Intramolecular directing group

Addition of p-tolyl magnesium bromide to o-benzyl benzonitrile (156), followed by copper-catalysed benzylic oxidation, yields dione (157), via unsubstituted imine (158), in one pot. The imine acts as an intramolecular directing group the formation of the benzoyl is suggested to be triggered by a 1,5-hydrogen transfer with a transient iminyl-copper species. 

C-H Bond Functionalization. The title corrpound is usually combined with metal acetates, such as NaOAc, to generate Cp Rh(OAc) species that is selective for ortho C-H bond activation with the aid of an intramolecular directing group, such as the imino group, to afford rhodacycle corr5>lexes (eq 1). The reactivity of these rhodacycle complexes and the reaction mechanism for the cyclometallation via C-H bond activation have been investigated. Recently, this method has been applied in the synthesis of various kinds of carho- and heterocycles via insertion into alkynes and alkenes. 

Compounds such as phenylacetate esters and phenylethyl ethers, which have oxygen substituents that can serve as directing groups, show high ortho. para ratios under these conditions.12 These reactions are believed to involve coordination of the N02+ at the substituent oxygen, followed by intramolecular transfer. 

Intramolecular process with rhodium catalyst has been described for the syntheses of indane, dihydroindoles, dihydrofurans, tetralins, and other polycyclic compounds. Wilkinson catalyst is efficient for the cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered to the K z-position of the imine-directing group. 

In contrast to the intramolecular process, simple allenes do not participate in the intermolecular [5 + 2]-reaction with VCP 18. However, when a second functionality is incorporated into the allene, an efficient and facile cycloaddition occurs, presumably assisted by a directing effect of the secondary functional group. The [5 + 2]-reaction also works with styrenyl- and cyano-substituted allenes as directing groups (Scheme 12). As would be expected from... 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

A hydrosilyloxy moiety also works as a directing group for the intramolecular silylformylation regardless of terminal and internal alkynes (Table 9)7 ... 

Although the regioselectivity for the silylformylation of 1-alkynes is excellent, that of internal alkynes is low except for 2-alkynoates (vide supra). Also, in the reactions of 1-alkynes, the silyl group is always delivered to the terminal position and the formyl to the C-2 position, thus it is impossible to synthesize 3-silyl-2-alkenals, which requires opposite regioselectivity. Intramolecular directed reactions can circumvent these limitations and expand the scope of the silylformylation of alkynes. 

Scheme 15. The polymer-bound alkoxybenzyl protecting group in 67 serves as a directing group and enabled the intramolecular aglycon delivery to afford a stereoselective formation of /1-mannosides 69. Byproducts such as 70 and 71 remained on the polymeric support.

Some other directing groups which involve the sp2 nitrogen can also function as a directing group in place of the pyridine ring. The reaction of aromatic imines with CO and ethylene in the presence of Ru3(CO)12 did not stop at the carbonylation step, but rather indenone derivatives were the final products and were formed via an intramolecular aldol-type reaction of the expected carbonylation products in situ (Eq. 27) [44]. The treatment of the reaction mixture with silica gel selectively afforded indenones in good yields. 

In a very clever reaction sequence, A-methylaziridines have been shown to be useful directing groups for ort o-metallation <2005OL3749>. Reaction of 170 with r-BuLi followed by trapping with a carbonyl compound provides alcohol 172. Subsequent intramolecular aziridine ring opening provides isobenzofuran derivative 173 (Scheme 45). 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

Palladium Catalysts Palladium catalysts are effective and powerful for C—H bond functionalization. Carbene precursors and directing groups are commonly used strategies. Generally, sp3 C—H bond activation is more difficult than sp2 C—H bond activation due to instability of potential alkylpalladium intermediates. By choosing specific substrates, such as these with allylic C—H bonds, palladium catalytic systems have been successful. Both intramolecular and intermolecular allylic alkylation have been developed (Scheme 11.3) [18]. This methodology has presented another alternative way to achieve the traditional Tsuji-Trost reactions. 

The total synthesis of veiutamine [53], which has a carbon side chain and a structure similar to makaluvamine D, has also been achieved via route a (Scheme 6). The 6-methoxyindole derivative 9 was converted to the Boc compound 11. Regio-selective ortholithiation at 6-position using the Boc group as a directing group and coupling with an aldehyde followed by intramolecular cyclization afforded the tetracyclic compound 12, which was converted to veiutamine [54]. 

Facilitation of intramolecular transfer reactions The proximity of two successive enzymes in the reaction sequence facilitates the direct group transfer. 

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