Pd-Catalyzed Amination in the Synthesis of a New Family of Macropolycyclic Compounds Comprising Diazacrown Ether Moieties

N,N'-bis(bromobenzyl) and N,N'-bis(halopyridinyl) derivatives of diaza-12-crown-4, diaza-15-crown-5 and diaza-18-crown-6 ethers were synthesized in high yields. The Pd-catalyzed macrocyclization reactions of these compounds were carried out using a variety of polyamines and oxadiamines were carried out to give novel macrobicyclic and macrotricyclic compounds of the cryptand type. The dependence of the yields of macropolycycles on the nature of the starting diazacrown derivatives and polyamines was established. Generally N,N'-bis(3-bromobenzyl)-substituted diazacrown ethers and oxadiamines provided better yields of the target products. The highest yield of the macrobicyclic products reached 57%.


Introduction
Macropolycyclic compounds (cryptands) attract the continued interest of researchers due to their unique selective ion binding properties. Macrobicycles of the cryptand type derived from azacrown ethers were among the first reported molecules of this type, e.g., di-and triazapolyoxacryptands [1,2], benzocryptands possessing 1,2-, 1,3-, and 1,4-disubstituted benzene [3,4], and 2,6-disubstituted pyridine fragments [5]. Compounds with two diazacrown ethers combined in macrotricyclic systems via aliphatic or benzyl linkers were also described [6,7]. So-called cross-bridged polycyclic compounds comprising diazacrown ethers constitute another class of cryptands called supercryptands [8]. Krakowiak and coauthors elaborated convenient and versatile synthetic approaches to various macropolycycles in 1990s based on simple nucleophilic substitution reactions [9][10][11]. Our interest in this field arises from the possibilities of the application of the catalytic Buchwald-Hartwig amination in the construction of the polymacrocyclic systems capable of selective metal cations coordination. We have already successfully used this approach for the synthesis of macrobicycles comprising tetraazamacrocyclic [12][13][14] moieties and made the first steps in the formation of polymacrocyclic structures based on aza-and diazacrown ethers [15,16].

Results and Discussion
Initially we attempted to synthesize a series of macrobicycles possessing diaza-12-crown-4 moieties because these compounds are of interest for selective coordination of Li ions. The search for efficient macrocyclic chelators of this ion is important for the sequestration of 7 Li and 6 Li isotopes. It is well known that a partial change of oxygen for nitrogen atoms in 12-member macrocycles and introduction of podands to these nitrogen atoms increases the stability constants of the lithium complexes by 2-3 orders of magnitude [17,18], thus we might expect that the macrobicycles with additional donor atoms will also form more stable complexes with Li cations. At the first step we synthesized N,N'-bis(bromobenzyl) derivatives of diaza-12-crown-4 by reacting 1 equiv. of compound 1 with 2 equiv. of 3-and 4-bromobenzyl bromides in boiling acetonitrile using K 2 CO 3 as a base. As a result, the corresponding derivatives 4 and 5 were obtained in almost quantitative yields (Scheme 1). The same method was applied for the modification of diaza-15-crown-5 (2) and diaza-18-crown-6 (3), and corresponding N,N'-bis(bromobenzyl) derivatives 6-9 were obtained in 89%-95% yields (Scheme 1). Na 2 CO 3 was used as a base in the case of diaza-18-crown-6.
The macrocyclization reactions of compounds 4-9 were carried out using a series of di-, tri-, tetraamines, and oxadiamines 10a-k differing in the chain length and the number of N and O atoms ( Figure 1). The investigation of the extended set of polyamines was necessary for elucidation of the scope and limitations of the proposed method and for the construction of macrobicycles with various macrocyclic cavities what would be useful for tuning their coordination properties towards different metal cations.  Macrocycles 4 and 5 were introduced in the Pd-catalyzed amination reactions with oxadiamines 10h,j,k using 8 mol% Pd(dba) 2 /BINAP catalytic system (dba-dibenzylideneacetone, BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) which previously was shown to be optimal in the majority of the amination reactions of aryl halides, and especially in the macrocyclization processes involving polyamines. The syntheses were carried out in boiling dioxane (c = 0.02 M) using sodium tert-butoxide as a base (Scheme 2). Macrobicycles 11 and 12 were isolated by column chromatography on silica gel. The yields are given in Table 1.
We did not observe any correlation between the structures of the starting compounds and the yields of the macrobicycles, which ranged from 13% to 31%. In some cases macrotricyclic cyclodimers 13 and 14 were isolated, in yields comparable to those of the target compounds (Table 1, entries 3, 4, 6). In two cases mixtures of cyclic oligomers were obtained in yields ca 40% (entries 1, 2). These facts imply that in some cases the intramolecular diamination is hindered, probably due to unfavorable mutual orientation of two bromine atoms.
Further investigations were carried out using N,N'-bis (3-bromobenzyl) derivative of diaza-15-crown-5 6 and a wide range of polyamines to study the process in details and to find out scope and limitations of the proposed approach. The reactions were conducted under the same conditions using 8 mol% catalyst (Scheme 3), the results are presented in Table 2.  In the majority of cases we obtained rather good yields of the target macrobicycles 15 ranging from 20% to 38%. The reactions with the shortest propane-1,3-diamine (10a) and butane-1,4-diamine (10b) gave poorer results (Table 2, entries 1, 2) due to the higher steric demands of these diamines for the mutual orientation of two bromine atoms in the starting compound 6. For the rest of di-and polyamines we did not observe any clear dependence of the product yields on the chain length and on the number of the nitrogen and oxygen atoms. In many cases we managed to isolate macrotricyclic by-products 19, and in the reaction with 10b the yield of 19b was twice as much as of the corresponding macrobicycle 15b. In all cases we also obtained complex mixtures of cyclic oligomers but their composition cannot be unambiguously established by NMR and mass spectroscopies because they possess almost the same structural fragments. Other derivatives of diazacrown ethers 7-9 were tested mainly in the cyclization reactions with oxadiamines to establish the dependence of the product yields on the ring size and substitution patterns. The reactions of the isomeric diazacrown derivative 7 containing 4-bromobenzyl substituents provided substantially lower yields of the cryptands 16 (entries [11][12][13][14][15]. Indeed, the use of the standard catalytic system in the macrocyclization reaction with trioxadiamine 10k afforded only 5% yield of the desired macrobicycle 16k (entry 11). The application of another ligand DavePhos (2-(dimethylamino)-2'-(dicyclohexylphosphino)biphenyl) was not successful either (entry 12), however, 16 mol% of the catalytic system Pd(dba) 2 /BINAP was helpful (entry 13) though the yield remained low. Only the reaction with dioxadiamine 10h proceeded better and produced the cryptand 16h in 18% yield (entry 15). In all cases the yields of cyclic dimers 20 exceeded those of macrobicycles 16.
The macrocyclization reactions with the derivative of diaza-18-crown-6 8 bearing two 3-bromobenzyl substituents were quite successful (entries 16-20) at 8 mol% catalyst loadings. While the use of triamine 10d, oxadiamine 10i,k provided average 25%-35% yields of the macrocyclization products 17d,i,k (entries 16,19,20), the reaction with dioxadiamine 10h resulted in 57% yield of the target cryptand 17h (entry 18), what is the best result ever observed among yields in the Pd-catalyzed macrocyclization reactions. On the other hand, macrotricyclic dimers 21 were isolated in certain cases in much lower yields. The reactions with isomeric derivative 9 were run using a 16 mol% catalytic system (entries 21, 22) and the yields of the target cryptands 18 were quite reasonable. It means that of four tested N,N'-bis(bromobenzyl) substituted diazacrowns, only compound 7 was recalcitrant in the intramolecular diamination processes.
The incorporation of the pyridine moiety in the structure of macrocyclic compounds can be useful as it increases the number of donor sites of the molecule what is favorable for the complexation of the cations with high coordination numbers. We synthesized N,N'-bis(halopyridinyl) derivatives of diazacrown ethers 23-26 differing in the nature of the halogen atom and the position of the nitrogen atom (Scheme 4). The reactions were conducted in boiling acetonitrile using sodium or potassium carbonates as bases, and the yields of the target compounds were excellent. All our attempts to induce the macrocyclization of compound 23 using the Pd(dba) 2 /BINAP catalytic system failed, however the application of DavePhos instead of BINAP was helpful (Scheme 5, Table 3). The same situation was observed with the derivative 24, however, the yields of the target macrobicycles 27, 28 were reasonable only in some cases (entries 1, 5). The analysis of the reaction mixtures and fractions after chromatography revealed the formation of complex mixtures of oligomers and other unidentified products which could arise from the side reactions other than catalytic amination. This is supported by the fact that the conversion of starting N,N'-bis(chloropyridinyl) derivatives 23 and 24 was complete whereas only half of the oxadiamines was consumed. Unfortunately, the efficiency of the bromosubstituted derivatives 25 and 26 to form macrobicycles was even poorer than that of compounds 23 and 24. Only in the reactions of 25 with trioxadiamine 10k and of 26 with dioxadiamine 10h did yields exceed 10% (entries 6,8), in other cases they were negligible and are not given in Table 3. A possible explanation is that bromine-containing derivatives 25 and 26 are more active than their chlorine-containing analogues 23 and 24 and participate in various side reactions. It is worth noting that both BINAP and DavePhos ligands can be used with limited success in the amination of compounds 25 and 26.  To summarize, we have conducted an extended investigation of the scope of Pd-catalyzed amination in the synthesis of macrobicycles based on diazacrown ether moieties, and determined the dependence of the yields of the target cryptands on the nature of halogen-containing substituents in the starting compounds. The macrocyclization processes were shown to proceed more efficiently with N,N'-bis (3-bromobenzyl) substituted diazacrown ethers 6 and 8, and the formation of valuable macrotricyclic compounds was demonstrated. The studies of the coordination properties of novel macrobicycles towards different metal cations are underway now.

General Method for the Synthesis of N,N'-bis(haloaryl)substituted Diazacrown Ethers
A one-neck flask equipped with a magnetic stirrer and reflux condenser was charged with diazacrown ether (0.86-2.3 mmol), aryl halide halogenomethyl derivative (1.7-4.6 mmol), dry acetonitrile (3-8 mL) and sodium or potassium carbonate (3.4-11.2 mmol). The reaction mixture was stirred under reflux for several hours, the residue was filtered off, washed with CH 2 Cl 2 , and the combined organic fractions were evaporated in vacuo, dissolved in CH 2 Cl 2 (5-20 mL), washed three times with equal volumes of distilled water, dried over 4 Å molecular sieves, and the CH 2 Cl 2 was evaporated in vacuo to give the pure target product. We have previously reported the synthesis and spectral data of compounds 6-9 [15].