Synthesis and Catalytic Activity of Two New Cyclic Tetraaza Ligands

Two new chiral cyclic tetraaza ligands were synthesized and characterized. Their catalytic activity was tested in the asymmetric addition of diethylzinc to benzaldehyde. The expected secondary alcohol was obtained in moderate yields, but with very low enantioselectivity.


Introduction
The importance of nitrogen-containing ligands as catalysts for many asymmetric transformations has grown in the last years [1] because of their high stability, easy preparation and promising results [2]. In 1969 Uhlemann developed the synthesis of a new chiral Schiff base 1 from o-aminobenzaldehyde and 1,2-cyclohexanediamine [3]. Compounds containing this optically active transcyclohexane-1,2-diamine moiety have proven to be very useful in both asymmetric synthesis [4] and diastereomeric recognition of peptides [5].
We report in this paper the synthesis and characterization of two new tetraaza ligands containing 1,2-cyclohexanediamine as the chiral unit and their ability to catalyse the addition of diethylzinc to benzaldehyde.

Results and Discussion
The ligand 2 was synthesized from compound 1 by reaction with oxalyl chloride in THF in the presence of Et 3 N as catalyst, according to a procedure reported in the literature [6] (Scheme 1). After flash chromatography of the crude product, the cyclic compound 2 was obtained in a 68 % yield as colorless crystals.
The synthesis of ligand 4 using 1 as starting material was attempted by reaction with di-tert-butyl dicarbonate (Boc 2 O) in CH 2 Cl 2 using 4-dimethylaminopyridine (DMAP) as catalyst. Such reactions for similar substrates have been reported to give yields of 87-96 % [7]. According to the mechanism shown in Scheme 2, an intermediate urethane B is formed by reaction of the amine nitrogen with the Boc 2 O. Intramolecular nucleophilic addition of the second arylamine to the urethane or an isocyanate, which may evolve from B by elimination of tert-butanol should yield urea 4.
After performing the reaction and successive chromatographic separations, a colorless product was obtained. This product, however, displays in its 13 C-NMR spectrum two carbonyl group signals at δ = 151.3 and δ = 151.7, while only one was expected. 1 H-NMR spectra and mass spectrometry (molecular ion m/z = 391) indicated a different product with structure 3. A likely mechanism for its formation is the reaction of 1 with Boc 2 O and loss of tert-butanol to A followed by intramolecular cyclization to yield 3. Only a few reports of stable carbamic anhydrides exist in the literature [8]. The proton and carbon NMR spectra of 3 indicate a non C 2 symmetric conformation of the molecule. The 1 H-13 C HMBC NMR data show that each N-H group can be correlated to one CO carbon.
It was thought that upon heating compound 3, it would release CO 2 , thus leading to 4. This was tested by differential scanning calorimetry (DSC) [9], which showed a reaction of 3 at 259 °C, which indeed led to a loss of weight corresponding to CO 2 elimination, however, the high temperature at which this reaction occurs makes it of limited synthetic interest [10].
The cyclic diimine ligands 2 and 3 were examined as catalysts for the asymmetric addition of diethylzinc to benzaldehyde (Scheme 3). Moderate yields (51 and 88 %, respectively) of 1-phenylpropanol (6) were obtained, but no or very low enantioselectivities were observed [11]. The possible cause of these low selectivities could be the small size of the available cavity, which is not large enough to accommodate the Zn atom to form the intermediate zincate essential for the intramolecular alkyl transfer reaction.

General
Melting points were determined with a Büchi SMP 20 and are uncorrected. IR-spectra were recorded with a Bio-Rad FTS 3000 MX FT-IR. 1 H-NMR and 13 C-NMR were recorded with a Bruker ARX 400 or a Bruker AC 250 instruments at 250 and 62.9 MHz, respectively. The 1 H chemical shifts are reported in δ (ppm) relative to CDCl 3 (7.26 ppm), DMSO-d 6 , (2.49 ppm) and TMS (0 ppm), while 13 C chemical shifts are reported in δ (ppm) relative to CDCl 3 (77 ppm), DMSO-d 6 (36.9 ppm) and TMS (0 ppm). MS-spectra were recorded on a Varian CH-5 (EI) and a Finnigan MAT SSQ 7000 (ESI). Solvents were distilled and dried according to standard laboratory methods [12]. Catalysis: Preparation of 1-Phenyl-1-propanol (6): The ligand (0.05 mmol, 5 mol %) was dissolved in dry toluene (6 mL) under nitrogen, diethylzinc (1.1 M solution in toluene, 0.1 mL, 0.11 mmol) was added, and the mixture was allowed to stir for 1 h at room temperature, then cooled to 0 °C or maintained at room temperature. The remaining diethylzinc (2.17 ml, 2.39 mmol) was added slowly. After five minutes the aldehyde (1 mmol) was added. The reaction was stirred until no more aldehyde was observed (TLC), then quenched with 2 M HCl (6 mL). The layers were separated and the aqueous phase was extracted with Et 2 O (3 x 10 mL). The combined organic extracts were dried with Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by short path distillation to give the alcohol as colorless oil.