51.8 bis- (1,7-dioxa-4,10-diaza- compl. 69.3 56.2 55.9 eyclododecane (22) 10,10.'-ethylene-bis- free 65.2 52.4 52.4 {1,4,7-trioxa-10-aza- compl. 71.1 56.5 56.0 cyclododecane (12) 10- (2-methoxyethyl)-1,4,7- free 65.2 51.4 ' 53.9 trioxa-10-azacyclo- compl. 71.0 56.6 56.9 dodecane (4) COMPOUNDS PREPARED IN THE EXAMPLES (3) R = CH 2 Ph (4) R = CH 2 CH OMe (5) R = CH 2 CH OH 6) R (8) R = CH 2 C0 2 E (9) R = CH 2 CONH do: R = H (11) R = Me (lib) R ■ = :o OH (-16) TsN \__V\_ OH NaOTs Ph = phenyl Ts = tosyl Me = meth l Et = ethy 1 -:

Claims: We claim : 1. New aza-crown ethers, characterized in that they have the general formula . . • in which a) X is oxygen and R is hydrogen, alkyl, aralkyl, aryl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylalkyl carbamoyl- * alkyl, nitrophenyldiazophenyl or in which n is 2 or 3, or b) X is N-R- and R and R 1 together form the group (CH,>n- -(CH_)n-, in which n is 2 or 3. 2. Aza-crown ether according to claim 1, characterized in that it is 1,2-bis (l-aza-4 , 1 ,10- trioxacyclodecan-1-yl)-ethane of the formula 3. Aza-crown-ether according to claim 1, characterized in that it is 1,4,10,13-tetraaza-7,16,21,2.6- tetracxa-tricyclo[11,5,5,5 4' " "Ojootacosane of the formula OMPI ' 4. Aza-crown-ether according to claim 1, characterized in .that it is 1,4,7-trioxa-lO-aza-cyclo- dodecane of the formula 5. The use of the aza-crown-ethers according to claims 1-4 as complexing agents. 6. The use according to claim 5 of the aza-crown-ethers according to claims 1-4, attached to a polymer.

Inventors: CALVERLEY MARTIN J, DALE JOHANNES
Applicants: BORREGAARD IND, CALVERLEY MARTIN J, DALE JOHANNES
Application year: 1982
Main classification: C07D273
IPC codes: C07D273, C07D413, C07D498, C09K3