Synthesis and characterization of new chiral azolinium salts , precursors to N-heterocyclic carbenes , derived from L-proline

A short and flexible procedure for the preparation of 7 chiral azolinium and 5 functionalized chiral azolinium salts, precursors to N-heterocyclic carbenes, derived from L-proline has been developed. Moderate to good overall yields were obtained. Some NHC dimers and thiones were isolated. X-ray structure determinations of two [Rh-NHC] complexes were also reported.

As part of our own program of studies, we have recently described the rhodium-catalyzed asymmetric transfer hydrogenation of aromatic ketones using chiral NHC ligands derived from (S)-pyroglutamic acid.Good yields and enantioselectivities (up to 94% yield and 90% ee) were observed (Scheme 1). 5 Here, we report the synthesis and characterization of novel functionalized chiral azolinium salts, precursors to NHCs, derived from L-proline, a naturally available product.

Scheme 1 Asymmetric transfer hydrogenation of aromatic ketones
As reported, azolium and azolinium salts are often used as precursors to metal-NHC complexes [1][2][3][4] , but they have also found applications on their own as organocatalysts 6 and ionic liquids. 7These research areas are currently well investigating because of their importance for developing 'greening' chemical processes.
The useful method for the preparation of azolinium salts containing a saturated backbone is a condensation of a N,N'-disubstituted alkanediamine and an inorganic ammonium salt with a trialkylorthoester using both as reagent and solvent, in the presence of a catalytic amount of acid. 8Several modifications of the experimental reaction conditions of this method have been reported in literature. 9In all cases, long reaction time (from few hours to some days) along with a prolonged reflux heating conditions are required for obtaining good conversions.In 2008, Delaude et al. described a facile microwave-assisted synthesis of cyclic amidinium salts.The transformation is highly compatible with a wide range of substituents and counter ions. 10r our synthesis, we chose N-CBz protected-L-proline ((S)-N-(benzyloxycarbonyl)-proline) 2 which is commercially available as starting material.
The synthetic route for the chiral azolinium salts 6 is summarized in Scheme 2.
Our synthesis was initiated by transforming (S)-N-(benzyloxycarbonyl)-proline 2 into corresponding amides 3 by treatment with ethyl chloroformate in the presence of Nmethylmorpholine and a variety of amines.The cleavage of N-CBz protective group of 3 by hydrogenolysis under hydrogen atmosphere at ordinary pressure in the presence of 5% Pd/C catalyst followed by the reduction of amide function using LiAlH 4 afforded the disubstituted alkanediamines 5 in moderate to good yields.Subsequently, the diamines 5 were converted to the azolinium salts 6 by heating with a large excess of triethylorthoformate along with an equivalent of KPF 6 at 80°C for 12h according to the protocol reported in literature. 11However, after many repeated experiments, no desired product was detected.Only the diamide 7 was isolated and its structure was determined by NMR and MS analysis methods (Scheme 3).
We turned our attention to the use of microwave irradiation.This technique was widely developed in our Laboratory and in other research groups. 12The combination of solvent-free synthesis conditions and MW irradiation considerably reduces reaction time, enhances conversions as well as selectivity and sometimes enables the preparation of molecules which are impossible to synthesize in classical heating conditions. 13, the cyclisation was carried out in 'one-pot' reaction using amines 5, triethylorthoformate and NH 4 PF 6 under microwave irradiation conditions at 145°C for 5 min.Generally speaking, azolinium salts 6 were isolated in moderate to good yields (Scheme 2).Under identical reaction conditions (same temperature, same reaction time,…) using a thermostated oil bath (conventional heating), only traces of desired products were detected.Using this experimental protocol, 7 new chiral azolinium salts were synthesized in 4 steps from (S)-N-(benzyloxycarbonyl)-proline 2 in 5-75% overall yields..We then proceeded to synthesize the functionalized chiral azolinium salts 11 possessing not only a hydroxyl function but also a supplementary stereogene center on the alkyl chain in order to study their effects on prospective applications of these chiral salts as precursors to NHCs in asymmetric catalysis.Thus, functionalized chiral azolinium salts 11 were synthesized from diamines 10 which were easily obtained in good overall yields (41% to 90%) in 3 steps from N-CBz protected-L-proline 2 (Scheme 4).
Using the same strategy previously described in Scheme 2, functionalized chiral azolinium salts 11a-d were isolated in moderate yields after purification by flash chromatography on silica gel.On the other hand, owing to the degradation under MW irradiation, the chiral azolinium salt 11e was synthesized by treatment of the diamine 10 with a large excess of trimethylorthoformate followed by an anion exchange with KPF 6 .Scheme 5 summarizes the synthesis of these functionalized chiral azolinium salts 11.
Next, we were interested in characterizing our NHCs.Some azolinium salts were selected for this study.Treatment of the chiral azolinium salts 6a-c and 6e with t-BuOK in THF at room temperature led to the formation of corresponding NHC dimers 12, and not free NHCs, in good yields.These NHC dimers are quite stable in keeping in the glove box and their structures were confirmed by NMR analysis (Scheme 6).To characterize the unstable free NHCs, the useful method is to transform directly a free NHC to its derivative by reaction with sulfur or selenium. 14These adducts are very stable and could be characterized by different analysis methods.Thus, treatment of NHC dimers 12b, 12c and 12e with S 8 in the presence of C 6 D 6 at room temperature for 2h conducted to the formation of thiones 13 in moderate to good yields.Their structures were confirmed by NMR and ESI analyses.The 13 C NMR signals for C=S appear at δ = 186.2,187.6, and 185.4 ppm for 13b, 13c and 13e respectively (Scheme 7).
Finally, the ability of the NHC dimers to the formation of transition metal complexes was also evaluated.The reaction of 12b, 12c and 12e with [Rh(COD)Cl] 2 in THF at room temperature for 24h led to the formation of the expected [Rh-NHC] complexes 14b, 14c 14e which were after purification by flash chromatography on silica gel, in 18-55% yields as air-stable yellow solids (Scheme 8).and ESI analyses and especially the X-ray diffraction (for 14b and 14e) (Figures 1 and 2) confirmed the formation of these [Rh-NHC] complexes.In summary, we have developed a short and flexible procedure for the synthesis of 7 chiral azolinium salts, and 5 functionalized chiral azolinium salts, precursors to N-heterocyclic carbene, derived from L-proline.Moderate to good overall yields were obtained in all cases.The structures of some NHC dimers, thiones and two [Rh-NHC] complexes were confirmed by different analysis methods in particular the X-ray diffraction analysis.The efficiency of these NHC ligands has been evaluated in asymmetric allylic substitution and in conjugate addition of Grignard reagent to α,β-unsaturated ketones.The results of these studies will be communicated in due course.