Palladium-catalyzed cyclocarbonylation of unsaturated amines. Chemo-and stereoselective synthesis of N -heteroaryl γ - and δ - lactams

Palladium-catalyzed cyclocarbonylation of N -heteroaryl- N -homoallyl amines led to γ - and δ - lactams with good yields and in a stereo-and regioselective way. The regio-and stereoselectivity of the methodology was investigated by changing the heterocycle attached to the amine and varying the reaction solvent and the metal ligand. In order to explain the obtained results, a cyclocarbonylation mechanism with the participation of the heterocyclic moiety is suggested.


Introduction
2][3][4][5] Its importance has led many researchers to investigate new synthetic methodologies for the preparation of azetidinones, 5,6 pyrrolidinones 7-10 and piperidinones. 11,12Among these preparations, particularly interesting is the metal-catalyzed carbonylation of aminovinyl halides, 13 imines, 14 aziridines, 15 and thiazines 16 leading to β-lactams with regio-and stereo-selectivity.Another convenient synthetic pathway is the intramolecular cyclization of o-allylphenols and o-allylanilines in the presence of CO/H 2 and Pd(II) complexed by phosphinic ligands as catalyst, which affords bicyclic and polycyclic γ-, δ-, and ε-lactones and lactams, respectively. 17Recently, we showed that, in an analogous way, the cyclocarbonylation can occur also on homoallylic, propargylic and allenic α-heteroaryl-substituted alcohols and amines leading to variously substituted γ-and δ-lactones and lactams, 18 according to Scheme 1.When toluene was used as solvent and 1,4-bis(diphenylphosphino)butane (dppb) as ligand we recorded a regioselectivity towards the six-membered ring; moreover, in these conditions, the five-membered ring was formed in the two isomeric forms cisand transwith a certain diastereoselectivity (trans>cis).It was found, in addition, that the use of CH 2 Cl 2 as solvent and R(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (binap) as ligand made the reaction regioselective towards the five-membered ring product.The presence of a heterocycle as a substituent in these structures is potentially useful for subsequent synthetic modifications such as freeing the acyl groups masked by some of the heterocycles. 19omforted by these interesting findings we continued our research by carrying out the cyclocarbonylation on N-heteroaryl amines in order to obtain lactams bearing a heterocyclic function on the amide nitrogen.This investigation aims at the understanding of the potentially different regio-and stereoselectivity of the methodology, and at the same time producing, new structures with interesting biological activity or useful synthetic applications.

Results and Discussion
The unsaturated amines 1-7 were prepared (yield > 90%) through the coupling reaction between allyl-magnesium bromide and the imines (Scheme 2) prepared previously according to the Taguchi's method. 20More details of these syntheses are given in the Experimental Section.Table 1 collects the data on the cyclocarbonylation of the N-heteroaryl amines 1-7 leading to γ-and δ-lactams in good yields.The reactions were performed in toluene or CH 2 Cl 2 , under a pressure (600 psi) of CO and H 2 , in the presence of a catalytic amount (10%) of Pd(AcO) 2 and dppb or binap as phosphinic ligands, at 120°C for 72-96 h.The relative geometries of the pyrrolidinone isomers were assigned on the basis of 2D-NOESY experiments.The NOE interaction between the CH 3 bonded on the C 3 of the γ-lactam, and the two different protons on the vicinal C 4 was evaluated.
A good regioselectivity was noticed using the substrates 1-3, having an α-aza heterocycle attached to the amide nitrogen.The reactions carried out in toluene as solvent and with dppb as ligand led to the δ-lactam as the major product (yields of 70-79 %, entries 1, 3, and 5, Table 1).Among the many cyclocarbonylation reactions performed under different conditions (varying the solvent and phosphinic ligand) in order to investigate the regio-and stereochemistry of these substrates, the more effective were those performed using CH 2 Cl 2 as solvent and binap as Pd ligand.The differences in yield between the γ-and the δ-adducts obtained from amines 1-3, increased even more using CH 2 Cl 2 as solvent and binap as ligand (yields of δ-lactam 75-88 %, entries 2, 4, and 6).Moreover, for all these reactions a high diastereoselectivity was observed among the pyrrolidinone derivatives.For example, only small amounts of the cisisomer were formed (entries 5, and 6) or it was not formed at all (entries 1-4).Using the other amines, bearing a β-or a γ-aza heterocycle (4, 5), or those not having an aza group in the nitrogen substituent (6 and 7), the percentage of the δ-lactam decreased, sometimes in a significant way (entries 10 and 14), while the γ-lactam yield increased (entries 7-14).Furthermore, the trans-/cis-ratio within the γ-lactams became almost unity, even by changing the solvent and the ligand.From the results given above, it seems that the presence or absence of an aza group in the position α-to the heterocyclic functionality, that could participate in the coordination of the Pd during the lactam formation, is of strategic importance.A mechanism presumed for the cyclocarbonylation of N-heteroaryl unsaturated amines is reported in Scheme 3. The aza group should influence the coordination in the A and B structures (Scheme 3) and, consequently, the isomers' distribution.For example, the participation of the α-aza heterocyclic nitrogen in the Pd coordination during the cyclocarbonylation process could particularly favor the formation of the six-membered ring and the transdiastereomer among the five-membered isomers.An attempt was made to carry out the reaction without a ligand, on substrates 3 and 5.With the amine 3, which has an α-aza group on the imine nitrogen, the reaction occurred anyway, although with modest transformation yields, and with longer reaction times (120 h), but with the γ-/δ-lactam ratio confirmed (entry 15).A lower yield was noticed when using the amine 5 which still has an aza group linked to the aminic nitrogen, but in the γ-position (entry 16).These results support the suggested mechanism reported in Scheme 3, with the strategic participation of the α-aza heterocyclic nitrogen to the metal coordination.Also, the higher reaction yields obtained with the substrates 1-3 with respect to the substrates 4-7 should support this hypothesis.
Finally, in order to verify that the Pd participates in the reaction in the oxidation state (0) the reaction reported in entry 15 was repeated using the commercial tetrakis(triphenylphosphine)palladium(0) [Pd(PPh 3 ) 4 ].An equally satisfactory yield was noted, and the metallic Pd(0) and the Ph 3 PO were observed at the end of the reaction. 21n conclusion, we have found that unsaturated N-heteroaryl amines undergo a Pd-catalyzed cyclocarbonylation reaction, leading to five-and six-membered ring lactams, with good yield and high stereo-and regioselectivity.The latter can be modified by changing the heterocycle bonded on the amine and by varying the reaction conditions, in particular the solvent and the ligand.This methodology represents a useful path to the synthesis of these new substrates, extensively studied in biology and pharmacology.

Scheme 3 .
Scheme 3. Suggested mechanism for the cyclocarbonylation of N-heteroaryl unsaturated amines.

Table 1 . Cyclocarbonylation of amines 1-7 under two different reaction conditions
a Isolated yields.b Measured by GC and 1 H-NMR spectroscopy.