- First general, direct, and regioselective synthesis of substituted methoxybenzoic acids by ortho metalation
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(Chemical Equation Presented) New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78°C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0°C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed (Table 1).
- Nguyen, Thi-Huu,Chau, Nguyet Trang Thanh,Castanet, Anne-Sophie,Nguyen, Kim Phi Phung,Mortier, Jacques
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p. 3419 - 3429
(2008/02/03)
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- Toward a better understanding on the mechanism of ortholithiation. Tuning of selectivities in the metalation of meta-anisic acid by an appropriate choice of base
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(Chemical Equation Presented) If employed in THF at 0°C, LTMP metalates meta-anisic acid at the doubly activated position. In contrast, n-BuLi/t-BuOK deprotonates position C-4 preferentially at low temperature. Functionalization at C-6 requires protection of the C-2 site beforehand. As a result of these findings, a new mechanism is proposed for the heteroatom-directed ortholithiation of aromatic compounds.
- Nguyen, Thi-Huu,Chau, Nguyet Trang Thanh,Castanet, Anne-Sophie,Nguyen, Kim Phi Phung,Mortier, Jacques
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p. 2445 - 2448
(2007/10/03)
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- Selective para metalation of unprotected 3-methoxy and 3,5-dimethoxy benzoic acids with n-butyl lithium-potassium tert-butoxide (LIC-KOR): Synthesis of 3,5-dimethoxy-4-methyl benzoic acid
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The potassium salt of 3-methoxy and 3,5-dimethoxy benzoic acids undergoes deprotonation at the position para to the carboxylate group selectively when treated with LIC-KOR in THF at -78°C and it has been extended to the synthesis of 3,5-dimethoxy-4-methyl benzoic acid. (C) 2000 Elsevier Science Ltd.
- Sinha, Surajit,Mandal, Bhubaneswar,Chandrasekaran, Srinivasan
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p. 3157 - 3160
(2007/10/03)
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- Baker's yeast-mediated enantioselective synthesis of the bisabolane sesquiterpenes (+)-curcuphenol, (+)-xanthorrhizol, (-)-curcuquinone and (+)-curcuhydroquinone
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Fermenting baker's yeast converts the unsaturated aldehydes 5a-c into the saturated alcohols 6a-c, respectively. The microbial saturation of substrates adsorbed on a nonpolar resin proceeds in high chemical yields and shows complete enantioselectivity in the formation of the (S)-(+) isomers. Enantiopure 6a-c are versatile chiral building blocks for the synthesis of bisabolane sesquiterpenes. Their usefulness is shown in the preparation of (S)-(+)-curcuphenol, (S)-(+)-xanthorrhizol, (S)-(-)-curcuquinone and (S)-(+)-curcuhydroquinone. The Royal Society of Chemistry 2000.
- Fuganti, Claudio,Serra, Stefano
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p. 3758 - 3764
(2007/10/03)
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- Directed lithiation of unprotected benzoic acids
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Benzoic acid gives the ortho-lithiated species 1 under standard conditions (s-BuLi-TMEDA-THF, -90 deg C).Reaction of 1 at -78 deg C with either methyl iodide, dimethyl disulfide, hexachloroethane, or 1,2-dibromotetrachloroethane gives the ortho-substituted product.Intramolecular competition between the carboxylic acid and methoxy, chloro, fluoro, or diethylamido functions in ortho- and -para-substituted benzoic acids establishes the carboxylic acid group to be of intermediate capacity in directing metallation.Complimentarity of directing effects is observed with the chloro and fluoro groups in the meta-substituted benzoic acid but not with the methoxy and trifluoromethyl groups.Electrophile introduction into meta- and para-lithiated benzoates occurs with equal efficacy and comparable scope.The 2,4-dihalogenobenzoic acids undergo hydrogen/metal exchange at the position flanked by both halogen substituents. 2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid undergoes lithiation adjacent to the oxygen atom.By use of such methods, routes to benzoic acids contiguously tri- and tetra-substituted with a variety of functionalities have been developed.
- Bennetau, Bernard,Mortier, Jacques,Moyroud, Joel,Guesnet, Jean-Luc
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p. 1265 - 1272
(2007/10/02)
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- The Carboxylic Acid Group as an Effective Director of Ortho-Lithiation
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Treatment of PhCO2H in tetrahydrofuran with 2.2 equiv of a 1:1 sec-butyllithium/N,N,N',N'-tetramethyl-1,2-ethylenediamine complex at -90 deg C gave o-LiC6H4CO2Li, which was treated with electrophiles to give o-RC6H4CO2H (R = Me, SMe, Cl, Br) in good yields.
- Mortier, Jacques,Moyroud, Joeel,Bennetau, Bernard,Cain, Paul A.
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p. 4042 - 4044
(2007/10/02)
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- ipso Nitration. XXIII. Reactions of cyclohexadiene adducts from nitration of 4-ethyltoluene in acetic anhydride
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The diastereoisomers of 4-ethyl-1-methyl-4-nitrocyclohexa-2,5-dienyl acetate (1) and 1-ethyl-4-methyl-4-nitrocyclohexa-2,5-dienyl acetate (2) are stereospecifically reduced to the corresponding nitrocyclohexadienols with aluminum hydride.Each dienol is stereospecifically methylated to the corresponding methyl ether with methyl iodide, silver oxide, and potassium hydroxide.Acid-catalysed solvolysis of the acetates 1 and 2 results in the substitution of the acetate moiety by other nucleophiles and these reactions are not stereospecific.The products of rearomatization of dienyl acetates, dienols and dienyl methyl ethers depend on the acidity and ionizing power of the solvents and are readily explained in terms of reactions involving a nitrocyclohexadienyl cation or acetoxy- (hydroxy-, methoxy-)cyclohexadienyl cation as key intermediates.In the 4-acetoxy-4-alkylcyclohexadienyl cation 1,2-migration of the acetoxyl group is more rapid then alkyl migration, but 1,2-alkyl migration is faster then migration of the hydroxyl or methoxyl groups in the corresponding cations. 1-Ethyl-4-methoxy-4-methylcyclohexa-2,5-dien-1-ol and 4-ethyl-3-nitrotoluene are significant minor products in the solvolysis of 1-ethyl-4-methyl-4-nitrocyclohexa-2,5-dien-1-ol in aqueous methanol.Nitration of p-ethyltoluene in the presence of sulfuric acid or in trifluoracetic anhydride gives a mixture of 4-ethyl-2-nitro- and 4-ethyl-3-nitrotoluene in a 2:1 ratio.
- Fischer, Alfred,Henderson, George N.
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p. 2314 - 2327
(2007/10/02)
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