Halogen-metal Exchange Research Articles

Enantiodivergent synthesis of P-chirogenic phosphines

Several approaches for the enantiodivergent synthesis of P-chirogenic mono- and diphosphines are described, using and phosphine borane chemistry. Firstly, both enantiomers of a tertiary phosphine can be obtained starting from the same oxazaphospholidine borane complex, prepared from (+)-ephedrine, when changing the order of addition of the organolithium reagents during the synthetic pathway. The second approach is based on the chlorophosphine boranes, which react with an organolithium reagent, to afford the corresponding phosphines with inversion of configuration. In the case where the chlorophosphine borane reacts with the t-butyl lithium reagent, a metal-halogen exchange occurs to afford the corresponding phosphide borane with retention of the configuration. The reaction of the phosphide borane with an alkyl halide leads to the same phosphine, but with the opposite configuration. Another approach depends on the diastereoselective preparation of the starting oxazaphospholidine borane complex from (−)-ephedrine, which leads according the case, to either one or the other enantiomer of a phosphine. Finally, the synthesis of (R,R)- and (S,S)-1,2-bis(methylphenylphosphino)ethane is also demonstrated using both enantiomers of the P-chirogenic diphosphinite diborane, which simultaneously allows the introduction of alkyl- or aryl substituents on the phosphorus atoms. In summary, these approaches show the great efficiency of the ephedrine methodology for the enantiodivergent synthesis of P-chirogenic mono- and diphosphines, and bearing alkyl or aryl substituents.

ChemInform Abstract: Organolithium Reagents Bearing Nonlinear Optical Chromophores. Synthesis of Triarylmethane Dyes.

Abstract Stilbenyllithiums bearing donor groups were generated by the halogenmetal exchange reaction and are shown to be useful in CC and Cheteroelement forming reactions. A series of triarylmethane dyes has thus been prepared.

ChemInform Abstract: Stereodivergent Synthesis of Sulfoxide-Containing Oxazolidinone Antibiotics.

Abstract Carbamate 5 was prepared under mild conditions via a novel metal–halogen exchange procedure without competing benzyne formation. Selection of an appropriate oxidation/reduction sequence afforded access to either the cis - or trans -1-oxo-4-aryltetrahydrothiopyran system, important intermediates in the synthesis of a new class of oxazolidinone antibiotics.

Isolation of Silenolates (R3Si)2SiC(OLi)Ad with a Doubly Bonded Silicon Atom

Metal enolates are an important class of reactive intermediates widely employed in organic synthesis. In contrast, little is known about silenolates, the silicon analogues of enolates. Enolates exist in two tautomeric forms, the enol form and the keto form, and their reactions reflect the coexistence of these two forms. The dominant structure of alkali metal enolates is the enol form both in nonsolvating media and in various solvating media such as THF, N,N,N’,N’-tetramethylethylenediamine, and [18]crown-6. Silenolates also exist in two tautomeric forms: the keto form a (acyl silyl anion) and the enol form b (silene) [Eq. (1)], and they also show ambident reactivity. The first silenolate (solvated), recently isolated and characterized by X-ray crystallography, has the keto form a. An enol-form silenolate bwas not yet reported. Isolation of an enol-form silenolate is challenging, because it has a Si=C p bond which is thermodynamically and kinetically less stable than a C=C bond. In addition, enol-form silenolates can be regarded as functional silenes, which are reagents of growing importance in silicon chemistry. Here we report the synthesis, isolation, and X-ray molecular structure of the first enol-form silenolates (tBuMe2Si)2Si=C(OLi)Ad (1) and (tBu2MeSi)2Si=C(OLi)Ad (2). We show by DFT quantum-mechanical calculations that, in contrast to organic enolates, which exist predominantly in the enol form regardless of solvation, the structure of silenolates 1 and 2 is strongly dependent on the solvent. Silenolate 1 was synthesized by metal–halogen exchange between tBuMe2SiLi (in excess) and bromo acyl silane Br(tBuMe2Si)2SiC(O)Ad (3) in hexane at 78 8C. Upon warming to room temperature pale yellow crystals of silenolate 1 precipitated (10% yield). The major product is substitution product 4 [Eq. (2)].

Novel multitopic diphos-type ligands.

Seven novel imidazole and thiazole derivatives of diphos-type ligands are presented. They are of the general structure R 2P(CH 2) 2PR 2, where R is imidazol-2-yl ( 1), 1-methylimidazol-2-yl ( 2), 1-methylbenzimidazol-2-yl ( 3), 1-methylimidazol-5-yl ( 4), 2-isopropylimidazol-4(5)-yl ( 5), thiazol-2-yl ( 6), benzothiazol-2-yl ( 7), thiazol-4-yl ( 8) or thiazol-5-yl ( 9). Syntheses involved direct metallation or halogen–metal exchange reactions. Their solubility, especially in aqueous solution, is strongly dependent on the nature of the substituents as is their partition coefficient log D. The crystal structures of compounds 2, 3, 7a and 9 as well as the structure of the rhodium complex [( 2) 2Rh 2Cl 2]Cl 2 ( 10) have been determined.

Domino reactions of 5-deoxy-5-iodo- d- xylo- and - l-arabinofuranose derivatives with organometallic reagents. A way towards polyfunctionalized building-blocks

Domino reactions involving metal–halogen exchange, furanose ring-opening and nucleophilic addition from 3- O-benzyl-5-deoxy-5-iodo-1,2- O-isopropylidene-α- d-xylofuranose and the epimeric l- arabino derivative with various organometallic reagents are reported. In anhydrous conditions, with a large excess of organolithium or Grignard reagents, vicinal diols are obtained with good yields and a fair diastereoselectivity. Interestingly, with α-trimethylsilyl organolithium reagents, the fragmentation of the furanose ring to the substituted pent-4-enal is followed by a Peterson olefination giving dienic compounds in a four-step one-pot process.

Synthesis of (R)-Orphenadrine

Orphenadrine is an antihistamine and anticholinergic drug. Sälinger and Brückner report a short synthesis of (R)-orphenadrine that features the first asymmetric ligand-accelerated halogen-metal exchange in which the pro-S bromoarene of the substrate B reacts faster than the pro-R bromoarene leading to kinetic selection for the organomagnesium derivative D. Simple protonolysis of D gave the key intermediate E.

Total syntheses of naamidine G and 14-methoxynaamidine G

Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position-specific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure described in the literature.

New synthesis of (±)- cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

We describe herein an efficient new route to the trikentrins and their related structures using a tandem 6,7-indolyne cycloaddition/Negishi cross-coupling reaction starting from a 4,6,7-tribromoindole (obtained in good yield via the Bartoli indole synthesis). The key step of this second generation route to the trikentrins is based on our observation that the 7-bromo substituent appears to undergo selective metal–halogen exchange and elimination to give the 6,7-indolyne, which is trapped in the presence of excess cyclopentadiene. Subsequent Negishi cross-coupling at the 4-bromoindole position with Et 2Zn gave directly the same intermediate obtained from our previous work. Application of this chemistry to the construction of trikentrin-related libraries using this general cycloaddition/cross-coupling tactic will also be described.

Factors influencing prenylation of an aromatic organolithium

An apparently routine metal–halogen exchange (MHE) reaction gave variable low yields under typical conditions. 13C and 7Li NMR studies suggested a diversity of organolithiums were formed in the MHE reaction leading to a plethora of products on subsequent electrophilic aromatic substitution with geranyl bromide. A reversal of reagent addition simplified the 7Li NMR spectrum and the product distribution, in addition to increasing the isolated yield of the desired product from a variable 5-40% to a consistent 65%.

Synthesis of σ receptor ligands with unsymmetrical spiro connection of the piperidine moiety

The symmetrically connected spiro[[2]benzopyran-1,4′-piperidines] 1 are highly potent and selective σ 1 receptor ligands. Changing the position of the spirocyclic nitrogen atom led to the unsymmetrically connected spiro[[2]benzopyran-1,3′-piperidines] 2 with a reduced distance between the aromatic system and the basic nitrogen atom. The synthesis of 2 was performed by halogen–metal exchange at the aryl bromide 3 followed by addition to the piperidone 5 and intramolecular transacetalization. The yield of 2a was considerably improved by transmetallation of the aryllithium intermediate 4a with CeCl 3 ( 4c). The cis and trans diastereomers cis- 2 and trans- 2 were separated and characterized by nuclear Overhauser effect. After removal of the benzyl group, the secondary amine 2b was alkylated with various alkyl and arylalkyl halides. The σ 1 and σ 2 receptor affinity of the spirocyclic piperidines 2 were determined with receptor binding studies. Compared with the spirocyclic piperidines 1, the unsymmetrically connected piperidines 2 show remarkably reduced σ 1 receptor affinities, whereas the selectivity over σ 2 and NMDA receptors was retained. A stereoselective interaction of the σ 1 receptor protein with the cis- or trans-configured spirocyclic compounds 2 was not observed. It was shown that alkyl residues at the N-atom can replace the lipophilic N-arylalkyl groups and interact with the primary hydrophobic binding site of the σ 1 receptor protein.

Expedient total syntheses of preclathridine A and clathridine A

A short and operationally simple total synthesis of two Leucetta-derived marine alkaloids has been developed, which rely on position specific halogen–metal exchange to introduce the benzyl-substituted side chain. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides preclathridine A on catalytic hydrogenation, which can be converted to clathridine A by a procedure described in the literature.

Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

The regioselectivity of Diels–Alder cycloadditions of indole arynes (indolynes) at all three benzenoid positions was examined. Cycloadditions with the 4,5-and 5,6-indolynes, derived via metal–halogen exchange from the corresponding o-dibromo indoles, showed essentially no selectivity with 2- t-butylfuran. In contrast, the 6,7-indolyne displayed virtually complete preference for the more sterically congested cycloadduct. This same cycloadduct undergoes a facile acid-catalyzed rearrangement to afford the annulated enone, or alternatively, undergoes hydrolysis and oxidation in the presence of air to give the indolobenzoquinone. The 5,6-difluoroindoles show anomalous behavior and give either 5-fluoro-6,7-indolynes with n-BuLi in ether, or 5,6-indolynes with n-BuLi in toluene. We have also demonstrated that benzenoid indolynes can be easily and conveniently generated by the fluoride-induced decomposition of o-trimethylsilyl triflates.

Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands. 1. N-Substituted Spiro[piperidine-4,4′-thieno[3,2-c]pyrans

Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.

A Convenient Preparation of C-Silylated Calixarenes

Calix[4]arenes having multiple silyl groups on the upper (wide) rim were prepared from the corresponding bromocalixarenes by halogen-metal exchange with t-BuLi followed by silylation. The best results were obtained using the clear supernatant from a mixture of chlorosilane and triethylamine. With the higher molecular weight chlorosilanes, an aqueous workup was replaced by a filtration through a column of silica gel. p-(Trimethylsilyl)calixarene 17, the silicon analogue of the well-studied p-tert-butylcalixarene 1, formed a crystalline complex with toluene having a toluene molecule in the cone cavity with the toluene methyl protruding out at an angle.

First synthesis of 7-amido-[1,2,4]triazolo[1,5- a]pyrimidines using halogen–metal exchange

A new and efficient methodology for the preparation of novel 7-carboxyl-triazolopyrimidine derivatives via the halogen–metal exchange is described. In addition, we showed that this new method can be useful for the synthesis of amides, esters, and ketones by using different carbamoyl chlorides, isocyanides or acyl chlorides as electrophile.

Novel, One-Pot Procedure for the Synthesis of 2-Arylethanol Derivatives

An efficient one-pot synthesis of 2-arylethanol derivatives using ethylene sulfate as a C 2 building block is described. High yields are obtained upon trapping of aryllithium intermediates generated by halogen-metal exchange or directed metalation with ethylene sulfate. The resulting heteroaryl or phenylethanol derivatives represent versatile building blocks for the synthesis of annulated pyran derivatives by oxa-Pictet-Spengler reaction.

Nucleophilicity of metal carbonyl anions in vinylic substitution reactions

AbstractSecond order rate constants are reported for the reactions of metal carbonyl anions ([M(CO)nL]−) with several vinyl halides: PhCClC(CN)2, Z‐ and E‐Ph(CN)CCHHal (Hal = Cl, Br) which follow the addition–elimination (AdNE) substitution mechanism. The obtained data show that the nucleophilic reactivity of [M(CO)nL]− anions towards vinyl halides increases in the same order as in aliphatic SN2 reactions, but much more steeply, by 14 orders of magnitude in the row log{$k_{[{\bf M}({\bf CO})_n {\bf L}]{\bf M'}} {\rm /}k_{[{\bf CpMo}({\bf CO})_3 ]{\bf K}}$}: [CpFe(CO)2]− (∼14), [Re(CO)5]− (7.8), [Mn(CO)5]− 2.1, [CpW(CO)3]− (0.7) > [CpMo(CO)3]− (0). A good correlation exists between nucleophilicities of [M(CO)nL]− anions towards vinyl (sp2‐carbon) and alkyl halides (sp3‐carbon) with slope 2.7. The reactivity of [M(CO)nL]− in a halogen–metal exchange process (with Z‐PhC(CN)CHI) follows a similar ‘large’ scale as in the AdNE process. The nucleophilicity of [M(CO)nL]− anions correlates better with their one‐electron oxidation potentials (Eox) than with their basicity (pKa of [M(CO)nL]H). Copyright © 2008 John Wiley & Sons, Ltd.

Highly selective and efficient conversion of aryl bromides to t-butyl benzoates with di- t-butyl dicarbonate

t-Butyl benzoates can be accessed from aromatic compounds bearing multiple halogen substituents via selective metal–halogen exchange with lithium tri- n-butylmagnesium ate complex followed by trapping with di- t-butyl dicarbonate.

Indium-mediated dehalogenation of haloheteroaromatics in water

It turned out that indium metal was applicable to the dehalogenation of aromatic halides in water. This method is facile and safe compared with the conventional methods such as Pd–C, Raney Ni, or halogen–metal exchange.