Addition with Nitroalkenes

The reaction of indole or its magnesium salt was first developed by Noland and coworkers [204] and applied to the synthesis of tryptamine [264] and serotonin [265]. The reaction can be done either under thermal conditions or using the magnesium salt. 

Because of its tendency to polymerize, nitroethylene is a somewhat challenging reactant. When the reaction with indole is conducted at room temperature the yield increases to 80% [266]. Recently, a comparison was done, using p-nitrostyrene, of the Mg salt, thermal and microwave irradiation. The microwave method was found most convenient. These conditions were also applicable to the a-methyl analog [267]. 

In recent years many other reaction conditions and catalysts, including chiral catalysts have been examined. The range of catalysts is similar to that for addition to enones. Generally speaking, the nitroalkenes would be expected to be somewhat 

Surfactant-type salts of aluminum [269] and scandium [270] also promote addition in water. A combination of Sc(OTf)3 (5 mol %) with a surfactant that is compatible with super-critical CO2, promoted reaction in that medium [271]. 

Basic alumina at 60°C gives good results for a number of nitroalkenes. 

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Asymmetric Conjugate Addition with NitroaLkenes and Sulfones. 157... 

Asymmetric Conjugate Addition with Nitroalkenes and Sulfones... 

In particular, as a more challenging nucleophile, acetaldehyde was also suitable for the Michael addition with nitroalkenes. Using diarylprolinol silyl ether 7 as catalyst. List and co-workers [8] and Hayashi et al. [9] independently developed the first organocatalytic Michael reaction of acetaldehyde to afford a-unsubstituted y-nitro aldehydes in moderate to good yields and with excellent enantioselectivities (Scheme 5.3). The synthetic utility of this reaction was illustrated by List and... 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

The reaction of enaminones with nitroalkenes gives a pentalenone system via the Michael addition and aldol reaction (Eq. 4.66).85a Linear a-keto enamines react with nitroalkenes to afford [3 + 2] carbocyclized products.8515... 

The chiral enamines provide the opportunity for the enantioselective Michael addition to nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with... 

Nitrostyrene reacts with allylzinc reagents in dry DMF at room temperature to give the addition products in excellent yield (Eq. 4.80).102 The reaction of allyl tin compounds or allyl silanes with nitroalkenes requires the assistance of Lewis acids to give the addition products in good yield (Eq. 4.81).103... 

Yosikoshi reported the synthesis of furan derivatives by the reaction of 1,3-diketones with nitroalkenes, in which the Michael addition of the anions of 1,3-diketones and the subsequent intramolecular displacement of the nitro group by enolate oxygen are involved as key steps (Eq. 7.40).42... 

Sequential Michael additions are versatile methods for the construction of cyclic compounds. Although a variety of these reactions have been developed, the use of alcohols as nucleophiles for the Michael addition to nitroalkenes has been little studied. Recently, Ikeda and coworkers have reported an elegant synthesis of octahydrobenzo[b]furans via the sequential Michael addition of 1-nitro-cyclohexene with methyl 4-hydroxy-2-butynoate in the presence of t-BuOK followed by radical denitration (Eq. 7.74).94... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

The Michael addition to nitroalkenes followed by cyclization provides a general method for the synthesis of various pyrroles. The reaction of nitroalkenes with acetoacetate followed by reduction with Zn in acetic acid provides another route to 2-methyl-3-pyrrolecarboxylates (Eq. 10.8).10... 

Poor stereoselectivity (<30% ee) is recorded for the Michael addition of 1,3-di-ketones with nitroalkenes using cinchona bases [50] and early work recorded <25% ee using N-methylquininium and quinidinium hydroxides [51, 52], In contrast, indanones have been reported to react with methyl vinyl ketone in the presence of a cinchoninium salts to produce a chiral (S)-product in >95% yield (80% ee) [7]. Surprisingly, the (R)-isomer is obtained less readily (ee 40-60%) using cinchoni-dinium salts. Both isomers are obtained in high optical purity (>80% ee) via alkylation with 1,3-dichlorobut-2-ene and subsequent ring closure yields the Robinson... 

The Ir(lll) complex also funchoned as a catalyst in a tandem Nazarov cyclization-Michael addition. The reaction of monocyclic a-alkylidene-P-keto-y.b-unsaturated ester with nitroalkene gave bicyclic cyclopentenones which possessed an alkyl side chain, with high yield and diastereoselectivity (Scheme 11.36) [47]. 

In conjunction with the Knoevenegal reaction, a Michael addition (Figure 22) reaction was also described by Jaekson et al. using the same siliea supported tertiary amines for the catalysis of conjugate addition of nitroalkenes to a,y9-unsaturated carbonyl compounds. At a flow rate of 6.6 pL/min the eonversion rate was constant with a high yield for 7 hours reaction time. 

The addition of Grignard reagents to nitroalkenes like 205 gives ad-salts 206, which can be further transformed into nitroalkanes, hydroxymoyl halides or carboxylic acids (equation 130) . Reaction of RMgX with nitroalkenes in the presence of CeCls, followed by treatment with 100% acetic acid, was developed as efficient synthesis of complex nitroalkanes . ... 

Recently, lithiodifluoromethylphosphonate was reacted with methyl vinyl ketone followed by rearrangement of the allylic alcohol to give the difluoromethylphosphonate derivative as the E isomer [263] (Scheme 89). This lithium reagent was also reacted with nitroalkenes in the presence of CeCl3 to produce the corresponding Michael addition products in moderate yield [264] (Scheme 90). 

Beak and co-workers have also produced the key alcohol intermediate 74 by the sparteine-mediated lithiation and conjugate addition of allylamines to nitroalkenes to give Z-enecarbamates in good yields with high enantio- and diastereoselectivty (Scheme 16). Thus treatment of the allylamine 87 with n-BuLi in the presence of (-)-sparteine followed by conjugate addition to nitroalkene 88 gave the desired enecarbamate 89 in... 

Nitroalkenes, e.g. 1 -nitrocyclohexene, 1-nitrocycloheptene, 1-nitrocyclooctene and (3-methyl-j8-nitrostyrene, undergo Michael addition with the enolate anions of (3-ketoesters. The resulting acids undergo a Nef reaction to give 1,4-diketones, which yield furans by subsequent ring closure (Scheme 18) (59LA(626)7l). 

When Michael additions of chiral enolates to nitroalkenes were studied, it was found that lithium enolates (132) of l,3-dioxolan-4-ones (131), derived from the corresponding a-hydroxy acids, afford the adducts (133) with high diastereoselectivity (Scheme 50).144 Recrystallization leads, in general, to diastereomerically pure products, which in turn can efficiently be converted to homochiral compounds like (134), (135) or (136). A number of other chiral enolates (137M140) were also shown to undergo highly selective additions to nitroalkenes however, product configurations were not determined in these cases. 

The Bu OK-promoted reaction of 4-chlorobut-2-yn-l-ol (11) with nitroalkenes (12) gives 3-vinylidenetetrahydrofurans (14) in good yields with complete dia-stereoselectivity.12 It is supposed that oxa-Michael addition to fonn the intermediate (13) is followed by intramolecular 5k 2 substitution. 

Further applications of the chiral ammonium bifluoride-catalyzed enantioselective Michael addition of silyl nitronates has been shown in the reactions with nitroalkenes as a Michael acceptor (Scheme 9.17). These studies were started by examining the reaction of nitropropane-derived silyl nitronate 23b with P-nitrostyrene, using the chiral quaternary ammonium bifluoride (R,.R)-6d. When P-nitrostyrene was treated with 23b (1.2 equiv.) in the presence of (K,f )-6d (2mol%) in THF at — 78 °C, the... 

The catalytic application of L-proline in the asymmetric Michael addition of unmodified aldehydes or ketones with nitroalkenes in ionic liquids has been studied. The ... 

The bis-prolinol-derived phenol (156) has been designed to facilitate the formation of heterodinuclear complexes based upon the large difference in pKH of the phenolic OH group and the tertiary OH groups. The first examples of its application involve hydroxyacetophenones (157) as donors in the asymmetric Michael addition to nitroalkene acceptors (158) the best stereocontrol was observed with a zinc- magnesium dinuclear complex, where enantiomeric excesses ranged up to 92% for the major anti diastereoisomer (159).212... 

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