C-Methylenation

Methylene chloride is one of the more stable of the chlorinated hydrocarbon solvents. Its initial thermal degradation temperature is 120°C in dry air (1). This temperature decreases as the moisture content increases. The reaction produces mainly HCl with trace amounts of phosgene. Decomposition under these conditions can be inhibited by the addition of small quantities (0.0001—1.0%) of phenoHc compounds, eg, phenol, hydroquinone, -cresol, resorcinol, thymol, and 1-naphthol (2). Stabilization may also be effected by the addition of small amounts of amines (3) or a mixture of nitromethane and 1,4-dioxane. The latter diminishes attack on aluminum and inhibits kon-catalyzed reactions of methylene chloride (4). The addition of small amounts of epoxides can also inhibit aluminum reactions catalyzed by iron (5). On prolonged contact with water, methylene chloride hydrolyzes very slowly, forming HCl as the primary product. On prolonged heating with water in a sealed vessel at 140—170°C, methylene chloride yields formaldehyde and hydrochloric acid as shown by the following equation (6). 

Formaldehyde reacts with proteins to form adducts and cross-links.31516 Metz et al.3 have identified three types of chemical modifications after treatment of proteins with formaldehyde (a) methylol (hydroxymethyl) adducts, (b) Schiff bases, and (c) methylene bridges. The reaction of formaldehyde with proteins is summarized in Figure 19.1, but briefly, formaldehyde reacts primarily with lysine and cysteine to form methylol adducts. The methylol adduct can subsequently undergo a dehydration reaction to form a Schiff base. Adducted primary amine and thiol groups can undergo a second reaction with arginine,... 

A. P. Rauter and H. Weidmann, Versuche zur Verzweigung von Hexofuranur-ono-6,3-lactonen Synthese von 5-Desoxy-l,2-0-isopropyliden-5-C-methylen-x-D-xyZo-hexofuranurono-6,3-lacton, Liebigs Ann. Chem. (1982) 2231-2237. 

Scheme 3.—Proposed Mechanism for Photochemieally Initiated, Radical Addition of 1,3-Dioxolane to 3-Deoxy-l,2 5,6-di-0-isopropylidene-3-C-methylene-a-D-riho-hexo-furanose (5).

Cp2TiMe2, THF or PhMe, 60-75 °C methylenation of aldehydes, ketones, esters, amides, imides, thioesters, acylsilanes, anhydrides, carbonates [708,709,720]... 

By varying R at C, (which is separated from the reaction site at Q by an oxygen) it is possible to influence the electron density at C in a defined way to change the heterolysis rate constant. Corrected for the incomplete transmission of electronic effects through the C methylene group and assuming that the transmission of the oxygen is 100%, the Taft p value for the effect of substitution on the heterolysis rate constant is equal to — 3.95, comparable to that ip = — 3.29) for the SnI hydrolysis of tertiary alkyl halides [21],... 

Example 56 the Isis Pharmaceutical group in their extensive investigations of antisense oligonucleotides as therapeutics has described the synthesis of 3 -C-methylene nucleoside phosphonoamidites for the new backbone modification of oligonucleotides [90]. This paper gives good insight into tricoordinate phosphorus and related H-phosphonate chemistry in the service of nucleotide synthesis. 

Spurred by these observations, we examined a relevant application of the method for nitrocyclopropane synthesis from nitroalkenes and dimethylsulfoxonium methylide (17), Equation 3. It had previously been employed for the synthesis of a 2,3-dideoxv-2,3-C-methylene-3-nitro-hexopyranoside, the first one of the small number of carhohvdrates containing the nitrocyclopropane structure thus far known (18). 

HPLC analysis of this product usually shows it to contain less than 1% of other calixarenes. If these are present in greater amounts (usually the cyclic tetramer, cyclic heptamer or cyclic octamer), their content can be reduced to less than 1% by triturating the product with hot acetone. The purity of the product can be qualitatively checked with TLC using a petroleum ether (30-60°C)/methylene chloride mixture (1 1) as eluant. The Rf of the cyclic hexamer is ca. 0.65, and the appearance of any spots with greater than 0.1 indicates the presence of other calixarenes. 

Tetrafluoroethylene. Grzybowska et al.69 studied the reaction of methylene with C2F4 in the pressure range 10-470 cm. at 20°C. Methylene was produced by CH2CO photolysis at X > 3100 A. with a C2F4/ CH2CO ratio of 9 1. 

On the other hand, optically active 43 and 44 were synthesized as follows.401 Treatment of 2,3,4-tri-0-benzyl-l,5-di-0-tosyl-D-arabinitol (277) with three equimolar proportions of methylenetriphenylphos-phorane gave the cyclic phosphorane (278), which was stereoselectively converted into the cyanohydrin (279) by way of the corresponding C-methylene and inosose derivatives. Compound 279 was converted into 43 and 44 by way of the corresponding carboxylic acid (280), and unsaturated nitrile (281), respectively. Compound 39 was derived from the inosose (282), obtained from quebrachitol, through a 21-step conversion.402 Introduction of a hydroxymethyl group into 282 was accom-... 

Another interesting approach is the use of l,l-dimethoxy-2-lithio-2-propene, as demonstrated by Depezay s group, for the synthesis of C-methylene branched-chain sugars [24,25], intermediates in the synthesis of hamamelose G, a naturally occurring branched-chain pentose [26,27]. In this cash, the condensation of this Kthio derivative was effected on the aldehydo group of D-glyceraldehyde 10 (Scheme 8) to give a 3 7 mixture of 11a... 

J. S. Brimacombe, J. A. Miller, and U. Zakir, An approach to the synthesis of branched chain amino sugars from C-methylene sugars, Carbohydr. Res. 49 233 (1976). 

Y. Ali and W. A. Szarek, Synthetic approaches to gem-di-C-alkyl derivatives of carbohydrates Nucleophilic addition reactions of 3-C-methylene compounds derived from l,2 5,6-di-0-isopropylidene-ot-D-rifto-hexofuranos-3-ulose using phase transfer catalysis, Carbohydr. Res. 67 Cll (1978). 

D. E. Iley,S.K.Tam,andB. Fraser-Reid, l,5-anhydro-4,6-0-benzylidene-l,2,3-trideoxy-3-C-methylene-D-e/ytfmo-hex-l-enitol Six synthetic routes, Carbohydr. Res- 55 193 (1977). 

Balch ei al. (306) have given a detailed report on novel A-frame-type methylene bridged palladium complexes of composition Pd2(dpm)2( p-CHR)X2 (X = I, Br, Cl R = H, CH3) and [Pd2(dpm)2(joi-CH2)L2]2+ (L = pyridine, methylisocyanide). It was demonstrated that the Pd—C (methylene) bond resists insertion of carbon monoxide, isocyanides, or sulfur dioxide. Protonation of Pd2(dpm)2(/x-CH2)I2 with fluoroboric acid yields the compound [Pd2(dpm)2(ju.-I)(CH3)I]BF4 in which the bridging methylene group of the precursor has been converted into a terminal methyl group, a process that has also been encountered in a previous example (52). 

Fig. 6 Dependence of e° versus the percentage of modifier in binary mixture A/B. A = apolar diluent (hexane), B = modifier, a = carbon tetrachloride, b = propyl chloride, c = methylene chloride, d = acetone, e = pyridine (normal phase chromatography).

The Effect of (a) Formaldehyde, (b) Hydroxymethyl formamide, (c) Methylene Diformamide... 

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