Synthesis of novel N-heterocyclic carbene-Rh complexes derived from L-proline and their catalysis in the addition of arylboronic acids to aldehydes

Novel chiral imidazolium salts and a stable N-heterocyclic carbene-Rh complex derived from L-proline have been synthesized. The N-heterocyclic carbene-Rh complexes either generated in situ or pre-synthesized are active catalysts for the addition reaction of arylboronic acids to aldehydes affording the corresponding secondary alcohols in excellent yields


Introduction
In recent years, the chemistry of N-heterocyclic carbenes (NHCs) and their transition-metal complexes have attracted much attention because these carbenes are readily generated from the corresponding imidazolium salts 1 and act as efficient ligands in a great variety of catalytic processes including alkene metathesis 2 , hydrogenation 3 , and C-C 4 and C-N 5 bond construction.On the other hand, although a few examples of chiral NHC-metal complexes have proven exhibiting good or excellent enantioselectivities [6][7][8][9][10] , chiral NHC-metal complex as catalyst has not been extensively investigated to date 11 .For instance, as good chiral sources, proline and their derivatives have been widely applied in asymmetric catalysis 12 , however, to the best of our knowledge, neither chiral NHC nor its metal complex based on proline has been documented in literature.We report herein the synthesis of novel chiral imidazolium salts (precursor of NHC) and a chiral NHC-Rh complex derived from L-proline, and an investigation of their applications in the catalytic addition of arylboronic acids to aldehydes.

Results and Discussion
The synthesis of the desired imidazolium compounds started from enantiopure L-proline 1, which was treated with 4-toluenesulfonyl chloride and Na 2 CO 3 in water giving 2 in 94% yield (Scheme 1).Reduction of 2 with NaBH 4 and BF 3 ⋅Et 2 O at room temperature followed by quenching the reaction with methanol gave (2S)-2-(hydroxymethyl)-1-(4tolylsulfonyl)pyrrolidine 3 in 81% yield.The resulting alcohol reacted with pyridine/TsCl affording the corresponding ester 4 in 83% yield, which then reacted with KI in acetone giving iodide 5 in 74% yield.After heating the mixture of iodide 5 and 1-substituted imidazole in MeCN, the desired imidazolium salts 6 were obtained in yields ranging from 50 to 62%.Their characteristic 1 H NMR chemical shifts at = 9.9-10.4ppm are consistent with the proposed structure N-CH-N in imidazolium ring. 6ext, we turned to the preparation of chiral NHC-Rh complex.[Rh(COD)Cl] 2 was treated with KOBu-t in THF, and subsequently reacted with imidazolium salt 6e and KI giving the NHC-Rh complex 7 in 76% yield (Scheme 2).It is a yellow, air-stable solid.The 1 H NMR spectra confirmed the structure that the low field absorption at δ 9.98 vanished, which is found in imidazolium salt 6e.The more direct evidence of the metalation of the ligand comes from 13 C NMR, which shows the carbene signal at 181.7 ppm and a coupling constant that is diagnostic of direct Rh binding ( 1 J Rh-C = 49.4Hz).HRMS also confirmed the proposed structure.6e was selected for the synthesis of NHC-Rh complex because it has a bulky mesityl group on N-atom which had previously been shown to be superior over other substituents in catalysis 9 .The addition of organometallic reagents to aldehydes has been one of the general methods for the synthesis of secondary alcohols.Of these reagents, organolithium and organomagnesium compounds are most frequently used for this purpose, but tolerate only a few electrophilic groups on themselves. 13Examples of using other functionalized organometallic species such as organocopper, chromium, tin, especially organozinc 14 , have been described.However, those organometallic regeants are usually toxic and sensitive to moisture.The progress that has been achieved by recent publications describing the addition of arylboronic acid derivatives to aldehydes in the presence of catalytic amounts of Rh (I) and phosphine 15 , nitrogen 16 , especially NHC ligands 17 deserve particular mention.These methods combine a high efficiency with a reasonable tolerance towards polar substituents in the substrates and benefit from the stability and readily accessibility of the nontoxic boron derivatives.Nevertheless, reports on the asymmetric version of this protocol are scare.So far, only two examples have been documented in literature 15,16 .One is the asymmetric addition of phenylboronic acid to 1-naphthaldehyde catalyzed by a chiral phosphine-Rh complex giving rise to (R)-(+)-(1-naphthyl)(phenyl)methanol in 41% ee.Another is the rhodium-catalyzed addition of arylboronic acids to aldehydes in the presence of enantiopure amine ligands, but leading to little enantioselectivity (<10% ee).To our knowledge, chiral NHC ligands have not been applied in the catalytic addition of arylboronic acids to aldehydes.

N
A combination of the ligand precursor 6e with Rh was then tested as catalyst for the catalytic addition of phenylboronic acid to p-chlorobenzaldehyde in dimethoxyethane (DME)-H 2 O (3:1) solution using KOBu-t as a base.The results are shown in Table 1.In the absence of NHC ligand, no product formation was observed (Table 1, entries 1, 3).The reaction was sensitive to changes in rhodium source.With 1 mol% of 6e and 0.5 mol% rhodium salt as the catalyst, [Rh(COD)Cl] 2 gave the alcohol in 95% yield (Table 1, entry 5), while RhCl 3 •3H 2 O led to the alcohol only in 21% yield (Table 1, entry 2).Temperature has significant effect on yield.At room temperature, a catalyst system of 6e (1 mol%) and [Rh(COD)Cl] 2 (0.5 mol %) gave only 23% yield (Table 1, entry 7).However, the yield increased to 95% when the reaction was performed at 80 o C (Table 1, entry 5).Reaction temperature at either 60 o C or 90 o C resulted in lower yield (Table 1, entries 8, 9).The catalyst loading has also important effect on yield.The catalyst loading of 1 mol% of 6e and 0.5 mol% of [Rh(COD)Cl] 2 gave excellent result, whereas the other catalyst loading turned out to be less efficient (Table 1, entries 4-6).
The activity evaluation of ligand precursors 6a-d was also carried out under comparable conditions.As can be seen from Table 1, all of the imidazolium salts in combination with [Rh(COD)Cl] 2 showed good catalytic activity in the addition reaction of phenylboronic acid to 4chlorobenzaldehyde.The imidazolium salt 6e bearing bulky substituent on its N-atom exhibited the best results (Table 1, entries 4, 10-13).Apparently, steric factor played a major role as indicated by the significant variation in yields when the R group changed from methyl to mesityl..e 72 h.f without addition of KOBu-t.h 60 h.
Table 2 summarizes the addition of other arylboronic acids to various aldehydes catalyzed by [Rh(COD)Cl] 2 /6e.The results reveal the wide scope of this method that is compatible with nitro, cyano, methoxy, chloro in aldehydes.All of the aldehydes investigated here reacted with arylboronic acids cleanly in excellent yields.
In summary, we have synthesized a series of novel chiral imidazolium salts derived from Lproline, which reacted with [Rh(COD)Cl] 2 to form chiral NHC-Rh complexes.These NHC-Rh complexes are highly active catalysts for the addition of arylboronic acids to aldehydes.were dried by Na, CH 2 Cl 2 by CaH 2 under inert gas Ar prior to use, respectively.All other reagents were used as they were received without any purification unless noted otherwise.

1-(4-Tolylsulfonyl)-L-proline (2).
To a solution of L-proline (1) (2.88 g, 25 mmol) in H 2 O (25 mL) were added Na 2 CO 3 (5.57g, 52.5 mmol) at 0 o C and 4-toluenesulfonyl chloride (5.72 g, 30 mmol) in three portions over a period of 1 h.The slurry were then warmed to room temperature and allowed to stir for 48 h.The reaction mixture was acidified with concentrated aqueous HCl solution to pH 2, and the product was isolated via filtration.

General procedure for preparation of imidazolium iodide (6)
The iodide (5) (2 mmol) and 1-substituted imidazole (2 mmol) were added to a Schlenk tube and the vessel was evacuated and flushed with Ar three times.MeCN (10 mL) was syringed in and the mixture was heated to 80 o C for 2 days.The solvent was then removed under vacuum.The residual solid was washed with Et 2 O and recrystallized from CH 2 Cl 2 /Et 2 O.The product (6) was obtained in yields ranging from 50% to 62%.

Table 1 .
Rhodium-catalyzed addition of phenyl boronic acid 8 to 4-chlorobenzaldehyde 9 a aqueous DME (DME 3 ml/H 2 O 1ml) under Ar, 24 h.b Isolated yield was based on aldehyde.c nd: Not determined d Absolute configration (R) was assigned by comparison with literature value