Tetrazoles 5-lithiation

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

Treatment of a THF solution of trimethylenetetrazole 44 with a solution of BuLi in hexane affords a yellow to orange solution of the lithiated tetrazole 45 (structure tentatively assigned). Alkylation with Mel gives 7-methyl-6,7-dihydro-5//-pynolo[ 1,2-c]tetrazolc 46 in 73% yield. Quaternization of 46 with dimethyl sulfate affords a mixture (3 1) of tetrazolium salts 47 and 48 from which PFg- salts were obtained by crystallization (Scheme 2) <1997MI671>. 

The ort/io-directing properties of the (aryloxy)tetrazole functionality has been demonstrated for the first time and rapid anionic rearrangement of the resulting lithiated derivative to form 5-(hydroxyaryl)-l-phenyl-l//-tetrazoles has been reported. ... 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

Oxazolines , imidazolines and tetrazoles can all be laterally lithiated. Oxazolines have been used in this regard rather less than for ortholithiation (Scheme 200). 

Recently the tetrazole moiety has attracted interest as a useful directing group for the lithiation of 5-aryl substituents, with the dianion derivative 62 being obtained in the case of the unsubstituted parent compound and the monolithio species 63 in the case of the 2-trityl derivative (91TL6857 91USP50398I4). With both systems, good yields of products were obtained after reaction with a variety of electrophiles. 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

Substituted 1,2,3-triazoles, 1,2,4-triazoles and tetrazoles are metallated by n-butyllithium at low temperature at the 5-position. At room temperature 5-lithium derivatives tend to undergo ring opening. No direct lithiation of a 2-substituted 1,2,3-triazole has been reported. 

Higher azoles - triazoles, tetrazoles, heterodiazoles - lithiate readily, but some of the lithio-compounds are relatively unstable. 

The difference in physical and chemical properties between 1- and 2-substituted tetrazoles can be large. The preparation of pure 2-methyltetrazole via alkylation (below) and the lithiation properties described later in this section, nicely demonstrate this differential reactivity, which can be put to good preparative use. 

C-Lithiation of 1-substituted tetrazoles occurs readily and the resulting lithio derivatives can be trapped with electrophiles, but there is a strong tendency for decomposition of the lithio compounds, which depends on the 1-substituent. 5-Lithiated 2-substituted tetrazoles appear to be significantly more stable than the 1-isomers, as shown below, by a comparison of the two A -benzyloxymethyl (BOM)-protected isomers. p-Methoxybenzyl can be removed finally by hydrogenation or oxidation with cerium(lV) ammonium nitrate. 

A tetrazole can also act as an ortho-dvrocXmg group, as in the lithiation of 5-phenyltetrazole. A tetrazol-5-yl ether similarly directs ort/jo-metaUation, but here the tetrazole migrates from the oxygen to the lithiated carbon. ... 

Synthesis and reactions of lithiated monocyclic azoles containing two or more hetero-atoms. Part VI Triazoles, tetrazoles, oxadiazoles and thi-adazoles , Grimmett, M. R. and Iddon, B., Heterocycles. 1995, 41, 1525. 

Alkyl groups in 1-substituted tetrazoles can be lithiated but in a 5-alky 1-2-methyltetrazole it is the A-methyl which is metallated but 5-methyl-2-trityltetrazole... 

Tetrazole can be lithiated on the 5-position however, attempts to carry out substitution reactions sometimes fail because the intermediates are easily cleaved and eliminate nitrogen above -50 A series of 1,5-disubstituted tetrazoles were synthesized from a Pd/Cu catalyzed direct arylation of 1-substituted tetrazoles in the presence of tris(2-furyl)phosphine (TFP) and cesium carbonate. ... 

Various 3-ribofuranosyl-indoles, -pyrroles and -pyrazoles have been made by reaction of V-blocked heterocycles with 2,3,5-tri-C -benzyl-3-D-ribofuranosyl fluoride.Lithiation of 2,6-dichloroimida2o[l,2-a]pyridine occurs predominantly at C-5, and reaction with a ribono-y-lactone derivative and anomeric deoxygenation gives the 5-ribofuranosyl system 151 with good P-selectivity. The alternative 3-glycosylation pattern 152 could be obtained by palladium-catalysed coupling of 2,6-dichloro-3-iodoimidazo[l,2-a]pyridine with 2,3-dihydrofuran, followed by hydroxylation. Various pyrazolo[4,3-c]pyridine C-nucleosides such as 153 have been made using an effective tetrazole-to-pyrazole transformation carried out on a C-ribofuranosyltetrazole. A paper on the conformational properties of some purine-like C-nucleosides is mentioned in Chapter 21. 

Boron Reagents. Tetrazole can be lithiated in the 5-position and brominated to yield a 5-bromo substrate that reacts with a vinylboronic acid to furnish the corresponding vinyltetrazole 133 (Scheme 56). ... 

The role of organolithium aggregates and mixed aggregates in organolithium mechanisms has been reviewed. The synthetic utility of the regio- and stereo-selective lithiation of aziridines has been highlighted. " The latest developments on the direct metallation (mainly lithiation chemistry) of various 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, and 1,3,4-oxadiazoles have been presented. ... 

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