Design and synthesis of new bis-hydrazones and pyridine bis-hydrazones: application in the asymmetric Diels-Alder reaction

The design of two different types of new chiral bis-hydrazones 5 (bidentate N,N ligands, type A ) and pyridine bis-hydrazones 7 ('pincer' N,N,N ligands, type B ) is discussed. Preliminary results on the copper(II)-catalyzed Diels-Alder reaction of N -( E )-crotyloxazolidin-2-one ( 8 ) with cyclopentadiene ( 9 ) revealed that the (2 S ,6 S )-2,6-diphenylpiperidine C 2 -symmetric substructure in pyridine bis-hydrazone ligand 7c is the key


Introduction
The design and synthesis of new families of chiral ligands has been the starting task for the many particular pieces of research that have contributed to the spectacular growth of asymmetric catalysis during the last 30 years. 1 Currently, there is a growing interest in nitrogen-based ligands, 2 which offer several distinct advantages compared to the widespread phosphorous-based ligands.Thus, nitrogen compounds offer an extraordinary structural variability, with many compounds available from cheap natural sources such as aminoacids, alkaloids, etc (the 'chiral pool').Moreover, they are in general easy to synthesize and manipulate, and possess fair stability, for instance against the oxidation that is a common problem in phosphines, and this stability also provides recycling opportunities by different methods.In particular, the chiral N(sp 2 )-based privileged bipyridine (I), 3 bis-imine (II), 4 bis-oxazoline (III), 5 or pyridine bis-oxazoline (IV) 6 ligands (Figure 1) have enabled the development of a vast number of asymmetric reactions.During the last few years we have accumulated some knowledge about the synthesis, reactivity and structural aspects of the chemistry of N,N-dialkylhydrazones. 7These compounds, viewed as N-dialkylamino-substituted imines, exhibit a higher thermal stability than Nalkyl(aryl) derivatives as a result of the n→π conjugation.The behaviour of the C=N bond is strongly dependent on the structure of the dialkylamino moiety, which in turn controls the efficiency of the conjugation.This group may also incorporate structural elements to modulate the steric crowding around the coordination site and eventually incorporate additional coordination positions.In addition, a variety of chiral, sterically tunable hydrazines are available from inexpensive starting materials such as amino acids (particularly proline), 8 carbohydrates, 9 diketones, 7f and others. 10In summary, the electronic characteristics and structural variability of hydrazones make these compounds to appear as an appealing class of potentially useful ligands.Despite these peculiarities, a literature survey revealed very few examples on the use of chiral hydrazones as ligands in asymmetric catalysis. 11Therefore, we decided to explore new nitrogen ligands based on chiral glyoxal bis-hydrazones V. We initially reported on the development of [Cu(OTf)2/V] catalysts, in which the introduction of C2-symmetric dialkylamino groups, making rotations around N-N bonds inconsequential, proved to be key design strategy to achieve high enantioselectivities in asymmetric Diels-Alder reactions 12 (Figure 2).Moreover, we have recently shown that [PdCl2/V] complexes, designed on the basis of a similar strategy, are highly active and selective precatalysts in Suzuki-Miyaura cross-couplings for the enantioselective synthesis of biaryls. 13
The proposed ligands V possess several interesting features: (a) availability in both enantiomeric forms, (b) bidentate coordination ability, (c) C2-symmetry, simplifying the analysis of the stereochemical outcome, (d) limited flexibility around N-N bonds, providing an adequate chiral environment for square-planar complexes and a considerable steric crowding, (e) a high electronic density at N provided by n→π conjugation in the bis-hydrazone ligand compared with the 1,4-diazabutadiene ligands. 14Despite the success achieved in the Diels Alder and Suzuki-Miyaura reactions mentioned above, the bis-hydrazones used have limitations related to the thermal and chemical stability of some of their metal complexes, on one hand, and the absence of a modular design, on the other, that in principle provide few tools for the modification of their structures.In continuation of our research on ligand design for asymmetric catalysis, herein we present the synthesis of new chiral bis-hydrazones with distinct properties complementary to those of the glyoxal bis-hydrazones previously assessed.

Design of new bis-hydrazones (type A) and pyridine bis-hydrazones (type B)
As an extension of our work in this field, we aim to expand the structural diversity of the ligands previously developed by introducing different spacers between the azomethine carbons.In addition to glyoxal bis-hydrazones (no spacer), the new designs comprise 1,1diformylcyclopentane-derived bis-hydrazones (cyclopentylidene spacer, type A) and 2,6diformylpyridine derived bis-hydrazones (pyridine spacer, type B) (Figure 3).We envisioned that the presence of a carbon atom spacer between C=N groups, leading to six-membered chelates, should result in a closer chiral environment as the dialkylamino group NR2 approaches the metal center in the active [type A ligand/M] complexes.Moreover, the corresponding complexes might have electronic properties that differ in the independence of the hydrazone π systems, interrupted here by a quaternary carbon atom.On the other hand, type B ligands consist of a pyridine ring flanked by two azomethine carbons.In this design, the hydrazone groups play the role of the oxazolidine moieties in the well established Pybox 'pincer' ligands, offering alternatives concerning structure variability.From these pyridine bis-hydrazones acting in tridentate coordination mode, more stable and rigid [type B ligand/M] complexes are expected.Moreover, the binding site should be suitable to host lanthanide cations, which have revealed extraordinary activity in many reactions of interest. 15he availability of numerous families of chiral hydrazines allows the direct synthesis of a wide range of hydrazones.For example, proline derivatives bearing 'hemilabile' coordination positions (such as methoxy groups) might be beneficial for the effectiveness of the catalyst, helping to generate and temporarily stabilize coordination vacancies on the metal center, while C2symmetric hydrazines essentially create stable chiral environments. 16Importantly, it is possible to access both enantiomers of the ligands object of study.

Synthesis of bis-hydrazones 5 (N,N ligands, type A)
Type A bis-hydrazones 5a-c were readily synthesized by simple condensation of hydrazines 1b and 3a,b with cyclopentane-1,1-dicarbaldehyde 4 in MeOH at room temperature, as outlined in Scheme 2. For the synthesis of dialdehyde 4, a procedure described by Kirchner and coworkers 19 was followed.

Synthesis of pyridine bis-hydrazones 7 (N,N,N ligands, type B)
For type B pyridine bis-hydrazones 7a-d, a similar condensation protocol involving hydrazines 1a, 3a-c and pyridine-2,6-dicarbaldehyde 6 afforded the desired products in good yields (Scheme 3).In this system, slow addition of dialdehyde over hydrazine solutions was required to increase the formation of bis-hydrazones, while alternative conditions afforded lower yields and mixtures containing mono-hydrazones.

Application in the asymmetric Diels-Alder reaction
The enantioselective Diels-Alder reaction 20 was chosen as the platform to evaluate the efficiency of the new ligands, enabling a direct comparison between glyoxal bis-hydrazones and the new bis-hydrazones synthesized.It should be noted that using [Cu(OTf)2/V] catalyst [V derived from (2S,5S)-2,5-diphenylpyrrolidine], it was possible to perform the highly enantioselective (ee > 90%) Diels-Alder reaction between N-acryloyloxazolidin-2-one and a wide range of dienes (flexible and even acyclic dienes). 12Despite these excellent results, a major drawback is that the [Cu(OTf)2/V] complexes are thermally unstable above −30 °C and, therefore, the extension to more substituted dienophiles was not possible.Taking this limitation into account, we decided to use the reaction of N-crotonyloxazolidin-2-one 8 with cyclopentadiene 9 as the model system.The preliminary results of the model reaction were collected using [M(bis-hydrazone)(OTf)x], generated in situ by stirring a solution of the corresponding ligand (5 or 7; 11 mol%) with the desired metal triflate [Sc(OTf)3, Mg(OTf)2, Zn(OTf)2, Cu(OTf)2; 10 mol%], in dry toluene at room temperature (Table 1).Under these conditions, bis-hydrazones 5 afforded disappointing results.Among the screened metal salts, only Sc(OTf)3 resulted in complete reactions in some cases, the reaction giving the endo cycloadduct 10, although without measurable enantioselectivities (entries 1,3).Use of Mg 2+ , Zn 2+ , and Cu 2+ complexes afforded partial conversions.In contrast, ligands 7 in combination with Cu(OTf)2 (entries 4,5,7 and 9) or Zn(OTf)2 (entries 6, 8 and 10) showed better catalytic performance.Thus, employing [Cu(OTf)2/7] catalyst containing pyrrolidine based N,N-dialkylamino groups (7a,7b and 7d), Having confirmed pyridine bis-hydrazone 7c in combination with Cu(OTf)2 or Zn(OTf)2 as the best catalytic system in terms of enantioselectivity, we started optimizing the reaction conditions.First, we screened several solvents as outlined in Table 2. Conducting the reaction in halogenated solvents like CH2Cl2 or CHCl3 had a detrimental effect on the reactivity of the reaction.Thus, in CH2Cl2 only trace amounts of cycloadduct were detected (entries 3 and 4), while use of CHCl3 afforded the product in 20% yield (entries 5 and 10).In toluene, the better solvent for the Zn(II)-catalyzed reaction, the reactivity was moderate (entries 1 and 2), but use of Bu2O as a coordinating solvent (entries 6 and 7) enhanced the catalytic activity and selectivity of the [Cu(OTf)2/7c] catalyst, giving 10 in 90% yield, 91:9 endo:exo ratio and 83:17 e.r.Next, experiments were performed in non-dried toluene (entries 8 and 9) or Bu2O (entries 11 and 12).Zn(OTf)2 Bu2O nr -a Reactions were performed in dry solvent using 8 (0.2 mmol), ligand 7c (11 mol%), M(OTf)2 (10 mol%), and 9 (0.8 mmol) in the presence of 4Å molecular sieves for 90 h.b Isolated yield.c Determined by HPLC on chiral stationary phases.d Reactions were performed in non-dried solvents.

Conclusions
In summary, we have reported the synthesis of new chiral bis-hydrazones 5 and pyridine bishydrazones 7. Preliminary results on the copper(II)-catalyzed Diels-Alder reaction of Ncrotonyloxazolidin-2-one 8 with cyclopentadiene 9 revealed that C2-symmetric dialkylamino substructures in pyridine bis-hydrazones 7 is the key combination.In contrast to the results previously collected with related catalysts 12,13 or auxiliaries, 21 the piperidine-based bis-hydrazone 7c provides better chiral environment than the pyrrolidine-based 7b, a fact that can be partly attributed to the higher conformational flexibility afforded by piperidine rings.Further applications of these nitrogen ligands, especially aqua-complexes, in metal-catalyzed organic reactions are currently being explored in our laboratories.

Experimental Section
General. 1 H NMR spectra were recorded at 300 MHz, 400 MHz or 500 MHz; 13 C NMR spectra were recorded at 75 MHz, 100 MHz or 125 MHz, with the solvent peak used as the internal standard.Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel 60-F plates and visualized by ultraviolet irradiation and KMnO4, anisaldehyde or phosphomolybdic acid stains.Optical rotations were measured on a Perkin-Elmer 341 MC polarimeter.The enantiomeric ratios (e.r.) of the products were determined by chiral stationary-phase HPLC (Daicel Chiralpak OD column).Unless otherwise noted, analytical grade solvents and commercially available reagents, or catalysts, were used without further purification.Solvents were purified and dried by standard procedures.For flash chromatography (FC) silica gel (0.040-0.063 mm) was used.

Figure 3 .
Figure 3. Novel bidentate bis-hydrazones (type A) and 'pincer' pyridine bis-hydrazones (type B).On the other hand, type B ligands consist of a pyridine ring flanked by two azomethine carbons.In this design, the hydrazone groups play the role of the oxazolidine moieties in the well established Pybox 'pincer' ligands, offering alternatives concerning structure variability.From these pyridine bis-hydrazones acting in tridentate coordination mode, more stable and rigid [type B ligand/M] complexes are expected.Moreover, the binding site should be suitable to host lanthanide cations, which have revealed extraordinary activity in many reactions of interest.15The availability of numerous families of chiral hydrazines allows the direct synthesis of a wide range of hydrazones.For example, proline derivatives bearing 'hemilabile' coordination positions (such as methoxy groups) might be beneficial for the effectiveness of the catalyst, helping to generate and temporarily stabilize coordination vacancies on the metal center, while C2symmetric hydrazines essentially create stable chiral environments.16Importantly, it is possible to access both enantiomers of the ligands object of study.