Ortho-lithiation amines

For conversion of functionalized diorganozincs into tertiary amines, aromatic compounds which contain a directed metallation group, such as Af,Af-dialkylbenzamides, methoxymethyl phenyl ether, phenyl oxazolines and phenyl Af,Af-dialkylcarbamates, were ortho-lithiated, transmetallated and then aminated with 2a in good yields, but with a slower reaction rate (Scheme 19). 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaUy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphorus [7723-14-0]y produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-lithiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has litde commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Lithiation of a series of cyclic aralkyl tertiary amines (25)—(28) with s-BuLi in various solvents has been studied.72 ortho -Lithiation has been observed only in the case of the eight-membered cyclic amine (28, R = H) and the ease of benzylic lithiation with respect to nitrogen was in the surprising order y > /S a, 8. 

As mentioned before structure of 2-2 was proposed by spectral analyses, the position of methylenedioxyl group in isoquinoline of 2-2 is in position C-5—C-6, but it did not exclude its possibility in position C-7—C-8. A total synthesis was accomplished in order to confirm the structure and to derive more samples for pharmacological tests. Piperonal 2-4 was used as starting material. It was oxidized by silver oxide in basic condition to get 2-5, then amidized with dimethyl amine to 2-6 and directed ortho-lithiation with n-butyl-lithium in THF (tetrahydrofuran) to get homogeneous yellow solution, which upon treatment with methyl iodide afforded toluamide 2-7, the yield was 85%. The model synthesis study showed that lithiated toluamide 2-7 could condense with compound 2-14 to achieve the final product 2-2 through several steps (see below). The intermediate compound 2-14 could be synthesized starting from the same piperonal 2-4. It was reacted with cyclohexylamine to get Shiff base 2-8, the latter was reacted with 1.13 equiv. of n-butyllithium at -78°C, the metalated intermediate was carbethoxylated in situ by addition of excess ethyl chloroformate and the aldehyde 2-9 was obtained by extraction with dilute acid. Combination of 2-9 with equimolar of propane-1,3-dithiol a compound 2-10 was obtained, then 2-10 was reduced by lithium aluminum hydride and benzylated with benzyl bromide to 2-12. After treatment with bis(trifluoroacetoxy) iodobenzene, the obtained compound 2-13 was reacted with benzylamine to get the key compound 2-14. 

The reactions of iV,A-dimethyl benzylamine [176] and benzylalcohol [177] with butyllithium and butyllithium TMEDA, respectively, result in specific ortho-lithiation, and are typical examples of the coordination only mechanism [1]. The benzylamine forms a complex with butyllithium, experimentally this is visible by a modest, but significant and promptly occurring heating effect when the amine is quickly added to the solution of butyllithium. Addition of benzylalcohol to two equivalents of BuLi TMEDA results also in the formation of a complex, viz. PhCH2OLi BuLi (analogous to the aggregates from alkali alkoxides and BuLi, e. g. 

In another variant of the Niementowski reaction, it was found that this transformation can be carried out under relatively mild, base-catalyzed conditions. Since a variety of substituted anthranilamides (29) can be prepared by a regiospecific ortho metalation-amination sequence, this method appears to be a very versatile modification of the Niementowski quinoline synthesis. Lithiation of 28 with 5-butyllithium was followed by treatment with tosyl azide. Reduction of the azide with sodium borohydride under phase transfer conditions furnished 29. After conversion of 29 into the corresponding imine 30, treatment of 30 with LDA afforded 31 in good yield. 

A 1,2 or 1,3 unsymmetrically disubstituted arene is prochi-ral and therefore the corresponding chromium tricarbonyl compounds are chiral. (Substituted arene) complexes with amine, carboxyl, and formyl groups at the ortho position are resolved into optically active chromium complexes through corresponding diastereomeric adducts (eq 25). Biocatalysts also perform the kinetic resolution of racemic chromium complexes (eq 26). The optically active chromium complexes can be prepared by di-astereoselective ortho lithiation of the chiral benzaldehyde or acetophenone acetal complexes, and diastereoselective chromium complexation of the chiral ort/io-substituted benzaldehyde am-inals (eq 27). Catalytic asymmetric cross-coupling of meso (1,2-haloarene)chromium complex produces chiral monosubstituted complexes. The chiral (arene)chromium complexes can be used as ligands in asymmetric reactions. ... 

These reactions complement recently developed palladium(0)amination reactions [146,147,148] and related procedures using a copper(I) [149] - or ni-ckel(O) [151] - catalysis. As indicated above, the mild reaction conditions are compatible with a range of functional groups. Functionalized arylmagnesium chlorides such as 309 prepared by an I/Mg-exchange readily undergo addition reactions to aryl oxazolines. The addition-elimination of 309 to the -methoxy aryloxa-zoline followed by an ortHo-lithiation and substitution with ethylene oxide leads to a polyfunctionalized aromatic intermediate 310 for alkaloid synthesis (Scheme 4.68) [165]. 

The problem of auxiliary removal is overcome when acetals are replaced with the much more labile aminals, formed by reaction of benzaldehydechromium tricarbonyl 403 with diamines, and readily cleaved with mild acid. The best choice of diamine is 404, because the aminal 405 lithiates with good to excellent regioselectivity in the ortho position (Scheme 167) the same could not be said for diamines lacking further lithium-coordinating side-chains . Treatment of 405 with three equivalents of n-BuLi in... 

By contrast, the lithiation of 479 with n-BuLi, which is assisted by coordination to the NMc2 group, is faster, reaching completion in less than 6 h at 25 °C, and completely regioselective ° °. The mesitylmethyl amine 480 is lithiated only at the methyl group ortho to the aminomethyl substituent (Scheme 189). 

Reed, J. N. Snieckus, V. ortho-Amination of lithiated tertiary benzamides. Short route to polysubstituted anthranilamides. Tetrahedron Lett. 1983, 24, 3795-3798. 

Hellwinkel (22) ingeniously removed the problem of para bromination by starting with tris(4-methylphenyl) amine, which exclusively bromi-nates in the required three ortho positions. Unfortunately, although ortho dimetallation occurs when diphenylamine is treated with alkyl-lithium reagents, triphenylamine is lithiated in the meta positions (23) presumably due to the steric effects the triphenyls of other Group V elements cleave when reacted with LiR derivatives. 

Imidazolidines may also act as ortho directing groups the lithiadon of l,3-dimethyl-2-phenylimidazo-lidine followed by addition to benzophenone proceeds in 63% yield. Carbazole aminals can be metal-ated ortho to the nitrogen, while benzo[a]carbazole may be dili iated at nitrogen and the 1-position. A 2-amino group of a biphenyl directs lithiation to the 2 -position of the other ring in a novel synthesis of a phenanthride. ... 

Aromatic methyl amines, as the N,N-dimethyl derivatives, are readily lithiated at ortho positions Indeed the —CH NMe group is a very good lithiation directing group. On treatment of the lithio derivative with CICOOEt, introduction of COOEt group takes place ortho to —CH NMCj. The dimethyl amino group is also displaced by —Cl to give the chloro ester which on thermal cyclisation furnishes the phthalide. 

With the nitrogen already at the oxidation level of amine, but carrying a t-butoxycarbonyl group to assist the ortho-methy (alkyl) lithiation, reaction with oxalate as in the classical sequence and final removal of the A-substituent with acid, again leads to an indole-2-ester. The synthesis of 2-unsubstituted indoles is achieved by reaction of the A,C-dilithiated species with dimethylformamide. °... 

One of the first uses of directed metalation as a route to heterocycles was the synthesis of phthalans (2,3-benzo-l,4-dihydrofurans) by the thermally induced cyclization of the methiodides of ortho-substituted di-methylbenzylamines (Reaction 37) (45). The amine was lithiated in the ortho position by n-butyllithium and condensed with benzaldehyde and benzophenone. The corresponding alcohols obtained upon aqueous work-up were converted to their respective methiodides. Heating the methiodides to 200°C for one hour under nitrogen gave the phthalans... 

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