New insight on the cycloaddition of aryl and heteroaryl azides with (trimethylsilyl)acetylene. Spectroscopic and x-ray crystallographic data of silylated 1,2,3-triazoles

Reactions of the dipolarophile (trimethylsilyl)acetylene with a number of aryl 1a - f and heteroaryl azides 1g - i have been examined as routes to the 1-aryl (or 1-heteroaryl) trimethylsilyl-1,2,3-triazoles 2a – i . Regioselectivity that privileges the formation of the corresponding C-4 silylated triazoles, over the C-5 ones was observed in all instances. The regiochemistry of the C-4 adducts was established by 1 H, 13 C-NMR spectroscopy and confirmed by X-ray crystallography of the 2,2,2-trifluoro-1-{5-[4-(trimethylsilyl)-1 H -1,2,3-triazol-1-yl]-2- thienyl}-1-ethanone 2i and 1-phenyl-4-(trimethylsilyl)-1 H -triazole 2l .


Introduction
In a previous paper we described the reaction of some aryl azides and the 2-and 3azidobenzo [b]thiophenes with (trimethylsilyl)acetylene to give 1-aryl (or 1-heteroaryl)-4trimethylsilyl-1,2,3-triazoles via 1,3-dipolar cycloaddition (1,3-DC). 1High yields of C-4 silylated triazoles as the unique isomer were obtained in all instances.Owing the practical applications of triazoles, for examples in agriculture and medicine 2 , the 1,3-DC provides the most useful route to triazole systems containing a large number of different functionalities. 3 the cases of terminal (or asymmetrically substituted) dipolarophiles, regioselectivity is an essential feature of the reaction mechanism that has long been the core topic for theoretical chemists. 4Normally, when steric effects are irrelevant the organic azide adds concertedly to the dipolarophile under the control of the frontier molecular orbital (FMO) with the possible formation of two isomers.Conversely, in the presence of severe steric hindrance at one of the end of the dipole (and/or the dipolarophile) stepwise cycloadditions can compete with the concerted process.Theoretical groundwork based on FMO theory 5 and, more recently, on electronic structure calculations 6 has been applied to explain the regiochemistry in 1,3-DC.
Further preliminary studies uncovered that some five-membered heteroaryl azides 7 react smoothly at room temperature with (trimethylsilyl)acetylene preferentially leading to the formation of C-4 silylated 1,2,3-triazoles.Electronic and steric factors operating in the same direction might be responsible for the high regioselectivity observed in the cases studied. 1 Our interest in this topic is focussed on the orientation of the cycloaddition of different azides fixing as a probe the dipolarophile (trimethylsilyl)acetylene. At the same time, we are interested in the possible activity against Mycobacterium avium and tuberculosis of the resulting silylated 1,2,3triazoles. 8These activity properties can be ascertained by using the large number of cycloaddition reactions available.
In the present work we report experimental evidences on the regiochemistry of 1,2,3-triazoles arising from 1,3-DC of a number of fluorinated (fluoro and trifluoromethyl) aryl azides 1a -f and para-like substituted heteroaryl azides 1g -i in neat (trimethylsilyl)acetylene.
The orientation of triazoles 2a -i is confirmed by 1

Results and Discussion
The transformation of aryl and heteroaryl azides 1a -i to 1,2,3-triazoles 2a -i by 1,3-DC occurs according to Scheme 1.In particular, the reactions of aryl azides 1a -f in the presence of neat (trimethylsilyl)acetylene proceed smoothly at room temperature to afford the corresponding silylated triazoles 2a -f in high yields.(Scheme 1 and Table 1, entries 1 -6) Reactions were carried out in the dark and were completed within 20-40 days (until TLC showed disappearance of the starting azide).The excess solvent-reagent was eliminated under vacuum and the residue analysed by NMR.Conversion of all these azides into C-4 silylated triazoles was found by NMR spectroscopy to be regiospecific, with the resulting spectral data fully consistent with the proposed structures (Tables 1 and 2).The H-5' chemical shifts of the triazole ring range at 7.05 - A number of studies have been devoted to the correlation between the chemical shifts and coupling constants of protons, carbon, and fluorine atoms in substituted aryl and heteroaryl derivatives, because of the well defined electrical effects of the substituent in such systems. 9The 1-phenyl-4-(trimethylsilyl)-1H-triazole 2l was utilized to determine the substituent chemical shifts (SCS) produced by the triazole ring on the aromatic carbon, while the effects of fluorine atom and trifluoromethyl group were from the literature.9a,c,d The C-1 signals of the phenyl ring range at 135-140 ppm except for the ortho-fluoro derivative 2d (125.5 ppm; Table 2).
Comparatively larger deviations between the measured and the calculated 13C NMR shifts were observed for ortho-substituted derivatives, particularly for the fluorine substituent.Nevertheless the average error of the global SCS prediction was < 1 ppm (n 32 r 0.998).9aThe structure of 2d would suffer from restricted rotation about the C1-N1 bond.That is, the molecule has its lowest energy in a planar conformation in which the orbitals of the fluorine atom have the greatest overlap with the adjacent H-5' orbital.It is of interest to note the high conjugation of the molecule 2d evidence also by the heteronuclear coupling (JH-F 2.9 Hz) between the fluorine atom and the H-5'.  1, entries 7 -9).In this latter case the major isomer 2i (97%) was obtained together with small amounts of the C-5 (Table 1, entry 9).IR, 1 H-, and 13 C-NMR ( To confirm the regiochemistry of C-4 silylated derivatives 2i and 2l, previously prepared from phenyl azide 1l, 1 we made an effort to obtain single crystals suitable for X-ray crystallography.The crystal structure definitely confirms the regiochemistry of 2i and 2l, whose significant bond length (Å) and angle (°) are reported in Figure 1 and 2.
In a preliminary communication 7a we reported that a similar reaction, entailing 5- 0.05) were obtained accompanied by small amounts of ring opening product, due to the low stability of the starting azide 1n making it unable to survive longer under the reaction conditions. 10In summary, we found general evidence that the 1,3-DC of aryl and heteroaryl azides to (trimethylsilyl) acetylene is a FMO and steric controlled process, resulting in the preferential formation of C-4 silylated triazoles.From our findings we infer that steric hindrance plays an important role in increasing the regioselectivity and decreasing the reactivity in these systems.In the cases of certain heteroaryl azides the formation of small but nontrivial amounts of the C-5 isomer shows the existence of a borderline between the two effects.Mass spectra were recorded on VG7070E instruments using electron impact ionisation.
The 2-selenophenyl azide 1g has been obtained following the procedure described for compound 1m 7a and was characterized by 1 H-, 13 C-NMR, IR and exact mass spectra.
Materials -Aryl azides 1a -f were prepared from diazonium compounds and azide ion in alkaline medium according to the general procedure described by Smith and co-workers. 11idothiophenes 1h and 1i, were prepared by selective bifunctionalization of the corresponding dibromothiophene. 12(Trimethylsilyl)acetylene was purchased from Aldrich Chimica Italiana and degassed with nitrogen before the use.Caution -Hydrazoic acid and organic azides are potentially explosive!This category of compounds has recently been subjected to risk evaluation. 13Explosions may be expected by handling phenyl or tosyl azide, although we experienced no problems in handling basic solutions of sodium azide or solid organic azides, which may be stored at -18 °C indefinitely.

Reactions of aryl azides 1a-f and heteroaryl azides 1g-i with (trimethylsilyl)acetylene at 25 °C. General procedure
A solution of the azide in neat (trimethylsilyl)acetylene (1:10 molar ratio) was allowed to react in a screw cap tube for the appropriate time, until tlc showed the absence of the starting azide.The solvent-reagent was removed under vacuum and the residue washed with pentane and then characterized.
The following new triazoles were obtained:   The intensity data were collected using the ω-scan technique within the limits 2.91<2θ<50.04°.

Crystallography of (2i) and (2l)
9426 reflections were read, of which 2641 independent reflections, 830 observed for I > 2 σ (I).The collected frames were processed by SAINT software for integration; an absorption correction was applied together with merging (SADABS) 14 .
The structures were solved in the space group P2(1)/n for 2i and P2(1)/c for 2l by direct methods and difference Fourier maps and subsequently refined by full-matrix least-squares against Fo using the SHELXTL V.5.1 suite of programs. 15All non-hydrogen atoms were refined anisotropically.Hydrogen atoms were first identified in difference Fourier maps, then included in idealized positions and refined riding on their carrier atoms with isotropic thermal parameters 1.2 times those of the pertinent atoms.The final difference Fourier maps were featureless.

Table 2 .
13C NMR spectroscopic data for triazoles 2a -i a internal standard.Spectra of compounds 2a-f were recorded at 75.4 MHz and 2g-i at 50.3 MHz.b JC-F.