Zirconium-catalyzed asymmetric Kabachnik–Fields reactions of aromatic and aliphatic aldehydes

An effective catalyst has been developed for the three-component reaction of aldehydes, anilines and phosphites in an asymmetric catalytic Kabachnik–Fields reaction to give α-aminophosphonates. A catalyst was sought that would give high asymmetric inductions for aromatic and, and more particularly, for aliphatic aldehydes since there has not previously been an effective catalyst developed for this class of aldehydes. The optimal catalyst is prepared from three equivalents of the 7,7′-di-t-butylVANOL ligand, one equivalent of N-methylimidazole and one equivalent of zirconium tetraisopropoxide. This catalyst was most efficient in the presence of 10 mol% benzoic acid. Optimal conditions for aryl aldehydes required the use of 3,5-diisopropyl-2-hydroxyaniline and gave the aryl α-aminophosphonates in up to 96% yield and 98% ee over 11 different aryl aldehydes. The best aniline for aliphatic aldehydes was found to be 3-t-butyl-2-hydroxyaniline and gave the corresponding phosphonates in up to 83% yield and 97% ee over 18 examples. The asymmetric inductions for aliphatic aldehydes were comparable with those for aromatic aldehydes with a mean induction of 90% ee for the former and 91% ee for the latter. The best method for the liberation of the free amine from the aniline substituted α-aminophosphonates involved oxidation with N-iodosuccinimide.

To a 100 mL round bottomed flask was added 2,4-diisopropyl-6-nitrophenol 81 (2.47 g, 11.1 mmol, 1.00 equiv.), graphite (1.58 g), hydrazine monohydrate (1.35 mL, 27.7 mmol, 2.5 equiv.) and ethanol (31.7 mL). The flask was equipped with a condenser and the top was sealed by a septum with a needle attached to it. The flask was heated in a 100 °C for 3.5 h (another 5.00 equiv. of hydrazine monohydrate was added in two equal portions every other hour). The solution was allowed to cool to room temperature, and filtered through a Celite pad, the filter cake was washed with dichloromethane (50.0 mL). The filtrate was concentrated with a rotary evaporation and flash chromatography (40 mm x 160 mm, Hexane/EtOAc 8:2) afford the crude product as a brown solid.

Procedures for the preparation of the aliphatic aldehydes 55d-m
General procedure C for the Swern oxidation of alcohols: To a solution of oxalyl chloride in dichloromethane at -78 °C under nitrogen was added dimethyl sulfoxide.
After 15 min, a solution of the corresponding alcohol in dichloromethane was added.
The mixture was stirred for 30 min before triethylamine was added. The resulting mixture was then warmed up to room temperature and diluted with dichloromethane.
The reaction was quenched by sat NaHCO 3 . The organic phase was separated, dried with NaSO 4 and concentrated. Purification of the crude aldehyde by silica gel chromatography (hexane/EtOAc as eluent) afforded the resulting aldehyde.

5a. Effect of molecular Sieves
In Table 1 in the text in entries 2 and 3 it was observed that the asymmetric induction from the reaction of benzaldehyde with amine 13b and diethyl phosphite the increased from 67% to 82% when the amount of molecular sieves was increased from 100 weight % relative to 13b to 82% with 200 weight %. However, further increasing the amount of molecular sieves to 400% did not significant change the result, and further, increasing the amount of sieves to 600 weight % resulted in a sharp decrease in the asymmetric induction to 47% ee (Table S1, entries 3 and 4).

Effect of Mono-Substitued Hydroxy-Anilines on the Reaction of
Benzaldehyde.
Given the fact that it was found that the mono-substituted aniline 13l was optimal for the Kabachnik-Fields reaction of aliphatic aldehydes (Scheme 5 in text) and the fact that these anilines were not screened during the optimization of the reaction with aromatic aldehydes, the reaction of benzaldehyde was screened with these monosubstituted anilines and the results are given in Scheme S1. The optimal di-substituted aniline for the reaction of benzaldehyde was the 3,5-diisopropyl-2-hydroxyaniline 13c (see Table 3 in the text) which gave phosphonate 51a in 90% yield and 93% ee. The optimal mono-substituted hydroxyaniline found in this screen was 3-t-butyl-2-

S-25
same induction (93%) as previously optimized di-substituted aniline 13c but with a reduced yield of 62%.

5c. Effect of Phosphite Esters on the Kabachnik-Fields Reaction of Benzaldehyde.
A number of phosphite esters were screened in the reaction of benzaldehyde with aniline 13c and the results are presented in Table S2. These reactions were not    The reaction with benzaldehyde 31a (                         configuration was determined to be (R) by comparing the optical rotation with a literature value reported for this compound [26] and by ECCD spectrum (vide infra).