7-Bromo-1-methyl-2-phenyl-1 H-indole-3-carbonitrile

The title compound was prepared by electrophilic aromatic substitution of 7-bromo-1methyl-2-phenyl-1H-indole with NCTS (N-cyano-N-phenyl-p-toluenesulfonamide). The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, APCI-MS). Purity was assessed by two independent HPLC methods.


Introduction
In recent years, inhibitors of tumor-related protein kinases were established as major therapeutic options for the treatment of various human cancers [1,2]. In the context of our studies directed to identify new protein kinase inhibitors based on the indole structure [3][4][5][6][7], we were interested in the synthesis of the title compound 7-bromo-1-methyl-2-phenyl-1H-indole 3-carbonitrile (3).

Results and Discussion
The preparation of the starting material 1 was accomplished employing methods published in the literature [8,9]. The cyanation of indoles in the 3 position has been described earlier by the use of chlorosulfonyl isocyanate [10]. However, our attempt to apply this reaction to the starting compound 1 failed, leading only to traces of the desired product 3. We therefore used NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) (2) [11] as an alternative reagent for the introduction of the nitrile group by electrophilic aromatic substitution [12] (Scheme 1). This reaction is carried out by heating the reagents in 1,2-dichloroethane in a closed vessel. Boron trifluoride diethyl etherate as a Lewis acid catalyzes the reaction by activating the cyanating reagent NCTS. The nitrile group acts as (2). Reagents and conditions: i) BF 3 ·OEt 2 , 1,2-dichloroethane, closed vessel, bath temperature: 100 • C, 24 h.

Results and Discussion
The preparation of the starting material 1 was accomplished employing methods published in the literature [8,9]. The cyanation of indoles in the 3 position has been described earlier by the use of chlorosulfonyl isocyanate [10]. However, our attempt to apply this reaction to the starting compound 1 failed, leading only to traces of the desired product 3. We therefore used NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) (2) [11] as an alternative reagent for the introduction of the nitrile group by electrophilic aromatic substitution [12] (Scheme 1). This reaction is carried out by heating the reagents in 1,2-dichloroethane in a closed vessel. Boron trifluoride diethyl etherate as a Lewis acid catalyzes the reaction by activating the cyanating reagent NCTS. The nitrile group acts as an electrophile and is transferred to position 3 of the indole. This method furnished the title compound with high regioselectivity in moderate yield. The crude product which was obtained after work-up was purified by crystallization from methanol.
Purity was assessed by two independent HPLC methods (isocratic and gradient) and proved to be sufficient for biological studies (>95%). The IR spectrum displayed the characteristic absorption maximum for the C≡N stretching vibration (2212 cm −1 ).

Materials
The reagents and solvents were purchased from Acros Organics, Geel, Belgium. The reagents were used without further purification. 1,2-Dichloroethane was purchased in extra dry quality. Purified water was used for sodium hydroxide solution and dilute hydrochloric acid as well as for washing. For HPLC analysis reagents of proper quality were used.