Chiral pyridine oxazoline and 1,2,4-triazine oxazoline ligands incorporating electron-withdrawing substituents and their application in the Cu-catalyzed enantioselective nitroaldol reaction

Eight pyridine-containing and four 1,2,4-triazine-containing chiral oxazoline ligands incorporating electron-withdrawing substituents have been synthesized by two-step route including Buchwald–Hartwig amination. Enantio-inducing activity of the ligands has been assessed in the copper-catalyzed asymmetric nitroaldol reactions and the influence of the electron-withdrawing substituents on the ligands' activity has been investigated.


Introduction
Metal-based asymmetric catalysis has proven to be a useful tool for preparation of enantiomerically pure compounds [1,2]. Since steric and electronic properties of metal catalysts, and consequently enantio-selectivity of asymmetric processes are determined by organic ligands, the development of efficient chiral ligands is still a major topic in the area of asymmetric catalysis. Chiral oxazoline derivatives constitute a huge group of versatile chiral ligands that utility was proved in diverse metal-catalyzed asymmetric reactions including cyclopropanations, hydrosilylations, hydrogenations, allylic alkylations, diethylzinc additions to aldehydes, Diels-Alder reactions, and nitroaldol reaction [3][4][5][6][7][8]. The asymmetric nitroaldol reaction is a powerful tool in the synthesis of chiral β-nitro-alcohols, which are useful starting materials in the synthesis of diverse bifunctional compounds [9]. Among the various transition metals tested as catalysts in the nitroaldol reaction, copper showed the highest catalytic activity. It forms highly active complexes not only with oxazoline ligands but also with a wide variety of chiral ligands, such as amine-based ligands, Schiff basebased ligands, salen-based ligands, amino alcohols-based ligands, salalen-based ligands, which have been recently summarized in two review papers [10,11]. According to our ongoing research project focusing on the synthesis and application of ligands that combine in their structures chiral oxazoline and six-membered aza-heteroaromatic rings, we have examined ligands with 1,2,4-triazine 1a-1d (ligands 1 3 type 1), pyridine, pyrimidine, and pyrazine ring 2a-2c, 3a-3c (ligands type 2 and 3) (Fig. 1) [12][13][14][15][16][17]. In the ligands, the chiral oxazoline ring and the aza-heteroaromatic ring are linked by N-phenylamine unit. The ability of the ligands to induce enantio-selectivity has been assessed in the coppercatalyzed asymmetric nitroaldol reaction of nitromethane with a variety of aromatic and aliphatic aldehydes. This study revealed that the ligands with 1,2,4-triazine scaffold 1a-1d exhibit significantly higher enantio-inducing activity than the ligands 2a-2c and 3a-3c possessing other sixmembered aza-heteroaromatic ring.
Among them, the ligands 1a and 1d appeared to be the most active. Asymmetric Henry reaction catalyzed by ligand 1a gave the nitro-alcohols with enantiomeric excess up to 82% [12] while utility of 1d as catalyst allowed to obtain the products with optical purity up to 92% and yield up to 95% [13]. For comparison, the highest optical purity obtained in the presence of ligands 2a-2c incorporating the pyridine ring was 34% [14]. Moderate enantio-selectivity up to 67% was observed in reactions catalyzed by ligands 3a-3c [14]. It is suggested that two factors can be responsible for the difference in activity of the 1,2,4-triazine-containing ligands 1a-1c and ligands possessing other six-membered aza-aromatic rings 2a-2c and 3a-3c [16]. The complexes formed between ligands of types 1, 2, and 3 and copper ions were not stable and an attempt to isolate them and to study their structures by X-ray diffraction analysis failed. The structures of the complexes were proposed by us on the basis of UV, MS, 1 H NMR study and theoretical calculations [16]. Ligands of type 1 that are more sterically hindered due to the presence of substituents in the 1,2,4-triazine ring tend to form slightly distorted tetrahedral quaternary complexes with the Cu(I) ion. Less bulky ligands of type 2 and 3 with an unsubstituted six-membered heterocyclic rings probably prefer to form square planar complexes with Cu(II) ions (Fig. 2) [16].
The difference in activity of type 1, type 2, and type 3 ligands can also be explained by considering the acidity of the copper ion in the 1-Cu, 2-Cu, and 3-Cu complexes they  [16] form. The more electron-withdrawing character of 1,2,4-triazine ring makes the copper ion in the 1-Cu complex more acidic, which provides better activation of the coordinating aldehyde. Type 2 and 3 ligands with heterocyclic rings of weaker electron-withdrawing character provide less activation [16]. Taking the above into account, introduction of electron-withdrawing group to the structures of ligands 2a-2c and 3a-3c should result in increase of their enantio-inducing activity. To investigate which of the above-mentioned factors has a decisive influence on the activity of ligands 1a-1c, 2a-2c, and 3a-3c, new pyridine oxazoline ligands 4a-4h, analogous to ligands 2a and 3a, whose structures were modified by introducing an electron-withdrawing group, were synthesized and examined in an enantioselective nitroaldol reaction. This studies are in line with still growing interest in pyridine-containing oxazoline ligands, the utility of which has recently been proved in many new asymmetric processes, e.g., aza-Wacker-type cyclization and C-H silylation [18][19][20][21][22][23]. Synthesis of new 1,2,4-triazine oxazoline ligands 5a-5d incorporating electron-withdrawing substituents was also performed and their activity in asymmetric nitroaldol reaction was investigated and compared to the activity of their counterparts 1a-1d without electronegative substituents. Herein we describe the results of the work.
The condensation reaction was run in the presence of threefold excess of ZnCl 2 which allowed to shorten the reaction time and gain better yield of the products in comparison to experiments run in the presence of catalytic amount of the catalyst. Subsequently, the Pd-catalyzed Buchwald-Hartwig amination of halopyridine derivatives 9a-9e with 2-(o-aminophenyl)oxazolines 8a-8c, 8g, and 8h was conducted to obtain the final ligands 4a-4h (Scheme 2).

Scheme 3
In the structures of 1,2,4-triazine-containing ligands 5a-5d, the fluorine or the nitro group is placed in the phenylamine linkage. Synthesis of the counterpart of the highly active ligand 1d incorporating the indane unit and fluorine atom in the phenylamine linkage was also undertaken. Unfortunately the ligand appeared highly insoluble in the solvents commonly used for purification and its isolation in chemically pure form did not succeed.

Enatio-selective nitroaldol reaction
With the chiral oxazoline ligands 4a-4h and 5a-5d in hand, we attempted to examine their enantio-inducing abilities in the copper-catalyzed asymmetric addition of nitromethane (12) to variety of aldehydes 11a-11i. To perform the nitro-aldol reactions, the conditions previously optimized for ligands 1, 2, and 3 were adopted. Thus, the reactions were carried out in the presence of 5 mol% of ligand and Cu(OAc) 2 ·H 2 O as pre-catalyst in 2-propanol at room temperature in the absence of any base. Yields and optical purities of the nitro-alcohols thus obtained are summarized in Table 1.
The results show that the ligands 4a-4g do not exhibit enantio-inducing activity ( Table 1, entries 1-9). The optical purity of the nitro-alcohols obtained in reactions catalyzed by these ligands did not exceed 29%. Ligand 4h appeared the most active among the pyridine oxazoline ligands. The highest enantiomeric excess, 48 and 71% were obtained in reactions catalyzed by ligand 4h what should be owed to the presence of the indane unit (Table 1, entries 10 and 11). Placement of a bromine atom in the C-6 position of the pyridine ring in ligands 4e and 4g makes the ligands highly inactive (Table 1, entries 7 and 9), although in the presence of the ligand 4e, the highest reaction rate was achieved. Both ligands 4g and the most active pyridine-containing ligand 4h possess indane unit in their structures, but they differ in activity ( Table 1, entries 9 and 10), which proves that the presence of the bromine atom in the C-6 position of the pyridine ring has unfavorable influence on the ligands activity. Comparing the results described above to the activity of previously investigated ligands types 2 and 3, it can be seen that presence of electron-withdrawing substituents in the structures of ligands 4a-4h did not improve the pyridine oxazoline ligands enantio-inducing ability [14]. The enantio-selectivities obtained in nitro-aldol reactions carried out in the presence of type 2 ligands were in the range of 4-28%. Ligands of type 3 having an indane system in the structure were showing better enantio-differentiating properties, and so the enantio-selectivity induced by them reached 64% in reactions with 2-substituted benzaldehydes [14]. This tendency is also observed for the activity of ligands 4a-4h possessing electron-withdrawing substituents. Conformationally rigid ligand 4h with indane system shows higher activity than ligands 4a-4g having flexible substituent in the oxazoline ring. Ligands 5a-5c are 1,2,4-triazine oxazoline ligands that possess the fluorine atom in the phenyl-amine unit, but they differ in the substituent in the oxazoline ring. In the presence of ligand 5a with phenyl substituent in the oxazoline ring, the highest yield and enantiomeric excess, 96 and 87%, respectively, were achieved in reaction of 2-chlorobenzaldehyde (Table 1, entry 18). In contrast, ligand 5a showed the lowest enantio-inducing activity in addition of nitromethane to 3-chlorobenzaldehyde (Table 1, entry 17). In this case, the product was formed in the yield of 17% and enantiomeric excess of 45%. Ligand 5b with isopropyl substituent in the oxazoline ring appeared to be a good catalyst in term of accelerating the reaction rate, but it shows poor enantio-inducing ability in the range of 32-49% ( Replacement of a fluorine atom with a nitro group in ligand 5d leads to a decrease in yield of the nitro-aldol reaction, while enantiomeric excess remained on a similar level in most cases in comparison to the results obtained in the presence of ligand 5a (Table 1, entries 27-31). Only in reaction of 2-bromobenzaldehyde significantly reduced yield and enantiomeric excess were observed. Utility of ligand 5c possessing tert-butyl group in the oxazoline ring in the reaction of 4-nitrobenzaldehyde allowed to achieve optical purity of only 24% and yield of 68% (Table 1, entry 26). That makes this ligand not promising candidate for catalyst in asymmetric nitro-aldol reaction. The presence of the fluorine atom in ligand 5a had no effect on the ligand enantio-inducing activity in comparison to its previously investigated counterpart 1a [12], whereas introduction of the nitro-substituent (ligand 5d) negatively influenced the reaction ratio. Similarly, the presence of fluorine in structures 5b and 5c did not make them good candidates for ligands in asymmetric nitroaldol reaction. The 1,2,4-triazine oxazoline ligands 5a-5d show much better enantio-inducing activity than the pyridine oxazoline ligands 4a-4g. Only the 4h ligand with indane unit showed activity similar to that of the 1,2,4-triazine oxazoline 5a and 5d ligands in reactions with 2-bromo-and 2-chlorobenzaldehydes, although the yields observed in the reactions with 4h were lower. The higher activity of ligand 4h is due to the presence of a conformationally rigid indane system rather than pyridine in its structure. Introduction of electron-withdrawing substituents to pyridine-containing oxazoline ligands did not result in increase of the ligand activity in comparison to the previously investigated ligands 2 and 3 without any electron-withdrawing group in the structure [14]. The findings described above indicate that the difference in the activity between 1,2,4-triazine oxazoline and pyridine oxazoline ligands is not a result of the more electron-withdrawing character of 1,2,4-triazine ring, as it was postulated [16]. It arises rather from the formation of different complexes with copper ions formed by the two types of ligands, the structures of which were proposed previously [16]. The more electron-withdrawing character of 1,2,4-triazine ring appeared less significant. Table 1 Screening of ligands 4a-4h and 5a-5d in the asymmetric nitro-aldol reaction All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and 5 mol % of Cu(OAc) 2 ·H 2 O in 2 cm 3 of 2-propanol at room temperature for 98 h a Yields of isolated products b Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The absolute configuration was assigned by comparing their specific rotations or the HPLC elution order with data from the literature [

Conclusion
In conclusion, we have obtained eight new pyridine-containing 4a-4h and four 1,2,4-triazine-containing 5a-5d chiral oxazoline ligands incorporating electron-withdrawing groups. To determine the influence of the substituents on catalytic and enantio-inducing activity of the ligands, they have been employed in copper-catalyzed asymmetric nitro-aldol reaction. It has been found that 1,2,4-triazine-containing ligands 5a-5d exhibit better activity that pyridine-containing ligands 4a-4g. Only ligand 4h shows activity comparable to that of triazine-oxazoline ligands 5a-5d. The activity of ligands 4a-4h and 5a-5d appeared similar to the activity of their previously investigated counterparts without electron-withdrawing substituents [12][13][14]. The introduction of an electron-withdrawing substituent into the structures of both types of ligands, triazine-oxazoline and pyridine oxazoline ligands, did not result in an increase in their enantio-differentiating properties. It has been proven that the more electron-withdrawing character of 1,2,4-triazine ring is not responsible for the better enantio-inducing ability of 1,2,4-triazine oxazoline ligands. The difference in activity of 1,2,4-triazine oxazoline and pyridine oxazoline ligands must be due to the difference in the structures of the copper complexes formed by the ligands (Fig. 2)