Of unactivated carbons

Galonic, P.D., Vaillancourt, FH. and Walsh, C.T. (2006) Halogenation of unactivated carbon centers in natural product biosynthesis trichlorination of leucine during barbamide biosynthesis. Journal of the American Chemical Society, 128, 3900-3901. 

Oxidative Functionalization of Unactivated Carbon Hydrogen Bonds in HCTD (22)... 

Galonic DP, Vaillancourt FH, Walsh CT (2006) Halogenation of Unactivated Carbon Centers in Natural Product Biosynthesis Trichlorination of Leucine During Barbamide Biosynthesis. J Am Chem Soc 128 3900... 

This new style of synthetic catalysis will of course not replace all normal synthetic methods. For many purposes, the standard methods and rules - e.g. aldehydes are more easily reduced than are ketones - will continue to dominate organic synthesis. However, when we require a synthetic transformation that is not accessible to normal procedures, as in the functionalization of unactivated carbons remote from functional groups, artificial enzymes can play a role. They must compete with natural enzymes, and with designed enzyme mutants, but for practical large-scale industrial synthesis there can be advantages with catalysts that are more rugged than proteins. 

In all these examples functionalization of unactivated carbons occurred, but at positions only a few carbons removed from a substrate functional group. The rest of this chapter shall consider cases in which this restriction is removed. 

Electrophilic fluorination by substitution of hydrogen at unactivated tertiary carbon has been achieved by use of either CF3OF or elementary fluorine (diluted with N2). Electron-attracting substituents direct the reaction to remote C—H bonds, suggesting that the reaction has electrophilic rather than free-radical character. Examples include the 9a-fluorination of 5a-androstane-3/8,17/8-diol esters (309), 14a-fluorination of various 5a,6j8-dichloro-3,17-disubstituted steroids of type (310), and 17a-fluorination of 5a-cholestan-3j8-yl esters or their 5a,6/8-dichloro-derivatives. Hypobromite and other hypohalite reactions for the functionalization of unactivated carbon atoms are reviewed. ... 

C. L. Hill, in C. L. Hill (Ed.), Activation and Functionalization of Alkanes, Catalytic Oxygenation of unactivated carbon-hydrogen bonds-. Superior oxo transfer catalysts and the inorganic metallopor-phyrin, Wiley, New York, 1989, p. 243. 

Suginome, H., Takakuwa, K., and Orito, K., FunctionaHsation of unactivated carbon involving photochemical intramolecular rearrangement of nitro group attached to tetrahedral carbon to nitrosooxy group, Chem. Lett., 1357, 1982. 

The limitations of this reagent are several. It caimot be used to replace a single unactivated halogen atom with the exception of the chloromethyl ether (eq. 5) to form difluoromethyl fluoromethyl ether [461 -63-2]. It also caimot be used to replace a halogen attached to a carbon—carbon double bond. Fluorination of functional group compounds, eg, esters, sulfides, ketones, acids, and aldehydes, produces decomposition products caused by scission of the carbon chains. 

As shown in the manganese- and ruthenium-catalyzed intermolecular nitrene insertions, most of these results supposed the transfer of a nitrene group from iminoiodanes of formula PhI=NR to substrates that contain a somewhat activated carbon-hydrogen bond (Scheme 14). Allylic or benzylic C-H bonds, C-H bonds a to oxygen, and very recently, Q spz)-Y bonds of heterocycles have been the preferred reaction sites for the above catalytic systems, whereas very few examples of the tosylamidation of unactivated C-H bonds have been reported to date. 

We also discovered the ability of 2-azadienes of this sort to cycloadd to unactivated carbon—carbon double and triple bonds in an intramolecular fashion (89CC267) (Scheme 50) such a process appears to be one of the first examples of intramolecular [4 + 2] cycloadditions of simple 2-azadienes. Azadiene 216 was made from O-allyl salicylaldehyde 215 (R = allyl) and heated at 120°C in toluene to furnish the trans-fused tricyclic adduct 217 in excellent yield further dehydrogenation of 217 with DDQ afforded 5H-[ 1 ]-benzopyran[4,3-6]pyridine 218. On the other hand, when 0-(2-butynyl) salicylaldehyde 215 (R = 2-butynyl) was transformed into azadiene 219 and subjected to heating in a sealed tube at 150°C, pyridine 222 was isolated in very high yield. Its formation can be rationalized to occur via the expected Diels-Alder intermediate 220 thus, [1,5]-H shift in 220 would give rise to tautomer 221, which would suffer electro-cyclic ring-opening and aromatization to pyridine derivative 222. 

A general method of introducing the acid fluoride functionality in aryl bromides 12 is their carbonylation under an atmospheric pressure of carbon monoxide in dimethylformamide in the presence of potassium fluoride.33 Several catalytic systems, solvent and the effects of temperature, amount of potassium fluoride used and pressure of carbon monoxide were systematically investigated to find the right conditions to obtain the aroyl fluorides 13. The carbonylation of unactivated aliphatic bromides was unsuccessful. 

Reductive removal of fluorine from alkyl fluorides requires a potent reducing agent and so is not normally encountered However, hydrogenolysis of an unactivated carbon-fluorine bond in, for example, 3 p-fluorocholestane has been efficiently accomplished in 88% yield with a solution of potassium and dicyclohexyl 18 crown-6 in toluene at 25 °C [/] Similarly, sodium naphthalene in tetrahydrofuran converts 6 fluorohexene-1 and 1-fluorohexane to hydrocarbons in 50% yield at 25 °C over a 7-h period [2]... 

The second main aspect of reactions of carbonyl compounds is one we have already touched upon in Chapter 3. The carbonyl group increases the acidity of C—H bonds on a carbon directly attached to it by many powers of ten over an unactivated carbon-hydrogen bond. Removal of such a proton leaves the conjugated ambident enolate ion (29), which can be reprotonated either at the carbon, to give back the original keto tautomer, or at oxygen to give the enol (Equation 8.61).135 Acid also promotes interconversion between enol and keto... 

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