Tandem pseudopericyclic processes in the cyclization of α - diazonitriles to 5-Halo-1,2,3-triazoles. Scope and limitations †

A series of α -carbonyl diazoacetonitriles has been synthesized and subjected to reaction with hydrogen halides. The scope and limitations of this reaction for preparing 5-halo-1,2,3-triazoles have been determined. The experimental energy of this cyclization is 15–20 Kcal mol -1 . A mechanism of this reaction consists of two steps—addition of HHal to α -carbonyl diazonitriles via a pseudopericyclic group transfer reaction leads to formation of intermediate α -diazo- haloimines which in subsequent hetero-electrocyclic reactions afford 5-halo-1,2,3-triazoles. Indeed, the cyclization of α -carbonyl diazonitriles is a series of tandem pseudopericyclic processes.


Introduction
The reaction of α-diazonitriles with hydrogen halides 2 is a good alternative to the method of synthesis of 5-halo-1,2,3-triazoles based on the Sandmeyer reaction of 5-diazo-1,2,3-triazoles with copper halides in hydrochloric acid. 3The 5-halo-1,2,3-triazoles were then used in the synthesis of riboside derivatives that are of great interest as potential biologically active compounds, owing to their similarity to components of nucleic acid metabolism.5][6] The mechanism, scope and limitations of this reaction have not been determined so far.
To extend these reactions to the synthesis of new 5-halo-1,2,3-triazoles, we have carried out a systematic study of the reactions of a series of diazo-acetonitriles (DAN) having a variety of substituents at the αposition, in various conditions.

Results and Discussion
The reaction of DAN with hydrogen chloride, hydrogen bromide, or hydrogen iodide in various organic solvents leads to 5-halo-1,2,3-triazoles in very good yields. 5We now show that the use of a non-polar solvent leads initially to formation of adducts 2a-n, and 4a-n, of DAN and hydrogen halides in the ratio of 1:2, which could be isolated as solid substances.These adducts have been found to be very sensitive to moisture.The treatment of the adducts 2-and 4a-n with water leads easily to the starting DAN.We have found that the adducts 2-, and 4a-n could be transformed into the 5-halo-1,2,3-triazoles 3, 5, 6 under heating in the solid state.The structures of the 5-halo-1,2,3-triazoles were confirmed by the synthesis of 5-chloro-1,2,3-triazole-4carboxamide by the Sandmeyer reaction from 5-diazo-1,2,3-triazole-4-carboxamide and copper chloride.To expand the scope of this reaction for the preparation of a series of 5-halo-1,2,3-triazoles we have carefully studied the behavior in this reaction of amides and esters of the 2-diazo-2cyanoacetic acid derivatives 1a-h, diazoketones 1j-n, the 2-aryl-2-diazoacetonitriles 7, 2phosphonyl-2-diazoacetonitrile 8, diazomalononitrile 9, and the parent DAN 10.

1a-h 13a-h 14a-h 12a-h
It is interesting to note that all of the diazo compounds that were transformed to 5-halotriazoles were able to form solid adducts with hydrogen halides which subsequently underwent heterocylization in the solid state.The appearance of hydroxy bond-stretching at 2500-3100cm-1, the reduction in intensity of valence stretching of the cyano group, and the long-wave shift of the carbonyl band by about 50-90 cm -1 in the IR spectra of adducts 2a-l in comparison with the parent diazonitriles indicate that the molecules of hydrogen halides are bound to the oxygen atom of the carbonyl-, and the nitrogen atom of cyano groups.We have found for diazoketones that if the shift of the carbonyl band in the IR of adducts is less than 50 cm -1 then the reaction would not occur.Thus, adducts of the diazoketones 2-, and 4-m and -n, in contrast to the other compounds 2-, and 4a-l, could not be transformed into the 5-halo-1,2,3-triazoles, 3-, and 5-m and -n.
Using all these facts we can conclude that intramolecular assistance of the carbonyl (or phosphonyl) group to the addition of H-Hal to the cyano group is necessary for the reaction to take place of DAN with hydrogen halides leading to 5-halo-1,2,3-triazoles.We have studied the kinetics of cyclization of the diazonitriles 1a-l in a solution of hydrogen chloride in ethanol into the 5-chloro-1,2,3-triazoles 3a-l, and the solid-phase cyclization of adducts 4 into the 5-bromo-1,2,3-triazoles, 5. We found that the cyclization in solution is a firstorder reaction for the diazo compounds 1, and second-order for HCl.The activation energy for the transformation of DAN into 5-halo-1,2,3-triazoles has been determined by kinetic study as 18-24 Kcal mol -1 in EtOH solution, and 15-18 Kcal mol -1 in the solid state (Table 1).It has also been shown that the introduction of electron-donating substituents in the phenyl ring of the diazoketones increases the rate of this heterocyclization.

Scheme 6
This process and the addition of hydrogen halides to the cyano group of α-carbonyl diazonitriles is similar and is consistent with the group-transfer type of pseudopericyclic reactions.In contrast to classic pericyclic group-transfer reactions, both these π-conjugated heteroatomic systems have the orbitals lying in the plane of molecule and new σ-bonding takes place from these orbitals rather than from π-orbitals.
The intermediate diazoimine 15 can cyclize to 1,2,3-triazoles 1 via two different mechanisms: electrocyclic, where the new N-N σ-bond occurs from the terminal orbitals of πsystems, and heteroelectrocyclic, where a new N-N σ-bond occurs from orbitals that are orthogonal to the π-system.In our previous work 24,28,30 we showed that the cyclization of diazoimines into 1,2,3-triazoles goes via the heteroelectrocyclic mechanism without rotation of the terminal bonds of the π-conjugated systems, and has a low energy of activation (in the range 8.8-12.2The classic electrocyclic route for these systems has a higher activation energy (about 21.9-26.0Kcal mol-1).
The experimental energies of cyclization of the diazo compounds, 1, and adduct 4 (Table 1) are 17-22, and 15-18 Kcal mol -1 .We can propose that this cyclization occurs via two steps.The first step is the addition of HHal to α-carbonyl-diazonitriles via a pseudopericyclic grouptransfer reaction to form intermediate α-diazo haloimines 15, and the second step is the cyclization of 15 to 5-halo-1,2,3-triazoles via the hetero-electrocyclic mechanism.Therefore, the cyclization of α-carbonyl-diazonitriles is a tandem of pseudopericyclic processes.

Conclusions
General Procedures.The scope and limitations have been determined for the reaction of DAN derivatives with hydrogen halides leading to a variety of 5-chloro-, 5-bromo-, and 5-iodo-1,2,3triazoles.This reaction is limited to diazo compounds bearing groups at the α-position that can form hydrogen-bonds with hydrogen halides and thus assist their addition to the cyano groups of the DAN derivatives.The mechanism of this new reaction includes the addition of two molecules to one molecule of α-carbonyl-(or α-phosphonyl) DAN, the carbonyl-(or phosphonyl-) function-assisted addition of HHal to the cyano group as a pseudopericyclic process, and hetero-electrocyclization of the intermediate diazo-imidoyl halides to give the final 5-halo-1,2,3-triazoles.

2-Hydroxyiminoacetonitriles 13a-h. General procedure
Sodium ethoxide (0.68 g, 0.1 mol) was added to a suspension of 0.1 mol 2-cyanoacetamides 12a-h in 150 mL ethanol.The solution was cooled to 0 o C and 10 mL (0.12 mol) ethyl nitrite was added.After stirring for 1 h, 10 mL HCl was added.The precipitate was filtered and washed (hot ethanol).The filtrate was concentrated and cooled.The product was filtered, crystallized from ethanol and dried.

2-Aminoacetonitriles 14a-h. General procedure
A solution of 0.02 mol oxime 7 in 30 mL ethanol was dropped onto aluminum amalgam (3.51 g, 0.13 mol) at 0 o C.After stirring for 4 h the reaction mixture was filtered and washed with hot ethanol.The filtrate was concentrated and cooled, the product filtered off, crystallized (EtOH) and dried.

2-Cyano-2-diazoacetamides 1a-h (General procedure)
A solution of 2.8 g (41 mmol) sodium nitrite in 15 mL H 2 O was added to the solution of 40 mmol of the amino-nitrile 8 in 120 mL 1M HCl at 0 о С.For compounds 1a-g: The precipitate was filtered, washed with water and dried to yield 1a-g as yellow crystals.For compound 1h: the reaction mixture was extracted with ether (3 x 60 ml).The combined organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.The residual oil was purified by flash chromatography (9:1 dichloromethane-petroleum) to yield 1h as a red oil.
General procedure for acylation of DAN 10 mmol acyl chloride (or acid anhydride) was added to the solution of 0.67 g (10 mmol) DAN and 1.4 mL (10 mmol) Et 3 N in 50 mL CH 2 Cl 2 at -10 to 0 o C.After stirring at this temperature for 2 hr the reaction mixture was washed by 3 x 50 mL water.The organic layer was dried by Na 2 SO 4 and concentrated under reduced pressure at 20 o C. The product was purified by chromatography on silica gel (60 mesh) with dichloromethane-petroleum (9:1) as eluent to yield 1i-n as yellow oils.
General procedure for preparation of adducts 2, 4 of diazonitrile with HHal A 4.54 N solution of HHal in dry diethyl ether (4 mL) was added to the solution of 1 mmol diazo compound 1 in 50 mL dry diethyl ether at 0 o C. The precipitate was filtered, washed with 50 mL dry ether and dried at 0 o C under reduced pressure.

Table 2 .
The