C -Cyanation with 1-Cyanobenzotriazole

1-Cyanobenzotriazole is a convenient source of NC + for C-cyanation with in situ -generated sp 3 and sp 2 carbanions providing α -cyano-sulfones, -ketones, -alkanecarboxylate esters, -cyanides, - alkylheterocycles, -diarylmethanes and heterylcarbonitriles in good to high yields (55–78%).

1-Cyanobenzotriazole 1 has been used previously in our group for cyanation of amines and thiols. 8More recently, Cava's group reported the C-cyanating ability of 1 for arylacetonitriles 9 and aromatic and heteroaromatic compounds, 1 where moderate to good yields were obtained for cyanation of simple alkyl-and arenyl-carbanions and the thiophene ring system.In the present work, we have expanded the application of 1-cyanobenzotriazole to the preparation of α-cyanosulfones, -ketones, -alkanecarboxylate esters, -cyanides, -alkylheterocycles, -diarylmethanes and heterylcarbonitriles.

Results and Discussion
1-Cyanobenzotriazole 1 was readily prepared in high yield (92%) following a slightly modified literature procedure 8 by the treatment of benzotriazole with sodium hydride followed by addition of cyanogen bromide (Scheme 1).Use of the sodium salt of benzotriazole, prepared in situ, affords the pure 1-cyanobenzotriazole 1 after simple filtration and evaporation of solvent.Alternative procedures require purification by sublimation.Synthesis of nitriles derivatives.The general utility of 1-cyanobenzotriazole for incorporation of the nitrile functional group into a diverse series of functionalized compounds 2 was investigated by reaction of the corresponding carbanions, again generated in situ, with cyanating reagent 1.For optimum yields, reactions of lithium diisopropylamide (LDA, prepared as detailed in method A) with substrates 2a-j required room temperature for 2 h followed by the addition of 1-cyanobenzotriazole at 0 o C. Then the reaction mixture was allowed to react at room temperature overnight and was quenched with a saturated solution of ammonium chloride.Extraction with ethyl acetate and purification by silica gel column chromatography provided αcyanoalkyl derivatives in average 65 % yield (Scheme 2, Table 1).Nitriles 3k,l were prepared by method B, which requires 2.2 molar equiv of n-BuLi and 12 h at room temperature for generation of the corresponding lithio derivatives.Treatment with 1-cyanobenzotriazole 1 gave the desired products 3k,l in 65 and 70% yields.a For designation of R and R 1 in 2 and 3 see Table 1.

Scheme 2
Lithio derivatives (generated in situ by treating the corresponding heterocycles 2m,n with 1 molar equiv of n-BuLi for 1 h (for 3m) or for 12 h (for 3n)) were treated with 1-cyanobenzotriazole 1 in dry THF at -78 o C. The reaction mixture was allowed to warm to room temperature while stirring overnight and afforded, after workup, heterylcarbonitriles 3m,n in 55-65% isolated yields (Scheme 3 and Table 1 The cyanation of ketone 2i under the standard lithiation conditions (method A) provided a mixture of two isomers 3i and 4 due to the generation of the two corresponding anions on treatment of methyl 2-(4-methoxyphenyl)acetate 2i with LDA 10 (Scheme 4).Our attempts to improve the yield of methyl 2-cyano-2-(4-methoxyphenyl)acetate 3i using shorter reaction times, lower temperatures and n-BuLi were unsuccessful.A variable amount of cyanomethyl 2-(4methoxyphenyl)acetate 4 beside the major product 3i was always detected in the reaction mixture.

Scheme 4
In summary, the utility of 1-cyanobenzotriazole for preparation of a broad variety of heterocyclic and functionalized α-nitriles has been established as a general and efficient methodology.1-Cyanobenzotriazole is an advantageous cyanation reagent because it is a stable, non-volatile, crystalline solid that limits the risk of possible toxic exposure.

Experimental Section
General Procedures.Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution.Elemental and mass spectroscopy analyses were performed by the Analytical Laboratories, Dept. of Chem., University of Florida.THF was distilled from sodium-benzophenone ketal prior to use.All the reactions were performed under a nitrogen atmosphere.Column chromatography was conducted with silica gel (200-425 mesh).
1-Cyano-1H-1,2,3-benzotriazole (1).Benzotriazole (10 g, 84 mmol) was dissolved in anhydrous THF (150 ml).The solution was cooled to 0 o C and 60% sodium hydride (3.36 g, 92.4 mmol) was added.The mixture was allowed to react at the same temperature for 30 minutes.A solution of cyanogen bromide (9.7 g, 92.4 mmol) in dry THF (25 mL) was added rapidly to a vigorously stirred solution of sodium benzotriazole.The reaction mixture was allowed to react at ambient temperature for 1.5 h.The precipitate was filtered off and washed with THF.The filtrate was evaporated and the residue was dissolved in ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to afford 1-cyanobenzotriazole as a colorless powder (92%), mp 74-76 o C (lit.

General procedure of preparation of sulfones 2f-h
To ethanol (100 mL) was added phenyl sulfonyl sodium salt (60.9 mmol) and the respective benzylbromide (60.9 mmol).The mixture was refluxed for 3 hours.The solvent was evaporated and the solid was washed with water and with isopropyl ether to afford compounds 3f-h.