Oxonitriles: Multicomponent Grignard Addition–Alkylations

Fleming, Fraser F.; Zhang, Zhiyu; Wang, Qunzhao; Steward, Omar W.

doi:10.1002/anie.200352920

Cited by 24 publications

(15 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cyclization of the resulting C-magnesiated nitrile 8 affords the cis-decalin 9 12 as the sole stereoisomer. The stereochemistry is consistent with a retentive S N i displacement resulting from attack of the carbon-magnesium bond on the C-Cl σ* orbital via a 3-centered transition structure (8). 10…”

mentioning

confidence: 57%

Metalated Nitriles: Cation-Controlled Cyclizations

et al. 2007

Self Cite

View full text Add to dashboard Cite

Judicious choice of cation allows the selective cyclization of substituted gamma-hydroxynitriles to trans- or cis-decalins and trans- or cis-bicyclo[5.4.0]undecanes. The stereoselectivities are consistent with deprotonations generating two distinctly different metalated nitriles: an internally coordinated nitrile anion with BuLi, and a C-magnesiated nitrile with i-PrMgCl. Employing cations to control the geometry of metalated nitriles permits stereodivergent cyclizations with complete control over the stereochemistry of the quaternary, nitrile-bearing carbon.

show abstract

mentioning

confidence: 57%

Metalated Nitriles: Cation-Controlled Cyclizations

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…39 Mechanistic experiments performed prior to finding the electrophile-dependent alkylations of C -magnesiated nitriles, implied that the intermediate dimagnesiated nitrile 27 , generated immediately following the axial conjugate addition, was particularly reactive and cyclized to 20 faster than a chair-to-chair conformational inversion ( 27 → 26 ) 29. The preferential cyclization of the C -magnesiated nitrile 26 to the cis -decalin 20 , coupled with an anticipated steric compression imposed by the two axial substituents in 27 , strongly implies that the Grignard addition-cyclization 21 → 20 actually proceeds from the dimagnesiated nitrile 27 through the C -magnesiated nitrile 26 to the cis -decalin 20 (Scheme 6).…”

Section: Resultsmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

Self Cite

View full text Add to dashboard Cite

Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cisfused hydrindanes, decalins, and bicyclo [5.4.0] undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis-and transhydrindanes, decalins, and [5. 4. 0] undecanes, and reveals the key geometric requirements for intramolecular S N 2 and S N 2′ displacements. IntroductionMetalated nitriles are nucleophilic chameleons, readily adapting to the local environment by adopting different structures. 2 X-ray crystallographic analyses of metalated nitriles 3 show two main structural classes: N-metalated nitriles in which the metal coordinates to the nitrile nitrogen, 4 and C-metalated nitriles 5 in which the metal is bound to the formally anionic carbon (Figure 1, 1 and 2, respectively). Crystallographically derived bond lengths for N-and Cmetalated nitriles reveal only a slight weakening of the C≡N triple bond (1.15-1.20 Å), relative to the C≡N bond length of neutral nitriles (1.14 Å), 6 indicative of a predominant inductive stabilization 7 of the negative electron density. Consistent with the inductive stabilization are short C-CN bonds 8 stemming from an electrostatic contraction between the formal anion and the powerful electron-withdrawing nitrile group. 9 Moderating the ligand or metal environment exerts a pronounced influence on the site of coordination in metalated nitriles. The solid-state N-and C-palladated nitriles 1 and 2 10 differ rather modestly in their structural features, essentially in the nature of the phosphine ligand, but exhibit completely different coordination modes to the same nitrile! 7 Li NMR reveals basically the same structural trends for metalated nitriles in solution; a preference for N-or C-metalation that depends intimately on ligand and solvent, 11 and minimal delocalization of the anion into the carbon-nitrogen triple bond. 9 Differences in the site of metal coordination relay into different reactivity modes for N-and C-metalated nitriles. For example, reductive elimination from the N-palladated nitrile 1 is ten Correspondence to: Fraser F. Fleming. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers th...

show abstract

“…Compared to dehydroabietic acid, callitrisic acid ( 16 ) and its derivatives are less‐well investigated due to the lack of commercial availability, although callitrisic acid is also a bioactive substance . Synthesis of callitrisic acid and other epimers of dehydroabietic acid have been investigated before, but the synthetic routes are often lengthy and give racemates . With the compound 9 synthesized from the Suzuki–Miyaura coupling reaction above, further steps were exploited to synthesize (+)‐callitrisic acid ( 16 ) (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

A Suzuki–Miyaura Coupling of ortho‐Hydroxyaryl Bromide with Isopropenylboronic Pinacol Ester: Synthesis of the Potassium‐Channel Opener (+)‐Callitrisic Acid

Ejneby

Ottosson

et al. 2018

Eur J Org Chem

View full text Add to dashboard Cite

A Suzuki–Miyaura coupling reaction of ortho‐hydroxyaromatic bromide 8 with isopropenylboronic acid pinacol ester has been investigated. It was found that the catalyst of Pd2(dba)3/PCy3 in dioxan‐water gave good yield by suppressing the formation of isomeric side product 14. (+)‐Callitrisic acid was synthesized from (+)‐podocarpic acid using this condition with an overall yield of 54 % in about five steps. (+)‐Callitrisic acid was found to be almost three times more potent than dehydroabietic acid to open a voltage‐gated potassium channel.

show abstract

Oxonitriles: Multicomponent Grignard Addition–Alkylations

Cited by 24 publications

References 26 publications

Metalated Nitriles: Cation-Controlled Cyclizations

Metalated Nitriles: Cation-Controlled Cyclizations

Metalated nitriles: stereodivergent cation-controlled cyclizations

A Suzuki–Miyaura Coupling of ortho‐Hydroxyaryl Bromide with Isopropenylboronic Pinacol Ester: Synthesis of the Potassium‐Channel Opener (+)‐Callitrisic Acid

Contact Info

Product

Resources

About