Acid-promoted direct C-C coupling of 1,3-diazines and 1,2,4-triazines with aryl-containing macrocyclic compounds and their open-chain analogues

A method of direct C-C coupling of azahetarenes with macrocycles (calix[4]arene, benzo-12-crown-4, 1,5-bis(2,6-dimethylphenoxy)-3-oxapentane), based on the nucleophilic addition to unsubstituted carbon atom in azines, has been developed.


Introduction
Macrocyclic compounds exhibit a large variety of functions: e.q. as building inclusion compounds and selective complexing agents for metal ions. 1,2Modification of such molecules by heterocyclic fragments makes it possible to increase their receptor ability and improve biological activity.For example, calix [4]arenes, containing imidazole moieties, have lately attracted considerable interest because of their potential as enzyme mimics. 3Much attention has been paid to the use of heterocycle-containing crown ethers in biological environments and for binding to biomolecules. 4arlier multistage processes have been based on consecutive building of a heterocyclic fragment onto a macrocyclic matrix by cyclization of open-chain structures or by nucleophilic substitution of the heterocycle by action of nucleophilic groups in the macrocycle.Recently we have worked out the method of one-stage modification of benzo crown ethers, their open-chain podand analogues or resorcinearenes by 1,2,4-triazine derivatives which are one of the most active azaheterocycles. 5,6In the present work we have developed the method of nucleophilic addition of arenes to unsubstituted carbon atom in azines for one-step coupling of some hetarenes with aryl-containing macrocycles. 7or the first time it is shown that calix [4]arene can be used as a nucleophilic component in this reaction both with benzo crown ethers and aryl containing podands.Moreover, it is demonstrated that not only 1,2,4-triazines but also 1,3-diazines can be introduced in the process as the electrophile by the synthesis of new macrocycles contaning 1,2,4-triazine and 1,3-diazine units.

Results and Discussion
It has been found that in spite of the presence of aza-groups in the molecule both 1,3-diazines and 1,2,4-triazines usually do not react with aromatic C-nucleophiles.8][9] To find out the optimal conditions for the functionalization of calix [4]arene with 3-methylthio-1,2,4-triazine (2a), 3-amino-1,2,4-triazine (2b) and quinazoline (2c), the interactions of azines with 2,6-dimethyl-phenol (1) as a model reaction were investigated (Scheme 1).In these reactions the corresponding very stable A N -adducts 3a-c were isolated.Calixarene 4 can be considered as a phenol derivative, so it seems very promising to use this macrocycle as a nucleophilic component in C-C coupling.
Thus, reaction of 4 with 2a-c gives rise to exhaustive heteroarylation of the upper rim of calixarene producing 5a-c in moderate yields.(Scheme 1).The reaction involves protonation of the azine nitrogen atom by TFA followed by addition of an aromatic nucleophile.The trifluoroacetates obtained interact with calixarene to form highly stable products which are sparingly soluble in water.
The structures were assigned by 1 H and 13 C NMR-spectroscopy.
In 5a-b the signals of bridging methylene groups were located in the regions δ 3.85-3.88ppm and 4.10-4.23 ppm as a pair broad doublets with J~ 13 Hz, which indicated the presence of the cone conformation. 10,11The saturated protons of the triazine and quinazoline rings appeared at δ 4.90-4.99ppm and 5.7-5.8ppm characteristic of addition products.The 13 C NMR spectra of 5a-b displayed a signal from the bridging methylene group at δ 32.1-32.8ppm supporting an adduct in the cone conformation In 5c the protons of bridging methylene groups were located as two broadened singlets at δ 4.26-4.27ppm and 3.33-3.34ppm, The bridging methylene carbon signal appeared at 32.5 ppm confirming the formation of an adduct in the cone conformation (bridging methylene groups of the 1,3-alternate conformation resonate at 37.7 ppm).

Scheme 3
Compound 7d with two pyrimidine rings was the main product while the substance 8 with one pyrimidine ring was isolated in 11 % yield.
The coupling of benzo-12-crown-4 (9) with protonated 1,3-diazines takes place under the same conditions and results in hetaryl-containing crown ethers 10c-d (Scheme 4).These addition products are stable unlike the corresponding 1,2,4-triazinederivatives.  As expected, pyrimidine and quinazoline were less reactive in the reaction with aromatic polyethers than with phenols.Thus, complete conversion of quinazoline with aromatic polyethers took place in 48h while 4h was sufficient for the reaction with phenol and resorcinol derivatives.This may be due to the sterical hindrance and unconcerted orientation of substituents in the benzo-12-crown-4.
The saturated protons absorbed in the region δ 5.52-6.30ppm.The location of the C2-H signals at the δ 8.4-8.7 ppm indicated formation of a C-C bond between pyrimidine C4 and the aromatic ring of the polyether.
In summary, a convenient one-step method for acid-promoted functionalization of macrocycles such as calix [4]arene, crown ethers and their open-chain podand analogues by nucleophilic addition to the unsubstituted carbon atom of 1,3-diazine and 1,2,4-triazine derivatives has been developed.

Experimental Section
General Procedures.Flash chromatography was performed on Kieselgel Woelm DC silica gel using CH 2 Cl 2 -CH 3 OH as an eluent.All melting points were measured on a Boetius melting point apparatus and are uncorrected.Elemental analyses were performed on a Perkin Elmer CHNO Analyzer PE 2400. 1 H and 13 C NMR spectra were recorded on a Bruker DRX 400 spectrometer with TMS as an internal standard.