From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes

Kim, Jeung Gon; Walsh, Patrick J.

doi:10.1002/anie.200600741

Cited by 138 publications

(46 citation statements)

References 40 publications

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“…Thus, metallation of an aryl bromide with n -BuLi, transmetallation to zinc, and enantioselective addition to aldehydes in the presence of the MIB-based69,70 catalyst can now be performed in a one-pot procedure (Equation 2). 68 To circumvent the need for tedious sublimation, filtration, or centrifugation of the intermediate arylzinc reagents, we introduced a method to sequester the LiCl byproduct, enabling the generation of diarylmethanols with high levels of enantioselectivity in the presence of lithium chloride. Unfortunately, this procedure was unsuccessful when applied to the generation of enantioenriched diheteroarylmethanols.…”

Section: Introductionmentioning

confidence: 99%

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

2009

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Enantioenriched diaryl-, aryl heteroaryl-and diheteroarylmethanols exhibit important biological and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from readily available aryl bromides are introduced. Thus, lithium-bromide exchange with commercially available aryl bromides and n-BuLi was followed by salt metathesis with ZnCl 2 to generate ArZnCl. A second equivalent of n-BuLi was added to form the mixed organozinc, ArZnBu. In the presence of enantioenriched amino alcohol-based catalysts, ArZnBu adds to aldehydes to afford essentially racemic diarylmethanols. The low enantioselectivities were attributed to a LiCl-promoted background reaction. To inhibit this background reaction, the chelating diamine TEEDA (tetraethylethylene diamine) was introduced prior to aldehyde addition. Under these conditions, enantioenriched diarylmethanols were obtained with >90% ee. Arylations of enals generated allylic alcohols with 81-90% ee. This procedure was unsuccessful, however, when applied to heteraryl bromides, which was attributed to decomposition of the heteroaryl lithium under the salt metathesis conditions. To avoid this problem, the metathesis was conducted with EtZnCl, which enabled the salt metathesis to proceed at low temperatures. The resulting EtZn(Ar Hetero ) intermediates (Ar Hetero =2-and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were successfully added to aldehydes and heteroaryl aldehydes with enantioselectivities between 81-99%. These are the first examples of catalytic and highly enantioselective syntheses of diheteroarylmethanols. In a similar fashion, ferrocenyl bromide was used to generate FcZnEt and the ferrocenyl group added to benzaldehyde and heteroaromatic aldehydes to form ferrocene-based ligand precursors in 86-95% yield with 96-98% ee. It was also found that the arylation and heteroarylation of enals could be followed by diastereoselective epoxidations to provide epoxy alcohols with high enantio-and diastereoselectivities in a one-pot procedure.

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Section: Introductionmentioning

confidence: 99%

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

2009

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“…2−4 Besides the extensive work on the catalytic asymmetric ZnEt 2 addition to aldehydes, recent years have seen rapid growth in the study of the addition of functional organozincs such as arylzincs, 5−7 vinylzincs, 8−11 and alkynylzincs 12−15 to carbonyl compounds. These reactions can produce a variety of functional chiral alcohols that are important in organic syntheses.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Functional Organozinc Additions to Aldehydes Catalyzed by 1,1′-Bi-2-naphthols (BINOLs)

2014

Acc. Chem. Res.

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ConspectusChiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C–C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account.Our laboratory has developed a series of 1,1′-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3′-dianisyl-substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3′-positions of the partially hydrogenated H8BINOL. These H8BINOL–amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL–amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL–amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols.We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(OiPr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(OiPr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL–ZnEt2–Ti(OiPr)4–Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity.The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis.

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“…We prepared n-butylphenylzinc by three different methods. In the in situ preparation methods [18][19][20], n-butylzinc bromide prepared by transmetallation of n-butylmagnesium bromide was allowed to react with phenylmagnesium bromide (Method A 1 ) or the same procedure was applied by reacting phenylzinc bromide with n-butylmagnesium bromide (Method A 2 ). We also mixed equimolar amounts of din-butylzinc and diphenylzinc (Method B).…”

Section: Resultsmentioning

confidence: 99%

“…Bolm and co-workers introduced successful combination of diethylzinc and diphenylzinc to increase the enantioselectivity in the asymmetric addition to aldehydes [13][14][15] and this methodology was applied by using combinations of dialkylzinc and diphenylzinc [16,17]. Recently, alkylarylzincs were used instead of diarylzincs in the asymmetric 1,2-addition to aldehydes [18] and 1,4-addition to enones [17].…”

Section: Introductionmentioning

confidence: 98%

Reactivities of mixed organozinc and mixed organocopper reagents: 1 – Solvent controlled organic group transfer from mixed diorganozincs

Erdık

Pekel

2008

Journal of Organometallic Chemistry

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From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes

Cited by 138 publications

References 40 publications

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

Asymmetric Functional Organozinc Additions to Aldehydes Catalyzed by 1,1′-Bi-2-naphthols (BINOLs)

Reactivities of mixed organozinc and mixed organocopper reagents: 1 – Solvent controlled organic group transfer from mixed diorganozincs

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