Organocatalytic, Enantioselective Conjugate Addition of Nitroalkanes to Nitroolefins

Abstract

An organocatalytic, enantioselective conjugate addition reaction of nitroalkanes with nitroolefins has been developed under neat conditions without using an organic solvent. The process, catalyzed by a modified Cinchona alkaloid, affords synthetically useful 1,3-dinitro compounds in good yields (70-82 %) with good degrees of enantioselectivity (67-88 % ee).Keywords: asymmetric catalysis; C À C bond formation; Michael addition; organic catalysisThe Michael addition of stabilized carbanions to electron-deficient a,b-unsaturated systems is one of the important means for the construction of C À C bonds in organic synthesis. [1][2][3] Versatile nitroalkanes have been demonstrated as a valuable stabilized carbanion for the conjugate addition process. Recently, an organometallic and organocatalytic asymmetric version of conjugate addition of nitroalkanes to a,b-unsaturated carbonyl compounds has been the subject of intensive investigation. For example, Shibasaki [4] and Jacobsen [5] have reported organometallic-promoted, highly enantioselective Michael additions to a,b-unsaturated ketones. Davis, [6] Hanessian, [7] Soós, [8] Jørgen-sen, [9] and Maruoka [10] have independently developed the "metal-free" organocatalyzed enantioselective processes. In these approaches, the acceptors employed have been restricted to a,b-unsaturated ketones, [6][7][8][9] aldehydes, [10a] and esters.[10b] The use of nitroolefins as Michael acceptors for the asymmetric reaction has proven to be a challenging task despite the fact that nitroolefins are more active than a,b-unsaturated carbonyls [11,12] and the versatile nitro groups can be readily transformed into a variety of functionalities.[2c] A single study has been disclosed recently using a chiral ligand-metal complex as a catalyst for the conjugate addition of nitroalkanes to nitroalkenes in moderate to high enantioselectivity. [13,14] It is noted that the catalytic system requires the use of Et 2 Zn (0.25 equivs.) and TiA C H T U N G T R E N N U N G (O-i-Pr) 4 (0.8 equivs.) as co-catalysts in addition to the chiral ligand (0.1 equiv.). Moreover, the method suffers from a narrow scope, only working for less hindered linear nitroalkanes. In this communication, we describe the results of an investigation which has led to the development of the first method for carrying out organocatalytic enantioselective Michael-type addition reactions of nitroalkanes with nitroolefins to afford synthetically useful enantiomerically enriched 1,3-dinitro compounds in good yields (70-82 %) and good enantioselectivities (67-88 % ee) under neat conditions without using organic solvent. The process has shown to be applicable for both linear and more steric hindered branch nitroalkanes.This investigation began with screening several chiral organocatalysts for their ability to promote asymmetric Michael-type addition reactions of 2-nitropropane (1a) to trans-b-nitrostyrene (2a) (Figure 1 and Table 1). The initial reaction was performed in toluene in the presence of 10 mol % of a modified Cinchona alk...

Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to α,β‐Unsaturated Aldehydes: Three‐Step Synthesis of Optically Active Baclofen

“…Furthermore, heteroaromatic (entry 11) and conjugated aromatic (entry 12) systems can participate in the processes as well. Finally, we probed the structural effect of the nitroalkanes 4 on the conjugate reactions (entries [13][14][15]. It is found that high ees (87-99 %) for both syn and anti diastereomers are obtained, albeit with an only poor dr when nitroethane 4b and nitropropane 4c are exploited.…”

“…[10] Notably, stabilized carbanions as nucleophiles for the conjugate addition to a,b-unsaturated systems, which involve the formation of new C À C bonds, have been intensively studied. Although significant progress has been made for a,b-unsaturated ketone, [11] ester, [12] amide/imide [13] and nitrostyrene [14] substrates, the development of a catalytic method to promote enantioselective conjugate additions of stabilized carbanions to a,b-unsaturated aldehydes has proven to be more challenging. One of the main reasons for this is the greater susceptibility of a,b-unsaturated aldehydes to 1,2-addition reactions as compared to other unsaturated systems.…”

Cinchona‐Catalyzed Nucleophilic Conjugate Addition to Electron‐Deficient CC Double Bonds

“…A range of other Michael donors such as nitroalkanes [35], anthrone [36], and N-heterocycles [37] were also shown to be applicable to the above-discussed catalyst system, that is, catalysts bearing a 6 0 -OH group such as 122 and 123. The enantioselective conjugate addition reaction of a range of cyclic and acyclic nitroalkanes 129 with aromatic and heteroaromatic nitroolefins 130 under neat conditions afforded the synthetically useful 1,3-dinitro compounds 131 in good yields (70-82%) and with good degrees of enantioselectivity (67-88% ee) using 122 (10 mol%) [35].…”

“…The enantioselective conjugate addition reaction of a range of cyclic and acyclic nitroalkanes 129 with aromatic and heteroaromatic nitroolefins 130 under neat conditions afforded the synthetically useful 1,3-dinitro compounds 131 in good yields (70-82%) and with good degrees of enantioselectivity (67-88% ee) using 122 (10 mol%) [35]. However, no reaction occurred in the case of less reactive aliphatic nitroolefins.…”

Highly Enantioselective Direct Michael Addition of Nitroalkanes to Nitroolefins Catalyzed by La(OTf)3/N,N′‐Dioxide Complexes

“…[7] Wang et al showed that a modified cinchona alkaloid was a useful asymmetric catalyst for the synthesis of 1,3-dinitroalkanes. [8] Subsequently, the Maruoka research group revealed that N-spiro chiral ammonium bifluorides could efficiently catalyze the asymmetric Michael addition with silyl nitronates. [9] Despite these important contributions, the development of new and efficient asymmetric catalytic systems is still an interesting challenge.…”