3-Carboxylate-Substituted Isoindolinones in K2CO3-Catalyzed Michael Reactions

Abstract Activated 3-substituted isoindolinones have proved to be efficient nucleophiles in K2CO3-catalyzed Michael reactions of several types of electron-deficient olefins. Moreover, tricyclic pyrrolizidines have been conveniently synthesized via a modification of the described general protocol as a consequence of a cascade Michael/cyclization reaction of unsaturated aldehydes. GRAPHICAL ABSTRACT


INTRODUCTION
Oxoisoindolines (isoindolinones) are one of the most important heterocyclic scaffolds ubiquitous in natural products [1] and incorporated in a number of synthetic compounds with a range of biological and pharmacological activities. [2][3][4] Accordingly, this class of molecules is highly popular in the pharmaceutical industry, medicinal chemistry, and chemical biology. Bioactive isoindolinones show a great structural diversification. This heterocyclic core can be either un-, mono-, or di-substituted at the benzylic position. In particular, the construction of a tetrasubstituted carbon on these heterocycles is particularly relevant, considering the increasing number of bioactive isoindolinones containing this feature. [3][4][5] Therefore, the development of new, quick, and effective methodologies devoted to their molecular diversification is of paramount interest for organic and medicinal chemists.
Among the wide range of organic transformations, the exploration of Michael reactions has been the focus of many research groups, since it leads to the formation of highly functionalized products in a single step. [6][7][8][9][10][11][12] Surprisingly, at the best of our knowledge, isoindolinones, substituted in the 3-position with an electronwithdrawing group, have not been attractive as nucleophiles in this fundamental reaction. As part of our ongoing studies on the synthesis of biologically relevant heterocycles, [13][14][15] we describe herein an unprecedented Michael reaction of activated isoindolinones for the construction of 3,3-disubstituted derivatives. Furthermore, among the efforts in this area [16] and in connection with our findings in the preparation of tricyclic benzoindolizidines via K 2 CO 3 -catalyzed cascade Michael=cyclization reactions, [14,15] we report a very convenient approach for the synthesis of structurally related pyrrolizidines.

DISCUSSION
In this investigation, we focused on three readily available isoindolinones, [16,17] bearing respectively a benzyl, n-butyl, or hydrogen atom at the nitrogen of the lactam ring, chosen as model nucleophiles. Pleasingly, the reaction of these heterocyclic compounds, under the conditions described in Scheme 1, with methyl vinyl ketone, afforded the Michael adducts with the tetra-substituted carbon in good yields simply by employing the inexpensive K 2 CO 3 in a substoichiometric amount.
Then, other classes of Michael acceptors were tested to enlarge the scope of this simple and effective methodology. In addition to a,b-unsaturated ketones such as methyl vinyl ketone ( Continuing the substrate screening, the reactivity of 3-penten-2-one and chalcone was strongly dependent on the used isoindolinone (Table 2). Probably due to the steric hindrance at the nucleophilic carbon, N-substituted isoindolinones 1a Scheme 1. K 2 CO 3 -catalyzed Michael reactions of isoindolinones. and 1b did not react at all ( Table 2, entries 1 and 2), whereas in the presence of the substrate 1c the Michael adducts 2h and 2i with contiguous quaternary and tertiary stereocenters were obtained in excellent yields and with good diastereoselectivity ( Table 2, entries 3 and 4).
If on one hand the reaction of the isoindolinone 1c with the unsaturated ketones led to the acyclic adducts, in the presence of unsaturated aldehydes a different outcome was observed. Thanks to an efficient cascade Michael=hemiaminalization reaction, in which the aldehyde group of the intermediate 4 reacts with the nitrogen of the lactam ring for the ring closure, aza-tricyclic derivatives, known as pyrrolizidines, were obtained in very good yields (Table 3). The formation of the tricyclic adduct is evident for the appearance of a new NMR peak for the CH  hemi-aminal group and the concomitant disappearance of the NH and the aldehyde signals respectively. It is worth noting that the developed new method, in comparison to other multistep methods reported in literature for the construction of related aza-tricyclic derivatives, [18] is particularly convenient in terms of efficiency and step economy. Moreover, the concomitant formation of the hemi-aminal functionality, which could be subjected to other transformations as reported for the analogues benzolizidines, [13][14][15] is useful for further elaboration of the tricyclic scaffold. Depending on the tested unsaturated aldehydes, the methodology allows obtaining derivatives with two or more stereocenters diastereoselectively. In the case of the acrolein, only one diastereomer was detected (Table 3, entry 1). The relative configuration of 3a was tentatively assigned by Spartan calculations, highlighting a higher stability of about 3 Kcal=mol of the diastereomer in which the OH and the COOEt are in cis. In the presence of the cinnamaldehyde, albeit the formation of three stereocenters, a mixture of only two diastereomers was obtained in about a 9=1 ratio (Table 3, entry 2). Further efforts were directed to get information on the geometry of 3b. To that purpose we exploit previous findings on the oxidation of hemi-aminal group of benzoindolizidines. [13][14][15] Removing the stereocenter at the hemi-aminal functionality by PCC oxidation led to the interesting imide derivative 5 with an unchanged dr with respect to 3b (Scheme 2).
This outcome highlights that 3b and consequently 5 are mixtures of diastereomers which differ for the relative configurations at the contiguous quaternary and tertiary stereocenters. In addition, calculations confirm greater stability by about 3Kcal=mol for the diastereomer 3b with 1,3-cis and 1,4-trans relative configuration. Other studies are in process to confirm the hypothesized stereochemistry and to enlarge the scope of the cascade reaction.

CONCLUSIONS
In this article we have described a simple and effective protocol for the Michael reaction at the heterocyclic ring of activated 3-substituted isoindolinones. Different classes of unsaturated Michael acceptors have been reacted, using K 2 CO 3 in a substochiometric amount, giving the final adducts from good to excellent yields. Moreover, as a particular application of the general protocol, the reaction of the N-unsubstituted isoindolinone 1c with unsaturated aldehydes allowed access to the interesting aza-tricyclic derivatives, known as pyrrolozidinones. This outcome was possible thanks to an efficient cascade Michael=hemi-aminalization process for the ring closure. Based on these preliminary results, other studies are in process to enlarge the scope of these reactions and develop asymmetric versions.

EXPERIMENTAL
General Procedure for K 2 CO 3 -Catalyzed Michael Reaction of Isoindolinones 1 The unsaturated compound (1.5 eq.) was added at rt to a solution of the isoindolinone 1 (0.10 mmol) and K 2 CO 3 (0.5 eq., 0.05 mmol) in CH 3 CN (1 mL). The reaction was stirred until the disappearance of 1 as detected by thin-layer chromatography (TLC), the solvent was evaporated, and the mixture was purified directly on chromatographic column in 8=2 hexane=ethyl acetate, affording the adducts 2 (or 3) in the range of 75-99% yields.