Further studies on the reductive–alkylation of chiral endo -himimide derived from ( R )-phenylglycinol

The scope of the reductive–alkylation of chiral endo-himimide derived from ( R )-phenylglycinol was studied. Careful structural studies by means of both X-ray crystallographical analysis and 1 H NMR spectroscopy analysis on the intermediates and products obtained during these studies allowed us to assign the structures of all the products obtained, and then to conclude that both the Grignard reagents addition (to 1) and the reductive deoxygenation of 2 / 3 via N -acyliminium intermediates A occurred stereospecifically from the convex face of either 1 or A


Introduction
We have long been interested in the reductive-alkylation of imides 1 .In our most recent paper 2 , the reduction-methylation of chiral endo-himimide (1) was disclosed (Scheme 1, R = Me).Among four possible products upon methyl magnesium iodide addition to 1, we observed only two isomers.The structure of one isomer was partially determined in an indirect manner, namely by X-ray crystallographical analysis of its cyclized product (6).In continuation of this study, we now describe further structural studies on the products obtained during the reductivemethylation both by 1 H NMR technique and by X-ray single crystal analysis and the scope of the reductive-alkylation.
Since the structure of one of two isomers (2a) obtained during the methyl magnesium iodide addition to 1 (Scheme 1) has been partially determined in our previous study, 1 we focused our attention, firstly, to determine the structure of the other isomer (3a).Fortunately, we were able to obtain a single crystal of this isomer.X-ray crystallographical analysis showed that the structure of this isomer is 3a (Figure 1).Scheme 1.The reductive-alkylation of chiral endo-himimide.Thus, the methyl magnesium iodide addition occurred from the less hindered convex face of the endo-himimide 1.This allowed us to assume that the addition of Grignard reagent to another carbonyl would occur from the convex face as well, and 1ead to 2a.N,O-acetal 2a was then subjected to ionic hydrogenation conditions 3 (Et 3 SiH, BF 3 ⋅OEt 2 , CH 2 Cl 2 ,-78°C∼rt) to give 4a as the single diastereomer.Similar treatment of 3a provided diastereoselectively 5a as the only isomer. 4The structure of both 4a and 5a were determined by mean of NOESY technology (Figure 2).Careful 1 H and 13 C-NMR analysis allowed us to fully assign the 1 H and 13 C-NMR peaks of 4a and 5a (Table 1).Next, we turned our attention to study the scope of this reductive-alkylation.As shown in Table 2, the reductive-alkylation of 1 with ethyl, n-butyl and n-heptyl magnesium reagents occurred in a similar way to methyl magnesium iodide (Table 2).However, when i-butyl magnesium bromide was used, its addition to 1 gave a more complex mixture of products in a combined yield of 71%.The subsequent deoxygenative reduction led to cyclized compound 7 (16%) and dehydrated compound 8 (58%, Figure 3) instead of the expected 4e and 5e.In addition, 20% of starting material 1 was recovered.Similarly, the attempted reductive-alkylation of 1 with phenyl magnesium bromide was unsuccessful: while the addition of phenyl magnesium bromide to 1 led to two isomers in a ratio of 68: 32 (determined by 1 H-NMR, combined yield 67%), the subsequent reductive deoxygenation led to, in addition to the desired 5f (44%), 2f' (16%) and an un-separable mixture of 9 and 10 in 57: 63 ratio (determined by 1 H NMR, combined yield 13%, Figure 4).The different behavior of 2e/3e and 2f/3f compared with 2a-2d/ 3a-3d may due to steric hindrance of i-butyl and phenyl groups, which slowed down the intermolecular hydride addition to the N-acyliminium intermediate (A, Figure 5). 5Thus the capture of the N-acyliminium intermediates (A) by intramolecular nucleophilic addition or water addition, or dehydration of A occurred, which led to 7 or 9/10 and 2f, or 8 respectively.To summarize, through careful structural studies, we were able to illustrate the stereochemical course of the reductive-alkylation of 1, namely, both the Grignard reagents addition (to 1) and the reductive deoxygenation of 2/3 via N-acyliminium intermediates A occurred stereospecifically from the convex face of either 1 or A. The reductive-alkylation is successful with un-branched alkyl magnesium reagent, but unsuccessful with i-butyl or phenyl analogues.Thus, the present study opens an easy access to various 4-azatricyclo[5.2.1.0 2,6 dec-8-en-3-one derivatives, which may be useful for the syntheses of either 5-substituted 3-pyrrolin-2-ones (after a retro-Diels-Alder reaction), 4 chiral auxiliaries (after cleavage of the 2-hydroxy-1phenylethyl group) or β-aminoalcohols (after carbonyl reduction).

Experimental Section
General Procedures.Melting points were determined on a Yanaco MP-500 micro melting point apparatus.Infrared spectra were measured with a Shimadza IR-408 spectrometer or a Nicolet Avatar 360 FT-IR spectrometer using film KBr pellet techniques. 1 H-NMR spectra were recorded in CDCl 3 on a Varian unity +500 spectrometer with tetramethylsilane as an internal standard.Chemical shifts are expressed in δ (ppm) units downfield from TMS. Mass spectra were recorded by Finnigan Mat-LCQ (ESI direct injection).Optical rotations were measured with Perkin-Elmer 341 automatic polarimeter.THF and diethyl ether used in the reactions were dried by distillation over metallic sodium and benzophenone; dichloromethane were distilled over P 2 O 5 .Silica gel (Zhifu, 300~400 mesh) was used for column chromatography, eluting (unless otherwise stated) with ethyl acetate/petroleum ether (PE) (60-90°C) mixtures.

General procedure for the preparation of by reductive alkylation of (R)-endo-himide derivative (1)
To an ice-bath cooled solution of 1 (1.0 mmol) in anhydrous THF (6 mL) was added dropwise a Grignard reagent (5 mmol) in Et 2 O under N 2 .After stirred at the same temperature for 2 h, the reaction was quenched with saturated aqueous NH 4 Cl (6 mL) and extracted with CH 2 Cl 2 (3×30 mL).The combined extracts were dried with anhydrous Na 2 SO 4 and concentrated in vacuo.Filtration with a short pad of column eluting with EtOAc/PE = 1:2 yielded a mixture of two diastereomers 2 and 3.
To a cooled (-78 o C) solution of diastereomer mixture of 2 and 3 (1.0 mmol) in dry CH 2 Cl 2 (10 mL) was added dropwise Et 3 SiH (10 mmol) and BF 3 ⋅OEt 2 (3.0 mmol) under N 2 .After stirring at -78°C for 6 h, the mixture was allowed to warm to ambient temperature and stirred overnight.The reaction was quenched by saturated aqueous NaHCO 3 and extracted with dichloromethane (3×20 mL).The combined extracts were washed with brine and dried over anhydrous Na 2 SO 4 then concentrated in vacuo.Flash chromatography (EtOAc/PE = 1:2) afforded the desired product 4 and a small amount of 5 (Table 2).

Figure 3 .
Figure 3. Products obtained from the reductive alkylation of 1 with i-butyl magnesium bromide.

Figure 4 .
Figure 4. Products obtained from the reductive alkylation of 1 with phenyl magnesium bromide.