Intramolecular ipso

Intramolecular ipso-acylationst Grisadienediones such as 2 can be obtained by treatment of a substituted o-phcnoxy benzoic acid ester (1) with dry hydrogen chloride and an excess of TiCL, at 0-25". The synthesis involves an intramolecular... 

Z)-Benzyl-3-(2-halophenyl)-3-hydroxy-2-(pyridin-2-yl)acrylates 664 can undergo competitive intramolecular ipso-substitutions to form the intermediates 665 and 666. The irreversible elimination of benzyl chloride from intermediate 666 affords 4-hydroxy-3-(2 -pyridyl)coumarins in high yield (Scheme 158) <2001CC639>. 

Scheme 13. Intramolecular ipso SnAr C-O bond formation.

Scheme 16. Intramolecular ipso SrgAr CO bond formation.

Scheme 19. Intramolecular ipso SNAr C-N bond formation.

Direct displacement reactions of 2-bromoimidazoles with nucleophiles are very difficult. For example, 1-methyl-2,4,5-tribromoimidazole fails to react with NaOMe <2003S659>. However, intramolecular ipso substitution reactions such as during the synthesis of 2,3-dihydroimidazo[2,l-/ ][l,3]oxazoles 952 (Scheme 230) via 951 work well <200282691>. 

In 1989 Kikugawa reported the intramolecular ipso attack of a nitrenium ion generated from the A-chloro-A-methoxyamide of anisole 35, to give the l-methoxy-l-azaspiro[4.5]decadienone 36 in 83% yield [27]. The same author went on to improve this process, which had already been done by Wardrop [10]. Both described the cyclization of the A-methoxy amide 35 using PIFA in trifluoroethanol (TFEA) [28] and... 

The reaction of terminal alkynes RC=CH (R = aryl, alkyl) with iodine, TSNHNH2, and Bu OOH has been found to afford ( )- -iodovinyl sulfones ArC(I)=CHTs. lodination of A -(alkynoyl)-6-methoxytetrahydroquinolines (21) has been found to trigger an intramolecular ipso-attack of the primary intermediate on the electron-rich aromatic ring, resulting in the formation of pyrrolo-[2,l-/ quinolones (22) (R = aryl, heteroaryl, vinyl, alkyl). ... 

G., Photoreactivity of some a-arylvinyl bromides in acetic acid. Selectivity toward bromide versus acetate ions as a mechanistic probe, J. Am. Chem. Soc., 113,4261,1991. See also (b) Kitamura, X, Kabashima, X, Kobayashi, S., and Taniguchi, H., Isolation and alcoholysis of an ipso adduct, vinylidenecyclohexadiene, from photolysis of l-(p-ethoxyphenyl)vinyl bromide. Tetrahedron Lett., 29, 6141, 1988 (c) Kitamura, X, Nakamura, I., Kabashima, X, Kobayashi, S., and Taniguchi, H., A novel spiro adduct from intramolecular ipso substitution in the photolysis of an a-[p-(2-hydroxyalkoxyjphenyl]vinyl bromide,/. Chem. Soc., Chem. Commun., 1154, 1989 (d) Kitamura, X, Kobayashi, S., and Xaniguchi, H., Photolysis of vinyl halides. Reaction of photogenerated vinyl cations with cyanate and thiocyanate ions,/. Org. Chem., 55, 1801, 1990 (e) Hori, K., Kamada,... 

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

Interesting results have been obtained in intramolecular acylation reactions involving pyrrole and thiophene derivatives. A muscone synthesis involves selective intramolecular acylation at a vacant a-position (Scheme 18) (80JOC1906). In attempts to prepare 5,5-fused systems via intramolecular acylation reactions on to a jS-position of a thiophene or a pyrrole, in some cases ipso substitution occurs with the result that rearranged products are formed (Scheme 19) (82TH30200). 

An interesting case of ipso intramolecular alkylation has been observed in the case of the acid-promoted cyclization of the amino alcohols (61). With trifluoroacetic acid the major product was the rearranged thienopyridine (62), whereas with polyphosphoric acid the product formed exclusively was the non-rearranged thienopyridine (63) (82CC793). 

An ipso attack on the fluorine carbon position of 4-fIuorophenol at -40 °C affords 4-fluoro-4-nitrocyclohexa-2 5-dienone in addtion to 2-nitrophenol The cyclodienone slowly isomenzes to the 2-nitrophenol Although ipso nitration on 4-fluorophenyl acetate furnishes the same cyclodienone the major by-product is 4 fluoro-2,6-dinitrophenol [25] Under similar conditions, 4-fluoroanisole pnmar ily yields the 2-nitro isomer and 6% of the cyclodienone The isolated 2 nitro isomer IS postulated to form by attack of the nitromum ion ipso to the fluorine with concomitant capture of the incipient carbocation by acetic acid Loss of the elements of methyl acetate follows The nitrodienone, being the keto tautomer of the nitrophenol, aromatizes to the isolated product [26] (equation 20) Intramolecular capture of the intermediate carbocation occurs in nitration of 2-(4-fluorophenoxy)-2-methyIpropanoic acid at low temperature to give the spiro products 3 3-di-methyl-8 fluoro 8 nitro-1,4 dioxaspiro[4 5]deca 6,9 dien 2 one and the 10-nitro isomer [2d] (equation 21)... 

A radical carboxyarylation approach was introduced as the key step in the total synthesis of several biologically important natural products (Scheme 27). Treatment of thiocarbonate derivatives 112 (R = Me or TBS) with 1.1 equiv of (TMS)3SiH in refluxing benzene and in the presence of AIBN (0.4 equiv added over 6h) as radical initiator, produced compound 113 in 44% yield. This remarkable transformation resulted from a radical cascade, involving (TMSlsSi radical addition to a thiocarbonyl function (112 114), 5-era cyclization (114->115) and intramolecular 1,5-ipso substitution (115 116) with the final ejection of (TMSlsSiS radical. 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

An example of this displacement between a pyridine nitrogen atom and an aryl halide is shown in Scheme 21. When 2-pyridyl acetates 138 were C-acylated with 2-halobenzoyl chlorides, the enolized products 139 resulting from the reaction suffered an intramolecular nucleophilic attack of the pyridine nitrogen atom onto the ipso-position to give benzo[c]quinolizinium salts 140 as intermediates. Loss of HC1 gas from 140 afforded benzo[c]quinolizine derivatives 141 <2002JOC2082>. 

In a closely related study, Tung and Sun discussed the microwave-assisted liquid-phase synthesis of chiral quinoxalines [80], Various L-a-amino acid methyl ester hydrochlorides were coupled to MeOPEG-bound ortho-fluoronitrobenzene by the aforementioned ipso-fluoro displacement method. Reduction under microwave irradiation resulted in spontaneous synchronous intramolecular cyclization to the corresponding l,2,3,4-tetrahydroquinoxalin-2-ones (Scheme 7.71). Retention of the chiral moiety could not be monitored during the reaction, but after release of the desired products it was found that about 10% of the product had undergone racemization. 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

The reactivity of allenyl ketones is also manifested in the Hg(II)-catalyzed ipso substitution that converts 54 to spirodione 55 (Eq. 13.17) [19]. The reaction presumably involves activation of the allene by Hg(II), followed by intramolecular electrophilic attack on the aromatic ring. Hydrolytic cleavage of the metal from the intermediate product of the reaction, followed by rearrangement leads to the observed spirocyclic dione. 

A highly efficient route to azacoumarins has been obtained by treatment of compounds 87 with (TMS)3SiH under standard experimental conditions (Reaction 7.91) [69]. The mechanism based on an unusual double intramolecular, 5-ipso and, 6-ipso substitution with the final ejection of MeO radical. 

Dihydroimidazo[2,l-b]oxazoles were prepared fi om an intramolecular nucleophilic ipso-substitution of 2-alkylsulfonylimidazoles <99S1613>. The synthesis of hitherto unknown 2-(2,4,6-triarylphenyl)substituted 4,5-dihydro-1/f-imidazolium perchlorates from 2-methyl imidazolium perchlorates and 2,4,6-triarylpyrylium perchlorate salts was published <99JC813>. Substituted aromatic heterocycles from reactions of 2,3-dihydrospiro[l/f-4-and... 

In view of the extensive documentation outlined above, the usefulness of the polarity alternation concept as a primary guide for evaluation of substituent effects can hardly be denied. The influence of a substituent on the ipso site has not been discussed in this article but an even more direct and important effect is implicit. Among the innumerable examples one may cite the preferential formation of geminal dimetallic species [5] in hydrometalation and carbometalation of vinylmetals and acetylenes. On the other hand, chemical systems are usually very complex, inter- and intramolecular forces including steric and stereoelectronic factors may dominate over polarity alternation. Thus, chelation by a proximal donor often directs metalation and stabilizes certain organometallic entities. In these instances the stability gaining from polarity alternation is overwhelmed. 

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