Cyclic Metalated Nitriles: Stereoselective Cyclizations to <i>cis</i>‐ and <i>trans</i>‐Hydrindanes, Decalins, and Bicyclo[4.3.0]undecanes

Fleming, Fraser F.; Gudipati, Subramanyham

doi:10.1002/ejoc.200800715

Cited by 33 publications

(23 citation statements)

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“…X-ray crystallography provides an excellent method for crystalline nitriles whereas axial and equatorial orientations of liquid cyclohexanecarbonitrile diastereomers can be differentiated by their infrared CN bond intensity 11. In contrast, using mechanistic arguments to assign the configuration of cyclic nitriles resulting from conjugate cyanations12 or alkylations13 is not always reliable. An illustrative case is the alkylation of 1 in which deprotonations with i -PrMgBr or LDA/BuLi and methylation leads to different nitrile diastereomers (Scheme 1, 1 → 2 → 3 and 1 → 4 → 5 ).…”

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Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Fleming

Wei

2009

J. Org. Chem.

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Abstract13 C NMR chemical shifts of the nitrile carbon in cyclohexanecarbonitriles directly correlate with the configuration of the quaternary, nitrile-bearing stereocenter. Comparing 13 C NMR chemical shifts for over 200 cyclohexanecarbonitriles reveals that equatorially oriented nitriles resonate 3.3 ppm downfield, on average, from their axial counterparts. Pairs of axial/equatorial diastereomers varying only at the nitrile-bearing carbon consistently exhibit downfield shifts of δ 0.4-7.2 for the equatorial nitrile carbon, even in angularly substituted decalins and hydrindanes.Cyclic nitriles are versatile synthetic intermediates 2 that are readily transformed into an array of bioactive targets. 3 Cylcohexanecarbonitriles in particular have a long and distinguished history as versatile synthetic intermediates, 2,4 partly because of the prevalence of 6-membered rings in nature 5 and partly because of the nitrile's small steric demand. 6 The miniscule steric demand of the nitrile group, a mere 0.2 kcal mol −1,6 allows efficient installation of hindered quaternary carbons through alkylations 7 and conjugate cyanations, 8 even in cases where other methods fail. 9Assigning the configuration of nitrile-bearing, quaternary centers is challenging. 10 X-ray crystallography provides an excellent method for crystalline nitriles whereas axial and equatorial orientations of liquid cyclohexanecarbonitrile diastereomers can be differentiated by their infrared CN bond intensity. 11 In contrast, using mechanistic arguments to assign the configuration of cyclic nitriles resulting from conjugate cyanations 12 or alkylations 13 is not always reliable. An illustrative case is the alkylation of 1 in which deprotonations with iPrMgBr or LDA/BuLi and methylation leads to different nitrile diastereomers (Scheme 1, 1→2→3 and 1→4→5). The divergent stereoselectivity is consistant with alkylations via Cor N-metalated cyclohexanecarbonitriles 2 and 4, respectively. 14 Correspondence to: Fraser F. Fleming. During the synthesis of several diastereomeric cyclohexanecarbonitriles, the 13 C chemical shift of the nitrile carbon was found to correlate with the orientation of the nitrile group (Scheme 1, compare 3 and 5). The attraction of using a simple NMR method to assign the stereochemistry of quaternary nitrile-bearing carbons stimulated an extensive examination of 13 C NMR shifts in a diverse population of substituted cyclohexanecarbonitriles. Comparison of the chemical shifts revealed distinct regions depending on the configuration at the quaternary center. Equatorially oriented nitriles on fully substituted carbons typically resonate downfield, between δ 126.8-124.4, whereas the axially oriented counterparts resonate further upfield, between δ 124.6-118.6. Equatorial cyclohexanecarbonitrile diastereomers consistently resonate downfield from their axial counterparts, even for angular nitriles embedded within cis-and trans-decalins. The 13 C NMR chemical shift provides a rapid, useful method for assigning the configuration of quaternary, nit...

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Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Fleming

Wei

2009

J. Org. Chem.

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“…[1] Formation of metalated nitriles is illustrative of the different metalation strategies used to generate organometallics:traditional base-promoted deprotonation (1!2 or 3;Scheme 1), [2] halogen-metal exchange (5!2 or 3), [3] sulfoxide-metal exchange (6!2 or 3), [4] and sulfide-metal exchange (7!2 or 3). [7] Conspicuously absent from the types of exchangeable functionality are sulfones such as 8. [7] Conspicuously absent from the types of exchangeable functionality are sulfones such as 8.…”

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“…[5] Each strategy has distinct advantages by providing selective access to either C-metalated (2)o rN -metalated nitriles (3)w hich intrinsically control the chemo-, [6] regio-, [3] and stereoselectivity of alkylations. [7] Conspicuously absent from the types of exchangeable functionality are sulfones such as 8. [8] Conceptually,as ulfone-metal exchange would combine the exceptionally rich chemistry of sulfones [9] with the diverse alkylation potential of organometallics while providing aversatile alternative to reductive desulfonylation.…”

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Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

et al. 2017

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The first general sulfone-metal exchange is described. Treating substituted 2-pyridylsulfonylacetonitriles with either BuLi or Bu MgLi generates metalated nitriles that efficiently intercept a variety of electrophiles to afford quaternary nitriles. The 2-pyridylsulfone is critical for the sulfone-metal exchange because chelation anchors the organometallic proximal to the electrophilic, tetrasubstituted sulfone to override complex-induced deprotonation. Alkylating commercial 2-pyridinesulfonylacetonitrile with mild bases, either K CO or DBU, and subsequent sulfone-metal exchange and alkylation rapidly assembles quaternary nitriles by three alkylations, only one of which requires an organometallic reagent.

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“…[3,4] Fleming and co-workers have studied the diastereoselectivity on alkylation of metalated nitriles, revealing differences depending on whether a lithium or magnesium cation is used. [5] This was ascribed to differences in the structures of the lithiated and magnesiated intermediates. [6] With a lithium cation, there is a preference for a planar intermediate with the lithium coordinating to the nitrogen atom (Figure 1 a).…”

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Remarkable Configurational Stability of Magnesiated Nitriles

et al. 2013

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Cyclic Metalated Nitriles: Stereoselective Cyclizations to cis‐ and trans‐Hydrindanes, Decalins, and Bicyclo[4.3.0]undecanes

Cited by 33 publications

References 144 publications

Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

Remarkable Configurational Stability of Magnesiated Nitriles

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Cyclic Metalated Nitriles: Stereoselective Cyclizations to cis‐ and trans‐Hydrindanes, Decalins, and Bicyclo[4.3.0]undecanes

Cited by 33 publications

References 144 publications

Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from 13C NMR CN Chemical Shifts

Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from 13C NMR CN Chemical Shifts

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

Remarkable Configurational Stability of Magnesiated Nitriles

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Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts