Ortho-directed lithiation

Chiral A-substitutcd benzisothiazole-3-one-1,1-dioxide (saccharin) derivatives 258 are synthesized via the direct ortho-lithiation of 3-A-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA <06TL6405>. Compounds 257 are readily prepared from (X)-amino acids. 

Pie, N. Turck, A. Heynderickx, A. Queguiner, G. Metalation of diazines. XI. Directed ortho-lithiation of fluoropyrimidines and application to synthesis of an azacarboline./. Heterocyclic Chem. 1994, 31, 1311-1315. 

Cochennec, C. Rocca, P. Marsais, F. Godard, A. Queguiner, G. Metalation of aryl iodides, part II directed ortho-lithiation of 3-iodo-N,N-diisopropyl-2-pyridinecarboxamide halogen dance and synthesis of an acyclic analogue of meridine. Synthesis 1995, 321-324. 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

High yield synthesis of biphenylboronates 205 and also 206 have been demonstrated.118 The directed ortho-lithiation for the synthesis of... 

The procedure described here offers a general route to 7-substituted indolines.3 The method is based on the directed ortho-lithiation of N-(tert-butoxycarbonyl)aniline derivatives.4 The teri-butoxycarbonyl group seems to be essential for C-7 selective lithiation, since other directing groups so far reported promote C-2 metalation on the Indoline ring.5 The C-7 selective lithiation of 1-(tert-butoxycarbonyl)indoline is in contrast to the C-2 selective lithiation of 1-(tert-butoxycarbonyl)indole.6... 

Secondary amides may direct ortho lithiation, but they must first be deprotonated. This makes them somewhat weaker ortho directors than tertiary amides, but they may still serve the purpose quite well. For example, the lithiation and addition of benzamide (12) to aldehyde (13) was us in a synthesis of 11-deoxycaiminomycinone (Scheme 8). More recently, it has been shown that the amide monoanion may be obtained by addition of a phenylsodium to an isocyanate. ... 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

Sibi, M. P., Snieckus, V. The directed ortho lithiation of O-aryl carbamates. An anionic equivalent of the Fries rearrangement. J. Org. Chem. 1983,48, 1935-1937. 

Snieckus, V. Directed ortho-lithiation of aromatic compounds. New methodologies and applications in organic synthesis. Bull. Soc. Chim. Fr. 1988, 67-78. 

Directed ortho lithiation of 2-, 3-, and 4-pyridyl diethylcarbamates provides a route to a variety of polysubstituted pyridines. The 2- and 4-pyridyl carbamates are metallated at C-3, whereas the 3-pyridyl carbamate is lithiated at C-4. For example, 3-pyridyl diethylcarbamate (118) on treatment with sec-BuLi/TMEDA/THF (TMEDA = N,N,A, Af -tetramethylethylenediamine) at — 78°C followed by McjSnCI gives 3,4-disubstituted pyridine 120 in 83% yield via lithiated intermediate 119. On warming, the metallated pyridyl... 

Scheme 2.46 Directed ortho lithiation of aromatics carrying an inductively electron-withdrawing substituent (X = CON/Pr2, OMe, NMe, F, OCF,). The reaction product is stabilized by interaction of the lone electron pairs of the group X with the neighboring lithium [104, 106].

Direct ortho lithiation of O-aryl carbamates and 0 to C carbamoyl migration to give salicylamides. 

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. 

We therefore wished to avoid the formation of the 4-lithio species, and examined the use of a non-exchangeable group at the 4- position in place of the iodide. We chose to study the 4-chloropyridine derivative 45 based on the fact that chlorine is known to direct ortho-lithiations at -78 °C and does not undergo halogen-metal exchange. Chloropyridines are also susceptible to nucleophilic aromatic substitution with alkoxides, and as such this compound contains a handle for the introduction of the methoxy group at the 4-position as required later in the synthesis. 

Directed ortho-lithiation of iodopyridine (62) with halogen dance has been observed (Scheme 30) (93JOC(58)7832). 

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