Thermal rearrangement of 1,1-difluorospiropentane

Sellers, Simon F.; Al-Sader, Basil H.; Elsheimer, Seth

doi:10.1021/ja00393a059

Cited by 14 publications

(11 citation statements)

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“…112 For example, consistent with the methylenecyclopropane results (section II.4.1.3), the two geminal fluorine substituents of 1,1-difluorospiropentane (28) exerted little overall kinetic effect on the homolysis of the proximal C(1)-C(2). 113 The observed regioselectivity of the reaction did not allow one to distinguish between the two possible peripheral homolysis mechanisms, a and b. However, simple analysis of the product ratios from thermal rearrangement of deuterium-labeled analogue 31 allowed determination of the ratio of mechanisms a and b to be 3:1.…”

Section: Unimolecular Thermal Homolytic Rearrangementsmentioning

confidence: 99%

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

2003

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Section: Unimolecular Thermal Homolytic Rearrangementsmentioning

confidence: 99%

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

2003

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“…However, fluorine substitution of a cyclopropane has been shown to impart unique effects different even from those of other halogens. 17 Experimentally, it has been shown to increase ring strain by 4.5-5.0 kcal/mol per fluorine, 18 it significantly weakens the bond opposite the carbon bearing the fluorine substituent, [19][20][21] and it has been suggested to slightly strengthen 20 or weaken 19 the adjacent bonds. Similarly, geminal difluoro substitution of cyclopropane has been experimentally estimated to weaken the bond opposite the CF 2 by 9-10 kcal/mol 21 but imparts much less effect on the adjacent bonds weakening them by 0-2 kcal/mol.…”

mentioning

confidence: 99%

“…Similarly, geminal difluoro substitution of cyclopropane has been experimentally estimated to weaken the bond opposite the CF 2 by 9-10 kcal/mol 21 but imparts much less effect on the adjacent bonds weakening them by 0-2 kcal/mol. 20 Consequently, it was unclear whether the gem difluoro substitution of the CBI cyclopropane would alter or enhance the stereoelectronicallycontrolled reaction regioselectivity for nucleophilic ring opening, and, a priori, it was not clear whether this substitution would enhance or diminish the inherent electrophilic functional reactivity. Consequently, we have prepared the F 2 CBI alkylation subunit in efforts to examine the effect of the difluoro substitution on the structure, reactivity, and reaction regioselectivity of the agent and its impact on the biological properties of the resulting analogs of 1-3.…”

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confidence: 99%

Synthesis, X-ray Structure, and Properties of Fluorocyclopropane Analogs of the Duocarmycins Incorporating the 9,9-Difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (F₂CBI) Alkylation Subunit

Boger

Jenkins

1996

J. Am. Chem. Soc.

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The synthesis of 9,9-difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (F2CBI), a difluorocyclopropane analog of the CC-1065 and duocarmycin alkylation subunits which represents the first such agent containing substitution of the reactive center in the natural products, is detailed. The core structure of F2CBI was prepared by an intramolecular metal carbenoid insertion reaction into a 1,1-difluoroalkene (74%) employing a p-quinonediazide, and its incorporation into F2CBI-TMI (24) provided a key analog of the duocarmycins. A study of the solvolysis of N-BOC-F2CBI (19) revealed that introduction of the difluorocyclopropane substitution increased the reactivity 500× without altering the inherent regioselectivity which occurred with nucleophilic addition to the difluoro substituted C9 cyclopropane carbon. A single-crystal X-ray structure analysis of 17 and its comparison with the X-ray structures of CBI and related agents beautifully reveal the structural origin of the difluoro substitution effects on the reactivity and regioselectivity of the cyclopropane cleavage reaction. The cyclopropane C−CF2−C bond angle is expanded, and the carbon−carbon bond opposite the difluoro substitution is lengthened to accommodate the preferentially compressed exocyclic F−C−F bond angle introducing additional strain energy. Consistent with this increased reactivity and following trends established to date, the agents were found to be 500−1000× less cytotoxic than the corresponding CBI derivative lacking the difluorocyclopropane substitution. Similarly, the gem difluoro substitution had no perceptible effect on the DNA alkylation selectivity of the agents, and they were found to undergo the characteristic adenine N3 addition to the C9 cyclopropane carbon but did so with a reduced (675−725×) efficiency following the cytotoxicity and stability correlations.

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“…Spiropentane rearrangements: Gajewsky found that the rearrangement of the hydrocarbon spiropentane to form methylenecyclobutane occurred with the cleavage of the C1–C2 bond [ 94 ]. Dolbier then used deuterium labeling to study the analogous reaction of 1,1-difluorospiropentane ( 101 ) ( Scheme 47 ) [ 95 ]. The cleavage of the C1–C2 bond that is proximal to the fluorine resulted in the formation of two isomeric methylenecyclobutane derivatives 102 and 103 by a radical cyclization ( Scheme 47 ).…”

Section: Reviewmentioning

confidence: 99%

“…[94]. Dolbier then used deuterium labeling to study the analogous reaction of 1,1-difluorospiropentane (101) (Scheme 47) [95]. The cleavage of the C1-C2 bond that is proximal to the fluorine resulted in the formation of two isomeric methylenecyclobutane derivatives 102 and 103 by a radical cyclization (Scheme 47).…”

Section: Scheme 38: Cis-trans-epimerizationmentioning

confidence: 99%

The preparation and properties of 1,1-difluorocyclopropane derivatives

Adekenova¹,

Wyatt²,

Адекенов³

2021

Beilstein J. Org. Chem.

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Recently, the functionalization of organic molecules with fluorine substituents has grown rapidly due to its applications in such fields as medicine, agriculture or materials sciences. The aim of this article is to review the importance of 1,1-difluorocyclopropane derivatives in synthesis. It will examine the role of the fluorine substituents in both ring-forming and ring-opening reactions, as well as methods for obtaining difluorocyclopropanes as single enantiomers. Several examples are provided to highlight the biological importance of this class of compounds.

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Thermal rearrangement of 1,1-difluorospiropentane

Cited by 14 publications

References 3 publications

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

Synthesis, X-ray Structure, and Properties of Fluorocyclopropane Analogs of the Duocarmycins Incorporating the 9,9-Difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (F₂CBI) Alkylation Subunit

The preparation and properties of 1,1-difluorocyclopropane derivatives

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Thermal rearrangement of 1,1-difluorospiropentane

Cited by 14 publications

References 3 publications

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

Structure, Synthesis, and Chemical Reactions of Fluorinated Cyclopropanes and Cyclopropenes

Synthesis, X-ray Structure, and Properties of Fluorocyclopropane Analogs of the Duocarmycins Incorporating the 9,9-Difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (F2CBI) Alkylation Subunit

The preparation and properties of 1,1-difluorocyclopropane derivatives

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Synthesis, X-ray Structure, and Properties of Fluorocyclopropane Analogs of the Duocarmycins Incorporating the 9,9-Difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (F₂CBI) Alkylation Subunit