Direct Copper‐Catalyzed C‐H Monofluoroalkylation of Benzoxazoles with 1‐Fluoro‐1‐haloalkanes

Li, Wei; Varenikov, Andrii; Gandelman, Mark

doi:10.1002/ejoc.201901929

“…In 2020, Gandelman and co-workers reported ac oppercatalyzed monofluoroalkylation of the most acidic C À Hbond of benzoxazoles with a-fluoro alkyl bromides (Scheme 16). [33] This reaction is proposed to proceed by metalation of the benzoxazole,followed by monofluoroalkylation of the resulting heteroaryl copper species.A lthough the scope of substrates that undergo this transformation is limited to benzoxazoles,t his method highlights the ability of organocopper intermediates to mediate monofluoroalkylation reactions and suggests that additional monofluoroalkylation reactions catalyzed or mediated by copper could be developed.…”

Section: Copper Catalyzed Cross Couplings Of A-fluoro Alkyl Halidesmentioning

confidence: 99%

Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

Butcher

¹

,

Amberg

²

,

Hartwig

³

2021

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Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.

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“…Copper is an abundant, non-expensive, and relatively nontoxic transition metal, and therefore copper-mediated reactions for direct functionalization of C-H bonds have emerged as promising tools for development of more sustainable methods for the synthesis of fine chemicals. Reactions involving copper-medi-ated C-H activations allow for a direct insertion of functional groups in unreactive C-H bonds and the formation of carbon-carbon bonds without the requirement of prefunctionalized substrates, which allow for shorter synthetic routes or latestage modifications of structurally complex compounds [304][305][306][307][308][309][310][311][312]. However, the development of efficient methods can be challenging due to the requirement of directing groups and control of selectivity.…”

Section: Copper-catalyzed C-h Activationmentioning

confidence: 99%

“…On the other hand, such heterocyclic moieties present in bioactive compounds, or their synthetic intermediates may eventually play the role of a directing group, thus providing an opportunity for convenient and straightforward transformations based on metal-mediated C-H activation [314]. Many methods potentially useful for the synthesis or modification of bioactive compounds based on copper-promoted activation of C-H bonds in (hetero)arenes have been reported in the last years, including methods for the formation of C-C [304][305][306][307][308][309][310][311][312], C-X [315][316][317][318][319], C-N [305,[320][321][322][323][324], C-O [325][326][327][328][329][330], and C-S [324,331,332] bonds. Some of these methods are highlighted herein.…”

Section: Copper-catalyzed C-h Activationmentioning

confidence: 99%

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

Carvalho¹,

Miranda²,

Nunes³

et al. 2021

Beilstein J. Org. Chem.

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Several valuable biologically active molecules can be obtained through C–H activation processes. However, the use of expensive and not readily accessible catalysts complicates the process of pharmacological application of these compounds. A plausible way to overcome this issue is developing and using cheaper, more accessible, and equally effective catalysts. First-row transition (3d) metals have shown to be important catalysts in this matter. This review summarizes the use of 3d metal catalysts in C–H activation processes to obtain potentially (or proved) biologically active compounds.

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“…In 2020, Gandelman and co‐workers reported a copper‐catalyzed monofluoroalkylation of the most acidic C−H bond of benzoxazoles with α‐fluoro alkyl bromides (Scheme 16). [33] This reaction is proposed to proceed by metalation of the benzoxazole, followed by monofluoroalkylation of the resulting heteroaryl copper species. Although the scope of substrates that undergo this transformation is limited to benzoxazoles, this method highlights the ability of organocopper intermediates to mediate monofluoroalkylation reactions and suggests that additional monofluoroalkylation reactions catalyzed or mediated by copper could be developed.…”

Section: Cross Couplingmentioning

confidence: 99%

Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

Butcher

¹

,

Amberg

²

,

Hartwig

³

2021

Angewandte Chemie

5

0

View full text Add to dashboard Cite

Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.

show abstract

Direct Copper‐Catalyzed C‐H Monofluoroalkylation of Benzoxazoles with 1‐Fluoro‐1‐haloalkanes

Abstract: The first example of direct C–H bond monofluoroalkylation with 1‐fluoro‐1‐haloalkanes with no adjacent functional groups and with β‐hydrogens has been developed. This transformation offers a straightforward route for the synthesis of a series of monofluoroalkylated benzoxazoles.

Cited by 14 publications

References 43 publications

Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

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