Synthesis and reactions of some bicyclic piperidine analogs. Formation of the 4-azatricyclo[2.2.1.02,6]heptane ring system

Boswell, Robert F.; Bass, R. G.

doi:10.1021/jo00904a039

Cited by 12 publications

(4 citation statements)

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“…It results, however, in moving the Li + ion away from the carbanion center and exposing it to both electrophiles and nucleophiles. In other dibromocyclopropanes, containing either flexible or better aligned substituents, such as methoxy, alkoxymethyl, , acetal, ,,– alkylthiomethyl, , and dialkylaminomethyl, , the heteroatom can effectively chelate the Li + ion increasing the overall stability of the salt and directing the insertion reaction . These single substituents, however, do not significantly affect the carbenic center, and the formation of carbenes (carbenoids) and their subsequent reactions (insertion or rearrangement) are the dominant processes.…”

Section: Discussionmentioning

confidence: 99%

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

et al. 2008

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Reactions of dibromocyclopropane 2a, containing two spiro-fused 1,3-dioxane rings, with MeLi gave only the methylation products 8 and 9 even at elevated temperatures. In contrast, the cyclohexane analogue 2b treated with MeLi underwent a smooth rearrangement to bicyclo[1.1.0]butane 11b at -78, -10, or +35 degrees C. Treatment of 2a with PhLi gave the alpha-Ph anion 13 as the only product, which underwent smooth methylation with MeI to give 14. Under the same conditions, 2b with PhLi gave bicyclo[1.1.0]butane 11b accompanied by bromophenyl derivative 8b. Treatment of either dibromide with t-BuLi gave a mixture of products including debrominated cyclopropanes 12. Experimental results were augmented with DFT calculations for salts 23 and MP2//DFT-level calculations for carbenes 22. They demonstrated a higher stability of the dioxane alpha-bromo anion with respect to alpha-elimination by 4.8 kcal/mol and also a lower tendency of the carbene 22a to undergo rearrangement by 4.0 kcal/mol than the cyclohexane analogues. These differences have been attributed to the inductive effect of the four oxygen atoms, which results in lower LUMO energy, the higher positive charge at the carbenic center, and the overall more electrophilic character of carbene 22a as compared to the cyclohexane derivative 22b. The rearrangement of carbenes 22 to the corresponding allenes 1, the thermodynamic products, requires a higher activation energy DeltaG(double dagger)(298) by 4.2 kcal/mol for dioxane and 6.4 kcal/mol for cyclohexane derivatives than for the formation of the bicyclo[1.1.0]butanes 11. The DeltaG(double dagger)(298) for intramolecular insertions to the CH bond is low and calculated as 6.0 kcal/mol for dioxane 22a and 2.0 kcal/mol for the formation of cyclohexane 22b.

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Section: Discussionmentioning

confidence: 99%

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

et al. 2008

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“…Since then, several different C−H bond insertion reactions of dihalocarbenes have been revealed . A dihalocarbene can insert into a C−H bond that has been activated by the presence of an adjacent heteroatom: oxygen, − nitrogen, or sulfur . In addition, activation using compounds containing π bonds, such as vinyl, − carbonyl, and phenyl 6-8,15b,19 moieties has also been studied.…”

Section: Introductionmentioning

confidence: 99%

Dihalocarbene Insertion Reactions into C−H Bonds of Compounds Containing Small Rings: Mechanisms and Regio- and Stereoselectivities^,

Brinker

Lin

et al. 2007

J. Org. Chem.

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Novel insertion reactions of dichloro- and dibromocarbene into carbon-hydrogen bonds adjacent to cyclopropane rings are reported. It is found that the predominant isomers formed in the reactions with bicyclo[4.1.0]heptane result from insertion into the endo carbon-hydrogen bonds alpha to the three-membered ring. In the reactions of bicyclo[3.1.0]hexane, however, the exo dihalocarbene insertion products are formed as the major isomers. In some compounds cyclopropane rings "activate" adjacent carbon-hydrogen bonds, whereas other systems containing three-membered rings do not. Moreover, the influence of various substituents (methyl, geminal dimethyl, phenyl, methoxy, and ethoxy) attached to bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane in dihalocarbene reactions has been studied. The findings can be explained by the concept of maximum orbital overlaps of Walsh orbitals of the cyclopropane rings and the alpha carbon-hydrogen bonds. In stark contrast, selective insertion into the tertiary carbon-hydrogen bonds of the cyclobutane ring in bicyclo[4.2.0]octane is observed.

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“…(27), with BuLi leading to cyclopropylidene-derived products. 35 In both cases, (10) and ( 27), there is a nitrogen at the 4position relative to the halogen ; this presumably enhances the rate of metallation and/or cyclopropylidene formation. Indeed the isomeric chloride (28) gives no cyclopropylidene-derived products with BuLi.…”

Section: Mementioning

confidence: 99%

The reaction of 1,1-dibromocyclopropanecarboxamides with methyllithium

Baird¹,

Baxter²

1979

J. Chem. Soc., Perkin Trans. 1

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upon Tyne, Newcastle upon Tyne NE1 7RUOn reaction with one equivalent of methyl-lithium at below -60 "C followed by aqueous quenching, the dibromoamides (5) and (6) were reduced to monobromides (10) and (9). An intermediate could be partially trapped as a mono-deuteride (1 5) by quenching with D20 at low temperature, or as (14) by addition of benzadehyde, but could not be trapped by addition of Me,SiCI or CO, ; however, quenching with D 2 0 after the reaction solution had been warmed to 35 'C led to (10) with no deuterium incorporation. The source of the proton in this last reaction was the solvent, ether. Treatment of (5) with 2 mot equiv. MeLi at -60 "C also led after low-temperature aqueous quenching to (10) ; if the temperature was rapidly raised to 35 'C two products, (20) (major) and (19) (minor), were isolated after quenching. If, however, (5) was treated with 1 mol equiv. MeLi at -60 "C, followed by very slow addition of a second mol equiv. at 35', (1 9) was the major product. The monobromide (1 0) is an intermediate in both these reactions, and indeed leads to (19) and (20) in similar proportions to those from (5) when treated with 1 equiv. MeLi either rapidly or dropwise at 25-35 "C; reaction of (9) with 1 equiv. MeLi leads, however, to the ketone (11 ; X = Me). A second (presumed) diastereoisomer of (14) was also obtained but this could not be effectively separated from a third product,. Compound (14) was unusual in that restricted rotation led t o four doublets in the n.m.r. spectrum for the isopropyl methyl groups, as well as two isopropyl-CH signals. Published on 01 January 1979. Downloaded by UNIVERSITY OF NEBRASKA on 16/09/2013 13:36:45.* The reaction is more rapid in the presence of TMEDA, being complete in ca. 24 h at 35 "C in ether. TMEDA is known to dramatically increase the rate of metallation by alkyl-lithiums.38

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Synthesis and reactions of some bicyclic piperidine analogs. Formation of the 4-azatricyclo[2.2.1.02,6]heptane ring system

Cited by 12 publications

References 0 publications

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

Dihalocarbene Insertion Reactions into C−H Bonds of Compounds Containing Small Rings: Mechanisms and Regio- and Stereoselectivities^,

The reaction of 1,1-dibromocyclopropanecarboxamides with methyllithium

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Synthesis and reactions of some bicyclic piperidine analogs. Formation of the 4-azatricyclo[2.2.1.02,6]heptane ring system

Cited by 12 publications

References 0 publications

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

Reactivity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward Organolithiums: Remarkable Resistance to the DMS Rearrangement

Dihalocarbene Insertion Reactions into C−H Bonds of Compounds Containing Small Rings: Mechanisms and Regio- and Stereoselectivities,

The reaction of 1,1-dibromocyclopropanecarboxamides with methyllithium

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Dihalocarbene Insertion Reactions into C−H Bonds of Compounds Containing Small Rings: Mechanisms and Regio- and Stereoselectivities^,