Catalytic Carbometalation/Cross‐Coupling Sequence across Alkynyl(2‐pyridyl)silanes Leading to a Diversity‐Oriented Synthesis of Tamoxifen‐Type Tetrasubstituted Olefins

Kamei, Toshiyuki; Itami, Kenichiro; Yoshida, Jun‐ichi

doi:10.1002/adsc.200404220

Cited by 50 publications

(24 citation statements)

References 79 publications

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“…Of note, the overall three‐step transformation of m ‐iodotoluene into pivaloxylated arene 16 constitutes a formal ortho ‐oxygenation of m ‐iodotoluene 32. Moreover, borodesilylation of the PyDipSi group in 4r with BCl 3 , followed by the protection of the generated aryldichloroborane with pinacol under basic conditions,7d,33 furnished a synthetically valuable arylboronate 17 34 in an excellent yield. Likewise, a one‐pot sequence involving the borodesilylation of 4r , followed by the oxidation step in the presence of H 2 O 2 /NaOH, led to 4‐methylcatechol ( 18 ) in 89% yield.…”

Section: Resultsmentioning

confidence: 99%

The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho‐Acyloxylation and ortho‐Halogenation Reactions of Arenes

et al. 2011

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A novel, easily removable and modifiable silicon-tethered pyridyldiisopropylsilyl directing group for C–H functionalizations of arenes has been developed. The installation of the pyridyldiisopropylsilyl group can efficiently be achieved via two complementary routes using easily available 2-(diisopropylsilyl)pyridine (5). The first strategy features a nucleophilic hydride substitution at the silicon atom in 5 with aryllithium reagents generated in situ from the corresponding aryl bromides or iodides. The second milder route exploits a highly efficient room-temperature rhodium(I)-catalyzed cross-coupling reaction between 5 and aryl iodides. The latter approach can be applied to the preparation of a wide range of pyridyldiisopropylsilyl-substituted arenes possessing a variety of functional groups, including those incompatible with organometallic reagents. The pyridyldiisopropylsilyl directing group allows for a highly efficient, regioselective palladium(II)-catalyzed mono-ortho-acyloxylation and ortho-halogenation of various aromatic compounds. Most impor-tantly, the silicon-tethered directing group in both acyloxylated and halogenated products can easily be removed or efficiently converted into an array of other valuable functionalities. These transformations include protio-, deuterio-, halo-, boro-, and alkynyldesilylations, as well as a conversion of the directing group into the hydroxy functionality. In addition, the construction of aryl-aryl bonds via the Hiyama–Denmark cross-coupling reaction is feasible for the acetoxylated products. Moreover, the ortho-halogenated pyridyldiisopropylsilylarenes, bearing both nucleophilic pyridyldiisopropylsilyl and electrophilic aryl halide moieties, represent synthetically attractive 1,2-ambiphiles. A unique reactivity of these ambiphiles has been demonstrated in efficient syntheses of arylenediyne and benzosilole derivatives, as well as in a facile generation of benzyne. In addition, preliminary mechanistic studies of the acyloxylation and halogenation reactions have been performed. A trinuclear palladacycle intermediate has been isolated from a stoichiometric reaction between diisopropyl-(phenyl)pyrid-2-ylsilane (3a) and palladium acetate. Furthermore, both C–H functionalization reactions exhibited equally high values of the intramolecular primary kinetic isotope effect (kH/kD = 6.7). Based on these observations, a general mechanism involving the formation of a palladacycle via a C–H activation process as the rate-determining step has been proposed.

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Section: Resultsmentioning

confidence: 99%

The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho‐Acyloxylation and ortho‐Halogenation Reactions of Arenes

et al. 2011

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“…Kamei et al have reported the synthesis of tamoxifen analogues using alkynyl(2-pyridyl)silanes (459) which were synthesized from the reaction of dimethylsilylchloride (455) with 1-butynylmagnesium chloride (456) in THF to give compound 457 in 51% yield followed by reaction with 2pyridylmagnesium chloride (458) in THF to afford 459 in 61% yield (Scheme 89). [94] Compound 459 was further reacted with Grignard reagent 460 in regio-and stereo-specific manner in the presence of CuI in diethyl ether to give 461. Further investigation in this reaction step led to the conclusion that the use of 3-pyridyl-, 4-pyridyl-, and phenyl(1-butynyl)silanes did not lead to any reaction which implicated the strong directing effect of 2-pyridyl group.…”

Section: Addition Reaction To Alkynesmentioning

confidence: 99%

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

et al. 2020

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Tamoxifen is one of the important tricyclicethylene moieties and recognized as an important drug candidate because of extensive applications in the field of medicinal and pharmaceutical chemistry. Recently, ample attention is given to this analogue by organic and medicinal chemistry community due to its successful utilization for the inhibition of estrogen receptor in MCF-7 breast cancer cell lines. Due to its structural character, tamoxifen is also useful in material chemistry. The synthesis of tamoxifen and its anlogues is desirable from easily available chemicals as an important drug candidate. Here, we report a review on various synthetic schemes for tamoxifen and its anlogues employing use of different strategies such as formation of CÀ C, C=C and C�C bonds, CÀ H functionalization, addition to alkynes, insertion reaction, nucleophilic substitution and addition reactions, elimination reaction, reductive couplings etc.

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“…Itami ist seit 1998 Assistant Professor an der Universität Kyoto, wo er neue Reagentien und Methoden für die organische Synthese entwickelt und deren Mechanismen erforscht. Kürzlich berichtete er über eine Reaktionsfolge aus katalytischer Carbometallierung und Kreuzkupplung zur Synthese vierfach substituierter Olefine 4. Itami studierte an der Universität Kyoto und promovierte dort 1998 unter der Anleitung von Y. Ito über übergangsmetallkatalysierte Cycloadditionen an Vinylallene.…”

Section: Ausgezeichnet…︁unclassified

Probing Small‐Molecule Binding to Cytochrome P450 2D6 and 2C9: An In Silico Protocol for Generating Toxicity Alerts

et al. 2010

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Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 and CYP2C9 would be beneficial for identifying cytochrome-mediated adverse effects triggered by drugs or chemicals (e.g., toxic reactions, drug-drug, and food-drug interactions). By identifying the binding mode by using pharmacophore prealignment, automated flexible docking, and by quantifying the binding affinity by multidimensional QSAR (mQSAR), we validated a model family of 56 compounds (46 training, 10 test) and 85 compounds (68 training, 17 test) for CYP2D6 and CYP2C9, respectively. The correlation with the experimental data (cross-validated r²=0.811 for CYP2D6 and 0.687 for CYP2C9) suggests that our approach is suited for predicting the binding affinity of compounds towards CYP2D6 and CYP2C9. The models were challenged by Y-scrambling and by testing an external dataset of binding compounds (15 compounds for CYP2D6 and 40 for CYP2C9). To assess the probability of false-positive predictions, datasets of nonbinders (64 compounds for CYP2D6 and 56 for CYP2C9) were tested by using the same protocol. The two validated mQSAR models were subsequently added to the VirtualToxLab (VTL, http://www.virtualtoxlab.org).

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Catalytic Carbometalation/Cross‐Coupling Sequence across Alkynyl(2‐pyridyl)silanes Leading to a Diversity‐Oriented Synthesis of Tamoxifen‐Type Tetrasubstituted Olefins

Cited by 50 publications

References 79 publications

The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho‐Acyloxylation and ortho‐Halogenation Reactions of Arenes

The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho‐Acyloxylation and ortho‐Halogenation Reactions of Arenes

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

Probing Small‐Molecule Binding to Cytochrome P450 2D6 and 2C9: An In Silico Protocol for Generating Toxicity Alerts

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