Rearrangements ortho substitution

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

Construction of the closely related NSAID bromefenac (46-8) depends on the Gassman indolone synthesis [46] for incorporation of the acetic acid chain. That reaction involves an anion-initiated electrocyclic rearrangement related conceptually to the little-known Hauser ortho substitution rearrangement. The simplest example of the latter depends on the formation of a carbanion by abstraction of one of the acidic protons from a benzyltrimethyl quaternary salt to give I (the... 

Lednicer, E. Hauser, C. R. A Novel Ring Enlargement Involving the Ortho Substitution Rearrangement by Means of Sodium Amide in Liquid Ammonia /. Aw. Chem. Soc. 1957, 79, 4449-4451. 

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

This carbyne was shown not to be the RCM active species. At —20 °C it rearranged spontaneously into the indenylidene complex XV with release of TfOH. This intramolecular transformation corresponds to the electrophilic ortho-substitution of one phenyl group by the electrophilic carbyne carbon of XIV. The carbene complex XV was identified as the species thermally formed in situ from the catalyst precursors Ia,b in the range 25-80 °C. 

Retrosynthesis a in Scheme 7.1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves ortho-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

Recall that the Claisen rearrangement converts an aryl allyl ether to an ortho-substituted allyl phenol. The presence of an allyl substituent in the product ortho to an aryl ether thus suggests the following retrosynthesis ... 

A related isomerization, that of phenylacetylcobalt carbonyl to o-toluyl-cobalt carbonyl, has recently been studied (143). It also appears to proceed via a tricarbonyl but could not proceed via Eqs. (9) and (10). This rearrangement has much in common with the so-called abnormal reactions of benzyl Grignard and benzyllithium reagents to produce ortho-substituted products (13, 13f). It is possible that a cyclic intermediate similar to that postulated in the Grignard rearrangements may be involved, Eq. (87). 

Roberts et al. have observed the unusual fragmentation of loss of formaldehyde in methyl esters of ortho-substituted ferrocenyl-benzenes 172). This novel fragmentation of loss of aldehyde has also been observed by Lupin et al. for methyl, ethyl, and n-propyl esters of ortho-substituted ferrocenyl benzenes as well as for methyl esters of alkenyl ferrocenes 134). The ortho effect, in a rearrangement depicting a six-membered transition state, has been proposed by Bursey et al. to explain this fragmentation, but it is more likely that the metal atom plays an important role, possibly with the migration of the methoxyl group to the metal 134). 

The similarly and equally accessible biaryl O-carbamate 142 (Scheme 38) requires ortho substitution (PG = OMe) or protection (PG = SiEts) to avoid anionic ortho Fries rearrangement (141) and to launch a DreM pathway leading to 144 using LDA under vigorous conditions [65]. For PG = TMS, carbamoyl migration to the incipient a-silylmethyl anion occurs... 

Based on their computational results, Kamey and Borden argued that an ortho substituent sterically hinders migration. When phenylnitrene is substituted at one ortho position, rearrangement occurs away from the blocked position with a barrier little different from that of phenylnitrene itself. However, when both ortho positions are occupied, the barrier for rearrangement is raised by 2-3 kcal mol , allowing for alternate reactions, especially intermolecular chemistry, to take place. 

Substiluled acrylic acids a-methylene-y-butyrolactones. The reaction of 1 with the allylic alcohol 2 at 170° gives the product (3) of Claisen ortho ester rearrangement. Oxidative elimination of GsHsSeOH gives the 2-substituted acrylic ester 4. 

The preparation and structure of homoannular diacetyl ferrocenes 164), and intramolecular cyclizations, both homoannular 168) and heteroannular I48, 168), have been exhaustively investigated. As part of this work, ferrocene carboxylic acids have been prepared 170). A rearrangement with ortho-substitution of a quaternary ammonium ion derived from ferrocene is also noteworthy 99). Work has been done on the isolation of optical isomers of substituted ferrocene derivatives 6, 166) and on cis-trans isomerism 169). 

Figure 2. Mechanism of the para-Claisen rearrangement of ortho substituted allyl phenyl ethers.

The total synthesis of the potent protein kinase C inhibitor (-)-balanol was accomplished by J.W. Lampe and co-workers. They took advantage of the anionic homo-Fries rearrangement to prepare the sterically congested benzophenone subunit. To this end, 2-bromo-3-benzyloxy benzyl alcohol was first acylated with a 1,3,5-trisubstituted benzoyl chloride to obtain the ester precursor in 84% yield. Next, the ester was treated with n-BuLi at -78 °C to perform a metal-halogen exchange. The resulting aryllithium rapidly underwent the anionic homo-Fries rearrangement to afford the desired tetra ortho-substituted benzophenone in 51% yield. 

V-Benzyl-/V,/V-dirnethy Ian Mini urn bromide 30 reacts with sodium amide in liquid ammonia to give both the product of 1,2-shift 33 (Stevens rearrangement) and the ortho-substituted compound 34 (Sommelet rearrangement) via the intermediate ylides 31 and 3254 (equation 13). 

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