New C 2 -symmetric six-membered carbene ligands for asymmetric diethylzinc addition of arylaldehydes

A series of new six-membered NHC precursors were prepared by simply esterification of their parent compounds. Their applicability in asymmetric diethylzinc addition of arylaldehydes has been demonstrated and the corresponding secondary alcohol was obtained with good yields and moderate enantioselectivities


Introduction
4][15][16][17][18] However, among the chiral NHCs synthesized, examples of chiral hydroxyalkyl NHC ligands are still rare.In 2004, Arnold and co-workers reported the synthesis of salt 1 (Figure 1), 19 the Cu I complex of this ligand was used as a catalyst in diethylzinc conjugated addition to cyclohexenone, affording the desired product in up to 51% ee.Almost at the same time, another type of hydroxy-bearing NHC salt 2 derived from (L)-valine was prepared by Mauduit's group and this compound showed high efficiency in chiral molecular recognition. 20Furthermore, the same group designed and synthesized a series of new bidentate NHC precursors 3 based on commercial available amino alcohols, 21- 23 which were successfully applied in Cu II -catalyzed asymmetric addition of diethylzinc to cyclohexanone, as well as asymmetric allylic substitution of allyl phosphates with Grignard reagents.Moreover, the same ligand 3 was proved to be an excellent ligand in multicomponent catalytic enantioselective transformations. 24With similar starting materials, Wilhelm's group prepared several new tridentate NHC precursors 4 as ionic liquids, [25][26] and these salts were also used as catalyst in asymmetric diethylzinc addition to arylaldehydes, giving the corresponding secondary alcohols in good yields and moderate ees (up to 66%).

Results and Discussion
Very recently, we reported the synthesis of several enantiopure 3,4,5,6-tetrahydropyrimidinium salts 5 incorporating two hydroxyl groups as effective ligands in Pd-catalyzed deprotonative cross-coupling process (DCCP). 27Next, we examined the activity of these ligands in asymmetric diethylzinc addition to aldehydes.The yields are good but the ee values are rather low (Table 1, entries 1-6).Usually, the hydroxy group in the Nsubstituent of the NHC ligand was introduced as a coordination group to block the rotation of N-substituent which subsequently elevates the enantioselectivity in catalytic transformations.On the other hand, little attention was paid to modifications the OH group with a steric functional group, which may result in an elevated chiral environment around the carbene center.With this expectation in mind, a series of derivatives of salts 5 are therefore prepared in this paper with the aim to improve their performance in asymmetric catalysis.As shown in Scheme 1, simple treatment of compounds 5a-f with 4-(tert-butyl)benzoyl chloride provided esterification product 6a-f in good yields (76-92%).Luckily, single crystals of 6f were obtained from CH 2 Cl 2 , and the ORTEP view of this compound was obtained (Figure 2).Scheme 1. Synthesis of NHC precursors 6a-f.Determined by chiral HPLC (CHIRALCEL OD Column) analysis.
The synthesized tetrahydropyrimidinium salts 6 were tested in asymmetric diethylzinc addition of 1naphthaldehyde (7a) according to our procedure in the same transformation with pyrimidone salts as catalysts. 28As presented in Table 1, all derivatives 6a-f showed better enantioselectivities than their parent compounds 5a-f, and 6b gave the best result (93% yield, 58% ee).We then tried various conditions of different bases and solvents.Unfortunately, all combinations didn't improve the enantioselectivity (see Supporting information for details).Futhermore, three new salts 6g-6i (Figure 3), derived from the same parent compound as 6b, were also prepared and tested in the same reaction, no improvement of ee value was observed as well (entries 13-15).

Conclusions
In summary, a series of new six-membered NHC precursors (6a-6i) have been prepared and the single-crystal X-ray diffraction further confirmed the structure of compound 6f.The catalytical activity of these ligands in asymmetric diethylzinc addition to arylaldehydes was tested and the corresponding secondary alcohols were obtained with excellent yields and moderate ees (up to 66%).Further work is currently underway to prepare more chiral six-membered NHC ligands, as catalysts in other asymmetric transformation, by modification the hydroxyl group in N-substituent.

Table 2 .
Scope of methodology b Isolated yields.c Determined by chiral HPLC (CHIRALCEL OD Column) analysis.