First Diels–Alder reaction of a N-nitrogen-substituted iminium ion as dienophile furnishing N-amino-substituted 1,2,5,6-tetrahydropyridines

The exploratory and preliminary work on the reaction of 1-(methoxydiphenylmethyl)-2-methyldiazene with 1,3-dienes reveals a remarkable dichotomy furnishing different heterocyclic Diels–Alder products depending on the presence or absence of water. In contrast to the acid-induced hydrolysis of the N,O-ketal starting material with 1,3-dienes furnishing 1-methyl-1,2,3,6-tetrahydropyridazines (preceding communication), the same acid-promoted reaction albeit under exclusion of water affords N-(methyleneamino)-1,2,5,6-tetrahydropyridines. The serendipitous discovery of the novel 1,2,5,6-tetrahydropyridines was corroborated by an alternative and independent synthesis providing the in situ generated formaldehyde benzophenone azine and its conjugate acid, 2-(diphenylmethylene)-1-methylenehydrazin-1-ium ion. The protonated azine serving as the putative dienophile resembles the first example of an N-nitrogen-substituted iminium ion employed as a dienophile in a bona fide normal electron-demand Diels–Alder reaction.

The decisive difference between routes a and b in generating dienophile 4H + is the requirement of water in route a, whereas the reaction sequence outlined in route b is devoid of water; aqueous work-up merely hydrolyzes cation 8 + .
Another conceivable way of forming cycloadduct 6 assumes that the two 1,2-dialkyl-substituted diazenium ions 1H + (N) may react as dienophiles and add to diene 5a.However, this alternative can be disregarded because of the known lack of dienophilicity of 1,2-dialkyldiazenes and their conjugate acids (a notable exception based on a special structural feature of the azo compounds has been reported [3,4]).

Alternative preparation of 1-diphenylmethyleneamino-1,2,5,6-tetrahydropyridines 9-method B
Inspired by the structure of cycloadducts 9 revealing their composition of the mixed azine 11 and the respective 1,3diene 5, an alternative synthesis was designed with the goal of further proving the structure of Diels-Alder products 9.
Analogous to the common practice of generating imines and iminium ions in situ by reacting primary amines with aldehydes in the presence of Brønsted acids [5][6][7][8][9], a bold one-pot reaction was chosen to provide the mixed azine 11.
To an acetonitrile solution of benzophenone hydrazone 10 and formalin (37% w/v formaldehyde in water) was added 2,3-dimethyl-1,3-butadiene (5a) and a solution of hydrogen chloride in diethyl ether (Scheme 2).Under the reaction conditions, the resulting azine 11 is converted into the conjugate acid 11H + , and the protonated methyleneamine moiety is presumed to react as the N-nitrogen-substituted iminium ion dienophile with diene 5a.Upon work-up with sodium hydroxide, yellowish crystals were obtained in 28% yield.Analytical and spectral data match those of Diels-Alder product 9a proving its identity.The same procedure was applied for the reaction of benzophenone hydrazone 10 with formaldehyde and 1,3-cyclohexadiene 5b providing the bicyclic cycloadduct 9b in 32% yield.
The mechanism of Diels-Alder reactions has long been controversial and there is growing evidence that certain [4 + 2] cycloaddition reactions are better interpreted as stepwise processes, in particular, when the reaction is carried out with polarized or charged reactants or in the presence of Brønsted or Lewis acids [5,[10][11][12][13][14][15].Therefore, the discussion of the formation of Diels-Alder products 9 based on a bona fide concerted cycloaddition reaction should be complemented by considering a stepwise process.
To account for an alternative stepwise reaction-exemplified for the reaction of diene 5a with dienophile 11H + on the way to product 9a (Scheme 3)-an additional allyl cation intermediate 12a + (or a transition state closely resembling it) may be considered.Nucleophilic addition of the diene methylene group onto the methaniminium ion moiety of 11H + forms the carbon-carbon bond between the two methylene groups in cation 12a + .Subsequent nitrogen-carbon bond formation initiated by the hydrazone NH-group of intermediate 12a + closes the ring yielding product 9a.However, making a definite statement about the mechanism of the reaction is beyond the scope of this work.
The serendipitous formation of Diels-Alder products 9 by the reaction of the in situ generated protonated azine 11H + as an N-nitrogen-substituted iminium ion dienophile prompted a literature search about any predecessors.
Melting points were determined on a Kofler hot stage microscope (Thermovar-Reichert).The spectroscopic data have been obtained with the following instruments: Bruker AM 300 ( 1 H and 13 C NMR, 300.13 and 75 MHz, respectively), Varian MAT 44S (MS).
Elementary microanalyses (C, H, N) were performed by Dr. J. Zak at the Institute of Physical Chemistry of the University of Vienna.The results are in good agreement with the calculated values.