Benzotriazolyl alkylations

Mannich-type Reactions. Due to the mild nature of rare earth triflates (RE(OTf)3), and their compatibility with basic nitrogen groups, they have been used extensively in Mannich-t)q)e reactions. Dysprosium triflate has been used to mediate the synthesis of benzotriazole derivatives from lV-(a-benzotriazolyl-alkyl)amides (eq 1). In this case, the more commonly employed Sc(OTf)3 and Yb(OTf)3 failed to produce appreciable quantities of the desired product. 

Reaction of lithiated allylbenzotriazole 452 with chloromethyltrimethylsilane yields silyl derivative 464 which can be further alkylated to give compound 465 (Scheme 76) <1999JOC1888>. Upon heating, product 465 is readily converted to diene 466 via vicinal elimination of benzotriazolyl and silyl substituents. Additions of lithiated silyl derivative 464 to carbonyl groups of aldehydes lead to alcohols 463 which readily eliminate benzotriazole and silane to furnish 2-(l-hydroxyalkyl)butadienes 466 (R1 = 1-hydroxyalkyl). 

The morpholin-4-yl substituent in 7-position behaves similarly to the ethoxy group. Compound 481 is easily prepared by double addition of benzotriazole to acrolein followed by elimination of one of the benzotriazolyl moieties induced by treatment with NaH. Lithiation of derivative 481 followed by addition to a Schiff base results in formation of diarylpyrrole 476. Lithiated product 481 is alkylated exclusively at the carbon a, in relation to the benzotriazolyl substituent, giving intermediate 482. Subsequent treatment with a Grignard reagent leads to enamine 483 (Scheme 79) <1995TL343>. 

Condensation of sulfoximine 717 with an aldehyde and benzotriazole produces Ar-[ -(bcnzotnazol-l -yl)alkyl]sul-foximine 718. Treatment with allyl silanes in the presence of BF3 etherate or with organozinc reagents allows substitution of the benzotriazolyl moiety in compound 718 to produce variety of substituted sulfoximines 719... 

Addition of a silyl substituent into a-position of the a-(benzotriazol-l-yl)alkyl ether brings additional possibilities. Thus, lithiation of silyl ether 770 followed by treatment with an aldehyde or ketone gives unstable P-hydroxy-a-silyl-a-(benzotriazol-l-yl)alkyl ether 771 that spontaneously eliminates silanol to give vinyl ether 772 (Scheme 121). Treatment with ZnBr2 followed by hydrolysis with a diluted acid removes both the benzotriazolyl and the methyl groups to furnish carboxylic acid 773. In this way, in a simple manner, aldehydes and ketones are converted to one-carbon homologated carboxylic acid <1996S1425>. 

The readily available benzotriazolyl derivative of dimethyl sulfide, compound 821, can be alkylated on a-carbon in a stepwise manner to provide (a,a-disubstituted)alkyl thioethers 823 (Scheme 131). Hydrolysis of these thioethers under mild conditions (5% H2S04 at room temperature) furnishes ketones 824 in high yields. The anion derived from mono substituted (benzotriazol-l-yl)methyl thioether 822 adds to butyl acrylate to give intermediate 826 that can be hydrolyzed to y-ketoester 825. In another example of reactivity of a-(benzotriazol-l-yl)alkyl thioethers, treatment of thioether 822 with BunLi followed by phenyl isocyanate converts it into a-ketoanilide 828, via intermediate adduct 827 <1998JOC2110>. 

Changing the base to triethylamine improves the yield of benzoylhydroxamic acid (96a) up to 91% the purification required column chromatography. Independently of the substituent in both Af-acylbenzotriazole and hydroxylamine, the desired O-alkyl, N-alkyl and 0,A-dialkyl hydroxamic acids were obtained as sole products as a result of nucleophilic displacement of the benzotriazolyl moiety by the hydroxylamine nitrogen. 

Alkyl- und 1-Aryl-piperidine erhalt man auch durch eine andere Zweistufen-Re-aktion, bei welcher man ein primares Amin mit Benzotriazol in Wassser mischt, nach 10 min Pentandial zugibt und das nach 1-2 h erhaltene 1-Alkyl- bzw. l-Aryl-2,6-bis-[lH-benzotriazolyl]-piperidin mit Natrium-boranat reduktiv zerlegt (Weg )3. Wenn man das Zwischenprodukt jedoch anstelle der Reduktion mit Alkyl-magnesiumbromiden umsetzt, erhalt man 1,2,6-trisubstituierte Piperidine (Weg )3. 

The addition of allylmagnesium halides (2 equiv.) to 1,3-azadienes affords after in situ alkylation dihomoallylamines, which are useful intermediates in the synthesis of azepines or related heterocycles. Activation of the C=N moiety of aldimines by 1-benzotriazolyltrimethylsilane minimizes side reactions. The mechanism involves reversible addition of BtTMS (216) to the imine 217 followed by displacement of the benzotriazolyl group by a Grignard reagent (equation 148). ... 

To suppress enamine-derived side products, we explored addition of benzotriazole (BtH) to the reaction mixture. The premise behind these experiments was the ability of BtH to form stable adducts with imines,23,24 thereby blocking tautomerization of 19 to 20 through in situ formation of the benzotriazolyl derivative 21. It was hoped that subsequent hydride displacement of the Bt moiety would afford the desired mono alkylated products 23. Indeed, analytical high-performance liquid chromatography (HPLC) revealed a remarkable improvement in terms of product purity, especially for reactions carried out at room temperature, with the desired secondary anilines 23 being essentially the only products detected. In... 

The synthesis of /-substituted thioamides by /V-alkylation is an unusual route, as, with most electrophiles, 5-alkylation is the rule. However, a two-step procedure based on the remarkable properties of a benzotriazolyl substituent has been proposed [168]. 

The 2-(benzotriazol-l-yl)methyl side chains of pyrrole 1232 or its 2-methyl analogs were elaborated by nucleophilic substitution and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety to afford a variety of 1,2,4-trisubstituted (Scheme 237) and 1,2,4,5-tetrasubstituted pyrroles <1989CL1107, 1996JOC1624>. 

Katritzky demonstrated the utility of a benzotriazolyl group (Bt) for a synthesis of 3-substituted benzofurans. o-Hydroxyphenyl ketones are reacted in a nucleophilic substitution with 1-benzotriazol-l-ylalkyl chlorides and the intermediates obtained are treated with base and then low-valent titanium to give the benzofuran products (Scheme 86). The sequence was found to work well for 3-aryl- and 3-fer7-butylbenzofurans but could not be extended to other 3-alkyl analogs <2001JOC5613>. 

In a new simple synthesis of pyrazino[l,2-a]indole derivatives, 3-methylindole 157 was A-alkylated to 158, followed by treatment with formaldehyde and benzotriazole to produce the system 159. Displacement of the benzotriazolyl moiety with various nucleophiles gave the final products 160 <03JOC4938>. 

Treatment of 0 -benzotriazolyl-Q ,/3-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring afforded unsymmetrical l,3,5-triaryl-4-alkylpyrazolines and -pyrazoles <2001JOC6787>. One-pot reactions of a,/3-unsaturated ketones 615 with hydrazinediium dithiocyanate gave... 

Alkylation under neutral conditions involves attack at a nuclear nitrogen Dimroth rearrangement (27.1.1.2) of these salts affords side-chain-alkylated purines. However, direct introduction of substituents onto a side-chain nitrogen can be achieved by reductive iV-alkylation. A related method involves reduction of an isolated benzotriazolyl intermediate, which allows more control over the process. ... 

P-Amino ketone synthesis. The benzotriazole derivatives enable 9-vinylcar-bazole to become an acetaldehyde 1,2-dianion equivalent. The acid-catalyzed reaction gives rise to 1,1,3-trifunctionalized propanes in which the migrated benzotriazolyl group activates the a-carbon for alkylation. Subsequent hydrolysis of the aminal unit reveals the keto group. 

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