Synthesis and Computational Analysis of Densely Functionalized Triazoles Using o-Nitrophenylalkynes

Abstract

Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regioselectivity of these cycloadditions. Several new substrates were predicted that would either give enhanced regiocontrol or invert the regiochemical preference. Experimentally, the alkynes were screened in the [3 + 2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition process and their subsequent orthogonal modification was demonstrated.

Unusual Reactivity of Aryl Aldehydes with Triethyl Phosphite and Zinc Bromide: A Facile Preparation of Epoxides, Benzisoxazoles, and α‐Hydroxy Phosphonate Esters

“…The reaction of 4-formylbenzonitrile (1r, 0.5 g, 3.81 mmol) with triethyl phosphite (1.2 g, 7.62 mmol) in the presence of ZnBr 2 (0.08 g, 0.38 mmol) at room temperature for 30 min followed by workup using general procedure II afforded cis-epoxide 2rЈ (0.14 g, 30 …”

“…The reaction of 2-methyl-6-nitrobenzaldehyde (3a, [30] 0.5 g, 3.02 mmol) with triethyl phosphite (1.5 g, 9.08 mmol) in the presence of ZnBr 2 (0.07 g, 0.30 mmol) at room temperature for 10 min followed by workup using general procedure B afforded 4-methylbenzo[c]isoxazole (4a, 0.33 g, 83 %) as a thick liquid. 1 H NMR (300 MHz, CDCl 3 ): δ = 9.11 (s, 1 H, ArH), 7.45 (d, J = 9.0 Hz, 1 H, ArH), 7.22-7.19 (m, 1 H, ArH), 6.75 (d, J = 6.3 Hz, 1 H, ArH), 2.50 (s, 3 H, Me) ppm.…”

Metal‐Free Cyclization of ortho‐Nitroaryl Ynamides and Ynamines towards Spiropseudoindoxyls

“…[8] Regardless,i nitial attempts towards generating these compounds were made based on copper-catalyzed ynamide chemistry,u sing dibromoalkene 1a or bromoalkyne 5 and tosyl amide 2a as the starting materials (Scheme 2). [8] Regardless,i nitial attempts towards generating these compounds were made based on copper-catalyzed ynamide chemistry,u sing dibromoalkene 1a or bromoalkyne 5 and tosyl amide 2a as the starting materials (Scheme 2).…”

“…In an attempt to expand the scope of nitro-alkyne cycloisomerization reactions,w ee nvisaged that ortho-nitrophenyl-substituted ynamides and ynamines might also serve as promising starting materials.H owever, these compounds are almost completely absent from the literature and described as difficult to synthesize owing to the "instability of the ynamine o-nitrophenyl species". [8] Regardless,i nitial attempts towards generating these compounds were made based on copper-catalyzed ynamide chemistry,u sing dibromoalkene 1a or bromoalkyne 5 and tosyl amide 2a as the starting materials (Scheme 2). [9] When bromoalkyne 5 was used in as imilar fashion as in the procedure developed by Hsung and co-workers, [9a] polycycle 4a was formed rather than the proposed ynamide 3a.In contrast, the use of dibromoalkene 1a resulted in the clean formation of ynamide 3a.…”

Novel synthesis of 1,5-disubstituted-1,2,3-triazolines catalysed by Zepto magnetic microspheres under the influence of a rotating magnetic field

“…In the year 1961, Rolf Huisgen was successful in an attempt for the synthesis by 1,3-dipolar cycloaddition reaction of organic azides with alkynes which afforded both the isomers such as 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles and couldn't be separated 12 . Later developments to modify Huisgen's reaction to achieve regioselective syntheses, number of methodologies have been established for 1,4-disubstituted-1,2,3triazoles [13][14][15] and 1,5-disubstituted 1,2,3-triazoles [16][17][18][19][20][21][22] . Compared to 1,4-disubstituted-1,2,3triazoles, 1,5-disubstituted-1,2,3-triazoles have shown multiple biological activities.…”