Thiazolium carbene catalysts for the fixation of CO2 onto amines

The catalytic N-formylation and N-methylation of amines using CO2 as the carbon source represents a facile and sustainable approach for the synthesis of pharmaceuticals and natural products. Herein, we describe highly effective and inexpensive thiazolium carbenebased catalysts derived from vitamin B1 for the N-formylation and N-methylation of amines, using polymethylhydrosiloxane (PMHS) as a reducing agent, which operate under ambient conditions.

discovery we investigated their applications for the synthesis of various N-methylated amines using Ph 2 SiH 2 as a hydrogen source.
In addition to the N-methylation of amines, N-formylation via CO 2 fixation is also an attractive reaction as N-formylated compounds are key chemical intermediates for the synthesis of drugs, agrochemicals, dyes and fragrances. 8Formyl groups may also be transformed into other functional groups, as in the Vilsmeier reaction, 9 allylation reactions, 10 etc. Their typical synthesis includes the use of chloral, formic acid, formaldehyde or formate, 11 and generating them from carbon dioxide would be advantageous.
In a seminal paper ruthenium-based catalysts were used to prepare N-formylated amines using carbon dioxide and hydrogen as the reducing agent. 12Subsequent papers describe the use of palladium-and copper-based heterogeneous catalysts for this reaction. 13,14Due to the relatively harsh conditions of these reactions employing H 2 , other reducing agents such as hydrosilanes have broad appeal, 15 especially as they are stable, easy to handle and commercially available. 16Inspired by the role of vitamin B1 in CO 2 fixation in animal tissues to synthesize oxaloacetate from pyruvate, we decided to evaluate thiazolium carbenes (Scheme 1) as alternatives to NHC catalysts. 17Compared to typical NHC catalysts, thiazolium carbenes are inexpensive and non-toxic.Additionally, the corresponding salt is air stable and can be stored without the need to exclude moisture and oxygen.Carbene catalysts employ silanes as reductants which can also help to control chemoselectivity. 19Polymethylhydrosiloxane (PMHS) is stable, inexpensive and easily removed after reaction and, therefore, was selected for this study.
Several thiazolium carbenes were investigated for the N-formylation of ethylphenylalaninate, used as a model substrate to identify and optimize the reaction and key reaction parameters (Table 1).In the presence of 7.5 mol% of B (Table 1) the corresponding ethyl formylphenylalaninate was obtained in 95% yield.The other catalysts evaluated are active, but gave lower yields of the product.The solvent used is critical, high yields were obtained in DMA and DMF in which the solubility of CO 2 is high.No activity was observed in toluene, THF and a Institut des Sciences et Inge ´nierie Chimiques, Ecole Polytechnique Fe ´de ´rale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.E-mail: paul.dyson@epfl.chb Institu ¨t fu ¨r Organische und Biomolekulare Chemie, Georg-August-Universita ¨t Go ¨ttingen, Tammann str.2, Germany.E-mail: sdas@gwdg.de† Electronic supplementary information (ESI) available.See DOI: 10.1039/c5cc08741d acetonitrile, possibly due to the instability of the catalyst in these solvents.
Based on the optimized reaction conditions the scope of the thiazolium carbene catalyzed N-formylation reaction was explored using catalyst B (Table 2).Aromatic, alicyclic and aliphatic amines afforded yields of up to 90%.Different amino acids such as methionine and tryptophan ethyl ester (substrates 1a-3a) reacted smoothly under the optimized reaction conditions.Moreover, para-bromo-substituted amines gave the corresponding products in 80% yield (e.g.substrate 9a) and reductive Scheme 1 Thiazolium carbene catalysts employed in the selective N-formylation or N-methylation of amines using CO 2 .dehalogenation was not observed.Notably, the reaction may also be performed on a multigram scale without the formation of N-methylated products.
The formyl group is used as an amino-protecting reagent in peptide synthesis, 20 subsequently being converted into isocyano acids.Formylation of peptides is achieved using formic anhydride, ammonium formate or related reagents. 21These methods have several limitations such as the thermal instability of peptides at elevated temperatures resulting in decomposition and the formation of by-products.We evaluated the N-formylation of dipeptides using catalyst B (10 mol%) and full conversion of the starting material was obtained (see the ESI †).N-Methylation of the amide bonds or other by-products was not observed.We also conducted a competition reaction in which N-methylbenzylamine and benzylamine were reacted in the same pot under the optimized conditions.The secondary amine was found to react faster (ca.2-3 times) than the primary amine and, hence, selectivity for a substrate containing both primary and secondary amines is expected to be low.
The thiazolium carbene catalyst may also be used for N-methylation reaction using CO 2 combined with PMHS under slightly more forcing conditions.Numerous reports describe methylation using CO 2 and hydrogen or silanes as the reducing agent. 22,23In the presence of catalyst B, 4-methoxyaniline was converted to the corresponding N,N-dimethylated aniline at 100 1C in 81% yield (Scheme 2).
N-Methylation of amines has been shown to enhance the biological activity of certain drug molecules. 24For example, inserting one or more methyl groups into a bioactive molecule can enhance lipophilicity and thereby facilitate transport through cell membranes.We successfully applied catalyst B to the N-methylation of cinacalcet (Scheme 3).The N-methylated products were purified in a facile fashion.
In summary, we have demonstrated that a bioinspired thiazolium carbene compound is an efficient catalyst for fixing CO 2 onto different amines in the presence of PMHS.The lead catalyst is cheap and non-toxic.The reaction product, i.e.N-formylation versus N-methylation, may be tuned by simply changing the reaction temperature.The catalyst shows a broad substrate scope and thereby has high application in CO 2 fixation reactions.
Full details are provided in the ESI †.The general procedure for the N-formylation reaction: the thiazolium salt (0.075 mmol) and sodium hydride (0.075 mmol) were dissolved in DMA (2 mL) in a 10 mL Schlenk flask and stirred for 30 min to generate carbene (7.5 mol% per mL solution).The solution was then stored in nitrogen without stirring, until the inorganic salts settled at the bottom of the flask. 1 mL of the carbene solution was transferred into a dry three neck flask (after three vacuum and CO 2 -purge cycles), already charged with the amine (0.5 mmol) and connected to a CO 2 balloon.Next, DMA (2.5 mL) and PMHS (200-300 mL) were introduced and the reaction was monitored by TLC and GC-MS.Upon completion, the reaction mixture was filtered through celite and washed with ethyl acetate and an aqueous work up was performed, the solution dried with anhydrous sodium sulfate, and the product purified using column chromatography using ethyl acetate/pentane and 1% triethyl amine.All yields are isolated yields unless otherwise stated.

Table 1
Optimization of reaction conditions for the N-formylation of ethylphenylalaninate employed as a model substrate a