Methylene synthons

Quinoxalinecarbaldehyde (64) gave 2-(p-cyanostyryl)qumoxaline (65) [Ph CH2CN, trace of HN(CH2)5 or Na0H-H20, EtOH, 20°C, briefly 60%] other well-activated methylene synthons likewise gave products such as 2-(2,2-diacetylvinyl)- (66, Q = R = Ac) (66%), 2-(2-acetyl-2-benzoylvinyl)-(66, Q = Ac, R = Bz) (94%), or 2-(2,2-dimethoxycarbonylvinyl)quinoxaline (66, Q = R = C02Me) (58%) but some such synthons produced only the intermediate secondary alcohols, such as 2-(l-hydroxy-2-nitroethyl)quinoxa-line (67) (36%), without final dehydration under these conditions. ... 

Pyrido[2,3-d pyrimidine (71) with malononitrile gave 2-amino-1,8-naphthyr-idine-3-carbonitrile (72, R=CN) (reactants, MeOH, 20°C 75%) or with ethyl cyanoacetate gave ethyl 2-amino-l,8-naphthyridine-3-carboxylate (72, R=CC>2Et) (likewise 8%) other activated methylene synthons also gave products but in very poor yield, even at appreciably increased temperatures.1030... 

Within a given series of heterocycles, differences in reactivity and stability are found compared to their corresponding benzo analogues (see Section 7.02.5). For example, 2,1-benzoisoxazoles are stable in mineral acids, while thieno[3,2-c]isoxazoles (1) and selenolo[3,2-c]isoxazoles (2) are not. Further, 2,1-benzoisoxazoles react with activated methylene synthons to afford quinoline V-oxides <67TL2337> whereas compounds (1) and (2) are inert. The isomer distribution from the pH dependent bromination of thieno[3,2-c]pyrazole (3) is similar to that found for indazole, while thieno[3,2-c]isoxazole (4) is relatively inert <76CS165,77CSi>. 

Little is known about the chemistry of pyridylfuroxans, but reaction of the [l,2,5]oxadiazolo[3,4-Z>]pyridine oxides (126) and (127) with activated methylene synthons provides pyrido[2,3-6]pyrazine-1,4-dioxides (130) in moderate yields (Beirut reaction) (Table 4, Scheme 21) <80M407, 82AF10). The actual reactive species is presumed to be the bis(nitroso)pyridine isomer (128). Direct oxidation... 

The reaction of 3-substituted triazolo[4,5- ]pyrimidines (8-azapurines) (213) with activated methylene synthons in the presence of sulfuric acid is reported to afford 5,6-disubstituted triazolo[4,5-i]pyridines (215). Since these reactions occur via 5-amino-4-formyltriazoles (214) (79CPB2861, 88BSCB85), similar cyclizations of other derivatives of 5-amino-4-formyltriazole have afforded additional analogues (Table 12) <73JCS(P1)1620>. Higashino and co-workers have also shown that 3//-triazolo[4,5- ]pyrimidines (213) participate in an inverse-electron Diels-Alder reaction with enamines (216) to afford the derivatives (215), albeit in low yields (Schemes 40 and 41) <91CPB282>. 

Alternatively, (217) react with activated methylene synthons in the presence of potassium bicarbonate to afford transient C=N adducts (218) which revert to the 4-amino-5-(/ ,/ -di substituted vinyl)triazoles (219) or (220). Recyclization of these products (219) or (220) affords (215). Similar transformations of l-substituted-l/7-pyrazolo[3,4-J]pyrimidines (77CPB535), pyrido[2,3-t/]py-rimidines (75CPB2939, 78CPB3242), and quinazolines <79CPB286l> have also been reported. 

Scheme 2.60 Bivalent methylene synthons as conjunctive reagents...

The synthetic access to a broad variety of nucleophilic [ C]methyl and [ " C]methylene synthons has significantly widened the scope of [ C]methyl iodide. Reaction with... 

Versatile [3 + 2]-cydoaddition pathways to five-membered carbocydes involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). Palladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n -2-methylene-l,3-propa-nediyl complex which reacts highly diastereoselectively with electron-deficient olefins. The resulting methylenecyclopentanes are easily modified, e. g., by ozonolysis, hydroboration etc., and thus a large variety of interesting cyclopcntane derivatives is accessible. 

D. 1-Methoxy Group as a Eormaldehyde Synthon Methylene Homologation. 115... 

The metallation of 3-methyl-4//-5,6-dihydro-l,2-oxazine has been shown to take place at the methyl group with hindered bases and at the methylene group with unhindered bases (81JA5916). Deprotonation of (753) with lithium dimethylamide at -65 °C followed by reaction with benzyl bromide gave (754) in 85% yield. This product was converted to enone (755) by reaction first with triethyloxonium tetrafluoroborate to produce an oxoiminium salt. The salt was stirred with trimethylamine and the resulting a,/3-unsaturated imine hydrolyzed with wet silica gel to the enone (Scheme 174). The lithiated derivative of (753) serves as a synthon for the unknown a-anion of methyl vinyl ketone. 

From a synthetic point of view, both thiophilic and carbophilic additions on dithioesters afford pathways for carbon-carbon bond formation, and as the dithioacetals formed in these reactions are easily converted into carbonyl or methylene groups the dithioesters are equivalent to the four synthons... 

A retrosynthetic disconnection in the case of each of these molecules gives a methylene group synthon, and benzylideneaniline and benzaldehyde from (7) and (8) respectively. 

Methylenecyclopentanes.2 Trost and Curran have used 1 as an electrophilic synthon for trimethylenemethane. Thus 1 reacts with the anion of 2 to give 3 in 72% yield. This product was oxidized to the disulfone, which was then cyclized to 4 by F. Various transformations are possible for the exocyclic methylene group. For the synthesis of coriolin (6), the group was converted to a pem-dimethyl group by cyclopropanation and hydrogenolysis. The product (5) was converted in several more steps into 6. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Analogues of complex saccharides, in which one or other of the acetal oxygens is replaced by a methylene residue or other heteroatoms, have received attention as biochemical probes and as potential therapeutic agents. The use of l-thio-1,2-isopropylidene acetals (TIA s) as annulating synthons for highly hydroxylated systems is illustrated by the synthesis of (3-C-, p-aza-C- and P-carba- galacto disaccharides. 

---