HETEROCYCLES

Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1341-1366
Received, 3rd July, 2012, Accepted, 21st August, 2012, Published online, 3rd September, 2012.
DOI: 10.3987/COM-12-S(N)88

■ Palladium-Catalyzed Amination in the Synthesis of Macrobicycles Incorporating Cyclen, Cyclam and Pyridine Moieties

Alexei D. Averin, Kanat S. Tyutenov, Anton V. Shukhaev, Sergei M. Kobelev, Alexei K. Buryak, Franck Denat, Roger Guilard, and Irina Petrovna Beletskaya*

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

Abstract

Palladium-catalyzed amination was successfully applied to the synthesis of macrobicyclic cryptands comprising cyclen or cyclam and pyridine moieties. Starting bis(halopyridylmethyl) substituted cyclen and cyclam were obtained from protected tetraazamacrocycles in good yields and introduced in the catalytic macrocyclization reactions with a number of polyamines and oxadiamines to give target macrobicycles. The yields of macrobicyclic cryptands were shown to be dependent on the cavity size of starting tetraazamacrocycle, on the nature of halogen atom and substitution pattern in the starting compounds, and on the nature of di- and polyamines. The best yields reached 33%.

INTRODUCTION
Polymacrocyclic compounds derived from tetraazamacrocycles possess several advantages over monomacrocycles, for example, their metal complexes are usually more thermodynamically and kinetically stable. Macropolycyclic compounds containing cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,4,8,11-tetraazacyclotetradecane) moieties are known for last decades and can be attributed to different classes of topology: macrobicyclic and macrotricyclic cryptands, macropolycycles of cylindrical shape, macropolycycles incrorporating other macrocyclic structures.
The simplest bicyclic compounds based on tetraazamacrocycles are various so-called cross-bridged cyclen and cyclam.1-3 The introduction of aromatic and heteroaromatic fragments in polymacrocyclic compounds often increases the conformational rigidity of the molecule thus fixing the cavity size.4 Also, these fragments are crucial in the creation of chemosensors because (hetero)aromatic moieties play the role of chromophores or fluorophores being responsible for the physical response to coordination. The majority of macropolycyclic compounds contain (hetero)aromatic groups linked to nitrogen atoms through methylene or methyne bridges.
Usually macrobicycles possessing cross-bridged cyclen and cyclam moieties do not contain many donor atoms like nitrogen, oxygen or sulfur in the second cycle,5-10 however, described are macrobicycles with several donor atoms.11 Some macrobicycles are formed via functionalization of neighboring nitrogen atoms of tetraazamacrocycles.12-15 Macrotricyclic compounds mainly posses two macrocycles cis-fused with the central tetraazamacrocycle.16-18 The most interesting macrotricycles are actually the cryptands of cylindrical shape and they often contain two cyclen or cyclam fragments arranged in a face-to-face manner via two symmetrical aromatic spacers.19,20 Additional macrocycles may be used as linkers to furnish macropentacyclic structures.21 Porphirin systems were successfully incorporated into heteropolycyclic systems with cyclen and cyclam.22-25
There are several examples of macropolycyclic compounds based on cyclen or cyclam and incorporating pyridine in the macrocyclic moiety. Macrobicycle with cyclam unit with a bridge containing 2,6-disubstituted pyridine was prepared either from 5,12-dioxocyclam26,27 or from free cyclam.9 Cryptands of cylindrical shape also may contain two pyridines and two cyclam20 or cross-bridged cyclam28 units. Our own interest in these compounds is due to the fact that pyridine incorporated in the macrocyclic system may increase the number of donor sites of the macrocyclic ligand what is important for coordinating cations of heavy and rare earth metals which possess high coordination numbers. Earlier we successfully applied Pd-catalyzed amination to the synthesis of various macrocycles possessing disubstituted benzene,29 biphenyl,30 naphthalene31, anthracene and anthraquinone,32 pyridine,33,34 bipyridine35 moieties, and recently we have shown the possibility to use this approach for the synthesis of macrobicyclic compounds.36,37 In this paper we demonstrate how Pd-catalyzed amination works in the synthesis of pyridine-containing macrobicyclic compounds based on cyclen and cyclam.

RESULTS AND DISCUSSION
Previously unknown bis(halogenopyridylmethyl) substituted cyclens and cyclams were synthesized using a described procedure36 from corresponding cis-glyoxal-cyclen 1 and formaldehyde-cyclam 2 (Scheme 1). The first step was the reaction of protected tetraazamacrocycles 1 and 2 with 2 equiv. of halogenomethyl halogenopyridines in acetonitrile. Di-salts 3-5 and 9-11 were formed in yields from 48 to 95% and were collected as white precipitates. The yields of these compounds were strongly dependent on their solubility in acetonitrile which generally was enough low. In the reactions with 5-(chloromethyl)-2-chloropyridine addition of KI was necessary to increase the rate of the substitution reaction. The second deprotection step proceeded using 3M NaOH solution at 80-90 oC and was almost quantitative in many cases. Compounds 6, 7 and 12, 13 were obtained in order to compare the reactivity of chlorine and bromine atoms in the Pd-catalyzed macrocyclization reactions. Compounds 8 and 14 were made in view of the synthesis of macrobicycles with isomeric 2,6-disubstituted pyridine moieties.

Compounds 6, 7 and 12, 13 were introduced in the Pd-catalyzed amination reactions with a number of polyamines and oxadiamines 15a-h (Scheme 2). Studied di- and polyamines possess various chain length and contain different number of nitrogen and oxygen atoms. At first a standard catalytic system Pd(dba)2/BINAP (BINAP = 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene) was applied in these reactions but it was shown to be inefficient for the synthesis of the target macrocycles though the conversion of starting halogenopyridyl derivatives was quantitative. The use of DavePhos (2-dimethylamino-2’-dicyclohexylphosphino)biphenyl) instead of BINAP was successful for the synthesis of desired macrobicycles. The reactions were run using normally 16 mol% of the catalytic system, in boiling 1,4-dioxane (c = 0.02 M), using tBuONa as a base. The reactions were complete in 24-30 h according to 1H NMR spectra of the reaction mixtures. Macrobicycles were isolated using column chromatography on silica gel, the yields are given in Table 1.

The reaction of bis(6-chloropyrid-3-yl) derivative of cyclen 6 with the shortest 1,3-propanediamine (15a) provided only 8% yield of the target macrobicycle 16a (entry 1), the increase in the polyamine length led to substantially better result in the case of triamine 15b (29%, entry 2). The reaction of a longer tetraamine 15e afforded almost the same yield of the cryptand 16e (27%, entry 5), however, the yields in the case of two other tetraamines, 15c,d were notably lower (entries 3, 4), possibly, due to the presence of ethylenediamine fragments in these molecules. These fragments can form more stable 5-member chelates with Pd(0) thus eliminating it from the catalytic cycle and diminishing the yields of the products, the feature already discussed by us in earlier publications.38 The yields of macrobicycles in the reactions with oxadiamines 15f-h were among the best (24-32%, entries 6, 8, 9), we also demonstrated that the catalyst loading can be diminished when using 1.5 equiv. of oxadiamine without altering the yield of the macrobicycle (entry 7). The reaction of the bromopyridyl derivative 7 was not advantageous over its chloropyridyl analogue and did not lead to an increase in the product yield (entry 10). Except two examples (entries 7, 10), no cyclic dimers were isolated as by-products in these reactions, in contrast to the results obtained in the reactions with bis(3-bromobenzyl) derivative of cyclen, where cyclic dimers were isolated in the majority of cases.36,37 This fact is in good correlation with the formation of cyclodimers in the macrocyclization reactions of 1,3-dibromobenzene with polyamines29 and the absence of such cyclodimers in the macrocyclization reactions with participation of 2,6- and 3,5-dibromopyridines.33,34

The reactions of bis(chloropyridyl) derivative of cyclam 12 provided macrobicycles 17 in lower yields, and their dependence on the nature of polyamines was not clear. The best yield (19%) of the target cryptand 17h (entry 19) was observed in the reaction with trioxadiamine 15h possessing the longest chain. We have already noted that generally bromobenzyl derivatives of cyclam gave poorer yields in macrocyclization reaction than their cyclen analogues,36 possibly it is due to a better coordination of Pd(0) to cyclam moiety. Application of 1.5 equiv. of oxadiamine 15f increased the yield of cryptand 17f (entries 15, 16), and the use of 8 mol% catalyst instead of 16 mol% did not change the yield or even slightly improved it (entries 16 and 17, 19 and 20). We suppose that small excess of polyamine could be favorable in other cases too, however, application of 16 mol% catalyst proved to be important in many other cases. As for the concentration of starting compounds, normally we used 0.02 M solutions, but the increase in the concentration up to 0.035-0.04 M did not affect the yields of the target macrobicycles 16, 17. The reaction of bromopyridyl analogue 13 with trioxadiamine 15h was not efficient providing only 10% yield of the desired product 17h (entry 21). In all above mentioned reactions full conversion of starting halogenopyridyl derivatives 6, 7, 12, 13 was observed, though the conversion of di- and polyamines was not full and sometimes did not exceed 50%, what suggests competing with the reactions other than catalytic amination, which are responsible for moderate or low yields of macrobicycles. Better results achieved with chloropyridyl derivatives 6, 12 may be explained by a lower reactivity of the chlorine atom in the side reactions which diminish the yields of the amination products. We could not isolate other by-products in these reactions as individual compounds, except above mentioned cyclic dimers, thus we can only suppose that catalytic homo-coupling and hydro-debromination processes took place.
The attempt to use BINAP in the reaction of trioxadiamine with bromopyridyl derivative 13 was useless as no macrobicycle 17h was formed even in the reaction mixture. Using the same cyclam derivative 13 we tried other donor phosphine ligands: 2-(dicyclohexylphosphino)biphenyl (L1), 2-(ditert-butylphosphinobiphenyl) (L2), several ferrocene-based ligands (L3-L6) (Figure 1). We found out that the use of the ligands L1, L3 and L4 led to macrobicycle 17h in 10-12% yields while other ligands did not provide good conversion of starting material.

The reactions of isomeric 3-bromopyrid-2-ylmethyl derivatives of cyclen and cyclam 8 and 14 with polyamines (Scheme 3) were also sensitive to the nature of the phosphine ligand, but in this case only BINAP was efficient, and the use of the donor DavePhos resulted in the formation of a complex mixture of unidentified products according to 1H NMR of the reaction mixtures. All reactions were conducted using 0.05 M concentration of starting compounds to optimize the reaction time. The results of the macrocyclization reactions are presented in Table 2.

It is clearly seen from the table that generally higher yields of cryptands 21 were provided by the use of di- and triamine while the application of tetraamines (entries 3-5) resulted in poorer yields of the target macrobicycles. Moreover, tetraamine 15c with two ethylenediamine fragments provided notably less yield of 21c (9%, entry 3) than tetraamine 15e without such fragments (16%, entry 5). The best yields (23 and 22%) were achieved with triamine 15b (entry 2) and dioxadiamine 15f (entry 6), this fact is in a good correlation with the results obtained with bis(6-chloropyrid-3-ylmethyl) substituted cyclen 6 (Table 1). Only in one case, in the reaction with 1,3-diaminopropane, we managed to isolated the cyclic dimer 22a which is an interesting example of a cylindrically shaped cryptand.
The reactions with the analogous cyclam derivative 14 were not as efficient, and the yields of corresponding macrobicycles 21 did not exceed 11% (entries 9-12). We did not carry out the reactions with more problematic reagents like tetraamines because the results were insufficient even with di- and trioxadimines 15f,h. Such low yields support an idea that cyclam-based substrates are in general less efficient in the Pd-catalyzed macrocyclization than cyclen derivatives and also they correlate with a similarly low yield of the cryptand in the reaction between isomeric bis(6-bromopyrid-3-ylmethyl) substituted cyclam 13 with trioxadiamine 15h (Table 1, entry 21).

CONCLUSION
To sum up, we synthesized a series of new bis(halogenopyridylmethyl) substituted cyclens and cyclams, the majority of them were obtained in very good yields. These compounds were introduced into the Pd-catalyzed amination reactions with a number of polyamines and oxadiamines for the synthesis of novel pyridine-containing macrobicyclic cryptands. The reactions were found to be sensitive to the nature of the phosphine ligand: 6-chloropyrid-3-yl and 6-bromopyrid-3-yl derivatives demanded the application of a donor phosphine ligand DavePhos whereas 6-bromopyrid-2-yl derivatives normally reacted when using BINAP. The best yields of target macrobicyles reached 33% in the case of bis(6-chloropyrid-3-ylmethyl) substituted cyclen. We showed that in some cases the catalyst loading can be diminished, concentration of the starting compounds increased without affecting the yields of macrobicycles. Application of 1.5 equivalents of polyamines can also be helpful for optimizing the yields of these compounds.

EXPERIMENTAL
All chemicals were purchased from Aldrich and Acros companies and used without further purification. Cis-glyoxal-cyclen 1 and formaldehyde-cyclam 2 were provided by CheMatech Co. Pd(dba)2 was synthesized according to a known procedure.39 2-Chloro-5-chloromethylpyridine, 2-bromo-6-methylpyridine, 2-bromo-5-methylpyridine, di- and polyamines 15a-h, phosphine ligands were purchased from Aldrich and Acros. 2-Bromo-5-bromomethylpyridine and 2-bromo-6-bromomethylpyridine were synthesized from commercial 2-bromo-5-methylpyridine and 2-bromo-6-methylpyridine by the bromination with NBS in CCl4 in the presence of AIBN and purified by column chromatography on silica gel (petrol ether – CH2Cl2). Commercial 1,4-dioxane was distilled over NaOH and sodium under argon, acetonitrile was distilled over P2O5 and CaH2, dichloromethane 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.

2a,6a-Bis[(6-chloropyridin-3-yl)methyl]decahydro-4a,8a-dizaz-2a,6a-diazoniacyclopenta[fg]acenaphthene diiodide (3). Cis-glyoxal-cyclen 1 (20 mmol, 3.88 g) was dissolved in MeCN (70 mL), 2-chloro-5-chloromethylpyridine (40 mmol, 6.48 g) and NaI (40 mmol, 6.0 g) were added, and the reaction mixture was stirred for 32 h at 50-60 °С and then 60 h at room temperature. The precipitate was filtered off, washed with MeCN (4х30 mL) and dried in vacuo. Compound 3 was obtained as a white crystalline powder. Yield 13.96 g (99%). 1H NMR (DMSO-d6): δ 2.98-3.08 (m, 2H), 3.29 (d, J = 12.4 Hz, 2H), 3.40-3.79 (m, 10H), 4.33 (td, J = 10.9 Hz, 3.3 Hz, 2H), 5.05 (d, J = 13.4 Hz, 2H), 5.18 (s, 2H), 5.30 (d, J = 13.4 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 8.30 (dd, J = 8.2 Hz, 2.4 Hz, 2H), 8.79 (d, J = 2.4 Hz, 2H).

N1,N7-Bis((6-chloropyridin-3-yl)methyl)cyclen (6). Compound 3 (13.96 g, 19.9 mmol) was dissolved in a water solution of KOH (16 g in 120 mL water) and stirred for 72 h at 80 °С. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (2x40 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 6 was obtained as a slightly beige crystalline powder, mp 122-124 °C. Yield 6.44 g (76% overall). 1H NMR (CDCl3): δ 2.38 (br.s, 2H), 2.51-2.57 (m, 8H), 2.58-2.65 (m, 8H), 3.53 (s, 4H), 7.37 (d, J = 8.2 Hz, 2H), 7.56 (dd, J = 8.2 Hz, 2.4 Hz, 2H), 8.26 (d, J = 2.4 Hz, 2H). 13C NMR (CDCl3): δ 45.2 (4C), 51.6 (4C), 56.4 (2C), 124.3 (2C), 133.3 (2C), 139.3 (2C), 149.9 (2C), 150.4 (2C). HRMS (MALDI-TOF) m/z calcd for C20H29Cl2N6 [M+H]+ 423.1831, found 423.1895.

2a,6a-Bis[(6-bromopyridine-3-yl)methyl]decahydro-4a,8a-diaza-2a,6a-diazoniacyclopenta[fg]acenaphthene dibromide (4). Cis-glyoxal-cyclene 1 (2.39 mmol, 0.47 g) was dissolved in MeCN (10 mL), 2-bromo-5-bromomethylpyridine (4.78 mmol, 1.2 g) was added, and the reaction mixture was stirred for 48 h at room temperature. The precipitate was filtered off, washed with MeCN (2х10 mL) and dried in vacuo. Compound 4 was obtained as white crystalline powder. Yield 0.801 g (48%). 1H NMR (DMSO-d6): δ 2.96 (q, J = 8.2 Hz, 2H), 3.10-3.77 (m, 12H), 4.26 (td, J = 10.7 Hz, 3.6 Hz, 2H), 4.94 (d, J = 13.6 Hz, 2H), 4.95 (s, 2H), 5.12 (d, J = 13.6 Гц, 2H), 7.88 (d J = 8.3 Hz, 2H), 8.13 (dd, J = 8.3 Hz, 2.0 Hz, 2H), 8.72 (d, J = 2.0 Hz, 2H). 13C NMR (DMSO-d6): δ 42.2 (2C), 46.4 (2C), 55.5 (2C), 56.4 (2C), 60.2 (2C), 76.5 (2C), 123.5 (2C), 128.8 (2C), 143.4 (2C), 143.9 (2C), 153.8 (2C).

N1,N7-Bis((6-bromopyridin-3-yl)methyl)cyclen (7). Compound 4 (1.15 mmol, 0.801 g) was dissolved in a water solution of KOH (3.4 g in 20 mL water) and stirred for 48 h at 80 oC. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (2x40 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 6 was obtained as a yellowish glassy compound. Yield 0.585 g (48% overall). 1H NMR (CDCl3): δ 2.60-2.68 (m, 16H), 3.60 (s, 4H), 7.47-7.57 (m, 4H), 8.28 (s, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 45.6 (4C), 51.6 (4C), 56.9 (2C), 128.2 (2C), 133.7 (2C), 139.2 (2C), 141.1 (2C), 150.3 (2C). HRMS (MALDI-TOF) m/z calcd for C20H29Br2N6 [M+H]+ 511.0820, found 511.0776.

2a,6a-Bis[(6-bromopyridin-2-yl)methyl]decahydro-4a,8a-diaza-2a,6a-diazoniacyclopenta[fg]-acenaphthene dibromide (5). Cis-glyoxal-cyclen 1 (0.848 g, 4.37 mmol) was dissolved in MeCN (15 mL) and 2-bromo-6-bromomethylpyridine (2.19 g, 8.7 mmol) was added. The reaction mixture was stirred for 72 h at 40-50 °C. The precipitate was filtered off, washed with MeCN (2х30 mL) and dried in vacuo. Compound 5 was obtained as a white crystalline powder. Yield 2.89 g (95%). 1H NMR (DMSO-d6): δ 2.95 (t, J = 8.6 Hz, 2H), 3.21-3.41 (m, 4H), 3.43-3.50 (m, 2H), 3.60 (d, J = 13.1 Hz, 2H), 3.76 (td, J = 13.0 Hz, 3.4 Hz, 2H), 3.89 (dt, J = 12.1 Hz, 7.6 Hz, 2H), 4.38 (td, J = 11.1 Hz 3.3 Hz, 2H), 4.90 (s, 2H), 4.94 (d, J = 13.5 Hz, 2H), 5.14 (d, J = 13.5 Hz, 2H), 7.83-7.88 (m, 4H), 7.98 (t, J = 7.8 Hz, 2H). 13C NMR (DMSO-d6): δ 42.9 (2C), 46.2 (2C), 56.6 (2C), 60.3 (2C), 61.5 (2C), 71.2 (2C), 126.9 (2C), 130.4 (2C), 141.0 (2C), 142.2 (2C), 147.9 (2C).

N1,N7-Bis((6-bromopyridin-2-yl)methyl)cyclen (8). Compound 5 (4.15 mmol, 2.89 g) was dissolved in a water solution of KOH (3.4 g in 25 mL water) and stirred for 48 h at 80 °C. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (2x40 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 8 was obtained as a beige powder. Yield 1.97 g (88% overall). 1H NMR (CDCl3): δ 2.84-2.90 (m, 8H), 2.90-2.97 (m, 8H), 3.78 (s, 4H), 7.32-7.42 (m, 4H), 7.48-7.54 (m, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 45.1 (4C), 52.1 (4C), 60.8 (2C), 121.8 (2C), 126.4 (2C), 138.7 (2C), 141.4 (2C), 161.2 (2C). HRMS (MALDI-TOF) m/z calcd for C20H29Br2N6 [M+H]+ 511.0820, found 511.0856.

1,8-Bis[(6-chloropyridin-3-yl)methyl]-4,11-diaza-1,8-diazoniatricyclo[9.3.1.14,8]hexadecane diodide (9). Formaldehyde-cyclam 2 (4.48 g, 20 mmol) was dissolved in MeCN (135 mL), 2-chloro-5-chloromethylpyridine (6.48 g, 40 mmol) and NaI (6.0 g, 40 mmol) were added. The reaction mixture was stirred for 48 h at room temperature. The precipitate was filtered off, washed with MeCN (2х30 mL) and dried in vacuo. Compound 9 was obtained as a white crystalline powder. Yield 11.03 g (75%). 1H NMR (DMSO-d6): δ 1.73 (d, J = 10.3 Hz, 2H), 2.38 (d, J = 7.0 Hz, 2H), 2.79 (t, J = 15.4 Hz, 4H), 3.13 (br.s, 2H), 3.30 (br.s, 4H), 4.41 (t, J = 13.5 Hz, 4H), 4.74 (s, 4H), 5.37 (d, J = 9.4 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.2 Hz, 2H), 8.63 (br.s, 2H) (4 aliphatic protons are overlapped by the signal of HDO).

N1,N8-Bis((6-chloropyridin-3-yl)methyl)cyclam (12). Compound 9 (11.03 g, 15.1 mmol) was dissolved in a water solution of KOH (30 g in 180 mL) and stirred at 90 °C for 24 h. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (3x50 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 12 was obtained as a slightly beige crystalline powder, mp 128-130 °C. Yield 5.21 g (58% overall). 1H NMR (CDCl3): δ 1.80 (quintet, J = 4.9 Hz, 4H), 2.45-2.55 (m, 8H), 2.65-2.73 (m, 8H), 3.64 (s, 4H), 7.24 (d, J = 8.1 Hz, 2H), 7.57 (dd, J = 8.1 Hz, 2.4 Hz, 2H), 8.30 (d, J = 2.4 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2C), 47.4 (2C), 49.6 (2C), 51.1 (2C), 54.0 (2C), 54.3 (2C), 123.8 (2C), 131.9 (2C), 139.7 (2C), 150.2 (2C), 150.3 (2C). HRMS (MALDI-TOF) m/z calcd for C22H33Cl2N6 [M+H]+ 451.2144, found 451.2093.

1,8-Bis[(6-bromopyridin-3-yl)methyl]-4,11-diaza-1,8-diazoniatricyclo[9.3.1.14,8]hexadecane dibromide (10). Formaldehyde-cyclam 2 (1.25 g, 5.6 mmol) was dissolved in MeCN (40 mL) and 2-bromo-5-bromomethylpyridine (2.81 g, 11.2 mmol) was added. The reaction mixture was stirred for 24 h at room temperature. The precipitate was filtered off, washed with MeCN (2х30 mL) and dried in vacuo. Compound 10 was obtained as white crystalline powder. Yield 2.05 g (50%). 1H NMR (DMSO-d6): δ 1.72 (d, J = 7.8 Hz, 2H), 2.39 (d, J = 7.0 Hz, 4H), 2.76 (d, J = 15.3 Hz, 2H), 2.86 (d, J = 14.8 Hz, 2H), 3.34 (br.s, 6H), 3.44 (d, J = 9.5 Hz, 2H), 3.62 (t, J = 14.5 Hz, 2H), 4.44 (t, J = 13.7 Hz, 2H), 4.82 (q, J = 13.3 Hz, 4H), 5.42 (d, J = 9.6 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 8.06 (dd, J = 8.3 Hz, 2.4 Hz, 2H), 8.67 (d, J = 2.4 Hz, 2H). 13C NMR (DMSO-d6): δ 19.1 (2C), 46.7 (2C), 48.1 (2C), 50.5 (2C), 57.8 (2C), 58.0 (2C), 75.7 (2C), 123.2 (2C), 128.3 (2C), 143.4 (2C), 143.9 (2C), 154.2 (2C).

N1,N8-Bis((6-bromopyridin-3-yl)methyl)cyclam (13). Compound 10 (2.05 g, 2.8 mmol) was dissolved in a water solution of KOH (6.3 g in 37 mL) and stirred at 80 °C for 48 h. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (2x40 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 13 was obtained as a yellow oil. Yield 1.1 g (36% overall). 1H NMR (CDCl3): δ 1.72 (br.s, 4H), 2.39-2.47 (m, 8H), 2.57-2.65 (m, 8H), 3.55 (s, 4H), 7.32 (d, J = 8.1 Hz, 2H), 7.42 (dd, J = 8.1 Hz, 2.1 Hz, 2H), 8.22 (d, J = 2.1 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.6 (2C), 47.2 (2C), 49.5 (2C), 50.9 (2C), 53.9 (2C), 54.2 (2C), 127.5 (2C), 132.3 (2C), 139.3 (2C), 140.6 (2C), 150.6 (2C). HRMS (MALDI-TOF) m/z calcd for C22H33Br2N6 [M+H]+ 539.1133, found 539.1187.

1,8-Bis[(6-bromopyridin-2-yl)methyl]-4,11-diaza-1,8-diazoniatricyclo[9.3.1.14,8]hexadecane dibromide (11). Formaldehyde-cyclam 2 (0.891 g, 3.95 mmol) was dissolved in MeCN (25 mL) and 2-bromo-6-bromomethylpyridine (1.99 g, 7.9 mmol) was added. The reaction mixture was stirred for 72 h at room temperature. The precipitate was filtered off, washed with MeCN (2х30 mL) and dried in vacuo. Compound 11 was obtained as white crystalline powder. Yield 1.93 g (67%). 1H NMR (DMSO-d6): δ 1.75 (d, J = 14.4 Hz, 2H), 2.32 (br.s, 2H), 2.45 (d, J = 11.5 Hz, 2H), 2.80 (d, J = 14.6 Hz, 2H), 2.99 (d, J = 15.1 Hz, 2H), 3.14 (br.s, 2H), 3.33-3.38 (m, 2H), 3.45-3.63 (m, 6H), 4.33 (t, J = 13.7 Hz, 2H), 4.73 (d, J = 13.4 Hz, 2H), 4.88 (d, J = 13.3 Hz, 2H), 5.42 (d, J = 9.2 Hz, 2H), 7.80-7.85 (m, 4H), 7.93 (t, J = 7.7 Hz, 2H). 13C NMR (DMSO-d6): δ 19.2 (2C), 47.1 (2C), 50.8 (2C), 59.2 (2C), 60.7 (2C), 76.8 (2C), 127.7 (2C), 129.4 (2C), 140.7 (2C), 141.2 (2C), 149.4 (2C), two aliphatic carbon atoms are overlapped by CD3 multiplet.

N1,N8-Bis((6-bromopyridin-2-yl)methyl)cyclam (14). Compound 11 (1.93 g, 2.65 mmol) was dissolved in a water solution of KOH (8.9 g in 53 mL) and stirred at 80 °C for 48 h. Aqueous layer was separated from the oily residue, extracted with CH2Cl2 (2x40 mL), organic phases were combined and dried over Na2SO4. Solvent was evaporated in vacuo and compound 14 was obtained as a yellowish glassy compound. Yield 1.39 g (65% overall). 1H NMR (CDCl3): δ 1.79 (quintet, J = 5.0 Hz, 4H), 2.54 (t, J = 5.6 Hz, 4H), 2.61-2.65 (m, 4H), 2.66-2.73 (m, 8H), 3.73 (s, 4H), 7.25 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), NH protons were not assigned. HRMS (MALDI-TOF) m/z calcd for C22H33Br2N6 [M+H]+ 539.1133, found 538.1097.

Typical procedure for the synthesis of macrobicycles 16, 17, 20, 21.
A two-neck flask (25 mL) flushed with dry argon, equipped with a magnetic stirrer and condenser was charged with cyclen or cyclam derivatives 6-8, 12-14 (0.25 mmol), Pd(dba)2 (16 mol%), DavePhos or BINAP (18 mol%), and absolute dioxane (12 mL). The mixture was stirred for 2 min, then appropriate amine 15a-h (0.25 mmol) and sodium tert-butoxide (0.6 mmol) were added. The reaction mixture was refluxed for 24 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 20:1 – 3:1, CH2Cl2-MeOH-NH3aq 100:20:1 – 10:4:1.

1,5,7,11,13,17,20,25-Octaazatetracyclo[15.5.5.23,6.212,15]hentriaconta-3,5,12,14,28,30-hexaene (16a) was synthesized from compound 6 (0.5 mmol, 212 mg) and diamine 15a (0.5 mmol, 37 mg) in the presence of Pd(dba)2 (46 mg, 16 mol%), DavePhos (36 mg, 18 mol%), tBuONa (1.2 mmol, 116 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 18 mg (8%). 1H NMR (CDCl3): δ 1.91 (quintet, J = 7.4 Hz, 2H), 2.38-2.45 (m, 4H), 2.63-2.71 (m, 4H), 2.74-2.82 (m, 4H), 2.95-3.03 (m, 4H), 3.36 (t, J = 7.1 Hz, 4H), 3.54 (s, 4H), 5.15 (br.s, 2H), 6.61 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 8.5 Hz, 2.1 Hz, 2H), 7.96 (d, J = 2.1 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 28.2 (1C), 39.7 (2C), 47.4 (4C), 51.3 (4C), 59.5 (2C), 107.6 (2C), 122.9 (2C), 138.9 (2C), 147.8 (2C), 157.8 (2C). HRMS (MALDI-TOF) m/z calcd for C23H37N8 [M+H]+ 425.3141, found 425.3100.

1,5,7,11,15,17,21,24,29-Nonaazatetracyclo[19.5.5.23,6.216,19]pentatriaconta-3,5,16,18,32,34-hexaene (16b) was synthesized from compound 6 (0.25 mmol, 106 mg) and triamine 15b (0.25 mmol, 33 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 36 mg (29%). 1H NMR (CDCl3): δ 1.79 (quintet, J = 5.9 Hz, 4H), 2.53-2.70 (m, 16H), 2.80 (t, J = 5.2 Hz, 4H), 3.43 (t, J = 6.5 Hz, 4H), 3.47 (s, 4H), 5.73 (br.s, 2H), 6.67 (d, J = 8.5 Hz, 2H), 7.41 (dd, J = 8.5 Hz, 2.1 Hz, 2H), 7.96 (d, J = 2.1 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 28.9 (2C), 42.5 (2C), 46.3 (4C), 48.9 (2C), 52.3 (4C), 58.8 (2C), 107.6 (2C), 123.0 (2C), 138.1 (2C), 147.8 (2C), 158.6 (2C). HRMS (MALDI-TOF) m/z calcd for C26H44N9 [M+H]+ 482.3720, found 482.3687.

1,5,7,10,14,17,19,23,26,31-Decaazatetracyclo[21.5.5.23,6.218,21]heptatriaconta-3,5,18,20,34,36-hexaene (16c) was synthesized from compound 6 (0.25 mmol, 106 mg) and tetraamine 15c (0.25 mmol, 40 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 21 mg (16%). 1H NMR (CDCl3): δ 1.87 (br.s, 2H), 2.50-2.80 (m, 16H), 2.90-2.98 (m, 8H), 3.47 (s, 4H), 3.52 (br.s, 4H), 5.87 (br.s, 2H), 6.61 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.92 (br.s, 2H), four NH protons were not assigned. 13C NMR (CD3OD): δ 26.0 (1C), 41.4 (2C), 47.8 (4C), 50.1 (2C), 52.9 (4C), 59.9 (2C), 110.7 (2C), 124.8 (2C), 140.2 (2C), 148.7 (2C), 159.9 (2C), two aliphatic carbon atoms are overlapped by CD3 multiplet. HRMS (MALDI-TOF) m/z calcd for C27H47N10 [M+H]+ 511.3985, found 511.3947.

1,5,7,11,14,18,20,24,27,32-Decaazatetracyclo[22.5.5.23,6.219,22]octatriaconta-3,5,19,21,35,37-hexaene (16d) was synthesized from compound 6 (0.25 mmol, 106 mg) and tetraamine 15d (0.25 mmol, 44 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. In the second experiment the reaction with the same amounts of starting compounds, catalyst and base was conducted in 5 mL dioxane. As the 1H NMR spectra of both reaction mixtures were identical, the chromatography of combined reactions mixtures was carried out. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 40 mg (15%). 1H NMR (CDCl3): δ 1.85 (quintet, J = 5.8 Hz, 4H), 2.55-2.70 (m, 16H), 2.80 (t, J = 6.5 Hz, 4H), 2.81 (s, 4H), 3.40 (t, J = 6.1 Hz, 4H), 3.43 (s, 4H), 6.58 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 8.5 Hz, 2.0 Hz, 2H), 7.92 (d, J = 2.0 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 28.3 (2C), 40.7 (2C), 46.4 (4C), 47.7 (2C), 48.4 (2C), 51.7 (4C), 58.4 (2C), 108.0 (2C), 122.5 (2C), 130.1 (2C), 147.9 (2C), 158.5 (2C). HRMS (MALDI-TOF) m/z calcd for C28H49N10 [M+H]+ 525.4142, found 525.3989.

1,5,7,11,15,19,21,25,28,33-Decaazatetracyclo[23.5.5.23,6.220,23]nonatriaconta-3,5,20,22,36,38-hexaene (16e) was synthesized from compound 6 (0.25 mmol, 106 mg) and tetraamine 15e (0.25 mmol, 47 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 37 mg (27%). 1H NMR (CDCl3): δ 1.76 (quintet, J = 6.2 Hz, 2H), 1.81 (quintet, J = 5.9 Hz, 4H), 2.50-2.70 (m, 16H), 2.77 (t, J = 6.4 Hz, 4H), 2.80 (t, J = 6.0 Hz, 4H), 3.38-3.42 (m, 8H), 6.55 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 8.5 Hz, J = 1.7 Hz, 2H), 7.90 (br.s, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 28.3 (3C), 40.9 (2C), 45.9 (4C), 47.7 (2C), 48.3 (2C), 51.8 (4C), 57.8 (2C), 108.1 (2C), 122.7 (2C), 138.1 (2C), 148.0 (2C), 158.5 (2C). HRMS (MALDI-TOF) m/z calcd for C29H51N10 [M+H]+ 539.4298, found 539.4275.

11,16-Dioxa-1,5,7,20,22,26,29,34-octaazatetracyclo[24.5.5.23,6.221,24]tetraconta-3,5,21,23,37,39-hexaene (16f) was synthesized from compound 6 (0.25 mmol, 106 mg) and dioxadiamine 15f (0.25 mmol, 37 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:2 – 100:20:3, pale-beige crystalline powder, mp 194-196 °C. Yield 39 mg (32%). In the second experiment (scale-up), compound 16f was synthesized using compound 6 (5 mmol, 2.115 g) and dioxadiamine 15f (7.5 mmol, 1.1 g) in the presence of Pd(dba)2 (245 mg, 8 mol%), DavePhos (177 mg, 9 mol%), tBuONa (15 mmol, 1.44 g) in 125 mL dioxane.. Yield 821 mg (33%). 1H NMR (CDCl3): δ 2.47 (br.s, 4H), 2.67 (br.s, 4H), 2.75 (br.s, 4H), 2.99 (br.s, 4H), 3.52 (q, J = 4.6 Hz, 4H), 3.56 (s, 4H), 3.69 (s, 4H), 3.73 (t, J = 5.0 Hz, 4H), 5.14 (s, 2H), 6.59 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 8.5 Hz, 1.9 Hz, 2H), 7.97 (d, J = 1.9 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 41.6 (2C), 47.3 (4C), 51.4 (4C), 59.4 (2C), 69.3 (2C), 70.1 (2C), 108.4 (2C), 123.2 (2C), 138.2 (2C), 148.0 (2C), 158.2 (2C). HRMS (MALDI-TOF) m/z calcd for C26H43N8O2 [M+H]+ 499.3509, found 499.3360.

10,13,37,40-Tetraoxa-1,5,7,16,18,22,25,28,32,34,43,45,49,52,57,66-hexadecaazaheptacyclo-[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 (18f) was isolated as the second product in the scaled-up synthesis of compound 16f. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 185 mg (7%). 1H NMR (CDCl3): δ 2.45-2.65 (m, 32H), 3.33-3.64 (m, 32H), 4.93 (br.s, 4H), 6.48 (d, J = 8.4 Hz, 4H), 7.29 (d, J = 8.4 Hz, 4H), 7.87 (br.s, 4H), four NH protons were not assigned. 13C NMR (CDCl3): δ 41.4 (4С), 45.5 (8C), 51.5 (8C), 57.1 (4C), 69.7 (4C), 69.9 (4C), 107.9 (4C), 122.8 (4C), 138.1 (4C), 147.7 (4C), 158.1 (4C). HRMS (MALDI-TOF) m/z calcd for C52H85N16O4 [M+H]+ 997.6940, found 997.6872.

10,13-Dioxa-1,5,7,16,18,22,25,30-octaazatetracyclo[20.5.5.23,6.217,20]hexatriaconta-3,5,17,19,33,35-hexaene (16g) was synthesized from compound 6 (0.25 mmol, 106 mg) and dioxadiamine 15g (0.25 mmol, 51 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:1 – 100:20:2, pale-yellow glassy compound. Yield 33 mg (24%). 1H NMR (CDCl3): δ 1.65-1.70 (m, 4H), 1.87 (quintet, J = 5.4 Hz, 4H), 2.65-2.75 (m, 16H), 3.41-3.46 (m, 8H), 3.47 (s, 4H), 3.57 (t, J = 5.2 Hz, 4H), 5.21 (br.s, 2H), 6.48 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.91 (br.s, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 26.9 (2C), 29.1 (2C), 40.9 (2C), 46.9 (4C), 51.7 (4C), 58.5 (2C), 70.1 (2C), 71.1 (2C), 107.3 (2C), 122.6 (2C), 138.4 (2C), 148.1 (2C), 158.5 (2C). HRMS (MALDI-TOF) m/z calcd for C30H51N8O2 [M+H]+ 555.4135, found 554.4079.

11,14,17-Trioxa-1,5,7,21,23,27,30,35-octatetracyclo[25.5.5.23,6.222,25]hentetraconta-3,5,22,24,38,40-hexaene (16h) was synthesized from compound 6 (0.25 mmol, 106 mg) and trioxadiamine 15h (0.25 mmol, 55 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:1 – 100:20:2, pale-yellow glassy compound. Yield 35 mg (24%). In the second experiment, compound 16h was synthesized using compound 7 (1.75 mmol, 898 mg) and trioxadiamine 15h (1.75 mmol, 386 mg) in the presence of Pd(dba)2 (80 mg, 8 mol%), DavePhos (62 mg, 9 mol%), tBuONa (5.25 mmol, 504 mg) in 50 mL dioxane. Yield 209 mg (21%). 1H NMR (CDCl3): δ 1.88 (quintet, J = 5.8 Hz, 4H), 2.68-2.75 (m, 16H), 3.44 (q, J = 5.3 Hz, 4H), 3.50 (s, 4H), 3.59-3.64 (m, 8H), 3.65-3.69 (m, 4H), 5.32 (br.s, 2H), 6.48 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.5 Hz, 2.0 Hz, 2H), 7.92 (br.s, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 28.8 (2C), 40.0 (2C), 47.2 (4C), 51.7 (4C), 59.0 (2C), 69.5 (2C), 70.0 (2C), 70.3 (2C), 107.5 (2C), 122.5 (2C), 138.3 (2C), 148.1 (2C), 158.5 (2C). HRMS (MALDI-TOF) m/z calcd for C30H51N8O3 [M+H]+ 571.4084, found 571.4071.

11,14,17,43,46,49-Hexaoxa-1,5,7,21,23,27,30,33,37,39,53,55,59,62,67,76-hexadecaazaheptacyclo-[57.5.5.527,33.23,6.222,25.235,38.254,57]dooctaconta-3,5,22,24,35,37,54,56,70,72,79,81-dodecaene (18h) was isolated as the second product in the synthesis of compound 16f from cyclen derivative 7. Eluent CH2Cl2-MeOH-NH3aq 100:20:2, pale-yellow glassy compound. Yield 35 mg (3%). 1H NMR (CDCl3): δ 1.83 (quintet, J = 6.0 Hz, 8H), 2.51-2.66 (m, 32H), 3.35 (s, 8H), 3.37 (br.s, 8H), 3.52-3.62 (m, 24H), 5.26 (br.s, 4H), 6.46 (d, J = 8.6 Hz, 4H), 7.32 (dd, J = 8.6 Hz, 1.7 Hz, 4H), 7.87 (br.s, 4H), four NH protons were not assigned. 13C NMR (CDCl3): δ 29.0 (4C), 39.7 (4C), 45.4 (8C), 51.3 (8C), 56.8 (4C), 69.4 (4C), 70.0 (4C), 70.4 (4C), 107.4 (4C), 122.2 (4C), 138.2 (4C), 148.0 (4C), 158.3 (4C). HRMS (MALDI-TOF) m/z calcd for C60H101N16O6 [M+H]+ 1141.8090, found 1141.8163.

1,5,7,11,13,17,20,26-Octaazatetracyclo[15.6.6.23,6.212,15]tritriaconta-3,5,12,14,30,32-hexaene (17a) was synthesized from compound 12 (0.5 mmol, 226 mg) and diamine 15a (0.5 mmol, 37 mg) in the presence of Pd(dba)2 (46 mg, 16 mol%), DavePhos (36 mg, 18 mol%), tBuONa (1.2 mmol, 116 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 15 mg (7%). 1H NMR (CDCl3): δ 1.73 (br.s, 2H), 1.82 (br.s, 2H), 1.87 (quintet, J = 6.3 Hz, 2H), 2.31-2.81 (m, 16H), 3.10 (d, J = 13.0 Hz, 2H), 3.26 (dq, J = 13.0 Hz, 5.4 Hz, 2H), 3.44 (d, J = 13.0 Hz, 2H), 3.45-3.53 (m, 2H), 4.72 (t, J = 6.0 Hz, 2H), 6.22 (d, J = 8.5 Hz, 2H), 7.25 (dd, J = 8.5 Hz, 2.0 Hz, 2H), 7.86 (d, J = 2.0 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 25.8 (2C), 29.7 (1C), 39.0 (2C), 48.9 (2C), 49.6 (2C), 53.5 (2C), 53.7 (2C), 57.6 (2C), 106.6 (2C), 123.1 (2C), 138.7 (2C), 148.3 (2C), 158.2 (2C). MS (MALDI-TOF) m/z calcd for C25H41N8 [M+H]+ 453.34, found 453.30.

1,5,7,10,14,17,19,23,26,32-Decaazatetracyclo[21.6.6.23,6.218,21]nonatriaconta-3,5,18,20,36,38-hexaene (17c) was synthesized from compound 12 (0.25 mmol, 113 mg) and tetraamine 15c (0.25 mmol, 40 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 16 mg (11%). 1H NMR (CDCl3): δ 1.69 (br.s, 2H), 1.77 (br.s, 4H), 2.30-2.85 (m, 24H), 3.26 (br.s, 4H), 3.40 (br.s, 4H), 5.51 (br.s, 2H), 6.20 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.90 (br.s, 2H), four NH protons were not assigned. HRMS (MALDI-TOF) m/z calcd for C29H51N10 [M+H]+ 539.4298, found 539.4275.

1,5,7,11,14,18,20,24,27,33-Decaazatetracyclo[22.6.6.23,6.219,22]tetraconta-3,5,19,21,37,39-hexaene (17d) was synthesized from compound 12 (0.5 mmol, 226 mg) and tetraamine 15d (0.5 mmol, 86 mg) in the presence of Pd(dba)2 (46 mg, 16 mol%), DavePhos (36 mg, 18 mol%), tBuONa (1.2 mmol, 116 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 40 mg (14%). 1H NMR (CD3OD): δ 1.81-1.94 (m, 8H), 2.40-2.98 (m, 24H), 3.38 (t, J = 6.4 Hz, 4H), 3.52 (s, 4H), 6.56 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 8.5 Hz, 2.2 Hz, 2H), 7.96 (d, J = 2.2 Hz, 2H), NH protons were not assigned. 13C NMR (CD3OD): δ 25.5 (2C), 29.0 (2C), 39.6 (2C), 46.6 (2C), 47.7 (2C), 48.0 (2C), 50.2 (2C), 52.0 (2C), 56.2 (2C), 110.1 (2C), 121.9 (2C), 140.9 (2C), 149.0 (2C), 160.1 (2C), two aliphtaic carbon atoms are overlapped by CD3 multiplet. MS (MALDI-TOF) m/z calcd for C30H53N10 [M+H]+ 552.46, found 552.39.

1,5,7,11,15,19,21,25,28,34-Decaazatetracyclo[23.6.6.23,6.220,23]hentetraconta-3,5,20,22,38,40-hexaene (17e) was synthesized from compound 12 (0.25 mmol, 113 mg) and tetraamine 15e (0.25 mmol, 47 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 27 mg (19%). 1H NMR (CDCl3): δ 1.73-1.84 (m, 10H), 2.40-2.55 (m, 8H), 2.55-2.67 (m, 8H), 2.70 (t, J = 5.9 Hz, 4H), 2.76 (t, J = 5.9 Hz, 4H), 3.33 (t, J = 6.0 Hz, 4H), 3.37 (s, 4H), 4.95 (br.s, 2H), 6.35 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz,. 2H), 7.93 (br.s, 2H), four NH protons were not assigned. 13C NMR (CDCl3): δ 24.9 (3C), 28.3 (2C), 40.1 (2C), 47.1 (2C), 47.8 (2C), 48.4 (2C), 49.2 (2C), 51.3 (2C), 51.8 (2C), 56.2 (2C), 107.7 (2C), 121.1 (2C), 138.8 (2C), 148.5 (2C), 158.3 (2C). HRMS (MALDI-TOF) m/z calcd for C31H55N10 [M+H]+ 567.4611, found 567.4661.

10,13-Dioxa-1,5,7,16,18,22,25,31-octaazatetracyclo[20.6.6.23,6.217,20]octatriaconta-3,5,17,19,35,37-hexaene (17f) was synthesized from compound 12 (0.25 mmol, 113 mg) and dioxadiamine 15f (0.25 mmol, 37 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 17 mg (13%). In the second experiment (scale-up), compound 17f was synthesized using compound 12 (5 mmol, 2.255 g) and dioxadiamine 15f (7.5 mmol, 1.1 g) in the presence of Pd(dba)2 (245 mg, 8 mol%), DavePhos (177 mg, 9 mol%), tBuONa (15 mmol, 1.44 g) in 125 mL dioxane. Yield 525 mg (20%). 1H NMR (CDCl3): δ 1.76 (br.s, 4H), 2.57 (br.s, 8H), 2.67 (br.s, 8H), 3.29 (br.s, 4H), 3.48 (s, 4H), 3.61 (s, 4H), 3.65 (br.s, 4H), 4.91 (t, J = 5.3 Hz, 2H), 6.24 (d, J = 8.4 Hz, 2H), 7.26 (dd, J = 8.4 Hz, 2.1 Hz, 2H), 7.93 (d, J = 2.1 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2C), 41.6 (2C), 48.7 (2C), 49.7 (2C), 52.9 (2C), 53.3 (2C), 57.3 (2C), 69.4 (2C), 70.0 (2C), 108.5 (2C), 122.8 (2C), 138.8 (2C), 148.3 (2C), 158.1 (2C). HRMS (MALDI-TOF) m/z calcd for C26H47N8O2 [M+H]+ 527.3822, found 527.3809.

10,13,38,41-Tetraoxa-1,5,7,16,18,22,25,29,33,35,44,46,50,53,59,69-hexadecaazaheptacyclo[48.6.6.622,29.23,6.217,20.231,34.245,48]-hexaheptaconta-3,5,17,19,31,33,45,47,63,65,73,75-dodecaene (19f) was isolated as the second product in the scaled-up synthesis of compound 17f. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 47 mg (2%). 1H NMR (CDCl3): δ 1.59 (quintet, J = 5.0 Hz, 8H), 2.30-2.45 (m, 16H), 2.51-2.61 (m, 16H), 3.34 (t, J = 5.1 Hz, 8H), 3.50-3.55 (m, 24H), 4.88 (t, J = 5.5 Hz, 4H), 6.16 (d, J = 8.5 Hz, 4H), 7.17 (d, J = 8.5 Hz, 4H), 7.84 (br.s, 4H), four NH protons were not assigned. 13C NMR (CDCl3): δ 25.2 (4C), 41.1 (4C), 47.9 (4C), 49.7 (4C), 53.4 (4C), 54.0 (4C), 56.4 (4C), 69.1 (4C), 69.6 (4C), 108.0 (4C), 122.4 (4C), 138.4 (4C), 147.8 (4C), 157.6 (4C). HRMS (MALDI-TOF) m/z calcd for C56H93N16O4 [M+H]+ 1053.7566, found 1053.7622.

10,15-Dioxa-1,5,7,18,20,24,27,33-octaazatetracyclo[22.6.6.23,6.219,22]tetraconta-3,5,19,21,37,39-hexaene (17g) was synthesized from compound 12 (0.25 mmol, 113 mg) and dioxadiamine 15g (0.25 mmol, 51 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:1-100:20:3, pale-yellow glassy compound. Yield 15 mg (10%). 1H NMR (CDCl3): δ 1.59-1.64 (m, 4H), 1.82 (quintet, J = 5.9 Hz, 4H), 1.84 (quintet, J = 5.6 Hz, 4H), 2.50-2.55 (m, 4H), 2.60-2.65 (m, 4H), 2.71 (t, J = 5.1 Hz, 4H), 2.73-2.77 (m, 4H), 3.36 (q, J = 5.9 Hz, 4H), 3.37-3.41 (m, 8H), 3.49 (t, J = 5.5 Hz, 4H), 4.95 (t, J = 5.1 Hz, 2H), 6.31 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 8.5 Hz, 2.1 Hz, 2H), 7.94 (d, J = 2.1 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 25.0 (2C), 26.5 (2C), 29.3 (2C), 41.7 (2C), 48.0 (2C), 49.0 (2C), 51.3 (2C), 51.5 (2C), 56.5 (2C), 69.5 (2C), 70.9 (2C), 106.8 (2C), 121.4 (2C), 138.9 (2C), 148.9 (2C), 158.4 (2C). HRMS (MALDI-TOF) m/z calcd for C32H55N8O2 [M+H]+ 583.4448, found 583.4391.

10,13,16-Trioxa-1,5,7,19,21,25,28,34-octaazatetracyclo[23.6.6.23,6.220,23]hentetraconta-3,5,20,22,38,40-hexaene (17h) was synthesized from compound 12 (0.25 mmol, 113 mg) and trioxadiamine 15h (0.25 mmol, 55 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), DavePhos (18 mg, 18 mol%), tBuONa (0.6 mmol, 58 mg) in 12 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 28 mg (19%). In the second experiment (scale-up), compound 17h was synthesized using compound 12 (4 mmol, 1.804 g) and trioxadiamine 15h (4 mmol, 880 mg) in the presence of Pd(dba)2 (183 mg, 8 mol%), DavePhos (142 mg, 9 mol%), tBuONa (12 mmol, 1.152 g) in 100 mL dioxane. Yield 455 mg (19%). 1H NMR (CDCl3): δ 1.81 (quintet, J = 5.8 Hz, 8H), 2.49-2.54 (m, 4H), 2.59-2.64 (m, 4H), 2.69-2.76 (m, 8H), 3.19 (br.s, 2H), 3.33 (q, J = 6.1 Hz, 4H), 3.36 (s, 4H), 3.54 (t, J = 5.6 Hz, 4H), 3.54-3.57 (m, 4H), 3.59-3.62 (m, 4H), 5.02 (t, J = 5.4 Hz, 2H), 6.26 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 8.5 Hz, 1.9 Hz, 2H), 7.93 (d, J = 1.9 Hz, 2H). 13C NMR (CDCl3): δ 25.1 (2C), 29.1 (2C), 40.0 (2C), 48.0 (2C), 49.5 (2C), 51.6 (2C), 52.1 (2C), 56.3 (2C), 69.5 (2C), 70.1 (2C), 70.3 (2C), 106.8 (2C), 121.4 (2C), 139.0 (2C), 148.8 (2C), 158.3 (2C). HRMS (MALDI-TOF) m/z calcd for C32H55N8O3 [M+H]+ 599.4397, found 598.4342.

11,14,17,44,47,50-Hexaoxa-1,5,7,21,23,27,30,34,38,40,54,56,60,63,69,79-hexadecaazaheptacyclo-[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 (19h) was isolated as the second product in the scaled-up synthesis of compound 17h. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 73 mg (3%). 1H NMR (CDCl3): δ 1.71-1.79 (m, 16H), 2.37-2.67 (m, 32H), 3.27 (br.s, 8H), 3.40-3.62 (m, 32H), 5.05 (br.s, 4H), 6.27 (d, J = 8.5 Hz, 4H), 7.29 (d, J = 8.5 Hz, 4H), 7.86 (br.s, 4H), four NH protons were not assigned. 13C NMR (CDCl3): δ 25.1 (4C), 28.98 (4C), 41.3 (4C), 44.7 (4C), 47.2 (4C), 50.9 (4C), 51.4 (4C), 54.6 (4C), 69.2 (4C), 69.8 (4C), 70.2 (4C), 106.6 (4C), 120.1 (4C), 138.6 (4C), 148.5 (4C), 158.0 (4C). HRMS (MALDI-TOF) m/z calcd for C64H109N16O6 [M+H]+ 1197.8716, found 1197.8597.

1,8,12,19,22,27,30,31-Octaazatetracyclo[17.5.5.13,7.113,17]hentriaconta-3(31),4,6,13(30),14,16-hexaene (20a) was synthesized from compound 8 (0.25 mmol, 128 mg) and diamine 15a (0.25 mmol, 19 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 21 mg (20%). 1H NMR (CDCl3): δ 1.84 (br.s, 2H), 2.68-2.73 (m, 16H), 3.38 (br.s, 4H), 3.67 (s, 4H), 5.79 (br.s, 2H), 6.29 (d, J = 8.2 Hz, 2H), 6.43 (d, J = 7.3 Hz, 2H), 7.35 (dd, J = 8.2 Hz, 7.3 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 28.2 (1C), 40.8 (2C), 46.3 (4C), 51.8 (4C), 62.3 (2C), 105.0 (2C), 112.6 (2C), 138.3 (2C), 156.2 (2C), 159.0 (2C). HRMS (MALDI-TOF) m/z calcd for C23H37N8 [M+H]+ 425.3141, found 425.3110.

1,8,12,19,22,25,32,36,43,46,51,54,55,58,61,62-Hexadecaazaheptacyclo[41.5.5.519,25.13,7.113,17.127,31.137,41]dohexaconta-3(62),4,6,13(61),14,16,27(55),28,30,37(54),38,40-dodecaene (22a) was isolated as the second product in the synthesis of compound 20a. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 6 mg (6%). 1H NMR (CDCl3): δ 2.07 (quintet, J = 5.5 Hz, 4H), 2.57-3.02 (m, 32H), 3.48 (t, J = 5.7 Hz, 8H), 3.67 (s, 8H), 5.94 (br.s, 4H), 6.54 (d, J = 7.3 Hz, 4H), 6.57 (d, J = 8.6 Hz, 4H), 7.44 (t, J = 7.9 Hz, 4H), NH protons were not assigned. 13C NMR (CDCl3): δ 27.9 (2C), 46.0 (4C), 46.5 (8C), 51.8 (8C), 64.0 (4C), 107.1 (4C), 114.6 (4C), 138.2 (4C), 155.5 (4C), 159.6 (4C). HRMS (MALDI-TOF) m/z calcd for C46H73N16 [M+H]+ 849.6204, found 849.6282.

1,8,12,16,23,26,31,34,35-Nonaazatetracyclo[21.5.5.13,7.117,21]pentatriaconta-3(35),4,6,17(34),18,20-Hexaene (20b) was synthesized from compound 8 (0.25 mmol, 128 mg) and triamine 15b (0.25 mmol, 33 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 27 mg (23%). 1H NMR (CDCl3): δ 1.67 (quintet, J = 5.4 Hz, 4H), 2.55-2.70 (m, 20H), 3.25 (br.s, 4H), 3.56 (s, 4H), 5.27 (br.s, 2H), 6.21 (d, J = 8.3 Hz, 2H), 6.54 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), three NH protons were not assigned. 13C NMR (CDCl3): δ 29.4 (2C), 40.5 (2C), 45.2 (4C), 47.2 (2C), 52.4 (4C), 61.3 (2C), 104.4 (2C), 111.9 (2C), 138.0 (2C), 157.3 (2C), 159.4 (2C). HRMS (MALDI-TOF) m/z calcd for C26H44N9 [M+H]+ 482.3720, found 482.3677.

1,8,11,15,18,25,28,33,36,37-Decaazatetracyclo[23.5.5.13,7.119,23]heptatriaconta-3(37),4,6,19(36),20,22-hexaene (20c) was synthesized from compound 8 (0.25 mmol, 128 mg) and tetraamine 15c (0.25 mmol, 40 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 11 mg (9%). 1H NMR (CDCl3): δ 1.55 (br.s, 2H), 2.20-2.85 (m, 24H), 3.24 (br.s, 4H), 3.51 (s, 4H), 6.20 (d, J = 8.0 Hz, 2H), 6.45 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), NH protons were not assigned. HRMS (MALDI-TOF) m/z calcd for C27H47N10 [M+H]+ 511.3985, found 511.3929.

1,8,12,15,19,26,29,34,37,38-Decaazatetracyclo[24.5.5.13,7.120,24]octatriaconta-3(38),4,6,20(37),21,23-hexaene (20d) was synthesized from compound 8 (0.25 mmol, 128 mg) and tetraamine 15d (0.25 mmol, 44 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 15 mg (11%). 1H NMR (CDCl3): δ 1.61 (quintet, J = 6.1 Hz, 4H), 2.44-2.90 (m, 24H), 3.15 (br.s, 4H), 3.59 (s, 4H), 6.15 (d, J = 8.3 Hz, 2H), 6.54 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 29.1 (2C), 40.8 (2C), 45.3 (4C), 47.3 (2C), 48.4 (2C), 52.1 (4C), 60.8 (2C), 103.6 (2C), 111.4 (2C), 138.0 (2C), 157.6 (2C), 159.1 (2C). HRMS (MALDI-TOF) m/z calcd for C28H49N10 [M+H]+ 525.4142, found 525.4159.

1,8,12,16,20,27,30,35,38,39-Decaazatetracyclo[25.5.5.13,7.121,25]nonatriaconta-3(39),4,6,21(38),22,24-hexaene (20e) was synthesized from compound 8 (0.25 mmol, 128 mg) and tetraamine 15e (0.25 mmol, 47 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 22 mg (16%). 1H NMR (CDCl3): δ 1.68 (br.s, 6H), 2.47-2.81 (m, 24H), 3.18 (br.s, 4H), 3.57 (s, 4H), 5.22 (br.s, 2H), 6.21 (d, J = 8.2 Hz, 2H), 6.60 (d, J = 6.8 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), four NH protons were not assigned. 13C NMR (CDCl3): δ 28.0 (1C), 28.8 (2C), 40.6 (2C), 45.0 (4C), 47.5 (2C), 49.2 (2C), 52.0 (4C), 60.7 (2C), 104.2 (2C), 111.7 (2C), 137.9 (2C), 157.1 (2C), 159.0 (2C). HRMS (MALDI-TOF) m/z calcd for C29H51N10 [M+H]+ 539.4298, found 539.4275.

11,14-Dioxa-1,8,17,24,27,32,35,36-octaazatetracyclo[22.5.5.13,7.118,22]hexatriaconta-3(36),4,6,18(35),19,21-hexaene (20f) was synthesized from compound 8 (0.25 mmol, 128 mg) and dioxadiamine 15f (0.25 mmol, 37 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:2, pale-yellow glassy compound. Yield 27 mg (22%). 1H NMR (CDCl3): δ 2.74-2.79 (m, 8H), 2.82-2.87 (m, 8H), 3.37 (q, J = 5.1 Hz, 4H), 3.58 (s, 4H), 3.63 (t, J = 5.4 Hz, 4H), 3.64 (s, 4H), 5.75 (br.s, 2H), 6.28 (d, J = 7.1 Hz, 2H), 6.42 (d, J = 7.1 Hz, 2H), 7.33 (dd, J = 8.3 Hz, 7.3 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 41.8 (2C), 46.0 (4C), 51.8 (4C), 61.6 (2C), 69.5 (2C), 70.0 (2C), 104.9 (2C), 112.2 (2C), 138.2 (2C), 156.5 (2C), 159.2 (2C). HRMS (MALDI-TOF) m/z calcd for C26H43N8O2 [M+H]+ 499.3509, found 499.3540.

11,16-Dioxa-1,8,20,27,30,35,38,39-octaazatetracyclo[25.5.5.13,7.121,25]nonatriaconta-3(39),4,6,21(38),22,24-hexaene (20g) was synthesized from compound 8 (0.25 mmol, 128 mg) and dioxadiamine 15g (0.25 mmol, 51 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 15 mg (11%). 1H NMR (CDCl3): δ 1.57-1.61 (m, 4H), 1.80 (quintet, J = 6.0 Hz, 4H), 2.75-2.80 (m, 8H), 2.89-2.92 (m, 8H), 3.24 (q, J = 5.9 Hz, 4H), 3.37-3.41 (m, 4H), 3.44 (t, J = 5.8 Hz, 4H), 3.65 (s, 4H), 5.59 (t, J = 5.1 Hz, 4H), 6.24 (d, J = 8.3 Hz, 2H), 6.40 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 26.3 (2C), 29.3 (2C), 40.0 (2C), 45.9 (4C), 52.0 (4C), 61.3 (2C), 68.4 (2C), 70.7 (2C), 104.0 (2C), 112.2 (2C), 138.2 (2C), 156.7 (2C), 159.4 (2C). HRMS (MALDI-TOF) m/z calcd for C30H51N8O2 [M+H]+ 555.4135, found 555.4081.

11,14,17-Trioxa-1,8,21,28,31,36,39,40-octaazatetracyclo[26.5.5.13,7.122,26]tetraconta-3(40),4,6,22(39),23,25-hexaene (20h) was synthesized from compound 8 (0.25 mmol, 128 mg) and trioxadiamine 15h (0.25 mmol, 55 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:20:3, pale-yellow glassy compound. Yield 26 mg (18%). 1H NMR (CDCl3): δ 1.79 (quintet, J = 6.1 Hz, 4H), 2.86-2.93 (m, 16H), 3.24 (br.s, 4H), 3.48 (t, J = 5.9 Hz, 4H), 3.49-3.52 (m, 4H), 3.57-3.61 (m, 4H), 3.63 (s, 4H), 5.69 (br.s, 2H), 6.30 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 29.1 (2C), 39.7 (2C), 45.4 (4C), 51.5 (4C), 61.1 (2C), 68.8 (2C), 70.2 (2C), 70.6 (2C), 104.8 (2C), 111.5 (2C), 138.5 (2C), 155.8 (2C), 159.4 (2C). HRMS (MALDI-TOF) m/z calcd for C30H51N8O3 [M+H]+ 571.4084, found 571.4071.

1,8,12,16,23,26,32,36,37-Nonaazatetracyclo[21.6.6.13,7.117,21]heptatriaconta-3(37),4,6,17(36),18,20-hexaene (21b) was synthesized from compound 14 (0.25 mmol, 135 mg) and triamine 15b (0.25 mmol, 33 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 10:4:1, pale-yellow glassy compound. Yield 8 mg (6%). 1H NMR (CDCl3): δ 1.76 (quintet, J = 6.0 Hz, 4H), 1.82 (quintet, J = 5.0 Hz, 4H), 2.56 (t, J = 5.1 Hz, 4H), 2.68-2.81 (m, 16H), 3.27 (br.s, 4H), 3.74 (s, 4H), 6.16 (d, J = 8.5 Hz, 2H), 6.33 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), NH protons were not assigned. 13C NMR (CDCl3): δ 25.7 (2C), 29.0 (2C), 41.1 (2C), 47.3 (2C), 47.4 (2C), 49.0 (2C), 51.9 (2C), 53.8 (2C), 59.0 (2C), 103.8 (2C), 112.5 (2C), 137.6 (2C), four quaternary carbon atoms were not assigned. HRMS (MALDI-TOF) m/z calcd for C28H48N9 [M+H]+ 510.4033, found 510.3989.

11,14-Dioxa-1,8,17,24,27,33,37,38-octaazatetracyclo[22.6.6.13,7.118,22]octatriaconta-3(38),4,6,18(37),19,21-hexaene (21f) was synthesized from compound 14 (0.25 mmol, 135 mg) and dioxadiamine 15f (0.25 mmol, 37 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 15 mg (11%). 1H NMR (CDCl3): δ 1.85 (br.s), 2.57 (t, J = 5.1 Hz, 4H), 2.72-2.87 (m, 12H), 3.39 (q, J = 5.5 Hz, 4H), 3.42 (s, 4H), 3.63 (s, 4H), 3.70 (t, J = 5.5 Hz, 4H), 5.57 (br.s, 2H), 6.21 (d, J = 8.3 Hz, 2H), 6.40 (d, J = 7.1 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 25.0 (2C), 42.1 (2C), 47.4 (2C), 49.3 (2C), 52.2 (2C), 52.8 (2C), 58.9 (2C), 69.7 (2C), 70.4 (2C), 104.2 (2C), 112.9 (2C), 137.7 (2C), 156.0 (2C), 159.0 (2C). HRMS (MALDI-TOF) m/z calcd for C28H47N8O2 [M+H]+ 527.3822, found 527.3751.

12,17-Dioxa-1,8,21,28,31,37,41,42-octaazatetracyclo[26.6.6.13,7.122,26]dotetraconta-3(42),4,6,22(41),23,25-hexaene (21g) was synthesized from compound 14 (0.25 mmol, 135 mg) and dioxadiamine 15g (0.25 mmol, 51 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 9 mg (6%). 1H NMR (CDCl3): δ 1.62 (br.s, 4H), 1.81 (quintet, J = 6.0 Hz, 4H), 1.84 (br.s, 4H), 2.60 (t, J = 5.0 Hz, 4H), 2.75-2.89 (m, 12H), 3.26 (q, J = 5.9 Hz, 4H), 3.38-3.47 (m, 8H), 3.48 (s, 4H), 5.59 (br.s, 2H), 6.18 (d, J = 8.3 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 7.25 (t, J = 7.7 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 25.0 (2C), 26.5 (2C), 29.5 (2C), 40.1 (2C), 47.4 (2C), 48.3 (2C), 52.1 (2C), 52.2 (2C), 54.8 (2C), 68.6 (2C), 70.7 (2C), 103.9 (2C), 112.0 (2C), 137.8 (2C), 156.6 (2C), 159.0 (2C). HRMS (MALDI-TOF) m/z calcd for C32H55N8O2 [M+H]+ 583.4448, found 583.4406.

12,15,18-Trioxa-1,8,22,29,32,38,42,43-octaazatetracyclo[27.6.6.13,7.123,27]tritetraconta-3(43),4,6,23(42),24,26-hexaene (21h) was synthesized from compound 14 (0.25 mmol, 135 mg) and trioxadiamine 15h (0.25 mmol, 55 mg) in the presence of Pd(dba)2 (23 mg, 16 mol%), BINAP (28 mg, 18 mol%), tBuONa (0.75 mmol, 72 mg) in 5 mL dioxane. Eluent CH2Cl2-MeOH-NH3aq 100:25:5, pale-yellow glassy compound. Yield 15 mg (10%). 1H NMR (CDCl3): δ 1.78 (quintet, J = 6.0 Hz, 4H), 1.87 (br.s, 4H), 2.62 (t, J = 5.1 Hz, 4H), 2.79-2.84 (m, 4H), 2.85-2.90 (m, 4H), 2.93-2.97 (m, 4H), 3.23 (q, J = 5.9 Hz, 4H), 3.49 (s, 4H), 3.52 (t, J = 5.9 Hz, 4H), 3.53-3.56 (m, 4H), 3.59-3.62 (m, 4H), 5.38 (br.s, 2H), 6.19 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), two NH protons were not assigned. 13C NMR (CDCl3): δ 24.5 (2C), 29.1 (2C), 39.9 (2C), 47.3 (2C), 48.3 (2C), 51.7 (2C), 52.3 (2C), 59.7 (2C), 69.2 (2C), 70.2 (2C), 70.5 (2C), 104.3 (2C), 112.2 (2C), 137.8 (2C), 156.2 (2C), 159.1 (2C). HRMS (MALDI-TOF) m/z calcd for C32H55N8O3 [M+H]+ 599.4397, found 599.4436.

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

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