Synthesis and Organocatalytic Asymmetric Nitro-aldol Initiated Cascade Reactions of 2-Acylbenzonitriles Leading to 3,3-Disubstituted Isoindolinones

Abstract

In this work, we investigated two strategies for the synthesis of the challenging ketones 2-acylbenzonitriles and we report their use as electrophiles in asymmetric organocatalytic cascade reactions with nitromethane. Promising results were obtained in the presence of chiral bifunctional ammonium salts under phase transfer conditions, which led to novel 3,3-disubstituted isoindolinones in quantitative yields and moderate enantioselectivity.

Chiral Phase Transfer Catalysis in the Asymmetric Synthesis of a 3,3-Disubstituted Isoindolinone and Determination of Its Absolute Configuration by VCD Spectroscopy

“…Searching a suitable chiral organocatalyst for the reaction between 2-acetylbenzonitrile and dimethyl malonate (Scheme 1) among four recently developed systems [27], we soon realized that bifunctional chiral ammonium salts as IV in the presence of inorganic bases under phase transfer conditions were more effective than other common PTCs or chiral tertiary amines (Figure 2 and Table 1). Albeit relatively moderate in enantioselectivity for this transformation (Entry 5), this class of bifunctional ammonium salts derived from trans-1,2-cyclohexanediamine can be considered privileged catalysts in asymmetric cascade reactions of 2-acetylbenzonitrile and 2-formylbenzonitriles [13,15]. With the aim to improve the enantioselectivity of the reaction further, a systematic screening of the reaction conditions with catalyst IV was performed next (Table 2).…”

“…In the course of our recent research activity, we have developed a straightforward approach to racemic 3,3-disubstituted isoindolinones via K 2 CO 3 catalyzed cascade reactions of 2-acylbenzonitriles in the presence of a range of nucleophiles [12]. Promising enantioselectivities have been obtained using nitromethane as pro-nucleophile in a nitro-aldol initiated cascade type reaction in the presence of bifunctional ammonium salts derived from trans-1,2-cyclohexanediamine [13]. Considering the importance to develop new asymmetric one-pot processes for atom-and step-economy [14], we were interested to investigate further asymmetric versions of such a straightforward strategy to access quaternary stereocenter-containing isoindolinones by using different nucleophiles.…”

Error bounds on goodness of fit indicators in vibrational circular dichroism spectroscopy

“…(R)-(+)-3-chloro-1-butyne 1 was synthesized from (S )-(−)-3-butyn-2-ol as described in literature [32,33]. 2 has been obtained by organocatalytic asymmetric nitro-aldol initiated cascade reactions of 2-acetylbenzonitrile with nitromethane ([α] D 20 = +21.7) [20]. However, the enantioselectivity reached in this reaction was only moderate (up to 45% ee) and only after a reverse crystallization process (the crystallization as racemate is favored), we were able to improve the ee up to 87%.…”

“…In this paper we will introduce estimates of the uncertainties of several GOFIs by the bootstrap method [18,19], and we will apply them in conjunction with the MA approach. After a short description of the MA method and the bootstrap calculations, we will first apply them to 3-chloro-1-butyne 1, which is a small rigid molecule of known AC, and we will then give results for the recently synthesized [20] (+)-3-methyl-3-nitromethyl-isoindolinone 2, whose AC is reported here for the first time.…”

Metal-Free Air Oxidation in a Convenient Cascade Approach for the Access to Isoquinoline-1,3,4(2H)-triones

“…The development of effective one-pot reactions is related to the rational design of multifunctional starting materials [2]. Within this context, we have recently investigated the reactivity as electrophiles in cascade reactions of easily accessible bifunctional aromatic ketones like 2-acylbenzonitriles [3,4,5], developing a particularly convenient process for the synthesis of highly functionalized isoindolinones [3,4,5], a valuable class of heterocyclic compounds [6]. Continuing the efforts to explore the chemistry of multifunctional ketones, we were interested to investigate the reactivity of readily available methyl 2-(2-bromoacetyl)benzoate 1 with primary amines (Scheme 1).…”