Amides benzyne intermediates

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

An early ease in whieh the existenee of benzyne as a reaetion intermediate was established was in the reaction of chlorobenzene with potassium amide. Carbon-14 label in the starting material was found to be distributed in the aniline as expeeted for a benzyne intermediate. ... 

Another reaction that is catalyzed by a base is that which leads to the formation of the benzyne intermediate. In this case, the strong base is the amide ion, NH2 . 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

Wikel and Paget153 showed that a benzyne intermediate was not participating in the cyclization of 154a to the fused benzothiazole 155 with sodium hydride since the isomeric chloro compound 154b did not give 155 either under the same conditions or on treatment with potassium amide in liquid ammonia. 

A route based on a benzyne intermediate can afford the isoindole ring via a category lb process. iV-Cyanomethyl-Af-methyl-0-chlorobenzylamine cyclizes to 1-methylisoindole under the influence of potassium amide in liquid ammonia (equation 36) (77T581). The cyano group plays two important roles. First, it provides stabilization of the carbanion... 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

B-5. Which of the following compounds gives a single benzyne intermediate on reaction with sodium amide ... 

One of the characteristics of reactions involving benzyne intermediates is that the nucleophile can bond to the same carbon to which the leaving group was bonded, or it can bond to the carbon adjacent to the one to which the leaving group was bonded. This often results in the formation of isomeric products when substituted aromatic halides are used. For example, the reaction of yo-bromotoluene with sodium dimethyl-amide in dimethylamine as the solvent gives a 50 50 mixture of the meta and para... 

The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy-, and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides to give any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates. 

The reaction of an aryl halide with potassium amide proceeds through a benzyne intermediate. Ammonia can then add to either end of the triple bond to produce the two methylanilines observed. 

Stevens and Bisacchi have carefully examined the trailing of benzynes, generated fiom a number of aryl bromides and sodium amide in THF, with 1,1-dimethylethylene and report procedures which afford 6 6% yields of 1,1-dimethoxycyclobutenes, e.g. (131). These compounds are hydrolyzed quantitatively to the corresponding benzocyclobutenones (132). Excellent regioselectivity was obtained with unsym-metrical benzynes derived from methoxy substituted bromobenzenes due to the polarized nature of the benzyne intermediate. Steric effects also influence regioselectivity o-bromotoluene afforded a 3 1 mixture of 3-methyl- and 6-methyl-benzocyclobutene. 

Pkenantkridine synthesis. Treatment of the haloanil (1) with potassium amide in liquid ammonia gives phenanthridine (2) in > 90 % yield. A benzyne intermediate is... 

Labelling can sometimes be carried out by introduction of an inert substituent group in the molecule, rather than by isotopic substitution. For example, 4-iodotoluene (4-iodomethylbenzene) can be used to detect the change of position of the substituent group in reaction (1.7). The products are a mixture of 3- and 4-aminotoluenes, but not the 2-isomer, again pointing to the benzyne intermediate, rather than to complete freedom of attack for the incoming amide ion. 

Homoeyelic ring closures. Bunnett and Skorcz31 found that several aliphatic esters, nitriles, sulfones, and ketones bearing an m-o-chlorophenyl group react with potassium amide in liquid ammonia to form homocyclic products of ring closure by way of a benzyne intermediate. The procedure has since been modified to use sodium amide (commercially available).32 The reaction is probably the method of choice for synthesis of 1 -substituted benzcyclobutenes. 

Watanabe et al. (84CPB1264) have reported a one-step synthesis of acronycine 208. Lithium methyl(2-methoxycarbonyl)phenyl amide 258 generated from methyl Al-methylanthranilate 257 in situ in the presence of excess lithium cyclohexylamide (LCA), was reacted with 6-bromo-2, 2-dimethyl-7-methoxychromene 259 to produce acronycine 208. A benzyne intermediate 260 is believed to be involved in this reaction (Scheme 44). 

Alternative approaches to aporphine alkaloids using benzyne intermediates have been reported.113-118 For example, treatment of the readily available bromo-benzylisoquinoline derivative (98 X = Br, Y = H) with potassium amide gave the corresponding amino-compound (98 X = H, Y = NH2), which upon... 

A synthesis employing a benzyne intermediate is a good way to prepare meto-amino-substituted aryl ethers (see Problem 31). The amide ion preferentially attacks the meta position because there is less steric hindrance at this position and the resulting negative charge can be stabilized by the adjacent electron-withdrawing oxygen atom. 

Earlier in this chapter, we described the reaction of chlorobenzene with amide ion to produce aniline. The mechanism for this reaction involves the removal of H by NH to form the benzyne intermediate. 

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