Ring opening and ring expansion of 8-cyano-tetrazolo[1,5-a ]pyridine with secondary amines. Reactions of azides, tetrazoles and nitrenes with nucleophiles, Part 2 1

8-Cyanotetrazolo[1,5-a ]pyridine 6T undergoes photochemical ring expansion to afford 1,3-diazepine 7 with diisopropylamine, but with stronger nucleophiles such as dimethylamine a rapid, quantitative ring opening reaction affords dienyltetrazoles 8 and 9 in the dark (an Addition of Nucleophile – Ring Opening reaction)


Scheme 1
Here we report that 8-cyanotetrazolo[1,5-a]pyridine/2-azido-3-cyanopyridine 6T/6A undergoes photochemical ring expansion to afford 1H-1,3-diazepine 7 in the presence of diisopropylamine.Other diazepines and a diazepinone analogous to 5 were obtained with alcohols and water. 5However, no diazepine product was isolable from the reaction with the more nucleophilic dimethylamine.Instead, a rapid ring opening reaction took place in the dark. .4][5] In the 1 H NMR spectrum a doublet at 5.78 ppm is assigned to H-5, and a broader doublet at 6.20 ppm to H-1.Assignment of two triplets at 5.06 and 5.70 ppm to H-6 and H-7, respectively, was confirmed by homonuclear decoupling experiments.In the IR spectrum, the NH and CN stretching absorptions appeared at 3375 and 2221 cm -1 , respectively.

Results and Discussion
The same type of diazepine synthesis could not be achieved with dimethylamine and other strong nucleophiles (diethylamine and pyrrolidine) because 6T reacts rapidly with these amines in the dark at room temperature by nucleophilic attack on C-5 of the pyridine ring to form the ring-opened butadienyltetrazoles 8, 9 as shown in Scheme 3.

Scheme 3
The acetonitrile solution of 6T turned yellow immediately upon admission of dimethylamine gas.After evaporation and recrystallization, the dimethylamine adduct 9 of the dienyltetrazole 8 was obtained as yellow needles.The 1 H NMR spectrum of 9 showed two singlets at 2.60 and 2.95 ppm, each integrating for six protons and assigned to the methyl groups.The latter signal was quite broad, probably due to hindered rotation of a dimethylamino moiety.A triplet at 6.50 ppm and two doublets at 6.97 and 7.12 ppm were assigned to the vinylic H-8, H-7 and H-9, respectively.No other geometric isomers were observed.The infrared spectrum showed a medium nitrile stretching vibration at 2201 cm -1 .The extraneous H-bonded dimethylamine was removed from 9 by dissolution in water and addition of HCl, thus affording the free base 8.In the 1 H NMR spectrum of 8 there were two broad methyl group signals at 2.97 and 3.18 ppm due to the slow rotation of the dimethylamino group.The H-8 proton signal (5.46 ppm) was at ca. 1 ppm higher field than the corresponding signal in 9, while those for H-7 and H-9 were shifted downfield by 0.5 -0.7 ppm.This can be explained by an allylic resonance whereby the NMe 2 lone pair is delocalized onto C8, whereas C9 becomes an iminium ion carbon.This gives the N-C9 bond some double bond character, as is clearly indicated in the X-ray structure described below.The 13 C NMR spectrum of 8 showed two methyl group signals at 37.2 and 44.8 ppm, the vinylic carbons C6 -C9 at 74.7, 152.2, 95.5, and 157.5 ppm, respectively, the tetrazole carbon C5 at 153.9, and the nitrile carbon at 117.7 ppm.The CN stretching absorption appeared at 2206 cm -1 in the infrared spectrum.
The crystal structure of compound 8, crystallized as its hemi-methanol solvate (8•½MeOH), was determined.The structure comprises four independent tetrazoles in the asymmetric unit in addition to a methanol molecule refined at half occupancy and disordered over four different sites.A view of molecule 'A' is shown in Figure 1.The four tetrazoles (molecules A, B, C and D) have the same Z-E configuration, where the NH group in the ring is anti to the cyano group.In each molecule, the terminal -NMe 2 group is conjugated with the diene backbone as evident from the C9n-N10n (n = A, B, C and D) bonds (1.312(4) -1.319(4) Å) which approach those of typical C=N double bonds.The four independent tetrazole molecules are essentially planar, and all atoms lie within 0.2 Å of the least squares plane calculated from all non-H atoms.Each NH group (N1n) donates an H-bond to N3n on an adjacent molecule.Both 8 and 9 eliminate dimethylamine when passed through a heated gas chromatography column.The GC trace and mass spectra demonstrated that tetrazolopyridine 6T was regenerated.This also happened when an acetonitrile solution of 9 was heated to 50 o C. We assume that E-Z isomerization in 8 can take place easily on heating.Cyclization can then take place via attack of the formally negatively charged tetrazole N4 on the iminium-type carbon atom C9 to regenerate the adduct 10 (a 'covalent amination' product), which reverts to 6T by elimination of dimethylamine, as illustrated in Scheme 4 below.Other examples of this type of nucleophilic ring opening reaction have been reported; the 2-(p-chlorophenyl)tetrazolo[1,5-a]pyridinium tetrafluoroborate 11 affords the ring-opened dienyltetrazoles 12 with dimethylamine. 6Tetrazole 6T reacts with sodium hydroxide to afford a mixture of Z,E-and E,E-dienyltetrazoles, 13 (Scheme 5).The ring opening of 6 to 8 and 9 described in Scheme 3 also takes place with other secondary amines, including diisopropylamine, diethylamine and pyrrolidine.Only the reaction with diisopropylamine is slow enough to allow the diazepine 7 to be prepared successfully by rapid room temperature photolysis.It should be possible to prepare diazepines analogous to 7 (Scheme 2) from the other, more reactive amines by using low temperature photolysis.

Conclusions
Photolysis of 8-cyanotetrazolo[1,5-a]pyridine/2-azidopyridine-3-carbonitrile 6T/6A in the presence of diisopropylamine permits the isolation of the 1,3-diazepine derivative 7.However, less hindered/more nucleophilic amines attack the tetrazole 6T in position 5 in a fast, dark reaction, which results in ring opening to cyanodienyltetrazole 8 and its dimethylamine adduct 9.The reaction is reversible: heating of compound 8 causes elimination of dimethylamine and regeneration of 6T.

Crystallography
Cell constants were determined by least-squares fits to the setting parameters of 25 independent reflections measured on an Oxford Diffraction Gemini CCD diffractometer employing graphitemonochromated Mo Kα radiation (0.71073 Å).Data reduction and absorption correction was performed with the CrysAllis package. 8The structure was solved by direct methods with SHELXS and refined by full-matrix least-squares analysis with SHELXL-97. 9All non-H atoms were refined with anisotropic thermal parameters.H-atoms were included in estimated positions using a riding model.Drawings were produced with ORTEP.