Ortho- Lithiations

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

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. 

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). 

Exclusive C-2 lithiation was also observed in the case of the 1-ben-zenesulfonyl-3-(l,3-dithian-2-yl) derivative, but when an excess of/j-BuLi was employed, in an attempt to promote deprotonation in the dithiane ring, ortho-lithiation of the phenyl substituent was observed forming instead (Scheme 18) (9IT79I1). 

The degree of 4-lithiation with n-BuLi can be increased by the presence of 3-substituents that favor ortho lithiation [68JCS(C)172 76JCS(P1 )994], but in no case has exclusive 4-metalation been seen. However, clean metalation at C-4, even in the presence of C-5 alkyl substituents, can be achieved by the use of halogen-metal exchange reactions (Scheme 73), and both bromo and iodo derivatives have successfully been used for... 

The synthesis of losartan potassium (1) by the process research chemists at Merck is outlined in the following (Griffiths et ak, 1999 Larsen et al., 1994). Phenyltetrazole (8) is protected as the trityl phenyltetrazole 9 (Scheme 9.3). Ortho-lithiation of 9 followed by quenching with triisopropyl borate afforded boronic acid 10 after treatment with aqueous ammonium chloride. Reaction of glycine (11) with methyl pentanimidate (12) in a methanol/water mixture yielded (pentanimidoylamino) acetic acid (13), which underwent a Vilsmeier reaction with phosphorous oxychloride in DMF followed by hydrolysis to give imidazole-4-carbaldehyde 14 in moderate yield. 

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). 

Ortho-lithiated halobenzenes, prepared by lithium-bromide exchange, undergo rapid benzyne formation at -30, -40, and -50°C for bromo, chloro, and fluoro derivatives [57JA(79)2625]. They normally require... 

The reaction of elemental sulfur with organometallic compounds is one of the standard methods of synthesis of thiols [3, 4], In this way, the ortho lithiation of lithium benzenethiolate led to the preparation of 1,2-benzenedithiol (1), and a convenient one-pot procedure which can be used on a large scale was worked out [5]. 

For other ortho lithiation reactions, see page 88, Section 2.1. 

Cz Symmetrical and enantiomerically pure thiepines were prepared <1999TL813, 20060BC2218>. Diaryl compounds with two chiral centers 176 were lithiated with sec-butyl lithium in THF at — 78 °C to give the bis-ortho-lithiated 177. Reaction of sulfur diimidazole led to thiepines 26 and 178 in 37—48% yield (Scheme 20). The use of elemental sulfur, thionyl chloride, sulfuryl chloride, SC12, S02(imidazolyl)2, SO(imidazolyl)2, sulfur ditriazole, and sulfur bisbenzotriazole, as a sulfur electrophile, gave cyclized products in poor results. 

Paleo, M. R. Lamas, C. Castedo, L. Dominguez, D. A new synthesis of phthalides by internal trapping in ortho-lithiated carbamates derived from benzylic alcohols. /. Org. Chem. 1992, 57, 2029-2033. 

Ogawa, S. Furukawa, N. Regiospecific ortho lithiation of o-halophenyl p-tolyl sulfoxides and synthesis of met -substituted optically active aryl alcohols./. Org. Chem. 1991, 56, 5723-5726. 

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. 

---