Nitrostyrenes ketone reactions

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

Similar cycloaddition reactions were observed with methyl vinyl sulfone (48) and )3-nitrostyrene (48,51). Methyl vinyl ketone, on the other hand, is reported to give dihydropyrans as the initial products (50,52,53). Thus (16) on reaction with methyl vinyl ketone at room temperature for 12 hr gave a 60% yield of 2-dimethylamino-3,3,6-trimethyl-3,4-dihydro-2H-pyran (59). 

A direct organocatalytic Michael reaction of ketones or aldehydes with /3-nitrostyrene has been reported in brine solution, using a bifunctional catalyst system proline-derived diamine (70) and TFA.203 In some cases the conversion, yield, de, and ee all exceeded 95%. Results in water were poor, mainly due to polymerization, which is catalysed by amines. It is proposed that sodium cations stabilize the anionic intermediate formed from (70) and /3-nitrostyrene, thus minimizing polymer formation. While organic co-solvent is not required, an organic-rich phase is proposed to concentrate the Michael reactants and catalysts, thus accelerating the reaction. 

The first reported synthesis of MDMA was from safrole by converting it to its bromo derivative followed by reaction with meth-ylamine (Biniecki et al., 1960). Bailey et al. describe the synthesis of MDMA from 3,4-methylenedioxyphenylacetone using a Leuckart reaction with N-methylformamide and hydrolysis of the N-formyl derivative (Bailey et al., 1975). A third synthesis for MDMA described in the literature starts with peperonal which is reacted with nitroethane, ammonium acetate, and acetic acid to form a nitrostyrene derivative that is reduced to the ketone and then reacted with methylamine to form MDMA (Rabjohns, 1963). Using the method of Borch et al., MDMA can be synthesized by the reductive amination of the appropriate ketone in the presence of sodium cyanoborohydride (Borch et al., 1971). The MDMA syntheses used in clandestine laboratories are analogous. 

Reaction of 3-substituted cyclohexanone enamines with / -nitrostyrene gives, on hydrolysis, a mixture of 6- and 2-alkylated ketones (59 and 57 ratio 4 1, respectively). Since the 6-alkylated ketone (59) is formed in much greater amount than enamine (58)... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

After investigating the reaction in order to control its stereochemistry, they succeeded in improving this approach considerably, as shown below. Introduction of a nitro group into the known styrene 302 by reaction with silver nitrite in the presence of iodine, gave the nitrostyrene 303 in 72% yield. Heating of 303 at 120°C gave the cis-fused adduct 304 stereoselecti-vely in 97% yield. Treatment of the nitro compound 304 thus obtained with titanium trichloride furnished the sensitive ketone 305. Concomitant reduction of the carbonyl and urethane groups of the crude product with LAH afforded ( )-chelidonine in 54% yield from 304 (146) (Scheme 111). 

It has also been demonstrated that ketimines may participate in reactions with nitrostyrenes providing fused pyrroles, as shown by the preparation of the system 311. The series of events leading to this outcome were suggested to involve a Michael-type addition of the enamine tautomer of the substrate 312 to the olefin, followed by annulation with concomitant elimination of the nitro functionality (Equation 92) <1999TL4177>. In addition, solid-state reactions of enamine esters or ketones with ( )-l,2-dibenzoylethene induced by milling gave excellent yields of pyrroles <1999AGE2896>. 

There have been only a limited number of developments in this area, the majority of which involve the use of lithium diisopropylamide (LDA) with chiral l,3-dioxolan-4-ones to deprotonate the C-5 position and allow reaction with a suitable electrophile (Equation 21). Electrophiles used to alkylate the enolate include iodomethane <1996HCA1696>, ethyl crotonate <1998SL102>, a,/ -unsaturated ketones <2006T9174>, various substituted nitrostyrenes <2004T165>, substituted nitroaryl fluorides <2003SL2325> and acylsilanes <2002TA1825>. 

An interesting variant of these Michael-type additions is the 1,6-addition of the anion of type (29) to a dienyl sulfone as a route to tagetones and 1,4-addition to nitrostyrene to form 3-nitro ketones. A key step in a synthesis of 11-deoxyanthracyclinone involves the regioselective reaction of complexed styrene with lithiated protected acetddehyde cyanohydrin. ... 

A solution of 11.5 g of 2,6-dimethoxy-B-methyl-B-nitrostyrene in 80 mL. warm acetic acid was added to a suspension of 35 g electrolytic iron dust in 150 mL. acetic acid. The mixture was heated on the steam bath until a vigorous reaction set in. The resulting paste was thinned with another 40 mL. acetic acid, and heating was maintained for an hour. The reaction was quenched in 1.5 L water with stirring, decanted from unreacted Fe, and extracted with three times 100 mL. CH2C12. The pooled extracts were washed with 50 mL. 5% NaOH, and the solvcmt was removed in vacuo to yield 10.5 g of a pale amber oil. This was distilled (95 -l 05° C./0.4 mm) yielding 8.7 g of the title ketone as a colorless oil. Source Sargent 1 987... 

Seebach and Golinski further examined the Michael addition of the enamines derived from ketones and morpholine to nitroolefins, as shown in Scheme 16 and Table 4 (33,35,36). The structure of the major product of entry 1 (Table 4) was assigned by chemical correlation. The remaining structures were assigned by analogy to entry 1. High levels of syn selectivity were uniformly observed. Control experiments revealed that the geometry of neither the enamine nor the nitroolefin influences the stereochemistry. Indeed, observation of the reaction of isomeric nitrostyrenes and the morpholine... 

Nitrobenzopyrans are potentially valuable intermediates in the synthesis of other 3-substituted derivatives, and are formed in good yield from the reaction of o-hydroxybenzaldehydes with j8-nitrostyrenes [3087]. The synthetic uses of nitroaikenes have been reviewed [3123]. An analogous method using acrolein or a vinyl ketone leads to a benzopyran-3-aldehyde or -3-ketone [2618] on the other hand, -cyanothioacetamide (reviews [3114, 3331]) gives 2-imino-l-benzopyran-3-thiocarboxamide [2926]. 

TBDPS ether (without a-substituents) also mediates Michael reaction of ketones with (3-nitrostyrenes. ... 

Michael reaction. The greatest number of research reports pertaining to methodology development for the asymmetric Michael reaction are based on the addition of ketones to P-nitrostyrene. Among catalysts 2 3 and 4, the first one is the simplest. 

Michael reaction Enantioselective addition of ketones to p-nitrostyrene is performed with the disubstituted triazole 1. Surprisingly, 1 is not a good catalyst for the aldol reaction. 

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