Halogen-lithium Exchange Reaction Research Articles

ChemInform Abstract: Reactions of Organolithium Reagents with Quinazoline Derivatives

AbstractReview: 159 refs.

Reactions of organolithium reagents with quinazoline derivatives

This review deals with directed and regioselective lithiation of various quinazoline derivatives by the use of alkyllithiums in anhydrous THF at low temperature. Reactions of the lithium reagents obtained from the lithiation reactions with a range of electrophiles give the corresponding substituted derivatives in high yields. The procedures are simple, efficient and general to provide derivatives which might be difficult to produce by other means. In some cases nucleophilic addition of alkyllithiums takes place to produce the corresponding addition products via 1,2- and 3,4-additions. In other cases nucleophilic substitution or halogen-lithium exchange reactions occur.

Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl3 promoted homocoupling

The use of FeCl3 resulted in a fast homocoupling of aryllithiums, and this enabled its integration with the halogen–lithium exchange reaction of aryl halides in a flow microreactor. This system allows the homocoupling of two aryl halides bearing electrophilic functional groups, such as CN and NO2, in under a minute.

ChemInform Abstract: One‐Pot Preparation of Hydroxylated Potassium Organotrifluoroborates and Subsequent Jones Oxidation to Potassium Organocarbonyltrifluoroborates.

AbstractDibromobenzenes (I) or (VII) and a range of aromatic and aliphatic aldehydes are sequentially transformed into alcohol‐containing organotrifluoroborates via lithium—halogen exchange reactions.

ChemInform Abstract: A Wide Mechanistic Spectrum Observed in Three Different Reactions with Organometallic Reagents

AbstractReview: 56 refs.

A wide mechanistic spectrum observed in three different reactions with organometallic reagents

AbstractThe halogen–lithium exchange reaction is of one of the most powerful method for the preparation of organolithium compounds, but its mechanism is still controversial. To afford some new elements, we synthesized a new suitable fast radical clock, bearing a phenyl group at the alkene C‐terminal. The examination of some mechanistic clues, as well as the identification of the unexpected by‐products allowed the conclusion that the reaction proceeds by a polar mechanism and no evidence for radicals were found. The second reaction discussed is the insertion of NO in the NLi bond of lithium amides. Evidence for the involving of paramagnetic and nitrosonium intermediates, as well as equilibria between different reactive species were essential for the proposal of a whole complex mechanism, which was confirmed by theoretical calculations. Finally, results on the addition of heteroaromatic organocuprates to α,β‐unsaturated substrates are presented. Several reaction conditions were looked for to lead the reaction toward the more interesting 1,4‐conjugated addition. Thus, addition of up to 6 equivalents of TMSCl to the reaction with arylcuprates leads to a clean addition yielding more than 95% of the 1,4‐addition product. A further objective of the paper is to show how the search of unexpected routes of reaction allowed developing original pathways to lead them toward the formation of appealing functionalized compounds. Copyright © 2010 John Wiley & Sons, Ltd.

ChemInform Abstract: HEPT: From an Investigation of Lithiation of Nucleosides Towards a Rational Design of Non-Nucleoside Reverse Transcriptase Inhibitors of HIV-1

Publisher Summary This chapter presents the alpha lithiation reaction at the base moiety of purine, imidazole, and pyrimidine nucleosides for the synthesis of their analogs and an anti-HIV-1 (Human Immunodeficiency Virus Type 1) lead compound HEPT which resulted from the lithiation studies. Lithiation chemistry of aromatic compounds started with a halogenlithium exchange reaction reflecting the historical finding that an aryllithium can be generated by treatment of an aryl halide with alkyllithium. The anti-HIV-1 activity of HEPT is only marginal when compared with that of AZT and ddC, but HEPT was found to be much less toxic than these nucleoside derivatives. In terms of activity (EC 50 ) and cytotoxicity (CC 50 ), HEPT is almost comparable to ddA. A salient feature of this compound lies in its highly specific antiviral property. When the activity of HEPT was examined by changing the virus as well as the cells, HEPT was uniformly active to various strains of HIV-1, but not to other retroviruses, including HIV-2, and other DNA viruses.

Thiophene decorated with Fischer carbene ligands

The activation of a section, or of all the carbons of thiophene by bromine in lithium-halogen exchange reactions, was implemented in a step-wise manner to facilitate the preparation of novel multiple Fischer carbene-bearing thiophene compounds.

Isolation of 1,4-Li2-C6H4 and its reaction with [(Ph3P)AuCl

The difficulty in generating 1,4-Li2-C6H4 utilising the lithium halogen exchange reaction on 1,4-Br2-C6H4, 1,4-I2-C6H4 and 1-Br-4-I-C6H4 is revisited and only on treatment of 1,4-I2-C6H4 with 2 molar equivalents of n-BuLi can 1,4-Li2-C6H4 1 be isolated in excellent yield. Treatment of 1 with two equivalents of [ClAu(PPh3)] gives [1,4-(Ph3PAu)2-C6H4] 2a in excellent yield. Subsequent treatment of 2a with 2.5 molar equivalents of PPh2Me, PPhMe2 or PMe3 affords the PPh3 substituted compounds [1,4-(LAu)2-C6H4] (L = PPh2Me 2b, PPhMe2 2c, PMe3 2d) in essentially quantitative yields. On treatment of 1,4-Br2-C6H4 or 1-Br-4-I-C6H4 with 2 molar equivalents of n-BuLi only mono-lithiation takes place to give 1-Br-4-Li-C6H4 3 as shown through the isolation of essentially 1:1 molar equivalents of Ph2PC6H4-4-Br and Ph2PBu on treatment with 2 molar equivalents of ClPPh2. Treatment of 3, prepared by lithium/iodine exchange on 1-Br-4-I-C6H4, with [ClAu(PPh3)] affords [(Ph3P)Au(C6H4-4-Br)] 4 as expected and in addition [(Ph3P)Au(n-Bu)(C6H4-4-Br)2] 5, indicating the straightforward chloride/aryl exchange at gold may proceed in competition with oxidative addition of the n-BuI, generated in the initial lithium/iodine exchange reaction, to some aurate complex Li[Au(C6H4-4-Br)2] 6 formed in situ followed by reductive elimination of Br-C6H4-4-n-Bu in a manner that mimics lithium diorganocuprate chemistry. All of the gold-containing compounds have been spectroscopically characterised by 1H and 31P-{1H} NMR and in addition compounds 2a-d and 5 by single crystal X-ray diffraction studies. The solid state structures observed for 2a-d are dictated by non-conventional hydrogen bonding and the packing requirements of the phosphine ligands. For 2a and 2b there is no close Au...Au approach, however for 2c and 2d the reduction in the number of phenyl rings allows the formation of Au...Au contacts. For 2c and 2d the extended structures appear to be helical chains with Au...Au contact parameters of 3.855(5) A and C-Au-Au-C 104.1(3)degrees for 2c and 3.139(4) A and C-Au-Au-C -92.0(2)degrees for 2d. The Au...Au approach in 2c is longer than is normally accepted for an AuAu contact and is dictated by ligand directed non-conventional hydrogen bonding to the aurated benzene ring and the pi-stacking requirements of the phosphine ligand. By comparison of the structures 2a-2d with other structures in the database it is evident that the aurophilic interaction is a poor supramolecular synthon in the presence of non-conventional hydrogen bond donors. Searches of the CCDC database suggest that the observed parameters for the Au...Au contact in 2c sit close to the cut-off point for observing this type of contact. In addition to aurophilic contacts and non-conventional hydrogen bonds there are a number of halogenated solvent C-Cl...Au contacts observed in the structures of 2a and 2d. The nature of these contacts have implications for the accepted van der Waals radius of gold which should be extended to 2 A.

Two aspects of the desymmetrization of selected prochiral aromatic or vinylic dihalides: enantioselective halogen–lithium exchange and prochiral recognition in chiral liquid crystals

Several classes of prochiral dihalides have been identified as potential candidates for asymmetric halogen–lithium exchange. Bis-aryl compounds 1 and 2, 2,3-dibromonorbornadiene 3, and 1,2-diiodoferrocene 4 were prepared and used as substrates in the asymmetric halogen–lithium exchange reaction. The enantioselective mono-lithiation was achieved in good yields by various combinations of n-BuLi and chiral ligands. Enantioselectivities in the range of 20–35% ee have been detected for this new type of asymmetric synthesis. The prochiral compounds 3 and 4 were also dissolved in a chiral liquid crystal based on organic solutions of poly- γ-benzyl- l-glutamate and analyzed using natural abundance deuterium 2D NMR spectroscopy. The spectroscopic discrimination of enantiotopic sites in these solutes has been observed and discussed from the point of view of orientational order.

Efficient and selective synthesis of quinoline derivatives

The bromination reaction of 1,2,3,4-tetrahydroquinoline ( 7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline ( 3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline ( 6) on bromination of 1,2,3,4-tetrahydroquinoline ( 7) in efficient yields (75 and 90%, respectively). 6-Bromo- ( 4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines ( 6) were converted to 6-bromo- ( 1) and 6,8-dibromo quinolines ( 2), respectively, by aromatization with DDQ in 83 and 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared via lithium–halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi followed by quenching with electrophiles [Si(CH 3) 3Cl, S 2(CH 3) 2, I 2] regioselectively proceeded at C-4 and C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation of tribromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield. Copper-induced nucleophilic substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxyquinoline ( 17) in 60% yield.

General Synthesis of Extended Fused Oligothiophenes Consisting of an Even Number of Thiophene Rings

The intramolecular double cyclization of bis(3-bromo-2-thienyl)acetylenes though a lithium-halogen exchange reaction with tBuLi followed by treatment with elemental sulfur produces two thiophene-fused thieno[3,2-c](1,2-dithiin)s. The subsequent dechalcogenation from the 1,2-dithiins with copper nanopowder affords tetrathienoacenes. On the basis of this two-step procedure, a series of trialkylsilyl-terminated, fused oligothiophenes, including hexathienoacene (a six thiophene-fused system) and octathienoacene (an eight thiophene-fused system), were synthesized. In the UV/Vis absorption and fluorescence spectra of the fused oligothiophenes, the absorption and emission maxima shift to longer wavelengths, as the pi-conjugation length increases. Their maximum wavenumbers have linear relationships with the reciprocal number of thiophene rings consisting of the pi-conjugated frameworks. In the cyclic voltammograms, all the compounds show reversible oxidation waves, the first oxidation potential of which shifts to less positive as the conjugation length increases. Among them, the octathienoacene also shows a reversible second oxidation process. Indeed, its chemical oxidation with an excess amount of NO(+)SbF(6) (-) produces the dication as a golden crystal. The crystal structures of the neutral octathienoacene and its dication were determined by X-ray crystallography. While in the neutral state, the octathienoacene has a benzenoid structure with a large bond alternation of about 0.04 A, its dication has a quinoid structure in which two cationic charges are mainly localized on the terminal rings.

Isolation of cyclopropenylidene-lithium adducts: the Weiss-Yoshida reagent.

Isolation of cyclopropenylidene-lithium adducts: the Weiss-Yoshida reagent.

Efficient halogen–lithium exchange reactions to functionalize poly(alkyl aryl ether) dendrimers

Abstract Poly(alkyl aryl ether) dendrimers were functionalized with bromophenyl groups at their peripheries, so as to have 3, 6, 12, and 24 groups in the zero, first, second, and third generation dendrimers, respectively. The new bromophenyl functionalized dendrimers were assessed for their reactivities in C–heteroatom and C–C bond forming reactions. For this purpose, the bromophenyl functionalized dendrimers were converted quantitatively to their polylithiated derivatives, using n -BuLi in benzene. The polylithiated dendrimers were reacted either with D 2 O or with CO 2 , so as to afford the corresponding deuterated and carboxylic acid functionalized dendrimers, respectively. The carboxylic acid functionalized dendrimers were modified further to the methyl esters during their characterization.

Thermochemistry of Organolithium Compounds

AbstractFor Abstract see ChemInform Abstract in Full Text.

Halogen—Lithium Exchange Reactions under in situ Quench Conditions: A Powerful Concept for Organic Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Halogen—Lithium Exchange Reaction of 3,3‐Dichloro‐2‐azetidinones: Application to the Synthesis of cis‐4‐Aryl‐3‐chloro‐2‐azetidinones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Halogen-Lithium Exchange Reaction of 3,3-Dichloro-2-azetidinones: Application to the Synthesis of cis -4-Aryl-3-chloro-2-azetidinones

A straightforward synthesis of new cis-4-aryl-3-chloro-2-azetidinones was developed, using a halogen-lithium exchange reaction on 4-aryl-3,3-dichloro-2-azetidinones. This methodology was further extended to the use of alkyl halides as electrophiles, while more complex electrophiles could not be introduced.

5‐Pyrimidylboronic Acid and 2‐Methoxy‐5‐pyrimidylboronic Acid: New Heteroarylpyrimidine Derivatives via Suzuki Cross‐Coupling Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Carbon—Carbon Bond Formation at the Sugar Portion of Nucleosides: Synthetic Potential of Unsaturated‐Sugar Nucleosides

AbstractFor Abstract see ChemInform Abstract in Full Text.