Lithium Halogen Research Articles

Generation of functionalized aryl and heteroaryl aluminum reagents by halogen–lithium exchange

Various functionalized aryl and heteroaryl aluminum reagents were obtained by performing I-Li or Br-Li exchange reactions with the corresponding unsaturated organic halides in the presence of i-Bu2AlCl. By means of an appropriate catalyst, the resulting new aluminum species were directly acylated, allylated or arylated. 1,4-Michael additions to enones have also been achieved.

Near-Ambient Temperature Halogen-Lithium Exchange of p-Bromoanisole and Related Substrates: Flow/Batch Studies

With the advent of flow chemistry, the norm has been reactions executed on the laboratory scale with flow rates of only a few mL/min. We bring to the community’s attention our investigation of the halogen–lithium (X–Li) exchange in a continuous flow reactor, the Synthetron™. This novel reactor is capable of orders of magnitude greater rates of flow than current microreactors. This paper details a problematic X–Li exchange using our promoted hydrocarbon media formulated batch studies as well as the comparative derived flow studies. All of these studies have the additional feature of being performed at ambient or near-ambient temperatures. From the initial discoveries of Wittig and Gilman in the late 1930s, it has been known that X–Li exchange of p-bromoanisole (p-BrA) is plagued by a secondary ortho-lithiation. Fine-tuning of promoted hydrocarbon media batch studies can increase the ratio of p-LiA/o-Li-p-BrA; results from the Synthetron™ studies afford a much superior ratio of >100:1. Gram quantities of derivatives from this exchange (employing two reactors) can be prepared in a few seconds. Rationales for these observations will be presented as well as initial studies and discussion for bromobenzene (PhBr), m-bromoanisole (m-BrA), and p-iodoanisole (p-IA).

Synthesis of functionalized diarylborinic 8-oxyquinolates via bimetallic boron–lithium intermediates

The simple one-pot approach to functionalized diarylborinic 8-oxyquinolates has been developed starting with selected dihalobenzenes (Hal = Br, I) and (dialkoxy)phenylboranes PhB(OR)2 (R = Me, Et). The initial step results in halogenated diarylborinic “ate” complexes which are prone to halogen–lithium exchange when treated with t-BuLi. The resultant dianionic lithiated diarylborinic “ate” complexes of the type [(LiAr)PhB(OR)2]Li were reacted with selected electrophiles followed by hydrolysis to give unsymmetrically substituted diarylborinic acids isolated in the form of respective 8-hydroxyquinoline complexes as the final products in moderate to good yields. The crystal structure of (2-fluoro-4-formylphenyl)(phenyl)borinic 8-oxyquinolinate has been determined by X-ray diffraction. The alternative method involving the lithiation of B-protected bis(halophenyl)borinic N,N-dimethylethanolamine esters followed by the quench with electrophiles has also been investigated.

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: 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.

Halogen–lithium exchange versus deprotonation: regioselective mono- and dilithiation of aryl benzyl sulfides. A simple approach to α,2-dilithiotoluene equivalents

Abstract Halogen–lithium exchange and deprotonation reactions between aryl benzyl sulfides and alkyllithiums were investigated. The resultant mono- and dilithiated intermediates were converted into the corresponding aldehydes and boronic, or carboxylic acids in good yields. It was found that diethyl ether stabilizes the ortho-lithiated compounds toward isomerisation to the benzylic derivatives. The process occurs easily in THF at low temperature and is a facile route to the α,2-dilithiotoluene derivative which can be transformed into a dicarboxylic acid on treatment with CO2.

Synthesis of Polyaryl Rigid-Core Carbosilane Dendrimers for Supported Organic Synthesis

Carbosilane dendrimers can be used as soluble supports for organic synthesis, since their structure allows separation of excess reagents from the supported products, eventually yielding products of high purity and in high yield, as in solid-phase organic synthesis (SPOS). In previous studies often loss of dendritic material during filtration was observed, due to the rather flexible structure of the conventional dendrimers. In order to improve the diafiltration retention of the carbosilane dendrimers, the synthesis of carbosilane dendrimers based on more rigid-core molecules was investigated. Both 1,3,5-tris(4-bromophenyl)benzene 1 and tetrakis(4-bromophenyl)silane 2 were selected on the basis of their rigid structure and suitable functional groups for further functionalization using organolithium chemistry. An optimized halogen lithium exchange (HLE) protocol was developed for the synthesis of 2 via 1-bromo-4-lithiobenzene. This protocol involves reaction of an aryl bromide with n-BuLi at room temperature, followed by partial removal of the solvent by evaporation (70%, v/v), addition of pentane to promote precipitation of the aryl lithium compound, and centrifugation and removal of the solvent to obtain, after repeating the last two steps once, the wet aryl lithium compound in pure form. This HLE protocol was proven to be effective for mono- and dilithiation, as well as for polylithiation reactions of aryl bromides. Furthermore, the rigid tris(4-bromophenyl)chlorosilane wedge 3 was synthesized to add a rigid generation to the prepared core molecules, and bromotriallylsilane 4 was synthesized for the introduction of triallylsilyl moieties on the periphery of the core molecules. With these four building blocks several rigid-core carbosilane dendrimers were synthesized, which can be applied as better retainable soluble supports for organic synthesis in a diafiltration setup

Synthesis of 1,3-Diaryl-2-methoxyindenes by Hydriodic Acid–Catalyzed Cyclization of Aryl[2-(1-aryl-2-methoxyvinyl)phenyl]methanols

An efficient two-step method for the synthesis of 1,3-diaryl-2-methoxyindenes from 1-(1-aryl-2-methoxyvinyl)-2-bromobenzenes has been developed. Thus, the reaction of 2-(1-aryl-2-methoxyvinyl)phenyllithiums, generated in situ by halogen–lithium exchange between 1-(1-aryl-2-methoxyvinyl)-2-bromobenzenes and butyllithium, with aromatic aldehydes gives aryl[2-(1-aryl-2-methoxyvinyl)phenyl]methanols, which in turn are treated with a catalytic amount of concentrated hydriodic acid to afford the corresponding 1,3-diaryl-2-methoxyindenes in reasonable yields.

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.

One‐Pot Generation of Lithium (Lithiophenyl)trialkoxyborates from Substituted Dihalobenzenes (Hal = Br, I) and Their Derivatization with Electrophiles

AbstractThe simple one‐pot approach to synthetically useful phenyltrialkoxyborates bearing lithium at the phenyl ring has been developed starting with 1,3‐ and 1,4‐diiodobenzene, as well as several activated dibromobenzenes and bromoiodobenzenes. The general sequence of transformations involves halogen–lithium exchange by using nBuLi and subsequent boronation with a trialkylborate. The resulting lithium (halophenyl)trialkoxyborates were then subjected to halogen–lithium exchange in situ with a second equivalent of nBuLi to give dianionic lithium (lithiophenyl)trialkoxyborates. Treatment with selected electrophiles afforded substituted arylboronic acids and/or their pinacol esters as final products in moderate‐to‐good yields.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Synthetic Studies on Coenzyme Q10. Part 3

AbstractAn efficient and stereoselective approach to the synthesis of coenzyme Q10 is described (Scheme). The MeOCH2‐protected p‐hydroquinone 4 containing the C5 (E)‐allyl (tert‐butyl)dimethylsilyl ether moiety was obtained via a halogen–lithium exchange of the MeOCH2‐proctected 2‐bromo‐5,6‐dimethoxy‐3‐methylhydroquinone 2 and subsequent addition to (E)‐(tBuMe2Si)‐OCH2C(Me)=CHCH2Br (3). The reductive desulfonylation of compound 8, obtained from 4 via 5–7, was successfully carried out by employing Li/EtNH2.

Halogen—Lithium Exchange versus Deprotonation: Synthesis of Diboronic Acids Derived from Aryl—Benzyl Ethers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Halogen–lithium exchange versus deprotonation: synthesis of diboronic acids derived from aryl–benzyl ethers

Lithiation of a series of aryl benzyl ethers containing halogen substituents (–F, –Br, –I) was investigated. The resultant mono- and diorganolithium intermediates were converted into the corresponding aldehydes or diboronic acids in good yields. The dilithiation of aryl benzyl ethers containing a reactive hydrogen atom and halogen atom capable of halogen–lithium exchange proceeds quantitatively in THF at −50 °C. It was found that mono aryllithiums formed in the reaction can remove the reactive hydrogen atom from a molecule of aryl benzyl ether thus decreasing the yield of dilithiated species. This effect does not occur when t-BuLi is used instead of n-BuLi.

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.

Intramolecular cyclisation of functionalised heteroaryllithiums. Synthesis of novel indolizinone-based compounds

The intramolecular cyclisation of heteroaryllithiums derived from N-heteroarylmethylpyrrole-2-carboxamides takes place smoothly at low temperature when N-methoxy-N-methyl and morpholine amides are used as internal electrophiles. Halogen–lithium exchange using n-BuLi is the method of choice to achieve metalation on the quinoline and pyridine derivatives, while directed lithiation (LDA) works better for furan. In the case of thiophene both methodologies can be applied. These metalation–cyclisation sequences provide a useful entry to several types of indolizidine based compounds (pyrrolo[1,2-b]acridinones, pyrrolo[1,2-g]quinolones, thieno and furo[3,2-f]indolizinones).

Thermochemistry of Organolithium Compounds

AbstractFor Abstract see ChemInform Abstract in Full Text.

Halogen—Lithium Exchange Between Substituted Dihalobenzenes and Butyllithium: Application to the Regioselective Synthesis of Functionalized Bromobenzaldehydes.

Halogen—Lithium Exchange Between Substituted Dihalobenzenes and Butyllithium: Application to the Regioselective Synthesis of Functionalized Bromobenzaldehydes.

Chromophoric Binaphthyl Derivatives

A short synthetic route is outlined, starting from bromo-BN derivatives, via halogen lithium exchange, subsequent Michael reaction with dimethylaminoacrolein, hydrolysis to the corresponding aldehyde, and final condensation with a benzothiazolium unit to produce a BN-pentamethinium system, which absorbs in the visible range around 450 nm. Enantiopure ligands show a decent Cotton effect in the CD spectrum. Preliminary data show potential of these compounds in the area of supramolecular chemistry (enantioselective recognition) and also for medicinal application (induction of apoptosis). [reaction: see text]

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

AbstractFor Abstract see ChemInform Abstract in Full Text.