Synthesis of α-Formylated <i>N</i>-Heterocycles and Their 1,1-Diacetates from Inactivated Cyclic Amines Involving an Oxidative Ring Contraction

Deconstructive functionalization involves C–C bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis 1 and olefin metathesis 2 , 3 have allowed each carbon in C–C double bonds to be viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of C–C double bonds, there are very few methods that achieve C( sp 3 )–C( sp 3 ) single bond cleavage/functionalization, especially in relatively unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, important moities in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C( sp 3 )–N/C( sp 3 )–C( sp 3 ) single bond cleavage followed by C( sp 3 )–halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.

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“…The virtue of this methodology is evident in the deconstructive functionalization/diversification of peptides 27 . As shown in Fig.…”

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confidence: 99%

Deconstructive diversification of cyclic amines

Roque

Kuroda

Göttemann

et al. 2018

Nature

196

116

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“…Once 3-formylpyrazolo[1,5- a ]pyrimidines 4 were obtained we developed some postfunctionalization reactions to generate novel PPs derivatives, knowing that the nitrogenous heteroaryl aldehydes are important intermediates in organic and medicinal chemistry. , The formyl group can be converted into hydrazone, imine, enone, alcohol, and carboxylic acid among other important functional groups, though the incorporation of such functional groups on the pyrazolo[1,5- a ]pyrimidine core has been poorly explored. Therefore, we study the possibility of chemically manipulating the formyl group in the representative aldehydes 4a , 4b , and 4j by an environmentally friendly synthetic protocol.…”

Section: Resultsmentioning

confidence: 99%

3-Formylpyrazolo[1,5-a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores

2018

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A one-pot route for the regioselective synthesis of 3-formylpyrazolo[1,5- a]pyrimidines 4a-k in good yields through a microwave-assisted process is provided. The synthesis proceeds via a cyclocondensation reaction between β-enaminones 1 with NH-3-aminopyrazoles 2, followed by formylation with an iminium salt moiety (Vilsmeyer-Haack reagent). These N-heteroaryl aldehydes 4 were successfully used as strategic intermediates for the preparation of novel functional fluorophores with yields up to 98%. The structures of the products obtained and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction analysis. Since pyrazolo[1,5- a]pyrimidines (PPs) 3 have shown an important fluorescence, photophysical properties of four 2-methylderivatives substituted at position 7 with different acceptor (A) or donor (D) groups were investigated. The compounds evaluated exhibited large Stokes shift in different solvents, but only the substituted p-methoxyphenyl (4-An) showed a strong fluorescence intensity with quantum yields up to 44% due to its greater ICT. Therefore, hybrid systems based on pyrazolo[1,5- a]pyrimidines could be used as fluorescent probes to detect biologically or environmentally relevant species.

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“…In particular, the reaction of cyclic amines is an important tool for conversion into acyclic amines bearing an amino group that is positioned far from a reactive site. In regard to the oxidative C−N bond cleavage reaction of amines, the ring contraction of cyclic amines by C−N bond cleavage using a transition metal catalyst was reported (Scheme 1A) [2] . A synthesis of sulfonamides from tertiary amines and sodium arylsulfinates was demonstrated as an oxidative C−N bond cleavage reaction using I 2 and TBHP systems (Scheme 1B) [3] .…”

Section: Methodsmentioning

confidence: 99%

“…In regard to the oxidative CÀ N bond cleavage reaction of amines, the ring contraction of cyclic amines by CÀ N bond cleavage using a transition metal catalyst was reported (Scheme 1A). [2] A synthesis of sulfonamides from tertiary amines and sodium arylsulfinates was demonstrated as an oxidative CÀ N bond cleavage reaction using I 2 and TBHP systems (Scheme 1B). [3] The CÀ N bond cleavage reaction of 1,2,3,4-tetrahydroisoquinolines and N,N'diarylimidazolines with tert-butylnitrite under O 2 atmosphere was developed to generate the corresponding N-nitrosoaminocarbonyl compounds (Scheme 1C).…”

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confidence: 99%

Formal Ring Contraction of Cyclic N‐Sulfonamides via C−N Bond Cleavage and α‐Amination by Oxidation of Halides

2020

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An oxidative CÀ N bond cleavage reaction of substituted cyclic sulfonamides that proceeds via oxidation of bromide ion in hydrogen bromide solution was developed to furnish N-sulfonamideprotected acyclic amino ketones in high yields. The subsequent α-amination of the amino ketones via the oxidation of iodide in tetrabutylammonium iodide provided 2-acyl cyclic sulfonamides in good yields. The combination of these transformations involving the oxidation of halides resulted in a formal ring contraction of substituted cyclic amides.

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Synthesis of α-Formylated N-Heterocycles and Their 1,1-Diacetates from Inactivated Cyclic Amines Involving an Oxidative Ring Contraction

Cited by 43 publications

References 48 publications

Deconstructive diversification of cyclic amines

Deconstructive diversification of cyclic amines

3-Formylpyrazolo[1,5-a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores

Formal Ring Contraction of Cyclic N‐Sulfonamides via C−N Bond Cleavage and α‐Amination by Oxidation of Halides

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