Synthesis and structural features of chiral cyclic squaramides and their application in asymmetric catalytic reaction

We report the synthesis and structural elucidation of two series of chiral cyclic squaramides, i.e. six-and twelve-membered ring squaramides 4 and 6 , based on the cyclobutenedione structure, containing enantiomerically pure (1 R ,2 R )-1,2-diphenylethylenediamine as the chiral element. Compounds 4a-d obtained from alkylation of 3 , crystallize in space groups of monoclinic P 2 1 , monoclinic P 2 1 , monoclinic chiral P 2 1 2 1 2 1 , and the orthorhombic C 222 1 , respectively. For the ﬁrst time the crystal structures of six-membered ring chiral cyclic squaramides are reported. These novel ligands have been tested in the enantioselective addition of diethylzinc to aryl aldehydes to give the corresponding alcohols in moderate yields, albeit with low enantioselectivity.


Introduction
Squaric acid is an aromatic four-membered ring cyclic compound with unique properties and applications.The squaric acid system possesses a rigid skeleton, two oxygen atoms with a pronounced Lewis base character, particularly as proton acceptor sites, and two reactive hydroxyl groups that can be submitted to a variety of substitution processes either in a simultaneous or a sequential manner, providing the potential for the preparation of a large number of compounds by substituent variation.This unique reactivity enables the employment of squarate molecules in multiple research areas such as advanced materials, 1 chemosensors, 2 enzyme inhibition, pharmaceutically active compounds, [3][4][5][6] and as a useful diene synthon in organic synthesis. 7[10][11][12] It is well known that these molecules also exhibit a dual donor-acceptor hydrogen bonding ability.In particular, the diamido-derivatives (also known as squaramides) have been studied in the conttext of molecular recognition, 13 supramolecular assemblies, 14,15 and as improved chiral organocatalysts.These properties have been applied to enhance the biological activity of several drugs and to functionalize organic molecules.7][18][19] Several crystal structures of squaramides have also been examined for a crystal engineering study using hydrogen bonding as a non-covalent force, in which secondary aromatic interactions such as CH- can also be observed. 20owever, to the best of our knowledge, there is no report on the synthesis and structural features of chiral cyclic squaramides and their use as catalysts in asymmetric reactions.In continuation of our interest in developing new squaramides that are of potential in asymmetric catalysis and crystal engineering sectors, we report herein the design, synthesis, and structural elucidation of six-membered and twelve-membered ring chiral cyclic squaramides based on the cyclobutenedione structure and containing an enantiomerically pure diamine as the chiral element, as well as their application in asymmetric catalytic addition of diethylzinc to aldehydes.

Synthesis
Chiral cyclic squaramide (3R,4R)-3,4-diphenyl-2,5-diaza-bicyclo[4.2.0]oct-1(6)-ene-7,8-dione 3 was prepared by the reaction of diethyl squarate 1 with one equivalent of (1R,2R)-1,2diphenylethylenediamine 2 in refluxing ethanol.Alkylation of 3 with haloalkyl reagents in the presence of potassium carbonate in DMF at ambient temperature afforded the alkyl substituted cyclic squaramides 4. Chiral twelve-membered cyclic squaramide 6 was prepared by the reaction of di-n-butyl squarate 5 with one equivalent of 2 in n-butanol/ethanol (1:1) at reflux in 10% yield, accompanied by 35% of 3 (Scheme 1).Identifying features in the 1 H NMR spectra of 3 and 6 include singlets for the methine protons at 4.32 and 4.76 ppm, respectively.The 13 C NMR spectra displayed seven signals for both compounds, indicating that the molecules are symmetric.The structures of ligands 4a-d were unambiguously established by X-ray determination. 21nfortunately, attempts to obtain a single crystal of 3 or 6 failed.Compound 4b also crystallizes in the monoclinic space group P21 (Figure 3).Similar to 4a, in the crystal structure of 4b, there exist also three hydrogen-bonding rings despite the different substituent component.The hydrogen-bonding cyclic [R1 2 (6), R1 2 (7), R2 2 4).Furthermore, each of the water molecules serve as µ2-linker to connect the 1-D chains into 2-D supramolecular network (Figure 5).The hydrogen bond separations of the adjacent water molecule and chains are 2.884 Å (angle: 129.73º) and 2.968 Å (angle: 155.47º), respectively.Apparently, intense steric hindrance occurs in compound 4b due to the presence of the isopropyl group.Interestingly, 4c was crystallized in the monoclinic chiral space group P212121, the asymmetric unit is depicted in Figure 6.The zig-zag helix chains along a axis (Figure 7) were formed by hydrogen-bonding cyclic R1 2 ( 6     In literature, 23 chiral macrocyclic tetra-and hexamine macrocycles derived from trans-1,2diaminocyclohexane (DACH) in complexes with diethylzinc efficiently catalyze the asymmetric hydrosilylation of aryl alkyl ketones with enantiomeric excesses up to 89%.A copper(II) complex of C2-symmetric cyclic diamine has also been proved to be an efficient catalyst for the enantioselective Henry reaction between nitroalkanes and various aldehydes. 24In view of these results, showing that chiral cyclic amines are useful catalysts for a number of organic transformations, and in continuation of our interest in developing new ligands for asymmetric catalytic reactions, we were intrigued with the possibility of developing chiral cyclic squaramides containing an inexpensive enantiomerically pure diamine.Indeed, our primary study showed that some of squaramides derived chiral diamine skeleton catalyzed the addition of diethylzinc to aldehyde with modest enantioselectivity. 25ere we present the reactivities of chiral cyclic squaramides 3, 4 and 6 in the asymmetric addition of diethylzinc to aldehydes.In order to find suitable conditions for using these ligands, we briefly optimized their use by changing the solvent and temperature, as well as the catalyst loading (Table 1), and found that in the addition of diethylzinc to aldehyde with 10 mol% 3, the use of 4 equivalents of diethylzinc in dicloromethane at -78 to r.t.provided a good yield and modest selectivity (Table 1, entry 6).Only enatioselectivity (40% ee), comparable to our previous result (Table 1, entry 4) 25 was obtained at lower temperature.
The optimized conditions were then used to assess the effectiveness of several related chiral squaramides.However, it was found that the chiral squaramides 4a-d, derived from the alkylation of 3, afforded the product in low yield, provided no enantioselectivity (Table 1, entries 12-15), which implied that the hydrogen bond might play a key role in the asymmetric addition.Furthermore, catalyst 6 having the twelve-membered ring core structure was examined, and was found to provide an inferior result compared to the six-membered cyclic squaramide 3 (entry 16).To demonstrate the influence of electronic and steric effects of the substrate in this asymmetric addition, a series of different aryl aldehydes were evaluated for ligand 3 and the results are summarized in Table 2.There was no apparent trend observed for the influence of substituent in the aryl aldehydes.The substrate with an electron-withdrawing groups afforded enantioselectivity at lower rate (entries 1 and 2).The aryl aldehyde with an electron-donating group (methoxy group) in the para-position of phenyl ring afforded no enantioselectivity (entry 5), but in the meta-positions gave the product in 8% ee (entry 3).

Conclusions
In summary, we report the synthesis and structural analysis of two series of chiral cyclic squaramides, a six-membered squaramide 4 and a twelve-membered squaramide 6, based on the cyclobutenedione structure, and containing an (1R,2R)-1,2-diphenylethylenediamine as the chiral element.For the first time the crystal structure of six-membered ring chiral cyclic squaramides is reported.Although there is no active proton, i.e. proton of an amide, in ligands 4a-d, supramolecular helix chains are obtained in all cases, formed by C-H•••O moderate intermolecular hydrogen bonding or relatively strong CH•••π interaction, suggesting that the Hbonding acceptor or CH•••π interaction ability of tertiary squaramides can be used as a synthon in crystal engineering in the future.As a first example of their application, these novel ligands were tested in the enantioselective addition of diethylzinc to aldehyde.Although the control of enantioselection of the reaction was modest, future modifications of the system based on this scaffold are now on course in our laboratories and will be reported in the future.These results may open a new way for the design and synthesis of novel chiral cyclic ligands derived from squaric acid for asymmetric reactions and also open new applications for crystal engineering.

Experimental Section
General.Tetrahydrofuran, diethyl ether and toluene were dried over Na/benzophenone, dichloromethane was dried over CaH2 and distilled prior to use.Glassware was oven-dried, assembled while hot, and cooled under an inert atmosphere.Unless otherwise noted, all reactions were conducted in an inert atmosphere.Reaction progress was monitored using analytical thinlayer chromatography (TLC) on 0.25 mm Merck F-254 silica gel glass plates.Visualization was achieved by either UV light (254 nm).Flash chromatography was performed with silica gel (Merck, 230-400 mesh).Unless otherwise specified, all NMR spectra were recorded using CDCl3 as the solvent with reference to residual CHCl3 ( 1 H at 7.24 ppm and 13 C at 77.0 ppm).Optical rotations were measured at room temperature on a Perkin-Elmer 241MC automatic polarimeter (concentration in g/100 mL).Melting points were obtained on a micro-melting apparatus and the data were uncorrected.Elemental analyses (C, H, N) were carried out on a VarioEL III (German) instrument.Determination of % ee was achieved using a chiral HPLC equipped with a chiralpak OD-H column with 99:1 n-hexane: 2-propanol as the mobile phase at a flow rate of 1 mL/min.

Single-crystal structure determination
Single-crystal X-ray diffraction intensities for complexes 4a-d were measured on a Bruker Smart APEX CCD-based diffractometer equipped with a graphite crystal monochromator for data collection at 292(2) K.The determinations of unit cell parameters and data collections were performed with Mo-Ka radiation (λ = 0.71073 Å), and unit cell dimensions were obtained with least-squares refinements.The program Bruke SAINT7 was used for reduction date.All structures were solved by direct methods using SHELXS-97 (Sheldrick, 1990) and refined with SHELXL-97 (Sheldrick, 1997); 26 non-hydrogen atoms were located in successive difference Fourier syntheses.The final refinement was performed by full matrix least-squares methods with anisotropic thermal parameters for non-hydrogen atoms on F 2 .The hydrogen atoms were treated by a mixture of independent and constrained refinement.Relevant crystallographic structure data and refinement details are presented in Table S1 in supplementary section.

Figure 1 .
Figure 1.ORTEP diagram of 4a.Displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are drawn at arbitrary size.

Figure 2 .
Figure 2. Linkage of the molecules of 4a.The hydrogen bonds are represented by dashed lines.

Figure 3 .
Figure 3. ORTEP diagram of 4b.Displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are drawn at arbitrary size.

Figure 4 .
Figure 4. Hydrogen-bonding 1D chain pattern in the structure of 4b.Hydrogen bonds are represented by dashed lines.

Figure 5 .
Figure 5. Hydrogen-bonding 2D network linked through the water molecule.Hydrogen bonds are represented by dashed lines.

Figure 6 .
Figure 6.ORTEP diagram of 4c.Displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are drawn at arbitrary size.

Figure 7 .
Figure 7. Supramolecular zig-zag and helix structure in 4c.The hydrogen bonds are represented by dashed lines.

Figure 8 .
Figure 8. ORTEP diagram of 4d.Displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are drawn at arbitrary size.Symmetry related atoms are labeled with "a".

Table 1 .
Asymmetric addition of diethylzinc to benzaldehyde catalyzed by 3, 4a-d and 6 a Determined by HPLC using OD-H column.b Isolated products.c Determined by measurement of the specific rotation and comparison with an authentic sample.d One equivalent of Ti(O-i-Pr)4 was added.

Table 2 .
Asymmetric addition of diethylzinc to substituted aldehydes catalyzed by 3a a Unless otherwise specified, the reaction was carried out with 1 mmol of aldehyde and 4 mmol of diethylzinc, 0.1 mmol of 3 in 3 mL dicloromethane at -78~ r.t for 12 h.b Isolated products.c Determined by HPLC using OD-H column.d Determined by measurement of the specific rotation and comparison with an authentic sample.