Synthesis of Precursor Imidazolium Salts for the Synthesis of N-heterocyclic Carbines Used as Ligands for the Enantioselective Preparation of Heterosteroids Compounds

Since the discovery of the first Nheterocyclic carbene (NHC) complexes in 1968 by Öfele1 and by Wanzlick2 and the isolation of the first stable free carbene in 1991 by Arduengo. A et al.,3 NHCs are playing an increasingly important role in major areas of organometallic, organic, and polymer chemistry4. Their metal complexes are known as extremely versatile and stable catalysts for a wide range of reactions including C-C coupling reactions5-11, olefin metathesis12-15, hydroformylation16-17 & polymirization reactions18-19. ORIENTAL JOURNAL OF CHEMISTRY

The control of the stereoselectivity in transition-metal-catalyzed organic transformation reactions depends on development of a versatile ligand that would strongly coordinate with the metal center 20 .Polydentate ligands having stereodirecting groups could help control the stability and reactivity of mrtals efficiently in a variety of homogeneous catalysis reactions.Thus, a ligand that combines a strongly coordinating unit with a functional group having great influence on the electronic and steric properties of the metal center has considerable potential.
In recent years, there has been growing interest in using N-heterocyclic carbene (NHC) as a ligand for homogenous catalysis 21 .An attractive feature of NHC is not only its strong -donating capability to metals but also the possibility of varying the susbstituents on the nitrogen atom.It is possible that introduction of chiral substituents into NHC would result in enantioselective transformations in asymmetric catalysis.However, the standard chiral NHC obtained by this strategy often leads to low chiral inductions, mainly because of rapid internal rotation of the chiral substituents around the C-N axis.Therefore, to lock the N substituents in fixed conformation, a proposed strategy employs an NHC that bears both a chiral center and a hard chelating functional group on the N substituents resulting in generation of polydentate ligands [20][21][22] .
In the last decade, heteroatomfunctionalized NHC-metal complexes having stereodirecting groups have been developed.These are classified as NHC-based chelate ligands that incorporate a neutral or an anionic functional group.For the neutral functionalized NHC, a breakthrough has been achieved by Burgess, who reports highly efficient asymmetric hydrogenation catalysis based on carbene/oxazoline iridium complexes 23 .Other important chiral bidentate NHC complexes have been developed by Gade et al., 24 and Douthwaite and coworkers 25 for enantioselective hydrosilylation and alkylation, respectively.For the anionic-functionalized NHC, anionic aryloxy-or alkoxo-tethered NHC has been designed and successfully applied in catalytic asymmetric transformations.Pioneering work was done by Hoveyda and coworkers 26 , where metathesis and alkylation reactions proceeded with high enantioselectivity by the use of NHC-Ag complexes as ligand precursors.Arnold et al., 27 as well as Mauduit and coworkers 28 independently introduced chelating alkoxy NHC-Cu compexes for asymmetric alkylations.Thus, the anionic, tightly coordinating polydentate NHC-ligand system is expected to enhance catalyst stability and to offer a key structure for the construction of efficient stereodirecting elements.
More recently, mixed systems, contaning one NHC and one pyrimidine coordinating site have been described as ligands for Ag(I) [30] and Hg(II) 30- 31 complexes.Neither palladium nor platinum complexes of these ligands had been reported when we filed the patent 29 until very recently similar palladium complexes were published [32][33][34] .Related palladium complexes with nitrogen based heterocyclic ligands like NHC coupled pyridines 35- 46 bbenzimidazoles 47 , pyridazine 48 , and pyrazoles 49- 50 have been described as ligands for transition metal complexes.
An important advance, Wang and Lin showed that Ag 2 O can be used to form a Ag-NHC complex from an imidazolium salt that readily transfers the NHC to palladium 51 .The great advantage of this method is the broad tolerance for sensitive N-substituents, which can be destroyed by conventional deprotonation of an imidazolium salt with strong bases.Transmetalation to various metal species gives a wide variety of NHCs coordinate to rhodium, copper, ruthenium, and iridium.However, Ag-induced oxidative degradation of the imidazolium precursors severely limits the use of this method 52 .
Herein, we present a nouvel series of mixed NHC-pyrimidine salts with alkyl, aryl and Lewis acid substituents.Moreover, the use of a Lewis acid could support the activation of an electrophile (aldehydes, imines,…) and confined the sphere of coordination by bringing closer the substrate to the catalytic center (metal) and to the chiral environment brought by the Lewis acid.
At present, the conception and the elaboration of new imidazolium salts for organometallic chemistry evolved towards a design with several functionalities to increase the affinity ligand/metal/substrate, so promoting, in most of the cases, bigger one reactivity and enantioslectivity in the catalytic process.
The design of our precursor imidazolium salts was so guided towards a multifunctional salt affording several complementary active sites for the metal and the substrate (scheme 1).

RESULTS AND DISCUSSION
The precursors 1, 2 and 3 for the synthesis of imidazolium salts have been prepared according to the (Scheme 2).
We recently performed the synthesis of imidazolium salts 4 and 5 from the precursors which have been prepared previously by conversion of N-substituted imidazole 1 or 2 with 2-(3-B r o m o p r o p y l ) -4 , 4 , 5 , 5 -t e t r a m e t h y l -1 , 3 , 2dioxaborolane 3 in CH 3 CN at 100 °C for 12h (Scheme 3).
The structure of compounds 4 and 5 was confirmed by NMR spectra.
Asolution of glacial acetic acid (30.25 mL, 528.47 mmol, 4.3 eq), ammonium acatate in water (9.47 g/ 6.15 mL), and aniline (11.2 mL, 122.9 mmol, 1eq) was added drop-wise to the flask over a period of 1 hour.The solution was continuously stirred and heated at 70 °C for 18 h.The reaction mixture was then cooled to room temperature and added dropewise to a stired solution of NaHCO 3 (88.9g) in water (900 mL), and the aqueous layer was extracted with diethyl ether (3x150 mL).o a flame-dried Schlenk test tube with a magnetic stirring bar was charged with CuI (0.76 g, 4.0 mmol, 0.2 equiv), Cs 2 CO 3 (13.00g, 40.0 mmol, 2.0 equiv), imidazole (1.90 g, 28.0 mmol, 1.4 equiv), 2-chloropyrimidine (2.28 g, 20.0 mmol, 1.0 equiv) and DMF (40 mL) under argon.A rubber septum was replaced with a glass stopper, and the system was then evacuated twice and back filled with argon.The reaction mixture was stirred for 30 min at room temperature, and then heated at 120 °C for 40 hours.The reaction mixture was then cooled to ambient temperature, diluted with (20 mL) of ethyl acetate, filtred throught a plug of silica gel, and washed with ethyl acetate (100 mL).The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel (Petroleum ether/ EtOAc = 20:80) to yield 2-(1H-imidazol-1yl)pyrimidine as a white solid (2.29 g, 78 % yield) m.p : 128-129 °C . 1 H NMR (300 MHz, CDCl 3 ): = 7.12 (s,1H), 7.16 (t, 3 J = 4.9 Hz, 1H), 7.85 (t, 4 J = 1.3 Hz, 1H), 8.58 (s, 1H), 8.65 (d, 3 J = 4.9 Hz, 2H) ppm. 13 5 To a mixture of allyl bromide (5.6 mL, 64.71 mmol, 1.0 equiv) and HSiEt 3 (10.95mL, 68.59 mmol, 1.06 equiv) was added a solution of BCl 3 (1 M in hexane, 72.0 mL, 72.47 mmol, 1.12 equiv) at -78 °C under argon atmosphere.The resulting suspension was stirred at this temperature for 30 min, after which it was allowed to warm to room temperature for 1 hour.The mixture was cooled to 0 °C , and a solution of pinacol (7.64 g, 64.71 mmol, 1.0 equiv) in diethyl ether (30 mL) was added dropwise, and the mixture was stirred for an additional 3 hours.The solution was diluted with water (80 mL) and diethyl ether (40 mL), and the aqueous layer was   1.74 g, 6.9 mmol, 1.0 eq) under argon was added acetonitrille (5 mL).The resulting solution was stirred at 100 °C under pressure for 24 hours, after which the product crashed out.The solid material was filtered and washed with dry pentan (5 mL), then collected and dried under vacuo to give the desired product (1.82 g, 4.6 mmol, 66 % yield) as a white solid.

CONCLUSION
In conclusion, we have developed a new concept for the design and synthesis of highly active precursor imidazolium salts for the synthesis of Nheterocyclic Carbines used as ligands for the preparation of heterosteroids compounds.