Unactivated methylene

Bisdecarboxylation of malonic acids 9-15 Oxidative decyanation of nitriles 9-16 Oxidation of activated or unactivated methylene groups 9-20 Oxidation of secondary alkyl halides and tosylates... 

The introduction of hydroxy and carbonyl groups at unactivated positions of terpenoids is usually accomplished by micro-organisms.35 However, recent studies have shown that rabbits can hydroxylate cedrol (72) at a remote unactivated methylene group to provide a mixture of products (73a and b) and (74a and b).36 Patchoulol (298) has also been functionalized in a similar fashion (c/. p. 90). 

The 20/1 y/5 ratio, when both carbons are unactivated methylenes, is also displayed by alkoxy radicals 75>. The slower 1,6-hydrogen transfer presumably reflects some of the strain in a 7-membered ring. It must also involve a more negative entropy. Rotations about three C—C bonds are frozen in the transition state, whereas only two C—C rotations need be frozen for y-hydrogen abstraction. 

Breslow, R., Winnik, M. A. (1969). Remote oxidation of unactivated methylene groups, J. 

Under special conditions (addition of lithium amide, phase-transfer catalysis), compounds with apparently unactivated methylene groups (e.g., 5-methoxy-l-tetra-lone, Lombardo and Mander, 1980) or even with a methyl group at an arylcarbonyl group (Sugihara et al., 1987) undergo diazo transfer with arenesulfonyl azides. This is also the case for esters of 4-arylbut-3-enoic acid and related compounds (Davies et al., 1989, and references therein). 

In an attempt toward syntheses of betulafolienetriol (13) and 20(5)-protopanaxadiol (26), the genuine sapogenin, introduction of an oxygen function at the unactivated methylene at c-12 of the dammarane skeleton was achieved 128, 129) by means of remote oxidation (130) using a photoexcited aromatic nitro group (131, 132, 133) (see Chart 18). Irradiation of the p-nitrophenyl-acetate (83) of 3-epidammaranediol-II (84)... 

Nakanishi M, Katayev D, Besnard C, Kiindig EP (2011) Fused indolines by palladium-catalyzed asymmetric C-C coupling involving an unactivated methylene group. Angew Chem Int Ed 50(32) 7438-7441... 

Hou X-F, Wang Y-N, Gottker-Schnetmann I. N-Heterocyclic carbene palladium catalyzed regioselective oxidative trifluoroacetoxylation of unactivated methylene sp C-H bonds in linear alkyl esters. Organometallics. 2011 30 6053-6056. 

The biosynthesis of the cyclopropane ring in natural products can occur through transfer of a methylene group from an ylide derived from S-adenosyl methionine to an unactivated olefin such as an oleic ester [468] via a copper(i) carbcne complex [469]. 

The formal addition of a C-H bond at activated methylenes and methynes (pronucleophiles) to activated alkenes in the presence of a base is well known as the Michael reaction (Scheme 1, Type A) [1]. In modem organic syntheses, the use of transition metal (TM) catalysts enables the C-H addition of activated methylenes and methynes to activated alkenes perfectly under neutral conditions (Scheme 1, Type B) [2]. In general, the nonfunctionalized carbon-carbon multiple bonds (for example, EWG2 = H in Scheme 1) are unreactive toward carbon nucleophiles because of their electron rich Jt-orbitals. The pioneering efforts by various research groups resulted in the development of transition metal-catalyzed addition of a C-H bond at active alkanes to such unactivated C-C multiple bonds. This reaction consists of the formal addition of a C-H bond across the C-C multiple bonds and is called a hydrocarbonation reaction. As a milestone in this hydro-carbonation area, early in the 1970s, Takahashi et al. reported the Pd-catalyzed addition of the C-H bond of pronucleophiles to 1,3-dienes [3], The first Pd-catalyzed reaction of activated methylenes with unsubstituted allenes was apparently reported by Coulson [4]. The synthetic applications of this reaction were very limited. In the last decade, the Pd-catalyzed addition of C-H bonds to various unacti-... 

A cortisone synthesis using remote functionalization at an unactivated carbon centre has been achieved.97 Cortexolone (224) was converted into the 5a-H,3j3-OH derivative (formation of the bismethylenedioxy-compound followed by lithium-ammonia-ethanol reduction). Inversion98 of 3)8- to 3 -OH followed by esterification with m-iodobenzoic acid produced (225), which on irradiation in methylene chloride containing phenyl iodide dichloride gave the 9 a -chloro-derivative (not isolated). This was dehydrohalogenated and saponified by methanolic potash to yield (226) (75%) and thence, by further known steps, cortisone acetate. 

While the hydrogenation of unactivated aliphatic aldehydes and ketones does not generally take place over palladium, this catalyst readily promotes the hydrogenolysis of aryl aldehydes and ketones to the methylene at room temperature and 1-4 atmospheres pressure. The use of an acidic solvent facilitates this reaction2 -29 but is not essential for obtaining good to excellent yields of the desoxy product (Eqn. 18.8). 0 With a basic substrate such as a 2- or 4-acyl-pyridine, however, the alcohol product was obtained (Eqn. 18.9).31... 

A much more highly diastereoselective process results when alkenic 3-keto ester and 3-ketoamide substrates can be utilized in the ketone-alkene reductive coupling process. Both electron deficient and unactivated alkenes can be utilized in the reaction (equations 65 and 66). In such examples, one can take advantage of chelation to control the relative stereochemistry about the developing hydroxy and car-boxylate stereocenters. Favorable secondary orbital interactions between the developing methylene radical center and the alkyl group of the ketyl,and/or electrostatic interactions in the transition state account for stereochemical control at the third stereocenter. 

The [3-1-2] methylenecyclopentane annulation of [(trimethylsilyl)methylene]-cyclopropane dicarboxylates with unactivated and electron-rich alkenes (vinyl ether, vinyl thioether, or vinyl silyl ether) are efficiently photocatalyzed by butyl disulfide or bis(tributyltin) [78]. 

Even the propargylic alcohol derivative 35 with an electronically almost unactivated triple bond smoothly undergoes palladium(0)-catalyzed cycloisomerization to give an 85% yield of the allylic alcohol, (3/ , 3a5 )-3-cyclohexyl-4-methylene-3,3a,4,5-tetrahydro-lff-cyclo-penta[c]furan-6-methanol (36)." The substrate molecule containing a rer/-butyldimethylsilyl substituent at the alkyne instead of a hydroxymethyl group, however, again failed to undergo the cycloisomerization, presumably due to steric hindrance. ... 

Palladium-based catalysts also bring about cyclopropanations in high-yield. With palladium acetate/CHjNj, styrene , unactivated terminal olefins strained olefins , 1,3-dienesan enamine , as well as a,3-unsaturated carbonyl compounds have been cyclopropanated (Table 1). Contrary to an earlier report, the reaction also works well with cyclohexene if the conditions are chosen appropriately it seems that the notniyst is rapidly deactivated in the presence of this olefin >. Trisubstituted a,p-unsaturated carbonyl compounds were found to be unreactive, and the same is true for the double bonds in diethyl fumarate, maleic anhydride, coumarin and 1,3-dimethyluracil. Whereas the latter two were totally unreactive, [3-1-2] cycloaddition of diazomethane gave pyrazolines in the former two cases. The last entry of Table 1 shows that an allyl alcohol function can still be cyclopropanated, but methylene insertion into the O—H bond is a competing process. 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

Zinc oxide, an inexpensive and commercially available inorganic solid, can be utilized as an efficient catalyst in the Friedel-Crafts acylation of activated and unactivated aromatic compounds with acyl chlorides at room temperature for 5 to 120 min (Table 4.14). Acylation is claimed to occur exclusively at the para-position of the monosubstituted aromatic compounds. The catalyst can be recovered and reused, after washing with methylene chloride, for at least two further cycles, showing quite similar high yield (-90%) in the model benzoylation of anisole. Mechanistically, it seems that zinc chloride can be the true catalyst, generated in situ by the reaction of zinc oxide with hydrogen chloride. 

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