Nitro-olefins Michael additions

Keywords nitroalkane, olefine, Michael addition, Amberlyst A-27, nitro compound... 

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

Bicychc pyrazinones foimd in several natural products were synthesized via Michael addition of heterocyclic amines to nitro olefin followed by reduction/cyclization of the nitro group of the adduct [20] (Scheme 5). Further elaboration of the C-6 methoxycarbonyl group in pyrazinone to the n-propyl guanidine group could result in the synthesis of indoloperamine. 

In the synthesis of N heterocycles, this technique also overcomes competitive retro Michael addition that lowers the yield of 1,4-adduct in the Michael addition of amines to nitro olefins. Thus, a toluene solution of nitro olefin 159 was treated with allylamine 160, EtgN, and TMSCI under nitrogen at ambient tern-... 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

Due to the toxicity of tin reagents, a new radical elimination without using Bu3SnH is highly desirable. B arton has reported that nitro olefins are converted into olefins via radical elimination of P-nitro trithiocarbonates (Eq. 7.116).160 The Michael addition of trithiocarbonate to nitroalke-nes is carried out in CS2 to avoid the addition of EtSH. 

Finally, Scheme 3.14 presents the Michael addition of bromomalonic ester to conjugated nitro olefins 10. This approach allows one to synthesize five-membered cyclic nitronates (5) doubly functionalized at the C-5 atom (Scheme 3.14, Eq. 5). 

In 2008, Chakraborty el al. reported that Michael addition of nitromethane to the sugar olefinic derivative 36 provided the sugar-based (I-nitro acid ester 37 (Scheme 14), which was used as starting material for the preparation of a novel type of cyclohexyl amines.36... 

Michael additions to sugar nitro olefins have received considerable less attention than the Henry reaction involving nitro sugars. Early examples of Michael addition include the synthesis54 of licoricidin by Paulsen in 1982, the addition of phosphorous nucleophiles to a D-glucose based nitro olefin55 by Yamashita in 1987 and the synthesis of the natural antibiotic polyoxin published by Barret in 1990.56... 

The base-catalysed Michael addition of a,/J-unsaturated nitro compounds 363 to electron-deficient olefins 364 (R4 = Ac, CC>2Me or CN) results in the formation of ally lie nitro compounds 365 aldehydes give alcohols 366 in this reaction409. 

Takemoto et al. were the first to report that hifunctional organocatalysts of the thiourea - tert-amine type efficiently promote certain Michael-reactions, e.g., the addition of P-dicarhonyl compounds to nitro olefins (Scheme 6) [43 5],... 

Wang and co-workers [57,58] reported several Michael-type enantioselective additions with nitro-olefins. Under neat conditions, 1,3-dinitro compounds were generated in the 74 addition of nitroalkanes 75 to various P-substituted nitro-olefins (Scheme 15). Other Michael-type involving nitro-olefins reactions were illustrated using triazole donors 77 to offer good yields and high enantioselectivities (Scheme 16). 

The conjugate addition of nitro olefins under chiral Cmc/mna-thiourea catalysis has shown promising results with a variety of Michael donors. Dixon conducted a screen of various chiral thioureas and identified catalyst 117 as a versatile catalyst that works well with p-substituted nitro-olefms (78) [74]. Aromatic, heteroaromatic... 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

Chen and co-workers utilized the chiral bifunctional catalysts to directly access vinylogous carbon-carbon bonds via the asymmetric Michael addition of a,a-dicy-ano-olefms to nitro-olefms [102]. The scope of the reaction was explored with a variety of substituted a,a-dicyano-olefins and P-substituted nitro-olefms (Scheme 50). The authors propose the catalysf s tertiary amine functionality depro-tonates the cyano-olefm, activating the nucleophile to add to the -face of the pre-coordinated nitro-olefm. 

Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,14 15 cf. the overview given in the Organic Syntheses preparation of nitroacetaldehyde diethyl acetal.16 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.14 18 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),19 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.20 21... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425... 

In a variation of the Michael condensation, nitroparaffins having active methylene groups add to reactive olefinic compounds including ot,/3-unsaturated esters (method 301), a.,y6-unsaturated cyanides (method 388), and a-nitro olefins. Interaction of primary or secondary aliphatic nitro compounds with the unsaturated nitro compounds in the presence of sodium ethoxide in alcohol yields 1,3-dinitroparaffins. The reaction is general, but the yields vary, depending on the degree of polymerization that the nitro olefin undergoes and the amount of addition of alcohol to it as well as on the reactivity of the product toward further condensation. 

Hori, K., Higuchi, S., Kamimura, A. Theoretical and experimental study on the stereoselectivity of Michael addition of alkoxide anion to nitro olefin. J. Org. Chem. 1990, 55, 5900-5905. 

Michael additions of nitro olefins. Potassium fluoride catalyzes the Michael addition of 1,3-diketones and simple nitro olefins (equation I). Products of further transformation of the initial adduct are formed in some cases (equation... 

Another comparatively new synthetic method, the nitrone-induced oxidative cyclization, has been applied to a novel synthesis of pseudotropine. Michael addition of 4-nitrobut-l-ene to acrolein in methanol containing sodium methoxide gave the nitro-acetal (26), which was converted into the nitrone olefin (27) by treatment with zinc in aqueous ammonium chloride. When heated in toluene the nitrone olefin (27) cyclized with concomitant stereospecific oxidation of C-3 to give the isoxazolidine (28), which with methyl iodide followed by LiAlH4 give pseudotropine (20). 

In addition to allylic organolithiums reacting with conventional electrophiles such as akyl halides and carbonyl compounds, activated olefins have also been employed to provide Michael addition products [86,87,105]. Both mono- and diactivated olefins including a,p-unsaturated ketones, esters, malonates, malo-nitriles and nitro compoimds are compatible (Scheme 49). Addition of the orga-nolithium to cyclic a,p-unsaturated carbonyl compoimds occurred with retention of configuration, whereas addition to other activated olefins proceeds with inversion. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Scheme 6.2 Michael addition to nitro-olefins and accepted transition-state model.

Sugar-hased prolinamide 16m has also been employed as catalyst for the asymmetric Michael addition of cyclohexanones to p-nitroslyrenes. During optimisation of the reaction conditions, the authors found that the polarity of the solvent does not modify the yield or stereoselectivity, but the best ee was obtained under neat conditions at -20 °C. Ammonium ionic liquids 41a,b are also efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitro-olefins giving the adducts with excellent yields and enantioselectivities and modest to high diastereoselectivities. 

The direct asymmetric conjugate addition of simple aldehydes to electrophiles is crucial in organic reactions. Barbas et al. developed the first example of a highly stereoselective direct Michael reaction that involved adding unmodified aldehydes to nitro-olefins. After various p3Trolidine-diamines were screened, (S)-2-(morpholinomethyl)pyrrolidine Ic was determined to be the ideal catalyst for obtaining satisfactory stereoselectivity in the reaction. These reactions afforded various 2,3-disubstituted y-formyl nitroalkanes with satisfactory yields and moderate to good enantioselectivity (Scheme 9.12). ... 

Scheme 9.13 Diamine Id TFA-catalysed asymmetric Michael addition to nitro-olefins.

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