CuCl2-catalyzed One-pot Formation of Tetrahydroquinolines from N-Methyl-N-alkylanilines and Vinyl Ethers in the Presence of t-Butylhydroperoxide

Tetrahydroquinoline skeletons can be formed by a CuCl2-catalyzed one-pot reaction of N-methyl-N-alkylanilines and vinyl ethers in the presence of t-butyl-hydroperoxide.


Introduction
Tetrahydroquinolines are an important structural subunit of natural products and many tetrahydroquinoline derivatives exhibit interesting biological and pharmaceutical activities [1].Consequently, synthetic methodologies for preparing tetrahydroquinoline derivatives have attracted considerable interest and several methods offering good results have been reported [2][3][4].Nonetheless, there are still some features requiring improvement in these methods, e.g. the catalysts used are expensive, the systems require special atmospheres and organic solvents are always needed.Thus, a procedure involving a low-cost catalyst and simple and eco-friendly conditions might be very useful.
Copper is one of the oldest transition metals used in organic synthesis and copper salts are still broadly employed nowadays [5,6].Among these copper salts, CuCl 2 , as a mild Lewis acid, is especially favored by chemists due to its inexpensiveness, lack of toxicity and easy-handling.Herein, we wish to report a one-pot synthesis of tetrahydroquinoline derivatives based on a CuCl 2 -catalyzed room temperature reaction of N-methyl-N-alkylanilines and vinyl ethers in the presence of tbutylhydroperoxide (TBHP).

Results and Discussion
Initailly, N,N-dimethylaniline (1a, 1 mmol) was reacted with n-butyl vinyl ether (2a, 1.0 mmol) in the presence of TBHP (1 mmol) at room temperature.No product was observed even after 2 days.On the other hand, when a catalytic amount of CuCl 2 (5 mol%) was added to the reaction mixture, a smooth reaction occurred and tetrahydroquinoline derivative 3a was isolated in 40% yield.To optimize the CuCl 2 -based system, different conditions were tested on N,N-dimethylaniline (1a), and a 1:1.2:2 ratio of 1a/2a/TBHP was found to work best.Several other catalysts (CuBr, FeCl 2 , CuCl, InCl 3 and SbCl 3 ) were examined under the optimized conditions (Table 1).CuBr, FeCl 2 , and CuCl were found to be effective in the reaction, but gave much lower yields.It is noteworthy that when CuCl was used as the catalyst, the N-demethylation product 4a was found to be the main product [4c].As for InCl 3 and SbCl 3 , none of the target product was detected.
Entry.The transformation was found to be general for various aniline derivatives under the optimal conditions.Representative examples are listed in Table 2.In most cases, moderate to good yields of the corresponding tetrahydroquinoline derivatives were obtained.The scope of the reaction could also be extended to substituted N-methyl-N-alkylanilines 1b-h.When para-chloro-N,N-dimethylaniline (1f) was used, the desired product 3f was formed in good yield (Table 2, entry 8).The reaction of paramethyl substituted substrate 1g also afforded the desired product 3g, however, the yield diminished to 35% (Table 2, entry 9).When N,N-3-trimethylbenzenamine (1h) was used, a 1:1 mixture of two isomers with the methyl group on either the 5-or 8-positions was observed (entry 10).When ethyl vinyl ether (2b) was employed as the olefin and reacted with the N-methyl-N-alkylanilines, the desired products were formed in lower yields.Under the optimal condition, when styrene and 1-octene were used as the olefin reacted with the N-methyl-N-alkylanilines, no target products were observed.

Conclusions
In summary, a one-pot reaction for the formation of tetrahydroquinolines based on the reaction of N-methyl-N-alkylanilines and vinyl ethers in the presence of t-butyl hydroperoxide using CuCl 2 as the catalyst was developed.The scope and synthetic applications of this reaction are currently under investigation.

4 3 Table 1 .
One-pot synthesis of tetrahedroquinonline catalyzed by Lewis acid

Table 2 .
Reaction of N-methyl-N-alkylanilines with vinyl ether catalyzed by CuCl 2

Scheme 2 .
It is known that tertiary N-methylanilines can be converted chemoselectively into the corresponding N-(t-butyl-dioxymethyl)anilines 5 efficiently by the ruthenium-catalyzed oxidation with TBHP [4b-c].However, such products were not obtained in this work, in which N-phenylformamide 7 was obtained after hydrolysis.To clarify whether the final product was formed from N-(t-butyldioxymethyl)aniline 5, the compound 5a was prepared according to literature [4b-c].The reaction of 5a with n-butyl vinyl ether (2a) in the presence of a catalytic amount of CuCl 2 at room temperature was carried out and the tetrahydroquinonline 3a was obtained in 58 % yield (Scheme 1).This result indicated that CuCl 2 acted as an effective Lewis acid in this reaction.It also explains why no formation of compounds 5 was observed in the presence of CuCl 2 .Although the mechanism of reaction presented here is not yet clear, based on the above mentioned results, one possible reaction pathway is shown in Scheme 2. First, N-methyl-N-alkylaniline 1 reacts with TBHP, catalyzed by CuCl 2 , to give compound 5.The latter transforms into the iminium ion intermediate 6 in the presence of the Lewis acid (CuCl 2 ), which can form N-phenylformamide 7 after quenching by water.Compound 6 then reacts with vinyl ether 2 to give the cationic intermediate 8. Finally, electrophilic aromatic ring closure affords the 1,4-disubstituted tetrahydroquinoline derivative 3. Proposed mechanism.
a Isolated yield based on the substrate; b Mixture of the two isomers, the ratio is one to one.