Anthranils cycloadditions

Benzocyclobutenone was first prepared from 1 -bromobenzocyclobutene by hydrolysis followed by chromium trioxide oxidation.3 More recent procedures involve hydrolysis of 1,1-dichloro- or 1,1-dimethoxybenzocyclobutene which in turn have been obtained through cycloaddition of the appropriate 1,1-disubstituted ethylenes to benzyne generated either from anthranilic acid through diazotization5 6 or from bromobenzene through sodium amide treatment.7.3 Benzocyclobutenone has... 

Benzotriazole and its derivatives are usually obtained by diazotization of o-phenylenediamines as discussed in Section 4.01.8.3 and in CHEC-1 <84CHEC-i(5)722>. Substituted o-phenylenediamines (e.g., 849) similarly give 1-substituted benzotriazoles (850) upon treatment with NaNOz (Equation (87)) <92JHC1519>. 1-Arylbenzotriazoles are alternatively synthesized from the cycloaddition of an aryl azide to benzyne or substituted benzynes, generated from the diazotization of anthranilic acid or its appropriately substituted derivatives (Scheme 169) <86CC399,87JCS(Pl)403, CHEC-i>. 

Alkynes react with anthranils in a cycloaddition reaction to form quinolines (Scheme 18). For a similar reaction of benzazetidine see Section 3.5.8.1.2. 

Cycloaddition of oxazoles with arynes provides a route to substituted polycyclic ethers and hydrocarbons (80TL3627). Oxazole (354), for example, reacted with anthranilic acid and isoamyl nitrite to provide the cyclic ether (357) by way of the benzofuran (356). The ether was then treated with zinc in glacial acetic acid to furnish hydrocarbon (358) in 70% yield based on the starting oxazole (Scheme 77). 

In a bimolecular cycloaddition reaction 1-phenylbenzotriazole (369) is obtained from dehydrobenzene (by diazotization of anthranilic acid) and phenyl azide (64joc3733, 6SCB3142). The synthesis of 1-glucosylbenzotriazole from glucosyl azides and dehydrobenzene has been accomplished in this way, 5delding, for example, l-(2,3,4,6-tetra-0-acetyl-j8-D-glucopyranosyl)benzotriazole (370) (68jhc699>. 

An unusual 1,3-cycloaddition of benzyne across a C=N-Se grouping in a 1,2,5-selenadiazole leads to the formation of the isoselenazole ring. The benzyne, generated from anthranilic acid, reacts with 3,4-diphenylselenadiazole 81 to afford 3-phenylbenzisoselenazole 82 as confirmed by mass spectrometry and the detection of benzonitrile, but the reaction has no practical synthetic value (Scheme 28) <1988J(P1)2141>. 

A new and very neat synthesis of evodiamine and rutaecarpine is described by the authors as a retro mass spectral synthesis , since the original conception was derived from the mode of fragmentation of these alkaloids in the mass spectrometer this involves a familiar retro Diels-Alder fission of ring c. Evodiamine (16a) was thus constructed by a 27r + 47r cycloaddition of 3,4-dihydro-/8-carboline with the keteneimine (17), prepared in situ by elimination of sulphur dioxide from the sulphinamide anhydride (18) (Scheme 7). When the anthranilic acid derivative (19) was used the product was rutaecarpine (20) itself, the initially formed dihydro-... 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

Simple pyrroles do not react as 4n components in Diels-Alder cycloadditions exposure of pyrrole to benzyne, for example, leads only to 2-phenylpyrrole, in low yield. However A-substitution, particularly with an electron-withdrawing group, does allow such reactions to occur, for example adducts with arynes are obtained using l-trimethylsilylpyrrole. Whereas pyrrole itself reacts with dimethyl acetylenedicar-boxylate only by a-substimtion, even at 15 kbar, ° A-acetyl- and A-alkoxycarbonyl-pyrroles give cycload-ducts, addition being much accelerated by high pressure or by aluminium chloride catalysis. The most popular A-substituted pyrrole in this context has been A-Boc-pyrrole, with benzyne (from diazotization of anthranilic acid) for example, a 60% yield of the cycloadduct is obtained. ... 

Figure 2.59 collects several [2t-2]-cycloadditions that can be carried out with C )-The reaction with dehydrobenzene is instructive as it reveals electronic properties of the fullerene The dehydrobenzene generated in situ from anthranilic acid reacts with Cso exclusively in a [2-i-2]-cycloaddition, although in principle a [4-f2]-reaction would also be possible, and dehydrobenzene usually enters into the latter when adding to electron-rich dienes. The nonoccurrence of this reaction clearly shows the electron-deficient character of C,so. For the same reason it never constitutes the diene part in a Diels-Alder reaction. Furthermore, the [24-2]-cycloaddition may be thermally effected, for example, the addition of long-chain cumulenes, allene amides or quadricyclan. The addition of ketenes as well occurs without irradiating the reaction mixture. Normally a reduced reactivity toward C,so should be expected for the electrophilic ketenes, but in reality the products of a [2-1-2]-cycloaddition are even found to be the major product. 

The formation of acridine in the reaction of benzyne with anthranil is thought to be a stepwise rather than a concerted (4 + 2)-cycloaddition.221 More interesting are the mercury sulfate-catalyzed cycloadditions of alicyclic ketones to anthranil in boiling xylene, which appear to involve the enol tautomers as indicated in Eq. (10).2 22 The yields of 2,3-cycloalkanoquinolines (163) range from 11% (n = 4) to 39% (n = 5). Phenylacetylene and diethyl maleate yield similar products. 

Alkoxy-l, 3-benzodithioles (1). Carbon disulfide undergoes 1,3-dipolar cycloaddition to benzyne generated from benzenediazonium-2-carboxylate (1,46)] to give 1,3-benzodithiole-2-carbene (a). This carbene reacts with alcohols to form (1) in 35-50% yields. The reaction can be carried out in one-step from anthranilic acid, since carbon disulfide is more reactive than alcohols toward benzyne. ... 

One of the early examples of an intramolecular Diels-Alder reaction of benzynes involved cycloaddition to a furan that was tethered to the benzyne moiety . Diazoti-zation of anthranilic acid 669 gave in 86% yield the cycloadduct 670, which was subsequently converted to the o-naphthoquinone 671 (mansonone E 7 steps) as well as to the structurally related mansonones F and I and biflorin. ... 

The first report of a [4 + 2] cycloaddition of an oxazole with benzyne was the reaction of a trisubstituted oxazole with benzyne generated from anthranilic acid and isoamyl nitrite in refluxing dioxane. The product of this reaction was not the oxazole Diels-Alder adduct or a furan, but rather the bisfbenzyne) adduct 163 resulting from initial cycloaddition to give 161, subsequent retro-Diels-Alder reaction to give the isobenzofuran 162 and then a second benzyne Diels-Alder reaction to afford 163 (Fig. 3.49). 

The action of a solution of potash in amyl alcohol on rutaecarpine produces anthranilic acid and a second acid which, when boiled with hydrochloric acid, is readily decarboxylated to tryptamine (6, 25, 94, 134, 135, 169). A close relationship between rutaecarpine and evodiamine was demonstrated by fusion of isoevodiamine hydrochloride. Rutaecarpine was formed with liberation of chloromethane. A number of syntheses of (63) have been reported 101, 135, 161), including some under so-called physiological conditions. Some of the more recent examples will be mentioned. Kametani et al. 102,108) obtained (63) in 80% yield through a regiospecificH s+n s cycloaddition of a keteneimine (generated in situ by extrusion of sulfur dioxide from the sulfmamide anhydride of anthranilic acid) with 3,4-dihydro-p-carboline or with 1,2,3,4-tetrahydro-l-keto-P-carboline 109) (also called 1,2,3,4-tetrahydronorharman-l-one or, as in Chemical Abstracts, 2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-one) ac-... 

One other miscellaneous cycloaddition reaction has been reported. Arynes generated from anthranilic acids 205 have been found to undergo cycUzation with Barton esters 206 to afford polycycUc heterocydes 207 in moderate yields (Scheme 12.59) [109], with the reaction presumably proceeding through a radical pathway. 

A nickel-catalysed cycloaddition has been reported where anthranilic acid derivatives react with alkynes to give substituted indoles initial oxidative addition of Ni(0) to an ester moiety allows intermolecular addition to alkynes via decarbonylation and [l,3]-acyl migration (Scheme 132). 

Azanickelacycle formation with partial replacement of the heterocyclic moiety substance by the nickel catalyst was also employed for the synthesis of indoles, an important class of heterocycles found in natural products and pharmaceuticals. Maizum et al. demonstrated a nickel-catalyzed decarbonylative cycloaddition by which anthranilic acid derivatives 39, which are readily available, react with alkynes to afford substituted indoles 41 (Scheme 12.17) [20]. The reaction is supposed to proceed via oxidative addition and decarbonylation to afford azanickelacycle 40, followed by alkyne insertion, 1,3-acyl migration, and reductive elimination, to afford A-pivaloyl-protected indole 41. Deprotected indole 42 was obtained as the final product upon workup, that is, treatment of the reaction crude reaction mixture with NaSMe in MeOH. 

Notably, the nickel-catalyzed decarbonylative cycloaddition affords a regioisomer opposite to that formed in the palladium-catalyzed Larock heteroannulation [21], For example, the nickel-catalyzed reaction of anthranilic acid derivatives 39 with l-trimethylsilyl-2-phenylacetylene (43) affords indole 44 with phenyl substituents at the 2-position [Scheme 12.18(a)], whereas the palladium-catalyzed reaction... 

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