Macrobicycles based on cyclen and cyclam containing 1,3-disubstituted adamantane moieties

Bis(bromobenzyl)derivatives of cyclen and cyclam obtained according to previously described procedures were introduced in a palladium-catalyzed reaction with 1,3-bis(aminomethyl)adamantane and 1,3-bis(2-aminoethyl)adamantane to produce macrobicycles in moderate yields. The formation of tricyclic cyclodimers was observed in many cases. Tetrabenzyl derivatives of cyclen and cyclam were synthesized from the corresponding dibenzyl derivatives and reacted with 1,3-bis(2-aminoethyl)adamantane to give macrobicyclic products in similar yields.

A special interest is evoked by the polyazamacrobicycles containing a bulky lipophilic adamanatane backbone that may improve their solubility in non-polar organic solvents and significantly change the geometry of the macrocyclic cavity.Also, such macrocycles can be viewed as potentially physiologically active compounds, like other adamantane-containing amines and diamines.For example, 1,3-bis(2-aminoethyl)adamantane together with its analogue, 1,3-bis(aminomethyl)adamantane, as well as their dihydrochlorides were tested as antiviral agents. 21While the first was found to be active against the poultry plague, 22 the latter was patented as an anti-viral agent for home animals. 23,24Cyclic Schiff bases were synthesized using 1,3-bis(2-aminoethyl)adamantane for biological activity studies. 25The N,N'-dipyridyl derivative of this amine was synthesized by us earlier 26 and showed nootropic effect in mice.Having acquired a good experience in the synthesis of polyazamacrocycles via Pd-catalyzed amination reactions, [27][28][29][30] we decided to investigate the applicability of this approach to previously unknown adamantane-containing macrobicycles derived from cyclen and cyclam.

Results and Discussion
Bis(bromobenzyl) derivatives of cyclens 3, 4 and cyclams 5, 6 were obtained in high yields according to previously described two-step synthetic procedures 30,31 starting from cis-glyoxalcyclen 1 and formaldehyde-cyclam 2 (Scheme 1).The first step of this process is quaternization of two nitrogen atoms in trans-positions, and the second one is the basic hydrolysis of iminium salts with the cleavage of two C-N bonds of CN2 fragments which leads to the formation of free amino groups.

Scheme 1
In our recent communication 31 we showed that the presence of two additional substituents in the tetraazamacrocyclyc fragment can dramatically change the macrocyclization path leading to preferable formation of macrotricyclic cryptands rather than to macrobicycles.For this reason we also synthesized tetrabenzyl derivatives of cyclens 9, 10 and cyclams 11, 12 in order to check their reactivity with adamantane-containing diamines.Dibenzyl substituted cyclen and cyclams 7, 8 were introduced in the reactions with two equivalents of 3-and 4-bromobenzyl bromides in a two-phase CH2Cl2/H2O 1:1 system containing excess of NaOH at room temperature.As a result, the desired tetrabenzyl derivatives 9-12 were obtained in excellent yields 91-95% (Scheme 2).It is to be noted that running the same reactions under standard conditions (CH3CN/K2CO3) or benzylation of compounds 3-6 with benzyl bromide were unsuccessful.

Scheme 2
The synthesis of macrobicycles 14-17 was carried out by the reaction of Pd-catalyzed amination of bis(bromobenzyl) derivatives 3-6 with equimolar amounts of 1,3bis(aminomethyl)adamantane 13a or 1,3-bis(2-aminoethyl)adamantane 13b (Scheme 3).The reaction with diamine 13b was catalyzed by the standard system Pd(dba)2/BINAP (BINAP 2,2'bis(diphenylphosphino)-1,1'-binaphthalene) which was found by us to be most appropriate for the synthesis of polyazamacrocycles. 29However, diamine 13a required the application of a donor ligand DavePhos (2-dimethylamino-2'-dicyclohexylphosphinobiphenyl) due to sterical hindrances in this diamine.All reactions were run in boiling dioxane at concentration c 0.02 M, tBuONa was used as a base.The reactions ran to completion in 24 h.The reaction mixtures were analyzed by 1 H NMR and then subjected to column chromatography on silica gel.The yields of isolated compounds 14-17 ranged from 20 to 35%, the best results were provided by the reactions of 1,8-bis(3-bromobenzyl)cyclam ( 6) with both diamines 13a,b (33 and 35%).The reaction of 1,7-bis(3-bromobenzyl)cyclen ( 4) with diamine 13b also gave quite good yield for the macrocyclization reactions (29%).The results suggest that cyclen and cyclam derivatives with m-bromobenzyl substituent are more suitable for the macrocyclization with adamantanediamines 13a,b with a rigid and bulky central fragment.In all reactions the formation of cyclic and linear oligomers was verified by NMR and MALDI mass spectra, but the isolation of these compounds in pure state by column chromatography was successful only in several cases.Cyclic dimers 18-20, which are actually macrotricyclic cryptands of cylindrical shape, were obtained as separate fractions in 8-19% yields.

Scheme 3
Tetrabenzyl substituted derivatives of cyclen and cyclam 9-12 were reacted with diamine 13b using the same reaction conditions, and the compounds were isolated by the column chromatography (Scheme 4).

Scheme 4
Target macrobicycles 21-24 were obtained in 24-31% yields which are almost the same as those of macrobicycles 14-17.It shows that the introduction of two additional benzyl derivatives in the tetraazamacrocycles did not affect their reactivity in the catalytic macrocyclization reaction.In two reactions we isolated cyclic dimers 25 (x=1) and 27 (x=1) and even cyclic trimers 26 (x=2) and 28 (x=2) in yields up to 20%.The 1 H and 13 C spectra of the compound 23 recorded at 298K could not be easily interpreted because the signals of several rotational conformers were observed simultaneously.At 363K in DMSO-d6 signals of the conformers in the 1 H NMR spectrum coalesced while the signals in the 13 C NMR spectrum were still too broad.

Conclusions
As a result of the experiments described above, a simple and sufficiently efficient synthetic approach to macrobicyclic cryptands containing cyclen or cyclam moieties and adamantane fragment was elaborated.The possibility to change the size and geometry of the macrocyclic cavity by using isomeric bromobenzyl derivatives of tetraazamacrocycles and diamines with various chain length was demonstrated.Valuable macrotricyclic cryptands of cylindrical shape were obtained as second products in some reactions.Similar reactivity of dibenzyl and tetrabenzyl substituted tetraazamacrocycles in the catalytic macrocyclization reactions was shown; this effect substantially broadens the scope of these reactions for further construction of macropolycyclic compounds of sophisticated architecture.Macropolycycles incorporating lipophilic and geometrically constrained adamantane moieties are thought to be useful for coordination studies with heavy and toxic metals, possessing high coordination numbers, in organic media like alcohols or acetone.

Experimental Section
General.All chemicals were purchased from the Aldrich and Acros companies and used without further purification.Cis-glyoxal-cyclen (1), formaldehyde-cyclam (2), 1,7-dibenzylcyclen (7) and 1,8-dibenzylcyclam (8) were supported by CheMatech Co. 1,3-Bis(aminomethyl)adamantane (13a) and 1,3-bis(2-aminoethyl)adamantane (13b) were synthesized according to a described procedure. 26Pd(dba)2 was synthesized according to a known method. 32Commercial 1,4-dioxane was distilled over NaOH and sodium under argon, dichloromethane and methanol were freshly distilled prior to use.Column chromatography was carried out using silica gel (40-60 mkm) purchased from Fluka. 1 H and 13 C NMR spectra were recorded in CDCl3 using a Bruker Avance 400 spectrometer at 400 and 100.6 MHz respectively.Chemical shift values  are given in ppm and coupling constants J in Hz.MALDI-TOF mass spectra of positive ions were recorded with Bruker Ultraflex spectrometer using 1,8,9trihydroxyanthracene as matrix and PEGs as internal standards.Synthetic procedures and spectral data for compounds 3, 5 are given in reference 31 and for compounds 4, 6 in reference 30.