HETEROCYCLES

Paper | Special issue | Vol. 82, No. 2, 2011, pp. 1447-1476
Received, 27th July, 2010, Accepted, 7th September, 2010, Published online, 8th September, 2010.
DOI: 10.3987/COM-10-S(E)98

■ Synthesis of Macrobi- and Macrotricyclic Compounds Comprising Pyrimidyl Substituted Cyclen and Cyclam

Sergei M. Kobelev, Alexei D. Averin, Alexei K. Buryak, Franck Denat, Roger Guilard,* and Irina P. Beletskaya*

Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-3, 119991, Moscow, Russia

Abstract

The synthesis of novel N1,N7-bis(bromobenzyl) cyclens and N1,N8-bis(bromobenzyl) cyclams is described. Arylation of these compounds with excess 4,6-dichloropyrimidine and 2-chloropyrimidine gave corresponding tetrasubstituted cyclen and cyclam in good yields. Bis(bromobenzyl)bis(pyrimidyl) substituted cyclens and cyclams were used in the Pd-catalyzed reactions with polyamines to give macrobi- and macrotricycles. The yields of macropolycyclic compounds were shown to be dependent on the nature of starting tetraazamacrocycles and polyamines. In the case of cyclam monopyrimidyl derivatives were also obtained and macropolycyclic compounds were synthesized on their base.

INTRODUCTION
Amino substituted pyrimidines attract a keen interest of chemists first of all due to an extremely broad spectrum of their physiological activity. More specifically, 4,6-diaminopyrimidines were tested as protein kinase inhibitors,1-4 as inhibitors of kinases of other types: CHK1,5 lymphocyte-specific tyrosine kinase,6,7 Janus kinase,8 VEGFR-2 kinase,9,10 and also as cannabioid receptor CB1 ligand.11 In other studies 4,6-diaminopyrimidines were tried for prevention and cure of the metabolism diseases,12 in the treatment of CNS diseases,13 their use as 5-HT7 ligands was also investigated.14
To the moment, several macrocycles which include pyrimidine moiety are known. Macrocycles comprising 4,6-diaminopyrimidine15-17 and 2,4-diaminopyrimidine18-22 were described in the literature, in some compounds 2,4-diaminopyrimidine fragment constitutes a part of the macrocycle by disubstitution in positions 4 and 5.23,24 Pyrimidocrown ethers were synthesized on the basis of 4,6-dioxy-, 4,6-dithiopyrimidines,25 and 2,4-diamino pyrimidines.26-29 Synthesis and physicochemical investigations of the macrocycles on the basis of 2-thio-4-aminopyrimidines were carried out.30-35 A number of macrocycles were tested for their medical applications: their antitumor18,19,22 and antiproliferative16,20,21 activity was studied, some derivatives were tried as gistamine H4 receptor modulators.23 All described macrocycles were synthesized using conventional multistep methods.
Earlier we demonstrated that the amination of 2-chloropyrimidine and 2,4-dichloropyrimidine with various linear diamines proceeded smoothly, moreover, the diamination of 2,4-dichloropyrimidine could be carried out under non-catalytic conditions.36 However, the monoamination of 2,4-dichloropyrimidine turned out not to be selective. The introduction of the symmetrical 4,6-dichloropyrimidine in the diamination process demanded the use of the palladium catalyst, as it has been shown by us quite recently.37 Using this approach several macrocycles containing 4,6-diaminopyrimidine fragment have been synthesized, thus the application of Buchwald-Hartwig amination38 extended the family of arene spacers which can be incorporated in the macrocycle using a convenient one-pot procedure. Taking these facts into consideration, we decided to modify various derivatives of tetraazamacrocycles like cyclen and cyclam with 6-chloropyrimidine moieties in order to synthesize novel macrotricyclic compounds.

RESULTS AND DISCUSSION

First of all, we synthesized a macrobicyclic compound containing trans-disubstituted cyclen (1,4,7,10-tetraazacyclododecane) and trioxadiamine chain according to a procedure published by us previously39 (Scheme 1). For this purpose we used N1,N7-bis(3-bromobenzyl)cyclen 1 in the Pd-catalyzed reaction with trioxadiamine 2a and obtained target macrobicycle 3a in 28% yield. Then it was reacted with 4 equivalents of 4,6-dichloropyrimidine to give trans-dipyrimidyl substituted macrobicycle 4a in 54% yield. Further attempts to introduce this compound in the cyclization with the second molecule of trioxadiamine to obtain macrotricycle of a new type were unsuccessful though 16 mol% Pd(dba)2/BINAP were used according to our method elaborated for the synthesis of 4,6-diamino-based macrocycles,37 and only inseparable mixture of unidentified products was obtained though no unreacted compound 4a was detected in the reaction mixture.
We assumed that possibly the trioxadiamine chain could be an obstacle in the formation of the third macrocycle and tried another approach. N1,N7-bis(3-bromobenzyl)cyclen 1 was modified with two 6-chloropyrimidyl substituents (Scheme 2) to give compound 5a in 66% yield.

This tetrasubstituted cyclen was reacted with trioxadiamine 2a using Pd catalysis, but in this case also no cyclization occurred. After failure with Cs2CO3 as a base, we tried the use of an excess tBuONa in order to substitute chlorine atoms in 6-chloropyrimidyl substituents by tert-butoxy groups and simultaneously to carry out the cyclization, but again the reaction gave only an inseparable mixture of unknown compounds. Such unfavorable behavior of the cyclen derivative bearing two pyrimidyl substituents led us to a deeper investigation of the cyclization processes in which pyrimidyl substituted cyclen and cyclam can participate in order to reveal how these substituents affect the cyclization. Moreover, the compounds which combine tetraazamacrocycles with pyrimidine fragment are of interest as host molecules for cations because they bear additional donor nitrogen atoms.
To create a representative series of trans-dipyrimidyl substituted tetraazamacrocycles for their further investigations in the macrocyclization reactions, besides N1,N7-bis(3-bromobenzyl)cyclen 1, we synthesized previously unknown N1,N7-bis(4-bromobenzyl) cyclen 8, N1,N8-bis(3-bromobenzyl)cyclam (1,5,8,11-tetraazacyclotetradecane) 12 and N1,N8-bis(4-bromobenzyl)cyclam 13 (Scheme 3). These compounds were obtained starting from cis-glyoxal-cyclen 6 or formaldehyde-cyclam 9 according to a procedure described previously.40, 41 This method has recently become a versatile tool for creating various derivatives of cyclen and cyclam.42 Intermediate salts 7, 10 and 11 were isolated in high yields, and treatment of these compounds with 3M solutions of NaOH at 80-90 oC gave trans-bis(bromobenzyl) substituted cyclen and cyclams 8, 12, 13 in high yields.

Compounds 1, 8, 12 and 13 were modified with 2-pyrimidyl substituents via simple reactions with 4-fold excess of 2-chloropyrimidine in boiling acetonitrile in the presence of K2CO3 (Scheme 4). The use of the excess of 2-chloropyrimidine was crucial in this case because the use of stoichiometric amounts of the reagents led to low yields of dipyrimidyl derivatives.

The reactions of cyclen-based compounds 1 and 8 afforded dipyrimidyl derivatives 14 and 17 in good yields (69% and 59%, respectively), however, derivatives containing cyclam 15 and 18 were obtained in low yields (22% and 25%), though the excess of the arylating reagent was used. Together with the target molecules monopyrimidyl derivatives 16 and 19 were isolated in comparable yields (36% and 20%). The reason for such poor reactivity of the cyclam derivatives may be explained by steric differences between cyclen- and cyclam-containing compounds.
Cyclen derivatives 14 and 17 were used in the Pd-catalyzed amination reactions with equimolar amounts of di- and polyamines 2a-d, the reactions were run in boiling dioxane (c = 0.02 M), Pd(dba)2/BINAP (16/18 mol%) catalytic system was employed, tBuONa was used as a base (Scheme 5). The results of the reactions are collected in Table 1. The reactions with all di- and polyamines provided corresponding macrobicyclic compounds 20 and 22, the yields being dramatically dependent on the substitution in the benzene ring. While compound 14 with 3-bromobenzyl substituents afforded target macrobicycles 20a,c,d in rather good yields (up to 31%, Table 1, entries 1, 2), the reactions of compound 17 with 4-bromobenzyl substituents gave lower yields of macrobicycles 22a-d (8-19%, entries 4-7). The most interesting feature of this reaction is the formation of great amounts of macrotricyclic compounds 21 and 23 which in fact are cyclic dimers of target molecules. In many cases their yields surpassed those of macrobicycles (entries 3-5, 7). These cryptands of cylindrical shape are undoubtedly very promising for the investigation of their coordination properties. In the reactions of 17 with oxadiamines 2a,c the formation of cyclic trimers 23a,c (n=2) and cyclic tetramer 23c (n=3) was observed.

MALDI-TOF mass spectroscopy was very useful in distinguishing between macrobi- and macropolycycles. 1H NMR spectra were also helpful: in macrobicycles 20 and 22 the signals of pyrimidine protons are shifted downfield by 0.1 ppm as compared to macrotri- and macropolycycles 21 and 23.

We verified the possibility of obtaining dipyrimidyl substituted macrobicycle 20a via an alternative route, by reacting macrobicycle 3a with 2-chloropyrimidine (Scheme 6). It proved to be quite successful, and the yield of 20a was 26%, which is close to that obtained in the macrocyclization reaction (29%, entry 1). It means that the approach via macrocyclization of tetrasubstituted cyclen is quite justified, moreover, it affords the introduction of the polyamine chain with dialkylamino groups in the macrobicycle at the final step, what is obviously impossible in the synthesis according alternative route (2-chloropyrimidine will readily arylate dialkylamino groups of the polyamine chain as well as those of cyclen).

Next we investigated the behavior of the cyclam derivatives 15, 16, 18, and 19 in the same reactions (Scheme 7, Table 2).

To our surprise, compound 15 did not form expected macrobicycles with tri- and dioxadiamines 2a,c but rather gave only macrotricyclic cyclodimers 25a,c (Table 2, entries 1, 2). Only with tetraamine 2d the cryptand 24d was obtained in 29% yield (entry 3). When using monopyrimidyl derivative 16, macrobicyclic cryptands 26a,c,d were synthesized in normal yields (entries 4-6), and corresponding macrotricycles 27a,c,d were as well isolated in all cases. One may suppose that the formation of only cyclodimers in the reactions with dipyrimidyl derivative 15 could occur due to steric hindrances caused by the presence of two pyrimidyl substituents. Cyclic trimers were obtained in the reactions of 15 with trioxadiamine 2a and tetraamine 2d. The reaction with trioxadiamine 2a carried out with bis(4-bromobenzyl) derivatives of cyclam 18, 19 demonstrated that in these cases p-bromo substituted species reacted more reluctantly than their m-bromo substituted isomers (entries 7, 8), the same observation was made for cyclen derivatives earlier. The yields of target macrobicycles 28a,b were low (5-6%), but the yields of cyclic dimers and trimers were substantially higher (12-19%). However, here dipyrimidyl derivative 18, contrary to its isomer 15, did give macrobicycles 29a,b with tri- and dioxadiamines 2a,b, possibly due to more favorable geometry provided by para position of bromine substituents. The use of a less sterically hindered monopyrimidyl compound 19 gave rise to 30% yield of the corresponding macrobicycle 30a (entry 9). It is to be noted that almost in all macrocyclization reactions the formation of quite substantial amounts of presumably linear oligomers was noted, but as these compounds were isolated only as complex mixtures and their composition could not be established neither by NMR nor by MALDI mass spectroscopy, their yields cannot be accurately evaluated.

CONCLUSION
The following conclusions can be drawn from the experimental data described above. While the substitution of the first chlorine atom for amino group in 4,6-dichloropyrimidine proceeds readily without catalyst, the substitution of the second chlorine atom is problematic. Though it is possible to obtain macrocycles by a one-pot intramolecular diamination reaction from 4,6-dichloropyrimidine, as it was described by us earlier,37 macrocyclization reaction did not occur in the case of bis(chloropyrimidyl) substituted tetraazamacrocycles. However, the substitution of remaining two nitrogen atoms in trans-bis(bromobenzyl) derivatives of cyclen and cyclam with 2-pyrimidyl groups provided interesting substrates for the synthesis of macrobi- and macrotricycles via Pd-catalyzed amination reactions. The reactions of N1,N7-bis(bromobenzyl)cyclen with 2-chloropyrimidine turned out to be more successful than those of N1,N8-bis(bromobenzyl)cyclam which provided almost equal amounts of di- and monopyrimidyl derivatives. The reactions of dipirymidyl derivatives of cyclen generally gave better yields of macrobicyclic compounds than those of cyclam derivatives, the latter provided only macrotricyclic cryptands in several cases, however, monopyrimidyl derivatives of cyclam gave reasonable yields of macrobicycles. It is clear that pyrimidyl substituents govern seriously the course of the macrocyclization reactions, and the combination of the type of initial tetraazamacrocycle, number of pyrimidine moieties, and the nature of polyamine influences the yields of macrobi- and macrotricycles. Macropolycyclic molecules synthesized in the course of the present investigation will surely find applications as host molecules, and such investigations are underway now.

EXPERIMENTAL
All chemicals were purchased from Aldrich and Acros companies and used without further purification. Cis-glyoxal-cyclen 6 and formaldehyde-cyclam 9 were provided by CheMatech Co. Pd(dba)2 was synthesized according to a procedure described.43 N1,N7-bis(3-bromobenzyl)cyclen (1) and macrocycle 3a were synthesized according to a described method.39 Commercial dioxane was distilled over NaOH and sodium under argon, acetonitrile was distilled over P2O5, dichlromethane and methanol were distilled prior to use. Column chromatography was carried out using silica gel (40-60 mkm) purchased from Fluka. 1H and 13C NMR spectra were registered in CDCl3 using Bruker Avance 400 spectrometer at 400 and 100.6 MHz respectively. Chemical shift values δ are given in ppm and coupling constants J in Hz. MALDI-TOF spectra were recorded with Bruker Ultraflex spectrometer using 1,8,9-trihydroxyanthracene as matrix and PEGs as internal standards.

(8bR,8cR)-2a,6a-Bis(4-bromobenzyl)decahydro-4a,8a-diaza-2a,6a-diazoniacyclopenta[fg]acenaphthylene dibromide (7). Cis-glyoxal-cyclen 6 (9 mmol, 1.74 g) was dissolved in dry acetonitrile (27 mL), p-bromobenzylbromide (18 mmol, 4.5 g) was added, and the reaction mixture was stirred at 50 °C for 72 h. After cooling to room temperature the solution was filtered off, the residue was washed with acetonitrile (2x15 mL) and dried in vacuo to give compound 7 as white crystalline powder. Yield 5.71 g (91%). 1H NMR (DMSO-d6): δ 2.93 (q, J = 8.3 Hz, 2H), 3.40-3.47 (m, 4H), 3.59-3.72 (m, 4H), 4.22 (td, J = 11.3 Hz, 3.6 Hz, 2H), 4.84 (d, J = 13.4 Hz, 2H), 4.87 (s, 2H), 5.01 (d, J = 13.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 4H), 7.79 (d, J = 8.4 Hz, 4H), 4 protons are hidden by CHD2 multiplet. 13C NMR (DMSO-d6): δ 42.2 (2C), 46.6 (2C), 55.4 (2C), 58.9 (2C), 60.2 (2C), 76.4 (2C), 124.6 (2C), 126.6 (2C), 132.4 (4C), 134.8 (4C).

1,7-Bis(4-bromobenzyl)-1,4,7,10-tetraazacyclododecane (8). Compound 7 (8.19 mmol, 5.71 g) was treated with KOH (143 mmol, 8g) in 50 mL water at 80-90 oC under stirring for 72 h. The reaction mixture was extracted with CH2Cl2 (2x30 mL), organic fractions were dried over anhydrous Na2SO4 and evaporated in vacuo to give compound 8 as slightly beige crystalline powder. Yield 3.79 g (91%), mp 135-136 oC. 1H NMR (CDCl3): δ 2.38 (bs, 2H), 2.45-2.58 (m, 8H), 2.58-2.68 (m, 8H), 3.52 (s, 4H), 7.17 (d, J = 8.2 Hz, 4H), 7.45 (d, J = 8.4 Hz, 4H). 13C NMR (CDCl3): δ 45.0 (4C), 51.8 (4C), 59.2 (2C), 121.1 (2C), 130.6 (4C) 131.5 (4C), 138.1 (2C). HRMS (MALDI-TOF) m/z calcd for C22H31Br2N4 [M+H]+ 509.0915, found 509.0924.

1,8-Bis(3-bromobenzyl)-1,4,8,11-tetraazacyclotetradecane (12). Formaldehyde-cyclam 9 (17.9 mmol, 4 g) was dissolved in dry acetonitrile (120 mL), m-bromobenzylbromide (35.8 mmol, 8.93 g) was added, and the reaction mixture was stirred at room temperature for 24 h. Then the solution was filtered off, the residue was washed with acetonitrile (20 mL) and dried in vacuo to give 1,8-bis(3-bromobenzyl)-4,11-diaza-1,8-diazoniatricyclo[9.3.1.14,8]hexadecane dibromide (10) as white crystalline powder practically insoluble in common solvents for NMR spectroscopy (D2O, DMSO-d6, CD3OD). Yield 10.7 g (83%). Then it was treated with NaOH (750 mmol, 30g) in 40 mL water at 80-90 oC under stirring for 24 h. The reaction mixture was extracted with CH2Cl2 (2x30 mL), organic fractions were dried over anhydrous Na2SO4 and evaporated in vacuo to give compound 12 as slightly beige crystalline powder. Yield 7.48 g (94%), mp 73-75 oC. 1H NMR (CDCl3): δ 1.82 (quintet, J = 5.0 Hz, 4H), 2.48 (t, J = 5.5 Hz, 4H), 2.58-2.63 (m, 4H), 2.70 (t, J = 5.2 Hz, 4H), 2.72-2.76 (m, 4H), 2.96 (bs, 2H), 3.64 (s, 4H), 7.10 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 7.41 (s, 2H). 13C NMR (CDCl3): δ 25.7 (2C), 47.4 (2C), 49.8 (2C), 52.3 (2C), 53.9 (2C), 57.5 (2C), 122.4 (2C), 127.9 (2C), 129.6 (2C), 130.0 (2C), 131.6 (2C), 140.4 (2C). HRMS (MALDI-TOF) m/z calcd for C24H35Br2N4 [M+H]+ 537.1228, found 537.1199.

1,8-Bis(4-bromobenzyl)-1,4,8,11-tetraazacyclotetradecane (13). Formaldehyde-cyclam 9 (17.4 mmol, 3.9 g) was dissolved in dry acetonitrile (120 mL), p-bromobenzylbromide (34.8 mmol, 8.7 g) was added, and the reaction mixture was stirred at room temperature for 24 h. Then the solution was filtered off, the residue was washed with acetonitrile (20 mL) and dried in vacuo to give 1,8-bis(4-bromobenzyl)-4,11-diaza-1,8-diazoniatricyclo[9.3.1.14,8]hexadecane (11) white crystalline powder practically insoluble in common solvents for NMR spectroscopy (D2O, DMSO-d6, CD3OD). Yield 10.8 g (86%). Then it was treated with NaOH (750 mmol, 30g) in 40 mL water at 80-90 oC under stirring for 24 h. The reaction mixture was extracted with CH2Cl2 (2x30 mL), organic fractions were dried over anhydrous Na2SO4 and evaporated in vacuo to give compound 13 as slightly yellow crystalline powder. Yield 7.86 g (98%), mp 134-135 oC. 1H NMR (CDCl3): δ 1.83 (quintet, J = 5.2 Hz, 4H), 2.50 (t, J = 5.5 Hz, 4H), 2.56-2.60 (m, 4H), 2.68-2.75 (m, 8H), 3.62 (s, 4H), 7.16 (d, J = 8.2 Hz, 4H), 7.40 (d, J = 8.2 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 (2C), 47.5 (2C), 49.7 (2C), 52.2 (2C), 53.8 (2C), 57.9 (2C), 121.0 (2C), 130.7 (4C) 131.6 (4C), 138.2 (2C). HRMS (MALDI-TOF) m/z calcd for C24H35Br2N4 [M+H]+ 537.1228, found 537.1253.

1,7-Bis(3-bromobenzyl)-4,10-dipyrimidin-2-yl-1,4,7,10-tetraazacyclododecane (14). N1,N7-Bis(3-bromobenzyl)cyclen (1) (0.25 mmol, 128 mg) was treated with 2-chloropyrimidine (1 mmol, 115 mg) in dry acetonitrile (5 mL) under reflux, in the presence of K2CO3 (138 mg) for 8 h. After cooling to room temperature the reaction mixture was filtered off, the residue was washed with 10 mL CH2Cl2, combined organic fractions were evaporated in vacuo and chromatographed on silica gel. Eluent CH2Cl2-MeOH 100:1-50:1. Yield 116 mg (69%). Pale-yellow crystalline powder, mp 90-92 oC. 1H NMR (CDCl3): δ 2.80 (t, J = 4.6 Hz, 8H), 3.66 (s, 4H), 3.71 (t, J = 4.6 Hz, 8H), 6.30 (t, J = 4.8 Hz, 2H), 6.96 (t, J = 7.7 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 7.21 (d, 7.8 Hz, 2H), 7.35 (s, 2H), 8.08 (d, J = 4.8 Hz, 4H). 13C NMR (CDCl3): δ 46.9 (4C), 54.1 (4C), 59.4 (2C), 108.9 (2C), 122.0 (2C), 127.7 (2C), 129.3 (2C), 129.6 (2C), 132.2 (2C), 141.8 (2C), 157.1 (4C), 161.6 (2C). HRMS (MALDI-TOF) m/z calcd for C30H35Br2N8 [M+H]+ 665.1351, found 665.1320.

1,8-Bis(3-bromobenzyl)-4,11-dipyrimidin-2-yl-1,4,8,11-tetraazacyclotetradecane (15). N1,N8-Bis(3-bromobenzyl)cyclam (12) (1 mmol, 538 mg) was treated with 2-chloropyrimidine (4 mmol, 458 mg) in dry acetonitrile (15 mL) under reflux, in the presence of K2CO3 (552 mg) for 18 h. After cooling to room temperature the reaction mixture was filtered off, the residue was washed with 15 mL CH2Cl2, combined organic fractions were evaporated in vacuo and chromatographed on silica gel. Eluent CH2Cl2-MeOH 100:1. Yield 153 mg (22%). Pale-yellow crystalline powder, mp 169-170 oC. 1H NMR (CDCl3): δ 1.89 (quintet, J = 6.9 Hz, 4H), 2.54 (t, J = 6.1 Hz, 4H), 2.75 (t, J = 6.2 Hz, 4H), 3.59 (s, 4H), 3.73 (t, J = 6.2 Hz, 4H), 3.79 (t, J = 7.7 Hz, 4H), 6.38 (t, J = 4.7 Hz, 2H), 7.08 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 7.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.46 (s, 2H), 8.21 (d, J = 4.7 Hz, 4H). 13C NMR (CDCl3): δ 26.0 (2C), 47.0 (2C), 47.6 (2C), 51.9 (2C), 52.4 (2C), 60.0 (2C), 109.0 (2C), 122.2 (2C), 127.6 (2C), 129.6 (2C), 129.8 (2C), 132.0 (2C), 141.9 (2C), 157.5 (4C), 161.5 (2C). HRMS (MALDI-TOF) m/z calcd for C32H39Br2N8 [M+H]+ 693.1664, found 693.1627.

1,8-Bis(3-bromobenzyl)-4-pyrimidin-2-yl-1,4,8,11-tetraazacyclotetradecane (16) was obtained as the second product in the synthesis of compound 15. Eluent CH2Cl2-MeOH 25:1. Yield 219 mg (36%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.64 (quintet, J = 6.2 Hz, 2H), 1.78 (quintet, J = 5.0 Hz, 2H), 2.35 (bs, 1H), 2.44 (t, J = 4.9 Hz, 2H), 2.59 (bs, 4H), 2.63 (t, J = 5.0 Hz, 2H), 2.68 (t, J = 5.7 Hz, 2H), 2.73 (t, J = 5.2 Hz, 2H), 3.41 (s, 2H), 3.55 (t, J = 5.4 Hz, 2H), 3.56 (s, 2H), 3.66 (t, J = 7.6 Hz, 2H), 6.26 (t, J = 4.8 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.7 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H), 8.08 (d, J = 4.8 Hz, 2H). 13C NMR (CDCl3): δ 26.0, 26.8, 45.8, 45.9, 47.4, 47.5, 50.9, 51.2, 52.8, 53.8, 57.8, 59.9, 108.5, 121.5, 122.4, 127.3, 127.5, 129.2, 129.4, 129.8, 130.1, 131.7, 132.1, 141.9, 142.0, 157.2 (2C), 160.8. HRMS (MALDI-TOF) m/z calcd for C28H37Br2N6 [M+H]+ 615.1446, found 615.1418.

1,7-Bis(4-bromobenzyl)-4,10-dipyrimidin-2-yl-1,4,7,10-tetraazacyclododecane (17). N1,N7-Bis(4-bromobenzyl)cyclen (8) (2 mmol, 1.02 mg) was treated with 2-chloropyrimidine (8 mmol, 916 mg) in dry acetonitrile (30 mL) under reflux, in the presence of K2CO3 (1.1 g) for 16 h. After cooling to room temperature the reaction mixture was filtered off, the residue was washed with 20 mL CH2Cl2, combined organic fractions were evaporated in vacuo and chromatographed on silica gel. Eluent CH2Cl2-MeOH 100:1-50:1. Yield 786 mg (69%). Pale-beige crystalline powder, mp 154-156 oC. 1H NMR (CDCl3): δ 2.76 (t, J = 4.4 Hz, 8H), 3.62 (s, 4H), 3.68 (t, J = 4.4 Hz, 8H), 6.31 (t, J = 4.7 Hz, 2H), 7.00 (d, J = 8.2 Hz, 4H), 7.20 (d, J = 8.2 Hz, 4H), 8.05 (d, J = 4.7 Hz, 4H). 13C NMR (CDCl3): δ 46.7 (4C), 54.1 (4C), 59.3 (2C), 108.9 (2C), 120.3 (2C), 130.8 (8C), 138.3 (2C), 157.0 (4C), 161.5 (2C). HRMS (MALDI-TOF) m/z calcd for C30H35Br2N8 [M+H]+ 665.1351, found 665.1382.

1,8-Bis(4-bromobenzyl)-4,11-dipyrimidin-2-yl-1,4,8,11-tetraazacyclotetradecane (18). N1,N8-Bis(4-bromobenzyl)cyclam (13) (2 mmol, 1.076 g) was treated with 2-chloropyrimidine (4 mmol, 916 mg) in dry acetonitrile (30 mL) under reflux, in the presence of K2CO3 (1.01 g) for 16 h. After cooling to room temperature the reaction mixture was filtered off, the residue was washed with 20 mL CH2Cl2, combined organic fractions were evaporated in vacuo and chromatographed on silica gel. Eluent CH2Cl2-MeOH 50:1. Yield 345 mg (25%). Pale-beige crystalline powder, mp 184-186 oC. 1H NMR (CDCl3): δ 1.86 (quintet, J = 6.7 Hz, 4H), 2.52 (t, J = 6.1 Hz, 4H), 2.74 (t, J = 6.0 Hz, 4H), 3.54 (s, 4H), 3.71 (t, J = 6.0 Hz, 4H), 3.79 (t, J = 7.6 Hz, 4H), 6.38 (t, J = 4.7 Hz, 2H), 7.14 (d, J = 8.2 Hz, 4H), 7.32 (d, J = 8.2 Hz, 4H), 8.18 (d, J = 4.7 Hz, 4H). 13C NMR (CDCl3): δ 26.0 (2C), 46.9 (2C), 47.5 (2C), 52.0 (2C), 52.5 (2C), 60.0 (2C), 109.0 (2C), 120.5 (2C), 130.7 (4C), 131.0 (4C), 138.5 (2C), 157.4 (4C), 161.3 (2C). HRMS (MALDI-TOF) m/z calcd for C32H39Br2N8 [M+H]+ 693.1664, found 693.1690.

1,8-Bis(4-bromobenzyl)-4-pyrimidin-2-yl-1,4,8,11-tetraazacyclotetradecane (19) was obtained as the second product in the synthesis of compound 18. Eluent CH2Cl2-MeOH 10:1. Yield 253 mg (20%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.60 (bs, 2H), 1.79 (bs, 2H), 2.36 (bs, 2H), 2.52-2.63 (m, 8H), 2.76 (bs, 2H), 3.34 (s, 2H), 3.50 (bs, 2H), 3.51 (s, 2H), 3.58 (t, J = 6.6 Hz, 2H), 6.27 (t, J = 4.4 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 4.4 Hz, 2H), NH proton was not assigned. 13C NMR (CDCl3): δ 25.9, 26.2, 45.9, 46.1, 47.1, 47.4, 50.7, 51.1, 52.5, 53.1, 57.7, 59.5, 108.7, 120.3, 121.0, 130.6, 130.8 (2C), 131.2, 137.7, 137.8, 157.2 (2C), 160.8. HRMS (MALDI-TOF) m/z calcd for C28H37Br2N6 [M+H]+ 615.1446, found 615.1429.

Typical procedure for the synthesis of macrobicycles 20a,c,d, 22a-d, 24d, 26a,c,d, 28a,b, 30a and macropolycycles 21a,c,d, 23a-d, 26a,c,d, 27a,c,d, 29a,b, 31a.
A two-neck flask (15 mL) flushed with dry argon, equipped with a magnetic stirrer and condenser was charged with cyclen or cyclam derivatives 14-19 (1) (0.1 - 0.22 mmol), Pd(dba)2 (16 mol%), BINAP (18 mol%), absolute dioxane was added to make 0.02 M concentration of the starting compounds. The mixture was stirred for 2 min, then appropriate amine 2a-d (0.1 - 0.22 mmol) was added followed by sodium tert-butoxide (0.3 – 0.66 mmol). The reaction mixture was refluxed for 24-30 h, after cooling to room temperature the residue was filtered off, dioxane evaporated in vacuo, and the residue was analyzed by NMR spectroscopy. Column chromatography was carried out using a sequence of eluents: CH2Cl2, CH2Cl2-MeOH 50:1 – 3:1, CH2Cl2-MeOH-NH3aq 100:20:1 – 10:4:1.

32,37-Dipyrimidin-2-yl-12,15,18-trioxa-1,8,22,29,32,37-hexaazatetracyclo-
[27.5.5.13,7.123,27]hentetraconta-3(41),4,6,23(40),24,26-hexaene (20a) was synthesized from compound 14 (0.12 mmol, 78 mg), trioxadiamine 2a (0.12 mmol, 26 mg), in the presence of Pd(dba)2 (11 mg), BINAP (13 mg), tBuONa (35 mg), in dioxane (5 mL). Eluent CH2Cl2-MeOH 10:1. Yield 25 mg (29%), pale-yellow crystalline powder, mp 134-135 oC. 1H NMR (CDCl3): δ 1.77 (bs, 4H), 3.10 (bs, 4H), 3.28 (bs, 4H), 3.38 (bs, 4H), 3.56 (t, J = 5.3Hz, 4H), 3.59-3.63 (m, 8H), 3.66-3.70 (m, 4H), 3.80 (bs, 4H), 3.89 (bs, 4H), 6.44 (bs, 4H), 6.48 (bs, 4H), 7.00 (bs, 2H), 8.18 (bs, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 28.8 (2C), 41.2 (2C), 47.2 (bs, 4C), 53.0 (4C), 59.2 (2C), 69.5 (2C), 70.0 (2C), 70.5 (2C), 110.8 (2C), 112.1 (bs, 2C), 115.3 (bs, 2C), 118.6 (2C), 129.1 (2C), 149.0 (2C), 157.4 (4C), 162.0 (2C), two aromatic quaternary carbon atoms were not assigned. HRMS (MALDI-TOF) m/z calcd for C40H57N10O3 [M+H]+ 725.4615, found 725.4589.

32,66,71,78-Tetrapyrimidin-2-yl-12,15,18,46,49,52-hexaoxa-1,8,22,29,32,35,42,
56,63,66,71,78-dodecaazaheptacyclo[61.5.5.529,35.13,7.123,27.137,41.157,61]-
dooctaconta-3(82),4,6,23(81),24,26,37(75),38,40,57(74),58,60-dodecaene (21a) was obtained as the second product in the synthesis of macrobicycle 20a. Eluent CH2Cl2-MeOH 3:1. Yield 12 mg (14%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.84 (bs, 8H), 3.13 (t, J = 5.4 Hz, 8H), 3.23 (bs, 16H), 3.50-3.70 (m, 32H), 3.85 (bs, 16H), 4.37 (bs, 4H), 6.39 (t, J = 4.8 Hz, 4H), 6.42-6.51 (m, 12H), 7.02 (t, J = 7.7 Hz, 4H), 8.11 (d, J = 4.8 Hz, 8H). HRMS (MALDI-TOF) m/z calcd for C80H113N20O6 [M+H]+ 1449.9152, found 1449.9107.

27,32-Dipyrimidin-2-yl-11,14-dioxa-1,8,17,24,27,32-hexaazatetracyclo-
[22.5.5.13,7.118,22]hexatriaconta-3(36),4,6,18(35),19,21-hexaene (20c) was synthesized from compound 14 (0.17 mmol, 114 mg), dioxadiamine 2c (0.17 mmol, 25 mg), in the presence of Pd(dba)2 (16 mg), BINAP (19 mg), tBuONa (50 mg), in dioxane (7 mL). Eluent CH2Cl2-MeOH 10:1. Yield 34 mg (31%), pale-yellow crystalline powder, mp 167-168 oC. 1H NMR (CDCl3): δ 3.08 (bs, 4H), 3.20-3.45 (m, 8H), 3.68 (s, 4H), 3.71 (bs, 8H), 3.60-4.05 (m, 8H), 4.20 (bs, 2H), 6.35 (bs, 2H), 6.41-6.48 (m, 4H), 6.58 (s, 2H), 6.91 (bs, 2H), 8.28 (bs, 4H). 13C NMR (CDCl3): δ 43.4 (2C), 45.1 (bs, 4C), 53.1 (bs, 4C), 57.0 (bs, 2C), 69.1 (bs, 2C), 70.1 (2C), 111.0 (2C), 112.2 (2C), 116.1 (2C), 118.7 (2C), 129.6 (2C), 148.9 (2C), 157.6 (4C), 162.0 (2C), two aromatic quaternary carbon atoms were not assigned. HRMS (MALDI-TOF) m/z calcd for C36H49N10O2 [M+H]+ 653.4040, found 653.4006.

27,56,61,68-Tetrapyrimidin-2-yl-11,14,40,43-tetraoxa-1,8,17,24,27,30,37,46,53,56,
61,68-dodecaazaheptacyclo[51.5.5.524,30.13,7.118,22.132,36.147,51]doheptaconta-3(72),4,6,18(71),19,21,32(65),33,35,47(64),48,50-dodecaene (21c) was obtained as the second product in the synthesis of macrobicycle 20c. Eluent CH2Cl2-MeOH 3:1. Yield 19 mg (17%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 3.00-3.27 (m, 16H), 3.24 (bs, 8H), 3.63 (s, 8H), 3.68 (bs, 16H), 3.86 (bs, 16H), 4.46 (bs, 4H), 6.39-6.51 (m, 12H), 6.63 (s, 4H), 6.99 (bs, 4H), 8.08 (bs, 8H). 13C NMR (CDCl3): δ 43.4 (4C), 46.1 (bs, 8C), 52.6 (bs, 8C), 56.7 (bs, 4C), 69.6 (4C), 70.1 (4C), 110.8 (4C), 113.0 (bs, 4C), 116.8 (bs, 4C), 120.2 (bs, 4C), 129.1 (4C), 148.6 (4C), 157.4 (8C), 161.5 (4C), for aromatic quaternary carbon atoms were not assigned. HRMS (MALDI-TOF) m/z calcd for C72H97N20O4 [M+H]+ 1305.8002, found 1304.7953.

30,62,67,74-Tetrapyrimidin-2-yl-1,8,12,16,20,27,30,33,40,44,48,52,59,62,67,74-hexadecaazaheptacyclo[57.5.5.527,33.13,7.121,25.135,39.153,57]octaheptaconta-
3(78),4,6,21(77),22,24,35(71),36,38,53(70),54,56-dodecaene (21d) was obtained as the second product in the synthesis of macrobicycle 20d. Eluent CH2Cl2-MeOH-NH3aq 100:25:5. Yield 17 mg (17%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.64-1.76 (m, 12H), 2.67 (bs, 16H), 2.79 (bs, 16H), 3.02 (bs, 8H), 3.60 (s, 8H), 3.74 (bs, 16H), 6.26 (t, J = 3.7 Hz, 4H), 6.33 (d, J = 7.6 Hz, 4H), 6.42 (s, 4H), 6.51 (d, J = 7.1 Hz, 4H), 6.92 (t, J = 7.5 Hz, 4H), 8.07 (d, J = 3.7 Hz, 8H), NH protons were not assigned. HRMS (MALDI-TOF) m/z calcd for C78H113N24 [M+H]+ 1385.9580, found 1385.9644.

30,35-Dipyrimidin-2-yl-11,14,17-trioxa-1,7,21,27,30,35-hexaazatetracyclo-
[25.5.5.23,6.222,25]hentetraconta-3,5,22,24,38,40-hexaene (22a) was synthesized from compound 17 (0.15 mmol, 100 mg), trioxadiamine 2a (0.15 mmol, 33 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH 10:1 – 3:1. Yield 21 mg (19%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.87 (quintet, J = 5.8 H, 4H), 2.67-2.82 (m, 4H), 2.84 (t, J = 4.7 Hz, 4H), 3.23 (t, J = 6.1 Hz, 4H), 3.55 (s, 4H), 3.59-3.72 (m, 20H), 6.37 (t, J = 4.7 Hz, 2H), 6.51 (d, J = 8.2 Hz, 4H), 7.15 (d, J = 8.2 Hz, 4H), 8.19 (d, J = 5.7 H, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 29.1 (2C), 42.4 (2C), 48.1 (4C), 53.7 (4C), 60.0 (2C), 70.1 (2C), 70.2 (2C), 70.7 (2C), 109.0 (2C), 112.3 (4C), 127.7 (2C), 130.6 (4C), 148.0 (2C), 157.2 (4C), 162.0 (2C). HRMS (MALDI-TOF) m/z calcd for C40H57N10O3 [M+H]+ 725.4615, found 725.4651.

30,63,68,77-Tetrapyrimidin-2-yl-11,14,17,43,46,50-hexaoxa-1,7,21,27,30,33,39,54,
60,63,68,77-dodecaazaheptacyclo[58.5.5.527,33.23,6.222,25.235,38.255,58]-
trioctaconta-3,5,22,24,35,37,55,57,71,73,80,82-dodecaene (23a, n=1) was obtained as the second product in the synthesis of macrobicycle 22a. Eluent CH2Cl2-MeOH 3:1. Yield 22 mg (20%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.86 (quintet, J = 5.8 Hz, 8H), 2.79 (bs, 8H), 2.88 (bs, 8H), 3.15 (t, J = 6.8 Hz, 8H), 3.53-3.76 (m, 48H), 6.26 (t, J = 4.7 Hz, 4H), 6.44 (d, J = 8.1 Hz, 8H), 7.03 (d, J = 8.1 Hz, 8H), 8.07 (d, J = 4.7 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 29.0 (4C), 41.7 (4C), 47.1 (8C), 54.1 (8C), 59.7 (4C), 69.7 (4C), 70.2 (4C), 70.6 (4C), 108.6 (4C), 112.2 (8C), 127.6 (4C), 130.5 (8C), 147.4 (4C), 157.1 (8C), 161.6 (4C). HRMS (MALDI-TOF) m/z calcd for C80H113N20O6 [M+H]+ 1449.9152, found 1449.9208.

Cyclic trimer (23a, n=2) was was obtained as the third product in the synthesis of macrobicycle 22a. Eluent CH2Cl2-MeOH 3:1. Yield 26 mg (23%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.83 (quintet, J = 5.8 Hz, 12H), 2.77 (bs, 24H), 3.13 (t, J = 6.3 Hz, 12H), 3.52-3.60 (m, 36H), 3.62-3.66 (m, 12H), 3.71 (bs, 24H), 6.27 (t, J = 4.5 Hz, 6H), 6.38 (d, J = 8.1 Hz, 12H), 6.95 (d, J = 8.1 Hz, 12H), 8.10 (d, J = 4.5 Hz, 12H), NH protons were not assigned. 13C NMR (CDCl3): δ 29.1 (6C), 41.7 (6C), 46.4 (12C), 53.8 (12C), 59.3 (6C), 69.7 (6C), 70.2 (6C), 70.6 (6C), 108.6 (6C), 112.2 (12C), 127.6 (6C), 130.3 (12C), 147.2 (6C), 57.1 (12C), 161.6 (6C). MS (MALDI-TOF) m/z calcd for C120H169N30O9 [M+H]+ 2174.37, found 2174.45.

29,34-Dipyrimidin-2-yl-11,16-dioxa-1,7,20,26,29,34-hexaazatetracyclo-
[24.5.5.23,6.221,24]tetraconta-3,5,21,23,37,39-hexaene (22b) was synthesized from compound 17 (0.15 mmol, 100 mg), dioxadiamine 2b (0.15 mmol, 31 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH-NH3aq 100:20:1. Yield 9 mg (8%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.70 (bs, 4H), 1.87 (quintet, J = 5.7 Hz, 4H), 2.90 (bs, 8H), 3.21 (t, J = 5.4 Hz, 4H), 3.45 (bs, 4H), 3.56 (t, J = 5.3 Hz, 4H), 3.58 (bs, 4H), 3.67 (bs, 8H), 6.37 (t, J = 4.4 Hz, 2H), 6.49 (bs, 4H), 7.14 (bs, 4H), 8.18 (d, J = 4.4 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 26.9 (2C), 29.4 (2C), 42.8 (2C), 48.0 (bs, 4C), 53.4 (bs, 4C), 59.6 (bs, 2C), 70.1 (2C), 71.1 (2C), 109.2 (2C), 112.3 (4C), 130.7 (4C), 147.8 (2C), 157.2 (4C), 162.0 (2C), two quaternary aromatic carbons were not assigned. HRMS (MALDI-TOF) m/z calcd for C40H57N10O2 [M+H]+ 709.4666, found 709.4644.

29,60,65,74-Tetrapyrimidin-2-yl-11,16,42,47-tetraoxa-1,7,20,26,29,32,38,51,57,60,
65,74-dodecaazaheptacyclo[55.5.5.526,32.23,6.221,24.234,37.252,55]octaconta-
3,5,21,23,34,36,52,54,68,70,77,79-dodecaene (23b, n=1) was obtained as the second product in the synthesis of macrobicycle 22b. Eluent CH2Cl2-MeOH-NH3aq 100:20:2. Yield 33 mg (31%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (bs, 8H), 1.83 (quintet, J = 5.8 Hz, 8H), 2.77 (bs, 16H), 3.14 (t, J = 6.5 Hz, 8H), 3.41-3.46 (m, 8H), 3.51 (t, J = 5.7 Hz, 8H), 3.57 (bs, 8H), 3.72 (bs, 16H), 6.27 (t, J = 4.5 Hz, 4H), 6.38 (d, J = 8.0 Hz, 8H), 6.96 (d, J = 8.0 Hz, 8H), 8.10 (d, J = 4.5 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 26.5 (4C), 29.4 (4C), 42.0 (4C), 46.5 (8C), 53.8 (8C), 59.3 (4C), 69.4 (4C), 70.8 (4C), 108.6 (4C), 112.2 (8C), 127.3 (4C), 130.3 (8C), 147.2 (4C), 157.1 (8C), 161.6 (4C). HRMS (MALDI-TOF) m/z calcd for C80H113N20O4 [M+H]+ 1417.9254, found 1417.9197.

25,30-Dipyrimidin-2-yl-10,13-dioxa-1,7,16,22,25,30-hexaazatetracyclo-
[20.5.5.23,6.217,20]hexatriaconta-3,5,17,19,33,35-hexaene (22c) was synthesized from compound 17 (0.15 mmol, 100 mg), dioxadiamine 2c (0.15 mmol, 22 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH 3:1. Yield 16 mg (16%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 2.95 (bs, 4H), 3.20 (t, J = 5.0 Hz, 4H), 3.30 (bs, 4H), 3.47 (bs, 4H), 3.63 (bs, 4H), 3.66 (s, 4H), 3.71 (t, J = 5.0 Hz, 4H), 3.92 (bs, 4H), 6.31 (bs, 4H), 6.44 (t, J = 4.6 Hz, 2H), 7.11 (bs, 4H), 8.18 (d, J = 4.6 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 43.5 (2C), 48.6 (bs, 4C), 51.4 (bs, 4C), 58.7 (bs, 2C), 69.5 (2C), 70.1 (2C), 110.1 (2C), 112.4 (4C), 127.7 (2C), 131.8 (4C), 147.6 (2C), 157.1 (4C), 162.0 (2C). HRMS (MALDI-TOF) m/z calcd for C36H49N10O2 [M+H]+ 653.4040, found
653.4081.

25,52,57,66-Tetrapyrimidin-2-yl-10,13,37,40-tetraoxa-1,7,16,22,25,28,34,43,49,
52,57,66-dodecaazaheptacyclo[47.5.5.522,28.23,6.217,20.230,33.244,47]-
doheptaconta-3,5,17,19,30,32,44,46,60,62,69,71-dodecaene (23c, n=1) was obtained as the second product in the synthesis of macrobicycle 22b. Eluent CH2Cl2-MeOH-NH3aq 100:20:1. Yield 3 mg (3%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 2.85 (bs, 16H), 3.23 (bs, 8H), 3.64 (s, 8H), 3.67 (s, 8H), 3.68-3.82 (m, 24H), 6.31 (t, J = 4.7 Hz, 4H), 6.42 (d, J = 8.1 Hz, 8H), 7.04 (d, J = 8.1 Hz, 8H), 8.07 (d, J = 4.7 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 43.6 (4C), 46.3 (8C), 53.4 (8C), 58.9 (4C), 69.7 (4C), 70.2 (4C), 108.9 (4C), 112.7 (8C), 131.4 (8C), 157.2 (8C), aromatic quaternary carbons were not assigned. HRMS (MALDI-TOF) m/z calcd for C72H97N20O4 [M+H]+ 1305.8002, found 1304.7962.

Cyclic trimer 23c (n=2) and cyclic tertramer 23c (n=3) were obtained as a separate fraction in the synthesis of macrobicycle 22c. Eluent CH2Cl2-MeOH-NH3aq 100:20:2. Yield 41 mg (41%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 2.79 (bs, 8(n+1)H), 3.22 (t, J = 4.4 Hz, 4(n+1)H), 3.60 (bs, 4(n+1)H), 3.63 (s, 4(n+1)H), 3.66 (t, J = 4.4 Hz, 4(n+1)H), 3.71 (bs, 8(n+1)H), 6.28 (t, J = 4.6 Hz, 2(n+1)H), 6.41 (d, J = 7.9 Hz, 4(n+1)H), 6.97 (d, J = 7.9 Hz, 4(n+1)H), 8.09 (d, J = 4.6 Hz, 4(n+1)H), NH protons were not assigned. 13C NMR (CDCl3): δ 43.6 (2(n+1)C), 46.5 (4(n+1)C), 53.7 (bs, 4(n+1)C), 59.2 (bs, 2(n+1)C), 69.6 (2(n+1)C), 70.2 (2(n+1)C), 108.7 (2(n+1)C), 112.6 (4(n+1)C), 127.6 (2(n+1)C), 130.4 (4(n+1)C), 146.9 (2(n+1)C), 157.2 (4(n+1)C), 161,6 (2(n+1)C). MS (MALDI-TOF) m/z calcd for C108H145N30O6 [M+H]+ 1958.20, found 1958.15 (23c (n=2)); calcd for C144H193N40O8 [M+H]+ 2610.59, found 2610.48 (23c (n=3).

28,33-Dipyrimidin-2-yl-1,7,11,15,19,25,28,33-octaazatetracyclo[23.5.5.23,6.220,23]-
nonatriaconta-3,5,20,22,36,38-hexaene (22d) was synthesized from compound 17 (0.15 mmol, 100 mg), tetraamine 2d (0.15 mmol, 28 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH-NH3aq 100:20:3. Yield 17 mg (16%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.72-1.82 (m, 6H), 2.76 (t, J = 6.4 Hz, 4H), 2.77 (t, J = 6.5 Hz, 4H), 2.84 (t, J = 4.7 Hz, 8H), 3.18 (t, J = 6.1 Hz, 4H), 3.53 (s, 4H), 3.66 (t, J = 4.7 Hz, 8H), 6.37 (t, J = 4.8 Hz, 2H), 6.49 (d, J = 8.2 Hz, 4H), 7.18 (d, J = 8.2 Hz, 4H), 8.18 (d, J = 4.7 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 28.4 (2C), 29.8 (1C), 43.5 (2C), 48.3 (2C), 48.4 (4C), 48.5 (2C), 53.9 (4C), 59.9 (2C), 109.1 (2C), 112.4 (4C), 127.6 (2C), 130.5 (4C), 147.6 (2C), 157.2 (4C), 162.0 (2C). HRMS (MALDI-TOF) m/z calcd for C39H57N12 [M+H]+ 693.4829, found 693.4788.

28,58,63,72-Tetrapyrimidin-2-yl-1,7,11,15,19,25,28,31,37,41,45,49,55,58,63,72-hexadecaazaheptacyclo[53.5.5.525,31.23,6.220,23.233,36.250,53]octaheptaconta-3,5,20,22,33,35,50,52,66,68,75,77-dodecaene (23d, n=1) was obtained as the second product in the synthesis of macrobicycle 22d. Eluent CH2Cl2-MeOH-NH3aq 100:35:6. Yield 21 mg (20%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66-1.80 (m, 12H), 2.65-2.79 (m, 32H), 3.08 (t, J = 6.1 Hz, 8H), 3.55 (s, 8H), 3.70 (bs, 16H), 6.26 (t, J = 4.5 Hz, 4H), 6.39 (d, J = 8.0 Hz, 8H), 6.96 (d, J = 8.0 Hz, 8H), 8.09 (d, J = 4.5 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 28.7 (4C), 29.8 (2C), 42.9 (4C), 46.5 (8C), 48.7 (8C), 53.9 (8C), 59.4 (4C), 108.6 (4C), 112.3 (8C), 127.4 (4C), 130.3 (8C), 147.2 (4C), 157.2 (8C), 161.6 (4C). HRMS (MALDI-TOF) m/z calcd for C78H113N24 [M+H]+ 1385.9580, found 1385.9537.

32,67,73,81-Tetrapyrimidin-2-yl-12,15,18,47,50,53-hexaoxa-1,8,22,29,32,36,43,57,
64,67,73,81-dodecaazaheptacyclo[62.6.6.629,36.13,7.123,27.138,42.158,62]-
hexaoctaconta-3(86),4,6,23(85),24,26,38(78),39,41,58(77),59,61-dodecaene (25a, n=1) was synthesized from compound 15 (0.1 mmol, 69 mg), trioxadiamine 2a (0.1 mmol, 22 mg), in the presence of Pd(dba)2 (8 mg), BINAP (10 mg), tBuONa (30 mg), in dioxane (5 mL). Eluent CH2Cl2-MeOH 10:1. Yield 8 mg (13%), pale-yellow crystalline powder, mp 112-113 oC. 1H NMR (CDCl3): δ 1.78-1.94 (m, 16H), 2.52 (bs, 8H), 2.75 (bs, 8H), 3.17 (t, J = 5.8 Hz, 8H), 3.49-3.60 (m, 24H), 3.63 (s, 8H), 3.77 (bs, 16H), 6.34 (t, J = 4.3 Hz, 4H), 6.41 (bs, 4H), 6.55 (bs, 4H), 6.59 (d, J = 8.1 Hz, 4H), 7.01 (t, J = 7.8 Hz, 4H), 8.18 (d, J = 4.3 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (4C), 29.2 (4C), 41.6 (4C), 46.7 (bs, 4C), 47.2 (bs, 4C), 51.7 (bs, 4C), 51.9 (4C), 60.4 (4C), 69.6 (4C), 70.2 (4C), 70.6 (4C), 108.9 (4C), 111.1 (4C), 113.4 (4C), 117.9 (4C), 128.8 (4C), 148.4 (4C), 157.4 (8C), 161.5 (4C), four quaternary aromatic carbon atoms were not assigned. HRMS (MALDI-TOF) m/z calcd for C84H121N20O6 [M+H]+ 1505.9778, found 1505.9721.

Cyclic trimer (25a, n=2) was obtained as the second product in the synthesis of macrotricycle 25a (n=1). Eluent CH2Cl2-MeOH 10:3. Yield 8 mg (10%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.85 (quintet, J = 5.8 Hz, 12H), 1.89 (bs, 12H), 2.54 (bs, 12H), 2.79 (bs, 12H), 3.17 (t, J = 6.0 Hz, 12H), 3.46-3.61 (m, 36H), 3.63 (s, 12H), 3.76 (bs, 24H), 6.36 (t, J = 4.5 Hz, 6H), 6.43 (d, J = 6.8 Hz, 6H), 6.58 (s, 6H), 6.64 (d, J = 7.1 Hz, 6H), 7.03 (t, J = 7.6 Hz, 6H), 8.19 (t, J = 4.5 Hz, 12H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (6C), 29.1 (6C), 41.6 (6C), 46.7 (bs, 12C), 51.6 (bs, 12C), 60.3 (6C), 69.6 (6C), 70.2 (6C), 70.5 (6C), 109.0 (6C), 111.2 (6C), 113.4 (6C), 117.9 (6C), 128.7 (6C), 148.4 (6C), 157.4 (12C), 161.5 (6C), six quaternary aromatic carbon atoms were not assigned. MS (MALDI-TOF) m/z calcd for C126H181N30O9 [M+H]+ 2258.46, found 2258.34.

27,57,63,71-Tetrapyrimidin-2-yl-11,14,41,44-tetraoxa-1,8,17,24,27,31,38,47,54,
57,63,71-dodecaazaheptacyclo[52.6.6.624,31.13,7.118,22.133,37.148,52]-
hexaheptaconta-3(76),4,6,18(75),19,21,33(68),34,36,48(67),49,51-dodecaene (25c, n=1) was synthesized from compound 15 (0.1 mmol, 69 mg), dioxadiamine 2c (0.1 mmol, 15 mg), in the presence of Pd(dba)2 (8 mg), BINAP (10 mg), tBuONa (30 mg), in dioxane (5 mL). Eluent CH2Cl2-MeOH 10:1. Yield 11 mg (16%), pale-yellow crystalline powder, mp 132-134 oC. 1H NMR (CDCl3): δ 1.87 (bs, 8H), 2.51 (bs, 8H), 2.73 (bs, 8H), 3.21 (t, J = 5.0 Hz, 8H), 3.51 (bs, 8H), 3.55 (s, 8H), 3.60 (s, 8H), 3.72 (t, J = 6.9 Hz, 8H), 3.77 (bs, 8H), 6.34 (t, J = 4.7 Hz, 4H), 6.41 (d, J = 7.6 Hz, 4H), 6.60 (d, J = 7.9 Hz, 4H), 6.62 (s, 4H), 7.00 (t, J = 7.6 Hz, 4H), 8.19 (d, J = 4.7 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (4C), 43.4 (4C), 47.0 (4C), 47.2 (4C), 51.8 (4C), 52.1 (4C), 60.5 (4C), 69.6 (4C), 70.1 (4C), 108.8 (4C), 111.5 (4C), 113.5 (4C), 118.3 (4C), 128.8 (4C), 140.5 (4C), 148.1 (4C), 157.4 (8C), 161.5 (4C). HRMS (MALDI-TOF) m/z calcd for C76H105N20O4 [M+H]+ 1361.8628, found 1361.8586.

29,35-Dipyrimidin-2-yl-1,7,11,15,19,26,29,35-octaazatetracyclo[24.6.6.23,6.120,24]-
hentetraconta-3,5,20(39),21,23,40-hexaene (24d) was synthesized from compound 15 (0.22 mmol, 153 mg), tetraamine 2d (0.22 mmol, 42 mg), in the presence of Pd(dba)2 (20 mg), BINAP (25 mg), tBuONa (64 mg), in dioxane (11 mL). Eluent CH2Cl2-MeOH-NH3aq 100:20:2-100:20:3. Yield 46 mg (29%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.72 (quintet, J = 5.8 Hz, 6H), 1.87 (bs, 4H), 2.52 (bs, 4H), 2.67-2.75 (m, 12H), 3.04 (t, J = 6.2 Hz, 4H), 3.48 (bs, 4H), 3.67 (bs, 4H), 3.82 (bs, 4H), 4.00 (bs, 2H), 6.33 (t, J = 4.7 Hz, 2H), 6.38 (d, J = 7.8 Hz, 2H), 6.60 (d, J = 7.9 Hz, 2H), 6.62 (s, 2H), 6.98 (t, J = 7.5 Hz, 2H), 8.17 (d, J = 4.7 Hz, 4H), two NH protons of dialkylamino groups were not assigned. 13C NMR (CDCl3): δ 26.1 (2C), 28.8 (3C), 43.0 (2C), 46.9 (2C), 47.3 (2C), 48.4 (2C), 48.8 (2C), 52.7 (2C), 54.2 (2C), 60.8 (2C), 108.7 (2C), 111.0 (2C), 113.2 (2C), 117.8 (2C), 128.7 (2C), 141.0 (2C), 148.6 (2C), 157.3 (4C), 161.6 (2C). HRMS (MALDI-TOF) m/z calcd for C41H61N12 [M+H]+ 721.5142, found 721.5167.

30,63,69,77-Tetrapyrimidin-2-yl-1,8,12,16,20,27,30,34,41,45,49,53,60,63,69,77-hexadecaazahepta-cyclo[58.6.6.627,34.13,7.121,25.136,40.154,58]dooctaconta-3(82),4,6,21(81),22,24,36(74),37,39,54(73),55,57-dodecaene (25d, n=1) was obtained as the second product in the synthesis of macrobicycle 24d. Eluent CH2Cl2-MeOH-NH3aq 100:20:3-100:35:6. Yield 15 mg (9%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (quintet, J = 6.5 Hz, 4H), 1.72 (quintet, J = 5.7 Hz, 8H), 2.50 (bs, 8H), 2.60-2.76 (m, 24H), 3.08 (t, J = 5.6 Hz, 8H), 3.51 (bs, 8H), 3.54 (s, 8H), 3.68-3.86 (m, 16H), 6.34 (t, J = 4.0 Hz, 4H), 6.39 (d, J = 7.6 Hz, 4H), 6.55 (d, J = 7.8 Hz, 4H), 6.59 (s, 4H), 7.00 (t, J = 7.7 Hz, 4H), 8.18 (d, J = 4.0 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.9 (4C), 29.3 (4C), 29.7 (2C), 42.6 (4C), 46.9 (4C), 47.4 (4C), 48.1 (4C), 48.5 (4C), 51.9 (4C), 52.2 (4C), 60.6 (4C), 108.8 (4C), 111.0 (4C), 113.1 (4C), 117.9 (4C), 128.8 (4C), 140.5 (4C), 148.4 (4C), 157.4 (8C), 161.6 (4C). HRMS (MALDI-TOF) m/z calcd for C82H121N24 [M+H]+ 1442.0206, found 1442.0269.

Cyclic trimer (25d, n=2) and cyclic tetramer (25d, n=3) were obtained as a separate fraction in the synthesis of macrobicycle 24d. Eluent CH2Cl2-MeOH-NH3aq 100:35:6. Yield 9 mg (6%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (quintet, J = 7.0 Hz, 2(n+1)H), 1.73 (bs, 4(n+1)H), 1.86 (bs, 4(n+1)H), 2.50 (bs, 4(n+1)H), 2.60-2.78 (m, 12(n+1)H), 3.10 (bs, 4(n+1)H), 3.54 (s, 4(n+1)H), 3.71-3.84 (m, 8(n+1)H), 6.34 (bs, 2(n+1)H), 6.40 (d, J = 7.1 Hz, 2(n+1)H), 6.54 (s, 2(n+1)H), 6.61 (d, J = 7.2 Hz, 2(n+1)H), 7.02 (t, J = 7.4 Hz, 2(n+1)H), 8.18 (d, J = 4.1 Hz, 4(n+1)H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2(n+1)C), 29.5 (2(n+1)C), 30.2 ((n+1)C), 42.7 (2(n+1)C), 46.8 (2(n+1)C), 47.3 (2(n+1)C), 48.3 (2(n+1)C), 48.4 (2(n+1)C), 51.8 (2(n+1)C), 51.9 (2(n+1)C), 60.6 (2(n+1)C), 108.8 (2(n+1)C), 111.0 (2(n+1)C), 113.3 (2(n+1)C), 117.8 (2(n+1)C), 128.8 (2(n+1)C), 140.5 (2(n+1)C), 148.8 (2(n+1)C), 157.4 (4(n+1)C), 161.5 (2(n+1)C). MS (MALDI-TOF) m/z calcd for C123H181N36 [M+H]+ 2162.53, found 2162.41 (25d (n=2)); calcd for C164H241N48 [M+H]+ 2883.03, found 2882.86 (25d (n=3).

37-Pyrimidin-2-yl-11,14,17-trioxa-1,7,21,28,31,37-hexaazatetracyclo-
[26.6.6.23,6.122,26]tritetraconta-3,5,22(41),23,25,42-hexaene (26a) was synthesized from compound 16 (0.18 mmol, 111 mg), trioxadiamine 2a (0.18 mmol, 40 mg), in the presence of Pd(dba)2 (17 mg), BINAP (20 mg), tBuONa (52 mg), in dioxane (7 mL). Eluent CH2Cl2-MeOH 10:1-3:1. Yield 37 mg (30%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.78 (quintet, J = 6.1 Hz, 2H), 1.84 (quintet, J = 6.0 Hz, 4H), 2.05 (bs, 2H), 2.48 (t, J = 5.2 Hz, 2H), 2.68 (bs, 2H), 2.77 (bs, 2H), 2.86 (bs, 2H), 2.95 (bs, 2H), 3.00 (bs, 2H), 3.12 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 6.3 Hz, 2H), 3.48 (s, 2H), 3.52 (s, 2H), 3.53-3.60 (m, 8H), 3.62-3.66 (m, 4H), 3.70 (bs, 2H), 3.93 (bs, 2H), 6.43 (t, J = 4.9 Hz, 1H), 6.46 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 6.78 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 8.24 (d, J = 4.9 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 23.6, 25.7, 28.9, 29.0, 41.4 (2C), 43.8, 46.1, 46.4, 49.4, 50.1, 51.6, 52.7, 53.8, 58.6, 60.3, 69.4, 69.5, 70.1, 70.2, 70.6 (2C), 109.1, 110.7, 110.9, 114.4, 114.9, 117.7, 118.1, 129.1 (2C), 137.9 (2C), 149.0, 149.2, 157.6 (2C), 161.6. HRMS (MALDI-TOF) m/z calcd for C38H59N8O3 [M+H]+ 675.4710, found 675.4729.

31,72-Dipyrimidin-2-yl-11,14,17,46,49,52-hexaoxa-1,7,21,28,31,35,42,56,63,66,
72,80-dodecaazaheptacyclo[61.6.6.628,35.23,6.122,26.137,41.157,61]hexaoctaconta-
3,5,22(84),23,25,37(77),38,40,57(76),58,60,85-dodecaene (27a, n=1) was obtained as the second product in the synthesis of macrobicycle 26a. Eluent CH2Cl2-MeOH-NH3aq 100:20:1. Yield 8 mg (7%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.68 (bs, 4H), 1.75 (bs, 4H), 1.83 (quintet, J = 5.8 Hz, 8H), 2.44 (bs, 4H), 2.62 (bs, 16H), 2.72 (bs, 4H), 3.10 (t, J = 6.3 Hz, 4H), 3.17 (t, J = 6.1 Hz, 4H), 3.42 (s, 4H), 3.49-3.60 (m, 20H), 3.63 (bs, 12H), 3.70 (bs, 4H), 6.29 (t, J = 4.6 Hz, 2H), 6.40-6.65 (m, 12H), 6.89 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.7 Hz, 2H), 8.11 (d, J = 4.6 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2C), 26.6 (2C), 29.1 (2C), 29.3 (2C), 41.4 (2C), 41.6 (2C), 45.8 (2C), 46.9 (2C), 47.0 (2C), 47.4 (2C), 51.0 (4C), 52.9 (2C), 53.5 (2C), 59.0 (2C), 60.5 (2C), 69.6 (4C), 70.2 (4C), 70.6 (4C), 108.4 (2C), 110.4 (2C), 111.4 (2C), 113.4 (2C), 113.6 (2C), 117.5 (2C), 118.0 (2C), 128.7 (2C), 129.0 (2C), 140.0 (2C), 140.1 (2C), 148.1 (2C), 148.5 (2C), 157.3 (4C), 161.0 (2C). HRMS (MALDI-TOF) m/z calcd for C76H117N16O6 [M+H]+ 1349.9342, found 1349.9301.

32-Pyrimidin-2-yl-10,13-dioxa-1,7,16,23,26,32-hexaazatetracyclo-
[21.6.6.23,6.117,21]octatriaconta-3,5,17(36),18,20,37-hexaene (26c) was synthesized from compound 16 (0.17 mmol, 103 mg), dioxadiamine 2c (0.17 mmol, 25 mg), in the presence of Pd(dba)2 (16 mg), BINAP (19 mg), tBuONa (52 mg), in dioxane (7 mL). Eluent CH2Cl2-MeOH 10:1-3:1. Yield 30 mg (29%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.92 (quintet, J = 5.2 Hz, 4H), 2.49 (bs, 4H), 2.77 (bs, 8H), 3.20 (t, J = 5.0 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 3.49 (bs, 4H), 3.68 (bs, 10H), 3.83 (t, J = 4.9 Hz, 2H), 6.43-6.53 (m, 5H), 6.61 (bs, 1H), 7.03 (bs, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 8.26 (d, J = 4.8 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 22.8, 26.2, 43.8, 44.1, 45.8 (2C), 48.9, 50.4, 51.0, 51.4, 53.4, 54.3, 59.6 (2C), 69.1, 69.6, 70.2, 70.3, 109.6, 111.0, 111.1, 115.9, 116.8, 118.2, 118.7, 129.2, 129.3, 135.8, 136.6, 148.9, 149.4, 157.7 (2C), 161.6. HRMS (MALDI-TOF) m/z calcd for C34H51N8O2 [M+H]+ 603.4135, found 603.4112.

26,62-Dipyrimidin-2-yl-10,13,40,43-tetraoxa-1,7,16,23,26,30,37,46,53,56,62,70-dodecaazaheptacyclo[51.6.6.623,30.23,6.117,21.132,36.147,51]hexaheptaconta-3,5,17(74),18,20,32(67),33,35,47(66),48,50,75-dodecaene (27c, n=1) was obtained as the second product in the synthesis of macrobicycle 26c. Eluent CH2Cl2-MeOH-NH3aq 100:20:2. Yield 8 mg (8%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.67 (bs, 4H), 1.75 (bs, 4H), 2.43 (bs, 4H), 2.62 (bs, 16H), 2.72 (bs, 4H), 3.20 (t, J = 4.6 Hz, 4H), 3.26 (bs, 4H), 3.41 (s, 4H), 3.48-3.72 (m, 28H), 6.36 (t, J = 4.8 Hz, 2H), 6.44-6.59 (m, 8H), 6.61 (d, J = 7.5 Hz, 4H), 6.92 (t, J = 7.7 Hz, 2H), 7.05 (t, J = 7.8 Hz, 2H), 8.21 (d, J = 4.8 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2C), 26.5 (2C), 43.4 (4C), 45.8 (2C), 46.4 (2C), 46.9 (2C), 47.4 (2C), 51.0 (2C), 51.7 (2C), 52.9 (2C), 53.4 (2C), 59.0 (2C), 60.3 (2C), 69.6 (2C), 69.7 (2C), 70.2 (4C), 108.4 (2C), 110.9 (2C), 111.7 (2C), 113.8 (2C), 114.1 (2C), 118.1 (2C), 128.7 (2C), 129.1 (2C), 140.0 (4C), 147.8 (2C), 148.2 (2C), 157.5 (4C), 161.1 (2C). HRMS (MALDI-TOF) m/z calcd for C68H101N16O4 [M+H]+ 1205.8192, found 1205.8134.

35-Pyrimidin-2-yl-1,7,11,15,19,26,29,35-octaazatetracyclo[24.6.6.23,6.120,24]-
hentetraconta-3,5,20(39),21,23,40-hexaene (26d) was synthesized from compound 16 (0.15 mmol, 93 mg), tetraamine 2d (0.15 mmol, 28 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH-NH3aq 100:20:3. Yield 23 mg (24%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.62-1.80 (m, 10H), 2.43 (bs, 2H), 2.52-2.80 (m, 18H), 3.04 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.1 Hz, 2H), 3.49 (s, 2H), 3.53 (s, 2H), 3.78 (bs, 4H), 6.30 (t, J = 4.8 Hz, 1H), 6.40-6.67 (m, 6H), 7.05 (t, J = 7.1 Hz, 2H), 8.17 (d, J = 4.8 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 24.9, 27.2, 28.6, 29.0, 29.7, 42.6, 43.0, 45.2, 45.7, 45.9, 48.0, 48.2, 48.4, 49.3 (2C), 51.2, 52.9, 53.2, 54.0, 60.1, 60.7, 108.5, 110.6, 111.2, 113.6, 113.9, 117.8, 118.2, 128.9, 129.0, 140.1, 140.2, 148.7, 148.8, 157.4 (2C), 161.3. HRMS (MALDI-TOF) m/z calcd for C37H59N10 [M+H]+ 643.4924, found 643.4892.

29,68-Dipyrimidin-2-yl-1,7,11,15,19,26,29,33,40,44,48,52,59,62,68,76-hexadecaazaheptacyclo[57.6.6.626,33.23,6.120,24.135,39.153,57]dooctaconta-3,5,20(80),21,23,35(73),36,38,53(72),54,56,81dodecaene (27d, n=1) was obtained as the second product in the synthesis of macrobicycle 26d. Eluent CH2Cl2-MeOH-NH3aq 100:35:6. Yield 28 mg (29%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.62-1.80 (m, 20H), 2.43 (bs, 4H), 2.52-2.80 (m, 36H), 3.05 (t, J = 5.9 Hz, 4H), 3.09 (t, J = 6.0 Hz, 4H), 3.42 (s, 4H), 3.53 (s, 4H), 3.62 (bs, 4H), 3.70 (bs, 4H), 6.27 (bs, 2H), 6.43 (d, J = 5.8 Hz, 4H), 6.56 (d, J = 7.6 Hz, 4H), 6.63 (bs, 4H), 6.89 (t, J = 7.5 Hz, 2H), 7.04 (t, J = 7.7 Hz, 2H), 8.10 (bs, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 (2C), 26.9 (2C), 29.4 (4C), 30.2 (2C), 52.7 (2C), 42.8 (2C), 45.4 (2C), 45.7 (2C), 45.8 (2C), 48.3 (2C), 48.5 (4C), 49.1 (4C), 51.1 (2C), 52.8 (2C), 53.0 (2C), 54.1 (2C), 60.2 (2C), 60.6 (2C), 108.4 (2C), 110.5 (2C), 111.3 (2C), 111.4 (2C), 113.5 (2C), 117.8 (2C), 118.2 (2C), 128.7 (2C), 128.9 (2C), 140.2 (4C), 148.7 (4C), 157.3 (4C), 161.1 (2C). HRMS (MALDI-TOF) m/z calcd for C74H117N20 [M+H]+ 1285.9770, found 1285.9722.

Cyclic trimer (27d, n=2) and cyclic tetramer (27d, n=3) were obtained as a separate fraction in the synthesis of macrobicycle 26d. Eluent CH2Cl2-MeOH-NH3aq 10:4:1. Yield 12 mg (12%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.68 (bs, 4(n+1)H), 1.75 (bs, 6(n+1)H), 2.44 (bs 2(n+1)H), 2.62 (bs, 10(n+1)H), 2.66 (bs 4(n+1)H), 2.70 (bs, 4(n+1)H), 3.06 (bs, 2(n+1)H), 3.13 (bs, 2(n+1)H), 3.43 (s, 2(n+1)H), 3.53 (s, 2(n+1)H), 3.63 (bs, 2(n+1)H), 3.71 (bs, 2(n+1)H), 6.27 (bs, (n+1)H), 6.44 (bs, 2(n+1)H), 6.55 (d, J = 7.6 Hz, 2(n+1)H), 6.64 (d, J = 6.8 Hz, 2(n+1)H), 6.90 (t, J = 6.1 Hz, (n+1)H), 7.06 (t, J = 7.1 Hz, (n+1)H), 8.11 (bs, 2(n+1)H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 ((n+1)C), 26.9 ((n+1)C), 29.4 ((n+1)C), 29.7 (2(n+1)C), 42.6 ((n+1)C), 42.8 ((n+1)C), 45.9 (2(n+1)C), 47.6 ((n+1)C), 48.2-48.5 (m, 5(n+1)C), 51.1 (2(n+1)C), 53.0 ((n+1)C), 53.8 ((n+1)C), 59.1 ((n+1)C), 60.6 ((n+1)C), 108.4 ((n+1)C), 110.5 ((n+1)C), 111.5 ((n+1)C), 113.5 ((n+1)C), 113.6 ((n+1)C), 117.7 ((n+1)C), 118.1 ((n+1)C), 128.7 ((n+1)C), 129.0 ((n+1)C), 140.2 (2(n+1)C), 148.6 (2(n+1)C), 157.3 (2(n+1)C), 161.0 ((n+1)C). MS (MALDI-TOF) m/z calcd for C111H175N30 [M+H]+ 1928.46, found 1928.52 (27d (n=2)); calcd for C148H233N40 [M+H]+ 2570.95, found 2570.81 (27d (n=3).

30,36-Dipyrimidin-2-yl-11,14,17-trioxa-1,7,21,27,30,36-hexaazatetracyclo-
[25.6.6.23,6.222,25]tritetraconta-3,5,22,24,40,42-hexaene (28a) was synthesized from compound 18 (0.15 mmol, 104 mg), trioxadiamine 2a (0.15 mmol, 33 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH 10:1. Yield 7 mg (6%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.78-1.90 (m, 8H), 2.45-2.56 (m, 4H), 2.74 (bs, 4H), 3.18 (t, J = 5.1 Hz, 4H), 3.55-3.67 (m, 16H), 3.76 (bs, 8H), 6.34 (t, J = 4.8 Hz, 2H), 6.46 (d, J = 8.2 Hz, 4H), 7.07 (d, J = 8.2 Hz, 4H), 8.20 (d, J = 4.8 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 (2C), 29.2 (2C), 41.8 (2C), 46.8 (2C), 47.3 (2C), 51.9 (2C), 53.4 (2C), 59.9 (2C), 69.7 (2C), 70.2 (2C), 70.6 (2C), 108.8 (2C), 112.3 (4C), 128.0 (2C), 130.2 (4C), 148.9 (2C), 157.4 (4C), 161.5 (2C). HRMS (MALDI-TOF) m/z calcd for C42H61N10O3 [M+H]+ 753.4928, found 753.4950.

30,63,69,79-Tetrapyrimidin-2-yl-11,14,17,44,47,50-hexaoxa-1,7,21,27,30,34,40,
54,60,63,69,79-dodecaazaheptacyclo[58.6.6.627,34.23,6.222,25.236,39.255,58]-
hexaoctaconta-3,5,22,24,36,38,55,57,73,75,83,85-dodecaene (29a, n=1) was obtained as the second product in the synthesis of macrobicycle 28a. Eluent CH2Cl2-MeOH 10:1-3:1. Yield 22 mg (19%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.75-1.91 (m, 16H), 2.43-2.58 (m, 8H), 2.73 (bs, 8H), 3.16 (bs, 8H), 3.42-3.67 (m, 32H), 3.76 (bs, 16H), 6.34 (t, J = 4.6 Hz, 4H), 6.48 (d, J = 8.1 Hz, 8H), 7.08 (d, J = 8.1 Hz, 8H), 8.17 (d, J =4.6 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (4C), 29.1 (4C), 41.8 (4C), 46.8 (4C), 47.4 (4C), 51.5 (4C), 51.6 (4C), 59.8 (4C), 69.7 (4C), 70.2 (4C), 70.6 (4C), 108.7 (4C), 112.3 (8C), 128.0 (4C), 130.1 (8C), 147.4 (4C), 157.4 (8C), 161.4 (4C). HRMS (MALDI-TOF) m/z calcd for C84H121N20O6 [M+H]+ 1505.9778, found 1505.9834.

Cyclic trimer (29a, n=2) was obtained as the third product in the synthesis of macrobicycle 28a. Eluent CH2Cl2-MeOH 3:1. Yield 15 mg (13%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.75-1.91 (m, 24H), 2.43-2.58 (m, 12H), 2.73 (bs, 12H), 3.16 (bs, 12H), 3.42-3.67(m, 48H), 3.76 (bs, 24H), 6.34 (t, J = 4.6 Hz, 6H), 6.48 (d, J = 8.1 Hz, 12H), 7.08 (d, J = 8.1 Hz, 12H), 8.19 (d, J =4.6 Hz, 12H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 (6C), 29.1 (6C), 41.8 (6C), 46.8 (6C), 47.4 (6C), 51.5 (6C), 51.6 (6C), 59.9 (6C), 69.7 (6C), 70.2 (6C), 70.6 (6C), 108.7 (6C), 112.3 (12C), 128.0 (6C), 130.1 (12C), 147.4 (6C), 157.4 (12C), 161.4 (6C). MS (MALDI-TOF) m/z calcd for C126H181N30O9 [M+H]+ 2258.46, found 2258.37.

29,35-Dipyrimidin-2-yl-11,16-dioxa-1,7,20,26,29,35-hexaazatetracyclo-
[24.6.6.23,6.221,24]dotetraconta-3,5,21,23,39,41-hexaene (28b) was synthesized from compound 18 (0.15 mmol, 104 mg), dioxadiamine 2b (0.15 mmol, 31 mg), in the presence of Pd(dba)2 (14 mg), BINAP (17 mg), tBuONa (44 mg), in dioxane (7.5 mL). Eluent CH2Cl2-MeOH 10:1. Yield 6 mg (5%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.64-1.68 (m, 4H), 1.81-1.90 (m, 8H), 2.50 (bs, 4H), 2.74 (bs, 4H), 3.16 (t, J = 6.3 Hz, 4H), 3.40-3.45 (m, 4H), 3.52 (t, J = 5.6 Hz, 4H), 3.52 (s, 4H), 3.67-3.80 (m, 8H), 6.34 (t, J = 4.7 Hz, 2H), 6.46 (d, J = 8.1 Hz, 4H), 7.08 (d, J = 8.1 Hz, 4H), 8.19 (d, J = 4.7 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (2C), 26.5 (2C), 29.4 (2C), 42.0 (2C), 46.8 (2C), 47.2 (2C), 51.5 (2C), 52.2 (2C), 59.7 (2C), 69.4 (2C), 70.8 (2C), 108.8 (2C), 112.3 (4C), 127.4 (2C), 130.3 (4C), 147.5 (2C), 157.4 (4C), 161.5 (2C). HRMS (MALDI-TOF) m/z calcd for C42H61N10O2 [M+H]+ 737.4979, found 737.4960.

29,61,67,77-Tetrapyrimidin-2-yl-11,16,43,48-tetraoxa-1,7,20,26,29,33,39,52,58,61,
67,77-dodecaazaheptacyclo[56.6.6.626,33.23,6.221,24.235,38.253,56]tetraoctaconta-3,5,21,23,35,37,53,55,71,73,81,83-dodecaene (29b, n=1) was obtained as the second product in the synthesis of macrobicycle 28b. Eluent CH2Cl2-MeOH 3:1. Yield 15 mg (14%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (bs, 8H), 1.86 (bs, 16H), 2.51 (bs, 8H), 2.76 (bs, 8H), 3.17 (bs, 8H), 3.44 (bs, 8H), 3.48-3.60 (m, 16H), 3.68-3.80 (m, 16H), 6.35 (t, J = 4.1 Hz, 4H), 6.48 (d, J = 7.5 Hz, 8H), 7.09 (d, J = 7.5 Hz, 8H), 8.20 (d, J = 4.1 Hz, 8H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (4C), 26.5 (4C), 29.4 (4C), 42.0 (4C), 46.8 (4C), 47.2 (4C), 51.5 (4C), 51.7 (4C), 59.7 (4C), 69.4 (4C), 70.8 (4C), 108.8 (4C), 112.3 (8C), 127.4 (4C), 130.3 (8C), 147.5 (4C), 157.4 (8C), 161.5 (4C). HRMS (MALDI-TOF) m/z calcd for C84H121N20O4 [M+H]+ 1473.9880, found 1473.9843.

Cyclic trimer (29b, n=2) was obtained as the third product in the synthesis of macrobicycle 28b. Eluent CH2Cl2-MeOH 3:1. Yield 13 mg (12%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (bs, 12H), 1.86 (bs, 24H), 2.51 (bs, 12H), 2.76 (bs, 12H), 3.17 (bs, 12H), 3.44 (bs, 12H), 3.48-3.60 (m, 24H), 3.68-3.80 (m, 24H), 6.34 (t, J = 4.1 Hz, 6H), 6.48 (d, J = 7.5 Hz, 12H), 7.09 (d, J = 7.5 Hz, 12H), 8.18 (d, J = 4.1 Hz, 12H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (6C), 26.6 (6C), 29.4 (6C), 42.1 (6C), 46.8 (6C), 47.5 (6C), 51.5 (6C), 51.6 (6C), 59.9 (6C), 69.4 (6C), 70.8 (6C), 108.7 (6C), 112.3 (12C), 127.5 (6C), 130.1 (12C), 147.4 (6C), 157.4 (12C), 161.5 (6C). MS (MALDI-TOF) m/z calcd for C126H181N30O6 [M+H]+ 2210.48, found 2210.59.

30-Pyrimidin-2-yl-11,14,17-trioxa-1,7,21,27,30,36-hexaazatetracyclo-
[25.6.6.23,6.222,25]tritetraconta-3,5,22,24,40,42-hexaene (30a) was synthesized from compound 19 (0.17 mmol, 105 mg), trioxadiamine 2a (0.17 mmol, 37 mg), in the presence of Pd(dba)2 (16 mg), BINAP (19 mg), tBuONa (50 mg), in dioxane (8.5 mL). Eluent CH2Cl2-MeOH 10:1-3:1. Yield 35 mg (30%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.76 (bs, 2H), 1.83 (quintet, J = 6.0 Hz, 4H), 1.96 (bs, 2H), 2.50-2.58 (m, 4H), 2.72 (bs, 2H), 2.79 (bs, 2H), 2.91 (bs, 4H), 3.19 (t, J = 5.9 Hz, 2H), 3.20 (t, J = 6.2 Hz, 2H), 3.44 (s, 2H), 3.45 (s, 2H), 3.56 (t, J = 5.1 Hz, 4H), 3.56-3.60 (m, 4H), 3.61-3.65 (4H), 3.74 (bs, 2H), 3.87 (bs, 2H), 6.39 (t, J = 4.8 Hz, 1H), 6.50 (d, J = 8.1 Hz, 2H), 6.53 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 4.8 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 23.7 (1C), 25.6 (1C), 29.1 (2C), 41.9 (2C), 44.5 (1C), 46.0 (1C), 47.1 (1C), 49.2 (1C), 52.0 (1C), 52.1 (1C), 53.0 (1C), 53.7 (1C), 60.0 (2C), 69.7 (2C), 70.2 (2C), 70.5 (2C), 109.0 (1C), 112.6 (4C), 127.6 (2C), 130.4 (2C), 130.9 (2C), 148.0 (2C), 157.6 (2C), 161.6 (1C). HRMS (MALDI-TOF) m/z calcd for C38H59N8O3 [M+H]+ 675.4710, found 675.4737.

30,69-Dipyrimidin-2-yl-11,14,17,44,47,50-hexaoxa-1,7,21,27,30,34,40,54,60,63,
69,79-dodecaazaheptacyclo[58.6.6.627,34.23,6.222,25.236,39.255,58]hexaoctaconta-3,5,22,24,36,38,55,57,73,75,83,85-dodecaene (31a, n=1) was obtained as the second product in the synthesis of macrobicycle 30a. Eluent CH2Cl2-MeOH-NH3aq 100:20:1. Yield 7 mg (6%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (bs 4H), 1.77 (bs, 4H), 1.84 (quintet, J = 5.9 Hz, 8H), 2.43 (bs, 4H), 2.60-2.75 (m, 20H), 3.12 (bs, 4H), 3.19 (bs, 4H), 3.42 (s, 4H), 3.45 (s, 4H), 3.50-3.72 (m, 32H), 6.31 (2H, J = 4.7 Hz, 2H), 6.39 (d, J = 8.1 Hz, 4H), 6.52 (d, J = 8.0 Hz, 4H), 6.99 (d, J = 8.1 Hz, 4H), 7.05 (d, J = 8.0 Hz, 4H), 8.14 d (J = 4.7 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (2C), 26.4 (2C), 29.2 (4C), 41.8 (4C), 46.0 (4C), 46.8 (2C), 47.5 (2C), 50.8 (2C), 52.0 (2C), 52.5 (2C), 54.0 (2C), 58.9 (2C), 59.9 (2C), 69.5 (2C), 69.6 (2C), 70.2 (4C), 70.6 (4C), 108.3 (2C), 112.3 (4C), 112.5 (4C), 126.7 (2C), 127.1 (2C), 129.9 (4C), 130.1 (4C), 147.3 (2C), 147.5 (2C), 157.2 (4C), 161.1 (2C). HRMS (MALDI-TOF) m/z calcd for C76H117N16O6 [M+H]+ 1349.9342, found 1348.9390.

Cyclic trimer (31a, n=2) was obtained as the third product in the synthesis of macrobicycle 30a. Eluent CH2Cl2-MeOH-NH3aq 100:20:1. Yield 5 mg (4%), pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.66 (bs, 6H), 1.77 (bs, 6H), 1.83 (bs, 12H), 2.42 (bs, 6H), 2.55-2.68 (m, 24H), 2.72 (bs, 6H), 3.11 (t, J = 5.7 Hz, 6H), 3.18 (bs 6H), 3.38 (s, 6H), 3.52 (s, 6H), 3.53-3.80 (m, 48H), 6.26 (bs, 3H), 6.35 (d, J = 7.8 Hz, 6H), 6.52 (d, J = 7.3 Hz, 6H), 6.97 (d, J = 7.8 Hz, 6H), 7.06 (d, J = 7.3 Hz, 6H), 8.12 (bs, 6H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (3C), 26.5 (3C), 29.1 (6C), 41.7 (6C), 45.9 (6C), 46.9 (3C), 47.5 (3C), 50.7 (3C), 51.3 (3C), 52.4 (3C), 52.8 (3C), 58.3 (3C), 59.4 (3C), 69.7 (6C), 70.2 (6C), 70.6 (6C), 108.3 (3C), 112.2 (6C), 112.4 (6C), 127.0 (3C), 127.1 (3C), 129.9 (6C), 130.3 (6C), 147.1 (3C), 147.6 (3C), 157.2 (6C), 161.0 (3C). MS (MALDI-TOF) m/z calcd for C114H175N24O9 [M+H]+ 2024.40, found 2024.31.

Additional information (synthesis of compounds 4a and 5a)

32,37-Bis(6-chloropyrimidin-4-yl)-12,15,18-trioxa-1,8,22,29,32,37-
hexaazatetracyclo[27.5.5.13,7.123,27]hentetraconta-3(41),4,6,23(40),24,26-hexaene (4a).
A flask flushed with argon was charged with macrobicycle 3a (93 mg, 0.16 mmol), 2,4-dichloropyrimidine (95 mg, 0.64 mmol), dry acetonitrile (2 mL) and K2CO3 (84 mg). The reaction mixture was stirred at room temperature for 24 h, filtered, the residue was washed with CH2Cl2 (5 mL), combined organic fractions were evaporated in vacuo and chromatographed on silica gel. Eluent CH2Cl2-MeOH 20:1. Yield 63 mg (54%). Pale-yellow glassy solid. 1H NMR (CDCl3): δ 1.82 (quintet, J = 6.0 Hz, 4H), 2.87 (bs, 8H), 3.10 (bs, 4H), 3.47-3.64 (m, 20H), 3.66-3.71 (m, 4H), 6.35 (s, 2H), 6.42 (s, 2H), 6.43 (d, J = 7.8 Hz, 2H), 6.51 (d, J = 7.2 Hz, 2H), 7.02 (t, J = 7.5 Hz, 2H), 8.16 (s, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 29.1 (2C), 41.7 (2C), 48.7 (4C), 53.2 (4C), 60.5 (2C), 69.7 (2C), 70.2 (2C), 70.5 (2C), 101.9 (2C), 112.1 (2C), 112.8 (2C), 118.0 (2C), 129.0 (2C), 139.2 (2C), 148.6 (2C), 157.5 (2C), 159.0 (2C), 162.7 (2C). HRMS (MALDI-TOF) m/z calcd for C40H55Cl2N10O3 [M+H]+ 793.3835, found 793.3876.

1,7-Bis(3-bromobenzyl)-4,10-bis(6-chloropyrimidin-4-yl)-1,4,7,10-tetraazacyclododecane (5a). A flask flushed with argon was charged with N1,N7-bis(3-bromobenzyl)cyclen (1) (0.25 mmol, 128 mg), 2,4-dichloropyrimidine (89 mg, 0.6 mmol), dry acetonitrile (2.5 mL) and K2CO3 (138 mg). The reaction mixture was stirred at room temperature for 24 h, filtered, the residue was washed with CH2Cl2 (5 mL), combined organic fractions were evaporated in vacuo to dryness. Yield 121 mg (66%). Pale-beige crystals, mp 186-187 oC. 1H NMR (CDCl3): δ 2.80 (bs, 8H), 3.57 (bs, 8H), 3.68 (s, 4H), 6.27 (s, 2H), 7.08 (bs, 4H), 7.32 (bs, 4H), 8.14 (s, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 47.9 (4C), 53.5 (4C), 59.3 (2C), 101.6 (2C), 122.5 (2C), 127.6 (2C), 129.9 (2C), 130.5 (2C), 132.1 (2C), 140.5 (2C), 157.7 (2C), 159.5 (2C), 162.6 (2C). HRMS (MALDI-TOF) m/z calcd for C30H33Br2Cl2N8 [M+H]+ 733.0572, found 733.0549.

ACKNOWLEDGEMENT
This work was supported by RFBR grants N 09-03-00735, 08-03-00628, by the Russian Academy of Sciences program "Elaboration of the methods for the synthesis of chemical compounds and construction of new materials” and by the ARCUS project Bourgogne-Russie. The authors are grateful for CheMatech Co for a generous provision of cyclen and cyclam.

References

1. S. Huang, Z. Liu, P. A. Albaugh, X. Wang, S. Pan, Y. Xie, and G. Zhang, PCT Int. Appl. WO 2008157131, 2008 (Chem Abstr., 2009, 150, 295952).
2. P. Albaugh, G. S. Chopiuk, Q. Ding, S. Huang, Z. Liu, S. Pan, P. Ren, X. Wang, X. Wang, Y. Xie, C. Zhang, Q. D. Poon, P. Rehhove, and S. Paul, PCT Int. Appl. WO 2008042639, 2008 (Chem Abstr., 2008, 148, 449654).
3. G. Zhang, P. Ren, X. Wang, N. S. Gray, and T. Sim, PCT Int. Appl. WO 2007005673, 2007 (Chem. Abstr., 2007, 146, 142671).
4. P. Ren, X. Wang, G. Zhang, Q. Ding, S. You, Q. Zhang, G. Chopiuk, P. A. Albaugh, T. Sim, and N. S. Gray, PCT Int. Appl. WO 2005123719, 2005 (Chem. Abstr., 2006, 144, 88305).
5. I. Collins, J. C. Reader, T. P. Matthews, K. M. Cheung, N. Proisy, D. H. Williams, S. S. Klair, J. E. Scanlon, N. Piton, G. J. Addison, and M. Cherry, PCT Int. Appl. WO 2009044162, 2009 (Chem. Abstr., 2009, 150, 398578).
6. G. Zhang, P. Ren, N. S. Gray, T. Sim, Y. Liu, X. Wang, J. Che, S.-S. Tian, M. L. Sandberg, and T. A. Spalding, Bioorg. Med. Chem. Lett., 2008, 18, 5618. CrossRef
7. J. A. Maier, T. A. Brugel, M. Sabat, A. Golebiowski, M. J. Laufrsweiler, J. C. Van Rens, C. R. Hopkins, B. De, L. C. Hsieh, and K. K. Brown, Bioorg. Med. Chem. Lett., 2006, 16, 3646. CrossRef
8. F. Salituro, M. Lodeboer, B. Ledford, J. Wang, A. Pierce, J. Duffy, and D. Messerschmith, U.S. Pat. Appl. 2006063756, 2006 (Chem. Abstr., 2006, 144, 331443).
9. J. T. Sisko, T. J. Tucker, M. T. Bilodeau, C. A. Buser, P. A. Ciecko, K. E. Coll, C. Fernandes, J. B. Gibbs, T. J. Koester, N. Kohl, J. J. Lynch, X. Mao, D. McLoughlin, C. M. Miller-Stein, L. D. Rodman, K. W. Rickert, L. Sepp-Lorenzino, J. M. Shipman K. A. Thomas, B. K. Wong, and G. D. Hartman, Bioorg. Med. Chem. Lett., 2006, 16, 1146. CrossRef
10. Q. Zhang, Y. Liu, F. Gao, Q. Ding, C. Chao, W. Hur, Y. Jin, T. Uno, C. A. P. Joazeiro, and N. Gray, J. Am. Chem. Soc., 2006, 128, 2182. CrossRef
11. M. J. Kim, J. Y. Kim, H. J. Seo, J. Lee, S.-H. Lee, M.-S. Kim, J. Kang, J. Kim, and J. Lee, Bioorg. Med. Chem. Lett., 2009, 19, 4692. CrossRef
12. R. M. Jones, G. Semple, Y. Xiong, Y.-J. Shin, A. S. Ren, J. Lehmann, B. Fioravanti, M. A. Bruce, and J. S. K. Choi, PCT Int. Appl. WO 2005121121, 2005 (Chem. Abstr., 2006, 144, 69843).
13. H. Kubota, M. Sugahara, M. Furukawa, M. Takano, and D. Motomura, PCT Int. Appl. WO 2005095409, 2005 (Chem. Abstr., 2005, 143, 386934).
14. D. J. Denhardt, A. V. Purandare, J. D. Catt, H. D. King, A. Gao, J. A. Deskus, M. A. Poss, A. D. Stark, J. R. Torrente, and G. Johnson, Bioorg. Med. Chem. Lett., 2004, 14, 4249. CrossRef
15. V. M. Cherkasov, I. O. Grafova, N. A. Kapran, and E. A. Ramanenko, DAN Ukr SSR Ser. B: geolog., khim. i biolog. nauki, 1989, N 5, 54.
16. E. J. E. Freyne, M. Willems, W. C. J. Embrechts, K. Van Emelen, S. F. A. Van Brandt, and F. J. R. Rombouts, PCT Int. Appl. WO 2006061415, 2006 (Chem. Abstr., 2006, 145, 83662).
17. L.-X. Wang, D.-X. Wang, Z.-T. Huang, and M.-X. Wang, J. Org. Chem., 2010, 75, 741. CrossRef
18. S. Jhaumeer-Laulloo and M. Witvrouw, Ind. J. Chem., 2000, 39B, 842.
19. U. Luecking, G. Siemeister, M. Schaefer, and H. Briem, Ger. Offen. DE 10239042, 2004 (Chem. Abstr., 2004, 140, 235737).
20. S. Blanchard, K. Ethirajulu, C. H. A. Lee, H. K. M. Nagaraj, A. Poulsen, E. T. Sun, Y. L. E. Tan, E. L. Teo, and A. D. William, PCT Int. Appl. WO 2007058628, 2007 (Chem. Abstr., 2007, 147, 9958).
21. S. Blanchard, K. Ethirajulu, C. H. A. Lee, H. K. M. Nagaraj, A. Poulsen, E. T. Sun, Y. L. E. Tan, E. L. Teo, and A. D. William, PCT Int. Appl. WO 2007058627, 2007 (Chem. Abstr., 2007, 147, 9957).
22. U. Luecking, Eur. Pat. EP 1710246, 2006 (Chem. Abstr., 2006, 145, 419188).
23. H. Liu, I. Drizin, J. R. Koenig, M. D. Cowart, C. Zhao, B. D. Wakefield, L. A. Black, and R. J. Altenbach, U.S. Pat. Appl. 2009253678, 2009 (Chem. Abstr., 2009, 151, 448445).
24. H. Liu, I. Drizin, M. D. Cowart, and R. J. Altenbach, PCT Int. Appl. WO 2009137492, 2009 (Chem. Abstr., 2009, 151, 550597).
25. G. R. Newkome, A. Nayak, M. G. Sorci, and W. H. Benton, J. Org. Chem., 1979, 44, 3812. CrossRef
26. G. R. Newkome, A. Nayak, J. Otemaa, D. A. Van, and W. H. Benton, J. Org. Chem., 1978, 43, 3362. CrossRef
27. K. T. Potts and M. J. Cipullo, J. Org. Chem., 1982, 47, 3038. CrossRef
28. J. T. Redd, J. S Bradshaw, P. Huzthy, and R. M. Izatt, J. Heterocycl. Chem., 1994, 31, 1047. CrossRef
29. J. T. Redd, J. S Bradshaw, P. Huzthy, R. M. Izatt, and N. K. Dalley J. Heterocycl. Chem., 1998, 35, 1. CrossRef
30. A. S. Mikhailov, N. G. Pashkurov, V. S Reznik, R. Kh. Giniyatullin, V. I. Skuzlova, Yu. Ya. Efremov, D. R. Sharafutdinova, R. R. Shagidullin, A. V. Chernova, G. M. Doroshkina, A. A. Nafikova, and N. M. Azancheev, Doklady AN, 1998, 362, 643.
31. R. R. Shagidullin, A. V. Chernova, G. M. Doroshkina, V. E. Kataev, Z. G. Bazhanova, S. A. Katsyuba, V. S. Reznik, A. S. Mikhailov, R. Kh. Giniyatullin, N. G. Pashkurov, Yu. Ya. Efremov, and A. A. Nafikova, Zh. Obshch. Khimii, 2002, 72, 1725.
32. A. S. Mikhailov, R. Kh. Giniyatullin, V. E. Semenov, V. S. Reznik, A. A. Nafikova, Sh. K. Latypov, Yu. Ya. Efremov, and D. R. Sharafutdinova, Izv. AN Ser. Khim., 2003, 52, 1324.
33. E. P. Zhil’tsova, L. A. Kudryavtseva, G. A. Gainanova, A. P. Timosheva, A. S. Mikhailov, R. Kh. Giniyatullin, A. A. Nafikova, V. S. Reznik, and A. I. Konovalov, Zh. Obshch. Khimii, 2005, 75, 1812.
34. V. E. Semenov, A. V. Chernova, G. M. Doroshkina, R. R. Shagidullin, R. Kh. Giniyatullin, A. S. Mikhailov, V. D. Akamsin, V. S. Reznik, Yu. Ya. Efremov, D. R. Sharafutdinova, A. A. Nafikova, and V. I. Morozov, Zh. Obshch. Khimii, 2006, 76, 309.
35. V. E. Semenov, A. S. Mikhailov, E. S. Romanova, A. D. Voloshina, N. V. Kulik, S. Yu. Uraleva, A. V. Kozlov, Sh. K. Latypov, and V. S. Reznik, Zh. Obshch. Khimii, 2009, 79, 138.
36. A. D. Averin, O. A. Ulanovskaya, and I. P. Beletskaya, Chem. Heterocyclic Comp., 2008, 1146.
37. S. M. Kobelev, A. D. Averin, A. K. Buryak, and I. P. Beletskaya, Russ. J. Org. Chem., 2010, in press.
38. J. P. Wolfe and S. L. Buchwald, J. Org. Chem., 2000, 65, 1144. CrossRef
39. A. D. Averin, A. V. Shukhaev, A. K. Buryak, F. Denat, R. Guilard, and I. P. Beletskaya, Tetrahedron Lett., 2008, 49, 3950. CrossRef
40. J. Rohovec, R. Gyepes, I. Cisarova, J. Rudovsky, and I. Lukes, Tetrahedron Lett., 2000, 41, 1249. CrossRef
41. F. Boschetti, F. Chaux, F. Denat, R. Guilard, and H. Ledon, PCT Int. Appl. 2005000823 (Chem. Abstr., 2004, 142, 56374).
42. Y. Gong, G. Xue, Y. Xiang, J. S.Bradshaw, M. L. Lee, and H. K. Lee, Tetrahedron Lett., 2002, 43, 2463. CrossRef
43. T. Ukai, H. Kawazura, Y. Ishii, J. J. Bonnet, and J. A. Ibers, J. Organomet. Chem., 1974, 65, 253. CrossRef