Stereoselective synthesis of cis -fused hexahydro-isoindolones

Allylamines, readily accessible by ene reactions of N , N -dibenzyliminium pentachlorostannates with 1,3-enynes, undergo domino reactions with maleic anhydride or maleic imide to give cis - fused hexahydroisoindolones, which were characterized by x-ray analysis


Scheme 1
Though ene reactions of iminium ions with CC-double bonds have also been reported, 4,5 CCtriple bonds are more reactive with the consequence that conjugated enynes 5 can selectively be converted into the corresponding dienylamines 6 (Equation 1).
We now report that the reactions of the dienylamines 6, thus readily available, with maleic anhydride and maleic imide provide a straightforward access to partially hydrogenated N-benzyl-3-oxoisoindolone-4-carboxylic acid derivatives 7, 6,7 a building block of a variety of natural products 8,9 and biologically active compounds. 10

Results
Heating equimolar amounts of the 2,4-dienylamine 6a with maleic anhydride or maleic imide in toluene gave rise to the formation of the bicyclic lactams rac-8 and rac-9, respectively.The moderate yields of both reactions given in Scheme 2 were mainly caused by the consecutive crystallization procedure, and no attempt of optimization was undertaken.

Scheme 2
Vicinal coupling constants of J 3a,7a = 6.8 Hz and 6.6 Hz were observed in the 1 H NMR spectra for the lactams 8 and 9, respectively, and additional 2D NMR experiments indicated the formation of cis-fused ring systems.In order to unequivocally establish the molecular structures of 8 and 9, crystals suitable for X-ray structure analysis were grown from ethyl acetate/petroleum ether mixtures.The ZORTEP plots in Figures 1 and 2 clearly demonstrate the cis-ring junction in both lactams rac-8 and rac-9.The crystal structure of 9 reveals the presence of intermolecular hydrogen bonds between the free amido groups with O2-N2A distances of 288.9 pm.Further, a stronger intramolecular hydrogen bond between N2 and O1 (279.4 pm) can be found (Figure 2) which also persists in CDCl 3 solution and gives rise to separate NMR resonances at δ 5.64 and 9.10 for the protons of the -NH 2 group.
In the crystal structure of the analogous lactam 8 that carries a -COOH group, intramolecular hydrogen bonds could not be observed.However, intermolecular O-H -O hydrogen bonds also play an important role in the solid state of 8 and induce the pairing of enantiomers as shown in Figure 3.In an analogous reaction of 6b with maleic anhydride, the silylated bicyclic lactam rac-10 was obtained (Scheme 3).Though the quality of the crystals was not high enough for an X-ray analysis, the cis-fusion of the carbon skeleton could clearly be derived from the NOESY spectrum which showed signal enhancements for 1-H (δ 3.42), 3a-H, 4-H, and 7-H when the protons of the trimethylsilyl group were irradiated.

Scheme 3
The reactions of the dienylamine 6c with maleic anhydride and maleic imide yielded the tricyclic lactams rac-11 and rac-12, respectively (Scheme 4).The cis-annelation of the lactam and the cyclohexene ring was already indicated by the small vicinal coupling constant of J 3a,9a = 6.3 Hz that was found in the 1 H NMR spectrum of 12. Furthermore, the X-ray analysis of crystals of 12 that precipitated from a ethyl acetate/petrolem ether mixture proved that all protons of the central six-membered ring are located at the same face which gives rise to a bowl-shaped molecular structure (Figure 4).This finding is in accord with the observations by Crisp and Gebauer 7 who reported analogous reactions of chiral dienylamines with maleic anhydride.

Scheme 4
Similar to the molecular structure of 9, the interatomic distance of 276.2 pm indicates the presence of an intramolecular hydrogen bond between the lactam oxygen O1 and the amido nitrogen N2 of 12. Furthermore, each of the -CONH 2 groups is involved in a weaker intermolecular hydrogen bond (296.1 pm) between N2 and O2A.In agreement with the properties in the solid state, the 1 H NMR signals of the two protons bound to N2 are observed at chemical shifts that differ by 4.10 ppm.

Discussion
The isoindolone derivatives 8-12 which could be isolated in moderate yields from the reactions of maleic acid or maleic imine with dienylamines uniformly showed cis-annelation of the lactam ring to the adjacent cyclohexenyl ring though the presence of smaller amounts of trans-annelated products in the crude reaction products cannot be excluded.This observation contrasts the report by Mellor and Wagland 6 who described that the reaction of maleic anhydride with N-benzylhexa-2,4-dienylamine in toluene gave rise to the formation of a trans-fused hexahydroisoindolone (yield: 82 %) with a coupling constant of J 3a,7a = 12.5 Hz.
Because Diels-Alder reactions generally show preference for the formation of endoproducts, 13 the observed cis-fusion of the bicyclic ring system in 8-12 can be rationalized by the two different reaction paths A and B in Scheme 5.

Scheme 5
Crisp and Gebauer demonstrated that Cbz-protected allylamines are not capable of attacking maleic anhydride.Therefore, they concluded that in the reactions of Cbz-protected dienylamines with maleic anhydride, the intermolecular Diels-Alder reaction precedes the N-attack on the anhydride, as suggested by path A in Scheme 5. 7a The situation is different for the N-benzyl substituted allylamines used in this work: When a solution of equimolar amounts of dibenzylamine (14) and maleic anhydride in d 8 -toluene was kept at 20 °C for 15 min and analyzed by 1 H NMR, 14

Scheme 6
As the corresponding intermolecular Diels-Alder reactions are considerably slower (4 d at 25 °C, 12 h at 40 °C) 7a we can rule out path A as a major pathway in the domino reactions 15 of the N-benzyl-substituted dienylamines with maleic anhydride.Because of the lower electrophilicity of maleic imide, the sequence of the two reaction steps may be different from the reactions with maleic anhydride.

Figure 2 .
Figure 2. ZORTEP plot of 9.The intramolecular hydrogen bond between N2 and O1 is shown by a dashed line.

Table 1 .
Crystallographic data and parameters of the crystal structure determinations