Synthesis and Intramolecular [4+2] Cycloaddition Reactions of 4-Pyridazinecarbonitriles with Alkyne Side Chains

The preparation of a series of new 3-(alkynyl-X)-substituted 4-pyridazinecarbonitriles 2-5 (X = O, NH) is described. The compounds are shown to undergo thermally induced intramolecular Diels-Alder reactions with inverse electron demand, affording the fused benzonitriles 6-8. Incorporation of a 1,2-phenylene unit into the side chain, as in the case of compounds 10 and 13, results in a more favorable conformation of the dienophilic substructure and thus to a pronounced acceleration of the [4+2] cycloaddition reaction.


Introduction
The intramolecular variant of the inverse-electrondemand Diels-Alder reaction of π-deficient N-heteroaromatics such as tetrazines, triazines, diazines and even pyridines has been shown to be of particular value for the construction of a wide variety of fused systems, becauseas a consequence of the "entropic assistance" which is associated with the linkage of diene and dienophile -it proceeds with remarkable ease, in many cases even with "unactivated" dienophiles like alkenes or alkynes [1].In the pyridazine series, for instance, this concept has been applied to the preparation of various indolines [2], indoles [3], and xanthenes [4][5][6], using 1,2-diazines with appropriate olefinic or acetylenic side chains tethered to position 3 of the heterocycle as the starting material.Here, we wish to report on further studies of this reaction type, using 4-pyridazinecarbonitriles as electronically activated diazadienes with either flexible or rigid acetylenic substructures as the side-chain dienophiles.

Results and Discussion
The preparation of the required 3-alkynyloxysubstituted 4-pyridazinecarbonitriles 2-4 as well as that of the amine 5 from readily available 3-chloro-4-pyridazinecarbonitrile (1) [7,8] and the corresponding alkynolates or butynylamine, respectively, is similar to the procedures reported for the synthesis of structurally related pyrimidine and pyrazine derivatives [9,10], although in our case these nucleophilic substitution reactions had to be carried out at much lower temperatures in order to minimize the formation of by-products.
Heating of the ether 2 in an inert solvent (bromobenzene) to 150°C was found to affect the expected cycloaddition reaction, followed by loss of nitrogen in a spontaneous cycloreversion step.After 96 hours, the transformation was complete (NMR monitoring), giving the known dihydrobenzofuran 6 [11] in 79% yield.It should be noted in this context that earlier attempts to cyclize the analogous 6-(alkynyloxy)-3-chloropyridazines had failed [2].Thus, the presence of an electronwithdrawing group like the cyano function in compound 2 must be regarded as essential.
Not surprisingly, the 3-pentynyl ether 3 was found to react significantly slower under identical conditions, as a result of the steric hindrance which is introduced by the terminal methyl group at the alkyne moiety.Here, completion of the reaction takes 36 days at reflux temperature in bromobenzene solution, affording the new disubstituted dihydrobenzofuran 7 in 67% yield.Elongation of the spacer chain by one methylene group, as in the case of the 4-pentyn-1-yloxy compound 4, however, was found to result in a complete loss of reactivity, even under very drastic conditions.Obviously, too much of the required "entropic assistance" is lost with the longer spacer.On the other hand, we were surprised to find that the butynylamino compound 5 does undergo a thermally induced intramolecular cycloaddition reaction, despite the unfavorable effect of the electron-donating amino function.Employment of a higher-boiling solvent (1,2,4-trichlorobenzene), together with a reaction temperature of 180°C for a period of 6 days, permitted the preparation of the indolinecarbonitrile 8 [12] in 49% yield.This successful transformation again shows the beneficial electronic effect of the nitrile function, particularly in view of the fact that comparable cycloadditions with butynylamino-substituted pyrimidines and pyrazines, lacking a cyano group, had failed unless the NH function had been converted into an N-acetyl derivative [9,10].
As an extension of the studies described so far, we investigated the cycloaddition behavior of 4-pyridazinecarbonitriles bearing an acetylenic side chain with a 1,2-phenylene unit incorporated.By this structural feature, the dienophile is fixed in a favorable geometry, hence the [4+2] cycloaddition step should be significantly facilitated, as was observed previously with other ring systems [13,14].The requisite cycloaddition educts were prepared from the chloro nitrile 1, following the pathways displayed in Scheme 3. Nucleophilic substitution of the chloro function by sodium 2-bromophenolate gave the diaryl ether 9, which was subjected to Pd 0 -catalyzed cross-coupling with trimethylsilylacetylene to afford the alkyne 10 in moderate yield.In a similar fashion, 1 was reacted with 2-bromoaniline to give the diarylamine 11, which -after N-acetylation -was cross-coupled with the acetylene unit to yield compound 13.
When the ether 10 as well as the amide 13 were heated in bromobenzene solution to 150°C, an intramolecular cycloaddition reaction was found to take place very smoothly within a few hours, despite the considerable steric hindrance of the dienophilic substructure which is caused by the bulky trimethylsilyl group.This clearly shows the important role of the fixed geometry of the dienophilic side chain in 10 and 13, compared with their much more flexible counterparts in compounds 2-5, with respect to the reaction rate in this type of cycloaddition.The new tricyclic nitriles 14 and 15 thus could be obtained in 62% and 65% yield, respectively.

Conclusion
The sequence described provides a convenient access to several bicyclic and tricyclic aromatic carbonitriles and demonstrates the usefulness of the intramolecular Diels-Alder reaction of appropriately substituted pyridazines for the construction of fused heterocyclic systems.

General
Melting points (uncorrected) were determined on a Kofler hot-stage microscope. 1 H NMR spectra were recorded on a Bruker AC 80 (80 MHz) spectrometer, using TMS as internal reference.IR spectra were taken on a Jasco IRA-1 instrument.High-resolution mass spectra were obtained on a Finnigan MAT 8230 spectrometer.For medium pressure liquid chromatography (MPLC), Merck Lobar ® columns, packed with LiChroprep Si 60, 40-63 µm, were used.Column chromatography was carried out on Merck Kieselgel 60, 63-200 µm, thin layer chromatography was done on Merck aluminium sheets pre-coated with Kieselgel F 254 .Microanalyses were performed at the Institute of Physical Chemistry (Microanalytical Laboratory), University of Vienna..

[4+2] Cycloaddition Reaction of Compound 10
A solution of compound 10 (50 mg, 0.17 mmol) in bromobenzene (1 ml) was heated to 150°C under an Ar atmosphere for 2 hours.The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluent: light petroleum) and subsequent recrystallization from light petroleum to give 1-trimethylsilyl-4-dibenzofurancarbonitrile (14)