The Baylis-Hillman reaction of substituted aminomethylbenzotriazoles

Aminomethylbenzotriazoles react as effective Baylis-Hillman electrophiles with ethyl acrylate in the presence of TiCl 4 at 20 ºC to afford the corresponding benzotriazolated adducts in 66-80% yield. These adducts are (i) readily transformed to the Baylis-Hillman olefins by sodium hydride and (ii) smoothly undergo substitution of Bt with thiols.


Scheme 1
We found only a single report of the Baylis-Hillman reaction using an iminium salt prepared in situ as an electrophile. 46The hygroscopicity, susceptibility to hydrolysis and the low stability of iminium salts with α-H atoms 47 hinder their isolation and encouraged coupling of electron deficient alkenes with the corresponding iminium salts bearing α-H.We report herein reactions of aminomethylbenzotriazoles 1 with ethyl acrylate and analogs.

Results and Discussion
Aminomethylbenzotriazoles 1 are easily prepared according to well-established condensations of benzotriazole, formaldehyde and a secondary amine. 48,49 inomethylbenzotriazoles 1 reacted with acrylates 4 in the presence of TiCl 4 (1.0 equiv) at 20 ºC for 16-20 h to give exclusively the benzotriazolated product 5 in 66-80% yield rather than 6 which is usually expected as the product of the Baylis-Hillman reaction (Table 1).Extension of the reaction time to 72 h gave the same yields, but less than 12 h resulted in the isolation of the compound 5 in lower yield.To our knowledge, this is the first Baylis-Hillman reaction using iminium salts with α-H atoms.
Table 1.Preparation of the Baylis-Hillman adducts 5 Conversion of compounds 5a-d into the Baylis-Hillman olefin 7a-d was accomplished in 65-71% yields by treatment of 5a-d with sodium hydride in THF at room temperature for 5 h.With one equivalent of sodium carbonate at 20 ºC, 5a gave 7a in low yield; a complex mixture was obtained under reflux conditions.
Compounds 7 are synthetic precursors for quaternary ammonium amphiphilic methacrylates, widely applied industrially, e.g., in waste-water treatment. 50,51Previous preparations of 7 from (i) mono ethyl malonate, formaldehyde, and a secondary amine 52 or (ii) halomethyl acrylates and a secondary amine 53,54 have several drawbacks such as tedious procedure, multi-step synthesis, slow reaction rates (days or weeks), and low yields and selectivity.Table 2. Preparation of the Baylis-Hillman olefin 7 Treatment of 5a-c with 2 equiv. of thiols in THF at 20-50 ºC for the time indicated in Table 3, monitoring the reactions by TLC, afforded novel compound 8a-g in 71-82% yield (Table 3).The use of less than 2 equiv. of sodium thiolate left some unreacted starting material.The structures of all compounds 5, 7 and 8 were elucidated by 1 H, 13 C NMR spectroscopy and elemental analysis.
In summary we have developed a novel and general access to functionalized esters possessing an amino group at the β-position via the Baylis-Hillman reaction of ethyl acrylate and ethyl butenoate utilizing an easily accessible N-(α-aminomethyl)benzotriazoles.The good yields of 5 demonstrate the convenience of N-(α-aminomethyl)benzotriazoles as imminium ion equivalents with α -H atoms generated in situ.

Experimental Section
General Procedures.Reagents were obtained form commercial suppliers and were used without further purification.All reactions were carried out under N 2 atmosphere. 1 H NMR (300 MHz) and 13 C (75 MHz) spectra were recorded on a 300 MHz NMR spectrometer in CDCl 3 using TMS as an internal standard.Column chromatography was performed on silica gel 200-425 mesh.THF was distilled from sodium-benzophenone ketyl and CH 2 Cl 2 was distilled from CaH 2 prior to use.

Table 3 .
Reaction of compounds 5 with thiols