Functionalization of aliphatic tertiary amines mediated by hexachloroethane/cat. copper: synthesis of propargylic amines and methylene-bridged bis -1,3-dicarbonyl derivatives

Copper-catalyzed functionalization of aliphatic tertiary amines with the assistance of C 2 Cl 6 is described. This method details the alkynylation of aliphatic tertiary amines and the synthesis of methylene-bridged bis -1,3-dicarbonyl derivatives. The mechanism of the selective oxidation of aliphatic tertiary amines was also discussed. A broad spectrum of aliphatic tertiary amines was examined in this methodology


Introduction
Carbon-hydrogen bond activation or oxidation has stimulated great interest in the past decades since it can conveniently enable the carbon-carbon or carbon-hetero bond formation without the pre-functionalization of substrates. 1 Considerable progress has been made recently to carry out this kind of unconventional bond formation in which, oxidative dehydrogenation and functionalization of the sp 3 CH bond adjacent to the heteroatom or functional groups have successfully been realized. 2mong these carbon-hydrogen oxidative dehydrogenation couplings, large efforts have been focused on the functionalizations of sp 3 C-H bond adjacent to nitrogen atom of the tertiary amines.A lot of oxidants were used in this oxidative dehydrogenation coupling system, such as O2, 3 benzoyl peroxide, 4 tert-butyl peroxide, 5 NBS, 6 DDQ, 7 DEAD, 8 and PhI(OAc)2 9 .To activate the oxidative dehydrogenation coupling more efficiently, the assistance of transition metal such as rhodium, 10 ruthenium, 11 copper, 2 or iron, 12 was frequently necessary.Mediated by a catalytic amount of transition metal and a suitable oxidant, several kinds of functionalizations with aromatic tertiary amines as the substrates were reported.However, research of aliphatic tertiary amines was relatively rare 13 owing probably to the relatively reduced stability of the reaction intermediates formed, and at the same time, the regioselectivity of oxidative dehydrogenation of aliphatic tertiary amines is hard to control.

Results and Discussion
Polyhalohydrocarbons were rarely used as the reactants since most of them are frequently very stable. 14Rare typical example is the Appel reaction, where the combination of PPh3 and CCl4 enabled the transformation of an alcohol into an alkyl chloride. 15Because of the similarity of tertiary phosphine and tertiary amine, the system of tertiary amine and polyhalohydrocarbon in organic synthesis should be worth investigating.Literature screening revealed that the reaction mechanism of aliphatic amines and polyhalohydrocarbons was studied intensively around 1960s. 16Malik and Vofsi 17 described the mechanism as an initial free-radical chain process followed by a number of ionic steps.
Despite the extensive investigation on the mechanism for this system, the application of polyhalohydrocarbon in organic synthesis has not been fully explored.Recently we reported that the combination of cat.CuCl and CCl4 mediated the synthesis of sulfonyl amidines from tertiary amines and sulfonyl azides. 18Herein we wish to report on the functionalizations of aliphatic tertiary amines mediated by hexachloroethane/catalytic copper salts.

Alkynylation of aliphatic tertiary methylamine with a terminal alkyne
Propargylic amine derivatives have drawn much attention and their synthesis is of high interest because of their important utility as synthons for drug synthesis, 19 and for their interesting bioactivity. 20The nucleophilic alkynylation of functionalized amines and transition metalcatalyzed Mannich type reaction of terminal alkynes to imines were the typical ways to synthesize these compounds. 21However in these effective traditional methods, the presence of a leaving group or the use of imines prepared from the prefunctionalized aldehydes and amines is necessary.Recently, the direct alkynylation to sp 3 C-H bond adjacent to nitrogen of a tertiary amine has emerged as an interesting method.Mild and efficient catalytic systems applied to dehydrogenation of tertiary amines were developed by several groups. 18,2n order to optimize the reaction conditions, several polyhalohydrocarbons, solvents and copper catalysts were screened (Table 1).We first chose CCl4 as a promoter.CuI proved to be the best catalyst over CuBr and CuCl (entries 1-3).CH3CN was the best solvent in contrast to other solvents such as ethyl acetate, hexane, 1,4-dioxane, DMSO, DMF, ClCH2CH2Cl (entries 4-9).Even with the use of CuI, the yield was still rather low until we found that C2Cl6 could be an alternative to CCl4 (entry 11).In this specific case, 3 equiv of N,N-dimethylcyclohexylamine was added, and the desired product was isolated in satisfactory yield (entry 12).Under the optimized conditions, a variety of terminal alkynes and aliphatic tertiary methylamines were investigated, and the corresponding alkynylation products were obtained in good to excellent yields (Table 2).There is no remarkable electronic and position effect of the substituents on the aryl ring of the terminal alkynes on this reaction (entries 2-6).Benzyl acetylene also served as a good candidate (entry 8).Especially, it should be noted that the 3ethynylthiophene as the starting material successfully afforded the corresponding propargylic amine (entry 9).The aliphatic alkyne 1-hexyne afforded the desired product in good yield as well (entry 10).Trimethylsilyl could be tolerated under the conditions (entry 11).A distinguishing feature was that several types of aliphatic tertiary methylamines can be used in this study, which was in sharp contrast with the previous results (entries 12-14).N-methyldicyclohexylamine also gave a better result (entry 15).Some aliphatic tertiary methylamines bearing cycloalkanes gave also better yields (entries 16-17).

Selective oxidation of aliphatic tertiary methylamines: synthesis of methylene-bridged bis-1,3-dicarbonyl derivatives
Recently, Li developed a new method of synthesizing methylene-bridged bis-1,3-dicarbonyl derivatives 22 by iron-catalyzed oxidative reactions of 1,3-dicarbonyl compounds and N,Ndimethylaniline derivatives.Herein, we further extended the tertiary amines methodology to aliphatic tertiary methylamines using our recently developed approach.Similar to the optimization conditions described above for the alkynylation, it was found the best result could be obtained by using 3.0 equiv of N,N-dimethylcyclohexylamine and 1.0 equiv of 1,3dibenzoylmethane.As shown in Table 3, a series of aliphatic tertiary methylamines were screened.The chained aliphatic tertiary methylamines gave the desired product in shorter time (entries 3-4), and slightly heating to 50 °C (entry 1) could accelerate the reaction remarkably.Cyclic amines showed lower activity than that of the acyclic amines (entry 2), which may indicate the difference in the stability of the corresponding iminium species.As shown in Table 4, several aromatic 1,3-diketones gave the corresponding methylenebridged bis-1,3-dicarbonyl products in good to excellent yields.The electronic effect of the substituents on the benzene ring has a great influence on the yields of the products.The substrates with electron-withdrawing group gave moderate yields, whereas those with electrondonating groups gave excellent yields.Also satisfactory yields were obtained when a thienyl substituted substrate was used.

Conclusions
In summary, functionalizations of aliphatic tertiary amines mediated by a catalytic amount of copper salt and hexachloroethane are established.The transformations including the alkynylation of aliphatic tertiary methylamines with terminal alkynes and the synthesis of methylene-bridged bis-1,3-dicarbonyl derivatives by selective oxidation of aliphatic tertiary methylamines were realized.The reactions described here are mild, general and efficient.

Experimental Section
General.Column chromatography was carried out on silica gel (200-300 mesh). 1 H and 13 C NMR spectra were recorded on Bruker AMX-500 MHz instrument and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3.The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet.The coupling constants, J, are reported in Hertz (Hz).Low-resolution MS was obtained using ESI ionization.HRMS was obtained using ESI ionization.GC-MS spectra were performed on an Agilent GC-6890, MS-5973 instrument.GC-HRMS spectra were performed on a Waters GCT Premier, HRMS-PerkinElmer Elan DRC-e instrument.All reagents were weighed and handled in air at room temperature and all reactions were performed without exclusion of air or moisture.Unless otherwise noted, all tertiary amines and alkynes were purchased from Sigma-Aldrich Company and used without further purification.1,3-Dicarbonyl compounds were synthesized according to the literatures. 23neral procedure for propargylic amines (3a-3q) CuI (0.05 mmol), C2Cl6 (1.2 mmol) were put into a 10 mL two-necked flask.CH3CN (4 mL), tertiary methylamine (3.0 mmol) were added successively by micro-syringe.The reaction mixture was stirred at room temperature for 1 h and then alkyne (1 mmol) was added.The resulting mixture was stirred for 24 hours at room temperature.When the reaction was completed, ethyl acetate (20 mL) and water (30 mL) were then added to the reaction mixture.The organic layer was extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with brine and dried over sodium sulfate.The solvent was evaporated and purified by column chromatography on silica gel with petroleum ether/ethyl acetate (3:1 -8:1) as eluent to give the product.

a
Scheme 1. Plausible mechanism for the formation of 3.

Table 2 .
Synthesis of 3 promoted by CuI/C2Cl6 a

Table 3 .
Reactions of 4a with aliphatic tertiary methylamines a

Table 4 .
Synthesis of methylene-bridged bis-1,3-dicarbonyl derivatives a dimethylcyclohexylamine reacted with C2Cl6 in the presence of CuI to give A, on which 4 performed a nucleophilic attack to give B. Product 5 was formed by either nucleophilic substitution reaction or a tandem Cope elimination and Michael addition via intermediate C.