Anionic Fries rearrangement

SCHEME 26.23 Synthesis of 4-fluoro-2-substituted-lH-indoles and benzoxazoles. 

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In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

Carbamate 613 under the same conditions also undergoes remote lithiation and a remote anionic Fries rearrangement, and then the product amide 614 proceeds to direct a remote benzylic lithiation, even though it has a free ortho position. Finally, the benzylic organo-lithium 615 cyclizes onto the amide to form 616—all in one pot (Scheme 240) . 

Accompanied by 169 3.5-disilylated material other electrophiles low yield. " 4-Pyridone product via anionic Fries rearrangement, f Formed in situ from 4-pyridone. 

Anionic Fries rearrangement see 87JOC1935. h 10% of 7-substituted product also obtained. 

The role of aggregates and mixed aggregates on the lithium diisopropylamide-mediated anionic Fries rearrangements of aryl carbamates (Scheme 7) has been described.57 Substituents at the meta -position of the arene (X = H, OMe, F) and the... 

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. 

Total synthesis has benefited from key DoM reactions. The sequence 48 —> 49 —> 50 —> 51 (Scheme 12) en route to the natural product ochratoxin A (52) takes multiple advantage of anion chemistry (53) ortho-metalation of the powerful OCONEtj group (step 1), anionic Fries rearrangement (step 2), in-between DoM and chain-extension by Li-Mg transmetalation (step 3) [12]. 

The O-carbamate, the most powerful of DMGs in competition experiments [13], is similarly plagued by stability as the N,N-diethyl derivative 13 (Scheme 6). However, the N-cumyl -N-methyl counterpart 14 undergoes unproblematic metalation-electrophile quench to give 15 and anionic Fries rearrangement (16) reactions. The very mild conditions for hydrolysis to 17, and hence to 18, as well as to 19 bode well for further useful chemistry of the N-cumyl DMG in context of more substituted aromatics [14]. 

The ortho lithiation of phenolic urethanes was reported by Snieckus in 1983. In addition to being an efficient ortho director (as expected considering the pllTt data in Table 1), the O-phenylurethane also is capable of an anionic Fries rearrangement. This rearrangement allows substitution ortho to the urethrae, then lithiation rad rearrangement at the ortho position, resulting in introduction of a tertiary... 

Hallberg, A., Svensson, A., Martin, A. R. An intramolecular anionic Fries rearrangement of N-acylphenothiazines. Tetrahedron Lett. 1986, 27, 1959-1962. 

Horne, S., Rodrigo, R. A complex induced proximity effect in the anionic Fries rearrangement of o-iodophenyl benzoates synthesis of dihydro-O-methylsterigmatocystin and other xanthones. J. Org. Chem. 1990, 55,4520-4522. 

We have come across the Fries rearrangement previously in this chapter before lithium had even made its entrance. A similar rearrangement can occur in the realm of orffto-lithiated species and is sometimes call the anionic Fries rearrangement. Compare the two. 

The amide is a good ort/zo-director but so is the acetal function. The regioselectivity (actually there is the issue of chemoselectivity here too) of the lithiation reaction will depend upon which of the two is the more potent. Amides were one of our three kings of the ortho-directors and are more powerful than acetals. Now it is time for an anionic Fries rearrangement (in the retrosynthetic direction) to give the starting material 127. 

It is important to recognise the element of choice that exists in the anionic Fries rearrangement. After the initial lithiation of 127 we can either let it warm up and do the rearrangement or, if we are careful, we can keep it cold so that the rearrangement does not take place and we can introduce another electrophile to react with the intermediate lithiated compound instead.11... 

We have also seen that ort/w-lithiation can be used in conjunction with other reactions - such as fluoride displacement or an anionic Fries rearrangement - that make ort/w-lithiation a particularly versatile strategy. 

A new approach to gilvocarcins features directed metallation and a Pd(0)-catalysed Suzuki cross coupling to produce the biaryl precursor. LDA remote metallation precipitates an anionic Fries rearrangement and generates the naphtho[ft,d]benzopyran system <97TL8149>. 

Directed ortho Metalation (DoM). The synthesis of the alkaloid schumarmiophytine requires a silicon protection of the more reactive ortho 0-carbamate site to set the stage for the key step, a remote anionic Fries rearrangement that results in a pyridine ring carbamoyl translocation (eq 48). ... 

Remote metalation of biaryls and m-teraryls provides a general synthesis of substituted and condensed fluorenones (eq47). Similarly, biaryl 0-carbamates undergo remote metalation and anionic Fries rearrangement to 2-hydroxy-2 -carboxamidobiaryls, which are efficiently transformed into dibenzo[fc,i/]pyranones. ... 

Anionic Fries Rearrangement. Lithiated O-aryl carbamates constitute one of the most powerful ortho directors in aromatic metallation chemistry. If allowed to warm in heu of quench-... 

Horne and Rodrigo reported in 1990 the synthesis of dihydro-O-methylsterigma-tocystin (868) (623) utilizing an iodide intermediate, 865, which they had developed for an earlier synthesis of aflatoxin B2 (2) (39), as part of an investigation for a general method leading to the synthesis of substituted xanthones. The key conversions are an esterification, anionic Fries rearrangement, and base-mediated cyclization of a phenol upon an aryl fluoride to deliver the xanthone core of 868 (623) (Scheme 13.5). 

Home S, Rodrigo R (1990) A Complex Induced Proximity Effect in the Anionic Fries Rearrangement of o-Iodophenyl Benzoates Synthesis of Dihydro-O-methylsterigmatocystin and Other Xanthones. J Org Chem 55 4520... 

Scheme 14.40 The DoM-Suzuki-Miyaura and Migita-Stille cross-coupling/remote anionic Fries rearrangement. Synthesis of isoschumanniophytine 201 (156).

DoM-derived intermediate 205 in a Suzuki-Miyaura cross-coupling reaction, which leads to the azabiaryl 206 in excellent yields. A DoM-protective silylation sequence of 206 and DreM-induced remote anionic Fries rearrangement results in smooth pyridine-ring carbamoyl translocation and affords, after acylation, the aryl nicotinamide 207 in good yields. This synthesis, albeit a few steps longer, is completed in 24% overall yield and compares favorably with that described in Scheme 14.39 [155] (10 steps vs 6 steps, 5% overall yield). 

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