Pd-catalyzed amination of dibromobiphenyls in the synthesis of macrocycles comprising two biphenyl and two polyamine moieties

Two approaches to the synthesis of polyazamacrocycles containing two biphenyl and two polyamine moieties are described. The first route comprises the synthesis of N,N'bis(bromobiphenyl) substituted diand poly-amines by the reactions of 2.2-3 equivalents of 4,4'or 3,3'-dibromobiphenyls with corresponding diand polyamines followed by the reaction with a second molecule of the amine. The second approach includes the synthesis of bis(polyamine) substituted biphenyls by the reactions of 4,4'or 3,3'-dibromobiphenyls with four equivalents of diand poly-amines with subsequent reaction of these in situ prepared intermediates with dibromobiphenyls. The yields of target macrocycles obtained according to two routes are compared and the advantage of the approach via bis(polyamine) substituted biphenyls in the majority of cases is established. Side products, when formed in all reactions, were analyzed.


Introduction
Macrocycles containing biphenyl units are of constant interest due to their interesting coordination possibilities which arise from the combination of flexible and tunable polyoxa-and polyaza-cycles with a rigid non-planar aryl moiety. Many cyclic polyethers were formed starting from 2,2'-dihydroxybiphenyl; 1-3 their coordination with organic cations like tert-butylammonium was studied, 2 as well as the transport of Li, Na, K cations 4,5 and of Hg(CF3)2 6,7 through a liquid membrane. In such macrocycles one or two polyoxaethylene chains were attached to one biphenyl unit. Molecular structures of various 2,2'-biphenyl-based crown ethers and their For this purpose 2.5 equivalents of 4,4'-dibromobiphenyl were reacted with trioxadiamine 2c using 4 mol% catalyst at c = 0.1 M. After 10 h the reaction mixture was diluted to get 0.02 M solution, additional amount of the catalyst (8 mol%) and one equivalent of trioxadiamine 2c were added, and the reaction was refluxed for 35 h. The chromatography gave 28% of the reduction product 8c, only 5% of pure cyclic dimer 6c, and a separate fraction containing cyclodimer 6c with cyclic trimer 7c (n=3) (9% yield). This unsatisfactory result demonstrates the difficulties in the separation of cyclic oligomers and thus the pressure to diminish their amount and diversity, which can be done only using pure N,N'-bis (4-biphenyl) derivatives of polyamines for the synthesis of cyclic dimers.
While macrocycles based on 4,4'-biphenyls are well documented in the literature, macrocycles incorporating 3,3'-biphenyls are quite rare examples, and this fact makes the synthesis of cyclic dimers with two 3,3'-biphenyl moieties an important task. At first we tried a one-step approach described above without isolation of the intermediate N,N'-diarylated derivatives of polyamines (Scheme 3).

Scheme 3
N,N'-diarylation of polyamines 2a,b,d was achieved using 2.5 equivalents of 3,3'dibromobiphenyl 9, 4 mol% catalyst, and 0.1 M solutions of polyamines in dioxane. After 10 h of reflux the reaction mixtures were analyzed by 1 H NMR to verify the formation of diaryl derivatives 10, they were diluted to make 0.02 M solutions and new portions of the catalyst (8 mol%) were added. The additional reflux for [35][36][37][38][39][40] h was necessary to complete the intramolecular diamination, and after it the reaction mixtures were subjected to chromatography on silica gel. The result was moderate only for tetraamine derivative 11d (19%), while in other cases pure cyclodimers 11a,b were obtained in low yields. Cyclic oligomers 13 were isolated in all reactions, and in the case of dioxadiamine 2b and tetraamine 2d also macrocycles 12b,d were obtained in comparable yields (10 and 18%, respectively). The reaction of equimolar amounts of 1,3-diaminopropane 2a with 3,3'-dibromobiphenyl 9 described by us previously afforded 24% yield of the cyclic dimer 11a. 31 Thus it is clear that the approach via in situ obtained N,N'-bis (3bromobiphenyl)diamine is not suitable for this compound.
Next we investigated the possibilities of this method with chromatographic isolation of compounds 10; this was thought also to reveal the formation of by-products (Scheme 4).

Scheme 4
According to a given consideration, diamine 2a was excluded from this series of experiments. The reactions were run using 2.2 equivalents of 9, and at first they were catalyzed by 4 mol% Pd(dba)2/BINAP. The reactions of trioxadiamine 2c and tetraamine 2d gave target products 10c,d in 21 and 26% yields, macrocycles 12c,d as well as linear oligomers 14c,d and 15d were also obtained. In the case of tetraamine 2d the application of 3 equivalents of 9 allowed to increase the yield of 10d to 34%. However, for dioxadiamine 2b it was found impossible to isolate the target compound 10b in pure state because it contained admixturesproducts of N,Ndiarylation and diamination reactions. The application of less amount of the catalyst (2 mol%) did not improve the situation. The change of BINAP ligand for a less active Xanthphos suppressed the undesirable reactions but the standard catalyst loading (4 mol%) together with the standard reaction time (10 h) led mainly to monoaryl derivative of dioxadiamine. The use of more catalyst (8 mol%) was unsuccessful because it promoted N,N-diarylation process, but the employment of 3 equivalents of 9 and prolonged reflux (45 h) with 4 mol% Pd(dba)2/Xanthphos resulted in 27% yield of pure product 10b. We tested the same conditions with trioxadiamine 2c and increased the yield of 10c to 35%.
The cyclization reactions of diaryl derivatives 10b-d were accomplished under standard conditions (Scheme 5) and their results were similar: the yields of target macrocycles 12b-d ranged from 25 to 30%, cyclic oligomers (cyclotetramers and cyclohexamers) were obtained as side products in comparable yields. In the case of the reaction of 10b with 2b cyclooligomers 13b (n=3, 5) were fully separated from the target cyclodimer 11b, while in other reactions the fractions containing cyclooligomers 13c,d contained also cyclodimers 11c,d what to some extent diminished the yields of the target macrocycles-cyclodimers. This macrocyclization was more successful than that with N,N'-bis(4-bromobiphenyl) derivatives 3 and here no influence of the nature of polyamine was noted.

Scheme 5
Having obtained data on the synthesis of the biphenyl-containing macrocycles via intermediate N,N'-bis(bromobiphenyl)polyamines, we tried an alternative approach, i.e. via intermediate bis(polyamine) substituted biphenyls. In this method intermediates were not isolated by column chromatography due to great difficulties caused by the presence of an excess of polyamines in the reaction mixture which possess very close Rf to that of bis(polyamine) derivatives of biphenyls.

Scheme 6
The reactions of 4,4'-dibromobiphenyl 1 with 4 equivalents of di-and polyamines 2b-d were run in boiling dioxane (C = 0.1 M) and catalyzed by 8 mol% Pd(dba)2/BINAP, they were complete in 8-10 h (Scheme 6). Intermediate 4,4'-bis(polyamine) biphenyls 16a-d were analyzed by NMR and MALDI-TOF mass-spectra in the reaction mixtures. Then 3 equivalents of 4,4'dibromobiphenyl, additional catalyst (8 mol%) and dioxane to make 0.02 M solution were added, and the reactions were refluxed for 35-40 h. Target cyclodimers 6b-d were isolated by column chromatography on silica gel. The best result was obtained for the macrocycle 6c (24%), the reactions with dioxadiamine 2b and tetraamine 2d gave poor yields of macrocycles (11 and 7% respectively). In these reactions substantial amounts of cyclic oligomers of higher masses were obtained (up to cyclononamer 7b (n=8)), obviously, they were formed via intermediate linear oligomers containing n biphenyl and n+1 polyamine units. It is notable that the reaction with trioxadiamine 2c gave rise to linear oligomers 17c with terminal biphenyl which were formed due to the reduction of the bromine atom.
A similar reaction with the isomeric 3,3'-dibromobiphenyl 9 conducted under the same conditions gave somewhat different results (Scheme 7).

Scheme 7
Intermediate 3,3'-bis(polyamine)biphenyls 18b-d, obtained in situ using 4 equivalents of corresponding di-and polyamines 2b-d, were analyzed by NMR and MALDI-TOF spectroscopy, and they were further reacted with 3 equivalents of 3,3'-dibromobiphenyl. The best result was recorded for the macrocycle 11b with its highest 44% yield, whereas the yields of compounds 11c and 11d were much more modest (15 and 9% respectively). In all cases the formation of the macrocycles 12 containing one set of biphenyl and polyamine units was observed, and with longer trioxadiamine 2c and tetraamine 2d their yields were about 40% which is equal to the yields of these compounds when the reactions were run with equimolar amounts of starting compounds. 31 Higher mass cyclooligomers were also formed in the case of dioxadiamine 2b and trioxadiamine 2c.

Conclusions
As a result of the experiments described above, we can outline the following general findings. The synthesis of the macrocycles containing two biphenyl and two polyamine moieties can be carried out using two approaches: via N,N'-bis(bromobiphenyl) substituted polyamines or via bis(polyamine)biphenyls. The first route in a two-step version affords target macrocycles in yields up to 30%, 3,3'-dibromobiphenyl providing better yields of the macrocycles than 4,4'dibromobiphenyl. One-step version with in situ obtained N,N'-bis(bromobiphenyl) derivative can be recommended only for the synthesis of the cyclodimer with two 3,3'-biphenyls and two tetraamine chains (yield 19%). The second approach via bis(polyamine)biphenyls provides better yields of some cyclodimers, and in this case the dependence of the result on the nature of starting compounds is pronounced: 4,4'-dibromobiphenyl gave 24% yield of the macrocycle with two trioxadiamine chains, whereas 3,3'-dibromobiphenyl afforded the cyclodimer with dioxadiamine in the highest yield (44%). We suppose that two main factors govern the results of these two-step syntheses: the conformational factors of di-and polyamine chains at the macrocyclization step and the activity of the bromine atom in 4,4'-and 3,3'-dibromobiphenyls in competitive amination and reduction reactions at both steps of the processes. The application of more powerful separation techniques like HPLC may undoubtedly increase the yields of the target macrocycles.