Ketones nitrostyrenes

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). 

In this process o-nitrobenzaldehyde is condensed in alkaline solution with acetone. The so-called o-nitrophenyUactic acid ketone thus formed loses acetic acid, and by further loss of a molecule of water is changed into indolone, which corresponds to half of the indigo molecule. Possibly o-nitrostyrene is an intermediate stage in this transformation. Indolone cannot exist in the free state, and hence polymerises at once to the dye ... 

The Tsogoeva group, in 2006, reported the introduction of newly designed bifunctional secondary amine-functionalized proline-based thioureas (95 and 96) and the primary amine-functionalized thioureas (97-99) for catalysis of the asymmetric addition of ketones to trans-P-nitrostyrenes (Figure 6.30) [260, 261]. Using... 

Scheme 6.101 Typical Michael products obtained from the 97- and 99-catalyzed addition of ketones to frans-P-nitrostyrenes.

Scheme 6.102 Bifunctional catalysis with primary amine thiourea 99 Proposed transition states to explain the onfi-diastereoselectivity (A) and the syn- diastereoselectivity (B) of the Michael addition of both acylic and cyclic ketones to frans-P-nitrostyrene.

Monomers with electron withdrawing groups are polymerized by phosphines (acrylic and methacrylic esters, acrolein, methyl vinyl ketone, /J-nitrostyrene, nitro-ethylene, acrylonitrile), whereas the phosphines have no effect on monomers more susceptible to acid catalysts (isobutylene, styrene). 

Asymmetric Michael addition to to-nitrostyrenes,2 The enamine (2) formed from cyclohexanone and this prolinol derivative reacts with 2-aryl-1-nitroethylenes (3) to form, after acid hydrolysis of the primary adduct, essentially only one (4) of the four possible y-nitro ketones. 

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

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. 

L-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to -nitrostyrenes, giving syn-de s up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. 

W/cbae/-adducts obtained by Enders and Seki (ret. 39) from ketones and frans-p-nitrostyrene, using 20 mol-% of L-proline as catalyst in methanol at ambient temperature... 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

Michael-adducts obtained by Alexakis and Andrey (ref. 41) from the addition of aldehydes and ketones to f/ans-p-nitrostyrene, using 15 mol-% of 52 as catalyst in CHCI3 at ambient temperature... 

Scheme 2.42 The thiourea/amine catalyst-mediated addition of acyclic ketones to nitrostyrenes.

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. 

Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the / -nitro-a-phenylethyl ketone on hydrolysis117. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-7V-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers107 (Scheme 39). 

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)... 

The morpholine enamine of fra/i.s-2-decalone exists as a 1 4 mixture of A1- and A2-isomers DAD reacts with the former by equatorial attack and the latter by axial attack351 (Scheme 177). In contrast, less electrophilic alkenes, such as / -nitrostyrene and phenyl vinyl ketone, react only with the A2-isomer at C-3 by axial attack (see Section III.B), unless sterically impeded. 

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... 

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