Subject activated methylenes

Method E (polymer supported catalyst) The alkene (50 mmol) is added to the activated methylene compound (50 mmol) at 0°C and the mixture is stirred for 10 min. Amberlyst A-27 (8 g) is added and the mixture is stirred for a further 15 min and then allowed to stand at room temperature for 4-25 h. The polymer is removed and washed with Et20 (4 x 40 ml). The combined organic solutions are evaporated and the residue subjected to flash chromatography to yield the Michael adduct (75-95%). 

Equimolar quantities of the aldehyde 1 (4 mmol) and the active methylene compound 2 were stirred in CH2C12 (30 mL) in the presence of K10, ZnCl2 (4 g). The solvent was evaporated in vacuo and the obtained solid was subjected to microwave irradiation in an open Erlenmeyer flask (25 mL). The condensation product was extracted into acetonitrile. The extract was filtered and the solvent was evaporated in vacuo. The colored solid was washed with ethanol-water (1 1) and recrystallized from ethanol. 

A mixture of aldehyde 1 (0.01 mole), active methylene compound 2 (0.01 mole) and LiCl or MgCl2 (0.001 mol) was subjected to microwave irradiation in a Py-rex test tube at output of about 600 W for a given time, then extracted with 50 mL of ethyl acetate and washed with water, dried over Na2S04 and concentrated in vacuo to afford pure products 3. 

Several types of substrate may be subjected to cyclization. In particular, compounds having two or more hydrogen atoms on the same reactive center (activated methylene or methyl group, phosphinic P atom, etc.) undergo reaction with formaldehyde and primary amine in the molar ratios I3U and 132 or with bis-aminc in the ratio 12M, in that order, affen-ding products 103-105 and 106,107, respectively (Fig. 40). 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

Although not particularly well known, nitrosoimidazoles appear to be quite stable compounds. The nitroso function can be reduced to amino, or oxidized to nitro. When 5-nitroso-2,4-diphenylimidazole is subjected to dropwise treatment with phenylhydrazine there is some reduction, but ring modification with the formation of the oxadiazole (224) accompanies this reaction (Scheme 123) (60G831). The nitroso function is able to take part in condensation reactions with compounds which possess active methylene groups, and related species (B-76MI40701). 

The C-H bond cleavage of active methylene compounds with a transition metal catalyst is another method for the functionalization of these C-H bonds. To date, several reactions have been developed. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers. One of the most attractive research subjects is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. The mthenium-catalyzed reaction active methylene compounds with carbonyl compounds involving aldehyde, ketones, and a,y3-unsatu-rated ketones and esters is described in this section. 

Disappointing results have been obtained from the Michael addition of compounds containing active methylene groups to vinylphosphonates. For example, cyanoacetate reacts with the diethyl vinyphosphonate under the conditions of base catalysis to give a mixture of 1 1 and 1 2 adduct resulting of one or two additions to the vinylphosphonate. When 2-pyridylacetonitrile and cyanomethylphosphonate are subjected to this reaction, diethyl 3-(2-pyridyl)- or 3-diethoxy-phosphinyl-3-cyanopropylphosphonates are obtained in 61% and 98% yields, respectively (Scheme 6.35). 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

Alkylation of malonic esters and other active methylene compounds is useful in synthesis because the alkylated products can be subjected to hydrolysis and decarboxylation (1.10). Direct decarboxylation under neutral conditions with an alkali metal salt (e.g. lithium chloride) in a dipolar aprotic solvent (e.g. DMF) is a popular alternative method. ... 

Enynylphosphine oxides were prepared and then subjected to carbocu-pration reactions to give dienylphosphine oxides, as shown in Scheme 29 Arylhydrazono-alkylphosphine oxides were converted to the corresponding azoalkene derivatives on treatment with iodic acid (Scheme 30). Otherwise unreactive chloroarylphosphine oxides have been shown to undergo Suzuki coupling on MW irradiation in the presence of a highly active palladium-catalyst (Scheme 31 Treatment of 2-fluoro-5-nitrobenzyl bromide with active methylene compounds, such as a p-keto phosphine oxide under suitable conditions led to 4/7-1-benzopyrans (Scheme 32)." ... 

Lengthening of the side chain of DMT by a single methylene group produces N,N-dimethylhomotryptamine (DMHT 76, R = H, n = 3), which produced hyperthermia when administered to rabbits (7,232) but was found to be inactive in man (235). Intravenous administration of 5 and 10 mg and intramuscular injection of 20 to 70 mg DMHT was without psychologic effect in 10 human subjects (235). Additional studies on DMHT homologs (i.e., 76, n = 4-10) did not show any interesting activity (7,232). 

It has recently been shown by Spikes150 that uracil and a number of substituted uracils are subject to dye-sensitized photooxidation under certain conditions. Methylene blue and Eosin Y were active photosensitizers in the pH range 8-11.5, but were inactive below pH 8. FMN was very active over the pH range of 2.4-11.5. Photooxidation was measured with a rotating platinum oxygen electrode. 

Several other allylic alcohols with primary C-2 substituents have been epoxidized with very good results (entries 7-10, 14). Epoxy alcohols have been obtained with 95-96% ee and, when the catalytic version of the reaction is used, as in entry 10, the yield is excellent. When the C-2 substituent is more highly branched, as in entries 11-13, there may be some interference with high enantiofacial selectivity by the bulky group, because the enantioselectivity in two cases (entries 11 and 12) is 86%. Another example that supports this possibility of steric interference to selective epoxidation is summarized in Eq. 6A.3a [39]. In this case the optically active allylic alcohol 12, (3/ )-3,7-dimethyl-2-methylene-6-penten-l-ol, was subjected to epoxidation with both antipodes of the Ti-tartrate catalyst. With (+)-DIPT, enantiofacial selectivity was 96 4... 

---