Acid-induced hydrolysis of 1-(methoxydiphenylmethyl)-2-methyldiazene: interception of methyldiazenium ion with 1,3-dienes affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products

The conversion of benzophenone methylhydrazone with bromine and pyridine into 1-[(methyldiazenyl)diphenylmethyl]pyridin-1-ium bromide followed by the solvolysis with methanol provides a facile synthesis of 1-(methoxydiphenylmethyl)-2-methyldiazene. The acid-induced hydrolysis of this N,O-ketal releases the methyldiazenyl moiety as the putative intermediate methyldiazenium ion. Reacting as a heterodienophile, methyldiazenium ion is intercepted with 1,3-dienes in [4 + 2+] cycloaddition reactions affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products which are transformed into stable and isolated N-benzoyl derivatives.

Already at this early stage, a common feature of 'normal electron demand' Diels-Alder reactions, namely the activation of the dienophile double bond by the attachment of electron-withdrawing groups (EWG) had been fortuitously practiced.This concept applies especially to diazenes (azo compounds) as heterodienophiles [3].
Monosubstituted diazenes-frequently postulated as reaction intermediates-can be prepared under stringent conditions.Physical and chemical properties of alkyland aryldiazenes (R-N = NH, R = alkyl, aryl) both in substance and in solutions have been studied [11][12][13].A common feature of monosubstituted diazenes is their fast decomposition.Major decomposition products of aryldiazenes (Ar-N = N-H) in neutral and in basic media are mostly the parent hydrocarbon ArH and N 2 [11].Exposed to aqueous acids, aryldiazenes decompose instantaneously although in a different way.
Aryldiazenyl group containing N,O-ketals (hemiaminal ethers, ArN = NC(Ph 2 )-OR)-a class of azo compounds first described by Huisgen and Koch [14]-are highly sensitive toward acids.Treatment of aryldiazenyl hemiaminal ethers with aqueous acid affords the hydrolysis products ROH, Ph 2 C = O, and the putative intermediates ArN = NH.Taking into account the reaction conditions, the conjugate acids, i.e. aryldiazenium ions (ArNH + = NH and/or ArN = NH 2 + ) may have to be considered as well.The formation of those intermediates has been indicated by the isolation of some of their redox products [14].
Similarly, a convenient source for generating aryldiazenium ions is the facile acid-induced hydrolysis of aminals (N,N-ketals) composed of an aryldiazenyl group as one of the two nitrogen containing groups (Ar-N = N-C(R 2 )-N < , R = alkyl or aryl) [15,16].In the absence of added scavengers only traces of the parent arene of the aryldiazenyl group have been detected.Instead, products derived from the aryldiazenyl group, ArNH 2 , ArN 2 + , ArNHNH 2 , and ArN 3 have been isolated as such or as derivatives [15][16][17][18].These disproportionation products are congruent with the nitrogen containing products NH 3 •H 2 SO 4 , N 2 , H 2 NNH 2 •H 2 SO 4 , and HN 3 obtained from the decomposition of diazene-1,2-dicarboxylic acid (HO 2 CN = NCO 2 H) with sulfuric acid resulting from the disproportionation of the parent diazene (diimide, diimine, HN = NH) [19,20] and-considering the reaction conditions-with the conceivable participation of the diazenium ion (H 2 N + = NH).
The decomposition of the smallest alkyldiazene, methyldiazene (CH 3 N = NH) with aqueous acids HA (A = OSO 3 H, Cl) has been thoroughly examined by Ackermann et al. [12].Beside small amounts of CH 4 a number of isolated products arise from nucleophilic displacement reactions at the carbon atom of the 1-methyldiazen-1-ium ion intermediate (CH 3 NH + = NH).Diazene (HN = NH) as the leaving group undergoes disproportionation to N 2 and H 2 NNH 2 , the latter, in turn, giving rise to methylated products CH 3 NHNH 2 and (CH 3 ) 2 NNH 2 in addition to CH 3 OH and CH 3 A derived from the aqueous acids employed.
For the preparation of the methyldiazenyl hemiaminal methyl ether 3a (Scheme 1) a solution of benzophenone methylhydrazone 1 in dichloromethane was added to a solution of bromine in pyridine.Subsequent addition of diethyl ether precipitated a mixture of salts, 1-[(methyldiazenyl)diphenylmethyl]pyridin-1-ium bromide (2) accompanied by pyridinium bromide.The salt mixture was filtered off and had to be used for the next step without delay because pyridinium salt 2 decomposed readily, in particular, in the presence of moist solvents, presumably by undergoing a facile 1,4-elimination of pyridinium bromide.Solvent-free samples of the inseparable pyridinium salts are stable for several days.A sample of the salt mixture was dissolved in acetone-d 6 and permitted to obtain the 1 H NMR spectrum displaying a singlet at δ = 4.13 ppm indicative of the methyldiazenyl group of 2. The salt mixture was dissolved in anhydrous methanol, anhydrous diethyl ether was added and precipitated pyridinium bromide.It is important to quickly remove pyridinium bromide by filtration to prevent its reaction as a protic acid with the hemiaminal ether 3a.From the filtrate (E)-1-[methoxy(diphenyl)methyl]-2-methyl-diazene (3a) was isolated in good yield.Analogously, treatment of the pyridinium salt mixture of 2 with anhydrous ethanol provided (E)-1-[ethoxy(diphenyl)methyl]-2-methyldiazene (3b).Methyldiazenyl hemiaminal ethers 3 (like aryldiazenyl hemiaminal ethers [14,[27][28][29][30]) are acid sensitive but pure and solvent-free samples can be stored for long periods.

Scheme 2
Under ice-cooling, a solution of the hemiaminal ether 3a in acetonitrile was added to a solution of aqueous tetrafluoroboric acid and an excess of 2,3-dimethyl-1,3-butadiene (5a) in acetonitrile and.The reaction conditions intended to ensure that diene 5a is available in excess for the reaction with the methyldiazenium ion (4H + ).Moreover, the purpose of the slow addition of the hemiaminal ether 3a to the aqueous acid solution was to maintain a low concentration of methyldiazene ( 4) and the conjugate acid 4H + , thus minimizing the risk of decomposition that these intermediates are inclined to suffer [12].
Work-up of the reaction included removal of excessive diene and the solvents, treatment of the residue with sodium hydroxide, repeated extraction of the residue with diethyl ether, removal of the solvent, addition of hydrochloric acid to the residue, and another extraction with ether.The two layers were separated, the aqueous phase was basified with sodium hydroxide but the isolation of the [4 + 2 + ] cycloadduct, 1,4,5-trimethyl-1,2,3,6-tetrahydropyridazine (6a) was not attempted because of the anticipated air sensitivity of the product.Instead, a Schotten-Baumann procedure [31,32] with benzoyl chloride produced the stable N-benzoyl derivative.Purification by column chromatography and recrystallisation afforded pure crystals of 1-benzoyl-2,4,5trimethyl-1,2,3,6-tetrahydropyridazine (7a) in 36% yield.
The ether phase-after separation from the aqueous acidic layer-was checked by thin layer chromatography (tlc) exhibiting two major spots assigned to benzophenone and a by-product that was identified by comparison with authentic N-(diphenylmethylene)-3,4-dimethyl-5,6dihydropyridin-1(2H)-amine.The preparation of such alternative Diels-Alder cycloadducts as the sole products from N,O-ketal 3a and 1,3-dienes 5 albeit under different reaction conditions will be presented and discussed in a forthcoming communication [33].

Spectra
The structures of the heterocyclic products 7 have been identified based on their spectral data ( 1 H and 13 C NMR spectra in Supplementary Materials).The 1 H and 13 C NMR spectra of 7d are complex and exhibit broadened signals at ambient probe temperature reminiscent of those of similar bridged and N,N-disubstituted 1,2,3,6-tetrahydropyridazines [34,35].The temperature dependence of the NMR spectra of symmetrically 2,3-disubstituted 2,3-diazabicyclo[2.2.2]oct-5-enes has been attributed to various effects [34,35]: hindered nitrogen inversion, ring twisting, and ring inversion for 2,3-dimethyl-substituted tetrahydropyridazines as as restricted rotation about the N-CO 2 Me bond for 2,3-dicarbomethoxy-substitited bridged tetrahydropyridazines [34,35].Thus, the complex and temperature dependent NMR spectra of 7d (two different groups-benzoyl and methyl-attached to the nitrogen atoms of the tetrahydropyridazine ring) are not unexpected.A detailed analysis of the NMR spectra of 7d was beyond the scope of this synthesis-oriented work.

Conclusion
This communication presents the preliminary and exploratory work on the acid-induced hydrolysis of methyldiazenyl hemiaminoketal methyl ether (3a), providing a convenient source for generating methyldiazenium ion (4H + ) in situ.As anticipated, intermediate 4H + acting as an electron-deficient heterodienophile was successfully intercepted with 1,3-dienes 5 in [4 + 2 + ] cycloaddition reactions affording the Diels-Alder products 1,2,3,6-tetrahydropyridazines 6 which were converted into the stable N-benzoyl derivatives 7. The low yields of the isolated N-benzoyl derivatives 7 may be due to the known decomposition reactions of the intermediates methyldiazene (4) and methyldiazenium ion (4H + ) [12] in competition with the interception by dienes 5 forming the Diels-Alder cycloadducts 6.
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.