COMMUNICATION Regio-, Diastereo-, and Enantioselective Organocatalytic Addition of 4-Substituted-Pyrazolones to Isatin-Derived Nitroalkenes Carlos Vila,* [a] Nisshanth Raj Dharmaraj, [a] Antonio Faubel, [a] Gonzalo Blay, [a] M. Luz Cardona, [a] M. Carmen Muñoz [b] and José R. Pedro* [a] Abstract: Hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2Pyr) catalyzed the regio-, diastereo- and enantioselective addition of 4-substituted pyrazolones to isatin-derived nitroalkenes, providing a variety of chiral alkenyl-pyrazolone adducts containing a tetrasubstituted stereocenter bearing an oxindole moiety with excellent yields, regioselectivity and diastereoselectivity and moderate enantioselectivity (up to 98% yield, >20:1 E:Z ratio dr and 78% ee). The reaction harness a nitroalkene as an alkenylating agent through a Nucleophilic Vinylic Substitution (SNV) reaction. Introduction Pyrazolones are an important class of nitrogen heterocycles that have shown a broad range of biological activities and have attracted the attention of the pharmaceutical industry and medicinal chemistry. [1] This scaffold is present in a large variety of synthetic compounds that exhibit pharmaceuticals properties, such as antipyretic, analgesic, neuroprotective, antibacterial, etc. [2] In view of the great importance of the pyrazolone skeleton, the asymmetric synthesis of pyrazolones bearing a quaternary stereocenter have become an attractive goal and many and efficient synthetic approaches have been established over the last years. [3] So, several asymmetric additions of 4-substituted- pyrazol-3-ones to different electrophiles have been reported employing organo- and metal-catalysts for the synthesis of chiral pyrazolones bearing a tetrasubstituted stereocenter at 4 position, particulary when the substituent at this position is an alkyl group. [4] Nevertheless, the examples in the literature of enantioselective synthesis of chiral 4-alkenyl-4-substituted-pyrazolones are scarce. [5,6] Feng an coworkers, [5] in 2012, described a Z-selective asymmetric 1,4-addition reaction of 4-substituted pyrazolones to alkynones catalyzed by an N,N-dioxide-scandium(III) complex obtaining 4-alkenyl-4-substituted-pyrazolones with high geometric control, high yields, and excellent enantioselectivities (Figure 1). In view of the limited examples described, the development of other methodologies for the synthesis of chiral 4- alkenyl-4-substituted-pyrazolones is the great interest for organic synthesis. N N O R 1 R 2 R 3 asymmetric catalysis N N O R 1 R 2 R 3 alkyl well-developed N N O R 1 R 2 R 3 asymmetric catalysis N N O R 1 R 2 R 3 alkenyl one example N N O R 1 R 2 R 3 R 4 Pyrazolone: prominent nitrogen heterocycle Figure 1. Enantioselective synthesis of chiral pyrazolones bearing a quaternary stereocenter at 4-position. On the other hand, 2-oxindole scaffold represents one of the most important structures for medicinal and pharmaceutical chemistry, due to the plenty of natural products and synthetic compounds bearing this motif that present biological activities. [7] As an important 2-oxindole structure, unsymmetrical 3- alkylideneoxindoles [8] are present in various natural products [9] and pharmaceutical drugs. [10] We envisioned that the synthesis of chiral pyrazolones bearing a 3-alkylideneoxindoles could be achieved by nucleophilic vinylic substitution (SNV) [11] of 4- substituted-pyrazolones and (E)-3-(nitromethylene)indolin-2- one [12] (Scheme 1). However, the nucleophilic vinylic substitution in isatin-derived nitroalkenes have been scarcely studied. [13] Such transformation presents three challenges: the regioselectivity of the nucleophilic addition (attack at the β-position of the nitroalkene or at the α-position), the stereoselectivity of the 1,2- elimination and the enantioselectivity of the reaction. We have recently described a stereoselective addition of pyrazolones to isatin-derived nitroolefins in a racemic form. [14] As a part of our ongoing interest in the asymmetric addition of pyrazolones, [15] herein, we wish to report the addition of 4-substituted pyrazolones to isatin-derived nitroalkenes using a (DHQ)2Pyr as an organocatalyst through a nucleophilic vinylic substitution (SNV), leading to chiral heterocyclic compounds containing both 3- alkylidene-2-oxindole and pyrazolone moieties bearing a fully carbon tetrasubstituted stereocenter with good yields, excellent regio- and diastereoselectivity and moderate enantioselectivity (Scheme 1). [a] Dr. C. Vila, N. Raj Dharmaraj, A. Faubel, Prof. Dr. G. Blay, Prof. Dr. L. Cardona, Prof. Dr. J. R. Pedro Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot, València (Spain) E-mail: carlos.vila@uv.es; jose.r.pedro@uv.es [b] Prof. Dr. M. C. Muñoz Departament de Física Aplicada, Universitat Politècnica de València, Camino de Vera s/n, 46022 València (Spain) Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))