Lithiation of imidazoles

Careful choice of reaction conditions also allows 2-lithiation of imidazoles even in the presence of groups susceptible to attack by the reagent. At -100°C in THF 4,5-dicyano-l-methylimidazole forms the 2-lithio compound at -80°C butyllithium attacks one of the nitrile functions (92JHC1091). 1-Alkoxyimidazoles are lithiated by n-butyllithium (THF, -78°C) at the 2-position (98JOC12). 

The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation-dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product (Scheme 70) <2005TL6847>. 

Direct 4-lithiation of imidazole can only be achieved in the presence of a large substituent at N-... 

Lithiation of l-aryl-17/-imidazoles followed by quenching with electrophiles provided a route to 1,2-diaryl, l-aryl-2-cycloalkyl- and l-aryl-2-heterocycle-substituted imidazoles <05H(65)2721>. Isoprene-catalyzed lithiation of imidazole provided a synthetic route to 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles <05X11148>. 2-Lithiobenzimidazoles were efficiently acylated with esters, lactones and lactams <05TL5081>. 

Synthesis of 2-Substituted Imidazoles via a-LiTHiATiON of N-Protected Derivatives... 

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. 

Directed metallation at the ortho position of the iV-phenyl imidazoles 989 during lithiation at imidazole C-2 in the presence of excess BuLi and TMEDA results in the formation of a dianion which was captured as the bis diphenylphosphine 990 or 991 <2004T10365>. The traditional Pictet-Spengler reaction has been extended to arylamines linked to the N-1 position of substituted imidazoles. Thus, polymer-supported 2-imidazol-l-yl aniline 992 was converted into imidazoquinoxaline 993 under mild conditions (Scheme 238) <2005JC0317>. The homolog triazabenzoazulene 994 was prepared in a similar way <2005JOC4889>. 

Lithiation of the methyl derivatives of such five-membered heteroaromatics as pyrrole , thiophene , l,3-thiazole ° , 1,3-oxazole , isoxazole , 1,3,4-thiadiazole , 1,3,4-oxadiazole and imidazole also occurs. For the sulfur heterocyclics, ring metallations and ring opening after lithiation are complications. 

A review on the metaiation and metal-h ogen exchange reactions of imidazole appeared in 1985. Generally, A -protected imidazoles metalate at the 2-position 1,2-disubstituted imidazoles usually met-alate at the 5-position, unless sterically hindered. Even 2,5-dilithiation of imidazoles has been achieved. 1-Substituted 1,3,4-triazoles can be metalated at the S-position and added to carbonyls in good yield. Oxazoles are easily lithiated at the 2-position, but the resultant anion readily fragments. l-(Phenylthiomethyl)benzimidazole can be lithiated at the 2-position at low temperature (Scheme 21), but higher temperatures afford rearrangement products. ... 

Reactions of Imidazoles. Thermolysis of 1-triphenylmethylimidazole results in migration of the imidazolyl group to yield compound (286). Sensitized photo-oxygenation of 4,5-diphenylimidazole in methanol affords a mixture of the imidazolinone (287) and the imidazolidinone (288). The imidazole (289 R = H) undergoes lithiation at C-5 subsequent treatment with diphenyl disulphide gives the di(phenylthio)-derivative (289 R = PhS). Copyrolysis of 2,4-dimethylimidazole and chloroform results in a complex mixture, containing imidazole and methyl-, dimethyl-, and chloromethyl-pyrimidines and -pyrazines. The confusion about the structures of N-methyl derivatives of iodo-nitro-imidazoles has been cleared up the supposed 1-methyl-2,5-di-iodoimidazole is actually the 4,5-di-iodo-compound it yields 4-iodo-l-methyl-5-nitroimidazole on nitration. The reaction of the bromo-... 

Comparative experiments with aryllithium compounds (phenyllithium and para-fluorophenyllithium), however, resulted in low yields of the methyl esters in spite of the fact that a 300 % excess of chloroformic ester had been used. Reactions of C1COOR with lithio derivatives of heterocycles containing an azomethine function (e.g. lithiated thiazole, imidazole, pyridine) cannot succeed, since the excess of chloroformate will react with the basic nitrogen atom. A comparable situation arises if the organolithium intermediate has been generated by means of LDA reaction of C1COOR with the diisopropylamine liberated in the metallation will provide HC1 which will of course inactivate the organolithio compound. 

Relatively few syntheses of (heteroaryl)phosphonic derivatives have been noted during the year. The C-phosphorylated imidazoles (127) (R = alkyl or aryl) were obtained from diethyl (cyanomethyl)phosphonate and (2-hydroxy-5-thiazolyl)-and [3-hydroxy-5-(l,2,4-triazolyl)]-phosphonic diesters were obtained by the lithiation of the corresponding 2- and 3-methoxy systems, followed by phosphorylation with (Et0)2P(0)Cl, and subsequent demethylation of the products with aqueous HCl or HBr. ... 

A synthesis of the tunicate-derived natural product grossularine-2 rested on two key features the lithiation of a l-blocked-2-substituted imidazole at C-5, allowing introduction of tin for a subsequent coupling, and the electrocyclic ring closure of an isocyanate (a 2-azatriene in which one of the double bonds was the imidazole 2,3-double bond). 

The initial research efforts focused on the preparation of the precursor, the omegar-r-butyldimethylsilyloxyalkyl halide, from the corresponding haloalcohol and /-butyldimethylsilyl chloride. The t-butyldimethylsilyl moiety was originally introduced as an alcohol protecting group by Corey. In this procedure, 1.2 equivalents of t-butyldimethylsilyl chloride and 2.5 equivalents of imidazole, as the acid acceptor, were utilized. The solvent employed was N,N-dimethylformamide. These reaction conditions afforded the desired product in excellent yield. However, the cost of the excess reagents, their subsequent removal, the utilization of an expensive, hydroscopic solvent, and an aqueous workup were not very practical from a commercial perspective. Since its inception in 1972, a variety of other procedures have been described for the preparation of t-butyldimethylsilyl ethers. These procedures typically require solvents that are expensive, difficult to recycle, or environmentally unfriendly. Furthermore, traces of some of these solvents, such as methylene chloride, in the precursor would be incompatible with lithium metal in the subsequent lithiation step. 

The sUylation of aromatic or heteroaromatic compounds can be performed via magnesiated or lithiated intermediates, which can be accessed by hydrogen-metal or halogen-metal atom exchange. Thus, C-4 silylation of imidazoles is achieved from4-iodo imidazoles (eq 45), while C-2 silylated oxazoles are prepared by addition of TMSOTf to the lithiated oxazole (eq 46) interestingly, for this reaction, the employment of TMSCl as electrophile... 

Lithiation-based and magnesation-based strategies for the functionalization of imidazole 12THC(29)77. 

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