Directed ortho-metalation

This protective group was used to improve the directed ortho metallation. Cleavage... 

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

Concerning the yldiide Ph3P=CH-Li, the question as to whether it could be obtained by direct lithiation of the ylides 23 (Y=H), for a long time in debate between Schlosser and Corey, could have found an answer. Effectively NMR studies seem to show that a directed ortho-metallation occurs on an aromatic ring when 23 is reacted with t-BuLi [65], leading thus to the formation of 24 whose evolution does not afford Ph3P=CH-Li (Scheme 13). 

Chamoin S, Houldsworth S, Kruse CG, Bakker WI, Snieckus V. The Suzuki-Miyaura cross coupling reactions on solid support. Link to solution phase directed ortho metalation. The Leznoff acetal linker approach to biaryl and heterobiaryl aldehydes. Tetrahedron Lett 1998 39 4179-4182. 

A new synthetic protocol consisting of sequential directed ortho metallation, crosscoupling and a carbamoyl Baker-Venkataraman rearrangement has been applied to an efficient construction of coumarins (see Scheme 10). The formation of o-nitrosobenzaldehyde during the hydrolysis of o-nitrobenzyl tosylate in aqueous acetonitrile has been presented as a strong indication that the nitro group participates in the departure of the tosylate group as shown in Scheme 11. 

Directed ortho-metalation does not always occur with oxazoline compounds, as was shown by the chiral derivative 185 where competitive chelation of the n-butyllithium with the methoxy group prevented it from approaching close enough to abstract a proton from the benzene ring... 

The formation of the chromene caibamate 21 from resorcinol dicarbamate involves directed ortho metallation and an intramolecular 0- 0 carbamoyl transfer. Further manipulation utilising directed metallation and transition metal catalysed reactions allows the synthesis of plicadin, a naturally occurring coumestan <99AG(E)1435>. 

The general synthesis of the Daniphos ligands starting from enantiomerically pure [(R)-l-(phenylethyl)dimethylamine]chromiumtricarbonyl 1, is depicted in Scheme 1.4.1 [15]. A directed ortho-metallation (DOM) and subsequent quench with a chlorophosphine leads to an enantiomerically pure planar-chiral complex, which after chlorination using ACE chloride (1-chloroethyl chloroformate) is transformed into the desired diphosphine by a nucleophilic substitution without any loss of optical purity (Scheme 1.4.1) [6, 10]. 

After completion of this chapter, Snieckus et al. published examples of the solid-phase Stille105 and Suzuki106 reactions in which were included stannanes and boronic acids synthesized in solution via a directed ortho metalation procedure,107 ultimately allowing for the construction of a range of tricyclic structures. 

Chamoin, S. Houldsworth, S. Kruse, C. G. Bakker, W. I. Snieckus, V. The Suzuki-Miyaura Cross Coupling Reactions on Solid Support. Link to Solution Phase Directed ortho Metalation. The Leznoff Acetal Linker Approach to Biaryl and Heterobiaryl Aldehydes, Tetrahedron Lett. 1998, 39, 4179-4182. 

Snieckus, V. Directed ortho Metalation—Tertiary Amide and o-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics, Chem. Rev. 1990, 90, 879-933. 

In a sequence that proceeds by tandem directed ortho metalation steps (Scheme 133) the N,N-diethyl isonicotinamide (447a) has been converted into the chemotherapeutic alkaloid ellipticine (589) (Scheme 182) (80JA1457). Thus, in a rapid, one-pot procedure, metalation of 447a followed by condensation with N-protected indole-3-carboxaldehyde derivatives leads to the intermediates 615 which, upon second metalation and aerial oxidation affords the quinones 616 in modest to good yields. Established steps were used to convert 616, R = CH2OMe into ellipticine (589), concluding a route which complements that based on the oxazolino DMG (Scheme 175). 

N-Methylbenzamides have been used as isocoumarin precursors (71T6171). Directed ortho metallation followed by reaction with ethylene oxide gave the dihydroisocoumarin via the alcohol (Scheme 184). 

This reaction type, known as directed ortho metalation reaction, requires strong bases, normally an alkyllithium reagent (most lithium dialkylamides are of insufficient kinetic basicity). Alkyllithium bases show high solubility in organic solvents due to association into aggregates of defined structure, typically as hexamers in hydrocarbon solvents e. g. hexane or tetramers-dimers in polar solvents e. g. THF (see Chapter 5). 

Addition of A/ -forrnyl-/V,/V,/V -trimethylethylenediamine to 21 yields a-amino alkoxide 22. A further directed ortho metalation takes place by coordination of nBuLi to the ethylenediamine moiety and subsequent deprotonation. As result intermediate 6 is formed. 

Anctil, E. J.-G. Snieckus, V. The directed ortho metalation-cross coupling symbiosis. Regioselective methodologies for biaryls and heterobiaryls. Deployment in aromatic and hetero-... 

Snieckus, V. The directed ortho metalation— Ullmann connection. A new Cu(I (-catalyzed 231 variant for the synthesis of substituted diaryl ethers. J. Org. Chem. 1999, 64, 2986—2987. 

Gissot, A. Becht, J.-M. Desmurs, J. R. Pevere, V. Wagner, A. Mioskowski, C. Directed ortho metalation, a new insight into organosodium chemistry. Angew. Chem. Int. Ed. 2002, 41, 340-343. 

Kondo, Y. Shilai, M. Uchiyama, M. Sakamoto, T. TMP—Zincate as highly chemoselec-tive base for directed ortho metalation./. Am. Chem. Soc. 1999, 121, 3539-3540. 

Focken, T. Hopf, H. Snieckus, V. Dix, I. Jones, P. G. Stereoselective lateral functionalization of monosubstituted [2.2]paracyclo-phanes by directed ortho metalation-homolo-gous anionic Fries rearrangement. Eur. J. Org. Chem. 2001, 2221-2228. 

Directed ortho-metallation of aryl O-carbamates and subsequent reaction with a,P-unsaturated carbonyl compounds affords 2//-chromenes (Equation 29) <2001S140>. 

Certain derivatives of benzene and naphthalene can be lithiated with sec-butyllithium (sec-BuLi). This reaction is regioselective. It takes place exclusively in the ortho-position (Directed ortho Metalation, DoM) to a so-called Directed-Metalation Group (DMG), whose presence, accordingly, is a prerequisite for such a metalation. Figure 5.37 gives examples of DMGs that are bound through a C, an O, or an N atom to the aromatic compound. 

V Snieckus, The Directed Ortho Metalation Reaction. Methodology, Applications, Synthetic Links, and a Nonaromatic RamificationP PureAppl. Chem. 1990, 62, 2047-2056. 

V Snieckus, Combined Directed Ortho Metalation-Cross Coupling Strategies. Design for Natural Product Synthesis, PureAppl. Chem. 1994, 66, 2155-2158. 

Stefinovic, M. and Snieckus, V. 1998. Connecting directed ortho metalation and olefin metathesis strategies. Benzene-fused multiring-sized oxygen heterocycles. First syntheses of Radulanin A and Heliannane. J. Org. Chem. 63, 2808-2809... 

Magnesium 2-ethaxye(hoxide, Mg(OCHjCHJ)CJIs)2. Preparation.3 This metal alkoxide (1) decreases the activity of RLi reagents to such an extent that they can be prepared in THF in the presence of 0.5 equiv. of 1. The advantages of this fact are that some unstable organolithiums can be generated by this technique and that directed ortho-metallation can be suppressed if desired.4... 

Victor Snieckus is well known for having developed powerful methodological tools for the synthesis of polysubstituted aromatics, in particular heteroaromatic directed ortho-metalation. Thus, in his chapter (No. 10), prepared with his co-author Christian Hartung, directed ortho-metalation is taken as a starting point for new synthetic aromatic chemistry. 

Snieckus and Fu reported a new general and regiospecific synthesis of 9-phenanthrols involving direct ortho-metalation, Suzuki cross-coupling, and an LDA-mediated directed remote metalation sequence (Eq. (11)) [27]. 

The Directed ortho Metalation Reaction - A Point of Departure for New Synthetic Aromatic Chemistry... 

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